COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES

Abstract: There are disclosed novel synthetic peptides of general formula (I), where the abbreviations A, B, D, E, F, G, J and m, n, p are further defined in the description. Compounds of formula (I) promote the release of growth hormone in humans and animals. Growth promoting compositions containing such compounds of formula (I) as the active ingredient thereof, methods of stimulating the release of growth hormone as well as use of such compounds of formula (I) are also disclosed.

Description: COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES FIELD OF INVENTION The present invention relates to novel compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone. BACKGROUND OF THE INVENTION Growth hormone is a hormone which stimulates growth of all tissues capable of growing. In addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilization and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism. Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine, L-3,4-dihydroxyphenylalanine (L-Dopa) , glucagon, vasopressin, PACAP (pituitary adenylyl cyclase activating peptide) , muscarinic receptor agonists and a synthethic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus. In disorders or conditions where increased levels of growt hormone is desired, the protein nature of growth hormone make anything but parenteral administration non-viable. Furthermore other directly acting natural secretagogues, e.g., GHRH and PACAP are longer polypeptides for which reason oral administration o them is not viable. The use of certain compounds for increasing the levels of growt hormone in mammals has previously been proposed, e.g. in EP 1 072, EP 83864, WO 89/07110, WO 89/01711, WO 89/10933, WO 88/9780 WO 83/02272, WO 91/18016, WO 92/01711, WO 93/04081, WO 95/17422 WO 95/17423 and WO 95/14666. The composition of growth hormone releasing compounds is importan for their growth hormone releasing potency as well as thei bioavailability. It is therefore the object of the presen invention to provide compounds with growth hormone releasin properties which have improved properties relative to know peptides of this type. SUMMARY OF THE INVENTION Accordingly, the present invention relates to a compound o general formula I Wherein n is 0 or 1; m is 1 or 2 ; p is 0, 1 or 2; A is -CH=CH — or N. / wherein R 1 is hydrogen or W is =0 or =S; B is R- ** -CH=CH— or wherein R 2 is hydrogen or C^-alkyl, W' is =0 or =S; D is \ N- (CH 2 )— (CR >7 * D R8 8 ) S -(CH 2 )— U N CH or / R c NN (CH 2 )— (CR 7 R 8 ) S (CH. 2)>t -(M) r " (CH,)— - wherein R 3 , R 4 , R 5 , R 6 , R 7 and R θ independently are hydrogen or C 1 _ € -alkyl optionally substituted with halogen, amino, hydroxy aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 )i-U-(CH 2 ) 3 -, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, C^-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4; E is hydrogen. wherein L is hydrogen, -OR 9 , -CONR 9 R 10 , Cj.g-alkyl obtionally substituted with hydroxy or Ci.g-alkoxy, or L is V // or \ / Y-V Y=V wherein R 9 and R 10 are independently hydrogen, or together form - (CH 2 ) k -U ' - (CH 2 ) ι~ > wherein k and 1 independently are 1, 2 or 3, and k+1 is 3, 4, 5 or 6, U' is -0-, -S- or a valence bond; X is -N(R n )-, -O- or -S-, V is -C(R 12 )= or -N=, Y is -C(R 13 )= or -N=, Z is -C(R 14 )= or -N=, R 12 , R 13 and R H independently are hydrogen, -COOR 15 , -CONR 16 R 17 , - (CH 2 ) V NR 16 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, branched or linear C_. 6 -alkyl, phenyl, oxazol-5-yl, 5-methyl-[l,2,4]oxadiazol-3-yl, R n , R 15 , R 16 and R 17 independently are hydrogen or branched or linear obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6; K is hydrogen or ,18 Q (CH.)- (CR 20 R 21 ) b "(CH 2 ) d - > R 19 wherein R 18 , R 19 , R 20 and R 21 are independently hydrogen, optionally substituted with halogen, amino, hydroxy or aryl; R lβ and R 19 , R 18 and R 21 , R 19 and R 20 or R 20 and R 21 optionally forming -(CH 2 ) k .-Z- (CH 2 ) -where k 1 and 1' independently are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -0-, -S- or a valence bond; b is 0 or 1; a and d are independently 0 , 1 , 2 , 3 or 4 ; and a+b is l to 4 ; Q is >CR 22 - or >N-, wherein R 22 is hydrogen or C^-alkyl, F is R 23 ■ CH=CH— , / w \/ or I wherein R 23 is hydrogen or W' ' is =0 or =S; G is hydrogen, optionally substituted with halogen, amino, hydroxy, or Ci.g-alkoxy; J is optionally substituted with halogen, amino, hydroxy, or Ci.g-alkoxy; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. Regarding the above compounds of the general formula I preferred substituents are mentioned in the dependent claims. Furthermore, especially preferred substituents are those mentioned below. Preferred groups of A are wherein R 1 and W are as defined above. Preferred groups of R 1 is such as methyl, ethyl, cyclopropyl and isopropyl. Preferably m is 1 and/or p is 1. Preferred groups of B are wherein R 2 and W 1 are as defined above. Preferably R 2 is C j .g-alkyl, and more preferred C^-alkyl such as methyl, ethyl, cyclopropyl and isopropyl. Preferably D is N (CH,)— (CR 7 R 8 ) S (CH 2 ) t (M) q (CH 2 )- wherein R 5 , R 6 , R R 8 , M, Ξ, t, q and o are as defined above. Preferably R 5 and R 6 , R 5 and R 7 , R 5 and R 8 or R 7 and R 8 are optionally forming -(CH 2 ) ,-U-(CH 2 ) ^ - , wherein U, i and j are as defined above. Preferably U is a valence bond. Preferably M is -0-,-CH=CH- or Preferably o, r and t are independently 0, 1, 2 or 3. Specifically preferred D is 4-piperidinyl, 3-piperidinyl, 3- aminomethylphenyl , 3-amino-3-methyl-butenyl or 4-amino-4-methyl- pentenyl. Preferably K is hydrogen. Preferably F is ?23 or _N. wherein R 23 is as defined above. Preferably G is The meanings of the above preferred substituents should in no way be construed as limiting the invention to such substituents Representative compounds of the present invention include the following: 3-Aminomethyl-N-( (1R, 2E, 4S)-4-carbamoyl-5-(2-naphthyl)-1- (2-naphthyl)methylpent-2-enyl)benzamide: Piperidine-4-carboxylic acid ( (IR,2E,4S)-4-carbamoyl-5-(2- naphthy1)-1-(2-naphthy1)methylpent-2-eny1) amide: N- ( (IR) -1- ( (IR) -1- ( (IS) -5-Amino-l- (dimethylcarbamoyl)pentylcarbamoyl) -2-phenylethoxy)methyl-2-( naphthyl) ethyl) -3-aminomethylbenzamide: N- ( ( IR, 4S) -4- ( ( (IS) -5-Amino-l- (dimethylcarbamoyl)pentyl)carbamoyl)-1-((2-naphthyl)methyl)-2-oxo- 5-phenylpentyl)-3-aminomethylbenzamide: N-((lR,2R,4S)-4-(((lS)-5-Amino-l- (dimethylcarbamoyl)pentyl)carbamoyl)-2-hydroxy-1- ((2-naphthyl)methyl)-5-phenylpentyl)-3-aminomethylbenzamide: Piperidine-3-carboxylic acid ((IR, 2R, 4S) -4-( ( (IS) -5-amino- 1- (dimethyl carbamoyl) pentyl) carbamoyl) -2-hydroxy-l-(2 naphthyl ) methyl ) -5-phenylpentyl ) amide : 5-( (lR)-l-(N-Methyl-N-( ( 2R) -3- (2 -naphthyl ) -2- ( piper idine- carbonylamino) propionyl) amino) -2- (2-naphthyl) ethyl) [l,2,4]oxadiazole-3-carboxylic acid ethylester: 5- ( ( IR) -1- (N- ( (2R) -2- ( 3 -Amino e thy lbenz oy 1 amino ) -3- ( naphthyl ) propionyl) - -methyl ami no) -2-(2-naphthyl) ethyl) [l,2,4]oxadiazole-3-carboxylic acid ethylester: 5-( (lR)-l-(N-( (2R)-2- ( 3-Aminomethy lbenzoylamino ) -3- (2 naphthyl) propionyl) -N-methyl amino) -2-phenylethyl) [1, 3,4]oxadiazole-2-carboxylic acid amide: It is believed that compounds of formula I exhibit an improved resistance to proteolytic degradation by enzymes because they are non-natural, in particular because the natural amide bonds are replaced by non-natural amide bond mimetics. The increased resistance to proteolytic degradation combined with the reduced size of the compounds of the invention in comparison with known growth hormone releasing peptides is expected to improve their bioavailability compared to that of the peptides suggested in the prior literature. In the above structural formulas and throughout the prese specification, the following terms have the indicated meanings The Ci.g-alkyl groups specified above are intended to include tho alkyl groups of the designated length in either a linear branched or cyclic configuration. Examples of linear alkyl a methyl, ethyl, propyl, butyl, pentyl and hexyl. Examples branched alkyl are isopropyl, sec-butyl, tert.-butyl, isopent and isohexyl. Examples of cyclic alkyl are cyclopropy cyclobutyl, cyclopentyl and cyclohexyl. Especially preferred groups are the C 1 _ 3 -alkyl group Preferred C^-alkyl groups are methyl, ethyl, isopropyl a cyclopropyl. The groups specified above are intended to inclu those alkoxy groups of the designated length in either a line or branched or cyclic configuration. Examples of linear alkoxy a methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples branched alkoxy are isopropoxy, sec-butoxy, ter.-butox isopentoxy and isohexoxy. Examples of cyclic alkoxy a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexylox Especially preferred C j .g-alkoxy groups are the C 1 _ 3 -alkoxy group Preferred C^ j -alkoxy groups are methoxy, ethoxy, isopropoxy a cyclopropoxy. The Ci.g-alkylamino groups specified above are intended to inclu those alkylamino groups of the designated length in either linear or branched or cyclic configuration. Examples of line alkylamino are methyla ino, ethylamino, propylamino, butylamin pentylamino and hexyla ino. Examples of branched alkylamino a isopropylamino, sec-butyla ino, tert.-butylamino, isopentylami and isohexylamino. Examples of cyclic alkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino. Especially preferred groups are the C j-alkylamino groups. Preferred C 1 _ 3 -alkylamino groups are methyla ino, ethylamino, isopropylamino and cyclopropylamino. In the present context, the term "aryl" is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected from the group consisting of phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, quinoline, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxalyl, thiopheneyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted by one or more aminohalogen or aryl. Aryl is preferably phenyl, thienyl, imidazolyl, pyridyl, indolyl or naphthyl optionally substituted with halogen, amino, hydroxy, Cj.g-alkyl or Cj.g-alkoxy. The term "halogen" is intended to include Cl, F, Br and I. The compounds of the present invention may have one or more asymmetric centres and it is intended that stereoisomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention. Compounds of the present invention may be prepared from natural and unnatural amino acid residues as described in the following general methods A to E, and where the starting amino acids can be prepared as known in the art: General Method A Reaction Scheme I; Compounds of formula I may be prepared as shown in reaction scheme I starting with an appropriate N-protected amino acid which can be converted to sulfone 1 using a known procedure (e.g. Spaltenstein, J. Org. Chem. 1987, 52, 3759). The other starting material 2 may be prepared from dimethyl malonate and an aromatic alkyl halide followed by reduction by LiAlH 4 , monosilylation with TBDMS and oxidation to aldehyde 2 under Swern conditions according to a known procedure (e.g. Jenmalm, J. Org. Chem 1994, 59, 1139). The reaction between 2 and 1 may be effected by strong base e.g. BuLi in an appropriate solvent e.g. THF followed by reductive conditions (e.g. sodium amalgam) and removal of the silyl protecting group by methods known in the art (e.g. T. W. Greene, Protective Groups in Organic Synthesis, 2nd Ed. John Wiley and Sons 1991) to give alkene 3. These steps can either be carried out one-pot or sequentially. The intermediate 3 may be oxidized by e.g. Jones reagent to a carboxylic acid 4 which may be converted to an amide 5 by treatment with e.g. thionyl chloride and ammonia. Compound 5 may finally be reacted with a protected amino acid using a suitable condensing agent (e.g. DCC) and deprotected by methods which are described by e.g. T.W. Greene (Protective Groups in Organic Chemistry, 2.ed. John Wiley and Sons, 1991) to form compound 6 which is a compound of formula I. General Method B Reaction Scheme II 17 Compound of formula I may be prepared as shown in reaction scheme II starting with the synthesis of intermediate 10 using the procedure of e.g. A. E. DeCarop et al. (Tetrahedron Letters, 1991, 32, 1867 - 1870.): The titanium-homoenolate 9 may be generated from 3-iodopropionic acid 8 and added onto a suitable aldehyde 7. A cyclization in e.g acetic acid may furnish the lactone 11. Alkylation of the lactone may be done as described by e.g. A. H. Fray et al. (J. Org. Chem., 1986, 51, 4828 - 4833). The enolate may be generated by treatment with base such as lithium hexamethyldisilazane (LHDS) or Lithium diisopropylamide (LDA) and reacted with a suitable alkylating reagent such as alkylchloride to give a compound of type 12. The lactone may be transferred into a silyl-protected hydroxy acid 13 as described by e.g. A. H. Fray et al (J. Org. Chem., 1986, 51, 4828 - 4833). Coupling with an amine, which may contain amino protective groups as e.g. phthalimido or FMOC, by reaction with EDAC and HOBT may give an amide of type 1 . Deprotection of the amino group using procedures known in the art (e.g. T.W. Greene, Protective Groups in Organic Chemistry, 2.ed. John Wiley and Sons 1991) is followed by coupling to a suitable acid, which may include a protection group, by reaction with e.g. EDAC and HOBT to give a compound of type 16. Finally, protection groups on the variable fragments may be removed by methods described in the art (e.g. T. W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York 1991.) to give the final product 17 which is a compound of formula I. General Method C Reaction Scheme III : oxidation 14 18 19 EDAC/HOBT 20 Compounds of formula I may be prepared as shown in scheme III starting with deprotection of an amide of type 14 by reaction with e.g. tetrabutylammonium fluoride and subsequent oxidation with a suitable reagent such as PCC or PDC to give a compound 19. The amino group may be deprotected with e.g. hydrochloric acid in ethyl acetate followed by coupling with a suitable acid which may contain a protection group. Finally, protection groups on the variable fragments may be removed by methods described in the art (e.g. T. W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York 1991.) to give the final product 20 which is a compound of formula I. General Method D Reaction Scheme IV: Cl H,N o NH /\ NaH -^OH Cl OH -(CH.) m 21 22 3.) resolution 25 26 28 27 Compounds of formula I may be prepared as shown in scheme IV starting with an amino-alcohol of type 21 which may be reacted with chloroacetyl chloride as described in the literature by e.g. E. D. Nicolaides et al. (J. Med. Chem. 1986, 29, 959 - 971.). Reaction with a base such as sodium hydride in THF may furnish a morpholinone 23 which can be alkylated by using a base such as LDA or LHDS and subsequent addition of a suitable alkylating reagent such as alkyl chloride. After separation of diastereoisomeres, the ring can be opened by reaction with acid as described by e.g. R. E. TenBrink (J. Org. Chem. 1987, 52, 418 - 422.) and the a ino- group can be protected to give a compound 25. The E-fragment, that may contain protected functionalities, can be attached by reaction of a suitable amine using e.g. l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDAC) and 1-hydroxybenzotriazole (HOBT) . The amino group in 26 can be deprotected by suitable conditions, such as hydrogene chloride in ethyl acetate, and reacted with a suitable acid, that may contain protection groups, EDAC, and HOBT. Removal of all protection groups by methods described in the art (e.g. T. W. Greene, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley and Sons, New York 1991.), may yield the final product 28 which is a compound of general formula I. General Method E Reaction Scheme V: 29 pyridine 31 32 33 35 36 Compounds of formula I may be prepared as shown in reaction sche V starting with an N-protected amino acid 29 which may activated with, e.g. EDAC and then reacted with an amido oxime in e.g. pyridine using a known procedure (e.g. J. Heterocycl Chem. 1989, 26, 125) to give 1,2,4-oxadiazole derivative 31. Aft deprotection of the amino group using methods known in the art a described by e.g. T.W. Greene (Protective Groups in Organ Synthesis, 2. ed. John Wiley and Sons 1991) the compound can be reductive alkylated using an aldehyde and a mild reducing reagent, such as sodium cyanoborohydride to give the desired intermediate 33. Further reaction of 33 with an N-protected natural or unnatural amino acid 34 using peptide coupling methodologies as described in the art (e.g. DCC coupling in DMF) can give intermediate 35, which after deprotection with e.g. hydrochloric acid in an appropriate solvent, such as ethyl acetate can be coupled with another N-protected aminoacid 37 using a known peptide coupling methodology such as DCC coupling in DMF to give an intermediate which after deprotection of the amino group with e.g. hydrochloric acid in an appropriate solvent, such as ethyl acetate can give the desired product 38 which is a compound of formula I. When R 12 is a functional group (e.g. an ester) this group may be derivatized at an appropriate step in the reaction sequence. General method F: Scheme VI 40 41 BOC o HO- R 4 i HN NH, PPtVj (CH 2 ) m O DEAD 42 43 44 A compound of formula I may be prepared as shown in scheme starting with lactone 40 which may be reacted with ammonia to g the amide 41. A reaction under Mitsunobu conditions as descri by M. S. Mannas et al. (J. Chem. Soc. Perkin Trans I, 1975, 46 463.) may give an ether 42 which may be deprotected under aci conditions. Coupling with a suitable acid, that might contai protected functionality, may give a compound of type 43, wh may be deprotected by methods described in the art (e.g. T. Greene, Protective Groups in Organic Synthesis, 2nd. edition, J Wiley and Sons, New York 1991.) to give the final product 44 which is a compound of formula I. General Method G Scheme VII 54 55 A compound of formula I may be prepared as shown in scheme VI starting with an amino acid 45, which may be acylated with e. an acid anhydride and - after work up - may be subsequent reduced with e.g. diborane, sodium borohydride/iodine or lithi 5 aluminumhydride as described by e.g. M. J. McKennon et. al. ( Org. Chem, 1993, 58, 3568 - 3571) in an appropriate solvent su as THF, diethylether, dioxane or hydrocarbons to give aminoalcohol 46. It may be protected with a method known in t art and described by e.g. T. W. Greene (Protective Groups 10 Organic Synthesis, 2. ed. , John Wiley and Sons, New York 1991 with e.g. di-tert-butoxy dicarbonate or benzoylcarbonyl chlori to give the protected alcohol 47. A reaction with eth diazoacetate under rhodium acetate catalysis (preferentially 0. - 15%) as described by e.g. J. Hlavaδeck and V. Krai (Collec 15 Czech. Chem. Commun., 1992, 57, 525 - 530) may furnish the est 48. The ester may be saponified with a method known in the art a described by e.g. T. W. Greene (Protective Groups in Organ Synthesis, 2. ed., John Wiley and Sons, New York 1991) with bas such as lithium hydroxide or potassium hydroxide to give the ac 2049, which may be activated by e.g. l-ethyl-3-( dimethylaminopropyl)carbodiimide hydrogenchloride or combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimi hydrogenchloride and 1-hydroxy-benzotriazole or l-hydroxy- azabenzotriazole and reacted with an amine 50 to give an amide 5 25 The amino group in 51 may be deprotected by a method known in t art and described by e.g. T. W. Greene (Protective Groups Organic Synthesis, 2. ed., John Wiley and Sons, New York 199 e.g. hydrogen chloride in ethyl acetate or trifluoroacetic aci An acid 34a may be activated by e.g. l-ethyl-3-( 30 dimethylaminopropyl)-carbodiimide hydrogenchloride or combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimi hydrogenchloride and 1-hydroxy-benzotriazole or l-hydroxy- azabenzotriazole and reacted in an appropriate solvent such e.g. DMF of dichloromethane with 52 to give the amide 53. T amine-protection group may be removed by a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 1991) such as e.g. hydrogenchloride in ethyl acetate or trifluoroacetic acid. A protected acid 37 may be activated by e.g. l-ethyl-3-(3- dimethylamino-propyl)carbodiimide hydrogenchloride or a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrogenchloride and 1-hydroxybenzotriazole or l-hydroxy-7- azabenzotriazole and may be reacted with the amine 54 in an appropriate solvent such as DMF or dichloromethane to give - after deprotection by a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New York 1991) such as e.g. hydrogen chloride in ethyl acetate or tifluoroacetic acid - 55, which is a compound of formula I. General Method H Scheme VIII 60 63 64 65 66 A compound of formula I may be prepared as shown in scheme VII starting with an amino acid 56. As described by e.g. S. Borg al. (J. Org. Chem. 1995, 60, 3112 - 3120.) 56 may be transform into an ester 57 by e. g. reaction with ethanol in the presen of N-(3-dimethylaminopropyl)-N ' -ethylcarbodiimide hydrochlori and 4-dimethylaminopyridine, which may be subsequently react with hydrazine hydrate to give the hydrazide 58. The ester 60 m be obtained from 58 by reaction with ethyl oxalyl cloride (59) the presence of a base such as e.g. triethylamine. The ri closure may proceed e.g. with thionyl chloride/pyridine a subsequent heat, furnishing and [1,3,4]oxadiazole 61. The ami 62 may be obtained by aminolysis of the ester moiety in e. liquid ammonia. Deprotection of the amino group by a method kno in the art and described by e.g. T. W. Greene (Protective Grou in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 1991 e. g. hydrogen chloride in ethyl acetate or trifluoroacetic ac may furnish the amine 63. A suitable protected amino acid 34a m be coupled to 63 using a coupling reagent known in the art su as e.g. N-(3-dimethylaminopropyl) -N ' -ethylcarbodiimi hydrochloride or a combination of N-(3-dimethylaminopropyl)-N ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole or hydroxy-7-azabenzotriazole to give 64. A deprotection, carried o with a method known in the art and described by e.g. T. W. Gre (Protective Groups in Organic Synthesis, 2. ed. , John Wiley a Sons, New York 1991.) e. g. hydrogen chloride in ethyl acetate trifluoracetic acid, may furnish the amine 65. This may be coupl with a coupling reagent known in the art such as e.g. N-( dimethylaminopropyl)-N ' -ethylcarbodiimide hydrochloride or combination of N-(3-dimethylaminopropyl)-N ' -ethylcarbodiimi hydrochloride and 1-hydroxybenzotriazole or l-hydroxy- azabenzotriazole with a suitable protected amino acid 37 to give after deprotection with a method known in the art and describ by e.g. T. W. Greene (Protective Groups in Organic Synthesis, ed., John Wiley and Sons, New York 1991.) e. g. hydrogen chlori in ethyl acetate or trifluoracetic acid - 66, which is a compound of formula I. General Method J Scheme IX 74 A compound of formula I may be prepared as shown in scheme IX, starting with a suitable protected amino alcohol e.g. 47, which may be oxidized by methods known in the art with reagents such as e.g. DMSO/oxalyl chloride/triethylamine (A. E. Decamp, A. T. Kawaguchi, R. P. Volante, I. Shinkai, Tetrahedron Letters, 1991, 32, 1867 - 1870; J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Soderquist, N. Yi, J. Org. Chem. 1987, 52, 1487 - 1492.) or DMSO/sulfur(IV)oxide pyridinium complex/triethylamine (J. S. Ng, C. A. Przybyla, C. Liu, J. C. Yen, F. W. Muellner, C. L. Weyker, Tetrahdron 1995, 51, 6397 - 6410; P. L. Beaulieu, D. Wernic, J.-s. Duceppe, Y. Guindon, Tetrahedron Letters, 1995, 36, 3317 - 3320.) to give the aldehyde 67. The aldehyde might be reacted with a Grignard reagent, e.g. allylmagnesium bromide to give an unsaturated compound 68. A hydroboration with e.g. 9- borabicyclo[3.3.1]nonane and subsequent treatment with hydrogen peroxide and sodium hydroxide may furnish the diol 69. The amino group may be deprotected with a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 1991)by reaction with e.g. hydrogen chloride in ethyl acetate or trifluoro acetic acid to give 70. A suitable protected amino acid 34a may be coupled to 70 using a coupling reagent known in the art such as e.g. l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride or a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride and 1-hydroxybenzotriazole or l-hydroxy-7- azabenzotriazole in an appropriate solvent such as e.g. DMF of dichloromethane to give 71. A deprotection carried out with a method known in the art and described by e.g. T. W. Greene (Protective Groups in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 1991) e.g. trifluoro acetic acid may furnish the amine 72. A suitable protected amino acid 37 may be coupled to 72 with a coupling reagent known in the art such as e.g. l-ethyl-3- (3-dimethylaminopropyl)carbodiimid hydrochloride or a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride a 1-hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole in appropriate solvent such as e.g. DMF of dichloromethane to gi - after deprotection with a method known in the art and describ by e.g. T. W. Greene (Protective Groups in Organic Synthesis, ed., John Wiley and Sons, New York 1991) by reaction with e. trifluoro actic acid - 73. 73 may be saponified by a method kno in the art and described by e.g. T. W. Greene (Protective Grou in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 199 by reaction with e.g. potassium hydroxide or sodium hydroxide give 74, which is a compound of formula I. General Method K Scheme X 77 78 79 The ether 48 may be reduced with a method known in the art e. lithium boronhydride, sodium borohydride, or diisobutylalumin hydride to give an alcohol 75. The amino group may be deprotect by a method known in the art and described by e.g. T. W. Gree (Protective Groups in Organic Synthesis, 2. ed. , John Wiley a Sons, New York 1991)by reaction with e.g. hydrogen chloride ethyl acetate or trifluoro acetic acid to give the amine 76. suitable protected amino acid 34a may be coupled to 76 using coupling reagent known in the art such as e.g. l-ethyl-3-(3 dimethylaminopropyl)carbodiimid hydrochloride or a combinati of l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride a 1-hydroxybenzotriazole or l-hydroxy-7-azabenzotriazole in appropriate solvent such as e.g. DMF of dichloromethane to gi 77. A deprotection carried out with a method known in the art a described by e.g. T. W. Greene (Protective Groups in Organ Synthesis, 2. ed. , John Wiley and Sons, New York 1991) e. trifluoro acetic acid or hydrogen chloride in ethyl acetate m furnish the amine 78. A suitable protected amino acid 37 may coupled to 78 with a coupling reagent known in the art such e.g. l-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochlori or a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiim hydrochloride and 1-hydroxybenzotriazole or l-hydroxy- azabenzotriazole in an appropriate solvent such as e.g. DMF dichloromethane to give - after deprotection with a method kno in the art and described by e.g. T. W. Greene (Protective Grou in Organic Synthesis, 2. ed. , John Wiley and Sons, New York 199 by reaction with e.g. trifluoro actic acid - 79, which is compound of formula I. To enhance the yield, it may be feasib to subject the crude product to a saponification with reagen known in the art and described by e.g. T. W. Greene (Protecti Groups in Organic Synthesis, 2. ed., John Wiley and Sons, New Yo 1991) such as e.g. potassium hydroxide in methanol to clea esters, that may have formed during the amide coupling steps. General Method L Scheme XI 80 81 Thioamides 81 can be incorporated by the same methods as in method K. They can be made from the corresponding amides 80 by the action of Lawesson's reagent (LR) . This methodology is described in S. Scheiby, B. S. Pedersen, S.O. Lawesson, Bull. Chim. Soc. Belg., 1978, 229-38. General Method M Scheme XII Tetrazole analogs 83 of amides 82 can be incorporated by much t same methods as in method K. They may be prepared by the acti of triphenylphosphine, diethylazodicarboxylate a trimethylsilylazide on amides like 82. This methodology described in J. V. Dunica, M. E. Pierce, J. B. Santella III, Org. Chem. 1991, 56, 2395-2400. General Method N Scheme XIII 84 86 88 89 Thiazoles 89 may be incorporated by the same methodology as in method F. 89 may be synthesized by acylation of the imine 84 using a strong base such as potassium tert butoxide or lithium diisopropylamide and an acylating reagent such as an acid chloride 85. The resulting 3-keto-aminoacid 86 could be coupled to the dipeptide 88 by known methods such as the asymmetrical anhydride method using a reagent such as isobutylchloroformate as coupling agent. The dipeptide 88 could be cyclised by a number of methods e.g. with Lawessons reagent (LR) to give the desired thiazoles 89. This methodology has been described in T. D. Gordon, J. Singh, P. H. Hansen, B. A. Morgan, Tett. Lett., 1993, 1901-1904. Pharmaceutically acceptable acid addition salts of compounds formula I include those prepared by reacting the compound with inorganic or organic acid such as hydrochloric, hydrobromi sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citri glutaric, gluconic, methanesulfonic, salicylic, succini tartaric, toluenesulfonic, trifluoracetic, sulfamic or fumar acid. In another aspect, the present invention relates to pharmaceutical composition comprising, as an active ingredien a compound of the general formula I or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier or diluent. Pharmaceutical compositions containing a compound of the prese invention may be prepared by conventional techniques, e.g. described in Remington's Pharmaceutical Sciences. 