Cyclic peptide modulators of FCRN and uses thereof

Abstract

Provided herein are cyclic peptides capable of covalently binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins, and methods of using the same for the treatment and / or prevention of various diseases, including conditions associated with FcRn activity and / or immunoglobulin G (IgG) autoantibody levels in a subject.

Description

[0001] CYCLIC PEPTIDE MODULATORS OF FCRN AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003]

[0001] The present application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application, U.S.S.N. 63 / 679,746, filed August 6, 2024, the entire contents of which are incorporated herein by reference.

[0004] BACKGROUND

[0005]

[0002] The neonatal fragment crystallizable receptor (FcRn) plays an important role in extending the halflife of immunoglobulin G (IgG) autoantibodies, which are associated with numerous pathological conditions in subjects including autoimmune diseases. Because inhibition of FcRn can modulate IgG half-life, FcRn inhibitors are useful for the treatment of various diseases and conditions, such as IgG- mediated autoimmune and inflammatory conditions. See, e.g., Low and Mezo, “Inhibitors of the FcR lgG Protein-Protein Interaction” 2009, The AAPS Journal, vol. 11, no. 3, pp. 432-434; Pyzik et al. “The therapeutic age of the neonatal Fc receptor” 2023, Nature Reviews Immunology, vol. 23, pp. 415- 432. Examples of peptide inhibitors of FcRn can be found in, e.g., International PCT Application Publication Nos. WO 2007 / 098420, WO 2009 / 020867, and WO 2010 / 014909. Agents capable of modulating FcRn activity have therapeutic promise in the treatment of various diseases.

[0006] SUMMARY

[0007]

[0003] Provided herein are cyclic peptides capable of covalently binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins, and methods of using the same for the treatment and / or prevention of various diseases, including conditions associated with FcRn activity and / or immunoglobulin G (IgG) autoantibody levels in a subject.

[0008]

[0004] In one aspect, provided herein are cyclic peptides, and pharmaceutically acceptable salts thereof, comprising: (i) an amino acid sequence capable of binding FcRn; and (ii) a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety. In certain embodiments, the amino acid sequence capable of binding FcRn comprises the amino acid sequence:

[0009] G-H-F-G-Sar-NMeL-Y (SEQ ID NO: 1), wherein:

[0010] Sar is sarcosine, and NMeL is N-methyl-leucine; and the amino acid sequence includes 0, 1, 2, 3, 4, or 5 amino acid substitutions.

[0011]

[0005] In certain embodiments, the amino acid sequence capable of binding FcRn has at least 80% sequence identity with SEQ ID NO: 1.

[0012]

[0006] For example, in certain embodiments, the cyclic peptide or a pharmaceutically acceptable salt thereof comprises the amino acid sequence:

[0013] R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* (SEQ ID NO: 2), wherein:

[0014] Pen is penicillamine, Sar is sarcosine, and NMeL is N-methyl-leucine; the amino acid sequence includes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions;

[0015] C1751.70001WO00 1 / 174

[0016] #14267371vl * denotes crosslinked amino acids connected via a crosslink; and one amino acid comprises a group of the formula: -E’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

[0017]

[0007] In certain embodiments, the amino acid sequence has at least 80% sequence identity with SEQ ID NO: 2.

[0018]

[0008] In certain embodiments, for example, a cyclic peptide disclosed herein is selected from those recited in Tables 2A-2B infra), and pharmaceutically acceptable salts thereof.

[0019]

[0009] Also provided herein are conjugates (“dimers” herein) comprising two cyclic peptides described herein, wherein the two cyclic peptides are conjugated to one another via a bond or a linker. One or both of the cyclic peptides of the dimer comprise a group of the formula: -L’-Rw. In certain embodiments, exactly one cyclic peptide of the dimer comprises a group of the formula: -L’-Rw. In certain embodiments, both cyclic peptides of the dimer independently comprise a group of the formula: -L’-Rw.

[0010] In certain embodiments, for example, a dimer disclosed herein is selected from those recited in Table 2B (infra), and pharmaceutically acceptable salts thereof.

[0020] [Oil] In another aspect, provided herein are pharmaceutical compositions comprising a cyclic peptide described herein, a dimer described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a cyclic peptide or dimer, or pharmaceutically acceptable salt thereof.

[0021]

[0012] As described, the cyclic peptides, dimers, and pharmaceutical compositions provided herein can covalently inhibit FcRn and are therefore useful for treating and / or preventing diseases, disorders, and conditions in a subject, including, e.g., indications in which FcRn activity and / or IgG antibodies are implicated.

[0022]

[0013] Provided herein are methods and uses of the cyclic peptides, dimers, and pharmaceutical compositions provided herein, including, but not limited to, the following:

[0023] (a) Methods of treating an FcRn-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0024] (b) Methods of treating an IgG-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0025] (c) Methods of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0026] C1751.70001WO00 2 / 174

[0027] #14267371vl (d) Methods of covalently inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0028] (e) Methods of decreasing IgG levels in a subject in need thereof comprising administering to the subject an effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0029]

[0014] Also provided herein cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in any of the foregoing (a)-(e). In another aspect, provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use as medicaments and / or for use in the manufacture of medicaments.

[0030]

[0015] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims.

[0031] DEFINITIONS

[0032] General Definitions

[0033]

[0016] The term “peptide” refers to a polymer of amino acid residues linked together by peptide bonds. Typically, a peptide will be at least three amino acids long, or at least the length required by an amino acid sequence provided herein. Peptides provided herein can include natural amino acids and / or unnatural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a peptide chain) in any combination. One or more of the amino acids in a peptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. A peptide may be naturally occurring, recombinant, synthetic, or any combination of these.

[0034]

[0017] A peptide provided herein can be of any length. In certain embodiments, a peptide is 25 amino acids or fewer in length. In certain embodiments, a peptide is 20 amino acids or fewer in length. In certain embodiments, a peptide is 15 amino acids or fewer in length. In certain embodiments, a peptide is 13 amino acids or fewer in length. In certain embodiments, a peptide is 7-20 amino acids in length, inclusive. In certain embodiments, a peptide is 10-20 amino acids in length, inclusive. In certain embodiments, a peptide is 10-15 amino acids in length, inclusive. In certain embodiments, a peptide is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length. In certain embodiments, a peptide is at least the length of an amino acid sequence provided herein. In certain embodiments, a peptide is the length of an amino acid sequence provided herein.

[0035]

[0018] “Cyclic peptide” refers to a peptide in which two amino acids of the peptide (“crosslinked amino acids”) are connected via a crosslink to form a macrocycle. For example, in certain embodiments, the a-

[0036] C1751.70001WO00 3 / 174

[0037] #14267371vl sidechains of the crosslinked amino acids are connected to form the crosslink. In certain embodiments, the crosslink connects the a-carbons of the crosslinked amino acids.

[0038]

[0019] In certain embodiments, the crosslinked amino acids are separated by 5-13 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 6-12 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 7-11 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 8-10 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 9 amino acids. In certain embodiments, the crosslinked amino acids are separated by 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids.

[0039]

[0020] The term “amino acid” refers to a molecule containing both an amino group and a carboxyl group. Unless otherwise indicated, an amino acid is an alpha-amino acid (a-amino acid), the generic structure of which is depicted below (wherein each R is independently H or an amino acid sidechain, i.e., an “a- sidechain”). Unless otherwise indicated, reference to a particular amino acid implies the L-isomer of the amino acid. Each amino acid referred to herein may be denoted by a 1- to 4- letter code (e.g. , R and Arg represent L- Arginine, NMeL represents N-methyl leucine, etc.). a— amino acid

[0040]

[0021] Suitable amino acids include, without limitation, natural a-amino acids such as D- and L-isomers of the 20 common naturally occurring a-amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, R S, T, W, Y, V, as provided below), and unnatural a-amino acids.

[0041]

[0022] Exemplary natural a-amino acids (with one-letter code provided in parentheses) include L-alanine (A), L-arginine (R), L-asparagine (N), L-aspartic acid (D), L-cysteine (C), L-glutamic acid (E), L- glutamine (Q), glycine (G), L-histidine (H), L-isoleucine (I), L-leucine (L), L-lysine (K), L-methionine (M), L-phenylalanine (F), L-proline (P), L-serine (S), L-threonine (T), L-tryptophan (W), L-tyrosine (Y), and L- valine (V).

[0042]

[0023] Exemplary unnatural a-amino acids include, without limitation, D-arginine, D-asparagine, D- aspartic acid, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine, D-valine, Di-vinyl, a-methyl-alanine (Aib), a-methyl-arginine, a-methyl-asparagine, a-methyl-aspartic acid, a- methyl-cysteine, a-methyl-glutamic acid, a-methyl-glutamine, a-methyl-histidine, a-methyl-isoleucine, a-methyl-leucine, a-methyl-lysine, a-methyl-methionine, a-methyl-phenylalanine, a-methyl-proline, a- methyl-serine, a-methyl-threonine, a-methyl-tryptophan, a-methyl-tyrosine, a-methyl-valine, norleucine, and terminally unsaturated a-amino acids. There are many known unnatural amino acids, any of which may be included in the peptides of the present disclosure. See for example, S. Hunt, The Non-Protein Amino Acids: In Chemistry and Biochemistry of the Amino Acids , edited by G. C. Barrett, Chapman and Hall, 1985.

[0043] C1751.70001WO00 4 / 174

[0044] #14267371vl

[0024] Unnatural amino acids also include amino acids comprising a substituent (z.e., non-hydrogen group) on the peptide nitrogen. For example, any amino acid described herein can comprise a Ci e alkyl group on the peptide nitrogen (“N-alkyl”-amino acid). In certain embodiments, any amino acid described herein can comprise a methyl group on the peptide nitrogen (“N-methyl”-amino acid). For example, “N- methyl-leucine” refers to L-leucine wherein the peptide nitrogen is substituted with methyl.

[0045]

[0025] Non-limiting examples of unnatural amino acids referenced in the disclosure are provided in Table 1A. In certain embodiments, the unnatural amino acid is selected from those in Table 1A, and D-isomers thereof.

[0046] Table 1A

[0047]

[0026] In certain embodiments, the unnatural amino acid is a phenylalanine replacement. “Phenylalanine replacement” refers to amino acid of Formula (a), or an amino acid provided in Table IB below. In certain embodiments, a phenylalanine replacement is of Formula (a): or a D-isomer thereof, wherein: m is 1, 2, 3, or 4; each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl; each R2is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, -CN, -NO2, -ORA, -Ci-6 alkyl-ORA, - N(RA)2, -SRA, -C(=O)RA, -C(=O)ORA, -C(=O)N(RA)2, -S(=O)RA, -S(=O)2RA, -S(=O)2ORB- S(=O)2N(RB)2, C3-8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl; each instance of RAis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -C(=O)RB, -S(=O)2RB, C3-8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RAattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl; each RBis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3 8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl;

[0048] R3is hydrogen or Ci e alkyl; and

[0049] C1751.70001WO00 5 / 174

[0050] #14267371vl n is 0, 1, 2, 3, 4 or 5.

[0051]

[0027] In certain embodiments, a phenylalanine replacement is of the formula:

[0052] D-isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -OCF3, -SO2Me, -NO2, -CN, -Ph, or -CH2-(Ce 10 aryl).

[0053]

[0028] In certain embodiments, a phenylalanine replacement is of the formula: isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -OCF3, -SChMc, -NO2, -CN, -Ph, or -CH2-(Ce 10 aryl).

[0054]

[0029] In certain embodiments, a phenylalanine replacement is of the formula: isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -OCF3, -SO2Me, -NO2, -CN, -Ph, or -CH2-(Ce 10 aryl).

[0055]

[0030] In certain embodiments, a phenylalanine replacement is an amino acid provided in Table IB, or a

[0056] D-isomer thereof.

[0057] C1751.70001WO00 6 / 174 #14267371vl

[0058] ģ14267371vl

[0059] C1751.70001WO00 8 / 174 #14267371vl

[0031] In certain embodiments, the unnatural amino acid is a tyrosine replacement. “Tyrosine replacement” refers to amino acid of Formula (a) (e.g., Formula (b)), or an amino acid provided in Table 1C below. In certain embodiments, a tyrosine replacement is of Formula (b): or a D-isomer thereof, wherein: each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl; and RAis Ci-6 alkyl or Ci-6 haloalkyl.

[0060]

[0032] In certain embodiments, a tyrosine replacement is of the formula: isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -NO2, -NH2, -CN, -CO2H, -OCF3, -CHF2, -CF3, - N(Me)2, -NHC(O)Me, -SO2Me, -SMe, -NHSO2Me, -SO2NH2, or -CH2OH.

[0061]

[0033] In certain embodiments, a tyrosine replacement is of the formula: -isomer thereof, wherein R2is -OH, F, Cl, Br, methyl, -CF3, -OMe, -NH2, -NO2, -CN, -CH2OH, -CO2H, -S(O)Me, or -C(O)NH2.

[0062]

[0034] In certain embodiments, a tyrosine replacement is an amino acid provided in Table 1C, or a D- isomer thereof.

[0063] C1751.70001WO00 9 / 174 #14267371vl

[0064] ģ14267371vl

[0065]

[0035] In certain embodiments, the unnatural amino acid is a histidine replacement. “Histidine replacement” refers to amino acid of Formula (c), or an amino acid provided in Table ID below. In certain embodiments, a histidine replacement is of Formula (c):

[0066] 0(c), or a D-isomer thereof, wherein: m is 1, 2, 3, or 4; each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0067] R3is hydrogen or Ci-6 alkyl; and

[0068] RNis hydrogen or Ci-6 alkyl.

[0069]

[0036] In certain embodiments, a histidine replacement is an amino acid provided in Table ID, or a D- isomer thereof.

[0070] Table ID

[0071] C1751.70001WO00 11 / 174 #14267371vl

[0072] ģ14267371vl

[0037] In certain embodiments, the unnatural amino acid is a proline replacement. “Proline replacement” refers to an amino acid of Formula (d): or a D-isomer thereof, wherein: pl is 0, 1, 2, or 3; each R4is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORA, -N(RA)2, -SRA, - C(=O)RA, -C(=O)ORA, -C(=O)N(RA)2, C3-8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two R4attached to the same carbon atom are joined together with the intervening atoms to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, or two R4are taken together to form =0; each instance of RAis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RAattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl; and p2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits.

[0073]

[0038] In certain embodiments, a proline replacement is an amino acid provided in Table IE, or a D- isomer thereof.

[0074] Table IE

[0075]

[0039] In certain embodiments, the unnatural amino acid is a cysteine replacement. “Cysteine replacement” refers to an amino acid of Formula (e): or a D-isomer thereof, wherein: m is 1, 2, 3, or 4; each R1is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0076] R3is hydrogen or Ci-6 alkyl; and

[0077] Rsis hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0078]

[0040] In certain embodiments, the unnatural amino acid is a threonine or serine replacement. “Threonine replacement” and “serine replacement” independently refer to an amino acid of Formula (f):

[0079] C1751.70001WO00 13 / 174

[0080] #14267371vl or a D-isomer thereof, wherein: m is 1, 2, 3, or 4; each R1is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0081] R3is hydrogen or Ci-6 alkyl; and

[0082] R° is hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0083]

[0041] In certain embodiments, the unnatural amino acid is a glycine replacement. “Glycine replacement” refers to an amino acid of Formula (g): or a D-isomer thereof, wherein: each R3is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl.

[0084]

[0042] In certain embodiments, the unnatural amino acid is a lysine replacement. “Lysine replacement” refers to an amino acid of Formula (h): or a D-isomer thereof, wherein: m is 1, 2, 3, or 4; each R1is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0085] R3is hydrogen or Ci-6 alkyl; each instance of RNis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -C(=O)RB, -S(=O)2RB, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RNattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl; and each RBis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3 8 carbocyclyl, Ce 10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0086]

[0043] The term “amino acid substitution” when used in reference to an amino acid sequence refers to an amino acid of the amino acid sequence being replaced by a different amino acid (e.g., replaced by a natural or unnatural amino acid described herein). An amino acid sequence provided herein may include one or more amino acid substitutions. In certain embodiments, an amino acid sequence provided herein includes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acid substitutions.

[0087] C1751.70001WO00 14 / 174

[0088] #14267371vl

[0044] The term “amino acid addition” when used in reference to an amino acid sequence refers to an amino acid (e.g., a natural or unnatural amino acid described herein) being inserted between two amino acids of the amino acid sequence, or added at either end of the sequence. In certain embodiments, an amino acid sequence herein includes 0, 1, 2, 3, 4, or 5 amino acid additions.

[0089]

[0045] The term “amino acid deletion” when used in reference to an amino acid sequence refers to an amino acid of the amino acid sequence being deleted from the amino acid sequence. In certain embodiments, an amino acid sequence herein includes 0, 1, 2, 3, 4, or 5 amino acid deletions.

[0090]

[0046] Throughout the present disclosure, references to “the peptide,” “a peptide,” “the cyclic peptide,” or “a cyclic peptide” provided herein are intended to encompass peptides comprising any amino acid sequence provided herein (including any disclosed amino acid substitutions, additions, deletions, and / or modifications), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof as described herein. Likewise, references to “a dimer,” “the dimer,” and the like, are intended to encompass any dimers provided herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof as described herein.

