Bicyclic peptide inhibitors of the interleukin-23 receptor

Abstract

The present invention relates to novel bicyclic 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 inflammation and related diseases and disorders.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Application No. 63 / 221,854, 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 before 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] (Incorporating sequence tables) The ST.26 XML formatted Sequence Listing, entitled 2948-15_ST26.xml, created on July 13, 2022, containing 1,941,221 bytes, prepared in accordance with 37 CFR 1.822-1.824 and submitted contemporaneously with the filing of this application, is hereby incorporated by reference in its entirety.

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

[0005] (background) Interleukin-23 (IL-23) cytokine has been proposed to play an important role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel 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 the interferon-γ (IFN-γ)-producing T helper 1 (T Helper 1) subunit. H 1) It is a heterodimer composed of IL-12, a cytokine involved in cell development, and a shared p40 subunit. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL-12 are susceptible to inflammatory autoimmune diseases, whereas IL-23-deficient animals are not, possibly due to the CD4+ subunits that produce IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. + This is due to the lower number of T cells. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. IL-23 binding to IL-23R activates 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 distinct 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 treating IL-23-related diseases and disorders. Several antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, which is 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, an anti-IL23 antibody approved for the treatment of plaque psoriasis, guselkumab, an anti-IL23 antibody approved for the treatment of psoriatic arthritis, and risankizumab, an anti-IL23 antibody approved for the treatment of plaque psoriasis in the United States and generalized pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis in Japan.

[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, e.g., U.S. Patent Application Publication No. 2013 / 0029907).

[0011] Thus, there remains a significant need in the art for effective small molecule and / or polypeptide therapeutics for treating and / or preventing IL-23-associated and / or IL23R-associated diseases and disorders, including, but not limited to, psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease. In particular, 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; and / or 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.

[0012] 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. 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.

[0013] The present invention aims to address these needs by providing bicyclic peptide inhibitors, or pharma- ceutical 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.

[0014] (overview) Generally, the present invention relates to novel bicyclic 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 autoimmune inflammatory diseases and / or related disorders.

[0015] In particular, the present invention relates to compounds of formula (I'), (I)-(III), or pharma- ceutically acceptable salts, solvates and / or other forms thereof, corresponding pharmaceutical compositions, methods and / or uses, for the treatment of autoimmune inflammatory diseases and related disorders.

[0016] The bicyclic 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') 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 the 18 amino acids and / or other corresponding chemical moieties or functional group substituents defined herein.

[0017] Specifically, in formula (I'): 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 the present invention; R1 represents the N-terminus, which may be, for example, hydrogen or a chemical moiety or functional group substituted on the amino group; 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 with 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, for example, X3 and / or X16-X18 may be absent; The peptide inhibitor may have a bond between positions X4 and X9 (e.g. a pair of Pen residues or an Abu residue and a Cys residue) that forms a disulfide bond or a thioether bond resulting in the formation of a first ring of the bicyclic ring structure, but the bond forming the first ring of the bicyclic ring structure may be located between other amino acids or chemical moieties other than X4 and X9; and / or The bond forming the second ring of a bicyclic ring system may result in a ring bridging the first ring system or separate ring systems linked by an intervening portion of the molecule.

[0018] In other embodiments, the second ring of the bicyclic structure may be formed by a bond between X3 and one of X10, X13, X15, X16, or X17. In further embodiments, the peptide may have a second ring of the bicyclic structure provided by a bond between X5 and X10. The second ring of the bicyclic structure may be provided by a bond between X8 and X12. Also included are bicyclic peptides having a second ring of the bicyclic structure provided by a bond between X10 and one of X13, X15, X16, R2, or R3. In some embodiments, the bond between X13 and either X15 or X16 forms the second ring of the bicyclic structure. In further embodiments, the second ring of the bicyclic structure is provided by a bond between R1 and R2. Further details are provided below.

[0019] The present invention relates to compounds of formula (I'), (I)-(XX), their salts, solvates or forms thereof, corresponding pharmaceutical compositions, and methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders.

[0020] In particular, the present invention relates to peptide inhibitors of IL-23R or pharma- ceutically acceptable salts, solvates and / or other forms thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of diseases, including autoimmune inflammatory diseases and related disorders; The IL-23R inhibitor of the present invention is represented by the formula (I'), (I) to (XX); or Tables 1A, 1B, 1C, 1D, 1E, 1F, 1G and 1H of this specification, respectively. It is identified by.

[0021] The present invention provides compounds that are bicyclic inhibitors of the IL-23 receptor comprising the amino acid sequence of formula XIX: R1-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-R2(XIX) During the ceremony, R1 is 7Ahp, 6Ahx, 5Ava, PEG2, AEEP, AEEP(Ns), GABA, pFS, bAla, PEG2PEGE2gEC16OH, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano, 5cpaCO, cPEG3aCO, or -H; X3 is dR, R, G, R5H, R6H, R7H, S5H, S6H, S7H, K, dK, Orn, dOrn, Dap, dDap, Dab, dDab, Dab(COCH2), dDab(COCH2), hE, dhE, hK, dhK, dK(Me)3, K(Me)3, dK(PEG2PEG2gEC18OH), or K(PEG2PEG2gEC18OH) or absent; X4 is Pen, Abu, or C; X5 is N, Q, N(N(Me)2), or K(PEG2PEG2gEC18OH); X7 is W or 7MeW; X8 is K(Ac), dK(Ac), Q, dQ, K(NMeAc), dK(NMeAc), K(PEG2PEG2gEC18OH), or dK(PEG2PEG2gEC18OH); X9 is Pen, Abu, or C; X10 is AEF or TMAPF; X11 is 2Nal, X12 is THP, Acpx, or aMeK; X13 is E, dE, hE, dhE, aMeE, d-aMeE, D, dD, Aad, dAad, K(Ac), dK(Ac), K, dK, hSer, dhSer, Dap(pF), R5H, R6H, R7H, S5H, S6H, S7H, C, dC, K(NMe), or dK(NMe); X14 is N; X15 is 3Pal, H, dH, 3MeH, 3MedH, F, dF, aMeF, aMedF, THP, bAla, NMeTyr, NMedY, K, dK; X16 is meG, NMedY, NMeK(PEG2PEG2gEC18OH), or NMedK(PEG2PEG2gEC18OH) or absent; X17 is absent or K(PEG2PEG2gEC18OH); R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between R1 and X13 or between X3 and X13, an aliphatic (generated from a ring-closing metathesis "RCM" reaction), an alkylamine bond, or a thioether bond. Concerning compounds.

[0022] The present invention also relates to compounds of formula XIX, their salts, solvates, or forms thereof, corresponding pharmaceutical compositions, and methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders.

[0023] The present invention provides compounds that are bicyclic inhibitors of the IL-23 receptor comprising the amino acid sequence of formula XX: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(XX) During the ceremony, R1 is selected from CF3CO, 5cpaCO, cPEG3aCO, -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with cyano, Cl, or F; X3 is R, dR, K, dK, K(Me)3, dK(Me)3, hK(Me)3, or dhK(Me)3, or absent; X4 is Pen, Abu, or C; X5 is selected from E, D, K, K(Ac), Dap, K(NMe), or K(NNs); X6 is selected from T, L; X7 is selected from W, 7MeW, 7PhW; X8 is selected from K(Ac), dK(Ac), hK(Me)3, dhK(Me)3, K(Me)3, dK(Me)3, K(NMeAc), dK(NMeAc), Q(N(Me)2), KPeg12, dKPeg12, KAcMor, A, Q, dKacMor, dQ(N(Me)2), K(mPEG12), dA, dQ, or dK(mPEG12); X9 is Pen, Abu, or C; X10 is selected from AEF, AEF(NMe), F4CONH2, or F4OMe; X11 is 2Nal; X12 is selected from THP, aMeLeu, or A; X13 is selected from E, dE, K(Ac), dK(Ac), K(Me)3, dK(Me)3, K(NMeAc), dK(NMeAc), Q(N(Me)2), dQ(N(Me)2), A, dA, L, or dL; X14 is selected from L, N, or S; X15 is selected from 3Pal, L, dL, or Aib, and X16 is selected from meG; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide or alkylamine bond between X5 and X10. Concerning compounds.

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

[0025] The present invention provides compounds that are bicyclic inhibitors of the IL-23 receptor comprising the amino acid sequence of formula I: R1-X4-X5-T-X7-X8-X9-AEF-X11-X12-X13-N-X15-meG-R2(I) During the ceremony, R1 is 7Ahp, 6Ahx, 5Ava, PEG2, AEEP, or AEEP(Ns); X4 is Pen, Abu, aMeC, hC, or C; X5 is N or K(PEG2PEG2gEC18OH); X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K(Ac), Q, K(NMeAc), K(PEG2PEG2gEC18OH), dK(Ac), dQ, dK(NMeAc), or dK(PEG2PEG2gEC18OH); X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP or aMeK; X13 is E, dE, hE, dhR, D, dD, hSer, or dhSer; X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; R2 is -NH2, N(H)C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide or thioether bond between R1 and X13 (between pFS and Dap(pF)). Concerning compounds.

[0026] The present invention also relates to compounds of formula I, their salts, solvates, or forms thereof, corresponding pharmaceutical compositions, and methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders.

[0027] The present invention relates to compounds that are bicyclic inhibitors of the IL-23 receptor comprising the amino acid sequences of Formulas II-XVIII.

[0028] The present invention also relates to compounds of formulas II-XVIII, their salts, solvates, or forms thereof, corresponding pharmaceutical compositions, and methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders.

[0029] The present invention relates to compounds that are bicyclic inhibitors of the IL-23 receptor comprising the amino acid sequence of Formula III.

[0030] In addition to the above, the present invention relates to methods or processes for making the compounds of Formulas (I)-(XX) or Tables 1A-1H).

[0031] The present invention also relates to a pharmaceutical composition comprising a bicyclic peptide inhibitor compound of IL-23R as described herein or a pharma- ceutically acceptable salt, solvate, or form thereof as described herein and a pharma- ceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition may or may not contain an absorption enhancer, depending on the intended delivery route or its use for the treatment of a particular indication. The absorption enhancer may be a permeation enhancer or an intestinal permeation enhancer. In one embodiment, the absorption enhancer improves oral bioavailability.

[0032] The present invention relates to a method and / or use for treating an inflammatory disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of one or more bicyclic peptide inhibitor compounds of IL-23R as described herein or a pharma- ceutically acceptable salt or solvate thereof, or a corresponding pharmaceutical composition as described herein, respectively. Such inflammatory diseases and related disorders may include, but are not limited to, Inflammatory Bowel Disease (IBD), Crohn's Disease (CD), Ulcerative Colitis (UC), Psoriasis (PsO), or Psoriatic Arthritis (PsA), etc.

[0033] The present invention provides the use of one or more compounds as described herein (e.g., compounds of Formulae (I)-(XX) or Tables 1A-1H) for the preparation of a pharmaceutical composition for use in the treatment of inflammatory diseases and related disorders, including, but not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA).

[0034] The present invention provides the use of one or more compounds of Formulae (I)-(XX) as described herein for the preparation of a pharmaceutical composition for use in the treatment of inflammatory diseases and related disorders, including but not limited to inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA).

[0035] The present invention provides kits comprising one or more compounds of Formulae (I)-(XX) as described herein and instructions for use in treating a condition in a patient. The condition may be an inflammatory disease or related disorder, including, but not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA).

[0036] (Detailed description) I. Overview The present invention relates to novel bicyclic peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharma- ceutical acceptable salts, solvates and / or other forms thereof, corresponding pharmaceutical compositions, methods and / or uses of the IL-23R inhibitors for the treatment of autoimmune inflammatory diseases and / or related disorders.

[0037] The present invention relates to bicyclic peptide inhibitors of IL-23R. The bicyclic peptide inhibitors of the present invention may exhibit enhanced properties, such as longer in vivo half-life, compared to the corresponding monocyclic peptide inhibitors of IL-23R.

[0038] 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.

[0039] "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 + / - 10% of the recited value at each of the 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.

[0040] "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.

[0041] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions proposed by the IUPAC Commission in Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)" Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims 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].

[0042] 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" can be used in front of an amino acid to indicate that it is the D-isomer form, e.g., D-lysine can be represented as dK.

[0043] For less common or non-naturally occurring amino acids, unless 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 (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0044] The D-isomer form of an 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 an amino acid may be located only at any one or more of X3, X5, X6, X8, X13, X16, and optionally one additional position. In other aspects, the D-isomer form of an amino acid may be located only at any one or more of X3, X8, X13, X16, and optionally one additional position. In other aspects, the D-isomer form of an 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 one additional position. In other aspects, the D-isomer form of an amino acid may be located only at X3 and optionally one additional position. In other aspects, the D-isomer form of an amino acid may be located only at X3 and optionally at two or three additional positions. In other aspects, the D-isomer form of an amino acid may be located only at one or two of positions X1-X18 that appear in the IL-23R inhibitors described herein. In other aspects, the D-isomer form of an amino acid may be located only at 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 those positions. In other aspects, the D-isomer form of an amino acid may be located only at five or six of positions X1-X18 that appear in the IL-23R inhibitors described herein.

[0045] As conventionally understood in the art or by those 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.

[0046] 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.

[0047] "Compounds of the invention", "inhibitors of the invention", "IL-23R inhibitors of the invention", "compounds described herein" and "compounds described herein" include the novel compounds disclosed herein, e.g., any of the compounds of the Examples, including compounds of Formulae (I)-(XX), such as those found in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G or Table 1H.

[0048] "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.

[0049] By "pharmaceutical acceptable" is meant that the carrier, diluent, salt, or excipient must be compatible with other components or ingredients of the compositions of the present invention, i.e., useful, safe, non-toxic, and acceptable for pharmaceutical use. According to the present invention, pharmaceutical acceptable means approved or approvable as described in the US Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, and particularly in humans.

[0050] A "pharmaceutical acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0051] "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.

[0052] 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.

[0053] "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.

[0054] 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 pharma- ceutically acceptable excipients, carriers, or diluents as described herein, for example, in specific amounts defined throughout the invention. A composition or pharmaceutical composition results from a combination of specific ingredients, such as specific ingredients in specific amounts as described herein.

[0055] 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, two or more different phases, including an inner phase, which may include a core, and an outer phase.The tablet composition may also include, but are not limited to, one or more coatings.

[0056] As used herein, "solvate" refers to a 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 some 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.

[0057] Pharmaceutically acceptable salts and tautomeric forms 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.

[0058] The IL-23R inhibitors of the present invention, or their pharma- ceutically acceptable salts or solvates, may contain one or more asymmetric centers and therefore may give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)- for amino acids, or as (D)- or (L)-. The present invention is meant to include all such possible isomers of the IL-23R inhibitors of the present invention, 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, but may also be 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 racemates (or racemates of salts or derivatives) using, for example, 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 tautomeric forms are intended to be included. When compounds are represented in their chiral form, it is understood that the embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. When no chirality is specified, it is understood that the embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms; or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers enantiomers in a ratio other than 1:1.

[0059] "Racemate" refers to a mixture of enantiomers. The mixture can contain equal or unequal amounts of each enantiomer.

[0060] "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 therefore may be produced as individual stereoisomers or mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th Edition, J. March, John Wiley and Sons, New York, 1992).

[0061] "Tautomer" refers to alternative forms of a compound which differ in the location of a proton, e.g., enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups which contain ring atoms attached to both the -NH- and =N- rings, e.g., pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0062] 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 chemical groups are written or the point at which the chemical groups are 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 group following has u to v carbon atoms. For example, "C1-6 alkyl" and "C1-C6 alkyl" both indicate that the alkyl group has from 1 to 6 carbon atoms.

[0063] 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) delaying or halting the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, slowing 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, slowing the progression of a disease, improving quality of life, and / or prolonging survival.

[0064] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including 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. An 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.

[0065] "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.

[0066] The abbreviation "(V / V)" refers to the phrase "volume for volume," i.e., the proportion of a particular substance in a mixture as measured by the volume or amount by volume of a component of the compositions disclosed herein relative to the total volume of the composition. Thus, the amount is unitless and represents the volume percentage amount of the component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture may indicate that there are 2 mL of one solvent in 100 mL of the solvent mixture.

[0067] 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 composition relative to the amount of the total weight of the compositions disclosed herein. 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.

[0068] 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 across the gastrointestinal tract), or parenteral (generally, by injection, infusion, or implantation, etc.).

[0069] "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.

[0070] 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.

[0071] "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 characteristics of the dosage form, which in turn depend in part on the design and manufacture of the dosage form.

[0072] As used herein, "gastrointestinal tissue" refers to all tissues comprising the organs of the gastrointestinal tract. For example, "gastrointestinal tissue" includes, but is not limited to, tissues of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.

[0073] III.Compound The present invention relates to novel bicyclic peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharma- ceutically acceptable salts thereof.

[0074] Specifically, the present invention relates to bicyclic 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, and Table 1H, or pharma- ceutically acceptable salts thereof.

[0075] In one embodiment, a bicyclic 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 1A.

[0076] In another aspect, a bicyclic 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.

[0077] In another aspect, a bicyclic 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 1C.

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

[0079] In another aspect, a bicyclic 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 1E.

[0080] In another aspect, a bicyclic 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.

[0081] In another aspect, the bicyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) or a pharma- ceutically acceptable salt thereof has the structure of a compound of Table 1G.

[0082] In another aspect, a bicyclic 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 1H.

[0083] [Table 1-1]

[0084] [Table 1-2]

[0085] [Table 1-3]

[0086] [Table 1-4]

[0087] [Table 1-5]

[0088] [Table 1-6]

[0089] [Table 1-7]

[0090] [Table 1-8] For example, Pen-Pen forms a disulfide bond or Abu-C forms a thioether bond.

[0091] [Table 2-1]

[0092] [Table 2-2]

[0093] [Table 2-3]

[0094] [Table 2-4]

[0095] [Table 2-5]

[0096] [Table 2-6]

[0097] [Table 2-7]

[0098] [Table 2-8]

[0099] [Table 2-9] Pen-Pen forms a disulfide bond or Abu-Cys forms a thioether bond.

[0100] [Table 3-1]

[0101] [Table 3-2]

[0102] [Table 3-3]

[0103] [Table 3-4]

[0104] [Table 3-5]

[0105] [Table 3-6]

[0106] [Table 3-7]

[0107] [Table 3-8] Pen-Pen forms a disulfide bond or Abu-C forms a thioether bond.

[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] Pen-Pen forms a disulfide bond or Abu-C forms a thioether bond.

[0116] [Table 5-1]

[0117] [Table 5-2]

[0118] [Table 5-3]

[0119] [Table 5-4]

[0120] [Table 5-5]

[0121] [Table 5-6]

[0122] [Table 5-7] Pen-Pen forms a disulfide bond or Abu-C forms a thioether bond.

[0123] [Table 6-1]

[0124] [Table 6-2]

[0125] [Table 6-3]

[0126] [Table 6-4]

[0127] [Table 6-5]

[0128] [Table 6-6]

[0129] [Table 6-7]

[0130] [Table 6-8]

[0131] [Table 6-9]

[0132] [Table 6-10] Pen-Pen forms a disulfide bond or Abu-C forms a thioether bond.

[0133] [Table 7-1]

[0134] [Table 7-2]

[0135] [Table 7-3]

[0136] [Table 7-4]

[0137]

Table 7-5

[0138]

Table 7-6

[0139]

Table 7-7

[0140]

Table 7-8

[0141]

Table 7-9

[0142]

Table 8-1

[0143]

Table 8-2

[0144]

Table 8-3

[0145]

Table 8-4

[0146]

Table 8-5

[0147]

Table 8-6

[0148]

Table 8-7

[0149]

Table 8-8

[0150]

Table 8-9

[0151]

Table 8-10

[0152]

Table 8-11

[0153]

Table 8-12

[0154]

Table 8-13

[0155]

Table 8-14

[0156]

Table 8-15

[0157]

Table 8-16

[0158]

Table 8-17

[0159]

Table 8-18

[0160]

Table 8-19

[0161]

Table 8-20

[0162]

Table 8-21

[0163]

Table 8-22

[0164]

Table 8-23

[0165]

Table 8-24

[0166]

Table 8-25

[0167]

Table 8-26

[0168] [Table 8-27]

[0169] [Table 8-28]

[0170] [Table 8-29]

[0171] [Table 8-30]

[0172] [Table 8-31]

[0173] 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 embodiments, the present invention provides methods of producing the compounds of the present invention (or monomeric subunits thereof), comprising 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)-(XX), Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, and Table 1H herein. In some embodiments, a portion of the peptide is recombinantly synthesized instead of being chemically synthesized. In some embodiments, the method of producing the compound further comprises cyclizing the compound precursor after the constituent subunits are joined. In certain embodiments, cyclization is achieved via any of the various methods described herein.

[0174] The present invention further describes the synthesis of compounds described herein, such as compounds of formulas (I)-(XX) and compounds of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, and Table 1H. In some embodiments, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently linked together 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 together 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.

[0175] The invention further describes the synthesis of compounds described herein, such as compounds of Formulas (I)-(XX) and compounds of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, and Table 1H. Exemplary synthetic methods are described in the Examples.

[0176] IV. Pharmaceutical Compositions The present invention relates to a pharmaceutical composition comprising an IL-23R inhibitor of the present invention.

[0177] The present invention includes pharmaceutical compositions comprising one or more inhibitors of the present invention and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0178] The pharma-ceutically acceptable carrier, diluent, or excipient may be a solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation auxiliary. For example, various antibacterial and antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid, etc., may be included to ensure the prevention of the action of microorganisms. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc.

[0179] The pharmaceutical compositions 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 compositions are formulated for delivery by any of these routes of administration. The pharmaceutical compositions may be formulated and administered orally. The pharmaceutical compositions may be formulated and administered parenterally.

[0180] 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. Once inserted into the body, the matrix is ​​acted upon by enzymes and body fluids. The sustained release matrix is ​​desirably a liposome, polylactide (polylactic acid), The biocompatible material is selected from polyglycolide (polymer of glycolic acid), polylactide-co-glycolide (copolymer of lactic acid and glycolic acid), 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 the biodegradable matrix is ​​a matrix of either polylactide, polyglycolide, or polylactide-co-glycolide (copolymer of lactic acid and glycolic acid).

[0181] The IL-23R inhibitors of the present invention can be prepared and / or formulated as pharmaceutically acceptable salts, or in appropriate cases, in neutral form. Pharmaceutically acceptable salts are non-toxic salts of neutral forms 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 basic nitrogen can be prepared as pharmaceutically 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-dioate, hexaphosphate ... Examples of suitable pharma- ceutically acceptable salts include 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, vol. 21. st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0182] 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. + (X is C1-C4 alkyl). Base addition salts such as sodium or potassium salts are also included.

[0183] 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 with a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As 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 their pharma- ceutically acceptable salts, isomers, or mixtures 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 with deuterium.

[0184] Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 Also included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as I. Positron-emitting isotopes, e.g. 11 C. 18 F, 15 O, and 13Substitution at N may be useful in Positron Emission Topography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples below, by substituting an appropriate isotopically labeled reagent for a conventionally used non-labeled reagent.

[0185] In some 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, β-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. These 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.

[0186] Injectable depot forms include those made by forming microencapsulated 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.

[0187] 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.

[0188] 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.

[0189] Alternatively, the pharmaceutical composition of the present invention 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.

[0190] 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.

[0191] 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).

[0192] 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, etc., in addition to the peptide inhibitors of the present invention. In certain embodiments, lipids include phospholipids, including phosphatidylcholines (lecithins) and serine, both natural and synthetic. Methods for forming liposomes are known in the art.