1985. T compositions may appear in conventional forms, for examp capsules, tablets, aerosols, solutions, suspensions or topic applications. The pharmaceutical carrier or diluent employed may be conventional solid or liquid carrier. Examples of solid carrie are lactose, terra alba, sucrose, cyclodextrin, talc, gelati agar, pectin, acacia, magnesium stearate, stearic acid or low alkyl ethers of cellulose. Examples of liquid carriers are syru peanut oil, olive oil, phospholipids, fatty acids, fatty ac amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustain release material known in the art, such as glyceryl monosteara or glyceryl distearate, alone or mixed with a wax. If a solid carrier is used for oral administration, t preparation may be tabletted, placed in a hard gelatin capsule powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) lOOmg Colloidal silicon dioxide (Aerosil) 1.5mg Cellulose, microcryst. (Avicel) 70mg Modified cellulose gum (Ac-Di-Sol) 7.5mg Magnesium stearate Coating: HPMC approx. 9mg *Mywacett 9-40 T approx. 0.9mg *Acylated monoglyceride used as plasticizer for film coating. For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes. Generally, the compounds of the present invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient together with a pharmaceutically acceptable carrier per un dosage. The dosage of the compounds according to this invention suitably 0.1-500 mg/day, e.g. from about 5 to about 50 mg, su as about 10 mg per dose, when administered to patients, e. humans, as a drug. It has been demonstrated that compounds of the general formula possess the ability to release endogenous growth hormone in viv The compounds may therefore be used in the treatment of conditio which require increased plasma growth hormone levels such as growth hormone deficient humans or in elderly patients livestock. Thus, in a particular aspect, the present invention relates to pharmaceutical composition for stimulating the release of grow hormone from the pituitary, the composition comprising, as active ingredient, a compound of the general formula I or pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carrier or diluent. In a further aspect, the present invention relates to a method stimulating the release of growth hormone from the pituitary, t method comprising administering to a subject in need thereof effective amount of a compound of the general formula I or pharmaceutically acceptable salt thereof. In a still further aspect, the present invention relates to t use of a compound of the general formula I or a pharmaceutical acceptable salt thereof for the preparation of a medicament f stimulating the release of growth hormone from the pituitary. To those skilled in the art, it is well known that the current and potential uses of growth hormone in humans are varied and multitudinous. Thus, compounds of formula I can be administered for purposes stimulating release of growth hormone from the pituitary and would then have similar effects or uses as growth hormone itself. The uses of growth hormone may be summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids, prevention and treatment of osteoporosis, stimulation of the immune system, acceleration of wound healing, accelerating bone fracture repair, treatment of growth retardation, treating renal failure or insufficiency resulting from growth retardation, treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness, treatment of obesity and growth retardation associated with obesity, treating growth retardation associated with the Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushing's syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients, treatment of osteochondrodysplasias, Noonan's syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and ventilator dependency, attenuation of protein catabolic responses after major surgery, reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treatment of hyperinsulinemia including nesidioblastosis, adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function, treatment of immunosuppressed patients, improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly, stimulation of osteoblasts, bone remodelling and cartilage growth, stimulation of the immune system in companion animals and treatment disorder of aging in companion animals, growth promoter livestock and stimulation of wool growth in sheep. For the above indications the dosage will vary depending on t compound of formula I employed, on the mode of administration a on the therapy desired. However, generally dosage levels betwe 0.0001 and 100 mg/kg body weight daily are administered patients and animals to obtain effective release of endogeno growth hormone. Usually, dosage forms suitable for oral, nasa pulmonal or transdermal administration comprise from about 0.00 mg to about 100 mg, preferably from about 0.001 mg to about 50 of the compounds of formula I admixed with a pharmaceutical acceptable carrier or diluent. The compounds of formula I may be administered in pharmaceutical acceptable acid addition salt form or, where appropriate, as alkali metal or alkaline earth metal or lower alkylammonium sal Such salt forms are believed to exhibit approximately the sa order of activity as the free base forms. Optionally, the pharmaceutical composition of the invention m comprise a compound of formula I combined with one or mo compounds exhibiting a different activity, e.g. , an antibiotic other pharmacologically active material. The route of administration may be any route which effective transports the active compound to the appropriate or desired si of action, such as oral, nasal, pulmonary, transdermal parenteral, the oral route being preferred. Apart from the pharmaceutical use of the compounds of formula they may be useful in vitro tools for investigating the regulati of growth hormone release. Compounds of formula I may also be useful in vivo tools for evaluating the growth hormone releasing capability of the pituitary. For example, serum samples taken before and after administration of these compounds to humans can be assayed for growth hormone. Comparison of the growth hormone in each serum sample would directly determine the ability of the patients pituitary to release growth hormone. Compounds of formula I may be administered to commercially important animals to increase their rate and extent of growth, and to increase milk production. A further use of growth hormone secretagogue compounds of formula I is in combination with other secretagogues such as GHRP (2 or 6) , GHRH and its analogues, growth hormone and its analogues or somatomedins including IGF-1 and IGF-2. Pharmacological Methods Compounds of formula I may be evaluated in vitro for their efficacy and potency to release growth hormone in rat pituitary primary cultures. The isolation of rat pituitary cells is a modification of O. Sartor et al., Endocrinology 116. 1985, pp. 952-957. Male albino Sprague-Dawley rats (250 +/" 25 grams) were purchased from Møllegaard, Lille Skensved, Denmark. The rats were housed in group cages (four animals/cage) and placed in rooms with 12 hour light cycle. The room temperature varied from 19-24'C and the humidity from 30 - 60%. The rats were decapitated and the pituitaries dissected. The neurointermediate lobes were removed and the remaining tissue was immediately placed in icecold isolation buffer (Gey's medium (Gibco 041-04030) supplemented with 0.25% D-glucose, 2% n essential amino acids (Gibco 043-01140) and 1% bovine se albumine (BSA) (Sigma A-4503)). The tissue was cut into sm pieces and transferred to isolation buffer supplemented with mg/ml of trypsin (Worthington #3707 TRL-3) and 330 μg/ml of DN (Sigma D-4527) . This mixture was incubated at 70 rotations/min 35 min at 37°C in a 95/5% atmosphere of 0 2 /C0 2 . The tissue was t washed three times in the above buffer. Using a standard past pipet, the tissue was then aspirated into single cells. Af dispersion, cells were filtered through a nylon filter (160 to remove undigested tissue. The cell suspension was washe times with isolation buffer supplemented with trypsin inhibi (0.75 mg/ml, Worthington #2829) and finally resuspended in cult medium; DMEM (Gibco 041-01965) supplemented with 25 mM HE (Sigma H-3375) , 4 mM glutamine (Gibco 043-05030H) , 0.075% sod bicarbonate (Sigma S-8875) , 0.1% non-essential amino acid, 2 fetal calf serum (FCS, Gibco 011-06290), 3% horse serum (Gi 034-06050) , 10% fresh rat serum, 1 nM T 3 (Sigma T-2752) and μg/L dexamethasone (Sigma D-4902) pH 7.3, to a density of 2 x cells/ml. The cells were seeded into microtiter plates (Nu Denmark), 200 μl/well, and cultured for 3 days at 37°C and 8% C Compound testing After culturing, the cells were washed twice with stimulat buffer (Hanks Balanced Salt Solution (Gibco 041-040 supplemented with 1% BSA (Sigma A-4503), 0.25% D-glucose (Si G-5250) and 25 mM HEPES (Sigma H-3375) pH 7.3) and preincuba for 1 hour at 37°C. The buffer was exchanged with 90 stimulation buffer (37°C) . Ten μl test compound solution was ad and the plates were incubated for 15 min at 37"C and 5% C0 2 . medium was decanted and analyzed for GH content in an rGH SPA t system. All compounds were tested in doses ranging from 10 pM to 100 μM. A dose-response relation was constructed using the Hill equation (Fig P, Biosoft) . The efficacy (maximal GH released, E max ) was expressed in % of the E max of GHRP-6. The potency (EC 50 ) was determined as the concentration inducing half maximal stimulation of the GH release. Compounds of formula I may be evaluated for their metabolic stability. Compounds were dissolved at a concentration of 1 μg/μl in water. 25 μl of this solution is added to 175 μl of the respective enzyme-solution (resulting in an enzyme:substrate ratio (w/w) of approximately 1:5). The solution is left at 37°C overnight. 10 μl of the various degradation solutions is analyzed against a corresponding zero-sample using flow injection electrospray mass spectrometry (ESMS) with selected ion monitoring of the molecular ion. If the signal has decreased more than 20% compared to the zero-sample, the remainder of the solution is analyzed by HPLC and mass spectrometry in order to identify the extent and site(s) of degradation precisely. Several standard peptides (ACTH 4-10, Angiotensin 1-14 and Glucagon) have been included in the stability tests in order to verify the ability of the various solutions to degrade peptides. Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) were purchased from Sigma, MO, USA) Enzymes (trypsin, chymotrypsin, elastase aminopeptidase M and carboxypeptidase Y and B) were all purchased from Boehringer Mannheim GmbH (Mannheim, Germany) Pancreatic enzyme mix: trypsin, chymotrypsin and elastase in 100 mM ammoniumbicarbonate pH 8.0 (all concentrations 0.025 μg/μl). Carboxypeptidase mix: carboxypeptidase Y and B in 50 ammoniumacetate pH 4.5 (all concentrations 0.025 μg/μl). Aminopeptidase M solution: aminopeptidase M (0.025 μg/μl) in 1 mM ammoniumbicarbonate pH 8.0 Mass spectrometric analysis was performed using two different ma spectrometers. A Sciex API III triple quadrupole LC-MS instrume (Sciex instruments, Thornhill, Ontario) equipped with electrospray ion-source and a Bio-Ion 20 time-of-flight Plas Desorption instrument (Bio-Ion Nordic AB, Uppsala, Sweden) . Quantification of the compounds (before and after degradation) w done on the API III instrument using single ion monitoring of t molecular ion in question with flow injection of the analyte. T liquid flow (MeOH:water 1:1) of 100 μl/min was controlled by ABI 140B HPLC unit (Perkin-Elmer Applied Biosystems Division Foster City, CA) . The instrument parameters were set to standa operation conditions, and SIM monitoring was performed using t most intense molecular ion (in most cases this corresponded to t doubly charged molecular ion) . Identification of degradation products furthermore involved t use of plasma desorption mass spectrometry (PDMS) with samp application on nitrocellulose coated targets and standa instrumental settings. The accuracy of the hereby determin masses is generally better than 0.1%. Separation and isolation of degradation products was done usi a HY-TACH C-18 reverse phase 4.6x105 mm HPLC column (Hewlet Packard Company, Palo Alto, CA) with a standard acetonitril: T separation gradient. The HPLC system used was HP1090M (Hewlet Packard Company, Palo Alto, CA) . +: Stable (less than 20% decrease in SIM signal after 24 h in degradation solution) -: Unstable (more than 20% decrease in SIM signal after 24 h in degradation solution) Any novel feature or combination of features described herein is considered essential to this invention. EXAMPLES : The process for preparing compounds of formula I and preparati containing them is further illustrated in the following exampel which however, are not to be construed as limiting. The structures of the compounds are confirmed by either elemen analysis (MA) nuclear magnetic resonance (NMR) or m spectrometry (MS) . NMR shifts (δ) are given in parts per mill (ppm) and only selected peaks are given, mp is melting point is given in °C. Column chromatography was carried out using technique described by W.C. Still at al, J. Org. Chem. 1978, 4 2923-2925 on Merck silica gel 60 (Art 9385) . Compounds used starting materials are either known compounds or compounds wh can readily be prepared by methods known per se. Abbrevations: TLC: thin layer chromatography DMSO: dimethylsulfoxide min: minutes h: hours ESMS = Electro Spray Mass Spectrometry PDMS = Plasma Desorption Mass Spectrometry HPLC-Analysis: Method a. The RP-HPLC analysis was performed using UV detection at 254nm a Lichrosorp RP-185μM column, which was eluted at lml/minute. solvent systems were used: Solvent system I: 0.1% Trifluoroacetic acid in acetonitri Solvent system II: 0.1% Trifluoroacetic acid in water. The column was equilibrated with a mixture composed of 20% solvent system I and 80% of solvent system II. After injection the sample a gradient of 20% to 80% of solvent system I in solvent system II was run over 30 min. The gradient was then extended to 100% of solvent system I over 5 min. followed by isocratic elution with 100% of this system for 6 min. Method b. The RP-analysis was performed using UV detections at 214, 254, 276, and 301 nm on a 218TP544.6 mm x 250 mm 5μ C-18 silica column (The Seperations Group, Hesperia) , which was eluted at 1 mL/min at 42°C. The column was equilibrated with 5% acetonitrile in a buffer consisting of 0.1 M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid. After injection the sample was eluted by a gradient of 5% to 60% acetonitrile in the same buffer during 50 min. Example 1 (3R)-Piperidine 3-carboxylic acid [ (lR)-l-((IR)-l-(3-methyl- [l,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl)-2-(2 naphthyl)ethyl]amide: Prepared according to method E. (R) [1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbami acid tertbutyl ester: 1,3-Dicyclohexylcarbodiimide (10.lg, 49mmol) was dissolved dichloromethane (100ml) and added to a solution of (R) N-ter butoxycarbonyl-phenylalanine (10.Og, 37.7mmol) in dichlorometha (250ml) at 0-5°C. The reaction mixture was heated to 20°C stirred at this temperature for lh. Acetamide oxime (3.63 49mmol) was suspended in pyridine (200ml) and N, dimethylformamide (40ml) and added to the reaction mixture. dichloromethane was evaporated and the reaction mixture was heat at reflux temperature for 18h. The reaction mixture was cooled 0°C and filtered. The filtrate was diluted with ethyl acet (100ml) and washed with aqueous citric acid (10%, 3x50ml) water (3x50ml) . After drying (magnesium sulfate) the solution concentrated in vacuo and crystallized from ethyl acetate heptane to give 5.48g of (R) [l-(3-methyl-[l,2,4]oxadiazol-5-yl 2-phenylethyl]carbamic acid tertbutyl ester. mp 94-98°C ^-NMR (DMSO-d 6 ) δ 1.30(s, 9H) ; 2.32 (s, 3H) ; 4.90-5.10( , 1 7.15-7.30(m, 5H) . HPLC: R t = 26.7 min (Method a) (R) 1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylamine hydrochloride: (R) [1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamic acid tertbutyl ester (2.4g, 7.9mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (40ml) . After 5h at 20°C the reaction mixture was concentrated in vacuo. The residue was crystallized from ethyl acetate to give 2.05g of (R) l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-phenylethylamine hydrochloride. m.p. 144-148°C. •* H-NMR (DMS0-d 6 ) δ 2.35(s, 3H) ; 3.21(dd, 1H) ; 3.49(dd, 1H) ; 5.05(dd, 1H) ; 7.13-7.35(m, 5H) . HPLC: R t = 9.2 min (Method a) { (IR)-1-{ (IR)-1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoyl}-2-(2-naphthyl)ethyl)carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlorid (6.3g, 32.9mmol) and 1-hydroxybenzotriazole monohydrate (5.0g 32.9mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)-alanine (10.4g, 32.9mmol) 5 in N,N-dimethylformamide (140ml) . After lh at 20°C a mixture of 1 (3-methyl-[1,2,4]oxadiazole-5-yl)-2-phenylethylamine hydrochlorid (5.6g, 23.5 mmol) and triethylamine (2.37g, 23.5mmol) in N,N dimethylformamide (100ml) were added. After 18h at 20°C th reaction mixture was poured onto water (1.4L) and extracte 10 several times with ethyl acetate (total 1.4L). The combine organic phases were washed with aqueous citric acid (10%, 200ml) a saturated solution of sodium hydrogencarbonate (200ml) an water (3x200ml) . After drying (magnesium sulfate) the solution wa concentrated in vacuo and crystallized from ethyl acetate an 15 heptane to give 9.45g of { (IR)-l-{ (IR)-1-(3-methyl [1, 2 , 4 ] oxadiazol-5-yl) -2-phenylethylcarbamoyl } -2- ( 2 naphthyl)ethyl)carbamic acid tertbutyl ester, m.p. 148-150°C. - ■ H-NMR (DMSO-d 6 ) δ 1.25(s, 9H) ; 2.29(s, 3H) ; 4.25-4.35(m, IH) 205.25-5.35 (s, IH) ; 7.15-7.85 (m, 12H) . HPLC: R t = 29.6 min (Method a) Calculated for C 29 H 32 N 4 0 4 : C, 69.58; H, 6.44; N, 11.19%; found: C, 69,40; H, 6.65; N, 10.93%. 25 (2R) -2-Amino-N-[ (IR) -1- (3 -methyl- [ 1 , 2 , 4 ] oxadiazol-5-yl ) -2- phenylethyl]-3-(2-naphthyl)propionamide hydrochloride: { (IR)-1-{ (IR)-1-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tertbutyl ester (4.5g, 8.99mmol) was suspended in ethyl acetate (50ml) and a saturated mixture of hydrogen chloride in ethyl acetate (45ml) was added. After 3h at 20°C, the reaction mixture was filtered to give 3.17g of (2R)-2-amino-N-[ (IR)-l-(3-methyl- [1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2- naphthyl)propionamide hydrochloride. mp 197-199°C. -Η-NMR (DMS0-d 6 ) δ 2.28(s, 3H) ; 3.15-3.35(m, 4H) ; 4.15(t, IH) ; 5.35(q, IH) ; 7.20-7.90(m, 12H) . HPLC: R t = 18.5 min . (Method a) Calculated for C 24 H 24 N 4 0 2 ,HC1: C, 65.97; H, 5.77; N, 12.82%; found: C, 66,20; H, 5.90; N, 12.57%. (3R) -3-{ (IR) -1-[ (IR) -1-(3-Methyl-[1,2,4]oxadiazol-5-yl) -2- phenylethylcarbamoyl]-2-(2-naphthyl) ethylcarbamoyl)piperidine-1- carboxylic acid tertbutyl ester: 5 N-(3-Dimethylaminopropyl) -N 1 -ethylcarbodiimide hydrochlorid (0.42g, 2.18mmol) and 1-hydroxybenzotriazole monohydrate (0.33g 2.18mmol) were added to a solution of (R) -N-tertbutoxycarbonyl-3 piperidine carboxylic acid (0.50g, 2.18mmol) in N,N dimethylformamide (7ml) . After 30 min at 20°C a mixture of (2R)-2 10 amino-N-[ (IR) -1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3 (2-naphthyl)propionamide hydrochloride (0.68g, 1.56mmol) an triethylamine (0.16g, 1.56mmol) in N,N-dimethylformamide (8ml) wa added. After 18h at 20°C the reaction mixture was poured on ic water (90ml) and extracted several times with ethyl acetate (tota 15 90ml) . The organic phases were collected and washed with aqueou citric acid (10%, 15ml) , a saturated solution of sodiu hydrogencarbonate (3x15ml) and water (3x15ml) . After dryin (magnesium sulfate) the solution was concentrated in vacuo an purified by flash chromatography on silica gel (90g) using ethy 20 acetate and heptane (3:2) as eluent to give 0.83g of (3R) -3-{ (IR) l- [ ( lR) -l- ( 3 -methyl- [ l , 2 , 4 ] oxadiazol-5-yl ) -2 phenylethylcarbamoyl]-2-(2-naphthyl) ethylcarbamoyl}piperidine-l carboxylic acid tertbutyl ester. -Η-NMR (DMSO-d 6 ) δ 1.37(s, 9H) ; 2.30(s, 3H) ; 4.60-4.70(m, IH) ; 5.25-5.35(m, IH) ; 7.15-7.85(m, 12H) . HPLC: R t = 31.6 min (Method a) 3-{ (lR)-[ (lR)-l-(3-Methyl-[l,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl}piperidine-l- carboxylic acid tertbutyl ester (0.80g, 1.31mmol) was dissolved in ethyl acetate (20ml) and a saturated solution of hydrogen chloride in ethyl acetate (20ml) was added. After 2h at 20°C the reaction mixture was concentrated in vacuo. The compound was crystallized from a mixture of methanol and ethyl acetate to give 0.66g of the title compound, m.p. 198-200°C --H-NMR (DMS0-d 6 ) δ 1.10-1.80(m, 4H) ; 2.30(s, 3H) ; 4.60-4.70(m, IH) ; 5.25-5.35(m, IH) ; 7.20-7.90(m, 12H) . HPLC: R t = 20.9 min (Method a) Calculated for C 3 oH 33 N 5 θ 5 ,HCl: C, 65.74; H, 6.25; N, 12.78%; found: C, 65,57; H, 6.35; N, 12.46%. Example 2 : 4-Amino-4-methyl-pent-2-enoic acid [ (IR)-l-{ (IR)-l-(3-methyl [l,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl}-2-(2 naphthy1)ethyl]amide: Prepared according to method E. N-2-Hydroxy-1,l-dimethylethyl carbamic acid tert-butyl ester: H. r CH 3 0H 3 C CM ■»c sL 1 H H ^0^NH^ 0H 102-Amino-2-methylpropan-l-ol (10.0 g, 112 mmol) was dissolved tetrahydrofuran (100 ml) . A IN solution of sodium hydroxide water (112 ml, 112 mmol) was added. A solution of di-tert-but dicarbonate (29.3 g, 134 mmol) in tetrahydrofuran (100 ml) w added over a period of 15 min. The solution was stirred at 20 15 for 16 h. Water (100 ml) was added. The phases were separated. T aqueous phase was extracted with ethyl acetate (3 x 150 ml) a the combined organic phases were dried (magnesium sulfate) . T solvent was removed in vacuo and the crude product w chromatographed on silica gel (180 g) with ethyl acetate/hepta 1:1 as eluent to give 19.6g of N-2-hydroxy-1,1-dimethylethyl carbamic acid tert-butyl ester, mp 53°C --H-NMR (CDC1 3 ) : δ 1.22 (s, 6 H) ; 1.45 (s, 9 H) ; 3.58 (d, 2 5 H) ; 4.05 (br, 1 H) ; 4.65 (br, 1 H) . _ 2-tert-Butoxycarbonylamino-2-methylpropanal : u CH 3 O H 3 C CH 3 H 3 C -^ 3 II r , C^O^NH ^ 0 DMSO (12.4 ml, 174.4 mmol) was dissolved in dichloromethane (240 ml)and the solution was cooled to -78 °C. Oxalyl chloride (7.6 ml, 1087 mmol) was added dropwise. The solution was stirred at -78 °C for 15 min. A solution of N-2-hydroxy-1,1-dimethylethyl carbamic acid tert-butyl ester in dichloromethane (30 ml) was added dropwise. The solution was stirred for 30 min at -78 °C. Triethylamine (55.23 ml, 396.3 mmol) was added slowly. After 5 min 15 at -78 °C the solution was allowed to warm to 20°C, diluted with dichloromethane (300 ml) and washed with IN hydrochloric acid (3 x 200 ml) . The combined aqueous phases were extracted with dichloromethane (2 x 200 ml) . The combined organic layers were washed with a saturated solution of sodium hydrogencarbonate (2 20 x 200 ml) and dried (magnesium sulfate) . The solvent was removed in vacuo and the crude product was chromatographed on silica gel (180 g) with ethyl acetate/heptane 1:4 as eluent to give 13.4g of 2-tert-butoxycarbonylamino-2-methylpropanal. mp 84 - 85°C 25 --H-NMR (CDC1 3 ) δ 1.35 (s, 6 H) ; 1.45 (s, 9 H) ; 5.00 (br, IH) ; 9.45 (s, 1 H) . (2E)-4-tert-Butoxycarbonylamino-4-methylpent-2-enoic acid ethy ester: Triethyl phosphonoacetate (9.6ml, 48mmol) was added slowly to suspension of potassium tert-butoxide (5.39g, 48mmol)i tetrahydrofuran (14Oml) . After 30min at 20°C 2-tert butoxycarbonylamino-2-methylpropanal (5.0g, 26mmol) was added After 2.5h at 20°C IN hydrochloric acid (80ml) was added slowly The mixture was extracted with ethyl acetate (120ml, 2 x 50ml) an the combined organic layers were washed with a saturated solutio of sodium hydrogencarbonate (100ml) and dried (magnesiu sulfate) . The solvent was removed in vacuo and the crude produc was chromatographed on silica gel (lOOg) with ethy acetate/heptane 1:4 as eluent to give 5.7g of (2E)-4-tert butoxycarbonylamino-4-methylpent-2-enoic acid ethyl ester. mp 40 - 41°C (Heptane) ^-NMR (CDC1 3 ) : δ 1.29 (t, 3 H) ; 1.41 (s, 6 H)'; 1.43 (s, 9H) ; 4.1 (q, 2 H) ; 4.65 (br, IH) ; 5.84 (d, J = 15.9 Hz, 1 H) ; 6.99 (d, = 16.0 Hz, 1 H) . (2E) -4-tert-Butoxycarbonylamino-4-methylpent-2-enoic acid: (2E) -4-tert-Butoxycarbonylamino-4-methylpent-2-enoic acid ethy ester (5.0g, 19.4mmol) was dissolved in dioxane (50ml). A solutio of lithium hydroxide (0.61 g, 25.3 mmol) in water (25 ml) wa added. The solution was stirred for 16 h at 20°C. Ethyl acetat (75 ml) and water (20 ml) were added. The phases were seperated, and the aqueous phase was extracted with ethyl acetate (20 ml) . The combined organic phases were extracted with IN sodium hydroxide solution (30 ml) . The combined aqueous phases were acidified with IN sodium hydrogensulfate solution until pH = 2. The aqueous phase was extracted with ethyl acetate (2 x 50 ml) . The combined organic phases were dried (magnesium sulfate) and the solvent removed in vacuo . The crude (2E)-4-tert-butoxycarbonylamino-4-methylpent- 2-enoic acid was used for further syntheses. ■ -H-NMR (CDClj): δ 1.39 (s, 6 H) ; 1.43 (s, 9 H) ; 4.79 (br, 1 H) ; 5.75 (d, 1 H) ; 7.12 (d, 1 H) ; 9.50 - 11.50 (br, 1 H) . { 1 , l-Dimethyl-3- [ ( IR) -1- ( ( IR) -1- (3-methyl- [1, 2 , 4 ] oxadiazol-5-yl) 2 -ph eny lethylcarbamoyl ) -2 - ( 2 -naphthyl ) ethyl carbamoyl ] allyl ) carbamic acid tertbutyl ester: N- ( 3 -Dimethylaminopropyl) -N ' -ethylcarbodiimide hydrochloride (0.42g, 2.18mmol) and 1-hydroxybenzotriazole monohydrate ( 0.33g, 2. 18mmol) were added to a solution of 4-tertbutoxycarbonylamino-4- methylpent-2-enoic acid (0.50g, 2. 18mmol) in N, N-dimethyl formamide (7ml). After 30 min at 20°C a mixture of (2R)-2-amino-N-[ (IR)-1 (3-methyl-[l,2,4]oxadiazol-5-yl) -2-phenylethyl ] -3- (2 naphthyl)propionamide hydrochloride (0.68g, 1.56mmol) an triethylamine (0.16g, 1.56ramol) in N,N-dimethylformamide (8ml were added. After 18h at 20°C the reaction mixture was poured o ice water (90ml) and extracted several times with ethyl acetat (total 90ml) . The organic phases were collected and washed wit aqueous citric acid (10%, 15ml) , a saturated solution of sodiu hydrogencarbonate (3x15ml) and water (3x15ml) . After dryin (magnesium sulfate) the solution was concentrated in vacuo an purified by flash chromatography on silica gel (95g) using ethy acetate and heptane (1:1) as eluent to give 0.90g of {1,1 dimethyl-3-[ (IR) -1-( (IR) -1-(3-methyl-[1,2,4]oxadiazol-5-yl) -2- phenylethylcarbamoyl) -2- (2-naphthyl) - ethylcarbamoyl]allyl)carbamic acid tertbutyl ester. --H-NMR (DMS0-d 6 ) δ 1.22(s, 3H) ; 2.28(s, 3H) ; 4.70-4.80(m, IH) 5.72-5.82(m, IH) ; 5.89(d, IH) ; 6.72(d, IH) ; 7.15-7.85(m, 12H) . HPLC: R t = 30.3 min (Method a) {1, l-Dimethyl-3-[ (IR)-1-( (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl) 2-phenylethylcarbamoyl )-2-(2-naphthyl)ethylcarbamoyl] allyl)carbamic acid tertbutyl ester (0.90g, 1.47mmol) wa dissolved in ethyl acetate (10ml) and a saturated solution o hydrogen chloride in ethyl acetate (20ml) was added. After 3h a 20°C the reaction mixture was concentrated in vacuo to give 0.70 of the title compound, mp 161-167°C ** H-NMR (DMSO-d 6 ) δ 1.32(s, 3H) ; 1.34 (s, 3H) ; 2.28(s, 3H) ; 4.75 4.83(m, IH) ; 5.23-5.33(m, IH) ; 6.12(d, IH) ; 6.61(d, IH) ; 7.15 7.88(m, 12H) . HPLC : R t = 20 . 