NMU receptor 2 agonist

Abstract

The present invention relates to NMU-8 analogs that are neuromedin U receptor 2 (NMUR2) agonists, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy, particularly in the treatment or prevention of diseases and / or conditions associated with or modulated by NMUR2 activation, such as obesity or obesity comorbidities.

Description

[Technical Field]

[0001] The present invention relates to NMU-8 analogs that are neuromedin U receptor 2 (NMUR2) agonists, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy, particularly in the treatment or prevention of diseases and / or conditions associated with or modulated by NMUR2 activation, such as obesity and its comorbidities. [Background technology]

[0002] Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. In this regard, overweight and obesity are major risk factors for several chronic diseases, including diabetes, particularly prediabetes and type 2 diabetes, cardiovascular disease, and certain types of cancer. Despite many years of efforts in related fields, the number of overweight and obese patients continues to increase. First-line treatments for overweight and obese patients include diet and exercise, but are often not sufficiently effective. Second-line treatment options are bariatric surgery and pharmacotherapy. Available pharmacological treatments largely lack sufficient efficacy and / or tolerability, and only a limited number of approved therapies are available in the United States and Europe. Therefore, there remains a high medical need for more effective, safe, and acceptable treatment options. Neuromedin U (hereinafter referred to as NMU) is a bioactive brain-gut peptide that was originally isolated from porcine spinal cord based on its ability to contract smooth muscle. Neuromedin U receptor 1 (NMUR1) and neuromedin U receptor 2 (NMUR2) are the major receptors for NMU and are primarily expressed in the gastrointestinal tract and central nervous system, respectively.

[0003] The sequence of NMU is highly conserved among species, indicating the physiological relevance of this peptide. The NMU peptide is a C-terminally amidated peptide, and the two major forms consist of 25 amino acid residues in humans and pigs (NMU-25) and 23 amino acid residues in rodents (NMU-23). ​​The human NMU-25 peptide consists of the following C-terminally amidated amino acid sequence: Phe-Arg-Val-Asp-Glu-Glu-Phe-Gln-Ser-Pro-Phe-Ala-Ser-Gln-Ser-Arg-Gly-Tyr-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2 (hNMU-25, SEQ ID NO: 89). A shorter form of the peptide consisting of the C-terminal eight amino acid residues was identified as the active cleavage product of NMU-25 in pigs (designated porcine NMU-8) and dogs (designated canine NMU-8). All mammalian species tested share the same C-terminal seven amino acid residues that are thought to be critical for biological activity (Brighton et al., Pharmacol. Rev. 2004, 56, 231-248). The C-terminal eight amino acid peptide derived from human NMU-25 consists of Tyr-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2 (hereinafter referred to as NMU-8, SEQ ID NO: 90). The amino acid sequence of the C-terminal eight residues of human NMU-25 is identical to that of porcine NMU-8.

[0004] The role of NMU in regulating feeding and energy homeostasis has been well documented (Teranishi et al., Int. J. Mol. Sci. 2021, 22, 4238). Intracerebroventricular administration of NMU attenuated food intake and feeding-related behaviors in rodents (Howard et al., Nature 2000, 406, 70-74), as well as increased locomotor activity and core body temperature (Nakazato et al., Biochem. Biophys. Res. Commun. 2000, 277, 191-194). It has been reported that local injection of NMU into the paraventricular nucleus (PVN) or arcuate nucleus (ARC) of the hypothalamus also exerts anorectic effects, similar to its intracerebroventricular administration; therefore, it is hypothesized that the primary site of action of NMU is the PVN and ARC (Wren et al., Endocrinology 2002, 143, 4227-4234). Furthermore, intracerebroventricular administration of NMU antiserum to rats has been shown to increase food intake, suggesting that central NMU exerts a physiological effect of suppressing food intake (Kojima et al., Biochem. Biophys. Res. Commun. 2000, 76, 435-438). It has also been reported that NMU knockout mice exhibit an obese phenotype (Hanada et al., Nat. Med. 2004, 10, 1067-1073), and that NMU overexpression in mice results in a lean phenotype due to improved glucose homeostasis (Kowalski et al., J. Endocrinol. 2005, 185, 151-164). Acute and chronic peripheral administration of NMU in rodents has been observed to dose-dependently reduce food intake and body weight (Peier et al., Endocrinology 2011, 152, 2644-2654).Furthermore, recent studies in lean and DIO (diet-induced obese) mice have shown that peripheral administration of a peptidic NMUR2 agonist with extended plasma stability due to N-terminal PEGylation resulted in neuronal activation in the ARC and dorsal vagal complex, resulting in inhibition of food intake and weight loss (Kaisho et al., Int. J. Obesity 2017, 41, 1790-1797; Kanematsu-Yamaki et al., J. Med. Chem. 2017, 60, 6089-6097; Nagai et al., British J. Pharmacol. 2018, 175, 359-373). Furthermore, mutations in the endogenous ligand of NMUR2 have been associated with obesity in humans; missense mutations in NMUR2 have been found in obese children and adults, and two different coding variants have been associated with an increased prevalence of overweight and obesity (Hainerova et al., Clin. Endocrinol Metab. 2006, 91, 5057-5063; Mitchel et al., British J. Pharmacol. 2009, 158, 87-103). Therefore, it has been suggested that NMU and its analogs may be effective in regulating and treating metabolic disorders such as obesity and diabetes. However, the in vivo activity of NMU and NMU analogs is often compromised by rapid degradation of the peptides after administration.

[0005] Unfavorable pharmacokinetic properties of native NMU (e.g., short mean residence time (MRT) or half-life (t 1 / 2(The half-life of native NMU after subcutaneous injection is less than 5 minutes) was improved by conjugation with high-molecular-weight polyethylene glycol (PEG) moieties (PEGylation) (Ingallinella et al., Bioorg. Med. Chem. 2012, 20, 4751-4759) or human serum albumin (HSA) (Neuner et al., J. Pept. Sci. 2014, 20, 7-19), both of which showed long-lasting and potent appetite-suppressing and glucose-normalizing activity.

[0006] NMU analogs containing polyethylene glycol (PEG) modifications are well known and have been studied. However, NMU analogs containing PEG moieties exhibit significant disadvantages: high-molecular-weight PEG chains are typically polydisperse, which poses significant challenges in the isolation, purification, and analysis of related NMU analogs. Meanwhile, the high stability of ether bonds in biological systems limits biodegradability, which can lead to accumulation and vacuolation in organs (Wang et al., Biomacromolecules 2020, 21, 3134-3139; Hong et al., J. Pharmacol. Toxicol. Methods 2020, 102, 106678).

[0007] Another strategy for modifying NMU or its analogs to provide increased and / or prolonged in vivo activity is by the addition of functional groups, such as lipids (lipidation), that result in binding to serum albumin (e.g., lipids can be added to C 10 -C 20 A fatty acid or a derivative thereof, e.g., a palmitate moiety. Bioorganic & Medicinal Chemistry Letters vol. 27 (2017) pages 4626-4629 describes a leucine (Leu) at position 20. 20 ) and asparagine at position 25 (Asn 25 and alkylated NMU-8 analogs containing phenylalanine (Phe) at position 19. 19 ) and arginine at position 24 (Arg 24) substitution plays a role in conferring selectivity for hNMUR2 over hNMUR1 (i.e., Table 1: NMU-8 and compounds 13-16 vs. compounds 17-21 in Bioorganic & Medicinal Chemistry Letters, supra).

[0008] WO2006 / 068326, WO2007 / 075439, WO2007 / 109135, WO2009 / 042053, WO2009 / 044918, WO2010 / 053830, WO2010 / 116752, WO2010 / 138343, WO2011 / 005611, WO2012 / 050227, WO2015 / 095719, WO2018 / 135641, WO2018 / 135642 and EP2842965A1 disclose PEGylated, lipidated or non-lipidated NMU analog peptides having agonist activity at the NMU receptor for use in the treatment of metabolic disorders such as obesity and diabetes. Summary of the Invention

[0009] Object of the invention The administration of NMU analog compounds with short in vivo half-lives must be repeated frequently, for example, once a day. Such administration is usually performed subcutaneously, which is disadvantageous for patients due to inconvenience. Such frequent administration can cause pain and discomfort to patients. There is a need in the art for long-acting NMU analogs that selectively act on NMU receptor 2, that are substantially safe and well tolerated when administered peripherally, and that exhibit appetite-reducing effects. In particular, it would be desirable to improve the pharmacokinetic profile of long-acting NMU analogs by extending their in vivo half-life (or mean residence time, MRT), since long-acting NMU analogs increase the interval between two consecutive drug administrations (e.g., once a week or even less frequently), improving patient compliance and reducing associated costs. Additionally, it would be desirable to provide NMU analogs that are well tolerated, particularly with regard to adverse gastrointestinal effects such as nausea, vomiting and / or diarrhea.

[0010] For example, it would be desirable to provide an NMUR2 agonist with high selectivity over NMUR1.NMUR2 selectivity generally leads to a compound that is better tolerated compared with non-selective compounds.NMUR1 is highly expressed in gastrointestinal tissue, and therefore plays a role in gastrointestinal motility, and NMUR1 agonists can cause adverse gastrointestinal effects such as diarrhea (Dass et al., British J. Pharmacol. 2007, 150, 502-508; Nagai et al., British J. Pharmacol. 2018, 175, 359-373). Additionally, it would be desirable to provide NMUR2 agonists that have solubility and chemical / physical stability suitable for administration to humans in need of therapy, particularly those suitable for subcutaneous administration. The present invention provides NMU-8 analog compounds according to general formula (I), which are potent agonists of NMUR2. U-Sp-LP-NH2(I) (wherein U, Sp, L and P are defined as follows): NMU-8 analogs according to general formula (I) exhibit high functional agonist activity (EC 50 ) and for peptides that retained binding affinity (Ki) (see Tables 4 and 5).

[0011] In addition to their agonistic properties at NMUR2, the compounds of the present invention offer further advantageous properties that make them viable for human therapy, such as selectivity over NMUR1 (Tables 4 and 5 and Tables 12A-B), extended in vivo half-lives or mean residence times (Tables 6 and 13A-B), high solubility in the pH range of 4-8, preferably in the pH range of 6-8 (Table 7), high chemical stability (Table 8) and / or favorable physical stability (Table 9). Thus, the compounds of the present invention have potential for human therapy in the treatment of diseases and / or conditions that can be affected by NMUR2 agonism, with the potential to be administered less frequently and still be effective. Accordingly, one aspect of the present invention refers to compounds according to general formula (I) or salts thereof, preferably pharmaceutically acceptable salts thereof, as agonists of NMUR2. A further aspect of the present invention refers to compounds according to general formula (I) or salts thereof, preferably pharmaceutically acceptable salts, as agonists of NMUR2 with high selectivity over NMUR1. A further aspect of the present invention refers to compounds according to general formula (I) or salts thereof, preferably pharmaceutically acceptable salts, as agonists of NMUR2 with high selectivity over NMUR1 and extended in vivo half-life.

[0012] A further aspect of the present invention refers to compounds according to general formula (I) or salts thereof, preferably pharmaceutically acceptable salts, as agonists of NMUR2 for human therapy, in particular those viable for subcutaneous administration, having high selectivity over NMUR1, extended in vivo half-life and suitable solubility in the pH range of 4 to 8, preferably in the pH range of 6 to 8.

[0013] A further aspect of the present invention refers to compounds according to general formula (I) or salts thereof, preferably pharmaceutically acceptable salts, as agonists of NMUR2 for human therapy, in particular those having high selectivity over NMUR1, extended in vivo half-life, suitable solubility in the pH range of 4 to 8, preferably in the pH range of 6 to 8, and suitable chemical and / or physical stability, which are feasible for subcutaneous administration. In a further aspect, the present invention relates to a pharmaceutical composition, preferably a pharmaceutical composition suitable for subcutaneous administration, comprising at least one compound according to general formula (I) or a pharmaceutically acceptable salt thereof, together with one or more inert adjuvants, diluents and / or carriers. In a further aspect, the present invention relates to a compound according to general formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, for therapeutic use in a method for the prevention or treatment of disorders due to activation of NMUR2, such as obesity, overweight conditions and their co-morbidities, as disclosed hereinbelow. In a further aspect, the present invention relates to a process for preparing the compounds of the present invention or salts thereof, particularly pharmaceutically acceptable salts thereof. The process may comprise the steps of synthesizing the NMU-8 analogue by solid-phase or solution-phase methodology, and optionally isolating and / or purifying the final product.

[0014] In a further aspect, the present invention relates to a compound of the invention for use in a method for the prevention or treatment of a disorder caused by activation of NMUR2 as disclosed below, wherein the compound is administered as part of a combination therapy with at least one further active agent suitable for treating the disorder or condition mentioned in the present application, preferably wherein the further active agent is an anti-obesity agent. In a further aspect, the present invention relates to pharmaceutical compositions comprising the compounds of the present invention and at least one further active agent suitable for treating the disorders or conditions mentioned in the present application, preferably an anti-obesity agent, as well as the use of the pharmaceutical compositions in methods for the prevention or treatment of the disorders that are the focus of the present invention. Further aspects and embodiments of the present invention will become apparent from the following disclosure. Each aspect, embodiment or invention disclosed above and below can be construed as a separate or independent invention. DETAILED DESCRIPTION OF THE INVENTION

[0015] General definition Terms not specifically defined herein should be given the meaning that would be given them by one of ordinary skill in the art in light of this disclosure and context. However, as used herein, unless specified to the contrary, the following terms have the meanings indicated and the following conventions are observed.

[0016] NMU-8 analogs of the present invention The term "NMU-8 analogs of the invention" or "compounds of the invention" refers to compounds of general formula (I). U-Sp-LP-NH2(I) (In the formula, P is a group represented by the general formula (II) Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 129) (II) a peptide having the amino acid sequence U, Sp and L are defined as follows: Peptide P of general formula (II) corresponds to the NMU-8 amino acid sequence set forth in SEQ ID NO:90, in which two or more amino acid residues are replaced by amino acid residues that are each independently a naturally occurring or non-naturally occurring amino acid residue as defined below. Thus, NMU-8 analogs of the invention according to general formula (I) are peptides whose structure is related to NMU-8 set forth in SEQ ID NO:90.

[0017] Throughout this specification, the amino acid positions in peptide P of general formula (II) are numbered according to the corresponding positions in NMU-8 shown below (the number shown in superscript after the amino acid represents the amino acid position number). Specifically, the position of tyrosine (Tyr) at the N-terminus of NMU-8 is considered to be position 1, and the position of asparagine (Asn) at the C-terminus is considered to be position 8. Tyr 1 -Phe 2 -Leu 3 -Phe 4 -Arg 5 -Pro 6 -Arg 7 -Asn 8 -NH2 (SEQ ID NO: 90) In peptide P of general formula (II), the amino acid residues at positions 1, 2 and 7 are amino acid residues that are not changed relative to NMU-8, the amino acid residues at positions 3, 4 and 8 are amino acid residues that are changed relative to NMU-8, and the amino acid residues at positions 5 and 6 can each independently be either amino acid residues that are changed or not changed relative to NMU-8.

