MXPA99010306A

MXPA99010306A - Protease inhibitors

Info

Publication number: MXPA99010306A
Application number: MXPA/A/1999/010306A
Authority: MX
Inventors: Edward Bondinell William; Frank Veber Daniel; Louise Desjarlais Renee; Shinji Yamashita Dennis
Original assignee: Smithkline Beecham Corporation
Priority date: 1997-05-08
Filing date: 1999-11-08
Publication date: 2000-05-01

Abstract

The present invention provides bis-aminomethylcarbonyl compounds that are inhibitors of cysteine and serine proteases. The compounds are particularly useful for treating diseases in which excess cysteine protease activity has been implicated, including osteoporosis, periodontitis and arthritis.

Description

PROTEASE INHIBITORS FIELD OF THE INVENTION This invention relates generally to inhibitors of bis-aminomethyl carbonyl protease, particularly, to inhibitors of cysteine and serine proteases, very particularly to compounds that inhibit cysteine proteases, still more particularly compounds that inhibit cysteine proteases from the papain superfamily, even more particularly to compounds that inhibit cysteine proteases of the cathepsin family, very particularly compounds that inhibit cathepsin K. Said compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive loss of bone or cartilage, for example , osteoporosis, periodontitis and arthritis.

BACKGROUND OF THE INVENTION Cathepsins are a family of enzymes that are part of the papain superfamily of cysteine proteases. Recently, the cathepsin K polypeptide and the cDNA encoding said polypeptide have been described in the patent of E.U.A. No. 5,501, 969 (called cathepsin O there). Cathepsin K has been expressed, purified and characterized recently. Bossard, M.J. and others, (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H. and others, (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D. And others (1996) J. Biol. Chem. 21? , 2126-2132. Cathepsin K has been called cathepsin O or cathepsin 02 differently in the literature. The designation cathepsin K is considered the most appropriate. Cathepsins function in the normal physiological process of protein degradation in animals, including humans, for example, in the degradation of connective tissue. However, the elevated levels of these enzymes in the body can result in pathological conditions that lead to diseases. In this manner, cathepsins have been implicated in various disease states, including but not limited to, infections by Pneumocystis carinii, Trypanosoma cruzi, Trypanosoma brucei brucei and Chrythidia fasciculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amitrophy and the like. See international publication number WO 94/04172, published March 3, 1994, and references cited therein. See also European patent application EP 0 606 873 A1 and references cited therein. Two bacterial cysteine proteases of P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.

It is believed that cathepsin K plays a causative role in diseases of excessive loss of bone or cartilage. The bone is composed of a matrix of proteins in which hydroxyapatite crystals are incorporated in the form of cylinders or plates. Collagen type 1 represents the main structural protein of bone that comprises approximately 90% of the structural protein. The remaining 10% of the matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin and bone sialoprotein. Skeletal bone undergoes remodeling in discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a phase of bone resorption followed by a phase of bone replacement. The bone resorption is carried out by osteoclasts, which are the multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the surface of the bone and form a narrow sealing zone, followed by an extensive membrane undulation on its apical surface (i.e., resorption). This creates a closed extracellular compartment on the surface of the bone that is acidified by pumping protons in the corrugated membrane, and within which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves the hydroxyapatite crystals on the surface of the bone, while the proteolytic enzymes digest the protein matrix. In this way, a resorption or pitting lagoon is formed. At the end of this phase of the cycle, osteoblasts establish a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget's disease, the normal balance between bone resorption and bone formation is altered, and there is a true actual bone loss in each cycle. Finally, this leads to weakening of the bone and can cause an increased risk of fracture with minimal trauma. Several published studies have shown that cysteine protease inhibitors are effective in inhibiting bone resorption mediated by osteoclasts, and indicate an essential role for cysteine proteases in bone resorption. For example Delaisse, et al., Biochem J. 1980, 192,365, describe a series of protease inhibitors in a culture of mouse bone organs and suggest that cysteine protease inhibitors (e.g., leupeptin, Z-Phe-Ala- CHN2) prevent bone resorption, whereas serine protease inhibitors were not ineffective. Delaisse, and others, Biochem. Biofis Res. Commun., 1984, 125,441, describe that E-64 and leupeptin are also effective in preventing bone resorption in vivo, as measured by acute changes in serum calcium levels in rats with calcium-deficient diets. Lerner et al., J. Bone Min. Res., 1992,7,433, describe that cystatin, an endogenous inhibitor of cysteine protease, inhibits bone resorption stimulated by PTH in mouse calvaries. Other studies, such as by Delaisse, et al., Bone, 1987,8305, Hill, and others J. Cell. Biochem., 1994, 56, 118 and Everts et al., J.

Cell. Physiol., 1992, 150, 221, also report a correlation between the inhibition of cysteine protease activity and bone resorption. Tezuka et al., J. Biol. Chem. 1994, 269, 1106, Inaoka et al., Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi et al., FEBS Lett, 1995, 357, 129 describe that under normal conditions cathepsin K (which has also been called cathepsin O), a cysteine protease, is expressed abundantly in osteoclasts. and it may be the largest cysteine protease present in these cells. The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K can provide effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, malignant hypercalcemia and metabolic disease. of bone. Cathepsin K levels have also been shown to be elevated in osteoarthritic synovium chondroclastics. In this way, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. In this way, selective inhibition of cathepsin K may also be useful in treating certain neoplastic diseases.

Several cysteine protease inhibitors are known. Palmer (1995) J. Med. Chem., 38, 3193, describes certain vinylsulfones which irreversibly inhibit cysteine proteases, such as cathepsins B, L, S, 02 and cruzain. Other classes of compounds have also been reported, such as aldehydes, nitriles, a-ketocarbonyl compound, halogenomethyl ketones, diazomethylketones, (acyloxy) methyl ketones, salts of cetomethylsulfonium and succinyl epoxies, which inhibit cysteine proteases. See Palmer, id, and references cited therein. The patent of E.U.A. No. 4,518,528 discloses peptidylfluoromethyl ketones as irreversible inhibitors of cysteine proteases. The published international patent application No. WO 94/04172, and the European patent applications Nos. EP 0 525 420 A1, EP 0 603 873 A1 and EP 0 611 756 A2, describe alkoxymethyl and mercaptomethyl ketones that inhibit cysteine proteases cathepsins B, H and L. International patent application No. PCT / US94 / 08868 and European patent application No. EP 0 623 592 A1 describe alkoxymethyl and mercaptomethyl ketones that inhibit the cysteine protease IL-1β convertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT / GB91 / 01479). Azapeptides which are designed to deliver the azaamino acid to the active site are serine proteases, and those which possess a good leaving group, are described by El more and others, Biochem. J., 1968, 107, 103, Garker et al., Biochem. J., 1974, 139, 555, Gray et al., Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al., J. Biol. Chem., 1984 , 259, 4288, and are known to inhibit serine proteases. In addition, J. Med. Chem., 35, 4279, discloses certain azapeptide esters as inhibitors of cysteine protease. Antipain and leupeptin are described as reversible inhibitors of cysteine proteases in McConnell et al., J. Med. Chem., 33, 86; and they have also been described as serine protease inhibitors in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well known cysteine protease inhibitors (Barrett, Biochem J., 201, 189 and Grinde, Biochem Biophys. Acta, 701, 328). The 1,3-diamido-propanones have been described as analgesic agents in the patents of E.U.A. Nos. 4, 749,792 and 4,638,010. In this way, a structurally diverse variety of cysteine protease inhibitors has been identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from several disadvantages. These disadvantages include lack of selectivity, cytotoxicity, poor solubility and too rapid plasma clearance. Therefore, there is a need for methods to treat diseases caused by pathological levels of proteases, especially cysteine proteases, including cathepsins, especially cathepsin K, and novel inhibitory compounds useful in such methods.

We have now discovered a novel class of bis-aminomethyl carbonyl compounds that are protease inhibitors, most particularly of cathepsin K.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide bis-aminomethyl carbonyl protease inhibitors, particularly inhibitors of cysteine and serine proteases, very particularly compounds that inhibit cysteine proteases, still more particularly compounds that inhibit cysteine proteases of the papain superfamily, still more particularly compounds which inhibit cysteine proteases of the cathepsin family, more particularly compounds that inhibit cathepsin K, and which are useful for treating diseases that can be therapeutically modified by altering the activity of said proteases. Accordingly, in the first aspect, this invention provides a compound according to formula I. In another aspect, this invention provides a pharmaceutical composition comprising a compound according to formula I and a pharmaceutically acceptable carrier, diluent or excipient. In still another aspect, this invention provides intermediates useful in the preparation of the compounds of formula I.

