WO2025255635A1 - Cyclic peptidomimetics as mc5r agonists - Google Patents

Cyclic peptidomimetics as mc5r agonists

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Publication number
WO2025255635A1
WO2025255635A1 PCT/AU2025/050638 AU2025050638W WO2025255635A1 WO 2025255635 A1 WO2025255635 A1 WO 2025255635A1 AU 2025050638 W AU2025050638 W AU 2025050638W WO 2025255635 A1 WO2025255635 A1 WO 2025255635A1
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Prior art keywords
group
lysine
hydrogen
alkyl
nhr
Prior art date
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Pending
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PCT/AU2025/050638
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French (fr)
Inventor
Philip Thompson
Michael Cowley
Colin William Pouton
Wenxiao Kay YUE
Rekha Shandre MUGAN
Nicholas BARLOW
Stephanie SIMONDS
Tomris MUSTAFA
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Monash University
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Monash University
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Publication date
Priority claimed from AU2024901821A external-priority patent/AU2024901821A0/en
Application filed by Monash University filed Critical Monash University
Publication of WO2025255635A1 publication Critical patent/WO2025255635A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links

Definitions

  • Cyclic peptidomimetics as MC5R agonists Field of the invention [0001]
  • the present invention relates to compounds that activate the melanocortin-5 receptor (MC5R) and uses thereof in the treatment or prevention of a disease or condition related to MC5R activity.
  • Background of the invention [0002]
  • the melanocortin system plays a pivotal role in energy homeostasis. Defective central and peripheral melanocortin signalling has been shown to cause alteration in insulin sensitivity and action, impairment in glucose tolerance and dysregulation of glucose homeostasis, ultimately contributing to obesity and diabetes (Yeo GSH, et al., Mol Metab. 2021 Jun;48:101206. Epub 2021 Mar 6. PMID: 33684608).
  • Skeletal muscle represents the largest organ in the human body, accounting for around 20% of total glucose disposal in the basal state. In the postprandial state, it is the major site responsible for insulin-stimulated glucose uptake from the circulation, with approximately 80% glucose disposal occurring in skeletal muscle following a meal (Merz KE, Thurmond DC. Compr Physiol.2020 Jul 8; 10(3):785-809. doi: 10.1002/cphy.c190029. PMID: 32940941).
  • MC5R is the predominant subtype expressed in skeletal muscles (Ji LQ, Hong Y, Tao YX. Int J Mol Sci. 2022 Aug 5;23(15):8727.
  • MC5R has an abundant distribution in the body, with expression of MC5R mRNA detected in a number of peripheral sites including skin, skeletal muscle, kidney, liver, exocrine glands, adipose tissues and other tissues. Emerging evidence has implied association of MC5R with multiple metabolic disorders (Xu Y, Guan X, Zhou R, Gong R. Cell Mol Life Sci. 2020 Oct;77(19):3831-3840.
  • MC5R agonists are known in the literature. PG-901 has been studied as an MC5R agonist, but also is an antagonist of MC3R and MC4R (Grieco P, et al., J Med Chem, 45 (24): 5287-94). Bednarek et al. described several potent and highly selective MC5R agonists (Bednarek, M. A., et al., J Med Chem 2007, 50, 2520-6; Bednarek M. A., et al. Chem Biol Drug Des. 2007 May;69(5):350-5.
  • the present invention provides a compound of formula (I) represented by the formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl; R 2 is a side chain of the amino acid alanine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R 2A ; each R 2A is independently selected from the group consisting of ⁇ OH, nitro, halo, C 1-4 alkyl and ⁇ OC 1-4 alkyl; R 3 is selected from the group consisting of C 1-4 alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 3A ; each R 3A is independently selected from the group consisting of halo, C1-4al
  • the present invention provides a compound of formula (I) represented by the formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of hydrogen and methyl; R 6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R 5 and R 6 , together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ⁇ X ⁇ is selected from the group consisting of: ⁇ CH(NHR 7 )CH2C(O)NH(CH2)4CH(R 8 ) ⁇ , ⁇ CH(NHR 7 )(CH2)4NHC(O)CH2CH(R 8 ) ⁇ , ⁇ CH(NHR 7 )(CH2)2C(O)NH(CH2)4
  • the invention provides a compound of formula (I) represented by the formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 1A ; each R 1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R 1B )2; each R 1B is independently selected from the group consisting of hydrogen and C 1- 6 alkyl; R 2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5
  • a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient.
  • Another aspect of the invention provides a method of treating or preventing a disease or condition related to melanocortin 5 receptor (MC5R) activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the invention, or a pharmaceutically acceptable salt thereof.
  • M5R melanocortin 5 receptor
  • the disease or condition related to MC5R activity is selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson-Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies.
  • FIG. 3 illustrates infusion of a metabolically healthy male longtail macaque (yrs) with Cpd 45 at a dose of 0.668mg/kg/hr for 45 minutes did not reduce fasting baseline glucose levels however reduced the peak height and rate of glucose disposal from the circulation following the administration of bolus glucose (600mg/kg) compared to sex- matched control that received saline alone.
  • an agent includes a single agent, as well as two or more agents
  • the composition or “formulation” includes a single composition or formulation, as well as two or more compositions or formulations; and so forth.
  • the term “about,” is understood to refer to a range of numbers that a person of skill in the art would consider equivalent to the recited value in the context of achieving the same function or result.
  • R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 1A ; each R 1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R 1B )2; each R 1B is independently selected from the group consisting of hydrogen and C 1- 6alkyl; R 2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R 2A ; each R 2A is independently selected from the group consisting of ⁇ OH, nitro, halo, C1-4al
  • alkyl used either alone or in compound words, denotes straight chain or branched alkyl. Prefixes such as “C 1 -C 6 " are used to denote the number of carbon atoms within the alkyl group (from 1 to 6 in this case).
  • straight chain and branched alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n- pentyl, hexyl, heptyl, 5-methylheptyl, 5-methylhexyl, octyl, nonyl, decyl, undecyl, dodecyl and docosyl (C 22 ).
  • amino acid is defined as having at least one primary, secondary, tertiary or quaternary amino group, and at least one acid group, wherein the acid group may be a carboxylic, sulfonic, or phosphonic acid, or mixtures thereof.
  • the acid group is a carboxylic acid group.
  • the amino groups may be "alpha”, “beta”, “gamma” ... to “omega” with respect to the acid group(s).
  • the backbone of the "amino acid” may be substituted with one or more groups selected from halogen, hydroxy, guanido, heterocyclic groups.
  • amino acids also includes within its scope glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophane, serine, threonine, cysteine, tyrosine, asparagine, glutamine, asparte, glutamine, lysine, arginine and histidine, taurine, betaine, N-methylalanine etc.
  • L and (D) forms of amino acids are included in the scope of this invention.
  • Reference to an amino acid “side chain” takes its standard meaning in the art.
  • non-naturally occurring amino acids include any compound with both amino and carboxyl functionality, derivatives thereof, or derivatives of a naturally occurring amino acid. These amino acids form part of the peptide chain through bonding via their amino and carboxyl groups. Alternatively, these derivatives may bond with other natural or non-naturally occurring amino acids to form a non-peptidyl linkage.
  • the term “residue” refers to a part of a compound resulting from the removal of one or more atoms.
  • the one or more atoms to be removed may be hydrogen atoms.
  • a person skilled in the art would understand, for example, where a compound comprises a carboxylic acid (-COOH) functional group, the residue that is found in the compound of Formula (I) comprises the carboxylate of the amino acid (i.e.
  • aryl refers to aromatic monocyclic (e.g. phenyl) or polycyclic groups (e.g. tricyclic, bicyclic, e.g., naphthalene, anthryl, phenanthryl). Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g. tetralin, methylenedioxyphenyl).
  • heteroaryl represents a monocyclic or bicyclic ring, typically of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzimidazole (otherwise known as benzoimadazole), acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indoiyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • benzimidazole otherwise known as benzoimadazole
  • acridinyl carbazolyl
  • cinnolinyl quinoxalinyl
  • pyrrazolyl indolyl
  • benzotriazolyl furanyl
  • heterocycle or “heterocyclyl”, used either alone or in compound words, denotes saturated or partially unsaturated monocyclic, bicyclic or fused polycyclic ring systems containing at least one heteroatom selected from the group consisting of O, N and S. Prefixes such as “C 5 -C 7 " are used to denote the number of carbon atoms within the cyclic portion of the group (from 5 to 7 in this case). “Heterocycle” includes dihydro and tetrathydro analogs of the above mentioned heteroaryl groups.
  • heterocyclic substituents include, but are not limited to, pyrroline, pyrrolidine, piperidine, piperazine, pyrazoline, pyrazolidine, imidazolidine, tetrahydrofuran, pyran, dihydropyran, tetrahydropyran, dioxane, oxalzoline, morpholine, thiomorpholine, tetrahydrothiophene, oxathiane, dithiane, 4H-1,2,3-triazole and dithiazine, each of which may be further substituted with 1 to 3 substituents.
  • halo refers to fluoro, chloro, bromo or iodo.
  • the compound of formula (I) as defined herein is represented by formula (Ia): (Ia) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 1A ; each R 1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R 1B )2; each R 1B is independently selected from the group consisting of hydrogen and C 1- 6alkyl; R 2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl,
  • the compound of formula (I) as defined herein is represented by formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 1A ; each R 1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R 1B )2; each R 1B is independently selected from the group consisting of hydrogen and C 1- 6alkyl; R 2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R 2A
  • R 7 is selected from the group consisting of hydrogen, ⁇ C(O)C1-6alkyl and ⁇ C(O)CH(R 7A )N(R 7B ) 2 , wherein the ⁇ C(O)C 1-6 alkyl is optionally substituted with halo, ⁇ C 4-7 cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl;
  • R 7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid;
  • each R 7B is independently selected from the group consisting of hydrogen, C 1-4 alkyl, benzyl and ⁇ C(O)R 7C ;
  • R 7C is selected from the group consisting of C1-18alkyl and ⁇ ((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ⁇ C4-C7ary
  • the compound of formula (I) as defined herein is represented by formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen and C1-4alkyl; R 2 is a side chain of the amino acid alanine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R 2A ; each R 2A is independently selected from the group consisting of ⁇ OH, nitro, halo, C1-4alkyl and ⁇ OC1-4alkyl; R 3 is selected from the group consisting of C 1-4 alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 3A ; each R 3A is independently selected from the group consisting of halo, C1-4
  • R 3 is C1-4alkyl; and R 4 is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine.
  • the compound of formula (II) as defined herein is represented by formula (IIa): (IIa) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl; R 2 is a side chain of the amino acid alanine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R 2A ; each R 2A is independently selected from the group consisting of ⁇ OH, nitro, halo, C1-4alkyl and ⁇ OC1-4alkyl; R 3
  • the compound of formula (II) as defined herein is represented by formula (IIb): (IIb) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl; R 2 is a side chain of the amino acid alanine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R 2A ; each R 2A is independently selected from the group consisting of ⁇ OH, nitro, halo, C 1-4 alkyl and ⁇ OC 1-4 alkyl; R 5 is selected from the group consisting of hydrogen and methyl; R 6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine,
  • R 1 is selected from the group consisting of hydrogen and C 1-4 alkyl
  • R 2 is a side chain of the amino acid alanine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R 2A
  • each R 2A is independently selected from the group consisting of ⁇ OH, nitro, halo, C 1-4 alkyl and ⁇ OC 1-4 alkyl
  • R 5 is selected from the group consisting of hydrogen and methyl
  • R 6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline and phenylalanine
  • R 9 is hydrogen, or, together with the nitrogen atom to
  • the compound of formula (III) as defined herein is represented by formula (IIIa): (IIIa) or a pharmaceutically acceptable salt thereof, wherein each R 14 is independently selected from the group consisting of halo, C 1-4 alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 0, 1, 2 or 3.
  • the compound of formula (I) as defined herein is represented by formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 1A ; each R 1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R 1B ) 2 ; each R 1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R 2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and
  • the compound of formula (IV) as defined herein is represented by formula (IVa): (IVa) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; each R 14 is independently selected from the group consisting of halo, C 1-4 alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 1, 2 or 3.
  • the compound of formula (IV) as defined herein is represented by formula (IVb): (IVb) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl;
  • R 7 is selected from the group consisting of ⁇ C(O)C 1-6 alkyl and ⁇ C(O)CH(R 7A )N(R 7B ) 2 , wherein the ⁇ C(O)C1-6alkyl is optionally substituted with halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur;
  • R 7A is hydrogen or is a side chain of the amino acid norleucine;
  • each R 7B is independently selected from the group consisting of hydrogen and ⁇ C(O)R 7C ;
  • R 7C is C2-6alkyl,
  • R 1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 1A ; each R 1A is independently selected from the group consisting of halo, C 1-4 alkyl, nitro and N(R 1B )2; each R 1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R 2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; each R 14 is independently selected from the group consisting of halo, C 1-4 alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 0, 1, 2 or 3.
  • R 1 and R 2 together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl
  • A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three R A
  • each R A is independently selected from the group consisting of halo, cyano, C 6-10 aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ⁇ OC1-4alkyl, ⁇ C1-4alkylC6-10aryl and ⁇ OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ⁇ C1-4alkylC6-10aryl and ⁇ OC 1-4 alkylC 6-10 aryl is optionally substituted with 1, 2 or 3
  • the compound of formula (IV) as defined herein is formula (IVe): (IVe) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-4 alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R 1A ; each R 1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R 1B ) 2 ; each R 1B is independently selected from the group consisting of hydrogen and C 1- 6alkyl; R 2 is hydrogen; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three R A ; each R A is
  • the compound of formula (I), as defined herein, or pharmaceutically D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 Ac Nle (D P D-Bip N-Bzl-Gly D Gly K) R-NH 2 NO: 15 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 Ac Nle (D P D-Bip N-Me-Val W K) NH 2 D NO: 41 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 PEG2 Nle (D P D-Bip Pip A K) NH 2 D NO: 67 D 8 D 9 D 0 D 1 D 2 D 3 D 4 Ac Nle (D P
  • the compounds of the present invention may exist in one or more stereoisomeric forms (e.g. diastereomers).
  • the present invention includes within its scope all of these stereoisomeric forms either isolated (in, for example, enantiomeric isolation), or in combination (including racemic mixtures and diastereomic mixtures).
  • the present invention contemplates the use of amino acids in both L and D forms, including the use of amino acids independently selected from L and D forms; for example, where the compound comprises two asparagine residues, each asparagine residue may have the same, or opposite, absolute stereochemistry.
  • the invention thus also relates to compounds in substantially pure stereoisomeric form with respect to the asymmetric centres of the amino acid residues, e.g., greater than about 90% de, such as about 95% to 97% de, or greater than 99% de, as well as mixtures, including racemic mixtures, thereof.
  • diastereomers may be prepared by asymmetric synthesis, for example, using chiral intermediates, or mixtures may be resolved by conventional methods, e.g., chromatography, or use of a resolving agent.
  • Known solid or solution phase techniques may be used in the synthesis of the compounds of the present invention, such as coupling of the N- or C-terminus to a solid support (typically a resin) followed by step-wise synthesis of the linear peptide.
  • An orthogonal protecting group strategy may be used to facilitate selective deprotection and cyclization to form the cyclic heptapeptide core of the compound.
