NZ621974B2 - Template-fixed peptidomimetics as inhibitors of fpr1 - Google Patents

Abstract

Disclosed herein are template-fixed ?-hairpin peptidomimetics of the general formula (I): cyclo[P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-T1-T] wherein the single elements T or P are ?-amino acid residues connected in either direction which, depending on their positions in the chain, are as defined in the description and the claims, and salts thereof, have the property of antagonizing the biological effect of the receptor FPR1. The compounds can be used as medicaments to treat or prevent diseases or conditions in the areas of inflammatory diseases, allergic conditions,immunological disorders, neuroinflammation, neurological disorders, obstructive airway diseases, infectious diseases, ischemic reperfusion injuries and proliferative disorders such as e.g. cancer. These ?-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy. ined in the description and the claims, and salts thereof, have the property of antagonizing the biological effect of the receptor FPR1. The compounds can be used as medicaments to treat or prevent diseases or conditions in the areas of inflammatory diseases, allergic conditions,immunological disorders, neuroinflammation, neurological disorders, obstructive airway diseases, infectious diseases, ischemic reperfusion injuries and proliferative disorders such as e.g. cancer. These ?-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

Description

W0 2013(050346 TEMPLATE-FIXED PEPTIDOMIME'PICS AS INHIBITORS OF FPRl The present invention provides peptidomimetics orating a chain of 14 a-amino acid es as defined below attached to a template which provides specific structural constraints for a B—hairpin like conformation. These template-fixed B-hairpin cs are able to inhibit the biological function of Formyl-Peptide Receptor 1, abbreviated FPR1, and are thus useful as pharmaceuticals in the treatment of a variety of diseases and disorders. The present invention also relates to pharmaceutical compositions and forms comprising one or more of these compounds and ent processes for the preparation and production of these nds and their intermediates.

Many medically relevant biological processes are mediated by signal uction that involves G protein—coupled receptors (GPCRs) and a plethora of their endo- or exogenic ligands. One of the best characterized groups of GPCRs, y dated back to the early 19705, are the formyl peptide receptors (FPRs) (N. Schiffmann et al., Proc. Nat. Acad.

Sci., 1975, 72, 1059-1062). This group ents a classical type of seven-trans- membrane domain receptors with pattern recognition for different chemoattractant 5, especially for small formylated peptide fragments such as e.g. N—formyl—methionyl— leucyl-phenylalanine (flVlLF). In human three members, FPRl, FPRZ/ALX and FPR3, have been fied and are all genetically clustered in the same chromosomal region (19q13.3), whereas in rodents at least eight equivalents have been described.

Being widely promiscuous for their ligands, these chemoattractant receptors are a major cornerstone in the host innate immune system to fight infections, other xeno— biotics and tissue damages. According to this major function, expression levels are upregulated predominantly in different phagocytic leucocytes but can as well be found in n tissues as indicated below for the different receptors.

The activation of FPR family members for example in leucocytes by chemoattractants induces GPCR coupling to 6.012 or Giag, which rs multiple secondary messengers through phospholipase C D and A2 activation (H. Ali et al., J.

, Biol. Chem, 1999, 274, 6027—6030). Subsequently shape changes, chemotaxis, adhesion, phagocytosis and/or the release of superoxide anions and other granule ts, leading to tissue damage can be observed in this disease state of mation or e.g. after infarction (Y. Le et al., Cytokine Growth Factor Rev., 2001, 12, 91-105; F. Gavins, Trends in Phorm.

Sciences, 2010, 31, 266-276).

FPRl was initially identified in phagocytic leukocytes as a high affinity receptor for the bacterial chemotactic peptide fMLF and other formyl—peptides and is an important key factor of the innate host e against microbial infections. it has been reported to mediate proinflammatory and acterial host responses (P. Murphy et al., Annu.

Rev. lmmunol., 1994, 12, 593-633; J.~F. Gauthier et al., Infection and Immunity, 2007, 5361—5367; R. Ye, P. Murphy et al., Pharmacol. Rev., 2009, 61, 119-161 and cited literature therein). In addition FPRl has been found in a broad variety of different cell types and tissues not only involved in inflammation, such as endothelial cells, neutrophils, tes, astrocytes or dendritic cells, but as well in e.g. malignant tumor cells of hematopoietic origin or glioblastoma cells (Y. Le et al., J. Neuroimmuno/., 2000, 111, 102-108; J. Huang et al., Cancer Letters, 2008, 267, 254—261).

Due to the cuous behavior of the FPR1 receptor, quite an array of different natural and synthetic ligands is known. Besides the already ned plurality of specific formyl~peptide ligands, other classes of microbe derived s contain ures like e.g. T20 (DP178) from HIV gp41 (5. Su et al., Blood, 1999, 93, 11, 3885— 3892). in addition host d agonists include the variety of e.g. the peptidase cathepsin G, the phospholipid-binding protein Annexin 1 and specific nts thereof as well as formyl peptides of mitochondrial origin (R. Sun et al., J. lmmunol., 2005, 173, 428-436; M. J. Ra biet et al., Eur. J. Immunol., 2005, 35, 2486-2495).

W0 2013I'050346 There are s antagonists known as well, ally those formed by ing the N—formyl group for example in fMLP by a t—butoxycarbonyl (t-Boc) or isopropyl urea group. Some more specific inhibitory ligands from natural sources are e.g. Coronavirus peptides, Spinorphin, the bile acids deoxycholic acid (DCA) and chenodeoxycholic acid , and, most prominent, Cyclosporin H and A. It has been shown that these s inhibit fMLP—induced monocyte and, in part, neutrophil migration and calcium mobilization, suggesting a mechanism for inhibition of inflammation and suppression of the innate immune response (eg. P. Yan et al., J. of Immunol., 2006, 177, 7050- 7085; F. Gavins, Trends in Pharm. Sciences, 2010, 31, 266—276 and cited literature therein).

In a more recent publication it is presented that FPRl is positively associated with periodontitis and stomach cancer, ting a new point of interference in the progression of these diseases (T. Otani et al., Biochemical and sical Research Communication, 2011, 405, 3, 356—361).

Therefore it would be advantageous to develop new chemical entities of limited complexity which address the need of binding selectively with high affinity to the FPRl receptor and interfering with the corresponding specific downstream signaling activity to ameliorate the associated disease conditions.

The present ion provides now new chemical entities for a potential use as potent, selective and drugable modulators for the GPC receptor FPRl. ln the compounds described below, a new strategy is utilized to stabilize B-hairpin conformations in backbone—cyclic peptidomimetics exhibiting selective antagonistic activity on the FPRl receptor. This involves transplanting a loop sequence of a natural or unnatural biopolymer onto a template, whose on is to restrain the‘peptide loop backbone into a B-hairpin geometry.

WO 2013050346 te—bound hairpin mimetic peptides have been described in the literature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem. 1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441) and the ability to generate B-hairpin peptidomimetics using atorial and parallel synthesis methods has now been established (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000, 83, 3097- 3112). These methods allow the synthesis and screening of large B-hairpin mimetic libraries, which in turn considerably facilitates structure—activity studies and hence the ery of new les with potent and, especially, selective antagonizing activity.

There are few studies in the field describing 14mer peptides linked to a template as pharmaceutically active compounds, e.g. as antimicrobials in the international patent application WOOZ/O70547 A1 where specifically a disulfide interstrand linkage is t either from position P5 to P10 or from P3 to P12. Some other related publications describe template—fixed peptidomimetics as antagonists against the GPCR CXCR4. The cyclic peptidomimetics of this category, such as disclosed in the WIPO publications W02004/O96840 A1 or W02010/127704 A1, feature different amino acid sequences in the peptidic chain part, e.g. being devoid of aromatic residues at on P5, are conjugated to dyes (W02006/117011 A1) or half—life prolonging extended functionalities (W02011/066869 A1), or containing a ent backbone tion, i.e. as depsipeptides in W02010/060479 A1.

The present ion is now providing novel nds which differ significantly in structure leading to a specific affinity for the FPRl receptor.

The B-Hairpin peptidomimetics obtained by the approach described here are useful as inhibitors of FPRl, i.e. as antagonists of downstream biological effects of this receptor and therefore as useful agents in the chemotherapy of especially the disease areas of inflammatory diseases, allergic conditions, immunological disorders, neuroinflam— mation, neurological disorders, obstructive airway diseases, infectious es, ischemic reperfusion injuries and proliferative disorders such as e.g. cancer.

Specific disease conditions falling under the areas described above are e.g. acute and chronic lung inflammation, COPD, asthma, emphysema, inflammation of the gastrointestinal tract, matory bowel disease (IBD), Crohn’s disease, acute skin inflammation, atopic itis, eczema, psoriasis, rosacea, acne, neutrophilic derma— tosis, neutrophil disorder, phil disorder, monocyte/macrophage associated diseases, Jobs syndrome, Chédiak—Higashi syndrome, chronic granulomatous disease, leukocyte adhesion deficiency, cystic fibrosis, nitis, periodontitis, sepsis, pneumonia, bacterial infection, and cancer.

The t invention s to novel B-hairpin peptidomimetics of formula (I), CYClolp1-P2-P3—P4-P5-P6-P7-P8-P9-P1O-P11—P12-P13—P14_T1_T2] wherein the single elements T or P are connected in either direction from the carbonyl (C20) point of attachment to the nitrogen (N) of the next element and wherein T1 is a naturally or non-naturally occurring D a—amino acid containing in total 1 to 25 carbon— and/or heteroatoms in a single side—chain; T2 is a naturally or non-naturally occurring L a—amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side—chain; P1, P3, P12, P13 and P14 are independently Gly or a naturally or non-naturally occurring L a—amino acid containing in total 1 to 25 carbon— and/or heteroatoms in a single side-chain; P2, P5 and P8 are independently a naturally or non-naturally occurring aromatic L a~amino acid containing in total 1 to 25 carbon— and/or heteroatoms in a single side—chain; P4 and P11 are naturally or turally occurring cross—linking L a—amino acids containing each in total 1 to 12 carbon- and/or heteroatoms in a single side—chain which together are connecting P4 and P11 by nt or electrostatic interaction; P6 is Gly; P7 is a naturally or non-naturally occurring D (ii—amino acid containing in total 1 to 25 - and/or heteroatoms in a single side—chain; P9 is a naturally or non—naturally occurring alcoholic L a—amino acid containing in total 1 to 25 carbon— and/or heteroatoms in a single side—chain; and P10 is a lly or non-naturally ing aliphatic L OL-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single hain; or a tautomer or rotamer thereof, or a salt, or a hydrate or e thereof. 2012/069412 A particular embodiment of the present invention relates to compounds according to general formula (I), wherein T1 and P7 are independently an D a—amino acid residue of one of the formulae 0 N" 'VfO O " ‘R1 f ‘R‘ t" a, v?‘R‘ " " H IR H e T2 is an L a—amino acid residue of one of the ae 1‘"RN"‘R‘ 5"M‘R1 3"M‘R1 H RAlk H RAr H RHet AA1 AA2 AAS WO 2013050346 O f O f O R3 I f I l ’ N R8 ’ N ' ’ N ’ t R:3 A: R9 i R2 R2 R7 R2 R7 R4 4 R5 R6 R4 R R5 R8 R5 R6 AA4 AA5 AAS I Nf R3 y" R9 \ R4 R10......— R2 P1, P3, P12, P13 and P14 are independently Gly; or an L d—amino acid residue of one of the formulae AA1 AA2 AA3 P2, P5 and P8 are independently an L o acid residue of formula k6,0 ' A ‘R1 H RAF P4 and P11 taken together form an interstrand linking bis(amino acid)-structure of formula fi‘.‘K‘Nf : \R‘ H 2 H R2\ x ,1 N a AA10 ; l P6 is Gly; P9 is an L o acid e of formula P10 is an L oz-amino acid residue of formula RAlkIS, with the proviso of containing less than 26 carbon- and/or heteroatoms, €1-12—alkyl; C2alkenyl; cycloalkyl; cycloalkyl-C1_6—alkyl; or C1a|koxy-C1_6—a|kyl; RAr is, with the proviso of containing less than 26 ca rbon- and/or heteroatoms, -(CR1R1)nR19; -(CH2)n0§J R20 R20 AR1 AR2 WO 50346 or a heteroaryl group of one of the formulae ‘5#X-/\\ \8/"x/R23 ’ / X‘ZX" R23 . if; . ‘55/F\)23 Ox \N/"x . :g’MX/2 gaze H1 H2 H3 H4 , R20 R23 R20 R23 R20 R23 ‘ X x \ \ \A ,, rfS\//‘/ A R24 ,555\//‘/ A l / l /R24 §\//‘/ _% K ist K I l R24 N o / s 2" y: x H5 H6 H7 H8 R23 R23 _§_ R32 .m'm.

L/X /\]R/R24 X N \ \\ R23 N \ \ X a [\ljl \I-R23 \X" / / / X'" X' ‘N H12 H13 H14 X, X’, X" and X’" are independently —CR2°; or N; R20 and R21 are independently H; F; Cl; Br; I; OH; NH2; N02; CN; CF3; OCHFZ; OCF3; C1_3-alkyl; |keny|; aryl; heteroaryl; 1_6—a|ky|; heteroaryl-C1.5-alkyl; —(CH2)0R22; -(CH2)OOR15; -O(CO)R15; -O(CH2)0R22; —(CH2)DSR15; -(CH2)ONR15R15; —(CH2)OOCONR15R16; -(CH2)ONR1CONR15R16; -(CH2)ONR1COR15; -(CH2)0COOR15; ~(CH2)0CONR15R16; —(CH2)OPO(OR1)2; -(CH2)osozR14; or -(CH2)oc0R1-"; W0 2013I'050346 R22 is an aryl group of the formula R23, R24 and R25 are independently H; F; Cl; Br; I; OH; NHZ; N02; CN; CFg; OCHFZ; OCF3; C1_3-a|kyl; CN;-alkenyl; -(CH2)OOR15; ~O(CO)R15; -(CH2)ONR1R15; —(CH2)OCOOR15; —(CH2)OCONR1R15; R26 is H; Ac; C1-8~alkyl; or aryl—C1.5-alkyl; n and m are independently an integer of 0-5 with the proviso that n+m s 6; o is 0-4; p is 2-6,- q is 1-6; and r is 1-3; or ceutically able salts thereof.

Each single group "Rx" with the same index-number x for x = 1 — 26 is independently selected on each occurrence in a specific a and, therefore, they can be the same or ent.

As used in this description, the term "alkyl", taken alone or in combinations (i.e. as part of another group, such as "aryl—C1_6~alkyl") designates saturated, straight—chain or branched hydrocarbon radicals and may be optionally substituted. The term "CH— alkyl" (x and y each being an integer) refers to an alkyl group as d before containing x to y carbon atoms. For example a C1alkyl group ns one to six carbon atoms. Representative examples ofalkyl groups include methyl, ethyl, n-propyl, iso—propyl, l, iso-butyl, sec—butyl, tert—butyl, n-pentyl, n-hexyl and the like.

The term "alkenyl", taken alone or in combinations, designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties are optionally substituted and can independently exist as E or Z configurations per double bond, which are all part of the invention. The term "Cx.y-alkenyl" (x and y each being an integer) refers to an alkenyl group as defined before containing x to y carbon atoms.

The term "cycloalky III , taken alone or in combinations, refers to a saturated or partially unsaturated alicyclic moiety having from three to ten carbon atoms and may be optionally substituted. Examples of this moiety include, but are not limited to, cyclohexyl, norbornyl, decalinyl and the like.

The term "heterocycloalkyl", taken alone or in combinations, describes a ted or partially unsaturated mono- or bicyclic moiety having from three to nine ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen or sulphur.

This term includes, for example, morpholino, piperazino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro—lH-indolyl, 1,7—diazaspiro[4.4]nonane and the like. Said heterocycloalkyl ) might be ally substituted.

The term "aryl", taken alone or in combinations, ates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be optionally substituted by up to three substituents such as Br, Cl, F, CF3, OH, OCF3, OCHFZ, NH2, N(CH3)2, N02, CN, C1.5—alky|, C2.5-alkenyl, phenyl or phenoxy.

The term "heteroaryl", taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five~ and/or mbered rings, at least one of them containing up to three heteroatoms selected from the group consisting of O, S and N and whereby the heteroaryl radicals or eric forms thereof may be ed via any suitable atom. Said heteroaryl ring(s) are optionally substituted, e.g. as indicated above for "aryl".

The term "aryI-CX.y-a|kyl", as used herein, refers to an Cx-y-alkyl group as defined above, tuted by an aryl group, as defined above. Representative es of aryI—Cx-y- alkyl moieties include, but are not d to, benzyl, l—phenylethyl, 2-phenylethyl, 3- phenylpropyl, 2-phenylpropyl and the like.

The term "heteroa ryl-Cx_y-alkyl", as used herein, refers to an |kyl group as defined above, substituted by a heteroaryl group, as d above. es of heteroaryl—q- y-alkyl groups include pyridin—3—ylmethyl, (1H~pyrro|—2—yl)ethy| and the like.

The term "aryl—cycloalkyl", as used herein, refers to a cycloalkyl group as defined above, tuted or annelated by an aryl group, as defined above. Examples of aryl- cycloalkyl moieties include, but are not limited to, phenylcyclopentyl, 2,3-dihydro-1H— indenyl, 1,2,3,4—tetra hydronaphthalenyl and the like.

The term "aryl-heterocycloalkyl", as used herein, refers to a heterocycloalkyl group as defined above, substituted or annelated by an aryl group, as defined above. Examples of aryl—heterocycloalkyl moieties include, but are not limited to, indolinyl, 1,23,4- tetrahydroquinolinyl and the like.

The term "heteroaryl—cycloalkyl", as used , refers to a cycloalkyl group as defined above, substituted or annelated by a heteroaryl group, as defined above. Examples of heteroaryl—cycloalkyl moieties include, but are not d to, 5,6,7,8—tetrahydro— quinolinyl and the like.

The term "heteroaryl—heterocycloaIkyl", as used herein, refers to a heterocycloalkyl group as defined above, substituted or annelated by a heteroaryl group, as defined above. Examples of heteroaryI—heterocycloalkyl moieties include, but are not limited to, 4-(thiazolyl)piperazinyl, 8—tetra hyd ro—1,6-naphthyridinyl and the like.

The terms "cycloalkyl—aryl", "heterocycloalkyl-aryl", "cycloaIkyl-heteroaryl", and "heterocycloalkyl-heteroaryl", as used herein, are d analog to the terms "aryl- cycloalkyl", "aryl-heterocycloaIkyl", "heteroaryl-cycloalkyl" and "heteroaryl—hetero- WO 50346 cycloalkyl", as defined above, but connected in the opposite direction, e.g. instead of 4-(thiazolyl)piperazinyl the term refers to 2-(piperazin-l-yl)thiazolyl and the like.

