Polycyclic peptide inhibitors of the interleukin-23 receptor

Abstract

The present disclosure relates to peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 480,042, filed January 16, 2023, which is incorporated herein by reference in its entirety.

[0002] (Incorporating sequence listing) The Sequence Listing in ST.26 XML format, entitled 739655_NTT-4252PC_SL, created on January 13, 2024, containing 29,940 bytes, prepared in accordance with 37 CFR 1.822-1.824, and submitted contemporaneously with the filing of this application, is hereby incorporated by reference in its entirety. [Background technology]

[0003] The interleukin-23 (IL-23) cytokine is a unique p19 subunit and a T helper 1 (T) subunit that produces interferon-γ (IFN-γ). H 1) IL-23 is a heterodimer composed of IL-12, a cytokine involved in cell development, and a shared p40 subunit. IL-23 and IL-12 both contain the p40 subunit, but have different phenotypic properties. For example, IL-12-deficient animals are prone to inflammatory autoimmune diseases, whereas IL-23-deficient animals are less susceptible to these diseases, possibly due to the CD4+ receptors that produce IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. +This is due to the lower number of T cells. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. IL-23 binding to IL-23R activates the Jak-Stat signaling molecules Jak2, Tyk2, Stat1, Stat3, Stat4, and Stat5. However, compared with IL-12, activation of Stat4 is substantially weaker, and distinct DNA-binding Stat complexes are formed in response to IL-23. IL-23R constitutively associates with Jak2 and with Stat3 in a ligand-dependent manner. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0004] IL-23 has been implicated as playing an important role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), e.g., ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed a key role for the interleukin-23 receptor (IL-23R) and downstream effector cytokines in the pathogenesis of disease. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are abundant in the intestine. Increased gene expression and protein levels of IL-23R have been found at the intestinal mucosal surface in IBD patients. IL-23 acts as a signaling pathway for pathogenic CD4 T cells, which produce IL-6, IL-17, and tumor necrosis factor (TNF). + It is thought to mediate this effect by promoting the development of T cell populations.

[0005] Thus, there remains a need for compositions that bind to IL-23R to inhibit IL-23 binding and signaling in patients. Summary of the Invention [Means for solving the problem]

[0006] Provided herein are peptide inhibitors of interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, and methods and / or uses of IL-23R inhibitors for the treatment of inflammatory diseases, autoimmune diseases, and / or related disorders.

[0007] In particular, the present disclosure provides a method for producing a medicament comprising the amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -NX 15 -X 16 -R2(I') or a pharmaceutically acceptable salt thereof, wherein X3, X4, X5, X6, X7, X8, X9, X 10 , X 12 , X 13 , X 15 , and X 16 Each of these is defined herein.

[0008] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: 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 X3, X4, X5, X7, X8, X9, X 10 , X 12 , X 13 , X 15 , and X 16 Each of these is defined herein.

[0009] The present disclosure further provides a pharmaceutical composition comprising a peptide described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] The present disclosure still further provides a method for treating an interleukin-23 (IL-23) / interleukin-23 receptor (IL-23R)-associated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide or 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 OF THE INVENTION

[0011] Provided herein are peptide inhibitors of IL-23R, and pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, and methods and / or uses for the treatment of inflammatory diseases, autoimmune diseases, and / or related disorders.

[0012] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those skilled in the art.

[0013] As used in the specification and claims, the terms "comprise(s)", "comprising", "include(s)", "having", "has", "can", "contain(s)", and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of specified features, groups, components, or steps and do not preclude the presence of additional features, groups, components, or steps. For example, "the amino acid sequence: X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12-X 13 -NX 15 -X 16 The term "peptide of formula (I) comprising (I)" refers to a peptide of formula (I) comprising amino acids X3 to X 17 This means, but is not limited to, that the peptide may include, in addition to, additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, N- or C-terminal capping groups, chemical or biological moieties conjugated to the peptide at any position (including, but not limited to, for example, lipophilic substituents, antibodies, imaging agents, etc.). The terms "comprise(s)", "comprising", "include(s)", "having", "has", "can", or "contain(s)" can include embodiments encompassed by the terms "consisting essentially of" or "consisting of".

[0014] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and typically refer to molecules 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.).

[0015] Unless otherwise indicated, both naturally occurring L-amino acids and D-amino acids are represented by either the conventional three letter or uppercase single letter amino acid symbols in Table 1. In some embodiments, naturally occurring L-amino acids are represented by either the conventional three letter or uppercase single letter amino acid symbols in Table 1. In some embodiments, D-amino acids are represented by lowercase single letter amino acid symbols corresponding to the single letter symbols in 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.

[0016] [Table 1]

[0017] As used herein, the term "L-amino acid" refers to the "L" isomeric form of an amino acid, and conversely, the term "D-amino acid" refers to the "D" isomeric form of an amino acid (e.g., (D)Asp or D-Asp, (D)Phe, or D-Phe). Any L-amino acid residue may be substituted with the D-isomer form of the amino acid residue, so long as the peptide retains the desired function. D-amino acids, when referred to using single-letter abbreviations, may by convention be designated by a lowercase letter. For example, D-arginine may be designated as "arg" or "r". Alternatively, a lowercase "d" may be used before an amino acid to indicate its D-isomer form, for example, D-lysine may be designated as dK.

[0018] For less common or non-naturally occurring amino acids, when not referred to by their full name (e.g., sarcosine, ornithine, etc.), the frequently used three- or four-letter abbreviation for the residue is used, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0019] The D-isomer form of an amino acid may be any of the positions in the IL-23R inhibitors described herein (e.g., X3 through X4 appearing in the molecule). 16 In some embodiments, the D-isomer form of an amino acid may be at any of X3, X5, X6, X8, X 13 In other embodiments, the D-isomer form of an amino acid may be located at only one or more of X, X, X, and optionally one additional position. 13 In other embodiments, the D-isomer form of an amino acid may be located at only one or more of X, X, and optionally one additional position. 13, and optionally one additional position. In other embodiments, the D-isomer form of an amino acid may be located only at X3 and optionally one additional position. In other embodiments, the D-isomer form of an amino acid may be located only at X3 and optionally two or three additional positions. In other embodiments, the D-isomer form of an amino acid may be located only at positions X3 through X4 appearing in the IL-23R inhibitors described herein. 16 In other embodiments, the D-isomer form of an amino acid may be located at only one or two of positions X3 through X4 appearing in the IL-23R inhibitors described herein. 16 For example, positions X3 to X 15 The IL-23R inhibitors described herein may have the D-isomer form of the amino acid present at three or four of these positions. In other embodiments, the D-isomer form of the amino acid is present at positions X3 through X4 that appear in the IL-23R inhibitors described herein. 17 In other embodiments, the D-isomer form of an amino acid may be located at only five or six of positions X3 through X4 appearing in the IL-23R inhibitors described herein. 16 can be located in only one or less of the

[0020] Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also contain additional groups that modify the amino acid chain, such as functional groups added by post-translational modifications. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation. The term "peptide" also includes peptides containing modifications of the amino and / or carboxy termini. Modifications of the terminal amino group include, but are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., lower alkyl is C1-C4 alkyl). The term "peptide" also includes modifications of amino acids between the amino and carboxy termini, such as, but not limited to, those described above.

[0021] As will be apparent to one of skill in the art, peptide sequences disclosed herein are presented from left to right, with the left-hand end of the sequence being the N-terminus of the peptide and the right-hand end of the sequence being the C-terminus of the peptide. Some sequences disclosed herein incorporate either an "-OH" or an "-NH" moiety at the carboxy-terminus (C-terminus) of the sequence. In such cases, unless otherwise indicated, the "-OH" or "-NH" moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, respectively, corresponding to the presence of a carboxylic acid (COOH) or amide (CONH) group at the C-terminus. In each sequence of the present disclosure, the C-terminal "-NH" moiety may be substituted for a C-terminal "-OH" moiety, or vice versa.

[0022] As used herein, the phrases "amino acid," "amino acid residue," or "residue" refer to an amino acid, modified amino acid, amino acid analog, or amino acid mimetic that is incorporated into a peptide by an amide bond or amide bond mimetic.

[0023] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions proposed by the IUPAC Commission in Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)," Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims deviate from these proposals, they 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 parentheses, e.g., lysine is designated as [K].

[0024] Those skilled in the art will understand that certain amino acids and other chemical moieties are modified when attached to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain; for example, one or more hydrogens may be removed or replaced upon attachment.

[0025] The term "therapeutically effective amount" or "pharmaceutically effective amount" refers to that amount of active peptide or drug that elicits the biological or medical response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician, including preventing, treating, or ameliorating the symptoms of the syndrome, disorder, or disease being treated.

[0026] The term "pharmaceutically acceptable" means approved or appropriable by a regulatory agency of the U.S. federal or state government, or a corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans.

[0027] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0028] As used herein, a "composition" or "pharmaceutical composition" is intended to encompass a product that includes a specific active pharmaceutical ingredient (API) (i.e., a peptide of the present disclosure), which may include a pharmaceutically acceptable excipient, carrier, or diluent as described herein, e.g., in specific amounts defined throughout this disclosure.

[0029] The composition or pharmaceutical composition of the present disclosure may be in different pharmaceutically acceptable forms, including, but not limited to, liquid compositions, tablet or matrix compositions, capsule compositions, etc. When the composition is a tablet composition, the tablet may include, but is not limited to, two or more different phases, including an internal phase that may include a core and an external phase. The tablet composition may also include, but is not limited to, one or more coatings.

[0030] Pharmaceutically acceptable salts and tautomeric forms of the peptides described herein are also provided.