  • Protecting group chemistries for the protection of amino acid residues, including side chains, are well known in the art and may be found, for example, in: Theodora W. Greene and Peter G. M.
  • synthesis of the compounds of the invention may be carried out in one or more stages.
  • amino acids may be protected for incorporation into the compound, such as the protection of lysine as Boc- lysine.
  • a protected or partially protected linear peptide may be synthesised using solid phase peptide synthesis techniques.
  • Cyclization of the compound may be performed while the compound is still on resin or the compound may be cleaved from the resin first and cyclized in solution to produce the protected cyclic peptide. Where necessary, the remaining side chain protecting groups may be deprotected to furnish the compound.
  • the compounds of the invention are cyclized using side-chain to side-chain cyclization through or a lactam bridge.
  • the compound may be prepared and/or isolated as a pharmaceutically acceptable salt. It will be appreciated that the compound may be zwitterionic at a given pH.
  • salt refers to the salt of a given compound, wherein the salt is suitable for administration as a pharmaceutical.
  • Such salts may be formed, for example, by the reaction of an acid or a base with an amine or a carboxylic acid group, respectively.
  • the salt may be an internal salt where the compound comprises suitable proton donating and accepting functional groups.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases.
  • Corresponding counter ions derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Organic bases include primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-ethylpiperidine.
  • Acid/base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid/base forms.
  • the compounds and methods of the present invention may be used in the treatment and/or prevention of a range of diseases or conditions related to melanocortin 5 receptor (MC5R) activity.
  • treatment may include alleviating or ameliorating the symptoms, diseases or conditions associated with the disease or condition being treated, including reducing the severity and/or frequency of the disease or condition.
  • prevention may include preventing or delaying the onset of, inhibiting the progression of, or halting or reversing altogether the onset or progression of the particular symptoms, disease or condition associated with MC5R activity.
  • the present invention provides a method of treating or preventing a disease or condition related to melanocortin 5 receptor (MC5R) activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.
  • M5R melanocortin 5 receptor
  • the disease or condition related to MC5R activity is selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson-Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies.
  • subject is intended to include organisms such as mammals, e.g.
  • the subject is a human, e.g. a human suffering from, at risk of suffering from, or potentially capable of suffering from a microbial infection.
  • the subject is a cell.
  • the term "effective amount" refers to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur once, or at intervals of minutes or hours, or continuously over any one of these periods. Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
  • a typical dosage is in the range of 1 ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • treatment covers any treatment of a condition or disease in an animal, preferably a mammal, more preferably a human, and includes: (i) inhibiting a microbial infection, e.g. arresting its proliferation; (ii) relieving the infection, e.g. causing a reduction in the severity of the infection; or (iii) relieving the conditions caused by the infection, e.g. symptoms of the infection.
  • prevention and preventing cover the prevention or prophylaxis of a condition or disease in an animal, preferably a mammal, more preferably a human and includes preventing the microbial infection from occurring in a subject which may be predisposed to infection but has not yet been diagnosed as being infected.
  • the present invention provides the use of a compound according to the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition related to melanocortin 5 receptor (MC5R) activity.
  • M5R melanocortin 5 receptor
  • the present invention provides a compound according to the invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or condition related to melanocortin 5 receptor (MC5R) activity.
  • M5R melanocortin 5 receptor
  • the present invention provides a compound according to the invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson- Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention, together with at least one pharmaceutically acceptable excipient.
  • the route of administration and the nature of the pharmaceutically acceptable excipient will depend on the nature of the condition and the subject to be treated. It is envisaged that compounds according to the invention will be administered to a subject subcutaneously. It is believed that the choice of a particular carrier or delivery system and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the compound according to the invention care should be taken to ensure that the activity of the compound is not destroyed in the process and that the compound is able to reach its site of action without being destroyed.
  • the route of administration chosen should be such that the compound reaches its site of action.
  • Those skilled in the art may readily determine appropriate formulations for the compounds of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art. Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA.
  • the compounds according to the invention will be prepared in parenteral dosage forms, including those suitable for subcutaneous, intravenous, intrathecal, and intracerebral or epidural delivery.
  • the pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against reduction or oxidation and the contaminating action of microorganisms such as bacteria or fungi.
  • the solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for the active compound, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include agents to adjust osmolarity, for example, sugars or sodium chloride.
  • the formulation for injection will be isotonic with blood.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.
  • Sterile injectable solutions are prepared by incorporating the aqueous liquids of the invention in the required amount in the appropriate solvent with various of the other ingredients such as those enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • Pharmaceutically acceptable vehicles and/or diluents include any and all solvents, dispersion media, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art.
  • Unit dosage form refers to physically discrete units suited as unitary dosages for the subjects to be diagnosed; each unit containing a predetermined quantity of the compound calculated to produce the desired efficacy in association with the required pharmaceutically acceptable vehicle.
  • novel unit dosage forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the compound and the particular outcome to be achieved, and (b) the limitations inherent in the art of compounding the compounds of the invention in living subjects having a diseased condition in which bodily health is impaired.
  • compounds of the invention may be compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable vehicle in unit dosage form.
  • a unit dosage form can, for example, contain the compound in amounts ranging from 0.25 ⁇ g to about 2000 mg. Expressed in proportions, the compound may be present in from about 0.25 ⁇ g to about 2000 mg/mL of carrier.
  • compositions containing supplementary active ingredients are determined by reference to the usual dose and manner of administration of the said ingredients.
  • the invention will now be described with reference to the following non-limiting examples: General methods Materials [0084] Unless otherwise specified, chemicals were obtained from commercial suppliers and used without further purification. Amino acids, coupling reagents and Rink Amide resin were purchased from either AK Scientific USA, Auspep Australia, Chem-Impex International, or Sigma Aldrich Australia.
  • Peptide purity were assessed by analytical reverse-phase HPLC on a Shimadzu LCMS-2020 system (Shimadzu Scientific Instrument) equipped with a Phenomenex Luna C8(2) column (100 ⁇ , 100 mm x 2 mm x 3 ⁇ m) using a gradient (0 – 100% acetonitrile in water, 0.05% trifluoroacetic acid buffer) over 20 minutes at a flow rate of 0.2 mL/min, monitored at multiple wavelengths (200 – 254 nm). Peptide sequence was confirmed by ESI- MS analysis.
  • High-resolution mass spectra were obtained on an Agilent 6224 ESI- TOF mass spectrometer (Agilent) coupled to an Agilent 1290 Infinity LC system. Molecular ions were denoted by [M + H] + . The purified peptides achieved a purity greater than 95% as determined by analytical HPLC.
  • RP-HPLC peptide purification [0086] Purification of crude products was achieved using reverse-phase preparative HPLC on an Agilent 1200 series HPLC system incorporating with an Agilent 1260 Infinity II Variable Wavelength Detector (VWD) with either a Phenomenex Luna C8(2) column (100 ⁇ , 250 mm x 21.2 mm x 10 ⁇ m) or a Phenomenex Luna Omega Polar C18 column (100 ⁇ , 150 mm x 21.2 mm x 5 ⁇ m). Purification was accomplished using gradient mixtures of water and acetonitrile, with 0.1% trifluoroacetic acid, at a flow rate of 10 mL/min.
  • VWD Variable Wavelength Detector
  • linear peptide-resin was mixed with DIPEA (5 equiv.) and acetic anhydride (20 equiv.). The resin mixture was agitated at room temperature for 30 min and washed with DMF (3 x 30 s).
  • Cleavage of linear peptide from the solid support was achieved using a cleavage solution of TFA, water, 1,3-dimethoxybenzene and triisopropylsilane (92.5 : 2.5 : 2.5 : 2.5, v/v), at a concentration of 5 mL/0.1 mmol resin. After agitating at room temperature for 2 hours, the resin was filtered and washed with TFA (3 mL).
  • the filtrate was concentrated under N 2 , and the linear peptide was recovered by precipitation using diethyl ether (30-40 mL). The resulting peptide suspension was centrifuged at 3000 rpm for 5 min, and the supernatant was decanted. The crude peptide was dissolved in a minimum amount of 50% acetonitrile in water and lyophilised to yield off-white solids. Sequence confirmation was achieved by LC-MS. The peptide was in some cases, purified by RP-HPLC at this stage or carried through directly. [0092] For macrocyclization, the linear peptide was dissolved in DMF at concentration of 2.5 mM.
  • N-alkyl substituted compounds [0095] The synthesis of some N-alkyl substituted compounds was performed by inclusion of a two-step N-alkylation (sub-monomer approach) where bromoacetylation of a resin- bound amine functionality was followed by nucleophilic substitution of the halogenated peptide as illustrated in Scheme 2 (Culf, A. S.; Ouellette, R. J. Molecules [Online], 2010, p. 5282-5335). Scheme 2.
  • amine-substituted peptide resin was treated with a solution of bromoacetic acid (10 equiv.) and diisopropylcarbodiimide (10 equiv.) in DMF (5 mL). The reaction mixture was stirred for 30 min, and the procedure was repeated. The resin was then washed with DMF (3 x 5 mL) and treated with a selection of amines (20 equiv.) in DMF (1 mL) for 2 hours. After the reaction was complete, the resin was rinsed with DMF (3 x 5 mL) and subjected to SPPS. The representative synthesis was applied to the synthesis of Compounds in Table 2 below.
  • the mixture was degassed with N 2 for 10 min and mixed with Pd(dppf)Cl 2 (0.1 equiv.).
  • the reaction mixture was heated at 100 °C for 4 hours in Discover SP Microwave Synthesiser (CEM Corporation) followed by agitating at room temperature for 12 hours.
  • the reaction mixture was concentrated to dryness in vacuo to afford the crude product as a brown oil.
  • the representative synthesis was applied to the synthesis of Compounds in Table 4 below. 81 10 39 17.916 1085.5793 Introduction of C-terminal basic amino acid residues and derivatives [0101]
  • the introduction of C-terminal residues bearing basic residues was achieved by the use of selective protection using the ivDde group.
  • cyclic peptides bearing a primary amine functionality were treated with a solution of N,N’-di-Boc-1H-pyrazole-1-carboxamidine (4.5 equiv.) and DIPEA (7.5 equiv.) in DMF for 48 hours. The reaction mixture was concentrated in vacuo. The remaining residue was treated with TFA for 2 hours and concentrated under N2.
  • HEK293 Human embryonic kidney (HEK293) cells were transfected with the human MC1R, MC3R, MC4R, and MC5R through the Flp-In system using lipofectamine LTX. Stable receptor populations were determined using hygromycin B selection (200 ug/mL). Cells were maintained in high glucose and pyruvate Dulbecco’s Modified Eagle Medium (DMEM)) supplemented with 10% heat inactivated fetal bovine serum, 1% penicillin ⁇ streptomycin (10,000 U/mL), and 1% glutamax supplement in a humidified environment at 37 °C/5% CO2.
  • DMEM Modified Eagle Medium
  • the LANCE cAMP assay is a homogenous time-resolved fluorescence energy transfer (TR-FRET) immunoassay measuring cAMP produced by cells upon stimulation with agonists, in which the cellular cAMP is in competition with Europium-W8044 labelled cAMP tracer complex for the binding site on Alexa Fluor 647 dye labelled anti-cAMP antibodies. Excitation of europium chelated molecular tracer at 340 nm would produce energy that transfers to the fluorophore labelled antibodies bound to the tracer, emitting light at 665 nm. The cAMP levels from test compounds would increase in the presence of an agonist, causing a reduction in fluorescence signal at 665 nm.
  • TR-FRET time-resolved fluorescence energy transfer
  • Flp-In HEK 293 cells stably expressing the melanocortin receptors were seeded at 15,000 cells/well into a 96-well cell culture plate and incubated overnight in DMEM medium at 37 °C/5% CO 2 .
  • growth media was replaced with stimulation buffer (90 ⁇ L) containing phenol red free DMEM medium, Bovine Serum Albumin (BSA; 0.1%, w/v), 3-isobutyl-1-methylxanthine (IBMX; 0.1 mM or 0.5 mM), and cells were incubated for an additional 30 minutes at 37 °C/5% CO 2 .
  • stimulation buffer 90 ⁇ L
  • BSA Bovine Serum Albumin
  • IBMX 3-isobutyl-1-methylxanthine
  • Cells were stimulated with increasing concentrations (0.1 pM to 1 ⁇ M) of peptide ligands (10 ⁇ L) diluted in stimulation buffer and incubated for 45 minutes at 37 °C/5% CO2. The reaction was ceased by removal of the buffer containing the peptide and addition of ice-cold absolute ethanol (50 ⁇ L). After ethanol evaporation, cells were lysed with lysis buffer (225 ⁇ L, pH 7.4) containing BSA (0.1%, w/v), Tween 20 (0.3%, v/v) and HEPES buffer (5 mM). Lysate (5 ⁇ L) was transferred to a 384- well optiplate.
  • lysis buffer 225 ⁇ L, pH 7.4
  • BSA 0.1%, w/v
  • Tween 20 0.3%, v/v
  • HEPES buffer 5 mM
  • the amount of cAMP produced in each sample was determined using the LANCE Ultra cAMP Detection Kit (PerkinElmer) with modifications to the instructions from the manufacturer. Briefly, 10 ⁇ L of Eu-cAMP tracer solution (1:200 dilution of Eu- cAMP tracer stock in detection buffer) and 5 ⁇ L of U-light anti cAMP solution (17:5000 dilution of U-light anti-cAMP stock in detection buffer) was added into each well containing lysate in reduced light conditions and the plate was left to incubate at room temperature for 1 hour. Time-resolved fluorescence (TR-FRET) for the samples was detected using Envision plate reader with excitation at 320 nm and emission at 615 nm.
  • TR-FRET Time-resolved fluorescence
  • Binding affinity of active melanocortin ligands for melanocortin receptors was determined in vitro utilising transfected human embryonic kidney (HEK-293) cells stably expressing the melanocortin receptors via fluorescence-Activated Cell Sorting (FACS) based competition binding assays with fluorophore labelled melanocortin peptides.
  • FACS fluorescence-Activated Cell Sorting
  • the binding of unlabelled ligands was measured in the presence of a fluorophore labelled melanocortin ligand, that would compete for binding to the same sites, at a fixed concentration to quantify the level of receptor binding and selectivity.
  • the inhibition of fluorescence signal by displacement of sCy5-[Nle 4 , ⁇ -Phe 7 ]- ⁇ - MSH (sCy5-MT-I) by peptide ligands was detected by a Stratedigm S1000EXI flow cytometer (Stratedigm). Binding assays were performed on HEK-293 cells stably expressing human melanocortin receptors 1, 3, 4 or 5.
  • Dissociation constant (K d ) of sCy5-MT-I was determined through a saturation binding assay, in which total binding and non-specific binding were determined by incubation of increasing concentrations of sCy5-MT-I (10 ⁇ L, 1 pM to 10 nM in binding buffer) in the absence and presence of 10 ⁇ M [Nle 4 , D-Phe 7 ]- ⁇ -MSH (MT-I; 10 ⁇ L) respectively for 2 hours.
  • sCy5- MT-I 10 uL, 3 nM for MC1R, 3R, 5R or 15 nM for MC4R
  • binding buffer 10 uL, 1 pM to 1 uM
  • PI propidium iodide
  • Florescence intensity of the cell suspension was analysed using Stratedigm S1000EXI flow cytometer (Stratedigm) with an excitation of 642 nm and an emission between 661 nm and 690 nm for sCy5 detection and with an excitation of 488 nm and an emission between 600 nm and 630 nm for PI detection.