The terms "hydroxy", y" and "aryloxy", taken alone or in combinations, refer to the groups of —OH, -O—alkyl and —O—ary| respectively, wherein an alkyl group or an aryl group is as defined above. The term "Cw-alkoxy" (x and y each being an integer) refers to an -O—alkyl group as defined before containing x to y carbon atoms attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, n— propoxy, iso-propoxy, n—butoxy, tert—butoxy and the like. Examples of aryloxy include e.g. phenoxy. For avoidance of doubt e.g. the term "hydroxy-C1_8-alkyl" represents, among others, groups like e.g. hydroxymethyl, 1—hydroxypropyl, 2-hydroxypropyl or 3— hydroxy—2,3-dimethylbutyl.

The term nally tuted" is in general intended to mean that a group, such as, but not limited to Cx_y-alkyl, Cx.y-alkenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, |koxy and aryloxy may be substituted with one or more substituents independently selected from amino (~NH2), dimethylamino, nitro , halogen (F, Cl, Br, I), CF3, cyano (—CN), hydroxy, methoxy, ethoxy, phenyloxy, benzyloxy, acetoxy, 0x0 (:0), carboxy, carboxamide, methyl, ethyl, phenyl, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. in the context of this ion the term "naturally or turally ing or—amino acid" typically comprises any natural a~amino acid, such as the proteogenic amino acids (examples listed below), their natural or ynthetic derivatives and as well 01— amino acids of purely synthetic . This term includes as well a—amino acid which are optionally tuted at the (Jr-nitrogen of the amino acid such as, but not limited to, acetylation or alkylation, e.g. methylation, or benzylation.

The term "aliphatic a-amino acid" refers to d-amino acids with an aliphatic side-chain, such as, but not limited to, alanine, valine, leucine, isoleucine, n—octylglycine etc.

W0 2013I050346 The term "aromatic d-amino acid" refer to a-amino acids with a side~chain sing an aromatic or heteroaromatic group, such as, but not limited to, phenylalanine, tryptophan, histidine, O-methyI-tyrosine, 4—trifluormethyl-phenylalanine, 3,4sdichloro- homophenylalanine etc.

The term "cross—linking o acid" refers to d-amino acids with a side—chain comprising a function able to cross—link to a second a-amino acid by a strong interaction such as a covalent bond or an electrostatic contact, such as, but not d to, cysteine, homocysteine etc.

The term "alcoholic a—amino acid" refers to o acids with a side—chain sing an alcoholic or thioalcoholic group, Le. a hydroxy or dryl function, such as, but not d to, serine, threonine etc.

For the avoidance of doubt the term "single hain" in the context of an a-amino acid refers to a structure where the a-carbon of the amino acid is covalently connected to the (in—chain) groups of the carbonyl (C20) and nitrogen (N) as well as to one hydrogen (H) and one variable side-chain, e.g. as defined above. A "single side-chain" may include as well a heterocyclic structure comprising the a—amino atom, such as but not limited to, proline, pipecolic acid etc.

For the avoidance of doubt the term "heteroatom" refers to any atom that is not carbon or hydrogen.

The ptors L respectively D refer to the stereochemistry at the deposition of an 01— amino acid and are used according the Fischer~Rosanoff convention of the IUPAC.

The peptidomimetlcs of the present invention can also be diastereomers (e.g. epimers) of compounds of formula (I) if no specific stereochemistry of the chiral center is determined in the description. These stereoisomers can be prepared by a modification of the process described below in which the appropriate isomers (e.g. epimers/ enantiomers) of chiral starting materials are used. In case of ambiguous stereochemistry in the above description each single epimer is part of the present invention as well as a mixture of both.

A further embodiment of the present invention may also include compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2H (D), 3H, 11C, 14C, 127| etc. These isotopic analogs and their pharmaceutical salts and ations are considered useful agents in the therapy and/or diagnostic, for example, but not limited to, where a fine—tuning of in vivo ife time could lead to an optimized dosage regimen.

A further particular ment of the invention s to derivatives of general formula (I), wherein specifically T1 is an D o acid residue of one of the formulae AAlD; AA30; AA40; AASD; or AASD; T2 is an L o acid residue of one of the formulae AA1;AA2; AA3; AA4;AA5; AA6; or AA8; and P7 is an D a—amino acid residue of one of the formulae AA10; AA40; AASD; or AA8D; An alternative particular embodiment of the invention relates to derivatives of general a (I), wherein specifically T1 is an D a—amino acid residue of one of the formulae AA4D; AASD; AA6D; AA7D; AASD; or AAQD; and T2 is an L OL-amino acid residue of one of the formulae AA4; AAS; AA6; AA7; AA8; or AA9; An other particular embodiment of the invention the elements of general formula (I) are d as follows P1, P3, P13, and P14 are independently Gly; Gly(tBu); Gly(cHex); Gly(cPr); Ala; Ala(tBu); ex); Ala(cPr); Val; Nva; Leu; lle; Nle; hLeu; OctG; Met; Ala(sz); Dab; Dab(Ac); Dab(cPr); Dab(iPr); Dab(MeSOz); Dap; Dap(Ac); Dap(cPr); Dap(iPr); Dap(Mesog); Lys; Lys(Bz); Lys(l\/le); Lys(Nic); Lys((5R)OH); Lys(40xa); hLys; Orn; Orn(Ac); Orn(cPr); Orn(iPr); Arg; hArg; Asn; Asp; Gln; Glu; Cit; Met(02); Ser; hSer; ); Ser(i\/le); Thr; alloThr; Thr(Bn); Thr(Me); Bip; Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(ZFuryl); Ala(3Furyl); m); m); hAIa(1lm); lm); Ala(Pyrazinyl); Ala(lerazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(SPyrimidin); Ala(ZQuin); uin); Ala(4Quin); Phe; Phe(2Cl); Phe(3CI); Phe(4Cl); 4C|2); Phe(ZF); Phe(3F); Phe(4F); N); Phe(4CN); PhE(2CF3),’ Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); OOMe); hPhe; Phg; 1Nal; 2Nal; N|e(60Bn); Trp; Trp(7Aza); Trp(SBr); Trp(GBr); Trp(6CF3); Trp(SCI); Trp(6C|); Trp(5,6Cl); Trp(SOH); hTrp; His; His(Me); His(Bn); hHis;Thi; Th2; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); HPh); hTyr; or Tza; P2, P5 and P8 are independently 2Pal; 3Pal; 4Pal; hZPaI; h3Pal; h4Pal; Ala(ZFuryl); Ala(3Furyl); Ala(llm); Ala(Zlm); hAla(1Im); hAIa(2lm); Ala(Pyrazinyl); Ala(lerazolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(5Pyrimidin); Ala(ZQuin); Ala(3Quin); Ala(4Quin); Phe; Phe(2Cl); Phe(3CI); Phe(4Cl); Phe(3,4C|2); Phe(ZF); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(ZCFg); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe);hPhe;Phg;1Nal;2Nal; N|e(6OBn);Trp;Trp(7Aza);Trp(SBr); Trp(SBr); Trp(6CF3); Trp(SCI); Trp(6C|); Trp(5,6Cl); Trp(SOH); hTrp; His; His(Me); His(Bn); hHis; Thi; Thz; Thz(5,5Me2); Tic; H); Tyr; Tyr(Bn); ); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P4 and P11 are independently Cys; or hCys; 2012/069412 Gly; DAla; DPro; DPro((4R)OH); or DTic; Ser; hSer; Thr; alloThr; Gly; Gly(tBu); Gly(cHex); Gly(cPr); Ala; Ala(tBu); Ala(cHex); Ala(cPr); Val; Nva; Leu; lle; Nle; hLeu; or OctG; and Ser; hSer; Thr; a/IoThr; 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl);Ala(1lm); m); hAla(1lm); hAla(2lm); Ala(Pyrazinyl); razolyl); Ala(3Pyrazolyl); Ala(2Pyrimidin); Ala(4Pyrimidin); Ala(SPyrimidin); Ala(ZQuin); Ala(3Quin); Ala(4Quin); Phe; Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl2); ); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF3); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Trp; Trp(7Aza); Trp(SBr); Trp(BBr); Trp(6CF3); Trp(5Cl); Trp(6C|); Trp(5,6Cl); Trp(SOH); hTrp; His; His(Me); His(Bn); hHis; Thi; Th2; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(AOHPh); hTyr; or Tza; or pharmaceutically acceptable salts thereof.

In a further particular embodiment of the invention the ts of general formula (I) are defined as follows T1 is DAla; DLys; DPro; 4$)NH2); DPro((4$)OH); DPip; DThr; or DTic; T2 is Ala; Dab; Lys; Glu; Pro; Pro((4R)NH2); Pro((45)NH2); Pro((4R)OH); Pro((4$)OH); Pip; Tic; Oic; or Trp; P1, P3, P13, and P14 are independently Gly; Gly(tBu); Gly(cHex); GlylcPr); Ala; Ala(tBu); ex); Ala(cPr); Val; Nva; Leu; lle; Nle; hLeu; OctG; Met; ); Dab; Dab(Ac); Dab(cPr); Dab(iPr); Dab(MeSOz); Dap; Dap(Ac); Dap(cPr); Dap(iPr); Dap(Mesoz); Lys; Lys(Bz); Lys(Me); c); Lys((5R)OH); xa); hLys; Orn; Orn(Ac); Orn(cPr); Orn(iPr); Arg; hArg; Asn; Asp; Gln; Glu; Cit; Met(02); Ser; hSer; Ser(Bn); Ser(Me); Thr; aIIoThr; Thr(Bn); Thr(Me); Bip; Bbta; 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(llm); Ala(Zlm); hAla(1lm); hAla(Zlm); Ala(Pyrazinyl); Ala(lerazolyl); Ala(3Pyrazolyl); Ala(ZPyrimidin); Ala(4Pyrimidin); W0 2013!050346 2012/069412 Ala(5Pyrimidin); Ala(2Quln); Ala(3Quin); A|a(4Quin); Phe; Phe(2C|); Phe(3C|); Phe(4Cl); Phe(3,4C|2); Phe(2F); Phe(3F); ); Phe(3CN); Phe(4CN); Phe(2CF3); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(GOBn); Trp; za); Trp(SBr); Trp(SBr); Trp(6CF3); Trp(5C|); Trp(6CI); Trp(5,6Cl); Trp(SOH); hTrp; His; His(Me); ); hHis;Thi; Thz; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P2, P5 and P8 are independently 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1lm); Ala(2lm); hAla(1Im),- hAla(2|m); Ala(Pyrazinyl); yrazolyl); Ala(3Pyrazo|yl); Ala(2Pyrimidln); yrimidin); Ala(5Pyrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(2Cl); Phe(3C|); Phe(4Cl); Phe(3,4Cl2); Phe(2F); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(2CF3); Phe(3CF3); Phe(4CF3); 4(CF3)2); Phe(4COOMe);hPhe;Phg;1Nal; 2Nal; Nle(6OBn);Trp;Trp(7Aza);Trp(SBr); Trp(GBr); Trp(6CF3); Trp(5C|); Trp(6CI); Trp(5,6Cl); Trp(50H); hTrp; His; His(Me); His(Bn); hHis; Thi; Thz; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(|Vle); Tyr(Ph); Tyr(40HPh); hTyr; or Tza; P4 and P11 are ndently Cys; or hCys; P6 is Gly; P7 is DAla; DPro; DPro((4R)OH); or DTic; P9 is Ser; hSer; Thr; alloThr; P10 is Gly; Gly(tBu); Gly(cHex); Gly(cPr); Ala; Ala(tBu); A|a(cHex); A|a(cPr); Val; Nva; Leu; lle; Nle; hLeu; or OctG; and P12 is Ser; hSer; Thr; r; 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(1lm); Ala(2lm); hAla(1Im); hAlalZlm); Ala(Pyrazinyl); Ala(1Pyrazolyl); Ala(3Pyrazolyl); Ala(2Pyrimldin); Alal4Pyrimidin); Ala(5Pyrimidln); Ala(2Quin); Ala(30uin); Ala(4Quin); Phe; Phe(2Cl); Phe(3Cl); l); Phe(3,4Clz); Phe(2F); Phe(3F); Phe(4F); N); Phe(4CN); Phe(2CF3); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOl\/le); hPhe; Phg; WO 50346 1Nal; 2Nal; Trp; Trp(7Aza); Trp(SBr); Trp(68r); Trp(6CF3); Trp(5CI); Trp(6Cl); Trp(5,6Cl); Trp(50H); hTrp; His; His(Me); His(Bn); hHis; Thi;Thz; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(llOHPh); hTyr; or Tza; or pharmaceutically acceptable salts thereof.

In an even further particular embodiment of the invention the ts of general formula (I) are d as follows T1 is DAla; DLys; DPro; DPro((£l$)NH2); DPro((4$)OH); DPip; DThr; or DTic; T2 is Ala; Dab; Lys; Glu; Pro; Pro((4R)NH2); Pro((4$)NH2); Pro((4R)OH); Pro((4$)OH); Pip; Tic; Oic; or Trp; P1 is Gly; Ala; Dab; Lys; Asp; Glu; Thr; His; or Tyr; P2 is His; or Tyr; P3 is Ala; lle; Dab; Dap; Lys; Orn; Glu; Thr; or Trp; P4 is Cys; P5 is Phe; F3); Tyr; Trp; Trp(50H); or His; P6 is Gly; P7 is DAia; DPro; DPro((4R)OH); or DTic,- P8 is Phe(4CF3); Trp; P9 is Thr; is He; Leu;orVaI; P11 is Cys; P12 is Thr; or Tyr; P13 is Ala; Dab; Asp; Glu; Gin; hSer; Thr; or Trp; and P14 is Gly; Ala; Dab; Lys; Glu; Gln; hSer; Thr; His; or Trp; or pharmaceutically acceptable salts thereof.

Hereinafter follows a list of abbreviations, corresponding to generally adopted usual practice, of amino acids which, or the es of which, are suitable for the purposes of the present invention and referred to in this document. in spite of this ic determination of amino acids, it is noted that, for a person skilled in the art, it is obvious that derivatives of these amino acids, resembling alike structural and physico-chemical properties, lead to functional analogs with similar biological activity, and ore still form part of the gist of this invention.

