Cyclic peptide inhibitors of IL-23

Abstract

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

Description

Technical Field

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

[0002] Reference sequence listing submitted electronically

[0003] This application contains a sequence listing, which is electronically submitted as an XML formatted sequence listing via the U.S. Patent and Trademark Center, with the file name "JBI6738WOPCT1sequencelisting.xml" and a creation date of July 13, 2023, with a size of 3,492 Kb. The sequence listing submitted via the Patent Center is part of this specification and is incorporated herein by reference. Background Art

[0004] Interleukin-23 (IL-23) cytokines have been considered to play a key 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), such as ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed the major role of interleukin-23 receptor (IL-23R) and downstream effector cytokines in the pathogenesis of the disease. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδT cells, natural killer (NK) cells, dendritic cells, macrophages and innate lymphoid cells found in large quantities in the intestine. At the intestinal mucosal surface, it was found that the gene expression and protein levels of IL-23R were elevated in IBD patients. It is believed that IL-23 promotes the production of pathogenic CD4 T cells that produce IL-6, IL-17 and tumor necrosis factor (TNF). + This effect is mediated by the development of T cell populations.

[0005] IL-23 production is abundant in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T cell-dependent and T cell-independent pathways of intestinal inflammation through its effects on T helper 1 (Th1) and Th17-related cytokines, and in limiting regulatory T cell responses in the intestine, thereby favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the key role of the IL-23 pathway in intestinal homeostasis.

[0006] Psoriasis, a chronic skin disease affecting approximately 2%-3% of the general population, has been shown to be mediated by the body's T-cell inflammatory response. IL-23 is one of several interleukins considered a key player in the pathogenesis of psoriasis, purportedly maintaining chronic autoimmune inflammation by inducing interleukin-17, regulating T memory cells, and activating macrophages. Expression of IL-23 and IL-23R has been shown to be increased in tissues of psoriasis patients, and antibodies neutralizing IL-23 have been shown to inhibit IL-23-dependent psoriasis progression in animal models of psoriasis.

[0007] IL-23 is a heterodimer composed of a unique p19 subunit and a p40 subunit shared with IL-12, a T helper 1 (T helper 1) molecule involved in the production of interferon-γ (IFN-γ). H 1) Cytokines for cell development. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. For example, animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while animals lacking IL-23 are resistant, which may be due to the production of IL-6, IL-17, and TNF in the CNS of animals lacking IL-23. + The number of T cells is reduced. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. The binding of IL-23 to IL-23R activates Jak-Stat signaling molecules, Jak2, Tyk2, and Stat1, Stat 3, Stat 4, and Stat 5, but Stat4 activation is significantly weaker and forms a different DNA-binding Stat complex in response to IL-23 compared to IL-12. IL-23R constitutively associates with Jak2 and associates with Stat3 in a ligand-dependent manner. Unlike IL-12, which primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0008] Therapeutic moieties that inhibit the IL-23 pathway have been developed for the treatment of IL-23-related diseases and disorders. A variety of antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, which has been approved for the treatment of moderate to severe plaque psoriasis (PSO), active psoriatic arthritis (PSA), moderate to severe active Crohn's disease (CD), and moderate to severe active ulcerative colitis (UC). Examples of such identified antibodies include: tirazumab, 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 in the United States for the treatment of plaque psoriasis and in Japan for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis.

[0009] Although targeted IL-23 antibody therapy is used clinically, there are no small molecule therapeutics that selectively inhibit IL-23 signaling. There are some identified polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R (see, for example, U.S. Patent Application Publication No. US2013 / 0029907). Therefore, there is still a significant need in the art for effective small molecule and / or polypeptide therapeutics to treat and / or prevent IL-23-related and / or IL23R-related diseases and disorders. Summary of the Invention

[0010] Generally speaking, 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 of IL-23R inhibitors for treating autoimmune inflammatory diseases and / or related disorders.

[0011] Specifically, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, which comprises an amino acid sequence of formula (A):

[0012] 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), where:

[0013] Position Z3 The amino acid residue at position is absent or is an r residue;

[0014] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0015] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0016] Position Z 6 The amino acid residue at is the residue of T;

[0017] Position Z 7 The amino acid residue at is a 7MeW residue;

[0018] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0019] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0020] Position Z 10 The amino acid residue at is the residue of TMAPF;

[0021] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0022] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0023] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0024] Position Z 14 The amino acid residue at position is an N residue;

[0025] Position Z 15 The amino acid residue at the position is absent or is a 3Pya residue;

[0026] Position Z 16 The amino acid residue at the position is absent or is a Sar residue;

[0027] When the amino acid residue is present at position Z 3 、Z 5 、Z 6 、Z 7 、Z 8 、Z 10 、Z11 、Z 12 、Z 13 、Z 14 、Z 15 and Z 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position; and

[0028] When the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one quaternary amine.

[0029] Specifically, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, which comprises an amino acid sequence of formula (B):

[0030] 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) where:

[0031] Position Z 3 The amino acid residue at position is absent or is an r residue;

[0032] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0033] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0034] Position Z 6 The amino acid residue at is the residue of T;

[0035] Position Z 7 The amino acid residue at is a 7MeW residue;

[0036] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0037] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0038] Position Z 10 The amino acid residue at is the residue of TMAPF;

[0039] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0040] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0041] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0042] Position Z 14 The amino acid residue at position is an N residue;

[0043] Position Z 15 The amino acid residue at the position is absent or is a 3Pya residue;

[0044] Position Z 16 The amino acid residue at the position is absent or is a Sar residue;

[0045] When the amino acid residue is present 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 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position; and

[0046] When the amino acid residue is present at position Z 3 、Z 5 、Z 6 、Z 7 、Z8 、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 at said position each independently comprises at least one masked amine and / or masked amide.

[0047] Specifically, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, which comprises an amino acid sequence of formula (C):

[0048] 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), where:

[0049] Position Z 3 The amino acid residue at position is absent or is an r residue;

[0050] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0051] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0052] Position Z 6 The amino acid residue at is the residue of T;

[0053] Position Z 7 The amino acid residue at is a 7MeW residue;

[0054] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0055] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0056] Position Z 10The amino acid residue at is the residue of TMAPF;

[0057] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0058] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0059] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0060] Position Z 14 The amino acid residue at position is an N residue;

[0061] Position Z 15 The amino acid residue at the position is absent or is a 3Pya residue;

[0062] Position Z 16 The amino acid residue at position is absent or is a Sar residue; and

[0063] When the amino acid residue is present 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 16 When eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position.

[0064] 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.

[0065] Specifically, the present invention relates to compounds of formula (I) to (X) or pharmaceutically acceptable salts, solvates and / or other forms thereof; corresponding pharmaceutical compositions, methods and / or uses for treating autoimmune inflammatory diseases and related disorders.

[0066] The present invention relates to novel peptide inhibitors of interleukin-23 receptor (IL-23R) of formula (I) to (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 treating autoimmune inflammatory diseases and / or related disorders.

[0067] The present invention also relates to a compound set forth in any one of Tables 1A-1H, or a pharmaceutically acceptable salt, solvate, or form thereof; corresponding pharmaceutical compositions, and methods and / or uses for treating autoimmune inflammatory diseases and related disorders.

[0068] The present disclosure also relates to pharmaceutical compositions comprising a peptide inhibitor compound as described herein or a pharmaceutically acceptable salt, solvate or form thereof as described herein, and a pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutical composition may or may not contain an absorption enhancer, depending on the intended route of delivery or its use for treating a specific indication. The absorption enhancer may be a permeation enhancer or an intestinal permeation enhancer. In one aspect, the absorption enhancer improves oral bioavailability.

[0069] The present invention relates to methods and / or uses for treating an inflammatory disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of one or more IL-23R peptide inhibitor compounds described herein, or pharmaceutically acceptable salts or solvates thereof, or corresponding pharmaceutical compositions as described herein. Such inflammatory diseases and related disorders may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA), among others.

[0070] The present invention provides the use of one or more compounds described herein (e.g., compounds of Formulas (I) to (X) or Tables 1A to 1H) for the preparation of a pharmaceutical composition for 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), or psoriatic arthritis (PsA).

[0071] The present invention provides for the use of one or more compounds of Formula (I) to (X) or Tables 1A to 1H as described herein for 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).

[0072] The present invention provides kits comprising one or more compounds of Formula (I) to (X) or Tables 1A to 1H as described herein and instructions for use in treating a disease in a patient. 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), or psoriatic arthritis (PsA). DETAILED DESCRIPTION

[0073] I. Overview

[0074] The cyclic peptides of the present invention include quaternary amines, masked amines, masked amides, or combinations thereof. The inclusion of quaternary amines, masked amines, and / or masked amides in the cyclic peptides of the present invention improves the pharmacokinetic properties of the cyclic peptides compared to other compounds targeting IL-23R. For example, the cyclic peptides of the present invention have highly desirable oral PK profiles and improved oral bioavailability. The cyclic peptides of the present invention also have lower projected human doses. It is expected that the quaternary amines and masked amines and / or masked amides achieve these improvements by altering the polar properties of the molecule, as reflected in the observed exposed polar surface area (EPSA) values.

[0075] 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 treating autoimmune inflammation and related diseases and disorders.

[0076] The present invention provides or relates to peptide inhibitors of IL-23R. Compared to the corresponding cyclic peptide inhibitors of IL-23R that do not have a ring structure, the peptide inhibitors of the present invention can exhibit enhanced properties, such as a longer half-life in vivo. Specifically, compounds and methods for specifically targeting IL-23R from the luminal side of the intestine can provide therapeutic benefits for IBD patients with localized inflammation of intestinal tissue; and / or orally bioavailable small molecules and / or polypeptide inhibitors of IL-23 can provide non-steroidal treatment options for patients with mild to moderate psoriasis, and provide treatment that does not require delivery by infusion for patients with moderate to severe psoriasis.

[0077] Compounds and methods for specifically targeting IL-23R from the luminal side of the intestine could provide therapeutic benefits for IBD patients with localized inflammation of intestinal tissue. In addition, orally bioavailable small molecule and / or peptide inhibitors of IL-23 could provide a nonsteroidal treatment option for patients with mild to moderate psoriasis and a treatment that does not require infusion for patients with moderate to severe psoriasis.

[0078] The present invention addresses these needs by providing peptide inhibitors that bind to IL-23R to inhibit IL-23 binding and signaling, or pharmaceutically acceptable salts, solvates, and / or other forms thereof, via various suitable routes of administration, which may include, but are not limited to, oral administration.

[0079] In one general aspect, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, comprising an amino acid sequence of formula (A):

[0080] Z 3 -Z 4 -Z5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (A), where:

[0081] Position Z 3 The amino acid residue at position is absent or is an r residue;

[0082] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0083] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0084] Position Z 6 The amino acid residue at is the residue of T;

[0085] Position Z 7 The amino acid residue at is a 7MeW residue;

[0086] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0087] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0088] Position Z 10 The amino acid residue at is the residue of TMAPF;

[0089] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0090] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0091] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0092] Position Z 14 The amino acid residue at position is an N residue;

[0093] Position Z 15The amino acid residue at the position is absent or is a 3Pya residue;

[0094] Position Z 16 The amino acid residue at the position is absent or is a Sar residue;

[0095] When the amino acid residue is present 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 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position; and

[0096] When the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one quaternary amine.

[0097] In another general aspect, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, comprising an amino acid sequence of formula (B):

[0098] 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) where:

[0099] Position Z 3The amino acid residue at position is absent or is an r residue;

[0100] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0101] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0102] Position Z 6 The amino acid residue at is the residue of T;

[0103] Position Z 7 The amino acid residue at is a 7MeW residue;

[0104] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0105] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0106] Position Z 10 The amino acid residue at is the residue of TMAPF;

[0107] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0108] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0109] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0110] Position Z 14 The amino acid residue at position is an N residue;

[0111] Position Z 15 The amino acid residue at the position is absent or is a 3Pya residue;

[0112] Position Z 16 The amino acid residue at the position is absent or is a Sar residue;

[0113] When the amino acid residue is present at position Z 3 、Z 5 、Z 6 、Z 7 、Z 8 、Z 10 、Z 11 、Z12 、Z 13 、Z 14 、Z 15 and Z 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position; and

[0114] When the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one masked amine and / or masked amide.

[0115] In another general aspect, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, comprising an amino acid sequence of formula (C):

[0116] 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), where:

[0117] Position Z 3 The amino acid residue at position is absent or is an r residue;

[0118] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0119] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0120] Position Z 6 The amino acid residue at is the residue of T;

[0121] Position Z 7 The amino acid residue at is a 7MeW residue;

[0122] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0123] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0124] Position Z 10 The amino acid residue at is the residue of TMAPF;

[0125] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0126] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0127] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0128] Position Z 14 The amino acid residue at position is an N residue;

[0129] Position Z 15 The amino acid residue at the position is absent or is a 3Pya residue;

[0130] Position Z 16 The amino acid residue at position is absent or is a Sar residue; and

[0131] When the amino acid residue is present 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 16 When eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position.

[0132] In some embodiments, position Z 4 The amino acid residue at is the residue of Abu or the residue of an amino acid containing a sulfhydryl group.

[0133] In some embodiments, position Z 9 The amino acid residue at is the residue of an amino acid containing a sulfhydryl group.

[0134] In some embodiments, when position Z 4 When the amino acid residue at position Z is an amino acid residue containing a sulfhydryl group, 4 The amino acid residue at position Z 4 The amino acid containing a sulfhydryl group and position Z 9 The disulfide bond formed between the amino acid containing a sulfhydryl group at position Z 9 The amino acid residues at the .

[0135] In some embodiments, position Z 4 The amino acid residue at position Z is the residue of an amino acid containing a sulfhydryl group, and 4 The amino acid residue at position Z 4 The amino acid containing a sulfhydryl group and position Z 9 The disulfide bond formed between the amino acid containing a sulfhydryl group at position Z 9 The amino acid residues at the .

[0136] In some embodiments, when position Z 4 When the amino acid residue at position Z is an Abu residue, 4 The amino acid residue at position Z 4 Abu at location Z 9 The thioether bond formed between the amino acid containing a sulfhydryl group at position Z 9 The amino acid residues at the .

[0137] In some embodiments, position Z 4 The amino acid residue at position Z is the residue of Abu, and 4 The amino acid residue at position Z 4 Abu at location Z 9 The thioether bond formed between the amino acid containing a sulfhydryl group at position Z 9 The amino acid residues at the .

[0138] In some embodiments, the cyclic peptide further comprises R NT , where R NT Binds to the N-terminal amine of the amino acid residue at the following position:

[0139] (i)Z 3 , when Z 3 When present, or

[0140] (ii) Z 4 , when Z3 when it does not exist; and

[0141] R NT Selected from the group consisting of: -C(O)-optionally substituted (C1-C 20 )alkyl and -C(O)-optionally substituted (C1-C 40 ) heteroalkyl.

[0142] In some embodiments, the cyclic peptide further comprises R CT , where R CT Binds to the carbonyl group of the C-terminal carboxylic acid derived from the amino acid residue at the following position:

[0143] (i)Z 16 , when Z 16 When it exists,

[0144] (ii) Z 15 , when Z 16 When it does not exist, or

[0145] (iii) Z 14 , when Z 15 and Z 16 when it does not exist; and

[0146] R CT Yes-N(R Y )(R Z ),in:

[0147] (i) Each R Y and R Z are independently selected from the group consisting of: hydrogen, optionally substituted (C1-C 15 )alkyl and optionally substituted (C1-C 30 ) heteroalkyl, or

[0148] (ii) Each R Y and R Z Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic or optionally substituted (C5-C 10 ) bicyclic heterocycle.

[0149] In some embodiments, the cyclic peptide further comprises R CT , where R CT Binds to the carbonyl group of the C-terminal carboxylic acid derived from the amino acid residue at the following position:

[0150] (i)Z 16 , when Z 16 When it exists,

[0151] (ii) Z 15 , when Z16 When it does not exist, or

[0152] (iii) Z 14 , when Z 15 and Z 16 when it does not exist; and

[0153] R CT Yes-N(R Y )(R Z ),in:

[0154] (i) Each R Y and R Z are independently selected from the group consisting of: hydrogen, optionally substituted (C1-C 15 )alkyl and optionally substituted (C1-C 30 ) heteroalkyl, provided that R Y and R Z Only one of them is hydrogen, or

[0155] (ii) Each R Y and R Z Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic or optionally substituted (C5-C 10 ) bicyclic heterocycle.

[0156] In some embodiments, the cyclic peptide further comprises R NT and R CT And has formula (D):

[0157] 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),

[0158] where R NT 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、Z 9 、Z 10 、Z11 、Z 12 、Z 13 、Z 14 、Z 15 、Z 16 and R CT As defined herein.

[0159] In some embodiments, when the amino acid residue is present 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 16 When a residue is present at a position, eight of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0160] In some embodiments, when the amino acid residue is present 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 16 When a position is specified, seven or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0161] In some embodiments, when the amino acid residue is present 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 16 When a residue is present at a position, seven of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0162] In some embodiments, when the amino acid residue is present 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 16 When a position is specified, six or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0163] In some embodiments, when the amino acid residue is present 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 16 When a residue is present at a position, six of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0164] In some embodiments, when the amino acid residue is present 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 16 When a position is specified, five or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0165] In some embodiments, when the amino acid residue is present 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 16When a residue is present at a position, five of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0166] In some embodiments, when the amino acid residue is present 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 16 When a residue is present at a position, four or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0167] In some embodiments, when the amino acid residue is present 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 16 When a residue is present at a position, four of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0168] In some embodiments, when the amino acid residue is present 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 16 When a position is specified, three or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0169] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 6 、Z 7 、Z8 、Z 10 、Z 11 、Z 12 、Z 13 、Z 14 、Z 15 and Z 16 When a residue is present at a position, three of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0170] In some embodiments, when the amino acid residue is present 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 16 When two or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0171] In some embodiments, when the amino acid residue is present 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 16 When a nucleotide sequence is specified, two of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0172] In some embodiments, when the amino acid residue is present 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 16When a position is specified, one or fewer of the amino acid residues at that position are independently replaced with an amino acid residue different from the amino acid residue listed at that position.

[0173] In some embodiments, when the amino acid residue is present 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 16 When a position is specified, one of the amino acid residues at that position is independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0174] In some embodiments, when the amino acid residue is present 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 16 When a position is specified, none of the amino acid residues at that position is independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0175] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a position is specified, seven or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0176] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16When a residue is present at a position, seven of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0177] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a position is specified, six or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0178] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a residue is present at a position, six of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0179] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a position is specified, five or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0180] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a residue is present at a position, five of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0181] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z16 When a residue is present at a position, four or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0182] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a residue is present at a position, four of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0183] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a position is specified, three or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0184] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a residue is present at a position, three of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0185] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When two or fewer of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0186] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z15 and Z 16 When a nucleotide sequence is specified, two of the amino acid residues at that position are independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0187] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a position is specified, one or fewer of the amino acid residues at that position are independently replaced with an amino acid residue different from the amino acid residue listed at that position.

[0188] In some embodiments, when the amino acid residue is present at position Z 3 、Z 5 、Z 8 、Z 10 、Z 13 、Z 15 and Z 16 When a position is specified, one of the amino acid residues at that position is independently substituted with an amino acid residue different from the amino acid residue listed at that position.

[0189] In some embodiments, position Z 5 、Z 8 、Z 10 and Z 13 Four or fewer of the amino acid residues at the positions are independently substituted with amino acid residues different from the amino acid residues listed at the positions.

[0190] In some embodiments, position Z 5 、Z 8 、Z 10 and Z 13 Four of the amino acid residues at the positions are independently substituted with amino acid residues different from the amino acid residues listed at the positions.

[0191] In some embodiments, position Z 5 、Z 8 、Z 10 and Z 13 Three or fewer of the amino acid residues at the positions are independently substituted with amino acid residues different from the amino acid residues listed at the positions.

[0192] In some embodiments, position Z 5 、Z 8 、Z 10 and Z13 Three of the amino acid residues at the positions are independently substituted with amino acid residues different from the amino acid residues listed at the positions.