[0193] 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.

[0194] 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 that are not disclosed herein but are well known in the art and are suitable for use in oral delivery of peptides.

[0195] Formulations for oral administration may contain auxiliary agents for artificially increasing the permeability of the intestinal wall (e.g., resorcinol and / or non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether), and enzyme inhibitors for inhibiting enzymatic degradation (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF), or trasylol). 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 oral formulations may also contain other types of additives, for example, inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbic acid, ascorbic acid, α-tocopherol, antioxidants such as cysteine, disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavorings, or perfuming agents.

[0196] 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 inhibitor and 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 examples, 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.

[0197] 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 (e.g., dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.). The pH of the composition is, for example, in the range of 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.

[0198] Oral pharmaceutical compositions that may include the IL-23R inhibitors of the present invention may include an enteric coating designed to delay the release of the IL-23R inhibitor in the small intestine. The present invention relates to pharmaceutical compositions that include the IL-23R inhibitors of the present invention and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation. The pharmaceutical compositions (e.g., oral pharmaceutical compositions) may include 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 hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, and similar derivatives of cellulose and other carbohydrate polymers.

[0199] The IL-23R inhibitor-containing oral pharmaceutical composition of the present invention comprising an IL-23R inhibitor may include an enteric coating designed to protect and release the pharmaceutical composition in a controlled manner in the lower digestive system of a subject and to avoid systemic side effects. In addition to an enteric coating, the peptide inhibitor 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 inhibitor of the present invention is provided in a lipid carrier system including at least one of polymeric hydrogels, nanoparticles, microspheres, micelles, and other lipid systems.

[0200] To overcome the problem of 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.

[0201] A variety of bioresponsive 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 used in combination with bioresponsive 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.

[0202] In certain aspects, pharmaceutical compositions and formulations may comprise 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.

[0203] The IL-23R inhibitors of the present invention may be formulated into formulation vehicles such as, for example, emulsions, liposomes, microspheres, or nanoparticles.

[0204] The present invention provides methods of 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.

[0205] 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.

[0206] The total daily usage of the IL-23R inhibitors and compositions of the present invention may be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend on a variety of factors, including: a) the disorder being treated and the severity of the disorder; b) the activity of the particular compound used; c) the specific 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.

[0207] In specific 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, for example, an amount of 0.0001-300 mg / kg body weight per day, or 1-300 mg / kg body weight per day.

[0208] The compositions may conveniently be provided in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. 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.

[0209] 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; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary or paste. The active ingredient may be administered as a buccal or sublingual formulation. The buccal or sublingual formulation may comprise the active ingredient in a matrix that releases the active ingredient for transport across the oral and / or sublingual membranes. The buccal or sublingual formulation may further comprise a rate-controlling matrix that releases the active compound at a predetermined rate for transport across the oral and / or sublingual membranes. The buccal or sublingual formulation may further comprise 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 may be permeation enhancers.

[0210] 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 may optionally be coated or scored and may optionally be formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0211] Non-invasive detection of V. enteritidis The IL-23R inhibitors of the present invention may 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 labeled 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.

[0212] VI. METHODS OF TREATMENT AND / OR USE The present invention relates to a method of 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 of 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.

[0213] 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.

[0214] The disease or disorder treated by treatment with an IL-23R inhibitor of the present invention can be autoimmune inflammation and related diseases and disorders, 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. Specifically, the disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis, ectopic acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), seronegative arthropathy-associated enteropathy, microscopic colitis, collagen colitis, eosinophilic gastroenteritis / esophagitis, radiation- or chemotherapy-associated colitis; disorders of innate immunity such as leukocyte adhesion deficiency-1. and colitis associated with 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.

[0215] The present invention relates to a method or use of an IL-23R inhibitor for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present invention or a pharma- ceutically acceptable solvate or salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present invention. In some aspects, the present invention provides a method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present invention or a pharma- ceutically acceptable solvate or salt thereof, or a composition of the present invention. Inflammatory diseases suitable for treatment with the compounds of the present invention or their pharma- ceutically acceptable salts or compositions may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (Ulcerative Colitis, UC), psoriasis (PsO), or psoriatic arthritis (PsA), etc. 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.

[0216] The present invention relates to a method of treating an inflammatory disease 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 Formulas (I)-(XX) or Tables 1A-1H). The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one aspect, the IBD can be ulcerative colitis. In one aspect, the IBD can be Crohn's disease. In one aspect, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0217] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula (I). The inflammatory disease may be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD may be ulcerative colitis. In one embodiment, the IBD may be Crohn's disease. In one embodiment, the inflammatory disease may be psoriasis (PsO) or psoriatic arthritis (PsA).

[0218] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula I. The inflammatory disease can be IBD, Crohn's disease, or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0219] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula II. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0220] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula III. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0221] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula IV. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0222] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula V. The inflammatory disease can be IBD, Crohn's disease, or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0223] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula VI. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0224] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula VII. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0225] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula VIII. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0226] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula IX. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0227] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula X. The inflammatory disease can be IBD, Crohn's disease, or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0228] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XI. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0229] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XII. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0230] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XIII. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0231] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XIV. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0232] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XV. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0233] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XVI. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0234] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XVII. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0235] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XVIII. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0236] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XIX. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0237] The present invention relates to a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of formula XX. The inflammatory disease can be IBD, Crohn's disease or ulcerative colitis. In one embodiment, the IBD can be ulcerative colitis. In one embodiment, the IBD can be Crohn's disease. In one embodiment, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[0238] 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.

[0239] 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., 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 specific 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 comprises providing a peptide inhibitor of the invention (i.e., a first therapeutic agent) to a subject (e.g., a subject in need thereof) in combination with a second therapeutic agent. 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 specific 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.

[0240] The present invention relates to a method of inhibiting IL-23 signaling by a cell, comprising contacting the IL-23R with a peptide inhibitor as described herein. In certain embodiments, the cell is a mammalian cell. In specific embodiments, the method is performed in vitro or in vivo. In specific embodiments, inhibition of IL-23 signaling can be determined by measuring changes in phospho-STAT3 levels in the cell.

[0241] 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 a peptide inhibitor or IL-23R described herein (e.g., any compound of Formula (I)-Formula (XX) or Tables 1A-1H, or a salt or solvate thereof) administered to a 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 inhibitors or IL-23R described herein may be from 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 can be in the dose range of about 20 mg to about 30 mg.

[0242] VII. Specific Aspects The following embodiments are illustrative of the present invention. These embodiments 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. 1. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (I) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-X12-X13-N-X15-meG-R2(I) During the ceremony, R1 is 7Ahp, 6Ahx, 5Ava, PEG2, AEEP, or AEEP(Ns); X4 is Pen, Abu, aMeC, hC, or C; X5 is N or K(PEG2PEG2gEC18OH); X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K(Ac), Q, K(NMeAc), K(PEG2PEG2gEC18OH), dK(Ac), dQ, dK(NMeAc), or dK(PEG2PEG2gEC18OH); X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP or aMeK; X13 is E, dE, hE, dhR, D, dD, hSer, or dhSer; X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide or thioether bond between R1 and X13 (between pFS and Dap(pF)). Bicyclic peptide inhibitors. 2. The bicyclic peptide inhibitor of embodiment 1, wherein X11 is 2Nal. 3. A bicyclic peptide inhibitor according to any of aspects 1 or 2, wherein X7 is W or 7MeW. 4. A bicyclic peptide inhibitor according to any one of aspects 1 to 3, wherein X15 is 3Pya, H, 3MeH, or F. 5. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (II) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-K(Ac)-X9-AEF-X11-THP-X13-N-X15-X16-R2(II) During the ceremony, R1 is GABA, pFS, bAla, or (HOC16gEPEG2PEG2)orn; X3 is dR, G, dK(PEG2PEG2gEC18OH)R, or K(PEG2PEG2gEC18OH); X4 is Pen, Abu, aMeC, hC, or C; X5 is N or Q; X7 is 7MeW or W; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, dD, Dap(pF(6)), or dDap(pF(6)); X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedYK, dK, NMeY, NMedY, N, dH, dN, dL, Aib, or L, or absent; X16 is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, D, or dD, or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond of the thioether between R1 and X13 (between pFS and Dap(pF(6))). Bicyclic peptide inhibitors. 6. The bicyclic peptide inhibitor of embodiment 5, wherein X11 is 2Nal. 7. A bicyclic peptide inhibitor according to any of aspects 5 or 6, wherein X15 is 3Pya or THP. 8. A bicyclic peptide inhibitor according to any of aspects 5-7, wherein X16 is meG or is absent. 9. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (III) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-N-X15-X16-R2(III) During the ceremony, R1 is C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, cyano, 5cpa, cPEG3aCO, or -H; X3 is R5H, S5H, R6H, S6H, R7H, S7H, K, dK, Orn, d-Orn, Dap, dDap, Dab(COCH2), dDab(COCH2), dhE, hE, hK, dhK; X4 is Pen, Abu, aMeC, hC, or C; X5 is N, Q, or N(N(Me)2); X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K(Ac), Q, K(NMeAc), dK(Ac), dQ, or dK(NMeAc); X9 is Pen, Abu, aMeC, hC, or C; X10 is AEF or TMAPF; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP, Acpx, or aMeK; X13 is R5H, R6H, R7H, S5H, S6H, S7H, C, E, hE, KNMe, dC, dE, dhE, or dKNMe; X15 is 3Pya, bAla, THP, dK, or aMePhe; X16 is meG, NMedY or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally being alkyl-substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide, thioether, or aliphatic (generated from a ring-closing metathesis "RCM" reaction) bond between X3 and X13. Bicyclic peptide inhibitors. 10. The bicyclic peptide inhibitor of embodiment 9, wherein X11 is 2Nal. 11. A bicyclic peptide inhibitor according to any of aspects 9 or 10, comprising (i) X7 is W or 7MeW; and / or (ii) X15 is 3Pya; and / or (iii) X16 is meG; Bicyclic peptide inhibitors. 12. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (IV) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-X15-X16-R2(IV) During the ceremony, R1 is C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F or cyano, -H, 7Ahp, 6Ahx, 5Ava, or GABA; X3 is dR, R, d-Orn, Orn, or absent; X4 is Pen, Abu, aMeC, hC, or C; X5 is Q or N; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is Q, K(Ac), dQ, dK(Ac); X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, aMeE, Aad, hE, K, dE, dAad, dhE, or dK; X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; X16 is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, D, or dD, or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between AEF and X13. Bicyclic peptide inhibitors. 13. The bicyclic peptide inhibitor of embodiment 12, wherein X11 is 2Nal. 14. A bicyclic peptide inhibitor according to any of aspects 12 or 13, wherein X15 is bAla, 3Pya, THP, or NMedY. 15. A bicyclic peptide inhibitor according to any of aspects 12-14, wherein X16 is meG or is absent. 16. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (V) comprising the following amino acid sequence: R1-X4-NT-X7-X8-X9-F4CONH2-X11-THP-X13-N-3Pya-meG-R2(V) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X4 is Pen, Abu, aMeC, hC, or C; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K or dK; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, dD; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between X8 and X13. Bicyclic peptide inhibitors. 17. The bicyclic peptide inhibitor of embodiment 16, wherein X11 is 2Nal. 18. A bicyclic peptide inhibitor according to any of aspects 16 or 17, wherein X7 is W or 7MeW. 19. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (VI) comprising the following amino acid sequence: R1-X3-A-X5-T-X7-X8-A-AEF-X11-THP-X13-N-X15-R2(VI) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X3 is K, dK, hdK, E, dE, D, dD; X5 is E, dE, D, dD; X7 is W or 7MeW; X8 is K(Ac) or dK(Ac); X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is K(Ac) or dK(Ac); X15 is K, dK, dH, hdK E, dE, D, dD; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first amide bond between X5 and X10 and a second amide bond between X3 and X15. Bicyclic peptide inhibitors. 20. The bicyclic peptide inhibitor of embodiment 19, wherein X11 is 2Nal. 21. A bicyclic peptide inhibitor according to any of aspects 19 or 20, wherein X7 is W or 7MeW. 22. A bicyclic peptide inhibitor according to any one of aspects 19 to 21, wherein X15 is K or dK. 23. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (VII) comprising the following amino acid sequence: R1-X3-X4-NT-X7-K(Ac)-X9-X10-X11-THP-X13-N-3Pya-X16-R2(VII) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X3 is D, dK, E, dDap, dD, K, dE, or Dap; X4 is Pen, Abu, aMeC, hC, or C; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X9 is Pen, Abu, aMeC, hC, or C; X10 is AEF, F4CONH2, or F4OMe; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is K(Ac) or dK(Ac); X16 is K, dK, E, dE, R, dR, D, dD or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between X3 and X16. Bicyclic peptide inhibitors. 24. The bicyclic peptide inhibitor of embodiment 23, wherein X11 is 2Nal. 25. A bicyclic peptide inhibitor according to any of aspects 23 or 24, wherein X7 is W or 7MeW. 26. A bicyclic peptide inhibitor according to any one of aspects 23 to 25, wherein X16 is K, dK, E, dE, R, dR, D, or dD. 27. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (VIII) comprising the following amino acid sequence: R1-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-3Pya-meG-R2(VIII) During the ceremony, R1 is selected from -H, CF3CO, 5cpaCO, cPEG3aCO, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with cyano, Cl, F, AcMorph, or PEG12OMe; X4 is Pen, Abu, aMeC, hC, or C; X5 is selected from E, K, Dap, or K(NMe); X6 is selected from T, L, and I; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is selected from K(Ac), KPeg12, KAcMor, Q(N(Me)2), K(Me)3, hK(Me)3; K(NMeAc), K(mPEG12), A, or Q, dKAc, dKPeg12, dKacMor, dQ(N(Me)2), dK(Me)3, dhK(Me)3, dK(NMeAc), dK(mPEG12), dA, or dQ; X9 is Pen, Abu, aMeC, hC, or C; X10 is selected from AEF, AEF(NMe), K, or E; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is selected from THP, aMeLeu, or A; X13 is selected from K(Ac), A, L, K(NMeAc), Q(N(Me)2), K(Me)3, E, dK(Ac), dA; dL, dK(NMeAc), dQ(N(Me)2)), dK(Me)3, or dE; X14 is selected from A, L, N or S; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide or alkylamine bond between X5 and X10 (between K(NMe) and AEF). Bicyclic peptide inhibitors. 28. The bicyclic peptide inhibitor of embodiment 27, wherein X11 is 2Nal. 29. A bicyclic peptide inhibitor according to any of aspects 27 or 28, wherein X7 is W, 7MeW, 7PhW, dW, d7MeW, or d7PhW. 30. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (IX) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X10-X11-THP-X13-X14-3Pya-meG-R2(IX) During the ceremony, R1 is selected from -H, C1-C4 alkylC(O)-, or Cl; F, or C1-C4 alkylC(O)- substituted with cyano, or HOC18gEPEG2PEG2CO; X3 is R, dR, K, dK, dK(Me)3, K(Me)3, dK(PEG2PEG2gEC18OH), or K(PEG2PEG2gEC18OH); X4 is Pen, Abu, aMeC, hC, or C; X5 is selected from E; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is selected from K(Ac) or dK(Ac); X9 is Pen, Abu, aMeC, hC, or C; X10 is selected from AEF or AEF(NMe); X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is selected from K(Ac), E, ​​dK(Ac), or dE; X14 is selected from N; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between X5 and X10. Bicyclic peptide inhibitors. 31. The bicyclic peptide inhibitor of embodiment 30, wherein X11 is 2Nal. 32. A bicyclic peptide inhibitor according to any of aspects 30 or 31, wherein X7 is W or 7MeW. 33. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (X) comprising the following amino acid sequence: X5-T-X7-X8-A-AEF-X11-THP-X13-3Pya(X) During the ceremony, X5 is E, dE, D, or dD; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K(Ac) or dK(Ac); X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and X13 is K(Ac), dK(Ac) or absent; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first amide bond between X5 and AEF, and a second cyclization between the amino terminus of X5 and the carboxy terminus of 3Pya. Bicyclic peptide inhibitors. 34. The bicyclic peptide inhibitor of embodiment 33, wherein X11 is 2Nal. 35. A bicyclic peptide inhibitor according to any of aspects 33 or 34, wherein X7 is W or 7MeW. 36. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XI) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-X15-R2(XI) During the ceremony, R1 is 7Ahp, 6Ahx, 5Ava, or AEEP; X4 is Pen, Abu, aMeC, hC, or C; X5 is N or Q; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K(Ac), Q, dK(Ac), or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, or dD; X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between R1 and X13. Bicyclic peptide inhibitors. 37. The bicyclic peptide inhibitor of embodiment 36, wherein X11 is 2Nal. 38. A bicyclic peptide inhibitor according to any of aspects 36 or 37, wherein X7 is W, 7MeW, dW, or d7MeW. 39. A bicyclic peptide inhibitor according to any one of aspects 36 to 38, wherein X15 is 3Pya THP, NMeY, or NMedY. 40. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XII) comprising the following amino acid sequence: R1-X4-N-X6-X7-X8-X9-AEF-2Nal-X12-X13-N-3Pya-X16-R2(XII) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X4 is Pen, Abu, aMeC, hC, or C; X6 is 3Hyp or 3OHPro; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is R5H, R6H, R7H, S5H, S6H, or S7H; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is R5H, R6H, R7H, S5H, S6H, or S7H; X13 is K, dK, KAc, dKAc, E, dE, D, or dD; X16 is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, D, or dD, or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide or aliphatic (generated from a ring-closing metathesis "RCM" reaction) bond between X8 and X12. Bicyclic peptide inhibitors. 41. The bicyclic peptide inhibitor of embodiment 40, wherein X11 is 2Nal. 42. A bicyclic peptide inhibitor according to any of aspects 40 or 41, wherein X6 is T and / or X7 is W, 7MeW, dW, or d7MeW. 43. A bicyclic peptide inhibitor according to any of aspects 36-39, wherein X16 is meG or is absent. 44. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XIII) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-X13-N-X15-X16-X17-R2(XIII) During the ceremony, R1 is 7Ahp, 6Ahx, 5Ava, or AEEP; X4 is Pen, Abu, aMeC, hC, or C; X5 is N; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K(Ac), Q, dK(Ac), or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, or dD; X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, NmedY, N, dH, dN, dL, Aib, or L or absent; X16 is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, D, dD, NMeK(PEG2PEG2gEC18OH), or dNMeK(PEG2PEG2gEC18OH), or absent; X17 is absent, K(PEG2PEG2gEC18OH), or dK(PEG2PEG2gEC18OH); R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally being alkyl-substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between R1 and X13. Bicyclic peptide inhibitors. 45. The bicyclic peptide inhibitor of embodiment 44, wherein X11 is 2Nal. 46. ​​A bicyclic peptide inhibitor according to any of aspects 44 or 45, wherein X7 is W, 7MeW, dW, or d7MeW. 47. A bicyclic peptide inhibitor according to any of aspects 44-46, wherein X15 is 3Pya THP, NMeY, or NMedY. 48. A bicyclic peptide inhibitor according to any of aspects 44-47, wherein X16 is meG or is absent. 49.

