Cyclic peptide inhibitor of IL-23

Abstract

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

Description

Technical Field

[0001] (Field of the Invention) The present invention relates to novel peptide inhibitors of interleukin-23 receptor (IL-23R), or pharmaceutically acceptable salts, solvates, and / or other forms thereof, corresponding pharmaceutical compositions, methods, and / or uses for the treatment of autoimmune inflammatory diseases and / or related disorders.

[0002] (Reference to Electronically Submitted Sequence Listing) This application includes a sequence listing submitted electronically via the Patent Center of the United States Patent and Trademark Office as an XML-formatted sequence listing, with the file name "JBI6738WOPCT1 sequence listing.xml", creation date July 13, 2023, and size 3,492 kb. The sequence listing submitted via the Patent Center is part of this specification and is incorporated herein by reference.

[0003] (Background) Interleukin-23 (IL-23) cytokine is thought to play an important role in the pathogenesis of autoimmune inflammation and related diseases and disorders such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), for example, ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed the main role of interleukin-23 receptor (IL-23R) and downstream effector cytokines in the pathogenesis of the disease. IL-23R is expressed in various adaptive and innate immune cells including Th17 cells, γδT cells, natural killer (NK) cells, dendritic cells, macrophages, and natural lymphoid cells that are abundant in the intestine. In patients with IBD, increased gene expression and protein levels of IL-23R have been found on the intestinal mucosal surface. IL-23 is thought to mediate this effect by promoting the development of pathogenic CD4 + T cell populations.

[0004] IL-23 is produced abundantly in the intestine, where, in addition to controlling the balance between tolerance and immunity via T cell-dependent and T cell-independent pathways of enteritis by affecting T helper 1 (Th1) and Th17-related cytokines, it is thought to play an important role in suppressing intestinal regulatory T cell responses favorable for inflammation. In addition, polymorphisms in the interleukin-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the important role of the IL-23 pathway in intestinal homeostasis.

[0005] Psoriasis, a chronic skin disease affecting approximately 2% to 3% of the general population, has been shown to be mediated by the body's T cell inflammatory response mechanism. IL-23 is said to be one of several interleukins that are key players in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation through the induction of interleukin-17, the control of T memory cells, and the activation of macrophages. The expression of IL-23 and IL-23R has been shown to increase in the tissues of psoriasis patients, and antibodies that neutralize IL-23 have shown IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0006] IL-23 is a heterodimer composed of the unique p19 subunit and the p40 subunit shared with interleukin-12 (IL-12), a cytokine involved in the development of interferon-γ (IFN-γ)-producing T helper 1 (T H 1) cells. Both IL-23 and IL-12 contain the p40 subunit but have different phenotypic properties. For example, animals deficient in IL-12 are prone to inflammatory autoimmune diseases, while IL-23-deficient animals are resistant, presumably due to a reduction in the number of CD4 + T cells that produce IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. IL-23 binds to IL-23R, a heterodimeric receptor composed of the IL-12Rβ1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, but the activation of Stat4 is substantially weaker compared to IL-12, and different DNA-binding Stat complexes are formed in response to IL-23. IL-23R associates constitutively with Jak2 and ligand-dependently with Stat3. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 acts preferentially on memory CD4(+) T cells.

[0007] Therapeutic moieties that inhibit the IL-23 pathway have been developed for use in treating diseases and disorders associated with IL-23. Several antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, which is approved for the treatment of moderate to severe plaque psoriasis (PSO), active psoriatic arthritis (PSA), moderate to severe active Crohn's disease (CD), and moderate to severe active ulcerative colitis (UC). Examples of such identified antibodies include tildrakizumab, an anti-IL23 antibody approved for the treatment of plaque psoriasis; guselkumab, an anti-IL23 antibody approved for the treatment of psoriatic arthritis; and risankizumab, an anti-IL23 antibody approved for the treatment of plaque psoriasis in the United States and for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis in Japan.

[0008] Targeted IL-23 antibody therapeutics are in clinical use, but there are no small molecule therapeutics that selectively inhibit IL-23 signaling. There are several identified polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R (see, e.g., U.S. Patent Application Publication No. 2013 / 0029907). Accordingly, there is a great need in the art for effective small molecule and / or polypeptide therapeutics for treating and / or preventing IL-23-related and / or IL23R-related diseases and disorders.

[0009] (Brief Summary) Generally, the present invention relates to novel peptide inhibitors of interleukin-23 receptor (IL-23R), or pharmaceutically acceptable salts, solvates, and / or other forms thereof, corresponding pharmaceutical compositions, methods, and / or uses thereof for the treatment of autoimmune inflammatory diseases and / or related disorders.

[0010] In particular, the present invention relates to a cyclic peptide comprising the amino acid sequence of formula (A), or a pharmaceutically acceptable salt or solvate thereof, Z3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (A), wherein, the amino acid residue at position Z 3 is absent or is the residue of r, the amino acid residue at position Z 4 is the residue of the amino acid linked to the amino acid residue at position Z 9 , the amino acid residue at position Z 5 is the residue of N(N(Me)2), the amino acid residue at position Z 6 is the residue of T, the amino acid residue at position Z 7 is the residue of 7MeW, the amino acid residue at position Z 8 is the residue of K(NMeAc), the amino acid residue at position Z 9 is the residue of the amino acid linked to the amino acid residue at position Z 4 , the amino acid residue at position Z 10 is the residue of TMAPF, the amino acid residue at position Z 11 is the residue of 2Nal, the amino acid residue at position Z 12 is absent or is the residue of THP, the amino acid residue at position Z 13 is the residue of K(NMeAc), the amino acid residue at position Z 14 is the residue of N, the amino acid residue at position Z 15 is absent or is the residue of 3Pya, the amino acid residue at position Z 16The amino acid residue is absent or is a Sar residue, Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 of the amino acid residues of which eight or less, when an amino acid residue is present at that position, are each independently replaced by an amino acid residue different from the listed amino acid residue at that position, Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 of the amino acid residues of which at least one, when an amino acid residue is present at that position, each independently contains at least one quaternary amine.

[0011] In particular, the present invention relates to a cyclic peptide containing the amino acid sequence of formula (B) below, or a pharmaceutically acceptable salt or solvate thereof, Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (B), wherein, Position Z 3 the amino acid residue is absent or is an r residue, Position Z 4 the amino acid residue is at position Z9 is the residue of an amino acid linked to the amino acid residue, Position Z 5 the amino acid residue of is the residue of N(N(Me)2), Position Z 6 the amino acid residue of is the residue of T, Position Z 7 the amino acid residue of is the residue of 7MeW, Position Z 8 the amino acid residue of is the residue of K(NMeAc), Position Z 9 the amino acid residue of is Position Z 4 is the residue of an amino acid linked to the amino acid residue, Position Z 10 the amino acid residue of is the residue of TMAPF, Position Z 11 the amino acid residue of is the residue of 2Nal, Position Z 12 the amino acid residue of is absent or is the residue of THP, Position Z 13 the amino acid residue of is the residue of K(NMeAc), Position Z 14 the amino acid residue of is the residue of N, Position Z 15 the amino acid residue of is absent or is the residue of 3Pya, Position Z 16 the amino acid residue of is absent or is the residue of Sar, Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Among the amino acid residues of, if an amino acid residue exists at that position, independently, when there are eight or fewer, it is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 3 , Z5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 At least one of the amino acid residues of, when the amino acid residue is present at that position, each independently contains at least one masked amine and / or masked amide.

[0012] In particular, the present invention relates to a cyclic peptide comprising the amino acid sequence of formula (C) below, or a pharmaceutically acceptable salt or solvate thereof, Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (C), wherein, the amino acid residue at position Z 3 is absent or is the residue of r, the amino acid residue at position Z 4 is the residue of the amino acid linked to the amino acid residue at position Z 9 , the amino acid residue at position Z 5 is the residue of N(N(Me)2), the amino acid residue at position Z 6 is the residue of T, the amino acid residue at position Z 7 is the residue of 7MeW, the amino acid residue at position Z 8 is the residue of K(NMeAc), the amino acid residue at position Z 9 is the residue of the amino acid at position Z 4is a residue of an amino acid linked to the amino acid residue, Position Z 10 the amino acid residue of is a residue of TMAPF, Position Z 11 the amino acid residue of is a residue of 2Nal, Position Z 12 the amino acid residue of is absent or is a residue of THP, Position Z 13 the amino acid residue of is a residue of K(NMeAc), Position Z 14 the amino acid residue of is a residue of N, Position Z 15 the amino acid residue of is absent or is a residue of 3Pya, Position Z 16 the amino acid residue of is absent or is a residue of Sar, Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Among the amino acid residues of, if an amino acid residue is present at that position, up to 8 of them are independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0013] The present invention also relates to a compound selected from any one of Tables 1A, 1B, 1C, 1D, 1E, and 1F, or a pharmaceutically acceptable salt or solvate thereof.

[0014] In particular, the present invention relates to compounds of formulas (I)-(X), or pharmaceutically acceptable salts, solvates and / or other forms thereof, corresponding pharmaceutical compositions, methods, and / or uses for the treatment of autoimmune inflammatory diseases and related disorders.

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

[0016] The present invention also relates to a compound as described in any of Tables 1A-H or a pharmaceutically acceptable salt, solvate or form thereof, corresponding pharmaceutical compositions, methods and / or uses thereof for the treatment of autoimmune inflammatory diseases and related disorders.

[0017] The present disclosure also relates to a pharmaceutical composition comprising the peptide inhibitor compound of the or a pharmaceutically acceptable salt, solvate, or form thereof described herein and a pharmaceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition may or may not include an absorption enhancer depending on the intended delivery route or its use for the treatment of a particular indication. The absorption enhancer may be a permeation enhancer or an intestinal permeation enhancer. In one aspect, the absorption enhancer improves oral bioavailability.

[0018] The present invention is a method and / or use for the treatment of an inflammatory disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of one or more of the peptide inhibitor compounds of IL-23R described herein or a pharmaceutically acceptable salt or solvate thereof, or a corresponding pharmaceutical composition described herein. Such inflammatory diseases and related disorders can include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA).

[0019] The present invention provides the use of one or more compounds described herein (e.g., compounds of formulas (I)-(X) or Tables 1A-1H) for the preparation of a pharmaceutical composition for use in the treatment of inflammatory diseases and related disorders including, but not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA).

[0020] The present invention provides the use of one or more compounds of formulas (I)-(X) or Tables 1A-1H described herein in the treatment of inflammatory diseases and related disorders including, but not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA).

[0021] The present invention provides a kit comprising one or more compounds of formulas (I)-(X) or Tables 1A-1H described herein and instructions for use in the treatment of a patient's disease. The disease can be an inflammatory disease or related disorder including, but not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), and psoriatic arthritis (PsA).

[0022] (Detailed description) I. Overview The cyclic peptides of the present invention include a quaternary amine, a masked amine, a masked amide, or a combination thereof. The inclusion of a quaternary amine, a masked amine, and / or a masked amide in the cyclic peptides of the present invention has improved the pharmacokinetic properties of the cyclic peptides as compared to other compounds targeting IL-23R. For example, the cyclic peptides of the present invention have a highly desirable oral PK profile and improved oral bioavailability. The cyclic peptides of the present invention also have a lower predicted human dose. The quaternary amine and the masked amine and / or masked amide are intended to achieve these improvements by changing the polar properties of the molecule as reflected in the observed Exposed Polar Surface Area (EPSA) values.

[0023] The present invention relates to novel peptide inhibitors of IL-23R, or pharmaceutically acceptable salts, solvates, or forms thereof, corresponding pharmaceutical compositions, methods, and / or uses for the treatment of autoimmune inflammation and related diseases and disorders.

[0024] The present invention provides, or relates to, peptide inhibitors of IL-23R. The peptide inhibitors of the present invention may exhibit enhanced properties such as a longer in vivo half-life compared to the corresponding cyclic peptide inhibitors of IL-23R that do not have a cyclic structure. In particular, compounds and methods for the specific targeting of IL-23R from the luminal side of the intestine can provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue, and / or orally bioavailable small molecules and / or polypeptide inhibitors of IL-23 can provide both non-steroidal treatment options for patients with mild to moderate psoriasis and treatments for moderate to severe psoriasis that do not require delivery by injection.

[0025] Compounds and methods for specifically targeting IL-23R from the luminal side of the intestine can provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue. In addition, orally bioavailable small molecules and / or polypeptide inhibitors of IL-23 can provide both non-steroidal treatment options for patients with mild to moderate psoriasis and treatments for moderate to severe psoriasis that do not require delivery by injection.

[0026] The present invention aims to address these needs by providing peptide inhibitors that bind to IL-23R and inhibit IL-23 binding and signaling, or pharmaceutically acceptable salts, solvates, and / or other forms thereof, via different suitable routes of administration including, but not limited to, oral administration.

[0027] In a general aspect, the present invention relates to a cyclic peptide comprising the amino acid sequence of formula (A), or a pharmaceutically acceptable salt or solvate thereof, Z 3-Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (A), Wherein, The amino acid residue at position Z 3 Is absent or is a residue of r, The amino acid residue at position Z 4 Is the residue of the amino acid linked to the amino acid residue at position Z 9 And is the residue of the amino acid linked to the amino acid residue at position Z The amino acid residue at position Z 5 Is a residue of N(N(Me)2), The amino acid residue at position Z 6 Is a residue of T, The amino acid residue at position Z 7 Is a residue of 7MeW, The amino acid residue at position Z 8 Is a residue of K(NMeAc), The amino acid residue at position Z 9 Is the residue of the amino acid linked to the amino acid residue at position Z 4 And is the residue of the amino acid linked to the amino acid residue at position Z The amino acid residue at position Z 10 Is a residue of TMAPF, The amino acid residue at position Z 11 Is a residue of 2Nal, The amino acid residue at position Z 12 Is absent or is a residue of THP, The amino acid residue at position Z 13 Is a residue of K(NMeAc), The amino acid residue at position Z 14 Is a residue of N, The amino acid residue at position Z 15 Is absent or is a residue of 3Pya, The amino acid residue at position Z 16The amino acid residue is absent or is a Sar residue, Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Among the amino acid residues of 16 , when an amino acid residue is present at that position, up to 8 of them are independently replaced with amino acid residues different from the listed amino acid residues at that position. Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 When an amino acid residue is present at that position, at least one of the amino acid residues of 16 each independently contains at least one quaternary amine.

[0028] In another general aspect, the present invention relates to a cyclic peptide comprising the amino acid sequence of formula (B), or a pharmaceutically acceptable salt or solvate thereof, Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (B), Wherein, Position Z 3 The amino acid residue is absent or is an r residue, Position Z 4The amino acid residue is at position Z 9 is the residue of the amino acid linked to the amino acid residue of position Z 5 The amino acid residue is the residue of N(N(Me)2), position Z 6 The amino acid residue is the residue of T, position Z 7 The amino acid residue is the residue of 7MeW, position Z 8 The amino acid residue is the residue of K(NMeAc), position Z 9 The amino acid residue is at position Z 4 is the residue of the amino acid linked to the amino acid residue of position Z 10 The amino acid residue is the residue of TMAPF, position Z 11 The amino acid residue is the residue of 2Nal, position Z 12 The amino acid residue is either absent or is the residue of THP, position Z 13 The amino acid residue is the residue of K(NMeAc), position Z 14 The amino acid residue is the residue of N, position Z 15 The amino acid residue is either absent or is the residue of 3Pya, position Z 16 The amino acid residue is either absent or is the residue of Sar, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Among the amino acid residues of, if the amino acid residue is present at that position, independently, when there are eight or fewer amino acid residues, they are replaced with amino acid residues different from the listed amino acid residues at that position, position Z3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 At least one of the amino acid residues of is, when the amino acid residue is present at that position, each independently contains at least one masked amine and / or masked amide

[0029] In another general aspect, the present invention relates to a cyclic peptide comprising the amino acid sequence of formula (C) below, or a pharmaceutically acceptable salt or solvate thereof, Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (C), Wherein, The amino acid residue at position Z 3 Is absent or is a residue of r, The amino acid residue at position Z 4 Is the residue of the amino acid linked to the amino acid residue at position Z 9 Of the amino acid residue at position Z The amino acid residue at position Z 5 Is a residue of N(N(Me)2), The amino acid residue at position Z 6 Is a residue of T, The amino acid residue at position Z 7 Is a residue of 7MeW, The amino acid residue at position Z 8 Is a residue of K(NMeAc), The amino acid residue at position Z 9 Is the amino acid residue at position Z 4is the residue of an amino acid linked to the amino acid residue, Position Z 10 the amino acid residue is the residue of TMAPF, Position Z 11 the amino acid residue is the residue of 2Nal, Position Z 12 the amino acid residue is either absent or is the residue of THP, Position Z 13 the amino acid residue is the residue of K(NMeAc), Position Z 14 the amino acid residue is the residue of N, Position Z 15 the amino acid residue is either absent or is the residue of 3Pya, Position Z 16 the amino acid residue is either absent or is the residue of Sar, Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Among the amino acid residues of, when the amino acid residue is present at that position, independently, up to 8 of them are replaced with amino acid residues different from the listed amino acid residues at that position.

[0030] In some embodiments, at position Z 4 the amino acid residue is the residue of Abu or an amino acid residue containing a sulfhydryl group.

[0031] In some embodiments, at position Z 9 the amino acid residue is the residue of an amino acid containing a sulfhydryl group.

[0032] In some embodiments, at position Z 4 when the amino acid residue is the residue of an amino acid containing a sulfhydryl group, at position Z 4The amino acid residue is at position Z 4 is linked to the amino acid residue at position Z 9 by a disulfide bond formed between the amino acid containing a sulfhydryl group at position Z 9 and the amino acid containing a sulfhydryl group at position Z

[0033] In some embodiments, the amino acid residue at position Z 4 is a residue of an amino acid containing a sulfhydryl group, and the amino acid residue at position Z 4 is linked to the amino acid residue at position Z 4 by a disulfide bond formed between the amino acid containing a sulfhydryl group at position Z 9 and the amino acid containing a sulfhydryl group at position Z 9

[0034] In some embodiments, when the amino acid residue at position Z 4 is a residue of Abu, the amino acid residue at position Z 4 is linked to the amino acid residue at position Z 4 by a thioether bond formed between the Abu at position Z 9 and the amino acid containing a sulfhydryl group at position Z 9

[0035] In some embodiments, the amino acid residue at position Z 4 is a residue of Abu, and the amino acid residue at position Z 4 is linked to the amino acid residue at position Z 4 by a thioether bond formed between the Abu at position Z 9 and the amino acid containing a sulfhydryl group at position Z 9

[0036] In some embodiments, the cyclic peptide further comprises R NT wherein R NT is (i) when Z 3 is present, at position Z 3 or (ii) when Z 3 is absent, at position Z​​​4 is attached to the N-terminal amine of the amino acid residue, R NT is -C(O)-optionally substituted (C1-C 20 ) alkyl and -C(O)-optionally substituted (C1-C 40 ) heteroalkyl, selected from the group consisting of.

[0037] In some embodiments, the cyclic peptide further comprises R CT and R CT is (i) When Z 16 is present, of position Z 16 (ii) When Z 16 is not present, of position Z 15 or (iii) When Z 15 and Z 16 are not present, is attached to the carbonyl derived from the C-terminal carboxylic acid of the amino acid residue at position Z 14 , R CT is -N(R Y )(R Z ), wherein (i) each R Y and R Z is independently selected from the group consisting of hydrogen, optionally substituted (C1-C 15 ) alkyl, and optionally substituted (C1-C 30 ) heteroalkyl, or (ii) each R Y and R Z together with the N atom to which they are attached form an optionally substituted (C3-C 14 ) heterocyclic ring or an optionally substituted (C5-C 10 ) bicyclic heterocyclic ring.

[0038] In some embodiments, the cyclic peptide further comprises R CT and R CT is (i) When Z 16 is present, of position Z 16 of​ (ii) Z 16 In the case where Z does not exist, position Z 15 of, or (iii) Z 15 and Z 16 In the case where they do not exist, position Z 14 is bonded to a carbonyl derived from the C-terminal carboxylic acid of the amino acid residue of Z R CT is -N(R Y )(R Z ), and in the formula (i) Each R Y and R Z is independently selected from the group consisting of hydrogen, optionally substituted (C1-C 15 ) alkyl, and optionally substituted (C1-C 30 ) heteroalkyl, provided that only one of R Y and R Z is hydrogen, or (ii) Each R Y and R Z together with the N atom to which they are attached form an optionally substituted (C3-C 14 ) heterocyclic ring or an optionally substituted (C5-C 10 ) bicyclic heterocyclic ring.

[0039] In some embodiments, the cyclic peptide further comprises R NT and R CT and has the following formula (D): R NT -Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 -R CT (D), wherein R NT , Z 3 , Z4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , Z 16 , and R CT are as defined herein.

[0040] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 of eight of the amino acid residues, if the amino acid residue is present at that position, are independently replaced with an amino acid residue different from the listed amino acid residue at that position.

[0041] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 of seven or fewer of the amino acid residues, if the amino acid residue is present at that position, are independently replaced with an amino acid residue different from the listed amino acid residue at that position.

[0042] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11, Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Seven of the amino acid residues, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0043] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Six or fewer of the amino acid residues, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0044] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Six of the amino acid residues, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0045] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z16 Of the amino acid residues, five or fewer, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0046] In some embodiments, position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and Z 16 Of the amino acid residues, five, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0047] In some embodiments, position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and Z 16 Of the amino acid residues, four or fewer, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0048] In some embodiments, position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and Z 16Of the four amino acid residues, if the amino acid residue is present at that position, it can be independently replaced with an amino acid residue different from the listed amino acid residue at that position.

[0049] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Of the three or fewer amino acid residues of Z 16 , if the amino acid residue is present at that position, it can be independently replaced with an amino acid residue different from the listed amino acid residue at that position.

[0050] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Of the three amino acid residues of Z 16 , if the amino acid residue is present at that position, it can be independently replaced with an amino acid residue different from the listed amino acid residue at that position.

[0051] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16Of the amino acid residues, two or fewer, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0052] In some embodiments, position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and Z 16 Of the amino acid residues of Z 16 , two, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0053] In some embodiments, position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and Z 16 Of the amino acid residues of Z 16 , one or fewer, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0054] In some embodiments, position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and Z 16One of the amino acid residues, if the amino acid residue is present at that position, can independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0055] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 None of the amino acid residues of Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 , if the amino acid residue is present at that position, can independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0056] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16 Among the amino acid residues of Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16 , seven or fewer, if the amino acid residue is present at that position, can independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0057] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16 Among the amino acid residues of Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16 , seven, if the amino acid residue is present at that position, can independently be replaced with an amino acid residue different from the listed amino acid residue at that position.

[0058] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15, and Z 16 Of the amino acid residues of 16 , when an amino acid residue is present at that position, six or fewer of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0059] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16 Of the amino acid residues of 16 , when an amino acid residue is present at that position, six of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0060] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16 Of the amino acid residues of 16 , when an amino acid residue is present at that position, five or fewer of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0061] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16 Of the amino acid residues of 16 , when an amino acid residue is present at that position, five of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0062] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 , and Z 16Of the amino acid residues, four or fewer, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the amino acid residue listed for that position.

[0063] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 and Z 16 Of the amino acid residues, four, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the amino acid residue listed for that position.

[0064] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 and Z 16 Of the amino acid residues, three or fewer, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the amino acid residue listed for that position.

[0065] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 and Z 16 Of the amino acid residues, three, if the amino acid residue is present at that position, may independently be replaced with an amino acid residue different from the amino acid residue listed for that position.

[0066] In some embodiments, position Z 3 , Z 5 , Z 8 , Z 10 , Z 13 , Z 15 and Z 16Among the amino acid residues, if the amino acid residue is present at that position, two or fewer of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0067] In some embodiments, position Z 3 Z 5 Z 8 Z 10 Z 13 Z 15 and Z 16 Among the amino acid residues of, if the amino acid residue is present at that position, two of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0068] In some embodiments, position Z 3 Z 5 Z 8 Z 10 Z 13 Z 15 and Z 16 Among the amino acid residues of, if the amino acid residue is present at that position, one or fewer of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0069] In some embodiments, position Z 3 Z 5 Z 8 Z 10 Z 13 Z 15 and Z 16 Among the amino acid residues of, if the amino acid residue is present at that position, one of them can be independently replaced with an amino acid residue different from the listed amino acid residue at that position.

[0070] In some embodiments, position Z 5 Z 8 Z 10 and Z 13 Among the amino acid residues of, four or fewer of them can be independently replaced with amino acid residues different from the listed amino acid residues at that position.

[0071] In some embodiments, position Z 5 , Z 8 , Z 10 , and Z 13 of the four amino acid residues may each independently be replaced with an amino acid residue different from the amino acid residue listed at that position.

[0072] In some embodiments, position Z 5 , Z 8 , Z 10 , and Z 13 of the three or fewer amino acid residues may each independently be replaced with an amino acid residue different from the amino acid residue listed at that position.

[0073] In some embodiments, position Z 5 , Z 8 , Z 10 , and Z 13 of the three amino acid residues may each independently be replaced with an amino acid residue different from the amino acid residue listed at that position.

[0074] In some embodiments, position Z 5 , Z 8 , Z 10 , and Z 13 of the two or fewer amino acid residues may each independently be replaced with an amino acid residue different from the amino acid residue listed at that position.

[0075] In some embodiments, position Z 5 , Z 8 , Z 10 , and Z 13 of the two amino acid residues may each independently be replaced with an amino acid residue different from the amino acid residue listed at that position.

[0076] In some embodiments, position Z 5 , Z 8 , Z 10 , and Z 13 of the one or fewer amino acid residues may each independently be replaced with an amino acid residue different from the amino acid residue listed at that position.

[0077] In some embodiments, position Z 5 , Z 8 , Z 10 , and Z 13 of the amino acid residues is independently replaced with an amino acid residue different from the listed amino acid residue at that position.

[0078] In some embodiments, the amino acid residue at position Z 3 is not replaced if an amino acid residue is present at that position.

[0079] In some embodiments, the amino acid residue at position Z 6 is not replaced.

[0080] In some embodiments, the amino acid residue at position Z 7 is not replaced.

