Peptide inhibitors of the interleukin-23 receptor

Abstract

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

Description

[Technical field]

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

[0002] Interleukin-23 (IL-23) is a heterodimeric cytokine composed of the unique p19 subunit and the p40 subunit of interleukin-12 (IL-12). IL-12 is a cytokine involved in the development of interferon-gamma (IFN-γ)-producing T helper 1 (Th1) cells. Although both IL-23 and IL-12 contain the p40 subunit, they have distinct phenotypic characteristics. IL-12-deficient animals are susceptible to inflammatory autoimmune diseases, whereas IL-23-deficient animals are resistant. This is because the CD4+ cells that produce interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor (TNF) are secreted in the central nervous system (CNS) of IL-23-deficient animals. + This is thought to be due to a decrease in the number of T cells. + In contrast to IL-12, which acts primarily on T cells, IL-23 inhibits memory CD4 + It acts preferentially on 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 by activating the Janus kinase (JAK) molecules JAK2 and tyrosine kinase 2 (TYK2), and the signal transducer and activator of transcription (STAT) proteins STAT1, STAT3, STAT4, and STAT5. Compared to IL-12, IL-23 responds with significantly weaker STAT4 activation and the formation of a distinct DNA-binding STAT complex. IL-23R constitutively associates with JAK2 and ligand-dependently associates with STAT3.

[0004] IL-23R is expressed on a variety of adaptive and innate immune cells, including T-helper 17 (Th17) cells, gamma-delta (γδ) T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphocytes. These cells are found in abundance in the intestine. In particular, gene expression and protein levels of IL-23R at the intestinal mucosal surface have been found to be elevated in patients with inflammatory bowel disease (IBD). IL-23 acts as a stimulator of pathogenic CD4+ cells that produce IL-6, IL-17, and TNF. + It is believed to mediate this effect by promoting the development of T cell populations.

[0005] IL-23 is produced primarily in the intestine, where it is believed to play a key role in controlling the balance between tolerance and immunity through both T cell-dependent and independent pathways of intestinal inflammation, through the effects of Th1 and Th17-associated cytokines. IL-23 is also believed to suppress regulatory T cell responses in the intestine and promote inflammation. Furthermore, polymorphisms in IL-23R have been associated with susceptibility to inflammatory bowel disease (IBD), further demonstrating the important role of the IL-23 pathway in maintaining intestinal homeostasis.

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

[0007] For example, psoriasis is a chronic skin disease that affects approximately 2%-3% of the general population. Psoriasis is known to be mediated by T cell inflammatory response mechanisms in the body. IL-23 is one of several interleukins that are thought to play an important role in the pathogenesis of psoriasis. IL-23 is thought to maintain chronic autoimmune inflammation through induction of IL-17, activation of macrophages, and control of T memory cells. Furthermore, expression of IL-23 and IL-23R has been shown to be increased in tissues of patients with psoriasis, and in an animal model of psoriasis, an antibody neutralizing IL-23 showed inhibition of IL-23-dependent psoriasis development.

[0008] Research has been conducted to investigate whether inhibitory portions of the IL-23 pathway can be used for therapeutic purposes in the treatment of IL-23-related diseases and disorders. Several antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab (a humanized antibody that binds to IL-23), which has been approved for the treatment of psoriasis. More recently, polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified (see, for example, US Patent Application Publication No. 2013 / 0029907). Furthermore, several clinical trials with ustekinumab and briakinumab (which target the common p40 subunit), as well as tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p19 subunit of IL-23) in the treatment of Crohn's disease or psoriasis, highlight the potential of blocking IL-23 signaling in the treatment of human inflammatory diseases.

[0009] Protagonist Therapeutics, Inc. currently has the peptide PTG-200 in Phase II clinical trials for Crohn's disease. Protagonist also has two second generation peptides: PN-235, which has completed Phase I clinical trials for psoriasis and will begin Phase II clinical trials; and PN-232, which is in Phase I clinical trials. Protagonist has filed several patent applications in the field of IL-23R inhibitors: WO 2016 / 011208, WO 2017 / 011820, WO 2018 / 022937, WO 2018 / 136646, WO 2020 / 014646, WO 2021 / 007433, WO 2021 / 146441, and WO 2021 / 146458. Protagonist has also disclosed another peptide compound C as an IL-23R inhibitor in WO 2016 / 011208, WO 2017 / 011820, and (Sayago et al., ACS Med. Chem. Lett., 2018, 9, 912-916).

[0010] WO 2016 / 011208 discloses oral peptide inhibitors of IL-23R and their use for treating inflammatory bowel disease. The peptides may be up to 20 amino acid residues in length and may contain a single chemical bridge between amino acid residue 4 (X4) and amino acid residue 9 (X9). The chemical bridge may be a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond. In particular, the chemical bridge is a disulfide or a thioether bond.

[0011] WO 2017 / 011820 discloses peptide inhibitors of IL-23R and related compositions and methods of using the peptide inhibitors to treat or prevent various diseases and disorders, including inflammatory bowel disease. The peptides are up to 20 amino acid residues in length and contain a single chemical bridge between amino acid residue 4 (X4) and amino acid residue 9 (X9). The chemical bridge can be a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond. In particular, the chemical bridge is a disulfide or a thioether bond.

[0012] WO 2018 / 022937 discloses peptide inhibitors of IL-23R and their use for treating inflammatory diseases such as inflammatory bowel disease, Crohn's disease and psoriasis. The disclosed peptides may be up to 39 amino acid residues in length and may have a single disulfide or thioether bond between amino acid residues 5 (X5) and 34 (X34).

[0013] WO 2018 / 136646 discloses peptide inhibitors of IL-23R and their use for treating inflammatory diseases, including inflammatory bowel disease. The disclosed peptides may be up to 24 amino acid residues in length and may optionally have a bridge bond between amino acid residue 5 (X4) and amino acid residue 10 (X9). The single bridge bond between amino acid residue 5 and amino acid residue 10 may be an intramolecular disulfide or thioether bond.

[0014] WO 2020 / 014646 discloses peptide inhibitors of IL-23R and their use for treating or preventing various diseases and disorders, including inflammatory bowel disease. The peptide sequence may be 5-12 amino acid residues in length and may have an intramolecular bond between amino acid residue 1 (X4) and amino acid residue 6 (X9). The intramolecular bond may be a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond or an olefin bond. In particular, the examples shown have a disulfide or thioether bond.

[0015] WO 2021 / 007433 discloses peptide inhibitors of IL-23R and their use for treating or preventing various diseases and disorders, including inflammatory bowel disease. The peptide sequence may be 5-8 amino acid residues in length and may optionally contain a bond between amino acid residue 1 (X4) and amino acid residue 6 (X9). The bond may be a disulfide or thioether bond.

[0016] WO 2021 / 146441 discloses peptide inhibitors of IL-23R and their use for treating or preventing various diseases and disorders, including inflammatory bowel disease. The peptides may be up to 14 amino acid residues in length and may optionally have a disulfide or thioether bond between amino acid residues 2 (X4) and 7 (X9).

[0017] WO 2021 / 146458 discloses peptide inhibitors of IL-23R and their use for treating or preventing various diseases and disorders, including inflammatory bowel disease, Crohn's disease, ulcerative colitis and psoriasis. The peptides may be up to 14 amino acid residues in length and may have a bond between amino acid residues 2 (X4) and 7 (X9). The bond may be a disulfide or thioether bond.

[0018] Notably, the peptides disclosed in the above Protagonist patent applications only have a single bridge moiety, none of which use two bridges to stabilize peptide inhibitors of IL-23R.

[0019] (Heinis et al., Nature Biomedical Engineering, 2020, 4, 560-571) disclose the development of therapeutic peptides for oral administration resistant to proteolysis. The authors generated peptides as inhibitors of coagulation factor XIa and other peptide antagonists of IL-23R resistant to gastrointestinal proteases. The peptides generated as antagonists of IL-23R consisted of two dithioether bridges (specifically 1,3-dithio-propan-2-one bridges) between two pairs of cysteine ​​residues in the peptide chain. The authors identified peptide I5 as the most promising candidate for further development as an oral treatment for inflammatory disorders, e.g., Crohn's disease, based on IL-23R inhibition.

[0020] However, challenges remain with regard to identifying stable and selective agents that preferentially target the IL-23 pathway in the intestine that can be used for the treatment of intestinal enteropathy, including enteritis, e.g., Crohn's disease, ulcerative colitis, and related disorders. In particular, the inventors have confirmed that the gastrointestinal stability and IL-23R potency of the peptides disclosed in (Heinis et al., Nature Biomedical Engineering, 2020, 4, 560-571) still leave room for further improvement. In particular, the most promising candidate, peptide I5, was less stable under simulated intestinal fluid (SIF) assays and less potent against IL-23R compared to Protagonist's compound C (Sayago et al., ACS Med. Chem. Lett., 2018, 9, 912-916).

[0021] Thus, there remains a need for novel therapeutic agents that target the IL-23 pathway that can be used to treat and prevent IL-23-associated diseases, including diseases associated with autoimmune inflammation in the intestinal tract. Furthermore, compounds and methods that specifically target IL-23R from the luminal side of the intestine may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.

[0022] The present invention addresses these needs by providing novel peptide inhibitors that bind to IL-23R and inhibit IL-23-mediated signaling. The novel peptide inhibitors are also stable in the gastrointestinal tract, making them suitable for oral administration. [Prior art documents] [Patent documents]

[0023] [Patent Document 1] US Patent Application Publication No. 2013 / 0029907 [Patent Document 2] International Publication No. 2016 / 011208 Brochure [Patent Document 3] International Publication No. 2017 / 011820 Brochure [Patent Document 4] International Publication No. 2018 / 022937 Brochure [Patent Document 5] International Publication No. 2018 / 136646 Brochure [Patent Document 6] International Publication No. 2020 / 014646 Brochure [Patent Document 7] International Publication No. 2021 / 007433 Brochure [Patent Document 8] International Publication No. 2021 / 146441 Brochure [Patent Document 9] International Publication No. 2021 / 146458 Brochure [Non-patent literature]

[0024] [Non-Patent Document 1] Sayago et al., ACS Med. Chem. Lett., 2018, 9, 912-916 [Non-Patent Document 2] Heinis et al., Nature Biomedical Engineering, 2020, 4, 560-571 Summary of the Invention [Problem to be solved by the invention]

[0025] The present invention relates to compounds that are peptide inhibitors of the interleukin-23 receptor (IL-23R). [Means for solving the problem]

[0026] In a first aspect, the present invention provides a compound of formula: R 1 -ZR 2 [In the formula, R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 alkyl or absent; R 2 NHR 3 , OH or absent, R 3 is hydrogen or C which may be substituted with NH 1-3 is alkyl; Z is a group of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) (In the formula, X1 is absent or selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gln, Val, Ile, N-Me-Ser, and Q (pyrrolidine); X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp; X6 is selected from the group consisting of Gln, Glu, Tyr, Cys, Val, His, N-Me-Gln, and Q (pyrrolidine); X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Val, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), {d}F(4-F), 4-Cl-Phe, alpha-Me-Trp, 3,3-diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and {d}6-F-Trp; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, {d}2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-Gln, D-Glu, D-His, 3-aminopropanoyl, and GABA, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, {d}[3-(3-pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge comprising a triazole ring), or a pharma- ceutically acceptable salt or solvate thereof.

[0027] In some embodiments, the present invention provides a compound of formula: R 1 -ZR 2 [In the formula, R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 alkyl or absent; R 2 NHR 3 , OH or absent, R 3 is hydrogen or C 1-3 is alkyl; Z is a group of formula Ia: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (Ia) (In the formula, X1 is absent or selected from the group consisting of Asp, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gln; X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, and Bip; X6 is selected from the group consisting of Gln, Glu, Tyr and Cys; X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharma- ceutically acceptable salt or solvate thereof.

[0028] In some embodiments, the compound is not: I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2]; (wherein (1a) is a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge).

[0029] In some embodiments, the compound is not: I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-OH; (wherein (1a) is a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge).

[0030] In some embodiments, Z is not: I3 (isomer 3) DC(1a)SC(2a)WQC(2a)WWLC(1a)R; (wherein (1a) is a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge).

[0031] In some embodiments, the bridge between X2 and X11 and the bridge between X4 and X7 are not both 1,3-dithio-propan-2-one bridges.

[0032] In some embodiments, the bridge between X2 and X11 and the bridge between X4 and X7 are not both dithioether bridges.

[0033] In some embodiments, X1 is absent or Asp.

[0034] In some embodiments, X1 is absent.

[0035] In some embodiments, X3 is Ser or Ile.

[0036] In some embodiments, X3 is Ser.

[0037] In some embodiments, X5 is Trp or 7-Me-Trp.

[0038] In some embodiments, X5 is Trp.

[0039] In some embodiments, X6 is Gln or Glu.

[0040] In some embodiments, X6 is Gln.

[0041] In some embodiments, X8 is Trp, Tyr, or 4-Me-Phe; the hydroxyl group of Tyr may be substituted with -CH2CH2NH2.

[0042] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2.

[0043] In some embodiments, X9 is 2-Nal, Trp, or 3,4-Me-Phe.

[0044] In some embodiments, X9 is 2-Nal or Trp.

[0045] In some embodiments, X9 is 2-Nal.

[0046] In some embodiments, X10 is Leu, 2-Me-Leu, or 2-Me-Val.

[0047] In some embodiments, X10 is Leu or 2-Me-Leu.

[0048] In some embodiments, X10 is Leu.

[0049] In some embodiments, X12 is Arg, D-Arg, and Dab.

[0050] In some embodiments, X12 is Arg.

[0051] In some embodiments, X13 is absent, 3-(3-pyridyl)-Ala, or 2-Me-3-(3-pyridyl)-Ala.

[0052] In some embodiments, X13 is absent.

[0053] In some embodiments, X14 is absent.

[0054] In some embodiments, R 1 , H, C 1-2 It is either acyl or absent.

[0055] In some embodiments, R 1 does not exist.

[0056] In some embodiments, R 1 is -C(=O)CH3.

[0057] In some embodiments, R 2 is NH2.

[0058] In some embodiments, the length of the bridge between X2 and X11 and / or the bridge between X4 and X7 is 5 to 10 atoms long.

[0059] In some embodiments, X is absent and R 1 is absent, and X2 and X11 are amino acid residues which together form a lactam bridge or a bridge containing a triazole ring via the N-terminus of X2.

[0060] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0061] In some embodiments, the dithioether bridge between X2 and X11 and / or the dithioether bridge between X4 and X7 is represented by the formula -SLYLS- (In the formula: each S is a sulfur atom and is part of an amino acid residue of X2 and X11 and / or X4 and X7; Each L is independently C 1-4 is alkylene; Y is absent, C(=O) or arylene.

[0062] In some embodiments, each L is independently C 1-2 It is alkylene.

[0063] In some embodiments, each L is methylene.

[0064] In some embodiments, Y is C(=O).

[0065] In some embodiments, Y is an arylene selected from phenylene.

[0066] In some embodiments, Y is a phenylene selected from 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene.

[0067] In some embodiments, Y is 1,2-phenylene.

[0068] In some embodiments, the bridge comprising a triazole ring between X2 and X11 and / or the bridge comprising a triazole ring between X4 and X7 comprises a 1,2,3-triazole ring.

[0069] In some embodiments, the bridge comprising a triazole ring between X2 and X11 and / or the bridge comprising a triazole ring between X4 and X7 is attached to the 1- and 4-positions of the triazole ring.

[0070] In some embodiments, the bridge comprising a triazole ring between X2 and X11 and / or the bridge comprising a triazole ring between X4 and X7 is attached to the 1- and 5-positions of the triazole ring.

[0071] In some embodiments, X2 and X11 are amino acid residues that together form a lactam bridge.

[0072] In some embodiments, the location of the amide bond in the lactam bridge is closer to X11 than to X2.

[0073] In some embodiments, one of the residues at positions X2 and X11 is selected from the group consisting of Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-fluoro-phenylacetyl, 4-aminomethyl-2-methyl ... -phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methoxy-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl, and the other is selected from Glu and Asp.

[0074] In some embodiments, X2 is Lys, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-fluoro-phenylacetyl, 4-aminomethyl-2-methyl-phenylacetyl, acetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methoxy-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl, and X11 is Glu and Asp.

[0075] In some embodiments, X2 is Lys and X11 is Glu; X2 is Orn and X11 is Glu; X2 is bAla and X11 is Glu; X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is (4-aminomethyl)benzoyl and X11 is Glu; X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu; X2 is 2-aminomethyl-phenylacetate. X2 is 3-aminomethyl-phenylacetyl, X11 is Glu; X2 is 4-aminomethyl-phenylacetyl, X11 is Glu; X2 is 6-aminohexanoyl, X11 is Glu; X2 is 6-amino-4-oxahexanoyl, X11 is Glu; X2 is trans-4-aminomethyl-cyclohexyl-1-carbonyl, X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Asp; X2 is 4-aminomethyl-2-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-3-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-2-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methyl- is 4-aminomethyl-3-methyl-phenylacetyl, X11 is Glu; is X2 4-aminomethyl-2-methoxy-phenylacetyl, X11 is Glu; is X2 4-aminomethyl-3-methoxy-phenylacetyl, X11 is Glu; is X2 Dab, X11 is Glu; is X2 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), X11 is Glu;Or X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu;

[0076] In some embodiments, X2 is Lys and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; or X2 is 4-aminomethyl-phenylacetyl and X11 is Glu.

[0077] In some embodiments, X2 is Lys and X11 is Glu.

[0078] In some embodiments, X2 is selected from Glu and Asp, and X11 is selected from Lys, Arg, and Dab.

[0079] In some embodiments, X2 is Glu and X11 is Lys; X2 is Glu and X11 is Dab; ​​or X2 is Asp and X11 is Arg.

[0080] In some embodiments, X2 and X11 are amino acid residues that together form a dithioether bridge.

[0081] In some embodiments, X2 and X11 are each independently selected from Cys and N-Me-Cys.

[0082] In some embodiments, X2 is Cys and X11 is Cys.

[0083] In some embodiments, X2 and X11 are amino acid residues that together form a bridge comprising a triazole ring.

[0084] In some embodiments, one of the residues at positions X2 and X11 is selected from Lys(N3), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and the other is selected from Pra, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid.

[0085] In some embodiments, X2 is selected from Lys(N3), azidoacetic acid, and (N3)-Ala; and X11 is selected from Pra, Glu (propargylamine), and Dab (3-butynoic acid).

[0086] In some embodiments, X2 is Lys(N3) and X11 is Pra; X2 is azidoacetic acid and X11 is Glu(propargylamine); X2 is azidoacetic acid and X11 is Dab(3-butynoic acid); X2 is (N3)-Ala and X11 is Glu(propargylamine); or X2 is (N3)-Ala and X11 is Dab(3-butynoic acid).

[0087] In some embodiments, X2 is Lys(N3) and X11 is Pra.

[0088] In some embodiments, X2 is selected from Pra, and but-3-ynoic acid; X11 is selected from Dab (azidoacetic acid), and Dab((N3)-Ala).

[0089] In some embodiments, X2 is Pra and X11 is a Dab (azidoacetic acid); X2 is Pra and X11 is a Dab ((N3)-Ala); X2 is but-3-ynoic acid and X11 is a Dab (azidoacetic acid); or X2 is but-3-ynoic acid and X11 is a Dab ((N3)-Ala). In some embodiments, X2 is Pra and X11 is a Dab (azidoacetic acid); or X2 is Pra and X11 is a Dab ((N3)-Ala). In some embodiments, X2 is but-3-ynoic acid and X11 is a Dab (azidoacetic acid); or X2 is but-3-ynoic acid and X11 is a Dab ((N3)-Ala).

[0090] In some embodiments, X4 and X7 are amino acid residues that together form a dithioether bridge.

[0091] In some embodiments, X4 and X7 are each independently selected from Cys and N-Me-Cys.

[0092] In some embodiments, X4 is Cys and X7 is Cys; or X4 is N-Me-Cys and X7 is Cys.

[0093] In some embodiments, X4 is Cys and X7 is Cys.

[0094] In some embodiments, X4 and X7 are amino acid residues that together form a lactam bridge.

[0095] In some embodiments, one of the residues at positions X4 and X7 is Lys, Dpr, Dab, or Orn, and the other is Glu.

[0096] In some embodiments, X4 is selected from Lys, Dpr, Dab, and Orn, and X7 is Glu.

[0097] In some embodiments, X4 is Dpr and X7 is Glu; X4 is Dab and X7 is Glu; or X4 is Orn and X7 is Glu.

[0098] In some embodiments, X4 is Glu and X7 is selected from Lys, Dpr, Dab, and Orn.

[0099] In some embodiments, X4 is Glu and X7 is Lys; X4 is Glu and X7 is Dpr; X4 is Glu and X7 is Orn; or X4 is Glu and X7 is Dab.

[0100] In some embodiments, X4 and X7 are amino acid residues that together form a bridge comprising a triazole ring.

[0101] In some embodiments, one of the residues at positions X4 and X7 is selected from Lys(N3) and Aha, and the other is Pra.

[0102] In some embodiments, X4 is Lys(N3) and X7 is Pra; or X4 is Aha and X7 is Pra.

[0103] In some embodiments, X8 is Trp; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0104] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr is optionally substituted with NH2. 1-3 X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0105] In some embodiments, X8 is Asn; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0106] In some embodiments, X8 is Ala; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0107] In some embodiments, X8 is His; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0108] In some embodiments, X8 is 2-Nal; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0109] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2; X10 is 2-Me-Leu; and X12 is Arg or absent.

[0110] In some embodiments, X8 is Trp; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0111] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr is optionally substituted with NH2. 1-3 X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0112] In some embodiments, X8 is Asn; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0113] In some embodiments, X8 is Ala; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0114] In some embodiments, X8 is His; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0115] In some embodiments, X8 is 2-Nal; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0116] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2; X10 is D-Leu; and X12 is Arg or absent.

[0117] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2; X10 is 2-Me-Leu; and X12 is Arg or absent.

[0118] In some embodiments, Z is [Table 1] JPEG2024543204000002.jpg240170 JPEG2024543204000003.jpg236170 JPEG2024543204000004.jpg245170 JPEG2024543204000005.jpg191170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. or a pharma- ceutically acceptable salt or solvate thereof.

[0119] In some embodiments, Z is [Table 2] JPEG2024543204000007.jpg235170 JPEG2024543204000008.jpg237170 JPEG2024543204000009.jpg246170 JPEG2024543204000010.jpg23170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. or a pharma- ceutically acceptable salt or solvate thereof.

[0120] In some embodiments, Z is [Table 3] JPEG2024543204000012.jpg235170 JPEG2024543204000013.jpg115170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. or a pharma- ceutically acceptable salt or solvate thereof.

