Peptide inhibitors of interleukin-23 receptor

Abstract

The present invention relates to compounds that are peptide inhibitors of interleukin-23 receptor (IL-23R) and to their use in the treatment or prevention of a variety of diseases, conditions or disorders, including inflammatory diseases, such as inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, psoriasis and psoriatic arthritis. Compounds of the invention exhibit good physical and chemical stability in the gastrointestinal tract.

Description

[0001] PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to peptide inhibitors of interleukin-23 receptor (IL-23R), and to their medical use in the treatment and / or prevention of a variety of diseases, conditions or disorders, including inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, psoriasis and psoriatic arthritis, and other conditions and disorders described herein.

[0004] BACKGROUND OF THE INVENTION

[0005] Interleukin-23 (IL-23) is a heterodimeric cytokine composed of a unique p19 subunit and the p40 subunit of interleukin-12 (IL-12). IL-12 is a cytokine involved in the development of interferon-gamma (IFN-y)-producing T helper 1 (Th1) cells. Although both IL-23 and IL- 12 contain the p40 subunit, they have different phenotypic properties. Animals deficient in IL-12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant. This is thought to be due to a reduced number of CD4+T cells producing interleukin-6 (IL-6), interleukin-17 (IL-17), and tumour necrosis factor (TNF) in the central nervous system (CNS) of IL-23-deficient animals. Furthermore, in contrast to IL-12 which acts mainly on naive CD4+T cells, IL-23 preferentially acts on memory CD4+T cells.

[0006] The receptor that binds IL-23 is the interleukin-23 receptor (IL-23R). IL-23R is a heterodimeric receptor composed of IL-12Rp1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the JAK-STAT signalling pathway: activating the Janus kinase (JAK) molecules JAK2 and tyrosine kinase 2 (TYK2), as well as the signal transducer and activator of transcription proteins (STATs) STAT1 , STAT3, STAT4, and STAT5. STAT4 activation is substantially weaker and different DNA-binding STAT complexes form in response to IL-23 as compared with IL-12. IL-23R associates constitutively with JAK2 and in a ligand-dependent manner with STAT3.

[0007] IL-23R is expressed on various adaptive and innate immune cells, including: T-helper 17 (Th17) cells, gamma-delta (y6) T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells. These cells are abundantly found in the intestine. In particular, the gene expression and protein levels of IL-23R at the intestine mucosal surface are found to be elevated in inflammatory bowel disease (IBD) patients. It is thought that IL-23 mediates this effect by promoting the development of a pathogenic CD4+T cell population that produces IL-6, IL-17, and TNF. IL-23 production is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through both T-cell-dependent and independent pathways of intestinal inflammation through effects on Th1 and Th17- associated cytokines. IL-23 is also thought to restrain regulatory T-cell responses in the gut, favouring inflammation. Furthermore, IL-23R polymorphisms have been associated with susceptibility to inflammatory bowel diseases (IBDs), further establishing the critical role of the IL-23 pathway in intestinal homeostasis.

[0008] The anti-IL-23 antibody risankizumab (ABBV-006) has been approved for the treatment of inflammatory diseases, including psoriasis, psoriatic arthritis and Crohn’s disease, and is also being investigated for the treatment of ulcerative colitis.

[0009] Therefore, IL-23 is thought to play a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel diseases (IBDs), e.g., ulcerative colitis and Crohn’s disease. Studies in acute and chronic mouse models of IBD have revealed a primary role of IL-23R and downstream effector cytokines in disease pathogenesis.

[0010] Protagonist Therapeutics, Inc. developed peptide PTG-200 which was in Phase II clinical trials for Crohn's disease. Protagonist in collaboration with Janssen Biotech, Inc. also have two second generation peptides in clinical trials: JNJ-77242113 (or JNJ-2113; formerly PN-235) for psoriasis; and PN-232. Protagonist have filed several patent applications in the area of IL-23R inhibitors: WO 2016 / 011208, WO 2017 / 011820, WO 2018 / 022937, WO 2018 / 136646, WO 2020 / 014646, WO 2021 / 007433, WO 2021 / 146441 , WO 2021 / 146458, WO 2023 / 288017, WO 2023 / 288019, and

[0011] WO 2023 / 288028. Protagonist also disclose another peptide, Compound C, as an IL-23R inhibitor in WO 2016 / 011208, WO 2017 / 011820, and Sayago et a!., 2018.

[0012] Kong et al., Nature Biomedical Engineering, 2020, 4, 560-571 discloses the development of proteolytically resistant therapeutic peptides for oral administration. The authors generated peptides as inhibitors of coagulation Factor Xia and other peptides as gastrointestinal-protease resistant peptide antagonists of IL-23R. The peptides generated as antagonists of IL-23R have two dithioether bridges (specifically 1 ,3-dithio-propan-2-one bridges) between two pairs of cysteine residues in the peptide chain. The authors identified peptide I5 as the most promising candidate for further development as an oral treatment of inflammatory disorders such as Crohn’s disease on the basis of IL-23R inhibition. WO 2023 / 288017 discloses bicyclic (and some tricyclic) peptide inhibitors of IL-23R. The peptides are up to 15 amino acid residues long, all of which have (at least) two bonds bridging between certain amino acid residues. WO 2023 / 288019 discloses lipidated peptide inhibitors of IL-23R. The peptides are up to 15 amino acid residues long, and either have one or two bonds bridging between certain amino acid residues. Of the peptides with two bridges, one is either a disulfide or dithioether bond and the other is an amide bond. Both applications propose the use of the inhibitors for the treatment of autoimmune inflammation and related diseases and disorders, including IBD, Crohn's disease, ulcerative colitis, psoriasis, and psoriatic arthritis.

[0013] WO 2023 / 099669 discloses peptide inhibitors of IL-23R comprising two bridges between the moieties defined therein as X2 and X11 and X4 and X7, respectively.

[0014] WO 2024 / 114762 describes peptides which are IL-23R inhibitors, their preparation, and their use. These compounds have a disulfide bridge between the first and sixth amino acid residues in the peptide chain.

[0015] WO 2024 / 155553 describes peptides which are IL-23R inhibitors, their preparation, and their use. These compounds comprise at least one lipophilic substituent.

[0016] WO 2024 / 155552 describes pharmaceutical formulations comprising an absorption enhancer and peptides which are IL-23R inhibitors. The peptides are lipidated and cyclised to form a ring comprising 4 to 14 amino acids.

[0017] Challenges still remain with respect to identifying stable and selective agents that preferentially target the IL-23 pathway, which can be used for the treatment of intestinal inflammation. In particular, the gastrointestinal stability and IL-23R potency of the peptides disclosed in Kong et al., 2020 are still not sufficient to enable any of these peptides to be developed as an orally dosed IL-23R peptide blocker. In particular, the most-promising candidate, peptide I5 from Kong et al., 2020, exhibited a lower stability under a simulated intestinal fluid (SIF) assay and a lower potency for IL-23R in comparison with Protagonist’s Compound C (Sayago et al., 2018).

[0018] Therefore, there remains a need for new therapeutics targeting the IL-23 pathway, which may be used to treat and prevent IL-23-associated diseases, including those associated with autoimmune inflammation in the intestinal tract. Furthermore, compounds and methods for specific targeting of IL-23R from the luminal side of the gut may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue. SUMMARY OF THE INVENTION

[0019] The present invention relates to compounds which are peptide inhibitors of interleukin-23 receptor (IL-23R). These compounds exhibit potent inhibition of IL-23R, and many of them also exhibit high stability in the gastrointestinal tract making them suitable for oral administration. Furthermore, the compounds described herein may be useful in the treatment of various diseases, conditions and disorders related to IL-23R such as inflammatory bowel disease including Crohn’s disease and ulcerative colitis, psoriasis and psoriatic arthritis.

[0020] In a first aspect, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof:

[0021] X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X13-X14-R2(I) wherein

[0022] R2is NR3R4wherein R3and R4are each independently selected from hydrogen, C- alkyl optionally substituted with a pyridyl group or -C(0)NR’R’ (where R and R’ are independently H or C1-4 alkyl); C3-10 cycloalkyl; a saturated 5 or 6-membered heterocyclic ring having 1 or 2 heteroatoms selected from N, O and S, the ring being optionally substituted;

[0023] X2 is absent or selected from the group consisting of 4-aminomethyl-phenylacetyl, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, 3-aminopropanoyl, Lys, Dpr, Dab, Orn, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta- homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0024] X3 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, any amino acid, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0025] X4 is absent or selected from the group consisting of Glu, Asp, Lys, Dab, Orn, Dpr, Cys, Vai, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0026] X5 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0027] X6 is selected from the group consisting of an optionally substituted Lys residue or iso-Lys residue, an optionally substituted Ala residue, Gin, iso-GIn, Gln(Me), Gln(2Me), Gin (pyrrolidin), Dab(Ac), Glu, iso-Glu, Tyr, Cys, Vai, His, Ala, Dab(optionally substituted with C2-6 alkanoyl), iso-Dab, Cit, Arg, Orn(optionally substituted with C2-6 alkanoyl), Asn, a D- isomeric form of any thereof, a beta analogue of either thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof;

[0028] X7 is selected from the group consisting of Ala, Aib, Phe, Dab, iso-Dab, Cys, Glu, iso-Glu, Asp, iso-Asp, Pra, Lys, Orn, Dpr, Hpg, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0029] X8 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an alanine residue substituted by an optionally substituted carbocyclic group or an optionally substituted aryl or heteroaryl group, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0030] X9 is selected from the group consisting of an optionally substituted phenylalanine residue, an optionally substituted tyrosine residue, an optionally substituted azatryptophan residue, an optionally substituted tryptophan residue, an alanine residue substituted by an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; X10 is selected from the group consisting of 4-Aminotetrahydro-2H-pyran-4-carbonyl, Aib, Leu, Ala, 2-Me-Leu, 2-Me-Lys, Trp, Asn, iso-Asn, Cys, Vai, Ala, He, 2-Me-Val, Dab, isoDab, Gly, Lys, iso-Lys, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0031] X11 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0032] X12 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the lipid and amino acid, 3-aminotetrahydrofuran-3- carbonyl, Ser(OMe), Arg, 2-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, iso-Glu, Asn, iso-Asn, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, [2-(trimethyl-2-aminoethoxy)ethoxy]- propyl, 3-aminopropanoyl, GABA, Dab, iso-Dab, Gly-CF3, Nle, Gin, iso-GIn, THP, 2-Me- Ser, His, His(1-Me), 3-(3-Quinolinyl)-Ala, Pro, 5-aminopentanoyl, 4-aminopiperidin-4- carbonyl, (R,S)-imidazolidin-2-carbonyl, 4-aminotetrahydropyran-4-carbonyl, 3- aminotetrahydrofuran-4-carbonyl, or Lys wherein the side chain -NH2 of the Lys is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0033] X13 is selected from the group consisting of 3-(3-Pyridyl)-Ala, D-3-(3-Pyridyl)-Ala, 3-(3,5- Pyrimidyl)-Ala, Asn, Gly, 3-(4-Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, {d}[3-(3-Pyridyl)-Ala], 3- amino-3-(3'-pyridyl)propionyl, Phe, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3- diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), 2-Me-3- (3-Pyridyl)-Ala, N-Me-3-(3-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, 3-(5-F-3-Pyridyl)-Ala, His, His(Me), a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0034] X14 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, Sar, His, Leu, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; wherein either: a) X2 is a residue that forms a bridge with a residue at X7 and a bridge with a residue at X11 , such that the compound of formula I is a compound of formula la or b) X2 is a residue that forms a bridge with a residue at X11 and X4 is a residue that forms a bridge with a residue at X7, such that the compound of formula I is a compound of formula lb or c) X2 to X4 are absent and X5 is a residue that forms a bridge with a residue at X11 via linker L, such that the compound of formula I is a compound of formula Ic wherein L optionally comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid; wherein the compound of formula I comprises a lipophilic substituent.

[0035] In some embodiments, the compound is selected from a compound from Table 1-1 , or a pharmaceutically acceptable salt or solvate thereof. The invention further provides a composition comprising a compound as described above. The composition may be a pharmaceutical composition, and may comprise a pharmaceutically acceptable carrier, excipient or vehicle.

[0036] The invention further provides a method for the synthesis of a compound as described above. The method may comprise the steps of synthesising the peptide by solid-phase or liquid-phase methodology, and optionally isolating and / or purifying the final product, and optionally further comprising the step of forming a bond between a) the amino acid residue at the X2 position and the amino acid residues at the X7 and X11 positions or b) the amino acid residue at the X2 position and the amino acid at the X11 position and the amino acid residue at the X4 position and the amino acid residue at the X7 position and c) the amino acid residue at the X5 position and the amino acid residue at the X11 position. In some embodiments, the bond is an amide bond. In some embodiments, the bond is a thioether bond. In some embodiments, the bond comprises a first bond between a first carbon of an alkyne and the first nitrogen of an azide, and a second bond between a second carbon of an alkyne and the third nitrogen of an azide, to complete a 1 ,2,3-triazole group.

[0037] The invention further provides a compound of the invention, or a pharmaceutical compositions comprising said compound, for use in a method of medical treatment.

[0038] The invention also provides a compound of the invention, or a pharmaceutical composition comprising said compound, for use in a method of prevention or treatment of a disease or condition selected from the group consisting of inflammatory bowel disease (IBD) such as Crohn’s Disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof.

[0039] In some embodiments, the condition is inflammatory bowel disease (IBD) and / or psoriasis.

[0040] The invention also provides use of a compound of the invention, or the pharmaceutical composition comprising said compound, in the manufacture of a medicament for the prevention or treatment of a disease or condition selected from the group consisting of inflammatory bowel disease (IBD) such as Crohn’s Disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof.

[0041] In some embodiments, the condition is inflammatory bowel disease (IBD) and / or psoriasis.

[0042] The invention also provides a method of prevention or treatment of a disease or condition selected from the group consisting of inflammatory bowel disease (IBD) such as Crohn’s Disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof; which method comprises administering to the subject an effective amount of the compound of the invention, or the pharmaceutical composition comprising said compound.

[0043] In some embodiments, the condition is inflammatory bowel disease (IBD) and / or psoriasis.

[0044] Further aspects and embodiments of the present invention will become apparent from the disclosure below.

[0045] DETAILED DESCRIPTION OF THE INVENTION

[0046] Definitions

[0047] Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature employed herein in connection with techniques of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, is that well known and commonly used in the art.

[0048] All publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0049] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or component, or of a stated group of integers or components, but not the exclusion of any other integer or component or group of integers or components.

[0050] The singular forms “a”, “an”, and “the” include the plurals unless the context clearly dictates otherwise.

[0051] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

[0052] The terms “patient”, “subject”, and “individual” may be used interchangeably and may refer to either a human or a non-human animal. Subjects are typically mammals, including humans, non-human primates (including great apes, Old World monkeys and New World monkeys), livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats). As used herein, the term “pharmaceutically acceptable salt” is intended to indicate a salt which is not harmful to a patient or subject to which the salt in question is administered. It may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts. Examples of basic salts include salts where the cation is selected among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type N(R1)(R2)(R3)(R4)+, where R1, R2, R3and R4independently will typically designate hydrogen, optionally substituted Ci-6-alkyl or optionally substituted C2-6-alkenyl. Examples of relevant Ci-6-alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl groups. Examples of C2-6-alkenyl groups of possible relevance include ethenyl, 1 -propenyl and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in “Remington’s Pharmaceutical Sciences”, 17thedition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the “Encyclopaedia of Pharmaceutical Technology”, 3rdedition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977).

[0053] The term “solvate” in the context of the present invention refers to a complex of defined stoichiometry formed between a solute ( / n casu, a peptide or pharmaceutically acceptable salt thereof according to the invention) and a solvent. The solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable - typically small- molecular - organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is normally referred to as a hydrate.

[0054] The term “antagonist” as employed in the context of the invention refers to a substance that inhibits the receptor type in question, typically by binding to it (i.e. as a ligand) and blocking it.

[0055] Each embodiment of the invention described herein may be taken alone or in combination with one or more other embodiments of the invention.

[0056] The term “therapeutically effective amount” or “effective amount” as used herein in the context of the above-described methods of treatment or other therapeutic interventions according to the invention refers to an amount that is sufficient to cure, ameliorate, alleviate or partially arrest the clinical manifestations of the particular disease, disorder or condition that is the object of the treatment or other therapeutic intervention in question e.g. as measured by established clinical endpoints or other biomarkers (established or experimental). A therapeutically relevant amount may be determined empirically by one skilled in the art based on the indication being treated or prevented and the subject to whom the therapeutically relevant amount is being administered. For example, the skilled worker may measure one or more of the clinically relevant indicators of bioactivity described herein, e.g. myeloperoxidase (MPO), interleukin-1 p (IL-1 p), interleukin-6 (IL-6), interleukin-22 (IL-22), interleukin-17A (IL-17A), interleukin-17F (IL-17F), lipocalin 2 (LCN2), matrix metallopeptidase 9 (MMP9), S100 calcium-binding protein A8 (S100A8), microRNA-223-3p (miR223-3p), Claudin 8 (CLDN8), and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) proteins, polynucleotides encoding any of the proteins, and polynucleotides comprising a region complementary to microRNA-223-3p or any of the polynucleotides that encode any of the proteins, as described in WO 2018 / 089693. The skilled worker may determine a clinically relevant amount through in vitro or in vivo measurements.

[0057] An amount adequate to accomplish any or all of these effects is defined as a therapeutically effective amount. The administered amount and the method of administration can be tailored to achieve optimal efficacy. An amount effective for a given purpose will depend, inter alia, on the severity of the disease, disorder or condition that is the object of the particular treatment or other therapeutic intervention, on the body weight and general condition of the subject in question, on diet, on possible concurrent medication, and on other factors well known to those skilled in the medical arts. Determination of an appropriate dosage size and dosing regimen most appropriate for administration of a peptide or pharmaceutically acceptable salt or solvate thereof according to the invention to a human may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials. An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are well known to the skilled person.

[0058] The terms "treatment" and grammatical variants thereof (e.g. “treated”, “treating”, “treat”) as employed in the present context refer to an approach for obtaining beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e. not worsening) of state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival relative to expected survival time if not receiving treatment. A subject (e.g. a human) in need of treatment may thus be a subject already afflicted with the disease or disorder in question. The term “treatment” includes inhibition or reduction of an increase in severity of a pathological state or symptoms (e.g. inflammation) relative to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant disease, disorder or condition.

[0059] The terms "prevention" and grammatical variants thereof (e.g., “prevented”, “preventing”, “prevent”) as employed in the present context refer to an approach for hindering or preventing the development of, or altering the pathology of, a condition, disease or disorder. Accordingly, "prevention" may refer to prophylactic or preventive measures. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, prevention or slowing of symptoms, progression or development of a disease, whether detectable or undetectable. A subject (e.g. a human) in need of “prevention” may thus be a subject not yet afflicted with the disease or disorder in question. The term “prevention” thus includes inhibiting or slowing the onset of disease relative to the absence of treatment, and is not necessarily meant to imply permanent prevention of the relevant disease, disorder or condition.

[0060] Amino acids nomenclature

[0061] The term “amino acid” is an organic compound that contains an amino or amine group (- NH2 or -NHR) and a carboxylic acid (-COOH) group. As is known to the person skilled in the art, the amine and carboxylic acid groups of amino acid residues react together to form peptides having an amide bond, also referred to as a peptide linkage, of the formula -NH-C(=O)- or -NR-C(=O)-.

[0062] The carbonyl of the carboxylic acid group may be further functionalised, such as converted to -CF3 in Gly-CFs and D-Gly-CFs. This further functionalisation may occur before, during, or after peptide coupling with the other amino acid residues in the peptide chain.

[0063] The term “amino acid” is thus not limited to including natural and unnatural alpha and beta amino-acids but also includes (when forming part of a peptide) residues such as 3- aminopropanoyl and 4-aminobutanoyl. The term also includes cyclic structures such as carbocyclic and heterocyclic structures, having an amine and a carboxylic acid functionality. The amine group of the amino acid may be further functionalised, such as an azide group (-N3), for example in (Ns)-Lys or D-(N3)-Lys.

[0064] Some amino acids described herein have the amine and carboxylic acid groups attached to the same carbon, called alpha (a) amino acids. Some amino acids described herein have the amine and carboxylic acid groups 1 , 2, 3, 4, 5, or 6 carbon atoms away. For example, beta-homo-Trp and beta-homo-Leu have the amine and the carboxylic acid groups 1 carbon away from each other, such that the carbon connected to the amine group and the carbon connected to the carboxylic acid group are adjacent to one another.

[0065] Some amino acids described herein have a side chain specific to each amino acid. The side chain may also be further functionalised.

