Soluble GLP1 / GIP / NPY2 receptor triple agonists

Abstract

The present invention relates to peptide compounds that agonize the GIP, GLP-1 and neuropeptide Y2 (NPY2) receptors, agonists, processes for their preparation, pharmaceutical compositions thereof, and their medical use in the treatment and / or prevention of a variety of diseases such as obesity, diabetes, metabolic syndrome, and / or MASH / NASH. The peptide compounds of the invention are suitable for subcutaneous administration.

Description

[0001] SOLUBLE GLP1 / GIP / NPY2 RECEPTOR TRIPLE AGONISTS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to peptide compounds that agonize the GIP, GLP-1 and neuropeptide Y2 (NPY2) receptors and to their medical use in the treatment and / or prevention of a variety of diseases, conditions or disorders, such as obesity, diabetes, metabolic syndrome, and / or MASH / NASH.

[0004] BACKGROUND INFORMATION

[0005] Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. A body mass index (BMI) over 27 kg / m2is considered as overweight, and a BMI over 30 kg / m2is considered as obese. The BMI is calculated based on body weight and height. Obesity has in the past 50 years reached pandemic levels. Worldwide obesity has nearly tripled since 1975. In 2016, more than 1.9 billion adults and more than 340 million children and adolescents were overweight or obese. Both overweight and obesity are a major risk factor for several chronic diseases, including type 2 diabetes, cardiovascular diseases and cancer which are the leading causes of morbidity and death in many countries. Obesity is thus a serious condition and associated with poorer mental health outcomes, reduced quality of life, and contributes to a decline in life expectancy.

[0006] Peptide YY (PYY) is a 36-amino acid peptide with the sequence YPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 181), found in endocrine L cells in the mucosa of the gastrointestinal tract, especially in the ileum and colon. PYY belongs to the pancreatic polypeptide (PP) family together with neuropeptide Y (NPY) and pancreatic polypeptide (PP). This family of peptides act upon the NPY receptors designated NPY1R (Yl), NPY2R (Y2), NPY4R (Y4), and NPY5R (Y5). The receptor family belongs to a class of G protein-coupled receptors (GPCRs) that are expressed in the CNS, especially in regions of the hypothalamus. The receptors NPY1R-NPY5R exhibit both anorectic (NPY2R, NPY4R) and orexigenic effects (NPY5R, NPY1R). The two major forms of peptide YY are PYYi-ssand PYY3-36. PYYI-36 is released postprandially from intestinal L cells in proportion to energy intake and in part truncated to PYY3-36, which is the main circulating form of PYY and a relatively selective Y2 receptor agonist. PYY1-36 and PYY3-36 inhibit gastric acid secretion, gastrointestinal transit, and food intake. Food intake is inhibited both via a stimulant effect on Y2 receptors on vagal afferent neurons and an interaction with Y2 receptors in the hypothalamus, which is consistent with the ability of PYY to gain access to the brain via circumventricular organs such as the area postrema and subfornical organ. Furthermore, it is known that PYY concentrations in the blood of people with obesity are lower than those of healthy individuals. Thus, NPY2R and / or NPY4R agonists may hold potential in the treatment of obesity.

[0007] Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), belong to the family of incretins. GLP-l(7-37) is a 31-amino acid peptide, with the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 182) and GIP is a 42-amino acid peptide, with the sequence YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO: 183). GLP-1 and GIP are secreted from small intestinal L cells and K cells, respectively. GLP-1 acts via GLP-1 receptors and is known to have a sugar-dependent insulinotropic action (i.e. stimulate insulin release) and a feeding suppressive action. GIP acts via GIP receptors and is also known to have a sugar-dependent insulinotropic action, though its influence on feeding is less clear. GLP-1 receptor / GIP receptor co-agonist peptide has been reported to show a stronger hypoglycaemic action and body weight-lowering action than those of a GLP-1 receptor agonist alone. Therefore, research efforts have been made to develop GLP-l / GIP receptor co-agonists for the treatment of obesity and / or diabetes, based on the structure of natural glucagon, GIP, or GLP-1.

[0008] The most noteworthy effects of GLP-1 agonists are their ability to promote insulin secretion in a glucosedependent manner by binding to GLP-1 receptors expressed on the pancreatic p cells. Almost as importantly, GLP-1 agonists have been shown to inhibit glucagon secretion at glucose levels above fasting levels. Critically, this does not affect the glucagon response to hypoglycaemia, making GLP-1 agonists a safe anti-diabetic drug with very low incidence of hypoglycaemia compared to insulin. In June 2021, Semaglutide, a GLP-1 agonist, was approved by the FDA for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, type 2 diabetes, or high cholesterol). As an anti-obesity drug, GLP-1 agonists work by binding to GLP-1 receptors in hypothalamus thereby supressing appetite. Furthermore, GLP-1 agonists bind to GLP-1 receptors in the stomach, inhibiting gastric emptying, acid secretion, and motility, which collectively promote satiety. Consequently, diabetic subjects treated with GLP-1 receptor agonists often also experience a beneficial weight loss in addition to a control of their blood sugar levels.

[0009] However, despite long-standing efforts, the number of overweight and obese patients is still growing. First line therapy for overweight and obese patients comprises diet and exercise but often are not sufficiently efficacious. Second line treatment options are bariatric surgery and pharmacotherapy. Available pharmacological treatments seem to lack in efficacy and / or safety, and only a limited number of approved therapies, such as Semaglutide and Tirzepatide, are available. Therefore, there is still a high medical need for more efficacious and safe treatment options. Future obesity treatments may benefit from targeting GLP1-R, GIPR and NPY2R simultaneously in view of the biological role of PYY, GIP, or GLP-1. In addition, developing mono-peptides able to target the above-mentioned three receptors are highly desirable compared to combination therapy with individual peptides for several reasons. First, mono peptides are easier to formulate into a single dosing unit as compared to mixtures of different polypeptides. This is primarily because different peptides may possess different physiochemical properties, e.g., isoelectric point, solubility, or chemical stability at a given pH, which means that one formulation developed for one peptide may be less optimal for or incompatible with a different polypeptide. Therefore, combination therapy with individual peptides may require individual dosing units. Secondly, mono peptides are cheaper to manufacture compared to individual polypeptides and also reduce the burden of regulatory approval.

[0010] EP3467106 Al discloses peptides that agonize receptors GLP-1, GIP and NPY2 for the treatment of obesity, diabetes, and the like. EP3467106 Al does not report any solubility data of the disclosed peptides.

[0011] Example 41, Example 42, and Example 40 of EP3467106 Al, termed in the present application as reference compounds Ref.l, Ref.2, and Ref.3 respectively (see Table B), result to have a solubility of <1 mg / ml at or around physiological pH as showed in Table 2 of the present application. Considering the structure similarity of Example 41, 42 and 40 of EP3467106 Al with all other peptides described in EP3467106 Al, it is credibly derivable that EP3467106 Al peptides are no soluble at or around physiological pH. Therefore, there is a need for novel peptide compounds that agonize receptors GLP-1, GIP and NPY2 and are soluble at or around physiological pH and therefore viable for human therapy.

[0012] Further peptides comprising forty-nine amino acids that agonize receptors GLP-1, GIP and NPY2 are disclosed in WO2024 / 133382 Al.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention relates to compounds of general formula (I) comprising a peptide and a fatty acid substituent.

[0015] The present invention set out to provide peptide compounds that agonize all of the receptors GLP1-R, GIPR and NPY2R (briefly, triple agonists) and that are viable for human therapy, in order to provide effective treatments for the diseases mentioned in the present specification, e.g. obesity, diabetes, metabolic syndrome, and / or MASH / NASH, by administration to a human in need thereof, preferably by administration via subcutaneous injection.

[0016] Particularly, the present invention set out to provide peptide compounds that agonize all the receptors GLP1-R, GIPR and NPY2R and are soluble at or around physiological pH for use in human therapy, preferably by administration via subcutaneous injection.

[0017] In the present contest, the term "at or around physiological pH" means at or around pH 7, e.g. pH 7 ± 0.5. Peptide therapeutics are usually provided as pharmaceutical liquid formulation in a ready-to-use injection device for subcutaneous administration. These peptide formulations for subcutaneous administration have limited application volumes. Therefore, good solubility of the peptides at or around physiological pH is a requirement for the application in a ready-to-use injection device.

[0018] A further aim of the present invention is to provide peptide compounds that agonize all the receptors GLP1-R, GIPR and NPY2R, are soluble at or around physiological pH, and have a long duration of action in the body (i.e. a long in-vivo half-life), in order to provide compounds suitable for the treatment of the diseases mentioned in the present specification by administration of the compound to a human in need thereof.

[0019] A further aim of the present invention is to provide peptide compounds that agonize all the receptors GLP1-R, GIPR and NPY2R, are soluble at or around physiological pH, and have a long duration of action in the body and are suitable for administration by subcutaneous injection to humans, preferably once weekly or once monthly. A further aim of the present invention is to provide peptide compounds triple agonists that are soluble at or around physiological pH, have a long duration of action in the body, and show good selectivity for the GLP-1, GIP and NPY2 receptors against other incretin or related receptors. For example, the compounds of the invention might not activate other receptors from the NPY receptor family, such as NPY1, NPY4 or NPY5 receptor, and / or might not activate GLP-2 or glucagon receptors.

[0020] A further aim of the present invention is to provide peptide compounds triple agonists, soluble at or around physiological pH, having a long duration of action in the body, and having high chemical and physical stability in a liquid formulation suitable for subcutaneous injection to humans.

[0021] A further aim of the present invention is to provide peptide compounds triple agonists, soluble at or around physiological pH, having a long duration of action in the body suitable for a safe and tolerate treatment of humans. In a first aspect, the invention provides compounds of general formula (I) or salt thereof, preferably a pharmaceutically acceptable salt thereof,

[0022] U-Z-P (I), wherein P is a peptide X1-X35 and U-Z is a lipid-linker moiety as defined in the present specification.

[0023] In a second aspect, the invention relates to a pharmaceutical composition, preferably suitable for administration by subcutaneous injection, comprising at least one compound according to the first aspect together with one or more pharmaceutically acceptable carrier and / or excipients.

[0024] In a third aspect, the invention relates to compounds according to the first aspect for use as a medicament, preferably for use in a method of treatment of a disease, disorder and / or condition disclosed in the present specification.

[0025] In a fourth aspect, the invention relates to a method for the treatment of a disease, disorder and / or condition disclosed in the present specification, preferably selected from the list consisting of excessive weight, obesity, type 1 and type 2 diabetes, eating disorders, hyperlipidemia, metabolic syndrome, MAFLD / NAFLD, MASH / NASH, cardiovascular diseases, comorbidities thereof, said method comprising administering a therapeutic effective amount of a compound of the present invention according to any of the aspects and embodiments disclosed herein, to an individual in need thereof.

[0026] In a fifth aspect, the invention relates to a method for preparing compounds of the present invention according to any of the aspects and embodiments disclosed herein. The method may comprise the steps of synthesizing the compound of the invention by solid-phase or liquid-phase methodology, and optionally isolating and / or purifying the final product.

[0027] TERMS, DEFINITIONS AND CONVENTIONS

[0028] The meanings of the residues U, Z, and P will be given hereinafter as embodiments of the invention (the indicate the attachment point to another moiety of the compound). Any and each of these definitions and embodiments may be combined with one another.

[0029] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

[0030] Peptides (P) and Amino acids

[0031] Peptides (P) of the present invention are peptides comprising, or alternatively, consisting of a sequence of 35 amino acids, wherein the amino acid residues are numbered from 1 to 35, i.e. Xi to X35 or X1-X35 (the number shown in subscript after an amino acid represents the amino acid position number). For example, when peptide (P) consists of 35 amino acids, the amino acid at the N-terminus is regarded as amino acid at position 1 (i.e. Xi) and the amino acid at the C-terminus is regarded as amino acid at position 35 (i.e. Xss). In the present contest, the position of the amino acid in peptide (P) can be indicated as subscript number (i.e. nr) if the amino acid is represented by X (i.e. Xnr), or as number in bracket after the amino acid conventional abbreviation (e.g. a lysine at position 29 can be indicated as K(29) or Lys(29)). The term "amino acid" refers to any amino acid, naturally occurring (including the 20 standard amino acids which are encoded by the standard genetic code in humans) or not naturally occurring. According to the present invention, unless otherwise stated, the amino acids are all L-amino acids (L-stereoisomer, natural amino acids). In the present specification, unless naturally occurring amino acids are referred to by their full name (e.g. alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g. Arg or R for arginine, etc.). In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full name, conventional abbreviations are employed according to the following table I or table III (the indicate the attachment point to another moiety of the compound). A hyphen in a term listed in table I and III may be present or omitted and in both case the term represents the same meaning. In the present context, substitution of one or more amino acid in peptide (P) may be substitution with natural amino acids as well as unnatural amino acids, including L- and D-stereoisomers thereof.

[0032] Table I

[0033] Lipid (U) and Linker (Z) moieties

[0034] The compounds of the invention of formula (I) U-Z-P comprise a peptide (P), a lipid moiety (U) and a linker moiety (Z), wherein the lipid (U) is covalently attached to the linker (Z) in one end and the peptide (P) is covalently attached to the linker (Z) in the opposite end (i.e. lipid-linker-peptide, U-Z-P), wherein the linker (Z) is bonded to the epsilon-amino group of Lys at position-29 (Lys(29)) of the peptide (P).

[0035] Without wishing to be bound by any theory, it is thought that such lipophilic substituents bind albumin and other plasma components in the blood stream, thereby shielding the compound of the invention from renal filtration as well as enzymatic degradation. Thus, lipidation of a peptide is typically performed to improve the pharmacokinetic profile of a peptide by e.g. improving metabolic stability, reducing enzymatic degradation, lowering excretion and metabolism, all in all resulting in a prolonged in vivo half-life (ti / 2). In addition, in the present contest it is thought that the lipid-linker moieties (U-Z) contribute to provide to compounds of formula (I) a suitable solubility at or around physiological pH for use in human therapy, preferably by administration via subcutaneous injection. In particular, the compound of general formula (I) comprising at least six (6) residues of amino acids selected from the group consisting of E and [gGlu] showed suitable solubility at or around physiological pH for use in human therapy, preferably by administration via subcutaneous injection.

[0036] The lipid (U) is a hydrocarbon chain, may be linear or branched, and may be saturated or unsaturated. Furthermore, it may include a functional group at the end of the hydrocarbon chain, e.g. a carboxylic acid group, a sulphonic acid group, or a tetrazole group.

[0037] In a preferred embodiment, lipid (U) is according to formula (II)

[0038] HOOC-(CH2)n-CO-* (II), wherein n is an integer in the range 12-20. Formula (II) may also be referred to as a C(n+2) diacid (briefly, C(n+2)DA), wherein n is an integer in the range 12-20, preferably n is 14, 16, or 18 (briefly, C16DA, C18DA, and C20DA respectively), illustrated in table II.

