Peptide inhibitors of the interleukin-23 receptor

Abstract

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

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 480,038, filed January 16, 2023, which is incorporated herein by reference in its entirety.

[0002] (Incorporating sequence listing) The Sequence Listing in ST.26 XML format, entitled 739650_NTT-4248PC_SL.xml, created on January 12, 2024, containing 1,212,736 bytes, prepared in accordance with 37 CFR §§ 1.822-1.824 and submitted contemporaneously with the filing of the present application, is hereby incorporated by reference in its entirety. [Background technology]

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

[0004] IL-23 has been implicated as playing an important role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), e.g., ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed a key role for the interleukin-23 receptor (IL-23R) and downstream effector cytokines in the pathogenesis of disease. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are abundant in the intestine. IL-23R gene expression and protein levels have been found to be elevated at the intestinal mucosal surface in patients with IBD. 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.

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

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

[0007] Specifically, the present disclosure provides a method for producing a medicament comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (I) or a pharmaceutically acceptable salt thereof, wherein X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , and X 17 each of which is defined herein.

[0008] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -NX 15 -X 16 -X 17 -R2(IB) or a pharmaceutically acceptable salt thereof, wherein R1, X3, X4, X5, X7, X8, X9, X 10 , X 11, X 12 , X 13 , X 15 , X 16 , X 17 and R2 are each as defined herein.

[0009] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: R1-X3-Pen-X5-T-7(3NAcPh)W-X8-Pen-X 10 -6OH2Nal-THP-X 13 -N-3Pya-Sar-X 17 -R2(IE) or a pharmaceutically acceptable salt thereof, wherein R1, X3, X5, X8, X 10 , X 13 , X 17 and R2 are each as defined herein.

[0010] The present disclosure further provides a pharmaceutical composition comprising a peptide described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] The present disclosure further provides a method for treating a disease or disorder associated with interleukin-23 (IL-23) / interleukin-23 receptor (IL-23R), comprising administering to a subject in need thereof a therapeutically effective amount of a peptide or pharmaceutical composition described herein. In some embodiments, the disease or disorder is selected from ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA). DETAILED DESCRIPTION OF THE INVENTION

[0012] Provided herein are peptide inhibitors of IL-23R, pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, and methods and / or uses for the treatment of inflammatory diseases, autoimmune diseases, and / or related disorders. The peptide inhibitors of the present disclosure may exhibit enhanced properties, such as a longer in vivo half-life, compared to corresponding cyclic peptide inhibitors of IL-23R that do not have a cyclic structure.

[0013] Peptide molecules that modulate the interaction between IL-23R and IL-23 represent a convenient and cost-effective treatment for autoimmune diseases when used as oral therapeutics. To achieve high binding interactions with the IL-23 receptor, it is important to maintain certain amino acid residues at selected positions, as shown in the peptide molecules described herein. In addition, X 11 Peptide molecules with hydroxy-substituted naphthalenes at positions 1 and 2 may offer greater potency than peptide molecules lacking such a feature. Thus, the peptide molecules described herein represent a series of more potent and efficient therapeutic agents for inhibiting IL-23R.

[0014] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those skilled in the art.

[0015] As used in the specification and claims, the terms "comprise," "comprising," "include," "having," "has," "can," "contain," and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of specified features, groups, components, or steps and do not exclude the presence of other features, groups, components, or steps. For example, "the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X15 -X 16 -X 17 The term "peptide of formula (I)" refers to a peptide of formula (I) comprising amino acids X3 to X 17 This means that the peptide may include, but is not limited to, additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, N- or C-terminal capping groups, chemical or biological moieties conjugated to the peptide at any position (including, but not limited to, lipophilic substituents, antibodies, imaging agents, etc.). The terms "comprise," "comprising," "include," "having," "has," "can," or "contain" can include embodiments encompassed by the terms "consisting essentially of" or "consisting of."

[0016] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and typically refer to molecules comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.).

[0017] Naturally occurring L-amino acids are represented by the conventional three-letter or uppercase single-letter amino acid symbols in Table 1. The corresponding D-amino acids are represented by the lowercase single-letter amino acid symbols or by the three-letter or uppercase single-letter amino acid symbols in Table 1 preceded by the letter "D" (e.g., r, dR, or D-Arg).

[0018] [Table 1]

[0019] As used herein, the term "L-amino acid" refers to the "L" isomeric form of an amino acid, and conversely, the term "D-amino acid" refers to the "D" isomeric form of an amino acid (e.g., (D)Asp or D-Asp, (D)Phe, or D-Phe). D-amino acids, when referred to using single-letter abbreviations, may conventionally be designated by a lowercase letter. For example, D-arginine may be designated as "arg" or "r". Alternatively, a lowercase "d" may be used in front of an amino acid to indicate its D isomeric form, for example, D-lysine may be designated as dK.

[0020] For less common or non-naturally occurring amino acids, when not referred to by their full name (e.g., sarcosine, ornithine, etc.), the frequently used three- or four-letter abbreviation for that residue is used, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0021] The D-isomer form of an amino acid may be any of the positions in the IL-23R inhibitors described herein (X3 to X4 that appear in the molecule). 17 In some embodiments, the D-isomer form of an amino acid may be at any of X3, X5, X6, X8, X 13 In other embodiments, the D-isomer form of an amino acid may be located at only one or more of X, X, X, and optionally one additional position. 13 In other embodiments, the D-isomer form of an amino acid may be located at only one or more of X, X, and optionally one additional position. 13, and optionally one additional position. In other embodiments, the D-isomer form of an amino acid may be located only at X3 and optionally one additional position. In other embodiments, the D-isomer form of an amino acid may be located only at X3 and optionally two or three additional positions. In other embodiments, the D-isomer form of an amino acid may be located only at positions X3 through X4 appearing in the IL-23R inhibitors described herein. 17 In other embodiments, the D-isomer form of an amino acid may be located at only one or two of positions X3 through X4 appearing in the IL-23R inhibitors described herein. 17 For example, positions X3 to X 15 IL-23R inhibitors described herein having only one amino acid in the D-form can have amino acids in the D-form present at three or four of these positions. In other embodiments, amino acids in the D-isomer form are present at positions X3 through X4 appearing in the IL-23R inhibitors described herein. 17 It can be located in only five or six of the

[0022] Peptides may be naturally occurring, synthetically produced, or recombinantly expressed. Peptides may also contain additional groups that modify the amino acid chain, such as functional groups added via post-translational modifications. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutamylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation, selenation, and C-terminal amidation. The term "peptide" also includes peptides containing modifications of the amino and / or carboxy termini. Modifications of the terminal amino group include, but are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include, but are not limited to, amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications (e.g., where the lower alkyl is a C1-C4 alkyl). The term "peptide" also includes modifications of amino acids between the amino and carboxy termini, such as, but not limited to, those described above.

[0023] As will be apparent to one of skill in the art, peptide sequences disclosed herein are presented from left to right, with the left-hand end of the sequence being the N-terminus of the peptide and the right-hand end of the sequence being the C-terminus of the peptide. Some sequences disclosed herein incorporate either an "-OH" or an "-NH" moiety at the carboxy-terminus (C-terminus) of the sequence. In such cases, unless otherwise indicated, the "-OH" or "-NH" moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, respectively, corresponding to the presence of a carboxylic acid (COOH) or amide (CONH) group at the C-terminus. In each sequence of the present disclosure, the C-terminal "-NH" moiety may be substituted for a C-terminal "-OH" moiety, or vice versa.

[0024] As used herein, the phrases "amino acid," "amino acid residue," or "residue" refer to an amino acid, modified amino acid, amino acid analog, or amino acid mimetic that is incorporated into a peptide by an amide bond or amide bond mimetic.

[0025] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions proposed by the IUPAC Commission in Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)," Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims deviate from these proposals, they will be made clear to the reader. In the amino acid sequences representing IL-23 inhibitors, individual amino acids are separated by a hyphen "-" or parentheses, e.g., lysine is designated as [K].

[0026] Those skilled in the art will understand that certain amino acids and other chemical moieties are modified when attached to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain; for example, one or more hydrogens may be removed or replaced upon attachment.

[0027] The term "therapeutically effective amount" or "pharmaceutically effective amount" refers to that amount of active peptide or pharmaceutical agent that elicits the biological or medical response in a tissue system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician, including preventing, treating, or ameliorating the symptoms of the syndrome, disorder, or disease being treated.

[0028] The term "pharmaceutically acceptable" means approved or appropriable by a regulatory agency of the U.S. federal or state government, or a corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0029] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0030] As used herein, a "composition" or "pharmaceutical composition" is intended to encompass a product containing a specified active pharmaceutical ingredient (API), which may include a pharmaceutically acceptable excipient, carrier, or diluent as described herein, e.g., in specific amounts defined throughout this disclosure.

[0031] The composition or pharmaceutical composition of the present disclosure may be in different pharmaceutically acceptable forms, including, but not limited to, liquid compositions, tablet or matrix compositions, capsule compositions, etc. When the composition is a tablet composition, the tablet may include two or more different phases, including, but not limited to, an internal phase that may include a core and an external phase. The tablet composition may also include, but is not limited to, one or more coatings.

[0032] Pharmaceutically acceptable salts and tautomeric forms of the peptides described herein are also provided.

[0033] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or free base of a peptide represented by Formula (I) that is non-toxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. It should retain the desired pharmacological activity of the parent compound. See generally G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database," J. Med. Chem., 2007, 50:6665-72; S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. The peptides of formula (I) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and therefore may react with many inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0034] The IL-23R inhibitors of the present disclosure, their pharmaceutically acceptable salts, and / or other forms may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible isomers of the IL-23R inhibitors of the present disclosure, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to encompass both the E and Z geometric isomers. Likewise, all tautomeric forms are intended to be encompassed. Where compounds are represented in their chiral form, it is understood that the embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that the embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms; or racemic or scalemic mixtures of such compounds.

[0035] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0036] "Stereoisomer" refers to a compound that differs in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. When a compound has one or more asymmetric centers or double bonds with asymmetric substitution, it may exist in stereoisomeric forms and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise indicated, the description is intended to encompass individual stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0037] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0038] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "scalemic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0039] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, e.g., enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to both the -NH- and =N- rings, e.g., pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0040] The term "administering" with respect to the methods of the present invention means a method for therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder, or disease described herein by using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof. Such a method includes administering therapeutically effective amounts of a peptide of the present disclosure, or a pharmaceutically acceptable salt thereof, a composition thereof, or a pharmaceutical thereof, either simultaneously or sequentially at different times during the course of treatment or as a combination therapy.

[0041] The terms "patient" or "subject," used interchangeably, refer to an organism, preferably a mammal, most preferably a human, that will be or has been treated by a method according to an embodiment of the present application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, and the like, more preferably humans.

[0042] As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent (i.e., a compound of the present disclosure (alone or in combination with another pharmaceutical agent)) to a patient having a disorder or disease, symptoms thereof, or likelihood of developing such a disorder or disease as described herein, or to isolated tissue or cell lines derived from a patient (e.g., for diagnostic or ex vivo applications), with the purpose of curing, curing, alleviating, mitigating, altering, curing, ameliorating, improving, or affecting the disorder or disease, symptoms thereof, or likelihood of developing said disorder or disease. Such treatments may be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics.

[0043] As used herein, the term "prevent" or "prevention" means the complete absence of onset of a disorder or disease in cases where no onset of a disorder or disease has occurred, or the absence of further onset of a disorder or disease in cases where there has already been onset of a disorder or disease. The ability of an individual to prevent some or all of the symptoms associated with a disorder or disease is also considered.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In the chemical arts, dashes at the beginning or end of chemical groups are for convenience; chemical groups may be depicted with or without one or more dashes without losing their usual meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or the point at which a chemical group is attached to the remainder of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be linked in either direction. Similarly, an "arylalkyl" group, for example, can be attached to the remainder of the molecule at either the aryl or alkyl portion of the group. "C u~v " or (C u -C v ) indicates that the following group has u to v carbon atoms. For example, "C 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has from 1 to 6 carbon atoms.

[0045] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon. For example, an alkyl group can be one to ten carbon atoms (i.e., C1-C 10) alkyl), 1 to 5 carbon atoms (i.e., (C1-C5) alkyl), 1 to 4 carbon atoms (i.e., (C1-C4) alkyl), or 1 to 3 carbon atoms (i.e., (C1-C3) alkyl). Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2 CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-trimethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2) 10 CH3), and dodecyl (-(CH2) 11 In one embodiment, alkyl includes, but is not limited to, C (1~6) In another embodiment, alkyl refers to C (1~4) In another embodiment, alkyl refers to C (1~3) refers to alkyl.

[0046] The term "alkylene" refers to a divalent alkyl group. For example, an alkylene group can be an alkylene group having 1 to 10 carbon atoms (i.e., C1 to C6). 10(C1-C5) alkylene), 1 to 5 carbon atoms (i.e., (C1-C5) alkylene), 1 to 2 carbon atoms (i.e., (C1-C2) alkylene), or 1 carbon atom (i.e., (C1) alkylene). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), n-butylene (-CH2CH2CH2CH2-), and the like.

[0047] The term "halo" or "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I). In one embodiment, halo refers to fluoro.

[0048] The term "haloalkyl" refers to a straight-chain or branched alkyl group having 1 to 12 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms in the chain, optionally replacing one or more H with halo. Examples of "haloalkyl" groups include trifluoromethyl (CF), difluoromethyl (CFH), monofluoromethyl (CHF), pentafluoroethyl (CFCF), tetrafluoroethyl (CHFCF), monofluoroethyl (CHCHF), trifluoroethyl (CHCF), tetrafluorotrifluoromethylethyl (CF(CF)), and groups considered equivalent to any one of the foregoing examples given the ordinary skill in the art and the teachings provided herein. In one embodiment, alkyl is a C (1~6) In another embodiment, haloalkyl is C (1~4) In another embodiment, alkyl is C (1~3) refers to haloalkyl.

[0049] The term "cycloalkyl" refers to alkyl groups containing 3 to 8 carbon atoms (i.e., C (3~8) cycloalkyl), preferably 3 to 6 carbon atoms (i.e., C (3~6)"Cycloalkyl" refers to a saturated or partially unsaturated all-carbocyclic ring system having a cycloalkyl ring system (cycloalkyl), where the cycloalkyl ring system has a single ring or multiple rings in spirocyclic or bicyclic form. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specifically stated herein, cycloalkyl groups can be unsubstituted or substituted. Some cycloalkyl groups can exist as spirocycloalkyls, where two cycloalkyl rings are fused through a single carbon atom, for example, but not limited to, an example of a spiropentyl group is:

[0050] [ka] For example, but not limited to, examples of spirohexyl groups include:

[0051] [ka] For example, but not limited to, examples of cycloheptyl groups include:

[0052] [ka] For example, but not limited to, examples of cyclooctyl groups include:

[0053] [ka] Unless stated otherwise specifically in the specification, siprocycloalkyl groups can be unsubstituted or substituted. Bicyclic cycloalkyl ring systems include:

[0054] [ka] Also included.

[0055] The term "heterocycle" or "heterocyclyl" refers to a saturated or partially unsaturated ring system having at least one atom other than carbon in the ring system, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. Heterocyclyl groups can, for example, consist of a single ring or multiple rings (e.g., in the form of a spirocyclic or bicyclic ring system). Exemplary heterocycles include, but are not limited to, oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.

[0056] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon within the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes a single aromatic ring having 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.

[0057] Furthermore, within the scope of the present invention, and particularly when referring to the peptides of the present disclosure or pharmaceutically acceptable salts thereof, any element is intended to include all isotopes and isotopic mixtures of that element, whether occurring in nature or synthetically produced, in either natural abundance or isotopically enriched form. For example, a reference to hydrogen includes within its scope: 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. For example, -C (1~6)A group represented by alkyl includes not only -CH but also CD, not only CHCH but also CDCD, etc. Similarly, references to carbon and oxygen include, within their scope, respectively: 12 C. 13 C, and 14 C, and 15 O, and 16 O, and 17 O, and 18 These isotopes may be radioactive or non-radioactive. Radiolabeled compounds of the present disclosure include: 3 H, 11 C. 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 The radioisotope may comprise a radioisotope selected from the group including Br. Preferably, the radioisotope is 3 H, 11 C, and 18 It is selected from the group F.

[0058] The abbreviation "(V / V)" refers to the phrase "volume for volume," i.e., the proportion of a particular substance in a mixture as measured by the volume or amount by volume of a component of a composition disclosed herein relative to the total volume of the composition. Thus, the amount is unitless and represents the volume percentage amount of the component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture may indicate that there are 2 mL of one solvent in 100 mL of solvent mixture.

[0059] 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 (a drug or oral preparation is taken by mouth and absorbed via the gastrointestinal tract), enteral (drug absorption also occurs throughout the gastrointestinal tract), or parenteral (generally, by injection, infusion, or implantation, etc.).

[0060] Bioavailability refers to the extent and rate at which an active moiety (drug or metabolite) enters the systemic circulation and thereby accesses the site of action. Drug bioavailability can be affected by factors such as the properties of the dosage form and the properties of the drug.

[0061] As used herein, "gastrointestinal tissue" refers to all tissues comprising the organs of the gastrointestinal tract. By way of example only, "gastrointestinal tissue" includes, but is not limited to, tissues of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.

[0062] compound The present invention provides peptide inhibitors of the interleukin-23 receptor. Specifically, the disclosure provides peptide inhibitors of the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 A peptide of formula (I), comprising (I): or a pharmaceutically acceptable salt thereof, wherein: X3 is any amino acid or is absent; X4 is any amino acid, X5 is any amino acid, X6 is any amino acid, X7,

[0063] [ka] and R A However, O, NH, NC (1~5) alkyl, or S; R B But, -H, halo, C (1~3) alkyl, or phenyl, where the phenyl is one -N(H)C(O)C (1~3) optionally substituted with alkyl groups; X8 is any amino acid; X9 is any amino acid, X 10 but,

[0064] [ka] and R C But -H or -C (1~3) is alkyl, R D -H, -OH, -CN, -C (1~3) Alkyl, -OC (1~3) Alkyl, -OC (1~3) alkyl-(5-membered heteroaryl), -C(O)NH2, or heterocyclyl, -OC (1~3) alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain and heterocyclyl optionally substituted with one -C(O)NH group; R E is —H or halo; R F But -C (1~6) an alkylene or divalent polyethylene glycol chain, R G But -H, -C (1~3) Alkyl, or X5 or X 13 is the bond to the amino acid R H But -H, -C (1~3)Alkyl, -C(NH)NH2, -C(O)-R H1 Or Or R G and R H together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, R H1 But -C (1~5) Alkyl, -OC (1~5) Alkyl, -C (1~3) Alkyl-phenyl, -phenyl-C (1~3) Alkyl-N(H)-S(O)2-C (1~3) ) alkyl or polyethylene glycol chain, -C (1~3) alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R J , R K , and R L However, each independently, C (1~3) Is it alkyl? or R J and R K together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, or Or X 10 but,

[0065] [ka] and A,

[0066] [ka] and R aa is -OCHF2, -O(CH2)9CO2H,

[0067] [ka] and R bbis -H, -CH3, -C(O)CH3, -C(NH)NH2, -(CH2)3O(CH2)2OCH3, -CH2CH2OCH3, -(CH2CH2O)3CH3, -(CH2CH2O)6CH3,

[0068] [ka] and R cc -H, -CH3, -(CH2)3O(CH2)2OCH3,

[0069] [ka] and n1 is 1, 2, or 3; R dd but,

[0070] [ka] and n2 is 1, 2, 3, 4, or 5; R gg But -OCH3,

[0071] [ka] and n3 is 3, 4, 5, 6, or 8; R hh -H, -(CH2)7CH3, -(CH2) 15 CH3, -(CH2)2OCH3, or -(CH2CH2O)3CH3; X 11 but,

[0072] [ka] and R M But halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3)haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X 12 is any amino acid, X 13 is any amino acid, X 14 is any amino acid, X 15 Ala, THP, or

[0073] [ka] and R Q But -H or -C (1~3) is alkyl, R S is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one -C(O)NH group; X 16 is any amino acid or is absent, X 17 is any amino acid or is absent, The peptide is cyclized to form a first ring, the first ring containing 4 to 11 or 14 amino acids.

[0074] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 A peptide of formula (I), comprising (I): or a pharmaceutically acceptable salt thereof, wherein: X3 is any amino acid or is absent; X4 is an amino acid linked to the amino acid of X9, X5 is any amino acid, X6 is any amino acid, X7,

[0075] [ka] and R A However, O, NH, NC (1~5) alkyl, or S; R B But, -H, halo, C (1~3) alkyl, or phenyl, where the phenyl is one -N(H)C(O)C (1~3) optionally substituted with alkyl groups; X8 is any amino acid; X9 is an amino acid linked to the amino acid of X4, X 10 is a substituted or unsubstituted aromatic amino acid, X 11 but,

[0076] [ka] and R M But halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X 12 is any amino acid, X 13 is any amino acid, X 14 is any amino acid, X 15 Ala, THP, or

[0077] [ka] and R Q But -H or -C (1~3) is alkyl, R S is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one -C(O)NH group; X 16is any amino acid or is absent, X 17 is any amino acid or is absent.

[0078] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 A peptide of formula (I), comprising (I): or a pharmaceutically acceptable salt thereof, wherein: X3 is any amino acid or is absent; X4 is an amino acid linked to the amino acid of X9, X5 is any amino acid, X6 is any amino acid, X7,

[0079] [ka] and R A However, O, NH, NC (1~5) alkyl, or S; R B But, -H, halo, C (1~3) alkyl, or phenyl, where the phenyl is one -N(H)C(O)C (1~3) optionally substituted with alkyl groups; X8 is any amino acid; X9 is an amino acid linked to the amino acid of X4, X 10 but,

[0080] [ka] and R C But -H or -C(1~3) is alkyl, R D -H, -OH, -CN, -C (1~3) Alkyl, -OC (1~3) Alkyl, -OC (1~3) alkyl-(5-membered heteroaryl), -C(O)NH2, or heterocyclyl, -OC (1~3) alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain and heterocyclyl optionally substituted with one -C(O)NH group; R E is —H or halo; R F But -C (1~6) an alkylene or divalent polyethylene glycol chain, R G But -H, -C (1~3) Alkyl, or X5 or X 13 is the bond to the amino acid R H But -H, -C (1~3) Alkyl, -C(NH)NH2, -C(O)-R H1 Or Or R G and R H together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, R H1 But -C (1~5) Alkyl, -OC (1~5) Alkyl, -C (1~3) Alkyl-phenyl, -phenyl-C (1~3) Alkyl-N(H)-S(O)2-C (1~3) ) alkyl or polyethylene glycol chain, -C (1~3) alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R J , R K , and R L However, each independently, C (1~3) Is it alkyl? or R J and R Ktogether with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, or Or X 10 but,

[0081] [ka] and A,

[0082] [ka] and R aa is -OCHF2, -O(CH2)9CO2H,

[0083] [ka] and R bb is -H, -CH3, -C(O)CH3, -C(NH)NH2, -(CH2)3O(CH2)2OCH3, -CH2CH2OCH3, -(CH2CH2O)3CH3, -(CH2CH2O)6CH3,

[0084] [ka] and R cc -H, -CH3, -(CH2)3O(CH2)2OCH3,

[0085] [ka] and n1 is 1, 2, or 3; R dd but,

[0086] [ka] and n2 is 1, 2, 3, 4, or 5; R gg But -OCH3,

[0087] [ka] and n3 is 3, 4, 5, 6, or 8; R hh -H, -(CH2)7CH3, -(CH2) 15 CH3, -(CH2)2OCH3, or -(CH2CH2O)3CH3; X 11 but,

[0088] [ka] and R M But halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X 12 is any amino acid, X 13 is any amino acid, X 14 is any amino acid, X 15 Ala, THP, or

[0089] [ka] and R Q But -H or -C (1~3) is alkyl, R S is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one -C(O)NH group; X 16 is any amino acid or is absent, X 17 is any amino acid or is absent.

[0090] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 A peptide of formula (I), comprising (I): or a pharmaceutically acceptable salt thereof, wherein: X3 is any amino acid or is absent; X4 is any amino acid, X5 is any amino acid, X6 is any amino acid, X7,

[0091] [ka] and R A However, O, NH, NC(1~5) alkyl, or S; R B But, -H, halo, C (1~3) alkyl, or phenyl, where the phenyl is one -N(H)C(O)C (1~3) optionally substituted with alkyl groups; X8 is any amino acid; X9 is any amino acid, X 10 but,

[0092] [ka] and R C But -H or -C (1~3) is alkyl, R D -H, -OH, -CN, -C (1~3) Alkyl, -OC (1~3) Alkyl, -OC (1~3) alkyl-(5-membered heteroaryl), -C(O)NH2, or heterocyclyl, -OC (1~3) alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain and heterocyclyl optionally substituted with one -C(O)NH group; R E is —H or halo; R F But -C (1~6) an alkylene or divalent polyethylene glycol chain, R G But -H, -C (1~3) Alkyl, or X5 or X 13 is the bond to the amino acid R H But -H, -C (1~3) Alkyl, -C(NH)NH2, -C(O)-R H1 Or Or R G and R H together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, RH1 But -C (1~5) Alkyl, -OC (1~5) Alkyl, -C (1~3) Alkyl-phenyl, -phenyl-C (1~3) Alkyl-N(H)-S(O)2-C (1~3) ) alkyl or polyethylene glycol chain, -C (1~3) alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R J , R K , and R L However, each independently, C (1~3) Is it alkyl? or R J and R K together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, X 11 but,

[0093] [ka] and R M But halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3)haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X 12 is any amino acid, X 13 is any amino acid, X 14 is any amino acid, X 15 Ala, THP, or

[0094] [ka] and R Q But -H or -C (1~3) is alkyl, R S is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one -C(O)NH group; X 16 is any amino acid or is absent, X 17 is any amino acid or is absent, X 17 is any amino acid or is absent, The peptide is cyclized to form a first ring, the first ring containing 4 to 11 or 14 amino acids.

[0095] In some embodiments, the present disclosure provides a polypeptide having the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 A peptide of formula (I), comprising (I): or a pharmaceutically acceptable salt thereof, wherein: X3 is any amino acid or is absent; X4 is an amino acid linked to the amino acid of X9, X5 is any amino acid, X6 is any amino acid, X7,

[0096] [ka] and R A However, O, NH, NC (1~5) alkyl, or S; R B But, -H, halo, C (1~3) alkyl, or phenyl, where the phenyl is one -N(H)C(O)C (1~3) optionally substituted with alkyl groups; X8 is any amino acid; X9 is an amino acid linked to the amino acid of X4, X 10 but,

[0097] [ka] and R C But -H or -C (1~3) is alkyl, R D -H, -OH, -CN, -C (1~3) Alkyl, -OC (1~3) Alkyl, -OC (1~3) alkyl-(5-membered heteroaryl), -C(O)NH2, or heterocyclyl, -OC (1~3) alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain and heterocyclyl optionally substituted with one -C(O)NH group; R E is —H or halo; R FBut -C (1~6) an alkylene or divalent polyethylene glycol chain, R G But -H, -C (1~3) Alkyl, or X5 or X 13 is the bond to the amino acid R H But -H, -C (1~3) Alkyl, -C(NH)NH2, -C(O)-R H1 Or Or R G and R H together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, R H1 But -C (1~5) Alkyl, -OC (1~5) Alkyl, -C (1~3) Alkyl-phenyl, -phenyl-C (1~3) Alkyl-N(H)-S(O)2-C (1~3) ) alkyl or polyethylene glycol chain, -C (1~3) alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R J , R K , and R L However, each independently, C (1~3) Is it alkyl? or R J and R K together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, X 11 but,

[0098] [ka] and R M But halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C(1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X 12 is any amino acid, X 13 is any amino acid, X 14 is any amino acid, X 15 Ala, THP, or

[0099] [ka] and R Q But -H or -C (1~3) is alkyl, R S is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one -C(O)NH group; X 16 is any amino acid or is absent, X 17 is any amino acid or is absent.

[0100] In some embodiments, the peptide is not MeCO-Pen-NT-7MeW-K(Ac)-Pen-AEF-6OHQui-THP-EN-3Pya-Sar-CONH2.

[0101] The linear structures of formula (I) are intended for illustrative and non-limiting purposes, as will become apparent from the examples described and illustrated throughout this specification, and for example, 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.

[0102] In some embodiments, the peptide is R1-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (I-A1), X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -R2(I-A2), and R1-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -R2(I-A3), or a pharmaceutically acceptable salt thereof.

[0103] R1 represents the N-terminus of the peptide, which may be, for example, hydrogen or a chemical moiety or functional group (eg, an acetate group) substituted on the amino group.

[0104] 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 (e.g., an amino group, e.g., -CONH2, to provide a terminal amide).

[0105] In some embodiments, R1 is 5cpaCO, CF3CO, CF3Propylamide, EtCO, MeCO, a polyethylene glycol chain, or a lipophilic substituent; or R1 is alkyl, or X 13 a polyethylene glycol chain linked to an amino acid of R2 is CONH2, CO(DiFPip), CON(Me)2, a polyethylene glycol chain, or a lipophilic substituent.

[0106] In some embodiments, the peptide has the formula (I-A1): R1-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 The amino acid sequence of (I-A1), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5cpaCO, CF3CO, CF3Propylamide, EtCO, MeCO, a polyethylene glycol chain, or a lipophilic substituent, or R1 is alkyl, or X 13 is a polyethylene glycol chain linked to an amino acid.

[0107] In some embodiments, the peptide has the formula (I-A2): X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17-R2(I-A2) amino acid sequence, or a pharmaceutically acceptable salt thereof, wherein: R2 is CONH2, CO(DiFPip), CON(Me)2, a polyethylene glycol chain, or a lipophilic substituent.

[0108] In some embodiments, the peptide has the formula (I-A3): R1-X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -R2(I-A3) amino acid sequence, or a pharmaceutically acceptable salt thereof, wherein: R1 is 5cpaCO, CF3CO, CF3Propylamide, EtCO, MeCO, a polyethylene glycol chain, or a lipophilic substituent, or R1 is alkyl, or X 13 a polyethylene glycol chain linked to an amino acid of R2 is CONH2, CO(DiFPip), CON(Me)2, a polyethylene glycol chain, or a lipophilic substituent.

