Macrocyclic peptides

Abstract

The present invention relates to a compound of formula (I) wherein AA1⁀AA11, NH*, C(O)*, R1 and R2 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P60054

[0003] Macrocyclic peptides

[0004] The present invention relates in particular to novel macrocyclic peptides (MCPs), their manufacture, pharmaceutical compositions comprising said derivatives and their use as medicaments. The compounds of the invention are Matrix Metalloproteinase 9 (MMP9) inhibitors and are in particular useful for the therapeutic or prophylactic treatment of ocular diseases.

[0005] The invention thus relates in particular to a compound of formula (I)

[0006]

[0007] (I) wherein

[0008] AAi^AAi i is a chain of 11 amino acids consisting of

[0009] (i) sequence F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle (Seq ID 1); or

[0010] (ii) a sequence having between 5 / 11 to 10 / 11 sequence identity to Seq ID 1;

[0011] NH* is the amino group of the amino acid AAi;

[0012] C(O)* is the carbonyl group of AAn;

[0013] R1and R2are independently absent or oxygen; and

[0014] DP / 20.02.26MeNle is the non-natural amino acid of formula

[0015]

[0016] (MeNle);

[0017] or a pharmaceutically acceptable salt thereof.

[0018] Matrix metalloproteases (MMPs) were intensively investigated as drug targets for the treatment of a variety of diseases in the past decades. MMPs are zinc dependent metallo-endopeptidases that are involved in many important biological processes such as for example tissue remodelling, wound healing, embryonic development, nerve growth or cell migration. In humans, about 24 different MMPs subdivided into several different subclasses with different substrate specificity are known as of today.

[0019] Imbalanced activity of MMP9 was associated with a number of different diseases in the past and hence this target was subject to different drug discovery programs, related for example to cardiovascular diseases, cancer, inflammatory and neurodegenerative disorders as well as lung diseases (for a more recent review, notably on MMP9 and cancer, see Mondal et al., Eur J Med Chem 194 (2020), 112260, and references cited therein). In the context of these programs, many compounds with various degrees of specificity towards other MMPs were made and are described in the literature. Several of them were investigated in clinical trials. For example, to name just a few, AZD-1236 was investigated for chronic obstructive pulmonary disease (COPD) up to clinical phase II, S-3304 for lung cancer in Ph I / II or tanomastat up to Ph III for rheumatoid arthritis and solid tumor.

[0020] However, all clinical trials were stopped due to lack of efficacy or side effects.

[0021] Topical administration of classical small molecule MMP inhibitors originating from different compound series for ocular surface diseases was not widely investigated. An experiment with the hydroxamate inhibitor tool compound PES 103 was described by Mori et al. (Basic Clin Pharmacol Toxicol 2012, 111, 289), and some data on tear production, but not on corneal surface integrity, were provided. Also, a number of approaches for indirect modulation of MMP9 activity were described in the literature. For a recent review see Alireza et al., Exp Eye Res 205 (2021), 108523, and references cited therein. The topical route of administration is believed to reduce systemic drug exposure which may alter safety or specificity requirements for the new MMP9 inhibitors that - in cases of systemic administration - may have been limiting before.Dry Eye Disease (DED) is the most common reason for seeking medical eye care and affects 5-30% of the population worldwide. DED impairs patient’s visual function and quality of life resulting in global costs of $4.9bn by 2029. The condition is defined as a multifactorial disease of the ocular surface characterized by a “loss of tear film homeostasis, and is accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles” (TFOS DEWS II report). Patients frequently experience ocular grittiness, discomfort, pain and loss of low contrast visual acuity, which can impact some visual functions such as reading. Symptoms and signs of the condition occur more frequently with advanced age and female sex. Risk factors include contact lens usage, laser-eye surgery, prolonged use of computer screens and certain low humidity environmental conditions.

[0022] Currently, mild forms of dry-eye can be treated using over-the-counter tear replacement drops. Standard of care (SoC) for more severe or chronic forms of the disease are two types of approved drugs targeting ocular surface inflammation. Cyclosporin-based drugs (usually given l-2x daily) like Restasis, Ikervis or Cequa inhibit calcineurin activity and thereby reduce T-cell activation and hence inflammatory cytokine production.

[0023] Unfortunately, these drugs are only effective in certain patient sub-populations, have a delayed onset (up to 6 months) and induce ocular irritation / burning in a significant number of patients. Xiidra (Lifitegrast solution dosed through eye drops 2x daily), has been approved in the USA as an additional SoC. The drug is an LFA-1 inhibitor, which prevents T-cell trafficking to the ocular surface. Although safe, Xiidra showed variable results in two Phase 3 trials and efficacy of the drug on the market remains to be demonstrated. Very recently, FDA approved Tyrvaya, a nasal spray of a nicotinic acetylcholine receptor agonist (varenicline solution), stimulating basal tear production.

[0024] In summary, there is a clear unmet medical need for developing new DED therapies targeting mechanisms of action beyond T-cell inhibition or lubrication with faster onset and better efficacy, tolerability and durability.

[0025] The matrix metalloproteinase (MMP) family of about 24 (in human) zinc-dependent endoproteinases together play important roles in the degradation of extracellular matrix proteins. MMP9 and MMP2 (both also known as gelatinases) are 92 kDa enzymes capable of binding and disrupting collagen types I, IV, V, VII, X, IX, elastin, fibronectin, aggrecan, vitronectin, laminin, occludin and many non-ECM molecules including pro-TNF-a, transforming growth factor (TGF)-P, pro-IL-ip, pro-IL-8 and monocyte chemoattractant protein (MCP)-3. Elevated protein and mRNA levels of MMP9 have been correlated with increased severity of human dry-eye disease. A point of care testmeasuring MMP9 level above 40 ng / ml within the tear film of dry-eye patients is currently marketed as a diagnostic tool for the condition (Inflammadry™).

[0026] Elevated expression and activity of MMP9 has also been observed in multiple mouse models of the condition (scopolamine-induced dry eye and concanavalin A-induced dryeye) and these models have been used to investigate the role of MMP9 in the disease. MMP9 knock-out mice are protected from experimental induction of dry-eye-dependent phenotypes, as measured by disruption of the corneal epithelial barrier by the fluorescein staining method. In these models, the protective effect of MMP9 inhibition was associated with preservation of epithelial occludin level, suggesting maintenance of the tight junction structure comprising the epithelial surface. In vitro, induction of MMP9 in corneal epithelial cells has been shown to occur in response to hyperosmolar or inflammatory stress along with decreased barrier function of the corneal epithelium as measured by transepithelial electrical resistance (TEER). In conclusion, MMP9 is a target with strong link to DED, good druggability on the ocular surface and a differentiated MoA (epithelial barrier break down, aggravation of inflammation) compared to the standard of care (SoC).

[0027] Therefore, inhibiting MMP9 activity is a promising therapeutic strategy for the treatment or prevention of MMP9-mediated ocular diseases or disorders, such as ocular surface diseases, in particular Dry Eye Disease (DED), Keratoconus (Abdullah, O. et al., Role of extracellular matrix remodelling gene SNPs in keratoconus, Brit J Biomed Sci 2019, 77 (1), 13-18), Pterygium (Tsai, Y.-Y. et al., Effect of TIMP-1 and MMP in pterygium invasion, Invest Ophth Vis Sci 2010, 51 (7), 3462-3467), Corneal Ulcers (Garcia-Lopez, C. et al., The role of matrix metalloproteinases in infectious corneal ulcers, Surv Ophthalmol 2023, 68 (5), 929-939; Wong, Y. et al., Lipopolysaccharide regulation of toll-like receptor-4 and matrix metalloprotease-9 in human primary corneal fibroblasts, Invest Ophthalmol Vis Sci 2011, 52 (5), 2796-2803), contact lens related complications (Alghamdi, W. et al., The relationship between tear film MMP-9 and meibomian gland changes during soft contact lens wear, Cont Lens Anterior Eye 2020, 43 (2), 154-158), Conjunctivochalasis (Acera, A. et al., Tear MMP-9 levels as a marker of ocular surface inflammation in conjunctivochalasis, Invest Ophthalmol Vis Sci 2013, 54, 8285-8291), Lasik Surgery (Sambursky, R. et al., MMP-9 and the perioperative management of LASIK surgery, Curr Opin Ophthalmol 2011, 22 (4), 294-303) and Neurotrophic keratitis (Ghalibafan, S. et al., Efficacy of plasma rich in growth factors (PRGF) in stage 1 Neurotrophic Keratitis, Eye 2024, 38, 1390-1391).

[0028] Furthermore, if delivered to the retina, the use of MMP9 inhibitiors can also serve as a potential therapy for Age-related Macular Degeneration (AMD) (Sohn, E. A. et al., Genetic association between MMP9 and choroidal neovascularization in Age-relatedMacular Degeneration, Ophthalmol Sci 2021, 1 (1), 1-10; Lauwen, S. et al., Mol Vis 2021, 27, 142-150), and Diabetic Retinopathy (DR) (Kowluru, R. A. et al., Matrix metalloproteinases in diabetic retinopathy: Potential role of MMP-9, Expert Opin Inv Drug, 21 (6), 797–805; Giebel, S. J. et al., Matrix metalloproteinases in early Diabetic Retinopathy and their role in alteration of the blood-retinal barrier, Lab Invest 2005, 85 (5), 597-607; Mohammad, G. et al., Diabetic Retinopathy and signaling mechanism for activation of matrix metalloproteinase 9, J Cell Physiol 2012, 227 (3), 1052-1061).

[0029] There is a high need for new compounds, formulations, treatments and therapies to treat or prevent MMP9-mediated ocular diseases or disorders.

[0030] The chain of 11 amino acids AAi^AAn having between 5 / 11 to 10 / 11 sequence identity to Seq ID 1 is a chain of 11 amino acids wherein, when starting from Seq ID 1, 1 to 6 amino acids of Seq ID 1 have been independently replaced at 1 to 6 positions by 1 to 6 amino acids that are different from the amino acids at said positions of Seq ID 1, in particular 1, 2, 3, 4, 5 or 6 amino acids, corresponding respectively to 10 / 11, 9 / 11, 8 / 11, 7 / 11, 6 / 11 and 5 / 11 sequence identity to Seq ID 1.

[0031] The chain of 11 amino acids AAi^AAn of Seq ID 1 or having between 5 / 11 to 10 / 11 sequence identity to Seq ID 1 is represented from left to right, where the leftmost amino acid is AAi and the rightmost amino acid is AAn. Therefore, in Seq ID 1, AA1 is F and AAn is MeNle.

[0032] In the present description, natural amino acids are sometimes designated by their usual one-letter code or three-letter code, which are well-known to the person of ordinary skill in the art. For example, C or Cys for cysteine, F or Phe for phenylalanine, L or Leu for leucine, Y or Tyr for tyrosine, H or His for histidine, S or Ser for serine, R or Arg for arginine, N or Asn for asparagine, A or Ala for alanine, K or Lys for lysine, W or Trp for tryptophan, T or Thr for threonine, Q or Gin for glutamine, E or Glu for glutamic acid, D or Asp for aspartic acid and V or Vai for valine. It is understood that this doesn’t apply to the arbitrary denominations of the non-natural amino acids as defined below.

[0033] The invention thus further relates to:

[0034] A compound of formula (I) wherein the amino acids are independently selected from natural amino acids and non-natural amino acids;

[0035] A compound of formula (I) wherein the chain of 11 amino acids is of formula (II)

[0036] AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-AA10-AA11 (II)wherein AAi to AAn are independently selected from natural amino acids and non-natural amino acids;

[0037] A compound of formula (I) wherein the natual amino acids are independently selected from the amino acids F, L, Y, H, S, R, N, A, K, W, T, Q, E, D and V; and

[0038] A compound of formula (I) wherein the non-natual amino acids are independently selected from (abbreviations into brackets):

[0039] (MeNle)

[0040] N

[0041] ((CH3F)

[0042] ((CH3F)

[0043] N

[0044] (CNF)

[0045]

[0046] (CNF)

[0047] (CF3F)

[0048] ((NH2F)COF)

[0049] ((NH2F)CH2F)

[0050] ((NH2F)COF)

[0051] (OHY)

[0052] ((NH2F)CH2F)

[0053] (GuF)

[0054] (OHCH2F)

[0055]

[0056] (benzodioxolAla)

[0057] ((NH2F)F)

[0058] (NH2F)

[0059] (MeA)

[0060] (Mea)

[0061] (4FPro)

[0062] (4FPro)

[0063] (MeK)

[0064] (MeOrn)

[0065] (Bip)

[0066]

[0067] (2Nal)

[0068] (BzTzA)

[0069] ((NH2F)F)

[0070] (YCH2COOH)

[0071] (ClBip)

[0072] (PyF)

[0073] (MeOBip)

[0074] (YOCH2Ch)

[0075]

[0076] (YOPh)(AcNHF)

[0077] (CH3Bip)

[0078] (PyF) (PyA) (PyA)

[0079] (ClBip)

[0080] (ClPyF)

[0081]

[0082] (IF) f(CF3Bip)

[0083] ( / ? ClmPyA) (AcAEF) ( / zMeOmPyA) (3,3QA)

[0084]

[0085] (AcPiperazineF)o

[0086] (3PheF)

[0087] (pMeOmPyF)

[0088] (diMeAsn)

[0089] (MeAsn)

[0090] (MeF)

[0091] (MeE)

[0092] (MeChA)

[0093] o

[0094] H2N^AO„

[0095] (4TzA)

[0096] o

[0097] (Orn)

[0098]

[0099] (NPyrAsn)

[0100] (PrG) o (DiEtAsn)

[0101] (MeTrp)

[0102] (MeH)

[0103] (CF3F) (COOHF)

[0104] (PheO3F)

[0105] (CF3F) (OCHF2Bip)

[0106]

[0107] 0H2N\ iA OH

[0108] o n^Y^OH LA, N <^pyrazj-nylPhe)

[0109] ^IST

[0110] H2NrL Uy (pMeOBip)

[0111] I

[0112] HVOH

[0113] X_<y^x (pOHBip) ^-OH (NPipAsn)

[0114] (MeAoc)

[0115] (MeAHepc)

[0116]

[0117] OH (Acca)

[0118]

[0119] (PheNH3F)

[0120] (30HY)

[0121] (pCNBip)

[0122] (MecPeG)

[0123]

[0124] ( / ? EtOBip)

[0125] (MePheG)

[0126] ( / ? COOHCH2F) and

[0127] (4FPhe).

[0128]

[0129] The invention further relates in particular to:

[0130] A compound of formula (I) wherein AAi is F, A, mCF₃F, mCH₃F, / ? CH3F mCNF, CNF, mCF₃F, / 7CF3F, / 7NH2COF, pNH₂CH₂F, mNH₂COF, 4FPhe, mY or 30HY;

[0131] A compound of formula (I) wherein AAi is F, 777CF3F or 4FPhe;

[0132] A compound of formula (I) wherein AAi is F;

[0133] A compound of formula (I) wherein AA2is L, A, R, V, Om, D, E, hGlu, Aib, Acca, / ? COOHF, Api, bisOctanoicAcid or / ? COOHCH2F;

[0134] A compound of formula (I) wherein AA2is L, R, E, / ? COOHF, hGlu, Api, / ? COOHCH2F or bisOctanoicAcid;

[0135] A compound of formula (I) wherein AA2is L, R, / ? COOHF, hGlu, Api, / ? COOHCH2F or bisOctanoicAcid;

[0136] A compound of formula (I) wherein AA3 is Y, A, W, H, / 7 / OHY, / 7? (NH2F)CH2F, GuF, / ? OHCH2F, benzodi oxol Ala, / 7? (NH2F)F, mNH₂COF or / nY;A compound of formula (I) wherein AA3 is Y or / 77NH2CH2F;

[0137] A compound of formula (I) wherein AA3 is / 77NH2CH2F;

[0138] A compound of formula (I) wherein AA4 is MeNle, MeA, A, 4RFPro, 4SFPro, MeK, MeOrn, MeH, MeTrp, MeAoc, MecPeG, MeF, MeChA, MeAHepc, MePheG, MeChG or Mea;

[0139] A compound of formula (I) wherein AA4 is MeNle, MecPeG, MeAoc, MeChA, MeChG or MeAHepc;

[0140] A compound of formula (I) wherein AA4 is MeNle or MeAHepc;

[0141] A compound of formula (I) wherein AA5 is Y or A;

[0142] A compound of formula (I) wherein AA5 is Y;

[0143] A compound of formula (I) wherein AAe is Y, A, K, R, Bip, 2Nal,? CF3F,? CH3F,? CNF, BzTzA, / ? (NH2F)F, YCH2COOH, / ? ClBip, / ? PyF, oMeOBip, YOCH2Ch, YOPh, AcNHF, CH^Bip, mPyF, Py A, mPyA, mQBip, / j / CI PyF, CNBip, IF, mCFsBip, CFsBip, Cl / J / PyA, AcAEF, MeO / J / Py A, W, 3,3QA, AcPiperazineF, 3PheF, MeO / J / PyF, mOCHF2Bip, / ? PyrazynylPhe, / ? OCHF2Bip, / ? CF3PyrazynylpPhe, / ? OHBip, (4CF3)3PyPhe, PheO3F, PheNH3F, / zMeOBip, / zEtOBip or / ? OcPrBip;

[0144] A compound of formula (I) wherein AA6is Y, Bip, / ? ClBip, / ? PyF, / ? CH3Bip, mPyF, / ? CNBip, / ? CF3Bip, MeO / ? PyF, BzTzA, / ? PyrazynylPhe, / ? OCHF2Bip, / ? CF3PyrazynylpPhe, (4CF3)3PyPhe, / ? MeOBip, / ? OHBip, / ? EtOBip or / ? OcPrBip;

[0145] A compound of formula (I) wherein AA6is / ? PyF, / ? OCHF2Bip, / ? CH3Bip, / ? ClBip or / ? OcPrBip;

[0146] A compound of formula (I) wherein AA7 is H, A or Y;

[0147] A compound of formula (I) wherein AA7 is H or Y;

[0148] A compound of formula (I) wherein AA7 is H;

[0149] A compound of formula (I) wherein AAs is S, A, T, 4TzA, NPyrAsn or PrG;

[0150] A compound of formula (I) wherein AAs is S;

[0151] A compound of formula (I) wherein AA9 is R, A, H, E, hGlu, / ? COOHF, Api, or / ? COOHCH2F;A compound of formula (I) wherein AA9 is R, E, hGlu, Api, / ? COOHF or / 2COOHCH2F;

[0152] A compound of formula (I) wherein AA9 is R or hGlu;

[0153] A compound of formula (I) wherein AA10 is N, A, diMeAsn, Y, mNH₂COF, Q, / 2NH2COF, E, D, MeAsn, V, NPipAsn, NPyrAsn or diEtAsn;

[0154] A compound of formula (I) wherein AA10 is N, diMeAsn, D or diEtAsn;

[0155] A compound of formula (I) wherein AA10 is diMeAsn;

[0156] A compound of formula (I) wherein AAn is MeNle, A, MeA, 4RFPro, 4SFPro, MeF, MeE or MeChA;

[0157] A compound of formula (I) wherein AAn is MeNle or MeChA;

[0158] A compound of formula (I) wherein AAn is MeNle; and

[0159] A compound of formula (I) wherein R1and R2are both absent at the same time.

[0160] The invention thus also relates to a compound of formula (I-a)

[0161]

[0162] (La)

[0163] wherein AA1⌢AA11, NH* and C(O)* are as defined above.

[0164] The invention relates in particular to a compound of formula (I) wherein AA1⌢AA11is a chain of formula (III)

[0165] AA1-AA2-AA3-AA4-Y-AA6-AA7-AA8-AA9-AA10-AA11 (III)

[0166] wherein AA1to AA4and AA6to AA11are as defined above.

[0167] The invention relates in particular to a compound of formula (I) wherein AA1⌢AA11is a chain of formula (IV)AA1-AA2-AA3-AA4-AA5-AA6-H-AA8-AA9-AA10-AA11 (IV)

[0168] wherein AA1to AA6and AA8to AA11are as defined above.

[0169] The invention relates in particular to a compound of formula (I) wherein AA1⌢AA11is a chain of formula (V)

[0170] AA1-AA2-AA3-AA4-Y-AA6-H-AA8-AA9-AA10-AA11 (V)

[0171] wherein AA1to AA4, AA6and AA8to AA11are as defined above.

[0172] The invention thus relates to a compound of formula (I) wherein AA1to AA11, R1and R2each are selected from any of the above definitions.

[0173] The invention further relates to a compound selected from:

[0174] CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0175] CycloAc*-A-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0176] CycloAc*-mCH3F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0177] CycloAc*-pCH₃F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0178] CycloAc*- / wCNF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0179] CycloAc*-pCNF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0180] CycloAc*-mCF3F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0181] CycloAc*-pCF₃F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0182] CycloAc*-pNH₂COF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*- / ? (NH2F)CH2F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-m(NH2F)COF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-A-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0183] CycloAc*-F-R-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0184] CycloAc*-F-L-A-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0185] CycloAc*-F-L-W-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-H-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-mOHY-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-pGuF-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-pOHCH₂F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-benzodioxolAla-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)COF-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeA-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-Mea-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0186] CycloAc*-F-L-Y-A-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0187] CycloAc*-F-L-Y-4RFPro-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-4SFPro-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeK-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeOm-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-A-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-A-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-K-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-R-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-2Nal-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCF3F-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCH3F-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-pCNF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-BzTzA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-p(NH2F)F-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-YCH2COOH-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-oMeOBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-YOCH2Ch-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-YOPh-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pAcNHF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pPyA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mPyA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mClpPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCNBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pIF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mCF3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCF3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pClmPyA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-AcAEF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pMeOmPyA-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-W-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-3,3QA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-AcPiperazineF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-3PheF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pMeOmPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-A-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-Y-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-A-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-T-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-A-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-A-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-Y-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-m(NH2F)COF-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-Q-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-p(NH2F)COF-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-E-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-D-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-MeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-V-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-A-C*-CO(NH2F)

[0188] CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeA-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-4RFPro-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-4SFPro-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeF-C*-CO(NH2F)

[0189] CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeE-C*-CO(NH2F)

[0190] CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeChA-C*-CO(NH2F) CycloAc*-pCH3F-R-benzodioxolAla-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0191] CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-Y-Y-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-D-MeNle-C*-CO(NH2F)

[0192] CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0193] CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-

[0194]

[0195] CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0196] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-mCF3F-L-Y-MeNle-Y- / ? ClBip-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-mNH2CH2F-MeNle-Y-BzTzA-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-R-Y-MeNle-Y-mPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-mCNF-L-mNH2CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)

[0197] CycloAc*-mCNF-L-Y-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CONH2

[0198] CycloAc*-F-R-Y-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-mNH2CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*- CONH2

[0199] CycloAc*-F-L-Y-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*- CONH2

[0200] CycloAc*-F-V-Y-MeNle-Y-Y-H-4TzA-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-Y-Y-S-H-N-MeNle-C*-CONH2 CycloAc*-F-Orn-Y-MeNle-Y-Y-H-4TzA-R-N-MeNle-C*-CONH2 CycloAc*-F-V-Y-MeNle-Y-Y-H-NPyrAsn-R-N-MeNle-C*-CONH2 CycloAc*-F-V-Y-MeNle-Y-Y-H-PrG-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-SO2-CONH2CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-SO-CO(NH2F) CycloAc*-F-Asp-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-C

[0201]

[0202] ONH2 CycloAc*-F-Glu-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0203] CycloAc*-F-pCOOHF-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)

[0204] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-Glu-diMeAsn-MeNle-C*-CO(NH2F)

[0205] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle-C*-CO(NH2F)

[0206] CycloAc*-F-L-m(NH2F)CH2F-MeH-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0207] CycloAc*-F-L-mNH2CH2F-MeTrp-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0208] CycloAc*-F-L-mNH2CH2F-MeNle-Y-mOCHF2Bip-H-S-R-diMeAsn- MeNle-C*-CO(NH2F)

[0209] CycloAc*-4FPhe-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0210] CycloAc*-F-L-mNH2CH2F-MeAoc-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0211] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pPyrazynylPhe-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-

[0212]

[0213] CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-NPipAsn-MeNle-C*-CONH2

[0214] CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-NPyrAsn-MeNle-C*- CONH2

[0215] CycloAc*-F-Aib-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2

[0216] CycloAc*-F-Acca-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2

[0217] CycloAc*-F-Glu-m(NH2F)CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle-C*-CO(NH2F)

[0218] CycloAc*-mY-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0219] CycloAc*-3OHY-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)

[0220] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0221] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-pPyrazynylPhe-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0222] CycloAc*-F-pCOOHF-m(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0223] CycloAc*-F-pCOOHF-m(NH2F)CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-

[0224]

[0225] diMeAsn-MeNle-C*-CO(NH2F)

[0226] CycloAc*-F-pCOOHF-m(NH2F)CH2F-MeNle-Y-pPyrazynylPhe-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0227] CycloAc*-F-L-m(NH2F)CH2F-MecPeG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-L-mNH2CH2F-MeF-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2

[0228] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-pCF3PyrazynylpPhe-H-S-hGlu-d

[0229]

[0230] iMeAsn-MeNle-C*-CO(NH2F)

[0231] CycloAc*-F-hGlu-m(NH2F)CH2F-MeAoc-Y-pCF3PyrazynylpPhe-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0232] CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? OHBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0233] CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-pCH3Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0234] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-pCF3Bip-H-S-hGlu-diMeAsn-M

[0235]

[0236] eNle-C*-CO(NH2F)

[0237] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-(4CF3)3PyPhe-H-S-R-diMeAsn-MeNle-C*-CONH2

[0238] CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? CNBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0239] CycloAc*-F-Api-(NH2F)CH2F-MeNle-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0240] CycloAc*-F-pCOOHCH2F-m(NH2F)CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0241] CycloAc*-F-Api-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0242] CycloAc*-F-pCOOHCH2F-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0243] CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-Api-diMeAsn-MeNle-C*- CONH2

[0244] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-Api-diMeAsn-M

[0245]

[0246] eNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeChA-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CONH2

[0247] CycloAc*-F-bisOctanoicAcid- / 77(NH2F)CH2F-MeNle-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0248] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-pCOOHCH2F-diMeAsn-MeNle-C*-CO(NH2F)

[0249] CycloAc*-F-hGlu-(NH2F)CH2F-MeChA-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0250] CycloAc*-F-hGlu-(NH2F)CH2F-MeAHepc-Y-CNBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0251] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y- / ? CH3Bip-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)

[0252] CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-PheO3F-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0253] CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y- / ? OCHF2Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0254] CycloAc*-F-pCOOHF-m(NH2F)CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle-C*-CO(NH2F)

[0255] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pCF3PyrazynylpPhe-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0256] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-PheNH3F-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)

[0257] CycloAc*-F-L-mY-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0258] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y- / ? MeOBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0259] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pOHBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pEtOBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0260] CycloAc*-F-L-m(NH2F)CH2F-MePheG-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0261] CycloAc*-F-L- / w(NH2F)CH2F-MePheG-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0262] CycloAc*-F-hGlu-m(NH2F)CH2F-MeAoc-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0263] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0264] CycloAc*-F-hGlu-m(NH2F)CH2F-MeAoc-Y- / ? ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0265] CycloAc*-F-hGlu- / w(NH2F)CH2F-MeAHepc-Y- / ? OCHF2Bip-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F)

[0266] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S- / ? COOHCH2F-diMeAsn- MeNle-C*-CO(NH2F)

[0267] CycloAc*-F-Api-m(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0268] CycloAc*-F- / ? COOHCH2F- / w(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F)

[0269] CycloAc*-F-Api-m(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-Api-diMeAsn-MeNle- C*-CO(NH2F)

[0270] CycloAc*-F-pCOOHCH2F-m(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S- / ? COOHCH2F-diMeAsn-MeNle-C*-CO(NH2F)

[0271] CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-R-diMeAsn-MeChA-C*- CO(NH2F)

[0272] CycloAc*-F-L- / w(NH2F)CH2F-MeChG-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-L- / 7? (NH2F)CH2F-MeNle-Y-pOcPrBip-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)

[0273] CycloAc*-F-hGlu-m(NH2F)CH2F-MecPeG-Y- / ? ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0274] CycloAc*-F-hGlu- / 7? (NH2F)CH2F-MeNle-Y-(4CF3)3PyPhe-H-S-hGlu-

[0275]

[0276] diMeAsn-MeNle-C*-CO(NH2F)

[0277] CycloAc*-F-hGlu- / w(NH2F)CH2F-MeNle-Y- / ? CNBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0278] CycloAc*-F-hGlu-m(NH2F)CH2F-MeAHepc-Y- / ? ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0279] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y- / ? EtOBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0280] CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-DiEtAsn-MeNle-C*- CO(NH2F)

[0281] CycloAc*-F-Api- / w(NH2F)CH2F-MeAHepc-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F) and

[0282] CycloAc*-F- / ? COOHCH2F-m(NH2F)CH2F-MeAHepc-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F);

[0283] or a pharmaceutically acceptable salt thereof;

[0284] wherein

[0285]

[0286] C*-CO(NH2F) denotes the fragment

[0287]

[0288] C*-SOCO(NH2F) denotes the fragment

[0289]

[0290] C*-SO2CO(NH2F) denotes the fragment,Ac* denotes the fragment C(0)-CH2; and

[0291] Cyclo denotes both at the same time (i) a covalent bond between the carbon of the CH2 group of the Ac* fragment and the sulfur atom of the C*-C0NH2, C*-SOCONH2 or C*-SO2CO(NH2F) fragment and (ii) a covalent bond between the carbonyl of the Ac* fragment and the α-NH group of the adjacent amino acid in the sequence, thereby forming a cyclic polypeptide.

[0292] In the above definition of Cyclo, said adjacent amino acid is thus AAi.

[0293] The invention further relates to a compound of formula (I) selected from

[0294] CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0295] CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F)

[0296] CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F)

[0297] CycloAc*-F-L-Y-MeNle-Y-pPyF-H-S-R-N-MeNle-C*-CO(NH2F)

[0298] CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F)

[0299] CycloAc*-F-L-Y-MeNle-Y-mPyF-H-S-R-N-MeNle-C*-CO(NH2F)

[0300] CycloAc*-F-L-Y-MeNle-Y-pCNBip-H-S-R-N-MeNle-C*-CO(NH2F)

[0301] CycloAc*-F-L-Y-MeNle-Y-pCF3Bip-H-S-R-N-MeNle-C*-CO(NH2F)

[0302] CycloAc*-F-L-Y-MeNle-Y- / ? MeOmPyF-H-S-R-N-MeNle-C*-CO(NH2F)

[0303] CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0304] CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2

[0305] CycloAc*-F-R-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0306] CycloAc*-F-R-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0307] CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0308] CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0309] CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-D-MeNle-C*-CO(NH2F)

[0310] CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-L-mNH2CH2F-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-mCF3F-L-Y-MeNle-Y- / ? ClBip-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F)

[0311] CycloAc* -F-R-Y-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C* -CO(NH2F)

[0312] CycloAc*-F-R-mNH2CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-Glu-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F- / ? COOHF-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0313] CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-Glu-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S- / ? COOHF-diMeAsn-MeNle-C*- CONH2

[0314] CycloAc*-4FPhe-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-pPyrazynylPhe-H-S-R-diMeAsn-MeNle-C*-CONH2

[0315] CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-NPipAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-NPyrAsn-MeNle-C*-CONH2 CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-pCOOHF-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0316] CycloAc*-F-L-mNH2CH2F-MecPeG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeNle-Y- / 2CF3PyrazynylpPhe-H-S-hGlu-diMeAsn- M

[0317]

[0318] eNle-C*-CO(NH2F) CycloAc*-F-hGlu-m(NH2F)CH2F-MeAoc-Y- / ? CF3PyrazynylpPhe -H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)

[0319] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y- / ? CH3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)

[0320] CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y- / ? CF3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2

[0321] CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-(4CF3)3PyPhe-H-S-R-diMeAsn-MeNle-C*- CONH2

[0322] CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? CNBip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-Api-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0323] CycloAc*-F-pCOOHCH2F-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0324] CycloAc*-F-Api-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F- / ? COOHCH2F-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2

[0325] CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-Api-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-Api-diMeAsn-MeNle-C*- CONH2

[0326] CycloAc*-F-L-mNH2CH2F-MeChA-Y- / ? ClBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0327] CycloAc*-F-bisOctanoicAcid- / 77(NH2F)CH2F-MeNle-Y- / 2OCHF2Bip-H-S-hGlii-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu- / 7? (NH2F)CH2F-MeNle-Y-pCdBip-H-S-pCOOHCH2F-diMeAsn- MeNle-C*-CO(NH2F)

[0328] CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? CH3Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F) CycloAc*-F-L-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F) CycloAc*-F-COOHF-(NH2F)CH2F-MeNle-Y-Bip-H-S-COOHF-diMeAsn-MeNle-

[0329]

[0330] C*-CO(NH2F)

[0331] CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? CF3PyrazynylpPhe-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)

[0332] CycloAc*-F-L-mY-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? MeOBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0333] CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? OHBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? EtOBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0334] CycloAc*-F-hGlu-mNH2CH2F-MeAoc-¥- / ? OCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0335] CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2

[0336] CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeAoc-Y- / 2CdBip-H-S-hGlii-diMeAsn-MeNle-C*- CONH2

[0337] CycloAc*-F-hGlu-m(NH2F)CH2F-MeAHepc-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- M

[0338]

[0339] eNle-C*-CO(NH2F)

[0340] CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S- / ? COOHCH2F-diMeAsn-MeNle-C*- CONH2

[0341] CycloAc*-F-Api-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2CycloAc*-F- / 7COOHCH2F- / 7? (NH2F)CH2F-MeNle-Y- / 7ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0342] CycloAc*-F-Api- / 7? (NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-Api-diMeAsn-MeNle-C*-CO(NH2F)

[0343] CycloAc*-F- / 7COOHCH2F- / 7? (NH2F)CH2F-MeNle-Y- / 7ClBip-H-S- / iCOOHCH2F-diMeAsn-MeNle-C*-CO(NH2F)

[0344] CycloAc*-F-L-777(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-R-diMeAsn-MeChA-C*-CO(NH2F) CycloAc*-F-L- / 77(NH2F)CH2F-MeChG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)

[0345] CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y-pOcPrBip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0346] CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeAHepc-Y- / ? ClBip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0347] CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y-Bip-H-S-R-DiEtAsn-MeNle-C*-CO(NH2F) CycloAc*-F-Api-777(NH2F)CH2F-MeAHepc-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F) and

[0348] CycloAc*-F- / ? COOHCH2F-mNH2CH2F-MeAHepc-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F);

[0349] or a pharmaceutically acceptable salt thereof;.