[0031] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or free base of a peptide represented by Formula (I) that is non-toxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. It should retain the desired pharmacological activity of the parent compound. See generally 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 patient tissues without undue toxicity, irritation, or allergic response. The peptides of formula (I) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and therefore may react with many inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0032] The IL-23R inhibitors of the present disclosure, their pharmaceutically acceptable salts, and / or other forms thereof may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined with respect to absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers of the IL-23R inhibitors of the present disclosure, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to encompass both the E and Z geometric isomers. Likewise, all tautomeric forms are intended to be encompassed. Where compounds are represented in their chiral form, it is understood that the embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that the embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms; or racemic or scalemic mixtures of such compounds.

[0033] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0034] "Stereoisomer" refers to a compound that differs in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. When a compound has one or more asymmetric centers or double bonds with asymmetric substitution, it may exist in stereoisomeric forms and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise indicated, the description is intended to encompass individual stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0035] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0036] "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 "scalemic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0037] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, e.g., enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to both the -NH- and =N- rings, e.g., pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0038] The term "administering" with respect to the methods of the present invention means a method for therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder, or disease described herein by using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof. Such a method comprises administering a therapeutically effective amount of a peptide of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof, either simultaneously or sequentially at different times during the course of treatment or as a combination therapy.

[0039] "Patient" or "subject" are used interchangeably and refer to an organism, preferably a mammal, most preferably a human, that is to be treated or has been treated by a method according to an embodiment of the present application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, and the like, more preferably humans.

[0040] As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent (i.e., a compound of the present disclosure (alone or in combination with another pharmaceutical agent)) to a patient having a disorder or disease, symptoms thereof, or likelihood of developing such a disorder or disease as described herein, or to isolated tissue or cell lines derived from a patient (e.g., for diagnostic or ex vivo applications), with the purpose of curing, curing, alleviating, mitigating, altering, curing, ameliorating, improving, or affecting the disorder or disease, symptoms thereof, or likelihood of developing said disorder or disease. Such treatments may be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics.

[0041] As used herein, the term "prevent" or "prevention" means the complete absence of onset of a disorder or disease in cases where no onset of a disorder or disease has occurred, or the absence of further onset of a disorder or disease in cases where there has already been onset of a disorder or disease. The ability of an individual to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In the chemical arts, dashes at the beginning or end of chemical groups are for convenience; chemical groups may be designated with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in structures indicate the point of attachment of the group. Dashed lines indicate optional bonds. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or the point at which a chemical group is attached to the remainder of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be linked in either direction. Similarly, "arylalkyl" groups, for example, can be attached to the remainder of the molecule at either the aryl or alkyl portion of the group. "C u~v " or (C u ~C v ) indicates that the following group has u to v carbon atoms. For example, "C 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has from 1 to 6 carbon atoms.

[0043] Furthermore, within the scope of the present invention, particularly when referring to the peptides of the present disclosure, or pharmaceutically acceptable salts thereof, any element is intended to include all isotopes and isotopic mixtures of that element, whether occurring in nature or synthetically produced, in either natural abundance or isotopically enriched form. For example, a reference to hydrogen includes within its scope: 1 H, 2 H (i.e., deuterium or D), and3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. For example, -C (1~6) A group represented by alkyl includes not only -CH but also CD, not only CHCH but also CDCD, etc. Similarly, references to carbon and oxygen include, within their scope, respectively: 12 C. 13 C, and 14 C, and 15 O, and 16 O, and 17 O, and 18 These isotopes may be radioactive or non-radioactive. Radiolabeled compounds of the present disclosure include: 3 H, 11 C. 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 The radioisotope may comprise a radioisotope selected from the group including Br. Preferably, the radioisotope is 3 H, 11 C, and 18 It is selected from the group F.

[0044] The abbreviation "(V / V)" refers to the phrase "volume for volume," i.e., the proportion of a particular substance in a mixture as measured by the volume or amount by volume of a component of a composition disclosed herein relative to the total volume of the composition. Thus, the amount is unitless and represents the volume percentage 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 100 mL of solvent mixture.

[0045] "Bioavailability" refers to the extent and rate at which an active moiety (drug or metabolite) enters the systemic circulation and thereby accesses the site of action. The bioavailability of a drug can be affected by factors such as the properties of the dosage form and the properties of the drug.

[0046] As used herein, "gastrointestinal tissue" refers to all tissues comprising the organs of the gastrointestinal tract. By way of example only, "gastrointestinal tissue" includes, but is not limited to, tissues of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.

[0047] compound The present invention provides peptide inhibitors of the interleukin-23 receptor. In particular, the disclosure provides peptide inhibitors of the interleukin-23 receptor having the amino acid sequence: R1-X3-X4-X5-X6-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, 6Ahx, 5Ava, or cPEG3aCO; X3 is hK, a ring-forming amino acid, or absent; X4 is any amino acid, X5 is N, N(NMe2), Q, Q(NMe2), or a ring-forming amino acid; X6 is any amino acid, X7 is 7MeW or W, X8 is K(Ac), K(NMeAc), Q, or a ring-forming amino acid; X9 is any amino acid, X 10 is AEF, APEG3F, F(4TzlAme2), TMAPF, or a ring-forming amino acid; X 12 is THP or a ring-forming amino acid, X 13 is E or a ring-forming amino acid, X15 is 3Pya, bAla, or a ring-forming amino acid, X 16 is Sar, a ring-forming amino acid, or is absent, R2 is CONH2 or CONMe2, (a) a first ring-forming amino acid is linked to a second ring-forming amino acid to form a first ring containing from 4 to 11 or 14 amino acids, and a third ring-forming amino acid is linked to a fourth ring-forming amino acid to form a second ring containing from 4 to 11 or 14 amino acids; or (b) a first ring-forming amino acid is linked to a second ring-forming amino acid to form a first ring containing 4 to 11 or 14 amino acids, and a third ring-forming amino acid is linked to the C-terminus of the peptide to form a second ring containing 4 to 11 or 14 amino acids.

[0048] Non-limiting examples of ring-forming 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.

[0049] In some embodiments, the first ring comprises 4 to 9 or 11 amino acids. In some embodiments, the first ring comprises 4, 6, or 10 amino acids. In some embodiments, the first ring comprises 4 amino acids. In some embodiments, the first ring comprises 5 amino acids. In some embodiments, the first ring comprises 6 amino acids. In some embodiments, the first ring comprises 7 amino acids. In some embodiments, the first ring comprises 8 amino acids. In some embodiments, the first ring comprises 9 amino acids. In some embodiments, the first ring comprises 10 amino acids. In some embodiments, the first ring comprises 11 amino acids. In some embodiments, the first ring comprises 14 amino acids.

[0050] In some embodiments, the first ring comprises a bond between two ring-forming amino acids having a structure selected from the following:

[0051] [Table 2-1]

[0052] [Table 2-2]

[0053] [Table 2-3]

[0054] [Table 2-4]

[0055] [Table 2-5]

[0056] [Table 2-6]

[0057] In some embodiments, the first ring is between X4 and X9, between X4 and X 13 Between X5 and X 10 Between X3 and X 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 Between X5 and X 10 Between X3 and X 13In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X5 and X 10 Between X3 and X 13 and between X6 and X9.

[0058] In some embodiments, the first ring is between X4 and X9, between X4 and X 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and between X6 and X9.

[0059] In some embodiments, a first ring is formed between X4 and X9. In some embodiments, a first ring is formed between X4 and X9 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, a first ring is formed between X4 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0060] In some embodiments, the first ring is composed of X and X 13In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0061] In some embodiments, the first ring comprises X and X 10 In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 It is formed between.

[0062] In some embodiments, the first ring comprises X and X 13 In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0063] In some embodiments, the first ring is formed between X6 and X9 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 first ring is formed between X6 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0064] In some embodiments, the second ring comprises 4 to 9 or 11 amino acids. In some embodiments, the second ring comprises 4, 6, 10, or 11 amino acids. In some embodiments, the second ring comprises 4 amino acids. In some embodiments, the second ring comprises 5 amino acids. In some embodiments, the second ring comprises 6 amino acids. In some embodiments, the second ring comprises 7 amino acids. In some embodiments, the second ring comprises 8 amino acids. In some embodiments, the second ring comprises 9 amino acids. In some embodiments, the second ring comprises 10 amino acids. In some embodiments, the second ring comprises 11 amino acids. In some embodiments, the second ring comprises 14 amino acids.

[0065] In some embodiments, the second ring comprises a bond between two ring-forming amino acids having a structure selected from the following:

[0066] [Table 3-1]

[0067] [Table 3-2]

[0068] [Table 3-3]

[0069] [Table 3-4]

[0070] [Table 3-5]

[0071] [Table 3-6]

[0072] In some embodiments, the second ring comprises a bond between the N-terminus of the peptide and the ring-forming amino acid, which has a structure selected from the following:

[0073] [Table 4]

[0074] In some embodiments, the second ring is between X4 and X9, between X4 and X 13 Between X5 and X 10 Between X3 and X 13 In some embodiments, the second ring is formed between X4 and X9, or between X4 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 Between X5 and X 10 Between X3 and X 13 In some embodiments, the second ring is formed between X4 and X9, or between X4 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X5 and X 10 Between X3 and X 13 and between X6 and X9.

[0075] In some embodiments, the second ring is a ring consisting of X and X 10 Between or X3 and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 Between or X3 and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles. 10 Between or X3 and X 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 Between or X3 and X 13 It is formed between.

[0076] In some embodiments, a second ring is formed between X4 and X9. In some embodiments, a second ring is formed between X4 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. In some embodiments, a second ring is formed between X4 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles.

[0077] In some embodiments, the second ring is a ring formed from X and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0078] In some embodiments, the second ring is a ring consisting of X and X 10 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 It is formed between.

[0079] In some embodiments, the second ring is a ring consisting of X and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0080] In some embodiments, a second ring is formed between X6 and X9. In some embodiments, a second ring is formed between X6 and X9 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, a second ring is formed between X6 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0081] In some embodiments, the second ring is X 13 and the N-terminus of the peptide. In some embodiments, the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 and the N-terminus of the peptide. In some embodiments, the second ring is connected to X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and the N-terminus of the peptide.