[0121] In some embodiments, Z is [Table 4] where * = crosslinking using an amine or carboxylic acid at the N- or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. or a pharma- ceutically acceptable salt or solvate thereof.

[0122] In some embodiments, Z is [Table 5] JPEG2024543204000016.jpg242170 JPEG2024543204000017.jpg49170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. or a pharma- ceutically acceptable salt or solvate thereof.

[0123] Particular compounds of the invention are [Table 6] JPEG2024543204000019.jpg244170 JPEG2024543204000020.jpg244170 JPEG2024543204000021.jpg239170 JPEG2024543204000022.jpg246170 JPEG2024543204000023.jpg235170 JPEG2024543204000024.jpg232170 JPEG2024543204000025.jpg77170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharma- ceutically acceptable salts and solvates thereof. Includes.

[0124] Other specific compounds of the present invention are [Table 7] JPEG2024543204000027.jpg244170 JPEG2024543204000028.jpg246170 JPEG2024543204000029.jpg245170 JPEG2024543204000030.jpg246170 JPEG2024543204000031.jpg140170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharma- ceutically acceptable salts and solvates thereof. Includes.

[0125] In some embodiments, certain compounds of the invention are [Table 8] JPEG2024543204000033.jpg241170 JPEG2024543204000034.jpg249170 JPEG2024543204000035.jpg155170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharma- ceutically acceptable salts and solvates thereof. Includes.

[0126] In some embodiments, certain compounds of the invention are [Table 9] JPEG2024543204000037.jpg20170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharma- ceutically acceptable salts and solvates thereof. Includes.

[0127] In some embodiments, certain compounds of the invention are [Table 10] JPEG2024543204000039.jpg241170 JPEG2024543204000040.jpg238170 JPEG2024543204000041.jpg37170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharma- ceutically acceptable salts and solvates thereof. Includes.

[0128] The present invention further provides a composition comprising the compound described above. The composition may be a pharmaceutical composition and may comprise a pharma- ceutically acceptable carrier, excipient or vehicle.

[0129] The present invention further provides a method for synthesizing the compounds described above. The method may include the steps of synthesizing peptides by solid-phase or liquid-phase methods and isolating and / or purifying any final product, and may further include the steps of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residue at position X2 and the amino acid residue at position X11, and may further include the steps of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residue at position X4 and the amino acid residue at position X7.

[0130] The present invention further provides a compound of the invention, or a pharmaceutical composition comprising said compound, for use in a method of medical treatment.

[0131] The invention also provides a compound of the invention, or a pharmaceutical composition comprising said compound, for use in a method for the prevention or treatment of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, leukocyte adhesion deficiency-I, chronic granulomatous disease, glycogen storage disease type 1b, colitis associated with impaired innate immunity such as in Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, or graft versus host disease, and combinations thereof, in a subject.

[0132] In some embodiments, the compounds of the invention, or pharmaceutical compositions comprising said compounds, are for use in methods for the prevention or treatment of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and psoriasis.

[0133] The invention also provides the use of a compound of the invention, or a pharmaceutical composition comprising said compound, in the manufacture of a medicament for the prevention or treatment of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, leukocyte adhesion deficiency-I, chronic granulomatous disease, glycogen storage disease type 1b, colitis associated with impaired innate immunity such as in Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, or graft versus host disease, and combinations thereof in a subject.

[0134] In some embodiments, the use of a compound of the invention, or a pharmaceutical composition comprising said compound, is in the manufacture of a medicament for the prevention or treatment of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and psoriasis.

[0135] The present invention also relates to the treatment of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, leukocyte adhesion deficiency-I, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome in a subject. The present invention provides a method for preventing or treating colitis associated with impaired innate immunity such as ileitis associated with rectal resection and pouchitis occurring after rectal colectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, or graft-versus-host disease, and combinations thereof, comprising the step of administering to a subject an effective amount of a compound of the present invention or a pharmaceutical composition comprising said compound.

[0136] In some embodiments, the method for preventing or treating inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and psoriasis comprises administering to a subject an effective amount of a compound of the invention, or a pharmaceutical composition comprising said compound.

[0137] Further aspects and embodiments of the present invention will become apparent from the following disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0138] definition Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used herein in connection with the techniques of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0139] All publications, patents and published patent applications mentioned in this application are specifically incorporated herein by reference. In the event of a conflict, the present specification, including its specific definitions, will control.

[0140] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to mean the inclusion of a stated integer or component, or group of stated integers or components, but not the exclusion of any other integers or components, or group of integers or components.

[0141] The singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0142] The term "including" is used to mean "including, but not limited to." "Including" and "including, but not limited to" are used interchangeably.

[0143] The terms "patient," "subject," and "individual" may be used interchangeably and may refer to either a human or a non-human animal. Subjects are typically mammals, and include humans, non-human primates (including great apes, Old World monkeys, and New World monkeys), livestock animals (e.g., cows, pigs), companion animals (e.g., dogs, cats), and rodents (e.g., mice and rats).

[0144] As used herein, the term "pharmaceutically acceptable salt" is intended to indicate a salt that is not harmful to the patient or subject to whom the salt is administered. Suitably, the salt may be, for example, selected from among acid addition salts and base salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts. Examples of base salts include salts in which the cations are 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 1 )(R 2 )(R 3 )(R 4 ) + Ions of the type (wherein R 1 , R 2 , R 3 and R 4 are independently hydrogen, optionally substituted C 1-6 -alkyl or optionally substituted C 2-6 -alkenyl) and salts selected from the group consisting of: 1-6 Examples of -alkyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. 2-6 Examples of -alkenyl groups include ethenyl, 1-propenyl and 2-propenyl. Other examples of pharma- ceutically acceptable salts are described in: "Remington's Pharmaceutical Sciences", 1 7th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), "Encyclopaedia of Pharmaceutical Technology", 3 rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977).

[0145] The term "solvate" in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (in this case a peptide according to the invention or a pharma- ceutically acceptable salt thereof) and a solvent. The solvent in this context can be, for example, water, ethanol, or another pharma- ceutically acceptable (typically small molecule) organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent is water, such a solvate is usually called a hydrate.

[0146] The term "antagonist" as used in the context of the present invention refers to a substance that inhibits a given receptor type, typically by binding to that type (ie, as a ligand) and blocking that type.

[0147] Each embodiment of the present invention described herein may be practiced alone or in combination with one or more other embodiments of the present invention.

[0148] The term "therapeutically effective amount", as used herein in the context of the above-described methods of treatment or other therapeutic intervention according to the invention, refers to an amount sufficient to cure, ameliorate, reduce or partially arrest the clinical symptoms of the particular disease, disorder or condition that is the subject of the treatment or other therapeutic intervention, as measured, for example, by established clinical endpoints or other biomarkers (established or experimental). Therapeutically suitable amounts can be empirically determined by one of ordinary skill in the art based on the indication to be treated or prevented and the subject to which the therapeutically suitable amount is being administered. For example, one of skill in the art can measure the clinically relevant bioactivity indicators described herein, such as one or more of the following bioactivity indicators: 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), S100 calcium-binding protein B1 (S100A1), S100 calcium-binding protein C2 (S100A2), S100 calcium-binding protein D3 (S100A3), S100 calcium-binding protein E4 (S100A4), S100 calcium-binding protein H1 (S100A5), S100 calcium-binding protein H2 (S100A6), S100 calcium-binding protein I (S100A7), S100 calcium-binding protein I (S100A8), S100 calcium-binding protein I (S100A1), S100 calcium-binding protein I (S100A1), S100 calcium-binding protein I (S100A2), S100 calcium-binding protein I (S100A3), S100 calcium-binding protein I (S100A4), S100 calcium-binding protein I (S100A5), S100 calcium-binding protein I (S100A1 ... A8), microRNA-223-3p (miR223-3p, microRNA-223-3p), Claudin 8 (CLDN8), and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) proteins, polynucleotides encoding any of these proteins, and polynucleotides comprising a region complementary to either microRNA-223-3p or a polynucleotide encoding any of these proteins. A person skilled in the art may determine a clinically relevant amount by in vitro or in vivo measurements.

[0149] An amount sufficient to achieve any or all of these effects is defined as a therapeutically effective amount. Dosage and administration methods can be adjusted to achieve optimal efficacy. The effective amount for a given purpose will depend, among other things, on the severity of the disease, disorder or condition that is the subject of a particular treatment or other therapeutic intervention, on the weight and general condition of the subject, on diet, on possible concomitant medications, and on other factors well known to those skilled in the medical field. The determination of the appropriate dosage size and dosage regimen that is most suitable for administering the peptide or its pharma-ceutically acceptable salt or solvate according to the invention to humans can be guided by the results obtained in the present invention and confirmed in appropriately designed clinical trials. Effective dosages and treatment protocols can be determined by the usual means of starting with low doses in experimental animals, then increasing the dosage while monitoring the effects, and systematically modifying the dosage regimen as well. Numerous factors can be taken into account when the clinician determines the optimal dosage for a given subject. Such considerations are well known to those skilled in the art.

[0150] The term "treatment" and grammatical variations thereof (e.g., "treated", "treating", "treat") as used in the context of this specification refers to an approach to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, attenuation of the extent of the disease, stabilization of the disease state (i.e., not worsening), slowing or delaying disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete remission), whether detectable or undetectable. "Treatment" may also mean a prolongation of survival compared to expected survival in the absence of treatment. Thus, a subject (e.g., a human) in need of treatment may be a subject already suffering from the disease or disorder in question. The term "treatment" includes inhibiting or reducing the increase in the severity of a pathological condition or symptom (e.g., inflammation) compared to the absence of treatment, and does not necessarily mean that the associated disease, disorder, or condition is completely cured.

[0151] The term "prevention" and its grammatical variants (e.g., "prevented", "preventing", "prevent") as used in the context of this specification refers to an approach to hinder or prevent the onset or change in pathology of a condition, disease or disorder. Thus, "prevention" can refer to preventative or prophylactic measures. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, preventing or delaying the symptoms, progression or onset of a disease, whether detectable or undetectable. Thus, a subject (e.g., a human) in need of "prevention" may be a subject not yet afflicted with the disease or disorder in question. Thus, the term "prevention" includes inhibiting or delaying the onset of a disease compared to the absence of treatment, and does not necessarily mean permanently preventing the associated disease, disorder or condition.

[0152] Amino Acid Nomenclature The term "amino acid" refers to an organic compound that contains an amino or amine group (-NH2 or -NHR) and a carboxylic acid group (-COOH). The amine group of the amino acid may be further functionalized, for example, an azido group (-N3), such as in azidoacetic acid or (N3)-Ala, or a propargyl group (-CH2C≡CH), such as in but-3-ynoic acid.

[0153] Some amino acids described herein have an amine group and a carboxylic acid group attached to the same carbon and are referred to as alpha (α) amino acids. Some amino acids described herein have an amine group and a carboxylic acid group that are 1, 2, 3, 4, 5, or 6 carbon atoms apart. For example, beta-alanine (bAla) has an amine group and a carboxylic acid group that are one carbon apart, such that the carbon linked to the amine group and the carbon linked to the carboxylic acid group are adjacent to each other.

[0154] Some amino acids described herein have side chains that are unique to each amino acid. The side chains can also be further functionalized. For example, the amine group of the side chain can be functionalized to an azide group (-N3), such as Lys(N3). Another example can be when the amine of the side chain can be functionalized to an amide with a pendant azide group (-N3), such as in Dab(azidoacetic acid) and Dab((N3)-Ala)). Another example can be when the amine of the side chain can be functionalized to an amide with a pendant alkyne group, such as in Dab(3-butynoic acid). Another example can be when the carboxylic acid of the side chain can be functionalized to an amide with a pendant alkyne group, such as in Glu(propargylamine).

[0155] Throughout this specification, naturally occurring amino acids are designated by their conventional three-letter or one-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.) unless referred to by their full name (e.g., alanine, arginine, etc.). For certain less common or unnatural amino acids (i.e., amino acids other than the 20 encoded by the standard mammalian genetic code), commonly used three-letter or four-letter codes are used for those residues, including 2-Nal (3-(2-naphthyl)-alanine), unless referred to by their full name (e.g., ornithine, etc.).

[0156] Unless otherwise specified, reference is made to the L-isomer form of the amino acid in question.

[0157] Further abbreviations include: 2-Nal 3-(2-naphthyl)-L-alanine {d}R or D-Arg D-Arginine {d} L or D-Leu D-leucine {d}C or D-Cys D-Cysteine {d}Q or D-Gln D-glutamine {d}E or D-Glu D-Glutamic acid {d}H or D-His D-histidine Alpha-Me-Trp α-Methyl-L-tryptophan 1-Me-Trp 1-Methyl-L-tryptophan 4-F-Trp 4-Fluoro-L-tryptophan 6-F-Trp 6-Fluoro-L-tryptophan {d}6-F-Trp 6-Fluoro-D-tryptophan 6-Cl-Trp 6-Chloro-L-tryptophan 7-Me-Trp 7-Methyl-L-tryptophan 7-F-Trp 7-Fluoro-L-tryptophan 7-Ph-Trp 7-Phenyl-L-tryptophan 7-(Naphth-2-yl)-Trp 7-(Naphth-2-yl)-L-tryptophan 3-(3-pyridyl)-Ala 3-(3-pyridyl)-L-alanine 3-(4-pyridyl)-Ala 3-(4-pyridyl)-L-alanine {d}[3-(3-pyridyl)-Ala] 3-(3-pyridyl)-D-alanine 2-Me-3-(3-pyridyl)-Ala (2S)-2-amino-2-methyl-3-(3-pyridyl)propanoic acid 3-(3-Quinolinyl)-Ala 3-(3-Quinolinyl)-L-Alanine also known as (2S)-2-Amino-3-(3-quinolinyl)propanoic acid F(3-F) or 3-F-Phe 3-Fluoro-L-phenylalanine F(4-F) or 4-F-Phe 4-Fluoro-L-phenylalanine {d}F(4-F) 4-Fluoro-D-phenylalanine F(4-Cl) or 4-Cl-Phe 4-Chloro-L-phenylalanine F(4-NH2) or 4-NH2-Phe 4-amino-L-phenylalanine F(4-Me) or 4-Me-Phe 4-Methyl-L-phenylalanine F(3,4-Me) or 3,4-Me-Phe 3,4-Dimethyl-L-phenylalanine F(3,5-F) or 3,5-F-Phe 3,5-Difluoro-L-phenylalanine 2-Me-F(4-F) (2S)-2-amino-3-(4-fluorophenyl)-2-methyl-propanoic acid 2-Me-Leu 2-Methyl-L-leucine 2-Me-Lys 2-Methyl-L-Lysine 2-Me-Arg 2-Methyl-L-Arginine 2-Me-Val 2-Methyl-L-valine 2-Me-Phe (2S)-2-Amino-2-methyl-3-phenyl-propanoic acid, also known as alpha-methyl-L-phenylalanine N-Me-Arg N2-Methyl-L-Arginine N-Me-Ser N-Methyl-L-serine N-Me-Cys N-Methyl-L-Cysteine N-Me-Trp Nα-Methyl-L-tryptophan, also known as L-Abrin N-Me-Gln N2-methyl-L-glutamine Bip Biphenyl-L-alanine 3,3-Diphenyl-Ala β-Phenyl-L-Alanine, also known as (S)-2-Amino-3,3-diphenylpropionic acid Aad (2S)-2-aminohexanedioic acid, also known as L-homoglutamic acid Apm (2S)-2-aminopimelic acid, also known as (2S)-2-aminoheptanedioic acid or L-bishomoglutamic acid Dab (2S)-2,4-diaminobutanoic acid Orn L-Ornithine, also known as 2,5-Diaminopentanoic Acid hLys (2S)-2-amino-7-amino-heptanoic acid, also known as L-homolysine bAla 3-aminopropionic acid, also known as beta-alanine or β-alanine beta-homo-Ser L-β-homoserine Ala(N3) 3-azido-L-alanine Aha Azidohomo-L-alanine or 4-azido-L-homoalanine Orn(N3) Azido-L-ornithine K(N3) or Lys(N3) Azido-L-Lysine Pra L-Propargylglycine Hpg L-Homopropargylglycine Bpg L-Bishomopropargylglycine Dpr (2S)-2,3-Diaminopropanoic Acid also known as 3-Amino-L-alanine Glu(propargylamine) (2S)-2-amino-5-oxo-5-(prop-2-ynylamino)pentanoic acid Dab(3-butynoic acid) (2S)-2-amino-4-(but-3-ynoylamino)butanoic acid Dab(Azidoacetic acid) (2S)-2-amino-4-[(2-azidoacetyl)amino]butanoic acid (N3)-Ala (2S)-2-azidopropanoic acid Dab((N3)-Ala)) (2S)-2-amino-4-[[(2S)-2-azidopropanoyl]amino]butanoic acid Abu (2S)-2-aminobutyric acid Y(2-aminoethoxy) (2S)-2-amino-3-[4-(2-aminoethoxy)phenyl]propanoic acid Y(Me) (2S)-2-amino-3-(4-methoxyphenyl)propanoic acid Q(Pyrrolidine) (2S)-2-Amino-5-oxo-5-pyrrolidin-1-yl-pentanoic acid GABA 4-Aminobutanoic Acid also known as Gamma Aminobutyric Acid Phg L-2-phenylglycine F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl) 2-[2-[3-[4-[(2S)-2-amino-2-carboxy-ethyl]anilino]-3-oxo-propoxy]ethoxy]ethyl-trimethyl-ammonium

[0158] [Table 11] JPEG2024543204000043.jpg243170 JPEG2024543204000044.jpg232170 JPEG2024543204000045.jpg249170

[0159] An amino acid residue is an amino acid moiety in a peptide chain. An unnatural amino acid residue can be identified as a fragment of a defined unnatural amino acid in a peptide chain (e.g., the unnatural amino acid 3-aminomethylbenzoic acid can be identified as the unnatural amino acid residue (3-aminomethyl)benzoyl in a peptide chain).

[0160] Linear peptides are written from left to right from N-terminus to C-terminus.

[0161] Unnatural (or non-naturally occurring) amino acids and amino acid residues are those that do not naturally occur in a peptide chain. Unnatural amino acids can be formed as secondary metabolites in bacteria, fungi, plants, or marine organisms, or can be chemically synthesized.

[0162] Lactam Lactams are cyclic amides of the formula cyclo(R-NH-C(=O)-R), where each R can be any other suitable functional group linked to the other R. Each R can be the same or different.

[0163] Dithioethers A thioether is a functional group of formula RSR, where R can be any other suitable functional group. A dithioether is a functional group that includes two thioether groups linked together by a linker, e.g., RSLYLSR, where the linker is -LYL-.

[0164] Triazole Triazoles (or triazole rings) are heterocyclic compounds with the molecular formula CHN, which have a five-membered ring of two carbon atoms and three nitrogen atoms. Triazoles exist in two sets of isomers based on the relative positions of the three nitrogen atoms: 1,2,3-triazoles and 1,2,4-triazoles. Preferably, the triazole in the bridge containing the triazole ring is a 1,2,3-triazole.

[0165] craniocaudal circularization The term "head-to-tail cyclization" refers to the cyclization of an N-terminal amine (or a derivative thereof) with a C-terminal carboxylic acid to form a cyclic peptide. Typically, this cyclization forms an amide bond.

[0166] C 1-4 Acyl group In the context of the compounds of the present invention, R 1 C that can exist as a group 1-4 Acyl groups include formyl (i.e., methanoyl), acetyl (i.e., ethanoyl or -C(=O)CH3), propanoyl, 1-butanoyl and 2-methylpropanoyl groups.

[0167] C 1-4 Alkyl group In the context of the compounds of the present invention, R 1 C that can exist as a group 1-4 The alkyl group is C 1-3 Alkyl groups include, but are not limited to, methyl (Me or -CH3), ethyl (-CH2CH3), 1-propyl (-CH2CH2CH3), or 2-propyl (-CH(CH3)2).

[0168] C 1-3 Alkyl group In the context of the compounds of the present invention, R 2 C groups and C that may exist as X8 1-3 Alkyl groups include methyl (Me or -CH3), ethyl (-CH2CH3), 1-propyl (-CH2CH2CH3), and 2-propyl (-CH(CH3)2).

[0169] For X8, C 1-3 The alkyl group may be substituted with NH2, for example, -CH2CH2NH2.

[0170] C 1-4 Alkylene group C which may be present as L group of the dithioether bridge in the context of the compounds of the invention 1-4 The alkylene group is C 1-2Alkylene groups include, but are not limited to, methylene (-CH2-) and ethylene (-CH2CH2-).

[0171] Arylene Group Arylene groups which may be present as the Y group of the dithioether bridge in the context of the compounds of the invention include, but are not limited to, phenylene (eg, 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene).

[0172] Bridge part The sequences disclosed herein contain bridges indicated by parentheses (e.g., (1a), (2a), etc.). These represent chemical bridges between particular pairs of residues. Each parentheses appears twice in a sequence as a pair to indicate a single bridge. Most sequences have two bridges indicated by four sets of parentheses, signifying two bridge pairs.

[0173] Numbers in parentheses indicate the specific cross-link pair (e.g., "1" indicates the cross-link between the amino acid residues at the 2nd and 11th positions, which is also indicated by the bracket notation that defines the specific chemical cross-link). Letters indicate the type of chemical cross-link (e.g., "a" indicates a 1,3-dithio-propan-2-one cross-link).

[0174] Certain chemical crosslinks are defined at the end of the table using brackets (e.g., [2,11], [4,7], etc.) to indicate the amino acid residues used in the crosslink relative to the original starting peptide (I3 peptide (isomer 3) described in Example 2), and therefore may not match exactly the actual amino acid numbering in the SEQ ID NO: (e.g., some of these sequences are missing the first amino acid residue compared to the original starting peptide).

[0175] The residue immediately preceding the parenthetical notation indicates that the particular residue is used in the cross-link.

[0176] Immediately after the parentheses, *" notation indicates that the terminal -NH2 (if it is at the beginning of the sequence, i.e., the N-terminus) or -COOH (if it is at the end of the sequence, i.e., the C-terminus) is used to form the bridge. * When the " notation is used at the N-terminus, the terminal -NH2 is converted to an azide (-N3) of the N-terminal amino acid residue.

[0177] compound The present invention provides compounds that are peptide inhibitors of IL-23R.

[0178] The present invention relates to a compound of formula: R 1 -ZR 2 [In the formula, R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 alkyl or absent; R 2 NHR 3 , OH or absent, R 3 is hydrogen or C which may be substituted with NH 1-3 is alkyl; Z is a group of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) (In the formula, X1 is absent or selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gln, Val, Ile, N-Me-Ser, and Q (pyrrolidine); X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp; X6 is selected from the group consisting of Gln, Glu, Tyr, Cys, Val, His, N-Me-Gln, and Q (pyrrolidine); X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Val, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), {d}F(4-F), 4-Cl-Phe, alpha-Me-Trp, 3,3-diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and {d}6-F-Trp; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, {d}2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-Gln, D-Glu, D-His, 3-aminopropanoyl, and GABA, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, {d}[3-(3-pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharma- ceutically acceptable salt or solvate thereof, The compound is I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2] wherein (1a) is a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge, or a pharma- ceutically acceptable salt or solvate thereof.

