MASP-INHIBITING COMPOUNDS AND THEIR USES

Description

[0001] The present invention relates to novel Mannose-binding lectin (MBL)-associated serine protease (MASP) inhibitory compounds, as well as analogues and derivatives thereof, to processes for the preparation thereof, to the use thereof alone or in combinations for treatment and / or prevention of diseases and to the use thereof for production of medicaments for treatment and / or prevention of diseases, especially for treatment and / or prevention of renal and cardiovascular disorders and of ischemia reperfusion injuries.

[0002] The complement system consists of a complex cascading network of proteins, receptors and enzymes of which many are circulating in the blood stream. The complement system is an important constituent of innate immunity and essential for the defense against invading pathogens and clearance of dead and virus infected cells. It forms a bridge between innate and adaptive immune responses. Activation of the complement system is also involved in the pathologies of sepsis and ischemia reperfusion injuries, e.g. after myocardial infarction, ischemic kidney injury or organ transplantation. Three branches of the complement system have been identified: the lectin pathway, the classical and the alternative pathway (Dunkelberger and Song, Complement and its role in innate and adaptive immune responses. Cell Res. 2010; 20(1): 34-50). The lectin pathway is activated by deposition of lectins which are circulating in the blood stream and under normal conditions have a sentinel function against invading pathogens and dead cells by recognizing foreign and altered carbohydrate surface patterns, respectively, and decorating their surfaces. Mannose-binding lectin (MBL), ficolins and collectins are the major representatives of these lectins which are produced in liver, kidney and other organs (Garred et al., A journey through the lectin pathway of complement-MBL and beyond. Immunol Rev. 2016;274(1):74-97). Their deposition is followed by further recruitment of zymogens of essentially two closely related serine proteases from the blood stream, mannose-binding lectin-associated serine protease 1 and 2 (MASP-1 and MASP-2) forming a complex in which the zymogens come into close proximity to each other. The current concept is that under in vivo conditions MASP-1 zymogen after recruitment is self-activating and then activates the MASP-2 zymogen by cleavage. Activated MASP-1 furthermore cleaves complement factor C2 into C2a and C2b. Activated MASP-2 also cleaves C2 and complement factor C4 into C4a and C4b which together with C2a forms the C4bC2a complex which serves as complement factor C3 convertase. Constitution of C3 convertase activity and consecutive C3 deposition to target cell surfaces represents the point of convergence of all three complement pathways activating the common downstream cascade that results in generation of inflammatory mediators and target cell lysis. In intact human serum activities of both MASP-enzymes are indispensable for C3 convertase formation (Héja et al, Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator ofMASP-2. Proc Natl Acad Sci USA. 2012;109(26):10498-503).

[0003] The microvascular system plays a crucial role during inflammatory and ischemic organ disorders. Barrier function, leukocyte trafficking and coagulation control are closely dependent on the integrity of the luminal endothelial cell surface in small blood vessels. The luminal endothelial surface is lined by a dense coat of glycosylation extensions from membrane integrated glycoproteins, proteoglycans, and glycolipids which in their entirety are called glycokalyx. Electron microscopic analyses of samples from animal experiments and human pathologies have shown that in particular the endothelial glycokalyx is rapidly and fundamentally being degraded upon ischemic challenge as well as under inflammatory conditions such as in sepsis. These changes lead to exposure of carbohydrate residues to the blood stream that under normal conditions are not detectable (for review see: Sieve et al., Regulation and function of endothelial gly-cocalyx layer in vascular diseases. Vascul Pharmacol. 2018; 100: 26-33). Beside other changes of the cell surface in particular the altered carbohydrate pattern is thought to activate the lectin pathway causing deposition of the pattern recognizing lectins, subsequent C3 deposition and initiation of cell lysis. MBL and C3 deposition was shown to occur after ischemia and acute kidney injury across species including man. The lectin pathway activation was of particular relevance for reperfusion damage as targeted deletion of MBL and MASP-2 protected mice from ischemia reperfusion damages in kidney heart and intestine (Møller-Kristensen et al., Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. Scand J Immunol. 2005; 61(5): 426-34; Schwaeble et al., Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemialreperfusion injury. Proc Natl Acad Sci U SA. 2011; 108(18): 7523-8). Moreover, deletion of collectin 11, another MASP activating lectin which is predominantly expressed in the kidney, made mice resistant against ischemic acute kidney injury (Farrar et al., Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J Clin Invest. 2016; 126(5): 1911-1925). Selective peptide inhibitors of MASP-1 and MASP-2 have been identified from phage display libraries employing natural trypsin inhibitors from sun flower or grass hoppers as a starting point. These peptides have been shown to inhibit the lectin pathway dependent C3 convertase formation in vitro (Kocsis et al., Selective inhibition of the lectin pathway of complement with phage display selected peptides against mannose-binding lectin-associated serine protease (MASP)-1 and -2: significant contribution ofMASP-1 to lectin pathway activation. J Immunol. 2010; 185(7): 4169-78; Héja et al., Monospecific inhibitors show that both mannan-binding lectin-associated serine protease-1 (MASP-1) and are essential for lectin pathway activation and reveal structural plasticity of MASP-2. J Biol Chem. 2012; 287(24): 20290-300). However, no evidence for pharmaceutical utility and in vivo efficacy of those peptide inhibitors is available, yet. Similarly, antibodies directed against MASP-2 which interfere with MASP zymogen interaction have been identified and brought to clinical development for atypical hemolytic uremic syndrome and other inflammatory kidney disorders (CliniccilTrials.gov Identifier: NCT03205995; NCT02682407; NCT03608033). However, clinical proof for utility in the prevention or treatment of acute, in particular ischemic organ damage is still missing.

[0004] WO2010 / 136831 relates to peptides according to general formula (I) GX1CSX2SX3PPX4CX5PD where X1 is Y, M, W, I, V, A, and X2 is R, K, and X3 is Y, F, I, M, L, E, D, H, and X4 is V, I, H, and X5 is I, V, Y, F, W; and to their pharmaceutically acceptable salts, esters and prodrugs. Furthermore, the invention relates to pharmaceutical preparations and kits containing them, and to screening and isolation procedures using them, and to their use in the production of pharmaceutical preparations.

[0005] D.Heja et al., 2012 discloses (abstract) monospecific peptide inhibitors of MASP-1 and MASP-2 as well as X-ray co-structures of MASP-1 and MAPS-2 in complex with their inhibitors. WO2010 / 065815 discloses peptides which exhibit hepcidin activity and methods of making and using thereof.

[0006] WO 2004 / 075837 discloses anti-MASP antibodies, functionally equivalent fragments thereof and MASP binding peptides for decreasing the morbidity and mortality caused by tissue damage associated with ischemia-reperfusion injury or TAAA repair by inhibition of the complement system. Small peptides such as the sunflower MASP inhibitor-1 (SFMI-1) and sunflower MASP inhibitor-2 (SFMI-2) as well as derivatives thereof for the treatment of diseases related to the complement system, primarily the lectin pathway were first described in WO 2010 / 136831.

[0007] WO 2015 / 054298 discloses methods for preserving vision or reducing vision loss in a subject and for inhibiting or reducing photoreceptor cell death in a subject by reducing the activity of MASP-1, MASP-2 or MASP-3. WO 2004 / 106384, WO 2005 / 123128, WO 2007 / 117996 and WO 2014 / 144542 disclose anti-MASP-2 antibodies for the therapy of diseases associated with MASP-2-dependent complement activation.

[0008] It was the object of the present invention to provide novel peptides, having inhibitory effects on MASP-1 and / or MASP-2 enzymes and other beneficial properties making them suitable as efficient and safe alternatives for the prophylaxis and / or treatment of MASP-1 and / or MASP-2-associated disorders as defined below. It was a further object to provide novel peptides, having an improved inhibitory effect on human MASP-1 and / or MASP-2 enzyme and / or rat MASP-1 and / or MASP-2 enzyme.

[0009] The present invention generally relates to peptides acting as inhibitors of MASP-1 and / or MASP-2 enzymes and methods of making and using the same.

[0010] In particular, the disclosure provides compounds, which are not encompassed by the wording of the claims, containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, the following structural formula (I):         (X 0< ) p (X 1< ) q (X 2< ) r X 3< X 4< X 5< X 6< X 7< X 8< X 9< X 10< X 11< X 12< (X 13< ) s (X 14< ) t (X 15< ) u      (I), or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 0< represents a group of the formula (IIa) wherein * marks the bond to a terminal amino group of the adjoining amino acid, A is a bond or C 1 -C 6 -alkylene, wherein one CH 2 group in C 1 -C 6 -alkylene may be exchanged for -O- or -S-, and wherein C 1 -C 6 -alkylene is up to trisubstituted identically or differently by a radical selected from the group consisting of hydroxyl, methoxy, ethoxy, carboxy, amino and halogen, B is absent, aryl, heteroaryl, C 3 -C 8 -cycloalkyl or C 3 -C 7 -heterocycloalkyl, wherein aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 7 -heterocycloalkyl can be up to trisubstituted identically or differently by a radical selected from the group of C 1 -C 4 -alkyl, hydroxyl, methoxy, ethoxy, carbonyl, carboxy, amino and halogen, and R 1< is hydrogen, halogen, amino, hydroxyl or C 1 -C 20 -alkyl, wherein C 1 -C 20 -alkyl is up to trisubstituted identically or differently by a radical selected from the group consisting of hydroxyl, carboxy, amino and halogen, prepresents the integer 0 or 1, X 1< represents any natural amino acid or an unnatural amino acid, whereas any natural amino acid and / or unnatural amino acid can be in D- or L-stereoconfiguration, and in case p is 0 and q is different from 0, the terminal amino group of X 1< is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl, qrepresents an integer of from 0 to 5, X 2< represents a natural amino acid selected from a list consisting of I, L, M, V and A, or an unnatural amino acid selected from a list consisting of L-N-Methylisoleucine ((N-Me)I), allo-L-Isoleucine (allo-I), L-Cyclobutylalanine (Cba), L-Norvaline (Nva), L-2-Aminobutyric acid (Abu), (2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoic acid, (2S,3S)-2-[2-Oxopiperazin-1-yl]-3-methylpentanoic acid, (2S,3S)-2-[(3S)-2-oxopiperazin-1-yl]-3-methylpentanoic acid, L-Methionine-L-sulfoxide, L-Methionine-sulfone and L-tert-butylglycine, whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, and in case p and q are both 0 and r is 1, the terminal amino group of X 2< is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-Penicillamine (Pen) and L-N-Methylcysteine ((N-Me)C), and in case p and q and r are all 0, the terminal amino group of X 3< is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl, X 4< represents a natural amino acid selected from a list consisting of S, C, T, R or K, or an unnatural amino acid selected from a list consisting of allo-L-Threonine (allo-T), L- Homoserine (hSer) and L-Ornithine (Orn), X 5< represents the natural amino acid R or N(5)-methyl-L-arginine ((Me)R), X 6< represents a natural amino acid selected from a list consisting of S, C or T, or an unnatural amino acid selected from a list consisting of allo-L-Threonine (allo-T) and L-2,3-diaminopropionic acid (Dap), X 7< represents a natural amino acid selected from a list consisting of L, F or N or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), L-4-Bro-mophenylalanine ((4-Bromo)F), 2,5-Difluoro-L-phenylalanine ((2,5-Difluoro)F), L-tert-Butylalanine ((tBu)A), 2-Chloro-L-phenylalanine ((2-Chloro)F), L-2-Bromophenylalanine ((2-Bromo)F), (S)-2-(Amino)-1,6-hexanedioic acid (AAD), (2S)-2-amino-4,4,4-trifluorobutanoic acid, L-2-amino-4-cyano-butyric acid (Cnba), 4-Fluoro-Leucine ((4-Fluoro)L), (S)-(trifluoromethyl)-L-cysteine, (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid, L-tert-Butylglycine ((tBu)G), 3-(Trimethylsilyl)-L-alanine, 2,5-difluoro-L-phenylalanine, 2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid, 5,5,5-Trifluoro-L-leucine ((Trifluoro)L), 2-Methyl-L-phenylalanine ((2-Me)F), L-Cyclobutylalanine (Cba), L-Cyclopentylalanine (Cpa), L-cyclopropylmethylalanine, L-trifluoromethylalanine, L-difluoromethylalanine, 2-Fluoro-L-phenylalanine ((2-Fluoro)F), (2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acid, (2S)-3-(3-Cyanophenyl)-2-aminopropanoic acid, and (2S)-3-(indol-4-yl)-2-(amino)propanoic acid, X 8< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, L-Hydroxyproline (Hyp), (3S)-Morpholine-3-carboxylic acid (Morpholine-3-carboxylic), L-Pipecolic acid (Pip), (4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid, trans-4-fluoroproline ((trans-4-Fluoro)P) and (1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, X 9< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), L-Hydroxyproline (Hyp), (2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P), (2S,4S)-4-fluoroproline ((cis-4-Fluoro)P), trans-4-fluoroproline ((trans-4-Fluoro)P), (2S)-2-amino-4,4,4-trifluorobutanoic acid, L-trans-3-hydroxyproline ((3S-OH)P, (1R,35,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (6S)-5-Azaspiro-[2.4]heptane-6-carboxylic acid, rel-(1R,3R,5R,6R)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S)-2-Amino-4,4,4-trifluorobutanoic acid, (2S,3aS,6aS)-octahydrocyclopenta[b]-pyrrole-2-carboxylic acid, trans-4-fluoroproline ((trans-4-Fluoro)P), (2S,4S)-4-fluoroproline ((cis-4-Fluoro)P), L-4,4-difluoroproline ((Difluoro)P), rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1) and rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2), X 10< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of L-Cyclopentylglycine (Cpg), L-Cyclohexylglycine (Chg), (S)-2-amino-3-ethyl-pentanoic acid, 3-Chlorophenylglycine ((3-Chloro-Ph)G), L-tert-butylglycine, allo-L-Isoleucine (allo-I), L-Cyclobutylglycine, L-Norvaline (Nva) and (2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid, X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen), X 12< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of allo-L-Isoleucine (allo-I), (S)-2-Amino-2-cyclobutylacetic acid (Cbg), (2S,3S)-2-((amino)methyl)-3-methylpentanoic acid, L-Phenylglycine (Phg), 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxa-zole-4-carboxylic acid, 2-methyl-D-alloisoleucine, L-Norvaline (Nva), L-2-Aminobutyric acid (Abu), L-tert-butylglycine and Aminoisobutyric acid (Aib), and in case u and t and s are all 0, the terminal carboxyl group of X 12< is unsubstituted or amidated, X 13< represents a natural amino acid selected from a list consisting of P, A, S, T, G, D, E, Q or N or an unnatural amino acid selected from a list consisting of N-Methyl-Glycine ((N-Me)G), 5-azaspiro-[2.4]heptane-6-carboxylic acid, L-2-Aminobutyric acid (Abu), 2-Aminoisobutyric acid (Aib), 2-Methyl-L-Proline (2-Me)P, Hydroxyproline (Hyp), 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), trans-4-fluoroproline ((trans-4-Fluoro)P), (2S,4S)-4-fluoroproline ((cis-4-Fluoro)P), L-4,4-difluoroproline ((Difluoro)P), L-Cyclopentylglycine (Cpg), (S)-2-Amino-2-cyclobutylacetic acid (Cbg) and (2S)-Pyrrolidin-2-ylacetic acid (beta-homo-P), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, and in case u and t are both 0 and s is different from 0, the terminal carboxyl group of X 13< is unsubstituted or amidated, srepresents an integer of from 0 to 3, X 14< represents any natural amino acid or an unnatural amino acid, whereas any natural amino acid and / or unnatural amino acid can be in D- or L-stereoconfiguration, and in case u is 0 and t is different from 0, the terminal carboxyl group of X 14< is unsubstituted or amidated, trepresents an integer of from 0 to 4, X 15< represents a group of the formula (IIb) wherein * marks the bond to a terminal carboxyl group of the adjoining amino acid, A 1< is a bond or C 1 -C 6 -alkylene, wherein one CH 2 group in C 1 -C 6 -alkylene may be exchanged for -O- or -S-, and wherein C 1 -C 6 -alkylene is up to trisubstituted identically or differently by a radical selected from the group consisting of hydroxyl, methoxy, ethoxy, carboxy, amino and halogen, B 1< is absent, aryl, heteroaryl, C 3 -C 8 -cycloalkyl or C 3 -C 7 -heterocycloalkyl, wherein aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 7 -heterocycloalkyl can be up to trisubstituted identically or differently by a radical selected from the group of C 1 -C 4 -alkyl, hydroxyl, methoxy, ethoxy, carbonyl, carboxy, amino and halogen, and R 2< is hydrogen, halogen, amino, hydroxyl or C 1 -C 20 -alkyl, wherein C 1 -C 20 -alkyl is up to trisubstituted identically or differently by a radical selected from the group consisting of hydroxyl, carboxy, amino and halogen, u represents the integer 0 or 1, with the proviso that at least one of X1 to X14 is an unnatural amino acid.

[0011] The disclosure further provides compounds, which are not encompassed by the wording of the claims, containing a peptide of the following formula (II),         (X 1< ) q (X 2< ) r X 3< X 4< X 5< X 6< X 7< X 8< X 9< X 10< X 11< X 12< (X 13< ) s (X 14< ) t      (II), or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 1< represents a natural amino acid or an unnatural amino acid, qrepresents the integer 0 or 1, X 2< represents the natural amino acid I, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen), X 4< represents the natural amino acid S, X 5< represents the natural amino acid R or the unnatural amino acid N(5)-Methyl-L-arginine ((Me)R), X 6< represents the natural amino acid S, X 7< represents the natural amino acid L or the unnatural amino acid L-tert-Butylalanine ((tBu)A), X 8< represents the natural amino acid P or the unnatural amino acid L-Proline (3,4- 2 H), X 9< represents the natural amino acid P or the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), X 10< represents the natural amino acid I, X 11< represents an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen) X 12< represents the natural amino acid I, X 13< represents the natural amino acid P, srepresents the integer 0 or 1, X 14< represents a natural amino acid selected from a list consisting of D, Q and E, trepresents the integer 0 or 1, wherein the N-terminus of the peptide is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl, wherein the C-terminus of the peptide is unsubstituted or amidated, and wherein the peptide is cyclized, preferably via a linkage connecting X 3< and X 11< .

[0012] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0013] Throughout this specification, the word "comprise" or variations thereof such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components). The singular forms "a", "an" and "the" include the plurals unless the context clearly dictates otherwise. The term "including" and "containing" is used to mean "including but not limited to", which expressions can be used interchangeably. In particular, the expression "compound containing a peptide" means a compound which contains a defined peptide sequence and which can optionally contain further chemical groups or substituents covalently bound to the peptide, e.g. amino acids, fatty acids, chemical groups to enhance pharmacodynamic or pharmacokinetic properties of the peptide or any other chemical groups. It is also to be understood that the expression "compound containing a peptide" explicitly includes the defined peptide sequence without any further chemical groups or substituents covalently bound to that peptide.

[0014] As used herein, the following terms have the meanings ascribed to them unless specified otherwise. "Essentially consisting of" is understood as a peptide being at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide it is compared to.

[0015] The terms "protein", "polypeptide" and "peptide" are used interchangeably to refer broadly to a sequence of two or more amino acids linked together, preferable by peptide (amide) bonds. Peptide (amide) bonds are formed when the carboxyl group of one amino acid reacts with the amino group of another. It should be further understood that the terms "protein", "polypeptide" and "peptide" do not indicate a specific length of a polymer of amino acids, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring. It should be further understood, that a peptide can contain one or more parts which are no amino acids under the definition of the present application. These parts are preferably present at the N- and C-terminal ends of the peptide.

[0016] The term "amino acid" or "any amino acid" as used herein refers to organic compounds containing amine (-NH 2 ) and carboxyl (-COOH) functional groups, along with a side chain and refers to any and all amino acids, including naturally occurring amino acids (e.g., α-L-amino acids), unnatural amino acids, modified amino acids, and non-natural amino acids. "Natural amino acids" include those found in nature, such as, e.g., the 23 amino acids that combine into peptide chains to form the building-blocks of a vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. The 20 proteinogenic, natural amino acids in the standard genetic code are listed in Table 2. The "non-standard" natural amino acids are pyrrolysine (found in methanogenic organisms and other eukaryotes), selenocysteine (present in many non-eukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria and chloroplasts).

[0017] "Unnatural" or "non-natural" amino acids are non-proteinogenic amino acids (i.e., those not naturally encoded or found in the genetic code) that either occur naturally or are chemically synthesized. Over 140 natural amino acids are known and thousands of more combinations are possible. Examples of "unnatural" amino acids include β-amino acids (β 3< and β 2< ), homo-amino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids. "Modified" amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include a group, groups, or chemical moiety not naturally present in the amino acid. According to the present invention preferred unnatural amino acids are listed in Table 1. Table 1 displays unnatural amino acids as D- and / or L-stereoisomers, however preferred unnatural amino acids according to the invention are both D- and L-stereoisomers of unnatural amino acids listed in Table 1. Table 1: Preferred unnatural amino acids(1R,2R)-2-Amino-1-cyclopentanecarboxylic acid (R,R-ACPC)(1R,3S)-3-(Amino)cyclopentanecarboxylic acid(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid(1S,2S)-2-Amino-1-cyclopentanecarboxylic acid (S,S-ACPC)(1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid(1R,2S,5S)-3-Azabicyclo[3.1.0]hexane-2-carboxylic acid(1S,3R)-3-(Amino)cyclopentanecarboxylic acid(1S,3R)-3-(Amino)cyclopentanecarboxylic acid(1S,3R,4R)-2-Azabicyclo[2.2.1]heptane-3-carboxylic acid(2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid(2S)-2-(Amino)-2-[(1S,35)-3-hydroxycyclohexyl]acetic acid(2R)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid(2S)-2-Amino-5-methyl-hexanoic acid(2S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-4-methylpentanoic acid(2S)-2[(amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid(2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid(2S)-2-amino-3-(2,3,4,5,6-pentafluorophenyl)propanoic acid(2S)-2-amino-3-(4-tert-butylphenyl)propanoic acid(2S)-2-Amino-4-(benzylamino)-4-oxobutanecarboxylic acid(2S)-2-amino-4,4,4-trifluorobutanoic acid(2S)-2-Amino-5-methyl-hexanoic acid(2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acid(2S)-3-(3-Cyanophenyl)-2-aminopropanoic acid(2S)-3-(4-carboxyphenyl)-2-aminopropanoic acid(2S)-3-(indol-4-yl)-2-(amino)propanoic acid(2S)-3-(Triazol-1-yl)-2-(amino)propanoic acid(2S)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid(2S)-Amino-2-[3-(Trifluoromethyl)bicyclo[1.1.1]pent-1-yl]acetic acid(2S)-Pyrrolidin-2-ylacetic acid (beta-homo-P)(2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid(2S,3S)-2-((Amino)methyl)-3-methylpentanoic acid(2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoic acid(2S,3S)-2-[(3S)-2-oxopiperazin-1-yl]-3-methylpentanoic acid(2S,4S)-4-fluoroproline ((cis-4-Fluoro)P)(2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P)(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1)(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2)(4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]aze-pine-9-carboxylic acid(6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid(R)-3-Aminoadipic acid(R)-4-Amino-6-methylheptanoic acid(R)-Piperidine-3-Carboxylic Acid(R)-Pyrrolidine-3-Carboxylic Acid(S)-(1-Piperidin-3-yl)-acetic acid(S)-(trifluoromethyl)-L-cysteine(S)-2-(Amino)-1,6-hexanedioic acid (AAD)(S)-2-Amino-2-cyclobutylacetic acid (Cbg)(S)-2-Amino-3-ethyl-pentanoic acid(S)-3-(1-Pyrrolidine-2-yl)-propionic acid(S)-4-Piperazine-2-carboxylic acid(S)-Piperidine-3-carboxylic acid(S)-Pyrrolidine-2-carboxylic acid (beta-P)[(2R)-4,4-Difluoropyrrolidin-2-yl]acetic acid1-(Aminomethyl)-cyclopropyl-1-carboxylic acid1,13-Diamino-4,7,10-trioxatridecan-succinamic acid12-Amino-4,7,10-trioxadodecanoic acid14-Amino-3,6,9,12-tetraoxatetradecanoic acid15-Amino-4,7,10,13-tetraoxa(Pen)tadecanoic acid17-Amino-3,6,9,12,15-(Pen)taoxaheptadecanoic acid18-Amino-4,7,10,13,16-(Pen)taoxaoctadecanoic acid1-Amino-3,6,9,12,15,18,21,24,27-nonaoxatriacontan-30-oic acid1-Amino-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oic acid1-Amino-3,6,9,12,15,18,21-heptaoxatetracosan-24-oic acid1-Amino-3,6,9,12,15,18-hexaoxahenicosan-21-oic acid1-Aminocyclobutane-1-carboxylic acid (ACBA)1-Benzyl-L-histidine (H(1-Bn))1-Methyl-L-histidine (H(1-Me))2-(Cyclohexylamino)acetic acid2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic)2,5-difluoro-L-phenylalanine2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid2-Amino-1,7-heptanedioic acid2-Amino-5,5,5-trifluoro-4-methyl-pentanoic acid2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid2-Aminoisobutyric acid (Aib)2-Chloro-L-phenylalanine ((2-Chloro)F)2-Fluoro-L-phenylalanine ((2-Fluoro)F)2-Methyl-D-alloisoleucine2-Methyl-L-phenylalanine ((2-Me)F)2-Methyl-L-Proline (2-Me)P,3-(1,3-Benzothiazol-2-yl)-L-alanine ((Bth)A)3-(Aminomethyl)benzoic acid3-(Trimethylsilyl)-L-alanine3-Amino-2,2-dimethylpropionic acid3-Aminomethylphenylacetic acid3-Azido-L-Alanine3-Carboxyphenylalanine3-Chloro-L-Phenylalanine3-Chlorophenylglycine ((3-Chloro-Ph)G)3-Cyano-L-phenylalanine3-Ethyl-L-Norvaline3-Fluoro-L-phenylalanine3-Methyl-L-phenylalanine4-(3,5-Dimethyl-1,2-oxazol-4-yl)-L-phenylalanine4-(Aminomethyl)benzoic acid4-Aminomethylphenylacetic acid4-Ethyl-L-norleucine4-Fluoro-Leucine ((4-Fluoro)L)4-Fluoro-L-phenylalanine ((4-Fluoro)F)5,5,5-Trifluoro-L-leucine ((Trifluoro)L)5-azaspiro[2.4]heptane-6-carboxylic acid6-Aminohexanoic acid (Ahx)8-Aminocubane-1-carboxylic acid9-Amino-4,7-dioxanonanoic acidallo-L-Isoleucine (allo-I)allo-L-Threonine (allo-T)Aminocyclobutanecarboxylic acid (ACBC)Aminoisobutyric acid (Aib)beta-Alanine (beta-A)Cyclohexylalanine (Cha)D-2-ChlorophenylalanineD-beta-ProlineD-cyclohexylalanineD-HydroxyprolineD-N-MethylalanineGamma-Aminobutyric acid (Gamma-Abu)Hydroxyproline (Hyp)Iminodiacetic acidL- Homoserine (hSer)L-1-Napthylalanine (1-Nal)L-2,3-Diaminopropionic acid (Dap)L-2,4-Diaminobutyric acid (Dab)L-2,6-DifluorophenylalanineL-2-Amino-4-cyanobutyric acidL-2-Aminobutyric acid (Abu)L-2-Bromophenylalanine ((2-Bromo)F)L-2-Napthylalanine (2-Nal)L-2-Pyridylalanine (2-Pal)L-2-ThienylalanineL-3-Bromophenylalanine ((3-Bromo)F)L-3-Methylhistidine (H(3-Me))L-3-Pyridylalanine (3-Pal)L-4,4-difluoroproline ((Difluoro)P)L-4-Aminophenylalanine ((4-Amino)F)L-4-BromophenylalanineL-4-PyridylalanineL-Citrulline (Cit)L-Cyclobutylalanine (Cba)L-CyclobutylglycindL-CyclohexylalanineL-CyclohexylglycineL-Cyclohexylglycine (Chg)L-CyclopentylalanineL-cyclopentylalanine (Cpa)L-Cyclopentylglycine (Cpg)L-CyclopropylmethylalanineL-DifluoromethylalanineL-Dihydroorotic acid (Hoo)L-HomocysteineL-Hydroxyproline (Hyp)L-Methionine-L-sulfoxideL-Methionine-sulfoneL-N,N-Dimethylalanine ((N,N-diMe)A)L-N-MethylalanineL-N-Methylcysteine ((N-Me)C)L-N-Methylisoleucine ((N-Me)I)L-N-Methylphenylalanine ((N-Me)F)L-Norleucine (Nle)L-Norvaline (Nva)L-Ornithine (Orn)L-Penicillamine (Pen)L-Phenylglycine (Phg)L-Pipecolic acid (Pip)L-PropargylglycineL-Pyroglutamic acid (Pyr)L-tert-Butylalanine ((tBu)A)L-tert-Butylglycine ((tBu)G)L-trans-3-Hydroxyproline ((3S-OH)P)L-TrifluoromethylalanineMorpholine-3-carboxylicN(5)-methyl-L-arginine ((Me)R)N-e-Isopropyl-L-lysineN-Methyl-Alanine (N-Me)AN-Methyl-Glycine ((N-Me)G)N-Phenylglycine ((N-Ph)G)Palmitic acid (Palm)rel-(1R,2S)-2-Amino-1-cyclopentanecarboxylic acid (ACPC)rel-(1R,3R,5R,6R)-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acidrel-(1R,35)-3-[(Amino)methyl]cyclohexanecarboxylic acidrel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1)rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2)S-2-amino-3-ethyl-pentanoic acidS-3-1-Pyrrolidin-2-yl-propionic acidTranexamic acid (Tranexamic)trans-2-(3-(Amino)cyclohexyl)acetic acidtrans-4-Fluoroproline ((trans-4-Fluoro)P)3-Amino-3-methylbutyric acid

[0018] More preferred unnatural amino acid are selected from a list consisting of N-Methyl-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid, L-3-Bromophenyl-alanine ((3-Bromo)F), L-N,N-Dimethylalanine ((N,N-diMe)A), N,N-Dimethylglycine ((N,N-diMe)G), N-Phenylglycine ((N-Ph)G), (R)-Piperidine-3-carboxylic acid, (S)-Piperidine-3-carboxylic acid, L-tert-Butylalanine ((tBu)A), L-2-Pyridylalanine (2-Pal), L-3-Pyridylalanine (3-Pal), L-4-Pyridylalanine (4-Pal), 3-(Aminomethyl)benzoic acid, 3-Amino-2,2-dimethylpropionic acid, 3-Amino-3-methylbutyric acid, 4-(Aminomethyl)benzoic acid, L-2-Aminobutyric acid (Abu), 1-Aminocyclobutane-1-carboxylic acid (ACBA), 6-Aminohexanoic acid (Ahx), 2-Aminoisobutyric acid (Aib), L-2-Thienylalanine (beta-2-thienylalanine), beta-Alanine (beta-A), beta-Proline (beta-P), L-Citrulline (Cit), L-2,4-Diaminobutyric acid (Dab), L-2,3-Diaminopropionic acid (Dap), Gamma-Aminobutyric acid (Gamma-Abu), L-3-Methylhistidine (3-Me)H), L-Dihydroorotic acid (Hoo), L-Norleucine (Nle), N-Methyl-L-proline ((N-Me)P), L-Norvaline (Nva), L-Ornithine (Orn), L-Pipecolic acid (Pip), (2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid; 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), L-N-Methylcysteine ((N-Me)C), N(5)-methyl-L-arginine ((Me)R), L-Penicillamine (Pen) and Tranexamic acid (Tranexamic).