[0082] In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles, and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0083] In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole, and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0084] In some embodiments, the first ring is connected to X and X 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. 13 and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 and between X6 and X9.

[0085] In some embodiments, the first ring is connected to X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 and between X6 and X9.

[0086] In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles, and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 Between X4 and X 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0087] In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole, and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X4 and X 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0088] In some embodiments, the peptide of formula (I') is a peptide of formula (I).

[0089] Thus, in some embodiments, the present disclosure provides a method for the treatment of a leukemia comprising administering to a patient ... 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 absent; X4 is 4AminoPro, 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 is AEF, APEG3F, F(4TzlAme2), or TMAPF, X 12 is R5, S5, B5, or THP; X 13 is E, R5H, or S5H, X 15 is 3Pya or bAla, X 16 is R5H, S5H, Sar or absent, R2 is CONH2 or CONMe2, When X3 is R7H or S7H, X5 is N(Me2) or Q(NMe2), and X8 is K(NmeAc), or X 10 But it is APEG3F, The peptide is (a) a first bond between residues at X4 and X9, and (b) 8Aoc and X in R1 13 The bond between E and 7Ahp and X in R1 13 The bond between E and R7H or S7H and X in X3 13 a bond between R5H or S5H in hK and X in X3 13 The bond between E and R5H or S5H and X in X8 12 a bond between R5 or S5 in X 10 F(4TzlAme2) and X in 13 The bond between E and X 10 AEF and X in 13 The bond between E and X 12 R5 or S5 and X in 16 a bond between R5H or S5H in X 12 Between B5 in and R5H or S5H in X8, and X 12 B5 and X in 16and R5H or S5H in the formula (I) are cyclized via a second bond selected from the group consisting of two bonds between R5H or S5H in the formula (I) and R5H or S5H in the formula (I).

[0090] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: 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 absent; X4 is 4AminoPro, 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 is AEF, APEG3F, F(4TzlAme2), or TMAPF, X 12 is R5, S5, B5, or THP; X 13 is E, R5H, or S5H, X 15 is 3Pya or bAla, X 16 is R5H, S5H, Sar or absent, R2 is CONH2 or CONMe2, When X3 is R7H or S7H, X5 is N(Me2) or Q(NMe2), and X8 is K(NmeAc), or X 10But it is APEG3F, The peptide is (c) a first bond between residues at X4 and X9, and (d) 8Aoc and X in R1 13 The bond between E and R7H or S7H and X in X3 13 a bond between R5H or S5H in hK and X in X3 13 The bond between E and R5H or S5H and X in X8 12 a bond between R5 or S5 in X 10 F(4TzlAme2) and X in 13 The bond between E and X 10 AEF and X in 13 The bond between E and X 12 R5 or S5 and X in 16 a bond between R5H or S5H in X 12 Between B5 in and R5H or S5H in X8, and X 12 B5 and X in 16 and R5H or S5H in the formula (I) are cyclized via a second bond selected from the group consisting of two bonds between R5H or S5H in the formula (I) and R5H or S5H in the formula (I).

[0091] In some embodiments, the peptide has the formula (IA): R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(IA) or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO, 8Aoc, or cPEG3aCO; X3 is R7H, S7H, hK or absent; X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is N or N(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 is AEF, APEG3F, F(4TzlAme2), or TMAPF, X 12 is R5, S5, B5, or THP; X 13 is E, R5H, or S5H, X 15 is 3Pya or bAla, X 16 is S5H or Sar, R2 is CONH2 or CONMe2, When X3 is R7H or S7H, X5 is N(Me2) and X8 is K(NmeAc), or X 10 But it is APEG3F, The peptide is (e) a first bond between residues at X4 and X9, and (f) 8Aoc and X in R1 13 The bond between E and R7H or S7H and X in X3 13 a bond between R5H or S5H in hK and X in X3 13 The bond between E and R5H or S5H and X in X8 12 a bond between R5 or S5 in X 10 F(4TzlAme2) and X in 13 The bond between E and X 10 AEF and X in 13The bond between E and X 12 R5 or S5 and X in 16 a bond between R5H or S5H in X 12 Between B5 in and R5H or S5H in X8, and X 12 B5 and X in 16 and R5H or S5H in the formula (I) are cyclized via a second bond selected from the group consisting of two bonds between R5H or S5H in the formula (I) and R5H or S5H in the formula (I).

[0092] In some embodiments, the peptide has the formula (IB): R1-X3-Pen-X5-T-7MeW-X8-Pen-X 10 -2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(IB) or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO, 8Aoc, or cPEG3aCO; X3 is R7H, S7H, hK or absent; X5 is N or N(NMe2), X8 is K(Ac), S5H, or K(NMeAc); X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF, X 12 is R5, S5, B5, or THP; X 13 is E, R5H, or S5H, X 16 is S5H or Sar, R2 is CONH2 or CONMe2, When X3 is R7H or S7H, X5 is N(Me2) or Q(NMe2), and X8 is K(NmeAc), or X 10 But it is APEG3F, The peptide is (g) a first bond between residues at X4 and X9, and (h) 8Aoc and X in R1 13 The bond between E and R7H or S7H and X in X3 13 a bond between R5H or S5H in hK and X in X3 13 The bond between E and R5H or S5H and X in X8 12 a bond between R5 or S5 in X 10 F(4TzlAme2) and X in 13 The bond between E and X 10 AEF and X in 13 The bond between E and X 12 R5 or S5 and X in 16 a bond between R5H or S5H in X 12 Between B5 in and R5H or S5H in X8, and X 12 B5 and X in 16 and R5H or S5H in the formula (I) are cyclized via a second bond selected from the group consisting of two bonds between R5H or S5H in the formula (I) and R5H or S5H in the formula (I).

[0093] In some embodiments, the peptide has the formula (IC): R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-THP-X 13 -N-3Pya-X 16 -R2(IC) or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO, 8Aoc, 7Ahp, or cPEG3aCO; X3 is R7H, S7H, hK or absent; X4 is 4AminoPro, 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), K(NMeAc), or Q; X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF, X 13 is E, R5H, or S5H, X 16 is Sar or absent, R2 is CONH2 or CONMe2, When X3 is R7H or S7H, X5 is N(Me2) or Q(NMe2), and X8 is K(NmeAc), or X 10 But it is APEG3F, The peptide is (i) a first bond between residues at X4 and X9, and (j) 8Aoc and X in R1 13 The bond between E and R7H or S7H and X in X3 13 a bond between R5H or S5H in hK and X in X3 13 The bond between E and R5H or S5H and X in X8 12 a bond between R5 or S5 in X 10 F(4TzlAme2) and X in 13 The bond between E and X 10 AEF and X in 13 and the ring is cyclized via a second bond selected from the group consisting of the bond between E in

[0094] In some embodiments, the peptide has the formula (ID): R1-X3-X4-X5-T-X7-X8-X9-X 10 -2Nal-X 12 -EN-3Pya-X 16-CONH2 (ID) wherein: R1 is MeCO or 8Aoc, X3 does not exist, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is N or Q; X7 is 7MeW or W, X8 is K(Ac), S5H, or Q; X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X 10 is AEF or F(4TzlAme2), X 12 is R5, S5, B5, or THP; X 16 is S5H or Sar, The peptide is (k) a first bond between residues X4 and X9, and (l) 8Aoc and X in R1 13 The bond between E and R5H or S5H and X in X8 12 a bond between R5 or S5 in X 10 F(4TzlAme2) and X in 13 The bond between E and X 10 AEF and X in 13 The bond between E and X 12 R5 or S5 and X in 16 a bond between R5H or S5H in X 12 Between B5 in and R5H or S5H in X8, and X 12 B5 and X in 16 and R5H or S5H in the formula (I) are cyclized via a second bond selected from the group consisting of two bonds between R5H or S5H in the formula (I) and R5H or S5H in the formula (I).

[0095] In some embodiments, R1 is 8Aoc, 7Ahp, cPEG3aCO, or MeOC, and 8Aoc is X 13 In some embodiments, R1 is 8Aoc, 7Ahp, cPEG3aCO, or MeCO, and 8Aoc is linked to an amino acid in X through an amino bond. 13 It is linked to the E residue in

[0096] 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.

[0097] In some embodiments, R is X 13 In some embodiments, R is an alkyl chain linked to an amino acid in X 13 In some embodiments, X is 8Aoc linked to an amino acid in 13 In some embodiments, R1 is 8Aoc linked to E in 13 In some embodiments, R1 is 7Ahp linked to an amino acid in X 13 In some embodiments, R1 is 7Ahp linked to E in the formula: In some embodiments, R1 is MeCO. In some embodiments, R1 is cPEG3aCO.

[0098] In some embodiments, X3 is hK, R7H, S7H, or is absent, and hK, R7H, and S7H are X 13 In some embodiments, X3 is hK, R7H, S7H, or is absent, and hK, R7H, and S7H are linked to an amino acid in X 13and hK is an L amino acid. In some embodiments, X3 is hk, R7H, S7H, or is absent, and hk, R7H, and S7H are linked to an amino acid in X 13 In some embodiments, X3 is hK, R7H, S7H, or absent. In some embodiments, X3 is hk, R7H, S7H, or absent.

[0099] In some embodiments, X3 is hk, R7H, S7H, or absent, and hk, R7H, and S7H are X 13 In some embodiments, X3 is hk, R7H, S7H, or absent, and hk, R7H, and S7H are connected to X through an aliphatic bond or an amide bond. 13 In some embodiments, X3 is hk, R7H, S7H, or is absent, and R7H and S7H are linked to X via an aliphatic bond. 13 In some embodiments, X3 is hk, R7H, S7H, or absent, and hk is connected to X via an amide bond. 13 It is linked to the E residue in

[0100] In some embodiments, X3 is R7H, hk, or absent. In some embodiments, X3 is hk, or absent.

