MASP inhibitory compounds and uses thereof 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 treat- ment and/or prevention of renal and cardiovascular disorders and of ischemia reperfusion injuries. 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 com- plement 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 pro- duced in liver, kidney and other organs (Garred et al., A journey through the lectin pathway of comple- ment-MBL and beyond. Immunol Rev. 2016;274(1):74-97). Their deposition is followed by further re- cruitment 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 cleav- age. 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 comple- ment 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 of MASP-2. Proc Natl Acad Sci U S A.2012;109(26):10498-503). 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 ex- periments 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., Tar- geting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury. Proc Natl Acad Sci U S A.2011; 108(18): 7523-8). Moreo- ver, 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 of MASP-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 path- way 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 avail- able, 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 (ClinicalTrials.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. 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 de- rivatives thereof for the treatment of diseases related to the complement system, primarily the lectin path- way were first described in WO 2010/136831. 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 activa- tion. 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 alter- natives 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. The present invention generally relates to peptides acting as inhibitors of MASP-1 and/or MASP-2 en- zymes and methods of making and using the same. In particular, the invention provides compounds containing a peptide, which may be isolated and/or puri- fied, 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 trisubsti- tuted 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 trisub- stituted identically or differently by a radical selected from the group consisting of hydroxyl, carboxy, amino and halogen, p represents 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, acet- ylated or mono- or disubstituted with C ₁ -C ₂₀ -alkyl, q represents 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-Methio- nine-L-sulfoxide, L-Methionine-sulfone and L-tert-butylglycine, whereas each natural amino acid and/or unnatural amino acid in L-stereoconfiguration can be re- placed 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, r represents 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-Cyclopentylala- nine (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-Cyano- phenyl)-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-Tri- fluoromethyl-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-hy- droxyproline ((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-azabicyclo[3.1.0]hex ane-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-Cyclobu- tylglycine, 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-Me- thyl-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 re- placed 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 unsub- stituted or amidated, s represents 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, t represents 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 trisubsti- tuted 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 trisub- stituted 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 X ¹ to X ¹⁴ is an unnatural amino acid. The invention further provides compounds containing a peptide of the following formula (II), (X ¹ )q(X ² )rX 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, q represents the integer 0 or 1, X ² represents the natural amino acid I, r represents 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, s represents the integer 0 or 1, X ¹⁴ represents a natural amino acid selected from a list consisting of D, Q and E, t represents 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 . 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, immu- nology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art. Throughout this specification, the word“comprise” or variations thereof such as“comprises” or“com- prising” 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 com- ponents). 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. As used herein, the following terms have the meanings ascribed to them unless specified otherwise.“Es- sentially 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. 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. 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., a-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). “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 b-amino acids (b ³ and b ² ), homo-amino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine deriva- tives, 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

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-Butyl- alanine ((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-(Ami- nomethyl)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). 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). It should be further understood, that a peptide according to the invention can contain one or more chemical groups which are no amino acid under the definition of the present invention. 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 invention are connected via peptide (amide) bonds. Generally peptides are formed by linking a-amino and carboxy groups of a- amino acids, which are then linked by a-peptide bonds. According to the present invention a peptide bond can be formed by any carboxyl- and amino group being present in a respective natural or unnatural amino acid. For example, a-amino acids which contain a second amino group in addition to the a-amino group (e.g. L-lysine) or a-amino acids which, in addition to the a-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. 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 a-peptide bonds. An amino acid linked via a peptide bond, which is not an a-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.). 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. According to the present invention the N-terminus can be formed by X ⁰ , in case p represents 1. Alterna- tively the N-terminus can be formed by X ¹ , in case q represents at least 1 and p represents 0. Alternatively the N-terminus can be formed by X ² , in case r represents 1 and p and q both represent 0. In case p, q and r all represent 0, the N-terminus is formed by X ³ in case of a linear peptide. 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. According to the present invention the C-terminus can be formed by X ¹⁵ , in case u represents 1. Alterna- tively 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. In case s, t and u all represent 0, the C-terminus is formed by X ¹² . In the present invention 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). 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 Acids

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). 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. 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 hydro- gen 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 respec- tive prefix (e.g. homo-Arg, homo-R, nor-Arg, nor-R, homo-Cys, homo-C etc.). 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-dime- thylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethyl- butyl, 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 par- ticularly 1, 2 or 3 carbon atoms (“C ₁ -C ₃ -alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group. Partic- ularly preferred is methyl, ethyl, n-propyl. Most preferred is methyl. 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. 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, b-methylethylene, a-ethylethylene, b-eth- ylethylene, butylene, a-methylpropylene, b-methylpropylene and g-methylpropylene. 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, b-methylethylene, a-ethylethylene, b-eth- ylethylene, butylene, a-methylpropylene, b-methylpropylene, g-methylpropylene, a-ethylpropylene, b- ethylpropylene, g-ethylpropylene, pentylene and hexylene. 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. 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, tetra- hydrothiopyranyl, 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. The term“aryl” means an unsaturated or partially unsaturated cycle having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl. 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, pyr- idazinyl, 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, ben- zothienyl, 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. 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. 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 alter- natives a C-terminal“-OH” moiety is preferred. 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). According to a further embodiment, the invention provides compounds containing a peptide, which may be isolated and/or purified, comprising, essentially consisting of, or consisting of, formula (I) or a deriva- tive, 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)ace- tyl), 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-Methylva- leric), 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 (Cyclohexyla- cetic), Cyclohexanecarboxylic acid (Cyclohexylcarboxylic), Cyclopentanecarboxylic acid, Cyclopen- tylacetic acid (Cyclopentylacetic), Cyclopropanecarboxylic acid (Cyclopropanecarboxylic), Cycloprop- ylacetic acid, D-(+)Biotin, Fumaric acid, 3-Phenylpropanoic acid (Hydrocinnamic), Isobutyric acid, Iso- valeric 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-py- ran-3-ylacetic acid and trans-2-(3-((t-butoxy)carbonylamino)cyclohexyl)acetic acid), p represents 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- 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-Aminocyclobu- tane-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 and Tranexamic acid (Tranexamic), whereas each natural amino acid and/or unnatural amino acid in L-stereoconfiguration can be re- placed by the stereoisomer in D-stereoconfiguration, q represents 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-methylpen- tanoic 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 re- placed by the stereoisomer in D-stereoconfiguration, r represents 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)-Morpho- line-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]pyrro lo[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]hex ane-3-carboxylic acid, (2S,4S)-4- Trifluoromethyl-pyrrolidine-2-carboxylic acid ((4-CF3)P), (2S,3aS,6aS)-octahydrocyclopenta[b]pyr- role-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]hep- tane-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-Cyclo- pentylglycine (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-cyclobutyla- cetic 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 re- placed 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 unsub- stituted or amidated, s represents 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 re- placed by the stereoisomer in D-stereoconfiguration, t represents 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, u represents the integer 0 or 1, with the proviso that the peptide contains at least one unnatural amino acid. According to a further embodiment, the invention provides compounds containing a peptide, which may be isolated and/or purified, comprising, essentially consisting of, or consisting of, formula (I) or a deriva- tive, 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-(Morpho- line)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, Phenyla- cetic acid, Piperidin-4-ylacetic acid, Tetrahydro-2H-pyran-3-ylacetic acid, Tranexamic acid and trans-2-(3-((t-butoxy)carbonylamino)cyclohexyl)acetic acid, p represents 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-dia- minobutyric 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-Nor- valine (Nva), L-Ornithine (Orn), L-Pipecolic acid (Pip), N-Methyl-L-proline ((N-Me)P), Tranex- amic 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 re- placed by the stereoisomer in D-stereoconfiguration, q represents 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 re- placed by the stereoisomer in D-stereoconfiguration, r represents 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-methylcyclopro- pyl)propanoic acid and 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic), 3-(Trimethylsi- lyl)-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,5R,6R)-6-(tri- fluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, (2S,3aS,6aS)-octahydrocyclopenta[b]pyr- role-2-carboxylic acid, rel-(3R,6R)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (enantio- mer 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 re- placed 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 unsubsti- tuted or amidated, s represents 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 re- placed 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, t represents 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, u represents the integer 0 or 1, with the proviso that the peptide contains at least one unnatural amino acid. According to a further embodiment, the invention provides compounds containing a peptide, which may be isolated and/or purified, comprising, essentially consisting of, or consisting of, formula (I) or a deriva- tive, prodrug, analogue, pharmaceutically acceptable salt, solvate or solvate of the salt, wherein p represents 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), q represents the integer 0 or 1, X ² represents the natural amino acid I, r represents 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 unsub- stituted or amidated, s represents 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, t represents the integer 0 or 1, u represents an integer of 0, with the proviso that the peptide contains at least one unnatural amino acid. According to a further embodiment, the invention provides a compound containing a peptide of the fol- lowing 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), q represents the integer 0 or 1, X ² represents the natural amino acid I, r represents 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, s represents the integer 0 or 1, X ¹⁴ represents a natural amino acid selected from a list consisting of D, Q and E, t represents 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 . According to a further embodiment, the invention 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, q represents the integer 0 or 1, X ² represents the natural amino acid I, r represents 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, s represents the integer 0 or 1, X ¹⁴ represents a natural amino acid selected from a list consisting of D, Q and E, t represents 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 . According to a further embodiment, the invention 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), q represents the integer 0 or 1, X ² represents the natural amino acid I, r represents 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, s represents the integer 0 or 1, X ¹⁴ represents a natural amino acid selected from a list consisting of D, Q and E, t represents 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 . In particular, the invention provides compounds containing a peptide of the formula (I) or compounds containing a peptide of the formula (II). According to the present invention, the following definitions of X ¹ to X ¹⁴ apply to peptides of formula (I) and peptides of formula (II), definitons of positions X ⁰ and X ¹⁵ apply to peptides of formula (I). According to the present invention X ⁰ , if present, can be a chemical group which is not an amino acid, according to the definition herein. According to a further embodiment of the invention, 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-Dioxoimid- azolidin-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-(Di- ethylamino)acetyl), 2-(Morpholine)acetic acid (2-(Morpholine)acetyl), 2-(N-Methyl-N-cyclopropyla- mino)acetic acid (2-(N-Methyl-N-cyclopropylamino)acetyl), 2-(Piperidin)acetic acid (2-(Piperidin)ace- tyl), 2-(Pyrrolidine)acetic acid (2-(Pyrrolidine)acetyl), 2-Hydroxyacetic acid (2-Hydroxyacetyl), 2-Hy- droxyisobutyric 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 (Cy- clobutylacetic), Cyclohexylacetic acid (Cyclohexylacetic), Cyclohexanecarboxylic acid (Cyclohexylcar- boxylic), Cyclopentanecarboxylic acid, Cyclopentylacetic acid (Cyclopentylacetic), Cyclopropanecar- boxylic acid (Cyclopropanecarboxylic), Cyclopropylacetic acid, D-(+)Biotin, Fumaric acid, 3-Phenylpro- panoic acid (Hydrocinnamic), Isobutyric acid, Isovaleric acid (Isovaleric), L-(+)-Lactic acid (Lactic), Phe- nylacetic acid, Piperidin-4-ylacetic acid, Pivalic acid (Pivalic), Suberic acid, tert-Butylacetic acid, Tetra- hydropyranyl-4-acetic acid, Tetrahydro-2H-pyran-3-ylacetic acid and trans-2-(3-((t-butoxy)carbonyla- mino)cyclohexyl)acetic acid). According to a further embodiment of the invention, 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-Thiomor- pholine)acetic acid, (N-Isopropyl-N-methylamino)acetic acid, 2-(3-Pyridyl)acetic acid, 2-(Cyclohexyla- mino)acetic acid, 2-(Diethylamino)acetic acid, 2-(Morpholine)acetic acid, 2-(Piperidin)acetic acid, 2-(Pyr- rolidine)acetic acid, 3-(Aminomethyl)benzoic acid, 4-(Aminomethyl)benzoic acid, 1-(Aminomethyl)-cyclo- propyl-1-carboxylic acid (ACMP), Azetidine-2-carboxylic acid, Benzoic acid, Cyclobutylacetic acid, Cy- clopropylacetic 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. According to a further embodiment of the invention, 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. According to a further embodiment of the invention, X ⁰ is Hoo, ODD or Ahx. According to a further embodiment of the invention, p represents an integer of 1. According to a further embodiment of the invention, p represents an integer of 0. According to a further embodiment, 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 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. According to a further embodiment of the invention, 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-azabicy- clo[2.2.1]heptane-3-carboxylic acid, L-3-Bromophenylalanine ((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-Amino- butyric 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-Pro- line (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 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. According to a further embodiment of the invention, 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-Orni- thine (Orn), whereas each natural amino acid and/or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration. According to a further embodiment of the invention, 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-Orni- thine (Orn). According to a further embodiment of the invention, X ¹ represents the natural amino acid A or the unnat- ural amino acid N-Methyl-Glycine ((N-Me)G). According to a further embodiment of the invention, 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. According to a further embodiment of the invention, X ¹ is methylated. According to a further embodiment of the invention, X ¹ is acetylated. According to a further embodiment of the invention, q represents an integer of 0. According to a further embodiment of the invention, q represents an integer of 1. According to a further embodiment, 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 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-methylpen- tanoic 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. According to a further embodiment of the invention, 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 un- natural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration. According to a further embodiment of the invention, 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. According to a further embodiment of the invention, X ² represents the natural amino acid I. According to a further embodiment of the invention, 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. According to a further embodiment of the invention, r represents an integer of 0. According to a further embodiment of the invention, r represents an integer of 1. According to a further embodiment, 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 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). According to a further embodiment of the invention, X ³ represents the natural amino acid C or the unnat- ural amino acid L-Penicillamine (Pen). According to a further embodiment of the invention, X ³ represents the natural amino acid C. According to a further embodiment of the invention, 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 monosub- stituited, with C ₁ -C ₂₀ -alkyl. According to a further embodiment, 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 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). According to a further embodiment of the invention, X ⁴ represents a natural amino acid selected from a list consisting of S, C, T, R and K. According to a further embodiment of the invention, X ⁴ represents a natural amino acid selected from a list consisting of S or T. According to a further embodiment of the invention, X ⁴ represents the natural amino acid S. According to a further embodiment, 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 ⁵ represents the natural amino acid R or the unnatural amino acid N(5)-methyl-L-arginine ((Me)R). According to a further embodiment of the invention, X ⁵ represents the natural amino acid R or the unnat- ural amino acid N(5)-methyl-L-arginine ((Me)R). According to a further embodiment of the invention, X ⁵ represents the natural amino acid R. According to a further embodiment, 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 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). According to a further embodiment of the invention, 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). According to a further embodiment of the invention, X ⁶ represents the natural amino acid S or the unnat- ural amino acid allo-L-Threonine (allo-T). According to a further embodiment of the invention, X ⁶ represents the natural amino acid S. According to a further embodiment, 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 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-Butylal- anine ((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-cyanobu- tyric 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 ((Tri- fluoro)L), 2-Methyl-L-phenylalanine ((2-Me)F), L-Cyclobutylalanine (Cba), L-Cyclopentylalanine (Cpa), L-cyclopropylmethylalanine, L-trifluoromethylalanine, L-difluoromethylalanine, 2-Fluoro-L-phe- nylalanine ((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-hexa- noic acid and (2S)-3-(indol-4-yl)-2-(amino)propanoic acid. According to a further embodiment of the invention, 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-Bromophenylalanine ((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-Butylala- nine ((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-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. According to a further embodiment of the invention, 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-Bromophenylalanine ((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-cys- teine, (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. According to a further embodiment of the invention, X ⁷ represents the natural amino acid L or the unnat- ural amino acid L-tert-Butylalanine ((tBu)A). According to a further embodiment of the invention, X ⁷ represents the unnatural amino acid L-tert-Butyl- alanine ((tBu)A). According to a further embodiment of the invention, X ⁷ represents the natural amino acid L. According to a further embodiment, 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 ⁸ rep- resents 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-car- boxylic 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]pyr- rolo[1,2-a]azepine-9-carboxylic acid, trans-4-fluoroproline ((trans-4-Fluoro)P) and (1R,2S,5S)-3-azabicy- clo[3.1.0]hexane-2-carboxylic acid. According to a further embodiment of the invention, 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. According to a further embodiment of the invention, X ⁸ represents the natural amino acid P, or an unnat- ural amino acid selected from a list consisting of L-Proline (3,4- ₂ H), (1S,2S,5R)-3-azabicyclo[3.1.0]hex- ane-2-carboxylic acid and (4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro- 1H-pyr- ido[3,2-e]pyrrolo[1,2-a]azepine-9-carboxylic acid. According to a further embodiment of the invention, X ⁸ represents the natural amino acid P or the unnat- ural amino acid L-Proline (3,4- ₂ H). According to a further embodiment of the invention, X ⁸ represents the natural amino acid P. According to a further embodiment, 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 ⁹ rep- resents 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,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-azabicyclo[3.1.0]hexane- 3-carboxylic acid, (2S)-2-Amino-4,4,4-tri- fluorobutanoic 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). According to a further embodiment of the invention, X ⁹ represents the natural amino acid P, or an unnat- ural 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-azabicy- clo[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). According to a further embodiment of the invention, X ⁹ represents the natural amino acid P, or an unnat- ural 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]hep- tane-6-carboxylic acid , rel-(1R,3R,5R,6R)-6-(trifluoromethyl)-2-azabicyclo[3.1.0]hex ane-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]hep- tane-6-carboxylic acid (enantiomer 2). According to a further embodiment of the invention, X ⁹ represents the natural amino acid P or the unnat- ural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic). According to a further embodiment of the invention, X ⁹ represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic). According to a further embodiment, 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 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-Chlo- rophenylglycine ((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. According to a further embodiment of the invention, X ¹⁰ represents the natural amino acid I, or an unnat- ural 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). According to a further embodiment of the invention, X ¹⁰ represents the natural amino acid I, or an unnat- ural 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). According to a further embodiment of the invention, X ¹⁰ represents the natural amino acid I. According to a further embodiment, 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). According to a further embodiment of the invention, 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). According to a further embodiment of the invention, X ¹¹ represents an unnatural amino acid selected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen). According to a further embodiment of the invention, X ¹¹ represents the unnatural amino acid L-Penicilla- mine (Pen). According to a further embodiment, 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 ⁹ represents the unnatural amino acid 2,3,3a,4,5,6,7,7a-Octahydroindole-2-carboxylic acid (Oic) and X ¹¹ rep- resents the unnatural amino acid L-N-Methylcysteine ((N-Me)C) or the unnatural amino acid L-Penicilla- mine (Pen). According to a further embodiment of the invention, 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). According to a further embodiment of the invention, 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 se- lected from a list consisting of L-N-Methylcysteine ((N-Me)C) and L-Penicillamine (Pen). According to a further embodiment, 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 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-car- boxylic acid, 2-methyl-D-alloisoleucine, L-Norvaline (Nva), L-2-Aminobutyric acid (Abu), L-tert-butyl- glycine and Aminoisobutyric acid (Aib). According to a further embodiment of the invention, X ¹² represents the natural amino acid I, or an unnat- ural amino acid selected from a list consisting of 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-car- boxylic 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. According to a further embodiment of the invention, X ¹² represents the natural amino acid I, or an unnat- ural amino acid selected from a list consisting of allo-L-Isoleucine (allo-I), (S)-2-Amino-2-cyclobutyla- cetic acid (Cbg) and 2-[(1S,2S)-1-(amino)-2-methylbutyl]-1,3-oxazole-4-carboxylic acid. According to a further embodiment of the invention, X ¹² represents the natural amino acid I. According to a further embodiment of the invention, in case u and t and s are all 0, the terminal carboxyl group of X ¹² is unsubstituted or amidated. According to a further embodiment, 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 ¹³ rep- resents 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. According to a further embodiment of the invention, 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-Amino- butyric acid (Abu), 2-Aminoisobutyric acid (Aib), Hydroxyproline (Hyp) and 2,3,3a,4,5,6,7,7a-Octahy- droindole-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. According to a further embodiment of the invention, 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 nat- ural amino acid and/or unnatural amino acid in L-stereoconfiguration can be replaced by the stereoisomer in D-stereoconfiguration. According to a further embodiment of the invention, X ¹³ represents the natural amino acid P. According to a further embodiment of the invention, s represents an integer of 0. According to a further embodiment of the invention, s represents an integer of 1. According to a further embodiment of the invention, 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. According to a further embodiment of the invention, in case t is 0 and s is 1, the terminal carboxyl group of X ¹³ is unsubstituted or amidated. According to a further embodiment, 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 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. According to a further embodiment of the invention, 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 (Tranex- amic), whereas each natural amino acid and/or unnatural amino acid in L-stereoconfiguration can be re- placed by the stereoisomer in D-stereoconfiguration. According to a further embodiment of the invention, 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-Carbox- yphenylalanine ((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. According to a further embodiment of the invention, X ¹⁴ represents a natural amino acid selected from a list consisting of D, Q or I. According to a further embodiment of the invention, X ¹⁴ represents the natural amino acid D. According to a further embodiment of the invention, the C-terminal "-OH" moiety at X ¹⁴ is substituted for a C-terminal "-NH ₂ " moiety. According to a further embodiment of the invention, q represents an integer of 0. According to a further embodiment of the invention, q represents an integer of 1. According to a further embodiment of the invention, in case s and t represent the integer 1, the terminal carboxyl group of X ¹⁴ is unsubstituted or amidated. According to a further embodiment of the invention, in case s and t represent the integer 1, the terminal carboxyl group of X ¹⁴ is unsubstituted. According to the present invention X ¹⁵ , if present, can be a chemical group which is not an amino acid. According to a further embodiment of the invention, 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)cyclopentane- carboxylic 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-Aza- spiro[2.4]heptane-1-carboxylic acid and (2S)-3-(Triazol-1-yl)-2-(amino)propanoic acid. According to a further embodiment of the invention, X ¹⁵ is a chemical group selected from -NH ₂ or -NH- C ₁ -C ₆ -alkyl, preferably -NH ₂ . According to a further embodiment of the invention, q represents an integer of 0. According to a further embodiment of the invention, q represents an integer of 1. According to a further embodiment of the invention, the N-terminus of the peptide is unsubstituated, acet- ylated or mono- or disubstituted with C ₁ -C ₂₀ -alkyl. According to a further embodiment of the invention, the N-terminus of the peptide is unsubstituated, acet- ylated or mono- or disubstituted with C ₁ -C ₄ -alkyl. According to a further embodiment of the invention, the N-terminus of the peptide is unsubstituated or acetylated. According to a further embodiment of the invention, the C-terminus is unsubstituted or amidated. According to a further embodiment of the invention, the N-terminus and C-terminus is unsubstituted. According to a further embodiment, 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, 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. The peptide of formular (I) or (II) can be linear or cyclized. 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. According to a further embodiment, 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 the pep- tide is cyclized. According to a further embodiment of the invention, the peptide of formula (I) or formula (II) is cyclized via a linkage connecting X ³ and X ¹¹ . According to a further embodiment of the invention, 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 -. According to a further embodiment of the invention, the peptide of formula (I) or 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-. The petide of the present invention 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 es- ters), polycarbonates, polyurethanes, polyacrylic acids, polyacrylamides, polyacrylates, polymethacrylates, polyorganophosphazenes, polysiloxanes, polyvinylpyrrolidone, polycyanoacrylates, and polyesters. The petides of the present invention 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. Prefer- ably 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. 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-Shulman et al., J. Med.Chem., 2004, 47, 4897-4904). A PEG group according to the invention 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 modifi- cation to a molecule is well known in the art. PEG group may consist of an interconnecting moiety, a polymer moiety, and an end group. lnterconntect- 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 hy- drogen 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 . Examples of PEG spacer according to the present invention 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.. 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 inven- tion. According to a further embodiment, 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 the peptide is substituted by at least one PEG group. According to a further embodiment of the invention, the peptide is substituted by one PEG group. According to a further embodiment of the invention, the peptide is substituted by one PEG group, wherein the PEG group is bound to the C-terminal end, preferably via an amide bond. According to a further embodiment of the invention, 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)

(IIIa), wherein * marks the attachment to a nitrogen or oxygen atom, D is C ₁ -C ₄ -alkylene, Y is selected from the group consisting of hydroxyl, methoxy, ethoxy, carboxy, carboxamide or amino and n represents an integer of from 2 to 15, or a group of the formula (IIIb)

(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 m represents an integer of from 2 to 15, or TTDS. According to a further embodiment of the invention, 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. The peptide of the present invention 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, prefera- bly 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 ³ C ₁₂ , more preferably a fatty acid ³ C14. 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 C14-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). 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. 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 sequences

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 present invention, 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. Proline mimetics according to the present invention 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,2S,5S)-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,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-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. Isoleucine mimetics according to the present invention 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. Leucine mimetics according to the present invention 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, cyclopropylmethylalanine, 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-hexa- noic acid or (2S)-3-(indol-4-yl)-2-(amino)propanoic acid. The invention 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 invention 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. Ex- amples comprise BLAST programs used with default parameters. An analogue or derivative of a peptide or an amino acid sequence of the invention 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 se- quence of the invention comprises conservative substitutions relative to the sequence of amino acids. 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, hydro- phobic 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, hydro- philic; 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 properties

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. 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 invention 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 modifi- cations 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, which are herein incorporated by reference. All peptides of this invention unless otherwise noted are TFA salts. The invention comprises further phar- maceutically acceptable salts of the peptides as defined herein and salt free forms. Therein, pharmaceuti- cally 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. Repre- sentative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesul- fonate, bisulfate, butyrate, camphorate, camphorsulfonate, carbonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hy- droxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthyl- enesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropri- onate, picrate, pivalate, propionate, succinate, sulfate, tartrate, trichloroacetate, trifluoroacetate, phos- phate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Preferred acid addition salts in- clude trifluoroacetate, formate, hydrochloride, and acetate. Also, amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myri- styl, 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 phar- maceutically acceptable salt may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Ex- amples of acid addition salts include chloride salts, citrate salts and acetate salts. 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. 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 Phar- maceutical 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. The invention 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. The compounds according to the invention have useful pharmacological properties and can be used for prevention and treatment of disorders in humans and animals. In the context of the present invention, 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”. In the context of the present invention, 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. The treatment or the prevention of a disease, a condition, a disorder, an injury or a health impairment may take place partially or completely. The compounds according to the invention are particularly suitable for the treatment and/or prevention of cardiovascular, cardiopulmonary, renal, pulmonary, fibrotic, thromboembolic, and inflammatory disorders. Accordingly, the compounds according to the invention can be used in medicaments for the treatment and/or prevention of cardiovascular and cardiopulmonary disorders and their sequels such as, for example inflam- matory heart diseases, myocarditis, endocarditis, pericarditis, rheumatic fever without and with heart in- volvement, 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 tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, 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 gan- grene) 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 in- flammatory response syndrome, vasoplegia after surgery, postcardiotomy syndrome, postprocedural hypo- tension and heart failure, for preventing and treating ischemia reperfusion injury and organ dysfunction for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneous translu- minal 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. The compounds according to the invention are furthermore suited for the treatment of shock such as car- diogenic shock, septic shock and anaphylactic shock by preveting MASP mediated end organ damages. Moreover, the compounds according to the invention 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. By virtue of their activity profile, the compounds according to the invention are particularly suitable for the treatment and/or prevention of cardiovascular, pulmonary, cerebral and renal sequels of sepsis and systemic inflammatory response syndrome. The compounds according to the invention 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, The compounds according to the invention 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 solu- tions 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. Furthermore, the compounds according to the invention 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 coag- ulation [defibrination syndrome], essential (haemorrhagic) thrombocythaemia, purpura fulminans, throm- botic thrombocytopenic purpura, allergic purpura, allergic vasculitis, lymphopenia and lgranulocytosis, and sarcoidosis. Furthermore, the compounds according to the invention are suitable for the treatment and/or prevention of sequels of diabetes mellitus sucha as renal complications of diabetes mellitus, diabetic nephropathy, intracapil- lary glomerulonephrosis, ophthalmic complications of diabetes mellitus, diabetic retinopathy, neurological complications, diabetic polyneuropathy, and circulatory complications such as microangiopathy and gangrene. Moreover, the compounds according to the invention are suitable for the treatment and/or prevention of inflammatory diseases of the nervous system such as multiple sclerosis, meningitis and encephalitis, bac- terial and viral meningitis and encephalitis, postimmunization encephalitis, inflammatory polyneuropathy, and polyneuropathy in infectious and parasitic diseases. The compounds according to the invention 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, chorioreti- nal 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, ne- ovascular) 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 oe- dema (DME), atrophic and hypertrophic lesions in the retinal pigment epithelium, retinal vein occlusion, cho- roidal retinal vein occlusion, macular oedema, macular oedema associated with retinal vein occlusion, postpro- cedural disorders of eye and adnexa, e.g. keratopathy following cataract surgery. Furthermore, the compounds according to the invention 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, res- piratory disorders in other diffuse connective tissue disorders, such as associated to systemic lupus erythe- matosus, sclerodermia and Wegener granulomatosis. Furthermore, the compounds according to the invention 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). Furthermore, the compounds according to the invention 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. By virtue of their activity profile, the compounds according to the invention 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, inflam- matory diseases of the prostate, and endometriosis. The compounds according to the invention 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 anu- ria, crush syndrome, renal failure following crushing, traumatic ischaemia of muscle, traumatic brain in- jury, 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. By virtue of their activity profile, the compounds according to the invention 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. 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 or pharmaceutically acceptable salts or solvates thereof for the use in the prophylaxis and/or treatment of diseases. 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 or pharmaceutically acceptable salts or solvates thereof for the use in the prophylaxis and/or treatment of MASP-associated disorders. According to a further embodiment, the invention 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. 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 or pharmaceutically acceptable salts or solvates thereof for the use in the prophylaxis and/or treatment of cardiovascular and cardiopulmonary disorders, shock, inflamma- tory disorders, cardiovascular, pulmonary, cerebral and renal sequels of sepsis, ischemia and/or reperfu- sion-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 dis- eases 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. According to a further embodiment, the invention 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 prophy- laxis 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 en- dometriosis. The invention further relates to a method of treating or ameliorating MASP-associated disorders, as de- fined 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. 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. According to the invention the at least one peptide, derivative or analogue as defined herein or the phar- maceutically 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 com- pound 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 thera- peutically effective amount will achieve a desired benefit/risk ratio applicable to any medical treatment. The present invention particularly comprises the following embodiments, wherein the substituents or moi- eties of the peptide according to formula (I) or formula (II) as defined below, may independently have the meanings as described below. A peptide or a compound containing a peptide, or derivative or analogue thereof as defined herein or the phar- maceutically 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”. 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 in- vention 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). The invention 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. 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. 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. 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. 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. 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. 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. 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 IC50 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 IC50 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. In some embodiments, a MASP inhibitory peptide of the present invention has a lower IC50 (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 IC50 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. 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. 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. 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. 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 mdeter- mined 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 inhib- itory peptide reference compound. 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. In further particular embodiments, the MASP-1 and/or MASP-2 inhibitory activity of the MASP inhibi- tory peptides according to the present invention is determined by measurement of their IC50 for inhibition of C3 deposition in vitro or in subjects (e.g. mice or humans). Determination of the IC50 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 IC50 for C3 deposition of < 1,000 nM, preferably £ 500 nM, more preferably £ 300 nM, more preferably £ 250 nM, more preferably £ 200 nM, more prefer- ably £ 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. 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. 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. 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. 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 suit- able for the use in in the prophylaxis and/or treatment of MASP-1 and/or MASP-2-associated disorders. 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. The compounds according to the invention can be used alone or in combination with other active com- pounds 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, neloc- iguat, 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, trepros- tinil, epoprostenol, NS-304, selexipag, or ralinepag;

• endothelin receptor antagonists, for example and preferably bosentan, darusentan, ambrisentan, mac- icentan 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 sys- tem 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 recep- tor, 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 adreno- medullin stabilizing agents, for example adrecizumab;

• compounds which inhibit hypoxia inducible factor prolyl hydroxylase (HIF-PH inhibitors), for exam- ple 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 antago- nistic 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 adminis- tered 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 adminis- tered 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 adminis- tered 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 adminis- tered 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 adminis- tered 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 adminis- tered 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 adminis- tered in combination with a mineralocorticoid-receptor antagonist, for example and preferably spiro- nolactone, eplerenone or finerenone.

• In a preferred embodiment of the invention, the compounds according to the invention are adminis- tered in combination with a diuretic, for example and preferably furosemide, bumetanide, Torsemide, bendroflumethiazide, chlorthiazide, hydrochlorthiazide, hydroflumethiazide, methyclothiazide, pol- ythiazide, 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 adminis- tered in combination with a PPAR-gamma agonist, for example and preferably pioglitazone or rosig- litazone.