[0039] Table II

[0040] The linker (Z) consists of three (3) to ten (10) linker sub-moieties termed Z1, Z2, Z3, Z4, Z5, Z5, Z7, Z8, Z9, and Z10covalently connected each other, wherein the linker sub-moieties are independently selected from monomer commonly used in the art or absent (i.e. *-Z1-Z2-Z3-*; *-Z1-Z2-Z3-Z4-*; *-z1-Z2-Z3-Z4-Z5-*; *-z1-Z2-Z3-Z4-Z5-Z5- *' *-Z1-Z2-Z3-Z4-Z5-Z6-Z7-*' *-Z1-Z2-Z3-Z4-Z5-Z6-Z7-Z8-*' *-Z1-Z2-Z3-Z4-Z5-Z6-Z7-Z8-Z9-*' or *-Z1-Z2-Z3-Z4-Z5-Z6- Z7-Z8-Z9-Z10-*). In a preferred embodiment the linker (Z) consists of three (3) to eight (8) linker sub-moieties. In a preferred embodiment, linker (Z) consists of three (3) to ten (10) linker sub-moieties termed Z1, Z2, Z3, Z4, Z5, Z5, Z7, Z8, Z9, and Z10covalently connected each other, wherein the linker sub-moieties are independently selected from the group consisting of: absent, [gGlu], [OEG], [eLys], [AHX], [TRX], [gDab], and [dtOrn], wherein at least one linker sub-moiety is [gGlu], and wherein the first linker sub-moieties is linked to lipid (U) and the last linker sub-moiety on the other end of the linker is linked to the epsilon-amino group of Lys at position-29 [Lys(29)J of the peptide (P) (i.e. U-Z1-Z2-Z3-Z4-Z5-Z5-Z7-Z8-Z9-Z10-P). In an even more preferred embodiment, the linker (Z) consists of three (3) to eight (8) linker sub-moieties. The meaning of linker sub-moieties abbreviations is illustrated in table III; the indicate the attachment point to another moiety of the compound; the "(Rn)" beside the represents the R-group number used; the bracket (i.e. [...]) in a term listed in table III may be present or omitted and in both case the term represents the same meaning. The represented in table III correspond to the R-group number of the Boehringer Ingelheim Line Notation (BILN) used for the nomenclature of the compounds of the invention, as described hereinafter, wherein the connected to the carboxy-group corresponds to the R"2"-group of the BILN and the connected to the amino-group corresponds to the R"l"-group of the BILN.

[0041] Table III

[0042] As an example, a lipid-linker moiety (U-Z) represented by HOOC-(CH2)n-CO-Z1-Z2-Z3-Z4-Z5-Z5-Z7-Z8-Z9-Z10-* is bonded to the epsilon-amino group of Lys at position-29 [Lys(29)], wherein linker sub-moiety Z1is bonded to the carboxy group of lipid (U) and linker sub-moiety Z10is bonded to the epsilon-amino group of Lys(29), to assume the following structure:

[0043] N- and C-terminal of peptide P

[0044] In the present context, peptides (P) are generally amidated at the C-terminal (-CONH2), like the native peptides. However, the peptides (P) of the present invention may also have either a free carboxylic acid (-COOH) or another post-translational modification, such as a methyl ester (-COOMe). In a preferred embodiment of the invention, the peptides are amidated at the C-terminal (P-NH2, i.e. U-L-P-NH2).

[0045] The peptides (P) according to the present invention may have a free amine (-NH2), be N-acylated (-NHCOR), N-methylated (-NHCH3 or -N(CH3)2), deaminated at the N-terminal, or N-lipidated. In a preferred embodiment of the invention, the peptides have a free amine at the N-terminal.

[0046] In a preferred embodiment of the invention, the peptides are amidated at the C-terminal (P-NH2) and have a free amine at the N-terminal.

[0047] Nomenclature of compounds:

[0048] Compounds of the present invention are represented in the Boehringer Ingelheim Line Notation (BILN), which describes complex peptides in a human-readable format (Fox et al, J. Chem. Inf. Model. 2022, 62, 17, 3942- 3947,). In BILN, chains are built up of monomers, e.g. A represents alanine, Aib represents isobutyric acid, and two monomers are linked by a hyphen Different chains are separated by a dot"." and connections between chains are explicitly defined in brackets following the monomer, which includes the link ID number and the R- group number, e.g. K(l,3) represents a lysine residue that is linked to another monomer carrying the same link ID "1" by its R"3"-group (i.e. epsilon-amino group). As an example, Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A- Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX-AHX(l,2) (SEQ ID NO: 1), wherein C20DA represents 19-carboxynonadecanoyl, gGlu represents gamma-L-glutamate connected via its amino-group to C20DA and via its gamma-carboxy-group to the amino-group of the next gGlu, which is repeated four times resulting in five gGlu residues, connected via the final gamma-carboxy-group to the aminogroup of 6-aminohexanoic acid (AHX), which is repeated one more time and connected via the final carboxygroup (i.e. AHX, R"2"-group) to the epsilon-amino-group (i.e. K, R"3"-group) of lysine (K) in position 29 of the peptide backbone, completely defines the following structure:

[0049] Structure discloses SEQ ID NO: 1

[0050] For clarity, as disclosed in the above-mentioned J. Chem. Inf. Model. 2022, 62, 17, 3942-3947, with respect to lysin residue at position 29 (Lys(29)) in the compounds of the invention, in the BILN used in the present specification the R-group number connected to the alpha-carboxy-group is termed R"2"-group, the R-group number connected to the alpha-amino-group is termed R"l"-group, and the R-group number connected to the epsilon-amino-group is termed R"3"-group.

[0051] Pharmaceutically acceptable salts

[0052] According to the present invention, the compound of the invention may be in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are intended to include any salts that are commonly used in formulations of peptides or derivative thereof. Such salts include both acid addition salts and basic salts, and examples may be found in e.g., Remington's pharmaceutical sciences, 17thedition and more recent editions thereof.

[0053] Additional definitions

[0054] The term "agonist" as employed in the context of the invention refers to a substance that activates the receptor type in question, typically by binding to it (i.e. as a ligand).

[0055] The terms "treatment” and grammatical variants thereof (e.g. "treated", "treating", "treat") as employed in the present context refer to an approach for obtaining beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e. not worsening) of state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival relative to expected survival time if not receiving treatment. A subject in need of treatment may thus be a subject already afflicted with the disease or disorder in question. The term "treatment" includes inhibition or reduction of an increase in severity of a pathological state or symptoms (e.g. weight gain or hyperglycemia) relative to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant disease, disorder or condition.

[0056] The terms "prevention" and grammatical variants thereof (e.g., "prevented", "preventing", "prevent") as employed in the present context refer to an approach for hindering or preventing the development of, or altering the pathology of, a condition, disease, or disorder. Accordingly, "prevention" may refer to prophylactic or preventive measures. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, prevention or slowing of symptoms, progression, or development of a disease, whether detectable or undetectable. A subject in need of "prevention" may thus be a subject not yet afflicted with the disease or disorder in question. The term "prevention" thus includes inhibiting or slowing the onset of disease relative to the absence of treatment and is not necessarily meant to imply permanent prevention of the relevant disease, disorder, or condition.

[0057] The terms "patient", "subject," and "individual" may be used interchangeably and refer to a human.

[0058] DETAILED DESCRIPTION OF THE INVENTION

[0059] In a first aspect, the invention provides a compound according to general formula (I)

[0060] U-Z-P (I), wherein P is a peptide comprising or, alternatively, consisting of the amino acid sequence, Y-Aib-E-X4-X5-F-T-S-D-Xio-Xii-Xi2-Xi3-L-Xi5-Xi6-Xi7-Xi8-Xi9-X2o-X2i-F-X23-R-X25-X26-X27-X28-K-X3o-T-R-X33-X34-X35 (SEQ ID NO: 184) wherein

[0061] X4 is selected from the group consisting of A, and G,

[0062] X5 is selected from the group consisting of A, E, and T,

[0063] X10 is selected from the group consisting of F, L, and Y,

[0064] Xu is selected from the group consisting of A, and S,

[0065] Xi2is selected from the group consisting of A, E, and I,

[0066] X13 is selected from the group consisting of A, Aib, E, L, and aMeL,

[0067] X15 is selected from the group consisting of D, and E,

[0068] Xie is selected from the group consisting of A, Aib, E, G, K, L, LysAc, N, Q, R,

[0069] X17 is selected from the group consisting of A, E, I, and Q,

[0070] Xis is selected from the group consisting of A, E and R,

[0071] X19 is selected from the group consisting of A, E, Q, and Y,

[0072] X2o is selected from the group consisting of A, Aib, E, and Y,

[0073] X2iis selected from the group consisting of A, E, and S,

[0074] X23 is selected from the group consisting of I, L, and V,

[0075] X25 is selected from the group consisting of A, H, Q, and Y,

[0076] X25is selected from the group consisting of A, and L,

[0077] X27 is selected from the group consisting of I, L, and Y,

[0078] X2s is selected from the group consisting of A, and N,

[0079] X30 is selected from the group consisting of A, Aib, I, L, V, and W,

[0080] X33 is selected from the group consisting of NMeQ, and Q,

[0081] X34 is selected from the group consisting of dOR, R, NMeR, MeR (ArgMe), bhR(bhArg), preferred dOR, R, X35 is selected from the group consisting of Phe4F, Y, and NMeY; wherein U is lipid moiety comprising a hydrocarbon chain; wherein Z is a linker moiety comprising at least one [gGlu] residue; wherein Z is linked to U in one end and to the epsilon-amino group of Lys at position-29 of the peptide P in the other end; wherein compound of general formula (I) comprises at least six (6) residues of amino acids selected from the group consisting of E and [gGlu], such as in the range 6 to 10 (i.e. 6, 7, 8, 9, 10); or salt thereof, preferably a pharmaceutically acceptable salt thereof.

[0082] For clarity, in general formula (I), in any embodiment thereof, and in any compound according to general formula (I) disclosed in the present specification the carboxy-group of the residue X28 is linked to the alphaamino group of Lys residue at position-29 of the peptide P.

[0083] EXAMPLES OF COMPOUNDS OF THE INVENTION

[0084] Table A

[0085] REFERENCE COMPOUND

[0086] Table B. *Ref. 1 is Example 41 of EP3467106 Al; "Ref. 2 is Example 42 of EP3467106 Al; "Ref. 3 is Example

[0087] 40 of EP3467106 Al.

[0088] The compounds of the invention according to general formula (I) and any embodiment disclosed herewith bind to and / or activate the GLP-1, the GIP and the NPY2 receptors.

[0089] The compounds of the present invention according to general formula (I) are able to agonize the hGLPIR, the hGIPR and the hNPY2R in the presence of human serum albumin (see table 1), the main protein present in human plasma. Activity of peptides of the invention in the presence of human plasma is an important prerequisite for viable compounds useful for the treatment of the disclosed diseases. The skilled person will be aware of suitable assay formats, and an example is provided hereinafter. For instance, for peptides of the present invention the EC50 values to the hGLPIR, the hGIPR and the hNPY2R in the presence of 100% human plasma (i.e. 100% hP) was evaluated by the assay as described in Example 1 hereinafter.

[0090] The compounds of the present invention show an EC50 towards hGLPIR 100% hP and hGIPR 100% hP below 100 nM (e.g. 0.1 nM to 100 nM), and towards hNPY2R 100% hP below 1000 nM (e.g. 1 nM to 1000 nM).

[0091] In a preferred embodiment of compounds of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 30 nM (e.g. 0.1 nM to 30 nM), and towards hNPY2R 100% hP is below 600 nM (e.g. 1 nM to 600 nM). In a highly preferred embodiment of compounds of the present invention, the EC50 towards hGLPIR 100% hP and GIPR 100% hP is below or equal to 20 nM (e.g. 0.1 nM to 20 nM), and towards hNPY2R 100% hP is below 200 nM (e.g. 1 nM to 200 nM).

[0092] Alternatively, in a highly preferred embodiment of compounds of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 10 nM (e.g. 0.1 nM to 10 nM), and towards hNPY2R 100% hP is below 100 nM (e.g. 1 nM to 100 nM).

[0093] The compounds of the invention according to formula (I) are soluble at or around physiological pH (see table 2), and therefore suitable for use in human therapy, preferably by administration via subcutaneous injection. In particular, the compound of formula (I) comprising at least six (6) residues of amino acids selected from the group consisting of E and [gGlu] showed suitable solubility at or around physiological pH.

[0094] In the context of the present invention the term "at or around physiological pH" means at or around pH 7, e.g. pH 7 ± 0.5. There are several techniques known to the skilled person in the art how to determine solubility. Preferably the solubility of the peptide of the invention is determined as disclosed in Example 2 hereinafter.

[0095] Generally, the solubility of the compounds of the invention is greater than or equal to 1.0 mg / ml at or around physiological pH.

[0096] In a preferred embodiment, the solubility of the compounds of the invention is greater than or equal to 3.0 mg / ml at or around physiological pH.

[0097] In a highly preferred embodiment, the solubility of the compounds of the invention is greater than or equal to 5.0 mg / ml at or around physiological pH.

[0098] In some further embodiments, the solubility at or around physiological pH of the compounds of the invention is equal or greater than 6.0 mg / ml, 7.0 mg / ml, 8.0 mg / ml, or 9.0 mg / ml.

[0099] In one embodiment of the compounds of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 100 nM, and towards hNPY2R 100% hP is below 1000 nM, and the solubility is greater than or equal to 1.0 mg / ml at or around physiological pH.

[0100] In a preferred embodiment of the compounds of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 30 nM, and towards hNPY2R 100% hP is below 600 nM, and the solubility is greater than or equal to 1.0 mg / ml at or around physiological pH.

[0101] In a highly preferred embodiment of the compounds of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 20 nM, and towards hNPY2R 100% hP is below 200 nM, and the solubility is greater than or equal to 3.0 mg / ml at or around physiological pH.

[0102] In an even highly preferred embodiment of the compounds of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 20 nM, and towards hNPY2R 100% hP is below 200 nM, and the solubility is greater than or equal to 5.0 mg / ml at or around physiological pH.

[0103] The compounds of the invention according to general formula (I) have favourable pharmacokinetic properties, in particular suitable in-vivo half-life for use in human therapy, for example by administration via subcutaneous injection. In this regard, the in-vivo half-life of the peptides of the invention may be greater than 4 hours or greater than 6 hours or greater than 8 hours or greater than 10 hours in the mouse (measurement described in Example 3 and table 3). In one embodiment of the compounds of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 100 nM (e.g. 0.01 nM to 100 nM), and towards hNPY2R 100% hP is below 1000 nM (e.g. 0.01 nM to 1000 nM), the solubility is greater than or equal to 1.0 mg / ml at or around physiological pH, and the in-vivo half-life is greater than 4 hours.

[0104] In a preferred embodiment of the peptides of the present invention, the EC50 towards hGLPIR 100% hP and hGIPR 100% hP is below or equal to 60 nM (e.g. 0.01 nM to 60 nM), and towards hNPY2R 100% hP is below 600 nM (e.g. 0.01 nM to 600 nM), the solubility is greater than or equal to 1.0 mg / ml at or around physiological pH, and the in-vivo half-life is greater than 4 hours.

[0105] In a highly preferred embodiment of the peptides of the present invention, the EC50 towards hGLPIR 100% hP and GIPR 100% hP is below or equal to 20 nM (e.g. 0.01 nM to 20 nM), and towards hNPY2R 100% hP is below 200 nM (e.g. 0.01 nM to 200 nM), the solubility is greater than or equal to 3.0 mg / ml at or around physiological pH, and the in-vivo half-life is greater than 6 hours.