[0101] In some embodiments, X is X 13 In some embodiments, X is R7H linked to an amino acid in 13 In some embodiments, X is R7H linked to R5H in X 13 In some embodiments, X is S7H linked to an amino acid in 13 In some embodiments, X is S7H linked to S5H in 13In some embodiments, X is an hk linked to an amino acid in 13 In some embodiments, X is an hk linked to E in X 13 In some embodiments, X is an hk linked to an amino acid in 13 In some embodiments, X3 is absent.

[0102] In some embodiments, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is 4AminoPro, 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, X4 is 4Amino-d-Pro, dAbu, d-aG, aMe-dC, c, dDap, dPen, dPen(oXyl), dPen(mXyl), dPen(pXyl), or dPra.

[0103] In some embodiments, X4 is 4AminoPro, aG, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is Abu, aMeC, C, Pen, Pen(oXyl), Pen(mXyl), or Pen(pXyl). In some embodiments, X4 is Abu, aMeC, C, or Pen. In some embodiments, X4 is Abu, C, or Pen. In some embodiments, X4 is Abu or Pen.

[0104] In some embodiments, X4 is 4AminoPro. In some embodiments, X4 is 4RAminoPro. In some embodiments, X4 is 4SAminoPro. In some embodiments, X4 is Abu. In some embodiments, X4 is aG. In some embodiments, X4 is aMeC. In some embodiments, X4 is C. In some embodiments, X4 is Dap. In some embodiments, X4 is Pen. In some embodiments, X4 is Pen(oXyl). In some embodiments, X4 is Pen(mXyl). In some embodiments, X4 is Pen(pXyl). In some embodiments, X4 is Pra.

[0105] In some embodiments, X4 is 4Amino-d-Pro. In some embodiments, X4 is 4RAmino-d-Pro. In some embodiments, X4 is 4SAmino-d-Pro. In some embodiments, X4 is dAbu. In some embodiments, X4 is d-aG. In some embodiments, X4 is aMe-dC. 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.

[0106] 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).

[0107] 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, X4 is Pen. In some embodiments, X5 is Q. In some embodiments, when X5 is Q, X4 is Abu.

[0108] 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.

[0109] 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.

[0110] 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, X5 is Q. In some embodiments, when X7 is W, X4 is Abu. In some embodiments, when X7 is W, X5 is Q and X4 is Abu.

[0111] In some embodiments, X8 is K(Ac), R5H, S5H, K(NMeAc), or Q. In some embodiments, X8 is K(Ac), R5H, S5H, K(NMeAc), or Q, wherein Q, K(Ac), and K(NMeAc) are L-amino acids. In some embodiments, X8 is k(Ac), R5H, S5H, k(NMeAc), or q.

[0112] In some embodiments, X8 is K(Ac), R5H, S5H, K(NMeAc), or Q, and R5H and S5H are X 12In some embodiments, X8 is K(Ac), R5H, S5H, K(NMeAc), or Q, and R5H and S5H are linked to X through an aliphatic bond. 12 is linked to an amino acid in

[0113] In some embodiments, X8 is K(Ac), S5H, K(NMeAc), or Q. In some embodiments, X8 is K(Ac), S5H, or Q. In some embodiments, X8 is K(Ac), K(NMeAc), or Q. In some embodiments, X8 is K(Ac) or Q. In some embodiments, X8 is K(Ac) or K(NMeAc). In some embodiments, X8 is K(Ac). In some embodiments, X8 is K(NMeAc). In some embodiments, X8 is Q. In some embodiments, X8 is k(Ac). In some embodiments, X8 is k(NMeAc). In some embodiments, X8 is q.

[0114] In some embodiments, X8 is R5H or S5H. In some embodiments, X8 is X 12 In some embodiments, X8 is S5H linked to S5 in 12 In some embodiments, X is R5H linked to R5 in X 12 In some embodiments, X is S5H linked to R in 12 is R5H linked to S5 in

[0115] In some embodiments, X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3). In some embodiments, X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3), each of which is an L-amino acid. In some embodiments, X9 is aMe-dC, d-aG, c, d, e, he, dPen, or dDap(N3).

[0116] In some embodiments, X9 is aG, D, E, hE, or Dap(N3). In some embodiments, X9 is aMeC, C, or Pen. In some embodiments, X9 is aMeC or Pen.

[0117] In some embodiments, X9 is aMeC. In some embodiments, X9 is aG. In some embodiments, X9 is C. In some embodiments, X9 is D. In some embodiments, X9 is E. In some embodiments, X9 is hE. In some embodiments, X9 is Pen. In some embodiments, X9 is Dap(N3).

[0118] In some embodiments, X9 is aMe-dC. In some embodiments, X9 is d-aG. In some embodiments, X9 is c. In some embodiments, X9 is d. In some embodiments, X9 is e. In some embodiments, X9 is he. In some embodiments, X9 is dPen. In some embodiments, X9 is dDap(N3).

[0119] In some embodiments, X 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF, and optionally AEF is X 13 In some embodiments, X is linked to an amino acid in 10 is AEF, APEG3F, F(4TzlAme2), or TMAPF, each of which is an L-amino acid; and optionally, AEF is 13 In some embodiments, X is linked to an amino acid in 10 is dAEF, dAPEG3F, f(4TzlAme2), or dTMAPF, and optionally dAEF is 13 is linked to an amino acid in

[0120] In some embodiments, X 10is AEF, APEG3F, F(4TzlAme2), or TMAPF. 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.

[0121] In some embodiments, X 10 In some embodiments, X is APEG3F. 10 is F(4TzlAme). In some embodiments, X 10 In some embodiments, X is TMAPF. 10 is AEF. In some embodiments, X 10 is X 13 In some embodiments, X is an AEF linked to an amino acid in 10 is X 13 In some embodiments, X is an AEF linked to E in 10 In some embodiments, X is dAPEG3F. 10 is f(4TzlAme). In some embodiments, X 10 In some embodiments, X is dTMAPF. 10 In some embodiments, X is dAEF. 10 is X 13 In some embodiments, X is dAEF linked to an amino acid in 10 is X 13 is dAEF linked to E in

[0122] In some embodiments, X 12 is THP, S5, R5, or B5. In some embodiments, X 12 is THP, S5, R5, or B5, and S5 and R5 are X 16 In some embodiments, X is linked to an amino acid in 12is THP, S5, R5, or B5, and B5 is the amino acid at X8 and X 16 In some embodiments, X is linked to an amino acid in 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.

[0123] In some embodiments, X 12 is connected to X via an aliphatic bond 16 In some embodiments, X is S5 linked to an amino acid in 12 is THP, S5, R5, or B5, and S5 and R5 are X 16 In some embodiments, X is linked to S5H or R5H in 12 is X 16 In some embodiments, X is S5 linked to S5H in 12 is connected to X via an aliphatic bond 16 In some embodiments, X is R linked to an amino acid in 12 is X 16 is R5 linked to R5H in

[0124] In some embodiments, X 12 is the amino acid at X8 and X 16 In some embodiments, X is B5 linked to an amino acid in 12 is linked to an amino acid at X8 through a first aliphatic bond and to an amino acid at X8 through a second aliphatic bond. 16 In some embodiments, X is B5 linked to an amino acid in 12The S5H and X in X8 16 In some embodiments, X is B5 linked to S5H. 12 R5H and X in X8 16 is B5 linked to R5H in

[0125] In some embodiments, X 13 is E, R5H or S5H, and R5H and S5H are linked to an amino acid in R1, X3, and optionally E is linked to an amino acid in R1, X3, or X 10 In some embodiments, X is linked to an amino acid in 13 is E, R5, or S5H, where E is an L-amino acid, and R5H and S5H are linked to an amino acid at X3, and optionally E is linked to R1, an amino acid at X3, or X 10 is linked to an amino acid in

[0126] In some embodiments, X 13 is e, R5H, S5H, where R5H and S5H are linked to an amino acid in X3, and optionally e is linked to R1, an amino acid in X3, or X 10 is linked to an amino acid in

[0127] In some embodiments, X 13 is E, R5H, or S5H. In some embodiments, X 13 is E or S5H. In some embodiments, X 13 is E or R5H. In some embodiments, X 13 is E.

[0128] In some embodiments, X 13 is E linked to R. In some embodiments, X 13 is E linked to R1 via an amide bond. In some embodiments, X 13 is E linked to 8Aoc in R1. In some embodiments, X 13is an E linked to the amino acid at X3. 13 is an E linked to the amino acid at X3 via an amide bond. 13 is an E linked to hK at X3. In some embodiments, X 13 is X 10 In some embodiments, X is an E linked to an amino acid in 13 is X 10 In some embodiments, X is an E linked to an amino acid in 13 is connected to X via an amide bond 10 In some embodiments, X is an E linked to an amino acid in 13 is X 10 In some embodiments, X is E linked to AEF. 13 is connected to X via a tetrazolyl bond 10 In some embodiments, X is an E linked to an amino acid in 13 is X 10 In some embodiments, X is an E linked to F(4TzlAme2). 13 In some embodiments, X 13 is S5H linked to X3. In some embodiments, X 13 is S5H linked to R7H in X3.

[0129] In some embodiments, X 14 is N. In some embodiments, X 14 is N, and N is an L-amino acid. 14 is n.

[0130] In some embodiments, X 15 is 3Pya or bAla. 15 is 3Pya or bAla, where 3Pya is an L amino acid. 15 is d-3Pya or bAla.

[0131] In some embodiments, X 15 In some embodiments, X is 3Pya. 15 In some embodiments, X is bAla. 15 is d-3Pya.