[0066] Throughout the present specification, unless naturally occurring amino acids are referred to by their full name (e.g. alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g. Ala or A for alanine, Arg or R for arginine, etc.). In the case of certain less common or non-naturally occurring amino acids (i.e. amino acids other than the 20 encoded by the standard mammalian genetic code), unless they are referred to by their full name (e.g. ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including 2-Nal (3-(2-naphthyl)- alanine).

[0067] Unless otherwise indicated, reference is made to the L- and D- isomeric forms of the amino acids in question. In one embodiment, unless otherwise stated, the amino acids referred to herein are in their L isomeric form. In one embodiment, unless otherwise stated, the amino acids referred to herein are in their D isomeric form. In a preferred embodiment, unless otherwise stated, the amino acids referred to herein are in their L isomeric form.

[0068] Unless otherwise indicated, reference is made to both the homo and non-homo forms of the amino acids in question. As evident from Table A below, the prefix “homo” to the name of an amino acid indicates the addition of a methylene group to the a-carbon of an amino acid. In one embodiment, unless otherwise stated, the amino acids referred to herein are in their non-homo form. In one embodiment, unless otherwise stated, the amino acids referred to herein are in their homo-form. In a preferred embodiment, unless otherwise stated, the amino acids referred to herein are in their non-form.

[0069] Unless otherwise indicated, reference is made to both the alpha and beta forms of the amino acids in question. As evident from Table A below, the prefix “beta” to the name of an amino acid indicates that the carbon skeleton has been lengthened by insertion of one carbon atom immediately after the acid group of the amino acid backbone. In one embodiment, unless otherwise stated, the amino acids referred to herein are in their alpha form. In one embodiment, unless otherwise stated, the amino acids referred to herein are in their beta-form. In a preferred embodiment, unless otherwise stated, the amino acids referred to herein are in their alpha form.

[0070] Amino acid residues are amino acid moieties within a peptide chain. Unnatural amino acid residues may be identified as the fragment of the unnatural amino acid defined in a peptide chain (for example, the unnatural amino acid 3-aminopropanoic acid may be identified as the unnatural amino acid residue 3-aminopropanoyl in a peptide chain).

[0071] Additional abbreviations for amino acid residues are described in Table A.

[0072] Table A

[0073]

[0074] Using the above Table A and the below Table A1 , the skilled person would be able to derive the structure of any D, beta, homo, homo-beta, N-Me and N3 analogues (and combinations thereof) of the amino acid residues disclosed herein. In particular, Table A1 outlines the relevant analogues for a lysine amino acid, which can subsequently be applied to derive the corresponding structures for any equivalent amino acid analogue disclosed herein.

[0075] Table A1

[0076] Linear peptides are written from / V-terminus to C-terminus, left to right.

[0077] Unnatural (or non-naturally occurring) amino acids and unnatural (or non-naturally occurring) amino acid residues are amino acids and amino acid residues that do not naturally occur in peptide chains. Unnatural amino acids may be formed as secondary metabolites in bacteria, fungi, plants, or marine organisms, or they can be synthesised chemically.

[0078] Unless otherwise stated, the peptide backbone (that is, the amide bonds between X2- X3-X4-X5-X6-X7-X8-X9-X10-X1 1-X12-X13-X14 in the peptide chain) is formed by the amino acid residues joined by amide bonds via their terminal -NH2 and -COOH groups. That is, the “terminal -NH2 group” is the alpha-amine group for alpha amino acids or betaamine group for beta amino acids such as bLys, {d}bLys and beta-hLys; and the “terminal -COOH group” is the alpha-carboxylic acid group for the alpha amino acids. The skilled person thus understands that the amino acids within the peptide chains (i.e., those specified for at least X2, X3, X4, X5, X6, X7, X8, X9, X10, X11 , X12, X13 and X14) will be in the form -NH-X-C(=O)-, wherein X represents the amino acid structure between the amine and carboxylic acids residues that form the amide backbone of the peptide chain.

[0079] Where the amino acid residue comprises two or more amine groups (-NH2, such as Lys and Dab) or carboxylic acid groups (-COOH, such as Glu), the peptide backbone may instead be formed using the side chain of the amino acid residue.

[0080] For example, the following nomenclature in Table B is used to distinguish the use of the terminal and the side chain -NH2 and -COOH groups. Table B

[0081] The following C-terminal derivatives (defined in this specification by the group R2) are disclosed in Table C: Table C

[0082] These groups are attached to the carbonyl carbon of the carboxylic acid group of the C- terminal amino acid residue (i.e. that defined by X13 orX14, if present). The attachment forms an amide bond.

[0083] Linker

[0084] As used herein, the term “linker” in its broadest sense covers any group capable of linking two particular chemical moieties together. In one embodiment when the compound of formula (I) is a compound of formula (Ic), the linker is not a sequence of three amino acids. In one embodiment, the linker is or includes an amide moiety, such as a lactam moiety, as defined herein. In one embodiment, the linker is or includes a triazole ring, as defined herein. In one embodiment, the linker is or includes a thioether moiety, as defined herein.

[0085] Amide

[0086] An amide moiety is a functional group of the formula R-NH-C(=O)-R wherein each R may be the same or different. The term “amide bond” and “peptide linkage” are synonymous.

[0087] Lactam

[0088] A lactam is a cyclic amide of formula cyclo(R-NH-C(=0)-R) wherein each R may be any other suitable functional group that joins to the other R. Each R may be the same or different. Thioether / Dithioether

[0089] A thioether is a functional group of the formula R-S-R, wherein R may be any other suitable functional group. A dithioether is a functional group comprising two thioether groups linked together by a linker, such as R-S-L-Y-L-S-R wherein the linker is -L-Y-L-.

[0090] Triazole ring

[0091] A triazole is a 5-membered heteroaromatic group (as defined above) containing three nitrogen atoms and two carbon atoms in the aromatic ring. The triazole may be a 1 ,2,3- triazole or a 1 ,2,4-triazole. Preferably, the triazole is a 1 ,2,3-triazole. 1 ,2,3-triazoles may be formed by coupling an azide with an alkyne, typically using “click” chemistry as outlined below.

[0092] Head-to-tail cyclisation

[0093] The term “head-to-tail cyclisation” is cyclisation of the / V-terminal amine (or derivative thereof) and the C-terminal carboxylic acid to form a cyclic peptide. Typically, this cyclisation forms an amide bond.

[0094] Alkyl

[0095] The term "alkyl" refers to a monoradical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 40, i.e., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39 or 40, carbon atoms, such as 1 to 30, such as 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl (also called 2-propyl or 1 methylethyl), butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neo-pentyl, 1 ,2-dimethylpropyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, ndecyl, n-undecyl, n-dodecyl, n- undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n- octadecyl, n-nonadecyl, n-icosyl, n-triacontyl, n-tetracontyl, and the like. A "substituted alkyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkyl group, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the alkyl is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituents selected from List A. Examples of a substituted alkyl include chloromethyl, dichloromethyl, fluoromethyl, and difluoromethyl.

[0096] C- alkyl groups

[0097] C1-4 alkyl groups that may be present as a group n the context of compounds of the present invention include, but are not limited to, C alkyl groups such as butyl (n-Bu or - CH2CH2CH2CH3), or C1-3 alkyl groups, such as methyl (Me or -CH3, that is a Ci alkyl group), ethyl (-CH2CH3, that is a C2 alkyl group), 1 -propyl (-CH2CH2CH3, that is a C3 alkyl group), or 2-propyl (-CH(CH3)2, that is a C3 alkyl group).

[0098] C1.3 alkyl groups

[0099] C1-3 alkyl groups that may be present as a group in the context of compounds of the present invention include methyl (Me or -CHs, that is a Ci alkyl group), ethyl (-CH2CH3, that is a C2 alkyl group), 1 -propyl (-CH2CH2CH3, that is a C3 alkyl group), and 2-propyl (- CH(CH3)2, that is a C3 alkyl group).

[0100] C1.2 alkyl groups

[0101] C1-2 alkyl groups that may be present as a group in the context of compounds of the present invention include methyl (Me or -CHs, that is a Ci alkyl group) and ethyl (-CH2CH3, that is a C2 alkyl group).

[0102] Alkylene

[0103] The term "alkylene" refers to a diradical of a saturated straight or branched hydrocarbon. Preferably, the alkylene group comprises from 1 to 40, i.e., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39 or 40, carbon atoms, such as 1 to 30, such as 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene (i.e., 1 ,1 -ethylene, 1 ,2-ethylene), propylene (i.e., 1 ,1 -propylene, 1 ,2-propylene (- CH(CH3)CH2-), 2,2-propylene (-C(CH3)2-), and 1 ,3-propylene), the butylene isomers (e.g., 1 ,1-butylene, 1 ,2-butylene, 2,2-butylene, 1 ,3-butylene, 2,3-butylene (cis or trans or a mixture thereof), 1 ,4-butylene, 1 ,1-iso-butylene, 1 ,2-iso-butylene, and 1 ,3-iso-butylene), the pentylene isomers (e.g., 1 ,1-pentylene, 1 ,2-pentylene, 1 ,3-pentylene, 1 ,4-pentylene, 1 ,5-pentylene, 1 ,1 -iso-pentylene, 1 ,1 -sec-pentyl, 1 ,1-neo-pentyl), the hexylene isomers (e.g., 1 ,1-hexylene, 1 ,2-hexylene, 1 ,3-hexylene, 1 ,4-hexylene, 1 ,5-hexylene, 1 ,6- hexylene, and 1 ,1-isohexylene), the heptylene isomers (e.g., 1 ,1-heptylene, 1 ,2- heptylene, 1 ,3-heptylene, 1 ,4-heptylene, 1 ,5-heptylene, 1 ,6-heptylene, 1 ,7-heptylene, and 1 ,1-isoheptylene), the octylene isomers (e.g., 1 ,1-octylene, 1 ,2-octylene, 1 ,3-octylene, 1 ,4-octylene, 1 ,5-octylene, 1 ,6-octylene, 1 ,7-octylene, 1 ,8-octylene, and 1 ,1 -isooctylene), and the like.

[0104] In one embodiment, alkylene is C1-20 alkylene. In one embodiment, alkylene is C2-14 alkylene. In one embodiment, alkylene is C3-9 alkylene. In one embodiment, alkylene is C7-9 alkylene.

[0105] The straight alkylene moieties having at least 3 carbon atoms and a free valence at each end can also be designated as a multiple of methylene (e.g., 1 ,4-butylene can also be called tetramethylene). Generally, instead of using the ending "ylene" for alkylene moieties as specified above, one can also use the ending "diyl" (e.g., 1 ,2-butylene can also be called butan-1 ,2-diyl). A "substituted alkylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkylene group, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituent may be the same or different). In one embodiment, the alkylene is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituents selected from List A.

[0106] C- alkylene groups

[0107] C1-4 alkylene groups that may be present in the context of compounds of the present invention include, but are not limited to, C1-2 alkylene groups, such as methylene (-CH2-, that is a Ci alkylene group) and ethylene (-CH2CH2-, that is a C2 alkylene group).

[0108] Alkyleneoxy

[0109] The term “alkyleneoxy” - means “alkylene-O-“, wherein alkylene is defined and exemplified above. In one embodiment, alkyleneoxy means (C2-3)alkyleneoxy. In one embodiment, alkyleneoxy means (C2)alkyleneoxy (ethyleneoxy). In one embodiment, alkyleneoxy means (C3)alkyleneoxy (propyleneoxy).

[0110] Alkenyl

[0111] The term "alkenyl" refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carbon-carbon double bonds in the alkenyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkenyl group by 2 and, if the number of carbon atoms in the alkenyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (such as 1 to 4), i.e., 1 , 2, 3, 4, 5, or 6, carbon-carbon double bonds. Preferably, the alkenyl group comprises from 2 to 40 carbon atoms, such as 2 to 30 carbon atoms, such as 2 to 20 carbon atoms, such as 2 to 12 carbon atoms, such as 2 to 10 carbon atoms, such as 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenyl group comprises from 2 to 40, such as 2 to 30, such as 2 to 20, such as 2 to 12, such as 2 to 10 carbon atoms and 1 , 2, 3, 4, 5, or 6 (e.g., 1 , 2, 3, 4, or 5) carbon-carbon double bonds, such as comprises 2 to 8 carbon atoms and 1 , 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6 carbon atoms and 1 , 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1 -octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6- octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7- nonenyl, 8-nonenyl, 1 -decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7- decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5 5- undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1- dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7- dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, and the like. A "substituted alkenyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkenyl group, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkenyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the alkenyl is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituent selected from List A.

[0112] Carbocyclic and Heterocyclic Groups - Cycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenylene, heterocyclyl

[0113] The terms "cycloalkyl" and “cycloalkenyl” represents cyclic non-aromatic versions of "alkyl" and "alkenyl" with preferably 3 to 40, such as 3 to 30, such as 3 to 20, such as 3 to 14 carbon atoms, such as 3 to 12 or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and adamantyl. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. The cycloalkyl or cycloalkenyl group may consist of one ring (monocyclic), two rings (bicyclic), or more than two rings (polycyclic). A "substituted cycloalkyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a cycloalkyl group, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the cycloalkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the cycloalkyl or cycloalkenyl is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituent selected from List A.

[0114] The terms "cycloalkylene" and “cycloalkenylene” represents cyclic non-aromatic versions of "alkylene" and "alkenylene" with preferably 3 to 40, such as 3 to 30, such as 3 to 20, such as 3 to 14 carbon atoms, such as 3 to 12 or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 10 carbon atoms, such as 5 to 10 carbon atoms. In one embodiment, cycloalkylene is (C5-io)cycloalkylene. In one embodiment, cycloalkylene is (C3- io)cycloalkylene. In one embodiment, cycloalkenylene is (C3-io)cycloalkenylene. In one embodiment, cycloalkenylene is (C5-io)cycloalkenylene. Exemplary cycloalkylene groups include; cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, and cyclodecylene. Exemplary cycloalkenylene groups include cyclopentenylene and cyclohexenylene. In one embodiment, the cycloalkylene or cycloalkenylene is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituent selected from List A.

[0115] The term "heterocyclyl" or "heterocyclic ring" means a cycloalkyl group as defined above in which from 1 , 2, 3, or 4 carbon atoms in the cycloalkyl group are replaced by heteroatoms of oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur, preferably O, S, or N. A heterocyclyl group has preferably 1 or 2 rings containing from 3 to 10, such as 3, 4, 5, 6, or 7, ring atoms. Preferably, in each ring of the heterocyclyl group the maximum number of O atoms is 1 , the 5 maximum number of S atoms is 1 , and the maximum total number of O and S atoms is 2. The term "heterocyclyl" is also meant to encompass partially or completely hydrogenated forms (such as dihydro, tetrahydro or perhydro forms) of the above-mentioned heteroaryl groups. Exemplary heterocyclyl groups include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl (also called piperidyl), piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydropyranyl, urotropinyl, lactones, lactams, cyclic imides, and cyclic anhydrides. A "substituted heterocyclyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heterocyclyl group, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heterocyclyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the heterocyclyl is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituents selected from List A.

[0116] Aromatic Groups - Aryl, heteroaryl, arylene, heteroarylene

[0117] The term "aryl" refers to a monoradical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, such as 5, 6, or 10) carbon atoms which can be arranged in one ring (e.g., phenyl) or two or more condensed rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenylium, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthryl, and phenanthryl. Preferably, "aryl" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. Aryl does not encompass fullerenes. A "substituted aryl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an aryl group, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 5 or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the aryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the aryl is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituent selected from List A. Examples of a substituted aryl include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, anilinyl, 4-hydroxyphenyl, and methoxyphenyl ( / .e., 2-, 3-, or 4-methoxyphenyl).

[0118] The term "heteroaryl" or "heteroaromatic ring" means an aryl group as defined above in which one or more carbon atoms in the aryl group are replaced by heteroatoms of O, S, or N. Preferably, heteroaryl refers to a five or six-membered aromatic monocyclic ring wherein 1 , 2, or 3 carbon atoms are replaced by the same or different heteroatoms of O, N, or S. Alternatively, it means an aromatic bicyclic or tricyclic ring system wherein 1 , 2, 3, 4, or 5 carbon atoms are replaced with the same or different heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group the maximum number of O atoms is 1 , the maximum number of S atoms is 1 , and the maximum total number of O and S atoms is 2. Exemplary heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, 1 H- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl, pyridazinyl, phenoxazinyl, thiazolopyrid inyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, and phenazinyl. Exemplary 5- or 6-memered heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl (e.g., 2-imidazolyl), pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl (e.g., 4-pyridyl), pyrimidinyl, pyrazinyl, triazinyl, and pyridazinyl. A "substituted heteroaryl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heteroaryl group, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heteroaryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). In one embodiment, the heteroaryl is substituted with one or more, such as 1 , 2 or 3, such as 1 or 2, such as 1 substituents selected from List A.

[0119] The term "arylene" refers to a diradical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, such as 5, 6, or 10) carbon atoms which can be arranged in one ring (e.g., phenyl) or two or more condensed rings (e.g., naphthyl). Preferably, "arylene" is C5-14 arylene. More preferably, "arylene" is Ce-14 arylene. Even more preferably "arylene" is Ce-io arylene. Preferably, "arylene" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenylene (which may be 1 ,2-phenylene, 1 ,3- phenylene or 1 ,4-phenylene) and naphthylene (which may be 1 ,2-naphthylene, 1 ,3- naphthylene, 1 ,4-naphthylene, 1 ,5-naphthylene, 1 ,6-naphthylene, 1 ,7-naphthylene or 1 ,8- naphthylene).

[0120] Acyl and Alkanoyl

[0121] The term “acyl” refers generally to a group of formula R-C(=O)-, wherein R is a hydrocarbyl group, such as an alkyl group, alkenyl group, aryl group, all as defined herein. When R is an alkyl group, the group is termed an alkanoyl group. Preferably, the alkanoyl group is a C2-20 alkanoyl group. Examples of alkanoyl groups include C2 alkanoyl (acetyl), C3 alkanoyl (propionyl), C alkanoyl (butyryl), C5 alkanoyl (valeryl), Ce alkanoyl (caproyl), C7 alkanoyl (enanthyl), Cs alkanoyl (caprylyl), C9 alkanoyl (petargonyl), C10 alkanoyl (capryl), Cn alkanoyl (undecanoyl), C12 alkanoyl (lauroyl), C13 alkanoyl (tridecanoyl), C14 alkanoyl (myristoyl), C15 alkanoyl (pentadcanoyl), C16 alkanoyl (palmitoyl), C17 alkanoyl (margaroyl), C18 alkanoyl (stearoyl), C19 alkanoyl (nonadecanoyl), and C20 alkanoyl (arachidoyl),

[0122] Composite Group Definitions

[0123] The term “alkylene-arylene” refers to an alkylene group, as defined and exemplified above, bonded to an arylene group, as defined and exemplified above. The alkylene part is bonded at a first position on the rest of the molecule and the arylene part is bonded at a second position on the rest of the molecule. Preferably, "alkylene-arylene" is (C-i.6)alkylene-C6-i4 arylene. More preferably "alkylene-arylene" is (Ci-6)alkylene- Ce-io arylene.

[0124] The term “alkylene-arylene-alkylene” refers to an arylene group, as defined and exemplified above, bonded at one position to a first alkylene group, as defined and exemplified above, and at one position to a second alkylene group, as defined and exemplified above. The first alkylene group is bonded at a first position on the rest of the molecule and the second alkylene group is bonded at a second position on the rest of the molecule. Preferably, "alkylene-arylene-alkylene" is (Ci-6)alkylene-C6-i4 arylene-(Ci. 6)alkylene. More preferably "alkylene-arylene" is (Ci-6)alkylene-C6-io arylene-(Ci-6)alkylene.

[0125] The term “alkylene-cycloalkylene” refers to an alkylene group, as defined and exemplified above, bonded to a cycloalkylene group, as defined and exemplified above. The alkylene part is bonded at a first position on the rest of the molecule and the cycloalkylene part is bonded at a second position on the rest of the molecule. Preferably, "alkylene- cycloalkylene" is (Ci-6)alkylene-C(3-8)cycloalkylene;. Even more preferably "alkylene- cycloalkylene" is (Ci-6)alkylene-C(5-8)cycloalkylene.

[0126] The term “alkylene-cycloalkylene-alkylene” refers to a cycloalkylene group, as defined and exemplified above, bonded at one position to a first alkylene group, as defined and exemplified above, and at one position to a second alkylene group, as defined and exemplified above. The first alkylene group is bonded at a first position on the rest of the molecule and the second alkylene group is bonded at a second position on the rest of the molecule. Preferably, "alkylene-cycloalkylene-alkylene" is (Ci-6)alkylene-C(3- 8)cycloalkylene-(Ci-6)alkylene. Even more preferably "alkylene-cycloalkylene-alkylene" is (Ci-6)alkylene- C(5-8)cycloalkylene-(Ci-6)alkylene.