[0350] wherein -C*-CO(NH2F), Ac* and Cyclo are as defined above.

[0351] The invention further relates to a compound of formula (I) selected from CycloAc*-F-R-777(NH2F)CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu- / 7? (NH2F)CH2F-MeNle-Y- / 7OCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0352] CycloAc*-F- / ? COOHF-777(NH2F)CH2F-MeNle-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0353] CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeNle-Y- / 7CH3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? CF3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)

[0354] CycloAc*-F-Api- / 77NH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C

[0355]

[0356] *-CO(NH2F) CycloAc*-F-pCOOHCH2F-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0357] CycloAc*-F-bisOctanoicAcid-mNH2CH2F-MeNle-Y- / ? OCHF2Bip-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F)

[0358] CycloAc*-F-L-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0359] CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)

[0360] CycloAc*-F-hGlu-mNH2CH2F-MeAHepc-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0361] CycloAc*-F-Api-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2

[0362] CycloAc*-F- / ? COOHCH2F-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0363] CycloAc*-F-L-mNH2CH2F-MeNle-Y-pOcPrBip-H-S-R-diMeAsn-MeNle-C*- CONH2 and

[0364] CycloAc*-F-Api-mNH2CH2F-MeAHepc-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F);

[0365] or a pharmaceutically acceptable salt thereof;

[0366] wherein -C*-C0NH2, Ac* and Cyclo are as defined above.

[0367] The chemical formula and chemical name of each individual compound mentioned above are given in Tables lb and 1c.

[0368] The invention also relates to a process for the preparation of a compound of formula (I) comprising the following step (a) and optionally step (b):(a) the reaction of a compound of formula (A)

[0369]

[0370] in the presence of a base;

[0371] to arrive at a compound of formula (I) as defined above wherein R1and R2are both absent at the same time; and optionally

[0372] (b) the reaction of a compound of formula (I) as defined above wherein R1and R2are both absent at the same time with an oxidizing agent to arrive at a compound of formula (I) as defined above wherein one of R1and R2is absent and the other one is oxygen or wherein R1and R2are both oxygen at the same time;

[0373] wherein [AA]n denotes the chain of 11 amino acids as defined above.

[0374] In the process of the invention, the base can be advantageously a tertiary amine, for example diisopropylethylamine (DIPEA).

[0375] The process of the invention can be advantageously carried out in a solvent like a mixture of acetonitrile and water.

[0376] The oxidizing agent can be for example hydrogen peroxide.

[0377] The reaction time of step (b) can be adjusted by a person of ordinary skill in the art to arrive at the sulfone (one of R1and R2is absent and the other one is oxygen) or the sulfoxide (R1and R2are both oxygen at the same time) analogue. For example, between around 10 min and around 1 hour, more parti culary around 30 minutes for the sulfoxide; between around 12 hours and around 48 hours, more particularly around 16 hours for the sulfone.

[0378] The invention further relates to:

[0379] A compound of formula (I) when manufactured according to a process according to the invention;

[0380] A compound of formula (I) for use as therapeutically active substance;

[0381] A pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier;The use of a compound of formula (I) for the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age-related Macular Degeneration (AMD) or diabetic retinopathy (DR);

[0382] The use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age-related Macular Degeneration (AMD) or diabetic retinopathy (DR);

[0383] A compound of formula (I) for use in the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age-related Macular Degeneration (AMD) or diabetic retinopathy (DR); and

[0384] A method for the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age-related Macular Degeneration (AMD) or diabetic retinopathy (DR), which method comprises administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0385] The synthesis of the compound of formula (I) follows the standard approach for Fmoc based Solid Phase Peptide Synthesis (SPPS), followed by appropriate derivatization and cyclisation under suitable conditions to afford the desired macrocyclic peptide of formula (I). Suitable non-natural amino acids are incorporated in the appropriate positions with the goal to modulate both the inhibitory potency against the target enzyme as well as the molecular properties of these compounds that enable for example topical ocular delivery via eye drop formulations or similar.

[0386] The compound of the present invention is particularly useful for the treatment or prophylaxis of front of the eye diseases (ocular surface diseases), more particularly Dry Eye Disease (DED).The linear peptide synthesis approach based on Fmoc chemistry and compatible amino acid side chain protecting groups (PGs are usually tert-Butyl, trityl, BOC or Pbf) is outlined in Scheme 1 according to procedures known in the art. The synthesis starts with coupling of suitably protected Cys to the Rink Amide solid support. Hereby, coupling of the suitably protected amino acid can be usually done in the presence of DIC and oxyma in DMF under microwave irradiation at a suitably elevated temperature. Then, the N-terminal Fmoc group is removed with 20% piperidine in DMF. Following a washing step, the coupling / deprotection sequences are repeated with the appropriate natural and unnatural amino acids to assemble the desired peptide sequence. In case of certain (also unnatural) amino acids which may lead to a more difficult coupling, a particular coupling step may be repeated several times with additional equivalents of the activated monomer. For example, double couplings were usually performed for the amino acid after an N-methylamino acid and for Arg. Suitable amino acids for sequence assembly comprise: 1) natural and unnatural amino acids with natural L-configuration (Ra= amino acid side chain, optionally with suitable protection PG, Rb = H; 2) amino acids with natural and unnatural side chains with D-configuration (Rb = amino acid side chain, optionally with suitable protection PG, Ra = H); 3) a,a-di-substituted amino acids where Raand Rb are both side chains and not H, or forming a ring; and 4) Re is independently either H or alkyl such as Me or Et, as outlined in the list of non-natural amino acids above. After complete assembly of the sequence, following removal of the N-terminal Fmoc group at the standard condition mentioned above, the N-term is then capped by treatment with chloroacetic acid anhydride to introduce the appropriate functionality enabling subsequent cyclization in solution.

[0387] The latter step concludes the linear peptide synthesis on the solid support and the linear peptide can be cleaved and simultaneously deprotected by treatment with TFA in the presence of suitable scavengers such as for example phenol and TIPS. Cyclization to the macrocycle is then ususally achieved by treatment with DIPEA in a mixture of ACN and water, followed by purification by preparative reverse-phase HPLC using various protocols. Initially, the purified cyclic peptide is commonly obtained as a TFA salt, whose stoichiometry depends on the sequence.DIG, oxyma,

[0388] O DMF, microwave NHFmoc HO

[0389]

[0390] Rink Amide AM '" STrt

[0391]

[0392] resin

[0393] piperidine DIG, oxyma, 20% in DMF R<

[0394] DMF, microwave O NFmoc " N H

[0395] (PG)Rf Ra(PG) C* AA^

[0396]

[0397] deprotection / Rc (PG)

[0398] coupling cycles TrtS (PG)

[0399] O (PG)

[0400] NH— AA V10- AA— -AA,— N H

[0401] "'N 2

[0402] O

[0403] (PH

[0404]

[0405] G)Rb* Ra(PG)

[0406] C* AA^

[0407] chloroacetic acid (PG) (PG) anhydride I

[0408] N - AA10AA,— N

[0409] (PG)Rb' Ra(PG)

[0410]

[0411] C* AA„

[0412] TFA, H2O

[0413] TIPS, phenol

[0414]

[0415] C* AA„

[0416] DIPEA ACN, H2O

[0417]

[0418] C* AA„Scheme 1: General procedure for the synthesis of the compound of formula (I). AAi and AAn are as defined in the present description. [AA]nrepresents the seqeunce AA2-AA9 as defined in the present description. Ra, Rb are independently the side chains of the natural or non-natural amino acids of the present invention, optionally protected by (PG). (PG) represents an optional protecting group, depending on the amino acid side chain and the synthetic conditions applied. Such resulting protected amino acids are for example as indicated in Table 2. Re is hydrogen or alkyl, such as methyl or ethyl, in particular as defined in the list of non-natural amino acids of the invention.

[0419] Oxidation of the thioether to form either a sulfoxide or the sulfone (a compound of formula (I) wherein one of R1and R2is oxygen and the other one is absent, or wherein R1and R2are both oxygen at the same time), is possible by treatment with a suitable amount of an oxidizing agent such as for example hydrogen peroxide and by using an appropriate reaction time. For example between around 10 min and around 1 hour, more parti culary around 30 minutes for the sulfoxide (one of R1and R2is oxygen and the other one is absent), and between around 12 hours and around 48 hours, more particularly 16 hours for the sulfone (R1and R2are both oxygen at the same time).

[0420] The term “pharmaceutically acceptable salt” therefore refers to those salts and more generally to salts which retain biological effectiveness and properties and which are not biologically or otherwise undesirable. The salts are formed depending on the composition of the amino acid side chains with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions.

[0421] Depending on the nature of the amino acid side chains in the individual peptide sequences, salt exchanges are possible that introduce other counterions than the counterion obtained during the preparation of the compound of formula (I). During the synthesis, thecompound of formula (I) is usually obtained as a TFA salt but other salts may often be more desirable. Examples of such alternative salt forms include, among others, for example chloride salts (by treatment with HC1) for basic side chains, or sodium salts (by treatment with NaHCCh), or similar, for acidic amino acid side chains.

[0422] The sodium salt of the compound of formula (I) as defined above is thus a particular object of the invention.

[0423] The compound of the invention acts as a potent inhibitor of MMP9 and with a good selectivity profile against some other MMPs, superior to the one of classical small molecule MMP9 inhibitors. The compound of the invention can therefore be used as therapeutic agents for example for ocular surface diseases such as DED and is particularly suitable for topical ocular application in eye drop formulations.

[0424] Further structure activity relationship (SAR) studies at the different positions of the macrocycle sequences were conducted. In particular, individual mutations showing improved MMP9 activity / selectivity profiles were combined to afford improved MMP9 potency, better solubility enabling topical ocular application in the form of eyedrops at higher concentrations and particularly at more neutral pH, and a narrower selectivity pattern against related MMP targets. It has to be noted in this context, that despite better selectivity against related human MMPs, many particular compounds of the invention are still very active on mouse MMP9, which enables profiling of selected and suitable molecules in in vivo mouse models of DED. Furthermore, some compounds according to the invention can exhibit prolonged enzymatic residence times (low off rates) resulting in prolonged enzymatic inhibition.

[0425] The macrocycle of Seq ID 2 demonstrated good activity. Through mutations of the macrocycle of Seq ID 2 at various positions, a big improvement on MMP9 inhibitory activity could be observed. Selectivity over a panel of MMPs was improved with mutations at positions 1, 3 and 10, respectively. By combining mutants at positions 1, 3, 6 and 10 it was possible to identify peptide sequences with: 1) IC50 on MMP9 <10 nM; 2) good specificity for example vs. MMP10 and MMP14; and 3) considerably improved aqueous solubility as a better basis for aqueous eye drop formulations. In addition, some of the most potent molecules exhibited low enzymatic off-rates (kofr) as mentioned above.

[0426]

[0427] Scheme 2: Schematic notation of the compound of formula (I) used in Table 1 and in the present description.

[0428] Examples of the compound of formula (I) are shown in Table la. The Seq ID of the corresponding amino acid sequence present in the 12-mer is indicated for each example.

[0429] The term CycloAc* represents an acetyl (-C(O)CH2-) bridge between the alpha-NEE of AAi (the N terminus) and the sulfur atom of the modified cysteine -C*-CONH2 as depicted in Scheme 2. The amino acids in Table la which are underlined represent either single mutations or combinations of mutations of Seq ID 2.

[0430] Srq II) I. XiillipIr Sequence

[0431] 2 1 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0432] 3 2 CycloAc*-A-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0433] 4 3 CycloAc*-»7CH3F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 5 4 CycloAc*-£CH3E-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 6 5 CycloAc*-»7CNE-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 7 6 CycloAc*-£CNE-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 8 7 CYcloAc*-wCF3F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 9 8 CycloAc*-£CF3F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 10 9 CvcloAc*-p(NH2F)COF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 11 10 CvcloAc*-p(NH2F)CH2F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 12 11 CvcloAc*-w(NH2F)COF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 13 12 CycloAc*-F-A-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0434] 14 13 CycloAc*-F-R-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)

[0435] 15 14 CycloAc*-F-L-A-MeNle-Y-Y-H-S-R-N-MeNle-C*-CONH

[0436]

[0437] 2Sv<| 11) l.xumplv Sequence

[0438] 16 15 CycloAc*-F-L-W-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 17 16 CycloAc*-F-L-H-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 18 17 CvcloAc*-F-L-mOHY-MeNle-Y-Y-H-S-R-N-MeNle-C*-CONH? 19 18 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 20 19 CycloAc*-F-L-£GuF-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 21 20 CvcloAc*-F-L-pOHCH₂F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 22 21 CvcloAc*-F-L-benzodioxolAla-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 23 22 CycloAc*-F-L-»7(NH2F)F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 24 23 CvcloAc*-F-L-iw(NH2F)COF-MeNle-Y-Y-H-S-R-N-MeNle-C*-CONH? 25 24 CycloAc*-F-L-Y-MeA-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 26 25 CycloAc*-F-L-Y-Mea-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 27 26 CycloAc*-F-L-Y-A-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 28 27 CvcloAc*-F-L-Y-4RFPro-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 29 28 CvcloAc*-F-L-Y-4SFPro-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 30 29 CvcloAc*-F-L-Y-MeK-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 31 30 CvcloAc*-F-L-Y-MeOm-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) 32 31 CycloAc*-F-L-Y-MeNle-A-Y-H-S-R-N-MeNle-C*-CO(NH2F) 33 32 CycloAc*-F-L-Y-MeNle-Y-A-H-S-R-N-MeNle-C*-CO(NH2F) 34 33 CycloAc*-F-L-Y-MeNle-Y-K-H-S-R-N-MeNle-C*-CO(NH2F) 35 34 CycloAc*-F-L-Y-MeNle-Y-R-H-S-R-N-MeNle-C*-CO(NH2F) 36 35 CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) 37 36 CycloAc*-F-L-Y-MeNle-Y-2Nal-H-S-R-N-MeNle-C*-CO(NH2F) 38 37 CycloAc*-F-L-Y-MeNle-Y-£CF3F-H-S-R-N-MeNle-C*-CO(NH2F) 39 38 CycloAc*-F-L-Y-MeNle-Y-pCH3F-H-S-R-N-MeNle-C*-CO(NH2F) 40 39 CvcloAc*-F-L-Y-MeNle-Y-pCNF-H-S-R-N-MeNle-C*-CO(NH2F) 41 40 CvcloAc*-F-L-Y-MeNle-Y-BzTzA-H-S-R-N-MeNle-C*-CO(NH2F) 42 41 CvcloAc*-F-L-Y-MeNle-Y-p(NH2F)F-H-S-R-N-MeNle-C*-CO(NH2F) 43 42 CvcloAc*-F-L-Y-MeNle-Y-YCH2COOH-H-S-R-N-MeNle-C*-CO(NH2F) 44 43 CycloAc*-F-L-Y-MeNle-Y-£ClBi2-H-S-R-N-MeNle-C*-CO(NH2F) 45 44 CycloAc*-F-L-Y-MeNle-Y2gPyF-H-S-R-N-MeNle-C*-CO(NH2F) 46 45 CvcloAc*-F-L-Y-MeNle-Y-oMeOBip-H-S-R-N-MeNle-C*-CO(NH2F) 47 46 CvcloAc*-F-L-Y-MeNle-Y-YOCH2Ch-H-S-R-N-MeNle-C*-CO(NH2F) 48 47 CycloAc*-F-L-Y-MeNle-Y-YOPh-H-S-R-N-MeNle-C*-CO(NH2F) 49 48 CvcloAc*-F-L-Y-MeNle-Y-pAcNHF-H-S-R-N-MeNle-C*-CO(NH2F) 50 49 CvcloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F) 51 50 CvcloAc*-F-L-Y-MeNle-Y-wiPvF-H-S-R-N-MeNle-C*-CONH

[0439]

[0440] 2Sv<| 11) l.xumplv Sequence

[0441] 52 51 CycloAc*-F-L-Y-MeNle-Y-pPvA-H-S-R-N-MeNle-C*-CONH7 53 52 CvcloAc*-F-L-Y-MeNle-Y-w7PvA-H-S-R-N-MeNle-C*-CONH7 54 53 CvcloAc*-F-L-Y-MeNle-Y-wiClBip-H-S-R-N-MeNle-C*-CO(NH2F) 55 54 CvcloAc*-F-L-Y-MeNle-Y-w7ClpPvF-H-S-R-N-MeNle-C*-CONH7 56 55 CycloAc*-F-L-Y-MeNle-Y-pCNBip-H-S-R-N-MeNle-C*-CONH7 57 56 CycloAc*-F-L-Y-MeNle-Y-£lF-H-S-R-N-MeNle-C*-CO(NH2F) 58 57 CvcloAc*-F-L-Y-MeNle-Y-wiCF3Bip-H-S-R-N-MeNle-C*-CO(NH2F) 59 58 CvcloAc*-F-L-Y-MeNle-Y-pCF3Bip-H-S-R-N-MeNle-C*-CONH? 60 59 CvcloAc*-F-L-Y-MeNle-Y-pClmPyA-H-S-R-N-MeNle-C*-CONH? 61 60 CycloAc*-F-L-Y-MeNle-Y-AcAEF-H-S-R-N-MeNle-C*-CO(NH2F) 62 61 CvcloAc*-F-L-Y-MeNle-Y-pMeOw7PvA-H-S-R-N-MeNle-C*-CO(NH2F) 63 62 CycloAc*-F-L-Y-MeNle-Y-W-H-S-R-N-MeNle-C*-CO(NH2F) 64 63 CvcloAc*-F-L-Y-MeNle-Y-3.3QA-H-S-R-N-MeNle-C*-CO(NH2F) 65 64 CvcloAc*-F-L-Y-MeNle-Y-AcPiperazineF-H-S-R-N-MeNle-C*-CO(NH2F) 66 65 CvcloAc*-F-L-Y-MeNle-Y-3PheF-H-S-R-N-MeNle-C*-CO(NH2F) 67 66 CvcloAc*-F-L-Y-MeNle-Y-pMeOw7PvF-H-S-R-N-MeNle-C*-CO(NH2F) 68 67 CycloAc*-F-L-Y-MeNle-Y-Y-A-S-R-N-MeNle-C*-CO(NH2F) 69 68 CycloAc*-F-L-Y-MeNle-Y-Y-Y-S-R-N-MeNle-C*-CO(NH2F) 70 69 CycloAc*-F-L-Y-MeNle-Y-Y-H-A-R-N-MeNle-C*-CO(NH2F) 71 70 CycloAc*-F-L-Y-MeNle-Y-Y-H-T-R-N-MeNle-C*-CO(NH2F) 72 71 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-A-N-MeNle-C*-CO(NH2F) 73 72 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-A-MeNle-C*-CO(NH2F) 74 73 CvcloAc*-F-L-Y-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 75 74 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-Y-MeNle-C*-CO(NH2F) 76 75 CvcloAc*-F-L-Y-MeNle-Y-Y-H-S-R-w(NH2F)COF-MeNle-C*-CO(NH2F) 77 76 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-2-MeNle-C*-CO(NH2F) 78 77 CvcloAc*-F-L-Y-MeNle-Y-Y-H-S-R-p(NH2F)COF-MeNle-C*-CO(NH2F) 79 78 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-E-MeNle-C*-CO(NH2F) 80 79 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-D-MeNle-C*-CO(NH2F) 81 80 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-MeAsn-MeNle-C*-CO(NH2F) 82 81 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-V-MeNle-C*-CO(NH2F) 83 82 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-A-C*-CO(NH2F) 84 83 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeA-C*-CO(NH2F) 85 84 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-4RFPrp-C*-CO(NH2F) 86 85 CvcloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-4SFPro-C*-CONH? 87 86 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeF-C*-CONH

[0442]

[0443] 2Sv<| 11) l.xumplv Sequence

[0444] 88 87 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeE-C*-CO(NH2F)

[0445] 89 88 CvcloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeChA-C*-CONH?

[0446] 90 89 CvcloAc*-pCH3F-R-benzodioxolAla-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0447] 91 90 CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 92 91 CYcloAc*-F-R-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CONH7 93 92 CvcloAc*-F-R-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CONH? 94 93 CvcloAc*-F-R-Y-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CONH? 95 94 CycloAc*-F-R-Y-MeNle-Y-Y-Y-S-R-N-MeNle-C*-CO(NH2F)

[0448] 96 95 CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) 97 96 CvcloAc*-F-R-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F) 98 97 CycloAc*-F-R-Y-MeNle-Y-^PyF-H-S-R-N-MeNle-C*-CO(NH2F) 99 98 CvcloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 100 99 CvcloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 101 100 CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 102 101 CvcloAc*-F-L-Y-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 103 102 CvcloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-D-MeNle-C*-CO(NH2F) 104 103 CvcloAc*-F-L-w7(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 105 104 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 106 105 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 107 106 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 108 107 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) 109 108 CvcloAc*-w7CF3F-L-Y-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) 110 109 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) 111 110 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-BzTzA-H-S-R-N-MeNle-C*-CO(NH2F) 112 111 CvcloAc*-F-R-Y-MeNle-Y-iwPvF-H-S-R-diMeAsn-MeNle-C*-CONH? 113 112 CvcloAc*-wCNF-L-w(NH2F)CH2F-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0449] 114 113 CvcloAc*-wCNF-L-Y-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CONH2 115 114 CvcloAc*-F-R-Y-MeNle-Y-pPvF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 116 115 CvcloAc*-F-R-w(NH2F)CH2F-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 117 116 CvcloAc*-F-L-Y-MeNle-Y-pPvF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 118 117 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 119 118 CvcloAc*-F-V-Y-MeNle-Y-Y-H-4TzA-R-N-MeNle-C*-CO(NH2F) 120 119 CycloAc*-F-L-Y-MeNle-Y-Y-Y-S-H-N-MeNle-C*-CO(NH2F)

[0450] 121 120 CvcloAc*-F-Om-Y-MeNle-Y-Y-H-4TzA-R-N-MeNle-C*-CO(NH2F) 122 121 CvcloAc*-F-V-Y-MeNle-Y-Y-H-NPyrAsn-R-N-MeNle-C*-CO(NH2F) 123 122 CycloAc*-F-V-Y-MeNle-Y-Y-H-PrG-R-N-MeNle-C*-CONH

[0451]

[0452] 2Sv<| 11) l.xumplv Sequence

[0453] 124 123 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-SO2-CO(NH2F) 125 124 CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-SO-CO(NH2F) 235 125 CycloAc*-F-Asp-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 236 126 CvcloAc*-F-Glu-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 237 127 CvcloAc*-F-pCOOHF-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0454] 238 128 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-Glu-diMeAsn-MeNle-C*-CO(NH2F) 239 129 CvcloAc*-F-L-w7(NH2F)CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle-C*- CO(NH2F)

[0455] 240 130 CvcloAc*-F-L-w(NH2F)CH2F-MeH-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 241 131 CvcloAc*-F-L-w(NH2F)CH2F-MeTrp-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 242 132 CvcloAc*-F-L-7w(NH2F)CH2F-MeNle-Y-7wOCHF2Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0456] 243 133 CycloAc*-4FPhe-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0457] 244 134 CycloAc*-F-L-w(NH2F)CH2F-MeAoc-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 245 135 Cyclo Ac *-F -L -W(NH2F)CH2F -MeNle- Y -pPyrazynylPhe-H- S -R-diMeAsn-MeNle-C* - CO(NH2F)

[0458] 246 136 CycloAc*-F-hGlu-w(NH2F)CH2F -MeNle- Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 247 137 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F) 248 138 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-NPipAsn-MeNle-C*-CO(NH2F) 249 139 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-NPyrAsn-MeNle-C*-CO(NH2F) 250 140 CvcloAc*-F-Aib-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 251 141 CvcloAc*-F-Acca-7w(NH2F)CH2F -MeNle- Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 252 142 CycloAc*-F-Glu-w(NH2F)CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle-C*- CO(NH2F)

[0459] 253 143 CvcloAc*-mY-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 254 144 CvcloAc*-3OHY-L-wi(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)

[0460] 255 145 CvcloAc*-F-hGlu-wi(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)

[0461] 256 146 CvcloAc*-F-hGlu-w(NH2F)CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0462] 257 147 CycloAc*-F -hGlu-w(NH2F)CH2F -MeNle- Y -pPyrazynylPhe-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0463] 258 148 CvcloAc*-F-pCOOHF-w(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)

[0464] 259 149 CvcloAc*-F-pCOOHF-7w(NH2F)CH2F -MeNle- Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0465] 260 150 CvcloAc*-F-pCOOHF-w(NH2F)CH2F-MeNle-Y-pPyrazynylPhe-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0466] 261 151 CvcloAc*-F-L-w(NH2F)CH2F-MecPeG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 262 152 CvcloAc*-F-L-w(NH2F)CH2F-MeF-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) 263 153 CycloAc*-F -hGlu-7w(NH2F)CH2F -MeNle- Y -pCF sPyrazyny IpPhe-14-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0467] 264 154 CycloAc*-F -hGlu-7w(NH2F)CH2F -MeAoc- Y - pCF sPyrazy nylpPhe -H-S-hGlu-

[0468]

[0469] diMeAsn-MeNle-C*-CO(NH2F)Sv<| 11) l.xumplv Sequence

[0470] 265 155 CvcloAc*-F-hGlu-wNH7CH7F-MeNle-Y-pOHBip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)

[0471] 266 156 CYcloAc*-F-hGlu-wNH7CH7F-MeNle-Y-pCH3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2

[0472] 267 157 CvcloAc*-F-hGlu-w7NH2. CH2F-MeNle-Y-pCF3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2

[0473] 268 158 CYcloAc*-F-L-w7(NH2F)CH2F-MeNle-Y-(4CF3)3PvPhe-H-S-R-diMeAsn-MeNle-C*- CONH2

[0474] 269 159 CvcloAc*-F-L-w7NH2. CH2F-MeNle-Y-pCNBip-H-S-R-diMeAsn-MeNle-C*-CONH2 270 160 CvcloAc*-F-Api-w7NH2. CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0475] 271 161 CvcloAc*-F-pCOOHCH2F-wNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F)

[0476] 272 162 CvcloAc*-F-Api-w7NH2. CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 273 163 CvcloAc*-F-pCOOHCH2F-wNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0477] 274 164 CvcloAc*-F-L-w7NH2. CH2F-MeNle-Y-Bip-H-S-Api-diMeAsn-MeNle-C*-CONH2 275 165 CvcloAc*-F-hGlu-wNH2CH2F-MeNle-Y-pClBip-H-S-Api-diMeAsn-MeNle-C*- CONH2

[0478] 276 166 CvcloAc*-F-L-w7NH2. CH2F-MeChA-Y- pClBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0479] 277 167 CvcloAc*-F-bisOctanoicAcid-wNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F)

[0480] 278 168 CvcloAc*-F-hGlu-wNH2CH2F-MeNle-Y-pClBip-H-S-pCOOHCH2F-diMeAsn- MeNle-C*-CO(NH2F)

[0481] 279 169 CvcloAc*-F-hGlu-w7NH2. CH2F-MeChA-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2

[0482] 280 170 CvcloAc*-F-hGlu-w7NH2. CH2F-MeAHepc-Y-pCNBip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0483] 281 171 CvcloAc*-F-L-wNH2CH2F-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0484] 282 172 CvcloAc*-F-L-w7NH2. CH2F-MeNle-Y-PheO3F-H-S-R-diMeAsn-MeNle-C*-CONH2 283 173 CvcloAc*-F-L-w7NH2. CH2F-MeNle-Y-pOCHF2Bip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0485] 284 174 CvcloAc*-F-pCOOHF-w7NH2. CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle- C*-CO(NH2F)

[0486] 285 175 CycloAc^F-L-ffiNFFCFFF-MeNle-Y-pCFaPyrazynylpPhe-H-S-R-diMeAsn- MeNle-C*-CO(NH2F)

[0487] 286 176 CvcloAc*-F-L-w7(NH2F)CH2F-MeNle-Y-PheNH3F-H-S-R-diMeAsn-MeNle-C*- CONH2

[0488] 287 177 CvcloAc*-F-L-mY-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 288 178 CvcloAc*-F-L-w7(NH2F)CH2F-MeNle-Y-pMeOBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0489] 289 179 CvcloAc*-F-L-w7NH2. CH2F-MeNle-Y-pOHBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0490] 290 180 CvcloAc*-F-L-w7NH2. CH2F-MeNle-Y-pEtOBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0491] 291 181 CvcloAc*-F-L-w7NH2. CH2F-MePheG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2:292 182 CvcloAc*-F-L-w7NH2. CH2F-MePheG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 293 183 CvcloAc*-F-hGlu-wNH2CH2F-MeAoc-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0492] 294 184 CvcloAc*-F-hGlu-w7NH2. CH2F-MeNle-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*-

[0493]

[0494] CONH2*■*<•<1 11) l.xumplv Sequence

[0495] 295 185 CvcloAc*-F-hGlu-w7NH7. CH7F-MeAoc-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*- CONHz

[0496] 296 186 CvcloAc*-F-hGlu-wNH? CH? F-MeAHepc-Y-pOCHF? Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0497] 297 187 CvcloAc*-F-L-w7NH7. CH7F-MeNle-Y-Bip-H-S-pCOOHCH7F-diMeAsn-MeNle-C*- CONHz

[0498] 298 188 CYcloAc*-F-Api-w7(NH2F)CH2F-MeNle-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*- CONHz

[0499] 299 189 CvcloAc*-F-pCOOHCH2F-wiNH2. CH2F-MeNle-Y-pClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0500] 300 190 CvcloAc*-F-Api-w7NH2. CH2F-MeNle-Y-pClBip-H-S-Api-diMeAsn-MeNle-C*- CONHz

[0501] 301 191 CvcloAc*-F-pCOOHCH2F-wiNH2. CH2F-MeNle-Y-pClBip-H-S-pCOOHCH2F- diMeAsn-MeNle-C*-CO(NH2F)

[0502] 302 192 CvcloAc*-F-L-w7NH2. CH2F-MeNle-Y-pClBip-H-S-R-diMeAsn-MeChA-C*-CONH2 303 193 CvcloAc*-F-L-w7NH2. CH2F-MeChG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 304 194 CYcloAc*-F-L-w7(NH2F)CH2F-MeNle-Y-pOcPrBip-H-S-R-diMeAsn-MeNle-C*- CONH2

[0503] 305 195 CvcloAc*-F-hGlu-wiNH2. CH2F-MecPeG-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*- CONHz

[0504] 306 196 CvcloAc*-F-hGlu-w7NH2CH2F-MeNle-Y-(4CF3)3PvPhe-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0505] 307 197 CvcloAc*-F-hGlu-w7NH2. CH2F-MeNle-Y-pCNBip-H-S-hGlu-diMeAsn-MeNle-C*- CONHz

[0506] 308 198 CvcloAc*-F-hGlu-w7NH2. CH2F-MeAHepc-Y-pClBip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)

[0507] 309 199 CvcloAc*-F-hGlu-w7NH2. CH2F-MeNle-Y-pEtOBip-H-S-hGlu-diMeAsn-MeNle-C*- CONHz

[0508] 310 200 CvcloAc*-F-L-w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-DiEtAsn-MeNle-C*-CONH2 311 201 CvcloAc*-F-Api-w7NH2. CH2F-MeAHepc-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)

[0509] 312 202 CvcloAc*-F-pCOOHCH2F-mNH2. CH2F-MeAHepc-Y-pOCHF2Bip-H-S-hGlu-

[0510]

[0511] diMeAsn-MeNle-C*-CO(NH2F)

[0512] Table la: Examples of compounds according to the invention shown by sequence.

[0513] Italic letters as well as subscript numbers are arbitrarily used in the individual abbreviations designating the non-natural amino acids. This is done for the sake of clarity only and the accidental omission of an italic or of a subscript doesn’t change the structural meaning of the corresponding non-natural amino acid. For example, mCH₃F and mCEEF, as well as mCF₃F and mCF3F designate the same amino acid, respectively.

[0514] The invention thus relates to a compound of formula (I) selected from Table la or a pharmaceutically acceptable salt thereof.

[0515] The chemical structures of all examples of the compound of formula (I) are shown in Table lb. The chemical structures are aligned to the sulfide bridge for reference. The SeqID of the corresponding amino acid sequence present in the 12-mer is indicated for each example.

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584] Table lb: Examples of compounds of formula (I) with chemical structure of the parent peptide aligned relative to the Cys*Ac sulfide bridge

[0585] The invention thus also relates to a compound of formula (I) selected from Table b or a pharmaceutically acceptable salt thereof.

[0586] The IUPAC chemical name of the compounds of Table la and Table lb are given in Table 1c below.