[0018] In particular, at position 3, the leucine (Leu) present in NMU-8 is changed to an N-methyl-leucine (NMeLeu) residue; at position 4, the phenylalanine (Phe) present in NMU-8 is changed to a norleucine (Nle) residue; and at position 8, the asparagine (Asn) present in NMU-8 is changed to a glycine (Gly) residue. Additionally, the arginine (Arg) and proline (Pro) present in NMU-8 at positions 5 and 6, respectively, may each independently be replaced by a X as disclosed below. 5 and X 6 The amino acid residues are either changed or not changed according to the definition of .

[0019] Throughout this specification, naturally occurring amino acids are designated by their conventional three-letter or one-letter abbreviations (e.g., Arg or R for arginine, etc.) unless referred to by their full name (e.g., alanine, arginine, etc.). In the case of certain less common or non-naturally occurring amino acids (i.e., amino acids other than the 20 encoded by the standard mammalian genetic code), unless referred to by their full name (e.g., γ-glutamic acid, etc.), the frequently used three- or four-letter code is used for the residue (e.g., g-Glu or γ-Glu for (S)-γ-glutamic acid, Dbu for (S)-2,4-diaminobutyric acid, etc.). Unless otherwise indicated, reference is made to the L-isomer form of the amino acid in question. Unless otherwise specified, compounds or residues containing chiral centers have the stereochemistry depicted.

[0020] The term "NMU-8 analog" or "compound" of the present invention refers to a peptide in which a "half-life extending group" (briefly U) is covalently attached to the amino group of the N-terminal amino acid residue (i.e., Tyr) of peptide P via a spacer and linker (briefly Sp and L, respectively), and an "NH group" is attached to the C-terminal amino acid residue (i.e., Gly) of peptide P, resulting in a C-terminal amidated peptide. The term "NMU-8 analog" or "compound" of the present invention refers to the compound of general formula (I) itself as well as to the compound of general formula (I) in an ionized state (e.g., (de)protonated). The meanings of residues U, Sp, L and P are given below as embodiments of the present invention ( 「*」 indicates a point of attachment to another part of the compound). Any and each of these definitions and embodiments can be combined with each other.

[0021] U is a half-life extending group (i.e., a lipophilic substituent) connected to a spacer Sp via an amide bond (i.e., U-Sp-), wherein the acyl group of U is linked to the amino group of Sp. U is selected from the group consisting of C16DA, C18DA, and C20DA; C16DA stands for 15-carboxy-pentadecanoyl [ka] C18DA denotes 17-carboxy-heptadecanoyl, [ka] C20DA denotes 19-carboxy-nonadecanoyl. [ka] Without wishing to be bound by any particular theory, it is believed that such lipophilic substituents U (or moieties U-Sp-) bind to albumin and other plasma components in the bloodstream, thereby shielding the compounds of the invention from renal filtration and enzymatic degradation, and thus possibly enhancing the half-life of the compounds in vivo.

[0022] Sp has the formula -(gGlu) n -(Sar) m- a spacer according to (SEQ ID NO: 149), wherein n is an integer selected from the group consisting of 1, 2, 3, and 4, m is an integer from 3 to 15, preferably from 6 to 15 (i.e., selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15), and gGlu and Sar are as defined below.

[0023] Most preferably, Sp has the formula -(gGlu) n -(Sar) m - a spacer according to (SEQ ID NO: 115), wherein n is an integer selected from the group consisting of 1, 2, 3 and 4, and m is an integer selected from the group consisting of 3, 6, 9, 12 and 15; gGlu (γGlu or isoGlu) refers to a residue of (S)-γ-glutamic acid (also known as (2S)-2-aminopentanedioic acid); [ka] Sar(MeGly) refers to a sarcosine residue (also known as N-methylglycine or 2-(methylamino)acetic acid or [2-(methylamino)acetyl]) [ka]

[0024] For example, the spacer "-(gGlu) n -(Sar) m -(where n is 3 and m is 9)" denotes the residues "-(gGlu)3-(Sar)9-", which corresponds to "-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-" and has the following structure: [ka] In the spacer depicted above, three residues of gGlu are connected to each other via amide bonds, the acyl group of the terminal gGlu residue is connected to the amino group of one terminal Sar residue via an amide bond, and the nine Sar residues are connected to each other via amide bonds.

[0025] The spacer Sp is connected to U via an amide bond and to L via an amide bond (i.e., U-Sp-L), the amino group of the terminal gGlu residue is connected to the acyl group of U via an amide bond, and the acyl group of the terminal Sar residue is connected to the amino group of L via an amide bond, i.e., U-gGlu-[...]-Sar-L.

[0026] L is a linker containing an amino group and an acyl group, the amino group being connected via an amide bond to the acyl group of the terminal Sar residue of the spacer Sp, and the acyl group being connected via an amide bond to the amino group of the amino acid at sequence position 1 of the peptide P (i.e., -Sp-L-Tyr-).

[0027] L is selected from the group consisting of AEPipAc, PipAc, and AECMP; AEPipAc refers to the residue of 2-[4-(2-aminoethyl)piperazin-1-yl]acetic acid; [ka] PipAc refers to the residue of 2-(piperazin-1-yl)acetic acid; [ka] AECMP refers to the residue of 2-[1-(2-aminoethyl)piperidin-4-yl]acetic acid. [ka] P is a peptide according to formula (II): Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 129) (II)

[0028] peptide P comprises both natural L-amino acids selected from the group consisting of Tyr (Y), Phe (F), Arg (R), Gly (G), His (H), Pro (P) and Lys (K), and unnatural amino acids selected from the group consisting of 2Pal, 3Pal, 4Pal, NMeLeu (NMeL), Nle, Dbu, Orn, NMeAla (NMeA), NMeArg (NMeR), hLys (hK) and bAla (bA); 2Pal refers to the residue of (2S)-2-pyridyl-alanine;

[0029] [ka] 3Pal refers to the residue of (2S)-3-pyridyl-alanine; [ka] 4Pal refers to the residue of (2S)-4-pyridyl-alanine; [ka] NMeLeu (NMeL) refers to the residue of (2S)-N-methyl-leucine;

[0030] [ka] Nle (norleucine) refers to a residue of (S)-norleucine or (2S)-2-aminohexanoic acid; [ka] Dbu refers to the residue of (2S)-2,4-diaminobutyric acid or (2S)-2,4-diaminobutanoic acid; [ka] Ornithine refers to the residue of (2S)-2,5-diaminopentanoic acid. [ka] NMeAla (NMeA) refers to the residue of (2S)-N-methyl-alanine; [ka] NMeArg (NMeR) refers to the residue of (2S)-N-methyl-arginine; [ka] hLys (hK, homo-lysine) refers to a residue of (2S)-2,6-diaminohexanoic acid; [ka] b-Ala (bA, beta-alanine) refers to the residue of 3-aminopropanoic acid. [ka]

[0031] Compound nomenclature: For example (compound number 26 in Table 3), C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-Tyr-Phe-NM eLeu-Nle-Dbu-Pro-Arg-Gly-NH2 (SEQ ID NO: 26) (i.e., C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sa r-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 26) or [17-carboxy-heptadecanoyl]-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 26) (In the formula, C18DA is connected to the terminal gGlu residue via its α-carboxy group; gGlu-gGlu-gGlu (i.e., (2S)-2-[(4S)-4-[(4S)-4-amino-4-carboxybutanamido]-4-carboxybutanamido]pentanedioic acid) is connected to C18DA via the amino group of a terminal gGlu residue and to a terminal Sar residue via the γ-carboxy group of another terminal gGlu residue; Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar (i.e., 2-{N-methyl-2-[N-methyl-2-(N-methyl-2-{N-methyl-2-[N-methyl-2-(N-methyl-2-{N-methyl-2-[N-methyl-2-(N-methyl-2-{N-methyl-2-[N-methyl-2-(N-methyl-2-{N-methyl-2-[N-methyl-2-(N-methyl-2-{N-methyl-2-[N-methyl-2-(methylamino)acetamido]acetamido}acetamido)acetamido]acetamido}acetamido)acetamido]acetamido}acetamido)acetamido]acetamido}acetamido)acetamido]acetamido}acetamido)acetamido}acetamido)acetamido}acetic acid) is connected to a terminal gGlu residue via the amino group of a terminal Sar residue and to AEPipAc via the carboxy group of another terminal Sar residue; AEPipAc (i.e., 2-[4-(2-aminoethyl)piperazin-1-yl]acetic acid) is attached to the terminal Sar residue via its amino group and to Tyr via its carboxy group; Tyr is connected to AEPipAc via its amino group and to Phe via its carboxy group; Phe is connected to Tyr through its amino group and to NMeLeu through its carboxy group; NMeLeu is connected to Phe through its amino group and to Nle through its carboxy group; Nle is connected to NMeLeu through its amino group and to Dbu through its carboxy group; Dbu is connected to Nle through its amino group and to Pro through its carboxy group; Pro is connected to Nle through its amino group and to Arg through its carboxy group; Arg is connected to Pro through its amino group and to Gly through its carboxy group; Gly is connected to Arg through its amino group and to NH2 through its carboxy group; NH2 is connected to the carboxy group of Gly) completely defines an NMU-8 analog with the following structure:

[0032] [ka] (SEQ ID NOs: 26 and 26, respectively, in order of appearance). Alternatively, the same compound can be defined in the following way: 17-{[(1S)-3-{[(1S)-3-{[(1S)-3-({[({[({[({[({[({[({[({2-[4-({[(1S)-1-{[(1S)-1-{[(1S)-1-{[(1S)-1-{[(2S)-4-amino-1-[(2S)-2-{[(1S)-4-carbamimidamido-1-[(carbamoyl butyl)carbamoyl]butyl]carbamoyl}pyrrolidin-1-yl]-1-oxobutan-2-yl]carbamoyl}pentyl]carbamoyl}-3-methylbutyl](methyl)carbamoyl}-2-phenylethyl]carbamoyl}-2-(4-hydroxyphenyl)ethyl]carbamoyl}methyl)piperazin-1-yl]ethyl}carbamoyl )methyl](methyl)carbamoyl}methyl)(methyl)carbamoyl]methyl}(methyl)carbamoyl)methyl](methyl)carbamoyl}methyl}(methyl)(methyl)carbamoyl)methyl](methyl)carbamoyl}methyl}(methyl)(methyl)carbamoyl)methyl](methyl)carbamoyl}methyl}(methyl)(methyl)carbamoyl)methyl](methyl)carbamoyl}methyl}(methyl)(methyl)carbamoyl)methyl](methyl)(methyl)carbamoyl]methyl}(methyl)carbamoyl)-1-carboxypropyl]carbamoyl}-1-carboxypropyl]carbamoyl}-1-carboxypropyl]carbamoyl}heptadecanoic acid (SEQ ID NO: 26) or 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 26)

[0033] Additional definitions As used herein, the term "pharmaceutically acceptable salt" is intended to refer to a salt that is not harmful to the patient or subject to whom the salt in question is administered. This may suitably be, for example, a salt selected from among acid addition salts and base salts. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed analogs or compounds, where the parent analog or compound is modified by making its acid or base salt. Examples of acid addition salts include trifluoroacetate, chloride, citrate, and acetate salts. Examples of base salts include substituted ammonium ions, such as N(R1)(R2)(R3)(R4), together with alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions. + wherein R, R, R, and R are independently hydrogen or an optionally substituted C 1-6-alkyl) ions. Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), "Encyclopaedia of Pharmaceutical Technology", 3 rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66: 1, pages 1-19 (1977).

[0034] The term "pharmaceutically acceptable adjuvants, diluents, and / or carriers" includes any standard pharmaceutical adjuvants, diluents, and / or carriers. Pharmaceutically acceptable adjuvants, diluents, and / or carriers for therapeutic use are well known in the pharmaceutical arts and are described, for example, in "Remington's Pharmaceutical Sciences," 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof). For example, sterile saline and phosphate-buffered saline at weakly acidic or physiological pH can be used. Suitable pH buffers can be, for example, phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine, or acetate, or a mixture thereof. The term further encompasses any adjuvant, diluent and / or carrier agent listed in the United States Pharmacopoeia for use in humans. The term "agonist", as used in the context of the present invention, refers to a substance that activates the receptor type in question, typically by binding to it (ie, as a ligand).

[0035] The term "treatment" and its grammatical variants (e.g., "treated," "treating," "treating"), when used in this context, refers to an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of the disease, stabilization of the disease state (i.e., not worsening), delaying or slowing of disease progression, palliation or alleviation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Thus, a subject in need of treatment may be one already suffering from the disease or disorder in question. The term "treatment" includes inhibition or reduction of the increase in severity of a pathological condition or symptom (e.g., weight gain or hyperglycemia) compared to the absence of treatment, and does not necessarily intend to imply a complete cessation of the associated disease, disorder, or condition.

[0036] The term "prevention" and its grammatical variants (e.g., "prevented," "preventing," "prevent"), when used in this context, refers to an approach for impeding or preventing the onset of or altering the pathology of a condition, disease, or disorder. Accordingly, "prevention" can refer to a prophylactic or preventative measure. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, preventing or slowing the symptoms, progression, or onset of a disease, whether detectable or undetectable. Thus, a subject in need of "prevention" may be a subject who does not yet suffer from the disease or disorder in question. Thus, the term "prevention" includes inhibiting or slowing the onset of a disease compared to the absence of treatment, and is not necessarily intended to imply permanent prevention of the associated disease, disorder, or condition. The terms "patient," "subject," and "individual" can be used interchangeably and refer to a human.

[0037] Detailed Description of the Invention In a first aspect, the present invention provides an NMU-8 analogue compound of general formula (I), or a salt thereof, preferably a pharmaceutically acceptable salt thereof: U-Sp-LP-NH2(I) [In the formula, U is selected from the group Ug1 consisting of 15-carboxy-pentadecanoyl (briefly, C16DA), 17-carboxy-heptadecanoyl (briefly, C18DA) and 19-carboxy-nonadecanoyl (briefly, C20DA); Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 149) wherein n is selected from the group consisting of 1, 2, 3, and 4; m is an integer of 3 to 15 (i.e., selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15), preferably an integer of 6 to 15; a terminal gGlu residue is linked to U and a terminal Sar residue is linked to L; L is selected from the group Lg1 consisting of AEPipAc, PipAc and AECMP; P is a group represented by the general formula (II) Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 112) (II) (In the formula, X 5 is a group X consisting of Arg, Dbu, NMeArg, Orn, Lys, His, hLys, 2Pal, 3Pal and 4Pal 5 selected from g1, X 6 is a group X consisting of Pro, NMeAla, bAla and Gly 6 g1)

[0038] Preferably, in a first aspect, the present invention provides an NMU-8 analogue compound of general formula (I), or a salt thereof, preferably a pharmaceutically acceptable salt thereof: U-Sp-LP-NH2(I) [In the formula, U is selected from the group Ug1 consisting of 15-carboxy-pentadecanoyl (briefly, C16DA), 17-carboxy-heptadecanoyl (briefly, C18DA) and 19-carboxy-nonadecanoyl (briefly, C20DA); Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 115) wherein n is selected from the group consisting of 1, 2, 3, and 4; m is selected from the group consisting of 6, 9, 12, and 15, and optionally 3 (i.e., 3, 6, 9, 12, and 15, or 6, 9, 12, and 15); the terminal gGlu residue is linked to U and the terminal Sar residue is linked to L; L is selected from the group Lg1 consisting of AEPipAc, PipAc and AECMP; P is a group represented by the general formula (II) Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 112) (II) (In the formula, X 5 is a group X consisting of Arg, Dbu, NMeArg, Orn, Lys, His, hLys, 2Pal, 3Pal and 4Pal 5 selected from g1, X 6 is a group X consisting of Pro, NMeAla, bAla and Gly 6 g1) Unless otherwise specified, groups, amino acid residues and substituents, in particular U, Sp, L, P, X 5 and X 6 are defined as above and below. Preferred values ​​of some of the radicals and amino acid residues of the compounds according to the invention are given below. In a further embodiment of the invention U is selected from the group Ug2 consisting of C18DA and C20DA. In a further embodiment of the invention U is selected from the group Ug3 consisting of C18DA. In a further embodiment of the invention U is selected from the group Ug4 consisting of C20DA.