[0193] In some embodiments, position Z 5 、Z 8 、Z 10 and Z 13 Two or fewer of the amino acid residues at the positions are independently substituted with amino acid residues different from the amino acid residues listed at the positions.

[0194] In some embodiments, position Z 5 、Z 8 、Z 10 and Z 13 Two of the amino acid residues at the positions are independently substituted with amino acid residues different from the amino acid residues listed at the positions.

[0195] In some embodiments, position Z 5 、Z 8 、Z 10 and Z 13 One or fewer of the amino acid residues at the positions listed are independently replaced with an amino acid residue different from the amino acid residue listed at that position.

[0196] In some embodiments, position Z 5 、Z 8 、Z 10 and Z 13 One of the amino acid residues at each position is independently replaced by an amino acid residue different from the amino acid residue listed at that position.

[0197] In some embodiments, when the amino acid residue is present at position Z 3 When , the amino acid residue at that position is not substituted.

[0198] In some embodiments, position Z 6 The amino acid residues at 347 were not substituted.

[0199] In some embodiments, position Z 7 The amino acid residues at 347 were not substituted.

[0200] In some embodiments, position Z 11 The amino acid residues at 347 were not substituted.

[0201] In some embodiments, when the amino acid residue is present at position Z 12 When , the amino acid residue at that position is not substituted.

[0202] In some embodiments, position Z 14 The amino acid residues at 347 were not substituted.

[0203] In some embodiments, when the amino acid residue is present at position Z 15 When , the amino acid residue at that position is not substituted.

[0204] In some embodiments, when the amino acid residue is present at position Z 16 When , the amino acid residue at that position is not substituted.

[0205] In some embodiments, position Z 6 and Z 11 The amino acid residues at 347 were not substituted.

[0206] In some embodiments, position Z 6 and Z 14 The amino acid residues at 347 were not substituted.

[0207] In some embodiments, position Z 11 and Z 14 The amino acid residues at 347 were not substituted.

[0208] In some embodiments, position Z 6 、Z 11 and Z 14 The amino acid residues at 347 were not substituted.

[0209] In some embodiments, position Z 6 、Z 7 、Z 11 and Z 14 The amino acid residues at 347 were not substituted.

[0210] In some embodiments, when the amino acid residue is present at position Z 6 、Z 11 、Z 12 and Z 14 When , the amino acid residue at that position is not substituted.

[0211] In some embodiments, when the amino acid residue is present at position Z 6 、Z 7 、Z 11 、Z 12 and Z 14 When , the amino acid residue at that position is not substituted.

[0212] In some embodiments, when the amino acid residue is present at position Z 3 、Z 6 、Z 7 、Z 11 、Z12 and Z 14 When , the amino acid residue at that position is not substituted.

[0213] In some embodiments, when the amino acid residue is present at position Z 6 、Z 7 、Z 11 、Z 12 、Z 14 and Z 15 When , the amino acid residue at that position is not substituted.

[0214] In some embodiments, when the amino acid residue is present at position Z 3 、Z 6 、Z 7 、Z 11 、Z 12 、Z 14 and Z 15 When , the amino acid residue at that position is not substituted.

[0215] In some embodiments, when the amino acid residue is present at position Z 6 、Z 7 、Z 11 、Z 12 、Z 14 and Z 16 When , the amino acid residue at that position is not substituted.

[0216] In some embodiments, when the amino acid residue is present at position Z 3 、Z 6 、Z 7 、Z 11 、Z 12 、Z 14 and Z 16 When , the amino acid residue at that position is not substituted.

[0217] In some embodiments, when the amino acid residue is present at position Z 6 、Z 7 、Z 11 、Z 12 、Z 14 、Z 15 and Z 16 When , the amino acid residue at that position is not substituted.

[0218] In some embodiments, when the amino acid residue is present at position Z 3 、Z 6 、Z 7 、Z 11 、Z 12 、Z 14 、Z15 and Z 16 When , the amino acid residue at that position is not substituted.

[0219] In some embodiments, position Z 3 、Z 12 、Z 15 and Z 16 Three or fewer of the amino acid residues at positions are absent.

[0220] In some embodiments, position Z 3 、Z 12 、Z 15 and Z 16 Three of the amino acid residues at are absent.

[0221] In some embodiments, position Z 3 、Z 12 、Z 15 and Z 16 Two or fewer of the amino acid residues at positions are absent.

[0222] 7 In some embodiments, position Z 3 、Z 12 、Z 15 and Z 16 Two of the amino acid residues at are absent.

[0223] In some embodiments, position Z 3 、Z 12 、Z 15 and Z 16 One or fewer of the amino acid residues at positions is absent.

[0224] In some embodiments, position Z 3 、Z 12 、Z 15 and Z 16 One of the amino acid residues at is absent.

[0225] In some embodiments, position Z 3 、Z 12 、Z 15 and Z 16 The amino acid residues at all sites are present.

[0226] In some embodiments, position Z 3 The amino acid residue at position Z is absent and 12 、Z 15 and Z 16 The amino acid residues are present.

[0227] In some embodiments, position Z 12 The amino acid residue at position Z is absent and 3 、Z 15 and Z 16 The amino acid residues are present.

[0228] In some embodiments, position Z 15 The amino acid residue at position Z is absent and 3 、Z 12 and Z 16 The amino acid residues are present.

[0229] In some embodiments, position Z 16 The amino acid residue at position Z is absent and 3 、Z 12 and Z 15 The amino acid residues are present.

[0230] In some embodiments, position Z 3 and Z 16 The amino acid residue at position Z is absent and 12 and Z 15 The amino acid residues are present.

[0231] In some embodiments, position Z 3 、Z 15 and Z 16 The amino acid residue at position Z is absent and 12 The amino acid residues are present.

[0232] In some embodiments, R NT (when present) and / or R CT (when 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 at position (when an amino acid residue is present at that position) each independently comprises at least one quaternary amine.

[0233] In some embodiments, R NT (when present) and / or R CT (when present) and / or 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 at position (when an amino acid residue is present at that position) each independently comprises a quaternary amine.

[0234] In some embodiments, when the amino acid residue is present 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 When at least one of the amino acid residues at that position each independently comprises at least one quaternary amine.

[0235] In some embodiments, when the amino acid residue is present 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 When at least one of the amino acid residues at that position independently comprises a quaternary amine.

[0236] In some embodiments, R NT (when present) and / or R CT (when present) and / or position Z 3 、Z 5 、Z 8 、Z 10 、Z 12 and / or Z 13 At least one of the amino acid residues at position (when an amino acid residue is present at that position) each independently comprises at least one quaternary amine.

[0237] In some embodiments, R NT(when present) and / or R CT (when present) and / or position Z 3 、Z 5 、Z 8 、Z 10 、Z 12 and / or Z 13 At least one of the amino acid residues at position (when an amino acid residue is present at that position) each independently comprises a quaternary amine.

[0238] In some embodiments, R NT (when present) and / or position Z 3 、Z 5 、Z 8 、Z 10 and / or Z 13 At least one of the amino acid residues at position (when an amino acid residue is present at that position) each independently comprises at least one quaternary amine.

[0239] In some embodiments, R NT (when present) and / or position Z 3 、Z 5 、Z 8 、Z 10 and / or Z 13 At least one of the amino acid residues at position (when an amino acid residue is present at that position) each independently comprises a quaternary amine.

[0240] In some embodiments, R NT and position Z 5 and Z 10 The amino acid residues at each independently contain at least one quaternary amine.

[0241] In some embodiments, R NT and position Z 5 and Z 10 The amino acid residues at each independently contain a quaternary amine.

[0242] In some embodiments, R NT and position Z 8 and Z 10 The amino acid residues at each independently contain at least one quaternary amine.

[0243] In some embodiments, R NT and position Z 8 and Z 10 The amino acid residues at each independently contain a quaternary amine.

[0244] In some embodiments, R NT and position Z 8 and Z13 The amino acid residues at each independently contain at least one quaternary amine.

[0245] In some embodiments, R NT and position Z 8 and Z 13 The amino acid residues at each independently contain a quaternary amine.

[0246] In some embodiments, position Z 8 、Z 10 and Z 13 The amino acid residues at each independently contain at least one quaternary amine.

[0247] In some embodiments, position Z 8 、Z 10 and Z 13 The amino acid residues at each independently contain a quaternary amine.

[0248] In some embodiments, R NT and position Z 3 The amino acid residues at each independently contain at least one quaternary amine.

[0249] In some embodiments, R NT and position Z 3 The amino acid residues at each independently contain a quaternary amine.

[0250] In some embodiments, R NT and R CT Each independently comprises at least one quaternary amine.

[0251] In some embodiments, R NT and R CT Each contains a quaternary amine.

[0252] In some embodiments, R NT and position Z 8 The amino acid residues at each independently contain at least one quaternary amine.

[0253] In some embodiments, R NT and position Z 8 The amino acid residues at each independently contain a quaternary amine.

[0254] In some embodiments, R NT and position Z 10 The amino acid residues at each independently contain at least one quaternary amine.

[0255] In some embodiments, R NT and position Z 10 The amino acid residues at each independently contain a quaternary amine.

[0256] In some embodiments, position Z 3 and Z 8 The amino acid residues at each independently contain at least one quaternary amine.

[0257] In some embodiments, position Z 3 and Z 8 The amino acid residues at each independently contain a quaternary amine.

[0258] In some embodiments, position Z 3 and Z 10 The amino acid residues at each independently contain at least one quaternary amine.

[0259] In some embodiments, position Z 3 and Z 10 The amino acid residues at each independently contain a quaternary amine.

[0260] In some embodiments, position Z 5 and Z 10 The amino acid residues at each independently contain at least one quaternary amine.

[0261] In some embodiments, position Z 5 and Z 10 The amino acid residues at each independently contain a quaternary amine.

[0262] In some embodiments, position Z 8 and Z 10 The amino acid residues at each independently contain at least one quaternary amine.

[0263] In some embodiments, position Z 8 and Z 10 The amino acid residues at each independently contain a quaternary amine.

[0264] In some embodiments, position Z 8 and Z 13 The amino acid residues at each independently contain at least one quaternary amine.

[0265] In some embodiments, position Z 8 and Z 13 The amino acid residues at each independently contain a quaternary amine.

[0266] In some embodiments, position Z 10 and Z 13 The amino acid residues at each independently contain at least one quaternary amine.

[0267] In some embodiments, position Z 10 and Z 13The amino acid residues at each independently contain a quaternary amine.

[0268] In some embodiments, R NT Contains at least one quaternary amine.

[0269] In some embodiments, R NT Contains quaternary amines.

[0270] In some embodiments, R CT Contains at least one quaternary amine.

[0271] In some embodiments, R CT Contains quaternary amines.

[0272] In some embodiments, position Z 3 The amino acid residue at position 1 comprises at least one quaternary amine.

[0273] In some embodiments, position Z 3 The amino acid residue at position contains a quaternary amine.

[0274] In some embodiments, position Z 5 The amino acid residue at position 1 comprises at least one quaternary amine.

[0275] In some embodiments, position Z 5 The amino acid residue at position contains a quaternary amine.

[0276] In some embodiments, position Z 8 The amino acid residue at position 1 comprises at least one quaternary amine.

[0277] In some embodiments, position Z 8 The amino acid residue at position contains a quaternary amine.

[0278] In some embodiments, position Z 10 The amino acid residue at position 1 comprises at least one quaternary amine.

[0279] In some embodiments, position Z 10 The amino acid residue at position contains a quaternary amine.

[0280] In some embodiments, position Z 12 The amino acid residue at position 1 comprises at least one quaternary amine.

[0281] In some embodiments, position Z 12 The amino acid residue at position contains a quaternary amine.

[0282] In some embodiments, position Z 13 The amino acid residue at position 1 comprises at least one quaternary amine.

[0283] In some embodiments, position Z13 The amino acid residue at position contains a quaternary amine.

[0284] In some embodiments, the at least one quaternary amine is one or two quaternary amines.

[0285] In some embodiments, each quaternary amine is independently selected from the group consisting of:

[0286] (a) Each R ZA are independently selected from the group consisting of: optionally substituted (C1-C 20 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl;

[0287] (b) 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;

[0288] (c) in:

[0289] (c)(i) Each R ZA 、R ZB and R ZC are independently selected from the group consisting of: optionally substituted (C1-C 20 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl,

[0290] (c)(ii) Each R ZA are 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 ZC Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic ring, or

[0291] (c)(iii) Each R ZA 、R ZB and R ZC Together with the N atom to which they are attached, they form an optionally substituted (C5-C 10 ) bicyclic heterocycle;

[0292] (d) in:

[0293] (d)(i) Each R ZAand R ZB are 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, they form an optionally substituted (C3-C 14 ) a heterocyclic group, or

[0294] (d)(ii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic group, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) a heterocyclic group, or

[0295] (d)(iii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic group, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic ring;

[0296] (e) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C5-C 14 ) heteroaromatic ring, and

[0297] (f) Each R ZA are 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 ZC Together with the N atom to which they are attached, they form an optionally substituted (C5-C 14 ) heteroaryl.

[0298] In some embodiments, each quaternary amine is independently selected from the group consisting of:

[0299] (a) Each R ZA are independently selected from the group consisting of: optionally substituted (C1-C 16)alkyl and optionally substituted (C1-C8)heteroalkyl;

[0300] (b) Each R ZA and R ZB are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl;

[0301] (c) in:

[0302] (c)(i) Each R ZA 、R ZB and R ZC are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl,

[0303] (c)(ii) Each R ZA are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl, and each R ZB and R ZC Together with the N atom to which they are attached, they form an optionally substituted (C6)heterocycle, or

[0304] (c)(iii) Each R ZA 、R ZB and R ZC together with the N atom to which they are attached form an optionally substituted (C8)bicyclic heterocycle;

[0305] (d) in:

[0306] (d)(i) Each R ZA and R ZB are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C6)heterocyclyl, or

[0307] (d)(ii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C6) heterocyclyl, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C6)heterocyclyl, or

[0308] (d)(iii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C6) heterocyclyl, and each R ZC and R ZD together with the N atom to which they are attached, form an optionally substituted (C6)heterocycle;

[0309] (e) Each R ZA and R ZB together with the N atom to which they are attached, form an optionally substituted (C6)heteroaryl ring; and

[0310] (f) Each R ZA are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl, and each R ZB and R ZC Together with the N atom to which they are attached they form an optionally substituted (C6)heteroaryl.

[0311] In some embodiments, each quaternary amine is independently selected from the group consisting of:

[0312] (a) Each R ZA are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl;

[0313] (b) Each R ZA and R ZB are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl;

[0314] (c) in:

[0315] (c)(i) Each R ZA 、R ZB and R ZC are independently selected from the group consisting of: optionally substituted (C1-C 16 )alkyl and optionally substituted (C1-C8)heteroalkyl,

[0316] (c)(ii) Each R ZA are independently selected from the group consisting of optionally substituted (C1-C3)alkyl and optionally substituted (C1-C3)heteroalkyl, and each RZB and R ZC Together with the N atom to which they are attached, they form an optionally substituted (C6)heterocycle, or

[0317] (c)(iii) Each R ZA 、R ZB and R ZC together with the N atom to which they are attached form an optionally substituted (C8)bicyclic heterocycle;

[0318] (d) in:

[0319] (d)(i) Each R ZA and R ZB are independently selected from the group consisting of optionally substituted (C1-C3)alkyl and optionally substituted (C1-C3)heteroalkyl, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C6)heterocyclyl, or

[0320] (d)(ii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C6) heterocyclyl, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C6)heterocyclyl, or

[0321] (d)(iii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C6) heterocyclyl, and each R ZC and R ZD together with the N atom to which they are attached, form an optionally substituted (C6)heterocycle;

[0322] (e) Each R ZA and R ZB together with the N atom to which they are attached, form an optionally substituted (C6)heteroaryl ring; and

[0323] (f) Each R ZA are independently selected from the group consisting of optionally substituted (C1-C3)alkyl and optionally substituted (C1-C3)heteroalkyl, and each R ZB and R ZC Together with the N atom to which they are attached they form an optionally substituted (C6)heteroaryl.

[0324] In some embodiments, when each R ZA、R ZB and / or R ZC When (when present) is an optionally substituted alkyl, each optionally substituted alkyl is unsubstituted.

[0325] In some embodiments, when each R ZA 、R ZB and / or R ZC When (when present) is an optionally substituted heteroalkyl, each optionally substituted heteroalkyl is unsubstituted.

[0326] In some embodiments, when each R ZB and R ZC When taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring, the optionally substituted heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluoro and (C1-C3)alkyl.

[0327] In some embodiments, when each R ZA 、R ZB and R ZC When taken together with the N atom to which they are attached to form an optionally substituted bicyclic heterocycle, the optionally substituted bicyclic heterocycle is unsubstituted.

[0328] In some embodiments, when each R ZA and R ZB When taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted heterocyclyl is unsubstituted.

[0329] In some embodiments, when each R ZB and R ZC Optionally substituted heteroaryl groups are unsubstituted when taken together with the nitrogen atom to which they are attached to form an optionally substituted heteroaryl group.

[0330] In some embodiments, when each R ZC and R ZD When taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl, the optionally substituted heterocyclyl is unsubstituted.

[0331] In some embodiments, when each R ZC and R ZD When taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring, the optionally substituted heterocyclic ring is unsubstituted.

[0332] In some embodiments, when each R ZA and R ZB When taken together with the N atom to which they are attached to form an optionally substituted heteroaryl ring, the optionally substituted heteroaryl rings are unsubstituted.

[0333] In some embodiments, each quaternary amine is independently selected from the group consisting of:

[0334] In some embodiments, each quaternary amine has an AN - a counterion that is the same for each quaternary amine and is selected from the group consisting of acetate, adipate, benzoate, benzenesulfonate, citrate, decanoate, chloride, lactate, maleate, methanesulfonate, oxalate, pivalate, propionate, succinate, sulfate, tartrate, or trifluoroacetate.

[0335] In some embodiments, when the amino acid residue is present 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 When at least one of the amino acid residues at that position each independently comprises at least one masked amine and / or masked amide.

[0336] In some embodiments, when the amino acid residue is present 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 When at least one of the amino acid residues at that position each independently comprises a masked amine and / or a masked amide.

[0337] In some embodiments, when the amino acid residue is present at position Z 5 、Z 7 、Z 8 、Z 10 、Z 13 、Z 14 、Z 15 and / or Z 16When at least one of the amino acid residues at that position each independently comprises at least one masked amine and / or masked amide.

[0338] In some embodiments, when the amino acid residue is present at position Z 5 、Z 7 、Z 8 、Z 10 、Z 13 、Z 14 、Z 15 and / or Z 16 When at least one of the amino acid residues at that position each independently comprises a masked amine and / or a masked amide.

[0339] In some embodiments, position Z 5 、Z 8 and / or Z 13 At least one of the amino acid residues at each of the positions independently comprises at least one masked amine and / or masked amide.

[0340] In some embodiments, position Z 5 、Z 8 and / or Z 13 At least one of the amino acid residues at each of the positions independently comprises a masked amine and / or a masked amide.

[0341] In some embodiments, position Z 5 The amino acid residue at position comprises at least one masked amine and / or masked amide.

[0342] In some embodiments, position Z 5 The amino acid residue at position comprises a masked amine and / or a masked amide.

[0343] In some embodiments, position Z 8 The amino acid residue at position comprises at least one masked amine and / or masked amide.

[0344] In some embodiments, position Z 8 The amino acid residue at position comprises a masked amine and / or a masked amide.

[0345] In some embodiments, position Z 13 The amino acid residue at position comprises at least one masked amine and / or masked amide.

[0346] In some embodiments, position Z 13 The amino acid residue at position comprises a masked amine and / or a masked amide.

[0347] In some embodiments, at least one of the masked amines is an amine in a backbone amide, wherein each amine in the backbone amide is independently substituted with a (C1-C3)alkyl group.

[0348] In some embodiments, at least one of a masked amine and / or a masked amide is present in the side chain of an amino acid residue comprising the masked amine and / or masked amide.