  • Cell Capture analysis software (Stratedigm) was used to extract the files and imported into FlowJo software (Flowjo Inc) to analyse the data. [0121] Gating was conducted to identify sCy5-positive living cells to be used for the measurement of mean fluorescence intensity (MFI).
  • the total binding and non-specific binding data acquired from saturation binding assays were fitted and analysed using a one- site binding model and non-linear regression analysis in GraphPad Prism 9 (GraphPad Software). Specific binding was determined by subtracting non-specific binding from total binding and the obtained values were fitted onto a one-site specific binding curve using non- linear regression analysis. The experiment was repeated four times with three replicates in each experiment. Ki values represent the mean of the experiments. All competition binding data were fitted using non-linear least-squared regression in GraphPad Prism 9 (GraphPad Software) for analysis. IC 50 values and the associated standard errors were calculated by the average of the experiment in triplicates.
  • K d values used for sCy5-MT-I were 1.6 nM (MC1R), 2.6 nM (MC3R), 5.2 nM (MC4R) and 3.4 nM (MC5R). Test compounds were subject to completion a binding assay (Table 11).
  • NHP Skeletal Muscle Satellite cells [0123] Cells were either seeded either on a 12 well plate coated with 0.01% (v/v) collagen from calf skin at a cell density of 50,000 cells per well or on a Corning 96 well white clear plate coated with 0.01% (v/v) collagen from calf skin at a cell density of 5000 cells per well.
  • differentiation Upon reaching 80% confluency, differentiation was induced by switching the medium to differentiation medium made up of low glucose DMEM (Gibco, Thermo Fisher Scientific, MA, USA) supplemented with sodium pyruvate, glutaMAX, 2% (v/v) heat inactivated HS, 1% (v/v) P/S, 25mM Hepes, 0.5 mg/mL sterile BSA and 0.5 mg/mL fetuin from FBS. Cells were monitored daily, and the medium was changed every second day. Cells were completely differentiated into multinucleated myotubes by Day 8.
  • the plate was immediately placed on a 37°C hot plate to maintain the incubation temperature and pre-warmed glucose starved medium (180 ⁇ L) was added into each well.
  • the cells were stimulated with either Actrapid ⁇ insulin (100 IU/mL) (McFarlane Medical, Vic, Aus), test compound or both (20 ⁇ L) and the cells were incubated for 2 hours at 37°C and 5% CO 2. All test compounds were dissolved in medium to obtain the desired concentration prior to stimulation. [0126]
  • the amount of glucose uptake in the cells was quantified using Promega’s glucose uptake Glo assay (Promega, WI, USA) with some alterations to the manufacturer’s instructions.
  • reaction was terminated by adding stop buffer (25 ⁇ L), neutralisation buffer (25 ⁇ L) and detection buffer (100 ⁇ L) made up of luciferase reagent (100 ⁇ L) supplemented with NADP+ (1 ⁇ L), G6DPH (2.5 ⁇ L), reductase (0.5 ⁇ L) and reductase substrate (0.0625 ⁇ L).
  • stop buffer 25 ⁇ L
  • neutralisation buffer 25 ⁇ L
  • detection buffer 100 ⁇ L
  • luciferase reagent 100 ⁇ L
  • NADP+ 1 ⁇ L
  • G6DPH 2.5 ⁇ L
  • reductase 0.5 ⁇ L
  • reductase substrate 0.0625 ⁇ L
  • Results obtained was plotted into an into a column graph with interleaved scatter with bar plot with each data point representing the mean signal for the experiment. To normalise the results, the signal produced by the test compound was compared to the signal produced by the vehicle. Statistical analysis was performed using analysis of variance (ANOVA), Dunnett's test. Asterisks represent statistical significance where ns denotes p> 0.05, * denotes p ⁇ 0.05, ** denotes p ⁇ 0.01, *** denotes p ⁇ 0.001 and **** denotes p ⁇ 0.0001. Table 12. Eval . 110 135 23 Table 13. Eval yotubes . 110 125 30 Example 5.
  • the filtrate was either diluted 1:5, 1:10 or 1:100 in ACN containing 1% (v/v) FA based on the size of the pellet and the sample was spiked with internal standard before being transferred to a clean tube for analysis on the LCMS.
  • Calibration curve of peptide (0, 1, 5, 10, 50, 100, 500, 1000, 5000, 10,000 ng/mL) was prepared on the day of analysis by spiking peptide and internal standard into PBS diluted in CAN containing 1% (v/v) FA acid to mirror the biological matrix.
  • Microsomal stability assay was conducted by the Centre for Drug Candidate Optimisation (CDCO) in MIPS. Briefly, the microsomal stability assay was performed by incubating test compounds at a final concentration of 1 ⁇ M with human liver microsomes (0.5 mg/mL) at 37°C. The metabolic reaction was initiated by the addition of preformed NADPH and quenched at various time points over 60 min by addition of ACN. Control samples with no cofactor were included to assess the contribution of NADPH-independent metabolic pathways. Quenched samples were left on ice for approximately 15 minutes.
  • test compounds were assessed in STZ induced T1D mouse models of glucose handling to demonstrate pharmacological efficacy in vivo.
  • STZ induced T1D mice instrumented with continuous intravenous glucose monitoring were treated with vehicle, reference melanocortin peptides, or test compounds via continuous infusion or bolus injection to measure their anti-hyperglycaemic activities, and subsequently underwent glucose challenge test to evaluate the effect of test compounds on the blood glucose level.
  • In-vivo evaluation [0132] The in vivo efficacy of the test compounds in stimulating glucose uptake was further characterised in T1D mouse models. In vivo evaluation was performed on STZ induced T1D mice. [0133] The test compounds were assessed in vivo in STZ induced T1D mice for glucose handling. Change in blood glucose for STZ-mice treated with 1 ⁇ g/g IP and blood samples were collected at shown time intervals.
  • STZ-mice have elevated blood glucose levels typically in the range on 15-20 mmol.
  • Method Adult C57Bl 6/J mice were made diabetic with 5 days STZ ip injections (50mg/kg). Once plasma blood glucose has risen above mol/L the experiment was started. Following the blood sampling at 0 mins, Mice were treated with vehicle or compound (1 ⁇ g/kg). Plasma blood glucose concentration was measured at 0, 15, 60, 90 and 120mins Table 17 of 45 -19.9 4.3 6 Mean and Peak change in blood glucose with or without insulin administration [0135] Method: Adult C57Bl 6/J mice were made diabetic with 5 days STZ ip injections (50mg/kg). Once plasma blood glucose has risen above mol/L the experiment was started.
  • Plasma blood glucose concentration was measured at 0, 5, 15, 30, 45, 60, 90 and 120mins. Following the blood sampling at 0mins, Mice were treated with veh or compound (1mg/kg) with or without insulin (1U/kg or 2U/kg) or veh ( Figure 1, Table 18).
  • Example 7 Activity of compounds in macaque animal model
  • Glucose handling was measured in a macaque animal model. In brief, animals were administered test compounds by infusion over a set time period, and blood glucose levels were measured. This data show effects of test compounds in reducing high blood glucose levels without affecting basal blood glucose levels.
  • Animal treatments included as shown in Figure 2a, a High Fat Diet (HFD)-induced diabetic (hyperglycaemic animal) female pigtail macaque (13 yrs. old) which was treated with Compound 30 at a dose of 0.334mg/kg/hr for 150 minutes. Fasting glucose levels were reduced from 401 to 257.4 mg/dL (37%) over a 90 minute period (n 1).
  • HFD High Fat Diet
  • Example 8 Study of chronic effects of constant compound infusions on hyperglycaemia and the need for insulin.
  • Adult C57Bl/6J mice were injected with STZ (50mg/kg) daily for 5 consecutive days. Mice were then implanted with Continuous blood glucose probes. Baseline blood glucose measurements (3-5 days) were collected and a HbA1c value taken. Mice were then implanted with a 28 day minipump containing veh or compound (PTM Cmp 5 or Cmp 9) (0.6mg/kg/hr).
  • mice were then injected with Insulin Determir (1U/kg) twice daily (AM and PM) for the next 28 days. As blood glucose was recording, it was checked that insulin dosing is not dropping plasma blood glucose too low. If insulin treated mice had a consistent peak drop in blood glucose of below 16.5mmol/l insulin dose would be reduced to 0.5U/kg. If insulin treated mice had a consistent peak drop in blood glucose of below 12.5mmol/l insulin treatment was stopped. Mice had blood glucose measured throughout the treatment period and HbA1c was measured weekly throughout the treatment period.
  • the treatment groups were 1. Minipump: Veh/SC daily injection Veh 2. Minipump: Veh/SC daily injection Insulin 3. Minipump: Cmp 5/SC daily injection insulin 4.
  • Minipump Cmp 9 /SC daily injection Insulin A 28-day treatment with Cmp 5 + insulin, Cmp 9 + insulin, and vehicle (veh) + insulin significantly reduced blood glucose levels compared to veh + veh-treated mice. This reduction in blood glucose was reflected in significantly lower HbA1c levels in the Cmp 5 + insulin group compared to the veh + veh and veh + insulin groups after 3 weeks of treatment. Cmp 5 + insulin reduced insulin requirements by 25.4% after 28 days of treatment compared to veh + insulin. Cmp 5 + insulin also shifted plasma glucose time-in-range toward lower blood glucose levels compared to veh + insulin and veh + veh over the 28-day treatment period. The results are shown below in Table 19.

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Abstract

The present invention relates to compounds of Formula I: (I) and their pharmaceutically acceptable salts that activate the melanocortin-5 receptor (MC5R) and uses thereof in the treatment or prevention of a disease or condition related to MC5R activity.

Description

Cyclic peptidomimetics as MC5R agonists Field of the invention [0001] The present invention relates to compounds that activate the melanocortin-5 receptor (MC5R) and uses thereof in the treatment or prevention of a disease or condition related to MC5R activity. Background of the invention [0002] The melanocortin system plays a pivotal role in energy homeostasis. Defective central and peripheral melanocortin signalling has been shown to cause alteration in insulin sensitivity and action, impairment in glucose tolerance and dysregulation of glucose homeostasis, ultimately contributing to obesity and diabetes (Yeo GSH, et al., Mol Metab. 2021 Jun;48:101206. Epub 2021 Mar 6. PMID: 33684608). [0003] Skeletal muscle represents the largest organ in the human body, accounting for around 20% of total glucose disposal in the basal state. In the postprandial state, it is the major site responsible for insulin-stimulated glucose uptake from the circulation, with approximately 80% glucose disposal occurring in skeletal muscle following a meal (Merz KE, Thurmond DC. Compr Physiol.2020 Jul 8; 10(3):785-809. doi: 10.1002/cphy.c190029. PMID: 32940941). [0004] Among all melanocortin receptors, MC5R is the predominant subtype expressed in skeletal muscles (Ji LQ, Hong Y, Tao YX. Int J Mol Sci. 2022 Aug 5;23(15):8727. doi: 10.3390/ijms23158727. PMID: 35955857; Enriori, P. J. et al., Mol. Metab.2016, 5 (10), 807- 822). The last melanocortin receptor to be discovered and characterised, MC5R has an abundant distribution in the body, with expression of MC5R mRNA detected in a number of peripheral sites including skin, skeletal muscle, kidney, liver, exocrine glands, adipose tissues and other tissues. Emerging evidence has implied association of MC5R with multiple metabolic disorders (Xu Y, Guan X, Zhou R, Gong R. Cell Mol Life Sci. 2020 Oct;77(19):3831-3840. doi: 10.1007/s00018-020-03511-0. Epub 2020 Apr 4. PMID: 32248247) [0005] MC5R agonists are known in the literature. PG-901 has been studied as an MC5R agonist, but also is an antagonist of MC3R and MC4R (Grieco P, et al., J Med Chem, 45 (24): 5287-94). Bednarek et al. described several potent and highly selective MC5R agonists (Bednarek, M. A., et al., J Med Chem 2007, 50, 2520-6; Bednarek M. A., et al. Chem Biol Drug Des. 2007 May;69(5):350-5. doi: 10.1111/j.1747-0285.2007.00513.x. PMID: 17539827). However, these have not been studied in mammalian pharmacology. [0006] Accordingly, there exists a need to provide novel MC5R agonists for use in the treatment or prevention of a disease or condition related to MC5R activity. Summary of the invention [0007] New compounds and methods are provided for reducing treatment or prevention of a disease or condition related to MC5R activity. [0008] Accordingly, in one aspect the present invention provides a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒OC1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1- 4alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, homoalanine, leucine, isoleucine, norleucine, valine and norvaline; or R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; and each R4A is independently selected from the group consisting of ‒OH, nitro, halo, C1- 4alkyl and ‒OC1-4alkyl; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; p is selected from 0, 1 and 2; and q is selected from 1, provided that when A is , one or more of the following apply: R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or aryl ring RA is substituted with 1, 2 or 3 RB; or R3 is selected from the group consisting of C1-4alkyl and optionally substituted benzyl and R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl; or R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid, arginine, norleucine, norvaline and phenylalanine; or R7C is optionally substituted C2-6alkyl or ‒((CH2)2O)2CH2CH3. [0009] In one aspect, the present invention provides a compound of formula (I) represented by the formula (II), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 is a side chain of the amino acid alanine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1-6alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, 2-aminoisobutyric acid, alanine, arginine, norleucine, norvaline and phenylalanine; R9 is hydrogen, C1-6alkyl or, together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine-toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; R11 is hydrogen or is a side chain of the amino acid norleucine; R12 is C1-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR12A; R12A is selected from the group consisting of halo, C1-4alkyl and C1-4haloalkyl; R13 is selected from the group consisting of hydrogen and C1-4alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; ‒X‒ is selected from the group consisting of: ‒CH2C(O)NH(CH2)4‒, ‒(CH2)4NHC(O)CH2‒, ‒(CH2)2C(O)NH(CH2)4‒ and ‒(CH2)4NHC(O)(CH2)2‒; and n is selected from 0, 1, 2 and 3. [0010] In another aspect, the present invention provides a compound of formula (I) represented by the formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; m is selected from 0, 1, 2 or 3; and q is selected from 1, 2 or 3. [0011] In a further aspect, the invention provides a compound of formula (I) represented by the formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; and each R4A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine and homophenylalanine; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; p is selected from 0, 1 and 2; and q is selected from 1, provided that when A is , one or more of the following apply: C6-10aryl ring RA is substituted with 1, 2 or 3 RB; or R7C is C2-6alkyl; or R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl. [0012] In yet another aspect of the invention there is provided a pharmaceutical composition comprising a compound according to the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient. [0013] Another aspect of the invention provides a method of treating or preventing a disease or condition related to melanocortin 5 receptor (MC5R) activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the invention, or a pharmaceutically acceptable salt thereof. [0014] In one embodiment, the disease or condition related to MC5R activity is selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson-Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies. [0015] These and other aspects of the present invention will become more apparent to the skilled addressee upon reading the following detailed description in connection with the accompanying