[0243] [ka] A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XIV) comprising the amino acid sequence: R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F or cyano; X3 is dK or K; X4 is Pen, Abu, aMeC, hC, or C; X5 is N, Q, or Dap (diaminopropionic acid, also called Dpr), and X6 is T dK, or K; X7 is W, 7MeW, dW, or d7MeW; X8 is K(Ac), Q, dK(Ac), or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP or aMeL; X13 is E, K(Ac), dE, E, D, dD, or dK(Ac); X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, 3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; X16 is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, D, or dD, or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally being alkyl-substituted with Cl, F, or cyano; R3 is PEG4 (-HN[(CH2)2O]4(CH2)2CO-), PEG4DA (-OC[(CH2)2O]4(CH2)2CO-), or a C6-C20 saturated or unsaturated dicarboxylic acid (e.g., 1,10-decanedioic acid, 1,12-dodecanedioic acid, 1,14-tetradecanedioic acid, or 1,16-hexadecanedioic acid); Bicyclic peptide inhibitors of the interleukin-23 receptor are provided by a first disulfide or thioether bond between X4 and X9, and an R3 group attached to the AEF residue at X10. (i) the Dpr residue at X5, (ii) K or dK in X6, or (iii) K, dK, or E at X13 and is cyclized by a second amide bond between Bicyclic peptide inhibitors. 50. The bicyclic peptide inhibitor of embodiment 49, wherein X11 is 2Nal or 3Quin, or X11 is 2Nal. 51. A bicyclic peptide inhibitor according to any of aspects 49 or 50, wherein X7 is W, 7MeW, dW, or d7MeW. 52. A bicyclic peptide inhibitor according to any one of aspects 49 to 51, wherein X15 is H, N, dH, or dN. 53. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XV) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-X15-R2(XV) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X4 is Pen, Abu, aMeC, hC, or C; X5 is E, dE, D, or dD; X7 is W, 7MeW, dW, or d7MeW; X8 is K(Ac), Q, dK(Ac), or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, K(Ac), dE, D dDor dK(Ac); X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between AEF and X5. Bicyclic peptide inhibitors. 54. The bicyclic peptide inhibitor of embodiment 53, wherein X11 is 2Nal. 55. A bicyclic peptide inhibitor according to any of aspects 53 or 54, wherein X7 is W, 7MeW, dW, or d7MeW. 56. A bicyclic peptide inhibitor according to any one of aspects 53 to 55, wherein X15 is dL, Aib or L. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XVI) comprising the amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-X15-X16-R2(XVI) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X4 is Pen, Abu, aMeC, hC, or C; X5 is N or L; X7 is W, 7MeW, dW, or d7MeW; X8 is K(Ac) or dK(Ac); X9 is Pen, Abu, aMeC, hC, or C; X10 is F4CONH2, 4AmF, or F4OMe; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dK, dDap, K, Dap, dE; X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; X16 is dK, dD, dE, Aib, G, bAla, meG, K, D, E, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3 AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, R, or dR, or absent; R2 is absent or -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between X13 and X15, X16, R2, or the carboxy terminus of X15 or X16 if R2 is absent. Bicyclic peptide inhibitors. 57. The bicyclic peptide inhibitor of embodiment 56, wherein X11 is 2Nal. 58. A bicyclic peptide inhibitor according to any of aspects 56 or 57, wherein X7 is W, 7MeW, dW, or d7MeW. 59. A bicyclic peptide inhibitor according to any of aspects 56-58, wherein X15 is dL, Aib or L and / or X16 is dK, dD, dE, Aib, G, bAla, meG or dK. 60. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XVII) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X10-X11-THP-X13-X14-X15-X16-R2(XVII) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X3 is Orn, E, dOrn, or dE; X4 is Pen, Abu, aMeC, hC, or C; X5 is N; X7 is W, 7MeW, dW, or d7MeW; X8 is K(Ac) or dK(Ac); X9 is Pen, Abu, aMeC, hC, or C; X10 is F4CONH2 or AEF; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, K(Ac), dK(Ac), or dE; X14 is N or absent; X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, d3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or absent; X16 is 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, D, dD, dDap, meG, or Dap, or is absent; R2 is absent or -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between X3 and one of X10, X13, or X16. Bicyclic peptide inhibitors. 61. The bicyclic peptide inhibitor of embodiment 60, wherein X11 is 2Nal. 62. A bicyclic peptide inhibitor according to any of aspects 60 or 61, wherein X7 is W, 7MeW, dW, or d7MeW. 63. A bicyclic peptide inhibitor according to any of aspects 60 to 62, wherein X15 is 3Pya or absent. 64. The bicyclic peptide inhibitor according to any one of aspects 60 to 63, wherein X16 is dDap, meG, Dap or dMeG. 64. A tricyclic peptide inhibitor of the interleukin-23 receptor of formula (XVIII) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-3Pya-meG-X17-R2(XVIII) During the ceremony, R1 is -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano; X3 is K, dK, E, dE; X4 is Pen, Abu, aMeC, hC, or C; X5 is E, dE, D, or dD; X7 is W or 7MeW; X8 is K(Ac) or dK(Ac); X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is K(Ac) or dK(Ac); X17 is E, dE, K, dK, D, or dD; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The tricyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, a second amide bond between X3 and X17, and a third amide bond between X5 and AEF. Tricyclic peptide inhibitors. 65. The bicyclic peptide inhibitor of embodiment 64, wherein X11 is 2Nal. 66. A bicyclic peptide inhibitor according to any of aspects 64 or 65, wherein X7 is W or 7MeW. 67. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XIX) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-R2(XIX) During the ceremony, R1 is 7Ahp, 6Ahx, 5Ava, PEG2, AEEP, AEEP(Ns), GABA, pFS, bAla, PEG2PEGE2gEC16OH, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with Cl, F, or cyano, 5cpaCO, cPEG3aCO, or -H; X3 is dR, R, G, R5H, R6H, R7H, S5H, S6H, S7H, K, dK, Orn, dOrn, Dap, dDap, Dab, dDab, Dab(COCH2), dDab(COCH2), hE, dhE, hK, dhK, dK(Me)3, K(Me)3, dK(PEG2PEG2gEC18OH), or K(PEG2PEG2gEC18OH) or absent; X4 is Pen, Abu, aMeC, or C; X5 is N, Q, N(N(Me)2), or K(PEG2PEG2gEC18OH); X7 is W, 7PhW, or 7MeW; X8 is K(Ac), dK(Ac), Q, dQ, K(NMeAc), dK(NmeAc), K(PEG2PEG2gEC18OH), or dK(PEG2PEG2gEC18OH); X9 is Pen, Abu, aMeC, or C; X10 is AEF or TMAPF; X11 is 2Nal, X12 is THP, Acpx, or aMeK; X13 is E, dE, hE, dhE, aMeE, d-aMeE, D, dD, Aad, dAadK, dK, hSer, dhSer, Dap(pF), R5H, R6H, R7H, S5H, S6H, S7H, C, dC, K(NMe) or dK(NMe); X14 is N or absent; X15 is 3Pal, H, dH, 3MeH, 3MedH, F, dF, aMeF, aMedF, THP, bAla, NMeTyr, NMedY, K, dK; X16 is meG, NMedY, NMeK(PEG2PEG2gEC18OH), or NMedK(PEG2PEG2gEC18OH) or absent; X17 is absent or is K(PEG2PEG2gEC18OH); and R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide bond between R1 and X13 or between X3 and X13, an aliphatic (generated from a ring-closing metathesis "RCM" reaction), an alkylamine bond, or a thioether bond. Bicyclic peptide inhibitors. 68. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XX) comprising the following amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2(XX) During the ceremony, R1 is selected from CF3CO, 5cpaCO, cPEG3aCO, -H, C1-C4 alkylC(O)-, or C1-C4 alkylC(O)- substituted with cyano, Cl, or F; X3 is R, dR, K, dK, K(Me)3, dK(Me)3, hK(Me)3, or dhK(Me)3, or absent; X4 is Pen, Abu, or C; X5 is selected from E, D, K, K(Ac), Dap, K(NMe), or K(NNs); X6 is selected from T, L; X7 is selected from W, 7MeW, 7PhW; X8 is selected from K(Ac), dK(Ac), hK(Me)3, dhK(Me)3, K(Me)3, dK(Me)3, K(NMeAc), dK(NMeAc), Q(N(Me)2), KPeg12, dKPeg12, KAcMor, A, Q, dKacMor, dQ(N(Me)2), K(mPEG12), dA, dQ, or dK(mPEG12); X9 is Pen, Abu, or C; X10 is selected from AEF, AEF(NMe), F4CONH2, or F4OMe; X11 is 2Nal or A; X12 is selected from THP, aMeLeu, or A; X13 is selected from E, dE, K(Ac), dK(Ac), K(Me)3, dK(Me)3, K(NMeAc), dK(NMeAc), Q(N(Me)2), dQ(N(Me)2), A, dA, L, or dL; X14 is selected from L, N, or S; X15 is selected from 3Pal, L, dL, or Aib; X16 was selected from meG; R2 is -NH2, N(H)(C1-C4 alkyl), -HN(C1-C4 alkyl), -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; The bicyclic peptide inhibitors of the interleukin-23 receptor are cyclized by a first disulfide or thioether bond between X4 and X9, and a second amide or alkylamine bond between X5 and X10. Bicyclic peptide inhibitors. 69. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein when X4 is Pen, aMeC, hC, or C and X9 is Pen, aMeC, hC, or C, X4 and X9 form a disulfide bond. 70. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein when X4 is Pen or C and X9 is Pen or C, X4 and X9 form a disulfide bond. 71. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein when X4 is Abu and X9 is Pen, aMeC, hC, or C, X4 and X9 form a thioether bond. 72. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein when X4 is Pen, aMeC, hC, or C and X9 is Abu, then X4 and X9 form a thioether bond. 73. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein X7 is W. 74. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein X7 is 7MeW. 75. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein X11 is 2Nal. 76. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein, if X15 is present, X15 is 3Pya. 77. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein, if X16 is present, X16 is meG. 78.D amino acids are (i) one or more of positions X3, X5, X6, X8 and X13, and optionally one of positions X1-X2, X4, X7, X9-X12, X14-X18 present in the inhibitor; or (ii) one or more of positions X3, X8 and X13 present in the inhibitor, and optionally one of positions X1 to X2, X4 to X7, X9 to X12, X14 to X18 78. A peptide inhibitor of interleukin-23 receptor according to any of embodiments 1 to 77, wherein said peptide inhibitor is present only in 79.D amino acid is (i) X3, and optionally one of positions X1-X2, X4-X18, present in the inhibitor; or (ii) one of positions X3 and X8, and optionally one of positions X1-X2, X4-X7, X9-X18 present in the inhibitor; 78. A peptide inhibitor of interleukin-23 receptor according to any of embodiments 1 to 77, wherein said peptide inhibitor is present only in 80. A peptide inhibitor of the interleukin-23 receptor according to any of aspects 1 to 77, wherein the inhibitor comprises an amino acid in the D-isomer form at only one or two of positions X1 to X18 appearing in the IL-23R inhibitors described herein. 81. A peptide inhibitor of the interleukin-23 receptor according to any of aspects 1 to 77, wherein the inhibitor comprises amino acids in the D-isomer form at only three or four of positions X1 to X18 appearing in the IL-23R inhibitors described herein. 82. A peptide inhibitor of the interleukin-23 receptor according to any of aspects 1 to 77, wherein the inhibitor comprises amino acids in the D-isomer form at only 5 or 6 of positions X1 to X18 appearing in the IL-23R inhibitors described herein. 83. A peptide inhibitor of the interleukin-23 receptor having the structure of a compound in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, or Table 1H, or a pharma- ceutically acceptable salt, solvate, or form thereof. 84. A peptide inhibitor of the interleukin-23 receptor having the structure of a compound in Table 1A or Table B, or a pharma- ceutically acceptable salt, solvate, or form thereof. 85. A peptide inhibitor of the interleukin-23 receptor having the structure of a compound in Table 1C or Table 1D, or a pharma- ceutically acceptable salt, solvate, or form thereof. 86. A peptide inhibitor of the interleukin-23 receptor having the structure of a compound in Table 1E or Table 1F, or a pharma- ceutically acceptable salt, solvate, or form thereof. 87. A peptide inhibitor of the interleukin-23 receptor having the structure of a compound in Table 1G or Table 1H, or a pharma- ceutically acceptable salt, solvate, or form thereof. 88. A peptide inhibitor of the interleukin-23 receptor according to any of the preceding aspects, wherein the interleukin-23 receptor is a human interleukin receptor, for example NCBI Reference Sequence: NP_653302.2. 89. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 88, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharma- ceutically acceptable carrier, excipient, or diluent; and 13. A pharmaceutical composition comprising: 90. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 79, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharma- ceutically acceptable carrier, excipient, or diluent; and 13. A pharmaceutical composition comprising: 91. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to embodiment 80 or 81, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharma- ceutically acceptable carrier, excipient, or diluent; and 13. A pharmaceutical composition comprising: 92. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to embodiment 82 or 83, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharma- ceutically acceptable carrier, excipient, or diluent; and 13. A pharmaceutical composition comprising: 93. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to embodiment 84 or 85, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharma- ceutically acceptable carrier, excipient, or diluent; and 13. A pharmaceutical composition comprising: 94. A pharmaceutical composition comprising: (i) a peptide inhibitor of the interleukin-23 receptor according to embodiment 86 or 87, or a pharma- ceutically acceptable salt, solvate, or form thereof; (ii) a pharma- ceutically acceptable carrier, excipient, or diluent; and 13. A pharmaceutical composition comprising: 95. Use of a peptide inhibitor of the interleukin-23 receptor according to any of aspects 1 to 88 for the preparation of a medicament. 96. Use of a peptide inhibitor of the interleukin-23 receptor according to any of aspects 1 to 88, or a pharmaceutical composition according to any of aspects 89 to 94, for the preparation of a medicament for the treatment of an inflammatory disorder or an autoimmune inflammatory disorder. 97. 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 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, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis 20. The use according to claim 18 for the preparation of a medicament for the treatment of autoimmune inflammation and associated diseases and disorders including, but not limited to, ectopic acne, enteropathy associated with seronegative arthropathy, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral associated enteropathy, pericholechial inflammation, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease. 98. The use according to aspect 97, 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). 99. A method for treating a disease or disorder associated with interleukin 23 (IL-23) / interleukin 23 receptor (IL-23R), comprising: (i) an effective amount of a peptide inhibitor of the interleukin-23 receptor according to any one of embodiments 1 to 88, or a pharma- ceutically acceptable salt, solvate, or form thereof; or (ii) administering the pharmaceutical composition according to any one of aspects 89 to 94 to a patient in need thereof. A method comprising: 100. The method of embodiment 99, wherein the disease or disorder is associated with autoimmune inflammation. 101. The method of aspect 99, wherein the disease or disorder is associated with 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. Specifically, the disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis, ectopic acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), seronegative arthropathy-associated enteropathy, microscopic colitis, collagen colitis, eosinophilic gastroenteritis / esophagitis, radiation- or chemotherapy-associated colitis; disorders of innate immunity such as leukocyte adhesion deficiency-1. and colitis associated with 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. 102. The method of aspect 99, wherein the disease or disorder is associated with ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA). 103. The method according to aspect 99, wherein the disease or disorder is ulcerative colitis (UC). 104. The method of embodiment 99, wherein the disease or disorder is Crohn's disease (CD). 105. The method according to aspect 99, wherein the disease or disorder is psoriasis (PsO). 106. The method of embodiment 99, wherein the disease or disorder is psoriatic arthritis (PsA). 107. A kit comprising a peptide inhibitor of the interleukin-23 receptor according to any one of aspects 1 to 88, or a pharmaceutical composition according to any one of aspects 89 to 94, and instructions for use of the inhibitor of the interleukin-23 receptor or the pharmaceutical composition. 108. The kit of aspect 107, wherein the instructions are directed to treating an inflammatory disease or disorder. 109. The kit according to aspect 108, wherein the disease is inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA). 110. A method for preparing a compound according to any one of embodiments 1 to 88, comprising linking one or more monomers, causing formation of a first bond and a second bond to provide a bicyclic structure. 111. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XXI) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-X12-X13-N-X15-meG-R2(A) During the ceremony, R1 is 7Ahp, 6Ahx, 5Ava, Peg2, AEEP, or AEEP(Ns); X4 is Pen, Abu, aMeC, hC, or C; X5 is N or K(PEG2PEG2gEC18OH); X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(6(2OxdeQuin8Me))W, 7(6(2OxIquin))W, 7(7(124TAZP))W, 7(7(2OMeQuin))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, D7MeW, or Trp substituted at position 7 with C1-C7 alkyl, halo, haloalkyl, OH, CN, C1-C7 alkoxy, 5-7 membered heteroaryl containing 1-2 nitrogens and / or sulfurs and / or oxygens. X8 is K-Ac, Q, K(NMeAc), K(PEG2PEG2gEC18OH), dK-Ac, dQ, dK(NMeAc), or dK(PEG2PEG2gEC18OH); X9 is Pen, Abu, aMeC, hC, or C; X12 is THP, aMeK, Aib, Acpx, Achx, 4diFAchx, aMeL, Pip(NMe), Pip(NMe2), or α,α-disubstituted (C1-C5 alkyl and C1-C5 alkyl, haloalkyl, alkoxy, carboxy, alkylamine, or 3-7 membered carbocyclic or heterocyclic ring containing 1-2 nitrogen, sulfur and / or oxygen atoms) glycine. X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, as well as heteroaromatic analogs thereof containing one to two nitrogens, sulfurs, and / or oxygens. X13 is E, dE, hE, dhE, D, dD, or hSer, dhSer; X15 is 3pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmP yridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NmeDTyr, K, dK, NMeY, NmedY, N, dH, dN, dL, Aib, L, 3pya substituted with C1-C7 alkyl, halo, haloalkyl, OH, CN, C1-C7 alkoxy, H substituted with C1-C7 alkyl, halo, haloalkyl, OH, CN, C1-C7 alkoxy, 5-7 membered heteroaromatic containing 1-2 nitrogens, sulfurs, and / or oxygens, or 5-7 membered heteroaromatic containing 1-2 nitrogens, sulfurs, and / or oxygens and substituted with C1-C7 alkyl, halo, haloalkyl, OH, CN, C1-C7 alkoxy, or absent; R2 is -NH2, N(H)C1-C4 alkyl, -H(C1-C4 alkyl, -N(C1-C4 alkyl)2, each alkyl optionally substituted with Cl, F, or cyano; Bicyclic peptide inhibitors of the interleukin-23 receptor are provided by a first disulfide or thioether bond between X4 and X9, and a second amide or thioether bond between R1 and X13 (between pFS and Dap(pF)), or Any aliphatic linker composition having a total covalent bond length of 10 to 18, or any aliphatic linker composition and / or aromatic linker composition having an equivalent length between the alpha carbons of X4 and X13. is cyclized by Bicyclic peptide inhibitors. 112. A pharmaceutical composition comprising an inhibitor of the interleukin-23 receptor of embodiment 111 and a pharma- ceutically acceptable excipient. 113. A method of treatment comprising administering an inhibitor of the interleukin-23 receptor according to embodiment 111 or a pharmaceutical composition according to embodiment 112 to a patient in need thereof. Some abbreviations useful in describing this invention are defined below in Tables 2A-2D.

[0244] [Table 9-1]

[0245] [Table 9-2]

[0246] [Table 9-3]

[0247] [Table 9-4]

[0248] [Table 9-5]

[0249] [Table 10]

[0250] [Table 11-1]

[0251] [Table 11-2]

[0252] [Table 11-3]

[0253] [Table 11-4]

[0254]

Table 11-5

[0255]

Table 11-6

[0256]

Table 11-7

[0257]

Table 11-8

[0258]

Table 11-9

[0259]

Table 11-10

[0260]

Table 11-11

[0261]

Table 11-12

[0262]

Table 11-13

[0263]

Table 11-14

[0264]

Table 11-15

[0265]

Table 11-16

[0266]

Table 11-17

[0267]

Table 11-18

[0268]

Table 11-19

[0269]

Table 11-20

[0270]

Table 11-21

[0271]

Table 11-22

[0272]

Table 11-23

[0273]

Table 11-24

[0274]

Table 11-25

[0275]

Table 11-26

[0276]

Table 11-27

[0277]

Table 11-28

[0278]

Table 11-29

[0279]

Table 11-30

[0280]

Table 11-31

[0281]

Table 11-32

[0282]

Table 11-33

[0283]

Table 11-34

[0284]

Table 11-35

[0285]

Table 11-36

[0286]

Table 11-37

[0287]

Table 11-38

[0288]

Table 11-39

[0289]

Table 11-40

[0290]

Table 11-41

[0291]

Table 11-42

[0292]

Table 11-43

[0293]

Table 11-44

[0294]

Table 11-45

[0295]

Table 11-46

[0296]

Table 11-47

[0297]

Table 11-48

[0298]

Table 11-49

[0299]

Table 11-50

[0300]

Table 11-51

[0301]

Table 11-52

[0302]

Table 11-53

[0303]

Table 11-54

[0304]

Table 11-55

[0305]

Table 11-56

[0306]

Table 11-57

[0307]

Table 11-58

[0308]

Table 11-59

[0309]

Table 11-60

[0310]

Table 11-61

[0311]

Table 11-62

[0312]

Table 11-63

[0313]

Table 11-64

[0314]

Table 12-1

[0315]

Table 12-2

[0316]

Table 12-3

[0317]

Table 12-4

[0318]

Table 12-5

[0319]

Table 12-6

[0320]

Table 12-7

[0321]

Table 12-8

[0322]

Table 12-9

[0323]

Table 12-10

[0324]

Table 12-11

[0325]

Table 12-12

[0326]

Table 12-13

[0327]

Table 12-14

[0328]

Table 12-15

[0329]

Table 12-16

[0330]

Table 12-17

[0331]

Table 12-18

[0332]

Table 12-19

[0333]

Table 12-20

[0334]

Table 12-21

[0335]

Table 12-22

[0336]

Table 12-23

[0337]

Table 12-24

[0338]

Table 12-25

[0339]

Table 12-26

[0340]

Table 12-27

[0341]

Table 12-28

[0342]

Table 12-29

[0343]

Table 12-30

[0344]

Table 12-31

[0345]

Table 12-32

[0346]

Table 12-33

[0347]

Table 12-34

[0348]

Table 12-35

[0349]

Table 12-36

[0350]

Table 12-37

[0351]

Table 12-38

[0352]

Table 12-39

[0353]

Table 12-40

[0354]

Table 12-41

[0355]

Table 12-42

[0356]

Table 12-43

[0357]

Table 12-44

[0358]

Table 12-45

[0359]

Table 12-46

[0360]

Table 12-47

[0361]

Table 12-48

[0362]

Table 12-49

[0363]

Table 12-50

[0364]

Table 12-51

[0365] [Table 12-52]

[0366] [Table 12-53]

[0367] VIII. Examples 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.

[0368] General peptide synthesis procedure 1 The IL-23R inhibitor compounds described herein were synthesized from amino acid monomers using standard Fmoc-based solid phase synthesis on various instruments, such as Protein Technology's Symphony multichannel synthesizer and CEM microwave peptide synthesizer. Peptides were assembled using various coupling conditions, such as HBTU (O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate) and diisopropylethylamine (DIEA), Oxyma / DIC, or PyAOP (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphanium hexafluorophosphate) and DIEA. For peptides with C-terminal amides, Rink Amide MBHA resin was used, and for peptides with C-terminal acids, Wang resin with preloaded N-α-Fmoc-protected amino acids or 2-chlorotrityl resin was used. The peptide inhibitors of the present invention were identified and screened based on medicinal chemistry optimization and / or phage display to identify those with superior binding and / or inhibitory properties.

[0369] Preparation of specific modified amino acids Certain modified amino acids appear in the sequences of the IL-23R inhibitors described herein. These modified amino acids and their precursors suitable for synthesizing the inhibitors described herein can be obtained from commercial sources, synthesized as described in the art, or synthesized by any suitable route. For example, 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-alkyl-tryptophan (e.g., 7-ethyl-L-tryptophan), along with other substituted tryptophans, is described, for example, in WO 2021 / 146441(A1). The synthesis of certain further modified amino acids is described herein below.

[0370] a. Synthesis of (S)-5-(4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carboxyethyl)phenoxy)-N,N,N-trimethylpentan-1-aminium (TMAPF)

[0371] [ka] To a mixture of 1 (6.60 g, 19.7 mmol), K2CO3 (4.09 g, 29.6 mmol) and acetone (50 mL) was added 2 (4.99 g, 21.7 mmol). The reaction mixture was heated to reflux and stirred for 12 h. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 5:1) to give the crude product 3 (5.26 g, yield: 54.8%) as a pale colorless oil. MS (ESI): C 23 H 36 Calculated mass of BrNO5: 486.44, measured m / z: 509.9 [M+23] + . 1H NMR(400MHz,CDCl3):δppm 7.07(d,J=8.4Hz,2H),6.81(d,J=8.6Hz,2H),4.97(br d,J=8.2Hz,1H),4.36-4.48(m,1H),3.95(t,J=6.3Hz,2H),3.45(t,J=6.8Hz,2H),3.00(br d,J=3.7Hz,2H),1.87-2.01(m,2H),1.76-1.86(m,2H),1.62-1.69(m,2H),1.42(d,J=2.8Hz,18H).

[0372] To a mixture of 3 (5.26 g, 10.8 mmol) in acetonitrile (50 mL) was added trimethylamine in acetonitrile (2 M, 8.11 mL). The reaction mixture was stirred at 50° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give the product 4 as a pale yellow solid (5.0 g, yield: 99.3%).

[0373] MS (ESI): Calculated mass of C26H45N2O5: 465.646, measured m / z: 465.2 [M] + A mixture of 4 (4.00 g, 8.59 mmol) in 4M HCl-dioxane (43.0 mL, 172 mmol) was stirred at room temperature for 12 h. The solvent was removed under reduced pressure to give the product 5 as a white solid (3.00 g, yield: crude), which was used directly in the next step. MS (ESI): 17 H 29 Calculated mass of N2O3: 309.424, measured m / z: 309.1 [M+H] + .

[0374] In a round bottom flask, compound 5 (3.00 g, 8.67 mmol) was dissolved in dioxane (20 mL) and water (20 mL). Na2CO3 (1.38 g, 13.0 mol) was added and the solution was cooled to 0 °C in an ice bath. Fmoc-OSu (3.22 g, 9.54 mol) was then dissolved in dioxane (20 mL) and added portionwise to the solution at 0 °C. The reaction was stirred at 0 °C for 2 h. The reaction was allowed to warm to room temperature overnight. The reaction was acidified with 2N HCl (50 mL). The reaction mixture was diluted with Xtimate C18 150 mL of 1H 2 SO 4 and diluted with 1H 2 SO 4 . *40mm * The product was purified by preparative HPLC using 5um (eluent: 20%-50% (v / v) CH3CN and HO containing 0.05% HCl) to give the product. The product was suspended in water (40 mL) and the mixture was frozen using dry ice / ethanol, then lyophilized to dryness to give the title compound 6 (TMAPF, 3.57 g, yield: 61.9%, purity: 99.2%) as a pale yellow solid. MS (ESI): C 32 H 39 Calculated mass of N2O5: 531.662, measured m / z: 531.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ ppm 7.89(d,J=7.6Hz,2H),7.73(d,J=8.2Hz,1H),7.65(t,J=7.2Hz,2H),7.39- 7.43(m,2H),7.27-7.34(m,2H),7.19(d,J=8.2Hz,2H),6.78-6.89(m,2H), 4.06-4.25(m,4H),3.84-3.99(m,2H),3.25-3.37(m,2H),3.05(s,9H),3.0 0(d,J=4.0Hz,1H),2.70-2.84(m,1H),1.63-1.82(m,4H),1.30-1.46(m,2H)

[0375] b. Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(7-(3-acetamidophenyl)-1H-indol-3-yl)propanoic acid (7-(3-N-acetyl-phenyl)-tryptophan or 7(3NAcPh)W)

[0376] [ka] 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): C 16 H 14 Calculated mass of N2O: 250.295, observed m / z: 251.0 [M+].