[0091]

[0047] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the peptides of this invention include those derived from inorganic and organic acids and bases.

[0092]

[0048] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the peptides of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate

[0093] C1751.70001WO00 15 / 174

[0094] #14267371vl salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0095] Chemical Definitions

[0096]

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modem Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0097]

[0050] Peptides and amino acids described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the peptides described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses peptides as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0098]

[0051] Unless otherwise provided, the disclosure includes peptides that do not include isotopically enriched atoms, and also includes peptides that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, peptides having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such peptides are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0099] C1751.70001WO00 16 / 174

[0100] #14267371vl

[0052] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, Ci^t, C1-3, C1-2, C2-6, C2-5, C2 -4, C2-3, C3-6, C3-5, C s 4, C4-6, C4-5, and C5-6 alkyl.

[0101]

[0053] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0102]

[0054] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0103]

[0055] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0104]

[0056] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). Examples of Ci-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n- propyl, isopropyl), butyl (C4) e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3- pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs), n-dodecyl (C12), and the like.

[0105]

[0057] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“Ci-20 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFQ2, -CF2CI, and the like.

[0106]

[0058] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position / s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkyl”).

[0107]

[0059] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“Ci-20 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 may be in the (E)- or (Z)-configuration.

[0108] C1751.70001WO00 17 / 174

[0109] #14267371vl

[0060] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position / s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkenyl”).

[0110]

[0061] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).

[0111]

[0062] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position / s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkynyl”).

[0112]

[0063] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0113]

[0064] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also

[0114] C1751.70001WO00 18 / 174

[0115] #14267371vl includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0116]

[0065] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce -14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

[0066] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.

[0117] “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom or the ring that does not contain a heteroatom.

[0118]

[0067] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent

[0119] C1751.70001WO00 19 / 174

[0120] #14267371vl moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0121]

[0068] A chemical moiety is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, acyl groups are optionally substituted. In general, the term “substituted” when referring to a chemical group means that at least one hydrogen present on the group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The invention is not limited in any manner by the exemplary substituents described herein.

[0122]

[0069] Exemplary substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci-2o alkyl, Ci-2o perhaloalkyl, Ci-2o alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5- 14 membered heteroaryl; wherein X“ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-2o alkynyl, heteroCi-2o alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rbbis, independently, selected from hydrogen, -OH, -OR311, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CI-20 alkyl, Ci-20 perhaloalkyl, Ci-2o alkenyl, Ci-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14

[0123] C1751.70001WO00 20 / 174

[0124] #14267371vl membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rccis, independently, selected from hydrogen, Ci-20 alkyl, Ci-20 perhaloalkyl, Ci- 20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each X" is a counterion.

[0070] In certain embodiments, each substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -N3, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2.

[0125]

[0071] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F", Cl", Br , I"), NO3 , CIO4 , OH , H2PO4 , HCOf HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2- sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4~, PEr, PFe", AsFe", SbFe", B[3,5-(CF3)2C6H3]4]-, BlCeFsjr”, BPt , A1(OC(CF3)3)4", and carborane anions (e.g., CB11H12 or (HCBnMesBre) ). Exemplary counterions which may be multivalent include CO32-, HPOr2-, POr3-, B4O?2-, SOr2-, S2O32-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0126]

[0072] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents.

[0127] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0128]

[0073] Provided herein are cyclic peptides capable of covalently binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins, dimers thereof, and pharmaceutical compositions thereof, and methods of using the same for treating and / or preventing diseases and conditions associated with FcRn activity in a subject, including diseases and conditions associated with immunoglobulin G (IgG) autoantibody levels (e.g., autoimmune diseases, inflammatory diseases).

[0129] Cyclic Peptides

[0130] Amino Acid Sequences

[0131]

[0074] Provided herein are cyclic peptides, and pharmaceutically acceptable salts thereof, comprising: (i) an amino acid sequence capable of binding a neonatal fragment crystallizable receptor (FcRn); and (ii) a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

[0132] C1751.70001WO00 21 / 174

[0133] #14267371vl

[0075] In certain embodiments, the amino acid sequence capable of binding FcRn comprises the amino acid sequence:

[0134] G-H-F-G-Sar-NMeL-Y (SEQ ID NO: 1), wherein:

[0135] Sar is sarcosine, and NMeL is N-methyl-leucine; and the amino acid sequence includes 0, 1, 2, 3, 4, or 5 amino acid substitutions. In certain embodiments, the amino acid sequence capable of binding FcRn is SEQ ID NO: 1, and the amino acid sequence includes 0, 1, 2, 3, 4, or 5 amino acid substitutions.

[0136]

[0076] In certain embodiments, SEQ ID NO: 1 includes 0, 1, 2, 3, or 4 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 0, 1, 2, or 3 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 0, 1, or 2 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 0 or 1 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 0 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 1 amino acid substitution. In certain embodiments, SEQ ID NO: 1 includes 2 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 3 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 4 amino acid substitutions. In certain embodiments, SEQ ID NO: 1 includes 5 amino acid substitutions.

[0137]

[0077] In certain embodiments, the amino acid sequence capable of binding FcRn has at least 80% sequence identity with SEQ ID NO: 1. In certain embodiments, the amino acid sequence capable of binding FcRn has at least 85% sequence identity with SEQ ID NO: 1. In certain embodiments, the amino acid sequence capable of binding FcRn has at least 90% sequence identity with SEQ ID NO: 1. In certain embodiments, the amino acid sequence capable of binding FcRn has at least 95% sequence identity with SEQ ID NO: 1. In certain embodiments, the amino acid sequence capable of binding FcRn has at least 98% sequence identity with SEQ ID NO: 1. In certain embodiments, the amino acid sequence capable of binding FcRn has 100% sequence identity with SEQ ID NO: 1.

[0138]

[0078] In certain embodiments, the cyclic peptide or a pharmaceutically acceptable salt thereof comprises the amino acid sequence:

[0139] R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* (SEQ ID NO: 2), wherein:

[0140] Pen is penicillamine, Sar is sarcosine, and NMeL is N-methyl-leucine; the amino acid sequence includes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions;

[0141] * denotes crosslinked amino acids connected via a crosslink; and one amino acid comprises a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

[0142]

[0079] In certain embodiments, SEQ ID NO: 2 includes 0, 1, 2, 3, 4, or 5 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 0, 1, 2, 3, or 4 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 0, 1, 2, or 3 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 0, 1, or 2 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 0 or 1 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 0 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 1 amino acid substitution. In certain

[0143] C1751.70001WO00 22 / 174

[0144] #14267371vl embodiments, SEQ ID NO: 2 includes 2 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 3 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 4 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 5 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 6 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 7 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 8 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 9 amino acid substitutions. In certain embodiments, SEQ ID NO: 2 includes 10 amino acid substitutions.

[0145]

[0080] In certain embodiments, the amino acid sequence has at least 80% sequence identity with SEQ ID NO: 2. In certain embodiments, the amino acid sequence has at least 85% sequence identity with SEQ ID NO: 2. In certain embodiments, the amino acid sequence has at least 90% sequence identity with SEQ ID NO: 2. In certain embodiments, the amino acid sequence has at least 95% sequence identity with SEQ ID NO: 2. In certain embodiments, the amino acid sequence has at least 98% sequence identity with SEQ ID NO: 2. In certain embodiments, the amino acid sequence has 100% sequence identity with SEQ ID NO: 2.

[0146]

[0081] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the amino acid sequence:

[0147] X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X"-X12-X13(REF ID NO: 3), wherein:

[0148] XIis arginine (R), lysine (K), a lysine replacement, or other amino acid;

[0149] X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;

[0150] X3and X13are each independently penicillamine (Pen), cysteine (C), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via a crosslink;

[0151] X4is threonine (T), a threonine replacement, serine (S), or a serine replacement;

[0152] X5is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), or a glycine replacement;

[0153] X6is histidine (H) or a histidine replacement;

[0154] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), a tyrosine replacement, or other amino acid;

[0155] X8is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), lysine (K), a glycine replacement, a lysine replacement, or other amino acid;

[0156] X9is sarcosine (Sar), glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), a glycine replacement, or another amino acid;

[0157] X10is N-methyl-leucine (NMeL), leucine (L), glycine (G), sarcosine (Sar), alanine (A), valine (V), isoleucine (I), or a glycine replacement;

[0158] XIIis tyrosine (Y), a tyrosine replacement, phenylalanine (F), a phenylalanine replacement, or other amino acid; and

[0159] X12is proline (P) or a proline replacement; and one of X’-X12is attached to a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

[0160] C1751.70001WO00 23 / 174

[0161] #14267371vl

[0082] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the amino acid sequence:

[0162] X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X"-X12-X13(REF ID NO: 96), wherein:

[0163] XIis arginine (R), D-arginine (D-Arg), lysine (K), a lysine replacement, or other amino acid;

[0164] X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;

[0165] X3and X13are each independently penicillamine (Pen), cysteine (C), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via a crosslink;

[0166] X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), or a serine replacement;

[0167] X5is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), or a glycine replacement;

[0168] X6is histidine (H) or a histidine replacement;

[0169] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), a tyrosine replacement, or other amino acid;

[0170] X8is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), lysine (K), a glycine replacement, a lysine replacement, or other amino acid;

[0171] X9is sarcosine (Sar), glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), a glycine replacement, or another amino acid;

[0172] X10is N-methyl-leucine (NMeL), leucine (L), glycine (G), sarcosine (Sar), alanine (A), valine (V), isoleucine (I), or a glycine replacement;

[0173] XIIis tyrosine (Y), a tyrosine replacement, phenylalanine (F), a phenylalanine replacement, or other amino acid; and

[0174] X12is proline (P) or a proline replacement; and one of X’-X12is attached to a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

[0175]

[0083] In certain embodiments of REF ID NO: 3,

[0176] X1is arginine (R), lysine (K), or a lysine replacement;

[0177] X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;

[0178] X3and X13are each independently penicillamine (Pen), cysteine (C), or a cysteine replacement;

[0179] X4is threonine (T), a threonine replacement, serine (S), or a serine replacement;

[0180] X5is glycine (G), alanine (A), valine (V), leucine (L), or isoleucine (I), or a glycine replacement;

[0181] X6is histidine (H) or a histidine replacement;

[0182] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;

[0183] X8is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), lysine (K), a glycine replacement, or a lysine replacement;

[0184] X9is sarcosine (Sar), glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), or a glycine replacement;

[0185] C1751.70001WO00 24 / 174

[0186] #14267371vl X10is N-methyl-leucine (NMeL), leucine (L), glycine (G), sarcosine (Sar), alanine (A), valine (V), isoleucine (I), or a glycine replacement;

[0187] X11is tyrosine (Y), a tyrosine replacement, phenylalanine (F), a phenylalanine replacement; and X12is proline (P) or a proline replacement.

[0188]

[0084] In certain embodiments of REF ID NO: 3,

[0189] XIis arginine (R) or lysine (K);

[0190] X2is phenylalanine (F) or tyrosine (Y);

[0191] X3and X13are each independently penicillamine (Pen) or cysteine (C);

[0192] X4is threonine (T) or serine (S);

[0193] X5is glycine (G), alanine (A), valine (V), leucine (L), or isoleucine (I);

[0194] X6is histidine (H);

[0195] X7is phenylalanine (F) or tyrosine (Y);

[0196] X8is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), or lysine (K);

[0197] X9is sarcosine (Sar), glycine (G), alanine (A), valine (V), leucine (L), or isoleucine (I);

[0198] X10is N-methyl-leucine (NMeL), leucine (L), glycine (G), sarcosine (Sar), alanine (A), valine (V), or isoleucine (I);

[0199] XIIis tyrosine (Y) or phenylalanine (F); and

[0200] X12is proline (P).

[0201]

[0085] In certain embodiments, X1is arginine (R). In certain embodiments, X1is D- arginine (D-Arg). In certain embodiments, X1is lysine (K). In certain embodiments, X1is a lysine replacement. In certain embodiments, X1is another amino acid.

[0202]

[0086] In certain embodiments, X2is phenylalanine (F). In certain embodiments, X2is D-phenylalanine (D-Phe). In certain embodiments, X2is a phenylalanine replacement. In certain embodiments, X2is tyrosine (Y). In certain embodiments, X2is a tyrosine replacement.

[0203]

[0087] In certain embodiments, X3is penicillamine (Pen). In certain embodiments, X3is cysteine (C). In certain embodiments, X3is a cysteine replacement. In certain embodiments, X3is another amino acid.

[0204]

[0088] In certain embodiments, X4is threonine (T). In certain embodiments, X4is D-threonine (D-Thr). In certain embodiments, X4is a threonine replacement. In certain embodiments, X4is serine (S). In certain embodiments, X4is a serine replacement.

[0205]

[0089] In certain embodiments, X5is glycine (G). In certain embodiments, X5is alanine (A). In certain embodiments, X5is valine (V). In certain embodiments, X5is leucine (L). In certain embodiments, X5is isoleucine (I). In certain embodiments, X5is a glycine replacement.

[0206]

[0090] In certain embodiments, X6is histidine (H). In certain embodiments, X6is a histidine replacement.

[0207] C1751.70001WO00 25 / 174

[0208] #14267371vl

[0209]

[0210]

[0092] In certain embodiments, X7is phenylalanine (F). In certain embodiments, X7is a phenylalanine replacement. In certain embodiments, X7is tyrosine (Y). In certain embodiments, X7is a tyrosine replacement. In certain embodiments, X7is another amino acid.

[0211]

[0093] In certain embodiments, X7is a phenylalanine replacement that

[0212]

[0094] In certain embodiments, X8is glycine (G). In certain embodiments, X8is alanine (A). In certain embodiments, X8is valine (V). In certain embodiments, X8is leucine (L). In certain embodiments, X8is isoleucine (I). In certain embodiments, X8is lysine (K). In certain embodiments, X8is a lysine replacement. In certain embodiments, X8is a glycine replacement. In certain embodiments, X8is another amino acid.

[0213]

[0095] In certain embodiments, X9is sarcosine (Sar). In certain embodiments, X9is glycine (G). In certain embodiments, X9is alanine (A). In certain embodiments, X9is valine (V). In certain embodiments, X9is leucine (L). In certain embodiments, X9is isoleucine (I). In certain embodiments, X9is a glycine replacement. In certain embodiments, X9is another amino acid.

[0214]

[0096] In certain embodiments, X10is N-methyl-leucine (NMeL). In certain embodiments, X10is leucine (L). In certain embodiments, X10is glycine (G). In certain embodiments, X10is sarcosine (Sar). In certain

[0215] C1751.70001WO00 26 / 174

[0216] #14267371vl embodiments, X10is alanine (A). In certain embodiments, X10is valine (V). In certain embodiments, X10is isoleucine (I). In certain embodiments, X10is a glycine replacement.

[0217]

[0097] In certain embodiments, X11is tyrosine (Y). In certain embodiments, X11is a tyrosine replacement. In certain embodiments, X11is phenylalanine (F). In certain embodiments, X11is a phenylalanine replacement. In certain embodiments, X11is another amino acid.

[0218]

[0099] In certain embodiments, X12is proline (P). In certain embodiments, X12is a proline replacement.

[0219]

[0100] In certain embodiments, X12is a proline replacement that is

[0220]

[0101] In certain embodiments, X13is penicillamine (Pen). In certain embodiments, X13is cysteine (C). In certain embodiments, X13is a cysteine replacement. In certain embodiments, X13is another amino acid.

[0221]

[0102] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises one of the following amino acid sequences:

[0222] R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y+-P-C* (SEQ ID NO: 4),

[0223] R-F-Pen*-T-G-H-F-K+-Sar-NMeL-Y-P-C* (SEQ ID NO: 5),

[0224] R-F-Pen*-T-G-H-F-G-G+-NMeL-Y-P-C* (SEQ ID NO: 6),

[0225] R-F-Pen*-T-G-H-F-G+-Sar-NMeL-Y-P-C* (SEQ ID NO: 7),

[0226] R-F-Pen*-T-G-H-F+-K-Sar-NMeL-Y-P-C* (SEQ ID NO: 8), wherein:

[0227] * denotes crosslinked amino acids connected via a crosslink; and

[0228] +denotes the amino acid attached to the group of the formula: -L’-Rw.

[0229]

[0103] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[0230] R-F-X3-T-G-H-F-G-Sar-NMeL-Y-P-X13(SEQ ID NO: 9), wherein X3and X13are each independently penicillamine (Pen), cysteine (C), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via a crosslink.

[0231]

[0104] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[0232] R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12-C* (SEQ ID NO: 10),

[0233] C1751.70001WO00 27 / 174

[0234] #14267371vl wherein:

[0235] X12is proline (P) or a proline replacement; and

[0236] * denotes crosslinked amino acids connected via a crosslink.

[0237]

[0105] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[0238] X1-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* (SEQ ID NO: 11), wherein:

[0239] XIis arginine (R), lysine (K), a lysine replacement, or other amino acid; and

[0240] * denotes crosslinked amino acids connected via a crosslink.