[0106] PHARMACEUTICAL COMPOSITIONS

[0107] In a second aspect, the invention provides pharmaceutical compositions (i.e. formulation) comprising at least one compound of general formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

[0108] The term "pharmaceutically acceptable carrier and / or excipient" includes any of the standard pharmaceutical carrier and excipient well known in the pharmaceutical art and commonly used in formulations of peptides or derivative thereof, and examples may be found in "Remington's Pharmaceutical Sciences" 17th edition and more recent editions thereof. The term further encompasses any carrier and / or excipients agents suitable for peptides formulation and listed in the US Pharmacopeia for use in humans.

[0109] Pharmaceutical compositions of the present invention are suitable for use in a method of preventing and / or treating diseases as disclosed hereinafter, such as obesity, diabetes, metabolic syndrome, MASH / NASH, and / or comorbidities thereof. Said pharmaceutical compositions, which are suited for administration to a human being in the need thereof, typically comprise a therapeutically effective amount of the active ingredient.

[0110] It should be appreciated that different formulation (e.g. solid or liquid formulation) may be used depending on physicochemical characteristic of the compound of the invention.

[0111] It should be appreciated that different routes of administration may be used depending on the choice of formulation and chemical and / or metabolic stability of the compound of invention. Such administration routes may include but are not limited to oral administration, parenteral administration (intravenous (IV), subcutaneous (SC), intradermal (ID) and intramuscular (IM)), or inhalation. In a preferred embodiment of the invention, the administration route is subcutaneous injection.

[0112] It should be appreciated that different pharmaceutical form (e.g. solid or liquid dosage form) may be used depending of the formulation and administration route. In a preferred aspect of the invention, the pharmaceutical form is an injectable solution (e.g. aqueous injectable solution).

[0113] The compounds of the invention may be administered subcutaneously using a suitable device such as a prefilled ready-to-use injection device like a syringe, a pen injector, or an auto-injector. The actual pharmaceutically effective amount or therapeutic dosage will usually depend on factors known by those skilled in the art such as age and physical condition of the patient, route of administration and severity of disease. In any case, the compounds will be administered at dosages and in a manner, which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.

[0114] METHOD OF TREATMENT / USE IN TREATMENT

[0115] In a third aspect, the invention provides compounds according to general formula (I) or pharmaceutical acceptable salts thereof, according to any of the aspects and embodiments disclosed herein, for use as a medicament. Since NPY2 receptors have a feeding suppressive action, a polypeptide having NPY2 agonistic activity may be useful in the treatment of symptoms associated with eating disorder, obesity (e.g. simple obesity or symptomatic obesity) and / or diabetes. Furthermore, the gut hormones GLP-1 and GIP (called incretins), promote insulin secretion from the pancreas. Since incretins are closely related to glucose metabolism by their ability to stimulate insulin secrection, a polypeptide having GLP-1 receptor agonistic activity and GIP receptor agonistic activity may be useful in the treatment of symptoms associated with a glucose metabolism disorder, including diabetes and obesity. Thus, the compounds of the present invention may have a feeding suppressive action, a body weight-lowering action, and / or a reducing body fat mass action.

[0116] The invention provides compounds for use in the prevention, treatment, and / or remission of a disease, disorder, or condition selected from the list consisting of excessive body weight (body overweight), obesity (e.g. simple obesity and chronic weight management, or symptomatic obesity), eating disorders, other obesity related diseases such as osteoporosis, sleep apnoea, obesity associated cancers, and obesity associated asthma. Examples of the symptomatic obesity include endocrine obesity (e.g. Cushing syndrome, hypothyroidism, insulinoma, obese type 2 diabetes, pseudohypoparathyroidism, hypogonadism and associated endocrine disorders, such as polycystic ovary syndrome (PCOS)), central obesity (e.g., hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome), hereditary obesity (e.g. Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, p-blocker-induced obesity).

[0117] The invention provides compounds for use in the prevention, treatment, and / or remission of a disease, disorder, or condition selected from the list consisting of insulin resistance, diabetes (e.g. type 1 diabetes or type 2 diabetes), prediabetes.

[0118] The invention provides compounds for use in the prevention, treatment, and / or remission of a disease, disorder, or condition selected from the list consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, and postprandial hyperlipemia.

[0119] Further, the invention provides a compound for use in the prevention, treatment, and / or remission of metabolic syndrome (three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL)).

[0120] The invention provides compounds for use in the prevention, treatment, and / or remission of liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), portal hypertension.

[0121] The invention provides compounds for use in the prevention, treatment, and / or remission of cardiovascular diseases (e.g. hypertension, atherosclerosis, stroke or cardiac failure); The invention provides compounds for use in the prevention, treatment, and / or remission of kidney diseases such as diabetic kidney disease (DKD), and chronic kidney disease (CKD).

[0122] The invention provides compounds for use in the prevention, treatment, and / or remission of neurodegenerative diseases (Alzheimer's or Parkinson 's disease).

[0123] In one preferred embodiment, compounds of the invention are suitable for use in the prevention, treatment, and / or remission of disease, disorder and / or condition selected from the list consisting of chronic weight management, excessive body weight, obesity, eating disorders, diabetes (type 1 or type 2), prediabetes, hyperlipidemia, metabolic syndrome, MAFLD / NAFLD, MASH / NASH, and cardiovascular diseases; preferably obesity, prediabetes and / or diabetes (type 1 or type 2).

[0124] The compounds of the invention may also be used for the prevention of obesity, or prevention or reversal of comorbidities of obesity and / or comorbidities of overweight, such as type 2 diabetes, high blood pressure, MAFLD / NAFLD, MASH / NASH, DKD, CKD, sleep apnoe, obesity associated cancers, or obesity associated asthma.

[0125] In a fourth aspect, the invention provides a method for the treatment of a disease, disorder and / or condition listed hereinbefore, said method comprising administering a therapeutic effective amount of a compounds of general formula (I) or pharmaceutically acceptable salts thereof, according to any of the aspects and embodiments disclosed herein, to an individual in need thereof. Preferably, the disease, disorder and / or condition is selected from the list consisting of chronic weight management, excessive body weight, obesity, eating disorders, diabetes (type 1 or type 2), prediabetes, hyperlipidemia, metabolic syndrome, MAFLD / NAFLD, MASH / NASH, and / or cardiovascular diseases. Most preferably the disease, disorder and / or condition is obesity, prediabetes and / or diabetes (type 1 or type 2).

[0126] Furthermore, the invention provides a method for the treatment of a disease, disorder and / or condition by activation of all the receptors GLP1-R, GIPR and NPY2R, said method comprising administering a therapeutic effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, according to any of the aspects and embodiments disclosed herein.

[0127] Likewise, the present invention relates to the use of compounds of general formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease, disorder and / or condition listed hereinbefore, according to any of the aspects and embodiments disclosed herein.

[0128] The dose range of the compound according to the general formula (I) applicable per week is usually from 0.01 to 100 mg for humans (subcutaneous administration).

[0129] The compound of the invention may be administered by subcutaneous injection using a suitable device such as a pre-filled ready-to-use injection device, a syringe, a pen injector, or an auto-injector.

[0130] The actual pharmaceutically effective amount or therapeutic dosage will usually depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case, the compounds will be administered at dosages and in a manner, which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition. EMBODIMENTS (briefly, Emb.)

[0131] Emb. 1. A compound according to general formula (I),

[0132] U-Z-P (I), wherein P is a peptide comprising or, alternatively, consisting of the amino acid sequence,

[0133] Y-Aib-E-X4-X5-F-T-S-D-Xio-Xii-Xi2-Xi3-L-Xi5-Xi6-Xi7-Xi8-Xi9-X2o-X2i-F-X23-R-X25-X26-X27-X28-K-X3o-T-R-X33-X34-X35

[0134] (SEQ ID NO: 185) wherein wherein n is an integer in the range 12 to 20, wherein Z is a linker moiety comprising at least one [gGlu] residue, wherein Z is linked to U on one end and to the epsilon-amino group of Lys at position-29 (Lys(29)) of the peptide P on the other end; and wherein compound of general formula (I) comprises at least six (6) residues of amino acids selected from the group consisting of E and [gGlu]; or salt thereof, preferably a pharmaceutically acceptable salt thereof.

[0135] Emb. 2. The compound according to embodiment 1, wherein Z is a linker moiety consisting of three (3) to ten (10) linker sub-moieties termed Z1, Z2, Z3, Z4, Z5, Z5, Z7, Z8, Z9, and Z10covalently connected each other, wherein the linker sub-moieties are independently selected from the group consisting of: absent, [gGlu], [eLys],

[0136] [OEG], [AHX], [TRX], [gDab], and [dtOrn], wherein Z comprises at least one [gGlu] residue (i.e. at least one (1) sub-moiety is [gGlu]), and wherein the first linker sub-moieties of the linker Z (i.e. Z1) is linked to U and the last linker sub-moiety on the other end of the linker Z is linked to the epsilon-amino group of Lys at position-29 of the peptide P.

[0137] Emb. 3. The compound according to any one of the preceding embodiments, wherein P is a peptide comprising or, alternatively, consisting of the amino acid sequence,

[0138] Y-Aib-E-X4-X5-F-T-S-D-Xio-Xii-Xi2-Xi3-L-Xi5-Xi6-Xi7-Xi8-Xi9-X2o-X2i-F-X23-R-X25-X26-X27-X28-K-X3o-T-R-X33-X34-X35

[0139] (SEQ ID NO: 186) wherein

[0140] X4 is selected from the group consisting of A, and G,

[0141] X5is T,

[0142] X10 is selected from the group consisting of F, L, and Y,

[0143] Xu is selected from the group consisting of A, and S,

[0144] Xi2is I,

[0145] X13 is selected from the group consisting of Aib, and aMeL,

[0146] X15 is selected from the group consisting of D, and E,

[0147] Xie is selected from the group consisting of K, N, and E,

[0148] X17 is selected from the group consisting of A, and Q,

[0149] Xis is selected from the group consisting of A, and R,

[0150] X19 is selected from the group consisting of A, E, and Q,

[0151] X2o is selected from the group consisting of A, Aib, and Y,

[0152] X2iis selected from the group consisting of A, and S,

[0153] X23 is selected from the group consisting of I, L, and V,

[0154] X25 is selected from the group consisting of A, H and Y,

[0155] X2s is L,

[0156] X27 is selected from the group consisting of I, and L,

[0157] X28is N,

[0158] X30 is selected from the group consisting of A, Aib, I, L, and V,

[0159] X33 is selected from the group consisting of NMeQ, and Q,

[0160] X34 is selected from the group consisting of dOR, and R,

[0161] X35 is selected from the group consisting of Phe4F, Y, and NMeY.

[0162] Emb 4. The compound according to any one of the preceding embodiments, wherein P is a peptide comprising or, alternatively, consisting of the amino acid sequence,

[0163] Y-Aib-E-X4-X5-F-T-S-D-Xio-Xii-Xi2-Xi3-L-Xi5-Xi6-Xi7-Xi8-Xi9-X2o-X2i-F-X23-R-X25-X26-X27-X28-K-X3o-T-R-X33-X34-X35

[0164] (SEQ ID NO: 187) wherein X4 is selected from the group consisting of A, and G,

[0165] X5is T,

[0166] Xio is selected from the group consisting of F, and Y,

[0167] Xu is selected from the group consisting of A, and S,

[0168] X12 is selected from the group consisting of A, E, and I,

[0169] X13 is selected from the group consisting of Aib, and aMeL,

[0170] X15 is selected from the group consisting of D, and E,

[0171] Xie is selected from the group consisting of K, and N,

[0172] X17 is Q,

[0173] Xis is A,

[0174] X19 is selected from the group consisting of A, E, and Q,

[0175] X20 is selected from the group consisting of A, Aib, and Y,

[0176] X21 is selected from the group consisting of A, and S,

[0177] X23 is selected from the group consisting of I, L, and V,

[0178] X25 is selected from the group consisting of H, and Y,

[0179] X26 is L,

[0180] X27 is selected from the group consisting of I, and L,

[0181] X28is N,

[0182] X30 is selected from the group consisting of A, Aib, I, L, and V,

[0183] X33 is Q,

[0184] X34 is selected from the group consisting of dOR, and R,

[0185] X35 is selected from the group consisting of Phe4F, and Y.

[0186] Emb. 5. The compound according to any one of the preceding embodiments, wherein the C-terminal of peptide P is amidate (i.e. C-terminal is a primary amide, compounds of the invention are represented by formula U-Z-P-NH2).

[0187] Emb. 6. The compound according to any one of the preceding embodiments, wherein U is a lipid moiety of formula (II)

[0188] HOOC-(CH2)n-CO-* (II), wherein n is an integer in the range 14 to 18.

[0189] Emb. 7. The compound according to any one of the preceding embodiments, wherein U is selected from the group consisting of 15-carboxy-pentadecanoyl (briefly, C16DA), 17-carboxy- heptadecanoyl (briefly, C18DA), and 19-carboxy-nonadecanoyl (briefly, C20DA).

[0190] Emb. 8. The compound according to any one of the preceding embodiments, wherein U is selected from the group consisting of 17-carboxy-heptadecanoyl (C18DA), and 19-carboxy- nonadecanoyl (C20DA).

[0191] Emb. 9. The compound according to any one of the preceding embodiments, wherein U is 17-carboxy-heptadecanoyl (C18DA).

[0192] Emb. 10. The compound according to any one of the preceding embodiments, wherein U is 19-carboxy-nonadecanoyl (C20DA). Emb. 11. The compound according to any one of the preceding embodiments, wherein Z is a linker moiety consisting of three (3) to eight (8) linker sub-moieties termed Z1, Z2, Z3, Z4, Z5, Z5, Z7, and Z8covalently connected each other, wherein the linker sub-moieties are independently selected from the group consisting of: absent, [gGlu], [eLys], [OEG], [AHX], [TRX], [gDab], and [dtOrn], wherein Z comprises at least one [gGlu] residue, and wherein the first linker sub-moieties Z1is linked to U and the last linker sub-moiety on the other end of the linker is linked to the epsilon-amino group of Lys at position-29 of the peptide P (e.g., U-Z1-Z2-Z3-Z4-Z5-Z5-Z7- Z8-P).

[0193] Emb. 12. The compound according to any one of the preceding embodiments, wherein U-Z is selected from the group consisting of:

[0194] U-[gGlu]-[OEG]-[OEG],

[0195] U-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]- [OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX]-[gGlu]-[AHX], U-[gGlu]- [gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu], U-[gGlu]- [gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu]-[gGlu],

[0196] U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]- [gGlu]-[gGlu]-[OEG]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [gGlu]-[eLys]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [AHX]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [eLys]-[gGlu],

[0197] U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]-[eLys], U- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gDab], U- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[dtOrn],

[0198] U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX],

[0199] U-[TRX]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[TRX]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]; preferably, wherein U is 17-carboxy-heptadecanoyl (C18DA) or 19-carboxy-nonadecanoyl (C20DA).

[0200] Emb. 13. The compound according to any one of the preceding embodiments, wherein Z comprises at least five (5) [gGlu] residues (i.e. at least five (5) sub-moieties are [gGlu]).

[0201] Emb. 14. The compound according to Emb. 11 and Emb. 13.

