Peptide inhibitors of the interleukin-23 receptor

Abstract

The present invention relates to novel cyclic peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharma- ceutically acceptable salts thereof, corresponding pharmaceutical compositions, methods, and / or uses for the treatment of autoimmune inflammatory diseases and related diseases and disorders. The inhibitors of the interleukin-23 receptor are cyclized by a disulfide bond between penicillamine, cysteine, homocysteine, or alpha-methylcysteine ​​residues at positions X4 and X9.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Patent Application No. 63 / 221806, filed July 14, 2021 (pending), each of which is incorporated by reference in its entirety, including its respective sequence listings.

[0002] (Parties to the Joint Research Agreement) This disclosure was made by or on behalf of the parties to the Joint Research Agreement listed below. The Joint Research Agreement was in effect on or prior to the date the claimed invention was made, and the claimed invention was part of and made as a result of activities conducted within the scope of the Joint Research Agreement. The parties to the Joint Research Agreement are JANSSEN BIOTECH, INC. and PROTAGONIST THERAPEUTICS, INC.

[0003] (Inclusion of sequence listing) The ST.26 XML format Sequence Listing, entitled 2948-22_ST26.xml, created on July 13, 2022, containing 2,769,116 bytes, prepared in accordance with 37 CFR 1.822 to 1.824, and submitted contemporaneously with the filing of this application, is hereby incorporated by reference in its entirety.

[0004] FIELD OF THEINVENTION The present invention relates to novel peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharma- ceutically acceptable salts, solvates and / or other forms thereof, and to corresponding pharmaceutical compositions, methods and / or uses of the IL-23R inhibitors for the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders.

[0005] (background) Interleukin-23 (IL-23) cytokine has been implicated as playing an important role in the pathogenesis of autoimmune inflammatory 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 disease pathogenesis. IL-23R is expressed on a variety of 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. Gene expression and protein levels of IL-23R have been found to be increased at the intestinal mucosal surface in IBD patients. IL-23 inhibits pathogenic CD4 T cells that 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.

[0006] IL-23 is produced in abundance in the intestine, where it is believed to play a key role in suppressing regulatory T cell responses in the intestine in favor of inflammation, in addition to controlling the balance between tolerance and immunity via T cell-dependent and T cell-independent pathways of intestinal inflammation by influencing T-helper 1 (Th1) and Th17-associated cytokines. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing a key role for the IL-23 pathway in intestinal homeostasis.

[0007] Psoriasis, a chronic skin disease affecting approximately 2%-3% of the general population, has been shown to be mediated by the body's T cell inflammatory response mechanism. IL-23 is one of several interleukins that is reportedly a key player in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation via induction of interleukin-17, regulation of T memory cells, and activation of macrophages. Expression of IL-23 and IL-23R has been shown to be increased in tissues of psoriasis patients, and antibodies neutralizing IL-23 have shown IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0008] IL-23 binds to a unique p19 subunit and to interferon-γ (IFN-γ)-producing T helper 1 (T H 1) It is a heterodimer composed of a shared p40 subunit with IL-12, a cytokine involved in cell development. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL-12 are prone to inflammatory autoimmune diseases, whereas IL-23-deficient animals are prone to inflammatory autoimmune diseases, presumably due to the CD4+ subunits that produce IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. + Resistance is due to a reduction in the 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 Jak-Stat signaling molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, but compared to IL-12, activation of Stat4 is substantially weaker, and a different DNA-binding Stat complex is formed in response to IL-23. IL-23R constitutively associates with Jak2 and ligand-dependently associates with Stat3. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 acts preferentially on memory CD4(+) T cells.

[0009] Therapeutic moieties that inhibit the IL-23 pathway have been developed for use in the treatment of IL-23-related diseases and disorders. Several antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, which has been approved for the treatment of moderate to severe plaque psoriasis (PSO), active psoriatic arthritis (PSA), moderate to severe active Crohn's disease (CD), and moderate to severe active ulcerative colitis (UC). Examples of such identified antibodies include: Tildrakizumab is an anti-IL23 antibody approved for the treatment of plaque psoriasis, guselkumab is an anti-IL23 antibody approved for the treatment of psoriatic arthritis, and risankizumab is an anti-IL23 antibody approved in the United States for the treatment of plaque psoriasis in the United States and in Japan for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis.

[0010] Although targeted IL-23 antibody therapeutics are in clinical use, there are no small molecule therapeutics that selectively inhibit IL-23 signaling. There are several identified polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R (see, for example, U.S. Patent Application Publication No. US2013 / 0029907). Thus, there is a great need in the art for effective small molecule and / or polypeptide therapeutics for treating and / or preventing IL-23-related and / or IL23R-related diseases and disorders, including, but not limited to, psoriasis (PsO), psoriatic arthritis (PsA), inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD).

[0011] especially, Compounds 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.

[0012] Orally bioavailable small molecule and / or polypeptide inhibitors of IL-23 could provide both a non-steroidal treatment option for patients with mild to moderate psoriasis and a treatment for moderate to severe psoriasis that does not require delivery by injection.

[0013] Compounds 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. In addition, orally bioavailable small molecule and / or polypeptide inhibitors of IL-23 may provide both a non-steroidal treatment option for patients with mild to moderate psoriasis and a treatment for moderate to severe psoriasis that does not require delivery by injection.

[0014] The present invention is directed to addressing these needs by providing peptide inhibitors, or pharma- ceutically acceptable salts, solvates and / or other forms thereof, that bind to IL-23R and inhibit IL-23 binding and signaling via different suitable routes of administration, which may include, but are not limited to, oral administration.

[0015] (overview) In general, the present invention relates to novel peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharma- ceutically acceptable salts, solvates and / or other forms thereof, corresponding pharmaceutical compositions, methods and / or uses of the IL-23R inhibitors, for the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders.

[0016] In particular, the present invention relates to compounds of formula (I'), (I)-(III), or pharma-ceutically acceptable salts, solvates and / or other forms thereof, and to corresponding pharmaceutical compositions, methods and / or uses for the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders.

[0017] The peptide inhibitors of IL-23R of the present invention are represented by the linear structure of formula (I'): R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-R2(I')

[0018] The linear structures of formula (I') are intended for illustrative and non-limiting purposes, as will be apparent from the examples described and illustrated throughout this specification; i.e., each such structure may be longer or shorter in length than 18 amino acids and / or other corresponding chemical moieties or functional group substituents defined herein.

[0019] Specifically, in the formula (I') of the present invention, · X3 to X17 each and individually represent an individual amino acid (aa) residue or other corresponding chemical moiety or functional group substituent as described below and in this invention. ·R1 represents the N-terminus, which may be, for example, a hydrogen or a chemical moiety or functional group substituted on the amino group.

[0020] Similarly, R2 represents the carboxyl terminus, which may be, for example, the OH of the carboxyl or a chemical moiety or functional group attached thereto or substituted at the OH group (for example an amino group to give a terminal amide, e.g., -C(O)HN2). Any of the residues shown in the linear structure may be present or absent, ie, for example, X3 and / or X16-X18 may be absent. In certain embodiments, the peptide inhibitor is may have a bond between positions X4 and X9 (e.g. a pair of Pen or Abu and Cys residues) that forms a disulfide or thioether bond leading to the formation of a first ring structure, (however, the bond forming the first ring structure may be located between other amino acids or chemical moieties other than X4 and X9), and in other embodiments, the peptide inhibitor is The second ring structure may have a bond resulting in a ring bridging the first ring structure or separate ring structures connected by an intervening portion of the molecule.

[0021] The present invention relates to compounds of formula (I'), (I)-(X) or pharma-ceutically acceptable salts, solvates or forms thereof, corresponding pharmaceutical compositions, methods and / or uses for inflammatory, autoimmune inflammatory diseases and / or related disorders.

[0022] In particular, the present invention relates to peptide inhibitors of IL-23R or pharma- ceutically acceptable salts, solvates or other forms thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of diseases, including inflammatory, autoimmune inflammatory diseases and / or related disorders. In particular, inhibitors of IL-23R of the present invention are identified. and / or as described herein and in the disclosure Formulae (I'), (I) to (XX) in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, and Table 1I herein, respectively.

[0023] In one aspect, the invention relates to a compound that is an inhibitor of the IL-23 receptor comprising the amino acid sequence of formula (I): R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(I) During the ceremony, R1 is hydrogen, CH3C(O)-, EtC(O)-, MeSO2, AzCO, BHCO, FPrp triazole MeCO, SMSBCO, biotin, biotinPEG2PEG2CO or DAGSuc; X3 is absent or is dR, dK, PEG6, gEPEG6; X4 is Pen, aMeC, hC, or C; X5 is A, N, Q, N-MeAsn, L, Asn(4C13_2N15), I or K(PEG2PEG2biotin); X6 is T, MeThr, V, K, Dbu, Dpr, or A; X7 is W7Me, W, W(4F7Me), 7MeW, 7PhW, 7EtW, 7FW, 7ClW, 5BrW, or 7(3NAcPh)W'; X8 is KAc, Q, N-MeGln, A, or Cit; X9 is Pen, aMeC, hC, or C; X10 is F4OMe, AEF, F, F4Me, F4Ad, Nal, AEF(Boc), 4PipPhe, AEF(Ac), Y, 4OMeF, 4AmF, D(Pip), Tzl(mPEG3), 3FTyr, Y(OTzl), Y(OTzl(mPEG3)), Tzl, or Tzl(PEG3OH); X11 is Nal, Quin_3, coumarin (7OMe), 2Nal, or 3Quin; X12 is aMeK, THP, Spiral_Pip_Ac, Spiral_Pip, MeK, aMeLeu, aMeL, or aMeK(Boc); X13 is KAc, K; X14 is A, N, L, N-MeAsn, MeLeu, Asn(4C13-2N15), or I; X15 is absent, 3Pya, bAla, thiozolidine, H, dL, N, A, F, aMePhe, Aib, dK, h, 3MeH, 1MeH, tetraFPhe, bMePhe(SR), 5PyrimidAla, v, dR, homoF, Y, y, F(CF3), Y(CHF2) or THP; X16 is MeGly, dL, MeLeu, N-MeNle, y, paf, maf, D3Pya, bAla, P, N(3Am benzyl)Gly, N(4Am benzyl)Gly, 4(R) hydroxyPro, 4(S) aminoPro, 5(R) diMePro or absent. R2 is -OH, -NH2, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, MeNH, or CONHMe; During the ceremony, Inhibitors of the interleukin-23 receptor are cyclized by forming a disulfide bond between penicillamine, cysteine, homocysteine, or alpha-methylcysteine ​​residues at positions X4 and X9.

[0024] The present invention also relates to compounds of formula I or their pharma- ceutically acceptable salts, solvates and / or other forms, corresponding pharmaceutical compositions, methods and / or uses, for the treatment of autoimmune inflammatory diseases and related disorders.

[0025] The present invention also relates to compounds of formulas II-XVIII, respectively, or pharma- ceutically acceptable salts, solvates and / or other forms thereof, corresponding pharmaceutical compositions, methods and / or uses, for the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders.

[0026] The present invention also relates to a compound as set forth in any of Tables 1A-I, respectively, or a pharma- ceutically acceptable salt, solvate and / or other form thereof, corresponding pharmaceutical composition, method and / or use, for the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders.

[0027] The present invention also relates to pharmaceutical compositions comprising a peptide inhibitor compound of the invention described herein, or a pharma- ceutically acceptable salt, solvate, or form thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent.

[0028] The present invention further relates to the use or inclusion of one or more compounds (i.e., for example, compounds of Formulae (I)-(X), Tables 1A-1I or as defined herein) for the preparation of a pharmaceutical composition which may be used for the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders as defined herein.

[0029] The pharmaceutical composition of the present invention may or may not also contain an absorption enhancer, depending on the intended route of delivery or its use for treating a particular indication. The absorption enhancer may be a permeation enhancer and / or an intestinal permeation enhancer. In one aspect, the absorption enhancer improves oral bioavailability.

[0030] The present invention relates to a method and / or use for treating inflammatory, autoimmune inflammatory diseases and / or related disorders, comprising administering to a subject or patient in need of such treatment, respectively: a therapeutically effective amount of one or more peptide inhibitor compounds of IL-23R described herein, or a pharma- ceutically acceptable salt, solvate, and / or other form thereof; or The corresponding pharmaceutical composition The present invention relates to methods and / or uses comprising administering

[0031] Inflammatory, autoimmune inflammatory diseases and / or related disorders contemplated for use with or defined in the present invention may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (pSA), and the like.

[0032] The present invention provides the use of one or more of the compounds described herein of Formulae (I)-(X) or Tables 1A-1I in the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders as defined herein.

[0033] The present invention provides kits comprising one or more compounds as described herein of Formulae (I)-(X) or Tables 1A-1I and instructions for use in treating a disease, inflammatory, autoimmune inflammatory disease, and / or related disorder in a patient or subject in need thereof.

[0034] (Detailed description) I. Overview The present invention relates to novel peptide inhibitors of IL-23R, or pharma- ceutically acceptable salts thereof, corresponding pharmaceutical compositions, methods and / or uses for treating inflammatory, autoimmune inflammatory diseases and / or related disorders. The present invention provides or relates to peptide inhibitors of IL-23R. The peptide inhibitors of the present invention may exhibit enhanced properties, such as longer in vivo half-life, compared to corresponding cyclic peptide inhibitors of IL-23R that do not have a cyclic structure.

[0035] II. Definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0036] "About" when referring to a value includes the recited value + / - 10% of the recited value. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to each of the recited values ​​+ / - 10% of the respective upper and lower limits of the recited range. For example, a ratio of about 1 to about 3 (weight / weight) includes the range of 0.9 to 3.3.

[0037] "Patient" or "subject", used interchangeably, refers to a living organism, including, but not limited to, a human subject suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples can include, but are not limited to, humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other mammals. In some aspects, the patient is a human.

[0038] 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 the 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 differ from those suggestions, they will be made clear to the reader. In the sequences of amino acids representing IL-23 inhibitors, individual amino acids are separated by a hyphen "-" or parentheses, e.g., lysine is indicated as [K].

[0039] Throughout this specification, naturally occurring amino acids, when not referred to by their full name (e.g., alanine, arginine, etc.), are represented by conventional three-letter or one-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless otherwise indicated, the three-letter and one-letter abbreviations of amino acids refer to the L-isomer form of the subject amino acid. As used herein, the term "L-amino acid" refers to the "L" isomeric form of a peptide, and conversely, the term "D-amino acid" refers to the "D" isomeric form of a peptide (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 one-letter abbreviations, may be conventionally represented in lower case. For example, L-arginine may be represented as "Arg" or "R", while D-arginine may be represented as "arg" or "r". Similarly, L-lysine can be represented as "Lys" or "K," and D-lysine can be represented as "lys" or "k." Alternatively, a lower case "d" before an amino acid can be used to indicate that it is in the D-isomeric form, e.g., D-lysine can be represented by dK.

[0040] For less common or non-naturally occurring amino acids, when not referred to by the full name (e.g., sarcosine, ornithine, etc.), the frequently used three- or four-letter abbreviations for the residue are used, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (alpha-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).

[0041] The D-isomer form of the amino acid may be located at any of the positions in the IL-23R inhibitors described herein (any of X1-X18 appearing in the molecule). In one aspect, the D-isomer form of the amino acid may be located only at any one or more of X3, X5, X6, X8, X13, and optionally at one additional position. In other aspects, the D-isomer form of the amino acid may be located only at any one or more of X3, X8, X13, and optionally at one additional position. In other aspects, the D-isomer form of the amino acid may be located only at any one or more of X8, X13 (e.g., X8 is dK(Ac) and X13 is dE), and optionally at one additional position. In other aspects, the D-isomer form of the amino acid may be located only at X3, and optionally at one additional position. In other aspects, the D-isomer form of the amino acid may be located only at X3, and optionally at two or three additional positions. In other aspects, the D-isomer form of the amino acid may be located at only one or two of positions X1-X18 that appear in the IL-23R inhibitors described herein. In other aspects, the D-isomer form of the amino acid may be located at only three or four of positions X1-X18 that appear in the IL-23R inhibitors described herein. For example, an IL-23R inhibitor described herein in which only positions X3-X15 are present may have an amino acid in the D form present at three or four of these positions. In other aspects, the D-isomer form of the amino acid may be located at only five or six of positions X1-X18 that appear in the IL-23R inhibitors described herein.

[0042] As will be apparent to one of skill in the art, peptide sequences disclosed herein are presented proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. Some sequences disclosed herein incorporate either an "-OH" or "-NH2" moiety at the carboxy terminus (C-terminus) of the sequence. In such cases, unless otherwise indicated, the "-OH" or "-NH2" moiety at the C-terminus of the sequence indicates a hydroxy or amino group, respectively, corresponding to the presence of a carboxylic acid (COOH) or amide (CONH2) group at the C-terminus. In each of the sequences of the invention, the C-terminal "-NH2" moiety may be substituted for the C-terminal "-OH" moiety, or vice versa.

[0043] One of skill in the art will appreciate 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, e.g., one or more hydrogens may be removed or replaced upon attachment.

[0044] "Compounds of the invention", "inhibitors of the disclosure", "IL-23R inhibitors of the disclosure", "compounds described herein", and "compounds described herein" may include, but are not limited to, novel compounds disclosed herein, e.g., any of the compounds of the Examples, i.e., for example, compounds of formulas (I)-(X), i.e., for example, those found in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, or Table 1I.

[0045] "Pharmaceutically effective amount" refers to the amount of a compound of the invention in a composition or combination thereof that provides the desired therapeutic or pharmaceutical result.

[0046] By "pharmaceutical acceptable" is meant that the carrier, diluent, salt, solvate or excipient must be compatible with the other components or ingredients of the composition of the present invention, i.e., useful to an extent that it is acceptably useful for pharmaceutical use, safe and non-toxic. According to the present invention, pharmacopoeia means approved or approvable as described in the US Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, and particularly in humans.

[0047] 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 United States Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0048] "Absorption enhancer" refers to a component that improves or facilitates mucosal absorption of a drug in the gastrointestinal tract, e.g., a permeation enhancer or intestinal permeation enhancer. As conventionally understood in the art, a permeation enhancer (PE) is an agent intended to improve the oral delivery of therapeutic agents that have poor bioavailability. PEs can increase the paracellular and / or transcellular passage of a drug.