In still another aspect, this invention provides methods for treating diseases in which the pathology of the disease can be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, most particularly cysteine protease, still more particularly cysteine proteases of the papain superfamily, even very particularly cysteine proteases of the cathepsin family, most particularly cathepsin K. In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive degradation of cartilage or matrix, such as osteoarthritis and rheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of formula I: where: R1, R2 and R3 are independently H; C.-6 alkyl, preferably methyl or isobutyl; C3-1 cycloalkyl; C2.6 alkenyl; C2_6 alkynyl; Ar, preferably phenyl; Het; C? -6-Ar alkyl, preferably benzyl; C3_n-Ar cycloalkyl; C2-6-Ar alkenyl; C2-6 alkynyl-Ar; C.-6-Het alkyl, preferably isonicotinyl; C3-11-Het cycloalkyl; C2-6-Het alkenyl; or C2-6 alkynyl-Het; R4 is N- (R6) -NHCH (C6-6 alkyl) -CO, preferably N-R6-leucinyl, N-R6-norleucinyl, N-R6-norvalinyl, N-R6-isoleucinyl, N-R6-a -alyl-glycine, N-R6-a- (cyclopropylmethyl) -glycyl, N-R6-ß-ér-butyl-alaninyl or N-R6-homo-leucinyl; N, N-R6- (C6-alkyl) -N (C6-6 alkyl) -CO, preferably N, N-R6-methyl-leucinyl; N- (R6) -NHCH (C2-6 alkenyl) -CO-; N- (R6) -NHCH (C2-6 alkynyl) -CO-; N- (R6) -NHCH (C1-6alkyl-Ar) -CO-; N- (R6) -NHCH (C2-6-Ar alkenyl) -CO-; N- (R6) -NHCH (C2-6 alkynyl-Ar) -CO-; N- (R6) -NHCH (d-6-Het alkyl) -CO-; N- (R6) -NHCH (C2-6 alkenyl-Het) -CO-; N- (R6) -NHCH (C2-6-Het alkynyl) -CO-; ArCO, preferably 3-phenoxy-benzoyl, 4-phenoxy-benzoyl or 2-benzyloxy-benzoyl; Ar-C6-CO-alkyl, preferably 4-biphenyl-acetyl, 2- (4-biphenyl) -4-methyl-valeryl, 2- (3-biphenyl) -4-methyl-valeryl, 1- ( 3-biphenyl) -but-3-ene-1-carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl, 1- (3-biphenyl) -3-methyl-but-3-ene -1-carbonyl, 3- (2-pyridyl) -phenylacetyl or 3- (3-pyridyl) -phenylacetyl; Ar-SO2, preferably 3-phenoxy-phenylsulfonyl, 4-phenoxy-phenylsulfonyl or 3- (4- (3-chloro-2-cyano-phenoxy) phenylsulfonyl; Ar-C? 6-S02 alkyl; Het-CO; Het-alkyl of C6-CO, Het-S02, preferably 8-quinolinesulfonyl, or Het-alkyl of C6-SO2; R5 is N-R7 amino acid, preferably N- (R7) -NHCH (alkyl C- | .6) -CO, more preferably N-R7-leucinyl, N-R7-norleucinyl, N-R7-norvalinyl, N-R7-isoleucinyl, N-R7-a-allyl-glycinyl, N-R7-a - (cyclopropylmethyl) -glycnyl, N-R7-ß-ér-butyl-alaninyl or N-R7-homo-leucinyl, preferably N- (R7) -NHCH (C2-6 alkenyl) -CO, preferably N-R7- NHCH (alkynyl C2.6) -CO, preferably N- (R7) -NHCH (C6-Ar alkyl) -CO, more preferably N- (R7) -phenylalaninyl, preferably N- (R7) -NHCH (C2-akenyl) -6-Ar) -CO, preferably N- (R7) -NHCH (C2_6-Ar alkynyl) -CO, preferably R7-γ-t-butyl-glutamyl, preferably R7-glutamyl or preferably N, N-R7- ( CrC6 alkyl) -leucylidene; C6-6C0 alkyl, preferably acetyl; C3-n-CO cycloalkyl; ArCO, preferably benzoyl, 3-phenoxy-benzoyl, 4-phenoxy-benzoyl, 2-benzyloxy-benzoyl, 3-benzyloxy-benzoyl or 4-benzyloxy-benzoyl; Ar-alkyl of C -? - 6-CO, preferably 2- (4-biphenyl) -4-methyl-valeryl, 2- (3-biphenyl) -4-methyl-valeryl, 1- (3-biphenyl) -but -3-ene-1-carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl, 1- (3-biphenyl) -3-methyl-but-3-ene-1-carbonyl, - (3-biphenyl) -but-3-ene-1-carbonyl, 3- (2-pyridyl) -phenyl-acetyl, 3- (3-pyridyl) -phenyl-acetyl, 4-biphenyl-acetyl or 3- biphenyl acetyl; Ar-SO 2, preferably 3-biphenyl sulfonyl, 4-cyano-phenyl sulfonyl, 2-carboxyl-phenyl-sulfonyl, 2-carboxymethyl-phenyl-sulfonyl, 4-C-tetrazolo-phenyl-sulfonyl, 1-naphthalene sulfonyl, 3-phenoxy-phenyl sulfonyl, 4-phenoxy-phenyl sulfonyl, 3- (4- (3-chloro-2-cyano-phenoxy) -phenyl-sulfonyl, 4-biphenyl-sulfonyl or 2-dibenzofuran-sulfonyl; -alkyl-C6-SO2; Het-CO, preferably 8-quinolino carbonyl, 6-quinolino carbonyl, 2-pyridino carbonyl, 5- (2-pyridyl) -thiophene carbonyl, N-benzyl-4-piperidinyl carbonyl or 2-quinolino carbonyl; C -? - 6-CO; Het-S02, preferably 2-pyridyl sulfonyl, 1,3-dimethyl-5-chloro-pyrazolo-4-sulfonyl, 3,5-dimethyl-isoxazolo-4-sulfonyl, benzo-2, 1,3-thiadiazole-4-sulfonyl, phenyl-sulfone-5-thiophene-2-sulfonyl, 2-carboxymethyl thiophene-sulfonyl, 2,5-dichlorothiophene-3-sulfonyl or 8-quinoline sulfonyl; 6; Ar-C6-alkyl, preferably phenyl; Het-alkyl of Co-β! R6 and R7 are independently Ar- (C? 6 alkyl) -O-CO, pre preferably benzyloxycarbonyl; Het- (C? _6 alkyl) -O-CO, preferably 2-pyridyl methyloxycarbonyl, 3-pyridyl methyloxycarbonyl or 4-pyridyl methyloxycarbonyl; Ar-CO, preferably benzoyl, 1-naphthoyl, 2-naphthoyl, 4-phenoxy-benzoyl, 3-phenoxy-benzoyl, 2-phenoxy-benzoyl, 2-chloro-benzoyl, 4-fluoro-benzoyl, 3,4-difluoro benzoyl, 4-trifluoromethyl benzoyl, 2-chlorobenzoyl, 4-carboxymethyl-benzoyl or 4-carboxyl-benzoyl; Ar-S02; Het-CO, preferably 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-quinolinecarbonyl, 3-quinolinecarbonyl, 4-quinolinecarbonyl, 5-quinolinecarbonyl, 6-quinolinecarbonyl, 7-quinolinecarbonyl, 8-quinoline carbonyl, 1-isoquinoline carbonyl, 3-isoquinoline carbonyl, 4-isoquinoline carbonyl, 5-isoquinoline carbonyl, 6-isoquinoline carbonyl, 7-isoquinoline carbonyl, 8-isoquinoline carbonyl, 1-benzothiophene carbonyl, 1- benzofurancarbonyl, 5-indole-carbonyl-sulfonyl, N-methyl-prolinyl, 2-quinoxalino-carbonyl, 5- (2,3-dihydrobenzofuran-carbonyl, 2-benzofuran-carbonyl, 2-benzothiophene-carbonyl, N-morpholino-carbonyl , N-methyl-piperidino-carbonyl or N-pyrazolo-carbonyl; Het-S02, preferably 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, 2-quinolino-sulfonyl, 3-quinolino-sulfonyl, 4-quinolino-sulfonyl, 5-quinoline sulphonyl, 6-quinoline sulfonyl, 7-quinoline sulfonyl, 8-quinoline sulfonyl, 1-isoquinoline sulphonyl, 3-isoquinoline inolino sulfonyl, 4-isoquinolino sulfonyl, 5-isoquinolino sulfonyl, 6-isoquinolino sulfonyl, 7-isoquinolino sulfonyl or 8-isoquinolino sulfonyl; Crß-CO alkyl, preferably acetyl; N, N-dimethyl glycinyl; cycloalkyl of C 3 -1 .CO, preferably fra 7s-4-propyl-cyclohexylcarbonyl or cyclohexylcarbonyl; alkyl of C.-6-SO2; C2-6-CO alkenyl; C2-6 alkenyl-SO2; C2-6 alkynyl-CO; C2-β-S02 alkynyl; Ar-C 1-6 alkyl-CO; Ar-Cr6-SO2 alkyl; C2-6-CO-alkenyl; C2-6-SO2 ar-alkenyl; C2-6-CO alkynyl; C2-6-SO2 ar-alkynyl; Het-C 6 -CO alkyl, preferably 4-imidazole acetyl, 2-pyridyl acetyl, 3-pyridyl acetyl, 4-pyridyl acetyl or N-morpholino acetyl, Het-alkyl of C.-6-SO 2; Het-alkenyl of C2-6-CO; Het-alkenyl of C2-6-SO2; Het-alkynyl of C2-6-CO; or C 2-6 Het-alkynyl-SO 2; and pharmaceutically acceptable salts, hydrates and solvates thereof. Preferred are compounds of formula I, wherein R 1, D 2 or R 2? R is H. Even more preferred are the compounds of formula I wherein: R 1 is H or C-β alkyl, preferably methyl; R2 and R3 are H; R 4 is N- (R 6) -NHCH (C-β-alkyl) -CO. preferably N-R6-leucinyl, more preferably N- (2-pyridylcarbonyl) -leucinyl, N- (8-quinolinecarbonyl) -leucinyl, N- (6-quinolinecarbonyl) -leucinyl, N- (4-imidazole acetyl) -leucynyl, N-benzoyl-leucinyl, N- (2-pyridyl sulfonyl) -leucinyl, N- (1-isoquinolino carbonyl) -leucinyl, N- (N-morpholino acetyl) -leucinyl, N- (N-methyl prolinyl) -leucinyl, N- (N, N-dimethyl glycine) -leucinyl, N- (8-quinolino-sulfonyl) -leucinyl, N-Cbz-leucinyl, N-pentafluorobenzoyl-leucinyl, N-2-naphthoyl-leucinyl, N-1-naphthoyl- leucinyl, N-4-fluorobenzoyl-leucinyl, N- (4-trifluoromethyl-benzoyl) -leucinyl, N-3,4-difluorobenzoyl-leucinyl, N-3,4-dimethoxybenzoyl-leucinyl, N- (1-benzothiophene) carbonyl) -leucinyl, N- (2-benzothiazolo-carbonyl) -leucinyl, N- (5-benzothiophene-carbonyl) -leucinyl, N- (6-benzothiophene-carbonyl) -leucinyl, N- (5-indole-carbonyl) -leucynyl, N- (fra 7S-4-propyl cyclohexylcarbonyl) -leucinyl, N- (2-quinoxaIino-carbonyl) -leucinyl, N-5- (2,3, dihydrobenzofuran) -carbonyl) -leucinyl, N- (2-benzofuran-carbonyl) -leucinyl, N- (N-methyl-2-indolo-carbonyl) -leucylidene, N- (2-chloro-benzoyl-carbonyl) -leucinyl, N- (4- phenoxy-phenylcarbonyl) -leucynyl, N- (3-methoxy-2-quinoline-carbonyl) -leucynyl, N- (2-pyridyl-methyleneoxycarbonyl) -leucylidene or N- ( cyclohexylcarbonyl) -leucinyl; or preferably N-R6-norleucinyl, more preferably N-Cbz norleucinyl, N- (2-naphthyl-carbonyl) -norleucinyl, N- (3,4, dimethoxy-benzoyl) -norleucinyl or N- (5-benzothiophene- carbonyl) -norleucinyl; or preferably N-R6-norvalinyl, more preferably N-Cbz-norvalinyl; or preferably N-R6-isoleucinyl, more preferably N-Cbz-isoleucinyl; or preferably N-R6-α-allyl-glycinyl; more preferably N-Cbz-α-allyl-glycinyl; or N, N-R6- (C.sub.6-alkyl) -N- (C.sub.6-alkyl) -CO, preferably N, N-R6-methyl-leucinyl, more preferably N-Cbz-N-methyl- leucinyl; or preferably N-R6-a- (cyclopropylmethyl) -glycinyl, more preferably N-Cbz-a- (cyclo-propylmethyl) -glycinyl; or preferably N-R6-L-ß-ér-butyl-alaninyl, more preferably N-Cbz-L-ß-ér-butyl-alaninyl or Ar-alkyl of Cr6-CO, preferably 2- (3-biphenyl) -4-methyl-valeryl or 1- (3-biphenyl) -but-3-ene-1-carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl; R5 is N-R7-norvalinyl, preferably N-Cbz-norvalinyl, C1-6-Aralkyl-CO, preferably 3- (2-pyridyl) -phenyl-acetyl, 3- (3-pyridyl) -phenyl-acetyl, 3- (3-biphenyl) -3-methyl-but-3-ene-1-carbonyl or 2- (3-biphenyl) -but-3-ene-1-carbonyl; or Het-SO, preferably 2-pyridyl sulfonyl, 8-quinoline sulfonyl, 1,3-dimethyl-5-chloro-pyrazolo-4-sulfonyl, 3,5-dimethyl-isoxazolo-4-sulfonyl, benzo-2,1, 3-thiadiazole-4-sulfonyl or 3-biphenyl sulfonyl; or Het-CO, preferably 8-quinolino carbonyl, 5- (2-pyridino) -thiophenecarbonyl, N-benzyl-4-piperidinylcarbonyl, 2-quinolinocarbonyl or 2-pyridinocarbonyl; or ArCO, preferably 4-phenoxy-phenyl-carbonyl or 2- (3-biphenyl) -3-methyl-valeryl; Ar-SO2, preferably 2-carboxymethyl-phenyl-sulfonyl, 2-carboxy-phenyl-sulfonium, 4-C-tetrazolo-phenylsulfonyl, 1-naphthalene-sulfonyl or 2-cyano-phenylsulfonyl; or Ar-alkyl of C.-β, preferably phenyl. Still more preferred are the compounds of formula I, wherein: R1 is H or Cr6 alkyl, preferably methyl; R2 and R3 are H; R4 is N (R6) -NHCH (C6-6 alkyl) -CO, preferably N-R6-leucinyl, more preferably Cbz-leucinyl, 2-naphthoyl-leucinyl, 4-fluorobenzoyl-leucinyl, 3,4-dimethoxybenzoyl- leucinyl, (l-benzothiophene carbonyl) -Iucynyl, (2-quinoxalino-carbonyl) -leucinyl, 5- (2,3-dihydro-benzofuran) -carbonyl) -leucinyl, (2-benzofuran-carbonyl) -leucinyl; or N-R6-norleucinyl, more preferably (2-naphthyl-carbonyl) -norleucinyl, (3,4-dimethoxy-benzoyl) -norleucinyl or (5-benzothiophene-carbonyl) -norleucinyl; or Ar-alkyl of Cr6-CO, preferably 2- (3-biphenyl) -4-methyl-valeryl; and R5 is Ar-alkyl of Cr6-CO, preferably 3- (2-pyridyl) -phenyl-acetyl; or Het-SO2; preferably 2-pyridyl sulfonyl. The compounds of formula I selected from the following group are particularly preferred embodiments of the present invention: 1-N- (N- (2-pyridylcarbonyl) -leucinyl) -amino-3-N- (2-pyridine) dil-sulfonyl) -amino-propan-2-one; 1-N- (N- (8-quinolinecarbonyl) -leucinyl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- (N- (2-quinoline carbonyl) -leucyl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- (N- (4-imidazolo acetyl) -leucinyl) -amino-3-N- (3-biphenyl-sulfonyl) -amino-propan-2-one; 1-N- (N- (2-pyridyl-carbonyl) -leuccinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N-benzoyl-leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (2-pyridyl-sulfonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (8-quinolinecarbonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (1-isoquinolino-carbonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (N-morpholino-acetyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (N-methyl prolinyl) -leucinyl) -amino-3-N- (8-quinolylcarbonyl) -amino-propan-2-one; 1-N- (N- (N, N-dimethylglycinyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (8-quinolino sulfonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-pentafluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-2-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1 - . 1-N- (N-1-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-pyridyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-4-fluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-3,4-difluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-3,4-dimethoxybenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (1-benzothiophene-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (5-indole-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-isoleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-norvalinyl) -amino-3-N- (3- (2-pyridyl) -phenyl] acetyl) -amino-propan-2-one; 1-N- (N-Cbz-α-allyl-glycinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-norleucinyl) -amino-3-N- (3- (2-pyridyl) -phene-1-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-N-methyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-a- (cyclopropyl) -methyl-glycol) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (N-benzyloxycarbonyl-L-β-fer-butylanine) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-carboxymethyl-phenyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (4-cyano-phenyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (2- (3-b-phenyl) -4-methylene-valerl) -amino-3-N- (3- (3-pyridyl) -3-phenyl-acetyl) -amino-propan -2-ona; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-pyridinocarbonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (5- (2-pyridin) -thiophene-carbonyl) -amino-propan-2- ona; 1-N- (2- (3-biphenyl) -4-methyl-vaaryl) -amino-3-N- (N-benzyl-4-piperidino-carbonyl) -amino-propan-2-one; 1-N- (2- (3-B-phenyl) -4-methyl-valeryl) -amino-3-N- (2-quinoline-carbonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-carboxyl-phenyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (4-C-tetrazolo-phenyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (2-pyridyl- (phenyl-acetyl) -amino- (S) -butan-2-one; 1-N- (2- (3-biphenyl) -3-methyl-valeryl) -1-N-methyl-amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino-propan-2-one; 1-N- (N-2-pyridyl carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenyl-carbonyl) -amino-propan-2 ona; 1-N- (N-8-quinoline-carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenyl-carbonyl) -amino-propan-2-one; 1-N- (N-2- quinoline-carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenyl-carbonyl) -amino-propan-2-one; 1-N- (N- (Cbz-norvalinyl) -amino-3-N- ( 8-quinolino-sulfonyl) -amino-propan-2-one; 1-N- (8-quinolino-sulfonyl) -amino-3-N- (8-quino-sulphonyl) -amino-propan -2-ona; 1-N- (2- (3-b-phenyl) -3-methyl-valeryl) -amino-3-N- (8-quinolino-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -3-methylene-valerl) -amino-3-N- (2- (3-biphenyl) -3-methyl-valeryl) -amino- propan-2-one; 1-N- (N- (Cbz-norvanl) -amino-3-N- (N- (Cbz-norvalinyl) -amino-propan-2-one; 1-N- (1- (3-b) phenyl) -but-3-ene-1-carbonyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- ( 1 - (3-biphenyl) -but-3-ene-1 -carbonyl) -amino-3-N- (1 - (3-biphenyl) -but-3-ene-1 -carbonyl) -propan-2-one; 1-N- (1 - (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2- ona; 1-N- (2- (3-bifenii) -3-methyl-but-3-ene-1-carbonyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino -propan-2-one; 1-N- (1 - (3-biphenyl) -3-methyl-but-3-ene-1 -carbonyl) -amino-3-N- (1 - (3-biphenyl) - 3-methyl-but-3-ene-1-carbonyl) -amino-propan-2-one; 1-N- (N- (trans-4-propyl-cyclohexyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) phenyl acetyl) -amino-propan-2-one; 1-N- (N- (2-quinoxalino-carbonyl) -leucinyl) -amino-3-N- (3- ( 2-pyridyl) -pheno-acetyl) -amino-propan-2-one; 1-N- (N- (5- (2,3-dihydro-benzofuran) -carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (N-methyl-2-indole-carbonyl) -leucyl] -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (N- (cyclohexyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-chloro-benzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-benzofuran-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (3-phenoxy-phenol-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan -2-ona; 1-N- (N- (4-phenoxy-phenyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (3-methoxy-2-quinoline-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-one; 1-N- (N- (4-fluorobenzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-one; 1-N- (N- (2-benzothiophenecarbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-one; 1-N- (N- ( 2-pyridyl-methyleneoxycarbonyl) -leucylnl) -amino-3-N- (1-naphthalene sulfonyl) -amino-propan-2-one; 1-N- (N- (2-pyridyl-methyleneoxycarbonyl) -leucinyl) -amino-3-N- (1,3-dimethyl-5-chloro-pyrazolo-4-sulfonyl) -amino-propan-2 -one; 1-N- (N- (2-pyridyl-methyleneoxycarbonyl) -leucyl] -amino-3-N- (benzo-2,1, 3-thiadiazole-4-sulfonyl) -amino-propan- 2-one; 1-N- (N- (2-pyridyl-methyleneoxycarbonyl) -leucinyl) -amino-3-N- (3,5-dimethyl-isoxazolo-4-sulfonyl) -amino-propan-2-one; 1-N- (N- (4-trifluoromethyl-benzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (6-benzothiazolo-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (6-quinolino-carbonyl) -Ieucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (4-fluoro-benzoyl) -norleucyl] -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-naphthyl-carbonyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (3,4-dimrtixi-benzoyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (5-benzothiophene-carbonyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; and (S) -3-N- (N-Cbz-leucinyl) -amino-1-N- (phenyl) -5-methyl-hexan-2-one. The compounds of formula I selected from the following group are the most preferred embodiments of the present invention: 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl) acetyl) -amino-propan-2-one; 1-N- (N-2-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-4-flurobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-3,4-dimethoxybenzoyl-leucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (1-benzothiophenecarbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (5-indole-carbonyl) -leucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (2-pyridylsulfonyl) -amino-propan-2-one; -N- (2- (3-b-phenyl) -4-methyl-valeral) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino- propan-2-one; 1-N- (N- (2-quinoxaline-carbonyl) -leucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (N- (5- (2,3-dihydro-benzofuran) -carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino- propan-2-one; 1-N- (N- (2-benzofuran-carbonyl) -leucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan -2-ona; 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) - (phenyl acetyl) -amino- (S) -butan-2-one; 1-N- (N- (2-benzothiophenecarbonyl) -Ieucinyl) -amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-one; 1-N- ( N- (4-trifluoromethyl-benzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N - (2-naphthyl-carbonyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl] -acetyl) -amino-propan-2-one; 1-N- (N- (3,4-D-methoxy-benzoyl) -norleucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; and 1-N - (N- (5-benzothiophene-carbonyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one.