examples and claims. Brief Description of the Drawings [0016] The invention will herein be described by way of example only with reference to the following non-limiting Figures in which: [0017] Figure 1 illustrates mean and peak change in blood glucose with or without insulin administration. A) Line graph, percentage change in blood glucose post treatment with Compound 5. B) Line graph, percentage change in blood glucose post treatment with Compound 9. Data Mean +/- SEM. B-c. One way ANOVA, Tukey's multiple comparisons test. *p<0.05, **p<0.01, ***p<0.001 [0018] Figure 2 illustrates infusion of a HFD-induced diabetic (hyperglycaemic animal) female pigtail macaque (13 yrs. old) with Cpd 30 at a dose of 0.334mg/kg/hr for 150 minutes reduced fasting glucose levels from 401 to 257.4 mg/dL (37%) over a 90 minute period. (n=1); b) Infusion of HDF-induced pre-diabetic female pigtail macaques (14-20 yrs. old) with Cpd 30 at a dose of 0.334mg/kg/hr for 150 minutes did not reduce fasting baseline glucose levels prior to the animals receiving a bolus glucose (600mg/kg). (n=2). [0019] Figure 3 illustrates infusion of a metabolically healthy male longtail macaque (yrs) with Cpd 45 at a dose of 0.668mg/kg/hr for 45 minutes did not reduce fasting baseline glucose levels however reduced the peak height and rate of glucose disposal from the circulation following the administration of bolus glucose (600mg/kg) compared to sex- matched control that received saline alone. The total area under the curve (amount of glucose in the circulation from 0-60min) in the presence of Cpd 45 was reduced by 19% compared to saline only during the intravenous glucose tolerance test. Cpd 45 Infusion (n=1), Saline Infusion (n=1). General definitions [0020] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [0021] Unless otherwise specified, the indefinite articles "a", "an" and "the" as used herein, include plural aspects. Thus, for example, reference to "an agent" includes a single agent, as well as two or more agents; reference to "the composition" or "formulation" includes a single composition or formulation, as well as two or more compositions or formulations; and so forth. [0022] In the context of this specification, the term "about," is understood to refer to a range of numbers that a person of skill in the art would consider equivalent to the recited value in the context of achieving the same function or result. [0023] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. [0024] The term "optionally" is used herein to mean that the subsequently described feature may or may not be present or that the subsequently described event or circumstance may or may not occur. Hence the specification will be understood to include and encompass embodiments in which the feature is present and embodiments in which the feature is not present, and embodiments in which the event or circumstance occurs as well as embodiments in which it does not. [0025] The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge. [0026] Other definitions may be found throughout the description. Detailed description of the invention [0027] The present inventors have surprisingly found that compounds according to the invention effectively activate MC5R. [0028] In one aspect the present invention provides a compound of formula (I):
(I), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1- 4alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, homoalanine, leucine, isoleucine, norleucine, valine and norvaline; or R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; and each R4A is independently selected from the group consisting of ‒OH, nitro, halo, C1- 4alkyl and ‒OC1-4alkyl; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; p is selected from 0, 1 and 2; and q is selected from 1, provided that when A is , one or more of the following apply: R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or aryl ring RA is substituted with 1, 2 or 3 RB; or R3 is selected from the group consisting of C1-4alkyl and optionally substituted benzyl and R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl; or R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid, arginine, norleucine, norvaline and phenylalanine; or R7C is optionally substituted C2-6alkyl or ‒((CH2)2O)2CH2CH3. [0029] As used herein, the term "alkyl", used either alone or in compound words, denotes straight chain or branched alkyl. Prefixes such as "C1-C6" are used to denote the number of carbon atoms within the alkyl group (from 1 to 6 in this case). Examples of straight chain and branched alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n- pentyl, hexyl, heptyl, 5-methylheptyl, 5-methylhexyl, octyl, nonyl, decyl, undecyl, dodecyl and docosyl (C22). [0030] In the context of this specification, the term "amino acid" is defined as having at least one primary, secondary, tertiary or quaternary amino group, and at least one acid group, wherein the acid group may be a carboxylic, sulfonic, or phosphonic acid, or mixtures thereof. Preferably, the acid group is a carboxylic acid group. The amino groups may be "alpha", "beta", "gamma" … to "omega" with respect to the acid group(s). The backbone of the "amino acid" may be substituted with one or more groups selected from halogen, hydroxy, guanido, heterocyclic groups. Thus term "amino acids" also includes within its scope glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophane, serine, threonine, cysteine, tyrosine, asparagine, glutamine, asparte, glutamine, lysine, arginine and histidine, taurine, betaine, N-methylalanine etc. (L) and (D) forms of amino acids are included in the scope of this invention. [0031] Reference to an amino acid “side chain” takes its standard meaning in the art. SH side chain of side chain of side chain of side chain of side chain of acid NH2 NH2 side chain of side chain of side chain of side chain of side chain of side chain of side chain of side chain of side chain of side chain of aspartic acid aspartate serine leucine side chain of phenylalanine [0032] As used herein, non-naturally occurring amino acids include any compound with both amino and carboxyl functionality, derivatives thereof, or derivatives of a naturally occurring amino acid. These amino acids form part of the peptide chain through bonding via their amino and carboxyl groups. Alternatively, these derivatives may bond with other natural or non-naturally occurring amino acids to form a non-peptidyl linkage. [0033] In addition to the negatively charged side chains shown above, it will be appreciated that a number of the side chains may also be protonated and so become positively charged, such as the side chain of lysine. The present invention contemplates within its scope these protonated side chains as well. [0034] As used herein, the term “residue” refers to a part of a compound resulting from the removal of one or more atoms. The one or more atoms to be removed may be hydrogen atoms. A person skilled in the art would understand, for example, where a compound comprises a carboxylic acid (-COOH) functional group, the residue that is found in the compound of Formula (I) comprises the carboxylate of the amino acid (i.e. –COO-), which is attached to the remainder of the compound. [0035] .The term "aryl" refers to aromatic monocyclic (e.g. phenyl) or polycyclic groups (e.g. tricyclic, bicyclic, e.g., naphthalene, anthryl, phenanthryl). Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g. tetralin, methylenedioxyphenyl). [0036] The term "heteroaryl", as used herein, represents a monocyclic or bicyclic ring, typically of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: benzimidazole (otherwise known as benzoimadazole), acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indoiyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. [0037] As used herein, the term “heterocycle” or “heterocyclyl”, used either alone or in compound words, denotes saturated or partially unsaturated monocyclic, bicyclic or fused polycyclic ring systems containing at least one heteroatom selected from the group consisting of O, N and S. Prefixes such as "C5-C7" are used to denote the number of carbon atoms within the cyclic portion of the group (from 5 to 7 in this case). “Heterocycle” includes dihydro and tetrathydro analogs of the above mentioned heteroaryl groups. Examples of suitable heterocyclic substituents include, but are not limited to, pyrroline, pyrrolidine, piperidine, piperazine, pyrazoline, pyrazolidine, imidazolidine, tetrahydrofuran, pyran, dihydropyran, tetrahydropyran, dioxane, oxalzoline, morpholine, thiomorpholine, tetrahydrothiophene, oxathiane, dithiane, 4H-1,2,3-triazole and dithiazine, each of which may be further substituted with 1 to 3 substituents. [0038] The term "halo" used herein refers to fluoro, chloro, bromo or iodo. [0039] In one embodiment, the compound of formula (I) as defined herein is represented by formula (Ia): (Ia) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1- 4alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, homoalanine, leucine, isoleucine, norleucine, valine and norvaline; or R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; each R10 is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6- 10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and n is selected from 0, provided that when A is , one or more of the following apply: R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or aryl ring RA is substituted with 1, 2 or 3 RB; or R3 is selected from the group consisting of C1-4alkyl and optionally substituted benzyl and R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl; or R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid, arginine, norleucine, norvaline and phenylalanine; or R7C is optionally substituted C2-6alkyl or ‒((CH2)2O)2CH2CH3. [0040] In another embodiment, the compound of formula (I) as defined herein is represented by formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1- 4alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, homoalanine, leucine, isoleucine, norleucine, valine and norvaline; or R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; and each R4A is independently selected from the group consisting of ‒OH, nitro, halo, C1- 4alkyl and ‒OC1-4alkyl; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH2C(O)NH(CH2)4‒, ‒(CH2)4NHC(O)CH2‒, ‒(CH2)2C(O)NH(CH2)4‒ and ‒(CH2)4NHC(O)(CH2)2‒. R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; each R10 is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6- 10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and n is selected from 0, provided that when A is , one or more of the following apply: R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or aryl ring RA is substituted with 1, 2 or 3 RB; or R3 is selected from the group consisting of C1-4alkyl and optionally substituted benzyl and R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl; or R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid, arginine, norleucine, norvaline and phenylalanine; or R7C is optionally substituted C2-6alkyl or ‒((CH2)2O)2CH2CH3. [0041] In one aspect, the compound of formula (I) as defined herein is represented by formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 is a side chain of the amino acid alanine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1-6alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, 2-aminoisobutyric acid, alanine, arginine, norleucine, norvaline and phenylalanine; R9 is hydrogen, C1-6alkyl or, together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine-toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine-isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]- stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine- palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; R11 is hydrogen or is a side chain of the amino acid norleucine; R12 is C1-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR12A; R12A is selected from the group consisting of halo, C1-4alkyl and C1-4haloalkyl; R13 is selected from the group consisting of hydrogen and C1-4alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; ‒X‒ is selected from the group consisting of: ‒CH2C(O)NH(CH2)4‒, ‒(CH2)4NHC(O)CH2‒, ‒(CH2)2C(O)NH(CH2)4‒ and ‒(CH2)4NHC(O)(CH2)2‒; and n is selected from 0, 1, 2 and 3. [0042] In one embodiment for the compound of formula (II), R3 is C1-4alkyl; and R4 is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine. [0043] In one embodiment, the compound of formula (II) as defined herein is represented by formula (IIa): (IIa) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 is a side chain of the amino acid alanine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1-6alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, 2-aminoisobutyric acid, alanine, arginine, norleucine, norvaline and phenylalanine; R9 is hydrogen, C1-6alkyl or, together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, aspartic acid, homoarginine, lysine-toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine-isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]- stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine- palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; R11 is hydrogen or is a side chain of the amino acid norleucine; R12 is C1-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR12A; R12A is selected from the group consisting of halo, C1-4alkyl and C1-4haloalkyl; R13 is selected from the group consisting of hydrogen and C1-4alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and n is selected from 0, 1, 2 and 3. [0044] In another embodiment, the compound of formula (II) as defined herein is represented by formula (IIb): (IIb) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 is a side chain of the amino acid alanine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline and phenylalanine; R9 is hydrogen, C1-6alkyl or, together with the nitrogen atom to which it is attached, is an amino acid selected from the group consisting of lysine, arginine, aspartic acid, homoarginine, lysine-toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine-isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]- stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine- palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla; optionally wherein the amino acid is amidated at the C-terminus; R11 is hydrogen or is a side chain of the amino acid norleucine; R12 is C1-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR12A; R12A is selected from the group consisting of halo, C1-4alkyl and C1-4haloalky; R13 is selected from the group consisting of hydrogen and C1-4alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; each R15 is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1-4alkyl, nitro and N(R15A)2; each R15A is independently selected from the group consisting of hydrogen, C1-6alkyl; and m and t are independently selected from 0, 1, 2 and 3. [0045] In another embodiment, the compound of formula (II) as defined herein is represented by formula (IIc):