Ala L—Alanine Arg nine Asn L—Asparagine Asp L—Aspartic acid Cit L-Citrulline Cys L—Cystei ne Gln L-Glutamine Glu L-Glutamic acid Gly Glycine His L-Histidine lle L-lsoleucine Leu L-Leucine Lys L-Lysine Met L—Methionine Orn L—Ornithine Phe L—Phenylala nine Pro L—Proline Ser L~Serine Thr L-Threonine Trp L-Tryptophan Tyr L—Tyrosine Val L-Valine Ala(tBu) amino-4,4-dimethy|pentanoic acid Ala(cHex) ($)amino—3—cyclohexylpropanoic acid Ala(cPr) (Sl—2-amino—3—cyclopropylpropanoic acid amino—3-(fu ran—2-yl)propanoic acid ($)amino-3—(fura ny|)propanoic acid ($)amino—3—(1H~imidazoi~1~yl)propanoic acid (5)—2-amino—3-(1H-imidazoIyl)propanoic acid ($)—2—amino—3-(piperazin—l—yi)pr0panoic acid ($)—2-amino—3-cyclopropylpropanoic acid razinyl) ($)—2~amino—3-(pyrazin-2—yi)propanoic acid Ala(lerazolyi) (S)—2—amino~3—(1H—pyrazo|—1~y|)propanoic acid Ala(3Pyrazolyl) ($)-2~amino-3—(1H—pyrazoI—3-yl)propanoic acid Ala(ZPyrimidin) ($)—2-amino(pyrimidin-2—yi)propanoic acid Ala(4Pyrimidin) (5)amino—3-(pyrimidinyl)propanoic acid Ala(SPyrimidin) (5)—2-amino(pyrimidin—5—yi)propanoic acid uin) (5)—2-amino—3—(quinoiin—2—yl)propanoic acid Ala(3Quin) ($)—2-amino—3—(quinolin-3—yi)propanoic acid Ala(4Quin) ($)—2-amino(quinoiinyl)propanoic acid Bbta ($)—2—amino~3—(1-benzothiophen-B-yl)propanoic acid a mino—3—(4—biphenyiyl)pro pa noic acid (S)—2,4—diaminobutanoic acid (S)—4—acetamido—Z—aminobutanoic acid (5)—2—amino—4—(cyclopropylamino)butanoic acid ($)amino—4—(isopr0pyiamino)butanoic acid (5)—2~amino—4—(methylsuIfonamido)butanoic acid (S)»2,3—diaminopr0panoic acid (5)-3—acetamido-Z-aminopropanoic acid ($)—2~amino-3—(cyclopropyiamino)propanoic acid (S)-2—amino—3—(isopropyiamino)propanoic acid ($)-2—amino—3—(methylsulfonamido)propanoic acid GIy(tBu) ($)—2-amino—3,3-dimethyibutanoic acid Giy(cHex) (S)—2-amino-Z-cyclohexylacetic acid G|y(cPr) ($)amino-Z—cyciopropylacetic acid hAla(1lm) (5)-2—amino-3—(1H—imidazoI—1-yl)—butanoic acid hAla(Zlm) amino(1H-imidazol-2—yl)-butanoic acid hArg (S)-2—amino—6—guanidinohexanoic acid hCha ($)—2-amino—4—cyciohexyibutanoic acid hCys ($)—2—amino—4—merca ptobutanoic acid hHis ($)amino—4—(1H—imidazolyl)butanoic acid hLeu ($)—2-amino—S—methylhexanoic acid hLys 7-diaminoheptanoic acid h2Pa| (5)~2-amino-4—(pyridinyi)-butanoic acid h3Pai ($)~2—amino—3-(pyridineyl)~butanoic acid h4Pa| ($)amino-3~(pyridine-4—yl)-butanoic acid hPhe (S)—2-amino~4—phenylbutanoic acid hSer (5)—2-amino-4—hvd roxybutanoic acid hTrp ($)amino—4—(1H—indol—3—yl)butanoic acid hTyr ($)amino—4-(4-hyd roxyphenyl)butanoic acid His(Me) (S)—2—amino—3-(1—methyi—1H—imidazol-S-yl)propanoic acid His(Bn) ($)—2-amino—3—(1-benzyi—1H-imidazol—S—yl)propanoic acid ) ($)—2—amino-6—benzamidohexanoic acid Lys(Me) (S)-2~amino—6—(methyiamino)hexanoic acid Lys(Nic) (5)—2-amino(nicotinamido)hexanoic acid Met(02) (S)—2-amino(methylsuIfonyl)butanoic acid 1Nal ($)—2-amino—3-naphthaien~1-ylpropan0ic acid ZNai ($)—2-amino-3—naphthaien-Z-yipropanoic acid Nle (S)~2-amino-hexanoic acid N|e(6OBn) ($)—2-amino—6—(benzyioxy)hexanoic acid Nva (S)—2-aminopentanoic acid OctG (S)aminodecanoic acid Oic (25,3a5,7a$)-octa hydro-lH-indole-Z-carboxylic acid Orn(Ac) (5)acetamido-Z—aminopentanoic acid r) ($)—2-amino—S—(cyciopropylamino)pentanoic acid W0 2013X050346 Orn(iPr) amino—5—(isopr0pyiamino)pentanoic acid 2Pa| ($)—2~amino—3—(pyridineyl) propionic acid 3Pa| ($)amino—3—(pyridine—3-yi)propionic acid 4Pai (5)—2—amino—3—(pyridineyl)propionic acid Phe(2C|) (S)—2-amino—3—(2~chloropheny|)propanoic acid ($)—2—amino—3-(3-chIorophenyi)propanoic acid amino—3—(4—chiorophenyl)propanoic acid ($)—2-amino—3—(3,4-dichiorophenyl)propanoic acid (S)amino—3~(2-f|uorophenyl)propanoic acid (S)amino—3—(3afiuoropheny|)propanoic acid (5)—2-amino—3—(4-fluorophenyi)propanoic acid ($)—2-amino-3—(3,4—difluorophenyl)propanoic acid (S)—2-amino(3-cyanophenyl)propanoic acid (5)amino—3-(4-cyanophenyl)propanoic acid (S)—2-amino—3-(2-(trifiuoromethyl))propanoic acid Phe 3CF3) ($)—2-amino—3—(3—(trifluoromethyl))propanoic acid Phe(4CF3) (S)amino—3—(4-(trifluor0methyl))propanoic acid Phe(3,4(CF3)2) amino-3—(3,4—bis(trifluoromethyl))propanoic acid Phe(4c00ivle) ($)amino—3-(4~(methoxycarbonyi)phenyi)propanoic acid Phg ($)~2-amino-Z—phenyiacetic acid Pip peridine—2~ca rboxylic acid Pro((4R)NH2) (25,4R)-4—aminopyrrolidine-Z-ca rboxylic acid Pro((4$)NH2) (25,45)—4~aminopyrroiidine~2-carboxylic acid Pro((4R)OH) (25,4R)~4—hydroxypyrrolidine-Z-carboxylic acid Pro((4$)OH) ( 25,4$)-4—hydroxypyrrolidine—Z—ca rboxylic acid Ser(Bn) (S)-2—amino—3-(benzyioxy)propanoic acid Ser(Me) (S)-2—amino—3-methoxy—propanoic acid Thi (S)amino(thiophen~2-yi)propanoic acid al/oThr (25,35)amino~3-hydroxybutanoic acid Thr(Bn) ( 25,3R)-2—amino(benzyloxy)butanoic acid WO 2013050346 Thr(Me) (25,3R)—2—amino—3-(methyloxy)butanoic acid Thz (R)—thiazo|idinecarboxylic acid Thz(5,5lVle2) (R)-2,2~dimethylthiazolidine—4-carboxylic acid Tic ($)—1,2,3,4-Tetrahydroisoquinoline—3-carboxylic acid Tic(7OH) ($)—7—hydroxy-1,2,3,4—tetra hydroisoquinolineca rboxylic acid Trp(7Aza) (Sl—Z-amino—3-(1H—pyrrolo[2,3-b]pyridin-3—y|)propanoic acid Trp(SBr) (5)-2—amino—3—(5—bromo-1H—indol—3-yl)propanoic acid (S)amino-3—(6-bromo—1H~indol~3-yl)propanoic acid ($)amino—3~(6—(trifluoromethyl)—1H-indol—3—yl)propanoic acid (S)amino—3-(5-chloro-1H-indol-3~yl)propanoic acid amino(6—chloro-lH—indol—3—yl)propanoic acid ($)—2~amino~3—(5,6-dichIoro-lH-indol—3—yl)propanoic acid ($)amino—3-(5—hydroxy—lH—indol-3—yl)propanoic acid (S)amino—3—(4—(benzyloxy)pheny|)propanoic acid (S)amino-3—(4-methoxyphenyl)propanoic acid ($)—2—amino—3—(4—phenoxyphenyl)propanoic acid (S)-2~amino—3-[4—(4-hydroxyphenoxy)phenyl]propanoic acid ($)—2—amino—3—(thiazolyl)propanoic acid The abbreviation of D-isomers, e.g. DLys corresponds to the epimer at the 2-position of the appropriate amino acid described above.

In a preferred embodiment of the invention the B-hairpin peptidomimetics of l formula (I) are selected from the group consisting of: cyclo(—Glu-His—Lys—Cys-His—Gly-DPro—Trp-Thr—l le-Cys—Tyr—Glu—Lys—DPro—Pro-); —Dab—His—Lys-Cys-His-GIy-DPro-Trp-Thr—IIe-Cys-Tyr—Glu-Lys—DPro-Glu-); cyclo(-Tyr—His—Lys—Cys-His-Gly-DP —Th r—l le—Cys—Tyr-GIu—Lys-DP ro—Glu—) ; cyclo(-Tyr-His-Lys—Cys-His~Gly-DAla-Trp-Thr-lle-Cys-Tyr-Glu-Lys-DPro~Glu-) l cyclo(-Tyr—His-Lys-Cys-His-Gly-DPro-Trp-Thr—lle-Cys~Tyr-G|u—Lys-DLys-Glu—); —Tyr—His—Lys—Cys-His-G Iy—DPro-Trp~Th r-l Ie-Cys—Tyr-Glu—Lys—DAla—Glu—) I cyclo(-Tyr—His-AIa-Cys-Trp-G Iy-DP ro-Trp—Th r-l Ie—Cys-Tyr-G | n-Lys-DPro-G lu-); cyclo(—Tyr-His-AIa-Cys-His-G o-Trp-Th r-! le-Cys-Tyr-G | n-Lys-DPro—Trp-); cyclo(—Tyr—His-Ala-Cys-Trp—G ly—DPro-Trp-Th r-l le—Cys—Tyr—Gln-Lys-DPro—Ala—); cyclo(—Tyr—His-Trp—Cys—Trp-G ly—DPro—Trp-Thr-I -Tyr-GIn-Lys-DPro-Pro—); cyclo(—Tyr-His—Trp~Cys—His—G ly-DP ro—Trp~Th r—I |e-Cys~Tyr-Gln-Lys-DP ro-Pro—); cyclo(—Tyr-His—Th r—Cys-H is—G Iy-DP ro-Trp~Thr—I Ie-Cys~Tyr-G In—Lys—DPro-Pro~); cyclo(—Tyr—His—Lys—Cys—Trp-G iy—DPro—Trp—Th r—l Ie—Cys—Tyr—Gln—Lys-DPro—Pro- ) ., cyc|o(-Tyr—His—l le-Cys-His—G Iy—DP ro—Trp~Thr-I |e—Cys~Tyr—GIn—Lys~DPro—Pro-); cyclo(—Tyr—His—G | u-Cys—H is—G o-Trp-Th r—l Ie-Cys—Tyr—Gln—Lys—DPro—Pro-); cyclo(—Tyr—His—Ala—Cys—His—G Iy—DPro—Trp—Th r—I Ie—Cys~Tyr-Trp—Lys-DPro-Pro-); cyclo(—Tyr—His~Ala-Cys~Trp-G |y~DP ro-Trp-Th r-I le-Cys—Tyr-Glu—Lys~DPro-Pro—); cyc|o(-Tyr—His-Ala-Cys-Trp—G ly-DPro-Trp-Th r-l le~Cys-Tyr-Trp-Lys-DPro-Pro—); cyclo(-Tyr—His—AIa—Cys-Trp—G Iy—DPro—Trp-Th r—I —Tyr-Gln-Glu-DPro—Pr0-); cyclo(-Tyr—His-AIa-Cys-Trp-G Iy—DP ro-Trp-Th r-l le—Cys—Tyr-Gln-AIa-DP ro-Pro-); cyclo(-Tyr-His-AIa-Cys-His—G ly-DPro~Trp-Th r—l le-Cys-Tyr~Gln-Glu-DPro-Pro-); —Tyr—His-AIa—Cys-Phe—Gly-DPro—Trp—Th r-I |e~Cys-Tyr‘G —DPro—Pro—); cyclo(—Tyr—His-Ala~Cys—Tyr—G ly—DP ro-Trp-Thr—l le-Cys-Tyr—Gln-Lys-DPro~Pro—); cyclo(—Glu—H is—AIa—Cys—Trp—G ly-DPrO—Trp—Thr—l Ie—Cys—Tyr-Gln—Lys~DPro—P ro-) ; cyclo(—Thr—His—Ala-Cys-Trp—G ly—DP ro—Trp~Thr—| -Tyr-G | n—Lys-DPro—Pro—); cyclo(—His-His-AIa—Cys—Tm—Gly-DP ro~Trp—Th r—l {e-Cys—Tyr~Gln-Lys-DPro-Pro— )I cyc|o(—Ala-His—AIa-Cys~Trp-G ly—DP —Th r-l Ie-Cys~Tyr-G | n-Lys-DPro—Pro*), cyclo(—Lys~His—A|a—Cys-His-G ly~DPro-Trp—Th r—l le-Cys—Tyr—Gln—Lys—DPro—Pro-); cyclo(—His—Tyr—Ala—Cys~Trp-Gly—DPro—Trp—Thr—I Ie-CysnTyr-GIn—Lys-DPro-Pro-),- cyclo(-Tyr-His—AIa—Cys~His—G ly—DPro—Trp-Th r—I |e~Cys~Tyr—Glu—Lys—DPro-Pro- ); cyclo(—Tyr—His-Ala—Cys-Trp—G Iy—DPro—Trp—Th r‘l le—Cys-Tyr—Thr—Lys-DPro—P ro-); —Tyr—His-AIa-Cys—Trp-G Iy—DP ro-Trp-Th r-I Ie—Cys-Tyr—AIa-Lys-DPro-Pro ) I cyclo(-Tyr—His—AIa-Cys-His-G ly—DPro—Trp—Th r—l Ie-Cys—Tyr—Thr-Lys-DPro-Pro—); cyclo(~Tyr—His-AIa-Cys-Trp-G Iy-DPro-Trp~Th r-l le-Cys-Th r-Gln-Lys-DPro-Pro-); cyclo(-Tyr-His-AIa-Cys-Trp-G ly-DAIa-Trp-Thr-I Ie—Cys-Tyr-G | n-Lys-DPro-Pro-); cyclo(-Tyr-His—AIa—Cys—His—G Iy—DAIa—Trp~Th r-I Ie—Cys-Tyr—Gln-Lys—DPro—Pro-); cyclo is—A|a—Cys-Trp—Gly—DPro-Trp—Thr—l le—Cys-Tyr—Gln-Lys-DLys-Pro—);( -Tyr-His-AIa-Cys-His-Gly-DPro-Trp—Thr-l -Tyr-GIn-Lys-DThr-Pro- J cyclo(-Tyr—His—Ala-Cys-Trp—GIy—DPro-Trp—Thr-lle—Cys-Tyr-GIn-Lys-DAla-Pro— ) I cyclo —Tyr—His—Ala-Cys-Trp-Gly—DPro—Trp-Thr—lle—Cys-Tyr-Gln—Lys—DPro—Pr0—);( cyclo(-Tyr—His—Lys—Cys~H is—G Iy—DPro-Trp—Th r-I -Tyr—G | u—Lys-DAla—Pro—); cyclo(-Tyr—His—Lys—Cys-Trp—G Iy—DPro—Trp—Th r-I Ie—Cys—Tyr-GIu-Lys-DAla—Pro- o I cyclo(—Tyr—His-Lys—Cys—Trp—G Iy-DPro—Trp-Th r—l le-Cys—Tyr—Glu—Lys—DLys—Pro— ) .I cyclo(—Tyr-His—Lys—Cys—H is-G ly~DPro-Trp—Th r—l le-Cys-Tyr-GIu-Lys—DLys—Pro—); cyclo(—Tyr~His—Lys—Cys—His-G Iy—DPro—Trp—Th r-I Ie-Cys—Tyr~G | u-Lys—DTic—Pro—),- cyclo(-Tyr—His—Lys—Cys—His-G ly-DPro—Trp-Thr—l Ie—Cys-Tyr-GIu~Lys—DPro((4S)OH )-Pro-) ; cyclo(—Tyr—His-Lys-Cys-H is-G o—Trp~Th r—l Ie—Cys—Tyr-Glu—Lys—DPro((4$)N H2)-P ro—); —Tyr—His—Lys—Cys-His-G o-Trp~Th r-I —Tyr-Glu-Lys-DPip—Pro—); cyclo(—Tyr—His-Lys—Cys-Tyr—G ly—DPro-Trp—Th r-I Ie-Cys~Tyr—G lu-Lys—DPro—Pr0-); cyclo(—Tyr—His—Lys-Cys—P he(4CF3)-G Iy—DPro-Trp—Th r-l Ie-Cys-Tyr-G lu-Lys-DPro—Pro-); cyclo(-Tyr-His—Lys-Cys-Trp—G ly-DP ro—Trp-Th r-l Ie-Cys-Tyr-Glu—Lys-DPro-Pro-); cyclo(—Tyr-His—Lys—Cys-Trpr ly—DPro—Trp—Th r-l |e~Cys—Tyr—G | u—Da b—DPro-Pro—); cyclo(-Tyr—His-Lys-Cys—His—G ly-DPro—Trp—Thr—l Ie—Cys—Tyr—Glu—Trp-DPro-Pro-); cyclo(—Tyr—His-Lys-Cys—His—G Iy-DPro—Trp—Th r—I le-Cys-Tyr—GIu-Glu—DPro—Pro-); cyclo(—Tyr-His—Lys-Cys~His-G Iy—DPr0~Trp—Th r~| le-Cys—Tyr~G | u—His—DPro~Pro—); cyclo(—Tyr—His-Lys-Cys—His-G Iy-DPro—Trp~Thr—l Ie—Cys-Tyr—G|u~Dab-DPro—Pro-); cyclo(—Tyr—His—Lys-Cys—His-G Iy-DPro—Trp-Thr—I |e~Cys—Tyr-Glu-Thr—DPro-Pro-); cyclo(—Tyr—His~Lys—Cys—H is—G Iy—DPr0~Trp-Th r—I Ie-Cys—Tyr~G|u-G Iy—DPro—Pro—); cyclo(—Tyr~His-Lys—Cys-His-G Iy-DPro—Trp—Th r—l Ie—Cys-Tyr—Glu-Hse-DPro-Pro-); cvclo(—Tyr—His~Lys—Cys—H is-G ly-DPro—Trp-Th r—l le—Cys—Tyr~Glu—Lys-DPro—Pro-); cyclo(—Tyr—His—Om-Cys—His—G Iy-DP ro-Trp~Thr-I Ie-Cys—Tyr—G lu-Lys—DP ro—Pro—); cyclo(—Tyr—His—Lys-Cys-His-G ly—DTic-Trp—ThH le—Cys—Tyr—Giu—Lys-DPro-Pro-); cyclo(-Tyr—His-Lys—Cys—H is—G Iy-DPro—Trp—Th r-I le-Cys—Tyr—Trp—Lys—DPro-Pro—); cyclo(-Tyr-His-Lys~Cys-H is-G ly-DPro-Trp-Th r-l le-Cys~Tyr-Asp-Lys-DPro-Pro-); cyclo(-GIy-His-Lys-Cys-His-G ly-DP ro—Trp-Th r~l Ie-Cys-Tyr-G | u-Lys-DP -); cyclo(—Asp—H is-Lys-Cys—His—G ly—DP ro-Trp-Thr—l le-Cys-Tyr—Glu—Lys-DP ro—Pro—); cyclo(*Da b- H is-Lys-Cys—His-G ly—DPro—Trp—Thr~l le-Cys-Tyr—Glu-Lys-DPro-Pro-); cyclo(—His—His-Lys-Cys-His-G ly-DPro-Trp-Thr-I le-Cys-Tyr-G | u—Lys-DPro-Pro-); cyclo(—Da b—H is-Lys-Cys—Trp—G o—Trp-Th r-I le-Cys—Tyr—Glu-Lys—DPro-Pro—); cyclo(—Tyr—His-Lys—Cys—Trp-G ly—DAla—Trp-Th r-l le~Cys-Tyr-Glu—Lys-DPro—Pro—); cyclo(—Tyr—His—Lys—Cys—H is—G ly-DAla-Trp—Thr—l le-Cys—Tyr-G lu—Lys—DPro—Pro—); cyclo(—Tyr-His—Lys—Cys-Trp-G ly—DP ro-Trp—Th r~l le-Cys-Tyr-Dab—Lys-DPro—Pro-); cyclo(-Tyr—His-Lys—Cys—His-G ly-DPro—Trp—Th r—I le-Cys-Tyr—Hse~Lys-DPro—Pro—),- ~Tyr—His-Lys—Cys—H is—G ly—DPro-Trp—Th r-Leu—Cys~Tyr—Glu—Lys—DPro—Pro—) ; cyclo(—Tyr—His—Lys-Cys-H is-G ly~DPro-Trp-Th r—Va l-Cys—Tyr—G lu-Lys-DPro-Pro—); cyclo(—Tyr-His-Lys—Cys—His-G 0~P 3)—Th r-l Ie-Cys-Tyr-Glu—Lys—DPro-Pro-); cyclo(—Tyr—His—| —H is—G ly—DPro-Trp—Thr-I Ie—Cys—Tyr-Glu-Lys—DPro-Pro-); cyclo(-Tyr-His-Da p-Cys—His-Gly—DPro-Trp~Thr—l le—Cys—Tyr—G lu—Lys—DPro—Pro-); cyclo(-Tyr—His—Da b—Cys—Trp~G ly-DP ro-Trp-Thr—l le-Cys—Tyr—G | u-Lys—DPro—Pro—); cyclo(—Tyr—H is~Da b-Cys-His-G o-Trp-Th r—l le—Cys-Tyr-G lu-Lys—DPro—Pro-); -Tyr-His-Lys-Cys-His-G ly-DPro-Trp—Th r-l le-Cys-Tyr—Glu-Lys~°Pro-Pro((45) N H2)-),- cyclo(—Tyr—His-Lys-Cys—H is-G ly—DPro-Trp—Th r—l le-Cys-Tyr—G | u—Lys—DPro— Pro((4R)O HH,- cyclo(—Tyr—HiseLys—Cys—His—G ly—DPro—Trp—Th r—l le-Cys—Tyr-Glu—Lys—DPro-Pro((4R) N H2)-); cyclo(-Tyr—His—Lys—Cys-His—G ly-DPro((4R)OH)-Trp~Th r—i le—Cys—Tyr—Glu—Lys-DP ro-Pro—l ; cyclo(-Tyr—His—Lys-Cys—Trp(50 H )-G ly-DPro-Trp—Th r~| le-Cys—Tyr—Glu-Lys—DPro—Pro—); cyclo(-Tyr—His-Lys—Cys—His-G ly—DPro—Trp-Thr—I le~Cys—Tyr-Glu-Lys—DPro—Lys—); cyc|o(—Tyr—His—Lys-Cys~Trp-G Iy—DPro—Trp—Th r—l le—Cys—Tyr-GIu-Lys—DPro-Lys-); cyclo(-Tyr—His—Ala-Cys-Trp-G ly—DP ro—Trp—Th r—l le—Cys—Tyr-Gln-Lys~DPro-Lys-); cyc|o(—Tyr~His—Lys-Cys-His-G ly~DPro-Trp—Thr—l le-Cys—Tyr—Glu—Lys—DPro-Da b-),- cyclo(-Tyr—His—Lys—Cys-H is—G o—Trp-Th r—l le—Cys—Tyr—Glu—Lys—DPro—Pip-); cyclo(—Tyr-His-Lys-Cys—His~G ly-DPro-Trp~Th r—I le—Cys—Tyr—Glu-Lys-DPro-Tic-); cyclo(~Tyr—His—Lys-Cys—H is—G o-Trp—Thr-l —Tyr—Glu—Lys-DPro-Oic—); or pharmaceutically acceptable salts thereof. in a particularly preferred embodiment of the invention the B-hairpin peptidomimetics of general formula (I) are selected from the group consisting of: cyclo(—Tyr—His—l le-Cys-His-G Iy-DP ro—Trp-Th r-l |e~Cys-Tyr-Gln-Lys-DPro-Pro-) ; cyclo(-Tyr-His-Lys-Cys-H is-G ly-DPro-Trp—Th r-l le-Cys-Tyr-Glu—Lys-DPro((4S)OH )-P ro-),- cyclo(—Tyr—l-lis—Lys-Cys—His—G o—Trp-Th r—l le-Cys—Tyr—G | u—Lys—DPro((4$)N H2)-P ro—); cyclo(—Tyr—His-Lys—Cys—His-G ly—DPro-Trp—Th r-l —Tyr—Glu—Lys-DPip-Pro—); cyclo(-Tyr-His—Lys—Cys-Tyr—G Iy—DP ro-Trp-Thr—l le-Cys—Tyr-Glu—Lys—DPro—Pro-); cyclo(—Tyr-His-Lys—Cys-Trp—G Iy-DPro—Trp—Th r—I leaCys-Tyr—G | DPro—Pro-); cyclo(—Tyr-His—Lys—Cys—His—G ly—DPro-Trp—Th r—I Ie-Cys—Tyr—Glu-Hse—DPro-Pro—); cyc|o(—Tyr—His~Lys—Cys~His-G Iy—DPro—Trp—Th r-l le—Cys—Tyr-Glu—Lys~DPro-Pro—); cyc|o(-Tyr—His—Lys—Cys-His-G Iy—DTic-Trp—Thr~l le—Cys-Tyr-G | u-Lys—DP ro—Pro-); cyclo(-Tyr—His—Lys—Cys~H is-G ly~DPro-Trp—Th r-I Ie—Cys~Tyr-Trp—Lys-DPro—Pro-); cyclo(—Tyr-His—Lys-Cys—His—G ly-DPro—Trp-Thr-I Ie-Cys—Tyr—Asp~Lys—DPro—Pro—); cyclo(—Tyr—His—l Ie—Cys—His—G ly—DPro—Trp~Thr-l le~Cys-Tyr—Glu-Lys—DPro-Pro—); cyclo(—Tyr-His—Lys—Cys-TrplSO H)-G ly—DPro—Trp-Thr—l le—Cys-Tyr—G | u—Lys-DPro-Pro-); cyclo(—Tyr-His—Lys-Cys—Trp-G ly—DPro-Trp—Th r-l le—Cys—Tyr—Glu-Lys-DPro-Lys—); or pharmaceutically acceptable salts thereof.