[0377] 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, measured m / z: 328.8 [M].

[0378] 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), 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, observed m / z: 574.1 [M+1].

[0379] A 250 mL round bottom flask was charged with intermediate 6 (11.0 g, 19.2 mmol), a stir bar, Me3SnOH (3.64 g, 20.1 mmol) and DCE (150 mL) and stirred at 50 °C for 12 h. The reaction mixture was adjusted to pH 6 by adding 2N HCl. A second reaction series was prepared starting from a solution of 1, and the combined reaction mixture was concentrated under reduced pressure to give crude product 7, which was purified by preparative HPLC using Xtimate C18 150 × 40 mm × 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, then lyophilized to dryness to give 7 (7(3NAcPh)W, 11.8 g, yield: 66.8%) as a white solid. MS (ESI): C 34 H29 Calculated mass of N3O5: 559.611, observed m / z: 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).

[0380] c. Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(tert-butoxy)naphthalen-2-yl)propanoic acid (5-methyl-pyridyl-alanine or 5MePyridinAla)

[0381] [ka] Activated Zn powder (8.18 g, 125 mmol), DMF (150 mL), and I2 (0.534 g, 2.11 mmol) were stirred at room temperature under N2 atmosphere for 20 min, after which (R)-methyl 2-((((9H-fluoren9-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, after which 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, measured m / z: 417.1 [M+H] + .

[0382] 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 (5MePyridinAla, 6.716 g, yield: 72.3%) as a white powder. MS (ESI): C 24 H 22 Calculated mass of N2O4: 402.442, measured m / z: 403.1 [M+H] + . 1 H NMR DMSO-d6(Bruker_400MHz):δ8.18(s,2H),7.88(d,J=7.6 Hz,2H),7.63(d,J=7.2 Hz,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).

[0383] d. Synthesis of (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 (AEF(G))

[0384] [ka] A 500 mL round bottom flask was charged with starting material 1 (9.9 g, 62.2 mmol), a stir bar, Et3N (14 mL, 101 mmol), and dichloromethane (DCM, 250 mL). 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 phase 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 then 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, measured m / z: 412.1 [M+H] + .

[0385] 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 (three times), 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, measured m / z: 466.1 [M+Na] + .

[0386] 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, measured m / z: 775.5 [M+H] + .

[0387] 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 12 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): C 25 H 34 Calculated mass of N4O6S: 518.6, measured m / z: 519.2 [M+H] + .

[0388] 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 the pH was adjusted to 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 product 8 (AEF(G), 4 g, 36%) as a white solid. MS (ESI): C 40 H 44 Calculated mass of N4O8S: 740.9, measured m / z: 741.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6):7.87(d,J=7.2 Hz,2H),7.71-7.62(m,2H),7.39(td,J=4.0,7.2 Hz,2H),7.29(td,J=7.6,12.0 Hz,2H),7.14(br d,J=8.0 Hz,2H),6.99-6.85(m,1H),6.77(br d,J=8.4 Hz,2H),6.59-6.50(m,1H),4.21-4.06(m,4H),3.88(br s,2H),3.42-3.36(m,4H),2.99(br dd,J=4.4,14.0 Hz,1H),2.92(s,2H),2.78(br dd,J=10.8,13.6 Hz,1H),2.47(br s,3H),2.41(s,3H),1.97(s,3H),1.38(s,6H).

[0389] e. Synthesis of 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethylethan-1-aminium (cPEG3a)

[0390] [ka] Mixture 1 (5.00 g, 16.8 mmol) and trimethylamine 2 (25 mL, 50 mmol, in THF) in dry THF (10 mL) were stirred under N at 50° C. for 16 h. The mixture was concentrated to give product 3 (6.0 g, yield: 99.8%) as a yellow oil. 1 H NMR (DMSO-d6, 400 MHz): δ 3.88-3.79 (m, 2H), 3.64-3.48 (m, 8H), 3.12 (s, 9H), 2.42 (t, J = 6.4 Hz, 2H), 1.39 (s, 9H). A mixture of 3 (6.00 g, 16.8 mmol) and HCl / dioxane (60 mL, 240 mmol) was stirred under N2 at 25 °C for 16 h. The mixture was concentrated to give product 4 (cPEG3a, 4.3 g, yield: 99.8%) as a yellow oil. 1 H NMR (D2O, 400MHz): δ3.96-3.87(m,2H),3.74(t,J=5.6 Hz,2H),3.64(s,4H),3.57-3.49(m,2H),3.12(s,9H),2.60(t,J=5.6 Hz,2H).

[0391] f. Synthesis of (S)-2-(2-(2-(4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-carboxyethyl)phenoxy)ethoxy)ethoxy)-N,N,N-trimethylethane-1-aminium (APEG3F)

[0392] [ka] To a mixture of 1 (50.0 g, 333 mmol) in THF (1.3 L), PPh3 (188 g, 716 mmol) was added, followed by CBr4 (243 g, 732 mmol) being added very slowly to the mixture at 0 °C. The mixture was stirred overnight (16 h) at room temperature and then concentrated under reduced pressure to give crude intermediate 2. Petroleum ether (2.0 L) and ethyl acetate (200 mL) were added to the mixture and stirred at 25 °C for 0.5 h. The mixture was filtered, concentrated under reduced pressure and purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 1:9) to give intermediate 2 (52 g, yield: 56.6%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d): 3.91-3.81 (m, 4H), 3.75-3.68 (m, 4H), 3.55-3.46 (m, 4H).

[0393] To a solution of 3 (45.9 g, 136 mmol) and K2CO3 (56.3 g, 408 mmol) in acetone (1 L) was added 2 (75.0 g, 272 mmol) under nitrogen atmosphere. The mixture was stirred at 70 °C for 16 h. The mixture was filtered, evaporated and the residue was purified by flash column chromatography FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 1:9) to give intermediate 4 (45 g, yield: 61.6%) as a pale yellow oil. MS (ESI): C 24 H 38 Calculated mass of BrNO7: 532.47, measured m / z: 433.8 [M-100] + .

[0394] A solution of 4 (51 g, 96 mmol) in trimethylamine (239 mL, 2 M in THF) was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure to give crude intermediate 5 (56 g, crude) as a pale yellow oil, which was used in the next step without purification. MS (ESI): mass calculated for C27H47N2O7: 511.67, m / z found: 511.4 [M] +

[0395] A mixture of 5 (56.0 g, 94.7 mmol) in HCl / dioxane (592 mL, 4 M) was stirred at 25 °C for 16 h, then concentrated under reduced pressure, dissolved in HO (200 mL), quenched with an aqueous solution of NaCO at 0 °C to adjust pH = 7. Then NaCO (15.0 g, 142 mmol) and Fmoc-OSu (31.9 g, 94.4 mmol) in acetone (150 mL) were added under nitrogen atmosphere and stirred at 25 °C for 3 h. The mixture was acidified with 2 M HCl, adjusted to pH = 4, and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (300 mL x 2). The aqueous phase was concentrated under reduced pressure to give the crude product 6 (in HO), which was purified by HPLC using Phenomenex Gemini Xtimate C18 150 mL. * 40mm * Purification by preparative HPLC using 5um, 100A (eluent: 53%-83% (v / v) water (0.225% FA)-ACN) afforded the title compound 6 (APEG3F, 43 g, yield: 78.8%) as an off-white solid. MS (ESI): C 18 H 31 N2O5 + Calculated mass: 355.45, measured m / z: 355.1 [M] + . 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.88(d,J=7.6 Hz,2H),7.66(d,J=7.2 Hz,2H),7.44-7.36(m,2H),7.31(q,J=7.2 Hz,2H),7.18-7.04(m,3H),6.77(d,J=8.4 Hz,2H),4.24-4.13(m,3H),4.00(d,J=3.6 Hz,3H),3.81(s,2H),3.73-3.67(m,2H),3.58(s,4H),3.54-3.48(m,2H),3.07(s,9H),3.05-2.98(m,1H),2.85-2.76(m,1H).

[0396] f. Synthesis of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N4,N4-dimethyl-L-asparagine (N(N(Me)2)

[0397] [ka] A solution of starting material 1 (50 g, 122 mmol), dimethylamine (10.9 mg, 134 mmol) and diisopropylethylamine (DIEA, 62.0 g, 365 mmol) in DMF (200 mL) at 0° C. was degassed with N2 three times, and propylphosphonic anhydride (T3P®, 109 g, 182 mmol) was added via syringe. The mixture was stirred at 20° C. for 12 h, then poured into ice water (500 mL) and extracted with ethyl acetate (500 mL×3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate 2, which was purified by high-performance column chromatography (FCC, eluent: petroleum ether: ethyl acetate = 1:0 to 1:2) to give 2 as a pale yellow solid (45 g, yield: 84.4%). MS (ESI): C 25 H 30 Calculated mass of N2O5: 438.52, measured m / z: 439.2 [M+H] + .

[0398] Intermediate 2 (45 g, 103 mmol) was stirred in HCl / dioxane (1 L, 4 M) at 20° C. for 16 h. The reaction mixture was filtered and concentrated. EtOAc (200 mL) was added to the concentrated material, followed by dropwise addition of petroleum ether (200 mL). The mixture was stirred at 20° C. for 3 h to give a solid, which was filtered to give 3 (N(N(Me)2), 25 g, yield: 62.3%) as a white solid. MS (ESI): C 21 H 22 Calculated mass of N2O5: 382.41, measured m / z: 383.1 [M+H] + . 1 H NMR (DMSO-d6,400MHz): δppm 12.59(s,1H),7.86(d,J=7.6 Hz,2H),7.67(d,J=7.2 Hz,2H),7.43-7.21(m,5H),4.39-4.31(m,1H),4.29-4.23(m,2H),4.21-4.15(m,1H),2.90(s,3H),2.78(s,3H),2.75-2.62(m,2H).

[0399] g. Synthesis of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-acetyl-N6-methyl-L-lysine (Lysine N-(MeAc) or K(NMeAc))

[0400] [ka] Starting material 1 (21 g, 57.0 mmol) and MeOH (300 mL) were combined in a flask under N2 atmosphere. Thionyl chloride (8.14 g, 68.4 mmol) was added dropwise to the flask over 15 min at a temperature of 25° C. to give a pale yellow mixture. The mixture was heated at reflux for 4 h. The resulting yellow solution was concentrated in vacuo. Ethyl acetate (50 mL) was added to the concentrated material and the mixture was stirred at 25° C. for 1 h. The solid was filtered to give crude intermediate 2 (23 g, crude) as a white solid. MS (ESI): C 22 H 26 Calculated mass of N2O4: 382.45, measured m / z: 383.5 [M+H] + .

[0401] To a solution of 2 (6.1 g, 14.6 mmol) and TEA (4.41, 43.7 mmol) in 100 mL of anhydrous CHCl / THF (100 mL) was added trityl chloride (Trt-Cl, 4.47 g, 16.0 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (80 mL), extracted with ethyl acetate (100 mL x 2), washed with brine (20 mL), and dried over NaSO. The combined organic extracts were filtered and concentrated under reduced pressure to give crude intermediate 3, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 1:2) to give 3 (7 g, yield: 76.7%) as a pale yellow solid. MS (ESI): C 41 H 40 Calculated mass for N2O4: 624.77, observed m / z: 647.3 [M+Na]+. 1H NMR (DMSO-d6,400MHz): δppm 7.84(d,J=7.5 Hz,2H),7.71(d,J=7.7 Hz,1H),7.66(d,J=6.8 Hz,2H),7.36(d,J=7.3 Hz,9H),7.29-7.20(m,8H),7.17-7.08(m,3H),4.29-4.22(m,2H),4.21-4.1 1(m,1H),3.97-3.91(m,1H),3.56(s,3H),2.56-2.50(m,1H),1.91(d,J=6.2 Hz,2H),1.55(m,2H),1.46-1.31(m,2H),1.26(d,J=7.5 Hz,2H).

[0402] A solution of 3 (5.20 g, 8.32 mmol), formaldehyde (20.3 g, 250 mmol) and NaBH3CN (2.62 g, 41.6 mmol) in methanol (100 mL) was stirred at 25 °C for 16 h. The mixture was quenched with water (100 mL) and extracted with dichloromethane (200 mL × 3), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (FCC, eluent: petroleum ether: ethyl acetate = 1:0 to 1:9) to give 4 (2.7 g, yield: 41.2%) as a pale yellow solid. MS (ESI): C 42 H 42 Calculated mass of N2O4: 638.79, measured m / z: 661.1 [M+Na] + .

[0403] Intermediate 4 (80 g, 125 mmol) was dissolved in HCl / MeOH (800 mL) and stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Ethyl acetate (100 mL) and petroleum ether (200 mL) were added and the reaction mixture was stirred at 20° C. for 4 h. The solid was filtered to give Intermediate 5 (60 g, crude) as a pale yellow solid. MS (ESI): 23 H 28 Calculated mass of N2O4: 396.48, measured m / z: 397.1 [M+H] + .

[0404] To a solution of 5 (120 g, 277 mmol) in CHCl (1200 mL) was added TEA (107 g, 832 mmol) at 0° C. Acetyl chloride (26.1 g, 333 mmol) was added and the reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with water (300 mL), extracted with CHCl (500 mL×2), washed with brine, and dried over NaSO. The combined organic extracts were filtered and concentrated under reduced pressure to give crude intermediate 6, which was purified by FCC (eluent: petroleum ether:ethyl acetate=1:0 to 1:2) to give 6 (67 g, yield: 38.0%) as a pale yellow oil. MS (ESI): C 25 H 30 Calculated mass of N2O5: 438.52, measured m / z: 439.6 [M+H] + .

[0405] To a solution of 6 (2.6 g, 5.93 mmol) in DCE (50 mL), Me3SnOH (1.61 g, 8.90 mmol) was added and stirred at 20 °C for 16 h. 1M HCl (5 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 0.5 h, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by FCC (eluent: CH2Cl2:MeOH = 1:0 to 95:5) to give 7 (K(NMeAc), 2.02 g, yield: 80.51%) as a pale yellow solid. MS (ESI): C 24 H 28 Calculated mass for N2O5: 424.49, observed m / z: 425.1 [M+H]+. 1 H NMR(DMSO-d6,400MHz):δ7.89(d,J=7.6 Hz,2H),7.73(d,J=7.2 Hz,2H),7.62(m,1H),7.46-7.38(m,2H),7.36-7.28(m,2H),4.33-4.16(m,3H),3.89(s,1H),3.22(m,2H),2.93-2.73(m,3H),1.94(d,J=7.2 Hz,3H),1.77-1.55(m,2H),1.55-1.36(m,2H),1.28(m,2H).

[0406] h. Synthesis of (S)-2-amino-N-(2-(dimethylamino)-2-oxoethyl)-N-methyl-3-(pyridin-3-yl)propanamide (NH2-3Pya-Sar-CON(Me)2)

[0407] [ka] A 100 mL vial was charged with starting material 1 (10 g, 82.3 mmol) and a solution of methylamine (51.1 g, 494 mmol, 30% in ethanol) was added. The reaction mixture was stirred at 25° C. for 16 h, after which the mixture was concentrated to give crude intermediate 2. Petroleum ether (30 mL) was added to the crude intermediate and the mixture was stirred at 25° C. for 0.5 h to give a solid. The resulting solid was filtered to give 2 (10 g, crude) as a light yellow solid. 1 H NMR (DMSO-d6, 400MHz): δppm 9.09-8.02 (m, 2H), 3.97 (s, 2H), 2.92 (s, 3H), 2.87 (s, 3H), 2.52 (s, 3H).

[0408] To a stirred solution of compound 3 (9 g, 23.2 mmol), intermediate 2 (3.23 g, 27.81 mmol) and DIEA (7.03 g, 69.5 mmol) in DMF (90 mL) was added HATU (10.6 g, 27.8 mmol). The reaction mixture was stirred at 25 °C for 2 h, then poured into ice water (100 mL) and extracted with ethyl acetate (200 mL x 4). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude intermediate 4, which was purified by FCC (eluent: CH2Cl2:MeOH = 1:0 to 95:5) to give 4 (11 g, yield: 96.5%) as a pale yellow solid. MS (ESI): C 28 H 30 Calculated mass of N4O4: 486.56, measured m / z: 487.2 [M+H] + .

[0409] To a solution of 4 (10.5 g, 21.6 mmol) in DCM (400 mL) was added piperidine (5 mL, 50.5 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 16 h, then it was concentrated in vacuo. The residue was purified by FCC (eluent: CH2Cl2:MeOH = 1:0 to 95:5) to give the crude product 5 (5.5 g, impure) as a pale yellow solid. The crude product was then purified by HPLC using Phenomenex Genimi NX C18 (150 * 40mm * The pure product was obtained by preparative HPLC using 5 μm) (eluent: 1%-25% (v / v) water (0.04% NH3H2O+10 mM NH4HCO3)-MeCN. The pure fractions were collected and lyophilized to dryness to give 5 (NH2-3Pya-Sar-CON(Me)2, 3.6 g, yield: 62.7%) as a gummy liquid. MS (ESI): C 13 H 20 Calculated mass for N4O2: 264.32, observed m / z: 265.1 [M+H]+. 1 H NMR(400MHz,D2O)δ ppm 8.44-8.22(m,2H),7.76-7.54(m,1H),7.34(m,1H),4.31-4.19(m,1H),4.18-3.96(m,2H),2.95(m,3H),2.92-2.85(m,6H),2.77(m,2H).

[0410] i. Synthesis of substituted tryptophan Synthesis of 7-methyltryptophan. 7-Methyltryptophan was purchased from a commercial source. Additionally, the compound can be synthesized according to one of the methods described below.

[0411] Synthesis of 7-ethyltryptophan. 7-Ethyltryptophan was synthesized according to the method shown in Scheme 1.

[0412] [ka]

[0413] Synthesis of 7-isopropyltryptophan 7-isopropyltryptophan was synthesized according to the method shown in Scheme 2.

[0414] [ka]

[0415] Synthesis of Additional 7-Substituted Tryptophans Additional 7-substituted tryptophans have been or can be synthesized according to the methods shown in Scheme 3A.

[0416] [ka] R is cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy. Synthesis of 7-aryl substituted tryptophans 7-aryl substituted tryptophans have been or can be synthesized according to the method shown in Scheme 3B.

[0417] [ka] R is aryl unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, or alkoxy.

[0418] Specific representative R groups are selected from phenyl or 3-Me-phenyl.

[0419] Synthesis of 7-phenyl substituted tryptophans. 7-Phenyl substituted tryptophans have been or can be synthesized according to the method shown in Scheme 4.

[0420] [ka]

[0421] Suzuki coupling with arylboronic acids. (S)-Methyl 3-(7-bromo-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.0 g, 10.0 mmol) in dry toluene (30 mL) was purged with nitrogen for 10 min. K2CO3 (2.0 g, 15.0 mmol) in 10 mL of water was added, followed by phenylboronic acid (1.47 g, 12.0 mmol) and the reaction mixture was purged with nitrogen for 10 min. Pd(dppf)Cl2.DCM (0.58 g, 0.71 mmol), ethanol (10 mL), and THF (20 mL) were added and the reaction mixture was stirred for 8 h at 100°C. o The mixture was heated to C. The reaction mixture was concentrated under vacuum and the residue was dissolved in DCM (200 mL). The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by 60-120 mesh silica gel column chromatography to give the product (3.6 g, 90%) as a foamy solid.

[0422] Hydrolysis. To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(7-phenyl-1H-indol-3-yl)propanoate (3.6 g, 9.1 mmol) in THF / MeOH / water (4:1:1) was added lithium hydroxide (1.15 g, 27.3 mmol) and the solution was stirred overnight. The solution was concentrated to remove the solvent, diluted with sufficient water and acidified with 10% citric acid. The aqueous layer containing the product was extracted with ethyl acetate (2×10 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give the desired product (3.3 g, 95%).

[0423] Boc deprotection. To an ice-cold solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-phenyl-1H-indol-3-yl)propanoic acid (3.3 g, 8.6 mmol) in dichloromethane (13 mL) was added trifluoroacetic acid (6.6 mL) and the solution was stirred at room temperature for 6 h. The solution was evaporated to dryness, redissolved in dichloromethane (10 mL), treated with HCl / ether and concentrated. The crude hydrochloride was suspended in MTBE (25 mL), stirred for 30 min and filtered to give (S)-2-amino-3-(7-phenyl-1H-indol-3-yl)propanoic acid hydrochloride (1.8 g, 66%).

[0424] Fmoc protection. To a solution of (S)-2-amino-3-(7-phenyl-1H-indol-3-yl)propanoic acid hydrochloride (1.8 g, 5.7 mmol) in THF / water (45 mL:13 mL) was added sodium bicarbonate (1.92 g, 22.8 mmol) followed by N-(9-fluorenylmethoxycarbonyloxy)succinimide (1.92 g, 5.7 mmol) in portions. The resulting mixture was stirred overnight and concentrated to remove THF. The residue was diluted with enough water, acidified with 2N HCl, and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water and brine, dried over Na2SO4, concentrated, and the residue was suspended in 20% MTBE / hexane to give the desired product (2.6 g, 92%).

[0425] Synthesis of 7-heteroaryl substituted tryptophans 7-heteroaryl substituted tryptophans have been or can be synthesized according to the methods shown in Scheme 5.

[0426] [ka] wherein R is heteroaryl unsubstituted or substituted with halo, halo, alkyl, cyano, haloalkyl, hydroxy, or alkoxy.

[0427] Synthesis of 7-heterocycloalkyl substituted tryptophans 7-heterocycloalkyl substituted tryptophans have been or can be synthesized according to the methods shown in Scheme 6.

[0428] [ka] R is heterocycloalkyl, unsubstituted or substituted with alkyl or halo.

[0429] Specific representative R groups are selected from thienyl, pyridyl, piperidinyl, and morpholinyl.

[0430] Synthesis of 7-Thienyl(thiophenyl)-Substituted Tryptophans 7-Thienyl(thiophenyl)-substituted tryptophans have been or can be synthesized according to the methods shown in Scheme 7.

[0431] [ka]

[0432] The Suzuki-Miyaura cross-coupling reaction was carried out using a modified approach described by Frese et al. (ChemCatChem 2016,8,1799-1803). Na2PdCl4 is used as the Pd source in combination with the Buchwald ligand SPhos. This system is known to catalyze difficult substrate combinations with excellent results even at low temperatures. In our case, the Suzuki-Miyaura cross-coupling reaction of 7-bromo Trp with boronic acid gave the desired product, which was then protected using Fmoc-OSu.

[0433] L-7-(Thiophen-3-yl)-tryptophan: 7-Bromo-L-tryptophan (0.283 g, 1 mmol), thiophene-3-boronic acid (0.383 g, 3.00 mmol, 3 equiv.), and K2CO3 (10 equiv.) were placed in a flask and purged with N2. Degassed water:1-butanol (9:1, 30 mL) was added via syringe and the reaction was stirred at 95 °C. To initiate the reaction, SPhos (6.2 mg, 15 mol%) and Na2Cl4Pd (15.2 mg, 5 mol%) were transferred to the mixture after pre-warming the Pd salt and ligand at 40 °C for 10 min.