6 min (Method a ) Calculated for C 30 H 33 N 5 O 5 , HCl , 0 . 75H 2 O : C, 64.16; H, 6.45; N, 12.47%; found: C, 64,42; H, 6.43; N, 12.03%. Example 3 : 3 -Aminomethyl-N- [ ( IR) -1- { ( IR) -1- (3-methyl- [1,2,4] oxadiazol-5-yl ) 2-phenylethylcarbamoyl}-2- (2-naphthyl) ethyl ]benzamide: Prepared according to method E. (3-{ (lR)-l-[ (1R)-1- (3 -Methyl- [1, 2 , 4] oxadiazol-5-yl) -2 phenylethylcarbamoyl] -2- (2-naphthyl) ethylcarbamoyl) benzyl) carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.92g, 4.82mmol) and 1-hydroxybenzotriazole monohydrate (0.74g, 4.83mmol) were added to a solution of N-tertbutoxycarbonyl-3 aminobenzoic acid (1.21g, 4.82mmol) in N,N-dimethylformamid (15ml). After lh at 20°C a mixture of (2R) -2-amino-N-[ (lR)-l-(3 methyl- [ 1 , 2 , 4 ] oxadiazol-5-yl) -2-phenylethyl] -3- ( 2 naphthyl)propionamide hydrochloride (1.50g, 3.43mmol) an triethylamine (0.35g, 3.46mmol) in N,N-dimethylformamide (15ml were added. After 18h at 20°C the reaction mixture was poured o ice water (180ml) and extracted several times with dichloromethan (total 180ml) . The organic phases were collected and washed wit aqueous citric acid (10%, 25ml) , a saturated solution of sodiu hydrogencarbonate (3x25ml) and water (3x25ml) . After dryin (magnesium sulfate) the solution was concentrated in vacuo an 1.80g of (3-{ (lR)-l-[ (lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2 phenylethylcarbamoyl]-2-(2-naphthyl) ethylcarbamoyl)- benzyl)carbamic acid tertbutyl ester was isolated from ethy acetate, mp = 176-178°C • -H-NMR (DMSO-d 6 ) δ 1.39(s, 9H) ; 2.30(s, 3H) ; 4.70-4.80(m, IH) 5.29-5.39(m, IH) ; 7.15-7.85(m, 17H) . HPLC: R t = 31.4 min (Method a) Calculated for C 37 H 39 N 5 θ 5 : C, 70.12; H, 6.20; N, 11.05%; found: C, 70.20; H, 6.34; N, 10.86%. (3-{ (lR)-l-[ (lR)-l-(3-Methyl-[l,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoyl]-2-(2-naphthyl) ethylcarbamoyl)- benzyl) carbamic acid tertbutyl ester (5.51g, 2.38mmol) wa suspended in ethyl acetate (20ml) and a saturated solution o hydrogen chloride in ethyl acetate (30ml) was added. After 4h a 20°C the reaction mixture was concentrated in vacuo a crystallized from ethyl acetate to give 1.26g of the titl compound. mp 240-241°C -Η-NMR (DMSO-d 6 ) δ 2.31(s, 3H) ; 4.03(s, 2H) ; 4.75-4.85(m, IH) ; 5.38-5.48(m, IH) ; 7.15-7.90(m, 16H) . HPLC: R t = 24.6 min (Method a) Calculated for C 32 H 31 N 5 0 3 ,HC1: C, 67.42; H, 5.66; N, 12.28%; found: C, 67.26; H, 5.76; N, 12.00%. Example 4 : Piperidine 4-carboxylic acid N-[ (IR)-l-{ (IR)-l-(3-methyl- [1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl)-2-(2- naphthyl)ethyl]amide: Prepared according to method E. 4-{ (lR)-l-[ (lR)-l-(3-Methyl-[l,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl}piperidine-l- carboxylic acid tertbutyl ester: N-(3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.92g, 4.82mmol) and 1-hydroxybenzotriazole monohydrate (0.74g, 4.83mmol) were added to a solution of N-tertbutoxycarbonyl-4 piperidine carboxylic acid (1.10g, 4.80mmol) in N,N dimethylformamide (15ml) . After 30 min at 20°C a mixture of (2R) 2-amino-N-[ (IR) -1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl] 3-(2-naphthyl)propionamide hydrochloride (1.50g, 3.43mmol) and triethylamine (0.35g, 3.46mmol) in N,N dimethylformamide (15ml) were added. After 18h at 20°C th reaction mixture was poured on ice water (180ml) and extracte several times with ethyl acetate (total 180ml) . The organic phase were collected and washed with aqueous citric acid (10%, 25ml) a saturated solution of sodium hydrogencarbonate (3x25ml) an water (3x25ml) . After drying (magnesium sulfate) the solution wa concentrated in vacuo and crystallized from ethyl acetate to giv 1.84g of 4-{ (lR)-l-[ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl) -2 phenylethylcarbamoyl]-2-(2- naphthyl) ethylcarbamoyl}piperidine-l-carboxylic acid tertbuty ester. mp 152-155°C ■ -H-NMR (DMS0-d 6 ) δ 1.35(s, 9H) ; 2.29(s, 3H) ; 4.60-4.70(m, IH) 5.25-5.35(m, IH) ; 7.15-7.85 (m, 12H) . HPLC: R t = 31.3 min (Method a) Calculated for C 35 H 41 N 5 0 5 : C, 68.72; H, 6.76; N, 11.45%; found: C, 68.65; H, 6.95; N, 11.34%. 4-{ (lR)-l-[ (lR)-l-(3-Methyl-[l,2,4]oxadiazol-5-yl)-2- phenylethylcarbamoy1]-2-(2-naphthyl)ethylcarbamoyl}piperidine-l- carboxylic acid tertbutyl ester (1.57g, 2.57mmol) was dissolved in ethyl acetate (20ml) and a saturated solution of hydrogen chloride in ethyl acetate (30ml) was added. After 4h at 20°C the reaction mixture was filtered affording 1.34g of the title compound. mp 238-241°C ■ Η-NMR (DMSO-d 6 ) δ 2.30(s, 3H) ; 4.60-4.70(m, IH) ; 5.25-5.35(m, IH) ; 7.20-7.85(m, 12H) . HPLC: R t = 23.7 min (Method a) Calculated for C 30 H 33 N 5 O 5 ,HCl: C, 64.74; H, 6.25; N, 12.78%; found: C, 65,91; H, 6.39; N, 12.42%. Example 5: 5-{ (lR)-l-[ (2R)-2-(3 -Am inomethyl ben z oyl amino ) -3 - ( 2 • naphthyl) propionylamino]-2-phenylethyl }-[l, 2 , 4]oxadiazole-3' carboxylic acid ethyl ester, triflouroacetic acid: Prepared according to method E. (R) 5-(l-tert-Butoxycarbonylamino-2-phenylethyl)- [l,2,4]oxadiazole-3-carboxylic acid ethyl ester. 1,3-Dicyclohexylcarbodiimide (2.1g, lOmmol) was dissolved i dichloromethane (25ml) and added to a solution of (R) N-ter butoxycarbonylphenylalanine (2.2g, lOmmol) in dichlorometha (50ml) at 0-5°C. The reaction mixture was heated to 20°C a stirred at this temperature for 30 min. Ethyl 2-amino-2 (hydroxyimino)acetate (1.3g, lOmmol) was dissolved in pyridi (50ml) and added to the reaction mixture. The dichloromethane w evaporated and the reaction mixture was heated at refl temperature for 18h. The reaction mixture was cooled to 0°C a filtered. The filtrate was diluted with ethyl acetate (25ml) a washed with aqueous citric acid (10%, 3x15ml) and water (3x15ml) After drying (magnesium sulfate) the solution was concentrated vacuo and purified by flash chromatography on silica gel (90 using ethyl acetate and heptane (1:1) to give l.68g of (R) 5-( tert-butoxycarbonylamino-2-phenylethyl) -[1,2,4]oxadiazole-3 carboxylic acid ethyl ester, mp 72-76°C -Η-NMR (DMSO-d 6 ) δ 1.30(s, 9H) ; 1.32 (t, 3H) ; 3.10-3.30(m, 2H) 4.41(q, 2H) ; 5.10(q, IH) ; 7.20-7.50(m, 5H) . (R) 5-(l-Amino-2-phenylethyl)-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride: (R) 5-(l-tert-Butoxycarbonylamino-2-phenylethyl)- [l,2,4]oxadiazole-3-carboxylic acid ethyl ester (l.5g, 4.2mmol) was dissolved in a saturated solution of hydrogen chloride in 5 ethyl acetate (40ml) . After 5h at 20°C the reaction mixture was concentrated in vacuo to give 1.2g of (R) 5-(l-amino-2- phenylethyl)-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride. -Η-NMR (DMSO-d 6 ) δ 1.32(t, 3H) ; 4.41(q, 2H) , 5.20(dd, IH) ; 7.10- 107.30(m, 5H) . 5-[ (lR)-l-{ (2R)-2-tert-Butoxycarbonylamino-3-(2- naphthyl)propionylamino)-2-phenylethyl]-[1,2,4]oxadiazole-3- carboxylic acid ethyl ester: 15 N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.77g, 4.03mmol) and 1-hydroxybenzotriazole monohydrate (0.62g, 32.9mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3- (2-naphthyl)alanine (1.27g, 4.03mmol) in N,N-dimethylformamide (20ml). After 30min at 20°C a solution of (R) ethyl 5-(l-amino-2 phenylethyl)-[1,2,4]oxadiazole-3-carboxylate hydrochloride (1.20 4.03mmol) in N,N-dimethylformamide (15ml) was added. The reacti mixture was heated to 50°C for 3h, poured on water (400ml) a extracted several times with dichloromethane (total 350ml) . T combined organic phases were washed with a saturated solution sodium hydrogencarbonate (2x50ml)and dried (magnesium sulfate) The solution was concentrated in vacuo and purified by fla chromatography on silica gel (40g) using ethyl acetate and hepta (3:7) to give 0.41g of 5-[ (IR)-l-( (2R)-2-tert-butoxycarbonylamin 3-(2-naphthyl)propionylamino)-2- phenylethyl]-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester. --H-NMR (DMSO-d ό ) δ 1.23(s, 9H) ; 1.32(t, 3H) ; 4.25-4.35(m, IH) 4.38-4.45(q, 2H) ; 5.38-5.48(m, IH) ; 7.20-7.85(m, 12H) . 5-[(1R)-1-{(2R) -2-Amino-3- (2-naphthyl)propionyl}amino-2 phenylethyl]-[l,2,4]oxadiazole-3-carboxylic acid ethyl est hydrochloride: 5-[ (IR) -1-{ (2R) -2-tert-Butoxycarbonylamino-3-(2- naphthyl)propionylamino}-2-phenylethyl]-[1, 2 , 4 ]oxadiazole-3- carboxylic acid ethyl ester (0.41g, 0.7mmol) was suspended in saturated mixture of hydrogen chloride in ethyl acetate (10ml) After 18h at 20°C, the reaction mixture was filtered to give 0.3 of 5-[ (lR)-l-{ (2R)-2-amino-3-(2- naphthyl) propionylamino)-2-phenylethyl] -[ 1, 2 , 4]oxadiazole-3- carboxylic acid ethyl ester hydrochloride. ■ Η-NMR (DMSO-d 6 ) δ 1. 32 (t , 3H) ; 4 . 10-4 . 20 (m , IH) ; 4 . 40-4 . 45 (m, 2H) ; 5 . 40-5 . 50 (m , IH) . 5-[ (lR)-l-( (2R)-2-((3-tert-Butoxycarbonylamino- methyl)benzoylamino)-3-(2-naphthyl)propionylamino)-2-phenylethyl]- [1,2,4]oxadiazole-3-carboxylic acid ethyl ester: N-(3-Dimethylaminopropyl)-N » -ethylcarbodiimide hydrochloride (0.23g, 1.20mmol) and 1-hydroxybenzotriazole monohydrate (0.18g, 1.2mmol) were added to a solution of 3-(tert- butoxycarbonylaminomethyl)benzoic acid (0.30g, l.2mmol) in N,N- dimethylformamide (8ml). After lh at 20°C a mixture of 5-[(lR)-l- { (2R) -2-amino-3-(2-naphthyl)propionylamino}-2-phenylethyl]- [l,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride (0.39g, 0.79mmol) and triethylamine (0.08g, 0.79mmol) in N,N- dimethylformamide (2ml) were added. After 18h at 20°C the reaction mixture was poured on water (70ml) and extracted several times with ethyl acetate (total 80ml) . The organic phases were collected and washed with aqueous citric acid (10%, 15ml) , a saturated solution of sodium hydrogencarbonate (10ml) and water (3x10ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from a mixture of ethyl acetate and heptane to give 0.44g of 5- [ ( IR) -1- { ( 2R) -2- ( ( 3-tert- butoxycarbonylaminomethyl) benzoylamino) -3- ( 2 - naphthyl)propionylamino}-2-phenylethyl]-[1,2,4]oxadiazole-3- carboxylic acid ethyl ester, mp =170-176°C - ■ H-NMR (DMSO-d 6 ) δ 1.30-1.40 (m, 12H) ; 4.42(q, 2H) , 4.80-4.90(m IH) ; 5.40-5.50 (m, IH) . 5-[ (lR)-l-{ (2R)-2-( (3-tert-Butoxycarbonyl- aminomethyl)benzoylamino)-3-(2-naphthyl)propionylamino)-2- 5 phenylethyl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl este (0.40g, 0.58mmol) was suspended in a saturated solution o hydrogen chloride in ethyl acetate (10ml) . After 5h at 20°C th reaction mixture was concentrated in vacuo. The compound wa purified by flash chromatography with silica gel (40g) using 0 mixture of dichloromethane and 10% ammonia in ethanol (9:1) a eluent to give 0.14g of the title compound. The compound wa further purified by semipreparative HPLC in three runs on a 25m x 250 mm column packed with 7μ C-18 silica which wa preequilibrated with 30% acetonitrile in a 0.5M solution o 5 ammonium sulfate, which was adjusted to pH 2.5 with sulfuric aci (4M) . The column was eluted with a gradient of 24% to 50 acetonitrile in 0.5M ammonium sufate, pH 2.5 at lOml/min durin 47min at 40°C and the fractions corresponding to the major pea were collected, diluted with three volumes of water and applie 20 to a Sep-Pak C-18 cartrigde (Waters part # WAT036915) . Afte preequilibration with 0.1% TFA, the compound was eluted from th Sep-Pak cartridge with 70% TFA and isolated from the eluate b lyophilisation. - ■ H-NMR (DMSO-d 6 ) δ 1.35(t, 3H) ; 4.40(q, 2H) ; 4.85-4.95(m, IH) 255.35-5.45(m, IH) ; 7.10-7.85(m, 16H) . HPLC: R t = 28.4 min (method: 0-90% 0.1% TFA in acetonitrile over 5 min) Calculated for C 34 H 33 N 5 0 5 ,TFA, 1.5H 2 0: C, 59.01; H, 5.09; N, 9.56%; found: 30 C, 68,89; H, 5.10; N, 9.74%. Example 6: 5-{ l-[2- (3-Aminomethylbenzoyl) -3- (2 -naphthyl) propionyl-N- methylamino] -2- (2 -naphthyl) ethyl } - [ 1 , 2 , 4 ] oxadiazol-3-carboxylic acid ethyl ester: Prepared according to method E. (R)-3-(2-Naphthyl)alanine methyl ester. Thionyl chloride (5 ml) was added dropwise over 15 min. to suspension of (R)-3-(2-naphthyl)alanine (5.0 g) in methanol ( ml) at 35°C. After addition the mixture was heated at 60°C for h, cooled and the solvent removed in vacuo. Water (75 ml) a ethyl acetate (125 ml) were added and pH was adjusted to 8.5 wi sodium carbonate. The organic phase was separated and dri (magnesium sulfate) to afford 4.86 g of (R)-3-(2-naphthyl)alani methyl ester. - ■ H-NMR (CDC1 3 ) d 1.50 (s(br), 2H) ; 3.03 (dd, IH) ; 3.27 (dd, IH 3.71 (s, 3H) ; 3.84 (dd, IH) ; 7.30-7.82 (m, 7H) . (R) -2-(3-(tert-Butoxycarbonylamino ethyl)benzoylamino) -3-( naphthyl)-propionic acid methyl ester: 3-(tert-Butoxycarbonylaminomethyl)benzoic acid (5.32 g; 21.2 mmo was dissolved in N,N-dimethylformamide (20 ml). l-Ethyl-3-( dimethylaminopropyl)-carbodiimide hydrochloride (4.06 g, 21 mmol) was added and the mixture was stirred for 20 min. A soluti of (R)-3-(2-naphthyl)alanine methyl ester (4.85 g, 21.2 mmol) N,N-dimethylformamide (20 ml) and triethylamine (4.4 ml) was add and stirring was continued for 18h. The mixture was diluted with ethyl acetate (400 ml) and the organic phase was washed with water (200 ml) , 10% aqueous sodium hydrogensulfate (50 ml) , 5 % aqueous sodium hydrogencarbonate (100 ml) and water (100 ml) . The phases were separated and the organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 8.9g of (R)-2-(3-(tert- butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propionic acid methyl ester. ■• H-NMR (CDC1 3 ) δ 1.44 (s, 9H) ; 3.40 (t, 2H) ; 3.76 (s, 3H) 4.28 (d, 2H) ; 5.00 (s(br), IH) ; 5.18 (q, IH) ; 6.75 (d, IH) ; 7.20-7.80 (m, 11H) (R) -2- ( 3 - (tert-Butoxycarbonylaminomethyl ) benzoylamino) -3 - ( 2 - naphthyl) propionic acid: (R)-2-(3-(tert-Butoxycarbonylaminomethyl)benzoylamino)-3-(2- naphthyl)propionic acid methyl ester (8.8 g, 19.1 mmol) was dissolved in methanol (100 ml) and lithium hydroxide (0.55 g, 22.2 mmol) was added. After 2 h dichloromethane (200 ml) , water (200 ml) and 3 M sodium hydrogen sulfate (50 ml) were added. The organic phase was separated and washed with water (100 ml) . The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to yield 7.9g of (R)-2-(3-(tert- butoxycarbonylaminomethyl) benzoylamino) -3-(2-naphthyl)propioni acid. -"H-NMR (DMSO) δ 1.38, 1.39 (two s, 9H) ; 3.30 (m, 2H) ; 4.12 (d 2H) ; 4.71 (m, IH) ; 6.10 (s(br), IH) ; 7.30-7.90 (m, 11 H) ; 8.75 (d IH) ; 12.80 (s(br) , IH) . (R)-5-(l-(N-Methyl-tert-butoxycarbonylamino)-2-(2- naphthyl)ethyl)-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester: 1,3-Dicyclohexylcarbodiimide (1.88g, 9.1mmol) was dissolved dichloromethane (25ml) and added to a solution of (R) N-ter butoxycarbonyl-(2-naphthyl)alanine (3.0g, 9.1mmol) dichloromethane (50ml) at 0-5°C. The reaction mixture was heat to 20°C and stirred at this temperature for 30 min. Ethyl 2-amin 2-(hydroxyimino)acetate (1.2g, 9.1mmol) was dissolved in pyridi (50ml) and added to the reaction mixture. The dichloromethane w evaporated and the reaction mixture was heated at refl temperature for 18h. The reaction mixture was cooled to 0C a filtered. The eluent was concentrated in vacuo, redissolved ethyl acetate (25ml) and washed with aqueous citric acid (10 3x15ml) and water (3x15ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (90g) using ethyl acetate and heptane (1:4) to give 1.59g of (R) 5-(l-(N-methyl-tert- butoxycarbonylamino)-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3- carboxylic acid ethyl ester, mp 99-102°C - ■ H-NMR (DMSO-d 6 ) δ 1.30-1.40(m, 3H) ; 4.40-4.50(m, 2H) ; 5.70-5.90(m, IH) ; 7.45-7.90(m, 7H) . (R) 5-(l-Methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3- carboxylic acid ethyl ester hydrochloride: (R) 5-(1- (N-Methyl-tert-butoxycarbonylamino) -2-(2-naphthyl) - ethyl) -[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.77g, l.δmmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (15ml) . After 5h at 20°C the reaction mixture was concentrated in vacuo to give 0.72g of (R) 5-(l- methylamino-2-(2-naphthyl) ethyl) -[1,2 ,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride. -"H-NMR (DMSO-d 6 ) δ 1.32(t, 3H) ; 2.71(s, 3H) ; 4.40(q, 2H) ; 5.45(q, IH) ; 7.30-7.90(m, 7H) . HPLC: R t = 19.7 min (Method a) 5- { l- [ 2- ( 3 - (tert-Butoxycarbonylaminomethyl ) benzoylamino) -3 - ( 2 naphthyl ) pr op i onyl - -methyl am i no ] - 2 - ( 2 -naphthy l ) ethy l } [ l , 2 , 4 ] oxadiazole-3-carboxylic acid ethyl ester: N-(3-Dimethylaminopropy1)-N'-ethylcarbodiimide hydrochlori (0.51g, 2.6mmol) and l-hydroxy-7-azabenzotriazole (0.36g, 2.6mmo were added to a solution of 2-(3-(ter butoxycarbonylaminomethyl)benzoylamino)-3-(2-naphthyl)propion acid (l.lδg, 2.6mmol) in N,N-dimethylformamide (15ml). After 30m at 20°C a mixture of (R) 5-(l-methylamino-2-(2-naphthyl)ethyl) [l,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochlori (0.69g, 1.9mmol) and triethylamine (0.19g, 1.9mmol) in N, dimethylformamide (10ml) were added. After 18h at 20°C t reaction mixture was poured onto water (175ml) and extract several times with ethyl acetate (total 175ml) . The combin organic phases were washed with aqueous citric acid (10%, 20ml) a saturated solution of sodium hydrogencarbonate (25ml) , wat (3x25ml) and dried (magnesium sulfate) . The solution w concentrated in vacuo and purified by flash chromatography silica gel (80g) using ethyl acetate and heptane (2:3) to gi 0.8g of a 1:1 mixture of two diastereoisomers of 5-{l-[2-(3-(ter butoxycarbonylamino- methyl)benzoylamino)-3-(2-naphthyl)propionyl-N-methylamino]-2-( naphthyl)ethyl}-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester. δi - ■ H-NMR (DMSO-d 6 ) δ 1.30-1.42 (m, 12H) , 4.40-4.4δ(m, 2H) ; 4.90- 5.20(m, IH) ; 6.00-6.10(m, IH) . HPLC: diastereoisomer I ; R.= 25.6 min (Method a) diastereoisomer II; R t = 30.81min (Method a) 5-{l-[2-(3-(tert-Butoxycarbonylaminomethyl)benzoylamino)-3-(2- naphthyl) propionyl-N-methylamino] -2- (2-naphthyl) ethyl )- [l,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.34g, 0.5mmol) was suspended in a mixture of trifluσroacetic acid and dichloromethane (1:1, 20ml). After lOmin at 20°C, the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (40g) using dichloromethane and a 10% mixture of ammonia in ethanol (65:15) to give 0.14g of two diastereoismers of the title compound. -Η-NMR (DMSO-d 6 ) δ 1.35-1.50(m, 3H) ; 4.40-4.50(m, 2H) ; 5.00-5.20(m, IH) ; 5.96-6.13(m, IH) . HPLC: diasteroisomer I ; R t = 26.9 min (Method a) diastereoisomer II; R t *= 37.7min (Method a) Calculated for C 39 H 37 N 5 0 5 : C, 71.43; H, 5.69; N, 10.66%; found: C, 71.05; H, 5.54; N, 10.41%. Example 7 : 5-{ (IR) -l-[ (2R)-2-(piperidine-4-carbonylamino) -3- ( naphthyl) propionyl-N-methylamino ] -2- ( 2 -naphthyl) ethyl [l,2,4]oxadiazole-3-carboxylic acid ethyl ester: Prepared according to method E. 5-{ (IR)-l-[ (2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)- propionyl-N-methylamino]-2-(2-naphthyl)ethyl}-[1,2,4]oxadiazole- carboxylic acid ethyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.54g, 2.8mmol) and l-hydroxy-7-azabenzotriazole (0.3δg, 2.δmmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)alanine (0.88g, 2.βmmol) in N,N-dimethylformamide (15ml) . After 30min at 20°C a solution of (R) 5-(l-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3- carboxylic acid ethyl ester hydrochloride (0.7g, 2.0mmol) in N,N- dimethylformamide (15ml) was added. The reaction mixture was heated to 50°C for 3h, poured on water (180ml) and extracted several times with ethyl acetate (total 200ml) . The combined organic phases were washed with aqueous citric acid (10%, 25ml) , a saturated solution of sodium hydrogencarbonate (30ml) , water (3x30ml) and dried (magnesium sulfate) . The solution was concentrated in vacuo to give 1.3g of 5-( (IR)-l-[ (2R)-2-tert- butoxycarbonylamino-3-(2-naphthyl)propionyl-N-methylamino]-2-(2- naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester. α H-NMR (DMS0-d 6 ) δ 1.00-1.40(m, 12H) ; 4.45(q, 2H) ; 5.90-6.20(m, IH) . 5-{ (IR)-l-[ (2R)-2-Amino-3-(2-naphthyl)propionyl-N-methylamino]-2- (2-naphthyl)ethyl}-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester: H,N 5-{ (lR)-l-[ (2R)-2-tert-butoxycarbonylamino-3-(2-naphthyl)- propionyl-N-methylamino]-2-(2-naphthyl)ethyl)- [l,2,4]oaxdiazole-3-carboxylic acid ethyl ester (1.3g, 2.0mmol was suspended in a saturated mixture of trifluoroacetic acid a dichloromethane (1:1, 50ml). After lOmin at 20°C, the reacti mixture was concentrated in vacuo and purified by fla chromatography on silica gel (lOOg) using dichloromethane and mixture of 10% ammonia in ethanol (95:5) as eluent to give 0.9 of 5-{ (lR)-l-[ (2R)-2-amino-3-(2-naphthyl)propionyl-N-methylamino] 2-(2-naphthyl)ethyl)-[l,2,4]oxadiazole-3-carboxylic acid eth ester. - ■ H-NMR (DMSO-d 6 ) δ 1.35(i, 3H) ; 4.45(q, 2H) ; 5.8δ-6.20(m, IH) . 4-( (IR)-l-( [ (IR)-l-(3-Ethoxycarbonyl-[l,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]-N-methylcarbamoyl)-2-(2-naphthyl)- ethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlori (0.40g, 2.1mmol) and 1-hydroxybenzotriazole monohydrate (0.32 2.1mmol) were added to a solution of N-tert-butoxycarbonyl- piperidinecarboxylic acid (0.48g, 2.1mmol) in N,N- dimethylformamide (10ml). After lh at 20°C a solution of 5-{(lR)- l-[ (2R)-2-amino-3-(2-naphthyl)propionyl)-N-methylamino]-2-(2- naphthyl)ethyl)-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.73g, 1.4mmol) in N,N-dimethylformamide (2ml) was added. After lδh at 20°C the reaction mixture was poured on water (120ml) and extracted several times with ethyl acetate (total 140ml) . The organic phases were combined and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (15ml) and water (3x20ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (40g) using ethyl acetate and heptane (1:1) to give 0.9g of 4-((lR)-l-{ [ (IR)-l-(3-ethoxycarbonyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}- 2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert¬ butyl ester. - ■ H-NMR (DMS0-d 6 ) δ 1.30-1.45(m, 9H) ; 6.00-6.15(m, IH) . HPLC: R t = 33.9 min (Method a) 4-((IR)-1-{ [ (IR)-1-(3-Ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]-N-methylcarbamoyl)-2-(2- naphthyl)ethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester (0.21g, 0.29mmol) was dissolved in a mixture trifluoroacetic acid and dichloromethane (1:1, 12ml). After 10 min at 20°C the reaction mixture was concentrated in vacuo. The compound was purified by flash chromatography with silica gel (40g) using a mixture of dichloromethane and 10% ammonia in ethanol (4:1) as eluent to give 0.12g of the title compound. -"H-NMR (DMS0-d 6 ) δ 1.30-1.40(m, 3H) ; 2.80-2.90(2s, 3H) , 4.40- 4.50(m, 2H) ; 5.98-6.20(m, IH) . HPLC : R t = 25 . 0 min (Method a) Calculated for C 37 H 39 N 5 θ 5 , H 2 0 : 66 C, 66.19; H, 6.34; N, 10.75%; found: C, 6δ,23; H, 6.25; N, 10.60%. Example 8 : Piperidine-4-carboxylic acid (l-{ [l-(3-carbamoyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}- (2-naphthyl)ethyl)amide: Prepared according to method E. 4-(1-( [1-(3-Carbamoyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)- ethyl]methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)piperidine- 1-carboxylic acid tert butyl ester: 4-((lR)-l-{ [ (lR)-l-(3-Ethoxycarbonyl-[l,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]-N-methylcarbamoyl)-2-(2- naphthyl)ethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester (0.67g, 0.91mmol) was suspended in refluxing liquid ammonia at 1 atm. After 18h the reaction mixture was concentrated in vacuo to give 0.58g of two diastereoisomers of 4-(l-{ [l-(3-carbamoyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)- ethyl]methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)piperidine- 1-carboxylic acid tert butyl ester. ""H-NMR (DMSO-d 6 ) δ 1.30-1.40(m, 9H) ; 4.80-4.95(m, IH) ; 6.00-6.13(m, IH) . HPLC: diastereoisomer I: R t = 28.9 min (Method a) diastereoisomer II: R t = 29.4 min (Method a) The diastereomer mixture of 4-(l-{l-(3-carbamoyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl)methylcarbamoyl}-2-(2 naphthyl)ethylcarbamoyl)-piperidine-1-carboxylic acid tert buty ester (0.58g, 0.29mmol) was dissolved in a mixture trifluoroaceti acid and dichloromethane (1:1, 12ml). After 5min at 20°C t reaction mixture was concentrated in vacuo. The compound wa purified by flash chromatography with silica gel (δOg) using mixture of dichloromethane and 10% ammonia in ethanol (7:3) a eluent to give 0.44g of two diastereoisomers of the titl compound. X H-NMR (DMSO-d 6 ) δ 2.88-2.92(2s, 3H) ; 4.79-5.00(m, IH) ; 6.00 6.13(m, IH) . HPLC: diastereoisomer I: R t = 21.2 min (Method a) diastereoisomer II: R t = 22.1 min (Method a) Example 9: 3-Aminomethyl-N-( (1R,2E)-4-(hydroxymethyl)-l-( (2-naphthyl)- methyl-5-phenylpent-2-enyl)benzamide: Prepared according to method A. ((IR,2E)-4-(tert-Butyldimethylsilanyloxymethyl)-l-(2- naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert-butyl ester: A solution of diisopropylaluminium methoxide was prepared by placing diisobutylaluminium hydride (17.9ml of a 25% solution in toluene; 26.6mmol) under nitrogen, cooling in an icebath and slowly treating with dry methanol (1.1ml, 26.6mmol). ((1R)-1- Benzenesulfonylmethyl-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (2.14g; 5.0mmol) (prepared by the method of Spaltenstein et al., J. Org. Chem., 52, 3759-66, 1987) was refluxed in dry tetrahydrofuran (250ml) . The reaction mixture was cooled to -70°C. n-Butyllithium (3.92 ml; 2.5M solution in hexane, 9.8mmol) was added over 10 min and the solution was left with stirring for 30 min. A solution of racemic 2-(tert-butyldimethylsilanyloxymethyl)- 3-phenylpropionaldehyde (2.1g; 7.6mmol) (prepared as in Jenmalm et al. J. Org. Chem., 59, 1139-48, 1994) in dry tetrahydrofuran (10 ml) under nitrogen was cooled to -70°C and treated with the previously prepared solution of diisopropylaluminium methoxide (5.4ml; 7.6mmol). Immediately after the addition, the aluminium complex was added via cannula to the sulfone-anion solution. Cooling was maintained for 30 min. Then aqueous ammonium chlori (40 ml; 10%), water (200 ml) and dichloromethane (200 ml) we added. The phases were separated, the organic phase was dri (magnesium sulfate) and the solvent removed in vacuo to give 5.5 of an oil. On suspension of this oil in methanol (150 ml) a sol precipitated, was filtered off and discarded. Disodi hydrogenphosphate (1.7g) was added to the methanol solutio cooled to 5°C and treated with sodium amalgam (150g; 2%) . After at 20°C the solvent was removed in vacuo and the residue w chromatographed on silica (80g) using diethylether/heptane (1: as eluent. This afforded 0.85g of a mixture of isomers ( (IR, 2E) -4- (tert-butyldimethylsi-lanyloxymethyl) -1- (2 naphthyl)methyl-5-phenylpent-2-eny1)carbamic acid tert-butyl est which was used in the next step without further purification. "-H-NMR (CDC1 3 ) δ -0.02-0.08 (four s, 6H) ; 0.85-0.90 (four s, 9H) 1.40-1.45 (four s, 9H) ; 2.40-3.60 (m, 7H) ; 4.45 (s(br), 2H) ; 5.2 5.46 (m, 2H) ; 7.02-7.82 (m, 12H) . R f : 0.2 diethylether/heptane (1:6) ( (1R,2E) -4-Hydroxymethyl-l-(2-naphthyl)methyl-5-phenylpent- enyl)carbamic acid tert butyl ester: ( (lR,2E)-4-(tert-Butyldimethylsilanyloxymethyl)-l-(2- naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert-butyl ester (0.75g, 1.3δ mmol) was dissolved in 2% hydrogen fluoride in acetonitrile (50 ml) and stirred at room temperature for 3h. The solvent was removed in vacuo and the residue was chromatographed on silica (80g) using dichloromethane/heptane/methanol (4/10/1) as eluent. Three fractions were isolated containing compounds with R f 0.1-0.2. The major fraction (eluting second) was concentrated in vacuo to give 0.35g of ((lR,2E)-4-hydroxymethyl-l-(2- naphthyl)methyl-5-phenylpent-2-enyl)carbamicacidtertbutyl ester as a mixture of diastereomers. -Η-NMR (CDC1 3 ) d 1.38,1.40 (two s, 9H) ; 2.46-3.55 (m, 7H) ; 4.35 (m, IH) ; 4.55 (s(br), IH) ; 5.28-5.43 (m, 2H) ; 7.01-7.62 (m, 12H) . (3E,5R)-5-Amino-2-benzyl-6-(2-naphthyl)hex-3-en-l-ol: ( (IR,2E) 4-Hydroxymethyl-l-(2-naphthyl)methyl-5-phenylpent-2- enyl)carbamic acid tert butyl ester (350mg, O.δl mol) was dissolved in dichloromethane and trifluoroacetic acid (5 ml) was added. After 90 min the solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 ml) and reevaporated. Finally the mixture was lyophilized in water acidified with 4 M HCI (2 ml) to afford 0.3g of two diastereoisomers of (3E,5R)-5- amino-2-benzyl-6-(2-naphthyl)hex-3-en-l-ol as a hydrochloride which were taken to the next step without further purification. -NMR ( CDCI 3 ) d 1. 