[0039] In a further embodiment of the invention, Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 116) (Wherein, n is 3 or 4, m is selected from the group Spg2 consisting of: 9, 12 and 15, preferably m is 12 or 15). In a further embodiment of the invention, Sp is -(gGlu) n -(Sar) m - (wherein n is 3, m is 12 or 15, preferably m is 15).

[0040] In a further embodiment of the invention, Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 118) (wherein n is 4, m is 12 or 15, preferably m is 15. In a further embodiment of the invention L is selected from the group Lg2 consisting of AEPipAc and PipAc. In a further embodiment of the invention, L is selected from the group Lg3 consisting of AEPipAc.

[0041] In a further embodiment of the invention, P is a group of general formula (II) Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 113) (II) (In the formula, X 5is a group X consisting of Arg, Dbu, NMeArg, Orn and Lys, preferably Arg, Dbu, NMeArg and Orn 5 Selected from g2; X 6 is a group X consisting of Pro and NMeAla 6 g2) It is a peptide having the amino acid sequence:

[0042] In a further embodiment of the invention, P is a group of general formula (II) Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 114) (II) (In the formula, X 5 is a group X consisting of Arg, Dbu and Orn 5 Selected from g3; X 6 is a group X consisting of Pro 6 g3) It is a peptide having the amino acid sequence: Each embodiment of the present invention described herein can be taken alone or in combination with one or more other embodiments of the present invention. According to one preferred embodiment of the present invention, the peptide P of general formula (II) is selected from the group consisting of Table 1: [Table 1]

[0043] According to another embodiment, the present invention provides NMU-8 analogs of general formula (I): (In the formula, U is selected from the group Ug2 consisting of C18DA and C20DA; Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 115) wherein n is selected from the group consisting of 1, 2, 3 and 4; m is selected from the group Spg1 consisting of: 6, 9, 12 and 15, and optionally 3; L is selected from the group Lg2 consisting of AEPipAc and PipAc; P is a peptide of formula (II) selected from the group consisting of Table 1

[0044] In another preferred embodiment, the present invention provides NMU-8 analogs of general formula (I): wherein U is selected from the group Ug2 consisting of C18DA and C20DA; Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 116) wherein n is selected from the group consisting of 3 and 4; m is selected from the group consisting of 9, 12 and 15, preferably m is 12 or 15; L is selected from the group Lg2 consisting of AEPipAc and PipAc; P is a peptide of formula (II) selected from the group consisting of Table 1

[0045] According to another preferred embodiment, the present invention provides NMU-8 analogues of general formula (I): wherein U is selected from the group Ug3 consisting of C18DA; Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 116) wherein n is selected from the group consisting of 3 and 4; m is selected from the group Spg2 consisting of: 9, 12 and 15, preferably m is 12 or 15; L is selected from the group Lg2 consisting of AEPipAc and PipAc; P is a peptide of formula (II) selected from the group consisting of Table 1).

[0046] In another preferred embodiment, the present invention provides NMU-8 analogs of general formula (I): wherein U is selected from the group Ug4 consisting of C20DA; Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 116) wherein n is selected from the group consisting of 3 and 4; m is selected from the group Spg2 consisting of: 9, 12 and 15, preferably m is 12 or 15; L is selected from the group Lg2 consisting of AEPipAc and PipAc; P is a peptide of formula (II) selected from the group consisting of Table 1.

[0047] Further preferred embodiments of the compound of general formula (I) U-Sp-LP-NH2 are shown as embodiments A-1 to A-25 in Table 2 below (including salts and pharmaceutical salts thereof), and the definitions of groups, amino acid residues, and substituents are used as described above. For example, the entry "Ug2" in the U column of column A-1 means that in embodiment A-1, the substituent U is selected from the Ug2 defined above. Similarly, the other variables Sp, L, X incorporated into general formula (I) are also used. 5 and X 6 The same applies to Embodiments A-2 and A-6 to A-25 in Table 2. More preferred embodiments are A-6, A-11, A-19 and / or A-25, most preferred.

[0048] [Table 2-1] [Table 2-2]

[0049] Accordingly, for example, embodiment A-6 of Table 2 covers compounds of formula (I), or a salt thereof, preferably a pharmaceutically acceptable salt. [In the formula, U is selected from the group Ug2 consisting of C18DA and C20DA; Sp is -(gGlu) n -(Sar) m -(SEQ ID NO: 116) wherein n is selected from the group consisting of 3 and 4; m is selected from the group Spg2 consisting of: 9, 12 and 15, preferably selected from the group consisting of 12 and 15; L is selected from the group Lg2 consisting of AEPipAc and PipAc; P is the peptide Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 113) (In the formula, X 5 is a group X consisting of Arg, Dbu, NMeArg, Orn and Lys, preferably Arg, Dbu, NMeArg and Orn 5 selected from g2, X 6 is a group X consisting of Pro and NMeAla 6 g2) is selected from More preferred are the following compounds or salts thereof, preferably pharmaceutically acceptable salts, listed in Table 3. In Table 3, the compound numbers correspond to the numbers assigned in the experimental section; all SEQ ID NOs refer to compounds of formula (I) U-Sp-LP-NH2.

[0050] [Table 3-1] [Table 3-2] The NMU-8 analogs of the present invention according to general formula (I), preferably the compounds of Table 3, are capable of binding to human NMU receptor 2 (hNMUR2) (see Table 4).

[0051] Binding to biological receptors can be measured by suitable assays known in the art. For example, the binding of the NMU-8 analogs of the present invention to human NMU receptor 2 (hNMUR2) can be assessed by a radioligand binding competition assay, for example, as described in Example 1 below. In some embodiments, the compounds of the present invention have a binding affinity (Ki) for hNMUR2 of less than 1000 nM (eg, 0.1 nM to 1000 nM). In some embodiments, the compounds of the present invention have a binding affinity (Ki) for hNMUR2 of less than 250 nM (eg, 0.1 nM to 250 nM). In some embodiments, the compounds of the present invention have a binding affinity (Ki) for hNMUR2 of less than 100 nM (eg, 0.1 nM to 100 nM). In some embodiments, the compounds of the present invention have a binding affinity (Ki) for hNMUR2 of less than 50 nM (eg, 0.1 nM to 50 nM). In some embodiments, the compounds of the present invention have a binding affinity (Ki) for hNMUR2 of less than 25 nM (eg, 0.1 nM to 25 nM). The NMU-8 analogs of the present invention activate human NMU receptor 2 (hNMUR2), ie, are NMU receptor 2 agonists (see Table 5).

[0052] Generally, it is preferable to use a biological assay that measures the intracellular signal transduction caused by the binding of a compound to the relevant receptor.The activation of NMU receptor by the compound of the present invention (which acts as an agonist of the receptor) increases the concentration of myo-inositol-1-phosphate (IP1), which leads to intracellular signal transduction pathways.Therefore, the increase in IP1 in cells expressing the receptor or any other suitable parameter can be used to monitor the agonist activity of the receptor.Those skilled in the art will be familiar with suitable assay formats, and examples are provided below. EC 50 The EC value can be used as a numerical measure of agonist potency at a given receptor. 50The value is a measure of the concentration of a compound required to achieve half of its maximal activity in a particular assay, such as the assay described in Example 3 below. In some embodiments of the compounds of the present invention, the EC 50 is below 200 nM (e.g., 0.01 nM to 200 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 100 nM (e.g., 0.01 nM to 100 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 50 nM (e.g., 0.01 nM to 50 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 15 nM (e.g., 0.01 nM to 10 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 5 nM (e.g., 0.01 nM to 5 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 2 nM (e.g., 0.01 nM to 2 nM).

[0053] The NMU-8 analogs of the present invention can activate human NMU receptor 2 (hNMUR2) in the presence of human serum albumin, a major protein present in human plasma and known to bind lipidated peptides (see Table 5). Therefore, activity of the described NMU-8 analogs in the presence of human plasma is an important prerequisite for in vivo activity. Activation of NMU receptor 2 in the presence of human plasma by the compounds of the present invention (which behave as receptor agonists) increases myo-inositol-1-phosphate (IP1) levels, which leads to intracellular signaling pathways. Therefore, agonist activity against the receptor can be monitored using the increase in IP1 in the presence of human plasma in receptor-expressing cells or any other suitable parameter. Those skilled in the art will be aware of suitable assay formats, and examples are provided below. For example, for the NMU-8 analogs of the present invention, the EC 200 activity for human NMU receptor 2 (hNMUR2) in the presence of human plasma 50 The value can be assessed by the assay described in Example 4 below. In some embodiments of the compounds of the invention, the EC 50 is below 1000 nM (e.g., 0.01 nM to 150 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 500 nM (e.g., 0.01 nM to 500 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 100 nM (e.g., 0.01 nM to 100 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 50 nM (e.g., 0.01 nM to 50 nM). In some embodiments of the compounds of the present invention, the EC 50 is below 10 nM (e.g., 0.01 nM to 10 nM). The NMU-8 analogs of the present invention exhibit high selectivity in terms of binding affinity and activation for human NMU receptor 2 (hNMUR2) over human NMU receptor 1 (hNMUR1), as disclosed below in Table 4 (see Example 2) and Table 5 (see Example 3), respectively.

[0054] The compounds of the present invention have favorable pharmacokinetic properties. In this regard, in some embodiments of the present invention, the in vivo mean residence time (MRT) after intravenous (iv) administration of an NMU-8 analog of the present invention is at least 3 hours in mice (e.g., inclusive of 3 hours to 50 hours; see measurements described in Example 5, Table 6). In some embodiments, the in vivo mean residence time is at least 5 hours in mice (e.g., inclusive of 5 hours to 50 hours). In some embodiments, the in vivo mean residence time is at least 7 hours in mice (e.g., inclusive of 7 hours to 50 hours). In some embodiments, the in vivo mean residence time is at least 10 hours in mice (e.g., inclusive of 10 hours to 50 hours). In some embodiments, the in vivo half-life is at least 15 hours in mice (e.g., 15 hours to 50 hours, including, e.g., about 16 hours (h / hour), 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, and 49 hours). The compounds of the present invention of general formula (I) are soluble at pH values ​​compatible with subcutaneous administration to patients. There are several techniques known to those skilled in the art for determining solubility. One such experiment is described below in Example 6 and the corresponding data in Table 7. In some embodiments of the compounds of the present invention, the solubility is greater than 0.2 mg / ml (eg, 0.2 mg / ml to 50 mg / ml) at pH 4 to 8, preferably pH 6 to 8, and more preferably around pH 7.4. In some embodiments of the compounds of the present invention, the solubility is greater than 1 mg / ml (eg, 1 mg / ml to 50 mg / ml) at pH 4 to 8, preferably pH 6 to 8, and more preferably around pH 7.4. In some embodiments of the compounds of the present invention, the solubility is greater than 5 mg / ml (eg, 5 mg / ml to 50 mg / ml) at pH 4 to 8, preferably pH 6 to 8, and more preferably around pH 7.4.

[0055] The compounds of the present invention of general formula (I) are chemically stable in a buffer system compatible with subcutaneous administration to patients. There are several techniques known to those skilled in the art for determining chemical stability. One such experiment is described below in Example 7 and the relative data in Table 8, which describes chemical stability by the percentage of decomposition of a given compound at a specific temperature over time. In some embodiments of the compounds of the present invention, the percentage of degradation is below 20%. In some embodiments of the compounds of the present invention, the percentage of degradation is below 15%. In some embodiments of the compounds of the present invention, the percentage of degradation is below 10%. In some embodiments of the compounds of the present invention, the percentage of degradation is below 5%. In some embodiments of the compounds of the present invention, the percentage of degradation is below 1%.

[0056] The compounds of the present invention of general formula (I) are physically stable in a buffer system compatible with subcutaneous administration to patients. There are several techniques known to those skilled in the art for determining physical stability. One such experiment is described below in Example 8 and the corresponding data in Table 9. The data in Table 9 show that no fibrillation is detected under the experimental conditions for the compounds of the present invention.

[0057] Pharmaceutical Composition The present invention also refers to a pharmaceutical composition comprising at least one compound of general formula (I) or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable adjuvant, diluent and / or carrier. In a further aspect, the present invention refers to a pharmaceutical composition for use in a method for preventing or treating the diseases disclosed hereinbelow, such as obesity, overweight conditions and their co-morbidities. Said pharmaceutical composition, suitable for administration to a human in need thereof, typically comprises a therapeutically effective amount of a compound of the present invention. The pharmaceutical compositions of the present invention may be in solid or liquid dosage form. In a preferred embodiment of the present invention, the dosage form is a liquid injectable form.

[0058] The pharmaceutical composition of the present invention can be a unit dosage form containing one dose (mono-dose) or multiple doses. In a preferred embodiment of the present invention, the unit dosage form can be provided in an injectable form in a device for application (for example, a pre-filled, ready-to-use injection device), and the device for application can be a syringe, a pen-type injector, or an autoinjector containing a liquid pharmaceutical composition.

[0059] Subcutaneous administration is generally the most common route of application of therapeutic peptides and is believed to be suitable for the compounds of general formula (I) or pharmaceutical compositions thereof. For subcutaneous administration, disposable devices (providing the amount of compound for a single dosage unit) or multi-use devices (providing the amount of compound for two or more dosage units) can be used. Suitable drug delivery devices for subcutaneous administration include autoinjectors (e.g., for a single dosage unit) or pen-type injectors (e.g., for two or more dosage units) containing a syringe or cartridge pre-filled with a liquid pharmaceutical composition of the compound of the present invention, such as an aqueous formulation. The present invention also refers to a drug delivery device for subcutaneous administration comprising at least a compound of general formula (I) or a pharmaceutical composition thereof (including a pharmaceutically acceptable salt thereof), preferably the device is an autoinjector or a pen-type injector.

[0060] Method of treatment / use in treatment The present invention relates to NMU-8 analogs of general formula (I) or pharmaceutical compositions comprising at least one compound of the present invention, including pharmacologically acceptable salts thereof, suitable for use in the prevention or treatment of diseases or conditions associated with or modulated by NMU receptor 2 (NMUR2) activation. Accordingly, the present invention relates to an NMU-8 analogue of general formula (I) or a pharmaceutical composition comprising at least one compound of the present invention, including a pharmacologically acceptable salt thereof, for use as a pharmaceutical. The present invention further provides an NMU-8 analogue according to general formula (I) or a pharmaceutical composition thereof, including a pharmacologically acceptable salt thereof, for use in a method for the prevention and / or treatment of the conditions and diseases mentioned below. The compounds of the present invention are suitable for use in reducing food intake, increasing energy expenditure, promoting weight loss (weight reduction) and / or inhibiting, reducing or preventing weight gain or in chronic weight management. By "preventing weight gain" it is intended to inhibit or reduce compared to the absence of treatment, and not necessarily to imply a complete cessation of weight gain.