[0049] Pharmaceutical excipients that can increase permeation are called "Absorption Modifying Excipients" (AMEs). AMEs can be used in oral compositions, for example, as wetting agents (sodium dodecyl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., macrogol glycerides), and can be included in particular compositions as PEs to improve bioavailability. PEs can be classified with respect to how they alter barrier integrity via paracellular or transcellular pathways.

[0050] "Intestinal Permeation Enhancer (IPE)" refers to a component that improves the bioavailability of a component. Representative IPEs suitable for use in the present invention include, but are not limited to, various surfactants, fatty acids, medium chain glycerides, steroid detergents, acylcarnitines and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, as well as chitosan, other mucoadhesive polymers, and the like. For example, an IPE suitable for use in the present invention may be sodium caprate.

[0051] A "composition" or "pharmaceutical composition" as used herein is intended to encompass an invention or product that includes a specific active product ingredient (API), which may include a pharma- ceutically acceptable excipient, carrier, or diluent as described herein, for example, in specific amounts defined throughout this disclosure. A composition or pharmaceutical composition results from a combination of specific components, such as specific ingredients in specific amounts as described herein.

[0052] The composition or pharmaceutical composition of the present invention may be in different pharma- ceutical acceptable forms, which may include, but are not limited to, liquid compositions, tablet or matrix compositions, and capsule compositions.When the composition is a tablet composition, the tablet may include, but are not limited to, different layers, two or more different phases, which may include, but are not limited to, an inner phase and an outer phase, which may include a core.The tablet composition may also include, but are not limited to, one or more coatings.

[0053] As used herein, "solvate" refers to the physical association of the compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of bonding, including hydrogen bonding. In certain cases, the solvate is isolable. The term "solvate" is intended to include both solution-phase solvates and isolable solvates. Non-limiting examples of suitable solvates include hydrates.

[0054] Pharmaceutically acceptable salts and tautomers of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0055] The IL-23R inhibitors of the present invention, their pharma- ceutically acceptable salts, solvates and / or other forms 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), for example, using chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomers are intended to be encompassed. When compounds are represented in their chiral form, it is understood that the embodiment includes, but is not limited to, the particular diastereomeric or enantiomerically enriched form. When chirality is not specified, it is understood that the embodiment is directed to either the particular diastereomeric or enantiomerically enriched form, or to a racemic or scalemic mixture of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomeric enantiomers in a ratio other than 1:1.

[0056] "Racemate" refers to a mixture of enantiomers. The mixture can contain equal or unequal amounts of each enantiomer.

[0057] "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 include individual stereoisomers as well as 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).

[0058] "Tautomer" refers to alternative forms of a compound which differ in the location of a proton, e.g., enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups which contain ring atoms bonded to both the -NH- and =N rings, e.g., pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by those 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 shown with or without one or more dashes without losing their normal 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 by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and both may be linked in either direction. Similarly, "arylalkyl" groups, for example, may 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.

[0060] As used herein, "treatment" or "treat" or "treating" refers to an approach to obtain a beneficial or desired result. For purposes of the present invention, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one aspect, "treatment" or "treating" includes one or more of the following: (a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of a disease or condition), (b) slowing or halting the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition), (c) relieving a disease or condition, e.g., causing regression of clinical symptoms, improving a disease state, delaying disease progression, improving quality of life, and / or prolonging survival.

[0061] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount effective to induce a desired biological or medical response, and includes an amount of a compound that, when administered to a subject to treat a disease, is sufficient to achieve such treatment of the disease. The effective amount varies depending on the compound, the disease and its severity, as well as the age, weight, etc., of the subject to be treated. The effective amount may include a range of amounts. As is understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired or beneficial result can be achieved or is achieved. The suitable dose of any co-administered compound may optionally be reduced due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0062] "Concurrent administration," as used herein, refers to administration of a unit dosage of a compound disclosed herein before or after administration of a unit dosage of one or more additional therapeutic agents, e.g., administration of a compound disclosed herein within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the invention is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound of the invention. In some embodiments, a unit dose of a compound of the invention is administered first, followed hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within hours (e.g., 1-12 hours) later by a unit dose of a compound of the invention. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0063] 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 of volume of a component of the compositions disclosed herein relative to the amount of the total volume of the composition. Thus, the amount is unit less 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 may indicate that 2 mL of one solvent is present in 100 mL of the solvent mixture.

[0064] The abbreviation "(w / w)" refers to the phrase "weight for weight," i.e., the proportion of a particular substance in a mixture as measured by the weight or mass or amount of weight of a component of the compositions disclosed herein relative to the amount of the total weight of the composition. Thus, the amount is unitless and represents the weight percentage amount of the component relative to the total weight of the composition. For example, a 2% (w / w) solution may indicate that 2 grams of solute are dissolved in 100 grams of solution.

[0065] A systemic route of administration, as conventionally understood in the medical or pharmaceutical arts, refers to or is defined as a route of administration in which a drug, pharmaceutical composition or formulation, or other substance enters the circulatory system, thereby exposing various body tissues and organs to the drug, formulation, or other substance. As conventionally understood in the art, administration can be oral (wherein a drug or oral preparation is taken by mouth and absorbed through the gastrointestinal tract), enteral (wherein drug absorption also occurs throughout the gastrointestinal tract), or parenteral (generally, by injection, infusion, or implantation, etc.).

[0066] "Systemically active" peptide pharmacotherapy in the context of the present invention generally refers to treatment with a pharmaceutical composition comprising a peptide active ingredient, where the peptide resists immediate metabolism and / or excretion, resulting in exposure of the peptide in various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous, or immune systems.

[0067] Systemic drug activity in the present invention also refers to treatments using substances that travel throughout the bloodstream to reach and affect cells in various body tissues and organs. Systemically active drugs are transported to their site of action and act throughout the body to attack the physiological processes that cause inflammatory diseases.

[0068] Bioavailability refers to the extent and rate at which an active moiety (drug or metabolite) enters the systemic circulation and thereby gains access to the site of action. The bioavailability of a drug is influenced by the properties of the dosage form, which in turn depend in part on the design and manufacture of the dosage form.

[0069] 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.

[0070] III.Compound The present invention relates to novel cyclic peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharma- ceutically acceptable salts thereof.

[0071] In particular, the present invention relates to cyclic peptide inhibitors of the interleukin-23 receptor (IL-23R), including those whose structures are identified in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, or Table 1I herein, or pharma- ceutically acceptable salts thereof.

[0072] In one embodiment, a cyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound in Table 1A.

[0073] In another embodiment, a cyclic peptide inhibitor compound of an interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound of Table 1B.

[0074] In another embodiment, a cyclic peptide inhibitor compound of an interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound of Table 1C.

[0075] In another embodiment, a cyclic peptide inhibitor compound of an interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound of Table 1D.

[0076] In another embodiment, a cyclic peptide inhibitor compound of an interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound of Table 1E.

[0077] In another embodiment, a cyclic peptide inhibitor compound of an interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound in Table 1F.

[0078] In another embodiment, a cyclic peptide inhibitor compound of an interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound of Table 1G.

[0079] In another embodiment, a peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound in Table 1H.

[0080] In another embodiment, a peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound, or a pharma- ceutically acceptable salt thereof, has the structure of a compound of Table 1I.

[0081] [Table 1]

[0082] [Table 2-1]

[0083] [Table 2-2]

[0084] [Table 2-3]

[0085]

Table 2-4

[0086]

Table 2-5

[0087]

Table 2-6

[0088]

Table 2-7

[0089]

Table 2-8

[0090]

Table 2-9

[0091]

Table 2-10

[0092]

Table 2-11

[0093]

Table 2-12

[0094]

Table 2-13

[0095]

Table 2-14

[0096]

Table 3-1

[0097]

Table 3-2

[0098]

Table 3-3

[0099]

Table 3-4

[0100]

Table 3-5

[0101]

Table 3-6

[0102]

Table 3-7

[0103]

Table 3-8

[0104]

Table 3-9

[0105]

Table 3-10

[0106]

Table 3-11

[0107]

Table 3-12

[0108]

Table 4-1

[0109]

Table 4-2

[0110]

Table 4-3

[0111]

Table 4-4

[0112]

Table 4-5

[0113]

Table 4-6

[0114]

Table 4-7

[0115]

Table 4-8

[0116]

Table 4-9

[0117]

Table 4-10

[0118]

Table 5-1

[0119]

Table 5-2

[0120]

Table 5-3

[0121]

Table 5-4

[0122]

Table 5-5

[0123]

Table 5-6

[0124]

Table 5-7

[0125]

Table 5-8

[0126]

Table 5-9

[0127]

Table 5-10

[0128]

Table 5-11

[0129]

Table 5-12

[0130]

Table 5-13

[0131]

Table 5-14

[0132]

Table 6-1

[0133]

Table 6-2

[0134]

Table 6-3

[0135]

Table 6-4

[0136]

Table 6-5

[0137]

Table 6-6

[0138]

Table 6-7

[0139]

Table 6-8

[0140]

Table 6-9

[0141]

Table 6-10

[0142]

Table 6-11

[0143]

Table 6-12

[0144]

Table 6-13

[0145]

Table 7-1

[0146]

Table 7-2

[0147]

Table 7-3

[0148]

Table 7-4

[0149]

Table 7-5

[0150]

Table 7-6

[0151]

Table 7-7

[0152]

Table 7-8

[0153]

Table 7-9

[0154]

Table 8-1

[0155]

Table 8-2

[0156]

Table 8-3

[0157]

Table 8-4

[0158]

Table 8-5

[0159]

Table 8-6

[0160]

Table 8-7

[0161]

Table 8-8

[0162]

Table 8-9

[0163]

Table 8-10

[0164]

Table 8-11

[0165]

Table 8-12

[0166]

Table 8-13

[0167]

Table 8-14

[0168]

Table 8-15

[0169]

Table 8-16

[0170]

Table 8-17

[0171]

Table 8-18

[0172]

Table 8-19

[0173]

Table 8-20

[0174]

Table 8-21

[0175]

Table 8-22

[0176]

Table 8-23

[0177]

Table 8-24

[0178]

Table 8-25

[0179]

Table 8-26

[0180]

Table 8-27

[0181]

Table 8-28

[0182]

Table 8-29

[0183]

Table 8-30

[0184]

Table 8-31

[0185]

Table 8-32

[0186]

Table 8-33

[0187]

Table 8-34

[0188]

Table 8-35

[0189]

Table 8-36

[0190]

Table 8-37

[0191]

Table 8-38

[0192]

Table 8-39

[0193]

Table 8-40

[0194]

Table 8-41

[0195]

Table 8-42

[0196]

Table 8-43

[0197]

Table 8-44

[0198]

Table 8-45

[0199]

Table 8-46

[0200]

Table 8-47

[0201]

Table 8-48

[0202]

Table 8-49

[0203]

Table 8-50

[0204]

Table 8-51

[0205]

Table 8-52

[0206]

Table 8-53

[0207]

Table 8-54

[0208]

Table 8-55

[0209]

Table 8-56

[0210]

Table 8-57

[0211]

Table 8-58

[0212]

Table 8-59

[0213]

Table 8-60

[0214]

Table 8-61

[0215]

Table 8-62

[0216]

Table 8-63

[0217]

Table 8-64

[0218]

Table 8-65

[0219]

Table 8-66

[0220]

Table 8-67

[0221]

Table 8-68

[0222]

Table 8-69

[0223]

Table 8-70

[0224]

Table 8-71

[0225]

Table 8-72

[0226]

Table 8-73

[0227]

Table 8-74

[0228]

Table 8-75

[0229]

Table 8-76

[0230]

Table 8-77

[0231]

Table 8-78

[0232]

Table 8-79

[0233]

Table 8-80

[0234]

Table 8-81

[0235]

Table 8-82

[0236]

Table 8-83

[0237]

Table 8-84

[0238]

Table 8-85

[0239]

Table 8-86

[0240]

Table 8-87

[0241]

Table 8-88

[0242]

Table 8-89

[0243]

Table 8-90

[0244]

Table 8-91

[0245]

Table 8-92

[0246]

Table 8-93

[0247]

Table 8-94

[0248]

Table 8-95

[0249]

Table 8-96

[0250]

Table 8-97

[0251]

Table 8-98

[0252]

Table 8-99

[0253]

Table 8-100

[0254]

Table 8-101

[0255]

Table 8-102

[0256]

Table 8-103

[0257]

Table 8-104

[0258]

Table 8-105

[0259]

Table 8-106

[0260]

Table 8-107

[0261]

Table 8-108

[0262]

Table 8-109

[0263]

Table 8-110

[0264]

Table 8-111

[0265]

Table 8-112

[0266]

Table 8-113

[0267]

Table 8-114

[0268]

Table 8-115

[0269]

Table 8-116

[0270]

Table 8-117

[0271]

Table 8-118

[0272]

Table 8-119

[0273]

Table 8-120

[0274]

Table 8-121

[0275]

Table 8-122

[0276]

Table 8-123

[0277]

Table 8-124

[0278]

Table 8-125

[0279]

Table 8-126

[0280]

Table 8-127

[0281]

Table 8-128

[0282]

Table 8-129

[0283]

Table 8-130

[0284]

Table 8-131

[0285]

Table 8-132

[0286]

Table 8-133

[0287]

Table 8-134

[0288]

Table 8-135

[0289]

Table 8-136

[0290]

Table 8-137

[0291]

Table 8-138

[0292]

Table 8-139

[0293]

Table 8-140

[0294]

Table 8-141

[0295]

Table 8-142

[0296]

Table 8-143

[0297]

Table 8-144

[0298]

Table 8-145

[0299]

Table 8-146

[0300]

Table 8-147

[0301]

Table 8-148

[0302]

Table 8-149

[0303]

Table 8-150

[0304]

Table 8-151

[0305]

Table 8-152

[0306]

Table 8-153

[0307]

Table 8-154

[0308]

[0309]

Table 8-155

[0310]

Table 9-1

[0311]

Table 9-2

[0312]

Table 9-3

[0313]

Table 9-4

[0314]

Table 9-5

[0315]

Table 9-6

[0316]

Table 9-7

[0317]

Table 9-8

[0318]

Table 9-9

[0319]

Table 9-10

[0320]

Table 9-11

[0321]

Table 9-12

[0322]

Table 9-13

[0323]

Table 9-14

[0324]

Table 9-15

[0325]

Table 9-16

[0326]

Table 9-17

[0327]

Table 9-18

[0328]

Table 9-19

[0329]

Table 9-20

[0330] [Table 9-21]

[0331] [Table 9-22]

[0332] synthesis The compounds described herein may be synthesized by a number of techniques known to those of skill in the art. In certain embodiments, the monomeric subunits are synthesized and purified using techniques described in the accompanying Examples. In some aspects, the invention provides methods of producing the compounds of the invention (or monomeric subunits thereof), which involve chemically synthesizing a peptide having an amino acid sequence as described herein, including, but not limited to, any of the amino acid sequences shown in the compounds of Formulas (I)-(X), Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, and Table 1I herein. In some aspects, a portion of the peptide is recombinantly synthesized instead of being chemically synthesized. In some aspects, the method of producing the compound further comprises cyclizing the compound precursor after the constituent subunits are joined. In certain aspects, cyclization is achieved via any of the various methods described herein.

[0333] Substituted tryptophans can be prepared by any suitable route. The preparation of certain substituted tryptophans, including those substituted at the 7-position, such as 7-ethyl-L-tryptophan, is described, for example, in WO 2021 / 146441(A1).

[0334] The present invention further describes the synthesis of compounds described herein, such as the compounds of formula (I)-(XX) and the compounds of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H and Table 1I. In some embodiments, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently linked to each other to form the compounds of the invention. In some embodiments, one or more of the amino acid residues or amino acid monomers are covalently linked to each other and lipidated at an intermediate oligomer stage, followed by attachment of additional amino acids and cyclization to form the compounds of the invention. In some embodiments, a cyclic peptide is synthesized and then lipidated to form the compounds of the invention. Exemplary synthetic methods are described in the Examples.

[0335] The invention further describes the synthesis of compounds of Formula (I) through Formula (X) and compounds described herein, such as those in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, and Table 1I. Exemplary synthetic methods are described in the Examples.

[0336] IV. Pharmaceutical Compositions The present invention relates to pharmaceutical compositions comprising the IL-23R inhibitors of the present invention. The present invention includes pharmaceutical compositions comprising one or more inhibitors of the present invention and a pharma- ceutically acceptable carrier, diluent, or excipient. The pharma-ceutically acceptable carrier, diluent, or excipient can be a solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation auxiliary. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid, etc. It may be desirable to include isotonic agents, such as sugars, sodium chloride, etc.

[0337] The pharmaceutical composition may be administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (by powder, ointment, eye drop, 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. The pharmaceutical composition may be formulated for oral administration. The pharmaceutical composition may be formulated for parenteral administration.

[0338] In certain embodiments, the IL-23R inhibitor of the present invention is suspended in a sustained release matrix. As used herein, a sustained release matrix is ​​a matrix made of materials, usually polymers, that are degradable by enzymatic or acid-base hydrolysis or by dissolution. When inserted into the body, the matrix is ​​acted upon by enzymes and body fluids. The sustained release matrix is ​​desirably selected from biocompatible materials such as liposomes, polylactides (polylactic acids), polyglycolides (polymers of glycolic acid), polylactide-co-glycolides (copolymers of lactic and glycolic acids), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicones. One embodiment of a biodegradable matrix is ​​a matrix of either polylactide, polyglycolide, or polylactide-co-glycolide (copolymers of lactic and glycolic acid).

[0339] The IL-23R inhibitors of the present invention can be prepared and / or formulated as their pharma- ceutically acceptable salts, solvates and / or other forms, or in neutral form, if appropriate. Pharmaceutically acceptable salts are non-toxic salts of the neutral form of compounds that have the desired pharmacological activity in 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 pharma- ceutically acceptable salts by contacting the compounds with inorganic or organic acids. Non-limiting examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-diol, hexylate ... Examples of suitable pharma- ceutically acceptable salts include 1,6-diaminobenzoate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharma-ceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0340] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium and NX4 salts. +(wherein X is C1-C4 alkyl). Base addition salts, such as sodium or potassium salts, are also included.