[0241]

[0106] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[0242] R-F-Pen*-X4-G-X6-F-G-Sar-NMeL-X”-P-C* (SEQ ID NO: 12), wherein:

[0243] X4is threonine (T), a threonine replacement, serine (S), or a serine replacement;

[0244] X6is histidine (H) or a histidine replacement;

[0245] XIIis tyrosine (Y), a tyrosine replacement, phenylalanine (F), or a phenylalanine replacement; and

[0246] * denotes crosslinked amino acids connected via a crosslink.

[0247]

[0107] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[0248] X1-X2-Pen*-X4-G-X6-X7-G-X9-NMeL-X11-X12-C* (SEQ ID NO: 97), wherein:

[0249] X1is arginine (R), D-arginine (D-Arg) or lysine (K);

[0250] X2is phenylalanine (F) or D-phenylalanine (D-Phe);

[0251] C1751.70001WO00 28 / 174

[0252] #14267371vl

[0253] X9is glycine (G) attached to a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety;

[0254] X” is tyrosine (Y) or a tyrosine replacement that i

[0255] * denotes crosslinked amino acids connected via a crosslink.

[0256]

[0108] A cyclic peptide provided herein can comprise one or more additional modifications. For example, in certain embodiments, the N-terminus of the cyclic peptide is acylated (denoted by “Ac-” at the N- terminus of an amino acid sequence). In certain embodiments, the C-terminus of the cyclic peptide is amidated, i.e., the traditional C-terminal -C(=O)OH is replaced with -C(=O)NH2 (denoted by “-NH2” at the C-terminus of an amino acid sequence). In certain embodiments, a cyclic peptide provided herein comprises an acylated N-terminus and an amidated C-terminus.

[0257] Cyclic Peptide Crosslinks

[0258]

[0109] As described herein, cyclic peptides comprise two amino acids connected via a crosslink (“crosslinked amino acids”) to form a macrocycle. The crosslink may be attached any position on the crosslinked amino acids (e.g., attached independently to the a-sidechain, the a-carbon, or the peptide nitrogen of a crosslinked amino acid). In certain embodiments, the crosslink connects the a-carbons of the crosslinked amino acids.

[0259] C1751.70001WO00 29 / 174

[0260] #14267371vl [HO] In certain embodiments, the crosslink is a bond, Ci-io alkylene, Ci-io haloalkylene, Ci-io heteroalkylene, Ci-io alkenylene, Ci-io heteroalkenylene, Ci-io alkynylene, Ci-io heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[0261]

[0111] In certain embodiments, the crosslink is a bond. In certain embodiments, the crosslink comprises optionally substituted Ci-10 alkylene. In certain embodiments, the crosslink comprises -CH2-. In certain embodiments, the crosslink comprises optionally substituted Ci-10 haloalkylene. In certain embodiments, the crosslink comprises optionally substituted Ci-10 heteroalkylene. In certain embodiments, the crosslink comprises optionally substituted Ci-10 alkenylene. In certain embodiments, the crosslink comprises optionally substituted Ci-10 heteroalkenylene. In certain embodiments, the crosslink comprises optionally substituted Ci-10 alkynylene. In certain embodiments, the crosslink comprises optionally substituted Ci-10 heteroalkynylene. In certain embodiments, the crosslink comprises optionally substituted C3-8 carbocyclylene. In certain embodiments, the crosslink comprises optionally substituted Ce-io arylene. In certain embodiments, the crosslink comprises optionally substituted 3-8 membered heterocyclylene. In certain embodiments, the crosslink comprises optionally substituted 5-10 membered heteroarylene.

[0262]

[0112] In certain embodiments, a-sidechains of the crosslinked amino acids are connected to form the crosslink. For example, in certain embodiments, a-sidechains of the crosslinked amino acids are

[0263] I — Lc— 1 connected to form:a 5 a, wherein Lcis a crosslink; and each a represents attachment to the a- carbon of a crosslinked amino acid.

[0264]

[0113] For example, in certain embodiments, the crosslinked amino acids are penicillamine (Pen) and cysteine (C), and the crosslinked amino acids are connected to form: or , wherein each a represents attachment to the a-carbon of a crosslinked amino acid. In certain embodiments, the crosslinked amino acids are penicillamine (Pen) and cysteine (C), and the crosslinked amino acids are connected to form: , wherein each a represents attachment to the a-carbon of a crosslinked amino acid. In certain embodiments, the crosslinked amino acids are penicillamine (Pen) and cysteine (C), and the crosslinked amino acids are connected to form: , wherein each a represents attachment to the a-carbon of a crosslinked amino acid.

[0265] C1751.70001WO00 30 / 174

[0266] #14267371vl Covalent Binding Moieties

[0267]

[0114] Cyclic peptides described herein comprise the group -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety. “Covalent binding moiety” as used herein refers to a chemical group capable of reacting with an amino acid residue of a target protein (e.g., FcRn) to form a covalent bond. Examples of covalent binding moieties are known in the art (often referred to as “covalent warheads”). Examples of covalent binding moieties can be found in, e.g., “The future of covalent drugs” C&EN Discovery Report, Q3 2022, pp. 1-20; Gehringer, M. and Laufer, S. A. “Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology” J. Med. Chem. 2019, 62, 5673-5724; and Abranyi-Balogh, P. and Keserii, G. M. “Warheads for designing covalent inhibitors and chemical probes” Advances in Chemical Proteomics 2022, chapter 2, pp. 47-73, each of which are incorporated herein by reference in their entireties.

[0268]

[0115] In certain embodiments, a covalent binding moiety comprises chemical group capable of reacting with an amine (e.g., on a lysine residue of the target protein). In certain embodiments, a covalent binding moiety comprises chemical group capable of reacting with a thiol e.g., a cysteine residue of the target protein). In certain embodiments, the covalent binding moiety (i.e., Rw) is a covalent binding moiety comprising a vinyl sulfone, a sulfonyl halide, a squarate, a benzaldehyde, or an a,P-unsaturated carbonyl.

[0269]

[0116] In certain embodiments, Rwcomprises a squarate. In certain embodiments, Rwis a squarate. In certain embodiments, Rwis of Formula (i): wherein Rwlis optionally substituted Ci-6 alkyl. In certain embodiments, Rwlis unsubstituted Ci-6 alkyl. In certain embodiments, Rwlis unsubstituted Ci-6 alkyl. In certain embodiments, Rwlis methyl, ethyl, or isopropyl. In certain embodiments, Rwlis methyl.

[0270]

[0117] In certain embodiments, Rwis: incertain embodiments,

[0271]

[0118] In certain embodiments, Rwcomprises a sulfonyl halide. In certain embodiments, Rwis a sulfonyl halide. In certain embodiments, Rwis of Formula (ii):

[0272] C> O S xR(ii), wherein Rw2is halogen or a leaving group. In certain embodiments, Rw2is halogen. In certain embodiments, Rw2is F.

[0273] C1751.70001WO00 31 / 174

[0274] #14267371vl [11’1 In certain embodiments, Rwis:

[0275]

[0120] In certain embodiments, Rwcomprises a vinyl sulfone. In certain embodiments, Rwis a vinyl sulfone. In certain embodiments, Rwis of Formula (iii): (iii), wherein each Rw3is independently hydrogen, halogen, optionally substituted Ci-6 alkyl, and Ci-6 haloalkyl. In certain embodiments, at least one Rw3is hydrogen. In certain embodiments, each Rw3is hydrogen.

[0276]

[0121] In certain embodiments, Rwis:

[0277]

[0122] In certain embodiments, Rwcomprises a benzaldehyde. In certain embodiments, Rwis a benzaldehyde. In certain embodiments, Rwis of Formula (iv): wherein:

[0278] Rw4is hydrogen, -OH, -OCi 6 alkyl, or Cm alkynyl; each instance of Rw5is halogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 haloalkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl; or any two instances of Rw5or Rw4on adjacent carbons are taken together to form optionally substituted C5-7 carbocyclyl, optionally substituted 5-7 membered heterocyclyl, optionally substituted G> 10 aryl, or optionally substituted 5-10 membered heteroaryl; and r is 0, 1, 2, or 3.

[0279] C1751.70001WO00 32 / 174

[0280] #14267371vl

[0281]

[0124] In certain embodiments, Rwcomprises an a,P-unsaturated carbonyl. In certain embodiments, Rwis an a,P-unsaturated carbonyl. In certain embodiments, Rwis of Formula (v): wherein each Rw6is independently hydrogen, halogen, optionally substituted Ci-6 alkyl, or Ci-6 haloalkyl. In certain embodiments, at least one Rw3is hydrogen. In certain embodiments, each Rw3is hydrogen. In certain embodiments, at least one Rw3is optionally substituted Ci-6 alkyl. In certain embodiments, at least one

[0282]

[0125] In certain embodiments,

[0283]

[0126] As described herein, L1is a bond or a linker.

[0284]

[0127] In certain embodiments, L1is a bond.

[0285]

[0128] In certain embodiments, L1is a linker selected from Ci-20 alkylene, Ci-20 haloalkylene, Ci-20 heteroalkylene, Ci-20 alkenylene, Ci-20 heteroalkenylene, Ci-20 alkynylene, Ci-20 heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[0286]

[0129] In certain embodiments, L1comprises optionally substituted Ci-20 alkylene. In certain embodiments, L1comprises optionally substituted Ci-20 haloalkylene. In certain embodiments, L1comprises optionally substituted Ci-20 heteroalkylene. In certain embodiments, L1comprises optionally substituted Ci-20 alkenylene. In certain embodiments, L1comprises optionally substituted Ci-20 heteroalkenylene. In certain embodiments, L1comprises optionally substituted Ci-20 alkynylene. In certain embodiments, L1comprises optionally substituted Ci-20 heteroalkynylene. In certain embodiments, L1comprises optionally substituted C3-8 carbocyclylene. In certain embodiments, L1comprises optionally substituted Ce-io arylene. In certain embodiments, L1comprises optionally substituted 3-8 membered heterocyclylene. In certain embodiments, L1comprises optionally substituted 5-10 membered heteroarylene.

[0287] C1751.70001WO00 33 / 174

[0288] #14267371vl

[0130] In certain embodiments, -L’-Rwis of one of the following formulae:

[0289] C1751.70001WO00 34 / 174 #14267371vl

[0290]

[0131] As described herein, in certain embodiments, -L’-Rwis attached to an amino acid of the cyclic peptide (e.g., attached to the a-carbon, a-sidechain, or peptide nitrogen of an amino acid). In certain embodiments, -L’-Rwis attached to the a-carbon of an amino acid. In certain embodiments, -L’-Rwis attached to the a-sidechain of an amino acid. In certain embodiments, -L’-Rwis attached to the peptide nitrogen of an amino acid.

[0291]

[0132] In certain embodiments, -L’-Rwis attached to the amino acid at position 1 of SEQ ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 2 of SEQ ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 3 of SEQ ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 4 of SEQ ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 5 of SEQ ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 6 of SEQ ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 7 of SEQ ID NO: 1.

[0292]

[0133] In certain embodiments, -L’-Rwis attached to the peptide nitrogen of an amino acid at position 5 of SEQ ID NO: 1. In certain embodiments, -L’-Rwis attached to the peptide nitrogen of a glycine at

[0293] R™ v ' g Ns position 5 of SEQ ID NO: 1 to form: .

[0294]

[0134] In certain embodiments, -L’-Rwis attached to the amino acid at position 1 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 2 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 3 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 4 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 5 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 6 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 7 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 8 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino

[0295] C1751.70001WO00 35 / 174

[0296] #14267371vl acid at position 9 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 10 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 11 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the amino acid at position 12 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L1- Rwis attached to the amino acid at position 13 of any one of SEQ ID NOs: 2-12.

[0297]

[0135] In certain embodiments, -L’-Rwis attached to the peptide nitrogen of an amino acid at position 9 of any one of SEQ ID NOs: 2-12. In certain embodiments, -L’-Rwis attached to the peptide nitrogen of a glycine at position 9 of any one of SEQ ID NOs: 2-12 to form: .

[0298]

[0136] In certain embodiments, -L’-Rwis attached to the amino acid X1of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X2of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X3of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X4of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X5of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X6of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X7of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X8of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X9of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X10of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X” of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X12of REF ID NO: 3. In certain embodiments, -L’-Rwis attached to the amino acid X13of REF ID NO: 3.

[0299] In certain embodiments, -L’-Rwis attached to the peptide nitrogen of amino acid X9of REF ID NO: 3. In certain embodiments, X3in REF ID NO: 3 is glycine, and -L’-Rwis attached to the peptide nitrogen of the glycine to form: >

[0300] Examples of Cyclic Peptides

[0301]

[0137] In certain embodiments, the cyclic peptide is selected from those in Table 2A, and pharmaceutically acceptable salts thereof. In certain embodiments, the cyclic peptide is selected from those in Table 2B, and pharmaceutically acceptable salts thereof. In certain embodiments, the cyclic peptide is selected from those in Tables 2A-2B, and pharmaceutically acceptable salts thereof.

[0302] C1751.70001WO00 36 / 174

[0303] #14267371vl Table 2A

[0304] C1751.70001WO00 37 / 174 #14267371vl

[0305] ģ14267371vl

[0306] ģ14267371vl

[0307] ģ14267371vl

[0308] ģ14267371vl

[0309] ģ14267371vl

[0310] ģ14267371vl

[0311] ģ14267371vl

[0312] ģ14267371vl

[0313] ģ14267371vl

[0314] ģ14267371vl

[0315]

[0316] C1751.70001WO00 48 / 174

[0317] #14267371vl

[0318] ģ14267371vl

[0319] ģ14267371vl

[0320] ģ14267371vl

[0321] ģ14267371vl

[0322] ģ14267371vl

[0323] ģ14267371vl

[0324] ģ14267371vl

[0325] ģ14267371vl

[0326] ģ14267371vl

[0327] ģ14267371vl

[0328] ģ14267371vl

[0329] ģ14267371vl

[0330] ģ14267371vl

[0331]

[0332] Cyclic Peptide Dimers

[0333]

[0138] Also provided herein are conjugates (“dimers” herein) comprising two cyclic peptides described herein, wherein the two cyclic peptides are conjugated to one another via a bond or a linker. One or both of the cyclic peptides of the dimer comprise a group of the formula: -L1-Rw. In certain embodiments, exactly one cyclic peptide of the dimer comprises a group of the formula: -L’-Rw. In certain embodiments, both cyclic peptides of the dimer independently comprise a group of the formula: -L’-Rw.

[0334]

[0139] In certain embodiments, for at least one of the cyclic peptides, the linker is attached at R1 of SEQ ID NO: 2. In certain embodiments, for at least one of the cyclic peptides, the linker is attached at X1of REF ID NO: 3.

[0335]

[0140] In certain embodiments, the linker is a bond, alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[0336]

[0141] In certain embodiments, the linker is a bond, C O alkylene, C O haloalkylene, C O heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene,

[0337] C1751.70001WO00 62 / 174

[0338] #14267371vl alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[0339] O O A

[0340]

[0142] In certain embodiments, the linker is *y' , wherein y is an integer between 1 and 20.

[0341] O

[0342]

[0143] In certain embodiments, the linker is O

[0343] Examples of Dimers

[0344]

[0144] In certain embodiments, the cyclic peptide dimer is selected from those in Table 2B, and pharmaceutically acceptable salts thereof.

[0345] C1751.70001WO00 63 / 174 #14267371vl

[0346]

[0347]

[0348]

[0349] ģ14267371vl

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376] Pharmaceutical Compositions, Kits, and Administration

[0377]

[0145] The present disclosure provides pharmaceutical compositions comprising a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a cyclic peptide or dimer described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0378]

[0146] The terms “composition” and “formulation” are used interchangeably herein.

[0379]

[0147] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the cyclic peptide or dimer described herein (z.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0380]

[0148] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0381]

[0149] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0382]

[0150] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0383]

[0151] The peptides and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0384] C1751.70001WO00 96 / 174

[0385] #14267371vl

[0152] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0386]

[0153] Peptides provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0387]

[0154] The exact amount of a peptide required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular peptide, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a peptide described herein.

[0388]

[0155] A peptide or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophy tactically active agents). The peptides or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0389]

[0156] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or peptide described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or peptide described herein. In some embodiments, the pharmaceutical composition or peptide described herein provided in the first container and the second

[0390] C1751.70001WO00 97 / 174

[0391] #14267371vl container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a peptide or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0392]

[0157] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0393] Methods of Treatment and Uses

[0394]

[0158] Cyclic peptides provided herein can covalently inhibit neonatal fragment crystallizable receptor (FcRn) proteins and are therefore useful in treating FcRn-mediated and immunoglobulin G (IgG)- mediated diseases, including autoimmune and inflammatory diseases.

[0395]

[0159] Provided herein are methods of treating an FcRn-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimer described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an FcRn-mediated disease. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating an FcRn-mediated disease.