[0061] Furthermore, the compounds of the present invention can be used in the direct or indirect treatment of any condition caused by or characterized by excessive body weight (e.g., BMI greater than 25), preferably for the treatment or prevention of obesity (e.g., a body mass index (BMI) greater than 30), morbid obesity (e.g., a BMI greater than 35 with at least one weight-related comorbidity, or a BMI greater than 40), obesity-related inflammation, obesity-related gallbladder disease, and / or obesity-related obstructive sleep apnea. It will thus be appreciated that the NMU-8 analogs of the present invention can be administered to subjects suffering from conditions characterized by improper control of appetite or otherwise excessive eating, such as binge eating disorder and Prader-Willi syndrome.

[0062] The compounds of the invention may also be suitable for use in the prevention or treatment of diseases or conditions apart from overweight control and obesity selected in the list including: Glucose metabolism disorders including type 2 diabetes (T2D), impaired fasting glucose (IFG) and impaired glucose tolerance (IGT); metabolic diseases, including metabolic syndrome, hypertension, dyslipidemia, and atherogenic dyslipidemia; Kidney and liver disease, including chronic kidney disease (CKD), hepatic steatosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); cardiovascular disease, including macrovascular disease, atherosclerosis, coronary heart disease, peripheral artery disease, stroke, and microvascular disease; Cartilage degeneration and osteoarthritis; Reproductive health complications of obesity or being overweight, such as infertility; cancer; and / or Neuropsychiatric conditions including cognitive impairment, anxiety and major depressive disorder. The effects of the NMU-8 analogs of the present invention in the aforementioned diseases or conditions other than overweight control and obesity (i.e., T2D, IGT, CKD, NAFLD, NASH, etc.) may be the result of or related to the effects of the compounds of the present invention in overweight / obesity, or may be independent thereof.

[0063] Thus, the compounds of the present invention may be suitable for use in the prevention or treatment of overweight- or obesity-related diseases (weight-related comorbidities) selected from the list comprising: glucose metabolism disorders, such as type 2 diabetes (T2D), impaired fasting glucose (IFG) and impaired glucose tolerance (IGT); metabolic disorders, such as metabolic syndrome, hypertension, dyslipidemia and atherogenic dyslipidemia; kidney and liver diseases, such as chronic kidney disease (CKD), hepatic steatosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); cardiovascular diseases, such as macrovascular disease, atherosclerosis, coronary heart disease, peripheral artery disease, stroke and microvascular disease; cartilage degeneration and osteoarthritis; reproductive health complications of obesity or overweight, such as infertility; cancer; and neuropsychiatric conditions, such as cognitive impairment, anxiety and major depressive disorder. The compounds of the present invention may also be used to lower circulating LDL cholesterol levels and / or increase the HDL / LDL ratio (LDL: low density lipoprotein, HDL: high density lipoprotein).

[0064] It has been reported that adequate weight loss is expected to improve obesity-related comorbidities, such as liver histology and function, found in patients with NASH (Promrat et al., Hepatology. 2010;51: 121-129; Al-Jiffri et al., Afr Health Sci. 2013;13: 667-672; Tilg, Moschen, Minerva Gastroenterol Dietol. 2010;56(2):159-167). The subject to be treated with the compounds of the present invention may suffer from overweight or obesity accompanied by at least one weight-related comorbidity mentioned above, preferably type 2 diabetes, metabolic disease such as hypertension or dyslipidemia, liver disease such as NASH, or cardiovascular disease. It will be apparent that the NMU-8 analogs of the present invention can be used to treat a combination of the above-described diseases, disorders or conditions. In a further aspect, the present invention relates to the use of an NMU-8 analogue according to general formula (I) or a pharmaceutical composition comprising at least one compound of the present invention, including its pharmacologically acceptable salts, for the preparation of a medicament for the treatment and / or prevention of the above-mentioned diseases or conditions.

[0065] In a further aspect, the present invention relates to a method for the treatment or prevention of the above-mentioned diseases and conditions, comprising the administration to a human being in need thereof of a therapeutically effective amount of an NMU-8 analogue according to general formula (I) or a pharmaceutical composition thereof, including its pharmaceutically acceptable salts.

[0066] The actual therapeutically effective amount or therapeutic dosage will typically depend on factors known by those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease, etc. In any case, the compound will be administered in a dosage and manner that allows a pharmaceutically effective amount to be delivered based on the patient's unique condition. The compounds of the present invention can be administered subcutaneously to a human in need thereof in a dosage range of 0.1 mg to 100 mg. The compounds of the present invention can be administered subcutaneously to a human in need thereof by weekly dosing, every other week dosing, or monthly dosing, depending on the pharmacokinetic profile (i.e., MRT) of the compound.

[0067] Combination therapy The NMU-8 analogs of the present invention can be administered to a subject in need thereof as part of a combination therapy with at least one additional active agent for use in methods for the prevention and / or treatment of one or more conditions or diseases that are the focus of this invention. Preferably, said further active agent is an agent known in the art for the treatment of obesity, diabetes, dyslipidemia or hypertension, more preferably an anti-obesity agent. The compound of the present invention and the at least one additional active agent can be administered as combined active ingredients in the same pharmaceutical composition or formulation (fixed dose combination, or simply FDC), or alternatively, as active ingredients in separate pharmaceutical compositions or formulations (free dose combination). In a free dose combination, the at least two pharmaceutical compositions can be administered simultaneously or sequentially. In a free-dose combination, the NMU-8 analogues of the present invention may be for use as an adjunct therapy (add-on therapy) to drugs used on the market for the treatment of one or more of the conditions or diseases mentioned above and below, preferably drugs used for the treatment of obesity or its co-morbidities.

[0068] Administration of the NMU-8 analogs of the present invention in combination with at least one further active agent, such as current appetite-reducing peptides, results in a medication for the prevention or treatment of the conditions or diseases mentioned above and below, preferably overweight conditions, obesity or their co-morbidities, that provides an additive or synergistic therapeutic effect (e.g., an appetite-reducing effect) compared to the effect provided by the individual active agents in said therapy. In one aspect, the present invention is directed to an NMU-8 analog of the present invention and at least one further active agent formulated together in a pharmaceutical composition (FDC), and their use in methods for the prevention and / or treatment of the conditions or diseases mentioned hereinbefore and hereinafter, such as overweight conditions, obesity, and / or their comorbidities. Preferably, the further active agent is an agent for use in the treatment of obesity, diabetes, dyslipidemia, or hypertension, more preferably an anti-obesity agent.

[0069] In one aspect, the present invention relates to a pharmaceutical composition comprising an NMU-8 analogue of the present invention and at least one further active agent, and its use in a method for the prevention and / or treatment of the conditions or diseases mentioned hereinbefore and hereinafter, such as an overweight condition, obesity, or their comorbidities. Preferably, the further active agent is an agent for use in the treatment of obesity (i.e., an anti-obesity agent), diabetes, dyslipidemia, or hypertension, more preferably an anti-obesity agent. In a preferred embodiment, the NMU-8 analogs of the present invention can be administered in combination with at least one additional anti-obesity agent in a fixed dose combination (FDC) or a free dose combination, where the at least one additional anti-obesity agent can be formulated for subcutaneous or oral administration.

[0070] The additional anti-obesity agent may be a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (including GIP or a GIP analogue, LY-3537021, LY-3532226) or a glucagon-like peptide-1 (GLP-1) receptor agonist (including GLP-1 or a GLP-1 analogue, exendin-4 or an exendin-4 analogue, liraglutide (Saxenda™ or Victoza™), semaglutide (Wegovy™ or oral formulation), dulaglutide, albiglutide, MK-8521, danuglipron (PF-068829614 oral formulation), PF-07081532 (oral formulation), LY-3502970, XW-003, XW014) or a glucagon receptor (GCGR) agonist (glucagon or glucagon receptor agonist). lucagon analogs, including HM-15136) or oxyntomodulin or oxyntomodulin analogs (e.g., TT-401) or GCGR / GLP-1R dual agonists (e.g., HM-12525, SAR-425899, MEDI-0382, NN-9277, marzdutide (LY-3305677), pemvidutide e) (ALT-801), DD-01) or GLP-1R / GIPR dual agonists (e.g., tirzepatide, LY-3493269, AMG-133, CT-388, CT-868, SCO-094, semaglutide / NN-9389) or GLP-1R / GIPR / GCGR triple agonists (e.g., NN-9423, LY-3437943).

[0071] The further anti-obesity agent may be peptide YY (PYY) or a PYY analogue (e.g., NN-9775, LY-3457263, Y-14) or neuropeptide Y (NPY) or an NPY analogue or an NPY1R antagonist or inverse agonist or an NPY2R agonist or an NPY4R agonist or an NPY5R antagonist; or a combination of a GLP-1 analogue and a PYY analogue (preferably an NPY2R agonist), such as a combination of semaglutide / PYY analogue (e.g., semaglutide / NN-9775) or dulaglutide / PYY analogue (e.g., dulaglutide / LY-3457263). or it may be a GLP-1R / GIPR / NPY receptor triple agonist, such as a combination of a GLP-1R / GIPR dual agonist and a PYY analogue or NPY receptor agonist, preferably an NPY2R agonist (e.g., tirzepatide / LY-3457263); or it may be a GLP-1R / GCGR / NPYR triple agonist, such as a combination of a GLP-1R / GCGR dual agonist and a PYY analogue or NPYR agonist, preferably an NPY2R agonist (e.g., mazdutide / PYY analogue, pembidutide / PYY analogue).

[0072] The further anti-obesity agent may be an amylin receptor agonist, including amylin or an amylin analogue, such as pramlintide, NN-9838, cagrilintide (AM-833); or may be a GLP-1R / amylin receptor dual agonist, such as the combination of semaglutide / cagrilintide (i.e., cagrisema) or amycretin (oral formulation).

[0073] Alternatively, the additional anti-obesity agent may be an additional NMUR2 agonist, orlistat, sibutramine, phentermine, a melanin-concentrating hormone receptor 1 antagonist, cholecystokinin (CCK), a leptin analog, a ghrelin O-acyltransferase (GOAT) inhibitor, a ghrelin-receptor antagonist, a cannabinoid receptor 1 antagonist, a beta-3 agonist, a lipase inhibitor, a human proislet peptide (HPE), a steroid hormone receptor 1 antagonist, ... IP), melanocortin receptor 4 agonist, adiponectin receptor agonist, G protein-coupled receptor 40 (GPR40; also known as free fatty acid receptor 1, FFAR1) agonist, mitochondrial modulator, thyroid hormone receptor agonist, growth differentiation factor 15 (GDF15) agonist (e.g., AMG-171, JNJ-9090, NNC0247-0829) or enteropeptidase inhibitors, as well as analogs thereof.

[0074] In a preferred embodiment, the NMU-8 analogue of general formula (I) or a pharmaceutically acceptable salt thereof, preferably a compound of Table 3, more preferably a compound of Table 6, may be administered as part of a combination therapy (free-dose combination) together with a further anti-obesity agent selected from the list consisting of semaglutide (subcutaneous or oral formulation), danugliplon, PF-07081532 (GLP-1Ra oral formulation), tirzepatide, pembidutide, LY-3437943 (GLP-1R / GIPR / GCGR triple agonist), caglisema, amicretin (oral formulation) and the combination semaglutide / NN-9775 (PYY analogue), for use in the methods for the prevention or treatment of obesity, an overweight condition and / or their co-morbidities disclosed above. In a more preferred aspect, an NMU-8 analogue of general formula (I) or a pharmaceutically acceptable salt thereof, preferably a compound of Table 3, more preferably a compound of Table 6, may be administered as part of a combination therapy (free-dose combination) together with semaglutide formulated for subcutaneous administration (Wegovy™) or oral administration, for use in the methods for the prevention or treatment of obesity, an overweight condition and / or their co-morbidities disclosed above (e.g. semaglutide and compound No. 1 in Table 3, semaglutide and compound No. 7 in Table 3, semaglutide and compound No. 26 in Table 3, semaglutide and compound No. 33 in Table 3, semaglutide and compound No. 42 in Table 3, semaglutide and compound No. 43 in Table 3, or semaglutide and compound No. 69 in Table 3).

[0075] In a preferred embodiment, an NMU-8 analogue of general formula (I), preferably an NMU-8 analogue of Table 3, more preferably an NMU-8 analogue of Table 6, or a pharmaceutically acceptable salt thereof, is administered in combination with a GCGR / GLP-1R dual agonist of formula (III) for use in the methods for preventing or treating obesity, an overweight condition and / or their co-morbidities disclosed above. HH-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-gGlu-GSGSGG-)-WLESA-NH2(III) (SEQ ID NOs: 87-88) or a pharmaceutically acceptable salt thereof, as part of a combination therapy (free dose combination or FDC) (e.g., a compound of formula (III) and compound No. 1 in Table 3, a compound of formula (III) and compound No. 7 in Table 3, a compound of formula (III) and compound No. 26 in Table 3, a compound of formula (III) and compound No. 33 in Table 3, a compound of formula (III) and compound No. 42 in Table 3, a compound of formula (III) and compound No. 43 in Table 3, or a compound of formula (III) and compound No. 69 in Table 3). In a fixed dose combination (FDC), an NMU-8 analog of general formula (I), preferably a compound of Table 3, more preferably a compound of Table 6, together with a GCGR / GLP-1R dual agonist of formula (III), including a pharmaceutically acceptable salt thereof, and optionally with at least one pharmaceutically acceptable adjuvant, diluent and / or carrier, can be formulated into a pharmaceutical composition. Preferably, the pharmaceutical composition is suitable for subcutaneous administration to a subject in need of therapy. The present disclosure further provides a pharmaceutical composition comprising a GCGR / GLP-1R dual agonist of formula (III), including an NMU-8 analog of general formula (I), preferably a compound of Table 3, more preferably a compound of Table 6, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0076] The GCGR / GLP-1R dual agonist of formula (III) is compound number 13 in paragraph

[0164] of patent EP3057984B1, which is incorporated herein by reference. Those skilled in the art will recognize that the term [17-carboxy-heptadecanoyl]-gGlu-GSGSGG-(SEQ ID NO: 88) is equivalent to the terms [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG-(SEQ ID NO: 88) and HOOC-(CH2) used in EP3057984B1. 16 It will be understood that the substituent [17-carboxy-heptadecanoyl]-gGlu-GSGSGG-(SEQ ID NO: 88) is a synonym for -(CO)-isoGlu-GSGSGG-(SEQ ID NO: 88). The structure of the substituent [17-carboxy-heptadecanoyl]-gGlu-GSGSGG-(SEQ ID NO: 88) (i.e., [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG-(SEQ ID NO: 88)) is disclosed in paragraphs

[0099] -(vii) of EP 3057984, which is incorporated herein by reference. In the compound of formula (III), the acyl group of the terminal residue G of the side chain [17-carboxy-heptadecanoyl]-gGlu-GSGSGG-(SEQ ID NO: 88) is linked via an amide bond to the amino group of the K residue at position 24 of the backbone chain. In the compound of formula (III), the Ac4c residue represents 1-amino-cyclobutanecarboxylic acid. In the compound of formula (III), the first H represents a hydrogen and the second H represents a histidine residue.