[0434] Upon completion, the aqueous reaction was diluted with HO (20 mL) and the solution was acidified to pH 1.0 by dropwise addition of 1 M HCl. Precipitated palladium black was removed by filtration (Whatman, pore size 20 μm) and the filtrate was freeze-dried. Finally, the resulting crude product was purified by preparative reversed-phase high-performance liquid chromatography (RP-HPLC) using a C18 column (5 μm, 250 × 50 mm) at a flow rate of 50 mL / min. Separation was achieved using a linear gradient of B in buffer A (Buffer A: aqueous 0.05% TFA; Buffer B: 0.043% TFA, 90% acetonitrile in water). Analysis was monitored and performed using a C18 column (3 μm, 50 × 2 mm) at a flow rate of 1 mL / min. The fractions containing the pure product were then freeze-dried in a lyophilizer. Yield 104 mg (36% yield). MS(ESI)m / z 287.08[M+H]+(calculated mass of C15H15O2NS: 287.12).

[0435] Fmoc-L-7-(thiophen-3-yl)-tryptophan: The amino acid, L-7-(thiophen-3-yl)-tryptophan (31.5 mg, 0.11 mmol), was dissolved in water and sodium bicarbonate (2 equiv.) with stirring. The resulting solution was cooled to 5° C. and Fmoc-OSu (44.53 mg, 1.05 equiv.) was added slowly as a dioxane solution. The resulting mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature overnight. Water was then added and the aqueous layer was extracted twice with EtOAc. The organic layer was back-extracted twice with saturated sodium bicarbonate solution. The combined aqueous layers were acidified to pH 1.0 with 10% HCl and then extracted three times with EtOAc. The combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2) using (toluene, ethyl acetate, (1:1), 1% acetic acid). Yield 50 mg (89%). MS (ESI) m / z 509.10 [M+H]+ (Calcd. mass calculated for C15H15O2NS: 508.59).

[0436] assembly Peptides were assembled using standard Fmoc-based solid phase synthesis on various instruments. In general, peptide sequences were assembled as follows: the resin in each reaction vial was washed twice with DMF, followed by treatment with 20% 4-methylpiperidine or 20% piperidine (Fmoc deprotection). The resin was then filtered, washed with DMF, and re-treated with 4-methylpiperidine or piperidine. The resin was washed again with DMF, followed by addition of amino acids and coupling reagents. After frequent stirring for the indicated times, the resin was filtered and washed with DMF. For a typical peptide of the invention, double coupling was performed for several amino acids. After the coupling reaction was completed, the resin was washed with DMF before proceeding to the next amino acid coupling.

[0437] Ring-closing metathesis to form olefins As an 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 first 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), then dried and cleaved.

[0438] 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.

[0439] 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.

[0440] 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.

[0441] Typically, the crude cleaved peptides, where X4 and X9 are either Cys, aMeCys, Pen, hCys, (D)Pen, (D)Cys, or (D)hCys, were dissolved in 20 mL of 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 (example conditions include Luna C18 support, 10u, 100A, mobile phase A: water with 0.1% TFA, mobile phase B: acetonitrile (ACN) with 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 in a lyophilizer.

[0442] 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.

[0443] Crude peptides bearing free thiols (e.g., Cys, Pen, aMeCys, hCys, (D)Pen, (D)Cys, or (D)hCys) at either the X4 and X9 positions or the 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 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 min at a flow rate of 15mL / min). Fractions containing pure product were then lyophilized on a lyophilizer.

[0444] purification Analytical and purification columns and methods are varied and known in the art. For example, 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 Angstrom (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).

[0445] Example 1B. ac-Pen(1:3)-ET-Trp_7Me-Lys_Ac-Pen(1:3)-Phe_4_2ae-Nal-THP-Lys_Ac-NH-Sar-am (intermediate peptide) The TFA (trifluoroacetic acid) salt of the intermediate peptide was synthesized on a 0.1 mmol scale. Upon completion, 60 mg of approximately 95% pure intermediate peptide was isolated as a white powder, representing an overall yield of approximately 30%.

[0446] The intermediate peptide was synthesized using Merrifield solid-phase synthesis technology on a Protein Technology Symphony multichannel synthesizer and assembled on Rink Amide MBHA (100-200 mesh, 0.8 mmol / g) resin using standard Fmoc-protected synthesis conditions. The assembled peptide was isolated from the resin and protecting groups by strong acid cleavage followed by precipitation. The crude lean peptide was then cyclized and purified by reversed-phase high performance liquid chromatography (RP-HPLC). Lyophilization of the pure fractions afforded the final product, intermediate peptide 2.

[0447] Swollen resin: 125 mg of Rink Amide MBHA resin (0.1 mmol, 0.8 mmol / g loading) was transferred to a 25 mL reaction vessel (for Symphony peptide synthesizer). The resin was swelled with 3.75 mL of DMF (3 x 10 min).

[0448] Step 1: Coupling of Fmoc-Sar-OH (Fmoc-N-methylglycine): Deprotection of the Fmoc group was achieved by treating the swollen Rink Amide resin with 2.5 mL of 20% piperidine in DMF twice for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 x 0.1 min), followed by the addition of 2.5 mL of a solution of the amino acid Fmoc-Sar-OH in DMF (200 mM) and 2.5 mL of a solution of the coupling reagent HBTU-DIEA in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the coupling reaction was completed, the resin was washed with 6.25 mL of DMF (3 x 0.1 min) before starting the next deprotection / coupling cycle.

[0449] Step 2: Coupling of Fmoc-His(Trt)-OH: The Fmoc group was removed from the N-terminus of Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 x 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 x 0.1 min), followed by the addition of 2.5 mL of amino acid Fmoc-His(Trt)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the coupling reaction was completed, the resin was washed with 6.25 mL of DMF (3 x 0.1 min) before starting the next deprotection / coupling cycle.

[0450] Step 3: Coupling of Fmoc-Asn(Trt)-OH: The Fmoc group was removed from the N-terminus of His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 x 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 x 0.1 min), followed by the addition of 2.5 mL of amino acid Fmoc-His(Trt)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the coupling reaction was completed, the resin was washed with 6.25 mL of DMF (3 x 0.1 min) before starting the next deprotection / coupling cycle.

[0451] Step 4: Coupling of Fmoc-Lys(Ac)-OH: The Fmoc group was removed from the N-terminus of the Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 x 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 x 0.1 min), followed by the addition of 2.5 mL of amino acid Fmoc-Lys(Ac)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the coupling reaction was completed, the resin was washed with 6.25 mL of DMF (3 x 0.1 min) before starting the next deprotection / coupling cycle.

[0452] Step 5: Coupling of Fmoc-THP-OH (Fmoc-4-amino-tetrahydropyran-4-carboxylic acid): The Fmoc group was removed from the N-terminus of Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 x 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 x 0.1 min), followed by the addition of 2.5 mL of amino acid Fmoc-THP-OH in DMF (100 mM) and 1.25 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0453] Step 6: Coupling of Fmoc-2Nal-OH (Fmoc-3-(2-naphthyl)-L-alanine): The Fmoc group was removed from the N-terminus of THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of a solution of the amino acid Fmoc-2Nal-OH in DMF (200 mM) and 2.5 mL of a mixture of the coupling reagents HBTU-DIEA in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0454] Step 7: Coupling of Fmoc-Phe_4_2ae-OH (Fmoc-4-[2-(Boc-amino)ethoxy]-L-phenylalanine): The Fmoc group was removed from the N-terminus of 2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of a solution of the amino acid Fmoc-Phe_4_2ae-OH in DMF (100 mM) and 1.25 mL of a solution of the coupling reagent HBTU-DIEA in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0455] Step 8: Coupling of Fmoc-L-Pen(Trt)-OH (Fmoc-S-Trityl-L-Penicillamine): The Fmoc group was removed from the N-terminus of Phe_4_ae-2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of a solution of the amino acid Fmoc-L-Pen(Trt)-OH in DMF (100 mM) and 1.25 mL of a solution of the coupling reagent HBTU-DIEA in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0456] Step 9: Coupling of Fmoc-Lys(Ac)-OH: The Fmoc group was removed from the N-terminus of Pen-Phe_4_ae-2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of amino acid Fmoc-Lys(Ac)-OH in DMF (200 mM) and 2.5 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0457] Step 10: Coupling of Fmoc-Trp-7Me-OH: The Fmoc group was removed from the N-terminus of Lys(Ac)-Pen-Phe_4_ae-2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of amino acid Fmoc-Trp_7Me-OH in DMF (100 mM) and 1.25 mL of coupling reagent HBTU-DIEA mixture in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0458] Step 11: Coupling of Fmoc-Thr(tBu)-OH: The Fmoc group was removed from the N-terminus of Trp_7Me-Lys(Ac)-Pen-Phe_4_ae-2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of a solution of the amino acid Fmoc-Thr(tBu)-OH in DMF (200 mM) and 2.5 mL of a mixture of the coupling reagents HBTU-DIEA in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0459] Step 12: Coupling of Fmoc-Glu(OtBu)-OH: The Fmoc group was removed from the N-terminus of Thr-Trp_7Me-Lys(Ac)-Pen-Phe_4_ae-2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of a solution of the amino acid Fmoc-Glu(OtBu)-OH in DMF (200 mM) and 2.5 mL of a mixture of the coupling reagents HBTU-DIEA in DMF (200 and 220 mM). The coupling reaction was mixed for 1 h, filtered, and repeated once (double coupling). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3×0.1 min) before starting the next deprotection / ligation cycle.

[0460] Step 13: Coupling of Fmoc-L-Pen(Trt)-OH (Fmoc-S-Trityl-L-Penicillamine): The Fmoc group was removed from the N-terminus of Glu-Thr-Trp_7Me-Lys(Ac)-Pen-Phe_4_ae-2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 × 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 × 0.1 min), followed by the addition of 2.5 mL of a solution of the amino acid Fmoc-L-Pen(Trt)-OH in DMF (100 mM) and 1.25 mL of a solution of the coupling reagent HBTU-DIEA in DMF (200 and 220 mM). The ligation reaction was mixed for 1 h, filtered, and repeated once (double ligation). After the ligation reaction was completed, the resin was washed with 6.25 mL of DMF (3 x 0.1 min) before starting the next deprotection / ligation cycle.

[0461] Step 14: Acetyl Capping: The Fmoc group was removed from the N-terminus of Pen-Glu-Thr-Trp_7Me-Lys(Ac)-Pen-Phe_4_ae-2Nal-THP-Lys(Ac)-Asn-His-Sar-Rink Amide resin by washing the resin with 3.75 mL of DMF (3 x 0.1 min) and treating twice with 2.5 mL of 20% piperidine in DMF for 5 and 10 min, respectively. After deprotection, the resin was washed with 3.75 mL of DMF (3 x 0.1 min) followed by the addition of 2.5 mL of 20% anhydride in DMF and 2.5 mL of 10% DIEA in DMF. The acetyl reaction was mixed for 1 h, filtered, and repeated once (double coupling). After acetylation was complete, the resin was washed with 6.25 mL of DMF (6×0.1 min) and 6.25 mL of DCM (6×0.1 min) and then dried under nitrogen for 20 min before cleavage with TFA.

[0462] Step 15: TFA cleavage and ether precipitation: After completion of peptide assembly, the dried resin was transferred to a 20 mL glass vial. To this, 10 mL of TFA cleavage cocktail (90 / 5 / 2.5 / 2.5 TFA / water / Tips / DODT) was added and stirred at room temperature for 2 hours. The cleavage reagent was able to cleave the peptide from the resin as well as all remaining side chain protecting groups. After that, most of the TFA was blown off under nitrogen, and then 20 mL of cold diethyl ether was added to the remaining peptide cleavage mixture to form a white precipitate. The ether mixture was centrifuged at 3000 rpm for 3 min at 4 °C, the ether layer (containing the side chain protecting groups) was decanted to waste, and two more ether washes (20 mL each) of the precipitate (cleaved peptide) were performed. The crude linear peptide (pellet) was dissolved in 40 mL of acetonitrile:water (1:1) and filtered through a 0.45 μm RC membrane to remove the resin.

[0463] Step 16: Disulfide bond formation by oxidation: The crude linear peptide was oxidized without purification. After the cleavage step, the crude linear peptide in 40 mL of 50% acetonitrile in water was diluted to 100 mL with water to make a final organic solvent content of 20% acetonitrile in water. To this, a saturated solution of iodine in methanol was added dropwise with stirring until the yellow color remained and did not disappear. The slightly colored solution was stirred for an additional 5 min, after which the excess iodine was quenched by adding small amounts of solid ascorbic acid until the solution was clear.

[0464] Step 17: RP-HPLC purification of monocyclic peptides (disulfide bonds): Purification was performed using RP-HPLC. A semi-preparative Gemini 5 μm C18 column (21.2 mm × 250 mm) (Phenomenex®) was equilibrated with 100% mobile phase A (MPA = 0.1% TFA in water) at a flow rate of 20 mL / min. 100 mL of quenched oxidized peptide was loaded directly onto the equilibrated column at 20 mL / min and washed with 20% mobile phase B (MPB = 0.1% TFA in acetonitrile) for 5 min. Separation was achieved using a linear gradient of 20-50% MPB over 30 min at 20 mL / min. The desired oxidized peptide eluted at approximately 30% MPB. Pure fractions were combined and lyophilized to give 60 mg of purified oxidized peptide in the form of TFA salt with a yield of 30%.

[0465] Step 18: Characterization: After lyophilization, a white powder was obtained with a purity of >95% by analytical HPLC. Low-resolution liquid chromatography-mass spectrometry (LC-MS) revealed a triply charged ion [M+3H] of 648.7. 3+ and 972.4 doubly charged ion [M+2H] 2+ The experimental mass is consistent with the theoretical molecular weight of 1943.27 Da.

[0466] Example 1C.ac-Pen(1:3)-E(2:3)-T-Trp_7Me-Lys_Ac-Pen(1:3)-Phe_4_2ae(2:3)-Nal-THP-Lys_Ac-NH-Sar-am The TFA (trifluoroacetate) salt of the bicyclic title compound was synthesized on a 0.01 mmol scale using the purified monocyclic peptide precursor (steps 1-17) as previously described, followed by lactam bond formation (between residues Glu and Phe_4_2ae) and purified by RP-HPLC. Upon completion, 10 mg of approximately 95% pure title compound was isolated as a white powder, representing a 50% yield for the lactam bond formation step and an overall yield of 15%.

[0467] Step 18: Lactam bond formation: 20 mg of purified oxidized intermediate peptide (approximately 0.01 mmol) was dissolved in 10 mL of N,N-dimethylformamide (DMF). To this was added (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.04 mmol, 4 equiv.) followed by N,N-diisopropylethylamine (DIEA) (0.05 mmol, 5 equiv.). The mixture was stirred at room temperature and the reaction was monitored by analytical HPLC. The reaction was complete within 30 min and the mixture was diluted to 100 mL with 20% acetonitrile in water to a final content of DMF <10% before loading onto the HPLC for purification.

[0468] Step 19: RP-HPLC purification of the bicyclic peptide (disulfide bond and lactam bond): A second purification was performed using the same procedure as described above in step 17. The desired bicyclic peptide eluted after the monocyclic peptide at about 35% MPB. Pure fractions were combined and lyophilized to give 10 mg of purified bicyclic peptide in TFA salt form with a 50% yield for the lactam bond formation step and an overall yield of 15%.

[0469] Step 20: Characterization: After lyophilization, the title compound gave a white powder with a purity of >95% by analytical HPLC. Low-resolution liquid chromatography-mass spectrometry (LC-MS) gave a triply charged ion [M+3H] of 642.5. 3+ and 963.5 doubly charged ion [M+2H] 2+ The experimental mass is consistent with the theoretical molecular weight of 1925.26 Da.

[0470] Example 1D.ac-Pen(1:3)-Dap(2:3)-T-Trp_7Me-Lys_Ac-Pen(1:3)-Phe_4_2ae(3:3)-Nal-THP-Lys_Ac-NH-Sar-am-PEG4DA(x,2:1,3:2) The TFA (trifluoroacetic acid) salt of the bicyclic title compound was synthesized on a 0.01 mmol scale using its corresponding purified monocyclic (disulfide-linked) peptide precursor, and subjected to a second cyclization using a pre-activated diacid linker conjugate to the primary amine on the side chain of residues Dap (2:3) and Phe_4_2ae, followed by purification using RP-HPLC. Upon completion, 10 mg of the title compound of approximately 95% purity was isolated as a white powder, representing a 50% yield for the second cyclization step and an overall yield of 15%.

[0471] Preparation of monocyclic precursor: Purified monocyclic precursor (disulfide bond) was prepared similarly to the intermediates described above (steps 1-17), except that in step 12, the amino acid Fmoc-L-Dap(Boc)-OH (Nα-Fmoc-Nβ-Boc-L-2,3-diaminopropionic acid) was used instead of Fmoc-Glu(OtBu)-OH.

[0472] Step 18: Diacid linker activation: Bis-PEG4-acid (PEG4DA) (294 mg, 1 mmol), N-hydroxysuccinimide (NHS) (2.2 mmol, 2.2 equiv.) and N,N'-dicyclohexylcarbodiimide (DCC) (2.2 mmol, 2.2 equiv.) were dissolved in 10 mL of N-methyl-2-pyrrolidone (NMP). The mixture was stirred at room temperature to completely dissolve the solid starting material. A precipitate appeared within 10 min and the reaction mixture was further stirred at room temperature overnight and then filtered to remove the precipitated dicyclohexylurea (DCU). The activated linker was kept at 4° C. in a sealed glass vial before being used for the second cyclization. The nominal concentration of the pre-activated linker was about 0.1 M.

[0473] Step 19: Bicycle formation via preactivated diacid linker (PEG4DA-NHS): 20 mg of purified monocyclic precursor (approximately 0.01 mmol) was dissolved in 10 mL of N,N-dimethylformamide (DMF). To this, preactivated diacid linker (PEG4DA-NHS) (0.1 M in NMP, 0.01 mmol, 1 equiv.) and N,N-diisopropylethylamine (DIEA) (0.1 mmol, 10 equiv.) were added stepwise over 10 min. The mixture was stirred at room temperature and the reaction was monitored by analytical HPLC. An excess of equivalents of PEG4DA-NHS may be required to drive the reaction to completion. The reaction was complete after 1 h and the mixture was diluted to 100 mL with 20% acetonitrile in water to a final DMF content of <10% before loading onto the HPLC for purification.

[0474] Step 20: RP-HPLC purification of the bicyclic peptide: A second purification was performed using the same procedure as described above in step 17. The desired bicyclic peptide eluted after the monocyclic peptide at about 35% MPB. Pure fractions were combined and lyophilized to give 10 mg of purified bicyclic peptide in TFA salt form with a 50% yield for the lactam bond formation step and an overall yield of 15%.

[0475] Step 21: Characterization: After lyophilization, the title compound gave a white powder with a purity of >95% by analytical HPLC. Low-resolution liquid chromatography-mass spectrometry (LC-MS) gave a triply charged ion [M+3H] of 720.1. 3+ and 1080.1 doubly charged ion [M+2H] 2+ The experimental mass is consistent with the theoretical molecular weight of 2158.52 Da.

[0476] Example 1E. Ac-[Pen] * -E ** -T-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)] ** -[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2( *Pen-Pen type disulfide bond) ( ** Side chains of Glu and Phe [4-(2-aminoethoxy)-type lactam bond] The synthesis of the title compound was prepared using FMOC solid phase peptide synthesis techniques.

[0477] The title compound was assembled on Rink Amide MBHA resin using standard FMOC-protected synthesis conditions reported in the literature. The assembled peptide was isolated from the resin and protecting groups by cleavage with strong acid followed by precipitation. Oxidation to form disulfide bonds was performed and subsequently purified by RPHPLC and counterion exchange. The final product was obtained by lyophilization of the pure fractions.

[0478] Swollen Resin: 10 g of Rink Amide MBHA solid phase resin (0.66 mmol / g loading) is transferred to a 250 mL peptide vessel equipped with a filter frit, ground glass joint, and vacuum side arm. The resin was washed 3 times with DMF.

[0479] Step 1: Coupling of FMOC-Sarc-OH: Deprotection of the resin-bound FMOC group was 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 an additional 20-30 minutes. After deprotection, the resin was washed 3 times with DMF while shaking. FMOC-Sarc-OH (3 eq., 6.2 g) was dissolved in 100 mL of DMF along with Oxyma (4.5 eq., 4.22 g). Preactivation of the acid was achieved by addition of DIC (3.9 eq., 4 mL) with shaking for 15 minutes prior to addition to the deprotected resin. An additional aliquot of DIC (2.6 eq., 2.65 mL) was then added after approximately 15 minutes of coupling. The progress of the ligation reaction was monitored by a colorimetric Kaiser test. Once the reaction was deemed complete, the resin was washed three times with DMF with shaking before starting the next deprotection / ligation cycle.

[0480] Step 2: Conjugation of FMOC-3Pal-OH: FMOC deprotection was again achieved by adding two successive resin bed volumes of 20% 4-methyl-piperidine in DMF for 3-5 min once and 20-30 min once again, with draining between treatments. The resin was then washed three times before conjugation with protected 3-Pyridyl alanine (3Pal). FMOC-3Pal-OH (3 eq, 7.8 g) was dissolved in DMF along with Oxyma (4.5 eq, 4.22 g). Preactivation with DIC (3.9 eq, 4 mL) for 15 min was performed prior to addition to the Sarc-amide resin. After 15 min, an additional aliquot of DIC (2.6 eq, 2.65 mL) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / ligation cycle.

[0481] Step 3: Coupling of FMOC-Asn(Trt)-OH: FMOC was removed from the N-terminus of resin-bound 3Pal and washed as above. FMOC-Asn(Trt)-OH (2 eq., 8 g) was dissolved in 100 mL of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 mL) was added for preactivation of the acid for approximately 15 min prior to addition to the 3Pal-Sarc-amide resin. After approximately 15 min, an additional aliquot of DIC (1.4 eq., 1.43 mL) was added to the reaction. Once the reaction was complete as determined by Kaiser test, the resin was washed three times with DMF before starting the next deprotection / coupling cycle.

[0482] Step 4: Coupling of FMOC-Lys(Ac)-OH: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as previously described. FMOC-Lys(Ac)-OH (2 eq., 5.4 g) was dissolved in 100 mL of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 mL) was added for preactivation of the acid for approximately 15 min prior to addition to the Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 min, an additional aliquot of DIC (1.4 eq., 1.43 mL) was added to the reaction. Once the reaction was complete as determined by Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0483] Step 5: Coupling of FMOC-THP-OH: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-THP-OH (3 eq., 7.36 g) was dissolved in 100 mL of DMF along with Oxyma (4.5 eq., 4.22 g). DIC (3.9 eq., 4 mL) was added for preactivation of the acid for approximately 15 min prior to addition to the Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq., 2.65 mL) was added to the reaction. Once the reaction was complete as determined by Kaiser test, the resin was washed three times with DMF before starting the next deprotection / coupling cycle.

[0484] Step 6: Coupling of FMOC-L-Ala(2-naphthyl)-OH(Nal): FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-L-Ala(2-naphthyl)-OH (3 eq., 8.66 g) was dissolved in 100 mL of DMF along with Oxyma (4.5 eq., 4.22 g). DIC (3.9 eq., 4 mL) was added for preactivation of the acid for about 15 min prior to addition to the THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After about 15 min, an additional aliquot of DIC (2.6 eq., 2.65 mL) was added. Upon completion of the reaction as determined by Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0485] Step 7: Conjugation of FMOC-4-[2-(Boc-amino-ethoxy)]-L-Phenylalanine (FMOC-AEF): FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-4-[2-(Boc-amino-ethoxy)]-L-Phenylalanine (3 eq., 10.8 g) was dissolved in 100 mL of DMF along with Oxyma (4.5 eq., 4.22 g). DIC (3.9 eq., 4 mL) was added for preactivation of the acid for about 15 min before addition to the Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 equiv, 2.65 mL) was added to the reaction. Once the reaction was complete as determined by Kaiser test, the resin was washed three times with DMF before starting the next deprotection / ligation cycle.