[0396]

[0160] “FcRn-mediated disease” refers to any disease or condition associated with FcRn protein activity in a subject, including diseases caused or exacerbated by FcRn activity, or for which inhibition of FcRn activity can provide therapeutic benefit. In certain embodiments, the FcRn-mediated disease is an autoimmune disease. In certain embodiments, the FcRn-mediated disease is an inflammatory disease.

[0397]

[0161] Inhibition of FcRn can decrease IgG levels in a subject and can therefore treat diseases and conditions in which autoantibodies are implicated. Provided herein are methods of treating an IgG- mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an IgG-mediated disease. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating an IgG-mediated disease.

[0398]

[0162] “IgG-mediated disease” refers to any disease or condition associated with IgG autoantibodies in a subject, including diseases caused or exacerbated by IgG antibodies, or for which decreasing levels of

[0399] C1751.70001WO00 98 / 174

[0400] #14267371vl IgG antibodies can provide a therapeutic benefit. In certain embodiments, the IgG-mediated disease is an autoimmune disease. In certain embodiments, the IgG-mediated disease is an inflammatory disease.

[0401]

[0163] Provided herein are methods of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an autoimmune disease. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments (e.g., for treating an autoimmune disease or inflammatory disease).

[0402]

[0164] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. Autoimmune diseases may be restricted to certain organs or involve a particular tissues in different places. The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. However, cyclic peptides and dimers described herein can provide therapeutic benefit in the treatment of autoimmune diseases.

[0403]

[0165] Autoimmune diseases include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, pemphigus vulgaris, bullous pemphigoid, Goodpasture’s syndrome, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune hepatitis, Celiac disease, Type 1 diabetes, multiple sclerosis, Sjogren’s syndrome, antiphospholipid syndrome, Wegener’s granulomatosis, polymyositis, dermatomyositis, scleroderma, and autoimmune encephalitis.

[0404]

[0166] Additional exemplary autoimmune diseases include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Behcet’s disease, bullous pemphigoid, cardiomyopathy, celiac spruedermatitis herpetiformis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, Degos’ disease, dermatomyositis, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves’ disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin dependent diabetes juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus e.g., pemphigus vulgaris), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis / giant cell

[0405] C1751.70001WO00 99 / 174

[0406] #14267371vl arteritis, transplant rejection, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis. In some embodiments, the autoimmune disease is bullous pemphigoid, idiopathic thrombocytopenia purpura, myasthenia gravis, pemphigus (e.g., pemphigus vulgaris), and transplant rejection.

[0407]

[0167] Autoimmune diseases can include inflammatory diseases and conditions. The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation.

[0408]

[0168] Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

[0409]

[0169] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline

[0410] C1751.70001WO00 100 / 174

[0411] #14267371vl arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo, and Wegener’s granulomatosis.

[0412]

[0170] In some embodiments, the inflammatory disease is selected from asthma, ulcerative colitis, inflammatory bowel syndrome, allergy (e.g., allergic rhinitis / sinusitis, skin allergies, food allergies, drug allergies, insect allergies), mastocytosis, arthritis (e.g., osteoarthritis, rheumatoid arthritis), and spondyloarthropathies. In some embodiments, the skin allergy is chosen from urticaria, angioedema, and atopic dermatitis.

[0413]

[0171] Also provided herein are methods of covalently inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in covalently inhibiting FcRn in vitro or in vivo. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for covalently inhibiting FcRn in a subject.

[0414]

[0172] As used herein the term “inhibit,” “inhibition,” or “inhibiting” in the context of proteins, for example, in the context of FcRn proteins, refers to a reduction in the activity of the protein or a downstream effect. In some embodiments, the term refers to a reduction in the level of protein activity

[0415] C1751.70001WO00 101 / 174

[0416] #14267371vl (e.g., FcRn activity) to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline or reference level of protein activity. In some embodiments, the term refers to a reduction of the level of protein activity (e.g., FcRn activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, of an initial level, which may, for example, be a baseline level of protein activity.

[0417]

[0173] “Covalently inhibiting,” “covalent inhibition,” “covalently inhibit” and the like, refers to inhibition of target protein (e.g., FcRn) activity resulting from covalent binding of an agent (e.g., a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof) to the target protein. In certain embodiments, the agent binds to an amino acid residue (e.g., an amino acid side chain) of the target protein. Covalent inhibitors can be orthosteric or allosteric. “Orthosteric” inhibitors covalently bind to the active site of the target protein, whereas “allosteric” inhibitors can bind elsewhere on the protein surface.

[0418]

[0174] Also provided herein are methods of decreasing IgG levels in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in decreasing IgG levels in a subject. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for decreasing IgG levels in a subject.

[0419]

[0175] In certain embodiments, the decrease in IgG levels in the subject is a reduction in the level of IgG in the subject which is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% of an initial level (e.g., before administration of an FcRn inhibitor).

[0420]

[0176] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non- human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease, disorder, or condition.

[0421]

[0177] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a peptide described herein, or a composition thereof, in, to or on a subject.

[0422] C1751.70001WO00 102 / 174

[0423] #14267371vl

[0178] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0424]

[0179] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0425]

[0180] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0426]

[0181] An “effective amount” of a peptide described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a peptide described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular peptide, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a peptide described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a peptide described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for covalently inhibiting FcRn and / or decreasing the levels of IgG (e.g., in a subject or in a cell in vitro).

[0427]

[0182] A “therapeutically effective amount” of a peptide described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a peptide means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with FcRn activity) in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for covalently inhibiting FcRn and / or decreasing the levels of IgG in a subject.

[0428]

[0183] A “prophylactically effective amount” of a peptide described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a peptide means an amount of a therapeutic agent, alone or in

[0429] C1751.70001WO00 103 / 174

[0430] #14267371vl combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with FcRn activity) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for covalently inhibiting FcRn and / or decreasing the levels of IgG.

[0431]

[0184] “Neonatal fragment crystallizable receptor” (also “FcRn”, “IgG receptor FcRn large subunit p51”, or “Brambell receptor”) refers to the protein that in humans is encoded by the FCGRT gene. See Uniprot accession number P55899 for human FcRn.

[0432] EXAMPLES

[0433] Example 1. Synthesis of building blocks for both SPPS and off -bead synthesis

[0434] Scheme 1. Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4- nitrophenyl)sulfonamido)ethoxy)ethyl)amino)-2-oxoethyl)glycine

[0435] Step 1 Step 2

[0436]

[0185] Step 1: To a solution of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (50 g, 244.8 mmol) and TEA (51 mL, 367.6 mmol) in DCM (300 mL) at 0-10°C was added NsCl (59.7 g, 293.7 mmol) in DCM (80 mL) slowly and the mixture was stirred at RT for 1.5 h. Then the reaction solution was quenched by 5% H3PO4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer were washed with 5% H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl-(2-(2-((4- nitrophenyl)sulfonamido)ethoxy)ethyl)-carbamate without further purification. MS ESI calculated for C15H23N3O7S [M+H]+ 389.42, found 389.4.

[0437]

[0186] Step 2: tert-butyl-(2-(2-((4-nitrophenyl)sulfonamido)ethoxy)ethyl)-carbamate (95.3 g, 244.8 mmol) cooled to 0-10°C was added 4N HC1 / EA (600 mL) , then stirred at RT for 1 h. A white solid precipitated and filtered. Then the solid was washed with EA (3 x 100 mL) and dried in vaccum to afford N-(2-(2-aminoethoxy)ethyl)-4-nitrobenzenesulfonamide without further purification. MS ESI calculated for C10H15N3O5S [M+H]+ 289.42, found 289.4.

[0438]

[0187] Step 3: To a solution of Fmoc-N-(tert-butyloxycarbonylmethyl)-glycine (46 g, 116.28 mmol) and N-(2-(2-aminoethoxy)ethyl)-4-nitrobenzenesulfonamide (34 g, 122.4 mmol) in DMF (300 mL) at 0-10°C was added NMM (40 mL, 367.2 mmol) and HATU (13.86 g, 36.5 mmol) and the solution was stirred at

[0439] C1751.70001WO00 104 / 174

[0440] #14267371vl RT for 2.5 h. The mixture was quenched by 5% H3PO4 (200 mL) and extracted with DCM (2 x 300 mL). The combined organic layer were washed with 5% H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na^SCh and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4- nitrophenyl)sulfonamido)ethoxy)ethyl)amino)-2-oxoethyl)glycinate without further purification. MS ESI calculated for C33H38N4O10S [M+H]+ 682.23, found 682.2.

[0441]

[0188] Step 4: tert-butyl-N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4- nitrophenyl)sulfonamido)ethoxy)ethyl)amino)-2-oxoethyl)glycinate (83.5 g, 122.4 mmol) was treated with 70%TFA / DCM (500 mL) at RT for 2 h. The mixture was concentrated under reduced pressure and extracted with 50% DCM / H2O (2 x 250mL). The combined organic layer were washed with saturated sodium chloride solution (200 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4- nitrophenyl)sulfonamido)ethoxy)ethyl)amino)-2-oxoethyl)glycine. MS ESI calculated for C29H30N4O10S [M+H]+ 626.64, found 626.6.

[0442] Scheme 2. Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-((4- nitrophenyl)sulfonamido)ethyl)amino)-2-oxoethyl)glycine

[0443] Step 1 Step 2

[0444]

[0189] Step 1 : To a solution of tert-butyl (2-aminoethyl)carbamate (31.16 g, 194.5 mmol) and TEA (40.5 mL, 291.75 mmol) in DCM (200 mL) at to 0-10°C was added NsCl (47.5 g, 214.3 mmol) in DCM (50 mL) slowly and the mixture was stirred at RT for 1 h. Then the reaction solution was quenched by 5% H3PO4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer were washed with 5% H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na2SOr and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (2-((4- nitrophenyl)sulfonamido)ethyl)carbamate without further purification. MS ESI calculated for Ci3H19N3O6S [M+H]+ 345.37, found 345.3.

[0445]

[0190] Step 2: tert-butyl (2-((4-nitrophenyl)sulfonamido)ethyl)carbamate (67.1 g, 194.5 mmol) cooled to 0-10°C was added 4N HC1 / EA (500 mL) and stirred at RT for 1 h. A white solid precipitated and filtered. Then the solid was washed with EA (3 x 100 mL) and dried in vacuum to afford N-(2-aminoethyl)-4- nitrobenzenesulfonamide without further purification. MS ESI calculated for C8H11N3O4S [M+H]+ 245.25, found 245.2.

[0446]

[0191] Step 3: To a solution of Fmoc-N-(tert-butyloxycarbonylmethyl)-glycine (18 g, 43.7 mmol) and N- (2-aminoethyl)-4-nitrobenzenesulfonamide (11.3 g, 46.1 mmol) in DMF (100 mL) at to 0-10°C was

[0447] C1751.70001WO00 105 / 174

[0448] #14267371vl added NMM (15.2 mL, 138.25 mmol) and HATU (16.6 g, 43.7 mmol) and the solution was stirred at RT for 3 h. Then the reaction solution was quenched by 5% H3PO4 (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer were washed with 5% H3PO4 (100 mL) and saturated sodium chloride solution (200 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-(((9H-fhroren-9-yl)methoxy)carbonyl)-N-(2-((2-((4- nitrophenyl)sulfonamido)ethyl)amino)-2-oxoethyl)glycinate without further purifiction. MS ESI calculated for C31H34N3O9S [M+H]+ 638.69, found 638.6.

[0449]

[0192] Step 4: tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N- (2-((2-((4-nitro phenyl)sulfonamido)ethyl)amino)-2-oxoethyl)glycinate (29.4 g, 46.1 mmol) was treated with 70% TFA / DCM (30 mL) at RT for 2 h. The mixture was concentrated under reduced pressure and extracted with 50% DCM / H2O (2 x 150 mL). The combined organic layer were washed with saturated sodium chloride solution (200 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-((4-nitrophenyl) sulfonamido)ethyl)amino)-2-oxoethyl) glycine. MS ESI calculated for C27H26N4O9S [M+H]+ 582.58, found 582.5.

[0450] Scheme 3. Synthesis of N-(4-aminobutyl)-N-methyl-4-nitrobenzenesulfonamide

[0451] Step 1 M Step 2 N

[0452]

[0193] Step 1 : To a solution of tert- butyl (4-(methylamino)butyl)carbamate (25 g, 123.5 mmol) and TEA (25.7 mL, 185.25 mmol) in DCM (200 mL) at to 0-10°C was added NsCI (30.1 g, 135.85 mmol) in DCM (50 mL) slowly and the mixture was stirred at RT for 1 h. Then the reaction solution was quenched by 5%H3PO4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer were washed with 5% H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (4-((N-methyl-4- nitrophenyl)sulfonamido)butyl)carbamate without further purification. MS ESI calculated for Ci6H25N3O6S [M+H]+387.45, found 387.4.

[0453]

[0194] Step 2: tert-butyl (4-((N-methyl-4-nitrophenyl)sulfonamido)butyl)carbamate (47.8 g, 123.5 mmol) was cooled to 0-10°C. Then 4N HCI / dioxane (100 mL) was added and stirred at RT for 1 h. A white solid precipitated and filtered. Then the solid was washed with DCM (3 x 100 mL) and dried in vacuum to afford N-(4-aminobutyl)-N-methyl-4-nitrobenzenesulfonamide. MS ESI calculated for C11H17N3O4S [M+H]+287.33, found 287.3.

[0454] Scheme 4. Synthesis of N-(3-aminopropyl)-N-methyl-4-nitrobenzenesulfonamide

[0455] Step 1 Step 2

[0456] L H, B i oc NsCI TEA Ns Boc 4N HCI / dioxane N i s

[0457] C1751.70001WO00 106 / 174

[0458] #14267371vl

[0195] Step 1 : To a solution of tert-butyl (3-(methylamino)propyl)carbamate (25 g, 132.8 mmol) and TEA (27.6 mL, 199.2 mmol) in DCM (250 mL) at 0-10°C was added NsCI (32.4 g, 146.1 mmol) in DCM (50 mL) slowly and the mixture was stirred at RT for 1.5 h. Then the reaction solution was quenched by 5% H3PO4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer were washed with 5% H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (3-((N-methyl-4- nitrophenyl)sulfonamido)propyl)carbamate without further purification. MS ESI calculated for C15H23N3O6S [M+H]+ 373.42, found 373.4.

[0459]

[0196] Step 2: tert-butyl (3-((N-methyl-4-nitrophenyl)sulfonamido)propyl)carbamate (49.6 g, 132.8 mmol) was cooled to 0-10°C. Then 4N HCI / dioxane (150 mL) was added and stirred at RT for 1 h. The mixture was concentrated and dried under vacuum to afford N-(3-aminopropyl)-N-methyl-4- nitrobenzenesulfonamide. MS ESI calculated for C10H15N3O4S [M+H]+ 273.31, found 273.3.

[0460] Scheme 5. Synthesis of N-(2-aminoethyl)-N-methyl-4-nitrobenzenesulfonamide

[0461] Step 1 Step 2

[0462]

[0197] Step 1 : To a solution of tert- butyl (2-(methylamino)ethyl)carbamate (25 g, 143.7 mmol) and TEA (30 mL,215.6 mmol) in DCM (250 mL) at 0-10°C was added NsCI (35.03 g, 158.07 mmol) in DCM (50 mL) slowly and the mixture was stirred at RT for 1.5 h. Then the reaction solution was quenched by 5% H3PO4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer was washed with 5% H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na^SCh and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (2-((N-methyl-4- nitrophenyl)sulfonamido)ethyl)carbamate without further purification. MS ESI calculated for CI4H21N3O6S [M+H]+359.40, found 359.4.

[0463]

[0198] Step 2: tert-butyl (2-((N-methyl-4-nitrophenyl)sulfonamido)ethyl)carbamate (51.6 g, 143.7 mmol) was cooled to 0-10°C. Then 4N HCI / dioxane (150 mL) was added and stirred at RT for 1 h. A white solid precipitated and filtered. Then the solid was washed with DCM (3 x 100 mL) and dried in vacuum to afford N-(2-aminoethyl)-N-methyl-4-nitrobenzenesulfonamide. MS ESI calculated for C9H13N3O4S [M+H]+ 259.06, found 259.0.

[0464] Scheme 6. Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((3-(((4- nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycine

[0465] Step 1 Step 2

[0466] DMF

[0467] C1751.70001WO00 107 / 174

[0468] #14267371vl

[0469]

[0199] Step 1 : To a solution of tert-butyl (3-(aminomethyl)benzyl)carbamate (5 g, 21.1 mmol) and TEA (4.4 mL, 34.65 mmol) in DMF(80 mL) at 0-10°C was added NsCl (5.16 g, 23.21 mmol) in DMF(10 mF) slowly and the mixture was stirred at RT for 2h. Then the reaction solution was quenched by 5% H3PO4 (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer were washed with 5% H3PO4 (100 mL) and saturated sodium chloride solution (100 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (3-(((4- nitrophenyl)sulfonamido)methyl)benzyl)carbamate without further purification. MS ESI calculated for C19H23N3O6S [M+H]+421.47, found 421.4.

