Polycyclic peptide inhibitors of interleukin-23 receptor

Abstract

The present disclosure relates to a peptide inhibitor of interleukin-23 receptor (IL-23R) or a pharmaceutically acceptable salt thereof; a corresponding pharmaceutical composition; methods and / or uses for treating autoimmune inflammation and related diseases and disorders.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 480,042, filed January 16, 2023, which is incorporated by reference herein in its entirety.

[0003] Incorporation by Reference of the Sequence Listing

[0004] The XML-formatted sequence listing in ST.26 format created on January 13, 2024, named 739655_NTT-4252PC_SL comprises 29,940 bytes and is filed herewith pursuant to 37 CFR 1.822 to 1.824, and is incorporated herein by reference in its entirety. BACKGROUND

[0005] Interleukin-23 (IL-23) cytokine is a heterodimer composed of a unique pl9 subunit and a p40 subunit shared with IL-12, which is a cytokine involved in the development of T helper 1 (Thl) cells that produce interferon-gamma (IFN-gamma) and T helper 17 (Thl7) cells that produce interleukin-17 (IL-17). Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. For example, animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while animals lacking IL-23 are resistant, which can be due to the reduced number of CD4 H T cells in the CNS of animals lacking IL-23. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL-12Rpl and IL-23R subunits. Binding of IL-23 to IL-23R activates Jak-Stat signaling molecules, Jak2, Tyk2, Statl, Stat3, Stat4, and Stat5, but Stat4 activation is significantly weaker and forms a different DNA-binding Stat complex in response to IL-23 compared to IL-12. IL-23R is constitutively associated with Jak2 and associated with Stat3 in a ligand-dependent manner. In sharp contrast to IL-12, which primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells. + T cells in the CNS of animals lacking IL-23. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL-12Rpl and IL-23R subunits. Binding of IL-23 to IL-23R activates Jak-Stat signaling molecules, Jak2, Tyk2, Statl, Stat3, Stat4, and Stat5, but Stat4 activation is significantly weaker and forms a different DNA-binding Stat complex in response to IL-23 compared to IL-12. IL-23R is constitutively associated with Jak2 and associated with Stat3 in a ligand-dependent manner. In sharp contrast to IL-12, which primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0006] IL-23 has been implicated as playing a key role in the pathogenesis of autoimmune inflammation and associated diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn’s disease. Studies in acute and chronic mouse models of IBD have revealed a central role for interleukin-23 receptor (IL-23R) and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on a variety of adaptive and innate immune cells, including Th17 cells, gd T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found in abundance in the intestine. At the surface of the intestinal mucosa, both gene expression and protein levels of IL-23R are found to be elevated in IBD patients. IL-23 is believed to mediate this effect by promoting the development of pathogenic CD4 + T cell populations.

[0007] Accordingly, there remains a need for compositions that bind IL-23R to inhibit IL-23 binding and signaling in a patient. SUMMARY

[0008] Provided herein are peptide inhibitors of interleukin-23 receptor (IL-23R) or a pharmaceutically acceptable salt thereof; corresponding pharmaceutical compositions; and methods and / or uses of IL-23R inhibitors for treating inflammatory diseases, autoimmune diseases, and / or related disorders.

[0009] In particular, the present disclosure provides a peptide of Formula (I’), comprising the following amino acid sequence:

[0010] R1-X3-X4-X5-X6-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-X 15 -X 16 -R2(I’),

[0011] or a pharmaceutically acceptable salt thereof, wherein each of X3, X4, X5, X6, X7, X8, X9, X 10 , X 12 , X 13 , X 15 , and X 16 are defined herein.

[0012] In some embodiments, the present disclosure provides a peptide of Formula (I), comprising the following amino acid sequence:

[0013] R1-X3-X4-X5-T-X7-X8-X9-X10 -2Nal-X 12 -X 13 -N-X 15 -X 16 -R2(I),

[0014] or a pharmaceutically acceptable salt thereof, wherein each of X3, X4, X5, X7, X8, X9, X 10 , X 12 , X 13 , X 15 and X 16 are defined herein.

[0015] The present disclosure further provides a pharmaceutical composition comprising a peptide described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0016] The present disclosure still further provides a method for treating a disease or disorder associated with interleukin 23 (IL-23) / interleukin 23 receptor (IL-23R), comprising administering to a subject in need thereof a therapeutically effective amount of a peptide or a pharmaceutical composition described herein. In some embodiments, the disease or disorder is selected from ulcerative colitis (UC), Crohn’s disease (CD), psoriasis (PsO), and psoriatic arthritis (PsA). DETAILED DESCRIPTION

[0017] Provided herein are peptide inhibitors of IL-23R and pharmaceutically acceptable salts thereof; corresponding pharmaceutical compositions; and methods and / or uses for treating inflammatory diseases, autoimmune diseases, and / or related disorders.

[0018] Definitions

[0019] Unless otherwise defined herein, scientific and technical terms used in this application have the meanings that would be given to them by one of ordinary skill in the art.

[0020] As used in the specification and claims, “comprising,” “including,” “having,” “can,” “containing” and variants thereof do not exclude the presence of other features, groups, ingredients, elements or steps. As used in the specification and claims, the phrase “at least” preceding the recitation of a step or ingredient in a claim means that the step or ingredient is present, but not exclusively, and can be included in addition to, in place of other steps or ingredients, or in combination with other steps or ingredients. For example, the language “a peptide of Formula (I) comprising the following amino acid sequence: X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-X 15 -X 16 (I)” means that the amino acids X3to X 17In addition, the peptides can include, but are not limited to, additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, capping groups at the N-terminus or C-terminus, chemical or biological moieties conjugated to the peptide at any position (including, but not limited to, for example, lipophilic substituents, antibodies, imaging agents, etc.), and the like. The terms“comprising,”“including,”“having”“can” or“containing” can include embodiments encompassed by the terms“consisting essentially of’ or“consisting of.”

[0021] The terms“peptide,”“polypeptide,” and“protein” are used interchangeably herein and generally refer to a molecule comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.).

[0022] Unless otherwise noted, both naturally occurring L-amino acids and D-amino acids are represented by the conventional three letter or capitalized single letter amino acid nomenclature of Table 1. In some embodiments, naturally occurring L-amino acids are represented by the conventional three letter or capitalized single letter amino acid nomenclature of Table 1. In some embodiments, D-amino acids are represented by the lower case single letter amino acid nomenclature corresponding to the single letter nomenclature of Table 1, i.e., g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t.

[0023] Table 1 : Naturally occurring amino acids

[0024]

[0025]

[0026] As used herein, the term“L-amino acid” refers to the“L” isomeric form of the amino acid, and conversely the term“D-amino acid” refers to the“D” isomeric form of the amino acid (e.g., (D)Asp or D-Asp; (D)Phe or D-Phe). A D isomeric form of an amino acid residue can be substituted for any L-amino acid residue so long as the peptide segment retains the desired functionality. When referred to using the one-letter abbreviation, the D-amino acid can be indicated in lower case by convention. For example, D-arginine can be denoted as“arg” or“r”. Alternatively, a lower case“d” preceding the amino acid can be used to indicate that it is the D isomeric form, e.g., D-lysine can be denoted by dK.

[0027] In the case of less common or non-naturally occurring amino acids, the three- character code or four-character code commonly employed is adopted for their residues, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (a-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid), unless they are referred to by their full name (e.g., sarcosine, ornithine, etc.).

[0028] Amino acids in the D-isomeric form can be positioned at any of the positions in the IL-23R inhibitors set forth herein (e.g., X3-X 16 In some embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X3, X5, X6, X8, X 13 In other embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X3, X8, X 13 In other embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X8, X 13 In other embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X3, X8, X 16 In other embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X3, X8, X 16 In other embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X3, X8, X 15 For example, an IL-23R inhibitor set forth herein in which positions X3-X 17 In other embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X3, X8, X 16 In other embodiments, the amino acid in the D-isomeric form can be positioned at any one or more of X3, X8, X

[0029] Peptides can be naturally occurring, synthetically produced, or recombinantly expressed. Peptides can also comprise additional groups that modify the amino acid chain, such as functional groups added via post-translational modification. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipidation, phosphopantetheinylation, phosphorylation, selenoylation, and C-terminal amidation. The term peptide also includes peptides comprising modifications at the amino and / or carboxyl terminus. Modifications of terminal amino groups include, but are not limited to, deamination, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of terminal carboxyl groups include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., where lower alkyl is C1-C4 alkyl). The term peptide also includes modifications such as, but not limited to, those described above, that modify the amino acids falling between the amino and carboxyl termini.

[0030] As will be clear to those skilled in the art, the peptide sequences disclosed herein are shown from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. The sequences disclosed herein are sequences that incorporate an “-OH” moiety or an “-NH2” moiety at the carboxyl terminus (C-terminus) of the sequence. In such cases, and unless otherwise specified, the “-OH” or “-NH2” moiety at the C-terminus of the sequence indicates a hydroxyl group or an amino group, respectively, corresponding to a formic acid (COOH) or amido (CONH2) group present at the C-terminus. In each sequence of the disclosure, the C-terminal “-OH” moiety can be substituted for the C-terminal “-NH2” moiety, and vice versa.

[0031] As used herein, the phrase “amino acid,” “amino acid residue,” or “residue” refers to an amino acid, a modified amino acid, an amino acid analog, or an amino acid mimetic incorporated into a peptide by a peptide bond or a peptide bond mimic.

[0032] The names of naturally occurring and non-naturally occurring amino acyl residues used herein follow the naming conventions suggested by the IUPAC Organic Chemistry Nomenclature Commission and the IUPAC-IUB Biochemical Nomenclature Commission as shown in “Nomenclature of α-Amino Acids (Recommendations, 1974),” Biochemistry, Vol. 14, No. 2 (1975), unless otherwise specified. Where the names and abbreviations of amino acids and amino acyl residues employed in the present specification and appended claims differ from those recommendations, this will be made clear to the reader. In the amino acid sequences representing IL-23 inhibitors, individual amino acids are separated by a hyphen “-” or by parentheses, e.g., lysine is shown as [K].

[0033] Those skilled in the art will appreciate that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, amino acid side chains can be modified when forming an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogens can be removed or replaced with a bond.

[0034] The term "therapeutically effective amount" or "pharmaceutically effective amount" means that amount of an active peptide or pharmaceutical agent that will elicit the biological or pharmacological response that is being sought in a tissue system, animal, or human, and includes the prevention, treatment, or amelioration of the symptoms of the disease, disorder, or condition being treated.

[0035] The term "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or state governments or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0036] "Pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening, diluent, preservative, dye / colorant, flavor enhancer, surface-active, wetting, dispersing, suspending, stabilizing, isotonic, solvent, or emulsor agent approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0037] "Composition" or "pharmaceutical composition" as used herein is intended to encompass a product comprising the specified active pharmaceutical ingredient (API) (i.e., the peptides of the present disclosure) that can include, for example, a specified amount of a pharmaceutically acceptable excipient, carrier, or diluent as described herein, as defined throughout the present disclosure.

[0038] The compositions or pharmaceutical compositions of the present disclosure can be in different pharmaceutically acceptable forms, which can include, but are not limited to, liquid compositions, tablet or matrix compositions, capsule compositions, and the like. When the composition is a tablet composition, the tablet can include, but is not limited to, different layers, two or more different phases, including an inner phase and an outer phase that can include a core. The tablet composition can also include, but is not limited to, one or more coatings.

[0039] Pharmaceutically acceptable salts and tautomeric forms of the peptides described herein are also provided.

[0040] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a peptide represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. In general, see G. S. Paulekuhn et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665-72, S. M. Berge et al., "Pharmaceutical Salts", J Pharm Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. The peptides of Formula (I) can have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and accordingly react with a variety of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0041] The IL-23R inhibitors, pharmaceutically acceptable salts, and / or other forms of the present disclosure can contain one or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor (e.g., an alcohol) or resolvation of a racemic form (or salt or derivative of the racemic form) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds, other geometric isomers can also be present. Unless indicated otherwise, the description is intended to embrace both E and Z geometric isomers. Likewise, it is intended to include all tautomeric forms of the compounds. When the compounds are represented in their chiral form, it is intended to encompass both the particular enantiomeric or diastereomeric form as well as the racemic or defined ratio mixtures thereof.