[0202] Emb. 15. The compound according to Emb. 14, wherein U-Z is selected from the group consisting of: U-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[eLys], U- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]- [gGlu]-[gGlu]-[OEG]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [gGlu]-[eLys]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-

[0203] [AHX]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-

[0204] [eLys]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]-[eLys], U-

[0205] [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gDab], U-

[0206] [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[dtOrn],

[0207] U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[TRX]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-rrRX]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]; preferably wherein U is 17-carboxy-heptadecanoyl (C18DA) or 19-carboxy-nonadecanoyl (C20DA).

[0208] Emb.16. The compound according to any one of the preceding embodiments, wherein compound of formula (I) comprises at least seven (7) amino acids selected from the group consisting of E and [gGlu]; such as in the range 7 to 10 (i.e. 7, 8, 9, 10).

[0209] Emb.17. The compound according to Emb. 14. and Emb. 16.

[0210] Emb.18. The compound according to any one of the preceding embodiments, wherein Z consists of seven (7) to eight (8) linker sub-moieties termed Z1, Z2, Z3, Z4, Z5, Z5, Z7, and Z8covalently connected each other; preferably wherein the linker sub-moieties are independently selected from the group consisting of absent, [gGlu], [eLys], [OEG], and [AHX],

[0211] Emb.19. The compound according to Emb. 17 and Emb. 18.

[0212] Emb.20. The compound according to Emb. 19, wherein U-Z is selected from the group consisting of: U-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[eLys], U- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [gGlu]-[AHX]; preferably, wherein U is 17-carboxy-heptadecanoyl (C18DA) or 19-carboxy-nonadecanoyl (C20DA). Emb. 21. The compound according to any one of the preceding embodiments, wherein X13 is Aib.

[0213] Emb. 22. The compound according to any one of the preceding embodiments, wherein X13 is aMeL.

[0214] Emb. 23. The compound according to any one of the preceding embodiments, wherein X15 is E.

[0215] Emb. 24. The compound according to any one of the preceding embodiments, wherein X15 is D.

[0216] Emb. 25. The compound according to any one of the preceding embodiments, wherein Xis is A.

[0217] Emb. 26. The compound according to any one of the preceding embodiments, wherein Xis is R.

[0218] Emb. J. The compound according to any one of the preceding embodiments, wherein X21 is A.

[0219] Emb. 28. The compound according to any one of the preceding embodiments, wherein X21 is S.

[0220] Emb. 29. The compound according to any one of the preceding embodiments, wherein X20 is Aib.

[0221] Emb. 30. The compound according to any one of the preceding embodiments, wherein X30 is Aib.

[0222] Emb. 31. The compound according to any one of the preceding embodiments, wherein X34 is R.

[0223] Emb. 32. The compound according to any one of the preceding embodiments, wherein X35 is Y.

[0224] Emb. 33. The compound according to any one of the preceding embodiments, wherein U-Z is C18DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys] .

[0225] Emb. 34. The compound according to any one of the preceding embodiments, wherein U-Z is C20DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys] .

[0226] Emb. 35. The compound according to any one of the preceding embodiments, wherein U-Z is C18DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG].

[0227] Emb. 36. The compound according to any one of the preceding embodiments, wherein U-Z is C20DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG].

[0228] Emb. 37. The compound according to any one of the preceding embodiments, wherein U-Z is C18DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX].

[0229] Emb. 38. The compound according to any one of the preceding embodiments, wherein U-Z is C20DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX].

[0230] Emb. 39. The compound according to any one of the preceding embodiments, wherein U-Z is C18DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys].

[0231] Emb. 40. The compound according to any one of the preceding embodiments, wherein U-Z is C20DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys].

[0232] Emb. 41. The compound according to any one of the preceding embodiments, wherein U-Z is C18DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX].

[0233] Emb. 42. The compound according to any one of the preceding embodiments, wherein U-Z is C20DA-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX].

[0234] Emb. 43. The compound according to any one of the preceding embodiments, wherein the compound is selected from the group consisting of Compound 1 (SEQ ID NO: 1) to Compound 176 (SEQ ID NO: 176) according to table 3 (table 3 incorporated by reference).

[0235] Emb. 44. The compound according to any one of the preceding embodiments, wherein the compound bind to and / or activate GLP-1, GIP and NPY2 receptors, preferably the human receptors. Emb. 45. The compound according to any one of the preceding embodiments, wherein the compound shows / has a EC50 in the presence of human plasma (i.e. circa 100% hP) towards hGLPIR and hGIPR below 100 nM, and towards hNPY2R below 1000 nM; preferably towards hGLPIR and hGIPR below or equal to 30 nM, and towards hNPY2R below 600 nM; more preferably towards hGLPIR and GIPR below or equal to 20 nM, and towards hNPY2R below 200 nM (as disclosed in Example 1).

[0236] Emb. 46. The compound according to any one of the preceding embodiments, wherein the compound shows / has a solubility at or around physiological pH greater than or equal to (around) 1.0 mg / ml; more preferably greater or equal to than 3.0 mg / ml; even more preferably greater or equal to than 5.0 mg / ml (as disclosed in Example 2).

[0237] Emb. 47. The compound according to any one of the preceding embodiments, wherein the compound has a half-life suitable for human therapy.

[0238] Emb. 48. The compound according to any one of the preceding embodiments, wherein the compound has a half-life in mouse greater than 4 hours; preferably greater than 6 hours; more preferably greater than 8 hours; even more preferably greater than 10 hours (as disclosed in Example 3).

[0239] Emb. 49. The compound according to

[0240] Emb. 3, Emb. 8 and Emb. 19; or Emb. 3, Emb. 9, and Emb. 20; or Emb. 3, Emb. 10, and Emb. 20; or Emb. 4, Emb. 9, and Emb. 20; or Emb. 4, Emb. 10, and Emb. 20; or Emb. 3, and any one of the embodiments selected from Emb. 33 to Emb. 42; or Emb. 4, and any one of the embodiments selected from Emb. 33 to Emb. 42; or Emb. 3, Emb. 21, and any one of the embodiments selected from Emb. 33 to Emb. 42; or Emb. 4, Emb. 22, and any one of the embodiments selected from Emb. 33 to Emb. 42; or Emb. 4, Emb. 9, Emb. 20, and Emb. 21; or Emb. 4, Emb. 10, Emb. 20, and Emb. 22; or Emb. 3, Emb. 8, Emb. 19, and Emb. 46; or Emb. 4, Emb. 8, Emb. 20, and Emb. 46.

[0241] BIOLOGICAL ASSAYS AND DATA

[0242] The following examples demonstrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and routine to those of skill in the art, except where otherwise described in detail.

[0243] Example 1: hGLPlR / hGIPR / hNPY2R CreLuc assay in 0.5% and 100% plasma

[0244] CHO and HEK-293 recombinant cell lines express a luciferase reporter gene under control of the cAMP responsive element (CRE). As a second recombinant protein the GLP-1 and NPY2 receptors were expressed in the reporter gene HEK cells, and the GIP receptor was expressed in the reporter gene CHO cells, respectively. Stimulation of these recombinant cells with an agonist leads to an increase of intracellular cAMP levels. In the presence of cAMP, the transcription factor CRE binding protein (CREB) binds to the CRE and to the CREB binding protein (CBP), which leads to transcription of the luciferase reporter gene. Peptides upon serial-dilution in 100% DMSO were transferred into 384-well assay plates with 5 pl pre-dispensed assay buffer (lx HBSS, 20mM HEPES, pH7.4 supplemented with 0.5 % human plasma) using acoustic dispensing on a Labcyte ECHO. Cryo-preserved transgenic reporter gene cells were thawed in assay buffer. 20 pl (10.000 cells / well) were added to the plate with the peptides and incubated for 4 hours at 37°C in a humidified incubator. Following incubation, assay plates are equilibrated to room temperature, followed by addition of 25 pl of Bright-Glo™ Luciferase reagent, incubation at room temperature for 10 minutes and analysis of luminescence (Envision Reader). Concentration response evaluation of compounds was performed with 8 concentrations of peptides (covering four decades). EC50 values were calculated by non-linear regression using sigmoid concentration -response with variable slope. The same assays were run in the presence of 100% plasma with no additional buffer constituents. The results are summarized in Table 1, below.

[0245] Table 1

[0246] Example 2: Solubility

[0247] Peptides (as TFA-salts) were weighed out in a filter unit (Mini-UniPrep Syringeless Filter 0.45 pm, Whatman PVDF), and 0.1 M phosphate buffer at pH 7 was added to achieve 10 mg / mL final peptide concentration. The peptides were dissolved by shaking the filter units horizontally at 600 rpm for 2 hours at room temperature.

[0248] Samples were then filtered to remove any insoluble particles. Controls were prepared by weighing out the corresponding peptide solid material and dissolving it in an appropriate vehicle (e.g. ACN : H2O) to a final concentration of 1 mg / mL. Both, the control and sample were analyzed by reversed phase chromatography. The area under the peak of the sample was compared to the control and the solubility was calculated based on that ratio. The pH was measured and recorded for each sample.

[0249] Solubility of compounds according to the invention and reference compounds have been measured and summarized in table 2 below.

[0250] Table 2

[0251] Example 3: Mouse PK

[0252] Pharmacokinetic parameters of the peptides were determined after intravenous application to NMRI mice (Naval Medical Research Institute mice). Male NMRI mice were obtained from Janvier Laboratories (France) weighing 30 g to 40 g. Mice were housed in standard cages with a 12: 12 hours light:dark cycle and standard food and water access ad libitum. Each test peptide was dissolved in 50 mM phosphate buffer (pH 7.4) / 3.5% mannitol. Intravenous application of 30-60 nmol / kg was performed via the tail vein. Serial blood samples from conscious mice were collected from the saphenous vein in EDTA-containing vials at different time points up to 56 hours post-dosing. Subsequently, plasma was prepared by centrifugation for 5 minutes at approximately 5000 rpm and stored at -20°C until quantification of the peptide plasma levels by liquid chromatography mass spectrometry (LC-MS). Individual plasma concentration - time profiles were analysed by a non-compartmental approach and the resulting pharmacokinetic parameters were calculated. Mouse mean residence times (MRT) of GGY peptides according to the invention have been measured and summarized in table 3 below. Table 3

[0253] Example 4: Effect on acute food intake in normal NMRI mice

[0254] Male NMRI mice were obtained from Janvier (Janvier Labs, France) or from Charles River (Charles River Research Models & Services Germany GmbH) at the age of 3 weeks. The animals get a microchip (Datamars, Slim Microchip T-SL) for individual identification after delivery. They were housed with 4 mice per cage under a 12 / 12 dark-light cycle, light off at 3 p.m. Room temperature was controlled to 21°C + / - 1°C and humidity 60% + / - 20%. Mice had ad libitum access to regular rodent chow (KLIBA Nafag 3040 or Altromin 1324, Brogaarden, Denmark) and tap water.

[0255] Latest transfer into the HM2-System of MBRose, Denmark (real-time monitoring system of food- and water intake) of the animals 5 days before study start, to allow acclimatization to experimental conditions. As the animals were uniquely identified with the microchips, each individual animal was identified by its own microchip upon entry and exit from the food channel via antennae. Randomization of the mice for each study group (n=8; age earliest 6 weeks old) was based on food intake (middle of last three days 24h-intervall) and bodyweight directly before start of the study. A vehicle treated (50 mM phosphate buffer pH 7.4 with 3.5% mannitol) group was included in each experiment. To have the same nutrition standard for each animal the food access was locked eight hours before dark phase. One hour before night, the animals were once treated subcutaneously with the test peptide. Food intake was reported hourly for a period of 24 hours. The food intake was normalized [%] to the average food intake of the vehicle group and the value are summarized in table 4 below.

[0256] Table 4

[0257] GENERAL PROCEDURE FOR SOLID PHASE SYNTHESIS OF PEPTIDE

[0258] All peptides were synthesized by standard Fmoc-based solid phase peptide chemistry on a Tentagel S RAM resin (loading 0.23-0.25 mmol / g, bead size 90 pm) supplied by Iris Biotech GmbH or Rapp Polymere GmbH. The following protected amino acids were used: Fmoc-Ala-OH, Fmoc-Aib-OH, Fmoc-Arg(Pbf)-OH, Fmoc- ArgMe(Pbf)-OH, Fmoc-NMeR(Pbf)-OH, Fmoc-bhArg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc- Gln(Trt)-OH, Fmoc-NMeQ(Trt)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu-OtBu, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-aMeL-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Phe-OH, Fmoc-Phe4F-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-NMeY(tBu)-OH, Boc-Tyr(tBu)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-Val-OH. The L-form of the amino acid building blocks was utilized if not specified otherwise.

[0259] The modular half-life extending group was built up by solid-phase peptide synthesis (SPPS) using protected building blocks such as, but not limited to, C18DA(tBu), C20DA(tBu), Fmoc-OEG-OEG-OH, Fmoc-OEG-OH, Boc- Lys(Fmoc)-OH, Fmoc-Glu-OtBu, Fmoc-Glu(tBu)-OH, Fmoc-AHX-OH, Fmoc-TRX-OH, Boc-ORN(Fmoc)-OH and Boc-DAB( Fmoc)-OH .

[0260] The amino acids, Fmoc-Glu-OtBu, Oxyma and DIC, were purchased from standard suppliers, e.g. Bachem, Novabiochem, ABCR GmbH & CO. KG., Iris Biotech GmbH, Sigma-Aldrich. C18DA(tBu) and C20DA(tBu) were supplied by Cool Pharm Ltd. or AstraTech, Fmoc-OEG-OEG-OH was supplied by ABCR GmbH 81 CO. KG or Iris Biotech GmbH, Fmoc-OEG-OH was supplied by Angene International Limited, Combi Blocks Inc., Iris Biotech GmbH or Hangzhou APIChem Technology Co., Ltd. Fmoc-AHX-OH was purchased from Activate Scientific GmbH, Fmoc-TRX-OH was purchased from ABCR GmbH 81 CO. KG.

[0261] Assembly of peptides started from the C-terminus by stepwise chain elongation towards the N-terminus according to the respective sequences until the N-terminal amino acid was reached. Deprotection of the side chain of the branching amino acid, e.g. Lys(Dde), was followed by assembly of the half-life extending group.

[0262] The peptides were obtained as TFA salts from cleavage / deprotection or from HPLC purification. The trifluoroacetate can be exchanged by common procedures, such as resin-ion exchange procedures, e.g. as disclosed in Roux, St. et al. J. Pept. Sci. 2008; 14: 354-359.

[0263] Synthesis Method 1 (SOI)

[0264] Peptides were synthesized by microwave-assisted solid-phase peptide synthesis (SPPS) on a CEM Liberty Blue Peptide Synthesizer at 0.25 mmol scale on Tentagel S RAM resin using the Fmoc strategy. The stoichiometry and concentrations for peptide coupling reactions were 4 eq of suitably protected amino acid in DMF (0.2 mol / l, 5 ml), 4 eq of Oxyma in DMF (1 mol / l, 1 ml) and 8 eq DIC in DMF (1 mol / l, 2 ml).