[0019] Most preferred unnatural amino acid are selected from a list consisting of N-Methyl-L-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), L-Norleucine (Nle), L-Norvaline (Nva), L-Ornithine (Orn), N(5)-methyl-L-arginine ((Me)R), L-tert-Butylalanine ((tBu)A), 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen).

[0020] It should be further understood, that a peptide according to the disclosure can contain one or more chemical groups which are no amino acid under the definition of the present disclosure. These chemical groups can be present at the N- and / or C-terminal ends of a peptid and are represented by formula X 0< and X 15< . It should be understood that all amino acids and chemical groups of the peptids of the present disclosure are connected via peptide (amide) bonds. Generally peptides are formed by linking α-amino and carboxy groups of α-amino acids, which are then linked by α-peptide bonds. According to the present disclosure a peptide bond can be formed by any carboxyl- and amino group being present in a respective natural or unnatural amino acid. For example, α-amino acids which contain a second amino group in addition to the α-amino group (e.g. L-lysine) or α-amino acids which, in addition to the α-carboxy group, contain a second carboxy group, (eg. L-aspartic acid and L-glutamic acid) can be connected via the additional amino- or carboxy group.

[0021] In accordance with the understanding of a person skilled in the art, the peptide sequences disclosed herein represent sequences of amino acids, which are connected via α-peptide bonds. An amino acid linked via a peptide bond, which is not an α-peptide bond, are marked by a "*". The "*" is either on the left or the right side of the amino acid, to illustrate wether the additional amino group or the additional carboxy group of that amino acid is used for the peptide bond to the adjoining amino acid (e.g. (*L), (E*), (*Dap) etc.).

[0022] In accordance with the understanding of a person skilled in the art, the peptide sequences disclosed herein are shown proceeding from left to right, with the left end of the sequence being the "N-terminus" ("amino terminus", "N-terminal end") of the peptide and the right end of the sequence being the "C-terminus" ("carboxy terminus", "C-terminal end") of the peptide. This terminology N-terminus (amino terminus, N-terminal end)" applies irrespective of whether the peptide actually contains an amino group at the N-terminus. This terminology C-terminus (carboxy terminus, C-terminal end) applies irrespective of whether the peptide actually contains a carboxy group at the C-terminus. The term "terminal amino group" refers to any amino group present at the N-terminus. The term "terminal carboxyl group" refers to any carboxyl group present at the C-terminus.

[0023] According to the present disclosure, the N-terminus can be formed by X 0< , in case p represents 1, which is not encompassed by the wording of the claims,. Alternatively the N-terminus can be formed by X 1< , in case q represents at least 1 and p represents 0, which is not encompassed by the wording of the claims. Alternatively the N-terminus can be formed by X 2< , in case r represents 1 and p and q both represent 0, which is not encompassed by the wording of the claims. In case p, q and r all represent 0, the N-terminus is formed by X 3< in case of a linear peptide, which is not encompassed by the wording of the claims. In case the peptide of the present invention is cyclized via a linkage connecting X 3< and X 11< and p, q and r all represent 0, the peptid does not comprise an N-terminus.

[0024] According to the present disclosure the C-terminus can be formed by X 15< in case u represents 1, which is not encompassed by the wording of the claims. Alternatively the the C-terminus can be formed by X 14< , in case t represents an integer of at least 1 and u represents 0. Alternatively the C-terminus can be formed by X 13< , in case s represents 1 and t and u both represent 0, which is not encompassed by the wording of the claims. In case s, t and u all represent 0, the C-terminus is formed by X 12< , which is not encompassed by the wording of the claims.

[0025] In the present disclosure the names of naturally occurring and non-naturally occurring aminoacyl residues used herein are preferably following the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in Nomenclature of a-Amino Acids (Recommendations, 1974), Biochemistry, 14(2), (1975).

[0026] In the present specification naturally occurring proteinogenic amino acids are usually designated by their conventional single-letter abbreviations. Alternatively, they can also be referred to by their three-letter abbreviations (e.g. in particular in the sequence listings) or by their full name as shown in Table 2 below: Table 2: Standard Abbreviations for Natural Amino Acids3-Letter 1-Letter Amino Acid AlaAAlanineArgRArginineAsnNAsparagineAspDAspartic acidCysCCysteineGluEGlutamic acidGlnQGlutamineGlyGGlycineHisHHistidineIleIIsoleucineLeuLLeucineLysKLysineMetMMethioninePheFPhenylalanineProPProlineSerSSerineThrTThreonineTrpWTryptophanTyrYTyrosineValVValine

[0027] In the case of non-proteinogenic or non-naturally occurring amino acids, unless they are referred to by their full name (e.g. ornithine, etc.), frequently employed three- to six-character codes are employed for residues thereof, including those abbreviations as indicated in the abbreviation list below (Table 3).

[0028] The term "L-amino acid" as used herein refers to the "L" isomeric form of an amino acid, and conversely the term "D-amino acid" refers to the "D" isomeric form of an amino acid. It is further a conventional manner to indicate the L-amino acid with capital letters such as Ala / A, Arg / R, etc. and the D-amino acid with small letters such as ala / a, arg / r, etc.

[0029] The three-letter code in the form as indicated in Table 2 above, i.e. Ala, Arg, Asn etc. and as generally used in the present specification, shall generally comprise the D- and L- form as well as homo- and nor-forms, unless explicitly indicated otherwise. The prefix "nor" refers to a structural analog that can be derived from a parent compound by the removal of one carbon atom along with the accompanying hydrogen atoms. The prefix "homo" indicates the next higher member in a homologous series. A reference to a specific isomeric form will be indicated by the capital prefix L- or D- as described above (e.g. D-Arg, L-Arg etc.). A specific reference to homo- or nor-forms will accordingly be explicitly indicated by a respective prefix (e.g. homo-Arg, homo-R, nor-Arg, nor-R, homo-Cys, homo-C etc.).

[0030] The term "C 1 -C 6 -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms ("C 1 -C 4 -alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms ("C 1 -C 3 -alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group. Particularly preferred is methyl, ethyl, n-propyl. Most preferred is methyl.

[0031] The term "C 1 -C 20 -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, to 20 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, tert-butyl or pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodecyl or eicosyl.

[0032] The term "C 1 -C 4 -alkylene" means a straight-chain or branched hydrocarbon bridge having 1 to 4 carbon atoms, e.g. methylene, ethylene, propylene, (a-methylethylene, β-methylethylene, α-ethylethylene, β-ethylethylene, butylene, α-methylpropylene, β-methylpropylene and γ-methylpropylene.

[0033] The term "C 1 -C 6 -alkylene" means a straight-chain or branched hydrocarbon bridge having 1 to 6 carbon atoms, e.g. methylene, ethylene, propylene, (a-methylethylene, β-methylethylene, α-ethylethylene, β-ethylethylene, butylene, α-methylpropylene, β-methylpropylene, γ-methylpropylene, α-ethylpropylene, β-ethylpropylene, γ-ethylpropylene, pentylene and hexylene.

[0034] The term "C 3 -C 8 -cycloalkyl" means a saturated hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms. Said C 3 -C 8 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl, or a bridged or caged saturated ring groups such as norborane or adamantane, and cubane.

[0035] The term "C 3 -C 7 -heterocycloalkyl" means a saturated heterocycle with 4, 5, 6 or 7 which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocy-cloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said C 3 -C 7 -heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6 membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, hexahydropyrimidinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example, or a 7 membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl, for example.

[0036] The term "aryl" means an unsaturated or partially unsaturated cycle having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

[0037] The term "heteroaryl" means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5 to 14 membered heteroaryl" group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and / or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency). Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

[0038] In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridine-2-yl, pyridine-3-yl and pyridine-4-yl; or the term thienyl includes thien-2 yl-and thien-3-yl.

[0039] Among sequences disclosed herein are sequences incorporating either an "-OH" moiety or an "-NH 2 " moiety at the carboxy terminus (C-terminus) of the sequence. An "-OH" or an "-NH 2 " moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, corresponding to the presence of a carboxy group or an amido (-(C=O)-NH 2 ) group at the C-terminus, respectively. In each sequence of the invention, a C-terminal "-OH" moiety may be substituted for a C-terminal "-NH 2 " moiety, which is also refered to as "amidated C-terminus" in the present invention, and vice-versa. However, among said alternatives a C-terminal "-OH" moiety is preferred.

[0040] The term "acetylated" (also abbreviated "Ac") refers to an acetyl protection of the N-terminal moiety through acetylation of the N-terminus of a peptide (N-terminus of the peptide is acetylated).

[0041] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 0< is a chemical group selected from the list consisting of, (1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylacetic acid, (2,4-Dioxoimidazolidin-1-yl)acetic acid, 2-(Thiomorpholine)acetic acid ((2-Thiomorpholine)acetyl), 2-(N-Isopropyl-N-methylamino)acetic acid, (S)-3-Methylvaleric acid ((S)-3-Methylpentanoic acid), 2-(3-Pyridyl)acetic acid, 2-(Cyclohexylamino)acetic acid (2-(Cyclohexylamino)acetyl), 2-(Di-ethylamino)acetic acid (2-(Diethylamino)acetyl), 2-(Morpholine)acetic acid (2-(Morpholine)acetyl), 2-(N-Methyl-N-cyclopropylamino)acetic acid (2-(N-Methyl-N-cyclopropylamino)acetyl), 2-(Piperi-din)acetic acid (2-(Piperidin)acetyl), 2-(Pyrrolidine)acetic acid (2-(Pyrrolidine)acetyl), 2-Hydroxyacetic acid (2-Hydroxyacetyl), 2-Hydroxyisobutyric acid (2-Hydroxyisobutyric), 3-(Aminomethyl)benzoic acid, 3-Methoxypropionic acid, 4-(Aminomethyl)benzoic acid, 4-Methylpentanoic acid (4-Methylvaleric), 5-Chorothiophene-carboxylic acid, 1-(Aminomethyl)-cyclopropyl-1-carboxylic acid (ACMP), Adipic acid, (S)-Azetidine-2-carboxylic acid, Benzoic acid (Benzoic), 4-(3,5-Dimethyl-1,2-oxazol-4-yl)-L-phenylalanine, Cyclobutanecarboxylic acid (Cyclobutanecarboxylic), 2-(Cyclobutyl)acetic acid (Cyclobutylacetic), Cyclobutylacetic acid (Cyclobutylacetic), Cyclohexylacetic acid (Cyclohexylacetic), Cyclohexanecarboxylic acid (Cyclohexylcarboxylic), Cyclopentanecarboxylic acid, Cyclopentylacetic acid (Cyclopentylacetic), Cyclopropanecarboxylic acid (Cyclopropanecarboxylic), Cyclopropylacetic acid, D-(+)Biotin, Fumaric acid, 3-Phenylpropanoic acid (Hydrocinnamic), Isobutyric acid, Isovaleric acid (Isovaleric), L-(+)-Lactic acid (Lactic), Phenylacetic acid, Piperidin-4-ylacetic acid, Pivalic acid (Pivalic), Suberic acid, tert-Butylacetic acid, Tetrahydropyranyl-4-acetic acid, Tetrahydro-2H-pyran-3-ylacetic acid and trans-2-(3-((t-butoxy)carbonylamino)cyclohexyl)acetic acid), prepresents the integer 0 or 1, X 1< represents a natural amino acid selected from the list consisting of A, F, G, H, I, K, L, P, R, S, T, V, W and Y or an unnatural amino acid selected from a list consisting of N-Methyl-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid, L-3-Bromophe-nylalanine ((3-Bromo)F), L-N,N-Dimethylalanine ((N,N-diMe)A), N,N-Dimethylglycine ((N,N-diMe)G), N-Phenylglycine ((N-Ph)G), (R)-Piperidine-3-carboxylic acid, (S)-Piperidine-3-carboxylic acid, L-tert-Butylalanine ((tBu)A), L-2-Pyridylalanine (2-Pal), L-3-Pyridylalanine (3-Pal), L-4-Pyridyl-alanine (4-Pal), 3-(Aminomethyl)benzoic acid, 3-Amino-2,2-dimethylpropionic acid, 3-Amino-3-me-thylbutyric acid, 4-(Aminomethyl)benzoic acid, L-2-Aminobutyric acid (Abu), 1-Aminocyclobutane-1-carboxylic acid (ACBA), 6-Aminohexanoic acid (Ahx), 2-Aminoisobutyric acid (Aib), L-2-Thienylal-anine (beta-2-thienylalanine), beta-Alanine (beta-A), beta-Proline (beta-P), L-Citrulline (Cit), L-2,4-Di-aminobutyric acid (Dab), L-2,3-Diaminopropionic acid (Dap), Gamma-Aminobutyric acid (Gamma-Abu), L-3-Methylhistidine (3-Me)H), L-Dihydroorotic acid (Hoo), L-Norleucine (Nle), N-Methyl-L-proline ((N-Me)P), L-Norvaline (Nva), L-Ornithine (Orn), L-Pipecolic acid (Pip), (2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid and Tranexamic acid (Tranexamic), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, qrepresents an integer of from 0 to 5, X 2< represents the natural amino acid I or an unnatural amino acid selected from a list consisting of L-N-Methylisoleucine ((N-Me)I), allo-L-Isoleucine (allo-I), L-Cyclobutylalanine (Cba), L-Norvaline (Nva), L-2-Aminobutyric acid (Abu), (2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoic acid, (2S,3S)-2-[2-Oxopiperazin-1-yl]-3-methylpentanoic acid and (2S,3S)-2-[(3S)-2-oxopi-perazin-1-yl]-3-methylpentanoic acid, whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen), X 4< represents a natural amino acid selected from a list consisting of S, C, T, R and K, X 5< represents the natural amino acid R or the unnatural amino acid N(5)-methyl-L-arginine ((Me)R), X 6< represents the natural amino acid S, or an unnatural amino acid selected from a list consisting of allo-L-Threonine (allo-T) and L-2,3-diaminopropionic acid (Dap), X 7< represents a natural amino acid selected from a list consisting of L and N, or an unnatural amino acid selected from a list consisting of 2,5-Difluoro-L-phenylalanine ((2,5-Difluoro)F), L-2-Bromophenylal-anine ((2-Bromo)F), 2-Chloro-L-phenylalanine ((2-Chloro)F), L-4-Bromophenylalanine ((4-Bromo)F), 4-Fluoro-L-Leucine ((4-Fluoro)L), L-tert-Butylalanine ((tBu)A), L-tert-Butylglycine ((tBu)G), 5,5,5-Trifluoro-L-leucine ((Trifluoro)L), (S)-2-(Amino)-1,6-hexanedioic acid (AAD), (2S)-2-amino-4,4,4-tri-fluorobutanoic acid, L-2-amino-4-cyanobutyric acid (Cnba), (S)-(trifluoromethyl)-L-cysteine, (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid, (2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acid, 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), 3-(Trimethylsilyl)-L-alanine and 2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid, X 8< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, (1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, trans-4-fluoroproline ((trans-4-Fluoro)P), L-Hydroxyproline (Hyp), (3S)-Morpholine-3-carboxylic acid (Morpholine-3-carboxylic), L-Pipecolic acid (Pip) and (4aR,6aR,9S,11aS)-11-Oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid, X 9< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), (6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, rel-(1R,3R,5R,6R)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P), (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid, (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S)-2-Amino-4,4,4-trifluorobutanoic acid, L-trans-3-hydroxyproline ((3S-OH)P, trans-4-fluoroproline ((trans-4-Fluoro)P), L-Hydroxyproline (Hyp), (2S,4S)-4-Fluoroproline ((cis-4-Fluoro)P), (3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1) and (3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2), X 10< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of (2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid, 3-Chlorophenylglycine ((3-Chloro-Ph)G), (S)-2-amino-3-ethyl-pentanoic acid, allo-L-Isoleucine (allo-I), L-Cyclohexylglycine (Chg), L-Cyclopentylglycine (Cpg), L-Cyclobutylglycine and L-Norvaline (Nva), X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen), X 12< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid, (S)-2-Amino-2-cyclobutylacetic acid (Cbg), allo-L-Isoleucine (allo-I), L-Phenylglycine (Phg), 2-methyl-D-alloisoleucine and (2S,3S)-2-((amino)methyl)-3-methylpentanoic acid, and in case u and t and s are all 0, the terminal carboxyl group of X 12< is unsubstituted or amidated, X 13< represents a natural amino acid selected from a list consisting of P, A and D or an unnatural amino acid selected from a list consisting of 2-Methyl-L-Proline (2-Me)P, N-Methyl-Glycine ((N-Me)G), trans-4-fluoroproline ((trans-4-Fluoro)P), L-2-Aminobutyric acid (Abu), 2-Aminoisobutyric acid (Aib), Hydroxyproline (Hyp) and 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, and in case u and t are both 0 and s is different from 0, the terminal carboxyl group of X 13< is unsubstituted or amidated, srepresents an integer of from 0 to 3, X 14< represents a natural amino acid selected from a list consisting of D, E, G, K, N, P and Q or an unnatural amino acid selected from a list consisting of 3-Carboxyphenylalanine ((3-Carboxy)F), (2S)-2-Amino-4-(benzylamino)-4-oxobutanecarboxylic acid ((N-Benzyl)D), N-Methyl-Glycine ((N-Me)G), 6-Aminohexanoic acid (Ahx), (2S)-Pyrrolidin-2-ylacetic acid (beta-homo-P), L-2,3-Diaminopropionic acid (Dap), L-Ornithine (Orn) and Tranexamic acid (Tranexamic), and in case u is 0 and t is different from 0, the terminal carboxyl group of X 14< is unsubstituted or amidated, whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, trepresents an integer of from 0 to 4, X 15< is a chemical group selected from the list consisting of (1R,3S)-3-(Amino)cyclopentanecarboxylic acid, (1S,3R)-3-(Amino)cyclopentanecarboxylic acid, (R)-4-Amino-6-methylheptanoic acid, (S)-(1-Piperidin-3-yl)-acetic acid, (S)-3-(1-Pyrrolidine-2-yl)-propionic acid, (S)-3-(2H-tetrazol-5-yl)propanoic acid, (S)-Pyrrolidine-3-carboxylic acid, 5-Azaspiro[2.4]heptane-1-carboxylic acid and (2S)-3-(Triazol-1-yl)-2-(amino)propanoic acid, urepresents the integer 0 or 1, with the proviso that the peptide contains at least one unnatural amino acid.

[0042] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 0< is a chemical group selected from the list consisting of (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid, (2-Thiomorpholine)acetic acid, (N-Isopropyl-N-methylamino)acetic acid, 2-(3-Pyridyl)acetic acid, 2-(Cyclohexylamino)acetic acid, 2-(Diethylamino)acetic acid, 2-(Morpholine)acetic acid, 2-(Piperidin)acetic acid, 2-(Pyrrolidine)acetic acid, 3-(Aminomethyl)benzoic acid, 4-(Aminomethyl)benzoic acid, 1-(Aminomethyl)-cyclopropyl-1-carboxylic acid (ACMP), Azetidine-2-carboxylic acid, Benzoic acid, Cyclobutylacetic acid, Cyclopropylacetic acid, Phenylacetic acid, Piperidin-4-ylacetic acid, Tetrahydro-2H-pyran-3-ylacetic acid, Tranexamic acid and trans-2-(3-((t-butoxy)carbonylamino)cyclohexyl)acetic acid, prepresents the integer 0 or 1, X 1< represents a natural amino acid selected from a list consisting of A, F, G, H, I, K, L, P, R, S, T, V, W and Y or an unnatural amino acid selected from a list consisting of L-N,N-Dimethylalanine ((N,N-diMe)A), N-Methyl-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), L-2-Pyridylalanine (2-Pal), L-3-Pyridylalanine (3-Pal), L-4-Pyridylalanine (4-Pal), L-2-Aminobutyric acid (Abu), 6-Aminohexanoic acid (Ahx), 2-Aminoisobutyric acid (Aib), 3-(Aminomethyl)benzoic acid, 3-Amino-2,2-dimethylpropionic acid, 3-Amino-3-methylbutyric acid, 4-(Aminomethyl)benzoic acid, beta-2-thienylalanine, (S)-Pyrrolidine-2-carboxylic acid (beta-P), L-Citrulline (Cit), L-2,4-diaminobutyric acid (Dab), L-2,3-diaminopropionic acid (Dap), Gamma-Aminobutyric acid (Gamma-Abu), L-3-Methylhistidine (H(3-Me)), L-Dihydroorotic acid (Hoo), L-Norleucine (Nle), L-Norvaline (Nva), L-Ornithine (Orn), L-Pipecolic acid (Pip), N-Methyl-L-proline ((N-Me)P), Tranexamic acid (Tranexamic), (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid and (2S)-2[(amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid, whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, qrepresents an integer of from 0 to 5, X 2< represents the natural amino acid I or an unnatural amino acid selected from a list consisting of L-N-Methylisoleucine ((N-Me)I), L-Cyclobutylalanine (Cba), L-Norvaline (Nva) and L-2-Aminobutyric acid (Abu), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen), X 4< represents a natural amino acid selected from a list consisting of S and T, X 5< represents the natural amino acid R, X 6< represents the natural amino acid S or the unnatural amino acid allo-L-Threonine (allo-T), X 7< represents a natural amino acid selected from a list consisting of N and L, or an unnatural amino acid selected from a list consisting of 2,5-Difluoro-L-phenylalanine ((2,5-Difluoro)F), L-2-Bromophenyl-alanine ((2-Bromo)F), 2-Chloro-L-phenylalanine ((2-Chloro)F), 4-Fluoro-L-Leucine ((4-Fluoro)L), L-tert-Butylalanine ((tBu)A), (S)-(trifluoromethyl)-L-cysteine, (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid and 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), 3-(Trimethylsilyl)-L-alanine, X 8< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and (4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid, X 9< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), (2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P), (6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, rel-(1R,3R,SR,6R)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid, rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1) and rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2), X 10< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of (2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid, (S)-2-amino-3-ethyl-pentanoic acid, L-Cyclohexylglycine (Chg) and L-Cyclopentylglycine (Cpg), X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen), X 12< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of allo-L-Isoleucine (allo-I), (S)-2-Amino-2-cyclobutylacetic acid (Cbg) and 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid, and in case u and t and s are all 0, the terminal carboxyl group of X 12< is unsubstituted or amidated, X 13< represents a natural amino acid selected from a list consisting of P and D or an unnatural amino acid selected from a list consisting of 2-Aminoisobutyric acid (Aib), 2-Methyl-L-Proline (2-Me)P and trans-4-fluoroproline ((trans-4-Fluoro)P), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, and in case u and t are both 0 and s is different from 0, the terminal carboxyl group of X 13< unsubstituted or amidated, srepresents an integer of from 0 to 3, X 14< represents a natural amino acid selected from a list consisting of D, Q, N, E and P or an unnatural amino acid selected from a list consisting of 3-Carboxyphenylalanine ((3-Carboxy)F), N-Methyl-Glycine ((N-Me)G), (2S)-Pyrrolidin-2-ylacetic acid (beta-homo-P), L-2,3-Diaminopropionic acid (Dap), L-Ornithine (Orn) and Tranexamic acid (Tranexamic), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration, and in case u is 0 and t is different from 0, the terminal carboxyl group of X 14< is unsubstituted or amidated, trepresents an integer of from 0 to 4, X 15< is a chemical group selected from the list consisting of (1R,3S)-3-(Amino)cyclopentanecarboxylic acid, (1S,3R)-3-(Amino)cyclopentanecarboxylic acid, (R)-4-Amino-6-methylheptanoic acid, (S)-(1-Piperidin-3-yl)-acetic acid, (S)-3-(1-Pyrrolidine-2-yl)-propionic acid, (S)-3-(2H-tetrazol-5-yl)propanoic acid, (S)-Pyrrolidine-3-carboxylic acid, 5-Azaspiro[2.4]heptane-1-carboxylic acid and (2S)-3-(Triazol-1-yl)-2-(amino)propanoic acid, urepresents the integer 0 or 1, with the proviso that the peptide contains at least one unnatural amino acid.

[0043] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein prepresents an integer of 0, X 1< represents a natural amino acid selected from the list consisting of A and G or an unnatural amino acid selected from a list consisting of N-Methyl-L-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), L-Norleucine (Nle), L-Norvaline (Nva) and L-Ornithine (Orn), qrepresents the integer 0 or 1, X 2< represents the natural amino acid I, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen), X 4< represents the natural amino acid S, X 5< represents the natural amino acid R or the unnatural amino acid N(5)-methyl-L-arginine ((Me)R), X 6< represents the natural amino acid S, X 7< represents the natural amino acid L or the unnatural amino acid L-tert-Butylalanine ((tBu)A), X 8< represents the natural amino acid P, X 9< represents the natural amino acid P or the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), X 10< represents the natural amino acid I, X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen), X 12< represents the natural amino acid I, and in case u and t and s are all 0, the terminal carboxyl group of X 12< is unsubstituted or amidated, X 13< represents the natural amino acid P, and in case u and t are both 0 and s is different from 0, the terminal carboxyl group of X 13< is unsubstituted or amidated, srepresents the integer 0 or 1, X 14< represents a natural amino acid selected from a list consisting of D, Q and E, and in case u is 0 and t is different from 0, the terminal carboxyl group of X 14< is unsubstituted or amidated, trepresents the integer 0 or 1, urepresents an integer of 0, with the proviso that the peptide contains at least one unnatural amino acid.

[0044] According to a further embodiment, which is not encompassed by the wording of the claims,the disclosure provides a compound containing a peptide of the following formula (II),         (X 1< ) q (X 2< ) r X 3< X 4< X 5< X 6< X 7< X 8< X 9< X 10< X 11< X 12< (X 13< ) s (X 14< ) t      (II), or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 1< represents a natural amino acid selected from a list consisting of A and G, or an unnatural amino acid selected from a list consisting of N-Methyl-L-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), L-Norleucine (Nle), L-Norvaline (Nva) and L-Ornithine (Orn), qrepresents the integer 0 or 1, X 2< represents the natural amino acid I, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen), X 4< represents the natural amino acid S, X 5< represents the natural amino acid R or the unnatural amino acid N(5)-Methyl-L-arginine ((Me)R), X 6< represents the natural amino acid S, X 7< represents the natural amino acid L or the unnatural amino acid L-tert-Butylalanine ((tBu)A), X 8< represents the natural amino acid P or the unnatural amino acid L-Proline (3,4- 2 H), X 9< represents the natural amino acid P or the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), X 10< represents the natural amino acid I, X 11< represents an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen), X 12< represents the natural amino acid I, X 13< represents the natural amino acid P, srepresents the integer 0 or 1, X 14< represents a natural amino acid selected from a list consisting of D, Q and E, trepresents the integer 0 or 1, wherein the N-terminus of the peptide is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl, wherein the C-terminus of the peptide is unsubstituted or amidated, and wherein the peptide is cyclized via a linkage connecting X 3< and X 11< .

[0045] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides a compound containing a peptide of formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 1< represents a natural amino acid or an unnatural amino acid, qrepresents the integer 0 or 1, X 2< represents the natural amino acid I, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen), X 4< represents the natural amino acid S, X 5< represents the natural amino acid R or the unnatural amino acid N(5)-Methyl-L-arginine ((Me)R), X 6< represents the natural amino acid S, X 7< represents the natural amino acid L or the unnatural amino acid L-tert-Butylalanine ((tBu)A), X 8< represents the natural amino acid P or the unnatural amino acid L-Proline (3,4- 2 H), X 9< represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), X 10< represents the natural amino acid I, X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen), X 12< represents the natural amino acid I, X 13< represents the natural amino acid P, srepresents the integer 0 or 1, X 14< represents a natural amino acid selected from a list consisting of D, Q and E, trepresents the integer 0 or 1, wherein the N-terminus of the peptide is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl, wherein the C-terminus of the peptide is unsubstituted or amidated, and wherein the peptide is cyclized via a linkage connecting X 3< and X 11< .

[0046] According to a further embodiment, which is not encompassed by the wording of the claims the disclosure provides a compound containing a peptide of formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 1< represents a natural amino acid selected from a list consisting of A and G, or an unnatural amino acid selected from a list consisting of N-Methyl-L-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), L-Norleucine (Nle), L-Norvaline (Nva) and L-Ornithine (Orn), qrepresents the integer 0 or 1, X 2< represents the natural amino acid I, rrepresents the integer 0 or 1, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen), X 4< represents the natural amino acid S, X 5< represents the natural amino acid R or the unnatural amino acid N(5)-Methyl-L-arginine ((Me)R), X 6< represents the natural amino acid S, X 7< represents the natural amino acid L or the unnatural amino acid L-tert-Butylalanine ((tBu)A), X 8< represents the natural amino acid P or the unnatural amino acid L-Proline (3,4- 2 H), X 9< represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), X 10< represents the natural amino acid I, X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen), X 12< represents the natural amino acid I, X 13< represents the natural amino acid P, srepresents the integer 0 or 1, X 14< represents a natural amino acid selected from a list consisting of D, Q and E, trepresents the integer 0 or 1, wherein the N-terminus of the peptide is unsubstituated or acetylated, wherein the C-terminus of the peptide is unsubstituted or amidated, and wherein the peptide is cyclized via a linkage connecting X 3< and X 11< .