[0132] In some embodiments, X 16 is Sar, R5H, S5H or absent, and S5H and R5H are X 12 In some embodiments, X is linked to an amino acid in 16 is Sar, R5h, S5H, or is absent, and S5H and R5H are connected to X through an aliphatic bond. 12 In some embodiments, X is linked to an amino acid in 16 is Sar, S5H, R5H or absent, and S5H and R5H are X 12 In some embodiments, X 16 is Sar, S5H, or absent. 16 is Sar, R5H or absent.

[0133] In some embodiments, X 16 is Sar or absent. 16 is Sar or S5H. In some embodiments, X 16 is Sar or R5H. In some embodiments, X 16 In some embodiments, X 16 is R5H. In some embodiments, X 16 is X 12 In some embodiments, X is R5H linked to B5. 16 is X 12 In some embodiments, X is S5H linked to an amino acid in 16 is X 12 In some embodiments, X is S5H linked to B5 in 16is Sar. In some embodiments, X 16 does not exist.

[0134] In some embodiments, R2 is CONH2 or CONMe2. In some embodiments, R2 is CONH2. In some embodiments, R2 is CON(Me)2.

[0135] In some embodiments, the peptide is cyclized via a bond between two amino acid residues (eg, residues X4 and X9) via a disulfide, thioether, amide, or alkylene bond.

[0136] In some embodiments, X4 is Abu and X9 is C. In some embodiments, X4 is Abu and X9 is aMeC. In some embodiments, X4 is Abu and X9 is Pen.

[0137] In some embodiments, X4 is C and X9 is C. In some embodiments, X4 is C and X9 is aMeC. In some embodiments, X4 is C and X9 is Pen.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] In some embodiments, X4 is Pra and X9 is Dap(N3). In some embodiments, X4 is aG and X9 is aG.

[0146] In some embodiments, the peptide is cyclized via a bond between two amino acid residues (eg, at X4 and X9) having a structure selected from the following:

[0147] [Table 5-1]

[0148] [Table 5-2]

[0149] In some embodiments, the peptide is cyclized via a bond between residues at X4 and X9 having a structure selected from the following:

[0150] [Table 6]

[0151] In some embodiments, the peptide is cyclized via a bond between residues at X4 and X9 having the following structure:

[0152] [ka]

[0153] In some embodiments, the peptide comprises R and X having a structure selected from: 13 This includes the bond between

[0154] [Table 7]

[0155] In some embodiments, the peptide comprises X and X having a structure selected from: 13 This includes the bond between

[0156] [Table 8]

[0157] In some embodiments, the peptide comprises X and X having the structure: 12 This includes the bond between

[0158] [Table 9]

[0159] In some embodiments, the peptide has a structure selected from the following: 10 and X 13 This includes the bond between

[0160] [Table 10]

[0161] In some embodiments, the peptide has the structure: X 12 and X 16 This includes the bond between

[0162] [Table 11]

[0163] In some embodiments, the peptide comprises X 12 One bond between X and X8 and X 12 and X 16 and one bond between the two bonds, which has the following structure:

[0164] [Table 12]

[0165] In some embodiments, the peptide comprises a sequence according to any one of the following formulas: R1-X3-Pen-X5-T-7MeW-X8-Pen-X 10 -2Nal-X 12 -EN-3Pya-X 16 -R2(IE) R1-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-X 13 -N-3Pya-R2(IF) R1-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-X 12 -EN-3Pya-CONH2 (IJ) MeCO-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-EN-3Pya-R2(IK) MeCO-X3-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-EN-3Pya-CONH2 (IL) R1-X3-Pen-X5-T-7MeW-X8-Pen-X 10 -2Nal-X 12 -ENX 15 -X 16 -R2(IM) R1-X3-Abu-QT-X7-X8-CX 10 -2Nal-X 12 -EN-3Pya-X 16 -R2(IN) R1-X3-Abu-QT-X7-QCX 10 -2Nal-X 12 -EN-3Pya-X 16 -R2(IO) MeCO-X3-X4-K(Ac)-T-7MeW-X8-X9-X 10 -2Nal-X 12 -EN-3Pya-Sar-R2(IP) R1-X3-X4-X5-T-X7-S5H-X9-X 10 -2Nal-B5-EN-3Pya-S5H-R2(IQ) R1-X3-X4-X5-T-7MeW-S5H-X9-X 10 -2Nal-B5-EN-3Pya-S5H-R2(IR) R1-X3-Pen-X5-T-X7-S5H-Pen-X 10 -2Nal-B5-EN-3Pya-S5H-R2(IS)

[0166] 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.

[0167] 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.

[0168] 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.

[0169] In some embodiments, the T between X5 and X7 is an L-amino acid. In some embodiments, the T between X5 and X7 is dT.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] In some embodiments, X 10 In some embodiments, the amino acid in X is an L-amino acid. 10 The amino acids in are D-amino acids.

[0174] In some embodiments, X 10 and X 12 and 2 NaI are L-amino acids. 10 and X 12 The 2Nal between is d2Nal.

[0175] In some embodiments, X 13 In some embodiments, the amino acid in X is an L-amino acid. 13 The amino acids in are D-amino acids.

[0176] In some embodiments, X 13 and X 15 and N is an L-amino acid. 13 and X 15 The N between is dN.

[0177] In some embodiments, X 15 In some embodiments, the amino acid in X is an L-amino acid. 15 The amino acids in are D-amino acids.

[0178] In some embodiments, the present disclosure provides peptides described herein, provided that they retain activity as inhibitors of the interleukin-23 receptor.

[0179] 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.

[0180] [Table 13-1]

[0181] [Table 13-2]

[0182] [Table 13-3]

[0183] [Table 13-4]

[0184] [Table 13-5]

[0185] [Table 13-6]

[0186] [Table 13-7]

[0187] In the peptide sequences shown above, when a particular residue is followed by a number in parentheses, that residue is linked to another residue in the sequence designated by the same number. For example, in the sequence MeCO-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-2Nal-S5(4)-EN-3Pya-S5H(4)-CONH2 (SEQ ID NO: 1), the two Pen(3) residues are linked to each other and the S5(4) residue is linked to the S5H(4) residue.

[0188] Synthesis method The compounds described herein can be synthesized by many techniques known to those of skill in the art. In some aspects, the present disclosure provides methods for chemically synthesizing the peptides of the present disclosure. In some aspects, portions of the peptide are recombinantly synthesized instead of chemically synthesized. In some aspects, the method of producing a peptide further comprises cyclizing the peptide precursor after the constituent subunits have been joined. In certain aspects, cyclization is achieved via any of the various methods described herein.

[0189] The present disclosure further describes the synthesis of the compounds described herein.In some embodiments, lipidation is performed on one or more of the amino acid residues or amino acid monomers, and then covalently bonded to each other to form the peptide of the present disclosure.In some embodiments, lipidation is performed on one or more of the amino acid residues or amino acid monomers, and then covalently bonded to each other at an intermediate oligomer stage, and then additional amino acids are attached and cyclized to form the peptide of the present disclosure.In some embodiments, cyclic peptides are synthesized, and then lipidation is performed to form the compound of the present disclosure.Exemplary synthesis methods are described in the examples.

[0190] Pharmaceutical Composition The present disclosure further relates to pharmaceutical compositions comprising the IL-23R inhibitors described herein. In particular, the present disclosure includes pharmaceutical compositions comprising one or more peptides of the present 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 microbial action can be ensured by including various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like.

[0191] Pharmaceutical compositions may be administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (by powder, ointment, eye drops, suppository, or transdermal patch), by inhalation (such as intranasal spray), ophthalmically (such as intraocularly), or bucally. As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intraarticular injection and infusion. Thus, in certain embodiments, the composition is formulated for delivery by any of these routes of administration. Pharmaceutical compositions may be formulated and administered orally. Pharmaceutical compositions may be formulated and administered parenterally.

[0192] The IL-23R inhibitors of the present disclosure can be prepared and / or formulated as their pharmaceutically acceptable salts and / or other forms, or, where appropriate, in neutral form. Pharmaceutically acceptable salts are neutral, non-toxic salts of compounds that possess the desired pharmacological activity in their 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, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0193] The present disclosure relates to pharmaceutical compositions comprising the IL-23R inhibitors described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one or more hydrogen atoms bonded to a carbon atom may be replaced with a deuterium atom or D. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and thus may be useful for increasing the half-life of the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures 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 by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0194] Also included are examples of isotopes that can be incorporated into the disclosed compounds: 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 Positron-emitting isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. 11 C. 18 F, 15 O, and 13Substitution at N may be useful in Positron Emission Topography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled peptides of the present disclosure may generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples as set forth below, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0195] When used in at least one of the treatment or delivery systems described herein, the peptide inhibitors of the present disclosure may be used in pure form or, if such forms exist, in a pharmaceutically acceptable salt form.

[0196] The total daily usage amount of the IL-23R inhibitors and compositions of the present disclosure may be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend on a variety of factors, including: a) the disorder being treated and the severity of the disorder; b) the activity of the particular compound employed; c) the specific composition employed, the patient's age, weight, general health, sex, and diet; d) the time of administration, route of administration, and excretion rate of the particular peptide inhibitor employed; e) the duration of treatment; f) drugs used in combination or concomitantly with the particular peptide inhibitor employed, as well as similar factors well known in the medical arts.

[0197] The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical arts. Techniques and compositions are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the 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.

[0198] Non-invasive detection of intestinal inflammation The IL-23R inhibitors of the present disclosure can be used to detect, assess, and diagnose intestinal inflammation by microPET imaging, where the peptide inhibitors are labeled with a chelating group or 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 chelator. In certain embodiments, the IL-23R inhibitors of the present disclosure are radiolabeled. The labeled IL-23R inhibitor is then administered orally or rectally to a subject. In certain embodiments, the IL-23R inhibitor is included in drinking water. Following uptake of the IL-23R inhibitor, microPET imaging can be used to visualize inflammation throughout the subject's intestine and digestive tract.