[0179] In some embodiments, the present invention provides a compound of formula: R 1 -ZR 2 [In the formula, R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 alkyl or absent; R 2 NHR 3 , OH or absent, R 3 is hydrogen or C1-3 is alkyl; Z is a group of formula Ia: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (Ia) (In the formula, X1 is absent or selected from the group consisting of Asp, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gln; X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, and Bip; X6 is selected from the group consisting of Gln, Glu, Tyr and Cys; X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharma- ceutically acceptable salt or solvate thereof, The compound is I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2] wherein (1a) is a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge, or a pharma- ceutically acceptable salt or solvate thereof.

[0180] In some embodiments, the present invention provides a compound of formula: R 1 -ZR 2 [In the formula, R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 alkyl or absent; R 2 NHR 3 , OH or absent, R 3 may be substituted with hydrogen or NH 1-3 is alkyl; Z is a group of formula II: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (II) (In the formula, X1 is absent or Asp; X3 is Ser or He; X5 is Trp or 7-Me-Trp; X6 is Gln or Glu; X8 is Trp, Tyr, or 4-Me-Phe; the hydroxyl group of Tyr may be replaced by -CH2CH2NH2; X9 is 2-Nal, Trp, or 3,4-Me-Phe; X10 is Leu, 2-Me-Leu, or 2-Me-Val; X12 is Arg, D-Arg, and Dab; X13 is absent, 3-(3-pyridyl)-Ala, or 2-Me-3-(3-pyridyl)-Ala; X14 does not exist; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharma- ceutically acceptable salt or solvate thereof, The compound is I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2] wherein (1a) is a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge, or a pharma- ceutically acceptable salt or solvate thereof.

[0181] In some embodiments of formula I, Ia, or II, X2 and X11 are amino acid residues that together form a lactam bridge or a dithioether bridge. In some embodiments of formula I, Ia, or II, X2 and X11 are amino acid residues that together form a lactam bridge. In some such embodiments, X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; X2 is Glu and X11 is Lys; or X2 is Lys and X11 is Glu.

[0182] In some embodiments of Formula I, Ia, or II, X4 and X7 are amino acid residues that together form a lactam bridge or a dithioether bridge.

[0183] In some embodiments of Formula I, Ia, or II, X4 and X7 are amino acid residues that together form a dithioether bridge. In some such embodiments, the dithioether bridge is of the formula -SLYLS-, e.g., -SCH2C(=O)CH2S-. In some such embodiments, X4 is Cys and X7 is Cys.

[0184] In some embodiments of Formula I, Ia, or II, X4 and X7 are amino acid residues that together form a lactam bridge. In some such embodiments, X4 is Glu and X7 is Dab.

[0185] In some embodiments of formula I, Ia, or II, X2 and X11 are amino acid residues that together form a lactam bridge; X4 and X7 are amino acid residues that together form a lactam bridge or a dithioether bridge. In some embodiments of formula I, Ia, or II, X2 and X11 are amino acid residues that together form a lactam bridge; X4 and X7 are amino acid residues that together form a dithioether bridge. In some embodiments of formula I, Ia, or II, X2 and X11 are amino acid residues that together form a lactam bridge; X4 and X7 are amino acid residues that together form a lactam bridge.

[0186] Truncations within any of the sequences, ie deletion of amino acid residues between X2 and X11, result in inactive compounds (see reference compounds Ref 5, Ref 6, and Ref 7 in the Examples below).

[0187] It will be understood that the invention encompasses salts and solvates of the compounds. Suitable peptide salts and solvates are known in the art.

[0188] It will also be understood that any of the references to embodiments below are applicable and can be combined with any of the formulae described herein.

[0189] R1 R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 It is either alkyl or absent.

[0190] In some embodiments, R 1 , H, C 1-2 In some embodiments, R 1 is H, -C(=O)CH3, or absent. In some embodiments, R 1 is H or C 1-2 In some embodiments, R 1 is H. In some embodiments, R 1 is -C(=O)CH3. In some embodiments, R 1 does not exist.

[0191] In some embodiments, X 1 If does not exist, R 1 does not exist.

[0192] In some embodiments, X is absent and R 1 is absent, and X2 and X11 are amino acid residues which together form a lactam bridge or a bridge containing a triazole ring via the N-terminus of X2.

[0193] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2 is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0194] R 2 R 2 NHR 3 , OH or absent, R 3 may be substituted with hydrogen or NH 1-3 It is an alkyl.

[0195] In some embodiments, R 2 NHR 3 , OH or absent, R 3 is hydrogen or C 1-3 It is an alkyl.

[0196] In some embodiments, R 2 is NH2, NH-(CH2)3-NH2 (i.e., NH-3-aminopropanoyl), OH, or is absent.

[0197] In some embodiments, R 2 NHR 3 In some embodiments, R 2 is NH—(CH2)3—NH2, i.e., NH-3-aminopropanoyl. In some embodiments, R 2 is NH2. In some embodiments, R 1 is OH. In some embodiments, R 2 does not exist.

[0198] Preferably, R 2 is NH2.

[0199] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2 is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0200] Z Z is a group of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) is the amino acid sequence X1 is absent or selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gln, Val, Ile, N-Me-Ser, and Q (pyrrolidine); X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp; X6 is selected from the group consisting of Gln, Glu, Tyr, Cys, Val, His, N-Me-Gln, and Q (pyrrolidine); X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Val, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), {d}F(4-F), 4-Cl-Phe, alpha-Me-Trp, 3,3-diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and {d}6-F-Trp; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, {d}2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-Gln, D-Glu, D-His, 3-aminopropanoyl, and GABA, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, {d}[3-(3-pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring).

[0201] In some embodiments, Z is of formula Ia: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (Ia) (In the formula, X1 is absent or selected from the group consisting of Asp, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gln; X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, and Bip; X6 is selected from the group consisting of Gln, Glu, Tyr and Cys; X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring).

[0202] In some embodiments, Z is represented by formula II: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (II) (In the formula, X1 is absent or Asp; X3 is Ser or He; X5 is Trp or 7-Me-Trp; X6 is Gln or Glu; X8 is Trp, Tyr, or 4-Me-Phe; the hydroxyl group of Tyr may be replaced by -CH2CH2NH2; X9 is 2-Nal, Trp, or 3,4-Me-Phe; X10 is Leu, 2-Me-Leu, or 2-Me-Val; X12 is Arg, D-Arg, and Dab; X13 is absent, 3-(3-pyridyl)-Ala, or 2-Me-3-(3-pyridyl)-Ala; X14 does not exist; X2, X4, X7, and X11 are amino acid sequences defined as above for Formula I).

[0203] In some embodiments, Z is represented by formula III: X1-X2-X3-X4-X5-Gln-X7-X8-X9-X10-X11-X12 (III) (wherein X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, and X12 are defined as above for Formula I, Ia, or II).

[0204] In some embodiments, Z is represented by formula IV: X2-Ser-X4-Trp-Gln-X7-X8-(2-Nal)-Leu-X11-Arg (IV) (wherein X2, X4, X7, X8, and X11 are defined as above for Formula I, Ia, or II).

[0205] In some embodiments, Z is of formula V: X2-Ser-X4-Trp-Gln-X7-X8-(2-Nal)-Leu-X11-Arg (V) (In the formula, X8 is selected from the group consisting of Trp and Tyr, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X2 is Lys and X11 is Gln, which together form a lactam bridge; X4 and X7 are both Cys, which together form a dithioether bridge).

[0206] In some embodiments, Z is [Table 12] JPEG2024543204000047.jpg240170 JPEG2024543204000048.jpg236170 JPEG2024543204000049.jpg245170 JPEG2024543204000050.jpg191170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. is an amino acid sequence selected from the group consisting of:

[0207] In some embodiments, Z is [Table 13] JPEG2024543204000052.jpg235170 JPEG2024543204000053.jpg237170 JPEG2024543204000054.jpg246170 JPEG2024543204000055.jpg23170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. is an amino acid sequence selected from the group consisting of:

[0208] X1 X1 is absent or selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys.

[0209] In some embodiments, X1 is absent or selected from the group consisting of Asp, Glu, Ser, Cys, and Lys.

[0210] In some embodiments, X1 is absent or selected from the group consisting of Asp, Gly, and Leu.

[0211] In some embodiments, X1 may be absent or may be Asp.

[0212] In some embodiments, X is absent and R 1 is absent, and X2 and X11 are amino acid residues which together form a lactam bridge or a bridge containing a triazole ring via the N-terminus of X2.

[0213] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2 is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0214] Preferably, X1 is absent. As shown in Example 2, compounds can be truncated by removing the N-terminal amino acid residue (ie, X1) to retain or increase the potency of the peptide.

[0215] X3 X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gln, Val, Ile, N-Me-Ser, and Q (pyrrolidine).

[0216] In some embodiments, X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Gln, Val, Ile, N-Me-Ser, and Q (pyrrolidine).

[0217] In some embodiments, X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gln.

[0218] In some embodiments, X3 is Ser or Ile.

[0219] In some embodiments, X3 is Ser.

[0220] X5 X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp.

[0221] In some embodiments, X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, and Bip.

[0222] In some embodiments, X5 is selected from the group consisting of Trp, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp.

[0223] In some embodiments, X5 is Trp or 7-Me-Trp. In some embodiments, X5 is Trp.

[0224] X6 X6 is selected from the group consisting of Gln, Glu, Tyr, Cys, Val, His, N-Me-Gln, and Q (pyrrolidine).

[0225] In some embodiments, X6 is selected from the group consisting of Gln, Glu, Val, His, N-Me-Gln, and Q (pyrrolidine).

[0226] In some embodiments, X6 is selected from the group consisting of Gln, Glu, Tyr and Cys.

[0227] In some embodiments, X6 is Gln or Glu. In some embodiments, X6 is Gln.

[0228] X8 X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Val, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), {d}F(4-F), 4-Cl-Phe, alpha-Me-Trp, 3,3-diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr may be replaced by NH2. 1-3 It may be substituted with alkyl.

[0229] In some embodiments, X8 is selected from the group consisting of Trp, Tyr, Ala, His, 2-Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Val, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), {d}F(4-F), 4-Cl-Phe, alpha-Me-Trp, 3,3-diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr may be replaced by NH2. 1-3 It may be substituted with alkyl.

[0230] In some embodiments, X8 is selected from the group consisting of Trp, Tyr, Ala, His, 2-Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Val, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), {d}F(4-F), 4-Cl-Phe, alpha-Me-Trp, 3,3-diphenyl-Ala, Phg, Y(2-aminoethoxy), and Y(Me).

[0231] In some embodiments, X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, and the hydroxyl group of Tyr is optionally substituted with NH2. 1-3 It may be substituted with alkyl.

[0232] In some embodiments, X8 is selected from the group consisting of Trp, Tyr, and 4-Me-Phe, and the hydroxyl group of Tyr is optionally substituted with NH2. 1-3 In some embodiments, X8 is selected from the group consisting of Trp, Tyr, and 4-Me-Phe, and the hydroxyl group of Tyr is substituted with -CH2CH2NH2.

[0233] In some embodiments, X8 is Trp or Tyr, and the hydroxyl group of Tyr is optionally substituted with NH2. 1-3 In some embodiments, X8 is Trp or Tyr, and the hydroxyl group of Tyr is substituted with -CH2CH2NH2.

[0234] In some embodiments, X8 is Trp.

[0235] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr is optionally substituted with NH2. 1-3 In some embodiments, X8 is Tyr and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2 or -CH3. In some embodiments, X8 is Tyr and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2. In some embodiments, X8 is Tyr and the hydroxyl group of Tyr may be substituted with -CH3.

[0236] In some embodiments, X8 is Tyr.

[0237] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr is optionally substituted with NH2. 1-3 In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr is substituted with NH2. 1-3 In some embodiments, X8 is Tyr and the hydroxyl group of Tyr is substituted with -CH2CH2NH2, i.e., Y (2-aminoethoxy).

[0238] In some embodiments, X8 is Tyr, and the hydroxyl group of Tyr is C 1-3 In some embodiments, X8 is Tyr and the hydroxyl group of Tyr may be substituted with -CH3, i.e., Y(Me). In some embodiments, X8 is Tyr and the hydroxyl group of Tyr is substituted with -CH3, i.e., Y(Me).

[0239] Preferably, X8 is selected from Trp, Y(2-aminoethoxy) and 4-Me-Phe. More preferably, X8 is Trp or Y(2-aminoethoxy).

[0240] X9 X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and {d}6-F-Trp.

[0241] In some embodiments, X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, 4-F-Phe, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and {d}6-F-Trp.

[0242] In some embodiments, X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala.

[0243] In some embodiments, X9 is selected from the group consisting of 2-Nal, Trp, and 3,4-Me-Phe.

[0244] In some embodiments, X9 is selected from the group consisting of 2-Nal and Trp.

[0245] In some embodiments, X9 is Trp. In some embodiments, X9 is 2-Nal.

[0246] X10 X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val.

[0247] In some embodiments, X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val.

[0248] In some embodiments, X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl.

[0249] In some embodiments, X10 is selected from the group consisting of Leu, 2-Me-Leu, and 2-Me-Val. In some embodiments, X10 is Leu or 2-Me-Leu. In some embodiments, X10 is 2-Me-Leu or 2-Me-Val.

[0250] In some embodiments, X10 is Leu. In some embodiments, X10 is 2-Me-Leu. In some embodiments, X10 is 2-Me-Val.

[0251] X12 X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, {d}2,4-diaminobutanoyl ([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-Gln, D-Glu, D-His, 3-aminopropanoyl, and GABA, or is absent.

[0252] In some embodiments, X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, 4-NH2-Phe, Tyr, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, {d}2,4-diaminobutanoyl ([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-Gln, D-Glu, D-His, 3-aminopropanoyl, and GABA, or is absent.

[0253] In some embodiments, X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0254] In some embodiments, X12 is selected from the group consisting of Arg, D-Arg, Dab, and Gly.

[0255] In some embodiments, X12 is Arg or Ser. In some embodiments, X12 is Arg or D-Arg. In some embodiments, X12 is Arg or Dab. In some embodiments, X12 is D-Arg or Dab.

[0256] In some embodiments, X12 is Arg. In some embodiments, X12 is D-Arg. In some embodiments, X12 is Dab. In some embodiments, X12 is Ser. In some embodiments, X12 is absent.

[0257] Preferably, X12 is selected from the group consisting of Arg, D-Arg, and Dab.

[0258] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2 is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0259] X13 X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, {d}[3-(3-pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-pyridyl)-Ala.

[0260] In some embodiments, X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala.

[0261] In some embodiments, X13 is absent, 3-(3-pyridyl)-Ala, or 2-Me-3-(3-pyridyl)-Ala.

[0262] In some embodiments, X13 is absent. In some embodiments, X13 is Asn. In some embodiments, X13 is Gly. In some embodiments, X13 is 3-(3-pyridyl)-Ala. In some embodiments, X13 is 2-Me-3-(3-pyridyl)-Ala.

[0263] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2 is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0264] Preferably, when X14 is absent such that X13 is the C-terminal amino acid residue, X13 is 3-(3-pyridyl)-Ala. In such an embodiment, the potency against hIL23 pSTAT3 is characterized by a low IC 50 As evidenced by the values, see, for example, compounds 78, 120-124, 147, 148, and 155-158 in Example 3, Table 3-1.

[0265] X14 X14 is absent or Gly.

[0266] In some embodiments, X14 is absent. In some embodiments, X14 is Gly.

[0267] Preferably, X14 is absent. In such embodiments, X13 may be 3-(3-pyridyl)-Ala.

[0268] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0269] X2 and X11 X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring.

[0270] Preferably, X2 and X11 are amino acid residues which together form a lactam bridge. As shown in Example 3, the lactam bridge between amino acid residues X2 and X11 is more stable than the corresponding diethioether bridge, 1,3-dithio-propan-2-one.

[0271] In some embodiments, X is absent and R 1 is absent, and X2 and X11 are amino acid residues which together form a lactam bridge or a bridge containing a triazole ring via the N-terminus of X2.

[0272] In some embodiments, X1 and X12-X14 are absent, and R 1 and R 2 is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0273] In some embodiments, X2 is Cys and X11 is Cys, which together form a dithioether bridge; X2 is Glu and X11 is Lys, which together form a lactam bridge; or X2 is Lys and X11 is Glu, which together form a lactam bridge.

[0274] Amino acid residue The lactam bridge is formed by one amino acid residue containing an amine group and another amino acid residue containing a carboxylic acid group. Preferably, the amine and / or carboxylic acid group of the amino acid residue is on the side chain of the amino acid residue, for example, Dpr, hLys, Lys, Arg, Orn, Dab, Glu and Asp. Alternatively, the amine and / or carboxylic acid group of the amino acid residue can be at the N- or C-terminus of the peptide chain, for example, the amine or carboxylic acid of any amino acid or peptide backbone, for example, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, and (4-(2-aminoethyl)-piperazin-1-yl)-acetyl.

[0275] Suitable amino acid residues for X2 and X11 which together form a lactam bridge are selected from the following: Amino acid residues containing an amine group: Dpr, hLys, Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, 2,4-diaminobutanoyl ([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl. · Amino acid residues containing a carboxylic acid group: Glu, Asp, Aad, and Apm.

[0276] The dithioether bridge is formed by two amino acid residues that contain 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.

[0277] Suitable amino acid residues for X2 and X11 which together form a dithioether bridge may be Cys or N-Me-Cys.

[0278] The bridge containing the triazole ring is formed with one amino acid residue containing an azide (-N3) group and another amino acid residue containing an alkyne group, in some embodiments, the azide and / or alkyne groups of the amino acid residue are on the side chain of the amino acid residue.

[0279] Suitable amino acid residues for X2 and X11 which together form a bridge containing a triazole ring may be selected from the following: Amino acid residues containing an azide group: Ala(N3), Aha, Orn(N3), Lys(N3), Lys(N3), Azidoacetate, (N3)-Ala, Dab(Azidoacetate), and Dab((N3)-Ala). · Amino acid residues containing an alkyne group: Pra, Hpg, Bpg, Glu (propargylamine), Dab (3-butynoic acid), and but-3-ynoic acid.

[0280] Bridge length The length of the bridge is counted as the number of atoms in the linear chain starting from the first atom bonded to an atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the first residue (X2 for the bridge between X2 and X11) (in other words, bonded to the alpha carbon of the corresponding residue for most amino acids) and ending with the first atom bonded to an atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the second residue (X11 for the bridge between X2 and X11).

[0281] The contribution of amino acid residue and cross-link type to cross-link length is described below.

[0282] In some embodiments, the length of the bridge between X2 and X11 is at least 5 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 10 atoms long or less. In some embodiments, the length of the bridge between X2 and X11 is 5 to 10 atoms long, for example, 5, 6, 7, 8, 9, or 10 atoms long.

[0283] Lactam Bridge The present inventors have found that replacing the lactam bridge with a dithioether bridge can increase the potency of IL-23R peptide inhibitors (see Example 2).

[0284] Thus, compounds of the invention may include a lactam bridge formed between an amino acid residue at position X2 and an amino acid residue at position X11. For simplicity, positions X2 and X11 are discussed with reference to the residues nominally present prior to lactam formation.

[0285] One of the residues at positions X2 and X11 is an amino acid residue containing an amine group and the other is an amino acid residue containing a carboxylic acid group, such that a lactam (cyclic amide) is formed between the amine and carboxylic acid groups.

[0286] Typically, the amine and / or carboxylic acid group is present on the side chain of the amino acid residue. The amine may be a primary or secondary amine, but is typically a primary amine. Suitable amino acid residues whose side chains may participate in lactam bridges include Dpr, Dab, Orn, hLys, Lys, and Arg (having a side chain containing an amine group), and Aad, Apm, Glu, and Asp, (having a side chain containing a carboxylic acid group). Any amino acid selected from Aad, Apm, Glu, and Asp can in principle form a lactam bridge with any amino acid residue selected from the group consisting of Dpr, Dab, Orn, hLys, Lys, and Arg.

[0287] Alternatively, the amine and / or carboxylic acid group of the amino acid residue may be at the N- or C-terminus of the peptide chain, e.g., the amine or carboxylic acid of any amino acid such as Arg or Asp, or the peptide backbone, e.g., bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, and (4-(2-aminoethyl)-piperazin-1-yl)-acetyl. Suitable amino acid residues that may participate in the lactam bridge via the N- or C-terminus of the peptide chain are Arg, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, ( ...3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4- noethyl)-piperazin-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl (with a terminal amine group), and Asp (with a terminal carboxylic acid group).

[0288] Thus, one of the residues at positions X2 and X11 may be selected from the group consisting of Dpr, Dab, Orn, hLys, Lys, Arg, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 2 ... aminoethyl)-piperazin-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl, and the other may be selected from Glu, Asp, Aad, and Apm. In some embodiments, one of the residues at positions X2 and X11 is Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4- (2-aminoethyl)-piperazin-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl, and the other may be selected from Glu and Asp.

[0289] In some embodiments, the amine component of the lactam bridge is derived from the amino acid at position X2, while the carboxylic acid component of the lactam bridge is derived from the amino acid at position X11. Thus, X2 can be selected from Dpr, Dab, Orn, hLys, Lys, Arg, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl) -piperazin-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl; and X11 may be selected from Aad, Apm, Glu, and Asp.In some embodiments, X2 is Lys, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)benzoyl, )-piperazin-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl, and X11 can be Glu and Asp.

[0290] Alternatively, in some embodiments, the carboxylic acid component of the lactam bridge is derived from the amino acid at position X2, while the amine component of the lactam bridge is derived from the amino acid at position X11. Thus, X2 may be selected from Aad, Apm, Glu, and Asp, and X11 is selected from Dpr, Dab, Orn, hLys, Lys, Arg, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl -cyclohexyl-1-carbonyl, (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl. In some embodiments, X2 may be selected from Glu and Asp, and X11 may be selected from Lys, Arg, and Dab.

[0291] Suitable pairings of residues at positions X2 and X11 to form a lactam bridge include: When X2 is an amine building block and X11 is a carboxylic acid building block: X2 is Lys and X11 is Glu; X2 is Orn and X11 is Glu; X2 is bAla and X11 is Glu; X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is (4-aminomethyl)benzoyl and X11 is Glu; X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu; X2 is 2-aminomethyl-phenylacetyl and X11 is Glu; X2 is 3-aminomethyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; X2 is 6-aminohexanoyl and X11 is Glu; X2 is 6-amino-4-oxahexanoyl and X11 is Glu; X2 is trans-4-aminomethyl-cyclohexyl-1-carbonyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Asp; X2 is 4-aminomethyl-2-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-3-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-2-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-methoxy-phenylacetyl and X11 is Glu; X2 is Dab and X11 is Glu; X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu; or X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu.