[0265] The reaction times and temperatures were different for the amino acids. Single coupling 4 minutes (i.e. min) at 90 °C was used for all standard amino acids except those mentioned below. Single coupling 15 min at 75 °C was used for Fmoc-Glu-OtBu. Double coupling 4 min at 90 °C was used for Fmoc-Arg(Pbf)-OH, C18DA(tBu), C20DA(tBu), Fmoc-OEG-OH, Boc-Lys(Fmoc)-OH, Fmoc-NMeR(Pbf)-OH, Fmoc-NMeQ(Trt)-OH and Fmoc-AHX- OH. The amino acid after FMOC-Aib-OH, NMeR and NMeQ was coupled twice. Fmoc-aMeL-OH, the first 8 amino acids and the last 10 amino acids in the main chain were coupled at 90 °C for 8 min. A capping step with 20% acetic anhydride in DMF (10 ml) for 5 min at 65 °C was performed prior to the coupling of Fmoc-Glu-OtBu and prior to the coupling of C18DA(tBu) and C20DA(tBu). NaFmoc deprotection was performed with 10% piperidine / DMF (10 ml) for 1 min at 90 °C and resin was deprotected two times prior to coupling the first amino acid. Deprotection of the Lys(Dde)-group was carried out 2 times with 5% hydrazine hydrate in DMF (10 ml) for 3 min at 90 °C. Raw products were washed on resin with DCM and dried prior to cleavage. Cleavage from resin and deprotection was performed with a mixture of 95% TFA / water (10 ml) and triisopropylsilane (250 pl) for 45 min at 40 °C. Crude peptides were precipitated with cold tertbutyl -methyl ether, dissolved in 50% acetonitrile / water and purified by preparative HPLC.

[0266] Purification Method 1 (L20)

[0267] Crude peptides were dissolved in DMF / acetonitrile / water and purified by reversed phase chromatography using an Agilent preparative HPLC-MS System with preparative pumps G7161B, G7111B and G7110B, a diode array detector G7115A, a mass-spectrometer G6135B and a fraction collector G7158B. A Waters Luna Prep C8(3) column (100 A, 10 pm, 300 g, self-filled steel column) served as stationary phase. The mobile phase was run with a gradient of buffer A (ACN) and buffer (H2O + 0.1% TFA) as described in the table below at a flow rate of 150 ml / min at 40 °C. The relevant fractions were pooled and lyophilized. The final product was characterized by analytical HPLC-MS (U046_001 and U046_006, see below).

[0268] Analytical Method 1 (U046_001 / U046_006 / 010_CA07)

[0269] Peptide purity and mass were estimated by analytical HPLC-MS on a Kinetex C8 column (4.6 mm x 150 mm, 2.6 urn, Phenomenex) using a Agilent 1260 HPLC system equipped with Mass Detector G6135 and Waters Acquity with 3100 MS. Analysis was performed by gradient elution with buffer A (0.3% TFA in H2O) and buffer B (0.24% TFA in ACN) at a temperature of 40 °C. Details of the gradient and flow rates are summarized in the tables below. Retention times and masses were recorded.

[0270] Peptide purities (relative peak areas @ 214 nm) were in the range from 80 % to 99 %, preferably greater than 95 %. List of further abbreviations

[0271] ACN: acetonitrile

[0272] Boc: tert-butyloxycarbonyl

[0273] C18DA(tBu): 18-(tert-butoxy)-18-oxooctadecanoic acid

[0274] C20DA(tBu): 20-(tert-butoxy)-20-oxoicosanoic acid DCM: dichloromethane

[0275] DIC: diisopropylcarbodiimide

[0276] DIPEA: diisopropylethylamine

[0277] Dde: (4,4-dimethyl-2,6-dioxocyclohex-l-ylidene)ethyl

[0278] DMF: N,N-dimethylformamid DODT: 3,6-dioxa-l,8-octanedithiol

[0279] DPBS: Dulbecco's phosphate-buffered saline

[0280] Fmoc: 9H-fluoren-9-ylmethoxycarbonyl

[0281] Fmoc-AHX: 6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid

[0282] Fmoc-OEG-OH: 2-[2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy] acetic acid Fmoc-OEG-OEG-OH:2-[2-[2-[[2-[2-[2-(9H-fluoren-9-ylmethoxycarbonyl- amino)ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid

[0283] HTRF: homogeneous time resolved fluorescence

[0284] IBMX: 3-isobutyl-l-methylxanthine

[0285] MRT: mean residence time

[0286] Mtt: 4-Methyl-trityl

[0287] NMP: l-methyl-pyrrolidine-2-one

[0288] Oxyma: 2-cyano-2-(hydroxyimino)acetic acid ethyl ester

[0289] Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[0290] Rt: retention time

[0291] RT : room temperature

[0292] SPPS: solid-phase peptide synthesis tBu: tert-butyl

[0293] Trt: trityl

[0294] TES: triethylsilane

[0295] TFA: trifluoroacetic acid

[0296] The following compounds were synthesised. All compounds were obtained as TFA salts:

[0297] Reference Compounds

[0298] Ref. 1 (i.e. Example 41 of EP3467106)

[0299] NMeY-Aib-E-G-T-aMeF-T-S-D-K(l,3)-S-I-Aib-L-E-K-Q-R-Q-Iva-E-F-V-R-H-L-L-N-K-Aib-T-R-Q-R-Y-NH2.C16A-G-

[0300] G-G-G(l,2) (SEQ ID NOs 177 and 178)

[0301] MW (calculated): 4720.5 Da

[0302] Synthesis and purification methods: SOI; L20

[0303] Ref. 2 (i.e. Example 42 of EP3467106)

[0304] NMeY-Aib-E-G-T-aMeF-T-S-D-K(l,3)-S-I-Aib-L-E-K-Q-R-Q-Iva-E-F-V-R-H-L-L-N-K-Aib-T-R-Q-R-Y-NH2.C18DA-

[0305] G-G-G-G(l,2) (SEQ ID NOS 179 and 180)

[0306] MW (calculated): 4778.6 Da

[0307] Synthesis and purification methods: SOI; L20

[0308] Ref. 3 (i.e. Example 40 of EP3467106)

[0309] Y-Aib-E-G-T-aMeF-T-S-D-K(l,3)-S-I-Aib-L-E-K-Q-R-Q-Iva-E-F-V-R-H-L-L-N-K-Aib-T-R-Q-R-Y-NH2.C18DA-G-G-

[0310] G-G(l,2) (SEQ ID NOS 188 and 189)

[0311] MW (calculated): 4764.5 Da

[0312] Synthesis and purification methods: SOI; L20

[0313] LCMS: U046_006; Rt: 30.3 min; m / 3: m / 4: 1191.4

[0314] In Reference Compounds the term "Iva" means isovaline. Compounds of the invention

[0315] Compound 1

[0316] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX-AHX(l,2) (SEQ ID NO 1)

[0317] MW (calculated): 5250.0 Da

[0318] Synthesis and purification methods: SOI; L20

[0319] LCMS: U046_001; Rt: 12.7 min; m / 3: m / 4: 1313.4

[0320] Compound 2

[0321] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-NMeQ-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 2)

[0322] MW (calculated): 5188.8 Da

[0323] Synthesis and purification methods: SOI; L20

[0324] LCMS: U046_001; Rt: 10.6 min; m / 3: m / 4: 1298.0

[0325] Compound 3

[0326] Structure discloses (SEQ ID NO 3)

[0327] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 3)

[0328] MW (calculated): 5202.9 Da

[0329] Synthesis and purification methods: SOI; L20

[0330] LCMS: U046_001; Rt: 12 min; m / 3: m / 4: 1301.1

[0331] Compound 4

[0332] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-A-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 4)

[0333] MW (calculated): 5274.0 Da

[0334] Synthesis and purification methods: SOI; L20

[0335] LCMS: U046_001; Rt: 11.6 min; m / 3: m / 4: 1319.3

[0336] Compound 5

[0337] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-Aib-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 5)

[0338] MW (calculated): 5259.9 Da

[0339] Synthesis and purification methods: SOI; L20

[0340] LCMS: U046_006; Rt: 34.8 min; m / 3: m / 4: 1315.7

[0341] Compound 6 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-N-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 6)

[0342] MW (calculated): 5288.9 Da

[0343] Synthesis and purification methods: SOI; L20

[0344] LCMS: U046_006; Rt: 31.5 min; m / 3: m / 4: 1323.0

[0345] Compound 7

[0346] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-OEG(l,2) (SEQ ID NO 7)

[0347] MW (calculated): 5218.9 Da

[0348] Synthesis and purification methods: SOI; L20

[0349] LCMS: U046_001; Rt: 11.9 min; m / 3: m / 4: 1305.0

[0350] Compound 8

[0351] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-OEG(l,2) (SEQ ID NO 8)

[0352] MW (calculated): 5248.9 Da

[0353] Synthesis and purification methods: SOI; L20

[0354] LCMS: 010_CA07; Rt: 9.1 min; m / 3: m / 4: 1313.4

[0355] Compound 9

[0356] Structure discloses (SEQ ID NO 9)

[0357] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 9)

[0358] MW (calculated): 5288.0 Da

[0359] Synthesis and purification methods: SOI; L20

[0360] LCMS: U046_001; Rt: 10.3 min; m / 3: m / 4: 1322.7

[0361] Compound 10

[0362] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-E-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 10)

[0363] MW (calculated): 5304.0 Da

[0364] Synthesis and purification methods: SOI; L20

[0365] LCMS: U046_001; Rt: 10.2 min; m / 3: m / 4: 1326.8

[0366] Compound 11

[0367] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys-eLys(l,2) (SEQ ID NO 11) MW (calculated): 5431.2 Da

[0368] Synthesis and purification methods: SOI; L20

[0369] LCMS: U046_001; Rt: 9.2 min; m / 3: m / 4: 1358.1

[0370] Compound 12

[0371] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 12)

[0372] MW (calculated): 5202.9 Da

[0373] Synthesis and purification methods: SOI; L20

[0374] LCMS: U046_001; Rt: 11.1 min; m / 3: m / 4: 1301.4

[0375] Compound 13

[0376] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 13)

[0377] MW (calculated): 5158.9 Da

[0378] Synthesis and purification methods: SOI; L20

[0379] LCMS: U046_001; Rt: 10.4 min; m / 3: m / 4: 1290.5

[0380] Compound 14

[0381] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 14)

[0382] MW (calculated): 5216.9 Da

[0383] Synthesis and purification methods: SOI; L20

[0384] LCMS: 010_CA07; Rt: 9.2 min; m / 3: m / 4: 1305.4

[0385] Compound 15

[0386] Y-Aib-E-G-T-F-T-S-D-F-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 15)

[0387] MW (calculated): 5315.0 Da

[0388] Synthesis and purification methods: SOI; L20

[0389] LCMS: U046_001; Rt: 11.9 min; m / 3: m / 4: 1329.6

[0390] Compound 16

[0391] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-dOR-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 16)

[0392] MW (calculated): 5432.1 Da

[0393] Synthesis and purification methods: SOI; L20

[0394] LCMS: U046_006; Rt: 31.3 min; m / 3: m / 4: 1358.8

[0395] Compound 17

[0396] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-NMeQ-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 17)

[0397] MW (calculated): 5318.0 Da

[0398] Synthesis and purification methods: SOI; L20

[0399] LCMS: U046_001; Rt: 9.9 min; m / 3: m / 4: 1330.0

[0400] Compound 18 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-I-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 18)

[0401] MW (calculated): 5460.2 Da

[0402] Synthesis and purification methods: SOI; L20

[0403] LCMS: 010_CA07; Rt: 9.5 min; m / 3: m / 4: 1366.4

[0404] Compound 19

[0405] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-OEG(l,2) (SEQ ID NO 19)

[0406] MW (calculated): 6057.8 Da

[0407] Synthesis and purification methods: SOI; L20

[0408] LCMS: 010_CA07; Rt: 11.1 min; m / 3: m / 4: 1515.6

[0409] Compound 20

[0410] Structure discloses (SEQ ID NO 20)

[0411] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 20)

[0412] MW (calculated): 5281.0 Da

[0413] Synthesis and purification methods: LP; L20

[0414] LCMS: U046_001; Rt: 12 min; m / 3: m / 4: 1321.0

[0415] Compound 21

[0416] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 21)

[0417] MW (calculated): 5295.0 Da

[0418] Synthesis and purification methods: SOI; L20

[0419] LCMS: U046_001; Rt: 12.1 min; m / 3: m / 4: 1324.6

[0420] Compound 22

[0421] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-D-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 22)

[0422] MW (calculated): 5373.1 Da

[0423] Synthesis and purification methods: SOI; L20

[0424] LCMS: U046_006; Rt: 33.4 min; m / 3: m / 4: 1344.0

[0425] Compound 23

[0426] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-Q-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 23) MW (calculated): 5302.9 Da

[0427] Synthesis and purification methods: SOI; L20

[0428] LCMS: U046_006; Rt: 31.6 min; m / 3: m / 4: 1326.4

[0429] Compound 24

[0430] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-I-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 24)

[0431] MW (calculated): 5288.0 Da

[0432] Synthesis and purification methods: SOI; L20

[0433] LCMS: U046_006; Rt: 32.5 min; m / 3: m / 4: 1322.7

[0434] Compound 25

[0435] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-E-E-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu(l,2) (SEQ ID NO 25)

[0436] MW (calculated): 4918.5 Da

[0437] Synthesis and purification methods: SOI; L20

[0438] LCMS: U046_001; Rt: 12.4 min; m / 3: 1640.3 m / 4:

[0439] Compound 26

[0440] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-NMeQ-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 26)

[0441] MW (calculated): 5345.1 Da

[0442] Synthesis and purification methods: SOI; L20

[0443] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1337.1

[0444] Compound 27

[0445] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 27)

[0446] MW (calculated): 5359.1 Da

[0447] Synthesis and purification methods: SOI; L20

[0448] LCMS: U046_001; Rt: 12 min; m / 3: m / 4: 1340.6

[0449] Compound 28

[0450] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-E-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 28)

[0451] MW (calculated): 5332.0 Da

[0452] Synthesis and purification methods: SOI; L20

[0453] LCMS: U046_001; Rt: 11.5 min; m / 3: m / 4: 1333.7

[0454] Compound 29

[0455] Y-Aib-E-G-T-F-T-S-D-Y-S-I-A-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 29)

[0456] MW (calculated): 5188.8 Da

[0457] Synthesis and purification methods: SOI; L20

[0458] LCMS: U046_001; Rt: 11.8 min; m / 3: m / 4: 1298.0

[0459] Compound 30 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 30)

[0460] MW (calculated): 5490.1 Da

[0461] Synthesis and purification methods: SOI; L20

[0462] LCMS: U046_001; Rt: 11.3 min; m / 3: m / 4: 1373.3

[0463] Compound 31

[0464] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-TRX-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 31)

[0465] MW (calculated): 5314.0 Da

[0466] Synthesis and purification methods: SOI; L20

[0467] LCMS: U046_001; Rt: 11.6 min; m / 3: m / 4: 1329.2

[0468] Compound 32

[0469] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 32)

[0470] MW (calculated): 5518.2 Da

[0471] Synthesis and purification methods: SOI; L20

[0472] LCMS: U046_001; Rt: 10.2 min; m / 3: m / 4: 1380.2

[0473] Compound 33

[0474] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-I-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 33)

[0475] MW (calculated): 5274.0 Da

[0476] Synthesis and purification methods: SOI; L20

[0477] LCMS: U046_006; Rt: 32.5 min; m / 3: m / 4: 1319.3

[0478] Compound 34

[0479] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-eLys-gGlu-gGlu(l,2) (SEQ ID NO 34)