[0047] In particular, the disclosure provides compounds containing a peptide of the formula (II), which are not encompassed by the wording of the claims.

[0048] According to the disclosure, the following definitions of X 1< to X 14< apply to peptides of formula (II) which are not encompassed by the wording of the claims.

[0049] According to the present disclosure X 0< , if present, can be a chemical group which is not an amino acid, according to the definition herein, which is not encompassed by the wording of the claims

[0050] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 0< represents a chemical group selected from the list consisting of 2-cyanobenzoic acid, (1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylacetic acid, (2,4-Dioxoimidazolidin-1-yl)acetic acid, 2-(Thiomorpholine)acetic acid ((2-Thiomorpholine)acetyl), 2-(N-Isopropyl-N-methylamino)acetic acid, (S)-3-Methylvaleric Acid ((S)-3-Methylpentanoic acid), 2-(3-Pyridyl)acetic acid, 2-(Cyclohexylamino)acetic acid (2-(Cyclohexylamino)acetyl), 2-(Diethylamino)acetic acid (2-(Diethylamino)acetyl), 2-(Morpholine)acetic acid (2-(Morpholine)acetyl), 2-(N-Methyl-N-cyclopropylamino)acetic acid (2-(N-Methyl-N-cyclopropylamino)acetyl), 2-(Piperidin)acetic acid (2-(Piperidin)acetyl), 2-(Pyrrolidine)acetic acid (2-(Pyrrolidine)acetyl), 2-Hydroxyacetic acid (2-Hydroxyacetyl), 2-Hydroxyisobutyric acid (2-Hydroxyisobutyric), 3-(Aminomethyl)benzoic acid, 3-Methoxypropionic acid, 4-(Aminomethyl)benzoic acid, 4-Methylpentanoic acid (4-Methylvaleric), 5-Chorothiophene-carboxylic acid, 1-(Aminomethyl)-cyclopropyl-1-carboxylic acid (ACMP), Adipic acid, (S)-Azetidine-2-carboxylic acid, Benzoic acid (Benzoic), 4-(3,5-Dimethyl-1,2-oxazol-4-yl)-L-phenylalanine, Cyclobutanecarboxylic acid (Cyclobutanecarboxylic), 2-(Cyclobutyl)acetic acid (Cyclobutylacetic), Cyclobutylacetic acid (Cyclobutylacetic), Cyclohexylacetic acid (Cyclohexylacetic), Cyclohexanecarboxylic acid (Cyclohexylcarboxylic), Cyclopentanecarboxylic acid, Cyclopentylacetic acid (Cyclopentylacetic), Cyclopropanecarboxylic acid (Cyclopropanecarboxylic), Cyclopropylacetic acid, D-(+)Biotin, Fumaric acid, 3-Phenylpropanoic acid (Hydrocinnamic), Isobutyric acid, Isovaleric acid (Isovaleric), L-(+)-Lactic acid (Lactic), Phenylacetic acid, Piperidin-4-ylacetic acid, Pivalic acid (Pivalic), Suberic acid, tert-Butylacetic acid, Tetrahydropyranyl-4-acetic acid, Tetrahydro-2H-pyran-3-ylacetic acid and trans-2-(3-((t-butoxy)carbonylamino)cyclohexyl)acetic acid).

[0051] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 0< represents a chemical group selected from the list consisting of 2-cyanobenzoic acid, (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid, (2-Thiomorpholine)acetic acid, (N-Isopropyl-N-methyla-mino)acetic acid, 2-(3-Pyridyl)acetic acid, 2-(Cyclohexylamino)acetic acid, 2-(Diethylamino)acetic acid, 2-(Morpholine)acetic acid, 2-(Piperidin)acetic acid, 2-(Pyrrolidine)acetic acid, 3-(Aminomethyl)benzoic acid, 4-(Aminomethyl)benzoic acid, 1-(Aminomethyl)-cyclopropyl-1-carboxylic acid (ACMP), Azetidine-2-carboxylic acid, Benzoic acid, Cyclobutylacetic acid, Cyclopropylacetic acid, Phenylacetic acid, Piperidin-4-ylacetic acid, Tetrahydro-2H-pyran-3-ylacetic acid, Tranexamic acid and trans-2-(3-((t-butoxy)carbonylamino)cyclohexyl)acetic acid.

[0052] According to a further embodiment of the disclosure, which is not encompassed by the wording of the claims, X 0< is a chemical group selected from an unnatural amino acid as defined above, 2-cyanobenzoic acid, a substituted benzoic acid or phenyl acetic acids.

[0053] According to a further embodiment of the disclosure, which is not encompassed by the wording of the claims, X 0< is Hoo, ODD or Ahx.

[0054] According to a further embodiment of the disclosure, which is not encompassed by the wording of the claims, p represents an integer of 1.

[0055] According to a further embodiment of the disclosure, p represents an integer of 0.

[0056] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 1< represents any natural amino acid, or an unnatural amino acid, preferably selected from a list consisting of unnatural amino acids listed in table 1, whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0057] According to a further embodiment of the disclosure, which is not encompassed by the wording of the claims, X 1< represents a natural amino acid selected from a list consisting of A, F, G, H, I, K, L, P, R, S, T, V, W and Y, or an unnatural amino acid selected from a list consisting of N-Methyl-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid, L-3-Bromo-phenylalanine ((3-Bromo)F), L-N,N-Dimethylalanine ((N,N-diMe)A), N,N-Dimethylglycine ((N,N-diMe)G), N-Phenylglycine ((N-Ph)G), (R)-Piperidine-3-carboxylic acid, (S)-Piperidine-3-carboxylic acid, L-tert-Butylalanine ((tBu)A), L-2-Pyridylalanine (2-Pal), L-3-Pyridylalanine (3-Pal), L-4-Pyridylal-anine (4-Pal), 3-(Aminomethyl)benzoic acid, 3-Amino-2,2-dimethylpropionic acid, 3-Amino-3-methyl-butyric acid, 4-(Aminomethyl)benzoic acid, L-2-Aminobutyric acid (Abu), 1-Aminocyclobutane-1-carboxylic acid (ACBA), 6-Aminohexanoic acid (Ahx), 2-Aminoisobutyric acid (Aib), L-2-Thienylalanine (beta-2-thienylalanine), beta-Alanine (beta-A), beta-Proline (beta-P), L-Citrulline (Cit), L-2,4-Diamino-butyric acid (Dab), L-2,3-Diaminopropionic acid (Dap), Gamma-Aminobutyric acid (Gamma-Abu), L-3-Methylhistidine (3-Me)H), L-Dihydroorotic acid (Hoo), L-Norleucine (Nle), N-Methyl-L-proline ((N-Me)P), L-Norvaline (Nva), L-Ornithine (Orn), L-Pipecolic acid (Pip), (2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid and Tranexamic acid (Tranexamic), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0058] According to a further embodiment of the disclosure, which is not encompassed by the wording of the claims, X 1< represents a natural amino acid selected from a list consisting of A and G, or an unnatural amino acid selected from a list consisting of N-Methyl-L-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), L-Norleucine (Nle), L-Norvaline (Nva) and L-Ornithine (Orn), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0059] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 1< represents a natural amino acid selected from a list consisting of A and G, or an unnatural amino acid selected from a list consisting of N-Methyl-L-Alanine (N-Me)A, N-Methyl-Glycine ((N-Me)G), L-Norleucine (Nle), L-Norvaline (Nva) and L-Ornithine (Orn).

[0060] According to a further embodiment of the disclosure, X 1< represents the natural amino acid A.

[0061] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, in case p is 0 and q is different from 0, the terminal amino group of X 1< is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 4 -alkyl, preferably monosubstituited, with C 1 -C 20 -alkyl.

[0062] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 1< is methylated.

[0063] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 1< is acetylated.

[0064] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims q represents an integer of 0.

[0065] According to a further embodiment of thedisclosure, q represents an integer of 1.

[0066] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 2< represents a natural amino acid selected from a list consisting of I, L, M, V and A, or an unnatural amino acid selected from a list consisting of L-N-Methylisoleucine ((N-Me)I), allo-L-Isoleucine (allo-I), L-Cyclobutylalanine (Cba), L-Norvaline (Nva), L-2-Aminobutyric acid (Abu), (2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoic acid, (2S,3S)-2-[2-Oxopiperazin-1-yl]-3-methylpentanoic acid, (2S,3S)-2-[(3S)-2-oxopiperazin-1-yl]-3-methylpentanoic acid, L-Methionine-L-sulfoxide, L-Methionine-sulfone and L-tert-butylglycine, whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0067] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 2< represents the natural amino acid I or an unnatural amino acid selected from a list consisting of L-N-Methylisoleucine ((N-Me)I), allo-L-Isoleucine (allo-I), L-Cyclobutylalanine (Cba), L-Norvaline (Nva), L-2-Aminobutyric acid (Abu), (2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoic acid, (2S,3S)-2-[2-Oxopiperazin-1-yl]-3-methylpentanoic acid and (2S,3S)-2-[(3S)-2-oxopiperazin-1-yl]-3-methylpentanoic acid, whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0068] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 2< represents the natural amino acid I or an unnatural amino acid selected from a list consisting of L-N-Methylisoleucine ((N-Me)I), L-Cyclobutylalanine (Cba), L-Norvaline (Nva) and L-2-Aminobutyric acid (Abu), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0069] According to a further embodiment of thedisclosure, X 2< represents the natural amino acid I.

[0070] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, in case p and q are both 0 and r is 1, the terminal amino group of X 2< is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl, preferably monosubstituited, with C 1 -C 4 -alkyl.

[0071] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, r represents an integer of 0.

[0072] According to a further embodiment of thedisclosure, r represents an integer of 1.

[0073] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 3< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-Penicillamine (Pen) and L-N-Methylcysteine ((N-Me)C).

[0074] According to a further embodiment of the invention, which is not encompassed by the wording of the claims, X 3< represents the natural amino acid C or the unnatural amino acid L-Penicillamine (Pen).

[0075] According to a further embodiment of thedisclosure, X 3< represents the natural amino acid C.

[0076] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, in case p and q and r are all 0, the terminal amino group of X 3< is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 4 -alkyl, preferably monosubstituited, with C 1 -C 20 -alkyl.

[0077] According to a further embodiment, which are not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 4< represents a natural amino acid selected from a list consisting of S, C, T, R or K, or an unnatural amino acid selected from a list consisting of allo-L-Threonine (allo-T), L- Homoserine (hSer) and L-Ornithine (Orn).

[0078] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 4< represents a natural amino acid selected from a list consisting of S, C, T, R and K.

[0079] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 4< represents a natural amino acid selected from a list consisting of S or T.

[0080] According to a further embodiment of thedisclosure, X 4< represents the natural amino acid S.

[0081] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 5< represents the natural amino acid R or the unnatural amino acid N(5)-methyl-L-arginine ((Me)R).

[0082] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 5< represents the natural amino acid R or the unnatural amino acid N(5)-methyl-L-arginine ((Me)R).

[0083] According to a further embodiment of thedisclosure, X 5< represents the natural amino acid R.

[0084] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 6< represents a natural amino acid selected from a list consisting of S, C or T, or an unnatural amino acid selected from a list consisting of allo-L-Threonine (allo-T) and L-2,3-diaminopropionic acid (Dap).

[0085] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 6< represents the natural amino acid S or an unnatural amino acid selected from a list consisting of allo-L-Threonine (allo-T) and L-2,3-diaminopropionic acid (Dap).

[0086] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 6< represents the natural amino acid S or the unnatural amino acid allo-L-Threonine (allo-T).

[0087] According to a further embodiment of thedisclosure, X 6< represents the natural amino acid S.

[0088] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 7< represents a natural amino acid selected from a list consisting of L, F or N or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), L-4-Bromophenylalanine ((4-Bromo)F), 2,5-Difluoro-L-phenylalanine ((2,5-Difluoro)F), L-tert-Butylalanine ((tBu)A), 2-Chloro-L-phenylalanine ((2-Chloro)F), L-2-Bromophenylalanine ((2-Bromo)F), (S)-2-(Amino)-1,6-hexanedioic acid (AAD), (2S)-2-amino-4,4,4-trifluorobutanoic acid, L-2-amino-4-cyanobutyric acid (Cnba), 4-Fluoro-Leucine ((4-Fluoro)L), (S)-(trifluoromethyl)-L-cysteine, (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid, L-tert-Butylglycine ((tBu)G), 3-(Trimethylsilyl)-L-alanine, 2,5-difluoro-L-phenylalanine, 2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid, 5,5,5-Trifluoro-L-leucine ((Trifluoro)L), 2-Methyl-L-phenylalanine ((2-Me)F), L-Cyclobutylalanine (Cba), L-Cyclopentylalanine (Cpa), L-cyclopropylmethylalanine, L-trifluoromethylalanine, L-difluoromethylalanine, 2-Fluoro-L-phenylalanine ((2-Fluoro)F), (2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acid, (2S)-3-(3-Cyanophenyl)-2-aminopropanoic acid, 2-Amino-5,5,5-trifluoro-4-methyl-pentanoic acid, (2S)-2-Amino-5-methyl-hexanoic acid and (2S)-3-(indol-4-yl)-2-(amino)propanoic acid.

[0089] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 7< represents a natural amino acid selected from a list consisting of L and N, or an unnatural amino acid selected from a list consisting of 2,5-Difluoro-L-phenylalanine ((2,5-Difluoro)F), L-2-Bromo-phenylalanine ((2-Bromo)F), 2-Chloro-L-phenylalanine ((2-Chloro)F), L-4-Bromophenylalanine ((4-Bromo)F), 4-Fluoro-L-Leucine ((4-Fluoro)L), L-tert-Butylalanine ((tBu)A), L-tert-Butylglycine ((tBu)G), 5,5,5-Trifluoro-L-leucine ((Trifluoro)L), (S)-2-(Amino)-1,6-hexanedioic acid (AAD), (2S)-2-amino-4,4,4-trifluorobutanoic acid, L-2-amino-4-cyanobutyric acid (Cnba), (S)-(trifluoromethyl)-L-cysteine, (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid, (2S)-3-(2,3-difluorophenyl)-2-ami-nopropanoic acid, 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), 3-(Trimethylsilyl)-L-alanine and 2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid.

[0090] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 7< represents a natural amino acid selected from a list consisting of N or L, or an unnatural amino acid selected from a list consisting of 2,5-Difluoro-L-phenylalanine ((2,5-Difluoro)F), L-2-Bromophenyl-alanine ((2-Bromo)F), 2-Chloro-L-phenylalanine ((2-Chloro)F), 4-Fluoro-L-Leucine ((4-Fluoro)L), L-tert-Butylalanine ((tBu)A), (S)-(trifluoromethyl)-L-cysteine, (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid and 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), 3-(Trimethylsilyl)-L-alanine.

[0091] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 7< represents the natural amino acid L or the unnatural amino acid L-tert-Butylalanine ((tBu)A).

[0092] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 7< represents the unnatural amino acid L-tert-Butylalanine ((tBu)A).

[0093] According to a further embodiment of thedisclosure, X 7< represents the natural amino acid L.

[0094] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 8< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of L-Proline (3,4- 2 H), (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, (1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, L-Hydroxyproline (Hyp), (3S)-Morpholine-3-carboxylic acid (Morpholine-3-carboxylic), L-Pipecolic acid (Pip), (4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid, trans-4-fluoroproline ((trans-4-Fluoro)P) and (1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid.

[0095] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 8< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of L-Proline (3,4- 2 H), (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, trans-4-fluoroproline ((trans-4-Fluoro)P), L-Hydroxyproline (Hyp), (3S)-Morpholine-3-carboxylic acid (Morpholine-3-carboxylic), L-Pipecolic acid (Pip) and (4aR,6aR,9S,11aS)-11-Oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid.

[0096] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 8< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of L-Proline (3,4- 2 H), (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and (4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid.

[0097] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 8< represents the natural amino acid P or the unnatural amino acid L-Proline (3,4- 2 H).

[0098] According to a further embodiment of thedisclosure, X 8< represents the natural amino acid P.

[0099] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 9< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), L-Hydroxyproline (Hyp), (2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P), (2S,4S)-4-fluoroproline ((cis-4-Fluoro)P), trans-4-fluoroproline ((trans-4-Fluoro)P), (2S)-2-amino-4,4,4-trifluorobuta-noic acid, L-trans-3-hydroxyproline ((3S-OH)P, (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, rel-(1R,3R,5R,6R)-6-(trifluoromethyl)-2-azabicy-clo[3.1.0]hexane-3-carboxylic acid, (2S)-2-Amino-4,4,4-trifluorobutanoic acid, (2S,3aS,6aS)-octahydrocyclo-penta[b]pyrrole-2-carboxylic acid, trans-4-fluoroproline ((trans-4-Fluoro)P), (2S,4S)-4-fluoroproline ((cis-4-Fluoro)P), L-4,4-difluoroproline ((Difluoro)P), rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1) and rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2).

[0100] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 9< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), (6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, rel-(1R,3R,5R,6R)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P), (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid, (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S)-2-Amino-4,4,4-trifluoro-butanoic acid, L-trans-3-hydroxyproline ((3S-OH)P, trans-4-fluoroproline ((trans-4-Fluoro)P), L- Hydroxyproline (Hyp), (2S,4S)-4-Fluoroproline ((cis-4-Fluoro)P), (3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1) and (3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2).

[0101] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 9< represents the natural amino acid P, or an unnatural amino acid selected from a list consisting of 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), (2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P), (6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, rel-(1R,3R,SR,6R)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid, rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1) and rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2).

[0102] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 9< represents the natural amino acid P or the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic).

[0103] According to a further embodiment of thedisclosure, X 9< represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic).

[0104] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 10< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of L-Cyclopentylglycine (Cpg), L-Cyclohexylglycine (Chg), (S)-2-amino-3-ethyl-pentanoic acid, 3-Chlorophenylglycine ((3-Chloro-Ph)G), L-tert-butylglycine, allo-L-Isoleucine (allo-I), L-Cyclobutylglycine, L-Norvaline (Nva) and (2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid.

[0105] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 10< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of (2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid, 3-Chlorophenylglycine ((3-Chloro-Ph)G), (S)-2-amino-3-ethyl-pentanoic acid, allo-L-Isoleucine (allo-I), L-Cyclohexylglycine (Chg), L-Cyclopentylglycine (Cpg), L-Cyclobutylglycine and L-Norvaline (Nva).

[0106] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 10< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of (2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid, (S)-2-amino-3-ethyl-pentanoic acid, L-Cyclohexylglycine (Chg) and L-Cyclopentylglycine (Cpg).

[0107] According to a further embodiment of the disclosure, X 10< represents the natural amino acid I.

[0108] According to a further embodiment, which is not encompassed by the wording of the claims, the invention provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen).

[0109] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 11< represents the natural amino acid C, or an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen).

[0110] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 11< represents an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen).

[0111] According to a further embodiment of thedisclosure, X 11< represents the unnatural amino acid L-Penicillamine (Pen).

[0112] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 9< represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic) and X 11< represents the unnatural amino acid L-N-Methylcysteine ((N-Me)C) or the unnatural amino acid L-Penicillamine (Pen).

[0113] According to a further embodiment of thedisclosure, X 9< represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic) and X 11< represents the unnatural amino acid L-Penicillamine (Pen).

[0114] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 9< represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic) and X 11< represents an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen).

[0115] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 12< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of allo-L-Isoleucine (allo-I), (S)-2-Amino-2-cyclobutylacetic acid (Cbg), (2S,3S)-2-((amino)methyl)-3-methylpentanoic acid, L-Phenylglycine (Phg), 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid, 2-methyl-D-alloisoleucine, L-Norvaline (Nva), L-2-Aminobutyric acid (Abu), L-tert-butylglycine and Aminoisobutyric acid (Aib).

[0116] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 12< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid, (S)-2-Amino-2-cyclobutylacetic acid (Cbg), allo-L-Isoleucine (allo-I), L-Phenylglycine (Phg), 2-methyl-D-alloisoleucine and (2S,3S)-2-((amino)methyl)-3-methylpentanoic acid.

[0117] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 12< represents the natural amino acid I, or an unnatural amino acid selected from a list consisting of allo-L-Isoleucine (allo-I), (S)-2-Amino-2-cyclobutylacetic acid (Cbg) and 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid.

[0118] According to a further embodiment of thedisclosure, X 12< represents the natural amino acid I.

[0119] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, in case u and t and s are all 0, the terminal carboxyl group of X 12< is unsubstituted or amidated.

[0120] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 13< represents a natural amino acid selected from a list consisting of P, A, S, T, G, D, E, Q or N or an unnatural amino acid selected from a list consisting of N-Methyl-Glycine ((N-Me)G), 5-azaspiro[2.4]heptane-6-carboxylic acid, L-2-Aminobutyric acid (Abu), 2-Aminoisobutyric acid (Aib), 2-Methyl-L-Proline (2-Me)P, Hydroxyproline (Hyp), 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), trans-4-fluoroproline ((trans-4-Fluoro)P), (2S,4S)-4-fluoroproline ((cis-4-Fluoro)P), L-4,4-difluoroproline ((Difluoro)P), L-Cyclopentylglycine (Cpg), (S)-2-Amino-2-cyclobutylacetic acid (Cbg) and (2S)-Pyrrolidin-2-ylacetic acid (beta-homo-P), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0121] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 13< represents a natural amino acid selected from a list consisting of P, A and D or an unnatural amino acid selected from a list consisting of 2-Methyl-L-Proline (2-Me)P, N-Methyl-Glycine ((N-Me)G), trans-4-fluoroproline ((trans-4-Fluoro)P), L-2-Aminobutyric acid (Abu), 2-Aminoisobutyric acid (Aib), Hydroxyproline (Hyp) and 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0122] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 13< represents a natural amino acid selected from a list consisting of P or D or an unnatural amino acid selected from a list consisting of 2-Aminoisobutyric acid (Aib), 2-Methyl-L-Proline (2-Me)P and trans-4-fluoroproline ((trans-4-Fluoro)P), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0123] According to a further embodiment of thedisclosure, X 13< represents the natural amino acid P.

[0124] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, s represents an integer of 0.

[0125] According to a further embodiment of thedisclosure, s represents an integer of 1.

[0126] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, in case u and t are both 0 and s is different from 0, the terminal carboxyl group of X 13< is unsubstituted or amidated.

[0127] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, in case t is 0 and s is 1, the terminal carboxyl group of X 13< is unsubstituted or amidated.

[0128] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein X 14< represents any natural amino acid or an unnatural amino acid, whereas any natural amino acid and / or unnatural amino acid can be in D- or L-stereoconfiguration.

[0129] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 14< represents a natural amino acid selected from a list consisting of D, E, G, K, N, P and Q or an unnatural amino acid selected from a list consisting of 3-Carboxyphenylalanine ((3-Carboxy)F), (2S)-2-Amino-4-(benzylamino)-4-oxobutanecarboxylic acid ((N-Benzyl)D), N-Methyl-Glycine ((N-Me)G), 6-Aminohexanoic acid (Ahx), (2S)-Pyrrolidin-2-ylacetic acid (beta-homo-P), L-2,3-Diaminopropionic acid (Dap), L-Ornithine (Orn) and Tranexamic acid (Tranexamic), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0130] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 14< represents a natural amino acid selected from a list consisting of D, Q, N, E and P or an unnatural amino acid selected from a list consisting of 3-Carboxyphenylalanine ((3-Carboxy)F), N-Methyl-Glycine ((N-Me)G), (2S)-Pyrrolidin-2-ylacetic acid (beta-homo-P), L-2,3-Diaminopropionic acid (Dap), L-Ornithine (Orn) and Tranexamic acid (Tranexamic), whereas each natural amino acid and / or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration.

[0131] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 14< represents a natural amino acid selected from a list consisting of D, Q or I.

[0132] According to a further embodiment of thedisclosure, X 14< represents the natural amino acid D.

[0133] According to a further embodiment of thedisclosure, the C-terminal "-OH" moiety at X 14< is substituted for a C-terminal "-NH 2 " moiety.

[0134] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, q represents an integer of 0.

[0135] According to a further embodiment of thedisclosure, q represents an integer of 1.

[0136] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, in case s and t represent the integer 1, the terminal carboxyl group of X 14< is unsubstituted or amidated.

[0137] According to a further embodiment of thedisclosure, in case s and t represent the integer 1, the terminal carboxyl group of X 14< is unsubstituted.

[0138] According to the present disclosure, X 15< , if present, can be a chemical group which is not an amino acid, which is not encompassed by the wording of the claims,

[0139] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 15< is a chemical group selected from the list consisting of -NH 2 , -NH-C 1 -C 6 -alkyl, (1R,3S)-3-(Amino)cyclopentanecarboxylic acid, (1S,3R)-3-(Amino)cyclopentanecarboxylic acid, (R)-4-Amino-6-methylheptanoic acid, (S)-(1-Piperidin-3-yl)-acetic acid, (S)-3-(1-Pyrrolidine-2-yl)-propionic acid, (S)-3-(2H-tetrazol-5-yl)propanoic acid, (S)-Pyrrolidine-3-carboxylic acid, 5-Azaspiro[2.4]heptane-1-carboxylic acid and (2S)-3-(Triazol-1-yl)-2-(amino)propanoic acid.

[0140] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, X 15< is a chemical group selected from -NH 2 or -NH-C 1 -C 6 -alkyl, preferably -NH 2 .

[0141] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, q represents an integer of 0.

[0142] According to a further embodiment of thedisclosure, q represents an integer of 1.

[0143] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the N-terminus of the peptide is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 20 -alkyl.

[0144] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the N-terminus of the peptide is unsubstituated, acetylated or mono- or disubstituted with C 1 -C 4 -alkyl.

[0145] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the N-terminus of the peptide is unsubstituated or acetylated.

[0146] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the C-terminus is unsubstituted or amidated.

[0147] According to a further embodiment of thedisclosure, the N-terminus and C-terminus is unsubstituted.

[0148] According to a further embodiment, the disclosure provides compounds for illustration containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, which are selected from the group consisting of example 29, 44, 45, 67, 75, 109, 166, 185, 443 and 466 or which are selected from the group consisting of example 29, 44, 45, 67, 75, 109, 166, 185, 443, 466 and 499.

[0149] The peptide of formular (I) or (II) can be linear or cyclized, which are not encompassed by the wording of the claims,. The term "cyclized," as used herein, refers to a reaction in which one part of a polypeptide molecule (e.g. Cys, (N-Me)Cys or Pen) becomes linked to another part of the polypeptide molecule (e.g. another Cys, (N-Me)Cys or Pen) to form a closed ring, such as by forming a disulfide bridge (-S-S-) or other similar bonds such as a carbon-sulphur bond (e.g. (-CH 2 -S-) or (-(CH 2 ) 2 -S-)), a sulphur-carbon bond (e.g. (-S-CH 2 -) or (-S-(CH 2 ) 2 -)), a carbon-sulphur-carbon bond (-CH 2 -S-CH 2 -) or a carbon-carbon bond (e.g. (-CH 2 -CH 2 -). According to the present invention a linkage between positions X 3< and X 11< of the peptide is preferred. An amino acid followed by a "+" in a sequence of a peptide according to the invention refers to a cyclic peptide, wherein the amino acid is linked to another amino acid followed by a "+" by a disulfide bridge forming a closed ring. Alternatively two linked chemical groups of a polypeptide molecule can be depicted by a connecting line.

[0150] According to a further embodiment, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein the peptide is cyclized.

[0151] According to a further embodiment of thedisclosure, the peptide of formula (I) or formula (II) is cyclized via a linkage connecting X 3< and X 11< .

[0152] According to a further embodiment of the disclosure, which is not encompassed by the wording of the claims, the peptide of formula (I) or formula (II) is cyclized via a linkage connecting X 3< and X 11< are and wherein X 3< and X 11< are connected via a linker of the formula -S-S-, -CH 2 -S-, -S-CH 2 -, -CH 2 -CH 2 -, -S-(CH 2 ) 2 -, -(CH 2 ) 2 -S- or -CH 2 -S-CH 2 -.

[0153] According to a further embodiment of the disclosure, the peptide of formula (II) is cyclized via a linkage connecting X 3< and X 11< and wherein X 3< and X 11< are connected via a disulfide bond of the formula -S-S-.

[0154] The petide of the present disclosure, which is not encompassed by the wording of the claims, can be substituted with a suitable watersoluble polymer characterized by repeating units. Suitable polymers may be selected from the group consisting of polyalkyloxy polymers, hyaluronic acid and derivatives thereof, polyvinyl alcohols, polyoxazolines, polyanhydrides, poly(ortho esters), polycarbonates, polyurethanes, polyacrylic acids, polyacrylamides, polyacrylates, polymethacrylates, polyorganophosphazenes, polysiloxanes, polyvinylpyrrolidone, polycyanoacrylates, and polyesters.

[0155] The petides of the present disclosure, which is not encompassed by the wording of the claims, can be substituted with at least one polyethylene group (PEG group). The at least one PEG group is preferably bound to the N-terminal and / or C-terminal end. The PEG group can be bound to any suitable functional group of a chemical group and / or amino acid of the peptide, e.g. hydroxyl group, carboxyl group, amino group, thiol group, preferably an amino or carboxy group. Preferably the peptide according to the invention contains one PEG group bound to the N-terminal end or one PEG group bound to the C-terminal end. More preferably the one PEG group is bound to the N-terminal or C-terminal end via an amide bond.

[0156] PEGylation of peptides may enhance their solubility, reduce immunogenicity, improve stability and / or increase half live by reducing renal clearance, which is a well known concept since early 1980s (Caliceti P.,Veronese F.M., Adv. Drug Deliv. Rev.2003, 55, 1261-1277). For several drugs this has been used with success, but with many examples the PEGylation reduces efficacy of drug substance to an extent that this concept is not suitable any more (T. Peleg-Shuhnan et al., J. Med.Chem., 2004, 47, 4897-4904).

[0157] A PEG group according to the disclosure, which is not encompassed by the wording of the claims, is any group containing at least two ethylene oxide units to form an oligomer or polymer ethylene oxide. The PEG group is covalently coupled to a peptide of the present invention (PEGylation), which is then referred to as a PEGylated peptide. Generally, this type of modification to a molecule is well known in the art.