Definitions The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently linked compound that releases the drug of active origin in vivo according to formula I. If a chiral center or other form of an isomeric center is present in a compound of the present invention, it is intended that all forms of said isomer or isomers, including enantiomers and diastereomers, are covered herein. The compounds of the invention containing a chiral center can be used as a racemic mixture, enantiomerically enriched mixture, or the racemic mixture can be separated using well known techniques and a single enantiomer alone can be used. In cases where the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of the invention. In cases where the compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention, whether it exists in equilibrium or predominantly in one form. The meaning of any substituent in any occurrence in formula I or in any sub-formula thereof is independent of its meaning, or any other meaning of the substituent, in any other occurrence, unless otherwise specified. The abbreviations and symbols commonly used in the peptide and chemistry techniques are used herein to describe the compounds of the present invention. In general, the abbreviations of amino acids follow the nomenclature of the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem, 158.9 (1984). The term "amino acid" as used herein, refers to the D or L isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine , proline, serine, threonine, tryptophan, tyrosine and valine. "C.-β alkyl" as applied herein is intended to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, stilpentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any alkyl group of C.-6 can be optionally and independently substituted by one or two halogens SR ', OR', N (R ') 2, C (o) N (R') 2, carbamyl or alkyl of d-, wherein R 'is C-β alkyl. C0 alkyl means that no alkyl group is present in the portion. In this way, Ar-alkyl of C0 is equivalent to Ar. "Cycloalkyl of C3-1." as applied herein, it is intended to include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, substituted or unsubstituted cycloundecane. When substituted, substituents are defined as for "C.-6 alkyl" above. "C2-6 alkenyl" as used herein means an alkyl group of 2 to 6 carbons in which an individual carbon-carbon bond is replaced by a carbon-carbon double bond. C2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the different isomeric pentenes and hexenes. Both cis and trans isomers are included. "C2-6 alkynyl" means an alkyl group of 2 to 6 carbons in which an individual carbon-carbon bond is replaced by a triple carbon-carbon bond. C2-6 alkynyl includes acetylene, 1-propin, 2-propin, 1-butin, 2-butin, 3-butin and the simple isomers of pentin and hexin. "Halogen" means F, Cl, Br and I.

"Ar" or "aryl" or "Af or" aryl "'means phenyl or naphthyl, optionally and independently substituted by one or more of Ph-C0-6 alkyl, Het-alkyl of Co-6, alkyl of C-? -6, C1-6 alkoxy, Ph-C06 alkoxy> Het-alkoxy of Co-6, OH, (CH2)? -6NR8R9, 0 (CH2)? -6NR8R9, C02, R 'or halogen. Two C.sub.-alkyl groups can be combined to form a 5-7 membered, saturated or unsaturated ring fused to the Ar ring. Ph can optionally be substituted with one or more of C? -6 alkyl, C? -6, OH, (CH2)? - 6NR8N9, O (CH2) .- 6NR8R9, CO2R 'or halogen As used herein, "Het" or "heterocyclic" represents a monocyclic heterocyclic ring of 5 to 7 stable or bicyclic members of 7 to 10 stable members, which is either saturated or unsaturated, and which consists of carbon atoms and one to three heterogeneous atoms selected from the group consisting of N, O and S, and in where the heterogeneous atoms of nitrogen and sulfur can be oxidized optionally, and the nitrogen heterogeneous atom may be optionally quaternized, and including any bicyclic group in which any of the heterocyclic rings mentioned above is fused to a benzene ring. The heterocyclic ring can be attached at any heterogeneous atom or carbon atom, which results in the creation of a stable structure, and can optionally be substituted with one or two portions selected from the group consisting of Ph-C6 alkyl, Het-Co-6-alkyl, Cr6-alkyl, C.-6-alkoxy, Ph-C0-6-alkoxy, Het-alkoxy-Co-6, OH, (CH2)? - 6NR8R9, O (CH2)? - 6NR8R9, CO2, R '. Two alkyl groups of C.-6 can be combined to form a 5-7 membered saturated or unsaturated ring, fused to the Het ring. Ph can be optionally substituted with one or more of C.sub.6-alkyl, C.sub.beta.-OH, OH, (CH.sub.2) .-6NR8R.sub.9, 0 (CH.sub.2) 1.6NR.sub.8 R.sub.9, C.sub.2, R.sub.a, or halogen. Examples of said heterocycles include the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxypiperinidyl, 2-oxypyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl. "HetAr" or "heteroaryl" means any heterocyclic moiety encompassed by the above definition of Het that is aromatic in character, eg, pyridine. It will be appreciated that the heterocyclic ring described when N-i includes thiazoles, oxazoles, triazoles, thiadiazoles, oxadiazoles, isoxazoles, isothiazoles, imidazoles, pyrazines, pyridazines, pyrimidines, triazines and tetrazines, which can be obtained by routine chemical synthesis and are stable The single and double bonds (ie, -) in said heterocycles are arranged based on the heteroatoms present, so that the heterocycle is aromatic (eg, is a heteroaryl group). The term "heteroatom," as used herein, refers to oxygen, nitrogen and sulfur. Here and throughout this application, the term C0 denotes the absence of the immediately consecutive substituent group; for example, of the Ar-alkyl portion of C0-6-, when C is 0, the substituent is Ar, for example, phenyl. Conversely, when the Ar-alkyl portion of Co-6 is identified as a specific aromatic group, for example phenyl, it is understood that C is 0. Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical and Cbz refers to the benzyloxycarbonyl radical. Certain reagents are abbreviated in the present. DCC refers to dicyclohexylcarbodiimide, DMAP is 2,6-dimethylaminopyridine, EDC refers to N-etiI-N '(dimethylaminopropyl) -carbodiimide. HOBT refers to 1-hydroxybenzotriazole, DMF refers to dimethylformamide, BOP refers to benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, DMAP is dimethylaminopyridine, NMM is N-methylmorpholine, TFA refers to trifluoroacetic acid and THF refers to tetrahydrofuran. Jones Reagent is a solution of chromium trioxide, water and sulfuric acid well known in the art.

METHODS OF PREPARATION The compounds of the present invention can be conveniently prepared by the methods described in the following schemes 1 to 5.

SCHEME 1 a) EDCl, DMF; b) R'S02CI, NMM, DMF; c) TFA, DCM; d) R "-CO2H, HBTU, NMM, DMF; e) Jones reagent or Dess-Martin periodinane 1,3-diamino-propan-2-ol (or a diaminopropanol substituted with N-alkyl) 1 -schema 1 , is coupled to a protected amino acid (Cbz- or Boc-) 2- scheme 1 to provide an intermediate amine 3-scheme 1. Another carboxylic acid or a sulfonyl chloride is then coupled to form the alcohol 4-scheme 1 (or the two couplings are made in a single reaction crucible.) Removal of the protecting group provides the amine 5-scheme 1. The acylation or sulfonylation gives the alcohol 6-scheme 1, and the oxidation of the alcohol provides the desired compounds 7-scheme 1 .

SCHEME 2 a) EDCi, DMF; b) R'C02H, EDCl or HBTU, NMM, DMF; c) Jones reagent or Dess-Martin periodinane. 1,3-diamino-propan-2-ol (or a diaminopropanol substituted with N-aikyl) 1 -scheme 2, is coupled to a protected Cbz-amino acid 2-scheme 2 to form the intermediate amine 3-scheme 2. Other acid The carboxylic acid or sulfonyl chloride is then coupled to provide the alcohol 4-scheme 2 (or the two couplings are carried out in a single reaction crucible). Oxidation of the alcohol provides the desired compound 5-scheme 2.

SCHEME 3 a) R-CO2H, R'-CO2H, EDCl or HBTU / NMM, DMF; b) Dess-Martin periodinane or Jones reagent. 1,3-diamino-propan-2-ol (or an N-alkyl-substituted diaminopropanol) 1 -scheme 3 is coupled to a protected carboxylic acid (R = R '), two different carboxylic acids, a carboxylic acid and a chloride of sulfonyl, a single sulfonyl chloride or two different sulfonyl chlorides, followed by oxidation of the alcohols to the ketones to provide the desired compounds 2-scheme 3, 3-scheme 3 and 4-scheme 3, which are then purified by chromatography of silica gel.

SCHEME 4 3: X = H, Br 4: X = H, N3 7 a) CI-C02iPr, NMM, THF; CH2N2; b) HBr; NaN3, KF; c) NaBH4, d) HS (CH2) 3SH, e) R'-C02H, HBTU, NMM, DMF; f) H2 / Pd / C, g) R "-CO2H, HBTU, NMM, h) Dess-Martin periodinane or Jones reagent Propan-2-ones substituted in the alpha position can be prepared with, for example, groups alkyl, converting an N-protected amino acid 1-scheme 4, to its bromine methyl ketone 3-scheme 4 by a diazo methyl ketone 2-scheme 4. Then, the bromide 3-scheme 4 is displaced with sodium azide to give the azide corresponding 4-scheme 4. The reduction of the carbonyl with a reducing agent such as sodium borohydride gives an azido alcohol 5-echema 4, which is reduced after the azide with a reducing agent such as 1,3-propanedithiol to give the free amine 6-scheme 4. Acylation or sulfonylation of the amine gives the amide or sulfonamide 7-scheme 4. Finally, the deprotection, acylation and oxidation steps of the carbinol with an oxidant such as Dess-Martin periodinane or Jones reagent , give the desired compounds.