[0292] When X2 is a carboxylic acid building block and X11 is an amine building block: X2 is Glu and X11 is Lys; X2 is Glu and X11 is Dab; ​​or X2 is Asp and X11 is Arg.

[0293] In some embodiments, X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; X2 is Glu and X11 is Lys; or X2 is Lys and X11 is Glu.

[0294] In some embodiments, X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; or X2 is Lys and X11 is Glu.

[0295] In some embodiments, X2 is (3-aminomethyl)benzoyl and X11 is Glu; or X2 is 4-aminomethyl-phenylacetyl and X11 is Glu.

[0296] In some embodiments, X2 is Glu and X11 is Lys; or X2 is Lys and X11 is Glu.

[0297] Preferably, X2 is Lys and X11 is Glu. The inventors have found that this combination of amino acid residues at positions 2 and 11 increases potency (see Example 2).

[0298] The contribution of a side chain to the length of the lactam bridge is counted as the number of atoms in the linear chain starting from the first atom of the side chain (attached to the peptide backbone atom, i.e., the alpha carbon of the residue corresponding to most amino acids) and including and ending with the atom involved in the amide bond of the lactam bridge (i.e., the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0299] Thus, typical acid and amine containing side chains may have the following side chain lengths: Amine-containing side chains: Dpr 2 atoms Dab 3 atoms Orn 4 atoms Lys 5 atoms hLys 6 atoms Arg 6 atoms Carboxylic acid-containing side chains: Asp 2 atoms Glu 3 atoms Aad 4 atoms Apm 5 atoms

[0300] 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 linear chain starting from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (in other words, the first atom attached to the alpha carbon of the residue for most amino acids) and including and ending with the atom involved in the amide bond of the lactam bridge (in other words, the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0301] Thus, the following amino acid residues would be considered to have the following lengths: N-terminus: Asp 1 atom Dab 1 atom 2,4-Diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) 1 atom bAla 2 atoms (3-Aminomethyl)benzoyl 4 atoms 2-Aminomethyl-phenylacetyl 4 atoms (4-Aminomethyl)benzoyl 5 atoms 3-Aminomethyl-phenylacetyl 5 atoms 6-Aminohexanoyl 5 atoms 6-Amino-4-oxahexanoyl 5 atoms trans-4-Aminomethyl-cyclohexyl-1-carbonyl 5 atoms 3-(4-aminophenyl)propanoyl 6 atoms 4-(2-aminoethyl)benzoyl 6 atoms 4-Aminomethyl-phenylacetyl 6 atoms 4-Aminomethyl-2-pyridineacetyl 6 atoms 4-Aminomethyl-3-pyridineacetyl 6 atoms 4-Aminomethyl-2-fluoro-phenylacetyl 6 atoms 4-Aminomethyl-3-methyl-phenylacetyl 6 atoms 4-Aminomethyl-3-methoxy-phenylacetyl 6 atoms 4-Methylaminomethyl-phenylacetyl 6 atoms (4-(2-aminoethyl)-piperazin-1-yl)-acetyl 7 atoms C-terminus: Arg 1 atom

[0302] The location of the amide bond in the lactam bridge may affect the potency of the compound. The inventors have observed that the closer the amide bond is to the 11th position (X11), the more active the compound is, and the closer it is to the 2nd position (X2), the less active it is (see Example 2 and Table 2-3b). For example, in compound 7, where X2 is Lys and X11 is Glu, the amide bond is 4 atoms away from the peptide backbone atom of X2 (i.e., the alpha carbon of Lys) and 2 atoms away from the peptide backbone atom of X11 (i.e., the alpha carbon of Glu), so the amide bond is closer to the 11th position (X11). By comparison, in compound 4, where X2 is Glu and X11 is Lys, the amide bond is 2 atoms away from the peptide backbone atom of X11 (i.e., the alpha carbon of Glu) and 4 atoms away from the peptide backbone atom of X2 (i.e., the alpha carbon of Lys), so the amide bond is closer to the 2nd position (X2). Table 2-3b shows that compound 7, in which the amide bond is closer to the 11th position (X11), is more active than compound 4, in which the amide bond is closer to the 2nd position (X2).

[0303] When the location of the amide bond in the formed lactam bridge is closer to position X11 than to position X2, suitable pairings of residues at positions X2 and X11 include: X2 is Lys and X11 is Glu; X2 is Orn and X11 is Glu; X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is (4-aminomethyl)benzoyl and X11 is Glu; X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu; X2 is 2-aminomethyl-phenylacetyl and X11 is Glu; X2 is 3-aminomethyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; X2 is 6-aminohexanoyl and X11 is Glu; X2 is 6-amino-4-oxahexanoyl and X11 is Glu; X2 is trans-4-aminomethyl-cyclohexyl-1-carbonyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Asp; X2 is 4-aminomethyl-2-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-3-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-2-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methoxy-phenylacetyl and X11 is Glu; or X2 is 4-aminomethyl-3-methoxy-phenylacetyl and X11 is Glu.

[0304] X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu.

[0305] Alternatively, if the location of the amide bond in the lactam bridge is closer to position X2 than to position X11, suitable pairings of residues at positions X2 and X11 include: X2 is bAla and X11 is Glu; X2 is Glu and X11 is Lys; X2 is Dab (N-terminus) and X11 is Glu; or X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu.

[0306] When the lactam bridge is formed from the side chains of the residues at position X2 and X11, the side chain of the residue at position X2 is longer than the side chain of the residue at position X11, such that the location of the amide bond in the formed lactam bridge is closer to the 11th position (X11) than to the 2nd position (X2). Thus, in some embodiments, the side chain of the residue at position X2 is longer than the side chain of the residue at position X11.

[0307] When the side chain at position X2 is longer than the side chain at position X11, suitable pairings of residues at positions X2 and X11 include: X2 is Lys and X11 is Glu; or X2 is Orn and X11 is Glu.

[0308] Alternatively, in some embodiments, the side chain of the residue at position X2 is shorter than the side chain of the residue at position X11, such that the location of the amide bond in the formed lactam bridge is closer to the second position (X2) than to the eleventh position (X11).

[0309] When the side chain at position X2 is shorter than the side chain at position X11, suitable pairings of residues at positions X2 and X11 include: X2 is Glu and X11 is Lys.

[0310] Desirably, the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 5, 6, 7, 8, 9, or 10 atoms; for example, 6, 7, 8, or 9 atoms; for example, 7 or 8 atoms.

[0311] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 5 atoms. When the lactam bridge has a length of 5 atoms, suitable pairings of residues at positions X2 and X11 include pairings of bAla with Glu.

[0312] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 6 atoms. When the lactam bridge has a length of 6 atoms, suitable pairing of residues at positions X2 and X11 includes pairing of Glu with Dab.

[0313] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 7 atoms. When the lactam bridge has a length of 7 atoms, suitable pairings of residues at positions X2 and X11 include: pairing of Orn with Glu; pairing of (3-aminomethyl)benzoyl with Glu; and pairing of 2-aminomethyl-phenylacetyl with Glu.

[0314] Preferably, the length of the lactam bridge after formation of the amide bond (not including the atoms in the peptide backbone) is 8 atoms. When the lactam bridge has a length of 8 atoms, suitable pairings of residues at positions X2 and X11 include: Glu with Lys; Aad with Orn; Asp with hLys; (4-aminomethyl)benzoyl with Glu; 3-aminomethyl-phenylacetyl with Glu; 6-aminohexanoyl with Glu; 6-amino-4-oxahexanoyl with Glu; and trans-4-aminomethyl-cyclohexyl-1-carbonyl with Glu.

[0315] In some embodiments, the length of the lactam bridge after the formation of the amide bond (not including the atoms in the peptide backbone) is 9 atoms. When the lactam bridge has a length of 9 atoms, suitable pairings of residues at positions X2 and X11 include: 3-(4-aminophenyl)propanoyl with Glu; 4-aminomethyl-phenylacetyl with Glu; (4-(2-aminoethyl)-piperazin-1-yl)-acetyl with Asp; 4-(2-aminoethyl)benzoyl with Glu; 4-aminomethyl-2-pyridineacetyl with Glu; 4-aminomethyl-3-pyridineacetyl with Glu; 4-aminomethyl-2-fluoro-phenylacetyl with Glu; 4-aminomethyl-3-methyl-phenylacetyl with Glu; 4-aminomethyl-3-methoxy-phenylacetyl with Glu; and 4-methylaminomethyl-phenylacetyl with Glu.

[0316] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 10 atoms. When the lactam bridge has a length of 10 atoms, suitable pairings of residues at positions X2 and X11 include pairing of (4-(2-aminoethyl)-piperazin-1-yl)-acetyl with Glu.

[0317] Dithioether bridge We found that a linker between the thiol side chains of the linked [2,11] and [4,7] cysteine ​​residues in the compounds was required to retain IL-23R inhibitory activity. Replacement of the dithioether bridge with a disulfide bridge reduced the inhibitory activity (see Example 2).

[0318] Thus, compounds of the invention may include a dithioether bridge formed between an amino acid residue at position X2 and an amino acid residue at position X11. For simplicity, positions X2 and X11 are discussed with reference to the residues nominally present prior to dithioether formation.

[0319] In some embodiments, the dithioether bridge between X2 and X11 has the formula -SLYLS- (In the formula: each S is a sulfur atom and is part of an amino acid residue of X2 and X11; Each L is independently C 1-4 is alkylene; Y is absent, C(=O) or arylene.

[0320] In some embodiments, the dithioether bridge of formula -SLYLS- is -SCH2C(=O)CH2S-, i.e., each L is -CH2- and Y is C(=O).

[0321] In some embodiments, the dithioether bridge of formula -SLYLS- is -SCH2(phenylene)CH2S-, e.g., -SCH2(1,2-phenylene)CH2S-, -SCH2(1,3-phenylene)CH2S-, and -SCH2(1,4-phenylene)CH2S-. In some embodiments, the dithioether bridge of formula -SLYLS is -SCH2(1,2-phenylene)CH2S-. That is, each L is -CH2- and Y is 1,2-phenylene.

[0322] The contribution of a side chain to the length of a dithioether bridge is counted as the number of atoms in a linear chain starting from the first atom of the side chain (attached to a peptide backbone atom, i.e., the alpha carbon of the residue that corresponds to most amino acids) and including and ending with the atom involved in the dithioether bond of the bridge (i.e., the sulfur atom).

[0323] Thus, typical sulfur-containing side chains may have the following side chain lengths: Cys: 2 atoms N-Me-Cys 2 atoms

[0324] In some embodiments, X2 and X11 are each independently selected from Cys and N-Me-Cys.

[0325] In some embodiments, X2 is Cys and X11 is Cys.

[0326] In some embodiments, X2 is Cys and X11 is N-Me-Cys. In some embodiments, X2 is N-Me-Cys and X11 is Cys.

[0327] Preferably, X2 is Cys and X11 is Cys.

[0328] The length of the bridge is then determined as the contribution of the linker between the sulfur moiety of the amino acid residue at position X2 and the sulfur moiety of the amino acid residue at position X11, plus the length of the side chains of X2 and X11. For embodiments in which the dithioether bridge is of the formula -SLYLS-, the contribution of the linker is counted as the number of atoms in -LYL- since the sulfur atom is already counted in the side chain length.

[0329] Desirably, the length of the dithioether bridge (not including atoms in the peptide backbone) after formation of the dithioether bond is 5, 6, 7, 8, 9, or 10 atoms, such as 6, 7, 8, or 9 atoms; such as 7, 8, or 9 atoms, such as 7 or 8 atoms.

[0330] In some embodiments, the bridge is 7 atoms long, such as, for example, the bridge -SCH2C(=O)CH2S-.

[0331] In some embodiments, the bridge length is 8 atoms long, such as, for example, a bridge -SCH2(1,2-phenylene)CH2S-. In some embodiments, the bridge length is 9 atoms long, such as, for example, a bridge -SCH2(1,3-phenylene)CH2S-. In some embodiments, the bridge length is 10 atoms long, such as, for example, a bridge -SCH2(1,4-phenylene)CH2S-.

[0332] Preferably, the dithioether bridge is 7 or 8 atoms long.

[0333] Triazole ring-containing bridge The compounds of the invention may include a bridge comprising a triazole ring formed between an amino acid residue at position X2 and an amino acid residue at position X11. For simplicity, positions X2 and X11 are discussed with reference to the residues nominally present prior to triazole formation.

[0334] One of the residues at positions X2 and X11 is an amino acid residue containing an azide (-N3) group, and the other is an amino acid residue containing an alkyne group, and a triazole (e.g., 1,2,3-triazole) is formed between the azide and alkyne groups. The reaction for the formation of the triazole ring is the Huisgen azide-alkyne 1,3-dipolar cycloaddition. Typically, this reaction forms a 1,4-disubstituted 1,2,3-triazole ring as the major isomer (as opposed to a 1,5-disubstituted 1,2,3-triazole ring). The 1,5-disubstituted 1,2,3-triazole ring can also usually be isolated as a minor isomer.

[0335] The azide and / or alkyne groups may be present on the side chain of the amino acid residue. The alkyne is preferably a terminal alkyne (-C≡CH). Suitable amino acid residues whose side chains may participate in the formation of a triazole ring (e.g., a 1,2,3-triazole ring) include Ala(N3), Aha, Orn(N3), and Lys(N3) (having a side chain containing an azide group), and Pra, Hpg, Bpg, Glu (propargylamine), and Dab (3-butynoic acid) (having a side chain containing an alkyne group).

[0336] Alternatively, the azide and / or alkyne groups of the amino acid residues may be at the N- or C-terminus of the peptide chain. For example, the azide group may be derived from the amine group of the peptide backbone of any amino acid, such as azidoacetic acid and (N3)-Ala, and may be at the N-terminus of the peptide chain. In another example, the alkyne group may be derived from the amine group of the peptide backbone of any amino acid, such as but-3-ynoic acid, and may be at the N-terminus of the peptide chain.

[0337] Thus, one of the residues at positions X2 and X11 may be selected from Ala(N3), Aha, Orn(N3), Lys(N3), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala), and the other may be selected from Pra, Hpg, Bpg, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid. In some embodiments, one of the residues at positions X2 and X11 is selected from Lys(N3), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala), and the other is selected from Pra, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid. In some embodiments, one of the residues at positions X2 and X11 can be Lys(N3) and the other can be Pra. In some embodiments, one of the residues at positions X2 and X11 can be Dab (azidoacetic acid) or Dab((N3)-Ala) and the other can be but-3-ynoic acid.

[0338] In some embodiments, the azide component of the bridge comprising the triazole ring is derived from the amino acid at position X2, while the alkyne component of the bridge comprising the triazole ring is derived from the amino acid at position X11. Thus, X2 may be selected from Ala(N3), Aha, Orn(N3), Lys(N3), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala), and X11 may be selected from Pra, Hpg, Bpg, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid. In some embodiments, X2 is selected from Lys(N3), azidoacetic acid, and (N3)-Ala; and X11 is selected from Pra, Glu(propargylamine), and Dab(3-butynoic acid). In some embodiments, X2 is Lys(N3) and X11 is Pra.

[0339] Alternatively, in some embodiments, the alkyne component of the bridge comprising the triazole ring is derived from an amino acid at position X2, while the azide component of the bridge comprising the triazole ring is derived from an amino acid at position X11. Thus, X2 may be selected from Pra, Hpg, Bpg, Glu (propargylamine), Dab (3-butynoic acid), and but-3-ynoic acid, and X11 may be selected from Ala(N3), Aha, Orn(N3), Lys(N3), azidoacetic acid, (N3)-Ala, Dab (azidoacetic acid), and Dab((N3)-Ala). In some embodiments, X2 is selected from Pra and but-3-ynoic acid; X11 is selected from Dab (azidoacetic acid), and Dab((N3)-Ala). In some embodiments, X2 is but-3-ynoic acid; and X11 is selected from Dab (azidoacetic acid), and Dab((N3)-Ala).

[0340] Suitable pairings of residues at positions X2 and X11 to form a bridge containing a triazole ring include the following: When X2 is the azide building block and X11 is the alkyne building block: X2 is Lys(N3) and X11 is Pra; X2 is azidoacetic acid and X11 is Glu (propargylamine); X2 is azidoacetic acid and X11 is Dab (3-butynoic acid); X2 is (N3)-Ala and X11 is Glu (propargylamine); or X2 is (N3)-Ala and X11 is Dab (3-butynoic acid).

[0341] When X2 is an alkyne building block and X11 is an azide building block: X2 is Pra and X11 is Dab (azidoacetic acid); X2 is Pra and X11 is Dab ((N3)-Ala); X2 is but-3-ynoic acid and X11 is Dab (azidoacetic acid); or X2 is but-3-ynoic acid and X11 is Dab ((N3)-Ala).

[0342] The contribution of the side chain to the length of the bridge involving the triazole ring starts from the first atom of the side chain (attached to the peptide backbone atom, i.e., the alpha carbon of the residue, which corresponds to most amino acids) and continues through the atoms participating in the formation of the triazole ring (i.e., the first nitrogen atom of the azide group attached to the side chain, in the case of both 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles) (i.e., - N =N + =N - or in the case of a 1,4-disubstituted 1,2,3-triazole, two carbon atoms of the alkyne group, or in the case of a 1,5-disubstituted triazole, one carbon atom of the alkyne group (i.e., - C The number of atoms in a straight chain that contains and ends with this atom is counted.

[0343] Thus, typical azide and alkyne containing side chains may have the following side chain lengths: Azide-containing side chains: Ala(N3) 2 atoms Aha 3 atoms Orn(N3) 4 atoms Lys(N3) 5 atoms Dab(azidoacetic acid) 6 atoms Dab((N3)-Ala) 6 atoms Alkyne-containing side chains (for 1,4-disubstituted 1,2,3-triazoles): Pra 3 atoms Hpg 4 atoms Bpg 5 atoms Glu(propargylamine) 7 atoms Dab(3-butynoic acid) 7 atoms Alkyne-containing side chains (for 1,5-disubstituted 1,2,3-triazoles): Pra 2 atoms Hpg 3 atoms Bpg 4 atoms Glu(propargylamine) 6 atoms Dab(3-butynoic acid) 6 atoms

[0344] Similarly, the contribution of the length of the N- or C-terminal amino acid residue to the length of the bridge containing the triazole ring begins with the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (in other words, the first atom attached to the alpha carbon of the residue for most amino acids) and continues through the atoms participating in the formation of the triazole ring (in other words, the first nitrogen atom of the azide group attached to the side chain in the case of both 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles (i.e., - N =N + =N - or in the case of a 1,4-disubstituted 1,2,3-triazole, two carbon atoms of the alkyne group, or in the case of a 1,5-disubstituted triazole, one carbon atom of the alkyne group (i.e., - C The number of atoms in a straight chain that contains and ends with this atom is counted.

[0345] Thus, the following amino acid residues would be considered to have the following lengths: N-terminus: Azidoacetic acid 1 atom (N3)-Ala 1 atom But-3-ynic acid 2 atoms (1,4-disubstituted 1,2,3-triazole) 1 atom (in the case of 1,5-disubstituted 1,2,3-triazole)

[0346] The location of the triazole in the crosslink may affect the potency of the compound.

[0347] If the location of the triazole in the bridge containing the resulting triazole ring (i.e., the number of atoms in the linear chain starting from the first atom bonded to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (in other words, the first atom bonded to the alpha carbon of the residue for most amino acids) and ending at the triazole ring) is closer to position X11 than to position X2, suitable pairings of residues at positions X2 and X11 include the following: X2 is Lys (N3) and X11 is Pra.

[0348] Alternatively, if the location of the triazole in the bridge containing the resulting triazole ring (i.e., the number of atoms in the linear chain starting from the first atom bonded to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (in other words, the first atom bonded to the alpha carbon of the residue for most amino acids) and ending at the triazole ring) is closer to position X2 than to position X11, suitable pairings of residues at positions X2 and X11 include: X2 is Pra and X11 is Dab (azidoacetic acid); X2 is Pra and X11 is Dab ((N3)-Ala); X2 is azidoacetic acid and X11 is Glu (propargylamine); X2 is azidoacetic acid and X11 is Dab (3-butynoic acid); X2 is (N3)-Ala and X11 is Glu (propargylamine); X2 is (N3)-Ala and X11 is Dab (3-butynoic acid); X2 is but-3-ynoic acid and X11 is Dab (azidoacetic acid); or X2 is but-3-ynoic acid and X11 is Dab ((N3)-Ala).

[0349] When a bridge containing a triazole ring is formed from the side chains of the residues at X2 and X11, the side chain of the residue at position X2 is longer than the side chain of the residue at position X11, such that the location of the triazole in the bridge containing a triazole ring after formation is closer to the 11th position (X11) than to the 2nd position (X2). Thus, in some embodiments, the side chain of the residue at position X2 is longer than the side chain of the residue at position X11.

[0350] When the side chain at position X2 is longer than the side chain at position X11, suitable pairings of residues at positions X2 and X11 include the following: X2 is Lys (N3) and X11 is Pra.

[0351] Alternatively, in some embodiments, the side chain of the residue at position X2 is shorter than the side chain of the residue at position X11, such that the location of the triazole in the bridge containing the triazole ring after formation is closer to the second position (X2) than to position (X11).

[0352] When the side chain at position X2 is shorter than the side chain at position X11, suitable pairings of residues at positions X2 and X11 include: X2 is Pra and X11 is Dab (azidoacetic acid); or X2 is Pra and X11 is Dab((N3)-Ala).

[0353] Desirably, the length of the bridge including the triazole ring after formation of the trazole (not including atoms in the peptide backbone) is 5, 6, 7, 8, 9, or 10 atoms, e.g., 6, 7, 8, or 9 atoms; e.g., 7, 8, or 9 atoms, e.g., 8 or 9 atoms.

[0354] In some embodiments, the length of the bridge containing the triazole ring obtained by the two side chains after triazole formation (not including the atoms in the peptide backbone) is 8 atoms. When the bridge containing the triazole ring has a length of 8 atoms, suitable pairings of residues at positions X2 and X11 include: pairing of Lys(N3) with Pra; pairing of azidoacetic acid with Glu(propargylamine); pairing of azidoacetic acid with Dab(3-butynoic acid); pairing of (N3)-Ala with Glu(propargylamine); pairing of (N3)-Ala with Dab(3-butynoic acid); pairing of but-3-ynoic acid with Dab(azidoacetic acid); and pairing of but-3-ynoic acid with Dab((N3)-Ala).