[0470]

[0200] Step 2: tert-butyl (3-(((4-nitrophenyl)sulfonamido)methyl)benzyl)carbamate (8.89 g, 21.1 mmol) cooled to 0-10°C was added 4N HCl / dioxane (30 mL), then stirred at RT for 1.5 h. The mixture was concentrated and dried under vacuum to afford N-(3-(aminomethyl)benzyl)-4-nitrobenzenesulfonamide without further purification. MS ESI calculated for C14H15N3O4S [M+H]+321.35, found 321.4.

[0471]

[0201] Step 3: To a solution of Fmoc-N-(tert-butyloxycarbonylmethyl)-glycine (8.25 g, 20.05 mmol) and N-(3-(aminomethyl)benzyl)-4-nitrobenzenesulfonamide (6.78 g, 21.1 mmol) in DMF (50 mL) at 0-10°C was added NMM (4.64 mL, 42.2mmol) and HATU (7.36 g, 21.05 mmol) and the solution stirred at RT for 2.5 h. The mixture was quenched by 5% H3PO4 (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with 5% H3PO4 (100 mL) and saturated sodium chloride solution (150 mL), dried over Na^SCh and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((3-(((4- nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycinate without further purification. MS ESI calculated for C37H38N4O9S [M+H]+714.79, found 714.8.

[0472]

[0202] Step 4: tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((3-(((4- nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycinate (14.33 g, 20.05 mmol) was treated with 70%TFA / DCM (500 mL) at RT for 1 h. The mixture was concentrated under reduced pressure and then diluted with 150 mL H2O and extracted with DCM (2 x 75 mL). The combined organic layer was washed with saturated sodium chloride solution (200 mL), dried over Na2SOr and filtered. The filtrate was concentrated under reduced pressure to afford N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((3- (((4-nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycine. MS ESI calculated for C33H30N4O9S [M+H]+ 658.68, found 658.7.

[0473] Scheme 7. Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((4-(((4-

[0474] C1751.70001WO00 108 / 174

[0475] #14267371vl nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycine

[0476]

[0203] Step 1 : To a solution of tert- butyl (4-(aminomethyl)benzyl)carbamate (3 g, 12.7 mmol) and TEA (2.64 mL, 19 mmol) in DMF(100 mL) at 0-10°C was added NsCl (3.09 g, 14 mmol) in DMF(10 mF) slowly and the mixture was stirred at RT overnight. Then the reaction solution was quenched by 5% H3PO4 (150 mL) and extracted with EA (3 x 100 mL). The combined organic layer were washed with 5% H3PO4 (100 mL) and saturated sodium chloride solution (100 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (4-(((4- nitrophenyl)sulfonamido)methyl)benzyl)carbamate without further purification. MS ESI calculated for C19H23N3O6S [M+H]+421.47, found 421.4.

[0477]

[0204] Step 2: tert-butyl (4-(((4-nitrophenyl)sulfonamido)methyl)benzyl)carbamate (5.35g, 12.7 mmol) cooled to 0-10°C was added 4N HCl / dioxane (10 mL), then stirred at RT for 1.5 h. The mixture was concentrated and dried under vacuum to afford N-(4-(aminomethyl)benzyl)-4-nitrobenzenesulfonamide without further purification. MS ESI calculated for C14H15N3O4S [M+H]+321.35, found 321.4.

[0478]

[0205] Step 3: To a solution of Fmoc-N-(tert-butyloxycarbonylmethyl)-glycine (4.94 g, 12.0 mmol) and N-(4-(aminomethyl)benzyl)-4-nitrobenzenesulfonamide (4.08 g, 12.7 mmol) in DMF (80 mL) at 0-10°C was added NMM (2.8 mL, 25.4 mmol) and HATU (4.57 g, 12 mmol) and the solution stirred at RT for 1.5 h. The mixture was quenched by 5% H3PO4 (100 mL) and extracted with EA (2 x 100 mL). The combined organic layer was washed with 5% H3PO4 (100 mL) and saturated sodium chloride solution (150 mL), dried over Na^SCh and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-(((9H-fhroren-9-yl)methoxy)carbonyl)-N-(2-((4-(((4- nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycinate without further purification . MS ESI calculated for C37H38N4O9S [M+H]+714.79, found 714.8.

[0479]

[0206] Step 4: tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((4-(((4- nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycinate (8.58 g, 12 mmol) was treated with 70%TFA / DCM (50mL) at RT for 1.5 h. The mixture was concentrated under reduced pressure and then diluted with 150 mL H2O and extracted with DCM (2 x 75 mL). The combined organic layer was washed with saturated sodium chloride solution (200 mL), dried over Na2SOr and filtered. The filtrate was concentrated under reduced pressure to afford N-(((9H-fhroren-9-yl)methoxy)carbonyl)-N-(2-((4-(((4-

[0480] C1751.70001WO00 109 / 174

[0481] #14267371vl nitrophenyl)sulfonamido)methyl)benzyl)amino)-2-oxoethyl)glycine. MS ESI calculated for C33H30N4O9S [M+H]+ 658.68, found 658.7.

[0482] Scheme 8. Synthesis of 3-((2-(2-aminoethoxy)ethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione

[0483]

[0207] Step 1 : To a solution of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (1.0 g, 4.9 mmol) and TEA (1.02 mL, 7.35 mmol) in DCM (5mL) at 0-10°C was added 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (0.661 g, 4.65 mmol) in DCM (2 mL) slowly and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to afford tert-butyl (2-(2-((2-methoxy-3,4-dioxocyclobut-l-en-l- yl)amino)ethoxy)ethyl)carbamate without further purification. MS ESI calculated for C14H22N2O6 [M+H]+314.34, found 314.3.

[0484]

[0208] Step 2: tert-butyl (2-(2-((2-methoxy-3,4-dioxocyclobut- 1 -en- 1 -yl)amino)ethoxy)ethyl)carbamate (1.46 g, 4.65mmol) cooled to 0-10°C was added 4N HCl / dioxane (20 mL) , then stirred at RT for 1 h. The mixture was concentrated under reduced pressure to afford 3-((2-(2-aminoethoxy)ethyl)amino)-4- methoxycyclobut-3-ene- 1,2-dione. MS ESI calculated for C9H14N2O4 [M+H]+214.22, found 214.2.

[0485] Scheme 9. Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(((6-(((4- nitrophenyl)sulfonamido)methyl)pyridin-2-yl)methyl)amino)-2-oxoethyl)glycine

[0486]

[0209] Step 1 : To a solution of pyridine-2,6-diyldimethanamine (6 g, 43.7 mmol) and TEA (9.2 mL, 65.6 mmol) in DMF (240 mL) cooled to 0-10°C was added NsCl (10.2 g, 46 mmol) in DMF (240 mL) slowly and the mixture was stirred at 25-35°Covernight. The mixture was purified by flash chromatography (DCM / MeOH = 10:1) afforded N-((6-(aminomethyl)pyridin-2-yl)methyl)-4-nitrobenzenesulfonamide. MS ESI calculated for C13H14N4O4S [M+H]+322.34, found 322.3.

[0487]

[0210] Step 2: To a solution of Fmoc-N-(tert-butyloxycarbonylmethyl)-glycine (3.64 g, 8.8 mmol) and N- ((6-(aminomethyl)pyridin-2-yl)methyl)-4-nitrobenzenesulfonamide (3g, 9.3 mmol) in DMF (250 mL) at 0-10°C was added NMM (3.1 mL, 27.9 mmol) and HATU (3.35 g, 8.8 mmol) and the solution stirred at RT for 2 h. The mixture was quenched by 5%H3PO4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer were washed with 5% H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na^SCh and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(((6-(((4-

[0488] C1751.70001WO00 110 / 174

[0489] #14267371vl nitrophenyl)sulfonamido)methyl)pyridin-2-yl)methyl)amino)-2-oxoethyl)glycinate without further purification. MS ESI calculated for C36H37N5O9S [M+H]+715.78, found 715.8.

[0490]

[0211] Step 3: tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(((6-(((4- nitrophenyl)sulfonamido)methyl)pyridin-2-yl)methyl)amino)-2-oxoethyl)glycinate (8.58, 8.8 mmol) was treated with 70% TFA / DCM (50mL) at RT for 1.5 h. The mixture was concentrated under reduced pressure and purified to afford N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(((6-(((4- nitrophenyl)sulfonamido)methyl)pyridin-2-yl)methyl)amino)-2-oxoethyl)glycine. MS ESI calculated for C32H29N5O9S [M+H]+ 659.68, found 659.7.

[0491] Scheme 10. Synthesis of N-(3-aminopropyl)-N-Methylethenesulfonamide Step 1 Step 2

[0492]

[0212] Step 1 : To a solution of tert-butyl (3-(methylamino)propyl)carbamate (0.94 g, 5 mmol) and TEA (1.04 mL, 7.5 mmol) in DCM (8 mL) at 0-10°Cwas added ethenesulfonyl chloride (0.5 mL, 5.5 mmol) slowly and the mixture was stirred at RT for 1.5 h. Then the reaction solution was quenched by 5% H3PO4 (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer were washed with 5% H3PO4 (10 mL) and saturated sodium chloride solution (10 mL), dried over Na^SOr and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (3-(N- methylvinylsulfonamido)propyl)carbamate without further purification. MS ESI calculated for C11H22N2O4S [M+H]+278.37, found 278.4.

[0493]

[0213] Step 2: tert-butyl (3-(N-methylvinylsulfonamido)propyl)carbamate (1.39 g, 5 mmol) cooled to 0- 10°C was added 4N HCI / dioxane (10 mL) , then stirred at RT for 1 h. The mixture was concentrated under reduced pressure to afford N-(3-aminopropyl)-N-methylethenesulfonamide. MS ESI calculated for C6H14N2O2S [M+H]+178.25, found 178.2.

[0494] Scheme 11. Synthesis of N-(2-(2-aminoethoxy)ethyl)ethenesulfonamide

[0495] Step 1 Step 2

[0496] H _ H2N^0^N.BQC +^SO2CITEA^SO2Boc4NHCI / dioxane ^'?°2

[0497] - - HN _ _ _ NH - ► HN. / x z\ .NH DCM ODCM 2O

[0498]

[0214] Step 1 : To a solution of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (1.0 g, 4.9 mmol) and TEA (1.02 mL, 7.35 mmol) in DCM (5 mL) at 0-10°C was added ethenesulfonyl chloride (0.68 g, 5.4 mmol) in DCM (2 mL) slowly and the mixture was stirred at RT for 1.5 h. Then the reaction solution was quenched by 5% H3PO4 (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with 5% H3PO4 (10 mL) and saturated sodium chloride solution (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (2-(2- (vinylsulfonamido)ethoxy)ethyl)carbamate without further purification. MS ESI calculated for C11H22N2O5S [M+H]+294.37, found 294.4.

[0499] C1751.70001WO00 111 / 174

[0500] #14267371vl

[0215] Step 2: To a solution of tert-butyl (2-(2-(vinylsulfonamido)ethoxy)ethyl)carbamate (1.44 g, 4.9 mmol) cooled to 0-10°C was added 4N HCl / dioxane (20 mL), then stirred at RT for 1 h. The mixture was concentrated under reduced pressure to afford N-(2-(2-aminoethoxy)ethyl)ethenesulfonamide. MS ESI calculated for C6H14N2O3S [M+H]+194.25, found 194.2.

[0501] Scheme 12. Synthesis of 3-((2-aminoethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione (Intermediate 414)

[0502] Boc Intermediate 414

[0503]

[0216] Step 1: To a solution of tert-butyl (2-aminoethyl)carbamate (500 mg, 3.122 mmol) in MeOH (20 ml), was added 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (488 mg, 3.434 mmol) at 25° C. The reaction mixture was stirred at 25° C for 16h. After 16h, it was concentrated under reduced pressure to get crude compound which was purified by flash column chromatography to get desired product tert-butyl (2-((2- methoxy-3,4-dioxocyclobut-l-en-l-yl)amino)ethyl)carbamate. MS ESI calculated for C12H18N2O5 [M-H] 269, found 269.

[0504]

[0217] Step 2: To a solution of tert-butyl (2-((2-methoxy-3,4-dioxocyclobut-l-en-l- yl)amino)ethyl)carbamate (700 mg, 2.591 mmol) in DCM (15 ml) was added TFA (0.297 ml, 3.887 mmol) at 0° C. The reaction mixture was stirred at 25°C for Ih. After Ih, the reaction mixture was concentrated under reduced pressure to get crude compound which was washed several times with Acetonitrile. The solid obtained was dried under vacuum to yield desired product 3-((2- aminoethyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione (Intermediate 414) as a white solid and used directly in the next step. MS ESI calculated for C7H10N2O3 [M+H] 171, found 171.

[0505] Scheme 13. Synthesis of 3-((2-(2-aminoethoxy)ethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione (Intermediate 415) Intermediate 415

[0506]

[0218] Step 1 : To a solution of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (500 mg, 2.449 mmol) in MeOH (20 ml), was added 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (382 mg, 2.694 mmol) at 25° C. The reaction mixture was stirred at 25° C for 16h. After 16h, it was concentrated under reduced pressure to get crude compound which was purified by flash column chromatography to get desired product tert-

[0507] C1751.70001WO00 112 / 174

[0508] #14267371vl butyl (2-(2-((2-methoxy-3,4-dioxocyclobut-l-en-l-yl)amino)ethoxy)ethyl)carbamate which was taken on to the next step. MS ESI calculated for C14H22N2O6 [M-H] 313, found 313.

[0509]

[0219] Step 2: To a solution of tert-butyl (2-(2-((2-methoxy-3,4-dioxocyclobut-l-en-l- yl)amino)ethoxy)ethyl)carbamate (700 mg, 2.228 mmol) in DCM (15 ml) was added HC1 in Dioxane (0.386 ml, 11.141 mmol) at 0° C. The reaction mixture was stirred at 25°C for Ih. After Ih, the reaction mixture was concentrated under reduced pressure to get crude compound which was washed several times with Acetonitrile. The solid obtained was dried under vacuum to yield desired product 3-((2-(2- aminoethoxy)ethyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione (Intermediate 415) as a white solid and used directly in the next step. MS ESI calculated for C9H14N2O4 [M+H] 215, found 215.

[0510] Scheme 14. Synthesis of 3-(3-(aminomethyl)azetidin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Intermediate 930) Intermediate 930

[0511]

[0220] Step 1 : To a solution of tert-butyl (azetidin-3-ylmethyl)carbamate (300 mg, 1.611 mmol) in MeOH (10 ml), was added 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (229 mg, 1.611 mmol) at 25° C. The reaction mixture was stirred at 25 °C for 16h. After 16h, it was concentrated under reduced pressure to get crude compound which was purified by flash column chromatography to get desired product tert- butyl ((l-(2- methoxy-3,4-dioxocyclobut-l-en-l-yl)azetidin-3-yl)methyl)carbamate. This was taken onto the next step. MS ESI calculated for C14H20N2O5 [M+H] 297, found 197 (Boc fragment).

[0512]

[0221] Step 2: To a solution of tert-butyl ((l-(2-methoxy-3,4-dioxocyclobut-l-en-l-yl)azetidin-3- yl)methyl)carbamate (285 mg, 0.962 mmol) in 2,2,2-Trifluoroethanol (5 ml), was added TMS-C1 (0.184 ml, 1.443 mmol) at 0° C. The reaction mixture was stirred at 25°C for 15 min. After 15 min, the reaction mixture was concentrated under reduced pressure to get crude compound which was washed several times with Acetonitrile. The solid obtained was dried under vacuum to yield desired product 3-(3- (aminomethyl)azetidin-l-yl)-4-methoxycyclobut-3-ene- 1,2-dione (Intermediate 930). This was taken on to the next step. MS ESI calculated for C9H12N2O3 [M+H] 197, found 197.

[0513]

[0222] The following were prepared in a method similar to Scheme 14:

[0514] C1751.70001WO00 113 / 174

[0515] #14267371vl

[0516] C1751.70001WO00 114 / 174 #14267371vl

[0517] Scheme 15. Synthesis of l-(piperazin-l-yl)prop-2-en-l-one (Intermediate 327)

[0518] Intermediate 327

[0519]

[0223] Step 1: To the stirred solution of tert-butyl piperazine- 1 -carboxylate (0.5 g, 2.686 mmol) in DCM (20 ml) was added DIPEA (0.935 ml, 5.360 mmol) and acryloyl chloride (0.260 ml, 3.223 mmol) at 0 °C, Then reaction mixture was stirred for 16h at RT. After 16h, it was concentrated under reduced pressure to get crude compound which was purified by flash column chromatography to get desired product tertbutyl 4-acryloylpiperazine-l -carboxylate. This was taken for next step. MS ESI calculated for C12H20N2O3 [M+H] 241, found 185 (t-butyl fragment).

[0520]

[0224] Step 2: To a solution product tert-butyl 4-acryloylpiperazine-l -carboxylate (600 mg, 2.498 mmol) in 2,2,2- Trifluoroethanol (20 ml) was added TMS-C1 (0.475ml, 3.747 mmol) at 0° C. The reaction mixture was stirred at 25 °C for 15min. After 15 min, the reaction mixture was concentrated under reduced pressure to get crude compound which was washed several times with Acetonitrile. The solid obtained was dried under vacuum to yield desired 1 -(piperazin- l-yl)prop-2-en-l -one (Intermediate 327). This was taken for next step. MS ESI calculated for C7H12N2O [M+H] 141, found 141.