[0127] Optional Substituents - Lists A, A1 and A2

[0128] “List A” substituents are selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 14-membered (such as 6- to 10-membered) aryl, 3- to 14-membered (such as 5- or 6- membered) heteroaryl, 3- to 14-membered (such as 3- to 7-membered) cycloalkyl, 3- to 14-membered (such as 3- to 7-membered) heterocyclyl, halogen, -CN, azido, -NO2, -OR’, -N(R’)2, -S(O)0-2R’, -S(O)I.2OR’, -OS(O)I.2R’, -OS(O)I.2OR’, -S(O)i.2N(R’)2, -OS(O)I-2N(R’)2, -N(R’)S(O)I-2R’, -N(R’)S(O)I-2OR’, -C(=X1)R’, -C(=X1)X1R’, - X1C(=X1)R’, and -X1C(=X1)X1R’, wherein X1is independently selected from O, S, NH and N(CHs); and each R’ is independently selected from the group consisting of H, C- alkyl, C2-4 alkenyl, C2. alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or e- membered heteroaryl, and 5- or 6-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(Ci-3 alkyl), -S(Ci-3 alkyl), -NH2, -NH(CI-3alkyl), -N(Ci.3alkyl)2, -NHS(O)2(CI-3alkyl), -S(O)2NH2.Z(CI.3alkyl)z, - C(=O)OH, -C(=O)O(C1-3alkyl), -C(=O)NH2.Z(CI.3alkyl)z, -NHC(=O)(C1-3 alkyl), - NHC(=NH)NHZ-2(C1 -3 alkyl)z, and -N(Ci-3alkyl)C(=NH)NH2.z(Ci.3alkyl)z, wherein each z is independently 0, 1 , or 2 and each C1-3 alkyl is independently methyl, ethyl,

[0129] In some embodiments, List A substituents are selected from List A1 , consisting of C1-3 alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH2-Z(CH3)Z, -C(=O)OH, and - C(=O)OCH3, wherein z is 0, 1 , or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl.

[0130] In some embodiments, List A substituents are selected from List A2, consisting of methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br), and -CF3.

[0131] Peg

[0132] The term “Peg” refers to a polyethylene glycol residue comprising one or more subunits of ethylene glycol:

[0133] As disclosed herein, the spacer of the compounds of the invention may comprise a moiety ZS2, wherein ZS2may be -(Peg)n-. In one embodiment, n is an integer from 1 to 15. In one embodiment, n is an integer from 1 to 5. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. Bridging moieties

[0134] The sequences disclosed herein contain bridging moieties noted in the rounded brackets (e.g., (cyclol), (cyclo2)). These represent chemical bridges between the specific residue pairs. Each rounded bracket will appear twice in the sequence as a pair to indicate a single bridging moiety. Most of the sequences have two bridging moieties, indicated by 4 sets of rounded brackets meaning two bridging moiety pairs.

[0135] The number in the rounded bracket indicates a specific bridging moiety pair (e.g. “1” indicates a bridge between amino acid residues at positions 2 and 11 , which is also indicated by the square bracket notation defining the specific chemical bridge).

[0136] The residue directly preceding the rounded bracket notation indicates that specific residue is used in the bridging moiety.

[0137] The “*” notation directly after the rounded bracket notation indicates that the terminal -NH2 (if at the start of the sequence i.e. the / V-terminus) or -COOH (if at the end of the sequence i.e. the C-terminus) is used to form the bridge.

[0138] SMILES strings

[0139] The Simplified Molecular-Input Line-Entry System (SMILES) strings are provided below the structures described by the amino acid sequence for each of the compounds disclosed herein. A SMILES string is a line notation for describing the structure of chemical species using short American Standard Code for Information Interchange (ASCII) strings. SMILES strings can be imported by most molecule editors (e.g. ChemDraw®, BIOVIA Draw) for conversion back into two-dimensional or three- dimensional drawings of the chemical structure. Where there is a discrepancy between the structure of the amino acid sequence and the structure provided by the SMILES string, the SMILES string prevails.

[0140] The invention provides compounds which are peptide inhibitors of IL-23R. These compounds exhibit potent inhibition of IL-23R and may thus be useful in the treatment of various diseases, conditions and disorders related to IL-23R such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and psoriasis. Many compounds of the invention furthermore exhibit excellent stability in the gastrointestinal tract making them suitable for oral administration. The invention provides a compound the formula (I) or a pharmaceutically acceptable salt thereof:

[0141] X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X13-X14-R2(I) wherein

[0142] R2is NR3R4wherein R3and R4are each independently selected from hydrogen, C- alkyl optionally substituted with a pyridyl group or -C(0)NR’R’ (where R and R’ are independently H or C1-4 alkyl); C3-10 cycloalkyl; a saturated 5 or 6-membered heterocyclic ring having 1 or 2 heteroatoms selected from N, O and S, the ring being optionally substituted;

[0143] X2 is absent or selected from the group consisting of 4-aminomethyl-phenylacetyl, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, 3-aminopropanoyl, Lys, Dpr, Dab, Orn, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta- homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0144] X3 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, any amino acid, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0145] X4 is absent or selected from the group consisting of Glu, Asp, Lys, Dab, Orn, Dpr, Cys, Vai, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0146] X5 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; X6 is selected from the group consisting of an optionally substituted Lys residue or iso-Lys residue, an optionally substituted Ala residue, Gin, iso-GIn, Gln(Me), Gln(2Me), Gin (pyrrolidin), Dab(Ac), Glu, iso-Glu, Tyr, Cys, Vai, His, Ala, Dab(optionally substituted with C2-6 alkanoyl), iso-Dab, Cit, Arg, Orn(optionally substituted with C2-6 alkanoyl), Asn, a D- isomeric form of any thereof, a beta analogue of either thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof;

[0147] X7 is selected from the group consisting of Ala, Aib, Phe, Dab, iso-Dab, Cys, Glu, iso-Glu, Asp, iso-Asp, Pra, Lys, Orn, Dpr, Hpg, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0148] X8 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an alanine residue substituted by an optionally substituted carbocyclic group or an optionally substituted aryl or heteroaryl group, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0149] X9 is selected from the group consisting of an optionally substituted phenylalanine residue, an optionally substituted tyrosine residue, an optionally substituted azatryptophan residue, an optionally substituted tryptophan residue, an alanine residue substituted by an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0150] X10 is selected from the group consisting of 4-Aminotetrahydro-2H-pyran-4-carbonyl, Aib, Leu, Ala, 2-Me-Leu, 2-Me-Lys, Trp, Asn, iso-Asn, Cys, Vai, Ala, He, 2-Me-Val, Dab, iso- Dab, Gly, Lys, iso-Lys, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; X11 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0151] X12 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the lipid and amino acid, 3-aminotetrahydrofuran-3- carbonyl, Ser(OMe), Arg, 2-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, iso-Glu, Asn, iso-Asn, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, [2-(trimethyl-2- aminoethoxy)ethoxy]propyl, 3-aminopropanoyl, GABA, Dab, iso-Dab, Gly-CF3, Nle, Gin, iso-GIn, THP, 2-Me-Ser, His, His(1-Me), 3-(3-Quinolinyl)-Ala, Pro, 5-aminopentanoyl, 4- aminopiperidin-4-carbonyl, (R,S)-imidazolidin-2-carbonyl, 4-aminotetrahydropyran-4- carbonyl, 3-aminotetrahydrofuran-4-carbonyl, or Lys wherein the side chain -NH2 of the Lys is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0152] X13 is selected from the group consisting of 3-(3-Pyridyl)-Ala, D-3-(3-Pyridyl)-Ala, 3-(3,5- Pyrimidyl)-Ala, Asn, Gly, 3-(4-Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, {d}[3-(3-Pyridyl)-Ala], 3- amino-3-(3'-pyridyl)propionyl, Phe, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3- diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), 2-Me-3- (3-Pyridyl)-Ala, N-Me-3-(3-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, 3-(5-F-3-Pyridyl)-Ala, His, His(Me), a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0153] X14 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, Sar, His, Leu, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; wherein either: a) X2 is a residue that forms a bridge with a residue at X7 and a bridge with a residue at X11 , such that the compound of formula I is a compound of formula la or b) X2 is a residue that forms a bridge with a residue at X11 and X4 is a residue that forms a bridge with a residue at X7, such that the compound of formula I is a compound of formula lb or c) X2 to X4 are absent and X5 is a residue that forms a bridge with a residue at X11 via linker L, such that the compound of formula I is a compound of formula Ic wherein L optionally comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid; wherein the compound of formula I comprises a lipophilic substituent.

[0154] In some embodiments, the invention provides a compound selected from a compound in Table 1-1 , or a pharmaceutically acceptable salt or solvate thereof.

[0155] It will be understood that the invention encompasses salts and solvates of the compounds. Suitable salts and solvates of peptides are known in the art.

[0156] It will also be understood any of the following references to embodiments may be applicable and are combinable with any of the formulae described herein.

[0157] L

[0158] L is a linker formed between X5 and X11 . In one embodiment, L is not a sequence of three amino acids. In one embodiment, L includes an amide moiety. In one embodiment, L includes a lactam moiety. In one embodiment, L includes a triazole ring. In one embodiment, L includes a thioether moiety.

[0159] In some embodiments, L forms a 13 to 17 atom bridge between the residue-bearing carbons on X5 and X11. In one embodiment, L forms a 14 to 16 atom bridge between the residue-bearing carbons on X5 and X11 . In some embodiments, L forms a 14 to 16 atom bridge between the residue-bearing carbons on X5 and X11 .

[0160] In some embodiments, L forms a 8 to 12 atom bridge between the residue-bearing carbons on X5 and X11 . In one embodiment, L forms a 9 to 11 atom bridge between the residue-bearing carbons on X5 and X11 . In some embodiments, L forms a 10 atom bridge between the residue-bearing carbons on X5 and X11 .

[0161] In some embodiments, L includes a moiety selected from the group consisting of (C-i. 2o)alkylene; (C2-2o)alkenylene; (C3-io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene-(C5-i4)arylene; (Ci-6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3- 8)cycloalkylene-(Ci-6)alkylene; (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; [(C2- 3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted.

[0162] In some embodiments, L includes a moiety selected from the group consisting of (C-i. 2o)alkylene and (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene. In some embodiments, L includes a moiety which is (Ci-2o)alkylene. In some embodiments, L includes a moiety which is (C2-i4)alkylene. In one embodiment, L includes a moiety which is (C3-9)alkylene.

[0163] In some embodiments, L includes a moiety which is (C7-9)alkylene.. In one embodiment, L includes a moiety which is (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene. In one embodiment, L includes a moiety which is (CH2)-phenylene-(CH2)-.

[0164] In some embodiments, L comprises a moiety (L1), as defined herein. In some embodiments, L comprises a moiety (L2), as defined herein. In some embodiments, L comprises a moiety (L3), as defined herein.

[0165] In some embodiments, L includes a threonine or serine moiety. In some embodiments, L includes a threonine moiety. In some embodiments, L includes a serine moiety.

[0166] L1

[0167] (L1) is a moiety of the formula *-NR-Y1-(C=O)-** wherein:

[0168] -* is a moiety on the amino acid residue X11 capable of bonding to an amino group;

[0169] -** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group; and Y1 and R are as defined herein.

[0170] L2

[0171] (L2) is a moiety of the formula *-NR-Y2-C(=O)-NR-Y3-C(=O)-** wherein:

[0172] -* is a moiety on the amino acid residue X11 capable of bonding to an amino group;

[0173] -** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group; and Y2, Y3 and each R are as defined herein.

[0174] L3

[0175] In some embodiments, L comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid. In such embodiments, L comprises a moiety (L3) and (L3) is a moiety of the formula

[0176] Lipid-spacer- wherein:

[0177] -* is a moiety on the amino acid residue X11 capable of bonding to a moiety on the Y5 residue;

[0178] -** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group; spacer may be present or absent; and lipid, spacer, Y4, Y5 and R are as defined herein.

[0179] Y1

[0180] Y1 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3- io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene-(C5-i4)arylene; (C-i.6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C-i.6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; [(C2-3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted.

[0181] In some embodiments, Y1 is selected from the group consisting of (Ci-2o)alkylene and (C2- 2o)alkenylene. In some embodiments, Y1 is (C2-i4)alkylene. In some embodiments, Y1 is (C3-9)alkylene. In some embodiments, Y1 is (C7-9)alkylene.

[0182] Y2

[0183] Y2 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3. io)cycloalkylene; (C3-io)cycloalkenylene; (Cs-i4)arylene; (Ci-6)alkylene-(C5-i4)arylene; (C-i.6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C-i. 6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; [(C2-3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted.

[0184] In some embodiments, Y2 is selected from the group consisting of (Ci-2o)alkylene, (C-i.6)alkylene-(C5-i4)arylene-, (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene and (Ci-6)alkylene- heteroarylene-(Ci-6)alkylene, the arylene moiety optionally substituted with a halogen atom. In some embodiments, Y2 is selected from the group consisting of (Ci-8)alkylene, - CH2-phenylene-, CH2-phenylene-CH2- and CH2-pyridylene-CH2-, wherein the phenylene moiety is optionally substituted with a halogen atom. In some embodiments, Y2 is selected from the group consisting of (C5-7)alkylene, CH2-phenylene-CH2- and CH2- pyridylene-CH2- wherein the phenylene moiety is optionally substituted with a fluorine atom.

[0185] Y3

[0186] Y3 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3- io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene-(C5-i4)arylene; (C-i.6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C-i.6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; [(C2-3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof.

[0187] In some embodiments, Y3 is selected from the group consisting of (Ci-2o)alkylene and (C-i.6)alkylene-arylene-(Ci-6)alkylene. In some embodiments, Y3 is selected from the group consisting of (Ci-i4)alkylene and methylene-phenylene-methylene. In some embodiments, Y3 is (Ci-8)alkylene. In one embodiment, Y3 is (Ci.g)alkylene. In one embodiment, Y3 is (C2-5)alkylene

[0188] Y4

[0189] Y4 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3- io)cycloalkylene; (C3-io)cycloalkenylene; (Cs-i4)arylene; (Ci-6)alkylene--(C5-i4)arylene; (C-i.6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C-i.6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; (Ci-6)alkylene-heteroarylene-(Ci-6)alkylene [(C2- 3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted.

[0190] In some embodiments, Y4 is selected from the group consisting of (Ci-2o)alkylene and (C-i.6)alkylene-arylene-(Ci-6)alkylene. In some embodiments, Y4 is selected from the group consisting of (Ci-i4)alkylene and methylene-phenylene-methylene. In some embodiments, Y4 is (Ci-8)alkylene. In one embodiment, Y4 is (Ci.g)alkylene. In one embodiment, Y4 is (C2-5)alkylene. In one embodiment, Y4 is Cs-alkylene Y5

[0191] Y5 is an amino acid residue comprising a side chain capable of forming a bridge with the residue at X11 .

[0192] In some embodiments, Y5 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof. In one embodiment, Y5 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu. In one embodiment, Y5 is Lys.

[0193] In one embodiment, the amine of the a-carbon of the amino acid residue at Y5 bonds to the optional spacer and lipid moiety and the functional group (e.g., amine or carboxylic acid) on the side chain of the amino acid at Y5 bonds to X11 to form the bridge. For example, when Y5 is Lys, the amine on the a-carbon of the Lys residue bonds to the optional spacer and lipid moiety and the amine on the s-carbon of the Lys residue bonds to the moiety at X11 to form the bridge.

[0194] R

[0195] R is H or C-i-6 alkyl. In some embodiments, R is H or C1-3 alkyl. In some embodiments, R is H or C1-3 alkyl. In some embodiments, R is H or methyl. In some embodiments, R is H. In one embodiment, R is methyl.

[0196] R2

[0197] R2is NR3R4wherein R3and R4are each independently selected from hydrogen, C1-4 alkyl optionally substituted with a pyridyl group or -C(G)NR’R” (where R’ and R” are independently H or C1-4 alkyl); C3-10 cycloalkyl; a saturated 5 or 6-membered heterocyclic ring having 1 or 2 heteroatoms selected from N, O and S, the ring being optionally substituted.

[0198] In some embodiments, R2is NR3R4wherein R3and R4are each independently H, C1-4 alkyl optionally substituted with pyridyl, or tetrahydropyranyl. In some embodiments, R2is NR3R4wherein R3and R4are each independently H, methyl or (pyrid in-3-yl)ethyl.

[0199] In some embodiments, R2is NHR3wherein R3is hydrogen or C1-4 alkyl optionally substituted with a pyridyl ring. In some embodiments, R2is NHR3wherein R3is hydrogen or C- alkyl optionally substituted with a pyrid-3-yl ring.

[0200] In some embodiments, R2is NHR3wherein R3is hydrogen or C1-4 alkyl. In some embodiments, R2is NHR3wherein R3is hydrogen or C1-3 alkyl. In some embodiments, R2is NHR3wherein R3is hydrogen or C1-2 alkyl. In some embodiments, R2is NHR3wherein R3is hydrogen or Ci alkyl (methyl or Me).

[0201] In some embodiments, R2is NHR3wherein R3is C1-4 alkyl optionally substituted with a pyridyl ring. In some embodiments, R2is NHR3wherein R3is C1-4 alkyl substituted with a pyridyl ring.

[0202] In some embodiments, R2is NHR3wherein R3is C1-4 alkyl optionally substituted with a pyrid-3-yl ring. In some embodiments, R2is NHR3wherein R3is C1-4 alkyl substituted with a pyrid-3-yl ring.

[0203] In some embodiments, R2is NHR3wherein R3is C alkyl substituted with a pyridyl ring. In some embodiments, R2is NHR3wherein R3is C alkyl substituted with a pyrid-3-yl ring.

[0204] In some embodiments, R2is NHR3wherein R3is n-Bu substituted with a pyrid-3-yl ring. In some embodiments, R2is NHR3wherein R3is -CH2CH2CH2CH2(pyrid-3-yl). That is, NHCH2CH2CH2CH2(pyrid-3-yl) or NH-(4-(pyridin-3-yl)butanyl). The group NH-(4-(pyridin- 3-yl)butanyl) has the structure:

[0205] In some embodiments, R2is NHR3wherein R3is C2 alkyl substituted with a pyridyl ring. In some embodiments, R2is NHR3wherein R3is C2 alkyl substituted with a pyrid-3-yl ring. In some embodiments, R2is NHR3wherein R3is ethyl (Et) substituted with a pyrid-3-yl ring.

[0206] In some embodiments, R2is NHMe. In some embodiments, R2is NH2. In some embodiments, R2is NHCH2CH2(pyrid-3-yl), that is NH-(2-(pyridin-3-yl)ethyl).

[0207] Preferably, R2is NHMe or NH2. Even more preferably, R2is NHMe.

[0208] X2

[0209] X2 is absent or selected from the group consisting of 4-aminomethyl-phenylacetyl, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, 3-aminopropanoyl, Lys, Dpr, Dab, Orn, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta- homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0210] In one embodiment, X2 is absent or selected from the group consisting of 4-aminomethyl- phenylacetyl and Lys. In one embodiment, X2 is absent. In one embodiment, X2 is 4- aminomethyl-phenylacetyl. In one embodiment, X2 is Lys.

[0211] X3

[0212] X3 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, any amino acid, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0213] In one embodiment, X3 is a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0214] In one embodiment, X3 is absent or selected from the group consisting is He and Ser. In one embodiment, X3 is absent. In one embodiment, X3 is He. In one embodiment, X3 is Ser.

[0215] X4

[0216] X4 is absent or selected from the group consisting of Glu, Asp, Lys, Dab, Orn, Dpr, Cys, Vai, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0217] In some embodiments, X4 is absent or selected from the group consisting of Glu and Vai. In one embodiment, X4 is absent. In one embodiment, X4 is Glu. In one embodiment, X4 is Vai. X5

[0218] X5 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof, the residue X5 having a moiety capable of being bonded to a moiety on X11 via the linker L. In some embodiments, X5 is selected from the group consisting of an optionally substituted tryptophan residue and an optionally substituted azatryptophan residue, the residue X5 having a moiety capable of being bonded to a moiety on X11 via the linker L. The optional substituents on the tryptophan or azatryptophan residue are selected from List A, as defined herein. In some embodiments, the optional substituents on the tryptophan or azatryptophan residue are selected from List A1 , as defined herein. In some embodiments, the optional substituents on the tryptophan or azatryptophan residue are selected from List A2, as defined herein.

[0219] X5 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, and an optionally substituted betahomotryptophan residue.

[0220] In some embodiments, X5 is selected from the group consisting of: a tryptophan residue optionally substituted with a C1-4 alkyl group, a phenyl group; a halogen atom, or a benzyloxy group; an azatryptophan residue; and a beta-homotryptophan residue.

[0221] In some embodiments, X5 is selected from the group consisting of Trp, 1-Me-Trp, 2-Me- Trp, 4-Me-Trp, 5-Me-Trp, 6-Me-Trp, 5-F-Trp, 6-F-Trp, 7-F-Trp, 5-Aza-Trp, 7-Aza-Trp, 6- benzyloxy-Trp, 7-Ph-Trp, and beta-homo-Trp.