[0109] In some embodiments, the peptide comprises X and X 13 Between the amino acids X5 and X 10 Between the amino acids, X 10 and X 13 between the amino acids R1 and X 13 In some embodiments, the amino acid at X further comprises a linkage between the amino acid at X 13 In some embodiments, the amino acid of X is linked to an amino acid of X 10 In some embodiments, X 10 The amino acid in X 13 In some embodiments, R is linked to an amino acid of X 13 is linked to an amino acid.

[0110] In some embodiments, X3, X5, X6, X8, X 12 , X 13 , X 14 , X 16 , or X 17 In some embodiments, the amino acids X, X, X, X are conjugated to a polyethylene glycol chain. 12 , X 13 , X 14 , X 16 , or X 17 In some embodiments, the amino acids X, X, X, X are conjugated to a polyethylene glycol chain. 12 , X 13 , X 14 , X 16 , or X 17 is conjugated to a lipophilic substituent.

[0111] In some embodiments, the peptide has the amino acid sequence: R1-X3-X4-X5-T-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -NX 15 -X 16 -X 17 - an amino acid sequence of formula (IB) containing R2(IB), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, Z peg , or Z lipid and X3 is Dab(COCH2), K(COCH2CH2), hK(Me)3, K, K(5cpa), KZ peg , K.Z. lipid , K(d), K(Me)3, Ser(MePEG2), R, SP6 or absent; X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), KZ peg , K.Z. lipid , L, N, N(NMe), N(NMe2), Q, Q(NMe), or Q(NMe2); X7 is 7(3NacPh)W, 7BrW, 7MeW, BT, or W; X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z peg , K.Z. peg , K.Z. lipid , Lys(N+Me2)-Z peg , Q, or Q(NMe2), X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X 10 However, 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z peg , AEF(NMe)-Z peg , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y; X 11 but,

[0112] [ka] and R M But halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- or 6-membered heteroaryl, and phenyl and 5- or 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X 12 is THP, aMeL, diFCpx, or Pip(NMe2), X 13 are C, D, Dab(NMeAc), Dab(NMecarn), E, ​​E(COcPEG3a), hE, K(Ac), K(Me)3, K(NMeAc), KZ peg , K.Z. lipid , L, or Q(NMe2), X 15 is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP; X 16 However, Sar, NMeK-Z lipid or not present, X 17 But, KZ lipid , NMeK-Z lipid or not present, R2 is CONH2, CO(DiFPip), CON(Me)2, or Z peg and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z lipid is, independently at each occurrence, a lipophilic substituent; the peptide is cyclized via a linkage between residues X4 and X9, During the ceremony, (a) When R1 is 5Ava, 6Ahx, 7Ahp, PEG2, or PEG2NMe, the peptide is 13 and a residue selected from E or hE, (b) When X3 is Dab(COCH2), k(COCH2CH2), or Ser(MePEG2), and optionally when X3 is k, the peptide is 13 and a residue selected from C, D, or hE of (c) When X5 is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), or K(NNs), and optionally when X5 is KZ peg or KZ lipid If so, the peptide has residues X5 and X 10 or AEF(NMe), (d)X 10 is AEF or AEF(NMe), the peptide may optionally comprise X 10 residues and X5 D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), KZ peg , and K.Z. lipid or X 13 and further comprising a linkage between the E residue of (e)X 13 is C, D, or hE, and optionally, X 13 is E, the peptide is X 13 and R1 is a residue selected from 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe, or X3 is a residue selected from Dab(COCH2), k(COCH2CH2), k, and Ser(MePEG2), or X 10 and a linkage between the AEF residue of However, if the peptide is 13 , X3 and X 13 , X5 and X 10 , and X10 and X 13 provided that the term "contains no more than one link between any one of the following:

[0113] In some embodiments, the peptide has the formula (IC): R1-X3-X4-X5-T-X7-X8-X9-X 10 -X 11 -THP-X 13 -NX 15 -Sar-X 17 -Amino acid sequence of R2(IC), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5cpaCO, CF3CO, MeCO, Z peg , or Z lipid and X3 is hk(Me)3, k, kZ peg , kZ lipid , k(d), k(Me)3, KZ peg , K.Z. lipid , r, R, SP6 or absent; X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), KZ peg , K.Z. lipid , N, N(NMe2), Q, or Q(NMe2), X7 is 7(3NAcPh)W, 7MeW, or W; X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , K(Ac), K(NMeAc), NMeK-Z peg , K.Z. peg , K.Z. lipid , Q, or Q(NMe2), X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X 10 However, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Zpeg , AEF(NMe)-Z peg , bMeAEF, MMoEF, or TMAPF; X 11 is 2Nal6((5CF3)3Pyrazole), 6OH2Nal, 2Nal6(Ph2OH), 2Nal6(Ph4(NMorph)), 2Nal6(3Pyrazole), 2Nal6(4OMePh), 5OMe2Nal, 5amido2Nal, 5Br2Nal, 5Me2Nal, 6MeQui, 6O(COCF3)2Nal, 6F2Nal, 6Br2Nal, or 7OH2Nal; X 13 is Dab(NMeAc), Dab(NMecarn), E, ​​K(Ac), K(NMeAc), KZ peg , or KZ lipid and X 15 is 3Pya, 5MePyridinAla, or THP; X 17 But, KZ lipid , NMeK-Z lipid or not present, R2 is CONH2, CON(Me)2, or Z peg and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z lipid is, independently at each occurrence, a lipophilic substituent; The peptide is cyclized via a linkage between residues X4 and X9; and When X5 is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), or K(NNs), and optionally when X5 is KZ peg or KZ lipid If so, the peptide has residues X5 and X 10 or AEF(NMe).

[0114] In some embodiments, the peptide has the formula (ID): R1-X3-Pen-X5-T-X7-X8-Pen-X 10 -6OH2Nal-THP-X 13 -N-3Pya-Sar-X 17 - the amino acid sequence of R2(ID), or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO, Z peg , or Z lipid and X3, kZ peg , kZ lipid , k(Me)3, r or absent, X5 is D, E, hE, N, N(NMe2), Q, or Q(NMe2); X7 is 7(3NAcPh)W, 7MeW, or W; X8 is K(Ac), K(NMeAc), NMeK-Z peg , K.Z. peg , or KZ lipid and X 10 is AEF or TMAPF, X 13 But E, K(Ac), K(NMeAc), KZ peg , or KZ lipid and X 17 But, KZ lipid , NMeK-Z lipid or not present, R2 is CONH2, CON(Me)2, or Z peg and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z lipid is, independently at each occurrence, a lipophilic substituent; The peptide is cyclized via a linkage between the Pen residue of X4 and the Pen residue of X9; and When X5 is D, E, or hE, the peptide is 10 and the AEF residue of

[0115] In some embodiments, the peptide has the formula (IE): R1-X3-Pen-X5-T-7(3NAcPh)W-X8-Pen-X 10 -6OH2Nal-THP-X 13 -N-3Pya-Sar-X 17 -R2(IE) amino acid sequence, or a pharmaceutically acceptable salt thereof, wherein: R1 is MeCO or Z peg and X3 is r or absent; X5 is E, N, or N(NMe2), X8 is K(Ac) or K(NMeAc), X 10 is AEF or TMAPF, X 13 is E, K(Ac), or K(NMeAc), X 17 But, KZ lipid or not present, R2 is CONH2 or CON(Me)2, Z peg is, independently at each occurrence, a polyethylene glycol chain; Z lipid is, independently at each occurrence, a lipophilic substituent; The peptide is cyclized via a linkage between the Pen residue of X4 and the Pen residue of X9; and When X5 is E, the peptide is 10 and the AEF residue of

[0116] In some embodiments, the peptide has the formula (IB): R1-X3-X4-X5-T-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -NX 15 -X 16 -X 17 - the amino acid sequence of R2(IB), or a pharmaceutically acceptable salt thereof, wherein: R1 is 5cpaCO, CF3CO, CF3Propylamide, EtCO, MeCO, Z peg , or Z lipid and X3 is hk(Me)3, k, k(5cpa), kZ peg , kZ lipid , k(d), k(Me)3, KZ peg , K.Z. lipid , r, R, SP6 or absent; X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5, KZ peg , K.Z. lipid , L, N, N(NMe2), Q, or Q(NMe2); X7 is 7(3NAcPh)W, 7BrW, 7MeW, BT, or W; X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z peg , K.Z. peg , K.Z. lipid , Lys(N+Me2)-Z peg , Q, or Q(NMe2), X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X 10 However, 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z peg , AEF(NMe)-Z peg , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y; X 11 but,

[0117] [ka] and R M But halo, -OH, -C (1~3)Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- to 6-membered heteroaryl, and phenyl and 5- to 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocycle; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- to 6-membered heteroaryl, and phenyl and 5- to 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocycle; X 12 is THP, aMeL, diFCpx, or Pip(NMe2), X 13 is Dab(NMeAc), Dab(NMecarn), E, ​​E(COcPEG3a), K(Ac), K(Me)3, K(NMeAc), KZ peg , K.Z. lipid , L, or Q(NMe2), X 15 is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP; X 16 However, Sar, NMeK-Z lipid or not present, X 17 But, KZ lipid , NMeK-Z lipid or not present, R2 is CONH2, CO(DiFPip), CON(Me)2, or Zpeg and Z peg is, independently at each occurrence, a polyethylene glycol chain; Z lipid is, independently at each occurrence, a lipophilic substituent; The peptide is cyclized via the linkage between residues X4 and X9.

[0118] In some embodiments, the peptide has the formula (IF): R1-X3-X4-X5-T-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -NX 15 -X 16 -R2(IF), During the ceremony, R1 is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, or Z peg and X3 is Dabb(COCH2), k(COCH2CH2), hk(Me)3, k, k(5cpa), k(d), k(Me)3, Ser(MePEG2), r, R, SP6 or is absent; X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X5 is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), KZ peg , L, N, N(NMe), N(NMe2), Q, Q(NMe), or Q(NMe2); X7 is 7(3NAcPh)W, 7BrW, 7MeW, BT, or W; X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z peg , K.Z. peg , Lys(N+Me2)-Zpeg , Q, or Q(NMe2), X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X 10 However, 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z peg , AEF(NMe)-Z peg , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y; X 11 but,

[0119] [ka] and R M But halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- to 6-membered heteroaryl, and phenyl and 5- to 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH, R O But, -OC (1~3) alkyl or —C(O)NH; R P But halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- to 6-membered heteroaryl, and phenyl and 5- to 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X 12 is THP, aMeL, diFCpx, or Pip(NMe2), X13 are C, D, Dab(NMeAc), Dab(NMecarn), E, ​​E(COcPEG3a), hE, K(Ac), K(Me)3, K(NMeAc), KZ peg , L, or Q(NMe2), X 15 is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP; X 16 is Sar or absent, R2 is CONH2, CO(DiFPip), CON(Me)2, or Z peg and Z peg is, independently at each occurrence, polyethylene glycol; the peptide is cyclized via a linkage between residues X4 and X9, During the ceremony, (a) When R1 is 5Ava, 6Ahx, 7Ahp, PEG2, or PEG2NMe, the peptide is 13 and a residue selected from E or hE, (b) When X3 is Dab(COCH2), k(COCH2CH2), or Ser(MePEG2), and optionally when X3 is k, the peptide is 13 and a residue selected from C, D, or hE of (c) When X5 is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), or K(NNs), and optionally when X5 is KZ peg If so, the peptide has residues X5 and X 10 or AEF(NMe), (d)X 10 is AEF or AEF(NMe), the peptide may optionally comprise X 10 and X5 D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), and KZ pegor X 13 and further comprising a linkage between the E residue of (e)X 13 is C, D, or hE, and optionally, X 13 is E, the peptide is X 13 and R1 is a residue selected from 5Ava, 6Ahx, 7Ahp, PEG2, and PEg2NMe, or X3 is a residue selected from Dab(COCH2), k(COCH2CH2), k, and Ser(MePEG2), or X 10 and a linkage between the AEF residue of However, if the peptide is 13 , X3 and X 13 , X5 and X 10 , and X 10 and X 13 provided that the term "contains no more than one link between any one of the following:

[0120] In some embodiments, R1 is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, Z peg (i.e., polyethylene glycol chain), or Z lipid (i.e., lipophilic substituent), and 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe are X 13 In some embodiments, R1 is linked to an amino acid of 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, Z peg (i.e., polyethylene glycol chain), or Z lipid (i.e., lipophilic substituent), and 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe are linked to X via an amide linkage. 13 or hE.

[0121] In some embodiments, R1 is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, a polyethylene glycol chain, or a lipophilic substituent, and 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe are X 13 In some embodiments, R1 is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, a polyethylene glycol chain, or a lipophilic substituent, and 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe are linked to an amino acid of X through an amide linkage. 13 or hE.

[0122] In some embodiments, R1 is 5cpaCO, CF3CO, MeCO, Z peg (i.e., polyethylene glycol chain), or Z lipid (i.e., a lipophilic substituent). In some embodiments, R1 is 5cpaCO, CF3CO, MeCO, cPEG3aCO, or Z lipid In some embodiments, R1 is 5cpaCO, CF3CO, MeCO, or cPEG3aCO. In some embodiments, R1 is MeCO, Z peg , or Z lipid In some embodiments, R is MeCO or Z peg In some embodiments, R1 is MeCO or cPEG3aCO.

[0123] In some embodiments, R1 is 5cpaCO, CF3CO, CF3Propylamide, EtCO, MeCO, Z peg , or Z lipid In some embodiments, R1 is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, or Z peg5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe are linked to X via an amide linkage. 13 or hE.

[0124] In some embodiments, R is alkyl, or X 13 In some embodiments, R is a polyethylene glycol chain linked to an amino acid of X 13 In some embodiments, X is 5Ava linked to an amino acid of X 13 In some embodiments, R1 is 5cpaCO. In some embodiments, R1 is X 13 In some embodiments, R1 is 6Ahx linked to an amino acid of X 13 R1 is 6Ahx linked to E. 13 In some embodiments, R1 is 7Ahp linked to an amino acid of X 13 In some embodiments, R1 is CF3CO. In some embodiments, R1 is CF3Propylamide. In some embodiments, R1 is EtCO. In some embodiments, R1 is MeCO. In some embodiments, R1 is X 13 In some embodiments, R is PEG2 linked to an amino acid of X 13 In some embodiments, R is PEG linked to hE of X 13 In some embodiments, R is PEGNMe linked to an amino acid of X 13 In some embodiments, R is PEGNMe linked to hE of Z peg In some embodiments, R1 is a polyethylene glycol chain terminated with an ammonium or methyl group. In some embodiments, R1 is cPEG3aCO. In some embodiments, R1 is Z lipid , i.e., a lipophilic substituent.

[0125] In some embodiments, X3 is Dab(COCH2), Dab(NMeAc), Dab(NMecarn), Dab-Z peg , Dab-Z lipid , K(COCH2CH2), hK(Me)3), K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , Ser(MePEG2), R, SP6 or absent, and Dab(COCH2), K(COCH2CH2), and Ser(MePEG2) are X 13 is linked to an amino acid of

[0126] In some embodiments, X3 is Dab(COCH2), Dab(NMeAc), Dab(NMecarn), Dab-Z peg , Dab-Z lipid , K(COCH2CH2), hK(Me)3), K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , Ser(MePEG2), R, SP6 or absent, and Dab(COCH2), K(COCH2CH2), and Ser(MePEG2) are X 13 and Dab(COCH2), Dab(NMeAc), Dab(NMecarn), Dab-Z. peg , Dab-Z lipid , K(COCH2CH2), hK(Me)3), K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , Ser(MePEG2), and R are L amino acids.

[0127] In some embodiments, X3 is dDab(COCH2), dDab(NMeAc), dDab(NMecarn), dDab-Z peg , dDab-Z lipid , k(COCH2CH2), hk(Me)3), k, k(5cpa), k(Ac), k(d), k(G), k(Me)3, k(NMe), k(NMeAc), k(NNs), kZ peg , kZ lipid , NMek-Z peg , NMek-Z lipid , dSer(MePEG2), r, SP6 or absent, and dDab(COCH2), k(COCH2CH2), and dSer(MePEG2) are X 13 is linked to an amino acid of

[0128] In some embodiments, X3 is Dab(COCH2), k(COCH2CH2), hk(Me)3, k, k(5cpa), kZ peg , kZ lipid , k(d), k(Me)3, KZ peg , K.Z. lipid , Ser(MePEG2), r, R, SP6 or absent, and Dab(COCH2), k(COCH2CH2), and Ser(MePEG2) are X 13 In some embodiments, X3 is linked to an amino acid of the formula: peg , kZ lipid , k(d), k(Me)3, KZ peg , K.Z. lipid , r, R, SP6, or absent. In some embodiments, X3 is kZ peg , kZ lipid , k(Me)3, r, or absent. In some embodiments, X3 is r or absent.

[0129] In some embodiments, X3 is hk(Me)3, k, k(5cpa), kZ peg , kZ lipid , k(d), k(Me)3, KZ peg , K.Z.lipid In some embodiments, X3 is Dab(COCH2), k(COCH2CH2), hk(Me)3, k, k(5cpa), k(d), k(Me)3, Ser(MePEG2), r, R, SP6, or absent, and Dab(COCH2), k(COCH2CH2), and Ser(MePEG2) are X 13 is linked to an amino acid of

[0130] In some embodiments, X is X 13 In some embodiments, X is a Dab(COCH) linked to an amino acid of X 13 In some embodiments, X3 is a Dab(COCH2) linked to C of peg In some embodiments, X3 is Dab-Z lipid In some embodiments, X is X 13 In some embodiments, X is K(COCHCH) linked to an amino acid of X 13 In some embodiments, X3 is K(COCH2CH2) linked to C by . In some embodiments, X3 is hK(Me)3). In some embodiments, X3 is K. In some embodiments, X3 is K(5cpa). In some embodiments, X3 is K(Ac). In some embodiments, X3 is K(d). In some embodiments, X3 is K(G). In some embodiments, X3 is K(Me)3. In some embodiments, X3 is K(NMe). In some embodiments, X3 is K(NMeAc). In some embodiments, X3 is K(NNs). In some embodiments, X3 is KZ peg In some embodiments, X3 is KZ lipid In some embodiments, X3 is NMeK-Z peg In some embodiments, X3 is NMeK-Z lipidIn some embodiments, X is X 13 In some embodiments, X is Ser(MePEG2) linked to an amino acid of X 13 In some embodiments, X3 is Ser(MePEG2) linked to D of the formula: In some embodiments, X3 is R. In some embodiments, X3 is SP6. In some embodiments, X3 is absent.

[0131] In some embodiments, X is X 13 In some embodiments, X is a dDab(COCH) linked to an amino acid of X 13 In some embodiments, X3 is a dDab(COCH2) linked to C by . In some embodiments, X3 is a dDab(NMeAc). In some embodiments, X3 is a dDab(NMecarn). In some embodiments, X3 is a dDab-Z peg In some embodiments, X3 is dDab-Z lipid In some embodiments, X is X 13 In some embodiments, X is k(COCHCH) linked to an amino acid of X 13 In some embodiments, X3 is k(COCH2CH2) linked to C by a . In some embodiments, X3 is hk(Me)3). In some embodiments, X3 is k. In some embodiments, X3 is k(5cpa). In some embodiments, X3 is k(Ac). In some embodiments, X3 is k(d). In some embodiments, X3 is k(G). In some embodiments, X3 is k(Me)3. In some embodiments, X3 is k(NMe). In some embodiments, X3 is k(NMeAc). In some embodiments, X3 is k(NNs). In some embodiments, X3 is kZ peg In some embodiments, X3 is kZ lipid In some embodiments, X3 is NMek-Z peg In some embodiments, X3 is NMek-Z lipid In some embodiments, X is X13 In some embodiments, X is dSer(MePEG2) linked to an amino acid of X 13 In some embodiments, X3 is r.

[0132] In some embodiments, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra, each of which is an L-amino acid. In some embodiments, X4 is 4Amino-d-Pro, dAbu, d-aG, aMe-dC, c, dDap, dPen, dPen(oXyl), dPen(mXyl), dPen(pXyl), or dPra.

[0133] In some embodiments, X4 is 4AminoPro, aG, Dap, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra. In some embodiments, X4 is Abu, aMeC, C, Pen, Pen(oXyl), Pen(mXyl), or Pen(pXyl). In some embodiments, X4 is Abu, aMeC, C, or Pen. In some embodiments, X4 is Abu, C, or Pen. In some embodiments, X4 is Abu or Pen.

[0134] In some embodiments, X4 is 4AminoPro. In some embodiments, X4 is 4RAminoPro. In some embodiments, X4 is 4SAminoPro. In some embodiments, X4 is Abu. In some embodiments, X4 is aG. In some embodiments, X4 is aMeC. In some embodiments, X4 is C. In some embodiments, X4 is Dap. In some embodiments, X4 is Pen. In some embodiments, X4 is Pen(oXyl). In some embodiments, X4 is Pen(mXyl). In some embodiments, X4 is Pen(pXyl). In some embodiments, X4 is Pra.

[0135] In some embodiments, X4 is 4Amino-d-Pro. In some embodiments, X4 is 4RAmino-d-Pro. In some embodiments, X4 is 4SAmino-d-Pro. In some embodiments, X4 is dAbu. In some embodiments, X4 is d-aG. In some embodiments, X4 is aMe-dC. In some embodiments, X4 is c. In some embodiments, X4 is dDap. In some embodiments, X4 is dPen. In some embodiments, X4 is dPen(oXyl). In some embodiments, X4 is dPen(mXyl). In some embodiments, X4 is dPen(pXyl). In some embodiments, X4 is dPra.

[0136] In some embodiments, X5 is D, E, hE, K, K(5cpa), K(a), K(Ac), K(d), K(G), K(Me), K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid, L, N, N(NMe), N(NMe2), Q, Q(NMe), or Q(NMe2), and D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), and K(NNs) are X 10 and optionally linked to an amino acid of peg or KZ lipid is X 10 In some embodiments, X5 is linked to an amino acid of the formula: D, E, hE, K, K(5cpa), K(a), K(Ac), K(d), K(G), K(Me), K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , L, N, N(NMe), N(NMe2), Q, Q(NMe), or Q(NMe2), each of which is an L amino acid; D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), and K(NNs) are X 10 and optionally linked to an amino acid of peg or KZ lipid is X 10 In some embodiments, X5 is linked to an amino acid of the formula: d, e, he, k, k(5cpa), k(a), k(Ac), k(d), k(G), k(Me), k(NMe), k(NMeAc), k(NNs), kZ peg , kZ lipid , NMek-Z peg , NMek-Z lipid , l, n, n(NMe), n(NMe2), q, q(NMe), or q(NMe2), and d, e, he, k, k(a), k(Ac), k(d), k(G), k(NMe), and k(NNs) are X 10 and optionally kZ peg or kZ lipid is X 10 is linked to an amino acid of

[0137] In some embodiments, X5 is E, K, K(5cpa), K(a), K(Ac), K(d), K(G), K(Me), K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , L, N, N(NMe), or Q, and E, K, K(a), K(Ac), K(K(G), K(NMe), and K(NNs) are X 10 and optionally linked to an amino acid of peg or KZ lipid is X 10 In some embodiments, X5 is linked to an amino acid of the formula: D, E, hE, K, K(a), K(Ac), K(d), K(G), K(Nme), K(NNs), KZ peg , K.Z. lipid , L, N, N(NMe2), Q, or Q(NMe2), and D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), and K(NNs) are X 10 and optionally linked to an amino acid of peg or KZ lipid is X 10 In some embodiments, X5 is linked to an amino acid of the formula: E, K, K(a), K(Ac), K(d), K(G), K(Nme), K(NNs), KZ peg , K.Z. lipid , L, N, N(NMe2), Q, or Q(NMe2), and E, K, K(a), K(Ac), K(K(G), K(NMe), and K(NNs) are X 10 and optionally linked to an amino acid of peg or KZ lipid is X 10 In some embodiments, X5 is D, E, hE, N, N(NMe2), Q, or Q(NMe2), and D, E, and hE are linked to an amino acid of X 10 In some embodiments, X5 is E, N, or N(NMe2), and E is linked to an amino acid of X 10is linked to an amino acid of

[0138] In some embodiments, X5 is KZ peg , K.Z. lipid In some embodiments, X5 is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), L, N, N(NMe), N(NMe), Q, Q(NMe), or Q(NMe), and D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), and K(NNs) are X 10 is linked to an amino acid of

[0139] In some embodiments, X5 is X 10 In some embodiments, X is D-linked to an amino acid of X 10 In some embodiments, X is a D linked to an AEF of X 10 In some embodiments, X is a D linked to an AEF(NMe). 10 In some embodiments, X is E-linked to an amino acid of X 10 In some embodiments, X is an E linked to an AEF of X 10 In some embodiments, X is an E linked to an AEF(NMe) of X 10 In some embodiments, X is hE linked to an amino acid of X 10 In some embodiments, X5 is a hE linked to an AEF of X 10 hE linked to AEF(NMe).

[0140] In some embodiments, X5 is X 10 In some embodiments, X is a K linked to an amino acid of X 10 In some embodiments, X is a K linked to an AEF of X 10 In some embodiments, X is a K linked to an AEF(NMe). 10In some embodiments, X is K(a) linked to an amino acid of X 10 In some embodiments, X is K(a) linked to an AEF of X 10 In some embodiments, X is K(a) linked to AEF(NMe). 10 In some embodiments, X is K(Ac) linked to an amino acid of X 10 In some embodiments, X5 is K(Ac) linked to an AEF of X 10 In some embodiments, X5 is K(Ac) linked to AEF(NMe). 10 In some embodiments, X is linked to an amino acid of X 10 In some embodiments, X is K(d) linked to an AEF of X 10 In some embodiments, X is K(d) linked to AEF(NMe). 10 In some embodiments, X is a K(G) linked to an amino acid of X 10 In some embodiments, X is K(G) linked to an AEF of X 10 In some embodiments, X is a K(G) linked to an AEF(NMe). 10 In some embodiments, X is K(NMe) linked to an amino acid at X 10 In some embodiments, X is K(NMe) linked to an AEF of X 10 In some embodiments, X is K(NMe) linked to AEF(NMe). 10 In some embodiments, X is a K(NNs) linked to an amino acid of X 10 In some embodiments, X is K(NNs) linked to an AEF of X 10 is K(NNs) linked to AEF(NMe).

[0141] In some embodiments, X5 is KZ peg In some embodiments, X5 is X 10 KZ linked to the amino acidpeg In some embodiments, X5 is X 10 KZ linked to AEF peg In some embodiments, X5 is X 10 KZ connected to AEF(NMe) peg In some embodiments, X5 is KZ lipid In some embodiments, X5 is X 10 KZ linked to the amino acid lipid In some embodiments, X5 is X 10 KZ linked to AEF lipid In some embodiments, X5 is X 10 KZ connected to AEF(NMe) lipid In some embodiments, X5 is L. In some embodiments, X5 is N. In some embodiments, X5 is N(NMe). In some embodiments, X5 is N(NMe2). In some embodiments, X5 is Q. In some embodiments, X5 is Q(NMe). In some embodiments, X5 is Q(NMe2).

[0142] In some embodiments, X5 is X 10 In some embodiments, X is d linked to an amino acid of X 10 In some embodiments, X is linked to an AEF of X 10 In some embodiments, X is linked to AEF(NMe). 10 In some embodiments, X is linked to an amino acid of X 10 In some embodiments, X is linked to an AEF of X 10 In some embodiments, X is linked to AEF(NMe). 10 In some embodiments, X is linked to an amino acid of X 10 In some embodiments, X is linked to an AEF of X 10 This is he linked to AEF(NMe).

[0143] In some embodiments, X5 is X 10 In some embodiments, X is linked to an amino acid of X 10 In some embodiments, X is linked to an AEF of X 10 In some embodiments, X is linked to AEF(NMe). 10 In some embodiments, X is k(a) linked to an amino acid of X 10 In some embodiments, X is k(a) linked to an AEF of X 10 In some embodiments, X is k(a) linked to AEF(NMe). 10 In some embodiments, X is k(Ac) linked to an amino acid of X 10 In some embodiments, X5 is k(Ac) linked to an AEF of X 10 In some embodiments, X5 is k(Ac) linked to AEF(NMe). 10 In some embodiments, X is linked to an amino acid of X 10 In some embodiments, X is k(d) linked to an AEF of X 10 In some embodiments, X is k(d) linked to AEF(NMe). 10 In some embodiments, X is k(G) linked to an amino acid of X 10 In some embodiments, X is k(G) linked to an AEF of X 10 In some embodiments, X is k(G) linked to AEF(NMe). 10 In some embodiments, X is k(NMe) linked to an amino acid of X 10 In some embodiments, X is k(NMe) linked to an AEF of X 10 In some embodiments, X is k(NMe) linked to AEF(NMe). 10 In some embodiments, X is k(NNs) linked to an amino acid of X10 In some embodiments, X5 is k(NNs) linked to an AEF of X 10 k(NNs) connected to AEF(NMe).

[0144] In some embodiments, X5 is kZ peg In some embodiments, X5 is X 10 kZ linked to the amino acid peg In some embodiments, X5 is X 10 kZ linked to AEF peg In some embodiments, X5 is X 10 kZ linked to AEF(NMe) peg In some embodiments, X5 is kZ lipid In some embodiments, X5 is X 10 kZ linked to the amino acid lipid In some embodiments, X5 is X 10 kZ linked to AEF lipid In some embodiments, X5 is X 10 kZ linked to AEF(NMe) lipid In some embodiments, X5 is 1. In some embodiments, X5 is n. In some embodiments, X5 is n(NMe). In some embodiments, X5 is n(NMe2). In some embodiments, X5 is q. In some embodiments, X5 is q(NMe). In some embodiments, X5 is q(NMe2).

[0145] In some embodiments, X6 is T. In some embodiments, X6 is T, wherein T is an L-amino acid. In some embodiments, X6 is t.

[0146] In some embodiments, X7 is

[0147] [ka] and During the ceremony, R A is NH or S, R B -H, halo, C (1~3) alkyl, or phenyl, where phenyl is one -N(H)C(O)C (1~3) It is optionally substituted with an alkyl group.

[0148] In some embodiments, X7 is

[0149] [ka] is.

[0150] In some embodiments, X7 is

[0151] [ka] is.

[0152] In some embodiments, X7 is

[0153] [ka] is.

[0154] In some embodiments, R B is C (1~3) alkyl or phenyl, and phenyl is one -N(H)C(O)C (1~3) In some embodiments, R B is C (1~3) In some embodiments, R B is one -N(H)C(O)C (1~3) It is a phenyl substituted with an alkyl group.