[0077] The compound of formula (III) is a glucagon receptor and GLP-1R dual agonist, as determined by its ability to stimulate intracellular cAMP formation in a suitable assay, as disclosed in Table 1 (Compound No. 13) on pages 2-21 of EP 3057984B1 and Tables 2-3 (Compound No. 13) on pages 3-4-22-23 of EP 3057984B1, which are incorporated herein by reference. Dual agonists can combine the effects of glucagon receptors, for example, on fat metabolism, with the effects of GLP-1R, for example, on blood glucose levels and food intake. Thus, compounds of formula (III) can act to accelerate the elimination of excess adipose tissue, induce sustainable weight loss, and improve glycemic control. It can thus be used as a therapeutic agent for preventing weight gain, promoting weight loss, reducing excess weight, treating an overweight condition, or treating obesity and related diseases and conditions in a subject in need thereof (e.g., as disclosed in EP3057984B1, paragraphs

[0135] to

[0145] , which are incorporated herein by reference).

[0078] In a further aspect of the present invention, the NMU-8 analogues of the present invention can be administered in addition to diet and / or physical exercise for use in a method for the prevention and / or treatment of one or more of the above-mentioned conditions or diseases, preferably overweight conditions, obesity and / or their co-morbidities, in a subject in need thereof.

[0079] Furthermore, the NMU-8 analogues of the present invention according to general formula (I), preferably the compounds of Table 3, more preferably the compounds of Table 6, can be administered in combination with other compounds such as metformin, sulfonylureas (e.g., glibenclamide, tolbutamide, glimepiride, glipizide, gliquidon, glibornuride, gliclazide or analogues thereof), alpha-glucosidase blockers (e.g., acarbose, voglibose, miglitol or analogues thereof), glinides (e.g., nateglinide, repaglinide or analogues thereof), glitamin B (e.g., riboflavin ... antihistamines (e.g., pioglitazone, rosiglitazone, or analogs thereof), DPP-IV inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin, or analogs thereof), SGLT2 inhibitors (e.g., gliflozins, e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, sotagliflozin, ertugliflozin, or analogs thereof), GLP-1R agonists (e.g., tirzepatide, semaglutide, liraglutide, exenatide (Byetta™, Bydureon™, Byetta LAR™ or lixisenatide), GPR40 agonists (FFAR1 / FFA1 agonists, e.g., fasiglifam), or insulin or insulin analogs (e.g., insulin glargine, insulin aspart, insulin lispro, human insulin (rDNA), insulin detemir, insulin degludec, and / or insulin glulisine).

[0080] The NMU-8 analogs of the present invention can be administered in combination with known types of anti-dyslipidemic agents, including, but not limited to, statins, fibrates, niacin, PSCK9 (proprotein convertase subtilisin / kexin type 9) inhibitors or cholesterol absorption inhibitors, for use in methods for the prevention and / or treatment of one or more of the conditions or diseases mentioned above. The NMU-8 analogs of the present invention can be administered in combination with medications targeting cardiovascular disease, such as those treating hypertension, dyslipidemia, inflammation, and platelet function, for use in methods for preventing and / or treating one or more of the conditions or diseases mentioned above. The medications treating hypertension can be selected from angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, and calcium channel blockers.

[0081] In a further aspect, the present disclosure provides a kit comprising an NMU-8 analog of general formula (I) or a pharmaceutically acceptable salt thereof, an optional pharmaceutically acceptable carrier, and a package insert containing instructions for administration to a subject in need of treatment for a disease, disorder, or condition associated with or modulated by NMUR2 activation, such as obesity, overweight, and their comorbidities. In a further aspect, the present disclosure provides a kit comprising an NMU-8 analog of general formula (I) or a pharmaceutically acceptable salt thereof, at least one further active agent for the treatment of obesity, diabetes, dyslipidemia or hypertension, preferably a further active agent for the treatment of obesity as mentioned above, and a package insert containing instructions for administration to a subject in need of treatment for a disease, disorder or condition as disclosed above. Biological Assays and Data [Example]

[0082] The following examples demonstrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and routine to those skilled in the art, unless otherwise specified. ( Example 1 ) Radioligand binding competition assay (RLB) Human NMUR2 receptor binding 1) Membrane The assay is based on membranes prepared from a human NMUR2 / Apoaequorin stable cell line (Creative Biogene, Cat. No. CSC-RG1309). Cell line description: The CHO-NMUR2 cell line is clonally derived from the CHO-K1 cell line transfected with a bicistronic expression plasmid containing sequences encoding human neuromedin U receptor 2 (AF242874.1). MOSAIC-ID: CL16550616. Membrane preparation: Cells were disrupted by nitrogen cavitation (900 psi, 1 hour). Intact cells were removed by centrifugation (400 rcf (relative centrifugal force), 10 minutes, 4°C), and then crude membrane fractions were collected by ultracentrifugation (20,000 rcf, 1 hour, 4°C).

[0083] 2) Human NMUR2 receptor binding assay (radiolind: [125I]-neuromedin U-25 (human)) In this scintillation proximity assay (SPA) design, membranes are directly immobilized on PVT-WGA-PEI type A beads (polyethyleneimine-treated polyvinyltoluene beads coupled to wheat germ agglutinin, Perkin Elmer) through interactions with wheat germ agglutinin and glycosylated membrane structures. This brings radiolabeled ligand bound to the NMUR2 receptor on the membrane into close proximity with the solid scintillator of the PVT beads. Radioactive human neuromedin U-25 then stimulates the scintillant to emit light. In contrast, radioligands not bound to the receptor are too far from the beads to elicit a signal.

[0084] For the scintillation proximity assay, CHO-K1 hNMUR2 cell membranes and SPA-beads are diluted to a concentration that ensures a robust signal-to-background ratio. SPA incubation buffer, consisting of 25 mM Hepes (pH=7.0), 5 mM MgCl, 1 mM CaCl, 10 μg / mL saponin, and 0.1% bovine serum albumin, is used for all dilutions. Final assay setup in a 96-well plate: 20 μL of 10× test compound dilution + 40 μL of 5× [125I]-Neuromedin U-25 (1× approximately 30 pM; 2000 μCi / mmol) + 60 μL membrane dilution (approximately 2.5 μg membrane protein) + 80 μL SPA bead dilution (0.75 mg).

[0085] The assay is incubated for 4 hours at room temperature and includes controls for specific binding (no displacer added) and nonspecific binding by adding 100 nM unlabeled hNMU-25. Bound radioactivity is determined by scintillation counting (MicroBeta Trilux 1450, Perkin Elmer, detection of 125I decay). Test compound affinity (Ki) is calculated as described below, relative to which the dissociation constant (Kd) and precise concentration of the radioligand in the assay are obtained. The system assumes a single binding site with no associated radioligand depletion (<10%) and that binding is reversible and at equilibrium. Ki = xC50 / ((ligand / Kd)+1) Y=bottom+(top-bottom) / (1+10^((LogIC50-X) * gradient))

[0086] ( Example 2 ) Radioligand binding competition assay (RLB) Human NMUR1 receptor binding 1) Membrane The test is based on membranes prepared from a human NMUR1 / apoaequorin stable cell line (Creative Biogene, catalog number CSC-RG1308). Cell line description: The CHO-NMUR1 cell line is clonally derived from the CHO-K1 cell line transfected with a bicistronic expression plasmid containing the sequence encoding human neuromedin U receptor 1 (NM_006056.4, 180-1391). Mosaic-ID: CL16550614 Membrane preparation: Cells were disrupted by nitrogen cavitation (900 psi, 1 hour). Intact cells were removed by centrifugation (400 rcf, 10 minutes, 4°C), and then crude membrane fractions were collected by ultracentrifugation (20,000 rcf, 1 hour, 4°C).

[0087] 2) Human NMUR1 receptor binding assay (radiolind: [125I]-neuromedin U-25) In this scintillation proximity assay (SPA) design, membranes are directly immobilized on PVT-WGA-PEI type A beads (polyethyleneimine-treated polyvinyltoluene beads coupled to wheat germ agglutinin, Perkin Elmer) through interactions with wheat germ agglutinin and glycosylated membrane structures. This brings radiolabeled ligand bound to the NMUR1 receptor on the membrane into close proximity with the solid scintillator of the PVT beads. Radioactive human neuromedin U-25 then stimulates the scintillant to emit light. In contrast, radioligands not bound to the receptor are too far from the beads to elicit a signal.

[0088] For the scintillation proximity assay, CHO-K1 hNMUR1 cell membranes and SPA-beads are diluted to a concentration that ensures a robust signal-to-background ratio. SPA incubation buffer, consisting of 25 mM Hepes (pH=7.0), 5 mM MgCl, 1 mM CaCl, 10 μg / mL saponin, and 0.1% bovine serum albumin, is used for all dilutions. Final assay setup in a 96-well plate: 20 μL of 10× test compound dilution + 40 μL of 5× [125I]-Neuromedin U-25 (1× approximately 30 pM; 2000 μCi / mmol (μCi = microcuries)) + 60 μL membrane dilution (approximately 1.0 μg membrane protein) + 80 μL SPA bead dilution (250 μg).

[0089] The assay is incubated for 4 hours at room temperature and includes controls for specific binding (no displacer added) and nonspecific binding by adding 100 nM unlabeled hNMU-25. Bound radioactivity is determined by scintillation counting (MicroBeta Trilux 1450, Perkin Elmer, detection of 125I decay). Test compound affinity (Ki) is calculated as described below, relative to which the dissociation constant (Kd) and precise concentration of the radioligand in the assay are obtained. The system assumes a single binding site with no associated radioligand depletion (<10%) and that binding is reversible and at equilibrium. Ki = xC50 / ((ligand / Kd)+1) Y=bottom+(top-bottom) / (1+10^((LogIC50-X) * gradient))

[0090] [Table 4]

[0091] ( Example 3 ) IP1 Gq HTRF assay Activation of human NMUR2 or human NMUR1 in buffer The application of homogeneous time-resolved fluorescence (HTRF) technology optimized for Gq-coupled receptors is described in detail in the Cisbio IP-One Gq Kit manual. Briefly, a FRET signal (FRET: fluorescence resonance energy transfer) is generated between the donor label of the IP-One antibody (anti-IP1-Tb) and the acceptor label of tagged IP-One (IP1-d2). Agonism of Gq-coupled receptors increases intracellular IP-One, which competes with the labeled IP-One, resulting in a reduction of the FRET signal.

[0092] Frozen stocks of CHO-K1 cells stably expressing the human NMUR1 or NMUR2 receptor were thawed, and 5,000 cells were seeded in culture medium (HAM's F12, 10% FCS) into each well of a 384-well assay plate. After seeding, the cells were incubated for 24 hours in a humidified incubator at 37°C and 5% CO2. The cells were then washed once with 50 μL of wash buffer (20 mM Hepes, 1×HBSS, pH 7.4), followed by the addition of 10 μL of stimulation buffer (20 mM Hepes, 1×HBSS, 50 mM LiCl, 0.1% BSA, pH 7.4). The peptide agonists to be tested were dissolved in 100% DMSO and prediluted in stimulation buffer at a concentration range appropriate for an 8-point dose-response curve. Next, 5 μL of peptide predilution was added to each well, followed by the addition of an additional 5 μL of stimulation buffer to obtain a final concentration of 1% DMSO. The samples were then incubated for 1 hour in a humidified incubator at 37°C. After the addition of 5 μL each of IP1-d2 and anti-IP1-Tb, the samples were incubated for another hour at room temperature, and the FRET signal (ratio 665 nm / 620 nm) was measured. 50 Values ​​were calculated by nonlinear regression using a four-parameter sigmoidal curve fit.

[0093] ( Example 4 ) IP1 Gq HTRF assay Activation of human NMUR2 in human plasma The application of homogeneous time-resolved fluorescence (HTRF) technology optimized for Gq-coupled receptors is described in detail in the Cisbio IP-One Gq Kit manual. Briefly, a FRET signal is generated between the donor labeling of an IP-One antibody (anti-IP1-Tb) and the acceptor labeling of tagged IP-One (IP1-d2). Agonism of Gq-coupled receptors increases intracellular IP-One, which competes with the labeled IP-One, resulting in a reduction of the FRET signal.

[0094] Frozen stocks of CHO-K1 cells stably expressing the human NMUR1 or NMUR2 receptor were thawed, and 5,000 cells were seeded in culture medium (HAM's F12, 10% FCS) into each well of a 384-well assay plate. After seeding, the cells were incubated for 24 hours in a humidified incubator at 37°C and 5% CO2. The cells were then washed once with 50 μL of wash buffer (20 mM Hepes, 1× HBSS, pH 7.4), followed by the addition of 10 μL of plasma (100% human plasma, 50 mM LiCl). The peptide agonists to be tested were dissolved in 100% DMSO and prediluted in plasma at a concentration range appropriate for an 8-point dose-response curve. Five μL of the peptide predilution was then added to each well, followed by the addition of an additional 5 μL of plasma to achieve a final concentration of 1% DMSO. The samples were then incubated for 1 hour in a humidified incubator at 37°C. The plasma solution was replaced with 20 μL of stimulation buffer. After the addition of 5 μL each of IP1-d2 and anti-IP1-Tb, the samples were incubated for another hour at room temperature, and the FRET signal (ratio 665 nm / 620 nm) was measured. EC 50 Values ​​were calculated by nonlinear regression using a four-parameter sigmoidal curve fit.

[0095] [Table 5-1] [Table 5-2]

[0096] ( Example 5 ) Pharmacokinetics Intravenous (iv) PK in mice Pharmacokinetic parameters of test compounds were determined after intravenous administration to Naval Medical Research Institute (NMRI) mice. Male NMRI mice, weighing approximately 30-40 g, were obtained from either Charles River (Germany) or Janvier (France). Mice were housed in standard cages with a 12-hour dark and 12-hour light photoperiod. Standardized food and water were provided ad libitum to the animals throughout the entire experimental period. Each peptide was dissolved in 50 mM phosphate buffer (pH 7.4) containing 3.5% mannitol. An intravenous dose of 30 nmol / kg was administered via the tail vein. Serial blood samples were collected from the saphenous vein (vena saphena) into tubes containing EDTA as an anticoagulant at different time points up to 48 hours after dosing. After approximately 5 minutes of centrifugation, plasma samples were transferred to a 96-well polymerase chain reaction (PCR) plate, immediately frozen, and kept at approximately -20°C until analyzed for plasma concentrations by liquid chromatography-mass spectrometry (LC-MS / MS). Individual plasma concentration-time profiles were analyzed by a non-compartmental approach and the resulting pharmacokinetic parameters were determined.

[0097] [Table 6]

[0098] ( Example 6 ) Solubility determination The peptide (as the TFA salt) was weighed into a filter unit (Mini-UniPrep Syringeless Filter 0.45 μm, Whatman PVDF) and 0.1 M phosphate buffer, pH 6–8, was added to achieve a final peptide concentration of 10 mg / mL. The peptide was dissolved by shaking the filter unit horizontally at 350 rpm for 2 hours at room temperature. The sample was then filtered to remove any insoluble particles. Controls were prepared by weighing the corresponding peptide solid material and dissolving it in an appropriate medium (e.g., buffer or DMSO) to a final concentration of 1 mg / mL. Both the control and the sample were analyzed by reverse-phase chromatography. The area under the peak of the sample was compared to that of the control, and the solubility was calculated based on the ratio. The pH was measured and recorded for each sample.