[0199] Treatment and Use The present disclosure relates to methods for treating a subject suffering from a condition or indication associated with IL-23 or IL-23R activity (e.g., activation of the IL-23 / IL-23R signaling pathway), comprising administering to the subject an IL-23R inhibitor disclosed herein. In one aspect, the present disclosure provides a method for treating a subject suffering from a condition or indication characterized by aberrant or dysregulated IL-23 or IL-23R activity or signaling, 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. Inhibition of IL-23 binding to IL-23R can occur in specific organs or tissues 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.

[0200] The present disclosure relates to a method comprising providing a peptide inhibitor described herein to a subject in need thereof. The subject in need thereof may be a subject who has been diagnosed or determined to be at risk for developing a disease or disorder associated with IL-23 / IL-23R. The subject may be a mammal. The subject may particularly be a human.

[0201] The disease or disorder treated by the IL-23R inhibitors of the present disclosure can be an inflammatory disease or disorder, an autoimmune inflammatory disease or disorder, and / or related disorder, such as multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent 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, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris ... vulgaris), or psoriatic erythroderma), atopic dermatitis, ectopic acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[0202] 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, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23R inhibitor of the present disclosure.

[0203] 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, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure.

[0204] 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, a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23R inhibitor of the present disclosure.

[0205] Inflammatory diseases, autoimmune inflammatory diseases, and / or related disorders suitable for treatment with the compounds or pharmaceutically acceptable salts thereof, or compositions of the present disclosure may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA). The inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis. The inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated may be psoriasis. The inflammatory disease to be treated may be psoriatic arthritis. The inflammatory disease to be treated may be IBD. The inflammatory disease to be treated may be Crohn's disease. The inflammatory disease to be treated may be ulcerative colitis.

[0206] IL-23 is abundantly produced in the intestine, where it is thought to play an important role in suppressing intestinal regulatory T cell responses that favor inflammation, as well as controlling the balance between tolerance and immunity through T cell-dependent and T cell-independent pathways of intestinal inflammation by influencing T-helper 1 (Th1) and Th17-associated cytokines. Additionally, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the important role of the IL-23 pathway in intestinal homeostasis. Peptides and methods for specifically targeting IL-23R from the luminal side of the intestine may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.

[0207] 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 present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising an IL-23 inhibitor. 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).

[0208] Psoriasis, a chronic skin disease affecting approximately 2% to 3% of the general population, has been shown to be mediated by the body's T cell inflammatory response. IL-23 is one of several interleukins that reportedly plays a key role in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation through the induction of interleukin-17, regulation of T memory cells, and activation of macrophages. IL-23 and IL-23R expression have been shown to be increased in tissues from psoriasis patients, and IL-23-neutralizing antibodies have demonstrated IL-23-dependent inhibition of psoriasis development in animal models of psoriasis. Orally bioavailable peptide inhibitors of IL-23 could provide both a nonsteroidal treatment option for patients with mild to moderate psoriasis and a treatment for moderate to severe psoriasis that does not require injection delivery.

[0209] 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 described herein comprising an IL-23 inhibitor. 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).

[0210] 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 administering 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 exposure of GI tissue (e.g., small intestine or colon) to the administered peptide inhibitor may be at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold greater than the exposure in the blood. In certain 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), comprising providing a peptide inhibitor to the subject, wherein the peptide inhibitor neither blocks the interaction between IL-6 and IL-6R nor antagonizes the IL-12 signaling pathway. In further related embodiments, the present disclosure provides a method of inhibiting GI inflammation and / or neutrophil infiltration into the GI tract, comprising providing a peptide inhibitor of the present disclosure to a subject in need thereof. In some embodiments, the method of the present disclosure comprises providing a peptide inhibitor of the present disclosure (i.e., a first therapeutic agent) in combination with a second therapeutic agent to a subject (e.g., a subject in need thereof). In certain embodiments, the second therapeutic agent is provided to the subject before, simultaneously with, and / or after the peptide inhibitor is administered to the subject. In certain embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug, a steroid, or an immunomodulatory agent. In certain embodiments, the method includes administering to the subject a third therapeutic agent, hi certain embodiments, the second therapeutic agent is an antibody that binds to IL-23 or IL-23R.

[0211] The present disclosure also relates to a method of inhibiting the binding of IL-23 to IL-23R on a cell, comprising contacting the IL-23R with a peptide inhibitor of the receptor disclosed herein. The cell may be a mammalian cell. The method may be performed in vitro or in vivo. Inhibition of binding may be determined by a variety of routine experimental methods and assays known in the art.

[0212] The present disclosure relates to a method for inhibiting IL-23 signaling by a cell, the method comprising contacting the IL-23R with a peptide inhibitor described herein. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the method is performed in vitro or in vivo. In certain embodiments, inhibition of IL-23 signaling can be determined by measuring changes in phospho-STAT3 levels in the cell. [Example]

[0213] The following examples are not intended to limit the scope of the disclosure, but rather to provide guidance to those of skill in the art for preparing and using the disclosed peptides, compositions, and methods. While specific embodiments of the disclosure have been described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the disclosure.

[0214] Some abbreviations useful in describing this disclosure are defined in the following table.

[0215] The following abbreviations may be used throughout this specification and application:

[0216] [Table 14]

[0217] [Table 15]

[0218] [Table 16]

[0219] The amino acid structures provided in Table 5 below are presented without a stereochemical designation at the alpha carbon. However, it is understood that these amino acids exist as either L- or D-amino acids. For example, "Dap" represents the L-stereoisomer:

[0220] [ka] or the D-stereoisomer (e.g., when referred to as "dap," "dDap," or "D-Dap"):

[0221] [ka] may be present in the peptides of the present disclosure as

[0222] [Table 17-1]

[0223] [Table 17-2]

[0224] [Table 17-3]

[0225] [Table 17-4]

[0226] [Table 17-5]

[0227] Example 1: General procedure for solid phase synthesis of peptides Peptides were chemically synthesized using an optimized 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis protocol. For the C-terminal amide, Rink amide MBHA resin was used. Side chain protecting groups were as follows: Asp: OAll; Glu: OAll; Thr: Otbutyl; Asn, Pen: Trityl; AEF: Boc. For coupling, a 2-5-fold excess solution containing the Fmoc amino acid, HATU, and DIEA (1:0.95:2) in DMF was added to the swollen resin for 1-48 h. Double coupling was used when coupling 2Nal. Removal of the Fmoc protecting group was achieved by treatment with a DMF, piperidine (4:1) solution for 30 min. The cycle was repeated until the full-length peptide was obtained. Removal of the OAll protecting group on Glu was achieved by treatment with a solution of Pd(PPh3)4 (0.1 equiv.), PhSiH3 (10 equiv.), and DCM for 15 min. * For amide cyclization, a solution containing DIC (3.0 equiv.) and HOBT (3.0 equiv.) in DMF was applied to the swollen resin for 16 h. * The cycle was repeated until the full-length peptide was obtained. For RCM cyclization, a solution containing Grubbs 1st (0.5 equiv.) in DCM was added to the swollen resin under microwave conditions at 40° C. for 2 hours. * Added twice.

[0228] Certain materials and reagents are listed below.

[0229] [Table 18-1]

[0230] [Table 18-2]

[0231] General procedure for cleaving peptides from the resin Side chain deprotection and cleavage of the peptide were 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 min) and decanted. The pellet was washed with MTBE and centrifuged. The pellet was lyophilized to yield the linear peptide.

[0232] Procedures for ring closing metathesis (RCM) cyclization For RCM cyclization, the peptide was dissolved in anhydrous DCM and stirred, followed by the addition of Grubbs' first generation catalyst (0.5 equiv.). The mixture was reacted at 40° C. for 16 h. When LCMS showed the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove the solvent.

[0233] General Procedure for Cyclization To effect cyclization of the thiol-containing residues, a solution of iodine in MeOH (0.1 M) was added dropwise to a solution of the linear peptide (20% MeCN / HO (1 mmol / L)) until a yellow color persisted. After approximately 2 h, analysis by LCMS showed that no linear peptide was present anymore. Excess iodine was quenched by the addition of 1 M aqueous NaSO (which immediately became colorless).

[0234] General Procedure for Peptide Purification Peptide purification was achieved using reverse-phase high-performance liquid chromatography (RP-HPLC). Purification of the cyclized peptide was achieved using preparative RP-HPLC with a C18 column at a flow rate of 20-250 mL / min. Separation was achieved using a gradient of buffer B in A (buffer A: 0.075% TFA in water; buffer B: ACN) (Note 1). Analytical analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0235] Note 1: Preparative HPLC method Preparative HPLC Method A: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B) Column: Welch Ultimate® XB-C18, 250 * 50mm, 10um, 120Å + Welch Xtimate® C18, 250 * 50 mm, 10 μm, 120 Å, flow rate: 80 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature

[0236] Preparative HPLC Method B: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B). Column: YMC-Actus Triart C18, 250 * 30 mm, 5 μm, 120 Å column, flow rate: 20 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature

[0237] Note 2: Analytical HPLC method: Mobile phase: 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), using an elution gradient of 10% to 80% (solvent B) over 0.9 min and 80% to 90% over 0.6 min, with a flow rate of 1.0 ml / min. Column: Xbridge C18, 3.5 um, 2.1 * 30 mm, wavelength: UV 220 nm and 254 nm, column temperature: 30°C, MS ionization: ESI

[0238] Example 2: Synthesis of SEQ ID NO:3

[0239] [ka]

[0240] Peptides were synthesized using standard Fmoc chemistry. 1) DMF and MBHA resin (0.30 mmol, 0.90 g, substitution: 0.33 mmol / g) were combined in a container and the resin was allowed to swell for 2 hours. 2) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 3) The resin was then drained and washed with DMF for 30 seconds. * Washed five times. 4) The Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, after which a solution of HATU and DIEA in DMF was added. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachloride color tests, and upon completion, the resin was washed five times with DMF. After peptide synthesis was complete, the resin was washed three times with MeOH and dried under vacuum.