[0042] “racemate” refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.

[0043] “one or more stereoisomers” refers to compounds that differ in their spatial arrangement of atoms. Stereoisomers include enantiomeric and diastereomeric forms. If a compound has one or more asymmetric centers, it can exist as single stereoisomers or as mixtures thereof. Unless otherwise indicated, the description is intended to embrace both individual stereoisomers and mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry 4thEd., J. March, John Wiley and Sons, New York, 1992).

[0044] “diastereomers” are stereoisomers that are not mirror images of each other.

[0045] “enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A “racemic” mixture is a 1 : 1 mixture of a pair of enantiomers. A “non-racemic” mixture of enantiomers is a mixture of enantiomers in a ratio other than 1 : 1.

[0046] “Tautomer” refers to an alternate form of a compound whose position of a proton is different, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring-NH- and a ring=N-, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0047] The term “administering” in relation to the methods of the disclosure means a method of therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder, or disease as described herein by using a compound of the disclosure or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof. Such methods include administering a therapeutically effective amount of a peptide of the disclosure or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof at different times during the course of therapy, or concurrently or sequentially as a combination therapy.

[0048] “Patient” or “subject” are used interchangeably and refer to a living organism, preferably a mammal, most preferably a human, who will be treated by or has been treated by a method according to the embodiments of the application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHP) such as monkeys or apes, humans, and the like, more preferably including humans.

[0049] The term “treatment” or “therapy” as used herein is defined as the application or administration of a therapeutic agent, i.e., a compound of the disclosure (alone or in combination with another pharmaceutical agent), to a patient who has a disorder or disease as described herein, a symptom thereof, or a likelihood of developing such a disorder or disease, or to a tissue or cell line isolated from a patient (e.g., for diagnostic or ex vivo applications); with the purpose to cure, heal, alleviate, relieve, alter, remedy, improve, or affect the disorder or disease, the symptom, or the likelihood of developing the disorder or disease. Such treatment can be modified or improved based on knowledge gained through the field of pharmacogenomics.

[0050] The term “prevention” or “preventing” as used herein means that a disease or disorder does not develop if it has not yet occurred, or that a disorder or disease does not further develop if it has already occurred. The ability to prevent some or all symptoms associated with a disorder or disease is also contemplated.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure belongs. In the chemical arts, a dash at the beginning or end of a chemical group denotes that the group is meant to be attached to the rest of the molecule at that point. A chemical group can be depicted with or without one or more dashes and not lose its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Dashed lines indicate optional bonds. Unless chemically or structurally necessary, the order of writing of chemical groups or the point of their attachment to the rest of the molecule does not indicate or imply directionality. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and both can be attached in either direction. Similarly, an "arylalkyl" group, for example, can be attached to the rest of the molecule at either the aryl or alkyl portion of the group. Prefixes such as "C u-v " or (C u -C v ) indicate that the group following has u to v carbon atoms. For example, "C 1-6 alkyl" and "Ci-C6alkyl" both indicate that the alkyl group has 1 to 6 carbon atoms.

[0052] Further, within the scope of the present application, any element, particularly when referred to by its natural abundance or isotopically enriched form, is intended to encompass all isotopes or isotopic mixtures of the element (naturally occurring or synthetically produced). For example, reference to hydrogen includes 1 H、 2 H(i.e., deuterium or D), and 3 H(i.e., tritium or T) within its scope. In some embodiments, the compounds described herein include 2 H(i.e., deuterium) isotopes. For example, a group representing -C (1-6) alkyl includes not only -CH3, but also CD3; not only CH2CH3, but also CD2CD3, and so on. Similarly, reference to carbon and oxygen includes 12 C、 13 C, and 14 C, respectively, within its scope. Similarly, reference to oxygen includes 15 O and 16 O, and 17 O, and 18 O within its scope. The isotopes can be radioactive or non-radioactive. Radioactively labeled compounds of the present disclosure can include a radioactive isotope selected from the group comprising: 3 H、 11 C、 18 F、 35 S、 122 I、 123 I、 125 I、 131 I,75 Br, 76 Br, 77 Br and 82 Br. Preferably, the radioisotope is selected from the group of 3 H, 11 C and 18 F.

[0053] The abbreviation “(V / V)” refers to the phrase “volume per volume,” i.e., the ratio of a particular substance within a mixture, as measured by the volume or volume amount of a component of a composition disclosed herein relative to the total volume amount of the composition. Thus, this quantity is in a unit that is smaller, and represents the volume percent amount of the component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture can indicate that there are 2 mL of one solvent in a 100 mL solvent mixture.

[0054] “Bioavailability” refers to the extent and rate at which an active moiety (drug or metabolite) enters systemic circulation and thus reaches the site of action. Bioavailability of a drug can be influenced by factors such as the nature of the dosage form and the nature of the drug

[0055] As used herein, “gastrointestinal tissue” refers to all tissue that makes up the organs of the gastrointestinal tract. For example only and without limitation, “gastrointestinal tissue” includes tissue of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.

[0056] Compounds

[0057] The present disclosure provides peptide inhibitors of interleukin-23 receptor. In particular, the present disclosure provides a peptide of Formula (I’), comprising the following amino acid sequence:

[0058] R1-X3-X4-X5-X6-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-X 15 -X 16 -R2(I’),

[0059] or a pharmaceutically acceptable salt thereof, wherein:

[0060] R1is MeCO, 8Aoc, 7Ahp, 6Ahx, 5Ava, or cPEG3aCO;

[0061] X3is hK, a cyclized amino acid, or absent;

[0062] X4is any amino acid;

[0063] X5is N, N(NMe2), Q, Q(NMe2), or a cyclized amino acid;

[0064] X6 is any amino acid;

[0065] X7 is 7MeW or W;

[0066] X8 is K(Ac), K(NMeAc), Q, or a cyclized amino acid;

[0067] X9 is any amino acid;

[0068] X 10 is AEF, APEG3F, F(4TzI Ame2), TMAPF, or a cyclized amino acid;

[0069] X 12 is THP or a cyclized amino acid;

[0070] X 13 is E or a cyclized amino acid;

[0071] X 15 is 3Pya, bAla, or a cyclized amino acid;

[0072] X 16 is Sar, a cyclized amino acid, or absent;

[0073] R2 is CONH2 or CONMe2;

[0074] wherein:

[0075] (a) the first cyclized amino acid is linked to the second cyclized amino acid to form a first ring comprising 4 to 11 or 14 amino acids; and the third cyclized amino acid is linked to the fourth cyclized amino acid to form a second ring comprising 4 to 11 or 14 amino acids; or

[0076] (b) the first cyclized amino acid is linked to the second cyclized amino acid to form a first ring comprising 4 to 11 or 14 amino acids; and the third cyclized amino acid is linked to the C-terminus of the peptide to form a second ring comprising 4 to 11 or 14 amino acids.

[0077] Non-limiting examples of cyclized amino acids include 4aminoPro, Abu, aG, aMeC, Api, C, D, Dap, Dap(N3), Dab, E, hA, hE, hK, K, Orn, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), Pra, R5H, R7H, R5Me, S5H, S7H, or S5Me.

[0078] In some embodiments, the first loop comprises 4 to 9 or 11 amino acids. In some embodiments, the first loop comprises 4, 6, or 10 amino acids. In some embodiments, the first loop comprises 4 amino acids. In some embodiments, the first loop comprises 5 amino acids. In some embodiments, the first loop comprises 6 amino acids. In some embodiments, the first loop comprises 7 amino acids. In some embodiments, the first loop comprises 8 amino acids. In some embodiments, the first loop comprises 9 amino acids. In some embodiments, the first loop comprises 10 amino acids. In some embodiments, the first loop comprises 11 amino acids. In some embodiments, the first loop comprises 14 amino acids.

[0079] In some embodiments, the first loop comprises a linkage between two looped amino acids having a structure selected from:

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] In some embodiments, the first loop is formed between X4and X9, X4and X 13 , X5and X 10 , X3and X 13 , or X6and X9. In some embodiments, the first loop is formed between X4and X9, X4and X 13 , X5and X 10 , X3and X 13 , or X6and X9via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. In some embodiments, the first loop is formed between X4and X9, X4and X 13 , X5and X 10 , X3and X 13 , or X6and X9via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole.

[0087] In some embodiments, the first loop is formed between X4and X9, X4and X 13or X6and X9. In some embodiments, the first ring is formed between X4and X9, X4and X 13 or X6and X9. In some embodiments, the first ring is formed between X4and X9, X4and X 13 or X6and X9.

[0088] In some embodiments, the first ring is formed between X4and X9. In some embodiments, the first ring is formed between X4and X

[0089] In some embodiments, the first ring is formed between X4and X 13 In some embodiments, the first ring is formed between X4and X 13 In some embodiments, the first ring is formed between X4and X 13

[0090] In some embodiments, the first ring is formed between X5and X 10 In some embodiments, the first ring is formed between X5and X 10 In some embodiments, the first ring is formed between X5and X 10

[0091] In some embodiments, the first ring is formed between X3and X 13 In some embodiments, the first ring is formed between X3and X 13 In some embodiments, the first ring is formed between X3and X 13

[0092] ​​​In some embodiments, the first loop is formed between X6and X9. In some embodiments, the first loop is formed between X6and X9via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. In some embodiments, the first loop is formed between X6and X9via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole.

[0093] In some embodiments, the second loop comprises 4 to 9 or 11 amino acids. In some embodiments, the second loop comprises 4, 6, 10, or 11 amino acids. In some embodiments, the second loop comprises 4 amino acids. In some embodiments, the second loop comprises 5 amino acids. In some embodiments, the second loop comprises 6 amino acids. In some embodiments, the second loop comprises 7 amino acids. In some embodiments, the second loop comprises 8 amino acids. In some embodiments, the second loop comprises 9 amino acids. In some embodiments, the second loop comprises 10 amino acids. In some embodiments, the second loop comprises 11 amino acids. In some embodiments, the second loop comprises 14 amino acids.

[0094] In some embodiments, the second loop comprises a linkage between two looped amino acids, having a structure selected from:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] In some embodiments, the second loop comprises a linkage between the N-terminus of the peptide and a looped amino acid, and has a structure selected from:

[0103]

[0104]

[0105] In some embodiments, the second loop is formed between X4and X9, X4and X 13 , X5and X 10 , X3and X 13or X6and X9. In some embodiments, the second ring is formed between X4and X9, X4and X 13 , X5and X 10 , X3and X 13 or X6and X9. In some embodiments, the second ring is formed between X4and X9, X4and X 13 , X5and X 10 , X3and X 13 or X6and X9.

[0106] In some embodiments, the second ring is formed between X5and X 10 or X3and X 13 . In some embodiments, the second ring is formed between X5and X 10 or X3and X 13 . In some embodiments, the second ring is formed between X5and X 10 or X3and X 13 . In some embodiments, the second ring is formed between X5and X 10 or X3and X 13 .

[0107] In some embodiments, the second ring is formed between X4and X9. In some embodiments, the second ring is formed between X4and X9via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. In some embodiments, the second ring is formed between X4and X9via a linker selected from the group consisting of disulfide, thioether, amide, olefin, and triazole.

[0108] In some embodiments, the second ring is formed between X4and X 13 . In some embodiments, the second ring is formed between X4and X 13 . In some embodiments, the second ring is formed between X4and X 13 .

[0109] In some embodiments, the second loop is formed between X5and X 10 In some embodiments, the second loop is formed between X5and X 10 In some embodiments, the second loop is formed between X5and X 10

[0110] In some embodiments, the second loop is formed between X3and X 13 In some embodiments, the second loop is formed between X3and X 13 In some embodiments, the second loop is formed between X3and X 13

[0111] In some embodiments, the second loop is formed between X6and X9. In some embodiments, the second loop is formed between X6and X9via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, the second loop is formed between X6and X9via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0112] In some embodiments, the second loop is formed between X 13 and the N-terminus of the peptide. In some embodiments, the second loop is formed between X 13 and the N-terminus of the peptide via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, the second loop is formed between X 13 and the N-terminus of the peptide via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0113] In some embodiments, the first loop is formed between X4and X9via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole; and the second loop is formed between X3and X 13 , X5and X 10 , X 10 and X 13 , or X 13 and the N-terminus of the peptide.​​

[0114] In some embodiments, the first loop is formed between X4and X9via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole; and the second loop is formed between X3and X 13 , X5and X 10 , X 10 and X 13 , or X 13 and the N-terminus of the peptide.