• 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. 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, pharmaceu- tically acceptable salt, solvate or solvate of the salt, in combination with one or more further active ingre- dients selected from the group consisting of inhibitors of phosphodiesterases, stimulators or activators of guanylate cyclase, IP receptor agonists, mineralocorticoid-receptor antagonist, diuretic, PPAR-gamma ag- onist, PPAR-delta agonist, corticosteroids, active ingredients which reduce damage to organs under oxi- dative stress, compounds which inhibit induction of cell death and apoptosis pathway, compounds which inhibit inflammatory response and T cell proliferation, antithrombotic agents, platelet aggregation inhibi- tor, thrombin inhibitor, GPIIb/IIIa antagonist, factor Xa inhibitor, heparin or a low molecular weight (LMW) heparin derivative and inhibitors of coagulation factor XI. 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 phar- maceutical composition as defined above, and at least one selected from a reagent, medical device, in- struction letter or any combination thereof. 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. The pharmaceutical composition, kit-of-parts combination or medical device as defined above is in par- ticular for the use in the prophylaxis and/or treatment of the disorders or diseases as defined as defined herein. It is possible for the MASP inhibitory peptide of the present invention to have systemic and/or local ac- tivity. 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, conjuncti- val, otic route or as an implant or stent. For these administration routes, it is possible for the compounds according to the invention to be admin- istered in suitable administration forms. 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/ly- ophylisates, 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 ac- cording to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms. 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 intra- muscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal, intraocular). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infu- sion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. 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. 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, pharmaceu- tically acceptable salt, solvate or solvate of the salt, in combination with one or more inert, nontoxic, pharmaceutically suitable excipients. 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. Pharma- ceutically 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 alco- hols, 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 tri- glycerides fatty oils, liquid polyethylene glycols, paraffins), • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospho- lipids, 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, polyoxyeth- ylene 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-so- dium, 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 alco- hols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockco- polymers),

• 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 ac- etate, sodium benzoate),

• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), • flavourings, sweeteners, flavour- and/or odour-masking agents. The present invention furthermore relates to a pharmaceutical composition comprising at least one pep- tide, derivative or analogue as defined herein or a pharmaceutically acceptable salt or solvate thereof or a complex as defined above. In particular, the present invention relates to a pharmaceutical composition comprising at least one pep- tide, 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 excipi- ent(s), and to their use according to the present invention. A pharmaceutical composition according to the present invention 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. 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 adminis- tered enterally or parenterally, including intravenous, intramuscular, intraperitoneal, intrasternal, subcu- taneous, intradermal and intraarticular injection and infusion, orally, intravaginally, intraperitoneally, in- trarectally, 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, plas- ters, topical extended-release formulations, dragees, pessaries, gels, ointments, syrup, granules, supposi- tories, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formula- tions, capsules, enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, in- halation sprays, powders, drops, nose drops, nasal sprays, aerosols, ampoules, solutions, juices, suspen- sions, infusion solutions or injection solutions, etc. 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, pharmaceu- tically 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, se- quels 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. 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 accepta- ble 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 ag- onist, 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 re- sponse 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. According to a further embodiment, the invention provides a method for treatment and/or prevention of of cardiovascular and cardiopulmonary disorders, shock, inflammatory disorders, cardiovascular, pulmo- nary, cerebral and renal sequels of sepsis, ischemia and/or reperfusion-related damage, acute kidney in- jury, 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 puri- fied, 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 puri- fied, 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 ingre- dients. The suitable dosage of the MASP inhibitory peptide of the present invention can be decided by the attend- ing 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. 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 admin- istration or another continuous drug administration method), or may be administered to a subject at inter- vals, typically at regular time intervals, depending on the desired dosage and the pharmaceutical compo- sition 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. The invention further comprises the use of the MASP inhibitory peptide as described herein for the man- ufacture 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. The invention 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. Generally, the MASP inhibitory peptide of the present invention may be manufactured synthetically, or semi-recombinantly. According to a further embodiment, the invention 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 solv- ates thereof by using solid phase peptide synthesis. According to a further embodiment, the invention 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.

According to a further embodiment, the invention 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.

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 biochem- ical 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. The present invention 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. The invention is further illustrated by the following examples, which relate to certain specific embodi- ments 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 in- vention. As such, they should not be construed in any way as limiting the scope of the present invention. Examples List of Abbreviations used in Experimental Section: Å Angstroms

aq. Aqueous, aqueous solution

bar Unit of pressure

BPR Back-pressure regulator

conc Concentrated

d Doublet (NMR)

dd Doublet of doublet (NMR)

DCM Dichloromethane

DEA Diethylamine

DIPEA N,N,-diisopropylethylamine (Hünig`s base)

DMAP 4-Dimethylaminopyridine

DMF N,N-dimethylformamide

DMSO Dimethylsulfoxide

dt Doublet of triplet (NMR)

EA Ethyl acetate

ee Enantiomeric excess

ent Enantiomeric

eq Equivalent(s)

equiv Equivalent(s) (ion chromatography)

ESI Electrospray-ionisation (mass spectroscopy)

Fmoc-OSu 1-{[(9H-Fluoren-9-ylmethoxy)carbonyl]oxy}pyrrolidine-2,5-dio ne

GC-MS Gas chromatography coupled with mass spectrometry

h Hour(s)

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexa fluorophosphate

HPLC High pressure liquid chromatography

IC Ion chromatography

ID Internal diameter

L Liter

LC-MS Liquid chromatography coupled to mass spectroscopy

LiHMDS Lithium bis(trimethylsilyl)amide lit. Literature

m Multiplet (NMR)

MALDI Matrix Assisted Laser Desorption/Ionization (mass spectrometry) Me Methyl

min Minute(s)

mm millimeter

^m micrometer (micron)

M Molar

MPLC Medium pressure liquid chromatography

MS Mass spectroscopy

MTBE tert-Butyl methyl ether

MTP Microtiter plate

m/z mass-to-charge ratioi (mass spectrometry)

nm nanometer

NMP N-Methyl-2-pyrrolidone

NMR Nuclear magnetic resonance spectroscopy

PBS Phosphate buffered saline

PE Petroleum ether

PEG Polyethylene glycol

pos Positive

ppm parts per million

Pr Propyl

Psi Pounds per square inch (pressure)

q / quart Quartet (NMR)

qd Quartet of doublet (NMR)

quint Quintet (NMR)

rac racemic

Rf Retention factor (TLC)

RP reversed-phase (for liquid chromatography)

Rt Retention time (chromatography)

s Singlet (NMR)

s Seconds (time)

SPPS solid phase peptide synthesis

t Triplet (NMR)

TBTU O (Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate tBu tert-Butyl

TEA triethylamine THF Tetrahydrofuran

TLC Thin layer chromatography

UPLC Ultra-performance liquid chromatography

UV Ultraviolet Further abbreviations can be found in Table 2 and 3. Analytical LC-MS Methods Method 1

Equipment type MS: ThermoFisherScientific LTQ-Orbitrap-XL; Equipment type HPLC: Agilent 1200SL; Column: Agilent, POROSHELL 120, 3 x 150 mm, SB– C182.7 µm; eluent A: 1 L water + 0.1% trifluoro- acetic 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 nm Method 2

Equipment type MS: ThermoFisherScientific LTQ-Orbitrap-XL; Equipment type HPLC: Agilent 1200SL; Column: Agilent, POROSHELL 120; 3 x 150 mm, SB– C182.7 µm; eluent A: 1 L water + 0.1% trifluoro- acetic 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 nm Method 3

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 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 ® 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 nm Method 4

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 nm Method 5

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 nm Method 6

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 nm Method 7

Instrument type MS: Agilent 6410 Triple Quad; Instrument type HPLC: Agilent 1200; Column: Gemini- NX C185 ^m 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 nm Method 8

Instrument type MS: Agilent 6410 Triple Quad; Instrument type HPLC: Agilent 1200; Column: Discovery BIO Wide Pore C18 5 ^m 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 nm Method 9

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T31.8 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 nm Method 10

Instrument MS: Thermo Scientific FT-MS; Instrument UHPLC: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C181.8 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 nm Method 11

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

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSST31.8 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

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

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 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

Exact mass measurements were performed on selected peptides using a Matrix Assisted Laser Desorp- tion/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 ^-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% acetoni- trile 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

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

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 The ¹ H-NMR data of selected compounds are listed in the form of ¹ H-NMR peaklists. Therein, for each signal peak the d value in ppm is given, followed by the signal intensity, reported in round brackets. The d value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is de- scribed by the general form: d1 (intensity1), d2 (intensity2), ... , di (intensityi), ... , dn (intensityn). 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, sig- nals 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 "by- product 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

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 syn- thesizer (Gyros Protein Technologies). Fmoc-protected amino acids (or intermediate amino acids used to prepare Fmoc amino acids) were pur- chased 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 (Fluorenylmethoxycar- bonyl = 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 pep- tides 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. 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 availa- ble) or, synthesized internally by methods described herein. Table 5 shows the CAS number of the chem- ical 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 Invention

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 syn- thesized 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% piper- idine 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 equiva- lents 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 equiva- lents 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. 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%H2O. For peptides con- taining 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: 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: N-terminal acetylation was performed using 10 equivalents acetic anhydride in DMF (2 mL) and 2.5 equiva- lents 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: 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 nitro- gen (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. 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 precipi- tate 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: 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. Frac- tions 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. 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, C1810 ^m, 110 Å) or a Gemini column (30 x 150 mm, C185 ^m,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 ^o 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. 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. All peptides of this invention unless otherwise noted are TFA Salts. General Method for the Automated SPPS of Masp Peptides (Method A) The synthesis of ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IPD-NH ₂ (Example 165) is representative. The peptide was synthesized using standard Fmoc chemistry. 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 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 per- formed 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. 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: Fmoc-Asp(t-Bu) (4.0 mL) was added. Activator 1 solution (DIC, 1.5 mL) and Activator 2 solution (Ox- yma, 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 (Ox- yma, 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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). If additional amino acids were present in the sequence, they were coupled using using the steps above. Test Cleavage: 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: 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 ^o 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: 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: The peptide was dissolved in 5% CH3CN and 95% water. Column screening was performed on each pep- tide to determine which preparative HPLC method to use for purification. The following analytical col- umns were screened. 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): 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) 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 C185µ 21,5x250mm + Cartridge 5µ

3) Column: Phenomenex, Kinetex 5µ Biphenyl 100A, AXIA Packed, 21,2x250mm + Cartridge 5µ 4) Column: YMC Actus Triart Prep. C1812nm, S-10µm 250x20mm + Cartridge 3µm (10x4mm) 5) Column: Waters, Xbridge Prep.C185µ OBD 19x250mm + Cartridge 10µ 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 CH3CN/water (1:1) and purified on a Phenom- enex Kinetex column C185µ, 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

General Method for the Automated SPPS of Masp Peptides (Method B) 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. The peptide was synthesized using standard Fmoc chemistry. 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. 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: 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. 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: 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 l = 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: The resin loading L301 in mmol/g is calculated by the following formula:

E = extinction

^ = 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: 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). The coupling of the subsequent Fmoc amino acids proceeded as described in Method A. 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

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 per- formed 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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 cou- pling 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: 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). If additional amino acids were present in the sequence, they were coupled using using the steps above. Test Cleavage: 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: 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 ^o 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: 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: The peptide was dissolved in 5% CH ₃ CN and 95% water. Column screening was performed on each pep- tide to determine which preparative HPLC method to use for purification. The following analytical col- umns were screened. 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): 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) 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 C185µ 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. C1812nm, S-10µm 250 x 20mm + Cartridge 3µm (10x4mm) 5) Column: Waters, Xbridge Prep.C185µ OBD 19 x 250mm + Cartridge 10µ 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 C185-95 in 18 min) and using one of the LC-MS methods described abouv For example 164, the crude peptide was dissolved in CH ₃ CN/water (1:1) and purified on a Phenomenex Kinetex column C185µ, 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

General Method for the Manual SPPS of Masp Peptides (Method C) The synthesis of sequence AIC+SRSLP-(Oic)-I-(Pen)+IPN-OH (example 418) is representative. Peptide Synthesis: 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 N2 for 2 h at 20 °C, then added MeOH (0.3 mL) and agitated with N2 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 N2 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

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: 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 con- taining 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 dis- solved 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, C1810 um, 110 Å column, then again over a Gemini 150 x 30 mm, C185 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) 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-NH ₂ (example 9) is representative. 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: 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 agi- tated 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

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: 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%H2O) was added to the flask contain- ing 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 concentra- tion. 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: CH3CN) and lyophi- lized 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; puri- fication over a Luna 25 x 200 mm, C1810 ^m, 110 Å column. Alternative General Method for the Manual SPPS of Masp Peptides (Method E) 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: The peptide was synthesized using standard Fmoc chemistry. 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)a cetic acid (Single Stereoisomer)

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 sus- pension was treated with water and extracted with MBTE two more times. The aqueous phase was acidi- fied 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] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [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

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 col- lected 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

Example 2A (15.2 g, 6.82 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 15 min at room temper- ature. 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

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

Example 4A (18.9 g, 8.51 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 15 min at room temper- ature. 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 dichloro- methane. The collected resin was dried under vacuum for the next step. Example 6A

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 cou- pling 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

Example 6A (20.0 g, 8.98 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 15 min at room temper- ature. 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 dichloro- methane. The collected resin was dried under vacuum for the next step. Example 8A

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

Example 8A (21.5 g, 9.68 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 30 min at room temper- ature. 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 di- chloromethane. The collected resin was dried under vacuum for the next step. Example 10A

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 week- end 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

Example 10A (20.4 g, 9.16 mmol) in 150 mL DMF/piperidine 4:1 was shaken for 30 min at room tem- perature. 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

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

Example 12A (20.9 g, 9.42 mmol) in 150 mL DMF/piperidine 4:1 was shaken for 30 min at room tem- perature. 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 14 A

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 15 A

(

Example 14A (21.4 g, 9.64 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 30 min at room tem- perature. 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

(

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 tempera- ture. 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

Example 16A (23.8 g, 10.7 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 30 min at room tem- perature. 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 18 A

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 19 A

Example 18A (24.7 g, 11.1 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 30 min at room tem- perature. 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 20 A

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 dichloro- methane. The collected resin was dried under vacuum for the next step.

Example 21 A

Example 20A (24.5 g, 11.0 mmol) in 200 mL DMF/piperidine 4:1 was shaken for 30 min at room tem- perature. 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

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

HE

Example 22A (1.00 g, 250 µmol) in 7.5 mL DMF/piperidine 4:1 was shaken for 30 min at room temper- ature. 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 col- lected resin was dried under vacuum for the next step. Example 24 A

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)a cetic 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

Example 24A (1.00 g, 250 µmol) in 7.5 mL DMF/piperidine 4:1 was shaken for 30 min at room temper- ature. 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 col- lected 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(hydro xymethyl)-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]pyrrol- idine-2-carbonyl}octahydro-1H-indole-2-carbonyl]amino}-3-met hylpentanoyl]amino}-3-sulfanylpropa- noyl]amino}-3-methylpentanoic acid (Single Stereoisomer)

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-carbamimidamidop ropyl)-9,15-bis(hydroxymethyl)-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]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucine (Single Stereoisomer)

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 The synthesis of AIC+SRS-((tBu)A)-PPI-((N-Me)C)+IPD-NH ₂ (HCl Salt) (example 30) is representa- tive. Procedure of Automatic Ion Exchange Station: Peristaltic pump of the company Hirschmann (Rotarus volume 50), Tubes: Tygon 2001 (ID 0,64mm) Settings: Washing with H2O : 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 H2O (or %ACN in H2O : run-time 1200 s; 80 min ^-1 ; 1 cycle (is 35 mL volume) 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). The peptide dissolved in 3 mL of a 5% ACN/H2O 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 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. 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: 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-meth ylglycyl-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]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-L-prolinamide, Acetic Acid salt 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 Ex- change 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 volume) The combined eluent was lyophilized to give 1120 mg (100 % purity, 97% yield) of the target acetate salt. Ion chromatography (chloride content): < 1% chloride

Ion chromatography (TFA content): < 1% TFA

Ion chromatography (acetate content): 7.1% acetate = 1.84 equiv

LC-MS (MCW-TOF-AQ-YMC-18min): Rt = 7.74 min; MS (ESIpos): m/z = 725 [M+2H] ⁺ Example 264 Sequence: ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IP-NH ₂ (L-Tartaric acid salt) (example 264) 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-meth ylglycyl-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]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-L-prolinamide (2R,3R)-2,3-dihydroxybutanedioic acid (L-(+) tartaric acid) salt IRA 410 chloride resin (12.5 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 Ex- change 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 L-tartaric 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)G)- IC+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 H2O: 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 H2O (or %ACN in H2O: run-time 3085 s; 80 min ^-1 ; 1 cycle (is 90 mL volume) The combined eluent was lyophilized to give 1170 mg (100% purity, 91% yield) of the target L-tartaric acid salt. Ion Chromotography (chloride content): <1% chloride Ion Chromotography (TFA content): <1% TFA Ion chromatography (acetate content): 13.4% acetate = 1.49 equiv LC-MS (MCW-TOF-AQ-YMC-18min): Rt = 7.62 min; MS (ESIpos): m/z = 725 [M+2H] ⁺ Example 376 Sequence: ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IP-NH ₂ (Citric acid salt) (example 376) 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-meth ylglycyl-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]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-L-prolinamide, 2-hydroxypropane-1,2,3-tricarboxylic acid (citric acid) salt

IRA 410 chloride resin (26 g) was placed into an empty 20 mL Biotage columns and the resin was washed with with a 5% solution of ACN-water (10 times). The cartridge was attached to the Automatic Ion Ex- change 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 citric 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 H2O : 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 %ACN in H ₂ O : run-time 3085 s; 80 min ^-1 ; 1 cycle (is 90 mL volume) The combined eluent was lyophilized to give 1370 mg (100 % purity, 97 % yield) of the target L-tartaric acid salt. Ion Chromotography (chloride content): <1% chloride

Ion Chromotography (TFA content): <1% TFA

Ion chromatography (acetate content): 19.0% acetate = 1.77 equiv

LC-MS (MCW-TOF-AQ-YMC-18min): Rt = 7.6 min; MS (ESIpos): m/z = 725 [M+2H] ⁺ One skilled in the art will recognize that although the stoichiometry by ion chromatography is not always stoichiometric (e.g.1:2 or 1:1), water content has not been taken into account, which where in a few cases that were measured, can be between 8-15% water content. General Method G: Preparation of a Salt-Free Form The preparation of AIC+SRSLP-(Oic)-I-(Pen)+IPD-NH ₂ (salt free form) (example 27) is representative. 5 Grams of the TFA salt (example 75) was purified by reversed-phase HPLC using an acetonitrile water gradient at 70 ^o C with no acid modifier. The desired fractions were combined and lyophilized.2.2 grams of the salt-free form (example 27) was obtained; LC-MS (> 99% pure); Ion Chromatography (< 1% TFA) General Method H: Large Scale Synthesis The synthesis of AIC+SRS-((tBu)A)-PPI-((N-Me)C)+IPD-NH ₂ (example 48) is representative

, The peptide was synthesized using standard Fmoc chemistry. 1) DMF was added to the vessel containing MBHA Resin (180 mmol) and the resin was allowed to swell for 2 hours.

2) The Fmoc-Rink amide linker was added and mixed for 30 seconds, then the ativation buffer was added. Mixing was done using N ₂ bubbling for about 1 hour.

3) The solution was drained from the resin and the resing was washed with DMF wash (30 sec x 3 times).

4) A solution of 20% piperidine/DMF was added and mixed with nitrogen bubbling for 30 min. 5) The solution was drained and the resin was washed with DMF (5 times).

6) The Fmoc-amino acid solution was added and mixed for 30 seconds, then the activation buffer was added. Mixing was done using N ₂ bubbling for about 1 hour.

7) Steps 3 to 6 were repeated for each amino acid coupling.

Table 10: Note of materials used and conditions

A solution of 20% piperidine in DMF was used for Fmoc deprotection for 30 min. The coupling reaction was monitored by ninhydrin test, and the resin was washed with DMF for 5 times. Peptide Cleavage and Purification: 1) The cleavage buffer (92.5% TFA: 2.5% EDT: 2.5% TIS: 2.5% H2O) was added to the flask con- taining the side chain protected peptide at room temperature and the mixture was stirred for 2 hours.

2) The peptide was precipitated with cold isopropyl ether and centrifuged (2 min at 5000 rpm). 3) The peptide was washed twice more with isopropyl ether.

4) The crude peptide was dried under vacuum for 2 hours. Disulfide Formation To a solution of the crude linear peptide (15 g, 9.92 mmol, 1.0 eq) (20 batches) in H ₂ O/I (3 L 2:1) was added NH ₄ HCO ₃ (7.84 g, 99.2 mmol, 10 eq). The mixture was stirred at 30 °C for 16 h, quenched with the addition of HCl to PH~6, and then the mixture was lyophilized. The lyophilizate was purified by Prep- HPLC to give the desired example 48 (41.8 g, 95.8%, 13.3% yield) as a white solid, 156.8 grams total. Purification conditions Equipment: Shimadzu 10A; Peptide was dissolved in DMF/H ₂ O. Mobile Phase: , A (H ₂ O (0.075% TFA in H ₂ O), B EtOH; gradient: 10-50%-60 min. Retention time: 47 min; Column: Luna, C18, 10 ^m,100A, 25 cm x 50 mm; flow rate: 80 mL/min; wavelength: 220/254 nm; oven temp: room temperature. Method I: Preparation of ((N-Me)A)-IC+SRSLP-(Oic)-I-(Pen)+IP-((N-Benzyl)D)-NH ₂ (example 462) 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-meth yl-L-alanyl-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]dithiaoctaaz acyclononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-L-prolyl-N ⁴ -benzyl-L-aspartamide

The peptide was prepared on Rink Amide MBHA resin (loading typically around 0.4-0.6 mmol/g) on 0.3 mmol scale. The first amino acid Fmoc-Asp(2-Phenylisopropyl ester)-OH (CAS 200336-86-3) was added to the resin using the method described in Method C. The peptide sequence was constructed using the steps described in Method C. Upon completion of the sequence, the 2-OPP protecting group was removed using 1%TFA in DCM, 30 minutes. N-Benzyl amine (3 equiv), DIC (3 equiv) and Oxyma (3 equiv) was added and the mixture was shaken for 2 hours. The peptide was cleaved, the disulfide bond was formed, and the peptide was purified according to Method C. General Method J. Preparation of ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IP-(*Dap)-OH (example 467) 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-meth ylglycyl-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]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-N-[(2S)-2-amino-2-carboxyethyl]-L-prolinamide

The peptide was prepared on 2-chlorotrityl resin according to Method C. BOC-Dap(Fmoc)-OH (CAS 122235-70-5) was added onto the resin according to Method C. The peptide was constructed and purified according to method C. General Method K. Preparation of (2-(Morpholine)acetyl)-IC+SRS-((tBu)A)-PPI-(Pen)+IPD-NH2 (example 283) Example 27A N-(bromoacetyl)-L-isoleucyl-L-cysteinyl-L-seryl-L-arginyl-L- seryl-4-methyl-L-leucyl-L-prolyl-L- prolyl-L-isoleucyl-3-sulfanyl-L-valyl-L-isoleucyl-L-prolyl-L -alpha-asparagine

The sequence IC+SRS-((tBu)A)-PPI-(Pen)+IPD-NH ₂ was prepared 12 times on Rinkamide ChemMatrix resin at 0.1 mmol scale according to Method A. To the resin-containing peptide (200 mg 100 µmol) was added N,N'-diisopropylcarbodiimide (31 µL, 200 µmol), ethyl(hydroxiimino)cyanoacetate (28.4 mg, 200 µmol) and bromoacetic acid (14 µL, 200µmol) and the mixture was shaken in 5 mL DMF overnight at room temperature on a thermomixer shaker. The resin was filtered, washed with DMF (6 x 5 mL), washed with DCM (6 x 5 mL) and then dried under vacuum for the next step. Example 283 N-[(5aS,11S,14S,17S,20S,23R,28R,31S,33aS)-31-[(2S)-butan-2-y l]-17-(3-carbamimidamidopropyl)-11- (2,2-dimethylpropyl)-14,20-bis(hydroxymethyl)-27,27-dimethyl -23-({N-[(morpholin-4-yl)acetyl]-L-iso- leucyl}amino)-5,10,13,16,19,22,30,33-octaoxooctacosahydro-1H ,5H,10H-dipyrrolo[2,1-j:2',1'- m][1,2,5,8,11,14,17,20,23,26]dithiaoctaazacyclononacosine-28 -carbonyl]-L-isoleucyl-L-prolyl-L-alpha- asparagine

j

‹

To example 27a (200 mg, 74% purity, 77.7 µmol) in NMP (10 mL) was added morpholine (34 µl, 390 µmol) and the suspension was shaken at 37 °C in thermomixer. The solid resin was collected by filtration, washed with 10 mL DMF and 10 mL dichloromethane each two times. The residue was treated with TFA/EDT/thionaisol (90:3:7) and shaken 2 h at room temperature. The reaction mixture was treated with cold diethyl ether (-10 ^o C), and then the suspension was centrifuged under nitrogen and washed three times (3 x 30 mL) with cold diethylether. To the residue was added a 0.1 M aqueous ammonium bicarbonate solution (400 mL) and the reaction mixture was shaken overnight in an open-to-the-air round-bottomed flask. The solution was lyophilized and the lyophilized powder was purified according to Method A, to provide 20.4 mg (98% purity, 16% yield) of example 283. Example 300 (2-Hydroxyacetyl)-IC+SRS-((tBu)A)-PPI-(Pen)+IPD-NH ₂ was isolated as a by-product. General Method L. Preparation of sodium and choline salt forms These salts were prepared from salt-free form peptides. The two examples below are representative of the general method: Example 431 N-[(6S,9S,12S,15S,18R,23R,26S,28aS,29aS,33aS,35aS)-18-[(L-al anyl-L-isoleucyl)amino]-26-[(2S)-bu- tan-2-yl]-12-(3-carbamimidamidopropyl)-9,15-bis(hydroxymethy l)-22,22-dimethyl-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]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-N-[(1S)-1,2-dicarboxylatoethyl]-L-prolinamide, Sodium salt

Sequence: AIC+SRSLP-(Oic)-I-(Pen)+IPD-OH (sodium salt) (example 431) To a solution of AIC+SRSLP-(Oic)-I-(Pen)+IPD-OH (salt-free form) (100 mg) in 20 mL acetonitrile/wa- ter 1:1 was added 1.3 mL of a 0.1 M sodium hydroxide solution. The mixture was dried under vacuum to give 109 mg (104% yield, 99% purity) of the target compound. LC-MS (MCW-TOF-AQ-YMC-18min): Rt = 8.62 min; MS (ESIpos): m/z = 783 [M+2H]2+ Ion chromatography (sodium content): 2.9% sodium = 2.03 equiv Example 432 N-[(6S,9S,12S,15S,18R,23R,26S,28aS,29aS,33aS,35aS)-18-[(L-al anyl-L-isoleucyl)amino]-26-[(2S)-bu- tan-2-yl]-12-(3-carbamimidamidopropyl)-9,15-bis(hydroxymethy l)-22,22-dimethyl-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]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-N-[(1S)-1,2-dicarboxylatoethyl]-L-prolinamide, 2-Hydroxy-N,N,N-trimethylethan-1-ammo- nium) (choline) salt

To a solution of AIC+SRSLP-(Oic)-I-(Pen)+IPD-OH (salt-free form) (100 mg) in 20 mL acetonitrile/wa- ter 1:1 was added 511 mL of a 0.25 M choline hydroxide solution. The mixture was dried under vacuum to give 122 mg (105% yield, 99% purity) of the target compound. LC-MS (MCW-TOF-AQ-YMC-18min): Rt = 8.65 min; MS (ESIpos): m/z = 783 [M+2H]2+ Ion chromatography (choline content): 11.7% choline = 1.97 equiv Example 13 AIC+SRSLP-(Oic)-I-(Pen)+IPD-OH (example 13)

(3S)-4-amino-3-({(2S)-1-[(2S,3S)-2-{[(2R)-2-{[(2S,3S)-2-{[(2 S,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)-4,7,10,13,16,19-hexaox o-14-(sulfanylmethyl)-3,6,9,12,15,18- hexaazahenicosanan-1-oyl]pyrrolidine-2-carbonyl}octahydro-1H -indole-2-carbonyl]amino}-3- methylpentanoyl]amino}-3-methyl-3-sulfanylbutanoyl]amino}-3- methylpentanoyl]pyrrolidine-2-car- bonyl}amino)-4-oxobutanoic acid

Peptide Synthesis The peptide was synthesized using standard Fmoc chemistry. 1） Resin preparation: to the CTC Resin (15.0 mmol, 15.0 g, 1.0 mmol/g) was added Fmoc- Asp(OtBu)-OH (15.0 mmol, 6.17 g, 1.0 eq) and DIEA (10.4 mL, 60.0 mmol, 4.0 eq) in DCM (300 mL). The mixture was agitated with N ₂ for 2 h at 20 °C. Methanol was then added (15.0 mL) and the resin agitated with N ₂ for another 30 min. The resin was washed with DMF (300 mL x 3). Then a solution of 20% piperidine in DMF (300 mL) was added and the mixture was agitated with N ₂ for 20 min at 20°C. Then the mixture was filtered to give the resin. The resin was washed with DMF (300 mL x 3) and filtered to give the resin. 2） Coupling: Fmoc-Pro-OH (15.2 g, 45.0 mmol, 3.0 eq), HBTU (16.2 g, 42.8 mmol, 2.85 eq) and DIEA (90.0 mmol, 15.6 mL, 6.00 eq) in DMF (100 mL) was added to the resin and the resin was agitated with N ₂ for 30 min at 20°C. The resin was then washed with DMF (300 mL x 5).

3） Deprotection: 20% piperidine in DMF (300 mL) was added to the resin and the mixture was agi- tated with N ₂ for 20 min at 20 °C.

4） Steps 2 and 3 were repeated for all other amino acids: Table 11: Reagents used for example 13

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 (300 mL) for 5 times. HBTU, DIEA supplier：Suzhou Highfine Biotech Co.,Ltd Peptide Cleavage and Purification 5） The resin was washed with MeOH (300 mL x 5) and dried under vacuum to get 41.5 g of the peptide resin. Then 400 mL of cleavage buffer (92.5%TFA/2.5%3-mercaptopropionic acid/2.5%TIS/2.5%H2O) was added to the flask containing the side chain protected peptide resin at 20 °C and the mixture was stirred for 2.5 h and then filtered.

6） The peptide was precipitated with cold tert-butyl methyl ether (4000 mL) and centrifuged (3 min at 3000 rpm) to get the crude solid peptide. The crude peptide precipitate was washed with tert- butyl methyl ether three more times (1000 mL x 3). The crude peptide was then dried under vac- uum for 2.0 h to give 21.8 g of the crude peptide.

7） The crude peptide (21.8 g) was dissolved in CH ₃ CN (6.5 L) and water (6.5 L). I ₂ (0.1 M in MeOH, 55 mL) was added at 20 °C until a yellow color persisted. Then the mixture was stirred at 20°C for 2 min. Sodium thiosulfate solution (0.1 M in water, 15 mL) was then added dropwise until the yellow color disappeared. The mixture was then lyophilized to give the crude powder (22.7 g). 8） Purification of the crude peptide by preparative HPLC (condition: A: 0.075% TFA in water B:

CH3CN), collection of product-containing fractions, and the lyophilization gave the target peptide (Sequenc ID 13); (4305.1 mg, 18.3% yield, 99.1% by 110 Å C18 RP-HPLC column (Gemini C18 5 ^m 110 Å 150 x 4.6 mm); 97.8% by 300 Å C18 RP-HPLC column (Discovery BIO Wide Pore C185 ^m 300 Å 150 x 4.6 mm), TFA salt) as a white solid. Table 12: Purification conditions

LC-MS: Rt = 1.369 min; 1564 [M+2H]+ Rt = 8.72 min (99.1% pure) Gemini C185 ^m 110Å 150 x 4.6 mm Rt = 9.42 min (97.8%) Discovery BIO Wide Porei C185 ^m 300Å 150 x 4.6 mm From example 13 (TFA salt), example 29 (HCl salt) can be prepared using General Method F; example 5 (salt-free form) can be prepared using General Method G. The preparations of example 431 (sodium salt) and example 432 (choline salt) from example 5 are shown below as Example 431 and Example 432, respectively. Example 237 AIC+SRSL-(L-dehydroproline)-(Oic)-I-(Pen)+IPD-OH (example 237) N-[(6S,9S,12S,15S,18R,23R,26S,28aS,35aS)-18-[(L-alanyl-L-iso leucyl)amino]-26-[(2S)-butan-2-yl]- 12-(3-carbamimidamidopropyl)-9,15-bis(hydroxymethyl)-22,22-d imethyl-6-(2-methylpropyl)- 5,8,11,14,17,25,28,35-octaoxo- 6,7,8,9,10,11,12,13,14,15,16,17,18,19,23,24,25,26,27,28,28a, 29,29a,30,31,32,33,33a,35,35a-tri- acontahydro-3H,5H,22H-pyrrolo[2',1':13,14][1,2,5,8,11,14,17, 20,23,26]dithiaoctaazacyclonon- acosino[11,10-a]indole-23-carbonyl]-L-isoleucyl-L-prolyl-L-a spartic acid

The peptide was prepared according to Method C (3.12 g). The analytical data for this peptide is shown in Table 16 and Table 17. Example 142 AIC+SRSL-(Pro-D2)-(Oic)-I-(Pen)+IPD-OH (example 142) N-[(1R,2S,6S,9S,12S,15S,18R,23R,26S,28aS,35aS)-18-[(L-alanyl -L-isoleucyl)amino]-26-[(2S)-butan- 2-yl]-12-(3-carbamimidamidopropyl)-9,15-bis(hydroxymethyl)-2 2,22-dimethyl-6-(2-methylpropyl)- 5,8,11,14,17,25,28,35-octaoxo(1,2- ² H2)dotriacontahydro-1H,5H,22H-pyr- rolo[2',1':13,14][1,2,5,8,11,14,17,20,23,26]dithiaoctaazacyc lononacosino[11,10-a]indole-23-carbonyl]- L-isoleucyl-L-prolyl-L-aspartic acid

The peptide from Example 237 (30 mg, 19.2 µmol) was dissolved in methanol-d4 (3 mL) (99.8% purity of D). Rhodium black (CAS 7440-16-6, ACBR, Article No. AB25746) (10 mol%, 1.9 µmol) was added to the solution under argon in an M-Braun Glovebox. The 8 mL reaction vial mixture was placed into an MTP pressure reactor block that is located on a Chemspeed Swing XL platform and is enclosed inside an M-Braun glovebox (Chemspeed Technologies AG, Wölferstrasse 8, 4414 Füllinsdorf, Switzerland, chemspeed@chemspeed.com). The reaction was shaken with an orbital speed of 650 rpm at room tem- perature under a pressure of 3 bar of deuterium gas for 16 h overnight. The pressure block was purged with argon and the vial was removed from the reactor block. The methanol-d4 was evaporated with a rotary evaporator and the resulting solid was dissolved in water (2 mL) and stirred for 1 hour to exchange the exchangeable deuterium atoms with hydrogen. After 1 hour, acetonitrile was added and the product was purified by reversed-phase HPLC [column: Phenomenex Aeris Peptide 5µ XB-C18, AXIA Packed, 21.2 x 250 mm + Cartridge 5µ, flow: 20 mL/min, focused gradient using H ₂ O / ACN with 0.1% TFA as acidic modifier. FOK30-40: 0 min 5%ACN, 0-13 min ramp to 30% ACN, 13-39 min flat ramp to 40% ACN, 39-46 min isocratic 40% ACN]. Chromatography fractions containing the product were analyzed by analytical HPLC (focused gradient) and by LC-MS and then pooled accordingly to provide two frac- tions of the pure product: 11.4 mg (90% purity, 34% yield) and 4.2 mg (99% purity, 14% yield). The analytical data for this peptide is in Table 16.