8 (s (br) , 2H) ; 2 . 45-3 . 70 (m , 7H) ; 4 . 35 (m , IH) 5 . 32-5 . 60 (m , 2H) ; 7 . 03 -7 . 72 (m, 12 H ) . 3-(tert-Butoxycarbonylaminomethyl)benzoic acid (407mg) wa dissolved in dichloromethane (6 ml) and then converted to t symmetrical anhydride by stirring with N-ethyl-N'-(3 dimethylaminopropyl)-carbodiimide hydrochloride (155mg) for 1 min. A solution of (3E,5R)-5-amino-2-benzyl-6-(2-naphthyl)hex-3 en-l-ol hydrochloride (149 mg) and N,N-diisopropylethylamine (7 μl) in dichloromethane (3 ml) was added to the mixture and th reacted for 20 h at 20°C. The reaction mixture was th concentrated to an oil and redissolved in ethyl acetate (50 ml) The solution was extracted successively with 5% aqueous sodi hydrogen carbonate (100 ml) and with water (2 X 100 ml) . T combined organic phases were dried (sodium sulfate) a concentrated in vacuo to an oil. The oil was dissolved dichloromethane / trifluoroacetic acid 1:1 (6 ml) and stirre After 10 min the mixture was concentrated by a stream of nitrog and the resulting oil was redissolved in acetic acid (1 ml) . Th water (40ml) and acetonitrile (12 ml) were added. The solution crude product of the title compound was then purified semipreparative HPLC in five runs on a 25 mm x 250 mm colu packed with 7μ C-18 silica. The column was preequilibrated wi 30% acetonitrile in 0.05M ammonium sulfate, and was adjusted pH 2.5 with 4M sulfuric acid. The column was eluted with a gradient of 30% - 45% acetonitri in 0.05M ammonium sulfate, pH 2.5 (using 4M sulfuric acid) at ml/min during 47 min at 40 °C and the fractions corresponding the two major components were each collected, diluted with volumes of water and applied to two Sep-Pak ® C18 cartridg connected in series (Waters part. #:51910 ) which we preequilibrated with 0.1% trifluoroacetic acid . The compoun were eluted from the Sep-Pak ® cartridges with 70% acetonitri 0.1% trifluoroacetic acid and isolated from the eluate by lyophilisation after dilution with water. The final products obtained were characterised by analytical RP- HPLC (retention time) and by plasma desorption mass spectrometry (molecular mass) . The molecular masses for isomer I and isomer II were found to 464.1 and 464.5 respectively which is in agreement with the expected structure within the experimental error of the method (± 0.9 amu) . The RP-HPLC analysis was performed using UV detection at 214 nm and a Vydac 218TP54 4.6mm x 250mm 5μ C-18 silica column (The Separations Group, Hesperia) which was eluted at l ml/min at 42 °C. Two different elution conditions were used: Al: The column was equilibrated with 5% acetonitrile in a buffer consisting of 0.1M ammonium sulphate, which was adjusted to pH 2.5 with 4M sulfuric acid and eluted by a gradient of 5% to 60% acetonitrile in the same buffer during 50 min. Bl: The column was equilibrated with 5% acetonitrile / 0.1% trifluoroacetic acid / water and eluted by a gradient of 5% acetonitrile / 0.1% trifluoroacetic acid / water to 60% acetonitrile / 0.1% trifluoroacetic acid / water during 50 min. The retention time using elution conditions Al and Bl was found to be 32.97 min and 34.52 min, respectively for isomer I and 33.67 min and 33.67 min, respectively for isomer II. Example 10 : (3R) Piperidine-3-carboxylic acid ( (1R,2E)-4-hydroxymethyl-l-( naphthyl)methyl-5-phenylpent-2-enyl)amide: Prepared according to method A. (3R) Piperidine-3-carboxylic acid ( (IR,2E)-4-hydroxymethyl-l-( naphthyl)methyl-5-phenylpent-2-eny1)amide was prepared a characterized using similar procedures as in example 10. T molecular masses for isomer I and isomer II were found to 442. and 442.5 respectively which is in agreement with the expect structure within the experimental error of the method (± 0.9 amu) The RP-HPLC retention time using elution conditions Al and Bl we found to be 30.02 min and 31.30 min, respectively for isomer I a 30.56 min and 31.95 min, respectively for isomer II. Example 11 : (2E)-5-Amino-5-methylhex-2-enoic acid { (IR)-l-[N-methyl-N-((IR)-1- (3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)- ethyl)carbamoyl]-2-(2-naphthyl)ethyl) amide: Prepared according to method E. 3-Hydroxy-l , 1-dimethylpropylcarbamic acid tert-butyl ester: At 0 °C, ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3- methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 ml, 13.8 mmol) in THF (10 ml). The solution was stirred for 40 min at 0 °C. The obtained precipitate was filtered off and washed with THF (20 ml) . The liquid was immediately cooled to 0 °C. A 2M solution of lithium boronhydride in THF (14.4 ml, 28.8 mmol) was added dropwise. The solution was stirred at 0 °C for 2 h, and then warmed to room temp, over a period of 4 h. It was cooled to 0 °C. Methanol (5 ml) was added carefully. IN Hydrochloric acid (100 ml) was added. The solution was extracted with ethyl acetate (2 x 100 ml, 3 x 50 ml) . The combined organic layers were washed with saturated solution of sodium hydrogencarbonate (100 ml) and drie over magnesium sulfate. The solvent was removed in vacuo. Th crude product was chromatographed on silica (110 g) with ethy acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-l,1 dimethylpropylcarbamic acid tert-butyl ester. 400 MHz-lH-NMR (CDC1 3 ) : 1.33 (s, 6 H) ; 1.44 (s, 9 H) ; 1.88 (t, H) ; 1.94 (br, 1 H) ; 3.75 (q, 2 H) ; 4.98 (br, 1 H) . 3-(tert-Butoxycarbonylamino)-3-methylbutanal: CH, O H 3 C CH 3 H 3 C H 3 C XX " .NH At -78 °C DMSO (1.22 ml, 17.2 mmol) was added to a solution o oxalyl chloride (1.1 ml, 12.9 mmol) in dichloromethane (15 ml) The mixture was stirred for 15 min at -78 °C. A solution of 3 hydroxy-1,l-dimethylpropylcarbamic acid tert-butyl ester (1.75 g 8.6 mmol) in dichloromethane (10 ml) was added dropwise over period of 15 min. The solution was stirred at -78 °C for anothe 15 min. Triethylamine (6.0 ml, 43 mmol) was added. The solutio was stirred at -78 °C for 5 min and then warmed to room temp. Th solution was diluted with dichloromethane (100 ml) and extracte with IN hydrochloric acid (100 ml) . The aqueous phase wa extracted with dichloromethane (50 ml) . The combined organi layers were washed with a saturated solution of sodiu hydrogencarbonate (100 ml) and dried over magnesium sulfate. Th solvent was removed in vacuo. The crude product was purified b column chromatography on silica (140 g) with ethyl acetate/heptan (1:3) to give 1.10 g of 3-(tert-butoxycarbonylamino)-3 methylbutanal. 400 MHz-lH-NMR (CDCl 3 ) : d = 1.39 (s, 6 H) ; 1.45 (s, 9 H) ; 2.85 (d 2 H) ; 4.73 (br. 1 H) ; 9.80 (t, 1 H) . Ethyl (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoate: Triethylphosphonoacetate (1.96 ml, 9.8 mmol) was dissolved in THF (30 ml). Potassium tert-butoxide (1.10 g, 9.8 mmol) was added. The solution was stirred for 40 min at room temp. A solution of 3- (tert-butoxycarbonylamino)-3-methylbutanal (1.10 g, 5.5 mmol) in THF (6 ml) was added slowly. The solution was stirred at room temp, for 75 min. It was diluted with ethyl acetate (100 ml) and IN hydrochloric acid (100 ml) . The aqueous phase was extracted with ethyl acetate (2 x 50 ml) . The combined organic layers were washed with a saturated solution of sodium hydrogencarbonate (60 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (90 g) with ethyl acetate/heptane (1:4) to give 1.27 g of ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate. 200 MHz-lH-NMR (CDC1 3 ) : δ = 1.30 (s, 6 H) ; 1.30 (t, 3 H) ; 1.46 (s, 9 H) ; 2.62 (d, 2 H) ; 4.27 (q, 2 H) ; 4.42 (br, 1 H) ; 5.88 (d, 1 H) ; 6.94 (td, 1 H) . (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid: Ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate (1.233 g, 4.54 mmol) was dissolved in dioxane (20 ml). Lithium hydroxide (0.120 g, 5.00 mmol) was added as a solid. Water (10 ml) 96 was added. The solution was stirred 16 h at room temp. Th solution was diluted with water (70 ml) and was extracted wit tert-butylmethylether (2 x 100 ml) . The aqueous phase wa acidified with IN sodium hydrogensulfate solution (pH = 1) an 5 was extracted with tert-butylmethylether (3 x 70 ml) . Thes organic layers were combined and dried over magnesium sulfate. Th solvent was removed in vacuo to give 1.05 g of (2E)-5-(tert butoxycarbonylamino)-5-methylhex-2-enoic acid. The crude produc was used for further synthesis. 10400 MHz-lH-NMR (DMSO d 6 ) : δ = 1.15 (s, 6 H) ; 1.35 (s, 9 H) ; 2.5 (d, 2 H) ; 5.75 (d, 1 H) ; 6.57 (br, 1 H) ; 6.75 (td, 1 H) ; 12.15 (s, 1 H) . (R) N-Methyl-N-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphtyl)ethyl]carbamic acid tertbutyl ester: Iso-butylchloroformate (1.22g, 9.0mmol) was dropwise added to solution of (R) N-methyl-N-tert-butoxycarbonyl-3-(2- naphthyl)alanine (3.0g, 9mmol) and N-methylmorpholine (0.91g, 9.0mmol) in dichloromethane (40ml) at -20°C. After 15 min at -20° 20 acetamidoxim (1.33g, lδmmol) was added followed by addition of N methyl-morpholine (0.91g, 9mmol) . After 30min at -20°C th reaction mixture was heated to 20°C and diluted with N,N dimethylformamide (40ml) . The dichloromethane was evaporated in vacuo and the reaction mixture was heated at 120°C for 16 h. The reaction mixture was poured into water (120ml) and extracted with ethyl acetate (total 180ml) . The organic phases were collected, washed with water (40ml) and dried (magnesium sulfate) . The solution was concentrated in vacuo to give 3.5g of crude (R) N- methyl-N-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphtyl)ethyl]carbamic acid tertbutyl ester that was used without further purification. (R) N-Methyl-N-( 1- (3-methyl-[1,2,4]oxadiazol-5-yl) -2- (2-naphthyl)ethyl)amine hydrochloride: (R) N-methyl-N-[1- (3-methyl-[1,2,4]oxadiazol-5-yl) -2- (2-naphtyl)ethyl]carbamic acid tertbutyl ester (3.3g, 9.0mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (75ml) . After 3h at 20°C the reaction mixture was filtered to give 1.52g of (R) N-methyl-N-{l-(3-methyl-[l,2,4]oxadiazol-5- yl)-2- (2-naphthyl)ethyl}amine hydrochloride. m.p. 19δ-202°C. J H-NMR (DMSO-d 6 ) δ 2.35(s, 3H) ; 2.66(s, 3H) ; 3.43 (dd, IH) ; 3.80(dd, IH) ; 5.29 (dd, IH) ; 7.30(d, IH) ; 7.45-7.90(m, 7H) . HPLC: R t = 16.3 min (Method a) Calculated for C, 63.26; H, 5.97; N, 13.83%; found: C, 63,37; H, 6.11; N, 13.53%. { (lR)-l-{N-Methyl-N-[(lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlorid (1.12g, 5.85mmol) and l-hydroxy-7-azabenzotriazole (0.8g 5.85mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3 (2-naphthyl)-alanine (1.84g, 5.65mmol) in N,N-dimethylformamid (45ml). After 30min at 20°C a mixture of (R) N-methyl-N-{l-(3 methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl)amine hydrochloride (1.27g, 4.18mmol) an triethylamine (0.42g, 4.18mmol) in N,N-dimethylformamide (15ml were added. After 18h at 20°C the reaction mixture was poured o water (200ml) and extracted several times with ethyl acetat (total 110ml) . The combined organic phases were washed wit aqueous citric acid (10%, 40ml), a saturated solution of sodiu hydrogencarbonate (3x40ml) and water (3x40ml) . After dryin (magnesium sulfate) the solution was concentrated in vacuo to giv 2.4g of crude { (IR)-l-{N-methyl-N-[ (IR)-1-(3-methyl-[1,2,4] oxadiazol-5-yl) -2- (2-naphthyl) ethyl] carbamoyl } -2- (2- naphthyl)ethyl)carbamic acid tertbutyl ester which was used for the next step without further purification. (2R)-2-Amino-N-methyl-N-[ (lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)- 2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid: { (lR)-l-{N-Methyl-N-[(lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester (2.4g, 4.2mmol) was dissolved in a mixture of trifluoroacetic acid (40ml) and dichloromethane (40ml) at 20°C. After lOmin the reaction mixture was concentrated in vacuo and coevaporated from dichloromethane (80ml) . The residue was crystallised from ethyl acetate to give 1.19g of (2R)-2-amino-N- methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)- ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid, mp 190-191°C. -Ε-NMR (DMSO-d 6 ) δ 2.33(s, 3H) ; 2.88(s, 3H) ; 3.00-3.15(m, 2H) ; 3.45(dd, IH) ; 3.65(dd, IH) ; 4.71(t, IH) ; 7.25-7.95(m, 14H) . HPLC: R t = 24.3 min (Method a) Calculated for C 29 H 28 N 4 0 2 ,CF 3 COOH: C, 64.35; H, 5.05; N, 9.68%; found: C, 64,30; H, 5.13; N, 9.44%. [1, l-Dimethyl-4- ( (lR) -l-{N-methyl-[ (lR) -l- ( 3 -methy 1- [1,2, 4]oxadiazol-5-yl) -2- (2 -naphthyl) ethyl ] carbamoyl } -2- (2- naphthyl) ethylcarbamoyl )but-3-enyl] carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.28g, 1.48mmol) and 1-hydroxybenzotriazole monohydrate (0.23g, 1.48mmol) were added to a solution of (2E)-5-(tert- butoxycarbonylamino)-5-methylhex-2-enoic acid (0.36g, 1.48mmol) in N,N-dimethylformamide (5ml) . After 30 min at 20°C a mixture of (2R)-2-amino-N-methyl-N-[ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)- 2-(2-naphthyl)-ethyl)-3-(2-naphthyl) ]propionamide, trifluoroacetic acid (0.61g, 1.06mmol) and triethylamine (O.llg, 1.06mmol) in N,N- dimethylformamide (7ml) were added. After 18h at 20°C the reaction mixture was poured on water (80ml) and extracted several times with ethyl acetate (total 40ml) . The organic phases were collected and washed with aqueous citric acid (10%, 15ml), a saturated solution of sodium hydrogencarbonate (3x15ml) and water (3x15ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo to give 0.71g of crude [l,l-dimethyl-4-( (IR)-l-{N-methyl- [(lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethylcarbamoyl)but-3- enyl]carbamic acid tertbutyl ester which was used for the next step without further purification. HPLC: R t = 34.9 min (Method a) [l,l-Dimethyl-4-((lR)-l-{N-methyl-[ (lR)-l-(3-methyl- [1,2,4]oxadiazol-5-yl) -2-(2-naphthyl)ethyl]carbamoyl)-2-(2- naphthyl)ethylcarbamoyl)but-3-enyl]carbamic acid tertbutyl ester (0.71g, 1.03mmol) was dissolved in a mixture trifluoroacetic acid (10ml) and dichloromethane (10ml) . After lOmin at 20°C the reaction mixture was concentrated in vacuo. The compound was chromatographed on silica (80g) using a 10% mixture of ammonia in ethanol and dichloromethane (9:91) as eluent to give 0.44g of the title compound. HPLC: R.= 23.6 min (Method a) Calculated for C 36 H 39 N 5 0 3 , 0.75H 2 O: C, 71.68; H, 6.77; N, 11.61%; found: C, 71.76; H, 6.73; N, 11.12%. Example 12: 4-Amino-4-methylpent-2-enoicacid [ (IR)-l-(N-methyl-N-[ (lR)-l-(3- methyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthy1)ethyl]carbamoyl)-2-(2-naphthyl)ethyl]amide: Prepared according to method E. { 1, l-Dimethyl-3-[ (IR) -1- {N-methy1-N- { (IR) -1- (3-methyl [1,2,4]oxadiazol-5-yl) -2- (2-naphthyl)ethyl}carbamoyl}-2-(2 naphthyl)ethylcarbamoyl]allyl)carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26g, 1.3δmmol) and l-hydroxybenzotriazole monohydrate (0.21g, 1.38mmol) were added to a solution of N-tertbutoxycarbonyl-4- amino-4-methylpent-2-enoic acid (0.32g, 1.38mmol) in N,N- dimethylformamide (5ml). After 30 min at 20°C a mixture of (2R)- 2-amino-N-methyl-N-[ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]-3-(2- naphthyl)propionamide, trifluoroacetic acid (0.57g, 0.99mmol) and triethylamine (0.10g, 0.99mmol) in N,N-dimethylformamide (6ml) were added. After 18h at 20°C the reaction mixture was poured on water (75ml) and extracted several times with ethyl acetate (total 30ml) . The organic phases were collected and washed with aqueous citric acid (10%, 15ml) , a saturated solution of sodium hydrogencarbonate (3x15ml) and water (3x15ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo to give 0.6δg of crude (1,l-dimethyl-3-[ (IR)-l-{N-methyl-N-{ (IR)-l-(3- ethyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}carbamoyl)-2-(2- naphthyl)ethylcarbamoyl]allyl)carbamic acid tertbutyl esterwhich was used for the next step without further purification. HPLC: R t = 33.4 min (Method a) (1,l-Dimethyl-3-[ (IR)-1-{N-methyl-N-{ (IR)-1-(3-methyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl)carbamoyl)-2-(2- naphthyl)ethylcarbamoyl]allyl)carbamic acid tertbutyl ester (0.6βg, l.Olmmol) was dissolved in a mixture of trifluoroacetic acid (10ml) and dichloromethane (10ml) . After lOmin at 20°C the reaction mixture was concentrated in vacuo and chromatographed on silica gel (80g) using a 10% mixture of ammonia in ethanol and dichloromethane (1:9) as eluent to give 0.48g of the title compound. HPLC: R t = 23.3 min (Method a) Calculated for C 35 H 37 N 5 0 3 , 0.5H 2 O: C, 71.90; H, 6.55; N, 11.98%; found: C, 71.82; H, 6.55; N, 11.71%. Example 13: (2E)-4-Amino-4-methylpent-2-enoic acid N-[ (IR)-l-{N-methyl-N [ (lR) -l-(3-methyl- [ l, 2 , 4 ] oxadiazol-5-yl) -2- (2 naphthyl)ethyl]carbamoyl)- 2-(2-naphthyl)ethyl]-N-methylamide: Prepared according to method E. N-Methyl-N- ( ( lR) -l- { N-methyl-N- [ ( IR) -l- ( 3-methyl- [1,2,4]oxadiazol-5-yl) -2- (2-naphthyl)ethyl]carbamoyl)-2-(2- naphthyl)ethyl)carbamic acid tertbutyl ester: 5 N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.34g, 7.0mmol) and l-hydroxy-7-azabenzotriazole (0.95g, 7.0mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2- naphthyl)alanine (2.31g, 7.0mmol) in N,N-dimethylformamide (50ml). After 30min at 20°C a mixture of (R) N-methyl-N-{1-(3-methyl- 10 [l,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl)amine hydrochloride (1.52g, S.Ommol) and triethylamine (0.51g, S.Ommol) in N,N-dimethylformamide (10ml) was added. After 18h at 20°C the reaction mixture was poured on water (250ml) and extracted several times with ethyl acetate (total 15130ml) . The collected organic phases were washed with aqueous citric acid (10%, 50ml) , a saturated solution of sodium hydrogencarbonate (3x50ml) and water (3x50ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and chromatographed on silica (llOg) using heptane and ethyl acetate 20 (1:1) to give 2.4g of N-methyl-N-((lR)-l-(N-methyl-N-[ (IR)-l-(3- methyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthyl) ethyl]carbamoyl }-2-(2-naphthyl) ethyl) carbamic aci tertbutyl ester. HPLC: R t = 36.5 min (Method a) (2R)-2-Methylamino-N-methyl-N-[ (IR)-1-(3-methyl- [1,2,4]oxadiazol-5-yl) -2-(2-naphthyl)ethyl]-3-(2- naphthyl)propionamide, trifluoroacetic acid: N-methyl-N-( (IR) -l-(Nmethyl-N-[ (IR) -1-(3-methyl [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2- naphthyl) ethyl) carbamic acid tertbutyl ester (2.4g, 4.2mmol) w dissolved in a mixture of trifluoroacetic acid (40ml) a dichloromethane (40ml) at 20°C. After lOmin the reaction mixtu was concentrated in vacuo and coevaporated from dichlorometha (80ml) . The residue was crystallised from ethyl acetate to gi 1.9g of (2R)-2-methylamino-N-methyl-N-[ (IR) -1- (3-methy [l,2,4]oxadiazol-5-yl) -2-(2-naphthyl) ethyl]-3- (2-naphthyl)propionamide, trifluoroacetic acid. mp 184-188°C. 'H-NMR (DMSO-d 6 ) δl.53(s, 3H) ; 2.34 (s, 3H) ; 2.63(s, 3H) ; 3.05(dd, IH) ; 3.21(dd, IH) ; 3.40(dd, IH) ; 3.55(dd, IH) ; 4.60(t, IH) ; 6.35(dd, IH) ; 7.25(d, IH) ; 7.40-7.90(m, 14H) . HPLC: R t = 24.9 min (Method a) Calculated for C 30 H 3 oN 4 0 2 ,CF 3 COOH: C, 64.86; H, 5.27; N, 9.45%; found: C, 65,01; H, 5.35; N, 9.32%. (2E)-{l,l-Dimethyl-3-[N-((lR)-l-{N-methyl-N-{ (IR) -l-(3-methyl- [1,2,4] oxadiazol-5-yl ) -2- ( 2-naphthyl ) ethyl ) carbamoyl ) -2- ( 2- naphthyl) ethyl) -N-methylcarbamoyl] allyl ) carbamic acid tertbutyl ester: N-(3-Dimethylaminopropyl)-N•-ethylcarbodiimide hydrochloride (0.3lg, l.6mmol) and l-hydroxy-7-azabenzotriazole (0.22g, 1.6mmol) were added to a solution of (2E)-4-tertbutoxycarbonylamino-4- methylpent-2-enoic acid (0.37g, 1.6mmol) in N,N-dimethylformamide (5ml). After 30 min at 20°C a mixture of (2R)-2-methylamino-N- methyl-N-[ (1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthy1)- ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid (0.68g 1.2mmol) and triethylamine (0.12g, 1.2mmol) in N,N dimethylformamide (5ml) were added. After lδh at 20°C the reactio mixture was poured on water (80ml) and extracted several time with ethyl acetate (total 55ml) . The organic phases were collecte and washed with aqueous citric acid (10%, 15ml), a saturate solution of sodium hydrogencarbonate (3x15ml) and water (3x15ml) After drying (magnesium sulfate) the solution was concentrated i vacuo and chromatographed on silica gel (80g) using heptane an ethyl acetate (3:7) as eluent to give 0.75g of { (2E)-1,1-dimethyl 3-[N-((IR)-1-{N-methyl-N-{ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl) 2- (2-naphthyl) ethyl }carbamoyl ) -2- (2-naphthyl) ethyl) -N methylcarbamoyl]allyl)carbamic acid tertbutyl ester. HPLC: R t = 33.6 min (Method a) { (2E)-l,l-Dimethyl-3-[N-( (IR)-l-{N-methyl-N-{ (IR) -1-(3-methyl [1,2,4]oxadiazol-5-yl) -2- (2-naphthyl)ethyl}carbamoyl)-2-(2 naphthyl)ethyl)-N-methylcarbamoyl]allyl)carbamic acid tertbuty ester (0.62g, 1.9mmol) was dissolved in a mixture o trifluoroacetic acid (9ml) and dichloromethane (9ml) . After lOmi at 20°C the reaction mixture was concentrated in vacuo an chromatographed on silica gel (80g) using a 10% mixture of ammoni in ethanol and dichloromethane (5:95) as eluent to give 0.44g o the title compound. HPLC: R t = 26.4 min (Method a) Calculated for C 36 H 39 N 5 0 3 ,0.75H 2 O: C, 71.68; H, 6.77; N, 11.61%; found: C, 71.81; H, 6.72; N, 11.17%. Example 14 : 3-Aminomethyl-N-((lR)-l-{N-[(1R)-1- ( ( (dimethylcarbamoyl)methoxy)methyl)-2-phenylethyl]-N- methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylbenzamide Prepared according to method G (2R)-2-(Methylamino)-3-phenylpropan-l-ol: (2R)-2-(Methylamino)-3-phenylpropan-l-ol was prepared analogusly to M. J. McKennon and A. I. Meyers, K. Drauz and M. Schwarm, J. Org. Chem. 1993 (58), 3568 - 3571. m.p. 69 - 69°C (lit: M. J. McKennon, A. I. Meyers, K. Drauz and M. Schwarm, J. Org. Chem. 1993 (58), 3568 - 3571: 71 - 74 °C; A. Karim, A. Mortreux, F. Petit, G. Buono, G. Peiffer, C. Siv, J. Organomet. Chem. 1986, 317, 93: 68 °C, for (2S)-2-(methylamino)-3- phenylpropan-1-ol) . N-( (IR)-l-Hydroxymethyl-2-phenylethyl)-N-methylcarbamaic aci tert-butylester: (2R)-2-(Methylamino)-3-phenylpropan-l-ol (6.00g, 36.3mmol) wa dissolved in THF (80ml). IN sodium hydroxide solution (36.3ml 36.3mmol) was added. A solution of di-tert-butyl dicarbonat (9.50g, 43.6mmol) in THF (60 ml) was slowly added at room temp The solution was stirred 16 h at room temp. Water (200ml) an ethyl acetate (200ml) were added. The phases were separated. Th aqueous phase was washed with ethyl acetate (2 x 100ml) . Th combined organic layers were dried over magnesium sulfate. Th solvent was removed in vacuo. The product was purified on silic (170g) with ethyl aceate/heptane (1:1) to give 7.85g o N-((IR)-l-hydroxymethyl-2-phenylethyl)-N-methylcarbarmic aci tert-butylester. - ■ H-NMR (CDC1 3 ) : δ 1.32 - 1.40 (br, 9H) ; 2.55 - 2.95 (m, 5 H) ; 3.6 - 3.67 (br, 2 H) ; 4.10 - 4.35 (br, IH) ; 7.05 - 7.35 (m, 5 H) . ( (2R) -2- ( (tert-Butoxycarbonyl) methylamino) -3-phenylpropoxy) aceti acid ethylester: N-( (IR)-l-Hydroxymethyl-2-phenylethyl)-N-methylcarbamaic aci (3.98g, 15.0mmol) was dissolved in 1,2-dichloroethane (150ml). Th solution was warmed to 75 - 80°C. Rhodium(II) acetate (O.lg, 0.4mmol) was added. During a time of 6h a solution of ethyl diazoacetate (2.4ml, 22.5mmol) in dichloromethane (100ml) was added. After 3h another portion of rhodium(II) acetate (O.lg, 50.4mmol) was added. After all ethyl diazoacetate was added, the solution was cooled to room temp. It was filtrated through a plug of eelite. The solvent was removed in vacuo. The crude product was chromatographed on silica (lOOg) to give 1.53g of ( (2R)-2-( (tert- butoxycarbonyl)methylamino)-3-phenylpropoxy)acetic acid ethyl 0 ester. •• H-NMR (CDC1 3 ) : δ 1.28 (m, 3 H) ; 1.39 and 1.48 (both s, together 9H) ; 2.65 - 2.95 (m, 9 H) ; 3.58 (m, 1 H) ; 3.67 (br, IH) ; 3.98 - 4.27 (m, 4 H) ; 4.35 - 4.55 (br, IH) ; 7.10 - 7.30 (m, 5 H) . ( (2R)-2-( (tert-Butoxycarbonyl)methylamino)-3-phenylpropoxy)acetic 5 acid: ((2R)-2-((tert.-butoxycarbonyl)methylamino)-3-phenylpropoxy)acetic acid ethyl ester (0.60g, 1.71mmol) was dissolved in dioxane (5ml). A solution of lithium hydroxide (0.05g, 2.20mmol) in water (2ml) 0 was added. The solution was stirred at room temp, for 56h. Ethyl acetate (10ml) and water (2ml) were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (10ml) . The combined organic layers were extracted with IN sodium hydroxide solution (20ml) . The combined aqueous phases were 5 acidified with a 1M sodium hydrogensulfate solution (pH = 2) and extracted with ethyl acetate (2 x 20ml) . These ethyl acetate layers were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 0.38g of crude ( (2R)-2-( (ter butoxycarbonyl)methylamino)-3-phenylpropoxy)acetic acid, that w used for the following steps. - * H-NMR (DMSO d 6 ):δl.l5 and 1.27 (both s, together 9H) ; 2.55 -2. (m, 5 H) ; 3.45 - 3.65 (m, 2 H) ; 4.00 - 4.10 (m, 2 H) ; 4.30 - 4. (m, IH) ; 7.15 - 7.35 (m, 5 H) ; 13.60 (br, IH) . N,N-Dimethyl-2-( (2R)-2-methylamino-3-phenylpropoxy)acetamide: ( (2R)-2-( (tert-Butoxycarbonyl)methylamino)-3-phenylpropoxy)acet acid (0.37g, 1.14mmol) and l-hydroxy-7-azabenzotriazole (0.26 1.14mmol) were dissolved in N,N-dimethylformamide (7ml). N-ethy N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 1.37mmol) was added. The solution was stirred for 30 min. A 3 solution of dimethylamine in ethanol (0.33ml, 1.26mmol) was adde The solution was stirred over night. Water (20ml) and eth acetate (15ml) were added. The organic phase was washed with a solution of sodium hydrogensulfate (30ml) and a saturated soluti of sodium hydrogencarbonate (30ml) . It was dried over magnesi sulfate. The solvent was removed in vacuo. The crude product w purified by column chromatography on silica (15g) using eth acetate and dichloromethane (1:1) as eluent. This product w dissolved in dichloromethane (3ml) and was cooled to 0° Trifluoroacetic acid (1ml) was added. The solution was stirred 0°C for 20min. The solvent was removed in vacuo. The residue w dissolved in dichloromethane (10ml) and IN sodium hydroxi solution (10ml) . The phases were separated. The aqueous phase w extracted with dichloromethane (4 x 10ml) . The combined organ layers were dried over magnesium sulfate. The solvent was remov in vacuo to give 140mg of crude N,N-dimethyl-2-( (2R)-2- methylamino-3-phenylpropoxy)acetamide, which was used for further syntheses. 'H-NMR (CDC1 3 ) : δ 2.25 (S, IH) ; 2,45 (s, 3 H) ; 2.60 - 3.10 (m, 3 H) ; 3.94 (s, 1 H) ; 3.99 (s, 3H) ; 3.35 - 3.55 (m, 2 H) ; 4.15 (s, 2 H) ; 7.10 - 7.40 (m, 5 H) . HPLC : R t =12.18 min (Method b) . N-( (lR)-l-{N-[ (lR)-l-(( (Dimethylcarbamoyl)methoxy)methyl)-2■ phenylethyl]-N-methylcarbamoyl }-2- { 2-naphthyl }ethyl) -N- methylcarbamic acid tert-butylester: N,N-Dimethyl-2-( (2R)-2-methylamino-3-phenylpropoxy)acetamide (126mg, 0.50 mmol), (2R)-2((tert-butoxycarbonyl)methylamino)-3-(2- naphthyl)propionic acid (250mg, 0.75 mmol) and l-hydroxy-7- azabenzotriazole (103mg, 0.76 mmol) were dissolved in dichloromethane (6ml) and N,N-dimethylformamide (5ml) and then stirred 30 min at 0°C with N-ethyl-N'-(3-dimethylaminopropyl)- carbodiimide hydrochloride (146mg) . Diisopropylethylamine (87μl) was added and stirring was continued for lh at 0°C. After this the dichloromethane was evaporated from the mixture by a stream of nitrogen and ethyl acetate (25ml) was added. The mixture was extracted sequentially with 5% aqueous sodium hydrogencarbonate (2 x 25ml) , 5% aqueous potassium hydrogensulfate (2 x 25ml) and water (25ml) and the organic phase was dried (sodium sulfate) and concentrated in vacuo yielding 265 mg of crude N-( (IR) -l-{N-[ (IR) 1- ( ( (dimethylcarbamoyl) methoxy) methyl ) -2- phenylethyl] -N-methylcarbamoyl) -2- {2 naphthyl) ethyl) -N-methylcarbamic acid tert-butylester. 