[0587] Example Chemical Name

[0588] 1 (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0589] 2 (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28,36- trimethyl-5, 8, 11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0590]

[0591] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-36-(m-tolylmethyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0592] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-36-(p-tolylmethyl)-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0593] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-36-[(3-cyanophenyl)methyl]-12-(3-guanidinopropyl)-15- (hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0594] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-36-[(4-cyanophenyl)methyl]-12-(3-guanidinopropyl)-15- (hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0595] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-36-[[3- (trifluoromethyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0596]

[0597] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-36-[[4- (trifluoromethyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0598] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-36-[(4-carbamoylphenyl)methyl]-12-(3-guanidinopropyl)-15- (hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-4- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0599] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-[[4- (aminomethyl)phenyl]methyl]-9-(2-amino-2-oxo-ethyl)-6,27-dibutyl-12-(3- guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0600] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-36-[(3-carbamoylphenyl)methyl]-12-(3-guanidinopropyl)-15- (hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0601] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-7,28,33- trimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0602]

[0603] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl- 12,33 -bi s(3 -guanidinopropyl)- 15-(hydroxymethyl)- 21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0604] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl- 7,28,30-trimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0605] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-30-(lH-indol-3- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0606] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24- bis[(4-hydroxyphenyl)methyl]-18,30-bis(lH-imidazol-5-ylmethyl)-33- isobutyl-7,28-dimethyl-5,8,l 1,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0607] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-30-[(3,4-dihydroxyphenyl)methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-21,24-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0608]

[0609] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27- dibutyl- 12-(3 -guanidinopropyl)- 15-(hydroxymethyl)-21,24-bis[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0610] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-30-[(4-guanidinophenyl)methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-21,24-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0611] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-30-[[4- (hydroxymethyl)phenyl]methyl]-21,24-bis[(4-hydroxyphenyl)methyl]-18-(lH- imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0612] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 30-(l,3-benzodioxol-5-ylmethyl)-36-benzyl-6,27-dibutyl-12-(3- guanidinopropyl)-15-(hydroxymethyl)-21,24-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0613] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 30-[(3-aminophenyl)methyl]-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)- 15-(hydroxymethyl)-21,24-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0614]

[0615] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-30-[(3-carbamoylphenyl)methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-21,24-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0616] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6-butyl- 12-(3 -guanidinopropyl)- 15 -(hy droxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl- 7,27,28-trimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0617] (3R,6S,9S,12S,15S,18S,21S,24S,27R,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6-butyl- 12-(3 -guanidinopropyl)- 15 -(hy droxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl- 7,27,28-trimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0618] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6-butyl- 12-(3 -guanidinopropyl)- 15 -(hy droxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,27- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0619] (3S,6S,9S,15R,18S,21S,24S,27S,30S,33S,36S,39S,41R)-21-(2-amino-2-oxo- ethyl)-9-benzyl-18-butyl-41-fluoro-24-(3-guanidinopropyl)-27- (hydroxymethyl)-3,33,36-tris[(4-hydroxyphenyl)methyl]-30-(lH-imidazol-5- ylmethyl)-6-isobutyl-19-methyl-2,5,8,ll,17,20,23,26,29,32,35,38-dodecaoxo- 13-thia-l,4,7,10,16,19,22,25,28,31,34,37- dodecazabi cy cl o [37.3.0] dotetracontane- 15 -carb oxami de

[0620]

[0621] (3S,6S,9S,15R,18S,21S,24S,27S,30S,33S,36S,39S,41S)-21-(2-amino-2-oxo- ethyl)-9-benzyl-18-butyl-41-fluoro-24-(3-guanidinopropyl)-27- (hydroxymethyl)-3,33,36-tris[(4-hydroxyphenyl)methyl]-30-(lH-imidazol-5- ylmethyl)-6-isobutyl-19-methyl-2,5,8,ll,17,20,23,26,29,32,35,38-dodecaoxo- 13-thia-l,4,7,10,16,19,22,25,28,31,34,37- dodecazabi cy cl o [37.3.0] dotetracontane- 15 -carb oxami de

[0622] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-27-(4-aminobutyl)-9-(2- amino-2-oxo-ethyl)-36-benzyl-6-butyl-12-(3-guanidinopropyl)-15- (hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0623] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 27-(3 -aminopropyl)-36-benzyl-6-butyl- 12-(3 -guanidinopropyl)- 15- (hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0624] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl- 7,24,28-trimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0625] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl- 7,21,28-trimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0626]

[0627] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-21-(4-aminobutyl)-9-(2- amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15- (hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0628] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12,21-bis(3-guanidinopropyl)-15-(hydroxymethyl)- 24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0629] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0630] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-21-(2-naphthylmethyl)-5,8,ll,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0631] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4- (trifluoromethyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0632]

[0633] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-(p-tolylmethyl)-l- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carb oxami de

[0634] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-21-[(4-cyanophenyl)methyl]-12-(3-guanidinopropyl)- 15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0635] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 21-(l,3-benzothiazol-2-ylmethyl)-36-benzyl-6,27-dibutyl-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0636] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 21-[(4-aminophenyl)methyl]-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)- 15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0637] 2-[4-[[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-32-(2-amino-2- oxo-ethyl)-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3-guanidinopropyl)-26- (hydroxymethyl)-l l,17-bis[(4-hydroxyphenyl)methyl]-23-(lH-imidazol-5- ylmethyl)-8-isobutyl-13,34-dimethyl-3,6,9,12,15,18,21,24,27,30,33,36- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacont-20-yl]methyl]phenoxy]acetic acid

[0638]

[0639] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-21-[[4-(4-chlorophenyl)phenyl]methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0640] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(4- pyridyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0641] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-21- [[4-(2-methoxyphenyl)phenyl]methyl]-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0642] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-21-[[4-(cyclohexylmethoxy)phenyl]methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0643] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenoxyphenyl)methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0644]

[0645] (3R,6S,9S,12S,15S,18S,21 S,24S,27S,30S,33S,36S)-21-[(4- acetamidophenyl)methyl]-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl-12- (3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0646] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(p- tolyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0647] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(3- pyridyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0648] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,1 l,14,17,20,23,26,29,32,35,38-dodecaoxo-21-(4-pyridylmethyl)- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0649] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,1 l,14,17,20,23,26,29,32,35,38-dodecaoxo-21-(3-pyridylmethyl)- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0650]

[0651] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-21-[[4-(3-chlorophenyl)phenyl]methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0652] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-21-[[4-(2-chloro-4-pyridyl)phenyl]methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0653] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-21-[[4-(4-cyanophenyl)phenyl]methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0654] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-21-[(4- iodophenyl)methyl]-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0655] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-[3- (trifluoromethyl)phenyl]phenyl]methyl]- 1 -thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0656]

[0657] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-[4- (trifluoromethyl)phenyl]phenyl]methyl]- 1 -thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0658] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-21-[(6-chloro-3-pyridyl)methyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0659] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-21-[[4-(2- acetamidoethoxy)phenyl]methyl]-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27- dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0660] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-21- [(6-methoxy-3-pyridyl)methyl]-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0661] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-21-(lH-indol-3- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0662]

[0663] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8, 11,14,17,20,23,26,29,32,35,38-dodecaoxo-21 -(3-quinolylmethyl)- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0664] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-21-[[4-(4-acetylpiperazin- l-yl)phenyl]methyl]-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 -carboxamide

[0665] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(3-phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0666] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30- bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-21-[[4-(6-methoxy-3-pyridyl)phenyl]methyl]-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0667] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-33-isobutyl-7,18,28-trimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0668]

[0669] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 18,21,24,30-tetrakis[(4-hydroxyphenyl)methyl]-33-isobutyl-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0670] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,15,28-trimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0671] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-[(1R)-1-hydroxyethyl]- 21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0672] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7, 12,28- trimethyl-5, 8, 11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0673] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,9,28- trimethyl-5, 8, 11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0674]

[0675] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0676] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 12-(3-guanidinopropyl)-15-(hydroxymethyl)-9,21,24,30-tetrakis[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0677] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [(3-carbamoylphenyl)methyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0678] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(3-amino-3-oxo-propyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0679] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [(4-carbamoylphenyl)methyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0680]

[0681] 3-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 3-carbamoyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-11-imino-33-isobutyl-7,28-dimethyl-5,8,14,17,20,23,26,29,32,35,38-undecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-9-yl]propanoic acid

[0682] 2-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 3-carbamoyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-11-imino-33-isobutyl-7,28-dimethyl-5,8,14,17,20,23,26,29,32,35,38-undecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-9-yl]acetic acid

[0683] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-9-[2-(methylamino)-2-oxo-ethyl]-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0684] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-9-isopropyl- 7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 -carboxamide

[0685] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36-benzyl-27-butyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-6,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0686]

[0687] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-27-butyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl- 6,7,28-trimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0688] (3S,6S,9S,12S,15S,18S,21S,24S,27S,30S,36R,39S,41R)-3-(2-amino-2-oxo- ethyl)-30-benzyl-21 -butyl-41 -fluoro-6-(3 -guanidinopropyl)-9- (hydroxymethyl)-15,18,24-tris[(4-hydroxyphenyl)methyl]-12-(lH-imidazol-5- ylmethyl)-27-isobutyl-22-methyl-2,5,8,11,14,17,20,23,26,29,32,38-dodecaoxo-34-thia-1,4,7,10,13,16,19,22,25,28,31,37-dodecazabicyclo[37.3.0]dotetracontane-36-carboxamide

[0689] (3S,6S,9S,12S,15S,18S,21S,24S,27S,30S,36R,39S,41S)-3-(2-amino-2-oxo-ethyl)-30-benzyl-21 -butyl-41 -fluoro-6-(3 -guanidinopropyl)-9-(hydroxymethyl)-15,18,24-tris[(4-hydroxyphenyl)methyl]-12-(1H-imidazol-5-ylmethyl)-27-isobutyl-22-methyl-2,5,8,11,14,17,20,23,26,29,32,38-dodecaoxo-34-thia-1,4,7,10,13,16,19,22,25,28,31,37- dodecazabicyclo[37.3.0]dotetracontane-36-carboxamide

[0690] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6.36-dibenzyl-27-butyl- 12-(3 -guanidinopropyl)- 15 -(hydroxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 -carboxamide

[0691] 3-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36-benzyl-27-butyl-3-carbamoyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacont-6-yl]propanoic acid

[0692]

[0693] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-27-butyl-6-(cyclohexylmethyl)-12-(3-guanidinopropyl)-15- (hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0694] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-(l,3-benzodioxol-5- ylmethyl)-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo-ethyl]-12,33-bis(3- guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(lH- imidazol-5-ylmethyl)-7,28-dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38- dodecaoxo-21 -[(4-phenylphenyl)methyl]-36-(p-tolylmethyl)- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 -carboxamide

[0695] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo-ethyl]-12,33-bis(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4-phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0696] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [2-(dimethylamino)-2-oxo-ethyl]-12,33-bis(3-guanidinopropyl)-15- (hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-7,28-dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4- (p-tolyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0697] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 21-[[4-(4-chlorophenyl)phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]- 12,33-bis(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0698]

[0699] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-21-(l,3-benzothiazol-2- ylmethyl)-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo-ethyl]-12,33- bis(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 -carboxamide

[0700] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl- 12,33 -bi s(3 -guanidinopropyl)- 15-(hydroxymethyl)-18,21,24,30-tetrakis[(4-hydroxyphenyl)methyl]-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 -carboxamide

[0701] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl- 12,33 -bi s(3 -guanidinopropyl)- 15-(hydroxymethyl)- 24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4-phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0702] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl- 12,33 -bi s(3 -guanidinopropyl)- 15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(p-tolyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0703] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl- 12,33 -bi s(3 -guanidinopropyl)- 15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(4-pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0704]

[0705] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33- isobutyl-7,28-dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0706] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 21-[[4-(4-chlorophenyl)phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]-12- (3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0707] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33- isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(p-tolyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0708] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-21-(1,3-benzothiazol-2-ylmethyl)-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0709] 2-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl- 3-carbamoyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4-phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-9-yl]acetic acid

[0710]

[0711] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4-phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0712] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3-(aminomethyl)phenyl]methyl]-21-(1,3-benzothiazol-2-ylmethyl)-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0713] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(4-pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0714] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3-(aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-21-[[4-(4-chloro phenyl)phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 -carboxamide

[0715] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3-(aminomethyl)phenyl]methyl]-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27-dibutyl-21-[[4-(4-chlorophenyl)phenyl]methyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0716]

[0717] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 6,27-dibutyl-21-[[4-(4-chlorophenyl)phenyl]methyl]-12-(3-guanidinopropyl)- 15-(hydroxymethyl)-30-[(3-hydroxyphenyl)methyl]-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-36-[[3- (trifluoromethyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0718] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-9-(2-amino-2-oxo-ethyl)-36-benzyl-6,27- dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0719] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-9-(2-amino-2-oxo-ethyl)-21-(l,3-benzothiazol- 2-ylmethyl)-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15- (hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)- 33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0720] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo-ethyl]-12,33-bis(3-guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(3-pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0721] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-6,27-dibutyl-36-[(3-cyanophenyl)methyl]-9-[2- (dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 24-[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(4-pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3-carboxamide

[0722]

[0723] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-6,27-dibutyl-36-[(3- cyanophenyl)methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]- 18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(4- pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0724] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [2-(dimethylamino)-2-oxo-ethyl]-12,33-bis(3-guanidinopropyl)-15- (hydroxymethyl)-24,30-bis[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5- ylmethyl)-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4- (4-pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0725] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12,33-bis(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5- ylmethyl)-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(4- pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0726] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 24,30-bis[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33- isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4- (4-pyridyl)phenyl]methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0727] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24-bis[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0728]

[0729] rac-(3R,9S,12S,15S,18S,21S,24S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36- benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isopropyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-15-(thiazol-5- ylmethyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0730] rac-(3R,9S,12S,15S,18S,21S,24S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36- benzyl-6,27-dibutyl-15-(hydroxymethyl)-18,21,24,30-tetrakis[(4- hydroxyphenyl)methyl]-12-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0731] rac-(3R,9S,12S,15S,18S,21S,24S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-33- (3-aminopropyl)-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-15-(thiazol-5-ylmethyl)-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0732] rac-(3R,9S,12S,15S,18S,21S,24S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36- benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isopropyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-15-(2-oxo-2- pyrrolidin-1-yl-ethyl)-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0733] rac-(3R,9S,12S,18S,21S,24S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36- benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-21,24,30-tris[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isopropyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-16-propyl-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0734]

[0735] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)- 36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30- tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33-isobutyl-7,28- dimethyl-1,1,5,8,11,14,17,20,23,26,29,32,35,38-tetradecaoxo-1lambda6-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0736] rac-(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo- ethyl)-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-5-ylmethyl)-33- isobutyl-7,28-dimethyl-1,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxo- 1lambda4-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0737] 2-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-32-[2- (dimethylamino)-2-oxo-ethyl]-29-(3-guanidinopropyl)-26-(hydroxymethyl)- 17-[(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]acetic acid

[0738] 3-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-32-[2- (dimethylamino)-2-oxo-ethyl]-29-(3-guanidinopropyl)-26-(hydroxymethyl)- 17-[(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]propanoic acid

[0739] 4-[[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-32-[2- (dimethylamino)-2-oxo-ethyl]-29-(3-guanidinopropyl)-26-(hydroxymethyl)- 17-[(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]methyl]benzoic acid

[0740]

[0741] 3-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-9-[2- (dimethylamino)-2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacont-12-yl]propanoic acid

[0742] 4-[[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-9-[2- (dimethylamino)-2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacont-12-yl]methyl]benzoic acid

[0743] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-9-[2-(dimethylamino)-2-oxo- ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-27-(1H-imidazol-5- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo-21-[(4-phenylphenyl)methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0744] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-9-[2-(dimethylamino)-2-oxo- ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-27-(1H-indol-3- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo-21-[(4-phenylphenyl)methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0745] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-21-[[4-[3- (difluoromethoxy)phenyl]phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]- 12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]- 18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0746]

[0747] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo- ethyl]-36-[(4-fluorophenyl)methyl]-12-(3-guanidinopropyl)-15- (hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)- 33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21- [(4-phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0748] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-9-[2-(dimethylamino)-2-oxo- ethyl]-12-(3-guanidinopropyl)-27-hexyl-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0749] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4-pyrazin-2- ylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0750] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-32-[2- (dimethylamino)-2-oxo-ethyl]-29-(3-guanidinopropyl)-26-(hydroxymethyl)- 17-[(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]butanoic acid

[0751] 4-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-9-[2- (dimethylamino)-2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacont-12-yl]butanoic acid

[0752]

[0753] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)- 15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo-9-[2-oxo-2-(1-piperidyl)ethyl]-21-[(4-phenylphenyl)methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0754] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-12-(3-guanidinopropyl)- 15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo-9-(2-oxo-2-pyrrolidin-1-yl-ethyl)-21-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0755] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-7,28,33,33-tetramethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0756] (9S,15R,18S,21S,24S,27S,30S,33S,36S,39S,42S)-42-[[3- (aminomethyl)phenyl]methyl]-9-benzyl-18,39-dibutyl-21-[2-(dimethylamino)- 2-oxo-ethyl]-24-(3-guanidinopropyl)-27-(hydroxymethyl)-36-[(4- hydroxyphenyl)methyl]-30-(1H-imidazol-4-ylmethyl)-19,40-dimethyl- 8,11,17,20,23,26,29,32,35,38,41,44-dodecaoxo-33-[(4-phenylphenyl)methyl]- 13-thia-7,10,16,19,22,25,28,31,34,37,40,43- dodecazaspiro[5.38]tetratetracontane-15-carboxamide

[0757] 4-[[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-33-(2- carboxyethyl)-9-[2-(dimethylamino)-2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-12- yl]methyl]benzoic acid

[0758]

[0759] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-6,27-dibutyl-9-[2-(dimethylamino)-2-oxo- ethyl] - 12-(3 -guanidinopropyl)- 15 -(hy droxymethyl)-36-[(3- hydroxyphenyl)methyl]-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo-21-[(4-phenylphenyl)methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0760] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-6,27-dibutyl-36-[(3,4-dihydroxyphenyl)methyl]- 9-[2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15- (hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)- 33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21- [(4-phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0761] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-l- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]butanoic acid

[0762] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-[4-(difluoromethoxy)phenyl]phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0763] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-pyrazin-2- ylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacont-8-yl]butanoic acid

[0764]

[0765] 4-[[(5S,8S,11S,14S,17S,20S,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-l- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]methyl]benzoic acid

[0766] 4-[[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-[4-(difluoromethoxy)phenyl]phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]methyl]benzoic acid

[0767] 4-[[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-pyrazin-2- ylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacont-8-yl]methyl]benzoic acid

[0768] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-27-cyclopentyl-9-[2- (dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0769] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-27,36-dibenzyl-6-butyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0770]

[0771] 4-[(5S,8S,11S,14S,17S,20S,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[[4-[5- (trifluoromethyl)pyrazin-2-yl]phenyl]methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0772] 4-[(5S,8S,11S,14S,17S,20S,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-14-hexyl-26- (hydroxymethyl)-17-[(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)- 13,34-dimethyl-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[[4-[5- (trifluoromethyl)pyrazin-2-yl]phenyl]methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0773] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-20-[[4-(4-hydroxyphenyl)phenyl]methyl]-23-(1H- imidazol-4-ylmethyl)-13,34-dimethyl-3,6,9,12,15,18,21,24,27,30,33,36- dodecaoxo-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacont-8-yl]butanoic acid

[0774] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[[4-(p-tolyl)phenyl]methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]butanoic acid

[0775] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[[4-[4- (trifluoromethyl)phenyl]phenyl]methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0776]

[0777] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-[6- (trifluoromethyl)-3-pyridyl]phenyl]methyl]-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0778] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-21-[[4-(4- cyanophenyl)phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]-12-(3- guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(lH- imidazol-4-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0779] 5-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-[4-(difluoromethoxy)phenyl]phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]pentanoic acid

[0780] 4-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-33-[[4- (carb oxy methyl )pheny 1 ] methyl ] -21 - [ [4- [4- (difluoromethoxy)phenyl]phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]- 15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4- ylmethyl)-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-12-yl]butanoic acid

[0781] 5-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-32-[2- (dimethylamino)-2-oxo-ethyl]-29-(3-guanidinopropyl)-26-(hydroxymethyl)- 17-[(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-1- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]pentanoic acid

[0782]

[0783] 2-[4-[[(5 S,8S, 11 S, 14S, 17S,20S,23 S,26S,29S,32S,35 S,38R)-11 -[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-32-[2- (dimethylamino)-2-oxo-ethyl]-29-(3-guanidinopropyl)-26-(hydroxymethyl)- 17-[(4-hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4-phenylphenyl)methyl]-l- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]methyl]phenyl]acetic acid

[0784] 5-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-9-[2- (dimethylamino)-2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acont- 12-y 1 ] pentanoi c aci d

[0785] 5-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-33-(3- carboxypropyl)-21-[[4-(4-chlorophenyl)phenyl]methyl]-9-[2-(dimethylamino)- 2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(lH- imidazol-4-ylmethyl)-7,28-dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacy cl ononatri acont- 12-y 1 ] pentanoi c aci d

[0786] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-21-[[4-(4- chlorophenyl)phenyl]methyl]-27-(cyclohexylmethyl)-9-[2-(dimethylamino)-2- oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0787] 6-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-[4-(difluoromethoxy)phenyl]phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]hexanoic acid

[0788]

[0789] 4-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-[[4- (carboxymethyl)phenyl]methyl]-20-[[4-(4-chlorophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0790] 4-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-chlorophenyl)phenyl]methyl]-14- (cyclohexylmethyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)- 17-[(4-hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0791] 4-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-cyanophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-14-pentyl-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0792] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-(p- tolyl)phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0793] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(3- phenoxyphenyl)methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0794]

[0795] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-21-[[4-[4- (difluoromethoxy)phenyl]phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]- 12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]- 18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0796] 4-[[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-[(4- carboxyphenyl)methyl]-32-[2-(dimethylamino)-2-oxo-ethyl]-26- (hydroxymethyl)-17-[(4-hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)- 13,34-dimethyl-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acont-8 -y 1 ] methyl ]b enzoi c aci d

[0797] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[[4-[5- (trifluoromethyl)pyrazin-2-yl]phenyl]methyl]- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0798] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-21-[(3-anilinophenyl)methyl]-36-benzyl-6,27- dibutyl-9-[2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15- (hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)- 33-isobutyl-7,28-dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l- thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carb oxami de

[0799] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-36-benzyl-6,27-dibutyl-9- [2-(dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 30-[(3-hydroxyphenyl)methyl]-24-[(4-hydroxyphenyl)methyl]-18-(lH- imidazol-4-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21 -[(4-phenylphenyl)methyl]- 1 - thia-4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carb oxami de

[0800]

[0801] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-21-[[4-(4- methoxyphenyl)phenyl]methyl]-7,28-dimethyl- 5.8.11.14.17.20.23.26.29.32.35,38-dodecaoxo- 1 -thia- 4.7.10.13.16.19.22.25.28.31.34.37-dodecazacyclononatriacontane-3 - carboxamide

[0802] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-21-[[4-(4-hydroxyphenyl)phenyl]methyl]-18-(lH- imidazol-4-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3- carboxamide

[0803] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(dimethylamino)- 2-oxo-ethyl]-21-[[4-(4-ethoxyphenyl)phenyl]methyl]-12-(3-guanidinopropyl)- 15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-4- ylmethyl)-33-isobutyl-7,28-dimethyl-5,8,11,14,17,20,23,26,29,32,35,38- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0804] (3R,6S,9S,12S,15S,18S,21S,24S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-9-[2-(dimethylamino)-2-oxo- ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-27-phenyl-21-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0805] (3R,6S,9S,12S,15S,18S,21S,24S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-9-[2-(dimethylamino)-2-oxo- ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-27-phenyl-21-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acontane-3 -carb oxami de

[0806]

[0807] 4-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-[4-(difluoromethoxy)phenyl]phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]- 14-hexyl-26-(hydroxymethyl)- 17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0808] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-chlorophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0809] 4-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-chlorophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]- 14-hexyl-26-(hydroxymethyl)- 17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0810] 4-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-[4-(difluoromethoxy)phenyl]phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-14-pentyl-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0811] 2-[4-[[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-9-[2- (dimethylamino)-2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)m ethyl]- 1 -thia-4,7, 10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acont- 12-y 1 ] methyl ]pheny 1 ] aceti c aci d

[0812]

[0813] 5-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-chlorophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]pentanoic acid

[0814] 4-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-3-carbamoyl-33-[[4- (carboxymethyl)phenyl]methyl]-21-[[4-(4-chlorophenyl)phenyl]methyl]-9-[2- (dimethylamino)-2-oxo-ethyl]-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-12-yl]butanoic acid

[0815] 5-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(4- carboxybutyl)-20-[[4-(4-chlorophenyl)phenyl]methyl]-32-[2-(dimethylamino)- 2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4-hydroxyphenyl)methyl]-23-(lH- imidazol-4-ylmethyl)-13,34-dimethyl-3,6,9,12,15,18,21,24,27,30,33,36- dodecaoxo- 1 -thia-4,7, 10, 13, 16, 19,22,25,28,31,34, 37- dodecazacy cl ononatri acont-8 -y 1 ] pentanoi c aci d

[0816] 2-[4-[[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-[[4- (carboxymethyl)phenyl]methyl]-20-[[4-(4-chlorophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8- yl]methyl]phenyl]acetic acid (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-27-butyl-21-[[4-(4- chlorophenyl)phenyl]methyl]-6-(cyclohexylmethyl)-9-[2-(dimethylamino)-2- oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(lH-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0817]

[0818] (3R,6S,9S, 12S, 15 S, 18S,21 S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-27-cyclohexyl-9-[2- (dimethylamino)-2-oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)- 24-[(4-hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0819] (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-21-[[4-[4- (cyclopropoxy)phenyl]phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]-12- (3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18- (lH-imidazol-4-ylmethyl)-33-isobutyl-7,28-dimethyl- 5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo- 1 -thia- 4,7, 10, 13, 16, 19,22,25,28,31,34,37-dodecazacyclononatriacontane-3 - carboxamide

[0820] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-chlorophenyl)phenyl]methyl]-14-cyclopentyl-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0821] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17- [(4-hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-20-[[4-[6-(trifluoromethyl)-3- pyridyl]phenyl]methyl]-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacy cl ononatri acont-8 -y 1 ]butanoi c aci d

[0822] 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-cyanophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0823]

[0824] 198 4-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-(4-chlorophenyl)phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-14-pentyl-l-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0825] 199 4-[(5S,8S,llS,14S,17S,20S,23S,26S,29S,32S,35S,38R)-ll-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-14,35-dibutyl-38-carbamoyl-29-(3- carboxypropyl)-32-[2-(dimethylamino)-2-oxo-ethyl]-20-[[4-(4- ethoxyphenyl)phenyl]methyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(1H-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-1-thia- 4,7,10,13,16,19,22,25,28,31,34,37-dodecazacyclononatriacont-8-yl]butanoic acid

[0826] 200 (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6,27-dibutyl-9-[2-(diethylamino)-2- oxo-ethyl]-12-(3-guanidinopropyl)-15-(hydroxymethyl)-24-[(4- hydroxyphenyl)methyl]-18-(1H-imidazol-4-ylmethyl)-33-isobutyl-7,28- dimethyl-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxo-21-[(4- phenylphenyl)methyl]-1-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[0827] 201 5-[(5S,8S,l 1S,14S,17S,2OS,23S,26S,29S,32S,35S,38R)-11-[[3- (aminomethyl)phenyl]methyl]-5-benzyl-35-butyl-38-carbamoyl-29-(3- carboxypropyl)-20-[[4-[4-(difluoromethoxy)phenyl]phenyl]methyl]-32-[2- (dimethylamino)-2-oxo-ethyl]-26-(hydroxymethyl)-17-[(4- hydroxyphenyl)methyl]-23-(lH-imidazol-4-ylmethyl)-13,34-dimethyl- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxo-14-pentyl-l-thia- 4,7,10,13,16,19,22,25,28,31,34, 37-dodecazacy cl ononatriacont-8-yl]pentanoic acid

[0828] 202 4-[(3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-30-[[3- (aminomethyl)phenyl]methyl]-36-benzyl-6-butyl-3-carbamoyl-33-[[4- (carb oxy methyl )pheny 1 ] methyl ] -21 - [ [4- [4- (difluoromethoxy)phenyl]phenyl]methyl]-9-[2-(dimethylamino)-2-oxo-ethyl]- 15-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-4- ylmethyl)-7,28-dimethyl-5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-27- pentyl-1 -thia-4,7, 10, 13, 16, 19, 22, 25, 28, 31,34, 37-dodecazacy cl ononatri acont- 12-yl]butanoic acid

[0829]

[0830] Table 1c: IUPAC name of the compounds of formula (I) illustrating the invention.

[0831] The invention thus also relates to a compound of formula (I) selected from Table 1c or a pharmaceutically acceptable salt thereof.The sodium salt of each compound described above, in particular in Tables la to 1c, is particularly advantageous.

[0832] The description of natural amino acids used in the sequences follow either the standard single letter or three letter codes. Any unnatural amino acids used in this invention are described with abbreviations which are defined in Table 2. Commercially available monomers which are suitably protected to be used in the synthesis as described above are indicated with the CAS number. If a monomer is not commercially available, the synthesis is described below or a literature reference is provided.