The product peptide was subjected to trypsin digestion followed by reaction with dithiothreitol and the resulting fragments were analyzed by TOF-MS-MS. Trypsin digestion cleaved the peptide between the arginine and serine (exact mass 1583.8384, found 1583.852 [M+2H]2+). Reaction with dithiothreitol pro- duced two fragments, AICSR-OH (exact mass 548.2741, found 548.283 [M+H]+) and SL-(Pro-D2)- (Oic)-I-(Pen)+IPD-OH (exact mass 1037.5800, found 1038.587 [M+H]+), with the fragments at 838.47 amu ((Pro-D2)-(Oic)-I-(Pen)+IPD-OH) and at 738.40 amu SL-((Oic)-I-(Pen)+IPD-OH) verifying the po- sition of the deuterium atoms.

Example 28A (2S,3aS,6aS)-Octahydrocyclopenta[b]pyrrole-2-carboxylic acid—hydrogen chloride (1/1) (single stere- moisomer)

The reaction was performed under argon atmosphere. To palladium on carbon (200 mg, 10%) was added 20 mL methanol and benzyl (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate—h ydrogen chlo- ride (1/1) (1.00 g, 3.55 mmol). The reaction flask was charged with hydrogen gas (1 atm) and the reaction mixture was stirred under hydrogen atmosphere overnight at room temperature. The reaction mixture was filtered over diatomaceous earth and the filter cake was washed with methanol. The filtrate was evaporated and dried under vacuum to give 698 mg of the target compound. (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid is also commercially available as a salt free form. Example 29A (2S,3aS,6aS)-1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}octahydro cyclopenta[b]pyrrole-2-carboxylic acid (single steremoisomer)

To (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid—hydrogen chloride (1/1) (680 mg, 3.55 mmol) in 12 mL water was added sodium bicarbonate (2.98 g, 35.5 mmol) and a solution of 1-({[(9H- fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-dione (Fmoc-OSu) (1.26 g, 3.73 mmol) in 18 mL acetone. The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water, acidified with 1 M hydrochloric acid and extracted with ethyl acetate two times. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, fil- trated and then evaporated. The residue was separated via silica gel chromatography (Biotage Isolera, column: 50 g SNAP Ultra; eluent: diechloromethan/methanol 100:2– 100:5). The appropriate fractions were combined, evaporated and dried under vacuum to give 1.27 g (99% purity, 94% yield) of the target compound. LC-MS (Method 10): Rt = 2.08 min; MS (ESI pos): m/z = 378 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.260 (1.76), 1.274 (1.85), 1.299 (1.78), 1.321 (2.09), 1.335 (2.38), 1.440 (0.92), 1.455 (1.10), 1.473 (0.87), 1.521 (3.61), 1.537 (3.86), 1.551 (2.28), 1.607 (4.53), 1.620 (3.68), 1.640 (3.08), 1.653 (1.66), 1.712 (2.02), 1.781 (1.38), 1.816 (2.30), 1.827 (2.26), 1.839 (2.37), 1.855 (1.68), 2.073 (1.20), 2.305 (0.83), 2.328 (1.99), 2.351 (1.35), 2.360 (1.64), 2.384 (0.92), 2.468 (0.60), 2.606 (1.50), 2.670 (1.11), 3.860 (0.94), 3.874 (1.94), 3.893 (1.95), 3.907 (0.92), 4.143 (2.61), 4.156 (3.68), 4.167 (5.16), 4.186 (5.89), 4.266 (1.43), 4.280 (3.20), 4.294 (2.11), 4.345 (1.31), 4.371 (3.19), 4.386 (3.83), 4.396 (4.39), 4.411 (3.74), 4.422 (2.40), 4.437 (0.98), 7.292 (0.97), 7.311 (3.89), 7.329 (6.99), 7.346 (6.08), 7.363 (2.49), 7.395 (9.91), 7.414 (16.00), 7.432 (6.98), 7.663 (9.73), 7.680 (6.46), 7.879 (12.31), 7.897 (11.49), 12.586 (0.80). Example 30A (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (single stereoisomer)

(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane -3-carboxylic acid (CAS RN: 197142-34- 0, 500 mg) was dissolved in 4M HCl-dioxane solution (3 mL) and stirred for 8 h at room temperature. The solvent was evaporated and the crude product was used directly for the next step Example 31A (1R,3S,5R)-2-{[(9H-fluoren-9-yl)methoxy]carbonyl}-2-azabicyc lo[3.1.0]hexane-3-carboxylic acid (sin- gle stereoisomer)

To a solution of (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (Example 30A, 280 mg, 2.20 mmol) in 3 mL water was added sodium bicarbonate (1.85 g, 22.0 mmol) and a solution of 1-({[(9H- fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-dione (0.78 g, 2.31 mmol) in 4.5 mL acetone. The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water and extracted with twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtrated, and then concentrated. The crude product was purified by preparative reversed-phase HPLC (Column: Reprosil; C18; 10 µm; 125 x 30 mm; eluant A: CAN, eluant B: water with 0.1% formic), and the product-containing fractions were combined and lyoph- ilized to give 88.0 mg (96% purity, 11% yield) of the target compound. LC-MS (Method 11): R _t = 1.32 min; MS (ESI pos): m/z = 372 [M+Na] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.149 (1.15), -0.008 (10.73), 0.008 (9.13), 0.146 (1.21), 0.468 (1.54), 0.534 (3.66), 0.803 (4.38), 1.682 (2.68), 2.072 (0.75), 2.128 (2.19), 2.142 (2.32), 2.223 (1.05), 2.293 (2.19), 2.327 (4.45), 2.349 (2.68), 2.366 (2.75), 2.523 (3.89), 2.670 (1.44), 2.710 (1.31), 2.816 (0.82), 3.413 (3.93), 3.757 (1.83), 4.010 (2.91), 4.140 (2.39), 4.211 (3.11), 4.285 (12.30), 6.929 (0.43), 6.950 (0.43), 7.340 (9.91), 7.358 (6.02), 7.406 (10.08), 7.425 (16.00), 7.443 (7.10), 7.650 (2.85), 7.702 (4.52), 7.724 (5.53), 7.746 (3.40), 7.892 (12.40), 7.910 (9.85), 12.680 (0.65). This amino acid was used in Fmoc SPPS. This fmoc amino acid is also commercially available. Example 32A Benzyl (2R,4R)-4-[(2S)-butan-2-yl]-2-tert-butyl-5-oxo-1,3-oxazolidi ne-3-carboxylate (single stereoiso- mer)

To a suspension of D-alloisoleucine (8.06 g, 61.4 mmol) in 120 mL ethanol, was added a sodium hydrox- ide solution made from 2.45 g sodium hydroxide in 11 mL water. The reaction mixture was stirred 90 min at room temperature and then evaporated. The residue was treated with 195 mL pentane and then 2,2- dimethylpropanal (10 mL, 92 mmol) was added. The reaction mixture was stirred 24 h at 45 °C with a Dean-Stark trap attached to the round-bottomed flask. After cooling, the solvents were evaporated and the residue was dried several times with toluene (azeotropic distillation). The residue was treated with 165 mL dichloromethane and cooled to 0°C. Benzyl carbonochloridate (13 mL, 92 mmol) was added and the the reaction mixture was stirred for one week at 0-4 °C.4-Dimethylaminopyridine (375 mg, 3.1 mmol) and 65 mL water were added to the reaction mixture, the reaction mixture was allowed to come to room temperature and then it was stirred overnight at room temperature. The reaction mixture was treated with ethyl acetate several times and extracted. The combined organic phase was washed twice with 10% aque- ous citric acid and then twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was reextracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtrated and then evaporated. The residue was purified via silica gel chromatography (Isolera; eluent: cyclohexane/ethyl acetate 100:3– 100:7). The product- containing fractions were combined, evaporated and then dried under vacuum to give 8.71 g of the target compound. Example 33A Benzyl (2R,4R)-4-[(2S)-butan-2-yl]-2-tert-butyl-4-methyl-5-oxo-1,3- oxazolidine-3-carboxylate (single stereoisomer)

The reaction was carried out under argon atmosphere. Benzyl (2R,4R)-4-[(2S)-butan-2-yl]-2-tert-butyl-5- oxo-1,3-oxazolidine-3-carboxylate (Example 32A, 8.12 g, 24.4 mmol) in 100 mL dry THF was cooled to -78 °C. Potassium hexamethyldisilazide (44 mL, 29 mmol) was added dropwise and the reaction mixture stirred for 2 h at -78 °C. Iodomethane (2.3 mL, 37 mmol) was added dropwise to the reaction mixture and the reaction mixture was stirred for 2.5 h at room temperature. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, the reaction mixture allowed to room temperature, and then the product was extracted into ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtrated, and then concen- trated. The residue was purified via silica gel chromatography (Isolera, column: 100 g SNAP Ultra; eluent: cyclohexane/ethyl acetate 100:3– 100:7). The product-containing fractions were combined, evaporated and then dried under vacuum to give 3.2 g of the target compound. Example 34A N-[(Benzyloxy)carbonyl]-2-methyl-D-alloisoleucine (single stereoisomer)

To a solution of benzyl (2R,4R)-4-[(2S)-butan-2-yl]-2-tert-butyl-4-methyl-5-oxo-1,3- oxazolidine-3-car- boxylate (Example 33A, 3.20 g, 9.21 mmol) in methanol (40 mL) was added 1 M sodium hydroxide solution (40 mL). The reaction mixture was stirred for 2 h at reflux. After cooling, the methanol was evaporated. The residue was treated with 10% citric acid solution and the product wsa extracted into ethyl acetate. The aqueous phase was extracted with ethyl acetate two more times. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtrated, evaporated and then dried under vacuum to give 2.77 g of the target compound. Example 35A 2-Methyl-D-alloisoleucine (single stereoisomer)

The reaction was carried out under argon atmosphere. To N-[(benzyloxy)carbonyl]-2-methyl-D-alloiso- leucine (Example 34A, 2.57 g, 9.20 mmol) in 190 mL methanol was added palladium on carbon (390 mg, 10%). The reaction mixture was stirred under a hydrogen atmosphere for 4 h at room temperature and normal pressure. The reaction mixture was filtrated over diatomaceous earth and the filtrate was concen- trated, then dried under vacuum to give 1.32 g (98% yield) of the target compound. Example 36A N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-2-methyl-D-alloisoleu cine (single stereoisomer)

To a solution of 2-methyl-D-alloisoleucine (Example 35 A, 1.32 g, 9.09 mmol) in a mixture of water (20 mL) and acetone (29 mL) was added sodium bicarbonate (7.64 g, 90.9 mmol) and then a solution of 1- ({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-dio ne (3.22 g, 9.55 mmol) in acetone (20 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with MTBE and extracted. The aqueous phase was acidified with conc. hydrochloric acid (pH 1) and extracted with ethyl acetate three more times. The combined organic phases were dried over mag- nesium sulfate, filtrated and evaporated. The residue was separated via silica gel chromatography (Isolera, column: 50 g SNAP Ultra; eluent: dichloromethane/methanol 100:3– 100:5). The appropriate fractions were combined, evaporated and then dried under vacuum. The MTBE phase was subsequently treated with a 5% sodium bicarbonate solution and extracted with ethyl acetate (600 mL). The aqueous phase was acidified with conc. hydrochloric acid (pH 1) and extracted with ethyl acetate each time. The combined organic phases were dried over magnesium sulfate, filtrated, evaporated and then dried under vacuum. The combined crude product yield was 2.53 g. The residue was purified via silica gel chromatography (Isolera, column: 50 g SNAP Ultra; eluent: di- chloromethane/methanol 97:3– 97:5). The product-containing fractions were combined, evaporated and then dried under vacuum to give 967.4 mg of the target compound. The product was further dissolved in water/acetonitrile and lyophilized prior to use. LC-MS (Method 10): R _t = 2.10 min; MS (ESI pos): m/z = 368.1857 [M+H] ⁺ This amino acid was used in Fmoc SPPS. Example 37A (6S)-1,1-Difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (mixture of stereoisomers)

To (6S)-5-(tert-butoxycarbonyl)-1,1-difluoro-5-azaspiro[2.4]hep tane-6-carboxylic acid (Omega, CAS 1357482-03-1) (2.50 g, 9.02 mmol) in 85 mL dichloromethane was added trifluoroacetic acid (15 mL, 250 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was con- centrated and dried under vacuum for the next step. Example 38A (6S)-5-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-1,1-difluoro-5-a zaspiro[2.4]heptane-6-carboxylic acid (mixture of stereoisomers)

To a solution of (6S)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid (mixture of stereoisomers) (Example 37A, 1.60 g, 9.03 mmol) in water (13 mL) was added sodium bicarbonate (7.59 g, 90.3 mmol) and then a solution of 1-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-d ione (3.20 g, 9.48 mmol) in acetone (20 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water and extracted twice with MTBE. The aqueous phase was acidified with hydrochloric acid to pH3 and extracted with dichloromethane three times. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtrated, evaporated and dried under vacuum to give 3.31 g (92% yield) of the target compound. LC-MS (Method 10): R _t = 1.99 min; MS (ESI pos): m/z = 400 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.106 (16.00), 1.589 (0.92), 1.605 (1.39), 1.619 (1.06), 1.627 (1.11), 1.655 (0.62), 1.682 (1.25), 1.703 (1.21), 1.916 (0.49), 1.949 (0.86), 1.978 (0.91), 2.012 (0.85), 2.042 (0.52), 2.086 (11.35), 2.558 (0.83), 2.568 (0.67), 2.591 (0.67), 2.645 (0.52), 2.670 (0.56), 3.077 (5.29), 3.442 (0.43), 3.452 (0.50), 3.471 (1.17), 3.479 (1.13), 3.500 (1.39), 3.527 (0.51), 3.562 (1.21), 3.627 (1.20), 3.652 (1.65), 3.677 (0.78), 4.186 (1.02), 4.200 (2.72), 4.223 (2.09), 4.238 (2.18), 4.257 (1.63), 4.279 (2.63), 4.294 (2.46), 4.306 (1.36), 4.322 (1.56), 4.348 (2.13), 4.359 (1.17), 4.372 (1.33), 4.382 (0.84), 4.477 (0.57), 4.499 (0.61), 4.510 (0.69), 4.518 (0.72), 4.533 (0.73), 4.541 (0.64), 5.754 (0.94), 7.300 (0.77), 7.316 (3.26), 7.334 (5.65), 7.353 (3.32), 7.406 (4.71), 7.425 (7.78), 7.443 (3.45), 7.640 (4.69), 7.659 (4.35), 7.683 (0.73), 7.884 (5.08), 7.903 (4.79). Example 39A (6S)-5-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-1,1-difluoro-5-a zaspiro[2.4]heptane-6-carboxylic acid (enantiomer 1) and (enantiomer 2)

The diastereomeric mixture was separated using a THAR supercritical fluid chromatography Prep 200 instrument using a Chiralpcel AD-H (SFC) 5µm, 250 x 30 mm column; eluent: CO2/iso-propanol (83:17); pressure: 135 bar; temperature eluent: 38°C; temperatur zyklon: 40°C; pressure zyklon: 24 bar; flow rate: 100 g/min; detection: UV 210nm; injection volume 0.4 mL/injection; under general operating conditions 1g/min of CO2 is approximately equivalent to 1 mL/min. Sequence Settings: cycle time = 11,2 min Fraction 1 was collected between 5.85 min and 8.0 min (enantiomer 1) Fraction 2 was collected between 8.4 min and 10.25 min (enantiomer 2) The fractions were concentrated. The fractions were analyzed using analytical SFC-MS (Agilent, column: Chiralpak AD-33 µm 100 x 4,6 mm, eluent: CO2/iso-Propanol (85:15); BPR pressure: 130 bar; BPR temperature: 60°C; column temper- ature: 40°C; flow rate: 3 mL/min; UV 210 nm. Fraction 1 (rt = 2.081 min) was assigned the addition“(enantiomer 1)”. Fraction 2 (rt = 2.838 min) was assigned the addition“(enantiomer 2)”. The stereochemistry of the two enantiomers was not assigned. Example 40A (3R*,6S)-5-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-1,1-difluoro -5-azaspiro[2.4]heptane-6-carboxylic acid (single enantiomer, enantiomer 1, stereochemistry at 3 position not defined)

From the chiral SFC preparative purification, 2,015 g of the title compound was obtained, 100% ee LC-MS (Method 10): Rt = 1.99 min; MS (ESI pos): m/z = 400 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.70), 0.008 (0.74), 1.032 (15.85), 1.047 (16.00), 1.285 (1.59), 1.568 (0.69), 1.589 (1.52), 1.617 (1.57), 1.635 (0.96), 1.656 (0.63), 1.686 (1.36), 1.702 (1.37), 1.941 (0.90), 1.974 (1.05), 2.008 (0.87), 2.041 (0.90), 2.073 (1.11), 2.557 (1.08), 2.566 (0.95), 2.591 (0.80), 2.645 (0.71), 2.670 (0.95), 2.701 (0.65), 3.451 (0.87), 3.468 (1.64), 3.479 (1.88), 3.495 (1.12), 3.505 (1.17), 3.626 (2.11), 3.651 (2.91), 3.677 (1.38), 3.770 (0.41), 3.778 (0.42), 4.169 (0.43), 4.186 (1.17), 4.200 (3.11), 4.221 (2.05), 4.238 (1.40), 4.256 (1.57), 4.279 (3.79), 4.293 (3.74), 4.304 (1.62), 4.322 (2.70), 4.336 (1.12), 4.348 (2.93), 4.358 (1.92), 4.371 (1.64), 4.381 (1.52), 4.509 (1.14), 4.517 (1.25), 4.531 (1.28), 4.540 (1.12), 7.300 (0.91), 7.315 (3.87), 7.334 (7.04), 7.350 (3.82), 7.352 (4.21), 7.406 (5.88), 7.424 (9.76), 7.443 (4.35), 7.640 (7.54), 7.658 (6.74), 7.885 (6.80), 7.904 (6.34), 10.194 (0.55), 10.991 (0.42). This amino acid was used in Fmoc SPPS. Example 41A (3S*,6S)-5-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-1,1-difluoro -5-azaspiro[2.4]heptane-6-carboxylic acid (single enantiomer, enantiomer 2, stereochemistry at cyclopropyl center not assigned)

From chiral SFC preparative purification, 1.041 g of the title compound was obtained, 94.58% ee LC-MS (Method 10): Rt = 1.93 min; MS (ESI pos): m/z = 400 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (1.19), 0.008 (1.31), 1.031 (0.55), 1.047 (0.56), 1.285 (0.60), 1.583 (1.53), 1.604 (4.87), 1.627 (5.45), 1.650 (3.25), 1.673 (2.78), 1.682 (3.76), 1.704 (3.11), 1.718 (0.95), 1.915 (3.17), 1.949 (3.55), 1.979 (3.13), 2.012 (3.33), 2.073 (3.85), 2.526 (1.60), 2.590 (1.44), 2.626 (1.61), 2.649 (0.89), 2.659 (0.80), 3.471 (2.04), 3.498 (5.50), 3.527 (3.26), 3.561 (7.96), 3.570 (4.68), 3.598 (0.84), 4.167 (0.94), 4.183 (2.75), 4.199 (6.46), 4.223 (7.75), 4.238 (9.60), 4.258 (5.95), 4.277 (4.06), 4.290 (3.98), 4.306 (3.80), 4.319 (4.63), 4.340 (4.17), 4.346 (4.47), 4.354 (2.34), 4.367 (3.96), 4.477 (3.66), 4.497 (3.66), 7.300 (1.97), 7.318 (8.34), 7.334 (11.70), 7.337 (12.42), 7.352 (6.35), 7.355 (6.41), 7.407 (9.62), 7.425 (16.00), 7.444 (7.11), 7.633 (6.46), 7.651 (10.65), 7.666 (6.62), 7.683 (4.36), 7.883 (9.71), 7.893 (10.32), 7.901 (9.57), 7.912 (8.99), 12.802 (0.79), 12.984 (0.67). This amino acid was used in Fmoc SPPS. Example 42A 3-[4-(tert-Butoxycarbonyl)-1H-1,2,3-triazol-1-yl]-N-{[(9H-fl uoren-9-yl)methoxy]carbonyl}-L-alanine (single stereoisomer) To 3-azido-N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-alanine (1.00 g, 2.84 mmol) in a mixture of 27 mL water/tert. butanol/dichloromethane (1:1:1) was added tert-butyl prop-2-ynoate (580 µL, 4.3 mmol), copper(II) sulfate pentahydrate (709 mg, 2.84 mmol) and a solution of sodium ascorbate (1.41 g, 7.10 mmol) in 14 mL water. The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water, acidified with diluted citric acid and extracted with dichloromethane three times. The organic phase was dried over sodium sulfate, filtrated and then evaporated. The residue was taken up in acetonitrile/water and separated in 2 portions via preparative HPLC (column: Chromatorex C1810µm 125 x 40mm; water-acetonitrile-gradient with 0.05% TFA: 0-2 min 25% acetonitrile, 2-22 min 25-75% acetonitrile, 23-26min 75% acetonitrile, 26-28 min back to 25% acetonitrile; flow 100 mL/min). The product-containing fractions were combined, evaporated and dried under vacuum to give 1.02 g (100% purity, 75% yield) of the target compound. LC-MS (Method 11): R _t = 1.30 min; MS (ESI neg): m/z = 477 [M-H]- This amino acid was used in Fmoc SPPS. Example 43A 5-Azaspiro[2.4]heptane-1-carboxylic acid—trifluoroacetic acid (1/1)

To a solution of 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-1-carboxylic acid (1.00 g, 4.14 mmol) in 25 mL dichloromethane was added TFA (960 µL, 12 mmol). The reaction mixture stirred 2 h at room temperature. The reaction mixture was evaporated and dried under vacuum to give 0.80 g (76% yield) of the target compound. LC-MS (Method 9): Rt = 0.18 min; MS (ESI pos): m/z = 142 [M+H] ⁺ Example 44A 5-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-5-azaspiro[2.4]heptan e-1-carboxylic acid

To a solution of 5-azaspiro[2.4]heptane-1-carboxylic acid—trifluoroacetic acid (1/1) (Example 43A, 994 mg, 3.90 mmol) in a mixture of 5 mL acetonitrile and 5 mL water was added 1-({[(9H-fluoren-9-yl)meth- oxy]carbonyl}oxy)pyrrolidine-2,5-dione (2.63 g, 7.79 mmol) and triethylamine (2.2 mL, 16 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water, acidified with 1 M hydrochloric acid to pH 4 and then extracted with dichloromethane three times. The combined organic phases were dried over sodium sulfate, filtrated and evaporated. The residue was tritu- rated with acetonitrile, then the precipitate was collected by filtration and washed with acetonitrile. The filtrate was purified in 3 portions via preparative HPLC (column: Chromatorex C18 10µm 125x40mm; water-acetonitrile-gradient with 0.05% TFA: 0-2 min 25% acetonitrile, 2-22 min 25-75% acetonitrile, 23- 26 min 75% acetonitrile, 26-28min back to 25% acetonitrile; flow 100 mL/min). The appropriate fractions were combined, evaporated and dried under vacuum to give 1.16 g (95% purity, 78% yield) of the target compound. LC-MS (Method 9): R _t = 0.99 min; MS (ESI pos): m/z = 364 [M+H] ⁺ This amino acid was used in Fmoc SPPS. Example 45A tert-Butyl (3S,5S,6R)-3-(2-methylallyl)-2-oxo-5,6-diphenyl-morpholine-4 -carboxylate

Two batches were run in parallel: To a solution of tert-butyl (2R,3S)-6-oxo-2,3-diphenyl-morpholine-4- carboxylate (90.0 g, 255 mmol) and 3-bromo-2-methyl-prop-1-ene (37.0 g, 27.6 mL, 274 mmol) in THF (1.8 L) and HMPA (180 mL) was added sodium bis(trimethylsilyl)amide (279 mL, 1 M in THF) dropwise at -70°C over a period of 60 mins under nitrogen atmosphere. Then the solution was stirred at -70°C for 30 mins. The reaction was combined and quenched by saturated aqueous ammonium chloride solution (2.5 L), then extracted with ethyl acetate (2.0 L x 2). The combined organic phase was washed with satu- rated aqueous sodium chloride solution (1.5 L x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate= 1/0, 10/1) to give the residue, the mixture of residue and Petroleum ether/EtOAc (2.0 L/0.2 L) was stirred for 0.5 h at 25°C, then filtered to give 145 g (89% purity, 62% yield) of the target compound. LC-MS: Rt = 1.027 min, MS+Na = 430.2 ¹ H NMR: CDCl ₃ : 7.35–7.00 (m, 8H), 6.52 (m, 2H), 6.35–6.28 (m, 1H), 5.15–4.82 (m, 4H), 2.95–2.70 (m, 2H), 1.87 (s, 3H), 1.41 (s, 3H), 1.03 (s, 6H) Example 46A (3S,5S,6R)-3-[(1-Methylcyclopropyl)methyl]-5,6-diphenyl-morp holin-2-one

Three batches were run in parallel. To a solution of tert-butyl (3S,5S,6R)-3-(2-methylallyl)-2-oxo-5,6- diphenyl-morpholine-4-carboxylate (Example 45A, 35.0 g, 76 mmol) in 1.3 L dichloromethane was added diethylzinc (400 mL, 1M in toluene) at 0 °C over 30 min, then chloro(iodo)methane (140 g, 793 mmol, 57.6 mL) was added at 0°C over 30 min. The reaction was stirred for 1.5 h at 0°C. The reaction was combined and poured into 2.0 L saturated aqueous sodium bicarbonate solution, the solution was filtered, and then the filtrate was extracted with dichloromethane (1.0 L x 2). The combined organic phase was washed with 1.5 L saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered through a short piece of silica. Then the filtrate was concentrated to give residue. The mixture of residue and petroleum ether/ethyl acetate/dichloromethane (10/1/1, 400 mL) was stirred for 0.5 h at 25 °C and filtered. The filtrate was concentrated to about 120 mL, then filtered to give 20 g (92% purity, 25% yield) of the target compound. LC/MS: Rt = 0.909 min, M+H+ = 322.2 Example 47A (2S)-2-(tert-Butoxycarbonylamino)-3-(1-methylcyclopropyl)pro panoic acid

To a stirred solution containing ethanol (50 mL) , liquid ammonia (600 mL), THF (500 mL) and (3S,5S,6R)-3-[(1-methylcyclopropyl)methyl]-5,6-diphenyl-morp holin-2-one (Example 46A, 57.4 g) that was cooled to -70 °C was added lithium (8 g, 1.15 mol) in small pieces over 0.5 h at -70 °C until a deep blue color persisted for 10 min at -70°C. The reaction was quenched by careful addition of 50 mL 20% aqueous ammonium chloride solution, the cold bath was removed, and the reaction was warmed to 25 °C. The reaction mixture was diluted with 300 mL water and extracted with MTBE (200 mL x 2). The aqueous phase was cooled in ice, acidified to pH= 1 with 1 M aqueous hxdrochlorid acid, and immediately ex- tracted with ethyl acetate (800 mL x 2). The combined ethyl acetate phases were washed with 300 mL saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated at reduced pres- sure to give 24 g (99 mmol) of the target compound. Example 48A (2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid hydrochloride

To the solution of (2S)-2-(tert-butoxycarbonylamino)-3-(1-methylcyclopropyl)pro panoic acid (Example 47A, 24.0 g, 99 mmol) in dichloromethane (60 mL) was added hydrochloric acid/dioxane (200 mL, 4M) over 15 min at 25 °C, then the solution was stirred for 0.5 h at 25 °C. The reaction was concentrated to give a residue. The residue was treated with 150 mL of MTBE and stirred for 15 min at 25 °C, then filtered to give 16 g (90% yield) of the target compound. ¹ H NMR: DMSO-d6: 0.21-0.33 (3 H, m), 0.37-0.51 (1 H, m), 1.64-1.81 (2 H, d), 3.88-3.92 (1 H, t), 8.41 (3 H, s), 13.73 (1 H, s) Example 49A (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(1-methylcycl opropyl)propanoic acid

To a solution of ((2S)-2-amino-3-(1-methylcyclopropyl)propanoic acid hydrochloride (Example 48A, 14 g, 77.9 mmol) and sodium carbonate (25 g, 236 mmol) in THF (200 mL) and water (200 mL) was added 1-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-d ione (25 g, 74.1 mmol) over 30 min at 0 °C, then the solution was stirred for 2 h at 0 °C.100 mL water was added. The solution was extracted with MTBE (300 mL x 2) before the the pH of aqueous phase was adjusted to 2 with 2 M aqueous hydrochloric acid. The combined organic phase was washed with 150 mL saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered through a small column of silica. The filtrate was concentrated to give a residue. The combined residue (from previous runs) was purified by silica gel chromatography (petroleum ether / ethyl acetate (10:1, 3:1) to afford a semi-pure residue. The residue was further purified by preparative HPLC (column: Phenomenex Luna C18250 x 50mm, 10 ^m; mobile phase: [water (0.05% HCl)-ACN]; B%: 38% - 68%, 31min, 50% min) to give 24.4 g (97% purity, 74% yield) of the target compound. LC-MS: Rt = 0.914 min, [M+H]+ = 366.1 ¹ H NMR: CDCl ₃ : d ppm 0.23- 0.40 (4 H, m), 1.02- 1.20 (3 H, m), 1.48- 1.95 (2 H, m), 4.22- 4.33 (1 H, m), 4.39 - 4.61 (3 H, m), 5.26- 5.33 (1 H, m), 7.31- 7.49 (4 H, m), 7.56- 7.81 (4 H, m). This amino acid was used in Fmoc SPPS. Example 50A Methyl N-(tert-butoxycarbonyl)-D-methionyl-L-isoleucinate

N-(tert-Butoxycarbonyl)-D-methionine (2.42 g, 9.71 mmol), methyl L-isoleucinate—hydrogen chloride (1/1) (1.76 g, 9.71 mmol), 1H-benzotriazol-1-ol (1.78 g, 11.6 mmol), 3-{[(Ethylimino)methylene]amino}- N,N-dimethylpropan-1-amine hydrochloride (1:1) (2.23 g, 11.6 mmol) and N,N-diisopropylethylamine (3.5 mL, 20 mmol) were dissolved in DMF (30 mL) . The mixture was stirred at ambient temperature for 16 h. Water(100 mL) was then added, the mixture was extracted with two portions of ethyl acetate. The combined organic extract was washed sequentially with hydrochloric acid, water (10 mL), saturated aque- ous sodium bicarbonate solution(10 mL) and brine, and then dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated. The residue was dissolved in ether and the product crystallized. The solid was filtered and washed sequentially with ether and pentane.3.13 g (99 % purity, 86 % yield) of the title compound were obtained. Example 51A Methyl (2S, 3S)-2-{(3R)-3-[(tert-butoxycarbonyl)amino]-2-oxopyrrolidin-1 -yl}-3-methylpentanoate

Methyl N-(tert-butoxycarbonyl)-D-methionyl-L-isoleucinate (Example 50A, 2.85 g, 7.57 mmol) was dis- solved in dichloromethane (40 mL) and the solution was cooled to 0°C. Trimethyloxonium tetrafluorob- orate (1.12 g, 7.57 mmol) was added and the mixture was stirred at room temperature for 3 h. Potassium carbonate(3.13 g, 22.71 mmol) was added. Then the mixcture was heated to reflux for 16 h. The reaction mixture was poured into 50 mL dichloromethane and washed with five portions of water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and crytallized from hexane yielding 2.01 g (100 % purity, 81 % yield) of the title compound. Example 52A (2S, 3S)-2-{(3R)-3-[(tert-Butoxycarbonyl)amino]-2-oxopyrrolidin-1 -yl}-3-methylpentanoic acid

Methyl (2S,3S)-2-{(3R)-3-[(tert-Butoxycarbonyl)amino]-2-oxopyrrolid in-1-yl}-3-methylpentanoate (ex- ample 51A, 1.96 g, 5.97 mmol) was dissolved in THF (7.8 mL) and methanol (7.8 mL). A solution of lithium hydroxide (300 mg, 12.5 mmol) in 8 mLof water was added and the mixture was stirred for 1 h at room temperature. After the reaction mixture was concentrated, the white residue was dissolved in water (40 mL), washed with DCM (6 mL), and then acidified with 1 M hydrochloric acid (12 mL). The mixture was extracted with three portions of ethyl acetate. The combined organic extract was dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was crystallized from ethyl acetate and hexane to provide 1.3 g (100 % purity, 67% yield) of the title compound. LC-MS (Method 11): Rt = 1.09 min; MS (ESI neg): m/z = 313 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.810 (0.96), 0.829 (2.41), 0.847 (1.25), 0.889 (2.53), 0.906 (2.59), 1.387 (16.00), 3.260 (0.71), 3.274 (0.56), 3.283 (0.75), 3.298 (0.64), 4.200 (0.97), 4.225 (0.94). Example 53A Methyl N-(tert-butoxycarbonyl)glycyl-L-isoleucinate