3-Aminomethyl-N- ( ( lR) -l-{N- [ (lR) -l- ( ( ( dimethylcarbamoyl ) methoxy ) methyl ) -2 -phenyl ethyl ] -N- methy lcarbamoyl ) -2- (2 -naphthyl ) ethyl) -N-methylbenzamide: Half of the crude N-( (lR)-l-{N-[ (1R)-1- ( ( (dimethylcarbamoyl)methoxy) methyl) -2-phenylethyl]-N- methylcarbamoyl)-2-{2-naphthyl)ethyl)-N-methylcarbamicacidtert- butylester (132 mg, 0.23 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid 1:1 (2 ml) and stirred for lOmin. The mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 1 ml IN hydrochloric acid, diluted with water to a volume of 50 ml and lyophilized. This lyophilized product was dissolved in dichloromethane (5ml) and diisopropylethyl amine (171μl) was added. To this mixture was added a solution in dichloromethane (5ml) of 3-tert- butyloxycarbonylaminomethylbenzoic acid (503mg, 2.0 mmol) which immediately before had been converted to the symmetrical anhydride by stirring with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (191.6mg, 1.0 mmol) for 15 min. The reaction mixture was then concentrated to an oil and redissolved in ethyl acetate (25ml) . This mixture was extracted sequentially with 5% aqueous sodium hydrogencarbonate (50ml) , 5% aqueous potassium hydrogen- sulfate (50ml) and water (50ml) and the organic phase was dried (sodium sulfate) and concentrated by a stream of nitrogen to dryness. This product was dissolved in a mixture of dichloromethane and trifluoroacetic acid 1:1 (4ml). After 10 min the mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 5ml 70% acetonitrile / 0. trifluoroacetic acid and diluted with water to a volume of 50 m The crude product of the title compound was then purified semipreparative HPLC in four runs on a 25 mm x 250 mm colu 5 packed with 7μ C-18 silica which was preequilibrated with 2 acetonitrile in 0.05M ammonium sulfate, which was adjusted to 2.5 with 4M sulfuric acid. The column was eluted with a gradient of 29% - 39% acetonitri in 0.05M ammonium sulfate, pH 2.5 at 10 ml/min during 47 min 1040 °C and the peptide containing fractions were collected, dilut with 3 volumes of water and applied to a Sep-Pak ® C18 cartrid (Waters part. #:51910 ) which was equilibrated with 0. trifluoroacetic acid . The peptide was eluted from the Sep-Pa cartridge with 70% acetonitrile/0.1% trifluoroacetic acid a 15 isolated from the eluate by lyophilisation after dilution wi water. The final product obtained was characterised by analytical RP-HP (retention time) and by Plasma desorption mass spectromet (molecular mass). The molecular mass found (MH + : 592.9amu) agre 20 with the expected structure (teor. MH + : 593.4amu) within t experimental error of the method. The RP-HPLC analysis was performed using UV detection at 214 and a Vydac 218TP54 4.6mm x 250mm 5μ C-18 silica column (T Separations Group, Hesperia) which was eluted at 1 ml/min at 25 °C. Two different elution conditions were used: Al: The column was equilibrated with 5% acetonitrile in buffer consisting of 0.1M ammonium sulfate, which w adjusted to pH 2.5 with 4M sulfuric acid and eluted a gradient of 5% to 60% acetonitrile in the same buff 30 during 50 min. Bl: The column was equilibrated with 5% acetonitrile / 0. trifluoroacetic acid / water and eluted by a gradie of 5% acetonitrile / 0.1% trifluoroacetic acid / wat to 60% acetonitrile / 0.1% trifluoroacetic acid / water during 50 min. The retention time using elution conditions Al and Bl was found to be 30.92 min and 35.15 min, respectively. Example 15 5-( (IR)-1-( ((2R)-2-(((2E)-4-Amino-4-methylpent-2- enoyl)methylamino) -3- (2-naphthyl)propionyl)methylamino) -2- phenylethyl)-[l,3,4]-oxadiazole-2-carboxylic acid amide: (2R)-2-((tert-Butoxycarbonyl)methylamino)-3-phenylpropionic acid ethyl ester: (2R)-2-( (tert-Butoxycarbonyl)methylamino)-3-phenylpropionic acid (4.0g, 14.27mmol) was dissolved in dichloromethane (5ml) and ethanol (0.95ml, 16.27mmol). 4-Dimethylaminopyridine (0.19g, 1.57mmol) was added. The solution was cooled to 0 °C and N-(3- dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (2.98g, 15.55mmol) was added. The reaction mixture was stirred for 2h at 0°C for 16h at room temp. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate/water (30ml/30ml) . T phases were separated. The organic phase was washed with saturated solution of sodium hydrogencarbonate and water and dri over magnesium sulfate. The crude product was purified by fla chromatography on silica (180g) with ethyl acetate/heptane 1:2 give 1.95g of (2R)-2-( (tert-butoxycarbonyl)methylamino)- phenylpropionic acid ethylester. •• H-NMR (CDC1 3 ) : 6 1.15 - 1.50 (m, 12 H) ; 2.71 (m, 3 H) ; 3.00 ( 1 H) ; 3.60 (m, 1 H) ; 4.20 (br q, 2 H) ; 4.55 and 4.90 (both br d together 1 H) ; 7.10 - 7.40 (m, 5 H) . ( (lR)-l-Hydrazinocarbonyl-2-phenylethyl)methylcarbamicacidter butyl ester: (2R)-2-( (tert-Butoxycarbonyl)methylamino)-3-phenylpropionic ac ethylester (1.9g, 6.16mmol) was dissolved in anhydrous ethan (15mL) . Hydrazine hydrate (3.0ml, 61.6mmol) was added dropwis The solution was stirred at room temp, over night. The solvent w removed in vacuo. The residue was dissolved in ethyl aceta (40ml) and washed with water (40ml) . The organic phase was dri over magnesium sulfate. After removal of the solvent in vac 1.40g of curde ( ( IR) - 1-hydraz inocarbony1 -2 phenylethyl)methylcarbamic acid tert-butylester was obtaine which was used for the further synthesis. 'H-NMR (CDCI 3 ) : 6 1.20 - 1.50 (m, 9 H) ; 2.76 (s, 3 H) ; 3.00 (m, 1 H) ; 3.35 (m, 1 H) ; 3.85 (br, 2 H) ; 4.75 and 4.85 (both m, together 1 H) ; 7.10 - 7.40 (m, 5 H) ; 7.45 (br, 1 H) . l-( (2R)-2-( (tert-Butoxycarbonyl)methylamino)-3- phenylpropionyl)-2-ethoxycarbonylformylhydrazine: ( (IR)-l-Hydrazinocarbonyl-2-phenylethyl)methylcarbamicacidtert butylester (1.4g, 4.76mmol) was dissolved in dichloromethan (40ml). Triethylamine (0.8ml, 5.71mmol) was added and the solutio was cooled to -15°C. Ethyl oxalyl chloride (0.59ml, 5.24mmol) wa added dropwise. The solution was stirred for 15min at - 15°C. I was warmed to room temp, and extracted with water (2x 20ml) an 5% citric acid (30ml) and washed with a saturated solution o sodium hydrogencarbonate. The organic layer was dried ove magnesium sulfate. The solvent was removed in vacuo and the crud product was purified by flash chromatography on silica (140g) wit ethyl acetate/dichloromethane 1:3 to give 1.40g of l-((2R)-2 ( (tert-butoxycarbonyl)methylamino)-3-phenylpropionyl)-2- ethoxycarbonylformylhydrazine. 'H-NMR (CDC1 3 ) : 6 1.30 - 1.50 (m, 12 H) ; 2.80 (br, 3 H) ; 3.05 (m 1 H) ; 3.35 (m, 1 H) ; 4.37 (br m, 2 H) ; 4.82 and 4.95 (br and b t, together IH) ; 7.05 - 7.35 (m, 5 H) ; 8.60, 8.95, 9.15, 9.45 (al br, together 2 H) . 5- ( ( IR) -l- ( (tert-Butoxycarbonyl ) methylamino) -2-phenylethyl ) [ l , 3 , 4 ] oxadiazole-2-carboxylic acid ethylester: l-((2R)-2-((tert-Butoxycarbonyl)methylamino)-3-phenylpropionyl)-2- ethoxycarbonylformylhydrazme (1.4g, 3.55mmol) was dissolved in ether (25ml) and THF (10ml). Pyridine (1.44ml 17.75mmol) was added, and the solution was cooled to 0°C. Thionyl chloride (0.3ml, 3.90mmol) was added dropwise. The reaction mixture was stirred at 0°C for 2h. The precipitation was filtered off. The solvent was removed in vacuo without warming. The residue was dissolved in toluene (25ml) and the solution was warmed to reflux for 2h. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70g) with ethyl acetate/dichloromethane 1:2 to give 721mg of 5-( (IR)-l-( (tert- butoxycarbonyl)methylamino)-2-phenylethyl)-[1,3,4]oxadiazole-2- carboxylic acid ethylester. 'H-NMR (CDC1 3 ) : δ 1.35 (br d, 9 H) ; 1.47 (t, 3 H) ; 2.70 (br, 3 H) ; 3.30 (br, 1 H) ; 3.50 (br, 1 H) ; 4.52 (br, 2 H) ; 5.55 and 5.88 (both br, together IH) ; 7.15 - 7.40 (m, 5 H) . ( (IR)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2- phenylethyl)methyl carbamic acid tert-butylester: 5-( (IR) -1-( (tert-Butoxycarbonyl)methylamino) -2-phenylethyl) [l,3,4]oxadiazole-2-carboxylic acid ethylester (600mg, 1.6mmol was dissolved in THF (4ml) and added to refluxing ammonia. Th solution was stirred for 3h. The the ammonia was removed in stream of nitrogen. The residue was dissolved in ethyl acetate/10 sodium hydrogensulfate solution (20ml/20ml) . The phases wer separated and the organic phase was washed with a saturate solution of sodium hydrogencarbonate and dried over magnesiu sulfate. The solvent was removed in vacuo. The crude product wa purified by flash chromatography on silica (40g) with ethy acetate/heptane 2:1 to give 383mg of ( (IR)-1-(5-carbamoyl [1,3,4]oxadiazol-2-yl)-2-phenylethyl)methyl carbamic acid tert butylester. 'H-NMR (CDC1 3 ) δ 1.30 (br, 9 H) ; 2.75 (br d, 3 H) ; 3.30 (dd, 1 H) 3.50 (br, 1 H) ; 5.55 and 5.85 (both br, together 1 H) ; 6.27 (br 1 H) ; 7.10 (br, 1 H) ; 7.20 - 7.40 (m, 5 H) . 5- ( (IR) -1-Methylamino-2-phenylethyl) -[l,3,4]oxadiazole-2 carboxylic acid amide: ( (IR)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2- phenylethyl)methylcarbamic acid tert-butylester (350mg, l.Olm ol) was dissolved in dichloromethane (6ml) . The solution was cooled 5 to 0°C. Trifluoroacetic acid (2ml) was added dropwise. The solution was stirred for 30min. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (6ml) and the solvent was removed in vacuo. The residue was again dissolved in dichloromethane (6ml) and the solvent was removed in vacuo. The 10 residue was dissolved in dichloromethane (10 ml) . This phase was washed with water. The aqueous phase was lyophilized to give 247mg of crude 5-((IR)-l-methylamino-2-phenylethyl)-[1,3,4]oxadiazole-2- carboxylic acid amide, which was used for the further synthesis. 'H-NMR (DMSO d 6 ) : δ 2.65 (s, 3H) ; 3.35 (dd, 1 H) ; 3.62 (dd, 1 H) ; 155.20 (dd, 1 H) ; 7.10 - 7.40 (m, 5 H) ; 8.35 (s, 1 H) ; 8.68 (s, 1 H). ( ( IR) -1- ( ( ( IR) -1- ( 5-Carbamoyl- [ 1 , 3 , 4 ] oxadiazol-2-yl ) -2- phenylethyl) methy lcarbamoyl) -2- (2-naphthyl) ethyl ) methylcarbamic 20 acid tert-butylester: 5-( (IR) -l-Methylamino-2-phenylethyl) -[1 , 3 ,4] oxadiazole-2- carboxylic acid amide (240mg, 0.98mmol), (R)-2-( (tert- butoxycarbonyl)methylamino)-3-(2-naphthyl)propionic acid (320mg, 50.98mmol) and l-hydroxy-7-azabenzotriazole (133mg, 0.98mmol) were dissolved in dichloromethane (8ml) and DMF (4ml) . The solution was cooled to 0°C and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (230mg, l.lβmmol) was added. After 10 min triethylamine (0.35ml, 2.46mmol) was added. The solution was 0 stirred for lh at 0°C and subsequently for 16h at room temp. The solution was diluted with ethyl acetate (30ml) and water (20ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (20ml) . The combined organic layers were washed with a saturated solution of sodium hydrogencarbonate (30ml) and dried 5 over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50g) with ethyl acetate to give 301mg of ((IR)-l-( ( (IR)-l-(5-carbamoyl- [1,3,4]oxadiazol-2-yl)-2- phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamic 0 acid tert-butylester. 'H-NMR (CDC1 3 ) : δ 0.84, 0.95, 1.07, 1.25 (all s, together 9 H) ; 2.05, 2.15, 2.42, 2.75, 2.76, 2.77, 2.87, 3.98 (all s, together 6 H) ; 6.90 - 7.90 (m, 12 H) . 5- ( ( lR) -l- (Methyl ( ( 2R) -2-methylamino-3- ( 2- naphthyl)propionyl)amino) -2-phenylethyl) -[1,3,4]oxadiazol-2- carboxylic acid amide: ( (IR)-1-( ( (IR)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2- phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamic acid tert-butylester (300mg, 0.55mmol) was dissolved in dichloromethane (3ml) and cooled to 0°C. Trifluoroacetic acid (3ml) was added dropwise. The solution was stirred for 5min at 0°C. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5ml) , and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5ml) , and the solvent was removed in vacuo. The residue was dissolved in 3M hydrogen chloride in ethyl acetate (5ml) , and the solvent was removed in vacuo. The residue was dissolved in 3M hydrogen chloride in ethyl acetate (5ml) , and the solvent was removed in vacuo to give 238mg of crude 5-( (IR)-1-(methyl( (2R)-2-methylamino-3-(2- naphthyl)propionyl)amino) -2-phenylethyl) -[1,3,4]oxadiazol-2- carboxylic acid amide, which was used for the further synthesis. Η-NMR (CDC1 3 ) : 6 2.40 (s, 3H) ; 2.55 - 4.40 (m, 9 H) ; 7.10 - 7.90 (m, 9H) . ( (E)-3-( ( (lR)-l-( ( (lR)-l-(5-Carbamoyl-[l,3,4]oxadiazol-2-yl)-2- phenylethyl)methylcarbamoyl)-2-(2- naphthyl)ethyl)methylcarbamoyl)-1,1-dimethylallyl)carbamic aci tert-butylester: (2E)-4-tert-Butoxycarbonylamino-4-methylpent-2-enoicacid (143mg, 50.62mmol) was dissolved in dichloromethane (4ml). l-Hydroxy-7 azabenzotriazole (85mg, 0.62mmol) and subsequently N-(3 dimethylaminopropyl)-N ' -ethylcarbodiimide hydrochloride (119mg, 0.62mmol) were added. The solution was stirred for 15min at roo temp. 5-((lR)-l-(Methyl((2R)-2-methylamino-3-(2 0 naphthyl)propionyl)amino) -2-phenylethyl) -[1,3,4]oxadiazol-2 carboxylic acid amide (230mg, 0.52mmol) was added. The solutio was stirred for 5min and ethyldiisopropylamine (0.11ml, 0.62mmol) was given to the reaction mixture. It was stirred for 16h at roo temp., diluted with ethyl acetate (20ml) and extracted with wate 5 (20ml) . The phases were separated. The aqueous phase was extracte with ethyl acetate (2 x 10ml) . The combined organic layers wer washed with a saturated solution of sodium hydrogencarbonate an dried over magnesium sulfate. The crude product was purified b flash-chromatography on silica (40g) with dichloromethane/ethy 0 acetate 1:1 to give 126mg of ( (E)-3-( ( (IR)-l-( ( (IR)-1-(5 carbamoyl-[l,3,4]oxadiazol-2-yl)-2-phenylethyl)methylcarbamoyl)-2 (2-naphthyl)ethyl)methylcarbamoyl)-1,1-dimethylallyl)carbamic aci tert-butyl ester. Η-NMR (CDC1 3 ) : 6 1.1 - 1.5 (m, 15 H) ; 2.6 - 3.7 (m, 12H) . HPLC (Method b) : R t = 44.95 min. PDMS: 66δ.8 ([M] + ) ( (E)-3-( ( (IR)-1-(( (IR)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2- phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamoyl)- 1,1-dimethylallyl)carbamic acid tert-butylester (120mg, O.lδmmol) was dissolved in dichloromethane (3ml) . The solution was cooled to 0°C. Trifluoroacetic acid (3ml) was added dropwise. The reaction mixture was stirred for 5min at 0°C. The solvent was removed in vacuo without warming. The residue was dissolved in dichloromethane (5ml) and the solvent was removed in vacuo. This last procedure was repeated two times. The residue was dissolved in water (5ml) and IN hydrochloric acid (1ml, lmmol) was added. The solvent was removed in vacuo. The residue was dissolved in 3M hydrogen chloride in ethyl acetate (3ml) , and the solvent was removed in vacuo. This last procedure was repeated. The crude product was purified by HPLC-chromatography on a 25mm x 250mm 5μ Clδ silica column with a gradient of 28% to 38% acetonitrile in a 0.1M ammonium sulfate buffer, which was adjusted to pH 2.5 with 4M sulfuric acid to give 64mg of the title compound. HPLC (Method b) : R t = 30.133 min PDMS: 569.6 ([M+H] + ) Example 16 Piperidine-4-carboxylic acid N-methyl-N-(-1(methyl-[l-(3- methy1-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl)-2- (2-naphthyl)ethyl)amide: Prepared according to method E, N-Methyl-N- { ( lR) -l- { N-methyl-N- [ ( lR) -l- ( 3-methyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl)-2-(2- naphthyl)ethyl)carbamic acid tertbutylester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.34g, 7.0mmol) and l-hydroxy-7-azabenzotriazole (0.95g, 7.0mmol) were added to a solution of (R) N-methyl-N-tert-butoxycarbonyl-3- (2-naphthyl)alanine (2.31g, 7.0mmol) in N,N-dimethylformamide (50ml). After 30min at 20°C a mixture of (R) N-methyl-N-{l-(3- methyl-[ l,2,4]oxadiazol-5-yl)-2- (2-naphthyl) ethyl }amine hydrochloride (1.52g, S.Ommol) and triethylamine (0.51g, S.Ommol) in N,N-dimethylformamide (10ml) were added. After 18h at 20°C the reaction mixture was poured on water (250ml) and extracted several times with ethyl acetate (total 130ml) . The collected organic phases were washed with aqueous citric acid (10%, 50ml) , a saturated solution of sodium hydrogencarbonate (50ml) and water (3x50ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (llOg) using ethyl acetate and heptane (1:1) as eluent to give 2.4g of N-methyl-N-{ (lR)-l-{N-methyl-N-[ (IR)-l-(3-methyl- [1,2,4]-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl)-2-(2- naphthyl)ethyl)carbamic acid tert-butylester as a foam. HPLC: R t = 36.5 min (method a) (2R) -2-Methylamino-N-methyl-N-[ (IR) -1-(3-methyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2- naphthyl)propionamide, trifluoroacetic acid: N-Methyl-N-{ (lR)-l-{N-methyl-N-[ (lR)-l-(3-methyl- [1,2,4]oxadiazol-5-yl) -2-(2-naphthyl) ethyl]carbamoyl}-2-(2- naphthyl)ethyl)carbamic acid tert-butylester (2.4g, 4.2mmol) wa dissolved in a mixture of trifluoroacetic acid (40ml) an dichloromethane (40ml) at 20°C. After lOmin the reaction mixtur was concentrated in vacuo and coevaporated from heptane (80ml) an dichloromethane (80ml) . The residue was crystallised from ethy acetate to give 1.12gof (2R)-2-methylamino-N-methyl-N-[ (IR)-l-(3 methyl- [1,2,4] oxadiazol-5-yl) -2- (2-naphthyl) ethyl ] -3- (2 naphthyl)propionamide, trifluoroacetic acid. mp 184-188°C. Η-NMR (DMS0-d 6 ) δl.52(ε,3H) ; 2.32(s,3H) ; 2.68(s,3H) ; 3.03(dd,lH) 3.22 (dd, IH) ; 3.55(dd, IH) ; 4.62 (t, IH) ; 6.35(dd, IH) ; 7.25 7.95(m, 14H) . HPLC: R t = 24.9min (Method a) Calculated for C 30 H 30 N 4 O 2 , CF 3 C00H, 0.25EtOAc: C, 64.49; H, 5.41; N, 9.12%; found: C, 65.01; H, 5.35; N, 9.32%. 4-{N-Methyl-N-{ (IR)-1-[N-methyl-N-((IR)-1-(3-methyl- [1,2,4]oxadiazol-5-y1)-2-(2-naphthyl)ethyl)carbamoyl]-2-(2- naphthyl)ethyl)carbamoyl)piperidine-l-carboxylic acid tert-butyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.37g, 1.91mmol) and 1-hydroxybenzotriazole monohydrate (0.26g, 1.91mmol) were added to a solution of N-tert-butoxycarbonyl-4- piperidine carboxylic acid (0.44g, 1.91mmol) in N,N- dimethylformamide (5ml) . After 45 min at 20°C a mixture of (2R)-2- methylamino-N-methyl-N-[ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl)-3-(2-naphthyl) ]propionamide, trifluoroacetic acid (O.δlg, 1.37mmol) and triethylamine (0.19g, 1.37mmol) in N,N-dimethylformamide (10ml) were added. After 18h at 20°C the reaction mixture was poured on water (100ml) and extracted several times with ethyl acetate (total 70ml) . The organic phases were collected and washed with aqueous citric acid (10%, 20ml) , a saturated solution of sodium hydrogencarbonate (20ml) and water (3x20ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (80g) using ethyl acetate and heptane (3:2) as eluent to give 0.88g of 4-{N-methyl-N-{ (IR)-l-[N-methyl- N- ( (IR) -1- (3-methyl-[l, 2 , 4]oxadiazol-5-yl) -2- ( 2 - naphthy1)ethyl)carbamoyl]-2-(2- naphthyl)ethyl)carbamoyl)piperidine-l-carboxylic acid tert-butyl ester. HPLC: R t = 36.1 min (Method a) 4-{N-Methyl-N-{ (IR)-l-[N-methyl-N-( (IR)-1-(3-methyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl)carbamoyl]-2-(2- naphthyl)ethyl)carbamoyl)piperidine-l-carboxylic acid tert-butyl ester (0.88g, 1.28mmol) was dissolved in a mixture of trifluoroacetic acid (12ml) and dichloromethane (12ml) . After lOmin at 20°C the reaction mixture was concentrated in vacuo. The compound was chromatographed on silica (75g) using a 10% mixture of ammonia in ethanol and dichloromethane (1:9) as eluent to give 0.56g of two isomers of the title compound. HPLC: diastereoisomer I: R_ = 25.24 min (Method a) diastereoisomer II: R t = 25.26 min (Method a) Calculated for C 30 H 39 N 5 O 3 ,H 2 O: C, 71.15; H, 6.80; N, 11.52%; found: C, 71.27; H, 6.68; N, 11.28%. Example 17 Piperidine-4-carboxylic acid N-{l-(N-[methyl-N-[l-(3- methyl-[1,2,4]-oxadiazole-5-yl)-2-(2- naphthy1)ethyl]carbamoyl)-2-(2-naphthyl)ethyl)amide: Prepared according to method E. 4-( (IR)-l-{N-Methyl-N-[ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]carbamoyl)-2-(2- naphthyl)ethyl)carbamoylpiperidine-1-carboxylic acid tert-butyl¬ ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42g, 2.2mmol) and 1-hydroxybenzotriazole monohydrate (0.34g, 2.2mmol) were added to a solution of N-tert-butoxycarbonyl-4- piperidine carboxylic acid (0.50g, 2.2mmol) in N,N- dimethylformamide (5ml). After 30 min at 20°C a mixture of (2R)-2- amino-N-methyl-N-[ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid (0.9g, 1.54mmol) and triethylamine (0.16g, 1.54mmol) in N,N-dimethylformamide (10ml) were added. After 18h at 20°C the reaction mixture was poured on water (85ml) and extracted several times with ethyl acetate (total 90ml) . The organic phases were collected and washed with aqueous citric acid (10%, 15ml) , a saturated solution of sodium hydrogencarbonate (15ml) and water (3x15ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (llOg) using ethyl acetate and heptane (1:1) as eluent to give 0.50g of 4-( (IR)-l-{N-methyl-N-[ (lR)-l-(3- methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl)-2-(2- naphthyl)ethyl)carbamoylpiperidine-1-carboxylic acid tert-butyl - ester. 'H-NMR (DMSO-d 6 ) δ 2.40(s,3H); 2.95(s,3H); 3.45(dd,lH); 3.60(dd,lH); 4.85(m,lH); 6.08(m, IH) ; 7.10(d, IH) ; 7.40-7.90(m, 13H) . HPLC: R t = 34.0 min (Method a) 4-( (IR)-1-{N-Methyl-N-[ (IR)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]carbamoyl}-2-(2- naphthyl)ethyl)carbamoylpiperidine-1-carboxylic acid tert-butyl¬ ester (0.50g, 0.74mmol) was dissolved in a mixture of trifluoroacetic acid (10ml) and dichloromethane (10ml) . Afte lOmin at 20°C the reaction mixture was concentrated in vacuo. Th compound was chromatographed on silica (38g) using a 10% mixtur of ammonia in ethanol and dichloromethane (3:7) as eluent to give 0.26g of the title compound. 'H-NMR (DMSO-d 6 ) δ 3.45(dd,lH); 3.61(dd,lH); 4.72(m,lH); 6.10(dd, IH) ; 7.20(d, IH) ; 7.40-8.00(m, 14H) . HPLC: R t = 24.6 min (Method a) Calculated for C 35 H 37 N 5 O 3 ,0.5 H 2 0: C, 71.90; H, 6.55; N, 11.98%; found: C, 71.77; H, 6.52; N, 12.09%. Example 18: 5-{ 1- [N- (2- (piperidine-4-carbonylamino) -3- (2- naphthyl ) propionyl) -N-methyl amino] -2- (2 -naphthyl) ethyl ) - [l,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester: (R) 5-(l-Methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3- carboxylic acid (2-propyl)ester: (R) 5-(l-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3- carboxylic acid ethyl ester hydrochloride (1.64g, 4.5mmol) was suspended in 2-propanol (35ml) . After addition of tetraisopropyl titanate (1.3g, 4.5mmol) the reaction mixture was refluxed fo lδh. Hydrochloric acid (IN, 30ml) was added and the reactio mixture was extracted with ethyl acetate (150ml) . The organi phase was washed with a saturated aqueous solution of sodiu hydrogencarbonate (50ml) and water (3x50ml) . After dryin (magnesium sulfate) the solution was concentrated in vacuo to giv 1.3g of (R) 5-(l-methylamino-2-(2-naphthyl)ethyl)- [1,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester that was use for the next step without further purification. 'H-NMR (DMS0-d 6 ) δ 1.31(d,6H); 2.21(d,3H); 3.3(m,2H); 4.40(t,lH); 5.72(m,lH); 7.35-7.95(m, 7H) . HPLC: R t = 20.5 min (Method a) 5- { (IR) -1- [N- ( (2R) -2-tert-Butoxycarbonylamino-3- ( 2-naphthyl) - propionyl ) -N-methylamino ] -2- ( 2-naphthyl ) ethyl ) - [ 1 , 2 , 4 ] oxadiazole- 3 -carboxylic acid (2-propyl) ester: N-(3-Dimethylaminopropyl)-N*-ethylcarbodiimide hydrochloride (2.15g, 6.8mmol) and l-hydroxy-7-azabenzotriazole (0.93g, 6.8mmol) were added to a solution of (R) N-tert-butoxycarbonyl-3-(2-naphthyl)alanine (2.15g, 6.δmmol) in N,N-dimethylformamide (50ml) . After 30min at 20°C a solution of (R) 5-(l-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3- carboxylic acid (2-propyl)ester (1.65g, 4.9mmol) in N,N- dimethylformamide (15ml) was added. After 18h the reaction mixture was poured on water (500ml) and extracted several times with ethyl acetate (total 450ml) . The collected organic phases were washed with aqueous citric acid (10%, 75ml) , a saturated solution of sodium hydrogencarbonate (75ml) , water (3x75ml) and dried (magnesium sulfate) . The solution was concentrated in vacuo and the residue was chromatographed on silica (160g) using ethyl acetate and heptane (1:2) as eluent to give 2.4g of 5-{ (IR)-l-[N- ( (2R) -2-tert-butoxycarbonylamino-3-(2-naphthyl)propionyl-N- methylamino] -2- (2 -naphthyl ) ethyl ) - [ 1 , 2 , 4 ] oaxdiazole-3 -carboxylic acid ( 2 -propyl ) ester . HPLC: R t = 36.5 min (Method a) 5-{ (lR)-l-[N-( (2R)-2-Amino-3-(2- naphthyl) propionyl ) -N-methyl ami no ] -2- (2 -naphthyl) ethyl ) - [l,2,4]oxadiazole-3-carboxylic acid (2 -propyl) ester, trifluoro acetic acid: 5-{ (IR)-1-[N-( (2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)- propionyl)-N-methylamino]-2-(2-naphthyl)ethyl}- [l,2,4]oxadiazole-3-carboxylic acid (2-propylJester (2.1g, 3.3mmol) was suspended in a saturated mixture of trifluoroacetic acid and dichloromethane (1:1, 60ml). After lOmin at 20°C, the reaction mixture was concentrated in vacuo to give 2.2g of 5- { (IR)-l-[N-( (2R)-2-amino-3-(2-naphthyl)propionyl)-N-methylamino]- 2-(2-naphthyl)ethyl)-[l,2,4]oxadiazole-3-carboxylic acid (2- propyl)ester, trifluoroacetate, that was used for the next ste without further purification. 4-( (IR)-1-{N-[ (IR)-1-(3-(2-propoxy)carbonyl-[1,2,4]oxadiazol-5- yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)- ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.22g, 6.35mmol) and 1-hydroxybenzotriazole monohydrate (0.97g, 6.35mmol) were added to a solution of N-tert-butoxycarbonyl-4- piperidinecarboxylie acid (1.46g, 6.35mmol) in N,N- dimethylformamide (20ml) . After 30min at 20°c a solution of 5- { (IR)-1-[N-(2R)-2-amino-3-(2-naphthyl)propionyl)-N-methylamino]-2- (2-naphthyl)ethyl)-[l,2,4]oxadiazole-3-carboxylic acid (2- propyl)ester (2.95g, 4.53mmol) and triethylamine (0.47g, 4.53mmol)in N,N-dimethylformamide (20ml) was added. After 18h at 20°C the reaction mixture was poured on water (240ml) and extracted several times with ethyl acetate (total 240ml) . The organic phases were collected and washed with aqueous citric acid (10%, 35ml), a saturated solution of sodium hydrogencarbonate (35ml) and water (3x35ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (llOg) using ethyl acetate and heptane (1:1) to give 2.6g of 4-( (IR)-l-{N-( [ (IR)-l-(3-(2- propoxy)carbonyl-[l,2, 4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl] carbamoyl)-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxyli acid tert-butyl ester. 'H-NMR (DMSO-d 6 ) δ HPLC: R t = 35.9 min (Method a) 4-((IR)-1-(N-([ (IR)-1-(3-(2-Propoxy)carbonyl-[1,2,4]oxadiazol-5 y1)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2- naphthyl)ethylcarbamoyl)piperidine-l-carboxylic acid tert-buty ester (l.Og, 1.34mmol) was dissolved in a mixture trifluoroaceti acid and dichloromethane (1:1, 25ml). After 10 min at 20°C th reaction mixture was concentrated in vacuo. The compound wa purified by flash chromatography with silica gel (75g) using mixture of dichloromethane and 10% ammonia in ethanol (9:1) a eluent to give 0.77g of the title compound. Η-NMR (DMSO-d 6 ) δ . Example 19: 5-{1-[N-(2-(piperidine-4-carbonylamino)-3-(2- naphthyl) propionyl) -N-methylamino] -2- (2-naphthyl) ethyl } [l,2,4]oxadiazole-3-carboxylic acid, trifluoro acetate: Prepared according to method E. 4-(1-{ [1-(3-Carboxy-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]-N-methylcarbamoyl)-2-(2-naphthyl)- ethylcarbamoyl)piperidine-l-carboxylie acid tert-butylester 4-( (IR)-1-{ [ (IR)-1-(3-Ethoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]-N-methylcarbamoyl)-2-(2-naphthyl)- ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester(0.79g, 1.06mmol) was dissolved in dioxane (5.5ml). Water (3ml) and solid lithium hydroxide (0.03g) was added. After lδh at 20°C the reaction mixture was diluted with water (15ml) and extracted with tert-butyl-methylether (2x10ml) . The aqueous phase was acidified with IN aqueous sodium hydrogenphosphate (2.5ml) and extracted with tert-butyl-methylether (3x4Oml) . The collected organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was chromatographed on silica (60g) using a mixture of dichloromethane and 10% ammonia in ethanol (4:1) as eluent to give 0.41g of 4-(l-{ [1-(3-carboxy-[l,2,4]oxadiazol-5- yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2- (2-naphthyl)-ethylcarbamoyl)piperidine-1-carboxylic acid tert- butylester. Η-NMR (DMSO-d 6 ) δ . 4-(1-{ [1-(3-Carboxy-[1,2,4]oxadiazol-5-yl)-2- (2-naphthy1)ethyl]-N-methylcarbamoyl)-2-(2-naphthyl)- ethylcarbamoyl)piperidine-1-carboxylic acid tert-butylester (0.41g, O.Sδmmol) was dissolved in a mixture trifluoroacetic acid and dichloromethane (1:1, 12ml). After 10 min at 20°C the reaction mixture was concentrated in vacuo to give 0.4g of the title compound as a crude product. PDMS: (teor. MH + = 606.7; found MH + = 605.9) Example 20: Piperidine-4-carboxylic acid (l-{N-[l-(3-methylcarbamoyl- [1,2,4] oxadiazol-5-yl ) -2 - ( 2 -naphthyl ) ethyl ] -N-methylcarbamoyl } -2- ( 2 -naphthy 1 ) ethyl ) amide : Prepared according to method E. 4-(1-(N-[1-(3-Methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthyl)ethyl]-N-methylcarbamoyl)-2-(2- naphthyl)ethylcarbamoyl)piperidine-l-carboxylic acid tertbutyl- ester: 4-( (IR)-l-{N-[ (IR)-1-(3-Propoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2- (2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2- naphthyl)ethylcarbamoyl)piperidine-1-carboxylie acid tert-butyl ester (O.δOg, 1.07mmol) was dissolved in 33% methylamine in ethanol and stirred at 90°C for lδh in a closed reaction vessel. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica (60g) using ethyl acetate and heptane (7:3) as eluent to give 0.15g of 4-(l-{-N-[l-(3- methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)- ethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)piperidine- 1-carboxylic acid tert butyl ester. HPLC: R L = 31.5 min (Method a) 4-(1-(N-[1-(3-Methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthyl)-ethyl]-N-methylcarbamoyl}-2-(2- naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert but ester (0.15g, 0.21mmol) was dissolved in a mixture trifluoroacetic acid and dichloromethane (1:1,4ml). After Smin 20°C the reaction mixture was concentrated in vacuo. The compou was purified by flash chromatography with silica gel (40g) usi a mixture of dichloromethane and 10% ammonia in ethanol (9:1) eluent to give 0.08g of the title compound. HPLC: R t = 20.9 min (Method a) Example 21 : (2E)-5-Amino-5-methylhex-2-enoic acid {l-[N-(l-(3- benzylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl)-N-methyl¬ carbamoyl]-2-(2-naphthyl)ethyl}amide: (R) 5-(l-Methylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid benzylamide: (R) 5-(l-Methylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethylester (3.3g, 9.0mmol) was dissolved in ethanol (30ml). Benzylamine (3ml) was added and the reaction mixture was stirred for lδh at 20°C. The reaction mixture was concentrated in vacuo and the residue was crystallised from ethanol to give 2.07g of (R) 5-(l-methylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid benzylamide. m.p. 128-126.5°C 'H-NMR (DMSO-d 6 ) δ 2.22 (s, 3H) ; 3.08 (dd, IH) ; 3.18 (dd, IH) 4.26 (t, IH) ; 4.45 (d, 2H) ,* 7.10-7.45 (m, IH) ; 9.50 (t, IH) . HPLC: R t = 17.3 min (Method a) Calculated for C 19 H 20 N 4 O 2< 0.25 EtOH: C, 67.32; H, 6.23; N, 16.10%; found: C, 67.35; H, 6.03; N, 16.25%. ( (IR)-1-{N-Methyl-N-[ (IR)-1-(3-benzylcarbamoyl-[1,2,4]oxadiazol- y1) -2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamic acid tert-butyl ester: N-(3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochlori (1.64g, 8.57mmol) and l-hydroxy-7-azabenzotriazole (1.17 δ.57mmol) were added to a solution of (R) N-tert-butoxycarbonyl- (2-naphthyl) alanine (2.70g, 8.57mmol) in N,N-dimethylformami (40ml). After 20min at 20°C a solution of (R) 5-(l-methylamino- phenylethyl) -[1,2,4]oxadiazole-3-carboxylic acid benzylamide (2.06g, 6.12mmol) in dimethylformamide (40ml) was added. After 1 at 20°C the reaction mixture was poured on water (250ml) a extracted several times with ethyl acetate (total 200ml) . T collected organic phases were washed with aqueous citric acid (10%, 50ml), a saturated solution of sodium hydrogencarbonate (3x50ml) and water (3x50ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (150g) using ethyl acetate and heptane (1:1) as eluent to give 3.9 of { (IR)-l-{N-methyl-N-[ (lR)-l-(3- benzylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamoyl)-2- (2-naphthyl)ethyl)carbamic acid tertbutyl ester. 2-Amino-N-methyl-N-[1-(3-benzylcarbamoyl- [1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide, trifluoro acetic acid: { (IR)-1-(N-methyl-N-[ (IR)-1-(3-benzylcarbamoyl-[1,2,4]oxadiazol-5- yl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (3.9g, 6.15mmol) was dissolved in a mixture of trifluoroacetic acid (40ml) and dichloromethane (40ml) at 20°C. After lOmin the reaction mixture was concentrated in vacuo and coevaporated from heptane and then from dichloromethane to give 4g of two isomers of crude 2-amino-N-methyl-N-[l-(3- benzylcarbamoyl-[1,2,4]oxadiazol-5-yl) -2-phenylethyl]-3-(2- naphthyl)propionamide, trifluoro acetic acid that was used for t next step without further purification. 'H-NMR (DMSO-d 6 ) δ 2.88 (s) ; 3.21 (s) ; 3.32 (m) ; 3.55 (m) ; 4.5 (m) ; 5.95 (m) ; 6.21 (m) . HPLC: isomer I: R t = 24.2 min (Method a) isomer II: R t = 25.4 min (Method a) [ (2E) -1, 1-Dimethy 1-4- (l-{ N-methyl -N-[l-( 3 -benzylcarbamoy 1 [l,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamoyl}-2-(2 naphthyl ) ethylcarbamoyl ) but-3 -eny 1 ] carbamic acid tert-butylester : N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlori (0.40g, 2.1mmol) and 1-hydroxybenzotriazole monohydrate (0.32 2.1mmol) were added to a solution of (2E)-5-(ter butoxycarbonylamino)-5-methylhex-2-enoic acid (0.51g, 2.1mmol) N,N-dimethylformamide (5ml) . After 30 min at 20°C a mixture of 2-amino-N-methyl-N-[1-(3-benzylcarbamoy1-[1,2,4]oxadiazol-5-yl)- phenylethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid (l.Og, 1.5mmol) and triethylamine (0.15g, 1.5mmol) in N, dimethylformamide (12ml) were added. After 18h at 20°C t reaction mixture was poured on water (100ml) and extracted several times with ethyl acetate (total 65ml) . The organic phases were collected and washed with aqueous citric acid (10%, 20ml), a saturated solution of sodium hydrogencarbonate (20ml) and water (3x20ml) . After drying (magnesium sulfate) the solution was concentrated in vacuo and the residue was chromatographed on silica (85g) using ethyl acetate and heptane (1:1) as eluent to give 0.77g of two isomers of [ (2E)-1,l-dimethyl-4-(l-{N-methyl-[1- (3-benzylcarbamoyl- [ 1 , 2 , 4 ] oxadiazol-5-yl) - 2 - phenylethyl]carbamoyl)-2-(2-naphthyl)ethylcarbamoyl)but-3- enyl]carbamic acid tert-butylester. HPLC: Isomer I: R t = 34.1 min (Method a) Isomer II: R t = 34.4 min (Method a) [ (2E)-1,l-Dimethyl-4-(1-{N-methyl-N-[1-(3-benzylcarbamoy1- [1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamoyl}-2-(2- naphthyl)ethylcarbamoyl)but-3-enyl]carbamic acid tert-butylester (0.77g, l.Ommol) was dissolved in a mixture trifluoroacetic acid (2ml) and dichloromethane (2ml) . After lOmin at 20°C the reaction mixture was diluted with dichloromethane (25ml) and neutralised with a saturated aqueous solution of sodium hydrogencarbonate. The organic phase was dried (magnesium sulfate) and concentrated in vacuo to give 0.7g of two isomers of the title compound. HPLC: Isomer I: R t = 24.5 min (Method a) Isomer II: R t = 25.3 min (Method a) Example 22: (2E)-5-Amino-5-methylhex-2-enoic acid N-{ (lR)-l-[N-( (1R)- benzyl-2 , 5-dihydroxypentyl) -N-methylcarbamoyl ] -2- ( 2 naphthyl ) ethyl ) -N-methylamide : Prepared according to method J. N-( (IR)-l-Formyl-2-phenylethyl)-N-methylcarbamic acid ter butylester: Oxalyl chloride (4.24 mL, 48.61 mmol) was dissolved dichloromethane (30 mL) . The solution was cooled to -63 °C. solution of DMSO (4.6 mL, 64.81 mmol) in dichloromethane (20 m was added dropwise. The solution was stirred for 5 min and solution of N-( (IR) -l-(hydroxymethyl) -2-phenylethyl)-N- methylcarbamic acid tert-butylester (8.6 g, 32.41 mmol) in dichloromethane (200 mL) was added dropwise over a period of 30 min. The reaction mixture was stirred for 20 min at -63 °C . A solution of triethylamine (18.07 mL, 129.62 mmol) in dichloromethane (40 L) was added over a period of 25 min. The solution was warmed to -35 °C and immediately cooled to -63 °C. It was stirred at this temp, for 1 h. Acetic acid (8.15 mL, 142.58 mmol) was added. The reaction mixture was warmed to 10 °C and washed with water (2 x 200 mL) and satd. sodium hydrogencarbonate solution (150 mL) . The org. phase was dried over magnesium sulfate. The solvent was removed in vacuo to give 7.536 of N- ((IR)-l-formyl-2-phenylethyl)-N-methylcarbamic acid tert- butylester Η-NMR (CDC1 3 ) : δ = 1.40 and 1.44 (both s, together 9H) ; 2.52 and 2.58 (both s, together 3H) ; 2.90 and 3.00 (both dd, together IH) ; 3.81 (dd, IH) ; 4.00 and 4.20 (both dd, together IH) ; 7.10 - 7.35 (m, 5H) . N-((lR)-l-Benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert- butylester N-( (IR)-l-Formyl-2-phenylethyl)-N-methylcarbamic acid tert butylester (6.0 g, 20.0 mmol) was dissolved in ether (150 mL) . Th solution was cooled to -78 °C and allylmagnesium bromide (22 mL o a 1.0 M solution in ether, 22 mmol) was added dropwise. Afte addition, the solution was warmed to room temp. It was given ont 10% ammonium chloride solution in water (200 mL) . The phases wer separated. The aqueous phase was extracted with ethyl acetate ( x 50 mL) . The organic layers were combined and washed with satd sodium hydrogencarbonate solution (100 mL) and dried ove magnesium sulfate. The solvent was removed in vacuo. The crud product was purified by flash chromatography on silica (260 g with ethyl acetate/heptane 1:1 to give 4.00 g of N-( (IR)-1-benzyl 2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester. 'H-NMR (CDC1 3 ) : δ = 1.10 - 1.50 (m, 9H) ; 1.90 - 3.40 (m, 8H) ; 3.5 - 4.10 (m, 2H) ; 5.00 - 5.30 (m, 2H) ; 5.90 (m, IH) ; 7.10 - 7.40 (m 5H) . ( (lR)-l-Benzyl-2,5-dihydroxypentyl)methyl carbamic acid tert butylester N-( (lR)-l-Benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert- butylester (3.95 g, 11.60 mmol) was dissolvend in THF (90 mL) and added to a solution of 9-borabicyclo[3.3.l]nonane (46.64 mL of a 0.5M solution in THF, 23.32 mmol) in THF (90 mL) . The solution was heated to reflux for 16 h. The mixture was cooled to room temp. Ethanol (22 mL) was added dropwise. 6N Sodium hydroxide solution in water (6.6 mL, 39,44 mmol) and subsequently hydrogen peroxide (35% solution in water) were added slowly. The reaction mixture was heated to reflux for 1 h and cooled to room temp. It was given onto IN sodium hydroxide solution (200 mL) . The phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with a 37% solution of sodium hydrogensulfite (150 mL) . The solution was dried over magnesium sulfate. It was washed with a 37% solution of sodium hydrogensulfite (200 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL) , washed with 37% solution of sodium hydrogensulfite (200 mL) and dried over magnesium sulfate. The crude product was chromatographed on silica (180 g) with ethyl acetate and subsequently on silica (100 g) with dichloromethane/methanol/25% aqueous ammonia 100:10:1 to give 586 mgof ((IR)-l-benzyl-2,5-dihydroxypentyl)methylcarbamicacidtert- butylester MS (El): 365 (20%; [M+l] + ) 'H-NMR (CDC1 3 ) : δ - 1.22 and 1.40 (both s, together 9H) ; 1.60 - 1.90 (m, 5H) ; 2.50, 2.60, and 2.73 (all s, together 3H);2.80 - 4.00 (m, 7H) ; 7.10 - 7.35 (m, 5H) . (5R) -4-Hydroxy-5-(methylamino)-6-phenylhexyl acetate ( (IR) -l-Benzyl-2, 5-dihydroxypentyl)methylcarbamic acid tert- butylester (560 mg, 1.52 mmol) was dissolved in ethyl acetate (10 L) . 3M Hydrogen chloride in ethyl acetate (2.0 L, 6.08 mmol) was added. The solution was stirred at room temp, for 1 h. It was diluted with ethyl acetate (10 mL) and extracted with IN sodium hydroxide solution (30 mL) . The aqueous phase was extracted with ethyl acetate (3 x 10 mL) . The combined organic phases were dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (5 mL) . The solution was cooled to 0 °C. Trifluoroacetic acid (5 mL) was added. The solution was stirred at this temp, for 5 min. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate (10 mL) . The solution was extracted with IN sodium hydroxide solution (10 mL) . The aqueous phase was extracted with ethyl acetate (2 x 5 mL) . The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g) with dichloromethane/methanol/25% aqueous ammonia 100:10:1 to give 136 mg of (5R)-4-hydroxy-5-(methylamino) -6-phenylhexyl acetate. 'H-NMR (CDC1 3 ) : δ = 1.50 - 2.05 (m, 4H) ; 2.07 (s, 3H) ; 2.30 (s, 3H) ; 2.55 (dd, IH) ; 2.65 (td, IH) ; 2.82 (dd, IH) ; 3.75 (td, IH) ; 4.15 (m, 2H) ; 7.15 - 7.35 (m, 5H) . HPLC (method B) : 17.87 min (85%) (5R)-5-({ (2R)-2-[((2E)-5-Amino-5-methylhex-2-enoyl)methylamino]-3- (2-naphthyl)propionylJmethylamino)-4-hydroxy-6-phenylhexyl acetate (5R)-4-Hydroxy-5-(methylamino)-6-phenylhexyl acetate (126 mg, 0.475 mmol), (2R)-2-(tert-butoxycarbonylmethylamino)-3-(2- naphthyl)propionic acid (313 mg, 0.95 mmol and l-hydroxy-7- azabenzotriazole (65 mg, 0.475 mmol) was dissolved in dichloromethane/dimethylformamide 2:1 (9 ml) at 0 °C. N-ethyl-N'- (3-dimethylaminopropyl)carbodiimide hydrochloride (91 mg, 0.475 mmol) was added and the the mixture stirred at 0 °C for h and then at room temp, for 48h. The dichloromethane was evaporated from the mixture using a stream of nitrogen and ethyl acetate (50 ml) was added. The resulting solution was extracted sequentially with 5% aqueous sodium hydrogencarbonate (50 ml) , water (50 ml) , 5% aqueous potassium hydrogen sulphate (50 ml) and water (50 ml) . The resulting organic phase was dried with sodium sulfate and concentrated in vacuum on a rotary evaporator to dryness. This dry material was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and allowed to react for 10 min and then concentrated to an oil using a stream of nitrogen and th resulting oil was dissolved in 70% acetonitrile (1 ml) . 1 hydrochloric acid (3 ml) and water (47 ml) were added and th resulting mixture was immediately frozen and lyophilized. This lyophilized product was dissolved in dichloromethane/ dimethylformamide 2:1 (9 ml) and (2E)-5-tert butyloxycarbonylamino-5-methylhex-2-enoic acid (231 mg, 0.95 mmol and l-hydroxy-7-azabenzotriazole (129 mg, 0.95 mmol) was added The mixture was cooled to 0°C, N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (91 mg) and diisopropylethylamine (8 μl, 0.475 mmol) was added and the mixture was stirred for lh a 0 °C and for 18 h at room temp. The dichloromethane was evaporate from the mixture using a stream of nitrogen and ethyl acetate (5 ml) was added. The resulting solution was extracted sequentiall with 5% aqueous sodium hydrogencarbonate (50 ml) , water (50 ml) 5% aqueous potassium hydrogen sulfate (50 ml) and water (50 ml) The resulting organic phase was dried with sodium sulfate an concentrated in vacuum on a rotary evaporator to dryness. The dry material was dissolved in dichloromethane (2 ml) an trifluoroacetic acid (2 ml) and allowed to react for 10 min an then concentrated to an oil using a stream of nitrogen. Th resulting oil was dissolved in 70% acetonitrile (5 ml) and wate (45 ml) . 15 ml Of the solution of crude (5R)-5-(( (2R)-2-[ ( (2E)-5-amino-5 m e t h y l h e x - 2 - e n o y l ) m e t h y l a m i n o ] - 3 - ( 2 naphthyl)propionyl)methylamino)-4-hydroxy-6-phenylhexyl acetat was cooled to 0 °C and 1M sodium hydroxide (15ml) was adde dropwise under stirring. After stirring 10 min at 0 °C acetic aci (2 ml) and water (50 ml) were added. The product was isolated fro this solution by semipreparative HPLC in three runs on a 25 mm 250 mm column packed with 7μ C-18 silica which was preequilibrat with 28% acetonitrile in 0.05M ammonium sulfate, which wa adjusted to pH 2.5 with 4M sulfuric acid. The column was eluted with a gradient of 28% - 38% acetonitrile in 0.05M ammonium sulfate, pH 2.5 at 10 ml/min during 47 min at 40 °C and the peptide containing fractions were collected, diluted with 3 volumes of water and applied to a Sep-Pak* C18 cartridge (Waters part. #:51910 ) which was equilibrated with 0.1% trifluoroacetic acid . The peptide was eluted from the Sep-Pak* cartridge with 70% acetonitrile 0.1% trifluoroacetic acid and isolated from the eluate by lyophilisation after dilution with water. The final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass) . Mass spectrometry which was performed using a Bio-Ion 20 time-of-flight instrument (Bio-Ion Nordic AB, Uppsala Sweden) . The result agreed with the expected structure (M+H found = 560.2,M+H theory = 560.6 ). The RP-HPLC analysis was performed using UV detection at 214 nm and a Vydac 218TP54 4.6mm x 250mm 5μ C-18 silica column (The Separations Group, Hesperia) which was eluted at 1 ml/min at 42 °C. Two different elution conditions were used: Al: The column was equilibrated with 5% acetonitrile in a buffer consisting of 0.1M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuric acid and eluted by a gradient of 5% to 60% acetonitrile in the same buffer during 50 min. Bl: The column was equilibrated with 5% acetonitrile / 0.1% trifluoroacetic acid / water and eluted by a gradient of 5% acetonitrile / 0.1% trifluoroacetic acid / water to 60% acetonitrile / 0.1% trifluoroacetic acid / water during 50 min. The retention time using elution conditions Al and Bl was found to be 30.08 min and 31.78 min, respectively. Example 23: 3-Aminomethyl-N- ( (IR) -1-{N- [ (IR) -1- (2 -hydroxyethoxymethyl) -2- phenylethyl ] -N-methylcarbamoyl ) -2- ( 2 -naphthyl) ethyl) -N- methy lbenzamide Prepared according to method K N- ( (IR) -1- (2 -Hydroxyethoxymethyl) -2 -phenylethyl) -N-methylcarbami acid tert-butylester: ( (2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropoxy)aceti acid ethyl ester (0.50 g, 1.42 mmol) was dissolved in THF (4 mL) . Lithium boronhydride (1.56 mL of a 2.0 M solution in THF, 3.1 mmol) was added dropwise. Ethanol (8 mL) was added. The reactio mixture was stirred 16 h at room temp. The solution was acidifie with 10% citric acid to pH = 4. The solvent was removed in vacuo. The residue was dissolved in water (50 mL) . This solution was extracted with dichloromethane (3 x 40 mL) . The combined organic layers were dried over magnesium sulfate. The solvent was removed 5 in vacuo. The crude product was purified by flash chromatography on silica (30 g) with dichloromethane/ethyl acetate 1:1 as eluent to give 0.29 g of N-((IR)-l-(2-hydroxyethoxymethyl)-2- phenylethyl)-N-methylcarbamic acid tert-butylester 'H-NMR (CDC1 3 ) : δ = 1.32 and 1.41 (both s, together 9H) ; 2.50 - 102.85 (m, 5H) ; 3.40 - 3.80 (m, 6H) ; 4.40 and 4.60 (both br, together IH) ; 7.10 - 7.35 (m, 5H) . 2-( (2R)-2-Methylamino-3-phenylpropoxy)ethanol N-((IR)-l-(2-Hydroxyethoxymethyl)-2-phenylethyl)-N-methylcarbamic 15 acid tert-butylester (0.29 g, 0.90 mmol) was dissolved in dichloromethane (3 mL) . Trifluoroacetic acid (1 mL) was added. The solution was stirred at 0 °C for 15 min. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (10 mL) and extracted with IN sodium hydroxide (10 mL) . The organic phase was 20 dried over magnesium sulfate. The solvent was removed in vacuo to give 0.11 g of crude 2-( (2R) -2-methylamino-3- phenylpropoxy)ethanol, which was used for further syntheses. HPLC (method b) : 9.10 min. 'H-NMR ( CDC1 3 ) : δ = 2 . 48 ( s , 3H) ; 2 . 75 (dd , IH) ; 2 . 80 - 3 . 00 (m 2H) ; 3 . 40 (dd , IH) ; 3 . 45 - 3 . 65 (m , 3H) ; 3 . 65 - 3 . 80 (m , 2H) ; 7 . 1 - 7 . 35 (m, 5H) . 2-( (2R)-2-Methylamino-3-phenylpropoxy)ethanol (91mg, 0.435mmol) (2R)-2-(tert-butoxycarbonylmethylamino)-3-(2- naphthyl)propionic acid (215 mg, 0.653 mmol)and l-hydroxy-7-aza benzotriazole (HOAT) (89 mg, 0.653 mmol) was dissolved i dichloromethane (10 ml) and N,N-Dimethylfermamide (5 ml) . Afte cooling to 0 °C N-(3-dimethylaminopropyl)-N ' -ethylcarbodiimid hydrochloride (125 mg, 0.653 mmol) was added and after stirrin 30 min at 0 °C diisopropylethylamine (75 μl, 0.435 mmol) was added After stirring at room temp, the dichloromethane was removed b a stream of nitrogen and ethyl acetate (25 ml) was added. Th mixture was extracted with 5% sodium hydrogencarbonate (2 x 2 ml) , 5% potassium hydrogensulfate and water (25 ml) . The organi phase was dried over sodium sulfate andd concentrated in vacuu to give N-( (IR) -1-(N-( (IR) -1-(2-hydroxyethoxymethyl)-2 phenylethyl) -N-methylcarbamoyl) -2- (2-naphthyl) ethyl) -N methylcarbamic acid tert-butylester as a dry residue (240 mg) . Half of this N-( (lR)-l-(N-((lR)-l-(2-hydroxyethoxymethyl)-2 phenylethyl) -N-methylcarbamoyl) -2- (2-naphthyl) ethyl) -N methylcarbamic acid tert-butylester (120 mg, 0.230 mmol) wa dissolved in dichloromethane (1 ml) and trifluoroacetic acid ( ml) and allowed to react for 10 min and then concentrated to a oil using a stream of nitrogen and the resulting oil was dissolve in 70% acetonitrile (1 ml) . I N hydrochloric acid (1 ml) and wate (50 ml) was added and the resulting mixture was immediately froze and lyophilized. This lyophilized product was dissolved in dichloromethane (5 ml and a solution of 3-(tert-butoxycarbonylaminomethyl)benzoic aci (503 mg, 2.0 mmol) and N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (192 mg, 1 mmol) in dichloromethane ( ml) which had been allowed to react at 0 °C for 15 min was added. Finally diisopropylethylamine (171 μl, 1.0 mmol) was added and the mixture was stirred for 72 h at room temp. The dichloromethane was evaporated from the mixture using a stream of nitrogen and ethyl acetate (25 ml) was added. The resulting solution was extracted sequentially with 5% aqueous sodium hydrogencarbonate (2 x 25 ml) , water (25 ml) , 5% aqueous potassium hydrogensulfate (25 ml) and water (25 ml) . The resulting organic phase was dried with sodium sulfate and concentrated in vacuum on a rotary evaporator to dryness. The dry material was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and allowed to react for 10 min and then concentrated to an oil using a stream of nitrogen. The resulting oil was dissolved in 70% acetonitrile (5 ml) and water (400 ml) . Analytical HPLC using conditions Al (described below) showed the prescence of two major peaks with the retention times 28.82 min and 35.67 min a minor peak at 29.98 min. Plasma desorption mass spectrometry of collected fractions. Mass spectrometry which was performed using a Bio-Ion 20 time-of-flight instrument (Bio-Ion Nordic AB, Uppsala Sweden) , indicated that the minor product was the desired product. The result agreed with the expected structure (M+H found ■ = 553.0, M+H theory = 554.7 ). The other two product resulted from acylations during synthesis of the hydroxy group left unprotected. All three compounds were isolated by semipreparative HPLC in four runs on a 25 mm x .250 mm column packed with 7μ C-18 silica which was preequilibrated with 37% acetonitrile in 0.05M ammonium sulphate, which was adjusted to pH 2.5 with 4M sulphuric acid. The column was eluted with a gradient of 37% - 44% acetonitrile in 0.05M ammonium sulfate, pH 2.5 at 10 ml/min during 47 min at 40 °C and each of the product containing fractions were collected, diluted with 3 volumes of water and applied to Sep-Pak* C18 cartridges (Waters part. #:51910 ) which were equilibrated with 0.1% trifluoroacetic acid . The products were eluted from the Sep- Pak* cartridges with 70% acetonitrile 0.1% trifluoroacetic aci and isolated from the eluate by lyophilisation after dilution wit water. The compounds corresponding to the two major peaks were saponifie to reverse the undesired acylations in order to increase the yiel of the target compound. The compounds were dissolved in 1.5 m 0.066 N sodium hydroxide for 15 min followed by neutralisatio with 1 ml IN hydrochloric acid. Then the target compound wa isolated by semipreparative HPLC using a procedure similar to th one described above. The final product obtained was characterised by analytical RP-HPL (retention time) . The RP-HPLC analysis was performed using U detection at 214 nm and a Vydac 218TP54 4.6mm x 250mm 5μ C-1 silica column (The Separations Group, Hesperia) which was elute at 1 ml/min at 42 °C. Two different elution conditions were used Al: The column was equilibrated with 5% acetonitrile in buffer consisting of 0.1M ammonium sulfate, which wa adjusted to pH 2.5 with 4M sulfuric acid and eluted b a gradient of 5% to 60% acetonitrile in the same buffe during 50 min. Bl: The column was equilibrated with 5% acetonitrile / 0.1 trifluoroacetic acid / water and eluted by a gradien of 5% acetonitrile / 0.1% trifluoroacetic acid / wate to 60% acetonitrile / 0.1% trifluoroacetic acid / wate during 50 min. The retention time using elution conditions Al and Bl was foun to be 29.87 min and 34.28 min, respectively. Example 24 : Piperidine-4-carboxylic acid ( (lR,2E)-4-hydroxymethyl-5-(2-naph- thyl)-l-( (2-naphthyl)methyl)pent-2-enyl)amide ( (lR)-4-(tert-Butyldimethylsilanyloxymethyl)-l-( (2- naphthyl)methyl)-5-(2-naphthyl)pent-2-enyl)carbamic acid tert- butylester This compound was prepared as in example 9. ( (IR) -l-benzenesulfo nylmethyl-2- (2-naphthyl) ethyl) carbamic acid tert-butylester (3.7 g; 8.74 mmol) and 2-(tert-butyldimethylsilanyloxymethyl)-3-(2 naphthyl)propionaldehyde (4.3 g; 13.11 mmol) were used as startin materials. Chromatography was carried out usin diethylether/heptane 1:3 as eluent on silica (5 x 25 cm) to affor 2.20 g of ( (lR)-4-(tert-butyldimethylsilanyloxymethyl)-l-( (2 naphthyl ) methyl) -5- (2 -naphthyl )pent-2 -enyl) carbamic acid tert butyl ester as a mixture of isomers. 'H-NMR (CDC1 3 ) (selected peaks) δ 0.0-0.05 (four s, 6H) , 0.85-0.9 (four s, 9H) , 1.30-1.40 (three s, 9H) , 5.2-5.5 (m, 2H) (3E,5R) 5-Amino-6-(2-naphthyl)-2-( ( 2 -naphthyl) methyl )hex-3-en-l-o ( (IR) -4-(tert-Butyldimethylsilanyloxymethyl) - 1- ( ( 2 naphthyl ) methyl ) -5- (2-naphthyl)pent-2-enyl) carbamic acid tert butylester (2.20 g; 3.60 mmol) was dissolved in a mixture o acetonitrile (100 ml) and an aqueous solution of hydrogen fluorid (48%, 4.5 ml). After stirring for 3 h a mixture of ethyl acetate (200 ml) and aqueous sodium carbonate (10%, 200 ml) was added. The phases were separated and the organic phase was dried (Magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (4 x 38 cm) using a mixture of ethyl acetate (85%) , ethanol (14%) and cone, aqueous ammonia (1%) as eluent. Two close spots were separated this way. The one that eluted first was clean on HPLC whereas the following contained several isomers. The first fraction had E-geometry and 220 mg of (3E,5R)-5-amino-6-( (2- naphthyl)-2-(2-naphthyl)methyl)hex-3-en-l-ol were taken to the next step. 'H-NMR (CDC1 3 ) δ 1.45 (s(br), 3H) ; 2.55-2.92 ( , 5H) ; 3.35-3.68 (m, 3H) ; 5.37 (dd, part of ABX-syst., J^lδHz, J 2 =7Hz, IH) , 5.52 (dd, part of ABX-syst., J^lδHz, J 2 =5Hz, IH) , 7.15-7.84 (m, 14 H) . (N-tert-Butyloxycarbonyl-piperidine-4-carboxylic acid ( (1R,2E) (4-hy-droxymethyl) -5-(2-naphthyl)-l-( (2- naphthy1)methyl)pent-2-enyl)amide N-tert-Butyloxycarbonylpiperidine-4-carboxylic acid (378 mg; 0.99 mmol) and EDAC (198 mg; 1.038 mmol) were dissolved in methylen chloride (15 ml) and stirred for 15 min. (3E,5R)-5-Amino-6-(2 naphthyl)-2-( (2-naphthyl)methyl)hex-3-en-l-ol (180mg; 0.472 mmol was added and the mixture was stirred for 6 h. The organic phas was washed with sodium hydrogensulfate (10%, 10 ml) and sodiu hydrogencarbonate (satd., 15 ml), dried (Magnesium sulfate). Th solvent was removed in vacuo and the residue was chromatogrape on silica (30 x 2.5 cm) using ethyl acetate/heptane 1:1 as eluen to afford 220 mg of N-tert-butyloxycarbonylpiperidine-4-carboxyli acid ( (IR,2E)-4-(hydroxymethyl)-5-(2 (-naphthyl)-1-(2 -naphthyl)methyl)-pent-2-eny1)amide 'H-NMR (CDC1 3 ) : δ: 1.35-1.55 (m, (s at 1.45); 15 H) ; 1.93-2.01 (m IH) ; 2.55-2.68 (m, 4H) ; 2.70-2.90 ( , 2H) ; 3.01 (dd, IH) ; 3.3 (dd, IH) ; 3.55 (d(br) , IH) ; 4.67 (p, IH) ; 5.18 (d, IH) ; 5.31 (dd IH) , 5.37 (dd, IH) , 7.15-7.79 (m, 14H) . N-tert-Butyloxycarbonylpiperidine-4-carboxylic acid ((1R,2E) 4-(hydroxymethyl)-5-(2-naphthyl)-1-( (2 -naphthyl)methyl)pent-2-enyl)-amide (220 mg; 0.371 mmol) wa dissolved in methylene chloride (5 ml) and trifluoroacetic aci (5 ml) and stirred for 90 min. The volatiles were removed in vac and methylene chloride (20 ml) was added and removed in vacuo times successively to afford 170 mg of the title compound. 'H-NMR (CDC1 3 ) (selected peaks) δ 4.60 (IH); 5.43 (m, 2H) ; 7.00-7.7 (14 H) , 8.7 and 9.05 (s(br), 2H) . ESMS: (M+H) + : 493.2 HPLC (Al) : R, = 36.15 min. Example 25: Piperidine-4-carboxylic acid ( (lR)-2-(2-naphthyl) -l-( (IR) -2 - (2 -naphthyl) -l-(l-phenethyl-lH-tetrazol-5-yl) ethyl carbamoyl ) ethyl ) amide : ( (IR) -2- (2-Naphthyl) -l-(phenethylcarbamoyl) ethyl) carbamic acid tert-butylester D-tert-Butyloxycarbonyl-(2-naphthyl) alanine (5.0 g, 15.85 mmol was dissolved in dry methylene chloride (80 ml). HOBT (2.14 g 15.85 mmol) and EDAC (3.34; 17.43 mmol) were added and the mixtur was stirred for 15 min. Phenethylamine (2.0 ml; 15.85 mmol) wa added and the mixture was stirred 24 h at room temperature Methylene chloride (200 ml) was added and the organic phase wa washed with water (100 ml) , sodium hydrogencarbonate (satd. 10 ml) and dried (Magnesium sulfate) . The solvent was removed i vacuo and the residue was chromatographed on silica (3.5 x 40 cm using methylene chloride/ethyl acetate (6:1) as eluent to affor 4 . 