[0158] PEG group may consist of an interconnecting moiety, a polymer moiety, and an end group. Interconntect-ing moieties may consist of a C 1 -C 20 alkyl, which is optionally interrupted or terminated by hetero atoms or functional groups selected from the group consisting of -O-, -S-, N(R X< ), C(O), C(O)R X< , C(O)N(R X< ), N(R X< )C(O), one or more C 3 -C 8 -cycloalkyl, C 3 -C 7 -heterocycloalkyl, aryl or heteraryl, wherein R X< is hydrogen or C 1 -C 6 -alkyl, which is optionally interrupted or terminated by one or more of the abovementioned atoms or groups, which further have a hydrogen as terminal atom. Polymer moieties consit of at least two ethylene oxide units, optionally interrupted or terminated by one or more hetero atoms or functional groups selected from the group consisting of -O-, -S-, N(R X< ), C(O), C(O)R X< , C(O)N(R X< ), N(R X< )C(O), C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 7 -heterocycloalkyl. aryl or heteraryl, wherein R X< is hydrogen or C 1 -C 6 -alkyl. The end group may consist of an hetero atoms or functional groups selected from OH, SH, N(R X< ) 2 , C(O)R X< ; COR X< , COOR X< , C(O)N(R X< ), N(R X< )C(O)NH 2 wherein R X< is hydrogen or C 1 -C 6 -alkyl. Preferred end groups are COOH and C(O)NH 2 .

[0159] Examples of PEG spacer according to the present disclosure, which are not encompassed by the wording of the claims, comprise PEG1(10 atoms) having 1 ethylene glycol unit (n=1; 10 atoms), PEG2(13 atoms) having 2 ethylene glycol units (n=2; 13 atoms), PEG3(16 atoms) having 3 ethylene glycol units (n=3; 16 atoms), PEG4(19 atoms) having 4 ethylene glycol units (n=4; 19 atoms), PEG5(22 atoms) having 5 ethylene glycol units (n=5; 22 atoms), PEG6(25 atoms) having 6 ethylene glycol units (n=6 ; 25 atoms) etc..

[0160] It is noted that the PEG groups as defined herein may be indicated with different names by commercial suppliers, which shall not exclude such identical compounds with different names from the present invention.

[0161] According to a further embodiment, which is not encompassed by the wording of the claims, the disclosure provides compounds containing a peptide, which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein the peptide is substituted by at least one PEG group.

[0162] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the peptide is substituted by one PEG group.

[0163] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the peptide is substituted by one PEG group, wherein the PEG group is bound to the C-terminal end, preferably via an amide bond.

[0164] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the peptide is substituted by at least one PEG group, whereas the at least one or more PEG group is a group of the formula (IIIa) wherein *marks the attachment to a nitrogen or oxygen atom, Dis C 1 -C 4 -alkylene, Yis selected from the group consisting of hydroxyl, methoxy, ethoxy, carboxy, carboxamide or amino and nrepresents an integer of from 2 to 15, or a group of the formula (IIIb) wherein *marks the bond to a carbonyl group, D 1< is C 1 -C 4 -alkylene, Y 1< is selected from the group consisting of hydroxyl, methoxy, ethoxy, carboxy, carboxamide or amino and mrepresents an integer of from 2 to 15, or TTDS.

[0165] According to a further embodiment of thedisclosure, which is not encompassed by the wording of the claims, the peptide is substituted by at least one PEG group, whereas the at least one or more PEG group selected from a list consisting of PEG1(10 atoms), PEG2(13 atoms), PEG3(16atoms), PEG4(19 atoms), PEG4-CH 2 CO 2 H (15 atoms), PEG5(22 atoms), PEG5-CH 2 CO 2 H (18 atoms), PEG7(25 atoms), PEG8(28 atoms), PEG9(31 atoms) and TTDS.

[0166] The peptide of the present disclosure, which is not encompassed by the wording of the claims, can comprise at least one C 8 -C 20 fatty acid. Generally, such fatty acid may be branched or cyclic. The at least one C 8 -C 20 fatty acid is preferably bound to the N-terminal and / or C-terminal end. The C 8 -C 20 fatty acid can be bound to any suitable functional group of a chemical group and / or amino acid of the peptide, e.g. hydroxyl group, carboxyl group, amino group, thiol group, preferably an amino or carboxy group. Preferably the peptide according to the invention contains one C 8 -C 20 fatty acid bound to the N-terminal end or one C 8 -C 20 fatty acid bound to the C-terminal end. More preferably the one C 8 -C 20 fatty acid is bound to the N-terminal or C-terminal end via an amide bond. Preferably the fatty acid side chain formed by X 0< or X 15< is a fatty acid > C 8 , more preferably a fatty acid ≥ C 12 , more preferably a fatty acid ≥ C 14 . It is further preferred that the fatty acid side chain formed by X 0< or X 15< is a C 12 -C 18 fatty acid, preferably a C 12 -C 16 fatty acid, or a C 14 -C 18 fatty acid, or a C 14 -C 16 fatty acid. Most preferred is a C 16 fatty acid such as palmitic acid (palmitoyl, Palm) and a C 18 fatty acid such as 1,18-Octadecanedioic acid (ODD).

[0167] It is further understood that the moiety at the N-terminus or C-terminus may be a bond, e.g., a covalent bond, particularly in situations where the amino terminus or carboxy terminus is bound to a linker or to another chemical moiety.

[0168] Chemical groups, unnatural amino acids or moieties may be abbreviated herein as shown in Table 3. Table 3: Abbreviations / expressions and nomenclature used for chemical groups, unnatural amino acids or further moieties in the sequencesAbbreviation / Expression Abbreviation / Expression Definition CyclohexylcarboxylicCyclohexanecarboxylic acid(2S)-Amino-2-[3-(Trifluoromethyl)bicy-clo[1.1.1]pent-1-yl]acetic acid(2S)-Amino-2-[3-(Trifluoromethyl)bicyclo[1.1.1]pent-1-yl]acetic acid(S)-3-(2H-tetrazol-5-yl)propanoic acid(S)-3-(2H-tetrazol-5-yl)propanoic acid(1R,3S)-3-(Amino)cyclopentanecarboxylic acid(1R,3S)-3-(Amino)cyclopentanecarboxylic acid(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid(1R,38,48)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid(1R,3S,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxylic acid(1R,3S,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxylic acid(1S,2S,4S)-Bicyclo[22.1]hept-5-en-2-ylacetic acid(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylacetic acid(1R,2S,5S)-3-Azabicyclo[3.1.0]hexane-2-carboxylic acid(1R,2S,5S)-3-Azabicyclo[3.1.0]hexane-2-carboxylic acid(1S,3R)-3-(Amino)cyclopentanecarboxylic acid(1S,3R)-3-(Amino)cyclopentanecarboxylic acid(1S,3R,4R)-2-Azabicyclo[2.2.1]heptane-3-carboxylic acid(15,3R,4R)-2-Azabicyclo[2.2.1]heptane-3-carboxylic acid(2,4-Dioxoimidazolidin-1-yl)acetic acid(2,4-Dioxoimidazolidin-1-yl)acetic acid(2-CN)F2-Cyano-L-phenylalanine(2-Fluoro)F2-Fluoro-L-phenylalanine(2-Me)F2-Methyl-L-phenylalanine(4-Pyranoyl)G(2S)-(tetrahydro-2H-pyran-4-yl)ethanoic acid(4-CF3)P(2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid(3,3-Difluorocyclobutyl)acetic acid(3,3-difluorocyclobutyl)acetic acid(3-CN)F3-Cyano-L-phenylalanine(3-Fluoro)F3-Fluoro-L-phenylalanine(4-Fluoro)F4-Fluoro-L-phenylalanine5-Azaspiro[2.4]heptane-1-carboxylic acid5-Azaspiro[2.4]heptane-1-carboxylic acidD-(+)BiotinD-(+)Biotin(N,N-diMe)AL-N,N-Dimethylalanine(N,N-diMe)GN,N-Dimethylglycine(N-Isopropyl-N-methylamino)acetyl2-(N-Isopropyl-N-methylamino)acetic acid((N-Me)A)L-N-Methylalanine((N-Me)a)D-N-Methylalanine((N-Me)C)L-N-Methylcysteine(N-Me)FL-N-Methylphenylalanine(N-Me)GN-Methyl-Glycine(N-Me)IL-N-Methylisoleucine(N-Ph)GN-Phenylglycine(R)-3-Aminoadipic acid(R)-3-Aminoadipic acid(R)-4-Amino-6-methylheptanoic acid(R)-4-Amino-6-methylheptanoic acid(R)-Piperidine-3-Carboxylic Acid(R)-Piperidine-3-Carboxylic Acid(R)-Pyrrolidine-3-Carboxylic Acid(R)-Pyrrolidine-3-Carboxylic Acid(S)-(1-Piperidin-3-yl)-acetic acid(S)-(1-Piperidin-3-yl)-acetic acid(S)-2-Amino-3-ethyl-pentanoic acid(S)-2-Amino-3-ethyl-pentanoic acid(S)-3-(1-Pyrrolidine-2-yl)-propionic acid(S)-3-(1-Pyrrolidine-2-yl)-propionic acid(S)-3-(2H-Tetrazol-5-yl)propionic acid(S)-3-(2H-Tetrazol-5-yl)propionic acid(S)-3-Methylpentanoic acid(S)-3-Methylvaleric Acid(S)-4-Piperazine-2-carboxylic acid(S)-4-Piperazine-2-carboxylic acid(S)-Piperidine-3-carboxylic acid(S)-Piperidine-3-carboxylic acid(S)-Pyrrolidine-3-carboxylic acid(S)-Pyrrolidine-3-carboxylic acid[(2R)-4,4-Difluoropyrrolidin-2-yl] acetic acid[(2R)-4,4-Difluoropyrrolidin-2-yl]acetic acid[(6S)-5-Azaspiro[2.4]hept-6-yl]acetic[(6S)-5-Azaspiro[2.4]hept-6-yl]acetic acid1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)acetic acid1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)acetic acid1-NalL-1-Napthylalanine2-(3-Pyridyl)acetic acid2-(3-Pyridyl)acetic acid2-(Aminomethyl)benzoic acid2-(Aminomethyl)benzoic acid2-(Cyclohexylamino)acetyl2-(Cyclohexylamino)acetic acid2-(Diethylamino)acetyl2-(Diethylamino)acetic acid2-(Morpholine)acetyl2-(Morpholine)acetic acid2-(N-Methyl-N-cyclopropylamino)acetyl2-(N-Methyl-N-cyclopropylamino)acetic acid2-(Piperidin)acetyl2-(Piperidin)acetic acid2-(Pyrrolidine)acetyl2-(Pyrrolidine)acetic acid2-(Thian-4-yl)acetic acid2-(Thian-4-yl)acetic acid2-(Thiomorpholine)acetyl2-(Thiomorpholine)acetic acid(2,3-Difluoro)F2,3-Difluoro-L-phenylalanine2-aminobenzoic acid2-Aminobenzoic acid2-Azaspiro[3.3]heptane-6-carboxylic acid2-Azaspiro[3.3]heptane-6-carboxylic acid(2-Bromo)FL-2-Bromophenylalanine(2-Chloro)F2-Chloro-L-phenylalanine2-Cyanobenzoic acid2-Cyanobenzoic acid2-Fluorobenzoic acid2-Fluorobenzoic acid2-Hydroxyacetyl2-Hydroxyacetic acid2-Hydroxyisobutyric2-Hydroxyisobutyric acid2-Methylbenzoic acid2-Methylbenzoic acid(2-Me)F2-Methyl-L-phenylalanine2-NalL-2-Napthylalanine2-PalL-2-Pyridylalaninebeta-homo-P(2S)-Pyrrolidin-2-ylacetic acid3-(2-Oxoimidazolidin-1-yl)benzoic acid3-(2-Oxoimidazolidin-1-yl)benzoic acid3-(3-Oxo-1,3,4,5,6,7-hexahydro-2H-in-dazol-2-yl)benzoic acid3-(3-Oxo-1,3,4,5,6,7-hexahydro-2H-indazol-2-yl)benzoic acid3-(Aminomethyl)benzoic acid3-(Aminomethyl)benzoic acid3-(Isobutyrylamino)benzoic acid3-(Isobutyrylamino)benzoic acid3-(Trifluoromethyl)bicyclo[1.1.1]pent-1-yl]acetic acid3-(Trifluoromethyl)bicyclo[1.1.1]pent-1-yl]acetic acid3-[(E)-(2-carboxycyclohexen-1-yl)azo]benzoic acid3-[(E)-(2-carboxycyclohexen-1-yl)azo]benzoic acid3-Acetamidobenzoic acid3-Acetamidobenzoic acid3-Amino-2,2-dimethylpropionic acid3-Amino-2,2-dimethylpropionic acid3-Amino-3-methylbutyric acid3-Amino-3-methylbutyric acid3-Aminobenzoic acid3-Aminobenzoic acid3-Aminomethylphenylacetic acid3-Aminomethylphenylacetic acid(3-Bromo)FL-3-Bromophenylalanine3-Carboxybenzoic acid3-Carboxybenzoic acid(3-Chloro)F3-Chloro-L-Phenylalanine(3-Chloro-Ph)G3-Chlorophenylglycine3-Cyanobenzoic acid3-Cyanobenzoic acid3-Fluorobenzoic acid3-Fluorobenzoic acid(3-Me)F3-Methyl-L-phenylalanine3-Methoxypropionic acid3-Methoxypropionic acid3-methylbenzoic acid3-Methylbenzoic acid3-PalL-3-Pyridylalanine4-(Aminomethyl)benzoic acid4-(Aminomethyl)benzoic acid4-Aminobenzoic acid4-Aminobenzoic acid4-Aminomethylphenylacetic acid4-Aminomethylphenylacetic acid(4-Amino)FL-4-Aminophenylalanine(4-Bromo)FL-4-Bromophenylalanine4-Carboxybenzoic acid4-Carboxybenzoic acid4-Cyanobenzoic acid4-Cyanobenzoic acid4-Fluorobenzoic acid4-Fluorobenzoic acid(4-Fluoro)L4-Fluoro-L-Leucine4-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid4-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid4-methylbenzoic acid4-Methylbenzoic acid4-Methylvaleric4-Methylpentanoic acid4-PalL-4-Pyridylalanine4-Piperidinepropanoic acid4-Piperidinepropanoic acid4-Tetrahydropyranoyl4-Tetrahydropyranoyl5-Chlorothiophene-2-carboxylic acid5-Chlorothiophene-2-carboxylic acid8-aminocubane-1-carboxylic acid8-Aminocubane-1-carboxylic acidAAD(S)-2-(Amino)-1,6-hexanedioic acidAbuL-2-Aminobutyric acidACBA1-Aminocyclobutane-1-carboxylic acidACBCAminocyclobutanecarboxylic acidACMP1-(Aminomethyl)-cyclopropyl-1-carboxylic acidS,S-ACPC(1S,2S)-2-Amino-1-cyclopentanecarboxylic acidR,R-ACPC(1R,2R)-2-Amino-1-cyclopentanecarboxylic acidACPCrel-(1R,2S)-2-Amino-1-cyclopentanecarboxylic acidAdipic acidAdipic acidAhx6-Aminohexanoic acidAib2-Aminoisobutyric acid(tBu)AL-tert-Butylalanineallo-Iallo-L-Isoleucineallo-Tallo-L-Threonine(2-Me)P2-Methyl-L-Proline(Me)RN(5)-methyl-L-arginineAzetidine-2-carboxylic acid(S)-Azetidine-2-carboxylic acidBenzoicBenzoic acidbeta-2-thienylalanineL-2-Thienylalaninebeta-Abeta-Alanine4-(3,5-Dimethyl-1,2-oxazol-4-yl)-L-phenylalanine4-(3,5-Dimethyl-1,2-oxazol-4-yl)-L-phenylalanine(2S)-2-amino-3-(4-tert-butylphenyl)propanoic acid(2S)-2-amino-3-(4-tert-butylphenyl)propanoic acid(2S)-2-Amino-5-methyl-hexanoic acid(2S)-2-Amino-5-methyl-hexanoic acid(2S)-2-Amino-4,4,4-trifluorobutanoic acid(2S)-2-Amino-4,4,4-trifluorobutanoic acid(2S)-3-(4-carboxyphenyl)-2-aminopropa-noic acid(2S)-3-(4-carboxyphenyl)-2-aminopropanoic acid(2S)-2-amino-3-(4-carbamoylphenyl)propanoic acid(2S)-2-amino-3-(4-carbamoylphenyl)propanoic acid(2S)-2-Amino-3-(2,3,4,5,6-(pentafluorophenyl)propanoic acid(2S)-2-Amino-3-(2,3,4,5,6-(pentafluorophenyl)propanoic acid(2S)-3-(3-Cyanophenyl)-2-aminopropanoic acid(2S)-3-(3-Cyanophenyl)-2-aminopropanoic acid3-Azido-L-Alanine3-Azido-L-Alanine2-Amino-5,5,5-trifluoro-4-methyl-pentanoic acid2-Amino-5,5,5-trifluoro-4-methyl-pentanoic acid(1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid(1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acidCbaL-CyclobutylalanineCbg(S)-2-Amino-2-cyclobutylacetic acidChaL-CyclohexylalanineChaD-cyclohexylalanineChgL-Cyclohexylglycine(Difluoro)PL-4,4-Difluoroproline(cis-Fluoro)P(2S,4S)-4-FluoroprolineCitL-CitrullineCnbaL-2-Amino-4-cyanobutyric acid3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid(S)-(trifluoromethyl)-L-cysteine(S)-(trifluoromethyl)-L-cysteine(2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid(2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid(2S)-3-(indol-4-yl)-2-(amino)propanoic acid(2S)-3-(indol-4-yl)-2-(amino)propanoic acid(2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acid(2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acidCpAL-CyclopentylalanineCpgL-CyclopentylglycineCyclobutanecarboxylicCyclobutanecarboxylic acidCyclobutylacetic2-(Cyclobutyl)acetic acidCyclobutylglycineL-CyclobutylglycineCyclohexylaceticCyclohexylacetic acidCyclopentanecarboxylic acidCyclopentanecarboxylic acidCyclopentylaceticCyclopentylacetic acidCyclopropanecarboxylicCyclopropanecarboxylic acidCyclopropylacetic acidCyclopropylacetic acid(2-Chloro)fD-2-ChlorophenylalanineDabL-2,4-Diaminobutyric acidDapL-2,3-Diaminopropionic acidbeta-pD-beta-ProlinehypD-Hydroxyproline(N-Benzyl)D(2S)-2-Amino-4-(benzylamino)-4-oxobutanecarboxylic acidFreidinger's Lactam(2S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-4-methylpentanoic acidFumaric acidFumaric acidGamma-AbuGamma-Aminobutyric acid(tBu)GL-tert-Butylglycine(1-Bn)H1-Benzyl-L-histidine(1-Me)H1-Methyl-L-histidine(3-Me)HL-3-MethylhistidineHomo-CL-HomocysteineHooL-Dihydroorotic acidHydrocinnamic3-Phenylpropanoic acidHypL-HydroxyprolineIdaIminodiacetic acidIsobutyric acidIsobutyric acidIsonipecotic acidIsonipecotic acidIsovalericIsovaleric acidK(ISP)N-e-Isopropyl-L-lysine(3-Et)Nva3-Ethyl-L-NorvalineLacticL-(+)-Lactic acid(Bth)A3-(1,3-Benzothiazol-2-yl)-L-alaninebeta-P(S)-Pyrrolidine-2-carboxylic acidL-PropargylglycineL-PropargylglycineMorpholine-3-carboxylic(3S)-Morpholine-3-carboxylic acidNicotinic acidNicotinic acidNleL-Norleucine(N-Me)PN-Methyl-L-prolineNvaL-NorvalineODD1,18-Octadecanedioic acidOic2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acidOrnL-OrnithinePalmPalmitic acidPEG1(10 atoms)9-Amino-4,7-dioxanonanoic acidPEG2(13 atoms)12-Amino-4,7,10-trioxadodecanoic acidPEG3(16 atoms)15-Amino-4,7,10,13-tetraoxa(Pen)tadecanoic acidPEG4(19 atoms)18-Amino-4,7,10,13,16-(Pen)taoxaoctadecanoic acidPEG4-CH2CO2H (15 atoms)14-Amino-3,6,9,12-tetraoxatetradecanoic acidPEG5(22 atoms)1-Amino-3,6,9,12,15,18-hexaoxahenicosan-21-oic acidPEG5-CH2CO2H (18 atoms)17-Amino-3,6,9,12,15-(Pen)taoxaheptadecanoic acidPEG7(25 atoms)1-Amino-3,6,9,12,15,18,21-heptaoxatetracosan-24-oic acidPEG8(28 atoms)1-Amino-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oic acidPEG9(31 atoms)1-Amino-3,6,9,12,15,18,21,24,27-nonaoxatriacontan-30-oic acidPenL-PenicillaminePhenylacetic acidPhenylacetic acidPhgL-PhenylglycinePicolinic acidPicolinic acidPipL-Pipecolic acidPiperidin-4-ylacetic acidPiperidin-4-ylacetic acidPivalicPivalic acid(3S-OH)PL-trans-3-HydroxyprolinePyrL-Pyroglutamic acidS-2-amino-3-ethyl-pentanoic acidS-2-amino-3-ethyl-pentanoic acidPyrrolidineacetyl2-(Pyrrolidin-1-yl)acetic acidS-3-1-Pyrrolidin-2-yl-propionic acidS-3-1-Pyrrolidin-2-yl-propionic acidSuberic acidSuberic acidtert-Butylacetic acidtert-Butylacetic acidTetrahydropyranyl-4-acetic acidTetrahydropyranyl-4-acetic acidTFATrifluoroacetic acidThiL-2-Thienylalanine(2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoicacid(2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoicacid(2S,3S)-2-[2-Oxopiperazin-1-yl]-3-methylpentanoic acid(2S,3S)-2-[2-Oxopiperazin-1-yl]-3-methylpentanoic acid(2S,3S)-2-[(3S)-2-oxopiperazin-1-yl]-3-methylpentanoic acid(2S,3S)-2-[(3S)-2-oxopiperazin-1-yl]-3-methylpentanoic acid(1R,3S,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxylic acid(1R,3S,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxylic acid3-(Trimethylsilyl)-L-alanine3-(Trimethylsilyl)-L-alanine(6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid(6S)-5-Azaspiro[2.4]heptane-6-carboxylic acidrel-(1R,3R,5R,6R)-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acidrel-(1R,3R,5R,6R)-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid(4aR,6aR,9S,11aS)-11-Oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid(4aR,6aR,9S,11aS)-11-Oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid(2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid(2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid(2S,3S)-2-((Amino)methyl)-3-methylpentanoic acid(2S,3S)-2-((Amino)methyl)-3-methylpentanoic acid2-[(18,25)-1-(Amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid2-[(1S,2S)-1-(Amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid(2S)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid(2S)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid(2R)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid(2R)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid(3-Carboxy)F3-Carboxyphenylalanine2-Methyl-D-alloisoleucine2-Methyl-D-alloisoleucine4-Ethyl-L-norleucine4-Ethyl-L-norleucineL-2,6-DifluorophenylalanineL-2,6-Difluorophenylalanine(2,5-Difluoro)F2,5-Difluoro-L-phenylalanine(2S,3aS,6aS)-Octahydrocyclo-penta[b]pyrrole-2-carboxylic acid(2S,3aS,6aS)-Octahydrocyclopenta[b]pyrrole-2-carboxylic acid(2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid(2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid(2S)-2-(Amino)-2-[(1S,3S)-3-hydroxycyclohexyl]acetic acid(2S)-2-(Amino)-2-[(1S,3S)-3-hydroxycyclohexyl]acetic acid2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid(2S)-3-(Triazol-1-yl)-2-(amino)propanoic acid(2S)-3-(Triazol-1-yl)-2-(amino)propanoic acidTetrahydro-2H-pyran-3-ylacetic acidTetrahydro-2H-pyran-3-ylacetic acidrel-(1R,3S)-3-[(Amino)methyl]cyclohexanecarboxylic acidrel-(1R,3S)-3-[(Amino)methyl]|cyclohexanecarboxylic acid(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1)(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1)(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2)(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2)TranexamicTranexamic acidtrans-2-(3-(Amino)cyclohexyl)acetic acidtrans-2-(3-(Amino)cyclohexyl)acetic acid(trans-4-Fluoro)Ptrans-4-Fluoroproline(Trifluoro)1 / L5,5,5-Trifluoro-DL-leucineTTDS1,13-Diamino-4,7,10-trioxatridecan-succinamic acid(R)-Pyrrolidine-3-acetic acid(R)-Pyrrolidine-3-acetic acidPro-D2L-Proline (3,4- 2 H) (deuterated)(2S)-2-(morpholin-4-yl)propanoic acid(2S)-2-(morpholin-4-yl)propanoic acidL-dehydroproline3,4-dehydro-L-proline(3S)-2-azaspiro[4.4]nonane-3-carboxylic acid(3S)-2-azaspiro[4.4]nonane-3-carboxylic acid(2R)-2-amino-3-(trifluoromethylsulfanyl)propanoic acid(2R)-2-amino-3-(trifluoromethylsulfanyl)propanoic acidArg(13C6,15N4)L-Arginine-N-Fmoc, Pbf-OH (13C6, 15N4)

[0169] The term "mimetic", used in context with some amino acids in the definition of several moieties of the peptide according to formula (I) or formula (II) of the presentdisclosure, represents a respective amino acid mimetic, such as e.g. an arginine mimetic, an isoleucine mimetic or a proline mimetic. Generally, a "protein mimetic" indicates a molecule such as a peptide, a modified peptide or any other molecule that biologically mimics the action or activity of some other protein. In context with the use of the term "mimetic" in connection with a certain amino acid said term "mimetic" analogously indicates any other amino acid, amino acid analogue, amino acid derivative, amino acid conjugate or the like, which biologically mimics the action or activity of the respective amino acid.

[0170] Proline mimetics according to the present disclosure comprise in particular (1S,2S,5R)-3-Azabicyclo-[3.1.0]hexane-2-carboxylic acid, Hyp, Morpholine-3-carboxylic, Pip, (4aR,6aR,9S,11aS)-11-Oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid or (trans-4-Fluoro)P, (1R,28,55)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, Oic, Hyp, (4-CF3)P, (cis-4-Fluoro)P, 3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid, (3S-OH)P, (1R,35,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxylic acid, (6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid, rel-(1R,3R,5R,6R)-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S,3aS,6aS)-Octahydrocyclopenta[b]pyrrole-2-carboxylic acid or difluoroproline, (3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1), (3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2) and substituted prolines.

[0171] Isoleucine mimetics according to the present disclosure comprise in particular (N-Methyl)-I, allo-Ile, Cba, Nva, Abu, Leu, Cpg, cyclohexyl-Gly, (S)-2-Amino-3-ethyl-pentanoic acid, 3-Chloro-Phg, allo-Ile, Chg, Cyclobutylglycine, allo-Ile, Cbg, (2S,3S)-2-((Amino)methyl)-3-methylpentanoic acid, Phg, 2-[(1S,2S)-1-(Amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid, 2-Methyl-D-alloisoleucine, Nva, Abu or Ala.

[0172] Leucine mimetics according to the present disclosure comprise in particular (tBu)A, (2-Chloro)F, (2-Bromo)F, AAD, (2S)-2-Amino-4,4,4-trifluorobutanoic acid, Cnba, (4-Fluoro)L, (S)-(trifluoromethyl)-L-cysteine, (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid, Gly(tBu), 3-(Trimethylsilyl)-L-alanine, 2,5-difluoro-L-phenylalanine, 2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid, 5,5,5-Trifluoro-L-leucine ((Trifluoro)L), (2-Me)F, Cba, Cpa, cyclopropyhnethylalanine, trifluoromethylalanine or difluoromethyl-alanine, (2-Fluoro)F, (2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acid, (2S)-3-(3-Cyanophenyl)-2-aminopropanoic acid, 2-Amino-5,5,5-trifluoro-4-methyl-pentanoic acid, (2S)-2-Amino-5-methyl-hexanoic acid or (2S)-3-(indol-4-yl)-2-(amino)propanoic acid.

[0173] The disclosure further comprises analogues and derivatives of the described peptides. The term "analogue" or "derivative" of a peptide or an amino acid sequence according to the present disclosure comprises in particular any amino acid sequence having a sequence identity of at least 80% or at least 85%, preferably at least 90%, more preferably at least 95%, and even more preferably of at least 99% identity to said sequence, and same or comparable properties or activity. Sequence identity can be determined by common techniques, such as visual comparison or by means of any computer tool generally used in the field. Examples comprise BLAST programs used with default parameters.

[0174] An analogue or derivative of a peptide or an amino acid sequence of the disclosure may result from changes derived from mutation or variation in the sequences of peptides of the invention, including the deletion or insertion of one or more amino acids or the substitution of one or more amino acids, or even to alternative splicing. Several of these modifications may be combined. Preferably, an analogue of an amino acid sequence of the invention comprises conservative substitutions relative to the sequence of amino acids.

[0175] The term "conservative substitution" as used herein denotes that one or more amino acids are replaced by another, biologically similar residue. Examples include substitution of amino acid residues with similar characteristics, e.g., small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids and aromatic amino acids. See, for example, the scheme in Table 4 below, wherein conservative substitutions of amino acids are grouped by physicochemical properties. I: neutral, hydrophilic; II: acids and amides; III: basic; IV: hydrophobic; V: aromatic, bulky amino acids, VI: neutral or hydrophobic; VII: acidic; VIII: polar. Table 4: Amino Acids grouped according to their physicochemical propertiesI II III IV V VI VII VIII AlaAsnHisMetPheAlaGluMetSerAspArgLeuTyrLeuAspSerThrGluLysIleTrpIleThrProGlnValProCysGlyCysGlyAsnValGln

[0176] A peptide analogue or derivative may also comprise one or more additional modifications such as, e.g., conjugation to another compound to form an amino acid conjugate.

[0177] Such a modification may, alternatively or additionally, result from conjugation to the side-chains of one or more amino acid residues in a peptide of the present disclosure for example a chemical group as defined above in context with the chemical group X 0< or a polymeric moiety such as a PEG group. Such modification may, for example, increase solubility and / or half-life in vivo (e.g. in plasma) and / or bioavailability of the peptide and are also known to reduce clearance (e.g. renal clearance) of therapeutic proteins and peptides. Suitable modifications are well known to a skilled person and comprise in particular, without being limited thereto, PEGylation of one or more side chains of the peptide of the present invention. Therein, "PEGylation" represents the act of coupling (e.g., covalently) a Polyethylene glycol (PEG) structure to the peptide of the invention. The skilled person knows well possible PEGs for coupling to the amino acid side chains of small peptides for forming a respective conjugate, e.g. from WO 2015 / 200916 A1,.