[0341] The present invention relates to a pharmaceutical composition comprising an IL-23R inhibitor of the present invention, or a pharma- ceutically acceptable salt, isomer, or mixture thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase the resistance to metabolism and thus may be useful in increasing the half-life of the compounds described herein or pharma- ceutically acceptable salts, isomers, or mixtures thereof when administered to a mammal. See, for example, 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 by deuterium.

[0342] Examples of isotopes that can be incorporated into the disclosed compounds include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 17 O 、15 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I and the like. Positron-emitting isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. 11 C. 18 F, 15O, and 13 Substitution with N may be useful in Positron Emission Topography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds of formula (I) 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.

[0343] In certain embodiments, pharmaceutical compositions for parenteral injection include pharma- ceutical acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, or sterile powders, for reconstitution immediately before use into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, -cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. For example, proper fluidity can be maintained by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0344] Injectable depot forms include those made by forming microencapsule matrices of the peptide inhibitor in one or more biodegradable polymers, for example (poly)glycols, such as polylactide-polyglycolide, poly(orthoesters), poly(anhydrides), and PEG. Depending on the ratio of peptide to polymer and the nature of the particular polymer employed, the rate of release of the peptide inhibitor can be controlled. Depot injectable formulations are also prepared by entrapping the peptide inhibitor in liposomes or microemulsions that are compatible with body tissues.

[0345] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium immediately before use.

[0346] Topical administration includes administration to the skin or mucous membranes, including the lungs and the surface of the eye. Compositions for topical pulmonary administration, including those for inhalation and intranasal use, can include solutions and suspensions in aqueous and non-aqueous formulations, and can be prepared as dry powders, which may or may not be pressurized. In non-pressurized powder compositions, the active ingredient may be in finely divided form or may be used in admixture with a pharma- ceutically acceptable inert carrier of larger size, including particles having a size of up to 100 micrometers in diameter. Suitable inert carriers include sugars, such as lactose.

[0347] Alternatively, the composition may be pressurized and contain compressed gas such as nitrogen or liquefied gas propellant. The liquefied propellant medium, and indeed the entire composition, may be such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surfactant, such as a liquid or solid non-ionic surfactant, or may be a solid anionic surfactant. It is preferred to use a solid anionic surfactant in the form of a sodium salt.

[0348] A further form of local administration is administration to the eye. The peptide inhibitor of the present invention can be delivered in a medicamentously acceptable ophthalmic vehicle so that the peptide inhibitor is maintained in contact with the ocular surface for a sufficient period of time to penetrate the cornea and inner regions of the eye, such as the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary body, lens, choroid / retina, and sclera. The medicamentously acceptable ophthalmic vehicle can be, for example, an ointment, vegetable oil, or an encapsulating material. Alternatively, the peptide inhibitor of the present invention can be directly injected into the vitreous body and aqueous humor.

[0349] Compositions for rectal or vaginal administration preferably include suppositories, which may be prepared by mixing the peptide inhibitors of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax (which is solid at room temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compound).

[0350] The peptide inhibitors of the present invention may also be administered in liposomes or other lipid-based carriers. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present composition in liposomal form may contain stabilizers, preservatives, excipients, and the like, in addition to the peptide inhibitors of the present invention. In certain embodiments, the lipids include phospholipids, including both natural and synthetic phosphatidylcholines (lecithins) and serine. Methods for forming liposomes are known in the art.

[0351] Pharmaceutical compositions suitable for parenteral administration in the methods or uses described herein may comprise sterile aqueous solutions and / or suspensions of an IL:-23R inhibitor, generally made isotonic with the blood of the recipient using sodium chloride, glycerin, glucose, mannitol, sorbitol, or the like.

[0352] The present invention provides pharmaceutical compositions for oral delivery. The compositions and peptide inhibitors of the present invention can be prepared for oral administration according to any of the methods, techniques, and / or delivery vehicles described herein. Furthermore, those skilled in the art will understand that the peptide inhibitors of the present invention can be modified or integrated into systems or delivery vehicles not disclosed herein, but well known in the art, that are compatible for use in oral delivery of peptides.

[0353] Formulations for oral administration may include adjuvants (e.g., resorcinol and / or non-ionic surfactants such as polyoxyethylene oleyl ethers and n-ethers) to artificially increase the permeability of the intestinal wall, and / or enzyme inhibitors (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF), or trasylol) to inhibit enzymatic degradation. In certain embodiments, the peptide inhibitor in a solid dosage form for oral administration may be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer, or glyceride. These dosage forms may also contain other types of additives, such as inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrants, binders, thickening agents, buffers, pH adjusting agents, sweetening agents, flavoring agents, or perfuming agents.

[0354] In certain aspects, oral dosage forms or unit doses suitable for use with the peptide inhibitors of the present invention may include a mixture of the peptide inhibitors with non-drug ingredients or excipients, as well as other non-recyclable materials that may be considered as either ingredients or packaging. Oral compositions may include at least one of liquid, solid, and semi-solid dosage forms. In some embodiments, oral dosage forms are provided that include an effective amount of the peptide inhibitor, the dosage forms including at least one of pills, tablets, capsules, gels, pastes, beverages, syrups, ointments, and suppositories. In some cases, oral dosage forms are provided that are designed and configured to achieve delayed release of the peptide inhibitor in the small intestine and / or colon of a subject.

[0355] Tablets may contain excipients, glidants, fillers, binders, etc. Aqueous compositions are prepared in sterile form and are generally isotonic when intended for delivery other than by oral administration. The compositions may optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents (e.g., EDTA), carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc. The pH of the composition is preferably about 3 to about 11. The pH of the composition may be, for example, in the range of about 5 to about 7 or about 7 to about 10.

[0356] The oral pharmaceutical composition of the present invention may comprise an IL-23R inhibitor of the present invention, which may comprise an enteric coating designed to delay the release of the IL-23R inhibitor in the small intestine. The present invention relates to a pharmaceutical composition comprising an IL-23R inhibitor of the present invention and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation. The pharmaceutical composition (e.g., oral pharmaceutical composition) may comprise an enteric coating that is soluble in gastric juices at a pH of about 5.0 or higher. Such enteric coatings may include polymers with dissociable carboxylic acid groups, such as derivatives of cellulose, including hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, and similar derivatives of cellulose and other carbohydrate polymers.

[0357] Oral pharmaceutical compositions comprising IL-23R inhibitors of the present invention may include an enteric coating designed to protect and release the pharmaceutical composition in a controlled manner in the lower gastrointestinal system of a subject and to avoid systemic side effects. In addition to enteric coatings, the peptide inhibitors of the present invention may be encapsulated, coated, bound, or otherwise associated with any compatible oral drug delivery system or component. For example, in some embodiments, the IL-23R inhibitors of the present invention are provided in a lipid carrier system including at least one of polymeric hydrogels, nanoparticles, microspheres, micelles, and other lipid systems.

[0358] To overcome peptide degradation of the IL-23R inhibitors of the present invention in the small intestine, pharmaceutical compositions may include hydrogel polymer carrier systems in which the peptide inhibitors of the present invention are contained, whereby the hydrogel polymer protects the IL-23R inhibitor from proteolytic degradation in the small intestine and / or colon. The IL-23R inhibitors may further be formulated to be suitable for use with carrier systems designed to increase the dissolution rate and enhance intestinal absorption of the peptide. These methods include the use of liposomes, micelles, and nanoparticles to increase GI tract penetration of the peptides.

[0359] A variety of biologically responsive systems may be combined with one or more of the IL-23R inhibitors of the present invention to provide pharmaceutical agents for oral delivery. For example, the IL-23R inhibitors of the present invention may be combined with biologically responsive systems such as hydrogels and mucoadhesive polymers with hydrogen-bonding groups (e.g., PEG, poly(methacrylic)acid (PMAA), cellulose, Eudragit®, chitosan, and alginates) to provide therapeutic agents for oral administration.

[0360] In certain embodiments, pharmaceutical compositions and formulations may include an IL-23R inhibitor of the present invention and one or more absorption enhancers, enzyme inhibitors, or mucoadhesive polymers. In one embodiment, the absorption enhancer may be an intestinal permeation enhancer.

[0361] The IL-23R inhibitors of the present invention can be formulated into formulation vehicles such as, for example, emulsions, liposomes, microspheres, or nanoparticles.

[0362] Other embodiments of the present invention provide methods for treating a subject with an IL-23R inhibitor of the present invention having an increased half-life. In one aspect, the present invention provides peptide inhibitors having a half-life of at least several hours to a day in vitro or in vivo (e.g., when administered to a human subject) sufficient to administer a therapeutically effective amount once a day (qd) or twice a day (bid). In certain embodiments, the IL-23R inhibitor has a half-life of 3 days or more sufficient to administer a therapeutically effective amount once a week (qw). In certain embodiments, the IL-23R inhibitor has a half-life of 8 days or more sufficient to administer a therapeutically effective amount once every two weeks (biw) or once a month. In certain embodiments, the IL-23R inhibitor is derivatized or modified to have a longer half-life compared to an underivatized or unmodified peptide inhibitor. In certain embodiments, the IL-23R inhibitor comprises one or more chemical modifications to increase serum half-life.

[0363] When used in at least one of the therapeutic or delivery systems described herein, the peptide inhibitors of the present invention may be used in pure form or, if such forms exist, in a pharma- ceutically acceptable salt form.

[0364] The total daily usage of the IL-23R inhibitors and compositions of the present invention can 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 used; c) the particular composition used, the age, weight, general health, sex, and diet of the patient; d) the time of administration, route of administration, and excretion rate of the particular peptide inhibitor used; e) duration of treatment; f) drugs used in combination or concomitantly with the particular peptide inhibitor used, as well as similar factors well known in the medical arts.

[0365] In certain embodiments, the total daily dose of an IL-23R inhibitor of the invention administered to a human or other mammalian host in single or divided doses can be in an amount of, for example, 0.0001-300 mg / kg body weight per day, or 1-300 mg / kg body weight per day.

[0366] The compositions may conveniently be provided in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. 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.

[0367] Compositions suitable for oral administration can be provided as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as powders or granules, as a solution or suspension in an aqueous or non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary or paste. The active ingredient can be administered as a buccal or sublingual formulation. The buccal or sublingual formulation can include the active ingredient in a matrix that releases the active ingredient for transport across the buccal and / or sublingual membranes. The buccal or sublingual formulation can further include a rate-controlling matrix that releases the active compound at a predetermined rate for transport across the buccal and / or sublingual membranes. The buccal or sublingual formulation can further include one or more compounds selected from the group consisting of (i) taste-masking agents, (ii) enhancers, (iii) complexing agents, and mixtures thereof, and (iv) other pharma- ceutically acceptable carriers and / or excipients. The enhancers can be permeation enhancers.

[0368] Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can be optionally coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient from the tablet.

[0369] V. Non-invasive detection of intestinal inflammation The IL-23R inhibitors of the present invention 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 invention are conjugated to a bifunctional chelator. In certain embodiments, the IL-23R inhibitors of the present invention are radioactively labeled. The labeled IL-23R inhibitor is then administered orally or rectally to the 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 intestine and digestive tract of the subject.

[0370] VI. Methods of Treatment and / or Use The present invention relates to a method for treating a subject suffering from a condition or indication associated with IL-23 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), comprising administering to the subject an IL-23R inhibitor as disclosed herein. In one aspect, the present invention relates to a method for treating a subject suffering from a condition or indication characterized by inappropriate, unregulated, or increased IL-23 or IL-23R activity or signaling, comprising administering to the individual a peptide inhibitor of the present invention in an amount sufficient to inhibit (partially or completely) binding of IL-23 to IL-23R in the subject. Inhibition of binding of IL-23 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.

[0371] The present invention relates to a method comprising providing a peptide inhibitor as 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, in particular, be a human.

[0372] The disease or disorder treated by the IL-23R inhibitors of the present invention may be an inflammatory, autoimmune inflammatory disease 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 may be psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, psoriasis purpurativa ... 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, collagen colitis, eosinophilic gastroenteritis / esophagitis, radiation or chemotherapy associated colitis, colitis associated with impaired 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, pericholechial inflammation, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[0373] The present invention relates to a method or use of an IL-23R inhibitor for treating an inflammatory disease in a subject, the method or use comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present invention or a pharma- ceutical acceptable solvate or salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present invention.

[0374] In some aspects, the present invention provides a method for treating an inflammatory disease or an autoimmune inflammatory disease and / or related disorder in a subject, comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present invention or a pharma- ceutical acceptable solvate or salt thereof, or a composition of the present invention.

[0375] Inflammatory, autoimmune inflammatory diseases and / or related disorders suitable for treatment with the compound or its pharma- ceutically acceptable salt or composition of the present invention 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.

[0376] The present invention relates to a method for treating inflammatory, autoimmune inflammatory diseases and / or related disorders in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor disclosed herein (e.g., a peptide inhibitor or IL-23R of any of Formulae (I)-(X) or Tables 1A-1I). The inflammatory disease may be IBD, Crohn's disease or ulcerative colitis. In one aspect, the IBD may be ulcerative colitis. In one aspect, the IBD may be Crohn's disease. In one aspect, the inflammatory disease may be psoriasis (PsO) or psoriatic arthritis (PsA).

[0377] The present invention relates to a method for treating inflammatory, autoimmune inflammatory diseases and / or related disorders in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of any of Formulas I-X) or Tables 1A-1I.

[0378] The inflammatory, autoimmune inflammatory disease and / or related disorder may be IBD, Crohn's disease, or ulcerative colitis. In one aspect, the IBD may be ulcerative colitis. In one aspect, the IBD may be Crohn's disease. In one aspect, the inflammatory disease may be psoriasis (PsO) or psoriatic arthritis (PsA).

[0379] The present invention relates to a method for treating inflammatory, autoimmune inflammatory diseases and / or related disorders in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of any of Formulae I-X) or Tables 1A-1I. The inflammatory disease may be IBD, Crohn's disease or ulcerative colitis. In one aspect, the IBD may be ulcerative colitis. In one aspect, the IBD may be Crohn's disease. In one aspect, the inflammatory disease may be psoriasis (PsO) or psoriatic arthritis (PsA).

[0380] The present invention 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.

[0381] The present invention includes and provides a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in a subject (e.g., or in a subject in need thereof), comprising providing to the subject a peptide inhibitor of IL-23R as described herein. The present invention 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), comprising providing to the subject a peptide inhibitor of IL-23R of the present invention 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 invention 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 does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In further related embodiments, the invention includes a method of inhibiting GI inflammation and / or neutrophil infiltration into the GI tract, comprising providing a peptide inhibitor of the invention to a subject in need thereof. In some embodiments, the method of the invention includes providing a peptide inhibitor of the invention (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 and / or 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.

[0382] The present invention relates to a method for inhibiting IL-23 signaling by a cell, comprising contacting IL-23R with a peptide inhibitor as 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.

[0383] In any of the aforementioned methods, administration of the IL-23R inhibitor to the subject may be oral, although other routes of administration are not excluded. Other routes of administration include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular routes. The dosage of the peptide inhibitor or IL-23R described herein (e.g., any compound of Formulae I-X or Tables 1A-1I) or a salt or solvate thereof administered to the subject can be determined by one of skill in the art, taking into consideration factors including the disease or condition being treated, including its severity, and age, weight, sex, and the like. Exemplary dose ranges include, but are not limited to, about 1 mg to about 1000 mg, or about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, or about 20 mg to about 30 mg. The dose range of the peptide inhibitor or IL-23R described herein may be about 600 mg to about 1000 mg. The dose range of the peptide inhibitors or IL-23R described herein may be from about 300 mg to about 600 mg. The dose range of the peptide inhibitors or IL-23R described herein may be from about 5 mg to about 300 mg. The dose range of the peptide inhibitors or IL-23R described herein may be from about 25 mg to about 150 mg. The dose range of the peptide inhibitors or IL-23R described herein may be from about 25 mg to about 100 mg. The dose range of the peptide inhibitors or IL-23R described herein may be from about 1 mg to about 100 mg. The dose range of the peptide inhibitors or IL-23R described herein may be from about 20 mg to about 40 mg. The dose range of the peptide inhibitors or IL-23R described herein may be from about 20 mg to about 30 mg.

[0384] Aspects of the invention The following embodiments are illustrative of the present invention and are not intended to limit the scope of the invention. Instead, these embodiments provide guidance to those of skill in the art on how to prepare and use the compounds, compositions and methods taught by the present invention, and such skilled artisans will recognize that modifications can be made without departing from the spirit and scope of the invention.

[0385] 1. A peptide inhibitor of the interleukin-23 receptor comprising the amino acid sequence of formula (I): R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 During the ceremony, R1 is hydrogen, CH3C(O)-, EtC(O)-, MeSO2, AzCO, BHCO, FPrp triazole MeCO, SMSBCO, biotin, biotin PEG2 PEG2 CO, DAGSuc; X3 is dR, dK, PEG6, gEPEG6, R, K or absent; X4 is Pen, aMeC, hC, or C; X5 is A, N, Q, N-MeAsn, L, Asn (4C13_2N15), I, K (PEG2PEG2 biotin), X6 is T, MeThr, V, K, Dbu, Dpr, or A; X7 is W7Me, W, W(4F7Me), 7MeW, 7PhW, 7EtW, 7FW, 7ClW, 5BrW, 7(3NAcPh)W'; X8 is KAc, Q, NMeGln, A, Cit, dK(Ac), dQ, dNMeGln, dA, or dCit; X9 is Pen, aMeC, hC, or C; X10 is F4OMe, AEF, F, F4Me, F4Ad, Nal, AEF(Boc), 4PipPhe, AEF(Ac), Y, 4OMeF, 4AmF, D(Pip), Tzl(mPEG3), 3FTyr, Y(OTzl), Y(OTzl(mPEG3)), Tzl, Tzl(PEG3OH), X11 is Nal, Quin_3, coumarin (7OMe), 2Nal, 3Quin, X12 is aMeK, THP, Spiral_Pip_Ac, Spiral_Pip, MeK, aMeLeu, aMeL, aMeK(Boc), X13 is KAc, K, dK(Ac), or dK; X14 is A, N, L, N-MeAsn, MeLeu, Asn(4C13_2N15), or I; X15 is 3Pya, bAla, thiozolidine, H, dL, N, A, F, aMePhe, Aib, dK, h, 3MeH, 1MeH, tetraFPhe, bMePhe(SR), 5PyrimidAla, v, dR, homoF, Y, y, F(CF3), Y(CHF2), THP or absent; X16 is MeGly, dMeGly, dL, MeLeu, dMeLeu, N-MeNle, dN-MeNle, y, paf, maf, d3Pya, bAla, dbAla, P, dP, N(3Am benzyl)Gly, N(4Am benzyl)Gly, 4(R) hydroxyPro, 4(S) aminoPro, 5(R) diMePro or absent; R2 is -OH, -NH2, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, MeNH, or CONHMe; A peptide inhibitor, wherein the inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between penicillamine, cysteine, homocysteine, or alpha-methylcysteine ​​residues at positions X4 and X9.