[0355] In some embodiments, the length of the bridge containing the triazole ring obtained by the two side chains after triazole formation (not including the atoms in the peptide backbone) is 9 atoms. When the bridge containing the triazole ring has a length of 9 atoms, suitable pairings of residues at positions X2 and X11 include: pairing of Pra with Dab (azidoacetic acid); and pairing of Pra with Dab ((N3)-Ala).

[0356] X4 and X7 X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring.

[0357] Preferably, X4 and X7 are amino acid residues which together form a lactam bridge, which is more stable than the corresponding dithioether bridge, 1,3-dithio-propan-2-one.

[0358] Amino acid residue The definitions for the dithioether bridge, the lactam bridge and the bridge containing a triazole ring are the same as those for X2 and X11 above.

[0359] Suitable amino acid residues for X4 and X7 which together form a dithioether bridge may be Cys or N-Me-Cys.

[0360] Suitable amino acid residues for X4 and X7 which together form a lactam bridge are selected from the following: Amino acid residues containing an amine group: Dpr, hLys, Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, 2,4-diaminobutanoyl ([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl. · Amino acid residues containing a carboxylic acid group: Glu, Asp, Aad, and Apm.

[0361] Suitable amino acid residues for X4 and X7 that together form a bridge containing a triazole ring may be selected from the following: Amino acid residues containing an azide group: Ala(N3), Aha, Orn(N3), Lys(N3), azidoacetate, (N3)-Ala, Dab(azidoacetate), and Dab((N3)-Ala). · Amino acid residues containing an alkyne group: Pra, Hpg, Bpg, Glu (propargylamine), Dab (3-butynoic acid), and but-3-ynoic acid.

[0362] Bridge length The length of the bridge is counted as the number of atoms in the linear chain starting from the first atom bonded to an atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the first residue (X4 for the bridge between X4 and X7) (in other words, bonded to the alpha carbon of the corresponding residue for most amino acids) and ending with the first atom bonded to an atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the second residue (X7 for the bridge between X4 and X7).

[0363] The contribution of amino acid residue and cross-link type to cross-link length is described below.

[0364] In some embodiments, the length of the bridge between X4 and X7 is at least 5 atoms long. In some embodiments, the length of the bridge between X4 and X7 is 10 atoms long or less. In some embodiments, the length of the bridge between X4 and X7 is 5 to 10 atoms long, for example, 5, 6, 7, 8, 9, or 10 atoms long.

[0365] Dithioether bridge We found that a linker between the thiol side chains of the linked [2,11] and [4,7] cysteine ​​residues in the compounds was required to retain IL-23R inhibitory activity. Replacement of the dithioether bridge with a disulfide bridge reduced the inhibitory activity (see Example 2).

[0366] Thus, the compounds of the invention may include a dithioether bridge formed between an amino acid residue at position X4 and an amino acid residue at position X7. The definition of the dithioether bridge given above for X2 and X11, e.g., the appropriate amino acid residues, is applicable in this case, with X2 and X11 substituted for X4 and X7. For simplicity, positions X4 and X7 are discussed with reference to the residues nominally present prior to dithioether formation.

[0367] In some embodiments, the dithioether bridge between X4 and X7 has the formula -SLYLS- (In the formula: each S is a sulfur atom and is part of an amino acid residue of X4 and X7; Each L is independently C 1-4 is alkylene; Y is absent, C(=O) or arylene.

[0368] In some embodiments, the dithioether bridge of formula -SLYLS- is -SCH2C(=O)CH2S-, i.e., each L is -CH2- and Y is C(=O).

[0369] In some embodiments, the dithioether bridge of the formula -SLYLS- is -SCH2(phenylene)CH2S-, e.g., -SCH2(1,2-phenylene)CH2S-, -SCH2(1,3-phenylene)CH2S-, and -SCH2(1,4-phenylene)CH2S-. In some embodiments, the dithioether bridge of the formula -SLYLS- is -SCH2(1,2-phenylene)CH2S-. That is, each L is -CH2- and Y is 1,2-phenylene.

[0370] In some embodiments, X4 and X7 are each independently selected from Cys and N-Me-Cys.

[0371] In some embodiments, X4 is Cys and X7 is Cys.

[0372] In some embodiments, X4 is Cys and X7 is N-Me-Cys. In some embodiments, X4 is N-Me-Cys and X7 is Cys.

[0373] Preferably, X4 is Cys and X7 is Cys.

[0374] In some embodiments, X4 is Cys and X7 is Cys, which together form a dithioether bridge.

[0375] In some embodiments, X4 is Cys and X7 is Cys, which together form a dithioether bridge, the dithioether bridge having the formula -SLYLS-, where each S is a sulfur atom and is part of an amino acid residue of X4 and X7; each L is independently C 1-4 alkylene; Y is absent, C(=O) or arylene.

[0376] In some embodiments, X4 is Cys and X7 is Cys, which together form a dithioether bridge, the dithioether bridge being of the formula -SCH2C(=O)CH2S- or -SCH2(phenylene)CH2S- (wherein each S is a sulfur atom and is part of the amino acid residue of X4 and X7).

[0377] In some embodiments, X4 is Cys and X7 is Cys, which together form a dithioether bridge, the dithioether bridge being of the formula -SCH2C(=O)CH2S- or -SCH2(1,2-phenylene)CH2S- (wherein each S is a sulfur atom and is part of the amino acid residue of X4 and X7).

[0378] The definitions for the length of the dithioether bridge given above for X2 and X11 are applicable in this case, with X4 and X7 replacing X2 and X11. Preferably, the dithioether bridge is 7 or 8 atoms long.

[0379] Lactam Bridge The compounds of the invention may include a lactam bridge formed between an amino acid residue at position X4 and an amino acid residue at position X7. The definition of the lactam bridge given above for X2 and X11, e.g., the appropriate amino acid residues, is applicable in this case, with X2 and X11 substituted with X4 and X7. For simplicity, positions X4 and X7 are discussed with reference to the residues nominally present prior to lactam formation.

[0380] In some embodiments, one of the residues at positions X4 and X7 is Lys, Dpr, Dab, or Orn, and the other is Glu.

[0381] In some embodiments, the amine component of the lactam bridge is derived from the amino acid at position X4, while the carboxylic acid component of the lactam bridge is derived from the amino acid at position X7. In some embodiments, X4 is selected from Lys, Dpr, Dab, and Orn, and X7 is Glu.

[0382] Alternatively, in some embodiments, the carboxylic acid component of the lactam bridge is derived from the amino acid at position X4, while the amine component of the lactam bridge is derived from the amino acid at position X7. In some embodiments, X4 can be Glu and X7 is selected from Lys, Dpr, Dab, and Orn.

[0383] Suitable pairings of residues at positions X4 and X7 to form a lactam bridge include: When X4 is an amine building block and X7 is a carboxylic acid building block: X4 is Dpr and X7 is Glu; X4 is Dab and X7 is Glu; or X4 is Orn and X7 is Glu.

[0384] When X4 is a carboxylic acid building block and X7 is an amine building block: X4 is Glu and X7 is Lys; X4 is Glu and X7 is Dpr; X4 is Glu and X7 is Orn; or X4 is Glu and X7 is Dab.

[0385] Preferably, X4 is Glu and X7 is Dab.

[0386] The definitions for the length of the lactam bridge given above for X2 and X11 are applicable in this case, replacing X2 and X11 with X4 and X7.

[0387] The location of the amide bond in the lactam bridge may affect the potency of the compounds described above against X2 and X11.

[0388] When the location of the amide bond in the formed lactam bridge is closer to position X7 than to position X4, suitable pairings of residues at positions X4 and X7 include: X4 is Orn and X7 is Glu; or X4 is Glu and X7 is Dpr.

[0389] Alternatively, if the location of the amide bond in the lactam bridge is closer to position X4 than to position X7, suitable pairings of residues at positions X4 and X7 include: X4 is Dpr and X7 is Glu; X4 is Glu and X7 is Lys; or X4 is Glu and X7 is Orn.

[0390] If the side chain at position X4 is longer than the side chain at position X7, such that the location of the amide bond in the formed lactam bridge is closer to the seventh position (X7) than to the fourth position (X4), suitable pairings of residues at positions X4 and X7 include: X4 is Orn and X7 is Glu; or X4 is Glu and X7 is Dpr.

[0391] Alternatively, if the side chain at position X4 is shorter than the side chain at position X7, such that the location of the amide bond in the formed lactam bridge is closer to the fourth position (X4) than to the seventh position (X7), suitable pairings of residues at positions X4 and X7 include: X4 is Dpr and X7 is Glu; X4 is Glu and X7 is Lys; or X4 is Glu and X7 is Orn.

[0392] Desirably, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 5, 6, 7, 8, 9, or 10 atoms; e.g., 6, 7, 8, or 9 atoms; e.g., 7 or 8 atoms. In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 5, 6, or 7 atoms.

[0393] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 5 atoms. When the lactam bridge has a length of 5 atoms, suitable pairing of residues at positions X4 and X7 includes pairing of Dpr with Glu.

[0394] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 6 atoms. When the lactam bridge has a length of 6 atoms, suitable pairing of residues at positions X4 and X7 includes pairing of Dab with Glu.

[0395] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 7 atoms. When the lactam bridge has a length of 7 atoms, suitable pairing of residues at positions X4 and X7 includes pairing of Orn with Glu.

[0396] In some embodiments, the length of the lactam bridge after formation of the amide bond (not including atoms in the peptide backbone) is 8 atoms. When the lactam bridge has a length of 8 atoms, suitable pairings of residues at positions X4 and X7 include: Glu with Lys; Aad with Orn; and Asp with hLys.

[0397] Triazole ring-containing bridge The compounds of the invention may include a bridge containing a triazole ring formed between an amino acid residue at position X4 and an amino acid residue at position X7. The definition of a bridge containing a triazole ring described above for X2 and X11, e.g., the appropriate amino acid residues, is applicable in this case, with X2 and X11 replaced by X4 and X7. For simplicity, positions X4 and X7 are discussed with reference to the residues nominally present prior to triazole formation.

[0398] In some embodiments, one of the residues at positions X4 and X7 is selected from Lys(N3) and Aha, and the other is Pra.

[0399] In some embodiments, X4 is Lys(N3) and X7 is Pra. In some embodiments, X4 is Aha and X7 is Pra.

[0400] Suitable pairings of residues at positions X4 and X7 to form a bridge containing a triazole ring include the following: When X4 is the azide building block and X7 is the alkyne building block: X4 is Lys(N3) and X7 is Pra; or X4 is Aha and X7 is Pra.

[0401] Alternatively, in some embodiments, X4 is an alkyne building block and X7 is an azide building block.

[0402] The definitions for the length of the bridge including the triazole ring given above for X2 and X11 are applicable in this case, replacing X2 and X11 with X4 and X7.

[0403] The location of the triazole in the bridge containing the triazole ring may affect the potency of the compounds described above for X2 and X11.

[0404] When the location of the triazole in the bridge containing the triazole ring after formation is closer to position X7 than to position X4, suitable pairings of residues at positions X4 and X7 include the following: X4 is Lys (N3) and X7 is Pra.

[0405] Alternatively, in some embodiments, the location of the triazole in the bridge containing the triazole ring after formation is closer to position X4 than to position X7.

[0406] When the side chain at position X4 is longer than the side chain at position X7, such that the location of the triazole in the bridge containing the triazole ring is closer to the seventh position (X7) than to the fourth position (X4), suitable pairings of residues at positions X4 and X7 include: X4 is Lys (N3) and X7 is Pra.

[0407] Alternatively, in some embodiments, the side chain at position X4 is shorter than the side chain at position X7.

[0408] L Each L is independently C 1-4 It is alkylene.

[0409] In some embodiments, L is C 1-2 In some embodiments, L is a C alkylene (methylene or -CH-). In some embodiments, L is a C alkylene (ethylene or -CHCH-).

[0410] Y Y is absent, C(=O), or arylene.

[0411] In some embodiments, Y is C(=O).

[0412] In some embodiments, Y is arylene, for example, phenylene.

[0413] In some embodiments, Y is a phenylene selected from 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene. In some embodiments, Y is 1,2-phenylene.

[0414] Synthesis of compounds The present invention further provides a method for the synthesis of the compounds of the invention. The compounds (which may also be referred to as peptides) may be suitably produced by standard synthesis methods. Thus, peptides may be synthesized, for example, by a method comprising the steps of synthesizing the peptide by standard solid-phase or solution-phase methods, either sequentially or by fragment assembly, and isolating and purifying any final peptide product. In this context, reference may be made to WO 98 / 11125, or, inter alia, Fields, GB et al., "Principles and Practice of Solid-Phase Peptide Synthesis"; in: Synthetic Peptides, Gregory A. Grant (ed.), Oxford University Press (2 nd edition, 2002) and the synthesis examples therein. The method typically further comprises the step of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residue at the second position (X2) and the amino acid residue at the eleventh position (X11), and may further comprise the step of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residue at the fourth position (X4) and the amino acid residue at the seventh position (X7), as described below. In the case of solid phase synthesis, cyclization can be carried out in situ on the solid phase (e.g., resin), i.e. before the peptide is removed from the solid phase.

[0415] The synthesis of some exemplary compounds of the present invention is shown in Example 1. Generally, the synthesis method of the above compounds includes the steps of synthesizing the compounds by solid-phase or liquid-phase peptide synthesis, isolating and / or purifying any final product, and may further include the steps of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residue at the 2nd position and the amino acid residue at the 11th position, and may further include the steps of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residue at the 4th position and the amino acid residue at the 7th position.

[0416] Compound Efficacy The compounds of the invention are interleukin-23 receptor (IL-23R) inhibitors, i.e., they are capable of binding to and blocking the signal transduction of one or more receptors or receptor complexes that are regarded as physiological receptors for interleukin-23 (IL-23).

[0417] Comparative activity can be measured by any suitable means, for example, IC 50 It can be measured by determining the value.

[0418] The compounds of the invention may exhibit many advantageous properties compared to other peptide IL-23R inhibitors, such as those analogs described in WO 2016 / 011208, WO 2018 / 022937, WO 2018 / 136646, WO 2020 / 014646, WO 2021 / 146441, WO 2021 / 146458, and (Heinis et al., Nature Biomedical Engineering, 2020). The compounds of the invention may exhibit improved efficacy compared to any of these analogs, such as in the form of improved in vitro potency against IL-23R.

[0419] Additionally, or alternatively, compounds of the invention may exhibit improved gastrointestinal (GI) stability compared to any of the peptide inhibitors of IL-23R described in the art.

[0420] Those skilled in the art will be aware of suitable assay formats, and examples are provided below. For example, an assay can be used utilizing measurements at human IL-23R (see example below). When referring to the sequence of a precursor protein, it is understood that the assay can use the mature protein lacking the signal sequence.

[0421] K d The K value can be used as a numerical measure of binding affinity at a given receptor. d The K value, also called the equilibrium dissociation constant, is a measure of how tightly a compound binds to a receptor in a particular assay. d is the compound, K d A compound with a higher K value indicates that it binds to the receptor with higher affinity than a compound with a higher K value. d [IL-23R] values ​​are K values ​​of other compound inhibitors of IL-23R d Compounds with a lower [IL-23R] value may be considered to have stronger binding affinity to IL-23R (or bind more tightly) than other compound inhibitors of IL-23R.

[0422] K for the compound's receptor d In the absence of an experimental method to directly determine K d is K i It can be estimated by calculating the inhibition constant K i is determined by the ability of a compound to compete with a labeled compound for the receptor. In such a competition assay, the concentration at which half of the labeled compound is displaced by the unlabeled compound from the receptor is called the IC 50 It is called the IC value. 50 The value is the affinity of the compound for the receptor (i.e., its K dvalue) but also depends on the concentration of labeled compound used and the affinity of the labeled compound for the receptor. Assuming that binding is reversible, at equilibrium, K i The value is K i and IC 50 The relationship between K and K is determined using the Cheng-Prussov equation, which states: i =IC 50 / (1+[L L ] / K dL )(wherein, [L L ] is the concentration of the labeled compound used, and K dL is the equilibrium dissociation constant of the labeled compound) (Cheng and Prusoff, Biochem. Pharmacol., 1973).

[0423] In some embodiments of the compounds of the present invention, the K i is less than 1000 nM (e.g., 0.001 to 1000 nM).

[0424] In some embodiments of the compounds of the present invention, the K i is less than 500 nM (e.g., 0.001 to 500 nM).

[0425] In some embodiments of the compounds of the present invention, the K i is less than 100 nM (e.g., 0.001 to 100 nM).

[0426] In some embodiments of the compounds of the present invention, the K i is less than 50 nM (e.g., 0.001 to 50 nM).

[0427] In some embodiments of the compounds of the present invention, the K i is less than 30 nM (e.g., 0.001 to 30 nM).

[0428] In some embodiments of the compounds of the present invention, the K iis less than 20 nM (e.g., 0.001 to 20 nM).

[0429] In some embodiments of the compounds of the present invention, the K i is less than 10 nM (e.g., 0.001 to 10 nM).

[0430] In some embodiments of the compounds of the present invention, the K i is less than 5 nM (e.g., 0.001 to 5 nM).

[0431] In some embodiments of the compounds of the present invention, the K i is less than 1 nM (e.g., 0.001 to 1 nM).

[0432] In some embodiments of the compounds of the present invention, the K i is less than 0.5 nM (e.g., 0.001 to 0.5 nM).

[0433] In cell-based assays, IC 50 The IC value can be used as a numerical measure of inhibitor potency in a functional assay format that measures the ability of a compound to inhibit IL-23-mediated signal transduction. 50 The IC value is a measure of the concentration of a compound required to achieve half of the compound's maximal activity in a particular assay. Thus, for example, a compound that has a lower IC than other compounds inhibitors of IL-23R in a particular assay. 50 Compounds with [IL-23R] values ​​may be considered to have stronger inhibitory potency than other peptide inhibitors of IL-23R, possibly by better blocking IL-23-mediated signaling.

[0434] In some embodiments of the compounds of the present invention, IC 50 is less than 1000 nM (e.g., 0.001 to 1000 nM).

[0435] In some embodiments of the compounds of the present invention, IC 50 is less than 500 nM (e.g., 0.001 to 500 nM).

[0436] In some embodiments of the compounds of the present invention, IC 50 is less than 100 nM (e.g., 0.001 to 100 nM).

[0437] In some embodiments of the compounds of the present invention, IC 50 is less than 50 nM (e.g., 0.001 to 50 nM).

[0438] In some embodiments of the compounds of the present invention, IC 50 is less than 30 nM (e.g., 0.001 to 30 nM).

[0439] In some embodiments of the compounds of the present invention, IC 50 is less than 20 nM (e.g., 0.001 to 20 nM).

[0440] In some embodiments of the compounds of the present invention, IC 50 is less than 10 nM (e.g., 0.001 to 10 nM).

[0441] Such an assay may be carried out under the conditions described in Example 3 below.

[0442] Additionally or alternatively, the compounds of the invention may exhibit gastrointestinal (GI) stability, i.e., resistance to degradation in the GI tract. This can be measured using a simulated intestinal fluid (SIF) assay. For example, the compounds of the invention may retain at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% of the compound or peptide remaining after incubation for 1 hour or 4 hours under conditions, e.g., as described in Example 3.

[0443] Pharmaceutical Compositions The invention also extends to compositions, such as pharmaceutical compositions, comprising the compounds of the invention. As with all aspects of the invention, it is understood that references to the compounds of the invention include references to the pharma-ceutically acceptable salts and solvates.

[0444] The compounds of the present invention may be formulated as pharmaceutical compositions, which are suitable for administration, with or without storage, and typically comprise a therapeutically effective amount of at least one peptide of the present invention together with a pharma- ceutically acceptable carrier, excipient or vehicle.

[0445] The term "pharmaceutical acceptable carrier" includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art and are described, for example, in "Remington's Pharmaceutical Sciences", 17 thThe term is described in the American Academy of Pediatrics, Vol. 13, No. 1, 1985. For example, sterile saline and phosphate buffered saline at slightly acidic or physiological pH can be used. Suitable pH buffers can be, for example, phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine or acetate (e.g., as sodium acetate), or mixtures thereof. The term further includes any carrier agent listed in the United States Pharmacopoeia for use in animals, including humans.

[0446] The pharmaceutical composition of the present invention may be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be presented as a packaged preparation, a package containing discrete amounts of the preparation, for example, packaged tablets, capsules, or powders in vials or ampoules. The unit dosage form may also be, for example, a capsule, cachet, or tablet per se, or the appropriate number of any of these packaged forms. The unit dosage form may also be provided in the form of a single dose of injectable form, for example, a pen device containing a liquid phase (typically aqueous) composition. The composition may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include, for example, those used in formulations suitable for oral, intravitreal, rectal, intravaginal, nasal, topical, enteral or parenteral (including subcutaneous (sc), intramuscular (im), intravenous (iv), intradermal and transdermal) administration, or administration by inhalation. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical formulation.

[0447] Subcutaneous or transdermal administration modes may be suitable for the peptides of the present invention.

[0448] Further embodiments relate to devices, dosage forms and packages used to deliver the pharmaceutical formulations of the present invention. Thus, at least one peptide in a stable or preserved formulation or solution as described herein can be administered to a patient in accordance with the present invention via a variety of delivery methods, including by sc or im injection, by transdermal, pulmonary or mucosal administration, by implants, or by use of osmotic pumps, cartridges, micropumps, or other means recognized by those skilled in the art.

[0449] Yet further embodiments relate to oral formulations and oral administration. Formulations for oral administration may rely on the co-administration of auxiliary agents that artificially increase the permeability of the intestinal wall (e.g., resorcinol and / or non-ionic surfactants, such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether), and / or the co-administration of enzyme inhibitors that inhibit enzymatic degradation (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) or trasylol). The active ingredient compound of the solid dosage form for oral administration may be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer, or glyceride. These dosage forms may also contain other types of additives, such as inert diluents, lubricants (e.g., magnesium stearate), parabens, preservatives (e.g., sorbic acid, ascorbic acid, or alpha-tocopherol), antioxidants (e.g., cysteine), disintegrants, binders, thickening agents, buffers, pH regulators, sweeteners, flavoring agents, or fragrances.

[0450] therapeutic use The compounds of the present invention, and pharmaceutical compositions comprising said compounds, are useful in a method for preventing or treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, colitis associated with impaired innate immunity such as in leukocyte adhesion deficiency-I, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, or graft versus host disease, and combinations thereof, in a subject.

[0451] The prophylactic or therapeutic method comprises the step of administering to the subject an effective amount of a compound of the present invention, or a pharmaceutical composition containing said compound.

[0452] In some embodiments, the condition may be selected from inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and psoriasis.