A further embodiment of the invention relates to the preparation of the present B- hairpin peptidomimetics by a process which ses the steps of (a) coupling an appropriately functionalized solid support with an appropriately N— protected derivative of that amino acid which in the d end—product is in position T1 or T2 or P1 to P14 as d above; any functional group which may be present in said N-protected amino acid derivative being likewise riately protected; removing the N-protecting group from the product obtained in step (a); coupling the product thus ed with an appropriately ected derivative of that amino acid which in the desired end-product is in the position of the next element (T or P), following counterclockwise or clockwise the sequence according to l formula (l) in —COOH to —NH2 orientation; any W0 50346 2012/069412 functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; removing the N-protecting group from the product thus obtained; repeating steps (c) and (cl) until all amino acid residues have been introduced; "hv38: if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and chemically transforming the reactive group(s) thus liberated; ing the product thus ed from the solid support; cyclizing the product cleaved from the solid support; removing any protecting groups present on onal groups of any members of the chain of amino acid residues and, if desired, any ting group(s) which may in addition be present in the molecule; if desired, forming a disulfide bridge between sulfhydryl containing residues at P4 and P11; if desired, implementing additional chemical transformations of one or more reactive group(s) present in the le; and if desired, ting the product thus obtained into a pharmaceutically acceptable salt or ting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula (l) or into a different, ceutically acceptable salt.

The process of the invention can advantageously be carried out as parallel array synthesis to yield libraries of template-fixed B—hairpin peptidomimetics of the above general formula (l). Such parallel synthesis allows one to obtain arrays of numerous (normally 24 to 192, typically 96) compounds of general formula (I) in high yields and defined purities, minimizing the formation of dimeric and polymeric by—products. The proper choice of the functionalized solid—support (i.e. solid support plus linker mole— cule), tes and site of cyclization play thereby key roles.

WO 2013f050346 The functionalized solid support is conveniently derived from polystyrene ("PS") crosslinked with, preferably 1-5%, divinylbenzene; yrene coated with polyethyleneglycol spacers (Tentagel®); and polyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M, "Solid—Supported atorial and Parallel Synthesis of Small- Molecular—Weight Compound Libraries", Tetrahedron Organic Chemistry , Vol. 17, on, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, Le. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures. For the es of the present invention two types of linkers are used: Type 1 linkers are designed to release the amide group under acidic conditions (Rink H, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers of this kind form amides of the carboxyl group of the amino acids; examples of resins functionalized by such linker structures include 4—[(((2,4—dimethoxyphenyl)Fmoc—aminomethyl)phenoxyacetamido)- aminomethyl] PS resin, 4—[(((2,4—dimethoxyphenyl)Fmoc—aminomethyl)phenoxyacet— amido)aminomethyl]—4—methylbenzydrylamine PS resin (Rink amide MBHA PS Resin), and 4-[(((2,4—dimethoxyphenyl)Fmoc—aminomethyl)phenoxyacetamido)aminomethyl]— benzhydrylamine PS—resin (Rink amide BHA PS resin). ably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, divinylbenzene and functionalized by means of the 4~(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxy~ acetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl group under acidic ions. s of this kind form acid-labile esters with the carboxyl group of the amino acids, usually acid-labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxyhydroxymethylphenoxy (Sasrin® linker), 4-(2,4- oxyphenyl—hydroxymethyl)—phenoxy (Rink linker), 4—(4—hydroxymethyl—3~meth— oxyphenoxylbutyric acid (HMPB linker), trityl and 2—chlorotrityl. Preferably, the support is derived from polystyrene crosslinked with, most preferably 1-5%, lbenzene and functionalized by means of the 2—chlorotrityl linker.

When carried out as parallel array syntheses the process of the invention can be advantageously carried out as described herein below but it will be immediately apparent to those skilled in the art how these ures will have to be modified in case it is desired to synthesize one single compound ofthe above formula (I).

A number of on vessels (normally 24 to 192, typically 96) equal to the total number of compounds to be synthesized by the parallel method are loaded with 25 to 1000 mg, preferably 100 mg, of the appropriate functionalized solid support which is preferably derived from polystyrene cross—linked with 1 to 3% of divinylbenzene, or from Tentagel resin.

The t to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), ylpyrrolidone (NMP), e, toluene, tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE), isopropylalcohol and the like. Solvent mixtures containing as at least one component a polar t (e. g. 20% TFE/DCM, 35% THF/NMP) are beneficial for ensuring high reactivity and solvation of the bound peptide chains (Fields, G. 8., Fields, C. G., J.

Am. Chem. Soc. 1991, 113, 207).

With the development of various linkers that release the C—terminal carboxylic acid group under mild acidic conditions, not affecting acid—labile groups protecting onal groups in the side chain(s), considerable progresses have been made in the synthesis of protected peptide fragments. The 2-methoxy-4—hydroxybenzylalcohol- derived linker (Sasrin® , Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008) is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) and is stable to Fmoc deprotection conditions during the peptide synthesis, Boc/tBu-based additional protecting groups being compatible with this protection scheme. Other linkers which are suitable for the processes of the invention include the super acid labile 4-(2,4- dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790), where the l of the peptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid in DCM; the 4-(4-hydroxymethyl—3—methoxy- phenoxy)butyric acid—derived linker (HMPB-linker, Florsheimer & Riniker, Peptides 1991,1990 131) which is also cleaved with 1% TFA/DCM in order to yield a peptide fragment containing all acid labile hain protective groups; and, in addition, the 2- chlorotritylchloride linker (Barlos et al., Tetrahedron Lett. 1989, 30, 3943—3946), which allows the peptide detachment using a e of glacial acetic acid/trifluoro— ethanol/DCM (1:227) for about 30 min.

Suitable ting groups for amino acids and, respectively, for their residues are, for example, - for the amino group (as is present e.g. also in the side-chain of lysine) Cbz benzyloxycarbonyl Boc tert.—butyloxycarbonyl Fmoc 9—fluorenylmethoxyca rbonyl Alloc allyloxycarbonyl Teoc trimethylsilylethoxycarbonyl ch trichloroethoxycarbonyl Nps o—nitrophenylsulfonyl Trt triphenymethyl or trityl — for the carboxyl group (as is present e.g. also in the side—chain of aspartic and glutamic acid) by conversion into esters with the alcohol components tBu butyl Bn benzyl Me methyl Ph phenyl Pac phenacyl W0 20137050346 allyl Tse trimethylsilylethyl Tce trichloroethyl — for the guanidino group (as is present e.g. in the side—chain of arginine) Pmc 2,2,5,7,8-pentamethylchroman-6—sulfonyl Ts tosyl (i.e. p-toluenesulfonyl) Cbz benzyloxycarbonyl be 2,2,4,6,7-pentamethyldihydrobenzofuran-S—sulfonyl — for the hydroxy group (as is present eg. in the side-chain of threonine and serine) tBu tert.—butyl Bn benzyl Trt trityl — and for the mercapto group (as is present e.g. in the side—chain of cysteine) Acm idomethyl tBu tert.—butyl Bn benzyl Trt trityl Mtr 4—methoxytrityl.

The 9—fluorenylmethoxycarbonyl- ~protected amino acid derivatives are pre- ferably used as the building blocks for the construction of the template-fixed pin loop mimetics of formula (I). For the deprotection, i. e. cleaving off of the Fmoc group, % piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.

The ty of the reactant, i. e. of the amino acid derivative, is usually 1 to 20 equi— valents based on the milliequivalents per gram (meq/g) loading of the functionalized solid support ally 0.1 to 2.85 meq/g for yrene resins) originally weighed into the reaction tube. Additional equivalents of reactants can be used, if required, to drive the reaction to completion in a reasonable time. The reaction tubes, in combi- nation with the holder block and the manifold, are reinserted into the reservoir block and the apparatus is fastened together. Gas flow through the ld is initiated to provide a lled environment, for example, nitrogen, argon, air and the like. The gas flow may also be heated or chilled prior to flow h the manifold. Heating or cooling of the reaction wells is achieved by heating the reaction block and, tively, cooling it externally with isopropanoI/dry ice and the like to bring about the desired synthetic reactions. Agitation is achieved by shaking or magnetic stirring (within the reaction tube). The preferred workstations (without, however, being limited thereto) are Labsource's Combi-chem station and MultiSyn Tech‘s-Syro synthesizer.

Amide bond formation requires the activation of the a-carboxyl group for the ion step. If this activation is being carried out by means of the ly used carbo— diimides, such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067—1068) or diisopropylcarbodiimide (DlC, akis et al Biochem.

Biophys. Res. Commun.1976, 73, 336-342), the resulting dicyclohexylurea and diisopropylurea is insoluble and, respectively, soluble in the solvents generally used. In a variation of the carbodiimide method 1—hydroxybenzotriazole (HOBt, Konig & Geiger, Chem. Ber 1970, 103, 788—798) is ed as an additive to the coupling e. HOBt prevents dehydration, suppresses racemization of the ted amino acids and acts as a catalyst to improve the sluggish coupling reactions. Certain phosphonium reagents have been used as direct coupling reagents, such as benzotriazoI—l-yl—oxy—tris— (dimethylamino)—phosphonium hexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14, 1219—1222; Synthesis, 1976, 751—752), or benzotriazol—l—yl-oxy—tris— pyrrolidino-phosphonium hexafluorophosphate (Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or 2-(1H-benzotriazol-l—yl-)1,1,3,3-tetramethyluronium tetra- borate (TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett. 1989, 30, 1927—1930); these phosphonium and uronium reagents are also suitable for in situ formation of HOBt esters with the protected amino acid derivatives. More recently diphenoxyphosphoryl azide (DPPA) or O—(7-aza-ben20triazo|y|)—N,N,N’,N'- tetramethyluronium tetrafluoroborate (TATU) or O—(7—aza-benzotriazol—l—yl)-N,N,N’,N'— tetramethyluronium hexafluorophosphate (HATU)/7—aza-1—hydroxy benzotriazole (HOAt, Carpino et al., Tetrahedron Lett. 1994, 35, 281) have also been used as coupling reagents.

Due to the fact that near—quantitative coupling ons are essential, it is ble to have experimental evidence for completion of the reactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970, 34, 595), where a positive colorimetric response to an aliquot of resin—bound e indicates qualitatively the presence of the primary amine, can easily and quickly be med after each coupling step. Fmoc chemistry allows the spectrophotometric detection ofthe Fmoc chromophore when it is released with the base hofer et al., Int. J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction tube is washed free of excess of retained reagents, of solvents, and of by-products by repetitive exposure to pure t(s).

Washing procedures are repeated up to about 30 times (preferably about 5 times), monitoring the efficiency of reagent, solvent, and by—product removal by methods such as TLC, GC, LC-MS or inspection of the gs.

The above described procedure of reacting the resin—bound compound with reagents within the reaction wells followed by removal of excess ts, by-products, and ts is repeated with each successive transformation until the final resin-bound fully protected linear peptide has been obtained.

Before this fully protected linear peptide is detached from the solid support, it is possible, if desired, to selectively deprotect one or several protected functional groupis) t in the molecule and to appropriately substitute the reactive group(s) thus liberated. To this effect, the functional group(s) in question must initially be protected by a protecting group which can be selectively removed without affecting the ing protecting groups present. Alloc (allyloxycarbonyl) is an example for such an amino protecting group which can be ively removed, e.g. by means of Pd° and phenylsilane in CHZClz, t affecting the remaining protecting groups, such as Fmoc, t in the molecule. The ve group thus ted can then be treated with an agent suitable for introducing the desired substituent. Thus, for example, an amino group can be acylated by means of an acylating agent corresponding to the acyl substituent to be introduced.

After detachment of the fully ted linear peptide from the solid support the individual solutions/extracts are then manipulated as needed to isolate the final compounds. Typical manipulations include, but are not limited to, evaporation, concentration, /liquid extraction, acidification, basification, neutralization or additional reactions in on.

The solutions containing fully protected linear e derivatives which have been cleaved off from the solid support and neutralized with a base, are evaporated.

Cyclization is then effected in solution using solvents such as DCM, DMF, dioxane, THF and the like. Various coupling reagents which were mentioned earlier as activators for the amide bond formation can be used for the cyclization. The on of the cyclization is about 648 hours, preferably about 16 hours. The progress of the reaction is followed, e.g. by RP—HPLC (Reverse Phase High Performance Liquid Chromato- graphy). Then the solvent is removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a solvent which is not miscible with water, such as DCM, and the on is extracted with water or a mixture of water-miscible solvents, in order to remove any excess of the coupling reagent.

Finally, the fully protected peptide derivative is treated with 95% TFA, 2.5% H20, 2.5% TIS, or 87.5% TFA, 2.5% DODT, 5% thioanisol, 5% H20 or another combination of scavengers for effecting the cleavage of protecting groups. The cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2.5 hours. The volatiles are ated to dryness and the crude peptide is dissolved in 20% AcOH in water and ted with pyl ether or other solvents which are suitable therefore. The s layer is collected and evaporated to dryness, and the fully deprotected cyclic peptide is obtained. Alternatively the deprotected cyclic peptide can be precipitated and washed using cold EtZO.

For some compounds of the present ion according general formula (I) additional synthetic steps are required. These transformations can be applied either on a partially deprotected cyclic or linear peptide, attached or already released from the solid support or on the final deprotected molecule.

For instance, the formation of the disulfide bridge can be carried out, as described herein below, by ng the crude fully deprotected and cyclized e for 24h in water containing DMSO up to 15% by volume, buffered with NH4HC03 to pH 5—6, or buffered with ammonium acetate to pH 7—8, or adjusted with ammonium hydroxide to pH 8. Alternatively, a solution of 10 equivalents of iodine solution is applied in DMF or in a mixture of CHzClz/MeOH for 1.5 h which is repeated for another 3h with a fresh iodine solution. Following evaporation to dryness, the fully deprotected and disulfide bridged cyclic peptide derivative of formula (l) is obtained as end—product.

Depending on its purity, this peptide tive can be used directly for biological assays, or it has to be further ed, for example by ative HPLC.

As mentioned earlier, it is thereafter possible, if desired, to convert a fully deprotected product of a (I) thus obtained into a pharmaceutically acceptable salt or to convert a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula (I) or into a different, pharmaceutically able, salt. Any of these operations can be carried out by methods well known in the art. ln l the building blocks for the omimetics of the present invention can be synthesized according to the literature methods (example described below), which are known to a person skilled in the art or are commercially available. A few additional new syntheses were d out for this invention and are described in the examples.