[0115] In some embodiments, the first loop is formed between X4and X 13 via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole; and the second loop is formed between X5and X 10 , or X6and X9.

[0116] In some embodiments, the first loop is formed between X4and X 13 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole; and the second loop is formed between X5and X 10 , or X6and X9.

[0117] In some embodiments, the first loop is formed between X6and X9via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole; and the second loop is formed between X3and X 13 , X4and X 13 , X5and X 10 , X 10 and X 13 , or X 13 and the N-terminus of the peptide.

[0118] In some embodiments, the first loop is formed between X6and X9via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole; and the second loop is formed between X3and X 13 , X4and X 13 , X5and X 10 , X 10 and X 13between, or X 13 between the N-terminus of the peptide.

[0119] In some embodiments, the peptide of Formula (I') is a peptide of Formula (I).

[0120] Thus, in some embodiments, the present disclosure provides a peptide of Formula (I) comprising the following amino acid sequence:

[0121] R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-X 15 -X 16 -R2(I),

[0122] or a pharmaceutically acceptable salt thereof, wherein:

[0123] R1is MeCO, 8Aoc, 7Ahp, or cPEG3aCO;

[0124] X3is R7H, S7H, hK, or absent;

[0125] X4is 4aminoPro, Abu, aG, aMeC, C, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra;

[0126] X5is N, N(NMe2), Q, or Q(NMe2);

[0127] X7is 7MeW or W;

[0128] X8is K(Ac), R5H, S5H, K(NMeAc), or Q;

[0129] X9is aMeC, aG, C, D, E, hE, Pen, or Dap(N3);

[0130] X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF;

[0131] X 12 is R5, S5, B5, or THP;

[0132] X 13 is E, R5H, or S5H;

[0133] X 15 is 3Pya or bAla;

[0134] X 16 is R5H, S5H, Sar, or absent;

[0135] R2 is CONH2 or CONMe2;

[0136] wherein when X3 is R7H or S7H, then X5 is N(Me2) or Q(NMe2), X8 is K(NmeAc), or X 10 is APEG3F;

[0137] wherein the peptide is cyclized via:

[0138] (a) a first linkage between the residue at X4 and the residue at X9; and

[0139] (b) a second linkage selected from the group consisting of:

[0140] a linkage between 8Aoc at R1 and E at X 13 ,

[0141] a linkage between 7Ahp at R1 and E at X 13 ,

[0142] a linkage between R7H or S7H at X3 and R5H or S5H at X 13 ,

[0143] a linkage between hK at X3 and E at X 13 ,

[0144] a linkage between R5H or S5H at X8 and R5 or S5 at X 12 ,

[0145] a linkage between F(4TzlAme2) at X 10 and E at X 13 ,

[0146] a linkage between AEF at X 10 and E at X 13 ;

[0147] a linkage between R5 or S5 at X 12 and R5H or S5H at X 16 ; and

[0148] two linkages between B5 at X 12 and R5H or S5H at X8 and between B5 at X 12 and R5H or S5H at X 16 .

[0149] In some embodiments, the present disclosure provides a peptide of Formula (I) comprising the following amino acid sequence:

[0150] R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -NX 15 -X 16 -R2(I),

[0151] Or its pharmaceutically acceptable salt, wherein:

[0152] R1 is MeCO, 8Aoc, 7Ahp, or cPEG3aCO;

[0153] X3 is R7H, S7H, hK or does not exist;

[0154] X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl) or Pra;

[0155] X5 is N, N(NMe2), Q, or Q(NMe2);

[0156] X7 is 7MeW or W;

[0157] X8 is K(Ac), R5H, S5H, K(NMeAc), or Q;

[0158] X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3);

[0159] X 10 It is AEF, APEG3F, F(4TzlAme2) or TMAPF;

[0160] X 12 It is R5, S5, B5 or THP;

[0161] X 13 It is E, R5H or S5H;

[0162] X 15 It is either 3Pya or bAla;

[0163] X 16 It is R5H, S5H, Sar, or it does not exist;

[0164] R2 is either CONH2 or CONMe2;

[0165] When X3 is R7H or S7H, then X5 is N(Me2) or Q(NMe2), X8 is K(NmeAc), or X 10 It is APEG3F;

[0166] The peptide is cyclized via the following pathway:

[0167] (c) a first linkage between the residue at X4 and the residue at X9; and

[0168] (d) a second linkage selected from the group consisting of:

[0169] a linkage between 8Aoc at R1 and E at X 13 ,

[0170] a linkage between R7H or S7H at X3 and R5H or S5H at X 13 ,

[0171] a linkage between hK at X3 and E at X 13 ,

[0172] a linkage between R5H or S5H at X8 and R5 or S5 at X 12 ,

[0173] a linkage between F(4TzlAme2) at X 10 and E at X 13 ,

[0174] a linkage between AEF at X 10 and E at X 13 ;

[0175] a linkage between R5 or S5 at X 12 and R5H or S5H at X 16 ; and

[0176] two linkages between B5 at X 12 and R5H or S5H at X8 and between B5 at X 12 and R5H or S5H at X 16 .

[0177] In some embodiments, the peptide comprises an amino acid sequence of Formula (I-A):

[0178] R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(I-A)

[0179] or a pharmaceutically acceptable salt thereof, wherein:

[0180] R1 is MeCO, 8Aoc, or cPEG3aCO;

[0181] X3 is R7H, S7H, hK, or absent;

[0182] X4 is 4aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra;

[0183] X5 is N or N(NMe2);

[0184] X7 is 7MeW or W;

[0185] X8 is K(Ac), R5H, S5H, K(NMeAc), or Q;

[0186] X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3);

[0187] X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF;

[0188] X 12 is R5, S5, B5, or THP;

[0189] X 13 is E, R5H, or S5H;

[0190] X 15 is 3Pya or bAla;

[0191] X 16 is S5H or Sar; and

[0192] R2 is CONH2 or CONMe2;

[0193] wherein when X3 is R7H or S7H, then X5 is N(Me2), X8 is K(NmeAc), or X 10 is APEG3F;

[0194] wherein the peptide is cyclized via:

[0195] (e) a first linkage between the residue at X4 and the residue at X9; and

[0196] (f) a second linkage selected from the group consisting of:

[0197] a linkage between 8Aoc at R1 and E at X 13 ,

[0198] a linkage between R7H or S7H at X3 and R5H or S5H at X 13 ,

[0199] a linkage between hK at X3 and E at X 13 ,

[0200] R5H or S5H at X 12 the linkage between R5 or S5 at X

[0201] X 10 the linkage between F(4TzlAme2) at X 13 and E at X

[0202] X 10 the linkage between AEF at X 13 and E at X

[0203] X 12 the linkage between R5 or S5 at X 16 and R5H or S5H at X

[0204] X 12 the two linkages between B5 at X 12 and R5H or S5H at X 16 and R5H or S5H at X

[0205] In some embodiments, the peptide comprises an amino acid sequence of Formula (I-B):

[0206] R1-X3-Pen-X5-T-7MeW-X8-Pen-X 10 -2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(I-B) or a pharmaceutically acceptable salt thereof, wherein:

[0207] R1 is MeCO, 8Aoc, or cPEG3aCO;

[0208] X3 is R7H, S7H, hK, or absent;

[0209] X5 is N or N(NMe2);

[0210] X8 is K(Ac), S5H, or K(NMeAc);

[0211] X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF;

[0212] X 12 is R5, S5, B5, or THP;

[0213] X 13 is E, R5H, or S5H;

[0214] X 16 is S5H or Sar; and

[0215] R2 is CONH2 or CONMe2;

[0216] wherein when X3 is R7H or S7H, then X5 is N(Me2) or Q(NMe2), X8 is K(NmeAc), or X 10 is APEG3F;

[0217] wherein the peptide is cyclized via:

[0218] (g) a first linkage between the residue at X4 and the residue at X9; and

[0219] (h) a second linkage selected from the group consisting of:

[0220] a linkage between 8Aoc at R1 and E at X 13 ,

[0221] a linkage between R7H or S7H at X3 and R5H or S5H at X 13 ,

[0222] a linkage between hK at X3 and E at X 13 ,

[0223] a linkage between R5H or S5H at X8 and R5 or S5 at X 12 ,

[0224] a linkage between F(4TzlAme2) at X 10 and E at X 13 ,

[0225] a linkage between AEF at X 10 and E at X 13 ;

[0226] a linkage between R5 or S5 at X 12 and R5H or S5H at X 16 ; and

[0227] two linkages between B5 at X 12 and R5H or S5H at X8 and between B5 at X 12 and R5H or S5H at X 16 .

[0228] In some embodiments, the peptide comprises an amino acid sequence of Formula (I-C):

[0229] R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-THP-X 13 -N-3Pya-X 16-R2(I-C)

[0230] or a pharmaceutically acceptable salt thereof, wherein:

[0231] R1is MeCO, 8Aoc, 7Ahp, or cPEG3aCO;

[0232] X3is R7H, S7H, hK, or absent;

[0233] X4is 4aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra;

[0234] X5is N, N(NMe2), Q, or Q(NMe2);

[0235] X7is 7MeW or W;

[0236] X8is K(Ac), K(NMeAc), or Q;

[0237] X9is aMeC, aG, C, D, E, hE, Pen, or Dap(N3);

[0238] X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF;

[0239] X 13 is E, R5H, or S5H;

[0240] X 16 is Sar or absent; and

[0241] R2is CONH2or CONMe2;

[0242] wherein when X3is R7H or S7H, then X5is N(Me2) or Q(NMe2), X8is K(NmeAc), or X 10 is APEG3F;

[0243] wherein the peptide is cyclized via:

[0244] (i) a first linkage between the residue at X4and the residue at X9; and

[0245] (j) a second linkage selected from the group consisting of:

[0246] a linkage between 8Aoc at R1and E at X 13 ,

[0247] a linkage between R7H or S7H at X3and R5H or S5H at X 13 ,

[0248] a bond between hK at X 13 and E at X

[0249] a bond between R5H or S5H at X 12 and R5 or S5 at X

[0250] X 10 is F(4TzlAme2) at X 13 and E at X

[0251] X 10 is AEF at X 13 and E at X

[0252] In some embodiments, the peptide comprises an amino acid sequence of Formula (I-D):

[0253] R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -E-N-3Pya-X 16 -CONH2(I-D)

[0254] wherein:

[0255] R1 is MeCO or 8Aoc;

[0256] X3 is absent;

[0257] X4 is 4aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra;

[0258] X5 is N or Q;

[0259] X7 is 7MeW or W;

[0260] X8 is K(Ac), S5H, or Q;

[0261] X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3);

[0262] X 10 is AEF or F(4TzlAme2);

[0263] X 12 is R5, S5, B5, or THP; and

[0264] X 16 is S5H or Sar;

[0265] wherein the peptide is cyclized via:

[0266] (k) a first linkage between the residue at X4 and the residue at X9; and

[0267] (l) a second linkage selected from the group consisting of:

[0268] a linkage between 8Aoc at R1 and E at X 13 ,

[0269] a linkage between R5H or S5H at X8 and R5 or S5 at X 12 ,

[0270] a linkage between F(4TzlAme2) at X 10 and E at X 13 ,

[0271] a linkage between AEF at X 10 and E at X 13 ;

[0272] a linkage between R5 or S5 at X 12 and R5H or S5H at X 16 ; and

[0273] two linkages between B5 at X 12 and R5H or S5H at X8 and between B5 at X 12 and R5H or S5H at X 16 .

[0274] In some embodiments, R1 is 8Aoc, 7Ahp, cPEG3aCO, or MeOC, wherein 8Aoc is attached to an amino acid at X 13 . In some embodiments, R1 is 8Aoc, 7Ahp, cPEG3aCO, or MeCO, wherein 8Aoc is attached to an E residue at X 13 via an amino linkage.

[0275] In some embodiments, R1 is 7Ahp, 8Aoc, or MeCO. In some embodiments, R1 is 7Ahp, cPEG3aCO, or MeCO. In some embodiments, R1 is 8Aoc, cPEG3aCO, or MeCO. In some embodiments, R1 is MeCO or 7Ahp. In some embodiments, R1 is 8Aoc or MeCO. In some embodiments, R1 is MeCO or cPEG3aCO.