[0178] All peptides of this disclosure unless otherwise noted are TFA salts. The disclosure comprises further pharmaceutically acceptable salts of the peptides as defined herein and salt free forms. Therein, pharmaceutically acceptable salts represent salts or zwitterionic forms of the peptides or compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit / risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, carbonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthyl-enesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Preferred acid addition salts include trifluoroacetate, formate, hydrochloride, and acetate.

[0179] Also, amino groups in the compounds of the present disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. A pharmaceutically acceptable salt may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts. citrate salts and acetate salts.

[0180] Examples of basic salts include salts where the cation is selected from alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type N(R 1< )(R 2< )(R 3< )(R 4< ) +< , where R 1< , R 2< , R 3< and R 4< independently from each other will typically designate hydrogen, optionally substituted C 1-6 -alkyl or optionally substituted C 2-6 -alkenyl. Examples of relevant C 1-6 -alkyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. Examples of C 2-6 -alkenyl groups of possible relevance include ethenyl, 1-propenyl and 2-propenyl. Therein, salts where the cation is selected among sodium, potassium and calcium are preferred.

[0181] Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the "Encyclopaedia of Pharmaceutical Technology", 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007. Also, for a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley- VCH, 2002). Other suitable base salts are formed from bases which form non-toxic salts. Representative examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts, preferably choline. Hemisalts of acids and bases may also be formed, e.g., hemisulphate and hemicalcium salts.

[0182] The disclosure further comprises solvates of the peptides as defined herein. Therein the term "solvate" refers to a complex of defined stoichiometry formed between a solute (e.g., a peptide according to the invention or pharmaceutically acceptable salt thereof) and a solvent. The solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small-molecular organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is normally referred to as a hydrate.

[0183] The compounds according to the disclosure have useful pharmacological properties and can be used for prevention and treatment of disorders in humans and animals.

[0184] In the context of the presentdisclosure, the references to methods of treatment by therapy or surgery or in vivo diagnosis methods in the examples of this description are to be interpreted as references to compounds, pharmaceutical compositions and medicaments of the present invention for use in those methods".

[0185] In the context of the presentdisclosure, the term "treatment" or "treat" includes the inhibition, delay, arrest, amelioration, attenuation, limitation, reduction, suppression, reversal or cure of a disease, a condition, a disorder, an injury or health impairment, of the development, course or the progression of such states and / or the symptoms of such states. Here, the term "therapy" is understood to be synonymous with the term "treatment".

[0186] In the context of the presentdisclosure, the terms "prevention", "prophylaxis" or "precaution" are used synonymously and refer to the avoidance or reduction of the risk to get, to contract, to suffer from or to have a disease, a condition, a disorder, an injury or a health impairment, a development or a progression of such states and / or the symptoms of such states.

[0187] The treatment or the prevention of a disease, a condition, a disorder, an injury or a health impairment may take place partially or completely.

[0188] The compounds according to the disclosure are particularly suitable for the treatment and / or prevention of cardiovascular, cardiopulmonary, renal, pulmonary, fibrotic, thromboembolic, and inflammatory disorders.

[0189] Accordingly, the compounds according to the disclosure can be used in medicaments for the treatment and / or prevention of cardiovascular and cardiopulmonary disorders and their sequels such as, for example inflammatory heart diseases, myocarditis, endocarditis, pericarditis, rheumatic fever without and with heart involvement, acute rheumatic pericarditis, acute rheumatic endocarditis, acute rheumatic myocarditis, chronic rheumatic heart diseases with and without endocarditis, valvulitis, pericarditis, ischemic heart diseases such as unstable angina pectoris and acute myocardial infarction, atrial and ventricular arrhythmias and impaired conduction such as, for example, grade I-III atrioventricular blocks, supraventricular tachy-arrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachy-arrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, stroke due to occlusion and stenosis of cerebral arteries (Cerebral infarction following e.g. thromboembolic, atherosclerotic, infectious and inflammatory vascular lesions), for the treatment and / or prevention of stroke due to intracerebral or intracranial haemorrhage, peripheral ischemic tissue damage (e.g. atherosclerotic gangrene) due to diseases of arteries, arterioles and capillaries (e.g. thromboembolic, atherosclerotic, infectious and inflammatory vascular lesions, endarteritis deformans or obliterans, and aneurysm dissection), phlebitis and thrombophlebitis, for preventing postprocedural disorders of the circulatory system, e.g. systemic inflammatory response syndrome, vasoplegia after surgery, postcardiotomy syndrome, postprocedural hypotension and heart failure, for preventing and treating ischemia reperfusion injury and organ dysfunction for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), bypass operations and heart, lung, liver and kidney transplants, and for the prevention and treatment of delayed graft function after kidney transplantation.

[0190] The compounds according to the disclosure are furthermore suited for the treatment of shock such as cardiogenic shock, septic shock and anaphylactic shock by preveting MASP mediated end organ damages.

[0191] Moreover, the compounds according to the disclosure have antiinflammatory action and can therefore be used as antiinflammatories for treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic bowel inflammations (IBD, Crohn's Disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders.

[0192] By virtue of their activity profile, the compounds according to the disclosure are particularly suitable for the treatment and / or prevention of cardiovascular, pulmonary, cerebral and renal sequels of sepsis and systemic inflammatory response syndrome.

[0193] The compounds according to the disclosure are particularly suitable for the treatment and / or prevention of ischemia and / or reperfusion-related damage to the heart and the kidney and other organs in the context of resuscitation and surgical interventions such as but not restricted to bypass operations, heart valve surgery, and aortic aneurysm surgery,

[0194] The compounds according to the disclosure can additionally also be used for preventing ischaemic and / or reperfusion-related damage to organs or tissues and also as additives for perfusion and preservation solutions of organs, organ parts, tissues or tissue parts of human or animal origin, in particular for surgical interventions or in the field of transplantation medicine.

[0195] Furthermore, the compounds according to the disclosure are suitable for the treatment and / or prevention of diseases of the blood and blood-forming organs and the immune system including but not limited to acquired haemolytic anaemia, haemolytic-uraemic syndrome, paroxysmal nocturnal haemoglobinuria [Marchiafava-Micheli], coagulation defects, purpura and other haemorrhagic conditions, disseminated intravascular coagulation [defibrination syndrome], essential (haemorrhagic) thrombocythaemia, purpura fulminans, thrombotic thrombocytopenic purpura, allergic purpura, allergic vasculitis, lymphopenia and lgranulocytosis, and sarcoidosis.

[0196] Furthermore, the compounds according to the disclosure are suitable for the treatment and / or prevention of sequels of diabetes mellitus sucha as renal complications of diabetes mellitus, diabetic nephropathy, intracapillary glomerulonephrosis, ophthalmic complications of diabetes mellitus, diabetic retinopathy, neurological complications, diabetic polyneuropathy, and circulatory complications such as microangiopathy and gangrene.

[0197] Moreover, the compounds according to the disclosure are suitable for the treatment and / or prevention of inflammatory diseases of the nervous system such as multiple sclerosis, meningitis and encephalitis, bacterial and viral meningitis and encephalitis, postimmunization encephalitis, inflammatory polyneuropathy, and polyneuropathy in infectious and parasitic diseases.

[0198] The compounds according to the disclosure are furthermore suitable for the treatment and / or prevention of diseases of the eye and its adnexa, such as acute and subacute iridocyclitis, choroidal degeneration, chorioretinal inflammation, chorioretinal inflammation in infectious and parasitic diseases, background retinopathy and retinal vascular changes, proliferative retinopathy, degeneration of macula and posterior pole, peripheral retinal degeneration, age-related macular degeneration (AMD) including dry (non-exudative) and wet (exudative, neovascular) AMD, choroidal neovascularization (CNV), choroidal neovascular membranes (CNVM), cystoid macular oedema (CME), epiretinal membranes (ERM) and macular perforations, myopia-associated choroidal neovascularization, angioid and vascular streaks, retinal detachment, diabetic retinopathy, diabetic macular oedema (DME), atrophic and hypertrophic lesions in the retinal pigment epithelium, retinal vein occlusion, choroidal retinal vein occlusion, macular oedema, macular oedema associated with retinal vein occlusion, postprocedural disorders of eye and adnexa, e.g. keratopathy following cataract surgery.

[0199] Furthermore, the compounds according to the disclosure are suitable for the treatment and / or prevention of diseases of the respiratory system including but not restricted to viral, bacterial, and mycotic pneumonia, radiation pneumonitis, pneumoconiosis, allergic alveolitis, airway disease due to specific organic dust, e.g. farmer lung, bronchitis, pneumonitis and pulmonary oedema due to chemicals, gases, fumes and vapours, drug-induced interstitial lung disorders, adult respiratory distress syndrome (ARDS) and acute lung injury (ALI), acute oedema of the lung, interstitial pulmonary diseases with fibrosis, rheumatoid lung disease, respiratory disorders in other diffuse connective tissue disorders, such as associated to systemic lupus erythematosus, sclerodermia and Wegener granulomatosis.

[0200] Furthermore, the compounds according to the disclosure are suitable for treatment and / or prevention of microvascular injury, thrombosis and consecutive thromboembolic events caused by viral infections such as, but not restricted to, Influenza viruses (e.g. caused by strains of serotypes H1N1, H5N1, H7N9), and Corona viruses (e.g. SARS-CoV, the pathogen of severe acute respiratory syndrome (SARS), MERS-CoV, the pathogen of Middle East respiratory syndrome (MERS), and SARS-CoV-2 the pathogen of COVID-19 pandemic).

[0201] Furthermore, the compounds according to the disclosure are suitable for the treatment and / or prevention of diseases of the digestive system including but not restricted to noninfective enteritis and colitis such as Crohn disease and ulcerative colitis, pancreatitis (including acute alcohol- and drug induced pancreatitis), cholecystitis, inflammatory liver diseases, hepatorenal syndrome, postprocedural disorders of the liver, e.g. after liver surgery.

[0202] By virtue of their activity profile, the compounds according to the disclosure are particularly suitable for the treatment and / or prevention of diseases of the genitourinary system including but not restricted to acute renal failure, acute kidney injury (AKI), surgery associated AKI, sepsis associated AKI, contrast media and chemotherapy induced AKI, ischaemia and infarction of the kidney, complications such as hypersensitivity in the context of hemodialysis and hemodiafiltration, cystitis, irradiation cystitis, inflammatory diseases of the prostate, and endometriosis.

[0203] The compounds according to the disclosure are furthermore suitable for the treatment and / or prevention of sequels of burns and injuries including but not restricted to early complications of trauma, traumatic anuria, crush syndrome, renal failure following crushing, traumatic ischaemia of muscle, traumatic brain injury, organ damage after exposure to electric current, radiation and extreme ambient air temperature and pressure, after exposure to smoke, fire and flames, after contact with venomous animals and plants.

[0204] By virtue of their activity profile, the compounds according to the disclosure are furthermore suitable for the treatment of inflammatory skin diseases for example dermal lupus erythematosus, bullous disorders and acantholytic skin diseases such as pemphigus subtypes, papulosquamous disorders such as psoriasis, dermatitis and eczema, urticaria and erythema.

[0205] According to a further embodiment, the disclosure provides a compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue or pharmaceutically acceptable salts or solvates thereof for the use in the prophylaxis and / or treatment of diseases.

[0206] According to a further embodiment, the disclosure provides a compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue or pharmaceutically acceptable salts or solvates thereof for the use in the prophylaxis and / or treatment of MASP-associated disorders.

[0207] According to a further embodiment, the disclosure provides a compound containing a peptidewhich may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, which acts as a MASP-1 and / or MASP-2 inhibitor and / or which inhibits C3 deposition, for the use in the prophylaxis and / or treatment of MASP-associated disorders.

[0208] According to a further embodiment, the disclosure provides a compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue or pharmaceutically acceptable salts or solvates thereof for the use in the prophylaxis and / or treatment of cardiovascular and cardiopulmonary disorders, shock, inflammatory disorders, cardiovascular, pulmonary, cerebral and renal sequels of sepsis, ischemia and / or reperfusion-related damage, acute kidney injury, transplant protection and delayed graft function, diseases of the blood and blood-forming organs and the immune system, sequels of diabetes mellitus, inflammatory diseases of the nervous system, diseases of the eye, diseases of the skin, diseases of the respiratory, digestive or genitourinary system and sequels of burns and injuries.

[0209] According to a further embodiment, the disclosure provides a compound containing a peptidewhich may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue or pharmaceutically acceptable salts or solvates thereof for the use in the prophylaxis and / or treatment of diseases of the genitourinary system including but not restricted to acute renal failure, acute kidney injury (AKI), surgery associated AKI, sepsis associated AKI, contrast media and chemotherapy induced AKI, ischaemia and infarction of the kidney, complications such as hypersensitivity in the context of hemodialysis and hemodiafiltration, cystitis, irradiation cystitis, inflammatory diseases of the prostate, and endometriosis.

[0210] The disclosure further relates to a method of treating or ameliorating MASP-associated disorders, as defined above, in a subject or patient by administering at least one peptide, derivative or analogue as defined herein or a pharmaceutically acceptable salt or solvate thereof, a complex or a pharmaceutical composition as defined above, to said subject or patient in need thereof.

[0211] As used herein, the terms "patient", "subject" or "individual" may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats). The term "mammal" refers to any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.

[0212] According to the description the at least one peptide, derivative or analogue as defined herein or the pharmaceutically acceptable salt or solvate thereof, or the complex as defined above is administered to a patient or subject in a therapeutically effective amount. wherein a "therapeutically effective amount" of a compound of the present invention is meant to describe a sufficient amount of a compound of the present invention to treat an MASP-associated disorder as defined herein. In particular embodiments, the therapeutically effective amount will achieve a desired benefit / risk ratio applicable to any medical treatment.

[0213] The present disclosure particularly comprises the following embodiments, wherein the substituents or moieties of the peptide according to formula (I) or formula (II) as defined below, may independently have the meanings as described below.

[0214] A peptide or a compound containing a peptide, or derivative or analogue thereof as defined herein or the pharmaceutically acceptable salt or solvate thereof or the complex or the pharmaceutical composition (as defined below), are hereinafter commonly also referred to as "MASP inhibitory peptide of the present invention".

[0215] In some embodiments, a MASP inhibitory peptide of the present invention binds to MASP-1 and / or MASP-2, e.g. human MASP-1 and / or MASP-2. In certain embodiments, a MASP inhibitory peptide of the present invention specifically binds to human MASP-1 and / or MASP-2. As used herein, "specifically binds" refers to a specific binding agent's preferential interaction with a given ligand over other agents in a sample. For example, a specific binding agent that specifically binds a given ligand binds the given ligand, under suitable conditions, in an amount or a degree that is observable over that of any nonspecific interaction with other components in the sample. Suitable conditions are those that allow interaction between a given specific binding agent and a given ligand. These conditions include pH, temperature, concentration, solvent, time of incubation, and the like, and may differ among given specific binding agent and ligand pairs, but may be readily determined by those skilled in the art. In some embodiments, a MASP inhibitory peptide of the present invention binds MASP-1 and / or MASP-2 with greater specificity than a MASP inhibitory peptide reference compound (e.g. any one of the MASP inhibitory peptide reference compounds provided herein).

[0216] The thus further relates to a complex comprising at least one peptide or compound containing a peptide, derivative or analogue as defined herein bound to MASP-1 or MASP-2.

[0217] In some embodiments, a MASP inhibitory peptide of the present invention exhibits specific binding to MASP-1 and / or MASP-2, especially human MASP-1 and / or MASP-2, that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, 1000%, or 10000% higher than a selected MASP inhibitory peptide reference compound.

[0218] In some embodiments, a MASP inhibitory peptide of the present invention exhibits specific binding to MASP-1 and / or MASP-2, especially human MASP-1 and / or MASP-2, that is at least about 1, 2, 3, 4, 5-fold, or at least about 10, 20, 50, or 100-fold higher than a selected MASP inhibitory peptide reference compound.

[0219] In some embodiments, a MASP inhibitory peptide of the present invention exhibits a binding affinity to MASP-1 and / or MASP-2 that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, 1000%, or 10000% higher than a selected MASP inhibitory peptide reference compound.

[0220] In some embodiments, a MASP inhibitory peptide of the present invention exhibits a binding affinity to MASP-1 and / or MASP-2 that is at least about 1, 2, 3, 4, 5-fold, or at least about 10, 20, 50, 100 or 1000-fold higher than a selected MASP inhibitory peptide reference compound.

[0221] In some embodiments, a MASP inhibitory peptide of the present invention exhibits an inhibition of MASP-1 and / or MASP-2 (e.g., rat or human MASP-1 and / or MASP-2) activity. In some embodiments, the activity is an in vitro or an in vivo activity, e.g. an in vitro or in vivo activity described herein. In some embodiments, a MASP inhibitory peptide of the present invention inhibits at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, 1000%, or 10000% of the MASP-1 and / or MASP-2 activity inhibited by a selected MASP inhibitory peptide reference compound.

[0222] In certain embodiments, the MASP inhibitory peptide of the present invention exhibits 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200-fold greater MASP-1 and / or MASP-2 inhibition than a selected MASP inhibitory peptide reference compound.

[0223] In further particular embodiments, the MASP-1 and / or MASP-2 inhibitory activity of the MASP inhibitory peptides according to the present invention is determined by measurement of their IC 50 for MASP-1 and / or MASP-2 (e.g., rat human MASP-1 and / or MASP-2). Determination of the IC 50 for MASP-1 and / or MASP-2 can be done with the biochemical assays shown herein. It is particularly preferred that a MASP inhibitory peptide of the present invention exhibits an IC 50 for MASP-1 and / or MASP-2 of < 1,000 nM, preferably ≤ 500 nM, more preferably ≤ 300 nM, more preferably ≤ 250 nM, more preferably ≤ 200 nM, more preferably ≤ 150 nM, more preferably ≤ 100 nM, more preferably ≤ 75 nM, more preferably ≤ 50 nM, more preferably ≤ 45 nM, more preferably ≤ 40nM, more preferably ≤ 35nM, more preferably ≤ 30 nM.

[0224] In some embodiments, a MASP inhibitory peptide of the present invention has a lower IC 50 (i.e. higher binding affinity) for MASP-1 and / or MASP-2, (e.g., rat or human MASP-1 and / or MASP-2) compared to a selected MASP inhibitory peptide reference compound. In some embodiments, a MASP inhibitory peptide according to the present invention has an IC 50 in a MASP-1 and / or MASP-2 competitive binding assay which is at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, 1000% or 10000% lower than that of a selected MASP inhibitory peptide reference compound.

[0225] In some embodiments, a MASP inhibitory peptide of the present invention exhibits at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or greater than 99%, 100%, 200%, 300%, 400%, 500%, 700%, 1000% or 10000% greater in vitro inhibition of human MASP-1 and / or MASP-2 activity as that of a selected MASP inhibitory peptide reference compound.

[0226] In some embodiments, a MASP inhibitory peptide of the present invention exhibits at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or greater than 99%, 100%, 200%, 300%, 400%, 500%, 700%, 1000% or 10000% greater in vivo inhibition of human MASP-1 and / or MASP-2 activity as that of a selected MASP inhibitory peptide reference compound.

[0227] As used herein, in certain embodiments, a MASP inhibitory peptide having a "MASP-1 and / or MASP-2 inhibitory activity" means that the compound has the ability to inhibit C3 deposition in vitro or in subjects (e.g. mice or humans), when administered thereto (e.g. by the parenteral route, e.g. by injection, or by the pulmonary, nasal, sublingual, lingual, buccal, dermal, transdermal, conjunctival, optic route or as implant or stent orally administered), in a dose-dependent and time-dependent manner.

[0228] In some embodiments, a MASP inhibitory peptide of the present invention exhibits an inhibition of C3 deposition (e.g., human C3 deposition. In some embodiments, the inhibition of C3 deposition is mdetermined by an in vitro or an in vivo inhibition. In some embodiments, a MASP inhibitory peptide of the present invention inhibits at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, 1000%, or 10000% of the C3 deposition inhibited by a selected MASP inhibitory peptide reference compound.

[0229] In certain embodiments, the MASP inhibitory peptide of the present invention exhibits 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200-fold greater inhibition of C3 deposition than a selected MASP inhibitory peptide reference compound.

[0230] In further particular embodiments, the MASP-1 and / or MASP-2 inhibitory activity of the MASP inhibitory peptides according to the present invention is determined by measurement of their IC 50 for inhibition of C3 deposition in vitro or in subjects (e.g. mice or humans). Determination of the IC 50 for C3-deposition can be done with the C3 Human Deposition assay shown herein. It is particularly preferred that a MASP inhibitory peptide of the present invention exhibits an IC 50 for C3 deposition of < 1,000 nM, preferably ≤ 500 nM, more preferably ≤ 300 nM, more preferably ≤ 250 nM, more preferably ≤ 200 nM, more preferably ≤ 150 nM, more preferably ≤ 100 nM, more preferably ≤ 75 nM, more preferably ≤ 50 nM, more preferably ≤ 45 nM, more preferably ≤ 40nM, more preferably ≤ 35nM, more preferably ≤ 30 nM.

[0231] In some embodiments, a MASP inhibitory peptide of the present invention exhibits at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or greater than 99%, 100%, 200% 300%, 400%, 500%, 700%, 1000% or 10000% greater in vitro inhibition of C3-deposition as that of a selected MASP inhibitory peptide reference compound.

[0232] In some embodiments, a MASP inhibitory peptide of the present invention exhibits at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or greater than 99%, 100%, 200% 300%, 400%, 500%, 700%, 1000% or 10000% greater in vivo inhibition of C3-deposition as that of a selected MASP inhibitory peptide reference compound.

[0233] It is particularly preferred that a peptide according to the present invention acts as a MASP inhibitory peptide with its activity being determined in accordance with at least one of the specific assays and / or the in vivo studies according to the examples of the present invention.

[0234] Due to their aforesaid MASP-1 and / or MASP-2 inhibitory activity and inhibitory activity of C3-deposition, a compound containing the peptide or the peptide of the present invention (including analogues, derivatives, and pharmaceutically acceptable salts or solvates thereof as well as the above mentioned complex) are suitable for the use in in the prophylaxis and / or treatment of MASP-1 and / or MASP-2-associated disorders.

[0235] According to a further embodiment, the invention provides a compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, which acts as a MASP-1 and / or MASP-2 inhibitor and / or which inhibits C3 deposition.

[0236] The compounds according to the invention can be used alone or in combination with other active compounds if necessary. The present invention further relates to medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prophylaxis of the aforementioned diseases. As suitable combination active compounds, we may mention for example and preferably: compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 4 inhibitors such as roflumilast or revamilast and PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil; NO-independent but haem-dependent stimulators of guanylate cyclase, in particular riociguat, nelociguat, vericiguat and the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549; NO-independent and haem-independent activators of guanylate cyclase, in particular Runcaciguat, BI 703704 and the compounds described in WO2012 / 139888, WO 2001 / 019780 and WO2014 / 012934; prostacyclin analogs and IP receptor agonists, for example and preferably iloprost, beraprost, treprostinil, epoprostenol, NS-304, selexipag, or ralinepag; endothelin receptor antagonists, for example and preferably bosentan, darusentan, ambrisentan, macicentan or sitaxsentan; vasopressin receptor antagonists, for example tolvaptan, conivaptan, relcovaptan; human neutrophile elastase (HNE) inhibitors, for example and preferably sivelestat or DX-890 (Reltran); compounds which inhibit the signal transduction cascade, in particular from the group of the tyrosine kinase inhibitors, for example and preferably dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib, masitinib, or tandutinib; signal transductuion modulators from the group of ASK1 kinase inhibitors, for example selonsertib; Rho kinase inhibitors, for example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049; active ingredients which reduce vascular wall permeability (oedema formation), by way of example and with preference inhibitors of the ALK1-Smad1 / 5 signalling pathway, inhibitors of the VEGF and / or PDGF signalling pathways, cyclooxygenase inhibitors, inhibitors of the kallikrein-kinin system or inhibitors of the sphingosine-1-phosphate signalling pathways; corticosteroids, for example cortisone, cortisol, prednisolone, methylprednisolone, triamcinolone or dexamethasone; active ingredients which reduce damage to organs under oxidative stress, by way of example and with preference inhibitors of the complement system, especially antagonists of the complement C5a receptor, anti C5 antibodies or agonists of the 5-HT1A receptor; modulators, stimulators and enhancers of the transcription factor Nrf2, for example CXA-10, Oltipraz, dimethyl fumarate or Bardoxolone; adrenomedullin and adrenomedullin derivatives, for example pegylated adrenomedullin, and adrenomedullin stabilizing agents, for example adrecizumab; compounds which inhibit hypoxia inducible factor prolyl hydroxylase (HIF-PH inhibitors), for example molidustat, vadadustat, roxadustat, daprodustat or desidustat; compounds which inhibit induction of cell death and apoptosis pathway, for example QPI-1002; C-Met agonists and hepatocyte growth factor mimetics, for example refanalin; alkaline phosphatase and recombinant alkaline phosphatase; compounds which inhibit inflammatory response and T cell proliferation, for example CD28 antagonistic compounds such as Reltecimod; compounds which modulate the activation of Th17 T cells, for example modulators of the RORc / ROR-gamma transcription factor; compounds antagonizing the Th17 T cell response for example anti IL-17 and anti IL-23 antibodies, for example Ixekizumab, Secukinumab, Brodalumab, Ustekinumab, Guselkumab or PTG-200; antithrombotic agents, for example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, for example and preferably ximelagatran, melagatran, dabigatran, bivalirudin or Clexane. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, for example and preferably tirofiban or abciximab. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, for example and preferably rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with direct inhibitors of coagulation factor XI, inhibitors of coagulation factor XI expression, and anti-coagulation factor XI antibodies such as Xisomab 3G3; In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid-receptor antagonist, for example and preferably spironolactone, eplerenone or fmerenone. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, for example and preferably furosemide, bumetanide, Torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example and preferably pioglitazone or rosiglitazone. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-delta agonist, for example and preferably GW 501516 or BAY 68-5042.

[0237] According to a further embodiment, the invention provides a pharmaceutical composition comprising at least one compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, in combination with one or more further active ingredients selected from the group consisting of inhibitors of phosphodiesterases, stimulators or activators of guanylate cyclase, IP receptor agonists, mineralocorticoid-receptor antagonist, diuretic, PPAR-gamma agonist, PPAR-delta agonist, corticosteroids, active ingredients which reduce damage to organs under oxidative stress, compounds which inhibit induction of cell death and apoptosis pathway, compounds which inhibit inflammatory response and T cell proliferation, antithrombotic agents, platelet aggregation inhibitor, thrombin inhibitor, GPIIb / IIIa antagonist, factor Xa inhibitor, heparin or a low molecular weight (LMW) heparin derivative and inhibitors of coagulation factor XI.

[0238] The invention further relates to a kit-of-parts combination comprising at least one peptide, derivative or analogue as defined herein or a pharmaceutically acceptable salt or solvate thereof, a complex or a pharmaceutical composition as defined above, and at least one selected from a reagent, medical device, instruction letter or any combination thereof.

[0239] The invention further relates to a medical device comprising at least one peptide, derivative or analogue as defined herein or a pharmaceutically acceptable salt or solvate thereof, a complex or a pharmaceutical composition as defined above, for delivery of the peptide, derivative, analogue or complex thereof or of the pharmaceutical composition to a subject.

[0240] The pharmaceutical composition, kit-of-parts combination or medical device as defined above is in particular for the use in the prophylaxis and / or treatment of the disorders or diseases as defined as defined herein.

[0241] It is possible for the MASP inhibitory peptide of the present invention to have systemic and / or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

[0242] For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

[0243] For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films / wafers, films / lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and / or amorphised and / or dissolved form into said dosage forms.

[0244] Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal, intraocular). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

[0245] Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, topical application, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

[0246] According to a further embodiment, the invention provides a pharmaceutical composition comprising at least one compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

[0247] The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ®< ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ®< )), ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette ®< ), sorbitan fatty acid esters (such as, for example, Span ®< ), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween ®< ), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor ®< ), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic ®< ), buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonicity agents (for example glucose, sodium chloride), adsorbents (for example highly-disperse silicas), viscosity-increasing agents, gel formers, thickeners and / or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ®< ); alginates, gelatine), disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ®< ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol ®< )), flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ®< )), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon ®< ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ®< )), capsule materials (for example gelatine, hydroxypropylmethylcellulose), synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ®< ), polyvinylpyrrolidones (such as, for example, Kollidon ®< ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), flavourings, sweeteners, flavour- and / or odour-masking agents.

[0248] The present disclosure furthermore relates to a pharmaceutical composition comprising at least one peptide, derivative or analogue as defined herein or a pharmaceutically acceptable salt or solvate thereof or a complex as defined above.

[0249] In particular, the present disclosure relates to a pharmaceutical composition comprising at least one peptide, derivative or analogue as defined herein or a pharmaceutically acceptable salt or solvate thereof or a complex as defined above, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

[0250] A pharmaceutical composition according to the present disclosure may comprise at least one additional active ingredient, such as preferably an additional active ingredient which is active in the prophylaxis and / or treatment of the disorders or diseases as defined herein.

[0251] The at least one peptide, derivative or analogue as defined herein or the pharmaceutically acceptable salt or solvate thereof or the complex or the pharmaceutical compositions as defined above may be administered enterally or parenterally, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intraarticular injection and infusion, orally, intravaginally, intraperitoneally, intrarectally, topically or buccally. Suitable formulations for the respective administration routes are well known to a skilled person and include, without being limited thereto: pills, tablets, enteric-coated tablets, film tablets, layer tablets, sustained-release or extended-release formulations for oral administration, plasters, topical extended-release formulations, dragees, pessaries, gels, ointments, syrup, granules, suppositories, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, powders, drops, nose drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, infusion solutions or injection solutions, etc.