[0222] In some embodiments, X5 is selected from the group consisting of Trp, 1-Me-Trp, 2-Me- Trp, 4-Me-Trp, 6-Me-Trp, 5-F-Trp, 6-F-Trp, 7-F-Trp, 5-Aza-Trp, 7-Aza-Trp and 6- benzyloxy-Trp.

[0223] In some embodiments, X5 is selected from the group consisting of Trp, 1-Me-Trp and 7- Aza-Trp. In some embodiments, X5 is selected from the group consisting of Trp and 1- Me-Trp.

[0224] In some embodiments, X5 is Trp. In some embodiments, X5 is 1-Me-Trp. In some embodiments, X5 is 2-Me-Trp. In some embodiments, X5 is 4-Me-Trp. In some embodiments, X5 is 5-Me-Trp. In some embodiments, X5 is 6-Me-Trp. In some embodiments, X5 is 5-F-Trp. In some embodiments, X5 is 6-F-Trp. In some embodiments, X5 is 7-F-Trp. In some embodiments, X5 is 5-Aza-Trp. In some embodiments, X5 is 7- Aza-Trp. In some embodiments, X5 is 6-benzyloxy-Trp. In some embodiments, X5 is 7- Ph-Trp. In some embodiments, X5 is beta-homo-Trp.

[0225] X6

[0226] X6 is selected from the group consisting of an optionally substituted Lys residue or iso-Lys residue, an optionally substituted Ala residue, Gin, iso-GIn, Gln(Me), Gln(2Me), Gin (pyrrolidin), Dab(Ac), Glu, iso-Glu, Tyr, Cys, Vai, His, Ala, Dab(optionally substituted with C2-6 alkanoyl), iso-Dab, Cit, Arg, Orn(optionally substituted with C2-6 alkanoyl), Asn, a D- isomeric form of any thereof, a beta analogue of either thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof.

[0227] In some embodiments, X6 is selected from the group consisting of an optionally substituted Lys residue or iso-Lys residue, an optionally substituted Ala residue, Gin, iso- GIn, Gln(Me), Gln(2Me), Gln(pyrrolidin), 2,4-diaminobutanoyl(Ac), Glu, iso-Glu, Tyr, Cys, Vai, His, Dab(optionally substituted with C2-4 alkanoyl), iso-Dab, Cit, Arg, Orn(optionally substituted with C2-4 alkanoyl), and Asn.

[0228] In some embodiments, X6 is selected from the group consisting of K(NMeAc), K(NMePEG3), Gin, Q(Me) 2,4-diaminobutanoyl(Ac), Glu, Tyr, Cys, Vai, His, N-Me-GIn, Gln(pyrrolidin), Gln(2Me), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn. In some embodiments, X6 is selected from the group consisting of K(NMeAc), K(NMePEG3), Gin, Gln(Me), Gln(2Me), Gln(pyrrolidin), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn. In some embodiments, X6 is selected from the group consisting of K(NMeAc), K(NMePEG3), Gin, Gln(Me) and 2,4-diaminobutanoyl(Ac).

[0229] In some embodiments, X6 is K(NMeAc). In some embodiments, X6 is K(NMePEG3). In some embodiments, X6 is Gin. In some embodiments, X6 is Gln(Me). In some embodiments, X6 is Gln(2Me). In some embodiments, X6 is Gin (pyrrolidin). In some embodiments, X6 is Ala. In some embodiments, X6 is Phe. In some embodiments, X6 is Lys(Ac). In some embodiments, X6 is Dab(Ac). In some embodiments, X6 is Cit. In some embodiments, X6 is Orn. Preferably, X6 is Gin

[0230] X7

[0231] X7 is selected from the group consisting of Ala, Aib, Phe, Dab, iso-Dab, Cys, Glu, iso-Glu, Asp, iso-Asp, Pra, Lys, Orn, Dpr, Hpg, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0232] In some embodiments, X7 is selected from the group consisting of Ala, Aib, Phe, {d}Ala, Dab, iso-Dab, Cys, Glu, D-Glu, homo-Glu, iso-Glu, Asp, iso-Asp, Pra, and Hpg.

[0233] In some embodiments, X7 is selected from the group consisting of Ala, Aib, Phe, {d}Ala, Dab, Cys, Glu, D-Glu, homo-Glu, Asp, Pra, and Hpg.

[0234] In some embodiments, X7 is selected from the group consisting of Ala, Aib, Phe, Glu, Dab and {d}Ala. In some embodiments, X7 is selected from the group consisting of Glu, Dab, Ala and {d}Ala. In some embodiments, X7 is Ala. In some embodiments, X7 is Aib. In some embodiments, X7 is Phe. In some embodiments, X7 is {d}Ala. In some embodiments, X7 is Glu. In some embodiments, X7 is Dab.

[0235] X8

[0236] X8 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an alanine residue substituted by an optionally substituted carbocyclic group or an optionally substituted aryl or heteroaryl group, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0237] In some embodiment, X8 is a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0238] In some embodiments, X8 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted beta-homotryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an optionally substituted homophenylalanine residue, and an alanine residue substituted by an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted. In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), Y(CH3), F-(4-morpholine), F(4-CONH2), F(4-F), F(Ac-4-NH2), Trp, 6-AzaTrp, 7-AzaTrp, 7- F-Trp, 4-F-Trp, 5-F-Trp, 6-F-Trp, 7-F-Trp, 1-Me-Trp, 2-Me-Trp, 4-Me-Trp, 5-Me-Trp, 6-Me- Trp, 7-Ph-Trp, 5-benzyloxy-Trp, homo-Phe, 3-quinolinylalanine, Y(nPr), Y(Bn), D-Phe, 2- Me-Phe, 3-(2-Pyridyl)-Ala, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, Cyclopropyl-Ala, Y(n-pentylamine-N+Me3), Y(2-aminoethoxy-NMe2), Y(trimethyl-PEG3), F(4-THP), Y(CH3-2-F), F(4-imidazole),Y(CH3-3-F), 5-AzaTrp, and Y(Ac-2-aminoethoxy).

[0239] In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), Y(CH3), F-(4-morpholine), F(4-CONH2), F(4-F), F(Ac-4-NH2), F(4-piperazine), 7-AzaTrp. 4-F-Trp, 5-F-Trp, 6-F-Trp, 7-F-Trp, 1-Me-Trp, 4-Me-Trp, 5-Me-Trp, 6-Me-Trp, 7-Ph-Trp. , Y(n-pentylamine-N+Me3), Y(2-aminoethoxy-NMe2), Y(trimethyl-PEG3), F(4-THP) and 3- quinolinylalanine.

[0240] In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), Y(CH3), F-(4-morpholine), F(4-CONH2), F(4-F), F(Ac-4-NH2), F(4-piperazine), 4-F-Trp, 5- F-Trp, 6-F-Trp, 1-Me-Trp, 4-Me-Trp, 7-Ph-Trp, and 7-AzaTrp.

[0241] In some embodiments, X8 is Y(2-aminoethoxy). In some embodiments, X8 is Y(CH3). In some embodiments, X8 is F-(4-morpholine). In some embodiments, X8 is F(4-CONH2). In some embodiments, X8 is F(Ac-4-NH2). In some embodiments, X8 is F(4-F). In some embodiments, X8 is Trp. In some embodiments, X8 is 7-AzaTrp. In some embodiments, X8 is 7-F-Trp. In some embodiments, X8 is 6-AzaTrp. In some embodiments, X8 is 4-F- Trp. In some embodiments, X8 is 5-F-Trp. In some embodiments, X8 is 6-F-Trp. In some embodiments, X8 is 1-Me-Trp. In some embodiments, X8 is 2-Me-Trp. In some embodiments, X8 is 4-Me-Trp. In some embodiments, X8 is 5-Me-Trp. In some embodiments, X8 is 6-Me-Trp. In some embodiments, X8 is 7-Ph-Trp. In some embodiments, X8 is 5-benzyloxy-Trp. In some embodiments, X8 is homo-Phe. In some embodiments, X8 is 3-quinolinylalanine. In some embodiments, X8 is Y(nPr). In some embodiments, X8 is Y(Bn). In some embodiments, X8 is D-Phe. In some embodiments, X8 is 2-Me-Phe. In some embodiments, X8 is 3-(2-Pyridyl)-Ala. In some embodiments, X8 is 3-(3-Pyridyl)-Ala. In some embodiments, X8 is 3-(4-Pyridyl)-Ala. In some embodiments, X8 is 3-(3,5-Pyrimidyl)-Ala. In some embodiments, X8 is Cyclopropyl-Ala. In some embodiments, X8 is Y(n-pentylamine-N+Me3). In some embodiments, X8 is Y(2- aminoethoxy-NMe2). In some embodiments, X8 is Y(trimethyl-PEG3). In some embodiments, X8 is F(4-THP). In some embodiments, X8 is Y(CH3-2-F). In some embodiments, X8 is F(4-imidazole). In some embodiments, X8 is Y(CH3-3-F). In some embodiments, X8 is 5-AzaTrp. In some embodiments, X8 is Y(Ac-2-aminoethoxy). X9

[0242] X9 is selected from the group consisting of an optionally substituted phenylalanine residue, an optionally substituted tyrosine residue, an optionally substituted azatryptophan residue, an optionally substituted tryptophan residue, an alanine residue substituted by an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0243] In some embodiments, X9 is selected from the group consisting of an optionally substituted azatryptophan residue, an optionally substituted beta-homotryptophan residue, and an alanine residue substituted by an optionally substituted carbocyclic group or aryl or heteroaryl group, each optionally substituted. In some embodiments, X9 is selected from the group consisting of an optionally substituted azatryptophan residue, an optionally substituted beta-homotryptophan residue, and an alanine residue substituted by an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted. The optional substituents on the azatryptophan, beta-homotryptophan, or the carbocyclic or aryl or heteroaryl substituent on the alanine residue are selected from List A, as defined herein. In some embodiments, the optional substituents are selected from List A1 , as defined herein. In some embodiments, the optional substituents are selected from List A2, as defined herein.

[0244] In some embodiments, X9 is an alanine residue substituted by an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted. The optional substituents on the phenyl, pyridyl, naphthyl and quinolinyl substituent of the alanine residue are selected from List A, as defined herein. In some embodiments, the optional substituents on the phenyl, pyridyl, naphthyl and quinolinyl substituent of the alanine residue are selected from List A1 , as defined herein. In some embodiments, the optional substituents on the phenyl, pyridyl, naphthyl and quinolinyl substituent of the alanine residue are selected from List A2, as defined herein.

[0245] In some embodiments, X9 is an alanine residue substituted by a naphthyl or quinolinyl group, each optionally substituted. The optional substituents on the naphthyl or quinolinyl substituent of the alanine residue are selected from List A, as defined herein. In some embodiments, the optional substituents on the naphthyl or quinolinyl substituent of the alanine residue are selected from List A1 , as defined herein. In some embodiments, the optional substituents on the naphthyl or quinolinyl substituent of the alanine residue are selected from List A2, as defined herein.

[0246] In some embodiments, X9 is an alanine residue substituted by a 2-naphthyl or 3-qu inolinyl group, each optionally substituted. The optional substituents on the 2-naphthyl or 3- quinolinyl substituent of the alanine residue are selected from List A, as defined herein. In some embodiments, the optional substituents on the 2-naphthyl or 3-quinolinyl substituent of the alanine residue are selected from List A1 , as defined herein. In some embodiments, the optional substituents on the 2-naphthyl or 3-quinolinyl substituent of the alanine residue are selected from List A2, as defined herein.

[0247] In some embodiments, X9 is selected from the group consisting of 2-Nal, Cyclopropyl-Ala, 7-AzaTrp, beta-homo-Trp, and 3-quinolinyl-Ala.

[0248] In some embodiments, X9 is selected from the group consisting of 2-Nal and 3-quinolinyl- Ala. In some embodiments, X9 is 2-Nal. In some embodiments, X9 is Cyclopropyl-Ala. In some embodiments, X9 is 7-AzaTrp. In some embodiments, X9 is beta-homo-Trp. In some embodiments, X9 is 3-quinolinyl-Ala.

[0249] X10

[0250] X10 is selected from the group consisting of 4-Aminotetrahydro-2H-pyran-4-carbonyl, Aib, Leu, Ala, 2-Me-Leu, 2-Me-Lys, Trp, Asn, iso-Asn, Cys, Vai, Ala, He, 2-Me-Val, Dab, isoDab, Gly, Lys, iso-Lys, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0251] In some embodiments, X10 is selected from the group consisting of 4-Aminotetrahydro- 2H-pyran-4-carbonyl, Aib, Leu, D-Leu, Ala, D-Ala, 2-Me-Leu, 2-Me-Lys, Trp, Asn, iso-Asn, Cys, 2-Me-Val, Dab, iso-Dab, Gly, Lys, and iso-Lys.

[0252] In some embodiments, X10 is 4-Aminotetrahydro-2H-pyran-4-carbonyl. In some embodiments, X10 is Aib. In some embodiments, X10 is Leu. In some embodiments, X10 is D-Leu. In some embodiments, X10 is Ala. In some embodiments, X10 is D-Ala. In some embodiments, X10 is 2-Me-Leu. In some embodiments, X10 is 2-Me-Lys. In some embodiments, X10 is Trp. In some embodiments, X10 is Asn. In some embodiments, X10 is iso-Asn. In some embodiments, X10 is Cys. In some embodiments, X10 is 2-Me-Val. In some embodiments, X10 is Dab. In some embodiments, X10 is iso-Dab. In some embodiments, X10 is Gly. In some embodiments, X10 is Lys. In some embodiments, X10 is iso-Lys.

[0253] X11

[0254] X11 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0255] In some embodiments, X11 is Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo- Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Asp, D-Asp, iso-Asp, D- iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp or N- Me-homo-Asp.

[0256] In some embodiments, X11 is Glu or Asp. In some embodiments, X1 1 is Glu. In some embodiments, X11 is Asp.

[0257] X12

[0258] X12 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the lipid and amino acid, 3-aminotetrahydrofuran-3- carbonyl, Ser(OMe), Arg, 2-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, iso-Glu, Asn, iso-Asn, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, [2-(trimethyl-2- aminoethoxy)ethoxy]propyl, 3-aminopropanoyl, GABA, Dab, iso-Dab, Gly-CF3, Nle, Gin, iso-GIn, THP, 2-Me-Ser, His, His(1-Me), 3-(3-Quinolinyl)-Ala, Pro, 5-aminopentanoyl, 4- aminopiperidin-4-carbonyl, (R,S)-imidazolidin-2-carbonyl, 4-aminotetrahydropyran-4- carbonyl, 3-aminotetrahydrofuran-4-carbonyl, or Lys wherein the side chain -NH2 of the Lys is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0259] In some embodiments, X12 is a lipidated amino acid residue optionally comprising a spacer between the lipid and amino acid.

[0260] In some embodiments, X12 is selected from the group consisting of 2,4-diaminobutanoyl, Ser(OMe), Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, {d}2,4-diaminobutanoyl, ([2-(trimethyl-2- aminoethoxy)ethoxy]propyl), D-GIn, D-Glu, D-His, 3-aminopropanoyl, GABA, Dab, isoDab, Gly-CF3, D-Gly-CF3, Nle, Gin, His, THP, D-Ser, 2-Me-Ser, homo-Ser, Dab, His, D- His, His(1 -Me), 3-(3-Quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidin-4- carbonyl, (R,S)-imidazolidin-2-carbonyl, and Lys wherein the side chain -NH2 of the Lys is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F.

[0261] In some embodiments, X12 is selected from the group consisting of Dab, Asn, Ser (OMe), 3-(3-Pyridyl)-Ala, 4-aminotetrahydropyran-4-carbonyl, and 3-amino-tetrahydrofuran-4- carbonyl.

[0262] In some embodiments, X12 is Dab, Asn, Ser(OMe) or 3-(3-Pyridyl)-Ala.

[0263] In some embodiments, X12 is Dab. In some embodiments, X12 is Ser(OMe). In some embodiments, X12 is Asn. In some embodiments, X12 is 3-(3-Pyridyl)-Ala. In some embodiments, X12 is 4-aminotetrahydropyran-4-carbonyl. In some embodiments, X12 is 3-amino-tetrahydrofuran-4-carbonyl.

[0264] X13

[0265] X13 is selected from the group consisting of 3-(3-Pyridyl)-Ala, D-3-(3-Pyridyl)-Ala, 3-(3,5- Pyrimidyl)-Ala, Asn, Gly, 3-(4-Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, {d}[3-(3-Pyridyl)-Ala], 3- amino-3-(3'-pyridyl)propionyl, Phe, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3- diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), 2-Me-3- (3-Pyridyl)-Ala, N-Me-3-(3-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, 3-(5-F-3-Pyridyl)-Ala, His, His(Me), a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0266] In some embodiments, X13 is selected from the group consisting of 3-(3-Pyridyl)-Ala, Asn, Gly, 3-(4-Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, {d}[3-(3-Pyridyl)-Ala], 3-amino-3-(3'- pyridyl)propionyl, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3- diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3- diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), and 2- Me-3-(3-Pyridyl)-Ala, N-Me-3-(3-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, His, D-His, and His(Me). In some embodiments, X13 is 3-(3-Pyridyl)-Ala or 3-(5-F-3-Pyridyl)-Ala. In some embodiments, X13 is 3-(3-Pyridyl)-Ala. In some embodiments, X13 is 3-(5-F-3-Pyridyl)- Ala.

[0267] X14

[0268] X14 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, Sar, His, Leu, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0269] In some embodiments, X14 is a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid. In some embodiments, X14 is absent.

[0270] Lipid

[0271] The compound of formula I comprises a lipid or lipidated amino acid residue. Lipidation of the compounds of formula (I) can offer advantageous physicochemical properties as compared to the corresponding unmodified polypeptides. Lipidated polypeptides can exhibit improved half-life, reduced immunogenicity, enhanced intracellular uptake and / or enhanced delivery across epithelia.

[0272] In one embodiment, when the compound of formula I is a compound of formula (la), one of X3, X8, X12 or X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid. In one embodiment, when the compound of formula I is a compound of formula (la), X12 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0273] In one embodiment, when the compound of formula I is a compound of formula (lb), one of X3, X8, X12 or X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid. In one embodiment, when the compound of formula I is a compound of formula (lb), one of X3 or X8 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0274] In one embodiment, when the compound of formula I is a compound of formula (Ic), one of X8, X12, X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid or L comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid. In one embodiment, when the compound of formula I is a compound of formula (Ic) one of X8 or X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid or L comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid.

[0275] In one embodiment, the lipid of linker L or the lipid of the lipidated amino acid residue is of the formula Z1-, wherein Z1- is CH3-(CH2)IO-22-(CO)-, HOOC-(CH2)IO-22-(CO)- or tetrazole- (CH2)IO-22-(CO)-. In one embodiment, Z1- is CH3-(CH2)IO-22-(CO)- or HOOC-(CH2)IO-22- (CO)-.

[0276] In one embodiment, Z1- is CH3-(CH2)IO-22-(CO)-. In one embodiment, Z1- is CH3-(CH2)i2-i9- (CO)-. In one embodiment, Z1- is CH3-(CH2)i3-is-(CO)-.

[0277] In one embodiment, Z1- is HOOC-(CH2)IO-22-(CO)-. In one embodiment, Z1- is HOOC- (CH2)i2-i9-(CO)-. In one embodiment, Z1- is HOOC-(CH2)i3-is-(CO)-.

[0278] In one embodiment, Z1- is tetrazolyl-(CH2)io-22-(CO)-. In one embodiment, Z1- is tetrazolyl- (CH2)i2-i9-(CO)-. In one embodiment, Z1- is tetrazolyl-(CH2)i3-is-(CO)-.

[0279] In Z1, the terminal denotes the point of attached to the optional spacer described herein or to the linker or amino acid of the lipidated amino acid residue described herein.

[0280] Certain examples of substituents Z1- include [Dodecanoyl], [Tetradecanoyl], [Hexadecanoyl], [Octadecanoyl], [Eicosanoyl], [13-Carboxy-tridecanoyl], [15-Carboxy- pentadecanoyl], [17-Carboxy-heptadecanoyl], [19-Carboxy-nonadecanoyl], [21-carboxy- heneicosanoyl].

[0281] Amino acid of the lipidated amino acid residue

[0282] In one embodiment, the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is selected from the group consisting of Lys, Dab, Phe(4NH), AEF, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof. In one embodiment, the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is Lys. In one embodiment, the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is Dab. In one embodiment, the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is Phe(4NH). In one embodiment, the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is AEF.

[0283] In one embodiment, the amino acid of the lipidated amino acid is bonded to the lipid and optional spacer via its side chain. For example, when the amino acid of the lipidated amino acid is Lys, the amine on the s-carbon of the Lys residue bonds to the lipid and optional spacer. In such embodiments, the amine of the a-carbon will be involved in the formation of the amide bond with the adjacent residue in the backbone of formula (I).