[0453] Dosage Typical dosages of compounds used in the context of the present invention may be administered in one or more doses, e.g., 1 to 3 doses, and may range from about 0.0001 to about 100 mg / kg body weight per day, e.g., from about 0.0005 to about 50 mg / kg body weight per day, e.g., from about 0.001 to about 10 mg / kg body weight per day, e.g., from about 0.01 to about 1 mg / kg body weight per day. The exact dosage used will depend, inter alia, on the nature and severity of the disease or disorder being treated, on the sex, age, weight and general condition of the subject being treated, on possible other concomitant diseases or disorders (being treated or to be treated), and on other factors known to those skilled in the art of medicine.

[0454] The compounds of the present invention may be administered to a subject continuously (e.g., by intravenous administration or another continuous drug administration method) or at intervals, typically at regular time intervals, depending on the desired dosage and pharmaceutical composition selected by the skilled artisan for a particular subject. The administration intervals for regular administration include, for example, once daily, twice daily, once every 2, 3, 4, 5 or 6 days, once or twice weekly, once or twice monthly, etc. Such a regular peptide administration regimen may be advantageous in certain circumstances, such as during chronic long-term administration, to be interrupted for a period of time so that the medicated subject's drug dosage level is reduced or the drug dosage is stopped (often referred to as taking a "drug holiday"). Drug holidays are useful, for example, to maintain or restore sensitivity to a drug, especially during long-term chronic treatment, or to reduce undesirable side effects of long-term chronic treatment of a subject with a drug. The timing of the drug holiday depends on the timing of the regular dosing regimen and the purpose of taking the drug holiday (e.g., to restore drug sensitivity and / or to reduce undesirable side effects of continuous long-term administration). In some embodiments, the drug holiday can be a reduction in the dosage of the drug (e.g., below the therapeutically effective amount for a certain time interval). In other embodiments, administration of the drug is stopped for a certain time interval, after which administration resumes using the same or a different dosing regimen (e.g., a lower or higher administration dose and / or dosing frequency). Thus, the 0A drug holiday of the present invention can be selected from a wide range of durations and dosage regimens. Exemplary drug holidays are 2 or 3 days or more, 1 or 2 weeks or more, or 1 or 2 months or more, up to about 24 months of drug holiday. Thus, for example, a regular daily dosing regimen with the peptides of the invention may be interrupted, such as by a drug-free period of one, two, or four weeks, after which the previous regular dosing regimen (e.g., a daily or weekly dosing regimen) is resumed. A variety of other drug-free period regimens are envisioned as useful for administering the peptides of the invention.

[0455] Thus, the peptides may be delivered via a regimen of administration comprising two or more administration phases separated by respective drug holiday phases.

[0456] During each administration phase, the peptide is administered to the recipient subject in a therapeutically effective amount according to a predetermined administration pattern. The administration pattern may include continuous administration of the drug to the recipient subject for the duration of the administration phase. Alternatively, the administration pattern may include administration of multiple doses of the peptide to the recipient subject, the doses being spaced apart by administration intervals.

[0457] The dosing pattern can include at least 2 doses per dosing phase, at least 5 doses per dosing phase, at least 10 doses per dosing phase, at least 20 doses per dosing phase, at least 30 doses per dosing phase, or more.

[0458] The dosing intervals may be regular dosing intervals depending on the particular dosage formulation, bioavailability, and pharmacokinetic profile of the peptide, which may be as described above, including once daily, twice daily, once every 2, 3, 4, 5, or 6 days, once or twice weekly, once or twice monthly, or regular and less frequent dosing intervals.

[0459] The administration period may have a duration of at least 2 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or longer.

[0460] If the dosing pattern includes multiple doses, the duration of the subsequent drug holiday period will be longer than the dosing interval used in the dosing pattern. If the dosing interval is irregular, the duration of the drug holiday period may be longer than the average interval between doses during the dosing period. Alternatively, the duration of the drug holiday may be longer than the longest interval between successive doses during the dosing period.

[0461] The duration of a possible drug holiday period may be at least twice the duration of the preferred dosing interval (or its average), at least three times, at least four times, at least five times, at least ten times, or at least twenty times the duration of the preferred dosing interval or its average.

[0462] Within these constraints, a drug holiday period may have a duration of at least 2 days, at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or longer, depending on the dosing pattern during the previous dosing period.

[0463] The dosing regimen with the use of drug holidays comprises at least two dosing periods. The consecutive dosing periods are separated by respective drug holiday periods. Thus, the dosing regimen can comprise at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 dosing periods, or more, each of which is separated by a drug holiday period.

[0464] The sequential administration phases may utilize the same administration pattern, although this is not always appropriate or necessary. However, when other drugs or active agents are administered in combination with the peptides of the invention, typically the same drug or active agent combination is administered in the sequential administration phases. In certain embodiments, the recipient subject is a human.

[0465] Devices and Kits In some embodiments, the present invention relates to a device for compound delivery to a subject, comprising a compound or pharmaceutical composition of the present invention. Via such a device, the compounds described herein can be administered to a patient via a variety of delivery methods, including: intravenous, subcutaneous, intramuscular or intraperitoneal injection; oral administration; transdermal administration; pulmonary or mucosal administration; administration by implants, osmotic pumps, cartridges or micropumps, or other means recognized by those skilled in the art.

[0466] In some embodiments, the present invention relates to a kit comprising a compound of the present invention or a pharmaceutical composition of the present invention. In certain embodiments, the kit further comprises packaging and / or instructions for use.

[0467] The device or kit may be useful for combination therapy as described above.Thus, the device or kit may further comprise an additional active agent, for example, in combination with a drug belonging to the drug classes of disease-modifying drugs (DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, and glucocorticoids; or in combination with other biologics, for example, anti-TNF; anti-integrins, for example, vedolizumab; or IL-23 antibodies, for example, ustekinumab, guselkumab, tildrakuzumab, and risankizumab. [Example]

[0468] The following examples show certain specific embodiments of the present invention. The following examples are carried out using well-known standard techniques that are routine for those skilled in the art, unless otherwise specified. It is understood that these examples are for illustrative purposes only and are not intended to be completely definitive on the conditions or scope of the present invention. Therefore, they should not be interpreted as limiting the scope of the present invention in any way.

[0469] Abbreviations used in the examples include the following: 2-Nal 3-(2-naphthyl)-L-alanine {d}R or D-Arg D-Arginine {d} L or D-Leu D-leucine {d}C or D-Cys D-Cysteine {d}Q or D-Gln D-glutamine {d}E or D-Glu D-Glutamic acid {d}H or D-His D-histidine Alpha-Me-Trp α-Methyl-L-tryptophan 1-Me-Trp 1-Methyl-L-tryptophan 4-F-Trp 4-Fluoro-L-tryptophan 6-F-Trp 6-Fluoro-L-tryptophan {d}6-F-Trp 6-Fluoro-D-tryptophan 6-Cl-Trp 6-Chloro-L-tryptophan 7-Me-Trp 7-Methyl-L-tryptophan 7-F-Trp 7-Fluoro-L-tryptophan 7-Ph-Trp 7-Phenyl-L-tryptophan 7-(Naphth-2-yl)-Trp 7-(Naphth-2-yl)-L-tryptophan 3-(3-pyridyl)-Ala 3-(3-pyridyl)-L-alanine 3-(4-pyridyl)-Ala 3-(4-pyridyl)-L-alanine {d}[3-(3-pyridyl)-Ala] 3-(3-pyridyl)-D-alanine 2-Me-3-(3-pyridyl)-Ala (2S)-2-amino-2-methyl-3-(3-pyridyl)propanoic acid 3-(3-Quinolinyl)-Ala 3-(3-Quinolinyl)-L-Alanine also known as (2S)-2-Amino-3-(3-quinolinyl)propanoic acid F(3-F) or 3-F-Phe 3-Fluoro-L-phenylalanine F(4-F) or 4-F-Phe 4-Fluoro-L-phenylalanine {d}F(4-F) 4-Fluoro-D-phenylalanine F(4-Cl) or 4-Cl-Phe 4-Chloro-L-phenylalanine F(4-NH2) or 4-NH2-Phe 4-amino-L-phenylalanine F(4-Me) or 4-Me-Phe 4-Methyl-L-phenylalanine F(3,4-Me) or 3,4-Me-Phe 3,4-Dimethyl-L-phenylalanine F(3,5-F) or 3,5-F-Phe 3,5-Difluoro-L-phenylalanine 2-Me-F(4-F) (2S)-2-amino-3-(4-fluorophenyl)-2-methyl-propanoic acid 2-Me-Leu 2-Methyl-L-leucine 2-Me-Lys 2-Methyl-L-lysine 2-Me-Arg 2-Methyl-L-Arginine 2-Me-Val 2-Methyl-L-valine 2-Me-Phe (2S)-2-Amino-2-methyl-3-phenyl-propanoic acid, also known as alpha-methyl-L-phenylalanine N-Me-Arg N2-Methyl-L-Arginine N-Me-Ser N-Methyl-L-serine N-Me-Cys N-Methyl-L-Cysteine N-Me-Trp Nα-Methyl-L-tryptophan, also known as L-Abrin N-Me-Gln N2-methyl-L-glutamine Bip Biphenyl-L-alanine 3,3-Diphenyl-Ala β-Phenyl-L-Alanine, also known as (S)-2-Amino-3,3-diphenylpropionic acid Aad (2S)-2-aminohexanedioic acid, also known as L-homoglutamic acid Apm (2S)-2-aminopimelic acid, also known as (2S)-2-aminoheptanedioic acid or L-bishomoglutamic acid Dab (2S)-2,4-diaminobutanoic acid Orn L-Ornithine, also known as 2,5-Diaminopentanoic Acid hLys (2S)-2-amino-7-amino-heptanoic acid, also known as L-homolysine bAla 3-aminopropionic acid, also known as beta-alanine or β-alanine beta-homo-Ser L-β-homoserine Ala(N3) 3-azido-L-alanine Aha Azidohomo-L-alanine or 4-azido-L-homoalanine Orn(N3) Azido-L-ornithine K(N3) or Lys(N3) Azido-L-Lysine Pra L-Propargylglycine Hpg L-Homopropargylglycine Bpg L-Bishomopropargylglycine Dpr (2S)-2,3-Diaminopropanoic Acid also known as 3-Amino-L-alanine Glu(propargylamine) (2S)-2-amino-5-oxo-5-(prop-2-ynylamino)pentanoic acid Dab(3-butynoic acid) (2S)-2-amino-4-(but-3-ynoylamino)butanoic acid Dab(Azidoacetic acid) (2S)-2-amino-4-[(2-azidoacetyl)amino]butanoic acid (N3)-Ala (2S)-2-azidopropanoic acid Dab((N3)-Ala)) (2S)-2-amino-4-[[(2S)-2-azidopropanoyl]amino]butanoic acid Abu (2S)-2-aminobutyric acid Y(2-aminoethoxy) (2S)-2-amino-3-[4-(2-aminoethoxy)phenyl]propanoic acid Y(Me) (2S)-2-amino-3-(4-methoxyphenyl)propanoic acid Q(Pyrrolidine) (2S)-2-Amino-5-oxo-5-pyrrolidin-1-yl-pentanoic acid GABA 4-Aminobutanoic Acid also known as Gamma Aminobutyric Acid Phg L-2-phenylglycine F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl) 2-[2-[3-[4-[(2S)-2-amino-2-carboxy-ethyl]anilino]-3-oxo-propoxy]ethoxy]ethyl-trimethyl-ammonium tBuOH tert-butanol DODT 2,2'-(ethylenedioxy)diethanethiol Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) PhSiH3 Phenylsilane PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate equiv. equivalent amount rt room temperature aq. Water-based IL-23R Interleukin-23 receptor hIL-23R Human interleukin-23 receptor GI gastrointestinal tract SIF artificial intestinal fluid SGF artificial gastric fluid Nluc NanoBRET luciferase assay SD standard deviation %Eff Percent Effectiveness pSTAT3 phosphorylation signal transducer and activator of transcription 3 BRET Bioluminescence Resonance Energy Transfer TAMRA 5'-Tetramethylrhodamine-5-carboxamide

[0470] The following examples are provided to illustrate certain embodiments of the invention and are not intended to limit the scope of the invention. EXAMPLES

[0471] Synthesis of compounds The following compounds in Table 1-1 below were synthesized: [Table 14] JPEG2024543204000057.jpg245170 JPEG2024543204000058.jpg245170 JPEG2024543204000059.jpg245170 JPEG2024543204000060.jpg247170 JPEG2024543204000061.jpg247170 JPEG2024543204000062.jpg245170 JPEG2024543204000063.jpg239170 JPEG2024543204000064.jpg254170 JPEG2024543204000065.jpg247170 JPEG2024543204000066.jpg246170 JPEG2024543204000067.jpg246170 JPEG2024543204000068.jpg247170 JPEG2024543204000069.jpg253170The bridge amino acid residue is the amino acid residue immediately preceding the brackets below. The brackets indicate the bridge amino acid residue. For example, [2,11] is the bridge between amino acid residue 2 and amino acid residue 11. Similarly, [4,7] is the bridge between amino acid residue 4 and amino acid residue 7. * = Crosslinking using amines or carboxylic acids at the N- or C-terminus of the peptide backbone rather than side chain amines or carboxylic acids (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge.

[0472] For comparative purposes, three compounds from (Heinis et al., Nature Biomedical Engineering, 2020, 4) with two 1,3-dithio-propan-2-one bridges were synthesized (Tables 1-2). [Table 15]

[0473] Additionally, compounds from Protagonist's patent applications (Compound C in WO 2016 / 011208, WO 2017 / 011820, and (Sayago et al., ACS Med. Chem. Lett., 2018)) with bridged cystathionine amino acid residues at [2,7] were synthesized (Tables 1-3). [Table 16] JPEG2024543204000072.jpg28170JPEG2024543204000073.jpg13170

[0474] Other reference compounds that were synthesized are listed in Tables 1-4. [Table 17]

[0475] Unless otherwise specified, reagents and solvents used below were commercially available of standard laboratory reagent or analytical grade and were used without further purification.

[0476] Apparatus and synthesis strategy Peptides were synthesized batchwise on a peptide synthesizer, e.g., a CEM Liberty Blue Peptide synthesizer, following solid-phase peptide synthesis procedures using 9-fluorenylmethyloxycarbonyl (Fmoc) as the N-α-amino protecting group and appropriate common protecting groups for the side chain functionalities.

[0477] As a polymer support-based resin, for example, TentaGel™ was used. The resin, which had been swollen with DMF prior to use, was loaded into the synthesis apparatus.

[0478] Non-naturally occurring amino acids and other appropriate building blocks were used without modification of the general procedures.

[0479] The following optical isomers of certain amino acids (including non-naturally occurring amino acids) were used in the synthesis of compounds: 2-Nal: 3-(2-naphthyl)-L-alanine {d}R or D-Arg D-Arginine {d} L or D-Leu D-leucine {d}C or D-Cys D-Cysteine {d}Q or D-Gln D-glutamine {d}E or D-Glu D-Glutamic acid {d}H or D-His D-histidine Alpha-Me-Trp α-Methyl-L-tryptophan 1-Me-Trp 1-Methyl-L-tryptophan 4-F-Trp 4-Fluoro-L-tryptophan 6-F-Trp 6-Fluoro-L-tryptophan {d}6-F-Trp 6-Fluoro-D-tryptophan 6-Cl-Trp 6-Chloro-L-tryptophan 7-Me-Trp 7-Methyl-L-tryptophan 7-F-Trp 7-Fluoro-L-tryptophan 7-Ph-Trp 7-Phenyl-L-tryptophan 7-(Naphth-2-yl)-Trp 7-(Naphth-2-yl)-L-tryptophan 3-(3-pyridyl)-Ala 3-(3-pyridyl)-L-alanine 3-(4-pyridyl)-Ala 3-(4-pyridyl)-L-alanine {d}[3-(3-pyridyl)-Ala] 3-(3-pyridyl)-D-alanine 2-Me-3-(3-pyridyl)-Ala (2S)-2-amino-2-methyl-3-(3-pyridyl)propanoic acid 3-(3-Quinolinyl)-Ala 3-(3-Quinolinyl)-L-Alanine also known as (2S)-2-Amino-3-(3-quinolinyl)propanoic acid F(3-F) or 3-F-Phe 3-Fluoro-L-phenylalanine F(4-F) or 4-F-Phe 4-Fluoro-L-phenylalanine {d}F(4-F) 4-Fluoro-D-phenylalanine F(4-Cl) or 4-Cl-Phe 4-Chloro-L-phenylalanine F(4-NH2) or 4-NH2-Phe 4-amino-L-phenylalanine F(4-Me) or 4-Me-Phe 4-Methyl-L-phenylalanine F(3,4-Me) or 3,4-Me-Phe 3,4-Dimethyl-L-phenylalanine F(3,5-F) or 3,5-F-Phe 3,5-Difluoro-L-phenylalanine 2-Me-F(4-F) (2S)-2-amino-3-(4-fluorophenyl)-2-methyl-propanoic acid 2-Me-Leu 2-Methyl-L-leucine 2-Me-Lys 2-Methyl-L-Lysine 2-Me-Arg 2-Methyl-L-Arginine 2-Me-Val 2-Methyl-L-valine 2-Me-Phe (2S)-2-Amino-2-methyl-3-phenyl-propanoic acid, also known as alpha-methyl-L-phenylalanine N-Me-Arg N2-Methyl-L-Arginine N-Me-Ser N-Methyl-L-serine N-Me-Cys N-Methyl-L-Cysteine N-Me-Trp Nα-Methyl-L-tryptophan, also known as L-Abrin N-Me-Gln N2-methyl-L-glutamine Bip Biphenyl-L-alanine 3,3-Diphenyl-Ala β-Phenyl-L-Alanine, also known as (S)-2-Amino-3,3-diphenylpropionic acid Aad 2-aminoadipic acid, also known as (2S)-2-aminohexanedioic acid or L-homoglutamic acid Dab (2S)-2,4-diaminobutanoic acid Orn L-Ornithine, also known as 2,5-Diaminopentanoic Acid hLys (2S)-2-amino-7-amino-heptanoic acid, also known as L-homolysine bAla 3-aminopropionic acid, also known as beta-alanine or β-alanine beta-homo-Ser L-β-homoserine Ala(N3) 3-azido-L-alanine Aha Azidohomo-L-alanine or 4-azido-L-homoalanine Orn(N3) Azido-L-ornithine K(N3) or Lys(N3) Azido-L-Lysine Pra L-Propargylglycine Hpg L-Homopropargylglycine Bpg L-Bishomopropargylglycine Dpr (2S)-2,3-Diaminopropanoic Acid also known as 3-Amino-L-alanine Glu(propargylamine) (2S)-2-amino-5-oxo-5-(prop-2-ynylamino)pentanoic acid Dab(3-butynoic acid) (2S)-2-amino-4-(but-3-ynoylamino)butanoic acid Dab(Azidoacetic acid) (2S)-2-amino-4-[(2-azidoacetyl)amino]butanoic acid (N3)-Ala (2S)-2-azidopropanoic acid Dab((N3)-Ala)) (2S)-2-amino-4-[[(2S)-2-azidopropanoyl]amino]butanoic acid Y(2-aminoethoxy) (2S)-2-amino-3-[4-(2-aminoethoxy)phenyl]propanoic acid Y(Me) (2S)-2-amino-3-(4-methoxyphenyl)propanoic acid Q(Pyrrolidine) (2S)-2-Amino-5-oxo-5-pyrrolidin-1-yl-pentanoic acid GABA 4-Aminobutanoic Acid also known as Gamma Aminobutyric Acid Phg L-2-phenylglycine F(4-NH2-(2-(trimethyl-2-aminoethoxy)ethoxy)propyl) 2-[2-[3-[4-[(2S)-2-amino-2-carboxy-ethyl]anilino]-3-oxo-propoxy]ethoxy]ethyl-trimethyl-ammonium

[0480] Coupling on a CEM Liberty Blue Peptide Synthesizer The Fmoc protected amino acid solution (4 equiv.) was added to the resin along with the coupling reagent solution (4 equiv.) and base solution (8 equiv.). The mixture was heated to 50° C. in a microwave unit and allowed to couple for 10 minutes or coupled without heating for 60 minutes. Nitrogen was bubbled through the mixture during coupling.

[0481] In the case of difficult couplings (e.g., coupling of a residue immediately following an N-methylated amino acid residue or other sterically hindering amino acid residue, as will be appreciated by those skilled in the art), the coupling was repeated one or more times.

[0482] Deprotection: The Fmoc group was deprotected using piperidine in DMF or other suitable solvent. The deprotection solution was added to the reaction vessel and the mixture was heated for 5 minutes to approximately 50° C. After draining the reaction vessel, the resin was washed with DMF or other suitable solvent.

[0483] Lactam formation: The following procedure for coupling of Glu and Lys is representative of all lactam formations when the amino acid side chain containing the carboxyl function is protected with Oall and the amino group is protected with Alloc. After assembly of the complete peptide sequence, deprotection of Glu(Oall) and Lys(Alloc) was performed using Pd(PPh3)4 (0.05 equiv.) and PhSiH3 (10 equiv.) in DCM. Subsequently, a lactam bridge was formed between the carboxylic acid in the side chain of Glu and the amine in the side chain of Lys using PyBOP (2 equiv.) and DIPEA (3.0 equiv.) in DMF. Both steps were performed while the peptide was still attached to the resin.

[0484] Peptides bearing lactams from the side chain to the N-terminal amine were prepared similarly. After assembly of the complete peptide sequence, the Fmoc protecting group on the N-terminal amine was left intact. Glu(Oall) was deprotected with Pd(PPh3)4 as described, followed by Fmoc deprotection (see "Cleavage" section). The lactam bridge was similarly formed with PyBOP.

[0485] Cutting: The dried peptide resin was treated with TFA and an appropriate scavenger for about 2 hours. The volume of the filtrate was reduced and the crude peptide was precipitated after adding diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried.

[0486] HPLC purification of crude peptide: The crude peptides were purified by preparative reversed-phase HPLC using a conventional HPLC system equipped with a column, e.g., a 5 x 25 cm Gemini NX 5u C18 110A column, and a fraction collector, e.g., a Gilson GX-281 and 331 / 332 pump combination (for binary gradient applications), with a flow rate of 20-40 ml / min, and an appropriate gradient of buffer A (0.1% formic acid, aq.) or A (0.1% TFA, aq.) and buffer B (0.1% formic acid, 90% MeCN, aq.) or B (0.1% TFA, 90% MeCN, aq.). Fractions were analyzed by analytical HPLC and MS, and selected fractions were pooled and lyophilized. The final products were characterized by HPLC and MS.

[0487] Dithioether formation: The dithioether formation from the reaction between two unprotected cysteines and a linker can be carried out as previously described (Heinis et al., Nature Biomedical Engineering, 2020) or by the following modified method.