[0252] According to a further embodiment, the disclosure provides a pharmaceutical composition comprising at least one compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients for the use in the prophylaxis and / or treatment of cardiovascular and cardiopulmonary disorders, shock, inflammatory disorders, cardiovascular, pulmonary, cerebral and renal sequels of sepsis, ischemia and / or reperfusion-related damage, acute kidney injury, transplant protection and delayed graft function, diseases of the blood and blood-forming organs and the immune system, sequels of diabetes mellitus, inflammatory diseases of the nervous system, diseases of the eye, diseases of the skin, diseases of the respiratory, digestive or genitourinary system and sequels of burns and injuries.

[0253] According to a further embodiment, the disclosure provides a pharmaceutical composition comprising at least one compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, in combination with one or more further active ingredients selected from the group consisting of inhibitors of phosphodiesterases, stimulators or activators of guanylate cyclase, IP receptor agonists, mineralocorticoid-receptor antagonist, diuretic, PPAR-gamma agonist, PPAR-delta agonist, corticosteroids, active ingredients which reduce damage to organs under oxidative stress, compounds which inhibit induction of cell death and apoptosis pathway, compounds which inhibit inflammatory response and T cell proliferation, antithrombotic agents, platelet aggregation inhibitor, thrombin inhibitor, GPIIb / IIIa antagonist, factor Xa inhibitor, heparin or a low molecular weight (LMW) heparin derivative and inhibitors of coagulation factor XI for the use in the prophylaxis and / or treatment of cardiovascular and cardiopulmonary disorders, shock, inflammatory disorders, cardiovascular, pulmonary, cerebral and renal sequels of sepsis, ischemia and / or reperfusion-related damage, acute kidney injury, transplant protection and delayed graft function, diseases of the blood and blood-forming organs and the immune system, sequels of diabetes mellitus, inflammatory diseases of the nervous system, diseases of the eye, diseases of the skin, diseases of the respiratory, digestive or genitourinary system and sequels of burns and injuries.

[0254] According to a further embodiment, the disclosure provides a method for treatment and / or prevention of of cardiovascular and cardiopulmonary disorders, shock, inflammatory disorders, cardiovascular, pulmonary, cerebral and renal sequels of sepsis, ischemia and / or reperfusion-related damage, acute kidney injury, transplant protection and delayed graft function, diseases of the blood and blood-forming organs and the immune system, sequels of diabetes mellitus, inflammatory diseases of the nervous system, diseases of the eye, diseases of the skin, diseases of the respiratory, digestive or genitourinary system and sequels of burns and injuries in humans and animals by administration of an effective amount of a pharmaceutical composition comprising at least one compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, or of a pharmaceutical composition comprising at least one compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients and / or one or more further active ingredients.

[0255] The suitable dosage of the MASP inhibitory peptide of the present invention can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including: a) the disorder being treated and the severity of the disorder; b) activity of the specific compound employed; c) the specific composition employed, the age, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific hepcidin analogue employed; e) the duration of the treatment; f) drugs used in combination or coincidental with the MASP inhibitory peptide employed, and like factors well known in the medical arts.

[0256] In particular embodiments, the total daily dose of the MASP inhibitory peptide of the invention to be administered to a subject or patient in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg / kg body weight daily or 1 to 300 mg / kg body weight daily, or from about 0.0001 to about 100 mg / kg body weight per day, such as from about 0.0005 to about 50 mg / kg body weight per day, such as from about 0.001 to about 10 mg / kg body weight per day, e.g. from about 0.01 to about 1 mg / kg body weight per day, administered in one or more doses, such as from one to three doses. Generally, the MASP inhibitory peptide of the invention may be administered continuously (e.g. by intravenous administration or another continuous drug administration method), or may be administered to a subject at intervals, typically at regular time intervals, depending on the desired dosage and the pharmaceutical composition selected by the skilled practitioner for the particular subject. Regular administration dosing intervals include, e.g., once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, and the like.

[0257] The disclosure further comprises the use of the MASP inhibitory peptide as described herein for the manufacture of a medicament, in particular for the manufacture of a medicament for the prophylaxis and / or treatment of a disorder or disease as defined herein.

[0258] The disclosure further comprises a process for manufacturing the peptids of the present invention, derivative or analogue or the pharmaceutically acceptable salt or solvate thereof or a complex, each as described herein. The process for manufacturing comprises the steps as shown in the examples of the present invention.

[0259] Generally, the MASP inhibitory peptide of the present disclosure may be manufactured synthetically, or semi-recombinantly.

[0260] According to a further embodiment, the dosclisure provides a process for preparing a compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue or pharmaceutically acceptable salts or solvates thereof by using solid phase peptide synthesis.

[0261] According to a further embodiment, the disclosure provides a process for preparing a compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, containing the steps 1. Use of a 2-chlorotrityl-type resin with a loading of 0.2 - 1.0 mmol / g, or a Wang-type resin with a loading of 0.2 - 1.0 mmol / gram, 2. Loading the c-terminal amino acid of the sequence onto the resin, 3. Removal of fmoc protection with a 15-25% piperidine solution in DMF or NMP, 4. Coupling of the next amino acid in the sequence with coupling reagents such as HBTU, HATU or DIC / Oxyma using stoichiometries between 3-8 equivalents, 5. Repeating steps 3 and 4 until the sequence is completed, 6. Cleavage of the peptide from the solid support using a cleavage cocktail that involves TFA and a thiol scavenger, 7. Cyclization of two cysteines in the sequence under oxidative conditions (air or I2), 8. Purification of the cleaved peptide using reversed-phase HPLC.

[0262] According to a further embodiment, the disclosure provides a process for preparing a compound containing a peptide which may be isolated and / or purified, comprising, essentially consisting of, or consisting of, formula (I) or formula (II) or a derivative, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, containing the steps 1. Use of a 2-chlorotrityl-type resin with a loading of 0.2 - 1.0 mmol / g, or a Wang-type resin with a loading of 0.2 - 1.0 mmol / gram, 2. Loading the c-terminal amino acid of the sequence onto the resin, 3. Removal of fmoc protection with a 15-25% piperidine solution in DMF or NMP, 4. Coupling of the next amino acid in the sequence with coupling reagents such as HBTU, HATU or DIC / Oxyma using stoichiometries between 3-8 equivalents, 5. Repeating steps 3 and 4 until the sequence is completed, 6. Cleavage of the peptide from the solid support using a cleavage cocktail that involves TFA and a thiol scavenger, 7. Cyclization of two cysteines in the sequence under oxidative conditions (air or I2), 8. Purification of the cleaved peptide using reversed-phase HPLC, 9. Conversion to the HCl salt.

[0263] The at least one peptide, derivative or analogue as defined herein or the pharmaceutically acceptable salt or solvate thereof or the complex as defined herein may also be used as a biochemical agent in a biochemical assay, such as e.g. in a diagnostic assay to measure responsiveness to MASP inhibitors or in any biochemical assay being based on MASP inhibitor binding.

[0264] The present disclosure also includes polynucleotides comprising a sequence encoding a MASP inhibitory peptide according to the present invention, as well as a vector comprising a polynucleotide comprising a sequence encoding a MASP inhibitory peptide according to the present invention.

[0265] The idisclosure is further illustrated by the following examples, which relate to certain specific embodiments of the present invention. The examples were carried out using well known standard techniques within the routine to those of skill in the art, unless indicated otherwise. The following examples are for illustrative purposes only and do not purport to be wholly definitive as to conditions or scope of the invention. As such, they should not be construed in any way as limiting the scope of the present invention.Examples

[0266] List of Abbreviations used in Experimental Section: ÅAngstroms aq.Aqueous, aqueous solution barUnit of pressure BPRBack-pressure regulator concConcentrated dDoublet (NMR) ddDoublet of doublet (NMR) DCMDichloromethane DEADiethylamine DIPEAN,N,-diisopropylethylamine (Hünig's base) DMAP4-Dimethylaminopyridine DMFN,N-dimethylformamide DMSODimethylsulfoxide dtDoublet of triplet (NMR) EAEthyl acetate eeEnantiomeric excess entEnantiomeric eqEquivalent(s) equivEquivalent(s) (ion chromatography) ESIElectrospray-ionisation (mass spectroscopy) Fmoc-OSu1-{[(9H-Fluoren-9-ylmethoxy)carbonyl]oxy}pyrrolidine-2,5-dione GC-MSGas chromatography coupled with mass spectrometry hHour(s) HATUO-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniutn-hexafluorophosphate HPLCHigh pressure liquid chromatography ICIon chromatography IDInternal diameter LLiter LC-MSLiquid chromatography coupled to mass spectroscopy LiHMDSLithium bis(trimethylsilyl)amide lit.Literature mMultiplet (NMR) MALDIMatrix Assisted Laser Desorption / Ionization (mass spectrometry) MeMethyl minMinute(s) mmmillimeter µmmicrometer (micron) MMolar MPLCMedium pressure liquid chromatography MSMass spectroscopy MTBEtert-Butyl methyl ether MTPMicrotiter plate m / zmass-to-charge ratioi (mass spectrometry) nmnanometer NMPN-Methyl-2-pyrrolidone NMRNuclear magnetic resonance spectroscopy PBSPhosphate buffered saline PEPetroleum ether PEGPolyethylene glycol posPositive ppmparts per million PrPropyl PsiPounds per square inch (pressure) q / quartQuartet (NMR) qdQuartet of doublet (NMR) quintQuintet (NMR) racracemic RfRetention factor (TLC) RPreversed-phase (for liquid chromatography) RtRetention time (chromatography) sSinglet (NMR) sSeconds (time) SPPSsolid phase peptide synthesis tTriplet (NMR) TBTUO (Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate tButert-Butyl TEAtriethylamine THFTetrahydrofuran TLCThin layer chromatography UPLCUltra-performance liquid chromatography UVUltraviolet

[0267] Further abbreviations can be found in Table 2 and 3.Analytical LC-MS Methods Method 1

[0268] Equipment type MS: ThermoFisherScientific LTQ-Orbitrap-XL; Equipment type HPLC: Agilent 1200SL; Column: Agilent, POROSHELL 120, 3 x 150 mm, SB - C18 2.7 µm; eluent A: 1 L water + 0.1% trifluoroacetic acid; eluent B: 1 L acetonitrile + 0.1% trifluoroacetic acid; gradient: 0.0 min 2% B → 1.5 min 2% B → 15.5 min 98% B → 18.0 min 98% B; oven: 40°C; flow rate: 0.75 mL / min; UV-detection: 210 nmMethod 2

[0269] Equipment type MS: ThermoFisherScientific LTQ-Orbitrap-XL; Equipment type HPLC: Agilent 1200SL; Column: Agilent, POROSHELL 120; 3 x 150 mm, SB - C18 2.7 µm; eluent A: 1 L water + 0.1% trifluoroacetic acid; eluent B: 1 L acetonitrile + 0.1% trifluoroacetic acid; gradient: 0.0 min 5% B → 0.3 min 5% B → 7.0 min 98% B → 10 min 98% B; oven: 40°C; flow rate: 0.75 mL / min; UV-detection: 210 nmMethod 3

[0270] Equipment type MS: Waters TOF instrument; Equipment type UPLC: Waters Acquity I-CLASS; Column: YMC, TRIART C18, 75 x 1 mm, 3.0 µm x 12mn ; eluent A: 1 L water + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 1% B → 2.0 min 1% B -8.0 min 95% B → 10.0 min 95% B; oven: 50°C; flow rate: 0.63 mL / min; UV-detection: 210 nmMethod 4

[0271] Equipment type MS: Waters TOF instrument; Equipment type UPLC: Waters Acquity I-CLASS; Column: YMC, TRIART C18, 75 x 1 mm, 3.0 µm 12nm ; eluent A: 1 L water + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 1% B → 1.0 min 1% B -15.0 min 50% B → 18.0 min 95% B; oven: 50°C; flow rate: 0.63 mL / min; UV-detection: 210 nmMethod 5

[0272] Equipment type MS: Waters TOF instrument; Equipment type UPLC: Waters Acquity I-CLASS; Column: Waters, HSST3, 2.1 x 50 mm, C18 1.8 µm; eluent A: 1 L water + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 2% B → 0.5 min 2% B → 7.5 min 95% B → 10.0 min 95% B; oven: 50°C; flow rate: 1.00 mL / min; UV-detection: 210 nmMethod 6

[0273] Equipment type MS: Waters Synapt G2S; Equipment type UPLC: Waters Acquity I-CLASS; Column: Waters, BEH300, 2.1 x 150 mm, C18 1.7 µm; eluent A: 1 L water + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 2% B → 1.5 min 2% B → 8.5 min 95% B → 10.0 min 95% B; oven: 50°C; flow rate: 0.50 mL / min; UV-detection: 220 nmMethod 7

[0274] Instrument type MS: Agilent 6410 Triple Quad; Instrument type HPLC: Agilent 1200; Column: Gemini-NX C18 5µm 110Å 150 x 4.6 mm; eluent A: 0.1%TFA in H 2 O; eluent B: 0.1%TFA in ACN; gradient: 0.0 min 20% B → 20 min 50% B → 20.1 min 90% B → 23 min 90% B; oven temperature: 50°C; flow rate: 1.0 mL / min; UV-detection: 220 nmMethod 8

[0275] Instrument type MS: Agilent 6410 Triple Quad; Instrument type HPLC: Agilent 1200; Column: Discovery BIO Wide Pore C18 5µm 300Å x 4.6 mm; eluent A: 0.1%TFA in H 2 O; eluent B: 0.1%TFA in ACN; gradient: 0.0 min 10% B → 20 min 80% B → 20.1 min 90% B → 23 min 90% B; oven temperature: 50°C; flow rate: 1.0 mL / min; UV-detection: 220 nmMethod 9

[0276] Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 1 mm; eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 99% formic acid; gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; oven: 50 °C; flow: 0.40 mL / min; UV-detection: 210 nmMethod 10

[0277] Instrument MS: Thermo Scientific FT-MS; Instrument UHPLC: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 µm; eluent A: 1 L watMethod 10er + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; oven: 50°C; flow rate: 0.90 mL / min; UV-detection: 210 nm / Optimum Integration Path 210-300 nmMethod 11

[0278] MS Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 2.1 mm; eluent A: 1 L water + 0.25 mL formic acid, eluent B: 1 L acetonitrile + 0.25 mL formic acid; gradient: 0.0 min 90% A → 0.3 min 90% A → 1.7 min 5% A → 3.0 min 5% A oven: 50°C; flow rate: 1.20 mL / min; UV-detection: 205 - 305 nm.Method 12

[0279] Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSST3 1.8 µm 50 x 1 mm; eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 99% formic acid; gradient: 0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A oven: 50°C; flow rate: 0.35 mL / min; UV-detection: 210 nm.Method 13

[0280] Instrument: Waters Single Quad MS System; Instrument Waters UPLC Acquity; column: Waters BEH C18 1.7 µm 50 x 2.1 mm; eluent A: 1 L water + 1.0 mL (25% ammonia) / L, eluent B: 1 L acetonitrile; gradient: 0.0 min 92% A → 0.1 min 92% A → 1.8 min 5% A → 3.5 min 5% A; oven: 50°C; flow rate: 0.45 mL / min; UV-detection: 210 nm.Method 14

[0281] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters Acquity UPLC Peptide BEH C18 300Å, 1.7 µm 150 x 2.1 mm; Eluent A: 1 l Water + 0.100 ml 99% Formic acid, Eluent B: 1 l Acetonitrile + 0.100 ml 99% Formic acid; Gradient: 0.0 min 90% A -0.25 min 90% A → 8.0 min 45% A → 10.0 min 2% → 12.0 min 2% A Oven: 50°C; Flow: 0.475 ml / min; UV-Detection: 210 nm.Method 15

[0282] MS instrument type: Agilent G6110A; HPLC instrument type: Agilent 1200 Series LC; UV DAD; column: Chromolith Flash RP-18e 25 x 2.0mm; mobile phase A: 0.0375% TFA in water (v / v), mobile phase B: 0.01875% TFA in acetonitrile (V / V); gradient: 0.01 min 5% B → 0.80 min 95% B → 1.20 min 95% B → 1.21 min 5% B → 1.5 min 5% B; flow rate: 1.50 mL / min; oven temperature: 50 °C; UV detection: 220 nm & 254 nm.MALDI Method

[0283] Exact mass measurements were performed on selected peptides using a Matrix Assisted Laser Desorption / Ionization (MALDI) mass spectrometry method on a Bruker autoflex maX LRF MALDI MS Time-of-Flight (ToF-MS) system. Samples were prepared on a Bruker MALDI target plate using α-cyano-4-hydroxycinnamic acid (CAS 28166-41-8) as the matrix. A solution of the sample peptide 0.1 to 1.0 mg in 1.0 mL acetonitrile-water (50 / 50 or 30 / 70) and a stock solution of the matrix (10 mg / mL) in 50% acetonitrile in water containing 0.05% trifluoroacetic acid are prepared. 1.0 uL of each solution is placed onto the MALDI target plate and allowed to dry. The sample is then ready for analysis. Recommended sample preparations for MALDI target plates can be found in the documention provided by Bruker.Analytical Ion Chromatography Method Method: IC - Quantitative

[0284] Quantitative Measurement of Cations and Anions using external standards; Instrument: Thermo Scientific ICS 5000+; Capillary IC Columns: IonPac AS11-HC und IonPac CS16; eluent: gradient eluent [H]+ [OH]- ; Detector: Conductivity detection; routine anions possible: acetate, bromide, citrate, chloride, fluoride, formate, lactate, mesylate, phosphate, sulfate, tartrate, trifluoroacetate; routine cations possible: ammonium, barium, calcium, potassium, lithium, sodium, magnesium, choline.Analytical Gas Chromatography Mass Spec Method GC-MS Method 1

[0285] Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 m x 200 µm x 0.33 µm; constant flow with Helium: 1.20 mL / min; oven: 60°C; Inlet: 220°C; gradient: 60°C, 30°C / min → 300°C (3.33 min hold).NMR

[0286] The 1< H-NMR data of selected compounds are listed in the form of 1< H-NMR peaklists. Therein, for each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ1 (intensity1), δ2 (intensity2), ... , δi (intensityi), ... , δn (intensityn).

[0287] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1< H-NMR peaklist is similar to a classical 1< H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities, 13C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "byproduct fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%.Preparation Examples General Methods for the Synthesis

[0288] Solid Phase Peptide Synthesis (SPPS) was carried out either using an automatic peptide synthesizer or performed manually by hand. Peptide synthesis was typically carried out in scale ranges from 0.1 to 1.0 mmol. When peptide synthesis was carried out by hand, the general procedures Methods C, D and E described below were used. Automated peptide synthesis was performed on a Symphony X peptide synthesizer (Gyros Protein Technologies).

[0289] Fmoc-protected amino acids (or intermediate amino acids used to prepare Fmoc amino acids) were purchased from Novabiochem, Bachem, Iris Biotech, Sigma-Aldrich, Alfa, Enamine, Amatek, Anichem, ACBR, ABC Laboratory, AP Bioscience, Combiblocks, ArZa Bioscience, Ark Pharm, Acroteinchem, Apollo Scientific, Biofine, Broadpharm, VWR. or Gyros Protein Technologies (Fluorenylmethoxycarbonyl = Fmoc), GL Biochem (Shanghai) Ltd, Chengdu Aminotp Pharmaceutical Technology Ltd, Suzhou Highfine Biotech Co., Ltd, WuXi AppTec, or sourced through other Chinese vendors. Some special fmoc-protected amino acids were synthesized internally, and these synthetic methods are described herein. Some of the fmoc amino acids synthesized internally are also commercially available. In some cases where the Fmoc-protected amino acid was not commercially available but the Boc-protected (tert-Butyloxycarbonyl = Boc) unnatural amino acid was commercially available, the fmoc-protected amino acid was prepared from the Boc-protected amino acid by deprotection and reprotection using methods commonly employed in the art. CAS Numbers for commercially available, unnatural amino acids used in the synthesis of peptides of this invention have in most cases been included in Table 5. In cases where a racemic amino acid (Fmoc or Boc) was purchased, one skilled in the art should recognize that the enantiomers can be separated using chiral chromatography, and this was in fact sometimes done to optain the enantiomerically pure amino acid prior to peptide synthesis.

[0290] The following unnatural amino acids have been used in preparing peptides of the invention. The Fmoc- or Boc- protected amino acids were either obtained through commercial sources (CAS Number is available) or, synthesized internally by methods described herein. Table 5 shows the CAS number of the chemical groups / amino acids which were used for the peptide synthesis (right column) and the corresponding chemical group / amino acid present in the peptides (left column). Table 5: Availability of unnatural amino acids and chemical groups of this InventionAbbreviation / Expression Definition CAS Number for Fmoc- / Boc-protected amino acid, chemical group or building block used for peptide synthesis Cyclohexanecarboxylic acid98-89-5(2S)-Amino-2-[3-(Trifluoromethyl)bicyclo[1.1.1]pent-1-yl]acetic acid914082-67-0(S)-3-(2H-tetrazol-5-yl)propanoic acid954147-35-4(1R,3S)-3-(Amino)cyclopentanecarboxylic acid220497-67-6(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid291775-59-2(1R,3S,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxylic acid1932624-93-5(1S,2S,4S)-Bicyclo[2.2.1]hept-5-en-2-ylacetic acid14734-13-5(1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid400720-05-0 (Boc); 854113-43-2(1S,3R)-3-(Amino)cyclopentanecarboxylic acid220497-66-5(1S,3R,4R)-2-Azabicyclo[2.2.1]heptane-3-carboxylic acid291775-53-6; 291775-53-6 (Boc)(2,4-Dioxoimidazolidin-1-yl)acetic acid94738-31-5; 94738-31-5 (NH)2-Cyano-L-phenylalanine401933-16-22-Fluoro-L-phenylalanine205526-26-72-Methyl-L-phenylalanine211637-75-1(2S)-(tetrahydro-2H-pyran-4-yl)ethanoic acid368866-31-3(2S,4S)-4-Trifluoromethyl-pyrrolidine-2-carboxylic acid1242934-32-2(3,3-difluorocyclobutyl)acetic acid1373503-48-03-Cyano-L-phenylalanine205526-36-93-Fluoro-L-phenylalanine8560-68-84-Fluoro-L-phenylalanine169243-86-15-Azaspiro[2.4]heptane-1-carboxylic acid150543-61-6D-(+)Biotin58-85-5L-N,N-Dimethylalanine2812-31-9N,N-Dimethylglycine1118-68-92-(N-Isopropyl-N-methylamino)acetic acid4747-21-1L-N-Methylalanine84000-07-7D-N-Methylalanine138774-92-2L-N-Methylcysteine944797-51-7L-N-Methylphenylalanine77128-73-5N-Methyl-Glycine77128-70-2L-N-Methylisoleucine138775-22-1N-Phenylglycine103-01-5(R)-3-Aminoadipic acid197006-18-1(R)-4-Amino-6-methylheptanoic acid269078-75-3(R)-Piperidine-3-Carboxylic Acid193693-67-3; 163438-09-3 (Boc)(R)-Pyrrolidine-3-Carboxylic Acid68464-02-8(S)-(1-Piperidin-3-yl)-acetic acid1217646-18-8(S)-2-Amino-3-ethyl-pentanoic acid1310680-47-7(S)-3-(1-Pyrrolidine-2-yl)-propionic acid1013997-51-7(S)-3-(2H-Tetrazol-5-yl)propionic acid954147-35-4(S)-3-Methylvaleric Acid1730-92-3(S)-4-Piperazine-2-carboxylic acid1217628-46-0(S)-Piperidine-3-carboxylic acid193693-68-4(S)-Pyrrolidine-3-carboxylic acid193693-66-2; 140148-70-5 (Boc)[(2R)-4,4-Difluoropyrrolidin-2-yl]acetic acid1402687-79-9[(6S)-5-Azaspiro[2.4]hept-6-yl]acetic acidOmegachem (OC-0701)1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)acetic acid1224869-02-6L-1-Napthylalanine96402-49-22-(3-Pyridyl)acetic acid501-81-52-(Aminomethyl)benzoic acid219640-94-52-(Cyclohexylamino)acetic acid108-91-82-(Diethylamino)acetic acid109-89-72-(Morpholine)acetic acid110-91-82-(N-Methyl-N-cyclopropylamino)acetic acid5163-20-22-(Piperidin)acetic acid110-89-42-(Pyrrolidine)acetic acid123-75-12-(Thian-4-yl)acetic acid137103-09-42-(Thiomorpholine)acetic acid123-90-02,3-Difluoro-L-phenylalanine1260605-30-82-Aminobenzoic acid150256-42-12-Azaspiro[3.3]heptane-6-carboxylic acid2138525-84-3L-2-Bromophenylalanine220497-47-22-Chloro-L-phenylalanine198560-41-72-Cyanobenzoic acid3839-22-32-Fluorobenzoic acid445-29-42-Hydroxyacetic acid7732-18-52-Hydroxyisobutyric acid594-61-62-Methylbenzoic acid118-90-12-Methyl-L-phenylalanine211637-75-1L-2-Napthylalanine112883-43-9L-2-Pyridylalanine185379-40-2(2S)-Pyrrolidin-2-ylacetic acid19693-60-63-(2-Oxoimidazolidin-1-yl)benzoic acid884504-86-33-(3-Oxo-1,3,4,5,6,7-hexahydro-2H-indazol-2-yl)benzoic acid885949-86-03-(Aminomethyl)benzoic acid117445-22-43-(Isobutyrylamino)benzoic acid28533-44-03-(Trifluoromethyl)bicyclo[1.1.1]pent-1-yl]acetic acid914082-67-03-[(E)-(2-carboxycyclohexen-1-yl)azo]benzoic acid885949-86-03-Acetamidobenzoic acid587-48-43-Amino-2,2-dimethylpropionic acid1076197-00-63-Amino-3-methylbutyric acid244031-65-0; 129765-95-3 (Boc)3-Aminobenzoic acid185116-42-13-Aminomethylphenylacetic acid631915-50-9L-3-Bromophenylalanine220497-48-33-Carboxybenzoic acid121-91-53-Chloro-L-Phenylalanine198560-44-03-Chlorophenylglycine10242-05-43-Cyanobenzoic acid1877-72-13-Fluorobenzoic acid455-38-93-Methyl-L-phenylalanine211637-74-03-Methoxypropionic acid2544-06-13-Methylbenzoic acid99-04-7L-3-Pyridylalanine175453-07-34-(Aminomethyl)benzoic acid33233-67-94-Aminobenzoic acid185116-43-24-Aminomethylphenylacetic acid176504-01-1; 71420-92-3 (Boc)L-4-Aminophenylalanine95753-56-3L-4-Bromophenylalanine198561-04-54-Carboxybenzoic acid100-21-04-Cyanobenzoic acid619-65-84-Fluorobenzoic acid456-22-44-Fluoro-L-Leucine1643928-01-14-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid141762-02-94-Methylbenzoic acid99-94-54-Methylpentanoic acid646-07-1L-4-Pyridylalanine169555-95-74-Piperidinepropanoic acid154938-68-84-Tetrahydropyranoyl368866-31-35-Chlorothiophene-2-carboxylic acid24065-33-68-Aminocubane-1-carboxylic acidEnamine EN300-88072 (MFCD09971721)(S)-2-(Amino)-1,6-hexanedioic acid159751-47-0L-2-Aminobutyric acid135112-27-51-Aminocyclobutane-1-carboxylic acid885951-77-9Aminocyclobutanecarboxylic acid885951-77-91-(Aminomethyl)-cyclopropyl-1-carboxylic acid1263045-62-0(1S,2S)-2-Amino-1-cyclopentanecarboxylic acid359586-64-4(1R,2R)-2-Amino-1-cyclopentanecarboxylic acid359586-69-9rel-(1R,2S)-2-Amino-1-cyclopentanecarboxylic acid352707-76-7Adipic acid124-04-96-Aminohexanoic acid88574-06-52-Aminoisobutyric acid94744-50-0L-tert-Butylalanine139551-74-9allo-L-Isoleucine251316-98-0allo-L-Threonine201481-37-02-Methyl-L-Proline167275-47-0N(5)-methyl-L-arginine1135616-49-7(S)-Azetidine-2-carboxylic acid136552-06-2; 51077-14-6 (Boc)Benzoic acid65-85-0L-2-Thienylalanine130309-35-2beta-Alanine35737-10-1Bromoacetyl79-08-34-(3,5-Dimethyl-1,2-oxazol-4-yl)-L-phenylalanine1381790-25-5(2S)-2-amino-3-(4-tert-butylphenyl)propanoic acid143415-62-7(2S)-2-Amino-5-methyl-hexanoic acid180414-94-2(2S)-2-Amino-4,4,4-trifluorobutanoic acid181128-48-3(2S)-3-(4-carboxyphenyl)-2-aminopropanoic acid183070-44-2(2S)-2-amino-3-(4-carbamoylphenyl)propanoic acid205126-71-2(2S)-2-Amino-3-(2,3,4,5,6-(pentafluorophenyl)propanoic acid205526-32-5(2S)-3-(3-Cyanophenyl)-2-aminopropanoic acid205526-36-93-Azido-L-Alanine684270-46-02-Amino-5,5,5-trifluoro-4-methyl-pentanoic acid777946-04-0(1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid167611-99-6 (Boc); 1219181-14-2 (rac)L-Cyclobutylalanine478183-62-9(S)-2-Amino-2-cyclobutylacetic acid1391630-31-1L-Cyclohexylalanine135673-97-1D-cyclohexylalanine144701-25-7L-Cyclohexylglycine161321-36-4L-4,4-Difluoroproline(2S,4S)-4-Fluoroproline203866-19-7L-Citrulline133174-15-9L-2-Amino-4-cyanobutyric acid913253-24-43,3-dimethyl-1,3-azasilolidine-5-carboxylic acid268224-29-9 (Boc)(S)-(trifluoromethyl)-L-cysteine1994331-25-7(2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid2350203-57-3(2S)-3-(indol-4-yl)-2-(amino)propanoic acid220499-20-7(2S)-3-(2,3-difluorophenyl)-2-aminopropanoic acid266360-64-9L-Cyclopentylalanine371770-32-0L-Cyclopentylglycine220497-61-0Cyclobutanecarboxylic acid3721-95-72-(Cyclobutyl)acetic acid6540-33-6L-Cyclobutylglycine49607-08-1Cyclohexylacetic acid5292-21-7Cyclopentanecarboxylic acid3400-45-1Cyclopentylacetic acid1123-00-8Cyclopropanecarboxylic acid1759-53-1Cyclopropylacetic acid5239-82-7D-2-Chlorophenylalanine205526-22-3L-2,4-Diaminobutyric acid125238-99-5; 607366-21-2 (ivDde); 851392-68-2 (MTT)L-2,3-Diaminopropionic acid162558-25-0; 607366-20-1 (ivDde); 654670-89-0 (MTT)D-beta-Proline193693-61-7D-Hydroxyproline464193-92-8(2S)-2-Amino-4-(benzylamino)-4-oxobutanecarboxylic acid100-46-9(2S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-4-methylpentanoic acid957507-85-6Fumaric acid110-17-8Gamma-Aminobutyric acid116821-47-7; 57294-38-9 (Boc)L-tert-Butylglycine132684-60-71-Benzyl-L-histidine84030-19-31-Methyl-L-histidine202920-22-7L-3-Methylhistidine84030-19-3L-Homocysteine167015-23-8L-Dihydroorotic acid5988-19-23-Phenylpropanoic acid501-52-0L-Hydroxyproline122996-47-8Iminodiacetic acid142-73-4Isobutyric acid79-31-2Isonipecotic acid148928-15-8Isovaleric acid503-74-2N-e-Isopropyl-L-lysine201003-48-73-Ethyl-L-Norvaline1310680-47-7L-(+)-Lactic acid79-33-43-(1,3-Benzothiazol-2-yl)-L-alanine959583-56-3(S)-Pyrrolidine-2-carboxylic acid193693-60-6L-Propargylglycine1435854-95-7(3S)-Morpholine-3-carboxylic acid281655-37-6Nicotinic acid59-67-6L-Norleucine77284-32-3N-Methyl-L-proline475-11-6L-Norvaline135112-28-61,18-Octadecanedioic acid871-70-52,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid130309-37-4L-Ornithine109425-55-0; 269062-80-8 (DDE); 1198321-33-3 (ivDDE); 147290-11-7 (Alloc)Palmitic acid57-10-39-Amino-4,7-dioxanonanoic acid872679-70-412-Amino-4,7,10-trioxadodecanoic acid867062-95-115-Amino-4,7,10,13-tetraoxa(Pen)tadecanoic acid557756-85-118-Amino-4,7,10,13,16-(Pen)taoxaoctadecanoic acid882847-32-714-Amino-3,6,9,12-tetraoxatetradecanoic acid437655-95-31-Amino-3,6,9,12,15,18-hexaoxahenicosan-21-oic acid882847-34-917-Amino-3,6,9,12,15-(Pen)taoxaheptadecanoic acid635287-26-21-Amino-3,6,9,12,15,18,21-heptaoxatetracosan-24-oic acid1863885-74-81-Amino-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oic acid756526-02-01-Amino-3,6,9,12,15,18,21,24,27-nonaoxatriacontan-30-oic acid1191064-81-9L-Penicillamine201531-88-6Phenylacetic acid103-82-2L-Phenylglycine102410-65-1Picolinic acid98-98-6L-Pipecolic acid86069-86-5Piperidin-4-ylacetic acid157688-46-5 (Boc); 180181-05-9Pivalic acid75-98-9L-trans-3-Hydroxyproline4298-08-2L-Pyroglutamic acid53100-44-0S-2-amino-3-ethyl-pentanoic acid1310680-47-7S-3-1-Pyrrolidin-2-yl-propionic acidMFCD09952617Suberic acid505-48-6tert-Butylacetic acid1070-83-3Tetrahydropyranyl-4-acetic acid85064-61-5Trifluoroacetic acid76-05-1L-2-Thienylalanine130309-35-2(2S,3S)-2-[(3R)-3-Amino-2-oxopyrrolidin-1-yl]-3-methylpentanoic acid301840-23-3(2S,3S)-2-[2-Oxopiperazin-1-yl]-3-methylpentanoic acid-(2S,3S)-2-[(3S)-2-oxopiperazin-1-yl]-3-methylpentanoic acid-(1R,3S,5R)-2-Azabicyclo[3.1.0]hexane-3-carboxylic acid1932624-93-53-(Trimethylsilyl)-L-alanine359766-59-9(6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid2170726-27-7rel-(1R,3R,5R,6R)-6-(Trifluoromethyl)-2-azabicy-clo[3.1.0]hexane-3-carboxylic acid1986905-54-7(4aR,6aR,9S,11aS)-11-Oxo-2,3,4,4a,6a,7,8,9,11,11a-decahy-dro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid1637768-88-7(2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid368866-31-3(2S,3S)-2-((Amino)methyl)-3-methylpentanoic acid671233-52-62-[(1S,2S)-1-(Amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid1238864-23-7(2S)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid-(2R)-Amino-(1-methyl-1H-indazol-5-yl)acetic acid-3-Carboxyphenylalanine-2-Methyl-D-alloisoleucine118904-37-34-Ethyl-L-norleucine1998613-43-6L-2,6-Difluorophenylalanine1235005-44-32,5-Difluoro-L-phenylalanine1004959-90-3(2S,3aS,6aS)-Octahydrocyclopenta[b]pyrrole-2-carboxylic acid87269-87-2(2S)-2-(Amino)-2-[(1S,3R)-3-hydroxycyclohexyl]acetic acid-(2S)-2-(Amino)-2-[(1S,3S)-3-hydroxycyclohexyl]acetic acid-2-Amino-7-(tert-butoxy)-7-oxoheptanoic acid159751-46-9(2S)-3-(Triazol-1-yl)-2-(amino)propanoic acid-Tetrahydro-2H-pyran-3-ylacetic acid1395922-27-6rel-(1R,3S)-3-[(Amino)methyl]cyclohexanecarboxylic acid2138238-33-0(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1)-(3R,6R)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantiomer 2)-Tranexamic acid167690-53-1; 27687-14-5 (Boc)trans-2-(3-(Amino)cyclohexyl)acetic acid347185-01-7trans-4-Fluoroproline203866-20-01,13-Diamino-4,7,10-trioxatridecan-succinamic acid172089-14-44-Piperazine-2-carboxylic acid1034574-30-5(2-Pyrrolidine-1-yl) acetic acid37386-15-5(S)-2-(Amino)-1,6-hexanedioic acid (AAD)159751-47-0Freidinger's Lactam145484-45-3(R)-Pyrrolidine-3-acetic acid2137100-59-3(2S)-2-(morpholin-4-yl)propanoic acid110582-65-5L-dehydroproline135837-63-7(3S)-2-azaspiro[4.4]nonane-3-carboxylic acid394734-78-2(2R)-2-amino-3-(trifluoromethylsulfanyl)propanoic acid1994331-25-7Arg(13C6,15N4)1217461-89-6