(IIc), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 is a side chain of the amino acid alanine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline and phenylalanine; R9 is hydrogen, or, together with the nitrogen atom to which it is attached, is an amino acid selected from the group consisting of lysine and arginine, wherein the amino acid is amidated at the C-terminus; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; each R15 is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1-4alkyl, nitro and N(R15A)2; each R15A is independently selected from the group consisting of hydrogen, C1-6alkyl; and m and t are independently selected from 0, 1, 2 and 3 [0046] In one aspect, the compound of formula (I) as defined herein is represented by formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; m is selected from 0, 1, 2 or 3; and q is selected from 1, 2 or 3. [0047] In one embodiment, the compound of formula (III) as defined herein is represented by formula (IIIa): (IIIa) or a pharmaceutically acceptable salt thereof, wherein each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 0, 1, 2 or 3. [0048] In one aspect, the compound of formula (I) as defined herein is represented by formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; and each R4A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; p is selected from 0, 1 and 2; and q is selected from 1, provided that when A is , one or more of the following apply: C6-10aryl ring RA is substituted with 1, 2 or 3 RB; or R7C is C2-6alkyl; or R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl. [0049] In one embodiment, the compound of formula (IV) as defined herein is represented by formula (IVa): (IVa) or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 1, 2 or 3. [0050] In another embodiment, the compound of formula (IV) as defined herein is represented by formula (IVb): (IVb) or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl; R7 is selected from the group consisting of ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; R7A is hydrogen or is a side chain of the amino acid norleucine; each R7B is independently selected from the group consisting of hydrogen and ‒C(O)R7C; R7C is C2-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 0, 1, 2 or 3. herein is (IVc) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 0, 1, 2 or 3. herein is (IVd) or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and p is selected from 0, 1 and 2. [0053] In yet a further embodiment, the compound of formula (IV) as defined herein is formula (IVe): (IVe) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; each R16 is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; p is selected from 0, 1 and 2; and u is selected from 0, 1 and 2. [0054] In one aspect, the compound of formula (I), as defined herein, or pharmaceutically D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 Ac Nle (D P D-Bip N-Bzl-Gly D Gly K) R-NH2 NO: 15 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 Ac Nle (D P D-Bip N-Me-Val W K) NH2 D NO: 41 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 PEG2 Nle (D P D-Bip Pip A K) NH2 D NO: 67 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 Ac Nle (D P , , P D TriF-Bip ip W K) NH2 NO: 93 D 4 D 5 D 6 D 7 D 8 D 9 D 00 D 01 D 02 D 03 D 04 D 05 D 06 D 07 D 08 D 09 D 10 D 11 D 12 D 13 D 14 D 15 D 16 D 17 D 18 Ac Nle (D P D-Bip Pro(OH) W K) NH2 D NO: 119 D 20 D 21 D 22 D 23 Ac Nle (D P D-Bip N-Bzl-Gly Nva K) D NH2 NO: 124 Ac = acetyl; Nle = Norleucine; D = Aspartic acid; P = Proline; D-Bip = D-biphenylalanine; N-4FBzl-Gly = N-(4-fluorobenzyl)glycine; W = Tryptophan; K = Lysine; NH2 = amine; N- 4MeOBzl-Gly = N-(4-methoxybenzyl)glycine; N-4NBzl-Gly = N-(4-Nitrobenzoyl)glycine; N-Bzl-Gly = N-Benzylglycine; Aib = 2-Aminoisobutyric acid; A = Alanine; R = Arginine; HArg = Homoarginine; Oic = Octahydroindole; k = D-lysine; G = Glycine; N-Me-Gly = N- Methylglycine; Nva = Norvaline; TBA = Toluylbutyric acid; LysTBA = N6-(4-(p- tolyl)butanoyl)-L-lysine; Lys(IPBA) = N6-(4-(4-isopropylphenyl)butanoyl)-L-lysine; LysTTBA = N6-(4-(4-(trifluoromethyl)phenyl)butanoyl)-L-lysine; LysSDA = (S)-18-((5- amino-5-carboxypentyl)amino)-18-oxooctadecanoic acid; LysPA = N6-palmitoyl-L-lysine; LysDHex = N6-hexyl-L-lysine; DFPro = 4,4-difluoroproline; NPrGly = N-propylgycine; E = Glutamic acid; F = Phenylalanine; W = Tryptophan; N-Me-Ala = N-methylalanine; D-4F- 3Me-Bip = D-4-(4-Fluoro-3-methylphenyl)phenylalanine; Dap = (S)-2,3-diaminopropanoic acid; GdnAla = (S)-guanidinylalanine; N-iPr-Gly = N-isopropylgycine; N-Me-Ala = N- methylalanine; D-4-Ac-Bip = (S)-2-amino-3-(4'-(prop-1-en-2-yl)-[1,1'-biphenyl]-4- yl)propanoic acid; N-Me-Leu = N-methylleucine; N-Me-Val = N-methylvaline; N-Pr-Gly = N-propylglycine; Hyp = Hydroxyproline; Pip = L-pipecolic acid; Abu = 2-Aminobutyric acid; D-4I-Phe = (R)-4-Iodo-phenylalanine; D-3,4,5-TriF-Bip = (R)-2-amino-3-(3',4',5'- trifluoro-[1,1'-biphenyl]-4-yl)propanoic acid; Orn = Ornithine; Dab = (S)-2,3- diaminobutanoic acid; p = D-proline; Faa = 2-Furanacetic acid; Hex = Hexanoic acid; But = Butyric acid; Suc = Succinic acid; NH-Me = N-methyl-amine; PEG = Amino-PEG1-amine (aminoethoxyethylamine); Pen = 1,5-Diaminopentane; Lys = Lysine; OH = Hydroxyl; D- Arg = D-Arginine; Asp = Aspartic acid; hPhe = L-homophenylalanine; PEG2 = 2-(2-(2- aminoethoxy)ethoxy)acetic acid; H = Histidine; a = D-alanine; p = D-proline; L = Leucine; D-3F-Bip = (S)-2-amino-3-(3'-fluoro-[1,1'-biphenyl]-4-yl)propanoic acid; D-4Ppd = (R)-2- amino-3-(4-(pyridin-4-yl)phenyl)propanoic acid; D-3Ppd = (R)-2-amino-3-(4-(pyridin-3- yl)phenyl)propanoic acid; D-5Pprd = (R)-2-amino-3-(4-(pyrimidin-5-yl)phenyl)propanoic acid; D-3,5-DiMeO-Bip = (R)-2-amino-3-(3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoic acid; D-2F-3Ppd = (R)-2-amino-3-(4-(2-fluoropyridin-3-yl)phenyl)propanoic acid; D-3- PhFuran = (R)-2-amino-3-(4-(furan-3-yl)phenyl)propanoic acid; L-3FBip = (S)-2-amino-3- (3'-fluoro-[1,1'-biphenyl]-4-yl)propanoic acid; S = Serine; Paa = 2-Pyridine acetic acid; Tfp = 3,3,3-Trifluoropropionic acid; D-3Br-Phe = D-3-bromophenylalanine; D-3-Bip = (R)-3- ([1,1'-biphenyl]-3-yl)-2-aminopropanoic acid; N-Me-Nva = N-Methylnorvaline; N-Me-Leu = N-methylleucine; D-Pgl = (R)-2-aminopent-4-ynoic acid; D-Oxa = (R)-2-amino-3-(3- (oxazol-3(2H)-yl)phenyl)propanoic acid; Pro = Proline; D-HPhe = D-homophenylalanine; D-4CNPhe = D-4-cyanophenylalanine; D-3CNPhe = D-3-cyanophenylalanine; D-His(Bn) = Ntheta-benzyl-D-histidine; D-Tyr(Bn) = Ntheta-benzyl-D-tyrosine; Pro(OH) = Hydroxyproline; 3FBip = 3’-Fluorobiphenylalanine; Ppd = Phenylpyridine; Pprd = Phenylpyrimidine; 3,5-DiMeO = dimethoxy; Oxa = 3-Phenyloxazole Alanine;; ;Dhex = N- Diaminohexane;; IPBA = Iodophenylbutyric acid; TTBA = Triflurotoluylbutyric acid; IBPBA = isobutylphenylbutyric acid; SDA = Stearic diacid; PA = Palmitic acid; AB1 = - [Lys-PEG2-PEG2-Glu]-stearic diacid; AB2 = -[PEG2-Lys-PEG2-Glu]-stearic diacid; IBPB = 4-(4-isobutylphenyl)butanoyl; MDA = myristic diacid
[0055] It will be understood that the compounds of the present invention may exist in one or more stereoisomeric forms (e.g. diastereomers). The present invention includes within its scope all of these stereoisomeric forms either isolated (in, for example, enantiomeric isolation), or in combination (including racemic mixtures and diastereomic mixtures). The present invention contemplates the use of amino acids in both L and D forms, including the use of amino acids independently selected from L and D forms; for example, where the compound comprises two asparagine residues, each asparagine residue may have the same, or opposite, absolute stereochemistry. [0056] The invention thus also relates to compounds in substantially pure stereoisomeric form with respect to the asymmetric centres of the amino acid residues, e.g., greater than about 90% de, such as about 95% to 97% de, or greater than 99% de, as well as mixtures, including racemic mixtures, thereof. Such diastereomers may be prepared by asymmetric synthesis, for example, using chiral intermediates, or mixtures may be resolved by conventional methods, e.g., chromatography, or use of a resolving agent. [0057] Known solid or solution phase techniques may be used in the synthesis of the compounds of the present invention, such as coupling of the N- or C-terminus to a solid support (typically a resin) followed by step-wise synthesis of the linear peptide. An orthogonal protecting group strategy may be used to facilitate selective deprotection and cyclization to form the cyclic heptapeptide core of the compound. Protecting group chemistries for the protection of amino acid residues, including side chains, are well known in the art and may be found, for example, in: Theodora W. Greene and Peter G. M. Wuts, Protecting Groups in Organic Synthesis (Third Edition, John Wiley & Sons, Inc, 1999), the entire contents of which is incorporated herein by reference. [0058] General techniques for preparing the peptides of the invention can be found, for example, in: a) Alewood, P.; Alewood, D.; Miranda, L.; Love, S.; Meutermans, W.; Wilson, D. Meth. Enzymol., 1997, 289, 14-28; b) Merrifield, R. B., J. Am. Chem. Soc., 1964, 85, 2149; c) Bodanzsky, "Principles of Peptide Synthesis", 2nd Ed., Springer-Verlag (1993); and d) Houghten, Proc. Natl. Acad. Sci. USA, 1985, 82, 5131. [0059] As a general strategy, synthesis of the compounds of the invention may be carried out in one or more stages. In the first stage, amino acids may be protected for incorporation into the compound, such as the protection of lysine as Boc- lysine. Next, a protected or partially protected linear peptide may be synthesised using solid phase peptide synthesis techniques. [0060] Cyclization of the compound may be performed while the compound is still on resin or the compound may be cleaved from the resin first and cyclized in solution to produce the protected cyclic peptide. Where necessary, the remaining side chain protecting groups may be deprotected to furnish the compound. The compounds of the invention are cyclized using side-chain to side-chain cyclization through or a lactam bridge. [0061] Where the compound comprises one or more functional groups that may be protonated or deprotonated (for example at physiological pH) the compound may be prepared and/or isolated as a pharmaceutically acceptable salt. It will be appreciated that the compound may be zwitterionic at a given pH. As used herein the expression “pharmaceutically acceptable salt” refers to the salt of a given compound, wherein the salt is suitable for administration as a pharmaceutical. Such salts may be formed, for example, by the reaction of an acid or a base with an amine or a carboxylic acid group, respectively. In the case of a zwitterionic compound, the salt may be an internal salt where the compound comprises suitable proton donating and accepting functional groups. [0062] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. [0063] Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases. Corresponding counter ions derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium and magnesium salts. Organic bases include primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-ethylpiperidine. [0064] Acid/base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid/base forms. [0065] The compounds and methods of the present invention may be used in the treatment and/or prevention of a range of diseases or conditions related to melanocortin 5 receptor (MC5R) activity. As used herein, treatment may include alleviating or ameliorating the symptoms, diseases or conditions associated with the disease or condition being treated, including reducing the severity and/or frequency of the disease or condition. As used herein, prevention may include preventing or delaying the onset of, inhibiting the progression of, or halting or reversing altogether the onset or progression of the particular symptoms, disease or condition associated with MC5R activity. [0066] In one aspect, the present invention provides a method of treating or preventing a disease or condition related to melanocortin 5 receptor (MC5R) activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof. [0067] In one embodiment, the disease or condition related to MC5R activity is selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson-Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies. [0068] The term “subject” is intended to include organisms such as mammals, e.g. humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, e.g. a human suffering from, at risk of suffering from, or potentially capable of suffering from a microbial infection. In another embodiment, the subject is a cell. [0069] As used herein, the term "effective amount" refers to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur once, or at intervals of minutes or hours, or continuously over any one of these periods. Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. A typical dosage is in the range of 1 μg to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage. [0070] The terms "treatment" and "treating" as used herein cover any treatment of a condition or disease in an animal, preferably a mammal, more preferably a human, and includes: (i) inhibiting a microbial infection, e.g. arresting its proliferation; (ii) relieving the infection, e.g. causing a reduction in the severity of the infection; or (iii) relieving the conditions caused by the infection, e.g. symptoms of the infection. The terms "prevention" and "preventing" as used herein cover the prevention or prophylaxis of a condition or disease in an animal, preferably a mammal, more preferably a human and includes preventing the microbial infection from occurring in a subject which may be predisposed to infection but has not yet been diagnosed as being infected. [0071] In one embodiment, the present invention provides the use of a compound according to the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition related to melanocortin 5 receptor (MC5R) activity. [0072] In another embodiment, the present invention provides a compound according to the invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or condition related to melanocortin 5 receptor (MC5R) activity. [0073] In a further embodiment, the present invention provides a compound according to the invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson- Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies. [0074] The present invention also provides a pharmaceutical composition comprising a compound according to the invention, together with at least one pharmaceutically acceptable excipient. [0075] As will be readily appreciated by those skilled in the art, the route of administration and the nature of the pharmaceutically acceptable excipient will depend on the nature of the condition and the subject to be treated. It is envisaged that compounds according to the invention will be administered to a subject subcutaneously. It is believed that the choice of a particular carrier or delivery system and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the compound according to the invention care should be taken to ensure that the activity of the compound is not destroyed in the process and that the compound is able to reach its site of action without being destroyed. Similarly, the route of administration chosen should be such that the compound reaches its site of action. [0076] Those skilled in the art may readily determine appropriate formulations for the compounds of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art. Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA. [0077] It is envisaged that the compounds according to the invention will be prepared in parenteral dosage forms, including those suitable for subcutaneous, intravenous, intrathecal, and intracerebral or epidural delivery. The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against reduction or oxidation and the contaminating action of microorganisms such as bacteria or fungi. [0078] The solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for the active compound, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include agents to adjust osmolarity, for example, sugars or sodium chloride. Preferably, the formulation for injection will be isotonic with blood. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion. [0079] Sterile injectable solutions are prepared by incorporating the aqueous liquids of the invention in the required amount in the appropriate solvent with various of the other ingredients such as those enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. [0080] Pharmaceutically acceptable vehicles and/or diluents include any and all solvents, dispersion media, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. [0081] It is especially advantageous to formulate the compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be diagnosed; each unit containing a predetermined quantity of the compound calculated to produce the desired efficacy in association with the required pharmaceutically acceptable vehicle. The specification for the novel unit dosage forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the compound and the particular outcome to be achieved, and (b) the limitations inherent in the art of compounding the compounds of the invention in living subjects having a diseased condition in which bodily health is impaired. [0082] As mentioned above, compounds of the invention may be compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable vehicle in unit dosage form. A unit dosage form can, for example, contain the compound in amounts ranging from 0.25 μg to about 2000 mg. Expressed in proportions, the compound may be present in from about 0.25 μg to about 2000 mg/mL of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients. [0083] The invention will now be described with reference to the following non-limiting examples: General methods Materials [0084] Unless otherwise specified, chemicals were obtained from commercial suppliers and used without further purification. Amino acids, coupling reagents and Rink Amide resin were purchased from either AK Scientific USA, Auspep Australia, Chem-Impex International, or Sigma Aldrich Australia. The following side chain protecting groups were used: Cys(Trt), Asp(Oδ-tBu), His(Nim-Trt), Lys(Nε-Boc), Arg(Nγ-Pbf), and Trp(Nin-Boc). ACS organic solvents of analytical reagent (AR) grade and were acquired from Ajax Finechem Australia and Merck. All anhydrous reactions were performed using anhydrous solvents under nitrogen gas. [0085] Peptide purity were assessed by analytical reverse-phase HPLC on a Shimadzu LCMS-2020 system (Shimadzu Scientific Instrument) equipped with a Phenomenex Luna C8(2) column (100 Å, 100 mm x 2 mm x 3 μm) using a gradient (0 – 100% acetonitrile in water, 0.05% trifluoroacetic acid buffer) over 20 minutes at a flow rate of 0.2 mL/min, monitored at multiple wavelengths (200 – 254 nm). Peptide sequence was confirmed by ESI- MS analysis. High-resolution mass spectra (HRMS) were obtained on an Agilent 6224 ESI- TOF mass spectrometer (Agilent) coupled to an Agilent 1290 Infinity LC system. Molecular ions were denoted by [M + H]+. The purified peptides achieved a purity greater than 95% as determined by analytical HPLC. RP-HPLC peptide purification [0086] Purification of crude products was achieved using reverse-phase preparative HPLC on an Agilent 1200 series HPLC system incorporating with an Agilent 1260 Infinity II Variable Wavelength Detector (VWD) with either a Phenomenex Luna C8(2) column (100 Å, 250 mm x 21.2 mm x 10 μm) or a Phenomenex Luna Omega Polar C18 column (100 Å, 150 mm x 21.2 mm x 5 μm). Purification was accomplished using gradient mixtures of water and acetonitrile, with 0.1% trifluoroacetic acid, at a flow rate of 10 mL/min. UV-HPLC absorption was monitored at 214 nm and 254 nm. Purified peptides were recovered by lyophilisation. In all cases, peptides exhibited a purity greater than 95%, as determined by analytical HPLC. [0087] Standard solid-phase peptide synthesis (SPPS) was used for the preparation of linear precursors, followed by a solution phase cyclisation reaction (Scheme 1). As will be described, additional synthetic steps to introduce alternate functionality were incorporated at appropriate points within this general schema. [0088] The linear precursors were prepared on Rink Amide resin under standard SPPS conditions to give the peptide-resin (I), which were acetylated on-resin to give I. TFA cleavage afforded the linear peptides (II) in good yield and purity. Macrocyclisation reactions were performed with activation by PyClock in situ in DMF at a concentration of 2.5 mM. Cyclisation generally proceeded to completion within 24 hours. The desired products were then purified by RP-HPLC. Scheme 1. General synthetic method Example 1. Methods for Preparing Compounds of the General Formula (I) [0089] According to Scheme 1, the peptides of Table 1 were prepared by a sequence of solid phase peptide synthesis and solution phase macrocyclization. [0090] Synthesis of linear peptides was conducted on a Protein Technologies PS3 or Prelude automated peptide synthesizer using standard Fmoc solid-phase peptide chemistry. Specifically, synthesis was undertaken using Rink Amide Resin at 0.1 mmol scale. Coupling of the Fmoc-amino acids was performed using the default instrument protocol: 3 molar equivalents (relative to resin loading) of Fmoc amino acid and HCTU in DMF with activation in situ, using 6 molar equivalents of DIPEA. This was carried out for 50 min at room temperature. Fmoc deprotection was conducted using the default instrument protocol: 20% piperidine in dimethylformamide (2 × 5 min) at room temperature. Acetylation of resin-bound peptides was performed in DMF (0.05 mmol/mL). The linear peptide-resin was mixed with DIPEA (5 equiv.) and acetic anhydride (20 equiv.). The resin mixture was agitated at room temperature for 30 min and washed with DMF (3 x 30 s). [0091] Cleavage of linear peptide from the solid support was achieved using a cleavage solution of TFA, water, 1,3-dimethoxybenzene and triisopropylsilane (92.5 : 2.5 : 2.5 : 2.5, v/v), at a concentration of 5 mL/0.1 mmol resin. After agitating at room temperature for 2 hours, the resin was filtered and washed with TFA (3 mL). The filtrate was concentrated under N2, and the linear peptide was recovered by precipitation using diethyl ether (30-40 mL). The resulting peptide suspension was centrifuged at 3000 rpm for 5 min, and the supernatant was decanted. The crude peptide was dissolved in a minimum amount of 50% acetonitrile in water and lyophilised to yield off-white solids. Sequence confirmation was achieved by LC-MS. The peptide was in some cases, purified by RP-HPLC at this stage or carried through directly. [0092] For macrocyclization, the linear peptide was dissolved in DMF at concentration of 2.5 mM. To this solution PyClock (3 equiv.) and DIPEA (6 equiv.) were added. The reaction mixture was stirred at room temperature and monitored by LC-MS until the full consumption of the linear precursor was observed. The crude cyclic product was concentrated in vacuo and recovered by precipitation using diethyl ether (30 mL). This product was purified by RP-HPLC to give the products as a white powder. Synthesis of [0093] Compound 78 was obtained as a white powder in a yield of 65.5 mg. The purity was 98.3% as estimated by RP-HPLC at 214 nm. The compound was confirmed as having the correct molecular weight (1161.1) by ESI-MS analysis: m/z (monoisotopic): [M+H]+ = 1003.5373. [0094] The representative synthesis was applied to the synthesis of Compounds in Table 1 below. 0 0 6 5 0 5 5 117 14.527 b 950.7 53 17.9 843.45 5 0 5 3 0 1 0 0 2 4 9 5 1 5 7 0 9 48 15.9 1056.95 28 12.168 b 1033.46 Synthesis of N-alkyl substituted compounds [0095] The synthesis of some N-alkyl substituted compounds was performed by inclusion of a two-step N-alkylation (sub-monomer approach) where bromoacetylation of a resin- bound amine functionality was followed by nucleophilic substitution of the halogenated peptide as illustrated in Scheme 2 (Culf, A. S.; Ouellette, R. J. Molecules [Online], 2010, p. 5282-5335). Scheme 2. Synthesis of N-alkyl substituted compounds [0096] According to Scheme 2, amine-substituted peptide resin was treated with a solution of bromoacetic acid (10 equiv.) and diisopropylcarbodiimide (10 equiv.) in DMF (5 mL). The reaction mixture was stirred for 30 min, and the procedure was repeated. The resin was then washed with DMF (3 x 5 mL) and treated with a selection of amines (20 equiv.) in DMF (1 mL) for 2 hours. After the reaction was complete, the resin was rinsed with DMF (3 x 5 mL) and subjected to SPPS. The representative synthesis was applied to the synthesis of Compounds in Table 2 below. 50 03 90 14 24 09 60 39 96 32 20.075 1137.5942 4 15.765b 950.55 Introduction of substituents to the phenyl ring Method 1 – Solid phase Suzuki-Miyaura cross-coupling reactions [0097] Compounds where Fmoc-substituted ^-halophenylalanine residues were incorporated to the resin-bound peptide segments via standard SPPS were subjected to microwave(mw)-assisted Suzuki-Miyaura cross coupling reactions with a range of boronic acids in the presence of palladium catalysts to introduce the corresponding substituent to the phenyl ring (Scheme 3). Syntheses were continued as for Scheme 1 to provide the compounds as summarised in Table 3. Scheme 3. Introduction of substituents to the phenyl ring via Suzuki-Miyaura reaction on resin [0098] According to Scheme 3, Fmoc-4-iodophenylalnine was introduced into peptide sequences via automated SPPS. 4-Iodo-functionalised resin (120 mg, 0.05 mmol) and aryl boronic acids (2 equiv.) were placed in a dry microwave reaction vessel, to which was added a solution of toluene and ethanol (7 : 3, v/v, 1 mL) and 2 M Na2CO3 (0.1 mL). The mixture was degassed with N2 for 10 min and mixed with Pd(PPh3)4 (5 mol%). The reaction mixture was sealed and heated at 90 °C for 90 min in Discover SP Microwave Synthesiser (CEM Corporation). After irradiation, the resin mixture was washed with DMF, ethanol, methanol and diethyl ether (2 x 3 mL each), dried, and subjected to SPPS to complete the sequence. Representative synthesis was applied to the synthesis of compounds in Table 3. 26 05 29 58 90 93 69 50 81 16.311 1070.5803 109 18.425 1015.5445 Method 2 – Solution phase Suzuki-Miyaura cross-coupling reactions [0099] Peptide bearing a ^-(4-iodophenylalanine) residue at position 7 (e.g. Compound 88) was prepared following the general method of Scheme 1. Compound 88 was subject to a selection of SMC conditions and highly efficient cross-couplings were obtained with ferrocene-containing PdCl2(dppf) as the catalyst and KOAc as the base in DMF, to give the compounds of Table 4. Scheme 4. Introduction of substituents to the phenyl ring via Suzuki-Miyaura reaction in solution [0100] According to Scheme 4, a microwave reaction vessel containing cyclic peptides functionalised with halo-phenylalanine entities, aryl boronic acid (3 equiv.) and potassium acetate (5 equiv.) were added in anhydrous DMF (0.1 M). The mixture was degassed with N2 for 10 min and mixed with Pd(dppf)Cl2 (0.1 equiv.). The reaction mixture was heated at 100 °C for 4 hours in Discover SP Microwave Synthesiser (CEM Corporation) followed by agitating at room temperature for 12 hours. The reaction mixture was concentrated to dryness in vacuo to afford the crude product as a brown oil. The representative synthesis was applied to the synthesis of Compounds in Table 4 below. 81 10 39 17.916 1085.5793 Introduction of C-terminal basic amino acid residues and derivatives [0101] The introduction of C-terminal residues bearing basic residues was achieved by the use of selective protection using the ivDde group. Peptides were prepared according to Scheme 1 was chosen and sidechain ivDde protected Fmoc-Lys(ivDde), Fmoc-Orn(ivDde), Fmoc-Dab(ivDde) and Fmoc-Dap(ivDde). The ivDde protecting group was removed by treatment with 2% hydrazine in DMF to afford the desired peptides listed in Table 5. Scheme 5. General synthesis of compounds bearing a lysine or arginine isostere. [0102] According to Scheme 5, the ivDde protecting group of lysine was removed using 2% hydrazine in DMF. The reaction mixture was stirred at room temperature and monitored by LC-MS until the deprotection proceeded to completion. The crude product was concentrated in vacuo and recovered by precipitation using diethyl ether (15 mL) to afford off-white solid. The representative synthesis was applied to the synthesis of compounds in Table 5 below. [0103] Compound 20 was treated with the corresponding acid (2.0 equiv.), DIPEA (5.0 equiv.), and PyClock (4.0 equiv.) in DMF for 25 hours. The reaction mixture was concentrated in vacuo and the product isolated by preparative HPLC to yield Compound 170 and Compound 25. 2 9 1 0 21 15.307 b 1146.67 Guanidinylation of the C-terminal basic amino acid residues [0104] These products were amenable to guanidinylation. Treatment of the peptide with N,N’-di-Boc-1H-pyrazole-1-carboxamidine in the presence of DIPEA, yielded bis-Boc- protected guanidine intermediates (VII) which were subjected to Boc deprotection using TFA to afford macrocyclic peptides bearing an exocyclic guanidinylated amino acid residue as shown it Table 6. Scheme 6. Guanidinylation of the C-terminal basic amino acid residues a, 4.5 equiv. N,N’- di-Boc-1H-pyrazole-1-carboxamidine, 7.5 equiv. DIPEA, DMF, 48 h, RT; b, TFA, 2 h, RT, precipitation in diethyl ether, preparative HPLC. [0105] According to Scheme 6, cyclic peptides bearing a primary amine functionality were treated with a solution of N,N’-di-Boc-1H-pyrazole-1-carboxamidine (4.5 equiv.) and DIPEA (7.5 equiv.) in DMF for 48 hours. The reaction mixture was concentrated in vacuo. The remaining residue was treated with TFA for 2 hours and concentrated under N2. The resulting guanidinylated peptides were recovered by precipitation using diethyl ether. [0106] The representative synthesis was applied to the synthesis of Compounds in Table 6 below. 55 24 . 1179.6084 Acetylation of C-terminal basic amino acid residues [0107] Compounds (Table 7) were prepared by preparing cycling peptide Compound 20 (prepared as described above). After the ivDde protecting group was removed the precipitated white solid was treated with the corresponding acid (2.0 equiv.), DIPEA (5.0 equiv.), and PyClock (4.0 equiv.) in DMF for 25 hours. The reaction mixture was concentrated in vacuo and the product isolated by preparative HPLC. Scheme 7. Acetylation of the C-terminal basic amino acid residues a, carboxylic acid, DIPEA, PyClock, DMF, 25h. 8 1 5 122 12.50 b b 1991.2 [0108] Compounds 123-125 can be prepared by following the methods followed for the preparation of compounds in Table 7. Compounds prepared by on-resin cyclisation [0109] Peptides of Table 8 were prepared by SPPS with cyclisation on resin (Scheme 8). In the linear synthesis, Lys and Asp side chains were protected with alloc and allyl groups respectively. The alloc and allyl groups were removed by treating the resin with phenylsilane (20 equiv.) and Pd(PPh3)4 (0.1 equiv.) in DCM. The resin was then washed with DMF and treated with Pyclock (2.0 equiv.) and DIPEA (5.0 equiv.) in DMF for 15 hours. The resin was then washed with DMF then DCM then diethyl ether and the cyclic peptide cleaved from the resin with TFA and purified by preparative HPLC. Scheme 8. Solid phase cyclisation of peptides [0110] Compound 62 and Compound 64 were prepared by SPPS on 2-chlorotrityl resin (CTR). The linear sequences were cleaved from the resin by treatment with 20% hexafluoro- 2-propanol in DCM and concentrated in vacuo. [0111] To prepare Compound 56, the compound 62 was redissolved DMF (200 µL) and treated with 40% methylamine solution (20 µL) and PyClock (3.0 equiv.) for 15 hours. Solvent was removed in vacuo and the product purified by preparative HPLC. [0112] For Compounds 65 and 68, linear synthesis was completed on Rink Resin with the N-terminal Fmoc group retained. After alloc and allyl group removal and cyclisation, the products were treated with 20% piperidine in DMF. The resin was then washed with DMF then DCM then diethyl ether and the cyclic peptide cleaved from the resin with TFA and purified by preparative HPLC. 8 6 64 15.182 b 1186.87 [0113] Compound 57 and 58 were prepared by SPPS on CTR starting with treatment of CTR with diaminoPEG2 or diaminopentane and ending with the hexanoic acid being used in the last SPPS step. The linear sequence was removed from the resin by treatment with TFA. 57 18.2 802.40 58 18.7 800.40 Example 2. In vitro functional assay Cell culture and transfection [0114] Human embryonic kidney (HEK293) cells were transfected with the human MC1R, MC3R, MC4R, and MC5R through the Flp-In system using lipofectamine LTX. Stable receptor populations were determined using hygromycin B selection (200 ug/mL). Cells were maintained in high glucose and pyruvate Dulbecco’s Modified Eagle Medium (DMEM)) supplemented with 10% heat inactivated fetal bovine serum, 1% penicillin−streptomycin (10,000 U/mL), and 1% glutamax supplement in a humidified environment at 37 °C/5% CO2. Cells were grown to 70−80% confluency in a 75 cm2 tissue culture flask before splitting. Assay of MCR agonist activity (cAMP assay) [0115] Potency of the compounds at MC1R, MC3R, MC4R and MC5R were evaluated in vitro utilising transfected human embryonic kidney (HEK-293) cells stably expressing the melanocortin receptors via the LANCE cAMP assay (Revvity). The LANCE cAMP assay is a homogenous time-resolved fluorescence energy transfer (TR-FRET) immunoassay measuring cAMP produced by cells