[0386] 2. An inhibitor of the interleukin-23 receptor according to aspect 1, wherein X4 and X9 are independently selected Pen or hC residues.

[0387] 3. An inhibitor of the interleukin-23 receptor according to aspect 1 or 2, wherein X15 is 3Pya.

[0388] 4. An inhibitor of interleukin-23 receptor according to any one of aspects 1 to 3, wherein X11 is 2Nal or 3Quin.

[0389] 5. An inhibitor of interleukin-23 receptor according to any one of aspects 1 to 4, wherein X7 is 7MeW or W.

[0390] 6. R1 is hydrogen or CH3C(O)-, and The inhibitor of interleukin-23 receptor according to any one of aspects 1 to 5, wherein R2 is -NH2, MeNH, or CONHMe.

[0391] 7. A peptide inhibitor of the interleukin-23 receptor comprising the amino acid sequence of formula (II): R1-X3-Abu-X5-T-X7-X8-X9-AEF-X11-X12-X13-X14-X15-X16-X17-R2(II) During the ceremony, R1 is hydrogen or CH3C(O)-; X3 is dR, R or absent; X4 is Abu, X5 is Q, N or T; X6 is T, X7 is W or 7MeW; X8 is Q, K, KAc, dQ, dK, or dK(Ac); X9 is Pen, C, hC, or aMeC; X10 is an AEF, X11 is 2Nal or Nal, X12 is THP, Acvc, or Achx; X13 is E, KAc, aMeE, Q, AIB, Achx, aMedE, dE, dK(Ac), or dQ; X14 is N or S; X15 is H, bAla, N, 3Pya, F, aMeF, aMeW, 1Nal, 4AmPhe, 2Nal, aMeFPhe, aMePhe, 3,4diFPhe, DY02, 5FW or absent; X16 is MeGly, AIB or absent; X17 is aMeK or absent, R2 is -OH, -NH2, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2; A peptide inhibitor, wherein the inhibitor of the interleukin-23 receptor is cyclized by a thioether bond between an Abu residue at X4 and a cysteine, homocysteine, or alpha-methylcysteine ​​residue at X9.

[0392] 8. The inhibitor of interleukin-23 receptor according to embodiment 7, wherein X9 is aMeC.

[0393] 9. An inhibitor of the interleukin-23 receptor according to aspect 7 or 8, wherein X5 is N.

[0394] 10. An inhibitor of the interleukin-23 receptor according to aspect 7 or 8, wherein X8 is KAc.

[0395] 11. An inhibitor of interleukin-23 receptor according to any one of aspects 7 to 10, wherein X11 is Nal.

[0396] 12. An inhibitor of interleukin-23 receptor according to any one of aspects 7 to 11, wherein X15 is 3Pya.

[0397] 13. R1 is CH3C(O)-, and 13. The inhibitor of interleukin-23 receptor according to any one of aspects 1 to 12, wherein R2 is -NH2.

[0398] 14. A peptide inhibitor of the interleukin-23 receptor comprising the amino acid sequence of formula III, R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(III) During the ceremony, R1 is hydrogen, CH3C(O)-, FPrp triazole MeCO, NH2, EtCO, AzCO, or BHCO; X3 is dR, R, K, or dK; X4 is Pen, Abu, AIB, aMeC, C, hC, Ala, 4R aminoPro, or 4S aminoPro; X5 is N, D, or E; X6 is T, Hyp, or 3OHPro; X7 is 7MeW, W, 3Pya, A, 7PyrW, or 7(3NAcPh)W; X8 is KAc or dKAc; X9 is Pen, C, S5H, AIB, D, E, hC, aMeC; X10 is AEF, AEF(EtCO), AEF(BH), AEF(Ac), bMeAEF(2S3R * ), bMeAEF(2S3S * ), Y, or A; X11 is 2Nal, A, Nal, or W; X12 is THP, X13 is E, KAc, S5H, dE, dKAc, or R5H; X14 is N, S, 3Pya, X15 is 3Pya, H, bAla, v, dR, hF, PAF, F, THP, l, 4Pya, oAMPhe, 3MeH, D3Pya, N, 5Mepyridine Ala, 5Ampyridine Ala, 3quinol Ala, 6OH3Pya, A; X16 is MeGly, R2 is -NH2-HN(C1-C4 alkyl), -N(C1-C4 alkyl)2 or -OH; the inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between penicillamine, cysteine, homocysteine ​​or alpha-methylcysteine ​​residues at positions X4 and X9, or The inhibitor of the interleukin-23 receptor is cyclized by a thioether bond between an Abu residue at X4 and a cysteine, homocysteine, or alpha-methylcysteine ​​residue at X9; or When X4 is 4R aminoPro or 4S aminoPro and X9 is E or D, the inhibitor of interleukin-23 receptor is cyclized by an amide bond between X4 and X9, or When X5 is D or E and X10 contains an AEF residue, the inhibitor of the interleukin-23 receptor is cyclized by an amide bond between X5 and X10, or A peptide inhibitor, wherein when X9 and X13 contain an S5H residue, the inhibitor of the interleukin-23 receptor is cyclized by an aliphatic bond between X9 and X13.

[0399] 15. X4 and X9 are independently selected from Pen, C, and aMeC, X9 is Abu, and the peptide is cyclized by formation of a thioether bond; or 15. A peptide inhibitor of the interleukin-23 receptor according to embodiment 14, wherein X4 and X9 are independently selected from Pen, C, hC and aMeC, and the inhibitor is cyclized by a disulfide bond between the amino acids at positions X4 and X9.

[0400] 16. An inhibitor of the interleukin-23 receptor according to aspect 14, wherein X15 is 5MepyridineAla or 5AmpyridineAla.

[0401] 17. An inhibitor of the interleukin-23 receptor according to any one of aspects 14 to 16, wherein X3 is dR and X4 is Pen.

[0402] 18. An inhibitor of interleukin-23 receptor according to any one of aspects 14 to 17, wherein X11 is 2Nal and X12 is THP.

[0403] 19. An inhibitor of interleukin-23 receptor according to any one of aspects 14 to 18, wherein one or both of X5 and X14 are N.

[0404] 20. An inhibitor of the interleukin-23 receptor according to any one of aspects 14 to 19, wherein R1 is CH3C(O)-.

[0405] 21. An inhibitor of the interleukin-23 receptor according to any one of aspects 14 to 20, wherein R2 is -NH2.

[0406] 22. A peptide inhibitor of the interleukin-23 receptor comprising the amino acid sequence of formula IV, R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(IV) During the ceremony, R1 is hydrogen, CH3C(O)-, Ac_Morph, or MorphCO; X3 is K(AcMorp), Kmorp, dK(AcMorp) or absent; X4 is Pen, C, hC, or aMeC; X5 is L, N, or nLeu; X6 is T or L; X7 is W or 7MeW; X8 is KAc, K(AcMorph), K(isobutyl_Ac), K(butyl_Ac), K(benzyl_Ac), KMorph, K, dKAc, dK(AcMorph), dK(isobutyl_Ac), dK(butyl_Ac), dK(benzyl_Ac), dKMorph, or dK; X9 is Pen, C, hC, or aMeC; X10 is F4OMe, F, AEF, F4Ad, L, F4CN, or 4OMeF; X11 is 2Nal or Nal, X12 is L, THP, Spiral_Pip, aMeK, or aMeL; X13 is L, dL, or nL (i.e., norleucine); X14 is N or L; X15 is 3Pya or absent, X16 is MeGly or absent; R2 is NH(2-(pyridin-3-yl)ethyl), -NH2, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, or -OH; A peptide inhibitor, wherein the inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between penicillamine, cysteine, homocysteine, or alpha-methylcysteine ​​residues at positions X4 and X9.

[0407] 23. An inhibitor of the interleukin-23 receptor according to aspect 22, wherein one or both of X4 and X9 is Pen.

[0408] 24. An inhibitor of the interleukin-23 receptor according to aspect 22 or 23, wherein X3 is absent.

[0409] 25. An inhibitor of the interleukin-23 receptor according to aspect 23 or 24, wherein X8 is KAc or K.

[0410] 26. An inhibitor of interleukin-23 receptor according to any one of aspects 22 to 25, wherein X11 is 2Nal.

[0411] 27. An inhibitor of the interleukin-23 receptor according to any one of aspects 22 to 26, wherein X12 is aMeL or THP.

[0412] 28. R1 is CH3C(O)-, and 28. An inhibitor of interleukin-23 receptor according to any one of aspects 22 to 27, wherein R2 is -OH or NH2.

[0413] 29. A peptide inhibitor of the interleukin-23 receptor comprising the amino acid sequence of formula V, R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-THP-X13-X14-X15-R2(V) During the ceremony, R1 is hydrogen or CH3C(O), propionic acid, EtCO, PentCO, AzCO, MeSO2, NH2, BHCO, FPrp triazole MeCO, (SulfoCy3), (SulfoCy3dPEG2), (SulfoCy3dPEG3), or SMSBCO; X3 is dR, R or absent; X4 is Abu, Pen, C, hC, aMeC, aG, or Dpr; X5 is Q or N; X6 is T, X7 is W, W7Me, 7MeW, bMeW(2S3R), bMeW(2S3S), 7FW, 7ClW, 5BrW, or 5MeW; X8 is Q, K, KAc, Q, dK, or dKAc; X9 is C, Pen, hC, aMeC, aG, E, or D; X10 is AEF, F4OMe, F4Ad, Phe(4(2(Ac)aminoethoxy)), ac, LY02, AEF(Boc), 4PipPhe, AEF(BH), or AEF(SMSB); X11 is 2Nal or Nal, X12 is THP, X13 is E, KAc, K, Q, aMeE, AIB, dE, dKAc, dK, dQ, aMedE, or Achx; X14 is N; The yz), D(N5In), D(NPrAm), dH, D(NEtNH2), 3MeH, 1MeH, TetraFPhe, bMePhe(SR), 5PyrimidAla, 3OHPhe, 4PyridineAla, 3Pya, 4TriazoleAla, bMePhe(2S3S), 2AmTyr, bMeH(2S3S * ), or 5MeH, R2 is -NH2, -OH, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, or CONHMe; the inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between penicillamine, cysteine, homocysteine ​​or alpha-methylcysteine ​​residues at positions X4 and X9, or The inhibitor of the interleukin-23 receptor is cyclized by a thioether bond between an Abu residue at X4 and a cysteine, homocysteine, or alpha-methylcysteine ​​residue at X9; or When X4 is Dpr and X9 is E or D, the inhibitor of interleukin-23 receptor is cyclized by an amide bond between X4 and X9; or When X4 and X9 are aG, the interleukin-23 receptor inhibitor is cyclized by an aliphatic bond between X4 and X9 (generated from a ring-closing metathesis "RCM" reaction).

[0414] 30. An inhibitor of interleukin-23 receptor according to aspect 29, wherein X4 and X9 are aG, and the inhibitor of interleukin-23 receptor is cyclized via an aliphatic bond between X4 and X9.

[0415] 31. An inhibitor of the interleukin-23 receptor according to aspect 29, wherein X4 is Dpr, X9 is E or D, and the inhibitor is cyclized via an amide bond between X4 and X9.

[0416] 32. An inhibitor of the interleukin-23 receptor according to aspect 29, wherein the inhibitor is cyclized by a thioether bond between an Abu residue at X4 and a cysteine, homocysteine, or alpha-methylcysteine ​​residue at X9.

[0417] 33. An inhibitor of the interleukin-23 receptor according to aspect 29, wherein X4 and X9 are independently selected from Pen, C, hC, and aMeC, and the inhibitor is cyclized by a disulfide bond between the amino acids at positions X4 and X9.

[0418] 34. A peptide inhibitor of the interleukin-23 receptor according to any one of aspects 29 to 33, wherein X3 is absent.

[0419] 35. An inhibitor of interleukin-23 receptor according to any one of aspects 29 to 34, wherein X7 is W or W7Me.

[0420] 36. An inhibitor of interleukin-23 receptor according to any one of aspects 29 to 35, wherein one or both of X10 is AEF.

[0421] 37. An inhibitor of interleukin-23 receptor according to any one of aspects 29 to 36, wherein X15 is F, aMePhe, D(NPh), bMePhe(SR), 3OHPhe, tetraFPhe, or bMePhe(2S3S).

[0422] 38.X15 is H, dH, 3MeH, 1MeH, 3MeH, bMeH(2S3S * 38. The inhibitor of interleukin-23 receptor according to any one of aspects 29 to 37, wherein the inhibitor is 5MeH, 5MeH, or 5MeH.

[0423] 39. An inhibitor of the interleukin-23 receptor according to any one of aspects 29 to 38, wherein R1 is CH3C(O)-.

[0424] 40. An inhibitor of the interleukin-23 receptor according to any one of aspects 29 to 39, wherein R2 is NH2.

[0425] 41. A peptide inhibitor of the interleukin-23 receptor, comprising the amino acid sequence of formula VI, R1-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(VI) During the ceremony, R1 is hydrogen or CH3C(O); X4 is Pen, Abu, C, hC, dPen, dC, or aMeC; X5 is L, N, Q, T, dN or absent; X6 is T, L, dT or absent; X7 is W7Me, W(4F7Me), 7PhW, 7MeW, 7EtW, W, 7BrW, 7(2ClPh)W, 7(4CF3Ph)W, 7(3CF3TAZP)W, 7(4NAcPh)W, 7(3NAcPh)W, 7(4OCF3Ph)W, 7(4 OMePh)W, 7(4Paz)W, 7(7Imzpy)W, 7(6(1)7dMeNDAZ))W, 7(3UrPh)W, 7(5(Ina7Pyr))W, 7(4(CpCNPh))W, 7(6(2MeNDAZ))W, BT, D7MeW, X8 is KAc, Q, K(Gly), dKAc, dQ, or dK(Gly); X9 is Pen, C, hC, aMeC, or dPen; X10 is AEF, F4Ad, F4OMe, F4Me, Nal, F, Spiral_Pip, L, 4AmF, AEF(G), dY, or Y; X11 is Nal, 3Quin, 2Nal, 2Quin, d2Nal, or W; X12 is THP, aMeLeu, Acvc, aMeK, or Acpx, A; X13 is E or dE; X14 is N, L, or dN; X15 is 3Pya, THP, N, H, dK, dL, dPaf, PAF, 3MeH, 3pya, or F; X16 is MeGly, dK, K or absent; R2 is -NH2, -OH, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, or CONHMe; The inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between the Pen, C, hC, dPen, dC, or aMeC residue at X4 and the Pen, C, hC, aMeC, or dPen residue at X9; or A peptide inhibitor, wherein the inhibitor of the interleukin-23 receptor is cyclized by a thioether bond between an Abu residue at X4 and a Pen, C, hC, or aMeC residue at X9.

[0426] 42. An inhibitor of the interleukin-23 receptor according to aspect 41, wherein the inhibitor is cyclized by a disulfide bond between Pen, Abu, C, hC, dPen, dC, or aMeC at X4 and Pen, C, hC, aMeC, or dPen X9, and the inhibitor is cyclized by a thioether bond between the Abu residue at X4 and the Pen, C, hC, or aMeC residue at X9.

[0427] 43. An inhibitor of the interleukin-23 receptor according to aspect 41, wherein the inhibitor is cyclized by a disulfide bond between a Pen, C, hC, dPen, dC, or aMeC residue at X4 and a Pen, C, hC, aMeC, or dPen residue at X9.

[0428] 44. An inhibitor of the interleukin-23 receptor according to aspect 43, wherein X4 is Pen or dPen.

[0429] 45. An inhibitor of the interleukin-23 receptor according to aspect 43 or aspect 44, wherein X9 is Pen or dPen.

[0430] 46. ​​An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 45, wherein X5 is N or dN.

[0431] 47. An inhibitor of the interleukin-23 receptor according to any one of aspects 43 to 46, wherein X6 is T or dT.

[0432] 48. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 47, wherein X7 is W, 7MeW, or d7MeW.

[0433] 49. An inhibitor of the interleukin-23 receptor according to any one of aspects 43 to 48, wherein X8 is KAc or dKAc.

[0434] 50. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 49, wherein X10 is AEF(G) or dY.

[0435] 51. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 50, wherein X10 is AEF, F4Ad, F4OMe, F4Me, Nal, F, Spiral_Pip, L, 4AmF, or Y.

[0436] 52. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 51, wherein X11 is 2Nal or d2Nal.

[0437] 53. An inhibitor of the interleukin-23 receptor according to any one of aspects 43 to 52, wherein X12 is THP.

[0438] 54. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 53, wherein X14 is N or dN.

[0439] 55. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 54, wherein X15 is 3Pya or 3pya.

[0440] 56. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 54, wherein X15 is THP, N, H, dK, dL, dPaf, PAF, 3MeH, or F.

[0441] 57. An inhibitor of interleukin-23 receptor according to any one of aspects 43 to 56, wherein X16 is MeGly.

[0442] 58. An inhibitor of the interleukin-23 receptor according to any one of aspects 43 to 56, wherein R2 is NH2.

[0443] 59. A peptide inhibitor of the interleukin-23 receptor, comprising the amino acid sequence of formula VII, R1-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(VII) During the ceremony, R1 is 7Ahp, 6Ahx, 8Aoc, or 5Ava; X5 is N or absent; X6 is T or absent; X7 is 7 MeW or absent, X8 is KAc or absent, X9 is Pen, Aib or absent; X10 is AEF or absent, X11 is 2Nal, X12 is THP, X13 is E, dE, hE, hdE, D, dD, or Q; X14 is N, D, or E; X15 is 3Pya or N; X16 is MeGly, R2 is absent, -NH2-HN(C1-C4 alkyl), -N(C1-C4 alkyl)2 or -OH; The inhibitors of the interleukin-23 receptor are peptide inhibitors which are cyclized by a bond between R1 and the residues at X13, R1 and the residues at X14, or R1 and the residue at X9.