[0521] Example 2: Preparation of Cyclic Peptides

[0522]

[0225] The following Examples are general methods which can be used to prepare the cyclic peptides described herein.

[0523] C1751.70001WO00 115 / 174

[0524] #14267371vl Scheme 16. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N-(5'-N(3-methoxy-3-cyclobutene- l,2-dione)-Amino-3-oxapentylcarbamoylmethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2 (Pen & Cys Crosslink) (Al) (SEQ ID NO: 13)

[0525]

[0226] Synthesis used Rink Amide MB HA resin with a loading of 0.392 mmol / g, 0.255g. The general solid phase peptide synthesis (SPPS) procedure is used with the following modifications:

[0526]

[0227] After the peptidyl resin was built up. The peptidyl resin was dried overnight to get the all protected peptidyl resin 0.40 g. Cleavage'. Cocktail (TFA / TIS / H2O (V:V:V) = 95:2.5:2.5, 5mL) was added into the C1751.70001WO00 116 / 174

[0527] #14267371vl peptidyl resin (0.40 g) to affect the cleavage for 3.0 hours, and a pale white crude, 131 mg with 51% purity was obtained after drying. Purification & Lyophilization-. The crude 131 mg was purified by using RP-HPLC with TFA buffer, and the product solution was collected and lyophilized to obtain the product, 8.0 mg as white powder with 97.9% purity.

[0528] Scheme 17. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N-(2-((2-((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)amino)ethyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys Bridge) (Ex. A2) (SEQ ID NO: 14)

[0529]

[0228] Synthesis used Rink Amide MB HA resin with a loading of 0.392 mmol / g, 0.255g. The general

[0530] SPPS procedure is used with the following modifications:

[0531] C1751.70001WO00 117 / 174 #14267371vl

[0532]

[0229] After the peptidyl resin was built up. The peptidyl resin was dried overnight to get the all protected peptidyl resin 0.434 g. Cleavage'. Cocktail (TFA / TIS / H2O (V:V:V) = 95:2.5:2.5, 5mL) was added into the peptidyl resin (0.434g) to affect the cleavage for 3.0 hours, and a pale white crude, 152 mg with 60% purity was obtained after dried. Purification & Lyophilization'. The crude 152 mg was purified by using RP-HPLC with TFA buffer, and the product solution was collected and lyophilized to get the product, 12.0 mg as white powder with 95.6% purity.

[0533] Example 3. Synthesis of linear peptide sequence (SPPS) and final cyclic peptides.

[0534] Table 3

[0535] C1751.70001WO00 118 / 174 #14267371vl

[0536]

[0537] General Procedure 1

[0538] Scheme 18. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-((3-(N- methylvinylsulfonamido)propyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys

[0539] Bridge) (Ex. A6) (SEQ ID NO: 18)

[0540] Cleavage:

[0541] C1751.70001WO00 119 / 174 #14267371vl

[0542]

[0230] Synthesis: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS. Reaction was performed at a 1.0 mmol scale using Rink Amide MB HA Resin (100-200 mesh, 0.28 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) Deprotection: 60 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 60 mL DMF, rt, 5x1 min; (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 6-10 mF DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5- 1.5 h; (5) Kaiser test: Negative; (6) Washing: 60-80 mL DMF, rt, 3x1 min.

[0543]

[0231] The peptide was synthesized as follows:

[0544] 232] Cleavage and Deprotection: After the peptide was built up, it was washed with DMF*6 and

[0545] MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / H2O = 87.5 / 2.5 / 5 / 2.5 / 2.5, 80 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (480 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (200 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0546]

[0233] Oxidation in Solution: The dry crude peptide was dissolved by ACN and water. L / McOH solution (20-40 g / L) was added dropwise to the peptide solution until it turned brown, then Vc solution was added until the solution changed to colorless.

[0547]

[0234] HPLC Purification of Oxidation Peptide: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography

[0548] C1751.70001WO00 120 / 174

[0549] #14267371vl system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 30%B to 60%B over 60 min, flow rate 40 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing oxidation peptide were confirmed by LC / MS, then lyophilized to get the oxidation peptide as a white solid.

[0550]

[0235] Side chain N-(3-aminopropyl)-N-methylethenesulfonamide coupling in Solution: The oxidation peptide was dissolved in DMF to 0.024M, then N-(3-aminopropyl)-N- methylethenesulfonamide (1.1 eq), PyAop (1.0 equiv), HOBt (1.0 equiv) and DIEA (8 equiv) were added sequentially and then shaken at RT for 1-2 h. The reaction was monitored by MS. After the reaction was completed, the reaction solution was diluted by ACN and water.

[0551]

[0236] HPLC Purification of Final Peptide: The diluted reaction solution was purified by using RP- HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 30%B to 60%B over 60 min, flow rate 20 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260 infinity II system, using Phenomenex-C18 (2) Luna 3 m, 100 A, 4.6* 100mm. Mobile phase: (A) 0.1% TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 37%B to 47%B in 10 min; injection volume: 10 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0552] General Procedure 2

[0553] Scheme 19. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(4-((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)(methyl)amino)butyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys Bridge)

[0554] C1751.70001WO00 121 / 174

[0555] #14267371vl

[0556]

[0237] Synthesis: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS. Reaction was performed at a 0.3 mmol scale using Rink Amide MB HA Resin (100-200 mesh, 0.28 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) Deprotection: 20 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 20 mL DMF, rt, 5x1 min; (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 2-3 mL DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5- 1.5 h; (5)

[0557] Kaiser test: Negative; (6) Washing: 20-25 mL DMF, rt, 3x1 min.

[0558]

[0238] The peptide was synthesized as follows:

[0559] C1751.70001WO00 122 / 174 #14267371vl

[0560] 239] Cleavage and Deprotection: After the peptide was built up, it was washed with DMF*6 and MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / H2O = 87.5 / 2.5 / 5 / 2.5 / 2.5, 20 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (120 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (40 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0561]

[0240] Oxidation in solution: The dry crude peptide was dissolved by ACN and water. L / McOH solution (20-40 g / L) was added dropwise to the peptide solution until it turned brown, then Vc solution was added until the solution changed to colorless.

[0562]

[0241] HPLC Purification: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase:

[0563] (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 30%B to 60%B over 60 min, flow rate 20 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then do further purification with TEAP buffer. The fractions was purified by using RP-HPLC on Luna C18 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 1% TEA and 1% Phosphoric acid in water and (B) 20% (1% TEA and 1 % Phosphoric acid in water) +80%ACN, following gradient of eluent B was used: 30%B to 60%B over 60 min, flow rate 20 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected, then Purified by TFA buffer. Mobile phase: (A) 0.1% TFA in water and

[0564] (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 32%B to 62%B over 60 min, flow rate 15 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260

[0565] C1751.70001WO00 123 / 174

[0566] #14267371vl infinity II system, using Phenomenex-C18 (2) Euna 3pm, 100 A, 4.6*100mm. Mobile phase: (A) 0.1%

[0567] TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 35%B to 45%B in 10 min; injection volume: 10 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0568] General Procedure 3

[0569] Scheme 20. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-((3-(((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)amino)methyl)benzyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-

[0570] NH2(Pen&Cys Bridge) (Ex. A12) (SEQ ID NO: 24)

[0571]

[0242] Synthesis: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS. Reaction was performed at a 0.2 mmol scale using Rink Amide MB HA Resin (100-200 mesh, 0.28 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) Deprotection: 20 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 20 mL DMF, rt, 5x1 min; (3)

[0572] C1751.70001WO00 124 / 174

[0573] #14267371vl Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 1.5-2.5 mL DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5- 1.5 h; (5) Kaiser test: Negative; (6) Washing: 20-25 mL DMF, rt, 3x1 min.

[0574]

[0243] The peptide was synthesized as follows:

[0575] MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / FLO = 87.5 / 2.5 / 5 / 2.5 / 2.5, 12 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (80 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (30 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0576]

[0245] Oxidation in solution: The dry crude peptide was dissolved by ACN and water. L / McOH solution (20-40 g / L) was added dropwise to the peptide solution until it turned brown, then Vc solution was added until the solution changed to colorless.

[0577]

[0246] HPLC Purification: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 1% TEA and 1% Phosphoric acid in water and (B) 20% (1% TEA and 1% Phosphoric acid in water) +80% ACN, following gradient of eluent B was used: 31%B to 61%B over 60 min, flow rate 15 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected, then Purified by TFA buffer. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 34%B to 64%B over 60 min, flow rate 15 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were

[0578] C1751.70001WO00 125 / 174

[0579] #14267371vl collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260 infinity II system, using Phenomenex-C18 (2) Luna 3pm, 100 A, 4.6* 100mm. Mobile phase: (A) 0.1% TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 37%B to 47%B in 10 min; injection volume: 10 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0580] General Procedure 4

[0581] Scheme 21. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-(2-formyl-3-hydroxy-N- methylbenzamido)ethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys Bridge) (Ex. A8) (SEQ ID NO:

[0582] C1751.70001WO00 126 / 174 #14267371vl

[0583]

[0584]

[0247] Synthesis: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS.

[0585] Reaction was performed at a 0.3 mmol scale using Sieber AM Resin (100-200 mesh, 0.46 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) Deprotection: 20 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 20 mL DMF, rt, 5x1 min; (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 2-3 mF DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5- 1.5 h; (5) Kaiser test: Negative; (6) Washing: 20-25 mL DMF, rt, 3x1 min.

[0586]

[0248] The peptide was synthesized as follows:

[0587] 249] Cleavage and Deprotection: After the peptide was built up, it was washed with DMF*6 and

[0588] MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / H2O = 95 / 5, 25 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (150 mL) was added,

[0589] C1751.70001WO00 127 / 174

[0590] #14267371vl the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (45 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0591]

[0250] HPLC Purification: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 32%B to 62%B over 60 min, flow rate 40 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260 infinity II system, using Phenomenex-C18 (2) Luna 3 pm, 100 A, 4.6* 100mm. Mobile phase: (A) 0.1% TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 35%B to 45%B in 10 min; injection volume: 10 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0592] General Procedure 5

[0593] Scheme 22. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-((2-(2-((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys- NH2(Pen&Cys S-CH2-S Bridge) (Ex. A49) (SEQ ID NO: 61)

[0594] Cleavage:

[0595]

[0251] Synthesis: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS.

[0596] Reaction was performed at a 0.5 mmol scale using Rink Amide MB HA Resin (100-200 mesh, 0.34

[0597] C1751.70001WO00 128 / 174

[0598] #14267371vl mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) Deprotection: 30 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 30 mL DMF, rt, 5x1 min; (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 3-5 mF DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5- 1.5 h; (5) Kaiser test: Negative; (6) Washing: 30-40 mL DMF, rt, 3x1 min.

[0599]

[0252] The peptide was synthesized as follows:

[0600] 253] Cleavage and Deprotection: After the peptide was built up, it was washed with DMF*6 and

[0601] MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / l-LO = 87.5 / 2.5 / 5 / 2.5 / 2.5, 75 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (450 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (150 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0602]

[0254] HPLC Purification of Linear Peptide: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 28%B to 58%B over 60 min, flow rate 30 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the linear peptide as a white solid.

[0603]

[0255] Methylene in Solution: The linear peptide was dissolved by THF and water to 0.002 M. TCEP.HC1 (1.5 equiv), CH2I2 (3 equiv) and TEA (5 equiv) were added sequentially and then shaken at RT overnight. The reaction was monitored by MS. After the reaction was completed, THF was removed by reduced pressure to get the cyclic peptide solution.

[0604]

[0256] HPLC Purification of Methylene Peptide: The peptide solution was purified by using RP-HPLC on Luna C18 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 25 %B to 55 %B over 60 min, flow rate 20 mL / min, UV wavelength 220

[0605] C1751.70001WO00 129 / 174

[0606] #14267371vl nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the methylene peptide as a white solid.

[0607]

[0257] Side chain 3-((2-(2-aminoethoxy)ethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione coupling in Solution: The methylene peptide was dissolved in DMF to 0.045M, then DIC (2.0 equiv), and HOBt (1.5 equiv) were added sequentially. The mixture was shaken for 0.5h at RT. Then 3-((2-(2- aminoethoxy)ethyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione (1.1 eq) was added and shaken at RT overnight. The reaction was monitored by MS. After the reaction was completed, the reaction solution was diluted by ACN and water.

[0608]

[0258] HPLC Purification of Final Peptide: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 30%B to 50%B over 60 min, flow rate 15 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260 infinity II system, using Phenomenex-C18 (2) Luna 3pm, 100 A, 4.6*100mm. Mobile phase: (A) 0.1% TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 32%B to 42%B in 10 min; injection volume: 8 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0609] General Procedure 6

[0610] Scheme 23. Synthesis of Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N-(2-((2-((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)amino)ethyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys

[0611] Bridge) (Ex. A2) (SEQ ID NO: 14)

[0612] SPPS

[0613] C1751.70001WO00 130 / 174

[0614] #14267371vl

[0259] Synthesis: The RAM -Resin was swollen with DMF (20 mL) for 20 minutes and was used for peptide synthesis. The linear synthesis of peptide was initiated using PL-RAM resin (0.264 mmol / g, 800 mg). First Fmoc deprotection was done twice using 0.025 M Oxyma in 10% Piperidine / DMF (t= 2 min followed by 5 min). Fmoc-(L-Cys(Trt))-OH was coupled using DIC / Oxyma. The chain elongation was performed using DIC / Oxyma as an activator (Fmoc AA: 3 Eq, DIC: 3 Eq, Oxyma: 6 Eq, t= 2 h)

[0615]

[0260] The peptide was synthesized as follows:

[0616] 261] Cleavage and Deprotection: The resin-peptide was washed with DMF (5 times) and DCM (5 times). This peptide was cleaved from the resin using a cleavage cocktail of TFA: TIPS: H2O: DODT (90.0: 2.5: 2.5: 5.0; t = 2 h). The resin was filtered, and the crude peptide was precipitated using chilled diethyl ether (v / v:l:9). The ether layer was centrifuged and decanted. Peptide was triturated 2-3 times with ether followed by vortexing and centrifuging to afford the crude linear peptide that was purified by reverse phase (Cl 8 column, mobile phase A: Acetonitrile, mobile phase B: 0.1% TFA in H2O, flow rate: 12 mL / min) Fractions were lyophilized to get the product as an off white solid. LCMS (M+H) =1597.

[0617]

[0262] Oxidation: To a solution of the isolated peptide (20 mg, 0.0128 mmol) in ACN: H2O purged with nitrogen, was added Iodine (4.05 mg, 0.0321 mmol) dissolved in 1 ml of acetic acid slowly. Addition was done till the yellow color persisted in the solution. Reaction was stirred for 20 mins after which it was submitted for LCMS which showed the desired product mass (M+H =1553.6). The reaction mixture was quenched with sodium ascorbate and then crude was freeze dried. After freeze drying for 16 h, the crude was purified by reverse phase (Cl 8 column, mobile phase A: Acetonitrile, mobile phase B: 0.1% TFA in H2O, flow rate: 12 mL / min), fractions were collected and lyophilized to get (Peptide 1) as a white solid. LCMS (M+H) = 1596.

[0618]

[0263] Amidation in Solution: To a solution of Peptide 1 (25 mg, 0.0156 mmol) and Intermediate 414 (4.1 mg, 0.0156 mmol), in DMF (1.0 ml), was added HATU (7.1 mg, 0.0188 mmol) and DIPEA (5.4 pl, 0.0313 mmol) at 25° C. The reaction mixture was stirred at 25 °C for 10 min. After 10 min, the reaction mixture was quenched with ice. The crude was purified by reverse phase column chromatography to get the desired product Ac-Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N-(2-((2-((2-methoxy-3,4-dioxocyclobut- 1-

[0619] C1751.70001WO00 131 / 174

[0620] #14267371vl en-l-yl)amino)ethyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2 (SEQ ID NO: 14) (Pen&Cys Bridge) (6.5 mg, 3.72 pmol, 23.80 % yield) as white solid. LCMS (M+H) = 1749.7, Purity 94%

[0264] Additional examples were prepared according to Scheme O using the corresponding intermediate from the table following Scheme 14.

[0621] General Procedure 7

[0622] Scheme 24. Synthesis of Dimer: (Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-((2-((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)amino)ethyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys

[0623] Bridge)) (Succinic acid to Arg to form the dimer) (Ex. B2) (SEQ ID NO: 65)

[0624]

[0265] Synthesis: The cyclic peptide was prepared according to General Procedure 3 and dimerized according to General Procedure 9.