[0081] In some embodiments, the amino acid residue at position Z 11 is not replaced.

[0082] In some embodiments, the amino acid residue at position Z 12 is not replaced if an amino acid residue is present at that position.

[0083] In some embodiments, the amino acid residue at position Z 14 is not replaced.

[0084] In some embodiments, the amino acid residue at position Z 15 is not replaced if an amino acid residue is present at that position.

[0085] In some embodiments, the amino acid residue at position Z 16 is not replaced if an amino acid residue is present at that position.

[0086] In some embodiments, position Z 6 and Z 11The amino acid residues cannot be replaced.

[0087] In some embodiments, position Z 6 and Z 14 The amino acid residues cannot be replaced.

[0088] In some embodiments, position Z 11 and Z 14 The amino acid residues cannot be replaced.

[0089] In some embodiments, position Z 6 , Z 11 , and Z 14 The amino acid residues cannot be replaced.

[0090] In some embodiments, position Z 6 , Z 7 , Z 11 , and Z 14 The amino acid residues cannot be replaced.

[0091] In some embodiments, position Z 6 , Z 11 , Z 12 , and Z 14 The amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0092] In some embodiments, position Z 6 , Z 7 , Z 11 , Z 12 , and Z 14 The amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0093] In some embodiments, position Z 3 , Z 6 , Z 7 , Z 11 , Z 12 , and Z 14 The amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0094] In some embodiments, position Z 6 , Z 7 , Z 11 , Z 12 , Z 14 , and Z 15 amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0095] In some embodiments, position Z 3 , Z 6 , Z 7 , Z 11 , Z 12 , Z 14 , and Z 15 amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0096] In some embodiments, position Z 6 , Z 7 , Z 11 , Z 12 , Z 14 , and Z 16 amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0097] In some embodiments, position Z 3 , Z 6 , Z 7 , Z 11 , Z 12 , Z 14 , and Z 16 amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0098] In some embodiments, position Z 6 , Z 7 , Z 11 , Z 12 , Z 14 , Z 15 , and Z 16 amino acid residues cannot be replaced if the amino acid residue is present at that position.

[0099] In some embodiments, position Z 3 , Z 6 , Z7 , Z 11 , Z 12 , Z 14 , Z 15 , and Z 16 The amino acid residues of and Z cannot be replaced if the amino acid residues are present at that position.

[0100] In some embodiments, position Z 3 , Z 12 , Z 15 , and Z 16 Less than or equal to 3 of the amino acid residues of do not exist.

[0101] In some embodiments, position Z 3 , Z 12 , Z 15 , and Z 16 3 of the amino acid residues of do not exist.

[0102] In some embodiments, position Z 3 , Z 12 , Z 15 , and Z 16 Less than or equal to 2 of the amino acid residues of do not exist.

[0103] 7 In some embodiments, position Z 3 , Z 12 , Z 15 , and Z 16 2 of the amino acid residues of do not exist.

[0104] In some embodiments, position Z 3 , Z 12 , Z 15 , and Z 16 Less than or equal to 1 of the amino acid residues of do not exist.

[0105] In some embodiments, position Z 3 , Z 12 , Z 15 , and Z 16 1 of the amino acid residues of does not exist.

[0106] In some embodiments, position Z 3, Z 12 , Z 15 , and Z 16 None of the amino acid residues of, and, shall be absent.

[0107] In some embodiments, the amino acid residue at position Z 3 is absent, and the amino acid residues at positions Z 12 , Z 15 , and Z 16 are present.

[0108] In some embodiments, the amino acid residue at position Z 12 is absent, and the amino acid residues at positions Z 3 , Z 15 , and Z 16 are present.

[0109] In some embodiments, the amino acid residue at position Z 15 is absent, and the amino acid residues at positions Z 3 , Z 12 , and Z 16 are present.

[0110] In some embodiments, the amino acid residue at position Z 16 is absent, and the amino acid residues at positions Z 3 , Z 12 , and Z 15 are present.

[0111] In some embodiments, the amino acid residues at positions Z 3 and position Z 16 are absent, and the amino acid residues at positions Z 12 and Z 15 are present.

[0112] In some embodiments, the amino acid residues at positions Z 3 , Z 15 , and Z 16 are absent, and the amino acid residue at position Z 12 is present.

[0113] In some embodiments, R NT(if present), and / or R CT (if present), and / or position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and / or Z 16 At least one of the amino acid residues (if the amino acid residue is present at that position) of Z contains, independently of each other, at least one quaternary amine.

[0114] In some embodiments, R NT (if present), and / or R CT (if present), and / or position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and / or Z 16 At least one of the amino acid residues (if the amino acid residue is present at that position) of Z contains, independently of each other, a quaternary amine.

[0115] In some embodiments, position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and / or Z 16 At least one of the amino acid residues of Z contains, independently of each other, at least one quaternary amine if the amino acid residue is present at that position.

[0116] In some embodiments, position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 of at least one of the amino acid residues, when the amino acid residue is present at that position, each independently contains a quaternary amine.

[0117] In some embodiments, R NT (if present), and / or R CT (if present), and / or position Z 3 , Z 5 , Z 8 , Z 10 , Z 12 , and / or Z 13 of the amino acid residues (when the amino acid residue is present at that position) of at least one of, each independently contains at least one quaternary amine.

[0118] In some embodiments, R NT (if present), and / or R CT (if present), and / or position Z 3 , Z 5 , Z 8 , Z 10 , Z 12 , and / or Z 13 of the amino acid residues (when the amino acid residue is present at that position) of at least one of, each independently contains a quaternary amine.

[0119] In some embodiments, R NT (if present), and / or position Z 3 , Z 5 , Z 8 , Z 10 , and / or Z 13Of the amino acid residues (if the amino acid residue is present at that position), at least one of each independently contains at least one quaternary amine.

[0120] In some embodiments, R NT (if present), and / or position Z 3 , Z 5 , Z 8 , Z 10 , and / or Z 13 Of the amino acid residues (if the amino acid residue is present at that position), at least one of each independently contains a quaternary amine.

[0121] In some embodiments, R NT and position Z 5 and Z 10 Of the amino acid residues, each independently contains at least one quaternary amine.

[0122] In some embodiments, R NT and position Z 5 and Z 10 Of the amino acid residues, each independently contains a quaternary amine.

[0123] In some embodiments, R NT and position Z 8 and Z 10 Of the amino acid residues, each independently contains at least one quaternary amine.

[0124] In some embodiments, R NT and position Z 8 and Z 10 Of the amino acid residues, each independently contains a quaternary amine.

[0125] In some embodiments, R NT and position Z 8 and Z 13 Of the amino acid residues, each independently contains at least one quaternary amine.

[0126] In some embodiments, R NTand position Z 8 and Z 13 The amino acid residues of ,

[0127] , and each independently contain a quaternary amine.

[0127] In some embodiments, the amino acid residues of position Z 8 , Z 10 , and Z 13 each independently contain at least one quaternary amine. 8 Z 10 and Z 13 The amino acid residues of ,

[0128] , and each independently contain at least one quaternary amine.

[0128] In some embodiments, the amino acid residues of position Z 8 , Z 10 , and Z 13 each independently contain a quaternary amine. 8 Z 10 and Z 13 The amino acid residues of ,

[0129] , and each independently contain a quaternary amine.

[0129] In some embodiments, the amino acid residues of R NT and position Z 3 each independently contain at least one quaternary amine. NT and position Z 3 The amino acid residues of ,

[0130] , and each independently contain at least one quaternary amine.

[0130] In some embodiments, the amino acid residues of R NT and position Z 3 each independently contain a quaternary amine. NT and position Z 3 The amino acid residues of ,

[0131] , and each independently contain a quaternary amine.

[0131] In some embodiments, the amino acid residues of R NT and R CT each independently contain at least one quaternary amine. NT and R CT The amino acid residues of ,

[0132] , and each independently contain at least one quaternary amine.

[0132] In some embodiments, the amino acid residues of R NT and R CT each contain a quaternary amine. NT and R CT The amino acid residues of ,

[0133] , and each contain a quaternary amine.

[0133] In some embodiments, the amino acid residues of R NT and position Z 8 each independently contain at least one quaternary amine. NT and position Z 8 The amino acid residues of ,

[0134] , and each independently contain at least one quaternary amine.

[0134] In some embodiments, the amino acid residues of R NT and position Z 8 each independently contain a quaternary amine. NT and position Z 8 The amino acid residues of and

[0135] each independently contain a quaternary amine.

[0135] In some embodiments, R NT and position Z 10 amino acid residues each independently contain at least one quaternary amine.

[0136] In some embodiments, R NT and position Z 10 amino acid residues each independently contain a quaternary amine.

[0137] In some embodiments, position Z 3 and Z 8 amino acid residues each independently contain at least one quaternary amine.

[0138] In some embodiments, position Z 3 and Z 8 amino acid residues each independently contain a quaternary amine.

[0139] In some embodiments, position Z 3 and Z 10 amino acid residues each independently contain at least one quaternary amine.

[0140] In some embodiments, position Z 3 and Z 10 amino acid residues each independently contain a quaternary amine.

[0141] In some embodiments, position Z 5 and Z 10 amino acid residues each independently contain at least one quaternary amine.

[0142] In some embodiments, position Z 5 and Z 10 amino acid residues each independently contain a quaternary amine.

[0143] In some embodiments, position Z 8 and Z 10 amino acid residues each independently contain at least one quaternary amine.

[0144] In some embodiments, position Z 8 and Z 10 of the amino acid residues each independently contain a quaternary amine.

[0145] In some embodiments, position Z 8 and Z 13 of the amino acid residues each independently contain at least one quaternary amine.

[0146] In some embodiments, position Z 8 and Z 13 of the amino acid residues each independently contain a quaternary amine.

[0147] In some embodiments, position Z 10 and Z 13 of the amino acid residues each independently contain at least one quaternary amine.

[0148] In some embodiments, position Z 10 and Z 13 of the amino acid residues each independently contain a quaternary amine.

[0149] In some embodiments, R NT contains at least one quaternary amine.

[0150] In some embodiments, R NT contains a quaternary amine.

[0151] In some embodiments, R CT contains at least one quaternary amine.

[0152] In some embodiments, R CT contains a quaternary amine.

[0153] In some embodiments, the amino acid residue at position Z 3 contains at least one quaternary amine.

[0154] In some embodiments, the amino acid residue at position Z 3 contains a quaternary amine.

[0155] In some embodiments, the amino acid residue at position Z 5 contains at least one quaternary amine.

[0156] In some embodiments, the amino acid residue at position Z 5 contains a quaternary amine.

[0157] In some embodiments, the amino acid residue at position Z 8 contains at least one quaternary amine.

[0158] In some embodiments, the amino acid residue at position Z 8 contains a quaternary amine.

[0159] In some embodiments, the amino acid residue at position Z 10 contains at least one quaternary amine.

[0160] In some embodiments, the amino acid residue at position Z 10 contains a quaternary amine.

[0161] In some embodiments, the amino acid residue at position Z 12 contains at least one quaternary amine.

[0162] In some embodiments, the amino acid residue at position Z 12 contains a quaternary amine.

[0163] In some embodiments, the amino acid residue at position Z 13 contains at least one quaternary amine.

[0164] In some embodiments, the amino acid residue at position Z 13 contains a quaternary amine.

[0165] In some embodiments, at least one quaternary amine is one or two quaternary amines.

[0166] In some embodiments, each quaternary amine is (a)

[0167] [Chemical Formula] (wherein each R ZA is independently selected from the group consisting of optionally substituted (C1-C 20 ) alkyl and optionally substituted (C1-C 20 ) heteroalkyl), (b)

[0168] [Chemical Formula] (wherein each R ZA and R ZB are independently selected from the group consisting of optionally substituted (C1-C 20 ) alkyl and optionally substituted (C1-C 20 ) heteroalkyl), (c)

[0169] [Chemical Formula] (wherein (c)(i) each R ZA , R ZB , and R ZC is independently selected from the group consisting of optionally substituted (C1-C 20 ) alkyl and optionally substituted (C1-C 20 ) heteroalkyl, or (c)(ii) each R ZA is independently selected from the group consisting of optionally substituted (C1-C 20 ) alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R ZB and R ZCtogether with the N atom to which they are attached, optionally form a substituted (C3-C 14 ) heterocyclic ring, or (c)(iii) each R ZA , R ZB , and R ZC together with the N atom to which they are attached, optionally form a substituted (C5-C 10 ) bicyclic heterocyclic ring), (d)

[0170] [Chemical formula] (wherein (d)(i) each R ZA and R ZB is independently selected from the group consisting of optionally substituted (C1-C 20 ) alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R ZC and R ZD together with the N atom to which they are attached, optionally form a substituted (C3-C 14 ) heterocyclyl, or (d)(ii) each R ZA and R ZB together with the N atom to which they are attached, optionally form a substituted (C3-C 14 ) heterocyclyl, and each R ZC and R ZD together with the N atom to which they are attached, optionally form a substituted (C3-C 14 ) heterocyclyl, or (d)(iii) each R ZA and R ZB together with the N atom to which they are attached, optionally form a substituted (C3-C 14 ) heterocyclyl, and each R ZC and R ZD together with the N atom to which they are attached, optionally form a substituted (C3-C 14 ) heterocyclic ring), (e)

[0171]

Chem.

[0172]

Chem.

[0173] In some embodiments, each quaternary amine is (a)

[0174]

Chem.

[0175]

Chem.

[0176]

Chemical formula

[0177]

Chemical formula

[0178]

Chemical formula

[0179]

Chemical formula

[0180] In some embodiments, each quaternary amine is (a)

[0181]

Chemical formula

[0182]

Chemical Structure

[0183]

Chemical Structure

[0184]

Chemical Structure

[0185]

Chemical formula

[0186]

Chemical formula

[0187] In some embodiments, each R ZA , R ZB , and / or R ZC (when present) is optionally substituted alkyl, each optionally substituted alkyl is unsubstituted.

[0188] In some embodiments, each R ZA , R ZB , and / or R ZC (when present) is optionally substituted heteroalkyl, each optionally substituted heteroalkyl is unsubstituted.

[0189] In some embodiments, each R ZB and R ZC when taken together with the N atom to which they are attached form an optionally substituted heterocyclic ring, the optionally substituted heterocyclic ring is unsubstituted or is substituted with one or more substituents independently selected from the group consisting of fluoro and (C1-C3) alkyl.

[0190] In some embodiments, each R ZA , R ZB , and R ZC when taken together with the N atom to which they are attached form an optionally substituted bicyclic heterocyclic ring, the optionally substituted bicyclic heterocyclic ring is unsubstituted.

[0191] In some embodiments, each R ZA and R ZB when taken together with the N atom to which they are attached form an optionally substituted heterosilyl, the optionally substituted heterosilyl is unsubstituted.

[0192] Some embodiments are each RZB and R ZC When R and R, together with the N atom to which they are attached, form an optionally substituted heteroaryl, the optionally substituted heteroaryl is unsubstituted.

[0193] In some embodiments, each R ZC and R ZD When R and R, together with the N atom to which they are attached, form an optionally substituted heterocyclyl, the optionally substituted heterocyclyl is unsubstituted.

[0194] In some embodiments, each R ZC and R ZD When R and R, together with the N atom to which they are attached, form an optionally substituted heterocyclic ring, the optionally substituted heterocyclic ring is unsubstituted.

[0195] In some embodiments, each R ZA and R ZB When R and R, together with the N atom to which they are attached, form an optionally substituted heteroaromatic ring, the optionally substituted heteroaromatic ring is unsubstituted.

[0196] In some embodiments, each quaternary amine is

[0197]

Chemical formula

[0198]

Chemical formula

[0199] In some embodiments, each quaternary amine, which is the same for each quaternary amine, has a counterion selected from the group consisting of acetate, adipate, benzoate, benzenesulfonate, citrate, decanoate, chloride, lactate, maleate, methanesulfonate, oxalate, pivalate, propionate, succinate, sulfate, tartrate, or trifluoroacetate. - has a counterion.

[0200] In some embodiments, at least one of the amino acid residues at position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 independently includes at least one masked amine and / or masked amide when an amino acid residue is present at that position.

[0201] In some embodiments, at least one of the amino acid residues at position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 independently includes a masked amine and / or masked amide when an amino acid residue is present at that position.

[0202] In some embodiments, at least one of the amino acid residues at position Z 5 , Z 7 , Z 8 , Z 10 , Z 13 , Z 14 , Z 15 , and / or Z 16At least one of the amino acid residues, when an amino acid residue is present at that position, each independently contains at least one masked amine and / or masked amide.

[0203] In some embodiments, the amino acid residue at position Z 5 Z 7 Z 8 Z 10 Z 13 Z 14 Z 15 and / or the amino acid residue at position Z 16 when an amino acid residue is present at that position, each independently contains a masked amine and / or masked amide.

[0204] In some embodiments, the amino acid residue at position Z 5 Z 8 and / or the amino acid residue at position Z 13 each independently contains at least one masked amine and / or masked amide.

[0205] In some embodiments, the amino acid residue at position Z 5 Z 8 and / or the amino acid residue at position Z 13 each independently contains a masked amine and / or masked amide.

[0206] In some embodiments, the amino acid residue at position Z 5 contains at least one masked amine and / or masked amide.

[0207] In some embodiments, the amino acid residue at position Z 5 contains a masked amine and / or masked amide.

[0208] In some embodiments, the amino acid residue at position Z 8 contains at least one masked amine and / or masked amide.

[0209] In some embodiments, the amino acid residue at position Z 8 comprises a masked amine and / or a masked amide.

[0210] In some embodiments, the amino acid residue at position Z 13 comprises at least one masked amine and / or a masked amide.

[0211] In some embodiments, the amino acid residue at position Z 13 comprises a masked amine and / or a masked amide.

[0212] In some embodiments, at least one of the masked amines is an amine in the backbone amide, and each amine in the backbone amide is independently substituted with (C1-C3) alkyl.

[0213] In some embodiments, at least one of the masked amine and / or the masked amide is present in the side chain of the amino acid residue comprising the masked amine and / or the masked amide.

[0214] In some embodiments, at least one of the masked amine and / or the masked amide is (a)

[0215]

Chemical formula

[0216]

Chem.

[0217]

Chem.

[0218]

Chem.

[0219] In some embodiments, at least one of the masked amine and / or masked amide is (a)

[0220]

Chem.

[0221]

Chem.

[0222]

Chem.

[0223]

Chem.

[0224] In some embodiments, each R YA 、 R YB R YC 、 R YD R YE 、 R YF R YG and / or R YH is optionally substituted alkyl, each optionally substituted alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -CO2H and the quaternary amines described herein, such as -N + (CH3)3.

[0225] In some embodiments, each R YA 、 R YB R YC 、 R YD R YE 、 R YF R YG and / or R YH is optionally substituted heteroalkyl, each optionally substituted heteroalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of -CO2H and the quaternary amines described herein, such as -N + (CH3)3.

[0226] In some embodiments, at least one of the masked amine and / or masked amide is independently selected from the group consisting of:

[0227] [Chem.]

[0228] In some embodiments, each independently at least one amino acid residue comprising at least one masked amine and / or masked amide is independently selected from the group consisting of NMe7MeW, AAMPhe, Paf(Ac), AEF(Ac), AcAEF, AEF(AcCh), AEF(Me)2, AEF(N(Me)2), AEF(MePrpa), AEF(NMe), Dab(NMeAc), Dab(NMecarn), Dab(NMeCOmPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dab(NMecPEG5a), Dab(NMecPEG5aCO)-, Dap(Ac), Dap(NMeAc), K(Ac), K(NMeAc), K(NMeCOmPEG6), K(NMeCOPEG4N+Me3), K(NMeCOPEG5a), K(NMecPEG5a), K(NMePEG5a), K(NMePEG3a), K(NmPEG6Ac), NMe3Pya, NMebAla, NMeDTyr, N(N(Me)), N(NMe), N(N(Me)2), Q(N(Me)2), Q(NHtBu), and tetrazole(NMe).

[0229] In some embodiments, each independently at least one amino acid residue comprising at least one masked amine is not K(Ac).

[0230] In some embodiments, when the amino acid residue at position Z 3 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 3 is APEG2ser, APEG2Ser, APEG2Ser(S *)、e(c), e(C), hk(Me)3, k(5cpa), k(cPEG3a), k(d), k(D), k(dPEG12Ac), k(dPEG6Ac), k(dPEG9Ac), k(Me)3, K(Me)3, k(PEG2PEG2gEC12), k(PEG2PEG2gEC14), k(PEG2PEG2PEG2PEG2gEC12), k(PEG2PEG6gEC12), SP6, APEG2Ser(RS), gPEG2Ser, and is replaced with an amino acid residue selected from the group consisting of k(PEG2PEG2gE(c)C12).

[0231] In some embodiments, position Z 3 When the amino acid residue at is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z 3 The amino acid residue at is replaced with an amino acid residue containing at least one quaternary amine selected from the group consisting of APEG2ser, APEG2Ser, e(c), e(C), hk(Me)3, k(5cpa), k(cPEG3a), k(d), k(D), K(Me)3, and k(Me)3.

[0232] In some embodiments, position Z 3 When the amino acid residue at is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z 3 The amino acid residue at is replaced with an amino acid residue substituted on the side chain with one or more groups selected from -OH, -(C1-C4) alkyl, -O(C1-C4) alkyl, and -CN.

[0233] In some embodiments, position Z 3 When the amino acid residue at is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z 3 The amino acid residue at is replaced with a hydrophilic amino acid residue.

[0234] In some embodiments, position Z 3 When the amino acid residue at is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z3 The amino acid residue of

[0235] In some embodiments, when the amino acid residue at position Z 3 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 3 is replaced with an acidic amino acid residue.

[0236] In some embodiments, the amino acid residue at position Z 3 is replaced with an amino acid residue different from the recited amino acid residue at that position.

[0237] In some embodiments, the amino acid residue at position Z 4 is a residue of Abu or a residue of an amino acid containing a sulfhydryl group selected from the group consisting of Pen, C, or aMeC.

[0238] In some embodiments, the amino acid residue at position Z 4 is a residue of Pen.

[0239] In some embodiments, when the amino acid residue at position Z 5 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 5 is replaced with an amino acid residue selected from the group consisting of A, APEG2Ser(S * ), Dab(Me)3, F, Gab, K(cPEG3a), K(Me)3, K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), L, N, N(N(Me)), N(NMe), Q, and W.

[0240] In some embodiments, when the amino acid residue at position Z 5 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 5 is APEG2Ser(S *) is replaced with an amino acid residue containing at least one quaternary amine selected from the group consisting of Dab(Me)3, K(cPEG3a), and K(Me)3.

[0241] In some embodiments, when the amino acid residue at position Z 5 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 5 is replaced with an amino acid residue in which the N(N(Me)2) is substituted on the side chain with one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0242] In some embodiments, when the amino acid residue at position Z 5 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 5 is replaced with an aromatic amino acid residue.

[0243] In some embodiments, when the amino acid residue at position Z 5 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 5 is replaced with an aliphatic amino acid residue.

[0244] In some embodiments, when the amino acid residue at position Z 5 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 5 is replaced with a hydrophilic amino acid residue.

[0245] In some embodiments, when the amino acid residue at position Z 5 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 5 is replaced with a basic amino acid residue.

[0246] In some embodiments, when the amino acid residue at position Z 5When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position 5 the amino acid residue is replaced with an acidic amino acid residue.

[0247] In some embodiments, at position Z 5 the amino acid residue is replaced with an amino acid residue different from the listed amino acid residue at that position.

[0248] In some embodiments, at position Z 6 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 6 the amino acid residue is replaced with an amino acid residue selected from the group consisting of A and L.

[0249] In some embodiments, at position Z 6 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 6 the amino acid residue is replaced with an amino acid residue having one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN substituted on the side chain with T.

[0250] In some embodiments, at position Z 6 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 6 the amino acid residue is replaced with an aliphatic amino acid residue.

[0251] In some embodiments, at position Z 6 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 6 the amino acid residue is replaced with a polar amino acid residue.

[0252] In some embodiments, at position Z 6The amino acid residue is replaced with an amino acid residue different from the listed amino acid residue at that position.

[0253] In some embodiments, when the amino acid residue at position Z 7 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 7 is replaced with an amino acid residue selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Nal, A, F, and L.

[0254] In some embodiments, when the amino acid residue at position Z 7 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 7 is replaced with an amino acid residue in which 7MeW is substituted with one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN on the side chain.

[0255] In some embodiments, when the amino acid residue at position Z 7 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 7 is replaced with an aromatic amino acid residue.

[0256] In some embodiments, when the amino acid residue at position Z 7 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 7 is replaced with an aliphatic amino acid residue.

[0257] In some embodiments, the amino acid residue at position Z 7 is replaced with an amino acid residue different from the listed amino acid residue at that position.

[0258] In some embodiments, the amino acid residue at position Z 8When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position 8 the amino acid residue is replaced with an amino acid residue selected from the group consisting of K(NMeAC), K(NMeAc), Q, 4AmPhe, A, AIB, APEG2Ser, APEG2Ser(R * ), APEG2Ser(S * ), Cit, Dab(NMeAc), Dab(NMecarn), Dab(NMeCarn), Dab(NMeCOmPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dab(NMecPEG5a), Dap(NMeAc), F, K(4cpg), K(Ac), K(cPEG3a), K(Me)3, K(NMeCOmPEG6), K(NMePEG3a), K(NmPEG6Ac), K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), L, Paf(Ac), Q(N(Me)2), Q(NHtBu), W, Y, and K(cPEG3aCO).

[0259] In some embodiments, when the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 8 is replaced with an amino acid residue containing at least one quaternary amine selected from the group consisting of APEG2Ser, APEG2ser, APEG2Ser(R * ), APEG2Ser(S * ), Dab(NMecarn), Dab(NMeCarn), Dab(NMecPEG2a), Dab(NMecPEG3a), Dab(NMecPEG5a), K(cPEG3a), K(Me)3, and K(NMePEG3a).

[0260] In some embodiments, when the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 8The amino acid residue is replaced with an amino acid residue in which one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN on the side chain are replaced with K(NMeAc).

[0261] In some embodiments, when the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 8 is replaced with an aromatic amino acid residue.