9 5 g o f ( ( 1 R ) - 2 - ( 2 naphthyl)-l-(phenethylcarbamoyl)ethyl) carbamic acid tert-buty ester H-NMR (CDC1 3 ) : δ: 1.39 (s, 9H) ; 2,52 (m, IH) ; 2.64 (m, IH) ; 3.1 (dd, IH) ; 3.23 (dd, IH) ; 3.36 (m; IH) ; 3.45 (m, IH) ; 4.31 (dd IH) ; 5.08 (s(br) ; IH) ; 5.62 (s(br) ; IH) ; 6.85-7.82 (12 arom.) ( ( 1 R ) - 2 - ( 2 Naphthyl) -1-(l-phenethyl-lH-tetrazol-5-yl)ethyl)carbamic aci tert-butylester ( (IR)-2-(2-Naphthyl)-1-(phenethylcarbamoyl)ethyl)carbamic acid tert-butyl ester (2.20 g, 5.26 mmol) was dissolved in dry THF (50 ml). Triphenylphosphine (2.76 g ; 10.52 mmol) diethyl- azodicarboxylate (1.66 g, 10.52 mmol) and trimethylsilyl azide (1.22 g; 10.52 mmol) were added. The mixture was stirred overnight at room temperature. Ammonium eerie nitrate (23.06 g; 21.04 mmol) was dissolved in water (400 ml) and added dropwise to the reation mixture. THF (120 ml) was added and the reaction mixture was extracted with methylene chloride (3 x 300 ml) . The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (5 x 40 cm) using ethyl acetate/heptane as eluent (1:1) to afford 0.30 g of ( (lR) -2- (2-naphthyl) -l- (l-phenethyl-lH-tetra- zol-5-yl)ethyl)carbamic acid tert-butylester H-NMR (CDC1 3 ) δ 1.32 (s, 9H) ; 2.72 (m, IH) ; 2.98 (m, IH) ; 3.13 (dd; IH) ; 3.41 (dd, IH) ; 4.42 (t, 2H) ; 4.99 (dd; IH) ; 5.12 (d, IH) ; 6.82-7.80 (12 arom.H) (lR)-2-(2-Naphthyl)-l-(l-phenethyl-lH-tetrazol-5-yl)ethylamine ( ( 1 R ) - 2 - ( 2 Naphthyl)-1-(l-phenethyl-lH-tetrazol-5-yl)ethyl)carbamic aci tert-butylester (0.30 g; 0.68 mmol) was dissolved in methylen chloride (20 ml) and trifluoroacetic acid (2 ml) was added. Th mixture was stirred for 3 h at RT. The solvent was removed i vacuo and the residue was dissolved in methylene chloride (50 ml and washed with sodium hydrogencarbonate (10 %; 30 ml). Th organic phase was dried (Magnesium sulfate) and the solven removed in vacuo. The residue was chromatographed on silica (2. X 15 cm) using ethyl acetate as eluent to afford 170 mg of (1R) 2-(2-naphthyl)-l-(l-phenethyl-lH-tetrazol-5-yl)ethylamine. H-NMR (CDC1 3 ) δ 1.75 (s(br); 2H) ; 3.00 (m 2H) ; 3.09 (d, 2H) ; 3.9 (t, IH) ; 4.25 (m, 2H) ; 6.85-7.85 (12 arom.H) . ( ( lR) -2- (2-Naphthyl) -l- ( ( lR) -2- ( 2- naphthyl ) -1- ( l-phenethyl-lH-tetrazol-5-yl ) ethylcarbamoyl ) ethyl carbamic acid tert-butyl ester D-tert-Butyloxycarbonyl-(2-Naphthyl)alanine (0.129 g; 0.408 mmol) was dissolved in methylene chloride (10 ml). HOBT (55 mg; 0.408 mmol) and EDAC (86 mg; 0.449 mmol) were added and the mixture was stirred for 15 min. at RT. (IR)-2-(2-Naphthyl) -l-(l-phenethyl-lH-tetrazol-5-yl)ethylamine (141 mg; 0.408 mmol) was added and the mixture was stirred overnight. Methylene chloride (25 ml) was added and the organic phase was washed with sodium hydrogen carbonate (10 %; 25 ml), sodium hydrogen sulfate (10 %; 25 ml) and water (25 ml). The organic phase was dried (Magnesium sulfate) and the solvent was removed in vacuo to afford 237 mg of ((lR)-2-(2-naphthyl)-l-((lR)-2-(2 -naphthyl)-1-(1-phenethyl-lH-tetrazol -5-yl)ethylcarbamoyl)ethyl)carbamic acid tert-butylester. H-NMR (CDC1 3 ) δ 1.30 (s, 9H) ; 2.75 (m, IH) ; 2.95 (m, 4H) ; 3.33 (dd, IH) ; 4.15 (m, 2H) ; 4.30 (m, IH) ; 4.65 (d(br) , IH) ; 5.18 (dd, IH) ; 6.60-7.85 (19 arom. H) . ( 2 R ) - 2 -Am i no- 3 - ( 2 -naphthyl ) -N- ( ( IR ) - 2 - ( 2 -naphthy l ) - 1 - ( l-phenethyl-lH-tetrazol-5-yl) ethyl) propionamide ( (IR) -2-(2-Naphthyl) -1-( (IR) -2-(2-naphthyl) -1-(1-phenethyl lH-tetrazol-5-yl)ethylcarbamoyl)ethyl)carbamic acid tert-buty ester (215 mg; 0.34 mmol) was dissolved in a mixture of methylen chloride (4 ml) and trifluoroacetic acid (2 ml) and stirred a room temperature for 30 min. The solvent was removed in vacuo an the residue was dissolved in ethyl acetate and aqueous sodiu hydrogencarbonate (10%; 10 ml). The phases were separated, th organic phase was dried (Magnesium sulfate) and the solven removed in vacuo. The residue was chromatographed on silica (3 20 cm) using ethyl acetate as eluent to afford 152 mg of (2R) 2-amino-3-(2-naphthyl) -N-( (IR)-2-(2-naphthyl)-1-(1-phenethyl lH-tetrazol-5-yl)ethyl)propionamide. H-NMR (CDC1 3 ) δ 2.16 (dd, IH) ; 2.80-3.15 (m, 4H) ; 3.35-3.55 (m 2H) ; 4.48 (dd, 2H) ; 5.19 (dd, IH) ; 6.90-8.02 (21 H) 4- ( ( lR) -2- ( 2-Naphthyl ) -l- ( ( IR) -2- ( 2-naphthyl ) -1- ( 1-phenethyl lH-tetra-zol-5-yl ) ethylcarbamoyl ) ethylcarbamoyl ) piperidine 1-carboxylic acid tert-butylester N-tert-butyloxycarbonylpiperidine-4-carboxylic acid (68 mg; 0.296 mmol) was dissolved in methylene chloride (7 ml) . HOBT (40 mg; 0.296 mmol) and EDAC (62 mg; 0.326 mmol) were added and the mixture was stirred 15 min at RT. (2R)-2-Amino-3-(2- δ n a p h t h y l ) - N - ( ( I R ) - 2 - ( 2 - n a p h t h y l ) - l-(l-phenethyl-lH-tetrazol-5-yl)ethyl)propionamide (152 mg ; 0.296 mmol) was added and stirring was continued overnight. Methylene chloride (25 ml) was added. The organic phase was washed with aqueous sodium hydrogencarbonate (25 ml) , aqueous sodium 0 hydrogensulfate (10%; 25 ml) and water (25 ml). The organic phase was dried (Magnesium sulfate) and the solvent removed in vacuo to afford 170 mg of 4-( (IR)-2-(2-Naphthyl)-l-( (IR)-2-(2- naphthyl)-1-(l-phenethyl-lH-tetrazol-5-yl)ethylcarbamoyl)ethyl¬ carbamoyl)piperidine-l-carboxylic acid tert-butylester. 5 H-NMR (CDC1 3 ) δ 1.25-1.52 (m and s, 13H) ; 1.79 (m, IH) ; 2.58 (m, 2H) ; 2.75 (m, IH) ; 2.86 (dd, IH) ; 2.96 (dd, IH) ; 3.05 (d, 2H) ; 3.27 (dd, IH) ; 3.98 (m, 2H) ; 4.15 (m, 2H) ; 4.57 (dd, IH) ; 5.04 (dd, IH) ; 5.72 (d(br) ; IH) ; 6.53 (d(br) ; IH) ; 6.71-7.80 (19 arom. H) 04-( (lR)-2-(2-Naphthyl)-l-((lR)-2-(2-naphthyl)-l-(l-phenethyl- lH-tetrazol-5-yl) ethylcarbamoyl) ethylcarbamoyl)piperidine- 1-carboxylic acid tert-butylester (164 mg; 0.218 mmol) was dissolved in methylene chloride (6 ml) and trifluoroacetic acid (3 ml) and stirred for 20 min at RT. The solvent was removed in 5 vacuo. Methylene chloride (10 ml) was added and the organic phase was washed with aqueous sodium hydrogencarbonate (10%; 10 ml) . The organic phase was dried (Magnesium sulfate) and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5 ml) and hydrogen chloride in ethyl acetate (3M; 2 ml) was added. 0 The solvent was removed in vacuo. The residue was dissolved in methanol (5 ml) and evaporated and this was repeated 3 times with methylene chloride to afford 110 mg of the title compound as hydrochloride. H-NMR (CDC1 3 ) (selected peaks) δ 2.50 (m, 2H) ; 2.73 (m, IH) ; 2.89 3.09 (m, 7H) ; 3.31 (dd, 1H);4.21 (m, 2H) ; 4.68 (dd, IH) ; 5.10 (dd IH) ; 6.70-7.75 (19 arom. H) HPLC: R t = 38.07 min (Al) Example 26: Piperidine-4-carboxylic acid N-methyl-N-( (IR)-2-(2-naphthyl)-1- ( (IR)2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)amide: (2R) -2- (N-tert-Butoxycarbonyl-N-methylamino) -3- (2-naphthyl) pro- pionic acid methylester (2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (10,0 g; 32.79 mmol) was dissolved in dry DMF (100 ml). Iodomethane (12.25 ml; 196.72 mmol) and silver oxide (26.6 g; 114.75 mmol) were added. The reaction mixture was stirred 12 hours at room temperature. The reaction mixture was filtered and methylene chloride (400 ml) was added to the filtrate. The organic phase was washed with aqueous potassium cyanide (5%; 2 x 100ml) , water (3 x 150 ml) and dried (MgS0 4 ) . The solvent was removed in vacuo to afford 10.9 g of (2R)-(N-tert-butoxycarbonyl-N-methylamino)-3-(2- naphthyl)propionic acid methylester. H-NMR (CDC1 3 ) δ (mixture of rotameres) 1.30, 1.35 (two s, 9H) ; 2.71, 2.74 (two S, 3H) ; 3.45, 3.19 (two m, 2H) ; 3.72, 3.74 (two s, 3H) ; 4.65, 5.06 (two dd, IH) ; 7.30-7.80 (7 arom. H) (2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)pro- pionic acid. (2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naph- thyl)propionic acid methylester (15.0 g; 43.73 mmol) was 5 dissolved in dioxane (150 ml) and cooled on an icebath. Water (115 ml) and lithium hydroxide (1.15 g; 48.10 mmol) were added. The reaction mixture was stirred 4 hours at room temperature. Ethyl acetate (300 ml) and water (200 ml) were added. Sodium hydrogensulfate (3%) was added until acidic reaction (pH = 102.5). The organic phase was washed with water (200 ml) and dried (Magnesium sulfate) . The solvent was removed in vacuo to afford 13.5 g of (2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)- 3-(2-naphthyl)propionic acid. H-NMR (CDC1 3 ) δ (mixture of rotameres) 1.30, 1.47 (two s, 9H) ; 152.66, 2.78 (two s, 3H) ; 3.21, 3.38 (two dd, IH) ; 3.48, 3.51 (two d, IH) ; 4.75, 4.83 (two dd, IH) ; 7.31-7.82 (7 arom. H) . ( (IR)-2-(2-Naphthyl)-l-thiocarbamoylethyl)carbamic acid tert-butyl ester. (2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid amide (1.058 g; 3.36 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2,4-disulfide (Lawesson's reagent) (0.71 g; 1.76 mmol) were dissolved in dioxane (6 ml) . The reaction mixture was heated 30 min at 60°C and stirred 12 hours at room temperature. The solvent was removed in vacuo and to the residue was added a mixture of water/sodium hydrogencarbonate (1:1; 15ml) and stirred 30 min at room temperature. The mixture was filtered. The solid was washed with water (2 x 5 ml) and chromatographed on silica (2 x 15cm) using ethyl acetate/heptane (2:1) to afford 0.914 g of ( (IR) -2-(2-naphthyl) -1-thiocarbamoylethyl) carbamic acid tert-butylester. H-NMR (CDC1 3 ) δ 1.44 (s,9H); 3.28 (m, 2H) ; 4.74 (dd, IH) ; 4.94 (d(br), IH) ; 7.35-7.79 (7 arom. H) . (2R) 2-Amino-3-(2-naphthyl)propionthioamide. ( (IR) -2-(2-Naphthyl) -1-thiocarbamoylethyl) carbamic aci tert-butyl¬ ester (0.45 g; 1.36 mmol) was dissolved in methylene chloride (1. ml) and trifluoroacetic acid (1.5 ml) was added. The reacti mixture was stirred for 40 min at room temperature. The solve was removed in vacuo and the residue was dissolved in methyle chloride. Aqueous sodium hydrogencarbonate was added until bas reaction and the aqueous phase was extracted with methyle chloride (3 x 15 ml) . The combined organic phases were dri (MgS0 4 ) and the solvent was removed in vacuo to afford 0,311 g (2R)-2-amino-3-(2-naphthyl)propionthioamide. Η-NMR (CDC1 3 ) δ 2.36 (dd, IH) ; 3.79 (dd, IH) ; 4.19 (dd, IH) ; 7.4 7.85 (7 arom. H) . N-Methyl-N-( (IR)-2-(2-naphthyl)-1-( (IR) -2-(2-naphthyl)-1-thio- carbamoylethylcarbamoyl)ethyl)carbamic acid tert-butylester. (2R)-2-Amino-3-(2-naphthyl)propionthioamide (0.290 g; 1.2 mmol), (2R)-2-(N-tert-butoxycarbonyl-N-methylamino) -3-(2-naphthyl)- propionic acid (0.436 g; 1.3mmol), HOBT (0.176 g; 1.3 mmol) and EDAC (0.267 g; 1.4 mmol) were dissolved in methylene chloride (20 ml) and stirred 12 hours at RT. Methylene chloride (40 ml) was added and the organic phase was washed with aqueous sodium hydrogensulfate (10%; 40ml), aqueous sodium hydrogencarbonate (satd. ; 40ml) and dried (Magnesium sulfate) . The solvent was removed in vacuo to afford 0,53 g of N-methyl-N-((IR)-2-(2- naphthyl)-1-((IR)-2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)- ethyl)carbamic acid tert-butylester. H-NMR (CDC1 3 ) δ (mixture of rotamers, selected peaks) 1.28 (s, 9H) ; 2.45, 2.51 (two s, 3H) ; 4.90 (m, IH) ; 5.12, 5.20 (two m, IH) . ( 2R) -2 -Methylamino-3 - ( 2 -naphthyl ) -N- ( ( IR ) - 2 - ( 2 -naphthyl ) 1-thiocarbamoylethyl ) propionamide N-Methyl-N- ( (IR) -2- (2-naphthyl) -1- ( (IR) -2- (2-naphthyl) -1 5 thiocarbamoylethylcarbamoyl)ethyl)carbamic acid tert-butyleste (0.25 g; 0.462 mmol) was dissolved in methylene chloride (1.5ml and trifluoroacetic acid (1.5 ml) was added. The reaction mixtur was stirred 1 h at RT. The solvent was removed in vacuo and t residue was dissolved in methylene chloride (5 ml) and washed wit 10 aqueous sodium hydrogencarbonate (5 ml) . The organic phase wa dried (Magnesium sulfate) and the solvent was removed in vacuo t afford 0.201 g of (2R)-2-methylamino-3-(2-naphthyl)-N-( (IR) 2-(2-naphthyl)-1-thiocarbamoylethy1)propionamide. H-NMR (CDC1 3 ) δ 2.16 (s, 3H) ; 2.46 (dd, IH) ; 3.07 (dd, IH) ; 3.20 153.41 (m, 4H) ; 5.09 (dd, IH) ; 7.12-8.13 (m, 16H) 4- (N-Methyl-N- ( ( lR) -2- (2-naphthyl) -l- ( ( lR) -2- (2- naphthyl) -1-thiocarbamoylethylcarbamoyl) ethyl ) carbamoyl) pi- peridine-1-carboxylic acid tert-butylester. N-tert-Butyloxycarbonylpiperidin-4-carboxylic acid (97 mg; 0.424 mmol) was dissolved in methylene chloride (2 ml) . HOAt (58 mg; 0.424 mmol) and EDAC (85 mg; 0.444 mmol) were added. The reaction mixture was stirred 15 min at RT. (2R)-2-Methyl- amino-3-(2-naphthyl)-N-( (IR)-2-(2-naphthyl) -1-thiocarbamoyl- ethyl)propionamide (17 mg; 0.386 mmol) was dissolved in methylene chloride (2 ml) and added. Diisopropylethylamine (0.073 ml; 0.424 mmol) was added and the reaction mixture was stirred 12 hours at room temperature. Tert-butylmethylether (25 ml) was added and the reaction mixture was washed with water (25 ml) , aqueous sodium hydrogencarbonate (15 ml) , aqueous sodiumhydrogensulfate (10%; 15 ml) , water (15 ml) and dried (magnesium sulfate) . The solvent was removed in vacuo and the residue was chromatographed on silica (3.5 x 30cm) using gradient elution, starting with ethyl acetate/heptane (1:1) increasing to ethyl acetate/heptane (2:1) to afford 0.190 g of 4-(N-methyl-N-((IR)-2-(2-naphtyl)-l-((IR)- 2 - ( 2 - n a p h t h y l ) - 1 - t h i o carbamoylethylcarbamoyl)ethyl)carbamoyl)piperidine-l-carboxyli acid tert-butylester. H-NMR (CDC1 3 ) δ (mixture of rotamers, selected peaks): 1.40, 1.4 (two s, 9H) ; 2.49, 2.70 (two s, 3H) ; 3.10 (dd, IH) ; 3.48 (dd, IH) 5.00, 5.09 (two dd, IH) 4- (N-Methyl-N- ( (IR) -2-(2-naphthyl) -1-( (IR) -2-(2-naphthyl) 1-thiocarbamoylethylcarbamoyl)ethyl)carbamoyl)piperidine-1-car boxylic acid tert-butylester (0.190 g; 0.291 mmol) was dissolve in methylene chloride (5 ml) . Trifluoroacetic acid (5 ml) wa added and the reaction mixture was stirred 15 min at RT. Th solvent was removed in vacuo and the residue was dissolved i methylene chloride and evaporated (2 x 5 ml) . The residue wa chromatographed on silica (2 x 30 cm) using 25 % aqueou ammonia/ethanol/methylene chloride (1:9:90) as eluent to affor 57 mg of the title compound. ESMS: (M+H) + : 553.2 HPLC (Al) : R t = 29.4 min. Example 27 : Piperidine-4-carboxylic acid ( (lR)-l-( (IR)-l-(4-carbamoyl-5-phe- nyl-1,3-thiazol-2-yl)-2-(2-naphthyl)ethylcarbamoyl)-2-(2-naph¬ thyl)ethyl)amide. 2-Amino-3-oxo-3-phenylpropionic acid methylester. Dry tetrahydrofuran (250 ml) was cooled to -78°C. Potassium tert- butoxide (6.37 g; 56.72 mmol) was dissolved in dry tetrahydrofuran (100 ml) and added. (Benzhydrylideneamino)acetic acid methyl ester (14.35 g; 56.72 mmol) was added and the reaction mixture was 168 stirred 30 min at -78°C. Benzoyl chloride (6.59 g; 56.72 mmol) wa added dropwise and the reaction mixture was stirred 30 min at 78°C. Hydrochloric acid (1.0 M; 175 ml) was added dropwise. Th reaction mixture was heated to room temperature and 2/3 of t 5 solvent was removed in vacuo. Water (700 ml) was added and t reaction mixture was washed with diethyl ether (400 ml) . T aqueous phase was evaporated in vacuo and the residue w dissolved in methanol and evaporated (2 x 150 ml) . Methanol (8 ml) was added. The mixture was filtrated and the filtrate wa 10 evaporated in vacuo. The residue was recrystallised fr tetrahydrofuran/diethyl ether to afford 8.86 g 2-amino-3-oxo-3-phenylpropionic acid methylester as hydrochloride. H-NMR (DMSO) δ 3.66 (s, 3H) ; 6.25 (s, IH) ; 7.57-8.17 (5 arom. H) 159.20 (s(br) ; 3H) . 2- ( (2R) -2-tert-Butoxycarbonylamino-3- (2-naphthyl) propionylamino) 3-oxo-3-phenylpropionic acid methylester . (2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (5. 20 g; 17.42 mmol) was dissolved in dry tetrahydrofuran (200 ml) a N-methylmorpholine (1.92 ml; 17.42 mmol) was added. The reacti mixture was cooled to -20°C and stirred 15 min. Isobutyl chloroformate (2.27 ml; 17.42 mmol) was dissolved in dry tetrahydrofuran (3 ml) and added dropwise to the reaction mixture at -20°C. N-methylmorpholine (1.92 ml; 17.42 mmol) and 2-amino-3-oxo-3-phenylpropionic acid methylester (4.0 g; 17.42 mmol) were added and and the mixture was stirred 30 min at -20°C. The reaction mixture was heated to room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride (200 ml) , washed with water (200 ml) and dried (magnesium sulfate) . The solvent was removed in vacuo and the residue was chromatographed on silica (5 x 45 cm) using heptane/ethyl acetate/methylene chloride (2:1:1) as eluent to afford 6.19 g of a diastereomeric mixture of 2-((2R)- 2-tert-butoxycarbonylamino-3-(2-naphthyl)propionylamino)-3-oxo-3- phenylpropionic acid methylester. H-NMR (CDC1 3 ) δ 1.48 (s, 9H) ; 3.28 (m, 2H) ; 3.59, 3.67 (two s, 3H) ; 4.58 (s(br), IH) ; 5.00, 5.03 (two m, IH) ; 6.13, 6.17 (two d, IH) ; 7.28-8.12 (m, 13 H) . 2 - ( ( IR ) - l -tert-Butoxycarbonyl am ino-2 - ( 2 -naphthyl ) ethyl ) 5-phenyl-l , 3-thiazole-4-carboxylic acid methylester . 2-( (2R) -2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionyl amino)-3-oxo-3-phenylpropionic acid methylester (2.2 g; 4.06 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson ' s reagent) (4.1 g; 10.17 mmol) wer refluxed 6 hours in 50 ml tetrahydrofuran. The solvent was remove in vacuo and the residue was chromatographed on silica; (4 x 4 cm) using ethyl acetate/heptane (1:1) as eluent and the residu was recrystalised from ethyl acetate/heptane (1:1; 50 ml) t afford 1.45 g of 2-( (IR)-1-(tert-butoxycarbonylamino)-2-(2 naphthyl) -ethyl) -5-phenyl-l, 3-thiazole-4-carboxylic aci methylester. H-NMR (CDC1 3 ) δ 1.39 (s, 9H) ; 3.48 (dd(br); IH) ; 3.55 (dd, IH) 3.85 (s, 3H) ; 5.26 (s(br), IH) ; 5.38 (m, IH) ; 7.24-7.81 (12 ar H). 2- ( (lR) -l- (l-tert-Butoxycarbonylamino) -2- (2 -naphthyl)ethyl)-5-phenyl-l,3-thiazole-4-carboxylic acid. 2-((IR)-1-(tert-Butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phe- nyl-l,3-thiazole-4-carboxylic acid methylester (0.35 g; 0.716 mmol) was dissolved in ethanol (99 %; 40 ml) and lithium hydroxide (0.112 g; 4.654 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in water (50 ml) and diethyl ether (50 ml) . The solution was made acidic with sodium hydrogensulfate (10 %) , and the organic phase was dried (magnesium sulfate) . The solvent was removed in vacuo to afford 0.185 g of 2-((IR)-1-(tert-butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phe- nyl-l,3-thiazole-4-carboxylic acid. H-NMR (DMSO) δ 1.24 (s, 9H) ; 3.20 (dd, IH) ; 3.55 (dd, IH) ; 5.11 (m, IH) ; 7.48-7.93 (12 arom. H) 2- ( (IR) -1- (tert-Butoxycarbonylamino) -2- ( 2 -naphthyl ) ethyl) -5-phe nyl-1 , 3-thiazole-4-carboxylic acid amide : 2-( (IR)-1-(tert-Butoxycarbonylamino)-2-(2-naphthyl)ethyl)-5-phe nyl-l,3-thiazole-4-carboxylic acid (0.17 g; 0.362 mmol) wa dissolved in methylene chloride (8 ml) . 1-Hydroxybenzotriazol (0.049 g; 0.362 mmol) and N-(3-dimethylaminopropyl)-N ' ethylcarbodiimide hydrochloride (0.083 g; 0.434 mmol) were added The reaction mixture was stirred 15 min at room temperature Ammonium hydrogencarbonate (0.057 g; 0.724 mmol) was added and th reaction mixture was stirred 12 h at room temperature. Methylen chloride (20 ml) was added and the reaction mixture was washe with sodium hydrogencarbonate (10%; 10 ml), sodiumhydrogensulfat (5 %; 2 x 10 ml) and dried (magnesium sulfate). The solvent wa removed in vacuo and the residue was chromatographed on silic (2 x 15 cm) using ethyl acetate/heptane (1:1) as eluent to affor 0.155 g of 2-( (IR)-1-(tert-butoxycarbonylamino)-2-(2-naphthyl) ethyl)-5-phenyl-l,3-thiazole-4-carboxylic acid amide. Η-NMR (CDCI 3 ) δ 1.38 (s, 9H) ; 3.39-3.52 (m, 2H) ; 5.17 (d(br) , IH) ; 5.35 (m, IH) ; 5.52 (s(br) ; IH) ; 7.15 (s(br) ; 7.22-7.82 (12 arom. H) . 2-( (IR) -l-Amino-2-(2-naphthyl)ethyl)-5-phenyl-l,3-thiazole- 4-carboxylic acid amide: 2-( (IR) -1-(tert-Butoxycarbonylamino) -2-(2-naphthyl) ethyl) - 5-phenyl-l,3-thiazole-4-carboxylic acid amide (0.155 g; 0.327 mmol) was dissolved in methylene chloride (4 ml) and trifluoroacetic acid (4 ml) was added. The reaction mixture was stirred 1 hour at room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and evaporated (2 x 2 ml) . The residue was dissolved in diethyl ether (2 ml) . Hydrochloric acid (1 N; 3 ml) and methanol (10 ml) were added. The solvent was removed in vacuo to afford 0.106 g of 2-( (lR)-l-amino-2-(2-naphthyl) -ethyl) -5-phenyl-l, 3- thiazole-4-carboxylic acid amide. 'H-NMR (CDC1 3 ) (selected peaks) δ 3.45-3.60 (m, 2H) ; 5.28 (m, IH) . ( (lR)-l-( (lR)-l-(4-Carbamoyl-5-phenyl-l,3-thiazole-2-yl)-2-(2 naphthyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic aci tert-butylester. (2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic aci (0.107 g; 0.341 mmol) was dissolved in methylene chloride/dimethy formamide (5:1; 20 ml). 1-Hydroxybenzotriazole (0.046 g; 0.34 mmol) and N-(3-dimethylaminopropyl)-N ' -ethylcarbodiimide hydro chloride (0.071 g; 0.369 mmol) were added. The reaction mixtur was stirred 15 min at room temperature and 2-( (lR)-l-amino-2-(2 naphthyl)ethyl)-5-phenyl-l,3-thiazole-4-carboxylic acid amid (0.106 g; 0.284 mmol) was added. The reaction mixture was stirre 12 hours at room temperature. The reaction mixture was washed wit water (20 ml), sodium hydrogensulfate (10 %; 20 ml), sodiu hydrogencarbonate (satd; 20 ml) , water (20 ml) and drie (magnesium sulfate) . The solvent was removed in vacuo and th residue was chromatographed on silica (2 x 15 cm) using ethy acetate/heptane (2:1) as eluent to afford 0.22 g of ( (IR)-l-( (IR) 1-(4-carbamoyl-5-phenyl-l, 3-thiazole-2-yl) -2- (2-naphthyl) ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester. 'H-NMR (CDC1 3 ) (selected peaks) δ 1.32 (s,9H); 3.13-3.41 (m, 4H) ; 4.42 (dd, IH) ; 5.56 (dd, IH) . 2-((lR)-l-((2R) -2-Amino-3-(2-naphthyl)propionylamino)-2-(2- naphthyl)ethyl)-5-phenyl-l,3-thiazole-4-carboxylic acid amide. ( (IR)-1-( (IR) -1-(4-Carbamoyl-5-phenyl-l,3-thiazol-2-yl)-2-(2- naphthyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (0.22 g; 0.328 mmol) was dissolved in methylene chloride (2.5 ml) and trifluoroacetic acid (2.5 ml) was added. The reaction mixture was stirred 1 h at room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and evaporated (2 x 5 ml) . The residue was dissolved in methylene chloride (10 ml) and washed with sodium hydrogencarbonate (satd; 10 ml) , water (10 ml) and dried (magnesium sulfate) . The solvent was removed in vacuo to afford 0. 155 g of 2 - ( ( IR ) - 1 - ( ( 2R ) -2 -amino- 3 - ( 2 naphthyl) propionylamino) -2- (2 -naphthyl) ethyl) -5-phenyl-l, 3 thiazole-4-carboxylic acid amide. H-NMR (CDC1 3 ) δ 2.55 (dd, IH) ; 3.22 (dd, IH) ; 3.40 (dd, IH) ; 3. (dd, IH) ; 3.69 (dd, IH) ; 5.53 (s(br) , IH) ; 5.67 (dd, IH) ; 7.13 8.12 (m, 22H) . 4-(((IR)-1-( (IR)-1-(4-Carbamoyl-5-phenyl-l,3-thiazol-2-yl)-2-(2 naphthyl)ethylcarbamoyl) -2-(2-naphthyl)ethyl) carbamoyl)pipe ridine-1-carboxylic acid tert-butylester. N-tert-Butyloxycarbonylpiperidine-4-carboxylic acid (0.140 0.612 mmol) was dissolved in methylene chloride (5 ml) and N-( dimethylaminopropyl)-N ' -ethylcarbodiimide hydrochloride (0.058 0.306 mmol) was added. The reaction mixture was stirred 15 min room temperature. 2-( (IR)-l-( (2R) -2-(Amino-3-(2-naphthyl) propionylamino)-2-(2-naphthyl)ethyl)-5-phenyl-l,3-thiazole-4-ca boxylic acid amide (0.155 g; 0.278 mmol) was dissolved methylene chloride (10 ml) and added to the reaction mixture. T reaction mixture was stirred 8 hours at room temperature a washed with water (20 ml) , sodium hydrogencarbonate (satd, 20 m and dried (magnesium sulfate) . The solvent was removed in vacuo and the residue was chromatographed on silica (2.5 x 30 cm) using ethyl acetate to afford 0.171 g of 4-( ( (IR)-l-( (1R)- l-(4-carbarooyl-5-phenyl-l,3-thiazol-2-yl)-2-(2-naphthyl)ethyl- carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)piperidine-1-carboxylic acid tert-butylester. 'H-NMR (CDClj) (selected peaks) δ 1.44 (s,9H); 2.81 (t, IH) ; 3.12 (m, 2H) ; 3.42 (dd, IH) ; 3.85-4.02 (m, 4H) ; 4.88 (dd, IH) ; 5.52 (dd, IH) ; 4-(((lR)-l-( (lR)-l-(4-Carbamoyl-5-phenyl-l,3-thiazol-2-yl)-2-(2- naphthyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)piperi- dine-1-carboxylic acid tert-butylester (0.171 g; 0.219 mmol) was dissolved in methylene chloride/trifluoroacetic acid (1:1; 10 ml) and stirred 20 min at room temperature. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and evaporated in vacuo three times (3 x 5 ml) to afford 0.175 g of the title compound. Η-NMR (CDC1 3 ) (selected peaks) δ 3.37 (m, 2H) ; 3.44 (dd; IH) ; 4.80 (m, IH) ; 5.55 (dd, IH) . ESMS: (M+H) + : 682.4 HPLC : (method B) : R t = 35 . 08 min . The following compound may be prepared using the same method a in example 21 using methylamine instead of benzylamine: (2E)-5-Amino-5-methylhex-2-enoic acid {l-[N-(l-(3- methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl)-N-methyl carbamoyl]-2-(2-naphthyl)ethyl)amide: The following compound may be prepared using the same method a in example 21 using dimethylmethylamine instead of benzylamine: (2E)-5-Amino-5-methylhex-2-enoic acid {l-[N-(l-(3- dimethylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl)-N-methyl carbamoyl]-2-(2-naphthyl)ethyl}amide: The following compound may be prepared according to method K, analougosly to example 23, using (2E)-5-tert-butoxycarbonylamino- 5-methylhex-2-onic acid instead of 3-tert-butoxycarbonyl- amino ethylbenzoic acid. (2E) -5-Amino-5-methyl-N- ( (IR) -l-(N- ( (IR) - 1- ( 2 - hydroxyethoxymethyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2- naphthyl)ethyl)-N-methylhex-2-enoic acid amide: The following compound may be prepared analougosly to example 23, using methyImagnesium bromide instead of lithium boronhydride and (2E)-5-tert-butoxycarbonylamino-5-methylhex-2-onic acid instead of 3-tert-butoxycarbonylaminomethylbenzoic acid. (2E) -5-Amino-5-methyl-N-( (IR) -1-(N- ( (IR) -1-(2-hydroxy-2- methylpropoxymethyl) -2-phenylethyl)-N-methylcarbamoyl) -2-(2- naphthyl)ethyl)-N-methylhex-2-enoic acid