[0155] In some embodiments, X7 is 7(3NacPh)W, 7BrW, 7MeW, BT, or W. In some embodiments, X7 is 7(3NacPh)W, 7BrW, 7MeW, BT, or W, each of which is an L-amino acid. In some embodiments, X7 is 7(3NacPh)w, 7Brw, 7Mew, dBT, or w.

[0156] In some embodiments, X7 is 7(3NAcPh)W or 7MeW.

[0157] In some embodiments, X7 is 7(3NacPh)W. In some embodiments, X7 is 7BrW. In some embodiments, X7 is 7MeW. In some embodiments, X7 is BT. In some embodiments, X7 is W.

[0158] In some embodiments, X7 is 7(3NacPh)w. In some embodiments, X7 is 7Brw. In some embodiments, X7 is 7Mew. In some embodiments, X7 is dBT. In some embodiments, X7 is w.

[0159] In some embodiments, X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , Dab-Z lipid , hK(Me)3, K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , Lys(N+Me2)-Z peg , Lys(N+Me2)-Z lipid , Q, or Q(NMe2). In some embodiments, X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , Dab-Z lipid, hK(Me)3, K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , Lys(N+Me2)-Z peg , Lys(N+Me2)-Z lipid , Q, or Q(NMe2), each of which is an L-amino acid. In some embodiments, X8 is dDab(NMeAc), dDab(NMecarn), dDab-Z peg , dDab-Z lipid , hk(Me)3, k, k(5cpa), k(Ac), k(d), k(G), k(Me)3, k(NMe), k(NMeAc), k(NNs), kZ peg , kZ lipid , NMek-Z peg , NMek-Z lipid , dLys(N+Me2)-Z peg , dLys(N+Me2)-Z lipid , q, or q(NMe2).

[0160] In some embodiments, X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z peg , K.Z. peg , K.Z. lipid , Lys(N+Me2)-Z peg , Q, or Q(NMe2).

[0161] In some embodiments, X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z peg , K.Z. peg , Lys(N+Me2)-Z peg , Q, or Q(NMe2). In some embodiments, X8 is Dab(NMeAc), Dab(NMecarn), Dab-Z peg, K(Ac), K(NMeAc), NMeK-Z peg , K.Z. peg , K.Z. lipid , Q, or Q(NMe2). In some embodiments, X8 is K(Ac), K(NMeAc), NMeK-Z peg , K.Z. peg , or KZ lipid In some embodiments, X8 is K(Ac) or K(NMeAc).

[0162] In some embodiments, X8 is Dab(NMeAc). In some embodiments, X8 is Dab(NMecarn). In some embodiments, X8 is Dab-Z peg In some embodiments, X8 is Dab-Z lipid In some embodiments, X8 is hK(Me)3. In some embodiments, X8 is K. In some embodiments, X8 is K(5cpa). In some embodiments, X8 is K(Ac). In some embodiments, X8 is K(d). In some embodiments, X8 is K(G). In some embodiments, X8 is K(Me)3. In some embodiments, X8 is K(NMe). In some embodiments, X8 is K(NMeAc). In some embodiments, X8 is K(NNs). In some embodiments, X8 is KZ peg In some embodiments, X8 is KZ lipid In some embodiments, X8 is NMeK-Z peg In some embodiments, X8 is NMeK-Z lipid In some embodiments, X8 is Lys(N+Me2)-Z peg In some embodiments, X8 is Lys(N+Me2)-Z lipid In some embodiments, X8 is Q. In some embodiments, X8 is Q(NMe2).

[0163] In some embodiments, X8 is dDab(NMeAc). In some embodiments, X8 is dDab(NMecarn). In some embodiments, X8 is dDab-Z peg In some embodiments, X8 is dDab-Z lipid In some embodiments, X8 is hK(Me)3. In some embodiments, X8 is k. In some embodiments, X8 is k(5cpa). In some embodiments, X8 is k(Ac). In some embodiments, X8 is k(d). In some embodiments, X8 is k(G). In some embodiments, X8 is k(Me)3. In some embodiments, X8 is k(NMe). In some embodiments, X8 is k(NMeAc). In some embodiments, X8 is k(NNs). In some embodiments, X8 is kZ peg In some embodiments, X8 is kZ lipid In some embodiments, X8 is NMek-Z peg In some embodiments, X8 is NMek-Z lipid In some embodiments, X8 is dLys(N+Me2)-Z peg In some embodiments, X8 is dLys(N+Me2)-Z lipid In some embodiments, X8 is q. In some embodiments, X8 is q(NMe2).

[0164] In some embodiments, X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3). In some embodiments, X9 is aMeC, aG, C, D, E, hE, Pen, or Dap(N3), each of which is an L-amino acid. In some embodiments, X9 is aMe-dC, d-aG, c, d, e, he, dPen, or dDap(N3).

[0165] In some embodiments, X9 is aG, D, E, hE, or Dap(N3). In some embodiments, X9 is aMeC, C, or Pen. In some embodiments, X9 is aMeC or Pen.

[0166] In some embodiments, X9 is aMeC. In some embodiments, X9 is aG. In some embodiments, X9 is C. In some embodiments, X9 is D. In some embodiments, X9 is E. In some embodiments, X9 is hE. In some embodiments, X9 is Pen. In some embodiments, X9 is Dap(N3).

[0167] In some embodiments, X9 is aMe-dC. In some embodiments, X9 is d-aG. In some embodiments, X9 is c. In some embodiments, X9 is d. In some embodiments, X9 is e. In some embodiments, X9 is he. In some embodiments, X9 is dPen. In some embodiments, X9 is dDap(N3).

[0168] In some embodiments, X 10 teeth,

[0169] [ka] and R C is -H or -C (1~3) is alkyl, R D -H, -OH, -CN, -C (1~3) Alkyl, -OC (1~3) Alkyl, -OC (1~3) alkyl-(5-membered heteroaryl), -C(O)NH2, or heterocyclyl, -OC (1~3)alkyl-(5-membered heteroaryl) is optionally substituted with a polyethylene glycol chain, and heterocyclyl is optionally substituted with one -C(O)NH group; R E is —H or halo, R F -C (1~6) an alkylene or divalent polyethylene glycol chain, R G -H, -C (1~3) Alkyl, or X5 or X 13 is the bond to the amino acid R H -H, -C (1~3) Alkyl, -C(NH)NH2, -C(O)-R H1 Or Or R G and R H together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, R H1 -C (1~5) Alkyl, -OC (1~5) Alkyl, -C (1~3) Alkyl-phenyl, -phenyl-C (1~3) Alkyl-N(H)-S(O)2-C (1~3) ) alkyl or polyethylene glycol chain, -C (1~3) alkyl-phenyl is optionally substituted with 1 to 3 groups selected from halo and —OH; R J , R K , and R L are each independently C (1~3) alkyl, and or R J and R K together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group.

[0170] In some embodiments, X 10 teeth,

[0171] [ka] is.

[0172] In some embodiments, X 10 teeth,

[0173] [ka] and During the ceremony, R C is -H or -C (1~3) is alkyl, R D -H, -OH, -CN, -C (1~3) Alkyl, -OC (1~3) Alkyl, -OC (1~3) alkyl-(5-membered heteroaryl), -C(O)NH2, or heterocyclyl, -OC (1~3) alkyl-(5-membered heteroaryl) is optionally substituted with a polyethylene glycol chain, and heterocyclyl is optionally substituted with one -C(O)NH group; R E is —H or halo.

[0174] In some embodiments, X 10 teeth,

[0175] [ka] is.

[0176] In some embodiments, X 10 teeth,

[0177] [ka] is.

[0178] In some embodiments, X 10 teeth,

[0179] [ka] is.

[0180] In some embodiments, X 10 teeth,

[0181] [ka] is.

[0182] In some embodiments, X 10 teeth,

[0183] [ka] is.

[0184] In some embodiments, R C is —H. In some embodiments, R C is -CH3.

[0185] In some embodiments, R D is -H, -OH, or -OC (1~3) It is alkyl.

[0186] In some embodiments, R E is —H. In some embodiments, R E is -F.

[0187] In some embodiments, X 10 teeth,

[0188] [ka] and During the ceremony, R C is -H or -C (1~3) is alkyl, R F -C (1~6) an alkylene or divalent polyethylene glycol chain, R G -H, -C (1~3) Alkyl, or X5 or X 13 is the bond to the amino acid R H -H, -C (1~3) Alkyl, -C(NH)NH2, -C(O)-R H1 Or Or R G and R H together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group, R H1 -C (1~5) Alkyl, -OC (1~5) Alkyl, -C (1~3) Alkyl-phenyl, -phenyl-C (1~3) Alkyl-N(H)-S(O)2-C (1~3) ) alkyl or polyethylene glycol chain, -C (1~3) The alkyl-phenyl is optionally substituted with 1 to 3 groups selected from halo and —OH.

[0189] In some embodiments, X 10 teeth,

[0190] [ka] is.

[0191] In some embodiments, X 10 teeth,

[0192] [ka] is.

[0193] In some embodiments, X 10 teeth,

[0194] [ka] is.

[0195] In some embodiments, R C is —H. In some embodiments, R C is -CH3.

[0196] In some embodiments, R F -C (1~6) In some embodiments, R is alkylene. F is a divalent polyethylene glycol chain having 1 to 12 polyethylene glycol units. In some embodiments, R F is a divalent polyethylene glycol chain having 1 to 8 polyethylene glycol units. In some embodiments, R F is a divalent polyethylene glycol chain having 1 to 4 polyethylene glycol units.

[0197] In some embodiments, R G is —H. In some embodiments, R G is —CH3. In some embodiments, R G is X5 or X 13 In some embodiments, R G is the bond to an amino acid of X5. In some embodiments, R G is X 13 is the binding to an amino acid.

[0198] In some embodiments, R H is —H. In some embodiments, R H is —CH3. In some embodiments, R H is -C(O)-R H1 is.

[0199] In some embodiments, R H1 is a polyethylene glycol chain. In some embodiments, R H1 is a polyethylene glycol chain terminated with an ammonium or methyl group.

[0200] In some embodiments, X 10 teeth,

[0201] [ka] During the ceremony, R C is -H or -C (1~3) is alkyl, R F -C (1~6) an alkylene or divalent polyethylene glycol chain, R J , R K , and R L However, each independently, C (1~3) Is it alkyl? or R J and R K together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group.

[0202] In some embodiments, X 10 teeth,

[0203] [ka] is.

[0204] In some embodiments, X 10 teeth,

[0205] [ka] is.

[0206] In some embodiments, X 10 teeth,

[0207] [ka] is.

[0208] In some embodiments, R Cis —H. In some embodiments, R C is -CH3.

[0209] In some embodiments, R F -C (1~6) In some embodiments, R is alkylene. F is a divalent polyethylene glycol chain having 1 to 12 polyethylene glycol units. In some embodiments, R F is a divalent polyethylene glycol chain having 1 to 8 polyethylene glycol units. In some embodiments, R F is a divalent polyethylene glycol chain having 1 to 4 polyethylene glycol units.

[0210] In some embodiments, R J , R K , and R L are each independently methyl.

[0211] In some embodiments, X 10 are 3FTyr, 4AmF, 4CNF, 4DMPzEF, 4OMeF, 4MeF, 4PipPhe, AEF, AEF(Ac), AEF(BH), AEF(Boc), AEF(EtCO), AEF(G), AEF(NMe), AEF(NMe2), AEF(NMe3), AEF(SMSB), AEF-Z peg , AEF(NMe)-Z peg , APEG3F, bMeAEF, F, MMoEF, TMAPF, Y, Y(OTzl), or Y(OTzl(mPEG3)), and optionally AEF or AEF(NMe) is an amino acid at X5 or X 13 In some embodiments, X 10 are 3FTyr, 4AmF, 4CNF, 4DMPzEF, 4OMeF, 4MeF, 4PipPhe, AEF, AEF(Ac), AEF(BH), AEF(Boc), AEF(EtCO), AEF(G), AEF(NMe), AEF(NMe2), AEF(NMe3), AEF(SMSB), AEF-Z peg , AEF(NMe)-Zpeg , APEG3F, bMeAEF, F, MMoEF, TMAPF, Y, Y(OTzl), or Y(OTzl(mPEG3)), each of which is an L-amino acid, and optionally AEF or AEF(NMe) is an amino acid of X or X 13 In some embodiments, X 10 are 3F-d-Tyr, d-4AmF, d-4CNF, d-4DMPzEF, d-4OMeF, d-4MeF, 4Pip-d-Phe, dAEF, dAEF(Ac), dAEF(B H), dAEF(Boc), dAEF(EtCO), dAEF(G), dAEF(NMe), dAEF(NMe2), dAEF(NMe3), dAEF(SMSB), dAEF-Z peg , dAEF(NMe)-Z peg , dAPEG3F, d-bMeAEF, f, dMMoEF, dTMAPF, y, y(OTzl), or y(OTzl(mPEG3)), and optionally dAEF or dAEF(NMe) is an amino acid of X5 or X 13 is linked to an amino acid of

[0212] In some embodiments, X 10 are 3FTyr, 4AmF, 4CNF, 4DMPzEF, 4OMeF, 4MeF, 4PipPhe, AEF, AEF(Ac), AEF(BH), AEF(Boc), AEF(EtCO), AEF(G), AEF(NMe), AEF(NMe2), AEF(NMe3), AEF(SMSB), AEF-Z peg , AEF(NMe)-Z peg , APEG3F, bMeAEF, F, MMoEF, TMAPF, Y, Y(OTzl), or Y(OTzl(mPEG3)).

[0213] In some embodiments, X 10 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z peg , AEF(NMe)-Z peg, APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y, and optionally AEF or AEF(NMe) is an amino acid at X5 or X 13 In some embodiments, X 10 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z peg , AEF(NMe)-Z peg , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y.

[0214] In some embodiments, X 10 are AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z peg , AEF(NMe)-Z peg , bMeAEF, MMoEF, or TMAPF, and optionally AEF or AEF(NMe) is an amino acid at X5 or X 13 In some embodiments, X 10 is AEF or TMAPF, and optionally AEF is X5 amino acid or X 13 In some embodiments, X 10 is AEF or TMAPF.

[0215] In some embodiments, X 10 is 3FTyr. In some embodiments, X 10 In some embodiments, X is 4AmF. 10 is 4CNF. In some embodiments, X 10 In some embodiments, X is 4DMPzEF. 10 is 4OMeF. In some embodiments, X 10 is 4MeF. In some embodiments, X 10 is 4PipPhe. In some embodiments, X 10 is AEF. In some embodiments, X 10is an AEF linked to the amino acid of X5. 10 is an AEF linked to the E of X5. 10 is an AEF linked to K of X5. In some embodiments, X 10 is an AEF linked to K(a) of X5. In some embodiments, X 10 is an AEF linked to K(Ac) of X5. In some embodiments, X 10 is an AEF linked to K(d) of X5. In some embodiments, X 10 is an AEF linked to the K(G) of X5. In some embodiments, X 10 is an AEF linked to the K(NMe) of X5. 10 is an AEF linked to K(NNs) of X5. In some embodiments, X 10 is the KZ of the X5 peg In some embodiments, X is an AEF linked to 10 is the KZ of the X5 lipid In some embodiments, X is an AEF linked to 10 is X 13 In some embodiments, X is an AEF linked to an amino acid of 10 is X 13 In some embodiments, X is an AEF linked to E. 10 is AEF(Ac). In some embodiments, X 10 is AEF(BH). In some embodiments, X 10 is AEF(Boc). In some embodiments, X 10 is AEF(EtCO). In some embodiments, X 10 is AEF(G). In some embodiments, X 10 is AEF(NMe). In some embodiments, X 10 is AEF(NMe) linked to the amino acid of X5. 10 is X 13In some embodiments, X is AEF(NMe) linked to an amino acid of 10 is AEF(NMe2). In some embodiments, X 10 is AEF(NMe). In some embodiments, X 10 is AEF(SMSB). In some embodiments, X 10 is AEF-Z peg In some embodiments, X 10 is AEF(NMe)-Z peg In some embodiments, X 10 In some embodiments, X is APEG3F. 10 In some embodiments, X is bMeAEF. 10 is F. In some embodiments, X 10 In some embodiments, X is MMoEF. 10 In some embodiments, X is TMAPF. 10 is Y. In some embodiments, X 10 is Y(OTzl). In some embodiments, X 10 is Y(OTzl(mPEG3)).

[0216] In some embodiments, X 10 is F-d-Tyr. In some embodiments, X 10 is d-4AmF. In some embodiments, X 10 is d-4CNF. In some embodiments, X 10 is d-4DMPzEF. In some embodiments, X 10 is d-4OMeF. In some embodiments, X 10 is d-4MeF. In some embodiments, X 10 is 4Pip-d-Phe. In some embodiments, X 10 In some embodiments, X is dAEF. 10 is dAEF linked to the amino acid of X5. 10is dAEF linked to the E of X5. 10 is a dAEF linked to the K of X5. 10 is dAEF linked to K(a) of X5. In some embodiments, X 10 is dAEF linked to K(Ac) of X5. In some embodiments, X 10 is dAEF linked to K(d) of X5. In some embodiments, X 10 is a dAEF linked to the K(G) of X5. In some embodiments, X 10 is dAEF linked to K(NMe) of X5. In some embodiments, X 10 is a dAEF linked to K(NNs) of X5. In some embodiments, X 10 is the KZ of the X5 peg In some embodiments, X is a dAEF linked to 10 is the KZ of the X5 lipid In some embodiments, X is a dAEF linked to 10 is X 13 In some embodiments, X is dAEF linked to an amino acid of 10 is X 13 In some embodiments, X is dAEF linked to E. 10 is dAEF(Ac). In some embodiments, X 10 is dAEF(BH). In some embodiments, X 10 is dAEF(Boc). In some embodiments, X 10 is dAEF(EtCO). In some embodiments, X 10 is dAEF(G). In some embodiments, X 10 is dAEF(NMe). In some embodiments, X 10 is dAEF(NMe) linked to amino acid X5. 10 is X 13 In some embodiments, X is dAEF(NMe) linked to an amino acid of 10is dAEF(NMe2). In some embodiments, X 10 is dAEF(NMe3). In some embodiments, X 10 is dAEF(SMSB). In some embodiments, X 10 dAEF-Z peg In some embodiments, X 10 dAEF(NMe)-Z peg In some embodiments, X 10 In some embodiments, X is dAPEG3F. 10 In some embodiments, X is d-bMeAEF. 10 is f. In some embodiments, X 10 In some embodiments, X is dMMoEF. 10 In some embodiments, X is dTMAPF. 10 is y. In some embodiments, X 10 is y(OTzl). In some embodiments, X 10 is y(OTzl(mPEG3)).

[0217] In some embodiments, X 10 teeth,

[0218] [ka] and During the ceremony, A is,

[0219] [ka] and R aa are -OCHF2, -O(CH2)9CO2H,

[0220] [ka] and R bbis -H, -CH3, -C(O)CH3, -C(NH)NH2, -(CH2)3O(CH2)2OCH3, -CH2CH2OCH3, -(CH2CH2O)3CH3, -(CH2CH2O)6CH3,

[0221] [ka] and R cc are -H, -CH3, -(CH2)3O(CH2)2OCH3,

[0222] [ka] and n1 is 1, 2, or 3; R dd teeth,

[0223] [ka] and n2 is 1, 2, 3, 4, or 5; R gg is -OCH3,

[0224] [ka] and n3 is 3, 4, 5, 6, or 8; R hh are -H, -(CH2)7CH3, -(CH2) 15 CH3, -(CH2)2OCH3, or -(CH2CH2O)3CH3.

[0225] In some embodiments, X 10 teeth,

[0226] [ka] is.

[0227] In some embodiments, X 11 teeth,

[0228] [ka] is.

[0229] In some embodiments, X 11 teeth,

[0230] [ka] and During the ceremony, R M are halo, -OH, -C (1~3) Alkyl, -OC(O)C (1~3) haloalkyl, phenyl, or 5- to 6-membered heteroaryl, and phenyl and 5- to 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R N is —H or —OH.

[0231] In some embodiments, X 11 teeth,

[0232] [ka] is.

[0233] In some embodiments, X 11 teeth,

[0234] [ka] is.

[0235] In some embodiments, X 11 teeth,

[0236] [ka] is.

[0237] In some embodiments, X 11 teeth,

[0238] [ka] is.

[0239] In some embodiments, X 11 teeth,

[0240] [ka] is.

[0241] In some embodiments, X 11 teeth,

[0242] [ka] is.

[0243] In some embodiments, X 11 teeth,

[0244] [ka] is.

[0245] In some embodiments, X 11 teeth,

[0246] [ka] is.

[0247] In some embodiments, X 11 teeth,

[0248] [ka] is.

[0249] In some embodiments, X 11 teeth,

[0250] [ka] is.

[0251] In some embodiments, X 11 teeth,

[0252] [ka] is.

[0253] In some embodiments, X 11 teeth,

[0254] [ka] is.

[0255] In some embodiments, X 11 teeth,

[0256] [ka] is.

[0257] In some embodiments, X 11 teeth,

[0258] [ka] is.

[0259] In some embodiments, X 11 teeth,

[0260] [ka] is.

[0261] In some embodiments, X 11 teeth,

[0262] [ka] is.

[0263] In some embodiments, X 11 teeth,

[0264] [ka] is.

[0265] In some embodiments, R M is —OH, —CH, —OC(O)CF, phenyl, or 5-membered heteroaryl, wherein phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1-3 groups selected from —OH, —OCH, —CF, and 6-membered heterocyclyl. In some embodiments, R M is -OH.

[0266] In some embodiments, R N is —H. In some embodiments, R N is -OH.

[0267] In some embodiments, X 11 teeth,

[0268] [ka] and In the formula, R O -OC (1~3) It is alkyl or —C(O)NH2.

[0269] In some embodiments, R O -OC(1~3) In some embodiments, R O is -C(O)NH2.

[0270] In some embodiments, X 11 teeth,

[0271] [ka] is.

[0272] In some embodiments, X 11 teeth,

[0273] [ka] and In the formula, R P are halo, -OH, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- to 6-membered heteroaryl, and phenyl and 5- to 6-membered heteroaryl are each -OH, -OC (1~3) Alkyl, -C (1~3) It is optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl.

[0274] In some embodiments, X 11 teeth,

[0275] [ka] is.

[0276] In some embodiments, X 11 teeth,

[0277] [ka] is.

[0278] In some embodiments, X 11 teeth,

[0279] [ka] is.

[0280] In some embodiments, X 11 teeth,

[0281] [ka] is.

[0282] In some embodiments, X 11 teeth,

[0283] [ka] is.

[0284] In some embodiments, X 11 teeth,

[0285] [ka] is.

[0286] In some embodiments, X 11 teeth,

[0287] [ka] is.

[0288] In some embodiments, X 11 teeth,

[0289] [ka] is.

[0290] In some embodiments, X 11 teeth,

[0291] [ka] is.

[0292] In some embodiments, X 11 teeth,

[0293] [ka] is.

[0294] In some embodiments, X 11 teeth,

[0295] [ka] is.

[0296] In some embodiments, X 11 teeth,

[0297] [ka] is.

[0298] In some embodiments, X 11 teeth,

[0299] [ka] is.

[0300] In some embodiments, R P Halo, -C (1~3) Alkyl, -OC (1~3) Alkyl, -C(O)NH2, -OC(O)C (1~3) haloalkyl, phenyl, or 5- to 6-membered heteroaryl, and phenyl and 5- to 6-membered heteroaryl are each -OH, -OC (1~3)Alkyl, -C (1~3) and optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl. P is -OH or -OC (1~3) In some embodiments, R P is —OH. In some embodiments, R P -OC (1~3) It is alkyl.

[0301] In some embodiments, X 11 is 2Nal((5CF)Pyrazole), 6OHNal, 6OHQui, 2Nal(PhOH), 2Nal(Ph(NMorph)), 2Nal(3Pyrazole), 2Nal(4OMePh), 5OMeNal, 5amidoNal, 5BrNal, 5MeNal, 6MeQui, 6O(COCF)Nal, 6FNal, 6BrNal, or 7OHNal. In some embodiments, X 11 is 2Nal((5CF)Pyrazole), 6OHNal, 6OHQui, 2Nal(PhOH), 2Nal(Ph(NMorph)), 2Nal(3Pyrazole), 2Nal(4OMePh), 5OMeNal, 5amidoNal, 5BrNal, 5MeNal, 6MeQui, 6O(COCF)Nal, 6FNal, 6BrNal, or 7OHNal, each of which is an L-amino acid. 11 are d-2Nal6((5CF3)3Pyrazole), d-6OH2Nal, d-6OHQui, d-2Nal6(Ph2OH), d-2Nal6(Ph4(NMorph)), d-2Nal6(3Pyrazole), d-2Nal6(4 OMePh), d-5OMe2Nal, d-5amido2Nal, d-5Br2Nal, d-5Me2Nal, d-6MeQui, d-6O(COCF3)2Nal, d-6F2Nal, d-6Br2Nal, or d-7OH2Nal.

[0302] In some embodiments, X11 is 2Nal((5CF)Pyrazole), 6OHNal, 2Nal(PhOH), 2Nal(Ph(NMorph)), 2Nal(3Pyrazole), 2Nal(4OMePh), 5OMeNal, 5amidoNal, 5BrNal, 5MeNal, 6MeQui, 6O(COCF)Nal, 6FNal, 6BrNal, or 7OHNal. In some embodiments, X 11 is 2Nal6((5CF3)3Pyrazole), 6OH2Nal, 2Nal6(Ph2OH), 2Nal6(Ph4(NMorph)), 2Nal6(3Pyrazole), 2Nal6(4OMePh), 5Br2Nal, 5Me2Nal, 6O(COCF3)2Nal, 6F2Nal, 6Br2Nal, or 7OH2Nal.

[0303] In some embodiments, X 11 is 2Nal6((5CF3)3Pyrazole). In some embodiments, X 11 is 6OHNal. In some embodiments, X 11 is 6OHQui. In some embodiments, X 11 is 2Nal(PhOH). In some embodiments, X 11 is 2Nal6(Ph4(NMorph)). In some embodiments, X 11 is 2Nal6(3Pyrazole). In some embodiments, X 11 is 2Nal6(4OMePh). In some embodiments, X 11 is 5OMe2Nal. In some embodiments, X 11 In some embodiments, X is 5amido2Nal. 11 is 5BrNal. In some embodiments, X 11 is 5Me2Nal. In some embodiments, X 11 is 6MeQui. In some embodiments, X 11 is 6O(COCF3)2Nal. In some embodiments, X 11is 6F2Nal. In some embodiments, X 11 is 6Br2Nal. In some embodiments, X 11 is 7OH2Nal.

[0304] In some embodiments, X 11 is d-2Nal((5CF)Pyrazole). In some embodiments, X 11 is d-6OHNal. In some embodiments, X 11 is d-6OHQui. In some embodiments, X 11 is d-2Nal(PhOH). In some embodiments, X 11 is d-2Nal6(Ph4(NMorph)). In some embodiments, X 11 is d-2Nal6(3Pyrazole). In some embodiments, X 11 is d-2Nal6(4OMePh). In some embodiments, X 11 is d-5OMe2Nal. In some embodiments, X 11 is d-5amido2Nal. In some embodiments, X 11 is d-5BrNal. In some embodiments, X 11 is d-5Me2Nal. In some embodiments, X 11 is d-6MeQui. In some embodiments, X 11 is d-6O(COCF3)2Nal. In some embodiments, X 11 is d-6F2Nal. In some embodiments, X 11 is d-6BrNal. In some embodiments, X 11 is d-7OH2Nal.

[0305] In some embodiments, X 12 is THP, aMeL, diFCpx, or Pip(Nme2). 12is THP, aMeL, diFCpx, or Pip(Nme2), and aMeL is an L-amino acid. 12 is THP, aMel, diFCpx, or Pip(Nme2).

[0306] In some embodiments, X 12 is THP. In some embodiments, X 12 In some embodiments, X is aMeL. 12 In some embodiments, X is aMel. 12 In some embodiments, X is diFCpx. 12 is Pip(Nme2).

[0307] In some embodiments, X 13 are C, D, Dab(NMeAc), Dab(NMecarn), Dab-Z peg , Dab-Z lipid , E, E(COcPEG3a), hE, K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , L, or Q(NMe2), and C, D, and hE are R1, X3 amino acids, or X 10 and optionally E is linked to an amino acid of R, an amino acid of X, or X 10 In some embodiments, X 13 are C, D, Dab(NMeAc), Dab(NMecarn), Dab-Z peg , Dab-Z lipid , E, E(COcPEG3a), hE, K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid, L, or Q(NMe2), each of which is an L-amino acid, and C, D, and hE are R1, X3 amino acids, or X 10 and optionally E is linked to an amino acid of R, an amino acid of X, or X 10 In some embodiments, X 13 are c, d, dDab(NMeAc), dDab(NMecarn), dDab-Z peg , dDab-Z lipid , e, e(COcPEG3a), he, k, k(5cpa), k(Ac), k(d), k(G), k(Me)3, k(NMe), k(NMeAc), k(NNs), kZ peg , kZ lipid , NMek-Z peg , NMek-Z lipid , l, or q(NMe2), and c, d, and he are amino acids of R1, X3, or X 10 and optionally, e is linked to an amino acid of R, an amino acid of X, or X. 10 is linked to an amino acid of

[0308] In some embodiments, X 13 are C, D, Dab(NMeAc), Dab(NMecarn), E, ​​E(COcPEG3a), hE, K(Ac), K(Me)3, K(NMeAc), KZ peg , K.Z. lipid , L, or Q(NMe2), and C, D, and hE are R1, X3 amino acids, or X 10 and optionally E is linked to an amino acid of R, an amino acid of X, or X 10 In some embodiments, X 13 is Dab(NMeAc), Dab(NMecarn), E, ​​K(Ac), K(NMeAc), KZ peg , or KZ lipid In some embodiments, X 13 are E, K(Ac), K(NMeAc), KZ peg , or KZ lipidIn some embodiments, X 13 is E, K(Ac), or K(NMeAc). In some embodiments, X 13 is E or K(Ac).