[0625] General Procedure 8

[0626] Scheme 25. Synthesis of Chain A: Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-((2-((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)amino)ethyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys

[0627] Bridge), Chain B: Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-Sar-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys

[0628] Bridge) (Succinic acid to Arg of Chain A and Arg of Chain B) (Ex. Bl) (SEQ ID NO: 64)

[0629] Intermediate 1 Intermediate 2

[0630] Scheme 26. Synthesis of Intermediate 1: Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-((2-((2-methoxy- 3,4-dioxocyclobut-l-en-l-yl)amino)ethyl)amino)-2-oxoethyl)-Gly-NMeLeu-Tyr-Pro-Cys-NH2 (SEQ

[0631] C1751.70001WO00 132 / 174

[0632] #14267371vl ID NO: 99)(Pen&Cys Bridge)

[0633]

[0266] Synthesis of Intermediate 1: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS. Reaction was performed at a 0.8 mmol scale using Rink Amide MB HA Resin (100- 200 mesh, 0.28 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) De-protection: 40 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 40 mL DMF, rt, 5x1 min; (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 8-10 mL DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5-

[0634] 1.5 h; (5) Kaiser test: Negative; (6) Washing: 40-50 mL DMF, rt, 3x1 min.

[0635]

[0267] The peptide was synthesized as follows:

[0636] C1751.70001WO00 133 / 174 #14267371vl

[0637]

[0638] 268] Cleavage and Deprotection of Intermediate 1: After the peptide was built up, it was washed with

[0639] DMF*6 and MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / H2O = 87.5 / 2.5 / 5 / 2.5 / 2.5, 70 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (420 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (150 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0640]

[0269] Oxidation in solution of Intermediate 1: The dry crude peptide was dissolved by ACN and water. L / McOH solution (20-40 g / L) was added dropwise to the peptide solution until it turned brown, then Vc solution was added until the solution changed to colorless.

[0641]

[0270] HPLC Purification of Intermediate 1 : The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 28%B to 58%B over 60 min, flow rate 40 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the intermediate 1 as a white solid.

[0642] Scheme 27. Synthesis of Intermediate 2: Succinic acid -Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-Sar-

[0643] NMeLeu-Tyr-Pro-Cys-NH2 (SEQ ID NO: 100) (Pen&Cys Bridge)

[0644] C1751.70001WO00 134 / 174

[0645] #14267371vl

[0646]

[0271] Synthesis of Intermediate 2: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS. Reaction was performed at a 0.3 mmol scale using Rink Amide MB HA Resin (100- 200 mesh, 0.28 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) De-protection: 20 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 20 mL DMF, rt, 5x1 min; (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 2-3 mF DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5-

[0647] 1.5 h; (5) Kaiser test: Negative; (6) Washing: 20-30 mL DMF, rt, 3x1 min.

[0648]

[0272] The peptide was synthesized as follows:

[0649] 273] Cleavage and Deprotection of Intermediate 2: After the peptide was built up, it was washed with

[0650] DMF*6 and MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / H2O = 87.5 / 2.5 / 5 / 2.5 / 2.5, 22 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (120 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (50 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0651]

[0274] Oxidation in solution of Intermediate 2: The dry crude peptide was dissolved by ACN and water. L / McOH solution (20-40 g / L) was added dropwise to the peptide solution until it turned brown, then Vc solution was added until the solution changed to colorless.

[0652]

[0275] HPLC Purification of Intermediate 2: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 30%B to 60%B over 60 min, flow rate 20 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the intermediate 2 as a white solid.

[0653] C1751.70001WO00 135 / 174

[0654] #14267371vl

[0276] Synthesis of Homodimer: To a solution of intermediate 1 (1.0 equiv) and intermediate 2 (1.0 equiv) in DMF (about 30 mg / mL) was added PyAOP (1.1 equiv ), HOBT (1.1 equiv ), DIEA (4.0 equiv) sequentially. The solution was stirred at RT overnight. The MS showed the reaction completed. Then the mixture was diluted by ACN / H2O and purified without further operation.

[0655]

[0277] HPLC Purification of Final Peptide: The diluted reaction solution was purified by using RP- HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 30%B to 60%B over 60 min, flow rate 10 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260 infinity II system, using Phenomenex-C18 (2) Luna 3 m, 100 A, 4.6* 100mm. Mobile phase: (A) 0.1% TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 37%B to 47%B in 10 min; injection volume: 15 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0656] General Procedure 9

[0657] Scheme 28. Synthesis of Dimer: (Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N((E)-(2-methyl-6,14-dioxo- 10-oxa-2,7,13-triazapentadec-4-en-15-yl))-Gly-NMeLeu-Tyr-Pro-Cys-NH2(Pen&Cys Bridge)) (Succinic acid to Arg to form the dimer) (Ex. B25) (SEQ ID NO: 88)

[0658] C1751.70001WO00 136 / 174

[0659] #14267371vl

[0660]

[0661]

[0278] Synthesis: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS.

[0662] Reaction was performed at a 1.0 mmol scale using Rink Amide MB HA Resin (100-200 mesh, 0.38 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) Deprotection: 60 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 60 mL DMF, rt, 5x1 min; (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 6-10 mF DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5- 1.5 h; (5)

[0663] Kaiser test: Negative; (6) Washing: 60-80 mL DMF, rt, 3x1 min.

[0664]

[0279] The peptide was synthesized as follows:

[0665] C1751.70001WO00 137 / 174 #14267371vl

[0666] 280] Cleavage and Deprotection: After the peptide was built up, it was washed with DMF*6 and MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / H2O = 87.5 / 2.5 / 5 / 2.5 / 2.5, 52 mL). The suspension was shaken at RT for 2.0 h. After filtered, cold ether (320 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (100 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0667]

[0281] Oxidation in Solution: The dry crude peptide was dissolved by CAN and water. L / McOH solution (20-40 g / L) was added dropwise to the peptide solution until it turned brown, then Vc solution was added until the solution changed to colorless.

[0668]

[0282] HPLC Purification of Oxidation Peptide: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 28 %B to 58%B over 60 min, flow rate 40 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing oxidation peptide were confirmed by LC / MS, then lyophilized to get the oxidation peptide as a white solid.

[0669]

[0283] Synthesis of Homodimer Intermediate: To a solution of the intermediate (2.4 equiv) in DMF (about 75 mg / mL) was added DIEA (4.8 equiv). Then N,N’-(Succinyldioxy)disuccinimide (1 equiv) was added at 15mins interval in three portions to the reaction solution, and stirred at RT for 1-2 h. The MS showed the reaction completed.

[0670]

[0284] HPLC Purification of Homodimer Intermediate: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm lOpm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 32%B to 52%B over 60 min, flow rate 40 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing homodimer peptide were confirmed by LC / MS, then lyophilized to get the homodimer peptide as a white solid.

[0671]

[0285] Side chain CAN-N-(2-(2-aminoethoxy)ethyl)-4-(dimethylamino)but-2-enamide coupling in Solution: The homodimer intermediate was dissolved in DMF to 0.022M, then CAN-N-(2-(2- aminoethoxy)ethyl)-4-(dimethylamino)but-2-enamide (4.0 eq), PyAop (2.2 equiv), HOBt (2.2 equiv) and DIEA (5.0 equiv) were added sequentially and then shaken at RT for 1-2 h. The reaction was monitored by MS. After the reaction was completed, the reaction solution was diluted by CAN and water.

[0672]

[0286] HPLC Purification of Final Peptide: The diluted reaction solution was purified by using RP- HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 27%B to 57%B over 60 min, flow rate

[0673] C1751.70001WO00 138 / 174

[0674] #14267371vl 20 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260 infinity II system, using Phenomenex-C18 (2) Luna 3pm, 100 A, 4.6* 100mm. Mobile phase: (A) 0.1% TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 31%B to 41%B in 10 min; injection volume: 10 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0675] General Procedure 10

[0676] Scheme 29. Synthesis of Dimer: (Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-N(2-((2-(2-((2-methoxy-3,4- dioxocyclobut-l-en-l-yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)-Gly-NmeLeu-Tyr-Pro-Cys- NH2(Pen&Cys S-CH2-S Bridge)) (Succinic acid to Arg to form the dimer) (Ex. B31) (SEQ ID NO:

[0677] Cleavage:

[0678] C1751.70001WO00 139 / 174

[0679] #14267371vl

[0680]

[0287] Synthesis: Peptide was synthesized on a clear glass reactor by using Fmoc / tBu chemistry of SPPS.

[0681] Reaction was performed at a 1.8 mmol scale using Rink Amide MB HA Resin (100-200 mesh, 0.38 mmol / g loading) while a stream of nitrogen bubbled through it. Every synthesis cycle included: (1) Deprotection: 100 mL 20% Piperidine in DMF (v / v), rt, 30 mins; (2) Washing: 100 mL DMF, rt, 5x1 min;

[0682] (3) Kaiser test: Positive; (4) Coupling: All the amino acids and bases were dissolved in 10-16 mF DMF and then added into reactor. Coupling reagents were added and reaction was kept at RT for 0.5- 1.5 h; (5) Kaiser test: Negative; (6) Washing: 100-120 mL DMF, rt, 3x1 min.

[0683]

[0288] The peptide was synthesized as follows:

[0684] 289] Cleavage and Deprotection: After the peptide was built up, it was washed with DMF*6 and

[0685] MeOH*2 and dried under vacuum overnight. Then it was cleaved by treatment with cocktail (TFA / EDT / Thioanisole / Phenol / H2O = 87.5 / 2.5 / 5 / 2.5 / 2.5, 128 mL). The suspension was shaken at RT for 2.5 h. After filtered, cold ether (800 mL) was added, the peptide was precipitated by centrifugation (3500 rpm). The white precipitation was washed with ether (250 mL) twice. Then the resulting crude peptide was dried under vacuum overnight.

[0686] C1751.70001WO00 140 / 174

[0687] #14267371vl

[0290] HPLC Purification of Linear Peptide: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 27%B to 57%B over 60 min, flow rate 80 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing linear peptide were confirmed by LC / MS, then lyophilized to get the linear peptide as a white solid.

[0688]

[0291] Methylene in Solution: The linear peptide was dissolved by THF and water to 0.002 M. TCEP.HC1 (1.5 equiv), CH2I2 (3 equiv) and TEA (5 equiv) were added sequentially and then shaken at RT overnight. The reaction was monitored by MS. After the reaction was completed, THF was removed by reduced pressure to get the methylene peptide solution.

[0689]

[0292] HPLC Purification of Methylene Peptide: The peptide solution was purified by using RP-HPLC on Luna Cl 8 100 A 450x50mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 28 %B to 58%B over 60 min, flow rate 100 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing methylene peptide were confirmed by LC / MS, then lyophilized to get the methylene peptide as a white solid.

[0690]

[0293] Synthesis of Homodimer: To a solution of the methylene peptide (2.4 equiv) in DMF (about 100 mg / mL) was added DIEA (4.8 equiv). Then N,N'-(Succinyldioxy)disuccinimide (1 equiv) was added at 15mins interval in three portions to the reaction solution, and stirred at RT for 1-2 h. The MS showed the reaction completed.

[0691]

[0294] HPLC Purification of Homodimer Peptide: The peptide solution was purified by using RP- HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 30%B to 60%B over 60 min, flow rate 20 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were collected and the fractions containing homodimer peptide were confirmed by LC / MS, then lyophilized to get the homodimer peptide as a white solid.

[0692]

[0295] Side chain 3-((2-(2-aminoethoxy)ethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione coupling in

[0693] Solution: The homodimer peptide was dissolved in DMF to 0.024M, then 3-((2-(2- aminoethoxy)ethyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione (1.1 eq), PyAop (1.0 equiv), HOBt (1.0 equiv) and DIEA (8 equiv) were added sequentially and then shaken at RT overnight. The reaction was monitored by MS. After the reaction was completed, the reaction solution was diluted by ACN and water.

[0694]

[0296] HPLC Purification of Final Peptide: The reaction solution was diluted by ACN and water. Then purified by using RP-HPLC on Luna Cl 8 100 A 450x25.4mm 10pm using Hanbon Newstyle® Laboratory liquid chromatography system. Mobile phase: (A) 0.1% TFA in water and (B) 0.1%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 31%B to 51%B over 60 min, flow rate 20 mL / min, UV wavelength 220 nm. UV absorbing fractions containing the target m / z ions were

[0695] C1751.70001WO00 141 / 174

[0696] #14267371vl collected and the fractions containing product were confirmed by LC / MS, then lyophilized to get the product as a white solid. Confirmation identity and purity assessment of final compounds were performed by Agilent Technologies 1260-6120 Quadrupole LC / MS and Agilent Technologies 1260 infinity II system, using Phenomenex-C18 (2) Luna 3pm, 100 A, 4.6* 100mm. Mobile phase: (A) 0.1% TFA in water and (B) 0.09%TFA in (80%ACN+20%H20), following gradient of eluent B was used: 35%B to 45%B in 10 min; injection volume: 10 pL; flow rate: 1 mL / min, UV wavelength 220 nm.

[0697] Example 4: FcRn Inhibition and Biological Data

[0698]

[0297] The following methods describe the assays referenced in Table 4.

[0699]

[0298] FcRn / b2m - Human IgG Homogeneous Time Resolved Fluorescence (HTRF) Protein-Protein Interaction Assay for IC50 Value Determination: This assay demonstrates the ability of described peptides to inhibit the FcRn / b2m - hlgG interaction. FcRn / b2m heterodimer Tb Cryptate stock (from HTRF FcRn Binding Kit Revvity 64FCRNPEH) was diluted 100-fold in 25mM Sodium Phosphate pH7.2, lOOmM Sodium Chloride, 0.01% bovine serum albumin, 0.01% T-20. 7.5ul of the FcRn - b2m Tb cryptate working solution was added to peptides dissolved in DMSO to a final concentration of 2% DMSO and incubated for 4 hours at 30°C. Human IgG d2 antibody stock was diluted 100-fold in Detection Buffer and 7.5ul of hlgG d2 working solution was added to the reaction mixture containing FcRn / b2m / peptides. The binding of the hlgG d2 to FcRn / b2m Tb Cryptate yielded a TR-FRET signal; addition of peptides that bound FcRn and prevented the binding of hlgG, resulted in a decrease of the TR-FRET signal. After 90 minutes incubation at room temperature, the signal was measured on a plate reader (BioTek Synergy Neo2 Hybrid Multimode Reader) using TR-FRET mode with wavelengths of 665nm / 620nm. The potency of peptides as FcRn / b2m - hlgG inhibitors was determined by IC50 value generated using a non-linear 4 parameter curve fit.

[0700]

[0299] FcRn / b2m - Human Serum Albumin Homogeneous Time Resolved Fluorescence (HTRF) Protein- Protein Interaction Assay for IC50 Value Determination: This assay demonstrates the ability of described peptides to inhibit the FcRn / b2m - HSA interaction. Biotinylated FcRn / b2m heterodimer (SinoBiological CT071-H27H-B) was diluted to 20nM and incubated with 2nM Streptavidin-Tb Cryptate (Revvity 610SATLB) in 25mM Sodium Phosphate pH7.2, lOOmM Sodium Chloride, 0.01% bovine serum albumin, 0.01% T-20. 7.5ul of the FcRn - b2m Tb cryptate working solution was added to peptides dissolved in DMSO to a final concentration of 2% DMSO and incubated for 4 hours at 30°C. HSA d2 antibody stock (HSA, Sigma-Aldrich A6608 custom-labeled by Revvity) was diluted to 500nM in Diluent Buffer 10 (Revvity 62DL10DDC) and 7.5ul of HSA d2 working solution was added to the reaction mixture containing FcRn / b2m / peptides. The binding of the HSA d2 to FcRn / b2m Tb Cryptate yielded a TR-FRET signal; addition of peptides that bound FcRn and prevented the binding of HSA, resulted in a decrease of the TR-FRET signal. After 90 minutes incubation at room temperature, the signal was measured on a plate reader (BioTek Synergy Neo2 Hybrid Multimode Reader) using TR- FRET mode with wavelengths of 665nm / 620nm. The potency of compounds as FcRn / b2m - HSA inhibitors was determined by IC50 value generated using a non-linear 4 parameter curve fit.

[0701] C1751.70001WO00 142 / 174

[0702] #14267371vl Results and Data

[0703]

[0300] Assay results are provided in Table 4.

[0704] Table 4

[0705] Example 5: Additional FcRn Inhibition and Biological Data

[0706]

[0301] FcRn / |32m - CY5-SYN1327 Homogeneous Time Resolved Fluorescence (HTRF) Assay for IC50 Value Determination: This assay demonstrates the ability of described peptides to inhibit the FcRn / [32m - CY5-SYN1327 interaction. Biotinylated FcRn / [32m heterodimer (SinoBiological CT071- H27H-B) was diluted to lOnM and mixed with lOOnM CY5-SYN1327 (CY5-Arg-Phe-Pen-Thr-Gly-His- Phe-Gly-Sar-NMeLeu-Tyr-Pro-Cys-NH2 (SEQ ID NO: 2) (Pen&Cys Bridge synthesized by CPC Scientific and sequence described in THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 36, pp. 27694 -27701, September 3, 2010) and InM Streptavidin- Tb cryptate (Revvity 610SATLB) in 25mM Sodium Phosphate pH7.2, lOOmM Sodium Chloride, 0.01% bovine serum albumin, 0.01% T-20. The working solution was pre-warmed to 30°C for 30mins and 15ul of the working solution was added to peptides dissolved in DMSO to a final concentration of 1 % DMSO and further incubated at 30°C. The binding of the CY5-SYN1327 to FcRn / [32m Tb Cryptate yielded a TR-FRET signal; addition of peptides that bound FcRn and displaced CY5-SYN1327, resulted in a decrease of the TR-FRET signal. The signal was measured after 4 hours on a plate reader (BioTek Synergy Neo2 Hybrid Multimode Reader) using TR-FRET mode with wavelengths of 665nm / 620nm. The potency of peptides as FcRn / b2m - CY5- SYN1327 inhibitors was determined by IC50 value generated using a non-linear 4 parameter curve fit.