[0284] Spacer

[0285] In one embodiment, a spacer is present between the amino acid of the lipidated amino acid residue (e.g., the side chain of the amino acid of the lipidated amino acid residue) and the lipid.

[0286] In one embodiment, there is no spacer between the amino acid (e.g., the side chain of the amino acid of the lipidated amino acid residue) and lipid. In this embodiment, the amino acid of the lipidated amino acid residue will bond directly to the lipid as described herein (e.g., via the side chain of the amino acid of the lipidated amino acid residue).

[0287] In one embodiment, when the compound of formula (I) is a compound of formula (Ic), L may be of the formula L3:

[0288] Lipid-spacer- wherein:

[0289] -* is a moiety on the amino acid residue X11 capable of bonding to a moiety on the Y5 residue;

[0290] -** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group; and

[0291] Y4, Y5 and each R are as defined herein; wherein the spacer is present.

[0292] In one embodiment of formula L3, the spacer is absent. In one embodiment, the spacer is of the formula -Z2-, wherein

[0293] -Z2- is selected from -ZS1-, -ZS1-ZS2-, -ZS2-ZS1-, -ZS2-, -ZS3-, -ZS1ZS3-, -ZS2ZS3-, -ZS3ZS2-, - 2S12S2ZS3- -ZS2ZS1ZS3- -ZS2ZS3ZS1- -ZS3ZS1ZS2- -ZS3ZS2ZS1- or -ZS2ZS3ZS2- wherein ZS1is (isoGlu)i-3, p-Ala, isoLys, 4-aminobutanoyl or (Piperazine-l-yl)-acetyl;

[0294] ZS2is -(Peg)n- where n is an integer from 1 to 15, or (8-Amino-3,6-dioxaoctanoyl)i-3; and -ZS3- is a peptide sequence of 1 -6 amino acid units independently selected from the group consisting of A, L, S, T, Y, Q, D, E, K, k, R, H, F and G.

[0295] In one embodiment, the spacer is of the formula -Z2-, wherein

[0296] -Z2- is selected from -ZS1-, -ZS1-ZS2-, -ZS2-ZS1-, -ZS2-, wherein

[0297] ZS1is (isoGlu)i-3, p-Ala, isoLys, 4-aminobutanoyl or (Piperazine-l-yl)-acetyl;

[0298] ZS2is -(Peg)n- where n is an integer from 1 to 15, or (8-Amino-3,6-dioxaoctanoyl)i-3.

[0299] In one embodiment, the spacer is of the formula -Z2-, wherein

[0300] -Z2- is selected from -ZS1-, -ZS1-ZS2-, -ZS2-ZS1-, -ZS2-, wherein

[0301] ZS1is (isoGlu)i-3, p-Ala, isoLys, 4-aminobutanoyl or (Piperazine-l-yl)-acetyl;

[0302] ZS2is (8-Amino-3,6-dioxaoctanoyl)i-3.

[0303] In one embodiment, the spacer is of the formula -Z2-, wherein -Z2- is -ZS1. In one embodiment, -ZS1is (isoGlu)i-3, or (Piperazine-l -yl)-acetyl. In one embodiment, -ZS1is isoGlu. In one embodiment, -ZS1is (isoGlu)2 In one embodiment, -ZS1is (Piperazine-1-yl)- acetyl.

[0304] In one embodiment, the spacer is of the formula -Z2-, wherein -Z2- is -ZS1-ZS2- or -ZS2-ZS1-. In one embodiment, ZS1is (isoGlu)i-3 and ZS2is -(Peg)n- where n is an integer from 1 to 15. In one embodiment, ZS1is (isoGlu)i-3 and ZS2is -(Peg)n- where n is 1 , 2 or 3. In one embodiment, ZS1is (isoGlu) and ZS2is -(Peg)n- where n is 1 , 2, or 3.

[0305] In one embodiment, ZS1is (isoGlu)i-3 and ZS2is 8-Amino-3,6-dioxaoctanoyl)i-3. In one embodiment, ZS1is (isoGlu)2 and ZS2is (8-Amino-3,6-dioxaoctanoyl)2. In one embodiment, ZS1is (isoGlu) and ZS2is (8-Amino-3,6-dioxaoctanoyl)2.

[0306] Lipidated amino acid residue

[0307] A lipidated amino acid residue means an amino acid as defined herein that is substituted (e.g., at its side chain) with an optional spacer as defined herein and a lipid or lipophilic substituent as defined herein. In one embodiment, the lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid is selected from the group consisting of:

[0308] [Lys([17-Carboxy-heptadecanoyl]-isoGlu)];

[0309] [Lys(Hexadecanoyl)];

[0310] [[2,4-Diaminobutanoyl]((17-Carboxy-heptadecanoyl)-[(Piperazine-1-yl)-acetyl])];

[0311] [Lys((17-Carboxy-heptadecanoyl)-[(Piperazine-1 -yl)-acetyl])];

[0312] Lys[17-Carboxy-heptadecanoyl]-[isoGlu][isoGlu][8-Amino-3,6-dioxaoctanoyl][8-Amino-3,6- dioxaoctanoyl];

[0313] {d}[Lys((17-Carboxy-heptadecanoyl)-[(Piperazine-1-yl)-acetyl])];

[0314] [Lys([17-Carboxy-heptadecanoyl])];

[0315] [Phe(4NH)(17-Carboxy-heptadecanoyl-isoGlu)];

[0316] [Phe(4NH)-Octadecanoyl];

[0317] [Phe(4NH)-(17-Carboxy-heptadecanoyl)-(Piperazine-1-yl-acetyl)];

[0318] [Phe(4NH)-(17-Carboxy-heptadecanoyl)-(Piperazine-1-yl-acetyl)];

[0319] [Phe(4NH)-(15-Carboxy-pentadecanoyl)];

[0320] [Phe(4NH)-(13-Carboxy-tridecanoyl)]; and [AEF([17-Carboxy-heptadecanoyl]-[isoGlu]-[8-Amino-3,6-dioxaoctanoyl][8-Amino-3,6- dioxaoctanoyl]].

[0321] Exemplary lipids (Z1) and lipid-spacers (Z1-Z2)

[0322] The structure of exemplary lipids and lipid-spacers of the invention are provided in Table

[0323] D below, wherein denotes the point of attachment to the linker (i.e., when the compound of formula (I) is a compound of formula (lc)) or to the amino acid of the lipidated amino acid residue, such as to the side chain of the amino acid of the lipidated amino acid residue.

[0324] TABLE D

[0325]

[0326] Lactam bridge In one embodiment, wherein when the compound of formula (I) is a compound of formula (la), the bridges between the residue at X2 and the residues at X7 and X11 are lactam bridges.

[0327] In one embodiment, when the compound of formula (I) is a compound of formula (lb), the bridge between the residue at X2 and the residue at X11 and the bridge between the residue at X4 and the residue at X7 are lactam bridges.

[0328] In one embodiment, when the compound of formula (I) is a compound of formula (Ic), linker L includes a lactam moiety.

[0329] A lactam bridge is formed of one amino acid residue comprising an amine group and another amino acid residue comprising a carboxylic acid group. The amine and / or carboxylic acid group of the amino acid residue may be on the side chain of the amino acid residue, such as Dab, Asp and Glu. Alternatively, the amine and / or carboxylic acid group of the amino acid residue may be the N- or C-terminus of the peptide chain, such as the amine or carboxylic acid of the peptide backbone of any amino acid, such as 4- aminomethyl-phenylacetyl, 3-(3-Pyridyl)-Ala, and 3-aminopropanoyl.

[0330] One of the amino acid residues comprise an amine group and the other amino acid residue comprises a carboxylic acid group, wherein a lactam (cyclic amide) is formed between the amine and carboxylic acid groups.

[0331] For simplicity, the amino acid residues who together form a lactam bridge will be discussed by reference to the residues nominally present before lactam formation.

[0332] Suitable amino acid residues who together form a lactam bridge may be selected from:

[0333] • Amino acid residues comprising an amine group: e.g. Lys, Orn, 4-aminomethyl- phenylacetyl, 3-(3-Pyridyl)-Ala, 3-aminopropanoyl, and Dab.

[0334] • Amino acid residues comprising a carboxylic acid group: e.g. Glu or Asp.

[0335] Lactam bridge -X2 with X7 and X11 - formula (la)

[0336] For example, a lactam bridge is formed between the Glu or Asp at X11 with the amino acid residue at X2 and a lactam bridge is formed between the Glu or Asp at X7 with the amino acid residue at X2, wherein the amino acid at X2 may be Lys. In this embodiment, it will be understood that the amines at both the a-carbon and s-carbon will be involved in forming the bridges with the X7 and X11 residues.

[0337] Lactam bridge - X2 with X11 and X4 with X7 - formula (lb)

[0338] For example, a lactam bridge is formed between the Glu or Asp at X11 with the amino acid residue at X2 and a lactam bridge is formed between the Glu or Asp at X4 with the amino acid residue at X7, wherein the amino acid at X2 and X7 may be Lys or Dab.

[0339] Lactam bridge - X5 and X11 - formula (Ic)

[0340] For example, a lactam bridge is formed between the Glu or Asp at X11 with the amino acid residue at X5 via linker L as defined herein.

[0341] Thioether bridge

[0342] A dithioether bridge is formed of two amino acid residues comprising sulfur moieties, such as -SH. Preferably, the sulfur moiety of the amino acid residue is on the side chain of the amino acid residue, such as Cys. For simplicity, the amino acid residues who together form a thioether bridge will be discussed by reference to the residues nominally present before thioether formation. Suitable amino acid residues who together form a thioether bridge may be Cys.

[0343] Lactam bridge - X2 with X11 and X4 with X7 - formula (lb)

[0344] For example, when the compound of formula (I) is a compound of formula (lb), a Cys residue at X4 and a Cys residue at X7 may form a thioether bridge between these two positions. Bridge length

[0345] The length of the bridge is counted as the number of atoms in a linear chain from (but not including) the first atom attached to the atom (carbon) adjacent to the residue-bearing carbon (i.e. the alpha-carbon of the amino acid residue to which the NH, C=O and, if present, side chain are attached) of the amino acid of the first residue (e.g., X5 in a compound of formula (lc)), i.e. attached to the alpha carbon of the relevant residue for most amino acids, up to the first atom attached to the residue-bearing alpha-carbon of the amino acid of the second residue ((e.g., X11 in a compound of formula (lc)). In each case, the bridge is measured between the residue-bearing carbons (i.e. the moiety of the amino acid residue to which the NH, C=O and side chain are attached) on X5 and X11 in the example of a compound of formula (lc).

[0346] The contribution to the length of the bridge for amino acid residues and the type of bridge is described below.

[0347] Compounds of formula (la)

[0348] In some embodiments, the length of the bridge between X2 and X11 is at least 3 atoms long. In some embodiments, the length of the bridge between X2 and X11 is no longer than 11 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 3 to 11 atoms long, such as 3, 4, 5, 6, 7, 8, 9, 10, or 11 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 4 to 11 atoms long, such as

[0349] 4, 5, 6, 7, 8, 9, 10, or 11 atoms long, such as 4, 5, 6, 7, 8, 9, or 11 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 4 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 5 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 6 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 7 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 8 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 9 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 11 atoms long.

[0350] In some embodiments, the length of the bridge between X2 and X7 is at least 3 atoms long. In some embodiments, the length of the bridge between X2 and X7 is no longer than 11 atoms long. In some embodiments, the length of the bridge between X2 and X7 is 3 to 11 atoms long, such as 3, 4, 5, 6, 7, 8, 9, 10, or 11 atoms long. In some embodiments, the length of the bridge between X2 and X7 is 3 to 6 atoms long, such as 3, 4, 5, 6 atoms long, such as 3, 4, or 6 atoms long. In some embodiments, the length of the bridge between X2 and X7 is 3 atoms long. In some embodiments, the length of the bridge between X2 and X7 is 4 atoms long. In some embodiments, the length of the bridge between X2 and X7 is 6 atoms long.

[0351] Lactam bridge

[0352] The contribution of the side chain to the length of the lactam bridge is counted as the number of atoms in a linear chain from the first atom of the side chain (which is bonded to an atom of the peptide backbone, i.e. to the alpha carbon of the relevant residue for most amino acids) up to and including the atom which participates in the amide bond of the lactam bridge (i.e. the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0353] Thus common acid- and amine-containing side chains are considered to have the following side chain lengths. It will be understood that the following can be used to decipher the bridge length for any amino acid residue disclosed herein.

[0354] Amine-containing side chains:

[0355] Carboxylic acid-containing side chains:

[0356] Similarly, the contribution of the length of the lactam bridge from the use of the amine or carboxylic acid of the amino acid residue that is conventionally used in the amide bonds of the peptide backbone (that is, the a-amine group (or p-amine group for bLys, {d}bLys and beta-hLys, or the a-amine converted into an azide group for (Ns)-K and {d}(Ns)-K), or the a carboxylic acid group) is counted as the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (i.e. the first atom attached to the alpha carbon of the relevant residue for most amino acids), up to and including the atoms which participate in the amide bond of the lactam bridge (i.e. the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0357] Thus the following amino acid residues are considered to have the following lengths:

[0358] Using the a-amine group (or fi-amine group for bLys, {d}bLys and beta-hLys, or the a- amine converted into an azide group for (Ns)-K and {d}(N3)-K) that is conventionally used in the peptide backbone in the lactam bridge: Using the a-carboxylic acid group that is conventionally used in the peptide backbone in the lactam bridge:

[0359] Compounds of formula (lb)

[0360] In some embodiments, the length of the bridge between X2 and X11 is at least 4 atoms long. In some embodiments, the length of the bridge between X2 and X11 is no longer than 10 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 4 to 10 atoms long, such as 4, 5, 6, 7, 8, 9, or 10 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 4 to 9 atoms long, such as 4, 5, 6, 7, 8, or 9 atoms long. In some embodiments, the length of the bridge between / X2 and X11 is either 4, 5, or 9 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 4 atoms long. In some embodiments, the length of the bridge between X2 and X11 is either 5 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 9 atoms long.

[0361] In some embodiments, the length of the bridge between X4 and X7 is at least 4 atoms long. In some embodiments, the length of the bridge between X4 and X7 is no longer than 10 atoms long. In some embodiments, the length of the bridge between X4 and X7 is 4 to 10 atoms long, such as 4, 5, 6, 7, 8, 9, or 10 atoms long. In some embodiments, the length of the bridge between X4 and X7 is 4 to 9 atoms long, such as 4, 5, 6, 7, 8, or 9 atoms long. In some embodiments, the length of the bridge between X4 and X7 is 6 or 7 atoms long. In some embodiments, the length of the bridge between X4 and X7 is 6 atoms long. In some embodiments, the length of the bridge between X4 and X7 is 7 atoms long.

[0362] Lactam bridge

[0363] The contribution of the side chain to the length of the lactam bridge is counted as the number of atoms in a linear chain from the first atom of the side chain (which is bonded to an atom of the peptide backbone, i.e. to the alpha carbon of the relevant residue for most amino acids) up to and including the atom which participates in the amide bond of the lactam bridge (i.e. the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0364] Similarly, the contribution of the length of the N- or C-terminus amino acid residue to the length of the lactam bridge is counted as the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (i.e. the first atom attached to the alpha carbon of the relevant residue for most amino acids), up to and including the atoms which participate in the amide bond of the lactam bridge (i.e. the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0365] Desirably, the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 4, 5, 6, 7, 8, 9, or 10 atoms; such as 4, 5, 6, or 9 atoms. For the lactam bridge between the amino acid residues at position X2 and X11 , the length of the lactam bridge after formation of the amide bond may be 4, 5, or 9 atoms long. For the lactam bridge between the amino acid residues at positions X4 and X7, the length of the lactam bridge after formation of the amide bond may be 6 atoms long.

[0366] Dithioether bridge

[0367] The contribution of the side chain to the length of the dithioether bridge is counted as the number of atoms in a linear chain from the first atom of the side chain (which is bonded to an atom of the peptide backbone, i.e. to the alpha carbon of the relevant residue for most amino acids) up to and including the atom which participates in the dithioether bond of the bridge (i.e. the sulfur atom).

[0368] Thus common sulfur-containing side chains are considered to have the following side chain lengths. It will be understood that the following can be used to decipher the bridge length for any amino acid residue disclosed herein.

[0369] The length of the side chains of X4 and X7 are then added to the contribution of the linker between the sulfur moieties of the amino acid residues at positions X4 and X7 to determine the length of the bridge.

[0370] Desirably, the length of the dithioether bridge after the formation of the dithioether bonds (not including any atoms in the peptide backbone) is 5, 6, 7, 8, 9, or 10 atoms, such as 6, 7, 8, or 9 atoms; such as 7, 8, or 9 atoms, such as 7 or 8 atoms.

[0371] In some embodiments, the length of the dithioether bridge is 5 atoms long. In some embodiments, the length of the dithioether bridge is 6 atoms long. In some embodiments, the length of the dithioether bridge is 8 atoms long. In some embodiments, the length of the dithioether bridge is 9 atoms long. In some embodiments, the length of the dithioether bridge is 10 atoms long. Preferably, the dithioether bridge is 7 atoms long.

[0372] Compounds of formula (Ic)

[0373] In some embodiments, the length of the bridge between X5 and X11 is at least 8 atoms long. In some embodiments, the length of the bridge between X5 and X11 is no longer than 17 atoms long. In some embodiments, the length of the bridge between X5 and X11 is 8 to 17 atoms long, such as 8, 9 10, 11 , 12, 13, 14, 15, 16 or 17 atoms long. In some embodiments, the length of the bridge between X5 and X11 is 8 to 12 atoms long, such as 8, 9, 10, 11 or 12 atoms long. In some embodiments, the length of the bridge between X5 and X11 is 9 to 11 atoms long. In some embodiments, the length of the bridge between X5 and X11 is 13 to 17 atoms long, such as 13, 14, 15, 16 or 17 atoms long. In some embodiments, the length of the bridge between X5 and X11 is 14 to 16 atoms long. In some embodiments, the length of the bridge between X5 and X11 is 15 atoms long.

[0374] Lactam bridge

[0375] When the bridge is a lactam bridge, the contribution of the side chain to the length of the lactam bridge is counted as the number of atoms in a linear chain from the first atom of the side chain (which is bonded to an atom of the peptide backbone, i.e. from (but not including) the residue-bearing alpha carbon of the relevant residue for most amino acids) up to and including the atom which participates in the amide bond of the lactam bridge (i.e. the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0376] Similarly, the contribution of the length of the N- or C-terminus amino acid residue to the length of the lactam bridge is counted as the number of atoms in a linear chain between (but not including) the residue-bearing alpha carbons of the relevant amino acid residue.

[0377] Desirably, the length of the lactam bridge after formation of the amide bond (between, but not including, the alpha carbons in the peptide backbone) is 8, 9, 10, 11 , 12, 13, 14, 15, 16 or 17 atoms. In some embodiments, the length of the lactam bridge after formation of the amide bond (between, but not including, the alpha carbons in the peptide backbone) is 8 to 12, such as 9 to 11 , such as 10 atoms. In some embodiments, the length of the lactam bridge after formation of the amide bond (between, but not including, the alpha carbons in the peptide backbone) is 13 to 17, such as 14 to 16, such as 15 atoms. For the lactam bridge between the amino acid residues at positions X5 and X11 , the length of the lactam bridge after formation of the amide bond may be 4, 5, or 9 atoms long.

[0378] Thioether bridge

[0379] When the bridge is a thioether bridge, the length of the thioether bridge is counted as the number of atoms in a linear chain between (but not including) the residue-bearing alpha carbon on X5 to the residue-bearing carbon on X11 . In some embodiments, the length of the thioether bridge is 13 to 17 atoms, such as 14 to 16 atoms, such as 15 atoms. In some embodiments, the length of the thioether bridge is 8 to 12 atoms, such as 9 to 11 atoms, such as 10 atoms.

[0380] Triazole-containing bridge

[0381] When the bridge is a triazole-containing bridge (typically, but not exclusively formed from a “click” reaction between an azide and an alkyne), the length of the triazole bridge is counted as the number of atoms in a linear chain between (but not including) the residuebearing alpha carbon on X5 to the residue-bearing carbon on X11 , and counting the 1 , 2 and 3-positions of the triazole as 3 atoms.

[0382] In some embodiments, the length of the triazole-containing bridge is 13 to 17 atoms, such as 14 to 16 atoms, such as 15 atoms. In some embodiments, the length of the triazole- containing bridge is 8 to 12 atoms, such as 9 to 11 atoms, such as 10 atoms. Synthesis of the compounds

[0383] The invention further provides a method of synthesis of a compound of the invention. The compounds (which may also be referred to as peptides) may suitably be manufactured by standard synthetic methods. Thus, the peptides may be synthesized by, e.g., methods comprising synthesizing the peptide by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and optionally isolating and purifying the final peptide product. In this context, reference may be made to WO 98 / 11125 or, inter alia, Fields, G.B. et al., “Principles and Practice of Solid-Phase Peptide Synthesis”; in: Synthetic Peptides, Gregory A. Grant (ed.), Oxford University Press (2ndedition, 2002) and the synthesis examples herein.