[0309] In some embodiments, X 13 are Dab(NMeAc), Dab(NMecarn), Dab-Z peg , Dab-Z lipid , E, E(COcPEG3a), K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid , L, or Q(NMe2). In some embodiments, X 13 are Dab(NMeAc), Dab(NMecarn), E, ​​E(COcPEG3a), K(Ac), K(Me)3, K(NMeAc), KZ peg , K.Z. lipid , L, or Q(NMe2).

[0310] In some embodiments, X 13 are C, D, Dab(NMeAc), Dab(NMecarn), Dab-Z peg , E, E(COcPEG3a), hE, K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), KZ peg , NMeK-Z peg , L, or Q(NMe2), and C, D, and hE are R1, X3 amino acids, or X 10 and optionally E is linked to an amino acid of R, an amino acid of X, or X 10 In some embodiments, X 13 are C, D, Dab(NMeAc), Dab(NMecarn), E, ​​E(COcPEG3a), hE, K(Ac), K(Me)3, K(NMeAc), KZ peg, L, or Q(NMe2), and C, D, and hE are R1, X3 amino acids, or X 10 and optionally E is linked to an amino acid of R, an amino acid of X, or X 10 is linked to an amino acid of

[0311] In some embodiments, X 13 is C-linked to the amino acid of X3. 13 is C-linked to dK(COCHCH) at X3. In some embodiments, X 13 is a C linked to the dab(COCH) of X. In some embodiments, X 13 is D-linked to the amino acid of X3. 13 is D linked to ser(MePEG2) of X3. In some embodiments, X13 is Dab(NMeAc). In some embodiments, X 13 is Dab(NMecarn). In some embodiments, X 13 Dab-Z peg In some embodiments, X 13 Dab-Z lipid In some embodiments, X 13 is E. In some embodiments, X 13 is E linked to R. In some embodiments, X 13 is an E linked to the 5A of R1. In some embodiments, X 13 is E linked to 6Ahx of R1. In some embodiments, X 13 is E linked to 7Ahp of R1. In some embodiments, X 13 is E-linked to the amino acid of X3. 13 is X 10 In some embodiments, X is E-linked to an amino acid of 13 is X 10 In some embodiments, X is an E linked to an AEF of 13is E(COcPEG3a). In some embodiments, X 13 In some embodiments, X is hE. 13 is hE linked to R1. In some embodiments, X 13 is hE linked to PEG2 of R1. In some embodiments, X 13 is hE linked to the PEG2NMe of R1. In some embodiments, X 13 is hE linked to the amino acid of X3. In some embodiments, X 13 is hE linked to K of X3. In some embodiments, X 13 is K. In some embodiments, X 13 is K(5 cpa). In some embodiments, X 13 is K(Ac). In some embodiments, X 13 is K(d). In some embodiments, X 13 is K(G). In some embodiments, X 13 is K(Me). In some embodiments, X 13 is K(NMe). In some embodiments, X 13 is K(NMeAc). In some embodiments, X 13 is K(NNs). In some embodiments, X 13 is KZ peg In some embodiments, X 13 is KZ lipid In some embodiments, X 13 is NMeK-Z peg In some embodiments, X 13 is NMeK-Z lipid In some embodiments, X 13 is L. In some embodiments, X 13 is Q(NMe2).

[0312] In some embodiments, X 13 is c-linked to the amino acid of X3. 13is c-linked to dK(COCH2CH2) at X3. In some embodiments, X 13 is c linked to the dab(COCH) of X. In some embodiments, X 13 is d linked to the amino acid of X3. 13 is d linked to ser(MePEG2) of X3. In some embodiments, X 13 is dDab(NMeAc). In some embodiments, X 13 is dDab(NMecarn). In some embodiments, X 13 dDab-Z peg In some embodiments, X 13 dDab-Z lipid In some embodiments, X 13 is e. In some embodiments, X 13 is e linked to R. In some embodiments, X 13 is linked to the 5A of R. In some embodiments, X 13 is e linked to 6Ahx of R1. In some embodiments, X 13 is e linked to 7Ahp of R1. In some embodiments, X 13 is e linked to the amino acid of X3. 13 is X 10 In some embodiments, X is linked to an amino acid of 13 is X 10 In some embodiments, X is linked to an AEF of 13 is e(COcPEG3a). In some embodiments, X 13 In some embodiments, X 13 is linked to R1. In some embodiments, X 13 is linked to PEG2 of R1. In some embodiments, X 13 is he linked to the PEG2NMe of R1. In some embodiments, X 13is he linked to the amino acid of X3. In some embodiments, X 13 is linked to K at X3. In some embodiments, X 13 is k. In some embodiments, X 13 is k(5cpa). In some embodiments, X 13 is k(Ac). In some embodiments, X 13 is k(d). In some embodiments, X 13 is k(G). In some embodiments, X 13 is k(Me). In some embodiments, X 13 is k(NMe). In some embodiments, X 13 is k(NMeAc). In some embodiments, X 13 is k(NNs). In some embodiments, X 13 is kZ peg In some embodiments, X 13 is kZ lipid In some embodiments, X 13 NMek-Z peg In some embodiments, X 13 NMek-Z lipid In some embodiments, X 13 is 1. In some embodiments, X 13 is q(NMe2).

[0313] In some embodiments, X 14 is N. In some embodiments, X 14 is N, and N is an L-amino acid. 14 is n.

[0314] In some embodiments, X 15 is

[0315] [ka] During the ceremony, RQ is -H or -C (1~3) is alkyl, R S is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one -C(O)NH2 group.

[0316] In some embodiments, X 15 teeth,

[0317] [ka] is.

[0318] In some embodiments, X 15 teeth,

[0319] [ka] is.

[0320] In some embodiments, X 15 teeth,

[0321] [ka] is.

[0322] In some embodiments, R Q is —H. In some embodiments, R Q is -CH3.

[0323] In some embodiments, R S is phenyl optionally substituted with one —C(O)NH group. In some embodiments, R S is a 5-6 membered heteroaryl, which is optionally substituted with one -C(O)NH2 group.

[0324] In some embodiments, X 15is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP. 15 is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP, and 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, and H are L-amino acids. 15 is 3AmPyrazol-d-Ala, d-3Pya, d-5AmPyridinAla, d-5MePyridinAla, dAla, dACIPA, aMe-d-Phe, h, or THP.

[0325] In some embodiments, X 15 In some embodiments, X is 3AmPyrazolAla. 15 In some embodiments, X is 3Pya. 15 In some embodiments, X is 5AmPyridinAla. 15 is 5MePyridinAla. In some embodiments, X 15 is Ala. In some embodiments, X 15 is ACIPA. In some embodiments, X 15 In some embodiments, X is aMePhe. 15 is H. In some embodiments, X 15 is THP.

[0326] In some embodiments, X 15 is 3AmPyrazol-d-Ala. In some embodiments, X 15 is d-3Pya. In some embodiments, X 15 In some embodiments, X is d-5AmPyridinAla. 15 is d-5MePyridinAla. In some embodiments, X15 is dAla. In some embodiments, X 15 In some embodiments, X is dACIPA. 15 is aMe-d-Phe. In some embodiments, X 15 is h.

[0327] In some embodiments, X 16 Sar, Dab-Z peg , Dab-Z lipid , K.Z. peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid In some embodiments, X 16 Sar, Dab-Z peg , Dab-Z lipid , K.Z. peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid or absent, Dab-Z peg , Dab-Z lipid , K.Z. peg , K.Z. lipid , NMeK-Z peg , and NMeK-Z lipid is an L-amino acid. 16 , Sar, dDab-Z peg , dDab-Z lipid , kZ peg , kZ lipid , NMek-Z peg , NMek-Z lipid or does not exist.

[0328] In some embodiments, X 16 Sar, NMeK-Z lipid In some embodiments, X 17 is Sar or absent. 16 is Sar or NMeK-Z lipid is.

[0329] In some embodiments, X 16 is Sar. In some embodiments, X 16 Dab-Z peg In some embodiments, X 16 Dab-Z lipid In some embodiments, X 16 is KZ peg In some embodiments, X 16 is KZ lipid In some embodiments, X 16 is NMeK-Z peg In some embodiments, X 16 is NMeK-Z lipid In some embodiments, X 16 does not exist.

[0330] In some embodiments, X 16 dDab-Z peg In some embodiments, X 16 dDab-Z lipid In some embodiments, X 16 is kZ peg In some embodiments, X 16 is kZ lipid In some embodiments, X 16 NMek-Z peg In some embodiments, X 16 NMek-Z lipid is.

[0331] In some embodiments, X 17 Dab-Z peg , Dab-Z lipid , K.Z. peg , K.Z. lipid , NMeK-Z peg , NMeK-Z lipid In some embodiments, X 17 Dab-Z peg , Dab-Z lipid , K.Z. peg , K.Z.lipid , NMeK-Z peg , NMeK-Z lipid or absent, Dab-Z peg , Dab-Z lipid , K.Z. peg , K.Z. lipid , NMeK-Z peg , and NMeK-Z lipid is an L-amino acid. 17 dDab-Z peg , dDab-Z lipid , kZ peg , kZ lipid , NMek-Z peg , NMek-Z lipid or does not exist.

[0332] In some embodiments, X 17 Dab-Z peg , Dab-Z lipid , K.Z. peg , K.Z. lipid , NMeK-Z peg , or NMeK-Z lipid In some embodiments, X 17 is KZ lipid , NMeK-Z lipid or does not exist.

[0333] In some embodiments, X 17 Dab-Z peg In some embodiments, X 17 Dab-Z lipid In some embodiments, X 17 is KZ peg In some embodiments, X 17 is KZ lipid In some embodiments, X 17 is NMeK-Z peg In some embodiments, X 17 is NMeK-Z lipid In some embodiments, X 17 does not exist.

[0334] In some embodiments, X 17 dDab-Z peg In some embodiments, X 17 dDab-Z lipid In some embodiments, X 17 is kZ peg In some embodiments, X 17 is kZ lipid In some embodiments, X 17 NMek-Z peg In some embodiments, X 17 NMek-Z lipid is.

[0335] In some embodiments, R2 is CONH2, CO(DiFPip), CON(Me)2, a polyethylene glycol chain terminating in an ammonium or methyl group, or a lipophilic substituent. In some embodiments, R2 is CONH2, CO(DiFPip), CON(Me)2, a polyethylene glycol chain terminating in an ammonium or methyl group, or a lipophilic substituent.

[0336] In some embodiments, R2 is CONH2, CO(DiFPip), CON(Me)2, or Z peg In some embodiments, R2 is CONH2, CON(Me)2, or Z peg In some embodiments, R2 is CONH2 or CON(Me)2.

[0337] In some embodiments, R2 is CONH2. In some embodiments, R2 is CO(DiFPip). In some embodiments, R2 is CON(Me)2. In some embodiments, R2 is Z peg (i.e., a polyethylene glycol chain). In some embodiments, R2 is Z lipid (i.e., lipophilic substituents).

[0338] When two amino acid positions in a peptide molecule are linked to form a ring, the linker between the α-carbon of one amino acid position and the α-carbon of the other amino acid position can be less than 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, or 4 Angstroms (Å). In some embodiments, the linker is 2-30 Å in length. In some embodiments, the linker is 4 Å-24 Å in length. In some embodiments, the linker is 4 Å-20 Å in length. In some embodiments, the linker is 10 Å-24 Å in length. In some embodiments, the linker can contain 4-18 atoms selected from C, N, S, and O. In some embodiments, the linker can contain one or more cycloalkyl, heterocyclyl, aryl, or heteroaryl groups. In some embodiments, the linker can consist of C, N, S, O, and H atoms and contain 2-16 carbon atoms. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 4 to 16 atoms selected from C, N, S, and O. In some embodiments, the linker is comprised of C, S, and H atoms and contains 4 to 16 carbon atoms selected from C and S. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 2 to 14 carbon atoms. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 2 to 14 carbon atoms. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 4 to 14 atoms selected from C, N, S, and O. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 4 to 12 carbon atoms selected from C, N, S, and O. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 2 to 12 carbon atoms.

[0339] In some embodiments, the peptide comprises a linker between the α-carbon of X4 and the α-carbon of X9. In some embodiments, the linker is less than 24 angstroms (Å) in length. In some embodiments, the linker is less than 20 Å in length. In some embodiments, the linker is 4 Å to 24 Å in length. In some embodiments, the linker is 4 Å to 20 Å in length. In some embodiments, the linker is 10 Å to 24 Å in length. In some embodiments, the linker can comprise one or more cycloalkyl, heterocyclyl, aryl, or heteroaryl groups. In some embodiments, the linker can comprise one or more heterocyclyl, aryl, or heteroaryl groups. In some embodiments, the linker consists of C, N, S, O, and H atoms and comprises 4 to 18 atoms selected from C, N, S, and O. In some embodiments, the linker consists of C, N, S, O, and H atoms and comprises 2 to 16 carbon atoms. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 4 to 16 atoms selected from C, N, S, and O. In some embodiments, the linker is comprised of C, S, and H atoms and contains 4 to 16 carbon atoms selected from C and S. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 2 to 14 carbon atoms. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 2 to 14 carbon atoms. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 4 to 14 atoms selected from C, N, S, and O. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 4 to 12 carbon atoms selected from C, N, S, and O. In some embodiments, the linker is comprised of C, N, S, O, and H atoms and contains 2 to 12 carbon atoms.

[0340] In some embodiments, X4 is Abu and X9 is C. In some embodiments, X4 is Abu and X9 is aMeC. In some embodiments, X4 is Abu and X9 is Pen.

[0341] In some embodiments, X4 is C and X9 is C. In some embodiments, X4 is C and X9 is aMeC. In some embodiments, X4 is C and X9 is Pen.

[0342] In some embodiments, X4 is Pen and X9 is C. In some embodiments, X4 is Pen and X9 is aMeC. In some embodiments, X4 is Pen and X9 is Pen.

[0343] In some embodiments, X4 is aMeC and X9 is C. In some embodiments, X4 is aMeC and X9 is aMeC. In some embodiments, X4 is aMeC and X9 is Pen.

[0344] In some embodiments, X4 is Pen(oXyl) and X9 is C. In some embodiments, X4 is Pen(oXyl) and X9 is aMeC. In some embodiments, X4 is Pen(oXyl) and X9 is Pen.

[0345] In some embodiments, X4 is Pen(mXyl) and X9 is C. In some embodiments, X4 is Pen(mXyl) and X9 is aMeC. In some embodiments, X4 is Pen(mXyl) and X9 is Pen.

[0346] In some embodiments, X4 is Pen(pXyl) and X9 is C. In some embodiments, X4 is Pen(pXyl) and X9 is aMeC. In some embodiments, X4 is Pen(pXyl) and X9 is Pen.

[0347] In some embodiments, X4 is 4AminoPro and X9 is D. In some embodiments, X4 is 4AminoPro and X9 is E. In some embodiments, X4 is 4AminoPro and X9 is hE.

[0348] In some embodiments, X4 is Dap and X9 is D. In some embodiments, X4 is Dap and X9 is E. In some embodiments, X4 is Dap and X9 is hE.

[0349] In some embodiments, X4 is Pra and X9 is Dap(N3). In some embodiments, X4 is aG and X9 is aG.

[0350] In some embodiments, the peptide is cyclized via a linkage between residues X4 and X9 having a structure selected from the following:

[0351] [Table 2-1]

[0352] [Table 2-2]

[0353] In some embodiments, the peptide is cyclized via a linkage between residues X4 and X9 having a structure selected from the following:

[0354] [Table 3]

[0355] In some embodiments, the peptide is cyclized via a linkage between residues X4 and X9 having the following structure:

[0356] [ka]

[0357] In some embodiments, the peptide comprises R and X 13 , X3 and X 13 , X5 and X 10 , and X 10 and X 13 In some embodiments, the peptide comprises one linkage between any one of R and X 13 , X3 and X 13 , X5 and X 10 , and X 10 and X 13 contains no more than one link between any one of

[0358] In some embodiments, the peptide comprises R and X having a structure selected from: 13 This includes connections between:

[0359] [Table 4]

[0360] In some embodiments, the peptide comprises X and X having a structure selected from: 13 This includes connections between:

[0361] [Table 5]

[0362] In some embodiments, the peptide comprises X and X having a structure selected from: 10 This includes connections between:

[0363] [Table 6-1]

[0364] [Table 6-2]

[0365] In some embodiments, the peptide has the structure: X 10 and X 13 This includes connections between:

[0366] [ka]

[0367] In some embodiments, the peptide is cyclized to form a first ring, wherein the first ring comprises 3 to 14 amino acids. In some embodiments, the peptide is cyclized to form a first ring, wherein the first ring comprises 4 to 11 or 14 amino acids. In some embodiments, the first ring comprises 4 to 9, or 11 amino acids. In some embodiments, the first ring comprises 4, 6, or 10 amino acids. In some embodiments, the first ring comprises 4 amino acids. In some embodiments, the first ring comprises 5 amino acids. In some embodiments, the first ring comprises 6 amino acids. In some embodiments, the first ring comprises 7 amino acids. In some embodiments, the first ring comprises 8 amino acids. In some embodiments, the first ring comprises 9 amino acids. In some embodiments, the first ring comprises 10 amino acids. In some embodiments, the first ring comprises 11 amino acids. In some embodiments, the first ring comprises 14 amino acids.

[0368] In some embodiments, the first ring comprises a linkage between two amino acids having a structure selected from the following:

[0369] [Table 7-1]

[0370] [Table 7-2]

[0371] [Table 7-3]

[0372] [Table 7-4]

[0373] [Table 7-5]

[0374] [Table 7-6]

[0375] In some embodiments, the first ring comprises the link between the N-terminus of the peptide and the amino acid and has a structure selected from the following:

[0376] [Table 8-1]

[0377] [Table 8-2]

[0378] In some embodiments, the first ring is a ring consisting of X and X, X and X 13 , X5 and X 10 , X3 and X 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, or between X6 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 , X5 and X 10 , X3 and X 13In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, or between X6 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 , X5 and X 10 , X3 and X 13 , or formed between X6 and X9.

[0379] In some embodiments, the first ring is a ring consisting of X and X, X and X 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, or between X6 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the first ring is formed between X4 and X9, or between X4 and X9, or between X6 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 , or formed between X6 and X9.

[0380] In some embodiments, a first ring is formed between X4 and X9. In some embodiments, a first ring is formed between X4 and X9 via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, a first ring is formed between X4 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0381] In some embodiments, the first ring is formed between X4 and X13. In some embodiments, the first ring is connected to X4 and X13 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0382] In some embodiments, the first ring comprises X and X 10 In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 It is formed between.

[0383] In some embodiments, the first ring is formed between X3 and X13. In some embodiments, the first ring is connected between X3 and X13 via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0384] In some embodiments, the first ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, the first ring is formed between X6 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0385] In some embodiments, the peptide is further cyclized to form a second ring, wherein the second ring comprises 3 to 14 amino acids. In some embodiments, the peptide is further cyclized to form a second ring, wherein the second ring comprises 4 to 11 or 14 amino acids. In some embodiments, the second ring comprises 4 to 9 or 11 amino acids. In some embodiments, the second ring comprises 4, 6, 10, or 11 amino acids. In some embodiments, the second ring comprises 4 amino acids. In some embodiments, the second ring comprises 5 amino acids. In some embodiments, the second ring comprises 6 amino acids. In some embodiments, the second ring comprises 7 amino acids. In some embodiments, the second ring comprises 8 amino acids. In some embodiments, the second ring comprises 9 amino acids. In some embodiments, the second ring comprises 10 amino acids. In some embodiments, the second ring comprises 11 amino acids. In some embodiments, the second ring comprises 14 amino acids.

[0386] In some embodiments, the second ring comprises a linkage between two amino acids having a structure selected from the following:

[0387] [Table 9-1]

[0388] [Table 9-2]

[0389] [Table 9-3]

[0390] [Table 9-4]

[0391] [Table 9-5]

[0392] [Table 9-6]

[0393] In some embodiments, the second ring comprises a link between the N-terminus of the peptide and an amino acid and has a structure selected from the following:

[0394] [Table 10-1]

[0395] [Table 10-2]

[0396] In some embodiments, the second ring is a ring consisting of X and X, X and X 13 , X5 and X 10 , X3 and X 13 In some embodiments, the second ring is formed between X4 and X9, or between X4 and X9, or between X6 and X9, via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 , X5 and X 10 , X3 and X 13 or X6 and X9. In some embodiments, the second ring is formed between X4 and X9, X4 and X9, or X6 and X9, via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 , X5 and X 10 , X3 and X 13 , or formed between X6 and X9.

[0397] In some embodiments, the second ring is a ring consisting of X and X 10 Or X3 and X 13In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 Or X3 and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles. 10 Or X3 and X 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 Or X3 and X 13 It is formed between.

[0398] In some embodiments, a second ring is formed between X4 and X9. In some embodiments, a second ring is formed between X4 and X9 via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. In some embodiments, a second ring is formed between X4 and X9 via a linker selected from the group consisting of disulfides, thioethers, amides, olefins, and triazoles.

[0399] In some embodiments, the second ring is a ring formed from X and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0400] In some embodiments, the second ring is a ring consisting of X and X 10 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 It is formed between.

[0401] In some embodiments, the second ring is a ring consisting of X and X 13 In some embodiments, the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 13 In some embodiments, the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 It is formed between.

[0402] In some embodiments, a second ring is formed between X6 and X9. In some embodiments, a second ring is formed between X6 and X9 via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. In some embodiments, a second ring is formed between X6 and X9 via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole.

[0403] In some embodiments, the second ring is X 13and the N-terminus of the peptide. In some embodiments, the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 and the N-terminus of the peptide. In some embodiments, the second ring is connected to X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and the N-terminus of the peptide.

[0404] In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles, and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0405] In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole, and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0406] In some embodiments, the first ring is connected to X and X via a linker having one or more groups selected from the group consisting of a disulfide, a thioether, an amide, an olefin, an ether, an alkylene, and a triazole. 13 and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole. 10 It is formed between X6 and X9 or between X6 and X9.

[0407] In some embodiments, the first ring is connected to X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 10 It is formed between X6 and X9 or between X6 and X9.

[0408] In some embodiments, the first ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles, and the second ring is formed between X and X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles. 13 Between X4 and X 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0409] In some embodiments, the first ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole, and the second ring is formed between X and X via a linker selected from the group consisting of a disulfide, a thioether, an amide, an olefin, and a triazole. 13 Between X4 and X 13 Between X5 and X 10 Between X 10 and X 13 Between or X 13 and the N-terminus of the peptide.

[0410] In some embodiments, the peptide comprises at least one polyethylene glycol chain, hi some embodiments, the peptide comprises no more than five, no more than four, no more than three, no more than two, or no more than one polyethylene glycol chain.

[0411] In some embodiments, each polyethylene glycol chain independently terminates in an ammonium group of a methyl group. In some embodiments, the polyethylene glycol chain terminates in an ammonium group. In some embodiments, the polyethylene glycol chain terminates in a methyl group.

[0412] In some embodiments, the peptide comprises a polyethylene glycol chain having the structure:

[0413] [ka] During the ceremony, Z A But -OCH3 or -N + (CH3)3, n is an integer from 2 to 24.

[0414] In some embodiments, the peptide comprises a polyethylene glycol chain having the following structure:

[0415] [ka] In some embodiments, the peptide comprises a polyethylene glycol chain having the structure:

[0416] [ka] During the ceremony, Z A But -OCH3 or -N + (CH3)3, n is an integer from 2 to 24.

[0417] In some embodiments, the peptide comprises a polyethylene glycol chain having the following structure:

[0418] [ka]

[0419] In some embodiments, Z A is —OCH. In some embodiments, Z A -N + (CH3)3.

[0420] In some embodiments, n is an integer from 2 to 15. In some embodiments, n is an integer from 2 to 5. 2. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 14. In some embodiments, n is 14. In some embodiments, n is 15.

[0421] In some embodiments, R1, R2, or any amino acid of the peptide is conjugated to a polyethylene glycol chain.

[0422] Non-limiting examples of polyethylene glycol chains are provided in Table 2.

[0423] [Table 11-1]

[0424] [Table 11-2]

[0425] In some embodiments, the peptide comprises at least one lipophilic substituent. In some embodiments, the peptide comprises one lipophilic substituent. In some embodiments, the peptide comprises no more than three, no more than two, or no more than one lipophilic substituent. In some embodiments, the peptide comprises no more than one lipophilic substituent.

[0426] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0427] [ka] During the ceremony, Z B but,

[0428] [ka] and Z C But Z C1 , Z C2 , or Z C3 and Z C1 but,

[0429] [ka] and Z C2 but,

[0430] [ka] and Z C3 but,

[0431] [ka] and Z D but,

[0432] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa, independently for each occurrence,

[0433] [ka] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; v is 0 or 1, w is independently 0 or 1 at each occurrence.

[0434] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0435] [ka] During the ceremony, Z C2 but,

[0436] [ka] and Z D but,

[0437] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa is

[0438] [ka] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; w is independently 0 or 1 at each occurrence.

[0439] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0440] [ka]

[0441] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0442] [ka]

[0443] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0444] [ka]

[0445] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0446] [ka]

[0447] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0448] [ka]

[0449] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0450] [ka]

[0451] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0452] [ka] During the ceremony, Z B but,

[0453] [ka] and Z C But Z C1 , Z C2 , or Z C3 and Z C1 but,

[0454] [ka] and Z C2 but,

[0455] [ka] and Z C3 but,

[0456] [ka] and Z D but,

[0457] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa, independently for each occurrence,

[0458] [ka] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; v is 0 or 1, w is independently 0 or 1 at each occurrence.

[0459] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0460] [ka] During the ceremony, Z C2 but,

[0461] [ka] and Z D but,

[0462] [ka] and Z E is —H, —COOH, or tetrazolyl; Z F is -H or -CH3, Xaa is

[0463] [ka] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; w is independently 0 or 1 at each occurrence.

[0464] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0465] [ka]

[0466] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0467] [ka]

[0468] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0469] [ka]

[0470] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0471] [ka]

[0472] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0473] [ka]

[0474] In some embodiments, the peptide comprises a lipophilic substituent having the structure:

[0475] [ka]

[0476] In some embodiments, Z c teeth,

[0477] [ka] is.

[0478] In some embodiments, Z D teeth,

[0479] [ka] is.

[0480] In some embodiments, Z D teeth,

[0481] [ka] is.

[0482] In some embodiments, Z E is —H. In some embodiments, Z E is —COOH. In some embodiments, Z E is tetrazolyl.

[0483] In some embodiments, Z F is —H. In some embodiments, Z F is -CH3.

[0484] In some embodiments, Xaa is independently at each occurrence:

[0485] [ka] is.

[0486] In some embodiments, Xaa is

[0487] [ka] is.

[0488] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0489] In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6.

[0490] In some embodiments, r is an integer between 10 and 20. In some embodiments, r is 10. In some embodiments, r is 11. In some embodiments, r is 12. In some embodiments, r is 13. In some embodiments, r is 14. In some embodiments, r is 15. In some embodiments, r is 16. In some embodiments, r is 17. In some embodiments, r is 18. In some embodiments, r is 19. In some embodiments, r is 20.

[0491] In some embodiments, w is 0. In some embodiments, w is 1.

[0492] In some embodiments, R1, R2, or any amino acid of the peptide is conjugated to a lipophilic substituent.

[0493] Non-limiting examples of lipophilic substituents are provided in Table 3A.

[0494] [Table 12-1]

[0495] [Table 12-2]

[0496] [Table 12-3]

[0497] [Table 12-4]

[0498] [Table 12-5]

[0499] [Table 12-6]

[0500] [Table 12-7]

[0501] [Table 12-8]

[0502] Further non-limiting examples of lipophilic substituents are provided in Table 3B.

[0503] [Table 13-1]

[0504] [Table 13-2]

[0505] [Table 13-3]

[0506] [Table 13-4]

[0507] [Table 13-5]

[0508] [Table 13-6]

[0509] [Table 13-7]

[0510] [Table 13-8]

[0511] [Table 13-9]

[0512] In some embodiments, the peptide comprises a sequence according to any one of the following formulas: X3-X4-X5-X6-7MeW-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (I-G1a), X3-X4-X5-X6-7(3NAcPh)W-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (I-G1b), X3-X4-X5-X6-X7-X8-X9-AEF-X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (I-H1), X3-X4-X5-X6-X7-X8-X9-X 10 -6OH2Nal-X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (I-I1)、 X3-X4-X5-X6-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -X 14 -3Pya-X 16 -X 17 (I-J1)、 X3-X4-X5-X6-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 -X 17 (I-K1a)、 X3-X4-X5-X6-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 -X 17 (I-K1b)、 r-X4-X5-X6-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 -X 17 (I-L1a)、 r-X4-X5-X6-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 -X 17 (I-L1b)、 X3-Pen-X5-X6-7MeW-X8-Pen-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 -X 17 (I-M1a)、 X3-Pen-X5-X6-7(3NAcPh)W-X8-Pen-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 -X 17 (I-M1b), X3-X4-X5-X6-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-Sar-X 17 (I-N1a), X3-X4-X5-X6-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-Sar-X 17 (I-N1b), X3-X4-X5-X6-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 (I-O1a), or X3-X4-X5-X6-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -X 14 -3Pya-X 16 (I-O1b).

[0513] In some embodiments, the peptide comprises a sequence according to any one of the following formulas: R1-X3-X4-X5-T-7MeW-X8-X9-X 10 -X 11 -X 12 -X 13 -NX 15 -X 16 -X 17 -R2(I-G2a), R1-X3-X4-X5-T-7(3NAcPh)W-X8-X9-X 10 -X 11 -X 12 -X 13 -NX 15 -X 16-X 17 -R2(I-G2b)、 R1-X3-X4-X5-T-X7-X8-X9-AEF-X 11 -X 12 -X 13 -N-X 15 -X 16 -X 17 -R2(I-H2)、 R1-X3-X4-X5-T-X7-X8-X9-X 10 -6OH2Nal-X 12 -X 13 -N-X 15 -X 16 -X 17 -R2(I-I2)、 R1-X3-X4-X5-T-X7-X8-X9-X 10 -X 11 -X 12 -X 13 -N-3Pya-X 16 -X 17 -R2(I-J2)、 R1-X3-X4-X5-T-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -X 17 -R2(I-K2a)、 R1-X3-X4-X5-T-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -X 17 -R2(I-K2b)、 R1-r-X4-X5-T-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -X 17 -R2(I-L2a)、 R1-r-X4-X5-T-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -X 17 -R2(I-L2b)、 R1-X3-Pen-X5-T-7MeW-X8-Pen-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -X 17 -R2(I-M2a), R1-X3-Pen-X5-T-7(3NAcPh)W-X8-Pen-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -X 17 -R2(I-M2b), R1-X3-X4-X5-T-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-Sar-X 17 -R2(I-N2a), R1-X3-X4-X5-T-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-Sar-X 17 -R2(I-N2b), R1-X3-X4-X5-T-7MeW-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(I-O2a), or R1-X3-X4-X5-T-7(3NAcPh)W-X8-X9-AEF-6OH2Nal-X 12 -X 13 -N-3Pya-X 16 -R2(I-O2b).