[0241] Monitoring Method: 1. Ninhydrin test: A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor / DMF, B: 2% aldehyde / DMF, 110°C for 3 minutes

[0242] Detailed synthetic methodology for ring-closing metathesis (RCM) cyclization: For RCM cyclization: Resin and Grubbs 1 in anhydrous DCM st The catalyst (0.5 equiv.) was added to the microwave tube, and the mixture was then heated under microwave conditions at 40° C. for 2 h. * After heating twice, LCMS showed the desired product. The resin was then washed five times with DMF and three times with MeOH before being dried under vacuum.

[0243] Peptide cleavage: 1) To the flask containing the side-chain protected peptide, 30 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added at room temperature, and the mixture was stirred for 3 hours. 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. 3) The residue was lyophilized to give Intermediate 1 (520 mg, 90.3% yield, crude).

[0244] [ka]

[0245] Peptide cyclization and purification: Crude peptide intermediate 1 (520 mg, 0.271 mmol) was dissolved in 20% MeCN / HO (300 mL). To the stirred solution of peptide, iodine solution in MeOH (0.1 M, 3.5 mL) was added dropwise until the solution remained yellow. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. 10–20 mL of MeCN was then added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method A) to give peptide SEQ ID NO:3 (38.4 mg, 96.4% purity, 6.37% yield for this step, 5.75% overall yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0246] LCMS summary: Method: 10-80-2 min-1.5_P2.amx, retention time: 1.518 min, calculated MW: 1917.25, observed MW: 959.3 [(M+2H) / 2].

[0247] Example 3: Synthesis of SEQ ID NO:2

[0248] [ka]

[0249] Peptides were synthesized using standard Fmoc chemistry. 1) DMF and MBHA resin (0.30 mmol, 0.90 g, substitution: 0.33 mmol / g) were combined in a container and the resin was allowed to swell for 2 hours. 2) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 3) The resin was then drained and washed with DMF for 30 seconds. * Washed five times. 4) The Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, after which a solution of HATU and DIEA in DMF was added. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachloride color tests, and upon completion, the resin was washed five times with DMF. After peptide synthesis was complete, the resin was washed three times with MeOH and dried under vacuum.

[0250] Monitoring Method: 1. Ninhydrin test: A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor / DMF, B: 2% aldehyde / DMF, 110°C for 3 minutes

[0251] Detailed synthetic methodology for ring-closing metathesis (RCM) cyclization: For RCM cyclization: Resin and Grubbs 1 in anhydrous DCM st The catalyst (0.5 equiv.) was added to the microwave tube, and the mixture was then heated under microwave conditions at 40° C. for 2 h. * After heating twice, LCMS showed the desired product. The resin was then washed five times with DMF and three times with MeOH before being dried under vacuum.

[0252] Peptide cleavage: 1) To the flask containing the side-chain protected peptide, 30 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added at room temperature, and the mixture was stirred for 3 hours. 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. 3) The residue was lyophilized to give Intermediate 2 (500 mg, 90.6% yield, crude).

[0253] [ka]

[0254] Peptide cyclization and purification: Crude peptide intermediate 2 (500 mg, 0.272 mmol) was dissolved in 20% MeCN / HO (300 mL). To the stirred solution of peptide, iodine solution in MeOH (0.1 M, 3.5 mL) was added dropwise until the solution remained yellow. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. 10–20 mL of MeCN was then added to reduce the turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method A) to give peptide SEQ ID NO:2 (38.3 mg, 98.0% purity, 6.69% yield for this step, 6.06% overall yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0255] LCMS summary: Method: 10-80-2 min-1.5_P2.amx, retention time: 1.497 min, calculated MW: 1837.13, observed MW: 919.2 [(M+2H) / 2].

[0256] Example 4: Synthesis of SEQ ID NO:5

[0257] [ka]

[0258] Peptides were synthesized using standard Fmoc chemistry. 1) DMF and MBHA resin (0.30 mmol, 0.96 g, substitution: 0.31 mmol / g) were combined in a container and the resin was allowed to swell for 2 hours. 2) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 3) The resin was then drained and washed with DMF for 30 seconds. * Washed five times. 4) The Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, after which a solution of HATU and DIEA in DMF was added. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachloride color tests, and upon completion, the resin was washed five times with DMF. After peptide synthesis was complete, the resin was washed three times with MeOH and dried under vacuum.

[0259] Monitoring Method: 1. Ninhydrin test: A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor / DMF, B: 2% aldehyde / DMF, 110°C for 3 minutes

[0260] Detailed synthetic method for amide cyclization: Desorption of OAll on Glu: The resin was washed with 50 mL of DMF (3 × 0.1 min) and DCM (3 × 0.1 min), followed by the addition of PhSiH (10 equiv.) and Pd(PPh) (0.1 equiv.) in DCM (10 mL). The mixture was allowed to react for 15 min and then washed five times with alternating DCM (50 mL) and DMF (50 mL) until the solution became colorless.

[0261] On-resin amide cyclization: After deprotection, the resin was washed with 50 mL of DMF (5 × 0.1 min), followed by the addition of DIC (3 eq.) and HOBT (3.0 eq.) in DMF (50 mL). The coupling reaction was mixed for 16 h. A ninhydrin color reaction showed a negative test. After the coupling reaction was complete, the resin was washed with 50 mL of DMF (3 × 0.1 min).

[0262] Peptide cleavage: 1) To the flask containing the side-chain protected peptide, 30 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added at room temperature, and the mixture was stirred for 3 hours. 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. 3) The residue was lyophilized to give Intermediate 3 (550 mg, 92.5% yield, crude).

[0263] [ka]

[0264] Peptide cyclization and purification: Crude peptide intermediate 3 (550 mg, 0.278 mmol) was dissolved in 20% MeCN / HO (300 mL). To the stirred solution of peptide, iodine solution in MeOH (0.1 M, 2.5 mL) was added dropwise until the solution remained yellow. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. 10–20 mL of MeCN was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method B) to give peptide SEQ ID NO:5 (19.3 mg, 98.5% purity, 3.10% yield for this step, 2.87% overall yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0265] LCMS summary: Method: 10-80-3 min-1.5_P2.amx, retention time: 1.384 min, calculated MW: 1979.33, observed MW: 990.2 [(M+2H) / 2].

[0266] Example 5: Synthesis of SEQ ID NO:4

[0267] [ka]

[0268] Peptides were synthesized using standard Fmoc chemistry. 1) DMF and MBHA resin (0.5 mmol, 1.5 g, substitution: 0.33 mmol / g) were combined in a container and the resin was allowed to swell for 2 hours. 2) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 3) The resin was then drained and washed with DMF for 30 seconds. * Washed five times. 4) The Fmoc-amino acid solution was then added and mixed with the resin for 30 seconds, after which a solution of HATU and DIEA in DMF was added. The reaction was allowed to proceed under nitrogen for 1-4 hours. 5) A solution of 20% piperidine / DMF was added and the suspension was mixed for 30 minutes. 6) Steps 2 to 5 were repeated for subsequent amino acid couplings. The coupling reactions were monitored by ninhydrin or tetrachloride color tests, and upon completion, the resin was washed five times with DMF. After peptide synthesis was complete, the resin was washed three times with MeOH and dried under vacuum.

[0269] Monitoring Method: 1. Ninhydrin test: A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine 2. Tetrachlor color test: A: 2% tetrachlor / DMF, B: 2% aldehyde / DMF, 110°C for 3 minutes

[0270] Peptide cleavage: 1) To the flask containing the side-chain protected peptide, 30 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added at room temperature, and the mixture was stirred for 3 hours. 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. 3) The residue was lyophilized to give intermediate 4a (0.9 g, 74.6% yield, crude).

[0271] [ka]

[0272] Peptide cyclization and purification: Crude peptide intermediate 4a (900 mg, 0.373 mmol) was dissolved in 20% MeCN / HO (500 mL). To the stirred solution of peptide, iodine solution in MeOH (0.1 M, 7.5 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (20 μL), which immediately became colorless. 10–20 mL of MeCN was then added to reduce the turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, 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 / min (Note 2).

[0273] [ka]

[0274] Peptide intermediate 4b (190 mg, 0.079 mmol) was dissolved in anhydrous DCM. To the stirred solution of peptide, Grubbs 1 stA catalyst (33 mg, 0.5 equiv.) was added, and the mixture was allowed to react at 40° C. for 16 h, at which point LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent and purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method B) to give the peptide of SEQ ID NO: 4 (10.5 mg, 94.8% purity, 4.64% yield for this step, 0.73% overall yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[0275] LCMS summary: Method: 10-80-2 min-1.5_P2.amx, retention time: 1.565 min, calculated MW: 2380.95, observed MW: 1190.1 [(M+2H) / 2].