[0833] Non-natural

[0834] Protected monomer used for SPPS CAS / origin amino acid

[0835] (2S)-2-((((9H-Fluoren-9- MeNle yl)methoxy)carbonyl)(methyl)amino)hexanoic 112883-42-8 acid

[0836] (2S)-2-(9H-Fluoren-9- mCH₃F ylmethoxycarbonylamino)-3-(3- 211637-74-0 methylphenyl)propanoic acid

[0837] (2S)-2-(9H-Fluoren-9- pCH₃F ylmethoxycarbonylamino)-3-(4- 199006-54-7 methylphenyl)propanoic acid

[0838] (2 S)-3 -(3 -Cy anophenyl)-2-(9H-fluoren-9- mCNF 205526-36-9 ylmethoxycarbonylamino)propanoic acid

[0839] (2 S)-3 -(4-Cy anophenyl)-2-(9H-fluoren-9- pCNF 265321-37-7 ylmethoxycarbonylamino)propanoic acid

[0840] (2S)-2-(9H-Fluoren-9- mCF₃F ylmethoxycarbonylamino)-3-[3- 205526-27-8 (trifluoromethyl)phenyl]propanoic acid

[0841] (2S)-2-(([(9H-Fluoren-9- pCF₃F yl)methoxy]carbonyl)amino)-3-[4- 247113-86-6 (trifluoromethyl)phenyl]propanoic acid

[0842] (2S)-3-(4-Carbamoylphenyl)-2-(9H-fluoren-9- pNH₂COF 1217610-39-3 ylmethoxycarbonylamino)propanoic acid

[0843] 4-[[[(l,l- Dimethy 1 ethoxy )carb ony 1 ] amino] methyl ] -N - pNH₂CH₂F 204715-91-3

[0844] [(9H-fluoren-9-ylmethoxy)carbonyl]-L- phenylalanine

[0845] (2S)-3-(3-Carbamoylphenyl)-2-(9H-fluoren-9- mNH₂COF 959573-22-9 ylmethoxycarbonylamino)propanoic acid

[0846] (aS)-a-[[(9H-Fluoren-9- mOHY ylmethoxy)carbonyl]amino]-2,2-dimethyl-l,3- 852288-18-7 benzodioxole-5-propanoic acid

[0847] mNH₂CH₂F 266999-24-0

[0848]

[0849] Dimethy 1 ethoxy )carb ony 1 ] amino] methyl ] -N -Non-natural

[0850] Protected monomer used for SPPS CAS / origin amino acid

[0851] [(9H-fluoren-9-ylmethoxy)carbonyl]-L- phenylalanine

[0852] 4-[[bis[[(l,l- Dimethy 1 ethoxy )carb ony 1 ] amino] methyl ene] ami pGuF 187283-25-6 no]-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L- phenylalanine

[0853] 4-[(l,l-Dimethylethoxy)methyl]-N-[(9H- pOHCH₂F 204384-68-9 fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine

[0854] (2S)-2-((((9H-Fluoren-9-benzodioxolAla yl)methoxy)carbonyl)amino)-3- 32161-31-2

[0855] (b enzo [d] [ 1, 3 ] di oxol -5 -y l)propanoi c aci d 3 - [ [( 1, 1 -Dimethyl ethoxy )carb ony 1 ] amino] -N- mNH₂F [(9H-fluoren-9-ylmethoxy)carbonyl]- L- 273221-84-4

[0856] Phenylalanine

[0857] (2S)-2-([[(9H-Fluoren-9- MeA yl)methoxy]carbonyl](methyl)amino)propanoic 84000-07-7 acid

[0858] (2R)-2-{[(9H-Fluoren-9- Mea ylmethoxy)carbonyl](methyl)amino}propanoic 138774-92-2 acid

[0859] (2S,4R)-l-(9H-Fluoren-9-ylmethoxycarbonyl)-4- 4RFPro 203866-20-0 fluoropyrrolidine-2-carboxylic acid

[0860] (2S,4S)-l-(9H-Fluoren-9-ylmethoxycarbonyl)-4- 4SFPro 203866-19-7 fluoropyrrolidine-2-carboxylic acid

[0861] (2S)-2-[9H-Fluoren-9- ylmethoxycarbonyl(methyl)amino]-6-[(2- MeK 197632-76-1 methylpropan-2-yl)oxycarbonylamino]hexanoic

[0862] acid

[0863] (2S)-2-[9H-Fluoren-9- ylmethoxycarbonyl(methyl)amino]-5-[(2- MeOrn 1793105-28-8 methylpropan-2-yl)oxycarbonylamino]pentanoic

[0864] acid

[0865] (2S)-2-((((9H-Fluoren-9- Bip yl)Methoxy)carbonyl)aMino)-3 -([1,1 '-biphenyl]- 199110-64-0

[0866] 4-yl)propanoic acid

[0867] (2S)-2-(9H-Fluoren-9- 2Nal ylmethoxycarbonylamino)-3-(2- 112883-43-9 naphthyl)propanoic acid

[0868] (2S)-3-(l,3-Benzothiazol-2-yl)-2-(9H-fluoren-9- BzTzA 959583-56-3 ylmethoxycarbonylamino)propanoic acid

[0869] (2S)-2-(9H-Fluoren-9- ylmethoxycarbonylamino)-3-[4-[(2- pNH₂F 174132-31-1 methylpropan-2- yl)oxycarbonylamino]phenyl]propanoic acid

[0870] (2S)-2-(9H-Fluoren-9- ylmethoxycarbonylamino)-3-[4-[2-[(2- YCH2COOH 181951-92-8 methylpropan-2-yl)oxy]-2-

[0871]

[0872] oxoethoxy]phenyl]propanoic acidNon-natural

[0873] Protected monomer used for SPPS CAS / origin amino acid

[0874] (2S)-2-((((9H-Fluoren-9- / tCIBip yl)methoxy)carbonyl)amino)-3 -(4'-chloro-[ 1,1'- 1270097-85-2 biphenyl]-4-yl)propanoic acid

[0875] (2S)-2-(9H-Fluoren-9- / zPyF ylmethoxycarbonylamino)-3-(4-pyridin-4- 1282042-56-1 ylphenyl)propanoic acid

[0876] (2S)-2-((((9H-Fluoren-9- oMeOBip yl)methoxy)carbonyl)amino)-3-(2'-methoxy- 225528-11-0

[0877] [1 J'-biphenyl]-4-yl)propanoic acid

[0878] (2S)-2-((((9H-Fluoren-9- YOCH2Ch yl)methoxy)carbonyl)amino)-3-(4- 960360-37-6

[0879] ( cy cl ohexy Imethoxy )pheny l)propanoi c aci d

[0880] (2S)-2-(9H-Fluoren-9- YOPh ylmethoxycarbonylamino)-3-(4- 180414-93-1 phenoxyphenyl)propanoic acid

[0881] (2S)-3-(4-Acetamidophenyl)-2-(9H-fluoren-9- pAcNHF 265321-34-4 ylmethoxycarbonylamino)propanoic acid

[0882] (2S)-2-((((9H-Fluoren-9- / ? CH3Bip yl)methoxy)carbonyl)amino)-3 -(4'-methyl-[ 1,1'- 1223105-45-0 biphenyl]-4-yl)propanoic acid

[0883] (2S)-2-({[(9H-Fluoren-9- / 7? PyF yl)methoxy] carbonyl } amino)-3 - [4-(pyri din-3 - 352525-25-8 yl)phenyl]propanoic acid

[0884] (2S)-2-((((9H-Fluoren-9- / zPyA yl)methoxy)carbonyl)amino)-3-(pyridin-4- 169555-95-7 yl)propanoic acid

[0885] (2S)-2-(9H-Fluoren-9- / 7? PyA ylmethoxycarbonylamino)-3-(3- 175453-07-3 pyridyl)propanoic acid

[0886] (2S)-2-((((9H-Fluoren-9- / 7 / CIBip yl)methoxy)carbonyl)amino)-3 -(3 '-chloro-[ 1,1'- 1380437-47-7 biphenyl]-4-yl)propanoic acid

[0887] (2S)-2-((((9H-Fluoren-9- Synthesis: / 7 / Cl / tPyF yl)methoxy)carbonyl)amino)-3-(4-(2- Intermediate S chloropyridin-4-yl)phenyl)propanoic acid

[0888] (2S)-2-(9H-Fluoren-9- / ? IF ylmethoxycarbonylamino)-3-(4- 82565-68-2 iodophenyl)propanoic acid

[0889] (2S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-(3'- mCFsBip 1380437-35-3

[0890] (trifluoromethyl)-[ 1, l'-biphenyl]-4-yl)propanoic

[0891] acid

[0892] (2S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-(4'- / tCFsBip 1381789-13-4

[0893] (trifluoromethyl)-[ 1, l'-biphenyl]-4-yl)propanoic

[0894]

[0895] acidNon-natural

[0896] Protected monomer used for SPPS CAS / origin amino acid

[0897] (2S)-2-((((9H-Fluoren-9- pCI / 7 / PyA yl)methoxy)carbonyl)amino)-3-(6-chloropyridin- 1270288-44-2

[0898] 3-yl)propanoic acid

[0899] (2S)-2-((((9H-Fluoren-9- 2973753-70-5 made according to AcAEF yl)methoxy)carbonyl)amino)-3-(4-(2- WO2023244554 acetami doethoxy )pheny l)prop anoi c aci d Al (2S)-2-({[(9H-Fluoren-9- yl)methoxy] carbonyl } amino)-3 -(6- pMeO / 7 / PyA 1821775-88-5 methoxypyri din-3 -yl)propanoic acid

[0900] (2S)-2-((((9H-Fluoren-9- 3,3QA yl)methoxy)carbonyl)amino)-3-(quinolin-3- 281655-61-6 yl)propanoic acid

[0901] (2S)-2-((((9H-Fluoren-9- Synthesis: AcPiperazineF yl)methoxy)carbonyl)amino)-3-(4-(4- Intermediate R acetylpiperazin- 1 -yl)phenyl)propanoic acid

[0902] (aS)-a-[[(9H-Fluoren-9- 3PheF ylmethoxy)carbonyl]amino][l, 1 '-biphenyl]-3- 1260616-69-0 propanoic acid

[0903] 2001041-51-4, (2S)-2-((((9H-Fluoren-9- made according to pMeO / 7 / PyF yl)methoxy)carbonyl)amino)-3-(4-(6- Qiao et al., J Org methoxypyri din-3 -yl)phenyl)propanoic acid Chem (2016), 81

[0904] (19), 9499 (2S)-3-(Dimethylcarbamoyl)-2-([[(9H-fluoren-9- diMeAsn 138585-02-1 yl)methoxy]carbonyl]amino)propanoic acid

[0905] (2S)-3-(Methylcarbamoyl)-2-([[(9H-fluoren-9- MeAsn 149204-93-3 yl)methoxy]carbonyl]amino)propanoic acid

[0906] (2S)-2-[9H-Fluoren-9- MeF ylmethoxycarbonyl(methyl)amino]-3- 77128-73-5 phenylpropanoic acid

[0907] (2S)-2-((((9H-Fluoren-9- MeE yl)methoxy)carbonyl)(methyl)amino)-5-(tert- 200616-40-6 butoxy)-5-oxopentanoic acid

[0908] (2 S)-3 -Cy clohexyl-2- [9H-Fluoren-9- MeChA ylmethoxycarbonyl(methyl)amino]propanoic 148983-03-3 acid

[0909] (aS)-a-[[(9H-Fluoren-9- 4TzA ylmethoxy)carbonyl]amino]-4-thi azolepropanoic 205528-32-1 acid

[0910] (2S)-2-(9H-Fluoren-9- Orn ylmethoxycarbonylamino)-5-[(2-methylpropan- 109425-55-0

[0911] 2-yl)oxycarbonylamino]pentanoic acid

[0912] (2S)-2-((((9H-Fluoren-9- 2973755-00-7 NPyrAsn yl)methoxy)carbonyl)amino)-4-oxo-4- Synthesis:

[0913] (pyrrolidin-l-yl)butanoic acid Intermediate C N-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N- PrG 1310680-42-2

[0914]

[0915] propylglycineNon-natural

[0916] Protected monomer used for SPPS CAS / origin amino acid

[0917] (2S)-4-(Diethylamino)-2-(9H-fluoren-9- Synthesis: DiEtAsn

[0918] ylmethoxycarbonylamino)-4-oxo-butanoic acid Intermediate B

[0919] (2S)-2-[9H-Fluoren-9- MeTrp ylmethoxycarbonyl(methyl)amino]-3-(lH-indol- 112913-63-0

[0920] 3-yl)propanoic acid

[0921] 1-[(1,1-Dimethylethoxy)carbonyl]-N-[(9H- MeH fluoren-9-ylmethoxy)carbonyl]-N-methyl-L- 2044711-07-9 histidine

[0922] (2S)-2-(9H-Fluoren-9- ylmethoxycarbonylamino)-3-[4-[(2- / ? COOHF 183070-44-2 methylpropan-2- yl)oxycarbonyl]phenyl]propanoic acid

[0923] (2S)-2-((((9H-Fluoren-9- PheO3F yl)methoxy)carbonyl)amino)-3 -(3 - 1313277-83-6 phenoxyphenyl)propanoic acid

[0924] (2S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-(3'- Synthesis: mOCHF2Bip

[0925] (difluoromethoxy)-[l,l'-biphenyl]-4- Intermediate P yl)propanoic acid

[0926] (2S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-(4'- Synthesis: / ? OCHF2Bip

[0927] (difluoromethoxy)-[l,l'-biphenyl]-4- Intermediate I yl)propanoic acid

[0928] (2S)-2-((((9H-Fluoren-9- Synthesis: / zPyrazynylPhe yl)methoxy)carbonyl)amino)-3-(4-(pyrazin-2- Intermediate L yl)phenyl)propanoic acid

[0929] (2S)-3-[4-[4-(Methoxy)phenyl]phenyl]-2-(9H- Synthesis: / zMeOBip fluoren-9-ylmethoxycarbonylamino)propanoic Intermediate G acid

[0930] (2S)-3-[4-[4-(tert-Butyloxy)phenyl]phenyl]-2- Synthesis: / ? OHBip (9H-fluoren-9- Intermediate H ylmethoxycarbonylamino)propanoic acid

[0931] (2S)-2-((((9H-Fluoren-9- Synthesis: NPipAsn yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin- Intermediate A l-yl)butanoic acid

[0932] (2S)-2-[[(9H-Fluoren-9- MeAoc 2389078-28-6 y Imethoxy )carb ony 1 ] methyl amino] octanoi c aci d

[0933] (2S)-2-((((9H-Fluoren-9- MeAHepc Synthesis:

[0934] yl)methoxy)carbonyl)(methyl)amino)heptanoic Intermediate D acid

[0935] (2S)-2-((((9H-Fluoren-9- / tCFsPyrazynylp yl)methoxy)carbonyl)amino)-3-(4-(5- Synthesis:

[0936] Phe (trifluoromethyl)pyrazin-2-yl)phenyl)propanoic Intermediate M acid

[0937] (2S)-2-((((9H-Fluoren-9- Synthesis: (4CF3)3PyPhe

[0938]

[0939] yl)methoxy)carbonyl)amino)-3-(4-(6- Intermediate NNon-natural

[0940] Protected monomer used for SPPS CAS / origin amino acid

[0941] (trifluoromethyl)pyridin-3-yl)phenyl)propanoic

[0942] acid

[0943] (2S)-2-((((9H-Fluoren-9- hGlu yl)methoxy)carbonyl)amino)-6-(tert-butoxy)-6- 159751-47-0 oxohexanoic acid

[0944] (2S)-2-((((9H-Fluoren-9- Api yl)methoxy)carbonyl)amino)-7-(tert-butoxy)-7- 159751-46-9 oxoheptanoic acid

[0945] (2S)-2-((((9H-Fluoren-9- bisOctanoicAcid yl)methoxy)carbonyl)amino)-8-(tert-butoxy)-8- 276869-41-1 oxooctanoic acid

[0946] 2-((((9H-Fluoren-9- Aib yl)methoxy)carbonyl)amino)-2-methylpropanoic 94744-50-0 acid

[0947] 1 -((((9H-Fluoren-9- Acca yl)methoxy)carbonyl)amino)cyclohexane-l- 162648-54-6 carboxylic acid

[0948] (2S)-2-((((9H-Fluoren-9- Synthesis: PheNH3F yl)methoxy)carbonyl)amino)-3 -(3 - Intermediate Q (phenylamino)phenyl)propanoic acid

[0949] (2S)-2-((((9H-Fluoren-9- mY yl)methoxy)carbonyl)amino)-3 -(3 -(tert- 204384-71-4 butoxy)phenyl)propanoic acid

[0950] (2S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-(2,2- 30HY 852288-18-7 dimethylbenzo[d][l,3]dioxol-5-yl)propanoic

[0951] acid

[0952] (2S)-2-((((9H-Fluoren-9- Synthesis: / tCNBip yl)methoxy)carbonyl)amino)-3 -(4'-cyano-[ 1,1'- Intermediate 0 biphenyl]-4-yl)propanoic acid

[0953] (2S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-(4'- Synthesis: / ? OcPrBip

[0954] cyclopropoxy-[ 1, 1 '-biphenyl]-4-yl)propanoic Intermediate F acid

[0955] (2S)-2-((((9H-Fluoren-9- MeChG yl)methoxy)carbonyl)(methyl)amino)-2- 1697377-42-6 cyclohexylacetic acid

[0956] (2S)-2-((((9H-Fluoren-9- MecPeG yl)methoxy)carbonyl)(methyl)amino)-2- 187475-29-2 cyclopentylacetic acid

[0957] (2S)-3-[4-[4-(Ethoxy)phenyl]phenyl]-2-(9H- Synthesis pEtOBip fluoren-9-ylmethoxycarbonylamino)propanoic Intermediate K

[0958]

[0959] acidNon-natural

[0960] Protected monomer used for SPPS CAS / origin amino acid

[0961] (2S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)(methyl)amino)-2- phenylacetic acid

[0962] MePheG 574739-36-9 Even if enantiopure material for this monomer was used for synthesis, racemization was usually observed for this moiety during peptide assembly, resulting in two separable epimers

[0963] (2S)-2-(((9H-Fluoren-9- / ? COOHCH2F yl)methoxy)carbonylamino)-3-(4-(2-tert-butoxy- 222842-99-1

[0964] 2-oxoethyl)phenyl)propanoic acid

[0965] (2S)-2-(9H-Fluoren-9- 4FPhe ylmethoxycarbonylamino)-3-(4- 169243-86-1

[0966]

[0967] fluorophenyl)propanoic acid

[0968] Table 2: protected monomers used in the synthesis of the examples

[0969] Another embodiment of the invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in 0.9% aqueous saline in a pH range of 3.0 - 8.6, more preferred 6.5 - 8.0 and most preferred 7.4 + / - 0.4.. If required, buffering is possible for example with approx. 20 mM PBS at the desired pH value. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0970] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0971] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal,parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0972] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0973] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0974] A particular mode of administration of the compound of formula (I) is a topical administration on the eye, for example using an eye drop solution or an ophthalmic ointment, in particular an eye drop solution. This is particularly useful for the treatment or prophylaxis of front of the eye diseases, particularly for DED.

[0975] The compound of formula (I) can also be administered via intravitreal injection or via the Port Delivery System, in particular for the treatment or prophylaxis of back of the eye diseases.

[0976] The invention also relates to the novel amino acids descrided herein.

[0977] The invention therefore also relates to a compound selected from

[0978] 2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;(25)-2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;

[0979] (27?)-2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;

[0980] 2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;

[0981] (25)-2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;

[0982] (27?)-2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;

[0983] 2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;

[0984] (25)-2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;

[0985] (27?)-2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;

[0986] 2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid;

[0987] (25)-2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid;

[0988] (27?)-2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid,

[0989] 2-amino-3-(3-anilinophenyl)propanoic acid;

[0990] (25)-2-amino-3-(3-anilinophenyl)propanoic acid;

[0991] (27?)-2-amino-3 -(3 -anilinophenyl)propanoic acid;

[0992] 2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid;

[0993] (25)-2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid; and

[0994] (27?)-2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid;

[0995] each optionally protected by an amino acid protecting group, in particular an amino acid protecting group protecting their amino functionality.

[0996] The invention also relates to a compound as defined above, wherein the amino acid protecting group is selected from te / 7-Butyl oxy carbonyl (Boc), Trityl (Trt), a,a-Dimethyl-3,5-dimethoxybenzyloxycarbonyl (Ddz), 2-(4-Biphenyl)isopropoxycarbonyl (Bpoc), 2-Nitrophenylsulfenyl (Nps), benzyloxycarbonyl (Z), 9-Fluorenylmethoxycarbonyl (Fmoc), 2-(4-Nitrophenylsulfonyl)ethoxycarbonyl (Nsc), (l,l-Dioxobenzo[b]thiophene-2-yl)methyloxy carbonyl (Bsmoc), (1, 1 -Dioxonaphthofl, 2-Z>]thiophene-2-yl)methyloxycarbonyl (a-Nsmoc), (l-(4,4-Dimethyl-2,6-dioxocyclohex-l-ylidene)-3-ethyl) (Dde), l-(4,4-Dimethyl-2,6-dioxocyclohex-l-ylidene)-3-methylbutyl (ivDde), 2,7-Di-tert-butyl-Fmoc (Fmoc*), 2-Fluoro-Fmoc (Fmoc(2F)), 2-Monoisooctyl-Fmoc (mio-Fmoc), 2,7-Diisooctyl-Fmoc (dio-Fmoc), Tetrachlorophthaloyl (TCP), 2-[Phenyl(methyl)sulfonio]ethyloxycarbonyl tetrafluoroborate (Pms), Ethanesulfonylethoxycarbonyl (Esc), 2-(4-Sulfophenylsulfonyl)ethoxycarbonyl (Sps), Allyloxy carbonyl (Alloc), o-Nitrobenzenesulfonyl (oNBS) and -nitrobenzenesulfonyl ( / zNBS), 2,4-Dinitrobenzenesulfonyl (dNBS), Benzothiazole-2-sulfonyl (Bts), 2,2,2-Trichloroethyloxycarbonyl (Troc), Dithiasuccinoyl (Dts), p-Nitrobenzyloxycarbonyl (pNZ), a-Azido Carboxylic Acids, Propargyloxycarbonyl (Poc), o-Nitrobenzyloxycarbonyl (oNZ) and 6-Nitroveratryloxycarbonyl (NVOC), 2-(2-Nitrophenyl)propyloxycarbonyl (NPPOC), 2-(3,4-Methylenedioxy-6-nitrophenyl)propyloxycarbonyl (MNPPOC), Ninhydrin (Nin), 9-(4-Bromophenyl)-9-fluorenyl (BrPhF) and Azidomethoxycarbonyl (Azoc), in particular Fmoc.

[0997] The invention thus relates also in particular to a compound selected from

[0998] (25)-2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;

[0999] (25)-2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;

[1000] (25)-2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;

[1001] (25)-2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid;

[1002] (25)-2-amino-3-(3-anilinophenyl)propanoic acid;

[1003] (25)-2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid;

[1004] (2S)-3-[4-[4-(Cyclopropoxy)phenyl]phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid;

[1005] (2S)-3-[4-[4-(Difluoromethoxy)phenyl]phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid;

[1006] (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-[4-[5-(trifluoromethyl)pyrazin-2- yl]phenyl]propanoic acid;

[1007] (2S)-3-[4-[3-(Difluoromethoxy)phenyl]phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid;

[1008] (2S)-3-(3-Anilinophenyl)-2-(9H-fluoren-9-ylmethoxy carbonylamino) propanoic acid; and(2S)-3-[4-(2-Chloro-4-pyridyl)phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid.

[1009] The invention further relates to the use of an amino acid compound as defined above in the manufacture of a peptide.

[1010] The invention will now be illustrated by the following examples which have no limiting character.Examples

[1011] The following methods were employed for the synthesis of compounds according to the invention, their purification and analysis:

[1012] • Resin: Rink Amide AM Resin LL 0.33 mmol / g (4-(2’,4’-Dimethoxyphenyl-Fmoc- aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin, Novabiochem), 100-200 mesh was used for the synthesis of all the peptide amides.

[1013] • Amino Acid Monomers: Fmoc-protected natural amino acids were purchased from Novabiochem, Iris Biotech, Bachem or Chem-Impex International. The following standard amino acids (protected monomers) were used in the synthesis: Fmoc-L- Phe-OH, Fmoc-L-Leu-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-His(BOC)-OH, Fmoc- L-Ser(tBu)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-R-Cys(Trt)-OH, Fmoc-L-Ala-OH, Fmoc-L-Lys(BOC)-OH, Fmoc-L-Trp(BOC)-OH, Fmoc-L- Thr(tBu)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(tBu)-OH, Fmoc-L- Asp(tBu)- OH, Fmoc-L-Val-OH.

[1014] • Purifications: Crude peptides were purified on a Waters 2489 HPLC preparative system. Preparative RP-C4-HPLC and C8 columns of different sizes and with different flow rates were used depending on the amount of crude peptide to be purified. Specifically, the following columns were used: Waters DeltaPak C4 (200x40mm, 300Å, 15μm); Dr. Maisch Reprosil gold C4 120A 5 uM 250x50 mm; Dr Maisch, Reprosil gold C4 120A 5 uM 250x40 mm; Dr. Maisch, Reprosil gold C8 120A 5 uM 250x50 mm. Acetonitrile (B) and water containing 0.1% TFA (A) were employed as eluents. Product-containing fractions were collected and lyophilized to obtain the purified product, typically as a TFA salt.

[1015] • Analytical characterization: Crude and purified peptides were analyzed by Ultra- high performance liquid chromatography (UPLC) with UV and single quadrupole mass spectrometry detection (UPLC-UV-MS). Analyses were performed on a Waters Acquity UPLC system equipped with an analytical column as follows:

[1016] ■ C1: Waters Acquity UPLC® Peptide BEH C18 (2.1x100 mm, 130 Å, 1.7μm, at 45°C)

[1017] ■ C2: Waters Acquity UPLC® Protein BEH C4 (2.1x100 mm, 300 Å, 1.7μm, at 45°C)C3: Waters XSelect®Peptide CSH C18 XP, (2.1x100 mm, 130, A, 2.5 μm, at 70°C)

[1018] • Mass analysis: Mass analysis was performed on a Waters SQ Detector with electrospray ionization in positive ion detection mode and the scan range of the mass- to-charge ratio was 400-1800. Analyses were performed using a linear gradient of binary mixtures of H₂O containing 0.1% TFA (A) and acetonitrile containing 0.1% TFA (B) or acetonitrile / methanol 7 / 3 containing 0.1% TFA (B’). The linear gradients of B were:

[1019] ■ Method 1 (Ml): 20%B-20%B (Imin), 20%B-60%B (5min), 60%B-80%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1020] ■ Method 2 (M2): 20%B-20%B (Imin), 20%B-40%B (5min), 40%B-90%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1021] ■ Method 3 (M3): 25%B-25%B (Imin), 25%B-45%B (5min), 45%B-90%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1022] ■ Method 4 (M4): 30%B-30%B (Imin), 30%B-50%B (5min), 50%B-90%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1023] ■ Method 5 (M5): 30%B-30%B (Imin), 30%B-50%B (4min), 50%B-90%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1024] ■ Method 6 (M6): 20%B-20%B (Imin), 20%B-40%B (4min), 40%B-80%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1025] ■ Method 7 (M7): 35%B-35%B (Imin), 35%B-55%B (4min), 55%B-80%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1026] ■ Method 8 (M8): 35%B-35%B (Imin), 35%B-50%B (5min), 50%B-90%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1027] ■ Method 9 (M9): 30%B-30%B (Imin), 30%B-50%B (4min), 50%B-90%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1028] ■ Method 10 (M10): 25%B-25%B (Imin), 25%B-45%B (4min), 45%B- 80%B(0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1029] ■ Method 11 (Mil): 15%B-15%B (Imin), 15%B-35%B (5min), 35%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1030] ■ Method 12 (M12): 10%B-10%B (Imin), 10%B-40%B (4min), 40%B- 90%B (0.2min); flow: 0.4 mL / min; column temperature: 45°C■ Method 13 (M13): 25%B-25%B (Imin), 25%B-45%B (4min), 45%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1031] ■ Method 14 (M14): 35%B-35%B (Imin), 35%B-55%B (5min), 55%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1032] ■ Method 15 (M15): 30%B’-30%B’ (Imin), 30%B’-50%B’ (5min), 50%B’- 90%B’(0.2min); flow: 0.4 mL / min; column temperature: 70°C

[1033] ■ Method 16 (M16): 25%B-25%B (Imin) 25%B-40%B (5min), 40%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 60°C

[1034] ■ Method 17 (M17): 30%B-30%B (Imin) 30%B-45%B (5min), 45%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 45°C

[1035] ■ Method 18 (M18): 30%B-30%B (Imin) 30%B-45%B (5min), 45%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 60°C

[1036] ■ Method 19 (M19): 35%B-35%B (Imin) 35%B-45%B (5min), 45%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 60°C

[1037] ■ Method 20 (M20): 30%B-30%B (Imin) 30%B-50%B (5min), 50%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 60°C

[1038] ■ Method 21 (M21): 30%B-30%B (Imin) 30%B-50%B (5min), 50%B- 80%B(0.2min); flow: 0.4 mL / min; Column temperature: 45°C

[1039] ■ Method 22 (M22): 35%B-35%B (Imin) 35%B-50%B (5min), 50%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 60°C

[1040] ■ Method 23 (M23): 35%B-35%B (Imin) 35%B-50%B (5min), 50%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 60°C

[1041] ■ Method 24 (M24): 35%B-35%B (Imin) 35%B-55%B (4min), 55%B- 90%B(0.2min); flow: 0.4 mL / min; column temperature: 45°C The following abbreviations are used in the present description.

[1042] AA: Amino acid

[1043] ACN: Acetonitrile

[1044] AHA: Acetohydroxamic acid

[1045] BOC: tert-butyloxy carbonyl (protecting group)

[1046] CHAPS: 3-((3-Cholamidopropyl) dimethylammonio)-1-propanesulfonate (detergent) C V: Column volume

[1047] DAD: Diode array detector

[1048] DIC: N, N'-DiisopropylcarbodiimideOxyma: Ethyl cyanohydroxyiminoacetate

[1049] DMF: N, N-Dimethylformamide

[1050] HOAT: 1-Hydroxy-7-azabenzotriazole

[1051] HPLC: High pressure liquid chromatography

[1052] LC-MS: Liquid chromatography coupled with mass spectrometry

[1053] MeOH: Methanol

[1054] DCM: Dichloromethane

[1055] Et₂O: Diethylether

[1056] FA: Formic acid

[1057] TFA: 2,2,2-Trifluoroacetic acid

[1058] TIPS: Triisopropylsilane

[1059] MTBE: Methyl tert-butyl ether

[1060] NPLC: Normal pressure liquid chromatography

[1061] NMM: N-methylmorpholine

[1062] HC1: Hydrochloric acid

[1063] HEPES: 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (buffer)

[1064] IPTG: Isopropyl-β-D-thiogalactopyranoside

[1065] DIPEA: N, N-Diisopropylethylamine

[1066] Oxyma: Oxyma Pure, ethyl(hydroxyimino)-cyanoacetate

[1067] Pbf: 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl (protecting group) RP: Reversed phase

[1068] RT: Room temperature

[1069] Rt: Retention time

[1070] SPPS: Solid phase petide synthesis

[1071] SPR: Surface Plasmon Resonance

[1072] TCEP: Tris(2-carboxyethyl)phosphine hydrochloride

[1073] TLCK: Tosyl-L-lysinchlorom ethylketone hydrochloride

[1074] Trt: Trityl (protecting group)

[1075] UPLC: Ultrahigh pressure liquid chromatography

[1076] Example 1: Synthesis of the compound of formula (I) with Seq ID 2 (3R,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S)-9-(2-amino-2-oxo-ethyl)-36-benzyl- 6,27-dibutyl-12-(3-guanidinopropyl)-15-(hydroxymethyl)-21,24,30-tris[(4-hydroxyphenyl)methyl]-18-(lH-imidazol-5-ylmethyl)-33-isobutyl-7,28-dim ethyl- 5,8,ll,14,17,20,23,26,29,32,35,38-dodecaoxo-l-thia-4,7,10,13,16,19,22,25,28,31,34,37- dodecazacyclononatriacontane-3-carboxamide

[1077] Step A

[1078]

[1079] Example 1

[1080] Step A - SPPS of linear Intermediate A2The peptide was synthesized by standard Solid-Phase Peptide Synthesis (SPPS) using Fmoc / t-Bu chemistry. The assembly was performed on a Rink-amide AM resin (200 pmol, 100-200Mesh; loading 0.33 mmol / g) on the CEM Liberty Blue microwave peptide synthesizer (CEM Inc.). During peptide assembly on solid phase, the side chain protecting groups were: trityl for Cys and Asn; Pbf for Arg, BOC for His, tert-butyl for Tyr and Ser side chains. All the amino acids were dissolved at a 0.2 M concentration in DMF. The acylation reactions were performed for 2 min at 90°C under microwave (MW) irradiation with 5 folds excess of activated amino acids over the resin free amino groups.

[1081] The amino acids were activated with equimolar amounts of 0.5M solution of DIC in DMF and Oxyma solution (IM) in DMF. Double acylation reactions were performed for MeNle4, Y5 and Y6, H7; triple acylation reactions were performed for Y3, R9 and N10. Fmoc deprotections were performed using 20% (V / V) piperidine in DMF. Capping of the free amino group after linear chain assembly was performed manually using 10 eq of chloroacetic anhydride in DMF. At the end of the assembly the resin was washed with DMF, MeOH, DCM, Et₂O. The peptide was cleaved from the solid support using 20 ml of TFA solution (V / V) (87.5% TFA, 5% Water, 2.5% TIPS, 5% Phenol) for approximately 1.5 hours, at room temperature. The resin was then filtered and precipitated in cold MTBE (135mL). After centrifugation, the peptide pellets were washed with fresh cold di ethylether to remove the organic scavengers. The process was repeated twice. Final pellets were freeze dried to afford the desired linear intermediate A2 (Y= 70%) as a white amorphous solid. UPLC-MS: Linear gradient: (%B) 20% in 1 min; 20 to 60% in 4 min; 60 to 90% in 0.1 min; 90% 0.2 min; Rt=3.63 min. MS (ESI+): M / z calc. for parent C₈₀H₁₁₂ClN₁₉O₁₈S: 1695.40; found: 1696.5 [M+H]⁺.

[1082] Step B - Synthesis of cyclic petide of Seq ID 2 (Example 1), obtained as bis TEA salt The crude linear peptide was dissolved in acetonitrile\water (at a concentration of 1 mg\mL). DIPEA (10 eq) was added to the mixture and stirring was continued at room temperature for 30 mins. The reaction was monitored by UPLC-MS until completed. Then, TFA (1 mL) was added. After lyophilization, the macrocycle crude peptide was purified by reverse-phase HPLC using a preparative Waters DeltaPak C4 (200x40mm, 300 A, 15pm) column. Mobile phase was A: H2O + 0.1% TFA, mobile phase B: Acetonitrile+ 0.1% TFA. The following gradient of eluent B was used: 25% B to 25% B over 5 min, to 40% B over 25 min, flow rate 80 mL / min, wavelength 214 nm. Collected fractions were lyophilized to afford Compound Seq ID 2 (352 mg, Y= 12%) as the TFA salt. UPLC-MS: Column: Acquity BEH C4; 10x2,1 mm;1,7 um; flow rate: 0.4 mL; 130A; Solvents: A = Water + 0.1% TFA; B = Acetonitrile + 0.1% TFA; Gradient: (%B): 25% in 1 min; 25 to45% in 5 min; 45 to 90% in 0.1 min; 90% 0.2 min; Rt= 3.55 min; 97% purity by UV. MS (ESI+): M / z calc. for parent C₈₀H₁₁₁N₁₉O₁₈S: 1658.92; found: 830.5 [M+2H]²⁺.

[1083] Examples 2-202: Peptides synthesized in analogy to Example 1:

[1084] The following peptides were synthesized in analogy to Example 1 shown above by following the procedures described for SPPS and by choosing the appropriate amino acid monomers according to the desired sequence. The respective sequences are given in Table la. The analytical data of these peptides which consist of the calculated and found masses as well as retention times are indicated in Table 3 below, along with the compound Seq ID and analytical method.