[0349] In some embodiments, at least one of the masked amine and / or the masked amide is independently selected from the group consisting of:

[0350] (a) Each R YA are independently selected from the group consisting of: optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R YB are independently selected from the group consisting of: hydrogen, optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl;

[0351] (b) Each R YC are independently selected from the group consisting of: optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R YD are independently selected from the group consisting of: hydrogen, optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl;

[0352] (c) Each R YE are independently selected from the group consisting of: optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R YF are independently selected from the group consisting of: hydrogen, optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl; and

[0353] (d) Each R YG and R YH are independently selected from the group consisting of: optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C20 ) heteroalkyl.

[0354] In some embodiments, at least one of the masked amine and / or the masked amide is independently selected from the group consisting of:

[0355] (a) Each R YA are independently selected from the group consisting of optionally substituted (C1-C5)alkyl and optionally substituted (C1-C 15 ) heteroalkyl, and each R YB are independently selected from the group consisting of hydrogen, optionally substituted (C1-C5)alkyl and optionally substituted (C1-C 15 ) heteroalkyl;

[0356] (b) Each R YC are independently selected from the group consisting of optionally substituted (C1-C5)alkyl and optionally substituted (C1-C 15 ) heteroalkyl, and each R YD are independently selected from the group consisting of hydrogen, optionally substituted (C1-C5)alkyl and optionally substituted (C1-C 15 ) heteroalkyl;

[0357] (c) Each R YE are independently selected from the group consisting of optionally substituted (C1-C5)alkyl and optionally substituted (C1-C 15 ) heteroalkyl, and each R YF are independently selected from the group consisting of hydrogen, optionally substituted (C1-C5)alkyl and optionally substituted (C1-C 15 ) heteroalkyl; and

[0358] (d) Each R YG and R YH are independently selected from the group consisting of optionally substituted (C1-C5)alkyl and optionally substituted (C1-C 15 ) heteroalkyl.

[0359] In some embodiments, when each R YA 、R YB 、R YC 、R YD 、R YE 、R YF 、R YG and / or R YHWhen 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 a quaternary amine as described herein, such as -N + (CH3)3.

[0360] In some embodiments, when each R YA 、R YB 、R YC 、R YD 、R YE 、R YF 、R YG and / or R YH When 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 a quaternary amine as described herein, such as -N + (CH3)3.

[0361] In some embodiments, at least one of the masked amine and / or the masked amide is independently selected from the group consisting of:

[0362]

[0363] In some embodiments, at least one amino acid residue, each independently 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(NMecPEG5 a), 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).

[0364] In some embodiments, at least one amino acid residue that each independently comprises at least one masked amine is not K(Ac).

[0365] In some embodiments, when position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at position is replaced by 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.

[0366] In some embodiments, when position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at position is replaced by 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.

[0367] In some embodiments, when position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at r is replaced by an amino acid residue, i.e., r substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0368] In some embodiments, when position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0369] In some embodiments, when position Z 3When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at position is replaced by a basic amino acid residue.

[0370] In some embodiments, when position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at position is replaced by an acidic amino acid residue.

[0371] In some embodiments, position Z 3 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0372] In some embodiments, position Z 4 The amino acid residue at is the residue of Abu or the residue of an amino acid containing a thiol group selected from the group consisting of Pen, C or aMeC.

[0373] In some embodiments, position Z 4 The amino acid residue at is the residue of Pen.

[0374] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at position is replaced by 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.

[0375] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at is replaced with an amino acid residue comprising at least one quaternary amine selected from the group consisting of APEG2Ser(S*), Dab(Me)3, K(cPEG3a) and K(Me)3.

[0376] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5The amino acid residue at position is replaced by an amino acid residue which is N(N(Me)2) substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl and -CN.

[0377] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0378] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0379] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0380] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at position is replaced by a basic amino acid residue.

[0381] In some embodiments, when position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at position is replaced by an acidic amino acid residue.

[0382] In some embodiments, position Z 5 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0383] In some embodiments, when position Z 6 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 6 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: A and L.

[0384] In some embodiments, when position Z 6 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 6The amino acid residue at position T is replaced by an amino acid residue, i.e., T substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0385] In some embodiments, when position Z 6 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 6 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0386] In some embodiments, when position Z 6 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 6 The amino acid residue at position is replaced by a polar amino acid residue.

[0387] In some embodiments, position Z 6 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0388] In some embodiments, when position Z 7 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 7 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Nal, A, F and L.

[0389] In some embodiments, when position Z 7 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 7 The amino acid residue at position is replaced by an amino acid residue, 7MeW substituted on the side chain by one or more groups selected from the group consisting of -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl and -CN.

[0390] In some embodiments, when position Z 7 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 7 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0391] In some embodiments, when position Z 7 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 7 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0392] In some embodiments, position Z 7 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0393] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by 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).

[0394] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by 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).

[0395] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by an amino acid residue, i.e., K(NMeAc) substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0396] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0397] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0398] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0399] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by a basic amino acid residue.

[0400] In some embodiments, when position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at position is replaced by an acidic amino acid residue.

[0401] In some embodiments, position Z 8 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0402] In some embodiments, position Z 9 The amino acid residue at is the residue of an amino acid containing a thiol group selected from the group consisting of Pen, C or aMeC.

[0403] In some embodiments, position Z 9 The amino acid residue at is the residue of Pen.

[0404] In some embodiments, when position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of 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(N Me), AEF(NMe2mPEG3), AEF(NMe3), AEF(NMeBismPEG3), AEF(NMePEG2a), AEF(NmPEG6), AEF(NsCh), AEF(PEG2a), AEF(SPD), APEG2F, APEG3F, dFPPEG 3F, diazabicyclooctane 6F, DMMMF, DMPMF, DMTASF, F(4G), F(4N3), F(4TzlDMA4mPEG), F(4TzlMME), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMMo4), F(4TzlTMA1), F(4 TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), GPEG3F, hFTMAPF, MMoEF, MMoPF, MMPEG3F, morfTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F , MPzPEG3F, MTASF, NPyEF, NPyPEG3F, piperazine quatF, 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(OZOXIM ECh), YC8CO(NHPEG3a), YC8COPip, YCF2H, ACHMF(R*,S*), ACHMF(S*,S*), AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7) and F(4TzlTMA7).

[0405] In some embodiments, when position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an amino acid residue comprising at least one quaternary amine 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(SP D), APEG2F, APEG3F, dFPPEG3F, diazabicyclooctane 6F, DMMMF, DMPMF, DMTASF, F(4TzlDMA4mPEG), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMMo 4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), F(4TzlMMo7), F(4TzlTMA7), hFTMAPF, MMoEF, MM oPF, MMPEG3F, morfTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, piperazinequatF, TBAPEG3F, TM A3F, TMA4F, TMA6F, TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OT zlC1aC8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh) and YC8CO(NHPEG3a).

[0406] In some embodiments, when position Z 10When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an amino acid residue, ie, TMAPF substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0407] In some embodiments, when position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an amino acid residue having the following structure:

[0408]

[0409] in:

[0410] Ln 1 Selected from the group consisting of: -O- atoms, The right hand side of each depicted structure is Ln 2 Combine;

[0411] Ln 2 is a linker moiety comprising:

[0412] (i) at least 4 atoms, such as optionally substituted alkylene containing at least C4 atoms, optionally substituted heteroalkylene containing at least C4 atoms, optionally substituted heteroalkenylene containing at least C4 atoms, optionally substituted alkynylene containing at least C4 atoms, optionally substituted alkylene-optionally substituted carbocyclyl containing at least C4 atoms or optionally substituted alkylene-optionally substituted heterocyclyl containing at least C4 atoms, such as optionally substituted (C4-C 20 )alkylene, optionally substituted (C4-C 20 )heteroalkylene, optionally substituted (C4-C 20 )heteroalkenylene, optionally substituted (C4-C 20 )alkynylene, optionally substituted (C1-C3)alkylene-optionally substituted (C3-C 10 )carbocyclyl or optionally substituted (C1-C3)alkylene-optionally substituted (C3-C 14 ) a heterocyclic group, or

[0413] (ii) At least 2 atoms, when Ln 1 yes When, for example, optionally substituted alkylene containing at least C2 atoms or optionally substituted heteroalkylene containing at least C2 atoms, for example optionally substituted (C2-C 20)alkylene or optionally substituted (C2-C 20 )heteroalkylene; and

[0414] Qu 1 It is a quaternary amine.

[0415] In some embodiments, when position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an amino acid residue having the following structure:

[0416]

[0417] Among them, Ln 1 、Ln 2 and Qu 1 As defined herein.

[0418] In some embodiments, Qu 1 is a quaternary amine as defined herein.

[0419] In some embodiments, Ln 1 It is an -O- atom.

[0420] In some embodiments, Ln 2 Selected from the group consisting of: 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)carbocyclyl, or optionally substituted (C1-C3)alkylene-optionally substituted (C5-C7)heterocyclyl.

[0421] In some embodiments, Ln 2 Selected from the group consisting of: 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)carbocyclyl, or optionally substituted (C1-C3)alkylene-optionally substituted (C6)heterocyclyl.

[0422] In some embodiments, Ln 2Selected 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)carbocyclyl or optionally substituted (C1-C3)alkylene-optionally substituted (C6)heterocyclyl.

[0423] In some embodiments, when Ln 1 yes When Ln 2 Selected from optionally substituted (C2-C 15 )alkylene or optionally substituted (C2-C 15 ) a group consisting of heteroalkylene.

[0424] In some embodiments, when Ln 1 yes When Ln 2 Selected from optionally substituted (C2-C 10 )alkylene or optionally substituted (C2-C 10 ) a group consisting of heteroalkylene.

[0425] In some embodiments, when Ln 1 yes When Ln 2 Selected from the group consisting of optionally substituted (C2-C5)alkylene or optionally substituted (C2-C5)heteroalkylene.

[0426] In some embodiments, when Ln 2 When optionally substituted alkylene, the optionally substituted alkylene is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluorine.

[0427] In some embodiments, when Ln 2 When is an optionally substituted heteroalkylene, the optionally substituted heteroalkylene is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C1-C3)alkyl, =O (ie, two geminal hydrogens on a carbon atom of the heteroalkylene group are replaced by a group =O) or a quaternary amine as described herein, for example, -N + (CH3)3.

[0428] In some embodiments, when Ln 2 When is optionally substituted heteroalkenylene, the optionally substituted heteroalkenylene is unsubstituted.

[0429] In some embodiments, when Ln 2 When it is an optionally substituted alkynylene group, the optionally substituted alkynylene group is unsubstituted.

[0430] In some embodiments, when Ln 2 In the case of an optionally substituted alkylene-optionally substituted carbocyclyl, the optionally substituted alkylene-optionally substituted carbocyclyl is unsubstituted.

[0431] In some embodiments, when Ln 2 In the case of an optionally substituted alkylene-optionally substituted heterocyclic group, the optionally substituted alkylene-optionally substituted heterocyclic group is unsubstituted.

[0432] In some embodiments, when position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an amino acid residue having the following structure:

[0433]

[0434] in:

[0435] Ln 3 Selected from the group consisting of: -O- atoms, The right hand side of each depicted structure is Ln 4 Combine;

[0436] Ln 4 is a linker moiety comprising at least 2 atoms, such as an optionally substituted alkylene group comprising at least C2 atoms, an optionally substituted heteroalkylene group comprising at least C2 atoms, or an optionally substituted alkynylene group comprising at least C2 atoms, such as an optionally substituted (C2-C 20 )alkylene, optionally substituted (C2-C 20 )heteroalkylene or optionally substituted (C2-C 20 )alkynylene; and

[0437] Qu 2 Yes (C3-C 14 ) heterocyclic quaternary amine, (C5-C 14 ) heteroaryl quaternary amine or (C5-C 14 ) bicyclic heterocyclic quaternary amine, for example, selected from the group consisting of (C3-C 14 ) Heterocyclic quaternary amine: (C5-C 14 ) Heteroaryl quaternary amine: Or choose free The group consisting of (C5-C 14 ) Bicyclic heterocyclic quaternary amine.

[0438] In some embodiments, when position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an amino acid residue having the following structure:

[0439]

[0440] Among them, Ln 3 、Ln 4 and Qu 2 As defined herein.

[0441] In some embodiments, Qu 2 is a quaternary amine as defined herein.

[0442] In some embodiments, Ln 3 It is an -O- atom.

[0443] In some embodiments, Ln 4 Selected from the group consisting of: optionally substituted (C2-C 15 )alkylene, optionally substituted (C2-C 15 )heteroalkylene or optionally substituted (C2-C 15 )alkynylene.

[0444] In some embodiments, Ln 4 Selected from the group consisting of: optionally substituted (C2-C 10 )alkylene, optionally substituted (C2-C 10 )heteroalkylene or optionally substituted (C2-C 10 )alkynylene.

[0445] In some embodiments, Ln 4 is selected from the group consisting of optionally substituted (C2-C8)alkylene, optionally substituted (C2-C8)heteroalkylene, or optionally substituted (C2-C8)alkynylene.

[0446] In some embodiments, when Ln 4 When optionally substituted alkylene, the optionally substituted alkylene is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluorine.

[0447] In some embodiments, when Ln 4 When is an optionally substituted heteroalkylene, the optionally substituted heteroalkylene is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: (C1-C3)alkyl, =O (ie, two geminal hydrogens on a carbon atom of the heteroalkylene group are replaced by a group =O) or a quaternary amine as described herein, for example, -N + (CH3)3.

[0448] In some embodiments, when Ln 4 When it is an optionally substituted alkynylene group, the optionally substituted alkynylene group is unsubstituted.

[0449] In some embodiments, when position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0450] In some embodiments, position Z 10 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0451] In some embodiments, when position Z 11 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 11 The amino acid residue at position is replaced with an amino acid residue selected from the group consisting of: A, F, L and W.

[0452] In some embodiments, when position Z 11 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 11 The amino acid residue at position is replaced by an amino acid residue, i.e. 2Nal substituted on the side chain naphthalene ring by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl and -CN.

[0453] In some embodiments, when position Z 11 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 11 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0454] In some embodiments, when position Z 11 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 11 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0455] In some embodiments, position Z 11 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0456] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by 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.

[0457] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced with an amino acid residue comprising at least one quaternary amine selected from the group consisting of: Pip(NMe2).

[0458] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by an amino acid residue, ie, THP substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0459] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0460] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0461] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by a polar amino acid residue.

[0462] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0463] In some embodiments, when position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by a basic amino acid residue.

[0464] In some embodiments, position Z 12 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0465] In some embodiments, when position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by 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.

[0466] In some embodiments, when position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13The amino acid residue at position is replaced by 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).

[0467] In some embodiments, when position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by an amino acid residue, i.e., K(NMeAc) substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0468] In some embodiments, when position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0469] In some embodiments, when position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0470] In some embodiments, when position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0471] In some embodiments, when position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by an acidic amino acid residue.

[0472] In some embodiments, position Z 13 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0473] In some embodiments, when position Z 14When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 14 The amino acid residue at is replaced with an amino acid residue selected from the group consisting of K(Ac) and N(NMe).

[0474] In some embodiments, when position Z 14 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 14 The amino acid residue at position is replaced by an amino acid residue wherein N is substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl and -CN.

[0475] In some embodiments, when position Z 14 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 14 The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0476] In some embodiments, position Z 14 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0477] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of 3pya, 5CF33Pya, 5MepyridineAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y and A.

[0478] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by an amino acid residue, i.e., 3Pya substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0479] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15The amino acid residue at position is replaced with an amino acid residue comprising at least one quaternary amine selected from the group consisting of: NMe3Pya.

[0480] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0481] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by an aliphatic amino acid residue.

[0482] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by a polar amino acid residue.

[0483] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0484] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by a basic amino acid residue.

[0485] In some embodiments, when position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by a non-polar amino acid residue.

[0486] In some embodiments, position Z 15 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0487] In some embodiments, when position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16The amino acid residue at position is replaced by 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(PEG2PEG2PEG2gEC12)2), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12), and NMeK(SP6PEG2PEG2gEC12.

[0488] In some embodiments, when position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at is replaced with an amino acid residue comprising at least one quaternary amine selected from the group consisting of NMeK(SP6PEG2PEG2C12) and NMeK(SP6PEG2PEG2gEC12).

[0489] In some embodiments, when position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at position is replaced by an amino acid residue, ie, Sar substituted on the side chain by one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl and -CN.

[0490] In some embodiments, when position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at position is replaced by an aromatic amino acid residue.

[0491] In some embodiments, when position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at position is replaced by an acidic amino acid residue.

[0492] In some embodiments, when position Z 16When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at position is replaced by a polar amino acid residue.

[0493] In some embodiments, when position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at position is replaced by a hydrophilic amino acid residue.

[0494] In some embodiments, when position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at position is replaced by a non-polar amino acid residue.

[0495] In some embodiments, position Z 16 The amino acid residue at that position is replaced by an amino acid residue different from the amino acid residue listed at that position.

[0496] In some embodiments, the designated amino acid residue at a given position is substituted on the side chain with one or more groups selected from the group consisting of: -OH, -(C1-C4)alkyl, -O(C1-C4)alkyl, and -CN.

[0497] In some embodiments, R NT Selected from the group consisting of: -C(O)-optionally substituted (C1-C 15 )alkyl and -C(O)-optionally substituted (C1-C 35 ) heteroalkyl.

[0498] In some embodiments, R NT Selected from the group consisting of: -C(O)-optionally substituted (C1-C 10 )alkyl and -C(O)-optionally substituted (C1-C 35 ) heteroalkyl.

[0499] In some embodiments, R NT Selected from the group consisting of: -C(O)-optionally substituted (C1-C8)alkyl and -C(O)-optionally substituted (C1-C8)alkyl 30 ) heteroalkyl.

[0500] In some embodiments, R NT Selected from the group consisting of: -C(O)-optionally substituted (C1-C6)alkyl and -C(O)-optionally substituted (C1-C6)alkyl 30 ) heteroalkyl.

[0501] In some embodiments, R NT Selected from the group consisting of: (d)gEPEG2PEG2CO, 4cpgCO, 5cpaCO, AcdPEG12CO, AcdPEG6CO, AcdPEG9CO, C12gEPEG2PEG2CO, C14gEPEG2PEG2CO, CF3CO, CF3propylamide, cPEG2gCO, cPEG3aCO, cPEG3gCO, cPEG5aCO, EtCO, F3CO, MeCO, mPEG3CO, mPEG6CO, cPEG3AmCO, DFNCO, DFNPEG2PEG2CO, IPBCO and IPBPEG2PEG2CO.

[0502] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 20 )alkyl, such as 4cpgCO, CF3CO, CF3propylamide, EtCO, F3CO, MeCO or 5cpaCO.

[0503] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 20 )alkyl, which contains a quaternary amine, such as 5cpaCO.

[0504] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 40 ) heteroalkyl, such as AcdPEG12CO, AcdPEG6CO, AcdPEG9CO, C12gEPEG2PEG2CO, cPEG2gCO, cPEG3gCO, mPEG3CO, mPEG6CO, (d)gEPEG2PEG2CO, cPEG3aCO and cPEG5aCO.

[0505] In some embodiments, R NT is -C(O)-optionally substituted (C1-C 40 ) heteroalkyl groups containing quaternary amines, such as (d) gEPEG2PEG2CO, cPEG3aCO, cPEG5aCO.

[0506] In some embodiments, R NT is -C(O)-optionally substituted heteroalkyl, which includes hydrophilic polymers such as polyethylene glycol (PEG).

[0507] In some embodiments, R NTis a -C(O)- optionally substituted heteroalkyl group comprising the formula -[O-CH2CH2]n-, wherein n is an integer, for example wherein:

[0508] (i) n is an integer from about 1 to about 20;

[0509] (ii) n is an integer from about 1 to about 15;

[0510] (iii) n is an integer from about 1 to about 10; or

[0511] (iv) n is an integer from about 2 to about 12.

[0512] In some embodiments, when R NT is -C(O)-optionally substituted heteroalkyl, the -C(O)-optionally substituted heteroalkyl is unsubstituted or 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 a carbon atom of the heteroalkyl are replaced by a group =O), or a quaternary amine as described herein, such as -N + (CH3)3.