[0514] In some embodiments, the amino acid at X3 is an L-amino acid. In some embodiments, the amino acid at X3 is a D-amino acid.

[0515] In some embodiments, the amino acid at X4 is an L-amino acid. In some embodiments, the amino acid at X4 is a D-amino acid.

[0516] In some embodiments, the amino acid at X5 is an L-amino acid. In some embodiments, the amino acid at X5 is a D-amino acid.

[0517] In some embodiments, the amino acid at X6 is an L-amino acid. In some embodiments, the amino acid at X6 is a D-amino acid.

[0518] In some embodiments, the amino acid at X7 is an L-amino acid. In some embodiments, the amino acid at X7 is a D-amino acid.

[0519] In some embodiments, the amino acid at X8 is an L-amino acid. In some embodiments, the amino acid at X8 is a D-amino acid.

[0520] In some embodiments, the amino acid at X9 is an L-amino acid. In some embodiments, the amino acid at X9 is a D-amino acid.

[0521] In some embodiments, X 10 In some embodiments, the amino acid in X is an L-amino acid. 10 The amino acids are D-amino acids.

[0522] In some embodiments, X 11 In some embodiments, the amino acid in X is an L-amino acid. 11 The amino acids are D-amino acids.

[0523] In some embodiments, X 12 In some embodiments, the amino acid in X is an L-amino acid. 12 The amino acids are D-amino acids.

[0524] In some embodiments, X 13 In some embodiments, the amino acid in X is an L-amino acid. 13 The amino acids are D-amino acids.

[0525] In some embodiments, X 14 In some embodiments, the amino acid in X is an L-amino acid. 14 The amino acids are D-amino acids.

[0526] In some embodiments, X 15 In some embodiments, the amino acid in X is an L-amino acid. 15 The amino acids are D-amino acids.

[0527] In some embodiments, X 16 In some embodiments, the amino acid in X is an L-amino acid. 16 The amino acids are D-amino acids.

[0528] In some embodiments, X 17 In some embodiments, the amino acid in X is an L-amino acid. 17 The amino acids are D-amino acids.

[0529] In some embodiments, the present disclosure provides a peptide as described herein, provided that the peptide retains activity as an inhibitor of the interleukin-23 receptor.

[0530] The present disclosure further provides a peptide of any one of SEQ ID NOs: 1-447 as shown in Table 4, or a pharmaceutically acceptable salt thereof.

[0531] In some embodiments, when the peptide comprises a cationic group (e.g., a quaternary ammonium moiety), the peptide further comprises a counteranion, such as, but not limited to, acetate, adipate, benzoate, benzenesulfonate, citrate, decanoate, chloride, lactate, maleate, methanesulfonate, oxalate, pivalate, propionate, succinate, sulfate, tartrate, or trifluoroacetate.

[0532] [Table 14-1]

[0533] Table 14-2

[0534] Table 14-3

[0535] Table 14-4

[0536] Table 14-5

[0537] Table 14-6

[0538] Table 14-7

[0539] Table 14-8

[0540] Table 14-9

[0541] Table 14-10

[0542] Table 14-11

[0543] Table 14-12

[0544] Table 14-13

[0545] Table 14-14

[0546] Table 14-15

[0547] Table 14-16

[0548] Table 14-17

[0549] Table 14-18

[0550] Table 14-19

[0551] Table 14-20

[0552] Table 14-21

[0553] Table 14-22

[0554] Table 14-23

[0555] Table 14-24

[0556] Table 14-25

[0557] Table 14-26

[0558] Table 14-27

[0559] Table 14-28

[0560] Table 14-29

[0561] Table 14-30

[0562] Table 14-31

[0563] Table 14-32

[0564] Table 14-33

[0565] Table 14-34

[0566] Table 14-35

[0567] Table 14-36

[0568] Table 14-37

[0569] Table 14-38

[0570] Table 14-39

[0571] Table 14-40

[0572] Table 14-41

[0573] Table 14-42

[0574] Table 14-43

[0575] Table 14-44

[0576] Table 14-45

[0577] Table 14-46

[0578] Table 14-47

[0579] Table 14-48

[0580] Table 14-49

[0581] Table 14-50

[0582] Table 14-51

[0583] Table 14-52

[0584] Table 14-53

[0585] Table 14-54

[0586] Table 14-55

[0587] Table 14-56

[0588] Table 14-57

[0589] Table 14-58

[0590] Table 14-59

[0591] Table 14-60

[0592] Table 14-61

[0593] Table 14-62

[0594] Table 14-63

[0595] Table 14-64

[0596] Table 14-65

[0597] Table 14-66

[0598] Table 14-67

[0599] Table 14-68

[0600] Table 14-69

[0601] Table 14-70

[0602] Table 14-71

[0603] Table 14-72

[0604] Table 14-73

[0605] Table 14-74

[0606] Table 14-75

[0607] Table 14-76

[0608] Table 14-77

[0609] Table 14-78

[0610] Table 14-79

[0611] Table 14-80

[0612] Table 14-81

[0613] Table 14-82

[0614] Table 14-83

[0615] Table 14-84

[0616] Table 14-85

[0617] Table 14-86

[0618] Table 14-87

[0619] Table 14-88

[0620] Table 14-89

[0621]

Table 14-90

[0622] Table 14-91

[0623] Table 14-92

[0624] Table 14-93

[0625] Table 14-94

[0626] Table 14-95

[0627] Table 14-96

[0628] Table 14-97

[0629] Table 14-98

[0630]

Table 14-99

[0631] Table 14-100

[0632] Table 14-101

[0633] Table 14-102

[0634] Table 14-103

[0635] Table 14-104

[0636] Table 14-105

[0637] Table 14-106

[0638] Table 14-107

[0639] Table 14-108

[0640] Table 14-109

[0641]

Table 14-110

[0642] Table 14-111

[0643] Table 14-112

[0644] Table 14-113

[0645] Table 14-114

[0646]

Table 14-115

[0647] Table 14-116

[0648] Table 14-117

[0649] Table 14-118

[0650] Table 14-119

[0651]

Table 14-120

[0652] Table 14-121

[0653] Table 14-122

[0654]

Table 14-123

[0655] Table 14-124

[0656]

Table 14-125

[0657] Table 14-126

[0658] Table 14-127

[0659] Table 14-128

[0660] Table 14-129

[0661] Table 14-130

[0662] Table 14-131

[0663] Table 14-132

[0664] Table 14-133

[0665] Table 14-134

[0666]

Table 14-135

[0667]

Table 14-136

[0668] Table 14-137

[0669] Table 14-138

[0670] Table 14-139

[0671] Table 14-140

[0672] Table 14-141

[0673] Table 14-142

[0674] Table 14-143

[0675] Table 14-144

[0676] Table 14-145

[0677] Table 14-146

[0678] Table 14-147

[0679] Table 14-148

[0680] Table 14-149

[0681]

Table 14-150

[0682] Table 14-151

[0683] Table 14-152

[0684] Table 14-153

[0685] Table 14-154

[0686]

Table 14-155

[0687] Table 14-156

[0688] Table 14-157

[0689] Table 14-158

[0690] Table 14-159

[0691] Table 14-160

[0692] Table 14-161

[0693] Table 14-162

[0694] Table 14-163

[0695] Table 14-164

[0696] Table 14-165

[0697] Table 14-166

[0698] Table 14-167

[0699] Table 14-168

[0700] Table 14-169

[0701]

Table 14-170

[0702] Table 14-171

[0703] Table 14-172

[0704] Table 14-173

[0705] Table 14-174

[0706]

Table 14-175

[0707] Table 14-176

[0708] Table 14-177

[0709] Table 14-178

[0710] Table 14-179

[0711] Table 14-180

[0712] Table 14-181

[0713] Table 14-182

[0714] Table 14-183

[0715] Table 14-184

[0716] Table 14-185

[0717] Table 14-186

[0718] Table 14-187

[0719] Table 14-188

[0720] Table 14-189

[0721] Table 14-190

[0722] Table 14-191

[0723] Table 14-192

[0724] Table 14-193

[0725] Table 14-194

[0726]

Table 14-195

[0727] Table 14-196

[0728] Table 14-197

[0729] Table 14-198

[0730] Table 14-199

[0731] Table 14-200

[0732] Table 14-201

[0733] Table 14-202

[0734] Table 14-203

[0735] Table 14-204

[0736] Table 14-205

[0737] Table 14-206

[0738] Table 14-207

[0739] Table 14-208

[0740]

Table 14-209

[0741] Table 14-210

[0742] Table 14-211

[0743] Table 14-212

[0744] Table 14-213

[0745] Table 14-214

[0746] Table 14-215

[0747] Table 14-216

[0748] Table 14-217

[0749] Table 14-218

[0750] Table 14-219

[0751] Table 14-220

[0752] Table 14-221

[0753] Table 14-222

[0754] Table 14-223

[0755] Table 14-224

[0756] Table 14-225

[0757] Table 14-226

[0758] Table 14-227

[0759] Table 14-228

[0760] Table 14-229

[0761] Table 14-230

[0762] Table 14-231

[0763] Table 14-232

[0764] Table 14-233

[0765] Table 14-234

[0766] Table 14-235

[0767] Table 14-236

[0768] Table 14-237

[0769] Table 14-238

[0770] Table 14-239

[0771] Table 14-240

[0772] Table 14-241

[0773] Table 14-242

[0774] Table 14-243

[0775] Table 14-244

[0776] Table 14-245

[0777] Table 14-246

[0778] Table 14-247

[0779] Table 14-248

[0780] Table 14-249

[0781] Table 14-250

[0782] Table 14-251

[0783] Table 14-252

[0784] Table 14-253

[0785] Table 14-254

[0786] Table 14-255

[0787] Table 14-256

[0788] Table 14-257

[0789] Table 14-258

[0790] Table 14-259

[0791] Table 14-260

[0792] Table 14-261

[0793] Table 14-262

[0794] Table 14-263

[0795] Table 14-264

[0796] Table 14-265

[0797] Table 14-266

[0798] Table 14-267

[0799] Table 14-268

[0800]

Table 14-269

[0801] Table 14-270

[0802] Table 14-271

[0803] Table 14-272

[0804] Table 14-273

[0805] Table 14-274

[0806] Table 14-275

[0807] Table 14-276

[0808] Table 14-277

[0809] Table 14-278

[0810] Table 14-279

[0811] Table 14-280

[0812] Table 14-281

[0813] Table 14-282

[0814] Table 14-283

[0815] Table 14-284

[0816] Table 14-285

[0817] Table 14-286

[0818] Table 14-287

[0819] Table 14-288

[0820]

Table 14-289

[0821] Table 14-290

[0822] Table 14-291

[0823] Table 14-292

[0824] Table 14-293

[0825] Table 14-294

[0826] Table 14-295

[0827] Table 14-296

[0828] Table 14-297

[0829] Table 14-298

[0830] Table 14-299

[0831] Table 14-300

[0832] Table 14-301

[0833] Table 14-302

[0834] Table 14-303

[0835] Table 14-304

[0836] Table 14-305

[0837] Table 14-306

[0838] Table 14-307

[0839] Table 14-308

[0840] Table 14-309

[0841]

Table 14-310

[0842] Table 14-311

[0843] Table 14-312

[0844] Table 14-313

[0845] Table 14-314

[0846]

Table 14-315

[0847] Table 14-316

[0848] Table 14-317

[0849] Table 14-318

[0850] Table 14-319

[0851] Table 14-320

[0852] Table 14-321

[0853] Table 14-322

[0854] Table 14-323

[0855] Table 14-324

[0856] Table 14-325

[0857] Table 14-326

[0858] Table 14-327

[0859] Table 14-328

[0860] Table 14-329

[0861] Table 14-330

[0862] Table 14-331

[0863] Table 14-332

[0864] Table 14-333

[0865] Table 14-334

[0866] Table 14-335

[0867] Table 14-336

[0868] Table 14-337

[0869] Table 14-338

[0870] Table 14-339

[0871] Table 14-340

[0872] Table 14-341

[0873] Table 14-342

[0874] Table 14-343

[0875] Table 14-344

[0876]

Table 14-345

[0877] Table 14-346

[0878] Table 14-347

[0879]

Table 14-348

[0880] Table 14-349

[0881] Table 14-350

[0882] Table 14-351

[0883] Table 14-352

[0884] Table 14-353

[0885] Table 14-354

[0886] Table 14-355

[0887] Table 14-356

[0888] Table 14-357

[0889] Table 14-358

[0890]

Table 14-359

[0891]

Table 14-360

[0892] Table 14-361

[0893] Table 14-362

[0894] Table 14-363

[0895] Table 14-364

[0896]

Table 14-365

[0897] Table 14-366

[0898] Table 14-367

[0899] Table 14-368

[0900]

Table 14-369

[0901]

Table 14-370

[0902] Table 14-371

[0903] Table 14-372

[0904] Table 14-373

[0905] Table 14-374

[0906] Table 14-375

[0907] Table 14-376

[0908] Table 14-377

[0909]

Table 14-378

[0910] Table 14-379

[0911]

Table 14-380

[0912] Table 14-381

[0913] Table 14-382

[0914] Table 14-383

[0915] Table 14-384

[0916] Table 14-385

[0917] Table 14-386

[0918] Table 14-387

[0919] Table 14-388

[0920]

Table 14-389

[0921]

Table 14-390

[0922] Table 14-391

[0923] Table 14-392

[0924] Table 14-393

[0925] Table 14-394

[0926] Table 14-395

[0927] Table 14-396

[0928] Table 14-397

[0929] Table 14-398

[0930] Table 14-399

[0931]

Table 14-400

[0932]

Table 14-401

[0933]

Table 14-402

[0934]

Table 14-403

[0935]

Table 14-404

[0936]

Table 14-405

[0937] Table 14-406

[0938]

Table 14-407

[0939] Table 14-408

[0940]

Table 14-409

[0941] Table 14-410

[0942] Table 14-411

[0943] Table 14-412

[0944] Table 14-413

[0945] Table 14-414

[0946]

Table 14-415

[0947] Table 14-416

[0948] Table 14-417

[0949] Table 14-418

[0950] Table 14-419

[0951] Table 14-420

[0952]

Table 14-421

[0953] Table 14-422

[0954]

Table 14-423

[0955] Table 14-424

[0956]

Table 14-425

[0957] Table 14-426

[0958] Table 14-427

[0959] Table 14-428

[0960] Table 14-429

[0961] Table 14-430

[0962]

Table 14-431

[0963]

Table 14-432

[0964] [Table 14-433]

[0965] In the peptide sequences set forth above, when a particular residue is followed by a number in parentheses, that residue is linked to another residue in the sequence designated by the same number. For example, in the sequence MeCO-k(d)-Pen(3)-E(2)-T-7MeW-K(Ac)-Pen(3)-AEF(2)-6OH2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 133), the two Pen(3) residues are linked to each other and the E(2) residue is linked to the AEF(2) residue.

[0966] In some embodiments, the present disclosure provides a peptide selected from the group consisting of: MeCO-k(Me)3-Pen(3)-NT-7(3NAcPh)WK(Ac)-Pen(3)-AEF(G)-6OH2Nal-THP-EN-5MePyridinAla-Sar-CONH2 (SEQ ID NO: 11), MeCO-r-Pen(3)-NT-7(3NAcPh)WK(Ac)-Pen(3)-AEF(G)-6OH2Nal-THP-EN-5MePyridinAla-Sar-CONH2 (SEQ ID NO: 15), cPEG3aCO-Pen(3)-NT-7(3NAcPh)WK(Ac)-Pen(3)-AEF(G)-6OH2Nal-THP-K(NMeAc)-N-3Pya-Sar-CONH2 (SEQ ID NO: 34), MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-TMAPF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 59), MeCO-k(Me)3-Pen(3)-NT-7(3NAcPh)WK(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 68), 5cpaCO-Pen(3)-K(5)-T-7MeW-K(Ac)-Pen(3)-AEF(5)-6OH2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 112) MeCO-r-Pen(3)-NT-7(3NAcPh)WK(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 287), MeCO-Pen(3)-N(NMe2)-T-7MeW-K(NMeAc)-Pen(3)-AEF(NMePEG3a)-6OH2Nal-THP-K(NMeAc)-N-3Pya-Sar-CONH(PEG3a) (SEQ ID NO: 315), cPEG3aCO-Pen(3)-NT-7MeW-K(NMecPEG3a)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 319), PEG2NMe(2)-Pen(3)-NT-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-hE(2)-N-3Pya-Sar-CONH2 (SEQ ID NO: 358), cPEG3aCO-Pen(3)-E(2)-T-7MeW-K(Ac)-Pen(3)-AEF(2)-6OH2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 364), cPEG3aCO-Pen(3)-N(N(Me)2)-T-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-Dab(NMeAc)-N-3Pya-Sar-CON(Me)2 (SEQ ID NO: 371), cPEG3aCO-k(2)-Pen(3)-N(N(Me)2)-T-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-hE(2)-N-3Pya-Sar-CON(Me)2 (SEQ ID NO: 373), and cPEG3aCO-Pen(3)-NT-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-Q(N(Me)2)-N-3Pya-Sar-CONH2 (SEQ ID NO: 392), or a pharmaceutically acceptable salt thereof.

[0967] In some embodiments, the present disclosure provides a peptide having the following structure:

[0968] [ka] or a pharmaceutically acceptable salt thereof.

[0969] In some embodiments, the present disclosure provides a peptide having the following structure:

[0970] [ka] or a pharmaceutically acceptable salt thereof.

[0971] In some embodiments, the present disclosure provides a peptide having the following structure:

[0972] [ka] or a pharmaceutically acceptable salt thereof.

[0973] In some embodiments, the present disclosure provides a peptide having the following structure:

[0974] [ka] or a pharmaceutically acceptable salt thereof.

[0975] In some embodiments, the present disclosure provides a peptide having the following structure:

[0976] [ka] or a pharmaceutically acceptable salt thereof.

[0977] In some embodiments, the present disclosure provides a peptide having the following structure:

[0978] [ka] or a pharmaceutically acceptable salt thereof.

[0979] In some embodiments, the present disclosure provides a peptide having the following structure:

[0980] [ka] or a pharmaceutically acceptable salt thereof.

[0981] In some embodiments, the present disclosure provides a peptide having the following structure:

[0982] [ka] or a pharmaceutically acceptable salt thereof.

[0983] In some embodiments, the present disclosure provides a peptide having the following structure:

[0984] [ka] or a pharmaceutically acceptable salt thereof.

[0985] In some embodiments, the present disclosure provides a peptide having the following structure:

[0986] [ka] or a pharmaceutically acceptable salt thereof.

[0987] In some embodiments, the present disclosure provides a peptide having the following structure:

[0988] [ka] or a pharmaceutically acceptable salt thereof.

[0989] In some embodiments, the present disclosure provides a peptide having the following structure:

[0990] [ka] or a pharmaceutically acceptable salt thereof.

[0991] In some embodiments, the present disclosure provides a peptide having the following structure:

[0992] [ka] or a pharmaceutically acceptable salt thereof.

[0993] In some embodiments, the present disclosure provides a peptide having the following structure:

[0994] [ka] or a pharmaceutically acceptable salt thereof.

[0995] Synthesis method The compounds described herein can be synthesized by many techniques known to those of skill in the art. In some aspects, the disclosure provides methods for chemically synthesizing the peptides of the disclosure. In some embodiments, portions of the peptide are recombinantly synthesized instead of chemically synthesized. In some aspects, the method of producing a peptide further comprises cyclizing the peptide precursor after the constituent subunits have been joined. In certain aspects, cyclization is achieved via any of the various methods described herein.

[0996] The present disclosure further describes the synthesis of the compounds described herein.In some embodiments, one or more of the amino acid residues or amino acid monomers are lipidated, and then covalently bonded to each other to form the peptide of the present disclosure.In some embodiments, one or more of the amino acid residues or amino acid monomers are covalently bonded to each other, lipidated at an intermediate oligomer stage, and then additional amino acids are attached and cyclized to form the peptide of the present disclosure.In some embodiments, the cyclic peptide is synthesized, and then lipidated to form the compound of the present disclosure.Exemplary synthesis methods are described in Examples.

[0997] Pharmaceutical Composition The present disclosure further relates to pharmaceutical compositions comprising the IL-23R inhibitors described herein. Specifically, the present disclosure includes pharmaceutical compositions comprising one or more peptides of the present disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutically acceptable carrier, diluent, or excipient can be a solid, semisolid, or liquid filler, diluent, encapsulating material, or any type of formulation auxiliary. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like.

[0998] Pharmaceutical compositions may be administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (by powder, ointment, eye drops, suppository, or transdermal patch), by inhalation (such as intranasal spray), ophthalmically (such as intraocularly), or bucally. As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intraarticular injection and infusion. Thus, in certain embodiments, the composition is formulated for delivery by any of these routes of administration. Pharmaceutical compositions may be formulated and administered orally. Pharmaceutical compositions may be formulated and administered parenterally. In some embodiments, the pharmaceutical composition is administered orally.

[0999] The IL-23R inhibitors of the present disclosure can be prepared and / or formulated as their pharmaceutically acceptable salts and / or other forms, or, where appropriate, in neutral form. Pharmaceutically acceptable salts are neutral, non-toxic salts of compounds that possess the desired pharmacological activity in their neutral form. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[1000] The present disclosure relates to pharmaceutical compositions comprising an IL-23R inhibitor described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, wherein one or more hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom or D. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and thus may be useful for increasing the half-life of the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures thereof when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12): 524-527 (1984). Such compounds are synthesized 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.

[1001] Also included are examples of isotopes that can be incorporated into the disclosed compounds: 2 H, 3 H, 11 C. 13 C. 14 C.13 N 、15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Positron-emitting isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. 11 C. 18 F, 15 O, and 13 Substitution at N may be useful in Positron Emission Topography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled peptides of the present disclosure may generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples as set forth below, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[1002] When used in at least one of the treatment or delivery systems described herein, the peptide inhibitors of the present disclosure may be used in pure form or, if such forms exist, in a pharmaceutically acceptable salt form.

[1003] The total daily usage amount of the IL-23R inhibitors and compositions of the present disclosure may be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend on a variety of factors, including: a) the disorder being treated and the severity of the disorder; b) the activity of the particular compound employed; c) the specific composition employed, the patient's age, weight, general health, sex, and diet; d) the time of administration, route of administration, and excretion rate of the particular peptide inhibitor employed; e) the duration of treatment; f) drugs used in combination or concomitantly with the particular peptide inhibitor employed, as well as similar factors well known in the medical arts.

[1004] The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical arts. Techniques and compositions are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[1005] Non-invasive detection of intestinal inflammation The IL-23R inhibitors of the present disclosure can be used to detect, assess, and diagnose enteritis by microPET imaging, where the peptide inhibitors are labeled with a chelating group or detectable label as part of a non-invasive diagnostic procedure. In certain embodiments, the IL-23R inhibitors of the present disclosure are conjugated to a bifunctional chelator. In certain embodiments, the IL-23R inhibitors of the present disclosure are radiolabeled. The labeled IL-23R inhibitor is then administered orally or intrarectally to a subject. In certain embodiments, the IL-23R inhibitor is included in drinking water. Following uptake of the IL-23R inhibitor, microPET imaging can be used to visualize inflammation throughout the subject's intestine and digestive tract.

[1006] Treatment and Use The present disclosure relates to methods for treating a subject suffering from a condition or indication associated with IL-23 or IL-23R activity (e.g., activation of the IL-23 / IL-23R signaling pathway), comprising administering to the subject an IL-23R inhibitor disclosed herein. In one aspect, the present disclosure provides a method for treating a subject suffering from a condition or indication characterized by aberrant or dysregulated IL-23 or IL-23R activity or signaling, comprising administering to the subject a peptide inhibitor of the present disclosure in an amount sufficient to inhibit (partially or completely) binding of IL-23 to IL-23R in the subject. Inhibition of IL-23 binding to IL-23R can occur in specific organs or tissues of the subject, such as the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels.

[1007] The present disclosure relates to a method comprising providing a peptide inhibitor described herein to a subject in need thereof. The subject in need thereof may be a subject who has been diagnosed or determined to be at risk for developing a disease or disorder associated with IL-23 / IL-23R. The subject may be a mammal. The subject may particularly be a human.

[1008] The disease or disorder treated by treatment with an IL-23R inhibitor of the present disclosure can be an inflammatory disease or disorder, an autoimmune inflammatory disease or disorder, and / or a related disorder, including multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, 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, psoriasis vulgaris, psoriasis genital warts ... vulgaris), or psoriatic erythroderma), atopic dermatitis, ectopic acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthritis, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation or chemotherapy, colitis associated with impaired innate immunity such as leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholecititis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[1009] The present disclosure provides a method or use of an IL-23R inhibitor for treating an inflammatory disease or disorder in a subject in need thereof, the method or use comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure.

[1010] The present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune disease or disorder in a subject in need thereof, the method or use comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure.

[1011] The present disclosure provides a method or use of an IL-23R inhibitor for treating an autoimmune inflammatory disease or disorder in a subject in need thereof, the method or use comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof, or a composition disclosed herein comprising an IL-23 inhibitor of the present disclosure.

[1012] Inflammatory diseases, autoimmune inflammatory diseases, and / or related disorders suitable for treatment with the compounds or pharmaceutically acceptable salts thereof, or compositions of the present disclosure may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA). The inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis. The inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated may be psoriasis. The inflammatory disease to be treated may be psoriatic arthritis. The inflammatory disease to be treated may be IBD. The inflammatory disease to be treated may be Crohn's disease. The inflammatory disease to be treated may be ulcerative colitis.

[1013] IL-23 is abundantly produced in the intestine, where it is thought to play an important role in suppressing intestinal regulatory T cell responses that favor inflammation, as well as controlling the balance between tolerance and immunity through T cell-dependent and T cell-independent pathways of intestinal inflammation by influencing T-helper 1 (Th1) and Th17-associated cytokines. Additionally, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the important role of the IL-23 pathway in intestinal homeostasis. Peptides and methods for specifically targeting IL-23R from the luminal side of the intestine may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.

[1014] Accordingly, the present disclosure also provides methods of treating or preventing inflammatory bowel disease (IBD), Crohn's disease (CD), or ulcerative colitis (UC) in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a peptide of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising an IL-23 inhibitor. In some embodiments, the method is for treating or preventing inflammatory bowel disease (IBD). In some embodiments, the method is for treating or preventing Crohn's disease (CD). In some embodiments, the method is for treating or preventing ulcerative colitis (UC).

[1015] Psoriasis, a chronic skin disease affecting approximately 2% to 3% of the general population, has been shown to be mediated by the body's T cell inflammatory response. IL-23 is one of several interleukins implicated as a key player in the pathogenesis of psoriasis, reportedly by maintaining chronic autoimmune inflammation through the induction of interleukin-17, regulation of T memory cells, and activation of macrophages. IL-23 and IL-23R expression have been shown to be increased in tissues from psoriasis patients, and IL-23-neutralizing antibodies have demonstrated IL-23-dependent inhibition of psoriasis development in animal models of psoriasis. Orally bioavailable peptide inhibitors of IL-23 could provide both a nonsteroidal treatment option for patients with mild to moderate psoriasis and a treatment for moderate to severe psoriasis that does not require injection delivery.

[1016] Accordingly, the present disclosure also provides a method of treating or preventing psoriasis (PsO) or psoriatic arthritis (PsA) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein comprising an IL-23 inhibitor. In some embodiments, the method is for treating or preventing psoriasis (PsO). In some embodiments, the method is for treating or preventing psoriatic arthritis (PsA).

[1017] The present disclosure further relates to a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in a subject (e.g., in a subject in need thereof), the method comprising administering to the subject a peptide inhibitor of IL-23R described herein. In some embodiments, the present disclosure includes and provides a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in the GI tract of a subject (e.g., a subject in need thereof), the method comprising providing to the subject a peptide inhibitor of IL-23R of the present disclosure by oral administration. The exposure of GI tissue (e.g., small intestine or colon) to the administered peptide inhibitor may be at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold greater than the exposure in the blood. In certain embodiments, the present disclosure includes a method of selectively inhibiting IL23 or IL23R signaling (or binding of IL23 to IL23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing a peptide inhibitor to the subject, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In further related embodiments, the present disclosure provides a method of inhibiting GI inflammation and / or neutrophil infiltration into the GI tract, comprising providing a peptide inhibitor of the present disclosure to a subject in need thereof. In some embodiments, the method of the present disclosure comprises providing a peptide inhibitor of the present disclosure (i.e., a first therapeutic agent) in combination with a second therapeutic agent to a subject (e.g., a subject in need thereof). In certain embodiments, the second therapeutic agent is provided to the subject before, simultaneously with, and / or after the peptide inhibitor is administered to the subject. In certain embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug, a steroid, or an immunomodulatory agent. In certain embodiments, the method includes administering to the subject a third therapeutic agent, hi certain embodiments, the second therapeutic agent is an antibody that binds to IL-23 or IL-23R.

[1018] The present disclosure also relates to a method for 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.

[1019] The present disclosure relates to a method for inhibiting IL-23 signaling by a cell, the method comprising contacting the IL-23R with a peptide inhibitor described herein. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the method is performed in vitro or in vivo. In certain embodiments, inhibition of IL-23 signaling can be determined by measuring changes in phospho-STAT3 levels in the cell.

[1020] In any of the aforementioned methods, administration of the IL-23R inhibitor to a subject may be oral, although other administration routes are not excluded. Other administration routes include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular routes. The dosage of the peptide inhibitor of IL-23R described herein, or a salt thereof, to be administered to a subject can be determined by one skilled in the art, taking into account factors including the disease or condition being treated, including its severity, as well as age, weight, sex, etc. [Example]

[1021] The following examples are not intended to limit the scope of the disclosure, but rather to provide guidance to those of skill in the art for preparing and using the disclosed peptides, compositions, and methods. While specific embodiments of the disclosure have been described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the disclosure.