[0488] The crude intermediate peptide was dissolved in a 3:7 mixture of water / acetonitrile (1 mg / mL). DODT (2 equiv.) was added and the mixture was stirred at room temperature for 10 min. The pH was adjusted to pH 8 by adding 0.2 M ammonium carbonate. The linker (2 equiv.) was added directly to the solution and the mixture was shaken at room temperature overnight. The solution was filtered through a 0.45 μm filter and loaded directly onto a preparative HPLC column for final purification.

[0489] Linkers used in the synthesized compounds include: ·1,3-Dibromopropan-2-one, CAS# 816-39-7; ·1,2-Bis(bromomethyl)benzene, CAS # 91-13-4; 1,3-Bis(bromomethyl)benzene, CAS # 626-15-3; and 1,4-Bis(bromomethyl)benzene, CAS # 623-24-5.

[0490] Triazole formation: The crude intermediate peptide was dissolved in HO / t The mixture was dissolved in BuOH (2:1) (1 mg / mL). To the mixture was added 4.4 equivalents of CuSO45H2O and 4.4 equivalents of L-ascorbic acid (CAS 50-81-7). The mixture was protected from light and stirred for 24 hours.

[0491] The solution was loaded directly onto a preparative HPLC column for final purification.

[0492] Analytical HPLC: Final purity was determined by analytical HPLC (Agilent 1100 / 1200 series) equipped with 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., Kinetex 2.6 μm XB-C18 100A 100x4,6 mm column. Compounds were detected and quantified at 215 nm. Buffer A (0.1% TFA, aq.) and Buffer B (0.1% TFA, 90% MeCN, aq.).

[0493] Mass spectrometry: Final MS analysis was performed on a conventional mass spectrometer, e.g., a Waters Xevo G2 Tof equipped with an electrospray detector with lock mass calibration and MassLynx software. It was operated in positive mode using direct injection and cone voltages of 15 V (1 TOF), 30 V (2 TOF) or 45 V (3 TOF) as specified in the chromatograms. The accuracy was 5 ppm and the typical resolution was 15,000-20,000.

[0494] Those skilled in the art will appreciate that standard peptide synthesis methods can be used to produce the compounds of the invention. EXAMPLES

[0495] Structure-Activity-Relationship (SAR) of compounds We synthesized peptides I1 (isomer 3), I3 (isomer 3), I4 (isomer 3), and I5 (isomer 3) identified by phage display from (Heinis et al., Nature Biomedical Engineering, 2020).

[0496] Hits specifically cited in this paper are peptides I3 and I4 (not under protease pressure, i.e., less GI stable) and peptide I1 (under protease pressure, i.e., more GI stable). The more GI stable I5 was obtained by further modifying I1 by one amino acid, i.e., replacing Leu at position 10 with 2-methyl-Leu.

[0497] [Table 18]

[0498] In the following, we define [2,11] as the bridge between amino acid residues 2 and 11. Similarly, [4,7] is the bridge between amino acid residues 4 and 7.

[0499] The inventors realized that it was virtually essential that the peptide had a linker between the cysteine ​​pairs, since the I3 peptide (isomer 3) (Ref 1), which formed two pairs of disulfide bridges without a linker, was inactive (Table 2-2b).

[0500] [Table 19]

[0501] [Table 20]

[0502] The inventors have found that the [2,11]1,3-dithio-propan-2-one bridge can be replaced with a lactam bridge, but the efficacy depends on the location and size of the bridge (e.g., compounds 4 and 7) (Tables 2-3a).

[0503] The location of the amide bond in the lactam bridge influenced the potency of the peptides, with the amide bond closer to the 11th position being more active (compound 7, Table 2-3b) and closer to the 2nd position being less active (compound 4, Table 2-3b).

[0504] [Table 21]

[0505] [Table 22]

[0506] Thus, compound 7 is superior to I3 (isomer 3) as shown in Table 2-3b, since one of the 1,3-dithio-propan-2-one bridges is replaced with a more stable lactam bridge.

[0507] The inventors further observed that the N-terminal Asp could be truncated while retaining and / or increasing potency (compound 10, Tables 2-4a and 2-4b). [Table 23] [Table 24]

[0508] The inventors evaluated several Trp analogs and found that potency could be optimized by introducing 7-Me-Trp at the 5th position (compound 16) or 2-Nal at the 9th position (compound 17, Tables 2-5a and 2-5b). [Table 25] [Table 26]

[0509] We observed that by combining various optimization parameters, potency was synergistically optimized from I3 (isomer 3) to compound 18 (Tables 2-6a and 2-6b). [Table 27] [Table 28]

[0510] The inventors have also shown that it is possible to replace the [4,7] bridge with alternative bridges, such as 1,2-phenylenedimethanethiol, while still retaining substantial potency (compound 20, Tables 2-7a and 2-7b). [Table 29] [Table 30]

[0511] The inventors further demonstrated that peptides can be directly N-terminally cyclized via an N-terminal unnatural amino acid residue (compound 37, Tables 8a and 8b). [Table 31] [Table 32]

[0512] The inventors further found that modifying the 8th position with, for example, Y (2-aminoethoxy) can improve potency (compound 18 vs. compound 29, Tables 2-9a and 2-9b). [Table 33] [Table 34]

[0513] We further evaluated direct cyclization to the N-terminus and showed that the location of the aromatic moiety influenced potency (compound 37, Tables 2-10a and 2-10b). [Table 35] [Table 36]

[0514] In summary, we have demonstrated that the synthesis of I3 (isomer 3) to compound 52 is achieved by the synthesis of K i The affinity as determined by the ELISA was improved from 38.0 nM to 57 pM. EXAMPLES

[0515] Biological assays Binding assay to estimate the binding affinity of compounds to human IL-23R The binding affinity of the compounds to IL-23R was estimated by the ability of the compounds to displace a fluorophore-labeled reference compound from human IL-23R. The assay principle relies on Bioluminescence Resonance Energy Transfer (BRET) between a fluorophore-labeled reference compound that binds to the IL-23R portion of a fusion protein consisting of IL-23R fused to Nanoluc luciferase enzyme (Nanoluc). Nanoluc is located at the N-terminus in close proximity to the binding domain of the ligand. When the fluorophore of the fluorophore-labeled compound and Nanoluc of the fusion protein are in close proximity, the bioluminescence energy generated by the conversion of the Nanoluc substrate is transferred to the fluorophore, resulting in an increase in BRET. In the presence of unlabeled compound, the unlabeled compound displaces the fluorophore-labeled peptide from the binding site, resulting in a decrease in BRET. The concentration at which half of the fluorophore-labeled peptide is displaced by the unlabeled compound depends on the affinity of the compound to IL-23R and is expressed as the IC 50 The estimated affinity of the unlabeled compound for IL-23R (K i ) can be calculated using the Cheng-Prussov equation, which takes into account the concentration of fluorophore-labeled compound used and the affinity of the fluorophore-labeled compound for IL-23R. Assuming that binding is reversible, at equilibrium, K i The value is K i and IC 50 The relationship between K and the i =IC 50 / (1+[L L ] / K dL )(wherein, [L L ] is the concentration of the labeled compound used, and K dL is the equilibrium dissociation constant of the labeled compound) (Cheng and Prusoff, Biochem. Pharmacol., 1973).

[0516] The fusion protein was generated by subcloning the cDNA encoding mature human IL-23R (primary accession number UniProtKB-Q5VWK5, amino acids 22-629) and a small linker sequence in frame into 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. A cell line stably expressing the Nluc-IL23R fusion protein was generated by transfecting HEK293 cells with the expression plasmid and selecting with hygromycin for 3 weeks in a growth medium consisting of DMEM (with Glutamax-I) containing 10% V / V FBS, 1% V / VP / S, ​​1 mM sodium pyruvate, and 1×NEAA, and 0.3 mg / mL hygromycin. The remaining cells were expanded to become a pool of stably expressing Nluc-IL23R fusion protein clones.

[0517] Cells expressing Nluc-IL23R fusion protein were expanded in growth medium and membranes were prepared by homogenizing cell pellets from 18 T175 flasks (4°C for subsequent steps). Cell pellets were lysed in 10 mM Tris(7.5), 1 mM EDTA and protease inhibitors (Complete, Roche) and homogenized with 50 strokes using a 15 mL glass dounce. The homogenate was spun at 1500 rpm for 10 min, the supernatant transferred to an SV-34 tube and spun at 40000g for 20 min at 4°C to pellet crude membranes. The supernatant was then removed and the pellet resuspended and homogenized in 5 mL buffer containing 50 mM HEPES (pH 7.4), 5 mM EGTA, and 5 mM MgCl2. Aliquots of resuspended and homogenized membranes containing Nluc-IL23R fusion protein were stored at -80°C until use.

[0518] Compounds to be tested for binding to IL-23R were 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 a volume of 6.25 μL to wells of a white 384-well plate (Corning 3572) along with 12.5 μL of diluted membrane containing Nluc-IL23R fusion protein (0.42 μg / well) and 6.25 μL of fluorescently labeled peptide (to give a final concentration of 3.1 nM), also prepared in assay buffer. Plates were sealed with light-tight plate seals and incubated at room temperature for 2 hours at 400 rpm on an orbital shaker. To determine the BRET ratio, plate seals were removed and 25 μL of 1:500 diluted Nanoluc substrate (N1572 from Promega) was added to each well and incubated for 1-2 minutes at 400 rpm on an orbital shaker. Plates were then read on an Envision plate reader equipped with an emission mirror module (barcode 404) using filters corresponding to the emission of the Nanoluc substrate (M470 filter; 470 nm, bandwidth 24 nm) and the fluorescence of TAMRA (M595p filter 595 nm, bandwidth 60 nm). BRET ratios were calculated as the fluorescence from TAMRA / bioluminescence of nanoluc. IC for each compound 50 was determined by computer-assisted curve fitting using a 4-parameter logistic (4PL) nonlinear model. i was calculated using the Cheng Prussov formula described above and is shown in Table 3-1.

[0519] K d was determined by performing saturation binding experiments using increasing concentrations of TAMRA-labeled peptides in the presence and absence of high concentrations of unlabeled compound (Stoddart et al., Nat. Methods, 2015). dwas determined to be 13.7 nM and the concentration of TAMRA-labeled peptide in the assay was 3.1 nM.

[0520] Functional inhibition of IL-23-mediated STAT3 signaling by compounds The ability of compounds to inhibit IL-23-mediated signal transduction was determined in a human-derived DB cell line (CRL-2289) (hereafter referred to as DB cells) that endogenously expresses human IL-23R and human IL-12R β1 subunit. Upon IL-23 binding, IL-23R forms a heterodimeric signaling complex with IL-12R β1, which promotes phosphorylation of STAT3 via the JAK2 / STAT3 pathway to form phospho-STAT3. In the assay, the functional antagonism by compounds of IL-23-mediated phospho-STAT3 formation in DB cells is quantified using a reagent capable of measuring the phosphorylation state of Tyr705 of STAT3 in the form of a phospho-STAT3 (Tyr705) MSD (Meso Scale Discovery) kit.

[0521] The assay was used to quantitate the functional antagonism of compounds and to rank inhibitor compounds according to their potency. For compounds tested in this assay, responses were normalized to control values ​​to obtain IC values ​​from concentration-response curves of compounds in the presence of a fixed concentration of human IL-23. 50 and the maximum inhibitory response was calculated.

[0522] The assay procedure was as follows: DB cells were maintained in 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-Streptomycin (Pen-Strep) solution [Invitrogen 15140]. On the day of the assay, cells were resuspended in assay buffer consisting of RPMI-1640 [Invitrogen 61870-010] supplemented with 0.1% w / v BSA [Sigma-Aldrich A9430] at 7.5 × 10 6 Density was in cells / mL. Compounds to be tested for inhibition of hIL-23-mediated signaling were serially diluted in assay buffer to 3× final concentration. 3×EC of hIL-23 80 A solution of hIL-23 equivalent to (1.7 nM) was also prepared in assay buffer. To start the assay, 20 μL of DB cell suspension (corresponding to 150.000 cells / well) was added to wells of a 96-well V-bottom polypropylene plate (Corning 3363) followed by addition of 3×20 μL of diluted test compound to each well. DB cells were pre-incubated with inhibitors in a cell incubator (37° C., 5% CO2) for 15 min, followed by addition of 3× the prepared EC 80 20 μL of the hIL-23 solution was added to each well and incubated for 90 minutes in a cell incubator (37° C., 5% CO2). Some wells contained buffer alone or EC 80Only IL-23 equivalent to 1000 g was added to obtain the required readings for normalization. To terminate the assay, the plate was spun at 1000 g for 5 min to pellet the cells, the supernatant was removed using an 8-channel manual pipette, and 50 μL / well of Complete Lysis Buffer from the MSD STAT3 kit (Cat# K150SVD, Mesoscale) was then added to the cell pellet. To completely lyse the cells and release phospho-STAT3 for detection, the plate was shaken (500 rpm) at room temperature for 10 min, sealed in aluminum foil, and placed at -80°C for a minimum of 15 min. Detection of phospho-STAT3 levels in cell lysates from each well was determined using the MSD STAT3 kit (Cat# K150SVD, Mesoscale) and read on a Meso QuickPlex SQ 120 plate reader (Mesoscale).

[0523] For data analysis, raw data counts from the Meso QuickPlex SQ 120 plate reader were analyzed using EC 80 Compound potency (IC) was normalized to responses from hIL-23 alone (no compound added) and buffer levels. 50 ) and maximum inhibitory response (inhibition rate (%)) were estimated by computer-assisted curve fitting using a four-parameter logistic (4PL) nonlinear model. Compound potency (IC 50 ) data is shown in Table 3-1.

[0524] In vitro activity results (K i hIL-23R and IC 50 (pSTAT3) (expressed as nM values) are summarized in Table 3-1 below. [Table 37] JPEG2024543204000095.jpg249170 JPEG2024543204000096.jpg250170

[0525] Determining the stability of peptides in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) SGF and SIF were prepared according to the United States Pharmacopeia standard (Test Solutions, United States Pharmacopeia 35, NF 30, 2012). SGF was prepared by dissolving sodium chloride (0.2 g) in 50 mL water. The pH of the solution was adjusted to 1.2 by adding a volume of 0.7 mL of 10 M HCl and the volume was made up to 100 mL with water. 64 mg porcine pepsin (P7125, Sigma Aldrich) was gently dissolved in 20 mL of preheated (37°C) solution (3.2 g / L) immediately before incubation. SIF was prepared by dissolving potassium dihydrogen phosphate (0.68 g) in 50 mL water and adjusting the pH to 6.8 with 1 M NaOH. The volume was then made up to 100 mL with water. 200 mg porcine pancreatin (P1625, Sigma Aldrich) was gently dissolved in 20 mL (10 g / L) of preheated (37° C.) solution immediately prior to incubation.

[0526] To start the incubation, 20 μL of peptide stock solution in 50% v / v isopropanol was precipitated to the bottom of the well plate and 580 μL matrix solution was added to give a final substrate concentration of 10 μM. Incubations were performed at 37° C. with gentle shaking. Aliquots of 70 μL were removed at 0, 1 and 4 hours and quenched in 210 μL ice-cold precipitant solution (95% v / v acetonitrile and 0.1% v / v formic acid). After the last time point, the sampling plate was mixed for 10 minutes on a shaking platform and centrifuged at 2200 g for 10 minutes. 70 μL of the resulting supernatant was diluted with 150 μL water, mixed and centrifuged before being analyzed by liquid chromatography-high resolution mass spectrometry. A zero sample was reinjected after 4 hours of sampling to ensure that no drift in instrument sensitivity had occurred during the run. The percent remaining at each time point was calculated relative to the zero time point based on absolute peak area.

[0527] The in vitro SIF results (expressed as % peptide remaining after defined periods of time) are summarized in Table 3-2 below. [Table 38] JPEG2024543204000098.jpg129170

[0528] The in vitro SGF results (expressed as % peptide remaining after the specified time periods) are summarized in Table 3-3 below. [Table 39] JPEG2024543204000100.jpg47170

[0529] (References) Cheng and Prusoff, Biochem. Pharmacol., 1973, 22(23), 3099-3108. Heinis et al., Nature Biomedical Engineering, 2020, 4, 560-571. Sayago et al., ACS Med. Chem. Lett., 2018, 9, 912-916. Stoddart et al., Nat. Methods, 2015, 12, 661-663. International Publication No. 2016 / 011208 Brochure International Publication No. 2017 / 011820 Brochure International Publication No. 2018 / 022937 Brochure International Publication No. 2018 / 089693 Brochure International Publication No. 2018 / 136646 Brochure International Publication No. 2020 / 014646 Brochure International Publication No. 2021 / 007433 Brochure International Publication No. 2021 / 146441 Brochure International Publication No. 2021 / 146458 Brochure US Patent Application Publication No. 2013 / 0029907

[0530] term 1. Formula: R 1 -ZR 2 [In the formula, R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 alkyl or absent; R 2 NHR 3 , OH or absent, R 3 is hydrogen or C 1-3 is alkyl; Z is a group of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) (In the formula, X1 is absent or selected from the group consisting of Asp, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gln; X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, and Bip; X6 is selected from the group consisting of Gln, Glu, Tyr and Cys; X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharma- ceutically acceptable salt or solvate thereof, The compound is I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2] or a pharma- ceutically acceptable salt or solvate thereof, wherein (1a) is not a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge.

[0531] 2. The compound according to item 1, wherein X1 is absent or Asp.

[0532] 3. The compound according to item 1 or 2, wherein X1 is absent.

[0533] 4. The compound according to any one of items 1 to 3, wherein X3 is Ser.

[0534] 5. The compound according to any one of items 1 to 4, wherein X5 is Trp.

[0535] 6. The compound according to any one of items 1 to 5, wherein X6 is Gln.

[0536] 7. The compound according to any one of items 1 to 6, wherein X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2.

[0537] 8. The compound according to any one of items 1 to 7, wherein X9 is 2-Nal or Trp.

[0538] 9. The compound according to any one of items 1 to 8, wherein X9 is 2-Nal.

[0539] 10. The compound according to any one of items 1 to 9, wherein X10 is Leu or 2-Me-Leu.

[0540] 11. The compound according to any one of items 1 to 10, wherein X10 is Leu.

[0541] 12. The compound according to any one of items 1 to 11, wherein X12 is Arg.

[0542] 13. The compound according to any one of items 1 to 12, wherein X13 is absent.

[0543] 14. The compound according to any one of items 1 to 13, wherein X14 is absent.

[0544] 15. R 1 , H, C 1-2 15. The compound according to any one of items 1 to 14, which is acyl or absent.

[0545] 16. R 1 Item 16. The compound according to any one of Items 1 to 15, wherein

[0546] 17. R 1 16. The compound according to any one of items 1 to 15, wherein is -C(=O)CH3.

[0547] 18. R 2 Item 18. The compound according to any one of items 1 to 17, wherein is NH2.

[0548] 19. The compound according to any one of items 1 to 18, wherein the length of the bridge between X2 and X11 and / or the bridge between X4 and X7 is 5 to 10 atoms in length.

[0549] 20. X1 does not exist and R 1 is not present, and X2 and X11 are amino acid residues which together form a lactam bridge or a bridge containing a triazole ring via the N-terminus of X2.

[0550] 21. X1 and X12 to X14 do not exist, and R 1 and R 2 is absent, and X2 and X11 are amino acid residues which together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11.

[0551] 22. The dithioether bridge between X2 and X11 and / or the dithioether bridge between X4 and X7 is a dithioether bridge of the formula -SLYLS- (In the formula: each S is a sulfur atom and is part of an amino acid residue of X2 and X11 and / or X4 and X7; Each L is independently C 1-4 is alkylene; 22. The compound according to any one of items 1 to 21, wherein Y is absent, C(═O) or arylene.

[0552] 23. Each L is independently C 1-2 Item 23. The compound according to item 22, wherein the compound is alkylene.

[0553] 24. The compound according to paragraph 22 or 23, wherein each L is methylene.

[0554] 25. The compound according to any one of items 22 to 24, wherein Y is C(=O).

[0555] 26. The compound according to any one of items 22 to 25, wherein Y is an arylene selected from phenylene.

[0556] 27. The compound according to paragraph 26, wherein Y is a phenylene selected from 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene.

[0557] 28. The compound according to item 26 or 27, wherein Y is 1,2-phenylene.

[0558] 29. The compound according to any one of items 1 to 28, wherein the bridge containing a triazole ring between X2 and X11 and / or the bridge containing a triazole ring between X4 and X7 contains a 1,2,3-triazole ring.

[0559] 30. The compound according to any one of items 1 to 29, wherein the bridge containing a triazole ring between X2 and X11, and / or the bridge containing a triazole ring between X4 and X7, is bonded to the 1-position and the 4-position of the triazole ring.

[0560] 31. The compound according to any one of items 1 to 30, wherein X2 and X11 are amino acid residues which together form a lactam bridge.

[0561] 32. The compound according to item 31, wherein the location of the amide bond in the lactam bridge is closer to X11 than to X2.

[0562] 33. One of the residues at positions X2 and X11 is selected from the group consisting of Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-fluoro-phenylacetyl, 33. The compound according to clause 31 or 32, wherein the arylacetyl group is selected from 4-aminomethyl-2-methyl-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methoxy-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, and (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, and the other is selected from Glu and Asp.

[0563] 34. X2 is Lys, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-fluoro-phenylacetyl 34. The compound according to claim 33, wherein X11 is selected from Glu and Asp, 4-aminomethyl-2-methyl-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methoxy-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, and (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, and X11 is selected from Glu and Asp.

[0564] 35. X2 is Lys and X11 is Glu; X2 is Orn and X11 is Glu; X2 is bAla and X11 is Glu; X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is (4-aminomethyl)benzoyl and X11 is Glu; X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu; X2 is 2-aminomethyl-phenylacetyl and X11 is Glu; X2 is 3-aminomethyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; X2 is 6-aminohexanoyl and X11 is Glu; X2 is 6-amino-4-oxahexanoyl and X11 is Glu; X2 is trans-4-aminomethyl-cyclohexyl-1-carbonyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Asp; X2 is 4-aminomethyl-2-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-3-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-2-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methoxy-phenylacetyl and X11 is Glu; or Item 35. The compound according to item 34, wherein X2 is 4-aminomethyl-3-methoxy-phenylacetyl and X11 is Glu.

[0565] 36. X2 is Lys and X11 is Glu. Item 34. The compound according to item 34 or 35.

[0566] 37. The compound according to clause 33, wherein X2 is selected from Glu and Asp, and X11 is selected from Lys, Arg, and Dab.

[0567] 38. X2 is Glu and X11 is Lys; X2 is Glu and X11 is Dab; ​​or Item 38. The compound according to item 37, wherein X2 is Asp and X11 is Arg.