[0513] In some embodiments, when R NT When it is -C(O)-optionally substituted alkyl, the -C(O)-optionally substituted alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluorine, -NH(C=NH)NH2, or a quaternary amine as described herein, such as -N + (CH3)3.

[0514] In some embodiments:

[0515] (i) Each R Y and R Z are independently selected from the group consisting of: hydrogen, optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 25 ) heteroalkyl, or

[0516] (ii)R Y and R Z Together with the N atom to which they are attached, they form an optionally substituted (C 5-7 )heterocycle or optionally substituted (C7-C9)bicyclic heterocycle.

[0517] In some embodiments:

[0518] (i) Each R Y and RZ are independently selected from the group consisting of hydrogen, optionally substituted (C1-C8)alkyl and optionally substituted (C1-C 20 ) heteroalkyl, or

[0519] (ii)R Y and R Z Together with the N atom to which they are attached they form an optionally substituted (C6) heterocycle or an optionally substituted (C8) bicyclic heterocycle.

[0520] In some embodiments, R CT 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.

[0521] In some embodiments, R CT Selected from the group consisting of optionally substituted amine, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl and optionally substituted 3-oxa-8-azabicyclo[3.2.1]octyl.

[0522] In some embodiments, R CT It is N(R Y )(R Z ), where R Y is hydrogen and R Z is optionally substituted (C1-C 30 ) heteroalkyl groups containing a quaternary amine, such as CO(NHPEG3a), CONH(PEG3a) or CONH(PEG5a).

[0523] In some embodiments, when R Y and / or R Z When optionally substituted alkyl, each optionally substituted alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of a quaternary amine as described herein, for example, -N + (CH3)3.

[0524] In some embodiments, when R Y and / or R Z When optionally substituted heteroalkyl, each optionally substituted heteroalkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of a quaternary amine as described herein, for example, -N +(CH3)3.

[0525] In some embodiments, when R Y and R Z When taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring, such as optionally substituted amine, optionally substituted piperidinyl, optionally substituted piperazinyl, and optionally substituted morpholinyl, the optionally substituted heterocyclic ring is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluorine, -OH, -CF3, (C1-C3)alkyl, or a quaternary amine as described herein, such as -N + (CH3)3.

[0526] In some embodiments, when R Y and R Z When taken together with the nitrogen atom to which they are attached to form an optionally substituted bicyclic heterocycle, such as optionally substituted 3-oxa-8-azabicyclo[3.2.1]octyl, the optionally substituted bicyclic heterocycle is unsubstituted or substituted with one or more substituents independently selected from the group consisting of fluorine, -OH, -CF3, (C1-C3)alkyl, or a quaternary amine as described herein, such as -N + (CH3)3.

[0527] In some embodiments, the cyclic peptide further comprises one or more natural or non-natural polymers or combinations thereof.

[0528] In some embodiments, the cyclic peptide further comprises a natural or non-natural polymer or a combination thereof.

[0529] In some embodiments, the cyclic peptide further comprises NT (when present) and / or R CT (when 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 The invention also provides one or more natural or non-natural polymers or combinations thereof conjugated to the amino acid residue at the position (when the amino acid residue is present at that position).

[0530] In some embodiments, the cyclic peptide further comprises NT (when present) or R CT (when present) or position Z 3 、Z 5 、Z 6、Z 7 、Z 8 、Z 10 、Z 11 、Z 12 、Z 13 、Z 14 、Z 15 or Z 16 The invention also provides a natural or non-natural polymer or a combination thereof conjugated to an amino acid residue at the position (when the amino acid residue is present at that position).

[0531] The properties of natural or non-natural polymers or combinations thereof can be optimized by changing the length, conformation (e.g., branched or linear) and / or functionalization (e.g., adding negatively charged groups) of the natural or non-natural polymers or combinations thereof. For example, natural or non-natural polymers or combinations thereof can be modified to increase the solubility of the cyclic peptides of the invention, avoid aggregation of the cyclic peptides of the invention, etc. For example, natural or non-natural polymers or combinations thereof can be modified by including hydrophilic or water-soluble polymers (including but not limited to PEG, charged PEG molecules, amino acids, or combinations thereof) to increase the solubility of the cyclic peptides of the invention and avoid aggregation of the cyclic peptides of the invention.

[0532] In one embodiment, the natural or non-natural polymer or combination thereof is water soluble, e.g., such that the cyclic peptide of the invention does not precipitate out in an aqueous (e.g., physiological) environment. In addition, the natural or non-natural polymer or combination thereof is biocompatible, e.g., does not cause damage, toxicity, or an immune response in vivo.

[0533] Non-limiting examples of natural polymer groups are amino acid sequences containing about 10 to about 30 amino acids, which are derived from (poly)peptides such as natriuretic peptide precursor C, atrial natriuretic peptide, brain natriuretic peptide, serum albumin, IgG, histidine-rich glycoproteins, fibronectin, fibrinogen, zinc finger-containing polypeptides, osteoin or fibroblast growth factor 2 (FGF2), or variants thereof with substitutions and / or deletions. Non-limiting examples of non-natural polymer groups (e.g., synthetic polymers) are polyethylene glycol (PEG, also known as polyethylene oxide (PEO)).

[0534] In one embodiment, natural or non-natural polymers comprise a residue selected from amino acids or carbohydrates or a combination thereof. In one embodiment, natural or non-natural polymers or a combination thereof comprise an amino acid sequence. In one embodiment, natural or non-natural polymers or a combination thereof comprise about 10 to about 30 amino acid residues. In one embodiment, natural or non-natural polymers or a combination thereof comprise about 10 to about 25 amino acid residues. In one embodiment, natural or non-natural polymers or a combination thereof comprise about 15 to about 20 amino acid residues.

[0535] 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).

[0536] In one embodiment, the natural or non-natural polymer or combination thereof comprises an optionally substituted heteroalkylene. In one embodiment, the natural or non-natural polymer or combination thereof is an optionally substituted heteroalkylene. In one embodiment, the natural or non-natural polymer or combination thereof comprises an optionally substituted (C 10 -C 200 In one embodiment, the natural or non-natural polymer or a combination thereof is optionally substituted (C 10 -C 200 In one embodiment, the natural or non-natural polymer or a combination thereof comprises an optionally substituted (C 10 -C 150 In one embodiment, the natural or non-natural polymer or a combination thereof is optionally substituted (C 10 -C 150 In one embodiment, the natural or non-natural polymer or a combination thereof comprises an optionally substituted (C 10 -C 100 In one embodiment, the natural or non-natural polymer or a combination thereof is optionally substituted (C 10 -C 100 In one embodiment, the natural or non-natural polymer or a combination thereof comprises an optionally substituted (C 10 -C 90 In one embodiment, the natural or non-natural polymer or a combination thereof is optionally substituted (C 10 -C 90 In one embodiment, the natural or non-natural polymer or a combination thereof comprises an optionally substituted (C 10 -C 80 In one embodiment, the natural or non-natural polymer or a combination thereof is optionally substituted (C 10 -C 80 In one embodiment, the natural or non-natural polymer or a combination thereof comprises an optionally substituted (C 10 -C 70 In one embodiment, the natural or non-natural polymer or a combination thereof is optionally substituted (C 10 -C 70In one embodiment, the natural or non-natural polymer or a combination thereof comprises an optionally substituted (C 10 -C 60 In one embodiment, the natural or non-natural polymer or a combination thereof is optionally substituted (C 10 -C 60 ) heteroalkylene. In one embodiment, for every 10 carbons in the optionally substituted heteroalkylene, the natural or non-natural polymer or combination thereof contains about 1 to about 7 heteroatoms independently selected from the group consisting of N, O, S, and P. In one embodiment, for every 10 carbons in the optionally substituted heteroalkylene, the natural or non-natural polymer or combination thereof contains about 1 to about 5 heteroatoms independently selected from the group consisting of N, O, S, and P. In one embodiment, the heteroatoms are independently selected from the group consisting of N, O, or S. In one embodiment, the heteroatoms are independently selected from the group consisting of N or O.

[0537] In one embodiment, the natural or non-natural polymer or combination thereof is a combination of naturally occurring monomeric units and synthetic monomeric units, such as a combination of amino acid monomeric units and PEG monomeric units.

[0538] In one embodiment, natural or non-natural polymers or their combination include hydrophilic polymers. In one embodiment, natural or non-natural polymers or their combination are hydrophilic polymers. In one embodiment, hydrophilic polymers can be side-chain or non-side-chain. In one embodiment, hydrophilic polymers are not side-chain. The present invention contemplates the use of hydrophilic or water-soluble polymers (e.g., PEG), its type (e.g., homopolymer or copolymer; random, alternating or block copolymer; straight or side-chain), bond (e.g., hydrolyzable or stable bond, such as amide, imine, aminal, alkylene or ester bond) and length (e.g., about 0.2kDa, 0.4kDa or 0.6kDa to about 2kDa, 3kDa, 4kDa or 5kDa, such as about 0.2kDa to about 5kDa) can vary. Non-limiting examples of hydrophilic polymers that can be used in the present invention include polymers formed from monomers with carboxylic acids (e.g., methacrylic acid (MA) and acrylic acid (AA)), polyvinyl alcohol, polymers formed from monomers with hydroxyl groups (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), trifluoroethanesulfonyl monomethoxy-PEG, aryloxy-PEG, PEG acrylate (PEGA), PEG methacrylate, PEG propionaldehyde, bissuccinimidyl carbonate PEG, copolymers of 2-methacryloyloxyethyl-phosphorylcholine (MPC) and N-vinylpyrrolidone (VP), hydroxyl-functional poly(N-vinylpyrrolidone) (PVP), SIS-PEG (SIS is polystyrene-polyisobutylene-polystyrene block copolymer), polystyrene-PEG, polyisobutylene-PEG, PCL-PEG (PCL is polycaprolactone), PLA-PEG (PLA is polylactic acid), PMMA-PEG (PMMA is poly(methyl methacrylate)), PDMS-PEG (PDMS is polydimethyloxycyclohexanone), PVDF-PEG (PVDF is polyvinylidene fluoride), PLURONIC TM Surfactants (polypropylene oxide-co-polyethylene glycol), poly(butylene 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(ethyleneimine-g-ethylene glycol) (PEI-g-PEG), poly(ethyleneimine-g-hyaluronic acid) (PEI-g-HA), poly(ethyleneimine-g-phosphorylcholine) (PEI-g-PC), poly(ethyleneimine-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 acid sulfate, acrylic acid sulfonate, acrylic acid sulfamate, methacrylic acid sulfate, methacrylic acid sulfonate, methacrylic acid sulfamate, polymers and copolymers thereof, and polymers and copolymers of combinations thereof.

[0539] In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises one or more aromatic compounds, such as dihydroxybenzoic acid (e.g., 3,5-dihydroxybenzoic acid), biphenyl diphenol (e.g., 4,4'-biphenyl diphenol), or 4-hydroxybenzyl alcohol, wherein each of the one or more aromatic compounds is linked to two hydrophilic polymers, such as PEG.

[0540] 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 speaking, "PEGn" polymers associated with the number n comprise the formula: -[O-CH2CH2]n-, where n is the number of ethylene oxide units. In one embodiment, natural or non-natural polymers or combinations thereof comprise 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 another embodiment, n is an integer from about 12 to about 24. In 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.

[0541] In one embodiment, natural or non-natural polymer or their combination is at least about 0.4kDa, 0.6kDa, 0.8kDa, 1kDa, 1.2kDa, 1.4kDa, 1.6kDa or 1.8kDa, or at most about 2kDa, 2.2kDa, 2.4kDa, 2.6kDa, 2.8kDa, 3kDa, 3.2kDa, 3.4kDa, 3.6kDa, 3.8kDa, 4kDa, 4.2kDa, 4.4kDa, 4.6kDa, 4.8kDa or 5kDa. In another embodiment, natural or non-natural polymer or their combination is in the range of about 0.4kDa to about 2.5kDa or about 0.6kDa to about 1.5kDa. In one embodiment, natural or non-natural polymer or their combination is at least about 0.2kDa. In one embodiment, natural or non-natural polymer or their combination is at least about 0.4kDa. 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, natural or non-natural polymers or their combination is from about 0.4kDa to about 2kDa. In one embodiment, natural or non-natural polymers or their combination is from about 0.4kDa to about 3kDa. In one embodiment, natural or non-natural polymers or their combination is from about 0.4kDa to about 4kDa. In one embodiment, natural or non-natural polymers or their combination is from about 0.6kDa to about 2kDa. In one embodiment, natural or non-natural polymers or their combination is from about 0.6kDa to about 3kDa. In one embodiment, natural or non-natural polymers or their combination is from about 0.6kDa to about 4kDa. In one embodiment, the size (in kDa) of natural or non-natural polymers or their combination can be measured using mass spectrometry.In one embodiment, the size (in kDa) of a natural or non-natural polymer or combination thereof is determined using mass spectrometry.

[0542] In one embodiment, the natural or non-natural polymer or combination thereof (e.g., a hydrophilic or water-soluble polymer (e.g., PEG)) is functionalized with one or more functional groups that impart a negative charge to the natural or non-natural polymer or combination thereof under physiological conditions (e.g., a carboxyl, sulfate, or phosphate group or a combination thereof). In one embodiment, the natural or non-natural polymer or combination thereof (e.g., a hydrophilic or water-soluble polymer (e.g., PEG)) is functionalized with one or more functional groups that impart a positive charge to the polymer under physiological conditions (such as an amine or tertiary amine).

[0543] In one embodiment, the natural or non-natural polymer, or a combination thereof, comprises one or more cleavable groups, such as disulfides, esters, and / or carbonates.

[0544] In some embodiments, the cyclic peptide is an inhibitor of the interleukin-23 (IL-23) receptor.

[0545] In some embodiments, the cyclic peptide inhibits the binding of interleukin-23 (IL-23) to the IL-23 receptor.

[0546] In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor to reduce or prevent activation of Jak-Stat signaling molecules, Jak2, Tyk2, Stat1, Stat 3, Stat 4, and / or Stat 5.

[0547] In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor to reduce or prevent Stat 3 phosphorylation.

[0548] In some embodiments, the cyclic peptides are expressed in reporter gene assays with an IC of less than about 6.3 μM. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 2 μM in a reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 1 μM in a reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.5 μM in a reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.25 μM in a reporter gene assay. 50In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.1 μM in a reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.05 μM in a reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.025 μM in a reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.01 μM in a reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.005 μM in an IL-23 reporter gene assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.0025 μM in a reporter gene assay. 50 The value inhibits the interleukin-23 (IL-23) receptor.

[0549] In some embodiments, the IL-23 reporter gene assay is as described in the specification. In some embodiments, the cyclic peptide is expressed in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay with an IC of less than about 0.05 nM. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.04 nM in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.03 nM in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.02 nM in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay. 50 In some embodiments, the cyclic peptide inhibits the interleukin-23 (IL-23) receptor with an IC value of less than about 0.01 nM in a peripheral blood mononuclear cell (PBMC) pSTAT3 assay. 50 In some embodiments, the peripheral blood mononuclear cell (PBMC) pSTAT3 assay is as described in the instructions.

[0550] In some embodiments, the cyclic peptide exhibits less than about In some embodiments, the cyclic peptide exhibits an exposed polar surface area (EPSA) of less than about In some embodiments, the cyclic peptide exhibits an exposed polar surface area (EPSA) of less than about In some embodiments, the cyclic peptide exhibits an exposed polar surface area (EPSA) of less than about In some embodiments, the cyclic peptide exhibits an exposed polar surface area (EPSA) of less than about In some embodiments, the cyclic peptide exhibits an exposed polar surface area (EPSA) of less than about In some embodiments, the cyclic peptide exhibits an exposed polar surface area (EPSA) of less than about In some embodiments, the cyclic peptide exhibits an exposed polar surface area (EPSA) of less than about In some embodiments, the exposed polar surface area (EPSA) is determined as described in the instructions.

[0551] In another general aspect, the present invention relates to one or more compounds 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:

[0552] In another general aspect, the present invention relates to a pharmaceutical composition comprising a cyclic peptide as described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0553] In some embodiments, the pharmaceutical composition further comprises an enteric coating.

[0554] In some embodiments, the enteric coating protects the pharmaceutical composition and releases the pharmaceutical composition within the lower gastrointestinal system of a subject.

[0555] In another general aspect, the present invention relates to a method for treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chedi A method for treating Ak-Higashi syndrome and Wiskott-Aldrich syndrome, pouchitis caused by proctocolectomy 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, which comprises providing to the subject an effective amount of a cyclic peptide as described herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described herein.

[0556] In some embodiments of the methods described herein, the cyclic peptide or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition is provided to the subject by oral, parenteral, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, aerosolization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topical, vaginal or local administration.

[0557] 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 a pharmaceutical composition thereof, is provided to the subject orally.

[0558] In some embodiments of the methods described herein for treating psoriasis, the cyclic peptide, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously.

[0559] In some embodiments, the cyclic peptides described herein or the pharmaceutical compositions described herein are useful in treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome in a subject. , Chediak-Higashi syndrome and Wiskott-Aldrich syndrome, pouchitis caused by proctocolectomy 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, which comprises providing to the subject an effective amount of the cyclic peptide as described herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described herein.

[0560] In some embodiments, the cyclic peptide or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition is provided to a subject by oral, parenteral, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, aerosolization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topical, vaginal or local administration.

[0561] In some embodiments, when the cyclic peptide for use or the pharmaceutical composition for use as described herein is used to treat 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 to the subject orally.

[0562] In some embodiments, when the cyclic peptide or pharmaceutical composition used as described herein is used to treat psoriasis, the cyclic peptide or a pharmaceutically acceptable salt or solvate thereof or the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneally or intravenously.

[0563] In some embodiments, the cyclic peptides or pharmaceutical compositions described herein are used as medicaments.

[0564] In some embodiments, the use of a cyclic peptide or pharmaceutical composition as described herein is for the manufacture of a medicament for treating a disease.

[0565] In some embodiments, the use of a cyclic peptide or pharmaceutical composition as described herein is for the manufacture of a medicament for treating a disease disclosed herein.

[0566] Specific cyclic peptides of the present invention

[0567] Specifically, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, which comprises an amino acid sequence of formula (A):

[0568] 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),

[0569] in:

[0570] Position Z 3 The amino acid residue at position is absent or is an r residue;

[0571] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0572] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0573] Position Z 6 The amino acid residue at is the residue of T;

[0574] Position Z 7 The amino acid residue at is a 7MeW residue;

[0575] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0576] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0577] Position Z 10 The amino acid residue at is the residue of TMAPF;

[0578] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0579] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0580] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0581] Position Z 14 The amino acid residue at position is an N residue;

[0582] Position Z 15 The amino acid residue at the position is absent or is a 3Pya residue;

[0583] Position Z 16 The amino acid residue at the position is absent or is a Sar residue;

[0584] When the amino acid residue is present 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 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position;

[0585] When the position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at is replaced by 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;

[0586] When the position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5The amino acid residue at position is replaced by 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;

[0587] When the position Z 6 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 6 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: A and L;

[0588] When the position Z 7 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 7 The amino acid residue at is replaced by an amino acid residue selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Nal, A, F and L;

[0589] When the position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 wherein the amino acid residue at position is replaced by 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);

[0590] When the position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of AEF, 4DMPEF, 4DMPzEF, 4TMABYF, ACHMF, AEF((Ch)cPEG3a), AEF(Ac), AEF(AcCh), AEF(aPEG2a), AEF(BisMEP), AEF(BisMEPa), AEF(BisPEG2a)(RS), AEF(BisPEG2a)(S*),

[0591] 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, Diazabicyclooctane 6F, DMMMF, DMPMF, DMTASF, F(4G), F(4N3), F(4TzlDMA4mPEG), F(4TzlMME), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMM o4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), GPEG3F, hFTMAPF, MMoEF, MMoPF, MMPEG3F, mor fTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, piperazine quatF, TBAPEG3F, TMA3F, TMA4F, TM A6F, TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(C9OH), Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OTzlC 1aC8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), YC8CO(NHPEG3a), Y C8COPip, YCF2H, ACHMF(R*,S*), ACHMF(S*,S*), AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7) and F(4TzlTMA7);

[0592] When the position Z 11 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 11 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: A, F, L and W;

[0593] When the position Z 12When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by 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;

[0594] When the position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by 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;

[0595] When the position Z 14 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 14 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: K(Ac) and N(NMe);

[0596] When the position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of 3pya, 5CF33Pya, 5MepyridineAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y, and A;

[0597] When the position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 wherein the amino acid residue at the alkylene oxide 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(PEG2PEG2PEG2gEC12)2), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12), and NMeK(SP6PEG2PEG2gEC12); and

[0598] When the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one quaternary amine.