[1085] SEQ Rt Theor Found Example Method / ColumnID (min) MW MW (M+2)²⁺ 2 1 See representative synthetic example 1

[1086] 3 2 M6 / C2 3.7 1582.85 792.44

[1087] 4 3 M3 / C2 3.89 1672.9 837.5

[1088] 5 4 M3 / C2 3.9 1672.97 837.2

[1089] 6 5 M3 / C2 3.44 1683.9 843

[1090] 7 6 M3 / C2 3.4 1683.95 842.8

[1091] 8 7 M4 / C2 3.13 1726.9 864.2

[1092] 9 8 M4 / C2 3.16 1726.9 864.2

[1093] 10 9 M2 / C2 3.69 1700.98 852

[1094] 11 10 M2 / C2 3.24 1687.99 845.0

[1095] 12 11 M2 / C2 3.82 1701.9 851.7

[1096] 13 12 M6 / C2 4.27 1616.86 809.45

[1097] 14 13 M2 / C1 4.07 1702 852.2

[1098] 15 14 M13 / C2 3.44 1566.85 784.18

[1099] 16 15 M2 / C2 5.59 1681.9 842.1

[1100] 17 16 M2 / C2 3.88 1632.9 817.3

[1101] 18 17 M2 / C2 4.4 1673.9 838.4

[1102] 19 18 M2 / C2 3.93 1671 837

[1103] 20 19 M2 / C2 3.94 1700 850.8

[1104] 21 20 M3 / C2 3.35 1672.9 837.5

[1105] 22 21 M3 / C2 4.54 1685.9 844.2

[1106] 23 22 M2 / C2 3.96 1658 829.8

[1107] 24 23 M3 / C2 3.4 1684.98 843.8

[1108] 25 24 M6 / C2 3.88 1616.86 809.31

[1109] 26 25 M2 / C2 3.96 1616.8 809.5

[1110] 27 26 M6 / C2 3.96 1602.84 802.17

[1111] 28 27 M2 / C2 3.98 1646.8 824.5

[1112] 29 28 M2 / C2 4.01 1646.8 824.4

[1113] 30 29 M11 / C2 4.57 1673.9 837.9

[1114]

[1115] 31 30 M11 / C2 4.59 1659.9 830.7SEQ Rt Theor Found Example Method / ColumnID (min) MW MW (M+2)²⁺ 32 31 M13 / C2 3.46 1566.85 784.25 33 32 M6 / C2 3.39 1566.85 784.32 34 33 M2 / C2 3.15 1623.9 813.0 35 34 M1 / C2 3.19 1650.9 827.1 36 35 M4 / C2 3.87 1718.05 860.3 37 36 M4 / C2 3.48 1692.02 847.3 38 37 M4 / C2 3.78 1709.95 860.3 39 38 M4 / C2 3.21 1655.98 856.2 40 39 M3 / C2 4.09 1666.97 834.7 41 40 M3 / C2 4.24 1699 850.8 42 41 M2 / C2 4.06 1657.9 829.8 43 42 M3 / C2 3.8 1717 859.3 44 43 M4 / C2 4.33 1753.48 877.7 45 44 M2 / C2 4.1 1719 861 46 45 M4 / C2 3.91 1748.1 875.3 47 46 M4 / C2 4.8 1754.1 878.3 48 47 M4 / C2 3.99 1734 868.3 49 48 M3 / C2 3.52 1699 850.8 50 49 M4 / C2 4.14 1732 867.3 51 50 M2 / C2 4.17 1719 860.8 52 51 M2 / C2 4.02 1643.9 823 53 52 M2 / C2 4.07 1643.9 822.9 54 53 M4 / C2 4.26 1754.5 878.2 55 54 M2 / C2 4.07 1643.9 822.8 56 55 M4 / C2 3.66 1744 872.7 57 56 M4 / C2 3.43 1768.8 885.2 58 57 M4 / C2 4.57 1787.04 894.3 59 58 M4 / C2 4.64 1787.04 894.5 60 59 M3 / C2 3.99 1678.4 839.8 61 60 M3 / C2 3.68 1744.05 873 62 61 M2 / C2 3.64 1673.96 838 63 62 M2 / C2 3.97 1681.98 842 64 63 M13 / C2 3.45 1693.99 848.13 65 64 M4 / C2 3.61 1769.1 885.5 66 65 M8 / C2 4.11 1719.04 860.5 67 66 M4 / C2 3.03 1750.06 875.7 68 67 M3 / C2 3.89 1592.8 797.5 69 68 M3 / C2 4.22 1685 843.4 70 69 M3 / C2 3.46 1642.9 822.5 71 70 M3 / C2 3.49 1673 837.7 72 71 M3 / C2 3.86 1573.8 788 73 72 M3 / C2 3.91 1615.9 809 74 73 M3 / C2 3.8 1687 844.3 75 74 M3 / C2 4.44 1708 855

[1116]

[1117] 76 75 M3 / C2 4.28 1735 868.4SEQ Rt Theor Found Example Method / ColumnID (min) MW MW (M+2)²⁺ 77 76 M3 / C2 3.64 1672.97 837.5 78 77 M3 / C2 4.06 1735.04 868.5 79 78 M3 / C2 3.89 1672.97 838 80 79 M3 / C2 3.65 1658.94 831 81 80 M3 / C2 3.61 1672.97 837 82 81 M3 / C2 4.47 1644 823.2 83 82 M2 / C2 3.98 1602.8 802.5 84 83 M2 / C2 4.09 1616.8 809.3 85 84 M2 / C2 4.25 1646.8 824.4 86 85 M2 / C2 4.36 1646.8 829.24 87 86 M3 / C2 3.74 1692.96 847.6 88 87 M2 / C2 3.31 1674.9 838.2 89 88 M3 / C2 4.1 1699.01 850.3 90 89 M14 / C2 3.7 1831.2 916.8 91 90 M4 / C3 4.48 1790.1 896.2 92 91 M4 / C1 4.46 1804.1 903 93 92 M4 / C2 4.8 1824.5 913.2 94 93 M3 / C1 4.04 1771.1 886.2 95 94 M3 / C1 3.38 1729 864.8 96 95 M3 / C2 4.3 1761 881.8 97 96 M4 / C2 3.37 1776.1 889 98 97 M2 / C2 3.06 1763.06 882.7 99 98 M4 / C2 4.03 1747.1 874.2 100 99 M1 / C2 4.82 1781.5 891.2 101 100 M4 / C2 4.37 1761.1 881.3 102 101 M4 / C2 3.16 1728 864.7 103 102 M4 / C2 3.96 1720 860.8 104 103 M4 / C2 3.61 1760.14 881.11 105 104 M3 / C2 3.54 1741.11 871.7 106 105 M2 / C2 4.6 1761.13 881.5 107 106 M4 / C2 3.61 1794.58 898.4 108 107 M4 / C2 3.38 1766.53 883.9 109 108 M8 / C2 3.8 1821.48 911.5 110 109 M4 / C2 2.92 1732.09 867.1 111 110 M3 / C2 3.35 1713.06 867.1 112 111 M2 / C2 3.57 1791.11 896.3 113 112 M2 / C2 4.47 1786.14 894 114 113 M3 / C2 4.01 1773.09 887.4 115 114 M2 / C2 3.4 1791.11 896.5 116 115 M11 / C2 3.8 1804.16 903.1 117 116 M10 / C2 3.36 1748.08 875.1 118 117 M13 / C2 2.87 1700.04 851 119 118 M13 / C2 3.7 1712.03 857.3 120 119 M13 / C2 4.1 1665.93 834

[1118]

[1119] 121 120 M13 / C2 2.7 1727.04 864.3SEQ Rt Theor Found Example Method / ColumnID (min) MW MW (M+2)²⁺ 122 121 M13 / C2 3.89 1726.03 864 123 122 M13 / C2 3.21 1656.97 829.5 235 125 M13 / C1 4.35 1762.07 881.7 236 126 M13 / C1 4.35 1776.09 889.5 237 127 M9 / C1 3.47 1838.17 920.2 238 128 M9 / C1 4.12 1733.06 867.3 239 129 M9 / C1 4.35 1795.14 898.3 240 130 M9 / C1 2.45 1784.12 892.9 241 131 M9 / C1 3.53 1833.19 917.4 242 132 M9 / C1 3.96 1826.15 913.8 243 133 M9 / C1 3.72 1778.13 889.9 244 134 M14 / C1 3.48 1788.19 895.5 245 135 M13 / C1 3.59 1762.11 882.5 246 136 M5 / C1 3.23 1790.12 896.5 247 137 M5 / C1 4.24 1747.09 874.9 248 138 M5 / C1 4.19 1800.2 901.6 249 139 M5 / C1 3.95 1786.18 894.5 250 140 M9 / C1 3.41 1732.08 866.8 251 141 M9 / C1 4.12 1772.15 887 252 142 M5 / C1 3.8 1811.09 906.9 253 143 M9 / C1 3.12 1776.14 889 254 144 M9 / C1 2.8 1792.14 896.9 255 145 M9 / C1 3.52 1777.07 889.4 256 146 M9 / C1 3.82 1843.08 922.3 257 147 M13 / C1 3.25 1779.05 890.4 258 148 M9 / C1 3.70 1825.12 913.4 259 149 M9 / C1 3.97 1891.12 946.4 260 150 M13 / C1 3.46 1827.09 914.4 261 151 M9 / C1 3.60 1772.15 887.4 262 152 M9 / C1 3.47 1794.16 897.8 263 153 M9 / C1 3.65 1847.05 924.4 264 154 M7 / C1 3.26 1875.1 938.5 265 155 M13 / C1 3.43 1793.07 898 266 156 M5 / C1 4.02 1791.1 896.9 267 157 M5 / C1 4.45 1845.07 924 268 158 M5 / C1 3.8 1829.13 915.9 269 159 M5 / C1 3.39 1785.15 893.7 270 160 M5 / C1 3.91 1857.11 929.7 271 161 M5 / C1 4.07 1905.15 953.7 272 162 M5 / C1 3.2 1804.15 903.2 273 163 M5 / C1 3.39 1852.19 927.5 274 164 M5 / C1 4.25 1761.12 881.9 275 165 M5 / C1 4.19 1825.54 913.9 276 166 M24 / C1 3.92 1834.65 918.5

[1120]

[1121] 277 167 M5 / C1 3.97 1871.13 936.8SEQ Rt Theor Found Example Method / ColumnID (min) MW MW (M+2)²⁺ 278 168 M14 / C1 3.42 1873.59 937.7

[1122] 279 169 M14 / C1 3.73 1851.58 926.7

[1123] 280 170 M5 / C1 3.56 1816.11 909.1 281 171 M24 / C1 2.97 1774.17 888.4

[1124] 282 172 M19 / C1 3.16 1776.14 889.3

[1125] 283 173 M21 / C1 4.35 1826.15 913.9

[1126] 284 174 M20 / C1 4.00 1873.16 937.7 285 175 M20 / C1 4.07 1830.11 916.2

[1127] 286 176 M20 / C1 3.65 1775.15 888.8 287 177 M21 / C1 4.07 1747.10 874.6 288 178 M18 / C1 4.00 1790.16 896.3

[1128] 289 179 M16 / C1 4.00 1776.14 889.3

[1129] 290 180 M23 / C1 2.94 1804.19 903.2 291 181 M17 / C1 3.87 1780.13 891.2

[1130] 292 182 M17 / C1 4.12 1780.13 891.0

[1131] 293 183 M23 / C1 3.73 1871.13 936.7

[1132] 294 184 M23 / C1 3.22 1811.52 906.6 295 185 M23 / C1 4.33 1839.57 920.7

[1133] 296 186 M23 / C1 3.32 1857.11 929.6

[1134] 297 187 M23 / C1 3.75 1809.16 905.5 298 188 M23 / C1 3.28 1825.54 913.6

[1135] 299 189 M23 / C1 3.73 1873.59 937.6

[1136] 300 190 M23 / C1 3.33 1839.57 920.7

[1137] 301 191 M23 / C1 4.01 1935.66 968.6

[1138] 302 192 M23 / C1 4.07 1834.65 918.2

[1139] 303 193 M18 / C1 4.74 1786.18 893.8

[1140] 304 194 M23 / C1 3.15 1816.2 909.1

[1141] 305 195 M23 / C1 3.21 1823.53 912.5

[1142] 306 196 M18 / C1 4.13 1846.06 923.8

[1143] 307 197 M18 / C1 3.33 1802.08 901.8

[1144] 308 198 M23 / C1 3.69 1825.54 913.8

[1145] 309 199 M18 / C1 4.48 1821.13 911.4

[1146] 310 200 M20 / C1 4.20 1788.19 895.0

[1147] 311 201 M24 / C1 3.11 1871.8 936.7

[1148]

[1149] 312 202 M24 / C1 3.26 1919.15 960.8

[1150] Table 3: Analytical gradient, column, retention times, calculated and found masses, along with purity of the example compounds. The peptide with Seq ID 2 is described above as a representative example.

[1151] Example 123: Formation of the sulfone derivative of peptide with Seq ID 2

[1152]

[1153] Seq ID 2, sulfide Seq ID 124, sulfone

[1154] To a 0.001 M solution of peptide Seq ID 2 (Example 1, 35.2 mg) in water / ACN (1 / 1) and TFA (1 mL) was added 35% (v / v) hydrogen peroxide solution (100 eq). The mixture was left stirring for 30 minutes at RT. UPLC-MS showed complete conversion of the starting material to the sulfoxide intermediate (Seq ID 15). More hydrogen peroxide was added in portions (3 x 100 eq) and the reaction mixture was checked by UPLC-MS until all sulfoxide was converted into the corresponding sulfone. This trasformation required a total of 400 eq of hydrogen peroxide and 16 hours of stirring at RT. The mixture was then freeze dried and purified by reverse phase HPLC: Column Reprosil C4, 30x250 mm, mobile phase: A (water+0.1% TFA) and B (acetonitrile +0.1% TFA), flow rate: 60 mL / min. Gradient: 20% B (5 min) to 40% of B in 20 min then to 45% of B in 5 min, to afford after lyophilization 13 mg of the sulfone peptide Seq ID 124 (Example 123) as a white solid (34% yield) as a TFA salt. Analytical characterization: Method M3 / column C2; Retention time: 3.58 min; Caclulated mass (parent): 1690.9; found: 846.6 [M+2H]2.

[1155] 1692.1 [M+H]+.

[1156] Example 124: Formation of the sulfoxide derivative of peptide Seq ID 2

[1157]

[1158] (NH2F) Seq ID 2, sulfide Seq ID 125, sulfoxide

[1159] To a 0.001 M solution of peptide Seq ID 2 (Example 1, 23.0 mg) in water / ACN (1 / 1) and TFA (1 mL) was added 35% (v / v) hydrogen peroxide solution (100 eq). The mixture was left stirring for 30 minutes at RT. UPLC-MS showed full conversion of the starting material to a new peak with different retention time and a mass difference of +16 compared to peptide Seq ID 2. The mixture was then freeze dried and purified by reverse phase HPLC: Column Reprosil C4, 30x250 mm, mobile phase: A (water+0.1% TFA) and B (acetonitrile +0.1% TFA); flow rate: 60 mL / min. Gradient: 20% B (5 min) to 40% of B in 20 min then to 45% of B in 5 min, to afford after lyophilization 5.8 mg of the sulfoxide peptide Seq ID 125 (Example 124) as a white solid (21% yield) as the TFA salt.

[1160] Analytical characterization: Method M3 / column C2; Retention time: 3.2 min;

[1161] Calculated mass (parent): 1674.9; found: 838.4 [M+2H]2+, 1675.9 [M+H]+.

[1162] Example 203: Conversion of peptide of Seq ID 2 bis TFA salt to peptide of Seq ID 2 bis HCI salt

[1163]

[1164] Seq ID 2 bis TFA salt Seq ID 2 bis HCI saltThe purified peptide with Seq ID 2 as the bis TFA salt (Example 1, 25 mg) was dissolved in ACN / water 1:1 (about 7 mL) and then 10 eq of HC1 (50 mM aq. solution) was added and the mixture was stirred for 0.5 h at RT. Then, the mixture was lyophilized to obtain 20.7 mg of peptide Seq ID 2 as the bis HC1 salt.19F-NMR confirmed that the salt exchange had happened by absence of any visible signal for TFA in the spectrum. UPLC-MS:

[1165] Column: Acquity BEH C4; 10x2,1 mm; 1,7 um; flow rate: 0.4 mL; Solvents: A = Water + 0.1% TFA; B = Acetonitrile + 0.1% TFA; Gradient: (%B): 25% in 1 min; 25 to 45% in 5 min; 45 to 90% in 0.1 min; 90% 0.2 min; Rt= 3.37 mins, 91% purity by UV. MS (ESI+): M / z calc, for parent C8oHiiiNi90i8S: 1658.92; found: 1660.2 [M+H]+.

[1166] This material had comparable in vitro potency as the corresponding bis TFA salt.

[1167] Example 204: Conversion of peptide Seq ID 256 bis TFA salt to peptide Seq ID 256 bis Na+salt

[1168]

[1169] Seq ID 256, bis TFA salt Seq ID 256, bis Na+salt

[1170] The purified peptide Seq ID 256 (Example 146, 450 mg) was dissolved in 5% ACN and was diluted with 95% of aq. NaHCCL (100 mM) to a concentration of 0.25 mg / mL. Then, the solution was allowed to stir for 40 min at RT. The mixure was purified by RP / HPLC (Column: DeltaPak C4300A, 100x40mm; Eluents: A: H2O, B: ACN; Detection X: 214 nm) under the following conditions:

[1171] • Peptide loading: The peptide was loaded to the column at 10 mL / min, 95%A-5%B • NaHCCE loading: 3 Column volumes (1 CV: 125 mL) of an aq. solution (100 mM) of NaHCCL were loaded into the column at 10 mL / min.• Column wash to remove NaHCCL excess: The column was washed with 95% A - 5% B at 60 mL / min for 40 min, until the pH indicator paper showed neutral pH of the eluent.

[1172] • Peptide elution: The peptide was then eluted at 50% B, and the appropriate fractions were collected and lyophilized.

[1173] • Lyophilization afforded 371 mg of the peptide with Seq ID 256 as the bis Na+salt.

[1174] UPLC-MS analysis: Column: BEH130 C18 Acquity Waters 2.1x100 mm, 1.7pm;

[1175] Eluents: A= H2O + 0.1% TFA; B= CH3CN + 0.1% TFA; Gradient: 30%B-30%B over 1 min, 30%B-50%B over 5 min; Flow: 0.4 mL / min; X: 214 nm; Temp: 45°C.

[1176] MS (ESI+): M / z calc, for parent C90H117F2N17O21S: 1843.1; found: 922.6 [M+2H]2+.19F-NMR (internal standard a,a,a-trifluoro toluic acid, -61 ppm) confirmed that the salt exchange had happened. TFA detected: <5%.

[1177] This material had comparable biological activity as the corresponding bis TFA salt.

[1178] Example 205: Intermediates: Synthesis of amino acid monomers

[1179] Intermediate A: (2S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-l-yl)butanoic acid

[1180] OH

[1181]

[1182] The synthesis of this material was conducted according to procedures given in J. Med. Chem. 2022, 65, 6, 5072-5084. To a 0.05 M solution of the starting material (S)-3-(3-(9H-fluoren-9-yl)propanamido)-4-(tert-butoxy)-4-oxobutanoic acid in DCM was added HO AT (1.5 eq) and then EDC HC1 (1.5 eq) and NMM (3 eq) were added. The mixture was left stirring at room temperature for 10 minutes. Piperidine (1.1 eq) was added dropwise in two portions (0.55 eq each) with a time lapse of 1 hours between the additions. At the end of the second addition the mixture was left stirring for an additional hour. The solution was extracted 3 times with 10% citric acid, 3 times with saturated sodium bicarbonate solution, and brine. The organic layer was dried (Na2SO4) and volatiles were removed at reduced pressure. The resulting colorless oil was treated with a solution of 1: 1 TFA / DCM (50 mL)and stirred until the reaction was completed monitoring by TLC. The volatiles were removed at reduced pressure and remaining residual TFA was successively evaporated with more DCM. Approximately 150 mL of diethyl ether / pentane (1 / 1) was added to the crude and the solution was stirred vigorously overnight until the white precipitate was formed. The white solid was filtered and rinsed with diethyl ether to obtain the title compound (2S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-l-yl)butanoic acid as a white powder (90% yield).JH NMR (400 MHz, CDCI3): 5 = 1.55 -1.76 (m, 6H), 2.60 - 2.72 (m, 1H), 3.27 - 3.38 (m, 1H), 3.40 - 3.51 (m, 2H), 3.54 - 3.73 (m, 2H), 4.19 - 4.28 (m, 1H), 4.32 - 4.40 (m, 1H), 4.40 - 4.47 (m, 1H), 4.54 - 4.63 (m, 1H), 6.06 - 6.15 (m, 1H), 7.29 - 7.37 (m, 2H), 7.38 - 7.45 (m, 2H), 7.58 - 7.65 (m, 2H), 7.78 (d, J=7.50 Hz, 2H). UPLC: Column Waters Acquity UPLC® Peptide BEH C18 (2.1x100 mm, 130, A, 1.7pm, at 45°C), flow rate 0.4 mL, A = Water + 0.1% TFA; B = Acetonitrile + 0.1% TFA. Gradient (B%): 10% in 1 min, 10-90% in 5 min, 90% 0.3 min. Rt = 4.87 min. LCMS (ESI+): 423.40 [M+H]+.

[1183] Intermediate B: (2S)-4-(Diethylamino)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoic acid

[1184]

[1185] N2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N4, N4-diethyl-L-asparagine was synthesized as described above for Intermediate A (dimethylamine was used instead of piperidine under the same conditions). The desired material was isolated as white powder (92% yield).1HNMR(400 MHz, CDCI3): 8 = 1.13 - 1.32 (m, 6H), 2.64 - 2.77 (m, 1H), 3.22 - 3.55 (m, 4H), 4.20 - 4.27 (m, 1H), 4.30 - 4.39 (m, 1H), 4.40 -4.49 (m, 1H), 4.51 - 4.59 (m, 1H), 6.00 - 6.40 (m, 1H), 6.15 - 6.21 (m, 1H), 7.30 - 7.36 (m, 2H), 7.38 - 7.45 (m, 2H), 7.62 (t, J=7.38 Hz, 2H), 7.78 (d, J=7.50 Hz, 2H). UPLC: Column Waters Acquity UPLC® Peptide BEH Cl 8 (2.1x100 mm, 130, A, 1.7pm, at 45°C), flow rate 0.4 mL, A = Water + 0.1% TFA; B = Acetonitrile + 0.1% TFA. Gradient (B%): 40% in 1 min, 40-90% in 5 min, 90% 0.3 min. Rt = 2.91 min. LCMS (ESI+): 411.30 [M+H]+.Intermediate C: (2S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(pyrrolidin-l-yl)butanoic acid

[1186]

[1187] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(pyrrolidin-l-yl)butanoic acid was synthesized as described above for Intermediate A (pyrrolidine used instead of piperidine under the same conditions). The desired material was isolated as a white powder (87% yield). 'HNMR (400 MHz, CDC13): 5 = 1.90 - 2.09 (m, 4H), 2.67 (br dd, J=16.70, 10.19 Hz, 1H), 3.13 - 3.31 (m, 1H), 3.39 - 3.63 (m, 4H), 4.18 - 4.28 (m, 1H), 4.32 - 4.47 (m, 2H), 4.53 (td, J=4.97, 2.56 Hz, 1H), 6.14 (br d, J=4.50 Hz, 1H), 7.33 (t, J=7.47 Hz, 2H), 7.42 (t, J=7.38 Hz, 2H), 7.61 (t, J=5.47 Hz, 2H), 7.78 (d, J=7.63 Hz, 2H). UPLC: column Waters Acquity UPLC® Peptide BEH C18 (2.1x100 mm, 130, A, 1.7pm, at 45°C), flow rate 0.4 mL, A = Water + 0.1% TFA; B = Acetonitrile + 0.1% TFA. Gradient (B%): 10% in 1 min, 10-90% in 5 min, 90% 0.3 min. Rt = 4.57 min. LCMS (ESI+): 409.4 [M+H]+.

[1188] Intermediate D: (2S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino) heptanoic acid

[1189]

[1190] To a 0.45 M solution of (S)-2-((tert-butoxycarbonyl)(methyl)amino)heptanoic acid in DCM was added dropwise TFA ( 5 ml). The mixture was stirred at RT until the starting material disappeared on TLC. The solvent was removed in vacuo to give the deprotected intermediate as a TFA salt which was used without further purification and analysis. The material was dissolved in a mixture of THF / Water (1 / 1, 10 mL), K2CO3 (3eq) in water (5mL) was added follow by FmocOSuc (1.2 eq) in THF (5 mL). The mixture was stirred at RT overnight. The organic solvent was removed in vacuo. The aqueous phase was extracted with diethyl ether (3 times) and then HC1 IN was added until pH 1 was reached and it was extracted with diethyl ether. The organic layer was dried QSfeSCU), filtered and evaporated at reduced pressure to obtain the final product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)heptanoic acid as yellow oil (96% yield).1H NMR (400 MHz, CDC13): 8 = 0.82 - 0.97 (m, 3H), 1.15 - 1.40 (m, 6H), 1.54 - 2.07 (m, 2H), 2.84 - 2.94 (m, 3H), 4.20 - 4.84 (m, 4H), 7.28 -7.45 (m, 4H), 7.53 - 7.64 (m, 2H), 7.73 - 7.82 (m, 2H). UPLC: column Waters Acquity UPLC® Peptide BEH C18 (2.1x100 mm, 130, A, 1.7pm, at 45°C), flow rate 0.4 mL, A = Water + 0.1% TFA; B = Acetonitrile + 0.1% TFA. Gradient (B%): 30% in 1 min, 30-90% in 5 min, 90% 0.3 min. Rt = 5.30 min: LCMS (ESI+): 382.4 [M+H]+.

[1191] Intermediate E: (2S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid

[1192]

[1193] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was synthesized as described above for Intermediate D starting from the commercially available N-Boc protected amino acid N-Boc-4-(4-pyridinyl)-L-phenylalanine (CAS: 1211448-61-1). The desired product was precipitated with diethyl ether and was isolated as a white powder (93% yield).XH NMR (400 MHz, DMSO-d6 ): 8 = 1.73 - 1.92 (m, 1H), 2.68 - 2.96 (m, 4H), 5.85 - 5.94 (m, 2H), 5.97 - 6.03 (m, 2H), 6.10 (d, J=8.25 Hz, 2H), 6.24 (dd, J=7.44, 4.32 Hz, 2H), 6.41 (d, J=8.63 Hz, 1H), 6.48 (dd, J=7.75, 5.13 Hz, 4H), 6.60 - 6.74 (m, 2H), 7.40 (d, J=6.38 Hz, 2H), 11.25 - 11.60 (m, 1H). UPLC: column Waters Acquity UPLC® Peptide BEH C18 (2.1x100 mm, 130, A, 1.7pm, at 45°C), flow rate 0.4 mL, A = Water + 0.1% TFA; B = Acetonitrile + 0.1% TFA.

[1194] Gradient (B%): 10% in 1 min, 10-90% in 5 min, 90% 0.3 min. Rt = 3.39 min. LCMS (ESI+): 465.3 [M+H]+.Intermediate F: (2S)-3- [4- [4-(Cyclopropoxy)phenyl] phenyl] -2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1195]

[1196] Pd(OAc)2 (385 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (4.0 g), [4-(cyclopropoxy)phenyl]boronic acid (3.05 g), K3PO4(3.64 g) and 1, l'-bis(di-tert-butylphosphino)ferrocene (407 mg) in THF (50 mL) and the flask was purged three times with N2. Then, the mixture was stirred at 50 °C for 72 h under nitrogen. LCMS confirmed formation of a new product with the desired mass. The mixture was concentrated in vacuo and then diluted with 100 mL EtOAc. The organic phase was washed 3 times with 80 mL brine and then the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient of petroleum ether: ethyl acetate = 1: 1 to 0: 1), followed by prep-NPLC (Column: Welch Ultimate XB-CN 250*50*10um, Condition: Hexane (A) - IPA (B), B% (l%-35%) Gradient time(min):15.) to afford a product, which was further purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10 um; Condition: water (A; containing 0.1% FA) - ACN (B), gradient of B (50%-80%) to afford, after lyophilization, the title compound (2S)-3-[4-[4-(cyclopropoxy)phenyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.0 g, 22% yield) as a white solid. 'H-NMR (400 MHz, MeOD): 5 = 0.69 - 0.75 (m, 2H), 0.79 - 0.86 (m, 2H), 2.05 (s, 1H), 2.99 (dd, J=13.88, 9.72 Hz, 1H), 3.27 (dd, J=13.75, 4.58 Hz, 1H), 3.78 - 3.86 (m, 1H), 4.12 - 4.18 (m, 1H), 4.19 - 4.26 (m, 1H), 4.30 - 4.38 (m, 1H), 4.45 - 4.53 (m, 1H), 7.09 (d, J=8.68 Hz, 2H) 7.23 - 7.33 (m, 4H), 7.34 - 7.42 (m, 2H), 7.43 - 7.51 (m, 4H), 7.58 - 7.65 (m, 2H), 7.80 (d, J=7.58 Hz, 2H). LCMS (ESI+): 442.2 [MNa]+.

[1197] Intermediate G: (2S)-3- [4- [4-(Methoxy)phenyl] phenyl] -2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1198]

[1199] Pd(OAc)2 (481 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (5.0 g), 4-methoxyphenylboronic acid (2.44 g, K3PO4(4.55 g) and l,l'-bis(di-tert-butylphosphino)ferrocene (509 mg) in DMSO (8 mL) and the flask was purged with N2. Then, the mixture was stirred at 50 °C for 72 h under nitrogen. LCMS showed formation of a product with the desired mass. The mixture was diluted with 500 mL EtOAc and the organic layer was washed 3 times with 200 mL brine. Then, the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by NPLC (column: Welch Ultimate XB-CN 250*50* lOum; condition hexane (A) - EtOH (B, containing 0.1% FA) gradient of B: 10%~50%. After evaporation, the material was further purified by prep-HPLC (column: Phenomenex luna Cl 8 250*70mm,10 um; condition: water (A, containing 0.1% FA) - ACN (B); gradient of B: 50%-80%) to afford (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[4-(4-methoxyphenyl)phenyl]propanoic acid (840 mg, 16 % yield) as a white solid. 'H-NMR (400 MHz, MeOD): 5 = 2.97 (dd, J=13.82, 9.69 Hz, 1H), 3.25 (dd, J=13.88, 4.50 Hz, 1H), 3.81 (s, 3H), 4.10 - 4.16 (m, 1H), 4.17 - 4.24 (m, 1H), 4.27 - 4.35 (m, 1H), 4.47 (br dd, J=9.44, 4.32 Hz, 1H), 6.94 (d, J=8.76 Hz, 2H), 7.20 - 7.31 (m, 4H), 7.32 - 7.39 (m, 2H), 7.45 (d, J=8.13 Hz, 4H), 7.59 (dd, J=7.00, 5.13 Hz, 2H), 7.77 (d, J=7.63 Hz, 2H). LCMS (EST): 492.2 [M-H]'.

[1200] Intermediate H: (2S)-3-[4-[4-(tert-Butyloxy)phenyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1201]

[1202] Pd(OAc)2 (481 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (5.00 g), (4-tert-butoxyphenyl)boronicacid (3.12 g), K3PO4(4.55 g) and l,l'-bis(di-tert-butylphosphino)ferrocene (509 mg) in DMSO (8 mL) and the flask was purged with N2. Then, the mixture was stirred at 50 °C for 72 h under nitrogen. LCMS showed a product with the desired mass being formed. The mixture was diluted with 400 mL EtOAc and the organic phase was washed 3 times with 200 mL. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by NPLC (column: Welch Ultimate XB-CN 250*50* lOum; condition: hexane (A) - EtOH (B, containing 0.1% FA), gradient of B: 15% - 45%). After evaporation, the material was further purified by prep-HPLC (column: Phenomenex luna C18250*70mm,10 um; condition: water (A, containing 0.1% FA) - ACN (B); gradient of B: 55% - 85%) to afford after lyophilization of the appropriate fractions the title compound (2S)-3-[4-(4-tert-butoxyphenyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.27 g, 22% yield) as a white solid. 'H-NMR (400 MHz, MeOD): 5 = 1.36 (s, 9H), 2.91 - 3.02 (m, 1H), 3.26 (br dd, J=13.82, 4.65 Hz, 1H), 4.06 - 4.14 (m, 1H), 4.15 - 4.24 (m, 1H), 4.27 - 4.36 (m, 1H), 4.48 (dd, J=9.72, 4.71 Hz, 1H), 7.00 (d, J=8.56 Hz, 2H), 7.19 - 7.39 (m, 6H) 7.44 (dd, J=16.69, 8.25 Hz, 4H), 7.54 - 7.62 (m, 2H), 7.77 (d, J=7.46 Hz, 2H). LCMS (ESI’): 534.2 [M-H]'.

[1203] Intermediate I: (2S)-3- [4- [4-(Difluoromethoxy)phenyl] phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1204]

[1205] Pd(OAc)2 (963 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (10.0 g), 4-(difluoromethoxy)phenylboronic acid (12.1 g), K3PO4(9.10 g) and 1, l'-bis(di-tert-butylphosphino)ferrocene (1.02 g) in THF (50 mL) and the flask was purged with N2. Then, the mixture was stirred at 50 °C for 36 h under nitrogen. LCMS confirmed formation of a product with the desired mass. The mixture was diluted with EtOAc (300 mL) and the organic phase was washed wit brine (3 times 60 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The material was purified by silica gel chromatography (gradient of PE: Et OAc 1:1 to 0:1). The appropriate fractions were combined and evaporated and the residue was purified by NPLC (column: Welch UltimateXB-CN 250*50* lOum; condition: Hexane (A) - EtOH (B, containing 0.1% FA), gradient of B: 15% - 45%) to afford after lyophilization a material which was further purified by prep HPLC (Column: Phenomenex luna C18 (250*70mm,10 um); condition: water (A, containing 0.1% FA) - ACN (B), gradient of B: 54 - 84%). Lyophilization if the appropriate fractions provided the title compound (2S)-3-[4-[4-(difluoromethoxy)phenyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (3.16 g, 28% yield) as a yellow solid. 'H-NMR (400 MHz, MeOD): 5 = 2.94 - 3.03 (m, 1H), 3.23 - 3.29 (m, 1H); 4.09 - 4.15 (m, 1H), 4.17 - 4.24 (m, 1H), 4.32 (dd, J=10.39, 7.09 Hz, 1H), 4.48 (dd, J=9.78, 4.65 Hz, 1H), 6.83 (t, J=74.09, 1H), 7.13 - 7.19 (m, 2H), 7.22 - 7.40 (m, 6H), 7.48 (d, J=8.19 Hz, 2H), 7.54 (d, J=8.68 Hz, 2H), 7.59 (br d, J=7.09 Hz, 2H), 7.78 (d, J=7.58 Hz, 2H). LCMS (ESI+): 552.1 [MNa]+.