SCHEME 5 a) CI-C02iPr, NMM, THF; b) CH2N2; c) HBr; d) R3NH2, KF, DMF. Propan-2-ones substituted at the alpha position with an N-aryl or alkyl group can be prepared by converting an N-protected diamino acid 1-scheme 5, to its bromine methyl ketone 2-scheme 5 by a diazo methyl ketone. Then, the bromide 2-scheme 5 is displaced with an amine such as aniline with potassium fluoride (or silver salt such as Ag2O) to give the corresponding amine 3-scheme 5. Periodine oxidation of Dess-Martin is described in J. Org. Chem. 1983, 48, 4155-4156. With respect to the methods of preparation of the compounds of formula I described in the above-mentioned schemes 1 to 5, the person skilled in the art will appreciate that the present invention includes all the novel intermediates required to obtain the compounds of formula I. Specifically, the present invention includes all the diamino-propan-2-oles of formula II which correspond to the compounds of formula I. More specifically, the present invention provides compounds of formula II: wherein: R1, R2 and R3 are independently H; C? _6 alkyl, preferably methyl or isobutyl; C3-1 cycloalkyl; C2-6 alkenyl; C2-6 alkynyl; Ar, preferably phenyl; Het; C? -6-Ar alkyl, preferably benzyl; cycloalkyl of C3-.? - Ar; C2-6-Ar alkenyl; C2-6 alkynyl-Ar; C? _6-Het alkyl, preferably isonicotinyl; C3_ 11-Het cycloalkyl; C2-6-Het alkenyl; or C2-6 alkynyl-Het; R4 is N- (R6) -NHCH (C6 alkyl) -CO, preferably N-R6-leucinyl, N-R6-norleucinyl, N-R6-norvalinyl, N-R6-isoleucinyl, N-R6-a -alyl-glycine, N-R6-a- (cyclopropylmethyl) -glycyl, N-R6-ß-ér-butyl-alaninyl or N-R6-homo-leucinyl; N, N-R6- (C? -6 alkyl) -N (C6 alkyl) -CO, preferably N, N-R6-methyl-leucinium; N- (R6) -NHCH (C2.6 alkenyl) -CO-; N- (R6) -NHCH (C2.6 alkynyl) -CO-; N- (R6) -NHCH (C6-Ar-alkyl) -CO-; N- (R6) -NHCH (C2.6-Ar alkenyl) -CO-; N- (R6) -NHCH (C2.6-Ar alkynyl) -CO-; N- (R6) -NHCH (C 1-6 alkyl-Het) -CO-; N- (R6) -NHCH (C2-6 alkenyl-Het) -CO-; N- (R6) -NHCH (C2-6 alkynyl-Het) -CO-; ArCO, preferably 3-phenoxy-benzoyl, 4-phenoxy-benzoyl or 2-benzyloxy-benzoyl; Ar-alkyl of C -? - 6-CO, preferably 4-biphenyl-acetyl, 2- (4-biphenyl) -4-methyl-valeryl, 2- (3-biphenyl) -4-methyl-valeryl, 1- (3 -biphenyl) -but-3-ene-1 -carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl, 1- (3-biphenyl) -3-methyl-but-3-ene- 1 -carbonyl, 3- (2-pyridyl) -phenylacetyl or 3- (3-pyridyl) -phenylacetyl; Ar-S 2, preferably 3-phenoxy-phenylsulfonyl, 4-phenoxy-phenylsulfonyl or 3- (4- (3-chloro-2-cyano-phenoxy) phenylsulfonyl; Ar-alkyl of C.-6-S02; Het-CO; Het-C1-6alkyl-CO; Het-SO2, preferably 8-quinolinesulfonyl; or Het-alkyl of C -? - 6-SO2; R5 is N-R7 amino acid, preferably N- (R7) -NHCH (C1-6 alkyl) -CO, more preferably N-R7-leucinyl, N-R7-norleucinyl, N-R7-norvalinyl, N-R7-isoleucinyl , N-R7-a-allyl-glycinyl, N-R7-a- (cyclopropylmethyl) -glycinyl, N-R7-β-te? -butyl-alaninyl or N-R7-homo-leucinyl, preferably N- (R7) -NHCH (C2-6 alkenyl) -CO, preferably N-R7-NHCH (C2-6 alkynyl) -CO, preferably N- (R7) -NHCH (C1-6 alkyl-Ar) -CO, more preferably N- (R7) -phenylalaninyl, preferably N- (R7) -NHCH (C2-6-Ar alkenyl) -CO, preferably N- (R7) -NHCH (C2-6 alkynyl-Ar) -CO, preferably R7 -? - t-butyl-glutamyl, preferably R7-glutamyl or preferably N, N-R7- (C? -C6 alkyl) -leucynyl; C 1-6 alkyl-CO, preferably acetyl; C3-p-CO cycloalkyl; ArCO, preferably benzoyl, 3-phenoxy-benzoyl, 4-phenoxy-benzoyl, 2-benzyloxy-benzoyl, 3-benzyloxy-benzoyl or 4-benzyloxy-benzoyl; -Alkyl of C-? -6-CO, preferably 2- (4-biphenyl) -4-methyl-valerate, 2- (3-biphenyl) -4-methyl-varyryl, 1- (3-biphenyl) -but-3 -neo-1 -carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl, 1- (3-biphenyl) -3-methyl-but-3-ene-1-carbonyl, 1- ( 3-biphenyl) -but-3-ene-1-carbonyl, 3- (2-pyridyl) -phenyl-acetyl, 3- (3-pyridyl) -phenyl-acetyl, 4-biphenyl-acetyl or 3-biphenyl-acetyl; Ar-SO 2, preferably 3-biphenyl sulfonyl, 4-cyano-phenyl sulfonyl, 2-carboxyl-phenyl-sulfonyl, 2-carboxymethyl-phenyl-sulfonyl, 4-C-tetrazolo-phenyl-sulfonyl, 1-naphthalene sulfonyl, 3-phenoxy-phenyl sulfonyl, 4-phenoxy-phenyl sulfonyl, 3- (4- (3-chloro-2-cyano-phenoxy) -phenyl-sulfonyl, 4-biphenyl-sulfonyl or 2-dibenzofuran-sulfonyl; -alkyl-6-SO2; Het-CO, preferably 8-quinolino carbonyl, 6-quinolino carbonyl, 2-pyridino carbonyl, 5- (2-pyridyl) -thiophene carbonyl, N-benzyl-4-piperidinyl carbonyl or 2-quinolino carbonyl; -? - 6-CO; Het-SO2, preferably 2-pyridyl sulfonyl, 1, 3-dimethyl-5-cioro-pyrazolo-4-sulfonyl, 3,5-dimethyl-isoxazo-4-sulfonyl, benzo-2.1 , 3-thiadiazole-4-sulfonyl, phenyl-sulfone-5-thiophene-2-sulfonium, 2-carboxymethyl thiophene-sulfonyl, 2,5-dichlorothiophene-3-sulfonyl or 8-quinolino-sulfonyl; C-β-alkyl; Ar-alkyl of Co-β, preferably phenyl; Het-alkyl of CO 6; R 6 and R 7 are independently Ar- (C 6 alkyl) -0-CO, pref preferably benzyloxycarbonyl; Het- (C6_6 alkyl) -0-CO, preferably 2-pyridyl methyloxycarbonyl, 3-pyridyl methyloxycarbonyl or 4-pyridyl methyloxycarbonyl; Ar-CO, preferably benzoyl, 1-naphthoyl, 2-naphthoyl, 4-phenoxy-benzoyl, 3-phenoxy-benzoyl, 2-phenoxy-benzoyl, 2-cioro-benzoyl, 4-fluoro-benzoyl, 3,4-difluoro benzoyl, 4-trifluoromethyl benzoyl, 2-chlorobenzoyl, 4-carboxymethyl-benzoyl or 4-carboxyl-benzoyl; Ar-S02; Het-CO, preferably 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-quinolinecarbonyl, 3-quinolino carbonyl, 4-quinolino carbonyl, 5-quinolino carbonyl, 6-quinolino carbonyl, 7-quinolino carbonyl, 8-quinolino carbonyl, 1-isoquinolino carbonyl, 3-isoquinolino carbonyl, 4-isoquinolino carbonyl, 5-isoquinolino carbonyl, 6-isoquinoline carbonyl, 7-isoquinoline carbonyl, 8-isoquinoline carbonyl, 1-benzothiophene carbonyl, 1-benzofurancarbonyl, 5-indole-carbonyl-sulfonyl, N-methyl-prolinyl, 2-quinoxaline-carbonyl, 5- (2,3 -dihydrobenzofuran-carbonyl, 2-benzofuran-carbonyl, 2-benzothiophene-carbonyl, N-morpholino-carbonyl, N-methyl-piperidino-carbonyl or N-pyrazolo-carbonyl; Het-SO2, preferably 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, 2-quinoline sulfonyl, 3-quinoline sulfonyl, 4-quinoline sulfonyl, 5-quinoline sulfonyl, 6-quinoline sulfonyl, 7-quinoline sulfonyl, 8-quinoline sulfonyl, 1-isoquinoline sulfonyl, 3-isoquinoline sulfonyl, 4-isoquinolino sulfonyl, 5-isoquinolino sulfonyl, 6-isoquinolino sulfonyl, 7-isoquinolino ulfonyl or 8-isoquinoline sulphonyl; C.sub.6 -CO alkyl, preferably acetyl; N, N-dimethyl glycinyl; cycloalkyl of C3-1 .CO, preferably rans-4-propyl-cyclohexylcarbonyl or cyclohexylcarbonyl; C? -6-S02 alkyl; C2-6-CO alkenyl; C2-6 alkenyl-SO2; C2-6 alkynyl-CO; C2-6 alkynyl-SO2; Ar-C 1-6 alkyl-CO; Ar-alkyl of C.-6-SO2; C2-6-CO-alkenyl; C2-6-SO2 ar-alkenyl; C2-6-CO alkynyl; C2-6-SO2 ar-alkynyl; Het-alkyl of C-i-6-CO, preferably 4-imidazole acetyl, 2-pyridyl acetyl, 3-pyridyl acetyl, 4-pyridyl acetyl or N-morpholino acetyl, Het-alkyl of C6-6-SO2; Het-alkenyl of C2-6-CO; Het-alkenyl of C2-6-S02; Het-alkynyl of C2-6-CO; or C2-6-S02 Het-alkynyl; and pharmaceutically acceptable salts, hydrates and solvates thereof. Preferred are compounds of formula II, wherein R1, R2 or R3 is H. Even more preferred are compounds of formula II, wherein: R1 is H or C6-6 alkyl, preferably methyl; R2 and R3 are H; R4 is N- (R6) -NHCH (Cr6 alkyl) -CO, preferably N-R6-leucinyl, more preferably N- (2-pyridylcarbonyl) -leucinyl, N- (8-quinolinecarbonyl) -leucinyl, N- (6-quinolino carbonyl) -leucinyl, N- (4-imidazolo acetyl) -leucinyl, N-benzoyl-leucinyl, N- (2-pyridyl sulfonyl) -leucinyl, N- (1-isoquinolino carbonyl) -leucinyl, N- (N-morpholino acetyl) -leucinyl, N- (N-methyl prolinyl) -leucinyl, N- (N, N-dimethyl glycine) -leucinyl, N- (8-quinolino sulfonyl) -leucinyl, N-Cbz-leucinyl, N-pentafluorobenzoyl-leucinyl, N-2-naphthoyl-leucinyl, N-1-naphthoyl-leucinyl, N-4-fluorobenzoyl-leucinyl, N- (4-trifluoromethyl-benzoyl) -leucinyl, N-3,4-difluoro-benzoyl-leucinyl , N-3,4-dimethoxybenzoyl-leucinyl, N- (1-benzothiophene-carbonyl) -leucinyl, N- (2-benzothiazolo-carbonyl) -leucinyl, N- (5-benzothiophene-carbonyl) -leucinyl, N- ( 6-benzothiophenecarbonyl) -leucine, N- (5-indole-carbonyl) -leucinyl, N- (ia 7s-4-propyl cyclohexyl-carbonyl) -leucinyl, N- (2-quinoxaline-carbonyl) -leucine , N-5- (2,3, dihydrobenzofuran) ) -carbonyl) -leucinyl, N- (2-benzofuran-carbonyl) -leucinyl, N- (N-methyl-2-indole-carbonyl) -leucinyl, N- (2-chloro-benzoyl-carbonyl) -leucinyl, N - (4-phenoxy-phenylcarbonyl) -leucynyl, N- (3-methoxy-2-quinolyl-carbonyl) -leucylidene, N- (2-pyridyl-methyleneoxy-carbonyl) -leucinyl or N- (cyclohexylcarbonyl) -leucinyl; or preferably N-R6-norleucinyl, more preferably N-Cbz norleucinyl, N- (2-naphthyl-carbonyl) -norleucinyl, N- (3,4, dimethoxy-benzoyl) -norleucylidene or N- (5-) benzothiophene carbonyl) -norleucinyl; or preferably N-R6-norvalinyl, more preferably N-Cbz-norvalinyl; or preferably N-R6-isoleucinyl, more preferably N-Cbz-isoleucinyl; or preferably N-R6-α-allyl-glycinyl; more preferably N-Cbz-α-allyl-glycinyl; or N, N-R6- (C6 alkyl) -N- (C6-alkyl) -CO, preferably N, N-R6-methyl-leucinyl, more preferably N-Cbz-N-methyl-leucinyl; or preferably N-R6-a- (cyclopropylmethyl) -glycinyl, more preferably N-Cbz-a- (cyclo-propylmethyl) -glycinyl; or preferably N-R6-L-ß-tert-butyl-alaninyl, more preferably N-Cbz-L-ß-ér-butyl-alaninyl or Ar-C-γ-6-CO alkyl, preferably 2- ( 3-biphenyl) -4-methyl-valeryl or 1- (3-biphenyl) -but-3-ene-1-carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl; R5 is N-R7-norvalinyl, preferably N-Cbz-norvalinyl, C6-C6-Aralkyl, preferably 3- (2-pyridyl) -phenyl-acetyl, 3- (3-pyridyl) -phenyl-acetyl, 3- ( 3-biphenyl) -3-methyl-but-3-ene-1-carbonyl or 2- (3-biphenyl) -but-3-ene-1-carbonyl; or Het-SO 2, preferably 2-pyridyl sulfonyl, 8-quinoline sulfonyl, 1,3-dimethyl-5-chloro-pyrazolo-4-sulfonyl, 3,5-dimethyl-isoxazolo-4-sulfonyl, benzo-2, 1,3-thiadiazole-4-sulfonyl or 3-biphenyl sulfonyl; or Het-CO, preferably 8-quinolinocarbonyl, 5- (2-pyridino) -thiophenecarbonium, N-benzyl-4-piperidinylcarbonyl, 2-quinolinocarbonyl or 2-pyridinocarbonyl; or ArCO, preferably 4-phenoxy-phenyl-carbonyl or 2- (3-biphenyl) -3-methyl-valeryl; Ar-S02, preferably 2-carboxymethyl-phenyl-sulfonyl, 2-carboxy-phenyl-sulfonyl, 4-C-tetrazolo-phenyl-sulfonyl, 1-naphthalene-sulfonyl or 2-cyano-phenyl-sulfonyl; or Ar-C alquilo alkyl, preferably phenyl. Still more preferred are the compounds of formula II, wherein: R is H or Cr6 alkyl, preferably methyl; R2 and R3 are H; R 4 is N (R 6) -NHCH (C 1 -6 alkyl) -CO, preferably N-R 6 -leucinyl, more preferably Cbz-leucinyl, 2-naphthoyl-leucinyl, 4-fluorobenzoyl-leucinyl, 3,4-dimethoxybenzoyl- leucinyl, (1-benzothiophene-carbonyl) -leucinyl, (2-quinoxaline-carbonyl) -leucinyl, 5- (2,3-dihydro-benzofuran) -carbonyl) -leucinyl, (2-benzofuran-carbonyl) -leucinyl; or N-R6-norleucinyl, more preferably (2-naphthyl-carbonyl) -norleucinyl, (3,4-dimethoxy-benzoyl) -norleucinyl or (5-benzothiophene-carbonyl) -norleucine; or Ar-alkyl of Cr6-CO, preferably 2- (3-biphenyl) -4-methyl-valeryl; and R5 is Ar-alkyl of Cr6-CO, preferably 3- (2-pyridyl) -phenyl-acetyl; or Het-SO2; preferably 2-pyridyl sulfonyl. Particularly preferred are the compounds of formula II, which are diamino-propan-2-ol analogs of the particularly preferred compounds of formula I. More preferred are the compounds of the formula which are diamino-propan-2-ol analogs of the most preferred compounds of formula I. The starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those skilled in the art, and can be found in standard reference books such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vols. I-VI (published by Wiley-lnterscience). Coupling methods for forming amide linkages herein are generally well known in the art. Peptide synthesis methods generally described by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J. M. Stewart and J. D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2nd ed., Pierce Chemical Co., Rockford, III., 1984, are generally illustrative of the art and are incorporated herein by reference. The synthesis methods for preparing the compounds of this invention often employ protecting groups to mask a reactive functionality or minimize unwanted side reactions. Said protecting groups are generally described in Green, T.W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof which are known in the art. Methods for protection and deprotection, and replacement of one amino protecting group with another portion are well known. The acid addition salts of the compounds of the formula I will be prepared in a standard manner in a suitable solvent from the compound of the origin and from an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic acid. , trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form internal salts or zwitterions that may be acceptable. The cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with a suitable organic amine. Cations such as Li +, Na +, K +, Ca ++, Mg ++ and NH4 + are specific examples of cations present in pharmaceutically acceptable salts. Halides, sue, phosphate, alkanoates (such as acetates and trifluoroacetate), benzoates and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts. This invention also provides a pharmaceutical composition comprising a compound according to formula I and a carrier, pharmaceutically acceptable diluent or excipient. Accordingly, the compounds of the formula I can be used in the manufacture of a medicament. The pharmaceutical compositions of the compounds of the formula I prepared as described hereinabove can be formulated as lyophilized solutions or powders for parenteral administration. Powders can be reconstituted by the addition of a suitable diluent or other pharmaceutically acceptable vehicle before use. The liquid formulation can be an aqueous solution of regulated and isotonic pH. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or sodium acetate or ammonium solution of regulated pH. Said formulation is especially suitable for parenteral administration, but can also be used for oral administration or be contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds can be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. The pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or to facilitate the preparation thereof. Solid carriers include starch, lactose, calcium sulfate dihydrate, alba earth, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid vehicles include syrup, peanut oil, olive oil, saline and water. The vehicle may also include a prolonged release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but will preferably be between about 20 mg to about 1 g per unit dose. The pharmaceutical preparations are made following the conventional techniques of the pharmacy including spraying, mixing, granulating and compressing, when necessary, for tablet forms; or spray, mix and fill for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said liquid formulation can be administered directly or filled into a soft gelatin capsule. For rectal administration, the compounds of this invention can also be combined with excipients such as cocoa butter glycerin, gelatin or polyethylene glycols and molded to create a suppository Utility of the present invention The compounds of formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, most particularly as inhibitors of cysteine proteases, still more particularly as inhibitors of cysteine proteases of the papain superfamily, still more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds. The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by Pneumocystis carinii, Trypanosoma cruzi, Trypanosoma brucei brucei and Chrythidia fasciculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amitrophy and especially diseases in which cathepsin K is involved, particularly diseases of excessive loss of bone or cartilage, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, very specifically osteoarthritis and rheumatoid arthritis, Paget's disease and malignant hypercalcemia, and metabolic bone loss. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasms can be effectively treated with the compounds of the invention. The present invention also provides methods of treating diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, very particularly cysteine proteases, still more particularly cysteine proteases of the papain superfamily, even very particularly cysteine proteases of the cathepsin family, which comprise administering to an animal, particularly a mammal, most particularly a human in need thereof, an effective amount of a compound or combination of compounds of the present invention. The present invention especially provides methods of treating diseases caused by pathological levels of cathepsin K, methods comprising administering to an animal, particularly a mammal, most particularly a human in need thereof, an effective amount of a cathepsin K inhibitor, including a compound or combination of compounds of the present invention. One skilled in the art will understand that the term "effective amount" is intended to mean that amount of a compound or combination of compounds of the present invention that is sufficient to decrease or cure the clinically undesirable manifestations of the disease (e.g., brittle bone). and weakened in osteoporosis) caused by said pathological levels of the target enzyme, eg, cathepsin K, by inhibiting the target enzyme. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by Pneumocystis carinii, Trypanosoma cruzi, Trypanosoma brucei brucei and Chrythidia fasciculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amitrophy and especially diseases in which cathepsin K is involved, particularly diseases of excessive loss of bone or cartilage, including osteoporosis, gingival disease including gingivitis and periodontitis , arthritis, very specifically osteoarthritis and rheumatoid arthritis, Paget's disease, malignant hypercalcemia and metabolic bone loss. This invention further provides a method for treating osteoporosis or inhibiting bone loss, comprising administering internally to an animal, particularly a mammal., very particularly a human in need thereof, of an effective amount of a compound or combination of compounds of the formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (ie, alendronate), replacement of hormones, anti-estrogens or calcitonin. In addition, the treatment of this invention and an anabolic agent, such as bone morphogenic protein or iproflavone can be used to prevent bone loss or to increase bone mass. For acute therapy, parenteral administration of a compound of formula I is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients is very effective, although an injection is also useful. in intramuscular bolus. Typically, the parenteral dose will be from about 0.01 to about 100 mg / kg; preferably between 0.1 and 20 mg / kg, such that the concentration of the drug in the plasma is maintained at a concentration effective to inhibit cathepsin K. Compounds are administered one to four times a day at a level that achieves a dose total daily from about 0.4 to about 400 mg / kg / day. The precise amount of a compound of the invention that is therapeutically effective, and the route by which said compound is best administered, is readily determined by one skilled in the art by comparing the blood level of the agent with the concentration required to have an effect therapeutic.