[0599] Specifically, the present invention relates to a cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, which comprises an amino acid sequence of formula (B):

[0600] Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 (B),

[0601] in:

[0602] Position Z 3 The amino acid residue at position is absent or is an r residue;

[0603] Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is attached;

[0604] Position Z 5 The amino acid residue at is an N(N(Me)2) residue;

[0605] Position Z 6 The amino acid residue at is the residue of T;

[0606] Position Z 7 The amino acid residue at is a 7MeW residue;

[0607] Position Z 8 The amino acid residue at is the residue of K(NMeAc);

[0608] Position Z 9 The amino acid residue at position Z 4 the amino acid residue to which the amino acid residue at is attached;

[0609] Position Z 10 The amino acid residue at is the residue of TMAPF;

[0610] Position Z 11 The amino acid residue at is the residue of 2Nal;

[0611] Position Z 12 The amino acid residue at the position is absent or is a THP residue;

[0612] Position Z 13 The amino acid residue at is the residue of K(NMeAc);

[0613] Position Z 14 The amino acid residue at position is an N residue;

[0614] Position Z 15 The amino acid residue at the position is absent or is a 3Pya residue;

[0615] Position Z 16 The amino acid residue at the position is absent or is a Sar residue;

[0616] When the amino acid residue is present 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 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position;

[0617] When the position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at is replaced by 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;

[0618] When the position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at position is replaced by 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;

[0619] When the position Z 6When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 6 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: A and L;

[0620] When the position Z 7 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 7 The amino acid residue at is replaced by an amino acid residue selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Nal, A, F and L;

[0621] When the position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 wherein the amino acid residue at position is replaced by 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);

[0622] When the position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of AEF, 4DMPEF, 4DMPzEF, 4TMABYF, ACHMF, AEF((Ch)cPEG3a), AEF(Ac), AEF(AcCh), AEF(aPEG2a), AEF(BisMEP), AEF(BisMEPa), AEF(BisPEG2a)(RS), AEF(BisPEG2a)(S*),

[0623] 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, Diazabicyclooctane 6F, DMMMF, DMPMF, DMTASF, F(4G), F(4N3), F(4TzlDMA4mPEG), F(4TzlMME), F(4TzlMMo1), F(4TzlMMo3), F(4TzlMM o4), F(4TzlTMA1), F(4TzlTMA2), F(4TzlTMA3), F(4TzlTMA4), F(4TzlTMA5), GPEG3F, hFTMAPF, MMoEF, MMoPF, MMPEG3F, mor fTMA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, piperazine quatF, TBAPEG3F, TMA3F, TMA4F, TM A6F, TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(C9OH), Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OTzlC 1aC8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), YC8CO(NHPEG3a), Y C8COPip, YCF2H, ACHMF(R*,S*), ACHMF(S*,S*), AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7) and F(4TzlTMA7);

[0624] When the position Z 11 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 11 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: A, F, L and W;

[0625] When the position Z 12When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at position is replaced by 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;

[0626] When the position Z 13 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 13 The amino acid residue at position is replaced by 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;

[0627] When the position Z 14 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 14 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: K(Ac) and N(NMe);

[0628] When the position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of 3pya, 5CF33Pya, 5MepyridineAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y, and A;

[0629] When the position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 wherein the amino acid residue at the alkylene oxide 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(PEG2PEG2PEG2gEC12)2), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12), and NMeK(SP6PEG2PEG2gEC12); and

[0630] When the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one masked amine and / or masked amide.

[0631] II. Definitions

[0632] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art.

[0633] When referring to a value, "about" includes the stated value + / - 10%. For example, about 50% includes a range of 45% to 55%, and about 20 molar equivalents includes a range of 18 molar equivalents to 22 molar equivalents. Thus, when referring to a range, "about" refers to the stated value + / - 10% of each end of the range. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0634] "Patient" or "subject" are used interchangeably and refer to a living organism, including but not limited to a human subject suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Additional non-limiting examples can include but are not limited to humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other mammals. In some aspects, the patient is a human.

[0635] Unless otherwise indicated, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions recommended by the IUPAC Organic Nomenclature Commission and the IUPAC-IUB Biochemical Nomenclature Commission, as set forth in "Nomenclature of α-Amino Acids (Recommendations, 1974)", Biochemistry, Vol. 14, No. 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 recommended, this will be made clear to the reader. In amino acid sequences representing IL-23 inhibitors, individual amino acids are separated by a hyphen "-" or brackets, e.g., lysine is shown as [K].

[0636] Throughout this specification, unless naturally occurring amino acids are referred to by their full names (e.g., alanine, arginine, etc.), they are designated by their conventional three-letter abbreviations or single-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless otherwise indicated, the three-letter abbreviations and single-letter abbreviations of amino acids refer to the L-isomer forms of the amino acids in question. As used herein, the term "L-amino acid" refers to the "L" isomer forms of peptides, and conversely the term "D-amino acid" refers to the "D" isomer forms of peptides (e.g., (D)Asp or D-Asp; (D)Phe or D-Phe). Amino acid residues in the D isomer form can replace any L-amino acid residue as long as the peptide segment retains the desired function. When referred to using single-letter abbreviations, D-amino acids can be indicated in lower case as is conventional. 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," and D-lysine can be represented as "lys" or "k." Alternatively, a lowercase "d" in front of an amino acid can be used to indicate that it is in the D isomeric form, for example, D-lysine can be represented by dK.

[0637] In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full names (e.g., sarcosine, ornithine, etc.), the commonly employed three-letter or four-letter codes for their residues are adopted, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid).

[0638] The D-isomerized amino acid may be positioned at any of the positions described herein (any of X1-X18 present in the molecule). In one aspect, the D-isomerized amino acid may be positioned only at any one or more of X3, X5, X6, X8, X13, and optionally at one additional position. In other aspects, the D-isomerized amino acid may be positioned only at any one or more of X3, X8, X13, and optionally at one additional position. In other aspects, the D-isomerized amino acid may be positioned only at any one or more of X8, X13 (e.g., X8 is dK(Ac) and X13 is dE), and optionally at one additional position. In other aspects, the D-isomerized amino acid may be positioned only at X3, and optionally at one additional position. In other aspects, the D-isomerized amino acid may be positioned only at X3, and optionally at one additional position. In other aspects, the D-isomerized amino acid may be positioned only at X3, and optionally at two or three additional positions. In other aspects, the D-isomer form of an amino acid may be located at only one or two of the positions X1 to X18 present in the IL-23R inhibitors described herein. In other aspects, the D-isomer form of an amino acid may be located at only three or four of the positions X1 to X18 present in the IL-23R inhibitors described herein. For example, an IL-23R inhibitor described herein that only has positions X3 to X15 may have the D-form of an amino acid present at three or four of these positions. In other aspects, the D-isomer form of an amino acid may be located at only five or six of the positions X1 to X18 present in the IL-23R inhibitors described herein.

[0639] As will be apparent to those skilled in the art, the peptide sequences disclosed herein are shown 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. The sequences disclosed herein are sequences in which a "-OH" moiety or a "-NH2" moiety is incorporated into the carboxyl end (C-terminus) of the sequence. In such cases, and unless otherwise indicated, the "-OH" or "-NH2" moiety at the C-terminus of the sequence indicates a hydroxyl group or an amino group corresponding to a carboxylic acid (COOH) or amide (CONH2) group present at the C-terminus, respectively. In each sequence of the present invention, the C-terminal "-OH" moiety can replace the C-terminal "-NH2" moiety, and vice versa.

[0640] 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; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. "Non-standard amino acid" refers to any amino acid other than the standard amino acids, whether synthetically prepared or obtained from a natural source. As used herein, "synthetic amino acid" encompasses chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides) and / or substitutions. Amino acids (including the carboxyl and / or amino terminal amino acids in peptides) can be modified by methylation, amidation, acetylation, protecting groups and / or substitution with other chemical groups that can alter the circulatory half-life of the peptide without adversely affecting its activity. Amino acid can participate in forming a bridge for cyclization, such as a thioether bond and a disulfide bond for forming the cyclic portion of a peptide, for example, as in the connection between the amino acid residue at position Z4 and the amino acid residue at position Z9 in the various embodiments discussed herein. Amino acid can comprise one or more post-translational modifications, such as association with one or more chemical entities (e.g., a methyl group, an acetate group, an acetyl group, a phosphate group, a formyl moiety, an isoprenoid group, a sulfate group, a polyethylene glycol moiety, a lipid moiety, a carbohydrate moiety, a biotin moiety, etc.). The term "amino acid" can be used interchangeably with "amino acid residue" and can refer to the amino acid residue of a free amino acid and / or a peptide. It will be apparent from the context in which the term is used whether it refers to a free amino acid or a residue of a peptide.

[0641] 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 zero according to the standardized 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).

[0642] 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 contained in a peptide or polypeptide. Acidic amino acids typically have negatively charged side chains at physiological pH due to loss of hydrogen ions. Examples of acidic amino acids include, but are not limited to, L-Glu (E) and L-Asp (D).

[0643] 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 positively charged side chains at physiological pH due to association with hydronium ions. Examples of basic amino acids include, but are not limited to, L-Arg (R) and L-Lys (K).

[0644] As used herein, "polar amino acid or residue" refers to a hydrophilic amino acid or residue having a side chain that is uncharged at physiological pH, but the side chain has at least one bond in which an electron pair shared by two atoms is more tightly held by one atom. Examples of polar amino acids include, but are not limited to, L-Asn (N), L-Gln (Q), L-Ser (S), and L-Thr (T).

[0645] 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 zero according to the standardized 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).

[0646] As used herein, "aromatic amino acid or residue" refers to a hydrophilic or hydrophobic amino acid or residue having a side chain comprising 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. Although L-His (H) is sometimes classified as a basic residue due to the pKa of its heteroaromatic nitrogen atom, histidine is classified as an aromatic residue herein because its side chain comprises a heteroaromatic ring.

[0647] As used herein, "non-polar amino acid or residue" refers to a hydrophobic amino acid or residue having a side chain that is uncharged at physiological pH, and the side chain has a bond in which an electron pair shared by two atoms is normally held equally by each of the two atoms (i.e., the side chain is not polar). Examples of non-polar 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).

[0648] As used herein, "aliphatic amino acid or residue" refers to a hydrophobic amino acid or residue with 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).

[0649] The amino acid L-Cys (C) is unusual in that it can form disulfide bridges with other L-Cys (C) amino acids or other amino acids containing sulfanyl or sulfhydryl groups. As used herein, "cysteine-like amino acids or residues" include cysteine ​​and other amino acids containing sulfhydryl moieties that can be used to form disulfide bridges. The ability of L-Cys (C) (and other amino acids with SH side chains) to be present in a peptide in the form of reduced free SH or oxidized disulfide bridges affects whether L-Cys (C) provides a net hydrophobic or hydrophilic characteristic to the peptide. Although L-Cys (C) exhibits a hydrophobicity of 0.29 according to Eisenberg's standardized consensus scale (Eisenberg et al., 1984, supra), it should be understood that for the purposes of this disclosure, 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).

[0650] The term "quaternary amine" has its ordinary meaning in the art. For example, a quaternary amine is a substituent containing one or more permanently positively charged nitrogen atoms. The permanent positive charge of the nitrogen atom can be independent of the surrounding pH. A non-limiting example of a quaternary amine can be a moiety having four organic substituents on the nitrogen atom.

[0651] The term "masked amine" means a substituent comprising one or more nitrogen atoms, wherein one or more nitrogen atoms are substituted. For example, one or more nitrogen atoms can be substituted with a group such as an alkyl or acetyl group to form a secondary amine, a tertiary amine, or an amide. In an embodiment, the masked amine is a secondary amine. In an embodiment, the masked amine is a tertiary amine. In an embodiment, the masked amine is an amide.

[0652] The term "masked amide" means a substituent comprising one or more nitrogen atoms, wherein the one or more nitrogen atoms are substituted with -C=O and at least one other substituent. For example, the one or more nitrogen atoms substituted with -C=O can be further substituted with a group (such as an alkyl or acetyl group) to form a secondary or tertiary amide. In embodiments, the masked amide is a secondary amide. In some embodiments, the masked amide is a tertiary amide.

[0653] Those skilled in the art will appreciate that certain amino acids and other chemical moieties are modified when combined with another molecule. For example, an amino acid side chain can be modified when forming an intramolecular bridge with another amino acid side chain, for example, one or more hydrogens can be removed or replaced by a bond.

[0654] "Compounds of the present invention," "inhibitors of the present disclosure," "IL-23R inhibitors of the present disclosure," "compounds described herein," and "compounds described herein" include novel compounds disclosed herein, e.g., compounds of any of the Examples, including compounds of Formulas (I) to (VI), such as those found in Table 1A, Table 1B, Table 1C, Table 1D, or Table 1E.

[0655] "Pharmaceutically effective amount" refers to the amount of a compound of the invention in a composition or combination thereof that provides the desired therapeutic or pharmaceutical result.

[0656] By "pharmaceutically acceptable" is meant that the carrier, diluent, salt or excipient must be compatible with the other components or ingredients of the composition of the present invention, i.e., it is useful, safe, non-toxic and acceptable for pharmaceutical use. According to the present invention, pharmaceutically acceptable means approved or approvable for use in animals, and more particularly in humans, as listed in the United States Pharmacopoeia or other generally recognized pharmacopeia.

[0657] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, glidant, sweetener, 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 U.S. Food and Drug Administration as acceptable for use in humans or veterinary animals.

[0658] "Absorption enhancer" refers to a component that improves or promotes mucosal absorption of a drug in the gastrointestinal tract, such as a permeation enhancer or intestinal permeation enhancer. As conventionally understood in the art, a permeation enhancer (PE) is an agent intended to improve the oral delivery of therapeutic drugs with poor bioavailability. PE can increase the intercellular and / or transcellular passage of a drug.

[0659] Pharmaceutical excipients that increase permeation have been termed "absorption-modifying excipients" (AMEs). AMEs can be used in oral compositions, for example, as wetting agents (sodium lauryl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., macrogol glycerides), and can be included in compositions, particularly as PEs, to improve bioavailability. PEs can be classified based on how they alter barrier integrity via paracellular or transcellular pathways.

[0660] "Intestinal permeation enhancer (IPE)" refers to a component that improves the bioavailability of a component. Suitable representative IPEs for use in the present invention include, but are not limited to, various surfactants, fatty acids, medium-chain glycerides, steroidal detergents, acylcarnitines and alkanoylcholines, N-acetylated α-amino acids and N-acetylated non-α-amino acids, as well as chitosan, other mucoadhesive polymers, and the like. For example, a suitable IPE for use in the present invention may be sodium caprate.

[0661] As used herein, "composition" or "pharmaceutical composition" is intended to encompass an invention or product comprising a specified active ingredient (API), which may comprise a pharmaceutically acceptable excipient, carrier, or diluent as described herein in a specified amount, such as defined throughout this disclosure. A composition or pharmaceutical composition results from the combination of specified components, such as specified ingredients in specified amounts, as described herein.

[0662] The compositions or pharmaceutical compositions of the present invention may be in different pharmaceutically acceptable forms, including but not limited to liquid compositions, tablet or matrix compositions, capsule compositions, and the like. When the composition is a tablet composition, the tablet may include but not limited to different layers, two or more different phases, including an inner phase and an outer phase that may contain a core. Tablet compositions may also include but not limited to one or more coatings.

[0663] As used herein, "solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of bonding, including hydrogen bonding. In some cases, the solvate will be capable of isolation. The term "solvate" is intended to encompass both solution-phase solvates and isolatable solvates. Non-limiting examples of suitable solvates include hydrates.

[0664] Also provided are pharmaceutically acceptable salts and tautomeric forms of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0665] The IL-23R inhibitors of the present disclosure, or their pharmaceutically acceptable salts or solvates, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R)- or (S)- in terms of absolute stereochemistry, or as (D)- or (L)- in the case of amino acids. The present disclosure is intended to encompass all such possible isomers of the IL-23R inhibitors of the present disclosure, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When a compound is represented in its chiral form, it is understood that this aspect encompasses but is not limited to a specific diastereomer or enantiomerically enriched form. When chirality is not specified but is present, it is understood that this aspect relates to a specific diastereomer or enantiomerically enriched form; or a racemic or fixed ratio mixture of such compounds. As used herein, a "fixed ratio mixture" is a mixture in which the ratio of the stereoisomer enantiomers is not 1:1.

[0666] Certain examples contain amino acids depicted or labeled as (R*) or (S*). When (R*) or (S*) is used in the name of an amino acid or in the chemical representation of an amino acid, it is intended to indicate that the amino acid is a pure single isomer at that stereocenter; however, the absolute configuration of that stereocenter has not been determined. Thus, a compound designated as (R*) refers to an amino acid that is a pure single isomer at that stereocenter with an absolute configuration of (R) or (S), and a compound designated as (S*) refers to an amino acid that is a pure single isomer at that stereocenter with an absolute configuration of (R) or (S). For example, ACHMF(S*):

[0667] Refers to one of the following amino acids:

[0668]

[0669] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0670] One or more "stereoisomers" refer to compounds with different chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. If a compound has one or more asymmetric centers or has an asymmetrically substituted double bond, they can exist in stereoisomeric forms and therefore can be produced as individual stereoisomers or as a mixture. Unless otherwise indicated, the description is intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th edition, J. March, John Wiley and Sons, New York, 1992).

[0671] "Tautomer" refers to alternating forms of compounds that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both the -NH- ring and the =N- ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0672] 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 front or end of a chemical group are for convenience; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure represents the point of attachment of the group. A dotted line indicates an optional bond. Unless chemically or structurally required, the order in which the chemical groups are written or the point at which they are attached to the rest of the molecule does not indicate or imply directionality. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and the two can be attached in either direction. Similarly, an "arylalkyl" group can be attached to the rest of the molecule, for example, at the aryl or alkyl portion of the group. Prefixes such as "C u-v " or (C u -C v ) indicates that the following group has u to v carbon atoms. For example, "C 1-6 "C1-C6 alkyl" and "C1-C6 alkyl" both indicate that the alkyl group has 1 to 6 carbon atoms.

[0673] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result. For the purposes of the present invention, beneficial or desired results include, but are not limited to, alleviating symptoms and / or alleviating the degree of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one aspect, "treatment" includes one or more of the following: (a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or alleviating the degree of a disease or condition); (b) slowing down or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and (c) alleviating a disease or condition, such as causing regression of clinical symptoms, improving the disease state, slowing the progression of a disease, improving the quality of life, and / or prolonging survival.

[0674] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that effectively elicits a desired biological or medical response, including an amount of a compound that is sufficient to achieve such treatment of the disease when administered to a subject to treat a disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. The effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and if a desired or beneficial result can be achieved or will be achieved, then an effective amount of a single agent may be considered to be administered in combination with one or more other agents. Due to the combined effects of the compounds (e.g., additive or synergistic effects), the appropriate dose of any co-administered compound may optionally be reduced.

[0675] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some aspects, a unit dose of a compound of the invention is first administered, followed by administering a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other aspects, a unit dose of one or more additional therapeutic agents is first administered, followed by administering a unit dose of a compound of the invention within seconds or minutes. In some aspects, a unit dose of a compound of the invention is first administered, followed by administering a unit dose of one or more additional therapeutic agents after a period of several hours (e.g., 1 hour to 12 hours). In other aspects, a unit dose of one or more additional therapeutic agents is first administered, followed by administering a unit dose of a compound of the invention after a period of several hours (e.g., 1 hour to 12 hours). Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially so that a therapeutically effective amount of each agent is present in the patient.