[0444] 60. A peptide inhibitor of the interleukin-23 receptor, comprising the amino acid sequence of formula VIII: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14(VIII) During the ceremony, R1 is hydrogen, CH3C(O)-, FPrp triazole MeCO, NH2, EtCO, AzCO, or BHCO; X3 is dR, R or absent; X4 is Pen, Abu, C, or aMeC; X5 is Q or N; X6 is T, X7 is W or 7MeW; X8 is Q, dQ, KAc, dKAc, X9 is Pen, Abu, C, or aMeC; X10 is AEF or absent, X11 is 2Nal or absent, X12 is THP or absent; X13 is E, dE, D, dD, KAc, dKAc or absent; X14 is N, THP, bAla, N, Pyr or absent; R2 is absent or is -NH2, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2 or -OH; The inhibitors of the interleukin-23 receptor are peptide inhibitors that are cyclized by a disulfide bond between the residues at X4 and X9.

[0445] 61. A peptide inhibitor of the interleukin-23 receptor comprising the amino acid sequence of formula IX, R1-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(IX) During the ceremony, R1 is hydrogen, CH3C(O)-, NH2, or EtCO; X6 is absent, 3OHPro, AIB, or T; X7 is W, 7MeW or absent; X8 is KAc, dKAc, AIB or absent; X9 is S5H, S5Me, aMeS5H, aMeK, aMeK(N3), E, ​​K, or aMePra; X10 is AEF, 4OMeF, or F; X11 is 2Nal, X12 is THP, aMeK, or aMeL; X13 is S5H, S5Me, aMeS5H, aMeK, aMeK(N3), E, ​​dE, D, dD, K, dK, or aMePra; X14 is N or L; X15 is 3Pya or absent, X16 is MeGly, N(iBu)Gly, N(cyclohexyl)Gly, N(3Ambenzyl)Gly, or N(3Ambenzyl)Gly; R2 is absent, -NH2-HN(C1-C4 alkyl), -N(C1-C4 alkyl)2 or -OH; The inhibitors of the interleukin-23 receptor are peptide inhibitors that are cyclized by a bond between the residue at X9 and the residue at X13.

[0446] 62. A peptide inhibitor of the interleukin-23 receptor, comprising the amino acid sequence of formula X, R1-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(X) During the ceremony, R1 is hydrogen, CH3C(O)-, NH2, or EtCO; X6 is AIB, 3OHPro, T or absent; X7 is W, 7MeW or absent; X8 is S5H, KAc or absent; X9 is AIB, S5H, A or absent; X10 is AEF, S5H, hLys, or 4OMeF; X11 is 2Nal, X12 is S5H, aMeK, S5Me, or THP; X13 is KAc, S5H, E, Q, Pen, Abu, C, aMeC, dKAc, dE, dQ, dC, or aMedC; X14 is N, hE, S5H, D or N; X15 is 3Pya, X16 is MeGly, R2 is absent, -NH2-HN(C1-C4 alkyl), -N(C1-C4 alkyl)2 or -OH; The interleukin-23 receptor inhibitor is a peptide inhibitor which is cyclized by a bond between the residues at X9 and X12, between the residues at X9 and X13, between the residues at X10 and X14, or between the residues at X4 and X9.

[0447] 63. An inhibitor of the interleukin-23 receptor provided in any of Tables 1A to 1G.

[0448] 64. Inhibitors of the interleukin-23 receptor provided in Table 1H.

[0449] 65. Inhibitors of the interleukin-23 receptor provided in Table 1I.

[0450] 66. An inhibitor of the interleukin-23 receptor selected from compounds 345, 469, 477 or 478 shown below.

[0451] [Table 10-1]

[0452] [Table 10-2]

[0453] 67. (i) one or more of positions X3, X5, X6, X8, X13 and X16 present in the inhibitor, and optionally one of positions X1 to X2, X4, X7, X9 to X12, X14 to X18; or (ii) A peptide inhibitor of interleukin-23 receptor according to any one of aspects 1 to 66, wherein a D-amino acid is present or substituted by a corresponding L-amino acid at only one or more of positions X3, X8 and X13, and optionally at only one of positions X1 to X2, X4 to X7, X9 to X12, X14 to X18 present in the inhibitor.

[0454] 68. (i) position X3, and optionally one of positions X1-X2, X4-X18 present in the inhibitor; or (ii) A peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 66, wherein a D amino acid is present or substituted with a corresponding L amino acid only at one of positions X3 and X8, and optionally at one of positions X1 to X2, X4 to X7, X9 to X18 present in the inhibitor.

[0455] 69. A peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 66, wherein the inhibitor comprises an amino acid in the D-isomer form or is substituted with a D amino acid in place of the corresponding L amino acid at only one or two of positions X1 to X18 appearing in the IL-23R inhibitors described herein.

[0456] 70. A peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 66, wherein the inhibitor comprises an amino acid in the D-isomer form or is substituted with a D amino acid in place of the corresponding L amino acid at only three or four of positions X1 to X18 appearing in the IL-23R inhibitors described herein.

[0457] 71. A peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 66, wherein the inhibitor comprises an amino acid in the D-isomer form or is substituted with a D amino acid in place of the corresponding L amino acid at only five or six of positions X1 to X18 appearing in the IL-23R inhibitors described herein.

[0458] 72. A peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1-71, wherein the interleukin-23 receptor is a human interleukin receptor.

[0459] 73. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 58, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0460] 74. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 59 to 66, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0461] 75. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to aspect 63 or 66, or a pharma- ceutically acceptable salt, solvate or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0462] 76. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to embodiment 63, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0463] 77. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to embodiment 64, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0464] 78. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to aspect 65, or a pharma- ceutically acceptable salt, solvate, or form thereof; and (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0465] 79. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to aspect 66 or a pharma- ceutical acceptable salt, solvate, or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0466] 80. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to aspect 67 or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0467] 81. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 68 to 72, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharmaceutical composition comprising a pharma- ceutically acceptable carrier, excipient, or diluent.

[0468] 82. Use of a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 73 for the preparation of a medicament.

[0469] 83. Use of a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 73, or a pharmaceutical composition according to any one of aspects 74 to 82, for the preparation of a medicament for the treatment of an inflammatory, autoimmune inflammatory disease and / or related disorder.

[0470] 84. Use of a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 73 or a pharmaceutical composition according to any one of aspects 74 to 82 for the preparation of a medicament for the treatment of an inflammatory, autoimmune inflammatory disease and / or related disorder, wherein the inflammatory, autoimmune inflammatory disease and / or related disorder is a disease or disorder associated with an inflammatory, autoimmune inflammatory disease 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, celiac disease (non-tropical sprue), microscopic colitis, collagen-related colitis, eosinophilic gastroenteritis / esophagitis, radiation or chemotherapy-associated colitis, 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) psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or psoriatic erythroderma, 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 following 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.

[0471] 85. The use according to aspect 84, wherein the disease or disorder is selected from inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO) or psoriatic arthritis (PsA).

[0472] 86. A method for treating a disease or disorder associated with interleukin 23 (IL-23) / interleukin 23 receptor (IL-23R), comprising administering to a patient in need of such treatment: (i) an effective amount of a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 73, or a pharma- ceutically acceptable salt or solvate thereof; or (ii) A method comprising administering a pharmaceutical composition according to any one of aspects 74 to 82.

[0473] 87. The method of embodiment 82, wherein the disease or disorder is associated with autoimmune inflammation.

[0474] 88. The disease or disorder is 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, collagen-related colitis, eosinophilic gastroenteritis / esophagitis, radiation or chemotherapy associated colitis, colitis associated with impaired 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 purpura ... vulgaris), or psoriatic erythroderma), 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 following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral associated enteropathy, pericholechiitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.

[0475] 89. The method of embodiment 82, wherein the disease or disorder is associated with ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

[0476] 90. The method of embodiment 82, wherein the disease or disorder is ulcerative colitis (UC).

[0477] 91. The method of embodiment 82, wherein the disease or disorder is Crohn's disease (CD).

[0478] 92. The method of embodiment 82, wherein the disease or disorder is psoriasis (PsO).

[0479] 93. The method of embodiment 82, wherein the disease or disorder is psoriasis, psoriatic arthritis (PsA).

[0480] 94. A kit comprising a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 72, or a pharmaceutical composition according to any one of aspects 73 to 82, and instructions for the use of the inhibitor of the interleukin-23 receptor or for the use of the pharmaceutical composition.

[0481] 95. The kit of embodiment 94, wherein the instructions are directed to treating an inflammatory disease or disorder.

[0482] 96. The kit according to aspect 95, wherein the disease is inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA). EXAMPLES

[0483] The following examples illustrate the present invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to those skilled in the art for preparing and using the compounds, compositions, and methods of the present invention. Although specific embodiments of the present invention 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 present invention.

[0484] Some abbreviations useful in describing this invention are defined below in Tables 2A-2D.

[0485] [Table 11-1]

[0486]

Table 11-2

[0487]

Table 11-3

[0488]

Table 11-4

[0489]

Table 11-5

[0490]

Table 11-6

[0491]

Table 11-7

[0492]

Table 12

[0493]

Table 13-1

[0494]

Table 13-2

[0495]

Table 13-3

[0496]

Table 13-4

[0497]

Table 13-5

[0498]

Table 13-6

[0499]

Table 13-7

[0500]

Table 13-8

[0501]

Table 13-9

[0502]

Table 13-10

[0503]

Table 13-11

[0504]

Table 13-12

[0505]

Table 13-13

[0506]

Table 13-14

[0507]

Table 13-15

[0508]

Table 13-16

[0509]

Table 13-17

[0510]

Table 13-18

[0511]

Table 13-19

[0512]

Table 13-20

[0513]

Table 13-21

[0514]

Table 13-22

[0515]

Table 13-23

[0516]

Table 13-24

[0517]

Table 13-25

[0518]

Table 13-26

[0519]

Table 13-27

[0520]

Table 13-28

[0521]

Table 13-29

[0522]

Table 13-30

[0523]

Table 13-31

[0524]

Table 13-32

[0525]

Table 13-33

[0526]

Table 13-34

[0527]

Table 13-35

[0528]

Table 13-36

[0529]

Table 13-37

[0530]

Table 13-38

[0531]

Table 13-39

[0532]

Table 13-40

[0533]

Table 13-41

[0534]

Table 13-42

[0535]

Table 13-43

[0536]

Table 13-44

[0537]

Table 13-45

[0538]

Table 13-46

[0539]

Table 13-47

[0540]

Table 13-48

[0541]

Table 13-49

[0542]

Table 13-50

[0543]

Table 13-51

[0544]

Table 13-52

[0545]

Table 13-53

[0546]

Table 13-54

[0547]

Table 13-55

[0548]

Table 13-56

[0549]

Table 13-57

[0550]

Table 13-58

[0551]

Table 13-59

[0552]

Table 13-60

[0553]

Table 13-61

[0554]

Table 13-62

[0555]

Table 13-63

[0556]

Table 13-64

[0557]

Table 13-65

[0558]

Table 13-66

[0559]

Table 13-67

[0560]

Table 13-68

[0561]

Table 13-69

[0562]

Table 14-1

[0563]

Table 14-2

[0564]

Table 14-3

[0565]

Table 14-4

[0566]

Table 14-5

[0567]

Table 14-6

[0568]

Table 14-7

[0569]

Table 14-8

[0570]

Table 14-9

[0571]

Table 14-10

[0572]

Table 14-11

[0573]

Table 14-12

[0574]

Table 14-13

[0575]

Table 14-14

[0576]

Table 14-15

[0577]

Table 14-16

[0578]

Table 14-17

[0579]

Table 14-18

[0580]

Table 14-19

[0581]

Table 14-20

[0582]

Table 14-21

[0583]

Table 14-22

[0584]

Table 14-23

[0585]

Table 14-24

[0586]

Table 14-25

[0587]

Table 14-26

[0588]

Table 14-27

[0589]

Table 14-28

[0590]

Table 14-29

[0591]

Table 14-30

[0592]

Table 14-31

[0593]

Table 14-32

[0594]

Table 14-33

[0595]

Table 14-34

[0596]

Table 14-35

[0597]

Table 14-36

[0598]

Table 14-37

[0599]

Table 14-38

[0600]

Table 14-39

[0601]

Table 14-40

[0602]

Table 14-41

[0603]

Table 14-42

[0604]

Table 14-43

[0605]

Table 14-44

[0606]

Table 14-45

[0607]

Table 14-46

[0608]

Table 14-47

[0609]

Table 14-48

[0610]

Table 14-49

[0611]

Table 14-50

[0612]

Table 14-51

[0613]

Table 14-52

[0614]

Table 14-53

[0615]

Table 14-54

[0616]

Table 14-55

[0617]

Table 14-56

[0618] General peptide synthesis procedure 1 The IL-23R inhibitor compounds described herein were synthesized from amino acid monomers using Merrifield solid phase synthesis technology on a Protein Technology Symphony multichannel synthesizer. Peptides were assembled using HBTU (O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate), diisopropylethylamine (DIEA) coupling conditions. For some amino acid couplings, PyAOP (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate) and DIEA conditions were used. For peptides with C-terminal amides, Rink amide MBHA resin (100-200 mesh, 0.57 mmol / g) was used, and for peptides with C-terminal acids, Wang resin with preloaded N-α-Fmoc protected amino acids was used. Coupling reagents (premixed HBTU and DIEA) were prepared at 100 mmol concentration. Similarly, amino acid solutions were prepared at 100 mmol concentration. The peptide inhibitors of the present invention were identified based on medicinal chemistry optimization and / or phage display and screened to identify those with superior binding and / or inhibitory properties.

[0619] Preparation of Certain Modified Amino Acids Synthesis of 7-(3-N-acetyl-phenyl)-tryptophan (7(3NAcPh)W) (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(7-(3-acetamidophenyl)-1H-indol-3-yl)propanoic acid

[0620] [ka]

[0621] To a solution of 1 (30.0 g, 153 mmol), compound 2 (41.1 g, 230 mmol) and K3PO4 (97.4 g, 459 mmol) in H2O / ethanol (500 mL) was added Pd(dppf)Cl2 (1.12 g, 1.53 mmol) under N2 atmosphere. The mixture was stirred at 80 °C for 16 h. The mixture was filtered. The mixture was concentrated and then extracted with ethyl acetate (500 mL × 2) and dried over anhydrous Na2SO4. The organic layer was concentrated and purified by FCC (eluent: petroleum ether / ethyl acetate = 1:0 to 55:45) to give 3 (25.0 g, yield: 62.5%) as a yellow oil. MS (ESI): mass calculated for C16H14N2O, 250.295, m / z, found 251.0 [M+].

[0622] To a 1 L round bottom flask containing a solution of 3 (12.0 g, 47.9 mmol) in DMF (300 mL), bromine (Br2, 2.422 mL, 47.0 mmol) was added slowly. The mixture was stirred at 25 °C for 16 h. The solution was added to aqueous sodium sulfite (500 mL) and the mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filter cake was mixed with H2O (400 mL) and stirred at 25 °C for 1 h. The mixture was filtered and the solid was collected to give 4 as a crude product, which was purified by preparative high performance liquid chromatography (column: Phenomenex C18 250 × 50 mm × 10 um, condition: water (FA)-CAN (20%-60%)). The mixture was concentrated, extracted with CHCl2 (1 L × 2), washed with brine, and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated to give 4 as an off-white solid (9.70 g, yield: 60.8%). MS(ESI):C 16 H 13 Calculated mass of BrNO: 329.191, m / z, measured mass: 328.8 [M].

[0623] A 250 mL three-necked round bottom flask was charged with activated Zn powder (5.84 g, 89.3 mmol), DMF (120 mL), and I2 (382 mg, 1.50 mmol) was added at room temperature under N2 atmosphere. After stirring for 20 min, a solution of 5 (13.6 g, 30.1 mmol) in DMF (30 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 30 min, after which 4 (9.70 g, 29.5 mmol), tris(dibenzylideneacetone)-palladium (826 mg, 0.902 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (617 mg, 1.50 mmol) were added under N2 atmosphere. The reaction mixture was stirred at 50 °C for 12 h, after which the solvent was removed under reduced pressure to give crude product 6. The crude product was extracted with ethyl acetate (1500 mL). The extract was washed with HO (500 mL x 2), followed by brine (500 mL), which was then dried over anhydrous NaSO, filtered, and concentrated to dryness in vacuo to give crude intermediate 6, which was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether (EtOAc / PE)) to give 6 (11.0 g, yield: 63.8%) as a tan oil. MS (ESI): C 35 H 31 Calculated mass for N3O5: 573.638, m / z, measured mass: 574.1 [M+1].

[0624] Intermediate 6 (11.0 g, 19.2 mmol), a stir bar, Me3SnOH (3.64 g, 20.1 mmol) and DCE (150 mL) were added to a 250 mL round bottom flask and stirred at 50 °C for 12 h. 2N HCl was added to the reaction mixture to adjust the pH to 6. A second reaction was carried out starting from intermediate 6 and the products were combined for further work-up. The combined reaction mixture was concentrated under reduced pressure to give the crude, which was purified by preparative HPLC using Xtimate C18 150 x 40 mm x 5 um (eluent: 38%-68% (v / v) CH3CN and H2O with 0.05% HCl) to give product 7. The product was suspended in water (100 mL) and the mixture was frozen using dry ice / ethanol and then lyophilized to dryness to give 7 (7(3NAcPh)W, 11.8 g, 66.8% yield) as a white solid. MS(ESI):C 34 H 29 Calculated mass for N3O5: 559.611, m / z, measured mass: 560.0 [M+1]. 1 H NMR DMSO-d6 (400MHz) δ10.73(s, 1H), 10.10(s, 1H), 7.52-8.02(m, 7H), 6.96-7.52(m , 9H), 4.03-4.44(m, 3H), 3.25(d, J=13.2Hz, 2H), 3.01-3.15(m, 1H), 2.08(s, 3H).