All other corresponding amino acids have been described either as unprotected or as Boc- or Fmoc—protected racemates, (D)— or (L)-isomers. lt will be appreciated that unprotected amino acid building blocks can be easily transformed into the corresponding Fmoc-protected amino acid building blocks required for the present invention by standard protecting group manipulations. Reviews describing general methods for the synthesis of a-amino acids include: R. Duthaler, Tetrahedron (Report) 1994, 349, 1540-1650; R. M. Williams, "Synthesis of optically active or-amino acids", Tetrahedron Organic Chemistry Series, Vol.7, 1. E. Baldwin, P. D. Magnus (Eds), Pergamon Press., Oxford 1989. An especially useful method for the synthesis of optically active a-amino acids relevant for this invention includes kinetic resolution using ytic enzymes (M. A. skaya, l. A. Ya mskov, Russian Chem. Rev. 1991, 60, 1163—1179; R. M. Williams, "Synthesis of optically active a—amino acids", Tetrahedron Organic Chemistry Series, Vol.7, 1. E. Baldwin, P. D. Magnus (Eds.), Pergamon , Oxford 1989, r 7, p.257—279). Kinetic resolution using hydrolytic s involves hydrolysis of amides and nitriles by aminopeptidases or nitrilases, cleavage of N—acyl groups by acylases, and ester hydrolysis by lipases or proteases. It is well documented that n enzymes will lead specifically to pure (L)- enantiomers whereas others yield the corresponding (D)—enantiomers (e.g.: R.

Duthaler, edron Report 1994, 349, 1540-1650; R. M. ms, "Synthesis of optically active a-amino acids", Tetrahedron Organic Chemistry Series, Vol.7, 1. E.

Baldwin, P. D. Magnus (Eds), Pergamon Press., Oxford 1989).

The B-hairpin peptidomimetics of the invention can be used in a wide range of applications in order to inhibit FPRl receptor activity leading to the desired therapeutic effect in man or, due to their similar etiology, in other mammals. ally they can be used as agents for ng and/or preventing diseases or ions in the disease areas of inflammatory diseases, allergic conditions, immuno- logical ers, neuroinflammation, neurological disorders, obstructive airway diseases, infectious es, ischemic reperfusion injuries and cancer. Specific disease conditions falling under the areas described above are e.g. acute and chronic lung inflammation, COPD, asthma, emphysema, inflammation of the gastrointestinal tract, inflammatory bowel disease (lBD), Crohn’s disease, acute skin inflammation, atopic dermatitis, , psoriasis, a, acne, neutrophilic dermatosis, neutrophil disorder, eosinophil disorder, monocyte/macrophage associated diseases, Jobs syndrome, Chédiak—Higashi syndrome, chronic granulomatous disease, leukocyte adhesion deficiency, cystic fibrosis, peritonitis, ontitis, sepsis, pneumonia, bacterial infection, and erative disorders such as e.g. cancer.

For use as active ingredients of a medicament the B—hairpin peptidomimetics of the ion can be administered singly, as mixtures of several B—hairpin peptidomimetics of the invention or in combination with other pharmaceutically active . The active ingredient(s) ting of, or containing the B—hairpin peptidomimetics of the invention may be administered per se or applied as a pharmaceutical preparation, e.g. an appropriate formulation together with carriers, diluents or excipients well known in the art.

Pharmaceutical compositions comprising B-hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, ving, granulating, coated tablet-making, levigating, fying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be ated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active B—hairpin peptidomimetics into preparations which can be used pharmaceutically. Proper ation depends upon the method of administration chosen.

For topical administration the B-hairpin peptidomimetics of the ion may be formulated as solutions, gels, ointments, , sions, etc. as are well—known in the art.

Systemic formulations include those designed for administration by injection, e.g. aneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administra- tion.

For injections, the B-hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible s such as Hink’s solution, Ringer’s solution, or logical saline buffer. The solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Alternatively, the B-hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen—free water, before use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.

For oral administration, the compounds of the invention can be readily formulated by combining the active B-hairpin peptidomimetics with pharmaceutically acceptable carriers well known in the art. Such carriers enable the pin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion of a patient to be d. For oral ations such as, for example, s, capsules and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxy— W0 50346 methylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or c acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms may be sugar—coated or enteric~coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets, es, etc. formulated as usual.

For administration by inhalation, the B-hairpin peptidomimetics of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebu- lizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, oro— fluoromethane, carbon dioxide or another suitable gas. in the case of a pressurized aerosol the dose unit may be determined by providing a valve to r a d amount. Capsules and cartridges of egg. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the B—hairpin peptidomimetics of the invention and a suitable powder base such as lactose or .

The compounds may also be ated in rectal or vaginal compositions such as solutions for enema or suppositories together with appropriate suppository bases such as cocoa butter or other glycerides. in addition to the formulations described previously, the pin peptidomimetics of the invention may also be formulated as depot preparations. Such long acting formu— lations may be administered by tation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the [3— W0 20131’050346 hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as gly e salts.

In addition, other ceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide also may be employed. Additionally, the B-hairpin peptidomimetics of the invention may be delivered using a sustained—release system, such as semipermeable matrices of solid polymers containing the therapeutic agent. Various sustained-release als have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 3 years. Depending on the chemical nature and the ical stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

As the B-hairpin peptidomimetics of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as — ceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic ts than are the corresponding free base forms.

In addition, the compounds of the present invention and their pharmaceutical acceptable salts may be used per se or in any appropriate formulation in morphological ent solid state forms, which may or may not contain different s of solvent, e.g. hydrate remaining from the crystallization process.

The B-hairpin peptidomimetics of the invention, or itions thereof, will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application.

W0 2013I050346 PCT/EPZO12/069412 For the use of treating or preventing diseases or disorders with an etiology comprising, or associated with, an increased activity of FPRl and/or its endo— or exogenous ligands (e.g. N—formylmethionine etc.), the B-hairpin peptidomimetics of the invention or compositions thereof, are administered or applied in a therapeutically effective amount. Determination of a therapeutically effective amount is well within the capacities of those d in the art, especially in view of the detailed disclosure provided herein.

The effective dosage of the active ingredients employed may vary ing on the particular compound or ceutical preparation employed, the mode of adminis- tration and the severity and type of the condition treated. Thus, the dosage regimen is selected in accordance with factors including the route of administration and the clearance pathway, e.g. the renal and c function of the patient. A physician, clinician or veterinarian d in the art can readily determine and ibe the amount of the single active ingredients required to prevent, ameliorate or arrest the progress of the condition or e. Optimal precision in achieving concentration of active ingredients without toxicity requires a regimen based on the kinetics of the active ingredients’ availability to the target sites. This involves a eration of the distribution, equilibrium, and elimination of the active ingredients.

In cases of local administration or selective uptake, the effective local concentration of the B—hairpin peptidomimetics of the invention may not be related to plasma concen— tration. One having the skills in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

The ion will now be further described in the Examples below, which are intended as an illustration only and not to be construed as ng the scope of the invention in any way.

WO 0346 PCTI‘EP2012/069412 The ing abbreviations are used: Ac Acetyl; BSA Bovine serum albumin; Boc tert—Butyloxyca rbonyl; DCHA Dicyclohexylamine; DEAD Diethyl azodicarboxylate; DIPEA Diisopropylethylamine; DMElVl Dulbecco's Modified Eagle's Medium; DODT 3,6—dioxa—1,8-octanedithioI; FCS Fetal Calf Serum; Fmoc Fluorenylmethyloxycarbonyl; HATU O—(7-Aza—benzotriazoIe-l—yl)~N,N,N’,N'-tetramethyluronoium hexafluorophosphate; H885 Hank's Buffered Salt Solution; HBTU O-(Benzotriazol-l—yI)—N,N,N’,N’-tetramethyluronium hexafluorophosphate; HCTU O-(G-Chlorobenzotriazol—l—yl)—N,N,N’,N’—tetramethyluronium hexafluorophosphate; Hepes 4—(2~hydroxyethyl)~1-piperazineethanesulfonic acid; HOAt 1—Hydroxy—7-azabenzotriazole; IMDM lscove's Modified co‘s Media; PyBop® (Benzotriazol—l-yloxy)tripyrrolidinophosphonium hexafluorophosphate; TIS Triisopropylsilane; TPP Triphenylphosphine; RPMI l Park Memorial Institute medium; Room temperature.

WO 50346 PCTIEP2012/069412 Examples 1. Peptide synthesis 1.1 General synthetic procedures A l method for the synthesis of the omimetics of the present invention is exemplified in the following. This is to demonstrate the principal t and does not limit or restrict the present invention in any way. A person skilled in the art is easily able to modify these procedures, especially, but not limited to, choosing a ent starting position within the ring system, to still achieve the preparation of the claimed cyclic peptidomimetic compounds of the present invention. ng of the first protected amino acid residue to the resin In a dried flask, 2-chlorotritylchloride resin (polystyrene, 1% crosslinked; loading: 1.4 mmol/g) was swollen in dry CHZCIZ for 30 min (7 ml CHZCIZ per g resin). A solution of0.8 eq of the Fmoc—protected amino acid and 6 eq of DIPEA in dry CHZClz/DMF (4/1) (10 ml per g resin) was added. After shaking for 2-4 h at rt the resin was filtered off and washed successively with CHZCI2, DMF, CHZClz, DMF and . Then a solution of dry CHZCIZ/MeOH/DIPEA (17:2:1) was added (10 ml per g resin). After shaking for 3 x 30 min the resin was filtered off in a pre—weighed sinter funnel and washed successively with CH2Cl2, DMF, CH2C|2, MeOH, CHZCIZ, MeOH, CHZClz (2x) and Et20 (2x). The resin was dried under high vacuum overnight. The final mass of resin was calculated before the qualitative control.

The following ded resins were prepared: Fmoc—Ala—Z-chlorotrityl resin, Fmoc- Cys-Z—chlorotrityl resin, Fmoc-Dab—Z—chlorotrityl resin, Fmoc—GIy-Z-chlorotrityl resin, Fmoc—Lys—Z—chlorotrityl resin, Fmoc-Oic—Z—chlorotrityl resin, Fmoc—Pip-Z-chlorotrityl resin, Fmoc-Pro-Z-chlorotrityl resin, Fmoc-DPro-Z-chlorotrityl resin, Fmoc—Tic-Z- chlorotrityl resin, Fmoc-Trp-Z-chlorotrityl resin.

Synthesis of the fully protected peptide fragment The synthesis was carried out on a Syro-peptide synthesizer (MultiSynTech GmbH) using 24 to 96 reaction vessels. In each vessel were placed approximately 80 mg of the above resin (weight of the resin before loading). The following reaction cycles were programmed and carried out: Step Reagent Time 1 CHZCIZ, wash and swell (manual) 1 x 3 min 2 DMF, wash and swell 2 x 30 min 3 20 % piperidine/DMF 1 x 5 min and 1 x 15 min 4 DMF, wash 5x1 min 3.5 eq. Fmoc amino acid/DMF + 3.5 eq. PyBOP +7eq. DIPEA 1x60 min 6 3.5 eq. Fmoc amino acid/DMF + 3.5 eq. HATU or PyBOP or HCTU +7eq. DIPEA 1x60 min 7 DMF, wash 5 x 1 min 8 20 % piperidine/DMF 1 x 5 min and 1 x 15 min 9 DMF, wash 5x1 min CHZCIZ, wash (at the end of the synthesis) 3 x 1 min Steps 5 to 9 are repeated to add each amino—acid residue.

After the synthesis of the fully protected peptide fragment had been ated, the cleavage, cyclization and work up procedures, as bed herein below, were used for the preparation of the final compounds. ge, backbone cyclization, deprotection and disulfide bridgeformation After assembly of the linear peptide, the resin was ded in 1 ml of 1% TFA in CH2Cl2 (v/v; 0.14 mmol) for 3 minutes and filtered, and the filtrate was neutralized with W0 2013(050346 1 ml of 20% DIPEA in CHZClz (v/v; 1.15 mmol). This ure was repeated four times to ensure tion of the cleavage. The resin was washed three times with 1 ml of CHZCIZ. The CHZCIZ layers containing product were evaporated to dryness.

The fully protected linear peptide was solubilised in 8 ml of dry DMF. Then 2 eq. of HATU and 2. eq. of HOAt in dry DMF (1—2 ml) and 4 eq. of DIPEA in dry DMF (1-2 ml) were added to the peptide, followed by stirring for ca. 16 h. The volatiles were removed by evaporation. The crude cyclic e was dissolved in 7 ml of CH2C|2 and washed three times with 4.5 ml 10% acetonitrile in water (v/v). The CHZCIZ layer was then evaporated to dryness.

To fully deprotect the peptide, 7 ml of cleavage il TFA/DODT/thioanisol/HZO (87.52.5525) were added, and the mixture was kept for 2.5-4 h at room temperature until the reaction was completed. The on mixture was evaporated close to dryness and the peptide precipitated with 7 ml of cold Etzo. The precipitate was washed 3 times with 4 ml of cold EtZO.

The deprotected cyclic peptide is finally treated with 0.5 ml of DMSO in a solution of HZO/AcOH (95:5; adjusted to pH = 6 with NH4HC03) for 24 h at RT to form the disulfide bridge. The reaction mixture was evaporated to dryness and the residue is purified by preparative reverse phase LC—MS.

Purification procedure (preparative reverse phase LC-MS} Compounds were purified by reverse phase tography using a Phenomenex Gemini nX-C18 column, 30 x 100 mm, 5 pm (Cat No. 00D—4435-U0-AX) or a Waters XBridge C18 OBD column, 30 x 100 mm, 5 pm (Cat No. 186002982).

Mobile phases used were: A: 0.1% TFA in Water/Acetonitrile 95/5 v/v B: 0.1 % TFA in Acetonitrile Gradient slopes in the preparative runs were adapted each time based on analytical LC-MS analysis of the crude product. As an example, a l run (purification of Ex. 11) was executed using the Phenomenex column with a flow rate of 35 ml/min running a gradient from 0-1 min 0% B, at 1.1 min 25% B to a final of 8 min 45% B (retention time: 5.96 min in this case).

Detection: MS and UV @ 220 nm Fractions collected were evaporated using a Genevac HT4 evaporator or a Biichi system.

Alternatively for larger s the ing ification system was used: Column: Waters XBridge C18 OBD column, 50 x 250 mm, 10 um (Cat No. 186003900) Mobile phase A: 0.1% TFA in Water Mobile phase B: Acetonitrile Flow rate: 150 ml/min Detection: UV @ 220 nm After lyophilisation the products were obtained typically as white to off-white powders and analysed by HPLC-ESl—MS methods as described below. Analytical data after preparative HPLC purification are shown in Table 1. 1.2 Analytical Methods ical method A: ical HPLC retention times (RT, in minutes) were determined using an Ascentis Express C18 column, 50 x 3.0 mm, (cod. 53811~U — Supelco) with the following solvents A (H20 + 0.1% TFA) and B (CH3CN + 0.085% TFA) and the gradient: 00.05 min: 97% A, 3% B; 3.4mm: 33% A, 67% B; 3.45—3.65 min: 3% A, 97% B; 3.67-3.7 min: 97% A, 3% B.

Flow rate = 1.3 ml/min at 55°C.

Analytical method B: Analytical HPLC retention times (RT, in minutes) were determined using an Ascentis Express C18 column, 50 x 3.0 mm, (cod. 53811-U — Supelco) with the following solvents A (H20 + 0.1% TFA) and B (CH3CN + 0.085% TFA) and the gradient: 0-0.05 min: 97% A, 3% B; 2.95 min: 3% A 97% B; .15 min: 3% A, 97% B; 3.17—3.2 min: 97% A, 3% B.

Flow rate = 1.3 ml/min at 45°C. 1.3 Synthesis of peptide sequences Examples 1 - 7 are shown in Table 1.

The es were sized according the general method starting with the amino acid L-tryptophan, which was grafted to the resin (Fmoc-Trp-2—chlorotrityl resin). The linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin—Trp—P7-P6—P5-P4-P3—P2-P1—T2—T1—P14—P13- Plz-Pn-Plo-PQ. The products were d from the resin, cyclized, deprotected, ed to form the ide bridge, and finally purified by preparative reverse phase LC—MS as described above.

After lyophilisation the products were obtained as white to off—white powders and characterised by HPLC—MS, analytical method A as described above. For ical data, see Ex. 1, 2, 3, 4, 5, 6, 7 in Table 1.

Example 8 is shown in Table 1.

The peptide was synthesized according the general method starting with the amino acid L—tryptophan, which was grafted to the resin (Fmoc—Trp—2~chlorotrityl resin). The linear peptide was sized on the solid support according to the procedure described above in the following sequence: Resin—Trp—DPro-Lys-Gln—Tyr—Cys-Ile-Thr-Trp- DPro-Gly—His—Cys—Ala—His-Tyr. The product was cleaved from the resin, cyclized, deprotected, ed to form the disulfide bridge, and finally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as an off—white powder and charac— terised by HPLC-MS, analytical method A as bed above. For analytical data, see Ex. 8 in Table 1.

Example 9 is shown in Table 1.

The peptide was synthesized according the general method starting with the amino acid L—alanine, which was grafted to the resin (Fmoc—Ala—Z-chlorotrityl resin). The linear peptide was sized on the solid support according to the procedure described above in the following sequence: Resin~Ala—DPro—Lys—G|n—Tyr—Cys~lle-Thr—Trp—DPro—Gly— s—Ala—His—Tyr. The product was cleaved from the resin, cyclized, deprotected, ed to form the disulfide bridge, and finally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as an ite powder and charac— terised by HPLC—MS, analytical method A as described above. For analytical data, see Ex. 9 in Table 1.

Examples 10 - 80 are shown in Table 1.

The peptides were synthesized according the general method starting with the amino acid L-proline, which was d to the resin (Fmoc-Pro-Z-chlorotrityl resin). The linear es were synthesized on the solid support according to the procedure described above in the following sequence: Resin—Pro—Tl-P14-P13~P12-P11-P10-Pg-Ps—P7—P6-P5—P4»P3- PZ-Pl. The products were cleaved from the resin, cyclized, deprotected, oxidized to form the ide bridge, and finally purified by ative reverse phase LC—MS as described above.

After lyophilisation the products were obtained as white to off—white powders and characterised by HPLC-MS, analytical method A as described above, except Ex. 40, for which analytical method B was used. For analytical data, see Ex. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 in Table 1. es 81 - 83 are shown in Table 1.