Methyl L-isoleucinate (3.00 g, 20.7 mmol) and N-(tert-butoxycarbonyl)glycine (3.98 g, 22.7 mmol) were dissolved in DMF (20 mL). This solution was cooled to 0-5°C in an ice bath. N,N-diisopropylethylamine (3.6 mL, 21 mmol), 1H-benzotriazol-1-ol hydrate (316 mg, 2.07 mmol) and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimidhydrochloride (4.36 g, 22.7 mmol) were added and the mixture was stirred at room temperature. The reaction mixture was quenched with concentrated aqueous ammonium chloride and ex- tracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 0 % to 10 %) to give the title compound, 5.40 g (90 % purity, 78 % yield). LC-MS (Method 11): R _t = 1.13 min; MS (ESI pos): m/z = 247 [M-tBu] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.819 (4.90), 0.835 (8.09), 0.853 (2.63), 1.152 (0.40), 1.174 (0.45), 1.354 (1.52), 1.375 (16.00), 1.459 (0.46), 3.561 (0.84), 3.571 (0.98), 3.577 (1.45), 3.594 (0.81), 3.630 (11.35), 4.220 (0.63), 4.237 (0.78), 4.240 (0.82), 4.257 Example 54A Methyl glycyl-L-isoleucinate

Methyl N-(tert-butoxycarbonyl)glycyl-L-isoleucinate (example 53A, 1.50 g, 4.96 mmol) was dissolved in DCM (27 mL). Trifluoroacetic acid (3.0 mL, 39 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated to afford the crude product, which was used directly for the next step. Example 55A Methyl N-(4-nitrobenzene-1-sulfonyl)glycyl-L-isoleucinate

Methyl glycyl-L-isoleucinate (Example 54A, 1.00 g, 4.96 mmol) was dissolved in dichloromethane (40 mL, 620 mmol), triethylamine (2.4 mL, 17 mmol) was added, and then the solution was cooled to 0°C.4- Nitrobenzene-1-sulfonyl chloride (1.21 g, 5.46 mmol) was added and the reaction mixture was stirred for 1 h. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and then concentrated, to give 1.70 g (71 % yield) of the title compound. The product was used directly for the next step. Example 56A Methyl (2S, 3S)-3-methyl-2-[4-(4-nitrobenzene-1-sulfonyl)-2-oxopiperazin -1-yl]pentanoate

Methyl N-(4-nitrobenzene-1-sulfonyl)glycyl-L-isoleucinate (Example 55A, 1.92 g, 4.96 mmol) and 1,2- dibromoethane (4.3 mL, 50 mmol) were dissolved in DMF. Potassium carbonate (6.86 g, 49.6 mmol) was added and the mixture was heated to 60°C for 3 h. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with three portions of ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and then evaporated. The crude product was pu- rified by column chromatography on silica gel (cyclohexane / ethyl acetate 6:1) to give title compound 1.40 g (97 % purity, 66 % yield). LC-MS (Method 11): Rt = 1.30 min; MS (ESI pos): m/z = 414 [M+H] ⁺ Example 57A Methyl (2S, 3S)-3-methyl-2-(2-oxopiperazin-1-yl)pentanoate

Methyl (2S, 3S)-3-methyl-2-[4-(4-nitrobenzene-1-sulfonyl)-2-oxopiperazin -1-yl]pentanoate (Example 56A, 1.40 g, 3.39 mmol) and benzenethiol (1.0 mL, 10 mmol) were dissolved in acetonitrile (20 mL). Potassium carbonate (936 mg, 6.77 mmol) was added and the mixture was stirred at room temperature. The mixture was filtered and evaporated. The residue was purified by flash chromatography on silica gel (gradient dichlormethane / methanol 100:0 to 95:5) to afford 310 mg (40 % yield) of the title compound, that was used directly for the next step. Example 58A tert-Butyl 4-[(2S,3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]-3-oxopiperaz ine-1-carboxylate

Methyl (2S, 3S)-3-methyl-2-(2-oxopiperazin-1-yl)pentanoate (Example 57A, 310 mg, 1.36 mmol) was diisolved in dichloromethane (1.7 mL, 26 mmol). Di-tert-butyl dicarbonate (370 µL, 1.6 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was then quenched with concentrated aqueous ammonium chloride and then extracted with three portions of DCM (20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and then concentrated, to afford 440 mg (99 % purity, 98 % yield) of the title compound. LC-MS (§Method 11): Rt = 1.27 min; MS (ESI pos): m/z = 273 [M+H-tBu] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.807 (0.86), 0.826 (2.27), 0.844 (1.20), 0.870 (2.25), 0.887 (2.30), 1.410 (16.00), 3.645 (6.00), 3.963 (0.63), 3.970 (0.62), 4.766 (0.82), 4.792 (0.80), 5.754 (0.87). Example 59A (2S, 3S)-2-[4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl]-3-methyl pentanoic acid tert-Butyl 4-[(2S, 3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]-3-oxopiperazine-1-c arboxylate (Example 58A, 440 mg, 80 % purity, 1.07 mmol) was dissolved in THF (1.4 mL) and methanol (1.4 mL). A solution of lithium hydroxide (53.9 mg, 2.25 mmol) in water (1.4 mL) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue was dissolved in water and then washed with DCM. The aqueous layer was separated, acidified to pH 3-4 with 1M hydrochloric acid, and then extracted three times with ethyl acetate. The combined organic layer was dried over anhy- drous magnesium sulfate, filtered, and then concentrated under reduced pressure to give 310 mg (95% purity, 87% yield) of the title compound as a colorless oil. LC-MS (Method 11): Rt = 1.11 min; MS (ESI neg): m/z = 313 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.809 (0.81), 0.827 (2.06), 0.845 (1.12), 0.908 (2.11), 0.924 (2.09), 1.411 (16.00), 3.438 (0.43), 3.968 (0.78), 4.688 (0.79), 4.713 (0.77). Example 60A Methyl N-(tert-butoxycarbonyl)-L-alanyl-L-isoleucinate

N-(tert-Butoxycarbonyl)-L-alanine (1.50 g, 7.93 mmol) and methyl L-isoleucinate—hydrogen chloride (1/1) (1.58 g, 8.72 mmol) were dissolved in DMF (7.7 mL). This solution was cooled to 0-5°C in an ice bath. N,N-diisopropylethylamine (1.4 mL, 7.9 mmol), 1H-benzotriazol-1-ol hydrate (121 mg, 793 µmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidhydrochloride (1.67 g, 8.72 mmol) were added and the mixture was stirred at room temperature. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with three portions of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 0% to 15%) to give 2.12 g (100 % purity, 84 % yield) of the title compound. LC LC-MS (Method 10): Rt = 1.70 min; MS (ESI pos): m/z = 317 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (1.00), 0.008 (0.77), 0.818 (3.17), 0.825 (4.25), 0.836 (7.51), 0.842 (4.72), 0.855 (3.30), 1.144 (4.07), 1.161 (4.10), 1.179 (0.54), 1.200 (0.53), 1.371 (16.00), 1.398 (13.44), 1.775 (0.49), 2.523 (0.85), 3.621 (15.73), 4.021 (0.46), 4.039 (0.60), 4.207 (1.06), 4.223 (1.19), 4.228 (1.22), 4.244 (1.06), 6.908 (0.61), 6.928 (0.58), 7.886 (0.57), 7.907 (0.60). Example 61A Methyl L-alanyl-L-isoleucinate

Methyl N-(tert-butoxycarbonyl)-L-alanyl-L-isoleucinate (Example 60A, 2.10 g, 6.64 mmol) was dis- solved in DCM (20 mL). Trifluoroacetic acid (20 mL, 260 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated and the crude dipeptide was used directly for the next step. Example 62A Methyl N-(4-nitrobenzene-1-sulfonyl)-L-alanyl-L-isoleucinate

Methyl L-alanyl-L-isoleucinate (Example 61A, 1.44 g, 6.64 mmol) was dissolved in dichloromethane (54 mL), triethylamine (3.2 mL, 23 mmol) was added, and then the solution was cooled to 0°C.4-Nitroben- zene-1-sulfonyl chloride (1.62 g, 7.30 mmol) was added and the reaction mixture was stirred. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with two portions of dichloromethane. The combined organic extracts were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and the concentrated to afford 1.65g (95 % purity, 59 % yield) of the title compound. LC-MS (Method 11): Rt = 1.18 min; MS (ESI neg): m/z = 400 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.008 (0.40), 0.676 (6.59), 0.693 (6.80), 0.740 (2.79), 0.758 (6.99), 0.777 (3.46), 1.013 (0.52), 1.025 (0.62), 1.047 (0.69), 1.066 (0.50), 1.117 (6.09), 1.135 (6.12), 1.175 (0.51), 1.192 (0.64), 1.203 (0.60), 1.210 (0.56), 1.222 (0.67), 1.237 (0.48), 1.243 (0.42), 1.551 (0.53), 1.568 (0.61), 1.578 (0.45), 1.584 (0.47), 1.988 (0.64), 3.577 (16.00), 3.933 (1.14), 3.948 (1.32), 3.953 (1.31), 3.968 (1.12), 4.056 (0.61), 4.073 (0.82), 4.091 (0.54), 7.994 (4.08), 7.999 (1.44), 8.012 (1.63), 8.016 (4.58), 8.135 (1.41), 8.155 (1.39), 8.365 (4.39), 8.383 (1.48), 8.388 (3.90), 8.463 (1.04), 8.482 (0.99). Example 63A Methyl (2S, 3S)-3-methyl-2-[(3S)-3-methyl-4-(4-nitrobenzene-1-sulfonyl)- 2-oxopiperazin-1-yl]pentano- ate

'

Methyl N-(4-nitrobenzene-1-sulfonyl)-L-alanyl-L-isoleucinate (Example 62A, 1.65 g, 4.11 mmol) and 1,2-dibromoethane (3.5 mL, 41 mmol) were dissolved in DMF (35 mL). Potassium carbonate (5.68 g, 41.1 mmol) was added and the reaction mixture was heated to 60°C for 3 h. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with three portions of ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 6:1) to give 1.60 g (70 % purity, 64 % yield) of the title compound. LC-MS (Method 11): Rt = 1.30 min; MS (ESI pos): m/z = 428 [M+H] ⁺ Example 64A Methyl (2S,3S)-3-methyl-2-[(3S)-3-methyl-2-oxopiperazin-1-yl]pentan oate H3C 00 CH3

)/

H _N ^Ni...

\ /

\

H ³ C':. CH3 Methyl (2S, 3S)-3-methyl-2-[(3S)-3-methyl-4-(4-nitrobenzene-1-sulfonyl)- 2-oxopiperazin-1-yl]pentano- ate (Example 63A, 900 mg, 2.11 mmol) and benzenethiol (650 µL, 6.3 mmol) were dissolved in acetoni- trile (12 mL). Potassium carbonate (582 mg, 4.21 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (gradient dichlormethane / methanol 100:0 to 95:5) to afford 336mg (100 % purity, 66 % yield) of the title compound. LC-MS (Method 13): Rt = 1.09 min; MS (ESI pos): m/z = 243 [M+H] ⁺ Example 65A tert-Butyl (2S)-4-[(2S, 3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]-2-methyl-3-oxopiper azine-1-carbox- ylate

Methyl (2S, 3S)-3-methyl-2-[(3S)-3-methyl-2-oxopiperazin-1-yl]pentanoate (Example 64A, 736 mg, 3.04 mmol) was dissolved in dichloromethane (8 mL). Di-tert-butyl dicarbonate (1.0 mL, 4.6 mmol) was added, and the reaction mixture was stirred at room temperature over the weekend. The reaction was then quenched with concentrated aqueous ammonium chloride and extracted with two portions of DCM. The combined organic extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulfate, filtened and then concentrated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 3:1) to afford 1.08 g (100 % purity, 104 % yield) of the title compound. LC-MS (Method 10): Rt = 1.98 min; MS (ESI pos): m/z = 343 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.800 (0.95), 0.818 (2.41), 0.837 (1.25), 0.875 (2.38), 0.892 (2.43), 1.305 (2.02), 1.323 (2.06), 1.414 (16.00), 3.645 (6.08), 4.769 (0.88), 4.795 (0.86). Example 66A (2S, 3S)-2-[(3S)-4-(tert-Butoxycarbonyl)-3-methyl-2-oxopiperazin- 1-yl]-3-methylpentanoic acid

tert-Butyl (2S)-4-[(2S,3S)-1-methoxy-3-methyl-1-oxopentan-2-yl]-2-methy l-3-oxopiperazine-1-carbox- ylate (Example 65A, 1.08 g, 3.15 mmol) was dissolved in a mixture of THF (4.5 mL) and methanol (4.5 mL). A solution of lithium hydroxide (159 mg, 6.62 mmol) in water (4.5 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue was dissolved in concentrated aqueous ammonium chloride. The aqueous layer was used acidified to pH 3-4 with 1M hydrochloric and extracted three times with DCM. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated to afford 952 mg (100 % purity, 92 % yield) of the title compound. LC-MS (Method 9): Rt = 0.87 min; MS (ESI pos): m/z = 329 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.802 (1.09), 0.820 (2.24), 0.838 (1.18), 0.911 (2.22), 0.927 (2.28), 1.295 (0.50), 1.308 (2.03), 1.326 (1.99), 1.415 (16.00), 3.342 (0.65), 4.691 (0.84), 4.717 (0.82). Example 67A (2R, 5R)-3,6-Dimethoxy-2-(propan-2-yl)-5-[(trimethylsilyl)methyl] -2,5-dihydropyrazine

(2R)-3,6-Dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (2.9 mL, 16 mmol) was dissolved in THF (58 mL) and the solution cooled to -78°C . n-Butyl lithium (10 mL, 1.6 M, 16 mmol) was added dropwise with stirring. Stirring was continued for 15 min at -78°C. (Chloromethyl)(trimethyl)silane (5.0 mL, 36 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with diethyl ether. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated. The crude product was purified by chro- matography on silica gel (cyclohexane / ethyl acetate 2%) to afford 3.0 g (87 % purity, 60 % yield) of the title compound. LC-MS (Method 9): Rt = 1.47 min; MS (ESI pos): m/z = 271 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.036 (0.45), -0.028 (9.14), -0.020 (0.46), -0.008 (1.38), 0.580 (3.69), 0.597 (3.75), 0.737 (0.61), 0.762 (0.63), 0.773 (0.73), 0.798 (0.73), 0.959 (3.60), 0.977 (3.69), 1.107 (0.73), 1.119 (0.75), 1.143 (0.66), 1.148 (0.47), 1.155 (0.63), 1.370 (1.30), 2.512 (16.00), 3.574 (8.95), 3.582 (8.85), 3.885 (0.64), 3.894 (1.26), 3.903 (0.72), 3.999 (0.49), 4.023 (0.47). Example 68A Methyl 3-(trimethylsilyl)-L-alaninate

(2R, 5R)-3,6-Dimethoxy-2-(propan-2-yl)-5-[(trimethylsilyl)methyl] -2,5-dihydropyrazine (Example 67A, 3.00 g, 11.1 mmol) was dissolved in methanol (30 mL, 740 mmol) and the solution was cooled to 0°C. Hydrochloric acid (10 mL, 10%) was added and the solution was stirred for 2 h. The solution was evapo- rated and the residue was dissolved in DCM and sodium carbonate solution (100 mL, 2.0 M, 200 mmol). The aqueous layer was extracted with two portions of DCM. The DCM extract was dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by chromatography on silica gel (2% methanol: (1% N,N-diethylethanamine in DCM)) to give 2.83g (68 % purity, 99 % yield) of the title compound. ¹ H-NMR (400 MHz, DMSO-d6) d[ppm]: -0.010 (3.10), 0.008 (1.81), 0.736 (0.85), 0.759 (0.89), 0.772 (1.48), 0.795 (1.56), 0.803 (1.89), 0.820 (1.90), 0.841 (1.84), 0.858 (2.43), 0.875 (1.64), 0.900 (4.19), 0.911 (1.07), 0.918 (8.65), 0.936 (4.28), 1.682 (1.42), 2.384 (1.35), 2.402 (4.11), 2.420 (4.02), 2.438 (1.25), 3.088 (0.55), 3.102 (0.54), 3.302 (1.19), 3.306 (1.81), 3.321 (1.27), 3.330 (1.15), 3.345 (1.03), 3.583 (16.00), 3.591 (0.48), 3.605 (4.33), 5.742 (4.37). Example 69A N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-3-(trimethylsilyl)-L- alanine

Methyl 3-(trimethylsilyl)-L-alaninate (Example 68A, 2.83 g, 68 % purity, 11.0 mmol) was dissolved in methanol (44 mL) and the solution cooled to 0°C. A sodium hydroxide solution (11 mL, 1.0 M, 11 mmol) was added and the reaction mixture was stirred over night at room temperature. Water (40 mL), sodium hydrogen carbonate (922 mg, 11.0 mmol) and sodium carbonate (1.53 g, 14.4 mmol) were added. The methanol was removed under reduced pressure and then 1,4-dioxane (32 mL) was added to the aqueous solution. This solution was cooled to 0°C in an ice bath. (9H-Fluoren-9-yl)methyl carbonochloridate (Fmoc-Cl) (4.26 g, 16.5 mmol) was then added and the reaction mixture was stirred for 5 h at room tem- perature. Additional Fmoc-Cl (1.42 g, 5.5 mmol) was added and the reaction mixture was stirred for an additional 2 h. Equal portions of water and tert-butyl methyl ether were added to the reaction mixture. The aqueous phase was separated and washed further with tert-Butyl methyl ether, then acidified with 1 M hydrochloric acid (pH 3-4). The acidified mixture was extracted with three portions of MTBE. The com- bined organic layer was dried over anhydrous magnesium sulfate sulfate, filtered, and then concentrated. The crude product was purified by preparative HPLC (column: Reprosil; C18; 10 µm; 125 x 40 mm; eluant: AcCN/H ₂ O with 0,1% HCOOH; flow rate: 100 mL/min; gradient: 0 - 5.50 min 10 : 90; sample injection at 3.00 min; 5.50 - 17.65 min to 95 : 5; 17.65 - 19.48 min 95 : 5; 19.48 - 19.66 min to 10 : 90; 19.66 - 20.72 min 10 :90;) to give 1.65 g (99 % purity, 39 % yield) of the title compound. LC-MS (Method 10): Rt = 2.20 min; MS (ESI pos): m/z = 384 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.006 (16.00), 0.987 (3.81), 1.006 (3.64), 3.309 (2.95), 3.950 (0.67), 3.970 (1.71), 3.991 (1.59), 4.010 (0.53), 4.182 (0.67), 4.199 (1.66), 4.217 (1.67), 4.228 (1.08), 4.253 (2.79), 4.268 (3.86), 4.287 (1.60), 4.293 (0.85), 4.313 (0.41), 7.286 (1.24), 7.291 (1.27), 7.293 (1.31), 7.302 (2.68), 7.304 (2.70), 7.309 (2.55), 7.321 (1.75), 7.323 (1.70), 7.328 (1.57), 7.389 (2.90), 7.408 (4.73), 7.426 (2.11), 7.566 (1.81), 7.587 (1.74), 7.697 (2.14), 7.714 (3.62), 7.731 (1.81), 7.872 (4.43), 7.891 (4.02), 12.451 (0.54). This amino acid was used in Fmoc SPPS. Example 70A Di-tert-butyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate (mixture of isomers)

Di-tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (CAS-RN: 91229-91-3, 21.0 g, 73.6 mmol) was dissolved in 250 mL THF and the solution was cooled to -78°C. Diisobutyl aluminum hydride (160 mL, 1.0 M, 160 mmol) was added dropwise and the mixture was stirred for 1 h at -78 °C. The reaction was then quenched with 2-propanol (25 mL). Potassium sodium (2R,3R)-2,3-dihydroxybutanedioate solution (200 mL) was added, the mixture was stirred at room temperature, and then the reaction mixture was diluted with MTBE and water. The water layer was separated and extracted further with two portions of MTBE. The combined organic extract was dried over anhydrous magnesium sulfate, filtered, and the res- idue concentrated under reduced pressure to give 19.53 g (79% purity, 73% yield) of the title compound as a colorless oil. Example 71A Di-tert-butyl (2S,)-5-methoxypyrrolidine-1,2-dicarboxylate (mixture of isomers)

Di-tert-butyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate (Example 70A ,19.5 g, 67.9 mmol) was dis- solved in methanol (160 mL). Pyridinium para-toluenesulfonate (341 mg, 1.36 mmol) was added to the solution and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (gradient cyclo- hexane - cyclohexane ethyl acetate 7:3) to afford 14.4 g (90 % purity, 64 % yield) of the title compound. ¹ H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.363 (9.51), 1.375 (8.10), 1.393 (2.67), 1.419 (16.00), 1.756 (0.58), 1.775 (0.93), 1.781 (0.88), 1.807 (0.46), 3.225 (3.77), 3.240 (1.93), 3.261 (2.02), 3.307 (4.01), 4.059 (0.64), 4.081 (0.82), 5.128 (0.56). Example 72A Di-tert-butyl (2S)-5-cyanopyrrolidine-1,2-dicarboxylate (mixture of isomers)

Di-tert-butyl (2S,)-5-methoxypyrrolidine-1,2-dicarboxylate (Example 71A, 14.4 g, 47.8 mmol) was dis- solved in DCM (125 mL) and the solution was cooled to -40°C. Trimethylsilyl trifluoromethanesulfonate (1.3 mL) (1 vol%) was added, then trimethylsilanecarbonitrile (7.0 mL, 53 mmol) was added dropwise over a 40 min period. The mixture was subsequently stirred for an additional 1.5 h at -40°C. The reaction mixture was quenched with methanol (19 mL) and then concentrated to afford 14.87 g (86 % yield) of the title compound were isolated. GC-MS (GC-MS Method 1): 195.2 (M+-Boc), 139.1 (-Boc, -t-Bu) Example 73A Di-tert-butyl (2S)-5-formylpyrrolidine-1,2-dicarboxylate (mixture of isomers)

Di-tert-butyl (2S)-5-cyanopyrrolidine-1,2-dicarboxylate (Example 72A, 14.0 g, 47.2 mmol) was dissolved in a mixture of pyridine (250 mL), acetic acid (130 mL) and water (130 mL). A Raney-Nickel-water suspension (70.0 g, 50 % purity) was added and the mixture was hydrogenated over 7 h at ambient pressure at 80°C. The catalyst was then removed by filtration over a layer of diatomaceous earth and the solvent was washed with 250 mL of water. The aqueous phase was extracted three times with MTBE (650 mL). The combined organic layer was washed with water three times, washed with brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (gradient cyclohexane– cyclohexane/ethyl acetate 7:3) to afford 7.40 g (85 % purity, 44 % yield) of a viscous oil. GC-MS (GC-MS Method 1): (M ⁺ - CO); (M+ - CO, - Boc) Example 74A Di-tert-butyl (2S)-5-ethenylpyrrolidine-1,2-dicarboxylate (mixture of isomers)

Methyl(triphenyl)phosphonium bromide (17.7 g, 49.4 mmol) was suspended in 180 mL of THF. Potas- sium bis(trimethylsilyl)amide solution (1M in toluene, 75 mL, 15 % solution, 49 mmol) was added at dropwise at room temperature and stirred for 1 h. The mixture was cooled to -78°C. Di-tert-butyl (2S)-5- formylpyrrolidine-1,2-dicarboxylate (Example 73A, 7.40 g, 24.7 mmol) was dissolved in THF (60 mL). The solution was added and stirred for 2 h at room temperature. The reaction mixture was poured into a solution of potassium sodium (2R,3R)-2,3-dihydroxybutanedioate (140 mL) and water (85 mL) and ex- tracted with three portions of MTBE (210 mL). The combined organic extract was washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered and then concentrated. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane - cyclohexane ethyl acetate (9:1)) to afford 4.25 g (100 % purity, 58 % yield) of the title compound were isolated. GC-MS (GC-MS Method 1): Rt = 5.07 min, 5.17 min; 197.3 (M+-Boc) Example 75A tert-Butyl 5-vinyl-L-prolinate (mixture of isomers) Di-tert-butyl (2S)-5-ethenylpyrrolidine-1,2-dicarboxylate (Example 74A, 4.25 g, 14.3 mmol) was dis- solved in 45 mL DCM and the solution was cooled to 0°C. Trimethylsilyl trifluoromethanesulfonate (2.6 mL, 14 mmol) was added dropwise and the resulting mixture was stirred for 5 min at 0 °C. The reaction was then quenched with concentrated aqueous sodium hydrogen carbonate solution (21 mL) and extracted with two portions of DCM. The combined organic layers were dried over magnesium sulfate, filtered and then concentrated. The crude product was purified by flash chromatography on silica gel (gradient meth- anol - dichlormethane (100:2)) to afford 2.09 g (100 % purity, 74 % yield) of the title compound. GC-MS (GC-MS Method 1): Rt = 3.37 min, 3.50 min; 197.3 (M+) Example 76A tert-Butyl (5R)-5-ethenyl-L-prolinate (single stereoisomer) Isomeric separation of tert-Butyl-5-ethenyl-L-prolinate (diasteromeric mixture) (Example 75A, 2.55 g, 12.9 mmol) by flash chromatography on silica gel (gradient cyclohexane - ethyl acetate - trimethylamine (70:30:1)) afforded 1.35 g (100% purity, 53 % yield) of the title compound. GC-MS (GC-MS Method 1): Rt = 3.50 min; 197.3 (M+) ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.3-1.4 (1H), 1.40 (9H), 2.4 (1H), 3.5 (2H), 4.9 (1H), 5.15 (1H), 5.8 (1H). Example 77A 1-tert-Butyl 2-methyl-3-ethenylpiperidine-1,2-dicarboxylate (mixture of isomers)

A solution of ethenylmagnesium bromide (39 mL, 0.70 M, 27 mmol) in anhydrous THF (20 mL) was cooled to -35°C and then a solution of copper (I) bromide– dimethyl sulfide (1:1) (741 mg, 3.61 mmol) was added. The reaction mixture was stirred for 1 h at -35°C. A solution of 1-tert-Butyl 2-methyl 5,6- dihydropyridine-1,2(4H)-dicarboxylate (CAS-RN: 155905-80-9, 4.35 g, 18.0 mmol) in THF (10 mL) was added to the mixture, and then the reaction mixture was stirred for 6 h at -35°C. The mixture was quenched with a mixture of aqueous ammonium chloride (85 mL) and aqueous ammonia (85 mL) and extracted with two portions of MTBE (285 mL). The combined organic layers were washed sequentially with aqueous ammonium chloride (570 mL) and brine (570 mL), dried over magnesium sulfate, filtered, and then con- centrated. The crude product was purified by chromatography on silica gel (gradient: cyclohexane- ethyl acetate (2%-20%)) to give 1.59 g (100% purity, 33 % yield) of the title compound. LC-MS (Method 12): R _t = 3.33 min; MS (ESI pos): m/z = 270 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.038 (0.51), 1.087 (0.77), 1.382 (16.00), 1.419 (0.83), 1.429 (0.59), 1.448 (0.73), 1.459 (0.80), 1.466 (0.54), 1.479 (1.01), 1.485 (1.09), 1.496 (0.73), 1.502 (0.66), 1.506 (0.59), 1.514 (0.47), 1.532 (0.47), 1.544 (0.42), 1.600 (0.64), 1.627 (0.61), 2.899 (0.88), 3.690 (13.11), 3.817 (0.47), 3.849 (0.45), 5.120 (2.03), 5.148 (0.90), 5.164 (1.49), 5.869 (0.57). Example 78A 1-(tert-Butoxycarbonyl)-3-ethenylpiperidine-2-carboxylic acid (mixture of isomers)

1-tert-Butyl 2-methyl 3-ethenylpiperidine-1,2-dicarboxylate (Example 77A,1.59 g, 5.90 mmol) was dis- solved in a mixture of methanol (5.9 mL) and THF (17.7 mL). A lithium hydroxide solution (5.9 mL, 2.0 M, 12 mmol) was added and the mixture was stirred for 5 h at 50°C, then cooled to room temperature. The reaction mixture was washed with MTBE (7.5 mL), cooled to 0°C, acidified with 1 M hydrochloric acid (14.5 mL), then extracted five times with DCM (15 mL). The combined organic extract was dried over magnesium sulfate, filtered, and then concentrated to afford 1.39 g (100 % purity, 92% yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.381 (16.00), 1.423 (0.70), 1.434 (0.57), 1.455 (0.77), 1.465 (1.32), 1.473 (0.93), 1.488 (1.66), 1.495 (1.29), 1.519 (0.46), 1.530 (0.40), 1.608 (0.80), 1.632 (0.75), 2.911 (0.96), 3.815 (0.50), 3.842 (0.47), 5.113 (1.95), 5.140 (0.73), 5.156 (1.59), 5.753 (0.50), 5.874 (0.51), 12.910 (0.69). Examplee 79A tert-Butyl 2-{[(2S, 5R)-2-(tert-butoxycarbonyl)-5-vinylpyrrolidin-1-yl]carbonyl} -3-vinylpiperidine-car- boxylate (mixture of isomers)

1-(tert-Butoxycarbonyl)-3-ethenylpiperidine-2-carboxylic acid (racemate) (Example 78A, 1.35 g, 5.30 mmol) and tert-butyl (5R)-5-ethenyl-L-prolinate (Example 76A, 950 mg, 4.82 mmol) were dissolved in acetonitrile (60 mL). N,N-diisopropylethylamine (2.5 mL, 14 mmol) was added and the reaction mixture was cooled to 0°C. A solution of 1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluoro- phosphate (3.26 g, 6.26 mmol) in acetonitrile (30 mL) was added to the mixture, and the reaction mixture was stirred for 20 h at room temperature. The reaction mixture was concentrated, redissolved in MTBE and washed with water. The aqueous phase re-extracted with MTBE. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate (85:15)) to give 2.03 g (88 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.60), 1.373 (10.15), 1.392 (16.00), 1.396 (14.53), 1.458 (0.57), 1.489 (0.46), 1.763 (0.46), 1.780 (0.56), 2.105 (0.42), 2.122 (0.42), 2.524 (0.41), 5.050 (0.44), 5.090 (0.70), 5.116 (0.79), 5.754 (1.04). Example 80A di-tert-Butyl (4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro- 1H-pyrido[3,2-e]pyr- rolo[1,2-a]azepine-1,9-dicarboxylate (single stereoisomer)

tert-Butyl 2-{[(2S,5R)-2-(tert-butoxycarbonyl)-5-vinylpyrrolidin-1-yl]c arbonyl}-3-vinylpiperidine-car- boxylate (Example 79A, 2.00 g, 4.60 mmol) was dissolved in DCM (100 mL) and [1,3-bis(2,4,6-trime- thylphenyl)imidazolidin-2-ylidene](dichloro)(phenylmethylide ne)ruthenium- tricyclohexylphosphane (1:1) (781 mg, 920 µmol) was added. The reaction mixture was stirred for 48 h under reflux, then it was cooled to room temperature. DMSO (2.0 mL) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the crude product was purified by chro- matography on silica gel (cyclohexane / ethyl acetate (25%-50%)) to afford title 805 mg (99 % purity, 42 % yield) of the title compound. LC-MS (Method 9): Rt = 1.12 min; MS (ESI pos): m/z = 407 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.296 (5.30), 1.361 (16.00), 1.378 (2.93), 5.540 (0.72), 5.562 (0.51). Example 81A (4aR,6aR,9S,11aS)-1-{[(9H-fluoren-9-yl)methoxy]carbonyl}-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 acid (single stereoisomer)

Di-tert-Butyl-(4aR,6aR,9S,11aS)-11-oxo-2,3,4,4a,6a,7,8,9,11, 11a-decahydro-1H-pyrido[3,2-e]pyr- rolo[1,2-a]azepine-1,9-dicarboxylate (Example 80A,800 mg, 1.97 mmol) was dissolved in 8 mL DCM and the solution cooled to 0°C. Trifluoroacetic acid (8.0 mL, 100 mmol) was added and the reaction mix- ture was stirred for 1 h at room temperature. The reaction mixture was concentrated and the residue was diluted with sodium hydrogen carbonate solution (20 mL, pH=8). A solution of (9H-fluoren-9-yl)methyl carbonochloridate (CAS-RN: 28920-43-6 ,764 mg, 2.95 mmol) in THF (24 mL) was added and the reac- tion mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with DCM (100 mL) and acidified with 1 M hydrochloric acid (40 mL) (pH=1). The solution was extracted two times with DCM (50 mL) and the combined organic extract was dried over magnesium sulfate, filtered and then concentrated. Purification of the crude product by column chromatography on silica gel (DCM/MeOH 95/5) gave 676 mg (100% purity, 73 % yield) of the title compound. LC-MS (Method 10): R _t = 1.86 min; MS (ESI pos): m/z = 473 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (2.87), 0.008 (2.54), 0.778 (0.66), 0.800 (1.51), 0.808 (1.58), 0.832 (2.85), 0.856 (1.93), 0.865 (2.01), 0.889 (0.79), 1.125 (0.77), 1.157 (1.38), 1.182 (0.90), 1.215 (0.50), 1.235 (1.06), 1.517 (2.61), 1.538 (3.44), 1.563 (6.49), 1.593 (6.17), 1.610 (5.67), 1.636 (4.98), 1.660 (3.92), 1.684 (2.46), 1.719 (2.25), 1.747 (2.01), 1.846 (4.49), 1.858 (7.62), 1.868 (6.96), 1.901 (3.19), 2.010 (0.57), 2.073 (9.83), 2.189 (2.95), 2.200 (3.74), 2.241 (3.30), 2.276 (2.71), 2.307 (1.21), 2.327 (1.10), 2.366 (0.52), 2.398 (0.80), 2.428 (1.41), 2.456 (0.84), 2.670 (0.63), 2.710 (0.50), 2.816 (1.60), 2.833 (1.66), 2.849 (2.51), 2.862 (2.28), 2.877 (2.34), 2.895 (1.47), 3.040 (0.69), 3.075 (1.10), 3.086 (1.04), 3.101 (1.03), 3.121 (0.69), 3.690 (1.24), 3.724 (4.64), 3.744 (6.62), 3.756 (6.47), 3.777 (4.44), 3.823 (8.20), 3.852 (7.84), 4.120 (4.36), 4.137 (4.86), 4.148 (4.24), 4.191 (3.57), 4.202 (7.64), 4.212 (4.19), 4.261 (1.02), 4.276 (2.33), 4.291 (4.52), 4.316 (4.20), 4.328 (5.37), 4.346 (4.61), 4.370 (3.31), 4.383 (5.08), 4.395 (4.54), 4.411 (5.53), 4.422 (5.83), 4.456 (3.22), 4.595 (1.63), 4.761 (4.95), 4.773 (5.04), 4.788 (4.59), 4.800 (4.19), 5.364 (2.72), 5.393 (7.67), 5.422 (7.48), 5.451 (2.73), 5.510 (0.98), 5.540 (4.23), 5.553 (4.14), 5.585 (0.91), 7.282 (3.12), 7.300 (7.84), 7.319 (10.54), 7.337 (13.57), 7.355 (9.71), 7.366 (2.95), 7.377 (5.06), 7.399 (12.17), 7.420 (16.00), 7.438 (6.68), 7.521 (8.10), 7.539 (6.98), 7.613 (12.53), 7.631 (11.16), 7.646 (3.71), 7.665 (3.16), 7.847 (8.31), 7.865 (15.04), 7.884 (10.42), 7.908 (4.87), 12.429 (2.52). This amino acid was used in Fmoc SPPS. Example 82A (6S)-5-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-5-azaspiro[2.4]h eptane-6-carboxylic acid