The compounds of this invention can also be administered orally to the patient, such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as described herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose between about 0.1. to approximately 50 mg / kg in a manner consistent with the patient's condition. Preferably, the oral dose will be from about 0.5 to about 20 mg / kg. Unacceptable toxicological effects are not expected when the compounds of the present invention are administered in accordance therewith.

Biological Tests The compounds of the present invention can be tested in one of several biological tests to determine the concentration of compound that is required to provide a certain pharmacological effect.

Determination of the proteolytic catalytic activity of cathepsin K All cathepsin K tests were carried out with a human recombinant enzyme. Standard test conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in sodium acetate at 100 mM at pH 5.5 containing 20 mM cysteine and EDTA a 5 mM. Substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with a final substrate concentration of 20 uM in the tests.

All tests contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on the activity of the enzyme or on the kinetic constants. All tests were carried out at room temperature. The fluorescence of the product (excitation at 360 nM, emission at 460 nM) was monitored with a fluorescent plate reader Perceptive Biosystems Cytofluor II. The product progress curves were generated 20 to 30 minutes after the formation of the AMC product.

Inhibition studies Potential inhibitors were evaluated using the progress curve method. The tests were carried out in the presence of varying concentrations of the test compound. Reactions were initiated by the addition of enzyme to solutions with regulated pH of inhibitor and substrate. The analysis of the data was carried out according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors. For the compounds whose progression curves were linear, the constants of apparent inhibition (K, app) were calculated according to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140): v = V "AI [Ka (1 + 1 / K "app) + A] (1) where v is the velocity of the reaction with maximum velocity Vm, A is the substrate concentration with Kais Michaelis constant e / is the inhibitor concentration. For the compounds whose progress curves showed a time-dependent decay curvature characteristic of inhibition, the data from individual sets was analyzed to give kobs according to equation 2: [AMC] = vsst + (vO - vss) [1- exp (-kobst)] / kobs (2) where [AMC] is the concentration of product formed during time t, vo is the initial reaction velocity and vss is the final velocity in a fixed state. The values for k0bs were then analyzed as a linear function of the inhibitor concentration to generate an apparent second order rate constant (kobs / inhibitor concentration or k0bs / [I]) describing the time-dependent inhibition. A full description of this kinetic treatment has been given completely in Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201.

Human osteoclast resorption test Aliquots of suspensions of osteoclastoma-derived cells were removed from storage in liquid nitrogen, heated rapidly to 37 ° C and washed x1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4 ° C). The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1: 3 in RPMI-1640 medium and incubated for 30 minutes on ice. The cell suspension was mixed frequently. The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4 ° C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber. Enough magnetic spheres (5 / mononuclear cell), coated with goat anti-rabbit IgG, were removed from their storage bottle and placed in 5 mL of fresh medium (this removes the toxic azide preservative). The medium was removed by immobilizing the spheres in a magnet and replaced with fresh medium. The spheres were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was mixed frequently. The cells coated with spheres were immobilized on a magnet and the remaining cells (fraction rich in osteoclasts) were decanted in a sterile 50 mL centrifuge tube. Fresh medium was added to the spider-coated cells to dislodge any entrapped osteoclasts. This washing procedure was repeated x10. The cells coated with spheres were discarded. The osteoclasts were enumerated in a counting chamber, using a large hole disposable plastic Pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of the osteoclasts was adjusted to 1.5x104 / mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate. Aliquots of 3 mL of the cell suspension (by treatment) were decanted in centrifuge tubes of 15 mL. These cells were pelleted by centrifugation. To each tube was added 3 mL of the appropriate treatment (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87 MEM1 diluted at 100 ug / mL) and an isotype control (IgG2a diluted at 100 ug / mL). The tubes were incubated at 37 ° C for 30 minutes. Aliquots of 0.5 mL of the cells were grown on sterile dentine nosepieces in a 48 cavity plate and incubated at 37 ° C for 2 hours. Each treatment was analyzed in quadruplicate. The slide holders were washed in six hot PBS changes (10 mL / well in a 6-well plate) and then placed in fresh or control treatment and incubated at 37 ° C for 48 hours. The objective slides were then washed in phosphate-buffered saline solution and fixed in 2% glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes, after which they were washed in water and incubated in pH regulator for 5 minutes at 37 ° C. The slide holders were then washed in cold water and incubated in cold acetate / red garnet pH regulator for 5 minutes at 4 ° C. The excess pH regulator was aspirated and the slides were air dried after washing in water. The positive TRAP osteoclasts were enumerated by bright field microscopy and then removed from the surface of the dentin by sonication. Sting volumes were determined using the Nikon / Lasertec ILM21W confocal microscope.

General The nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuterium dimethylsulfoxide and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) down from the internal standard tetramethylsilane. The abbreviations of the NMR data are as follows: s = single band, d = doublet, t = triplet, q = quartet, m = multiple band, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz (Hz). The continuous wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer and the Fourier transform infrared spectra (FTIR) were recorded on a Nicolet Impact 400D infrared spectrometer. The IR and FTIR spectra were recorded in transmission mode, and the positions of the band are reported in inverse wave numbers (cm-1). The mass spectra are taken on VG 70 PE instruments, PE Syx Pl III or VG ZAB HF, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. The elemental analyzes are obtained using a Perkin-Elmer 240C elemental analyzer. The melting points are taken in a Thomas-Hoover melting point apparatus and are not corrected. All temperatures report in degrees centigrade. Thin-film plates of Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 are used for thin layer chromatography. Both vaporization and gravity chromatographs are carried out on E. Merck Kieselgel 60 silica gel (230-400 mesh). When indicated, certain of the materials were purchased from Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey and Advanced Chemtech, Louisville, Kentucky.

EXAMPLES In the following synthesis examples, the temperature is in degrees centigrade (° C). Unless otherwise stated; all starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. These examples are given to illustrate the invention and not to limit its scope.

Reference is made to the claims for which it is reserved to the inventors.

EXAMPLE 1 Preparation of 1-N- (N- (2-pyridylcarbonyl) -leucinyl) -amino-3-N- (2-pyridyl-sulfonyO-amino-propan-2-one) a) 1-N- (N-Boc-leuci-n-1-amino-3-N- (2-pyridyl) -amino-propan-2-ol was dissolved. , 3-diamino-propan-2-ol (3.375 g, 37.5 mmol) in DMF (65 ml). Then, hydrated HOBT (5.5 g, 40.7 mmol), Boc-L-leucine (9.34 g, 37.5 mmol), EDCl (7.77 g, 40.7 mmol) and NMM (4.4 mL, 40 mmol) were added, and the reaction mixture was added. stirred for 4 hours; then 2-pyridylsulfonyl chloride (3.7 g, 20.8 mmol) was added and the reaction was stirred another 2 hours. The reaction mixture was concentrated in vacuo and then chromatographed on silica gel to yield a white solid (4.3 g, 26%) (ES +) 445.2 (M + H +). b) 1-N-peucinyl) -amino-3-N- (2-pyridyl) -amino-propan-2-ol 1-N- (N-Boc-leucil ) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-ol (2.1 g, 4.73 mmol) in TFA: DCM 1: 1 (60 ml), and stirred at room temperature for 1 hour. Toluene (100 ml) was added, then the reaction mixture was concentrated in vacuo and used in the next reaction without further purification (1.6 g, quant). c) 1-N- (N- (2-pyridylcarbonyl, -leucinyl) -amino-3-N-, 2-pyridyl-suphionl, -amino-propan-2-ol. HBTU ( 0.6 g, 1.6 mmol) to a solution of 1-N- (leucinyl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-ol (0.9 g, 1.58 mmoles), NMM (0.87 ml, 8 mmol) and 2-pyridine carboxylic acid (0.194 g, 1.58 mmol) in DMF (11.5 ml) The reaction mixture was stirred overnight, then washed with brine / EtOAc and NaOH to 1 N, the combined organic extracts were dried with MgSO 4, filtered, concentrated and used in the next reaction without further purification: MS (ES) (ES +) 450.1 (M + H +). d) 1-N- (N- (2-pyridylcarbonyl, -leucinyl, -amino-3-N- (2-pyridyl-sulfonyl, -amino-propan-2-one) 1-N- was dissolved (N- (2-pyridylcarbonyl) -leucinyl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-ol (from example 1c) in acetone (10 ml), then 1N HCl (5 ml) was added dropwise in ether, and the solution was concentrated in vacuo The solid was redissolved in acetone (10 ml), and then Jones reagent (1 N, 1) was added dropwise. ml) and the reaction was stirred overnight.The reaction was quenched with isopropanol (1 ml), and then the reaction mixture was basified with 1N NaOH and then extracted repeatedly with EtOAc.The combined organic extracts were dried with MgSO 4, filtered, concentrated and chromatographed on silica gel to yield a white solid (109 mg, 15.4%, 2 steps): MS (ES +) 448.1 (M + H +), 470.2 (M + Na +).

EXAMPLE 2 Preparation of 1-N- (N- (8-quinolino carbonyl) -leucinyl) -amino-3-N-.2-pyridyl-sulfoniD-amino-propan-2-one a) 1-N- (N- (8-quinolino carbonyl, -leucinyl, -amino-3-N-, 2-pyridyl-sulfonyl) -amino-propan-2-one Following the procedure of example 1 (ad), except by substituting "8-quinoline carboxylic acid" with "2-pyridine carboxylic acid", the title compound was prepared: MS (ES +) 498.3 (M + H +).

EXAMPLE 3 Preparation of 1-N- (N- (2-quinolino carbonyl) -leucinyl) -amino-3-N-, 2-pyridyl-sulfonyl) -amino-propan-2-one a) 1-N- (N- (2-quinolinecarbonyl) -leucinyl, -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-one Following the procedure of example 1 (ad), except by substituting "2-quinoIin carboxylic acid" with "2-pyridine carboxylic acid", the title compound was prepared: MS (ES +) 498.1 (M + H +).

EXAMPLE 4 Preparation of 1-N- (N- (4-imidazolo acetyl) -leucinyl) -amino-3-N-.3-biphenyl-sulfonyl) -amino-propan-2-one a) 1-N- (N- (4-imidazolo acetyl, -leucinyl) -amino-3-N-.3-biphenylisulfonyl) -amino-propan-2-one Following the procedure of example 1 ( ad), except substituting "4-imidazole carboxylic acid" with "2-pyridine carboxylic acid", and with "3-biphenyl sulfonyl chloride" the "2-pyridyl sulfonyl chloride", the title compound was prepared: MS (ES +) 526.3 (M + H +).

EXAMPLE 5 Preparation of 1-N- (N- (2-pyridyl-carbonyl) -le? Cinyl) -amino-3-N- (8-q? Inolino carbonyl) -amino-propan-2-one a) 1-N- (N-, 2-pyridyl-carbonyl, -leucyl, -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one Following the procedure of Example 1 (ad), except substituting "8-quinoline carboxylic acid and EDCI" with the "2-pyridyl sulfonyl chloride", the title compound was prepared: MS (ES +) 462.2 (M + H +), 484.2 ( M + Na +).

EXAMPLE 6 Preparation of 1-N- (N-benzoyl-leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one a) 1-N- (N-benzoyl-leucinyl) -amino-3-N-.8-quinolinecarbonyl) -amino-propan-2-one Following the procedure of example 5, except substituting "benzoic acid" with " 2-pyridine carboxylic acid ", the title compound was prepared: MS (ES +) 461.3 (M + H +), 483.2 (M + Na +).

EXAMPLE 7 Preparation of 1-N- (N- (2-pyridyl sulfonyl) -leucine D-amino-3-N- (8-quinolino carboniO-amino-propan-2-one) a) 1-N- (N- (2-pyridyl sulfonyl, -leucinyl) -amino-3-N-.8-quinolinecarbonyl) -amino-propan-2-one Following the procedure of Example 5, except substituting with "2-pyridine sulfonyl chloride" the "2-pyridine carboxylic acid and HBTU", the title compound was prepared: MS (ES +) 498.2 (M + H +).

EXAMPLE 8 Preparation of 1-N- (N-, 8-quinolinylcarbonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one a) 1-N- (N- (8-quinolino carbonyl, -leucylnl) -amino-3-N-.8-quinolino carbonyl) -amino-propan-2-one Following the procedure of example 5, except substituting with "8-quinoline carboxylic acid" the "2-pyridine carboxylic acid", the title compound was prepared: MS (ES +) 512.3 (M + H +), 534.2 (M + Na +).

EXAMPLE 9 Preparation of 1-N-f N- (1-isoquinolino-carbonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one a) 1-N- (N- (1-isoquinolyl-carbonyl) -leucyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one Following the procedure of Example 5, except by substituting "1-isoquinoline carboxylic acid" with "2-pyridine carboxylic acid", the title compound was prepared: MS (ES +) 512.4 (M + H +), 534.1 (M + Na +).

EXAMPLE 10 Preparation of 1-N- (N- (N-morpholino-acetyl) -leucinyl) -amino-3-N-, 8-quinolinecarbonyl) -amino-propan-2-one a) 1-N-.N- (N-morpholino-acetyl) -leucinyl) -amino-3-N- (8-quinolinecarbon) -amino-propan-2-one Following the procedure of Example 5 , except by substituting "N-morpholine acetic acid" with "2-pyridine carboxylic acid", the title compound was prepared: MS (ES +) 484.3 (M + H +).

EXAMPLE 11 Preparation of 1-N-. N-, N-methyl prolinyl) -leucinyl) -amino-3-N- (8-quinolino carboniO-amino-propan-2-one) a) 1-N- (N- (N-methyl prolinyl) -leucinyl) -amino-3-N- (8-quinolino-carboniD-amino-propan-2-one) Following the procedure of Example 5, except substituting "N-methyl proline" with "2-pyridine carboxylic acid", the title compound was prepared: MS (ES +) 468.2 (M + H +).

EXAMPLE 12 Preparation of 1-N- (N- (N, N-dimethylglycinyl) -leucinyl) -amino-3-N-, 8-quinolinecarbonyl) -amino-propan-2-one a) 1-N- (N- (N, N-dimethyl-cyclinyl, -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one Following the procedure of Example 5, except substituting with "N, N-dimethyl glycine" the "2-pyridine carboxylic acid", the title compound was prepared: MS (ES +) 442.1 (M + H +).

EXAMPLE 13 Preparation of 1-N-, N- (8-quinolino sulfonyl) -leucinyl) -amino-3-N-, 8-quinolino carbonyl) -amino-propan-2-one a) 1-N- (N- (8-quinolino-sulfonyl) -leucinyl) -amino-3-N- (8-quinolino-carbonyl) -amino-propan-2-one Following the procedure of Example 5, except by substituting "8-quinolino sulfonyl chloride" with "2-pyridine carboxylic acid and HBTU", the title compound was prepared: MS (ES +) 548.3 (M + H +).