[0099] UPLC method: System: Waters UPLC Mobile phase A: 0.1% trifluoracitic acid in water Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile Gradient: 95% mobile phase A, 5% mobile phase B (0 min) to 5% mobile phase A, 95% mobile phase B (2 min) to 5% mobile phase A, 95% mobile phase B (2.6 min) to 95% mobile phase A, 5% mobile phase B (2.8 min) Injection volume: 3 μL and 0.3 μL Flow rate: 0.8mL / min Column: ACQUITY UPLC BEH C18, 1.7 μm, 50 x 2.1 mm Column temperature: 40℃ Detection wavelength: 220nm, 230nm, 254nm, 280nm

[0100] [Table 7]

[0101] ( Example 7) chemical stability The peptides were dissolved in the test medium (50 mM HEPES buffer, pH 7.4) to a concentration of 1 mg / mL. From each vial, a sample was analyzed by reversed-phase chromatography to obtain starting data (T0). The vials were incubated for the indicated time and temperature (40°C for 14 days). Then, a sample from each vial was analyzed by reversed-phase chromatography (T1). Relative peak area values ​​(% area) were obtained from the corresponding chromatograms by normalizing the peak area of ​​the peptide signal to the total peak area of ​​the chromatogram for the T0 and T1 measurements. The chemical stability of the peptides was then calculated by subtracting the T1% area value from the T0% area value for each peptide.

[0102] UPLC method: System: Waters UPLC Mobile phase A: 0.3% trifluoroacetic acid in water Mobile phase B: 0.3% trifluoroacetic acid in acetonitrile Gradient: 60% mobile phase A, 40% mobile phase B (0 min) to 35% mobile phase A, 65% mobile phase B (28 min) to 60% mobile phase A, 40% mobile phase B (28.1 min) Injection volume: 3 μL Flow rate: 0.5mL / min Column: Kinetex C8, 2.6 μm, 100 Å, 150 × 4.6 mm Column temperature: 50℃ Detection wavelength: 220nm, 277nm

[0103] The retention time of the analyte peak should be in the range of 5 to 20 minutes. If the standard method did not achieve the corresponding retention time, the mobile phase gradient was changed to achieve the appropriate retention time of the analyte. [Table 8]

[0104] Example 8 physical stability The amyloid-specific fluorescent dye thioflavin T (ThT) was used to detect the physical instability of peptides in the form of amyloid fibril formation. Peptides were dissolved in buffer (50 mM HEPES buffer, pH 7.4) and ThT was added to a final concentration of 1 mg / mL peptide and 40 μM ThT. Samples (80 μL each) were then loaded in triplicate into a 384-well black fluorescent plate (clear bottom). Fluorescence intensity data were collected at fixed intervals of 10 minutes, each preceded by 300 seconds of automated mixing (agitation), over a 96-hour period at 40°C using a fluorescent plate reader. Peptides were assessed as physically unstable if a substantial increase in total fluorescence intensity (>5× background) with a sigmoidal curve shape was observable over the course of the experiment. Fluorescence measurements: - Extinction: 448nm - Emission: 482nm

[0105] [Table 9]

[0106] Example 9 Pharmacodynamics Effects on acute food intake in normal NMRI mice Male NMRI mice were obtained from Charles River (Charles River, Research Models & Services Germany GmbH) or JanVier (JanVier Labs, France) at 3 weeks of age. Animals were group-housed, four mice per cage, under a 12 / 12-hour light / dark cycle with lights off at 3 pm. Room temperature was controlled at 21°C ± 1°C with 60% ± 20% humidity. Animals had free access to regular rodent chow (KLIBA Nafag 3430 or Altromin 1324, Brogaarden, Denmark) and tap water. At 6 weeks of age, 5–7 days before the start of the study, animals were transferred to a real-time food intake monitoring system, the HM-2 system (MBRose, Denmark), and acclimated to the experimental conditions. Animals were uniquely identified by microchip, and each individual animal was identified by its microchip upon entering and exiting the food channel. Randomization of mice per study group (n = 8-11) was based on body weight measured the day before the start of the study. A vehicle-treated (50 mM acetate buffer pH 7.4 with 3.5% mannitol) group was included in each experiment. Animals were fasted 6 hours before the onset of the night phase. Animals received a single subcutaneous dose of the test peptide 1 hour before the dark phase. Food intake was reported hourly over a 24-hour period. Food intake of the treatment groups was normalized to the mean food intake of the group receiving vehicle (in %) (Table 10). Statistical significance was assessed using one-way analysis of variance with Bonferroni's multiple comparison test. P < 0.05 was considered statistically significant.

[0107] [Table 10]

[0108] ( Example 10 ) Pharmacodynamics Effect of the NMUR2 agonist of the present invention on body weight after chronic repeated administration in diet-induced obese C57BL6 mice Male C57BL6 / J mice pre-fed with a 60% high-fat diet are obtained from The Jackson Laboratories (Bar Harbor, ME, USA) at >16 weeks of age. Upon arrival, mice are housed singly to obtain accurate and individual food intake measurements for each animal. Animals are housed at a room temperature of 21°C ± 1°C, a relative humidity of 60 ± 20%, and a reversed 12:00 h light / dark cycle (lights off at 10 am). Throughout the study, animals have free access to food (high-fat diet D12492; Research Diets, Inc., New Brunswick, NJ, USA) and tap water. Prior to the start of the study, animals are randomized (e.g., n = 11 / group) based on their body weight, measured 1 week before the start of treatment. At the start of the study, mice are >22 weeks of age. Mice are administered chronic repeated subcutaneous (SC) doses of vehicle or NMUR2 agonist of the present invention daily 1 hour before the dark cycle for 28 (or 14) days, and body weight and food intake are measured daily. The body weight of the treatment group is normalized to the average body weight of the group receiving the vehicle (in %). Statistical significance is assessed using one-way analysis of variance on day 28 (or 14) with Bonferonni's multiple comparison test. P<0.05 is considered statistically significant.

[0109] ( Example 11 ) Pharmacodynamics Effects of the NMUR2 agonist of the present invention and further active agents, such as GCCR / GLP-1R dual agonists, on body weight after chronic repeated administration in diet-induced obese C57BL6 mice Male C57BL6 / J mice pre-fed with a 60% high-fat diet are obtained from Jackson Laboratories (Bar Harbor, ME, USA) at >16 weeks of age. Upon arrival, mice are housed singly to obtain accurate and individual food intake measurements for each animal. Animals are housed at a room temperature of 21°C ± 1°C, a relative humidity of 60 ± 20%, and a reversed 12-hour light / dark cycle (lights off at 10 am). Throughout the study, animals have free access to food (high-fat diet D12492; Research Diets, Inc., New Brunswick, NJ, USA) and tap water. Prior to the start of the study, animals are randomized (e.g., n = 11 / group) based on their body weight, measured 1 week before the start of treatment. At the start of the study, mice are over 22 weeks old. Mice are administered chronic repeated SC administration of vehicle, the NMUR2 agonist of the present invention, another active agent, for example, a GCCR / GLP-1R dual agonist (preferably a dual agonist of formula (III)), or a combination of the NMUR2 agonist of the present invention and another active agent, one hour before the dark cycle, for 28 days, and body weight and food intake are measured daily. The body weight of the treatment group is normalized to the average body weight of the group receiving the vehicle (% units). Statistical significance is evaluated using one-way analysis of variance on day 14 with Bonferroni's multiple comparison test. P<0.05 is considered statistically significant.

[0110] reference compound [Table 11]

[0111] The following compilation shows the selectivity for neuromedin U receptor 2 (NMUR2) over neuromedin U receptor 1 (NMUR1) of compounds of the invention according to general formula (I) relative to the corresponding reference compounds, which contain a monocarboxylic acid half-life extending group (i.e., C18A or C20A) instead of a dicarboxylic acid half-life extending group (i.e., C18DA or C20DA) (see Table 12A), or alternatively, a leucine (Leu) at position 3 of peptide P instead of N-methylleucine (NMeLeu) (see Table 12B), i.e., the selectivity according to the activity measured in Example 3 (EC 50 [hNMUR1] / EC 50 [hNMUR2]) to illustrate the relative advantages.

[0112] The compounds of the present invention showed higher selectivity for NMUR2 over NMUR1 relative to the corresponding reference compounds. [Table 12]

[0113] [Table 13]

[0114] The following compilation illustrates the relative advantages of compounds of the invention according to general formula (I) over corresponding reference compounds which contain a monocarboxylic acid half-life extending group (i.e., C18A or C20A) instead of a dicarboxylic acid half-life extending group (i.e., C18DA or C20DA) (see Table 13A), or alternatively, a leucine (Leu) at position 3 of peptide P instead of N-methylleucine (NMeLeu) (see Table 13B), with reference to the extended half-life determined by mean residence time (MRT) after intravenous application as in Example 5.

[0115] The compounds of the present invention exhibited an extended half-life relative to the corresponding reference compounds. [Table 14]

[0116] [Table 15]

[0117] Experimental Section List Abbreviations ACN: acetonitrile Boc: tertbutyloxycarbonyl- DCM: dichloromethane DIC: diisopropylcarbodiimide DMF: N,N-dimethylformamide Fmoc: 9H-fluoren-9-ylmethoxycarbonyl m / z: mass-to-charge ratio (MS signal); z is an integer NMP: N-methyl-2-pyrrolidone oxyma: ethyl cyano(hydroxyimino)acetate Pbf: 2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-sulfonyl- Pfp: pentafluorophenyl- Rt: retention time RT: room temperature tBu: tertbutyl TFA: Trifluoroacetic acid Trt: triphenylmethyl-(trityl-)

[0118] General Procedure for Solid Phase Synthesis of Peptides All peptides were synthesized by standard Fmoc-solid phase peptide chemistry on Tentagel S RAM resin (loading 0.2-0.4 mmol / g, 90 μM) supplied by Rapp Polymere GmbH.

[0119] The following protected amino acids were used: Fmoc-Arg(Pbf)-OH, Fmoc-Dbu(Boc)-OH, Fmoc-Glu-OtBu, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-hLys(Boc)-OH, Fmoc-NMeL-OH, Fmoc-NMeA-OH, Fmoc-Orn(Boc)-OH, Fmoc-2Pal-OH, Fmoc-3Pal-OH, Fmoc-4Pal-OH, Fmoc-Nle-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Tyr(tBu)-OH, Fmoc-PipAc-OH, and Fmoc-AEPipAc-OH·2HCl. Unless otherwise specified, the L-configuration of the amino acid building blocks was used. Modular half-life extending moieties were assembled by SPPS (solid phase peptide synthesis) using protected building blocks including, but not limited to, stearic acid (C18A), icosanoic acid (arachidic acid, C20A), 18-(tert-butoxy)-18-oxooctadecanoic acid (C18DA(tBu)), 20-(tert-butoxy)-20-oxoicosanoic acid (C20DA(tBu)), Fmoc-Glu-OtBu, Fmoc-Sar-OH, Fmoc-Sar-OH, and Fmoc-Sar-OPfp.

[0120] The amino acid building blocks, Fmoc-Glu-OtBu, oxyma, DIC, and all reagents were purchased from standard suppliers, such as Bachem AG, Merck KGaA (Novabiochem®, Sigma-Aldrich®), ABCR GmbH, and Iris Biotec GmbH. 18-(Tert-butoxy)-18-oxooctadecanoic acid (C18DA(OtBu)) was purchased from Cool Pharm Ltd., 20-(tert-butoxy)-20-oxoicosanoic acid (C20DA(OtBu)) was purchased from Angene, and icosanoic acid was purchased from EGA-Chemie. Assembly of the peptides began from the C-terminus by stepwise chain elongation according to their respective sequences, with alternating Fmoc-deblocking and coupling steps. NMU-8 analogs were obtained as TFA salts from cleavage / deprotection or HPLC purification. The trifluoroacetate can be exchanged by common procedures, such as the resin ion exchange procedure disclosed in Roux, St. et al. J. Pept. Sci. 2008; 14: 354-359.

[0121] Synthesis method (S01) Peptides were synthesized by microwave-assisted solid-phase peptide synthesis (SPPS) on a CEM Liberty Blue peptide synthesizer at 0.10 mmol to 0.25 mmol scale on Rink amide resin using the Fmoc strategy.

[0122] Coupling of amino acids was effected by adding a DMF solution of the appropriately protected amino acid building blocks (0.2 mol / L, 4-5 equiv.), oxyma (1 mol / L, 4-5 equiv.), and DIC (1 mol / L, 1 ml, 8-10 equiv.) to the resin and heating the resulting suspension to 90°C by microwave irradiation for 4 minutes (min). For coupling of Fmoc-Arg(Pbf)-OH, Fmoc-Pro-OH, and fatty acid building blocks (C18DA, C18A, C20DA, C20A), the coupling cycle was repeated (double coupling, 2 × 4 min, 90°C). Fmoc-PipAc-OH, Fmoc-AEPipAc-OH·2HCl, Fmoc-2Pal-OH, Fmoc-3Pal-OH, Fmoc-4Pal-OH, Fmoc-NMeL-OH, and Fmoc-NMeA-OH were coupled at 75°C for 20 min. In some cases, Fmoc-AEPipAc-OH·2HCl was coupled at 90°C (1 × 20 min). Sar was introduced using Fmoc-Sar-OH, Fmoc-Sar3-OH, or Fmoc-Sar-OPfp (4 or 20 min couplings at 75°C). Fmoc-Glu-OtBu was coupled twice at 75°C for 20 min. Fmoc-His(Trt)-OH was coupled at 50°C (2 × 12 min). NMeL or NMeA was followed by double coupling of the amino acid. Prior to conjugation of the fatty acid building block in the final coupling cycle, the peptidyl resin was treated with acetic anhydride for 5 min at 65° C. (capping). Removal of the Fmoc protecting group was carried out using excess 10% piperidine / DMF for 1 min at 90° C.; this step was repeated for removal of the first Fmoc group.

[0123] After completion of peptide chain assembly, the resin was carefully washed with DCM and dried prior to cleavage. Concomitant resin cleavage and side-chain deprotection were carried out using a mixture of TFA / water / triisopropylsilane (95:5:2.5) at 40 °C for 45 min. The crude peptide was precipitated with cold diethyl ether, dissolved in 50% acetonitrile / water, and purified by preparative HPLC (P01 or P02).

[0124] Synthesis method (S02) In a similar manner, peptides were synthesized at elevated temperatures on a PurePep® Chorus (Gyros Protein Technologies) automated peptide synthesizer. For peptide chain elongation, a suitably protected building block (0.2 mol / L, 4 equivalents) dissolved in DMF was added to the solid-phase resin in a reaction vessel and treated with a DMF solution of oxyma (1 mol / L, 4 equivalents) and DIC (1 mol / L, 8 equivalents). The resulting suspension was heated and maintained at a final temperature of 85°C for 4 min. Fmoc-Arg(Pbf)-OH and a fatty acid building block (C20DA) were introduced by double coupling (2 × 4 min, 85°C). Fmoc-Glu-OtBu, Fmoc-AEPipAc-OH·2HCl, Fmoc-Sar-OH, and Fmoc-NMeL-OH were coupled at 75°C for 20 min. NMeL or NMeA was followed by an amino acid by double coupling. Prior to conjugation of the fatty acid building block in the final coupling cycle, the peptidyl resin was treated with acetic anhydride for 5 min at 65° C. (capping). Removal of the Fmoc protecting group was carried out using excess 10% piperidine / DMF for 1 min at 85° C.; this step was repeated for removal of the first Fmoc group.