[0291] Solid-phase resins were purchased from Novabiochem, Bachem, Iris Biotech, Pcas Biomatrix, GL Biochem (Shanghai) Ltd, CEM, or Protein Technologies. The resin loading was 0.3 - 1.0 mmol / g. Peptides were synthesized on 2-Chlorotrityl resin, on Wang resin, or on Rink amide-type resins depending on the desired C-terminus. Cleavage of the fluorenylmethoxycarbonyl (Fmoc) protecting group was achieved using 20% piperidine in dimethylformamide at room temperature. Each Fmoc cleavage step was carried out twice. Amino acids were coupled on an automated synthesizer (Symphony X) using 8 equivalents of the Fmoc-amino acid, with 8 equivalents of DIC (Diispropylcarbodiimide) (0.5 M in DMF) and 8 equivalents of Oxyma (Ethyl cyanohy-droxyiminoacetate) (0.5M in DMF). Amino acid couplings were conducted at room temperature and under a nitrogen atmosphere, when the Symphony X was used. When expensive or self-prepared fmoc-amino acids were used, the coupling was performed manually using 3 equivalents of the Fmoc-amino acid, with 3 equivalents of DIC (0.5 M in DMF) and 3 equivalents of Oxyma (0.5M in DMF). Each amino acid coupling step was carried out twice (double coupling). Alternatively, peptides were prepared by SPPS manually using 3 equivalents of the Fmoc-amino acid, 2.85 equivalents of HBTU ((2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylu-ronium hexafluorophosphate, Hexafluorophosphate Benzotriazole Tetramethyl Uronium) (0.5 M in DMF) and 6 equivalents of DIPEA (0.5M in DMF). The coupling reaction was monitored using the ninhydrin test.

[0292] Peptides were completely deprotected using trifluoroacetic acid (TFA) / thioanisole (TA) / 1,2-ethanedithiol (EDT) (90:7:3) or with 92.5%TFA / 2.5%EDT / 2.5%TIS (triisopropylsilane) / 2.5%H 2 O. For peptides containing methionine, the peptides were treated with a solution of 1.6% EDT and 1.2% trimethylsilylbromide in TFA for 2 h at room temperature to reduce oxidized methionine.Disulfide Cyclization:

[0293] Disulfide bridges were formed by shaking peptides in 0.1 M ammonium bicarbonate buffer (pH 7.83) at a concentration of 0.5 mg / mL overnight. The solution was then lyophilized. Alternatively, disulfide bridges were formed formed by shaking peptides in mixture of acetonitrile / water (often 3:7) adjusted to pH 9.0 with solid ammonium bicarbonate buffer at a concentration of 1-3 mg / mL overnight. Alternatively, disulfide bridges were prepared by oxidation with iodine (I 2 ) (0.1 M in MeOH) at a concentration of 1 - 1.3 mg / mL in acetonitrile / water (1:1) at 20°C for 2min, followed by treatment with sodium thiosulfate (0.1 M in water) followed by lyophilization.Optional Acetylation:

[0294] N-terminal acetylation was performed using 10 equivalents acetic anhydride in DMF (2 mL) and 2.5 equivalents DIPEA by shaking the suspension at RT for 1 h on an orbital shaker. The solvent was removed and the resin was washed with DMF (5x) and DCM (5x). The procedure was then repeated again. Alternatively, N-terminal acetylation was performed using 10 mL of a capping solution consisting of acetic anhydride / N-methyl morpholine (NMM) / DMF (10:5:85) by shaking the suspention at RT for 30 min on an orbital shaker.Peptide cleavage:

[0295] A cleavage cocktail containing TFA / EDT / Thioanisol (90:3:7) was prepared. The cleavage cocktail (2 mL) was added to the peptide containing resin and the suspension was shaken on an orbital shaker for 2.5 hours. Cold ether (-20°C) was added to precipitate the peptide. The resulting solution was centrifuged under nitrogen (Sigma 2-16KL), and the resulting solid obtained after decantation was washed with cold ether 3 more times, by centrifugation and decantation. The resulting solid was purified by preparative HPLC.

[0296] Alternatively, a cleavage cocktail containing TFA / EDT / TIS / H 2 O (92.5:2.5:2.5:2.5) was prepared. The cleavage cocktail (6 mL (0.3 mmol scale)) was added to the peptide containing resin and the suspension was shaken on an orbital shaker for 2.5 hours. Cold tert-butyl methyl ether (-20°C) was added to precipitate the peptide. The resulting solution was centrifuged at 3000 rpm for 3 min, and the resulting solid obtained after decantation was washed with cold tert-butyl methyl ether 3 more times (20 mL x 3), by centrifugation and decantation. The resulting crude peptide was dried over vacuum for 2 hours and then purified by preparative HPLC.Preparative HPLC:

[0297] An Agilent 1260 Prep reversed-phase HPLC or a Knauer AZURA Prep reversed-phase HPLC was used for purification. The column is chosen based on the results of a column screen. The peptide is dissolved in 10 - 30% ACN / water (typically the starting point of the gradient). Water and acetonitrile both contain 0.1% TFA. Flow rate 20 mL / min, 10-30% ACN / water to 85-90% ACN / water was typically used. Fractions were analysed by HPLC (Agilent 1260 Infinity) using using a Chromolith Speedrod column, 5-95% ACN / water gradient over 8 min) and by one or more of the following LC-MS methods: Method 1, Method 2, Method 3, Method 4, Method 5, Method 6.

[0298] Alternatively, a Gilson GX-281 Prep reversed-phase HPLC was used for purification. The column was chosen based on the results of a column screen. The peptide is dissolved in 10 - 30% ACN / water (typically the starting point of the gradient). The water contained 0.075% TFA. Normally a Luna column (25 x 200 mm, C18 10 µm, 110 Å) or a Gemini column (30 x 150 mm, C18 5 µm,110 Å) was used. Conditions for prep HPLC: flow rate 20 mL / min, 10-30% ACN / water to 85-90% ACN / water, wavelength 214 / 254 nm, oven temperature 30°C. Fractions were analysed by HPLC (Agilent 1260 Infinity) using Method W1 or Method 7. The peptides were thereafter analyzed by one or more of the following methods: Method 1, Method 2, Method 3, Method 4, Method 5, Method 6.

[0299] Disulfide mimetics, wherein the -S-S- disulfide bond is replaced by a -CH 2 -S-, -S-CH 2 -, -CH 2 -CH 2 -, -S-(CH 2 ) 2 -, -(CH 2 ) 2 -S- or a -CH 2 -S-CH 2 - can be prepared according to procedure described in the following references in combination with methods described herein: (1) Hong-Kui Cui, Ye Guo, Yao He, Feng-Liang Wang, Hao-Nan Chang, Yu-Jia Wang, Fang-Ming Wu, Chang-Lin Tian, Lei Liu Angew. Chem. Int. Ed. 2013, 52, 9558-9562; (2) Ye Guo, De-Meng Sun, Feng-Liang Wang, Yao He, Lei Liu, Chang-Lin Tian Angew. Chem. Int. Ed. 2015, 54, 14276-14281; (3) Yang Xu, Tao Wang, Chao-Jian Guan, Yi-Ming Li, Lei Liu, Jing Shi, Donald Bierer Tetrahedron Letters 2017, 58, 1677-1680; (4) Tao Wang, Yi-Fu Kong, Yang Xu, Jian Fan, Hua-Jian Xu, Donald Bierer, Jun Wang, Jing Shi, Yi-Ming Li Tetrahedron Letters 2017, 58, 3970-3973; (5) Tao Wang, Jian Fan, Xiao-Xu Chen, Rui Zhao, Yang Xu, Donald Bierer, Lei Liu, Yi-Ming Li, Jing Shi, Ge-Min Fang Org. Lett. 2018, 20, 6074-6078; (6) Jan-Patrick Fischer, Ria Schönauer, Sylvia Els-Heindl, Donald Bierer, Johannes Koebberling, Bernd Riedl, Annette G. Beck-Sick-inger J Pep Sci. 2019; e3147; (7) Dong-Liang Huang, Jing-Si Bai, Meng Wu, Xia Wang, Bernd Riedl, Elisabeth Pook, Carsten Alt, Marion Erny, Yi-Ming Li, Donald Bierer, Jing Shi, Ge-Min Fang Chem. Commun., 2019, 55, 2821-2824; (8) Shuai-Shuai Sun, Junyou Chen, Rui Zhao, Donald Bierer, Jun Wang, Ge-Min Fang, Yi-Ming Li Tetrahedron Letters 2019, 60, 1197-1201; (9) C. M. B. K. Kourra and N. Cramer Chem. Sci., 2016, 7, 7007-7012.

[0300] All peptides of this invention unless otherwise noted are TFA Salts.General Method for the Automated SPPS of Masp Peptides (Method A)

[0301] The synthesis of ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IPD-NH 2 (Example 165) is representative.

[0302] The peptide was synthesized using standard Fmoc chemistry.

[0303] Automated SPPS was performed on a Symphony X peptide synthesizer (Protein Technologies). Chem-Matrix Rink Amide resin was typically used (loading 0.5 mmol / gram) on a 0.1 mmol scale. The resin was placed into the reaction vessel and placed onto the instrument. The following soluitons were prepared and used during the synthesis: 1) Fmoc Amino Acids: 0.2 M (8 eq) 2) Activator 1: 0.5 M DIC in DMF (7,5 eq) 3) Activator 2: 0.5 M Oxyma in DMF (7,5 eq) 4) Fmoc Deprotection : 20% Piperidine in DMF 5) Acetic anhydride (10 equivalents) in 2 mL DMF

[0304] Double couplings were typically performed for each amino acid. For expensive unnatural Fmoc or Boc amino acids, in-house synthesized Fmoc amino acids, or N-methylated amino acid, the sequence was interrupted and this amino acid was coupled manually (double coupling, but typically with less reagent (3-5 equiv). After this coupling was completed, the synthesis was typically continued on the synthesizer. If an N-methyl amino acid was added to the sequence, typically the next amino acid was coupled manually as well. All steps were performed at room temperature under nitrogen. Fmoc-Pen and Fmoc-Oic were typically coupled using automated SPPS. Fmoc(N-Me)G was typically coupled manually. Ahx was always coupled manually.

[0305] The resin was swelled and washed with DMF (3 x 3 mL, 10 min). If the resin contained Fmoc, then the Fmoc was removed with 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0306] Fmoc-Asp(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Asp(Ot-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0307] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0308] Fmoc-Pro (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Pro (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0309] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0310] Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0311] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0312] Fmoc-Pen(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Pen(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0313] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0314] Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0315] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0316] Fmoc-Oic (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Oic (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0317] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0318] Fmoc-Pro (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Pro (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0319] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0320] Fmoc-Leu (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Leu (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0321] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0322] Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0323] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0324] Fmoc-Arg(Pbf) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Arg(Pbf) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0325] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0326] Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0327] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0328] Fmoc-Cys(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Cys(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0329] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0330] Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0331] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Manual Coupling during automated SPPS:

[0332] Fmoc-(N-Me)G (0.2 M in DMF, 5 equiv) was added to the resin. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with shaking (Thermomixer, rt) for 2 hours. The solution was filtered and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-(N-Me)G (0.2 M in DMF, 5 equiv) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with shaking (Thermomixer, rt) for 2 hours. The solution was filtered and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0333] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).

[0334] If additional amino acids were present in the sequence, they were coupled using using the steps above.Test Cleavage:

[0335] When manual couplings were performed, a test cleavage was typically performed to monitor the reactions. The test cleavage cocktail was TFA / EDT / Thioanisol (90:3:7); 1,5 h shaking on a Thermomixer at room temperature and 750 rpm. Analysis was performed by LC-MS using one of the methods above.Full Cleavage:

[0336] The resin containing the peptide was placed into a syringe and 3.0 mL of cleavage buffer TFA / EDT / Thi-oanisol (90:3:7) was added to the resin. The mixture was shaken at room temperature for 2.5 hours. The solution was collected by filtration and the peptide was precipitate by adding cold diethyl ether (-20°C). The solution was centrifuged (3000 rpm) in a Falcon tube (60 mL) under a nitrogen atmosphere. The ether was decanted and the solid residue was washed repeatedly with cold diethyl ether (5 x 10 mL). The solid residue was then dried.Disulfide Cycliztion:

[0337] The crude peptide was dissolved in 0.1M ammonium bicarbonate (pH 7.8-8.2) at a concentration of 1 mg / 2 mL. The solution was allowed to shake on an orbital shaker overnight in a round-bottomed flask open to the air. The solution was then lyophilized to obtain a white powder.Column Screening for HPLC Purification:

[0338] The peptide was dissolved in 5% CH 3 CN and 95% water. Column screening was performed on each peptide to determine which preparative HPLC method to use for purification. The following analytical columns were screened.

[0339] Two methods are available for column screening: 1) 5-60% ACN_8 Min_1 mL / min_25°C 2) 30-85% ACN_8 Min_1 mL / min_25°C Available columns (50 mm x ID 4,6 mm) (available also as as Prep columns):

[0340] 1) Aeris C18 (Phenomenex) 2) X-Bridge C18 (Waters) 3) Kinetex C18 (Coreshell Material) (Phenomenex) 4) YMC Triart C18 (elution with 100% water possible) 5) Kinetix Biphenyl (Phenomenex) 6) X-Select C18 (positive charge) 7) Jupiter Proteo C18 (Phenomenex) 8) Luna C18 (Phenomenex)

[0341] For peptides of this invention, one of the following 5 preparative columns was used: 1) Column: Phenomenex, Aeris Peptide 5µ XB-C18, AXIA Packed, 21,2x250mm + Cartridge 5µ 2) Column: Phenomenex, Kinetex C18 5µ 21,5x250mm + Cartridge 5µ 3) Column: Phenomenex, Kinetex 5µ Biphenyl 100A, AXIA Packed, 21,2x250mm + Cartridge 5µ 4) Column: YMC Actus Triart Prep. C18 12nm, S-10µm 250x20mm + Cartridge 3µm (10x4mm) 5) Column: Waters, Xbridge Prep.C18 5µ OBD 19x250mm + Cartridge 10µ

[0342] Once the column was chosen, one of the following methods was used: 1) method: Gradient 5-60% ACN in water (0,10% TFA) 2) method: Gradient 30-85% ACN in water (0,10% TFA) 3) focused gradient based on results of the column screening. Flow rate 20 mL / min The combined fractions were analyzed by HPLC (5-95 in 8in, Chromolith SpeedROD & YMC C18 5-95 in 18 min) and using one of the LC-MS methods described above. For Example 165, the crude peptide was dissolved in CH 3 CN / water (1:1) and purified on a Phenomenex Kinetex column C18 5µ, 21.5 x 250 mm + 5µ Cartridge, Flow rate: 20 mL / min, Method: 5-60% ACN in water (each containing 0.10% TFA) over 48 min. The combined fractions were lyophilized to provide 39 mg of example 165 (95% pure). Table 6: Note of materials used and conditions #Materials Coupling reagents Coupling time 1Rink Amide ChemMatrix resin, loading 0.5mmol / g (0.1 mmol)---2Fmoc-Asp(t-Bu)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min3Fmoc-Pro-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min4Fmoc-Ile-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min5Fmoc-Pen(Trt)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min6Fmoc-Ile-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min7Fmoc-Oic-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min8Fmoc-Pro-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min9Fmoc-Leu-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min10Fmoc-Ser(tBu)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min11Fmoc-Arg(Pbf)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min12Fmoc-Ser(t-Bu)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min13Fmoc-Cys(Trt)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min14Fmoc-Ile-OH (3.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min15Fmoc-(N-Me)G-OH (8 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min General Method for the Automated SPPS of Masp Peptides (Method B)

[0343] The synthesis of ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+I-((5-Azaspiro[2.4]heptane-1-carboxylic acid)-OH (example 164) is representative.

[0344] The peptide was synthesized using standard Fmoc chemistry.

[0345] When possible, preloaded Wang resin with the first amino acid (e.g. preloaded with Fmoc-Asp(t-Bu)-OH, Fmoc-Pro-OH, etc were used, with a typical loading of 0.55 - 0,7 mmol / g. When the first amino acid was not available, it was added manually.

[0346] When the first amino acid was not available as a preloaded resin, it was added manually and chlorotrityl resin was used for the synthesis.Loading of first amino acid on 2-chlorotrityl resin:

[0347] 2-Chlortritylresin (500 mg, 0.775 mmol) was allowed to swell with 10 mL of DCM in a 50 mL Falcon tube for 15 min 5-[(9H-fluoren-9-ylmethoxy)carbonyl]-5-azaspiro[2.4]heptane-1-carboxylic acid (281 mg, 0.775 mmol) was dissolved in DCM with DIEA (6 equiv, 0.81 mL) added, and the solution was added to the resin. The solution was purged with argon and shaken overnight at room temperature. The mixture was filtered and washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). Methanol was added (5 mL), the mixture was shaken for 30 minutes, and then filtered. The resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). Methanol was again added (5 mL), the mixture was shaken for 30 minutes, and then filtered. The resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The loading was determined to be 0.42 mmol / g based on the determination of loading procedure described below.

[0348] The resin was then used for automated SPPS on the Symphony X synthesizer from Protein Technologies on 0.1 mmol scale.Determination of Resin Loading:

[0349] To determine the loading of a resin the FMOC protecting group is cleaved from a defined amount of resin and afterwards the concentration of the resulting fluorenyl compound in the supernatant cleavage solution is measured via photometry at 301nm. This correlates directly with the amount of amino acid loaded on the resin. 1) 1-3 mg of resin are weighed into a 2 mL Eppendorf tube or similar (note the exact amount) 2) 1000 µL of a solution of 20% piperidine in DMF are added. 3) The mixture is agitated for 30 minutes to cleave the FMOC group. 4) 100 µL of the supernatant solution are then transferred into a quartz glass cuvette and diluted with 900µL of 20% piperidine / DMF 5) A blank sample of 1000µl piperidine / DMF is prepared in a second cuvette. 6) After determining the blank value from the reference sample, the extinction of the test sample at λ = 301nm is then measured in a UV-Vis photometer (Thermo Scientific Evolution 201). 7) For greater accuracy, multiple test samples (typically two) can be fashioned; the arithmetic mean of the measured extinctions is then used for calculation. Calculation of resin loading:

[0350] The resin loading L 301 in mmol / g is calculated by the following formula: L 301 = E 301 nm ⋅ V ε 301 nm ⋅ D ⋅ m ⋅ VF ⋅ 1000 E = extinction ε = extinction coefficient at 301nm wavelength (7800 L / mol*cm) m = amount of resin used (g) V = volume of sample (L) D = layer thickness of the cuvette (cm) VF = dilution factor ( = 10) Fmoc cleavage:

[0351] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).

[0352] The coupling of the subsequent Fmoc amino acids proceeded as described in Method A.

[0353] The following solutions were prepared and used during the synthesis: 1) Fmoc Amino Acids: 0.2 M (8 eq) 2) Activator 1: 0.5 M DIC in DMF (7,5 eq) 3) Activator 2: 0.5 M Oxyma in DMF (7,5 eq) 4) Fmoc Deprotection : 20% Piperidine in DMF 5) Acetic anhydride (10 equivalents) in 2 mL DMF

[0354] Double couplings were typically performed for each amino acid. For expensive unnatural Fmoc or Boc amino acids, in-house synthesized Fmoc amino acids, or N-methylated amino acid, the sequence was interrupted and this amino acid was coupled manually (double coupling, but typically with less reagent (3-5 equiv). After this coupling was completed, the synthesis was typically continued on the synthesizer. If an N-methyl amino acid was added to the sequence, typically the next amino acid was coupled manually as well. All steps were performed at room temperature under nitrogen. Fmoc-Pen and Fmoc-Oic were typically coupled using automated SPPS. Fmoc(N-Me)G was typically coupled manually. Ahx was always coupled manually.Fmoc cleavage:

[0355] The resin was swelled and washed with DMF (3 x 3 mL, 10 min). If the resin contained Fmoc, then the Fmoc was removed with 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0356] Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0357] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0358] Fmoc-Pen(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Pen(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0359] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0360] Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0361] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0362] Fmoc-Oic (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Oic (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0363] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0364] Fmoc-Pro (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Pro (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0365] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0366] Fmoc-Leu (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Leu (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0367] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0368] Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0369] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0370] Fmoc-Arg(Pbf) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Arg(Pbf) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0371] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0372] Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ser(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0373] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0374] Fmoc-Cys(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Cys(Trt) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0375] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Coupling:

[0376] Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-Ile (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with nitrogen bubbling for 2 hours. The solution was drained and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0377] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).Manual Coupling during automated SPPS:

[0378] Fmoc-(N-Me)G (0.2 M in DMF, 5 equiv) was added to the resin. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with shaking (Thermomixer, rt) for 2 hours. The solution was filtered and washed with DMF (1 x 3 mL, 30 sec). The coupling step was repeated. Fmoc-(N-Me)G (0.2 M in DMF, 5 equiv) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Oxyma, 1.5 mL) were added and the coupling was allowed to proceed with shaking (Thermomixer, rt) for 2 hours. The solution was filtered and washed with DMF (6 x 3 mL, 30 sec).Fmoc cleavage:

[0379] The Fmoc protecting group was removed by adding 20% piperidine solution (2 x 3 mL, 10 min). The resin was washed with DMF (6 x 3 mL, 30 sec).

[0380] If additional amino acids were present in the sequence, they were coupled using using the steps above.Test Cleavage:

[0381] When manual couplings were performed, a test cleavage was typically performed to monitor the reactions. The test cleavage cocktail was TFA / EDT / Thioanisol (90:3:7); 1,5 h shaking on a Thermomixer at room temperature and 750 rpm. Analysis was performed by LC-MS using one of the methods above.Full Cleavage:

[0382] The resin containing the peptide was placed into a syringe and 3.0 mL of cleavage buffer TFA / EDT / Thi-oanisol (90:3:7) was added to the resin. The mixture was shaken at room temperature for 2.5 hours. The solution was collected by filtration and the peptide was precipitate by adding cold diethyl ether (-20°C). The solution was centrifuged (3000 rpm) in a Falcon tube (60 mL) under a nitrogen atmosphere. The ether was decanted and the solid residue was washed repeatedly with cold diethyl ether (5 x 10 mL). The solid residue was then dried.Disulfide Cycliztion:

[0383] The crude peptide was dissolved in 0.1M ammonium bicarbonate (pH 7.8-8.2) at a concentration of 1 mg / 2 mL. The solution was allowed to shake on an orbital shaker overnight in a round-bottomed flask open to the air. The solution was then lyophilized to obtain a white powder.Column Screening for HPLC Purification:

[0384] The peptide was dissolved in 5% CH 3 CN and 95% water. Column screening was performed on each peptide to determine which preparative HPLC method to use for purification. The following analytical columns were screened.