[0384] The method typically further comprises the step of forming a suitable bond between either a) the amino acid residue at the X2 position and the amino acid residues at the X7 and X11 positions or b) the amino acid residue at the X2 position and the amino acid at the X11 position, and the amino acid residue at the X4 position and the amino acid residue at the X7 position or c) the amino acid residue at the X5 position and the amino acid residue at the X11 position. In the case of solid phase synthesis, cyclisation may be performed in situ on the solid phase (e.g. resin), i.e. before removal of the peptide from the solid phase. In some embodiments, the bond is an amide bond. In some embodiments, the bond is a thioether bond. In some embodiments, the bond comprises a first bond between a first carbon of an alkyne and the first nitrogen of an azide, and a second bond between a second carbon of an alkyne and the third nitrogen of an azide, to complete a 1 ,2,3-triazole group.

[0385] The synthesis of some example compounds of the invention are provided in Example 1. Generally, the method for the synthesis of said compound comprises synthesising the compound by solid-phase or liquid-phase peptide synthesis methodology, optionally isolating and / or purifying the final product, and optionally further comprising the step of forming a bond between either a) the amino acid residue at the X2 position and the amino acid residues at the X7 and X11 positions or b) the amino acid residue at the X2 position and the amino acid at the X11 position, and the amino acid residue at the X4 position and the amino acid residue at the X7 position or c) the amino acid residue at the X5 position and the amino acid residue at the X11 position. In some embodiments, the bond is an amide bond. In some embodiments, the bond is a thioether bond. In some embodiments, the bond comprises a first bond between a first carbon of an alkyne and the first nitrogen of an azide, and a second bond between a second carbon of an alkyne and the third nitrogen of an azide, to complete a 1 ,2,3-triazole group. The order of the steps in the synthesis of the compounds are not necessarily in the order mentioned above.

[0386] Efficacy of the compounds

[0387] The compounds of the invention are interleukin-23 receptor (IL-23R) inhibitors, i.e. they are capable of binding to, and blocking signalling by, one or more receptors or receptor complexes regarded as physiological receptors for interleukin-23 (IL-23).

[0388] Comparative activity may be measured by any suitable means, such as via determination of IC50 values as described below.

[0389] Compounds of the present invention may exhibit a number of advantageous properties in relation to other peptide IL-23R inhibitors thereof, such as analogues described in

[0390] WO 2016 / 011208, WO 2018 / 022937, WO 2018 / 136646, WO 2020 / 014646,

[0391] WO 2021 / 146441 , WO 2021 / 146458, WO 2023 / 288017, WO 2023 / 288019,

[0392] WO 2023 / 288028, Kong et al., 2020, WO 2023 / 099669, WO 2024 / 114762,

[0393] WO2024 / 155552 and WO2024 / 155553. As compared with any of these analogues, compounds of the invention may, for example, exhibit improved effects, e.g., in the form of improved in vitro potency at IL-23R.

[0394] Additionally or alternatively, compounds of the invention may exhibit improved gastrointestinal (Gl) stability as compared to any of the peptide inhibitors of IL-23R described in the art.

[0395] Additionally, or alternatively, some compounds of the invention exhibit improved rat PK properties over JNJ-2113.

[0396] The skilled person will be aware of suitable assay formats, and examples are provided below. For example, the assays may make use of employing measurements on the human IL-23R (see the examples below). Where sequences of precursor proteins are referred to, it should be understood that assays may make use of the mature protein, lacking the signal sequence.

[0397] Kd values may be used as a numerical measure of the binding affinity at a given receptor. A Kd value, also termed the equilibrium dissociation constant, is a measure of how tightly a compound binds to a receptor in a particular assay. A small Kd indicates the compound binds tighter with higher affinity to the receptor as compared to a compound with a higher Kd value. Thus, for example, a compound having a Kd [IL-23R] value lower than the Kd [IL- 23R] value of another compound inhibitor of IL-23R in a particular assay may be considered to have a stronger binding affinity (or binds more tightly) to IL-23R than that of the other compound inhibitor of IL-23R.

[0398] In absence of an experimental method to directly determine the Kd of a compound for a receptor, the binding affinities for compounds may be estimated by means of determining the IC50 of a compound. The IC50 is determined by the compound’s ability to compete with a labelled compound for the receptor. In such a competition assay, the concentration for which half of the labelled compound is displaced from the receptor by the unlabelled compound is termed the IC50 value. The IC50 value is proportional to the affinity of the compound for the receptor (that is, its Kd value), and is assay system dependent as it depends on factors such as the concentration of the labelled compound used, the affinity of the labelled compound for the receptor, and assay incubation times.

[0399] In a binding assay format an IC50 value may be used as a numerical format to measure how tightly a compound binds to a receptor in a particular assay. A small IC50 indicates the compound binds tighter with higher affinity to the receptor as compared to a compound with a higher IC50 value. Thus, for example, a compound having a IC50 [IL-23R] value lower than the IC50 [IL-23R] value of another compound inhibitor of IL-23R in a particular assay may be considered to have a stronger binding affinity (or binds more tightly) to IL-23R than that of the other compound inhibitor of IL-23R.

[0400] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 1000 nM (e.g. 0.0001 to 1000 nM).

[0401] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 500 nM (e.g. 0.0001 to 500 nM).

[0402] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 100 nM (e.g. 0.0001 to 100 nM).

[0403] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 50 nM (e.g. 0.0001 to 50 nM).

[0404] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 30 nM (e.g. 0.0001 to 30 nM).

[0405] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 20 nM (e.g. 0.0001 to 20 nM).

[0406] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 10 nM (e.g. 0.0001 to 10 nM). In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 5 nM (e.g. 0.0001 to 5 nM).

[0407] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 1 nM (e.g. 0.0001 to 1 nM).

[0408] In some embodiments of compounds of the present invention, the IC50 towards IL-23R is below 0.5 nM (e.g. 0.0001 to 0.5 nM).

[0409] In a functional assay format, measuring the ability of compounds to inhibit IL-23 mediated signalling in a cell-based assay, IC50 values may be used as a numerical measure of inhibitor potency. An IC50 value is a measure of the concentration of a compound required to achieve half of that compound’s maximal activity in a particular assay. Thus, for example, a compound having an IC50 [IL-23R] value lower than that of another compound inhibitor of IL-23R in a particular assay may be considered to have a stronger inhibitory potency, presumably by better blocking of the IL-23 mediated signalling, than that of the other peptide inhibitor of IL-23R.

[0410] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 1000 nM (e.g. 0.0001 to 1000 nM).

[0411] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 500 nM (e.g. 0.0001 to 500 nM).

[0412] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 100 nM (e.g. 0.0001 to 100 nM).

[0413] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 50 nM (e.g. 0.0001 to 50 nM).

[0414] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 30 nM (e.g. 0.0001 to 30 nM).

[0415] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 20 nM (e.g. 0.0001 to 20 nM).

[0416] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 10 nM (e.g. 0.0001 to 10 nM).

[0417] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 5 nM (e.g. 0.0001 to 5 nM). In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 1 nM (e.g. 0.0001 to 1 nM).

[0418] In some embodiments of compounds of the present invention, the IC50 towards IL-23 mediated signalling is below 0.5 nM (e.g. 0.0001 to 0.5 nM).

[0419] Such assays may be performed under the conditions described in Examples 2-1 and 2-2 below.

[0420] Additionally or alternatively, compounds of the invention may show gastrointestinal (Gl) stability, i.e. resistance to degradation in the gastrointestinal tract. This can be measured using a simulated intestinal fluid (SIF) assay. For example, the compounds of the invention may retain at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least

[0421] 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the remaining compound or peptide after incubation for 1 hour, or for 4 hours, e.g. under the conditions described in Example 2-3. Preferably, the compounds retain at least 70% (or more) of the compound after incubation for at least 1 minute, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 70 minutes, at least 80 minutes, at least 90 minutes, or at least 100 minutes, under the SIF assay.

[0422] Pharmaceutical compositions

[0423] The invention also extends to compositions, such as pharmaceutical compositions, comprising the compounds of the invention. As with all aspects of the invention, it is to be understood that reference to a compound of the invention encompasses reference to pharmaceutically acceptable salts and solvates.

[0424] The compounds of the present invention may be formulated as pharmaceutical compositions which are suited for administration with or without storage, and which typically comprise a therapeutically effective amount of at least one peptide of the invention, together with a pharmaceutically acceptable carrier, excipient or vehicle.

[0425] The term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art and are described, for example, in “Remington's Pharmaceutical Sciences”, 17thedition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. Therapeutic uses

[0426] The compounds of the invention, and pharmaceutical compositions comprising said compounds, are useful in a method of prevention or treatment of various conditions. The method of prevention or treatment comprises administering to the subject an effective amount of the compound of the invention, or the pharmaceutical composition comprising said compound.

[0427] In some embodiments, the conditions may be selected from Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-l, chronic granulomatous disease, glycogen storage disease type 1 b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, and graft versus host disease. In a preferred embodiment, the conditions are selected from inflammatory bowel disease (IBD), Crohn’s Disease, ulcerative colitis, psoriasis and psoriatic arthritis.

[0428] The subject or patient may be an animal subject or patient. The subject or patient may be a human subject or patient.

[0429] Preferably, the subject is a human subject or patient.

[0430] Dosages

[0431] A typical dosage of a compound as employed in the context of the present invention may be in the range from about 0.0001 to about 100 mg / kg body weight per day, such as from about 0.0005 to about 50 mg / kg body weight per day, such as from about 0.001 to about 10 mg / kg body weight per day, e.g. from about 0.01 to about 1 mg / kg body weight per day, administered in one or more doses, such as from one to three doses. The exact dosage employed will depend, inter alia, on: the nature and severity of the disease or disorder to be treated, on the sex, age, body weight and general condition of the subject to be treated, on possible other, concomitant, disease or disorder that is undergoing or is to undergo treatment, as well as on other factors that will be known to a medical practitioner of skill in the art. EXAMPLES

[0432] The following examples demonstrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and routine to those of skill in the art, except where otherwise described in detail. It is to be understood that these examples are for illustrative purposes only and do not purport to be wholly definitive as to conditions or scope of the invention. As such, they should not be construed as limiting the scope of the present invention in any way.

[0433] Abbreviations employed for the amino acids and particular R2groups may be found in Tables A-C in the definitions. Other abbreviations employed in the examples include:

[0434] ‘BuOH tert-Butanol

[0435] DODT 2,2'-(Ethylenedioxy)diethanethiol Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)) PhSiH3phenylsilane PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) equiv. equivalents r.t. room temperature aq. Aqueous

[0436] IL-23R interleukin-23 receptor hlL-23R human interleukin-23 receptor Gl gastrointestinal SIF simulated intestinal fluid

[0437] SGF simulated gastric fluid

[0438] NIuc NanoBRET luciferase assay

[0439] SD standard deviation

[0440] %Eff percentage efficacy pSTAT3 phosphorylated signal transducer and activator of transcription 3

[0441] BRET Bioluminescence Resonance Energy Transfer

[0442] TAMRA 5’-tetramethylrhodamine-5-carboxamide

[0443] The following examples are provided to illustrate certain embodiments of the invention and are not intended to limit the scope of the invention. Example 1 : Synthesis of compounds

[0444] The following compounds were synthesised in Table 1-1 below, which lists their full structure, the amino acid sequence (excluding any C-terminal substituents) and SMILES string.

[0445] In Table 1-1 , (cycloX) denotes the bridging moieties and thus the bridge locations in the synthesised compounds. In particular, the amino acid residue preceding (cycloX) forms a bridge with the amino acid preceding the corresponding (cycloX). For example, the amino acid preceding (cyclol) will form a bridge with the amino acid preceding the corresponding (cyclol) and where relevant, the amino acid preceding (cyclo2) will form a bridge with the amino acid preceding the corresponding (cyclo2).

[0446] Compounds 1 to 4 each include “(cyclol )(cyclo2)-K”, which denotes the fact that K (Lys) will form a bridge with both the amino acids preceding the corresponding (cyclol) and (cyclo2).

[0447] co

[0448]

[0449]

[0450]

[0451]

[0452]

[0453] Structural formulae for the above compounds are provided in Table 1-2. When a nitrogen (N) atom is shown in the structure, it can be understood that a sufficient number of hydrogen atoms are attached to the nitrogen to make it trivalent.

[0454] Table 1-2: Synthesised compounds - Structural formulae

[0455] 

[0456] Unless otherwise specified, reagents and solvents employed in the following were available commercially in standard laboratory reagent or analytical grade, and were used without further purification.

[0457] Apparatus and synthetic strategy

[0458] Peptides were synthesized batchwise on a peptide synthesiser, such as a CEM Liberty Blue Peptide Synthesizer, according to solid phase peptide synthetic procedures using 9- fluorenylmethyloxycarbonyl (Fmoc) as N-a-amino protecting group and suitable common protection groups for side chain functionalities.

[0459] As polymeric support based resins, such as e.g. TentaGel™, was used. The synthesizer was loaded with resin that prior to usage was swelled in DMF.

[0460] Non-naturally occurring amino acids and other suitable building blocks were employed without any changes to the general procedure.

[0461] Optical isomers of particular amino acids (including non-naturally occurring amino acids) were employed in the synthesis of the compounds and may be found in Tables A and B in the definitions. Definitions of particular R2groups may be found in Table C in the definitions.

[0462] Coupling on a CEM Liberty Blue Peptide Synthesizer

[0463] A solution of Fmoc-protected amino acid (4 equiv.) was added to the resin together with a coupling reagent solution (4 equiv.) and a solution of base (8 equiv.). The mixture was either heated by the microwave unit to 50 °C and coupled for 10 minutes or coupled with no heat for 60 minutes. During the coupling nitrogen was bubbled through the mixture.

[0464] In the case of difficult couplings (e.g. coupling of a residue immediately after an N- methylated amino acid residue or other sterically hindered amino acid residue as recognized by a person of skill in the art) the coupling was repeated one or more times.

[0465] Deprotection:

[0466] The Fmoc group was deprotected using piperidine in DMF or other suitable solvents. The deprotection solution was added to the reaction vessel and the mixture was heated for 5 minutes reaching approx. 50 °C. After draining the reaction vessel the resin was washed with DMF or other suitable solvents. Lactam formation:

[0467] The following procedure for the coupling of Glu and Lys is representative for all lactam formations where the amino acid side chain containing the carboxyl-function is protected with Oall and the amino acid side chain containing the amino group is Alloc-protected. After assembly of the full peptide sequence, deprotection of Glu(Oall) and Lys(Alloc) was performed using Pd(PPhs)4 (0.05 equiv.) and PhSiHs (10 equiv.) in DCM. Subsequently, the lactam bridge was formed between the side chain carboxylic acid of Glu and side chain amine of Lys using PyBOP (2 equiv.) and DIPEA (3.0 equiv.) in DMF. Both steps were performed with the peptide still attached to the resin.

[0468] Peptides with a lactam from a side chain to the / V-terminal amine were prepared similarly. After assembly of the full peptide sequence, the Fmoc protection group of the / V-terminal amine is left intact. Glu(Oall) is deprotected as described with Pd(PPti3)4 followed by a Fmoc deprotection (see section “cleavage”). The lactam bridge was formed similarly with PyBOP.

[0469] Cleavage:

[0470] The dried peptide resin was treated with TFA and suitable scavengers for approximately 2 hours. The volume of the filtrate was reduced and the crude peptide was precipitated after addition of diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried.

[0471] HPLC purification of the crude peptide:

[0472] The crude peptide was purified by preparative reverse phase HPLC using a conventional HPLC apparatus, such as a Gilson GX-281 with 331 / 332 pump combination, for binary gradient application equipped with a column, such as 5 x 25 cm Gemini NX 5u C18 110A column, and a fraction collector using a flow 20-40 ml / min with a suitable gradient of buffer A (0.1% Formic acid, aq.) or A (0.1% TFA, aq.) and buffer B (0.1% Formic acid, 90% MeCN, aq.) or B (0.1 % TFA, 90% MeCN, aq.). Fractions were analysed by analytical HPLC and MS and selected fractions were pooled and lyophilized. The final product was characterized by HPLC and MS.

[0473] Iso-amino acids:

[0474] Peptides with iso-amino acids were synthesized by standard Fmoc SPPS, using amino acid building blocks where the protecting groups at the / V-terminal and side chain are switched or interchanged. For example, a peptide with a standard Lysine in its sequence is synthesised with the building block Fmoc-Lys(Boc)-OH, where Fmoc is the protecting group at the N- terminal amine and Boc at the side chain. In contrast, a peptide with iso-Lys would thus be synthesised with a building block of Boc-Lys(Fmoc)-OH instead of Fmoc-Lys(Boc)-OH. Coupling conditions for attaching the building block to the peptide and subsequent deprotecting conditions for removal of the Fmoc group are the same as described for standard Fmoc SPPS synthesis.

[0475] The side-chain protecting group “Boc” may be replaced with an “Alloc” protecting group in cases where side chain on-resin modifications are performed.

[0476] Analytical HPLC:

[0477] Final purities were determined by analytic HPLC (Agilent 1100 / 1200 series) equipped with auto sampler, degasser, 20 pl flow cell and Chromeleon software. The HPLC was operated with a flow of 1 .2 ml / min at 40 °C using an analytical column, such as Kinetex 2.6 pm XB- C18 100A 100x4,6 mm column. The compound was detected and quantified at 215 nm. Buffers A (0.1% TFA, aq.) and buffer B (0.1% TFA, 90% MeCN, aq.).

[0478] Mass spectroscopy:

[0479] Final MS analysis was performed on a conventional mass spectrometer, e.g. Waters Xevo G2 Tof, equipped with electrospray detector with lock-mass calibration and MassLynx software. It was operated in positive mode using direct injection and a cone voltage of 15V (1 TOF), 30 V (2 TOF) or 45 V (3 TOF) as specified on the chromatogram. Precision was 5 ppm with a typical resolution of 15,000-20,000.

[0480] One of skill in the art will appreciate that standard methods of peptide synthesis may be used to generate the compounds of the invention.

[0481] Example 2: Biological Assays

[0482] Example 2-1 : Binding assay for estimating binding affinity of compounds to human IL- 23R

[0483] The compound binding affinity for IL-23R was estimated by the ability of compounds to displace a fluorophore-labelled reference compound from the human IL-23R. The assay principle relies on Bioluminescence Resonance Energy Transfer (BRET) between a fluorophore-labelled reference compound binding to the IL-23R part of a fusion protein consisting of the IL-23R fused to a Nanoluc luciferase enzyme (Nanoluc). The Nanoluc is placed in the / V-terminus in close proximity to the binding domain of the ligand. Upon close proximity between the fluorophore of the fluorophore-labelled compound and the Nanoluc of the fusion protein, bioluminescence energy generated from conversion of a Nanoluc substrate, is transferred to the fluorophore resulting in an increase in BRET. In presence of an unlabelled compound, the unlabelled compound displaces the fluorophore-labelled peptide from its binding site resulting in a decrease in BRET. The concentration for which half of the fluorophore-labelled peptide is displaced by the unlabelled compound depends on the affinity of the compound for the IL-23R, and is termed the IC50 concentration.

[0484] The fusion protein was generated by subcloning of the cDNA encoding the mature human IL-23R (primary accession number UniProtKB - Q5VWK5, amino acids 22-629) and a small linker sequence in frame with a mammalian expression plasmid encoding a secretion signal and the Nanoluc protein (N1371 , Promega). The plasmid also contained a gene to confer resistance for the antibiotic hygromycin. A cell line stably expressing the Nluc-IL23R fusion protein was generated by transfection of HEK293 cells with the expression plasmid and selected with hygromycin for 3 weeks in Growth medium consisting of DMEM w / Glutamax-I containing, 10% V / V FBS, 1 % VA / P / S, 1 mM Sodium Pyruvate, and 1X NEAA, and 0.3 mg / mL hygromycin. The remaining cells were propagated and considered a stable expressing Nluc-IL23R fusion protein pool clone.

[0485] Cells expressing the Nluc-IL23R fusion protein were expanded in Growth medium and membranes prepared by homogenization of a cell pellet from 18 T175 flasks (4 °C in subsequent steps). The cell pellet was lysed Tris 10 mM, 7.5, 1 mM EDTA and protease inhibitors (Complete, Roche) and homogenized using a 15 mL glass-dounce by 50 strokes. The homogenate was spun at spin @1500 rpm for 10 min, the supernatant transferred to SV-34 tubes and spun at 40000g for 20 min at 4 °C to pellet the crude membranes. The supernatant was then removed, the pellet resuspended in 5 mL buffer containing 50 mM HEPES pH 7.4, 5 mM EGTA, and 5 mM MgC , and homogenized. Aliquots of the resuspended and homogenized membranes containing the Nluc-IL23R fusion protein were stored at -80 °C until use.