[1022] Some abbreviations useful in describing this disclosure are defined in the following table.

[1023] The following abbreviations may be used throughout this specification and application:

[1024] [Table 15]

[1025] [Table 16-1]

[1026] [Table 16-2]

[1027] [Table 17]

[1028] The amino acid structures provided in Table 7 below are presented without a stereochemical designation at the alpha carbon. However, it is understood that these amino acids occur as either L- or D-amino acids. Unless an amino acid residue in Table 7 is represented by a lowercase abbreviation or preceded by the letter D, all amino acid abbreviations listed in the table refer to the L-amino acid configuration. For example, "Dab" refers to the L-stereoisomer:

[1029] [ka] The corresponding D-stereoisomer is designated as "dab", "dDab", or "D-Dab".

[1030] [ka]

[1031] [Table 18-1]

[1032] Table 18-2

[1033] Table 18-3

[1034] Table 18-4

[1035] Table 18-5

[1036] Table 18-6

[1037] Table 18-7

[1038] Table 18-8

[1039] Table 18-9

[1040] Table 18-10

[1041] Table 18-11

[1042] Table 18-12

[1043] Table 18-13

[1044] Table 18-14

[1045] Table 18-15

[1046] Table 18-16

[1047] Table 18-17

[1048] Table 18-18

[1049] Table 18-19

[1050] Table 18-20

[1051] Table 18-21

[1052] [Table 18-22]

[1053] Example 1: General procedure for solid phase synthesis of peptides Peptides were chemically synthesized using an optimized 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis protocol. For C-terminal amides, Rink-amide MBHA resin or CTC resin was used, which was then coupled to the amide after cleavage. Side chain protecting groups were as follows: D-Arg: Pbf; Thr, 6OH2Nal: Otbutyl; E: Otbutyl or OAll; Asn, Pen: Trityl; AEF: Boc; D-Lys: Fmoc; Lys(NMe): Alloc; Lys(Dde): Dde. For coupling, a 2- to 5-fold excess of a solution containing the Fmoc amino acid, HATU, and DIEA (1:0.95:2) in DMF was added to the swollen resin for 1 to 16 hours. When coupling 6OH2Nal, 6F2Nal, or other sterically hindered amino acids, double coupling was used (i.e., the resin was treated twice with the amino acid and coupling reagent to drive the reaction to completion). Removal of the Fmoc protecting group was achieved by treatment with a DMF:piperidine (4:1) solution for 30 minutes. The cycle was repeated until the full-length peptide was obtained.

[1054] Removal of the Dde protecting group was achieved by treatment with 3% hydrazine hydrate in DMF for 20 minutes (this process was repeated three times). Removal of the Alloc and OAll protecting groups was achieved by treatment with a mixture of Pd tetrakis / NDMBA (1,3-dimethylbarbituric acid) / phenylsilane (0.3:10:50 equivalents) in dry DCM under N2 atmosphere for 30 minutes, or with a mixture of Pd tetrakis / phenylsilane (0.1:10) in dry DCM under N2 atmosphere for 15 minutes. The resin was then washed with DCM, and the cycle was repeated twice.

[1055] Certain materials and reagents are listed below.

[1056] [Table 19-1]

[1057] [Table 19-2]

[1058] General procedure for cleaving peptides from the resin Side chain deprotection and cleavage of the peptide were achieved by stirring the dried resin in a solution of trifluoroacetic acid, water, DTT, and tri-isopropylsilane (90:2.5:5:2.5) for 3 hours. The mixture was then filtered, and cold methyl tert-butyl ether (MTBE) was added to the combined filtrate to precipitate the peptide. The resulting mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The pellet was lyophilized to yield the linear peptide.

[1059] General Procedure for Cyclization To effect cyclization of the thiol-containing residues, a solution of iodine in MeOH (0.1 M) was added dropwise to a solution of the linear peptide (20% MeCN / HO (1 mmol / L)) until a yellow color persisted. After approximately 2 h, analysis by LCMS showed that the linear peptide was no longer present. The excess iodine was quenched by the addition of 1 M NaSO in water (which immediately became colorless).

[1060] General Procedure for Peptide Purification Peptide purification was achieved using reverse-phase high-performance liquid chromatography (RP-HPLC). Purification of the cyclized peptide was achieved using preparative RP-HPLC with a C18 column at a flow rate of 20-250 mL / min. Separation was achieved using a gradient of buffer B in A (buffer A: 0.075% TFA in water; buffer B: ACN). (Note 1) Analysis was performed using a C18 column at a flow rate of 1 mL / min. (Note 2)

[1061] Note 1: Preparative HPLC method Preparative HPLC Method A: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B) Column: Phenomenex Luna® C18, 250 * 100 mm, 10 μm, 120 Å column, flow rate: 250 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature Preparative HPLC Method B: Description: Mobile phase: 0.5% AcOH in water (solvent A) and acetonitrile (solvent B) Column: Phenomenex Luna® C18, 250 * 100 mm, 10 μm, 120 Å column, flow rate: 250 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature Preparative HPLC Method C: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B). Column: Luna 100 * 25mm, C18, 10um, 100Å+Gemini® 150 * 30 mm, C18, 5 μm, 110 Å column, flow rate: 20 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature Preparative HPLC Method D: Description: Mobile phase: 0.5% AcOH in water (solvent A) and acetonitrile (solvent B). Column: Luna 100 * 25mm, C18, 10um, 100Å+Gemini® 150 * 30 mm, C18, 5 μm, 110 Å column, flow rate: 20 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature Preparative HPLC Method E: Description: Mobile phase: Water in 0.075% TFA (solvent A) and acetonitrile (solvent B). Column: Welch Ultimate XB-C18, 250 * 50mm, 7um, 120A+Welch Xtimate C18, 250 * 50mm, 10um, 120A column, flow rate: 80mL / min, wavelength: UV 220nm and 254nm, oven temperature: room temperature Preparative HPLC Method F: Description: Mobile phase: 0.5% AcOH in water (solvent A) and acetonitrile (solvent B) Column: Welch Ultimate® XB-C18, 250 * 50mm, 10um, 120Å + Welch Xtimate® C18, 250 * 50 mm, 10 μm, 120 Å column, flow rate: 80 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature Preparative HPLC Method G: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B) Column: Luna C18, 200 * 25mm, 10um, 100A+Gemin C18, 150 * 30mm, 5um, 110A column, flow rate: 20mL / min, wavelength: UV 220nm and 254nm, oven temperature: room temperature Preparative HPLC Method H: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B). Column: YMC-Actus Triart C18, 250 * 30 mm, 5 μm, 120 Å column, flow rate: 20 mL / min, wavelength: UV 220 nm and 254 nm, oven temperature: room temperature Preparative HPLC Method I: Description: Mobile phase: 0.075% TFA in water (solvent A) and acetonitrile (solvent B). Column: Luna 8 cm * 250mm, C18, 5um, 100Å column, flow rate: 150mL / min, wavelength: UV 220nm and 254nm, oven temperature: room temperature Note 2: Analytical HPLC method: Mobile phase: 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), flow rate 1.0 mL / min, elution gradient 10% to 80% (solvent B) over 0.9 min, elution gradient 80% to 90% over 0.6 min, Column: Xbridge C18, 3.5 μm, 2.1 * 30 mm, wavelength: UV 220 nm and 254 nm, column temperature: 30°C, MS ionization: ESI

[1062] Example 2: Synthesis of SEQ ID NO: 349-MeCO-k(d)-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2

[1063] [ka]

[1064] Step A - Synthesis of Intermediate 1: The peptide was synthesized by 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, the side-chain protecting groups were tert-butyl for Thr and Glu, trityl for Pen and Asn, and tert-butoxycarbonyl for AEF. The D-Lys at the X3 position was protected with an orthogonal Dde protecting group.

[1065] All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were carried out at 90 °C for 3 min under MW irradiation using a 5-fold excess of activated amino acids over the 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. Double acylation reactions were carried out using X 15 Manual coupling was performed on 3Pya using DIC-HOAT (3 equiv., 1:1:1) at room temperature to give X 11The reaction was carried out on 6OH2Nal. Fmoc deprotection was carried out using 20% ​​(V / V) piperidine in DMF. Capping of the free amino groups was carried out manually using 10 equivalents of acetic anhydride in DMF.

[1066] At the end of the peptide assembly on the solid phase, the resin was treated with 100 mL of a 3% hydrazine solution in DMF. The solution was drained, and the resin was washed with DCM (3 × 5 mL) and DMF (5 × 5 mL). Carnitine succinate (3 equiv., d) was coupled to the lysine residue at position X3 using HATU / DIPEA (1:1:2) at room temperature.

[1067] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. The peptide was cleaved from the solid support using 30 mL of TFA solution (v / v) (87.5% TFA, 5% HO, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 hours. The resin was then filtered, and the filtrate was triturated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with fresh cold diethyl ether. The process was repeated twice. The final pellet was dried and resuspended in 1:1 HO and acetonitrile + 0.1% TFA and stirred overnight. The suspension was then lyophilized to give intermediate 1 (yield = 88%). 107 H 153 N 24 O 28 S 2+ LCMS analysis calculated value: 2287.66 Da, found value: 1144.6 (M+2) 2+ Step B—SEQ ID NO: 349: Synthesis of MeCO-k(d)-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OHNal-THP-EN-3Pya-Sar-CONH: Intermediate 1 was dissolved in ACN¥H2O (5 mg¥ml). Saturated iodine in acetic acid was then added dropwise to the solution with stirring until a yellow color persisted. The reaction was complete in 20 min (as monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the cyclized peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200 × 40 mm, 300 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: 10% B over 5 min to 10% B over 25 min to 25% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give SEQ ID NO: 349: MeCO-k(d)-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OHNal-THP-EN-3Pya-Sar-CONH (yield = 31%). 107 H 151 N 24 O 28 S2 + LCMS analysis calculated value: 2285.64 Da, found value: 1143.3 (M+2) 2+

[1068] Example 3: Synthesis of SEQ ID NO: 339-MeCO-Pen(3)-N(N(Me)2)-T-7MeW-Dab(NMecarn)-Pen(3)-AEF-6OH2Nal-THP-Dab(NMecarn)-N-3Pya-Sar-CON(Me)2

[1069] [ka]

[1070] Step A—Synthesis of Intermediate 2: The peptide was synthesized by 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). The first amino acid was manually loaded using an equimolar solution of Fmoc-Asp-OAll, HOAt, and DIC in DMF at room temperature. Complete acylation was monitored by the ninhydrin test. The resin was then treated with 0.25 equivalents of Pd tetrakis and 24 equivalents of phenylsilane in 5 ml of dry DCM under a N atmosphere for 30 minutes (the process was repeated twice), washed with DCM, DMF, and a solution of 0.5% sodium dimethyldithiocarbamate (0.5%) and DIPEA (0.5%) in DMF. Fmoc-OSu and DIPEA (1:1, 2 equivalents) in DCM were added and stirred at room temperature for 30 minutes. The resin was manually preactivated with HATU (1.2 equiv.), DIPEA (2.2 equiv.), and then further peptide elongation was carried out by adding a solution of DIPEA (2.2 equiv.) and 3Pya-Sar-CON(Me)2 dimer (2.2 equiv.) in DMF. The reaction mixture was stirred at room temperature for 1 h. Complete acylation was monitored by test cleavage. The resin was then placed in a microwave reaction vessel, and assembly continued on 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, and trityl for Pen and Asn. All amino acids were dissolved in DMF at a concentration of 0.4 M. Acylation reactions were carried out at 90 °C under MW irradiation for 3 min using a 5-fold excess of activated amino acid over resin-free amino groups. The amino acids were activated with equimolar amounts of 0.5 M DIC solution in DMF and 1 M Oxyma solution in DMF. The double acylation reaction was carried out using X 15 I followed 3Pya. X 11 6OH2Nal, X8 DabNMeAlloc, and X 13DabNMeAlloc was manually coupled using DIC-HOAT (3 equivalents, 1:1:1), and complete acylation was monitored by the ninhydrin test. Fmoc deprotection was performed using 20% ​​(V / V) piperidine in DMF. Capping of the free amino group was performed manually using 10 equivalents of acetic anhydride in DMF.

[1071] The resin was then treated with 0.3 equivalents of Pd tetrakis, 50 equivalents of phenylsilane, and 10 equivalents of barbituric acid in 5 ml of dry DCM for 20 minutes under a N atmosphere (the process was repeated twice), and washed with DCM, DMF, and a solution of sodium dimethyldithiocarbamate (0.5%) and DIPEA (0.5%) in DMF. Further side chain derivatization was performed manually using HATU (4 equivalents), DIPEA (8 equivalents), followed by the addition of 4 equivalents of carnitine succinate. The reaction was complete after 1 hour.

[1072] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. The peptide was cleaved from the solid support using 30 ml of TFA solution (v / v) (87.5% TFA, 5% HO, 2.5% TIPS, 5% phenol) at room temperature for approximately 1.5 hours. The resin was then filtered, and the filtrate was triturated in cold MTBE (135 mL). After centrifugation, the peptide pellet was washed with cold diethyl ether. This process was repeated twice. The final pellet was dried and resuspended in 1:1 HO and acetonitrile + 0.1% TFA and stirred overnight. The suspension was then lyophilized to give the desired linear intermediate 2 (yield = 78%). 113 H 167 N 25 O 28 S2 + LCMS analysis calculated value: 2387.84 Da, found value: 1193.7 (M+2) 2+

[1073] Step B—Synthesis of MeCO-Pen(3)-N(N(Me)2)-T-7MeW-Dab(NMecarn)-Pen(3)-AEF-6OH2Nal-THP-Dab(NMecarn)-N-3Pya-Sar-CON(Me)2, SEQ ID NO: 339: The peptide (Intermediate 2) was dissolved in ACN¥HO (5 mg¥ml). Saturated iodine in acetic acid was then added dropwise to the solution with stirring until a yellow color persisted. The reaction was complete in 30 min (monitored by UPLC-MS). Solid ascorbic acid was added until the solution became clear. After lyophilization, the cyclized peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200 × 40 mm, 300 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: 10% B over 5 minutes to 10% B over 25 minutes to 25% B, flow rate 80 mL / min, wavelength 214 nm. The collected fractions were lyophilized to give SEQ ID NO: 339 (yield = 23%). 113 H 165 N 25 O 28 S2 + LCMS analysis calculated value: 2384.17, found value: 1192.5 (M+2) 2+

[1074] Example 4: Synthesis of SEQ ID NO: 112-5cpaCO-Pen(3)-K(5)-T-7MeW-K(Ac)-Pen(3)-AEF(5)-6OHNal-THP-K(Ac)-N-3Pya-Sar-CONH

[1075] [ka]

[1076] Step A - Synthesis of Intermediate 3: The synthesis was carried out using a CEM Liberty Blue automated microwave peptide synthesizer on solid-phase Rink amide MBHA resin (Novabiochem, 0.42 mmol / g, 100-200 mesh) using Fmoc-protected amino acids. 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).

[1077] 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 DIC (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 coupling was used for 3Pya, THP, and Thr, and for residues incorporated after THP and Thr (6OH2Nal and K(NNs)). Residue Y (OEtOTBDMS) and 5cpa were coupled using manual coupling conditions: a mixture of Fmoc-protected amino acid (0.75 mmol), HATU (0.75 mmol), and 4-methylmorpholine (1.5 mmol) in DMF (8 mL) was added to the resin (0.25 mmol) and then mixed at room temperature for 2 h. At the end of the assembly, the peptide-resin intermediate 3 was washed with DCM.

[1078] Step B—Synthesis of Intermediate 3a: Intermediate 3 (0.25 mmol) was swelled in THF (8 mL) for 15 minutes, then TBAF (2.5 mL, 1 M in THF, 2.5 mmol) was added. The reaction was mixed at room temperature for 1 hour. 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 (20 mL) was added TEA (0.523 mL, 0.728 g / mL, 3.75 mmol) in DCM (5 mL), followed by the slow addition of a solution of methanesulfonyl chloride (0.195 mL, 1.48 g / mL, 2.5 mmol) in DCM (5 mL). The reaction was mixed at room temperature for 1 hour, then drained and washed with DCM (3×). Fine cleavage of the resin with TFA indicated the desired product. 109 H 155 N 22 O 28 LCMS analysis of S4: Calculated value: 2349.824, Found value: 784 (M+3) 2+

[1079] Step C—Synthesis of Intermediate 3b: Intermediate 3a (0.25 mmol) was swollen in DMF (10 mL) for 15 min and then added to a saturated solution of CsCO in DMF (200 mL). The reaction mixture was heated at 68° C. for 1 h. The resin was then cooled to room temperature, drained, and washed with water (3×), DMF (3×), and DCM (3×). Fine cleavage of the resin with TFA revealed the desired product. 108 H 151 N 22 O 25 S3 + LCMS analysis calculated value: 2252.03, found value: 752 (M+3) 3+

[1080] Step D - Synthesis of Intermediate 3c: To intermediate 3b (0.5 mmol) in DMF (20 mL) was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (373.5 μL, 1.019 g / mL, 2.5 mmol) in DMF (3 mL), followed by 2-mercaptoethanol (350.7 μL, 1.114 g / mL, 5 mmol) in DMF (3 mL). The reaction mixture was mixed for 20 minutes, and the resin was washed with DCM and DMF. This procedure was repeated once more. Fine cleavage of the resin with TFA indicated the desired product. The resin was washed with DMF, MeOH, and DCM. 102 H 148 N 21 O 21 S2 + LCMS analysis calculated value: 2067.06, observed value: 689.9 (M+3) 3+

[1081] Step E—Synthesis of Intermediate 3d: Intermediate 3c (0.15 mmol) was treated with a solution of TFA / H2O / TIPS 92.5 / 5 / 2.5 for 30 minutes at 42°C on a CEM Razor cleavage station. The mixture was then 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 process was repeated twice. The final pellet was dried, resuspended in H2O and acetonitrile, and then lyophilized to afford the desired protected intermediate 3d as a pale yellow solid. 102 H 148 N 21 O 21 S2 + LCMS analysis calculated value: 2067.06, observed value: 1034.3 (M+2) 2+

[1082] Step E - Synthesis of SEQ ID NO: 112: Intermediate 3d was dissolved in 40% ACN / water (50 mL). Iodine (0.1 M) in methanol was then added dropwise with stirring until a yellow color persisted. The reaction was monitored by UPLC-MS. Upon completion of the reaction, solid ascorbic acid was added until the solution became clear. The solvent mixture was then lyophilized, and the resulting material was then dissolved in DMSO and purified by C18 reverse-phase HPLC (Waters XBridge OBD C18, 50x150 mm, 5 μm, 130 Å) using (A) 0.1% TFA in water and (B) 0.1% TFA in acetonitrile as eluents, with a gradient starting at 15% B and changing to 30% B over 25 minutes at a flow rate of 80 ml / min. Fractions containing the pure product were collected and then lyophilized to give the desired product as a white powder. LCMS analysis calculated: C 102 H 146 N 21 O 21 S2 + :2065.04, Actual value:1033.3(M+2) 2+

[1083] Example 5: Synthesis of SEQ ID NO: 287-MeCO-r-Pen(3)-NT-7(3NAcPh)WK(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2

[1084] [ka]

[1085] Step A - Synthesis of Intermediate 4: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing Rink Amide MBHA Resin (2.0 mmol, 6.0 g, sub: 0.33 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin for 1-4 hours under N2. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1086] To cleave the peptide from the resin, 120 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 4 (3.6 g).

[1087] Step B - Peptide Cyclization and Purification: Intermediate 4 (3.6 g, 1.6 mmol) was dissolved in 20% MeCN / HO (2000 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 12.0 mL) was added dropwise until the solution remained yellow in color. After approximately 2 hours, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10-20 mL) was then added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method A) and preparative HPLC (A: 0.5% AcOH in HO, B: ACN) (Note 1: Method B) to give SEQ ID NO: 287 (1117.4 mg, 90.8% purity, 26.0% yield for this step, 21.4% overall yield) as a white solid. Analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1088] LCMS summary: Calculated MW: 2189.47, Measured MW: 1095.5 (M+2H) 2+ .

[1089] Example 6: Synthesis of SEQ ID NO: 407-MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6F2Nal-THP-EN-3Pya-Sar-CONH2

[1090] [ka]

[1091] Step A—Synthesis of Intermediate 5: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.20 mmol, 0.64 g, sub: 0.31 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N2 for 1-4 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1092] To cleave the peptide from the resin, 12 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 5 (350 mg).

[1093] Step B - Peptide Cyclization and Purification: Intermediate 5 (350 mg, 0.17 mmol) was dissolved in 20% MeCN / HO (200 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 0.8 mL) was added dropwise until the solution remained yellow in color. After approximately 2 hours, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10-20 mL) was then added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method C) and preparative HPLC (A: 0.5% AcOH in HO, B: ACN) (Note 1: Method D), and the product was then re-lyophilized with a 0.1% TFA mobile phase to give SEQ ID NO: 407 (92.8 mg, 97.0% purity, 22.1% yield for this step, 18.6% overall yield) as a white solid.

[1094] The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1095] LCMS summary: Calculated MW: 2072.3, Measured MW: 1036.9 (M+2H) 2+ , 691.8(M+3H) 3+

[1096] Example 7: Synthesis of SEQ ID NO: 405-CFCO-k(5cpa)-Pen(3)-N(N(Me))-T-7MeW-Q(N(Me))-Pen(3)-AEF(N(Me))-6OHNal-THP-Q(N(Me))-N-3Pya-Sar-CON(Me)

[1097] [ka]

[1098] Step A—Synthesis of Intermediate 6: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing Sar-CTC Resin (0.50 mmol, 1.6 g, sub: 0.31 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin for 1-4 hours under N2. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1099] To cleave the peptide from the resin, 80 mL of cleavage buffer (20% HFIP / DCM) was added to the resin and stirred for 30 minutes. The mixture was then concentrated under reduced pressure. The peptide was dissolved in ACN / water and lyophilized overnight to give intermediate 5b (1.2 g).

[1100] Step B—Preparation of Intermediate 6c: To a solution of Intermediate 6b (1.2 g, 0.40 mmol) in DMF (10.0 mL) was added dimethylamine hydrochloride (65.2 mg, 2.00 equiv.), DIC (123 uL, 2.00 equiv.), HOAT (108 mg, 2.00 equiv.), and DIEA (136 uL, 2.00 equiv.). The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS. LCMS indicated that the starting material had not completely reacted, so an additional 1 equiv. of each of dimethylamine hydrochloride, DIC, HOAT, and DIEA was added, and the reaction was continued for 16 hours. After that, LCMS indicated that the starting material had been consumed. The filtrate was triturated with cold methyl tert-butyl ether (MTBE) (50 mL) and centrifuged (3000 rpm, 3 min) to give an oily liquid. The ether was dried with nitrogen to give intermediate 5c.

[1101] Step C - Preparation of Intermediate 6d: To a flask containing the side-chain protected peptide at room temperature, 35 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added at room temperature. The mixture was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give Intermediate 5d (600 mg).

[1102] Step D—Synthesis of SEQ ID NO:405: Intermediate 6d (600 mg, 0.255 mmol) was dissolved in 20% MeCN / HO (500 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 3.5 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10–20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method C) to give SEQ ID NO:405 (99 mg, 93.43% purity, 13.4% yield for this step, 6.87% overall yield) as a white solid.

[1103] The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1104] LCMS overview: Calculated MW: 2349.76, measured MW: 784.0 [(M+3H) / 3].

[1105] Example 8: Synthesis of SEQ ID NO: 389-MeCO-hk(Me)3-Pen(3)-N(N(Me)2)-T-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CON(Me)2

[1106] [ka]

[1107] Step A—Synthesis of Intermediate 6d: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing Rink Amide MBHA resin (1.0 mmol, 3.33 g, sub: 0.3 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-4 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1108] To cleave the peptide from the resin, 60 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 15 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 6d (2.0 g).

[1109] Step B—Peptide Cyclization and Purification: Intermediate 6d (2.0 g, 0.92 mmol) was dissolved in 20% MeCN / HO (1000 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 2.5 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10–20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method E) to give SEQ ID NO:389 (270.4 mg, 94.6% purity, 11.0% yield for this step, 10.1% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1110] LCMS summary: Calculated MW: 2169.5, Measured MW: 1085.1 (M+2H) 2+ , 724.1(M+3H) 3+ .

[1111] Example 9: Synthesis of SEQ ID NO: 328-cPEG3aCO-Pen(3)-NT-7MeW-K(NMecPEG3a)-Pen(3)-AEF-6OH2Nal-THP-K(NMecPEG3a)-N-3Pya-Sar-CONH2

[1112] [ka]

[1113] Step A—Synthesis of Intermediate 7: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.30 mmol, 1.15 g, sub: 0.26 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-4 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1114] To cleave the peptide from the resin, 25 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 7 (600 mg).

[1115] Step B - Peptide Cyclization and Purification: Intermediate 7 (600 mg, 0.24 mmol) was dissolved in 20% MeCN / HO (400 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 3.0 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (which immediately became colorless). MeCN (10-20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method C) to give SEQ ID NO:328 (89.6 mg, 96.9% purity, 11.7% yield for this step, 9.54% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1116] LCMS overview: Calculated MW: 2464.0, measured MW: 821.0 [(M+3H) / 3].

[1117] Example 10: Synthesis of SEQ ID NO: 414-MeCO-Pen(3)-E(2)-T-7MeW-K(Ac)-Pen(3)-AEF(2)-6OHNal-THP-K(Ac)-N-3Pya-Sar-CONH

[1118] [ka]

[1119] Step A—Synthesis of Intermediate 8b: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.2 mmol, 0.65 g, sub: 0.31 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-4 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1120] To cleave the peptide from the resin, 12 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 8b (350 mg).

[1121] Step B—Peptide Cyclization and Purification: Intermediate 8b (350 mg, 0.17 mmol) was dissolved in 20% MeCN / HO (200 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 0.8 mL) was added dropwise until the solution remained yellow. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10–20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method G) to give SEQ ID NO:414 (31.2 mg, 98.2% purity, 8.28% yield for this step, 7.41% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1122] LCMS summary: Calculated MW: 1952.2, Measured MW: 976.9 (M+2H) 2+ .

[1123] Example 11: Synthesis of SEQ ID NO: 115-MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OHNal-THP-EN-3Pya-Sar-K(PEG2NMePEG2NMegENMeC18Tetrazole)-CONH2

[1124] [ka]

[1125] Step A—Synthesis of Intermediate 9: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.2 mmol, 0.65 g, sub: 0.31 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-4 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1126] To cleave the peptide from the resin, 20 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 9 (451 mg).

[1127] Step B - Peptide Cyclization and Purification: Intermediate 9 (451 mg, 0.151 mmol) was dissolved in 20% MeCN / HO (300 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 1.0 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10-20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method H) to give SEQ ID NO: 115 (43.7 mg, 96.1% purity, 8.08% yield for this step, 6.08% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1128] LCMS overview: Calculated MW: 2994.53, measured MW: 998.89 [(M+3H) / 3].

[1129] Example 12: Synthesis of SEQ ID NO: 283-MeCO-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OHNal-THP-EN-3Pya-Sar-K(PEGPEGECOH)-CONH

[1130] [ka]

[1131] Step A—Synthesis of Intermediate 10: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.3 mmol, 1.0 g, sub: 0.28 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-16 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1132] To cleave the peptide from the resin, 75 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 10 (680 mg).

[1133] Step B - Peptide Cyclization and Purification: Intermediate 10 (680 mg, 0.246 mmol) was dissolved in 20% MeCN / HO (300 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 1.5 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10-20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method H) to give SEQ ID NO:283 (99.4 mg, 96.1% purity, 12.9% yield for this step, 10.6% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1134] LCMS summary: Calculated MW: 2758.21, Measured MW: 1380.2 (M+2H) 2+ .

[1135] Example 13: Synthesis of SEQ ID NO: 282-MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OHNal-THP-EN-3Pya-Sar-K(PEGPEGECOH)-CONH

[1136] [ka]

[1137] Step A—Synthesis of Intermediate 11: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.3 mmol, 1.0 g, sub: 0.28 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin for 1-16 hours under N2. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1138] To cleave the peptide from the resin, 25 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 11 (750 mg).

[1139] Step B - Peptide Cyclization and Purification: Intermediate 11 (750 mg, 0.257 mmol) was dissolved in 20% MeCN / HO (300 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 1.5 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10-20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method H) to give SEQ ID NO:282 (109.2 mg, 93.2% purity, 12.1% yield for this step, 10.4% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1140] LCMS summary: Calculated MW: 2914.4, Measured MW: 1458.3 (M+2H) 2+ .

[1141] Example 14: Synthesis of SEQ ID NO: 273-MeCO-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OHNal-THP-K(PEGPEGECOH)-N-3Pya-Sar-CONH

[1142] [ka]

[1143] Step A—Synthesis of Intermediate 12: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (1.0 mmol, 2.9 g, sub: 0.35 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-16 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1144] To cleave the peptide from the resin, 90 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 12 (2.0 g).

[1145] Step B - Peptide Cyclization and Purification: Intermediate 12 (2.0 g, 0.76 mmol) was dissolved in 20% MeCN / HO (1000 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 5.0 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10-20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method F) to give SEQ ID NO:273 (434.5 mg, 97.6% purity, 19.5% yield for this step, 14.8% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1146] LCMS summary: Calculated MW: 2629.1, Measured MW: 1314.8 (M+2H) 2+ .

[1147] Example 15: Synthesis of SEQ ID NO: 442-MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2

[1148] [ka]

[1149] Step A—Synthesis of Intermediate 13: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.20 mmol, 0.64 g, sub: 0.31 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-4 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1150] To cleave the peptide from the resin, 12 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 13 (400 mg).

[1151] Step B - Peptide Cyclization and Purification: Intermediate 13 (400 mg, 0.193 mmol) was dissolved in 20% MeCN / HO (200 mL). To the stirred solution of peptide, iodine in MeOH (0.1 M, 1.0 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (10-20 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method C) to give SEQ ID NO:442 (50.8 mg, 94.2% purity, 10.3% yield for this step, 9.9% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1152] LCMS summary: Calculated MW: 2070.3, Measured MW: 1036.2 (M+2H) 2+ , 691.1(M+3H) 3+ .

[1153] Resin 16: Synthesis of SEQ ID NO: 428-MeCO-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2

[1154] [ka]

[1155] Step A—Synthesis of Intermediate 14: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (0.10 mmol, 0.32 g, sub: 0.31 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-4 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1156] To cleave the peptide from the resin, 8 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 5 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 14 (195 mg).