upon stimulation with agonists, in which the cellular cAMP is in competition with Europium-W8044 labelled cAMP tracer complex for the binding site on Alexa Fluor 647 dye labelled anti-cAMP antibodies. Excitation of europium chelated molecular tracer at 340 nm would produce energy that transfers to the fluorophore labelled antibodies bound to the tracer, emitting light at 665 nm. The cAMP levels from test compounds would increase in the presence of an agonist, causing a reduction in fluorescence signal at 665 nm. [0116] Flp-In HEK 293 cells stably expressing the melanocortin receptors were seeded at 15,000 cells/well into a 96-well cell culture plate and incubated overnight in DMEM medium at 37 °C/5% CO2. Before the experiment, growth media was replaced with stimulation buffer (90 μL) containing phenol red free DMEM medium, Bovine Serum Albumin (BSA; 0.1%, w/v), 3-isobutyl-1-methylxanthine (IBMX; 0.1 mM or 0.5 mM), and cells were incubated for an additional 30 minutes at 37 °C/5% CO2. Cells were stimulated with increasing concentrations (0.1 pM to 1 μM) of peptide ligands (10 μL) diluted in stimulation buffer and incubated for 45 minutes at 37 °C/5% CO2. The reaction was ceased by removal of the buffer containing the peptide and addition of ice-cold absolute ethanol (50 μL). After ethanol evaporation, cells were lysed with lysis buffer (225 μL, pH 7.4) containing BSA (0.1%, w/v), Tween 20 (0.3%, v/v) and HEPES buffer (5 mM). Lysate (5 μL) was transferred to a 384- well optiplate. The amount of cAMP produced in each sample was determined using the LANCE Ultra cAMP Detection Kit (PerkinElmer) with modifications to the instructions from the manufacturer. Briefly, 10 μL of Eu-cAMP tracer solution (1:200 dilution of Eu- cAMP tracer stock in detection buffer) and 5 μL of U-light anti cAMP solution (17:5000 dilution of U-light anti-cAMP stock in detection buffer) was added into each well containing lysate in reduced light conditions and the plate was left to incubate at room temperature for 1 hour. Time-resolved fluorescence (TR-FRET) for the samples was detected using Envision plate reader with excitation at 320 nm and emission at 615 nm. All data was analysed using GraphPad Prism 9. EC50 values represent the mean of the experiment performed in triplicates. EC50 estimated and its associated standard errors were determined by fitting the data using a non-linear regression analysis. The maximal cAMP produced at 1 μM of each compound in relation to the amount generated by the reference compound MT-II was expressed as a percentage. [0117] [0118] Table 10. Assay Data for In vitro functional assay 5 03 M M M M M M M M M M 22 0.013 2.09 >25 >500 M M M M M M M M M M M M M M M M M M M M M M M M M M M 6.9 ± 0.2 327 ± 133 49%@1uM 1%1uM M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M 0.35 110 >100 >100 Example 3. In vitro binding assay – Fluorescence Activated Cell Sorting based competition binding assay [0119] Binding affinity of active melanocortin ligands for melanocortin receptors was determined in vitro utilising transfected human embryonic kidney (HEK-293) cells stably expressing the melanocortin receptors via fluorescence-Activated Cell Sorting (FACS) based competition binding assays with fluorophore labelled melanocortin peptides. Saturation binding assays performed on fluorescent peptide ligands allowed determination of their dissociation constants (Kd) and the number of binding sites. The binding of unlabelled ligands was measured in the presence of a fluorophore labelled melanocortin ligand, that would compete for binding to the same sites, at a fixed concentration to quantify the level of receptor binding and selectivity. [0120] The inhibition of fluorescence signal by displacement of sCy5-[Nle4, ^-Phe7]-α- MSH (sCy5-MT-I) by peptide ligands was detected by a Stratedigm S1000EXI flow cytometer (Stratedigm). Binding assays were performed on HEK-293 cells stably expressing human melanocortin receptors 1, 3, 4 or 5. On the day of the experiment whole cells were washed twice with freshly prepared binding buffer (pH 7.4) made up in 10 X Hanks’s Balanced Salt Solution supplemented with 20 mM N-(2-hydroxyethyl)- piperazine-N′-(2- ethanesulfonic acid) (HEPES; pH 7.4), and BSA (0.5%, w/v). Cells were seeded at 100,000 cells/well in ice cold binding buffer (80 μL) in a clear u-bottom 96-well plate. Dissociation constant (Kd) of sCy5-MT-I was determined through a saturation binding assay, in which total binding and non-specific binding were determined by incubation of increasing concentrations of sCy5-MT-I (10 μL, 1 pM to 10 nM in binding buffer) in the absence and presence of 10 μM [Nle4, D-Phe7]-α-MSH (MT-I; 10 μL) respectively for 2 hours. For competition binding assay, cells were stimulated with a fixed concentration of labelled sCy5- MT-I (10 uL, 3 nM for MC1R, 3R, 5R or 15 nM for MC4R) in the presence of increasing concentrations of unlabelled peptide ligand diluted in binding buffer (10 uL, 1 pM to 1 uM). After incubation for 2 h at 4°C, cells were washed twice with ice-cold binding buffer (100 uL, pH 7.4) and resuspended in binding buffer (100 μL) containing propidium iodide (PI) solution (1:2000 dilution of stock). Florescence intensity of the cell suspension was analysed using Stratedigm S1000EXI flow cytometer (Stratedigm) with an excitation of 642 nm and an emission between 661 nm and 690 nm for sCy5 detection and with an excitation of 488 nm and an emission between 600 nm and 630 nm for PI detection. Cell Capture analysis software (Stratedigm) was used to extract the files and imported into FlowJo software (Flowjo Inc) to analyse the data. [0121] Gating was conducted to identify sCy5-positive living cells to be used for the measurement of mean fluorescence intensity (MFI). The total binding and non-specific binding data acquired from saturation binding assays were fitted and analysed using a one- site binding model and non-linear regression analysis in GraphPad Prism 9 (GraphPad Software). Specific binding was determined by subtracting non-specific binding from total binding and the obtained values were fitted onto a one-site specific binding curve using non- linear regression analysis. The experiment was repeated four times with three replicates in each experiment. Ki values represent the mean of the experiments. All competition binding data were fitted using non-linear least-squared regression in GraphPad Prism 9 (GraphPad Software) for analysis. IC50 values and the associated standard errors were calculated by the average of the experiment in triplicates. Ki values were calculated from the IC50 values using the Cheng-Prusoff equation Ki = IC50/(1 + [R]/Kd), where [R] and Kd represent the fixed concentration and equilibrium dissociation constant of sCy5-MT-I, respectively. Kd values used for sCy5-MT-I were 1.6 nM (MC1R), 2.6 nM (MC3R), 5.2 nM (MC4R) and 3.4 nM (MC5R). Test compounds were subject to completion a binding assay (Table 11). 9 6.5 ± 0.10 6.9 ± 0.10 <6.0 8.4 ± 0.30 43.60 20.60 >50 60 8.1 ± 0.20 7.6 ± 0.20 <6.0 9.0 ± 0.20 9.75 35.0 >50 Example 4. In vitro glucose uptake assay Differentiation of L6 cells [0122] Cells were either seeded either on a 12 well plate at a cell density of 100,000 cells per well or on a Corning 96 well white clear plate at a cell density of 10,000 cells per well. Upon reaching 80% confluency, differentiation was induced by switching the medium to high glucose DMEM supplemented with sodium pyruvate, glutaMAX, 2% (v/v) heat inactivated FBS and 1% (v/v) P/S. Cells were monitored daily, and the medium was changed every second day. Cells had completely differentiated into multinucleated myotubes by Day 7. Differentiation of NHP Skeletal Muscle Satellite cells [0123] Cells were either seeded either on a 12 well plate coated with 0.01% (v/v) collagen from calf skin at a cell density of 50,000 cells per well or on a Corning 96 well white clear plate coated with 0.01% (v/v) collagen from calf skin at a cell density of 5000 cells per well. Upon reaching 80% confluency, differentiation was induced by switching the medium to differentiation medium made up of low glucose DMEM (Gibco, Thermo Fisher Scientific, MA, USA) supplemented with sodium pyruvate, glutaMAX, 2% (v/v) heat inactivated HS, 1% (v/v) P/S, 25mM Hepes, 0.5 mg/mL sterile BSA and 0.5 mg/mL fetuin from FBS. Cells were monitored daily, and the medium was changed every second day. Cells were completely differentiated into multinucleated myotubes by Day 8. [0124] Prior to the experiment, fully differentiated L6 myotubes were serum starved overnight for 18 hours in high glucose DMEM supplemented with sodium pyruvate and glutaMAX. Similarly, fully differentiated NHP skeletal muscle myotubes were serum starved overnight for 18 hours in low glucose DMEM supplemented with sodium pyruvate, glutaMAX, 25mM Hepes and 0.5 mg/mL sterile BSA. [0125] On the day of the assay, cells were gently rinsed twice with pre-warmed glucose starved DMEM supplemented with glutaMAX (Gibco, Thermo Fisher Scientific, MA, USA). Following the wash, the plate was immediately placed on a 37°C hot plate to maintain the incubation temperature and pre-warmed glucose starved medium (180 ^L) was added into each well. The cells were stimulated with either Actrapid^ insulin (100 IU/mL) (McFarlane Medical, Vic, Aus), test compound or both (20 ^L) and the cells were incubated for 2 hours at 37°C and 5% CO2. All test compounds were dissolved in medium to obtain the desired concentration prior to stimulation. [0126] The amount of glucose uptake in the cells was quantified using Promega’s glucose uptake Glo assay (Promega, WI, USA) with some alterations to the manufacturer’s instructions. Briefly, after the incubation, cells were rinsed twice with pre-warmed PBS and the plate was placed on a 37°C hot plate to maintain incubation temperature.0.1 mM of 2- deoxyglucose diluted in prewarmed PBS (50 ^L) in the presence of test compound diluted in PBS (5 ^L) was added into each well and the cells were incubated for a further 30 minutes at 37°C and 5% CO2. The reaction was terminated by adding stop buffer (25 ^L), neutralisation buffer (25 ^L) and detection buffer (100 ^L) made up of luciferase reagent (100 ^L) supplemented with NADP+ (1 ^L), G6DPH (2.5 ^L), reductase (0.5 ^L) and reductase substrate (0.0625 ^L). The lysate was left to incubate at RT for 1 hour and the luminescence was measured using Envision plate reader containing an aperture attached with a 96 well plate luminescence mirror module. [0127] Glucose uptake assays were conducted at least in triplicate with duplicates biological replicates in each experiment. Results obtained was plotted into an into a column graph with interleaved scatter with bar plot with each data point representing the mean signal for the experiment. To normalise the results, the signal produced by the test compound was compared to the signal produced by the vehicle. Statistical analysis was performed using analysis of variance (ANOVA), Dunnett's test. Asterisks represent statistical significance where ns denotes p> 0.05, * denotes p ≤ 0.05, ** denotes p ≤ 0.01, *** denotes p ≤ 0.001 and **** denotes p ≤ 0.0001. Table 12. Eval . 110 135 23 Table 13. Eval yotubes . 110 125 30 Example 5. Pharmacokinetic studies Solubility studies of MC5R agonists [0128] The kinetic solubility of peptides was determined in PBS (pH 7.4). Compound (10 μL) dissolved in DMSO at a final concentration of 10mM was spiked into PBS (240 μL) and the tube containing the sample was incubated at RT in the dark for 24 hours. The next day, the sample was centrifuged at 18,000g for 15 minutes and the supernatant was filtered using a 25mm 0.22 μM syringe filter (Millipore, Sigma, MA, USA). The filtrate was either diluted 1:5, 1:10 or 1:100 in ACN containing 1% (v/v) FA based on the size of the pellet and the sample was spiked with internal standard before being transferred to a clean tube for analysis on the LCMS. Calibration curve of peptide (0, 1, 5, 10, 50, 100, 500, 1000, 5000, 10,000 ng/mL) was prepared on the day of analysis by spiking peptide and internal standard into PBS diluted in CAN containing 1% (v/v) FA acid to mirror the biological matrix. Table 14. Ev .4) 110 0.80 ± 0.60 In vitro and ex vivo plasma stability assays [0129] In vitro stability of peptide was accessed in rat plasma obtained from the Monash animal research platform (Monash University, Vic, Australia). The plasma (96.9 μL) was diluted to pH7.4 with PBS (21.9 μL) and heated to 37°C in an Eppendorf tube before use. The reaction was initiated by spiking peptide (1.2 μL) into the prepared plasma to yield a final concentration of 1 μM. The tube containing the plasma was vortexed for 15 to 30 seconds before being placed onto a thermomixer comfort (Eppendorf, Hamburg, Germany) at 37°C. Samples (10 μL) were taken at 0, 15, 30, 60, 120, 180 mins. Calibration curve of peptide (0, 5, 10, 50, 100, 500, 1000 ng/mL) was prepared on the day of analysis by spiking prepared peptide stock solutions into plasma diluted with PBS. All plasma samples were treated with 80% ACN in 1% (v/v) FA to extract the peptide. Samples were spiked with internal standard and vortexed for 30 seconds before being subjected to centrifugation at 18,000g for 15 minutes in a microcentrifuge (5425R) (Eppendorf, Hamburg, Germany) at 4°C. The supernatant was transferred to a clean tube for analysis on the LCMS. Table 15. Pla 110 2.59 Table ) 00 45 5 230 ± 40 480 ± 60 In vitro microsome stability assay [0130] Microsomal stability assay was conducted by the Centre for Drug Candidate Optimisation (CDCO) in MIPS. Briefly, the microsomal stability assay was performed by incubating test compounds at a final concentration of 1 μM with human liver microsomes (0.5 mg/mL) at 37°C. The metabolic reaction was initiated by the addition of preformed NADPH and quenched at various time points over 60 min by addition of ACN. Control samples with no cofactor were included to assess the contribution of NADPH-independent metabolic pathways. Quenched samples were left on ice for approximately 15 minutes. The samples were spiked with internal standard, centrifuged and the supernatant was removed and analysed on the LCMS. The samples containing test compounds were analysed by the LCMS method described above. 1) 110 0.0188 0.61 37.7 Example 6. In vivo efficacy evaluation in pharmacological models of glucose handling [0131] Test compounds were assessed in STZ induced T1D mouse models of glucose handling to demonstrate pharmacological efficacy in vivo. STZ induced T1D mice instrumented with continuous intravenous glucose monitoring were treated with vehicle, reference melanocortin peptides, or test compounds via continuous infusion or bolus injection to measure their anti-hyperglycaemic activities, and subsequently underwent glucose challenge test to evaluate the effect of test compounds on the blood glucose level. In-vivo evaluation [0132] The in vivo efficacy of the test compounds in stimulating glucose uptake was further characterised in T1D mouse models. In vivo evaluation was performed on STZ induced T1D mice. [0133] The test compounds were assessed in vivo in STZ induced T1D mice for glucose handling. Change in blood glucose for STZ-mice treated with 1μg/g IP and blood samples were collected at shown time intervals. STZ-mice have elevated blood glucose levels typically in the range on 15-20 mmol. [0134] Method: Adult C57Bl 6/J mice were made diabetic with 5 days STZ ip injections (50mg/kg). Once plasma blood glucose has risen above mol/L the experiment was started. Following the blood sampling at 0 mins, Mice were treated with vehicle or compound (1μg/kg). Plasma blood glucose concentration was measured at 0, 15, 60, 90 and 120mins Table 17 of 45 -19.9 4.3 6 Mean and Peak change in blood glucose with or without insulin administration [0135] Method: Adult C57Bl 6/J mice were made diabetic with 5 days STZ ip injections (50mg/kg). Once plasma blood glucose has risen above mol/L the experiment was started. Plasma blood glucose concentration was measured at 0, 5, 15, 30, 45, 60, 90 and 120mins. Following the blood sampling at 0mins, Mice were treated with veh or compound (1mg/kg) with or without insulin (1U/kg or 2U/kg) or veh (Figure 1, Table 18).