[0276] In some embodiments, R1 is an alkyl chain attached to an amino acid at X 13 . In some embodiments, R1 is an alkyl chain attached to an amino acid at X 13The amino acid linked to 8Aoc at the position. In some embodiments, X1 is with X 13 The E connection at the location is 8Aoc. In some implementations, R1 is 7Ahp. In some implementations, R1 is connected to X. 13 The amino acid linked to 7Ahp. In some embodiments, R1 is with X. 13 The E-connector is 7Ahp. In some embodiments, R1 is MeCO. In some embodiments, R1 is cPEG3aCO.

[0277] In some implementations, X3 is hK, R7H, S7H, or does not exist; wherein hK, R7H, and S7H are related to X. 13 The amino acid linkage at the location. In some embodiments, X3 is hK, R7H, S7H, or absent; wherein hK, R7H, and S7H are linked to X. 13 The amino acid linkage is defined at the location, where hK is an L amino acid. In some embodiments, X3 is hk, R7H, S7H, or absent; wherein hk, R7H, and S7H are associated with X. 13 The amino acid linkage at the location. In some embodiments, X3 is hK, R7H, S7H, or absent. In some embodiments, X3 is hK, R7H, S7H, or absent.

[0278] In some implementations, X3 is hk, R7H, S7H, or does not exist; wherein hk, R7H, and S7H are related to X. 13 The R5H, S5H, or E residue is linked to X. In some embodiments, X3 is hk, R7H, S7H, or absent; wherein hk, R7H, and S7H are linked to X via aliphatic or amide bonds. 13 The amino acid linkage at the location. In some embodiments, X3 is hk, R7H, S7H, or absent; wherein R7H and S7H are linked to X via an aliphatic bond. 13 The R5H or S5H residue is linked at the site. In some embodiments, X3 is hk, R7H, S7H, or absent; wherein hk is linked to X via an amide bond. 13 The E residues at the location are linked.

[0279] In some implementations, X3 is R7H, hk, or does not exist.

[0280] In some implementations, X3 is related to X 13 The amino acid R7H is linked at the location. In some embodiments, X3 is associated with X. 13 R5H is connected to R7H. In some implementations, X3 is connected to X. 13 The amino acid S7H is linked at the location. In some embodiments, X3 is associated with X. 13X3is hk connected to E at the X 13 X3is hk connected to E at the X 13 X3is hk connected to E at the X 13 X3is hk connected to E at the X 13 X3is hk connected to E at the X

[0281] In some embodiments, X4is 4amino Pro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4is 4amino Pro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra, each of which is an L amino acid. In some embodiments, X4is 4amino-d-Pro, dAbu, d-aG, aMe-d-C, c, dDap, dPen, dPen(oXyl), dPen(mXyl), dPen(pXyl), or dPra.

[0282] In some embodiments, X4is 4amino Pro, aG, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4is Abu, aMeC, C, Pen, Pen(oXyl), Pen(mXyl), or Pen(pXyl). In some embodiments, X4is Abu, aMeC, C, or Pen. In some embodiments, X4is Abu, C, or Pen. In some embodiments, X4is Abu or Pen.

[0283] In some embodiments, X4is 4amino Pro. In some embodiments, X4is 4R amino Pro. In some embodiments, X4is 4S amino Pro. In some embodiments, X4is Abu. In some embodiments, X4is aG. In some embodiments, X4is aMeC. In some embodiments, X4is C. In some embodiments, X4is Dap. In some embodiments, X4is Pen. In some embodiments, X4is Pen(oXyl). In some embodiments, X4is Pen(mXyl). In some embodiments, X4is Pen(pXyl). In some embodiments, X4is Pra.

[0284] In some embodiments, X4 is 4amino-d-Pro. In some embodiments, X4 is 4R amino-d-Pro. In some embodiments, X4 is 4S amino-d-Pro. In some embodiments, X4 is dAbu. In some embodiments, X4 is d-aG. In some embodiments, X4 is aMe-d-C. In some embodiments, X4 is c. In some embodiments, X4 is dDap. In some embodiments, X4 is dPen. In some embodiments, X4 is dPen(oXyl). In some embodiments, X4 is dPen(mXyl). In some embodiments, X4 is dPen(pXyl). In some embodiments, X4 is dPra.

[0285] In some embodiments, X5 is N, N(NMe2), Q, or Q(NMe2). In some embodiments, X5 is N, N(NMe2), Q, or Q(NMe2), each of which is an L amino acid. In some embodiments, X5 is n, n(NMe2), q, or q(NMe2).

[0286] In some embodiments, X5 is N, N(NMe2), or Q. In some embodiments, X5 is N, Q, or Q(NMe2). In some embodiments, X5 is N or Q. In some embodiments, X5 is N. In some embodiments, when X5 is N, then X4 is Pen. In some embodiments, X5 is Q. In some embodiments, when X5 is Q, then X4 is Abu.

[0287] In some embodiments, X6 is T. In some embodiments, X6 is T, wherein T is an L-amino acid. In some embodiments, X6 is t.

[0288] In some embodiments, X7 is 7MeW or W. In some embodiments, X7 is 7MeW or W, each of which is an L-amino acid. In some embodiments, X7 is 7Mew or w.

[0289] In some embodiments, X7 is 7MeW. In some embodiments, X7 is 7Mew. In some embodiments, X7 is W. In some embodiments, X7 is w. In some embodiments, when X7 is W, then X5 is Q. In some embodiments, when X7 is W, then X4 is Abu. In some embodiments, when X7 is W, then X5 is Q and X4 is Abu.

[0290] In some embodiments, X8is K(Ac), R5H, S5H, K(NMeAc), or Q. In some embodiments, X8is K(Ac), R5H, S5H, K(NMeAc), or Q, wherein Q, K(Ac), and K(NMeAc) are L-amino acids. In some embodiments, X8is k(Ac), R5H, S5H, k(NMeAc), or q.

[0291] In some embodiments, X8is K(Ac), R5H, S5H, K(NMeAc), or Q, wherein R5Hand S5Hare attached to the amino acid at X 12 In some embodiments, X8is K(Ac), R5H, S5H, K(NMeAc), or Q, wherein R5Hand S5Hare attached to the amino acid at X 12 In some embodiments, X8is K(Ac), R5H, S5H, K(NMeAc), or Q, wherein R5Hand S5Hare attached to the amino acid at X

[0292] In some embodiments, X8is K(Ac), S5H, K(NMeAc), or Q. In some embodiments, X8is K(Ac), S5H, or Q. In some embodiments, X8is K(Ac), K(NMeAc), or Q. In some embodiments, X8is K(Ac) or Q. In some embodiments, X8is K(Ac) or K(NMeAc). In some embodiments, X8is K(Ac). In some embodiments, X8is K(NMeAc). In some embodiments, X8is Q. In some embodiments, X8is k(Ac). In some embodiments, X8is k(NMeAc). In some embodiments, X8is q.

[0293] In some embodiments, X8is R5H or S5H. In some embodiments, X8is S5H attached to S5 at X 12 In some embodiments, X8is R5H attached to R5 at X 12 In some embodiments, X8is S5H attached to R5 at X 12 In some embodiments, X8is S5H attached to R5 at X 12 In some embodiments, X8is R5H attached to S5 at X

[0294] In some embodiments, X9is aMeC, aG, C, D, E, hE, Pen, or Dap(N3). In some embodiments, X9is aMeC, aG, C, D, E, hE, Pen, or Dap(N3), each of which is an L-amino acid. In some embodiments, X9is aMe-d-C, d-aG, c, d, e, he, dPen, or dDap(N3).

[0295] In some embodiments, X9is aG, D, E, hE, or Dap(N3). In some embodiments, X9is aMeC, C, or Pen. In some embodiments, X9is aMeC or Pen.

[0296] In some embodiments, X9is aMeC. In some embodiments, X9is aG. In some embodiments, X9is C. In some embodiments, X9is D. In some embodiments, X9is E. In some embodiments, X9is hE. In some embodiments, X9is Pen. In some embodiments, X9is Dap(N3).

[0297] In some embodiments, X9is aMe-d-C. In some embodiments, X9is d-aG. In some embodiments, X9is c. In some embodiments, X9is d. In some embodiments, X9is e. In some embodiments, X9is he. In some embodiments, X9is dPen. In some embodiments, X9is dDap(N3).

[0298] In some embodiments, X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF, optionally wherein AEF is connected to the amino acid at X 13 In some embodiments, X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF, each of which is an L-amino acid, optionally wherein AEF is connected to the amino acid at X 13 In some embodiments, X 10 is dAEF, dAPEG3F, f(4TzlAme2), or dTMAPF, optionally wherein dAEF is connected to the amino acid at X 13 In some embodiments, X

[0299] In some embodiments, X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF. In some embodiments, X 10 is AEF, TMAPF, or APEG3F. In some embodiments, X 10 is AEF, TMAPF, or F(4TzlAme2). In some embodiments, X 10 is AEF or TMAPF.

[0300] In some embodiments, X 10 is APEG3F. In some embodiments, X 10 is F(4TzlAme). In some embodiments, X 10TMAPF. In some embodiments, X 10 is AEF. In some embodiments, X 10 is AEF linked to the amino acid at X 13 In some embodiments, X 10 is AEF linked to E at X 13 In some embodiments, X 10 is dAPEG3F. In some embodiments, X 10 is f(4TzIAme). In some embodiments, X 10 is dTMAPF. In some embodiments, X 10 is dAEF. In some embodiments, X 10 is dAEF linked to the amino acid at X 13 In some embodiments, X 10 is dAEF linked to E at X 13

[0301] In some embodiments, X 12 is THP, S5, R5, or B5. In some embodiments, X 12 is THP, S5, R5, or B5, wherein S5 and R5 are linked to the amino acid at X 16 In some embodiments, X 12 is THP, S5, R5, or B5, wherein B5 is linked to the amino acid at X8 and the amino acid at X 16 In some embodiments, X 12 is THP, S5, or R5. In some embodiments, X 12 is THP, S5, or B5. In some embodiments, X 12 is THP or S5. In some embodiments, X 12 is THP or B5. In some embodiments, X 12 is THP. In some embodiments, X 12 is S5. In some embodiments, X 12 is R5. In some embodiments, X 12 is B5.

[0302] In some embodiments, X 12 is S5 linked to the amino acid at X 16 In some embodiments, X 12 is THP, S5, R5, or B5, wherein S5 and R5 are linked to S5H or R5H at X 16 In some embodiments, X 12 is S5 linked to S5H at X 16 ​S5 is connected to S5H at location S5H. In some implementations, X 12 It is through aliphatic bonds and X 16 The amino acid R5 is linked at the location. In some implementations, X 12 Is with X 16 R5 is connected to R5H at point R5H.

[0303] In some implementation schemes, X 12 It is the amino acid at X8 and X 16 The amino acid B5 is linked at the location. In some implementations, X 12 It is linked to the amino acid at X8 via a first aliphatic bond and to X via a second aliphatic bond. 16 The amino acid B5 is linked at the location. In some implementations, X 12 It is S5H and X at X8 16 B5 is connected to S5H at location S5H. In some implementations, X 12 It is R5H and X at X8 16 B5 is connected to R5H at that location.

[0304] In some implementation schemes, X 13 It is E, R5H, or S5H; wherein R5H and S5H are linked to the amino acids at R1 and X3, and optionally E is linked to the amino acids at R1 and X3 or X. 10 Amino acid linkage at the location. In some implementations, X 13 It is E, R5, or S5H, where E is an L-amino acid; wherein R5H and S5H are linked to the amino acid at X3, and optionally E is linked to the amino acid at R1, X3, or X. 10 Amino acid linkage at the location. In some implementations, X 13 It is e, R5H, S5H; wherein R5H and S5H are linked to the amino acid at X3, and optionally e is linked to the amino acid at R1, X3, or X. 10 The amino acid linkage at the location.

[0305] In some implementation schemes, X 13 It is E, R5H, or S5H. In some implementations, X 13 It is E or S5H. In some implementations, X 13 It is E or R5H. In some implementations, X 13 It is E.