The es were synthesized according the general method starting with the amino acid D~proline, which was grafted to the resin (Fmoc—DPro—2—chlorotrityl . The linear peptides were synthesized on the solid support according to the procedure bed above in the following sequence: DPro-Lys-Glu-Tyr—Cys—lle—Thr-Trp— DPro-Gly—His-Cys-Lys-His-Tyr-TZ. The products were cleaved from the resin, cyclized, deprotected, ed to form the disulfide bridge, and finally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the products were obtained as white to off—white powders and characterised by HPLC-MS, analytical method A as described above. For analytical data, see Ex. 81, 82, 83 in Table 1.

Example 84 is shown in Table 1.

The peptide was synthesized according the general method starting with the amino acid glycine, which was grafted to the resin (Fmoc-Gly-Z-chlorotrityl resin). The linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Gly-His-Cys—Lys-His—Tyr—Pro—DPro-Lys—Glu-Tyr» e—Thr-Trp»DPro((4R)OH). The product was cleaved from the resin, cyclized, deprotected, oxidized to form the disulfide bridge, and finally purified by preparative reverse phase LC—MS as described above.

After lyophilisation the t was obtained as a white powder and characterised by HPLC-MS, analytical method A as described above. For analytical data, see Ex. 84 in Table 1.

Example 85 is shown in Table 1.

The peptide was synthesized according the general method starting with the amino acid L—cysteine, which was grafted to the resin Cys—Z-chlorotrityl resin). The linear peptide was synthesized on the solid support according to the procedure described above in the ing sequence: Resin-Cys—Lys-His-Tyr-Pro-DPro~Lys-Glu-Tyr- Cys—lle—Thr-Trp—DPro-Gly-Trp(50H). The product was cleaved from the resin, cyclized, ected, oxidized to form the disulfide bridge, and finally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as a white to off-white powder and characterised by HPLC-MS, analytical method A as described above. For analytical data, see Ex. 85 in Table 1. es 86 - 88 are shown in Table l.

The es were synthesized according the general method starting with the amino acid L—lysine, which was grafted to the resin (Fmoc-Lys-Z-chlorotrityl resin). The linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Lys—DPro—Lys—PB—Plz—Pn-Plo-Pg—Ps-P7-P6-P5-P4— P3-P2~P1. The products were cleaved from the resin, cyclized, deprotected, ed to form the disulfide bridge, and finally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the products were obtained as white to off-white powders and characterised by HPLC—MS, analytical method A as bed above. For analytical data, see Ex. 86, 87, 88 in Table 1.

Example 89 is shown in Table 1.

The peptide was synthesized according the general method starting with the amino acid ($)-2,4—diaminobutanoic acid, which was grafted to the resin (Fmoc—Dab-Z- chlorotrityl resin). The linear peptide was synthesized on the solid t according to the procedure described above in the following sequence: Resin-Dab—DPro-Lys-Glu-Tyr- Cys-Ile—Thr-Trp-DPro-Gly-His—Cys—Lys—His—Tyr. The product was cleaved from the resin, cyclized, deprotected, oxidized to form the disulfide , and finally purified by preparative reverse phase LC—MS as described above.

After lyophilisation the product was obtained as a white to off-white powder and characterised by HPLC-lVIS, analytical method A as bed above. For analytical data, see Ex. 89 in Table 1.

WO 2013050346 Example 90 is shown in Table 1.

The peptide was synthesized according the general method starting with the amino acid ($)—piperidine—Z—carboxylic acid, which was grafted to the resin (Fmoc~Pip-2— trityl resin). The linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin—Pip—DPro—Lys—Glu—Tyr— Cys-ile—Thr—Trp-DPro—G|y—His—Cys—Lys~His—Tyr. The product was cleaved from the resin, cyclized, deprotected, oxidized to form the disulfide bridge, and finally purified by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as a white to off—white powder and characterised by HPLC—MS, analytical method A as described above. For analytical data, see Ex. 90 in Table 1.

Example 91 is shown in Table 1.

The peptide was synthesized according the general method starting with the amino acid (35)-1,2,3,4—Tetrahydroisoquinolinecarboxylic acid, which was grafted to the resin Tic—Z-chlorotrityl resin). The linear peptide was synthesized on the solid support according to the ure described above in the following sequence: Resin— ro—Lys—Glu—Tyr—Cys—IIe-Thr-Trp—DPro—Gly—His—Cys—Lys—His-Tyr. The t was cleaved from the resin, cyclized, deprotected, oxidized to form the disulfide bridge, and finally purified by preparative reverse phase LC~MS as described above.

After lisation the product was obtained as a white to off—white powder and characterised by HPLC~MS, ical method A as described above. For analytical data, see Ex. 91 in Table 1.

Example 92 is shown in Table l.

The peptide was synthesized ing the general method starting with the amino acid (25,3a$,7aS)—octahydro—lH-indoIe-Z-carboxylic acid, which was grafted to the resin (Fmoc-Oic-Z-chlorotrityl resin). The linear peptide was synthesized on the solid support ing to the procedure described above in the following sequence: Resin-Oic-DPro- Lys-Glu-Tyr-Cys-lle—Thr-Trp—DPro-Gly-His—Cys—Lys—His-Tyr. The product was cleaved from the resin, cyclized, deprotected, oxidized to form the disulfide bridge, and finally ed by preparative reverse phase LC-MS as described above.

After lyophilisation the product was obtained as a white to off—white powder and characterised by S, analytical method A as described above. For analytical data, see Ex. 92 in Table 1.

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Lyophilized peptides were d on a Microbalance er MXS) and dissolved in aqueous 90 % DMSO to a final concentration of 10 mM unless otherwise stated. Stock solutions were kept at +4°C, and ted from light. 2.2 FPR1 B—arrestin recruitment assay The PathHunter CHO—FPRl (DiscoverX) assay was performed according to the manufacturer’s protocol. in brief, CHO FPR1 B—arrestin cells were seeded at a density of 9000 cells per well in 20ul of Ham’s F12 medium (Invitrogen) in black 384—well culture plates and incubated overnight at 37°C in a humidified atmosphere with 5% C02. The next day, serial ons of the B—hairpin peptidomimetics of this invention have been prepared in DMSO and subsequently diluted in HBSS buffer supplemented with ZOmM Hepes and 0.1% BSA.

For antagonistic assay, 5 ul of nd solution or buffer was added to the cells with a final DMSO concentration of 0.5% (v/v). The plate was incubated for 60 min at 37°C with 5% CO2 before addition of 10u| per well of the reference agonist fMLF peptide (Sigma—Aldrich) at its EC80 concentration. After 90 min of incubation at 37°C with 5% CO2, 15w of lo detection reagent (Promega) were added. Reaction was developed for 20 min at room temperature and chemiluminescence was measured with a VictorZV (Perkin Elmer) scence reader.

Furthermore FPR1 antagonistic activity of the compounds of the current invention can be ed e.g. in a calcium flux assay or a cell migration assay using cells stably transfected with human FPR1, and fMLF peptide as agonist. General protocols, which might be easily d to a specific setting by a person skilled in the art are provided in the following. 2.3 FPR1 m release antagonism assays The calcium flux can be assessed using human FPR1 expressing Calcium Optimized cells. These cells are dispensed in a 384—well black plate and loaded with Calcium4 Reagent (Molecular Devices, Sunnyvale, CA) in HBSS + 20mM Hepes buffer.

After 45 min at 37°C with 5% C02, the entire plate is placed in a FLIPR (Molecular devices) at room temperature. After recording a 20 s ne, a concentrated on of the B-hairpin peptidomimetics of this invention diluted in HBSS + 0.1% BSA + 0.5% DMSO (final concentration) is added to the cells. Fluorescence is recorded during 5 min before the dispensing of the agonist fM LF peptide at its ECgo tration. The signal is followed for an additional 120 s. The maximum signal is determined from control wells t inhibitor. tages of inhibition are then calculated from a range of compound concentrations, which are uently used to calculate |C50 values (Softmax Pro, Molecular Devices). 2.4 FPR1 Cell ion assays The chemotactic response ofdibutyryl—CAM P-differentiated HL—60 cells to a gradient of fMLF is measured using disposable Transwell® l chemotaxis assay plates from Corning (3 pm pore size) according to the protocol of the manufacturer. Briefly, cells are grown under sterile conditions at 37°C with 5% C02 in flasks containing 15% DMEM, 15% Ham’s F12 medium (Invitrogen), 30% lMDM, 30% RPM! media, 10% FCS, ine, penicillin/streptomycin (all media components are from Life Technologies) and lnsulin—Transferrin—Selenium supplements at 1X (from lnvitrogen). 2 Days before use dibutyryl—cAMP is added at 500 pM to induce cell differentiation. For the assay, cells are pelleted by centrifugation, washed once in RPMI + 0.5% bovine serum albumin (BSA), and resuspended to give 4 x 106 cells/ml in RPMI + 0.5% BSA. 50 pl of cell suspension is applied to the top of the assay filter. The B-hairpin peptidomimetics, diluted in the same assay medium, are added to both top and bottom chambers. The cells are allowed to migrate for 2 hours at 37°C into the bottom chamber of the assay plate containing 10 nM of fMLF. Migrated cells are transfered to a new microtiter plate and CellTiterGlo reagent (Promega) is added. After 10 min incubation at room W0 201311050346 temperature, luminescence signal is measured using a Victor2V n Elmer) multimode reader. Data normalization is performed using the number of any cells that had migrated in the e of the B—hairpin peptidomimetic and the number of cells that had randomly migrated in absence of fMLF [these values are taken as 100% (no inhibitory activity) and 0%, respectively]. From a range of compound concentrations |C50 are ined using PrismS (GraphPad software). 2.5 Results Table 2: Biological Results: FPRl B-arrestin recruitment assay B-Arrestin B-Arrestin Ic50 (nM) ICso (W) 1 165 1 76 76 1 16 2 144 1 101 21 132 1 14 n 169 1 7o 22 166 1 1 4 77 1 22 23 184 1 43 124 1 67 24 131 1 37 6 124 1 1o 25 294 1 44 7 6O 1 3 26 342 1 115 8 147 1 88 27 404 1 141 9 188 1 6 28 590 1 69 1o 89 1 5 29 735 1 38 11 177 1 121 30 189 1 79 12 178 1 17 31 202 1 58 13 71 1 33 32 278 1 21 14 35 1 17 33 598 1 169 321 1 77 34 685 1 68 16 36 1 7 35 213 1 96 68 1 13 36 458 1 156 18 62 1 1o 37 195 1 11 19 63 1 15 38 641 1 129 Tabte 2: Biological Results (continued) __—___ -Arrestin -Arrestin [ Ex. I:i’Cso (nM) Ex. ITcso (nM) 39 133 i 18 67 194 i 79 4O 96 i 30 68 239 i 163 41 65 i 36 69 248 i 163 t 42 126 i 78 70 69 i 18 43 126 i 53 71 77 i 4 44 385 i 79 72 633 i 295 45 56 i 36 73 138 i 61 46 39 i 14 74 153 i 16 47 41 i 8 j 75 232 i 71 48 29 i 13 76 114 t 71 49 22 i 1 77 50 i 20 50 172 i 121 78 271 i 95 51 54 i- 21 79 93 i 54 52 53 i 29 80 290 i 148 53 16 i 4 81 530 t 3 54 57 i 33 82 376 i 276 55 73 i 2 83 82 i 51 56 82 i 29 84 485 i 61 [—57 197 i O 85 13 i 3 58 250 i 129 86 109 i 35 59 24 i 9 87 54 i 21 60 44 i 10 88 325 i 19 61 313 i 110 89 189 i 65 62 21 i 13 90 161 i 73 63 15 i 13 91 115 i 27 64 37 i 24 92 267 i 115 111 1 59 66 177 i 28

Claims (22)

1. A compound of the general formula (I), CYCIOIP1-P2-P3-P4—P5-P6-P7—P8-P9-P10-P11-P12-P13-P14-T1—T2] n the single elements T or P are connected in either direction from the yl (C=O) point of ment to the nitrogen (N) of the next element and wherein T1 is a naturally or non—naturally occurring D a—amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; T2 is a naturally or non—naturally occurring L a-amino acid containing in total 1 to 25 carbon— and/or heteroatoms in a single side-chain; P1, P3, P12, P13 and P14 are independently Gly or a naturally or non-naturally occurring L a-amino acid containing in total 1 to 25 carbon~ and/or heteroatoms in a single hain; P2, P5 and P8 are independently a naturally or non—naturally occurring aromatic L o acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; P4 and P11 are naturally or non-naturally occurring linking L a-amino acids containing each in total 1 to 12 carbon— and/or heteroatoms in a single side-chain which together are ting P4 and P11 by covalent or electrostatic interaction; P6 is Gly; P7 is a naturally or non-naturally occurring D a-amino acid containing in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; P9 is a naturally or non—naturally occurring alcoholic L a—amino acid containing in total 1 to 25 carbon— and/or heteroatoms in a single side-chain; and P10 is a naturally or non-naturally occurring aliphatic L a-amino acid ning in total 1 to 25 carbon- and/or heteroatoms in a single side-chain; or a tautomer or rotamer thereof, or a salt, or a e or solvate thereof.

2. A compound according to claim 1 wherein T1 and P7 are independently an D a—amino acid residue ofone of the formulae 3 Ni 0' Ni 0! Ni / ‘R1 r , ‘Ri / .. ‘R1 H /RAlk H ’RAr H RHet T2 is an L a-amino acid residue of one of the formulae 9 f Ci / ‘l f H RAlk H RAI’ H RHet AA’i AA2 AA3 O O O ’ N N R3 ’ R9 r N r ’ ’ R4 5 R6 R4 R4 R R5 R6 R5 R6 AA4 AA5 AA6 P1, P3, P12, P13 and P14 are independently Gly; or an L a-amino acid residue of one of the formulae 01 f 0| l ’I’RMW ”'RN‘W [,RMW‘l‘f H RAIK H RAr H RHet AA1 AA2 AA3 P2, P5 and P8 are independently an L a—amino acid residue of a 0R”, I’ \ ; R1 H RAr P4 and P11 taken together form an interstrand linking bis(amino acid)-structure of formula P6 is Gly; P9 is an L u—amino acid e of formula RN”0 ;’ ‘R1 H ROH AA11 P10 is an L o acid residue of formula RAlk is, with the proviso of containing less than 26 carbon- and/or heteroatoms, €1-12—alkyl; C2_12-a|kenyl; cycloalkyl; cycloalkyl—C1_5—a|kyl; or C1_6—alkoxy-C1_5-alkyl; RAr is, with the proviso of containing less than 26 carbon- and/or heteroatoms, -(CR‘R4)nR19; n0(CH2>mR19; nS(CH2)mR19; or -(CHzinNR“(CH2)mR19; RHEt is, with the proviso of containing less than 26 carbon- and/or heteroatoms, heterocycloalkyl; heterocycloalkyl~C1_6~alkyl; aryl; heteroaryl-C1_6-alkyl; —(CR1R13)qNR15R16; —(CH2)qC(=NR13)NR15R16; -(CH2)qC(=NOR17)NR15R16; -(CH2)qC(=NNR15R16)NR17R18; -(CR1R13)qNR2C(=NR17)NR15R16; -(CR1R13)qN=C(NR15R16)NR17R18; ~(CR1R13)qOR14; 13)qSR15; —(CR1R13)qSOZR15; -(CR1R13)q502NR1R14; —(CR1R13)qSOZNR15R16; —(CR1R13)qN R14sozR15; -(CR1R13)qNR14SOZNRlsRlfi; —(CR1R13)qPO(ORl)2; ~(CH2)nO(CH2)mNR15R16; —(CH2)n0(CH2)mC(=NR17)NR15R16; -(CH2)nO(CH2)mC(=NORl7)NR15R16; -(CH2)nO(CH2)mC(=NNR15R16)NR17R18; -(CH2)nO(CH2)mNR1C(=NR17)NR15R16; -(CH2)nO(CH2)mN=C(NR15R16)NR17R18; -(CH2)nS(CH2)mNR15R16; -(CH2)nS(CH2)mC(=NR17)NR15R16; -(CH2)nS(CH2)mC(=NOR17)NR15R16; -(CH2)nS(CH2)mC(=NNR15R16)NR17R18; -(CH2)nS(CH2)mNR1C(=NR17)NR15R16; -(CH2)nS(CH2)mN=C(NR15R16)NR17R18; -(CR1R13)qc00R15; or -(CR1R13)qCONR15R16; Z is, with the o of containing less than 25 carbon- and/or heteroatoms, '(CHzln-S-S-lCHzlm-; -(CH2)nCH=CHlCH2)m-; -(CH2)n-heteroaryl-(CH2)m-; -(CH2)nCONR1(CH2)m—; or —(CH2)nNR1CONR2(CH2)m-; ROH is, with the proviso of containing less than 26 carbon- and/or heteroatoms, -(CR1R13)q0H; -(CR1R13)qSH; -(CH2)n0(CH2)m0H; -(CH2)nS(CH2)m0H; —(CH2)nNR1(CH2)mOH; hydroxy—C1_8-alkyl; hydroxy—C2-g-a|kenyl; hydroxy- - cycloalkyl; or hydroxy-heterocycloalkyl; R1, R2 and R3 are ndently H; CF3; C1-g-alkyl; C2_g-alkenyl; or aryl-C1_5-alkyl; R4, R5, R6, R7 and R8 are independently H; F; CF3; C1_g—alkyl; C2_8—a|keny|; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl—C1_6—alkyl; heteroaryI-C1_6-alkyl; 3)OOR15; -O(CO)R15; -(CHR13)OSR15; —(CHR13)DNR15R16; -(CHR13)OOCONR15R15; -(CHR13)°NR1CONR15R16; -(CHR13)ONR1COR15; -(CHR13)OCOOR15; -(CHR13)OCONR15R16; -(CHR13)0PO(OR1)2; —(CHR13)OSOZR15; —(CHR13)°NR1502R15; -(CHR13)OSO;_NR15R16; —(CR1R13)0R23; or -(CHR1)nO(CHR2)mR23; or R4 and R2; or R5 and R6 taken together can form: =0; =NR1; =NOR1; =NOCF3; or )p—; R4 and R5; R6 and R7; R7 and R8; or R6 and R9 taken er can form: -(CHR1)p-; -(CH2)n0(CH2)m—; nS(CHz)m-; or —(CH2)nNR1(CH2)m-; R9 is H; F; CF3; C1_g-alkyl; C2_3—a|kenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_5-a|kyl; heteroaryl-C1.5—alkyl; —(CHR13)rOR15; -O(CO)R15; -(CHR13)rSR15; °),NR15R15; -(CHR13)rOCONR15R16; —(CHR13),NR1CONR15R16; -(CHR13),NR1COR15; -(CHR13)OCOOR15; ~(CHR13)0CONR15R16; -(CHR13)rPO(OR1)2; -(CHR13),SOZR15; -(CHR13),NR1502R15; -(CHR13),502NR15R16; -(CR1R13)OR23; or -(CHR1),O(CHR1)OR23; R10, R11 and R12 are independently H; F; Cl; Br; I; CF3; OCF3; OCHFZ; CN; N02; C1_g-alkyl; C2-3—alkenyl; aryl; heteroaryl; aryl-C1_5-a|kyl,' heteroaryI—C1_6—alkyl; -(CHR13)OOR15; —O(CO)R15; -(CHR13)OSR15; -(CHR13)ONR15R16; -(CHR13)OOCONR15R16; -(CHR13)ONR1CONR15R16; —(CHR13)0NR1COR15; -(CHR13)OCOOR15; -(CHR13)0CONR15R16; -(CHR13)0PO(OR1)2; —(CHR13)OSOZR15; 3)ONR1502R15; -(CHR13)OSOZN R15R15; or -(CR1R13)OR23; R13 is H; F; CF3; |kyl; C2_g-a|kenyl; cycloalkyl; heterocycloalkyl; cycloalkyl-C1_5-alkyl; heterocycloalkyl-C1_6—alkyl; aryl; heteroaryl; aryl—C1_5—alkyl; heteroaryl-C1-6valkyl; )OOR15; ; -(CHR1)0N R15R16; -COOR15; —CON ; 502R”; or —502N R15R16; R14 is H; CF3; C1-g~alkyl; C2alkenyl; cycloalkyl; heterocycloalkyl; cycloalkyl-C1alkyl; heterocycloalkyl-C1_5-alkyl; aryl; heteroaryl; aryl-C1_5-alkyl; heteroaryl—C1_6-alkyl; cycloalkyl—aryl; heterocycloalkyl-aryl; cycloalkyl—heteroaryl; heterocycloalkyl-heteroaryl; archycloalkyl; aryl-heterocycloalkyl; heteroaryl-cycloalkyl; heteroaryl-heterocycloalkyl; -(CHR1)OOR15; —(CHR1)OSR15; -(CHR1)°NR15R16; -(CHR1)0COOR15; -(CHR1)0CONR15R16; or )OSOZR15; R15, R16, R17 and R18 are ndently H; |kyl; C2_g-a|kenyl; C1_6-alkoxy; cycloalkyl; heterocycloalkyl; cycloalkyLCLs—alkyl; heterocycloalkyl-C1_5-alkyl; aryl; heteroaryl; aryl—C1_5-alkyl; heteroaryl—C1alkyl; cycloalkyl—aryl; heterocycloalkyl-aryl; cycloalkyl-heteroaryl; heterocycloalkyl-heteroaryl; aryl-cycloalkyl; aryl—heterocycloalkyl; heteroaryl-cycloalkyl; or heteroaryl-heterocycloalkyl; or the structural elements —NR15R16 and —NR17R18 can independently form: heterocycloalkyl; aryl-heterocycloalkyl; or heteroaryl-heterocycloalkyl; R19 is an aryl group of one of the formulae R23 R24 _§ / \/\§R3 EEK/l \/:\/R25 __ :/\ R24 \’\ )KJ R20 R20 or a heteroaryl group of one of the formulae R23 R23 R23 5%?X' 35%;“X' L5}?.>,<—/,\\X' H" R22 , /N\ 7 N X H1 H2 H3 H4 IZO/W/R24R23 20 R23 R20 R23 EH] X" 23 if Egg/l VJRZ“ Big/l \/>R24 , /, \R\N// o s / 5“ X/J H5 H6 H7 H8 R23 R23 /\ N L N _HO _HS/ fiRM _ / HM/ f>R24X/) RZIS H9 H10 H10 | | R20 R32 JVVV «m x x L:- ér/z 1 3 > 1 3 L N / / x" X'" X'/ N‘N/ H12 H13 H14 X, X’, X” and X’” are ndently —CR20; or N; R20 and R21 are ndently H; F; Cl; Br; I; OH; NHZ; N02; CN; CFg; OCHFZ; OCFg; C1_8-alkyl; C2_3-a|kenyl; aryl; heteroaryl; aryl-C1_5—a|kyl; heteroaryI-C1.6—alkyl; —(CH2)0RR22; —(,-CH2)OOR15 O(CO)R15; -O(CH2)RR;22 -;(CH2)OSR15 —R(CH2)0NR1516; -(CH2)OOCONR15R16; -(CH2)0NR1CONR15R16; -(CH2)ONR1COR15; -(CH2)0COOR15; -(CH2)0CONR15R16; -(CH2)DPO(OR1)2; -(CHz)osozR“; or '(CH2)oCOR15} R22 is an aryl group of the formula R23, R24 and R25 are independently H; F; Cl; Br; I; OH; NH; N02; CN; CFg; OCHFZ; OCF3; C1.8-a|kyl; C2_8-alkeny|; —(CH2)OOR15; -O(CO)R15; 0N R1R15; OCOOR15; -(CH2)0CONR1R15; R26 is H; Ac; C1-g-alkyl; or aryl-C1-5—alkyl; n and m are independently an integer of 0-5 with the proviso that n+m s 6; o is 0-4; p is 2-6; q is 1-6; and r is 1-3; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 wherein T1 is an D a-amino acid residue of one of the formulae AA1D; AA3D; AA4D; AASD; or AASD; T2 is an L a-amino acid residue of one of the formulae AA1;AA2;AA3;AA4;AA5; AA6; or AA8; and P7 is an D a-amino acid residue of one of the formulae AA10; AA40; AA50; or AASD; or a pharmaceutically acceptable salt f.