[0486] Step 8: Coupling of FMOC-Pen(Trt)-OH: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-Pen(Trt)-OH (3 eq., 12.14 g) was dissolved in 100 mL of DMF along with Oxyma (4.5 eq., 4.22 g). DIC (3.9 eq., 4 mL) was added for preactivation of the acid for approximately 15 min prior to addition to the AEF-Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq., 2.65 mL) was added to the reaction. Upon completion of the reaction as determined by Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0487] Step 9: Coupling of FMOC-Lys(Ac)-OH: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-Lys(Ac)-OH (2 eq., 5.4 g) was dissolved in 100 mL of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 mL) was added for preactivation of the acid for about 15 min prior to addition to the Pen(Trt)-AEF-Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After about 15 min, an additional aliquot of DIC (1.4 eq., 1.43 mL) was added to the reaction. Once the reaction was complete as determined by Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0488] Step 10: Coupling of FMOC-7-Me-Trp-OH: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-7-Me-Trp-OH (2 eq., 5.81 g) was dissolved in 100 mL of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 mL) was added for preactivation of the acid for approximately 15 min prior to addition to the Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 min, an additional aliquot of DIC (1.4 eq., 1.43 mL) was added to the reaction. Upon completion of the reaction as determined by Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0489] Step 11: Coupling of FMOC-Thr(tBu)-OH: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-Thr(tBu)-OH (4 eq., 10.5 g) was dissolved in 100 mL of DMF along with Oxyma (6 eq., 5.62 g). DIC (5.2 eq., 5.3 mL) was added for preactivation of the acid for approximately 15 min prior to addition to the 7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After approximately 15 min, an additional aliquot of DIC (2.6 eq., 2.65 mL) was added to the reaction. Upon completion of the reaction as determined by Kaiser test, the resin was washed again three times with DMF before starting the next deprotection / coupling cycle.

[0490] Step 12: Conjugation of FMOC-Glu(OtBu)-OH: FMOC was removed from the N-terminus of the resin-bound asparagine and the resin was washed with DMF as above. FMOC-Glu(OtBu)-OH (2 eq., 5.91 g) was dissolved in 100 mL of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 mL) was added for preactivation of the acid for about 15 min prior to addition to the Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After about 15 min, an additional aliquot of DIC (1.4 eq., 1.43 mL) was added to the reaction. Once the reaction was complete as determined by the Kaiser test, the resin was washed three times with DMF before starting the next deprotection / ligation cycle.

[0491] Step 13: Coupling of FMOC-Pen(Trt)-OH: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. FMOC-Pen(Trt)-OH (2 eq., 8.1 g) was dissolved in 100 mL of DMF along with Oxyma (3 eq., 2.81 g). DIC (2.6 eq., 2.65 mL) was added for preactivation of the acid for about 15 min before addition to the Glu(OtBu)-Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin. After about 15 min, an additional aliquot of DIC (2.6 eq., 2.65 mL) was added to the reaction. Upon reaction completion as determined by Kaiser test, the resin was washed again three times with DMF prior to final deprotection and acetate capping of the assembled peptide.

[0492] Step 14: Acetyl Capping: FMOC was removed from the N-terminus of the resin-bound peptide and the resin was washed as above. 150 mL of Capping Reagent A (THF / Acetic Anhydride / Pyridine, 80:10:10) was added to the assembled Pen(Trt)-Glu(OtBu)-Thr(tBu)-7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Lys(Ac)-Asn(Trt)-3Pal-Sarc-amide resin and shaken for 30 min. The resin was washed 3 times with DMF followed by 5 times with DCM. The resin was divided into 5-50 mL centrifuge tubes and placed under vacuum for 1.5 h before cleavage with TFA.

[0493] Step 15: TFA cleavage and ether precipitation: 200 mL of TFA cleavage cocktail (90 / 5 / 2.5 / 2.5 TFA / water / Tips / DODT) was prepared. 40 mL of the cleavage cocktail was added to each of the five tubes containing the protected resin-bound peptide and shaken for 2 h. The spent resin was filtered off and the filtrate was divided equally into 18-50 mL centrifuge tubes for precipitation. Cold diethyl ether was added to each to form a white precipitate, which was then centrifuged. The ether was decanted and discarded, and the precipitate was washed with ether two more times. The resulting white precipitate cake was dried overnight in a hood to give the crude reduced peptide.

[0494] Step 16: Disulfide oxidation: The crude peptide was oxidized and purified in four 1 L batches. Approximately 2.5 g of crude peptide was dissolved in 1 L of 20% ACN / water. With stirring, a saturated solution of iodine in acetic acid / methanol was added dropwise to the 1 L peptide solution until the yellow / brown color of I2 remained and did not dissipate. The light yellow solution was allowed to stand for 5 min before the excess I2 was quenched with a small amount of ascorbic acid.

[0495] Step 17: RP-HPLC purification: RP-HPLC purification was performed immediately after each I2 oxidation. A preparative purification column (Phenomenex, Luna, C18(2), 100A, 250 x 50 mm) was 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 was loaded onto the equilibrated column at 70 mL / min. After the solvent front eluted, a gradient of 25-45% MPB at 70 mL / min was run over 60 min. The desired material was isolated in fractions, each of which was analyzed by analytical RPHPLC. Pure fractions from all four purifications were combined and lyophilized to give the purified TFA salt ready for bicyclization via lactam formation.

[0496] Step 18: Lactam formation to obtain the bicyclic compound: The purified Pen-Pen disulfide monocyclic peptide (800 mg) was dissolved in 150 mL of 50 / 50 DMF / DCM (approximately 5 mg / mL). To the stirring peptide was added diisopropylethylamine (approximately 5 eq., 360 ul) followed by PyBop (approximately 4 eq., 864 mg). The reaction was monitored by RP-HPLC. Once all the monocyclic starting material had been converted to the bicyclic form, the solution was neutralized and diluted to 1 L with 10% acetonitrile in water. The diluted solution was ready for RP-HPLC purification.

[0497] Step 19: RP-HPLC purification: RP-HPLC purification was performed immediately after lactam formation and dilution. A preparative purification column (Phenomenex, Luna, C18(2), 100A, 250 x 50 mm) was equilibrated at 70 mL / min with 20% MPB in MPA (MPA = 0.1% TFA / water, MPB = 0.1% TFA in ACN). 1 L of neutralized bicyclic peptide was loaded onto the equilibrated column at 70 mL / min. After the solvent front eluted, a gradient of 25-45% MPB at 70 mL / min was run over 60 min. The desired material was isolated in fractions, each of which was analyzed by analytical RPHPLC. Pure fractions from all four purifications were combined and lyophilized to yield the purified TFA salt ready for counterion exchange.

[0498] Step 20: Counterion exchange to acetate: The same preparative RP-HPLC column was 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. Purified peptide TFA salt was dissolved in 50 / 50 ACN / water and diluted to 15% ACN. The solution was loaded onto the equilibrated column at 70 mL / min and the solvent front was eluted. The captured peptide was washed with 5% MPB in MPA for 5 min. The captured peptide was then washed with 5% MPB in MPC for 40 min at 70 mL / min to exchange the counterion to acetate. The captured peptide was washed with 5% MPB in MPA for 10 min at 70 mL / min to remove all NHOAc from the system. Finally, peptides were eluted with a gradient of 5-70% MPB in MPA over 60 min and collected in fractions.

[0499] Step 21: Final lyophilization and analysis: The collected fractions were analyzed by analytical RP-HPLC and all fractions with purity >95% were combined. Lyophilization of the combined fractions afforded the title compound as a white powder with a purity >95% as determined by RPHPLC. The peptide identity was confirmed using LC / MS of the purified title compound, giving two charge state peptides, an M+2 / 2 of 969 amu and a molecular ion of 1936 amu.

[0500] Example 1F. Ac-O2R-Pen-QTWQ-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-O2R-N-[bA]-NH2

[0501] [ka] The synthesis of compound 1 was carried out using Fmoc-protected amino acids on solid-phase Rink Amide MBHA (NovaBiochem, 0.33 meq / g, 100-200 mesh) using a CEM Liberty Blue automated microwave peptide synthesizer. The peptide was synthesized on a 0.22 mmol scale. The first residue (bAla) was manually incorporated using 3 equivalents of amino acid, 3 equivalents of HOAt and 3 equivalents of DIC in NMP overnight at room temperature. Typical reaction conditions were as follows: deprotection conditions: 20% piperidine (v / v) in DMF (90 °C for 2 min); residue coupling conditions: protected amino acid (2.5 mL of 0.4 M amino acid stock solution in DMF) followed by DIC activator (2 mL of 0.5 M solution in DMF) and Oxyma Pure (1 mL of 1 M solution in DMF) were delivered to the resin and reacted at 90 °C for 2 min. For 2Nal, a double coupling was performed. Capping of free amino groups was carried out using 10 equivalents of acetic anhydride in DMF.

[0502] At the end of the assembly, the peptide resin was washed with DMF, MeOH, DCM, Et2O. The peptide was cleaved from the solid support using 87.5% TFA, 5% phenol, 2.5% triisopropylsilane and 5% water for 1.5 h at room temperature. The resin was filtered and then added to cold methyl-t-butyl ether to precipitate the peptide. After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in H2O and acetonitrile 1:1 + 0.1% TFA and stirred overnight. It was then lyophilized to give the desired protected intermediate compound 1 (yield: 80.4%). LCMS analysis calculated mass for C88H121N19O20S2: 1829.17; found: 916.4 (M+2) 2+ .

[0503] The precipitated solid crude intermediate 13-1 was dissolved in water:acetonitrile (1 mg / mL). Saturated iodine in acetic acid was then added dropwise with stirring until a yellow color persisted. The solution was stirred for 30 min and the reaction was monitored by analytical UPLC-MS. Once the reaction was complete, solid ascorbic acid was added until the solution was clear. DIPEA was added until the solution was basic. 1.5 equivalents of Boc anhydride were added. The solution was stirred for 60 min and the reaction was monitored by analytical UPLC-MS. The reaction mixture was quenched with CH3COOH. The solvent mixture was then lyophilized and the resulting material was then dissolved in 2.5 mL of DMSO and purified by C4 reverse phase HPLC (Waters Deltapak C4 (40×200 mm, 15 μm, 300 Å) using (A) 0.1% TFA in water and (B) 0.1% TFA as eluents, gradient starting at 30% B and changing to 45% B over 20 min at a flow rate of 80 mL / min). Fractions containing pure product were collected and then lyophilized to give intermediate compound 2 (yield: 40%). LCMS analysis calculated mass for C93H129N19O22S2: 1929.29; found: 965.5 (M+2). 2+ .

[0504] Intermediate 2 was dissolved in dry DCE (1 mg / mL) containing 5% AcOH. Grubbs 2 catalyst (0.25 equiv.) (CAS: 246047-72-3) was added and stirred at 60 °C under N2 atmosphere and monitored by UPLC-MS. The reaction was nearly complete after 30 min, after which another 0.2 equiv. of catalyst was added. After 2 h, the reaction mixture was cooled to room temperature and SilaMet DMT scavenger resin was added (loading: 0.57 mmol / g, 8 equiv. relative to catalyst). Stirred overnight. The reaction mixture was then concentrated to dryness under reduced pressure to give a mixture of isomer 3 and isomer 4. The mixture was treated with 10 mL of solution (v / v) (95% TFA, 5% H2O) to remove the Boc protecting group for 10 min and then concentrated to dryness. The crude reaction was redissolved in 2 mL of DMSO and purified by reverse phase HPLC (Phenomenex Luna C18, 30×250 mm, 5 μm, 100 Å). Mobile phase A: +0.1% TFA, Mobile phase B: Acetonitrile (ACN) +0.1% TFA, gradient started at 20% B and changed to 30% B over 25 min at a flow rate of 45 mL / min. The collected fractions containing the first eluting isomer were then lyophilized to give the first isomer of the title compound. LCMS analysis calculated mass for C86H117N19O20S2: 1801.12; found: 1801.6 (M+1). + The collected fractions containing the second eluting isomer were then lyophilized to give the second isomer 4. LCMS analysis calculated mass for C86H117N19O20S2: 1801.12; found: 901.1 (M+2) 2+ .

[0505] Example 1G. 7Ahp(2)-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-2Nal-THP-E(2)-N-3Pya-Sar-CONH2

[0506] [ka] Linear peptides were synthesized using a CEM Liberty Blue automated microwave peptide synthesizer using standard Fmoc peptide synthesis with Rink Amide MBHA resin (NovaBiochem, 0.34 mmol / g, 100-200 mesh). Fmoc-protected amino acids (5 mL, 0.2 M, 1 mmol) were coupled at 90 °C for 3.5 min using DIC (2 mL, 0.5 M, 1 mmol) and Oxyma Pure (1 mL, 1 M, 1 mmol). Double couplings were used for Sar, THP, and Thr, and for residues incorporated after Sar, THP, and Thr. Fmoc deprotection was performed with 20% piperidine (v / v) in DMF at 90 °C for 1 min. The peptide was deprotected and cleaved from the solid support by treatment with 92.5% TFA, 2.5% triisopropylsilane, 2.5% 2,2'-(ethylenedioxy)diethanethiol (DODT), and 2.5% water on a CEM Razor cleavage system at 42°C for 30 min. The solid was filtered and washed with TFA. The filtrate was concentrated and precipitated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged and the pellet was washed with fresh cold MTBE. This was repeated twice. The peptide pellet was dried, redissolved in water / acetonitrile + 0.1% TFA, and lyophilized overnight to give the desired intermediate 1 (yield: 97%). 95 H 133 N 21 O 22 LCMS analysis of S2: Calculated: 1983.94; Found: 1984.9 (M+H) + , 993.0(M+2H) 2+ .

[0507] Crude intermediate 1 was dissolved in 30% acetonitrile / H2O (2 mg / mL). Iodine (0.1 M) in methanol was added dropwise with stirring until a yellow color persisted. After stirring for approximately 2 hours, the reaction was complete as determined by HPLC. The reaction was quenched by adding 1 M ascorbic acid in water until the solution was clear. The solution was concentrated and lyophilized. The resulting pellet was dissolved in DMSO and purified by reverse phase on a Biotage Selekt (Biotage Sfar Bio C18 D-Duo 300 Å, 20 um, 25 g column) using eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile and a gradient of 20% B to 55% B over 10 CV. Fractions containing pure product were collected and lyophilized to give intermediate 2. (Yield: 30.3%). C 95 H 131 N 21 O 22 LCMS analysis of S2 calculated: 1983.35; found: 992.0 (M+2H) 2+ and 1983.8 (M+H) + .

[0508] The purified intermediate 2 was dissolved in DMF (0.005M). To this solution was added PyBOP (2 eq.) and DIEA (4 eq.) and the reaction was stirred at room temperature. Upon completion of the reaction as determined by LCMS, the reaction was concentrated and purified by reverse phase HPLC (Waters XSelect CSH Prep C18, 5um OBD column, 19×150mm, 25mL / min) using eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile with a gradient of 26% B to 33% B over 10 minutes. Fractions containing pure product were collected and lyophilized to give the title compound 3. (Yield: 13%). 95 H 129 N 21 O 21 LCMS analysis of S2: Calculated: 1965.3; Found: 1964.8 (M+H) + , 1986.8 (M+Na) + , and 983.0 (M+2H) 2+ .

[0509] Example 1H.6Ahx(2)-Abu(1)-NTWQC(1)-AEF-2Nal-THP-E(2)-N-3Pya-Sar-CONH2

[0510] [ka]

[0511] [ka] The synthesis of linear peptide 1 was carried out using a CEM Liberty Blue automated microwave peptide synthesizer using standard Fmoc peptide synthesis with Rink Amide MBHA resin (NovaBiochem, 0.34 mmol / g, 100-200 mesh). Fmoc-protected amino acids (5 mL, 0.2 M, 1 mmol) were coupled at 90 °C for 3.5 min using DIC (2 mL, 0.5 M, 1 mmol) and Oxyma Pure (1 mL, 1 M, 1 mmol). Double coupling was used for Sar, THP, and Thr, as well as for residues incorporated after Sar, THP, and Thr. Fmoc deprotection was performed with 20% piperidine (v / v) in DMF at 90 °C for 1 min.

[0512] The resin-bound peptide intermediate 1 was treated with a solution of dichlorotriphenylphosphorane (10 equiv.), α-pinene (15 equiv.), and thioanisole (15 equiv.) in dry DCM for 15 min. The resin was drained and washed with DCM. A fresh solution of dichlorotriphenylphosphorane (10 equiv.), α-pinene (15 equiv.), and thioanisole (15 equiv.) in dry DCM was added and the mixture was incubated for 3 h using a rotary shaker. The resin was washed with DMF and DCM. The peptide was deprotected and cleaved from the solid support by treatment with 92.5% TFA, 2.5% triisopropylsilane, 2.5% 2,2'-(ethylenedioxy)diethanethiol (DODT), and 2.5% water for 2 h at room temperature. The solid was filtered and washed with TFA. The filtrate was concentrated and precipitated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged and the pellet was washed with fresh cold MTBE. This was repeated twice. The peptide pellet was dried, redissolved in water / acetonitrile + 0.1% TFA, and lyophilized overnight to give intermediate 2 (yield: 76%). 87 H 116 ClN 21 O 22 LCMS analysis of S calculated: 1873.80; found: 938.5 (M+2H) 2+ .

[0513] The crude peptide was dissolved in DMF (2 mg / mL). NaI (1.5 eq.) and EDTA (1.5 eq.) were added to the peptide solution as a 10 mg / mL solution, followed by 0.1 M Na2CO3 (10 eq.). The reaction was stirred at room temperature overnight, quenched with TFA, concentrated and purified by reverse phase on an ISCO (Biotage Sfar Bio C18 D-Duo 300 Å, 20 um, 25 g column) using eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile and a gradient of 20% B to 55% B over 10 CV. Fractions containing the pure product were collected and lyophilized to give intermediate 3. (Yield: 21%). C 87 H 115 N 21 O 22LCMS analysis of S calculated: 1837.82; found: 1838.8 (M+H) + , 1860.7(M+Na) + , 920.0(M+2H) 2+ .

[0514] The purified peptide was dissolved in DMF (0.005M). To this solution was added PyBOP (2 eq.) and DIEA (4 eq.) and the reaction was stirred at room temperature. Upon completion of the reaction as determined by LCMS, the reaction was concentrated and purified by reverse phase HPLC (Waters XSelect CSH Prep C18, 5um OBD column, 19x150mm, 25mL / min) using eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile with a gradient of 20%B to 28%B over 10 minutes. Fractions containing pure product were collected and lyophilized to give the title compound. (Yield: 5%). 87 H 113 N 21 O 21 LCMS analysis of S calculated: 1819.81; found: 1820.8 (M+H) + , 1842.7(M+Na) + , 911(M+2H) 2+ .

[0515] Example 1I.MeCO-Glu-Pen-NT-7MeW-K(Ac)-Pen-AEF-2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2

[0516] [ka]

[0517] [ka] Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) using Fmoc / t-Bu chemistry. Assembly was performed on Rink-amide AM resin (220 μmol, 100-200 mesh; loading 0.35 mmol / g) using a Cem Liberty Blue microwave peptide synthesizer (CEM Inc.). During peptide assembly on the solid phase, side chain protecting groups were tert-butyl for Thr and Glu; trityl for Pen and Asn; and tert-butoxy-carbonyl for AEF. All amino acids were dissolved in DMF at 0.4 M concentration. Acylation reactions were performed at 90 °C for 3 min under MW irradiation with a 5-fold excess of activated amino acids over resin-free amino groups. Amino acids were activated with equimolar amounts of 0.5 M DIC solution in DMF and 1 M Oxyma solution in DMF. Dual acylation reactions were performed for 3Pya15 and 2Nal10. Fmoc deprotection was carried out using 20% ​​(V / V) piperidine in DMF. Capping of free amino groups was carried out manually using 10 equivalents of acetic anhydride in DMF.

[0518] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et2O. The peptide was cleaved from the solid support using 30 mL of TFA solution (v / v) (87.5% TFA, 5% H2O, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 h. The resin was then filtered and precipitated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in H2O and acetonitrile 1:1 + 0.1% TFA, stirred overnight, then lyophilized to give the desired linear intermediate 166-1 (83.4% yield). LCMS analysis calculated for C98H136N22O24S2: 2070.42 Da; found: 1036.6 (M+2) 2+ .

[0519] The crude peptide was dissolved in CAN / H2O (5 mg / mL). Saturated iodine in acetic acid was then added dropwise under stirring until a yellow color persisted. The Rxn was completed in 20 min (monitored by UPLC-MS). Solid ascorbic acid was added until the solution was clear. After lyophilization, the crude intermediate 166-2 was used directly in the next step. LCMS analysis calculated for C98H134N22O24S2: 2068.40 Da; found; 1035.4 (M+2) 2+ .

[0520] Intermediate 166-2 was dissolved in DMF (0.5 mg / mL). HATU (2 eq.) and Dipea (4 eq.) were added. The reaction was left stirring at room temperature for 60 min (monitored by UPLC-MS). The solvent was evaporated in vacuum. Purification was carried out by reversed-phase HPLC using a preparative Waters DeltaPak C18 (200×40 mm, 100 Å, 15 μm). Mobile phase A: +0.1% TFA, mobile phase B: acetonitrile (ACN) +0.1% TFA. The following gradient of eluent B was used: 20% B over 5 min to 20% B over 25 min to 35% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give the title compound 1 (yield 10%). LCMS analysis calculated for C98H132N22O23S2: 2050.39 Da; found: 1025.84 (M+2) 2+ .

[0521] Example 1 J. MeCO-k(2)-Pen(3)-QTWQ-Pen(3)-AEF-2Nal-THP-E(2)-N-bAla-CONH2

[0522] [ka]

[0523] [ka] Step A - Synthesis of intermediate compound 1. The synthesis was carried out using Fmoc-protected amino acids on solid phase Rink Amide MBHA (NovaBiochem, 0.33 meq / g, 100-200 mesh) using a CEM Liberty Blue automated microwave peptide synthesizer. The peptide was synthesized on a 0.22 mmol scale. The first residue (bAla) was manually incorporated using 3 equivalents of amino acid, 3 equivalents of HOAt and 3 equivalents of DIC in NMP overnight at room temperature. Typical reaction conditions were as follows: deprotection conditions: 20% piperidine (v / v) in DMF (90 °C for 2 min); residue coupling conditions: protected amino acid (2.5 mL of 0.4 M amino acid stock solution in DMF) followed by DIC activator (2 mL of 0.5 M solution in DMF) and Oxyma Pure (1 mL of 1 M solution in DMF) were delivered to the resin and reacted at 90 °C for 2 min. For 2Nal, a double coupling was performed. Capping of free amino groups was carried out using 10 equivalents of acetic anhydride in DMF.