[0125] Synthesis method (S03) Instead, peptides were synthesized in an in-house designed, fully automated parallel peptide synthesizer based on a liquid handling platform (TECAN AG, Switzerland) and equipped with a temperature-controlled heating block. Peptide chain assembly was achieved by adding a DMF solution of the appropriately protected building blocks (0.2 mol / L, 4–6 equiv.), oxyma (1 mol / L, 4–6 equiv.), and DIC (1 mol / L, 8–12 equiv.) to a reaction vessel containing an aliquot of resin (0.05–0.1 mmol scale). The resulting suspension was stirred by intermittent shaking (12-second intervals every 2 min) and heated at 75 °C for 10 min. Fmoc-PipAc-OH, Fmoc-AEPipAc-OH·2HCl, Fmoc-2Pal-OH, Fmoc-3Pal-OH, and Fmoc-4Pal-OH were coupled at 75 °C for 40 min. Fmoc-Arg(Pbf)-OH and fatty acid building blocks (C18DA, C20DA) were introduced by double coupling (2 × 10 min, 75 °C). Fmoc-Glu-OtBu, Fmoc-NMeL-OH, and Fmoc-NMeA-OH were coupled for 2 × 40 min at 75 °C.

[0126] Fmoc-His(Trt)-OH was coupled for 2 × 20 min at 50 °C. Amino acids were introduced by double coupling after NMeL or NMeA. Capping with acetic anhydride (20% in DMF, 1.5 ml) was performed prior to conjugation with the fatty acid in the final coupling step. For Fmoc deprotection, the resin was treated with 10% piperidine in DMF (1.0 mL) at elevated temperature (75 °C) for 5 min; in the first cycle, the piperidine treatment was repeated for an additional 5 min. To release the fully deprotected peptide from the solid support, the resin was washed with DCM (5 × 2.5 mL), dried, and treated with a mixture of 95% TFA (2.5 mL) and triisopropylsilane (0.05 mL) for 30 min at 40 °C. The crude peptide solution was drained, combined with two additional washes (2 × 2 mL 95% TFA), and concentrated under reduced pressure. The residue was redissolved in DMF / ACN / water.

[0127] Purification method (P01) The crude peptide was dissolved in DMF / acetonitrile / water and purified by reversed-phase chromatography using an Agilent preparative HPLC-MS system equipped with a preparative pump G1361A, a diode array detector G1315B, a mass spectrometer G1956B, and a fraction collector CTC PAL IFC. The stationary phase was a Waters XSelect CSH Prep column (phenylhexyl, 5 μm, 30 × 150 mm). The peptide was eluted with a linear gradient of eluent A (0.1% TFA in H2O) and eluent B (ACN) at a flow rate of 50 ml / min and a temperature of 40 °C. Homogeneous fractions were pooled and lyophilized. The final products were characterized by HPLC-MS (A01, A02, A03, or A04).

[0128] Purification method (P02) The crude peptide was dissolved in DMF / acetonitrile / water (e.g., NMP) and purified by reverse-phase chromatography using an Agilent preparative HPLC-MS system equipped with preparative pumps G7161B, G7111B, and G7110B, a diode array detector G7115A, a mass spectrometer G6135B, and an autosampler / fraction collector G7159B. The stationary phase was a Phenomenex LUNA C8 10 μm Prep column (50 × 250 mm). The peptide was eluted with a linear gradient of eluent A (0.1% TFA in HO) and eluent B (0.1% TFA in ACN) at a flow rate of 120 ml / min and a temperature of 40 °C. Homogeneous fractions were pooled and lyophilized. The final product was characterized by HPLC-MS (A03, A04).

[0129] Analysis Methods (A01, A02, A03 and A04) Peptide purity and mass were estimated by analytical HPLC-MS on a Kinetex C8 column (4.6 mm × 150 mm, 2.6 μm, Phenomenex) using a Waters Acquity HPLC system equipped with a 3100 mass detector (A01, A02), an Agilent 1260 HPLC system equipped with a mass detector G6135 (A03), or an Agilent 1290 HPLC system equipped with a time-of-flight (TOF) MS G6230 (A04). Analysis was performed by gradient elution with eluent A (0.3% TFA in HO) and eluent B (0.24% TFA in ACN) at 40 °C. Gradient and flow rate details are summarized in Tables 14, 15, 16, and 17. Chromatographic retention times and most prominent m / z signals (+ESI mode) were recorded, where m = molecular weight and z = net charge of the observed molecular species.

[0130] Peptide purity (relative peak area at 214 nm) was in the range of 80% to 99%, preferably above 95%. [Table 16]

[0131] [Table 17]

[0132] [Table 18]

[0133] [Table 19]

[0134] The following compounds were synthesized. All compounds were obtained as TFA salts: compound 1 SEQ ID NO: 1 [ka] MW (calculated value): 2939.50 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 1) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 1) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 32.4 minutes m / 2:1469.8

[0135] compound 2 SEQ ID NO: 2 MW (calculated): 2869.37 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 2) C18DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 2) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 28.6 minutes m / 3:957.2

[0136] compound 3 SEQ ID NO.3 MW (calculated value): 3068.62 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn5,G 8 ]NMU-8 (SEQ ID NO: 3) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 3) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 31.1 minutes m / 3:1023.6

[0137] compound 4 SEQ ID NO:4 MW (calculated value): 3054.59 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 4) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 4) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 31.1 minutes m / 3:1019.0

[0138] compound 5 SEQ ID NO:5 MW (calculated value): 2827.32 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 5) C18DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 5) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 29 minutes m / 3:943.2

[0139] compound 6 SEQ ID NO:6 MW (calculated value): 2768.30 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 6) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 6) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.8 minutes m / 3:923.7

[0140] compound 7 SEQ ID NO:7 [ka] MW (calculated value): 2953.49 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 7) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 7) Synthesis and purification methods: S01; P02 LCMS:A03 Rt: 29.3 minutes m / 3:985.2

[0141] compound 8 SEQ ID NO:8 MW (calculated value): 2712.24 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 8) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 8) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 32.7 minutes m / 2:1356.7

[0142] compound 9 SEQ ID NO:9 MW (calculated value): 2981.54 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 9) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 9) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 32.5 minutes m / 3:994.6

[0143] compound 10 SEQ ID NO: 10 MW (calculated): 2969.53 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 10) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-R-NMeA-RG-NH2 (SEQ ID NO: 10) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 32.5 minutes m / 2:1485.4

[0144] compound 11 SEQ ID NO: 11 MW (calculated value): 2941.48 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 11) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-R-NMeA-RG-NH2 (SEQ ID NO: 11) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.5 minutes m / 3:982.5

[0145] compound 12 SEQ ID NO: 12 MW (calculated value): 2728.24 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 12) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-R-NMeA-RG-NH2 (SEQ ID NO: 12) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.9 minutes m / 3:911.4

[0146] compound 13 SEQ ID NO: 13 MW (calculated value): 2843.37 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 13) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-NMeA-RG-NH2 (SEQ ID NO: 13) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.3 minutes m / 3:949.8

[0147] compound 14 SEQ ID NO: 14 MW (calculated value): 3056.60 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 14) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-NMeA-RG-NH2 (SEQ ID NO: 14) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.0 min m / 3:1020.9

[0148] compound 15 SEQ ID NO: 15 MW (calculated value): 2841.35 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 15) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 15) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.3 minutes m / 3:949.1

[0149] compound 16 SEQ ID NO: 16 MW (calculated value): 3042.58 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 16) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 16) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.1 minutes m / 3:1016.2

[0150] compound 17 SEQ ID NO: 17 MW (calculated value): 3082.64 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 5 ,G 8 ]NMU-8 (SEQ ID NO: 17) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-KPRG-NH2 (SEQ ID NO: 17) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.0 min m / 3:1029.6

[0151] compound 18 SEQ ID NO: 18 MW (calculated value): 3070.63 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 5 ,NMeA 6,G 8 ]NMU-8 (SEQ ID NO: 18) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-K-NMeA-RG-NH2 (SEQ ID NO: 18) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.0 min m / 3:1024.4

[0152] compound 19 SEQ ID NO: 19 MW (calculated value): 2857.39 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 19) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-K-NMeA-RG-NH2 (SEQ ID NO: 19) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.3 minutes m / 3:954.5

[0153] compound 20 SEQ ID NO: 20 MW (calculated value): 2686.20 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 20) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-NMeA-RG-NH2 (SEQ ID NO: 20) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 29.7 minutes m / 2:1343.6

[0154] compound 21 SEQ ID NO: 21 MW (calculated value): 2911.45 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 21) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 21) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.6 minutes m / 3:972.7

[0155] compound 22 SEQ ID NO: 22 MW (calculated value): 2899.44 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 22) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-NMeA-RG-NH2 (SEQ ID NO: 22) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.5 minutes m / 3:968.6

[0156] compound 23 SEQ ID NO: 23 MW (calculated value): 2885.41 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 23) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 23) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.6 minutes m / 3:963.9

[0157] compound 24 SEQ ID NO: 24 MW (calculated value): 2470.95 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 24) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 24) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 29.4 minutes m / 3:825.7

[0158] compound 25 SEQ ID NO: 25 MW (calculated value): 2740.25 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 25) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 25) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.9 minutes m / 3:914.3

[0159] compound 26 SEQ ID NO: 26 [ka] MW (calculated value): 2897.42 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 26) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 26) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.5 minutes m / 3:966.6

[0160] compound 27 SEQ ID NO: 27 MW (calculated value): 2684.18 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 27) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 27) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 29.9 minutes m / 2:1342.8

[0161] compound 28 SEQ ID NO: 28 MW (calculated value): 2458.93 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 28) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 28) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 30.3 minutes m / 2:1230.1

[0162] compound 29 SEQ ID NO: 29 MW (calculated value): 2899.44 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 6 ,G 8 ]NMU-8 (SEQ ID NO: 29) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-GRG-NH2 (SEQ ID NO: 29) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 31.9 minutes m / 2:1450.3

[0163] compound 30 SEQ ID NO: 30 MW (calculated value): 2913.46 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,bAla 6 ,G 8 ]NMU-8 (SEQ ID NO: 30) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-bAla-RG-NH2 (SEQ ID NO: 30) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 31.9 minutes m / 2:1457.3

[0164] compound 31 SEQ ID NO: 31 MW (calculated value): 2829.34 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 31) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 31) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.0 min m / 2:1416.4

[0165] compound 32 SEQ ID NO: 32 MW (calculated value): 2869.41 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 5 ,G 8 ]NMU-8 (SEQ ID NO: 32) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-KPRG-NH2 (SEQ ID NO: 32) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.0 min m / 2:1436.3

[0166] compound 33 SEQ ID NO: 33 [ka] MW (calculated value): 2484.97 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 33) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 33) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 29.0 minutes m / 3:829.1

[0167] compound 34 SEQ ID NO: 34 MW (calculated value): 2927.49 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 34) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-NMeA-RG-NH2 (SEQ ID NO: 34) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 32.3 minutes m / 3:976.7

[0168] compound 35 SEQ ID NO: 35 MW (calculated value): 2754.28 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeR 5 ,G 8 ]NMU-8 (SEQ ID NO: 35) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-NMeR-PRG-NH2 (SEQ ID NO: 35) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 8.7 minutes m / 3:918.9

[0169] compound 36 SEQ ID NO: 36 MW (calculated value): 2983.56 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeR 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 36) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-NMeR-NMeA-RG-NH2 (SEQ ID NO: 36) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.6 minutes m / 2:1492.7

[0170] compound 37 SEQ ID NO: 37 MW (calculated value): 2742.27 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeR 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 37) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-NMeR-NMeA-RG-NH2 (SEQ ID NO: 37) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 8.7 minutes m / 3:914.9

[0171] compound 38 SEQ ID NO: 38 MW (calculated value): 2672.17 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 38) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 38) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 29.8 minutes m / 2:1336.8

[0172] compound 39 SEQ ID NO: 39 MW (calculated value): 2897.42 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 39) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 39) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.3 minutes m / 3:968.0

[0173] compound 40 SEQ ID NO: 40 MW (calculated value): 2855.38 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 40) C20DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 40) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.0 min m / 3:952.7

[0174] compound 41 SEQ ID NO: 41 MW (calculated value): 2813.3 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 41) C18DA-gGlu-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 41) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 7.9 minutes m / 3:938.6

[0175] compound 42 SEQ ID NO: 42 [ka] MW (calculated value): 2925.47 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 42) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 42) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 32.8 minutes m / 3:975.9

[0176] compound 43 SEQ ID NO: 43 [ka] MW (calculated value): 2913.46 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 43) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 43) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 32.7 minutes m / 2:1457.4

[0177] compound 44 SEQ ID NO: 44 MW (calculated value): 2343.85 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 44) C18DA-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-NMeA-RG-NH2 (SEQ ID NO: 44) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 8.9 minutes m / 3:782.3

[0178] compound 45 SEQ ID NO: 45 MW (calculated value): 2945.46 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,4Pal 5 ,G 8 ]NMU-8 (SEQ ID NO: 45) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-4Pal-PRG-NH2 (SEQ ID NO: 45) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.3 minutes m / 3:982.9

[0179] compound 46 SEQ ID NO: 46 MW (calculated value): 2925.47 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 5 ,G 8 ]NMU-8 (SEQ ID NO: 46) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-KPRG-NH2 (SEQ ID NO: 46) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.4 minutes m / 1:2925.4

[0180] compound 47 SEQ ID NO: 47 MW (calculated value): 2913.46 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 47) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-K-NMeA-RG-NH2 (SEQ ID NO: 47) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.3 minutes m / 3:972.1

[0181] compound 48 SEQ ID NO: 48 MW (calculated value): 2933.45 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,2Pal 5 ,NMeA 6 ,G 8]NMU-8 (SEQ ID NO: 48) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-2Pal-NMeA-RG-NH2 (SEQ ID NO: 48) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 31.7 minutes m / 3:978.3

[0182] compound 49 SEQ ID NO: 49 MW (calculated value): 2953.53 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 6 ,G 8 ]NMU-8 (SEQ ID NO: 49) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-KPRG-NH2 (SEQ ID NO: 49) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 31.6 minutes m / 3:985.6

[0183] compound 50 SEQ ID NO:50 MW (calculated value): 2941.52 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,K 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 50) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-K-NMeA-RG-NH2 (SEQ ID NO: 50) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 32.3 minutes m / 3:981.4

[0184] compound 51 SEQ ID NO:51 MW (calculated value): 2934.44 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 51) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-HPRG-NH2 (SEQ ID NO: 51) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 28.8 minutes m / 3:979.1

[0185] compound 52 SEQ ID NO:52 MW (calculated): 2967.51 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeR 5 ,G 8 ]NMU-8 (SEQ ID NO: 52) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-NMeR-PRG-NH2 (SEQ ID NO: 52) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.8 minutes m / 3:990.3

[0186] compound 53 SEQ ID NO:53 MW (calculated): 2955.5 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeR 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 53) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-NMeR-NMeA-RG-NH2 (SEQ ID NO: 53) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.8 minutes m / 3:986.4

[0187] compound 54 SEQ ID NO:54 MW (calculated value): 2945.46 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,3Pal 5 ,G 8 ]NMU-8 (SEQ ID NO: 54) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-3Pal-PRG-NH2 (SEQ ID NO: 54) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.5 minutes m / 3:982.9

[0188] compound 55 SEQ ID NO: 55 MW (calculated value): 2922.43 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,H 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 55) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-H-NMeA-RG-NH2 (SEQ ID NO: 55) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.4 minutes m / 3:975.3