[0568] 39. The compound according to any one of items 1 to 30, wherein X2 and X11 are amino acid residues which together form a dithioether bridge.

[0569] 40. The compound according to paragraph 39, wherein X2 is Cys and X11 is Cys.

[0570] 41. The compound according to any one of items 1 to 30, wherein X2 and X11 are amino acid residues which together form a bridge containing a triazole ring.

[0571] 42. The compound according to item 41, wherein one of the residues in positions X2 and X11 is selected from Lys(N3), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala), and the other is selected from Pra, Glu(propargylamine), and Dab(3-butynoic acid).

[0572] 43. The compound according to clause 42, wherein X2 is selected from Lys(N3), azidoacetic acid, and (N3)-Ala; and X11 is selected from Pra, Glu (propargylamine) and Dab (3-butynoic acid).

[0573] 44. X2 is Lys(N3) and X11 is Pra; X2 is azidoacetic acid and X11 is Glu (propargylamine); X2 is azidoacetic acid and X11 is Dab (3-butynoic acid); X2 is (N3)-Ala and X11 is Glu (propargylamine); or Item 44. The compound according to item 43, wherein X2 is (N3)-Ala and X11 is Dab (3-butynoic acid).

[0574] 45. Item 45. The compound according to item 43 or 44, wherein X2 is Lys(N3) and X11 is Pra.

[0575] 46. ​​The compound according to clause 42, wherein X2 is Pra; and X11 is selected from Dab (azidoacetic acid), and Dab((N3)-Ala).

[0576] 47. X2 is Pra and X11 is Dab (azidoacetic acid); or Item 47. The compound according to item 46, wherein X2 is Pra and X11 is Dab((N3)-Ala).

[0577] 48. The compound according to any one of items 1 to 47, wherein X4 and X7 are amino acid residues which together form a dithioether bridge.

[0578] 49. The compound according to paragraph 48, wherein X4 is Cys and X7 is Cys.

[0579] 50. The compound according to any one of items 1 to 47, wherein X4 and X7 are amino acid residues which together form a lactam bridge.

[0580] 51. The compound according to paragraph 50, wherein one of the residues at positions X4 and X7 is Lys, Dpr, Dab, or Orn, and the other is Glu.

[0581] 52. The compound according to paragraph 51, wherein X4 is selected from Lys, Dpr, Dab, and Orn, and X7 is Glu.

[0582] 53. X4 is Dpr and X7 is Glu; X4 is Dab and X7 is Glu; or Item 53. The compound according to item 52, wherein X4 is Orn and X7 is Glu.

[0583] 54. The compound according to clause 51, wherein X4 is Glu and X7 is selected from Lys, Dpr, Dab, and Orn.

[0584] 55. X4 is Glu and X7 is Lys; X4 is Glu and X7 is Dpr; or 55. The compound according to item 54, wherein X4 is Glu and X7 is Orn.

[0585] 56. The compound according to any one of items 1 to 47, wherein X4 and X7 are amino acid residues which together form a bridge containing a triazole ring.

[0586] 57. The compound according to paragraph 56, wherein one of the residues at positions X4 and X7 is selected from Lys(N3) and Aha, and the other is Pra.

[0587] 58. X4 is Lys(N3) and X7 is Pra; or Item 58. The compound according to item 57, wherein X4 is Aha and X7 is Pra.

[0588] 59. The compound according to any one of paragraphs 1 to 6, 8, 9, and 12 to 58, wherein X8 is Trp; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0589] 60. X8 is Tyr, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 The compound according to any one of items 1 to 9 and 12 to 58, wherein X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0590] 61. The compound according to any one of paragraphs 1 to 6, 8, 9, and 12 to 58, wherein X8 is Asn; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0591] 62. The compound according to any one of paragraphs 1 to 6, 8, 9, and 12 to 58, wherein X8 is Ala; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0592] 63. The compound according to any one of paragraphs 1 to 6, 8, 9, and 12 to 58, wherein X8 is His; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0593] 64. The compound according to any one of paragraphs 1 to 6, 8, 9, and 12 to 58, wherein X8 is 2-Nal; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0594] 65. The compound according to any one of items 1 to 10 and 12 to 58, wherein X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2; X10 is 2-Me-Leu; and X12 is Arg or absent.

[0595] 66. The compound according to any one of items 1 to 6, 8 to 10, and 12 to 58, wherein X8 is Trp; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0596] 67. X8 is Tyr, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 The compound according to any one of items 1 to 10 and 12 to 58, wherein X10 is optionally substituted with alkyl; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0597] 68. The compound according to any one of items 1 to 6, 8 to 10, and 12 to 58, wherein X8 is Asn; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0598] 69. The compound according to any one of items 1 to 6, 8 to 10, and 12 to 58, wherein X8 is Ala; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0599] 70. The compound according to any one of items 1 to 6, 8 to 10, and 12 to 58, wherein X8 is His; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0600] 71. The compound according to any one of items 1 to 6, 8 to 10, and 12 to 58, wherein X8 is 2-Nal; X10 is 2-Me-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent.

[0601] 72. The compound according to any one of items 1 to 9 and 12 to 58, wherein X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2; X10 is D-Leu; and X12 is Arg or absent.

[0602] 73. The compound according to any one of items 1 to 10 and 12 to 58, wherein X8 is Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2; X10 is 2-Me-Leu; and X12 is Arg or absent.

[0603] 74. Z is [Table 40] JPEG2024543204000102.jpg240170 JPEG2024543204000103.jpg236170 JPEG2024543204000104.jpg245170 JPEG2024543204000105.jpg191170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. or a pharma- ceutically acceptable salt or solvate thereof.

[0604] 75. [Table 41] JPEG2024543204000107.jpg236170 JPEG2024543204000108.jpg249170 JPEG2024543204000109.jpg244170 JPEG2024543204000110.jpg251170 JPEG2024543204000111.jpg243170 JPEG2024543204000112.jpg187170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharma- ceutically acceptable salts and solvates thereof. The compound according to item 1, selected from:

[0605] 76. A pharmaceutical composition comprising a compound according to any one of items 1 to 75 in combination with a pharma- ceutically acceptable carrier, excipient or vehicle.

[0606] 77. A method for synthesizing a compound according to any one of items 1 to 75, comprising the steps of synthesizing an analog by solid-phase or liquid-phase peptide synthesis and isolating and / or purifying any final product, and optionally further comprising the step of forming an amide bond, forming two thioether bonds using a linker, or forming a triazole between the amino acid residue at position X2 and the amino acid residue at position X11, and optionally further comprising the step of forming an amide bond, forming two thioether bonds using a linker, or forming a triazole between the amino acid residue at position X4 and the amino acid residue at position X7.

[0607] 78. A compound according to any one of items 1 to 75, or a pharmaceutical composition according to item 76, for use in a medical treatment method.

[0608] 79. In a subject with inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, leukocyte adhesion deficiency-I, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich disease Item 77. The compound according to any one of Items 1 to 75, or the pharmaceutical composition according to Item 76, for use in a method for preventing or treating colitis associated with impaired natural immunity such as in symptoms, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, or graft-versus-host disease, or a combination thereof.

[0609] priorities 1. Formula: R 1 -ZR 2 [In the formula, R 1 , H, C 1-4 Acyl, Benzoyl, C 1-4 alkyl or absent; R 2 NHR 3 , OH or absent, R 3 is hydrogen or C 1-3 is alkyl; Z is a group of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) (In the formula, X1 is absent or selected from the group consisting of Asp, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gln; X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, and Bip; X6 is selected from the group consisting of Gln, Glu, Tyr and Cys; X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, and the hydroxyl group of Tyr may be replaced by NH2. 1-3 optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl; X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or is absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala; X14 is absent or Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharma- ceutically acceptable salt or solvate thereof, The compound is I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2] or a pharma- ceutically acceptable salt or solvate thereof, wherein (1a) is not a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge.

[0610] 2. X1 is absent or Asp; X3 may be Ser; X5 may be Trp; X6 can be Gln; X8 may be Tyr, and the hydroxyl group of Tyr may be substituted with -CH2CH2NH2; X9 can be 2-Nal or Trp; X10 may be Leu or 2-Me-Leu; X12 may be Arg; X13 does not have to be present; X14 may not be present; R 1 , H, C 1-2 may or may not be acyl; R 2 may be NH2; Item 2. The compound according to item 1, wherein the bridge between X2 and X11 and / or the bridge between X4 and X7 may be 5 to 10 atoms long.

[0611] 3. The dithioether bridge between X2 and X11 and / or the dithioether bridge between X4 and X7 is represented by the formula -SLYLS- (In the formula: each S is a sulfur atom and is part of an amino acid residue of X2 and X11 and / or X4 and X7; Each L is independently C 1-4 is alkylene; Item 3. The compound according to item 1 or 2, wherein Y is absent, C(=O) or arylene.

[0612] 4. the bridge containing a triazole ring between X2 and X11 and / or the bridge containing a triazole ring between X4 and X7 contains a 1,2,3-triazole ring; The compound according to any one of items 1 to 3, wherein a bridge containing a triazole ring between X2 and X11 and / or a bridge containing a triazole ring between X4 and X7 may be bonded to the 1-position and the 4-position of the triazole ring.

[0613] 5. X2 and X11 are amino acid residues which together form a lactam bridge; The location of the amide bond in the lactam bridge may be closer to X11 than to X2; One of the residues at positions X2 and X11 is selected from the group consisting of Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-fluoro-phenyl ... 5. The compound according to any one of items 1 to 4, wherein the other one is optionally selected from Glu and Asp, and the other one is optionally selected from Glu and Asp.

[0614] 6. X2 and X11 are amino acid residues which together form a dithioether bridge; The compound according to any one of items 1 to 4, wherein X2 may be Cys and X11 may be Cys.

[0615] 7. X2 and X11 are amino acid residues which together form a bridge containing a triazole ring; The compound according to any one of items 1 to 4, wherein one of the residues at positions X2 and X11 may be selected from Lys(N3), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala), and the other may be selected from Pra, Glu(propargylamine), and Dab(3-butynoic acid).

[0616] 8. X4 and X7 are amino acid residues which together form a dithioether bridge; X4 is Cys and X7 is Cys; or X4 and X7 may be amino acid residues which together form a lactam bridge; 8. The compound according to any one of items 1 to 7, wherein one of the residues at positions X4 and X7 may be Lys, Dpr, Dab, or Orn, and the other may be Glu.

[0617] 9. X4 and X7 are amino acid residues which together form a bridge containing a triazole ring; 8. The compound according to any one of items 1 to 7, wherein one of the residues at positions X4 and X7 may be selected from Lys(N3) and Aha, and the other may be Pra.

[0618] 10. Z is [Table 42] JPEG2024543204000114.jpg240170 JPEG2024543204000115.jpg236170 JPEG2024543204000116.jpg245170 JPEG2024543204000117.jpg191170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. or a pharma- ceutically acceptable salt or solvate thereof.

[0619] 11. The compound according to item 1, selected from the following: [Table 43] JPEG2024543204000119.jpg236170 JPEG2024543204000120.jpg249170 JPEG2024543204000121.jpg244170 JPEG2024543204000122.jpg251170 JPEG2024543204000123.jpg243170 JPEG2024543204000124.jpg187170 [wherein * = crosslinking using an amine or carboxylic acid at the N-terminus or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharma-ceutically acceptable salts and solvates thereof.

[0620] 12. A pharmaceutical composition comprising a compound according to any one of items 1 to 11 in combination with a pharma- ceutically acceptable carrier, excipient or vehicle.

[0621] 13. A method for synthesizing a compound according to any one of items 1 to 11, comprising the steps of synthesizing an analog by solid-phase or liquid-phase peptide synthesis and isolating and / or purifying any final product, and optionally further comprising the step of forming an amide bond, forming two thioether bonds using a linker, or forming a triazole between the amino acid residue at position X2 and the amino acid residue at position X11, and optionally further comprising the step of forming an amide bond, forming two thioether bonds using a linker, or forming a triazole between the amino acid residue at position X4 and the amino acid residue at position X7.

[0622] 14. A compound according to any one of items 1 to 11, or a pharmaceutical composition according to item 12, for use in a medical treatment method.

[0623] 15. Inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, leukocyte adhesion deficiency-I, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich disease in a subject. Item 17. The compound according to any one of Items 1 to 11, or the pharmaceutical composition according to Item 12, for use in a method for preventing or treating colitis associated with impaired natural immunity such as in symptoms, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, or graft-versus-host disease, or a combination thereof.

Claims

1. formula: R １ -Z-R ２ [In the formula, R １ is H, C １－４ Acyl, benzoyl, C １－４ alkyl or absent; R ２ is NHR ３ , OH or absent, R ３ is hydrogen or NH ２ C optionally substituted with １－３ is alkyl; Z is a group of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) (In the formula, X1 is absent or selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gln, Val, He, N-Me-Ser, and Q (pyrrolidine); X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp; X6 is selected from the group consisting of Gln, Glu, Tyr, Cys, Val, His, N-Me-Gln, and Q (pyrrolidine); X8 is Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4-diaminobutanoyl ([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH ２ -(2-(trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Val, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), {d}F(4-F), 4-Cl-Phe, alpha-Me-Trp, 3,3-diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr is selected from the group consisting of NH ２ C optionally substituted with １－３ optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and {d}6-F-Trp; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val; X12 is Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH ２ - selected from the group consisting of Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, {d}2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-Gln, D-Glu, D-His, 3-aminopropanoyl, and GABA, or absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, {d}[3-(3-pyridyl)-Ala], 3-amino-3-(3′-pyridyl)propionyl, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-pyridyl)-Ala; X14 is absent or is Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharmaceutically acceptable salt or solvate thereof, The compound is I3 (isomer 3) H-DC (1a) SC (2a) WQC (2a) WWLC (1a) R-[NH2] wherein (1a) is a [2,11]1,3-dithio-propan-2-one bridge and (2a) is a [4,7]1,3-dithio-propan-2-one bridge, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound is I3 (isomer 3) H-DC (1a) SC (2a) WQC (2a) WWLC (1a) R-[NH2] wherein (1a) is a [2,11] 1,3-dithio-propan-2-one bridge and (2a) is a [4,7] 1,3-dithio-propan-2-one bridge, formula: R １ -Z-R ２ [In the formula, R １ is H, C １－４ Acyl, benzoyl, C １－４ alkyl or absent; R ２ is NHR ３ , OH or absent, R ３ is hydrogen or C １－３ is alkyl; Z is a group of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) (In the formula, X1 is absent or selected from the group consisting of Asp, Glu, Ser, Cys, and Lys; X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gln; X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7-(naphth-2-yl)-Trp, 2-Nal, and Bip; X6 is selected from the group consisting of Gln, Glu, Tyr and Cys; X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, and the hydroxyl group of Tyr is NH ２ C optionally substituted with １－３ optionally substituted with alkyl; X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala; X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl; X12 is Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH ２ - selected from the group consisting of Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala, or absent; X13 is absent or selected from the group consisting of Asn, Gly, 3-(3-pyridyl)-Ala, and 3-(4-pyridyl)-Ala; X14 is absent or is Gly; X2 and X11 are amino acid residues which together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; X4 and X7 are amino acid residues that together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring), or a pharmaceutically acceptable salt or solvate thereof.

3. X1 is absent or Asp; and / or X3 is Ser or He; and / or X5 is Trp or 7-Me-Trp; and / or X6 is Gln or Glu; and / or X8 is Trp, Tyr, or 4-Me-Phe, wherein the hydroxyl group of Tyr may be replaced by -CH 2 CH 2 NH 2 ; and / or X9 is 2-Nal, Trp, or 3,4-Me-Phe; and / or X10 is Leu, 2-Me-Leu, or 2-Me-Val; and / or X12 is Arg, D-Arg, or Dab; ​​and / or X13 is absent, 3-(3-pyridyl)-Ala, or 2-Me-3-(3-pyridyl)-Ala; and / or X14 does not exist; 3. The compound according to claim 1 or 2.

4. R １ is H, C １－２ acyl or absent; and / or R 1 is —C(═O)CH 3 ; and / or R2 is NH2; 3. The compound according to claim 1 or 2.

5. the length of the bridge between X2 and X11 and / or the bridge between X4 and X7 is 5 to 10 atoms long; and / or X1 is absent, R 1 is absent, and X2 and X11 are amino acid residues which together form a lactam bridge or a bridge containing a triazole ring via the N-terminus of X2; and / or X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclized lactam bridge via the N-terminus of X2 and the C-terminus of X11; 3. The compound according to claim 1 or 2.

6. The dithioether bridge between X2 and X11 and / or the dithioether bridge between X4 and X7 is of the formula -SLYLS- (In the formula: each S is a sulfur atom and is part of an amino acid residue of X2 and X11, and / or X4 and X7; Each L is independently C １－４ is alkylene, Y is absent, C(=O) or arylene; and / or each L is independently C 1-2 alkylene; and / or each L is methylene; and / or Y is C(=O); and / or Y is an arylene selected from phenylene; and / or Y is a phenylene selected from 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene; 3. The compound according to claim 1 or 2.

7. 3. The compound according to claim 1 or 2, wherein X2 and X11 are amino acid residues which together form a lactam bridge, The position of the amide bond in the lactam bridge is closer to X11 than to X2; and / or One of the residues in positions X2 and X11 is Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-fluoro-phenylacetyl, 4-aminomethyl-2-methyl-phenyl selected from acetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methoxy-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl, the other selected from Glu and Asp; and / or X2 is Lys, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3-fluoro-phenylacetyl, 4-aminomethyl-2-methyl-phenylacetyl, 4- aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methoxy-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4-(2-aminoethyl)-piperazin-1-yl)-acetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4-methylaminomethyl-phenylacetyl, and X11 is selected from Glu and Asp; and / or X2 is Lys and X11 is Glu; X2 is Orn and X11 is Glu; X2 is bAla and X11 is Glu; X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is (4-aminomethyl)benzoyl and X11 is Glu; X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu; X2 is 2-aminomethyl-phenylacetyl and X11 is Glu; X2 is 3-aminomethyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; X2 is 6-aminohexanoyl and X11 is Glu; X2 is 6-amino-4-oxahexanoyl and X11 is Glu; X2 is trans-4-aminomethyl-cyclohexyl-1-carbonyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Glu; X2 is (4-(2-aminoethyl)-piperazin-1-yl)-acetyl and X11 is Asp; X2 is 4-aminomethyl-2-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-3-pyridineacetyl and X11 is Glu; X2 is 4-aminomethyl-2-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-fluoro-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-2-methoxy-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-methoxy-phenylacetyl and X11 is Glu; X2 is Dab and X11 is Glu; or X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu; and / or X2 is Lys and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; or X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; or X2 is selected from Glu and Asp, and X11 is selected from Lys, Arg, and Dab; ​​and / or X2 is Glu and X11 is Lys; X2 is Glu and X11 is Dab; ​​or X2 is Asp and X11 is Arg; The compound.

8. 3. The compound according to claim 1 or 2, wherein X2 and X11 are amino acid residues which together form a dithioether bridge, The compound, wherein X2 and X11 are each independently selected from Cys and N-Me-Cys.

9. 3. The compound according to claim 1 or 2, wherein X2 and X11 are amino acid residues which together form a bridge containing a triazole ring, one of the residues in positions X2 and X11 is selected from Lys(N 3 ), azidoacetic acid, (N 3 )-Ala, Dab(azidoacetic acid) and Dab((N 3 )-Ala), and the other is selected from Pra, Glu(propargylamine), Dab(3-butynoic acid) and but-3-ynoic acid; and / or X2 is selected from Lys(N 3 ), azidoacetic acid, and (N 3 )-Ala; X11 is selected from Pra, Glu (propargylamine) and Dab (3-butynoic acid); and / or X2 is Lys(N 3 ) and X11 is Pra; X2 is azidoacetic acid and X11 is Glu (propargylamine); X2 is azidoacetic acid and X11 is Dab (3-butynoic acid); X2 is (N 3 )-Ala and X11 is Glu (propargylamine); or X2 is (N 3 )-Ala and X11 is Dab (3-butynoic acid); and / or X2 is selected from Pra and but-3-ynoic acid; X11 is selected from Dab (azidoacetic acid) and Dab((N 3 )-Ala); and / or X2 is Pra and X11 is Dab (azidoacetic acid); X2 is Pra and X11 is Dab ((N 3 )-Ala); Or, X2 is but-3-ynoic acid and X11 is Dab (azidoacetic acid); Or, X2 is but-3-ynoic acid and X11 is Dab ((N 3 )-Ala); The compound.

10. X4 and X7 are amino acid residues which together form a dithioether bridge, X4 and X7 are each independently selected from Cys and N-Me-Cys; and / or X4 is Cys and X7 is Cys; or X4 is N-Me-Cys and X7 is Cys; or X4 and X7 are amino acid residues which together form a lactam bridge, one of the residues in positions X4 and X7 is Lys, Dpr, Dab, or Orn, and the other is Glu; and / or X4 is selected from Lys, Dpr, Dab, and Orn, and X7 is Glu; and / or X4 is Glu and X7 is selected from Lys, Dpr, Dab, and Orn; or X4 and X7 are amino acid residues which together form a bridge containing a triazole ring; and / or one of the residues at positions X4 and X7 is selected from Lys(N 3 ) and Aha, and the other is Pra; 3. The compound according to claim 1 or 2.

11. Z is Table 1 where * = crosslinking using an amine or carboxylic acid at the N- or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the amino acid sequence is selected from the group consisting of: 【Request Item 12】 【Table 2】 where * = crosslinking using an amine or carboxylic acid at the N- or C-terminus of the peptide backbone rather than a side chain amine or carboxylic acid; (1a) = [2,11] 1,3-dithio-propan-2-one bridge; (1c) = [2,11] lactam bridge; (1g) = [2,11] 1,4-disubstituted 1,2,3-triazole bridge; (1h) = [2,11] 1,5-disubstituted 1,2,3-triazole bridge; (2a) = [4,7] 1,3-dithio-propan-2-one bridge; (2c) = [4,7] lactam bridge; (2d) = [4,7] 1,2-phenylenedimethanethiol bridge; (2e) = [4,7] 1,3-phenylenedimethanethiol bridge; (2f) = [4,7] 1,4-phenylenedimethanethiol bridge; (2g) = [4,7] 1,4-disubstituted 1,2,3-triazole bridge. and pharmaceutically acceptable salts and solvates thereof 2. The compound of claim 1 selected from:

13. 10. A pharmaceutical composition comprising a compound according to claim 1 or 2 in combination with a pharmaceutically acceptable carrier, excipient or vehicle.

14. 10. A compound according to claim 1 or 2 for use in a method of medical treatment.

15. A pharmaceutical composition according to claim 1 or 2 for use in a method for preventing or treating inflammatory bowel diseases (IBD) such as Crohn's disease or ulcerative colitis, and psoriasis.

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