[0385] Two methods are available for column screening: 1) 5-60% ACN_8 Min_1 mL / min_25°C 2) 30-85% ACN_8 Min_1 mL / min_25°C Available columns (50mm x ID 4.6 mm) (available also as as Prep columns):

[0386] 1) Aeris C18 (Phenomenex) 2) X-Bridge C18 (Waters) 3) Kinetex C18 (Coreshell Material) (Phenomenex) 4) YMC Triart C18 (elution with 100% water possible) 5) Kinetix Biphenyl (Phenomenex) 6) X-Select C18 (positive charge) 7) Jupiter Proteo C18 (Phenomenex) 8) Luna C18 (Phenomenex)

[0387] For peptides of this invention, one of the following 5 preparative columns was used: 1) Column: Phenomenex, Aeris Peptide 5µ XB-C18, AXIA Packed, 21,2 x 250mm + Cartridge 5µ 2) Column: Phenomenex, Kinetex C18 5µ 21,5x250mm + Cartridge 5µ 3) Column: Phenomenex, Kinetex 5µ Biphenyl 100A, AXIA Packed, 21,2 x 250mm + Cartridge 5µ 4) Column: YMC Actus Triart Prep. C18 12nm, S-10µm 250 x 20mm + Cartridge 3µm (10x4mm) 5) Column: Waters, Xbridge Prep.C18 5µ OBD 19 x 250mm + Cartridge 10µ

[0388] Once the column was chosen, one of the following methods was used: 1) method: Gradient 5-60% ACN in water (0,10% TFA) 2) method: Gradient 30-85% ACN in water (0,10% TFA) 3) focused gradient based on results of the column screening. Flow rate 20 mL / min

[0389] The combined fractions were analyzed by HPLC (5-95 in 8in, Chromolith SpeedROD & YMC C18 5-95 in 18 min) and using one of the LC-MS methods described abouv

[0390] For example 164, the crude peptide was dissolved in CH 3 CN / water (1:1) and purified on a Phenomenex Kinetex column C18 5µ, 21.5 x 250 mm + 5µ Cartridge, Flow rate: 20 mL / min, Method: 5-60% ACN in water (each containing 0.10% TFA) over 48 min. The combined fractions were lyophilized to provide 29.8 mg of example 164 (98.3% pure). Table 7: Note of materials used and conditions# Materials Coupling reagents Coupling time 1Rink Amide ChemMatrix resin, loading 0.5mmol / g (0.1 mmol)---25-Fmoc-5-Azaspiro[2.4]heptane-1-carboxylic acidDIPEA (6 eq)ovenight3Fmoc-Ile-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min4Fmoc-Pen(Trt)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min5Fmoc-Ile-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min6Fmoc-Oic-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min7Fmoc-Pro-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min8Fmoc-Leu-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min9Fmoc-Ser(tBu)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min10Fmoc-Arg(Pbf)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min11Fmoc-Ser(t-Bu)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min12Fmoc-Cys(Trt)-OH (8.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min13Fmoc-Ile-OH (3.0 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min14Fmoc-(N-Me)G-OH (8 eq)DIC (7.5 eq) Oxyma (7.5 eq)120 min General Method for the Manual SPPS of Masp Peptides (Method C)

[0391] The synthesis of sequence AIC+SRSLP-(Oic)-I-(Pen)+IPN-OH (example 418) is representative.Peptide Synthesis:

[0392] The peptide was synthesized using standard Fmoc chemistry. 1) Resin preparation: To the chlorotrityl resin (CTC Resin) (0.3 mmol, 0.3 g, 1.0 mmol / g) was added Fmoc-Asn(Trt)-OH (0.3 mmol, 0.18 g, 1.0 eq) and DIEA (0.21 mL, 1.2 mmol, 4.0 eq) in DCM (6.0 mL). The mixture was agitated with N 2 for 2 h at 20 °C, then added MeOH (0.3 mL) and agitated with N 2 for another 30 min. The resin was washed with DMF (6.0 mL x 3). Then 20% piperidine in DMF (6.0 mL) was added and the mixture was agitated with N 2 for 20 min at 20°C. Then the mixture was filtered to get the resin. The resin was washed with DMF (6.0 mL x 3) and filtered to get the resin. 2) Coupling: Fmoc-Pro-OH (0.30 g, 0.9 mmol, 3.0 eq) HBTU (0.32 g, 0.85 mmol, 2.85 eq) and DIEA (1.80 mmol, 0.32 mL, 6.00 eq) in DMF (3.0 mL) was added to the resin and agitated with N 2 for 30 min at 20°C. The resin was then washed with DMF (6.0 mL x 5). 3) Deprotection: 20% piperidine in DMF (6.0 mL) was added to the resin and the mixture was agitated with N 2 for 20 min at 20 °C. 4) Repeat Step 2 to 3 for all other amino acids: Table 8: Note of materials used and conditions #Materials Coupling reagents Coupling time 1Fmoc-Asn(Trt)-OH (1.0 eq)DIEA(4.0 eq)2.0 h2Fmoc-Pro-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min3Fmoc-Ile-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min4Fmoc-Pen(Trt)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min5Fmoc-Ile-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min6Fmoc-Oic-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min7Fmoc-Pro-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min8Fmoc-Leu-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min9Fmoc-Ser(tBu)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min10Fmoc-Arg(Pbf)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min11Fmoc-Ser(tBu)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min12Fmoc-Cys(Trt)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min13Fmoc-Ile-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min14Fmoc-Ala-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min

[0393] 20% piperidine in DMF was used for Fmoc deprotection for 30 min. The coupling reaction was monitored by ninhydrin (all amino acids except Pro) and chloranil test (Pro), and the resin was washed with DMF (5.0 mL) for 5 times.Peptide Cleavage and Purification:

[0394] 1) The resin was washed with MeOH (6.0 mL x 5) and dried under vacuum to get 0.62 g peptide resin. Then 6.0 mL of cleavage buffer (92.5%TFA / 2.5%EDT / 2.5%TIS / 2.5%H 2 O) was added to the flask containing the side chain protected peptide resin at 20 °C and the mixture was stirred for 2.5 h. 2) The peptide was precipitated with cold tert-butyl methyl ether (50 mL) and centrifuged (3 min at 3000 rpm) to get the solid crude. Wash the crude peptide precipitation with tert-butyl methyl ether for two more times (20.0 mL x 3). Dry the crude peptide over vacuum for 2.0 h to give 0.4 g crude peptide. 3) The crude (0.4 g) was dissolved in CH 3 CN (150 mL) and water (150 mL). Iodine (I 2 ) (0.1 M in MeOH, 1.5 mL) was added at 20 °C until yellow color persists. Then the mixture was stirred at 20°C for 2 min. Then sodium thiosulfate (0.1 M in water, 0.05 mL) was added dropwise until yellow color disappears. The mixture was lyophilized to give the crude powder (0.41 g) 4) The crude peptide was purified by prep-HPLC (conditions: A: 0.075% TFA in water B: CH 3 CN) and lyophilized to get the desired peptide (example 418) (108.1 mg, 23.0% yield, 97.3% pure by Method W1; 97.4% pure by Method 7) as a white solid and TFA salt. Purification conditions: Peptide was dissolved in TFA / H 2 O (7:3); flow rate 20 mL / min; gradient 12-42% over 60 min; Retention time = 42 min; purification over a Luna 25 x 200 mm, C18 10 um, 110 Å column, then again over a Gemini 150 x 30 mm, C18 5 um, 110 Å column to reach the desired purity. If C-terminal amides were prepared according to this method, the synthesis began with Rink Amide MBHA resin (loading typically around 0.4-0.6 mmol / g, with the above steps being the same.General Method for the Manual SPPS of Masp Peptides (Method D)

[0395] If C-terminal amides were prepared, the synthesis began with Rink Amide MBHA resin (loading typically around 0.4-0.6 mmol / g. The synthesis of sequence PIC+SRS-((tBu)A)-PPI-(Pen)+IPD-NH2 (example 9) is representative.

[0396] If C-terminal acids were prepared, the synthesis began with 2-chlorotrityl resin, with the first Fmoc amino acid being added according to the method described in Method C.Peptide Synthesis:

[0397] The peptide was synthesized using standard Fmoc chemistry. 1) Resin preparation: The Rink Amide MBHA resin (0.66 g, 0.30 mmol, loading = 0.45 mmol / g) in DMF (10.0 mL) was agitated with N 2 for 0.5 h at 20°C. Then 20% piperidine in DMF (10 mL) was added and the mixture was agitated with N 2 for 20 min at 20°C. Then the mixture was filtered to get the resin. The resin was washed with DMF (10 x 5 mL) and filtered to get the resin. 2) Coupling: Fmoc-Asn(Trt)-OH (0.9 mmol. 0.37 g, 3.0 eq) HBTU (0.32 g, 0.85 mmol, 2.95 eq) and DIEA (1.80 mmol, 0.32 mL, 6.00 eq) in DMF (3.0 mL) was added to the resin and agitated with N 2 for 30 min at 20°C. The resin was then washed with DMF (10.0 mL x 3). 3) Deprotection: 20% piperidine in DMF (10.0 mL) was added to the resin and the mixture was agitated with N 2 for 20 min at 20 °C. 4) Repeat Step 2 to 3 for all other amino acids. Table 9: Note of materials used and conditions#Materials Coupling reagents Coupling time 1Fmoc-Asn(Trt)-OH (1.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min2Fmoc-Pro-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min3Fmoc-Ile-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min4Fmoc-Pen(Trt)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min5Fmoc-Ile-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min6Fmoc-Pro-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min7Fmoc-Pro-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min8Fmoc-Ala(t-Bu)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min9Fmoc-Ser(tBu)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min10Fmoc-Arg(Pbf)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min11Fmoc-Ser(tBu)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min12Fmoc-Cys(Trt)-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min13Fmoc-Ile-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min14Fmoc-Pro-OH (3.0 eq)HBTU(2.85 eq) DIEA(6.0 eq)30 min

[0398] 20% piperidine in DMF was used for Fmoc deprotection for 30 min. The coupling reaction was monitored by ninhydrin (all amino acids except Pro) and chloranil test (Pro), and the resin was washed with DMF (5.0 mL) for 5 times.Peptide Cleavage and Purification:

[0399] 1) The resin was washed with MeOH (6.0 mL x 5) and dried under vacuum to get 0.66 g peptide resin. Then 6.0 mL of cleavage buffer (90%TFA / 5%EDT / 2.5%TIS / 2.5%H 2 O) was added to the flask containing the side chain protected peptide resin at 20 °C and the mixture was stirred for 2.5 h. 2) The peptide was precipitated with cold tert-butyl methyl ether (50 mL) and centrifuged (3 min at 3000 rpm) to get the solid crude. The crude peptide precipitation was washed with tert-butyl methyl ether for three more times (20.0 mL x 3). Dry the crude peptide over vacuum for 2.0 h to give 0.4 g crude peptide. 3) The crude (0.4 g) was dissolved in CH 3 CN (15 mL) and water (15 mL) to achieve a 0.1 mM concentration. NH 4 HCO 3 solution (1M) was added to adjust the pH to about 8-9. The solution was allowed to shake at room temperature for about 8 hours. The reaction was monitored by HPLC. After the reaction was complete, the reaction was quenched with acetic acid to adjust the pH to about 6. The reaction mixture was then lyophilized and the resulting solid was purified by reversed-phase HPLC. 4) Purified the crude peptide by prep-HPLC (conditions: A: 0.075% TFA in water B: CH 3 CN) and lyophilized to get the desired peptide (example 9) (202.40 mg, 41.4.0% yield, 93.7% pure by Method W1; 95.1% pure by Method 7) as a white solid and TFA salt. Purification conditions: Peptide was dissolved in TFA / H 2 O (7:3); flow rate 20 mL / min; gradient 12-42% over 60 min; Retention time = 42 min; purification over a Luna 25 x 200 mm, C18 10 µm, 110 Å column. Alternative General Method for the Manual SPPS of Masp Peptides (Method E)

[0400] The synthesis of sequence ((2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid)-IC+SRSLP-(Oic)-IC+I-OH (example 184) is representative.Peptide Synthesis:

[0401] The peptide was synthesized using standard Fmoc chemistry.

[0402] The dark ball in the chemical structures below indicates the solid polymer support used for solid-phase peptide synthesis (SPPS), e.g. 2-chlorotrityl resin, Rink amide resin, etc.Example 1A (2S)-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)(oxan-4-yl)acetic acid (Single Stereoisomer)

[0403]

[0404] To (2S)-amino(oxan-4-yl)acetic acid (950 mg, 5.97 mmol) in acetone / water (15 mL / 10 mL) was added sodium bicarbonate (5.01 g, 59.7 mmol) and 1-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-dione (2.11 g, 6.27 mmol). The mixture was stirred over the weekend at room temperature. The suspension was treated with water and extracted with MBTE two more times. The aqueous phase was acidified with 1 M aqueous hydrochloric acid and was extracted with dicloromethane three more times. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (Isolera; 50 g SNAP Ultra; gradient: cychohexane 50% / ethyl acetate 50% + 1% acetic acid to cychohexane 20% / ethyl acetate 80% + 1% acetic acid). The appropriate fractions were combined and evaporated. The residue was taken up in toluene and evaporated two more times, then the residue was dried under vacuum to give 1.08 g (100% purity, 47% yield) of the target compound. LC-MS (Method 9): Rt = 0.90 min; MS (ESIpos): m / z = 382 [M+H] +< 1< H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.43), -0.008 (4.33), 0.008 (3.74), 0.146 (0.43), 1.280 (1.03), 1.300 (2.26), 1.309 (2.36), 1.331 (2.75), 1.341 (2.92), 1.371 (2.77), 1.401 (2.54), 1.411 (2.32), 1.430 (1.49), 1.464 (6.34), 1.496 (3.49), 1.932 (1.76), 1.942 (2.14), 1.951 (1.93), 1.960 (2.08), 2.327 (0.64), 2.366 (0.64), 2.670 (0.64), 2.710 (0.65), 3.169 (2.11), 3.212 (2.67), 3.237 (6.32), 3.265 (6.90), 3.704 (0.49), 3.715 (0.49), 3.840 (4.66), 3.854 (5.62), 3.867 (4.30), 3.879 (6.28), 3.899 (5.14), 3.918 (3.56), 4.201 (2.11), 4.218 (5.83), 4.237 (9.07), 4.263 (8.42), 4.274 (9.80), 4.293 (5.14), 4.318 (1.05), 7.309 (6.35), 7.328 (15.12), 7.347 (9.86), 7.400 (9.65), 7.419 (15.88), 7.437 (7.02), 7.652 (5.77), 7.674 (5.52), 7.735 (8.21), 7.740 (8.28), 7.754 (7.63), 7.883 (16.00), 7.902 (14.80), 12.609 (0.56). Example 2A

[0405]

[0406] The reaction was carried out under an argon atmosphere. To N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-isoleucine (9.40 g, 26.6 mmol) in 53 mL dichloromethane was added N,N-diisopropylethylamine (19 mL, 110 mmol) and 2-chlorotritylchlorid resin (10.0 g, 13.3 mmol). The reaction mixture was shaken overnight at room temperature. The precipitate was collected by filtration and washed with DMF three times. The collected resin was shaken with dichloromethane / methanol 1:1 for 30 min. The resin was collected by filtration and washed three times in rotation with methanol and dichloromethane. The collected resin was dried under vacuum for the next step.Example 3A

[0407]

[0408] Example 2A (15.2 g, 6.82 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 15 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 4A

[0409]

[0410] Example 3A (11.4 g, 5.13 mmol) was swelled in 100 mL DMF at room temperature for 5 min. A mixture of N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-S-(triphenylmethyl)-L-cysteine (6.01 g, 10.3 mmol) in 50 mL DMF, DIC (1.5 mL, 10 mmol) and Oxyma (1.42 g, 10.0 mmol) was added and the reaction mixture was shaken for 2 h at room temperature. The resin was collected by filtration and washed with DMF for three times. The coupling step was repeated overnight. The resin was collected by filtration and washed with 150 mL DMF for three times and then three more times in rotation with 150 mL methanol and 150 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 5A

[0411]

[0412] Example 4A (18.9 g, 8.51 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 15 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 6A

[0413]

[0414] Example 5A (16.3 g, 7.32 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-isoleucine (5.18 g, 14.6 mmol) in 50 mL DMF, DIC (2.2 mL, 14 mmol) and Oxyma (2.03 g, 14.3 mmol) was added and the reaction mixture was shaken for 2 h at room temperature. The resin was collected by filtration and washed with DMF for three times. The coupling step was repeated overnight. The resin was collected by filtration and washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 7A

[0415]

[0416] Example 6A (20.0 g, 8.98 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 15 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 8A

[0417]

[0418] Example 7A (17.8 g, 7.99 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of (2S,3aS,7aS)-1-{ [(9H-fluoren-9-yl)methoxy]carbonyl}octahydro-1H-indole-2-carboxylic acid (6.25 g, 16.0 mmol) in 50 mL DMF, DIC (2.4 mL, 16 mmol) and Oxyma (2.21 g, 15.6 mmol) was added and the reaction mixture was shaken for 2 h at room temperature. The resin was collected by filtration and washed with DMF for three times. The coupling step was repeated over the weekend. The resin was collected by filtration and washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 9A

[0419]

[0420] Example 8A (21.5 g, 9.68 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration, washed with DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. To the collected resin was added 200 mL DMF / piperidine 4:1 and shaken for 1 h at room temperature. The resin was collected by filtration, washed with DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 10A

[0421]

[0422] Example 9A (18.1 g, 8.13 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of 1-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-proline (11.0 g, 32.5 mmol) in 50 mL DMF, DIC (4.9 mL, 32 mmol) and Oxyma (4.51 g, 31.7 mmol) was added and the reaction mixture was shaken over the weekend at room temperature. The resin was collected by filtration, washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 11A

[0423]

[0424] Example 10A (20.4 g, 9.16 mmol) in 150 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 12A

[0425]

[0426] Example 11A (18.2 g, 8.18 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-leucine (11.6 g, 32.7 mmol) in 50 mL DMF, DIC (4.9 mL, 32 mmol) and Oxyma (4.53 g, 31.9 mmol) was added and the reaction mixture was shaken overnight at room temperature. The resin was collected by filtration, washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 13A

[0427]

[0428] Example 12A (20.9 g, 9.42 mmol) in 150 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 14A

[0429]

[0430] Example 13A (18.0 g, 8.11 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of O-tert-butyl-N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-serine (12.4 g, 32.4 mmol) in 50 mL DMF, DIC (4.9 mL, 32 mmol) and Oxyma (4.49 g, 31.6 mmol) was added and the reaction mixture was shaken overnight at room temperature. The resin was collected by filtration, washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 15A

[0431]

[0432] Example 14A (21.4 g, 9.64 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 16A

[0433]

[0434] Example 15A (18.9 g, 8.51 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of N 2< -{[(9H-fluoren-9-yl)methoxy]carbonyl}-N 5< -[N-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-sulfonyl)carbamimidoyl]-L-ornithine (22.1 g, 34.0 mmol) in 50 mL DMF, DIC (5.1 mL, 33 mmol) and Oxyma (4.72 g, 33.2 mmol) was added and the reaction mixture was shaken overnight at room temperature. The resin was collected by filtration, washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 17A

[0435]

[0436] Example 16A (23.8 g, 10.7 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 18A

[0437]

[0438] Example 17A (22.1 g, 9.95 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of O-tert-butyl-N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-serine (15.3 g, 39.8 mmol) in 50 mL DMF, DIC (6.0 mL, 39 mmol) and Oxyma (5.51 g, 38.8 mmol) was added and the reaction mixture was shaken overnight at room temperature. The resin was collected by filtration, washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 19A

[0439]

[0440] Example 18A (24.7 g, 11.1 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 20A

[0441]

[0442] Example 19A (22.2 g, 9.99 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-S-(triphenylmethyl)-L-cysteine (23.4 g, 40.0 mmol) in 50 mL DMF, DIC (6.0 mL, 39 mmol) and Oxyma (5.54 g, 39.0 mmol) was added and the reaction mixture was shaken overnight at room temperature. The resin was collected by filtration, washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 21A

[0443]

[0444] Example 20A (24.5 g, 11.0 mmol) in 200 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 22A

[0445]

[0446] Example 21A (22.3 g, 10.0 mmol) was swelled in 150 mL DMF for 5 min at room temperature. A mixture of N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-isoleucine (14.2 g, 40.1 mmol) in 50 mL DMF, DIC (6.0 mL, 39 mmol) and Oxyma (5.55 g, 39.0 mmol) was added and the reaction mixture was shaken over the weekend at room temperature. The resin was collected by filtration, washed with 200 mL DMF for three times and then three more times in rotation with 200 mL methanol and 200 mL dichloromethane. The collected resin was dried under vacuum for the next step.Example 23A

[0447]

[0448] Example 22A (1.00 g, 250 µmol) in 7.5 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with methanol and dichloromethane. The collected resin was dried under vacuum for the next step.Example 24A

[0449]

[0450] Example 23A (1.00 g, 250 µmol) was swelled in 5 mL DMF for 5 min at room temperature. A mixture of (2S)-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)(oxan-4-yl)acetic acid (381 mg, 1.00 mmol) in 1 mL DMF, DIC (150 µL, 980 µmol) and Oxyma (139 mg, 975 µmol) was added and the reaction mixture was shaken over the weekend at room temperature. The resin was collected by filtration, washed with DMF for three times and then three more times in rotation with methanol and dichloromethane. The collected resin was dried under vacuum for the next step.Example 25A

[0451]

[0452] Example 24A (1.00 g, 250 µmol) in 7.5 mL DMF / piperidine 4:1 was shaken for 30 min at room temperature. The resin was collected by filtration and washed with DMF for three times. Both steps were repeated and the collected resin was washed three times in rotation with methanol and dichloromethane. The collected resin was dried under vacuum for the next step.Example 26A (2S,3S)-2-{[(2R)-2-{[(2S,3S)-2-{[(2S,3aS,7aS)-1-{(2S)-1-[(2S,5S,8S,11S,14R,17S,20S)-20-amino-17-[(2S)-butan-2-yl]-8-(3-carbamimidamidopropyl)-5,11-bis(hydroxymethyl)-2-(2-methylpropyl)-20-(oxan-4-yl)-4,7,10,13,16,19-hexaoxo-14-(sulfanylmethyl)-3,6,9,12,15,18-hexaazaicosanan-1-oyl]pyrrolidine-2-carbonyl}octahydro-1H-indole-2-carbonyl]amino}-3-methylpentanoyl]amino}-3-sulfanylpropa-noyl]amino}-3-methylpentanoic acid (Single Stereoisomer)

[0453]

[0454] To Example 25A (1.00 g, 250 µmol) was added the cleavage cocktail of TFA / EDT / Thioanisol (90:3:7) and the mixture was shaken for 2 h at room temperature. The filtrate was collected, and the resin was washed with dichloromethane. The combined filtrate was evaporated. The residue was stirred with diethyl ether and the solid was collected by filtration. The solid was washed several times with diethyl ether and dried under vacuum for the next step.Example 184 ((2S)-2[(Amino)-2-(tetrahydro-2H-pyran-4-yl)]acetic acid)-IC+SRSLP-(Oic)-IC+I-OH (example 184)N-[(6S,9S,12S,15S,18R,23R,26S,28aS,29aS,33aS,35aS)-18-({N-[(2S)-2-amino-2-(oxan-4-yl)acetyl]-L-isoleucyl}amino)-26-[(2S)-butan-2-yl]-12-(3-carbamimidamidopropyl)-9,15-bis(hydroxymethyl)-6-(2-methylpropyl)-5,8,11,14,17,25,28,35-octaoxodotriacontahydro-1H,5H,22H-pyrrolo[2',1':13,14][1,2,5,8,11,14,17,20,23,26]dithiaoctaazacyclononacosino[11,10-a]indole-23-carbonyl]-L-isoleucine (Single Stereoisomer)

[0455]

[0456] To Example 26A (425 mg, 304 µmol) was added 850 mL 0.1 M aqueous ammonium bicarbonate solution (pH 7.86). Air was bubbled though the reaction mixture for 5 min. The reaction mixture was stirred in a open flask overnight at room temperature. The solvents were lyophilized to give 580 mg of a white solid. Purification using reversed-phase HPLC as described above (Method B) gave three fractions 7.4 mg (> 99%), 24.5 mg (98%) and 15 mg (95%) of the desired example 184.General Method F: Conversion of Peptide TFA salts to HCl salts

[0457] The synthesis of AIC+SRS-((tBu)A)-PPI-((N-Me)C)+IPD-NH2 (HCl Salt) (example 30) is representative.Procedure of Automatic Ion Exchange Station:

[0458] Peristaltic pump of the company Hirschmann (Rotarus volume 50), Tubes: Tygon 2001 (ID 0,64mm)Settings:

[0459] Washing with H 2 O : run-time 1200 s; 80 min -1< ; 1 cycle (is 35 mL volume) Sample circulation with peptide: run-time 1200 s; 80 min -1< ; 1 cycle (is 70 mL volume) Wash with H 2 O (or %ACN in H 2 O : run-time 1200 s; 80 min -1< ; 1 cycle (is 35 mL volume)

[0460] Amberlite IRA 410 (HCl form) was used. 1500 mg of the resin was placed into 2 filter cartridges and washed with deionized water (10 times).

[0461] The peptide dissolved in 3 mL of a 5% ACN / H 2 O solution was loaded onto the column and cycled through the column 10 times. The column was washed with water, and the solution collected into a Falcon tube and lyophilized

[0462] 72.83 mg of the desired peptide was obtained as the HCl salt: LC-MS (> 99%); Ion Chromatography analysis: 3.7 wt% Cl- (1.57 eq Cl-) , <1 wt % TFA.

[0463] The ion exchange process can also be performed using the following protocol: Amberlite IRA 410 resin (HCl form) (1-2 g) was placed into a 10 mL frit-syringe (100 mg Peptide needs 1g IRA 410 resin) 1) The resin is washed with water (10 times x 3 mL) 2) The resin is washed with 5% ACN in water (1 time x 3 mL) 3) The peptide was dissolved in 5% ACN in water 4) The peptide was added to the syringe and the solution was cycled through the column 10 -20 times. The eluent is collected into a Falcon Tube. 5) The resin is washed with 5%ACN in water (10 times x 3 mL); this solution is added to the solution in the Falkon-tube 6) The combined solution is lyophilized. General Method FA: Conversion of Peptide TFA salts to other salts Other salt forms:

[0464] The chloride counter ion can be exchanged with other counterions by passing a solution of the desired salt form (e.g sodium acetate) repeatedly through the column, then washing the column repeatedly with water. The peptide is then loaded and the above procedures followed. Peptide acetate, tartrate, citrate, and lactate salts have thus been prepared. The following three examples are representative:Example 249 Sequence: ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IP-NH 2 (Acetate salt) (example 249)N-[(6S,9S,12S,15S,18R,23R,26S,28aS,29aS,33aS,35aS)-26-[(2S)-butan-2-yl]-12-(3-carbamimidami-dopropyl)-9,15-bis(hydroxymethyl)-22,22-dimethyl-18-[(N-methylglycyl-L-isoleucyl)amino]-6-(2-methylpropyl)-5,8,11,14,17,25,28,35-octaoxodotriacontahydro-1H,5H,22H-pyr-rolo[2',1':13,14][1,2,5,8,11,14,17,20,23,26]dithiaoctaazacyclononacosino[11,10-a]indole-23-carbonyl]-L-isoleucyl-L-prolinamide, Acetic Acid salt

[0465] IRA 410 chloride resin (12 g) was placed into an empty 20 mL Biotage column and the resin was washed with with a 5% solution of ACN-water (10 times). The cartridge was attached to the Automatic Ion Exchange Station. The resin was washed with 20 column volumes of a 1M NaOH solution (2x 1800s rotation speed 80 min -1< ). The column was washed with water until the pH of the eluent was < pH 9 (10 column volumes). The column was then eluted with 1 M acetic acid solution (10 column volumes), then washed with water until the pH of the eluent was > 5 (about 10 column volumes). The peptide (N-Me)GIC+SRSLP-(Oic)-I-Pen+IP-NH 2 (TFA salt) (1200 mg) was loaded onto the column in 12 mL of 5% ACN / water and allowed to cycle through the column 10 times according to the General Method F. The resin was then washed with a 5% ACN / water solution 10 times and the eluent was collected into 50 mL Falcon tubes. The parameter settings used for this scale were: Washing with H 2 O: run-time 3085 s; 80 min-1; 1 cycle (is 90 mL volume) Sample circulation with peptide: run-time 3085 s; 80 min-1; 1 cycle (is 180 mL volume) Wash with H 2 O (or with %ACN in H 2 O: run-time 3085 s; 80 min-1; 1 cycle (is 90 mL vol...

Claims

1. A compound containing a peptide of the structure: or a pharmaceutically acceptable salt, solvate or solvate of the salt.

2. A compound containing a peptide according to Claim 1, or a pharmaceutically acceptable salt, solvate or solvate of the salt, which acts as a MASP-1 and / or MASP-2 inhibitor and / or which inhibits C3 deposition.

3. A process for preparing a compound containing a peptide according to any of Claims 1 to 2, or a pharmaceutically acceptable salt, solvate or solvate of the salt, using solid phase peptide synthesis.

4. A compound containing a peptide according to any of Claims 1 to 2, pharmaceutically acceptable salt, solvate or solvate of the salt, for the use in the prophylaxis and / or treatment of diseases.

5. A compound containing a peptide according to any of Claims 1 to 2, or a pharmaceutically acceptable salt, solvate or solvate of the salt, for the use in the prophylaxis and / or treatment of cardiovascular and cardiopulmonary disorders, shock, inflammatory disorders, cardiovascular, pulmonary, cerebral and renal sequels of sepsis, ischemia and / or reperfusion-related damage, acute kidney injury, transplant protection and delayed graft function, diseases of the blood and blood-forming organs and the immune system, sequels of diabetes mellitus, inflammatory diseases of the nervous system, diseases of the eye, diseases of the skin, diseases of the respiratory, digestive or genitourinary system and sequels of burns and injuries.

6. A pharmaceutical composition comprising at least one compound containing a peptide according to Claim 1, or a pharmaceutically acceptable salt, solvate or solvate of the salt, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

7. A pharmaceutical composition comprising at least one compound containing a peptide according to Claim 1, or a pharmaceutically acceptable salt, solvate or solvate of the salt, in combination with one or more further active ingredients selected from the group consisting of inhibitors of phosphodiesterases, stimulators or activators of guanylate cyclase, IP receptor agonists, mineralocorticoid-receptor antagonist, diuretic, PPAR-gamma agonist, PPAR-delta agonist, corticosteroids, active ingredients which reduce damage to organs under oxidative stress, compounds which inhibit induction of cell death and apoptosis pathway, compounds which inhibit inflammatory response and T cell proliferation, antithrombotic agents, platelet aggregation inhibitor, thrombin inhibitor, GPIIb / IIIa antagonist, factor Xa inhibitor, heparin or a low molecular weight (LMW) heparin derivative and inhibitors of coagulation factor XI.

8. The pharmaceutical composition according to Claims 6 or 7, for use in the prophylaxis and / or treatment of cardiovascular and cardiopulmonary disorders, shock, inflammatory disorders, cardiovascular, pulmonary, cerebral and renal sequels of sepsis, ischemia and / or reperfusion-related damage, acute kidney injury, transplant protection and delayed graft function, diseases of the blood and blood-forming organs and the immune system, sequels of diabetes mellitus, inflammatory diseases of the nervous system, diseases of the eye, diseases of the skin, diseases of the respiratory, digestive or genitourinary system and sequels of burns and injuries.