[0676] The abbreviation "(V / V)" refers to the phrase "volume to volume," i.e., the ratio of a particular substance within a mixture, as measured by the volume or volume amount of a component of a composition disclosed herein relative to the total volume of the composition. Thus, the quantity is smaller in units and represents the volume percent amount of the component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture may indicate that 2 mL of one solvent is present in 100 mL of the solvent mixture.

[0677] The abbreviation "(w / w)" refers to the phrase "weight to weight," i.e., the ratio of a particular substance within a mixture, as measured by the weight or mass or weight amount of a component of a composition disclosed herein relative to the total weight of the composition. Thus, the amount is smaller in units and represents the weight percent amount of the component relative to the total weight of the composition. For example, a 2% (w / w) solution may indicate that 2 grams of solute are dissolved in 100 grams of solution.

[0678] Systemic administration routes, as conventionally understood in the medical or pharmaceutical arts, refer to or are defined as routes by which a drug, pharmaceutical composition or formulation, or other substance is administered into the circulatory system such that various body tissues and organs are exposed to the drug, formulation, or other substance. As conventionally understood in the art, administration can be by oral administration (wherein the drug or oral formulation is taken orally and absorbed via the gastrointestinal tract), enteral administration (drug absorption also occurs via the gastrointestinal tract), or parenteral administration (usually by injection, infusion, or implantation, etc.).

[0679] When referring to the present invention, "systemically active" peptide drug therapy generally refers to treatment by means of a pharmaceutical composition comprising a peptide active ingredient, wherein the peptide resists immediate metabolism and / or excretion, resulting in its exposure to various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous or immune systems.

[0680] Systemic drug activity in the present invention also refers to treatment with substances that travel through the bloodstream, reach and affect cells in various body tissues and organs. Systemically active drugs are transported to their site of action and act throughout the body to attack the physiological processes that cause inflammatory diseases.

[0681] "Bioavailability" refers to the extent and rate at which the active moiety (drug or metabolite) enters the systemic circulation and thereby reaches the site of action. The bioavailability of a drug is affected by the properties of the dosage form, which depends in part on its design and manufacture.

[0682] As used herein, "digestive tract tissue" refers to all tissues that constitute the digestive tract organs. For example only, but not limited to, "digestive tract tissue" includes tissues of the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus.

[0683] As used herein, the term "natural polymer" adopts its common meaning in the art. For example, a polymer that can be found in living 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. The type of natural polymer (e.g., homopolymer or copolymer; random, alternating or block copolymers; linear or branched) can vary. Non-limiting examples of natural polymer groups are amino acid sequences containing about 10 to about 30 amino acids, which are derived from (poly) peptides, such as natriuretic peptide precursor C, atrial natriuretic peptide, brain natriuretic peptide, serum albumin, IgG, histidine-rich glycoproteins, fibronectin, fibrinogen, zinc finger-containing polypeptides, osteoblast growth factor 2 (FGF2), or variants thereof with substitutions and / or deletions.

[0684] As used herein, the term "non-natural polymer" is used in its ordinary sense in the art. For example, a synthetic polymer that does not naturally occur in living systems (such as plants, animals, bacteria, and fungi). The type of non-natural polymer (e.g., homopolymer or copolymer; random, alternating, or block copolymer; linear or branched) can vary. A non-limiting example of a non-natural polymer group is polyethylene glycol (PEG) (also known as polyethylene oxide (PEO)).

[0685] As used herein, "hydrophilic polymer" has its ordinary meaning in the art. For example, a polymer that dissolves in water. The hydrophilic polymer may contain polar or charged functional groups that make the polymer soluble in water. The hydrophilic polymer may be a natural polymer or a non-natural polymer or a combination thereof. The type of hydrophilic polymer (e.g., homopolymer or copolymer; random, alternating or block copolymer; linear or branched) may vary. Non-limiting examples of hydrophilic polymers include polyethylene glycol (PEG).

[0686] Chemical definition

[0687] Acyl: As used herein, the term "acyl" refers to an R Z -(C=O)-, where R Z is, for example, any alkyl, alkenyl, alkynyl, heteroalkyl, or heteroalkenyl group.

[0688] Aliphatic: As used herein, in the context of chemical substituents, the term aliphatic refers to hydrocarbons and includes both saturated and unsaturated hydrocarbons. Aliphatic can be straight chain, branched, or cyclic. For example, C1-C 10 Aliphatic compounds may include C1-C 10 Alkyl groups (e.g., straight or branched C1-C 10 Saturated alkyl), C2-C 10 Alkenyl groups (e.g., straight or branched C4-C 10 Diene, straight chain or branched C6-C 10 trienes, etc.) and C2-C 10 Alkynyl groups (e.g., straight or branched C2-C 10 Alkynyl groups). C1-C 10 Aliphatic compounds may include C3-C 10 Cyclic aliphatic compounds (e.g., C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or C8-C 10 In certain embodiments, the aliphatic group may comprise one or more cyclic aliphatic groups 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, alkoxy, hydroxy, amino, aryl, ether, ester, or amide). The aliphatic group is unsubstituted or substituted with one or more substituent groups as described herein. For example, the aliphatic group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -C0H, -CONH2, -C0R", -CN, -OH, -OR", -OCOR", -OC0R", -NH2, -NHR", -N(R")2, -SR", or -S0R", wherein each instance of R" is independently C1-C10 Aliphatic (e.g., C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). 10 In an embodiment, R" is independently unsubstituted C1-C3 alkyl. In an embodiment, the aliphatic is unsubstituted. In an embodiment, the aliphatic does not include any heteroatoms.

[0689] Alkyl: As used herein, the term "alkyl" refers to a group of acyclic straight and branched hydrocarbon groups, for example, "C1-C6 alkyl" refers to an alkyl group having 1-6 carbon atoms. The alkyl group can be straight 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, straight or branched. In view of the benefit of this disclosure, other alkyl groups will be apparent to those skilled in the art. The alkyl group can be unsubstituted or substituted with one or more substituent groups as described herein. For example, the alkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -CO2H, -CONH2, -CO2R", -CN, -OH, -OR", -OCOR", -OCOR", -NH2, -NHR", -N(R")2, -SR", or -SO2R", wherein each instance of R" is independently C1-C 10 Aliphatic (e.g., C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). 10 In some embodiments, R" is independently unsubstituted C1-C3 alkyl. In some embodiments, the alkyl group is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In some 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 an -OH group and "alkyl" is as described herein.

[0690] For example, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C1-C 10In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-C9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-C7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, 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), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise indicated, each example of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents. In certain embodiments, an alkyl group is an unsubstituted C1-C6 alkyl. In certain embodiments, an alkyl group is a substituted C1-C6 alkyl.

[0691] Appending the suffix "-ene" to a group indicates that the group is a divalent moiety, for example, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0692] Alkylene: As used herein, the term "alkylene" refers to a saturated divalent straight or branched chain hydrocarbon group and is exemplified by methylene, ethylene, isopropylene, and the like. Likewise, as used herein, the term "alkenylene" refers to an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, and the term "alkynylene" herein refers to an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur at any stable point along the chain. In certain embodiments, an alkylene, alkenylene, or alkynylene group may contain one or more cyclic aliphatic groups 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, alkoxy, hydroxy, amino, aryl, ether, ester, or amide). For example, an alkylene, alkenylene, or alkynylene group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -CO2H, -CONH2, -CO2R", -CN, -OH, -OR", -OCOR", -OCOR", -NH2, -NHR", -N(R")2, -SR", or -SO2R", wherein each instance of R" is independently C1-C 10 Aliphatic (e.g., C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). 10 In some embodiments, the alkylene, alkenylene, or alkynylene groups are unsubstituted. In some embodiments, the alkylene, alkenylene, or alkynylene groups do not include any heteroatoms.

[0693] Alkenyl: As used herein, "alkenyl" refers to any straight or branched hydrocarbon chain radical having one or more unsaturated carbon-carbon double bonds which may occur at any stable point along the chain, for example, "C2-C 10"Alkenyl" refers to an alkenyl group having 2-10 carbons. For example, alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In embodiments, the alkenyl group contains 1, 2, or 3 carbon-carbon double bonds. In embodiments, the alkenyl group contains a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. Alkenyl groups can be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkenyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -COR", -CO2H, -CONH2, -CO2R", -CN, -OH, -OR", -OCOR", -OCOR", -NH2, -NHR", -N(R")2, -SR", or -SO2R", wherein each instance of R" is independently C1-C 10 Aliphatic (e.g., C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). 10 In some embodiments, R" is independently unsubstituted C1-C3 alkyl. In some embodiments, alkenyl is unsubstituted. In some embodiments, alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). In some embodiments, alkenyl groups are substituted with -OH groups and may also be referred to herein as "hydroxyalkenyl" groups, where the prefix indicates an -OH group and "alkenyl" is as described herein.

[0694] For example, "alkenyl" refers to a group ("C2-C 10In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-C9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-C7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). One or more carbon- The carbon double bond can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include, but are not limited to, vinyl (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 groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. In certain embodiments, an alkenyl group is an unsubstituted C2-C4 alkenyl group. 10 In certain embodiments, an alkenyl group is a substituted C2-C 10 Alkenyl.

[0695] Alkynyl: As used herein, "alkynyl" refers to any hydrocarbon chain radical having one or more carbon-carbon triple bonds occurring at any stable point along the chain, in a straight or branched configuration, e.g., "C2-C 10 "Alkynyl" refers to an alkynyl group having 2-10 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, and the like. In an embodiment, the alkynyl group contains one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more substituent groups as described herein. For example, the alkynyl group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of 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-C10 Aliphatic (e.g., C1-C 10 In an embodiment, R" is independently unsubstituted alkyl (e.g., unsubstituted C1-C8 alkyl, C1-C6 alkyl, or C1-C3 alkyl). 10 In one embodiment, R" is independently unsubstituted C1-C3 alkyl. In one embodiment, alkynyl is unsubstituted. In one embodiment, alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0696] For example, "alkynyl" refers to a straight or branched chain hydrocarbon radical 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 groups with one or more triple bonds and one or more double bonds are also known as “alkene-ynes.” In some embodiments, alkynyl groups have 2 to 9 carbon atoms (“C2-C9 alkynyl”). In some embodiments, alkynyl groups have 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, alkynyl groups have 2 to 7 carbon atoms (“C2-C7 alkynyl”). In some embodiments, alkynyl groups have 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, alkynyl groups have 2 to 5 carbon atoms (“C2-C5 alkynyl”). In some embodiments, alkynyl groups have 2 to 4 carbon atoms (“C2-C4 alkynyl”). In some embodiments, alkynyl groups have 2 to 3 carbon atoms (“C2-C3 alkynyl”). In some embodiments In the embodiment of the present invention, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-triple bonds can be internal (such as in 2-butynyl) or terminal (such as 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 alkenyl 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 an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents. In certain embodiments, an alkynyl group is an unsubstituted C2-C4 alkynyl group. 10 In certain embodiments, an alkynyl group is a substituted C2-C 10 Alkynyl.

[0697] Aryl: The term "aryl" used alone or as part of a larger moiety as in "aralkyl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of six to fourteen ring members, wherein the ring system has a single point of attachment to the rest of the molecule, at least one ring in the system is aromatic, and wherein each ring in the system contains 4 to 7 ring members. In an embodiment, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Exemplary aryl groups include phenyl, naphthyl, and anthracene.

[0698] As used herein, "aryl" also refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Unless otherwise indicated, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6-C 14 In certain embodiments, the aryl group is a substituted C6-C 14 Aryl.

[0699] Arylene: As used herein, the term "arylene" refers to a divalent aryl group (ie, having two points of attachment to the molecule). Exemplary arylene groups include phenylene (eg, unsubstituted phenylene or substituted phenylene).

[0700] Carbocyclyl: As used herein, "carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C3-C 10In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-C8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-C7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-C6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-C6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-C6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-C 10 Carbocyclyl”). Exemplary C3-C6 carbocyclyl 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), and the like. Exemplary C3-C8 carbocyclyl groups include, but are not limited to, the aforementioned C3-C6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. Exemplary C3-C 10 Carbocyclyl groups include but are not limited to the aforementioned C3-C8 carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As illustrated in the foregoing examples, in certain embodiments, the carbocyclyl group is a monocyclic ring ("monocyclic carbocyclyl") or a polycyclic ring (for example, containing a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")), and can be saturated or can contain one or more carbon-carbon double bonds or triple bonds. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such examples, the carbon number continues to represent the carbon number in the carbocyclyl ring system. Unless otherwise indicated, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-C 10 In certain embodiments, a carbocyclyl group is a substituted C3-C 10 Carbocyclic group.

[0701] In some embodiments, "carbocyclyl" or "carbocycle" refers to a "cycloalkyl" group, which is a monocyclic saturated carbocyclyl group ("C3-C 10 In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, cycloalkyl groups have 4 to 6 ring carbon atoms (“C4-C6 cycloalkyl”). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms (“C5-C6 cycloalkyl”). In some embodiments, cycloalkyl groups have 5 to 10 ring carbon atoms (“C5-C 10 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 a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-C6 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C6 cycloalkyl.

[0702] Halogen: As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0703] Heteroalkyl: The term "heteroalkyl" refers to a group having a branched or unbranched alkyl, alkenyl, or alkynyl group having, in addition to heteroatoms independently selected from the group consisting of N, O, S, and P, carbon atoms. For example, "heteroalkyl" may refer to a branched or unbranched alkyl, alkenyl, or alkynyl group having, in addition to 1, 2, 3, and 4 heteroatoms independently selected from the group consisting of N, O, S, and P, from 1 to 8 carbon atoms. For example, the term "heteroalkyl" refers to a group having, in addition to heteroatoms independently selected from the group consisting of N, O, S, and P, from 1 to 40 carbon atoms ("C1-C 40 In one embodiment, the term "heteroalkyl" refers to a group having a branched or unbranched alkyl group of 1 to 40 carbon atoms in addition to heteroatoms independently selected from the group consisting of N, O, S and P ("C1-C 40In one embodiment, the "heteroalkyl" may 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, the "heteroalkyl" may 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 heteroatoms are independently selected from the group consisting of N, O, or S. In one embodiment, the heteroatoms are independently selected from the group consisting of N or O. Heteroalkyl groups include tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. The heteroalkyl group may optionally include a monocyclic, bicyclic, or tricyclic ring, wherein each ring ideally has three to eight members, for example, the heteroalkyl group may optionally include one or more triazole rings. Examples of heteroalkyl groups include polyethers such as methoxymethyl and ethoxyethyl and hydrophilic polymers such as polyethylene glycol (PEG).

[0704] Heteroalkylene: As used herein, the term "heteroalkylene" refers to a divalent form of a heteroalkyl group as described herein.

[0705] Heteroaryl: As used herein, the term "heteroaryl" is a fully unsaturated heteroatom-containing ring in which at least one ring atom is a heteroatom, such as, but not limited to, nitrogen and oxygen.

[0706] As used herein, "heteroaryl" also refers to a group of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in the cyclic array) having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4 ring heteroatoms) ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, where valence permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such examples, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such examples, the number of ring members refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For polycyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl).

[0707] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-6 membered heteroaryl”). In some embodiments, 5-6 yuan heteroaryl has 1 or more (for example, 1, 2 or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon and phosphorus. In some embodiments, 5-6 yuan heteroaryl has 1 or 2 ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon and phosphorus. In some embodiments, 5-6 yuan heteroaryl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon and phosphorus. In some embodiments, 5-6 yuan heteroaryl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon and phosphorus. Unless otherwise indicated, each instance of heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") by one or more substituents. In certain embodiments, heteroaryl group is unsubstituted 5-14 yuan heteroaryl. In certain embodiments, heteroaryl group is substituted 5-14 yuan heteroaryl.

[0708] 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, azacycloheptatrienyl, oxepantatrienyl, and thiepantatrienyl. Exemplary 5,6-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-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0709] As used herein, "heterocyclyl" or "heterocycle" refers to a group 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, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus ("3-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged, or spirocyclic ring system, such as a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. A heterocyclyl polycyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on a carbocyclyl or heterocyclyl ring, or includes a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on a heterocyclyl ring, and in such examples, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each example of a heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, a heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0710] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) ring heteroatoms, wherein each heteroatom is independently selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1 or more (e.g., 1, 2, or 3) ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclyl has 1 or 2 ring heteroatoms selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from oxygen, sulfur, nitrogen, boron, silicon, and phosphorus.

[0711] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thienanyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thienanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-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 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, triazacyclohexanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiepanyl. Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthylimidyl, chromanyl, benzopyranyl, 1H-benzo[e][1,4]diazepine yl, 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.

[0712] Heterocycloalkyl: As used herein, the term "heterocycloalkyl" is 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 In some embodiments, heterocycloalkyl groups have 3 to 8 ring carbon atoms (“C3-C8 heterocycloalkyl”). In some embodiments, heterocycloalkyl groups have 3 to 6 ring carbon atoms (“C3-C6 heterocycloalkyl”). In some embodiments, heterocycloalkyl groups have 4 to 6 ring carbon atoms (“C4-C6 heterocycloalkyl”). In some embodiments, heterocycloalkyl groups have 5 to 6 ring carbon atoms (“C5-C6 heterocycloalkyl”). In some embodiments, heterocycloalkyl groups have 5 to 10 ring carbon atoms (“C5-C 10 In some embodiments, the heterocycloalkyl group is an unsubstituted C3-C6 heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a substituted C3-C6 heterocycloalkyl group.

[0713] As will be appreciated from above, alkyl, assorted alkyl, alkenyl, alkynyl, acyl, carbocyclyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl and heteroaryl groups as defined herein are optionally substituted in certain embodiments. Optionally substituted refers to a group that can be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" assorted alkyl, "substituted" or "unsubstituted" assorted alkenyl, "substituted" or "unsubstituted" assorted alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" heterocycloalkyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced by an allowable substituent, for example, a substituent that produces a stable compound (for example, a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination or other reactions) when substituted. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. The term "substituted" is intended to include substitution with all allowable substituents of an organic compound, any substituent described herein, which substitution results in the formation of a stable compound. The present invention contemplates any and all such combinations to obtain a stable compound. For purposes of the present invention, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent that satisfies the valence of the heteroatom as described herein and results in the formation of a stable moiety.

[0714] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2, -SO3H, -OH, -OR aa 、-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(Rbb )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 group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0715] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =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 replacement;

[0716] R aa Each instance of is independently selected from C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Carbocyclic group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0717] Rbb Each instance of is independently selected from 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 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 、-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 group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R bb The groups, together with the heteroatoms to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0718] R cc Each instance of is independently selected from hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Carbocyclic group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R cc The groups, together with the heteroatoms to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0719] R dd Each instance of is independently selected from 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)R ee 、-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)SRee 、-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 group, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may be linked to form =O or =S;

[0720] R ee Each instance of is independently selected from C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Carbocyclic, C6-C 10 Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0721] R ff Each instance of is independently selected from hydrogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Carbocyclic group, 3-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, or two R ff The groups, together with the heteroatoms to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R gg group substitution; and

[0722] R gg Each instance of is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-C 10 Alkyl, -ON(C1-C 10 Alkyl)2, -N(C1-C 10Alkyl)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-C10 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, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - It is a counter ion.

[0723] As used herein, the term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0724] As used herein, a "counterion" is a negatively charged group that is associated with a positively charged quaternary amine to maintain electronic neutrality. Exemplary counterions include halides (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, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0725] The nitrogen atoms may be substituted or unsubstituted as valence permits, and include 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 group, 3-14 membered heterocyclic group, C6-C 14 Aryl and 5-14 membered heteroaryl, or two R cc The groups, together with the nitrogen atom to which they are attached, form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As defined above.

[0726] 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 are included in those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0727] For example, a nitrogen protecting group such as an amide group (e.g., -C(=O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyamido)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0728] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl 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-biphenyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), vinyl carbamate Propyl ester (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, 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) carbamate ethyl ester, [2-(1,3-dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonium ethyl carbamate (Peoc), 2-triphenylphosphonium isopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-Dimethoxy-6-nitrobenzyl ester, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isobenzoyl carbamate , isobutyl carbamate, isonicotinoyl carbamate, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0729] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R aa ) include, but are not limited to, 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 phenacylmethylsulfonamide.