[0306] In some implementation schemes, X 13 It is E connected to R1. In some implementations, X 13 It is E connected to R1 via an amide bond. In some embodiments, X 13is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 10 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 10 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 10 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 10 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 10 is E connected to the amino acid at X3. In some embodiments, X 13 is E connected to the amino acid at X3. In some embodiments, X 10 is E connected to the amino acid at X3. In some embodiments, X 13 is S5H. In some embodiments, X 13 is S5H connected to X3. In some embodiments, X 13 is S5H connected to R7H at X3.

[0307] In some embodiments, X 14 is N. In some embodiments, X 14 is N, wherein N is an L-amino acid. In some embodiments, X 14 is n.

[0308] In some embodiments, X 15 is 3Pya or bAla. In some embodiments, X 15 is 3Pya or bAla, wherein 3Pya is an L amino acid. In some embodiments, X 15 is d-3Pya or bAla.

[0309] In some embodiments, X 15 is 3Pya. In some embodiments, X 15 is bAla. In some embodiments, X 15 is d-3Pya.

[0310] In some embodiments, X 16 is Sar, R5H, S5H, or absent, wherein S5H and R5H are connected to X12 Amino acid linkage at the location. In some implementations, X 16 It is Sar, R5h, S5H or not present, where S5H and R5H are aliphatic-linked to X. 12 Amino acid linkage at the location. In some implementations, X 16 It is Sar, S5H, R5H or does not exist, where S5H and R5H are related to X. 12 The B5 connection at that location. In some implementations, X 16 It is Sar, S5H, or does not exist. In some implementations, X 16 It is Sar, R5H, or does not exist.

[0311] In some implementation schemes, X 16 It is either Sar or does not exist. In some implementations, X 16 It is either Sar or S5H. In some implementations, X 16 It is either Sar or R5H. In some implementations, X 16 It is S5H. In some implementations, X 16 It is R5H. In some implementations, X 16 Is with X 12 R5H is connected to B5 at location B5. In some implementations, X 16 Is with X 12 The amino acid S5H is linked at the location. In some embodiments, X 16 Is with X 12 The S5H is connected to B5 at location B5. In some implementations, X 16 It is Sar. In some implementations, X 16 It does not exist.

[0312] In some implementations, R2 is CONH2 or CONMe2. In some implementations, R2 is CONH2. In some implementations, R2 is CON(Me)2.

[0313] In some embodiments, the peptide is cyclized via a disulfide, thioether, amide, or olefin bond through a bond between two amino acid residues (e.g., residue X4 and residue X9).

[0314] In some implementations, X4 is Abu and X9 is C. In some implementations, X4 is Abu and X9 is aMeC. In some implementations, X4 is Abu and X9 is Pen.

[0315] In some implementations, X4 is C and X9 is C. In some implementations, X4 is C and X9 is aMeC. In some implementations, X4 is C and X9 is Pen.

[0316] In some embodiments, X4 is Pen and X9 is C. In some embodiments, X4 is Pen and X9 is aMeC. In some embodiments, X4 is Pen and X9 is Pen.

[0317] In some embodiments, X4 is aMeC and X9 is C. In some embodiments, X4 is aMeC and X9 is aMeC. In some embodiments, X4 is aMeC and X9 is Pen.

[0318] In some embodiments, X4 is Pen(oXyl) and X9 is C. In some embodiments, X4 is Pen(oXyl) and X9 is aMeC. In some embodiments, X4 is Pen(oXyl) and X9 is Pen.

[0319] In some embodiments, X4 is Pen(mXyl) and X9 is C. In some embodiments, X4 is Pen(mXyl) and X9 is aMeC. In some embodiments, X4 is Pen(mXyl) and X9 is Pen.

[0320] In some embodiments, X4 is Pen(pXyl) and X9 is C. In some embodiments, X4 is Pen(pXyl) and X9 is aMeC. In some embodiments, X4 is Pen(pXyl) and X9 is Pen.

[0321] In some embodiments, X4 is 4aminoPro and X9 is D. In some embodiments, X4 is 4aminoPro and X9 is E. In some embodiments, X4 is 4aminoPro and X9 is hE.

[0322] In some embodiments, X4 is Dap and X9 is D. In some embodiments, X4 is Dap and X9 is E. In some embodiments, X4 is Dap and X9 is hE.

[0323] In some embodiments, X4 is Pra and X9 is Dap(N3). In some embodiments, X4 is aG and X9 is aG.

[0324] In some embodiments, the peptide is cyclized via a linkage between two amino acid residues (e.g., at X4 and X9) having a structure selected from the group consisting of:

[0325]

[0326]

[0327] In some embodiments, the peptide is cyclized via a linkage between residues at X4 and X9 having a structure selected from the group consisting of:

[0328]

[0329] In some embodiments, the peptide cyclizes via a linkage between residues at X4and X9, having the structure:

[0330]

[0331] In some embodiments, the peptide comprises a linkage between R1and X 13 having a structure selected from:

[0332]

[0333] In some embodiments, the peptide comprises a linkage between X3and X 13 having a structure selected from:

[0334]

[0335] In some embodiments, the peptide comprises a linkage between X8and X 12 having the structure:

[0336]

[0337] In some embodiments, the peptide comprises a linkage between X 10 and X 13 having a structure selected from:

[0338]

[0339] In some embodiments, the peptide comprises a linkage between X 12 and X 16 having the structure:

[0340]

[0341] In some embodiments, the peptide comprises two linkages, one between X 12 and X8, and one between X 12 and X 16 having the structure:

[0342]

[0343]

[0344] In some embodiments, the peptide comprises a sequence according to any one of the following formulae:

[0345] R1-X3-Pen-X5-T-7MeW-X8-Pen-X10 -2Nal-X 12 -E-N-3Pya-X 16 -R2(I-E)

[0346] R1-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-X 13 -N-3Pya-R2(I-F)

[0347] R1-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-X 12 -E-N-3Pya-CONH2(I-J)

[0348] MeCO-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-E-N-3Pya-R2(I-K)

[0349] MeCO-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-E-N-3Pya-CONH2(I-L)

[0350] R1-X3-Pen-X5-T-7MeW-X8-Pen-X 10 -2Nal-X 12 -E-N-X 15 -X 16 -R2(I-M)

[0351] R1-X3-Abu-Q-T-X7-X8-C-X 10 -2Nal-X 12 -E-N-3Pya-X 16 -R2(I-N)

[0352] R1-X3-Abu-Q-T-X7-Q-C-X 10 -2Nal-X 12 -E-N-3Pya-X 16 -R2(I-O)

[0353] MeCO-X3-X4-K(Ac)-T-7MeW-X8-X9-X 10 -2Nal-X 12 -E-N-3Pya-Sar-R2(I-P)

[0354] R1-X3-X4-X5-T-X7-S5H-X9-X 10 -2Nal-B5-E-N-3Pya-S5H-R2(I-Q)

[0355] R1-X3-X4-X5-T-X7-S5H-X9-X 10 -2Nal-B5-E-N-3Pya-S5H-R2 (I-R)

[0356] R1-X3-Pen-X5-T-X7-S5H-Pen-X 10 -2Nal-B5-E-N-3Pya-S5H-R2 (I-S)

[0357] In some embodiments, the amino acid at X3 is an L-amino acid. In some embodiments, the amino acid at X3 is a D-amino acid.

[0358] In some embodiments, the amino acid at X4 is an L-amino acid. In some embodiments, the amino acid at X4 is a D-amino acid.

[0359] In some embodiments, the amino acid at X5 is an L-amino acid. In some embodiments, the amino acid at X5 is a D-amino acid.

[0360] In some embodiments, T between X5 and X7 is an L-amino acid. In some embodiments, T between X5 and X7 is dT.

[0361] In some embodiments, the amino acid at X7 is an L-amino acid. In some embodiments, the amino acid at X7 is a D-amino acid.

[0362] In some embodiments, the amino acid at X8 is an L-amino acid. In some embodiments, the amino acid at X8 is a D-amino acid.

[0363] In some embodiments, the amino acid at X9 is an L-amino acid. In some embodiments, the amino acid at X9 is a D-amino acid.

[0364] In some embodiments, X 10 is an L-amino acid. In some embodiments, X 10 is a D-amino acid.

[0365] In some embodiments, X 10 and X 12 is an L-amino acid. In some embodiments, X 10 and X 12 is d2Nal.

[0366] In some embodiments, X 13 is an L-amino acid. In some embodiments, X 13 is a D-amino acid.

[0367] In some embodiments, N between X 13 and X 15 is an L-amino acid. In some embodiments, N between X 13 and X 15 is a dN.

[0368] In some embodiments, the amino acid at X 15 is an L-amino acid. In some embodiments, the amino acid at X 15 is a D-amino acid.

[0369] In some embodiments, the present disclosure provides a peptide described herein, provided that the peptide retains activity as an interleukin-23 receptor inhibitor.

[0370] The present disclosure further provides a peptide of any one of SEQ ID NOs: 1-8 as shown in Table 2, or a pharmaceutically acceptable salt thereof.

[0371] Table 2. Peptide Examples

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379] In the peptide sequences shown above, when a number in parentheses follows a particular residue, that residue is connected to another residue in the sequence that is represented by the same number. For example, in the sequence MeCO-Pen(3)-N-T-7MeW-K(Ac)-Pen(3)-AEF-2Nal-S5(4)-E-N-3Pya-S5H(4)-CONH2 (SEQ ID NO: 1), the two Pen(3) residues are connected to each other, and the S5(4) residue is connected to the S5H(4) residue.

[0380] Synthetic Methods

[0381] The compounds described herein can be synthesized by a number of techniques known to those of skill in the art. In some aspects, the disclosure provides methods of chemically synthesizing the peptides of the disclosure. In some aspects, a portion of the peptide is synthesized recombinantly, rather than chemically. In some aspects, the method of producing the peptide further comprises cyclizing the peptide precursor after the component subunits have been linked. In particular aspects, cyclization is accomplished via any of the various methods described herein.

[0382] The disclosure further describes synthesis of the compounds described herein. In some aspects, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently linked to one another to form a peptide of the disclosure. In some aspects, one or more of the amino acid residues or amino acid monomers are covalently linked to one another and lipidated at an intermediate oligomer stage prior to linking additional amino acids and cyclization to form a peptide of the disclosure. In some aspects, a cyclic peptide is synthesized and then lipidated to form a compound of the disclosure. Exemplary synthetic methods are described in the Examples below.

[0383] Pharmaceutical Compositions

[0384] The disclosure further relates to pharmaceutical compositions comprising the IL-23R inhibitors described herein. In particular, the disclosure includes pharmaceutical compositions comprising one or more peptides of the disclosure, and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutically acceptable carrier, diluent, or excipient can be a solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation auxiliary. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like.

[0385] The pharmaceutical compositions can be administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, rectally, topically (e.g., by powders, ointments, solutions, or patches), by inhalation (e.g., as an aerosol), by ocular (e.g., as an ophthalmic solution), or bucally. As used herein, the term "parenterally" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intraarticular injection and infusion. Thus, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration. The pharmaceutical compositions can be formulated for oral and oral administration. The pharmaceutical compositions can be formulated for parenteral and parenteral administration.

[0386] The IL-23R inhibitors of the present disclosure can be prepared and / or formulated as their pharmaceutically acceptable salts and / or other forms, or as the neutral form when appropriate. Pharmaceutically acceptable salts are non-toxic salts of the neutral forms of the compounds which possess the desired pharmacological activity of the neutral form. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21stEd., Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0387] The present disclosure relates to pharmaceutical compositions comprising an IL-23R inhibitor described herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, wherein one or more hydrogen atoms attached to a carbon atom can be replaced with a deuterium atom or D. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism, and thus can be used to increase the half-life of a compound described herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized in ways known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0388] Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Isotopes that emit positrons (such as 11 C, 18 F,15 O and 13 N) Substitution can be useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled peptides of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described below using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.

[0389] When used in at least one of the therapeutic or delivery systems described herein, the peptide inhibitors of the present disclosure can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form.

[0390] The total daily dosage of the IL-23R inhibitors and compositions of the present disclosure can be decided by the attending physician, within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including: a) the disorder being treated and the severity of the disorder; b) the activity of the specific compound employed; c) the specific composition employed, the age, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific peptide inhibitor being employed; e) the duration of the treatment; f) drugs used in combination or coincidental with the specific peptide inhibitor employed, and like factors well known in the medical arts.