4. A compound according to claim 2 wherein T1 is an D a-amino acid residue of one of the formulae AA4D; AASD; AASD; AA7D; AASD; or AAQD; and T2 is an L a-amino acid e of one of the formulae AA4; AAS; AA6; AA7; AA8; or AA9; or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4 wherein P1, P3, P13, and P14 are independently Gly; Gly(tBu); ex); GIy(cPr); Ala; Ala(tBu); Ala(cHex); Ala(cPr); Val; Nva; Leu; lle; Nle; hLeu; OctG; Met; Ala(sz); Dab; ); Dab(cPr); Dab(iPr); Dab(MeSOz); Dap; Dap(Ac); Dap(cPr); Dap(iPr); Dap(MeSOz); Lys; Lys(Bz); Lys(Me); c); Lys((5R)OH); Lys(40xa); hLys; Orn; Orn(Ac); Orn(cPr); Orn(iPr); Arg; hArg; Asn; Asp; Gln; Glu; Cit; ); Ser; hSer; Ser(Bn); Ser(Me); Thr; alloThr; Thr(Bn); Thr(Me); Bip; Bbta; 2Pal; 3Pal; 4Pal; h2Pal; h3Pal; h4Pal; Ala(2Furyl);Ala(3Furyl);Ala(1lm); Ala(Zlm); hAla(1lm); hAla(2lm);Ala(Pyrazinyl); Ala(lerazolyl); Ala(3Pyrazolyl); yrimidin); Ala(4Pyrimidin); Ala(SPyrimidin); Ala(ZQuin); Ala(3Quin); Ala(4Quin); Phe; Phe(ZCI); Phe(3Cl); Phe(4Cl); Phe(3,4Cl2); ); Phe(3F); Phe(4F); Phe(3CN); N); Ph8(2CF3); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe); hPhe; Phg; lNal; 2Nal; Nle(6OBn); Trp; Trp(7Aza); Trp(SBr); r); F3); Trp(SCl); Trp(6Cl); Trp(5,6C|); Trp(SOH); hTrp; His; His(Me); His(Bn); hHis; Thi; Thz; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P2, PS and P8 are independently 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3FuryI); Ala(llm); Ala(Zlm); hAla(1lm); hAla(2lm); Ala(Pyrazinyl); Ala(lerazolyl); Ala(3Pyrazolyl); Ala(ZPyrimidin); Ala(4Pyrimidin); Ala(SPyrimidin); Ala(ZQuin); Ala(3Quin); Ala(4Quin); Phe; Phe(ZCl); Phe(3Cl); Phe(4Cl); 4Cl2); Phe(ZF); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(ZCFg); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe); hPhe; Phg; lNal; 2Nal; Nle(GOBn); Trp; Trp(7Aza); Trp(SBr); Trp(GBr); Trp(6CF3); Trp(SCl); Trp(6Cl); Trp(5,6C|); Trp(SOH); hTrp; His; His(Me); His(Bn); hHis; Thi; Thz; Thz(5,5Me2); Tic; Tic(7OH); Tyr; ); Tyr(Me); ); Tyr(4OHPh); hTyr; or Tza; P4 and P11 are independently Cys; or hCys; P6 is le; DAla; DPro; DPro((4R)OH); or DTic; Ser; hSer; Thr; alloThr; Gly; u); Gly(cHex); GIy(cPr); Ala; Ala(tBu); Ala(cHex); Ala(cPr); Val; Nva; Leu; lle; Nle; hLeu; or OctG; and Ser; hSer; Thr; alloThr; 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(llm); Ala(2lm); hAla(1lm); hAla(Zlm); Ala(Pyrazinyl); razolyl); Ala(3Pyrazolyl); Ala(ZPyrimidin); Ala(4Pyrimidin); Ala(SPyrimidin); uin); Ala(BQuin); uin); Phe; Phe(ZCl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl2); Phe(ZF); ); Phe(4F); Phe(3CN); Phe(4CN); Phe(ZCFg); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Trp; Trp(7Aza); Trp(SBr); Trp(6Br); Trp(6CF3); Trp(5Cl); Trp(6C|); Trp(5,6Cl); Trp(50H); hTrp; His; His(Me); His(Bn); hHis; Thi; Th2; Thz(5,5Me2); Tic; H); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; and wherein P4 and P11 are optionally forming a disulfide bridge; or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 5 wherein T1 is DAla; DLys; DPro; DPro((4$)NH2); DPro((4$)OH); DPip; DThr; or DTic; T2 is Ala; Dab; Lys; Glu; Pro; Pro((4R)NH2); S)NH2); R)OH); Pro((45)OH); Pip; Tic; Oic; or Trp; P1, P3, P13, and P14 are independently Gly; GIy(tBu); Gly(cHex); Gly(cPr); Ala; Ala(tBu); Ala(cHex); Ala(cPr); Val; Nva; Leu; Ile; Nle; hLeu; OctG; Met; Ala(sz); Dab; ); Dab(cPr); Dab(iPr); Dab(MeSOz); Dap; Dap(Ac); Dap(cPr); Dap(iPr); Dap(MeSOz); Lys; Lys(Bz); Lys(Me); Lys(Nic); Lys((5R)OH); Lys(40xa); hLys; Orn; Orn(Ac); Orn(cPr); Orn(iPr); Arg; hArg; Asn; Asp; Gln; Glu; Cit; Met(02); Ser; hSer; Ser(Bn); Ser(Me); Thr; alloThr; Thr(Bn); Thr(Me); Bip; Bbta; 2Pal; 3Pal; 4Pal; hZPaI; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(llm); Ala(2lm); hAla(1lm); hAla(Zlm); razinyl); Ala(lerazolyl); Ala(3Pyrazolyl); Ala(ZPyrimidin); yrimidin); Ala(SPyrimidin); Ala(ZQuin); Ala(3Quin); Ala(4Quin); Phe; Phe(ZCl); Phe(3Cl); Phe(4Cl); Phe(3,4C|2); Phe(ZF); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); F3); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; N|e(6OBn); Trp; Trp(7Aza); Trp(SBr); Trp(6Br); Trp(6CF3); Trp(5C|); Trp(6Cl); Trp(5,6Cl),' Trp(SOH); hTrp; His; His(Me); His(Bn); hHis; Thi; Thz; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P2, PS and P8 are independently 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); Ala(llm); Ala(2lm); hAla(llm); lm); Ala(Pyrazinyl); Ala(lerazolyl); Ala(3Pyrazolyl); Ala(ZPyrimidin); Ala(4Pyrimidin); yrimidin); Ala(2Quin); Ala(3Quin); Ala(4Quin); Phe; Phe(ZCl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl2); Phe(ZF); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Fg); Phe(3CF3); Phe(4CF3); Phe(3,4(CF3)2); Phe(4COOMe); hPhe; Phg; 1Nal; 2Nal; Nle(SOBn); Trp; za); Trp(SBr); Trp(6Br); F3); Trp(5C|); Trp(6Cl); Trp(5,6C|); Trp(SOH); hTrp; His; His(Me); His(Bnl; hHis; Thi; Thz; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; P4 and P11 are independently Cys; or hCys; Gly; DAla; l)Pro; DPro((4R)OH); or DTic; Ser; hSer; Thr; al/oThr; Gly; Gly(tBu); Giy(cHex); Gly(cPr); Ala; Ala(tBu); Ala(cHex); Ala(cPr); Val; Nva; Leu; lle; Nle; hLeu; or OctG; and Ser; hSer; Thr; alloThr; 2Pal; 3Pal; 4Pal; hZPal; h3Pal; h4Pal; Ala(2Furyl); Ala(3Furyl); m); Ala(2lm); hAla(llm); lm); Ala(Pyrazinyl); Ala(lerazolyl); Ala(3Pyrazolyl); Ala(ZPyrimidin); Ala(4Pyrimidin); Ala(SPyrimidin); Ala(ZQuin); Ala(3Quin); Ala(4Quin); Phe; Phe(ZCl); Phe(3Cl); Phe(4Cl); Phe(3,4C|2); Phe(ZF); Phe(3F); Phe(4F); Phe(3CN); Phe(4CN); Phe(ZCFg); F3); Phe(4CF3); 4(CF3)2); OOMe); hPhe; Phg; 1Nal; 2Nal; Trp; Trp(7Aza); Trp(SBr); r); Trp(6CF3); Trp(5C|); Trp(6Cl); Trp(5,6Cl); Trp(SOH); hTrp; His; His(Me); His(Bn); hHis; Thi; Th2; Thz(5,5Me2); Tic; Tic(7OH); Tyr; Tyr(Bn); Tyr(Me); Tyr(Ph); Tyr(4OHPh); hTyr; or Tza; and wherein P4 and P11 are optionally forming a ide ; or a pharmaceutically acceptable salt thereof.