[0625] Synthesis of 5-methyl-pyridyl-alanine (5MePyridinAla) (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methylpyridin-3-yl)propanoic acid

[0626] [ka]

[0627] Activated Zn powder (8.18 g, 125 mmol), DMF (150 mL) and I2 (0.534 g, 2.11 mmol) were stirred at room temperature for 20 min under N2 atmosphere, then (R)-methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (19.0 g, 42.1 mmol) in DMF (25 mL) was added. The reaction mixture was stirred at room temperature for 30 min, then a mixture of 1 (7.97 g, 46.3 mmol), tris(dibenzylideneacetone)-palladium (1.16 g, 1.26 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.864 g, 2.11 mmol) in DMF (25 mL) was added under N2 atmosphere. The resulting reaction mixture was stirred at 50 °C for 12 h. The solvent was removed under reduced pressure to give the crude product, which was purified by FCC (eluent: petroleum ether:ethyl acetate=1:0 to 0:1 and ethyl acetate:methanol=1:0 to 2:1) to give the product 2 (10.00 g, 57.0% yield) as a pale yellow liquid. MS(ESI): 25 H 24 Calculated mass of N2O4: 416.469, m / z, measured mass: 417.1 [M+H] + .

[0628] To a mixture of 2 (9.50 g, 22.8 mmol) in THF (100 mL) was added LiOH·H2O (1.91 g, 45.6 mmol) in H2O (10 mL). The mixture was stirred at 0 °C for 1 h. TLC showed that most of the SM was consumed. HCl (1N) was added dropwise to the reaction mixture in an ice bath until pH = 5. The reaction mixture was concentrated under reduced pressure, then poured into water (200 mL), and the mixture was extracted with THF (200 mL × 3). The organic layers were combined, washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the organic layer was concentrated under reduced pressure to give the crude product 3, which was purified by FCC (eluent: ethyl acetate:methanol = 1:0 to 2:1) to give 3 (5MePyridine Ala, 6.716 g, yield: 72.3%) as a white powder. MS (ESI): C 24 H 22 Calculated mass of N2O4: 402.442, m / z, measured mass: 403.1 [M+H]+ . 1 H NMR DMSO-d6 (Bruker_400MHz): δ8.18(s, 2H), 7.88(d, J=7.6Hz, 2H), 7.63(d, J=7.2Hz, 2H), 7.45-7.26(m, 5H), 6.81 (s, 1H), 4.33-4.21(m, 1H), 4.20-4.09(m, 2H), 3.95(s, 1H), 3.06-3.05(m, 1H), 2.92-2.89(m, 1H), 2.18(s, 3H).

[0629] Synthesis of AEF(G) (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)ethoxy)phenyl)propanoic acid

[0630] [ka]

[0631] Starting material 1 (9.9 g, 62.2 mmol), a stir bar, Et3N (14 mL, 101 mmol), and dichloromethane (DCM, 250 mL) were added to a 500 mL round bottom flask. The resulting mixture was treated with 2 (10 g, 34.6 mmol) in small portions under ice-water bath. The reaction mixture was then stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (800 mL) and extracted with DCM (400 mL x 2). The organic extracts were combined, washed with brine (800 mL), and concentrated to give crude intermediate 3 as a yellow solid. The crude intermediate was triturated with ethyl acetate (50 mL) and the suspension was isolated by filtration. The filter cake was washed with ethyl acetate (20 mL x 3) and dried under reduced pressure to give 3 (7.12 g, 49%) as a white solid. MS (ESI): C 19 H 29 Calculated mass of N3O5S6: 411.5, m / z, measured mass: 412.1 [M+H] + .

[0632] Starting material 4 (50.0 g, 148 mmol), a stir bar, DMF (300 mL), and K2CO3 (102 g, 739 mmol) were added to a nitrogen-purged 1000 mL round-bottom flask. The flask was then evacuated and backfilled with nitrogen (×3), after which 1,2-dibromoethane (154 mL, 1.78 mol) was added and the resulting mixture was stirred at 80 °C under N2 atmosphere for 16 h. The reaction mixture was filtered and concentrated to dryness under reduced pressure to give the crude product, which was subjected to silica gel chromatography (eluent: EtOAc:petroleum ether = 0-60%) to give 5 (64 g, 96%) as a light yellow oil. MS (ESI): C 20 H 30 Calculated mass of BrNO5: 444.36, m / z, measured mass: 466.1 [M+Na] + .

[0633] Intermediate 5 (6.1 g, 13.7 mmol), 3 (6.2 g, 15.1 mmol), K2CO3 (7.6 g, 55.0 mmol), a stir bar, and CH3CN (100 mL) were placed in a 250 mL round bottom flask. The reaction mixture was stirred at 80 °C under N2 atmosphere for 16 h. The reaction mixture was cooled to room temperature, diluted with H2O (200 mL), and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with brine (300 mL), and concentrated to give crude intermediate 6. The crude intermediate was purified by flash column chromatography (FCC, eluent: ethyl acetate / petroleum ether = 0:1 to 2:1) to give 6 (6.62 g, 44.2%) as a white solid. MS (ESI): C 39 H 58 N4O 10 Calculated mass of S: 774.9, m / z, measured mass: 775.5 [M+H] + .

[0634] Intermediate 6 (6.6 g, 8.52 mmol), HCl / 1,4-dioxane (90 mL, 4 M), a stir bar, and 1,4-dioxane (30 mL) were placed in a 250 mL round bottom flask. The resulting mixture was stirred at 25° C. for 1 h. The solvent was removed under reduced pressure to give Intermediate 7 (7.8 g, crude) as a colorless oil, which was used directly in the next step. MS (ESI): 25 H34 Calculated mass of N4O6S: 518.6, m / z, measured mass: 519.2 [M+H] + .

[0635] Intermediate 7 (7.80 g, 15.0 mmol), stir bar, Na2CO3 (3.19 g, 30.1 mmol), Fmoc-OSu (5.58 g, 16.5 mmol), 1,4-dioxane (50 mL), and HO (50 mL) were added to a 250 mL round bottom flask at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours, after which it was adjusted to pH = 5-6 with HCl (2M) and the resulting reaction mixture was extracted with EtOAc (150 mL x 3). The organic phases from the extraction were combined, washed with brine (200 mL), and concentrated to give crude intermediate 7. The crude intermediate was purified by preparative HPLC using column: Phenomenex C18 150 x 40 mm x 5 um (eluent: 42%-72% (v / v) CH3CN and HO with 0.1% HCl) to give the pure product. The product was suspended in water (100 mL) and the mixture was frozen using dry ice / ethanol and then lyophilized to dryness to give the desired compound 8 (AEF(G), 4 g, 36%) as a white solid. MS (ESI): C 40 H 44 Calculated mass of N4O8S: 740.9, m / z, measured mass: 741.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): 7.87 (d, J=7.2Hz, 2H), 7.71-7.62 (m, 2H), 7.39 (td, J=4.0, 7.2Hz, 2H), 7.29 (td, J=7.6, 12.0Hz, 2H), 7.14(brd, J=8.0Hz, 2H), 6.99-6.85(m, 1H), 6.77(brd, J=8.4Hz, 2H), 6.59- 6.50(m, 1H), 4.21-4.06(m, 4H), 3.88(brs, 2H), 3.42-3.36(m, 4H), 2.99(brdd, J=4.4, 14.0Hz, 1H), 2 .92(s, 2H), 2.78(brdd, J=10.8, 13.6Hz, 1H), 2.47(brs, 3H), 2.41(s, 3H), 1.97(s, 3H), 1.38(s, 6H).

[0636] assembly Peptides can be assembled using standard Symphony protocols. Peptide sequences were assembled as follows: Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4 ml DMF, followed by treatment with 2.5 ml 20% 4-methylpiperidine (Fmoc deprotection) for 10 min. The resin was then filtered, washed twice with DMF (4 ml), and treated again with N-methylpiperidine for another 30 min. The resin was washed again three times with DMF (4 ml), followed by addition of 2.5 ml of amino acid and 2.5 ml of HBTU-DIEA mixture. After frequent mixing for 45 min, the resin was filtered and washed three times with DMF (4 ml each). For a typical peptide of the invention, double coupling was performed. After the coupling reaction was completed, the resin was washed three times with DMF (4 ml each) before proceeding to the next amino acid coupling.

[0637] Ring-closing metathesis to form olefins Example of ring-closing metathesis: The resin (100 μmol) was washed with 2 ml of DCM (3×1 min) and then with 2 ml of DCE (3×1 min) before being treated with 2 ml of a 6 mM solution of Grubbs 1st generation catalyst in DCE (4.94 mg ml-1; 20 mol % with respect to resin substitution). The solution was refluxed under nitrogen overnight (12 h) and then drained. The resin was washed three times with DMF (4 ml each); DCM (4 ml) before being dried and cleaved.

[0638] Disconnect After the peptide assembly was complete, the peptide was cleaved from the resin by treatment with a cleavage reagent such as Reagent K (82.5% trifluoroacetic acid, 5% water, 5% thioanisole, 5% phenol, 2.5% 1,2-ethanedithiol), which was able to successfully cleave the peptide from the resin as well as all remaining side chain protecting groups.

[0639] The cleaved peptide was precipitated in cold diethyl ether, followed by two washes with ethyl ether. The filtrate was discarded, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered. The quality of the linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Micromass / Waters ZQ) before purification.

[0640] Oxidation-mediated disulfide bond formation Peptides containing a free thiol (e.g., diPen) were assembled on Rink amide MBHA resin following the general Fmoc-SPPS procedure. The peptide was cleaved from the resin by treatment with the cleavage reagent 90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% triisopropylsilane). The cleaved peptide was precipitated into cold diethyl ether, followed by two washes with ethyl ether. The filtrate was discarded, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered to obtain the desired unoxidized peptide crude peptide.

[0641] The crude cleaved peptides, with e.g., Cys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys at positions X4 and X9, were dissolved in 20 ml water:acetonitrile. Saturated iodine in acetic acid was then added dropwise with stirring until a yellow color persisted. The solution was stirred for 15 minutes and the reaction was monitored by analytical HPLC and LCMS. Once the reaction was complete, solid ascorbic acid was added until the solution was clear. The solvent mixture was then purified by first diluting with water and then loading onto a reverse-phase HPLC instrument (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 5% B and changing to 50% B over 60 minutes at a flow rate of 15 ml / min). The fractions containing the pure product were then freeze-dried on a lyophilizer.

[0642] Thioether bond formation Peptides containing free thiols (e.g., Cys) and hSer(OTBDMS) were assembled on Rink amide MBHA resin following the general Fmoc-SPPS procedure. Chlorination was carried out by treating the resin with PPh3 (10 equiv.) and Cl3CCN (10 equiv.) in DCM for 2 h. The peptides were cleaved from the resin by treatment with the cleavage reagent 90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% triisopropylsilane. The cleaved peptides were precipitated into cold diethyl ether, followed by two washes with ethyl ether. The filtrate was discarded, a second aliquot of cold ether was added, and the procedure was repeated. The crude peptides were dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered to give the desired uncyclized crude peptides.

[0643] Crude peptides bearing free thiols (e.g., Cys, Pen, aMeCys, hCys, (D)Pen, (D)Cys or (D)hCys) at either X4 and X9 or X9 and X4 positions, and alkyl halides (hSer(Cl)) were dissolved in 0.1M TRIS buffer pH 8.5. Cyclization was carried out overnight at room temperature. The solvent mixture was then purified by first diluting 2-fold with water, followed by loading onto a reversed-phase HPLC instrument (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 5% B and changing to 50% B over 60 min at a flow rate of 15ml / min). Fractions containing pure product were then lyophilized on a lyophilizer.

[0644] purification Analytical reversed-phase high performance liquid chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm x 250 mm) (Phenomenex). Semi-preparative reversed-phase HPLC was performed on a Gemini 10 μm C18 column (22 mm x 250 mm) (Phenomenex) or a Jupiter 10 μm, 300 (Å) C18 column (21.2 mm x 250 mm) (Phenomenex). Separation was achieved using a linear gradient of B in buffer A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 15 mL / min (preparative). Separation was achieved using a linear gradient of buffer B in buffer A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 15 mL / min (preparative).

[0645] General Procedure 1A The IL-23R inhibitor compounds described herein were synthesized from amino acid monomers using standard Fmoc solid phase synthesis techniques on a CEM Liberty Blue™ microwave peptide synthesizer. Peptides were assembled using Oxyma / DIC (ethyl cyanohydroxyiminoacetate / diisopropylcarbodiimide) with microwave heating. Rink amide MBHA resin (100-200 mesh, 0.66 mmol / g) was used for peptides with C-terminal amides, and Wang resin with preloaded N-α-Fmoc protected amino acids was used for peptides with C-terminal acids. Oxyma was prepared as a 1 M solution in DMF containing 0.1 M DIEA. DIC was prepared as a 0.5 M solution in DMF. Amino acids were prepared at 200 mM. Peptide inhibitors of the invention were identified based on medicinal chemistry optimization and / or phage display and screened to identify those with superior binding and / or inhibitory properties.

[0646] assembly Alternatively, peptides may be made using standard CEM Liberty Blue™ protocols. The peptide sequence was assembled as follows: Resin (400 mg, 0.25 mmol) was suspended in 10 ml of 50 / 50 DMF / DCM. The resin was then transferred to a reaction vessel in a microwave cavity. Repeated Fmoc deprotection and Oxyma / DIC coupling cycles were used to assemble the peptides. For deprotection, 20% 4-methylpiperidine in DMF was added to the reaction vessel and heated to 90° C. for 65 seconds. The deprotection solution was drained and the resin was washed three times with DMF. For most amino acids, 5 equivalents of amino acid, Oxyma, and DIC were then added to the reaction vessel and the reaction mixture was rapidly heated to 90° C. for 4 minutes with microwave irradiation. For arginine and histidine residues, milder conditions were used to prevent racemization using temperatures of 75 and 50° C., respectively, for 10 minutes. Rare and expensive amino acids were often coupled manually overnight at room temperature using only 1.5-2 equivalents of reagent. Difficult couplings were often double coupled for 2 × 4 min at 90 °C. After coupling, the resin was washed with DMF and the entire cycle was repeated until assembly of the desired peptide was complete.

[0647] Disconnect After peptide assembly was complete, the peptide was then cleaved from the resin by treatment with a standard cleavage cocktail of 91:5:2:2 TFA / HO / TIPS / DODT for 2 h. If more than one Arg(pbf) residue was present, cleavage was allowed to continue for an additional hour.

[0648] The cleaved peptide was precipitated in cold diethyl ether. The filtrate was decanted, a second aliquot of cold ether was added, and the procedure was repeated. The quality of the linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Waters® Micromass® ZQ™) before purification.

[0649] Oxidation-mediated disulfide bond formation Peptides containing a free thiol (eg, diPen) were assembled on Rink amide MBHA resin following the general Fmoc solid phase synthesis, cleavage, and isolation described above.

[0650] The crude cleaved peptides containing two thiols, containing amino acids independently selected from Cys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys, were dissolved in 50 / 50 acetonitrile / water at approximately 2 mg / mL. Saturated iodine in acetic acid was then added dropwise with stirring until a yellow color persisted. The solution was stirred for several minutes and the reaction was monitored by analytical HPLC and LCMS. Once the reaction was complete, solid ascorbic acid was added until the solution was clear. The solvent mixture was then purified by first diluting with water and then loading onto a reverse phase HPLC column (Luna® C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient starting at 15% B and changing to 50% B over 60 minutes at a flow rate of 15 ml / min). The fractions containing the pure product were then freeze-dried on a lyophilizer.

[0651] purification Analytical reversed-phase high performance liquid chromatography (HPLC) was performed on a Gemini® C18 column (4.6 mm x 250 mm) (Phenomenex). Semi-preparative reversed-phase HPLC was performed on a Gemini® 10 μm C18 column (22 mm x 250 mm) (Phenomenex) or a Jupiter® 10 μm, 300 (Å) C18 column (21.2 mm x 250 mm) (Phenomenex). Separation was achieved using a linear gradient of B in buffer A (mobile phase A: water containing 0.15% TFA, mobile phase B: acetonitrile (ACN) containing 0.1% TFA) at flow rates of 1 mL / min (analytical) and 20 mL / min (preparative).

[0652] Example 1. Preparation of peptide of SEQ ID NO:1 Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen]* -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2 ( * Pen-Pen form disulfide bond) (SEQ ID NO: 1)

[0653] [ka]

[0654] The synthesis of SEQ ID NO:1 is prepared using FMOC solid phase peptide synthesis techniques.

[0655] Peptides are assembled on Rink amide MBHA resin using standard FMOC-protected synthesis conditions reported in the literature. The assembled peptides are isolated from the resin and protecting groups by cleavage with strong acid followed by precipitation. Oxidation to form disulfide bonds is performed, followed by purification by reverse phase HPLC (RP-HPLC) and counterion exchange. The final product is obtained by lyophilization of the pure fractions.

[0656] Swollen Resin: Transfer 10 g of Rink Amide MBHA solid phase resin (0.66 mmol / g loading) to a 250 ml peptide vessel equipped with a filter frit, ground glass joint, and vacuum side arm. Wash the resin 3 times with DMF.

[0657] Step 1: Coupling of FMOC-Sarc-OH: Deprotection of the resin-bound FMOC group is achieved by adding 2 resin bed volumes of 20% 4-methyl-piperidine in DMF to the swollen resin, shaking for 3-5 minutes before draining, and adding a second 2 resin bed volumes of 4-methyl-piperidine solution and shaking for another 20-30 minutes. After deprotection of the resin, the resin is washed 3x DMF with shaking. FMOC-Sarc-OH (3 eq, 6.2 g) is dissolved in 100 ml of DMF along with Oxyma (4.5 eq, 4.22 g). Before adding to the deprotected resin, the acid is preactivated by adding DIC (3.9 eq, 4 ml) with shaking for 15 minutes. An additional aliquot of DIC (2.6 eq, 2.65 ml) is then added after approximately 15 minutes of coupling. The progress of the coupling reaction is monitored by a colorimetric Kaiser test. Once the reaction is deemed complete, the resin is washed three times with DMF with shaking before starting the next deprotection / coupling cycle.