[0262] In some embodiments, when the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 8 is replaced with an aliphatic amino acid residue.

[0263] In some embodiments, when the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 8 is replaced with a hydrophilic amino acid residue.

[0264] In some embodiments, when the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 8 is replaced with a basic amino acid residue.

[0265] In some embodiments, when the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 8 is replaced with an acidic amino acid residue.

[0266] In some embodiments, the amino acid residue at position Z 8 is replaced with an amino acid residue different from the listed amino acid residue at that position.

[0267] In some embodiments, the amino acid residue at position Z 9 is a residue of an amino acid containing a sulfhydryl group selected from the group consisting of Pen, C, or aMeC.

[0268] In some embodiments, the amino acid residue at position Z 9 is a residue of Pen.

[0269] In some embodiments, when the amino acid residue at position Z 10 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 10 is AEF, 4DMPEF, 4DMPzEF, 4TMABYF, ACHMF, AEF((Ch)cPEG3a), AEF(Ac), AEF(AcCh), AEF(aPEG2a), AEF(BisMEP), AEF(BisMEPa), AEF(BisPEG2a)(RS), AEF(BisPEG2a)(S * ) AEF(G), AEF(Me)2, AEF(MEP), AEF(MePrpa), AEF(N(Me)2), AEF(NHCh), AEF(NHcPEG3a), AEF(NMe), AEF(NMe2mPEG3), AEF(NMe3), AEF(NMeBismPEG3), AEF(NMePEG2a), AEF(NmPEG6), AEF(NsCh), AEF(PEG2a), AEF(SPD), APEG2F, APEG3F, dFPPEG3F, Diazabiclyclooctane6F, DMMMF, DMPMF, DMTASF, F(4G), F(4N3), F(4TzlDMA4mPEG), F(4TzlMME), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMMo4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), GPEG3F, hFTMAPF, MMoEF, MMoPF, MMoPEG3F, morfTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, PiperazinequatF, TBAPEG3F, TMA3F, TMA4F, TMA6F, TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(C9OH), Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OTzlC1aC8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), YC8CO(NHPEG3a), YC8COPip, YCF2H, ACHMF(R * ,S * ), ACHMF(S * ,S * ), and is replaced with an amino acid residue selected from the group consisting of AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7), and F(4TzlTMA7).

[0270] In some embodiments, position Z 10If the amino acid at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position 10 the amino acid residue is selected from the group consisting of 4DMPEF, 4DMPzEF, 4TMABYF, ACHMF, ACHMF(R * ,S * ), ACHMF(S * ,S * ), AEF((Ch)cPEG3a), AEF(AcCh), AEF(aPEG2a), AEF(cPEG3a), AEF(BisMEPa), AEF(BisPEG2a)(RS), AEF(BisPEG2a)(S * ), AEF(MePrpa), AEF(NHcPEG3a), AEF(NMe2mPEG3), AEF(NMe3), AEF(NMeBismPEG3), AEF(NMePEG2a), AEF(NsCh), AEF(NHCh), AEF(PEG2a), AEF(SPD), APEG2F, APEG3F, dFPPEG3F, Diazabiclyclooctane6F, DMMMF, DMPMF, DMTASF, F(4TzlDMA4mPEG), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMMo4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), F(4TzlMMo7), F(4TzlTMA7), hFTMAPF, MMoEF, MMoPF, MMPEG3F, morfTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, PiperazinequatF, TBAPEG3F, TMA3F, TMA4F, TMA6F, TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OTzlC1aC8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), and YC8CO(NHPEG3a) and is replaced with an amino acid residue containing at least one quaternary amine selected from the group

[0271] In some embodiments, when the amino acid residue at position Z 10 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 10 is replaced with an amino acid residue in which one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN on the side chain are TMAPF-substituted.

[0272] In some embodiments, when the amino acid residue at position Z 10 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 10 is replaced with an amino acid residue having the following structure,

[0273] [Chemical formula] wherein, Ln 1 is an -O-atom,

[0274] [Chemical formula] is selected from the group consisting of, wherein the right side of each structure shown is bonded to Ln 2 ; Ln 2 is (i) Optionally substituted alkylene containing at least 4 atoms, for example, at least C4 atoms, optionally substituted heteroalkylene containing at least C4 atoms, optionally substituted heteroalkenylene containing at least C4, optionally substituted alkynylene containing at least C4, optionally substituted alkylene-optionally substituted carbocyclyl containing at least C4 atoms, or optionally substituted alkylene-optionally substituted heterocyclyl containing at least C4 atoms, for example, optionally substituted (C4-C 20 ) alkylene, optionally substituted (C4-C 20heteroalkylene, optionally substituted (C4-C 20 ) heteroalkenylene, optionally substituted (C4-C 20 ) alkynylene, optionally substituted (C1-C3) alkylene - optionally substituted (C3-C 10 ) carbocyclic, or optionally substituted (C1-C3) alkylene - optionally substituted (C3-C 14 ) heterocyclic, or (ii) Ln 1 is

[0275]

Chemical formula

[0276] In some embodiments, when the amino acid residue at position Z 10 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 10 is replaced with an amino acid residue having the following structure,

[0277]

Chemical formula

[0278] In some embodiments, Qu 1 is a quaternary amine as defined herein.

[0279] In some embodiments, Ln 1 is an -O- atom.

[0280] In some embodiments, Ln 2 is optionally substituted (C4-C 15 ) alkylene, optionally substituted (C4-C 15 ) heteroalkylene, optionally substituted (C4-C 15 ) heteroalkenylene, optionally substituted (C4-C 15 ) alkynylene, optionally substituted (C1-C3) alkylene - optionally substituted (C5-C7) carbocyclic, or optionally substituted (C1-C3) alkylene - optionally substituted (C5-C7) heterocyclic, selected from the group consisting of.

[0281] In some embodiments, Ln 2 is optionally substituted (C4-C 10 ) alkylene, optionally substituted (C4-C 10 ) heteroalkylene, optionally substituted (C4-C 10 ) heteroalkenylene, optionally substituted (C4-C 10 ) alkynylene, optionally substituted (C1-C3) alkylene - optionally substituted (C6) carbocyclic, or optionally substituted (C1-C3) alkylene - optionally substituted (C6) heterocyclic, selected from the group consisting of.

[0282] In some embodiments, Ln 2is selected from the group consisting of optionally substituted (C4-C8) alkylene, optionally substituted (C4-C8) heteroalkylene, optionally substituted (C4-C8) heteroalkenylene, optionally substituted (C4-C8) alkynylene, optionally substituted (C1-C3) alkylene-optionally substituted (C6) carbocyclic, or optionally substituted (C1-C3) alkylene-optionally substituted (C6) heterocyclic.

[0283] In some embodiments, Ln 1 is

[0284]

Chemical formula

[0285] In some embodiments, Ln 1 is

[0286]

Chemical formula

[0287] In some embodiments, Ln 1 is

[0288]

Chemical formula

[0289] In some embodiments, when Ln 2 is optionally substituted alkylene, the optionally substituted alkylene is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro.

[0290] In some embodiments, when Ln 2 is optionally substituted heteroalkylene, the optionally substituted heteroalkylene is unsubstituted or (C1-C3) alkyl,

[0291] [Chemical formula] =O (i.e., two geminal hydrogens on the carbon atom of the heteroalkylene are replaced by the group =O), or a quaternary amine described herein, for example, -N + (CH3)3 and is substituted with one or more substituents independently selected from the group consisting of.

[0292] In some embodiments, when Ln 2 is optionally substituted heteroalkenylene, the optionally substituted heteroalkenylene is unsubstituted.

[0293] In some embodiments, when Ln 2 is optionally substituted alkynylene, the optionally substituted alkynylene is unsubstituted.

[0294] In some embodiments, when Ln 2 is optionally substituted alkylene - optionally substituted carbocyclyl, the optionally substituted alkylene - optionally substituted carbocyclyl is unsubstituted.

[0295] In some embodiments, Ln 2 is optionally substituted alkylene - optionally substituted heterocyclyl, and when it is optionally substituted alkylene - optionally substituted heterocyclyl, the optionally substituted alkylene - optionally substituted heterocyclyl is unsubstituted.

[0296] In some embodiments, when the amino acid residue at position Z 10 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 10 is replaced with an amino acid residue having the following structure,

[0297] [Chemical formula] wherein, Ln 3 is an -O-atom,

[0298] [Chemical formula] is selected from the group consisting of, wherein the right side of each structure shown is bonded to Ln 4 , Ln 4 is a linker moiety containing at least 2 atoms, for example, optionally substituted alkylene containing at least C2 atoms, optionally substituted heteroalkylene containing at least C2 atoms, or optionally substituted alkynylene containing at least C2 atoms, for example, optionally substituted (C2 - C 20 ) alkylene, optionally substituted (C2 - C 20 ) heteroalkylene, or optionally substituted (C2 - C 20 ) alkynylene, Qu 2 is a (C3 - C 14 ) heterocyclyl quaternary amine, a (C5 - C 14 ) heteroaryl quaternary amine, or a (C5 - C 14 ) bicyclic heterocyclyl quaternary amine, for example,

[0299] [Chemical formula] A (C3 - C 14 ) heterocyclic quaternary amine selected from the group consisting of,

[0300] [Chemical formula] A (C5 - C 14 ) heteroaryl quaternary amine selected from the group consisting of, or

[0301] [Chemical formula] A (C5 - C 14 ) bicyclic heterocyclic quaternary amine.

[0302] In some embodiments, when the amino acid residue at position Z 10 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 10 is replaced with an amino acid residue having the following structure,

[0303] [Chemical formula] wherein Ln 3 , Ln 4 , and Qu 2 are as defined herein.

[0304] In some embodiments, Qu 2 is a quaternary amine as defined herein.

[0305] In some embodiments, Ln 3 is an -O- atom.

[0306] In some embodiments, Ln 4 is an optionally substituted (C2 - C 15) alkylene, optionally substituted (C2 - C 15 ) heteroalkylene, or optionally substituted (C2 - C 15 ) alkynylene, and is selected from the group consisting of.

[0307] In some embodiments, Ln 4 is optionally substituted (C2 - C 10 ) alkylene, optionally substituted (C2 - C 10 ) heteroalkylene, or optionally substituted (C2 - C 10 ) alkynylene, and is selected from the group consisting of.

[0308] In some embodiments, Ln 4 is optionally substituted (C2 - C8) alkylene, optionally substituted (C2 - C8) heteroalkylene, or optionally substituted (C2 - C8) alkynylene, and is selected from the group consisting of.

[0309] In some embodiments, when Ln 4 is optionally substituted alkylene, the optionally substituted alkylene is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro.

[0310] In some embodiments, when Ln 4 is optionally substituted heteroalkylene, the optionally substituted heteroalkylene is unsubstituted or (C1 - C3) alkyl,

[0311]

Chemical formula

[0312] In some embodiments, when Ln 4 is an optionally substituted alkynylene, the optionally substituted alkynylene is unsubstituted.

[0313] In some embodiments, when the amino acid residue at position Z 10 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 10 is replaced with an aromatic amino acid residue.

[0314] In some embodiments, the amino acid residue at position Z 10 is replaced with an amino acid residue different from the recited amino acid residue at that position.

[0315] In some embodiments, when the amino acid residue at position Z 11 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 11 is replaced with an amino acid residue selected from the group consisting of A, F, L, and W.

[0316] In some embodiments, when the amino acid residue at position Z 11 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 11 is replaced with an amino acid residue in which one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN on the side chain naphthalene ring are substituted for 2Nal.

[0317] In some embodiments, when the amino acid residue at position Z 11 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 11 is replaced with an aromatic amino acid residue.

[0318] In some embodiments, the amino acid residue at position Z 11When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position 11 the amino acid residue is replaced with an aliphatic amino acid residue.

[0319] In some embodiments, at position Z 11 the amino acid residue is replaced with an amino acid residue different from the listed amino acid residue at that position.

[0320] In some embodiments, at position Z 12 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 12 the amino acid residue is replaced with an amino acid residue selected from the group consisting of A, Achx, Achx(diF), Acpx, Aib, AIB, aMeK, aMeL, Chg, diFCpx, F, L, Pip(NMe), Pip(NMe2), W, and diFAchx.

[0321] In some embodiments, at position Z 12 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 12 the amino acid residue is replaced with an amino acid residue containing at least one quaternary amine selected from the group consisting of Pip(NMe2).

[0322] In some embodiments, at position Z 12 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 12 the amino acid residue is replaced with an amino acid residue in which one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN on the side chain are THP-substituted.

[0323] In some embodiments, at position Z 12 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, at position Z 12The amino acid residue is replaced with an aromatic amino acid residue.

[0324] In some embodiments, when the amino acid residue at position Z 12 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 12 is replaced with an aliphatic amino acid residue.

[0325] In some embodiments, when the amino acid residue at position Z 12 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 12 is replaced with a polar amino acid residue.

[0326] In some embodiments, when the amino acid residue at position Z 12 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 12 is replaced with a hydrophilic amino acid residue.

[0327] In some embodiments, when the amino acid residue at position Z 12 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 12 is replaced with a basic amino acid residue.

[0328] In some embodiments, the amino acid residue at position Z 12 is replaced with an amino acid residue different from the recited amino acid residue at that position.

[0329] In some embodiments, when the amino acid residue at position Z 13 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 13 is K(NMeAC), E, A, AIB, aMeE, APEG2Ser, APEG2Ser(S *) is replaced with an amino acid residue selected from the group consisting of Cit, Dab(NMeAc), Dab(NMecarn), Dab(NMeCOmPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dap(Ac), Dap(NMeAc), E(c), E(C), F, K(5cpa), K(Ac), K(cPEG3a), K(d), K(D), K(dPEG12Ac), K(dPEG6Ac), K(dPEG9Ac), K(Me)3, K(NMeCOmPEG6), K(NMeCOPEG4N+Me3), K(NMePEG3a), K(NmPEG6Ac), K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), K(PEG2PEG2PEG2gEC12), L, Q(N(Me)2), tetrazole, tetrazole(NMe), W, K(DFN), K(IPB), and Nle.

[0330] In some embodiments, when the amino acid residue at position Z 13 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 13 is replaced with an amino acid residue containing at least one quaternary amine selected from the group consisting of APEG2Ser, APEG2Ser(S * ), Dab(NMecarn), Dab(NMecPEG2a), Dab(NMecPEG3a), K(5cpa), K(cPEG3a), E(c), E(C), K(d), K(D), K(Me)3, K(NMeCOPEG4N+Me3), and K(NMePEG3a).

[0331] In some embodiments, when the amino acid residue at position Z 13 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 13 is replaced with an amino acid residue in which one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN on the side chain are substituted for K(NMeAc).

[0332] In some embodiments, when the amino acid residue at position Z 13If the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position 13 the amino acid residue is replaced with an aromatic amino acid residue.

[0333] In some embodiments, if the amino acid residue at position Z 13 is replaced with an amino acid residue different from the listed amino acid residue at that position, for position Z 13 the amino acid residue is replaced with an aliphatic amino acid residue.

[0334] In some embodiments, if the amino acid residue at position Z 13 is replaced with an amino acid residue different from the listed amino acid residue at that position, for position Z 13 the amino acid residue is replaced with a hydrophilic amino acid residue.

[0335] In some embodiments, if the amino acid residue at position Z 13 is replaced with an amino acid residue different from the listed amino acid residue at that position, for position Z 13 the amino acid residue is replaced with an acidic amino acid residue.

[0336] In some embodiments, if the amino acid residue at position Z 13 is replaced with an amino acid residue different from the listed amino acid residue at that position.

[0337] In some embodiments, if the amino acid residue at position Z 14 is replaced with an amino acid residue different from the listed amino acid residue at that position, for position Z 14 the amino acid residue is replaced with an amino acid residue selected from the group consisting of K(Ac) and N(NMe).

[0338] In some embodiments, if the amino acid residue at position Z 14 is replaced with an amino acid residue different from the listed amino acid residue at that position, for position Z 14The amino acid residue is replaced with an amino acid residue N-substituted on the side chain with one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0339] In some embodiments, when the amino acid residue at position Z 14 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 14 is replaced with a hydrophilic amino acid residue.

[0340] In some embodiments, when the amino acid residue at position Z 14 is replaced with an amino acid residue different from the recited amino acid residue at that position,

[0341] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 15 is replaced with an amino acid residue selected from the group consisting of 3pya, 5CF33Pya, 5MePyridinAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y, and A.

[0342] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 15 is replaced with an amino acid residue N-substituted on the side chain with one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN with 3Pya.

[0343] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the recited amino acid residue at that position, the amino acid residue at position Z 15The amino acid residue is replaced with an amino acid residue containing at least one quaternary amine selected from the group consisting of NMe3Pya.

[0344] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 15 is replaced with an aromatic amino acid residue.

[0345] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 15 is replaced with an aliphatic amino acid residue.

[0346] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 15 is replaced with a polar amino acid residue.

[0347] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 15 is replaced with a hydrophilic amino acid residue.

[0348] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 15 is replaced with a basic amino acid residue.

[0349] In some embodiments, when the amino acid residue at position Z 15 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 15 is replaced with a nonpolar amino acid residue.

[0350] In some embodiments, the amino acid residue at position Z 15 is replaced with an amino acid residue that is different from the listed amino acid residue at that position.

[0351] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue that is different from the listed amino acid residue at that position, the amino acid residue at position Z 16 is replaced with an amino acid residue selected from the group consisting of 4diFPro, NMeDTyr, NMeK(PEG2PEG2C12), NMeK(PEG2PEG2C14), NMeK(PEG2PEG2gEC12), NMeK(PEG2PEG2gEC14), NMeK(PEG2PEG2K(PEG2PEG2gEC12)2), NMeK(PEG2PEG2K(PEG2PEG2PEG2PEG2gEC12)2), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12), and NMeK(SP6PEG2PEG2gEC12).

[0352] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue that is different from the listed amino acid residue at that position, the amino acid residue at position Z 16 is replaced with an amino acid residue containing at least one quaternary amine selected from the group consisting of NMeK(SP6PEG2PEG2C12) and NMeK(SP6PEG2PEG2gEC12).

[0353] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue that is different from the listed amino acid residue at that position, the amino acid residue at position Z 16The amino acid residue is replaced with an amino acid residue substituted with one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN on the side chain by Sar.

[0354] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 16 is replaced with an aromatic amino acid residue.

[0355] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 16 is replaced with an acidic amino acid residue.

[0356] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 16 is replaced with a polar amino acid residue.

[0357] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 16 is replaced with a hydrophilic amino acid residue.

[0358] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue different from the listed amino acid residue at that position, the amino acid residue at position Z 16 is replaced with a nonpolar amino acid residue.

[0359] In some embodiments, when the amino acid residue at position Z 16 is replaced with an amino acid residue different from the listed amino acid residue at that position.

[0360] In some embodiments, the amino acid residue specified at a given position is substituted on the side chain with one or more groups selected from -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0361] In some embodiments, R NT is selected from the group consisting of -C(O)-optionally substituted (C1-C 15 )alkyl and -C(O)-optionally substituted (C1-C 35 )heteroalkyl.

[0362] In some embodiments, R NT is selected from the group consisting of -C(O)-optionally substituted (C1-C 10 )alkyl and -C(O)-optionally substituted (C1-C 35 )heteroalkyl.

[0363] In some embodiments, R NT is selected from the group consisting of -C(O)-optionally substituted (C1-C8)alkyl and -C(O)-optionally substituted (C1-C 30 )heteroalkyl.

[0364] In some embodiments, R NT is selected from the group consisting of -C(O)-optionally substituted (C1-C6)alkyl and -C(O)-optionally substituted (C1-C 30 )heteroalkyl.

[0365] In some embodiments, R NTis selected from the group consisting of (d)gEPEG2PEG2CO, 4cpgCO, 5cpaCO, AcdPEG12CO, AcdPEG6CO, AcdPEG9CO, C12gEPEG2PEG2CO, C14gEPEG2PEG2CO, CF3CO, CF3 propylamide, cPEG2gCO, cPEG3aCO, cPEG3gCO, cPEG5aCO, EtCO, F3CO, MeCO, mPEG3CO, mPEG6CO, cPEG3AmCO, DFNCO, DFNPEG2PEG2CO, IPBCO, and IPBPEG2PEG2CO.

[0366] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 20 ) alkyl, for example, 4cpgCO, CF3CO, CF3 propylamide, EtCO, F3CO, MeCO, or 5cpaCO.

[0367] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 20 ) alkyl containing a quaternary amine, for example, 5cpaCO.

[0368] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 40 ) heteroalkyl, for example, AcdPEG12CO, AcdPEG6CO, AcdPEG9CO, C12gEPEG2PEG2CO, cPEG2gCO, cPEG3gCO, mPEG3CO, mPEG6CO, (d)gEPEG2PEG2CO, cPEG3aCO, and cPEG5aCO.

[0369] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 40 ) heteroalkyl containing a quaternary amine, for example, (d)gEPEG2PEG2CO, cPEG3aCO, cPEG5aCO.

[0370] In some embodiments, R NTis a -C(O)-optionally substituted heteroalkyl containing a hydrophilic polymer, such as polyethylene glycol (PEG).

[0371] In some embodiments, R NT is a -C(O)-optionally substituted heteroalkyl containing the formula -[O-CH2CH2]n-, where n is an integer, e.g., (i) n is an integer from about 1 to about 20, or (ii) n is an integer from about 1 to about 15, or (iii) n is an integer from about 1 to about 10, or (iv) n is an integer from about 2 to about 12.

[0372] In some embodiments, when R NT is a -C(O)-optionally substituted heteroalkyl, the -C(O)-optionally substituted heteroalkyl is unsubstituted or is substituted with one or more substituents independently selected from the group consisting of -OH, -NH2, -CO2H, -CO2CH3, -NH(C=NH)NH2, =O (i.e., two geminal hydrogens on the carbon atom of the heteroalkyl are replaced by the group =O),

[0373]

Chemical formula

[0374] In some embodiments, when R NT is a -C(O)-optionally substituted alkyl, the -C(O)-optionally substituted alkyl is unsubstituted or is substituted with fluoro, -NH(C=NH)NH2,

[0375]

Chemical formula

[0376] In some embodiments, (i) each R Y and R Z is independently selected from the group consisting of hydrogen, optionally substituted (C1-C 10 ) alkyl, and optionally substituted (C1-C 25 ) heteroalkyl, or (ii) R Y and R Z together with the N atom to which they are attached form an optionally substituted (C 5~7 ) heterocyclic ring or an optionally substituted (C7-C9) bicyclic heterocyclic ring.

[0377] In some embodiments, (i) each R Y and R Z is independently selected from the group consisting of hydrogen, optionally substituted (C1-C8) alkyl, and optionally substituted (C1-C 20 ) heteroalkyl, or (ii) R Y and R Z together with the N atom to which they are attached form an optionally substituted (C6) heterocyclic ring or an optionally substituted (C8) bicyclic heterocyclic ring.

[0378] In some embodiments, R CT is selected from the group consisting of CONH2, CO(DiFPip), CO(Morph), CO(mPEG8), CO(NHPEG3a), CO(OAZBO), CO(TFMOHPip), CON(Me)2, CON(MePEG2), CON(mPEG2), CON(NMePip), CONH(PEG3a), CONH(PEG5a), CONHMe, and CONMe2.

[0379] In some embodiments, R CT is selected from the group consisting of optionally substituted aminyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, and optionally substituted 3-oxa-8-azabicyclo[3.2.1]octanyl.

[0380] In some embodiments, R CT is N(R Y )(R Z ), where R Y is hydrogen and R Z is an optionally substituted (C1-C 30 ) heteroalkyl containing a quaternary amine such as CO(NHPEG3a), CONH(PEG3a), or CONH(PEG5a).

[0381] In some embodiments, when R Y and / or R Z is an optionally substituted alkyl, each optionally substituted alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of quaternary amines described herein, such as -N + (CH3)3.

[0382] In some embodiments, when R Y and / or R Z is an optionally substituted heteroalkyl, each optionally substituted heteroalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of quaternary amines described herein, such as -N + (CH3)3.

[0383] In some embodiments, R Y and R Zwhen, together with the N atom to which they are attached, form an optionally substituted heterocyclic ring, such as an optionally substituted aminyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, and an optionally substituted morpholinyl, the optionally substituted heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, -OH, -CF3, (C1-C3) alkyl, or a quaternary amine as described herein, such as -N + substituted with one or two or more substituents independently selected from the group consisting of (CH3)3.

[0384] In some embodiments, R Y and R Z when, together with the N atom to which they are attached, form an optionally substituted bicyclic heterocyclic ring, such as an optionally substituted 3-oxa-8-azabicyclo[3.2.1]octanyl, the optionally substituted bicyclic heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro, -OH, -CF3, (C1-C3) alkyl, or a quaternary amine as described herein, such as -N + substituted with one or two or more substituents independently selected from the group consisting of (CH3)3.

[0385] In some embodiments, the cyclic peptide further comprises one or more natural or non-natural polymers, or combinations thereof.

[0386] In some embodiments, the cyclic peptide further comprises a natural or non-natural polymer, or combinations thereof.

[0387] In some embodiments, the cyclic peptide is R NT (if present), and / or R CT (if present), and / or position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z12 and Z 13 and Z 14 and Z 15 and / or Z 16 and further comprises one or more natural or non-natural polymers, or combinations thereof, that conjugate to the amino acid residue (if the amino acid residue is present at that position) of

[0388] In some embodiments, the cyclic peptide is R NT (if present), or R CT (if present), or position Z 3 and Z 5 and Z 6 and Z 7 and Z 8 and Z 10 and Z 11 and Z 12 and Z 13 and Z 14 and Z 15 or Z 16 and further comprises a natural or non-natural polymer, or combination thereof, that conjugates to the amino acid residue (if the amino acid residue is present at that position) of

[0389] The properties of the natural or non-natural polymer, or combination thereof, can be optimized by modifying the length, conformation (e.g., branched or linear), and / or functionalization (e.g., addition of a negatively charged group) of the natural or non-natural polymer, or combination thereof. For example, the natural or non-natural polymer, or combination thereof, can be modified to increase the solubility of the cyclic peptide of the present invention, avoid aggregation, etc. For example, the natural or non-natural polymer, or combination thereof, can be modified to increase the solubility of the cyclic peptide of the present invention and avoid aggregation by including a hydrophilic or water-soluble polymer including, but not limited to, PEG, charged PEG molecules, amino acids, or combinations thereof.