[0391] The compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Techniques and compositions generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

[0392] Non-invasive detection of intestinal inflammation

[0393] The IL-23R inhibitors of the present disclosure can be used for detection, assessment, and diagnosis of intestinal inflammation by microPET imaging, wherein the peptide inhibitors are labeled with a chelating group or a detectable label as part of a non-invasive diagnostic procedure. In certain embodiments, the IL-23R inhibitors of the present disclosure are conjugated to a bifunctional chelating agent. In certain embodiments, the IL-23R inhibitors of the present disclosure are radiolabeled. The labeled IL-23R inhibitors are then administered orally or rectally to a subject. In certain embodiments, the IL-23R inhibitors are included in drinking water. After uptake of the IL-23R inhibitors, inflammation in the intestines and digestive tract of the entire subject can be visualized using microPET imaging.

[0394] Methods of Treatment and Uses

[0395] The present disclosure relates to methods for treating a subject having a disorder or indication associated with IL-23 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), wherein the methods comprise administering to the subject an IL-23R inhibitor disclosed herein. In one aspect, the present disclosure provides a method for treating a subject having a disorder or indication characterized by abnormal or dysregulated IL-23 or IL-23R activity or signaling, the method comprising administering to the subject a peptide inhibitor of the present disclosure in an amount sufficient to inhibit (partially or completely) binding of IL-23 to IL-23R in the subject. The inhibition of IL-23 binding to IL-23R can occur specifically in a particular organ or tissue of the subject, such as the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's Patches, mesenteric lymph nodes, or lymphatic vessels.

[0396] The present disclosure relates to methods comprising providing a peptide inhibitor described herein to a subject in need thereof. The subject in need thereof can be a subject who has been diagnosed with a disease or disorder associated with IL-23 / IL-23R or who has been identified as being at risk of developing a disease or disorder associated with IL-23 / IL-23R. The subject can be a mammal. The subject can specifically be a human.

[0397] The disease or disorder to be treated by treatment with an IL-23R inhibitor of the present disclosure can be an inflammatory disease or disorder, an autoimmune inflammatory disease or disorder, and / or a related disorder, including multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, young adult IBD, Crohn’s disease, ulcerative colitis, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis or psoriasis. In particular, the disease or disorder can be psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne excoriee, ulcerative colitis, Crohn’s disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis following colectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, uveitis, or graft-versus-host disease.

[0398] The present disclosure provides a method or use of an IL-23R inhibitor for treating an inflammatory disease or disorder in a subject in need thereof, the method or use comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, or a composition comprising an IL-23 inhibitor of the present disclosure disclosed herein.

[0399] The present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune disease or disorder in a subject in need thereof, the method or use comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, or a composition comprising an IL-23 inhibitor of the present disclosure disclosed herein.

[0400] The present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune inflammatory disease or disorder in a subject in need thereof, the method or use comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, or a composition comprising an IL-23 inhibitor of the present disclosure disclosed herein.

[0401] Suitable inflammatory diseases, autoimmune inflammatory diseases, and / or related disorders for treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a composition comprising the same, can include, but are not limited to, inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA), and the like. The inflammatory disease to be treated can be inflammatory bowel disease (IBD), Crohn’s disease, or ulcerative colitis. The inflammatory disease to be treated can be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated can be psoriasis. The inflammatory disease to be treated can be psoriatic arthritis. The inflammatory disease to be treated can be IBD. The inflammatory disease to be treated can be Crohn’s disease. The inflammatory disease to be treated can be ulcerative colitis.

[0402] IL-23 production is abundant in the gut, where it is believed to play a key role in tipping the balance between tolerance and immunity through T cell-dependent and T cell- independent pathways of intestinal inflammation, through its influence on T helper 1 (Th1) and Th17-associated cytokines, and in limiting regulatory T cell responses in the gut, thus favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the key role of the IL-23 pathway in gut homeostasis. Peptides and methods for specifically targeting IL-23R from the luminal side of the gut can provide therapeutic benefit to IBD patients with localized inflammation of the gut tissue.

[0403] Accordingly, the present disclosure also provides a method of treating or preventing inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a peptide of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an IL-23 inhibitor as described herein. In some embodiments, the method is for treating or preventing inflammatory bowel disease (IBD). In some embodiments, the method is for treating or preventing Crohn’s disease (CD). In some embodiments, the method is for treating or preventing ulcerative colitis (UC).

[0404] Psoriasis, a chronic skin disease affecting about 2-3% of the general population, has been shown to be mediated by the body's T cell inflammatory response mechanism. IL-23 is believed to be one of several interleukins that play a key role in the pathogenesis of psoriasis, purportedly maintaining chronic autoimmune inflammation via induction of interleukin-17, regulatory T memory cells, and activation of macrophages. Expression of IL-23 and IL-23R has been shown to be increased in tissues of psoriasis patients, and antibodies that neutralize IL-23 have shown IL-23-dependent inhibition of psoriasis development in animal models of psoriasis. An orally bioavailable peptide inhibitor of IL-23 can provide a non-steroidal treatment option for mild-to-moderate psoriasis patients, and a treatment that does not require delivery by infusion for moderate-to-severe psoriasis patients.

[0405] Accordingly, the present disclosure also provides a method of treating or preventing psoriasis (PsO) or psoriatic arthritis (PsA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a peptide of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an IL-23 inhibitor as described herein. In some embodiments, the method is for treating or preventing psoriasis (PsO). In some embodiments, the method is for treating or preventing psoriatic arthritis (PsA).

[0406] The present disclosure further relates to a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in a subject (e.g., a subject in need thereof), the method comprising providing to the subject a peptide inhibitor of IL-23R described herein. In some embodiments, the present disclosure includes and provides a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in the GI tract of a subject (e.g., a subject in need thereof), the method comprising providing to the subject a peptide inhibitor of IL-23R of the present disclosure by oral administration. The amount of exposure (level) of the GI tissue (e.g., small intestine or colon) to the administered peptide inhibitor can be at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold greater than the exposure (level) in the blood. In particular embodiments, the present disclosure includes a method of selectively inhibiting IL23 or IL23R signaling (or binding of IL23 to IL23R) in the GI tract of a subject (e.g., a subject in need thereof), the method comprising providing to the subject a peptide inhibitor, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In another related embodiment, the present disclosure provides a method of inhibiting GI inflammation and / or neutrophil infiltration into the GI, the method comprising providing to a subject in need thereof a peptide inhibitor of the present disclosure. In some embodiments, the methods of the present disclosure comprise providing to a subject (e.g., a subject in need thereof) a peptide inhibitor of the present disclosure (i.e., a first therapeutic agent) in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is provided to the subject prior to and / or concurrently with and / or after administration of the peptide inhibitor to the subject. In particular embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a non-steroidal anti-inflammatory drug, a steroid, or an immunomodulatory agent. In certain embodiments, the method comprises administering to the subject a third therapeutic agent. In certain embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R.

[0407] The present disclosure relates to methods of inhibiting the binding of IL-23 to IL-23R on a cell, the methods comprising contacting the IL-23R with a peptide inhibitor of the receptor disclosed herein. The cell can be a mammalian cell. The method can be performed in vitro or in vivo. Inhibition of binding can be determined by a variety of routine experimental methods and assays known in the art.

[0408] The present disclosure relates to methods of inhibiting IL-23 signaling by a cell, the methods comprising contacting IL-23R with a peptide inhibitor described herein. In certain embodiments, the cell is a mammalian cell. In particular embodiments, the method is performed in vitro or in vivo. In particular embodiments, inhibition of IL-23 signaling can be determined by measuring changes in levels of phospho-STAT3 in the cell.

[0409] Examples

[0410] The following examples are not intended to limit the scope of the present disclosure, but rather to provide guidance to the skilled artisan for preparing and using the peptides, compositions, and methods of the present disclosure. While specific aspects of the present disclosure are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the present disclosure.

[0411] Some abbreviations that can be used to describe the present disclosure are defined below in the following table.

[0412] The following abbreviations can be used herein and throughout the application.

[0413]

[0414]

[0415] Table 3. N-terminal modification abbreviations

[0416]

[0417]

[0418] Table 4. C-terminal modification abbreviations

[0419]

[0420] The amino acid structures provided in Table 5 below are presented without stereochemical indicators at the alpha carbons; however, it is understood that the amino acids are present as L-amino acids or D-amino acids. For example, “Dap” can be present as an L-stereoisomer:

[0421]

[0422] or as a D-stereoisomer in the peptides of the present disclosure (e.g., when referred to as “dap,” “dDap,” or “D-Dap”):

[0423]

[0424] Table 5. Monomer abbreviations

[0425]

[0426]

[0427]

[0428]

[0429]

[0430] Example 1 : General procedure for solid phase synthesis of peptides

[0431] Peptides were chemically synthesized using an optimized 9-fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis protocol. For C-terminal amide, Rink-amide MBHA resin was used. Side chain protecting groups were as follows: Asp: OAll; Glu: OAll; Thr: O-t-butyl; Asn, Pen: trityl; AEF: Boc. For coupling, a two to five fold excess of a solution of Fmoc amino acid, HATU and DIEA (1 : 0.95:2) in DMF was added to the swelled resin for 1 hour to 48 hours. Double coupling was employed when coupling 2Nal. Removal of the Fmoc protecting group was achieved by treatment with a solution of DMF, piperidine (4: 1) for 30 minutes. This cycle was repeated until the full length peptide was obtained. Removal of the OAll protecting group on Glu was achieved by treatment with Pd(PPh3)4(0.1 equivalent), PhSiH3(10 equivalents) and DCM solution for 15 minutes * 3 times. For amide cyclization, a solution of DIC (3.0 equivalents) and HOBT (3.0 equivalents) in DMF was added to the swelled resin for 16 hours * 3 times. This cycle was repeated until the full length peptide was obtained. For RCM cyclization, a solution of Grubbs 1stgeneration (0.5 equivalents) in DCM was added to the swelled resin for 2 hours * 2 times under microwave conditions at 40 °C.

[0432] Certain materials and reagents are listed below.

[0433]

[0434]

[0435] General procedure for cleavage of peptides from resin

[0436] Side chain deprotection and cleavage of the peptide was achieved by stirring the dried resin in a solution of trifluoroacetic acid, water, DTT and triisopropylsilane (90:2.5:5:2.5) for 3 hours. The mixture was then filtered and cold methyl-tert-butyl ether (MTBE) was added to the combined filtrate to precipitate the peptide. The resulting mixture was centrifuged (3000 rpm, 3 minutes) and decanted. The pellet was washed with MTBE and centrifuged. The pellet was lyophilized to provide the linear peptide.

[0437] Procedure for ring closing metathesis (RCM)-cyclization

[0438] For RCM cyclization, the peptide was dissolved in dry DCM and stirred, then Grubbs 1stgeneration catalyst (0.5 eq) was added. The mixture was allowed to react at 40 °C for 16 hours. LCMS showed completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent.

[0439] General procedure for cyclization

[0440] To effect cyclization of the thiol-containing residue, a solution of iodine in MeOH (0.1 M) was added dropwise to a solution of the linear peptide (20% MeCN / H2O (1 mmol / L)) until the yellow color persisted. After about 2 hours, analysis by LCMS showed that the linear peptide was no longer present. Excess iodine was quenched by the addition of 1 M aqueous Na2S2O3 (immediately turned colorless).

[0441] General procedure for purification of peptides

[0442] Purification of the peptides was achieved using reverse phase high performance liquid chromatography (RP-HPLC). Purification of the cyclized peptides was achieved using preparative RP-HPLC with a C18 column at a flow rate of 20 mL / minute to 250 mL / minute. Separation was achieved using a gradient of buffer B in A (buffer A: 0.075% TFA in water; buffer B: ACN). (Note 1). Analysis was performed using a C18 column at a flow rate of 1 mL / minute (Note 2).