EXAMPLE 14 Preparation of 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one a) 3- (Trifluoromethyl sulphonyloxy-phenyl acetic acid methyl ester To a flask dried in an oven under an argon atmosphere containing sodium hydride (2.54 g, 60% dispersion in mineral oil, 63. 5 mmole), anhydrous pentane (20 ml) was added. The suspension was stirred for 5 minutes, allowed to settle, most of the pentane was removed and anhydrous THF (40 ml) was added. To this suspension was added a solution of 3-hydroxyphenylacetic acid methyl ester (9.99 g, 60.1 mmol) in anhydrous THF (20 ml), and the reaction was stirred at room temperature for 20 minutes. To this mixture was then added a solution of N-phenyltrifluoromethanesulfonimide (22.53 g, 63.1 mmol) in anhydrous THF (40 ml), and the reaction was stirred at room temperature until the TLC will indicate the complete consumption of the starting material (1.5 h). The reaction was quenched by the addition of H20 (10 mL), concentrated to half the original volume, then diluted with CHCl3 (200 mL) and washed with H2O. The aqueous layer was washed with fresh CHCl3 (50 ml), the combined organic layers were washed with 3 to 10% Na2C3, H20 and brine, and then dried (MgSO4), filtered and concentrated. Column chromatography of the residue (silica gel, EtOAc: hexanes 5:95, then EtOAc: hexanes :90) gave 17.47 g of the title compound: 1 H NMR (400 M + Hz, CDCl 3) 7.42 (m, 1 H), 7.31-7.19 (m, 3H), 3.72 (s, 3H), 3.68 (s, 2H). b) 3- (2-Pyridyl) -phenyl-acetic acid methyl ester To a solution of the compound 3- (trifluoromethyl-sulphonyloxy) -phenyl-acetic acid methyl ester (6.86 g, 23.0 mmol) in anhydrous dioxane (100 ml) , 2-pyridylstannane (8.89 g, 24.1 mmol), LiCI (2.94 g, 69.3 mmol), 2,6-di-tert-butyl-4-methylphenol (a few crystals) and Pd (PPh3) 4 (632.1 mg) were added. , 0.55 mmole). The reaction was protected from light with aluminum foil and heated to reflux overnight. Column chromatography of the residue (silica gel, EtOAc: hexanes 1: 3, then EtOAc: hexanes 1: 2) gave 3.85 g of the title compound: MS (ES +) 228.1 (M + H +). c) 3- (2-pyridyl) -phenyl acetic acid To a solution of the compound 3- (2-pyridyl) -phenyl acetic acid methyl ester (3.8 g, 16.7 mmol) in THF (50 ml), a solution was added from LiOH * H2O (780.2 mg, 18.6 mmol) in H2O (10 mL). The reaction was stirred at room temperature until the TLC analysis indicated complete consumption of the starting material (2 h). The reaction mixture was concentrated to remove the THF, then neutralized to pH = 7 by the addition of HCl at 1 N, diluted with brine (50 ml) and washed with CHCl3 (100 ml). The aqueous layer was again adjusted to pH = 7 by the addition of 1 N NaOH, and washed with fresh CHCl 3 (100 ml). After repeating this procedure once more, the organic layers were combined, dried, filtered (MgSO4) and concentrated to give 3.79 g of the title compound: MS (ES +) 214.3 (M + H +). d) 1-N- (N-Cbz-leucin-1) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl, -amino-propan-2-ol Following the procedure of Example 1 (ac), except substituting "Cbz-leucine" with "Boc-Leucine", and with "3- (2-pyridyl) phenyl acetic acid and EDCl" the "2-pyridyl sulfonyl chloride" , the title compound was prepared: MS (ES +) 533.3 (M + H +). e) 1-N- (N-Cbz-leucin-1) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one Following the procedure of Example 1 (d), except substituting with "1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -ol "el" 1-N- (N-2-pyridylcarbonyl-leucinyl) -amino-3-N- (3- (2-pyridyl-sulfonyl) -amino-propan-2-ol ", the compound was prepared of the title: MS (ES +) 531. 4 (M + H +).

EXAMPLE 15 Preparation of 1-N- (N-pentafluorobenzoyl-leucyl) -amino-3-N- (3- (2-pyridiD-phenyl acetyl) -amino-propan-2-one a) Leucunyl-amino-3-N- (3-.2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol was dissolved (example 1d, 5.5 g, 114 mmol) in EtOH (100 ml), and then 10% Pd / C (1.1 g, mmoles) was added, and the solution was hydrogenated with Parr stirrer at 50 atmospheres for 12 hours. The reaction mixture was filtered through Celite, concentrated in vacuo and then used in the next reaction without further purification (3.5 g, quant): MS (ES +) 303.2 (M + H +). b) 1-N- (N-pentafluarobenzoyl-leucinyl) -amino-3-N- (3-, 2-pyridyl, phenyl acetyl) -amino-propan-2 -ol HBTU (0.2 g, 0.53 mmol) was added to a solution of leucinyl-amino-3-N- (3- (2-pyridyl) -phenyl acetyl) -amino-propan-2-ol (0.23 g, 0.58 mmol ), pentafluorobenzoic acid (0.106 g, 0.5 mmol), NMM (0.23 mL, 2 mmol) in DMF (5 mL), and stirred overnight. The reaction mixture was poured into water, extracted with EtOAc; the organic layer was dried with MgSO 4, filtered, concentrated in vacuo and chromatographed on silica gel to give a white solid (0.146 g, 50%): MS (ES +) 595.1 (M + H +). c) 1-N- (N-pentafluorobenzoyl-leucylnl) -amino-3-N- (3- (2-pyridyl) -phenyl acetyl) -amino-propan-2-one. Dess-Martin (J. Org. Chem. 1983, 48, 4155-4156, 0.12 g, 0.28 mmole) to a solution of 1-N- (N-pentafluorobenzoyl-leucinyl) -amino-3-N- (3- ( 2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol (0.146 g, 0.25 mmol) in CH2Cl2 (40 mL), and stirred for 3 hours. The reaction was diluted with 50 mL of CH2CI2, then 10% aqueous Na2S2? 3 (10 mL), and 10% aqueous NaHCO3 (10 mL) was added, and the reaction was stirred for 10 minutes. The organic layer was dried with MgSO 4, filtered, concentrated in vacuo and chromatographed on silica gel to yield a white solid (44 mg, 30%): MS (ES +) 593.1 (M + H +).

EXAMPLE 16 Preparation of 1-N- (N-2-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl acetyl-amino-propan-2-one a) 1-N- (N-2-naphthoyl-leucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except substituting "2-naphthoic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 551.2 (M + H +).

EXAMPLE 17 Preparation of 1-N-IN-1-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridiD-phenyl-acetyl) -amino-propan-2-one a) 1-N- (N-1-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -yl-acetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except by substituting "1-naphthoic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 551.1 (M + H +).

EXAMPLE 18 Preparation of 1-N- (N-2-pyridyl-carboniO-leucineH) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl-amino-propan-2-one) a) 1-N- (N- (2-pyridyl-carbonyl) -leucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except substituting "2-pyridine carboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 502.3 (M + H + ).

EXAMPLE 19 Preparation of 1-N-. N-4-fluorobenzoyl-leucino-N-amino-3-N- (3- (2-pyridyl) -phenyl-acetyl-amino-propan-2-one a) 1-N- (N-4-fluorobenzoyl-leucine) -amino-3-N- (3- (2-pyridyl) -phene-acetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except substituting "4-fluorobenzoic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 519.4 (M + H +), 541.4 (M + Na +).

EXAMPLE 20 Preparation of 1-N- (N-3,4-difluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridi-Q-phenyl acetyl) -amino-propan-2-one a) 1-N- (N-3,4-difluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan -2-one Following the procedure of Example 15 (ac), except substituting "3,4-difluorobenzoic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 537.2 (M + H +), 559.2 (M + Na +).

EXAMPLE 21 Preparation of 1-N- (N-3,4-dimethoxybenzoyl-leucinyl) -amino-3-N- (3- (2-pyridiD-phenyl-acetyl) -amino-propan-2-one) a) 1-N- (N-3,4-dimethoxybenzoyl-leucine) -amino-3-N- (3- (2-pyridyl-phenyl) -amino-propan- 2-one Following the procedure of Example 15 (ac), except substituting "3,4-dimethoxybenzoic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 561.2 (M + H +), 593.2 ( M + Na +).

EXAMPLE 22 Preparation of 1-N- N-1 - (benzothiophene-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridiP-phenyl-acetyl) -amino-propan-2-one a) 1-N- (N-1-benzothiophene-carbonyl-leucinyl) -amino-3-N-, 3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except substituting "benzothiocarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 557.2 (M + H +).

EXAMPLE 23 Preparation of 1-N- (N-5- (indolo-carbonyl) -leucinyl) -amino-3-N-.3- (2-pyridiD-phenyl acetyl) -amino-propan-2-one a) 1-N- (N- (5-indolo-carbonyl) -leucinyl.-amino-3-N- (3-.2-pyridyl) -phenyl-acetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except by substituting "5-indolecarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 540.2 (M + H +).

EXAMPLE 24 Preparation of 1-N- (N-Cbz-isoleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one a) 1-N- (N-Cbz-isoleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-1 -one. Following the procedure of Example 14 (ae), except by substituting "Cbz-isoleucine" for "Cbz-leucine", the title compound was prepared: MS (ES +) 531.1 (M + H +), 553.1 (M + Na +).

EXAMPLE 25 Preparation of 1-N- (N-Cbz-norvalinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl-amino-propan-2-one) a) 1-N- (N-Cbz-valinyl, -amino-3-N- (3- (2-pyridyl, phenyl-acetyl-amino-propan-2-one) the procedure of Example 14 (ae), except substituting "Cbz-norvaline" for "Cbz-leucine", prepared the title compound: MS (ES +) 517.2 (M + H +).

EXAMPLE 26 Preparation of 1-N- (N-Cbz-α-allyl-phenyl) -P-amino-3-N- (3- (2-pyridiP-phenyl-acety-P-amino-propan-2-one) a) 1-N- (N-Cbz-a-allyl-q-phenyl-p-amino-3-N- (3- (2-pyridiP-phene) acetiD-amino-propan-2-one Following the procedure of example 14 (ae), except substituting "Cbz-a-allyl-glycine" for "Cbz-leucine", the title compound was prepared: MS (ES +) 517.2 (M + H +).

EXAMPLE 27 Preparation of 1-N- (N-Cbz-norle? CniP-amino-3-N- (3- (2-pyridyl-P-phenyl-acetyl) -amino-propan-2-one) a) 1-N-.N-Cbz-norleuciniP-amino-3-N- (3- (2-pyridiP-phenyl) acetyP-amino-propan-2-one Following the procedure of Example 14 (ae), except substituting the "Cbz-leucine" with "Cbz-norleucine", the title compound was prepared: MS (ES +) 531.3 (M + H +).

EXAMPLE 28 Preparation of 1-N- (N-Cbz-N-methyl-leuciniP-amino-3-N- (3- (2-pyridyl) -phenyl-acetylamino-propan-2-one a) 1-N- (N-Cbz-N-methyl-leucine P-amino-3-N- (3- (2-pyridyl-P-phenyl-acetyl-P-amino-propan-2-one) Following the procedure of example 14 (ae), except substituting "Cbz-N-methyl-leucine" for "Cbz-leucine", the title compound was prepared: MS (ES +) 545.3 (M + H +).

EXAMPLE 29 Preparation of 1-N-f N-Cbz-a- (cyclopropyl) -methyl-glycinyl) -amino-3-N- (3- (2-pyridiP-phenyl-acetyl) -amino-propan-2-one a) N-Cbz-a- (cyclopropiP-methyl-qlycine methyl ester) Diazomethane (4.8 mmol in 18 ml of Et20) was added to a solution of N-Cbz-La-allyl-glycine (0.210 g, 0.48 mmol) in 1 mL of Et20 at room temperature and stirred for 5 minutes, then Pd (OAc) 2 was added and the reaction was stirred overnight, filtered through silica gel, concentrated in vacuo and used in the next reaction without further purification (205 mg, 95% yield): MS (ES +) 300.1 (M + Na +). b) N-Cbz-a- (c-chloropropyl-P-methyl) N-Cbz-a- (cyclopropyl) -methyl-glycine methyl ester (205 mg, 0.75 mmol) was dissolved in MeOH (5 ml), then 1N NaOH (0.75 ml) was added dropwise, and the reaction was stirred at room temperature for 12 hours.The reaction mixture was diluted with AcOH, extracted with EtOAc, dried with MgSO4 , filtered, concentrated in vacuo and chromatographed (silica gel, 3% MeOH-CH2CI) to give the title compound as a white solid (165 mg, 82%): MS (ES +) 264.2 (M + H + ), 286.3 (M + Na +), 549.2 (2M + Na +). c) 1-N- (N-Cbz-a- (cyclopropyl-P-methyl-q-phenyl-amino-3-N- (3- (2-pyridiP-phenyl-acetyl-p-amino-propan -2-one Following the procedure of Example 14 (ae), except substituting "Cbz-leucine" with "N-Cbz-a- (cyclopropyl) -methyl-glycine", the title compound was prepared: MS (ES +) 529.3 (M + H +), 551.4 (M + Na +).

EXAMPLE 30 Preparation of 1-N- (N-benzyloxycarbonyl-L-β-tert-butylalanine) -amino-3-N- (3- (2-pyridiP-phenyl-acetiP-amino-propan-2-one) a) N-benzyloxycarbonyl-L-β-tert-butylanine To a stirred solution of L-β-tert-butylanine (1.0 g, 6.89 mmol) in water (2.1 ml) and 5 N NaOH (1.38 ml) at 0 ° C, benzyl chloroformate (1.3 g, 7.58 mmol) and 2 N NaOH (3.8 ml) were added in 10 alternating portions for 1.5 hours. After the additions were complete, the mixture was stirred for another 30 minutes at room temperature. The pH was then brought to 10, and the mixture was extracted with ether (50 ml). The aqueous layer was acidified to pH 3 with 3 N HCl and extracted with ether (3 x 50 mL). The organic layers were combined, dried (MgSO 4), filtered and concentrated to yield the title compound as a colorless oil (1.59 g, 83%). MS (ESI): 278.2 (M + H) ". b) 1-N- (N-benzyloxycarbonyl-L-β-tert-butylanine) -amino-3-N-, 3- (2-pyridiP-phenyl acetyl) -amino-propan-2-one Following the procedure of the example 14 (ae), except substituting "N-benzyloxycarbonyl-L-β-tert-butylalanine" for "Cbz-leucine", the title compound was prepared: MS (ES +) 545.2 (M + H +), 567.3 (M + Na +).

EXAMPLE 31 Preparation of 1-N- (2- (3-biphen-P-4-methyl-valeriP-amino-3-N- (2-pyridyl-sulfoniP-amino-propan-2-one) a) 3-Bromo-phenyl methyl acetate 3-Bromo-phenyl acetic acid (2.15 g, 10 mmol) was dissolved in ether, and then treated with a diazomethane solution until the yellow color persisted. The reaction was then quenched with AcOH, concentrated in vacuo and used in the next reaction without further purification. b) 3-biphenyl methyl acetate 3-bromo-phenyl methyl acetate was dissolved with (2.29 g, 10 mmol) in toluene (30 ml). Then phenyl boronic acid (1.46 g, 12 mmol) was added followed by aqueous sodium carbonate (2M, 4.24 ml, 40 mmol), then tetrakis (triphenylphosphine) palladium (0.35 g, 0.3 mmol) and refluxed overnight . The reaction was cooled to room temperature, diluted with saturated ammonium chloride and then extracted with EtOAc (2 x 10 mL). The combined organic layers were dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel, 5% EtOAc: hexanes) to provide the desired product as a white solid (1.93 g, 84%): MS ( ES): M + H + = 263. c) 3-biphenyl acetic acid 3-biphenyl acetyl methyl ester was dissolved in MeOH (40 ml) and water (6 ml), then hydrated LiOH (0.7 g, 16.8 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml) and then with EtOAc (2 x 10 ml). The combined organic layers were dried with magnesium sulfate, filtered and concentrated to give the desired product as a white solid (1.66 g, 93%): 1 H NMR: d: 7.6-7.25 (m, 9H), 3.7 ( s, 2H). d) 2- (3-bipheni-4-methyl-pent-4-enoic acid) nBuLi (3.26 mL, 1.6 M in hexanes) was added dropwise to a solution of diisopropylamine (0.74 mL, 5.3 mmol) in THF (6 ml) at 0 ° C. The reaction was stirred for 15 minutes and then cooled to -78 ° C. 3-biphenyl acetic acid (0.5 g, 2.35 mmol) was dissolved in THF (2 ml) and added dropwise. The reaction was warmed to 0 ° C, stirred for 40 minutes and then cooled to -78 ° C. Isobutenyl bromide was added. (0.475 g, 3.52 mmol), and the reaction was stirred for 1 hour. Water was added (2 ml), and the THF was removed in vacuo. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml) and then with EtOAc (2 x 10 ml).