7. A compound according to any one of claims 1 to 6 wherein T1 is l)Ala; DLys; DPro; DPro((45)NH2); DPro((45)OH); DPip; DThr; or DTic; T2 is Ala; Dab; Lys; Glu; Pro; Pro((4R)NH2); Pro((45)NH;_); Pro((4R)OH); Pro((4S)OH); Pip; Tic; Oic; or Trp; P1 is Gly; Ala; Dab; Lys; Asp; Glu; Thr; His; or Tyr; P2 is His; or Tyr; P3 is Ala; lle; Dab; Dap; Lys; Orn; Glu; Thr; or Trp; P4 is Cys; P5 is Phe; Phe(4CF3); Tyr; Trp; Trp(SOH); or His; P6 is Gly; P7 is DAla; DPro; 4R)OH); or DTic; P8 is Phe(4CF3); Trp; P9 is Thr; P10 is He; Leu; or Val; P11 is Cys; P12 is Thr; or Tyr; P13 is Ala; Dab; Asp; Glu; Gln; hSer; Thr; or Trp; and P14 is Gly; Ala; Dab; Lys; Glu; Gln; hSer; Thr; His; or Trp; and wherein P4 and P11 are optionally forming a disulfide bridge; or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 which is selected from cyclo(-Glu-His—Lys-Cys-His-Gly-DPro-Trp—Thr-lle-Cys-Tyr-Glu-Lys-DPro-Pro-); cyclo(-Dab-His-Lys-Cys—His—Gly—DPro—Trp—Thr—lle-Cys-Tyr-Glu-Lys-DPro-Glu—); cyclo(-Tyr-His-Lys-Cys-His-Gly—DPro—Trp-Thr~lle-Cys-Tyr—Glu-Lys-DPro-Glu—); cyc|o(—Tyr-His-Lys—Cys-His-Gly—DAla-Trp-Th r-Ile-Cys—Tyr-Glu-Lys-DPro-Glu—); cyc|o(-Tyr-His-Lys-Cys-His—GIy-DPro-Trp—Thr—lle-Cys-Tyr-Glu-Lys-DLys-Glu-); cyclo(-Tyr-His-Lys-Cys—His-Gly—DPro-Trp-Thr-lle-Cys—Tyr—Glu-Lys—DAla—Glu-); cyclo(-Tyr—His-Ala-Cys-Trp—Gly—DPro-Trp—Thr—Ile—Cys-Tyr-Gln—Lys-DPro-Glu-); cyclo(-Tyr-His-Ala-Cys-His-GIy—DPro—Trp-Thr-lIe-Cys—Tyr—Gln-Lys-DPro—Trp-); cyclo(-Tyr-His-AIa—Cys~Trp—Gly-DPro-Trp—Th r—lle—Cys—Tyr-GIn—Lys-DPro-Ala-); cyc|o(-Tyr-His—Trp—Cys-Trp-Gly-DPro~Trp-Th r—lle-Cys—Tyr-Gln—Lys~DPro-Pro-); cyc|o(-Tyr-His-Trp-Cys—His—Gly—DPro-Trp-Thr~lIe—Cys-Tyr-Gln-Lys-DPro-Pro-); cyclo(—Tyr-His-Thr-Cys—His-Gly-DPro~Trp-Thr-Ile-Cys—Tyr—Gln-Lys-DPro-Pro—); cyclo(-Tyr—His-Lys-Cys-Trp-Gly—DPro-Trp-Thr-He—Cys-Tyr—Gln—Lys~DPro-Pro-); cyc|o(—TyroHis-lIe-Cys—His—GIy—DPro-Trp—Th r-Ile—Cys-Tyr-Gln—Lys-DPro-Pro-); cyc|o(—Tyr—His-G|u-Cys-His—Gly—DPro-Trp-Thr—lIe-Cys-Tyr-Gln-Lys-DPro-Pro—); cyclo(-Tyr-His—Ala—Cys—His-GIy-DPro-Trp-Thr-lle—Cys-Tyr—Trp-Lys-DPro—Pro-); cyclo(-Tyr—His-AIa—Cys-Trp—GIy—DPro-Trp-Th r-lle-Cys-Tyr-GIu—Lys-DPro-Pro-); cyclo(—Tyr-His-AIa-Cys-Trp-Gly-DPro-Trp—Th Cys-Tyr-Trp-Lys-DPro-Pro-); cyc|o(-Tyr-His-AIa-Cys—Trp-Gly-DPro—Trp-Th Cys—Tyr-Gln-Glu-DPro—Pro-); cyclo(—Tyr-His—Ala-Cys—TrpoGly—DPro—Trp—Thr-He—Cys-Tyr-Gln-Ala-DPro-Pro-); cyclo(-Tyr-His-Ala—Cys—His—Gly—DPro—Trp-Thr—lle-Cys—Tyr—Gln-Glu-DPro—Pro-); cyclo(~Tyr-His-AIa—Cys-Phe—Gly-DPro—Trp—Th Cys-Tyr-GIn-Lys-DPro-Pro—); cyc|o(-Tyr-His~A|a—Cys-Tyr-Gly-DPro—Trp—Th r—lle—Cys—Tyr-Gln-Lys-DPro-Pro-); cyclo(-G|u~His—Ala-Cys-Trp-Gly—DPro-Trp-Th r—lle—Cys-Tyr—Gln—Lys-DPro—Pro-» cyc|o(-Thr-His-Ala—Cys-Trp-G|y~DPro-Trp-Th Cys—Tyr-Gln-Lys-DPro-Pro-); cyc|o(-His-His-Ala-Cys-Trp-GIy-DPro-Trp—Thr-lle-Cys—Tyr—Gln—Lys-DPro-Pro-); cyclo(-A|a-His—Ala~Cys—Trp-Gly—DPro—Trp—Th r—Ile-Cys—Tyr-GIn-Lys-DPro—Pro-); cyc|o(-Lys-His-AIa-Cys—His—Gly-DPro-Trp—Thr-lle—Cys—Tyr—Gln-Lys-DPro-Pro-) I cyclo(-His-Tyr-Ala—Cys-Trp-Gly-DPro-Trp-Th r-lIe—Cys—Tyr—Gln-Lys-DPro-Pro-); cyclo(-Tyr-His-Ala-Cys-His-Gly-DPro-Trp-Th r-He-Cys-Tyr-Glu-Lys-DPro—Pro-), cyclo(-Tyr-His-AIa-Cys-Trp-Gly-DPro—Trp-Thr-Ile-Cys-Tyr-Thr-Lys-DPro-Pro-); cyclo(-Tyr—His-AIa-Cys-Trp-Gly-DPro-Trp-Th r—IIe-Cys-Tyr-Ala—Lys-DPro-Pro-) I cyclo(~Tyr—His~A|a-Cys~His-Gly-DPro-Trp-Thr-lle-Cys-Tyr-Thr—Lys-DPro-Pro- ) ,' cyclo(—Tyr-His-AIa-Cys-Trp-GIy-DPro-Trp—Thr-lle—Cys—Thr-Gln-Lys-DPro-Pro-); cyc|o(-Tyr-His-AIa-Cys-Trp-GIy-DAIa-Trp—Thr—IIe-Cys-Tyr-GIn-Lys-DPro-Pro-); —Tyr—His-Ala-Cys—His-GIy-DAla-Trp-Th r-Ile-Cys-Tyr-Gln-Lys-DPro-Pro-); cyc|o(-Tyr—His~Ala-Cys—Trp~GIy-DPro-Trp-Thr-lIe-Cys-Tyr-Gln—Lys-DLys—Pro-); cyc|o(-Tyr—His-Ala-Cys-His-Gly-DPro-Trp—Thr—He—Cys—Tyr-Gln—Lys—DThr-Pro-); cyclo(-Tyr-His-Ala—Cys-Trp-Gly—DPro—Trp-Thr—Ile—Cys-Tyr-Gln-Lys—DAIa-Pro-); cyclo(-Tyr-His-Ala-Cys-Trp-Gly-DPro-Trp—Thr—lle-Cys»Tyr-Gln-Lys-DPro-Pro-); cyclo(—Tyr—His—Lys-Cys—His-Gly-DPro-Trp-Thr-lle-Cys-Tyr-GIu—Lys—DAla-Pro-); cyclo(-Tyr—His-Lys-Cys-Trp-Gly-DPro-Trp‘Th r—lle—Cys—Tyr—Glu-Lys-DAIa-Pro-); cyclo(—Tyr-His-Lys-Cys-Trp-Gly-DPro-Trp—Thr—lIe—Cys-Tyr~Glu-Lys-DLys—Pro—); -Tyr—His—Lys—Cys-His-Gly-DPro-Trp—Th r-lle-Cys-Tyr-GIu-Lys-DLys-Pro—); cyc|o(—Tyr—His-Lys—Cys-His-GIy-DPro—Trp—Th r-He—Cys—Tyr-Glu-Lys—DTic—Pro—); cyc|o(-Tyr-His-Lys-Cys—His—Gly—DPro-Trp-Thr-lle—Cys-Tyr-Glu-Lys-DPro((4S)OH)-Pro-); -Tyr-His-Lys-Cys-His-Gly-DPro-Trp-Thr-lIe—Cys—Tyr—Glu—Lys-DPro((4S)NH2)-Pro-); cyclo(-Tyr-His-Lys-Cys-His-Gly-DPro-Trp-Thr-He-Cys-Tyr-Glu-Lys-DPip-Pro-); cyclo(-Tyr-His-Lys-Cys-Tyr-GIy-DPro-Trp—Th r—IIe—Cys—Tyr—Glu-Lys—DPro—Pro—); cyclo(—Tyr—His-Lys—Cys—Phe(4CF3)-Gly-DPro-Trp-Th r-Ile-Cys-Tyr-Glu—Lys—DPro-Pro-); cyclo(—Tyr-His—Lys~Cys-Trp-Gly~DPro-Trp—Th r-lle—Cys—Tyr-Glu-Lys-DPro-PrO-); cyclo(-Tyr—His-Lys—Cys-Trp-Gly-DPro—Trp-Th r-IIe~Cys~Tyr-Glu—Dab—DPro-Pro—); -Tyr-His-Lys-Cys-His-Gly—DPro—Trp—Th r-lle—Cys-Tyr-GIu—Trp-DPro-Pro—); cyc|o(—Tyr—His—Lys-Cys—His-Gly-DPro—Trp—Thr-lle—Cys—Tyr—Glu-GIu—DPro—Pro—); cyclo(-Tyr—His-Lys-Cys—His-GIy-DPro-Trp-Thr-lle—Cys-Tyr—Glu—His-DPro-Pro-); cyc|o(-Tyr-His-Lys—Cys-His—GIy-DPro-Trp—Thr-lIe—Cys-Tyr-Glu-Dab—DPro-Pro-); cyc|o(—Tyr—His-Lys-Cys—His—Gly—DPro-Trp—Thr-|le—Cys—Tyr-Glu-Thr-DPro-Pro-); cyclo(-Tyr-His-Lys-Cys-His-Gly-DPro—Trp-Thr—lle—Cys—Tyr-Glu-G|y-°Pro—Pro—); cyc|o(—Tyr—His-Lys—Cys—His—Gly—DPro-Trp-Thr-He-Cys—Tyr-Glu-Hse-DPro-Pro-); cyclo(-Tyr—His—Lys—Cys—His—GIy—DPro-Trp—Thr—lle—Cys-Tyr—GIu-Lys—DPro-Pro-); cyclo(—Tyr—His-Orn-Cys-His-Gly-DPro—Trp-Thr-lle-Cys-Tyr-Glu-Lys-DPro-Pro-); cyclo(—Tyr—His—Lys-Cys~His-Gly—DTic—Trp-Th r-lIe-Cys-Tyr-Glu-Lys-DPro-Pro-),' cyclo(—Tyr-His-Lys—Cys-His-GIy—DPro-Trp-Thr-Ile-Cys-Tyr-Trp-Lys-DPro-Pro-); cyclo(-Tyr—His-Lys-Cys-His—Gly-DPro-Trp-Th r-lle—Cys-Tyr-Asp-Lys-DPro-Pro-); cyclo(-Gly—His-Lys-Cys-His-Gly-DPro-Trp-Thr-lle-Cys-Tyr-Glu-Lys-DPro-Pro-); cyclo(-Asp-His-Lys—Cys-His-Gly-DPro-Trp-Thr—lle—Cys-Tyr-Glu-Lys—DPro-Pro-); cyclo(-Dab-His-Lys-Cys—His—GIy—DPro-Trp—Thr-lIe-Cys—Tyr-Glu-Lys-DPro-Pro-); cyclo(-His-His-Lys—Cys—His—Gly-DPro—Trp—Thr—lIe-Cys-Tyr-Glu—Lys-DPro-Pro—); cyclo(—Dab—His-Lys-Cys-Trp—GIy-DPro-Trp-Thr-lle-Cys-Tyr-GIu-Lys—DPro-Pro-); cyc|o(-Tyr-His-Lys-Cys-Trp—Gly—DAla—Trp-Th Cys-Tyr-Glu-Lys-DPro-Prm); cyclo(—Tyr-His-Lys—Cys-His-GIy-DAla-Trp—Th Cys—Tyr—Glu-Lys-DPro—Pro-); cyclo(—Tyr-His-Lys—Cys—Trp-Gly-DPro-Trp-Thr-Ile—Cys-Tyr-Dab—Lys—DPro-Pro—); —Tyr-His-Lys-Cys-His—GIy-DPro-Trp-Thr—lIe—Cys-Tyr—Hse—Lys—DPro—Pro-); cyclo(—Tyr-His-Lys-Cys-His-Gly-DProvTrp-Thr—Leu—Cys—Tyr-Glu—Lys—DPro-Pro-); cyclo(—Tyr—His-Lys—Cys-His-Gly-DPro-Trp—Th r-Va!-Cys‘Tyr-Glu-Lys~DP ro-Pro-); cyclo(-Tyr-His—Lys—Cys-His-Gly—DPro-Phe(4CF3)—Th r-lle-Cys—Tyr-Glu-Lys—DPro—Pro-); cyclo(—Tyr—His-Ile-Cys—His-GIy-DPro—Trp-Th r-Ile—Cys-Tyr-Glu-Lys-DPro—Pro-); -Tyr-His-Dap-Cys-His-Gly-DPro-Trp-Thr-lle-Cys-Tyr-Glu-Lys—DPro-Pro-); cyclo(—Tyr-His—Dab-Cys-Trp—Gly-DPro-Trp—Thr—IIe-Cys-Tyr-Glu-Lys-DPro—Pro-); cyclo(-Tyr~His-Dab—Cys-His-Gly-DPro~Trp-Thr-lie-Cys—Tyr-Glu-Lys—DPro-Pro-); cyc|o(-Tyr—His—Lys-Cys-His—Gly—DPro-Trp-Th r—lIe-Cys—Tyr—Glu-Lys-DPro—Pr0((4$)NH2)-); cyc|o(—Tyr-His-Lys—Cys—His-Gly—DPro—Trp-Thr-Ile-Cys-Tyr-Glu—Lys—DPro- Pro((4R)OH)—); cyclo(-Tyr~His—Lys-Cys-His~Gly-DPro-Trp—Thr-He-Cstyr—Glu-Lys-DPro-Pro((4R)NH2)-); cyc|o(—Tyr—His-Lys-Cys—His-GIy—DPro((4R)OH)-Trp-Th r-lIe-Cys-Tyr—Glu—Lys-DPro—Pro-); cyclo(-Tyr—His-Lys—Cys—Trp(50H)-Gly-DPro-Trp-Thr—Ile-Cys-Tyr-Glu-Lys-DPro—Pro-); cyc|o(—Tyr-His-Lys-Cys—His—Gly-DPro—Trp—Thr—lle-Cys—Tyr—Glu-Lys-DPro-Lys-); cyclo(-Tyr-His-Lys-Cys-Trp—Gly—DPro—Trp—Th r—lle-Cys—Tyr-Glu-Lys—DPro-Lys-); cyc|o(—Tyr—His—Ala-Cys-Trp—Gly—DPro-Trp-Thr—lle-Cys-Tyr—Gln-Lys-DPro-Lys-); cyc|o(—Tyr—His—Lys-Cys-His~Gly-DPro-Trp—Thr-IIe-Cys-Tyr-Glu-Lys-DPro-Dab-),' cyclo(—Tyr—His—Lys-Cys—His—GIy—DPro-Trp—Thr-lle-Cys-Tyr—GIu-Lys-DPro-Pip-); cyclo(-Tyr-His-Lys-Cys-His-Gly-DPro-Trp-Thr-Ile-Cys-Tyr-Glu-Lys-DPro—Tic-); cyclo(-Tyr-His—Lys-Cys-His-Gly~DPro-Trp-Th r—IIe-Cys-Tyr—Glu—Lys-DPro-Oic—); wherein the Cys residues are optionally forming a disulfide bridge; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8 which is selected from cyc|o(-Tyr-His—lle-Cys-His—Gly-DPro-Trp-Thr-lle-Cys—Tyr—Gln—Lys-DPro-Pro-); cyclo(-Tyr—His-Lys-Cys-His-Gly-DPro-Trp-Thr-lle-Cys—Tyr—Glu-Lys-DPro((4$)OH)-Pro—); —Tyr-His—Lys-Cys—His—Gly~DPro~Trp—Thr—lle-Cys-Tyr—Glu-Lys—DPro((4$)NH2)-Pro—); cyclo(-Tyr—His-Lys-Cys-His-Gly-DPro-Trp-Thr-lle-Cys—Tyr—Glu-Lys-DPip-Pro-); cyclo(—Tyr-His—Lys—Cys-Tyr—Gly-DPro-Trp-Th r-lIe-Cys-Tyr—Glu—Lys-DPro—Pro-); cyclo(-Tyr—His—Lys-Cys-Trp—Gly-DPro—Trp-Thr—lle-Cys-Tyr-Glu-Lys—DPro-Pro—); cyclo(-Tyr-His-Lys-Cys—His-Gly-DPro-Trp-Thr—lle-Cys-Tyr~Glu-Hse-DPro—Pro-); cyc|o(-Tyr-His-Lys—Cys—His-Gly—DPro-Trp-Thr—lle—Cys—Tyr-Glu-Lys-DPro—Pro-); —Tyr—His—Lys-Cys—His-Gly-DTic-Trp-Thr—lle—Cys-Tyr-G|u~Lys—DPro—Pro-); cyclo(—Tyr-His-Lys~Cys-His—Gly—DPro-Trp-Thr-lle-Cys—Tyr—Trp-Lys-DPro-Pro—); cyclo(—Tyr—His-Lys-Cys-His-Gly-DPro-Trp—Thr-lle—Cys-Tyr-Asp-Lys-DPro-Pro-); cyc‘lo(-Tyr—His-lle-Cys-His-Gly-DPro—Trp-Thr—lle-Cys-Tyr-Glu-Lys-DPro-Pro-); cyclo(—Tyr—His—Lys-Cys-Trp(50H)—Gly—DPro—Trp-Thr-lle-Cys—Tyr-Glu-Lys-DPro-Pro-); cyclo(-Tyr—His-Lys-Cys—Trp-Gly-DPro-Trp-Thr-lle-Cys—Tyr—Glu—Lys-DPro-Lys-); wherein the Cys residues are optionally forming a disulfide bridge; or a pharmaceutically acceptable salt thereof.

10. A diastereomer or epimer of a compound of formula (I) as defined in claim 1 based on one or more chiral center(s) not explicitly specified in formula (I).

11. A ceutical composition ning a compound or a mixture of nds according to any one of claims 1 to 10 and at least one pharmaceutically inert carrier.

12. A pharmaceutical composition according to claim 11 in formulated for oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration, or formulated as tablets, s, capsules, solutions, liquids, gels, plaster, , ointments, syrup, slurries, suspensions, spray, nebulizer or suppositories.

13. A compound of formula (l) according to any one of claims 1 to 10, or a ceutically acceptable salt thereof, for use as a ment.

14. The use of a compound according to any one of claims 1 to 10, or a composition according claim 11 or 12, for the treatment or prevention of diseases or conditions in a non—human subject, wherein the diseases or conditions are selected from inflammatory diseases, allergic conditions, immunological disorders, neuro— inflammation, neurological disorders, pain, prion-mediated diseases, amyloid— mediated diseases, obstructive airway diseases, infectious diseases, cardiovascular disorders, and proliferative disorders.

15. A process for the preparation of a compound according to any one of claims 1 to 10 which comprises (a) coupling an appropriately functionalized solid support with an appropriately N- protected derivative of that amino acid which in the desired end—product is in position T1 or T2 or P1 to P14 as defined above; any functional group which may be present in said ected amino acid derivative being likewise appropriately ted; (b) removing the N-protecting group from the product obtained in step (a); (c) coupling the product thus obtained with an appropriately N—protected derivative of that amino acid which in the d end-product is in the position of the next t (T or P), following counterclockwise or clockwise the sequence according to general formula (l) in -COOH to —NH;_ orientation; any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (d) removing the N—protecting group from the product thus obtained; (e) repeating steps (c) and (cl) until all amino acid residues have been introduced; (f) if desired, selectively ecting one or several ted functional group(s) present in the le and chemically transforming the reactive group(s) thus liberated; (g) detaching the product thus obtained from the solid support; (h) cyclizing the product cleaved from the solid t; (i) ng any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule; (j) if desired, forming a disulfide bridge n the sulfhydryl containing residues at P4 and P“; (k) if desired, implementing additional chemical transformations of one or more reactive s) present in the molecule; and (I) if desired, ting the product thus obtained into a pharmaceutically acceptable saltor converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula (I) or into a different, pharmaceutically acceptable salt.

16. The use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament having antagonistic activity against the FPR1 receptor.

17. The use of a compound according to any one of claims 1 to 10 for the cture of a medicament to treat or prevent diseases or conditions in the areas of inflammatory diseases, allergic conditions, immunological disorders, neuro- inflammation, neurological ers, pain, prion—mediated diseases, amyloid» mediated diseases, obstructive airway diseases, infectious diseases, cardiovascular disorders, and proliferative disorders.

18. The use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of diseases or disorders associated with the FPR1 receptor, wherein the e or condition is selected from acute and chronic lung inflammation, COPD, asthma, emphysema, inflammation of the gastrointestinal tract, inflammatory bowel disease (lBD), s disease, acute skin inflammation, atopic dermatitis, eczema, psoriasis, rosacea, acne, neutrophilic dermatosis, neutrophil disorder, eosinophil disorder, monocyte/macrophage ated diseases, Jobs syndrome, Chédiak-Higashi syndrome, chronic granulomatous disease, leukocyte adhesion deficiency, cystic fibrosis, peritonitis, ontitis, sepsis, pneumonia, bacterial infection, and proliferative disorders.

19. The use according to any one of claims 14, 17 or 18, wherein the proliferative disorder is cancer.

20. The compound according to claim 1, substantially as herein bed with reference to any one of the accompanying examples.

21. The process according to claim 15, ntially as herein described with reference to any one of the accompanying examples.

22. The use ing to any one of claims 14, 16, 17 or 18, substantially as herein described with reference to any one of the accompanying examples.