[0390] In one embodiment, the natural or non-natural polymer, or combination thereof, is water-soluble, for example, such that the cyclic peptide of the present invention does not precipitate in an aqueous (e.g., physiological) environment. Further, the natural or non-natural polymer, or combination thereof, is biocompatible and, for example, does not cause injury, toxicity, or an immune response in vivo.

[0391] Non-limiting examples of natural polymer groups are amino acid sequences containing about 10 to about 30 amino acids derived from (poly)peptides such as pro-atrial natriuretic peptide C, atrial natriuretic peptide, brain natriuretic peptide, serum albumin, IgG, histidine-rich glycoprotein, fibronectin, fibrinogen, zinc finger-containing polypeptides, osteocalcin or fibroblast growth factor 2 (FGF2), or variants thereof having substitutions and / or deletions. Non-limiting examples of non-natural polymer groups (e.g., synthetic polymers) are polyethylene glycol (PEG, also called polyethylene oxide (PEO)).

[0392] In one embodiment, the natural polymer or non-natural polymer comprises residues selected from amino acids or carbohydrates, or combinations thereof. In one embodiment, the natural or non-natural polymer, or combination thereof, comprises an amino acid sequence. In one embodiment, the natural or non-natural polymer, or combination thereof, comprises about 10 to about 30 amino acid residues. In one embodiment, the natural or non-natural polymer, or combination thereof, comprises about 10 to about 25 amino acid residues. In one embodiment, the natural or non-natural polymer, or combination thereof, comprises about 15 to about 20 amino acid residues.

[0393] In one embodiment, the natural or non-natural polymer, or combination thereof, is a combination of a natural polymer and a non-natural polymer, for example, a combination of an amino acid sequence and a hydrophilic polymer such as polyethylene glycol (PEG).

[0394] In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises an optionally substituted heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, is an optionally substituted heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises an optionally substituted (C 10 ~C 200 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, is an optionally substituted (C 10 ~C 200 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises an optionally substituted (C 10 ~C 150 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, is an optionally substituted (C 10 ~C 150 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises an optionally substituted (C 10 ~C 100 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, is an optionally substituted (C 10 ~C 100 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises an optionally substituted (C 10 ~C 90 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, is an optionally substituted (C 10 ~C 90 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises an optionally substituted (C 10 ~C 80 ) heteroalkylene. In one embodiment, the natural or non-natural polymer, or a combination thereof, is an optionally substituted (C 10 ~C80 ) is a heteroalkylene. In one embodiment, a natural or non-natural polymer, or a combination thereof, optionally substituted (C 10 ~C 70 ) contains heteroalkylene. In one embodiment, a natural or non-natural polymer, or a combination thereof, optionally substituted (C 10 ~C 70 ) is heteroalkylene. In one embodiment, a natural or non-natural polymer, or a combination thereof, optionally substituted (C 10 ~C 60 ) contains heteroalkylene. In one embodiment, a natural or non-natural polymer, or a combination thereof, optionally substituted (C 10 ~C 60 ) is heteroalkylene. In one embodiment, a natural or non-natural polymer, or a combination thereof, contains about 1 to about 7 heteroatoms independently selected from the group consisting of N, O, S, and P for every 10 carbons in the optionally substituted heteroalkylene. In one embodiment, a natural or non-natural polymer, or a combination thereof, contains about 1 to about 5 heteroatoms independently selected from the group consisting of N, O, S, and P for every 10 carbons in the optionally substituted heteroalkylene. In one embodiment, the heteroatom is independently selected from the group consisting of N, O, or S. In one embodiment, the heteroatom is independently selected from the group consisting of N or O.

[0395] In one embodiment, a natural or non-natural polymer, or a combination thereof, is a combination of naturally occurring monomer units and synthetic monomer units, for example, a combination of amino acid monomer units and PEG monomer units.

[0396] In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises a hydrophilic polymer. In one embodiment, the natural or non-natural polymer, or a combination thereof, is a hydrophilic polymer. In one embodiment, the hydrophilic polymer can be branched or unbranched. In one embodiment, the hydrophilic polymer is not branched. The present invention contemplates the use of hydrophilic or water-soluble polymers (e.g., PEG) that can differ in type (e.g., homopolymer or copolymer, random, alternating, or block copolymer, linear or branched), linkage (e.g., hydrolyzable or stable linkages such as amide, imine, aminals, alkylene, or ester bonds), and length (from about 0.2, 0.4, or 0.6 kDa to about 2, 3, 4, or 5 kDa, e.g., from about 0.2 kDa to about 5 kDa, etc.). Non-limiting examples of hydrophilic polymers that can be used in the present invention include polymers formed from carboxylic acid-bearing monomers (e.g., methacrylic acid (MA) and acrylic acid (AA)), polyvinyl alcohol, hydroxyl-bearing monomers (e.g., hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA), hydroxypropyl methacrylamide, and 3-trimethylsilylpropyl methacrylate (TMSPMA)), polyalkylene oxides, polyoxyethylated polyols (e.g., glycerol), poly(ethylene glycol) (PEG), poly(propylene glycol), mono-C1-C 10Alkoxy-PEG (e.g., monomethoxy-PEG), tresyl monomethoxy-PEG, aryloxy-PEG, PEG acrylate, PEG methacrylate, PEG propionaldehyde, bis-succinimidyl carbonate PEG, copolymer of 2-methacryloyloxyethyl-phosphorylcholine and N-vinyl pyrrolidone, hydroxy-functional poly(N-vinyl pyrrolidone), SIS-PEG (where SIS is a polystyrene-polyisobutylene-polystyrene block copolymer), polystyrene-PEG, polyisobutylene-PEG, PCL-PEG (where PCL is polycaprolactone), PLA-PEG (where PLA is polylactic acid), PMMA-PEG (where PMMA is poly(methyl methacrylate)), PDMS-PEG (where PDMS is polydimethyloxanone), PVDF-PEG (where PVDF is polyvinylidene(fluoride), PLURONIC (trademark) surfactant (polypropylene oxide - co - polyethylene glycol), poly(tetramethylene glycol), poly(L - lysine - g - ethylene glycol) (PLL - g - PEG), poly(L - lysine - g - hyaluronic acid) (PLL - gHA), poly(L - lysine - g - phosphorylcholine) (PLL - g - PC), poly(L - lysine - g - vinylpyrrolidone) (PLL - g - PVP), poly(ethylimine - g - ethylene glycol) (PEI - g - PEG), poly(ethylimine - g - hyaluronic acid) (PEI - g - HA), poly(ethylimine - g - phosphorylcholine) (PEI - g - PC), poly(ethylimine - g - vinylpyrrolidone) (PEI - g - PVP), PLL - co - HA, PLL - co - PC, PLL - co - PVP, PEI - co - PEG, PEI - co - HA, PEI - co - PC, PEI - co - PVP, cellulose and its derivatives (e.g., hydroxyethyl cellulose), dextran, dextrin, hyaluronic acid and its derivatives (e.g., sodium hyaluronate), elastin, chitosan, acrylic sulfate, acrylic sulfonate, acrylic sulfamate, methacrylic sulfate, methacrylic sulfonate, methacrylic sulfamate, their polymers and copolymers, and polymers and copolymers of combinations thereof are included.

[0397] In one embodiment, the natural or non - natural polymer, or a combination thereof, contains one or more aromatic compounds such as dihydroxybenzoic acid (e.g., 3,5 - dihydroxybenzoic acid), biphenol (e.g., 4,4’ - biphenol), or 4 - hydroxybenzyl alcohol, and each of the one or more aromatic compounds connects two hydrophilic polymers such as PEG.

[0398] In one embodiment, the hydrophilic polymer comprises polyethylene glycol (PEG). In one embodiment, the hydrophilic polymer is PEG. In one embodiment, the hydrophilic polymer comprises PEG18. In one embodiment, the hydrophilic polymer is PEG18. In one embodiment, the hydrophilic polymer comprises PEG21. In one embodiment, the hydrophilic polymer is PEG21. Generally, the "PEGn" polymer associated with the number n comprises the formula: -[O-CH2CH2]n-, where n is the number of ethylene oxide units. In one embodiment, a natural or non-natural polymer, or a combination thereof, comprises the formula: -[O-CH2CH2]n-, where n is an integer. In one embodiment, n is an integer from about 6 to about 100. In one embodiment, n is an integer from about 6 to about 100 and the PEG polymer is from about 0.3 kDa to about 5 kDa. In another embodiment, n is an integer from about 12 to about 50. In another embodiment, n is an integer from about 12 to about 50 and the PEG polymer is from about 0.6 kDa to about 2.5 kDa. In yet another embodiment, n is an integer from about 12 to about 24. In yet another embodiment, n is an integer from about 12 to about 24 and the PEG polymer is from about 0.6 kDa to about 1.2 kDa.

[0399] In one embodiment, the natural or non-natural polymer, or a combination thereof, is at least about 0.4, 0.6, 0.8, 1, 1.2, 1.4, 1.6, or 1.8 kDa, or up to about 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, or 5 kDa. In additional embodiments, the natural or non-natural polymer, or a combination thereof, is in the range of about 0.4 kDa to about 2.5 kDa, or about 0.6 kDa to about 1.5 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is at least about 0.2 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is at least about 0.4 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is at least about 0.6 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is less than about 2 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is less than about 3 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is less than about 4 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is less than about 5 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.2 kDa to about 5 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.4 kDa to about 5 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.6 kDa to about 5 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.2 kDa to about 2 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.2 kDa to about 3 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.2 kDa to about 4 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.4 kDa to about 2 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is about 0.4 kDa to about 3 kDa.In one embodiment, the natural or non-natural polymer, or a combination thereof, is from about 0.4 kDa to about 4 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is from about 0.6 kDa to about 2 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is from about 0.6 kDa to about 3 kDa. In one embodiment, the natural or non-natural polymer, or a combination thereof, is from about 0.6 kDa to about 4 kDa. In one embodiment, the size of the natural or non-natural polymer, or a combination thereof, in kDa units can be determined using mass spectrometry. In one embodiment, the size of the natural or non-natural polymer, or a combination thereof, in kDa units is determined using mass spectrometry.

[0400] In one embodiment, the natural or non-natural polymer, or a combination thereof (e.g., a hydrophilic or water-soluble polymer such as PEG), is functionalized with one or more functional groups that impart a negative charge to the natural or non-natural polymer, or a combination thereof, under physiological conditions, such as carboxyl, sulfate, or phosphate groups, or a combination thereof. In one embodiment, the natural or non-natural polymer, or a combination thereof (e.g., a hydrophilic or water-soluble polymer such as PEG), is functionalized with one or more functional groups that impart a positive charge to the polymer under physiological conditions, such as amines or tertiary amines.

[0401] In one embodiment, the natural or non-natural polymer, or a combination thereof, contains one or more cleavable groups such as disulfides, esters, and / or carbonates.

[0402] In some embodiments, the cyclic peptide is an inhibitor of the interleukin-23 (IL-23) receptor.

[0403] In some embodiments, the cyclic peptide inhibits the binding of interleukin-23 (IL-23) to its receptor.

[0404] In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor and reduces or prevents the activation of Jak-Stat signaling molecules, Jak2, Tyk2, Stat1, Stat3, Stat4, and / or Stat5.

[0405] In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor and reduces or prevents the phosphorylation of Stat3.

[0406] In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 6.3 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 2 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 1 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 0.5 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 0.25 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 0.1 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 0.05 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC 50 value of less than about 0.025 μM in a reporter assay. In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC50 Inhibit the interleukin-23 (IL-23) receptor with a value. In some embodiments, the cyclic peptide has an IC in an IL-23 reporter assay of less than about 0.005 μM 50 Inhibit the interleukin-23 (IL-23) receptor with a value. In some embodiments, the cyclic peptide has an IC in a reporter assay of less than about 0.0025 μM 50 Inhibit the interleukin-23 (IL-23) receptor with a value.

[0407] In some embodiments, the IL-23 reporter assay is as described herein. In some embodiments, the cyclic peptide has an IC in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay of less than about 0.05 nM 50 Inhibit the interleukin-23 (IL-23) receptor with a value. In some embodiments, the cyclic peptide has an IC in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay of less than about 0.04 nM 50 Inhibit the interleukin-23 (IL-23) receptor with a value. In some embodiments, the cyclic peptide has an IC in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay of less than about 0.03 nM 50 Inhibit the interleukin-23 (IL-23) receptor with a value. In some embodiments, the cyclic peptide has an IC in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay of less than about 0.02 nM 50 Inhibit the interleukin-23 (IL-23) receptor with a value. In some embodiments, the cyclic peptide has an IC in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay of less than about 0.01 nM 50 Inhibit the interleukin-23 (IL-23) receptor with a value. In some embodiments, the peripheral blood mononuclear cell (PBMC) pSTAT3 assay is as described herein.

[0408] In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) assay of about 275 Å2 shows less than EPSA. In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) of less than about 250 Å in an EPSA assay 2 shows less than EPSA. In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) of less than about 225 Å in an EPSA assay 2 shows less than EPSA. In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) of less than about 200 Å in an EPSA assay 2 shows less than EPSA. In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) of less than about 175 Å in an EPSA assay 2 shows less than EPSA. In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) of less than about 150 Å in an EPSA assay 2 shows less than EPSA. In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) of less than about 145 Å in an EPSA assay 2 shows less than EPSA. In some embodiments, the cyclic peptide has an exposed polar surface area (EPSA) of less than about 140 Å in an EPSA assay 2 shows less than EPSA. In some embodiments, the exposed polar surface area (EPSA) assay is as described herein

[0409] In another general aspect, the present invention relates to a compound(s) selected from any one of Tables 1A, 1B, 1C, 1D, 1E, and 1F, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cyclic peptide has the following structure, or a pharmaceutically acceptable salt or solvate thereof

[0410] In another general aspect, the present invention relates to a pharmaceutical composition comprising a cyclic peptide described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent

[0411] In some embodiments, the pharmaceutical composition further comprises an enteric coating

[0412] In some embodiments, the enteric coating protects and releases the pharmaceutical composition within the lower digestive system of the subject.

[0413] In another general aspect, the invention provides a method for treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (nontropical sprue), enteropathy associated with seronegative arthritis, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, radiation- or chemotherapy-associated colitis, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogenosis, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis occurring after colectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, psoriasis, psoriatic arthritis, or graft-versus-host disease in a subject, the method comprising providing to the subject an effective amount of a cyclic peptide described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0414] In some embodiments of the methods described herein, the cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject by an oral, parenteral, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topical, intravaginal, or local route of administration.

[0415] In some embodiments of the methods described herein for treating inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease, the cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided orally to the subject.

[0416] In some embodiments of the methods described herein for treating psoriasis, the cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, is provided to a subject orally, topically, parenterally, intravenously, subcutaneously, intraperitoneally, or intrathecally.

[0417] In some embodiments, a cyclic peptide described herein, or a pharmaceutical composition described herein, for use in the treatment of inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (nontropical sprue), enteropathy associated with seronegative arthritis, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, radiation- or chemotherapy-associated colitis, colitis associated with a disorder of innate immunity such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogenosis, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome, pouchitis occurring after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, psoriasis, psoriatic arthritis, or graft-versus-host disease, comprising providing to the subject an effective amount of a cyclic peptide described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.

[0418] In some embodiments, the cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition is provided to the subject by an oral, parenteral, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topical, intravaginal, or local route of administration.

[0419] In some embodiments, when the cyclic peptide for use described herein, or the pharmaceutical composition for use described herein, is used for the treatment of inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease, the cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, is provided orally to a subject.

[0420] In some embodiments, when the cyclic peptide or pharmaceutical composition for use described herein is used for the treatment of psoriasis, the cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, is provided to a subject orally, topically, parenterally, intravenously, subcutaneously, intraperitoneally, or intramuscularly.

[0421] In some embodiments, the cyclic peptide or pharmaceutical composition described herein is for use as a medicament.

[0422] In some embodiments, the use of the cyclic peptide or pharmaceutical composition described herein is for the manufacture of a medicament for treating a disease.

[0423] In some embodiments, the use of the cyclic peptide or pharmaceutical composition described herein is for the manufacture of a medicament for treating a disease disclosed herein.

[0424] The specific cyclic peptides of the present invention In particular, the present invention relates to a cyclic peptide comprising the amino acid sequence of formula (A) below, or a pharmaceutically acceptable salt or solvate thereof, Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (A), In the formula, the amino acid residue at position Z 3 is either absent or is the residue of r, the amino acid residue at position Z 4 is the residue of the amino acid linked to the amino acid residue at position Z 9 ; the amino acid residue at position Z is the residue of N(N(Me)2), 5 the amino acid residue at position Z is the residue of T, 6 the amino acid residue at position Z is the residue of 7MeW, 7 the amino acid residue at position Z is the residue of K(NMeAc), 8 the amino acid residue at position Z is the residue of the amino acid linked to the amino acid residue at position Z 9 ; the amino acid residue at position Z 4 is the residue of the amino acid linked to the amino acid residue at position Z the amino acid residue at position Z 10 is the residue of TMAPF, the amino acid residue at position Z 11 is the residue of 2Nal, the amino acid residue at position Z 12 is either absent or is the residue of THP, the amino acid residue at position Z 13 is the residue of K(NMeAc), the amino acid residue at position Z 14 is the residue of N, the amino acid residue at position Z 15 is either absent or is the residue of 3Pya, the amino acid residue at position Z 16 is either absent or is the residue of Sar, the amino acid residue at position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16Among the eight or fewer amino acid residues, if an amino acid residue is present at that position, it can be independently replaced with an amino acid residue different from the listed amino acid residue at that position. Position Z 3 When the amino acid residue at 3 is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 3 The amino acid residue at 3 is replaced with an amino acid residue selected from the group consisting of APEG2ser, APEG2Ser, APEG2Ser(S * )、e(c)、e(C)、hk(Me)3、k(5cpa)、k(cPEG3a)、k(d)、k(D)、k(dPEG12Ac)、k(dPEG6Ac)、k(dPEG9Ac)、k(Me)3、K(Me)3、k(PEG2PEG2gEC12)、k(PEG2PEG2gEC14)、k(PEG2PEG2PEG2PEG2gEC12)、k(PEG2PEG6gEC12)、SP6、APEG2Ser(RS)、gPEG2Ser, and k(PEG2PEG2gE(c)C12. Position Z 5 When the amino acid residue at 5 is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 5 The amino acid residue at 5 is replaced with an amino acid residue selected from the group consisting of A, APEG2Ser(S * )、Dab(Me)3、F、Gab、K(cPEG3a)、K(Me)3、K(PEG2PEG2gEC12)、K(PEG2PEG2gEC14)、L、N、N(N(Me))、N(NMe)、Q, and W. Position Z 6 When the amino acid residue at 6 is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 6 The amino acid residue at 6 is replaced with an amino acid residue selected from the group consisting of A and L. Position Z 7 When the amino acid residue at 7 is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 7The amino acid residue is replaced with an amino acid residue selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Nal, A, F, and L, Position Z 8 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, 8 the amino acid residue is replaced with an amino acid residue selected from the group consisting of K(NMeAC), Q, 4AmPhe, A, AIB, APEG2Ser, APEG2Ser(R * ), APEG2Ser(S * ), Cit, Dab(NMeAc), Dab(NMecarn), Dab(NMeCarn), Dab(NMeCOmPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dab(NMecPEG5a), Dap(NMeAc), F, K(4cpg), K(Ac), K(cPEG3a), K(Me)3, K(NMeCOmPEG6), K(NMePEG3a), K(NmPEG6Ac), K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), L, Paf(Ac), Q(N(Me)2), Q(NHtBu), W, Y, and K(cPEG3aCO), Position Z 10 When the amino acid residue at position Z is replaced with an amino acid different from the listed amino acid at that position, 10 the amino acid residue is AEF, 4DMPEF, 4DMPzEF, 4TMABYF, ACHMF, AEF((Ch)cPEG3a), AEF(Ac), AEF(AcCh), AEF(aPEG2a), AEF(BisMEP), AEF(BisMEPa), AEF(BisPEG2a)(RS), AEF(BisPEG2a)(S * ), AEF(G), AEF(Me)2, AEF(MEP), AEF(MePrpa), AEF(N(Me)2), AEF(NHCh), AEF(NHcPEG3a), AEF(NMe), AEF(NMe2mPEG3), AEF(NMe3), AEF(NMeBismPEG3), AEF(NMePEG2a), AEF(NmPEG6), AEF(NsCh), AEF(PEG2a), AEF(SPD), APEG2F, APEG3F, dFPPEG3F, Diazabiclyclooctane6F, DMMMF, DMPMF, DMTASF, F(4G), F(4N3), F(4TzlDMA4mPEG), F(4TzlMME), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMMo4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), GPEG3F, hFTMAPF, MMoEF, MMoPF, MMPEG3F, morfTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, PiperazinequatF, TBAPEG3F, TMA3F, TMA4F, TMA6F, TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(C9OH), Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OTzlC1aC8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), YC8CO(NHPEG3a), YC8COPip, YCF2H, ACHMF(R * ,S * ), ACHMF(S * ,S * ), and is replaced with an amino acid residue selected from the group consisting of AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7), and F(4TzlTMA7), Position Z 11 when the amino acid residue at the position is replaced with an amino acid residue different from the listed amino acid residues at that position, Position Z 11The amino acid residue is replaced with an amino acid residue selected from the group consisting of A, F, L, and W, Position Z 12 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, 12 the amino acid residue is replaced with an amino acid residue selected from the group consisting of A, Achx, Achx(diF), Acpx, Aib, AIB, aMeK, aMeL, Chg, diFCpx, F, L, Pip(NMe), Pip(NMe2), W, and diFAchx, Position Z 13 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, 13 the amino acid residue is replaced with an amino acid residue selected from the group consisting of K(NMeAC), E, A, AIB, aMeE, APEG2Ser, APEG2Ser(S * ), Cit, Dab(NMeAc), Dab(NMecarn), Dab(NMeCOmPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dap(Ac), Dap(NMeAc), E(c), E(C), F, K(5cpa), K(Ac), K(cPEG3a), K(d), K(D), K(dPEG12Ac), K(dPEG6Ac), K(dPEG9Ac), K(Me)3, K(NMeCOmPEG6), K(NMeCOPEG4N+Me3), K(NMePEG3a), K(NmPEG6Ac), K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), K(PEG2PEG2PEG2gEC12), L, Q(N(Me)2), tetrazole, tetrazole(NMe), W, K(DFN), K(IPB), and Nle, Position Z 14 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, 14 the amino acid residue is replaced with an amino acid residue selected from the group consisting of K(Ac) and N(NMe), Position Z 15 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position,15 The amino acid residue is replaced with an amino acid residue selected from the group consisting of 3pya, 5CF33Pya, 5MePyridinAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y, and A, Position Z 16 when the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, 16 the amino acid residue is replaced with an amino acid residue selected from the group consisting of 4diFPro, NMeDTyr, NMeK(PEG2PEG2C12), NMeK(PEG2PEG2C14), NMeK(PEG2PEG2gEC12), NMeK(PEG2PEG2gEC14), NMeK(PEG2PEG2K(PEG2PEG2gEC12)2), NMeK(PEG2PEG2K(PEG2PEG2PEG2PEG2gEC12)2), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12), and NMeK(SP6PEG2PEG2gEC12), and Position Z 3 Z 5 Z 6 Z 7 Z 8 Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and / or Z 16 at least one of the amino acid residues, when the amino acid residue is present at that position, each independently contains at least one quaternary amine.