[0189] compound 56 SEQ ID NO:56 MW (calculated value): 2945.46 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,2Pal 5 ,G 8 ]NMU-8 (SEQ ID NO: 56) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-2Pal-PRG-NH2 (SEQ ID NO: 56) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.8 minutes m / 3:982.9

[0190] compound 57 SEQ ID NO:57 MW (calculated value): 2933.45 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,3Pal 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 57) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-3Pal-NMeA-RG-NH2 (SEQ ID NO: 57) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.4 minutes m / 3:979.1

[0191] compound 58 SEQ ID NO:58 MW (calculated value): 2933.45 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,4Pal 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 58) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-4Pal-NMeA-RG-NH2 (SEQ ID NO: 58) Synthesis and purification methods: S03; P01 LCMS:A02 Rt: 28.3 minutes m / 3:978.6

[0192] compound 59 SEQ ID NO:59 MW (calculated value): 2700.23 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 59) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 59) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.5 minutes m / 3:901.1

[0193] compound 60 SEQ ID NO: 60 MW (calculated value): 2499.00 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 60) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 60) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.9 minutes m / 3:833.9

[0194] compound 61 SEQ ID NO: 61 MW (calculated value): 2486.99 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 61) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 61) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.9 minutes m / 3:829.9

[0195] compound 62 SEQ ID NO: 62 MW (calculated value): 2543.06 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 62) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-R-NMeA-RG-NH2 (SEQ ID NO: 62) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 11.1 minutes m / 3:848.6

[0196] compound 63 SEQ ID NO: 63 MW (calculated value): 2756.29 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 63) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-R-NMeA-RG-NH2 (SEQ ID NO: 63) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 10.7 minutes m / 3:919.8

[0197] compound 65 SEQ ID NO: 65 MW (calculated value): 2555.07 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 65) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 65) Synthesis and purification methods: S02; P02 LCMS:A03 Rt: 33.9 minutes m / 2:1278.2

[0198] compound 66 SEQ ID NO: 66 MW (calculated value): 2385.89 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 66) C18DA-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-R-NMeA-RG-NH2 (SEQ ID NO: 66) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 9.2 minutes m / 3:796.3

[0199] compound 67 SEQ ID NO: 67 MW (calculated value): 2397.90 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 67) C18DA-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 67) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 30.0 min m / 3:800.1

[0200] compound 68 SEQ ID NO: 68 MW (calculated value): 2313.78 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle4 ,G 8 ]NMU-8 (SEQ ID NO: 68) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 68) Synthesis and purification methods: S01; P01 LCMS:A02 Rt: 29.8 minutes m / 3:772.2

[0201] compound 69 SEQ ID NO: 69 [ka] MW (calculated value): 2698.21 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 69) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 69) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 29.7 minutes m / 2:1349.8

[0202] compound 70 SEQ ID NO: 70 MW (calculated value): 2472.96 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 70) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-NMeA-RG-NH2 (SEQ ID NO: 70) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 30.1 minutes m / 2:1237.2

[0203] compound 71 SEQ ID NO: 71 MW (calculated value): 2184.66 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 71) C18DA-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 71) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 31.8 minutes m / 3:729.0

[0204] compound 72 SEQ ID NO:72 MW (calculated value): 2527.01 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 72) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 72) Synthesis and purification methods: S01; P01 LCMS:A03 Rt: 30.7 minutes m / 3:843.2

[0205] compound 73 SEQ ID NO: 73 MW (calculated value): 2515.00 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 73) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-R-NMeA-RG-NH2 (SEQ ID NO: 73) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 8.8 minutes m / 3:839.6

[0206] compound 74 SEQ ID NO:74 MW (calculated value): 2513.03 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,hLys 5 ,G 8 ]NMU-8 (SEQ ID NO: 74) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-hLys-PRG-NH2 (SEQ ID NO: 74) Synthesis and purification methods: S03; P01 LCMS:A01 Rt: 8.7 minutes m / 3:838.4

[0207] compound 75 SEQ ID NO: 75 MW (calculated value): 2910.42 Da 2-[4-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 75) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-PipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 75) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 29.9 minutes m / 2:1455.3

[0208] compound 76 SEQ ID NO:76 MW (calculated value): 2854.35 Da 2-[4-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,G 8 ]NMU-8 (SEQ ID NO: 76) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-PipAc-YF-NMeL-Nle-Dbu-PRG-NH2 (SEQ ID NO: 76) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 29.6 minutes m / 2:1427.3

[0209] compound 77 SEQ ID NO:77 MW (calculated value): 2697.18 Da 2-[4-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 77) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-PipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 77) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 30.4 minutes m / 2:1348.8

[0210] compound 78 SEQ ID NO:78 MW (calculated value): 2725.24 Da 2-[4-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 78) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-PipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 78) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 33.5 minutes m / 2:1362.8

[0211] compound 79 SEQ ID NO:79 MW (calculated value): 2842.34 Da 2-[4-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Dbu 5 ,NMeA 6 ,G 8 ]NMU-8 (SEQ ID NO: 79) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-PipAc-YF-NMeL-Nle-Dbu-NMeA-RG-NH2 (SEQ ID NO: 79) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 29.6 minutes m / 2:1421.3

[0212] compound 80 SEQ ID NO: 80 MW (calculated value): 2896.43 Da 2-[4-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 80) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-PipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 80) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 32.7 minutes m / 2:1448.3

[0213] Reference compound Ref.1 SEQ ID NO: 81 [ka] MW (calculated value): 2923.51 Da 2-[4-(2-(stearoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 81) C18A-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-RPRG-NH2 (SEQ ID NO: 81) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 38.6 minutes m / 2:1461.9

[0214] Reference compound Ref.2 SEQ ID NO:82 [ka] MW (calculated value): 2939.46 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[Nle 4 ,G 8 ]NMU-8 (SEQ ID NO: 82) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YFL-Nle-RPRG-NH2 (SEQ ID NO: 82) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 32.2 minutes m / 2:1469.9

[0215] Reference compound Ref.3 SEQ ID NO: 83 [ka] MW (calculated value): 2909.52 Da 2-[4-(2-(icosanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 83) C20A-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 83) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 43.9 minutes m / 2:1454.9

[0216] Reference compound Ref.4 SEQ ID NO:84 [ka] MW (calculated value): 2925.47 Da 2-[4-(2-(19-carboxynonadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 84) C20DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YFL-Nle-Orn-PRG-NH2 (SEQ ID NO: 84) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 35.4 minutes m / 2:1462.9

[0217] Reference compound Ref.5 SEQ ID NO: 85 [ka] MW (calculated value): 2668.23 Da 2-[4-(2-(stearoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[NMeL 3 ,Nle 4 ,Orn5 ,G 8 ]NMU-8 (SEQ ID NO: 85) C18A-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YF-NMeL-Nle-Orn-PRG-NH2 (SEQ ID NO: 85) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 42.0 minutes m / 2:1334.3

[0218] Reference compound Ref.6 SEQ ID NO:86 [ka] MW (calculated value): 2684.18 Da 2-[4-(2-(17-carboxyheptadecanoyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycyl-N-methylglycylamino)ethyl)piperazin-1-yl]acetyl-[Nle 4 ,Orn 5 ,G 8 ]NMU-8 (SEQ ID NO: 86) C18DA-gGlu-gGlu-gGlu-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-Sar-AEPipAc-YFL-Nle-Orn-PRG-NH2 (SEQ ID NO: 86) Synthesis and purification methods: S01; P01 LCMS:A04 Rt: 29.7 minutes m / 2:1342.3

Claims

1. A compound of formula (I). U-Sp-L-P-NH 2 (I) [In the formula, U is selected from the group Ug1 consisting of 15-carboxy-pentadecanoyl (C16DA), 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl (C20DA); Sp is -(gGlu) n - (Sar) m - (SEQ ID NO: 149) (In the formula, n is selected from the group consisting of 1, 2, 3 and 4; m is selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15; -gGlu- is linked to U and -Sar- is linked to L; L is selected from the group Lg1 consisting of 2-[4-(2-aminoethyl)piperazin-1-yl]acetic acid (AEPipAc), 2-(piperazin-1-yl)acetic acid (PipAc) and 2-[1-(2-aminoethyl)piperidin-4-yl]acetic acid (AECMP); P is a group represented by the formula (II) Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 112) (II) (In the formula, X 5 is a group X consisting of Arg, Dbu, NMeArg, Orn, Lys, His, hLys, 2Pal, 3Pal and 4Pal 5 g1; X 6 is a group X consisting of Pro, NMeAla, bAla, and Gly. 6 g1)

2. U is selected from the group Ug1 consisting of 15-carboxy-pentadecanoyl (C16DA), 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl (C20DA); Sp is -(gGlu) n - (Sar) m - (SEQ ID NO: 115) (In the formula, n is selected from the group consisting of 1, 2, 3 and 4; m is selected from the group consisting of 3, 6, 9, 12 and 15; -gGlu- is linked to U and -Sar- is linked to L; L is selected from the group Lg1 consisting of 2-[4-(2-aminoethyl)piperazin-1-yl]acetic acid (AEPipAc), 2-(piperazin-1-yl)acetic acid (PipAc) and 2-[1-(2-aminoethyl)piperidin-4-yl]acetic acid (AECMP); P is a group represented by the formula (II) Tyr-Phe-NMeLeu-Nle-X 5 -X 6 -Arg-Gly (SEQ ID NO: 112) (II) (In the formula, X 5 is a group X consisting of Arg, Dbu, NMeArg, Orn, Lys, His, hLys, 2Pal, 3Pal and 4Pal 5 g1; X 6 is a group X consisting of Pro, NMeAla, bAla, and Gly. 6 2. The compound of formula (I) according to claim 1, which is a peptide having an amino acid sequence of:

3. 3. A compound of formula (I) according to claim 1 or 2, wherein U is selected from the group Ug2 consisting of 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl (C20DA).

4. Sp is -(gGlu) n - (Sar) m - (SEQ ID NO: 116) wherein n is selected from the group consisting of 3 and 4; Compounds of formula (I) according to any one of claims 1 to 3, selected from the group Spg2 consisting of: m is selected from the group consisting of 9, 12 and 15, preferably m is 12 or 15.

5. L is selected from the group Lg2 consisting of 2-[4-(2-aminoethyl)piperazin-1-yl]acetic acid (AEPipAc) and 2-(piperazin-1-yl)acetic acid (PipAc); Compounds of formula (I) according to any one of claims 1 to 4, wherein L is preferably selected from the group Lg3 consisting of 2-[4-(2-aminoethyl)piperazin-1-yl]acetic acid (AEPipAc).

6. X 5 is a group X consisting of Arg, Dbu, NMeArg, Orn and Lys 5 g2 is selected from; X 6 is a group X consisting of Pro and NMeAla 6 The compound of formula (I) according to any one of claims 1 to 5, selected from: g2.

7. U is selected from the group Ug2 consisting of C18DA and C20DA; Sp is -(gGlu) n - (Sar) m - (SEQ ID NO: 116) wherein n is selected from the group consisting of 3 and 4; m is selected from the group Spg2 consisting of: 9, 12 and 15, preferably m is 12 or 15; L is selected from the group Lg2 consisting of 2-[4-(2-aminoethyl)piperazin-1-yl]acetic acid (AEPipAc) and 2-(piperazin-1-yl)acetic acid (PipAc); The compound of formula (I) according to any one of claims 1 to 5, wherein P is a peptide of formula (II) selected from the group consisting of the following Table 1: Table 1

8. A compound of formula (I) according to claim 1, selected from the group consisting of Compound No. 1 to Compound No. 80 in the following Table 3: Table 2-1 Table 2-2

9. A compound of formula (I) according to any one of claims 1 to 8 in the form of a salt, preferably a pharmaceutically acceptable salt.

10. A compound of formula (I) according to any one of claims 1 to 9, which is part of a pharmaceutical composition together with at least one pharmaceutically acceptable adjuvant, diluent and / or carrier.

11. A compound according to any one of claims 1 to 10 for use as a pharmaceutical.

12. (i) inhibiting, reducing or preventing weight gain, promoting weight loss, chronic weight management; (ii) the prevention or treatment of an overweight condition; (iii) preventing or treating obesity, morbid obesity, obesity-related inflammation, obesity-related gallbladder disease, or obesity-related sleep apnea; and / or (iv) preventing or treating a condition characterized by inappropriate control of appetite, a condition characterized by overeating, binge eating disorder, or Prader-Willi syndrome A compound according to any one of claims 1 to 10 for use in the method of

13. (v) reducing circulating LDL cholesterol levels or increasing the HDL / LDL ratio; (vi) type 2 diabetes (T2D), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT); (vii) metabolic syndrome, hypertension, dyslipidemia or atherogenic dyslipidemia, (viii) chronic kidney disease (CKD), hepatic steatosis, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH); (ix) macrovascular disease, atherosclerosis, coronary heart disease, peripheral artery disease, stroke, or microvascular disease; (x) cartilage degeneration or osteoarthritis; (xi) Reproductive health complications of obesity or overweight, or infertility; (xii) cancer; and / or (xiii) cognitive impairment, anxiety or major depressive disorder 11. A compound according to any one of claims 1 to 10 for use in a method for the prevention or treatment of a condition, disorder or disease selected from the group consisting of:

14. A compound according to any one of claims 1 to 10 for use in any method of prevention or treatment according to claim 12 or 13, the compound is administered as part of a combination therapy with at least one additional active agent, wherein the at least one additional active agent is for use in the treatment of obesity, diabetes, dyslipidemia, or hypertension; Preferably, the compound wherein the at least one further active agent is for use in the treatment of obesity.

15. and / or the at least one additional active agent for use in the treatment of obesity is a GIP receptor agonist, a GLP-1 receptor agonist, a GCG receptor agonist, an oxyntomodulin or oxyntomodulin analog, a GCGR / GLP-1R dual agonist, a GLP-1R / GIPR dual agonist, a GLP-1R / GIPR / GCGR triple agonist, peptide YY (PYY) or a PYY analog, neuropeptide Y (NPY) or a NPY analog, an agonist of NPY2R, NPY4R, or NPY5R. an agonist, an antagonist or inverse agonist of NPY1R, a GLP-1R / NPY receptor dual agonist, a GLP-1R / NPY2R dual agonist, a GLP-1R / GIPR / NPYR triple agonist, a GLP-1R / GIPR / NPY2R triple agonist, a GLP-1R / GCGR / NPYR triple agonist, a GLP-1R / GCGR / NPY2R triple agonist, an amylin receptor agonist, and a GLP-1R / amylin receptor dual agonist; 15. The compound for use according to claim 14, wherein the at least one further active agent for use in the treatment of obesity is selected from the group consisting of semaglutide, danugliplon, the GLP-1R agonist PF-07081532, tirzepatide, pembidutide, the GLP-1R / GIPR / GCGR triple agonist LY-3437943, caglisema, amicretin, the combination semaglutide / PYY analogue NN-9775.

16. wherein the at least one further agent for use in treating obesity is a GCGR / GLP-1R dual agonist of formula (III) H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-gGlu-GSGSGG-)-WLESA-NH 2 (SEQ ID NOs: 87-88) (III) 15. The compound for use according to claim 14, wherein

17. 15. The compound for use according to claim 14, wherein the at least one further agent for use in the treatment of obesity is semaglutide.