[0480] MW (calculated): 5303.0 Da

[0481] Synthesis and purification methods: SOI; L20

[0482] LCMS: U046_001; Rt: 9.6 min; m / 3: m / 4: 1326.5

[0483] Compound 35

[0484] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 35)

[0485] MW (calculated): 5460.2 Da

[0486] Synthesis and purification methods: SOI; L20

[0487] LCMS: U046_001; Rt: 11.2 min; m / 3: m / 4: 1365.8

[0488] Compound 36

[0489] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-E-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 36)

[0490] MW (calculated): 5361.0 Da

[0491] Synthesis and purification methods: SOI; L20

[0492] LCMS: U046_001; Rt: 9.7 min; m / 3: m / 4: 1341.0 Compound 37

[0493] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-L-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 37)

[0494] MW (calculated): 5317.0 Da

[0495] Synthesis and purification methods: SOI; L20

[0496] LCMS: U046_001; Rt: 9.6 min; m / 3: m / 4: 1330.1

[0497] Compound 38

[0498] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 38)

[0499] MW (calculated): 5303.9 Da

[0500] Synthesis and purification methods: SOI; L20

[0501] LCMS: U046_001; Rt: 10.4 min; m / 3: m / 4: 1326.8

[0502] Compound 39

[0503] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 39)

[0504] MW (calculated): 5417.1 Da

[0505] Synthesis and purification methods: SOI; L20

[0506] LCMS: U046_001; Rt: 12 min; m / 3: m / 4: 1355.0

[0507] Compound 40

[0508] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 40)

[0509] MW (calculated): 5289.9 Da

[0510] Synthesis and purification methods: SOI; L20

[0511] LCMS: U046_006; Rt: 32.4 min; m / 3: m / 4: 1323.2

[0512] Compound 41

[0513] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-I-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu(l,2) (SEQ ID NO 41)

[0514] MW (calculated): 5073.7 Da

[0515] Synthesis and purification methods: SOI; L20

[0516] LCMS: U046_001; Rt: 11.3 min; m / 3: m / 4: 1269.0

[0517] Compound 42

[0518] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-Q-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 42)

[0519] MW (calculated): 5045.6 Da

[0520] Synthesis and purification methods: SOI; L20

[0521] LCMS: 010_CA07; Rt: 9.9 min; m / 3: m / 4: 1262.6

[0522] Compound 43

[0523] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-NMeR-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 43)

[0524] MW (calculated): 5317.0 Da

[0525] Synthesis and purification methods: SOI; L20 LCMS: U046_001; Rt: 9.9 min; m / 3: m / 4: 1330.1

[0526] Compound 44

[0527] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX-AHX(l,2) (SEQ ID NO 44)

[0528] MW (calculated): 5272.0 Da

[0529] Synthesis and purification methods: SOI; L20

[0530] LCMS: U046_006; Rt: 30.8 min; m / 3: m / 4: 1318.7

[0531] Compound 45

[0532] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 45)

[0533] MW (calculated): 5244.9 Da

[0534] Synthesis and purification methods: SOI; L20

[0535] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1312.0

[0536] Compound 46

[0537] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gDab(l,2) (SEQ ID NO 46)

[0538] MW (calculated): 5303.0 Da

[0539] Synthesis and purification methods: SOI; L20

[0540] LCMS: U046_001; Rt: 11.3 min; m / 3: m / 4: 1326.5

[0541] Compound 47

[0542] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-OEG(l,2) (SEQ ID NO 47)

[0543] MW (calculated): 5320.0 Da

[0544] Synthesis and purification methods: SOI; L20

[0545] LCMS: U046_001; Rt: 10.1 min; m / 3: m / 4: 1330.7

[0546] Compound 48

[0547] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 48)

[0548] MW (calculated): 5174.8 Da

[0549] Synthesis and purification methods: SOI; L20

[0550] LCMS: U046_006; Rt: 32.4 min; m / 3: m / 4: 1294.4

[0551] Compound 49

[0552] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 49)

[0553] MW (calculated): 5244.9 Da

[0554] Synthesis and purification methods: SOI; L20

[0555] LCMS: 010_CA07; Rt: 11.7 min; m / 3: m / 4: 1312.4

[0556] Compound 50

[0557] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-Q-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 50)

[0558] MW (calculated): 5036.7 Da Synthesis and purification methods: SOI; L20

[0559] LCMS: U046_001; Rt: 10.7 min; m / 3: m / 4: 1260.0

[0560] Compound 51

[0561] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 51)

[0562] MW (calculated): 5152.8 Da

[0563] Synthesis and purification methods: SOI; L20

[0564] LCMS: U046_001; Rt: 12.7 min; m / 3: 1718.4 m / 4:

[0565] Compound 52

[0566] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-eLys-gGlu-gGlu(l,2) (SEQ ID NO 52)

[0567] MW (calculated): 5331.0 Da

[0568] Synthesis and purification methods: SOI; L20

[0569] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1333.5

[0570] Compound 53

[0571] Structure discloses (SEQ ID NO 53)

[0572] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 53)

[0573] MW (calculated): 5387.1 Da

[0574] Synthesis and purification methods: SOI; L20

[0575] LCMS: U046_006; Rt: 32.1 min; m / 3: m / 4: 1347.0

[0576] Compound 54

[0577] Y-Aib-E-G-E-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 54)

[0578] MW (calculated): 5331.0 Da

[0579] Synthesis and purification methods: SOI; L20

[0580] LCMS: U046_001; Rt: 9.3 min; m / 3: m / 4: 1333.5

[0581] Compound 55

[0582] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-A-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 55)

[0583] MW (calculated): 5231.9 Da

[0584] Synthesis and purification methods: SOI; L20

[0585] LCMS: U046_006; Rt: 34.1 min; m / 3: m / 4: 1308.7 Compound 56

[0586] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 56)

[0587] MW (calculated): 5232.8 Da

[0588] Synthesis and purification methods: SOI; L20

[0589] LCMS: 010_CA07; Rt: 8.9 min; m / 3: m / 4: 1309.4

[0590] Compound 57

[0591] Y-Aib-E-G-T-F-T-S-D-Y-S-I-L-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 57)

[0592] MW (calculated): 5230.9 Da

[0593] Synthesis and purification methods: SOI; L20

[0594] LCMS: 010_CA07; Rt: 11.6 min; m / 3: m / 4: 1308.9

[0595] Compound 58

[0596] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-Y-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 58)

[0597] MW (calculated): 5353.0 Da

[0598] Synthesis and purification methods: SOI; L20

[0599] LCMS: U046_001; Rt: 8.9 min; m / 3: m / 4: 1339.0

[0600] Compound 59

[0601] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 59)

[0602] MW (calculated): 5201.9 Da

[0603] Synthesis and purification methods: SOI; L20

[0604] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1301.2

[0605] Compound 60

[0606] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-eLys-gGlu(l,2) (SEQ ID NO 60)

[0607] MW (calculated): 5281.0 Da

[0608] Synthesis and purification methods: SOI; L20

[0609] LCMS: U046_001; Rt: 12.1 min; m / 3: m / 4: 1321.1

[0610] Compound 61

[0611] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-A-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 61)

[0612] MW (calculated): 5289.0 Da

[0613] Synthesis and purification methods: SOI; L20

[0614] LCMS: U046_001; Rt: 9.6 min; m / 3: m / 4: 1323.0

[0615] Compound 62

[0616] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu(l,2) (SEQ ID NO 62)

[0617] MW (calculated): 5045.7 Da

[0618] Synthesis and purification methods: SOI; L20 LCMS: U046_001; Rt: 10.5 min; m / 3: m / 4: 1262.0

[0619] Compound 63

[0620] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-LysAc-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu(l,2) (SEQ ID NO 63)

[0621] MW (calculated): 4958.6 Da

[0622] Synthesis and purification methods: SOI; L20

[0623] LCMS: U046_001; Rt: 12.7 min; m / 3: m / 4: 1240.5

[0624] Compound 64

[0625] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-E-E-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu(l,2) (SEQ ID NO 64)

[0626] MW (calculated): 4976.5 Da

[0627] Synthesis and purification methods: SOI; L20

[0628] LCMS: U046_001; Rt: 12.6 min; m / 3: m / 4: 1244.9

[0629] Compound 65

[0630] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-L-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 65)

[0631] MW (calculated): 5288.0 Da

[0632] Synthesis and purification methods: SOI; L20

[0633] LCMS: U046_001; Rt: 13.9 min; m / 3: m / 4: 1322.8

[0634] Compound 66

[0635] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-I-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 66)

[0636] MW (calculated): 5331.0 Da

[0637] Synthesis and purification methods: SOI; L20

[0638] LCMS: 010_CA07; Rt: 9.7 min; m / 3: m / 4: 1334.2

[0639] Compound 67

[0640] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-D-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 67)

[0641] MW (calculated): 5331.0 Da

[0642] Synthesis and purification methods: SOI; L20

[0643] LCMS: U046_006; Rt: 31 min; m / 3: m / 4: 1333.5

[0644] Compound 68

[0645] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-A-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 68)

[0646] MW (calculated): 5260.0 Da

[0647] Synthesis and purification methods: SOI; L20

[0648] LCMS: U046_001; Rt: 9.5 min; m / 3: m / 4: 1315.8

[0649] Compound 69

[0650] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 69)

[0651] MW (calculated): 5186.9 Da Synthesis and purification methods: SOI; L20

[0652] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1297.5

[0653] Compound 70

[0654] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-Q-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 70)

[0655] MW (calculated): 5159.8 Da

[0656] Synthesis and purification methods: SOI; L20

[0657] LCMS: U046_006; Rt: 31.9 min; m / 3: m / 4: 1290.7

[0658] Compound 71

[0659] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 71)

[0660] MW (calculated): 5303.9 Da

[0661] Synthesis and purification methods: SOI; L20

[0662] LCMS: U046_001; Rt: 11.3 min; m / 3: m / 4: 1326.7

[0663] Compound 72

[0664] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-ArgMe-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 72)

[0665] MW (calculated): 5317.0 Da

[0666] Synthesis and purification methods: SOI; L20

[0667] LCMS: U046_001; Rt: 9.7 min; m / 3: m / 4: 1330.1

[0668] Compound 73

[0669] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-OEG-OEG(l,2) (SEQ ID NO 73)

[0670] MW (calculated): 5264.9 Da

[0671] Synthesis and purification methods: SOI; L20

[0672] LCMS: U046_001; Rt: 10.2 min; m / 3: m / 4: 1317.0

[0673] Compound 74

[0674] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 74)

[0675] MW (calculated): 5317.0 Da

[0676] Synthesis and purification methods: LP; L20

[0677] LCMS: U046_006; Rt: 32.5 min; m / 3: m / 4: 1330.0

[0678] Compound 75

[0679] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu(l,2) (SEQ ID NO 75)

[0680] MW (calculated): 5046.6 Da

[0681] Synthesis and purification methods: SOI; L20

[0682] LCMS: 010_CA07; Rt: 10.6 min; m / 3: m / 4: 1262.8

[0683] Compound 76

[0684] Structure discloses (SEQ ID NO 76)

[0685] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 76)

[0686] MW (calculated): 5359.1 Da

[0687] Synthesis and purification methods: LP; L20

[0688] LCMS: U046_006; Rt: 31.1 min; m / 3: m / 4: 1340.5

[0689] Compound 77

[0690] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu(l,2) (SEQ ID NO 77)

[0691] MW (calculated): 4916.6 Da

[0692] Synthesis and purification methods: SOI; L20

[0693] LCMS: U046_001; Rt: 10.7 min; m / 3: 1639.5 m / 4:

[0694] Compound 78

[0695] Structure discloses (SEQ ID NO 78)

[0696] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 78)

[0697] MW (calculated): 5502.2 Da

[0698] Synthesis and purification methods: SOI; L20

[0699] LCMS: U046_001; Rt: 11.5 min; m / 3: m / 4: 1376.4

[0700] Compound 79

[0701] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu(l,2) (SEQ ID NO 79)

[0702] MW (calculated): 4974.6 Da

[0703] Synthesis and purification methods: SOI; L20

[0704] LCMS: U046_001; Rt: 10.7 min; m / 3: m / 4: 1244.4

[0705] Compound 80 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-L-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 80)

[0706] MW (calculated): 5331.0 Da

[0707] Synthesis and purification methods: SOI; L20

[0708] LCMS: U046_001; Rt: 11.2 min; m / 3: m / 4: 1333.6

[0709] Compound 81

[0710] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 81)

[0711] MW (calculated): 5331.0 Da

[0712] Synthesis and purification methods: SOI; L20

[0713] LCMS: U046_006; Rt: 32.9 min; m / 3: m / 4: 1333.5

[0714] Compound 82

[0715] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-E-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys-eLys(l,2) (SEQ ID NO 82)

[0716] MW (calculated): 5460.2 Da

[0717] Synthesis and purification methods: SOI; L20

[0718] LCMS: U046_001; Rt: 11 min; m / 3: m / 4: 1365.8

[0719] Compound 83

[0720] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 83)

[0721] MW (calculated): 5389.1 Da

[0722] Synthesis and purification methods: SOI; L20

[0723] LCMS: U046_001; Rt: 10.4 min; m / 3: m / 4: 1348.1

[0724] Compound 84

[0725] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Y-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 84)

[0726] MW (calculated): 5338.0 Da

[0727] Synthesis and purification methods: SOI; L20

[0728] LCMS: U046_001; Rt: 10.4 min; m / 3: m / 4: 1335.3

[0729] Compound 85

[0730] Y-Aib-E-G-A-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 85)

[0731] MW (calculated): 5273.0 Da

[0732] Synthesis and purification methods: SOI; L20

[0733] LCMS: U046_001; Rt: 9.5 min; m / 3: m / 4: 1319.0

[0734] Compound 86

[0735] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Phe4F-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 86)

[0736] MW (calculated): 5305.0 Da

[0737] Synthesis and purification methods: SOI; L20

[0738] LCMS: U046_001; Rt: 10.3 min; m / 3: m / 4: 1327.0 Compound 87

[0739] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-dtOrn(l,2) (SEQ ID NO 87)

[0740] MW (calculated): 5289.0 Da

[0741] Synthesis and purification methods: SOI; L20

[0742] LCMS: U046_001; Rt: 9.5 min; m / 3: m / 4: 1323.0

[0743] Compound 88

[0744] Structure discloses (SEQ ID NO 88)

[0745] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 88)

[0746] MW (calculated): 5317.0 Da

[0747] Synthesis and purification methods: SOI; L20

[0748] LCMS: U046_006; Rt: 38.9 min; m / 3: m / 4: 1330.0

[0749] Compound 89

[0750] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 89)

[0751] MW (calculated): 5374.1 Da

[0752] Synthesis and purification methods: LP; L20

[0753] LCMS: U046_006; Rt: 34.3 min; m / 3: m / 4: 1344.2

[0754] Compound 90

[0755] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-dOR-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 90)

[0756] MW (calculated): 5290.0 Da

[0757] Synthesis and purification methods: SOI; L20

[0758] LCMS: U046_001; Rt: 9.2 min; m / 3: m / 4: 1322.9

[0759] Compound 91

[0760] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-R-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 91)