[0425] In particular, the present invention relates to a cyclic peptide containing the amino acid sequence of formula (B) below, or a pharmaceutically acceptable salt or solvate thereof, Z 3 -Z 4 -Z 5 -Z6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (B), wherein, the amino acid residue at position Z 3 is absent or is the residue of r, the amino acid residue at position Z 4 is the residue of the amino acid linked to the amino acid residue at position Z 9 ; the amino acid residue at position Z 5 is the residue of N(N(Me)2), the amino acid residue at position Z 6 is the residue of T, the amino acid residue at position Z 7 is the residue of 7MeW, the amino acid residue at position Z 8 is the residue of K(NMeAc), the amino acid residue at position Z 9 is the residue of the amino acid linked to the amino acid residue at position Z 4 ; the amino acid residue at position Z 10 is the residue of TMAPF, the amino acid residue at position Z 11 is the residue of 2Nal, the amino acid residue at position Z 12 is absent or is the residue of THP, the amino acid residue at position Z 13 is the residue of K(NMeAc), the amino acid residue at position Z 14 is the residue of N, the amino acid residue at position Z 15 is absent or is the residue of 3Pya, the amino acid residue at position Z 16 is absent or is the residue of Sar, the amino acid residue at position Z 3 , Z5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and Z 16 Of the amino acid residues of, when the amino acid residue is present at that position, independently, it is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 3 When the amino acid residue at is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z 3 The amino acid residue at is replaced with an amino acid residue selected from the group consisting of APEG2ser, APEG2Ser, APEG2Ser(S * ), e(c), e(C), hk(Me)3, k(5cpa), k(cPEG3a), k(d), k(D), k(dPEG12Ac), k(dPEG6Ac), k(dPEG9Ac), k(Me)3, K(Me)3, k(PEG2PEG2gEC12), k(PEG2PEG2gEC14), k(PEG2PEG2PEG2PEG2gEC12), k(PEG2PEG6gEC12), SP6, APEG2Ser(RS), gPEG2Ser, and k(PEG2PEG2gE(c)C12, Position Z 5 When the amino acid residue at is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z 5 The amino acid residue at is replaced with an amino acid residue selected from the group consisting of A, APEG2Ser(S * ), Dab(Me)3, F, Gab, K(cPEG3a), K(Me)3, K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), L, N, N(N(Me)), N(NMe), Q, and W, Position Z 6 When the amino acid residue at is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z 6 The amino acid residue at is replaced with an amino acid residue selected from the group consisting of A and L, Position Z 7 If the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, then position Z 7 's amino acid residue is replaced with an amino acid residue selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Nal, A, F, and L, Position Z 8 If the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, then position Z 8 's amino acid residue is K(NMeAC), Q, 4AmPhe, A, AIB, APEG2Ser, APEG2Ser(R * )、APEG2Ser(S * )、Cit、Dab(NMeAc)、Dab(NMecarn)、Dab(NMeCarn)、Dab(NMeCOmPEG6)、Dab(NMecPEG2a)、Dab(NMecPEG3a)、Dab(NMecPEG5a)、Dap(NMeAc)、F、K(4cpg)、K(Ac)、K(cPEG3a)、K(Me)3、K(NMeCOmPEG6)、K(NMePEG3a)、K(NmPEG6Ac)、K(PEG2PEG2gEC12)、K(PEG2PEG2gEC14)、L、Paf(Ac)、Q(N(Me)2)、Q(NHtBu)、W、Y、and K(cPEG3aCO), and is replaced with an amino acid residue selected from the group consisting of Position Z 10 If the amino acid residue at position Z is replaced with an amino acid different from the listed amino acid residue at that position, then position Z 10 's amino acid residue is AEF, 4DMPEF, 4DMPzEF, 4TMABYF, ACHMF, AEF((Ch)cPEG3a), AEF(Ac), AEF(AcCh), AEF(aPEG2a), AEF(BisMEP), AEF(BisMEPa), AEF(BisPEG2a)(RS), AEF(BisPEG2a)(S * )、 AEF(G), AEF(Me)2, AEF(MEP), AEF(MePrpa), AEF(N(Me)2), AEF(NHCh), AEF(NHcPEG3a), AEF(NMe), AEF(NMe2mPEG3), AEF(NMe3), AEF(NMeBismPEG3), AEF(NMePEG2a), AEF(NmPEG6), AEF(NsCh), AEF(PEG2a), AEF(SPD), APEG2F, APEG3F, dFPPEG3F, Diazabiclyclooctane6F, DMMMF, DMPMF, DMTASF, F(4G), F(4N3), F(4TzlDMA4mPEG), F(4TzlMME), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMMo4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), GPEG3F, hFTMAPF, MMoEF, MMoPF, MMPEG3F, morfTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, PiperazinequatF, TBAPEG3F, TMA3F, TMA4F, TMA6F, TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(C9OH), Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OTzlC1aC8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), YC8CO(NHPEG3a), YC8COPip, YCF2H, ACHMF(R * ,S * ), ACHMF(S * ,S * ), and is replaced with an amino acid residue selected from the group consisting of AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7), and F(4TzlTMA7), Position Z 11 when the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residues at that position, position Z 11The amino acid residue is replaced with an amino acid residue selected from the group consisting of A, F, L, and W, Position Z 12 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 12 the amino acid residue is replaced with an amino acid residue selected from the group consisting of A, Achx, Achx(diF), Acpx, Aib, AIB, aMeK, aMeL, Chg, diFCpx, F, L, Pip(NMe), Pip(NMe2), W, and diFAchx, Position Z 13 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 13 the amino acid residue is replaced with an amino acid residue selected from the group consisting of K(NMeAC), E, A, AIB, aMeE, APEG2Ser, APEG2Ser(S * ), Cit, Dab(NMeAc), Dab(NMecarn), Dab(NMeCOmPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dap(Ac), Dap(NMeAc), E(c), E(C), F, K(5cpa), K(Ac), K(cPEG3a), K(d), K(D), K(dPEG12Ac), K(dPEG6Ac), K(dPEG9Ac), K(Me)3, K(NMeCOmPEG6), K(NMeCOPEG4N+Me3), K(NMePEG3a), K(NmPEG6Ac), K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), K(PEG2PEG2PEG2gEC12), L, Q(N(Me)2), tetrazole, tetrazole(NMe), W, K(DFN), K(IPB), and Nle, Position Z 14 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z 14 the amino acid residue is replaced with an amino acid residue selected from the group consisting of K(Ac) and N(NMe), Position Z 15 when the amino acid residue at Position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, Position Z15 The amino acid residue is replaced with an amino acid residue selected from the group consisting of 3pya, 5CF33Pya, 5MePyridinAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y, and A, Position Z 16 When the amino acid residue at position Z is replaced with an amino acid residue different from the listed amino acid residue at that position, position Z 16 The amino acid residue is replaced with an amino acid residue selected from the group consisting of 4diFPro, NMeDTyr, NMeK(PEG2PEG2C12), NMeK(PEG2PEG2C14), NMeK(PEG2PEG2gEC12), NMeK(PEG2PEG2gEC14), NMeK(PEG2PEG2K(PEG2PEG2gEC12)2), NMeK(PEG2PEG2K(PEG2PEG2PEG2PEG2gEC12)2), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12), and NMeK(SP6PEG2PEG2gEC12), and Position Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , Z 15 , and / or Z 16 when at least one of the amino acid residues is present at that position, each independently contains at least one masked amine and / or masked amide.

[0426] II. Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art.

[0427] When referring to a value, "about" includes the recited value + / - 10% of the recited value. For example, about 50% includes the range from 45% to 55%, and about 20 molar equivalents includes the range from 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to + / - 10% of each upper and lower limit of the recited range of the recited value. For example, a ratio of about 1 to about 3 (weight / weight) includes the range from 0.9 to 3.3.

[0428] As used interchangeably, "patient" or "subject" refers to a living organism, which includes, but is not limited to, a human subject having or likely to have a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples can include, but are not limited to, humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, horses, and other mammals. In some embodiments, the patient is a human.

[0429] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming rules proposed by the IUPAC Commission in Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature, as described in "Nomenclature of α-Amino Acids (Recommendations, 1974)", Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims differ from those proposals, they will be apparent to the reader. In the amino acid sequence representing the IL-23 inhibitor, the individual amino acids are separated by a hyphen "-" or parentheses, and for example, lysine is shown as [K].

[0430] Throughout this specification, when a naturally occurring amino acid is not referred to by its full name (e.g., alanine, arginine, etc.), it is denoted by the conventional three-letter or one-letter abbreviation (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless otherwise indicated, the three-letter and one-letter abbreviations of amino acids refer to the L-isomeric form of the amino acid in question. As used herein, the term "L-amino acid" refers to the "L" isomeric form of a peptide, and conversely, the term "D-amino acid" refers to the "D" isomeric form of a peptide (e.g., (D)Asp, or D-Asp; (D)Phe, or D-Phe). As long as the peptide retains its desired function, any L-amino acid residue may be substituted with an amino acid residue in the D-isomeric form. D-amino acids, when referred to using the one-letter abbreviation, may be denoted in lower case by convention. For example, L-arginine can be represented as "Arg" or "R", while D-arginine can be represented as "arg" or "r". Similarly, L-lysine can be represented as "Lys" or "K", while D-lysine can be represented as "lys" or "k". Alternatively, a lower case "d" before the amino acid can be used to indicate that it is in the D-isomeric form, e.g., D-lysine can be represented as dK.

[0431] For amino acids that are less common or not naturally occurring, when not referred to by their full name (e.g., sarcosine, ornithine, etc.), the three-letter or four-letter notations that are frequently used for their residues are used, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0432] Amino acids in D-isomeric form can be located at any of the positions in the IL-23R inhibitors described herein (any of X1 to X18 that appear in the molecule). In one aspect, the amino acids in D-isomeric form can be located at only one or more than one of X3, X5, X6, X8, X13, and optionally one additional position. In another aspect, the amino acids in D-isomeric form can be located at only one or more than one of X3, X8, X13, and optionally one additional position. In another aspect, the amino acids in D-isomeric form can be located at only one or more than one of X8, X13 (for example, X8 is dK(Ac) and X13 is dE), and optionally one additional position. In another aspect, the amino acids in D-isomeric form can be located at only X3 and optionally one additional position. In another aspect, the amino acids in D-isomeric form can be located at only X3 and optionally two or three additional positions. In another aspect, the amino acids in D-isomeric form can be located at only one or two of positions X1 to X18 that appear in the IL-23R inhibitors described herein. In another aspect, the amino acids in D-isomeric form can be located at only three or four of positions X1 to X18 that appear in the IL-23R inhibitors described herein. For example, an IL-23R inhibitor described herein in which only positions X3 to X15 are present can have D-type amino acids present at three or four of these positions. In another aspect, the amino acids in D-isomeric form can be located at only five or six of positions X1 to X18 that appear in the IL-23R inhibitors described herein.

[0433] As will be apparent to those skilled in the art, the peptide sequences disclosed herein are shown as proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. Among the sequences disclosed herein, there are sequences that incorporate either an "-OH" moiety or an "-NH2" moiety at the carboxy terminus (C-terminus) of the sequence. In such cases, unless otherwise indicated, the "-OH" or "-NH2" moiety at the C-terminus of the sequence represents a hydroxy group or an amino group corresponding to the presence of a carboxylic acid (COOH) or amide (CONH2) group at the C-terminus, respectively. In each sequence of the present invention, the "-NH2" moiety at the C-terminus may be replaced with the "-OH" moiety at the C-terminus, and vice versa.

[0434] As used herein, the term "amino acid" in its broadest sense refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid, in some embodiments, the amino acid is a D-amino acid, and in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. "Non-standard amino acid" refers to any amino acid other than a standard amino acid, whether it is synthetically prepared or obtained from a natural source. As used herein, "synthetic amino acid" includes chemically modified amino acids (salts, amino acid derivatives (e.g., amides), and / or substitutions, including but not limited to these). Amino acids including carboxy- and / or amino-terminal amino acids in a peptide can be modified by methylation, amidation, acetylation, protecting groups, and / or substitution with other chemical groups that can change the circulating half-life of the peptide without adversely affecting their activity. Amino acids can be involved in the formation of cross-links for cyclization, such as thioether bonds and disulfide bonds, to form the cyclic portion of a peptide, as seen, for example, in the connection between the amino acid residue at position Z4 and the amino acid residue at position Z9 in the various embodiments considered herein. Amino acids can include one or more post-translational modifications, such as association with one or more chemical entities (e.g., methyl group, acetate group, acetyl group, phosphate group, formyl moiety, isoprenoid group, sulfate group, polyethylene glycol moiety, lipid moiety, carbohydrate moiety, biotin moiety, etc.). The term "amino acid" is used interchangeably with "amino acid residue" and can refer to a free amino acid and / or an amino acid residue of a peptide. Whether it refers to a free amino acid or a residue of a peptide will be apparent from the context in which the term is used.

[0435] As used herein, "hydrophilic amino acid or residue" refers to an amino acid or residue having a side chain that exhibits a hydrophobicity less than 0 according to the normalized consensus hydrophobicity scale of Eisenberg et al., 1984, J. Mol. Biol. 179:125-142. Examples of hydrophilic amino acids include, but are not limited to, L-Thr (T), L-Ser (S), L-His (H), L-Glu (E), L-Asn (N), L-Gln (Q), L-Asp (D), L-Lys (K), and L-Arg (R).

[0436] As used herein, "acidic amino acid or residue" refers to a hydrophilic amino acid or residue having a side chain that exhibits a pK value of less than about 6 when the amino acid is included in a peptide or polypeptide. Acidic amino acids typically have a side chain that is negatively charged at physiological pH due to the loss of a hydrogen ion. Examples of acidic amino acids include, but are not limited to, L-Glu (E) and L-Asp (D).

[0437] As used herein, "basic amino acid or residue" refers to a hydrophilic amino acid or residue having a side chain that exhibits a pK value greater than about 6 when the amino acid is included in a peptide or polypeptide. Basic amino acids typically have a side chain that is positively charged at physiological pH due to association with a hydronium ion. Examples of basic amino acids include, but are not limited to, L-Arg (R) and L-Lys (K).

[0438] As used herein, "polar amino acid or residue" refers to a hydrophilic amino acid or residue having a side chain that is not charged at physiological pH but has at least one bond in which a pair of electrons shared by two atoms is held closer to one of the atoms. Examples of polar amino acids include, but are not limited to, L-Asn (N), L-Gln (Q), L-Ser (S), and L-Thr (T).

[0439] As used herein, "hydrophobic amino acid or residue" refers to an amino acid or residue having a side chain that exhibits a hydrophobicity greater than 0 according to the normalized consensus hydrophobicity scale of Eisenberg et al., 1984, J. Mol. Biol. 179: 125-142. Examples of hydrophobic amino acids include, but are not limited to, L-Pro (P), L-Ile (I), L-Phe (F), L-Val (V), L-Leu (L), L-Trp (W), L-Met (M), L-Ala (A), and L-Tyr (Y).

[0440] As used herein, "aromatic amino acid or residue" refers to a hydrophilic or hydrophobic amino acid or residue having a side chain that contains at least one aromatic or heteroaromatic ring. Examples of aromatic amino acids include, but are not limited to, L-Phe (F), L-Tyr (Y), L-His (H), 2-Nal, substituted 2-Nal, AEF, substituted AEF, L-Trp (W), Trp, or substituted Trp. Due to the pKa of its heteroaromatic nitrogen atom L-His (H), it may be classified as a basic residue, but herein, histidine is classified as an aromatic residue because its side chain contains a heteroaromatic ring.

[0441] As used herein, "nonpolar amino acid or residue" refers to a hydrophobic amino acid or residue having a side chain that is not charged at physiological pH and has a bond in which the pair of electrons shared by two atoms is generally held equally by each of the two atoms (i.e., the side chain is not polar). Examples of nonpolar amino acids include, but are not limited to, L-Gly (G), L-Leu (L), L-Val (V), L-Ile (I), L-Met (M), L-Pro (P), and L-Ala (A).

[0442] As used herein, "aliphatic amino acid or residue" refers to a hydrophobic amino acid or residue having an aliphatic hydrocarbon side chain. Examples of aliphatic amino acids include, but are not limited to, L-Ala (A), L-Val (V), L-Leu (L), and L-Ile (I).

[0443] The amino acid L-Cys(C) is unique in that it can form disulfide bridges with other L-Cys(C) amino acids or other sulfanyl- or sulfhydryl-containing amino acids. As used herein, "cysteine-like amino acid or residue" includes cysteine and other amino acids containing a sulfhydryl moiety available for the formation of disulfide bridges. The ability of L-Cys(C) (and other amino acids with SH-containing side chains) to be present in a peptide in either its reduced free SH or oxidized disulfide-bridged form affects whether L-Cys(C) confers net hydrophobic or hydrophilic properties to the peptide. L-Cys(C) exhibits a hydrophobicity of 0.29 according to the normalized consensus scale of Eisenberg (Eisenberg et al., 1984, supra), but for the purposes of the present disclosure, it should be understood that L-Cys(C) is classified into its own unique group. Examples of "cysteine-like amino acids or residues" include, but are not limited to, (R)-2-amino-3-mercapto-3-methylbutanoic acid (Pen) and L-homocysteine (hC).

[0444] The term "quaternary amine" has its ordinary meaning in the art. For example, a quaternary amine is a substituent containing one or more nitrogen atoms that are permanently positively charged. The permanent positive charge of the nitrogen atom can be independent of the surrounding pH. One non-limiting example of a quaternary amine can be a moiety having four organic substituents on a nitrogen atom.

[0445] The term "masked amine" means a substituent containing one or more nitrogen atoms, wherein one or more of the nitrogen atoms are substituted. For example, one or more of the nitrogen atoms may be substituted with a group such as alkyl or acetyl to form a secondary amine, a tertiary amine, or an amide. In embodiments, the masked amine is a secondary amine. In embodiments, the masked amine is a tertiary amine. In embodiments, the masked amine is an amide.

[0446] The term "masked amide" refers to a substituent containing one or more nitrogen atoms, wherein one or more nitrogen atoms are substituted with -C=O and at least one other substituent. For example, one or more nitrogen atoms substituted with -C=O may be further substituted with a group such as alkyl or acetyl to form a secondary amide or a tertiary amide. In embodiments, the masked amide is a secondary amide. In some embodiments, the masked amide is a tertiary amide.

[0447] One of ordinary skill in the art will understand that certain amino acids and other chemical moieties may be modified when attached to another molecule. For example, an amino acid side chain may be modified when forming an intramolecular bridge with another amino acid side chain, and for example, one or more hydrogens may be removed or substituted by a bond.

[0448] "The compounds of the present invention", "the inhibitors of the present disclosure", "the IL-23R inhibitors of the present disclosure", "the compounds described herein", and "the compounds described herein" include any of the compounds of the examples, including the novel compounds disclosed herein, such as the compounds of formulas (I)-(VI) as found in Table 1A, Table 1B, Table 1C, Table 1D, or Table 1E.

[0449] "A pharmaceutically effective amount" refers to the amount of a compound of the present invention in a composition or combination thereof that provides a desired therapeutic or pharmaceutical result.

[0450] "Pharmaceutically acceptable" means that a carrier, diluent, salt, or excipient must be compatible with the other constituents or components of the composition of the present invention, i.e., useful, safe, non-toxic, and acceptable for pharmaceutical use. According to the present invention, pharmaceutically acceptable means approved or approvable for use in animals, particularly in humans, as described in the U.S. Pharmacopoeia or other generally recognized pharmacopeias.

[0451] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the US Food and Drug Administration as acceptable for use in humans or livestock.

[0452] "Absorption enhancer" refers to a component that improves or facilitates the mucosal absorption of a drug in the gastrointestinal tract, such as a permeation enhancer or an intestinal permeation enhancer. As conventionally understood in the art, a permeation enhancer (PE) is a drug intended to improve the oral delivery of therapeutic drugs with poor bioavailability. A PE can increase the paracellular and / or transcellular passage of a drug.

[0453] Pharmaceutical excipients that can increase permeation are referred to as "Absorption Modifying Excipients" (AME). AMEs can be used in oral compositions, for example, as wetting agents (sodium dodecyl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., macrogol glycerides), and in particular, can be included as PEs in a composition to improve bioavailability. PEs can be classified with respect to how they alter barrier integrity via the paracellular or transcellular pathway.

[0454] "Intestinal Permeation Enhancer" (IPE) refers to a component that improves the bioavailability of a component. Representative IPEs suitable for use in the present invention include, but are not limited to, various surfactants, fatty acids, medium-chain glycerides, steroid detergents, acylcarnitines and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, and chitosan, other mucoadhesive polymers, etc. For example, a sodium caprate can be an IPE suitable for use in the present invention.

[0455] As used herein, "composition" or "pharmaceutical composition" is intended to encompass an invention or product containing a specific active product ingredient (API), which may contain pharmaceutically acceptable excipients, carriers or diluents as defined herein, for example, in specific amounts as defined throughout the present disclosure. A composition or pharmaceutical composition results from a combination of specific components such as specific amounts of specific components described herein.

[0456] The compositions or pharmaceutical compositions of the present invention can be in different pharmaceutically acceptable forms, and the different pharmaceutically acceptable forms can include, but are not limited to, liquid compositions, tablet or matrix compositions, capsule compositions, etc. When the composition is a tablet composition, the tablet can include two or more different phases including an inner phase that can include a core and an outer phase, but is not limited thereto. The tablet composition can also include one or more coatings, but is not limited thereto.

[0457] As used herein, "solvate" means a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves variations in the degree of bonding including hydrogen bonding. In certain instances, the solvate can be isolable. The term "solvate" is intended to encompass both solution phase solvates and isolable solvates. Non-limiting examples of suitable solvates include hydrates.

[0458] Also provided are pharmaceutically acceptable salts and tautomers of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful for preparing pharmaceutically suitable compositions for veterinary or human pharmaceutical use.

[0459] The IL-23R inhibitors of the present disclosure, or pharmaceutically acceptable salts or solvates thereof, may contain one or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- for amino acids, or as (D)- or (L)- from the perspective of absolute stereochemistry. The present disclosure means that it includes all such possible isomers of the IL-23R inhibitors of the present disclosure, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagent, or may be resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor, or resolution of a racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. When the compounds are represented in their chiral forms, it is understood that the embodiments include, but are not limited to, specific diastereomer-enriched or enantiomer-enriched forms. When chirality is not specified but is present, it is understood that the embodiments are directed to either a specific diastereomer-enriched or enantiomer-enriched form; or a racemic mixture or scalemic mixture of such compounds. As used herein, "scalemic mixture" is a mixture of stereoisomeric enantiomers in a ratio other than 1:1.

[0460] A particular example contains amino acids designated or labeled as (R * ) or (S * ). (R * ) or (S *) When used in the name of an amino acid or the chemical representation of an amino acid, it is intended to convey that the amino acid is a pure single isomer at its stereocenter. However, the absolute configuration of that stereocenter has not been established. Thus, the compound denoted as (R * ) refers to an amino acid that is a pure single isomer at its stereocenter having either the (R) or (S) absolute configuration, and the compound denoted as (S * ) refers to an amino acid that is a pure single isomer at its stereocenter having either the (R) or (S) absolute configuration. For example, ACHMF(S * ):

[0461]

Chem.

[0462]

Chem.

[0463] "Racemate" refers to a mixture of enantiomers. The mixture can contain equal or unequal amounts of each enantiomer.

[0464] "Stereoisomer" refers to a compound in which the chirality of one or more stereocenters is different. Stereoisomers include enantiomers and diastereomers. A compound may exist in stereoisomeric forms if it has one or more asymmetric centers or a double bond with an asymmetric substitution, and thus can be produced as individual stereoisomers or as a mixture. Unless otherwise indicated, this description is intended to encompass individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0465] "Tautomers" refer to alternative forms of compounds in which the position of a proton is different, such as enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both ring-NH- and ring=N-, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0466] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In the chemical arts, dashes at the beginning or end of a chemical group are for convenience; chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn on a line within a structure indicates the point of attachment of a group. A dashed line indicates an optional bond. Unless required chemically or structurally, the order in which chemical groups are written or the point at which a chemical group is attached to the remainder of the molecule does not indicate or imply directionality. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be linked in either direction. Similarly, an "arylalkyl" group can be attached to the remainder of the molecule by either the aryl portion or the alkyl portion of the group. " u~v C" or a prefix such as ( u ~C v ) indicates that the following group has u to v carbon atoms. For example, both " 1~6 alkyl" and "C1-C6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0467] As used herein, "treatment" or "treating" or "treatment" refers to an approach for obtaining a beneficial or desired result. For the purposes of the present invention, beneficial results or desired results include, but are not limited to, alleviation of symptoms and / or reduction in the degree of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In one aspect, "treatment" or "treatment" includes one or more of the following: (a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the degree of the disease or condition); (b) delaying or arresting the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); (c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the disease state, delaying the progression of the disease, improving the quality of life, and / or prolonging the survival period.

[0468] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount effective to induce a desired biological or medical response, including an amount of a compound that is sufficient to achieve such treatment of a disease when administered to a subject for treating the disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated. The effective amount may include a range of amounts. As is understood in the art, the effective amount may be a single dose or multiple doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. The effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in combination with one or more other agents, a desired or beneficial result can be achieved or, if achieved, is achieved. The preferred dosage of any co-administered compound may optionally be reduced due to the combined action (e.g., additive or synergistic effect) of the compounds.

[0469] "Co-administration", as used herein, refers to the administration of a unit dosage of a compound disclosed herein, before or after the administration of one or more additional therapeutic agents of the unit dosage, e.g., the administration of a compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dosage of a compound of the invention is administered first, followed by the administration of a unit dosage of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dosage of one or more additional therapeutic agents is administered first, followed by the administration of a unit dosage of a compound of the invention within seconds or minutes. In some embodiments, a unit dosage of a compound of the invention is administered first, followed by the administration of a unit dosage of one or more additional therapeutic agents hours (e.g., 1 - 12 hours) later. In other embodiments, a unit dosage of one or more additional therapeutic agents is administered first, followed by the administration of a unit dosage of a compound of the invention hours (e.g., 1 - 12 hours) later. Co-administration of a compound disclosed herein and one or more additional therapeutic agents generally refers to co-administration or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0470] The abbreviation "(V / V)" refers to the phrase "volume for volume", i.e., the proportion of a particular substance in a mixture as measured by the volume or volume amount of a constituent of a composition disclosed herein relative to the total volume amount of the composition. Thus, the amount is unit less and represents the volume percentage amount of the constituent relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture may indicate that 2 mL of one solvent is present in 100 mL of the solvent mixture.

[0471] The abbreviation "(w / w)" refers to the phrase "weight for weight", that is, the proportion of a particular substance in a mixture, measured by the weight or mass or amount of weight of a constituent of the composition relative to the total weight of the composition disclosed herein. Thus, the quantity is dimensionless and represents the weight percentage amount of the constituent relative to the total weight of the composition. For example, a 2% (w / w) solution may indicate that 2 grams of solute are dissolved in 100 grams of solution.

[0472] As conventionally understood in the medical or pharmaceutical arts, a systemic administration route refers to, or is defined as, an administration route by which a drug, pharmaceutical composition or formulation, or other substance enters the circulatory system and, as a result, various body tissues and organs are exposed to the drug, formulation or other substance. As conventionally understood in the art, administration may be oral (where the drug or oral preparation is ingested through the mouth and absorbed through the gastrointestinal tract), enteral (where absorption of the drug also occurs throughout the gastrointestinal tract), or parenteral (generally, which can be effected by injection, infusion, or implantation, etc.).

[0473] The "systemically active" peptide drug therapy according to the present invention generally refers to a treatment with a pharmaceutical composition containing a peptide active ingredient, in which the peptide resists immediate metabolism and / or excretion, resulting in exposure of the peptide in various body tissues and organs such as the cardiovascular, respiratory, gastrointestinal, nervous, or immune systems.

[0474] Systemic drug activity in the present invention also refers to a treatment using a substance that moves across the bloodstream to reach cells in various body tissues and organs and exerts an effect. Systemically active drugs are transported to the site of action of the systemically active drug and act throughout the body to attack the physiological processes that cause inflammatory diseases.

[0475] Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters the systemic circulation and thereby accesses the site of action. The bioavailability of a drug is affected by the characteristics of the dosage form, which are partially dependent on the design and manufacture of the dosage form.

[0476] As used herein, "gastrointestinal tissue" refers to all tissues including the organs of the gastrointestinal tract. By way of example only, "gastrointestinal tissue" includes, but is not limited to, the tissues of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.