[0443] Note 1 : Preparative HPLC method

[0444] Preparative HPLC Method A: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B); Column: Welch XB-C18, 250*50 mm, 10 um, C18, 250*50 mm, 10 um, Flow rate: 80 mL / minute; Wavelength: UV 220 nm and 254 nm; Column temperature room temperature

[0445] Preparative HPLC Method B: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B); Column: YMC-Actus Triart C18, 250*30mm, 5um, Column; Flow rate: 20 mL / min; Wavelength: UV 220 nm and 254 nm; Column temperature room temperature

[0446] Note 2: Analytical HPLC method:

[0447] Mobile phase: 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B) using a gradient of 10-80% (solvent B) over 0.9 min and 80-90% over 0.6 min at a flow rate of 1.0 ml / min; Column: Xbridge C18, 3.5um, 2.1*30mm; Wavelength: UV 220 nm and 254 nm; Column temperature: 30°C; MS ionization: ESI

[0448] Example 2: Synthesis of SEQ ID NO: 3

[0449]

[0450] Peptides were synthesized using standard Fmoc chemistry.

[0451] 1) DMF and MBHA resin (0.30 mmol, 0.90 g, degree of substitution: 0.33 mmol / g) were combined in a vessel and the resin was allowed to swell for two hours.

[0452] 2) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0453] 3) The resin was then drained and washed with DMF for 30 seconds * 5 times.

[0454] 4) A Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, followed by the addition of a DMF solution of HATU and DIEA. The reaction was allowed to proceed under nitrogen for 1 to 4 hours.

[0455] 5) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0456] 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or chloranil color tests, and upon completion the resin was washed with DMF 5 times.

[0457] Once the peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum.

[0458] Monitoring methods:

[0459] 1. Indantrione test: A: 5% indantrione / EtOH; B: 80% phenol / EtOH; C: pyridine

[0460] 2. Tetrachloro color test: A: 2% tetrachloro / DMF; B: 2% aldehyde / DMF 110°C for 3 minutes

[0461] Detailed synthesis method for ring closing metathesis (RCM) cyclization:

[0462] For RCM cyclization: resin and Grubbs 1stgeneration catalyst (0.5 eq) in dry DCM were added to a microwave tube. The mixture was then heated under microwave conditions at 40 °C for 2 hours * 2 times, after which LCMS showed the desired product. The resin was then washed with DMF 5 times and with MeOH 3 times, then dried under vacuum.

[0463] Peptide cleavage:

[0464] 1) To the flask containing the side chain protected peptide was added 30 mL cleavage buffer (5.0% DTT / 2.5% H2O / 2.5% TIS / 90% TFA) at room temperature and the mixture was stirred for 3 hours.

[0465] 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 minutes) and decanted. The pellet was washed with MTBE and centrifuged.

[0466] 3) The residue was lyophilized to give Intermediate 1 (520 mg, 90.3% yield, crude).

[0467]

[0468] Peptide cyclization and purification:

[0469] The crude peptide intermediate 1 (520 mg, 0.271 mmol) was dissolved in 20% MeCN / H20 (300 mL). To the stirred solution of the peptide was added iodine in MeOH (0.1 M, 3.5 mL) dropwise until the solution color remained yellow. After about 2 hours, LCMS showed the reaction had completed. The excess iodine was quenched by the addition of 1 M aqueous Na2S203solution (15 pL) (immediately turned colorless). Then 10 mL to 20 mL of MeCN was added to reduce the turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in H20, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 3 as a white solid (38.4 mg, 96.4% purity, yield for this step: 6.37%; overall yield: 5.75%). Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0470] LCMS summary: Method: 10-80-2min-1.5_P2.amx, Ret Time: 1.518 min, Calcd MW: 1917.25, Obs MW: 959.3 [(M+2H) / 2].

[0471] Example 3: Synthesis of SEQ ID NO: 2

[0472]

[0473] The peptides were synthesized using standard Fmoc chemistry.

[0474] 1) DMF and MBHA resin (0.30 mmol, 0.90 g, degree of substitution: 0.33 mmol / g) were combined in a vessel and the resin was allowed to swell for two hours.

[0475] 2) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0476] 3) The resin was then drained and washed with DMF for 30 seconds * 5 times.

[0477] 4) A Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, followed by the addition of a DMF solution of HATU and DIEA. The reaction was allowed to proceed for 1 to 4 hours under nitrogen.

[0478] 5) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0479] 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or chloranil color tests, and upon completion the resin was washed with DMF 5 times. Once the peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum.

[0480] Monitoring methods:

[0481] 1. Ninhydrin test: A: 5% ninhydrin / EtOH; B: 80% phenol / EtOH; C: pyridine

[0482] 2. Tetrachloro color test: A: 2% tetrachloro / DMF; B: 2% aldehyde / DMF 110°C for 3 minutes Detailed synthesis method for ring closing metathesis (RCM) cyclization: Peptide cleavage:

[0483] For RCM cyclization: resin and Grubbs 1stgeneration catalyst (0.5 eq) in dry DCM were added to a microwave tube. The mixture was then heated under microwave conditions at 40 °C for 2 hours * 2 times, after which LCMS showed the desired product. The resin was then washed with DMF 5 times and with MeOH 3 times, then dried under vacuum.

[0484] Peptide cyclization and purification:

[0485] 1) To the flask containing the side chain protected peptide was added 30 mL cleavage buffer (5.0% DTT / 2.5% H2O / 2.5% TIS / 90% TFA) at room temperature and the mixture was stirred for 3 hours.

[0486] 2) The mixture was filtered and washed with 5 mL TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 minutes) and decanted. The pellet was washed with MTBE and centrifuged.

[0487] 3) The residue was lyophilized to give intermediate 2 (500 mg, 90.6% yield, crude).

[0488]

[0489] Example 4: Synthesis of SEQ ID NO: 5

[0490] The crude peptide intermediate 2 (500 mg, 0.272 mmol) was dissolved in 20% MeCN / H2O (300 mL). To the stirred solution of the peptide was added iodine in MeOH (0.1 M, 3.5 mL) dropwise until the solution color remained yellow. After about 2 hours, LCMS showed the reaction had completed. The excess iodine was quenched by the addition of 1 M aqueous Na2S203solution (15 μL) (immediately turned colorless). Then 10 mL to 20 mL of MeCN was added to reduce the turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method A) to give the peptide of SEQ ID NO: 2 as a white solid (38.3 mg, 98.0% purity, yield for this step: 6.69%; overall yield: 6.06%). Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0491] LCMS summary: Method: 10-80-2min-1.5_P2.amx, Ret Time: 1.497 min, Calcd MW: 1837.13, Obs MW: 919.2 [(M+2H) / 2].

[0492] Monitoring methods:

[0493]

[0494] The peptides were synthesized using standard Fmoc chemistry.

[0495] 1) DMF and MBHA resin (0.30 mmol, 0.96 g, degree of substitution: 0.31 mmol / g) were combined in a vessel and the resin was allowed to swell for two hours.

[0496] 2) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0497] 3) The resin was then drained and washed with DMF for 30 seconds * 5 times.

[0498] 4) A Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, followed by the addition of a DMF solution of HATU and DIEA. The reaction was allowed to proceed for 1 to 4 hours under nitrogen.

[0499] 5) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0500] 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or chloranil color tests, and upon completion the resin was washed with DMF 5 times. Once the peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum.

[0501] Detailed synthesis method for amide cyclization:

[0502] 1. Ninhydrin test: A: 5% ninhydrin / EtOH; B: 80% phenol / EtOH; C: pyridine

[0503] 2. Tetrazolium color test: A: 2% tetrazolium / DMF; B: 2% aldehyde / DMF 110°C for 3 minutes

[0504] Peptide cleavage:

[0505] De-OAll on Glu: The resin was washed with 50 mL DMF (3 x 0.1 min) and DCM (3 x 0.1 min) before the addition of PhSiH3(10 eq) and Pd(PPh3)4(0.1 eq) in DCM (10 mL). The mixture was allowed to react for 15 min and washed 5 times with alternating DCM (50 mL) and DMF (50 mL) until the solution turned colorless.

[0506] Amide cyclization on resin: After deprotection, the resin was washed with 50 mL DMF (5 x 0.1 min) before the addition of DIC (3 eq) and HOBT (3.0 eq) in DMF (50 mL). The coupling reaction mixture was allowed to react for 16 h. A ninhydrin color test showed a negative test. After the completion of the coupling reaction, the resin was washed with 50 mL DMF (3 x 0.1 min).

[0507] Peptide cyclization and purification:

[0508] 1) To the flask containing the side chain protected peptide, 30 mL of cleavage buffer (5.0% DTT / 2.5% H2O / 2.5% TIS / 90% TFA) was added at room temperature and the mixture was stirred for 3 h.

[0509] 2) The mixture was filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged.

[0510] 3) The residue was lyophilized to give intermediate 3 (550 mg, 92.5% yield, crude).

[0511]

[0512] Monitoring methods:

[0513] The crude peptide intermediate 3 (550 mg, 0.278 mmol) was dissolved in 20% MeCN / H20 (300 mL). To the stirred solution of the peptide was added iodine in MeOH (0.1 M, 2.5 mL) drop wise until the solution color remained yellow. After about 2 hours, LCMS showed that the reaction had completed. The excess iodine was quenched by the addition of 1 M aqueous Na2S203(15 pL) (immediately turned colorless). 10 mL to 20 mL of MeCN was added to reduce the turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in H20, B: ACN) (Note 1: Method B) to give the peptide of SEQ ID NO: 5 as a white solid (19.3 mg, 98.5% purity, yield for this step: 3.10%; overall yield: 2.87%). Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0514] LCMS summary: Method: 10-80-3min-1.5_P2.amx, Ret Time: 1.384 min, Calcd MW: 1979.33, Obs MW: 990.2 [(M+2H) / 2].

[0515] Example 5: Synthesis of SEQ ID NO: 4

[0516]

[0517] The peptides were synthesized using standard Fmoc chemistry.

[0518] 1) DMF and MBHA resin (0.5 mmol, 1.5 g, degree of substitution: 0.33 mmol / g) were combined in a vessel and the resin was allowed to swell for two hours.

[0519] 2) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0520] 3) The resin was then drained and washed with DMF for 30 seconds * 5 times.

[0521] 4) A Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, followed by the addition of a DMF solution of HATU and DIEA. The reaction was allowed to proceed for 1 to 4 hours under nitrogen.

[0522] 5) A 20% piperidine / DMF solution was added and the suspension was mixed for 30 minutes.

[0523] 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or chloranil color tests, and upon completion the resin was washed with DMF 5 times. Once the peptide synthesis was complete, the resin was washed with MeOH 3 times and dried by vacuum.

[0524] Peptide cleavage:

[0525] 1. Ninhydrin test: A: 5% ninhydrin / EtOH; B: 80% phenol / EtOH; C: pyridine

[0526] 2. Tetrachloro chromogenic test: A: 2% tetrachloro / DMF; B: 2% aldehyde / DMF 110°C for 3 minutes

[0527] Peptide cyclization and purification:

[0528] 1) To a flask containing the side chain protected peptide, 30 mL of cleavage buffer (5.0% DTT / 2.5% H2O / 2.5% TIS / 90% TFA) was added at room temperature and the mixture was stirred for 3 hours.

[0529] 2) The mixture was filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 minutes) and decanted. The pellet was washed with MTBE and centrifuged.

[0530] 3) The residue was lyophilized to give intermediate 4a (0.9 g, 74.6% yield, crude).

[0531]

[0532] Example 6: IL23R receptor assay

[0533] The crude peptide intermediate 4a (900 mg, 0.373 mmol) was dissolved in 20% MeCN / H2O (500 mL). To the stirred solution of the peptide, iodine in MeOH (0.1 M, 7.5 mL) was added dropwise until the solution color remained yellow. After about 2 hours, LCMS showed the reaction had completed. The excess iodine was quenched by the addition of 1 M aqueous Na2S2O3solution (20 uL) (immediately turned colorless). Then 10 mL to 20 mL of MeCN was added to reduce the turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in H2O, B: ACN) (Note 1: Method B) to give intermediate 4b (190 mg, 21.1% yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / minute (Note 2).

[0534]

[0535] Peptide intermediate 4b (190 mg, 0.079 mmol) was dissolved in dry DCM. To the stirred solution of the peptide, Grubbs 1stgeneration catalyst (33 mg, 0.5 eq) was added and the mixture was allowed to react at 40 °C for 16 h, at which time LCMS showed completion of the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent and purified by preparative HPLC (A: 0.075% TFA in H20, B: ACN) (Note 1: Method B) to obtain the peptide of SEQ ID NO: 4 as a white solid (10.5 mg, 94.8% purity, yield for this step: 4.64%; overall yield: 0.73%). Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0536] LCMS summary: Method: 10-80-2min-1.5_P2.amx, Ret Time: 1.565 min, Calcd MW: 2380.95, Obs MW: 1190.1 [(M+2H) / 2].