[0486] Compounds to be tested for binding to IL-23R were serially diluted in Assay buffer (50 mM HEPES pH 7.4, 5 mM EGTA, 5 mM MgC , 0.005% Tween-20, and 0.05% casein) and added to the wells of a white 384-well plate (Corning 3572) in a volume of 6.25 pL, together with 12.5 pL diluted membranes containing the Nluc-IL23R fusion protein (0.42 pg / well) and 6.25 pL fluorescently labelled peptide to a final at a concentration of 3.1 nM, also prepared in Assay buffer. The plate was sealed with light impermeable plate seals, and incubated on an orbital shaker 400 rpm for 2 hours at room temperature. To determine the BRET ratio, the plate seal was removed and 25 pL of the Nanoluc substrate (Promega N1572) diluted 1 :500 was added to each well and incubated for 1 -2 minutes on an orbital shaker at 400 rpm. Then plate was read on an Envision plate reader equipped with a luminescence mirror module (barcode 404) using filters corresponding to Nanoluc substrate luminescence (M470 filter; 470 nm, bandwidth 24 nm) and TAMRA fluorescence (M595p filter 595 nm, bandwidth 60 nm). The BRET ratio was calculated as the fluorescence from the TAMRA / nanoluc bioluminescence.

[0487] For data analysis BRET ratios were normalized relative to the BRET signal by 3.1 nM TAMRA-labelled peptide alone (no unlabelled compound added) and the BRET signal under complete displacement (by adding a very high concentration of unlabelled peptide).

[0488] Compound potency (IC50) and maximal displacement (% displacement) were estimated by computer-aided curve fitting using a 4-parameter logistic (4PL) non-linear model. The IC50 and maximal for each compound was determined by computer-aided curve fitting using a 4- parameter logistic (4PL) non-linear model. Data for the compound potency (IC50) and maximal displacement (% displacement) are shown in Table 2-1. Typically compounds with low IC50 are desired. Typically compounds with a high degree of displacement of the TAMRA-labelled peptide are desired. Due to experimental errors in the particular assay, values equal to or above 90% are typically considered as capable of completely the TAMRA- labelled peptide.

[0489] In WO 2023 / 099669 the data were provided as calculated Ki values. In this application, the inventors provide the data as IC50 values. The Cheng-Prussov equation describes the relationship between the Ki and the IC50 as: K = IC501 (1 +[Li_] / Kdi_), where [LL] is the concentration of labelled compound used and Kdi_ is the equilibrium dissociation constant for the labelled compound (Cheng and Prusoff, 1973).

[0490] Table 2-1: IC50 (hlL-23R binding) and % displacement (hlL-23R binding) data

[0491] Example 2-2: Functional inhibition of IL-23 mediated STAT3 signalling by compounds

[0492] The ability of compounds to inhibit IL-23 mediated signalling was determined in the human- derived DB cell line (CRL-2289) (hereafter referred to as DB cells), which endogenously expresses the human IL-23R and human IL-12R p1 subunits. Upon binding of IL-23, the IL- 23R forms a heterodimer signalling complex together with IL-12R p1 , which through the JAK2 / STAT3 pathway promotes phosphorylation of STAT3 to form phospho-STAT3. In the assay, the functional antagonism of IL-23 mediated phospho-STAT3 formation in DB cells by the compound is quantified using reagents capable of measuring the phosphorylation state of Tyr705 of STAT3 in the form of a phospho-STAT3 (Tyr705) MSD (Meso Scale Discovery) kit.

[0493] The assay was used to quantify the functional antagonism of a compound and to rank order the inhibitor compounds according to their potency. For compounds tested in this assay, the response was normalized relative to control values to calculate the IC50 and maximal inhibitory response from a concentration response curve of the compound in presence of a fixed concentration of human IL-23.

[0494] The assay procedure was as follows. DB cells were maintained in growth medium consisting of RPMI-1640 [Invitrogen 61870-010] supplemented with 10% V / V Foetal Bovine Serum (FBS) [(heat inactivated), Invitrogen 10270-106], and 1% V / V Penicillin-Streptomycin (Pen- Strep) Solution [Invitrogen 15140], On the day of assay, cells were resuspended in Assay buffer consisting of RPMI-1640 [Invitrogen 61870-010] supplemented with 0.1 % w / V BSA [Sigma-Aldrich A9430] to a density of 7.5x106cells / mL. Compounds to be tested for inhibition of hlL-23 mediated signalling were serially diluted in Assay buffer to 3X the final concentration. A solution of h IL-23 corresponding to 3X the ECso of h IL-23 (1 .7 nM) was also prepared in Assay buffer. To initiate the assay, 20 pL of DB cell suspension (corresponding to 150.000 cells / well) was added to the wells of a 96-well V-bottom Polypropylene plate [Corning 3363] followed by addition of 3X 20 pL of the diluted test compounds to separate wells. Following preincubation of the DB cells with inhibitor for 15 min in a cell incubator (37 °C, 5% CO2), 20 pL of the prepared 3X the ECso of h IL-23 solution was added to each well and incubated for 90 min in a cell incubator (37 °C, 5% CO2). For some wells buffer only or IL-23 only corresponding to the ECso was added to obtain readouts needed for normalization. To terminate the assay, the plate was spun at 1000 G for 5 min to pellet cells, the supernatant removed using an 8-channel manual pipette, and then added 50 pL / well Complete Lysis Buffer from the MSD STAT3 kit (Cat# K150SVD, Mesoscale) to the cell pellet. To completely lyse cells to release phospho-STAT3 for detection, the plate was shaken for 10 min at room temperature (500 rpm) sealed with aluminium foil and placed at -80 °C for a minimum of 15 min. Detection of the phospho- STAT3 level in the cell lysate from the individual wells was determined using the MSD STAT3 kit (Cat# K150SVD, Mesoscale) and read on a Meso QuickPlex SQ 120 plate reader (Mesoscale).

[0495] For data analysis raw data counts from the Meso QuickPlex SQ 120 plate reader were normalized relative to the response by the ECso of hlL-23 alone (no compound added) and the buffer level. Compound potency (IC50) and maximal inhibitory response (% inhibition) were estimated by computer-aided curve fitting using a 4-parameter logistic (4PL) non-linear model. Data for the compound potency (IC50) and maximal inhibitory response (% displacement) are shown in Table 2-2. The lower the IC50 value, the more potent the compound. Typically compounds with a low IC50 are desired. Typically compounds capable of completely inhibiting the IL23-induced response are desired. Due to experimental errors in the particular assay, values equal to or above 95% are typically considered as capable of completely inhibiting IL23R-induced signalling.

[0496] Table 2-2: hlL-23 (pSTAT3) antagonist IC50 and % inhibition data

[0497] Example 2-3: Determination of peptide stability in simulated intestinal fluid (SIF)

[0498] SIF buffer used in the study contained 3 mM sodium taurocholate, 0.75 mM lecithin, 8.7 mM NaOH, 28.7 mM NaH2PC>4 • H2O, 106 mM NaCI and 1 % pancreatin in MilliQ water adjusted to pH to 6.8 with NaOH.

[0499] To initiate the incubations, 5 pL of peptide stock solution (300 pM) in 50 % v / v isopropanol was deposited at the bottom of a well plate and 145 pL FaSSIF buffer was added to give a final substrate concentration of 10 pM. The incubation was performed at 37 °C with gentle shaking. 70 pL aliquots were removed at 0, 0.5, 1 , 4 and 6 hours and quenched into 210 pL ice-cold precipitant solution (95 % v / v acetonitrile with 0.1 % v / v formic acid). After the last timepoint, the sampling plate was mixed for 10 min on a shaking table and centrifuged 10 min at 2200 g. 70 pL resulting supernatant was diluted with 150 pL water, mixed and centrifugated before analysis by liquid chromatography high resolution mass spectrometry. The zero sample was reinjected after the 6-hour sample to confirm that no drift in instrument sensitivity had occurred during the run. Percent remaining at each timepoint was calculated relative to timepoint zero based on absolute peak areas.

[0500] The in vitro SIF results (expressed as % peptide remaining after the specified time period) are summarized in Table 2-3 below. SIF stability values above 100% are due to assay uncertainty and indicate the compound has not degraded. Table 2-3: SIF data CLAUSES

[0501] 1 . A compound of the formula (I) or a pharmaceutically acceptable salt thereof:

[0502] X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X13-X14-R2(I) wherein

[0503] R2is NR3R4wherein R3and R4are each independently selected from hydrogen, C- alkyl optionally substituted with a pyridyl group or -C(0)NR’R’ (where R and R’ are independently H or C1-4 alkyl); C3-10 cycloalkyl; a saturated 5 or 6-membered heterocyclic ring having 1 or 2 heteroatoms selected from N, O and S, the ring being optionally substituted;

[0504] X2 is absent or selected from the group consisting of 4-aminomethyl-phenylacetyl, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, 3-aminopropanoyl, Lys, Dpr, Dab, Orn, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo- analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0505] X3 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, any amino acid, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0506] X4 is absent or selected from the group consisting of Glu, Asp, Lys, Dab, Orn, Dpr, Cys, Vai, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0507] X5 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0508] X6 is selected from the group consisting of an optionally substituted Lys residue or iso-Lys residue, an optionally substituted Ala residue, Gin, iso-GIn, Gln(Me), Gln(2Me), Gin (pyrrolidin), Dab(Ac), Glu, iso-Glu, Tyr, Cys, Vai, His, Ala, Dab(optionally substituted with C2-6 alkanoyl), iso-Dab, Cit, Arg, Orn(optionally substituted with C2-6 alkanoyl), Asn, a D- isomeric form of any thereof, a beta analogue of either thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof;

[0509] X7 is selected from the group consisting of Ala, Aib, Phe, Dab, iso-Dab, Cys, Glu, iso-Glu, Asp, iso-Asp, Pra, Lys, Orn, Dpr, Hpg, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0510] X8 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an alanine residue substituted by an optionally substituted carbocyclic group or an optionally substituted aryl or heteroaryl group, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0511] X9 is selected from the group consisting of an optionally substituted phenylalanine residue, an optionally substituted tyrosine residue, an optionally substituted azatryptophan residue, an optionally substituted tryptophan residue, an alanine residue substituted by an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo- analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0512] X10 is selected from the group consisting of 4-Aminotetrahydro-2H-pyran-4-carbonyl, Aib, Leu, Ala, 2-Me-Leu, 2-Me-Lys, Trp, Asn, iso-Asn, Cys, Vai, Ala, He, 2-Me-Val, Dab, iso-Dab, Gly, Lys, iso-Lys, a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0513] X11 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; X12 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the lipid and amino acid, 3-aminotetrahydrofuran-3-carbonyl, Ser(OMe), Arg, 2-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, iso-Glu, Asn, iso- Asn, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, [2-(trimethyl-2-aminoethoxy)ethoxy]propyl, 3- aminopropanoyl, GABA, Dab, iso-Dab, Gly-CF3, Nle, Gin, iso-GIn, THP, 2-Me-Ser, His, His(1-Me), 3-(3-Quinolinyl)-Ala, Pro, 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)- imidazolidin-2-carbonyl, 4-aminotetrahydropyran-4-carbonyl, 3-aminotetrahydrofuran-4- carbonyl, or Lys wherein the side chain -NH2 of the Lys is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0514] X13 is selected from the group consisting of 3-(3-Pyridyl)-Ala, D-3-(3-Pyridyl)-Ala, 3-(3,5- Pyrimidyl)-Ala, Asn, Gly, 3-(4-Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, {d}[3-(3-Pyridyl)-Ala], 3- amino-3-(3'-pyridyl)propionyl, Phe, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3- diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3- diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), 2-Me-3-(3- Pyridyl)-Ala, N-Me-3-(3-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, 3-(5-F-3-Pyridyl)-Ala, His, His(Me), a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;

[0515] X14 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, Sar, His, Leu, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; wherein either: a) X2 is a residue that forms a bridge with a residue at X7 and a bridge with a residue at X11 , such that the compound of formula I is a compound of formula la b) X2 is a residue that forms a bridge with a residue at X11 and X4 is a residue that forms a bridge with a residue at X7, such that the compound of formula I is a compound of formula lb or c) X2 to X4 are absent and X5 is a residue that forms a bridge with a residue at X11 via linker L, such that the compound of formula I is a compound of formula Ic wherein L optionally comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid; wherein the compound of formula I comprises a lipophilic substituent.

[0516] 2. A compound according to clause 1 , wherein when the compound of formula (I) is a compound of formula (la), the bridge between the residue at X2 and the residue X11 is a lactam bridge.

[0517] 3. A compound according to clause 1 or 2, wherein when the compound of formula (I) is a compound of formula (la), the bridge between the residue at X2 and the residue X7 is a lactam bridge.

[0518] 4. A compound according to clause 1 , wherein when the compound of formula (I) is a compound of formula (lb), the bridge between the residue at X2 and the residue at X11 is a lactam bridge.

[0519] 5. A compound according to clause 1 or 4, wherein when the compound of formula (I) is a compound of formula (lb), the bridge between the residue at X4 and the residue at X7 is a lactam bridge.

[0520] 6. A compound according to clause 1 , wherein when the compound of formula (I) is a compound of formula (Ic), L includes an amide moiety, such as a lactam moiety. 7. A compound according to clause 1 , wherein when the compound of formula (I) is a compound of formula (Ic), L includes a triazole ring.

[0521] 8. A compound according to clause 1 , wherein when the compound of formula (I) is a compound of formula (Ic), L includes a thioether moiety.

[0522] 9. A compound according to clause 1 or 6 to 8, wherein L forms a 13 to 17 atom bridge between the residue-bearing carbons on X5 and X11 .

[0523] 10. A compound according to clause 9, wherein L forms a 14 to 16 atom bridge between the residue-bearing carbons on X5 and X11 .

[0524] 11. A compound according to clause 10, wherein L forms a 15 atom bridge between the residue-bearing carbons on X5 and X11 .

[0525] 12. A compound according to clause 1 or 6 to 8, wherein L forms a 8 to 12 atom bridge between the residue-bearing carbons on X5 and X11 .

[0526] 13. A compound according to clause 12, wherein L forms a 9 to 11 atom bridge between the residue-bearing carbons on X5 and X11 .

[0527] 14. A compound according to clause 13, wherein L forms a 10 atom bridge between the residue-bearing carbons on X5 and X11 .

[0528] 15. A compound according to clause 1 , 6 or 9 to 14, wherein when the compound of formula (I) is a compound of formula (Ic), L comprises a moiety (L1):

[0529] *-NR-Y1-(C=O)-** (L1) wherein:

[0530] -* is a moiety on the amino acid residue X11 capable of bonding to an amino group;

[0531] -** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group;

[0532] Y1 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3- io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene-(C5-i4)arylene; (C1-6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C-i.6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; [(C2-3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted; and R is H or C1-6 alkyl.

[0533] 16. A compound according to clause 15, wherein Y1 is (C2-i4)alkylene.

[0534] 17. A compound according to clause 16, wherein Y1 is (C3-9)alkylene.

[0535] 18. A compound according to clause 17, wherein Y1 is (C7-9)alkylene.

[0536] 19. A compound according to clause 1 , 6 or 9 to 14, wherein when the compound of formula (I) is a compound of formula (Ic), L comprises a moiety (L2):

[0537] *-NR-Y2-C(=O)-NR-Y3-C(=O)-** (L2) wherein:

[0538] -* is a moiety on the amino acid residue X11 capable of bonding to an amino group;

[0539] -** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group;

[0540] Y2 and Y3 are independently selected from the group consisting of (Ci-2o)alkylene; (C2- 2o)alkenylene; (C3-io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene--(C5- i4)arylene; (Ci-6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci.

[0541] 6)alkylene; (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; (Ci-6)alkylene-heteroarylene-(Ci. 6)alkylene [(C2-3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted; and each R is independently H or C1-6 alkyl.

[0542] 20. A compound according to clause 19, wherein Y2 is selected from the group consisting of (Ci-2o)alkylene, (Ci-6)alkylene-(C5-i4)arylene-, (Ci-6)alkylene-(C5-i4)arylene-(Ci. 6)alkylene and (Ci-6)alkylene-heteroarylene-(Ci-6)alkylene, the arylene moiety optionally substituted with a halogen atom.

[0543] 21 . A compound according to clause 20, wherein Y2 is selected from the group consisting of (Ci-8)alkylene, -CH2-phenylene-, CH2-phenylene-CH2- and CH2-pyridylene-CH2- , wherein the phenylene moiety is optionally substituted with a halogen atom.

[0544] 22. A compound according to clause 21 , wherein Y2 is selected from the group consisting of (C5-7)alkylene, CH2-phenylene-CH2- and CH2-pyridylene-CH2- wherein the phenylene moiety is optionally substituted with a fluorine atom. 23. A compound according to clause 22, wherein Y2 is (C5-7)alkylene.

[0545] 24. A compound according to clause 19 to 23, wherein Y3 is selected from the group consisting of (Ci-2o)alkylene and (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene.

[0546] 25. A compound according to clause 24, wherein Y3 is selected from the group consisting of (Ci.i4)alkylene and methylene-phenylene-methylene.

[0547] 26. A compound according to clause 25, wherein Y3 is selected from the group consisting of (Ci-9)alkylene.

[0548] 27. A compound according to clause 26, wherein Y3 is selected from the group consisting of (C2-5)alkylene.

[0549] 28. A compound according to clause 1 , 6 or 9 to 14, wherein when the compound of formula (I) is a compound of formula (Ic), L comprises a moiety (L3):

[0550] Lipid-spacer- wherein:

[0551] -* is a moiety on the amino acid residue X11 capable of bonding to a moiety on the Y5 residue;

[0552] -** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group; the spacer is absent or present;

[0553] Y4 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3- io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene--(C5-i4)arylene; (C-i. 6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C1-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; (Ci-6)alkylene-heteroarylene-(Ci-6)alkylene [(C2- 3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted; Y5 is an amino acid residue comprising a side chain capable of forming a bridge with the residue at X11 ;

[0554] R is independently H or C1-6 alkyl.

[0555] 29. A compound according to clause 28, wherein Y4 is selected from the group consisting of (Ci-2o)alkylene and (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene. 30. A compound according to clause 29, wherein Y4 is selected from the group consisting of (Ci.g)alkylene.

[0556] 31 . A compound according to clause 30, wherein Y4 is selected from the group consisting of (C2-5)alkylene.

[0557] 32. A compound according to clause 28 to 31 , wherein Y5 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo- analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0558] 33. A compound according to clause 32, wherein Y5 is Lys.

[0559] 34. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (la), X3 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0560] 35. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (la), X8 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0561] 36. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (la), X12 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0562] 37. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (la), X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0563] 38. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (lb), X3 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0564] 39. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (lb), X8 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid. 40. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (lb), X12 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0565] 41 . The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (lb), X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0566] 42. The compound of any of clauses 1 to 27, wherein when the compound of formula I is a compound of formula (Ic), X8 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0567] 43. The compound of any of clauses 1 to 27, wherein when the compound of formula I is a compound of formula (Ic), X12 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0568] 44. The compound of any of clauses 1 to 27, wherein when the compound of formula I is a compound of formula (Ic), X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

[0569] 45. The compound of any of clauses 1 to 33, wherein when the compound of formula I is a compound of formula (Ic), L comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid.

[0570] 46. The compound of any preceding clause, wherein the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is selected from the group consisting of Lys, Dab, Phe(4NH), AEF, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

[0571] 47. The compound of clause 46, wherein the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is selected from the group consisting of Lys, Dab, Phe(4NH), AEF.

[0572] 48. The compound of any preceding clause, wherein the lipid of linker L or the lipid of the lipidated amino acid residue is of the formula Z1-, wherein

[0573] Z1- is CH3-(CH2)IO-22-(CO)-, HOOC-(CH2)IO-22-(CO)-, tetrazolyl-(CH2)i0-22-(CO)-. 49. The compound of clause 48, wherein the lipid of linker L or the lipid of the lipidated amino acid residue is of the formula Z1-, wherein

[0574] Z1- is CH3-(CH2)IO-22-(CO)- or HOOC-(CH2)IO-22-(CO)-.

[0575] 50. The compound of clause 49, wherein Z1- is CH3-(CH2)IO-22-(CO)-.

[0576] 51 . The compound of clause 50, wherein Z1- is CH3-(CH2)i2-i9-(CO)-.

[0577] 52. The compound of clause 51 , wherein Z1- is CH3-(CH2)i3-is-(CO)-.

[0578] 53. The compound of clause 49, wherein Z1- is HOOC-(CH2)IO-22-(CO)-.

[0579] 54. The compound of clause 53, wherein Z1- is HOOC-(CH2)i2-i9-(CO)-.

[0580] 55. The compound of clause 54, wherein Z1- is HOOC-(CH2)i3-is-(CO)-.