Table 18. Mean and Peak change in blood glucose with or without insulin administration Mean percentage change in blood Peak percentage reduction in blood M M 02 886 14 186 79 45 64 46 42 85 44 37 18 578 .0 785 87 989 57 716 83 886 .0 .65 80 345 55 741 95 423 70 745 .8 .79 26 + INSULIN 1U 7 -31.72 6.618 26 + INSULIN 1U 7 -56.26 8.923 [0136] It should also be noted that no toxic effects were seen in any test animals. Collectively, the dataset provided proof-of-concept evidence supporting MC5R selective agonist therapeutics as a promising addition to the treatment of T1D. Example 7 Activity of compounds in macaque animal model [0137] Glucose handling was measured in a macaque animal model. In brief, animals were administered test compounds by infusion over a set time period, and blood glucose levels were measured. This data show effects of test compounds in reducing high blood glucose levels without affecting basal blood glucose levels. [0138] Animal treatments included as shown in Figure 2a, a High Fat Diet (HFD)-induced diabetic (hyperglycaemic animal) female pigtail macaque (13 yrs. old) which was treated with Compound 30 at a dose of 0.334mg/kg/hr for 150 minutes. Fasting glucose levels were reduced from 401 to 257.4 mg/dL (37%) over a 90 minute period (n=1). In Figure 2b, infusion of HDF-induced pre-diabetic (normal basal glucose) female pigtail macaques (14- 20 yrs. old) with Compound 30 at a dose of 0.334mg/kg/hr for 150 minutes did not reduce fasting baseline glucose levels prior to the animals receiving a bolus glucose (600mg/kg). (n=2) [0139] A shown in Figure 3, a metabolically healthy male longtail macaque (yrs) was treated with an infusion of Compound 45 at a dose of 0.668mg/kg/hr for 45 minutes. Fasting baseline glucose levels were not reduced. Bolus glucose (600mg/kg), was administered at t = 0 min and glucose levels measured for 60 minutes. The amount of glucose in the circulation from 0-60min in the presence of Compound 45 (n=1) was reduced by 19% as compared to a sex-matched control that received saline alone, (Total area under the curve). Example 8 Study of chronic effects of constant compound infusions on hyperglycaemia and the need for insulin. Adult C57Bl/6J mice were injected with STZ (50mg/kg) daily for 5 consecutive days. Mice were then implanted with Continuous blood glucose probes. Baseline blood glucose measurements (3-5 days) were collected and a HbA1c value taken. Mice were then implanted with a 28 day minipump containing veh or compound (PTM Cmp 5 or Cmp 9) (0.6mg/kg/hr). Mice were then injected with Insulin Determir (1U/kg) twice daily (AM and PM) for the next 28 days. As blood glucose was recording, it was checked that insulin dosing is not dropping plasma blood glucose too low. If insulin treated mice had a consistent peak drop in blood glucose of below 16.5mmol/l insulin dose would be reduced to 0.5U/kg. If insulin treated mice had a consistent peak drop in blood glucose of below 12.5mmol/l insulin treatment was stopped. Mice had blood glucose measured throughout the treatment period and HbA1c was measured weekly throughout the treatment period. The treatment groups were 1. Minipump: Veh/SC daily injection Veh 2. Minipump: Veh/SC daily injection Insulin 3. Minipump: Cmp 5/SC daily injection insulin 4. Minipump: Cmp 9 /SC daily injection Insulin A 28-day treatment with Cmp 5 + insulin, Cmp 9 + insulin, and vehicle (veh) + insulin significantly reduced blood glucose levels compared to veh + veh-treated mice. This reduction in blood glucose was reflected in significantly lower HbA1c levels in the Cmp 5 + insulin group compared to the veh + veh and veh + insulin groups after 3 weeks of treatment. Cmp 5 + insulin reduced insulin requirements by 25.4% after 28 days of treatment compared to veh + insulin. Cmp 5 + insulin also shifted plasma glucose time-in-range toward lower blood glucose levels compared to veh + insulin and veh + veh over the 28-day treatment period. The results are shown below in Table 19. Table 19: Effects of chronic treatment with vehicle or test compounds upon (A) Plasma Glucose (B) HbA1c (C) required insulin dose and (D) time spent in Plasma Glucose se radiotelemetry of veh + veh or veh + insulin or Cmp5 + insulin or Cmp9 + insulin hr. lin ly. of ted ed. 01, mp ns ay 9.99 0 4.8 ± 1.67 10.34 ± 1.50 6.53 ± 2.02 p-5 ed to veh + veh, veh + insulin, Cmp 9 + insulin. Mean +/- SEM, n=4-6

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A : (I), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; A is selected from the group consisting of phenyl, 5 to 7-membered heteroaryl and cyano, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1-4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1- 4alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, homoalanine, leucine, isoleucine, norleucine, valine and norvaline; or R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; and each R4A is independently selected from the group consisting of ‒OH, nitro, halo, C1- 4alkyl and ‒OC1-4alkyl; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine- isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; p is selected from 0, 1 and 2; and q is selected from 1, 2 or 3; provided that when A is , one or more of the following apply: R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or aryl ring RA is substituted with 1, 2 or 3 RB; or R3 is selected from the group consisting of C1-4alkyl and optionally substituted benzyl and R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl; or R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, 2-aminoisobutyric acid, arginine, norleucine, norvaline and phenylalanine; or R7C is optionally substituted C2-6alkyl or ‒((CH2)2O)2CH2CH3. 2. A compound according to claim 1, of formula (Ia):
(Ia) or a pharmaceutically acceptable salt thereof, wherein each R10 is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6- 10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and n is selected from 0, 1, 2 and 3. 3. A compound according to claim 1 or 2, of formula (Ib): (Ib) or a pharmaceutically acceptable salt thereof, wherein ‒X‒ is selected from the group consisting of: ‒CH2C(O)NH(CH2)4‒, ‒(CH2)4NHC(O)CH2‒, ‒(CH2)2C(O)NH(CH2)4‒ and ‒(CH2)4NHC(O)(CH2)2‒. 4. A compound according to claim 1 of formula (II):
(II), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 is a side chain of the amino acid alanine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R3 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R3A; each R3A is independently selected from the group consisting of halo, C1-4alkyl, ‒OC1- 4alkyl, nitro and N(R3B)2; each R3B is independently selected from the group consisting of hydrogen and C1-6alkyl; R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, 2-aminoisobutyric acid, alanine, arginine, norleucine, norvaline and phenylalanine; R9 is hydrogen, C1-6alkyl or, together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, aspartic acid , homoarginine, lysine-toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine-isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]- stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine- palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; R11 is hydrogen or is a side chain of the amino acid norleucine; R12 is C1-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR12A; R12A is selected from the group consisting of halo, C1-4alkyl and C1-4haloalkyl; R13 is selected from the group consisting of hydrogen and C1-4alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; ‒X‒ is selected from the group consisting of: ‒CH2C(O)NH(CH2)4‒, ‒(CH2)4NHC(O)CH2‒, ‒(CH2)2C(O)NH(CH2)4‒ and ‒(CH2)4NHC(O)(CH2)2‒; and n is selected from 0, 1, 2 and 3. 5. A compound according to claim 4 of formula (IIa): (IIa) or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 5 of formula (IIb):
(IIb), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 is a side chain of the amino acid alanine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl, wherein the 4 to 10-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1, 2, or 3 R2A; each R2A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline and phenylalanine; R9 is hydrogen, C1-6alkyl or, together with the nitrogen atom to which it is attached, is an amino acid selected from the group consisting of lysine, arginine, aspartic acid , homoarginine, lysine-toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine-isobutylphenylbutyric acid, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]- stearic diacid, lysine-[PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine- palmitic acid, lysine-N-dihexane, diaminopropionic acid and GdnAla; optionally wherein the amino acid is amidated at the C-terminus; R11 is hydrogen or is a side chain of the amino acid norleucine; R12 is C1-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR12A; R12A is selected from the group consisting of halo, C1-4alkyl and C1-4haloalky; R13 is selected from the group consisting of hydrogen and C1-4alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; each R15 is independently selected from the group consisting of halo, C1-4alkyl, ‒O C1-4alkyl, nitro and N(R15A)2; each R15A is independently selected from the group consisting of hydrogen, C1-6alkyl; and m and t are independently selected from 0, 1, 2 and 3. 7. A compound according to claim 6 of formula (IIc): (IIc), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5, R6, R14, R15, m and t are as defined in claim 6; and R9 is hydrogen, or, together with the nitrogen atom to which it is attached, is an amino acid selected from the group consisting of lysine and arginine, wherein the amino acid is amidated at the C-terminus. 8. A compound according to claim 4, wherein: R3 is C1-4alkyl; and R4 is a side chain of an amino acid selected from the group consisting of alanine, leucine and valine. 9. A compound according to claim 1 or 2 of formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of hydrogen and methyl; R6 is hydrogen or is a side chain of an amino acid selected from the group consisting of tryptophan, alanine, homoalanine, arginine, norleucine, norvaline, histidine, phenylalanine and homophenylalanine; or R5 and R6, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-6alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-isobutylphenylbutyric acid, lysine- [PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N- dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; or R9 is selected from the group consisting of hydrogen and C1-6alkyl; each R14 is independently selected from the group consisting of halo and C1-4alkyl; m is selected from 0, 1, 2 or 3; and q is selected from 1, 2 or 3. 10. A compound according to claim 9 of formula (IIIa) (IIIa) or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 1 of formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl, 5 to 7-membered heteroaryl and cyano, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; R3 and R4, together with the atoms to which they are attached, combine to form a 5 or 6- membered monocyclic heterocyclyl, wherein the 5 or 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 R4A; and each R4A is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; ‒X‒ is selected from the group consisting of: ‒CH(NHR7)CH2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒CH(NHR7)(CH2)4NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)3CH(R8)‒,‒CH(NHR7)(CH2)3NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)(CH2)3NHC(O)(CH2)2CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)CH2CH(R8)‒, ‒CH(NHR7)(CH2)2C(O)NH(CH2)2CH(R8)‒, ‒CH(NHR7)(CH2)2NHC(O)(CH2)2CH(R8)‒, ‒(CH2)2C(O)NH(CH2)4CH(R8)‒, ‒(CH2)2C(O)NH(CH2)3CH(R8)‒, ‒CH(NHR7)CH2C(O)NH(CH2)2O(CH2)2‒ and ‒CH(NHR7)CH2C(O)NH(CH2)5‒; R7 is selected from the group consisting of hydrogen, ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, ‒C4-7cycloalkyl a 5 to 7-membered heterocyclyl, or a 5 to 7-membered heteroaryl; R7A is hydrogen or is a side chain of an amino acid selected from the group consisting of norleucine, homophenylalanine and diaminopropionic acid; each R7B is independently selected from the group consisting of hydrogen, C1-4alkyl, benzyl and ‒C(O)R7C; R7C is selected from the group consisting of C1-18alkyl and ‒((CH2)2O)2CH2CH3, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; R8 is selected from the group consisting of ‒C(O)NHR9 and ‒C(O)OH; R9 together with the nitrogen atom to which it is attached, is an amino acid residue selected from the group consisting of lysine, arginine, homoarginine, aspartic acid, lysine- toluylbutyric acid, lysine-iodophenylbutyric acid, lysine-TTBA, lysine-stearic diacid, lysine-[Lys-PEG2-PEG2-Glu]-stearic diacid, lysine-isobutylphenylbutyric acid, lysine- [PEG2-Lys-PEG2-Glu]-stearic diacid, lysine-myristic diacid, lysine-palmitic acid, lysine-N- dihexane, diaminopropionic acid and GdnAla, optionally wherein the amino acid residue is amidated at the C-terminus; R9 is selected from the group consisting of hydrogen and C1-6alkyl; p is selected from 0, 1 and 2; and q is selected from 1, 2 or 3; provided that when A is , one or more of the following apply: C6-10aryl ring RA is substituted with 1, 2 or 3 RB; or R7C is C2-6alkyl; or R4 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; or R3 and R4, together with the atoms to which they are attached, combine to form a 5- membered monocyclic heterocyclyl. 12. A compound according to claim 11 of formula (IVa):
(IVa) or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 1, 2 or 3. 13. A compound according to claim 11 of formula (IVb): (IVb) or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10- membered monocyclic or bicyclic heterocyclyl; R7 is selected from the group consisting of ‒C(O)C1-6alkyl and ‒C(O)CH(R7A)N(R7B)2, wherein the ‒C(O)C1-6alkyl is optionally substituted with halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; R7A is hydrogen or is a side chain of the amino acid norleucine; each R7B is independently selected from the group consisting of hydrogen and ‒C(O)R7C; R7C is C2-6alkyl, wherein C1-C6alkyl is optionally substituted with ‒C4-C7arylR7D, halo, C4-7cycloalkyl or a 5 to 7 membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur; or R7C together with the carbonyl group to which it is attached, is an amino acid residue selected from the group consisting of arginine, histidine and serine, optionally wherein the amino acid residue is acylated at the N-terminus; R7D is selected from the group consisting of hydrogen, halo and C1-6alkyl; each R14 is independently selected from the group consisting of halo, C1-4alkyl and ‒OC1-4alkyl; and m is selected from 0, 1, 2 or 3. 14. A to claim 11 of formula (IVc): (IVc) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen or is a side chain of an amino acid selected from the group consisting of alanine, norvaline and leucine; each R14 is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and m is selected from 0, 1, 2 or 3. 15. (IVd) or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; and p is selected from 0, 1 and 2. 16. A to claim 11 of formula (IVe): (IVe) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C1-4alkyl and benzyl, wherein benzyl is optionally substituted with 1, 2 or 3 R1A; each R1A is independently selected from the group consisting of halo, C1-4alkyl, nitro and N(R1B)2; each R1B is independently selected from the group consisting of hydrogen and C1- 6alkyl; R2 is hydrogen; or R1 and R2, together with the atoms to which they are attached, combine to form a 4 to 10 membered monocyclic or bicyclic heterocyclyl; A is selected from the group consisting of phenyl and 5 to 7-membered heteroaryl, wherein the phenyl and 5 to 7-membered heteroaryl are optionally substituted with one, two or three RA; each RA is independently selected from the group consisting of halo, cyano, C6-10aryl, 5 to 7-membered heteroaryl, C1-4alkyl, ‒OC1-4alkyl, ‒C1-4alkylC6-10aryl and ‒OC1- 4alkylC6-10aryl, wherein the C6-10aryl, 5 to 7-membered heteroaryl, ‒C1-4alkylC6-10aryl and ‒OC1-4alkylC6-10aryl is optionally substituted with 1, 2 or 3 RB; each RB is independently selected from the group consisting of halo, C1-4alkyl, -OC1-4alkyl, and –C(O)C1-4alkyl; each R16 is independently selected from the group consisting of ‒OH, nitro, halo, C1-4alkyl and ‒OC1-4alkyl; p is selected from 0, 1 and 2; and u is selected from 0, 1 and 2. 17. A compound according to claim 1, or pharmaceutically acceptable salt thereof, selected from the group consisting of: D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 Ac Nle (D P D-Bip N-Bzl-Gly Nva K) D NH2 NO: 23 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 Ac Nle (D P D-Bip Pip A Orn) NH D 2 NO: 49 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 Ac Nle (D P D-Bip Pip L K) NH D 2 NO: 75 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 0 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 00 aa Nle (D P D-Bip Pip W K) NH D 2 NO: 101 D 02 D 03 D 04 D 05 D 06 D 07 D 08 D 09 D 10 D 11 D 12 D 13 D 14 D 15 D 16 D 17 D 18 D 19 D 20 D 21 D 22 D 23 Ac Nle (D P D-Bip N-Bzl-Gly Nva K) D NH2 NO: 124 18. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: . 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient. 20. A method of treating or preventing a disease or condition related to melanocortin 5 receptor (MC5R) activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof. 21. The method according to claim 20, wherein the disease or condition related to MC5R activity is selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson-Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies. 22. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition related to melanocortin 5 receptor (MC5R) activity. 23. Use according to claim 22, wherein the disease or condition related to melanocortin 5 receptor (MC5R) activity is selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson- Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies. 24. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or condition related to melanocortin 5 receptor (MC5R) activity. 25. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition selected from the group consisting of diabetes, obesity, cardiomyopathy, heart failure, kidney diseases, insulin receptoropathies, Rabson-Mendenhall syndrome, Donohue syndrome, type a and B insulin resistance syndromes and lipodystrophies.
PCT/AU2025/050638 2024-06-14 2025-06-13 Cyclic peptidomimetics as mc5r agonists Pending WO2025255635A1 (en)

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BEDNAREK MARIA A., MACNEIL TANYA, TANG RUI, FONG TUNG M., CABELLO M. ANGELES, MAROTO MARTA, TERAN ANA: "Potent and Selective Agonists of Human Melanocortin Receptor 5: Cyclic Analogues of α-Melanocyte-Stimulating Hormone", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 50, no. 10, 1 May 2007 (2007-05-01), US , pages 2520 - 2526, XP093385692, ISSN: 0022-2623, DOI: 10.1021/jm0614275 *

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