[1157] Step B—Peptide Cyclization and Purification: Intermediate 14 (195 mg, 0.10 mmol) was dissolved in 20% MeCN / HO (100 mL). To a stirred solution of this peptide, iodine in MeOH (0.1 M, 0.5 mL) was added dropwise until the solution remained yellow. After approximately 2 h, LCMS analysis indicated that no more intermediate 14 was present. Excess iodine was quenched by the addition of 1 M NaSO in water (15 mL). MeCN (10–20 mL) was added to reduce the turbidity of the solution. The peptide was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method C) to give SEQ ID NO:428 (18.9 mg, 99.3% purity, 8.61% yield for this step, 8.6% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1158] LCMS summary: Calculated MW: 1914.17, Measured MW: 958.0 (M+2H) 2+ .

[1159] Example 17: Synthesis of SEQ ID NO: 444-MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-6BrNal-THP-EN-THP-CONH

[1160] [ka]

[1161] Step A—Synthesis of Intermediate 15: The peptide was synthesized by solid-phase peptide synthesis using Fmoc chemistry. DMF was added to a vessel containing MBHA Resin (3 mmol, 9.6 g, sub: 0.31 mmol / g) and allowed to swell for 2 hours. 20% piperidine / DMF was then added to the resin and mixed for 30 minutes. The mixture was drained and washed five times with DMF (30 seconds each). The Fmoc-amino acid solution was then added to the resin and mixed for 30 seconds, followed by the addition of activation buffer. The amino acid was allowed to react with the resin under N for 1-16 hours. 20% piperidine / DMF was then added and mixed for 30 minutes. This procedure was repeated for subsequent amino acid couplings. The coupling reaction was monitored by ninhydrin (A: 5% ninhydrin / EtOH, B: 80% phenol / EtOH, C: pyridine) or tetrachloro (A: 2% tetrachloro / DMF, B: 2% aldehyde / DMF for 3 min at 110°C) color test. The resin was then washed five times with DMF and then three times with MeOH before being dried under vacuum.

[1162] To cleave the peptide from the resin, 200 mL of cleavage buffer (5.0% DTT / 2.5% HO / 2.5% TIS / 90% TFA) was added to the flask containing the side-chain protected peptide on the resin at room temperature, and the solution was stirred for 3 hours. The mixture was then filtered and washed with 20 mL of TFA. The combined filtrate was triturated with cold methyl tert-butyl ether (MTBE). The mixture was centrifuged (3000 rpm, 3 min) and decanted. The pellet was washed with MTBE and centrifuged. The residue was lyophilized to give intermediate 15 (6.0 g).

[1163] Step B - Peptide Cyclization and Purification: Intermediate 15 (6.0 g, 2.93 mmol) was dissolved in 20% MeCN / HO (3.0 L). To the stirred solution of peptide, iodine in MeOH (0.1 M, 15 mL) was added dropwise until the solution remained yellow in color. After approximately 2 h, LCMS indicated the reaction was complete. Excess iodine was quenched by the addition of 1 M aqueous NaSO (15 μL), which immediately became colorless. MeCN (150-200 mL) was added to reduce turbidity. The solution was purified by preparative HPLC (A: 0.075% TFA in HO, B: ACN) (Note 1: Method I) to give SEQ ID NO:444 (2.35 g, 96.7% purity, 34.1% yield for this step, 33.4% overall yield) as a white solid. The analysis was performed using a C18 column at a flow rate of 1 mL / min (Note 2).

[1164] LCMS summary: Calculated MW: 2041.1, Measured MW: 1021.3 (M+2H) 2+ .

[1165] Example 18: Synthesis of SEQ ID NO: 432-MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-AEF-2Nal6(Ph4(NMorph))-THP-EN-THP-CONH2

[1166] [ka]

[1167] In a glovebox, a 1-dram vial was charged with Intermediate 16 (15 mg, 7.4 μmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (4.3 mg, 15 μmol, 2 equiv.), CatacXium A Pd G4 (13.6 mg, 18.4 μmol, 2.5 equiv.), and K2CO3 (6.6 mg, 48 μmol, 6.5 equiv.), followed by the addition of TFE (0.37 mL), water (0.37 mL), and DCM (75 μL). The reaction vial was sealed, removed from the glovebox, and heated at 50 °C with stirring for 20 h. After cooling to room temperature, SiliaMet DMT scavenger (15 mg) and DMF (0.5 mL) were added and stirred for an additional 3 h. The resulting mixture was acidified by the addition of a 9:1 MeCN / water (1% TFA) mixture, filtered, rinsed with a minimal amount of DMF, and concentrated to a volume of approximately 1 mL by rotary evaporation. Purification by mass-directed liquid chromatography (HPLC (Waters XSelect CSH C18, 5μ, 19 × 100 mm) using a gradient of 20–28% B over 25 min at a flow rate of 25 mL / min (Mobile Phase A: water + 0.16% formic acid, Mobile Phase B: acetonitrile + 0.16% formic acid)) afforded SEQ ID NO: 432 as a white solid 2 (4.5 mg, 27% yield). LCMS calculated for CHNOS: 2123.49; found (m / z): 1062.2 [M+2H]. 2+ .

[1168] Example 19: IL23R reporter assay Compounds were serially diluted in 100% (v / v) DMSO and plated into 1536-well untreated black assay plates (Corning #9146) using an echo acoustic dispenser (Labcyte). 3 μL of HEK293 cells containing IL-23R, IL-12Rβ1, and a firefly luciferase reporter gene driven by a STAT inducible promoter (Promega) were added to the plate (4000 cells / well), followed by 3 μL of 10 ng / mL IL-23 (EC 90After 5 h at 37°C, 5% CO2, 95% relative humidity, cells were placed at 20°C and treated with BioGlo reagent (Promega) according to the manufacturer's instructions. Luminescence was measured on a Pherastar FSX (BMG LabTech). Data were normalized to IL-23 treatment (0% inhibition) and 30 μM control inhibitor (100% inhibition), and IC 50 Values ​​were determined using the four parameter Hill equation. Data for exemplary compounds are shown below.

[1169] A:IC 50 <0.01mM, B: 0.01 mM ≤ IC 50 <0.1mM, C: 0.1 mM ≤ IC 50 ND: Not decided

[1170] [Table 20-1]

[1171] [Table 20-2]

[1172] [Table 20-3]

[1173] [Table 20-4]

[1174] [Table 20-5]

[1175] [Table 20-6]

[1176] Example 19: 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 cultured at 2–6 × 10 per mL in XF-TCEM supplemented with penicillin / streptomycin and 100 ng / mL IL-1β (BioLegend, 579404). 5 Cells were resuspended in RPMI-1640 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 approximately 4 hours at 37°C in 5% CO2. After this "starvation," a total of 6 x 104 cells in 30 μL of RPMI-BSA were transferred to each well of a 384-well plate pre-spotted with peptide or DMSO. Cells were incubated for 30 minutes before adding IL-23 at a final concentration of 5 ng / mL. Cells were stimulated with cytokines for 30 minutes at 37°C in 5% CO2, transferred to ice for 10 minutes, and lysed. Cell lysates were stored at -80°C until phosphorylated STAT3 was measured using a phospho-STAT panel kit (Meso Scale Discovery, K15202D). The results are shown below.

[1177] A:IC 50 <0.01nM, B: 0.01 nM ≤ IC 50 <0.1nM, C: 0.1 nM ≤ IC 50 <1 nM, D: 1nM ≤ IC 50 , ND: Not decided

[1178] [Table 21-1]

[1179] [Table 21-2]

[1180] [Table 21-3]

[1181] [Table 21-4]

[1182] [Table 21-5]

[1183] [Table 21-6]

[1184] While the foregoing specification, together with examples given for purposes of illustration, teaches the principles of the present invention, it will be understood that the practice of the invention encompasses all ordinary variations, adaptations and / or modifications that come within the scope of the following claims and equivalents thereof.

Claims

1. Amino acid sequence: X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ A peptide of formula (I), comprising (I): or a pharmaceutically acceptable salt thereof, wherein: X ３ is any amino acid or is absent, X ４ is any amino acid, X ５ is any amino acid, X ６ is any amino acid, X ７ but, 【Chemistry 1】 and R Ａ But, O, NH, NC （１～５） alkyl, or S; R Ｂ But, -H, halo, C （１～３） alkyl, or phenyl, wherein the phenyl is one —N(H)C(O)C （１～３） optionally substituted with alkyl groups; X ８ is any amino acid, X ９ is any amino acid, X １０ but, 【Chemistry 2】 and R Ｃ is -H or -C （１～３） is alkyl, R Ｄ -H, -OH, -CN, -C （１～３） Alkyl, —OC （１～３） Alkyl, —OC （１～３） Alkyl-(5-membered heteroaryl), —C(O)NH ２ or heterocyclyl, （１～３） alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain, wherein said heterocyclyl is one -C(O)NH ２ optionally substituted with a group; R Ｅ is —H or halo; R Ｆ But, -C （１～６） an alkylene or divalent polyethylene glycol chain, R Ｇ But -H, -C （１～３） Alkyl or X ５ or X １３ to said amino acid, R Ｈ But -H, -C （１～３） Alkyl, —C(NH)NH ２ , —C(O)—R Ｈ１ Or Or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; R Ｈ１ But, -C （１～５） Alkyl, —OC （１～５） Alkyl, —C （１～３） Alkyl-phenyl, -phenyl-C （１～３） Alkyl-N(H)-S(O) ２ -C （１～３） ) alkyl, or polyethylene glycol chain, （１～３） alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R Ｊ , R Ｋ , and R Ｌ However, each independently, C （１～３） Is it alkyl? or R Ｊ and R Ｋ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; or Or X １０ but, 【Transformation 3】 and A is, 【Chemistry 4】 and R ａａ が、-OCHF ２ 、-O(CH ２ ) ９ CO ２ H、 【Transformation 5】 and R ｂｂ が、-H、-CH ３ 、-C(O)CH ３ 、-C(NH)NH ２ ,-(EH ２ ) ３ O(CH ２ ) ２ OCH ３ 、-CH ２ CH ２ OCH ３ ,-(EH ２ CH ２ O) ３ CH ３ ,-(EH ２ CH ２ O) ６ CH ３ 、 【Transformation 6】 and R ｃｃ が、-H、-CH ３ ,-(EH ２ ) ３ O(CH ２ ) ２ OCH ３ 、 【Transformation 7】 and n1 is 1, 2, or 3; R ｄｄ but, 【Transformation 8】 and n2 is 1, 2, 3, 4, or 5; R ｇｇ Yes, -OCH ３ 、 【Chemistry 9】 and n3 is 3, 4, 5, 6, or 8; R ｈｈ -H, -(CH ２ ) ７ CH ３ , -(CH ２ ) １５ CH ３ , -(CH ２ ) ２ OCH ３ , or -(CH ２ CH ２ O) ３ CH ３ and X １１ but, 【Chemistry 10】 and R Ｍ But halo, -OH, -C （１～３） Alkyl, —OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R Ｎ is —H or —OH, R Ｏ But, -OC （１～３） Alkyl or —C(O)NH ２ and R Ｐ But halo, -OH, -C （１～３） Alkyl, —OC （１～３） Alkyl, —C(O)NH ２ , -OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X １２ is any amino acid, X １３ is any amino acid, X １４ is any amino acid, X １５ is Ala, THP, or 【Chemistry 11】 and R Ｑ is -H or -C （１～３） is alkyl, R Ｓ is phenyl or 5- to 6-membered heteroaryl, each of which is one —C(O)NH ２ optionally substituted with a group, X １６ is any amino acid or is absent, X １７ is any amino acid or is absent, A peptide, or a pharmaceutically acceptable salt thereof, wherein the peptide is cyclized to form a first ring, and the first ring contains 4 to 14 amino acids.

2. The amino acid sequence: X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I) During the ceremony, X ３ is any amino acid or is absent, X ４ But, X ９ and an amino acid linked to said amino acid of X ５ is any amino acid, X ６ is any amino acid, X ７ but, 【Chemistry 12】 and R Ａ But, O, NH, NC （１～５） alkyl, or S; R Ｂ But, -H, halo, C （１～３） alkyl, or phenyl, wherein the phenyl is one —N(H)C(O)C （１～３） optionally substituted with alkyl groups; X ８ is any amino acid, X ９ But, X ４ and an amino acid linked to said amino acid of X １０ but, 【Chemistry 13】 and R Ｃ is -H or -C （１～３） is alkyl, R Ｄ -H, -OH, -CN, -C （１～３） Alkyl, —OC （１～３） Alkyl, —OC （１～３） Alkyl-(5-membered heteroaryl), —C(O)NH ２ or heterocyclyl, （１～３） alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain, wherein said heterocyclyl is one -C(O)NH ２ optionally substituted with a group; R Ｅ is —H or halo; R Ｆ But, -C （１～６） an alkylene or divalent polyethylene glycol chain, R Ｇ But -H, -C （１～３） Alkyl or X ５ or X １３ to said amino acid, R Ｈ But -H, -C （１～３） Alkyl, —C(NH)NH ２ , —C(O)—R Ｈ１ Or Or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; R Ｈ１ But, -C （１～５） Alkyl, —OC （１～５） Alkyl, —C （１～３） Alkyl-phenyl, -phenyl-C （１～３） Alkyl-N(H)-S(O) ２ -C （１～３） ) alkyl, or polyethylene glycol chain, （１～３） alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R Ｊ , R Ｋ , and R Ｌ However, each independently, C （１～３） Is it alkyl? or R Ｊ and R Ｋ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; or Or X １０ but, 【Chemistry 14】 and A is, 【Chemistry 15】 and R ａａ が、-OCHF ２ 、-O(CH ２ ) ９ CO ２ H、 【Chemistry 16】 and R ｂｂ が、-H、-CH ３ 、-C(O)CH ３ 、-C(NH)NH ２ ,-(EH ２ ) ３ O(CH ２ ) ２ OCH ３ 、-CH ２ CH ２ OCH ３ ,-(EH ２ CH ２ O) ３ CH ３ ,-(EH ２ CH ２ O) ６ CH ３ 、 【Chemistry 17】 and R ｃｃ が、-H、-CH ３ ,-(EH ２ ) ３ O(CH ２ ) ２ OCH ３ 、 [Chemistry 18] and n1 is 1, 2, or 3; R ｄｄ but, 【Chemistry 19】 and n2 is 1, 2, 3, 4, or 5; R ｇｇ Yes, -OCH ３ 、 【Chemistry 20】 and n3 is 3, 4, 5, 6, or 8; R ｈｈ -H, -(CH ２ ) ７ CH ３ , -(CH ２ ) １５ CH ３ , -(CH ２ ) ２ OCH ３ , or -(CH ２ CH ２ O) ３ CH ３ and X １１ but, 【Chemistry 21】 and R Ｍ But halo, -OH, -C （１～３） Alkyl, —OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R Ｎ is —H or —OH, R Ｏ But, -OC （１～３） Alkyl or —C(O)NH ２ and R Ｐ But halo, -OH, -C （１～３） Alkyl, —OC （１～３） Alkyl, —C(O)NH ２ , -OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X １２ is any amino acid, X １３ is any amino acid, X １４ is any amino acid, X １５ is Ala, THP, or 【Chemistry 22】 and R Ｑ is -H or -C （１～３） is alkyl, R Ｓ is phenyl or 5- to 6-membered heteroaryl, each of which is one —C(O)NH ２ optionally substituted with a group, X １６ is any amino acid or is absent, X １７ The peptide of claim 1, or a pharmaceutically acceptable salt thereof, wherein is any amino acid or is absent.

3. The amino acid sequence: X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I) During the ceremony, X ３ is any amino acid or is absent, X ４ is any amino acid, X ５ is any amino acid, X ６ is any amino acid, X ７ but, 【Chemistry 23】 and R Ａ But, O, NH, NC （１～５） alkyl, or S; R Ｂ But, -H, halo, C （１～３） alkyl, or phenyl, wherein the phenyl is one —N(H)C(O)C （１～３） optionally substituted with alkyl groups; X ８ is any amino acid, X ９ is any amino acid, X １０ but, 【Chemistry 24】 and R Ｃ is -H or -C （１～３） is alkyl, R Ｄ -H, -OH, -CN, -C （１～３） Alkyl, —OC （１～３） Alkyl, —OC （１～３） Alkyl-(5-membered heteroaryl), —C(O)NH ２ or heterocyclyl, （１～３） alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain, wherein said heterocyclyl is one -C(O)NH ２ optionally substituted with a group; R Ｅ is —H or halo; R Ｆ But, -C （１～６） an alkylene or divalent polyethylene glycol chain, R Ｇ But -H, -C （１～３） Alkyl or X ５ or X １３ to said amino acid, R Ｈ But -H, -C （１～３） Alkyl, —C(NH)NH ２ , —C(O)—R Ｈ１ Or Or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; R Ｈ１ But, -C （１～５） Alkyl, —OC （１～５） Alkyl, —C （１～３） Alkyl-phenyl, -phenyl-C （１～３） Alkyl-N(H)-S(O) ２ -C （１～３） ) alkyl, or polyethylene glycol chain, （１～３） alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R Ｊ , R Ｋ , and R Ｌ However, each independently, C （１～３） Is it alkyl? or R Ｊ and R Ｋ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; X １１ but, 【Chemistry 25】 and R Ｍ But halo, -OH, -C （１～３） Alkyl, —OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R Ｎ is —H or —OH, R Ｏ But, -OC （１～３） Alkyl or —C(O)NH ２ and R Ｐ But halo, -OH, -C （１～３） Alkyl, —OC （１～３） Alkyl, —C(O)NH ２ , -OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X １２ is any amino acid, X １３ is any amino acid, X １４ is any amino acid, X １５ is Ala, THP, or 【Chemistry 26】 and R Ｑ is -H or -C （１～３） is alkyl, R Ｓ is phenyl or 5- to 6-membered heteroaryl, each of which is one —C(O)NH ２ optionally substituted with a group, X １６ is any amino acid or is absent, X １７ is any amino acid or is absent, X １７ is any amino acid or is absent, 2. The peptide of claim 1, or a pharmaceutically acceptable salt thereof, wherein the peptide is cyclized to form a first ring, and the first ring comprises 4 to 14 amino acids.

4. The amino acid sequence: X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I) During the ceremony, X ３ is any amino acid or is absent, X ４ But, X ９ and an amino acid linked to said amino acid of X ５ is any amino acid, X ６ is any amino acid, X ７ but, 【Chemistry 27】 and R Ａ But, O, NH, NC （１～５） alkyl, or S; R Ｂ But, -H, halo, C （１～３） alkyl, or phenyl, wherein the phenyl is one —N(H)C(O)C （１～３） optionally substituted with alkyl groups; X ８ is any amino acid, X ９ But, X ４ and an amino acid linked to said amino acid of X １０ but, 【Chemistry 28】 and R Ｃ is -H or -C （１～３） is alkyl, R Ｄ -H, -OH, -CN, -C （１～３） Alkyl, —OC （１～３） Alkyl, —OC （１～３） Alkyl-(5-membered heteroaryl), —C(O)NH ２ or heterocyclyl, （１～３） alkyl-(5-membered heteroaryl) optionally substituted with a polyethylene glycol chain, wherein said heterocyclyl is one -C(O)NH ２ optionally substituted with a group; R Ｅ is —H or halo; R Ｆ But, -C （１～６） an alkylene or divalent polyethylene glycol chain, R Ｇ But -H, -C （１～３） Alkyl or X ５ or X １３ to said amino acid, R Ｈ But -H, -C （１～３） Alkyl, —C(NH)NH ２ , —C(O)—R Ｈ１ Or Or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; R Ｈ１ But, -C （１～５） Alkyl, —OC （１～５） Alkyl, —C （１～３） Alkyl-phenyl, -phenyl-C （１～３） Alkyl-N(H)-S(O) ２ -C （１～３） ) alkyl, or polyethylene glycol chain, （１～３） alkyl-phenyl optionally substituted with 1 to 3 groups selected from halo and —OH; R Ｊ , R Ｋ , and R Ｌ However, each independently, C （１～３） Is it alkyl? or R Ｊ and R Ｋ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl group; X １１ but, 【Chemistry 29】 and R Ｍ But halo, -OH, -C （１～３） Alkyl, —OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R Ｎ is —H or —OH, R Ｏ But, -OC （１～３） Alkyl or —C(O)NH ２ and R Ｐ But halo, -OH, -C （１～３） Alkyl, —OC （１～３） Alkyl, —C(O)NH ２ , -OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X １２ is any amino acid, X １３ is any amino acid, X １４ is any amino acid, X １５ is Ala, THP, or 【Transformation 30】 and R Ｑ is -H or -C （１～３） is alkyl, R Ｓ is phenyl or 5- to 6-membered heteroaryl, each of which is one —C(O)NH ２ optionally substituted with a group, X １６ is any amino acid or is absent, X １７ The peptide according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is any amino acid or is absent.

5. Formula (I-A1): R １ -X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I-A1), During the ceremony, R １ is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, a polyethylene glycol chain, or a lipophilic substituent, and the 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe are １３ The peptide according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

6. Formula (I-A2): X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ -R ２ (I-A2) During the ceremony, R ２ The peptide according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is CONH2, CO(DiFPip), CON(Me)2, a polyethylene glycol chain, or a lipophilic substituent.

7. Formula (I-A3): R １ -X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ -R ２ (I-A3), During the ceremony, R １ is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, a polyethylene glycol chain, or a lipophilic substituent, and the 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe are １３ linked to said amino acid R ２ The peptide according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is CONH2, CO(DiFPip), CON(Me)2, a polyethylene glycol chain, or a lipophilic substituent.

8. X ３ The amino acid of １３ The peptide according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

9. X ５ The amino acid of １０ The peptide according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

10. X １０ The amino acid of １３ The peptide according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

11. R １ But, X １３ 8. The peptide according to claim 1, wherein the amino acid is linked to the amino acid:

12. X ３ , X ５ , X ６ , X ８ , X １２ , X １３ , X １４ , X １６ , or X １７ The peptide according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the amino acid of the formula (I) is conjugated to a polyethylene glycol chain.

13. X ３ , X ５ , X ６ , X ８ , X １２ , X １３ , X １４ , X １６ , or X １７ 113. The peptide of any one of claims 1 to 112, or a pharmaceutically acceptable salt thereof, wherein said amino acid is conjugated to a lipophilic substituent.

14. Amino acid sequence: R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -N-X １５ -X １６ -X １７ -R ２ (IB) During the ceremony, R １ 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, Z ｐｅｇ , or Z ｌｉｐｉｄ and X ３ is Dab(COCH2), K(COCH2CH2), hK(Me)3, K, K(5cpa), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , K(d), K(Me)3, Ser(MePEG2), R, SP6 or absent; X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , L, N, N(NMe), N(NMe2), Q, Q(NMe), or Q(NMe2), and X ７ is 7(3NacPh)W, 7BrW, 7MeW, BT, or W; X ８ are Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z ｐｅｇ , K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , Lys(N+Me2)-Z ｐｅｇ , Q, or Q(NMe2), X ９ is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X １０ 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z ｐｅｇ , AEF(NMe)-Z ｐｅｇ , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y; X １１ but, 【Chemistry 31】 and R Ｍ But halo, -OH, -C （１～３） Alkyl, —OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R Ｎ is —H or —OH, R Ｏ But, -OC （１～３） Alkyl or —C(O)NH ２ and R Ｐ But halo, -OH, -C （１～３） Alkyl, —OC （１～３） Alkyl, —C(O)NH ２ , -OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X １２ is THP, aMeL, diFCpx, or Pip(NMe2), X １３ are C, D, Dab (NMeAc), Dab (NMecarn), E, ​​E (COcPEG3a), hE, K (Ac), K (Me) 3, K (NMeAc), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , L, or Q(NMe2), X １５ is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP; X １６ However, Sar, NMeK-Z ｌｉｐｉｄ or not present, X １７ But K-Z ｌｉｐｉｄ , NMeK-Z ｌｉｐｉｄ or not present, R ２ is CONH2, CO(DiFPip), CON(Me)2, or Z ｐｅｇ and Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z ｌｉｐｉｄ is, independently at each occurrence, a lipophilic substituent; The peptide is X ４ Residues of and X ９ and cyclized via a linkage between the residues of During the ceremony, (a) R １ is 5Ava, 6Ahx, 7Ahp, PEG2, or PEG2NMe, the peptide is １ Residues of and X １３ and a residue selected from E or hE, (b) X ３ is Dab(COCH2), k(COCH2CH2), or Ser(MePEG2), and optionally, X ３ is k, the peptide is ３ Residues of and X １３ and a residue selected from C, D, or E of (c) X ５ is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), or K(NNs), and optionally X ５ But K-Z ｐｅｇ or K-Z ｌｉｐｉｄ When the peptide is ５ Residues of and X １０ or AEF(NMe), (d) X １０ is AEF or AEF(NMe), the peptide optionally comprises X １０ Residues of and X ５ D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), K-Z ｐｅｇ , and K-Z ｌｉｐｉｄ or X １３ and further comprising a linkage between the E residue of (e) X １３ is C, D, or hE, and optionally X １３ is E, the peptide is １３ Residues of and R １ a residue selected from 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe, or X ３ a residue selected from Dab(COCH2), k(COCH2CH2), k, and Ser(MePEG2), or X １０ and a linkage between the AEF residue of provided that the peptide is １ and X １３ , X ３ and X １３ , X ５ and X １０ , and X １０ and X １３ 14. The peptide of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, provided that it contains no more than one linkage between any one of:

15. Formula (IC): R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -X １１ -THP-X １３ -N-X １５ -Sar-X １７ -R ２ (IC) During the ceremony, R １ But 5cpaCO, CF3CO, MeCO, Z ｐｅｇ , or Z ｌｉｐｉｄ and X ３ is hk(Me)3,k,kZ ｐｅｇ , k-Z ｌｉｐｉｄ , k(d), k(Me)3, K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , r, R, SP6 or absent; X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , N, N(NMe2), Q, or Q(NMe2), and X ７ is 7(3NAcPh)W, 7MeW, or W; X ８ are Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , K(Ac), K(NMeAc), NMeK-Z ｐｅｇ , K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , Q, or Q(NMe2), X ９ is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X １０ However, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z ｐｅｇ , AEF(NMe)-Z ｐｅｇ , bMeAEF, MMoEF, or TMAPF; X １１ is 2Nal6((5CF3)3Pyrazole), 6OH2Nal, 2Nal6(Ph2OH), 2Nal6(Ph4(NMorph)), 2Nal6(3Pyrazole), 2Nal6(40MePh), 50Me2Nal, 5amido2Nal, 5Br2Nal, 5Me2Nal, 6MeQui, 6O(COCF3)2Nal, 6F2Nal, 6Br2Nal, or 7OH2Nal; X １３ is Dab(NMeAc), Dab(NMecarn), E, ​​K(Ac), K(NMeAc), K-Z ｐｅｇ , or K-Z ｌｉｐｉｄ and X １５ is 3Pya, 5MePyridinAla, or THP; X １７ But K-Z ｌｉｐｉｄ , NMeK-Z ｌｉｐｉｄ or not present, R ２ is CONH2, CON(Me)2, or Z ｐｅｇ and Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z ｌｉｐｉｄ is, independently at each occurrence, a lipophilic substituent; The peptide is X ４ Residues of and X ９ and X ５ is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), or K(NNs), and optionally X ５ But K-Z ｐｅｇ or K-Z ｌｉｐｉｄ When the peptide is ５ Residues of and X １０ 14. The peptide of claim 1, further comprising a linkage between a residue selected from AEF(NMe) and AEF(NMe), or a pharmaceutically acceptable salt thereof.