[0730] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazide adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, ketones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolidin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- Dichloro-9-fluorenylmethyleneamine, N-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'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyleneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine , N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylphosphinothioamide (Mpt), diphenylphosphinothioamide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidates, diphenylphosphoramidates, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0731] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group). Oxygen protecting groups are well known in the art and are included in those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0732] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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-methylenebenzofuran-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-(phenyloxyseleno)ethyl, tert-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'-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl , bis(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromophenacylmethoxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinyloxyphenyl)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-benzodithiofuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetic acid Ester, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid acetal), pivalate, adamantane ester, 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 (TMSEC), 2-(phenylsulfonyl) carbonate ) ethyl carbonate (Psec), 2-(triphenylphosphonium) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, 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-methylvalerate, 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, N,N,N',N'-tetramethylphosphorodiamidate alkyl ester, N-phenylcarbamic acid alkyl ester, borate, dimethylphosphinothioate, 2,4-dinitrophenylsulfonic acid alkyl ester, sulfate, methanesulfonate (mesylate), benzylsulfonate and toluenesulfonate (Ts).

[0733] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known 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, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0734] 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-quinolylmethyl, 2-picolyl N-oxide, 9-anthrylmethyl, 9-fluorenylmethyl, xanthenyl, ferrocenylmethyl, diphenylmethyl, bis(4-methoxyphenyl)methyl, 5-dibenzosuberyl, triphenylmethyl, diphenyl-4-pyridylmethyl, phenyl, 2,4-dinitrophenyl, tert-butyl, 1-adamantyl, methoxymethyl (MOM), isobutoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl, thiazolidinyl, acetamidomethyl, trimethylacetamidomethyl, benzamidomethyl, allyloxycarbonylaminomethyl, phenylacetamido methyl, phthalimidomethyl, acetylmethyl, carboxymethyl, cyanomethyl, (2-nitro-1-phenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl, 2-cyanoethyl, 2-(trimethylsilyl)ethyl, 2,2-bis(ethoxycarbonyl)ethyl, (1-m-nitrophenyl-2-benzoyl)ethyl, 2-phenylsulfonylethyl, 2-(4-methylphenylsulfonyl)-2-methylprop-2-yl, ethyl Acyl, benzoyl, trifluoroacetyl, N-[[(p-biphenyl)isopropoxy]carbonyl]-N-methyl]-γ-aminothiobutyrate, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, N-ethyl, N-methoxymethyl, sulfonate, sulfinylthiocarbonate, 3-nitro-2-pyridinesulfinyl sulfide, oxathiolone.

[0735] In one embodiment, the optionally substituted heteroalkyl group is unsubstituted or substituted by one or more substituents independently selected from -CONH , -CO H , -COCH NH , -NH , -NH (C=NH) NH , or =O (i.e., two geminal hydrogens on a carbon atom of the heteroalkyl group are replaced by a group =O). In one embodiment, the optionally substituted heteroalkyl group is unsubstituted. In one embodiment, the optionally substituted heteroalkyl group is substituted by one or more substituents independently selected from -CONH , -CO H , -COCH NH , -NH , -NH (C=NH) NH , or =O (i.e., two geminal hydrogens on a carbon atom of the heteroalkyl group are replaced by a group =O).

[0736] III. Compounds

[0737] The present invention relates to novel cyclic peptide inhibitors of interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts, solvates or forms thereof.

[0738] Specifically, the present invention relates to cyclic peptide inhibitors of interleukin-23 receptor (IL-23R) or pharmaceutically acceptable salts thereof, including those whose structures are identified in Table 1A, Table 1B, Table 1C, Table 1D or Table 1F of the present specification.

[0739] In one aspect, the cyclic peptide inhibitor compound of an interleukin-23 receptor (IL-23R) compound or a pharmaceutically acceptable salt thereof has the structure of a compound in Table 1A.

[0740] 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 in Table IB.

[0741] 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 in Table 1C.

[0742] 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 in Table ID.

[0743] 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 in Table IE.

[0744] 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 in Table IF.

[0745] Table 1A. Compounds

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005] Table 1B. Compounds

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017] Table 1C. Compounds

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028] Table 1D. Compounds

[1029]

[1030]

[1031] Table 1E. Compounds

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038] Table 1F. Compounds

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126] ·synthesis

[1127] The compounds described herein can be synthesized by many techniques known to those skilled in the art. In some aspects, monomeric subunits are synthesized and purified using the techniques described in the accompanying examples. In some aspects, the present invention provides a method for producing a compound of the present invention (or its monomeric subunit), the method comprising chemically synthesizing a peptide having an amino acid sequence as described herein, including but not limited to any of the amino acid sequences described in the compounds of formula (I) to formula (VI), Table 1A, Table 1B, Table 1C, Table 1D, and Table 1E herein. In some aspects, a portion of the peptide is recombinantly synthesized rather than chemically synthesized. In some aspects, the method for producing the compound further comprises cyclizing the compound precursor after the component subunits have been connected. In particular aspects, cyclization is accomplished via any of the various methods described herein.

[1128] Substituted tryptophans can be prepared by any suitable route. The preparation of certain substituted tryptophans (including those substituted at position 7 such as 7-ethyl-L-tryptophan) is described in, for example, WO 2021 / 146441A1.

[1129] The present invention also describes the synthesis of compounds described herein, such as compounds of Formula (I) to (X) and compounds of Table 1A, Table 1A, Table 1B, Table 1C, Table 1D, and Table 1E. In some aspects, one or more of the amino acid residues or amino acid monomers are lipidated and then covalently linked to each other to form a compound of the present invention. In some aspects, one or more of the amino acid residues or amino acid monomers are covalently linked to each other and lipidated at the intermediate oligomer stage before linking additional amino acids and cyclization to form a compound of the present invention. In some aspects, cyclic peptides are synthesized and then lipidated to form a compound of the present invention. Exemplary synthetic methods are described in the following examples.

[1130] This disclosure also describes the synthesis of compounds described herein, such as compounds of Formula (I) through Formula (X), and compounds of Table 1A, Table 1B, Table 1C, Table 1D, and Table 1 E. Exemplary synthetic methods are described in the following Examples.

[1131] IV. Pharmaceutical Compositions

[1132] The present invention relates to pharmaceutical compositions comprising an IL-23R inhibitor of the present invention. The present invention includes pharmaceutical compositions 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, semisolid, or liquid filler, diluent, encapsulating material, or any type of formulation aid. Protection against microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like.

[1133] The pharmaceutical composition can be administered orally, parenterally, intracisternal, intravaginal, intraperitoneal, rectal, topically (e.g., by powder, ointment, drops, suppository, or transdermal patch), by inhalation (such as nasal spray), ophthalmic (such as intraocular), or buccally. As used herein, the term "parenteral" refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal, and intraarticular injection and infusion. Therefore, in certain embodiments, the composition is formulated for delivery by any of these routes of administration. The pharmaceutical composition can be formulated for oral and oral administration. The pharmaceutical composition can be formulated for parenteral and parenteral administration.

[1134] In certain aspects, the IL-23R inhibitor of the present invention is suspended in a sustained-release matrix. As used herein, a sustained-release matrix is ​​a matrix made of a material (typically a polymer) that is degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is ​​acted upon by enzymes and body fluids. The sustained-release matrix is ​​desirably selected from biocompatible materials such as liposomes, polylactide (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide-co-glycolide (copolymer of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids (such as phenylalanine, tyrosine, isoleucine), polynucleotides, polyethylene propylene, polyvinyl pyrrolidone, and silicone. One embodiment of a biodegradable matrix is ​​a matrix of any one of polylactide, polyglycolide, or polylactide-co-glycolide (copolymer of lactic acid and glycolic acid).

[1135] The IL-23R inhibitors of the present invention can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, neutral forms. Pharmaceutically acceptable salts are non-toxic salts of the neutral form of a compound that have the desired pharmacological activity of the neutral form. These salts can be derived from inorganic or organic acids or bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butynes, benzoates, benzophenones, benzoates ... -1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts is found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[1136] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include those derived from suitable bases such as alkali metals (eg, sodium, potassium), alkaline earth metals (eg, magnesium), ammonium, and NX4. + (wherein X is C1-C4 alkyl). Also included are base addition salts, such as sodium or potassium salts. Those skilled in the art will recognize that although quaternary ammonium salts can be incorporated into the structure of compounds of formula (I)-(VI), the remaining basic residues can combine with acids to form additional salt sites. Therefore, compounds of formula (I)-(VI) of the present invention may encompass quaternary ammonium salts at certain positions, as well as acid addition salts at any basic site on the molecule.

[1137] The present invention relates to pharmaceutical compositions comprising an IL-23R inhibitor of the present invention, or a pharmaceutically acceptable salt, isomer, or mixture thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and, therefore, may be used to increase the half-life of the compounds described herein, or a pharmaceutically acceptable salt, isomer, or mixture 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 methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[1138] Examples of isotopes that may be incorporated into the compounds disclosed herein also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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 I. Positron-emitting isotopes (such as 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples set forth below using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[1139] In some aspects, the pharmaceutical composition for parenteral injection includes pharmaceutically acceptable sterile aqueous solution or non-aqueous solution, dispersion, suspension or emulsion or for being reconstituted into sterile injectable solution or the sterile powder of dispersion before about to use.The example of suitable aqueous and non-aqueous carrier, diluent, solvent or vehicle includes water, ethanol, polyol (such as glycerol, propylene glycol, polyethylene glycol etc.), carboxymethyl cellulose and suitable mixture thereof, beta-cyclodextrin, vegetable oil (such as olive oil) and injectable organic ester (such as ethyl oleate).For example, by utilizing coating material such as lecithin, in the case of dispersion, keep required particle size, and utilize surfactant, suitable fluidity can be kept.These compositions can also contain adjuvant, such as preservative, wetting agent, emulsifying agent and dispersant.The extended absorption of injectable drug form can be obtained by comprising the reagent that delays absorption, such as aluminum monostearate and gelatin.

[1140] Injectable depot forms include those made by forming a microencapsulated 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 peptide to polymer and the properties of the particular polymer employed, the rate of release of the peptide inhibitor can be controlled. Depot injectable formulations can also be prepared by encapsulating the peptide inhibitor in liposomes or microemulsions that are compatible with body tissues.

[1141] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[1142] Topical administration includes administration to the skin or mucous membranes (including the surfaces of the lungs and eyes). Compositions for topical pulmonary administration (including those for inhalation and intranasal administration) can relate to solutions and suspensions in aqueous and non-aqueous formulations and can be prepared as dry powders that can be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient can be in finely divided form and can be mixed with a pharmaceutically acceptable inert carrier of larger size, which comprises particles of size (e.g., diameter) up to 100 microns. Suitable inert carriers include sugars, such as lactose.

[1143] Alternatively, the pharmaceutical composition of the present invention can be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and, in fact, the total composition can be such that the active ingredient is not dissolved therein to any substantial extent. The pressurized composition can also contain a surfactant, such as a liquid or solid nonionic surfactant, or can be a solid anionic surfactant. Preferably, a solid anionic surfactant in the form of a sodium salt is used.

[1144] Another form of topical administration is administration to the eye. The peptide inhibitors of the present invention can be delivered in a pharmaceutically acceptable ophthalmic vehicle so that the peptide inhibitor remains in contact with the ocular surface for a sufficient period of time to allow the peptide inhibitor to penetrate the corneal region and internal regions of the eye, such as the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary body, lens, choroid / retina and sclera. Pharmaceutically acceptable ophthalmic vehicles can be, for example, ointments, vegetable oils or encapsulating materials. Alternatively, the peptide inhibitors of the present invention can be injected directly into the vitreous humor and aqueous humor.

[1145] Compositions for rectal or vaginal administration include suppositories which can be prepared by mixing the peptide inhibitors of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[1146] The peptide inhibitors of the present invention can also be used in liposomes or other lipid-based carriers. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid that can form liposomes can be used. In addition to the peptide inhibitors of the present invention, the compositions of the present invention in liposome form can also contain stabilizers, preservatives, excipients, etc. In certain embodiments, lipids comprise phospholipids, including natural and synthetic phosphatidylcholine (lecithin) and serine. Methods for forming liposomes are known in the art.

[1147] Pharmaceutical compositions suitable for parenteral administration in the methods or uses described herein can include sterile aqueous solutions and / or suspensions of IL-23R inhibitors, typically made isotonic with the blood of the recipient using sodium chloride, glycerol, glucose, mannitol, sorbitol, or the like.

[1148] The present invention provides pharmaceutical compositions for oral delivery. According to any of the methods, techniques and / or delivery vehicles described herein, the compositions and peptide inhibitors of the present invention can be prepared for oral administration. In addition, those skilled in the art will appreciate that the peptide inhibitors of the present invention can be modified or incorporated into systems or delivery vehicles not disclosed herein, but are well known in the art and compatible for oral delivery of peptides.

[1149] Preparations for oral administration may include adjuvants (e.g., resorcinol and / or nonionic surfactants such as polyoxyethylene oleyl ethers and orthoethers) to artificially increase the permeability of the intestinal wall, and / or enzyme inhibitors (e.g., trypsin inhibitors, diisopropylfluorophosphate (DFF) and aprotinin (trasylol)) to inhibit enzymatic degradation. In certain embodiments, the peptide inhibitor in a solid dosage form for oral administration may be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth, gum arabic, gelatin, collagen, casein, albumin, a synthetic or semisynthetic polymer or glyceride. These preparations for oral administration may also contain other types of additives, for example, inactive diluents, lubricants (such as magnesium stearate, parabens), preservatives (such as sorbic acid, ascorbic acid, α-tocopherol), antioxidants (such as cysteine), disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavorings, or aromas.

[1150] In certain aspects, oral dosage forms or unit doses compatible with the peptide inhibitors of the present invention may include a mixture of the peptide inhibitor and non-drug components or excipients, as well as other non-reusable materials that may be considered ingredients or packaging. Oral compositions may include at least one of liquid, solid, and semisolid dosage forms. In some embodiments, an oral dosage form is provided, comprising an effective amount of the peptide inhibitor, wherein the dosage form comprises at least one of a pill, tablet, capsule, gel, paste, beverage, syrup, ointment, and suppository. In some cases, an oral dosage form is provided that is designed and configured to achieve delayed release of the peptide inhibitor in the small intestine and / or colon of a subject.

[1151] Tablets can contain excipients, glidants, fillers, binders, etc. Aqueous compositions are prepared in sterile form and, when intended for delivery by non-oral administration, will generally be isotonic. Compositions can optionally contain excipients, such as those described in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, 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.

[1152] The oral pharmaceutical composition of the present invention may comprise an IL-23R inhibitor of the present invention and may comprise an enteric coating designed to delay the release of the IL-23R inhibitor in the small intestine. The present invention relates to a pharmaceutical composition comprising an IL-23R inhibitor of the present invention and a protease inhibitor, such as aprotinin, in a delayed-release pharmaceutical formulation. The pharmaceutical composition (e.g., an oral pharmaceutical composition) may comprise an enteric coating that is soluble in gastric fluid at a pH of about 5.0 or higher. Such enteric coatings may comprise polymers having dissociable carboxyl groups, such as derivatives of cellulose, including hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate, as well as similar derivatives of cellulose and other carbohydrate polymers.

[1153] Oral pharmaceutical compositions comprising an IL-23R inhibitor of the present invention may include an enteric coating designed to protect and release the pharmaceutical composition in a controlled manner within the lower gastrointestinal system of a subject and to avoid systemic side effects. In addition to enteric coatings, the peptide inhibitors of the present invention may also be encapsulated, coated, conjugated, or otherwise associated with any compatible oral drug delivery system or component. For example, in some embodiments, the IL-23R inhibitors of the present invention are provided in a lipid carrier system comprising at least one of the following: a polymer hydrogel, nanoparticles, microspheres, micelles, and other lipid systems.

[1154] To overcome peptide degradation of the IL-23R inhibitors of the invention in the small intestine, pharmaceutical compositions can include a hydrogel polymer carrier system containing the peptide inhibitor of the invention, whereby the hydrogel polymer protects the IL-23R inhibitor from proteolysis in the small intestine and / or colon. The IL-23R inhibitor can also be formulated for use with carrier systems designed to increase dissolution kinetics and enhance intestinal absorption of the peptide. These approaches include the use of liposomes, micelles, and nanoparticles to increase GI tract penetration of the peptide.

[1155] Various bioreactive systems can also be combined with one or more IL-23R inhibitors of the present invention to provide a pharmaceutical agent for oral delivery. For example, the IL-23R inhibitors of the present invention can be used in combination with bioreactive systems such as hydrogels and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly(methacrylic acid) [PMAA], cellulose, chitosan and alginate) to provide therapeutic agents for oral administration.

[1156] In certain aspects, pharmaceutical compositions and formulations may include an IL-23R inhibitor of the invention and one or more absorption enhancers, enzyme inhibitors, or mucoadhesive polymers. In one embodiment, the absorption enhancer may be an intestinal permeation enhancer.

[1157] The IL-23R inhibitors of the present invention can be formulated in a formulation vehicle such as, for example, an emulsion, liposomes, microspheres, or nanoparticles.

[1158] The present invention provides a method for treating a subject with an IL-23R inhibitor of the present invention having an increased half-life. In one aspect, the present invention provides a peptide inhibitor having a half-life of at least several hours to one day in vitro or in vivo (e.g., when administered to a human subject), sufficient for administration of a therapeutically effective amount once a day (qd) or twice a day (bid). In certain embodiments, the IL-23R inhibitor has a half-life of three days or longer, sufficient for administration of a therapeutically effective amount once a week (qw). In certain embodiments, the IL-23R inhibitor has a half-life of eight days or longer, sufficient for administration of a therapeutically effective amount once every two weeks (biw) or once a month. In certain embodiments, the IL-23R inhibitor is derivatized or modified so as to have a longer half-life compared to an underivatized or unmodified peptide inhibitor. In certain embodiments, the IL-23R inhibitor contains one or more chemical modifications to increase serum half-life.

[1159] When used in at least one of the treatment or delivery systems described herein, the peptide inhibitors of the invention may be employed in pure form or, where such forms exist, in the form of a pharmaceutically acceptable salt.

[1160] The total daily dosage of the IL-23R inhibitors and compositions of the present invention can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular subject will depend on a variety of factors, including: a) the disorder being treated and the severity of the disorder; b) the activity of the specific compound employed; c) the specific composition employed, the patient's age, weight, general health, sex, and diet; d) the time of administration, route of administration, and excretion rate of the specific peptide inhibitor employed; e) the duration of treatment; f) drugs used in combination or co-administered with the specific peptide inhibitor employed, and similar factors well known in the medical arts.

[1161] In certain embodiments, the total daily dose of an IL-23R inhibitor of the invention to be administered to a human or other mammalian host in single or divided doses can be, for example, in an amount of 0.0001 mg / kg to 300 mg / kg body weight per day, or 1 mg / kg to 300 mg / kg body weight per day.

[1162] The compositions can be conveniently presented in unit dosage form and can be prepared by any of the methods 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 auxiliary ingredients. Typically, 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.

[1163] Compositions suitable for oral administration can be presented as discrete units, each containing a predetermined amount of the active ingredient, such as capsules, cachets, or tablets; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, electuary, or paste. The active ingredient can also be administered as an oral or sublingual formulation. The oral or sublingual formulation can contain the active ingredient in a matrix that releases the active ingredient for transport across the oral cavity and / or sublingual membrane. The oral or sublingual formulation can also contain a rate-controlling matrix that releases the active compound at a predetermined rate for transport across the oral cavity and / or sublingual membrane. The oral or sublingual formulation can also contain 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 can be a penetration enhancer.

[1164] Tablet is prepared by optionally compressing or molding together with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient of a free-flowing form (such as a powder or granule) optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of a powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablet can be optionally coated or scored and optionally formulated to provide slow or controlled release of active ingredient therefrom.