[0276] Example 6: IL23R reporter assay Compounds were serially diluted in 100% (v / v) DMSO and plated into 1536-well untreated black assay plates (Corning #9146) using an echo acoustic dispenser (Labcyte). 3 μL of HEK293 cells containing IL-23R, IL-12Rβ1, and a firefly luciferase reporter gene driven by a STAT inducible promoter (Promega) were added to the plate (4000 cells / well), followed by 3 μL of 10 ng / mL IL-23 (EC 90 After 5 h at 37°C, 5% CO2, 95% relative humidity, 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 normalized to IL-23 treatment (0% inhibition) and 30 μM control inhibitor (100% inhibition), and IC 50 Values ​​were determined using the four parameter Hill equation. Data for example compounds are shown below. A:IC 50 <0.01 μM, B: 0.01 μM ≦ IC 50 <0.5 μM, C: 0.5 μM ≦ IC 50 ND: Not decided

[0277] [Table 19]

[0278] Example 7: PBMC pSTAT3 assay Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy donors were thawed and washed twice with ImmunoCult-XF T cell expansion medium (XF-TCEM) supplemented with CTL anti-agglutinin washing solution. The cells were counted and cultured at 2–6 × 10 cells per mL in XF-TCEM supplemented with penicillin / streptomycin and 100 ng / mL IL-1β (BioLegend, 579404). 5 Cells were resuspended in 100% RPMI-1640 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 for approximately 4 hours at 37°C in 5% CO2. After this "starvation," a total of 6 x 104 cells in 30 μL of RPMI-BSA were transferred to each well of a 384-well plate pre-spotted with peptide or DMSO. Cells were incubated for 30 minutes before adding IL-23 at a final concentration of 5 ng / mL. Cells were stimulated with cytokines 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 phosphorylated STAT3 was measured using a phospho-STAT panel kit (Meso Scale Discovery, K15202D). The results are provided below. A:IC 50 <1 nM, B: 1nM ≤ IC 50 <10nM, C: 10 nM ≤ IC 50 , ND: Not decided

[0279] [Table 20]

[0280] While the foregoing specification, together with examples given for purposes of illustration, teaches the principles of the present invention, it will be understood that the practice of the invention encompasses all ordinary variations, adaptations and / or modifications that come within the scope of the following claims and equivalents thereof.

Claims

1. Amino acid sequence: R １ -X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -2Nal-X １２ -X １３ -N-X １５ -X １６ -R ２ (I’) or a pharmaceutically acceptable salt thereof, wherein R １ is MeCO, 8Aoc, 7Ahp, 6Ahx, 5Ava, or cPEG3aCO; X ３ is hK, a ring-forming amino acid, or is absent, X ４ is any amino acid, X ５ is N, N(NMe2), Q, Q(NMe2), or a ring-forming amino acid; X ６ is any amino acid, X ７ is 7MeW or W, X ８ is K(Ac), K(NMeAc), Q, or a ring-forming amino acid; X ９ is any amino acid, X １０ is AEF, APEG3F, F(4TzlAme2), TMAPF, or a ring-forming amino acid; X １２ is a THP or a ring-forming amino acid, X １３ is an E or ring-forming amino acid, X １５ is 3Pya, bAla, or a ring-forming amino acid; X １６ is Sar, a ring-forming amino acid, or is absent, R ２ is CONH ２ or CONMe ２ and (a) a first ring-forming amino acid is linked to a second ring-forming amino acid to form a first ring containing from 4 to 11 or 14 amino acids, and a third ring-forming amino acid is linked to a fourth ring-forming amino acid to form a second ring containing from 4 to 11 or 14 amino acids; or (b) A peptide, or a pharmaceutically acceptable salt thereof, in which a first ring-forming amino acid is linked to a second ring-forming amino acid to form a first ring containing 4 to 11 or 14 amino acids, and a third ring-forming amino acid is linked to the C-terminus of the peptide to form a second ring containing 4 to 11 or 14 amino acids.

2. The peptide has the formula (I): R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -2Nal-X １２ -X １３ -N-X １５ -X １６ -R ２ (I) or a pharmaceutically acceptable salt thereof, wherein: R １ is MeCO, 8Aoc, 7Ahp, or cPEG3aCO; X ３ is R7H, S7H, hK or absent, X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ is N, N(NMe2), Q, or Q(NMe2), X ７ is 7MeW or W, X ８ is K(Ac), R5H, S5H, K(NMeAc), or Q; X ９ is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X １０ is AEF, APEG3F, F(4TzlAme2), or TMAPF; X １２ is R5, S5, B5, or THP; X １３ is E, R5H, or S5H; X １５ is 3Pya or bAla, X １６ is R5H, S5H, Sar or absent, R ２ is CONH ２ or CONMe ２ and X ３ is R7H or S7H, X ５ is N(Me2) or Q(NMe2), and X ８ is K(NmeAc), or X １０ is APEG3F, The peptide is (a) X ４ and X ９ a first bond between residues in (b) R １ 8Aoc and X in １３ The bond between E in R １ 7Ahp and X in １３ The bond between E in X ３ R7H or S7H and X in １３ a bond between R5H or S5H in X ３ hk and X in １３ The bond between E in X ８ R5H or S5H and X in １２ a bond between R5 or S5 in X １０ F(4TzlAme2) and X in １３ The bond between E in X １０ AEF and X in １３ The bond between E in X １２ R5 or S5 and X in １６ and a bond between R5H or S5H in X １２ B5 and X in ８ Between R5H or S5H in １２ B5 and X in １６ a second bond selected from the group consisting of two bonds between R5H or S5H in The peptide of claim 1, which is cyclized via

3. X ３ If hk, then X １５ 3. The peptide of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is bAla.

4. Formula (IA): R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -2Nal-X １２ -X １３ -N-3Pya-X １６ -R ２ (I-A) wherein: R １ is MeCO, 8Aoc, or cPEG3aCO; X ５ is N or N(NMe ２ ) and X １６ is S5H or Sar, or a pharmaceutically acceptable salt thereof.

5. Formula (IB): R １ -X ３ -Pen-X ５ -T-7MeW-X ８ -Pen-X １０ -2Nal-X １２ -X １３ -N-3Pya-X １６ -R ２ (I-B) wherein: R １ is MeCO, 8Aoc, or cPEG3aCO; X ５ is N or N(NMe ２ ) and X ８ is K(Ac), SH, or K(NMeAc), X １６ is S5H or Sar, or a pharmaceutically acceptable salt thereof.

6. Formula (IC): R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -2Nal-THP-X １３ -N-3Pya-X １６ -R ２ (I-C) wherein: X ８ is K(Ac), K(NMeAc), or Q; X １６ The peptide according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is Sar or absent.

7. Formula (ID): R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -2Nal-X １２ -E-N-3Pya-X １６ -CONH2 (I-D) wherein: R １ is MeCO or 8Aoc, X ３ does not exist, X ５ is N or Q, X ８ is K(Ac), SH, or Q; X １０ is AEF or F(4TzlAme2), X １６ is S5H or Sar, or a pharmaceutically acceptable salt thereof.

8. Formulae IE to IK: R １ -X ３ -Pen-X ５ -T-7MeW-X ８ -Pen-X １０ -2Nal-X １２ -E-N-3Pya-X １６ -R ２ (I-E) R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -AEF-2Nal-THP-X １３ -N-3Pya-R ２ (I-F) R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -AEF-2Nal-X １２ -E-N-3Pya-CONH2 (I-J) MeCO-X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -AEF-2Nal-THP-EN-3Pya-R ２ 3. The peptide according to claim 1 or 2, having a sequence according to any one of (I-K), or a pharmaceutically acceptable salt thereof.

9. X ４ is Pen, and X ９ is Pen, or X ４ is Abu, and X ９ The peptide according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein

10. The second bond is R １ 8Aoc and X in １３ The peptide according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the bond between E and the amino group is an amide bond.

11. The second bond is X １０ AEF and X in １３ The peptide according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the bond between E and the amino group is an amino bond between E and the amino group.

12. The second bond is X ３ R7H or S7H and X in １３ 3. The peptide of claim 2, or a pharmaceutically acceptable salt thereof, wherein the bond between R5H or S5H is an aliphatic bond.

13. The second bond is X ３ hK and X in １３ The peptide according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the bond between E and the amino group is an amide bond.

14. The second bond is X ８ R5H or S5H and X in １２ 3. The peptide of claim 2, or a pharmaceutically acceptable salt thereof, wherein the bond between R5 or S5 is an aliphatic bond.

15. The second bond is X １０ F(4TzlAme2) and X in １３ The peptide according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the bond between E and the amino group is an ester bond.

16. The second bond is X １２ R5 or S5 and X in １６ 3. The peptide of claim 2, or a pharmaceutically acceptable salt thereof, wherein the bond between R5H or S5H is an aliphatic bond.

17. The second bond is X １２ B5 and X in ８ Between R5H or S5H in, and X １２ B5 and X in １６ Between R5H or S5H in The peptide of claim 2, or a pharmaceutically acceptable salt thereof, wherein:

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

19. R ２ But CONH ２ The peptide according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof,

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

21. The first ring is X ４ and X ９ Between ４ and X １３ Between ５ and X １０ Between ３ and X １３ Between or X ６ and X ９ The peptide of claim 1, wherein

22. The first ring is X ４ and X ９ Between ４ and X １３ Between or X ６ and X ９ The peptide of claim 21 , wherein

23. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ４ and X ９ The peptide of claim 22, wherein

24. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ４ and X １３ The peptide of claim 22, wherein

25. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ６ and X ９ The peptide of claim 22, wherein

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

27. The second ring is X ５ and X １０ Between ３ and X １３ Between or X １３ and the N-terminus of the peptide.

28. the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ３ and X １３ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ５ and X １０ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １０ and X １３ or the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １３ and the N-terminus of the peptide.

29. the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ５ and X １０ or the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ６ and X ９ The peptide of claim 24, formed between

30. the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ３ and X １３ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ４ and X １３ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ５ and X １０ Is it formed between the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １０ and X １３ or the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; １３ and the N-terminus of the peptide.

31. A peptide having any one of the amino acid sequences of SEQ ID NOs: 1 to 6 or 8, or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising the peptide according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, 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), comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of any one of claims 1 to 19 or the pharmaceutical composition of claim 20.

34. The disease or disorder may be multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, ulcerative colitis, celiac disease (non-tropical sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, psoriasis ulcerata ... vulgaris), or psoriasis erythrodermic), atopic dermatitis, ectopic acne, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholechial inflammation, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

35. 22. 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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