16. Formula (ID): R １ -X ３ -Pen-X ５ -T-X ７ -X ８ -Pen-X １０ -6OH2Nal-THP-X １３ -N-3Pya-Sar-X １７ -R ２ (I-D) During the ceremony, R １ But MeCO, Z ｐｅｇ , or Z ｌｉｐｉｄ and X ３ But k-Z ｐｅｇ , k-Z ｌｉｐｉｄ , k(Me)3, r or absent; X ５ is D, E, hE, N, N(NMe2), Q, or Q(NMe2); X ７ is 7(3NAcPh)W, 7MeW, or W; X ８ However, K(Ac), K(NMeAc), NMeK-Z ｐｅｇ , K-Z ｐｅｇ , or K-Z ｌｉｐｉｄ and X １０ is AEF or TMAPF, X １３ But E, K(Ac), K(NMeAc), KZ ｐｅｇ , or K-Z ｌｉｐｉｄ and X １７ But K-Z ｌｉｐｉｄ , NMeK-Z ｌｉｐｉｄ or not present, R ２ is CONH2, CON(Me)2, or Z ｐｅｇ and Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z ｌｉｐｉｄ is, independently at each occurrence, a lipophilic substituent; The peptide is X ４ Pen residue and X ９ and X ５ is D, E, or hE, the peptide is ５ Residues of and X １０ 16. The peptide of any one of claims 1 to 13 or 15, or a pharmaceutically acceptable salt thereof, further comprising a linkage between the AEF residue of

17. Formula (IE): R １ -X ３ -Pen-X ５ -T-7(3NAcPh)W-X ８ -Pen-X １０ -6OH2Nal-THP-X １３ -N-3Pya-Sar-X １７ -R ２ (I-E) During the ceremony, R １ MeCO or Z ｐｅｇ and X ３ is r or absent, X ５ is E, N, or N(NMe2), X ８ is K(Ac) or K(NMeAc), X １０ is AEF or TMAPF, X １３ is E, K(Ac), or K(NMeAc); X １７ But K-Z ｌｉｐｉｄ or not present, R ２ is CONH2 or CON(Me)2, Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z ｌｉｐｉｄ is, independently at each occurrence, a lipophilic substituent; The peptide is X ４ The Pen residue and X ９ and X ５ is E, the peptide is ５ E residue and X １０ 17. The peptide of any one of claims 1 to 13, 15, or 16, or a pharmaceutically acceptable salt thereof, further comprising a linkage between said AEF residue and said AEF residue:

18. R １ is 5cpaCO, CF3CO, CF3Propylamide, EtCO, MeCO, Z ｐｅｇ , or Z ｌｉｐｉｄ and X ３ is hk(Me)3, k, k(5cpa), k-Z ｐｅｇ , k-Z ｌｉｐｉｄ , k(d), k(Me)3, K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , r, R, SP6 or absent; X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ But K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , L, N, N(NMe2), Q, or Q(NMe2); X ７ is 7(3NAcPh)W, 7BrW, 7MeW, BT, or W; X ８ are Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z ｐｅｇ , K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , Lys(N+Me2)-Z ｐｅｇ , Q, or Q(NMe2), X ９ is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X １０ 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z ｐｅｇ , AEF(NMe)-Z ｐｅｇ , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y; X １１ but, 【Chemistry 32】 and R Ｍ But halo, -OH, -C （１～３） Alkyl, —OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocycle; R Ｎ is —H or —OH, R Ｏ But, -OC （１～３） Alkyl or —C(O)NH ２ and R Ｐ But halo, -OH, -C （１～３） Alkyl, —OC （１～３） Alkyl, —C(O)NH ２ , -OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocycle; X １２ is THP, aMeL, diFCpx, or Pip(NMe2), X １３ are Dab(NMeAc), Dab(NMecarn), E, ​​E(COcPEG3a), K(Ac), K(Me)3, K(NMeAc), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , L, or Q(NMe2), X １５ is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP; X １６ However, Sar, NMeK-Z ｌｉｐｉｄ or not present, X １７ But K-Z ｌｉｐｉｄ , NMeK-Z ｌｉｐｉｄ or not present, R ２ is CONH2, CO(DiFPip), CON(Me)2, or Z ｐｅｇ and Z ｐｅｇ is, independently at each occurrence, a polyethylene glycol chain; Z ｌｉｐｉｄ is, independently at each occurrence, a lipophilic substituent; The peptide is X ４ Residues of and X ９ 14. The peptide of claim 1, wherein the peptide is cyclized via a linkage between the residues of:

19. Formula (IF): R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -N-X １５ -X １６ -R ２ (I-F) During the ceremony, R １ is 5Ava, 5cpaCO, 6Ahx, 7Ahp, CF3CO, CF3Propylamide, EtCO, MeCO, PEG2, PEG2NMe, or Z ｐｅｇ and X ３ is Dab(COCH2), k(COCH2CH2), hk(Me)3, k, k(5cpa), k(d), k(Me)3, Ser(MePEG2), r, R, SP6 or absent; X ４ is 4AminoPro, Abu, aG, aMeC, C, Dap, Pen, Pen(oXyl), Pen(mXyl), Pen(pXyl), or Pra; X ５ is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), K-Z ｐｅｇ L, N, N(NMe), N(NMe2), Q, Q(NMe), or Q(NMe2), and X ７ is 7(3NAcPh)W, 7BrW, 7MeW, BT, or W; X ８ are Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z ｐｅｇ , K-Z ｐｅｇ , Lys(N+Me2)-Z ｐｅｇ , Q, or Q(NMe2), X ９ is aMeC, aG, C, D, E, hE, Pen, or Dap(N3); X １０ 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z ｐｅｇ , AEF(NMe)-Z ｐｅｇ , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y; X １１ but, 【Transformation 33】 and R Ｍ But halo, -OH, -C （１～３） Alkyl, —OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; R Ｎ is —H or —OH, R Ｏ But, -OC （１～３） Alkyl or —C(O)NH ２ and R Ｐ But halo, -OH, -C （１～３） Alkyl, —OC （１～３） Alkyl, —C(O)NH ２ , -OC(O)C （１～３） haloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are each —OH, —OC （１～３） Alkyl, —C （１～３） optionally substituted with 1 to 3 groups selected from haloalkyl, and 3- to 6-membered heterocyclyl; X １２ is THP, aMeL, diFCpx, or Pip(NMe2), X １３ are C, D, Dab (NMeAc), Dab (NMecarn), E, ​​E (COcPEG3a), hE, K (Ac), K (Me) 3, K (NMeAc), K-Z ｐｅｇ , L, or Q(NMe2), X １５ is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP; X １６ is Sar or absent, R ２ is CONH2, CO(DiFPip), CON(Me)2, or Z ｐｅｇ and Z ｐｅｇ is, independently at each occurrence, polyethylene glycol; The peptide is X ４ Residues of and X ９ and cyclized via a linkage between the residues of During the ceremony, (a) R １ is 5Ava, 6Ahx, 7Ahp, PEG2, or PEG2NMe, the peptide is １ Residues of and X １３ and a residue selected from E or hE, (b) X ３ is Dab(COCH2), k(COCH2CH2), or Ser(MePEG2), and optionally, X ３ is k, the peptide is ３ Residues of and X １３ and a residue selected from C, D, or E of (c) X ５ is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), or K(NNs), and optionally X ５ But K-Z ｐｅｇ When the peptide is ５ Residues of and X １０ or AEF(NMe), (d) X １０ is AEF or AEF(NMe), the peptide optionally comprises X １０ and X ５ D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), K(NNs), and KZ ｐｅｇ or X １３ and further comprising a linkage between the E residue of (e) X １３ is C, D, or hE, and optionally X １３ is E, the peptide is １３ Residues of and R １ a residue selected from 5Ava, 6Ahx, 7Ahp, PEG2, and PEG2NMe, or X ３ a residue selected from Dab(COCH2), k(COCH2CH2), k, and Ser(MePEG2), or X １０ and a linkage between the AEF residue of provided that the peptide is １ and X １３ , X ３ and X １３ , X ５ and X １０ , and X １０ and X １３ 12. The peptide of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, provided that it contains no more than one linkage between any one of:

20. 20. The peptide of any one of claims 1 to 14, 18, or 19, or a pharmaceutically acceptable salt thereof, wherein the peptide is not MeCO-Pen-N-T-7MeW-K(Ac)-Pen-AEF-6OHQui-THP-E-N-3Pya-Sar-CONH2.

21. R １ MeCO or Z ｐｅｇ 21. The peptide according to any one of claims 5, 7 to 16, or 18 to 20, or a pharmaceutically acceptable salt thereof, wherein:

22. R １ The peptide according to any one of claims 5, 7 to 20, or a pharmaceutically acceptable salt thereof, wherein is MeCO.

23. X ３ are Dab(COCH2), Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , Dab-Z ｌｉｐｉｄ , K(COCH2CH2), hK(Me)3), K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , NMeK-Z ｐｅｇ , NMeK-Z ｌｉｐｉｄ , Ser(MePEG2), R, SP6 or absent; The Dab(COCH2), K(COCH2CH2), and Ser(MePEG2) are １３ 23. The peptide according to any one of claims 1 to 13 or 20 to 22, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

24. X ３ are dDab(COCH2), dDab(NMeAc), dDab(Nmecarn), dDab-Z ｐｅｇ , dDab-Z ｌｉｐｉｄ , k (COCH2CH2), hk (Me) 3, k, k (5 cpa), k (Ac), k (d), k (G), k (Me) 3, k (NMe), k (NMeAc), k (NNs), k-Z ｐｅｇ , k-Z ｌｉｐｉｄ , NMek-Z ｐｅｇ , NMek-Z ｌｉｐｉｄ , dSer(MePEG2), r, SP6 or absent; The dDab(COCH2), k(COCH2CH2), and dSer(MePEG2) are １３ 23. The peptide according to claim 1 to 13 or 20 to 22, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

25. X ３ is Dab(COCH2), k(COCH2CH2), hk(Me)3, k, k(5cpa), k-Z ｐｅｇ , k-Z ｌｉｐｉｄ , k(d), k(Me)3, K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , Ser(MePEG2), r, R, SP6 or absent; The Dab(COCH2), k(COCH2CH2), and Ser(MePEG2) are １３ 23. The peptide according to any one of claims 1 to 13 or 20 to 22, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

26. X ３ But k-Z ｐｅｇ , k-Z ｌｉｐｉｄ , k(Me)3, r, or absent, or a pharmaceutically acceptable salt thereof.

27. X ３ The peptide according to any one of claims 1 to 13, 15, 16, 18 to 22, or 24 to 26, or a pharmaceutically acceptable salt thereof, wherein is r.

28. X ３ The peptide according to any one of claims 1 to 16 or 18 to 27, or a pharmaceutically acceptable salt thereof, wherein

29. X ４ The peptide according to any one of claims 1 to 13 or 20 to 28, or a pharmaceutically acceptable salt thereof, wherein is Abu, C, or Pen.

30. X ５ is D, E, hE, K, K(5 cPa), K(a), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , NMeK-Z ｐｅｇ , NMeK-Z ｌｉｐｉｄ is L, N, N(NMe), N(NMe2), Q, Q(NMe), or Q(NMe2), The D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), and K(NNs) are X １０ and optionally linked to said amino acid of K-Z ｐｅｇ or K-Z ｌｉｐｉｄ But, X １０ 30. The peptide according to any one of claims 1 to 13 or 20 to 29, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

31. X ５ is D, E, hE, K, K(a), K(Ac), K(d), K(G), K(Nme), K(NNs), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , L, N, N(NMe2), Q, or Q(NMe2), and The D, E, hE, K, K(a), K(Ac), K(d), K(G), K(NMe), and K(NNs) are X １０ and optionally linked to said amino acid of K-Z ｐｅｇ or K-Z ｌｉｐｉｄ But, X １０ 31. The peptide according to any one of claims 1 to 13 or 20 to 30, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

32. X ５ is E, N, or N(NMe2), and the E is X １０ 32. The peptide according to any one of claims 1 to 15 or 19 to 31, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

33. X ５ But, X １０ 33. The peptide of any one of claims 1 to 15 or 19 to 32, or a pharmaceutically acceptable salt thereof, wherein:

34. X ５ The peptide according to any one of claims 1 to 15 or 19 to 32, or a pharmaceutically acceptable salt thereof, wherein

35. X ６ The peptide according to any one of claims 1 to 13 or 20 to 34, or a pharmaceutically acceptable salt thereof, wherein

36. X ７ but, 【Transformation 34】 36. The peptide according to any one of claims 1 to 13 or 20 to 35, or a pharmaceutically acceptable salt thereof.

37. X ７ The peptide according to any one of claims 1 to 13 or 20 to 35, or a pharmaceutically acceptable salt thereof, wherein is 7(3NacPh)W, 7BrW, 7MeW, BT, or W.

38. X ７ The peptide according to any one of claims 1 to 16 or 18 to 37, or a pharmaceutically acceptable salt thereof, wherein is 7(3NAcPh)W or 7MeW.

39. X ８ are Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , Dab-Z ｌｉｐｉｄ , hK(Me)3, K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , NMeK-Z ｐｅｇ , NMeK-Z ｌｉｐｉｄ , Lys(N+Me2)-Z ｐｅｇ , Lys(N+Me2)-Z ｌｉｐｉｄ , Q, or Q(NMe2), or a pharmaceutically acceptable salt thereof.

40. X ８ are Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , hK(Me)3, K(Ac), K(Me)3, K(NMeAc), NMeK-Z ｐｅｇ , K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , Lys(N+Me2)-Z ｐｅｇ 40. The peptide of any one of claims 1 to 13 or 20 to 39, or a pharmaceutically acceptable salt thereof, wherein Q is NMe2, Q, or Q(NMe2).

41. X ８ However, K(Ac), K(NMeAc), NMeK-Z ｐｅｇ , K-Z ｐｅｇ , or K-Z ｌｉｐｉｄ 41. The peptide according to any one of claims 1 to 15, 18, or 20 to 40, or a pharmaceutically acceptable salt thereof.

42. X ８ The peptide according to any one of claims 1 to 15 or 18 to 41, or a pharmaceutically acceptable salt thereof, wherein is K(Ac) or K(NMeAc).

43. X ９ The peptide according to any one of claims 1 to 13 or 20 to 42, or a pharmaceutically acceptable salt thereof, wherein is aMeC, C, or Pen.

44. X ４ is Abu, and X ９ is aMeC or X ４ is Abu, and X ９ is C or X ４ is C and X ９ is aMeC, or X ４ is Pen, and X ９ The peptide according to any one of claims 1 to 15 or 18 to 43, or a pharmaceutically acceptable salt thereof, wherein is Pen.

45. X ４ is Pen, and X ９ The peptide according to any one of claims 1 to 15 or 18 to 44, or a pharmaceutically acceptable salt thereof, wherein is Pen.

46. X １０ but, 【Chemistry 35】 46. ​​The peptide according to any one of claims 1 to 13 or 20 to 45, or a pharmaceutically acceptable salt thereof.

47. X １０ 4DMPzEF, 4OMeF, AEF, AEF(G), AEF(NMe), AEF(NMe2), AEF-Z ｐｅｇ , AEF(NMe)-Z ｐｅｇ , APEG3F, bMeAEF, F, MMoEF, TMAPF, or Y. Optionally, said AEF or AEF(NMe) is X ５ or X １３ 46. ​​The peptide of any one of claims 1 to 13 or 20 to 45, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

48. X １０ The peptide according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein is AEF.

49. X １１ but, 【Transformation 36】 49. The peptide according to any one of claims 1 to 13 or 20 to 48, or a pharmaceutically acceptable salt thereof, wherein:

50. X １１ but, 【Chemistry 37】 50. The peptide according to any one of claims 1 to 13 or 20 to 49, or a pharmaceutically acceptable salt thereof, wherein:

51. X １１ 49. The peptide according to any one of claims 1 to 14 or 18 to 48, wherein R is 2Nal((5CF3)3Pyrazole), 6OH2Nal, 2Nal6(Ph2OH), 2Nal6(Ph4(NMorph)), 2Nal6(3Pyrazole), 2Nal6(40MePh), 50Me2Nal, 5amido2Nal, 5Br2Nal, 5Me2Nal, 6MeQui, 6O(COCF3)2Nal, 6F2Nal, 6Br2Nal, or 7OH2Nal, or a pharmaceutically acceptable salt thereof.

52. X １１ 50. The peptide according to any one of claims 1 to 15 or 18 to 49, wherein is 2Nal6((5CF3)3Pyrazole), 6OH2Nal, 2Nal6(Ph2OH), 2Nal6(Ph4(NMorph)), 2Nal6(3Pyrazole), 2Nal6(40MePh), 5Br2Nal, 5Me2Nal, 6O(COCF3)2Nal, 6F2Nal, 6Br2Nal, or 7OH2Nal, or a pharmaceutically acceptable salt thereof.

53. X １１ The peptide according to any one of claims 1 to 15 or 18 to 52, or a pharmaceutically acceptable salt thereof, wherein is 6OH2Nal.

54. X １２ The peptide according to any one of claims 1 to 13 or 20 to 53, or a pharmaceutically acceptable salt thereof, wherein is THP, aMeL, diFCpx, or Pip(Nme2).

55. X １２ The peptide according to any one of claims 1 to 14 or 18 to 54, or a pharmaceutically acceptable salt thereof, wherein is THP.

56. X １３ is C, D, Dab(NMeAc), Dab(NMecarn), Dab-Z ｐｅｇ , Dab-Z ｌｉｐｉｄ , E, E(COcPEG3a), hE, K, K(5cpa), K(Ac), K(d), K(G), K(Me)3, K(NMe), K(NMeAc), K(NNs), K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , NMeK-Z ｐｅｇ , NMeK-Z ｌｉｐｉｄ , L, or Q(NMe2), and The C, D, and hE are R １ , X ３ or X １０ and optionally E is linked to said amino acid of １ , X ３ or X １０ 56. The peptide of any one of claims 1 to 13 or 20 to 55, or a pharmaceutically acceptable salt thereof, wherein the amino acid is linked to the amino acid:

57. X １３ is Dab(NMeAc), Dab(NMecarn), E, ​​K(Ac), K(NMeAc), K-Z ｐｅｇ , or K-Z ｌｉｐｉｄ 57. The peptide according to any one of claims 1 to 13 or 20 to 56, or a pharmaceutically acceptable salt thereof, wherein:

58. X １３ The peptide according to any one of claims 1 to 16 or 18 to 57, or a pharmaceutically acceptable salt thereof, wherein is E, K(Ac), or K(NMeAc).

59. X １３ The peptide according to any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein

60. X １３ The peptide according to any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein is K(Ac).

61. X １４ The peptide according to any one of claims 1 to 13 or 20 to 60, or a pharmaceutically acceptable salt thereof, wherein

62. X １５ but, 【Transformation 38】 62. The peptide according to any one of claims 1 to 13 or 20 to 61, or a pharmaceutically acceptable salt thereof.

63. X １５ 62. The peptide of any one of claims 1 to 13 or 20 to 61, or a pharmaceutically acceptable salt thereof, wherein is 3AmPyrazolAla, 3Pya, 5AmPyridinAla, 5MePyridinAla, Ala, ACIPA, aMePhe, H, or THP.

64. X １５ The peptide according to any one of claims 1 to 15 or 18 to 63, or a pharmaceutically acceptable salt thereof, wherein is 3Pya.

65. X １６ However, Sar, Dab-Z ｐｅｇ , Dab-Z ｌｉｐｉｄ , K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , NMeK-Z ｐｅｇ , NMeK-Z ｌｉｐｉｄ 65. The peptide of any one of claims 1 to 13 or 20 to 64, or a pharmaceutically acceptable salt thereof, wherein:

66. X １６ However, Sar, NMeK-Z ｌｉｐｉｄ 66. The peptide of any one of claims 1 to 13 or 20 to 65, or a pharmaceutically acceptable salt thereof, wherein:

67. X １６ The peptide according to any one of claims 1 to 14 or 18 to 66, or a pharmaceutically acceptable salt thereof, wherein is Sar.

68. X １７ But Dab-Z ｐｅｇ , Dab-Z ｌｉｐｉｄ , K-Z ｐｅｇ , K-Z ｌｉｐｉｄ , NMeK-Z ｐｅｇ , NMeK-Z ｌｉｐｉｄ 68. The peptide of any one of claims 1 to 13 or 20 to 67, or a pharmaceutically acceptable salt thereof, wherein:

69. X １７ But K-Z ｌｉｐｉｄ , NMeK-Z ｌｉｐｉｄ 69. The peptide of any one of claims 1 to 13 or 20 to 68, or a pharmaceutically acceptable salt thereof, wherein:

70. X １７ But K-Z ｌｉｐｉｄ 70. The peptide according to any one of claims 1 to 18 or 20 to 69, or a pharmaceutically acceptable salt thereof, wherein:

71. X １７ The peptide according to any one of claims 1 to 18 or 20 to 70, or a pharmaceutically acceptable salt thereof, wherein

72. R ２ The peptide according to any one of claims 6 to 71, or a pharmaceutically acceptable salt thereof, wherein is CONH2.

73. The following formula: X ３ -X ４ -X ５ -X ６ -7MeW-X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I-G1a)、 X ３ -X ４ -X ５ -X ６ -7(3NAcPh)W-X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I-G1b)、 X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -AEF-X １１ -X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I-H1)、 X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -6OH2Nal-X １２ -X １３ -X １４ -X １５ -X １６ -X １７ (I-I1)、 X ３ -X ４ -X ５ -X ６ -X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -X １４ -3Pya-X １６ -X １７ (I-J1)、 X ３ -X ４ -X ５ -X ６ -7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ -X １７ (I-K1a)、 X ３ -X ４ -X ５ -X ６ -7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ -X １７ (I-K1b)、 r-X ４ -X ５ -X ６ -7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ -X １７ (I-L1a)、 r-X ４ -X ５ -X ６ -7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ -X １７ (I-L1b)、 X ３ -Pen-X ５ -X ６ -7MeW-X ８ -Pen-AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ -X １７ (I-M1a)、 X ３ -Pen-X ５ -X ６ -7(3NAcPh)W-X ８ -Pen-AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ -X １７ (I-M1b)、 X ３ -X ４ -X ５ -X ６ -7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-Sar-X １７ (I-N1a)、 X ３ -X ４ -X ５ -X ６ -7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-Sar-X １７ (I-N1b)、 X ３ -X ４ -X ５ -X ６ -7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ (I-O1a), or X ３ -X ４ -X ５ -X ６ -7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -X １４ -3Pya-X １６ (I-O1b), or a pharmaceutically acceptable salt thereof.

74. The following formula: R １ -X ３ -X ４ -X ５ -T-7MeW-X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -N-X １５ -X １６ -X １７ -R ２ (I-G2a)、 R １ -X ３ -X ４ -X ５ -T-7(3NAcPh)W-X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -N-X １５ -X １６ -X １７ -R ２ (I-G2b)、 R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -AEF-X １１ -X １２ -X １３ -N-X １５ -X １６ -X １７ -R ２ (I-H2)、 R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -6OH2Nal-X １２ -X １３ -N-X １５ -X １６ -X １７ -R ２ (I-I2)、 R １ -X ３ -X ４ -X ５ -T-X ７ -X ８ -X ９ -X １０ -X １１ -X １２ -X １３ -N-3Pya-X １６ -X １７ -R ２ (I-J2)、 R １ -X ３ -X ４ -X ５ -T-7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -X １７ -R ２ (I-K2a)、 R １ -X ３ -X ４ -X ５ -T-7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -X １７ -R ２ (I-K2b)、 R １ -r-X ４ -X ５ -T-7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -X １７ -R ２ (I-L2a)、 R １ -r-X ４ -X ５ -T-7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -X １７ -R ２ (I-L2b)、 R １ -X ３ -Pen-X ５ -T-7MeW-X ８ -Pen-AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -X １７ -R ２ (I-M2a)、 R １ -X ３ -Pen-X ５ -T-7(3NAcPh)W-X ８ -Pen-AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -X １７ -R ２ (I-M2b)、 R １ -X ３ -X ４ -X ５ -T-7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-Sar-X １７ -R ２ (I-N2a)、 R １ -X ３ -X ４ -X ５ -T-7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-Sar-X １７ -R ２ (I-N2b)、 R １ -X ３ -X ４ -X ５ -T-7MeW-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -R ２ (I-O2a), or R １ -X ３ -X ４ -X ５ -T-7(3NAcPh)W-X ８ -X ９ -AEF-6OH2Nal-X １２ -X １３ -N-3Pya-X １６ -R ２ (I-O2b), or a pharmaceutically acceptable salt thereof.

75. 75. The peptide of any one of claims 1, 3, 5-7, 12, 13, or 21-74, wherein the first ring comprises 4 to 9 or 11 amino acids.

76. The first ring is X ４ and X ９ , X ４ and X １３ , X ５ and X １０ , X ３ and X １３ , or X ６ and X ９ The peptide of any one of claims 1, 3, 5 to 7, 12, 13, or 21 to 74, which is formed between

77. The first ring is X ４ and X ９ , X ４ and X １３ , or X ６ and X ９ 77. The peptide of claim 76, which is formed between

78. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ４ and X ９ 78. The peptide of claim 77, which is formed between

79. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ４ and X １３ 78. The peptide of claim 77, which is formed between

80. the first ring is connected to X via a linker having one or more groups selected from the group consisting of disulfide, thioether, amide, olefin, ether, alkylene, and triazole; ６ and X ９ 78. The peptide of claim 77, which is formed between

81. 81. The peptide of any one of claims 1, 3, 5-7, 12, 13, or 21-80, wherein the peptide is further cyclized to form a second ring containing 4 to 11 or 14 amino acids.

82. 82. The peptide of claim 81, wherein the peptide is further cyclized to form a second ring containing 4, 6, 10, or 11 amino acids.

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

84. the peptide is further cyclized to form a second ring; the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ５ and X １０ or the second ring is connected to X via a linker having one or more groups selected from the group consisting of disulfides, thioethers, amides, olefins, ethers, alkylenes, and triazoles; ６ and X ９ 80. The peptide of claim 79, which is formed between

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

86. 86. The peptide of any one of claims 1 to 85, or a pharmaceutically acceptable salt thereof, wherein each polyethylene glycol chain independently terminates in an ammonium group or a methyl group.

87. Each polyethylene glycol chain, independently at each occurrence, 【Chemistry 39】 and During the ceremony, Z Ａ But, -OCH ３ or -N ＋ (CH ３ ) ３ and 87. The peptide according to any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 2 to 15.

88. R １ , R ２ or any amino acid in the amino acid sequence is conjugated to a polyethylene glycol chain, or a pharmaceutically acceptable salt thereof.

89. each lipophilic substituent independently at each occurrence: 【Chemistry 40】 and During the ceremony, Z Ｂ but, 【Chemistry 41】 and Z Ｃ But Z Ｃ１ , Z Ｃ２ , or Z Ｃ３ and Z Ｃ１ but, 【Chemistry 42】 and Z Ｃ２ but, 【Chemistry 43】 and Z Ｃ３ but, 【Chemistry 44】 and Z Ｄ but, 【Chemistry 45】 and Z Ｅ is —H, —COOH, or tetrazolyl; Z Ｆ is —H or —CH ３ and Xaa is, independently for each occurrence: 【Chemistry 46】 and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; v is 0 or 1; 89. The peptide of any one of claims 5-7, 13-18, or 20-88, or a pharmaceutically acceptable salt thereof, wherein w is, independently at each occurrence, 0 or 1.

90. each lipophilic substituent independently at each occurrence: 【Chemistry 47】 and During the ceremony, Z Ｃ２ but, 【Chemistry 48】 and Z Ｄ but, 【Chemistry 49】 and Z Ｅ is —H, —COOH, or tetrazolyl; Z Ｆ is —H or —CH ３ and Xaa is [Transformation 50] and p is, independently at each occurrence, 1, 2, 3, 4, 5, or 6; q is 1, 2, 3, 4, 5, or 6; r is an integer from 6 to 24; 90. The peptide of any one of claims 12-18 or 20-89, or a pharmaceutically acceptable salt thereof, wherein w is, independently at each occurrence, 0 or 1.

91. R １ , R ２ or any amino acid in said amino acid sequence is conjugated to a lipophilic substituent, or a pharmaceutically acceptable salt thereof.

92. 92. The peptide of any one of claims 12 to 18 or 20 to 91, wherein the peptide comprises no more than one lipophilic substituent.

93. A peptide having any one of the amino acid sequences of SEQ ID NOs: 1 to 447, or a pharmaceutically acceptable salt thereof.

94. MeCO-k(Me)3-Pen(3)-NT-7(3NAcPh)W-K(Ac)-Pen(3)-AEF(G)-6OH2Nal-THP-EN-5MePyridinAla-Sar-CONH2 (SEQ ID NO: 11), MeCO-r-Pen(3)-NT-7(3NAcPh)W-K(Ac)-Pen(3)-AEF(G)-6OH2Nal-THP-EN-5MePyridinAla-Sar-CONH2 (SEQ ID NO: 15), cPEG3aCO-Pen(3)-N-T-7(3NAcPh)W-K(Ac)-Pen(3)-AEF(G)-6OH2Nal-THP-K(NMeAc)-N-3Pya-Sar-CONH2 (SEQ ID NO: 34), MeCO-r-Pen(3)-NT-7MeW-K(Ac)-Pen(3)-TMAPF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 59), MeCO-k(Me)3-Pen(3)-N-T-7(3NAcPh)W-K(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 68), 5cpaCO-Pen(3)-K(5)-T-7MeW-K(Ac)-Pen(3)-AEF(5)-6OH2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 112) MeCO-r-Pen(3)-NT-7(3NAcPh)W-K(Ac)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 287), MeCO-Pen(3)-N(NMe2)-T-7MeW-K(NMeAc)-Pen(3)-AEF(NMePEG3a)-6OH2Nal-THP-K(NMeAc)-N-3Pya-Sar-CONH(PEG3a) (SEQ ID NO: 315), cPEG3aCO-Pen(3)-NT-7MeW-K (NMecPEG3a)-Pen(3)-AEF-6OH2Nal-THP-EN-3Pya-Sar-CONH2 (SEQ ID NO: 319), PEG2NMe(2)-Pen(3)-NT-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-hE(2)-N-3Pya-Sar-CONH2 (SEQ ID NO: 358), cPEG3aCO-Pen(3)-E(2)-T-7MeW-K(Ac)-Pen(3)-AEF(2)-6OH2Nal-THP-K(Ac)-N-3Pya-Sar-CONH2 (SEQ ID NO: 364), cPEG3aCO-Pen(3)-N(N(Me)2)-T-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-Dab(NMeAc)-N-3Pya-Sar-CON(Me)2 (SEQ ID NO: 371), cPEG3aCO-k(2)-Pen(3)-N(N(Me)2)-T-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-hE(2)-N-3Pya-Sar-CON(Me)2 (SEQ ID NO: 373), and 94. The peptide of claim 93, having an amino acid sequence selected from the group consisting of: cPEG3aCO-Pen(3)-N-T-7MeW-K(NMeAc)-Pen(3)-AEF-6OH2Nal-THP-Q(N(Me)2)-N-3Pya-Sar-CONH2 (SEQ ID NO: 392). or a pharmaceutically acceptable salt thereof.

95. A peptide having the following structure: 【Chemistry 51】 or a pharmaceutically acceptable salt thereof.

96. A peptide having the following structure: 【Chemistry 52】 or a pharmaceutically acceptable salt thereof.

97. A peptide having the following structure: 【Chemistry 53】 or a pharmaceutically acceptable salt thereof.

98. A peptide having the following structure: 【Chemistry 54】 or a pharmaceutically acceptable salt thereof.

99. A peptide having the following structure: 【Transformation 55】 or a pharmaceutically acceptable salt thereof.

100. A peptide having the following structure: 【Transformation 56】 or a pharmaceutically acceptable salt thereof.

101. A peptide having the following structure: 【Chemistry 57】 or a pharmaceutically acceptable salt thereof.

102. A peptide having the following structure: 【Transformation 58】 or a pharmaceutically acceptable salt thereof.

103. A peptide having the following structure: 【Chemistry 59】 or a pharmaceutically acceptable salt thereof.

104. A peptide having the following structure: 【Transformation 60】 or a pharmaceutically acceptable salt thereof.

105. A peptide having the following structure: 【Chemistry 61】 or a pharmaceutically acceptable salt thereof.

106. A peptide having the following structure: 【Transformation 62】 or a pharmaceutically acceptable salt thereof.

107. A peptide having the following structure: 【Transformation 63】 or a pharmaceutically acceptable salt thereof.

108. A peptide having the following structure: 【Chemistry 64】 or a pharmaceutically acceptable salt thereof.

109. A pharmaceutical composition comprising the peptide according to any one of claims 1 to 108, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

110. A method for treating a disease or disorder associated with interleukin-23 (IL-23) / interleukin-23 receptor (IL-23R), comprising administering to a subject in need thereof a therapeutically effective amount of a peptide according to any one of claims 1 to 108 or a pharmaceutical composition according to claim 109.

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

112. 111. The method of claim 110, wherein the disease or disorder is selected from ulcerative colitis (UC), Crohn's disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).

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