[0761] MW (calculated): 5388.1 Da

[0762] Synthesis and purification methods: SOI; L20

[0763] LCMS: U046_001; Rt: 9.4 min; m / 3: m / 4: 1347.0

[0764] Compound 92

[0765] Structure discloses (SEQ ID NO 92)

[0766] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 92)

[0767] MW (calculated): 5303.0 Da

[0768] Synthesis and purification methods: SOI; L20

[0769] LCMS: U046_001; Rt: 9.5 min; m / 3: m / 4: 1326.6

[0770] Compound 93

[0771] Y-Aib-E-A-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 93)

[0772] MW (calculated): 5317.0 Da

[0773] Synthesis and purification methods: SOI; L20

[0774] LCMS: U046_001; Rt: 9.6 min; m / 3: m / 4: 1330.0

[0775] Compound 94

[0776] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-eLys-gGlu(l,2) (SEQ ID NO 94)

[0777] MW (calculated): 5331.0 Da

[0778] Synthesis and purification methods: SOI; L20

[0779] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1333.6

[0780] Compound 95

[0781] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-G-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 95)

[0782] MW (calculated): 5231.9 Da

[0783] Synthesis and purification methods: SOI; L20

[0784] LCMS: U046_001; Rt: 11.9 min; m / 3: m / 4: 1308.7

[0785] Compound 96

[0786] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-dOR-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 96)

[0787] MW (calculated): 5031.7 Da

[0788] Synthesis and purification methods: SOI; L20

[0789] LCMS: U046_001; Rt: 9.9 min; m / 3: m / 4: 1258.7

[0790] Compound 97

[0791] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-dtOrn(l,2) (SEQ ID NO 97) MW (calculated): 5317.0 Da

[0792] Synthesis and purification methods: SOI; L20

[0793] LCMS: U046_001; Rt: 11.2 min; m / 3: m / 4: 1330.0

[0794] Compound 98

[0795] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-OEG-OEG(l,2) (SEQ ID NO 98)

[0796] MW (calculated): 5394.0 Da

[0797] Synthesis and purification methods: SOI; L20

[0798] LCMS: U046_001; Rt: 10 min; m / 3: m / 4: 1349.3

[0799] Compound 99

[0800] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-OEG(l,2) (SEQ ID NO 99)

[0801] MW (calculated): 5348.0 Da

[0802] Synthesis and purification methods: SOI; L20

[0803] LCMS: U046_001; Rt: 11.7 min; m / 3: m / 4: 1337.8

[0804] Compound 100

[0805] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-E-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu(l,2) (SEQ ID NO 100)

[0806] MW (calculated): 4975.6 Da

[0807] Synthesis and purification methods: SOI; L20

[0808] LCMS: U046_001; Rt: 10.9 min; m / 3: m / 4: 1244.7

[0809] Compound 101

[0810] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 101) MW (calculated): 5332.0 Da

[0811] Synthesis and purification methods: SOI; L20

[0812] LCMS: U046_001; Rt: 12 min; m / 3: m / 4: 1333.8

[0813] Compound 102

[0814] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 102)

[0815] MW (calculated): 5303.0 Da

[0816] Synthesis and purification methods: SOI; L20

[0817] LCMS: U046_006; Rt: 30.7 min; m / 3: m / 4: 1326.5

[0818] Compound 103

[0819] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-K-Q-A-E-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 103)

[0820] MW (calculated): 5374.1 Da

[0821] Synthesis and purification methods: SOI; L20

[0822] LCMS: U046_001; Rt: 11.7 min; m / 3: m / 4: 1344.3

[0823] Compound 104 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-E-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 104)

[0824] MW (calculated): 5332.0 Da

[0825] Synthesis and purification methods: SOI; L20

[0826] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1333.8

[0827] Compound 105

[0828] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 105)

[0829] MW (calculated): 5289.0 Da

[0830] Synthesis and purification methods: SOI; L20

[0831] LCMS: U046_006; Rt: 30.5 min; m / 3: m / 4: 1323.0

[0832] Compound 106

[0833] Structure discloses (SEQ ID NO 106)

[0834] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX-AHX(l,2) (SEQ ID NO 106)

[0835] MW (calculated): 5300.1 Da

[0836] Synthesis and purification methods: LP; L20

[0837] LCMS: U046_001; Rt: 11.9 min; m / 3: m / 4: 1325.8

[0838] Compound 107

[0839] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-L-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 107)

[0840] MW (calculated): 5303.0 Da

[0841] Synthesis and purification methods: SOI; L20

[0842] LCMS: U046_001; Rt: 9.5 min; m / 3: m / 4: 1326.5

[0843] Compound 108

[0844] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 108)

[0845] MW (calculated): 5160.8 Da

[0846] Synthesis and purification methods: SOI; L20

[0847] LCMS: U046_006; Rt: 32.6 min; m / 3: m / 4: 1290.9

[0848] Compound 109

[0849] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-I-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 109) MW (calculated): 5345.1 Da

[0850] Synthesis and purification methods: SOI; L20

[0851] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1337.0

[0852] Compound 110

[0853] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-OEG(l,2) (SEQ ID NO 110)

[0854] MW (calculated): 5061.7 Da

[0855] Synthesis and purification methods: SOI; L20

[0856] LCMS: U046_001; Rt: 10.6 min; m / 3: m / 4: 1266.3

[0857] Compound 111

[0858] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-A-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 111)

[0859] MW (calculated): 5245.9 Da

[0860] Synthesis and purification methods: SOI; L20

[0861] LCMS: U046_001; Rt: 11.5 min; m / 3: m / 4: 1312.2

[0862] Compound 112

[0863] Y-Aib-E-G-T-F-T-S-D-Y-S-E-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 112)

[0864] MW (calculated): 5318.9 Da

[0865] Synthesis and purification methods: SOI; L20

[0866] LCMS: U046_001; Rt: 9 min; m / 3: m / 4: 1330.5

[0867] Compound 113

[0868] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 113)

[0869] MW (calculated): 5217.9 Da

[0870] Synthesis and purification methods: SOI; L20

[0871] LCMS: U046_006; Rt: 30.5 min; m / 3: m / 4: 1305.2

[0872] Compound 114

[0873] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-NMeQ-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 114)

[0874] MW (calculated): 5216.9 Da

[0875] Synthesis and purification methods: SOI; L20

[0876] LCMS: U046_001; Rt: 12.2 min; m / 3: m / 4: 1305.0

[0877] Compound 115

[0878] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-L-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 115)

[0879] MW (calculated): 5281.0 Da

[0880] Synthesis and purification methods: SOI; L20

[0881] LCMS: U046_001; Rt: 12 min; m / 3: m / 4: 1321.0

[0882] Compound 116 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-NMeY-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 116)

[0883] MW (calculated): 5317.0 Da

[0884] Synthesis and purification methods: SOI; L20

[0885] LCMS: U046_001; Rt: 10 min; m / 3: m / 4: 1330.0

[0886] Compound 117

[0887] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-OEG-OEG(l,2) (SEQ ID NO 117)

[0888] MW (calculated): 5336.0 Da

[0889] Synthesis and purification methods: SOI; L20

[0890] LCMS: U046_001; Rt: 10.1 min; m / 3: m / 4: 1334.8

[0891] Compound 118

[0892] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-TRX-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 118)

[0893] MW (calculated): 5470.2 Da

[0894] Synthesis and purification methods: SOI; L20

[0895] LCMS: U046_001; Rt: 12.9 min; m / 3: m / 4: 1368.3

[0896] Compound 119

[0897] Structure discloses (SEQ ID NO 119)

[0898] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 119)

[0899] MW (calculated): 5345.1 Da

[0900] Synthesis and purification methods: SOI; L20

[0901] LCMS: U046_001; Rt: 9.9 min; m / 3: m / 4: 1337.1

[0902] Compound 120

[0903] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gDab(l,2) (SEQ ID NO 120)

[0904] MW (calculated): 5274.9 Da

[0905] Synthesis and purification methods: SOI; L20

[0906] LCMS: U046_001; Rt: 9.6 min; m / 3: m / 4: 1319.6

[0907] Compound 121

[0908] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 121) MW (calculated): 5432.1 Da

[0909] Synthesis and purification methods: SOI; L20

[0910] LCMS: U046_001; Rt: 9.4 min; m / 3: m / 4: 1358.8

[0911] Compound 122

[0912] Y-Aib-E-G-T-F-T-S-D-Y-S-I-L-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu(l,2) (SEQ ID NO 122)

[0913] MW (calculated): 5073.7 Da

[0914] Synthesis and purification methods: SOI; L20

[0915] LCMS: U046_001; Rt: 10.8 min; m / 3: m / 4: 1269.2

[0916] Compound 123

[0917] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-A-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 123)

[0918] MW (calculated): 5245.9 Da

[0919] Synthesis and purification methods: SOI; L20

[0920] LCMS: U046_001; Rt: 12.3 min; m / 3: m / 4: 1312.3

[0921] Compound 124

[0922] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-R-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 124)

[0923] MW (calculated): 5331.0 Da

[0924] Synthesis and purification methods: SOI; L20

[0925] LCMS: U046_006; Rt: 30.9 min; m / 3: m / 4: 1333.5

[0926] Compound 125

[0927] Structure discloses (SEQ ID NO 125)

[0928] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 125) MW (calculated): 5331.0 Da

[0929] Synthesis and purification methods: SOI; L20

[0930] LCMS: U046_001; Rt: 11.2 min; m / 3: m / 4: 1333.5

[0931] Compound 126

[0932] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-V-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 126)

[0933] MW (calculated): 5317.0 Da

[0934] Synthesis and purification methods: SOI; L20 LCMS: 010_CA07; Rt: 9.4 min; m / 3: m / 4: 1330.5

[0935] Compound 127

[0936] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 127)

[0937] MW (calculated): 5331.0 Da

[0938] Synthesis and purification methods: SOI; L20

[0939] LCMS: U046_001; Rt: 10.5 min; m / 3: m / 4: 1333.5

[0940] Compound 128

[0941] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-A-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 128)

[0942] MW (calculated): 5236.9 Da

[0943] Synthesis and purification methods: SOI; L20

[0944] LCMS: U046_001; Rt: 9.9 min; m / 3: m / 4: 1310.0

[0945] Compound 129

[0946] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-E-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu(l,2) (SEQ ID NO 129)

[0947] MW (calculated): 4975.6 Da

[0948] Synthesis and purification methods: SOI; L20

[0949] LCMS: U046_001; Rt: 12.2 min; m / 3: 1659.2 m / 4:

[0950] Compound 130

[0951] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-E-E-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-OEG-

[0952] OEG(1,2) (SEQ ID NO 130)

[0953] MW (calculated): 4879.5 Da

[0954] Synthesis and purification methods: SOI; L20

[0955] LCMS: U046_001; Rt: 13.3 min; m / 3: 1627.2 m / 4:

[0956] Compound 131

[0957] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 131)

[0958] MW (calculated): 5347.0 Da

[0959] Synthesis and purification methods: SOI; L20

[0960] LCMS: U046_006; Rt: 30.4 min; m / 3: m / 4: 1337.5

[0961] Compound 132

[0962] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-eLys-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 132)

[0963] MW (calculated): 5331.0 Da

[0964] Synthesis and purification methods: SOI; L20

[0965] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1333.5

[0966] Compound 133

[0967] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-TRX-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 133)

[0968] MW (calculated): 5342.1 Da Synthesis and purification methods: SOI; L20

[0969] LCMS: U046_001; Rt: 13.4 min; m / 3: m / 4: 1336.3

[0970] Compound 134

[0971] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 134)

[0972] MW (calculated): 5174.8 Da

[0973] Synthesis and purification methods: SOI; L20

[0974] LCMS: U046_001; Rt: 10.3 min; m / 3: m / 4: 1294.5

[0975] Compound 135

[0976] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 135)

[0977] MW (calculated): 5410.1 Da

[0978] Synthesis and purification methods: LP; L20

[0979] LCMS: U046_001; Rt: 12 min; m / 3: 1804.1 m / 4:

[0980] Compound 136

[0981] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-OEG-gGlu-gGlu(l,2) (SEQ ID NO 136)

[0982] MW (calculated): 5348.0 Da

[0983] Synthesis and purification methods: SOI; L20

[0984] LCMS: U046_001; Rt: 11.6 min; m / 3: m / 4: 1337.8

[0985] Compound 137

[0986] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-TRX-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 137)

[0987] MW (calculated): 5442.2 Da

[0988] Synthesis and purification methods: SOI; L20

[0989] LCMS: U046_001; Rt: 11 min; m / 3: m / 4: 1361.3

[0990] Compound 138

[0991] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 138)

[0992] MW (calculated): 5188.8 Da

[0993] Synthesis and purification methods: SOI; L20

[0994] LCMS: U046_006; Rt: 34.3 min; m / 3: m / 4: 1298.0

[0995] Compound 139

[0996] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-A-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 139)

[0997] MW (calculated): 5260.9 Da

[0998] Synthesis and purification methods: SOI; L20

[0999] LCMS: U046_001; Rt: 8.8 min; m / 3: m / 4: 1316.0

[1000] Compound 140

[1001] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-OEG(l,2) (SEQ ID NO 140) MW (calculated): 5190.8 Da

[1002] Synthesis and purification methods: SOI; L20

[1003] LCMS: U046_001; Rt: 10.3 min; m / 3: m / 4: 1298.4

[1004] Compound 141

[1005] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 141)

[1006] MW (calculated): 5173.9 Da

[1007] Synthesis and purification methods: SOI; L20

[1008] LCMS: U046_001; Rt: 9.7 min; m / 3: m / 4: 1294.2

[1009] Compound 142

[1010] Y-Aib-E-G-T-F-T-S-D-Y-A-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 142)

[1011] MW (calculated): 5287.0 Da

[1012] Synthesis and purification methods: SOI; L20

[1013] LCMS: U046_001; Rt: 9.9 min; m / 3: m / 4: 1322.6

[1014] Compound 143

[1015] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-A-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 143)

[1016] MW (calculated): 5245.9 Da

[1017] Synthesis and purification methods: SOI; L20

[1018] LCMS: U046_001; Rt: 10.4 min; m / 3: m / 4: 1312.2

[1019] Compound 144

[1020] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-S-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 144)

[1021] MW (calculated): 5319.0 Da

[1022] Synthesis and purification methods: SOI; L20

[1023] LCMS: U046_001; Rt: 9.4 min; m / 3: m / 4: 1330.5

[1024] Compound 145

[1025] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 145)

[1026] MW (calculated): 5361.0 Da

[1027] Synthesis and purification methods: SOI; L20

[1028] LCMS: U046_001; Rt: 9.6 min; m / 3: m / 4: 1341.0

[1029] Compound 146

[1030] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-bhArg-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 146)

[1031] MW (calculated): 5317.0 Da

[1032] Synthesis and purification methods: SOI; L20

[1033] LCMS: U046_001; Rt: 9.7 min; m / 3: m / 4: 1330.0

[1034] Compound 147 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-R-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 147)

[1035] MW (calculated): 5317.0 Da

[1036] Synthesis and purification methods: SOI; L20

[1037] LCMS: U046_006; Rt: 30.9 min; m / 3: 1773.0 m / 4:

[1038] Compound 148

[1039] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-E-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-OEG-gGlu-eLys(l,2) (SEQ ID NO 148)