[0537] Table 6. IL-23 binding data

[0538] Compounds were serially diluted in 100% (v / v) DMSO and seeded into 1536-well untreated black assay plates (Corning #9146) using an Echo acoustic dispenser (Labcyte). 3 pL of HEK293 cells containing IL-23R, IL-12Rb1 and a firefly luciferase reporter driven by a STAT-inducible promoter (Promega) were added to the plates (4000 cells / well), followed by 3 pL of 10 ng / mL IL-23 (equivalent to EC 90 concentration). After 5 hours at 37 °C, 5% CO2, 95% relative humidity, the cells were placed at 20 °C and treated with BioGlo reagent (Promega) according to the manufacturer’s instructions. Luminescence was measured on a Pherastar FSX (BMG LabTech). Data were normalised against IL-23 treatment (0% inhibition) and 30 mM control inhibitor (100% inhibition) and IC 50 values were determined using a 4-parameter Hill equation. Data for example compounds are shown below.

[0539] A: IC 50 <0.01 mM;

[0540] B: 0.01 mM < IC 50 <0.5 mM;

[0541] C: 0.5 mM < IC 50

[0542] ND: Not determined

[0543] SEQ ID NO

[0544] ND IC 50 ]]> 1 A 2 A 3 C 4 A 5 A 6 A 7 Example 7: PBMC pSTAT3 assay 8 B

[0545] Table 7. PBMC pSTAT3 assay results

[0546] Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy donors were thawed and washed twice in ImmunoCult-XF T cell expansion medium (XF-TCEM) supplemented with CTL Anti-Aggregate Wash. Cells were counted, resuspended at 2-6 x 10 5 cells / mL in XF-TCEM supplemented with penicillin / streptomycin and 100 ng / mL IL-1β (BioLegend, 579404), and cultured in tissue culture flasks coated with anti-CD3 (eBioscience, 16-0037-85 or BD Pharmingen, 555329) at 37°C in 5% CO2. On day 4 of culture, PBMCs were collected, washed twice in RPMI-1640 supplemented with 0.1% BSA (RPMI-BSA), and incubated in RPMI-BSA in upright tissue culture flasks at 37°C in 5% CO2 for 4 hours. After this “fasting”, a total of 6 x 104cells in 30 μL RPMI-BSA were transferred to each well of a 384-well plate pre-dotted with peptide or DMSO. Cells were incubated for 30 minutes, then IL-23 was added at a final concentration of 5 ng / mL. Cells were stimulated with cytokine for 30 minutes at 37°C in 5% CO2, transferred to ice for 10 minutes, and lysed. Cell lysates were stored at -80°C until measurement of phosphorylated STAT3 using the Phospho-STAT Panel kit (Meso Scale Discovery, K15202D). Results are provided below.

[0547] A: IC < 1 nM 50 <1 nM;

[0548] B: 1 nM < IC < 10 nM 50 <10 nM;

[0549] C: 10 nM < IC 50 ;

[0550] ND: Not determined

[0551] ​

[0552]

[0553] While the foregoing specification teaches the principles of the present application, with examples provided for the purpose of illustration, it will be understood that the practice of the application encompasses all variations of the generic principles illustrated herein, which variations encompass all specific embodiments falling within the scope of the following claims and their equivalents.

Claims

1. A peptide of formula (I'), wherein the peptide of formula (I') comprises the following amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-X 15 -X 16 -R2(I'), Or its pharmaceutically acceptable salt, wherein: R1 is MeCO, 8Aoc, 7Ahp, 6Ahx, 5Ava, or cPEG3aCO; X3 is hK, a cyclic amino acid, or absent; X4 can be any amino acid; X5 is N, N(NMe2), Q, Q(NMe2) or a cyclic amino acid; X6 can be any amino acid; X7 is 7MeW or W; X8 is a K(Ac), K(NMeAc), Q, or a cyclic amino acid; X9 is any amino acid; X 10 It is AEF, APEG3F, F(4TzlAme2), TMAPF, or a cyclic amino acid; X 12 It is THP or a cyclic amino acid; X 13 It is an E or cyclic amino acid; X 15 It is 3Pya, bAla, or a cyclic amino acid; X 16 It is Sar, a cyclic amino acid, or absent; R2 is either CONH2 or CONMe2; in: (a) A first cyclic amino acid is linked to a second cyclic amino acid to form a first ring comprising 4 to 11 or 14 amino acids; and a third cyclic amino acid is linked to a fourth cyclic amino acid to form a second ring comprising 4 to 11 or 14 amino acids; or (b) A first cyclic amino acid is linked to a second cyclic amino acid to form a first ring comprising 4 to 11 or 14 amino acids; and a third cyclic amino acid is linked to the C-terminus of the peptide to form a second ring comprising 4 to 11 or 14 amino acids.

2. The peptide according to claim 1, wherein the peptide comprises the amino acid sequence of formula (I): R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -NX 15 -X 16 -R2(I), or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO, 8Aoc, 7Ahp, or cPEG3aCO; X3 is R7H, S7H, hK or does not exist; X4 is 4-aminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl) or Pra; X5 is N, N(NMe2), Q, or Q(NMe2); X7 is 7MeW or W; X8 is K(Ac), R5H, S5H, K(NMeAc), or Q; X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X 10 It is AEF, APEG3F, F(4TzlAme2) or TMAPF; X 12 It is R5, S5, B5 or THP; X 13 It is E, R5H or S5H; X 15 It is either 3Pya or bAla; X 16 It is R5H, S5H, Sar, or it does not exist; R2 is either CONH2 or CONMe2; When X3 is R7H or S7H, then X5 is N(Me2) or Q(NMe2). X8 is K(NmeAc), or X 10 It is APEG3F; The peptide is cyclized in the following manner: (a) The first bond between the residue at X4 and the residue at X9; as well as (b) Select the second key link from the group consisting of the following: 8Aoc at R1 and X 13 The bonding between E at the location, 7Ahp at R1 and X 13 The bonding between E at the location, R7H or S7H at X3 and X 13 The bonding between R5H or S5H at the location, hk at X3 and X 13 The bonding between E at the location, R5H or S5H at X8 and X 12 The bonding between R5 or S5 at the location, X 10 F(4TzlAme2) and X at the location 13 The bonding between E at the location, X 10 AEF and X at the location 13 The bonding between E at the location; X 12 R5 or S5 at X 16 The bonding between R5H or S5H at the location; and X 12 Between B5 and R5H or S5H at X8 and X 12 B5 and X at the location 16 The two bonds between R5H or S5H at the location.

3. The peptide or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein when X3 is hk, then X 15 It is bAla; 4. The peptide or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein the peptide has an amino acid sequence of formula (IA): R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(I-A) in: R1 is MeCO, 8Aoc, or cPEG3aCO; X5 is N or N(NMe2); and X 16 It is either S5H or Sar.

5. The peptide according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence of formula (IB): R1-X3-Pen-X5-T-7MeW-X8-Pen-X 10 -2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(I-B) in: R1 is MeCO, 8Aoc, or cPEG3aCO; X5 is N or N(NMe2); X8 is K(Ac), S5H, or K(NMeAc); and X 16 It is either S5H or Sar.

6. The peptide according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the peptide has an amino acid sequence of formula (IC): R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-THP-X 13 -N-3Pya-X 16 -R2(I-C) in: X8 is K(Ac), K(NMeAc), or Q; and X 16 It is either Sar or does not exist.

7. The peptide or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein the peptide has an amino acid sequence of formula (ID): R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -E-N-3Pya-X 16 -CONH2(I-D) in: R1 is either MeCO or 8Aoc; X3 does not exist; X5 is N or Q; X8 is K(Ac), S5H, or Q; X 10 It is AEF or F(4TzlAme2); and X 16 It is either S5H or Sar.

8. The peptide or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein the peptide has a sequence according to any one of formulas IE to IK: R1-X3-Pen-X5-T-7MeW-X8-Pen-X 10 -2Nal-X 12 -E-N-3Pya-X 16 -R2(I-E)R1-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-X 13 -N-3Pya-R2(I-F) R1-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-X 12 -E-N-3Pya-CONH2(I-J) MeCO-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-EN-3Pya-R2(IK).

9. The peptide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: X4 is a Pen, and X9 is a Pen; or X4 is Abu, and X9 is C.

10. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bond is 8Aoc at R1 and X 13 Amide bonds between E atoms at the location.

11. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bond is X. 10 AEF and X at the location 13 The amino bonds between E at the site.

12. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bonding is R7H or S7H at X3 with X. 13 Aliphatic bonds between R5H or S5H at the site.

13. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bond is hK at X3 and X. 13 Amide bonds between E atoms at the location.

14. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bonding is R5H or S5H at X8 with X. 12 Aliphatic bonds between R5 or S5 at the location.

15. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bond is X. 10 F(4TzlAme2) and X at the location 13 Ester bonds between E atoms at the site.

16. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bond is X. 12 R5 or S5 at X 16 Aliphatic bonds between R5H or S5H at the site.

17. The peptide of claim 2 or a pharmaceutically acceptable salt thereof, wherein the second bond is: X 12 Between B5 and R5H or S5H at X8; and X 12 B5 and X at the location 16 Two aliphatic bonds between R5H or S5H at the location.

18. The peptide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or 12 to 17, wherein R1 is MeCO.

19. The peptide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R2 is CONH2.

20. The peptide of claim 1, wherein the first ring comprises 4 to 9 or 11 amino acids.

21. The peptide of claim 1, wherein the first ring is at X4 and X9, X4 and X 13 X5 and X 10 X3 and X 13 It may be formed between X6 and X9.

22. The peptide of claim 21, wherein the first ring is at X4 and X9, X4 and X 13 It may be formed between X6 and X9.

23. The peptide of claim 22, wherein the first ring is formed between X4 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles.

24. The peptide of claim 22, wherein the first ring is connected at X4 and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles. 13 Formed between them.

25. The peptide of claim 22, wherein the first ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles.

26. The peptide according to claim 1 or any one of 20 to 25, wherein the second ring comprises 4, 6, 10 or 11 amino acids.

27. The peptide according to claim 1 or any one of 20 to 26, wherein the second ring is at X5 and X 10 X3 and X 13 or X 13 It forms between the N-terminus of the peptide.

28. The peptide according to claim 23, wherein: The second ring is connected at X3 and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles. 13 Formed between; The second ring is connected at X5 and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles. 10 Formed between; The second ring is connected via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles at X. 10 With X 13 Formed between; or The second ring is connected via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles at X. 13 It forms between the N-terminus of the peptide.

29. The peptide according to claim 24, wherein: The second ring is connected at X5 and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles. 10 Formed between; or The second ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles.

30. The peptide according to claim 25, wherein: The second ring is connected at X3 and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles. 13 Formed between; The second ring is connected at X4 and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles. 13 Formed between; The second ring is connected at X5 and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles. 10 Formed between; The second ring is connected via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles at X. 10 With X 13 Formed between; or The second ring is connected via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, alkenes, ethers, alkylene compounds, and triazoles at X. 13 It forms between the N-terminus of the peptide.

31. A peptide or a pharmaceutically acceptable salt thereof, said peptide having an amino acid sequence of any one of SEQ ID NO: 1-6 or 8.

32. A pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, and a pharmaceutically acceptable carrier.

33. A method for treating a disease or disorder associated with interleukin-23 (IL-23) / interleukin-23 receptor (IL-23R), the method comprising administering to a subject in need a therapeutically effective amount of the peptide according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 20.

34. The method of claim 21, wherein the disease or disorder is selected from: multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, young adult IBD, Crohn's disease, ulcerative colitis, celiac disease (non-tropical stomatitis), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiotherapy or chemotherapy, colitis associated with congenital immune disorders such as leukocyte adhesion defect-1, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, reversal psoriasis, pustular psoriasis). Herpetic psoriasis, palmoplantar pustulosis, psoriasis vulgaris or erythrodermic psoriasis), atopic dermatitis, acne atopic, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis following rectocele and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, virus-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis or graft-versus-host disease.

35. The method of claim 21, wherein the disease or disorder is selected from: ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

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