Claims: CLAIMS : 1. A compound of general formula I Wherein n is 0 or 1 ; m is 1 or 2 ; p is 0 , 1 or 2 ; A is R1 -CH=CH- or I N _ wherein R' is hydrogen or C^-alkyl W is =0 or =S; B is -CH=CH- or ,N, wherein R 2 is hydrogen or W' is =0 or =S; D is NN (CH 2 ) r (C 7 R 8 ). (CH 2 ) t (M) q —(CH 2 ) o — wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 independently are hydrogen or Ci.g-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 ) 1 -U-(CH 2 )_-, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, C^-alkyl o Cj.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4 ; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4 ; E is hydrogen, wherein L is hydrogen, -OR 9 , -CONR 9 R 10 , Cj.g-alkyl obtionall substituted with hydroxy or Cj.g-alkoxy, or L is W // or \ / Y— Y=V wherein R 9 and R 10 are independently hydrogen, C^-alkyl o together form -(CH 2 ) k -U'-(CH 2 ) : -, wherein k and 1 independently are 1, 2 or 3, and k+1 is 3, 4, or 6, U' is -0-, -S- or a valence bond; X is -N(R")-, -O- or -S-, V is -C(R 12 )= or -N=, Y is -C(R U )= or -N=, Z is -C(R' 4 )= or -N=, R' 2 , R' 3 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , (CH 2 ) V NR 16 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, C^-alkyl, phenyl oxazol-5-yl, 5-methyl-[l,2,4]oxadiazol-3-yl, R", R 15 , R 16 and R 17 independently are hydrogen or C^-alkyl obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6; K is hydrogen or (CR 20 R 21 ) b -<CH 2 ) d - wherein R 18 , R 19 , R 20 and R 2 ' are independently hydrogen, C^-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R 18 and R 19 , R 18 and R 21 , R 19 and R 20 or R 20 and R 21 optionally forming -(CH 2 ) k .-Z-(CH 2 ) _ .-where k' and 1' independently are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -0-, -S- or a valence bond; b is 0 or 1; a and d are independently 0, 1, 2, 3 or 4; and a+b is 1 to 4; Q is >CR 22 - or >N-, wherein R 22 is hydrogen or Cj.g-alkyl, F is wherein R 23 is hydrogen or W' • is =0 or =S; G is hydrogen, optionally substituted with halogen, amino, hydroxy, C^-alkyl or Cj. e -alkoxy; J is optionally substituted with halogen, amino, hydroxy, C^-alkyl or or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 2. A compound of general formula I Wherein n is 0 or 1; m is 1 or 2; p is 0, 1 or 2; A is R 1 wherein R 1 is hydrogen or C^e-alkyl, W is =0 or =S; with the proviso that when n is l and A is a secondary or tertiary amide or a secondary or tertiary amine, B or F is not an amide or an amine; B is -CH=CH — or ,N ^ wherein R 2 is hydrogen or C^-alkyl , W ' is =0 or =S ; D is \ N— (CH 2 )|— (CR 7 R 8 ) S -(CH 2 )- °U N— CH- or / / 6 R 3 NN — (CH 2 ) Γ (CR 7 R 8 ). (CH. 2)>t -(M) f • (CH 2 ) o — R 6 wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 independently are hydrogen or Ci.g-al yl optionally substituted with halogen, amino, hydroxy o aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 ).-U-(CH 2 )--, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0- , -S- , -CH=CH- , optionally substituted with halogen, amino, hydroxy, C^-alkyl or Cj.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4; E is hydrogen, K X. XI X CH L "^ / Z or " \ / * Y-V Y=V wherein L is hydrogen, -OR 9 , -CONR 9 R 10 , C^-alkyl obtionally substituted with hydroxy or or L is wherein R 9 and R 10 are independently hydrogen, Ci.g-alkyl or together form -(CH 2 ) k -U'-(CH 2 )-.-, wherein k and 1 independently are 1, 2 or 3, and k+1 is 3, 4, 5 or 6, U' is -0-, -S- or a valence bond; X is -N(R")-, -O- or -S-, V is -C(R' 2 )= or -N=, Y is -C (R' 3 ) = or -N= , Z is -C (R' ) = or -N= , R' 2 , R 13 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , (CH 2 ) V NR' 6 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, C^-alkyl, phenyl 5 oxazol-5-yl, 5-methyl-[l,2,4]oxadiazol-3-yl, R", R 15 , R 16 and R 17 independently are hydrogen or obtionally substituted with aryl, and u and v are independentl 0 or 1, 2, 3, 4, 5 or 6; K is hydrogen or (CR 20 R 21 ) ■ <CH 2 ) d - wherein R 18 , R 19 , R 20 and R 2 ' are independently hydrogen, optionally substituted with halogen, amino, C^-alkylamino hydroxy or aryl; R 18 and R 19 , R 18 and R 21 , R 19 and R 20 or R 20 and R optionally forming -(CH 2 ) k .-Z-(CH 2 ) x .-where k' and 1' independentl 15 are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -0-, -S- or a valence bond; b is 0 or 1; a and d are independently 0, 1, 2 , 3 or 4 ; and a+b is 1 to 4 ; 20 Q is >CR 22 - or >N-, wherein R 22 is hydrogen or C^-alkyl, F is .R 23 ,23 ,23 -CH=CH — or .N. wherein R 23 is hydrogen or Cj.g-alkyl, W' • is =0 or =S; G is hydrogen. optionally substituted with halogen, amino, hydroxy, Cj.g-alkyl or Cj.g-alkoxy; J is optionally substituted with halogen, amino, hydroxy, or or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 3. A compound of general formula I Wherein n is 0 or 1 ; m is 1 or 2 ; p is 0 , 1 or 2 ; A is -CH=CH— or ,N. wherein R' is hydrogen W is =0 or =S; with the proviso that when A contains a secondary or tertiary amide or a secondary or tertiary amine, either B or F do not contain a secondary or tertiary amide or a secondary or tertiary amine; B is -CH=CH— or ,N. wherein R 2 is hydrogen or C-,_ 6 -alkyl, W' is =0 or =S; D is \ I N—(CH 2 )— (CR 3 7'R D 8 B ) S -(CH 2 )—U N CH or / N (CH 2 ) r (CR 7 R 8 ) S (CH 2 ) t (M) q - -Wo— wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 independently are hydrogen or Cj.g-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 )i-U-(CH 2 ) _ - , wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, or o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4; E is hydrogen, wherein L is hydrogen, -OR 9 , -CONR 9 R 10 , Ci.g-alkyl obtionally substituted with hydroxy or Cj.g-alkoxy, or L is W // or \ / Y-V Y=V wherein R 9 and R 10 are independently hydrogen, Ci.g-alkyl or together form -(CH 2 ) k -U'-(CH 2 ) 1 - , wherein k and 1 independently are 1, 2 or 3, and k+1 is 3, 4, 5 or 6, ϋ* is -0-, -S- or a valence bond; X is -N(R")-, -0- or -S-, V is -C(R' 2 )= or -N=, Y is -C(R 13 )= or -N=, Z is -C(R' 4 )= or -N=, R' 2 , R' 3 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , - (CH 2 ) V NR 16 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, C-^-alkyl, phenyl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, R", R 15 , R 16 and R 17 independently are hydrogen or obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6; K is hydrogen or (CR 20 R 21 ) b "(CH 2 ) d - wherein R 18 , R 19 , R 20 and R 21 are independently hydrogen, optionally substituted with halogen, amino, hydroxy or aryl; R 18 and R 19 , R 18 and R 21 , R 19 and R 20 or R 20 and R 21 optionally forming -(CH 2 ) k .-Z-(CH 2 ) v -where k' and l 1 independently are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -O-, -S- or a valence bond; b is 0 or 1; a and d are independently 0, 1, 2, 3 or 4 ; and a+b is 1 to 4 ; Q is >CR 22 - or >N-, wherein R 22 is hydrogen or F is R 23 CH=CH — or I ,N_ wherein R 23 is hydrogen or C^-alkyl, W' * is =0 or =S; G is hydrogen, optionally substituted with halogen, amino, hydroxy, or Cj-g-alkoxy; J is optionally substituted with halogen, amino, hydroxy, Ci.g-al yl or Cj.g-alkoxy; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 4. A compound of formula I according to any one of claims 1-3 wherein m and p are independently 1 or 2; G is optionally substituted with halogen, amino, hydroxy, or Ci-g-alkoxy; and A, B, D, J, E, F and n are defined as in the preceding claims. 5. A compound of formula I according to any one of the preceding claims wherein A is wherein R 1 is hydrogen or Ci.g-alkyl, W is =0 or =S; and B, D, G, J, E, F, n, m and p are defined as in the preceding claims. 6. A compound of formula I according to any one of the preceding claims wherein D is NN (CH 2 )—(CR 7 R 8 ) S ( (CCHH 22 )) t (M) q - -(CH 2 )— optionally substituted with halogen, amino, hydroxy, C j .g-alkyl or Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; 5 and r+s+t is 1, 2, 3 or 4; and A, B, G, J, E, F, n, m and p are defined as in the preceding claims. 7. A compound of formula I according to any one of the preceding claims 10 wherein G and J independently are optionally substituted with halogen, amino, hydroxy, or C : . 6 -alkoxy; and A, B, D, E, F, n, m and p are defined as in the preceding claims. 158. A compound of formula I according to any one of the preceding claims wherein D is R 5 NN (CH 2 ) j —(CR 7 R 8 ) S (CH 2 ) t (M) q —(CH 2 ) o — R 6 wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or 20 Ci.g-alkyl optionally substituted with halogen, amino, hydroxy or aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 ).-U-(CH 2 )--, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; 25 M is -0-, -S-, -CH=CH-, or optionally substituted with halogen, amino, hydroxy, C j .g-alkyl or Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is l, 2, 3 or 4; and A, B, G, J, E, F, n, m and p are defined as in the preceding claims. 9. A compound of formula I according to any one of the preceding claims wherein D is R 5 SN (CH 2 ) j —(CR 7 R 8 ) S (CH 2 ) t (M) q (CH 2 )- R 6 wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or Ci.g-alkyl optionally substituted with halogen, amino, hydroxy o aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 ) i -U-(CH 2 )_ | -, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, or optionally substituted with halogen, amino, hydroxy, C 1-6 -alkyl o o, r and t are independently 0, 1, 2, 3 or 4; q is 1; s is 0 or 1; and r+s+t is 1, 2, 3 or 4; and A, B, G, J, E, F, n, m and p are defined as in the preceding claims. 10. A compound of formula I according to any one of the preceding claims wherein E is E is hydrogen, K CH * W // or \ / Y-V Y=V wherein L is hydrogen , -OR 9 , -CONR 9 R 10 , C^-alkyl obtionally substituted with hydroxy or Ci.g-alkoxy W // or \ / Y-V Y=V wherein R 9 and R'° are independently hydrogen, Cj.g-alkyl or together form -(CHz -U'-fCH;,) ! -, wherein k and 1 independently are 1, 2 or 3, and k+1 is 3, 4, 5 or 6, U' is -0-, -S- or a valence bond; X is -N(R")-, -O- or -S-, V is -C(R 12 )= or -N=, Y is -C(R' 3 )= or -N=, Z is -C(R' 4 )= or -N=, R 12 , R' 3 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , -(CH 2 ) V NR' 6 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, phenyl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, R", R 15 , R 16 and R 17 independently are hydrogen or obtionally substituted with aryl, and u and v are independentl 0 or 1, 2 , 3 , 4 , 5 or 6 ; K is .18 N (CH 2 )_ (CR 20 R 21 ) b "(CH 2 ) d - > R 19 wherein R 18 , R 19 , R 20 and R 21 are independently hydrogen, C j .g-alky optionally substituted with halogen, amino, C j .g-alkylamino hydroxy or aryl; R 18 and R 19 , R 18 and R 2: , R 19 and R 20 or R 20 and R 2 optionally forming -(CH 2 ) k .-Z-(CH 2 ) -where k' and l' independentl are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -O-, -S- or a valence bond; b is 0 or 1; a and d are independently 0, 1, 2 , 3 or 4 ; and a+b is 1 to 4 ; and A, B, D, G, J, F, n, m and p are defined as the precedin claims. 11. A compound of formula I according to any one of the precedin claims wherein E is wherein X is -N(R")-, -O- or -S-, V is -C(R' 2 )= or -N=, Y is -C(R 13 )= or -N=, Z is -C (R 14 ) = or -N= , R 12 , R 13 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , -(CH 2 ) V NR' 6 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, phenyl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, R", R 15 , R 16 and R 17 independently are hydrogen or obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6; and A, B, D, G, J, F, n, m and p are defined as in the preceding claims. 12. A compound of formula I according to any one of the preceding claims, wherein E is wherein X is -N(R")- or -0-, V is -C(R' 2 )= or -N=, Y is -N=, Z is -C(R' )= or -N=, R 12 and R' 4 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , -(CH 2 ) V NR' 6 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, C-,_ 6 -alkyl, phenyl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, R", R 15 , R 16 and R 17 independently are hydrogen or obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6; and A, B, D, G, J, F, n, m and p are defined as in the preceding claims; 13. A compound of formula I according to any one of the preceding claims wherein E is wherein X is -N(R")- or -0-, V is -C(R 12 )=, Y is -N=, Z is -C(R 14 )= or -N=, R 12 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , -(CH 2 ) V NR 16 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, C^-alkyl, phenyl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, R", R 15 , R 16 and R 17 independently are hydrogen or obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6; and A, B, D, G, J, F, n, m and p are defined as in the preceding claims; 14. A compound of formula I according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 selected from the group consisting of (3R) Piperidine-3-carboxylic acid ((1R,2E)- 4-hydroxymethyl-1-(2- naphthyl)methyl-5-phenylpent-2-enyl)amide, 3-Aminomethyl-N-( (IR,2E)-4-hydroxymethyl-l-(2- naphthyl)methyl-5-phenylpent-2-enyl)benzamide, Piperidine-4-carboxylic acid (l-( [1-(3-carbamoyl- [1,2,4] oxadiazol-5-yl ) -2- ( 2 -naphthyl ) ethyl ] -N-methylcarbamoyl ) -2- ( 2 -naphthyl ) ethyl ) amide , 5-{ (lR)-l-[ (2R) -2-(Piperidine-4-carbonylamino)-3-(2- naphthyl) propionyl-N-methylamino] -2- (2 -naphthyl ) ethyl ) - [l,2,4]oxadiazole-3-carboxylic acid ethylester, 5-{ 1- [2- (3-Aminomethylbenzoyl) -3- (2 -naphthyl) propionyl-N- methylamino] -2- (2 -naphthyl) ethyl } - [ 1 , 2 , 4 ] oxadiazol-3 -carboxylic acid ethylester, 5-( (lR)-l-[ (2R)-2-(3-Aminomethylbenzoylamino) -3- (2- naphthyl) propionylamino] -2-phenylethyl )-[ 1,2 , 4]oxadiazole-3- carboxylic acid ethylester, or the triflouroacetic acid salt thereof, Piperidine 4-carboxylic acid [ (IR) -l-( (IR) -l-(3-methyl- [1,2,4] oxadiazol-5-yl) -2-phenylethylcarbamoyl ) -2- (2- naphthyl ) ethyl ] amide , 3 -Aminomethyl-N- [ ( IR) -1- { ( IR) -1- (3-methyl- [1,2,4] oxadiazol-5-yl ) - 2 -phenylethylcarbamoyl ) -2- (2 -naphthyl ) ethyl ] benzamide, 4-Amino-4-methyl-pent-2-enoic acid [ (IR) -l-{ (IR) -l-(3-methyl- [1, 2 , 4 ] oxadiazol-5-yl) -2-phenylethylcarbamoyl ) -2- ( 2 - naphthyl ) ethyl ] amide , (3R) -Piperidine 3-carboxylic acid [ (lR)-l-( (IR) -l-(3-methyl- [ 1 , 2 , 4 ] oxadiazol-5-yl ) -2-phenylethylcarbamoyl ) -2- ( 2 - naphthy 1 ) ethyl ] amide , 3-Aminomethyl-N-( (IR, 2E, 4S) -4 -carbamoyl -5- (2 -naphthyl) -l-(2- naphthyl ) methy lpent-2 -enyl ) benzamide , Piperidine-4-carboxylic acid ( (1R,2E,4S)-4-carbamoyl-5-(2- naphthy1)-1-(2-naphthyl)methylpent-2-eny1)amide, N-( (lR)-l-( ( (lR)-l-( ( (lS)-5-Amino-l- (dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethoxy)methy1)-2-(2- naphthyl)ethyl)-3-aminomethylbenzamide, N-((lR,4S)-4-(((lS)-5-Amino-l- (dimethylcarbamoyl ) pentyl ) carbamoyl ) -1- ( ( 2-naphthyl ) methyl ) -2-oxo- 5-phenylpentyl) -3-aminomethylbenzamide, N-( (lR,2R,4S)-4-( ( (IS) -5-Amino-l- (dimethylcarbamoyl) pentyl) carbamoyl) -2-hydroxy-l- ( 2 -naphthyl ) methy 1-5-phenylpentyl ) -3 -aminomethylbenzamide , Piperidine-3-carboxylic acid ((IR, 2R, 4S) -4-( ( (IS) -5-amino-l- (dimethyl-carbamoyl) pentyl) carbamoyl) -2 -hydroxy- 1- ( (2- naphthyl ) methyl ) -5-phenylpentyl ) amide , 5-( (1R)-1- (N-Methyl-N- ( (2R) -3- (2-naphthyl) -2- (piperidin-4-yl- carbonylamino) propionyl) amino) -2- (2-naphthyl) ethyl) - [1, 2, 4]oxadiazole-3-carboxylic acid ethylester, 5-( (lR)-l-(N-( (2R)-2- ( 3 -Aminomethy lbenz oy 1 amino ) -3- (2- naphthyl) propionyl) -N-methylamino) -2- (2 -naphthyl ) ethyl) - [1,2 ,4]oxadiazole-3-carboxylic acid ethylester, 5-( ( IR) -1- (N- ( (2R) -2- ( 3 -Aminomethy lb en z oyl amino ) -3- ( 2- naphthyl) propionyl) -N-methylamino) -2 -phenylethyl) - [l,3,4]oxadiazole-2-carboxylic acid amide, (2E)-5-Amino-5-methylhex-2-enoic acid { (IR) -1- [N-methyl-N- ( (IR) -1- ( 3 -methyl- [1,2,4 ]oxadiazol-5-yl) -2- (2 -naphthyl )- ethyl ) carbamoyl ] -2 - ( 2 -naphthyl ) ethyl ) amide , 4-Amino-4-methylpent-2-enoic acid N-[ (IR)-l-{N-methyl-N-[ (1R)-1- (3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2- naphthy1)ethyl]carbamoyl)-2-(2-naphthyl)ethyl]-N-methylamide, (2E)-4-Amino-4-methylpent-2-enoic acid N-[ (IR)-l-{N-methyl-N- [ (lR)-l-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-(2- naphthy 1 ) ethyl ] carbamoyl ) -2 - ( 2 -naphthyl ) ethyl ] amide , 3 -Aminomethyl-N- ( ( IR) -1- { N- [ ( IR) -1- ( ( (dimethylca rbamoyl) methoxy) methyl) -2 -phenylethyl ]-N- methylcarbamoyl )-2- (2 -naphthyl) ethyl) -N-methylbenzamide, 5- ( (IR) -1- ( ( (2R) -2- ( ( (2E) -4-Amino-4-methylpent-2- enoyl)methylamino) -3-(2-naphthyl)propionyl)methylamino) -2- phenylethyl)-[l,3,4]-oxadiazole-2-carboxylic acid amide Piperidine-4-carboxylic acid N-methyl-N-(l-(methyl-[l-(3- methyl-[1,2,4]oxadiazole-5-yl)-2-(2-naphthyl)ethyl]carbamoyl)-2- (2-naphthyl)ethyl)amide, Piperidine-4-carboxylic acid N-{l-(N-[methyl-N-[l-(3- methyl-[1,2,4]-oxadiazole-5-yl)-2-(2-naphthyl)ethyl]carbamoyl)-2- (2-naphthyl)ethyl)amide, 5-{l-[N-2-(piperidine-4-carbonylamino)-3-(2- naphthyl) propionyl) -N-methylamino] -2- (2-naphthyl) ethyl )- [l,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester, 5-(l-[N-(2-(Piperidine-4-carbonylamino)-3-(2- naphthyl ) propionyl) -N-methylamino] -2- (2 -naphthyl) ethyl ) - [l,2,4]oxadiazole-3-carboxylic acid, trifluoro acetic acid, Piperidine-4-carboxylic acid (l-{N-[l-( 3 -methylcarbamoyl- [1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2 (2-naphthyl)ethyl)amide, (2E)-5-Amino-5-methylhex-2-enoic acid {l-[N-(l-(3- benzylcarbamoyl-[l,2,4]oxadiazol-5-yl)-2-phenylethyl)-N-methyl carbamoyl]-2-(2-naphthyl)ethyl)amide, (2E)-5-Amino-5-methylhex-2-enoic acid N-{ (IR)-l-[N-( (IR)-1 -benzyl-2 , 5-dihydroxypentyl ) -N-methylcarbamoyl ] -2- (2 naphthy1)ethyl}-N-methylamide, 3-Aminomethyl-N-( (IR)-1-{N-[ (IR)-1-(2-hydroxyethoxymethyl)-2 -phenylethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N- methylbenzamide, Piperidine-4-carboxylic acid ( (1R,2E)-4-hydroxymethyl-5-(2-naph thyl)-l-( (2-naphthyl)methyl)pent-2-enyl)amide, Piperidine-4-carboxylic acid ( (IR)-2-(2-naphthyl)-1-( (IR)-2- (2-naphthyl)-l-(l-phenethyl-lH-tetrazol-5-yl)ethyl¬ carbamoyl)ethyl)amide, Piperidine-4-carboxylic acid N-methyl-N-( (IR)-2-(2-naphthyl)-1- ( (IR)2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)amide, Piperidine-4-carboxylic acid ( (IR)-l-( (IR)-l-(4-carbamoyl-5-phe nyl-1,3-thiazol-2-yl)-2-(2-naphthyl)ethylcarbamoyl)-2-(2-naph- thy1)ethyl)amide, (2E)-5-Amino-5-methylhex-2-enoic acid {l-[N-(l-(3- methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl)-N-methyl¬ carbamoyl]-2-(2-naphthyl)ethyl)amide, (2E)-5-Amino-5-methylhex-2-enoic acid {l-[N-(l-(3- dimethylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl)-N-methyl¬ carbamoyl]-2-(2-naphthyl)ethyl)amide, (2E)-5-Amino-5-methyl-N-( (IR)-1-(N-( (IR)-l-(2- hydroxyethoxymethyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2- naphthyl)ethyl)-N-methylhex-2-enoic acid amide, (2E)-5-Amino-5-methyl-N-((lR)-l-(N-((lR)-l-(2-hydroxy-2- methylpropoxymethyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2- naphthy1)ethyl)-N-methylhex-2-enoic acid, or a pharmaceutically acceptable salt thereof or all possible optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof. 15. The compound of the general formula wherein D, G and J are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 16. The compound according to claim 15, wherein D is R 5 NN (CH,)—(CR 7 R 8 ) S (CH 2 ) t ( ) q —(CH 2 ) o — R 6 wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or Ci.g-alkyl optionally substituted with halogen, amino, hydroxy o aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 )i-U-(CH 2 ) j - , wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, o Cj.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is l, 2, 3 or 4. 17. The compound according to any one of claims 15 or 16, wherei J is 18. The compound according to any one of claims 15, 16 or 17 wherein G is 19. The compound of the general formula wherein D, J, G, E, m and p are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 20. The compound according to claim 19, wherein D is N (CH 2 )—(CR 7 R 8 ) S (CH 2 ) t ( ) q —(CH 2 )^ wherein R , R 6 , R 7 and R independently are hydrogen or Cj.g-alkyl optionally substituted with halogen, amino, hydroxy o aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R θ or R 7 and R 8 optionally forming -(CH 2 ).-U-fCHj),-, wherein i and j independently are l or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, C j .g-alkyl o Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4. 21. The compound according to any one of claims 19 or 20, wherei J is 22. The compound according to any one of claims 19, 20 or 21, wherein G is -co . -a or - 23. The compound according to any one of claims 19, 20, 21 or 22, wherein E is hydrogen. wherein L is hydrogen, -OR 9 , -CONR 9 R 10 , obtionally substituted with hydroxy or Cj.g-alkoxy or Y-V ~~ x -X γ=v wherein R 9 and R 10 are independently hydrogen , Cι_ 6 -alkyl or together form -(CH 2 ) k -U'-(CH 2 )i-, wherein k and 1 independently are 1, 2 or 3, and k+1 is 3, 4, 5 or 6, U' is -o-, -s- or a valence bond; X is -N(R")-, -O- or -S-, V is -C(R' 2 )= or -N=, Y is -C(R' 3 )= or -N=, Z is -C(R 1 )= or -N=, R 12 , R 13 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , -(CH 2 ) V NR 16 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, Cι_ δ -alkyl, phenyl, oxazol-5-yl , 5-methyl- [1,2,4] oxadiazol-3-yl , R 11 , R 15 , R 16 and R 17 independently are hydrogen or C j .g-alkyl obtionally substituted with aryl, and u and v are independently 0 or 1 , 2 , 3 , 4 , 5 or 6 ; K is >18 N (CH 2 ) a — (CR 0 R 21 ) b (CH 2 ) d - R 19 wherein R 18 , R 19 , R 20 and R 2 ' are independently hydrogen, Ci.g-alkyl optionally substituted with halogen, amino, Ci.g-alkylamino, hydroxy or aryl; R 18 and R 19 , R 18 and R 21 , R 19 and R 20 or R 20 and R 21 optionally forming -(CH 2 ) k .-Z-(CH 2 )i.-where k' and l' independently are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -0-, -S- or a valence bond; b is 0 or 1; a and d are independently 0, 1, 2, 3 or 4; and a+b is 1 to 4. 24. The compounds of the general formula wherein D, J, G, E, m and p are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 525. The compound according to claim 24, wherein D is N (CH 2 ) j - (CR 7 R 8 ). (CH 2 ) t ( ) q —(CH 2 )- R 6 wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or Cj.g-alkyl optionally substituted with halogen, amino, hydroxy or 0 aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 )i-U-(CH 2 ) j -, wherein i and j independently are 1 or 2, and U is -O-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, Cj.g-alkyl or C ι _ 6 -alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; 0 and r+s+t is 1, 2, 3 or 4. 26. The compound according to any one of claims 24 or 25, wherein J is 27. The compound according to any one of claims 24, 25 or 26, wherein G is 28. The compound according to any one of claims 24, 25, 26 or 27 wherein E is hydrogen, CH * z // or X, Y-V Y=V wherein L is hydrogen, -OR 9 , -CONR 9 R 10 , Cj.g-alkyl obtionall substituted with hydroxy or Ci.g-alkoxy W // or \ / Y-V Y=V wherein R 9 and R 10 are independently hydrogen, Cj.g-alkyl or together form -(CH 2 ) k -U'-(CH 2 )i-, wherein k and 1 independently are 1, 2 or 3, and k+1 is 3, 4, 5 or 6, U' is -0-, -S- or a valence bond; X is -N(R")-, -O- or -S-, V is -C(R 12 )= or -N=, Y is -C(R 13 )= or -N=, Z is -C(R' 4 )= or -N=, R 12 , R 13 and R 14 independently are hydrogen, -COOR 15 , -CONR 16 R 17 , -(CH 2 ) V NR 16 R 17 , -(CH 2 ) u OR 15 , halogen, hydroxy, Ci.g-alkyl, phenyl, oxazol-5-yl , 5-methyl- [ 1,2,4] oxadiazol-3-yl , R 1 ', R 15 , R 16 and R 17 independently are hydrogen or C j .g-alkyl obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6; K is .18 >N (CH 2 )_ (CR 20 R 21 ) b -<CH 2 ) d - > >19 wherein R 18 , R 19 , R 20 and R 21 are independently hydrogen, Cj.g-alkyl optionally substituted with halogen, amino, C ι . 6 -alkylamino, hydroxy or aryl; R 18 and R 19 , R 18 and R 21 , R 19 and R 20 or R 20 and R 21 optionally forming -(CH 2 ) k .-Z-(CH 2 ) : . -where k' and l' independently are 1, 2 or 3, and k'+l' are 3, 4, 5 or 6; Z is -0-, -s- or a valence bond; b is 0 or 1; a and d are independently 0, l, 2, 3 or 4; and a+b is l to 4 . 29. The compounds of the general formula wherein D, J, G, E, m and p are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 30. The compounds of the general formula wherein D, J, R 1 , G, and R 12 are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 31. The compound according to claim 30, wherein D is R 5 N (CH 2 )— (CR 7 R 8 ) S (CH 2 ) t (M) q — (CH 2 ) o — R 6 wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or C ι . 6 -alkyl optionally substituted with halogen, amino, hydroxy or aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 )i-U-(CH 2 ) j -, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, Cj.g-alkyl or Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4. 32. The compound according to any one of claims 30 or 31, wherein J is χ *^o 33. The compound according to any of claims 30, 31 or 32, wherein G is 34. The compounds of the general formula 5 wherein D, J, R 4 and m are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof, 1035. The compound according to claim 34, wherein D is N (CH 2 )—(CR 7 R 8 ) S (CH 2 ) t (M)- wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or Cι_ 6 -alkyl optionally substituted with halogen, amino, hydroxy or aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R a optionally forming wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, Ci.g-alkyl or Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4. 36. The compound according to any one of claims 34 or 35, wherein J is 37. The compound of the general formula wherein D, R 2 , J, R 1 , G, R 9 , R 10 and p are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 538. The compound according to claim 37, wherein D is N (CH 2 )—(CR 7 R 8 ) S (CH 2 ) t -(M) f -(CH 2 V—- wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or Ci-g-alkyl optionally substituted with halogen, amino, hydroxy o 0 aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 ) 1 -U-(CH 2 ) j -, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, Cj.g-alkyl o Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; 0 and r+s+t is 1, 2, 3 or 4. 39. The compound according to any one of claims 37 or 38, wherei J is 40. The compound according to any of claims 37, 38 or 39, wherein G is 41. The compound of the general formula wherein D, R 2 , J, R 1 , G, and p are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 42. The compound according to claim 41, wherein D is N (CH 2 ) r (CR 7 R 8 ). (CH 2 2)>t -(M) r ■ (c H 2) — wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or Ci.g-alkyl optionally substituted with halogen, amino, hydroxy o aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 ) .-U-(CH 2 ) _ - , wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, Cj_ 6 -alkyl o Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4. 43. The compound according to any one of claims 41 or 42, wherei J is x °< O 44. The compound according to any one of claims 41, 42 or 43, wherein G is 545. The compound of the general formula wherein D, R 2 , J, R 1 , G, and p are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic 0 mixtures thereof. 46. The compound according to claim 45, wherein D is R- NN (CH 2 )—(CR 7 R 8 ) S (CH 2 ), ■(M) q —(CH 2 ) o — wherein R 5 , R 6 , R 7 and R 8 independently are hydrogen or C j .g-alkyl optionally substituted with halogen, amino, hydroxy o aryl; R 5 and R 6 , R 6 and R 7 , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 )i-U-(CH 2 ) j -, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, C j .g-alkyl o C ι _ 6 -alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4. 47. The compound according to any one of claims 45 or 46, wherei J is 48. The compound according to any of claims 45, 46 or 47, wherei G is hydrogen, 49. The compound of the general formula wherein D, R 2 , J, R 1 , G, and p are as defined in claim 1; or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. 50. The compound according to claim 49, wherein D is N (CH 2 )—(CR 7 R 8 ) S (CH 2 ) t - -(M) q —(CH 2 )- wherein R 5 , R 5 , R 7 and R θ independently are hydrogen or Cj.g-alkyl optionally substituted with halogen, amino, hydroxy o aryl; R 5 and R 6 , R 6 and R , R 5 and R 8 or R 7 and R 8 optionally forming -(CH 2 ).-U-fCHz),-, wherein i and j independently are 1 or 2, and U is -0-, -S- or a valence bond; M is -0-, -S-, -CH=CH-, optionally substituted with halogen, amino, hydroxy, C j _ 6 -alkyl o Ci.g-alkoxy; o, r and t are independently 0, 1, 2, 3 or 4; q and s are independently 0 or 1; and r+s+t is 1, 2, 3 or 4. 51. The compound according to any one of claims 49 or 50, wherei J is 52. The compound according to any one of claims 49, 50 or 51 wherein G is 53. A pharmaceutical composition comprising, as an active ingredient, a compound of the general formula I according to any 5 one of claims 1-52 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 54. A composition according to claim 53 in unit dosage form, comprising from about 10 to about 200 mg of the compound of the general formula I or a pharmaceutically acceptable salt thereof. 1055. A pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound of the general formula I according to any one of claims 1-52 or a pharmaceutically acceptable salt thereof together with a pharmaceutically 15 acceptable carrier or diluent. 56. A method of stimulating the release of growth hormone from the pituitary, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula I according to any one of claims 1-52 or a 20 pharmaceutically acceptable salt thereof. 57. A method of increasing the rate and extent of growth, the mil and wool production, or for the treatment of ailments, the metho comprising administering to a subject in need thereof an effectiv amount of a compound of the general formula I according to any on of claims 1-52 or a pharmaceutically acceptable salt thereof. 58. A method according to claim 56 or 57, wherein the effectiv amount of the compound of the general formula I o pharmaceutically acceptable salt or ester thereof is in the rang of from about 0.0001 to about 100 mg/kg body weight per day preferably from about 0.001 to about 50 mg/kg body weight per day 59. Use of a compound of the general formula I according to an one of claims 1-52 or a pharmaceutically acceptable salt thereo for the preparation of a medicament. 60. Use of a compound of the general formula I according to an one of claims 1-52 or a pharmaceutically acceptable salt thereo for the preparation of a medicament for stimulating the releas of growth hormone from the pituitary. 61. Use of a compound of the general formula I according to an one of claims 1-52 or a pharmaceutically acceptable salt thereo for the preparation of a medicament for administration to animal to increase their rate and extent of growth, to increase thei milk and wool production, or for the treatment of ailments.

Inventors: ANKERSEN MICHAEL, HANSEN THOMAS KRUSE, JOHANSEN NILS LANGELAND, LAU JESPER, PESCHKE BERND, ANKERSEN, MICHAEL, HANSEN, THOMAS, KRUSE, JOHANSEN, NILS, LANGELAND, LAU, JESPER, PESCHKE, BERND
Applicants: ANKERSEN MICHAEL, HANSEN THOMAS KRUSE, JOHANSEN NILS LANGELAND, LAU JESPER, NOVONORDISK AS, PESCHKE BERND, ANKERSEN, MICHAEL, HANSEN, THOMAS, KRUSE, JOHANSEN, NILS, LANGELAND, LAU, JESPER, NOVO NORDISK A/S, PESCHKE, BERND
Application year: 1996
Main classification: C07K5
IPC codes: A61K31, A61K38, A61P43, C07C233, C07C237, C07D211, C07D257, C07D271, C07D277, C07D401, C07D413, C07D417, C07K5, C07K14