[1040] MW (calculated): 5349.0 Da

[1041] Synthesis and purification methods: SOI; L20

[1042] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1337.7

[1043] Compound 149

[1044] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 149)

[1045] MW (calculated): 5389.1 Da

[1046] Synthesis and purification methods: SOI; L20

[1047] LCMS: U046_001; Rt: 11.2 min; m / 3: m / 4: 1348.0

[1048] Compound 150

[1049] Structure discloses (SEQ ID NO 150)

[1050] Y-Aib-E-G-T-F-T-S-D-Y-S-I-aMeL-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 150)

[1051] MW (calculated): 5373.1 Da

[1052] Synthesis and purification methods: SOI; L20

[1053] LCMS: U046_001; Rt: 11.9 min; m / 3: m / 4: 1344.1

[1054] Compound 151

[1055] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Y-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 151)

[1056] MW (calculated): 5381.1 Da

[1057] Synthesis and purification methods: SOI; L20

[1058] LCMS: U046_001; Rt: 9.4 min; m / 3: m / 4: 1346.1

[1059] Compound 152

[1060] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys-eLys(l,2) (SEQ ID NO 152) MW (calculated): 5489.2 Da

[1061] Synthesis and purification methods: SOI; L20

[1062] LCMS: U046_001; Rt: 9.2 min; m / 3: m / 4: 1373.1

[1063] Compound 153

[1064] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-A-F-V-R-Y-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 153)

[1065] MW (calculated): 5315.0 Da

[1066] Synthesis and purification methods: SOI; L20

[1067] LCMS: U046_006; Rt: 31 min; m / 3: m / 4: 1329.5

[1068] Compound 154

[1069] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 154)

[1070] MW (calculated): 5417.1 Da

[1071] Synthesis and purification methods: SOI; L20

[1072] LCMS: U046_001; Rt: 10.1 min; m / 3: m / 4: 1355.1

[1073] Compound 155

[1074] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-E-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-eLys-eLys(l,2) (SEQ ID NO 155)

[1075] MW (calculated): 5317.0 Da

[1076] Synthesis and purification methods: SOI; L20

[1077] LCMS: U046_006; Rt: 34 min; m / 3: m / 4: 1330.0

[1078] Compound 156

[1079] Y-Aib-E-G-T-F-T-S-D-Y-S-A-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 156)

[1080] MW (calculated): 5260.9 Da

[1081] Synthesis and purification methods: SOI; L20

[1082] LCMS: U046_001; Rt: 9.1 min; m / 3: m / 4: 1316.0

[1083] Compound 157

[1084] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 157)

[1085] MW (calculated): 5316.0 Da

[1086] Synthesis and purification methods: SOI; L20

[1087] LCMS: U046_001; Rt: 11.7 min; m / 3: m / 4: 1329.8

[1088] Compound 158

[1089] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu(l,2) (SEQ ID NO 158)

[1090] MW (calculated): 5073.7 Da

[1091] Synthesis and purification methods: SOI; L20

[1092] LCMS: U046_001; Rt: 11.5 min; m / 3: m / 4: 1269.2

[1093] Compound 159 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-A-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 159)

[1094] MW (calculated): 5289.0 Da

[1095] Synthesis and purification methods: SOI; L20

[1096] LCMS: U046_001; Rt: 9.1 min; m / 3: m / 4: 1323.0

[1097] Compound 160

[1098] Y-Aib-E-G-T-F-T-S-D-Y-S-I-E-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 160)

[1099] MW (calculated): 5347.0 Da

[1100] Synthesis and purification methods: SOI; L20

[1101] LCMS: U046_001; Rt: 9.4 min; m / 3: m / 4: 1337.5

[1102] Compound 161

[1103] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-E-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-OEG-eLys(l,2) (SEQ ID NO 161)

[1104] MW (calculated): 5349.0 Da

[1105] Synthesis and purification methods: SOI; L20

[1106] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1337.8

[1107] Compound 162

[1108] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-E-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-OEG-gGlu-gGlu-eLys(l,2) (SEQ ID NO 162)

[1109] MW (calculated): 5348.1 Da

[1110] Synthesis and purification methods: SOI; L20

[1111] LCMS: U046_001; Rt: 11.4 min; m / 3: m / 4: 1337.9

[1112] Compound 163

[1113] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-eLys(l,2) (SEQ ID NO 163)

[1114] MW (calculated): 5102.8 Da

[1115] Synthesis and purification methods: SOI; L20

[1116] LCMS: U046_001; Rt: 9.8 min; m / 3: m / 4: 1276.5

[1117] Compound 164

[1118] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-E-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 164)

[1119] MW (calculated): 5304.0 Da

[1120] Synthesis and purification methods: SOI; L20

[1121] LCMS: U046_001; Rt: 10 min; m / 3: m / 4: 1326.7

[1122] Compound 165

[1123] Y-Aib-E-G-T-F-T-S-D-Y-S-I-A-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 165)

[1124] MW (calculated): 5289.0 Da

[1125] Synthesis and purification methods: SOI; L20

[1126] LCMS: U046_001; Rt: 9.8 min; m / 3: m / 4: 1323.0 Compound 166

[1127] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-eLys-gGlu-gGlu(l,2) (SEQ ID NO 166)

[1128] MW (calculated): 5281.0 Da

[1129] Synthesis and purification methods: SOI; L20

[1130] LCMS: U046_001; Rt: 12.1 min; m / 3: m / 4: 1321.2

[1131] Compound 167

[1132] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu-AHX(l,2) (SEQ ID NO 167)

[1133] MW (calculated): 5186.9 Da

[1134] Synthesis and purification methods: SOI; L20

[1135] LCMS: U046_001; Rt: 11.9 min; m / 3: m / 4: 1297.5

[1136] Compound 168

[1137] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-eLys-gGlu-gGlu-gGlu(l,2) (SEQ ID NO 168)

[1138] MW (calculated): 5303.0 Da

[1139] Synthesis and purification methods: SOI; L20

[1140] LCMS: U046_001; Rt: 9.7 min; m / 3: m / 4: 1326.6

[1141] Compound 169

[1142] Y-Aib-E-G-T-F-T-S-D-L-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 169)

[1143] MW (calculated): 5253.0 Da

[1144] Synthesis and purification methods: LP; L20

[1145] LCMS: U046_001; Rt: 10.5 min; m / 3: 1751.7 m / 4:

[1146] Compound 170

[1147] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-E-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 170)

[1148] MW (calculated): 5347.0 Da

[1149] Synthesis and purification methods: SOI; L20

[1150] LCMS: U046_001; Rt: 9.2 min; m / 3: m / 4: 1337.5

[1151] Compound 171

[1152] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-R-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 171)

[1153] MW (calculated): 5359.0 Da

[1154] Synthesis and purification methods: SOI; L20

[1155] LCMS: U046_001; Rt: 11.5 min; m / 3: m / 4: 1340.5

[1156] Compound 172

[1157] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-W-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 172)

[1158] MW (calculated): 5404.1 Da

[1159] Synthesis and purification methods: SOI; L20 LCMS: U046_001; Rt: 10 min; m / 3: m / 4: 1351.9

[1160] Compound 173

[1161] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-Q-A-Q-Aib-A-F-V-R-H-L-L-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu- gGlu-gGlu-gGlu-gGlu-gGlu-eLys(l,2) (SEQ ID NO 173)

[1162] MW (calculated): 5289.0 Da

[1163] Synthesis and purification methods: SOI; L20

[1164] LCMS: U046_006; Rt: 30.4 min; m / 3: m / 4: 1322.9

[1165] Compound 174

[1166] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu- gGlu-gGlu-gGlu-eLys-gGlu(l,2) (SEQ ID NO 174)

[1167] MW (calculated): 5303.0 Da

[1168] Synthesis and purification methods: SOI; L20

[1169] LCMS: U046_001; Rt: 9.6 min; m / 3: m / 4: 1326.5

[1170] Compound 175

[1171] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-AHX-gGlu-AHX(l,2) (SEQ ID NO 175)

[1172] MW (calculated): 5300.1 Da

[1173] Synthesis and purification methods: SOI; L20

[1174] LCMS: U046_001; Rt: 11.9 min; m / 3: m / 4: 1325.8

[1175] Compound 176

[1176] Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-R-H-L-I-N-K(l,3)-Aib-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu- gGlu-gGlu-gGlu(l,2) (SEQ ID NO 176)

[1177] MW (calculated): 5073.7 Da

[1178] Synthesis and purification methods: SOI; L20

[1179] LCMS: U046_001; Rt: 11 min; m / 3: m / 4: 1269.2

Claims

CLAIMS1. A compound of formula (I),U-Z-P (I), wherein P is a peptide comprising the amino acid sequence,Y-Aib-E-X4-X5-F-T-S-D-Xio-Xii-Xi2-Xi3-L-Xi5-Xi6-Xi7-Xi8-Xi9-X2o-X2i-F-X23-R-X25-X26-X27-X28-K-X3o-T-R-X33-X34-X35(SEQ ID NO: 185) whereinwherein n is an integer in the range 12 to 20, wherein Z is a linker moiety comprising at least one [gGlu] residue, wherein Z is linked to U on one end and to the epsilon-amino group of Lys at position-29 of the peptide P on the other end; and wherein the compound of formula (I) comprises at least six residues of amino acids selected from the group consisting of E and [gGlu]; or salt thereof.

2. The compound according to claim 1, wherein Z is a linker moiety consisting of three to ten linker sub-moieties covalently connected each other,wherein the linker sub-moieties are independently selected from the group consisting of: absent, [gGlu], [eLys], [OEG], [AHX], [TRX], [gDab], and [dtOrn], wherein [gGlu], [eLys], [OEG], [AHX], [TRX], [gDab], and [dtOrn] are residues of formula according to the following tableand wherein the first linker sub-moiety of the linker Z is linked to U and the last linker sub-moiety on the other end of the linker Z is linked to the epsilon-amino group of Lys at position-29 of the peptide P; preferably, wherein Z is a linker moiety consisting of three to eight linker sub-moieties.

3. The compound according to any one of the preceding claims, wherein P is a peptide comprising the amino acid sequenceY-Aib-E-X4-X5-F-T-S-D-Xio-Xii-Xi2-Xi3-L-Xi5-Xi6-Xi7-Xi8-Xi9-X2o-X2i-F-X23-R-X25-X26-X27-X28-K-X3o-T-R-X33-X34-X35(SEQ ID NO: 186), whereinX4 is selected from the group consisting of A, and G, X5 is T,X10 is selected from the group consisting of F, L, and Y,Xn is selected from the group consisting of A, and S,X12 is I,X13 is selected from the group consisting of Aib, and aMeL,X15 is selected from the group consisting of D, and E,Xie is selected from the group consisting of K, N, and E,X17 is selected from the group consisting of A, and Q,Xis is selected from the group consisting of A, and R,X19 is selected from the group consisting of A, E, and Q,X20 is selected from the group consisting of A, Aib, and Y,X21 is selected from the group consisting of A, and S,X23 is selected from the group consisting of I, L, and V,X25 is selected from the group consisting of A, H and Y,X26 is L,X27 is selected from the group consisting of I, and L,X28is N,X30 is selected from the group consisting of A, Aib, I, L, and V,X33 is selected from the group consisting of NMeQ, and Q,X34 is selected from the group consisting of dOR, and R,X35 is selected from the group consisting of Phe4F, Y, and NMeY; preferably, wherein P is a peptide comprising the amino acid sequence SEQ ID NO: 187.

4. The compound according to any one of the preceding claims, wherein the C-terminal of peptide P is amidate.

5. The compound according to any one of the preceding claims, wherein U is the lipid moiety of formula (II)HOOC-(CH2)n-CO-* (II), wherein n is an integer in the range 14 to 18; preferably, wherein U is selected from the group consisting of 15-carboxy-pentadecanoyl (C16DA), 17-carboxy- heptadecanoyl (C18DA), and 19-carboxy-nonadecanoyl (C20DA).

6. The compound according to any one of the preceding claims, wherein U is 17-carboxy-heptadecanoyl (C18DA).

7. The compound according to any one of the preceding claims, wherein U is 19-carboxy-nonadecanoyl (C20DA).

8. The compound according to any one of the preceding claims, wherein U-Z is selected from the group consisting of:U-[gGlu]-[OEG]-[OEG],U-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu]-[gGlu]-[gGlu],U-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]- [OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX]-[gGlu]-[AHX], U-[gGlu]- [gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[el_ys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[gGlu]-[gGlu], U-[gGlu]- [gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]- [gGlu]-[gGlu]-[OEG]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [gGlu]-[eLys]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys], U-[gGlu]- [gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[OEG], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]-[eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gDab], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[dtOrn], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]- [eLys], U-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[AHX], U-[TRX]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu], U-rrRX]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[gGlu]-[eLys]; preferably, wherein U is 17-carboxy-heptadecanoyl (C18DA) or 19-carboxy-nonadecanoyl (C20DA).

9. The compound according to any one of the preceding claims, wherein Z comprises at least five [gGlu] residues.

10. The compound according to any one of the preceding claims, wherein Z consists of seven to eight linker sub-moieties covalently connected each other; preferably, wherein the linker sub-moieties are independently selected from the group consisting of absent, [gGlu], [eLys], [OEG], and [AHX],11. The compound according to any one of the preceding claims, wherein the compound is selected from the group consisting of Compound SEQ ID NO: 1 to Compound SEQ ID NO: 176 according to the following table12. The compound according to any one of the preceding claims, wherein the compound is in the form of a salt or in the form of a pharmaceutically acceptable salt.

13. The compound according to any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical composition together with one or more pharmaceutically acceptable carrier and / or excipients.

14. The compound according to any one of the preceding claims, wherein the compound is for use as a medicament.

15. The compound according to any one of the preceding claims, wherein the compound is for use in a method of treatment and / or prevention of: overweight, chronic weight management, obesity, symptomatic obesity, eating disorders; endocrine obesity, Cushing syndrome, hypothyroidism, insulinoma, obese type 2 diabetes, pseudohypoparathyroid ism, hypogonad ism ; obesity associated endocrine disorders, polycystic ovary syndrome (PCOS);central obesity, hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome; hereditary obesity, Prader-Willi syndrome, Laurence-Moon-Biedl syndrome; drug-induced obesity, steroid-induced obesity, phenothiazine-induced obesity, insulin-induced obesity, sulfonylurea agent-induced obesity, p-blocker-induced obesity; co-morbidities of obesity, co-morbidities of overweight, obesity associated type 2 diabetes, obesity associated high blood pressure, obesity associated metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD), obesity associated metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steato-hepatitis (NASH), obesity associated diabetic kidney disease (DKD), obesity associated chronic kidney disease (CKD), obesity associated osteoporosis, obesity associated sleep apnoe, obesity associated cancers, obesity associated asthma; insulin resistance, diabetes, type 1 diabetes, type 2 diabetes, prediabetes; hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL- cholesterolemia, postprandial hyperlipemia; metabolic syndrome, abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, low serum high-density lipoprotein (HDL); liver diseases, metabolic dysfunction-associated fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steato-hepatitis (NASH), portal hypertension; cardiovascular diseases, hypertension, atherosclerosis, stroke, cardiac failure; kidney diseases, diabetic kidney disease (DKD), chronic kidney disease (CKD); neurodegenerative diseases, Alzheimer's disease, Parkinson 's disease.

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