[1165] V. Non-invasive detection of intestinal inflammation

[1166] The IL-23R inhibitors of the present invention can be used for the detection, assessment, and diagnosis of intestinal inflammation by microPET imaging, wherein 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 inhibitors of the present invention are conjugated to a bifunctional chelator. In certain embodiments, the IL-23R inhibitors of the present invention are radiolabeled. The labeled IL-23R inhibitor is then administered to the subject orally or rectally. In certain embodiments, the IL-23R inhibitor is included in the drinking water. Following ingestion of the IL-23R inhibitor, microPET imaging can be used to visualize inflammation throughout the subject's intestinal and digestive tracts.

[1167] VI. Methods of Treatment and / or Uses

[1168] The present invention relates to methods for treating a subject having a condition or indication associated with IL-23 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), wherein the methods comprise administering to the subject an IL-23R inhibitor disclosed herein. In one aspect, the present invention relates to a method for treating a subject having a condition or indication characterized by inappropriate, deregulated, or increased IL-23 or IL-23R activity or signaling, comprising administering to the subject an amount of a peptide inhibitor of the invention sufficient to inhibit (partially or completely) the binding of IL-23 to IL-23R in the subject. Inhibition of IL-23 binding to IL-23R can occur specifically 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.

[1169] The present invention relates to methods comprising providing a peptide inhibitor as described herein to a subject in need thereof. The subject in need thereof can be a subject who has been diagnosed with a disease or disorder associated with IL-23 / IL-23R or has been 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 specifically be a human.

[1170] The disease or disorder to be treated by treatment with an IL-23R inhibitor of the invention can be autoimmune inflammatory and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, young adult IBD, Crohn's disease, ulcerative colitis, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In particular, the disease or disorder can be psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, atopic acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, or Enteritis, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis following proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-related enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft-versus-host disease.

[1171] The present invention relates to a method or use of an IL-23R inhibitor for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present invention, or a pharmaceutically acceptable solvate or salt thereof, or a composition comprising an IL-23 inhibitor of the present invention disclosed herein. In some aspects, the present invention provides a method of treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of an IL-23R inhibitor of the present invention, or a pharmaceutically acceptable solvate or salt thereof, or a composition of the present invention. Suitable inflammatory diseases treated with a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a composition of the present invention may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA), etc. The inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis. The inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated may be psoriasis. The inflammatory disease to be treated may be psoriatic arthritis. The inflammatory disease to be treated may be IBD.

[1172] The present invention relates to methods for treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor disclosed herein (e.g., a peptide inhibitor or an IL-23R of any one of Formula (I) to Formula (VI) or Tables 1A-1E). The inflammatory disease can be IBD, Crohn's disease, or ulcerative colitis. In one aspect, the IBD can be ulcerative colitis. In one aspect, the IBD can be Crohn's disease. In one aspect, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[1173] The present invention relates to methods for treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of any one of Formulas I to X) or Tables 1A-1E. The inflammatory disease can be IBD, Crohn's disease, or ulcerative colitis. In one aspect, the IBD can be ulcerative colitis. In one aspect, the IBD can be Crohn's disease. In one aspect, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[1174] The present invention relates to methods for treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an IL-23R inhibitor of any one of Formulas I to X) or Tables 1A-1E. The inflammatory disease can be IBD, Crohn's disease, or ulcerative colitis. In one aspect, the IBD can be ulcerative colitis. In one aspect, the IBD can be Crohn's disease. In one aspect, the inflammatory disease can be psoriasis (PsO) or psoriatic arthritis (PsA).

[1175] The present invention relates to methods for inhibiting the binding of IL-23 to IL-23R on cells, comprising contacting IL-23R with a peptide inhibitor of the receptor disclosed herein. The cells can be mammalian cells. The methods can be performed in vitro or in vivo. Inhibition of binding can be determined by various routine experimental methods and assays known in the art.

[1176] The present invention relates to a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in a subject (e.g., a subject in need thereof), the method comprising providing to the subject a peptide inhibitor of IL-23R as described herein. The present invention includes and provides a method of selectively inhibiting IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in the GI tract of a subject (e.g., a subject in need thereof), the method comprising providing to the subject a peptide inhibitor of IL-23R of the invention by oral administration. The exposure of GI tissue (e.g., small intestine or colon) to the administered peptide inhibitor can be at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold greater than the exposure (level) in the blood. In a specific embodiment, the present invention includes a method for selectively inhibiting IL23 or IL23R signaling (or binding of IL23 to IL23R) in the GI tract of a subject (e.g., a subject in need thereof), the method comprising providing a peptide inhibitor to the subject, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In another related embodiment, the present invention includes a method for inhibiting GI inflammation and / or neutrophil infiltration into the GI tract, the method comprising providing a peptide inhibitor of the present invention to a subject in need thereof. In some embodiments, the method of the present invention includes providing a peptide inhibitor of the present invention (i.e., a first therapeutic agent) in combination with a second therapeutic agent to a subject (e.g., a subject in need thereof). In certain embodiments, the second therapeutic agent is provided to the subject before and / or simultaneously with and / or after the peptide inhibitor is administered to the subject. In a specific embodiment, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug, a steroid, or an immunomodulator. In certain embodiments, the method includes administering a third therapeutic agent to the subject. In certain embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R.

[1177] The present invention relates to methods for inhibiting IL-23 signaling in cells, comprising contacting IL-23R with a peptide inhibitor described herein. In certain embodiments, the cells are mammalian cells. In certain embodiments, the methods are performed in vitro or in vivo. In certain embodiments, inhibition of IL-23 signaling can be determined by measuring changes in phospho-STAT3 levels in the cells.

[1178] In any of the foregoing methods, administration of the IL-23R inhibitor to the subject can be performed orally, but other routes of administration are not excluded. Other routes of administration include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular routes. The dosage of the peptide inhibitor described herein or IL-23R (e.g., a compound of any one of Formulas (I) to (X) or Tables 1A-1E) or a salt or solvate thereof administered to the subject can be determined by one skilled in the art considering the disease or condition being treated (including its severity) and factors (including age, weight, sex, etc.). Exemplary dosage ranges include, but are not limited to, about 1 mg to about 1000 mg, or about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, or about 20 mg to about 30 mg. The dosage range of the peptide inhibitor or IL-23R described herein can be about 600 mg to about 1000 mg. The dosage range of the peptide inhibitors or IL-23R described herein may be from about 300 mg to about 600 mg. The dosage range of the peptide inhibitors or IL-23R described herein may be from about 5 mg to about 300 mg. The dosage range of the peptide inhibitors or IL-23R described herein may be from about 25 mg to about 150 mg. The dosage range of the peptide inhibitors or IL-23R described herein may be from about 25 mg to about 100 mg. The dosage range of the peptide inhibitors or IL-23R described herein may be present in a dosage range of about 1 mg to about 100 mg. The dosage range of the peptide inhibitors or IL-23R described herein may be present in a dosage range of about 20 mg to about 40 mg. The dosage range of the peptide inhibitors or IL-23R described herein may be present in a dosage range of about 20 mg to about 30 mg.

[1179] Example

[1180] The following examples illustrate the present invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to those skilled in the art for preparing and using the compounds, compositions, and methods of the present invention. While specific aspects of the present invention have been described, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present invention.

[1181] Certain abbreviations that may be used to describe the present invention are defined below in Tables 2A and 2B below.

[1182] Table 2A. Amino acid abbreviations

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201]

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211] Table 2B. Abbreviations for Substituents, Reagents, and Solvents

[1212]

[1213]

[1214] Table 2C. Abbreviations of Substituents

[1215]

[1216]

[1217] Method for preparing the cyclic peptide of the present invention

[1218] The cyclic peptides of the present invention can be prepared by solid phase peptide synthesis (SPPS) using Fmoc / t-Bu chemistry and purified according to methods known in the art, for example, according to E. Atherton and RC Sheppard, Solid Phase Peptide Synthesis: a Practical Approach, IRL Press (Oxford, England (1989)); or Amblard et al., Methods and Protocols of Modern Solid Phase Peptide Synthesis, Molecular Biotechnology, 2006, Vol. 33, 239-254. Amino acid protecting groups that can be used to synthesize BMPR2 cyclic peptides are summarized in Table A; or Isidro-Llobet et al., Amino Acid-Protecting Groups, Chem. Rev. 2009, 109, 2455-2504, which also describes examples of orthogonal protection schemes that can be used to conjugate, for example, natural polymers or non-natural polymers or combinations thereof to specific sites.

[1219] Generally, natural polymers or non-natural polymers or combinations thereof (e.g., hydrophilic or water-soluble polymers) can be conjugated to the first or second BMPR2 cyclic peptide by N-hydroxysuccinimide (NHS), click, or maleimide-based chemistry or other chemistry, as known in the art. Canalle et al., Polypeptide-polymer bioconjugates, Chem. Soc. Rev., 2010, 39, 329-353; and Gauthier et al., Peptide / protein-polymer conjugates: synthetic strategies and design concepts, Chem. Commun., 2008, 2591-2611 provide an overview of some methods for constructing peptide-polymer bioconjugates....

Claims

1. A cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclic peptide comprises an amino acid sequence of formula (A): WITH 3 -WITH 4 -WITH 5 -WITH 6 -WITH 7 -WITH 8 -WITH 9 -WITH 10 -WITH 11 -WITH 12 -WITH 13 -WITH 14 -WITH 15 -WITH 16 (AND), in: Position Z 3 The amino acid residue at is absent or is an r residue; Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is connected; Position Z 5 The amino acid residue at is a N(N(Me)2) residue; Position Z 6 The amino acid residue at is the residue of T; Position Z 7 The amino acid residue at is a 7MeW residue; Position Z 8 The amino acid residue at is the residue of K(NMeAc); Position Z 9 The amino acid residue at position Z is 4 The amino acid residue to which the amino acid residue at is connected; Position Z 10 The amino acid residue at is the residue of TMAPF; Position Z 11 The amino acid residue at is the residue of 2Nal; Position Z 12 The amino acid residue at is absent or is a THP residue; Position Z 13 The amino acid residue at is the residue of K(NMeAc); Position Z 14 The amino acid residue at is the residue of N; Position Z 15 The amino acid residue at is absent or is a 3Pya residue; Position Z 16 The amino acid residue at the position is absent or is a Sar residue; When the amino acid residue is present 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 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position; and When the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one quaternary amine.

2. A cyclic peptide or a pharmaceutically acceptable salt or solvate thereof, wherein the cyclic peptide comprises an amino acid sequence of formula (B): WITH 3 -WITH 4 -WITH 5 -WITH 6 -WITH 7 -WITH 8 -WITH 9 -WITH 10 -WITH 11 -WITH 12 -WITH 13 -WITH 14 -WITH 15 -WITH 16 (B), in: Position Z 3 The amino acid residue at is absent or is an r residue; Position Z 4 The amino acid residue at position Z 9 The amino acid residue to which the amino acid residue at is connected; Position Z 5 The amino acid residue at is a N(N(Me)2) residue; Position Z 6 The amino acid residue at is the residue of T; Position Z 7 The amino acid residue at is a 7MeW residue; Position Z 8 The amino acid residue at is the residue of K(NMeAc); Position Z 9 The amino acid residue at position Z is 4 The amino acid residue to which the amino acid residue at is connected; Position Z 10 The amino acid residue at is the residue of TMAPF; Position Z 11 The amino acid residue at is the residue of 2Nal; Position Z 12 The amino acid residue at is absent or is a THP residue; Position Z 13 The amino acid residue at is the residue of K(NMeAc); Position Z 14 The amino acid residue at is the residue of N; Position Z 15 The amino acid residue at is absent or is a 3Pya residue; Position Z 16 The amino acid residue at the position is absent or is a Sar residue; When the amino acid residue is present 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 16 when eight or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position; and When the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one masked amine and / or masked amide.

3. A cyclic peptide according to any one of the preceding claims, wherein position Z 4 The amino acid residue at is the residue of Abu or the residue of an amino acid comprising a thiol group, optionally wherein the amino acid comprising a thiol group is selected from the group consisting of Pen, C or aMeC.

4. A cyclic peptide according to any one of the preceding claims, wherein position Z 9 The amino acid residue at is the residue of an amino acid comprising a thiol group, optionally wherein the amino acid comprising a thiol group is selected from the group consisting of: Pen, C or aMeC.

5. A cyclic peptide according to any one of the preceding claims, wherein: (a) When position Z 4 When the amino acid residue at position Z is a residue of an amino acid containing a sulfhydryl group, 4 The amino acid residue at position Z 4 The amino acid at position Z contains a thiol group 9 The disulfide bond formed between the amino acid containing a sulfhydryl group at position 9 or (b) Position Z 4 The amino acid residue at position Z is the residue of an amino acid containing a sulfhydryl group, and 4 The amino acid residue at position Z 4 The amino acid at position Z contains a thiol group 9 The disulfide bond formed between the amino acid containing a sulfhydryl group at position 9 or (c) When position Z 4 When the amino acid residue at position Z is the residue of Abu, 4 The amino acid residue at position Z 4 The Abu and position Z 9 The thioether bond formed between the amino acid containing a sulfhydryl group at position Z 9 or (d) Position Z 4 The amino acid residue at position Z is the residue of Abu, and 4 The amino acid residue at position Z 4 The Abu and position Z 9 The thioether bond formed between the amino acid containing a sulfhydryl group at position Z 9 The amino acid residue at the position is connected.

6. The cyclic peptide according to any one of the preceding claims, wherein the cyclic peptide further comprises R NT , where R NT Binds to the N-terminal amine of the amino acid residue at the following position: (i) Z 3 , when Z 3 When present, or (ii) Z 4 , when Z 3 does not exist; and R NT Selected from the group consisting of: -C(O)-optionally substituted (C1-C 20 )alkyl and -C(O)-optionally substituted (C1-C 40 ) heteroalkyl.

7. The cyclic peptide according to any one of the preceding claims, wherein the cyclic peptide further comprises R CT , where R CT is bound to the carbonyl group of the C-terminal carboxylic acid of said amino acid residue derived from: (i) Z 16 , when Z 16 When it exists, (ii) Z 15 , when Z 16 When it does not exist, or (iii) Z 14 , when Z 15 and Z 16 does not exist; and R CT Yes-N(R Y )(R Z ),in (i) Each R Y and R Z are 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, they form an optionally substituted (C3-C 14 ) heterocyclic or optionally substituted (C5-C 10 ) bicyclic heterocycle.

8. A cyclic peptide according to any one of the preceding claims, wherein when the amino acid residue is present 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 16 When four or fewer of the amino acid residues at said positions are independently substituted with an amino acid residue different from the amino acid residue listed at said position.

9. A cyclic peptide according to any one of the preceding claims, wherein when the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one quaternary amine.

10. The cyclic peptide according to any one of the preceding claims, wherein each quaternary amine is independently selected from the group consisting of: (a) Each R ZA are independently selected from the group consisting of: optionally substituted (C1-C 20 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl; (b) Each R ZA and R ZB Independently selected from the group consisting of: Optionally substituted (C1-C 20 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl; (c) in (c)(i) Each R ZA , R ZB and R ZC are independently selected from the group consisting of: optionally substituted (C1-C 20 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl, (c)(ii) Each R ZA are 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 ZC Together with the N atom to which they are attached, they form an optionally 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, they form an optionally substituted (C5-C 10 ) bicyclic heterocycle; (d) in (d)(i) 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, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) a heterocyclic group, or (d)(ii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic group, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) a heterocyclic group, or (d)(iii) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic group, and each R ZC and R ZD Together with the N atom to which they are attached, they form an optionally substituted (C3-C 14 ) heterocyclic ring; (e) Each R ZA and R ZB Together with the N atom to which they are attached, they form an optionally substituted (C5-C 14 ) a heteroaromatic ring, and (f) Each R ZA are 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 ZC Together with the N atom to which they are attached, they form an optionally substituted (C5-C 14 ) heteroaryl.

11. A cyclic peptide according to any one of the preceding claims, wherein when the amino acid residue is present 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 When at least one of the amino acid residues at said position each independently comprises at least one masked amine and / or masked amide.

12. The cyclic peptide according to any one of the preceding claims, wherein at least one of the masked amines and / or masked amides is independently selected from the group consisting of: (a) Each R YA are independently selected from the group consisting of: optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R YB are independently selected from the group consisting of hydrogen, optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl; (b) Each R YC Independently selected from the group consisting of: Optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R YD are independently selected from the group consisting of hydrogen, optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl; (c) Each R YE Independently selected from the group consisting of: Optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl, and each R YF are independently selected from the group consisting of hydrogen, optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl; and (d) Each R YG and R YH are independently selected from the group consisting of: optionally substituted (C1-C 10 )alkyl and optionally substituted (C1-C 20 ) heteroalkyl.

13. A cyclic peptide according to any one of the preceding claims, wherein: (a) When position Z 3 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 3 The amino acid residue at is replaced by 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; and / or (b) When position Z 5 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 5 The amino acid residue at is replaced by 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; and / or (c) When position Z 6 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 6 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: A and L; and / or (d) When position Z 7 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 7 The amino acid residue at is replaced by an amino acid residue selected from the group consisting of W, 7(3NAcPh)W, 7CF3W, NMe7MeW, 2Nal, A, F and L; and / or (e) When position Z 8 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 8 The amino acid residue at is replaced by 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); and / or (f) When position Z 10 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 10 The amino acid residue at is replaced by an amino acid residue selected from the group consisting of 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(N Me3), AEF(NMeBismPEG3), AEF(NMePEG2a), AEF(NmPEG6), AEF(NsCh), AEF(PEG2a), AEF(SPD), APEG2F, APEG3F, dFPPEG3F, II Azabicyclooctane 6F, 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, morfT MA4F, mPEG2TMA2F, mPEG2TMA4F, mPEG3TMA4F, MPzPEG3F, MTASF, NPyEF, NPyPEG3F, piperazine quatF, TBAPEG3F, TMA3F, TMA4F, TMA6F , TMA8F, Tzl(Ch), TzlChmPEG, TzlChmPEG3, Y(C9OH), Y(OEOXIMECh), Y(OTzlCh), Y(OTzlChC16), Y(OTzlChC8), Y(OTzlC1aC 8), Y(OTzlChmPEG), Y(OTzlChmPEG3), Y(OTzlPEG3a), Y(OTzlPEG4a), Y(OTzlTMA4), Y(OZOXIMECh), YC8CO(NHPEG3a), YC8C OPip, YCF2H, ACHMF(R*,S*), ACHMF(S*,S*), AEF(cPEG3a), APF, F(4TzlAme2), F(4TzlG2), F(4TzlMMo7), and F(4TzlTMA7); and / or (g) When position Z 11 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 11 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: A, F, L and W; and / or (h) When position Z 12 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 12 The amino acid residue at is replaced by 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; and / or (i) When the amino acid residue at position Z 13 is replaced with an amino acid residue different from the amino acid residue listed at said position, the amino acid residue at position Z 13 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; and / or (j) When position Z 14 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 14 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: K(Ac) and N(NMe); and / or (k) When position Z 15 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 15 The amino acid residue at position is replaced by an amino acid residue selected from the group consisting of: 3pya, 5CF33Pya, 5MepyridineAla, bAla, dK, dL, F, f, H, h, k, N, NMe3Pya, NMebAla, NMeDTyr, orn, Paf, s, t, THP, v, y and A; and / or (l) When position Z 16 When the amino acid residue at position Z is replaced by an amino acid residue different from the amino acid residue listed at the position, 16 The amino acid residue at is replaced by 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(PEG2PEG2PEG2gEC12)2), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG2PEG2gEC12), NMeK(PEG2PEG6gEC12), NMeK(PEG2PEG6gEC14), NMeK(SP6PEG2PEG2C12) and NMeK(SP6PEG2PEG2gEC12.

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

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

16. A method for treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome and Wisconsin-Madison syndrome in a subject. Kott-Aldrich syndrome, pouchitis caused by proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis or graft-versus-host disease, the method comprising providing the subject with an effective amount of a cyclic peptide according to any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any one of the preceding claims.

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