(6S)-5-Azaspiro[2.4]heptane-6-carboxylic acid (CAS-RN:152723-57-4, 1.38 g, 9.79 mmol) was dissolved in water (14 mL) and sodium hydrogen carbonate (8.23 g, 97.9 mmol) was added. Then a solution from 1-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-d ione (CAS-RN:82911-69-1, 3.47 g, 10.3 mmol) in acetone (21 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted two times with MTBE. The aqueous layer was acidified to pH 3-4 with 1M hydrochloric and extracted three times with DCM. The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and then concentrated, to afford 3.3 g (100 % purity, 93 % yield) of the title compound. LC-MS (Method 9): Rt = 1.04 min; MS (ESI pos): m/z = 364 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.497 (1.67), 0.510 (2.34), 0.527 (5.55), 0.559 (3.82), 0.567 (5.51), 0.590 (9.33), 0.598 (11.21), 0.619 (1.87), 0.636 (0.58), 1.106 (9.23), 1.714 (2.14), 1.723 (2.15), 1.745 (2.40), 1.755 (2.50), 1.764 (1.94), 1.772 (1.85), 1.796 (2.02), 1.804 (1.93), 2.086 (7.36), 2.280 (2.12), 2.301 (2.47), 2.311 (2.21), 2.333 (2.24), 2.390 (1.75), 2.412 (2.07), 2.421 (1.87), 2.443 (1.71), 2.524 (0.88), 2.594 (3.10), 3.076 (2.73), 3.219 (3.24), 3.245 (4.13), 3.283 (3.41), 3.309 (5.19), 3.385 (5.05), 3.403 (4.32), 3.410 (3.56), 3.429 (3.16), 3.747 (1.01), 4.160 (0.68), 4.175 (1.57), 4.187 (3.09), 4.192 (3.69), 4.209 (6.08), 4.218 (4.18), 4.224 (3.09), 4.237 (2.43), 4.247 (1.22), 4.254 (2.15), 4.272 (16.00), 4.284 (3.83), 4.297 (4.75), 4.306 (2.72), 4.427 (2.10), 4.435 (2.31), 4.449 (2.34), 4.457 (2.02), 5.754 (0.45), 7.301 (1.47), 7.318 (5.18), 7.320 (5.43), 7.325 (2.74), 7.336 (7.24), 7.339 (7.37), 7.344 (4.81), 7.348 (3.25), 7.352 (3.50), 7.354 (3.84), 7.357 (3.67), 7.403 (9.03), 7.422 (14.80), 7.440 (6.64), 7.640 (8.10), 7.647 (7.82), 7.658 (7.43), 7.666 (6.87), 7.884 (10.09), 7.902 (9.58). This amino acid was used in Fmoc SPPS. This Fmoc amino acid was also prepared from (6S)-5-azaspiro[2.4]heptane-6-carboxylic acid prepared in Example 124A. Example 83A (1S,3S,5S,6S)-2-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-6-(trif luoromethyl)-2-azabicyclo[3.1.0]hexane- 3-carboxylic acid and rel-(1R,3R,5R,6R)-2-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-6-( trifluoromethyl)- 2-azabicyclo[3.1.0]hexane-3-carboxylic acid

(1S, 3S, 5S, 6S)-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxyl ic acid (450 mg, 2.31 mmol) was dissolved in water (6 mL) and sodium hydrogen carbonate (1.94 g, 23.1 mmol) was added. Then a solution from 1-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-d ione (CAS-RN: 82911-69- 1, 817 mg, 2.42 mmol) in acetone (9 mL) was added and the resulting suspension was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted two times with MTBE. The aqueous layer was acidified to pH 3-4 with 1M hydrochloric and extracted three times with DCM. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and then concentrated. The crude product was purified by preparative HPLC (column: Reprosil; C18; 10 µm; 125 x 40 mm; solvent: AcCN/H2O containing 0,1% HCOOH; flow rate: 100 mL/min ; gradient: 0 - 5.50 min 10 : 90; sample injection at 3.00 min; 5.50 - 17.65 min gradient to 95 : 5; 17.65 - 19.48 min at 95 : 5; 19.48 - 19.66 min to 10 : 90; 19.66 - 20.72 min 10 :90;), affording 571 mg (96 % purity, 57 % yield) of the title compound. LC-MS (Method 9): Rt = 1.06 min; MS (ESI pos): m/z = 418 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 2.073 (0.99), 2.203 (4.88), 2.345 (2.00), 2.366 (1.94), 3.755 (2.94), 4.078 (1.74), 4.221 (1.50), 4.253 (4.04), 4.270 (5.55), 4.290 (4.95), 4.337 (2.21), 7.293 (3.93), 7.301 (4.07), 7.312 (9.32), 7.319 (8.88), 7.330 (6.19), 7.337 (5.57), 7.407 (9.40), 7.425 (16.00), 7.444 (7.29), 7.695 (5.70), 7.887 (13.98), 7.906 (12.87), 12.866 (0.63). The substance is also commercially available (CAS RN: 1986905-54-7) The racemic amino acid using rel-(1R, 3R, 5R, 6R)-6-(Trifluoromethyl)-2-azabicyclo[3.1.0]hexane-3-car- boxylic acid (Enamine) was prepared in a similar manner. These amino acids were used in SPPS. Example 84A Methyl N-(tert-butoxycarbonyl)-L-isoleucylserinate (mixture of diastereomers)

N-(tert-Butoxycarbonyl)-L-isoleucine (7.50 g, 32.4 mmol) and Methyl DL-serinate—hydrogen chloride (1/1) (5.05 g, 32.4 mmol) were dissolved in dichloromethane (65 mL). (Benzotriazol-1-yloxy)tris(dime- thylamino)phosphonium hexafluorophosphate (14.9 g, 33.6 mmol) and N,N-diisopropylethylamine (11 mL, 65 mmol) were added and the reaction mixture was stirred overnight at room temperature. Dichloro- methane (250 mL) was added and the reaction mixture was washed sequentially with water, aqueous hy- drochloric acid (1M) and aqueous sodium hydrogen carbonate solution. The combined organic extract was dried over magnesium sulfate, filtered and then concentrated. The crude product was dissolved in DCM and thoroughly washed with water, two times again with aqueous hydrochloric acid (1M) and then two more times with aqueous sodium hydrogen carbonate. Subsequently the combined organic phase was dried over magnesium sulfate, filtered, and then concentrated. The crude product was used directly for the next step. LC-MS (Method 11): 355.2 (M ⁺ Na ⁺ ) Example 85A Methyl 2-{(1S,2S)-1-[(tert-butoxycarbonyl)amino]-2-methylbutyl}-4,5 -dihydro-1,3-oxazole-4-carbox- ylate (mixture of diastereomers)

Methyl N-(tert-butoxycarbonyl)-L-isoleucylserinate (Example 84A, 4.62 g, 13.9 mmol) was dissolved in dichloromethane (51 mL) and the solution cooled to -78°C. N-Ethyl-N-(trifluoro-lambda ⁴ -sulfanyl)eth- anamine (2.2 mL, 17 mmol) was added and the reaction mixture was stirred at -78°C for 1.5 h. The reaction was quenched with potassium carbonate (7.68 g, 55.6 mmol) and then allowed to cool to room tempera- ture. The solution was stirred for 1 h at room temperature. Then the solution was diluted with DCM (50 mL) and washed three times with saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was further extracted with DCM. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to afford 5.75 g of the desired product. LC-MS (Method 11): 315.2 (M ⁺ H ⁺ ), 337.2 (M ⁺ Na ⁺ ) Example 86A Methyl 2-{(1S,2S)-1-[(tert-butoxycarbonyl)amino]-2-methylbutyl}-1,3 -oxazole-4-carboxylate

Methyl 2-{(1S,2S)-1-[(tert-butoxycarbonyl)amino]-2-methylbutyl}-4,5 -dihydro-1,3-oxazole-4-carbox- ylate (Example 85A, 4.37 g, 13.9 mmol) was dissolved in dichloromethane (35 mL, 540 mmol) and the solution was cooled at -40°C. Bromo(trichloro)methane (2.7 mL, 27 mmol) was added, then 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine(4.6 mL, 31 mmol) was also added. The reaction solu- tion was stirred for 2.5 h at 0°C and then diluted with DCM. The reaction mixture was washed five times with a 10% citric acid solution. The combined aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (gradient: cyclohexane / ethyl acetate (4:1)) to give 2.2 g (50.7% yield) of the title compound. LC-MS (Method 10): 335.15 (M ⁺ Na ⁺ ) Example 87A

2-{(1S,2S)-1-[(tert-Butoxycarbonyl)amino]-2-methylbutyl}- 1,3-oxazole-4-carboxylic acid

Methyl 2-{(1S,2S)-1-[(tert-butoxycarbonyl)amino]-2-methylbutyl}-1,3 -oxazole-4-carboxylate (Example 86A, 2.21 g, 7.06 mmol) was dissolved in methanol (13.5 mL). Aqueous sodium hydroxide solution (4.3 mL, 3M) was added and the reaction mixture was stirred for 40 min and then concentrated to remove the methanol. The aqueous solution was acidified with aqueous 1M hydrochloric acid (14 mL) and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to give 12.0 g (95% purity, 51% yield) of the title compound. LC-MS (MCW_OA_S1): Rt = 1.13 min; MS (ESI neg): m/z = 297 [M+H]- Example 88A (4R)-3-[(3S)-3-methylpentanoyl]-5,5-diphenyl-4-(propan-2-yl) -1,3-oxazolidin-2-one A solution of (3S)-3-methylpentanoic acid (867 mg, 7.46 mmol) in anhydrous THF (50 mL) was cooled to -30°C.2,2-Dimethylpropanoyl chloride (920 µl, 7.5 mmol) was added dropwise and the reactiom mix- ture was stirred for 1.5 h at -30°C. Dry lithium chloride (347 mg, 8.17 mmol) and (4R)-5,5-diphenyl-4- (propan-2-yl)-1,3-oxazolidin-2-one (2.00 g, 7.11 mmol) ((R)-DIOZ) were sequentiall added and the reac- tion mixture was slowly allowed to come to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and water. The water layer was separated and extracted with ethyl acetate. The combined ethyl acetate layer was washed with aqueous sodium chloride solution, dried over magne- sium sulfate, filtered, and then concentrated, to give 2.87 g of a white solid. The crude product was dis- solved in DCM with a small amount of methanol and was purified by column chromatography over silica gel (Biotage Isolera, 50 g cartridge) with cyclohexane / ethyl acetate (80:20) as eluant. The product-con- taining fractions were combined, concentrated and dried to give 2.25 g (98 % purity, 82 % yield) of the target compound. LC-MS (Method 10): R _t = 2.69 min; MS (ESI pos): m/z = 380 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.616 (13.33), 0.633 (13.58), 0.650 (7.84), 0.660 (16.00), 0.668 (15.61), 0.676 (15.27), 0.686 (7.40), 0.719 (0.40), 0.875 (12.87), 0.893 (12.59), 0.940 (0.92), 0.958 (1.50), 0.975 (2.08), 0.993 (2.23), 1.011 (1.38), 1.028 (0.84), 1.045 (1.41), 1.061 (1.93), 1.079 (1.89), 1.095 (1.16), 1.112 (0.62), 1.541 (0.55), 1.557 (1.29), 1.574 (1.91), 1.590 (1.82), 1.607 (1.10), 1.623 (0.40), 2.020 (0.71), 2.036 (1.44), 2.049 (1.78), 2.065 (1.28), 2.082 (0.50), 2.449 (2.60), 2.468 (2.84), 2.755 (2.63), 2.771 (2.50), 2.793 (2.05), 2.808 (1.92), 5.557 (5.98), 5.563 (5.64), 7.271 (2.61), 7.289 (6.37), 7.307 (5.02), 7.352 (5.04), 7.368 (10.74), 7.385 (9.60), 7.403 (3.47), 7.557 (8.45), 7.577 (6.54), 7.639 (8.45), 7.659 (6.92). Example 89A Benzyl {(2S,3S)-3-methyl-2-[(4R)-2-oxo-5,5-diphenyl-4-(propan-2-yl) -1,3-oxazolidine-3-carbonyl]pen- tyl}carbamate

The literature procedure (Sebesta and Seebach, Helv. Chim. Acta 2003, 86, 4061-4072) was followed. (4R)-3-[(3S)-3-methylpentanoyl]-5,5-diphenyl-4-(propan-2-yl) -1,3-oxazolidin-2-one (Example 88A, 2.20 g, 5.80 mmol) was dissolved in DCM (20 mL) and the solution was cooled to -15°C. A solution of Titanium (IV) chloride (6.1 mL, 1.0 M in DCM, 6.1 mmol) was added dropwise while maintaining the temperature at -15 ^o C. Triethylamine (890 µl, 6.4 mmol) was then added and the reaction mixture was stirred for 30 min at -15 ^o C. In a separate round-bottomed flask a solution of benzyl (methoxymethyl)carbamate (1.24 g, 6.38 mmol, CAS RN: 94471-35-9) in DCM (10 mL) was cooled to 0 ^o C. A solution of Titanium (IV) chloride (6.4 mL, 1.0 M in DCM, 6.4 mmol) was added dropwise, and then the entire solution was added dropwise to the flask containing (4R)-3-[(3S)-3-methylpentanoyl]-5,5-diphenyl-4-(propan-2-yl) -1,3-oxazolidin-2-one. The reaction mixture was stirred for 4 h at 0 ^o C, then it was allowed to stir at room temperature overnight. The reaction was quenched by adding an aqueous ammonium chloride solution and then diluted with additional DCM. The separated organic layer was washed with aqueous 1M HCl solution, aqueous 1M NaOH solution, and then with aqueous sodium chloride solution. The organic layer was filtered and then concentrated, to give 3.39 g of a yellow oil. The crude product was purified by column chromatography over silica gel (Biotage Isolera 100g cartridge) with cyclohexane/ethyl acetate (85:15) eluant. The prod- uct-containing fractions were combined, concentrated and then dried to give 1.50 g (96 % purity, 46 % yield, selectivity) of the title compound with a diastereoselectivity of 96,3% (lit.96%). LC-MS (Method 10): Rt = 2.63 min; MS (ESI pos): m/z = 543 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.429 (3.22), 0.446 (3.32), 0.480 (1.44), 0.498 (3.18), 0.516 (1.79), 0.595 (4.27), 0.611 (4.65), 0.643 (0.49), 0.663 (0.46), 0.768 (0.45), 0.786 (0.46), 0.874 (3.86), 0.891 (4.01), 1.098 (0.48), 1.397 (16.00), 1.993 (0.45), 2.010 (0.57), 2.023 (0.45), 3.146 (0.44), 3.169 (0.66), 3.180 (1.02), 3.192 (0.63), 3.206 (0.44), 3.222 (0.53), 3.243 (0.48), 3.816 (0.57), 4.920 (0.59), 4.952 (1.85), 4.978 (2.04), 5.010 (0.65), 5.539 (1.70), 5.544 (1.73), 7.187 (0.53), 7.201 (0.87), 7.282 (3.41), 7.289 (5.28), 7.306 (4.14), 7.322 (1.84), 7.342 (2.69), 7.362 (3.73), 7.385 (3.47), 7.405 (1.52), 7.566 (3.08), 7.584 (2.46), 7.662 (2.88), 7.681 (2.48). Example 90A (2S,3S)-2-({[(Benzyloxy)carbonyl]amino}methyl)-3-methylpenta noic acid

A solution of benzyl {(2S,3S)-3-methyl-2-[(4R)-2-oxo-5,5-diphenyl-4-(propan-2-yl) -1,3-oxazolidine-3- carbonyl]pentyl}carbamate (Example 89A, 1.49 g, 2.75 mmol) in THF (15 mL) was prepared. A solution of LiOH (105 mg, 4.39 mmol) in water (5 mL) was added and the reaction mixture was stirred at room temperature for 24 h. HPLC analysis indicated that the reaction was not completed, so an additional equiv- alent of LiOH (65.8 mg, 2.75 mmol) in water (3 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether, the mixture was stirred for 5 minutes, and then filtered. The filter cake was washed with water and with ether, and then the layers were separated. The aqueous layer was acidified with aqueous 1M HCl solution to pH 1 and extracted three times with diethyl ether. The combined ether phase was washed with sodium chloride solution, dried over magnesium sulfate, filtered, and then concentrated. After drying under high vacuum, 715 mg (100 % purity, 93 % yield) of the title compound was obtained. LC-MS (Method 10): Rt = 1.71 min; MS (ESI pos): m/z = 280 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.837 (6.34), 0.856 (14.23), 0.863 (13.72), 0.880 (12.65), 1.098 (0.91), 1.117 (1.35), 1.133 (1.47), 1.151 (1.49), 1.170 (0.95), 1.348 (0.42), 1.367 (1.02), 1.380 (1.33), 1.398 (1.53), 1.414 (1.09), 1.431 (0.72), 1.596 (0.82), 1.611 (1.42), 1.627 (1.61), 1.644 (1.16), 1.660 (0.53), 1.908 (3.41), 2.396 (1.17), 2.413 (2.79), 2.429 (2.67), 2.445 (1.07), 2.501 (16.00), 3.139 (4.27), 3.155 (7.41), 3.171 (4.60), 5.000 (15.52), 7.221 (1.46), 7.234 (2.66), 7.248 (1.41), 7.283 (0.89), 7.290 (0.97), 7.300 (2.98), 7.318 (5.22), 7.332 (11.34), 7.339 (12.29), 7.356 (5.30), 7.375 (1.45), 12.135 (3.58). Example 91A (2S,3S)-2-(Aminomethyl)-3-methylpentanoic acid

10% Palladium on carbon (100 mg) was weighed out into a round-bottomed flask and the flask was flushed with Argon. A solution of (2S,3S)-2-({[(benzyloxy)carbonyl]amino}methyl)-3-methylpenta noic acid (Example 90A, 710 mg, 2.54 mmol) in methanol (40 mL) was added and the reaction mixture was stirred at room temperature under a normal pressure of H2 gas. HPLC analysis indicated that after 2 hours at room temperature, the reaction was completed. The reaction mixture was filtered through a plug of silica gel and the filter cake was washed several times with methanol. The combined filtrate was concentrated under reduced pressure to provide 345 mg (93%) of the title compound. The compound was used directly for the next step. Example 92A (2S,3S)-2-[({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)methyl ]-3-methylpentanoic acid

(2S,3S)-2-(Aminomethyl)-3-methylpentanoic acid (Example 91A, 344 mg, 2.37 mmol) was dissolved in aqueous sodium carbonate solution (32 mL, 0.15 M, 4.7 mmol). 1-({[(9H-fluoren-9-yl)methoxy]car- bonyl}oxy)pyrrolidine-2,5-dione (959 mg, 2.84 mmol) was dissolved in acetone (30 mL) and this solution was added to the previous solution and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was the concentrated to remove the acetone. The aqueous solution was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified to pH 3-4 with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and then concentrated. The crude product was purified by prepar- ative HPLC (column: Reprosil; C18; 10 µm; 125 x 30 mm; solvents: AcCN/H ₂ O containing 0,1% HCOOH; flow rate: 75 mL/min ; gradient: 0 - 5.50 min (10:90); sample injection at 3.00 min; 5.50 - 17.65 min gradient to 95:5; 17.65 - 19.48 min (95:5); 19.48 - 19.66 min gradient to 10:90; 19.66 - 20.72 min (10:90) to give 795 mg (96 % purity, 88 % yield) of the title compound. LC-MS (Method 9): R _t = 1.06 min; MS (ESI pos): m/z = 368 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (1.04), 0.008 (0.54), 0.752 (0.73), 0.841 (7.69), 0.860 (16.00), 0.870 (15.28), 0.878 (10.54), 0.887 (13.22), 1.085 (0.41), 1.103 (0.99), 1.123 (1.45), 1.139 (1.58), 1.157 (1.60), 1.176 (1.00), 1.371 (1.16), 1.384 (1.50), 1.403 (1.71), 1.418 (1.23), 1.435 (0.83), 1.604 (0.88), 1.619 (1.50), 1.636 (1.70), 1.651 (1.23), 2.408 (1.27), 2.425 (2.91), 2.441 (3.13), 2.458 (1.88), 2.524 (0.87), 2.749 (0.82), 3.143 (4.18), 3.158 (6.08), 3.174 (3.40), 4.176 (1.25), 4.194 (3.04), 4.211 (4.04), 4.241 (8.74), 4.255 (4.27), 4.263 (3.35), 7.303 (5.42), 7.322 (12.94), 7.340 (10.81), 7.353 (1.98), 7.394 (7.49), 7.413 (11.83), 7.431 (5.34), 7.673 (5.88), 7.683 (5.84), 7.691 (5.19), 7.701 (4.30), 7.876 (12.54), 7.895 (11.30), 12.176 (1.21). This amino acid was used in SPPS. Example 93A 2-[(1S,2S)-1-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-m ethylbutyl]-1,3-oxazole-4-carboxylic acid

2-{(1S,2S)-1-[(tert-Butoxycarbonyl)amino]-2-methylbutyl}-1,3 -oxazole-4-carboxylic acid (Example 87A, 1.85 g, 6.21 mmol) was dissolved in trifluoroacetic acid (7.6 mL, 99 mmol) and the solution was stirred for 15 min. Then the solution was diluted with toluene and evaporated. This step was repeated again. The crude product was dissolved in 1,4-dioxane (20 mL, 230 mmol) and water (20 mL). Potassium carbonate (1.60 g, 11.6 mmol) and 1-{[(9H-fluoren-9-ylmethoxy)carbonyl]oxy}pyrrolidine-2,5-dio ne (2.35 g, 6.96 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (65 mL) and acidified to pH 2-3 with a 10% aqueous citric acid solution. The reaction mixture was extracted with ethyl acetate (three times), and the combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane - methanol (3-7% + 1% acetic acid), and the product-containing fractions were combined, diluted with toluene, and then concentrated. Toluene was then added again and then the solution was concentrated, to provide 2.09 g (100% purity, 80 % yield) of the title compound. LC-MS (MCW_FT_MS_M1): Rt = 2.01 min; MS (ESI pos): m/z = 421 [M+H] ⁺ This amino acid was used in SPPS. Example 94A di(Prop-2-en-1-yl)amino](1-methyl-1H-indazol-5-yl)acetic acid (racemate)

(1-Methyl-1H-indazol-5-yl)boronic acid (CAS-RN: 590418-08-9, 500 mg, 2.84 mmol), oxoacetic acid (CAS-RN: 298-12-4, 310 µl, 50 % purity, 2.8 mmol) and N-(Prop-2-en-1-yl)prop-2-en-1-amine (CAS- RN:124-02-7, 350 µl, 2.8 mmol) were dissolved in acetonitrile (7.5 mL) and the reaction mixture ws stirred for 40 h at 60°C . After cooling, the resulting solid was filtered, washed with ethyl acetate and dried to give 740 mg (100 % purity, 91 % yield) of the title compound. LC-MS (Method 9): Rt = 0.44 min; MS (ESI neg): m/z = 284 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.008 (1.87), 2.073 (0.51), 3.110 (0.68), 3.125 (0.77), 3.147 (2.14), 3.161 (2.16), 3.176 (2.32), 3.193 (2.28), 3.213 (0.90), 3.230 (0.96), 4.030 (16.00), 4.531 (3.61), 5.110 (2.47), 5.134 (4.58), 5.174 (2.56), 5.752 (0.60), 5.768 (1.07), 5.778 (0.73), 5.783 (0.73), 5.794 (1.49), 5.810 (1.35), 5.820 (0.63), 5.826 (0.67), 5.837 (0.87), 5.852 (0.49), 6.514 (1.52), 7.432 (1.39), 7.435 (1.47), 7.454 (1.77), 7.457 (1.87), 7.602 (2.26), 7.624 (1.75), 7.699 (3.10), 8.041 (4.18). Example 95A ({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)(1-methyl-1H-inda zol-5-yl)acetic acid (racemate)

1,3-dimethyl-1,3-diazinane-2,4,6-trione (CAS-RN: 769-42-6,1.97 g, 12.6 mmol) and tetrakis(tri- phenylphosphine)palladium(0) (48.6 mg, 42.1 µmol) were placed into a round-bottomed flask under Ar- gon. A solution of [di(Prop-2-en-1-yl)amino](1-methyl-1H-indazol-5-yl)acetic acid (Example 94A, 600 mg, 2.10 mmol) in dry DCM was then added, and the reaction mixture was stirred for 2 h at 35°C. The suspension was diluted with water acetone and water and then the reaction mixtue was concentrated to remove the DCM. Sodium hydrogen carbonate (2.65 g, 31.5 mmol) was added (attention gas formation) . 1-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-d ione (780 mg, 2.31 mmol) was added to the suspension and the reaction mixture was stirred overnight at room temperature. Water and an aqueous solution of sodium carbonate (10%) were added and the solution was extracted two times with MTBE. The aqueous phase was acidified with aqueous citric acid solution and then extracted three times with DCM. The combined organic layers were washed with brine, dried of magnesium sulfate, filtered, and then concentrated. The residue was purified by preparative HPLC (column: Reprosil; C18; 10 µm; 125 x 40 mm; solvent: AcCN/H ₂ O containing 0.1% HCOOH; flow rate: 100 mL/min ; gradient: 0 - 5.50 min (10:90); sample injection at 3.00 min; 5.50 - 17.65 min gradient to 95 : 5; 17.65 - 19.48 min (95:5); 19.48 - 19.66 min gradient to 10:90; 19.66 - 20.72 min (10:90) to give 422 mg (100 % purity, 47 % yield) of the title compound. LC-MS (Method 9): R _t = 0.94 min; MS (ESI pos): m/z = 428 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 2.073 (0.59), 4.041 (16.00), 4.198 (0.63), 4.215 (1.87), 4.231 (3.51), 4.253 (1.84), 4.269 (1.50), 4.280 (1.92), 4.298 (1.70), 4.319 (0.59), 5.256 (1.81), 5.276 (1.80), 7.275 (0.90), 7.293 (2.03), 7.320 (2.08), 7.339 (1.26), 7.388 (1.98), 7.406 (3.38), 7.424 (1.73), 7.445 (1.60), 7.467 (1.96), 7.621 (2.30), 7.643 (1.76), 7.744 (3.56), 7.763 (3.31), 7.792 (3.19), 7.875 (4.81), 7.893 (4.48), 8.063 (4.53), 8.213 (1.70), 8.232 (1.65), 12.835 (1.03). Example 96A ({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)(1-methyl-1H-inda zol-5-yl)acetic acid (enantiomer 1)

The diastereomeric mixture (Example 95A, 600 mg) was dissolved in methanol / acetonitrile (60 mL) and separated using a THAR supercritical fluid chromatography Prep 200 instrument using a Chiralpak AD- H (SFC) 5µm, 250 x 30 mm column; eluent: CO2/iso-propanol (80:20); pressure: 135 bar; temperature eluent: 38°C; flow rate: 100 g/min; detection: UV 210 nm; injection volume 0.4 mL/injection; under gen- eral operating conditions 1g/min of CO2 is approximately equivalent to 1 mL/min. Sequence Settings: cycle time = 11.2 min Fraction 1 was collected at 5.8 min (enantiomer 1); Fraction 2 was collected between 7.7 min (enantiomer 2). The fractions were concentrated. The fractions were analyzed using analytical SFC-MS (Agilent, column: Daicel AD-3 3 µm 100 x 4,6 mm, eluent: CO2/methanol (80:20); BPR pressure: 130 bar; BPR temperature: 60°C; column temperature: 40°C; flow rate: 3 mL/min; UV 210 nm. The stereochemistry of the two enantiomers was not assigned. 185 mg of enantiomer 1 (100% purity, 99.5% ee) were obtained (stereochemistry not determined) LC-MS (Method 10): Rt = 1.80 min; MS (ESI pos): m/z = 428 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 4.040 (16.00), 4.197 (0.54), 4.214 (1.44), 4.230 (2.80), 4.251 (1.59), 4.268 (1.38), 4.278 (1.68), 4.295 (1.46), 4.316 (0.48), 5.241 (1.20), 5.261 (1.19), 7.275 (0.78), 7.294 (1.73), 7.321 (1.78), 7.339 (1.11), 7.386 (1.77), 7.394 (1.54), 7.405 (2.97), 7.412 (2.26), 7.423 (1.63), 7.444 (1.36), 7.466 (1.53), 7.617 (1.85), 7.638 (1.42), 7.742 (3.01), 7.761 (2.84), 7.787 (2.53), 7.874 (4.50), 7.893 (4.19), 8.058 (4.56), 8.183 (0.93), 8.201 (0.92). This amino acid was used in SPPS. Example 97A ({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)(1-methyl-1H-inda zol-5-yl)acetic acid (enantiomer 2)

Using the chiral separation method described in Example 96A, 145 mg (100 % purity, 94.3%) of the enantiomer 2 were obtained (stereochemistry not determined). LC-MS (Method 10): Rt = 1.80 min; MS (ESI pos): m/z = 428 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.78), 0.008 (0.70), 4.040 (16.00), 4.198 (0.41), 4.214 (1.16), 4.230 (2.33), 4.252 (1.27), 4.268 (1.03), 4.278 (1.36), 4.295 (1.14), 4.300 (0.99), 5.243 (0.98), 5.262 (0.98), 7.276 (0.59), 7.294 (1.34), 7.313 (1.11), 7.321 (1.38), 7.340 (0.86), 7.387 (1.36), 7.394 (1.12), 7.406 (2.32), 7.413 (1.70), 7.424 (1.22), 7.431 (0.89), 7.444 (1.06), 7.466 (1.21), 7.618 (1.52), 7.640 (1.16), 7.743 (2.38), 7.762 (2.23), 7.787 (2.02), 7.875 (3.68), 7.894 (3.45), 8.059 (3.94), 8.188 (0.73), 8.207 (0.72). This amino acid was used in SPPS. Example 98A Benzyl N-[(benzyloxy)carbonyl]-3-bromo-L-phenylalaninate

N-[(Benzyloxy)carbonyl]-3-bromo-L-phenylalanine (15.3 g, 40.5 mmol) was dissolved in methanol (113 mL). Caesium carbonate (6.59 g, 20.2 mmol) was added and the mixture was stirred until gas no evolution ceased. The solution was evaporated to dryness. The residue was dissolved in DMF (140 mL, 1.8 mol) and (bromomethyl)benzene (5.3 mL, 44 mmol) was added dropwise. After a short time a solid precipi- tated. The suspension was diluted with ether and water. The organic phase was separated, and the aqueous phase was extracted two times with diethyl ether. The combined organic layers were washed with water, washed with brine, and then dried over magnesium sulfate. The crystalline residue was dissolved in ether and after the addition of pentane, a precipitate formed. The solid was filtered and dried. The ether/pentane solution was evaporated and dissolved in ether; after the addition of pentane a precipitate formed. The solid was filtered and dried, to give 16.0 g (100 % purity, 84 % yield) of the title compound. LC-MS (Method 10): Rt = 2.42 min; MS (ESI pos): m/z = 468 [M+H]+ ¹H-NMR (500 MHz, DMSO-d6) d [ppm]: 2.874 (2.41), 2.895 (2.86), 2.902 (3.10), 2.923 (2.76), 3.071 (2.84), 3.082 (2.96), 3.099 (2.26), 3.109 (2.09), 3.636 (0.82), 4.336 (1.73), 4.347 (2.20), 4.353 (2.43), 4.357 (2.48), 4.363 (2.48), 4.373 (1.83), 4.383 (1.37), 4.921 (0.55), 4.963 (1.81), 4.989 (12.84), 4.994 (11.01), 5.020 (1.18), 5.043 (0.96), 5.093 (1.11), 5.119 (12.74), 5.139 (0.55), 5.147 (0.97), 7.174 (0.85), 7.211 (3.13), 7.226 (9.23), 7.241 (11.35), 7.248 (16.00), 7.263 (11.82), 7.298 (10.22), 7.313 (14.37), 7.316 (14.35), 7.321 (12.62), 7.332 (10.08), 7.336 (11.10), 7.344 (8.08), 7.351 (11.64), 7.366 (7.19), 7.379 (2.35), 7.414 (5.80), 7.429 (4.73), 7.499 (7.87), 7.880 (4.47), 7.896 (4.30). Example 99A 3-[(2S)-3-(Benzyloxy)-2-{[(benzyloxy)carbonyl]amino}-3-oxopr opyl]benzoic acid