[0707]

[0302] FcRn / p2m - CY5-SYN1436 Homogeneous Time Resolved Fluorescence (HTRF) Assay for IC50 Value Determination: This assay demonstrates the ability of described peptides to inhibit the FcRn / [32m - CY5-SYN1436 interaction. Biotinylated FcRn / [32m heterodimer (SinoBiological CT071- H27H-B) was diluted to InM and mixed with 200nM CY5-SYN1436 (CY5-(3-amido-pentanedioyl)- (Arg-Phe-Pen-Thr-Gly-His-Phe-Gly-Sar-NMeLeu-Tyr-Pro-Cys-NH2- (SEQ ID NO: 2)(Pen & Cys bridge))2 synthesized by CPC Scientific and sequence described in THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 36, pp. 27694 -27701, September 3, 2010) and 0.5nM Streptavidin-Tb cryptate (Revvity 610SATLB) in 25mM Sodium Phosphate pH7.2, lOOmM Sodium Chloride, 0.01% bovine serum albumin, 0.01% T-20. The working solution was pre- warmed to 30°C for 30mins and 15ul of the working solution was added to peptides dissolved in DMSO to a final concentration of 1% DMSO and further incubated at 30°C. The binding of the CY5-SYN1436 to FcRn / [32m Tb Cryptate yielded a TR-FRET signal; addition of peptides that bound FcRn and displaced CY5-SYN1436, resulted in a decrease of the TR-FRET signal. The signal was measured after 4 hours on a plate reader (BioTek Synergy Neo2 Hybrid Multimode Reader) using TR-FRET mode with wavelengths of 665nm / 620nm.

[0708] C1751.70001WO00 143 / 174

[0709] #14267371vl The potency of peptides as FcRn / [32m - CY5-SYN1436 inhibitors was determined by IC50 value generated using a non-linear 4 parameter curve fit.

[0710] C1751.70001WO00 144 / 174 #14267371vl Table 5

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723] EQUIVALENTS AND SCOPE

[0724]

[0303] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0725]

[0304] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element / s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0726]

[0305] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0727]

[0306] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes

[0728] C1751.70001WO00 158 / 174

[0729] #14267371vl and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

[0730] C1751.70001WO00 159 / 174 #14267371vl

Claims

CLAIMSWhat is claimed is:

1. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising: (i) an amino acid sequence capable of binding a neonatal fragment crystallizable receptor (FcRn); and (ii) a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

2. The cyclic peptide of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence capable of binding FcRn comprises the amino acid sequence:G-H-F-G-Sar-NMeL-Y (SEQ ID NO: 1), wherein:Sar is sarcosine, and NMeL is N-methyl-leucine; and the amino acid sequence includes 0, 1, 2, 3, 4, or 5 amino acid substitutions.

3. The cyclic peptide of claim 2, or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence includes 0, 1, 2, or 3 amino acid substitutions.

4. The cyclic peptide of claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence includes 1 amino acid substitution.

5. The cyclic peptide of claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence includes 0 amino acid substitutions.

6. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence:R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* (SEQ ID NO: 2), wherein:Pen is penicillamine, Sar is sarcosine, and NMeL is N-methyl-leucine; the amino acid sequence includes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions;* denotes crosslinked amino acids connected via a crosslink; and one amino acid comprises a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

7. The cyclic peptide of claim 6, or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence includes 0, 1, 2, 3, 4, or 5 amino acid substitutions.

8. The cyclic peptide of claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence includes 0, 1, 2, or 3 amino acid substitutions.C1751.70001WO00 160 / 174#14267371vl9. The cyclic peptide of any one of claims 6-8, or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence includes 1 amino acid substitution.

10. The cyclic peptide of any one of claims 6-8, or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence includes 0 amino acid substitutions.

11. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence:X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(REF ID NO: 96), wherein:X1is arginine (R), D-arginine (D-Arg), lysine (K), a lysine replacement, or other amino acid;X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;X3and X13are each independently penicillamine (Pen), cysteine (C), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via a crosslink;X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), or a serine replacement;X5is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), or a glycine replacement;X6is histidine (H) or a histidine replacement;X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), a tyrosine replacement, or other amino acid;X8is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), lysine (K), a glycine replacement, a lysine replacement, or other amino acid;X9is sarcosine (Sar), glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), a glycine replacement, or another amino acid;X10is N-methyl-leucine (NMeL), leucine (L), glycine (G), sarcosine (Sar), alanine (A), valine (V), isoleucine (I), or a glycine replacement;X” is tyrosine (Y), a tyrosine replacement, phenylalanine (F), a phenylalanine replacement, or other amino acid; andX12is proline (P) or a proline replacement; and one of X’-X12is attached to a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

12. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence:X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X"-X12-X13(REF ID NO: 3),C1751.70001WO00 161 / 174#14267371vlwherein:XIis arginine (R), lysine (K), a lysine replacement, or other amino acid;X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;X3and X13are each independently penicillamine (Pen), cysteine (C), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via a crosslink;X4is threonine (T), a threonine replacement, serine (S), or a serine replacement;X5is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), or a glycine replacement;X6is histidine (H) or a histidine replacement;X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), a tyrosine replacement, or other amino acid;X8is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), lysine (K), a glycine replacement, a lysine replacement, or other amino acid;X9is sarcosine (Sar), glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), a glycine replacement, or other amino acid;X10is N-methyl-leucine (NMeL), leucine (L), glycine (G), sarcosine (Sar), alanine (A), valine (V), isoleucine (I), or a glycine replacement;XIIis tyrosine (Y), a tyrosine replacement, phenylalanine (F), a phenylalanine replacement, or other amino acid; andX12is proline (P) or a proline replacement; and one of X’-X12is attached to a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

13. The cyclic peptide of claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein:XIis arginine (R), lysine (K), or a lysine replacement;X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;X3and X13are each independently penicillamine (Pen), cysteine (C), or a cysteine replacement;X4is threonine (T), a threonine replacement, serine (S), or a serine replacement;X5is glycine (G), alanine (A), valine (V), leucine (L), or isoleucine (I), or a glycine replacement;X6is histidine (H) or a histidine replacement;X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement;X8is glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), lysine (K), a glycine replacement, or a lysine replacement;X9is sarcosine (Sar), glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), or a glycine replacement;X10is N-methyl-leucine (NMeL), leucine (L), glycine (G), sarcosine (Sar), alanine (A), valine (V), isoleucine (I), or a glycine replacement;XI Iis tyrosine (Y), a tyrosine replacement, phenylalanine (F), a phenylalanine replacement; andX12is proline (P) or a proline replacement.C1751.70001WO00 162 / 174#14267371vl14. The cyclic peptide of any one of claims 11-13, or a pharmaceutically acceptable salt thereof, wherein X1is arginine (R), D-arginine (D-Arg) or lysine (K).

15. The cyclic peptide of any one of claims 11-14, or a pharmaceutically acceptable salt thereof, wherein X1is R.

16. The cyclic peptide of any one of claims 11-15, or a pharmaceutically acceptable salt thereof, wherein X2is phenylalanine (F) or D-phenylalanine (D-Phe).

17. The cyclic peptide of any one of claims 11-16, or a pharmaceutically acceptable salt thereof, wherein X2is F.

18. The cyclic peptide of any one of claims 11-17, or a pharmaceutically acceptable salt thereof, wherein X3is Pen.

19. The cyclic peptide of any one of claims 11-18, or a pharmaceutically acceptable salt thereof, wherein X4is threonine (T) or D-threonine (D-Thr).

20. The cyclic peptide of any one of claims 11-9, or a pharmaceutically acceptable salt thereof, wherein X4is T.

21. The cyclic peptide of any one of claims 11-20, or a pharmaceutically acceptable salt thereof, wherein X5is G.

22. The cyclic peptide of any one of claims 11-21, or a pharmaceutically acceptable salt thereof, wherein X6is histidine (H) or a histidine replacement that iC1751.70001WO00 163 / 174#14267371vl23. The cyclic peptide of any one of claims 11-22, or a pharmaceutically acceptable salt thereof, wherein X6is H.

24. The cyclic peptide of any one of claims 11-23, or a pharmaceutically acceptable salt thereof, wherein X7is phenylalanine (F) or a phenylalanine replacement that25. The cyclic peptide of any one of claims 11-24, or a pharmaceutically acceptable salt thereof, wherein X7is F.

26. The cyclic peptide of any one of claims 11-25, or a pharmaceutically acceptable salt thereof, wherein X8is G or K.

27. The cyclic peptide of any one of claims 11-26, or a pharmaceutically acceptable salt thereof, wherein X8is G.

28. The cyclic peptide of any one of claims 11-27, or a pharmaceutically acceptable salt thereof, wherein X9is Sar or G.C1751.70001WO00 164 / 174#14267371vl29. The cyclic peptide of any one of claims 11-28, or a pharmaceutically acceptable salt thereof, wherein X9is glycine (G) attached to a group of the formula: -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety.

30. The cyclic peptide of any one of claims 11-29, or a pharmaceutically acceptable salt thereof, wherein X10is NMeL.

31. The cyclic peptide of any one of claims 11-30, or a pharmaceutically acceptable salt thereof, wherein X” is tyrosine (Y) or a tyrosine replacement that i32. The cyclic peptide of any one of claims 11-31, or a pharmaceutically acceptable salt thereof, wherein X” is Y.

33. The cyclic peptide of any one of claims 11-32, or a pharmaceutically acceptable salt thereof, wherein X12is proline (P) or a proline replacement that is34. The cyclic peptide of any one of claims 11-33, or a pharmaceutically acceptable salt thereof, wherein X12is P.

35. The cyclic peptide of any one of claims 11-34, or a pharmaceutically acceptable salt thereof, wherein X13is C.

36. The cyclic peptide of any one of claims 11-35, or a pharmaceutically acceptable salt thereof, wherein the amino acid X7, X8, X9, or X11is attached the group of the formula: -L’-Rw.

37. The cyclic peptide of any one of claims 11-36, or a pharmaceutically acceptable salt thereof, wherein the amino acid X9is attached to the group of the formula: -L’-Rw.

38. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising one of the following amino acid sequences:R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y+-P-C* (SEQ ID NO: 4),C1751.70001WO00 165 / 174#14267371vlR-F-Pen*-T-G-H-F-K+-Sar-NMeL-Y-P-C* (SEQ ID NO: 5), R-F-Pen*-T-G-H-F-G-G+-NMeL-Y-P-C* (SEQ ID NO: 6), R-F-Pen*-T-G-H-F-G+-Sar-NMeL-Y-P-C* (SEQ ID NO: 7), R-F-Pen*-T-G-H-F+-K-Sar-NMeL-Y-P-C* (SEQ ID NO: 8), wherein+denotes the amino acid attached to the group of the formula: -L’-Rw.

39. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising the following amino acid sequence:R-F-X3-T-G-H-F-G-Sar-NMeL-Y-P-X13(SEQ ID NO: 9), wherein X3and X13are each independently penicillamine (Pen), cysteine (C), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via a crosslink.

40. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising the following amino acid sequence:R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12-C* (SEQ ID NO: 10), wherein X12is proline (P) or a proline replacement.

41. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising the following amino acid sequence:X1-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* (SEQ ID NO: 11), wherein X1is arginine (R), lysine (K), a lysine replacement, or other amino acid.

42. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising the following amino acid sequence:R-F-Pen*-X4-G-X6-F-G-Sar-NMeL-X11-P-C* (SEQ ID NO: 12), wherein:X4is threonine (T), a threonine replacement, serine (S), or a serine replacement;X6is histidine (H) or a histidine replacement; andX” is tyrosine (Y), a tyrosine replacement, phenylalanine (F), or a phenylalanine replacement.

43. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising the following amino acid sequence:X1-X2-Pen*-X4-G-X6-X7-G-X9-NMeL-X11-X12-C* (SEQ ID NO: 97), wherein:X1is arginine (R), D-arginine (D-Arg) or lysine (K);X2is phenylalanine (F) or D-phenylalanine (D-Phe);X4is threonine (T) or D- threonine (D-Thr);C1751.70001WO00 166 / 174#14267371vlX6is histidine (H) or a histidine replacement thatX7is phenylalanine (F) or a phenylalanine replacement thatX9is glycine (G) attached to a group of the formula: -L’-Rw, wherein L1is a bond or a linker, andRwis a covalent binding moiety;X” is tyrosine (Y) or a tyrosine replacement that iandX12is proline (P) or a proline replacement that is44. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein a-sidechains of the crosslinked amino acids are connected to form the crosslink.C1751.70001WO00 167 / 174 #14267371vl45. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the crosslink connects the a-carbons of the crosslinked amino acids.

46. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the crosslink is a bond, Ci-io alkylene, Ci-io haloalkylene, Ci-io heteroalkylene, Ci-io alkenylene, Ci-io heteroalkenylene, Ci-io alkynylene, Ci-io heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

47. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the crosslinked amino acids are connected to form:, wherein each a represents the point of attachment to the a-carbon of a crosslinked amino acid.

48. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salta represents the point of attachment to the a-carbon of a crosslinked amino acid.

49. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the group of the formula: -L’-Rwis attached to the a-carbon of an amino acid.

50. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the group of the formula: -L’-Rwis attached to the a-sidechain of an amino acid.

51. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the group of the formula: -L’-Rwis attached to the peptide nitrogen of an amino acid.

52. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the group of the formula: -L’-Rwis attached to the amino acid at position 5 of SEQ IDNO: 1, or position 9 of any one of SEQ ID NOs: 2-12, to form:C1751.70001WO00 168 / 174#14267371vl53. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L1is a bond, or a linker selected from Ci-20 alkylene, Ci-20 haloalkylene, Ci-20 heteroalkylene, Ci-20 alkenylene, Ci-20 heteroalkenylene, Ci-20 alkynylene, Ci-20 heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

54. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -L’-Rwis of one of the following formulae:C1751.70001WO00 169 / 174#14267371vl55. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Rwis a covalent binding moiety comprising a vinyl sulfone, a sulfonyl halide, a squarate, a benzaldehyde, or an a,P-unsaturated carbonyl.C1751.70001WO00 170 / 174 #14267371vl56. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Rwis a covalent binding moiety selected from one of the following formulae:

57. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Rwis a covalent binding moiety selected from:

58. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the N-terminus of the cyclic peptide is acylated.

59. The cyclic peptide of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the C-terminus of the cyclic peptide is amidated (-NH2).

60. The cyclic peptide of any one of the preceding claims, wherein the cyclic peptide is selected from those in Tables 2A-2B, and pharmaceutically acceptable salts thereof.

61. The cyclic peptide of any one of the preceding claims, as a free base.

62. A dimer, or pharmaceutically acceptable salt thereof, comprising two cyclic peptides, wherein: the two cyclic peptides are independently cyclic peptides of any one of claims 1-61; the two cyclic peptides are conjugated to each other via a bond or a linker; and one or both cyclic peptides comprise the group of the formula: -L’-Rw.

63. The dimer of claim 62, or a pharmaceutically acceptable salt thereof, wherein exactly one of the cyclic peptides comprises a group of the formula: -L’-Rw.C1751.70001WO00 171 / 174#14267371vl64. The dimer of claim 62, or a pharmaceutically acceptable salt thereof, wherein both cyclic peptides comprise a group of the formula: -L’-Rw.

65. The dimer of any one of claims 62-64, wherein the dimer is selected from those in Table 2B, and pharmaceutically acceptable salts thereof.

66. A pharmaceutical composition comprising a cyclic peptide of any one of claims 1-61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

67. A method of treating a neonatal fragment crystallizable receptor (FcRn)-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any one of claims 1-61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

68. A method of treating an immunoglobulin G (IgG)-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any one of claims 1-61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

69. A method of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any one of claims 1- 61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

70. A method of covalently inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a cyclic peptide of any one of claims 1-61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

71. A method of decreasing IgG levels in a subject in need thereof comprising administering to the subject an effective amount of a cyclic peptide of any one of claims 1-61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

72. A cyclic peptide of any one of claims 1-61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in:(a) treating a FcRn-mediated disease in a subject;(b) treating an IgG-mediated disease in a subject;(c) treating an autoimmune disease in a subject;C1751.70001WO00 172 / 174#14267371vl(d) covalently inhibiting an FcRn activity in vitro or in vivo,' and / or(e) decreasing IgG levels in a subject.

73. Use of a cyclic peptide of any one of claims 1-61 or a dimer of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament.C1751.70001WO00 173 / 174 #14267371vl

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