[0524] At the end of the assembly, the peptide resin was washed with DMF, MeOH, DCM, Et2O. The peptide was cleaved from the solid support using 87.58% TFA, 5% phenol, 2.5% triisopropylsilane and 5% water for 1.5 h at room temperature. The resin was filtered and then added to cold methyl-t-butyl ether to precipitate the peptide. After centrifugation, the peptide pellet was washed with fresh cold diethyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried and resuspended in H2O and acetonitrile 1:1 + 0.1% TFA and stirred overnight. It was then lyophilized to give the desired protected intermediate compound 1 (yield: 86%). LCMS analysis calculated mass for C95H132N20O24S2: 2002.34; found: 1001.9 (M+2)2+

[0525] Step B - Synthesis of intermediate compound 2 The precipitated solid crude peptide from step A was dissolved in water / acetonitrile 1:1 (1 mg / mL). Saturated iodine in acetic acid was then added dropwise with stirring until a yellow color persisted. The solution was stirred for 15 min and the reaction was monitored by analytical UPLC-MS. Once the reaction was complete, solid ascorbic acid was added until the solution was clear. The solvent mixture was then lyophilized and the resulting material was then dissolved in DMSO and purified by reverse phase HPLC (Deltapak C4, 40 x 200 mm, 15 μm, 300 Å). Mobile phase A: + 0.1% TFA, mobile phase B: acetonitrile (ACN) + 0.1% TFA, gradient started at 20% B and changed to 35% B over 25 min at a flow rate of 80 mL / min. The collected fractions containing the pure product were then lyophilized to give compound 2 (yield: 48%). LCMS analysis calculated for C95H130N20O24S2: 2000.32; found: 1001.1 (M+2)2+

[0526] Step C - Synthesis of intermediate compound 3 Compound 2 was dissolved in DMF (0.5 mg / mL). HATU (1.1 eq.) and DIPEA (3 eq.) in DMF (5 mL) were added dropwise. The resulting solution was stirred at room temperature for 5 min (monitored by UPLC-MS). After completion of cyclization, hydrazine monohydrate (20 eq.) was added to remove the Dde protecting group. Deprotection was complete after 30 min (monitored by UPLC-MS). The reaction mixture was quenched with TFA and concentrated to dryness. The crude reaction was redissolved in 4 mL of DMSO and purified twice by reverse phase HPLC (Deltapak C18, 40 x 200 mm, 15 μm, 100 Å). Mobile phase A: +0.1% TFA, mobile phase B: acetonitrile (ACN) +0.1% TFA, gradient started at 20% B and changed to 35% B over 25 min at a flow rate of 80 mL / min. The collected fractions containing pure product were then lyophilized to give compound 3 (yield: 49%). LCMS analysis calculated for C85H116N20O21S2: 1818.10; found: 909.9 (M+2)2+

[0527] Example 1K.PEG2(2)-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-2Nal-THP-hE(2)-N-3Pya-Sar-CONH2

[0528] [ka]

[0529] [ka] Step A - Synthesis of intermediate compound 1. Synthesis was performed using standard Fmoc solid phase peptide synthesis on Rink Amide MBHA LL resin (NovaBiochem, 0.34 mmol / g, 100-200 mesh). Resin-bound peptides were synthesized on a 1 mmol scale using a CEM Liberty Blue automated microwave peptide synthesizer. Typical reaction conditions were as follows: deprotection conditions: 20% piperidine (v / v) in DMF (10 mL, 90 °C for 1.5 min); residue coupling conditions: protected amino acid (5 mL of 0.4 M amino acid stock solution in DMF) followed by DIC activator (2 mL of 0.5 M solution in DMF) and Oxyma Pure (1 mL of 1 M solution in DMF) were delivered to the resin and reacted at 90 °C for 3.5 min. Double coupling was performed for Sar, 3Pya, THP, and 2Nal. Manual coupling of AEF(Dde) was performed. Fmoc-AEF(Dde)-OH (1.5 eq.) was activated with HOAt (1.5 eq.) and DIC (1.5 eq.) in DMF for 20 min, then added to the resin and mixed at room temperature for 16 h.

[0530] Step B - Synthesis of intermediate compound 2 After the assembly was completed, the peptide resin was washed with DMF, MeOH, DCM. The peptide was deprotected and cleaved from the solid support by treating the resin with 92.5% TFA, 2.5% water, 2.5% triisopropylsilane (TIPS), and 2.5% 3,6-dioxa-1,8-octanedithiol (DODT) at 42°C for 30 minutes on a CEM Razor cleavage station. The solid was filtered and washed with TFA. The mixture was concentrated and added to cold methyl-t-butyl ether to precipitate the peptide. After centrifugation, the peptide pellet was washed with fresh cold methyl-t-butyl ether. This was repeated once more. The final pellet was dried, resuspended in water and acetonitrile (1:1) + 0.1% TFA, and lyophilized to give the desired intermediate 2 (yield: 89.7%). 105 H 145 N 21 O 26 LCMS analysis of S2 calculated: 2181.56; found: 1091.3 (M+2H) 2+ and 727.8 (M+3H) 3+ .

[0531] Step C - Synthesis of intermediate compound 3 Intermediate 2 was dissolved (1 mg / mL) in water:acetonitrile (1:1). Iodine (0.1 M) in methanol was added dropwise with stirring until the yellow color persisted. The reaction was monitored by HPLC-MS. Once the reaction was complete, ascorbic acid (1 M) in water was added until the solution was clear. The reaction was concentrated and lyophilized. The crude material was dissolved in DMSO and purified by reverse phase on an ISCO (Biotage Sfar Bio C18 D-Duo 300 Å, 20 uM, 50 g column, 40 mL / min) using eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile and a gradient from 20% B to 55% B over 10 CV. Fractions containing pure product were collected and lyophilized to give intermediate 3. (Yield: 32%). C 105 H 143 N 21 O 26 LCMS analysis of S2 calculated: 2119.55; found: 1090.4 (M+2H) 2+and 727.1 (M+3H) 3+ .

[0532] Step D - Synthesis of Compound 4 Intermediate 3 (292.1 mg, 0.121 mmol) was dissolved in DMF (25 mL, 0.005 M). To this solution, HATU (69.2 mg, 0.182 mmol) and N,N-diisopropylethylamine (84.5 uL, 0.485 mmol) were added and stirred at room temperature. The reaction was monitored by HPLC-MS. Upon completion of the reaction, hydrazine (38.9 uL, 1.21 mmol) was added and stirred at room temperature for 1 h. The mixture was concentrated, dissolved in DMSO and purified by reverse phase HPLC (Waters XSelect CSH Prep C18, 5 um OBD column, 19 x 150 mm, 25 mL / min) using eluents (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile with a gradient of 22% B to 27% B over 10 min. The fractions containing the pure product were collected and lyophilized to give compound 3. (Yield: 14%). 95 H 129 N 21 O 23 LCMS analysis of S2: calculated: 1997.33; found: 1996.6 (M+H) + and 998.9 (M+2H) 2+ .

[0533] Example 1L.MeCO-Pen(3)-K(NMe)(5)-T-7MeW-K(Ac)-Pen(3)-AEF(5)-2Nal-THP-EN-3Pya-Sar-CONH2

[0534] [ka] Step A - Synthesis of intermediate compound 1 - The synthesis was carried out using Fmoc-protected amino acids on solid-phase Rink amide MBHA resin (Novabiochem, 0.42 mmol / g, 100-200 mesh) using a Biotage Syro II parallel peptide synthesizer. The peptide was synthesized on a 0.05 mmol scale. Typical reaction conditions were as follows: Deprotection conditions: Fmoc deprotection was performed in two steps with 40% piperidine in DMF (1 mL) for 3 min at room temperature, followed by 20% piperidine in DMF (1 mL) for 9 min. Residue coupling conditions: Fmoc-protected amino acid (0.5 mL of 0.5 M amino acid stock solution in DMF, 0.25 mmol), followed by HATU (0.52 mL of 0.48 M stock solution in DMF, 0.25 mmol), and 4-methylmorpholine (0.25 mL, 2 M, 0.5 mmol) were delivered to the resin and reacted at room temperature for 1 h. The residue [Y(OEtOTBDMS)] was coupled using manual coupling conditions: a mixture of Fmoc-protected amino acid (0.125 mmol), HATU (0.125 mmol) and 4-methylmorpholine (0.35 mmol) in DMF (8 mL) was added to the resin (0.05 mmol) and then mixed at room temperature for 2 h. The peptide was capped with Ac2O / NMM / DMF (1:1:3) (1 mL).

[0535] Step B - Synthesis of intermediate compound 2 - Intermediate 1 (0.15 mmol) was swollen in THF (8 mL) for 15 min, then TBAF (1.5 mL, 1 M in THF, 1.5 mmol) was added. The reaction was mixed at room temperature for 1 h. The resin was then drained and washed with DMF (8 mL, 3 times) and DCM (8 mL, 3 times). To the resulting resin in DCM (10 mL) was added TEA (0.834 mL, 0.728 g / mL, 6 mmol) in DCM (5 mL), then a solution of methanesulfonyl chloride (0.233 mL, 1.48 g / mL, 3 mmol) in DCM (5 mL) was added slowly. The reaction was mixed at room temperature for 1 h, then drained and washed with DMF (3x) and DCM (3x). Fine cleavage of the resin with TFA indicates the desired product. C 97 H 133 N 19 O 24LCMS analysis of S2: Calculated: 2013.368; Found: 1007.0 (M+2) 2+ .

[0536] Step C - Synthesis of intermediate compound 3 - To intermediate 2 (0.15 mmol) in DCM (5 mL) was added phenylsilane (0.286 mL, 0.877 g / mL, 2.25 mmol) in DCM (2 mL) and 1,3-dimethylbarbituric acid (354.9 mg, 2.25 mmol) in DCM (2 mL) under N2 for 1-2 min. Tetrakis(triphenylphosphine)palladium(0) (87.5 mg, 0.075 mmol) in DCM (2 mL) was added and the reaction was mixed at room temperature for 40 min. The resin was drained and washed with DCM (8x). Fine cleavage of the resin with TFA indicates the desired product. C 93 H 129 N 19 O 22 LCMS analysis of S2: Calculated: 1929.293; Found: 965.0 (M+2) 2+ .

[0537] Step D - Synthesis of intermediate compound 4 - Intermediate 3 (0.15 mmol) was swollen in DMF (10 mL) for 15 min and then added to a saturated solution of Cs2CO3 in DMF (400 mL). Lithium bromide (1302.6 mg, 15 mmol) was then added and the reaction mixture was heated at 60°C for 1 h. The resin was then cooled to room temperature, drained and washed with water (3x), DMF (3x) and DCM (3x). Fine cleavage of the resin with TFA indicates the desired product. C 93 H 127 N 19 O 21 LCMS analysis of S2: Calculated value: 1911.278, Found value: 956.3 (M+2) 2+ .

[0538] Step E - Synthesis of Compound 5 - Intermediate compound 4 (0.15 mmol) was treated with a cocktail solution of TFA / H2O / TIPS 92.5 / 5 / 2.5 on a CEM Razor cleavage station for 30 min at 42°C. The mixture was then concentrated and then added to cold methyl-t-butyl ether to precipitate the peptide. After centrifugation, the peptide pellet was washed with fresh cold methyl-t-butyl ether to remove organic scavengers. This process was repeated twice. The final pellet was dried, resuspended in H2O and acetonitrile, and then lyophilized to give the desired protected intermediate compound 5 as a pale yellow solid. C 93 H 127 N 19 O 21 LCMS analysis of S2: Calculated value: 1911.278, Found value: 956.3 (M+2) 2+ .

[0539] Step F - Synthesis of Compound 1 - The intermediate crude peptide 5 from step E was dissolved in 40% ACN / water (50 mL). Iodine in methanol (0.1 M) was then added dropwise with stirring until a yellow color persisted. The reaction was monitored by UPLC-MS. Once the reaction was complete, solid ascorbic acid was added until the solution was clear. The solvent mixture was then lyophilized and the resulting material was then dissolved in DMSO and purified by preparative HPLC. Fractions containing pure product were collected and then lyophilized to give the desired product as a white powder. LCMS analysis calculated C 93 H 125 N 19 O 21 For S2, 1909.26; Actual value: 955.0 (M+2) 2+ .

[0540] Example 1 M.AEEP(5)-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-2Nal-THP-hSer(5)-N-3Pya-Sar-CONH2

[0541] [ka]

[0542] [ka] Step A - Synthesis of Intermediate 1 - The synthesis was carried out using Fmoc-protected amino acids on solid-phase Rink amide MBHA resin (Novabiochem, 0.42 mmol / g, 100-200 mesh) using a CEM Liberty Blue automated microwave peptide synthesizer. The peptide was synthesized on a 0.25 mmol scale. Typical reaction conditions were as follows: Deprotection conditions: Fmoc deprotection was carried out using 20% ​​piperidine in DMF (10 mL) under microwave conditions (90 °C, 1 min). Residue coupling conditions: Fmoc-protected amino acid (5 mL of 0.2 M amino acid stock solution in DMF, 1 mmol) was added to the resin followed by N,N'-DIISOPROPYLCARBODIIMIDE (2.041 mL, 0.5 M, 1 mmol) and ethyl (hydroxyimino) cyanoacetate (1 mL, 1 M, 1 mmol) at 90 °C for 3.5 min. Double linkages were used for 3Pya, THP and Thr, as well as residues incorporated after THP and Thr (2Nal and N). Fmoc deprotection was carried out using 20% ​​piperidine in DMF (10 mL) at 90° C. for 1 min under microwave conditions. Fine cleavage of the resin with TFA indicates the desired product. 94 H 133 N 21 O 23 LCMS analysis of S2: Calculated: 1989.349; Found: 995.5 (M+2) 2+ .

[0543] Step B - Synthesis of Intermediate 2 - To the resin Intermediate 1 (0.25 mmol) was added a solution of 2-nitrobenzenesulfonyl chloride (221.6 mg, 1 mmol) and 2,4,6-trimethylpyridine (330.4 μL, 0.917 g / mL, 2.5 mmol) in NMP (20 mL). The resin was mixed at room temperature for 50 min. The resin was drained and washed with DMF (3×) and DCM (3×). Fine cleavage of the resin indicates the formation of the desired product. C 100 H 136 N 22 O27 LCMS analysis of S3: Calculated: 2174.509; Found: 1087.8 (M+2) 2+ .

[0544] Step C - Synthesis of intermediate 3 - Resin intermediate 2 (0.5 mmol) was swollen in DMF (50 mL) for 10 min. To this mixture, iodine (636 mg, 2.5 mmol) in DMF (10 mL) was slowly added and another 2 mL of DMF was used to rinse the vial and added to the reaction vessel. The resin was mixed at room temperature for 0.5 h. The resin was drained. The resin was then washed with DMF, saturated sodium ascorbate solution in DMF, DMF and DCM. The resin was dried and used in the next step. Fine cleavage of the resin indicates the formation of the desired product. C 100 H 134 N 22 O 27 LCMS analysis of S3 calculated: 2172.493; found: 1086.8 (M+2) 2+ .

[0545] Step D - Synthesis of intermediate 4 - Resin intermediate 3 (0.5 mmol) was swollen in THF (40 mL) for 15 min, then TBAF (1 M in THF) (2.5 mL, 1 M, 2.5 mmol) was added. The reaction was mixed at room temperature for 1 h. The resin was drained and washed with DMF (3x) and DCM (3x).

[0546] Step E - Synthesis of intermediate 5 - Resin intermediate 4 (0.32 mmol) was swollen in DMF (30 mL) for 15 min and then heated to 50°C. A premixed solution of iodine (812 mg, 3.2 mmol), TPP (1678 mg, 6.4 mmol) and imidazole (217.85 mg, 3.2 mmol) in DMF (13 mL) was added. The reaction was mixed at 50°C for 30 min, then drained and washed with DMF (3x) and DCM (3x). Fine cleavage of the resin indicates the formation of the desired product. C 100 H 133 IN 22 O 26 LCMS analysis of S3 calculated: 2282.39; found: 1141.4 (M+2) 2+ .

[0547] Step F - Synthesis of intermediate 6 - Resin intermediate 5 (0.32 mmol) was swollen in DMF (10 mL) for 15 min, then added to a saturated solution of CsCO3 in DMF (80 mL) and the reaction mixture was heated at 60 °C for 1 h. The resin was cooled to room temperature, drained and washed with water (3x), DMF (3x) and DCM (3x). Fine cleavage of the resin indicates the formation of the desired product. 100 H 132 N 22 O 26 LCMS analysis of S3 calculated: 2154.478; found: 1077.8 (M+2) 2+ .

[0548] Step G - Synthesis of intermediate 7 and intermediate 8 - Intermediate 6 (0.3 mmol) was swollen in DMF (12 mL) for 15 min, then 1,8-diazabicyclo[5.4.0]undec-7-ene solution (224.1 μL, 1.019 g / mL, 1.5 mmol) in DMF (3 mL) was added, followed by 2-mercaptoethanol (210.4 μL, 1.114 g / mL, 3 mmol) in DMF (3 mL). The reaction mixture was mixed for 20 min and the resin was washed with DCM and DMF. Fresh solutions of B and C were added to the resin and mixed for another 20 min. The resin was washed with DMF, MeOH, and DCM and used in the next step. Fine cleavage of the resin indicates the formation of a mixture of the desired product intermediate 7 and the by-product intermediate 8. C 94 H 129 N 21 O 22 S2 and C 94 H 131 N 21 O 22 LCMS analysis of S2: calculated values: 1969.318 and 1971.334, found values: 985.0 and 986.0 (M+2) 2+ .

[0549] Step H - Synthesis of Example 02 - A mixture of intermediate compounds 7 and 8 was treated on a CEM Razor cutting station with a cocktail solution of TFA / H2O / TIPS 92.5 / 5 / 2.5 for 30 minutes at 42°C. The mixture was then concentrated and then added to cold methyl-t-butyl ether to precipitate the peptide. After centrifugation, the peptide pellet was washed with fresh cold methyl-t-butyl ether to remove organic scavengers. This process was repeated twice. The crude was then dissolved in 50% ACN / water (0.005M). To this stirred solution, iodine (0.1M) in MeOH was added dropwise until the yellow color remained and did not disappear. The reaction was stirred for 10 minutes and then quenched with 1M ascorbic acid in water. The reaction was lyophilized and subjected to purification by preparative HPLC. The fractions containing the product were combined and dried to give a white solid as the title compound. C 94 H 129 N 21 O 22 LCMS analysis of S2: Calculated: 1969.318; Found: 985.0 (M+2) 2+ .

[0550] Example 2. Peptide inhibition of binding of interleukin-23 to the interleukin-23 receptor Peptide optimization was performed to identify peptide inhibitors of IL-23 signaling that are active at low concentrations (e.g., IC50<10 nM). As described below, peptides were tested to identify peptides that inhibit IL-23 binding to human IL-23R and inhibit IL-23 / IL-23R functional activity.

[0551] Assays were performed to determine peptide activity as described below, and the results of these assays are provided in Tables 3A-H. Human ELISA refers to the IL23-IL23R competitive assay described below, rat ELISA refers to the rat IL-23R competitive binding ELISA assay described below, and pStat3HTRF refers to the DB cell IL-23R pSTAT3 cell assay described below. The peptides shown in Tables 3A-H were cyclized via a disulfide bridge formed between the two Pen residues in these peptides. The peptides shown in Tables 3A-H were cyclized via a thioether bond between the amino acid residues indicated. For certain peptides, the residue Abu is present at the indicated location, however, in other embodiments, e.g., those relating to the non-cyclized form, Abu may be referred to as a hSer(Cl) or homoSer residue.

[0552] IL23-IL23R competitive binding ELISA Immulon® 4HBX plates were coated with 50ng / well IL23R_huFC and incubated overnight at 4°C. Wells were washed 4 times with PBST, blocked with PBS containing 3% non-fat milk for 1 hour at room temperature, and washed again 4 times with PBST. Test peptides at a final concentration of 2nM and serial dilutions of IL-23 diluted in assay buffer (PBS containing 1% non-fat milk) were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected by incubation with 50ng / well goat anti-p40 polyclonal antibody (R&D Systems #AF309) diluted in assay buffer for 1 hour at room temperature. Wells were washed again 4 times with PBST. Secondary antibody HRP-conjugated donkey anti-goat IgG (Jackson ImmunoResearch Laboratories #705-035-147) diluted 1:5000 in assay buffer was then added and incubated for 30 minutes at room temperature. Finally, the plates were washed as above, and the signal was visualized with TMB One Component HRP Membrane Substrate, quenched with 2M sulfuric acid, and read in a spectrophotometer at 450 nm.

[0553] Rat IL-23R competitive binding ELISA Assay plates were coated with 300 ng / well rat IL-23R_huFC and incubated overnight at 4°C. Wells were washed, blocked, and washed again. Serial dilutions of test peptides and IL-23 at a final concentration of 7 nM were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected with a goat anti-p40 polyclonal antibody, followed by HRP-conjugated donkey anti-goat IgG. Signals were visualized with TMB One Component HRP Membrane Substrate and quenched with 2 M sulfuric acid. IC50 values ​​for the various test peptides determined from these data are shown in Tables 3A-H.

[0554] DB cell IL23R pSTAT3 cell assay IL-23 plays a central role in supporting and maintaining Th17 differentiation in vivo. This process is thought to be mediated primarily through signal transducer and activator of transcription 3 (STAT3), and phosphorylation of STAT3 (to yield pSTAT3) leads to upregulation of RORC and proinflammatory 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. DB cells (ATCC#CRL-2289) cultured in RPMI-1640 medium (ATCC#30-2001) supplemented with 10% FBS and 1% glutamine were seeded at 5x10E5 cells / well in 96-well tissue culture plates. Serial dilutions of test peptides and IL-23 at a final concentration of 0.5 nM were added to each well and incubated at 37°C in a 5% CO2 humidified incubator for 30 minutes. Changes in phospho-STAT3 levels in cell lysates were detected using the Cisbio HTRF pSTAT3 Cellular Assay Kit following the manufacturer's two-plate assay protocol. IC50 values ​​determined from these data are shown in Tables 3A-H. If not shown, data was undetermined.

[0555] Example 3. NK cell-based assay Natural killer (NK) cells purified from human peripheral blood of healthy donors by negative selection (Miltenyi Biotech, Cat. No. 130-092-657) were cultured in complete medium (RPMI1640 containing 10% FBS, L-glutamine, and penicillin-streptomycin) in the presence of 25 ng / mL IL-2 (RnD, Cat. No. 202-IL-010 / CF). After 7 days, cells were centrifuged and resuspended in complete medium at 1E6 cells / mL. The given EC 50 ~EC 75 Recombinant IL-23 at 10 ng / mL and IL-18 at 10 ng / mL (RnD, Cat. No. B003-5) were mixed with various concentrations of peptides and added to NK cells seeded at 1E5 cells per well. After 20-24 hours, IFNγ was quantified in the supernatants using a Quantikine ELISA (RnD, Cat. No. DIF50). The IC determined from these data was: 50 Values ​​are shown. If not shown, data were undetermined.

[0556] Example 4. IL-23R reporter assay Compounds were serially diluted in 100% (v / v) DMSO) and plated into 1536-well untreated black assay plates (Corning #9146) using an echo acoustic dispenser (Labcyte). 3 μL of HEK293 cells containing IL-23R, IL-12Rβ1, and a firefly luciferase reporter gene driven by a STAT inducible promoter (Promega) were added to the plate (4000 cells / well), followed by 3 μL of 20 ng / mL IL-23 (equivalent to the EC90 concentration). 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 50Values ​​were determined using the four-parameter Hill equation. Data are shown in the table below. When multiple measurements were made, the average was calculated as IC 50 The values ​​are indicated with the number of replicates shown in parentheses following the value.