[0658] Step 2: Coupling of FMOC-3Pal-OH: FMOC deprotection is again performed by adding 2 resin bed volumes of 20% 4-methyl-piperidine in DMF twice in succession, once for 3-5 min and once for 20-30 min, draining between treatments. The resin is then washed three times before coupling with protected 3-pyridylalanine (3Pal). FMOC-3Pal-OH (3 eq, 7.8 g) is dissolved in DMF along with Oxyma (4.5 eq, 4.22 g). Preactivate with DIC (3.9 eq, 4 ml) for 15 min before adding to Sarc-amide resin. After 15 min, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is determined to be complete by Kaiser test, the resin is again washed three times with DMF before starting the next deprotection / coupling cycle.

[0659] Step 3: Coupling of FMOC-Asn(Trt)-OH: FMOC is removed from the N-terminus of resin-bound 3Pal and washed as previously described. FMOC-Asn(Trt)-OH (2 eq., 8 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) is added to preactivate the acid for approximately 15 minutes prior to addition to the 3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (1.4 eq., 1.43 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is washed three times with DMF before beginning the next deprotection / coupling cycle.

[0660] Step 4: Coupling of FMOC-Glu(OtBu)-OH: FMOC is removed from the N-terminus of the resin-bound asparagine and the resin is washed with DMF as previously described. FMOC-Glu(OtBu)-OH (2 eq., 5.91 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) is added to preactivate the acid for approximately 15 minutes prior to addition to the Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (1.4 eq., 1.43 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is washed three times with DMF before beginning the next deprotection / coupling cycle.

[0661] Step 5: Coupling of FMOC-THP-OH: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as previously described. FMOC-THP-OH (3 eq., 7.36 g) is dissolved in 100 ml of DMF along with Oxyma (4.5 eq., 4.22 g). DIC (3.9 eq., 4 ml) is added to preactivate the acid for approximately 15 minutes prior to addition to the Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (2.6 eq., 2.65 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is washed three times with DMF before beginning the next deprotection / coupling cycle.

[0662] Step 6: Coupling of FMOC-L-Ala(2-naphthyl)-OH(Nal): FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as described above. FMOC-L-Ala(2-naphthyl)-OH (3 eq, 8.66 g) is dissolved in 100 ml of DMF along with Oxyma (4.5 eq, 4.22 g). DIC (3.9 eq, 4 ml) is added to preactivate the acid for approximately 15 minutes before adding to the THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added. Once the reaction was determined to be complete by Kaiser test, the resin was again washed three times with DMF before starting the next deprotection / coupling cycle.

[0663] Step 7: Coupling of FMOC-4-[2-(Boc-amino-ethoxy)]-L-phenylalanine (FMOC-AEF): FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as described above. FMOC-4-[2-(Boc-amino-ethoxy)]-L-phenylalanine (3 eq, 10.8 g) is dissolved in 100 ml of DMF along with Oxyma (4.5 eq, 4.22 g). DIC (3.9 eq, 4 ml) is added to preactivate the acid for approximately 15 minutes prior to addition to the Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is washed three times with DMF before starting the next deprotection / coupling cycle.

[0664] Step 8: Coupling of FMOC-Pen(Trt)-OH: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as before. FMOC-Pen(Trt)-OH (3 eq., 12.14 g) is dissolved in 100 ml of DMF along with Oxyma (4.5 eq., 4.22 g). DIC (3.9 eq., 4 ml) is added to preactivate the acid for approximately 15 minutes before adding to the AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (2.6 eq., 2.65 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is again washed three times with DMF before starting the next deprotection / coupling cycle.

[0665] Step 9: Coupling of FMOC-Lys(Ac)-OH: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as described above. FMOC-Lys(Ac)-OH (2 eq., 5.4 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) is added to preactivate the acid for approximately 15 minutes before adding to the Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (1.4 eq., 1.43 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is again washed three times with DMF before starting the next deprotection / coupling cycle.

[0666] Step 10: Coupling of FMOC-7-Me-Trp-OH: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as described above. FMOC-7-Me-Trp-OH (2 eq., 5.81 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) is added to preactivate the acid for approximately 15 minutes before adding to the Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (1.4 eq., 1.43 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is again washed three times with DMF before starting the next deprotection / coupling cycle.

[0667] Step 11: Coupling of FMOC-Thr(tBu)-OH: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as described above. FMOC-Thr(tBu)-OH (4 eq., 10.5 g) is dissolved in 100 ml of DMF along with Oxyma (6 eq., 5.62 g). DIC (5.2 eq., 5.3 ml) is added to preactivate the acid for approximately 15 minutes before adding to the 7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (2.6 eq., 2.65 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is again washed three times with DMF before starting the next deprotection / coupling cycle.

[0668] Step 12: Coupling of FMOC-Asn(Trt)-OH: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as described above. FMOC-Asn(Trt)-OH (4 eq., 15.8 g) is dissolved in 100 ml of DMF along with Oxyma (6 eq., 5.62 g). DIC (5.2 eq., 5.3 ml) is added to preactivate the acid for approximately 15 minutes before addition to the Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 minutes, an additional aliquot of DIC (2.6 eq., 2.65 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is again washed three times with DMF before starting the next deprotection / coupling cycle.

[0669] Step 13: Coupling of FMOC-Pen(Trt)-OH: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as described above. FMOC-Pen(Trt)-OH (2 eq., 8.1 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 ml) is added to preactivate the acid for about 15 minutes before addition to the Asn(Trt)-Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin. After about 15 minutes, an additional aliquot of DIC (2.6 eq., 2.65 ml) is added to the reaction. Once the reaction is complete as determined by the Kaiser test, the resin is again washed three times with DMF prior to final deprotection and acetate capping of the assembled peptide.

[0670] Step 14: Acetyl Capping: FMOC is removed from the N-terminus of the resin-bound peptide and the resin is washed as previously described. 150 ml of Capping Reagent A (THF / Acetic Anhydride / Pyridine, 80:10:10) is added to the assembled Pen(Trt)-Asn(Trt)-Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-amide resin and shaken for 30 minutes. The resin is washed 3 times with DMF followed by 5 times with DCM. The resin is washed 3 times with DMF followed by 5 times with DCM. The resin is divided into 5-50 ml centrifuge tubes and placed under vacuum for 1.5 hours before cleavage with TFA.

[0671] Step 15: TFA cleavage and ether precipitation: Prepare 200 ml of TFA cleavage cocktail (90 / 5 / 2.5 / 2.5 TFA / water / TIPS / DODT). Add 40 ml of cleavage cocktail to each of the 5 tubes containing the peptide bound to the protected resin and shake for 2 h. Filter the spent resin and divide the filtrate equally between 18-50 ml centrifuge tubes for precipitation. Add cold diethyl ether to each, which forms a white precipitate, which is then centrifuged. Decant and discard the ether, and wash the precipitate two more times with ether. Allow the resulting white precipitate cake to dry overnight in the hood to obtain the crude reduced peptide.

[0672] Step 16: Disulfide oxidation: The crude peptide is oxidized and purified in four 1 L batches. Approximately 2.5 g of crude peptide is dissolved in 1 L of 20% ACN / water. With stirring, a saturated solution of iodine in acetic acid / methanol is added dropwise to the 1 L peptide solution until the yellow / brown color of I2 remains and does not dissipate. The light yellow solution is allowed to stand for 5 min before quenching the excess I2 with a trace of ascorbic acid.

[0673] Step 17: RP-HPLC purification: RP-HPLC purification is performed immediately after each I2 oxidation. A preparative purification column (Phenomenex, Luna, C18(2), 100 Å, 250x50 mm) is equilibrated with 20% MPB in MPA (MPA = 0.1% TFA / water, MPB = 0.1% TFA in ACN) at 70 ml / min. 1 L of quenched oxidized peptide is loaded onto the equilibrated column at 70 ml / min. After the solvent front elutes, a gradient of 25-45% MPB at 70 ml / min is run over 60 min. The desired material is isolated in fractions and each is analyzed by analytical HPLC. Pure fractions from all four purifications are combined and lyophilized to obtain the purified TFA salt ready for counterion exchange.

[0674] Step 18: Counterion exchange to acetate: The same preparative RP-HPLC column is equilibrated with 5% MPB in MPA (MPA=0.3% AcOH in water, MPB=0.3% AcOH in ACN, MPC=0.5M NHOAc in water) at 70 ml / min. The purified peptide TFA salt is dissolved in 50 / 50 ACN / water and diluted to 15% ACN. The solution is loaded onto the equilibrated column at 70 ml / min, where the solvent front elutes. The captured peptide is washed with 5% MPB in MPA for 5 min. The captured peptide is then washed with 5% MPB in MPC at 70 ml / min for 40 min to exchange the counterion to acetate. The captured peptide is washed with 5% MPB in MPA for 10 min at 70 ml / min to remove all NHOAc from the system. Finally, peptides are eluted with a gradient of 5-70% MPB in MPA over 60 min and collected in fractions.

[0675] Step 19: Final lyophilization and analysis: The collected fractions are analyzed by analytical RP-HPLC and all fractions with purity >95% are combined. The combined fractions are lyophilized to give SEQ ID NO:1 as a white powder with a purity of >95% as determined by RP-HPLC. The peptide identity is confirmed by LC / MS of the purified peptide of SEQ ID NO:1, which contains two charged states of the peptide, an M of 950 amu. + 2 / 2, and gives a molecular ion of 1899 amu.

[0676] Example 2. Synthesis of MeCO-r-Pen-NT-7MeW-K(Ac)-Pen-AEF-2Nal-THP-EN-5Mepyridine Ala-Sar-CONH2 (Compound 345, SEQ ID NO: 345)

[0677] [ka]

[0678] Solid Phase Peptide Synthesis: Peptides were chemically synthesized using an optimized 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis protocol. For C-terminal amides, Rink amide MBHA resin was used. Side chain protecting groups were as follows: D-Arg: Pbf; Thr, Glu: Ot butyl; Asn, Pen: trityl; AEF: Boc. For coupling, a 2-3 fold excess of a solution containing Fmoc amino acid, HATU and DIEA (1:0.95:2) in DMF was added to the swollen resin for 1-4 h. Double coupling is used when coupling 2Nal. Removal of the Fmoc protecting group was achieved by treatment with DMF, piperidine (4:1) solution for 30 min. The cycle is repeated until the full-length peptide is obtained.

[0679] Peptide cleavage: The peptide was cleaved from the resin by adding 75 mL of cleavage buffer (5.0% DTT / 2.5% H2O / 2.5% TIS / 90% TFA) to the flask containing the side-chain protected peptide at room temperature and stirring for 3 h. The resin was filtered and washed with 5 mL of TFA. The combined filtrate was precipitated with cold methyl tertbutyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. Crude compound 1 (1.8 g) was obtained from the lyophilized residue.

[0680] Peptide cyclization and purification: Crude peptide compound 1 (1.8 g, 0.86 mmol) was dissolved in 20% MeCN / HO (1000 mL). To the stirred solution of peptide, a solution of iodine in MeOH (0.1 M, 5.0 mL) was added dropwise until the solution remained yellow. After 2 h, LCMS showed the reaction was complete. Excess iodine was quenched by addition of 1 M aqueous NaSO (15 uL), which quickly 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) to give compound 345 (371 mg, 96.4% purity, 17.0% yield for this step, 14.8% overall yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min. LCMS calculated MW: 2068.38, found MW: 1034.5 [(M+2H) / 2].

[0681] Example 3. Synthesis of MeCO-Pen-NT-7MeW-K(Ac)-Pen-AEF(G)-2Nal-THP-EN-3Pya-Sar-CONH2 (Compound 477 SEQ ID NO: 477)

[0682] [ka]

[0683] Solid Phase Peptide Synthesis: Peptides were chemically synthesized using an optimized 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis protocol. For C-terminal amides, Rink amide MBHA resin was used. Side chain protecting groups were as follows: AEF(G): Pbf; Thr, Glu: Ot butyl; Asn, Pen: trityl. For coupling, a 2-3 fold excess of a solution containing Fmoc amino acid, HATU and DIEA (1:0.95:2) in DMF was added to the swollen resin for 1-4 h. Double coupling is used when coupling 2Nal. Removal of the Fmoc protecting group was achieved by treatment with DMF, piperidine (4:1) solution for 30 min. The cycle is repeated until the full-length peptide is obtained.

[0684] Peptide cleavage: The peptide was cleaved from the resin by adding 75 mL of cleavage buffer (5.0% DTT / 2.5% H2O / 2.5% TIS / 90% TFA) to the flask containing the side-chain protected peptide at room temperature and stirring for 3 h. The resin was filtered, washed with 5 mL of TFA, and the combined filtrate was precipitated 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. Crude compound 1 (1.6 g) was obtained from the lyophilized residue.

[0685] Peptide cyclization and purification: Crude peptide compound 1 (1.6 g, 0.824 mmol) was dissolved in 20% MeCN / HO (1000 mL). To the stirred solution of peptide, iodine solution in MeOH (0.1 M, 2.0 mL) was added dropwise until the solution remained yellow. After 2 h, LCMS showed the reaction was complete. Excess iodine was quenched by addition of 1 M aqueous NaSO (15 uL), which quickly 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) to give compound 477 (575 mg, 96.4% purity, 31.0% yield for this step, 25.5% overall yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min (analytical LCMS method). LCMS calculated MW: 1940.21, found MW: 970.7 [(M+2H) / 2].

[0686] Example 4. Synthesis of MeCO-r-Abu(1)-NTWK(Ac)-aMeC(1)-AEF-2Nal-THP-EN-3Pya-Sar-CONH2 (Compound 478, SEQ ID NO: 478)

[0687] [ka]

[0688] Solid Phase Peptide Synthesis: Peptides were chemically synthesized using an optimized 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis protocol. For C-terminal amides, Rink amide MBHA resin was used. Side chain protecting groups were as follows: D-Arg: Pbf; Thr, Glu: Ot butyl; Asn, aMeCys: trityl; AEF, Trp: Boc. For coupling, a 2-3 fold excess of a solution containing Fmoc amino acid, HATU and DIEA (1:0.95:2) or Fmoc amino acid, DIC and HOAT (1:1:1) in DMF was added to the swollen resin for 1-32 h. Double coupling is used when coupling 2Nal, Lys(Ac) and Fmoc-4-Br-L-homoAla-OH. Removal of the Fmoc protecting group was achieved by treatment with DMF, piperidine (4:1) solution for 30 min. Removal of the trityl ("Trt") protecting group for aMeCys was achieved by treatment with a solution of trifluoroacetic acid, triisopropylsilane, and DCM (2.5:2.5:95) for 3 min x 10. For thioether cyclization, a solution containing DIEA (5 equiv.) in DMF was added to the swollen resin for 1 h x 2. The cycle was repeated until the full-length peptide was obtained.

[0689] Synthetic Methods for Thioether Cyclization: Coupling of Fmoc-4-Br-L-HomoAla-OH. After deprotection, the resin was washed with 30 mL of DMF (5 × 0.1 min) followed by the addition of 2.5 mL of Fmoc-4-Br-L-HomoAla-OH in DMF (400 mM) and 2.5 mL of coupling reagents HOAT and DIC (0.16 mL, 1.0 mmol) in DMF (400 mM). The coupling reaction was mixed for 16 h. It was then washed with 30 mL of DMF (5 × 0.1 min) and the coupling was repeated one more time for 16-32 h. After the coupling reaction was completed, the resin was washed with 30 mL of DMF (3 × 0.1 min) before starting the next step.

[0690] Removal of the trityl group on aMeCys was achieved by washing with 30 mL of DMF (5×0.1 min) and DCM (5×0.1 min), followed by addition of 3% TFA and 2.5% TIS in DCM (30 mL) for 3 min×10 (the reaction solution turned from orange to colorless), and washing 3 times with DCM, 5% DIEA in DMF, and DMF.

[0691] On-resin thioether cyclization was achieved by washing the resin with 30 mL of DMF (5×0.1 min) followed by the addition of DIEA (5 eq.) in DMF (30 mL) and mixing the coupling reaction for 1 h. Cleavage test and LCMS showed the reaction was complete. After the coupling reaction was complete, the resin was washed with 30 mL of DMF (3×0.1 min) before starting the next step.

[0692] Peptide cleavage: The peptide was cleaved from the resin by adding 75 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) to the flask containing the side-chain protected peptide at room temperature and stirring for 3 h. The resin was filtered and washed with 5 mL of TFA. The combined filtrate was precipitated 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. The residue was lyophilized to give compound 1 (750 mg, 75.7% yield, crude).

[0693] Peptide purification: The crude peptide was purified by preparative HPLC (A: 0.075% TFA in H2O, B: ACN) to give compound 478 (82 mg, 95.2% purity, 6.72% yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min. LCMS calculated MW: 1980.21, observed MW: 990.6 [(M+2H) / 2].

[0694] Example 5. Biological Assays IL23R reporter assay Compounds were serially diluted in 100% (v / v) DMSO and seeded into 1536-well non-treated 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 exemplary compounds are shown in Table 3b.

[0695] [Table 15-1]

[0696] [Table 15-2]

[0697] DB cell IL23R pSTAT3 cell assay IL-23 is believed to play a central role in supporting and maintaining Th17 differentiation in vivo. This process is thought to be primarily mediated through Signal Transducer and Activator of Transcription 3 (STAT3), and phosphorylation of STAT3 (to yield pSTAT3) leads to upregulation of RORC and pro-inflammatory IL-17. This cellular assay examines the levels of pSTAT3 in IL-23R-expressing DB cells upon stimulation with IL-23 in the presence of test compounds. Serial dilutions of test peptides and IL-23 (Humanzyme #HZ-1261) at a final concentration of 0.5 nM were added to each well of a 96-well tissue culture plate (Corning #CLS3894). DB cells (ATCC#CRL-2289) cultured in RPMI-1640 medium (Thermo Scientific#11875093) supplemented with 10% FBS were added at 5x10E5 cells / well and incubated at 37°C for 30 min in a humidified incubator with 5% CO2. Changes in phospho-STAT3 levels in cell lysates were detected using the Cisbio HTRF pSTAT3(Tyr705) Cell Assay Kit (Cisbio#62AT3PEH) following the manufacturer's 2-plate assay protocol. From these data, IC 50 IC values ​​were determined for exemplary compounds. 50 The data are shown in Table 4.