The reaction was set up under argon. In a 2L autoclave (stirring speed 750 rpm) are added palladium(II)ac- etate (2.16 g, 9.61 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (10.63 g, 19.22 mmol) and potassium acetate (47.1 g, 480 mmol). The autoclave is flushed with argon and the reagents are dissolved by adding dry DMF (450 mL). A solution of benzyl N-[(benzyloxy)carbonyl]-3-bromo-L-phenylalaninate (Example 98A, 45.0 g, 96.1 mmol) in dry DMF (930 mL) was added to the autoclave, followed the addition of water (18 mL). The Autoclave was sealed, purged repeatedly with nitrogen and allowed to stir briefly. The autoclave was pressurized with carbon monoxide (3 bar) and then heated to 80°C and 3bar for 960 min. After the reaction was completed, the autoclave was purged, opened, and then the contents were dissolved in water (13 L). The reaction mixture was extracted 3 times with ethyl acetate (7 L) and the combined organic layer was washed with brine, and then concentrated. The crude product was purified by prepara- tive normal phase chromatography (10 kg silica gel) with DCM/MeOH (95/5) and then further purified by preparative chromatography (DCM/MeOH gradient, Biotage Isolera) to provide 10.7 g (92% purity) of the title compound. LC-MS (Method 10): Rt = 1.92 min; MS (ESI neg): m/z = 432.14 [M-H]- Example 100A Benzyl N-[(benzyloxy)carbonyl]-3-(tert-butoxycarbonyl)-L-phenylalan inate

To 3-[(2S)-3-(Benzyloxy)-2-{[(benzyloxy)carbonyl]amino}-3-oxopr opyl]benzoic acid (Example 99A,18.0 g, 41.5 mmol) was added dichloromethane (280 mL, 4.4 mol). Cyclohexane (140 mL, 1.3 mol), tert-butyl 2,2,2-trichloroethanimidate (36.3 g, 166 mmol) and (diethyl ether)(trifluoro)boron (1.6 mL, 12 mmol) were added and the reaction mixture was stirred at room temperature. After 1 h, additional diethyl ether)(trifluoro)boron (1.6 mL, 12 mmol) was added and the reaction mixture was stirred overnight at room temperature. (diethyl ether)(trifluoro)boron (1 mL, 7.5 mmol) was added and reaction mixtue was stirred for 2 h at room temperature. Additonal tert-Butyl 2,2,2-trichloroethanimidate (9.0 g, 40.5 mmol) and additional (diethyl ether)(trifluoro)boron (1 mL, 7.5 mmol) were added and the reaction mixture was stirred overnight at room temperature. The suspension was filtered and the precipitate was washed with DCM : cyclohexane (2:1). The solution was diluted with concentrated aqueous sodium hydrogen car- bonate solution. The combined water layers were extracted two times with DCM. The combined organic layers were then dried over magnesium sulfate, filtered and then evaporated. The resulting black oil was stirred with cyclohexane and ethyl acetate (2%), the precipitate was filtered, and the filtrate was evapo- rated. The resulting black oil was purified by column chromatography on silica gel (cyclohexane– ethyl acetate (9 :1)) to yield 12.1 g (100 % purity, 60 % yield) of the title compound. LC-MS (Method 9): Rt = 1.34 min; MS (ESI pos): m/z = [M+H] ⁺ 490 Example 101A 3-(tert-Butoxycarbonyl)-L-phenylalanine

Benzyl N-[(benzyloxy)carbonyl]-3-(tert-butoxycarbonyl)-L-phenylalan inate (Example 100A, 13.0 g, 26.6 mmol) was dissolved in methanol (250 mL). 10% Palladium on charcoal (1.54 g) was added and the mixture was hydrogenated at ambient pressure for 4 hours at room temperature. A precipitate was formed. The suspension was dissolved in methanol and was stirred at reflux. The warm solution was filtered over a layer of diatomaceous earth and the filter cake was washed with methanol (ca.1L). The combined filtrate was concentrated and dried, affording 6.10 g (94% purity, 81% yield) of the title compound. LC-MS (Method 9): Rt = 0.59 min; MS (ESI neg): m/z = 264 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.525 (5.74), 1.546 (16.00), 2.326 (0.50), 2.366 (0.48), 2.670 (0.50), 2.709 (0.48), 3.169 (0.57), 7.400 (0.89), 7.419 (0.66), 7.501 (0.76), 7.739 (0.84), 7.759 (0.85), 7.796 (1.02). Example 102A 3-(tert-Butoxycarbonyl)-N-{[(9H-fluoren-9-yl)methoxy]carbony l}-L-phenylalanine

3-(tert-Butoxycarbonyl)-L-phenylalanine (Example 101A, 6.10 g, 23.0 mmol) was dissolved in water (100 mL) and acetone (100 mL). Sodium hydrogen carbonate (19.3 g, 230 mmol) was added. A solution of 1- ({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-dio ne (8.14 g, 24.1 mmol) was dissolved in acetone (100 mL) was added and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with one portion of MTBE. The aqueous layer was acidified with 1M hydrochloric and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to afford 8.90 g (100% purity, 79% yield) of the title compound. Product was also present in the organic layer. The organic layer was concen- trated. DCM and 1M hydrochloric were added to the residue and the mixture was stirred for 5 min. The residue was filtered and washed with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was then dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by flash chromatography on silica gel (gradient DCM : methanol (0-10%)). The residue was taken up in acetonitrile and purified by preparative HPLC (column: Reprosil; C18; 10 µm; 125 x 40 mm; solvent: AcCN/H2O containing 0,1% HCOOH; flow rare: 100 mL/min ; gradient: 0 - 5.50 min (10 : 90); sample injection at 3.00 min; 5.50 - 17.65 min gradient to 95 : 5; 17.65 - 19.48 min (95 : 5); 19.48 - 19.66 min gradient to 10 : 90; 19.66 - 20.72 min (10 :90). In total, 1.58 g (100 % purity, 14 % yield) of the title compound was obtained. LC-MS (Method 10): Rt = 2.27 min; MS (ESI neg): m/z = 486 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.106 (1.34), 1.144 (4.63), 1.519 (16.00), 1.544 (0.64), 2.086 (1.34), 2.119 (1.97), 2.483 (1.16), 2.595 (0.68), 3.077 (0.43), 3.319 (1.89), 4.158 (0.42), 4.169 (0.81), 4.181 (2.03), 4.195 (0.76), 4.203 (0.48), 4.541 (0.43), 7.259 (0.80), 7.277 (0.76), 7.293 (0.68), 7.312 (0.44), 7.378 (0.62), 7.384 (0.86), 7.397 (1.11), 7.403 (1.62), 7.415 (0.62), 7.422 (0.90), 7.521 (0.63), 7.540 (0.45), 7.583 (0.68), 7.605 (0.86), 7.626 (0.62), 7.747 (0.59), 7.766 (0.57), 7.784 (0.68), 7.806 (0.63), 7.847 (1.02), 7.864 (1.58), 7.883 (1.42). This amino acid was used in SPPS. Example 103A (2S,5R)-2-(2-Ethylbutyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-d ihydropyrazine

(2R)-3,6-Dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (CAS-RN: 109838-859, 2.9 mL, 16 mmol) was dissolved in anhydrous THF (60 mL, 740 mmol) and the solution was cooled to -78°C. n-Butyllithium (10 mL, 1.6 M, 16 mmol) was added dropwise slowly and dropwise over a 15 minute period while stirring at -78°C. 3-(Bromomethyl)pentane (5.91 g, 35.8 mmol) was added and the reaction mixture was stirred for 2 h at -78°C, then allowed to come to room temperature overnight. The solution was cooled to 0 ^o C and slowly quenched with water. Diethyl ether was added and after stirring several minutes, the organic layer was separated. The aqueous phase was extracted two times with diethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 2%) to give 2.60 g (95 % purity, 57 % yield) of the title compound. LC-MS (Method 10): Rt = 2.90 min; MS (ESI pos): m/z = 269 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.51), 0.008 (0.45), 0.608 (6.77), 0.624 (6.91), 0.771 (3.04), 0.790 (7.57), 0.796 (3.51), 0.808 (4.20), 0.815 (7.45), 0.833 (3.54), 0.999 (6.56), 1.016 (6.71), 1.179 (0.65), 1.197 (0.97), 1.215 (0.95), 1.223 (0.51), 1.232 (0.73), 1.240 (0.81), 1.257 (1.26), 1.275 (1.64), 1.294 (1.28), 1.310 (0.57), 1.343 (0.55), 1.356 (1.67), 1.364 (0.66), 1.369 (0.83), 1.376 (1.52), 1.388 (1.40), 1.398 (0.66), 1.403 (0.63), 1.409 (1.04), 1.422 (0.43), 1.459 (0.56), 1.474 (0.63), 1.489 (0.45), 1.637 (0.66), 1.647 (0.68), 1.656 (0.56), 1.667 (0.69), 1.670 (0.69), 1.681 (0.54), 1.690 (0.48), 1.700 (0.44), 2.191 (0.54), 2.199 (0.55), 2.208 (0.71), 2.216 (0.71), 2.225 (0.52), 2.233 (0.51), 3.597 (16.00), 3.616 (15.85), 3.916 (1.08), 3.925 (2.24), 3.933 (1.46), 3.959 (0.67), 3.969 (1.06), 3.980 (0.99), 3.990 (1.00), 4.000 (0.49). Example 104A Methyl 4-ethyl-L-norleucinate

A solution (2S,5R)-2-(2-Ethylbutyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-d ihydropyrazine (Example 103A, 2.60 g, 9.69 mmol) in methanol (30 mL) was cooled to 0°C and a 10% aqueous solution of hydro- chloric acid (10 mL) was added and then the reaction mixture was stirred for 2 h. The solution was evap- orated and the residue was diluted with DCM and sodium carbonate solution (100 mL, 2.0 M). The sepa- rated aqueous layer was extracted two times with DCM. The combined organic layer was dried over mag- nesium sulfate, filtered and then concentrated to give 3.49 g (48% purity, 100% yield) of the title com- pound. GC-MS (GC-MS Method 1): Rt = 3.18 min, m/z = 173 [M+] Example 105A 4-Ethyl-N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-L-norleucine

To methyl 4-ethyl-L-norleucinate (Example 104A, 3.97 g, 48% purity, 11.0 mmol) was added methanol (100 mL) and the resulting solution was cooled to 0°C. Sodium hydroxide solution (24 mL, 1.0 M) was added and the reaction mixture was stirred for 1 h at 0°C, then warmed to room temperature and stirred further for 4 h. Water (80 mL), sodium hydrogen carbonate (2.03 g, 24.2 mmol) and sodium carbonate (4.00 g, 37.7 mmol) were sequentially added to the solution. The methanol was removed from the reaction mixture by rotary evaporation and the aqueous solution was diluted with 1,4-dioxane (60 mL). The sus- pension was cooled to 0°C and (9H-fluoren-9-yl)methyl carbonochloridate (CAS-RN: 28920-43-6, 8.54 g, 33.0 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water and MTBE were added, stirred briefly, and then the organic layer was separated. The aqueous layer was ex- tracted with MTBE and then the combined organic layer was washed with 5% sodium carbonate solution. The combined aqueous layer was acidified to pH 1 with potassium hydrogen sulfate and the aqueous suspension was extracted three times with DCM. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by preparative HPLC (column: Reprosil; C18; 10 µm; 125 x 40 mm; solvent: AcCN/H2O containing 0,1% HCOOH; flow rate: 100 mL/min ; gradient: 0 - 5.50 min (10 : 90); sample injection at 3.00 min; 5.50 - 17.65 min gradient to 95 : 5; 17.65 - 19.48 min (95 : 5); 19.48 - 19.66 min gradient to 10 : 90; 19.66 - 20.72 min (10 :90), affording 1.57 g (100 % purity, 37 % yield) of the title compound. LC-MS (Method 11): Rt = 1.49 min; MS (ESI pos): m/z = 404 [M+Na] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (3.19), 0.008 (3.01), 0.774 (6.73), 0.792 (16.00), 0.809 (13.36), 0.826 (14.04), 0.844 (7.32), 1.181 (0.92), 1.197 (1.90), 1.216 (3.12), 1.234 (3.84), 1.253 (2.82), 1.273 (1.79), 1.293 (2.23), 1.308 (3.41), 1.331 (4.60), 1.339 (4.12), 1.505 (0.45), 1.557 (3.55), 1.575 (5.01), 1.590 (3.09), 3.950 (1.22), 3.970 (2.67), 3.989 (2.69), 4.009 (1.11), 4.204 (1.35), 4.220 (3.90), 4.238 (7.46), 4.263 (5.22), 4.279 (3.57), 4.286 (5.10), 4.304 (3.43), 4.310 (2.32), 4.328 (1.06), 7.299 (2.60), 7.306 (2.93), 7.317 (5.73), 7.322 (5.59), 7.336 (3.69), 7.341 (3.48), 7.400 (6.17), 7.419 (10.33), 7.437 (4.62), 7.626 (4.21), 7.647 (3.80), 7.711 (8.98), 7.729 (8.16), 7.884 (9.94), 7.903 (9.15), 12.540 (0.98). This amino acid was used in SPPS. Example 106A N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-2,6-difluoro-L-phenyl alanine

To methyl 2,6-difluoro-L-phenylalaninate (CAS-RN: 1192057-28-5, 1.03 g, 4.79 mmol) was added meth- anol (18.5 mL) and the solution was cooled to 0°C. Sodium hydroxide solution (4.8 mL, 1.0 M) was added and the reaction mixture was stirred for 1 h at room temperature. Water (17 mL), sodium hydrogen car- bonate (402 mg, 4.79 mmol) and sodium carbonate (667 mg, 6.29 mmol) were added to the solution. The methanol was removed by rotary evaporation and the aqueous layer was diluted with 1,4-dioxane (14 mL). The suspension was cooled to 0°C and (9H-fluoren-9-yl)methyl carbonochloridate (CAS-RN: 28920-43- 6, 1.86 g, 7.18 mmol) was added. The mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water and washed with MTBE. The aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and the concentrated, to afford 1.74 g (100% purity, 86% yield) of the title compound. LC-MS (Method 10): Rt = 2.00 min; MS (ESI pos): m/z = 424 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.157 (0.74), 1.175 (1.50), 1.193 (0.76), 1.988 (2.79), 2.992 (0.74), 3.014 (0.87), 3.025 (1.22), 3.048 (1.17), 3.118 (1.24), 3.134 (1.32), 3.153 (0.81), 3.169 (0.76), 3.316 (16.00), 4.021 (0.71), 4.039 (0.70), 4.131 (0.95), 4.149 (1.39), 4.166 (2.72), 4.194 (4.15), 4.213 (2.65), 4.235 (0.72), 7.013 (1.71), 7.033 (3.28), 7.053 (2.07), 7.290 (1.33), 7.307 (3.44), 7.323 (4.18), 7.341 (2.36), 7.357 (0.48), 7.397 (2.41), 7.415 (4.00), 7.434 (1.83), 7.639 (2.22), 7.659 (3.87), 7.679 (1.99), 7.818 (1.97), 7.839 (1.95), 7.876 (4.80), 7.894 (4.40), 12.793 (0.81). This amino acid was used in SPPS. Example 107A N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-2,5-difluoro-L-phenyl alanine To methyl 2,5-difluoro-L-phenylalaninate (CAS-RN: 1213491-95-2) (2.27 g, 10.5 mmol) was added in methanol (40 mL) and the resulting solution was cooled to 0°C. Sodium hydroxide solution (11 mL, 1.0 M) was added and the reaction mixture was stirred for 1.5 h at room temperature. Water (35 mL), sodium hydrogen carbonate (886 mg, 10.5 mmol) and sodium carbonate (1.47 g, 13.9 mmol) were added to the solution. The methanol was removed by rotary evaporation and the aqueous layer was diluted with 1,4- dioxane (30 mL). The suspension was cooled to 0°C and (9H-fluoren-9-yl)methyl carbonochloridate (CAS-RN: 28920-43-6, 4.09 g, 15.8 mmol) was added, and the reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with water and washed with MTBE. The aqueous layer was acidified to pH 1 with 1 M hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and the concentrated. The crude product was purified by flash chromatography on silica gel (gradient DCM : methanol 0-5%), then the residue was taken up in acetonitrile and purified again by preparative HPLC (column: Reprosil; C18; 10 µm; 125 x 40 mm; solvent: AcCN/H2O containing 0,1% HCOOH; flow rate: 100 mL/min ; gradient: 0 - 5.50 min (10 : 90); sample injection at 3.00 min; 5.50 - 17.65 min gradient to 95 : 5; 17.65 - 19.48 min (95 : 5); 19.48 - 19.66 min bis 10 : 90; 19.66 - 20.72 min (10 :90) to give 1.82 g (100 % purity, 41 % yield) of the title compound. LC-MS (Method 9): Rt = 1.04 min; MS (ESI pos): m/z = 424 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (2.88), 0.008 (2.75), 1.234 (0.68), 2.329 (0.47), 2.671 (0.46), 2.843 (2.48), 2.870 (3.13), 2.877 (3.47), 2.904 (3.10), 3.166 (3.44), 3.177 (3.74), 3.200 (2.97), 3.212 (2.73), 4.141 (1.90), 4.158 (5.16), 4.173 (9.08), 4.196 (12.08), 4.201 (12.22), 4.211 (8.55), 4.221 (7.38), 4.233 (3.76), 4.246 (2.97), 4.259 (2.15), 7.084 (0.87), 7.093 (1.61), 7.106 (2.33), 7.114 (3.81), 7.124 (3.21), 7.135 (2.97), 7.144 (2.17), 7.175 (3.13), 7.187 (4.77), 7.197 (6.58), 7.210 (7.69), 7.220 (4.45), 7.232 (3.61), 7.263 (4.47), 7.282 (9.79), 7.301 (7.22), 7.305 (7.95), 7.325 (4.82), 7.349 (0.45), 7.389 (6.78), 7.408 (11.73), 7.426 (5.46), 7.489 (0.48), 7.509 (0.67), 7.532 (0.46), 7.610 (7.40), 7.628 (12.92), 7.646 (6.48), 7.791 (6.23), 7.812 (6.10), 7.871 (16.00), 7.890 (14.50), 12.862 (3.43). This amino acid was used in SPPS. This amino acid was also prepared from methyl 2,5-difluoro-L-phenylalaninate prepared in Example 126A. The amino acid can also be prepared from 2,5-difluoro-L-phenylalaninate (CAS RN: 31105-92-7) using the procedure described in Example 106A. Example 108A Benzyl tetrahydro-2H-pyran-3-ylacetate (racemate)

Tetrahydro-2H-pyran-3-ylacetic acid (1.00 g, 6.94 mmol) was dissolved in methanol (10 mL, 250 mmol). Cesium carbonate (1.13 g, 3.47 mmol) was added and the reaction mixture was stirred at room temperature until the evolution of gas ceased. The solution was then evaporated. The residue was dissolved in DMF (10 mL), (bromomethyl)benzene (1.3 mL, 11 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Additional (bromomethyl)benzene (325 µL, 2.75 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The suspension was then diluted with water and ether. After stirring for a few minutes, the organic layer was separated. The aqueous layer was ex- tracted three times with diethyl ether. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by chro- matography on silica gel (cyclohexane / ethyl acetate (85/15)) to give 1.50 g (100 % purity, 92 % yield) of the title compound. LC-MS (Method 10): R _t = 1.84 min; MS (ESI pos): m/z = 235 [M+H] ⁺ ¹H-NMR (500 MHz, DMSO-d6) d [ppm]: 1.161 (0.45), 1.170 (0.51), 1.183 (0.89), 1.187 (0.68), 1.191 (0.98), 1.196 (0.60), 1.204 (0.68), 1.208 (1.03), 1.212 (0.77), 1.217 (1.00), 1.229 (0.62), 1.238 (0.63), 1.428 (0.47), 1.447 (0.62), 1.449 (0.74), 1.455 (0.95), 1.463 (0.63), 1.468 (0.83), 1.476 (1.42), 1.484 (0.80), 1.489 (0.56), 1.498 (0.98), 1.501 (0.53), 1.506 (1.11), 1.509 (1.00), 1.516 (1.65), 1.523 (1.08), 1.532 (0.56), 1.543 (0.70), 1.550 (0.40), 1.747 (0.90), 1.751 (0.77), 1.755 (0.89), 1.764 (0.62), 1.773 (0.82), 1.777 (0.69), 1.781 (0.77), 1.887 (0.41), 1.894 (0.68), 1.901 (0.68), 1.908 (0.76), 1.914 (0.90), 1.921 (0.74), 1.927 (0.68), 1.934 (0.63), 2.194 (1.30), 2.208 (1.18), 2.225 (3.67), 2.239 (3.41), 2.255 (3.55), 2.270 (3.23), 2.286 (1.23), 2.301 (1.12), 3.018 (2.02), 3.038 (2.30), 3.041 (2.34), 3.059 (2.06), 3.246 (1.05), 3.252 (1.07), 3.267 (1.61), 3.273 (1.61), 3.289 (1.21), 3.295 (1.19), 3.685 (0.75), 3.692 (1.34), 3.705 (1.77), 3.708 (1.89), 3.713 (2.24), 3.716 (2.16), 3.726 (1.17), 3.730 (1.14), 3.734 (1.08), 3.738 (0.97), 5.089 (16.00), 7.310 (0.41), 7.315 (0.73), 7.320 (0.71), 7.327 (2.21), 7.334 (1.16), 7.339 (1.36), 7.342 (1.95), 7.345 (2.49), 7.348 (2.36), 7.351 (1.63), 7.360 (9.48), 7.364 (11.33), 7.371 (1.08), 7.376 (3.55), 7.378 (3.74), 7.382 (1.62), 7.390 (0.55), 7.393 (1.20), 7.395 (0.74). Example 109A Benzyl tetrahydro-2H-pyran-3-yl acetate

The diastereomeric mixture (Example 108A, 1.5 g) was dissolved in methanol / acetonitrile (30 mL) and separated using a THAR supercritical fluid chromatography Prep 200 instrument using a Chiralpak AZ- H (SFC) 5µm, 250 x 30 mm column; eluent: CO2/ethanol (90:10); pressure: 135 bar; temperature eluant: 35°C; flow rate: 100 g/min; detection: UV 210 nm; injection volume 0.4 mL/injection; under general operating conditions 1g/min of CO2 is approximately equivalent to 1 mL/min. Sequence Settings: cycle time = 11,2 min Fraction 1 was collected at 1.48 min (enantiomer 1) Fraction 2 was collected between 1.89 min (enantiomer 2) The product-containing fractions combined and were concentrated. The fractions were analyzed using analytical SFC-MS (Agilent, column: Daicel AZ-33 µm 100 x 4,6 mm, eluent: CO2/ethanol (90:10); BPR pressure: 130 bar; BPR temperature: 60°C; column temperature: 40°C; flow rate: 3 mL/min; UV 210 nm. The stereochemistry of the two enantiomers was not assigned. Benzyl tetrahydro-2H-pyran-3-ylacetate (enantiomer 1) was obtained with 99.5% ee (641 mg (100 % pu- rity). LC-MS (Method 9): R _t = 0.98 min; MS (ESI pos): m/z = 235 [M+H] ⁺ ¹H-NMR (500 MHz, DMSO-d6) d [ppm]: 1.161 (0.45), 1.170 (0.51), 1.183 (0.89), 1.187 (0.67), 1.191 (0.98), 1.196 (0.61), 1.204 (0.67), 1.209 (1.03), 1.213 (0.77), 1.217 (1.00), 1.230 (0.61), 1.238 (0.62), 1.428 (0.48), 1.447 (0.61), 1.449 (0.75), 1.455 (0.95), 1.463 (0.64), 1.468 (0.82), 1.476 (1.41), 1.484 (0.79), 1.489 (0.56), 1.498 (0.98), 1.501 (0.52), 1.507 (1.05), 1.510 (1.00), 1.516 (1.65), 1.523 (1.07), 1.532 (0.55), 1.543 (0.70), 1.747 (0.90), 1.751 (0.78), 1.755 (0.89), 1.764 (0.63), 1.773 (0.81), 1.777 (0.69), 1.781 (0.78), 1.887 (0.40), 1.894 (0.69), 1.901 (0.68), 1.908 (0.76), 1.914 (0.91), 1.921 (0.74), 1.927 (0.67), 1.934 (0.64), 2.194 (1.30), 2.208 (1.18), 2.225 (3.69), 2.239 (3.42), 2.255 (3.56), 2.270 (3.24), 2.286 (1.23), 2.301 (1.12), 3.019 (2.02), 3.038 (2.29), 3.041 (2.36), 3.060 (2.07), 3.246 (1.05), 3.252 (1.08), 3.268 (1.63), 3.273 (1.63), 3.289 (1.24), 3.295 (1.23), 3.686 (0.75), 3.692 (1.34), 3.705 (1.73), 3.708 (1.90), 3.713 (2.19), 3.715 (2.20), 3.726 (1.19), 3.730 (1.13), 3.734 (1.08), 3.738 (0.97), 5.089 (16.00), 7.310 (0.40), 7.315 (0.74), 7.321 (0.69), 7.328 (2.23), 7.334 (1.13), 7.339 (1.36), 7.342 (1.99), 7.345 (2.52), 7.347 (2.34), 7.350 (1.66), 7.360 (9.33), 7.364 (11.16), 7.371 (1.09), 7.376 (3.58), 7.378 (3.72), 7.382 (1.63), 7.390 (0.54), 7.393 (1.20), 7.396 (0.75). Benzyl tetrahydro-2H-pyran-3-ylacetate (enantiomer 2) was also obtained with 99.5% ee (611 mg (100 % purity). Example 110A Tetrahydro-2H-pyran-3-ylacetic acid (enantiomer 1)

10% Palladium on charcoal (84.0 mg) was humidified with methanol under argon. A solution of benzyl tetrahydro-2H-pyran-3-ylacetate (Example 109A, 641 mg, 2.74 mmol)added. The reaction mixture was then hydrogenated for 2 h at ambient pressure at room temperature. The catalyst was removed by filtration over a layer of diatomaceous earth, the filter cake was washed with methanol, and the solvent was removed by rotary distillation, to provide 364 mg (100 % purity, 92 % yield) of the title compound. GC-MS (GC-MS Method 1): Rt = 3.57 min, m/z = 144 [M+] ¹H-NMR (500 MHz, DMSO-d6) d [ppm]: 1.145 (1.98), 1.154 (2.21), 1.166 (4.03), 1.171 (3.11), 1.175 (4.45), 1.180 (2.85), 1.188 (3.11), 1.192 (4.69), 1.196 (3.55), 1.201 (4.57), 1.213 (2.68), 1.222 (2.75), 1.428 (1.03), 1.436 (1.93), 1.445 (1.35), 1.449 (1.65), 1.455 (2.72), 1.458 (3.25), 1.463 (4.18), 1.471 (2.92), 1.476 (3.82), 1.484 (6.50), 1.493 (3.67), 1.498 (2.58), 1.506 (5.73), 1.514 (6.62), 1.521 (7.99), 1.528 (5.13), 1.537 (2.67), 1.548 (3.18), 1.554 (1.80), 1.563 (0.64), 1.759 (1.78), 1.767 (4.22), 1.771 (3.85), 1.775 (4.26), 1.784 (2.89), 1.793 (3.85), 1.797 (3.49), 1.801 (3.85), 1.809 (1.56), 1.824 (0.81), 1.832 (1.31), 1.839 (1.87), 1.846 (3.17), 1.853 (3.16), 1.859 (3.72), 1.866 (4.34), 1.873 (3.58), 1.879 (3.34), 1.886 (3.00), 1.893 (1.65), 1.900 (1.44), 1.908 (0.69), 2.023 (6.18), 2.036 (5.11), 2.054 (16.00), 2.068 (14.33), 2.087 (15.54), 2.101 (13.64), 2.118 (5.69), 2.133 (5.09), 2.999 (9.23), 3.018 (10.90), 3.021 (11.02), 3.040 (9.47), 3.134 (0.64), 3.247 (6.14), 3.253 (6.29), 3.269 (9.57), 3.275 (9.49), 3.291 (7.06), 3.297 (6.90), 3.586 (0.59), 3.696 (3.77), 3.703 (6.42), 3.709 (4.14), 3.717 (8.63), 3.725 (11.12), 3.739 (5.37), 3.743 (5.40), 3.747 (5.21), 3.750 (4.68). This substance was used in SPPS. Example 111A (3S)-3-[(2S,5R)-3,6-Dimethoxy-5-(propan-2-yl)-2,5-dihydropyr azin-2-yl]cyclohexan-1-one

(2R)-3,6-Dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (4.61 g, 25.0 mmol) was dissolved in THF (20 mL) and cooled to -78°C . Butyllithium (16 mL, 1.6 M, 25 mmol) was added dropwise with stirring. Stirring was continued for 15 min at -78°C. Lithium (azanidylidenemethylidene)(thiophen-2-yl)copper (100 mL, 0.25 M, 25 mmol) was added and the mixture was stirred for 15 min at -78°C. A solution from cyclohex-2-en-1-one (2.4 mL, 25 mmol) in THF (10 mL) was added and the reaction mixture was stirred for 10 min at -78°C, then it was further stirred at ambient temperature for 2 h. The reaction was quenched with water and extracted two times with ethyl acetate. The combined organic layer was washed with so- dium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then the residue was concentrated under reduced pressure to give 6.8 g of a colorless oil. The crude product was purified by flash chromatography on silica gel (gradient cyclohexane - ethyl acetate 85-15) to give 5.7 g (90 % purity, 64 % yield) of the title compound. LC-MS (Method 12): Rt = 3.14 min; MS (ESI pos): m/z = 281.2 [M+H] ^{+ 1} H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.587 (0.94), 0.604 (1.17), 0.617 (6.04), 0.634 (6.04), 0.971 (0.51), 0.988 (5.87), 0.995 (1.32), 1.005 (5.67), 1.012 (0.98), 1.032 (0.88), 1.049 (0.91), 1.575 (0.55), 1.596 (0.42), 1.607 (0.61), 1.750 (0.61), 1.760 (0.78), 1.784 (1.05), 1.794 (1.28), 1.816 (0.50), 1.837 (0.50), 1.843 (0.57), 1.874 (0.43), 1.979 (0.82), 2.012 (1.26), 2.024 (0.52), 2.032 (0.55), 2.044 (0.95), 2.057 (0.40), 2.122 (0.46), 2.148 (0.80), 2.156 (1.00), 2.164 (1.00), 2.173 (0.67), 2.181 (0.70), 2.190 (0.69), 2.199 (0.54), 2.207 (0.59), 2.225 (0.71), 2.242 (0.64), 2.259 (0.74), 2.275 (0.64), 2.294 (0.45), 2.310 (0.65), 2.319 (0.47), 2.329 (0.48), 2.338 (0.58), 2.348 (0.54), 3.602 (0.89), 3.631 (16.00), 3.642 (4.12), 3.652 (14.26), 3.902 (1.14), 3.911 (2.10), 3.920 (1.33), 3.943 (0.45), 4.069 (1.14), 4.078 (1.82), 4.086 (0.98), 4.492 (0.55), 5.674 (0.91). Example 112A (1R,3S)-3-[(2S,5R)-3,6-Dimethoxy-5-(propan-2-yl)-2,5-dihydro pyrazin-2-yl]cyclohexan-1-ol (2 stereoi- somers present)

(3S)-3-[(2S,5R)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydro pyrazin-2-yl]cyclohexan-1-one (Example 111A, 5.70 g, 20.3 mmol) was dissolved in methanol (50 mL) and cooled to 0°C. Sodium tetrahydroborate (769 mg, 20.3 mmol) was added and the reaction mixture was stirred overnight at room temperature. Additional sodium tetrahydroborate (769 mg, 20.3 mmol) was added and stirring was continued at room temperature. This step is repeated 2 more times with 0.5 eq sodium tetrahydroborate. The methanol was evaporated and the residue was diluted with water and ethyl acetate. After stirring for several minutes, the layers were seperated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the residue concentrated under reduced pressure to give 5.7 g of a yellow oil. The crude product was purified by flash chromatog- raphy on silica gel (gradient cyclohexane - cyclohexane ethyl acetate 5%-30%) to give 4.95 g (86 % yield) of the title compound. LC-MS (Method 10): R _t = 1.87 min; MS (ESI pos): m/z = 283.2 [M+H] ⁺ ; R _t = 1.91 min; MS (ESI pos): m/z = 283.2 [M+H] ^{+ 1} H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.589 (1.83), 0.600 (6.10), 0.605 (2.52), 0.617 (6.02), 0.739 (0.91), 0.768 (0.96), 0.798 (0.42), 0.898 (0.47), 0.934 (0.50), 0.997 (6.80), 1.014 (7.00), 1.157 (0.53), 1.175 (0.92), 1.193 (0.73), 1.203 (0.72), 1.211 (0.59), 1.227 (0.47), 1.235 (0.72), 1.243 (0.51), 1.313 (0.52), 1.321 (0.63), 1.352 (0.99), 1.398 (2.43), 1.485 (0.59), 1.515 (0.56), 1.668 (0.44), 1.676 (0.56), 1.684 (0.44), 1.708 (0.51), 1.745 (0.57), 1.774 (0.54), 1.879 (0.58), 1.887 (0.56), 1.988 (1.39), 2.185 (0.54), 2.193 (0.57), 2.202 (0.73), 2.210 (0.75), 2.219 (0.55), 2.227 (0.55), 3.611 (7.06), 3.617 (3.03), 3.622 (16.00), 3.629 (14.28), 3.845 (0.55), 3.854 (0.50), 3.862 (1.17), 3.871 (2.39), 3.880 (1.79), 3.933 (1.11), 3.942 (1.74), 3.951 (0.86), 4.215 (0.59), 4.223 (0.57), 4.431 (2.16), 4.443 (2.10). Example 113A Methyl (2S)-amino[(1S)-3-hydroxycyclohexyl]acetate (2 stereoisomers present)