[0557] [Table 13]

[0558] [Table 14]

[0559] 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. Cells were counted and resuspended at 2×105 cells per mL in XF-TCEM supplemented with penicillin / streptomycin and 100 ng / mL IL-1β (BioLegend, 579404) and cultured in tissue culture flasks coated with anti-CD3 (eBioscience, 16-0037-85 or BDPharmingen, 555329) at 37°C in 5% CO2. On day 4 of culture, PBMCs were collected, washed twice with 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 6 x 10 4Cells were transferred to wells of 384-well plates pre-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 obtained with PBMCs are provided below in Table 5 for some examples, along with data from the IL23R reporter assay utilizing HEK293 cells described above. Results are reported for single assays or as the average of replicate assays, indicated by the numbers in parentheses following the IC50 values.

[0560] [Table 15]

[0561] Although the present invention above has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications may be made within the scope of the appended claims. 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. Also, each reference provided herein is incorporated by reference in its entirety as if each reference were individually incorporated by reference. In the event that a conflict exists between this application and a reference provided herein, this application shall control.

Claims

1. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (I) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-X12-X13-N-X15-meG-R2 (I) Wherein, R1 is 7Ahp, 6Ahx, 5Ava, Peg2, AEEEP, or AEEEP(Ns); X4 is Pen, Abu, aMeC, hC, or C; X5 is N or K(PEG2PEG2gEC18OH); X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMePip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is KAc, Q, K(NMeAc), K(PEG2PEG2gEC18OH), dKAc, dQ, dK(NMeAc), or dK(PEG2PEG2gEC 18OH); X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP or aMeK; X13 is E, dE, hE, D, dD, or hSer; X15 is absent or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, NmedY, N, dH, dN, dL, Aibor L; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ wherein; Said bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond or thioether bond between R1 and X13; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

2. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (II) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-K(Ac)-X9-AEF-X11-THP-X13-N-X15-X16-R2 (II) wherein R1 is Gab, pFS, bAla or HOC16gEPEG2PEG2orn (also referred to as dOrn(HOC16gEPEG2PEG2)); X3 is dR, G, K(PEG2PEG2gEC18OH), R, dG, or dK(PEG2PEG2gEC18OH); X4 is Pen, Abu, aMeC, hC, or C; X5 is N or Q; X7 is 7MeW or W; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, dD, or Dap(pF(6)); X15 is absent or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, NMedY, N, dH, dN, dL, Aib, or L; X16 is absent or is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(IsoButyl)Gly, P, dP, K, dK, E, dE, R, dR, B, or dD; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ wherein; Said bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second bond between R1 and X13; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano; a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

3. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (III') comprising the following amino acid sequence: R1 - X3 - X4 - X5 - T - X7 - X8 - X9 - X10 - X11 - X12 - X13 - N - X15 - X16 - R2 (III') wherein R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-, 5Cpa, or cPEG3aCO; X3 is R5H, R6H, R7H, S5H, S6H, S7H, K, dK, Orn, d-Orn, Dap, Dab(COCH2), dHe, or hK; X4 is Pen, Abu, aMeC, hC, or C; X5 is N, Q or N(N(Me)2), dN, dQ or dN(N(Me)2); X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMe pip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyr azPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ)), 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or 7MedW; X8 is K(Ac), Q, K(NMeAc), dK(Ac), dQ, or dK(NMeAc); X8 is KAc, Q, K(NMeAc), dK, dQ, dKAc, or dK(NMeAc); X9 is Pen, Abu, aMeC, hC, or C; X10 is AEF or TMAPF; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP or aMeK; X13 is R5H, R6H, R7H, S5H, S6H, S7H, C, E, hE, KNMe, dC, dE, dhE, or dKNMe; X15 is 3Pya; X16 is meG; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and is; The bicyclic peptide inhibitor of interleukin-23 receptor is · A first disulfide bond or thioether bond between X4 and X9; and · A second amide bond, thioether bond, or aliphatic bond between X3 and X13; Cyclized by forming Each alkyl of R2 is optionally substituted with Cl, F, or cyano, A bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof. [

4. ] A bicyclic peptide inhibitor of interleukin-23 receptor of formula (IV) comprising the following amino acid sequence: R1 - X3 - X4 - X5 - T - X7 - X8 - X9 - AEF - X11 - THP - X13 - N - X15 - X16 - R2 (IV) Wherein, R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-, 7Ahp, 6Ahx, or 5Ava; X3 is absent, or is dR, R, dOrn, or Orn; X4 is Pen, Abu, aMeC, hC, or C; X5 is Q, dQ, dN, or N; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMe pip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrolonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ)), 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or 7MedW; X8 is KAc, Q, dKAc, or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, aMeE, Aad, hE, K, dE, dAad, dhE, or dK; X15 is absent, or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L; X16 is absent or is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(IsoButyl)Gly, P, dP, K, dK, E, dE, R, dR, B, or dD; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ ; Said bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond between AEF and X13; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

5. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (V) comprising the following amino acid sequence: R1-X4-N-T-X7-X8-X9-F4CONH2-X11-THP-X13-N-3Pya-meG-R2 (V) wherein R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X4 is Pen, Abu, aMeC, hC, or C; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMePip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrolonePh)W, 7(3UPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is K or dK; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, or dD; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ wherein; Said bicyclic peptide inhibitor of interleukin-23 receptor is ・ A first disulfide bond or thioether bond between X4 and X9; ・ A second amide bond between X8 and X13; is cyclized by forming, each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

6. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (VI) comprising the following amino acid sequence: R1-X3-A-X5-T-X7-X8-A-AEF-X11-THP-X13-N-X15-R2 (VI) wherein, R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X3 is E, dE, D, or dD; X5 is E, dE, D, or dD; X7 is W or 7MeW; X8 is KAc or dK(Ac); X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is KAc or dK(Ac); X15 is absent or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMedY, N, dH, dN, dL, Aib, or L, or is absent; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and is; the bicyclic peptide inhibitor of interleukin-23 receptor ・ A first amide bond between X5 and X10; and ・ A second amide bond between X3 and X15; is cyclized by forming, each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

7. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (VII) comprising the following amino acid sequence: R1-X3-X4-N-T-X7-K(Ac)-X9-X10-X11-THP-X13-N-3Pya-X16-R2 (VII) wherein, R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X3 is D, dK, E, dDap, dD, K, dE, or Dap; X4 is Pen, Abu, aMeC, hC, or C; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMe pip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrolonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X9 is Pen, Abu, aMeC, hC, or C; X10 is AEF, F4CONH2, or F40me; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is KAc or dKAc; X16 is absent or meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, B, or dD; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ wherein; Said bicyclic peptide inhibitor of interleukin-23 receptor is ·a first disulfide bond or thioether bond between X4 and X9; and ·a second amide bond between X3 and X16; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

8. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (VIII) comprising the following amino acid sequence: R1-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-3Pya-meG-R2 (VIII) In the formula, R1 is CF3CO, 5cpaCO, cPeg3aCO, C １ ~C ４ alkyl C(O)-, or C substituted with cyano, Cl, F, or MeCo １ ~C ４ alkyl C(O)-; X4 is Pen, Abu, aMeC, hC, or C; X5 is E, Dap, or K(NMe), dE, D, dD, or dK(NMe); X6 is T, L, dT, dL, I, or dI; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMePip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrolonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is KAc, KPEG12, KAcMor, Q(N(Me)2), K(Me)3, hK(Me)3; K(NMeAc), K(mPEG12), A, or Q, dKAc, dKPEG12, dKacMor, dQ(N(Me)2), KAc; kPEG12, KPEG12, KacMor, Q(N(Me)2), K(Me)3, hK(Me)3, K(NMeAc); K(mPEG12), dA, dQ, dhK(Me)3, dK(NMeAc), dK(mPEG12), dA, or dQ; X9 is Pen, Abu, aMeC, hC, or C; X10 is AEF or AEF(NMe); X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP, aMeLeu, or A; X13 is KAc, A, L, K(NMeAc), Q(N(Me)2)), K(Me)3, E, dKAc, dA; dL, dK(NMeAc), dQ(N(Me)2)), dK(Me)3, or dE; X14 is L, N, or S; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and; The bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond or aliphatic (RCM) bond between X5 and X10; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

9. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (IX) comprising the following amino acid sequence: R1 - X3 - X4 - X5 - T - X7 - X8 - X9 - X10 - X11 - THP - X13 - X14 - 3Pya - meG - R2 (IX) wherein R1 is C １ ~C ４ alkyl C(O)-, or Cl; C substituted with F, or cyano １ ~C ４ alkyl C(O)-, or HO C18g EPEG2 PEG2 CO; X3 is R, dR, K, dK, dK(Me)3, K(Me)3, dK(PEG2PEG2gEC18OH), or K(PEG2PEG2gEC18OH); X4 is Pen, Abu, aMeC, hC, or C; X5 is E or dE; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMe pip)pyr az)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyr azPh)W, 7(3Npyr lonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is KAc or dK(Ac); X9 is Pen, Abu, aMeC, hC, or C; X10 is AEF or AEF(NMe); X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is KAc, E, dK(Ac) or dE; X14 is L, N or S; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and is; The bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond or aliphatic (RCM) bond between X5 and X10; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof. **Claim 10** A bicyclic peptide inhibitor of interleukin-23 receptor of formula (X) comprising the following amino acid sequence: X5-T-X7-X8-A-AEF-X11-THP-X13-3Pya (X) wherein X5 is E, dE, D, or dD; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMe pip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is KAc or dK(Ac); X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is absent or KAc or dK(Ac); the bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X5 and AEF; and · a second cyclization between the amino terminus of X5 and the carboxy terminus of 3Pya; cyclized by forming a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof. **Claim 11** A bicyclic peptide inhibitor of interleukin-23 receptor of formula (XI) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-X15-R2(XI) wherein R1 is 7Ahp, 6Ahx, 5Ava AEEP, or dK(PEG2PEG2gEC18OH); X4 is Pen, Abu, aMeC, hC, or C; X5 is N, Q, dN or dQ; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMe pip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyr azPh)W, 7(3Npyr lonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is KAc, Q, dKAc, or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, or dD; X15 is absent or 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5Pyrimid Ala, 5MePyridin Ala, 5MeH, 5AmPyridin Ala, 4Triazol Ala, 4Pyridin Ala, 4Pya, 3Quinol Ala, 3OHPhe, 3AmPyrazol Ala, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ ; the bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and ・ A second amide bond or an aliphatic (RCM) bond between R1 and X13; is cyclized by formation of, each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

12. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (XII) comprising the following amino acid sequence: R1-X4-N-X6-X7-X8-X9-AEF-2Nal-X12-X13-N-3Pya-X16-R2 (XII) wherein R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X4 is Pen, Abu, aMeC, hC, or C; X6 is 3Hyp, T, 3OHPro, or dT; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(1NMe pip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NAcPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NAcPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is R5H, R6H, R7H, S5H, S6H, or S7H; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is R5H, R6H, R7H, S5H, S6H, or S7H; X16 is absent or meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(IsoButyl)Gly, P, dP, K, dK, E, dE, R, dR, B, or dD; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and is; The bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond or aliphatic (RCM) bond between X3 and one of X10, X13, or X16; is cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

13. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (XIII) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-2Nal-THP-X13-N-X15-X16-X17-R2 (XIII) wherein R1 is 7Ahp, 6Ahx, 5Ava, AEEP, or dK(PEG2PEG2gEC18OH); X4 is Pen, Abu, aMeC, hC, or C; X5 is N, Q, dN or dQ; X7 is W, 7MeW, 3Pya, 7(2ClPh)W, 7(3(INMepip)pyraz)W, 7(3(6AzaInd1Me))W, 7(3CF3TAZP)W, 7(3NacPh)W, 7(3NPyrazPh)W, 7(3NpyrlonePh)W, 7(3UrPh)W, 7(4(CpCNPh))W, 7(4CF3Ph)W, 7(4NacPh)W, 7(4OCF3Ph)W, 7(4OMePh)W, 7(4Paz)W, 7(5(2(4OMePh)Pyr))W, 7(5(Ina7Pyr))W, 7(6(1)7dMeNDAZ))W, 7(6(2MeNDAZ))W, 7(7(124TAZP))W, 7(7Imzpy)W, 7BrW, 7EtW, 7PhW, 7PyrW, A, BT, or D7MeW; X8 is KAc, Q, dKAc, or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dE, D, or dD; X15 is absent or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L; X16 is absent or is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(IsoButyl)Gly, P, dP, K, dK, E, dE, R, dR, D, dD, or NMeK(PEG2PEG2gEC 18OH); X17 is absent or is K(PEG2PEG2gEC18OH), or dK(PEG2PEG2gEC18OH); R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ wherein; Said bicyclic peptide inhibitor of interleukin-23 receptor is ·a first disulfide bond or thioether bond between X4 and X9; and ·a second amide bond between R1 and X13; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

14. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (XIV) comprising the following amino acid sequence: 【Chemical 1】 wherein, R1 is -H, C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F or cyano １ ~C ４ alkyl C(O)-; X3 is dK or K; X4 is Pen, Abu, aMeC, hC, or C; X5 is N, Q, or Dap; X6 is T dK or K; X7 is W, 7MeW, dW, or d7MeW; X8 is K(Ac), Q, dK(Ac), or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is THP or aMeL; X13 is E, K(Ac), dE, E, D, dD, or dK(Ac); X15 is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, 3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L, or is absent; X16 is meG, 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(Isobutyl)Gly, P, dP, K, dK, E, dE, R, dR, D, or dD, or is absent; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ wherein each alkyl may optionally be substituted with Cl, F, or cyano; R3 is PEG4(−HN[(CH2)2O]4(CH2)2CO−), PEG4DA(−OC[(CH2)2O]4(CH2)2CO−), or a C6-C20 saturated or unsaturated dicarboxylic acid (e.g., 1,10-decanedioic acid, 1,12-dodecanedioic acid, 1,14-tetradecanedioic acid, or 1,16-hexadecanedioic acid); Said bicyclic peptide inhibitor of interleukin-23 receptor is a first disulfide bond or thioether bond between X4 and X9, and an R3 group added to the AEF residue at X10 and (i) the Dpr residue at X5, (ii) K or dK at X6, or (iii) K, dK, or E at X13 is cyclized by a second amide bond therebetween, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

15. A bicyclic peptide inhibitor of interleukin-23 receptor comprising the amino acid sequence of the following formula (XV): R1-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-X15-R2 (XV) wherein, R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X4 is Pen, Abu, aMeC, hC, or C; X5 is E, dE, D, or dD; X7 is W, 7meW, dW, or d7MeW; X8 is KAc, Q, dKAc, or dQ; X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, KAc, dE, D, dD, or dKAc; X15 is absent or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, NmedY, N, dH, dN, dL, Aib, or L; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and is; Said bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond between AEF and X5; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

16. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (XVI) comprising the following amino acid sequence: R1-X4-X5-T-X7-X8-X9-AEF-X11-THP-X13-N-X15-R2 (Formula XVI) wherein, R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X4 is Pen, Abu, aMeC, hC, or C; X5 is N, L, dN, or dL; X7 is W, 7meW, dW, or d7MeW; X8 is KAc or dKAc; X9 is Pen, Abu, aMeC, hC, or C; X10 is F4CONH ２ , 4AmF, or dF4CONH ２ ; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, dK, dDap, K, Dap, or dE; X15 is absent or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ ; Said bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond between X13 and X15 or between X13 and X16; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

17. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (XVII) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X10-X11-THP-X13-X14-X15-X16-R2 (XVII) wherein R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X3 is Orn, E, dOrn, or dE; X4 is Pen, Abu, aMeC, hC, or C; X5 is N or dN; X7 is W, 7meW, dW, or d7MeW; X8 is KAc or dKAc; X9 is Pen, Abu, aMeC, hC, or C; X10 is F4CONH2 or AEF; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is E, KAc, dKAc, or dE; X14 is absent or is N; X15 is absent or is 3Pya, 3MeH, H, F, hF, Y, dY, Y(CHF2), PAF, oAMPhe, F(CF3), dPaf, D3Pya, ACIPA(SR), 6OH3Pya, 5PyrimidAla, 5MePyridinAla, 5MeH, 5AmPyridinAla, 4TriazolAla, 4PyridinAla, 4Pya, 3QuinolAla, 3OHPhe, 3AmPyrazolAla, 2AmTyr, 1MeH, THP, bAla, NMedY, K, dK, NMeY, N, dH, dN, dL, Aib, or L; X16 is absent or is 4(R)OHPro, 4(S)AminoPro, 4diFPro, 5(R)diMePro, aMeP, N(3AmBenzyl)Gly, N(Cyclohexyl)Gly, N(IsoButyl)Gly, P, dP, K, dK, E, dE, R, dR, D, dD, dDap, meG, Dap, or dMeG; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and is; Said bicyclic peptide inhibitor of interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond between X3 and one of X10, X13, or X16; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

18. A tricyclic peptide inhibitor of interleukin-23 receptor of formula (XVIII) comprising the following amino acid sequence: R1 - X3 - X4 - X5 - T - X7 - X8 - X9 - AEF - X11 - THP - X13 - N - 3Pya - meG - X17 - R2 (XVIII) wherein R1 is C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-; X3 is K, dK, E, or dE; X4 is Pen, Abu, aMeC, hC, or C; X5 is E, dE, D, or dD; X7 is W or 7MeW; X8 is KAc or dK(Ac); X9 is Pen, Abu, aMeC, hC, or C; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X13 is KAc or dK(Ac); X17 is E, dE, K, dK, D, or dD; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ wherein; Said tricyclic peptide inhibitor of interleukin-23 receptor is · A first disulfide bond or thioether bond between X4 and X9; · A second bond between X3 and X17; and · A third bond between X5 and AEF; Cyclized by forming Each alkyl of R2 is optionally substituted with Cl, F, or cyano, A tricyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

19. A bicyclic peptide inhibitor of interleukin-23 receptor of formula (XIX) comprising the following amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-R2 (XIX) Wherein R1 is 7Ahp, 6Ahx, 5Ava, Peg2, PEGNMe, AEPP, AEPP(Ns), Gaba, pFS, bAla, C １ ~C ４ alkyl C(O)-, or C substituted with Cl, F, or cyano １ ~C ４ alkyl C(O)-, 5cpaCO, or cPEG3aCO; X3 is absent or is dR, R, G, R5H, R6H, R7H, S5H, S6H, S7H, K, dK, Orn, dOrn, Dap, dDap, Dab, dDab, Dab(COCH2), dDab(COCH2), hE, dhE, hK, dhK, dSer(MePEG2), or Ser(MePEG2); X4 is Pen, Abu, or C; X5 is N, dN, Q, dQ, N(N(Me)2), or dN(N(Me)2); X7 is W, dW, 7MeW, or d7MeW; X8 is K(Ac), dK(Ac), Q, dQ, K(NMeAc), or dK(NMeAc); X9 is Pen, Abu, or C; X10 is AEF, TMAPF, or AEF(NHPEG3a); X11 is 2Nal, X12 is THP, Acpx, or aMeK; X13 is E, dE, hE, dhE, aMeE, d-aMeE, D, dD, Aad, dAad, K, dK, hSer, dhSer, Dap(pF), R5H, R6H, R7H, S5H, S6H, S7H, C, dC, K(NMe) or dK(NMe); X14 is absent or is N; X15 is 3Pal, H, dH, 3MeH, 3MedH, F, dF, aMeF, aMedF, THP, bAla, NMeTyr, NMedY, K, or dK; X16 is absent or is meG; X17 is absent or is K(PEG2PEG2gEC18OH); R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ and is; Said bicyclic peptide inhibitor of interleukin-23 receptor is - A first disulfide bond or thioether bond between X4 and X9; and - A second amide bond, aliphatic (RCM) bond, alkylamine bond, or thioether bond between R1 and X13, or between X3 and X13; is cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

20. A bicyclic peptide inhibitor of the interleukin-23 receptor of formula (XX') comprising the following amino acid sequence: R1-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R2 (XX') wherein R1 is CF3CO, 5cpaCO, cPEG3aCO, C1-C4 alkyl C(O)-, or C1-C4 alkyl C(O)- substituted with cyano, Cl, or F; X3 is absent or is R, dR, K, dK, K(Me)3, dK(Me)3, hK(Me)3, dhK(Me)3, K(d), or dK(d); X4 is Pen, Abu, or C; X5 is E, dE, D, dD, K, dK, K(a), K(Ac), K(cPEG3aCO), K(d), K(G), Dap, or K(NMe), dK(NMe), K(NNs), or dK(NNs); X6 is selected from T, L, dT, dL, I, or dI; X7 is W, 7MeW, 7PhW, dW, d7MeW, d7PhW, or 7(3NAcPh)W; X8 is K(Ac), dK(Ac), hK(Me)3, dhK(Me)3, K(Me)3, dK(Me)3, K(NMeAc), dK(NMeAc), K(NMecPEG3a), Q(N(Me)2), KPEG12, dKPEG12, KAcMor, A, Q, dKacMor, dQ(N(Me)2), K(mPEG12), dA, dQ, or dK(mPEG12); X9 is Pen, Abu, or C; X10 is AEF or AEF(NMe); X11 is 2Nal, X12 is THP, aMeLeu, or A; X13 is E, dE, K(Ac), dK(Ac), K(Me)3, dK(Me)3, K(NMeAc), dK(NMeAc), K(NMecPEG3a), Q(N(Me)2), dQ(N(Me)2), A, dA, L, or dL; X14 is L, N or S; X15 is 3Pal, L, dL, or Aib; X16 is meG; R2 is -NH ２ , N(H)(C １ -C ４ alkyl), -HN(C １ -C ４ alkyl), or -N(C １ -C ４ alkyl) ２ wherein; The bicyclic peptide inhibitor of the interleukin-23 receptor is · a first disulfide bond or thioether bond between X4 and X9; and · a second amide bond or alkylamine bond between X5 and X10; cyclized by forming each alkyl of R2 is optionally substituted with Cl, F, or cyano, a bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof.

21. A bicyclic peptide inhibitor or a pharmaceutically acceptable salt thereof, which is a compound selected from Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, or Table 1H, respectively, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising · the bicyclic or tricyclic peptide inhibitor or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 21; and · a pharmaceutically acceptable carrier, excipient, or diluent A pharmaceutical composition comprising.

23. The pharmaceutical composition according to Claim 22, further comprising an enteric coating.

24. The pharmaceutical composition according to Claim 23, wherein the enteric coating protects and releases the pharmaceutical composition in the lower digestive system of a patient or subject.

25. A pharmaceutical composition for use in a method of treating an autoimmune disease, an inflammatory disease, or a related disorder, wherein the pharmaceutical composition contains the bicyclic or tricyclic peptide inhibitor or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 21, and the method comprises administering a therapeutically effective amount of the bicyclic or tricyclic peptide inhibitor or a pharmaceutically acceptable salt thereof to a subject or patient in need thereof.

26. Use of a therapeutically effective amount of the bicyclic or tricyclic peptide inhibitor or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 21 in the manufacture of a medicament for treating an autoimmune disease, an inflammatory disease, or a related disorder.

27. The autoimmune disease, inflammatory disease 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, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis, acne inversa, ulcerative colitis, Crohn's disease, celiac disease (nontropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, radiation- or chemotherapy-related colitis; colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1; chronic granulomatous disease, type 1b glycogenosis, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, cystitis, cystitis occurring after rectal colectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, 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 25.

28. The autoimmune disease, inflammatory disease or related disorder is selected from inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO) or psoriatic arthritis (PsA), the pharmaceutical composition according to claim 27.

29. A pharmaceutical composition for use in a method of treating an inflammatory disease that is inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, psoriasis or psoriatic arthritis, wherein the pharmaceutical composition contains a bicyclic or tricyclic peptide inhibitor according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject or patient in need thereof a therapeutically effective amount of the bicyclic or tricyclic peptide inhibitor or a pharmaceutically acceptable salt thereof, a pharmaceutical composition.

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