[1206] Intermediate K: (2S)-3- [4- [4-(Ethoxy)phenyl] phenyl] -2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1207]

[1208] Pd(OAc)₂ (481 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (5.00 g), 4-ethoxyphenylboronic acid (2.67 g), K3PO4(4.55 g) and l,l'-bis(di-tert-butylphosphino)ferrocene (509 mg) in THF (100 mL) and the flask was purged with N2, Then, the mixture was stirred at 50 °C for 72 h under nitrogen. LCMS confirmed formation of the desired product. The mixture was diluted with 100 mL EtOAc and washed 3 times with 60 mL brine. Then, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by NPLC (column: Welch Ultimate XB-CN 250*50* lOum; condition; hexane (A) - EtOH (B, containing 0.1% FA); gradient of B: 1% - 40%), followed by prep-HPLC (column: Phenomenex luna C18250*70mm,10 um; condition: water (A, containing 0.1% FA) -CAN (B), gradient of B: 55% - 85%) to afford after lyophilization (2S)-3-[4-(4-ethoxyphenyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.40 g, 26% yield) as a pink solid. 'H-NMR (400 MHz, MeOD): 5 = 1.40 (t, J=7.00 Hz, 3H), 2.91- 3.02 (m, 1H), 3.25 (dd, J=13.88, 4.63 Hz, 1H), 4.05 (q, J=6.92 Hz, 2H), 4.10 - 4.16 (m, 1H), 4.17 - 4.24 (m, 1H), 4.27 - 4.36 (m, 1H), 4.46 (dd, J=9.69, 4.69 Hz, 1H), 6.92 (d, J=8.63 Hz, 2H), 7.21 - 7.31 (m, 4H), 7.32 - 7.40 (m, 2H), 7.40 - 7.49 (m, 4H), 7.56 - 7.62 (m, 2H), 7.77 (d, J=7.50 Hz, 2H). LCMS (ESI’): 506.2 [M-H]'.

[1209] Intermediate L: (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(4-pyrazin-2-ylphenyl)propanoic acid

[1210]

[1211] Step 1: (2S)-2-Amino-3-(4-pyrazin-2-ylphenyl)propanoic acid

[1212]

[1213] A 20-mL Smith Process Vial containing a magnetic stir bar was charged with (2S)-2-amino-3-(4-boronophenyl)propanoic acid (1.00 g), 2-bromopyrazine (761 mg), Pd(PPh₃)₂Cl₂ (168 mg), Na₂CO₃ (1M aqueous solution, 9.57 mL), acetonitrile (10 mL) and water (3mL). After degassing in vacuo, the vial was sealed and the suspension was heated in a Smith SynthesizerlO microwave for 0.5 h. LCMS showed formation of the desired product.

[1214] Four additional reactions (3 of 1.00 g, each, and one of 200 mg of (2S)-2-amino-3-(4-boronophenyl)propanoic acid) were run in the same way. Alle the crude reaction mixtures from the different vials were combined for work up. The mixture was extracted with 100 mL EtOAc and the organic layer was washed 3 times with 80 mL brine (brine phase not used, as it did not contain any product as judged by LC-MS). After extraction with EtOAc, the original water phase was lyophilized and the residue was purified by reverse phase chromatography (column: Welch Ultimate XB_C18 20-40μm; eluent A: water (0.1% FA), eluent B: ACN; gradient of B: 1% - 40%) to give after lyophilization the desired material(2S)-2-amino-3-(4-pyrazin-2-ylphenyl)propanoic acid as a white solid (3.80 g, 78% yield). LCMS (ESP): 242.0 [M-H]’.

[1215] Step 2: (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(4-pyrazin-2-ylphenyl)propanoic acid

[1216]

[1217] In an ice-water bath, a mixture of (2S)-2-amino-3-(4-pyrazin-2-ylphenyl)propanoic acid (3.60 g) in a mixture of ACN (40 mL) and water (40 mL) was stirred. After complete dissolution of the solid, sodium hydrogencarbonate (2.49 g) was added in portions, and then FMOC-OSu (9-fluorenylmethyl N-succinimidyl carbonate, 4.99 g) were added slowly and the reaction was stirred for 16 h at RT. LCMS confirmed formation of the desired product. Then, the reaction mixture was lyophilized and the residue was purified by reverse phase chromatography (column: Welch Ultimate XB_C18 20-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient of B: 1% - 65%) to give a crude product as white solid. LCMS showed purity of 71%. Then, the crude material was triturated with a mixture of ACN (10 mL) and MeOH (10 mL) to give after filtration (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-pyrazin-2-ylphenyl)propanoic acid (900 mg, 12% yield) as white solid, and after repetition of the procedure a second crop (700 mg, 10% yield) of the same material with essentially the same analytical data. 'H-NMR (400 MHz, MeOD): 5 = 2.97 - 3.08 (m, 1H), 3.28 - 3.36 (m, 1H, covered by solvent signal), 4.07 - 4.16 (m, 1H), 4.17 - 4.25 (m, 1H), 4.27 - 4.35 (m, 1H), 4.46 - 4.56 (m, 1H), 7.21 - 7.30 (m, 2H), 7.35 (br t, J=7.09 Hz, 2H), 7.38 - 7.44 (m, 2H), 7.53 - 7.62 (m, 2H), 7.71 - 7.82 (m, 2H), 7.97 (d, J=8.19 Hz, 2H), 8.43 - 8.53 (m, 1H), 8.60 - 8.67 (m, 1H), 8.98 (s, 1H). LCMS (ES ): 464.2 [M-H]’.

[1218] Intermediate M: (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3- [4- [5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid

[1219]

[1220] Step 1: (2S)-2-Amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid

[1221]

[1222] This material was obtained in close analogy to Step 1 of the example shown above for Intermediate L from (2S)-2-amino-3-(4-boronophenyl)propanoic acid and 2-bromo-5-(trifluoromethyl)pyrazine as a white solid. 'H-NMR (400 MHz, DMSO-d6): 5 = 2.73 - 2.93 (m, 1H), 3.03 - 3.16 (m, 2H), 7.34 - 7.49 (m, 2H), 8.11 (br d, J=7.82 Hz, 2H), 9.23 (s, 1H), 9.35 - 9.51 (m, 1H).

[1223] Step 2: (2S)-2-Amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid

[1224]

[1225] This material was obtained in close analogy to Step 2 of the example shown above for Intermediate L from (2S)-2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid and FMOC-OSu and was obtained as a white solid. 'H-NMR (400 MHz, MeOD): 5 = 2.99 (s, 1H), 3.33 - 3.39 (m, 1H, partially covered by solvent peak), 4.03 - 4.12 (m, 1H), 4.15 - 4.24 (m, 1H), 4.27 - 4.36 (m, 1H), 4.48 - 4.59 (m, 1H), 7.20 - 7.30 (m, 2H), 7.31 -7.39 (m, 2H), 7.45 (d, J=8.19 Hz, 2H), 7.53 - 7.63 (m, 2H), 7.71 - 7.80 (m, 2H), 8.09 (d, J=8.31 Hz, 2H), 8.99 (s, 1H), 9.11 - 9.19 (m, 1H). LCMS (ESI⁻): 532.2 [M-H]⁻.Intermediate N: (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3- [4- [6-(trifluoromethyl)-3-pyridyl] phenyl] propanoic acid

[1226]

[1227] Pd(OAc)₂ (385 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (4.00 g), 2-trifluoromethylpyridine-5-boronic acid (3.28 g), K₃PO₄ (3.64 g) and 1,1'-bis(di-tert-butylphosphino)ferrocene (407 mg) in THF (100 mL) and the flask was purged with N₂. Then, the reaction mixture was stirred at 50 °C for 72 h. LCMS showed the desired product being formed. The mixture was cooled, diluted with 100 mL EtOAc and washed 3 times with 60 mL brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by NPLC (column: Welch Ultimate XB-CN 250*50* lOum, Eluent: hexanes (A) -EtOH (B, containing 0.1% FA); gradient of B: 15% - 45%), followed by a second NPLC purification (column: Welch Ultimate XB-CN 250*50* lOum; Eluent: Hexanes (A) -EtOH (B, containing 0.1% FA); gradient of B: 15% - 45%) to afford a more pure product, which was further separated by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 10 um); condition: water (A, containing 0.1% FA) - ACN (B); gradient of B: 55% -85%) to afford after lyophilization of the appropriate fractions the title compound (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[4-[6-(trifluoromethyl)-3-pyridyl]phenyl]propanoic acid (2.18 g, 47% yield) as a white solid. 'H-NMR (400 MHz, MeOD): 5 = 3.04 (dd, J=13.82, 9.90 Hz, 1H), 3.32 - 3.38 (m, 1H, parially covered by solvent signal), 4.07 - 4.15 (m, 1H), 4.18 - 4.26 (m, 1H), 4.29 - 4.37 (m, 1H), 4.50 - 4.58 (m, 1H), 7.23 - 7.32 (m, 2H), 7.37 (t, J=7.46 Hz, 2H), 7.44 (d, J=7.95 Hz, 2H), 7.56 - 7.67 (m, 4H), 7.75 - 7.86 (m, 3H), 8.15 (br d, J=8.19 Hz, 1H), 8.88 (s, 1H). LCMS (ESI+): 533.2 [MH]+.

[1228] Intermediate O: (2S)-3-[4-(4-Cyanophenyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1229]

[1230] Pd(OAc)2 (385 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (4.00 g), 4-cyanophenylboronic acid (2.52 g), K3PO4(3.64 g) and l,l'-bis(di-tert-butylphosphino)ferrocene (407 mg) in DMSO (8 mL) and the flask was purged with N. Then, the mixture was stirred at 50 °C for 72 h under nitrogen. LCMS showed formation of a product with the desired mass. The mixture was diluted with 80 mL EtOAc and washed 3 times with 60 mL brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by NPLC (column: Welch Ultimate XB-CN 250*50* lOum; eluent: hexanes (A) - EtOH (B, containing 0.1% FA); gradient of B: 15% - 45%) to afford a material which was further purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um); eluent: water (A, containing 0.1% FA) - ACN (B), gradient of B: 50% - 80%) to afford the title compound (2S)-3-[4-(4-cyanophenyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.125 g, 27% yield). A second crop of (2S)-3-[4-(4-cyanophenyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid was also obtained (330 mg). 'H-NMR (400 MHz, MeOD): 5 = 2.95 - 3.06 (m, 1H), 3.26 - 3.32 (m, 1H, covered by solvent signal), 4.05 - 4.13 (m, 1H), 4.15 - 4.23 (m, 1H), 4.26 - 4.35 (m, 1H), 4.46 - 4.56 (m, 1H), 7.19 - 7.30 (m, 2H), 7.32 - 7.40 (m, 4H), 7.53 - 7.61 (m, 4H), 7.65 - 7.82 (m, 6H). LCMS (ESI+): 511.1 [MNa]+.

[1231] Intermediate P: (2S)-3-[4-[3-(Difluoromethoxy)phenyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1232]

[1233] Pd(0Ac)2 (96.3 mg) was added to a stirred mixture of (2S)-3-(4-bromophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.00 g), 3-(difluoromethoxy)phenylboronic acid (605 mg), K3PO4(910 mg) and 1, l'-bis(di-tert-butylphosphino)ferrocene (102 mg) in DMSO (8 mL) and the flask was purged with N2. Then, the mixture was stirred at 70 °C for 36 h under nitrogen. LCMS showed a peak with the desired mass. The mixture was diluted with 200 mL EtOAc and the organic phase was washed three times with 100 mL brine. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by NPLC (column: Welch Ultimate XB-CN 250*50* lOum; eluent: hexanes (A) - EtOH (B, containing 0.1% FA); gradient of B: 5% - 45%) to afford, after lyophilization of the desired fractions, the title compound (2S)-3-[4-[3-(difluoromethoxy)phenyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (300 mg, 26% yield) as a yellow solid.

[1234] 'H-NMR (400 MHz, MeOD): 5 = 2.99 (dd, J=13.75, 9.72 Hz, 1H), 3.24 - 3.30 (m, 1H, partially covered by solvent signal), 4.09 - 4.15 (m, 1H), 4.17 - 4.24 (m, 1H), 4.32 (dd, J=10.39, 6.97 Hz, 1H), 4.44 - 4.52 (m, 1H), 6.85 (t, J=74.3 Hz, 1H), 7.05 - 7.12 (m, 1H), 7.21 - 7.45 (m, (8H)), 7.50 (d, J=8.19 Hz, 2H), 7.59 (d, J=7.46 Hz, 2H) 7.77 (d, J=7.58 Hz, 2H).

[1235] Intermediate Q: (2S)-3-(3-Anilinophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino) propanoic acid

[1236]

[1237] Step 1: Methyl (2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoate

[1238]

[1239] To a solution of methyl (2S)-2-amino-3-(3-bromophenyl)propanoate hydrochloride (28.0 g), TEA (52.9 mL) inDCM (20 mL) was added di -t-butyl di carb onate (31.1 g) at 0°C. Then, the mixture was stirred at 20 °C for 12 h. TLC (EtOAc / PE = 1 / 5, product R / =0.5) showed a new spot being formed. LCMS confirmed full consumption of the starting material and a major peak with the desired desired product mass. The mixture was diluted with H2O (300 mL) and the aqueous phase was extracted with more DCM (2 times 200 mL). The organic layers were washed with brine (200 mL), dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to give the crude product which was then purificated by silica gel chromatography (elution with a gradient of PE: EtOAc = 20: 1 to 5:1) to give the desired product methyl (2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoate (32.0 g, 89% yield) as a light yellow solid. ‘H-NMR (400 MHz, CDCI3): δ = 1.53(s, 9H) 3.05 - 3.15 (m, 1H), 3.17 - 3.27 (m, 1H), 3.83 (s, 3H), 4.62 - 4.73 (m, 1H), 5.05 - 5.17 (m, 1H), 7.13 - 7.20 (m, 1H), 7.23 - 7.31 (m, 1H), 7.35 - 7.42 (m, 1H) 7.45 - 7.52 (m, 1H). Step 2: Methyl (2S)-3-(3-anilinophenyl)-2-(tert-butoxycarbonylamino)propanoate

[1240] H

[1241]

[1242] Pd2(dba)s (1.0 g) and K3PO3 (7.0 g) was added to a solution of aniline (1.47 mL), methyl (2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoate (4.3 g) and XPhos (1.0 g) under N2 atmosphere and then the mixture was stirred at 90 °C for 16 h. The mixture was diluted with 80 mL EtOAc and the organic layer was washed three times with 100 mL brine. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash column chromatography eluting with 16%EtOAc in PE and the desired fractions were combined and concentrated to afford methyl (2S)-3-(3-anilinophenyl)-2-(tert-butoxycarbonylamino)propanoate (5.2 g, 117% yield) as yellow solid which was slightly contaminated with residual solvents. 'H-NMR (400 MHz, CDCI3): 5 = 1.42 (s, 9H), 2.94 - 3.12 (m, 2H), 3.71 (s, 3H), 4.53 - 4.64 (m, 1H), 4.94 - 5.05 (m, 1H), 6.69 (d, J=7.58 Hz, 1H), 6.82 - 6.87 (m, 1H), 6.91 - 6.98 (m, 2H), 7.04 - 7.11 (m, 2H), 7.15 - 7.22 (m, 1H), 7.24 - 7.32 (m, 3H).

[1243] Step 3: (2S)-2-Amino-3-(3-anilinophenyl)propanoic acid hydrochloride

[1244]

[1245] o

[1246] HCI

[1247] A mixture of methyl (2S)-3-(3-anilinophenyl)-2-(tert-butoxycarbonylamino)propanoate (3.7 g) in 4 M HCI in dioxane (50.0 mL) was stirred at 25 °C for 16 h. Then, the mixture was concentrated in vacuo to dryness to afford crude (2S)-2-amino-3-(3-anilinophenyl)propanoic acid hydrochloride (3.50 g, 120% crude yield) as yellow solid which was used without further purification.1H-NMR (400 MHz, MeOD): 5 = 3.06 - 3.15 (m, 1H), 3.17 - 3.29 (m, 1H), 4.19 - 4.27 (m, 1H), 6.81 (br d, J=7.21 Hz, 1H), 6.86 - 6.95 (m, 1H), 7.01 - 7.09 (m, 2H), 7.13 (br d, J=8.44 Hz, 2H), 7.20 - 7.30 (m, 3H).

[1248] Step 4: (2S)-3-(3-Anilinophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1249]

[1250] (2S)-2-amino-3-(3-anilinophenyl)propanoic acid hydrochloride (3.0 g) was dissolved in ACN (40 mL) and water (8 mL) and the mixture was then cooled to 0 °C with an ice bath. Sodium hydrogencarbonate (3.0 g) was added, followed by addition of FMOC-OSu (3.8 g) in several batches, Then, the mixture was stirred for 16 h at 25 °C. LCMS showed formation of the desired product. The reaction mixture was diluted with 50 mL ethyl acate and was washed three times with 50 mL brine. The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo to afford a crude product. This was then purified by prep-NPLC (column: Welch Ultimate XB-CN 250*50* lOum; mobile phase: hexanes (A) -EtOH (B, containing 0.1% FA); gradient of B: 25% - 55%) and the desired fractions were combined and evaporated to afford the title compound (2S)-3-(3-anilinophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.30 g, 26% yield) as an off-white solid. 'H-NMR (400 MHz, DMSO-d6): 5 = 2.76 - 2.87 (m, 1H), 2.97 - 3.08 (m, 1H), 4.10 - 4.27 (m, 4H), 6.70 - 6.84 (m, 2H), 6.86 - 6.95 (m, 1H), 7.00 - 7.09 (m, 3H), 7.14 (t, J=7.76 Hz, 1H), 7.17 - 7.24 (m, 2H), 7.24 - 7.43 (m, 2H), 7.35 - 7.45 (m, 2H), 7.60 - 7.70(m, 2H), 7.71 - 7.79 (m, 1H), 7.82 - 7.93 (m, 2H), 8.07 - 8.16 (m, 1H), 12.56 - 12.95 (br s, 1H). LCMS (ESI+): 479.3 [MH]+.

[1251] Intermediate R: (2S)-3-[4-(4-Acetylpiperazin-l-yl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1252] 0

[1253]

[1254] Step 1: (S)-3-(4-(4-Acetylpiperazin-l-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[1255]

[1256] (S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.0 g), 1-(piperazin-l-yl)ethan-l-one (0.372 g) were dissolved / suspended in toluene (30 ml) and bubbling with N2 was performed for 5 minutes. Then, the mixture was heated at 90-100 °C and XPhos Pd G2 (349 mg) and cesium carbonate (1.420 g) were added under nitrogen flux and the mixture was heated at 110 °C for 16 h under nitrogen. UPLC MS showed formation of desired product. Then, the mixture was cooled to RT and poured into water. The acqueous phase was acidified with citric acid and extracted with EtOAc. The organic extract was washed with brine and dried (Na₂SO₄) and filtered. The solvent was removed under reduced pressure to give the crude product which was purified by reverse phase flash chromatography (C18 column 120 g HP Lucknova, eluent water / acetonitrile 0,1 % TFA in both eluents, gradient from 100:0 to 30:70 in 10 CV) to give after lyophilization the title compound (756 mg). UPLC-MS: Column; Acquity BEH C18; 100 x 2,1mm; l,7um; 300A. Eluent: (%B): 10 to 90% in 4min,; A= H2O + 0.1%TFA; B= ACN + 0.1%TFA; flow: 0.4mL / min. Diode array UV detector. RT: 3.10 min. LCMS (ESI+): 392.4 [M+H]+.Step 2: (2S)-3-[4-(4-Acetylpiperazin-l-yl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[1257] o

[1258]

[1259] The material from Step 1 (756 mg) was suspended in THF and treated with HC1 (4M in dioxane, 10 mL) for 16 h at RT. Then, the volatiles were removed and the crude residue was dissolved in water (22 mL) and acetone (11 mL) and treated with sodium bicarbonate (615 mg) and (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-l-yl) carbonate (689 mg) for 16h. EtOAc (50 mL) was added and the mixture was acidified and washed with HC1 (IN, 50 mL). The phases were separated and the aqueous layer was extracted with another 50 mL of EtOAc. The combined organic layers were dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude product which was purified by reverse phase flash crhomatography (Cl 8 column 120 g HP Lucknova, eluent water / acetonitrile 0,1 % TFA in both eluents, gradient from 100:0 to 10:90 in 10 CV) to give after lyophilization from water / acetonitrile 1:1 the title compound (2S)-3-[4-(4-acetylpiperazin- 1 -yl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (279 mg, 54% yield over two steps). UPLC-MS, column: Acquity BEH Cl 8;

[1260] 100x2, lmm;l,7um; 300A. Eluent (%B): 25 to 55% in 4min; A= H2O + 0.1% TFA; B= ACN + 0.1% TFA; flow: 0.4 mL / min. Diode array UV detector. RT: 3.06 min. LCMS (ESI+): 514.4 [M+H]+.

[1261] Intermediate S: F

[1262]

[1263] To a N2-flushed 20 mL scintillation vial equipped with a magnetic stir bar were added (2S)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(4-iodophenyl)propanoic acid (1.0 g),2-chloropyridine-4- boronic acid (766 mg) and 10 mL of dry THF. The suspension was degassed by bubbling N2into the vial for several minutes. Then, 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride toluene adduct (80 mg) and K3PO4(1.65 g) were added. The suspension was degassed again for several minutes and then the vial was capped with a septum. The reaction mixture was stirred at 50 °C for 16 h. After being cooled, 20% citric acid was added to acidify the reaction. The organic layer was separated and the aqueous layer was extracted two times with EtOAc. The acqueous phase was made basic with Na2CO3solution and was back extracted with ethyl acetate. The organic layers were joined and dried over Na2SO4, filtered and concentrated to obtain a crude residue. This material was purified by RP cromatograpy: Biotage Isolera; cartride: Luknova C18, 120 g; Eluents: A) water+0.1% TFA; B) Acetonitrile+0.1% TFA; gradient from 20% B to 60% in 15 CV. The fractions containing the desired product were freeze dried which gave 300 mg (28% yield) of the title compound as pale yellow solid with a purity of about 90% by UV. UPLC-MS: Column: Acquity BEH C18; 100x2, lmm;l,7um; 300A; eluents: A= H2O + 0.1%TFA, B= ACN + 0.1%TFA; gradient: (%B): 10% in 1 min; 10 to 90% in 5 min,; flow: 0.4mL / min. Diode array UV detector (: 200-400 nm); Rt: 5.85 min. MS (ESI+): 499 [M+H]+.

[1264] Example 206: Inhibition of Matrix Metalloproteases

[1265] Assay Protocols:

[1266] Matrix Metalloproteinase 9 (MMP9) inhibitors were characterized using a biochemical assay that measures the increase of a fluorescence signal upon cleavage of the peptidic substrate of the enzyme.

[1267] Peptides were dissolved at 10 mM in 100% DMSO and transferred to 384-well assay plate (Corning® Low Volume plate, #3821) using an acoustic droplet ejection instrument.

[1268] Peptides were tested in 16-point dose response curves with a dilution factor of 2.5 starting from 208 pM or 500 nM for the most active molecules.

[1269] Procedure:

[1270] • 5 pL of hMMP9 enzyme (hMMP9(19-707)WT_C-TEV-Avi-10xHis-EPEA, see below for an expression procedure) diluted to 0.5 nM in assay buffer (25 mM Hepes pH 7.4, 10 mM CaCl2, 100 mM NaCl, 0.1% CHAPS, 1 mM TCEP) was added to peptide containing assay plates.• After 20 minutes of incubation at room temperature, the enzymatic reaction was started with the addition of 5 pL of the MR121-cPLGLW substrate diluted in assay buffer to achieve a final concertation of 2 pM.

[1271] • After 1 h incubation at room temperature, the fluorescence signal was collected reading the plate on the Envision plate reading (Ex / Em: 620 / 685 nm).

[1272] • Data were normalized between 0 and 100% inhibition (2% DMSO wells and a reference compound from the public domain (AZD-1236, CAS 459814-89-2, (5S)- 5-[[4-(5-chloropyridin-2-yl)oxypiperidin-l-yl]sulfonylmethyl]-5- methylimidazolidine-2, 4-dione) at 5 pM respectively). For EC50determinations, the dose-response curve was fitted with a 4 parameters logistic regression equation.

[1273] To verify the selectivity of the compounds, other matrix metalloproteinases assays were performed using essentially the same procedure as described for MMP9, except for:

[1274] • hMMP2 (from SignalChem Cat. #M846-40N-100) was used at 5 nM final concentration and the fluorescence signal was acquired after 90 minutes incubation at room temperature.

[1275] • hMMPIO (from Aviva system Cat. #OPED00091) was used at 8.5 nM final concentration and the fluorescence signal was acquired after 90 minutes incubation at room temperature.

[1276] • hMMP14 (from Biovision Cat. #8009-10) was used at 6 nM final concentration and the fluorescence signal was collected after an overnight incubation at room temperature.

[1277] • mMMP9: Mouse MMP9 (obtained from Cepter Biopartners. Construct:

[1278] mMMP9(l 13-215, 391-444)del(216-390)_Q391T, see below for an expression procedure) was used at 0.5 nM final concentration and the fluorescence signal was collected after 30 minutes incubation at room temperature.

[1279] Expression and purification of non-commercial MMP protein constructs used for in vitro activity assays

[1280] Human full length MMP9: hMMP9(19-707)WT C-TEV-Avi-lOxHis-EPEA:Full-length human MMP9 (19-707) was cloned into pExpreS2.1 with C-terminal Avi-10-His-EPEA tag and a TEV cleavage site. The endogenous signal sequence was replaced by the Drosophila immunoglobulin heavy chain-binding protein (BiP) sequence resulting in the final construct BiP-hMMP9 (19-707)WT_C-TEV-Avi-10His-EPEA. Stable, polyclonal S2 cell lines were generated using manufacturer’s instructions (Expres2ion Biotechnologies). After cultivation, the cell culture media containing the recombinant protein was concentrated and buffer exchanged using an AKTA Crossflow (30K MWCO, 3 x 100cm2) into Buffer A (50 mM HEPES pH 7.8, 0.5 M NaCl, 10% glycerol, 0.35% CHAPS, 0.02% NaN3). The His-tagged protein was purified via a HisTRAP column (Cytiva) and eluted with buffer A supplemented with 0.5 M imidazole. The elution fractions were concentrated and further purified on size exclusion chromatography (Superdex200 increase GL10 / 300) in 50 mM TRIS / C1 pH 8, 0.5 M NaCl, 5 mM CaCl2, 0.1 mM Zn acetate, 0.35% CHAPS, 0.02% NaN3. In order to activate the enzyme, MMP9 is incubated with Trypsin (Thermo) for ca. 17 hours at room temperature at a 100: 1 w / w ratio. The reaction is stopped with TLCK at 0.5 mM end concentration. To remove trypsin and TLCK, activated MMP9 is further purified on a second size exclusion chromatography step using a Superdex 200 Increase GL10 / 300 in 50 mM TRIS / C1 pH 8, 0.5 M NaCl, 5 mM CaCl2, 0.1 mM Zn acetate, 0.35% CHAPS, 0.02% NaN3.

[1281] Mouse MMP9: mMMP9(l 13-215, 391-444)del(216-390) Q391T:

[1282] A construct encoding mouse MMP9(113-215,391-444) Q391T was cloned into pET26 and expressed in BL21(DE3) cells after induction with 1 mM IPTG at 23 °C overnight. All subsequent steps were executed at 4 °C unless stated otherwise. Cell pellets were resuspended in 500 mM NaCl, 50 mM Tris / HCl pH 7.5, 10% glycerol, lysed using a microfluidizer and inclusion bodies were collected at 29753 g, 40 min. Inclusion bodies were resuspended in 50 mM Tris / HCl (pH 7.5), 6 M urea and incubated overnight. After overnight incubation, denatured protein was diluted 15-fold in 50 mM Tris / HCl (pH 7.5), 6 M urea and refolded stepwise by dialysis: overnight against 50 mM Tris / HCl (pH 7.5), 100 mM NaCl, 10 mM CaCl2, 0.1 mM ZnCl2, 3 M urea, 120 mM acetohydroxamic acid (AHA), for 8 h against 50 mM Tris / HCl (pH 7.5), 100 mM NaCl, 10 mM CaCl2, 0.1 mM ZnCl2, 120 mM AHA, and again overnight against 50 mM Tris / HCl (pH 7.5), 100 mM NaCl, 10 mM CaCl2, 120 mM AHA. Refolded protein was incubated with Pro-Leu-Gly-Sepharose (1 mL of resin per 52 mL of refolded protein solution, preparation see below) and incubated in batch for 1 h. Resin was transferred to gravity flow columns, washed with50 mM Tris / HCl (pH 7.5), 50 mM NaCl, 10 mM CaCl2until no protein eluted (determined by Bradford), eluted with 25 ml / 5 ml resin / fraction with 20 mM Tris / HCl (pH 11.3), and pH was rapidly adjusted with 1 mL of 1 M Tris / HCl (pH 7.5) per fraction. Fractions containing the protein of interest were pooled and concentrated using an Ami con Ultra- 15 10 kDa MWCO. Concentrated protein was loaded onto a Superdex 7526 / 60 column equilibrated in 50 mM Tris / HCl (pH 7.5), 50 mM NaCl, 10 mM CaCl2. Peak fractions were pooled and concentrated using an Amicon Ultra-15 10 kDa MWCO.

[1283] H-Pro-Leu-Gly-coupled NHS Sepharose preparation:

[1284] 25 mL bed volume NHS-activated Sepharose 4 FF (GE Healthcare) was washed with 10 -15 CV of cold 1 mM HC1 and H-Pro-Leu-Gly-NHOH HC1 peptide (Bachem) was coupled at 5 mg / mL in 0.2 M sodium bicarbonate (pH 8.3), 0.5 M NaCl for 3 h at room temperature. The peptide solution was removed and the resin was blocked with 0.1 M Tris / HCl (pH 8.5) for 2-3 h. After blocking, the resin was washed first with 0.1 M Tris / HCl (pH 8.5) and then with 0.1 M sodium acetate (pH 5.0), 0.5 M NaCl.

[1285] Inhibitory potencies against MMP9 and some other selected MMPs for the examples are provided in Table 4 below.