[0477] As used herein, the term "natural polymer" has its ordinary meaning in the art. For example, polymers that can be found in biological systems such as plants, animals, bacteria, and fungi. Natural polymers can be polypeptides, polysaccharides, or polynucleotides. The subunits of natural polymers can be amino acids, monosaccharides, or nucleotides. Natural polymers can vary in type (e.g., homopolymers or copolymers, random, alternating, or block copolymers, linear or branched). Non-limiting examples of natural polymer groups are amino acid sequences containing about 10 to about 30 amino acids derived from (poly)peptides such as pro-atrial natriuretic peptide C, atrial natriuretic peptide, brain natriuretic peptide, serum albumin, IgG, histidine-rich glycoprotein, fibronectin, fibrinogen, zinc finger-containing polypeptides, osteocalcin or fibroblast growth factor 2 (FGF2), or variants thereof having substitutions and / or deletions.

[0478] As used herein, the term "non-natural polymer" has its ordinary meaning in the art. For example, synthetic polymers that do not naturally occur in biological systems such as plants, animals, bacteria, and fungi. Non-natural polymers can vary in type (e.g., homopolymers or copolymers, random, alternating, or block copolymers, linear or branched). Non-limiting examples of non-natural polymer groups include polyethylene glycol (PEG) (also referred to as polyethylene oxide (PEO)).

[0479] As used herein, the term "hydrophilic polymer" has its ordinary meaning in the art. For example, polymers that dissolve in water. Hydrophilic polymers can contain polar or charged functional groups that make the polymer water-soluble. Hydrophilic polymers can be natural polymers, non-natural polymers, or combinations thereof. Natural polymers can vary in type (e.g., homopolymers or copolymers, random, alternating, or block copolymers, linear or branched). Non-limiting examples of hydrophilic polymers include polyethylene glycol (PEG).

[0480] Chemical Definitions Acyl: As used herein, the term "acyl" refers to R Z -(C=O)-, where R Z is, for example, any alkyl, alkenyl, alkynyl, heteroalkyl, or heteroalkenyl.

[0481] Aliphatic: As used herein, the term aliphatic in the context of chemical substituents refers to hydrocarbons and includes both saturated and unsaturated hydrocarbons. Aliphatic can be linear, branched, or cyclic. For example, C1-C 10 Aliphatic is C1-C 10 alkyl (e.g., linear or branched C1-C 10 saturated alkyl), C2-C 10 alkenyl (e.g., linear or branched C4-C 10 dienyl, linear or branched C6-C 10triphenyl, etc.), and C2 - C 10 alkynyl (e.g., linear or branched C2 - C 10 alkynyl) may be included. C1 - C 10 aliphatic may include C3 - C 10 cyclic aliphatic (e.g., C3 - C 10 cycloalkyl, C4 - C 10 cycloalkenyl, or C8 - C 10 cycloalkynyl). In certain embodiments, the aliphatic may include one or more cyclic aliphatics and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. The aliphatic group is unsubstituted or substituted with one or more of the substituents described herein. For example, the aliphatic may be halogen, -COR”, -CO2H, -CONH2, -CO2R”, -CN, -OH, -OR”, -OCOR”, -OCO2R”, -NH2, -NHR”, -N(R”)2, -SR”, or -SO2R” (wherein each instance of R” is independently C1 - C 10 aliphatic (e.g., C1 - C 10 alkyl, C1 - C8 alkyl, C1 - C6 alkyl, or C1 - C3 alkyl) with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents). In an embodiment, R” is independently unsubstituted alkyl (e.g., unsubstituted C1 - C 10 alkyl, C1 - C8 alkyl, C1 - C6 alkyl, or C1 - C3 alkyl). In an embodiment, R” is independently unsubstituted C1 - C3 alkyl. In an embodiment, the aliphatic is unsubstituted. In an embodiment, the aliphatic contains no heteroatoms.

[0482] Alkyl: As used herein, the term "alkyl" refers to radicals of acyclic straight-chain and branched hydrocarbon groups. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbons. The alkyl group can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentylhexyl, isohexyl, etc. The term "lower alkyl" means an alkyl group having 1 to 6 carbon atoms, a straight-chain or branched alkyl. Other alkyl groups will be readily apparent to those skilled in the art in view of the benefits of the present disclosure. The alkyl group can be unsubstituted or substituted with one or more substituents described herein. For example, the alkyl group can be halogen, -COR", -CO2H, -CONH2, -CO2R", -CN, -OH, -OR", -OCOR", -OCO2R", -NH2, -NHR", -N(R")2, -SR", or -SO2R" (wherein each instance of R" is independently C1-C 10 aliphatic (e.g., C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl) with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents). In embodiments, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). In embodiments, R" is independently unsubstituted C1-C3 alkyl. In embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents described herein). In embodiments, the alkyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkyl" group, where the prefix indicates the -OH group and "alkyl" is as described herein.

[0483] For example, "alkyl" is a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C1-C 10refers to "alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C1-C9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C1-C7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanol (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of the alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C1-C6 alkyl. In certain embodiments, the alkyl group is substituted C1-C6 alkyl.

[0484] Attaching the suffix "-ene" to a group indicates that the group is a divalent moiety. For example, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0485] Alkylene: As used herein, the term "alkylene" represents a saturated divalent straight or branched chain hydrocarbon group, exemplified by methylene, ethylene, isopropylene, etc. Similarly, as used herein, the term "alkenylene" represents an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that can be present at any stable point along the chain, and the term "alkynylene" as used herein represents an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that can be present at any stable point along the chain. In certain embodiments, the alkylene, alkenylene, or alkynylene group may contain one or more cycloaliphatic and / or one or more heteroatoms such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. For example, alkylene, alkenylene, or alkynylene is halogen, -COR", -CO2H, -CONH2, -CO2R", -CN, -OH, -OR", -OCOR", -OCO2R", -NH2, -NHR", -N(R")2, -SR", or -SO2R" (wherein each instance of R" is independently C1-C 10 aliphatic (e.g., C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl) of one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents). In embodiments, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). In embodiments, R" is independently unsubstituted C1-C3 alkyl. In certain embodiments, alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, alkylene, alkenylene, or alkynylene contains no heteroatoms.

[0486] Alkenyl: As used herein, "alkenyl" refers to the radical of any straight-chain or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C2-C 10 alkenyl" refers to an alkenyl group having 2 to 10 carbons. For example, alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hexa-2-enyl, hexa-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In embodiments, alkenyl contains 1, 2, or 3 carbon-carbon double bonds. In embodiments, alkenyl contains a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. The alkenyl group may be unsubstituted or substituted with one or more of the substituents described herein. For example, the alkenyl group may be halogen, -COR", -CO2H, -CONH2, -CO2R", -CN, -OH, -OR", -OCOR", -OCO2R", -NH2, -NHR", -N(R")2, -SR", or -SO2R" (wherein each instance of R" is independently C1-C 10 aliphatic (e.g., C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl)) of one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents). In embodiments, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). In embodiments, R" is independently unsubstituted C1-C3 alkyl. In embodiments, alkenyl is unsubstituted. In embodiments, alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 of the substituents described herein). In embodiments, the alkenyl group is substituted with an -OH group and may also be referred to herein as a "hydroxyalkenyl" group, where the prefix indicates the -OH group and "alkenyl" is as described herein.

[0487] For example, "alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) ( 10 "C2-C alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ( 10 "C2-C9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ( 10 "C2-C8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (

[0488] "C2-C7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ( "C2-C6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ( "C2-C5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ( "C2-C4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ( "C2-C3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ( "C2 alkenyl"). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkenyl groups include, but are not limited to, ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl groups include the aforementioned C2-C4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), etc. Unless otherwise specified, each instance of the alkenyl group is independently unsubstituted ( "unsubstituted alkenyl") or substituted with one or more substituents ( "substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C2-C 10 alkenyl. In certain embodiments, the alkenyl group is 10 substituted C2-C

[0488] alkenyl. Alkynyl: As used herein, "alkynyl" refers to the radical of any hydrocarbon chain of either linear or branched configuration having one or more carbon-carbon triple bonds present at any stable point along the chain. For example, "C2-C 10 alkynyl" refers to an alkynyl group having 2 to 10 carbons. Examples of alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. In an embodiment, alkynyl contains one carbon-carbon triple bond. The alkynyl group may be unsubstituted or substituted with one or more of the substituents described herein. For example, the alkynyl group may be halogen, -COR", -CO2H, -CONH2, -CO2R", -CN, -OH, -OR", -OCOR", -OCO2R", -NH2, -NHR", -N(R")2, -SR", or -SO2R" (wherein each instance of R" is independently C1-C 10 aliphatic (e.g., C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl) of one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents). In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C 10 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). In an embodiment, R" is independently unsubstituted C1-C3 alkyl. In an embodiment, alkynyl is unsubstituted. In an embodiment, alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 of the substituents described herein).

[0489] For example, "alkynyl" refers to the radical of a linear or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C2-C 10"alkynyl"). An alkynyl group having one or more triple bonds and one or more double bonds is also called an "en-yne". In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C2-C9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C2-C7 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-C5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-C4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-C3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon--triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-C4 alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. Examples of C2-C6 alkynyl groups include the aforementioned C2-C4 alkynyl groups, as well as pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each instance of the alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C2-C 10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-C 10 alkynyl.

[0490] Aryl: The term "aryl", used alone or as part of a larger moiety such as "aralkyl", refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, the ring system having a single point of attachment to the remainder of the molecule, at least one ring in the system being aromatic, and each ring in the system containing 4 to 7 ring members. In embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 aryl", e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups and the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0491] As used herein, "aryl" also refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) ("C6-C 14 aryl"). In embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl", for example, anthracyl). Unless otherwise specified, each instance of an aryl group is, independently, unsubstituted ( "unsubstituted aryl") or substituted with one or more substituents ( "substituted aryl"). In certain embodiments, the aryl group is unsubstituted C6-C 14 aryl. In certain embodiments, the aryl group is substituted C6-C 14 aryl.

[0492] Arylene: As used herein, the term "arylene" refers to an aryl group that is divalent (i.e., has two points of attachment to the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted phenylene or substituted phenylene).

[0493] Carbocyclic: As used herein, "carbocyclic" or "carbocyclic ring" refers to a radical of a non-aromatic ring system having 3 to 10 ring carbon atoms ( "C3-C 10 carbocyclic") and 0 heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ( "C3-C8 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 7 ring carbon atoms ( "C3-C7 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ( "C3-C6 carbocyclic"). In some embodiments, the carbocyclic group has 4 to 6 ring carbon atoms ( "C4-C6 carbocyclic"). In some embodiments, the carbocyclic group has 5 to 6 ring carbon atoms ( "C5-C6 carbocyclic"). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms ( "C5-C 10("carbocyclic"). Exemplary C3-C6 carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C3-C8 carbocyclic groups include, but are not limited to, the aforementioned C3-C6 carbocyclic groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C3-C 10 carbocyclic groups include, but are not limited to, the aforementioned C3-C8 carbocyclic groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), etc. As shown by the foregoing examples, in certain embodiments, the carbocyclic group is either monocyclic ("monocyclic carbocyclic") or polycyclic (e.g., containing a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic carbocyclic") or a tricyclic system ("tricyclic carbocyclic")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclic" also includes ring systems in which the carbocyclic ring defined above is fused to one or more aryl or heteroaryl groups and the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to specify the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclic group is independently unsubstituted ("unsubstituted carbocyclic") or substituted with one or more substituents ("substituted carbocyclic"). In certain embodiments, the carbocyclic group is unsubstituted C3-C 10It is carbocyclic. In certain embodiments, the carbocyclic group is a substituted C3-C 10 It is carbocyclic.

[0494] In some embodiments, "carbocyclic" or "carbocyclic ring" is referred to as "cycloalkyl", that is, a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C3-C 10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C4-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 cycloalkyl"). Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of the cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C3-C6 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C6 cycloalkyl.

[0495] Halogen: As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0496] Heteroalkyl: The term "heteroalkyl" refers to a radical of a branched or unbranched alkyl, alkenyl, or alkynyl group having carbon atoms in addition to a heteroatom independently selected from the group consisting of N, O, S, and P. For example, "heteroalkyl" can mean a branched or unbranched alkyl, alkenyl, or alkynyl group having 1 to 8 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. For example, the term "heteroalkyl" refers to a radical of a branched or unbranched alkyl, alkenyl, or alkynyl group having 1 to 40 carbon atoms in addition to a heteroatom independently selected from the group consisting of N, O, S, and P ( "C1-C 40 heteroalkyl"). In one embodiment, the term "heteroalkyl" refers to a radical of a branched or unbranched alkyl group having 1 to 40 carbon atoms in addition to a heteroatom independently selected from the group consisting of N, O, S, and P ( "C1-C 40"Heteroalkyl"). In one embodiment, "heteroalkyl" can contain from about 1 to about 7 heteroatoms independently selected from the group consisting of N, O, S, and P for every 10 carbons in the "heteroalkyl". In one embodiment, "heteroalkyl" can contain from about 1 to about 5 heteroatoms independently selected from the group consisting of N, O, S, and P for every 10 carbons in the "heteroalkyl". In one embodiment, the heteroatom is independently selected from the group consisting of N, O, or S. In one embodiment, the heteroatom is independently selected from the group consisting of N or O. Heteroalkyl includes tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. The heteroalkyl group may optionally contain a monocyclic, bicyclic, or tricyclic ring, where each ring preferably has from 3 to 8 members. For example, the heteroalkyl group may optionally contain one or more triazole rings. Examples of heteroalkyl include polyethers such as methoxymethyl and ethoxyethyl, and hydrophilic polymers such as polyethylene glycol (PEG).

[0497] Heteroalkylene: As used herein, the term "heteroalkylene" represents the divalent form of the heteroalkyl groups described herein.

[0498] Heteroaryl: As used herein, the term "heteroaryl" is a completely unsaturated heteroatom-containing ring in which at least one ring atom is a heteroatom, including but not limited to, nitrogen and oxygen.

[0499] As used herein, "heteroaryl" also refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms provided in the aromatic ring system and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5- to 14-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valence permits. The heteroaryl polycyclic ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups and the point of attachment is on the heteroaryl ring, in which case the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused to one or more aryl groups and the point of attachment is on either the aryl or heteroaryl ring, in which case the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For a polycyclic heteroaryl group in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., either on the ring bearing the heteroatom (e.g., 2-indolyl) or on the ring containing no heteroatoms (e.g., 5-indolyl).

[0500] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom being independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom being independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom being independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has one or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5- to 6-membered heteroaryl has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. Unless otherwise specified, each instance of the heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0501] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0502] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("3- to 14-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, e.g., bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")). It can be saturated or can contain one or more carbon-carbon double or triple bonds. The heterocyclyl polycyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl ring defined above is fused to one or more carbocyclyl groups and the point of attachment is on either the carbocyclyl or heterocyclyl ring, or a ring system in which the heterocyclyl ring defined above is fused to one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0503] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom being independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5- to 10-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom being independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5- to 8-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) ring heteroatoms, each heteroatom being independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has one or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5- to 6-membered heterocyclyl has one or two ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.

[0504] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0505] Heterocycloalkyl: As used herein, the term "heterocycloalkyl" refers to a non-aromatic ring in which at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. In some embodiments, the heterocycloalkyl group has 3 to 10 ring carbon atoms ("C3-C 10"heterocycloalkyl"). In some embodiments, the heterocycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 heterocycloalkyl"). In some embodiments, the heterocycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 heterocycloalkyl). In some embodiments, the heterocycloalkyl group has 4 to 6 ring carbon atoms ("C4-C6 heterocycloalkyl"). In some embodiments, the heterocycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 heterocycloalkyl"). In some embodiments, the heterocycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 heterocycloalkyl"). Examples of C3-C6 heterocycloalkyl groups include tetrahydropyranyl (C5) and piperazinyl (C4). Unless otherwise specified, each instance of the heterocycloalkyl group is independently unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). In certain embodiments, the heterocycloalkyl group is unsubstituted C3-C6 heterocycloalkyl. In certain embodiments, the heterocycloalkyl group is substituted C3-C6 heterocycloalkyl.

[0506] As understood from the above, alkyl heteroalkyl, alkenyl, alkynyl, acyl, carbocyclic, cycloalkyl, heterocyclic, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted in certain embodiments, as defined herein. Optionally substituted refers to a group that may or may not be substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" heterocycloalkyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group. Generally, the term "substituted" means that at least one hydrogen present on the group is replaced by an acceptable substituent, i.e., a substituent that results in a stable compound, e.g., a compound that does not undergo spontaneous conversion by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when two or more positions in any given structure are substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution by any of the acceptable substituents of organic compounds, among those described herein that result in the formation of stable compounds. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have any suitable substituent described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom and results in the formation of a stable moiety.

[0507] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2, -SO3H, -OH, -ORaa , -ON(R bb )2, -N(R bb )2, -N(R bb )3+X - , -N(OR cc )R bb , -SeH, -SeR aa , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3 - OSi(R aa )3 - C(=S)N(R bb)2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc )、C1~C 10 alkyl, C2~C 10 alkenyl, C2~C 10 alkynyl, C3~C 14 carbocyclic, 3- to 14-membered heterocyclic, C6~C 14 aryl, and 5- to 14-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, or alternatively, two geminal hydrogens on a carbon atom are a group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa, =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by R aa In each case of 10 alkyl, C2 - C 10 alkenyl, C2 - C 10 alkynyl, C3 - C 10 carbocyclic, 3 - to 14 - membered heterocyclic, C6 - C 14 aryl, and 5 - to 14 - membered heteroaryl are independently selected, or two R aa groups are joined to form a 3 - to 14 - membered heterocyclic or 5 - to 14 - membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, R bb In each case of aa is hydrogen, -OH, -OR cc , -N(R aa )2, -CN, -C(=O)R cc , -C(=O)N(R aa )2, -CO2R aa , -SO2R cc , -C(=NR aa )OR cc , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR aa , -SOR cc , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR aa , -P(=O)2R aa , -P(=O)(R cc )2, -P(=O)2N(R cc )2, -P(=O)(NR 10 )2, C1 - C 10 alkyl, C2 - C 10 alkenyl, C2 - C 10Carbocyclic, 3- to 14-membered heterocyclic, C6-C 14 Aryl, and 5- to 14-membered heteroaryl, are independently selected, or two R bb Groups, together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd Groups, R cc In each case, is hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Carbocyclic, 3- to 14-membered heterocyclic, C6-C 14 Aryl, and 5- to 14-membered heteroaryl, are independently selected, or two R cc Groups, together with the heteroatom to which they are attached, form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd Groups, R dd In each case, is halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)Ree , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C1 - C 10 alkyl, C2 - C 10 alkenyl, C2 - C 10 alkynyl, C3 - C 10 carbocyclic, 3 - to 10 - membered heterocyclic, C6 - C 10 aryl, 5 - to 10 - membered heteroaryl, independently selected from, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents may be joined to form =O or =S, R ee In each case, independently, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 carbocyclic, C6-C 10 aryl, 3- to 10-membered heterocyclic, and 3- to 10-membered heteroaryl are independently selected, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, R ff In each case, independently, is hydrogen, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C2-C 10 carbocyclic, 3- to 10-membered heterocyclic, C6-C 10 aryl, and 5- to 10-membered heteroaryl are independently selected, or two R ff groups together with the heteroatom to which they are attached form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, R gg In each case, independently, is halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-C 10 alkyl, -ON(C1-C 10 alkyl)2, -N(C1-C 10 alkyl)2, -N(C1-C 10 alkyl)3+X - 、-NH(C1-C 10 alkyl)2+X - 、-NH2(C1-C 10 alkyl)+X - 、-NH3+X - 、-N(OC1-C 10 alkyl)(C1-C 10(alkyl), -N(OH)(C1-C 10 (alkyl), -NH(OH), -SH, -SC1-C 10 (alkyl), -SS(C1-C 10 (alkyl), -C(=O)(C1-C 10 (alkyl), -CO2H, -CO2(C1-C 10 (alkyl), -OC(=O)(C1-C 10 (alkyl), -OCO2(C1-C 10 (alkyl), -C(=O)NH2, -C(=O)N(C1-C 10 (alkyl)2, -OC(=O)NH(C1-C 10 (alkyl), -NHC(=O)(C1-C 10 (alkyl), -N(C1-C 10 (alkyl)C(=O)(C1-C 10 (alkyl), -NHCO2(C1-C 10 (alkyl), -NHC(=O)N(C1-C 10 (alkyl)2, -NHC(=O)NH(C1-C 10 (alkyl), -NHC(=O)NH2, -C(=NH)O(C1-C 10 (alkyl), -OC(=NH)(C1-C 10 (alkyl), -OC(=NH)OC1-C 10 (alkyl), -C(=NH)N(C1-C 10 (alkyl)2, -C(=NH)NH(C1-C 10 (alkyl), -C(=NH)NH2, -OC(=NH)N(C1-C 10 (alkyl)2, -OC(NH)NH(C1-C 10 (alkyl), -OC(NH)NH2, -NHC(NH)N(C1-C 10 (alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-C 10 (alkyl), -SO2N(C1-C 10 (alkyl)2, -SO2NH(C1-C 10 (alkyl), -SO2NH2, -SO2(C1-C 10 (alkyl), -SO2O(C1-C 10 (alkyl), -OSO2(C1-C6 alkyl), -SO(C1-C6 alkyl), -Si(C1-C 10(alkyl)3, -OSi(C1-C6 alkyl)3, -C(=S)N(C1-C 10 alkyl)2, C(=S)NH(C1-C 10 alkyl), C(=S)NH2, -C(=O)S(C1-C6 alkyl), -C(=S)S(C1-C6 alkyl), -SC(=S)S(C1-C6 alkyl), -P(=O)2(C1-C 10 alkyl), -P(=O)(C1-C 10 alkyl)2, -OP(=O)(C1-C 10 alkyl)2, -OP(=O)(OC1-C 10 alkyl)2, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 carbocyclic, C6-C 10 aryl, 3- to 10-membered heterocyclic, 5- to 10-membered heteroaryl, or two geminal R gg substituents can be joined to form =O or =S; wherein X - is a counterion.

[0508] As used herein, the terms "halo" or "halogen" refer to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0509] As used herein, a "counterion" is a negatively charged group that associates with a positively charged quaternary amine to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HSO4 -, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanolate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.) are included.

[0510] The nitrogen atom may be substituted or unsubstituted as long as the valence allows, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -CH2(CO2H), -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 carbocyclic, 3- to 14-membered heterocyclic, C6-C 14 aryl, and 5- to 14-membered heteroaryl are included, or two Rscc The groups, together with the N atom to which they are attached, form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, where R aa , R bb , R cc , and R dd are as defined above.

[0511] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0512] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyl-oxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0513] A nitrogen protecting group such as a carbamate group (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyldamansylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acetyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclophenylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamide)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isoborolinylcarbamate, isobutinylcarbamate, isonicotinylcarbamate, p-(p’-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-l-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.,

[0514] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide, but are not limited thereto.,

[0515] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-, 3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberlylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (phenylfluorenylamine, PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (ferrocenylmethylamino, Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylideneamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylboric acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramidate, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys), but are not limited thereto.,

[0516] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is hereby incorporated by reference in its entirety.,

[0517] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-penten yloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl, S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-oxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate ((trimethylsilyl)ethyl carbonate, TMSEC), 2-(phenylsulfonyl)ethyl carbonate (phenylsulfonyl)ethyl carbonate, Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (tosylate, Ts) are mentioned, but not limited thereto.,

[0518] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is hereby incorporated by reference.

[0519] Exemplary sulfur protecting groups include, but are not limited to, alkyl, benzyl, p - methoxybenzyl, 2,4,6 - trimethylbenzyl, 2,4,6 - trimethoxybenzyl, o - hydroxybenzyl, p - hydroxybenzyl, o - acetoxybenzyl, p - acetoxybenzyl, p - nitrobenzyl, 4 - picolyl, 2 - quinolinylmethyl, 2 - picolyl N - oxide, 9 - anthrylmethyl, 9 - fluorenylmethyl, xanthenyl, ferrocenylmethyl, diphenylmethyl, bis(4 - methoxyphenyl)methyl, 5 - dibenzosuberil, triphenylmethyl, diphenyl - 4 - pyridylmethyl, phenyl, 2,4 - dinitrophenyl, t - butyl, 1 - adamantyl, methoxymethyl (methoxymethyl, MOM), isobutoxymethyl, benzyloxymethyl, 2 - tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl, thiazolidino, acetamidomethyl, trimethylacetamidomethyl, benzamidomethyl, allyloxycarbonylaminomethyl, phenylacetamidomethyl, phthalimidomethyl, acetylmethyl, carboxymethyl, cyanomethyl, (2 - nitro - 1 - phenyl)ethyl, 2 - (2,4 - dinitrophenyl)ethyl, 2 - cyanoethyl, 2 - (trimethylsilyl)ethyl, 2,2 - bis(carbethoxy)ethyl, (1 - m - nitrophenyl - 2 - benzoyl)octyl, 2 - phenylsulfonylethyl, 2 - (4 - methylphenylsulfonyl)-2 - methylprop - 2 - yl, acetyl, benzoyl, trifluoroacetyl, N - [[(p - biphenylyl)isopropoxy]carbonyl]-N - methyl]-γ - aminothiobutyrate, 2,2,2 - trichloroethoxycarbonyl, t - butoxycarbonyl, benzyloxycarbonyl, p - methoxybenzyloxycarbonyl, N - ethyl, N - methoxymethyl, sulfonate, sulfenylthiocarbonate, 3 - nitro - 2 - pyridinesulfenyl sulfide, oxathiolone.

[0520] In one embodiment, the optionally substituted heteroalkyl is unsubstituted or substituted with one or more substituents independently selected from -CONH2, -CO2H, -COCH2NH2, -NH2, -NH(C=NH)NH2, or =O (i.e., two geminal hydrogens on the carbon atom of the heteroalkyl are replaced by the group =O). In one embodiment, the optionally substituted heteroalkyl is unsubstituted. In one embodiment, the optionally substituted heteroalkyl is substituted with one or more substituents independently selected from -CONH2, -CO2H, -COCH2NH2, -NH2, -NH(C=NH)NH2, or =O (i.e., two geminal hydrogens on the carbon atom of the heteroalkyl are replaced by the group =O).