[0581] 56. The compound of clause 48, wherein Z1- is tetrazolyl-(CH2)io-22-(CO)-.

[0582] 57. The compound of clause 56, wherein Z1- is tetrazolyl-(CH2)i2-i9-(CO)-.

[0583] 58. The compound of clause 57, wherein Z1- is tetrazolyl-(CH2)i3-is-(CO)-.

[0584] 59. The compound of any preceding clause, wherein the spacer is of the formula -Z2-, wherein

[0585] -Z2- is selected from -ZS1-, -ZS1-ZS2-, -ZS2-ZS1-, -ZS2-, -ZS3-, -ZS1ZS3-, -ZS2ZS3-, -ZS3ZS2-, - 2S12S2ZS3- -ZS2ZS1ZS3- -ZS2ZS3ZS1- -ZS3ZS1ZS2- -ZS3ZS2ZS1- or -ZS2ZS3ZS2- wherein ZS1is (isoGlu)i-3, p-Ala, isoLys, 4-aminobutanoyl or (Piperazine-l-yl)-acetyl;

[0586] ZS2is -(Peg)n- where n is an integer from 1 to 15, or (8-Amino-3,6-dioxaoctanoyl)i-3; and -ZS3- is a peptide sequence of 1 -6 amino acid units independently selected from the group consisting of A, L, S, T, Y, Q, D, E, K, k, R, H, F and G.

[0587] 60. The compound of clause 59, wherein -Z2- is selected from -ZS1-, -ZS1-ZS2-, -ZS2-ZS1-, -ZS2-, wherein

[0588] ZS1is (isoGlu)i-3, p-Ala, isoLys, 4-aminobutanoyl or (Piperazine-l-yl)-acetyl;

[0589] ZS2is -(Peg)n- where n is an integer from 1 to 15, or (8-Amino-3,6-dioxaoctanoyl)i-3.

[0590] 61. The compound of any one of clauses 60, wherein -Z2- is -ZS1. 62. The compound of clause 61 , wherein -ZS1is (isoGlu)i-3, or (Piperazine-l-yl)-acetyl.

[0591] 63. The compound of clause 62, wherein-Zs1is (isoGlu).

[0592] 64. The compound of clause 62, wherein -ZS1is (isoGlu)2.

[0593] 65. The compound of clause 62, wherein -ZS1is (Piperazine-l-yl)-acetyl.

[0594] 66. The compound of any of clauses 60, wherein -Z2- is -ZS1-ZS2- or -ZS2-ZS1-.

[0595] 67. The compound of clause 66, wherein ZS1is (isoGlu)i-3 and ZS2is -(Peg)n- where n is an integer from 1 to 15.

[0596] 68. The compound of clause 67, wherein ZS1is (isoGlu)i-3 and ZS2is -(Peg)n- where n is 1 , 2, or 3.

[0597] 69. The compound of clause 68, wherein ZS1is (isoGlu) and ZS2is -(Peg)n- where n is 1 , 2, or 3.

[0598] 70. The compound of clause 66, wherein ZS1is (isoGlu)i-3 and ZS2is 8-Amino-3,6- dioxaoctanoyl)i-3.

[0599] 71 . The compound of clause 70, wherein ZS1is (isoGlu) or (isoGlu)2 and ZS2is (8-Amino- 3,6-dioxaoctanoyl)2.

[0600] 72. The compounds of any preceding clause, wherein when the compound of formula (I) is a compound of formula (la) or (lb), X2 is selected from the group consisting of Lys and 4- aminomethyl-phenylacetyl.

[0601] 73. The compounds of any preceding clause, wherein when the compound of formula (I) is a compound of formula (la) or (lb), X3 is selected from the group consisting of He, Ser and a lipidated amino acid residue.

[0602] 74. The compounds of clause 73, wherein the amino acid of the lipidated amino acid residue is Lys or d-Lys. 75. The compounds of any preceding clause, wherein when the compound of formula (I) is a compound of formula (la) or (lb), X4 is Vai or Glu.

[0603] 76. The compound of any preceding clause, wherein X5 is Trp.

[0604] 77. The compound of any preceding clause, wherein X6 is Gin.

[0605] 78. The compound of any preceding clause, wherein X7 is selected from the group consisting of Glu, Dab and Ala.

[0606] 79. The compound of any preceding clause, wherein X8 is Y(2-aminoethoxy), F(4-THP) or a lipidated amino acid residue.

[0607] 80. The compound of clause 79, wherein the amino acid of the lipidated amino acid residue is Phe-4NH or AEF.

[0608] 81 . The compound of any preceding clause, wherein X9 is 2Nal.

[0609] 82. The compound of any preceding clause, wherein X10 is selected from the group consisting of 4-Aminotetrahydro-2H-pyran-4-carbonyl, 2-Me-Leu or Aib.

[0610] 83. The compound of any preceding clause, wherein X11 is Glu.

[0611] 84. The compound of any preceding clause, wherein X12 is Dab or a lipidated amino acid residue.

[0612] 85. The compound of clause 84, wherein the amino acid of the lipidated amino acid residue is Lys or Dab.

[0613] 86. The compound of any preceding clause, wherein X13 is 3-(3-Pyridyl)-alanyl.

[0614] 87. The compound of any preceding clause, wherein X14 is absent or a lipidated amino acid residue.

[0615] 88. The compound of clause 87, wherein the amino acid of the lipidated amino acid residue is Lys. 89. A compound according to any preceding clause, wherein R2is NR3R4wherein R3and R4are each independently H, C- alkyl optionally substituted with pyridyl, or tetrahydropyranyl.

[0616] 90. A compound according to clause 89, wherein R2is NR3R4wherein R3and R4are each independently H, methyl or (pyridin-3-yl)ethyl.

[0617] 91 . A compound according to clause 90, wherein R2is NHMe.

[0618] 92. A compound according to any preceding clause, selected from the group consisting of:

[0619]

[0620] 93. A pharmaceutical composition comprising a compound of any one of clauses 1 to 92, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0621] 94. A compound of any one of clauses 1 to 92, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to clause 93, for use as a medicament.

[0622] 95. A compound of any one of clauses 1 to 92, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to clause 93, for use in a method of prevention or treatment of a disease or condition selected from the group consisting of inflammatory bowel disease (IBD) such as Crohn’s Disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof.

[0623] 96. Use of a compound of any one of clauses 1 to 92, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to clause 93, in the manufacture of a medicament for prevention or treatment of a disease or condition selected from the group consisting of inflammatory bowel disease (IBD) such as Crohn’s Disease and ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof.

[0624] 97. A method of prevention or treatment of a disease or condition selected from the group consisting of inflammatory bowel disease (IBD) such as Crohn’s Disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof; which method comprises administering to the subject an effective amount of the compound of any one of clauses 1 to 92, or the pharmaceutical composition according to clause 93.

[0625] 98. A method for the synthesis of a compound according to any one of clauses 1 to 92, comprising synthesising the analogue by solid-phase or liquid-phase peptide synthesis methodology, optionally isolating and / or purifying the final product, and optionally further comprising the step of forming a bond between either a) the amino acid residue at the X2 position and the amino acid residues at the X7 and X11 positions or b) the amino acid residue at the X2 position and the amino acid at the X11 position, and the amino acid residue at the X4 position and the amino acid residue at the X7 position or c) the amino acid residue at the X5 position and the amino acid residue at the X11 position.

Claims

CLAIMS1 . A compound of the formula (I) or a pharmaceutically acceptable salt thereof:X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X13-X14-R2(I) whereinR2is NR3R4wherein R3and R4are each independently selected from hydrogen, C- alkyl optionally substituted with a pyridyl group or -C(0)NR’R’ (where R and R’ are independently H or C1-4 alkyl); C3-10 cycloalkyl; a saturated 5 or 6-membered heterocyclic ring having 1 or 2 heteroatoms selected from N, O and S, the ring being optionally substituted;X2 is absent or selected from the group consisting of 4-aminomethyl-phenylacetyl, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, 3-aminopropanoyl, Lys, Dpr, Dab, Orn, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo- analogue of any thereof, and / or an N-methyl analogue of any thereof;X3 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, any amino acid, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X4 is absent or selected from the group consisting of Glu, Asp, Lys, Dab, Orn, Dpr, Cys, Vai, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X5 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X6 is selected from the group consisting of an optionally substituted Lys residue or iso-Lys residue, an optionally substituted Ala residue, Gin, iso-GIn, Gln(Me), Gln(2Me), Gin (pyrrolidin), Dab(Ac), Glu, iso-Glu, Tyr, Cys, Vai, His, Ala, Dab(optionally substituted withC2-6 alkanoyl), iso-Dab, Cit, Arg, Orn(optionally substituted with C2-6 alkanoyl), Asn, a D- isomeric form of any thereof, a beta analogue of either thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof;X7 is selected from the group consisting of Ala, Aib, Phe, Dab, iso-Dab, Cys, Glu, iso-Glu, Asp, iso-Asp, Pra, Lys, Orn, Dpr, Hpg, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X8 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an alanine residue substituted by an optionally substituted carbocyclic group or an optionally substituted aryl or heteroaryl group, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X9 is selected from the group consisting of an optionally substituted phenylalanine residue, an optionally substituted tyrosine residue, an optionally substituted azatryptophan residue, an optionally substituted tryptophan residue, an alanine residue substituted by an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo- analogue of any thereof, and / or an N-methyl analogue of any thereof;X10 is selected from the group consisting of 4-Aminotetrahydro-2H-pyran-4-carbonyl, Aib, Leu, Ala, 2-Me-Leu, 2-Me-Lys, Trp, Asn, iso-Asn, Cys, Vai, Ala, He, 2-Me-Val, Dab, iso-Dab, Gly, Lys, iso-Lys, a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X11 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X12 is selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the lipid and amino acid, 3-aminotetrahydrofuran-3-carbonyl, Ser(OMe), Arg, 2-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, iso-Glu, Asn, iso- Asn, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, [2-(trimethyl-2-aminoethoxy)ethoxy]propyl, 3- aminopropanoyl, GABA, Dab, iso-Dab, Gly-CF3, Nle, Gin, iso-GIn, THP, 2-Me-Ser, His, His(1-Me), 3-(3-Quinolinyl)-Ala, Pro, 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)- imidazolidin-2-carbonyl, 4-aminotetrahydropyran-4-carbonyl, 3-aminotetrahydrofuran-4- carbonyl, or Lys wherein the side chain -NH2 of the Lys is substituted with -C(=O)(CH2)nRKwherein n is 0-2 and RKis imidazolyl, pyrimidyl, or pyridyl optionally substituted with F, a D- isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X13 is selected from the group consisting of 3-(3-Pyridyl)-Ala, D-3-(3-Pyridyl)-Ala, 3-(3,5- Pyrimidyl)-Ala, Asn, Gly, 3-(4-Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, {d}[3-(3-Pyridyl)-Ala], 3- amino-3-(3'-pyridyl)propionyl, Phe, 3-F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3- diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3- diaminopropanoyl(3-fluorobenzoyl), 2,3-diaminopropanoyl(3-fluorophenylacetyl), 2-Me-3-(3- Pyridyl)-Ala, N-Me-3-(3-Pyridyl)-Ala, 3-(3,5-Pyrimidyl)-Ala, 3-(5-F-3-Pyridyl)-Ala, His, His(Me), a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof;X14 is absent or selected from the group consisting of a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, Sar, His, Leu, an alanine residue substituted by a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, a D-isomeric form of any thereof, a beta analogue of any thereof, a homoanalogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof; wherein either: d) X2 is a residue that forms a bridge with a residue at X7 and a bridge with a residue at X11 , such that the compound of formula I is a compound of formula laor e) X2 is a residue that forms a bridge with a residue at X11 and X4 is a residue that forms a bridge with a residue at X7, such that the compound of formula I is a compound of formula lbor f) X2 to X4 are absent and X5 is a residue that forms a bridge with a residue at X11 via linker L, such that the compound of formula I is a compound of formula Icwherein L optionally comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid; wherein the compound of formula I comprises a lipid or lipidated amino acid residue.

2. A compound according to claim 1 , wherein when the compound of formula (I) is a compound of formula (la), the bridges between the residue at X2 and the residues at X7 and X11 are lactam bridges, and wherein when the compound of formula (I) is a compound of formula (lb), the bridge between the residue at X2 and the residue at X11 and the bridge between the residue at X4 and the residue at X7 are lactam bridges3. A compound according to claim 1 , wherein when the compound of formula (I) is a compound of formula (Ic), L includes an amide moiety, a triazole ring, or a thioether moiety, preferably an amide moiety, such as a lactam moiety.

4. A compound according to claim 3, wherein when the compound of formula (I) is a compound of formula (Ic), either: L forms a 13 to 17, such as 14 to 16, such as 15 atom bridge between the residuebearing carbons on X5 and X11 ; or L forms a 8 to 12, such as 9 to 11 , such as 10 atom bridge between the residue-bearing carbons on X5 and X11 .

5. The compound of any one of claims 1 , 3, or 4, wherein eitherL comprises a moiety (L1):*-NR-Y1-(C=O)-** (L1) wherein:-* is a moiety on the amino acid residue X11 capable of bonding to an amino group;-** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group;Y1 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3- io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene-(C5-i4)arylene; (C-i. 6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C-i. 6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; [(C2-3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted; and R is H or C1-6 alkyl; preferably wherein Y1 is (C2-i4)alkylene, more preferably (C3-9)alkylene, even more preferably (C?-9)alkylene; orL comprises a moiety (L2):*-NR-Y2-C(=O)-NR-Y3-C(=O)-** (L2) wherein:-* is a moiety on the amino acid residue X11 capable of bonding to an amino group;-** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group;Y2 and Y3 are independently selected from the group consisting of (Ci-2o)alkylene; (C2- 2o)alkenylene; (C3-io)cycloalkylene; (C3-io)cycloalkenylene; (Cs-i4)arylene; (Ci-e)alkylene--(C5- i4)arylene; (Ci-6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci. 6)alkylene; (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; (Ci-6)alkylene-heteroarylene-(Ci. 6)alkylene [(C2-3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted; and each R is independently H or C1-6 alkyl; preferably wherein Y2 is selected from the group consisting of (Ci-2o)alkylene, (C-i. 6)alkylene-(C5-i4)arylene-, (Ci-6)alkylene-(C5-i4)arylene-(Ci-6)alkylene and (Ci-e)alkylene- heteroarylene-(Ci-6)alkylene, the arylene moiety optionally substituted with a halogen atom; more preferably wherein Y2 is selected from the group consisting of (Ci-8)alkylene, -CH2- phenylene-, CH2-phenylene-CH2- and CH2-pyridylene-CH2-, wherein the phenylene moiety isoptionally substituted with a halogen atom; even more preferably wherein Y2 is selected from the group consisting of (C5-7)alkylene, CH2-phenylene-CH2- and CH2-pyridylene-CH2- wherein the phenylene moiety is optionally substituted with a fluorine atom; and / or. preferably wherein Y3 is selected from the group consisting of (Ci-2o)alkylene and (C-i.6)alkylene-(C5-i4)arylene-(Ci-6)alkylene, more preferably wherein Y3 is selected from the group consisting of (Ci-i4)alkylene and methylene-phenylene-methylene; even more preferably wherein Y3 is selected from the group consisting of (Ci.g)alkylene; orL comprises a moiety (L3):Lipid-spacer-wherein:-* is a moiety on the amino acid residue X11 capable of bonding to a moiety on the Y5 residue;-** is a moiety on the amino acid residue X5 capable of bonding to a carbonyl group; the spacer is absent or present;Y4 is selected from the group consisting of (Ci-2o)alkylene; (C2-2o)alkenylene; (C3- io)cycloalkylene; (C3-io)cycloalkenylene; (C5-i4)arylene; (Ci-6)alkylene--(C5-i4)arylene; (C-i.6)alkylene-C(3-8)cycloalkylene; (Ci-6)alkylene-C(3-8)cycloalkylene-(Ci-6)alkylene; (C-i.6)alkylene-(C5-i4)arylene-(Ci-6)alkylene; (Ci-6)alkylene-heteroarylene-(Ci-6)alkylene [(C2- 3)alkyleneoxy]nwherein n is 1 to 10, or any combination thereof, each optionally substituted; Y5 is an amino acid residue comprising a side chain capable of forming a bridge with the residue at X11 ;R is independently H or C1-6 alkyl; preferably wherein Y4 is selected from the group consisting of (Ci-2o)alkylene and (C-i.6)alkylene-(C5-i4)arylene-(Ci-6)alkylene, more preferably wherein Y4 is selected from the group consisting of (Ci.g)alkylene; preferably wherein Y5 is selected from the group consisting of Dpr, Dab, Orn, optionally substituted Lys, Asp, Glu, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof, more preferably wherein Y5 is Lys.

6. The compound of claim 1 or 2, wherein when the compound of formula I is a compound of formula (la), one of X3, X8, X12 or X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, preferably wherein X12 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

7. The compound of claim 1 or 2, wherein when the compound of formula I is a compound of formula (lb), one of X3, X8, X12 or X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid, preferably wherein one of X3 or X8 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid.

8. The compound of any one of claims 1 or 3 to 5, wherein when the compound of formula I is a compound of formula (Ic), one of X8, X12, X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid or L comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid, preferably wherein one of X8 or X14 represents a lipidated amino acid residue optionally comprising a spacer between the amino acid and lipid or L comprises a side chain comprising a lipid and optionally a spacer between the linker and lipid.

9. The compound of any one of claims 1 to 8, wherein the amino acid of the lipidated amino acid residue at any one of positions X3, X8, X12 and X14 is selected from the group consisting of Lys, Dab, Phe(4NH), AEF, a D-isomeric form of any thereof, a beta analogue of any thereof, a homo-analogue of any thereof, a beta-homo-analogue of any thereof, and / or an N-methyl analogue of any thereof.

10. The compound of any one of claims 1 to 9, wherein the lipid of linker L or the lipid of the lipidated amino acid residue is of the formula Z1-, whereinZ1- is CH3-(CH2)IO-22-(CO)-, HOOC-(CH2)IO-22-(CO)-, tetrazolyl-(CH2)i0-22-(CO)-, preferably wherein Z1- is CH3-(CH2)I0-22-(CO)- or HOOC-(CH2)I0-22-(CO)-.11 . The compound of any one of claims 1 to 10, wherein the spacer is of the formula - Z2-, wherein-Z2- is selected from -ZS1-, -ZS1-ZS2-, -ZS2-ZS1-, -ZS2-, -ZS3-, -ZS1ZS3-, -ZS2ZS3-, -ZS3ZS2-, - 2S12S2ZS3- -ZS2ZS1ZS3- -ZS2ZS3ZS1- -ZS3ZS1ZS2- -ZS3ZS2ZS1- or -ZS2ZS3ZS2- wherein ZS1is (isoGlu)i.3, p-Ala, isoLys, 4-aminobutanoyl or (Piperazine-l-yl)-acetyl;ZS2is -(Peg)n- where n is an integer from 1 to 15, or (8-Amino-3,6-dioxaoctanoyl)i.3; and-ZS3- is a peptide sequence of 1-6 amino acid units independently selected from the group consisting of A, L, S, T, Y, Q, D, E, K, k, R, H, F and G.

12. The compounds of any one of claims 1 to 11 , wherein when the compound of formula (I) is a compound of formula (la) or (lb), X2 is selected from the group consisting of Lys and 4-aminomethyl-phenylacetyl and / or X3 is selected from the group consisting of He, Ser and a lipidated amino acid residue, preferably wherein the amino acid of the lipidated amino acid residue is Lys or d-Lys and / or wherein X4 is Vai or Glu.

13. The compound of any one of claims 1 to 12, wherein X5 is Trp and / or wherein X6 is Gin and / or wherein X7 is selected from the group consisting of Glu, Dab and Ala and / or wherein X8 is Y(2-aminoethoxy), F(4-THP) or a lipidated amino acid residue, preferably wherein the amino acid of the lipidated amino acid residue is Phe-4NH or AEF.

14. The compound of any one of claims 1 to 13, wherein X9 is 2Nal and / or wherein X10 is selected from the group consisting of 4-Aminotetrahydro-2H-pyran-4-carbonyl, 2-Me-Leu or Aib and / or wherein X11 is Glu and / or wherein X12 is Dab or a lipidated amino acid residue, preferably wherein the amino acid of the lipidated amino acid residue is Lys or Dab and / or wherein X13 is 3- (3-Py ridy l)-a la ny I and / or wherein X14 is absent or a lipidated amino acid residue, preferably wherein the amino acid of the lipidated amino acid residue is Lys.

15. A compound according to any one of claims 1 to 14, wherein R2is NR3R4wherein R3and R4are each independently H, C- alkyl optionally substituted with pyridyl, or tetrahydropyranyl; preferably wherein R2is NR3R4wherein R3and R4are each independently H, methyl or (pyridin-3-yl)ethyl; more preferably wherein R2is NHMe.

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