[1286] M <_> hMMI’9 in MM 1’9 hMMI’10 hMMI‘14 liMMI’2 ID l< |n\l| l< |n\l | l< |n\l| l<... |n\l| l<... |n\l|

[1287] 7.02 5.35 7.2 5.54 278.59 100.91 2 1 8320 (n 18) 8320 (n 30)

[1288] (n 106) (n 18) (n 36) 2799.72 ± 333.39 62894.33 ± 149668.98 ± 3 2 nd nd

[1289] (n=2) 10544.92 (n=2) 27584.04 (n=2)

[1290] 4.57 ± 2.28 2213.71 ± 224.56 ± 58.49 4 3 nd >4000 (n=4)

[1291] (n=ll) 275.47 (n=4) (n=2) 5.67 ± 2.41 328.24 ± 21.18 5 4 nd >1000 (n=2) >1000 (n=2)

[1292] (n=7) (n=2) 14.27 ± 4.3 695.32 ± 330.46 6 5 nd >1000 (n=2) >1000 (n=2)

[1293] (n=5) (n=2) 14.43 ± 1.88 653.59 ± 281.54 7 6 nd >1000 (n=2) >1000 (n=2)

[1294] (n=5) (n=2) 7.31 ± 2.67 751.56 ± 55.75 8 7 nd >2000 (n=2) >2000 (n=2)

[1295] (n=4) (n=4) 14.42 ± 4.36 1149.61 ± 176.08 9 8 nd >2000 (n=2) >2000 (n=2)

[1296] (n=4) (n=4) 48.11 ± 17.88 1214.1 ± 372.76 10 9 nd >2000 (n=2) >2000 (n=2)

[1297] (n=6) (n=6)

[1298]

[1299] O hMMI’10 h\l\ll*l4 hMMI’2 ID.. l<... |nM| l< ■„ |nM| l<... |nM| l< |nM| l<... |n\l|

[1300] 121.94 ± 45.02

[1301] 11 10 nd >5000 (n=2) >5000 (n=2) >5000 (n=2)

[1302] (n=4)

[1303] 564.97 ± 185.46 12 11 31.67 ± 12.68 nd >10000 (n=2) >10000 (n=2)

[1304] (n=6) (n=2) 165.39 ± 24.51 24348.46 ± 37818.48 ±

[1305] 13 12 nd nd (n=2) 3202.13 (n=2) 3965.84 (n=2)

[1306] 7.45 ± 3.93 26708.73 ± 4709.65 ± 662.3 194.23 ±.29 14 13 nd

[1307] (n=14) 7769.78 (n=6) (n=4) (n=2) 143.88 ± 8.98 45554.06 ± 60500.88 ±

[1308] 15 14 nd nd (n=2) 4567.46 (n=2) 6597.69 (n=2)

[1309] 6.29 ± 2.36 4017.07 ± 817.43 1822.55 ± 392.1 ± 109.37 16 15 nd

[1310] (n=6) (n=6) 792.72 (n=8) (n=2) 17.8 ± 8.25 2613.04 ± 752.32 ± 351.19 17 16 nd >4000 (n=4)

[1311] (n=18) 987.73 (n=6) (n=10)

[1312] 379.58 ± 135.86 18 17 7.88 ± 1.71 (n=6) nd >2000 (n=2) >2000 (n=2)

[1313] (n=6) 6.25 ± 1.82 770.27 ± 160.14 19 18 nd >10000 (n=6) >10000 (n=6)

[1314] (n=8) (n=2)

[1315] 8074.37 ± 0 448.65 ± 109.69 20 19 5.7 ± 5.15 nd >10000 (n=2)

[1316] (n=8) (n=l) (n=6) 4.23 ± 2.05 415.09 ± 118.79 21 20 nd >10000 (n=4) >10000 (n=4)

[1317] (n=ll) (n=4) 3.93 ± 1.43 3177.87 ± 456.43 ± 185.1 22 21 nd >4000 (n=4)

[1318] (n=9) 841.31 (n=4) (n=4) 6.83 ± 2.42 283.03 ± 136.87 23 22 nd >2000 (n=4) >2000 (n=4)

[1319] (n=7) (n=4) 12.95 ± 2.78 554.35 ± 241.51 24 23 nd >2000 (n=2) >2000 (n=2)

[1320] (n=4) (n=4) 1550.17 ± 286.95 44764.17 ±

[1321] 25 24 nd >83200 (n=2) nd (n=2) 3161.17 (n=2)

[1322] 7862.13 ± 5248.41 28560.52 ± 15432.09 ±

[1323] 26 25 nd nd (n=6) 23167.56 (n=4) 12236.37 (n=4)

[1324] 31488.01 ± 60941.28 ±

[1325] 27 26 nd >83200 (n=2) nd 1782.77 (n=2) 8301.17 (n=2)

[1326] 18047.14 ± 17292.24 ± 2991.88 ±

[1327] 28 27 nd >50000 (n=2)

[1328] 17237.87 (n=6) 2294.43 (n=4) 321.29 (n=4)

[1329] 12150.82± 16053.04 ± 2500.32 ±

[1330] 29 28 nd >50000 (n=2)

[1331] 8367.23 (n=6) 3761.61 (n=4) 715.96 (n=4)

[1332] 1713.94 ± 145.4

[1333] 30 29 nd >10000 (n=2) >10000 (n=2) nd (n=2)

[1334] 2751.49 ± 589.58

[1335] 31 30 nd >10000 (n=2) >10000 (n=2) nd (n=2)

[1336] 10097.38 ± 688.9 52315.08±

[1337] 32 31 nd >208000 (n=2) nd (n=2) 4935.77 (n=2)

[1338]

[1339] O hMMI’10 h\l\ll*l4 hMMI’2 ID.. l<... |nM| l< ■„ |nM| l<... |nM| l< |nM| l<... |n\l|

[1340] 578.27 ± 272.16 8030.49 ± 0

[1341] 33 32 nd >10000 (n=2) nd (n=4) (n=2)

[1342] 8773.74 ± 3275.04 19838.88 ± 9561.57± 34 33 nd nd (n=2) 7248.55 (n=2) 966.17 (n=2)

[1343] 9098.47 ± 644.93 3952.61 ± 35 34 nd 9284.18 ± 0 (n=2) nd (n=2) 1249.62 (n=2)

[1344] 1.07 ± 1.36 376.18 ± 35.43 13.84 ± 2.75 36 35 nd >1331.2 (n=10)

[1345] (n=15) (n=6) (n=2) 325.82 ± 144.85 1903.56 ± 1739.76 ± 198.79 37 36 nd >1600 (n=4)

[1346] (n=10) 856.45 (n=6) (n=2) 64.53 ± 19.42 1379.58 ± 641.99 ± 88.01 38 37 nd >4000 (n=4)

[1347] (n=8) 531.64 (n=4) (n=2) 10.2 ± 2.72 6924.19 ± 1421.64 2519.9 ± 46.28 491.65 ± 90.06 39 38 nd

[1348] (n=8) (n=4) (n=4) (n=2) 1713.94 ± 145.4 1449.14 ± 0 40 39 nd >10000 (n=2) >10000 (n=2)

[1349] (n=2) (n=2) 2.85 ± 1.16 357.2 ± 22.05 41 40 nd >4000 (n=6) >4000 (n=5)

[1350] (n=10) (n=2) 12.47 ± 2.43 1165.83 ± 218.88 42 41 nd >10000 (n=4) >10000 (n=4)

[1351] (n=6) (n=2) 3899.41 ± 1735.35

[1352] 43 42 nd >10000 (n=2) >10000 (n=2) nd (n=4)

[1353] 0.47 ±.25 256.59 ±.57 6.04 ± 1.42 44 43 nd >500 (n=4)

[1354] (n=8) (n=4) (n=2) 1.96 ± 1.19 1260.62 ± 44.1 ± 12.54 45 44 nd 2258.59 ± 0 (n=4)

[1355] (n=8) 255.31 (n=4) (n=4) 327.74 ± 49.27 612.44 ± 0 1160.61 ± 899.45 ± 386.5 46 45 nd

[1356] (n=4) (n=4) 462.07 (n=4) (n=2) 8.18 ± 3.52 423.87 ± 95.22 62.18 ± 17.8 47 46 nd >1000 (n=2)

[1357] (n=7) (n=2) (n=2) 165.14 ± 21.07 1184.99 ± 865.67 ± 300.26 48 47 nd >2000 (n=2)

[1358] (n=4) 101.99 (n=2) (n=2) 34.23 ± 8.11 674.72 ± 430.52 49 48 nd >400 (n=2) >1000 (n=2)

[1359] (n=5) (n=2) 0.66 ±.27 680.54 ± 23.65 6.65 ± 1.22 50 49 nd >1000 (n=2)

[1360] (n=7) (n=2) (n=2) 2.58 ± 1.49 55.04 ± 10.68 51 50 nd >2000 (n=2) >2000 (n=2)

[1361] (n=8) (n=2) 21.03 ± 6.17

[1362] 52 51 nd >1000 (n=2) >1000 (n=2) >1000 (n=2)

[1363] (n=5)

[1364] 19.22 ± 5.46 737.15 ± 225.03 53 52 nd >1000 (n=2) >1000 (n=2)

[1365] (n=5) (n=2)

[1366] 1354.98 ± 307.36 ± 38.59 54 53 21.35 ± 6.12 nd 2141.12 ± 0 (n=4)

[1367] (n=4) 569.56 (n=4) (n=4)

[1368]

[1369] O hMMI’10 h\l\ll*l4 hMMI’2 ID.. l<... |nM| l< ■„ |nM| l<... |nM| l< |nM| l<... |n\l|

[1370] 17.92 ± 4.47 3248.29 ± 0 304.35 ± 45.13 55 54 nd >4000 (n=4)

[1371] (n=4) (n=4) (n=4) 1.22 ±.32 1254.98 ± 158.55 1700.59 ± 15.07 ± 4.69 56 55 nd

[1372] (n=4) (n=4) 324.87 (n=4) (n=4) 1.49 ±.29 2550 ± 0 2686.9 ± 417.52 89.45 ± 35.17 57 56 nd

[1373] (n=4) (n=4) (n=4) (n=4) 199.15 ± 97.28 2936.55 ± 698.41 1990.74 ± 60.58 947.81 ± 287.17 58 57 nd

[1374] (n=2) (n=2) (n=2) (n=2) 1.33 ± 0.57 2433.85 ± 0 1319.1 ± 147.43 15.69 ± 6.37 59 58 nd

[1375] (n=4) (n=l) (n=2) (n=4)

[1376] 313.04 ± 126.78 60 59 8.19 ± 1.98 (n=2) nd nd nd

[1377] (n=2) 496.22 ± 101.65 61 60 61.14 ± 5.1 nd >4000 (n=2) >4000 (n=2)

[1378] (n=2) (n=2) 6.07 ± 2.81 61.41 ± 19.19 62 61 nd >4000 (n=2) >4000 (n=2)

[1379] (n=2) (n=2) 1217.24 ± 222.73

[1380] 63 62 nd >4000 (n=2) >4000 (n=2) >4000 (n=2)

[1381] (n=2)

[1382] 41.51 ± 7.07 904.08 ± 233.74 64 63 nd >4000 (n=4) >4000 (n=3)

[1383] (n=4) (n=4) 535.11 ± 82.05 462.58 ± 198.95 65 64 nd >4000 (n=4) >4000 (n=3)

[1384] (n=4) (n=4)

[1385] 2226.54 ± 0 814.62 ± 45.46 2267.06 ± 0 66 65 >4000 (n=2) nd

[1386] (n=2) (n=2) (n=2) 1.39 ±.41 21.73 ± 12.23 67 66 nd >2000 (n=2) >2000 (n=2)

[1387] (n=4) (n=4) 808.79 ± 413.71

[1388] 68 67 nd >10000 (n=2) >10000 (n=2) nd (n=4)

[1389] 55.82 ± 36.42 3130.03 ± 364.55 ± 88.96 69 68 nd >4000 (n=6)

[1390] (n=14) 306.23 (n=6) (n=2) 16.27 ± 6.68 3276.6 ± 1242.12 1178 ± 539.68 1087.09 ± 49.69 70 69 nd

[1391] (n=6) (n=4) (n=4) (n=2)

[1392] 1903.76 ± 624.63 71 70 27.38 ± 6.69 (n=4) nd >5000 (n=2) >5000 (n=2)

[1393] (n=4) 27.45 ± 2.49 3794.95 ± 949.74 72 71 nd >5000 (n=2) >5000 (n=2)

[1394] (n=4) (n=4) 19.12 ± 5.41

[1395] 73 72 nd >2000 (n=2) >2000 (n=2) >2000 (n=4)

[1396] (n=4)

[1397] 2.67 ± 1.02 448.78 ± 120.4 74 73 nd >10000 (n=4) >10000 (n=4)

[1398] (n=10) (n=4) 7.83 ± 4.81 1990.4 ± 527.59 305.69 ± 112.73 69.79 ± 16.8 75 74 nd

[1399] (n=13) (n=6) (n=4) (n=4) 20.62 ± 2.99

[1400] 76 75 nd >2000 (n=2) >2000 (n=2) >2000 (n=2)

[1401] (n=6)

[1402]

[1403] O hMMI’10 h\l\ll*l4 hMMI’2 ID.. l<... |nM| l< ■„ |nM| l<... |nM| l< |nM| l<... |n\l|

[1404] 74.63 ± 51.38

[1405] 77 76 nd >2000 (n=2) >2000 (n=2) >2000 (n=2)

[1406] (n=4)

[1407] 22.63 ± 10.87 1366.76 ± 0 78 77 nd >2000 (n=2) >2000 (n=2)

[1408] (n=4) (n=2) 19.73 ± 2.96

[1409] 79 78 nd >2000 (n=2) >2000 (n=2) >2000 (n=2)

[1410] (n=4)

[1411] 665.95 ± 168.12 80 79 9.05 ± 2.59 (n=7) nd >1000 (n=2) >1000 (n=2)

[1412] (n=4) 2.28 ±.25

[1413] 81 80 nd >4000 (n=2) >4000 (n=2) 158.16 ± 0

[1414] (n=2) (n=l) 14.17± 2.91 3400.93 ± 0 874.35 ± 341.22 82 81 nd >5000 (n=2)

[1415] (n=4) (n=2) (n=4) 2765.97 ± 305.68

[1416] 83 82 nd nd nd nd (n=2)

[1417] 409.18 ± 196.21

[1418] 84 83 nd >5000 (n=2) >5000 (n=2) >5000 (n=2)

[1419] (n=4)

[1420] 1148.49 ± 410.32

[1421] 85 84 nd >10000 (n=2) >10000 (n=2) nd (n=6)

[1422] 2643.89 ± 407.14 5685.23 ± 3956.43 2644.43 ±

[1423] 86 85 nd nd (n=6) (n=4) 1497.92 (n=4)

[1424] 152.47 ± 42.54 3190.31 ±

[1425] 87 86 nd >10000 (n=4) nd (n=4) 991.99 (n=4)

[1426] 297.19 ± 91.13

[1427] 88 87 nd >5000 (n=2) >5000 (n=2) >5000 (n=2)

[1428] (n=4)

[1429] 6.28 ± 2.67 530.75 ± 225.66 89 88 nd >2000 (n=2) >2000 (n=2)

[1430] (n=6) (n=6) 5.18 ± 3.48 61.72 ± 16.92 90 89 nd >1000 (n=2) >1000 (n=2)

[1431] (n=ll) (n=6) 0.52 ±.15 2170.1 ± 503.9 881.5 ± 285.72 10.24 ± 5.05 91 90 nd

[1432] (n=12) (n=12) (n=ll) (n=12) 0.51 ±.08 1744.72 ± 276.99 984.2 ± 175.17 9.22 ± 3.57 92 91 nd

[1433] (n=4) (n=4) (n=4) (n=4) 0.46 ±.06 1126.52 ± 246.45 758.07 ± 474.99 11.11 ± 5.58 93 92 nd

[1434] (n=4) (n=4) (n=4) (n=4) 3.69 ± 1.06 395.3 ± 146.24 94 93 nd >4000 (n=6) >4000 (n=4)

[1435] (n=6) (n=6) 23.14± 11.56 291.09 ± 13.74 2611.13 ± 283.02 ± 125.73 95 94 >4000 (n=6)

[1436] (n=27) (n=2) 150.52 (n=2) (n=4) 0.55 ±.23 10.48 ± 1.83 96 95 nd >800 (n=2) >800 (n=2)

[1437] (n=9) (n=4)

[1438] 1266.21 ± 1.91 ± 1.13 97 96 0.14 ±.09 nd >2000 (n=2)

[1439] (n=4) 313.99 (n=2) (n=4) 2.37 ± 1.24 1411.88 ± 25.05 ± 9.27 98 97 nd >4000 (n=4)

[1440] (n=4) 259.28 (n=3) (n=4)

[1441]

[1442] O hMMI’10 h\l\ll*l4 hMMI’2 ID.. l<... |nM| l< ■„ |nM| l<... |nM| l< |nM| l<... |n\l|

[1443] 1430.81 ± 742.64 1112.74 ± 69.16 18.29 ± 8.75 99 98 0.84 ±.26 (n=4) nd

[1444] (n=4) (n=4) (n=4) 0.74 ±.2 807.57 ± 153.85 15.21 ± 4.39 00 99 nd 1211.24 ± 0

[1445] (n=6) (n=4) (n=4) (n=6) 0.71 ±.09 2313.53 ± 328.11 1041.99 ± 129.4 13.79 ± 4.72 01 100 nd

[1446] (n=4) (n=4) (n=4) (n=4) 3.03 ± 1.59 492.08 ± 163.55 02 101 nd >4000 (n=6) >4000 (n=4)

[1447] (n=6) (n=6) 1.12 ±.32 1784.05 ± 0 26.64 ± 7.35 03 102 nd >2000 (n=4)

[1448] (n=4) (n=4) (n=4) 0.82 ± 0.5 1.03 ± 0.33 2098.46 ± 631.5 1734.25 ± 8.69 ± 6.64 04 103

[1449] (n=58) (n=24) (n=2) 1287.27 (n=10) (n=28) 3.19 ± 1.44 298.82 ± 165.08 05 104 3.14 ± 1.1 (n=2) >5000 (n=14) >3601.2 (n=l)

[1450] (n=20) (n=16) 1.63 ±.17 26.88 ± 2.31 06 105 nd >4000 (n=2) >4000 (n=2)

[1451] (n=2) (n=2) 0.49 ±.13 2965.2 ± 83.28 1658.01 ± 32.03 7.41 ±.45 07 106 nd

[1452] (n=4) (n=2) (n=2) (n=4) 0.34 ±.02 2399.14 ± 534.3 6.15 ± 1.54 08 107 nd >4000 (n=2)

[1453] (n=4) (n=2) (n=4) 1.67 ±.57 2449.4 ± 378.65 1238.8 ± 260.42 62.45 ± 17.96 09 108 nd

[1454] (n=4) (n=2) (n=2) (n=4) 0.62 ±.06 10.1 ± 1.91 10 109 nd >4000 (n=2) >4000 (n=2)

[1455] (n=4) (n=4) 3.04 ±.34 472.27 ± 78.13 11 110 nd >4000 (n=4) >4000 (n=3)

[1456] (n=6) (n=6) 3.19 ± 1.44 1601 ± 329.21 82.57 ± 40.28 12 111 nd >4000 (n=4)

[1457] (n=4) (n=3) (n=4) 3.79 ± 1.3 60.72 ± 8.71 13 112 nd >4000 (n=2) >4000 (n=2)

[1458] (n=2) (n=2) 3.99 ±.28 76.37 ± 23.7 14 113 nd >4000 (n=2) >4000 (n=2)

[1459] (n=2) (n=2) 1.96 ±.23 36.01 ± 1.98 15 114 nd >4000 (n=2) >4000 (n=2)

[1460] (n=2) (n=2) 2.6 ± 1.69 3.11 ± 1.71 8.66 ± 9.56 16 115 >5000 (n=6) >5000 (n=8)

[1461] (n=15) (n=5) (n=9)

[1462] 60.99 ± 13.6 17 116 3.12 ±.59 nd >4000 (n=2) >4000 (n=2)

[1463] (n=2) (n=2) 4.9 ± 2.11 22.22 ± 12.97 943.63 ± 434.11 18 117 >5000 (n=10) >5000 (n=ll)

[1464] (n=18) (n=2) (n=10) 332.12 ± 18.05

[1465] 19 118 nd >4000 (n=2) >4000 (n=2) >4000 (n=2)

[1466] (n=2)

[1467] 32.99 ± 3.68 342.75 ± 53.63 20 119 nd >4000 (n=2) >4000 (n=2)

[1468] (n=2) (n=2)

[1469]

[1470] O hMMI’10 h\l\ll*l4 hMMI’2 ID.. l<... |nM| l< ■„ |nM| l<... |nM| l< |nM| l<... |n\l|

[1471] 695.85 ± 221.43

[1472] 21 120 nd >4000 (n=2) >4000 (n=2) >4000 (n=2)

[1473] (n=2)

[1474] 343.49 ± 36.74

[1475] 22 121 nd >4000 (n=2) >4000 (n=2) >4000 (n=2)

[1476] (n=2)

[1477] 23 122 >4000 (n=2) nd >4000 (n=2) >4000 (n=2) >4000 (n=2)

[1478] 26.75 ± 4.29 1651.6 ± 578.56 24 123 nd >4000 (n=2) >4000 (n=2)

[1479] (n=6) (n=6) 17.13 ± 5.43 1043.16 ± 172.87 25 124 nd >4000 (n=2) >4000 (n=2)

[1480] (n=2) (n=2) 22.98 ± 14.59 5.81 ±.19 137.26 ± 52.55 35 125 >800 (n=2) >800 (n=2)

[1481] (n=6) (n=2) (n=4)

[1482] 51.18 ± 9.84 36 126 4.78 ± 2.46 (n=4) nd >800 (n=2) >800 (n=2)

[1483] (n=4) 1.3 ±.22 1.19 ±.06 10.96 ± 2.05 37 127 >320 (n=2) >320 (n=2)

[1484] (n=4) (n=2) (n=4) 5.08 ± 1.45 3.47 ±.12 62.43 ± 13.08 38 128 >800 (n=2) >800 (n=2)

[1485] (n=6) (n=2) (n=4) 2.87 ± 1.1 3.63 ±.11 46.12 ± 8.59 39 129 >320 (n=2) >320 (n=2)

[1486] (n=6) (n=2) (n=4) 60.91 ± 19.44 5.34 ± 2.29 40 130 nd >800 (n=2) >800 (n=2)

[1487] (n=4) (n=2) 2.35 ±.93 712.55 ± 101.87 956.83 ± 140.24 16.63 ± 6.97 241 131 nd

[1488] (n=4) (n=2) (n=2) (n=6) 13.47 ± 2.58 4.87 ±.31 110.22 ± 21.64 42 132 >320 (n=2) >800 (n=2)

[1489] (n=6) (n=2) (n=4) 1.7 ± 1.12 1931.96 ± 93.02 1721.82 ± 4.95 ± 1.53 243 133 0.94 ±.05 (n=2)

[1490] (n=6) (n=2) 435.91 (n=2) (n=6) 5.04 ± 1.74 3.05 ±.43 494.67 ± 151.38 137.39 ± 23.73 44 134 >800 (n=2)

[1491] (n=4) (n=2) (n=2) (n=4) 3.49 ± 2.08 3.63 ±.86 18.32 ± 5.86 45 135 >5000 (n=2) >5000 (n=2)

[1492] (n=6) (n=4) (n=4) 1.79 ±.76 3.32 ± 2.76 16.28 ± 2.13 46 136 nd >800 (n=3)

[1493] (n=7) (n=5) (n=5) 1.6 ±.56 2.23 ±.5 28.05 ± 4.97 47 137 nd >320 (n=2)

[1494] (n=8) (n=3) (n=5) 1.15 ±.49 1.6 ± 1 3.98 ±.92 48 138 nd >320 (n=3)

[1495] (n=5) (n=3) (n=5) 1.33 ±.88 1.92 ±.82 3.62 ±.91 49 139 nd >320 (n=3)

[1496] (n=7) (n=5) (n=5) 15.43 ± 5.02 8.75 ± 2.05 123.65 ± 15.66 50 140 nd >4000 (n=2)

[1497] (n=4) (n=4) (n=4) 10 ±.95 6.34 ±.94 116.53 ± 13.48 51 141 nd >4000 (n=2)

[1498] (n=4) (n=4) (n=4)

[1499]

[1500] O hM MI’10 hMM I’14 hMM I’2 ID.. l<... |nM| l< ■„ |nM | l<... |nM| l< |nM| l<... |n\l|

[1501] 13.37 ± 4.03 11.33 ± 5.7 206.09 ± 97.57 52 142 nd >800 (n=3)

[1502] (n=5) (n=2) (n=5) 1.27 ±.55 1.26 ±.35 5.2 ±.65 53 143 nd >4000 (n=2)

[1503] (n=4) (n=4) (n=4) 2.28 ± 0.48 2.7 ± 0.7 16.62 ± 5.57 54 144 nd >4000 (n=2)

[1504] (n=4) (n=4) (n=4) 12.12 ± 3.79 8.57 ±.37 207.01 ± 74.5 55 145 nd >4000 (n=2)

[1505] (n=4) (n=4) (n=4) 0.55 ±.24 3.41 ± 1.17 22.91 ± 7.27 56 146 nd >4000 (n=8)

[1506] (n=27) (n=19) (n=12) 18.57 ± 3.65 22.32 ± 3.86 703.04 ± 158.09 57 147 nd >4000 (n=2)

[1507] (n=7) (n=4) (n=4) 5.77 ± 2.3 6.15 ± 1.89 144.29 ± 50.01 58 148 nd >4000 (n=4)

[1508] (n=15) (n=8) (n=8) 0.64 ±.23 2.95 ±.99 17.54 ± 6.21 59 149 nd >4000 (n=4)

[1509] (n=15) (n=8) (n=8) 12.96 ± 1.45 12.87 ± 1.27 349.43 ± 182.17 60 150 nd >4000 (n=2)

[1510] (n=4) (n=4) (n=3) 0.83 ± 0.08 0.94 ± 0.04 41.87 ± 10.92 261 151 nd 2228.47 (n=1)

[1511] (n=4) (n=2) (n=2) 6.44 ± 1.19 0.56 ±.18 3290.2 ± 1.32 43.67 ± 13.79 262 152 nd

[1512] (n=4) (n=2) (n=2) (n=2) 1.95 ±.29 3.82 ± 0.64 143.19 ± 11.44 63 153 nd >4000 (n=2)

[1513] (n=4) (n=2) (n=2) 3.71 ± 0.78 5.33 ± 0.58 221.44 ± 49.44 64 154 nd >4000 (n=4)

[1514] (n=6) (n=4) (n=2) 10.32 ± 1.69 11.79 ± 3.38 179.88 ± 18.77 65 155 nd >4000 (n=4)

[1515] (n=5) (n=2) (n=2) 1.29 ± 0.44 31.57 ± 10.54 66 156 1.14 ± 0.13 nd >4000 (n=4)

[1516] (n=7) (n=4) (n=4) 1.76 ± 0.58 1.49 ± 0.22 34.82 ± 1.62 67 157 nd >4000 (n=2)

[1517] (n=4) (n=2) (n=2) 0.68 ± 0.03 17.93 ± 9.85 68 158 0.53 (n=l) nd >4000 (n=2)

[1518] (n=4) (n=2) 0.44 ± 0.1 3.65 ± 0.09 69 159 0.52 (n=l) nd >4000 (n=2)

[1519] (n=4) (n=2) 0.39 ±.15 1.8 ± 0.05 12.64 ± 3.36 70 160 nd >4000 (n=4)

[1520] (n=5) (n=2) (n=2) 0.43 ±.13 2.85 ± 0.29 19.02 ± 3.01 71 161 nd >4000 (n=4)

[1521] (n=5) (n=2) (n=2) 0.58 ± 0.08 13.49 ± 8.73 72 162 1.18 ± 0.61 nd >4000 (n=4)

[1522] (n=6) (n=3) (n=4) 0.62 ± 0.11 12.57 ± 0.45 73 163 0.56 (n=l) nd >4000 (n=2)

[1523] (n=4) (n=2)

[1524]

[1525] O hM MI’10 hMM I’14 hMM I’2 ID.. l<... |nM| l< ■„ |nM | l<... |nM| l< |nM| l<... |n\l|

[1526] 1.42 ± 0.38 2.54 ± 0.14 44.73 ± 13.93 74 164 nd >4000 (n=2)

[1527] (n=3) (n=2) (n=2) 1.07 ± 0.67 1.59 ± 0.79 40.67 ± 11.68 75 165 nd >4000 (n=4)

[1528] (n=5) (n=4) (n=4) 1 ± 0.3 1.95 ± 1.47 1149.93 ± 57.58 ± 31.64 276 166 nd

[1529] (n=6) (n=3) 207.69 (n=3) (n=4) 0.37 ±0.04 1.82 ± 0.65 13.96 ± 3.27 77 167 nd >4000 (n=4)

[1530] (n=6) (n=3) (n=4)

[1531] 1.92 ± 0.12 34 ± 8.51 78 168 1.64 ± 1.11 (n=5) nd >4000 (n=2)

[1532] (n=2) (n=2) 9.32 ± 3.27 4.21 ± 0.11 176.23 ± 14.93 79 169 nd >4000 (n=2)

[1533] (n=5) (n=2) (n=2) 11.94 ± 7.36 6.69 ± 0.38 109.54 ± 7.5 80 170 nd >4000 (n=2)

[1534] (n=5) (n=2) (n=2) 0.68 ± 0.15 0.49 ± 0.01 1215.88 ± 6.55 ± 1.38 281 171 nd

[1535] (n=2) (n=2) 378.16 (n=2) (n=2) 702.08 ± 362.95

[1536] 82 172 >800 (n=5) nd >800 (n=3) >320 (n=3)

[1537] (n=3)

[1538] 0.39 ± 0.07 0.55 ± 0.01 1.03 ± 0.36 83 173 >320 (n=4) >800 (n=4)

[1539] (n=10) (n=4) (n=8) 5.16 ± 2.48 5.17 ± 2.42 85.45 ± 29.19 84 174 nd >4000 (n=4)

[1540] (n=15) (n=8) (n=8) 1.03 ± 0.61 2.03 ± 0.33 10.3 ± 5.75 85 175 nd >4000 (n=2)

[1541] (n=7) (n=4) (n=4) 82.59 ± 37.59 56.72 ± 14.17 545.61 ± 72.47 86 176 nd >4000 (n=2)

[1542] (n=4) (n=4) (n=2) 1.11 ±.66 1.55 ± 0.73 2106.97 ± 5.19 ± 2.83 287 177 nd

[1543] (n=4) (n=4) 127.09 (n=2) (n=4) 0.57 ± 0.29 0.77 ± 0.27 4.03 ± 1.56 88 178 nd >4000 (n=2)

[1544] (n=4) (n=4) (n=4) 0.71 ± 0.32 1.05 ± 0.22 6.97 ± 3.26 89 179 nd >4000 (n=2)

[1545] (n=4) (n=4) (n=4) 0.62 ± 0.45 7.02 ± 1.3 290 180 1.21 ± 0.56 (4) nd 3800.48 (n=1)

[1546] (n=4) (n=4) 22.88 ± 0.73 288.87 ± 4.51 91 181 5.48 (n=l) nd >4000 (n=2)

[1547] (n=2) (n=2) 6.54 ± 0.19 1.45 ± 0.13 407.7 ± 15.99 92 182 nd >4000 (n=2)

[1548] (n=2) (n=2) (n=2) 2.9 ± 0.84 120.89 ± 68.69 93 183 3.3 ± 1.08 (n=4) nd >4000 (n=2)

[1549] (n=4) (n=4) 0.59 ± 0.2 1.99 ± 0.52 30.46 ± 8.71 94 184 nd >4000 (n=2)

[1550] (n=14) (n=8) (n=3) 2.07 ± 0.54

[1551] 95 185 1.51 ± 0.18 nd >4000 (n=2) 58.51 (n=l)

[1552] (n=4) (n=2)

[1553]

[1554] M O,, liMMI’9 niMMI’9 hMMPIO hMMP14 hMMP2 ID.. l<... |nM| l< |nM| l<... |nM| l< |nM| l<... |n\l|

[1555] 0.6 ± 0.23 1.79 ± 0.27 50.95 ± 4.9 296 186 nd >4000 (n=4)

[1556] (n=5) (n=4) (n=2) 1.38 ± 0.59 4.69 ± 0.87 65.09 ± 19.13 297 187 nd >4000 (n=2)

[1557] (n=4) (n=2) (n=2) 0.48 ± 0.13 2.32 ± 0.57 31.77 ± 2.08 298 188 nd >4000 (n=2)

[1558] (n=4) (n=2) (n=2) 0.5 ± 0.21 35.78 ± 7.02 299 189 2.7 ± 0.32 (n=2) nd >4000 (n=2)

[1559] (n=4) (n=2) 0.42 ± 0.12 1.55 ± 0.07 22.93 ± 6.29 300 190 nd >4000 (n=2)

[1560] (n=4) (n=2) (n=2) 0.51 ±0.11 2.16 ± 0.19 29.29 ± 3.22 301 191 nd >4000 (n=2)

[1561] (n=3) (n=2) (n=2)

[1562] 1.17 ± 0.43 1333.62 ± 6.07 ± 0.88 302 192 0.51 ± 0.09 (n=6) nd

[1563] (n=3) 158.17 (n=3) (n=4) 0.87 ± 0.08 12.19 ± 5.24 303 193 0.55 (n=l) nd 1569.03 (n=l)

[1564] (n=4) (n=2) 0.87 ± 0.07 0.56 ± 0.14 1263.88±39.2 11.52 ± 4.38 304 194 nd

[1565] (n=2) (n=2) (n=2) (n=2) 8.18 ± 0.35 1.77 ± 0.05 107.05 ± 33.6 305 195 nd >4000 (n=2)

[1566] (n=2) (n=2) (n=2) 12.07 ± 2.82 4.15 ± 1.32 374.9 ± 54.51 306 196 nd >4000 (n=2)

[1567] (n=2) (n=2) (n=2) 17.08 ± 2.38 3.23 ± 1.48 45.44 ± 15.3 307 197 nd >4000 (n=2)

[1568] (n=2) (n=2) (n=2) 1.9 ± 0.5 1.53 ± 0.65 74.75 ± 8.49 308 198 nd >4000 (n=2)

[1569] (n=2) (n=2) (n=2)

[1570] 6.58 ± 4.19 148.12 ± 30.27 309 199 11.78 (n=l) nd >4000 (n=2)

[1571] (n=2) (n=2) 1.22 ± 0.51 1.46 ± 0.09 592.04 ± 177.34 753.03 ± 202.03 5.96 ± 1.7 310 200

[1572] (n=6) (n=2) (n=3) (n=2) (n=6) 0.52 ±0.06

[1573] 311 201 1.51 ± 0.11 *14130.8 *58163.8 *526.51

[1574] (n=3) (n=3)

[1575] 0.56 ±0.16

[1576] 312 202 1.5 ± 0.15 *42842.9 *9988.4 *446.50

[1577] (n=3) (n=3)

[1578]

[1579] #The data for Examples 201 and 202 were collected from the corresponding assays with the same format, but were run at a different site.

[1580] Table 4: Inhibitory potencies for example compounds of formula (I) against MMP9 and against other selected MMPs. hMMP9, hMMP2, hMMPIO, hMMP14 mean Human MMP9, 2, 10 and 14. mMMP9: Mouse MMP9. nd. values not determined.

[1581] Specificity patterns of examples of formula (I) against a panel of 10 MMPsThis investigation of a larger panel of human matrix metalloprotease assays was run at Reaction Biology, 1 Great Valley Parkway, Suite 2, Malvern, 19355, PA, USA, using their standard MMP assay protocols, which are similar to the ones used in house and reported in Table 4. However, due to the fact that the assays were run by a different provider, the measured IC50 from this site can be slightly different than the values given in Table 4 and the calculated specificity factors can thus vary as well. MMP specificity factors (fold selectivity = IC50 MMPx / ICso MMP9) for selected examples from this larger specificity screen at Reaction Biology are given in the following Table 5.

[1582] Fold Selectivity MMP9 vs MMPx: IC₅₀ MMPx / IC₅₀ MMP9

[1583] s>'l 1 Mllliplc MMP1 MMP2 MMP3 MMP" MMPS MMP1II MMP12 MMP13 MMP14 ID

[1584] 2 1 1000 4.9 1000 1000 1000 1000 1000 2.1 1000 5 4 >5000 1598 >5000 >5000 >5000 >5000 >5000 4.9 >5000 45 44 >10000 22.9 >10000 >10000 >10000 >10000 >10000 6.7 >10000 74 73 >5000 618 >5000 >5000 >5000 >5000 >5000 5.5 >5000 75 74 >1000 >1000 >1000 >1000 >1000 >1000 >1000 6.1 >1000 105 104 >1000 116 >1000 >1000 >1000 >1000 >1000 >122 >1000 116 115 >10000 3.5 >10000 >10000 >10000 >10000 >10000 2.0 >10000 256 146 >10000 34.2 >10000 >10000 >10000 >10000 2643 5.1 >10000 259 149 >10000 41.6 >10000 >10000 >10000 >10000 8819 1.7 >10000 294 184 >5000 44.4 >5000 >5000 >5000 >5000 >5000 15.0 >5000

[1585]

[1586] Table 5: Selectivity factors of selected peptides towards a panel of 9 different MMPs.