[0521] III. Compounds The present invention relates to novel cyclic peptide inhibitors of interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts, solvates, or forms thereof.

[0522] In particular, the present invention relates to cyclic peptide inhibitors of interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, including those having the structures specified in Table 1A, Table 1B, Table 1C, Table 1D, or Table 1F herein.

[0523] In one aspect, the cyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound, or a pharmaceutically acceptable salt thereof, has the structure of the compound of Table 1A.

[0524] In another aspect, the cyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound or a pharmaceutically acceptable salt thereof has the structure of the compound of Table 1B.

[0525] In another aspect, the cyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound or a pharmaceutically acceptable salt thereof has the structure of the compound of Table 1C.

[0526] In another aspect, the cyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound or a pharmaceutically acceptable salt thereof has the structure of the compounds in Table 1D.

[0527] In another aspect, the cyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound or a pharmaceutically acceptable salt thereof has the structure of the compounds in Table 1E.

[0528] In another aspect, the cyclic peptide inhibitor compound of the interleukin-23 receptor (IL-23R) compound or a pharmaceutically acceptable salt thereof has the structure of the compounds in Table 1F.

[0529] [Table 1-1]

[0530] [Table 1-2]

[0531] [Table 1-3]

[0532] [Table 1-4]

[0533] [Table 1-5]

[0534] [Table 1-6]

[0535] [Table 1-7]

[0536]

Table 1-8

[0537]

Table 1-9

[0538]

Table 1-10

[0539]

Table 1-11

[0540]

Table 1-12

[0541]

Table 1-13

[0542]

Table 1-14

[0543]

Table 1-15

[0544]

Table 1-16

[0545]

Table 1-17

[0546]

Table 1-18

[0547]

Table 1-19

[0548]

Table 1-20

[0549]

Table 1-21

[0550]

Table 1-22

[0551]

Table 1-23

[0552]

Table 1-24

[0553]

Table 1-25

[0554]

Table 1-26

[0555]

Table 1-27

[0556]

Table 1-28

[0557]

Table 1-29

[0558]

Table 1-30

[0559]

Table 1-31

[0560]

Table 1-32

[0561]

Table 1-33

[0562]

Table 1-34

[0563]

Table 1-35

[0564]

Table 1-36

[0565]

Table 1-37

[0566]

Table 1-38

[0567]

Table 1-39

[0568]

Table 1-40

[0569]

Table 1-41

[0570]

Table 1-42

[0571]

Table 1-43

[0572]

Table 1-44

[0573]

Table 1-45

[0574]

Table 1-46

[0575]

Table 1-47

[0576]

Table 1-48

[0577]

Table 1-49

[0578]

Table 1-50

[0579]

Table 1-51

[0580]

Table 1-52

[0581]

Table 1-53

[0582]

Table 1-54

[0583]

Table 1-55

[0584]

Table 1-56

[0585]

Table 1-57

[0586]

Table 1-58

[0587]

Table 1-59

[0588]

Table 1-60

[0589]

Table 1-61

[0590]

Table 1-62

[0591]

Table 1-63

[0592]

Table 1-64

[0593]

Table 1-65

[0594]

Table 1-66

[0595]

Table 1-67

[0596]

Table 1-68

[0597]

Table 1-69

[0598]

Table 1-70

[0599]

Table 1-71

[0600]

Table 1-72

[0601]

Table 1-73

[0602]

Table 1-74

[0603]

Table 1-75

[0604]

Table 1-76

[0605]

Table 1-77

[0606]

Table 1-78

[0607]

Table 1-79

[0608]

Table 1-80

[0609]

Table 1-81

[0610]

Table 1-82

[0611]

Table 1-83

[0612]

Table 1-84

[0613]

Table 1-85

[0614]

Table 1-86

[0615]

Table 1-87

[0616]

Table 1-88

[0617]

Table 1-89

[0618]

Table 1-90

[0619]

Table 1-91

[0620]

Table 1-92

[0621]

Table 1-93

[0622]

Table 1-94

[0623]

Table 1-95

[0624]

Table 1-96

[0625]

Table 1-97

[0626]

Table 1-98

[0627]

Table 1-99

[0628]

Table 1-100

[0629]

Table 1-101

[0630]

Table 1-102

[0631]

Table 1-103

[0632]

Table 1-104

[0633]

Table 1-105

[0634]

Table 1-106

[0635]

Table 1-107

[0636]

Table 1-108

[0637]

Table 1-109

[0638]

Table 1-110

[0639]

Table 1-111

[0640]

Table 1-112

[0641]

Table 1-113

[0642]

Table 1-114

[0643]

Table 1-115

[0644]

Table 1-116

[0645]

Table 1-117

[0646]

Table 1-118

[0647]

Table 1-119

[0648]

Table 1-120

[0649]

Table 1-121

[0650]

Table 1-122

[0651]

Table 1-123

[0652]

Table 1-124

[0653]

Table 1-125

[0654]

Table 1-126

[0655]

Table 1-127

[0656]

Table 1-128

[0657]

Table 1-129

[0658]

Table 1-130

[0659]

Table 1-131

[0660]

Table 1-132

[0661]

Table 1-133

[0662]

Table 1-134

[0663]

Table 1-135

[0664]

Table 1-136

[0665]

Table 1-137

[0666]

Table 1-138

[0667]

Table 1-139

[0668]

Table 1-140

[0669]

Table 1-141

[0670]

Table 1-142

[0671]

Table 1-143

[0672]

Table 1-144

[0673]

Table 1-145

[0674]

Table 1-146

[0675]

Table 1-147

[0676]

Table 1-148

[0677]

Table 1-149

[0678]

Table 1-150

[0679]

Table 1-151

[0680]

Table 1-152

[0681]

Table 1-153

[0682]

Table 1-154

[0683]

Table 1-155

[0684]

Table 1-156

[0685]

Table 1-157

[0686]

Table 1-158

[0687]

Table 1-159

[0688]

Table 1-160

[0689]

Table 1-161

[0690]

Table 1-162

[0691]

Table 1-163

[0692]

Table 1-164

[0693]

Table 1-165

[0694]

Table 1-166

[0695]

Table 1-167

[0696]

Table 1-168

[0697]

Table 1-169

[0698]

Table 1-170

[0699]

Table 1-171

[0700]

Table 1-172

[0701]

Table 1-173

[0702]

Table 1-174

[0703]

Table 1-175

[0704]

Table 1-176

[0705]

Table 1-177

[0706]

Table 1-178

[0707]

Table 1-179

[0708]

Table 1-180

[0709]

Table 1-181

[0710]

Table 1-182

[0711]

Table 1-183

[0712]

Table 1-184

[0713]

Table 1-185

[0714]

Table 1-186

[0715]

Table 1-187

[0716]

Table 1-188

[0717]

Table 1-189

[0718]

Table 1-190

[0719]

Table 1-191

[0720]

Table 1-192

[0721]

Table 1-193

[0722]

Table 1-194

[0723]

Table 1-195

[0724]

Table 1-196

[0725]

Table 1-197

[0726]

Table 1-198

[0727]

Table 1-199

[0728]

Table 1-200

[0729]

Table 1-201

[0730]

Table 1-202

[0731]

Table 1-203

[0732]

Table 1-204

[0733]

Table 1-205

[0734]

Table 1-206

[0735]

Table 1-207

[0736]

Table 1-208

[0737]

Table 1-209

[0738]

Table 1-210

[0739]

Table 1-211

[0740]

Table 1-212

[0741]

Table 1-213

[0742]

Table 1-214

[0743]

Table 1-215

[0744]

Table 1-216

[0745]

Table 1-217

[0746]

Table 1-218

[0747]

Table 1-219

[0748]

Table 1-220

[0749]

Table 1-221

[0750]

Table 1-222

[0751]

Table 1-223

[0752]

Table 1-224

[0753]

Table 1-225

[0754]

Table 1-226

[0755]

Table 1-227

[0756]

Table 1-228

[0757]

Table 1-229

[0758]

Table 1-230

[0759]

Table 1-231

[0760]

Table 1-232

[0761]

Table 1-233

[0762]

Table 1-234

[0763]

Table 1-235

[0764]

Table 1-236

[0765]

Table 1-237

[0766]

Table 1-238

[0767]

Table 1-239

[0768]

Table 1-240

[0769]

Table 1-241

[0770]

Table 1-242

[0771]

Table 1-243

[0772]

Table 1-244

[0773]

Table 1-245

[0774]

Table 1-246

[0775]

Table 1-247

[0776]

Table 1-248

[0777]

Table 1-249

[0778]

Table 1-250

[0779]

Table 1-251

[0780]

Table 1-252

[0781]

Table 1-253

[0782]

Table 1-254

[0783]

Table 1-255

[0784]

Table 1-256

[0785]

Table 1-257

[0786]

Table 1-258

[0787]

Table 1-259

[0788]

Table 1-260

[0789]

Table 1-261

[0790]

Table 1-262

[0791]

Table 1-263

[0792]

Table 1-264

[0793]

Table 1-265

[0794]

Table 1-266

[0795]

Table 1-267

[0796]

Table 1-268

[0797]

Table 1-269

[0798]

Table 1-270

[0799]

Table 1-271

[0800]

Table 1-272

[0801]

Table 1-273

[0802]

Table 1-274

[0803]

Table 1-275

[0804]

Table 1-276

[0805]

Table 2-1

[0806]

Table 2-2

[0807]

Table 2-3

[0808]

Table 2-4

[0809]

Table 2-5

[0810]

Table 2-6

[0811]

Table 2-7

[0812]

Table 2-8

[0813]

Table 2-9

[0814]

Table 2-10

[0815]

Table 3-1

[0816]

Table 3-2

[0817]

Table 3-3

[0818]

Table 3-4

[0819]

Table 3-5

[0820]

Table 3-6

[0821]

Table 3-7

[0822]

Table 3-8

[0823]

Table 4-1

[0824]

Table 4-2

[0825]

Table 5-1

[0826]

Table 5-2

[0827]

Table 5-3

[0828]

Table 5-4

[0829]

Table 5-5

[0830]

Table 6-1

[0831]

Table 6-2

[0832]

Table 6-3

[0833]

Table 6-4

[0834]

Table 6-5

[0835]

Table 6-6

[0836]

Table 6-7

[0837]

Table 6-8

[0838]

Table 6-9

[0839]

Table 6-10

[0840]

Table 6-11

[0841] [Table 6-12]

[0842] [Table 6-13]

[0843] [Table 6-14]

[0844] [Table 6-15]

[0845] [Table 6-16]

[0846] (Continued from Table 1F)

[0847] [Table 6-17]

[0848] [Table 6-18]

[0849] [Table 6-19]

[0850] [Table 6-20]

[0851]

Table 6-21

[0852]

Table 6-22

[0853]

Table 6-23

[0854]

Table 6-24

[0855]

Table 6-25

[0856]

Table 6-26

[0857]

Table 6-27

[0858]

Table 6-28

[0859]

Table 6-29

[0860]

Table 6-30

[0861]

Table 6-31

[0862]

Table 6-32

[0863]

Table 6-33

[0864]

Table 6-34

[0865]

Table 6-35

[0866]

Table 6-36

[0867]

Table 6-37

[0868]

Table 6-38

[0869]

Table 6-39

[0870]

Table 6-40

[0871]

Table 6-41

[0872]

Table 6-42

[0873]

Table 6-43

[0874]

Table 6-44

[0875]

Table 6-45

[0876]

Table 6-46

[0877]

Table 6-47

[0878]

Table 6-48

[0879]

Table 6-49

[0880]

Table 6-50

[0881]

Table 6-51

[0882]

Table 6-52

[0883]

Table 6-53

[0884]

Table 6-54

[0885]

Table 6-55

[0886]

Table 6-56

[0887]

Table 6-57

[0888]

Table 6-58

[0889]

Table 6-59

[0890]

Table 6-60

[0891]

Table 6-61

[0892]

Table 6-62

[0893]

Table 6-63

[0894]

Table 6-64

[0895]

Table 6-65

[0896]

Table 6-66

[0897]

Table 6-67

[0898]

Table 6-68

[0899]

Table 6-69

[0900]

Table 6-70

[0901]

Table 6-71

[0902]

Table 6-72

[0903]

Table 6-73

[0904]

Table 6-74

[0905]

Table 6-75

[0906]

Table 6-76

[0907]

Table 6-77

[0908]

Table 6-78

[0909]

Table 6-79

[0910]

Table 6-80

[0911]

Table 6-81

[0912]

Table 6-82

[0913]

Table 6-83

[0914]

Table 6-84

[0915]

Table 6-85

[0916]

Table 6-86

[0917]

Table 6-87

[0918] ·Synthesis The compounds described herein can be synthesized by many techniques known to those skilled in the art. In certain embodiments, the monomer subunits are synthesized and purified using the techniques described in the accompanying examples. In some embodiments, the present invention provides a method for generating a compound of the present invention (or its monomer subunit), the method comprising chemically synthesizing a peptide having an amino acid sequence described herein, including but not limited to any of the amino acid sequences shown in the compounds of Formulas (I)-(VI), Table 1A, Table 1B, Table 1C, Table 1D, and Table 1E herein. In some embodiments, a portion of the peptide is recombinantly synthesized instead of being chemically synthesized. In some embodiments, the method for generating the compound further comprises cyclizing the compound precursor after the constituent subunits are coupled. In certain embodiments, cyclization is achieved via any of the various methods described herein.

[0919] Substituted tryptophan can be prepared by any suitable route. The preparation of certain substituted tryptophans, including those substituted at the 7-position such as 7-ethyl-L-tryptophan, is described, for example, in International Publication No. WO 2021 / 146441 (A1).

[0920] The present invention further describes the synthesis of compounds of Formulas (I)-(X) and compounds described herein such as those in Table 1A, Table 1A, Table 1B, Table 1C, Table 1D, and Table 1E. In some embodiments, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently bonded to each other to form a compound of the present invention. In some embodiments, one or more of the amino acid residues or amino acid monomers are covalently bonded to each other, lipidated at an intermediate oligomer stage, and then additional amino acids are bonded and cyclized to form a compound of the present invention. In some embodiments, a cyclic peptide is synthesized and then lipidated to form a compound of the present invention. Exemplary synthetic methods are described in the examples.

[0921] The present invention further describes the synthesis of compounds of formula (I) to formula (X), and compounds described herein such as the compounds of Table 1A, Table 1B, Table 1C, Table 1D, and Table 1E. Exemplary synthetic methods are described in the Examples.

[0922] IV. Pharmaceutical Compositions The present invention relates to a pharmaceutical composition comprising an IL-23R inhibitor of the present invention. The present invention includes a pharmaceutical composition comprising one or more inhibitors of the present invention and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutically acceptable carrier, diluent, or excipient can be a solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation aid. For example, the action of microorganisms can be reliably prevented by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc.

[0923] The pharmaceutical composition can be administered orally, parenterally, intravesically, vaginally, intraperitoneally, rectally, topically (by powder, ointment, eye drops, suppository, or transdermal patch), by inhalation (such as intranasal spray), into the eye (such as intravitreally), or into the oral cavity. As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intra-articular injections and infusions. Thus, in certain embodiments, the composition is formulated for delivery by any of these routes of administration. The pharmaceutical composition can be formulated for oral use and administered orally. The pharmaceutical composition can be formulated for parenteral use and administered.

[0924] In certain embodiments, the IL-23R inhibitors of the invention are suspended in a sustained release matrix. As used herein, a sustained release matrix is a matrix made of a material, usually a polymer, that is degradable by enzymatic hydrolysis or acid-base hydrolysis, or by dissolution. When inserted into the body, the matrix is acted upon by enzymes and body fluids. The sustained release matrix is preferably selected from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolides (polymers of glycolic acid), polylactide-co-glycolides (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicones. One embodiment of the biodegradable matrix is a matrix of any one of polylactide, polyglycolide, or polylactide-co-glycolide (a copolymer of lactic acid and glycolic acid).

[0925] The IL-23R inhibitors of the present invention can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, in the neutral form. Pharmaceutically acceptable salts are non-toxic salts of the neutral form of the compounds having the desired pharmacological activity in the neutral form. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. Lists of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st nd Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0926] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 +Salts derived from suitable bases such as (wherein X is C1-C4 alkyl) are also included. Base addition salts such as sodium salts or potassium salts are also included. One of ordinary skill in the art will recognize that while quaternary ammonium salts can be incorporated into the structure of the compounds of formulas (I)-(VI), the remaining basic residues can be combined with sites of additional salts in the acid form. Thus, the compounds of formulas (I)-(VI) of the present invention can include quaternary ammonium salts at certain positions, but can also include acid addition salts at any basic site on the molecule.

[0927] The present invention relates to a pharmaceutical composition comprising an IL-23R inhibitor of the present invention, or a pharmaceutically acceptable salt, isomer, or mixture thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom may be replaced with deuterium atoms or D, and n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and, thus, can be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced with deuterium.

[0928] Examples of isotopes that can be incorporated into the disclosed compounds also include 2 H, 3 H, 11 C, 13 C, 14 C, 13 N 、15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S,18 F, 36 Cl, 123 I, and 125 each isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Positron-emitting isotopes, for example, 11 C, 18 F, 15 O, and 13 substitution with N may be useful in positron emission topography (PET) studies for investigating substrate receptor occupancy. Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the examples below using appropriate isotope-labeled reagents in place of the unlabeled reagents previously used.

[0929] In certain embodiments, a pharmaceutical composition for parenteral injection comprises a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension, or emulsion, or sterile powder for reconstitution into a sterile injection solution or dispersion immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose, and suitable mixtures thereof, β-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. For example, the use of coating materials such as lecithin, maintenance of the required particle size in the case of dispersions, and the use of surfactants can maintain appropriate fluidity. The composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of injectable pharmaceutical forms can be brought about by including agents that delay absorption such as aluminum monostearate and gelatin.

[0930] Injectable depot forms include those prepared by forming a microencapsulation matrix of the peptide inhibitor in one or more biodegradable polymers such as polylactide - polyglycolide, poly(orthoesters), poly(anhydrides), and (poly)glycols such as PEG. Depending on the ratio of the peptide to the polymer and the nature of the specific polymer used, the release rate of the peptide inhibitor can be controlled. Depot injection formulations can also be prepared by encapsulating the peptide inhibitor in liposomes or microemulsions that are compatible with body tissues.

[0931] Injectable formulations can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media immediately prior to use.

[0932] Topical administration includes administration to the skin or mucosa, including the surfaces of the lung and eye. Compositions for topical lung administration, including those for inhalation and intranasal use, can include solutions and suspensions in aqueous and non - aqueous formulations and can be prepared as dry powders, which may or may not be pressurized. In non - pressurized powder compositions, the active ingredient may be in a finely divided form and may be used in admixture with a pharmaceutically acceptable inert carrier of larger size, for example, particles having a size up to 100 micrometers in diameter. Suitable inert carriers include sugars such as lactose.

[0933] Alternatively, the pharmaceutical compositions of the invention may be pressurized and contain a compressed gas such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and indeed the entire composition may be such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surfactant such as a liquid or solid non - ionic surfactant or may be a solid anionic surfactant. It is preferred to use a solid anionic surfactant in the form of a sodium salt.

[0934] A further form of topical administration is administration to the eye. The peptide inhibitor of the present invention is maintained in contact with the eye surface for a period sufficient for the peptide inhibitor to penetrate the cornea and internal regions of the eye, such as the anterior chamber, posterior chamber, vitreous, aqueous humor, vitreous humor, cornea, iris / ciliary body, lens, choroid / retina, and sclera. It can be delivered in a pharmaceutically acceptable ophthalmic vehicle. The pharmaceutically acceptable ophthalmic vehicle can be, for example, an ointment, a vegetable oil, or an encapsulating material. Alternatively, the peptide inhibitor of the present invention may be directly injected into the vitreous and aqueous humor.

[0935] Compositions for rectal or vaginal administration preferably include a suppository prepared by mixing a peptide inhibitor of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax (which is solid at room temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound).

[0936] The peptide inhibitor of the present invention may also be administered in liposomes or other lipid-based carriers. As is known in the art, liposomes generally are derived from phospholipids or other lipid substances. Liposomes are formed by a monolayer or multilayer hydrated liquid crystal dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, metabolizable lipid capable of forming liposomes can be used. The composition in liposome form may contain, in addition to the peptide inhibitor of the present invention, stabilizers, preservatives, excipients, and the like. In certain embodiments, the lipids include phospholipids including both natural and synthetic phosphatidylcholines (lecithins) and serine. Methods for forming liposomes are known in the art.

[0937] Pharmaceutical compositions suitable for parenteral administration in the methods or uses described herein may generally include a sterile aqueous solution and / or suspension of an IL-23R inhibitor that is isotonic with the recipient's blood, using, for example, sodium chloride, glycerin, glucose, mannitol, sorbitol, and the like.

[0938] The present invention provides a pharmaceutical composition for oral delivery. The compositions and peptide inhibitors of the present invention can be prepared for oral administration according to any of the methods, techniques, and / or delivery vehicles described herein. Further, one of ordinary skill in the art will understand that the peptide inhibitors of the present invention, although not disclosed herein, are well known in the art and can be modified or incorporated into systems or delivery vehicles that are suitable for use in the oral delivery of peptides.

[0939] Formulations for oral administration can include adjuvants (e.g., resorcinol and / or nonionic surfactants such as polyoxyethylene oleyl ether and n-ether) for artificially increasing the permeability of the intestinal wall, and / or enzyme inhibitors (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF), or trasylol) for inhibiting enzymatic degradation. In certain embodiments, peptide inhibitors in solid dosage forms for oral administration can be mixed with at least one additive such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. These dosage forms for oral administration can also contain other types of additives, such as inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavoring agents, or fragrances.

[0940] In certain embodiments, an oral dosage form or unit dose suitable for use with the peptide inhibitors of the present invention can include a mixture of the peptide inhibitor and non-drug components or excipients, as well as other non-reusable materials that can be considered as either components or packaging. The oral composition can include at least one of liquid, solid, and semi-solid dosage forms. In some embodiments, there is provided an oral dosage form comprising an effective amount of a peptide inhibitor and including at least one of pills, tablets, capsules, gels, pastes, beverages, syrups, ointments, and suppositories. In some cases, there is provided an oral dosage form designed and configured to achieve delayed release of the peptide inhibitor in the small intestine and / or colon of a subject.

[0941] Tablets may contain excipients, glidants, fillers, binders, etc. Aqueous compositions are prepared in a sterile form and are generally isotonic if delivery by means other than oral administration is intended. The composition may optionally contain excipients such as those described in "Handbook of Pharmaceutical Excipients" (1986). Examples of excipients include ascorbic acid and other antioxidants, chelating agents (e.g., EDTA), carbohydrates (e.g., dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.). The pH of the composition is, for example, in the range of about 3 to about 11. The pH of the composition can be, for example, in the range of about 5 to about 7 or about 7 to about 10.

[0942] The oral pharmaceutical composition that may contain the IL-23R inhibitor of the present invention may include an enteric coating designed to delay the release of the IL-23R inhibitor in the small intestine. The present invention relates to a pharmaceutical composition containing the IL-23R inhibitor of the present invention and a protease inhibitor such as aprotinin in a sustained-release pharmaceutical formulation. The pharmaceutical composition (e.g., an oral pharmaceutical composition) may include an enteric coating that is soluble in gastric juice at a pH of about 5.0 or higher. Such enteric coatings may include derivatives of cellulose including hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, and polymers having dissociable carboxylic acid groups such as similar derivatives of cellulose and other carbohydrate polymers.

[0943] The IL-23R inhibitor-containing oral pharmaceutical composition of the present invention containing an IL-23R inhibitor may include an enteric coating designed to protect and release the pharmaceutical composition in a controlled manner within the lower digestive system of a subject and to avoid systemic side effects. In addition to the enteric coating, the peptide inhibitor of the present invention can be encapsulated, coated, bound, or otherwise associated within any suitable oral drug delivery system or component. For example, in some embodiments, the IL-23R inhibitor of the present invention is provided in a lipid delivery system including at least one of a polymeric hydrogel, nanoparticles, microspheres, micelles, and other lipid-based systems.

[0944] To overcome the problem of peptide degradation of the IL-23R inhibitor of the present invention in the small intestine, the pharmaceutical composition may include a hydrogel polymer delivery system in which the peptide inhibitor of the present invention is contained, whereby the hydrogel polymer protects the IL-23R inhibitor from proteolysis in the small intestine and / or colon. The IL-23R inhibitor can be further formulated to be compatible for use with a delivery system designed to increase the dissolution rate and enhance the intestinal absorption of the peptide. These methods include the use of liposomes, micelles, and nanoparticles to increase the GI tract permeability of the peptide.

[0945] To provide a pharmaceutical for oral delivery, various biological response systems may be combined with one or more IL-23R inhibitors of the present invention. For example, the IL-23R inhibitor of the present invention may be used in combination with a biological response system such as a hydrogel and a mucoadhesive polymer having a hydrogen bonding group (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan, and alginate) to provide a therapeutic agent for oral administration.

[0946] In certain embodiments, the pharmaceutical compositions and formulations may comprise an IL-23R inhibitor of the present invention and one or more absorption enhancers, enzyme inhibitors, or mucoadhesive polymers. In one embodiment, the absorption enhancer may be an intestinal permeation enhancer.

[0947] The IL-23R inhibitor of the present invention may be formulated in a formulation vehicle such as an emulsion, liposome, microsphere, or nanoparticle.

[0948] The present invention provides a method of treating a subject with an IL-23R inhibitor of the present invention having an increased half-life. In one aspect, the present invention provides a peptide inhibitor having a half-life of at least several hours to 1 day in vitro or in vivo (e.g., when administered to a human subject) sufficient to administer a therapeutically effective amount once daily (q.d.) or twice daily (b.i.d.). In certain embodiments, the IL-23R inhibitor has a half-life of at least 3 days sufficient to administer a therapeutically effective amount once weekly (q.w.). In certain embodiments, the IL-23R inhibitor has a half-life of at least 8 days sufficient to administer a therapeutically effective amount once every two weeks (b.i.w.) or once monthly. In certain embodiments, the IL-23R inhibitor is derivatized or modified to have a longer half-life compared to an underivatized or unmodified peptide inhibitor. In certain embodiments, the IL-23R inhibitor comprises one or more chemical modifications to increase the serum half-life.