The combined organic layers were dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel, MeOH: 5% methylene chloride) to give the desired product as a white solid (1.66 g, 93%): 1 H NMR: d: 7.6-7.3 (m, 9H), 4.75 (d, 2H), 3.87 (t, 1 H), 2.87 (dd, 1 H), 2. 50 (dd, 1 H), 1.70 (s, 3H). e) 2- (3-bipheniD-4-methyl-pentanoic acid) 2- (3-biphenyl) -4-methyl-pent-4-enoic acid (0.5 g, 1.87 mmol) was dissolved in EtOAc (25 mL). , Pd / C at 10% (60 mg) was added, and the reaction was stirred for 2.5 hours under a gaseous hydrogen balloon.The reaction was filtered, concentrated in vacuo and then redissolved in EtOAc: EtOH 1: 5 (15 ml) Then, 10% Pd / C (80 mg) was added, and the reaction was stirred under a balloon of hydrogen gas overnight.The reaction was filtered, concentrated in vacuo and chromatographed (gel of silica, MeOH: 5% methylene chloride) to give the desired product as a white solid (1.66 g, 93%): 1 H NMR: d: 7.6-7.3 (m, 9H), 3.7 (t, 1 H), 2.07 -1.95 (m, 1H), 1.8-1.7 (m, 1 H), 1.6-1.45 (m, 1 H). f) 1-N- (2- (3-biphen-P-4-methyl-valer-P-amino-3-N- (2-pyridyl-sulfoniP-amino-propan-2-one) Following the procedure of Example 1 (a) and (d), except substituting "3- (4-biphenyl) -4-methyl-pentanoic acid" with "Boc-leucine", the title compound was prepared: MS (ES +) 480.2 (M + H + ).

EXAMPLE 32 Preparation of 1-N- (2- (3-bipheniD-4-methyl-valeriD-amino-3-N- (2-carboxymethyl-phenyl-sulfoniP-amino-propan-2-one a) 1-N- (2- (3-bipheniD-4-methyl-valeryl) -amino-3-N-.2-carboxymethyl-phenyl-sulfoniP-amino-propan-2-one Following the procedure of example 31 (af), except substituting "2-carboxymethyl-phenyl sulfonyl chloride" with "2-pyridyl sulfonyl chloride", prepared the title compound: MS (ES +) 537.1 (M + H +), 559.1 (M + Na +), 1073.5 (2M + H +), 1095.3 (2M + Na +).

EXAMPLE 33 Preparation of 1-N- (2- (3-bipheniP-4-methyl-valeriP-amino-3-N- (4-cyano-phenylsulfon-P-amine-propan-2-one) a) 1-N- (2- (3-b-phenyl) -P-4-methyl-valeriP-amino-3-N- (4-cyano-phenyl-sulfoniP-amino-propan-2-one) Following procedure of Example 31 (af), except by substituting "4-cyano-phenyl sulfonyl chloride" with "2-pyridyl sulfonyl chloride", the title compound was prepared: MS (ES +) 504.3 (M + H +).

EXAMPLE 34 Preparation of 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (8-quinolino carboniP-amino-propan-2-one) a) 1-N- (2- (3-bipheniP-4-methyl-valeriP-amino-3-N- (8-quinolino carboniP-amino-propan-2-one) Following the procedure of Example 31 (af) , except by substituting "8-quinoline carboxylic acid and EDCl" with "2-pyridyl sulfonyl chloride", the title compound was prepared: MS (ES +) 494.2 (M + H +).

EXAMPLE 35 Preparation of 1-N- (2- (3-bipheniP-4-methyl-valeryl) -amino-3-N- (3- (2-pyridyl) -phenyl-acety-P-amino-propan-2-one) a) 1-N- (2- (3-b-phenyl-4-methyl-valeriP-amino-3-N- (3- (2-pyridyl-P-phenyl-acety-P-amino-propan-2-a) Following the procedure of Example 34 (a), except substituting "3- (2-pyridyl) -phenyl acetic acid" with "8-quinoline carboxylic acid", the title compound was prepared: MS (ES +) 534.3 (M + H +).

EXAMPLE 36 Preparation of 1-N- (2- (3-bipheniP-4-methyl-valeriP-amino-3-N- (3- (3-pyridiP-3-phenyl-acetiD-amino-propan-2-one) a) 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (3-pyridyl) -3-phenyl-acetyl) -amino- propan-2-one Following the procedure of Example 34 (a), except substituting "3- (3-pyridyl) -phenyl acetic acid" with "8-quinoline carboxylic acid", the title compound was prepared: MS (ES + ) 534.3 (M + H +).

EXAMPLE 37 Preparation of 1-N- (2- (3-biphenyl) -4-methyl-valer? L) -amino-3-N- (2-pyridinocarbonD-amino-propan-2-one) a) 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-pyridinocarbonyl) -amino-propan-2-one Following the procedure of Example 34 (a), except by substituting "2-pyridine carboxylic acid" with "8-quinoline carboxylic acid", the title compound was prepared: MS (ES +) 444.3 (M + H +).

EXAMPLE 38 Preparation of 1-N- (2- (3-bipheniP-4-methyl-valeriP-amino-3-N- (5- (2-pyridino) -thiophene-carbon-P-amine-propan-2 -one a) 1-N- (2- (3-biphen-P-4-methyl-valeriP-amino-3-N- (5- (2-pyridino) -thiophene-carbon-P-amino) -propan-2-one Following the procedure of Example 34 (a), except substituting "5- (2-pyridino) -thiophenecarboxylic acid" with "8-quinoline carboxylic acid", the title compound was prepared: MS (ES + ) 526.3 (M + H +), 1051.3 (2M + H +).

EXAMPLE 39 Preparation of 1-N-f2- (3-bipheniP-4-methyl-valeryl) -amino-3-N- (N-benzyl-4-piperidino-carboniP-amino-propan-2-one) a) 1-N- (2- (3-bipheniP-4-methyl-valeryl, -amino-3-N- (N-benzyl-4-pyridine-carbon) P-amino-propan-2-one Following the procedure of Example 34 (a), except substituting "N-benzyl-4-piperidine carboxylic acid" with "8-quinoline carboxylic acid", the title compound was prepared: MS (ES +) 540.3 (M + H +).

EXAMPLE 40 Preparation of 1-N- (2- (3-biphen-P-4-methyl-valeryl) -amino-3-N- (2-quinolinecarbon D-amino-propan-2-one) a) 1-N- (2- (3-bipheniP-4-methylene-valer) -P-amino-3-N- (2-quinoline-carboniP-amino-propan-2-one) Following the procedure of Example 35 (a), except by substituting "2-quinoline carboxylic acid" with "8-quinoline carboxylic acid", the title compound was prepared: MS (ES +) 494.2 (M + H +) - EXAMPLE 41 Preparation of 1-N- (2- (3-bipheniP-4-methyl-valeriP-amino-3-N- (2-carboxyl-phenyl-sulfoniP-amino-propan-2-one) a) 1-N- (2- (3-biphenyl, -4-methyl-valeriP-amino-3-N- (2-carboxyl-phenyl-sulfoniP-amino-propan-2-one) 1-N was dissolved - (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-carboxymethyl-phenyl-sulfonyl) -amino-propan-2-one (94 mg, 0.175 mmol) in MeOH ( 10 ml), water (1 ml), and then L¡OH-H20 (8 mg, 0.18 mmol) was added and the reaction was stirred for 15 minutes at room temperature, then the reaction mixture was quenched with 1 N HCl. in ether (0.2 ml), concentrated in vacuo and then chromatographed on silica gel (EtOAc: hexanes: AcOH 60: 40: 1) to give a white solid (60 mg, 66%): MS (ES +) 523.2 ( M + H +), 555.2 (M + Na +).

EXAMPLE 42 Preparation of 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (4-C-tetrazolo-phenyl-sulfon-P-amino-propan) -2-one a) 1-N- (2- (3-bipheniP-4-methyl-valeriP-amino-3-N- (4-C-tetrazolo-phenyl-sulfoniP-amino-propan-2-one) 1-N- (2- (3-biphenyl) -4-methyl-valeri) -amino-3-N- (4-cyano-phenylisulfonyl) -amino-propan-2-one (300 mg , 0.6 mmol) in N-methyl-pyrrolidinone (3 ml), and then sodium azide (116 mg, 1.8 mmol) and triethylamine-HCl (0.124 g, 0.9 mmol) were added and the reaction was heated to 0.degree. 100 ° C and stirred for 5.5 hours. The crude reaction mixture was cooled to room temperature and then chromatographed on silica gel (5% MeOH - AcOH- at 1% - 94% methylene chloride) to yield a white solid (125 mg, 38%): MS (ES +) 547.2 (M + H +).

EXAMPLE 43 Preparation of 1-N- (2- (3-bipheniP-4-methyl-valeriP-amino-3-N- (3- (2-pyridyl) phenyl-acety-P-amino- (S) -butan-2-one a) Cbz-L-ala-bromo methyl ketone Isobutyl chloroformate (2.74 ml, 21.2 mmol) was added dropwise to a solution of Cbz-L-alanine (4.7 g, 21.2 mmol) and N-methyl morpholine (2.32 ml). , 21.2 mmol) in THF (40 ml) at -40 ° C. The reaction was stirred for 15 minutes, then filtered and washed with ether. Diazomethane was added from 12 g of 1-methyl-3-nitro-nitroso-guanidine and 36 ml of 40% KOH in ether (300 ml), and the reaction was placed in a refrigerator overnight at 0 ° C. . 30% HBr / AcOH (14 ml) was added dropwise to the crude reaction mixture and stirred for 5 minutes. The solution was washed with aqueous citric acid (50 ml x 2), saturated aqueous sodium bicarbonate (3 x 150 ml) and then with brine (100 ml). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated in vacuo to give a solid which was used in the next step without further purification: MS (ES +) 360.3 (M + H +). b) Cbz-ala-azido methyl ketone Cbz-L-ala-bromo methyl ketone (1.5 g, 5 mmol) was dissolved in DMF (10 ml) and then sodium azide (0.39 g, 6 mmol) and sodium fluoride were added. potassium (0.58 g, 7.5 mmol) and the reaction was stirred overnight. The reaction was separated between EtOAc and water, and then the combined organic extracts were dried with magnesium sulfate, filtered, concentrated in vacuo and chromatographed (2 to 5% MeOH, methylene chloride, silica gel) to provide the title compound as a white solid (0.5 g, 38%), IR (thin film): 2106.4 cm "1 c) (S) -N-Cbz-3-amino-1-azido-butane-2-ol Cbz-ala-azido methyl ketone (0.5, 1.9 mmol) was dissolved in MeOH (10 ml) and sodium borohydride (0.144 g, 3.8 mmol) was added at 10 ° C, and the reaction was stirred for 15 minutes. The reaction was warmed with water (10 mL) and extracted with EtOAc (25 mL). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated to give the title compound without further purification (0.5 g, quant). d) (S, -N-Cbz-3-amino-1 -amino-butan-2-ol) (S) -N-Cbz-3-amino-azido-butan-2-ol (0.5 g, 1.9 mmol) was dissolved. ) in MeOH (7.5 ml), and triethylamine (1.0 ml, 7.1 mmol), propan-1,3-dithiol (1.07 ml, 10 mmol) was added, and the reaction was stirred overnight, concentrated in vacuo, and then the white solid was washed with hexane to provide the title compound which was used in the next reaction without further purification: MS (ES +) 239.3 (M + H +). e) 1-N-, Cbz, -amino-3-N- (3- (2-pyridyl- (phenyl-acetyl-P-amino-.S) -butan-2-ol) (S) -N-Cbz were dissolved 3-amino-1-amino-butan-2-ol (0.452 g, 1.9 mmol) and 3- (2-pyridyl) -phenyl acetic acid (0.4 g, 1.9 mmol) in DMF (15 mL) and HOBT were added. H2O (0.27 g, 2 mmol), EDCl (0.38 g, 2 mmol), and the reaction was stirred overnight, the reaction was separated between EtOAc and 1 N NaOH, the combined organic extracts were dried with magnesium sulfate , filtered and concentrated to give the title compound (0.33g, 40%): MS (ES +) 434.2 (M + H +). f) 1-N-, 3-, 2-pyridyl- (phenyl acetyP-amino- (S) -butan-2-ol-3-amine 1-N- (Cbz) -amino-3-N was dissolved - (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-ol (0.33 g, 0.76 mmole) in EtOH (12 ml), and then added Pd / C at 10% (0.08 g), and the reaction was stirred under a gaseous hydrogen balloon overnight. The reaction was filtered through Celite, concentrated in vacuo and used in the next reaction without further purification: MS (ES +) 300.3 (M + H +). q) 2- (3-β-phenylD 4 -methyl-valeryl chloride) Thionyl chloride (0.25 ml, 3.4 mmol) was added dropwise to a solution of 2- (3-biphenyl) -4- methyl-pentanoic acid (0.54 g, 2 mmol) in toluene (25 ml), and then a drop of DMF was added, and the reaction mixture was stirred for 2 hours at room temperature. used in the following reaction without further purification: IR (thin film): 1790.65 cm-1 h) 1-N- (3- (2-b-phenyl-4-methylene-valer-P-amino-3-N- (3- (2-pyridyl- (phenyl-acetyl) -amino- ( S) -butan-2-ol 2- (3-biphenyl) -4-methyl-valeryl chloride (0.22g) was added dropwise., 0.76 mmole) to a solution of 1-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-ol-3-amine (0.28 g, 0.76 mmole), NMM ( 0.42 mL, 3.8 mmol) in DMF (10 mL), and the reaction was stirred for one hour, the reaction was extracted with EtOAc, 1 N NaOH, and the combined organic extracts were dried with MgSO, filtered, concentrated and were chromatographed (silica gel, 4% MeOH-CH 2 Cl 2) to give a white foam (0.24 g, 57%): MS (ES +) 550.3 (M + H +). i) 1-N- (3- (2-biphenyl) -4-methyl-valerate-P-amino-3-N- (3- (2-pyridyl- (phenyl-acetyl) -amino- (S ) -butan-2-one Following the procedure of Example 15 (c), except substituting "1-N- (2- (3-b-phenyl) -4-methyl-valeryl) -amino-3-N - (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-ol "the" 1-N- (N-pentafluorobenzoyl-leucine) -amino-3- N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol ", the title compound was prepared: MS (ES +) 494.2 (M + H +).

EXAMPLE 44 Preparation 1-N- (2- (3-biphen-P-3-methyl-valer-P-1-N-methyl-amino-3-N- (3- (2-pyridyl- (phenyl-acetyl-amino) -propan-2-one a) N- (2- (3-bipheniP-3-methyl-valer-P-1-N-methyl-qlycine ethyl ester) 2- (3-biphenyl) -4-methyl-valeryl chloride ( example 44 (g), 2 g, 7 mmol) was added to a solution of sarcosine ethyl ester hydrochloride (1.07 g, 7 mmol) in NMM (1.9 ml, 17.5 mmol) in DMF (10 ml). The reaction was stirred at room temperature for 2.5 hours, concentrated in vacuo and chromatographed (silica gel, 10% EtOAc / hexanes) to yield a clear liquid (2g, 78%): MS (ES +) 368.4 (M + H +). b) N- (2- (3-β-phenylD-3-methyl-valeriD-1-N-methyl-qlycine) LiOH-H20 (0.25 g, 6 mmol) was added to a solution of N- (2-ethyl ester). - (3-biphenyl) -3-methyl-valeryl) -1-N-methyl-glycine (2 g, 5.45 mmol) in THF (30 ml) / H20 (3 ml), and stirred for 2 hours at room temperature.