[0698] [Table 16]

[0699] 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-agglutination wash solution, the cells were counted and resuspended at 2x105 cells per mL in XF-TCEM supplemented with penicillin / streptomycin and 100ng / mL IL-1 (BioLegend, 579404) and cultured in tissue culture flasks coated with anti-CD3 (eBioscience, 16-0037-85 or BDPharmingen, 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 4 hours at 37°C in 5% CO2. After this "starvation", a total of 6x104 cells in 30μL of RPMI-BSA were transferred to each well of a 384-well plate that had previously been spotted with peptide or DMSO. Cells were incubated for 30 minutes before adding IL-23 at a final concentration of 5ng / 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). Results are shown below.

[0700] [Table 17]

[0701] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be made within the scope of the appended claims upon review of the specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and by reference to the specification, along with such variations. In addition, each reference provided herein is incorporated by reference in its entirety, as if each reference were individually incorporated by reference. In the event of a conflict between this application and a reference provided herein, this application shall control.

Claims

1. A peptide inhibitor of the interleukin-23 receptor of formula (I), comprising the following amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (I) Wherein: R1 is hydrogen, CH3C(O)-, EtC(O)-, MeSO2, AzCO, BHCO, FPrp triazole MeCO, SMSBCO, biotin, biotin PEG2PEG2CO, DAGSuc; X3 is dR, dK, PEG6, gEPEG6, R, K, or absent; X4 is Pen, aMeC, hC, or C; X5 is A, N, Q, N-MeAsn, L, Asn(4C13_2N15), I, or K(PEG2PEG2 biotin); X6 is T, MeThr, V, K, Dbu, Dpr, or A; X7 is W7Me, W, W(4F7Me), 7MeW, 7PhW, 7EtW, 7FW, 7ClW, 5BrW, or 7(3NAcPh)W'; X8 is KAc, Q, NMeGln, A, Cit, dK(Ac), dQ, dNMeGln, dA, or dCit; X9 is Pen, aMeC, hC, or C; X10 is F4OMe, AEF, F, F4Me, F4Ad, Nal, AEF(Boc), 4PipPhe, AEF(Ac), Y, 4OMeF, 4AmF, D(Pip), Tzl(mPEG3), 3FTyr, Y(OTzl), Y(OTzl(mPEG3)), Tzl, or Tzl(PEG3OH); X11 is Nal, Quin_3, coumarin(7OMe), 2Nal, or 3Quin; X12 is aMeK, THP, Spiral_Pip_Ac, Spiral_Pip, MeK, aMeLeu, aMeL, or aMeK(Boc); X13 is KAc, K, dK(Ac), or dK; X14 is A, N, L, N-MeAsn, MeLeu, Asn(4C13_2N15), or I; X15 is 3Pya, bAla, thiazolidine, H, dL, N, A, F, aMePhe, Aib, dK, h, 3MeH, 1MeH, tetraFphe, bMePhe(SR), 5PyrimidAla, v, dR, homoF, Y, y, F(CF3), Y(CHF2), THP, or absent. X16 is MeGly, dMeGly, dL, MeLeu, dMeLeu, N-MeNle, dN-MeNle, y, paf, maf, d3Pya, bAla, dbAla, P, dP, N(3Am benzyl)Gly, N(4Am benzyl)Gly, 4(R)hydroxyPro, 4(S)aminoPro, 5(R)diMePro, or is absent, R2 is -OH, -NH2, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, MeNH, or CONHMe, The inhibitor of the interleukin-23 receptor is a peptide inhibitor cyclized by a disulfide bond between penicillamine residues, cysteine residues, homocysteine residues, or alpha-methylcysteine residues at positions X4 and X9, or a pharmaceutically acceptable salt, solvate, or form thereof.

2. A peptide inhibitor of the interleukin-23 receptor of formula (II), comprising the following amino acid sequence, R1-X3-Abu-X5-T-X7-X8-X9-AEF-X11-X12-X13-X14-X15-X16-X17-R2 (II) Wherein, R1 is hydrogen or CH3C(O)-, X3 is dR, R, or is absent, X4 is Abu, X5 is Q, N, or T, X6 is T, X7 is W or 7MeW, X8 is Q, K, KAc, dQ, dK, or dK(Ac), X9 is Pen, C, hC, or aMeC, X10 is AEF, X11 is 2Nal or Nal, X12 is THP, Acvc, or Achx, X13 is E, KAc, aMeE, Q, AIB, Achx, aMedE, dE, dK(Ac), or dQ, X14 is N or S, X15 is H, bAla, N, 3Pya, F, aMeF, aMeW, 1Nal, 4AmPhe, 2Nal, aMeFPhe, aMePhe, 3,4diFPhe, DY02, 5FW, or is absent, X16 is MeGly, AIB, or is absent, X17 is aMeK, or is absent, R2 is -OH, -NH2, -HN(C1-C4 alkyl), or -N(C1-C4 alkyl)2, The inhibitor of the interleukin-23 receptor is a peptide inhibitor cyclized by a thioether bond between the Abu residue at X4 and the cysteine residue, homocysteine residue, or alpha-methylcysteine residue at X9, or a pharmaceutically acceptable salt, solvate, or form thereof. **Claim 3** A peptide inhibitor of the interleukin-23 receptor of formula (III), comprising the following amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (III) Wherein: R1 is hydrogen, CH3C(O)-, FPrp triazole MeCO, NH2, EtCO, AzCO, or BHCO; X3 is dR, R, K, or dK; X4 is Pen, Abu, AIB, aMeC, C, hC, Ala, 4R amino Pro, or 4S amino Pro; X5 is N, D, or E; X6 is T, Hyp, or 3OHPro; X7 is 7MeW, W, 3Pya, A, 7PyrW, or 7(3NAcPh)W; X8 is KAc, or dKAc; X9 is Pen, C, S5H, AIB, D, E, hC, or aMeC; X10 is AEF, AEF(EtCO), AEF(BH), AEF(Ac), bMeAEF(2S3R*), bMeAEF(2S3S*), Y, or A; X11 is 2Nal, A, Nal, or W; X12 is THP; X13 is E, KAc, S5H, dE, dKAc, or R5H; X14 is N, S, or 3Pya; X15 is 3Pya, H, bAla, v, dR, hF, PAF, F, THP, l, 4Pya, oAMPhe, 3MeH, D3Pya, N, 5Me pyridine Ala, 5Am pyridine Ala, 3 quinole Ala, 6OH3Pya, or A; X16 is MeGly; R2 is -NH2-HN(C1-C4 alkyl), -N(C1-C4 alkyl)2 or -OH; The inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between the penicillamine residue, cysteine residue, homocysteine residue, or alpha-methylcysteine residue at positions X4 and X9, or The inhibitor of the interleukin-23 receptor is cyclized by a thioether bond between the Abu residue at X4 and the cysteine residue, homocysteine residue, or alpha-methylcysteine residue at X9, or when X4 is 4R amino Pro or 4S amino Pro and X9 is E or D, the inhibitor of the interleukin-23 receptor is cyclized by an amide bond between X4 and X9, or when X5 is D or E and X10 contains an AEF residue, the inhibitor of the interleukin-23 receptor is cyclized by an amide bond between X5 and X10, or when X9 and X13 contain an S5H residue, the inhibitor of the interleukin-23 receptor is cyclized by an aliphatic bond between X9 and X13, a peptide inhibitor, or a pharmaceutically acceptable salt, solvate, or form thereof.

4. A peptide inhibitor of the interleukin-23 receptor of formula IV, comprising the following amino acid sequence, R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (IV) wherein R1 is hydrogen, CH3C(O)-, Ac_Morph, or MorphCO, X3 is K(AcMorph), Kmorph, dK(AcMorph), or does not exist, X4 is Pen, C, hC, or aMeC, X5 is L, N, or nLeu, X6 is T or L, X7 is W or 7MeW, X8 is KAc, K(AcMorph), K(isobutyl_Ac), K(butyl_Ac), K(benzyl_Ac), K Morph, K, dKAc, dK(AcMorph), dK(isobutyl_Ac), dK(butyl_Ac), dK(benzyl_Ac), dK Morph, or dK, X9 is Pen, C, hC, or aMeC, X10 is F4OMe, F, AEF, F4Ad, L, F4CN, or 4OMeF, X11 is 2Nal or Nal, X12 is L, THP, Spiral_Pip, aMeK, or aMeL, X13 is L, dL, or nL (i.e., norleucine), X14 is N or L, X15 is 3Pya or does not exist, X16 is MeGly or does not exist, R2 is NH(2-(pyridin-3-yl)ethyl), -NH2, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, or -OH, wherein the inhibitor of interleukin-23 receptor is a peptide inhibitor cyclized by a disulfide bond between penicillamine residues, cysteine residues, homocysteine residues, or alpha-methylcysteine residues at positions X4 and X9, or a pharmaceutically acceptable salt, solvate, or form thereof. **Claim 5** A peptide inhibitor of interleukin-23 receptor of formula (V), comprising the following amino acid sequence, R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-THP-X13-X14-X15-R2 (V) wherein, R1 is hydrogen, or CH3C(O), propionic acid, EtCO, PentCO, AzCO, MeSO2, NH2, BHCO, FPrp triazole MeCO, (SulfoCy3), (SulfoCy3dPEG2), (SulfoCy3dPEG3), or SMSBCO, X3 is dR, R, or absent, X4 is Abu, Pen, C, hC, aMeC, aG, or Dpr; X5 is Q or N, X6 is T, X7 is W, W7Me, 7MeW, bMeW(2S3R), bMeW(2S3S), 7FW, 7ClW, 5BrW, or 5MeW, X8 is Q, K, KAc, Q, dK, or dKAc, X9 is C, Pen, hC, aMeC, aG, E, or D, X10 is AEF, F4OMe, F4Ad, Phe(4(2(Ac)aminoethoxy)), ac, LY02, AEF(Boc), 4PipPhe, AEF(BH), or AEF(SMSB), X11 is 2Nal or Nal, X12 is THP, X13 is E, KAc, K, Q, aMeE, AIB, dE, dKAc, dK, dQ, aMedE, or Achx, X14 is N, X15 is H, bAla, N, F, aMePhe, aMeF, aMeW, 1Nal, 4AmPhe, 2Nal, aMeFPhe, 3,4-diFPhe, DY02, 5FW, D(NBzl), D(NPh), D(NoAn), D(N Pip), D(N Pyr), D(NpAn), D(NmAn), D(N4Pyz), D(N5In), D(NPrAm), dH, D(NEtNH2), 3MeH, 1MeH, tetraFPhe, bMePhe(SR), 5Pyrimid Ala, 3OHPhe, 4-pyridine Ala, 3Pya, 4-triazole Ala, bMePhe(2S3S), 2AmTyr, bMeH(2S3S*), or 5MeH, R2 is -NH2, -OH, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, or CONHMe, the inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between penicillamine residues, cysteine residues, homocysteine residues, or alpha-methylcysteine residues at positions X4 and X9, or the inhibitor of the interleukin-23 receptor is cyclized by a thioether bond between the Abu residue at X4 and a cysteine residue, homocysteine residue, or alpha-methylcysteine residue at X9, or when X4 is Dpr and X9 is E or D, the inhibitor of the interleukin-23 receptor is cyclized by an amide bond between X4 and X9, or when X4 and X9 are aG, the inhibitor of the interleukin-23 receptor is a peptide inhibitor cyclized by an aliphatic bond (generated from a ring-closing metathesis "RCM" reaction) between X4 and X9, or a pharmaceutically acceptable salt, solvate, or form thereof. Claim 6 A peptide inhibitor of the interleukin-23 receptor of formula (VI), comprising the following amino acid sequence, R1-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (VI) wherein, R1 is hydrogen or CH3C(O), X4 is Pen, Abu, C, hC, dPen, dC, or aMeC, X5 is L, N, Q, T, dN, or does not exist, X6 is T, L, dT, or does not exist, X7 is W7Me, W(4F7Me), 7PhW, 7MeW, 7EtW, W, 7BrW, 7(2ClPh)W, 7(4CF3Ph)W, 7(3CF3TAZP)W, 7(4NAcPh)W, 7(3NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(7Imzpy)W, 7(6(1)7dMeNDAZ)), 7(3UrPh)W, 7(5(Ina7Pyr)), 7(4(CpCNPh)), 7(6(2MeNDAZ)), BT, D7MeW, X8 is KAc, Q, K(Gly), dKAc, dQ, or dK(Gly), X9 is Pen, C, hC, aMeC, or dPen, X10 is AEF, F4Ad, F4OMe, F4Me, Nal, F, Spiral_Pip, L, 4AmF, AEF(G), dY, or Y, X11 is Nal, 3Quin, 2Nal, 2Quin, d2Nal, or W, X12 is THP, aMeLeu, Acvc, aMeK, or Acpx, A, X13 is E or dE, X14 is N, L, or dN, X15 is 3Pya, THP, N, H, dK, dL, dPaf, PAF, 3MeH, 3pya, or F, X16 is MeGly, dK, K or does not exist, R2 is -NH2, -OH, -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, or CONHMe, The inhibitor of the interleukin-23 receptor is cyclized by a disulfide bond between Pen, C, hC, dPen, dC, or aMeC at X4 and the Pen, C, hC, aMeC, or dPen residue at X9, or The inhibitor of the interleukin-23 receptor is a peptide inhibitor cyclized by a thioether bond between the Abu residue at X4 and the Pen, C, hC, or aMeC residue at X9, or a pharmaceutically acceptable salt, solvate, or form thereof.

7. A compound having the structure of the compounds described in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table 1I, or a pharmaceutically acceptable salt thereof, and a peptide inhibitor of the interleukin-23 receptor selected from the following compounds 345, 469, 477, or 478, or a pharmaceutically acceptable salt, solvate, or form thereof. 【Table 1-1】 【Table 1-2】

8. The D-amino acid is present in (i) one or more of positions X3, X5, X6, X8 and X13 present in said inhibitor, and optionally one of positions X1-X2, X4, X7, X9-X12, X14-X18, or present only in (ii) one or more of positions X3, X8 and X13 present in said inhibitor, and optionally one of positions X1-X2, X4-X7, X9-X12, X14-X18, or substituted with the corresponding L-amino acid. The peptide inhibitor of interleukin-23 receptor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or form thereof.

9. The D-amino acid is present in (i) position X3 present in said inhibitor, and optionally one of positions X1-X2, X4-X18, or present only in (ii) one of positions X3 and X8 present in said inhibitor, and optionally one of positions X1-X2, X4-X7, X9-X18, or substituted with the corresponding L-amino acid. The peptide inhibitor of interleukin-23 receptor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or form thereof.

10. Said inhibitor contains an amino acid in D-isomeric form at 1 to 6 of positions X1-X18 appearing in said inhibitor, or is substituted with a D-amino acid instead of said corresponding L-amino acid. The peptide inhibitor of interleukin-23 receptor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or form thereof.

11. Said inhibitor contains an amino acid in D-isomeric form at one or two of positions X1-X18 appearing in said inhibitor, or is substituted with a D-amino acid instead of said corresponding L-amino acid. The peptide inhibitor of interleukin-23 receptor according to claim 10, or a pharmaceutically acceptable salt, solvate, or form thereof.

12. Said inhibitor contains an amino acid in D-isomeric form at three or four of positions X1-X18 appearing in said inhibitor, or is substituted with a D-amino acid instead of said corresponding L-amino acid. The peptide inhibitor of interleukin-23 receptor according to claim 10, or a pharmaceutically acceptable salt, solvate, or form thereof.

13. The peptide inhibitor of interleukin-23 receptor according to claim 10, or a pharmaceutically acceptable salt, solvate, or form thereof, wherein the inhibitor contains an amino acid in D-isomeric form at 5 or 6 of positions X1 to X18 appearing in the inhibitor, or is substituted with a D-amino acid in place of the corresponding L-amino acid.

14. A pharmaceutical composition comprising: (i) the peptide inhibitor of interleukin-23 receptor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or form thereof; and (ii) a pharmaceutically acceptable carrier, excipient, or diluent.

15. A pharmaceutical composition comprising: (i) the peptide inhibitor of interleukin-23 receptor according to claim 7, or a pharmaceutically acceptable salt, solvate, or form thereof; and (ii) a pharmaceutically acceptable carrier, excipient, or diluent.

16. A pharmaceutical composition comprising: (i) the peptide inhibitor of interleukin-23 receptor according to claim 8, or a pharmaceutically acceptable salt, solvate, or form thereof; and (ii) a pharmaceutically acceptable carrier, excipient, or diluent.

17. Use of the peptide inhibitor of interleukin-23 receptor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or form thereof, for preparing a medicament for treating inflammatory, autoimmune inflammatory diseases and / or related disorders.

18. Use according to claim 17 for the preparation of a medicament for the treatment of inflammatory, autoimmune inflammatory diseases and / or related disorders, wherein the inflammatory, autoimmune inflammatory diseases and / or related disorders are 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, radiation or chemotherapy-related colitis, colitis associated with innate immune disorders 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, or erythrodermic psoriasis), atopic dermatitis, acne inversa, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogenosis type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, ileitis, ileitis occurring after ileal pouch-anal anastomosis following rectal colectomy, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, virus-related enteropathy, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, uveitis, or graft-versus-host disease.

19. Use according to claim 18 for the preparation of a medicament for the treatment of a disease or disorder selected from inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO) or psoriatic arthritis (PsA).

20. A pharmaceutical composition for use in a method for treating a disease or disorder associated with interleukin 23 (IL-23) / interleukin 23 receptor (IL-23R), the pharmaceutical composition comprising a peptide inhibitor of the interleukin-23 receptor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or form thereof, the method comprising administering to a patient in need thereof an effective amount of the peptide inhibitor of the interleukin-23 receptor, or a pharmaceutically acceptable salt, solvate, or form thereof.

21. The pharmaceutical composition according to claim 20, wherein the disease or disorder is associated with an inflammatory, autoimmune inflammatory disease and / or related disorder.

22. The disease or disorder associated with an inflammatory, autoimmune inflammatory disease and / or related disorder is selected from 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, radiation- or chemotherapy-related colitis, 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, or psoriatic erythroderma), atopic dermatitis, acne inversa, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, ileitis, ileitis occurring after colectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, virus-related enteropathy, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, uveitis, or graft-versus-host disease; the pharmaceutical composition according to claim 21.

23. The pharmaceutical composition according to claim 22, wherein the disease or disorder is associated with an autoimmune disease selected from ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

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