[1587] Other properties determined for selected examples in this invention

[1588] Aqueous solubility

[1589] In the course of combining selected mutations in various positions, compounds with considerably improved aqueous solubilities at neutral pH could be identified. The following Table 6 lists specific examples with their thermodynamic solubilities at specific pH values.Method for determination of thermodynamic solubility: Approximately 1 mg of each compound is weighed into a test tube and 350 pL of medium is added. The sample is placed in a thermodynamic water bath at 25 °C and 120 rpm of orbital shaking for 24 hours. The pH is measured at TO of the buffer (blank buffer) and of the saturated sample solution after 24 h (before filtration). The same batch of test compound is used as a standard, assigning the purity of 100%, in order to prepare the calibration curve. Test compound stock solution is prepared at a concentration of 1 mg / mL in DMSO and diluted to cover the calibration range from 0.0001 - 0.1 mg / mL. For LC / DAD analysis the sample is centrifuged if needed and filtered through a 0.2 pm PTFE filter mounted onto a syringe, and then analyzed neat and accurately diluted 10 and 100 times.

[1590] Data analysis: Solubility is reported in pg / mL in a given medium (for example PBS: 20 mM Na2HPO4 / NaH2PO4+ 130 mM NaCl) and in combination with the pH-value of the saturated sample solution. A control compound of known solubility value is included in each run to monitor the reproducibility of the assay. In addition to the DAD detection for the quantification, MS is used to confirm the parent compound.

[1591] Basic Salt form 1 Thermodynamic solubility

[1592] Seq ID PH Example counterion |ug / mL|

[1593] 445 5.0

[1594] 2 1 ci- 100 7.4

[1595] 19 18 CF3COO- >3000 5.0 203 5.0

[1596] 41 40 CF3COO- 19 7.4 279 5.0

[1597] 45 44 CF3COO- 9 7.4

[1598] 91 90 CF3COO- 18 7.4 99 98 CF3COO- <9 7.4 >2874 7.5 256 146 Na+

[1599] 25900* 6.9* 258 148 Na+>2929 7.3

[1600] 2884 7.5 259 149 Na+

[1601] 25500* 7.2* 270 160 CF3COO- 2196 6.9 294 184 Na+27200* 6.8*

[1602]

[1603] Table 6: Thermodynamic solubilities of examples of formula (I). The solubilities highlighted with an “#” were determined by a different provider with a similar assay setup,but using much more material (not limited by an amount of only 1 mg as is normally used for screening purposes).

[1604] Binding Kinetics to MMP9

[1605] Surprisingly, it was found that many potent macrocyclic compounds according to the invention exemplified in this invention show enzymatic binding kinetics with low off rates. Low off rates (= long enzymatic residence times) are considered benficial for topical ocular delivery of inhibitors as this may compensate rapid dilution on the ocular surface after administration. Binding kinetics were determined by Surface Plasmon Resonance (SPR) and examples of selected compounds in this invention are shown in Table 7 below.

[1606] Seq ID Example KDkin [uM] kon[M-1s-1] koff[s-1] Residence Time [min] Residence Time [h]

[1607] 2 1 na na 0.0001871 89 1.5 50 49 0.0002 20660 0.0000035 4735 79 74 73 0.0038 8419 0.0000316 527 8.8 91 90 0.0006 61130 0.0000362 461 7.7 95 94 0.0112 152600 0.001712 9.7 0.16 105 104 0.0307 11283 0.0003050 55 0.02 118 117 0.0132 15210 0.0002004 83 1.4 256 146 0.0006 37920 0.0000221 754 12.6 283 173 0.0004 93290 0.0000043 3867 64.4 294 184 0.0009 17840 0.0000159 1048 17.5

[1608]

[1609] Table 7: Binding kinetics of specific examples determined by SPR

[1610] Method for SPR analysis: SPR experiments were run at Beactica Therapeutics, Uppsala, Sweden, using the following protocol.

[1611] • Protein used: MMP9 - NHS-biotinylated (107-444 with truncation at C term), MW 52043.59 Da, 1.12 mg / mL (28.1 pM)• Instrument: Biacore T200; Biacore 8K

[1612] • Sensor chip: SA sensor from GE Healthcare

[1613] • Protein immobilization: The protein was immobilized via the biotin-streptavidin capturing approach, and remaining free streptavidin on the sensor surface was blocked with biotin.

[1614] • The protein was diluted to 0.5 pM in the running buffer (50 mM Tris HC1 pH 7.6, 100 mM NaCl, 1 mM TCEP, 10 mM CaCl2, 0.35 % Chaps, 50 μM EDTA ) and contacted 6-10 minutes (flow rate of 5 pl / min) with a sensor surface to achieve immobilization levels of - 4000 RUs.

[1615] • Running buffers were prepared fresh before each experiment, (buffer is generally not filtrated before experiment (however, filtration of the assay buffer was also tested without no effect on the SPR data)

[1616] • Immobilization buffer: 50 mM Tris HC1 pH 7.6, 100 mM NaCl, 1mM TCEP, 10mM CaCl2, 0.35% Chaps, 50μM EDTA

[1617] • Binding assay buffer: 50 mM Tris HCl pH 7.6, 100 mM NaCl, 1mM TCEP, 10mM CaCl2, 0.35% Chaps, 50μM EDTA + 2% DMSO

[1618] • Details for buffer stock solution:

[1619] Buffer Source Reference # Stock Cone. Units Final Cone. Buffer pH adjusted at 7.6

[1620] Tris HC1 Sigma 93313-1L 1000 mM 50.00 NaCl Sigma 71386-500mL 5000 mM 100.00 CaCl2Sigma 21115-100mL 1000 mM 10.00 Chaps Biochemica A 1099-0050 10 % 0.35

[1621] TCEP Sigma 646547 500 mM 1.00

[1622] EDTA Sigma 03690 500 mM 0.0500

[1623]

[1624] Alternative Chaps powder tested give similar SPR results:

[1625] Chaps: Sigma C5070-5g; 10 %.

[1626] • Temperature: The surface was prepared at 22°C.

[1627] • Sample preparation: Samples are diluted from 10 mM stock solution (100% DMSO) with running buffer to the start concentration of the dilution series (adapted to the affinity of the compound). 8 or 5 points concentration series (dilution factor: 2.67 or 3) were prepared with either a HP300 Dispenser or manually and analyzed inmulticycle titration mode or single cycle kinetic mode. If the highest concentration of the compound serial dilution is higher than lOpM, the compound serial dilution is done in 100% DMSO at 50X final concentration. 50X compound dilution is performed in assay buffer (no DMSO) to reach final tested concentration.

[1628] • Measuring protocol: Binding measurements were all performed at 22°C.

[1629] Compounds series were injected starting with the lowest concentration. Each concentration series starts with the inj ection of a negative (DMSO solution or buffer) and a positive reference sample (MMP9 reference inhibitor N-[[5-[2-(4- Methylphenyl)ethynyl]-2-thienyl]sulfonyl]-D-tryptophan, CAS 203640-27-1). Injection is performed at a flow rate of 30 pl / min. The protein on the surface is contacted for 1 to 4 min (depending on cpd binding kinetics) with tested concentrations of the sample and the change in signal is monitored in real time. Dissociation time (60 s to 3600 s) is adapted to compounds based on kinetic profile.

[1630] • Data evaluation: Compounds showing fast kinetics (with non resolved time course of the binding reaction) are analyzed using an equilibrium type analysis. The responses were plotted against the logarithm of the concentration and the resulting sigmoid curve is fitted with a respective sigmoid equation. Data from compounds with time resolved binding kinetics were subjected to a kinetic analysis. The timedependent binding curves is not double subtracted with DMSO solution and are fitted to a 1 / 1 kinetic binding model with drift using the software of the instrument supplier.

Claims

Claims1. A compound of formula (I)(I)whereinAA1⌢AA11is a chain of 11 amino acids consisting of(i) sequence F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle (Seq ID 1); or(ii) a sequence having between 5 / 11 to 10 / 11 sequence identity to Seq ID 1;NH* is the amino group of the amino acid AAi;C(O)* is the carbonyl group of AAn;R1and R2are independently absent or oxygen; andMeNle is the non-natural amino acid of formulaOH(MeNle);or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein the amino acids are independently selected from natural amino acids and non-natural amino acids.

3. A compound according to claim 1 or 2, wherein the chain of 11 amino acids is of formula (II)AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-AA10-AA11 (II)wherein AAi to AAn are independently selected from natural amino acids and nonnatural amino acids.

4. A compound according to claim 2 or 3, wherein the natual amino acids are independently selected from the amino acids F, L, Y, H, S, R, N, A, K, W, T, Q, E, D and V.

5. A compound according to claim 2 or 3, wherein the non-natual amino acids are independently selected from(MeNle)((CH3F)(CH3F)(mCNF)(CNF)m(CNF)f / ? (CNF)((NH2F)COF)((NH2F)CH2F)((NH2F)COF)(OHY)((NH2F)CH2F)(GuF)(OHCH2F)(benzodioxolAla)((NH2F)F)(MeA)(Mea)HO(4FPro)(4FPro)(MeK)(NH2F)(MeOrn)(Bip)(2Nal)(BzTzA)((NH2F)F)(YCH2COOH)(ClBip)•ci(PyF) f(MeOBip) (YOCH2Ch) (YOPh) (AcNHF) (pCH3Bip) (mPyF) (PyA)(PyA)mCIBip)(ClPyF)(IF)(CF3Bip)(CF3Bip)(ClPyA)(AcAEF)(pMeOmPyA)(3,3QA)(AcPiperazineF)o(3PheF)(MeOPyF)(diMeAsn)0(MeAsn)(MeF)(MeE)HO(MeChA)(4TzA)(Orn)(NPyrAsn)(PrG)(DiEtAsn)(MeTrp)(MeH)(COOHF)(PheO3F)(OCHF2Bip)(OCHF2Bip)(PyrazynylPhe)(MeOBip)(OHBip)(NPipAsn)(MeAoc)(MeAHepc)(pCF3PyrazynylpPhe)((4CF3)3PyPhe)(hGlu)(Api)(bisOctanoicAcid)(Aib)o(Acca)o(PheNH3F)(CF3F)(mY)OHo(30HY)(? CNBip)(? OcPrBip)(MeChG)(MecPeG)(pEtOBip)(MePheG)( / ? COOHCH2F) and(4FPhe).

6. A compound according to any one of claims 3 to 5, wherein AAi is F, A, mCF₃F, mCH₃F, / 1CH3F mCNF, CNF, mCF₃F, / 7CF3F, / 7NH2COF, pNH₂CH₂F, 777NH2COF, 4FPhe, m Y or 30HY as defined in claim 5.

7. A compound according to any one of claims 3 to 6, wherein AAi is F, 777CF3F or 4FPhe as defined in claim 5.

8. A compound according to any one of claims 3 to 7, wherein AAi is F.

9. A compound according to any one of claims 3 to 8, wherein AA2 is L, A, R, V, Orn, D, E, hGlu, Aib, Acca, COOHF, Api, bisOctanoicAcid or / iCOOHCEEF as defined in claim 5.

10. A compound according to any one of claims 3 to 9, wherein AA2 is L, R, E, / ? COOHF, hGlu, Api, / 1COOHCH2F or bisOctanoicAcid as defined in claim 5.

11. A compound according to any one of claims 3 to 10, wherein AA2 is L, R, / ? COOHF, hGlu, Api, / 1COOHCH2F or bisOctanoicAcid as defined in claim 5.

12. A compound according to any one of claims 3 to 11, wherein AA3 is Y, A, W, H, / TIOHY, / 77NH2CH2F, GuF, / 1OHCH2F, benzodi oxol Ala, mNH₂F, mNH₂COF or m Y as defined in claim 5.

13. A compound according to any one of claims 3 to 12, wherein AA3 is Y or 777NH2CH2F as defined in claim 5.

14. A compound according to any one of claims 3 to 13, wherein AA3 is / 77NH2CH2F as defined in claim 5.

15. A compound according to any one of claims 3 to 14, wherein AA4 is MeNle, MeA, A, 4RFPro, 4SFPro, MeK, MeOm, MeH, MeTrp, MeAoc, MecPeG, MeF, MeChA, MeAHepc, MePheG, MeChG or Mea as defined in claim 5.

16. A compound according to any one of claims 3 to 15, wherein AA4 is MeNle, MecPeG, MeAoc, MeChA, MeChG or MeAHepc as defined in claim 5.

17. A compound according to any one of claims 3 to 16, wherein AA4 is MeNle or MeAHepc as defined in claim 5.

18. A compound according to any one of claims 3 to 17, wherein AA5 is Y or A.

19. A compound according to any one of claims 3 to 18, wherein AA5 is Y.

20. A compound according to any one of claims 3 to 19, wherein AAe is Y, A, K, R, Bip, 2Nal, CF3F, CH3F, CNF, BzTzA, / ? (NH2F)F, YCH2COOH, CIBip, PyF, oMeOBip, YOCH2CI1, YOPh, / ? AcNHF, / iCHsBip, / 7? PyF, Py A, / 7? PyA, / 7 / ClBip, / 7 / ClpPyF, CNBip, IF, mCFsBip, CHBip, / ? CI / 7 / Pv.\. AcAEF, MeO / i / PyA, W, 3,3QA, AcPiperazineF, 3PheF, MeO / i / PyF, / 7? OCHF2Bip, PyrazynylPhe, / ? OCHF2Bip, / ? CF3PyrazynylpPhe, / ? OHBip, (4CF3)3PyPhe, PheO3F, PheNH3F, MeOBip, EtOBip or / ? OcPrBip as defined in claim 5.

21. A compound according to any one of claims 3 to 20, wherein AAe is Y, Bip, / ? ClBip, PyF, / iCHsBip, mPyF, / ? CNBip, / iCFsBip, MeO / i / PyF, BzTzA, / ? PyrazynylPhe, / ? OCHF2Bip, / ? CF3PyrazynylpPhe, (4CF3)3PyPhe, / zMeOBip, / ? OHBip, EtOBip or / ? OcPrBip as defined in claim 5.

22. A compound according to any one of claims 3 to 21, wherein AAe is PyF, / ? OCHF2Bip, / ? CH3Bip, / ? ClBip or / ? OcPrBip as defined in claim 5.

23. A compound according to any one of claims 3 to 22, wherein AA7 is H, A or Y.

24. A compound according to any one of claims 3 to 23, wherein AA? is H or Y.

25. A compound according to any one of claims 3 to 24, wherein A As is S, A, T, 4TzA, NPyrAsn or PrG as defined in claims 4 and 5.

26. A compound according to any one of claims 3 to 25, wherein AAs is S.

27. A compound according to any one of claims 3 to 26, wherein AA9 is R, A, H, E, hGlu, / ? COOHF, Api, or / ? COOHCH2F as defined in claim 5.

28. A compound according to any one of claims 3 to 27, wherein AA9 is R, E, hGlu, Api, / ? COOHF or / ? COOHCH2F as defined in claim 5.

29. A compound according to any one of claims 3 to 28, wherein AA9 is R or hGlu, as defined in claim 5.

30. A compound according to any one of claims 3 to 29, wherein AA10 is N, A, diMeAsn, Y, mNH₂COF, Q, pNH₂COF, E, D, MeAsn, V, NPipAsn, NPyrAsn or diEtAsn as defined in claim 5.

31. A compound according to any one of claims 3 to 30, wherein AA10 is N, diMeAsn, D or diEtAsn as defined in claim 5.

32. A compound according to any one of claims 3 to 31, wherein AA10 is diMeAsn as defined in claim 5.

33. A compound according to any one of claims 3 to 32, wherein AAn is MeNle, A, MeA, 4RFPro, 4SFPro, MeF, MeE or MeChA as defined in claim 5.

34. A compound according to any one of claims 3 to 33, wherein AAn is MeNle or MeChA, as defined in claim 5.

35. A compound according to any one of claims 3 to 34, wherein AAn is MeNle as defined in claim 5.

36. A compound according to any one of claims 1 to 35 selected from:CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-A-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*- / wCH3F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-pCH₃F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-mCNF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-pCNF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*- / wCF3F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-pCF₃F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-pNH₂COF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*- / ? (NH2F)CH2F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*- / w(NH2F)COF-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-A-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-A-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-W-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-H-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-mOHY-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-pGuF-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-pOHCH₂F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-benzodioxolAla-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)F-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)COF-MeNle-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeA-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-Mea-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-A-Y-Y-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-4RFPro-Y-Y-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-4SFPro-Y-Y-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeK-Y-Y-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeOm-Y-Y-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-A-Y-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-A-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-K-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-R-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-2Nal-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-pCF₃F-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-pCH₃F-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-pCNF-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-BzTzA-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-p(NH2F)F-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-YCH2COOH-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-oMeOBip-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-YOCH2Ch-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-YOPh-H-S-R-N-MeNle-C*-CONH2 CycloAc*-F-L-Y-MeNle-Y-pAcNHF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-mPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pPyA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mPyA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mClpPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCNBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pIF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-mCF3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCF3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pClmPyA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-AcAEF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pMeOmPyA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-W-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-3,3QA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-AcPiperazineF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-3PheF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pMeOmPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-A-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-Y-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-A-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-T-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-A-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-A-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-Y-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-m(NH2F)COF-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-Q-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-p(NH2F)COF-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-E-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-D-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-MeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-V-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-A-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeA-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-4RFPro-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-4SFPro-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeF-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeE-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeChA-C*-CO(NH2F) CycloAc*-pCH3F-R-benzodioxolAla-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-Y-Y-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-pPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-D-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*- / wCF3F-L-Y-MeNle-Y- / ? ClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-BzTzA-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-mPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-mCNF-L-m(NH2F)CH2F-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-mCNF-L-Y-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-R-Y-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-m(NH2F)CH2F-MeNle-Y-pPyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-V-Y-MeNle-Y-Y-H-4TzA-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-Y-S-H-N-MeNle-C*-CO(NH2F) CycloAc*-F-Orn-Y-MeNle-Y-Y-H-4TzA-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-V-Y-MeNle-Y-Y-H-NPyrAsn-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-V-Y-MeNle-Y-Y-H-PrG-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-SO2-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-SO-CO(NH2F) CycloAc*-F-Asp-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-Glu-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-pCOOHF-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-Glu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeH-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeTrp-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-mOCHF2Bip-H-S-R-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-4FPhe-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L- / w(NH2F)CH2F-MeAoc-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pPyrazynylPhe-H-S-R-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-hGlu- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-NPipAsn-MeNle-C*- CONH2CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-NPyrAsn-MeNle-C*- CONH2CycloAc*-F-Aib- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-Acca- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-Glu-(NH2F)CH2F-MeNle-Y-Bip-H-S-COOHF-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-mY-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-3OHY-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-PyrazynylPhe-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-COOHF-(NH2F)CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-COOHF-(NH2F)CH2F-MeNle-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-COOHF-(NH2F)CH2F-MeNle-Y-PyrazynylPhe-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MecPeG-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MeF-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-hGlu-m(NH2F)CH2F-MeNle-Y-pCF3PyrazynylpPhe-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeAoc-Y- CF3PyrazynylpPhe -H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-OHBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-CH3Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-CF3Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-(4CF3)3PyPhe-H-S-R-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-CNBip-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-Api-(NH2F)CH2F-MeNle-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-pCOOHCH2F-m(NH2F)CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-Api- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-COOHCH2F-(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-Api-diMeAsn-MeNle-C*- CONH2CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-ClBip-H-S-Api-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MeChA-Y- / ? ClBip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-bisOctanoicAcid-(NH2F)CH2F-MeNle-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-ClBip-H-S-COOHCH2F-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeChA-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeAHepc-Y-CNBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-CH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-PheO3F-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-OCHF2Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-COOHF-(NH2F)CH2F-MeNle-Y-Bip-H-S-COOHF-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-CF3PyrazynylpPhe-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-PheNH3F-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-mY-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-MeOBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-OHBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-EtOBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MePheG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MePheG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeAoc-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeAoc-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeAHepc-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / 7? (NH2F)CH2F-MeNle-Y-Bip-H-S- / 7COOHCH2F-diMeAsn- MeNle-C*-CO(NH2F) CycloAc*-F-Api- / 7? (NH2F)CH2F-MeNle-Y- / 7ClBip-H-S-hGlii-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-COOHCH2F-(NH2F)CH2F-MeNle-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-Api- / 77(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-Api-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-COOHCH2F-(NH2F)CH2F-MeNle-Y-ClBip-H-S-COOHCH2F-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-R-diMeAsn-MeChA-C*- CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeChG-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y-pOcPrBip-H-S-R-diMeAsn-MeNle- C*-CO(NH2F)CycloAc*-F-hGlu- / 77(NH2F)CH2F-MecPeG-Y- / ? ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-hGlu- / 7? (NH2F)CH2F-MeNle-Y-(4CF3)3PyPhe-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeNle-Y- / ? CNBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F) CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeAHepc-Y- / ? ClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F) CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-EtOBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y-Bip-H-S-R-DiEtAsn-MeNle-C*- CO(NH2F)CycloAc*-F-Api-(NH2F)CH2F-MeAHepc-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F) andCycloAc*-F-COOHCH2F-(NH2F)CH2F-MeAHepc-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F);or a pharmaceutically acceptable salt thereof;whereinC*-CO(NH2F) denotes the fragmentC*-S0C0NH2 denotes the fragmentC*-SO2CONH2 denotes the fragment,Ac* denotes the fragment C(O)-CH2; andCyclo denotes both at the same time (i) a covalent bond between the carbon of the CH2group of the Ac* fragment and the sulfur atom of the C*-C0NH2, C*- SOCONH2 or C*-SO2CO(NH2F) fragment and (ii) a covalent bond between the carbonyl of the Ac* fragment and the α-NH group of the adjacent amino acid in the sequence, thereby forming a cyclic polypeptide.

37. A compound according to any one of claims 1 to 36 selected fromCycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-N-MeNle-C*-CONH2CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CONH2CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-pPyF-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-mPyF-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-pCNBip-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc*-F-L-Y-MeNle-Y-pCF3Bip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pMeOmPyF-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-R-Y-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-R-Y-MeNle-Y- / ? CH3Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-R-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pClBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-pCH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L-Y-MeNle-Y-Bip-H-S-R-D-MeNle-C*-CO(NH2F)CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-BzTzA-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-pClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*- / wCF3F-L-Y-MeNle-Y- / ? ClBip-H-S-R-N-MeNle-C*-CO(NH2F) CycloAc*-F-L-m(NH2F)CH2F-MeNle-Y-Bip-H-S-R-N-MeNle-C*-CO(NH2F)CycloAc* -F-R-Y-MeNle-Y- PyF-H-S-R-diMeAsn-MeNle-C* -CO(NH2F)CycloAc*-F-R-mNH2CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Y-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-Glu-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F- / ? COOHF-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-Glu-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y-Bip-H-S-pCOOHF-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-4FPhe-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-pPyrazynylPhe-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-hGlu-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-NPipAsn-MeNle-C*-CONH2 CycloAc*-F-L-mNH2CH2F-MeNle-Y-Bip-H-S-R-NPyrAsn-MeNle-C*-CONH2 CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-pCOOHF-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-L-mNH2CH2F-MecPeG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? CF3PyrazynylpPhe-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-mNH2CH2F-MeAoc-Y- CFsPyrazynylpPhe -H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-pCH3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CONH2CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-pCF3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-L-mNH2CH2F-MeNle-Y-(4CF3)3PyPhe-H-S-R-diMeAsn-MeNle-C*- CONH2CycloAc*-F-L-mNH2CH2F-MeNle-Y- / ? CNBip-H-S-R-diMeAsn-MeNle-C*-CONH2CycloAc*-F-Api- / 7? (NH2F)CH2F-MeNle-Y- / 7OCHF2Bip-H-S-hGlii-diMeAsn-MeNle- C*-CO(NH2F) CycloAc*-F- / 7COOHCH2F- / 7? (NH2F)CH2F-MeNle-Y- / 7OCHF2Bip-H-S-hGlii-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-Api- / 77(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F- / ? COOHCH2F- / 77(NH2F)CH2F-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y-Bip-H-S-Api-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-Api-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeChA-Y- / ? ClBip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-bisOctanoicAcid-(NH2F)CH2F-MeNle-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu- / 77(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S- / ? COOHCH2F-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-CH3Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y- / ? OCHF2Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-COOHF-(NH2F)CH2F-MeNle-Y-Bip-H-S-COOHF-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-CF3PyrazynylpPhe-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-mY-MeNle-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y- / ? MeOBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / 77(NH2F)CH2F-MeNle-Y- / ? OHBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-(NH2F)CH2F-MeNle-Y-EtOBip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu-(NH2F)CH2F-MeAoc-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F) CycloAc*-F-hGlu-(NH2F)CH2F-MeNle-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CONH2 CycloAc*-F-hGlu-(NH2F)CH2F-MeAoc-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeAHepc-Y-OCHF2Bip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S- / ? COOHCH2F-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-Api-(NH2F)CH2F-MeNle-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-COOHCH2F-(NH2F)CH2F-MeNle-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-Api-(NH2F)CH2F-MeNle-Y-ClBip-H-S-Api-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-COOHCH2F-(NH2F)CH2F-MeNle-Y-ClBip-H-S-COOHCH2F-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y- / ? ClBip-H-S-R-diMeAsn-MeChA-C*-CO(NH2F) CycloAc*-F-L- / w(NH2F)CH2F-MeChG-Y-Bip-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-pOcPrBip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-hGlu-(NH2F)CH2F-MeAHepc-Y-ClBip-H-S-hGlu-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L- / w(NH2F)CH2F-MeNle-Y-Bip-H-S-R-DiEtAsn-MeNle-C*-CO(NH2F)CycloAc*-F-Api-mNH2CH2F-MeAHepc-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F) andCycloAc*-F-pCOOHCH2F-mNH2CH2F-MeAHepc-Y-pOCHF2Bip-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F)wherein -C*-C0NH2, Ac* and Cyclo are as defined in claim 36.

37. A compound according to any one of claims 1 to 36 selected fromCycloAc*-F-R-m(NH2F)CH2F-MeNle-Y- / ? PyF-H-S-R-diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)CycloAc*-F-pCOOHF-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-pCH3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-pCF3Bip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-Api-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn-MeNle- C*-CO(NH2F)CycloAc*-F-pCOOHCH2F-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-bisOctanoicAcid-m(NH2F)CH2F-MeNle-Y-pOCHF2Bip-H-S-hGlu- diMeAsn-MeNle-C*-CO(NH2F)CycloAc*-F-L-mNH2CH2F-MeNle-Y-pOCHF2Bip-H-S-R-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-hGlu-mNH2CH2F-MeNle-Y-pClBip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-hGlu-m(NH2F)CH2F-MeAHepc-Y-pOCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-Api-mNH2CH2F-MeNle-Y- / ? ClBip-H-S-hGlu-diMeAsn-MeNle-C*- CO(NH2F)CycloAc*-F-pCOOHCH2F-mNH2CH2F-MeNle-Y-pClBip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F)CycloAc*-F-L-mNH2CH2F-MeNle-Y-pOcPrBip-H-S-R-diMeAsn-MeNle-C*- CONH2 andCycloAc*-F-Api-mNH2CH2F-MeAHepc-Y- / ? OCHF2Bip-H-S-hGlu-diMeAsn- MeNle-C*-CO(NH2F);or a pharmaceutically acceptable salt thereof;wherein C*-CO(NH2F), Ac* and Cyclo are as defined in claim 36.

38. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 37 comprising the following step (a) and optionally step (b):(a) the reaction of a compound of formula (A)HS(CF3F)^in the presence of a base;to arrive at a compound of formula (I) as defined above wherein R1and R2are both absent at the same time; and optionally(b) the reaction of a compound of formula (I) as defined above wherein R1and R2are both absent at the same time with an oxidizing agent to arrive at a compound of formula (I) as defined above wherein one of R1and R2is absent and the other one is oxygen or wherein R1and R2are both oxygen at the same time;wherein [AA]n denotes the chain of 11 amino acids as defined in any one of claims 1 to 34.

39. A compound according to any one of claims 1 to 37, when manufactured according to a process of claim 38.

40. A compound according to any one of claims 1 to 37 for use as therapeutically active substance.

41. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 37 and a therapeutically inert carrier.

42. The use of a compound according to any one of claims 1 to 37 for the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age- related Macular Degeneration (AMD) or diabetic retinopathy (DR).

43. The use of a compound according to any one of claims 1 to 37 for the preparation of a medicament for the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age-related Macular Degeneration (AMD) or diabetic retinopathy (DR).

44. A compound according to any one of claims 1 to 37 for use in the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age- related Macular Degeneration (AMD) or diabetic retinopathy (DR).

45. A method for the treatment or prophylaxis of ocular diseases, in particular of front of the eye diseases (ocular surface diseases), like Dry Eye Disease (DED), Keratoconus, Corneal Ulcers, Contact lens related complications, Conjunctivochalasis, Lasik surgery or Neurotrophic keratitis, or of back of the eye diseases (retinal diseases), like Age-related Macular Degeneration (AMD) or diabetic retinopathy (DR), which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 37 to a patient in need thereof.

46. A compound selected from2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;(25)-2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;(2R)-2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;(25)-2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;(2R)-2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;(25)-2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;(27?)-2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid;(25)-2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid;(27?)-2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid,2-amino-3-(3-anilinophenyl)propanoic acid;(25)-2-amino-3-(3-anilinophenyl)propanoic acid;(2R)-2-amino-3-(3-anilinophenyl)propanoic acid;2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid;(25)-2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid; and(2R)-2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid;each optionally protected by an amino acid protecting group, in particular an amino acid protecting group protecting their amino functionality.

47. A compound according to claim 46, wherein the amino acid protecting group is selected from te / 7-Butyl oxy carbonyl (Boc), Trityl (Trt), a,a-Dimethyl-3,5- dimethoxybenzyloxycarbonyl (Ddz), 2-(4-Biphenyl)isopropoxycarbonyl (Bpoc), 2- Nitrophenylsulfenyl (Nps), benzyloxycarbonyl (Z), 9-Fluorenylmethoxycarbonyl (Fmoc), 2-(4-Nitrophenylsulfonyl)ethoxycarbonyl (Nsc), (1,1- Dioxobenzo[b]thiophene-2-yl)methyloxy carbonyl (B smoc), (1,1 -Di oxonaphtho [ 1,2- Z>]thiophene-2-yl)m ethyloxy carbonyl (a-Nsmoc), (l-(4,4-Dimethyl-2,6-di oxocyclohex- 1 -ylidene)-3 -ethyl) (Dde), 1 -(4, 4-Dimethyl-2,6-di oxocyclohex- 1 - ylidene)-3 -methylbutyl (ivDde), 2,7-Di-tert-butyl-Fmoc (Fmoc*), 2-Fluoro-Fmoc (Fmoc(2F)), 2-Monoisooctyl-Fmoc (mio-Fmoc), 2,7-Diisooctyl-Fmoc (dio-Fmoc), Tetrachlorophthaloyl (TCP), 2-[Phenyl(methyl)sulfonio]ethyloxycarbonyl tetrafluoroborate (Pms), Ethanesulfonylethoxycarbonyl (Esc), 2-(4- Sulfophenylsulfonyl)ethoxycarbonyl (Sps), Allyloxycarbonyl (Alloc), o- Nitrobenzenesulfonyl (oNBS) and -nitrobenzenesulfonyl ( / ? NBS), 2,4- Dinitrobenzenesulfonyl (dNBS), Benzothiazole-2-sulfonyl (Bts), 2,2,2- Trichloroethyloxycarbonyl (Troc), Dithiasuccinoyl (Dts), p-Nitrobenzyloxycarbonyl (pNZ), a-Azido Carboxylic Acids, Propargyloxycarbonyl (Poc), o- Nitrobenzyloxycarbonyl (oNZ) and 6-Nitroveratryloxycarbonyl (NVOC), 2-(2- Nitrophenyl)propyloxycarbonyl (NPPOC), 2-(3,4-Methylenedioxy-6- nitrophenyl)propyloxycarbonyl (MNPPOC), Ninhydrin (Nin), 9-(4-Bromophenyl)-9- fluorenyl (BrPhF) and Azidomethoxycarbonyl (Azoc), in particular Fmoc.

48. A compound according to claim 46 or 47 selected from(25)-2-amino-3-[4-[4-(cyclopropoxy)phenyl]phenyl]propanoic acid;(25)-2-amino-3-[4-[4-(difluoromethoxy)phenyl]phenyl]propanoic acid;(25)-2-amino-3-[4-[5-(trifluoromethyl)pyrazin-2-yl]phenyl]propanoic acid;(25)-2-amino-3-[4-[3-(difluoromethoxy)phenyl]phenyl]propanoic acid;(25)-2-amino-3-(3-anilinophenyl)propanoic acid;(25)-2-amino-3-[4-(2-chloro-4-pyridyl)phenyl]propanoic acid;(2S)-3-[4-[4-(Cyclopropoxy)phenyl]phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid;(2S)-3-[4-[4-(Difluoromethoxy)phenyl]phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid;(2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-[4-[5-(trifluoromethyl)pyrazin-2- yl]phenyl]propanoic acid;(2S)-3-[4-[3-(Difluoromethoxy)phenyl]phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid;(2S)-3-(3-Anilinophenyl)-2-(9H-fluoren-9-ylmethoxy carbonylamino) propanoic acid; and(2S)-3-[4-(2-Chloro-4-pyridyl)phenyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoic acid.

49. The use of a compound according to any one of claims 46 to 48 in the manufacture of a peptide.

50. The invention as hereinbefore described.***

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