(3S)-3-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin -2-yl]cyclohexanol (Example 112A, 4.95 g, 17.5 mmol) was dissolved in methanol (45 mL) and the solution was cooled to 0°C. A 10% aqueous hydrochloric acid solution (15 mL) was added and the reaction mixture was stirred for a short time at 0°C, then it was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated, the residue was diluted with DCM and then an aqueous sodium carbonate solution (150 mL, 2.0 M, 300 mmol) was added. The mixture was stirred and then the layers were separated. The aqueous layer was extracted two times with DCM. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated. The crude product was purified by flash chromatography on silica gel (DCM: methanol 95+5) to give 1.92 g (58 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (1.04), 0.008 (0.93), 0.760 (0.69), 0.777 (0.71), 0.834 (0.61), 0.867 (1.92), 0.875 (1.16), 0.885 (1.54), 0.892 (1.18), 0.910 (0.45), 0.922 (0.61), 0.942 (1.05), 0.951 (0.95), 0.973 (1.17), 0.981 (1.06), 1.003 (0.54), 1.012 (0.50), 1.157 (0.67), 1.165 (0.41), 1.190 (0.65), 1.198 (0.44), 1.223 (0.42), 1.375 (0.69), 1.407 (0.79), 1.498 (0.52), 1.513 (0.89), 1.519 (0.95), 1.527 (0.74), 1.549 (0.69), 1.633 (2.72), 1.671 (0.69), 1.680 (0.78), 1.753 (1.26), 1.783 (1.67), 1.959 (0.49), 2.086 (0.85), 3.096 (0.46), 3.110 (0.48), 3.138 (1.12), 3.151 (1.10), 3.162 (1.07), 3.175 (1.02), 3.276 (0.43), 3.288 (0.55), 3.593 (0.71), 3.603 (4.85), 3.612 (16.00), 3.626 (1.87), 3.633 (0.96), 3.637 (1.57), 4.232 (0.60), 4.240 (0.55), 4.481 (1.83), 4.492 (1.73), 5.754 (0.68). Example 114A (2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-2-[(1S)-3-h ydroxycyclohexyl]acetic acid (2 stereo- isomers present)

Methyl (2S)-amino[(1S)-3-hydroxycyclohexyl]acetate (Example 113A, 1.92 g, 10.3 mmol) was added to methanol (40 mL) and the solution was cooled to 0°C. Sodium hydroxide solution (10 mL, 1.0 M, 10 mmol) was added and the reaction mixture was stirred for 1.5 h at room temperature and then for 1 h at 50°C. Water (37 mL), sodium hydrogen carbonate (861 mg, 10.3 mmol), and sodium carbonate (1.43 g, 13.5 mmol) were added to the solution. The methanol was evaporated and the aqueous layer was diluted with 1,4-dioxane (30 mL). The suspension was cooled to 0°C and (9H-fluoren-9-yl)methyl carbono- chloridate (CAS-RN: 28920-43-6, 3.98 g, 15.4 mmol) was added. The mixture was stirred over night at room temperature. Water and MTBE were added and the organic layer was separated. The aqueous layer was acidified and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and filtered. The crude product was purified by flash chroma- tography on silica gel (DCM: methanol/HOAc 95+5+1) to give 2.22 g (55 % yield) of the title compound. LC-MS (Method 10): Rt = 1.62 min; MS (ESI pos): m/z = 396.18 [M+H] ⁺ ; Rt = 1.67 min; MS (ESI pos): m/z = 396.18 [M+H] ⁺ Example 115A (2S)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-[(1S,3R )-3-hydroxycyclohexyl]acetic acid (di- astereomer 1)

Diastereomer 1 (2S)-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}[(1S)-3-hydrox ycyclohexyl]acetic acid (Example 114A, 2.22 g) was purified by chiral chromatography using the method described in Example 96 A to provide 890 mg (100 % purity, 40 % yield, 99% ee) of diastereomer 1. LC-MS (Method 10): Rt = 1.62 min; MS (ESI pos): m/z = 396.2 [M+H] ⁺ H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.878 (0.88), 0.909 (1.80), 0.940 (2.23), 0.962 (1.87), 0.986 (2.99), 1.025 (4.63), 1.053 (3.69), 1.083 (1.14), 1.151 (1.18), 1.184 (2.16), 1.217 (1.71), 1.249 (0.53), 1.492 (2.55), 1.523 (2.32), 1.668 (2.86), 1.701 (2.42), 1.779 (6.54), 1.802 (4.90), 2.073 (4.22), 3.875 (0.46), 3.900 (3.08), 3.916 (3.51), 3.921 (3.52), 3.936 (2.67), 4.197 (1.31), 4.211 (3.35), 4.223 (9.23), 4.238 (12.01), 4.242 (10.59), 4.253 (6.34), 4.270 (3.91), 4.296 (0.72), 4.563 (2.04), 7.312 (6.21), 7.331 (14.61), 7.349 (9.50), 7.402 (9.30), 7.420 (15.31), 7.439 (6.83), 7.603 (4.81), 7.624 (4.95), 7.752 (11.74), 7.770 (10.65), 7.884 (16.00), 7.903 (14.82), 8.155 (0.69). This amino acid was used in SPPS. Example 116A (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-2-[(1S,3S )-3-hydroxycyclohexyl]acetic acid (dia- stereomer 2)

Also isolated during the chiral chromatography of the diastereomeric mixtue of (2S)-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)[(1S,3S)-3-hydroxycyclohexyl]aceti c acid (Example 114A) was 280 mg (95 % purity, 12 % yield) of diastereomer 2. LC-MS (Method 10): Rt = 1.67 min; MS (ESI pos): m/z = 396.2 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.862 (0.81), 0.879 (0.71), 1.024 (0.76), 1.055 (1.68), 1.084 (1.84), 1.113 (1.00), 1.274 (1.39), 1.308 (2.53), 1.339 (1.79), 1.404 (4.60), 1.430 (3.90), 1.498 (3.23), 1.531 (6.31), 1.566 (4.20), 1.609 (2.04), 1.640 (1.55), 2.179 (1.80), 2.328 (0.51), 2.670 (0.47), 3.820 (0.62), 3.839 (0.86), 3.858 (0.76), 3.904 (4.71), 3.920 (3.46), 3.925 (3.34), 3.941 (2.46), 4.195 (1.38), 4.210 (3.69), 4.223 (9.20), 4.238 (10.72), 4.244 (8.66), 4.254 (7.18), 4.272 (6.16), 7.309 (5.80), 7.328 (13.47), 7.346 (8.67), 7.400 (9.17), 7.419 (15.07), 7.437 (6.77), 7.487 (3.68), 7.508 (3.60), 7.546 (0.67), 7.637 (0.61), 7.748 (11.33), 7.767 (10.18), 7.883 (16.00), 7.901 (14.74). This amino acid was used in SPPS. Example 117A 3-({[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}methyl)cyclohexa necarboxylic acid (racemate)

3-{[(tert-Butoxycarbonyl)amino]methyl}cyclohexanecarboxylic acid (racemate) (CAS RN: 145149-55- 9, 1.00 g, 3.89 mmol) was dissolved in dichloromethane (20 mL, 310 mmol), trifluoroacetic acid (20 mL, 260 mmol) was added, and the reaction mixture was stirred for 30 min at room temperature. The solution was evaporated and the residue was dissolved in acetone (15 mL). Water (10 mL), sodium hydrogen carbonate (6.53 g, 77.7 mmol) and 1-({[(9H-fluoren-9-yl)methoxy]carbonyl}oxy)pyrrolidine-2,5-d ione (CAS-RN: 82911-69-11.38 g, 4.08 mmol) were added. The suspension was stirred overnight at room temperature. Sodium hydrogen carbonate (6.53 g, 77.7 mmol) was added and the reaction mixture was allowed to stir for 1 h at room temperature. The suspension was diluted with water and extracted with MTBE. The aqueous layer was acidifed with aqueous hydrochloric acid (1M) and then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and then concentrated and evaporated, to provide three product-containing fractions: 130 mg (96 % purity, 8 % yield), 127 mg (96 % purity, 8 % yield), 51.0 mg (3 % yield). LC-MS (Method 9): R _t = 1.01 min; MS (ESI pos): m/z = 380 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.736 (0.49), 0.759 (1.44), 0.790 (1.73), 0.821 (0.80), 0.851 (0.96), 0.882 (2.75), 0.913 (2.99), 0.944 (1.23), 1.083 (0.45), 1.120 (0.52), 1.153 (1.38), 1.182 (3.81), 1.206 (3.18), 1.235 (1.28), 1.418 (1.48), 1.598 (1.97), 1.630 (2.23), 1.717 (2.24), 1.739 (1.48), 1.747 (1.53), 1.835 (1.93), 1.862 (3.95), 1.897 (2.04), 2.074 (2.00), 2.123 (1.19), 2.130 (1.10), 2.152 (2.02), 2.174 (0.85), 2.181 (0.95), 2.524 (1.06), 2.785 (0.60), 2.801 (1.06), 2.818 (2.22), 2.835 (3.08), 2.849 (2.89), 2.862 (3.29), 2.878 (2.21), 2.895 (1.16), 2.911 (0.57), 4.188 (1.46), 4.206 (3.84), 4.223 (3.22), 4.238 (0.88), 4.253 (0.91), 4.287 (11.07), 4.304 (6.87), 4.333 (0.64), 4.351 (0.40), 4.451 (0.68), 7.306 (6.09), 7.324 (16.00), 7.341 (10.19), 7.392 (6.85), 7.410 (10.96), 7.429 (4.86), 7.459 (0.43), 7.626 (0.73), 7.643 (0.75), 7.683 (9.67), 7.702 (8.66), 7.875 (11.34), 7.894 (10.10), 12.028 (1.95). This amino acid was used in SPPS. Example 118A

Benzyl (2S)-2-(morpholin-4-yl)propanoate

L-alanine (589 mg, 6.61 mmol), 1-bromo-2-(2-bromoethoxy)ethane (910 µL, 7.3 mmol) and sodium car- bonate were dissolved in ethanol and the solution was refluxed for 2 days. The suspension was allowed to come to room temperature and the suspension was filtered. The filtrate was evaporated, suspended in ethanol (30 mL) and 3M hydrochloric acid was added to adjust the pH (to pH = 3). The suspension was filtered, and the filtrate was evaporated. The residue was dissolved in DMF (20 mL). Cesium carbonate (1.08 g, 3.30 mmol) and (bromomethyl)benzene (1.6 mL, 13 mmol) were added and the mixture was stirred for 2 days at room temperature. Then water was added and then the solution was purified by re- versed-phase HPLC (column: Reprosil; C18; 10 µm; 125 x 30 mm; eluent ACN/H2O with 0.1% HCOOH modifier; flow: 75 mL/min ; gradient: 0-5.50 min 10/ 90; Sample injection until 3.00 min; 5.50-17.65 min gradient to 95/5; 17.65-19.48 min 95/5; 19.48-19.66 min gradient to 10/90; 19.66-20.72 min 10/90;). The desired fractions were combined and lyophilized to provide 800 mg (98 % purity, 48 % yield) of the title compound as a colorless oil; ee >99%. LC-MS (Method 9): R _t = 0.51 min; MS (ESI pos): m/z = 250 [M+H] ⁺ ¹H-NMR (500 MHz, DMSO-d6) d [ppm]: 1.191 (10.46), 1.205 (10.52), 2.462 (0.66), 2.469 (0.77), 2.473 (0.76), 2.485 (1.55), 2.521 (1.43), 2.562 (0.63), 3.330 (0.93), 3.344 (2.66), 3.358 (2.62), 3.372 (0.86), 3.499 (0.46), 3.506 (0.63), 3.511 (0.45), 3.521 (2.34), 3.530 (3.52), 3.532 (3.50), 3.538 (3.54), 3.549 (2.18), 3.564 (0.56), 5.101 (0.60), 5.126 (5.99), 5.131 (5.75), 5.156 (0.57), 7.323 (0.69), 7.327 (0.52), 7.332 (1.27), 7.341 (1.23), 7.343 (0.94), 7.350 (1.14), 7.358 (0.50), 7.369 (1.15), 7.377 (16.00), 7.386 (6.48), 7.392 (0.46). Example 119A

(2S)-2-(Morpholin-4-yl)propanoic acid

Palladium (10% on activated carbon) (100 mg) was moistened with methanol under argon. After that, benzyl (2S)-2-(morpholin-4-yl)propanoate (Example 118A, 800 mg, 3.21 mmol) was dissolved in meth- anol (100 mL) and the moistened palladium on activated carbon was added to the solution under argon. The suspension then was hydrogenated for 2 hours at ambient pressure under a hydrogen atmosphere. The vessel was purged of hydrogen with argon and the suspension was filtered over celite. The filtrate was evaporated, and the residue was dissolved in MeCN/H2O and lyophilized to provide 501 mg (>99 % pu- rity, 98 % yield) of the title compound as a light-brown solid.

LC-MS (Method 9): Rt = 0.16 min; MS (ESI pos): m/z = 160 [M+H] ⁺ ¹H-NMR (500 MHz, deuterium oxide) d [ppm]: 1.519 (16.00), 1.534 (15.96), 3.695 (1.39), 3.709 (4.02), 3.724 (3.89), 3.738 (1.30).

Example 120A

1-(Tert-butoxycarbonyl)-4-ethylidene-L-proline

Methyl(triphenyl)phosphonium bromide (34.7 g, 97.1 mmol) was suspended in 400 mL THF. A solution of KHMDS solution in toluene (146.6 mL, 15% w/v, 97.1 mmol) was added dropwise at room temperature and stirred for one hour at room temperature. After that, the solution was cooled to 0°C, and 1-(tert- butoxycarbonyl)-4-oxo-L-proline (11.1 g, 48.6 mmol) was added in portions. The mixture was stirred 2.5 hours at room temperature. Water was added to the reaction mixture. The mixture was made slightly acidic with 10% citric acid solution and the extracted three times with ethyl acetate. The combined ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then dried under vacuum to give a thick orange resin. The crude product was used for the next step without further purification.

Example 121A

1-Tert-butyl 2-methyl (2S)-4-methylidenepyrrolidine-1,2-dicarboxylate

The crude 1-(tert-butoxycarbonyl)-4-ethylidene-L-proline (example 120A) (11.0 g, 48.6 mmol) was dis- solved in DMF (60 mL). Potassium carbonate (10.1 g, 72.9 mmol) was added, then iodomethane (4.5 ml, 73 mmol) was added, and then the mixture was stirred overnight at room temperature. The DMF was removed with a rotary evaporator, ethyl acetate was added, and then the mixture was washed one time with water. The aqueous phase was one time re-extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then dried under vacuum to give the crude product. The crude product was dissolved in DCM and purified by normal-phase chromatography using a Biotage Isolara flash chromatography system, using an eluant of cyclohexane– ethyl acetate (85/15) to give 10.2 g (80%) of the title compound as a yellow oil. LC-MS (Method 10): Rt = 1.77 min; MS (ESI pos): m/z = 186 M-C4H8 ⁺ ¹H-NMR (500 MHz, DMSO-d6) d [ppm]: 1.339 (16.00), 1.405 (10.53), 3.313 (10.02), 3.627 (3.90), 3.938 (2.21), 3.967 (0.60), 4.331 (0.51), 4.337 (0.54), 4.350 (0.57), 4.356 (0.59), 4.363 (0.47), 4.367 (0.42), 4.992 (1.33), 5.019 (1.17).

Example 122A

5-Tert-butyl 6-methyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate

Under argon, diethylzinc (22 mL, 1.0 M in hexane, 22 mmol) was dissolved in anhydrous DCM (27 mL). The solution was cooled to 5°C and then a solution of TFA (1.7 ml, 22 mmol) in DCM (17 mL) was added dropwise over a 1 hour period. The solution was stirred at 5°C for an additional 30 min. A solution of diiodomethane (1.8 mL, 22 mmol) in anhydrous DCM (5 mL) was added dropwise quickly, and the re- sulting solution was stirred at 5°C for 30 min. After that, a solution of 1-tert-butyl 2-methyl (2S)-4-me- thylidenepyrrolidine-1,2-dicarboxylate (example 121A) (2.70 g, 11.2 mmol) in anhydrous DCM (5 mL) was added to the reaction mixture. The reaction mixture was stirred in a thawing ice-bath for 90 hours, then quenched with saturated, aqueous ammonium chloride solution. The phases were separated, and the aqueous phase was re-extracted with DCM one time. The organic phases were combined, dried over mag- nesium sulfate, and then evaporated to provide 1.57 g the crude product as a yellow oil. The oil was dissolved in ethyl acetate (54 mL), di-tert-butyldicarbonate (2.6 mL, 11 mmol) and triethylamine (3.1 mL, 22 mmol) were sequentially added, and then the reaction mixture was stirred overnight at room tempera- ture. The reaction was controlled using TLC (petroleum ether/ethyl acetate 10/1; colored with ninhydrin). The crude product was purified by normal-phase chromatography using a Biotage Isolara flash chroma- tography system (100 g Biotage cartridge Ultra), using an eluant gradient of petroleum ether– ethyl acetate (EA) (2% to 18% EA) to provide 1.02 g of the title compound as a colorless oil.

Example 123A

(6S)-5-(Tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-car boxylic acid

5-Tert-butyl 6-methyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (example 122A) (2.50 g, 9.79 mmol) was dissolved in 50% THF/water (40 mL). Lithium hydroxide (703 mg, 29.4 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The THF was removed using a rotary evaporator, and the aqueous solution was diluted with additional water (20 mL) water and washed once with MTBE. The separated aqueous phase was acidified with 1M hydrochloric acid (30 mL) and then extracted two times with DCM. The combined organic phase was dried over magnesium sulfate, filtered, and then concentrated to give 2.4 g of the title compound as a colorless oil.

Example 124A

(6S)-5-azaspiro[2.4]heptane-6-carboxylic acid

(6S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carbox ylic acid (example 123A) (2.36 g, 9.79 mmol) was dissolved in DCM (50 mL). Trifluoroacetic acid (10 mL, 250 mmol) was added, and the reac- tion mixture was stirred 2 hours at room temperature. The reaction control was made using TLC (DCM/MeOH 9/1). The solution was evaporated and the crude product was dried under vacuum to provide the title compound as a brown residue. This was used directly for the next step (Fmoc protection, see Example 82A).

Example 15A

(2S,5R)-2-[(2,5-difluorophenyl)methyl]-3,6-dimethoxy-5-(p ropan-2-yl)-2,5-dihydropyrazine

The reaction was performed under argon. (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (CAS-RN: 109838-85-9) (2.9 ml, 16 mmol) was dissolved in anhydrous THF (40 mL) and the solution was cooled to -78°C. At this temperature, an n-butyl lithium solution (10 mL, 1.6 M in hexane, 16 mmol) was slowly added dropwise, and the resulting solution was stirred 15 min at -78°C. Then a solution of 2- (bromomethyl)-1,4-difluorobenzene (4.05 g, 19.5 mmol) in anhydrous THF (15 mL) was added and stir- ring was continued until the reaction came to room temperature. The reaction mixture was stirred for an additional hour at room temperature, while monitoring the reaction progress by HPLC. The mixture was quenched with water and extracted two times with ethyl acetate. The combined organic phases were washed one time with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated to give 5.46 g of a crude yellow oil. The oil was purified by normal phase chromatog- raphy using a Biotage Isolara flash chromatography system (100 g Biotage cartridge Ultra), using an elu- ant of cyclohexane– ethyl acetate (EA) (95/5) to afford 4.16 g (82%) of the title compound as an oil. LC-MS (Method 10): Rt = 2.44 min; MS (ESI pos): m/z = 311 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.563 (6.79), 0.580 (6.97), 0.933 (6.65), 0.951 (6.88), 2.103 (0.58), 2.111 (0.61), 2.120 (0.78), 2.129 (0.79), 2.137 (0.59), 2.145 (0.57), 2.864 (0.79), 2.882 (0.83), 2.898 (1.08), 2.915 (1.09), 3.089 (1.06), 3.101 (1.10), 3.123 (0.82), 3.134 (0.81), 3.313 (7.20), 3.518 (1.28), 3.527 (2.46), 3.535 (1.37), 3.566 (16.00), 4.293 (0.58), 4.304 (1.07), 4.313 (1.08), 4.321 (1.01), 4.330 (0.58), 6.992 (0.47), 7.000 (0.66), 7.005 (0.63), 7.015 (1.06), 7.023 (0.71), 7.028 (0.64), 7.037 (0.63), 7.075 (0.63), 7.084 (0.91), 7.095 (0.74), 7.105 (0.66), 7.131 (0.68), 7.143 (0.73), 7.154 (1.05), 7.166 (1.04), 7.177 (0.45), 7.189 (0.40).

Example 126A

Methyl 2,5-difluoro-L-phenylalaninate

(2S,5R)-2-[(2,5-difluorophenyl)methyl]-3,6-dimethoxy-5-(prop an-2-yl)-2,5-dihydropyrazine (example 125A) (4.15 g, 13.4 mmol) was dissolved in methanol (35 mL) and the solution was cooled to 0°C. A solution of a aqueous 10% hydrochloric acid (12 mL) was added and the solution was stirred 0°C for some minutes. Then the reaction solution was allowed to come to room temperature and then stirred three hours at this temperature. The methanol was evaporated. The residue was diluted with DCM, 2M aqueous so- dium carbonate solution (120 mL) was added and ther resulting mixture was stirred vigorously for a few minutes. The layers were separated, and the aqueous phase was extracted two times with DCM. The com- bined organic phases were dried over magnesium sulfate, filtered, and then concentrated to give 3.97 g of a colorless liquid. The crude liquid was purified by normal phase chromatography using a Biotage Isolara flash chromatography system (100 g Biotage cartridge Ultra), using a gradient eluant of cyclohexane– ethyl acetate (EA) (10% to 75% EA) to provide 2.27 g (79%) of the title compound as a colorless liquid. LC-MS (Method 13): R _t = 1.20 min; MS (ESI pos): m/z = 216 [M+H] ⁺ ¹H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.833 (16.00), 2.733 (3.07), 2.753 (3.26), 2.767 (4.81), 2.787 (5.01), 2.889 (4.71), 2.904 (4.91), 2.923 (3.10), 2.938 (3.19), 3.315 (15.20), 3.401 (0.42), 3.553 (5.22), 3.568 (6.29), 3.572 (6.60), 3.768 (0.41), 7.060 (0.89), 7.069 (1.71), 7.081 (2.21), 7.090 (4.07), 7.101 (3.20), 7.111 (2.84), 7.120 (1.89), 7.151 (5.97), 7.163 (5.82), 7.174 (9.84), 7.186 (7.52), 7.196 (4.42), 7.208 (2.10).

Example 127A tert-Butyl (2R)-2-amino-3-[[(2R)-2-amino-3-tert-butoxy-3-oxo-propyl]dis ulfanyl]propanoate

To the suspension of L-Cystine (CAS RN: 56-89-3) (10.00 g, 41.61 mmol) in tert-butyl acetate (63.22 g, 544.24 mmol, 73 mL) was added HClO ₄ (18.26 g, 127.23 mmol, 11 mL, 70% purity) (70% in H ₂ O) drop- wise at 0 °C over 0.5 h, then the solution was stirred for 17 h at 20 °C. Ice was added and the solution was used for the next step without further purification (14.67 g in theory). Example 128A tert-Butyl (2R)-3-[[(2R)-3-tert-butoxy-2-(tert-butoxycarbonylamino)-3-o xo-propyl]disulfanyl]-2-(tert- butoxycarbonylamino)propanoate

To the mixture of tert-butyl (2R)-2-amino-3-[[(2R)-2-amino-3-tert-butoxy-3-oxo-propyl]dis ulfanyl]pro- panoate (14.67 g in theory, from Example 127A) in water (200 mL) and EA (200 mL) was added Na ₂ CO ₃ (30.00 g, 283.08 mmol) and Boc ₂ O (27.25 g, 124.85 mmol) at 0°C, and the mixture (pH was 8- 9) was stirred for 17 h at 20°C. The mixture was diluted with EA (100 mL) and water (200 mL). The or- ganic layer was separated, and aqueous layer was extracted with EA (200 mL). The combined organic layer was washed with brine (200 mL), concentrated to give a residue, the residue was purified by silical gel chromatography (PE/EA=1/0 to 1/1) to give two batches of the title compound: 8.5 g crude as a light brown oil and 6.5 g as a light brown oil. ¹H-NMR (400 MHz, CDCl3) d [ppm]: 1.51, 1.61, 1.62.1.64, 3.11, 3.12, 3.14, 3.16, 3.19, 3.203, 3.23, 3.24, 4.44, 4.46, 4.48, 4.49, 5.35, 5.37. Example 129A tert-Butyl (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoate

To the solution of tert-butyl (2R)-3-[[(2R)-3-tert-butoxy-2-(tert-butoxycarbonylamino)-3-o xo-propyl]di- sulfanyl]-2-(tert-butoxycarbonylamino)propanoate (8.5 g, crude, from example 128A) in THF (150 mL) and water (15 mL) was added tributylphosphane (3.77 g, 4.6 mL) at 0 °C over 0.5 h, then the solution was stirred for 2 h at 20 °C. The mixture was worked up with another batch, prepared from 6.5 g of rare material (from Example 128A). Both reaction mixtures were poured into water (300 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic phase was washed with brine (300 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA = 40/1 to 10/1) to afford 12.5 g of the title compound as a colorless oil, which was used as pure.6.5 g of an impure batch containing residual tributylphosphine was also obtained but discarded. ¹H-NMR (400 MHz, CDCl3) d [ppm]: 1.45, 2.94, 2.95, 2.96, 2.97, 4.46, 4.47, 4.48, 4.49, 5.39, 5.41 Example 130A tert-Butyl (2R)-2-(tert-butoxycarbonylamino)-3-(trifluoromethylsulfanyl )propanoate

To a solution of 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (18 g, 54.53 mmol) in MeOH (150 mL) was added a solution of tert-butyl (2R)-2-(tert-butoxycarbonylamino)-3-sulfanyl-propanoate (14 g, 50.47 mmol, from Example 129A) in MeOH (20 mL) at -78°C under N2 over 30 min, and the reaction was stirred for 1 h at this temperature, upon which it becomes colorless solution. The reaction mixture was warmed to 20°C, stirred for 1 h, and concentrated to give a residue, which was purified by silica gel chromatography (PE/EA=1/0 to 40/1) twice to give 13.2 g of the title compound as a colorless oil. ¹H-NMR (400 MHz, CDCl3) d [ppm]: 1.47, 3.26, 3.28, 3.30, 3.31, 3.45, 3.46, 3.48, 3.50, 4.47, 4.48, 5.34, 5.35. Example 131A tert-Butyl (2R)-2-amino-3-(trifluoromethylsulfanyl)propanoate hydrochloride

To a solution of tert-butyl (2R)-2-(tert-butoxycarbonylamino)-3-(trifluoromethylsulfanyl )-propanoate (12.20 g, 35.32 mmol, from example 130A) in DCM (10 mL) was added a solution of HCl/dioxane (4 M, 50 mL) and the reaction was stirred for 3 h at 10°C. The mixture was concentrated to give a white glassy solid, which was used for next step directly. Example 132A tert-Butyl (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(trifluoromet hylsulfanyl)-propanoate

To the mixture of tert-butyl (2R)-2-amino-3-(trifluoromethylsulfanyl)propanoate hydrochloride (crude from Example 131A) in dioxane (80 mL) was added saturated NaHCO3 (80 mL), and Fmoc-OSu (19 g, 56.33 mmol), and the reaction (pH ~7-8) was stirred for 17 h at 10°C. The mixture was concentrated, and the residue was diluted with water (100 mL), then extracted with EA (100 mL x 2). The organic layer was washed with brine (100 mL), concentrated, and then purified by silica gel chromatography (PE/EA=40/1~10/1) to give 13 g of the title compound as a colorless oil. LC-MS (Method 15): Rt = 1.028 min; MS (ESI pos): m/z = 490.2 [M+Na] ⁺ ¹H-NMR (400 MHz, CDCl3) d [ppm]: 1.45, 3.32, 3.47, 3.36, 3,49, 3.50, 4.16, 4.22, 4.24, 4.26, 4.37, 4.44, 4.46, 4.58, 5.62, 5.64, 7.33, 7.35, 7.40, 7.42, 7.44, 7.56, 7.61, 7.77, 7.79. ¹⁹ F-NMR: (376 MHz, CDCl3) d [ppm]: -40.85. Example 133A 2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(trifluorometh ylsulfanyl)propanoic acid

To a solution of tert-butyl (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(trifluoromet hylsulfanyl)- propanoate (13 g, 27.81 mmol) in DCM (15 mL) was added TFA (30 mL) and thioanisole (15.75 g, 126.81 mmol, 15 mL), and the reaction mixture was stirred for 17 h at 10°C. The mixture was concentrated to give a residue, which was diluted with saturated NaHCO ₃ solution (100 mL), and then extracted with EA (50 mL x 2). The organic layer was washed with 1M HCl (50 mL), concentrated, and then purified by silica gel chromatography (PE/EA=10/1, then with DCM/MeOH=40/1 to 5/1) to give 10 g of the title compound as a white glassy solid purity: 98.8%. ¹H-NMR indicated that the product contained ethyl ace- tate, so the solid was re-dissolved in DCM (80 mL), concentrated and then dried under high vacuum to give 9.67 g (23.22 mmol, 83.5% yield, 98.8% purity) of the title compound as a white glassy solid. LC-MS (Method 15): Rt = 0.895 min; MS (ESI pos): m/z = 434.1 [M+Na] ⁺ ¹H-NMR (400 MHz, CDCl3) d [ppm]: 3.25, 3.26, 3.32, 3.33, 3.93, 3.95, 4.22, 4.24, 4.26, 4.28, 4.30, 4.31, 6.95, 6.98, 7.31, 7.32, 7.33, 7.34, 7.39, 7,41, 7.42, 7.68, 7.70, 7.87, 7.89. ¹⁹ F-NMR: (376 MHz, CDCl3) d [ppm]: -40.89 Chiral SFC: Rt = 2.49 min, 99% ee Chiral SFC condition: AD-3_5CM_IPA (DEA)_10_20_3ML_T35 Column: Chiralpak AD-350 x 4.6 mm I.D., 3 ^m Mobile phase: iso-propanol (0.05% DEA) in CO ₂ from 10% to 20% Flow rate: 3 mL/min Wavelength: 220 nm. This amino acid was used in SPPS. This amino acid is also commercially available (CAS-RN: 1994331- 25-7. Example 134A Di-tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate

To a solution of compound tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (CAS-RN: 35418-16-7) (290 g, 1.57 mol, 1.00 eq) and DMAP (1.91 g, 15.66 mmol, 0.01 eq) in CH ₃ CN (2.00 L), was added Boc ₂ O (341 g, 1.57 mol, 359 mL, 1.00 eq) at 5 °C. After the addition, the mixture was stirred at 20 °C for 12 h. TLC showed that the starting material was completely consumed, and two new spots (TLC) were formed (PE/EA = 3/1, Rf = 0.43, Rf = 0.9). The reaction mixture was concentrated under reduced pressure to remove CH ₃ CN and the residue was partitioned between DCM (1000 mL) and water (1000 mL). The organic layer was washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated under re- duced pressure to give the crude product. The residue was purified by column chromatography (SiO ₂ , PE/EA=100/1 to 10/1) to afford the title compound (260.00 g, 874.75 mmol, 55.72% yield, 96% purity) as off-white solid. LC-MS (Method 15): Rt = 0.873 min; MS (ESI pos): m/z = 308.0 [M+Na] ⁺ , 331 [M+2Na] ⁺ ¹H-NMR (400 MHz, CDCl3) d [ppm]: 1.44-1.42 (d, J=8.4, 8H), 1.97-1.92 (m, 1H), 2.22-2.19 (m, 1H), 2.43-2.40 (m, 1H), 2.58-2.49 (m, 1H), 4.42-4.39 (m, 1H).

Example 135A Di-tert-butyl (2S)-4,4-diallyl-5-oxo-pyrrolidine-1,2-dicarboxylate

To a solution of di-tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (61.9 g, 208 mmol, 1.00 eq, from Example 134A) in THF (40.0 mL) was added LiHMDS (1 M, 437 mL, 2.10 eq) dropwise at -73 °C and then stirred at -73 °C for 1 h. To the mixture was added compound allyl bromide (50.4 g, 416 mmol, 2.00 eq) dropwise. After the addition, the mixture was stirred at 15 °C for 2 h. TLC showed compound that the starting material was completely consumed, and four new spots were formed (PE/EA = 3/1, R _f = 0.9, R _f = 0.8, R _f = 0.7, R _f = 0.1). The reaction mixture was quenched with saturated aqueous ammonium chloride (1000 mL), extracted with DCM (500 mL x 3), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 100/1 to 30/1) to afford the title compound (100 g, 38% yield, 86% purity) as a colorless oil.

LC-MS (Method 15): R _t = 1.044 min; MS (ESI pos): m/z = 411.4 [M+2Na] ⁺ ¹H-NMR (400 MHz, CDCl ₃ ) d [ppm]: 1.49-1.43 (d, J=8.4, 8H), 1.87-1.82 (m, 1H), 2.22-2.18 (m,3H), Example 136A Di-tert-butyl (2S)-4,4-diallylpyrrolidine-1,2-dicarboxylate

To a solution of di-tert-butyl (2S)-4,4-diallyl-5-oxo-pyrrolidine-1,2-dicarboxylate (80.0 g, 188 mmol, 1.00 eq, from Example 135A) in THF (300 mL) was added LiBHEt ₃ (1 M, 225 mL, 1.20 eq) at -78 °C. After the addition, the mixture was stirred at -78 °C for 3 h. LCMS showed the desired MS was detected. TLC showed two new spots were formed (PE/EA = 3/1, R _f = 0.65, R _f = 0.8). The reaction mixture was quenched with saturated aqueous sodium carbonate (50 mL) at 0°C and then 30% H ₂ O ₂ (1 mL) was added dropwise at 0 °C. The mixture was concentrated under reduced pressure to remove the THF and then the residue was diluted with water (1000 mL) and DCM (1000 mL). The water phase was extracted with DCM (300 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography (SiO ₂ , PE/EA = 80/1 to 30/1) to afford the title compound (56.0 g, 69% yield, 85% purity) as a colorless oil.