[0949] When used in at least one of the therapeutic or delivery systems described herein, the peptide inhibitors of the invention can be used in pure form or, if such form exists, in pharmaceutically acceptable salt form.

[0950] The total daily dosage of the IL-23R inhibitors and compositions of the invention can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular subject depends on a variety of factors including: a) the disorder being treated and the severity of the disorder; b) the activity of the specific compound used; c) the specific composition used, the age, weight, general health, sex, and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific peptide inhibitor used; e) the duration of the treatment; f) drugs used in combination with or concurrently with the specific peptide inhibitor used, and similar factors well known in the medical arts.

[0951] In certain embodiments, the total daily dosage of the IL-23R inhibitors of the invention administered to a human or other mammalian host in a single or divided dose can be, for example, in an amount of 0.0001 to 300 mg / kg (body weight) per day or 1 to 300 mg / kg (body weight) per day.

[0952] The compositions may conveniently be provided in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Techniques and compositions are generally found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of associating the active ingredient with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0953] Compositions suitable for oral administration can be provided as individual units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as water-in-oil or oil-in-water liquid emulsions. The active ingredient can also be administered as a bolus, lozenge or paste. The active ingredient may be administered as a buccal or sublingual preparation. The buccal or sublingual preparation may contain the active ingredient in a matrix that releases the active ingredient for transport through the oral mucosa and / or sublingual mucosa. The buccal or sublingual preparation may further comprise a rate-controlling matrix that releases the active compound at a predetermined rate for transport through the oral mucosa and / or sublingual mucosa. The buccal or sublingual preparation may further comprise one or more compounds selected from the group consisting of (i) taste masking agents, (ii) enhancers, (iii) complexing agents, and mixtures thereof; and (iv) other pharmaceutically acceptable carriers and / or excipients. The enhancer may be a permeation enhancer.

[0954] Tablets are optionally made by compression or molding, together with one or more accessory ingredients. Compressed tablets can be prepared by mixing the active ingredient in a free-flowing form such as powder or granules, optionally with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent, and compressing with a suitable machine. Molded tablets can be produced by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent with a suitable machine. Tablets can optionally be coated or scored and can optionally be formulated to provide for slow or controlled release of the active ingredient from the tablet.

[0955] V. Non-invasive detection of enteritis The IL-23R inhibitor of the present invention can be used for the detection, evaluation, and diagnosis of enteritis by microPET imaging, and the peptide inhibitor is labeled with a chelating group or a detectable label as part of a non-invasive diagnostic procedure. In certain embodiments, the IL-23R inhibitor of the present invention is conjugated with a bifunctional chelating agent. In certain embodiments, the IL-23R inhibitor of the present invention is radiolabeled. The labeled IL-23R inhibitor is then orally or rectally administered to a subject. In certain embodiments, the IL-23R inhibitor is included in drinking water. Following the uptake of the IL-23R inhibitor, microPET imaging can be used to visualize inflammation throughout the intestine and digestive tract of the subject.

[0956] VI. Methods of Treatment and / or Use The present invention relates to a method for treating a subject suffering from a condition or disorder associated with IL-23 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), the method comprising administering to the subject an IL-23R inhibitor disclosed herein. In one aspect, the present invention relates to a method for treating a subject suffering from a condition or disorder characterized by inappropriate, disordered, or increased IL-23 or IL-23R activity or signaling, the method comprising administering to the individual a peptide inhibitor of the present invention in an amount sufficient to (partially or completely) inhibit the binding of IL-23 to IL-23R in the subject. Inhibition of the binding of IL-23 to IL-23R can occur in a specific organ or tissue of the subject, such as the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels.

[0957] The present invention relates to a method comprising providing the peptide inhibitor described herein to a subject in need thereof. The subject in need thereof can be a subject that has been diagnosed or determined to be at risk of developing a disease or disorder associated with IL-23 / IL-23R. The subject can be a mammal. The subject can particularly be a human.

[0958] Diseases or disorders treatable by treatment with the IL-23R inhibitor of the present invention include autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, ulcerative colitis, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In particular, the disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne inversa, ulcerative colitis, Crohn's disease, celiac disease (nontropical sprue), enteropathy associated with seronegative arthritis, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, radiation- or chemotherapy-associated colitis, colitis associated with disorders of innate immunity such as leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, cystitis, cystitis occurring after rectal colectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, virus-related enteropathy, pericholangitis, chronic bronchitis, chronic rhinosinusitis, asthma, uveitis, or graft-versus-host disease.

[0959] The present invention relates to a method or use of an IL-23R inhibitor for treating a target inflammatory disease, comprising administering to the target a therapeutically effective amount of the IL-23R inhibitor of the present invention or a pharmaceutically acceptable solvate or salt thereof, or a composition disclosed herein comprising the IL-23 inhibitor of the present invention. In some embodiments, the present invention provides a method for treating a target inflammatory disease, comprising administering to the target a therapeutically effective amount of the IL-23R inhibitor of the present invention or a pharmaceutically acceptable solvate or salt thereof, or a composition of the present invention. Inflammatory diseases suitable for treatment with the compounds of the present invention or pharmaceutically acceptable salts or compositions thereof may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA). The inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis. The inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated may be psoriasis. The inflammatory disease to be treated may be psoriatic arthritis. The inflammatory disease to be treated may be IBD.

[0960] The present invention relates to a method for performing it in a subject in need of treatment for an inflammatory disease, comprising administering to the subject an IL-23R inhibitor disclosed herein (e.g., any of the peptide inhibitors or IL-23R of Formulas (I)-(VI) or Tables 1A-1E). The inflammatory disease may be IBD, Crohn's disease or ulcerative colitis. In one embodiment, IBD may be ulcerative colitis. In one embodiment, IBD may be Crohn's disease. In one embodiment, the inflammatory disease may be psoriasis (PsO) or psoriatic arthritis (PsA).

[0961] The present invention relates to a method for treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject an IL-23R inhibitor of any one of formulas I-X) or Tables ...

Claims

1. A cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, comprising the amino acid sequence of the following formula (A): Z ３ -Z ４ -Z ５ -Z ６ -Z ７ -Z ８ -Z ９ -Z １０ -Z １１ -Z １２ -Z １３ -Z １４ -Z １５ -Z １６ (A)、 During the ceremony, Position Z ３ The amino acid residue is either absent or an r residue. Position Z ４ The amino acid residue is at position Z ９ It is an amino acid residue linked to an amino acid residue, Position Z ５ The amino acid residue is N(N(Me) ２ ) is a residue, Position Z ６ The amino acid residue is a T residue, Position Z ７ The amino acid residue is a 7 MeW residue, Position Z ８ The amino acid residue is a K (NMeAc) residue, Position Z ９ The aforementioned amino acid residue is at position Z ４ It is an amino acid residue linked to the aforementioned amino acid residue, Position Z １０ The amino acid residues are the residues of TMAPF, Position Z １１ The amino acid residue is a 2Na residue, Position Z １２ The amino acid residue is either absent or a THP residue. Position Z １３ The amino acid residue is a K (NMeAc) residue, Position Z １４ The amino acid residue is an N residue, Position Z １５ The amino acid residue is either absent or a 3Pya residue. Position Z １６ The amino acid residue is either absent or a Sar residue. Position Z ３ Z ５ Z ６ Z ７ Z ８ Z １０ Z １１ Z １２ Z １３ Z １４ Z １５ , and Z １６ Eight or fewer of the aforementioned amino acid residues are independently replaced by amino acid residues different from the listed amino acid residues at the aforementioned positions, if an amino acid residue is present at the aforementioned position. Position Z ３ Z ５ Z ６ Z ７ Z ８ Z １０ Z １１ Z １２ Z １３ Z １４ Z １５ , and / or Z １６ A cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of the aforementioned amino acid residues, when present in the aforementioned position, independently comprises at least one quaternary amine.

2. A cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, comprising the amino acid sequence of the following formula (B): Z ３ -Z ４ -Z ５ -Z ６ -Z ７ -Z ８ -Z ９ -Z １０ -Z １１ -Z １２ -Z １３ -Z １４ -Z １５ -Z １６ (B)、 During the ceremony, Position Z ３ The amino acid residue is either absent or an r residue. Position Z ４ The amino acid residue is at position Z ９ It is an amino acid residue linked to an amino acid residue, Position Z ５ The amino acid residue is N(N(Me) ２ ) is a residue, Position Z ６ The amino acid residue is a T residue, Position Z ７ The amino acid residue is a 7 MeW residue, Position Z ８ The amino acid residue is a K (NMeAc) residue, Position Z ９ The aforementioned amino acid residue is at position Z ４ It is an amino acid residue linked to the aforementioned amino acid residue, Position Z １０ The amino acid residues are the residues of TMAPF, Position Z １１ The amino acid residue is a 2Na residue, Position Z １２ The amino acid residue is either absent or a THP residue. Position Z １３ The amino acid residue is a K (NMeAc) residue, Position Z １４ The amino acid residue is an N residue, Position Z １５ The amino acid residue is either absent or a 3Pya residue. Position Z １６ The amino acid residue is either absent or a Sar residue. Position Z ３ , Z ５ , Z ６ , Z ７ , Z ８ , Z １０ , Z １１ , Z １２ , Z １３ , Z １４ , Z １５ , and Z １６ Among the eight or fewer of the amino acid residues of, when an amino acid residue is present at the position, independently, it is replaced with an amino acid residue different from the listed amino acid residue at the position, Position Z ３ Z ５ Z ６ Z ７ Z ８ Z １０ Z １１ Z １２ Z １３ Z １４ Z １５ , and / or Z １６ A cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of the aforementioned amino acid residues, when the amino acid residue is present in the aforementioned position, independently comprises at least one masked amine and / or masked amide.

3. Position Z ４ The cyclic peptide according to any one of claims 1 to 2, wherein the amino acid residue is an Abu residue or an amino acid residue containing a sulfhydryl group, and optionally, the amino acid containing a sulfhydryl group is selected from the group consisting of Pen, C, or aMeC.

4. Position Z ９ The cyclic peptide according to any one of claims 1 to 2, wherein the amino acid residue is the residue of an amino acid containing a sulfhydryl group, and optionally, the amino acid containing a sulfhydryl group is selected from the group consisting of Pen, C, or aMeC.

5. (a) Position Z ４ If the amino acid residue is the residue of an amino acid containing a sulfhydryl group, then position Z ４ The aforementioned amino acid residue is at position Z ４ The amino acid containing a sulfhydryl group and position Z ９ A disulfide bond formed between the amino acid containing a sulfhydryl group and position Z ９ It is linked to the aforementioned amino acid residue, or (b) Position Z ４ The aforementioned amino acid residue is the aforementioned amino acid residue containing a sulfhydryl group, and position Z ４ The aforementioned amino acid residue is at position Z ４ The amino acid containing a sulfhydryl group and position Z ９ A disulfide bond formed between the amino acid containing a sulfhydryl group and position Z ９ It is linked to the aforementioned amino acid residue, or (c) Position Z ４ If the amino acid residue of is the residue of Abu, then position Z ４ The aforementioned amino acid residue is at position Z ４ The Abu and position Z ９ A thioether bond formed between the amino acid containing the sulfhydryl group at position Z ９ It is linked to the aforementioned amino acid residue, or (d) Position Z ４ The aforementioned amino acid residue is the aforementioned residue of Abu, at position Z ４ The aforementioned amino acid residue is at position Z ４ The Abu and position Z ９ A thioether bond formed between the amino acid containing the sulfhydryl group at position Z ９ A cyclic peptide according to any one of claims 1 to 2, which is linked to the aforementioned amino acid residues.

6. The cyclic peptide is R ＮＴ It further includes R ＮＴ but, (i) Z ３ If it exists, position Z ３ of, or (ii) Z ３ If it does not exist, position Z ４ It is bound to the N-terminal amine of the aforementioned amino acid residue, R ＮＴ However, -C(O)- is optionally substituted (C １ ~C ２０ ) alkyl and -C(O)- optionally substituted (C １ ~C ４０ A cyclic peptide according to any one of claims 1 to 2, selected from the group consisting of heteroalkyl groups.

7. The cyclic peptide is R ＣＴ It further includes R ＣＴ but, (i) Z １６ If it exists, position Z １６ of, (ii) Z １６ If it does not exist, position Z １５ of, or (iii) Z １５ and Z １６ If it does not exist, position Z １４ It is bonded to the carbonyl derived from the C-terminal carboxylic acid of the aforementioned amino acid residue, R ＣＴ However, -N(R Ｙ ) (Caution Ｚ ) and in the formula, (i) Each R Ｙ and R Ｚ is hydrogen, optionally substituted (C １ ~C １５ ) alkyl, and optionally substituted (C １ ~C ３０ ) Independently selected from the group consisting of heteroalkyls, or (ii) Each R Ｙ and R Ｚ These, together with the N atom to which they are bonded, are optionally substituted (C ３ ~C １４ ) A complex ring or an optionally substituted (C ５ ~C １０ A cyclic peptide according to any one of claims 1 to 2, which forms a bicyclic or heterocyclic ring.

8. Position Z ３ Z ５ Z ６ Z ７ Z ８ Z １０ Z １１ Z １２ Z １３ Z １４ Z １５ , and Z １６ The cyclic peptide according to any one of claims 1 to 2, wherein four or fewer of the aforementioned amino acid residues are independently replaced by amino acid residues different from the listed amino acid residues at the aforementioned positions, if any amino acid residues are present at those positions.

9. Position Z ３ Z ５ Z ６ Z ７ Z ８ Z １０ Z １１ Z １２ Z １３ Z １４ Z １５ , and / or Z １６ The cyclic peptide according to any one of claims 1 to 2, wherein at least one of the aforementioned amino acid residues independently comprises at least one quaternary amine when the amino acid residue is present in the aforementioned position.

10. Each quaternary amine, (a) 【Chemistry 1】 (In the formula, each R ＺＡ (C) is optionally replaced １ ~C ２０ ) alkyl and optionally substituted (C １ ~C ２０ (Independently selected from the group consisting of heteroalkyls), (b) 【Chemistry 2】 (In the formula, each R ＺＡ and R ＺＢ (C) is optionally replaced １ ~C ２０ ) alkyl and optionally substituted (C １ ~C ２０ (Independently selected from the group consisting of heteroalkyls), (c) 【Transformation 3】 (In the formula, (c) (i) Each R ＺＡ , R ＺＢ , and R ＺＣ (C) is optionally replaced １ ~C ２０ ) alkyl and optionally substituted (C １ ~C ２０ ) Independently selected from the group consisting of heteroalkyls, (c)(ii) Each R ＺＡ (C) is optionally replaced １ ~C ２０ ) alkyl and optionally substituted (C １ ~C ２０ ) Independently selected from the group consisting of heteroalkyls, each R ＺＢ and R ＺＣ These, together with the N atom to which they are bonded, are optionally substituted (C ３ ~C １４ ) Forms a complex ring, or (c) (iii) Each R ＺＡ , R ＺＢ , and R ＺＣ These, together with the N atom to which they are bonded, are optionally substituted (C ５ ~C １０ (Forms a biring or heterocyclic ring) (d) 【Chemistry 4】 (In the formula, (d) (i) Each R ＺＡ and R ＺＢ (C) is optionally replaced １ ~C ２０ ) alkyl and optionally substituted (C １ ~C ２０ ) Independently selected from the group consisting of heteroalkyls, each R ＺＣ and R ＺＤ These, together with the N atom to which they are bonded, are optionally substituted (C ３ ~C １４ ) form heterocyclines, or (d) (ii) Each R ＺＡ and R ＺＢ These, together with the N atom to which they are bonded, are optionally substituted (C ３ ~C １４ ) forms heterocyclines, and each R ＺＣ and R ＺＤ These, together with the N atom to which they are bonded, are optionally substituted (C ３ ~C １４ ) form heterocyclines, or (d)(iii) Each R ＺＡ and R ＺＢ These, together with the N atoms to which they are bonded, are optionally substituted (C ３ ~C １４ ) forms heterocyclines, and each R ＺＣ and R ＺＤ These, together with the N atoms to which they are bonded, are optionally substituted (C ３ ~C １４ (Forms a complex ring) (e) 【Transformation 5】 (In the formula, each R ＺＡ and R ＺＢ These, together with the N atom to which they are bonded, are optionally substituted (C ５ ~C １４ (forming heteroaromatic rings), and (f) 【Transformation 6】 (In the formula, each R ＺＡ (C) is optionally replaced １ ~C ２０ ) alkyl and optionally substituted (C １ ~C ２０ ) Independently selected from the group consisting of heteroalkyls, each R ＺＢ and R ＺＣ These, together with the N atom to which they are bonded, are optionally substituted (C ５ ~C １４ A cyclic peptide according to any one of claims 1 to 2, independently selected from the group consisting of (a heteroaryl molecule).

11. Position Z ３ Z ５ Z ６ Z ７ Z ８ Z １０ Z １１ Z １２ Z １３ Z １４ Z １５ , and / or Z １６ The cyclic peptide according to any one of claims 1 to 2, wherein at least one of the amino acid residues comprises, if the amino acid residue is present in the position, independently at least one masked amine and / or masked amide.

12. At least one of the masked amines and / or masked amides is (a) 【Transformation 7】 (In the formula, each R ＹＡ (C) is optionally replaced １ ~C １０ ) alkyl and optionally substituted (C １ ~C ２０ ) Independently selected from the group consisting of heteroalkyls, each R ＹＢ is hydrogen, optionally substituted (C １ ~C １０ ) alkyl, and optionally substituted (C １ ~C ２０ (Independently selected from the group consisting of heteroalkyls), (b) 【Transformation 8】 (In the formula, each R ＹＣ (C) is optionally replaced １ ~C １０ ) alkyl and optionally substituted (C １ ~C ２０ ) Independently selected from the group consisting of heteroalkyls, each R ＹＤ is hydrogen, optionally substituted (C １ ~C １０ ) alkyl, and optionally substituted (C １ ~C ２０ (Independently selected from the group consisting of heteroalkyls), (c) 【Chemistry 9】 (In the formula, each R ＹＥ (C) is optionally replaced １ ~C １０ ) alkyl and optionally substituted (C １ ~C ２０ ) Independently selected from the group consisting of heteroalkyls, each R ＹＦ is hydrogen, optionally substituted (C １ ~C １０ ) alkyl, and optionally substituted (C １ ~C ２０ (Independently selected from the group consisting of heteroalkyls), and (d) 【Chemistry 10】 (In the formula, each R ＹＧ and R ＹＨ (C) is optionally replaced １ ~C １０ ) alkyl and optionally substituted (C １ ~C ２０ A cyclic peptide according to any one of claims 1 to 2, which is independently selected from the group consisting of (a heteroalkyl group).

13. (a) Position Z ３ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z ３ The aforementioned amino acid residues are APEG2ser, APEG2Ser, APEG2Ser(S ＊ ), e(c), e(C), hk(Me)3, k(5cpa), k(cPEG3a), k(d), k(D), k(dPEG12Ac), k(dPEG6Ac), k(dPEG9Ac), k(Me)3, K(Me)3, k(PEG2PEG2gEC12), k(PEG2PEG2gEC14), k(PEG2PEG2PEG2PEG2gEC12), k(PEG2PEG6gEC12), SP6, APEG2Ser(RS), gPEG2Ser, and k(PEG2PEG2gE(c)C12) are replaced by amino acid residues selected from the group consisting of ), e(c), e(C), hk(Me)3, k(5cpa), k(cPEG3a), k(dPEG), k(D), k(dPEG12Ac), k(dPEG6Ac), k(Me)3, k(PEG2PEG2gEC12), k(PEG2PEG6gEC12), SP6, APEG2Ser(RS), gPEG2Ser, and k(PEG2PEG2gE(c)C12), and / or (b) Position Z ５ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z ５ The aforementioned amino acid residues are A, APEG2Ser(S ＊ ), replaced by an amino acid residue selected from the group consisting of Dab(Me)3, F, Gab, K(cPEG3a), K(Me)3, K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), L, N, N(N(Me)), N(NMe), Q, and W, and / or (c) Position Z ６ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z ６ The aforementioned amino acid residue is replaced by an amino acid residue selected from the group consisting of A and L, and / or (d) Position Z ７ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z ７ The aforementioned amino acid residues are replaced with amino acid residues selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Na, A, F, and L, and / or (e) Position Z ８ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z ８ The aforementioned amino acid residues are K(NMeAC), Q, 4AmPhe, A, AIB, APEG2Ser, APEG2Ser(R ＊ ), APEG2Ser(S ＊ ), replaced by an amino acid residue selected from the group consisting of Cit, Dab(NMeAc), Dab(NMecarn), Dab(NMeCarn), Dab(NMeCOMPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dab(NMecPEG5a), Dap(NMeAc), F, K(4cpg), K(Ac), K(cPEG3a), K(Me)3, K(NMeCOMPEG6), K(NMePEG3a), K(NMPEG6Ac), K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), L, Paf(Ac), Q(N(Me)2), Q(NHtBu), W, Y, and K(cPEG3aCO), and / or (f) Position Z １０ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z １０ The aforementioned amino acid residues are AEF, 4DMPEF, 4DMPzEF, 4TMABYF, ACHMF, AEF((Ch)cPEG3a), AEF(Ac), AEF(AcCh), AEF(aPEG2a), AEF(BisMEP), AEF(BisMEPa), AEF(BisPEG2a)(RS), AEF(BisPEG2a)(S ＊ ), AEF(G), AEF(Me)2, AEF(MEP), AEF(MePrpa), AEF(N(Me)2), AEF(NHCh), AEF(NHcPEG3a), AEF(NMe), AEF(NMe2mPEG 3), AEF (NMe3), AEF (NMeBismPEG3), AEF (NMePEG2a), AEF (NmPEG6), AEF (NsCh), AEF (PEG2a), AEF (SPD), APEG2F, A PEG3F, dFPPEG3F, Diazabiclyoctane6F, DMMMF, DMPMF, DMTASF, F(4G), F(4N3), F(4TzlDMA4mPEG), F(4TzlMME ), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMMo4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTM A5), GPEG3F, hFTMAPF, MMoEF, MMoPF, MMPEG3F, morphTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTA SF, NPyEF, NPyPEG3F, PiperazinequatF, TBAPEG3F, TMA3F, TMA4F, TMA6F, TMA8F, Tzl (Ch), TzlChmPEG, TzlChmPEG 3, Y (C9OH), Y (OEOXIMECh), Y (OTzlCh), Y (OTzlChC16), Y (OTzlChC8), Y (OTzlC1aC8), Y (OTzlChmPEG), Y (OTzlChm PEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), YC8CO(NHPEG3a), YC8COPip, YCF2H, ACHMF(R ＊ , S ＊ ), ACHMF (S ＊ , S ＊ ), replaced by an amino acid residue selected from the group consisting of AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7), and F(4TzlTMA7), and / or (g) Position Z １１ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z １１ The aforementioned amino acid residue is replaced by an amino acid residue selected from the group consisting of A, F, L, and W, and / or (h) Position Z １２ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z １２ The aforementioned amino acid residues are replaced by amino acid residues selected from the group consisting of A, Achx, Achx(diF), Acpx, Aib, AIB, aMeK, aMeL, Chg, diFCpx, F, L, Pip(NMe), Pip(NMe2), W, and diFAchx, and / or (i) Position Z １３ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z １３ The aforementioned amino acid residues are K(NMeAC), E, ​​A, AIB, aMeE, APEG2Ser, APEG2Ser(S ＊ ), Cit, Dab(NMeAc), Dab(NMecarn), Dab(NMeCOmPEG6), Dab(NMecPEG2a), Dab(NMecPEG3a), Dap(Ac), Dap(NMeAc) , E(c), E(C), F, K(5cpa), K(Ac), K(cPEG3a), K(d), K(D), K(dPEG12Ac), K(dPEG6Ac), K(dPEG9Ac), K(Me)3, K(NMeC) Replaced with an amino acid residue selected from the group consisting of OmPEG6), K(NMeCOPEG4N+Me3), K(NMePEG3a), K(NmPEG6Ac), K(PEG2PEG2gEC12), K(PEG2PEG2gEC14), K(PEG2PEG2PEG2gEC12), L, Q(N(Me)2), tetrazole, tetrazole(NMe), W, K(DFN), K(IPB), and Nle, and / or (j) Position Z １４ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z １４ The aforementioned amino acid residue is replaced by an amino acid residue selected from the group consisting of K (Ac) and N (NMe), and / or (k) Position Z １５ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z １５ The aforementioned amino acid residues are replaced with amino acid residues selected from the group consisting of 3pya, 5CF33Pya, 5MePyridinAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y, and A, and / or (l) Position Z １６ If the aforementioned amino acid residue is replaced by an amino acid residue different from the listed amino acid residue at the position Z, then position Z １６ The aforementioned amino acid residues are 4diFPro, NMeDTyr, NMeK (PEG2PEG2C12), NMeK (PEG2PEG2C14), NMeK (PEG2PEG2gEC12), NMeK (PEG2PEG2gEC14), NMeK (PEG2PEG2K (PEG2PEG2gEC12)2), NMeK (PEG2PEG2K (PEG2PEG2PEG2PEG2gEC12)2), NMeK (PE A cyclic peptide according to any one of claims 1 to 2, wherein the amino acid residue is replaced by an amino acid residue selected from the group consisting of G2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12), and NMeK(SP6PEG2PEG2gEC12).

14. A compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from any one of Tables 1A, 1B, 1C, 1D, 1E, and 1F.

15. A pharmaceutical composition comprising a cyclic peptide according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

16. The pharmaceutical composition according to claim 15, This method is intended for use in treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthritis, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, colitis associated with impaired innate immunity such as leukocyte adhesion disorder-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermanski-Puddlach syndrome, Chediak-Higashi syndrome, and Wiscott-Aldrich syndrome, cystitis occurring after colectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft-versus-host disease. The method comprises providing the pharmaceutical composition to the subject.

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