LC-MS (Method 15): R _t = 1.192 min; MS (ESI pos): m/z = 390.3 [M+K] ⁺ ¹H-NMR (400 MHz, CDCl3) d [ppm]: 1.53-1.47 (m, 18H), 2.13-1.98 (m, 2H), 2.22-2.15 (m,3H), 2.39- 2.24 (m, 1H), 2.92-2.91 (m, 1H), 4.22-4.08 (m, 1H), 5.18-5.06 (m, 5H), 5.85-5.77 (m, 2H). Example 137A Di-tert-Butyl (3S)-2-azaspiro[4.4]non-7-ene-2,3-dicarboxylate

To a solution of the Grubb’s 1 ^st generation catalyst (CAS RN: 172222-30-9) (2.85 g, 3.47 mmol, 0.05 eq) in DCM (400.00 mL) was added di-tert-butyl (2S)-4,4-diallylpyrrolidine-1,2-dicarboxylate (25.0 g, 69.4 mmol, 1.00 eq, from Example 136A) dropwise at 34 °C. After the addition was completed, the mixture was stirred at 34 °C under N2 for 1 h. TLC showed two new spots were formed (PE/EA = 5/1, Rf = 0.6, Rf = 0.7). The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO ₂ , PE/EA = 1/0 to 80/1) to afford the title compound (12.0 g) as a colorless oil. ¹H-NMR (400 MHz, CDCl3) d [ppm]: 1.46-1.43 (m, 18H), 1.92-1.87 (m, 1H), 2.45-2.22 (m, 5H), 3.49- 3.29 (m, 2H), 4.21-4.19 (m, 1H), 5.64 (s, 2H). Example 138A Di-tert-butyl (3S)-2-azaspiro[4.4]nonane-2,3-dicarboxylate

To a solution of di-tert-butyl (3S)-2-azaspiro[4.4]non-7-ene-2,3-dicarboxylate (12.0 g, 37.1 mmol, 1.0 eq, from Example 137A) in EtOH (100 mL) was added Pd/C (10%, 0.1 g) under a N ₂ atmosphere. The sus- pension was degassed and purged 3 times with H ₂ gas. The mixture was stirred under H ₂ (15 Psi) at 25 °C for 16 h. Part of suspension was filtered, and the filtrate was concentrated, and proton NMR was taken, which showed that the desired product was formed. The reaction mixture was filtered, and the filtrate was concentrated to give 10.0 g (crude) of the title compound as a white solid. ¹H-NMR (400 MHz, CDCl ₃ ) d [ppm]: 4.12-4.02 (m, 1H), 3.65-3.60 (m, 2H), 3.12-3.38 (m, 5H), 2.11-2.06 (m, 1H), 1.80-1.77 (m, 1H), 1.57-1.56 (m, 6H), 1.40-1.36 (m, 18H). Example 139A (3S)-2-Azaspiro[4.4]nonane-3-carboxylic acid The compound di-tert-butyl (3S)-2-azaspiro[4.4]nonane-2,3-dicarboxylate (12 g, 36.8 mmol, 1 eq, from Example 138A) was added into a solution of HCl/EtOAc (150 mL), and then the mixture was stirred at 15 °C for 1 h. LC-MS analysis showed that the starting material was consumed, and the desired target mass was found. The reaction mixture was concentrated in vaccum to remove the solvent, affording 7.5 g (36.4 mmol, 99% yield) of the crude title compound as a white solid as a hydrochloride salt. ¹H-NMR (400 MHz, DMSO) d [ppm]: 10.07 (s, 1H), 8.81 (s, 1H), 4.38-4.27 (m, 1H), 3.16-3.02 (m, 2H), 2.22-2.21 (m, 1H), 1.96-1.90 (m, 1H), 1.63-1.56 (m, 8H). Example 140A (3S)-2-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-2-azaspiro[4.4]n onane-3-carboxylic acid

To a solution of (3S)-2-azaspiro[4.4]nonane-3-carboxylic acid (5.1 g, 24.8 mmol, from Example 139A) and Fmoc-OSu (10.0 g, 29.7 mmol, 1.2 eq) in THF (70 mL) and H2O (70 mL) was added NaHCO3 (8.5 g, 101 mmol, 3.94, 4.08 eq). The mixture was stirred at 15 °C for 1 h. LCMS analysis showed that the starting material was consumed, and the desired target mass was obtained. Water (200 ml) was added, and then the mixture was extracted with DCM (200 mL x 2). The combined organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and then concentrated. The crude product was purified for reversed-phase MPLC (EA) to afford 6.9 g (17.5 mmol, 70 % yield, 99% purity) of the title compound as a yellow solid. LC-MS (Method 15): R _t = 2.501 min; MS (ESI pos): m/z = 392.2 [M+H] ⁺ ¹H-NMR (400 MHz, CDCl3) d [ppm]: 7.80-7.79 (d, J = 7.2, 2H), 7.59-7.54 (m, 2H), 7.44-7.42 (m, 2H), 7.36-7.35(m, 2H), 4.55-4.52 (m, 2H), 4.42-4.38 (m, 1H), 4.31-4.20(m, 1H), 3.34-3.17(m,2H), 2.33-2.28 (m, 1H), 2.13-2.08 (m, 1H), 1.73-1.50 (m, 8H). This amino acid was used in SPPS. This amino acid is also commercially available (CAS-RN: 394734- 78-2). Example 141A

(2S,4R)-4-(Trifluoromethyl)pyrrolidine-2-carboxylic acid

To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-(trifluoromethyl)pyrrolidine -2-carboxylic acid (7 g, 24.7 mmol, 1 eq) in DCM (70 mL) was added TFA (8.00 mL, 108 mmol, 4.37 eq). The mixture was stirred at 10 °C for 4 h. LCMS analysis showed that the starting material was consumed and that the desired target mass was found. The reaction mixture was concentrated under vacuum and the crude product was used directly for the next step. The title compound (7.34 g, 24.7 mmol, 100% yield, TFA salt) was obtained as a white solid. LC-MS (Method 15): R _t = 0.18 min; MS (ESI pos): m/z = 184.1 [M+H] ⁺ ¹H-NMR (400 MHz, CDCl ₃ ) d [ppm]: 4.51-4.48 (m, 1H), 3.82 (m, 1H), 3.57-3.55 (m, 1H), 2.65-2.62 (m, 2H), 2.53-2.49 (m, 1H). Example 142A

(2S,4R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-(trifluorome thyl)pyrrolidine-2-carboxylic acid

To a solution of the crude (2S,4R)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (2 g, 6.73 mmol, 1 eq, TFA salt, from Example 141A) in H2O (70 mL) and acetone (70 mL) was added Na2CO3 (2.85 g, 26.9 mmol, 4 eq) and Fmoc-OSu (2.72 g, 8.08 mmol, 1.2 eq). The mixture was stirred at 10 °C for 12 h. LCMS analysis showed only one peak and that the desired mass was found. TLC analysis (DCM/MeOH = 10/1) showed that the starting material was consumed, and that a main spot (Rf = 0.4) appeared. HCl solution (1M, 30 mL) was added to the mixture until the pH = 2. The mixture was extracted with DCM (70 mL x 2), and the combined organic layer was washed with brine (70 ml), dried over Na2SO4, filtered, and then concentrated. The residue was purified by column chromatography (SiO2, PE/ EA = 10/1 to 5/1), provid- ing 1.7g (61%, 97% purity) of the title compound as a yellow solid.

LC-MS (Method 15): R _t = 2.425 min; MS (ESI pos): m/z = 406.2 [M+H] ⁺ , 406.2 [M+Na] ⁺ ¹H-NMR (400 MHz, DMSO) d [ppm]: 7.92-7.89 (m, 2H), 7.66-7.64 (m, 2H), 7.42-7.41 (m, 2H), 7.35- 7.32 (m, 2H), 4.16-4.19 (m, 4H), 3.72-3.50 (m, 3H), 2.38-2.30 (m, 2H), 2.18 (s, 1H). ¹⁹ F-NMR (400 MHz, DMSO) d [ppm]: -70.128, -70.275. Chiral SFC: R _t = 2.33 min, 99% ee Chiral SFC condition: AD-3_5CM_IPA (DEA)_10_20_3ML_T35 Column: Chiralpak AD-350 x 4.6 mm I.D., 3 ^m Mobile phase: iso-propanol (0.05% DEA) in CO ₂ from 10% to 20% Flow rate: 3 mL/min Wavelength: 220 nm. This amino acid was used for SPPS.

Table 15: Analytical data for the reference peptides

Table 16: Analytical data for the peptides prepared according to the invention

Table 17: Maldi mass spectral data for selected peptides

In the following, examples 29, 44, 45, 67, 75, 109, 166, 185, 347, 443, 466 and 499 are exemplified by their chemical structure. The present invention includes pharmaceutically acceptable salts, solvates or solvates of the salts of these examples. Chemical structures are displayed as salt free forms. Example 29, Sequence: AIC+SRSLP-(Oic)-I-(Pen)+IPD-OH (HCl salt)

Example 44, Sequence: ((N-Me)G)-IC+SRS-((tBu)A)-PPI-(Pen)+IP-(PEG9(31 atoms))-NH ₂

Example 45, Sequence: AI-C+SRS-((tBu)A)-P-((6S)-5-Azaspiro[2.4]heptane-6-carboxyli c acid)-I- (Pen)+IPD-NH ₂

Example 67, Sequence: ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IP-NH ₂ (HCl salt)

Example 75, Sequence: AIC+SRSLP-(Oic)-I-(Pen)+IPD-NH ₂

Example 109, Sequence: ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IP-NH ₂

Example 166, Sequence: (3-Amino-2,2-dimethylpropionic acid)-IC+SRS-((tBu)A)-PPI-(Pen)+IPD- NH ₂

(

Example 185, Sequence: AIC+SRSLP-(Oic)-I-((N-Me)C)+IPD-NH2

Example 347, Sequence: IC+SRSLP-(Oic)-I-(Pen)+IPD-OH

Example 443, Sequence: ((N-Me)A)-IC+SRS-((tBu)A)-P-((3R,6R)-1,1-Difluoro-5-azaspiro [2.4]hep- tane-6-carboxylic acid (enantiomer 1))-I-(Pen)+IP-NH ₂

Example 466, Sequence: ((N-Me)G)-IC+SRSLP-(Oic)-I-(Pen)+IPDD-OH

Example 499, Sequence: AIC+S-(Arg(13C6,15N4))-SLP-(Oic)-I-(Pen)+IPD-OH

Biological in vitro Testings 1. Serine protease profiling of test compounds Test compounds were tested in a protease panel consisting of different human serine proteases including kallikrein, plasmin, FXIa, thrombin, factor Xa, tPA, and trypsin. Test description Inhibitory potency and/or selectivity of test compounds were determined. The assays are based on the fluorescent detection of aminomethylcoumarine (AMC), released from the fluorogenic peptidic protease substrates upon protease catalyzed cleavage. The active proteases or zymogenes, typically purified from human plasma or for trypsin from human pancreas, and corresponding substrates are commercially avail- able. Serine protease assays comprise of the following enzymes and substrates. All enzymes and substrates are diluted in assay buffer (50 mM Tris/HCl pH7.4, 100 mM NaCl, 5 mM CaCl2, 0.1% BSA). The final assay concentrations are given: • Kallikrein (Kordia; 0.2 nM), H-Pro-Phe-Arg-AMC (Bachem I-1295; 5 µM)

• Plasmin (Kordia; 0.1 µg/mL, 1.2 nM), MeOSuc-Ala-Phe-Lys-AMC (Bachem I-1275; 50 µM) • Factor XIa (Kordia; 0.15 nM), Boc-Glu(OBzl)-Ala-Arg-AMC (Bachem I-1575; 5 µM) • Thrombin (Kordia; 0.02 nM), Boc-Asp(OBzl)-Pro-Arg-AMC (Bachem I-1560; 5 µM) • Factor Xa (Kordia; 1.3 nM), Boc-Ile-Glu-Gly-Arg-AMC (Bachem I-1100; 5 µM)

• Tissue plasminogen activator (tPA, Loxo; 2 nM), CH3SO2-D-Phe-Gly-Arg-AMC (Pentapharm 091-06; 5 µM)

• Trypsin (Sigma; 0.042 U/mL), substrate Boc-Ile-Glu-Gly-Arg-AMC (Bachem I-1100; 5 µM) For determination of test compound potency, the enzyme and corresponding substrate dilutions are used to perform protease assays: To 384 well microtiter plates (white, Greiner), containing 1 µL/well serial dilutions of test or reference compounds, 20 µL assay buffer, 20 µl enzyme dilution, and 20 µl substrate are added. Control reactions do not contain test compound (DMSO only). After incubation for typically 30 min (linear reaction kinet- ics) at room temperature, fluorescence (ex 360 nm, em 465 nm) is measured in a microtiter plate fluores- cence reader (e.g Tecan Safire II). IC50 values are determined by plotting log test compound concentration against the percentage protease activity. 2. Biochemical Human MASP-1 and MASP-2 assay 2.1 Recombinant expression and protein production of recombinant human MASP1 and MASP2 active proteases. A truncated cDNA sequence of human MASP1encoding the fragment corresponding to the amino acids 297-699 with an C-terminal His Tag and N-terminal Ig-kappa secretion signal (SEQ ID No: 2) was sub- cloned into the mammalian expression vector pcDNA3.1 (Invitrogen). A truncated cDNA sequence of human MASP1encoding the fragment corresponding to the amino acids 297-686 with an C-terminal His Tag and N-terminal Ig-kappa secretion signal (SEQ ID No: 3) was sub- cloned into the mammalian expression vector pcDNA3.1 (Invitrogen). The MASP1 or MASP2 expression vectors were transfected into the HEK293 (ATCC No. CRL-1573) cell line using Lipofectamine LTX® Reagent (Thermo-Fischer), as described by the manufacturer. The mature form of the recombinant human MASP1 and MASP2 proteases were secreted into the culture medium. The MASP1 and MASP2 proteins were purified from the conditioned media by affinity chroma- tography on Ni-NTA Superflow resin (Qiagen) as described by the manufacturer. 2.2 Biochemical human MASP1 assay Recombinant human MASP1 enzyme produced in the HEK 293 cells was diluted in the reaction buffer (50 mM HEPES pH 8,0; 100 mM NaCl; 0,01% CHAPS; 0,5 mM Gluthathione) to the concentration of 20 nM and 25 µl was transferred into each single well of 384-well white microtiter plate (Greiner Bio One 781075).1 µl of the inhibitor compound solution (dissolved in DMSO, at the corresponding concentration) or pure DMSO as a control was added to the same wells. The enzymatic reaction was initiated by addition of 25 µl of 20 µM solution of the FRET substrate ABZ-MYGGARRL-Lys (Dnp)-NH ₂ ; (ABZ - 2-amino- benzoyl; DNP - 2,4-dinitrophenyl; custom synthesis by Jerini Peptide Technologies, Berlin) in the reaction buffer. The microtiter plate was incubated for 60-120 min at the temperature of 32 C. The increase of fluorescence intensity was measured in appropriate fluorescence plate reader (e.g. TECAN Ultra) using excitation wavelength of 320 nm and emission wavelength of 420 nm. IC50 values were calculated from percentage of inhibition of human MASP1 activity as a function of test compound concentration. 2.3 Biochemical human MASP2 assay Recombinant human MASP2 enzyme produced in the HEK 293 cells was diluted in the reaction buffer (50 mM HEPES pH 8,0; 100 mM NaCl; 0,01% CHAPS; 0,5 mM Gluthathione) to the concentration of 20 nM and 25 µl was transferred into each single well of 384-well white microtiter plate (Greiner Bio One 781075).1 µl of the inhibitor compound solution (dissolved in DMSO, at the corresponding concentration) or pure DMSO as a control was added to the same wells. The enzymatic reaction was initiated by addition of 25 µl of 60 µM solution of the FRET substrate DABCYL-KISPQGYGRR-Glu(EDANS)-NH ₂ ; (Dabcyl - 4 - ((4 - (dimethylamino)phenyl)azo)benzoic acid; Edans - 5-[(2-Aminoethyl) amino]naphthalene-1-sul- fonyl; custom synthesis by Jerini Peptide Technologies, Berlin) in the reaction buffer. The microtiter plate was incubated for 60-120 min at the temperature of 32 C. The increase of fluorescence intensity was measured in appropriate fluorescence plate reader (e.g. TECAN Ultra) using excitation wavelength of 340 nm and emission wavelength of 490 nm. IC50 values were calculated from percentage of inhibition of human MASP2 activity as a function of test compound concentration. 3. C3 Deposition assay (human, rat, mouse, dog, mini-pig) The C3 deposition assay was conducted essentially as described (reference). Multiwell plates (Greiner- Nunc 384 Maxi Sorp #464718) were coated over night with Mannan from Saccharomyces cerevisiae (Sigma M7504, 10 µg/mL in 0.05 M carbonate-bicarbonate buffer, pH 9.6) at 4°C. Wells were washed three times with TBS and subsequently incubated for 2 hours with 50 µL of 1% bovine serum albumin (BSA) in Tris-buffered saline (TBS) at 37°C in order to block non-specific binding. After this step and each of the following incubation steps wells were washed three times with C3 wash buffer (TBS; 0.05% Tween 20; 5 mM CaCl2). Wells were next incubated for 30 min at 37°C with 50 µL of a mixture of test compounds with diluted serum in Veronal buffer (Veronal Puffer (Lonza 12624E). Serum was used at concentrations that did not show detectable C3 deposition to uncoated plates in pre-tests. Appropriate dilutions were found to be in the range of 1:100– 1:200 for human, rat, mouse and dog serum and 1:20– 1:100 for mini pig serum, respectively. In typical experiments compounds were tested in a range of con- centrations between 1x10 ^-9 and 5x10 ^-5 mol/L. After washing C3 deposition was detected by incubation with a polyclonal rabbit anti-human C3 antibody (Dako (Biozol) A0062) for 1 hour followed by washing and incubation with a peroxidase conjugated Anti Rabbit IgG (Sigma A1949) for 30 min at 37°C and subsequent washing and incubation with TMB substrate solution in the dark. When appropriately devel- oped the color reaction was stopped by addition of 25 µL of stop solution (Sigma S5814) and quantified on a photometer by measuring absorption at a wavelength of 450 nm. Antibodies were diluted in C3 wash buffer supplemented with 0.5% BSA. 4. Biochemical Rat MASP-1 and MASP-2 assay 4.1 Recombinant expression and protein production of recombinant human and rat MASP1 and MASP2 active proteases. A truncated cDNA sequence of rat MASP1encoding the fragment corresponding to the amino acids 302- 704 with an C-terminal His Tag and N-terminal Ig-kappa secretion signal (SEQ ID No: 4) was subcloned into the mammalian expression vector pcDNA3.1 (Invitrogen). A truncated cDNA sequence of rat MASP2 encoding the fragment corresponding to the amino acids 296- 685 with a C-terminal His Tag and N-terminal Ig-kappa secretion signal (SEQ ID No: 5) was subcloned into the mammalian expression vector pcDNA3.1 (Invitrogen). The MASP1 or MASP2 expression vectors were transfected into the HEK293 (ATCC No. CRL-1573) cell line using Lipofectamine LTX® Reagent (Thermo-Fischer), as described by the manufacturer. The mature form of the recombinant rat MASP1 and MASP2 proteases were secreted into the culture medium. The MASP1 and MASP2 proteins were purified from the conditioned media by affinity chromatography on Ni-NTA Superflow resin (Qiagen) as described by the manufacturer. 4.2 Biochemical rat MASP1 assay. Recombinant rat MASP1 enzyme produced in the HEK 293 cells was diluted in the reaction buffer (50 mM HEPES pH 8,0; 100 mM NaCl; 0,01% CHAPS; 0,5 mM Gluthathione) to the concentration of 4 nM and 25 µl was transferred into each single well of 384-well white microtiter plate (Greiner Bio One 781075).1 µl of the inhibitor compound solution (dissolved in DMSO, at the corresponding concentration) or pure DMSO as a control was added to the same wells. The enzymatic reaction was initiated by addition of 25 µl of 40 µM solution of the FRET substrate Dabcyl-MYGGARRL-Glu(Edans)-NH ₂ ; (Dabcyl - 4 - ((4 - (dimethylamino)phenyl)azo)benzoic acid; Edans - 5-[(2-Aminoethyl) amino]naphthalene-1-sulfonyl; custom synthesis by Jerini Peptide Technologies, Berlin) in the reaction buffer. The microtiter plate was incubated for 60-120 min at the temperature of 32 C. The increase of fluorescence intensity was measured in appropriate fluorescence plate reader (e.g. TECAN Ultra) using excitation wavelength of 340 nm and emission wavelength of 490 nm. IC50 values were calculated from percentage of inhibition of rat MASP2 activity as a function of test compound concentration. 4.3 Biochemical rat MASP2 assay. Recombinant rat MASP2 enzyme produced in the HEK 293 cells was diluted in the reaction buffer (50 mM HEPES pH 8,0; 100 mM NaCl; 0,01% CHAPS; 0,5 mM Gluthathione) to the concentration of 20 nM and 25 µl was transferred into each single well of 384-well white microtiter plate (Greiner Bio One 781075).1 µl of the inhibitor compound solution (dissolved in DMSO, at the corresponding concentration) or pure DMSO as a control was added to the same wells. The enzymatic reaction was initiated by addition of 25 µl of 30 µM solution of the FRET substrate Abz-IEGRTSED-(Lys)Dnp-NH2; (ABZ - 2-aminoben- zoyl; DNP - 2,4-dinitrophenyl; custom synthesis by Jerini Peptide Technologies, Berlin) in the reaction buffer. The microtiter plate was incubated for 60-120 min at the temperature of 32 C. The increase of fluorescence intensity was measured in appropriate fluorescence plate reader (e.g. TECAN Ultra) using excitation wavelength of 320 nm and emission wavelength of 420 nm. IC50 values were calculated from percentage of inhibition of rat MASP2 activity as a function of test compound concentration. Table 18: Average IC50 of the reference peptides

Table 19: Average IC50 of the peptides of the invention

Table 20: Average IC50 of the reference peptides

Table 21: Average IC50 of the peptides of the invention

4. Kidney ischemia reperfusion injury in rats after unilateral nephrectomy

All procedures conformed to national legislation (dt. Tierschutzgesetz) and EU directives for the use of animals for scientific purposes and were approved by the institutional animal care office of Bayer AG and by the competent regional authority (LANUV Recklinghausen). Standard laboratory diet and tap water were available ad libitum. In a typical experiment, the number of animals used was n = 6 to 12. Animals were randomly assigned to experimental groups. Kidney ischemia reperfusion injury (IRI) was performed in male unilaterally nephrectomized Wistar rats of a preferred body weight in the range of 250 to 350 g. For unilateral nephrectomy rats were kept anesthetized under inhalation of 2% isoflurane in air. Analgesia was provided as a subcutaneous injection of 400 µl/kg of a mixture of 25% Ketavet and 8% Rompun in 0.9 NaCl. Unilateral nephrectomy was performed after protruding the right kidney through a small incision in the dorsolateral abdominal wall and ligating of its peduncle. After unilateral nephrectomy abdominal incision was closed by surgical sutures in layers and animals were allowed to recover for 7 to 8 days before IRI. IRI was performed under anesthesia and analgesia as described above. The remnant left kidney was protruded through a small incision of the abdominal wall and blood vessels of the kidney peduncle were clamped with an atraumatic microvascular clamp for 45 minutes in a typical setting. During this time the kidney together with the clamp in situ was repositioned into the abdominal cavity to ensure warm ische- mia. After 45 min the clamp was opened and removed, and the incision closed by sutures as described above. Test compound or vehicle was administered intravenously via a polyethylene catheter placed be- fore surgery into the jugular vein. Compounds were dissolved in appropriate vehicle and administered either preventive before IRI or ther- apeutically after completion of IRI. Typical dose range applied was 0.1– 30 mg/kg i.v.. Vehicle without compound was administered to animals that served as controls. Sham control animals underwent the whole procedure described above without closure of the clamp for induction of ischemia. Blood samples were taken under anesthesia at day 1 and 8 after IRI. In a typical setting, animals were sacrificed 8 days after IRI and kidneys were sampled and frozen in liquid nitrogen. In another typical setting the animals were sacrificed 1 day after IRI. Typical laboratory parameters measured in plasma samples to assess kidney function were creatinine and urea. For determination of creatinine clearance animals were kept in metabolic cages and urine was col- lected for at least 16 hours. After determination of urine volume flow (V _U ) and determination of urinary and plasma creatinine concentrations ([Crea] _U and [Crea] _Pl , respectively) creatinine clearance (Cl _Crea ) was calculated according to the standard formula: Cl _Crea = V _U * [Crea] _U / [Crea] _Pl RNA Extraction and Quantitative Real-Time Polymerase Chain Reaction: Total RNA was extracted from tissue samples by the Trizol method. Integrity of obtained RNA was checked on a Bioanalyzer (Agilent). For reverse transcription, 1 mg of total RNA was first digested with RNase-free DNase I (Gibco) for 15 min at room temperature and then reversetranscribed using Promiscript (Promega) in a total reaction vol- ume of 40 ml according to the standard protocol of the kit supplier. After inactivation of the enzyme by heating for 15 min to 65 °C, the obtained cDNA was diluted to a final volume of 150 ml with bidest. water and 4 ml were chosen per PCR reaction. Real-Time PCR including normalization of raw data to cytosolic beta-actin as a housekeeping gene was carried out as described (Ellinghaus et al., 2005). The resulting expression is given in arbitrary units. Sequences of used oligonucleotide primers and probes are given in table 1. 5. Kidney ischemia reperfusion injury (IRI) in pigs after aortic balloon occlusion All procedures conformed to national legislation (dt. Tierschutzgesetz) and EU directives for the use of animals for scientific purposes and were approved by the institutional animal care office of Bayer AG and by the competent regional authority (LANUV Recklinghausen). Female Göttingen mini pigs (Ellegaard, Denmark) of a body weight ranging preferably from 12 to 16 kg were used for the experiments. Animals were randomly assigned to experimental groups. Minimal invasive methods were applied with modifications as described (Simon et al., Effects of intrave- nous sulfide during porcine aortic occlusion-induced kidney ischemia/reperfusion injury. Shock. 2011;35:156-163; Matejkova et al., Carbamylated erythropoietin-FC fusion protein and recombinant hu- man erythropoietin during porcine kidney ischemia/reperfusion injury. Intensive Care Med.2011;39:497– 510). In brief: Pigs were kept anesthetized by a continuous i.v.-infusion of Ketavet®, Dormicum® and Pancuronium® after premedication with an intramuscular injection of Ketavet® / Stresnil®. After in- tratracheal intubation animals were artificially ventilated using a pediatric respirator (Avance CS², GE Healthcare) with an oxygen air mixture at a tidal volume of 6 to 8 mL/kg at a constant positive end- expiratory pressure (PEEP) of 3 - 4 cm H ₂ O and a frequency of 13 to 20 min ^-1 . Ventilation was adjusted to keep arterial PaCO2 at about 40 mmHg at baseline. A catheter was placed into the right jugular vein for drug and fluid administration. Ringer-lactate solution was infused intravenously at a constant rate of 10 mL/kg/h. Animals received 50 i.E./kg Heparin i.v.. Routinely the following cardiovascular and respir- atory parameters were measured after placement of necessary probes and catheters fitted to appropriate pressure transducers and recording equipment: central venous pressure (via left jugular vein), arterial blood pressure and heart rate (BP and HR; via left carotid artery) and cardiac output (CO) and systemic vascular resistance (SVR) by use of the PiCCO® system (Pulsion, Germany) connected to a Pulsion 4F Thermodilution-catheter (PV2014L08N) placed into the right carotid artery. Catheters for measurement of CVP, BP and HR were fitted to a Ponemah recording system via Combitrans transducers (Braun, REF 5203660). A Fogarty occlusion catheter (8F/14F, Edwards Lifesiences, REF 6208014F) was inserted into the abdominal aorta via the left femoral artery so that the tip with the inflatable balloon was placed up- stream of the kidney arteries. A catheter was introduced into the urinary bladder via a small abdominal incision and urine continuously collected. Arterial blood samples were collected at regular intervals in which creatinine, urea, liver enzymes, blood cells and compound concentrations were determined. Arterial pO2, pCO2 and pH were determined on a Stat Profile® PRIME® (Nova Biomedical) blood gas analyzer at regular intervals in arterial blood samples. Kidney perfusion was assessed at regular intervals by Dop- pler ultrasound determination of the resistive index using a LOGIQ e Veterinary ultrasound apparatus (General Electrics) fitted with a 2,0 to 5,0 MHz broad-spectrum convex transducer (C1-5-RS, REF 5384874). Renal resistive index (RRI) is a suitable parameter to assess severity of acute kidney injury in patients (Darmon et al., Diagnostic accuracy of Doppler renal resistive index for reversibility of acute kidney injury in critically ill patients. Intensive Care Med.2011;37(1):68-76) When cardiovascular parameters showed a stable baseline (which was normally the case 60 min after surgery) recordings were started and samples for baseline parameters were collected. HR and MABP were continuously measured and for recording averaged over 2 min intervals. At the end of experimentation pigs were sacrificed by exsanguination. Kidney injury was induced by inflating the balloon of the Fogarty balloon catheter with saline which immediately interrupted blood flow to the kidneys and the abdominal organs and led to a sharp increase of aortic blood pressure upstream of the balloon. Stop of blood flow was further confirmed by Doppler ultrasound examination of the kidney blood vessels. In typical experiments the aorta is kept occluded for 90 to 120 min until reperfusion by deflating the balloon. After reperfusion the Ringer-lactate infusion rate is doubled to 20 mL/kg/h in order to stabilize blood pressure and to enable diuresis. All parameters were monitored for up to 6 hours after reperfusion. Compounds were dissolved in appropriate vehicle and administered either preventive before IRI or ther- apeutically after completion of IRI. Typical dose range applied was 0.1– 10 mg/kg i.v.. In a typical ex- periment up to three doses were tested in up to 6 animals per dose group. Vehicle without compound was administered to animals that served as controls. Sham control animals underwent the whole procedure described above without induction of ischemia. As a measure for kidney function after reperfusion preferably but not exclusively changes in diuresis, serum creatinine, serum potassium, serum bicarbonate and in resistive index determined by Doppler ul- trasound examination were used.

Table 22: Sequence Listing

References • Caliceti P., Veronese F.M., Adv. Drug Deliv. Rev.2003, 55, 1261-1277

• Darmon et al., Diagnostic accuracy of Doppler renal resistive index for reversibility of acute kidney injury in critically ill patients. Intensive Care Med.2011;37(1):68-76

• 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

• Dunkelberger and Song, Complement and its role in innate and adaptive immune responses. Cell Res.2010;20(1):34-50

• Ellinghaus et al., J Thorac Cardiovasc Surg.2005 Jun;129(6):1383-90

• Encyclopaedia of Pharmaceutical Technology", 3rd edition, James Swarbrick (Ed.),pp.3177- 3187

• Farrar et al., Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial in- jury. J Clin Invest.2016;126(5):1911–1925

• Garred et al., A journey through the lectin pathway of complement-MBL and beyond. Immunol Rev.2016;274(1):74-97

• Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley- VCH, 2002)

• Héja et al, Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2. Proc Natl Acad Sci U S A. 2012;109(26):10498-503

• Héja et al., Monospecific inhibitors show that both mannan-binding lectin-associated serine pro- tease-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

• 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

• http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Num- ber 605005, 2014, 01 Aug 2014

• Jan‐Patrick Fischer, Ria Schönauer, Sylvia Els‐Heindl, Donald Bierer, Johannes Koebberling, Bernd Riedl, Annette G. Beck‐Sickinger J Pep Sci.2019; e3147

• Kocsis et al., Selective inhibition of the lectin pathway of complement with phage display se- lected peptides against mannose-binding lectin-associated serine protease (MASP)-1 and -2: sig- nificant contribution of MASP-1 to lectin pathway activation. J Immunol.2010;185(7):4169-78 • Kourra CMBK and Cramer N; Chem. Sci., 2016, 7, 7007–7012 • Matejkova et al., Carbamylated erythropoietin-FC fusion protein and recombinant human eryth- ropoietin during porcine kidney ischemia/reperfusion injury. Intensive Care Med.2011;39:497– 510

• 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 • Nomenclature of a-Amino Acids (Recommendations, 1974), Biochemistry, 14(2), (1975) • Remington's Pharmaceutical Sciences, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985

• Schwaeble et al., Targeting of mannan-binding lectin-associated serine protease-2 confers pro- tection from myocardial and gastrointestinal ischemia/reperfusion injury. Proc Natl Acad Sci U S A.2011;108(18):7523-8

• Sebesta and Seebach, Helv. Chim. Acta 2003, 86, 4061-4072

• Shuai-Shuai Sun, Junyou Chen, Rui Zhao, Donald Bierer, Jun Wang, Ge-Min Fang, Yi-Ming Li Tetrahedron Letters 2019, 60, 1197–1201

• Sieve et al., Regulation and function of endothelial glycocalyx layer in vascular diseases. Vascul Pharmacol.2018;100:26-33

• Simon et al., Effects of intravenous sulfide during porcine aortic occlusion-induced kidney is- chemia/reperfusion injury. Shock.2011;35:156-163

• T. Peleg-Shulman et al., J. Med.Chem., 2004, 47, 4897-4904

• 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

• 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;

• Yang Xu, Tao Wang, Chao-Jian Guan, Yi-Ming Li, Lei Liu, Jing Shi, Donald Bierer Tetrahe- dron Letters 2017, 58, 1677–1680

• Ye Guo, De-Meng Sun, Feng-Liang Wang, Yao He, Lei Liu, Chang-Lin Tian Angew. Chem.

Int. Ed.2015, 54, 14276–14281