The reaction mixture was treated with 1N HCl in ether (7 ml), and then concentrated in vacuo to yield a white solid which was used in the next reaction without further purification: 1 H NMR (d): 7.2-2.6 (m, 9H), 4.3 (d, 1H), 4.0 (d, 1 H), 3.05 (s, 3H), 3.0 (s, rotater), 0.8-1.0 (m, 6H). c) 1-N- (2- (3-b-phenyl) -3-methylene-valer-P-1-N-methyl-amino-3-N- (3- (2-pyridyl- (phenyl acetyp- amino-propan-2-ol Following the procedure of example 43 (ae), except substituting with "N- (2- (3-b-phenyl) -3-methyl-valeri) -1-N-methyl -glycine "Cbz-L-alanine", the title compound was prepared: MS (ES +) 550.3 (M + H +). d) 1-N- (2- (3-b-phenyl-3-methyl-valeriP-1-N-methyl-amino-3-N- (3- (2-pyridyl- (phenyl acetyl) P-amino-propan-2-one Following the procedure of Example 15 (c), except substituting with "1-N- (2- (3-biphenyl-valeryl) -1-N-methyl-amino-3- N- (3- (2-pyridyl- (phenyl acetyl) -amino-propan-2-ol "el" 1-N- (N-pentafluorobenzoyl-leucinyl) -amino-3-N- (3- (2 -pyridyl) -phenyl-acetyl) -amino-propan-2-ol ", the title compound was prepared: MS (ES +) 548.2 (M + H +).

EXAMPLE 45 Preparation 1-N- (N-2-pyridyl carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenyl-carboniP-amino-propan-2-one) a) 1-N- (N-2-pyridyl) carbonyl-leucinyl, -amino-3-N-, 4-phenoxy-phenyl-carboniP-amino-propan-2-one Following the procedure of Example 1 (ac ), except by substituting "4-phenoxy-phenyl carboxylic acid and EDCI" with "2-pyridine sulfonyl chloride", and example 15 (c), except substituting 1-N- (N-2-pyridyl carbonyl) leucinyl) -amino-3-N- (4-phenoxy-phenylcarbonyl) -amino-propan-2-ol "1-N- (N-pentafluorobenzoyl-leucinyl) -amino-3-N- (3- (2 -pyridyl) -phenyl acetyl) -amino-propan-2-ol ", the title compound was prepared: MS (ES +) 503.3 (M + H +).

EXAMPLE 46 Preparation 1-N- (N-8-quinolino carbonyl-leuciniP-amino-3-N- (4-phenoxy-phenyl-carboniP-amino-propan-2-one a) 1-N-.N-8-quinolyl-carbonyl-leucyl-P-amino-3-N-.4-phenoxy-phenyl-carbonyl) -amino-propan-2-one Following the procedure of Example 1 (ac), except substituting "4-phenoxy-phenyl carboxylic acid and EDCI" with "2-pyridine sulfonyl chloride", and with "8-quinolinecarboxylic acid" with "2-pyridinecarboxylic acid", and of Example 15 (c), except substituting 1-N- (N-8-quinolino-carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenyl-carbonyl) -amino-propan-2-ol "1-N- (4-pentafluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol", the compound of Title: MS (ES +) 553.3 (M + H +), 575.2 (M + Na +).

EXAMPLE 47 Preparation 1-N- (N-2-quinolino carbonyl-leuciniP-amino-3-N-.4-phenoxy-phenyl-carboniP-amino-propan-2-one) a) 1-N- (N-2-quinolino carbonyl-leucinyl, -amino-3-N- (4-phenoxy-phenyl-carboniP-amino-propan-2-one) Following the procedure of example 1 (a-c), except by substituting "4-phenoxy-phenyl carboxylic acid and EDCl" with "2-pyridine sulfonyl chloride", and with "2-quinolinecarboxylic acid" the "2-pyridinecarboxylic acid", and example 15 (c), except by substituting "1-N- (N-8-quinolino-carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenol-carbonyl) -amino-propan-2-ol" the " 1-N- (N-pentafluorobenzoyl-leucyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol ", was prepared The title compound: MS (ES +) 553.2 (M + H +), 575.2 (M + Na +).

EXAMPLE 48 Preparation of 1-N- (N- (Cbz-norvaliniP-amino-3-N- (8-quinolino-sulfoniP-amino-propan-2-one a) 1-N- (N- (Cbz-norvalin-P-amino-3-N- (8-quinolinesulfonyl-P-amino-propan-2-one) Following the procedure of Example 14 (de), except substituting "Cbz-norvaline" with "Cbz-leucine", and with "8-quinolino-sulfonyl chloride" the "3- (2-pyridyl) phenyl acetic acid and EDCI", the Title compound: MS (ES +) 513.2 (M + H +).

EXAMPLE 49 Preparation of 1-N- (8-quinolino-sulfoniP-amino-3-N-, 8-quinolinosulfonyl) -amino-propan-2-one a) 1-N-.8-quinolino-sulphonyl, -amino-3-N- (8-quinolyl-sulfonyl-P-amino-propan-2-one) Following the procedure of example 48, the compound of title (byproduct): MS (ES +) 471.2 (M + H +).

EXAMPLE 50 Preparation of 1-N- (2- (3-biphen-P-3-methyl-valeriP-amino-3-N- (8-quinolino-sulfoniP-amino-propan-2-one) a) 1-N- (2- (3-b-phenyl) -P-3-methyl-valer-P-amino-3-N- (8-quinolino-sulfon-P-amine-propan-2-one) Following the procedure of Example 31 (ad), except substituting "8-quinolino sulfonyl chloride" with "2-pyridyl-sulfonyl", and example 15 (c), except substituting "1-N- (2- ( 3-biphenyl) -4-methyl-pentamido) -amino-3-N- (8-quinolino-sulfonyl) -amino-propan-2-ol "el" 1-N- (N-pentafluorobenzoyl-leucinyl) -amino- 3-N- (3- (2-pyridyl) -phenyl] -acetyl) -amino-propan-2-ol ", the title compound was prepared: MS (ES +) 530.3 (M + H +).

EXAMPLE 51 Preparation of 1-N- (2- (3-bipheniP-3-methyl-valeriP-amino-3-N- (2- (3-bipheniP-3-methyl-valeriP-amino-propan-2-one) a) 1-N- (2- (3-biphen-P-3-methyl-valer-P-amino-3-N-f2- (3-bipheniP-3-methyl-valeryl) -amino-propan- 2-one Following the procedure of Example 50, the title compound (secondary product) was prepared: MS (ES +) 611.3 (M + Na +).

EXAMPLE 52 Preparation of 1-N- N-, Cbz-norvaliniP-amino-3-N- (N-, Cbz-norvalin-P-amino-propan-2-one) a) 1-N- (N- (Cbz-norvalin-P-amino-3-N- (N- (Cbz-norvaliniP-amino-propan-2-one) Following the procedure of example 48, the title compound was prepared (secondary product): MS (ES +) 577.3 (M + Na +).

EXAMPLE 53 Preparation of 1 - ((3-biphenyl) -but-3-ene-1 -carboniP-amino-3-N- (3- (2-pyridyl-P-phenyl-acet-P-amino-propan-2 -one a) 2- (3-biphen-P-pent-4-enoic acid) Following the procedure of Example 31 (d), except substituting "allyl bromide" with "isobutenyl bromide", the title compound was prepared: H NMR: d: 7.29-7.58 (m, 9H), 5.71-5.82 (m, 1 H), 5.04 (d, 1H), 5.08 (d, 1 H), 3.67 (t, 1 H), 2.77-2.84 (m, 1 H), 2.46-2.56 (m, 1 H). b) 1 - ((3-b-phenyl-P-but-3-ene-1-carbon-P-amino-3-N- (3- (2-pyridiP-phenyl-acetyl) -am) No-propan-2-one Following the procedure of example 14 (ad), except substituting "2- (3-biphenyl) -pent-4-enoic acid" with "Cbz-leucine", and example 15 (c) ), except substituting "1 - ((3-biphenyl) -but-3-ene-1-carbonyl) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -am no-propan-2-ol "el" 1-N- (N-pentafluorobenzoyl-leucyl) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -amino-propan- 2-ol ", the title compound was prepared: MS (ES +) 518.3 (M + H +), 540.3 (M + Na +).

EXAMPLE 54 Preparation of 1-N- (2- (3-biphenyl) -but-3-ene-1 -carbonyl) -amino-3-N-2- (3-bipheniP-but-3-ene-1-carbon P-propan-2-one a) 1-N- (2- (3-biphen-P-but-3-ene-1-carboniP-amino-3-N-2- (3-bipheniP-but-3-ene-1-carbonP -propan-2-one Following the procedure of Example 53, the title compound (secondary product) was prepared: MS (ES +) 557.3 (M + H +), 579.2 (M + Na +).

EXAMPLE 55 Preparation of 1- (3-biphenyl) -ethyl-cyclopropane-1-carbonyl-P-amino-3-N- (3- (2-pyridyl-phenyl-acetyl) -amino-propan-2-one) a) 2- (3-bipheniP-3-cyclopropyl-propane) acid Following the procedure of Example 29 (ad), except substituting with "2- (3-biphenyl) -pent-4-enoic acid" the "Cbz- La-allyl-glycine ", the title compound was prepared: 1 H NMR: d: 7.33-7.73 (m, 9H), 3.77 (t, 1 H), 1. 93-2.01 (m, 1 H), 1.78-1.85 (m, 1 H), 0.66-0.71 (m, 1 H), 0.41-0.48 (m, 2H), 0. 05-0.17 (m, 2H). b) 1 - (3-bipheniD-ethyl-cyclopropane-1 -carbonyl, -amino-3-N- (3-, 2-pyridyl) -phenyl-acetiP-amine-propan-2-one Following the procedure of example 14 (ad), except substituting "2- (3-biphenyl) -3-cyclopropyl-propanoic acid" for "Cbz-leucine", and for example 15 (c), except substituting "1- (3-biphenyl)" ) -ethyl-cyclopropane-1-carbonyl) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -amino-propan-2-ol "el" 1-N- (N-pentafluorobenzoyl- leucinyl) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -amino-propan-2-ol ", the title compound was prepared: MS (ES +) 532.2 (M + H + ).

EXAMPLE 56 Preparation of 1-N- (2- (3-bipheniD-3-methyl-but-3-ene-1 -carbonyl) -amino-3-N- (3- (2-pyridiP-phenylacetiP-amino-propan -2-one a) 1-N-.2- (3-bipheniP-3-methyl-but-3-ene-1 -carbonyl, -amino-3-N- (3- (2-pyridiP-phenylacetyP-amino-propan-2 -one Following the procedure of Example 14 (ad), except substituting "2- (3-biphenyl) -4-methyl-pent-4-enoic acid" (example 31 (d) the "Cbz-leucine", and Example 15 (c), except substituting "1- (3-biphenyl) -3-methyl-but-3-ene-1-carbon-1) -amino-3-N- (3- (2-pyridyl) - phenylacetyl) -amino-propan-2-ol "the" 1-N- (N-pentafluorobenzoyl-leucine) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -amino-propan -2-ol ", the title compound was prepared: MS (ES +) 532.2 (M + H +), 554.2 (M + Na +).

EXAMPLE 57 Preparation of 1- (3-biphenyl) -3-methyl-but-3-ene-1 -carbon-P-amino) -3- (3-biphen-P-methyl-but-3-ene-1- carbon-P-amino-propan-2-one a) 1- (3-biphen-P-3-methyl-but-3-ene-1 -carbonyl. -amino-3-, 3-biphen-P-3-methyl-but-3-ene- 1-carbon P-amino-propan-2-one Following the procedure of Example 56, the title compound (secondary product) was prepared: MS (ES +) 585.3 (M + H +), 607.3 (M + Na +).

EXAMPLE 58 Preparation of 1-N- (N- (fra /? S-4-propyl cyclohexyl-carboniP-leucineP-amino-3-N-.3- (2-pyridiP-phenylacetyp-amino-propan-2-one a) Preparation of 1-N- (N- (frans-4-propyl cyclohexyl-carbonyl) -leuciniP-amino-3-N- (3- (2-pyridiP-phenylacetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except substituting "zra /? S-4-propyl-cyclohexylcarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 549.3 (M + H +).

EXAMPLE 59 Preparation of 1-N-, N-.2-quinoxalino-carboniP-leuci-N-amino-3-N-, 3-.2-pyridiP-phenylacetiP-amino-propan-2-one a) Preparation of 1-N- (N- (2-quinoxal) -no-carboniP-leucine-D-amino-3-N- (3-, 2-p ?? id¡P-phenylacet) L) -amino-propan-2-one Following the procedure of example 15 (ac), except substituting "2-quinoxalincarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 553.1 (M + H +).

EXAMPLE 60 Preparation of 1-N-. N- (5- (2,3-dihydro-benzofuran) -carboniP-leuciniP-amino-3-N- (3-, 2-pyridiP-phenylacetyP-amino-propan-2- ona a) 1-N- (N- (2- (2,3-dihydro-benzofuran) -carboniP-leucinyl) -amino-3-N- (3- (2-pyridiP-phenylacetylP-amino-propan-2 -one Following the procedure of Example 15 (ac), except substituting "5- (2,3-dihydro-benzofuran) -carboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 543.2 (M + H +).

EXAMPLE 61 Preparation of 1-N- (N- (N-methyl-2-indolo-carboniP-leucineP-amino-3-N- (3-, 2-pyridiD-phenylacetyP-amino-propan-2-one a) Preparation of 1-N- (N- (N-methyl-2-indolo-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -amino-propan-2- Following the procedure of Example 15 (ac), except substituting "N-methyl-2-indolecarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 554.1 (M + H +).

EXAMPLE 62 Preparation of 1-N- (N-.cyclohexyl-carbonyl) -leucinyl) -amino-3-N-.3-, 2-pyridyl) -phenylacetyl) -amino-propan-2 ona a) Preparation of 1-N- (N- (cyclohexyl-carbonyl, -leucyl, -amino-3-N- (3- (2-pyridyl-phenylacetyl, -amino -propan-2-one Following the procedure of example 15 (ac), except substituting "cidohexylcarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 507.4 (M + H +).

EXAMPLE 63 Preparation of 1-N- (N- (2-chloro-benzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -arnino-propan-2-one a) 1-N- (N- (2-chloro-benzoyl) -leucin-1) -amino-3-N- (3- (2-pyridyl, -phenylacetyl) -amino-propan-2-one Following the procedure of example 15 (ac), except substituting "2-chlorobenzoic acid" with "pentafluorobenzoic acid", prepared the title compound: MS (ES +) 535.2 (M + H +).

EXAMPLE 64 Preparation of 1-N-. N- (2-benzofuran-carbonyl) -leucinyl) -amino-3-N-, 3-, 2-pyridyl) -phenolacetyl) -amino-propan- 2-one a) 1-N- (N- (2-benzofuran-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenylacetyl) -amino-propan-2-one Following the procedure of the example 15 (ac), except substituting "2-benzofurancarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 541.2 (M + H +), 573.3 (M + Na +).

EXAMPLE 65 Preparation of 1-N- (N- (3-phenoxy-phenyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridiD-phenyl-acetyl) -amino-propan-2-one) a) 1-N- (N- (3-phenoxy-phenyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridiD-phenyl-acetyl) -amino-propan-2-one) the procedure of example 15 (ac), except substituting "3-phenoxyphenylcarboxylic acid" with "pentafluorobenzoic acid", prepared the title compound: MS (ES +) 593.2 (M + H +).

EXAMPLE 66 Preparation of 1-N- (N- (4-phenoxy-phenyl-carbonyl) -leucine-D-amino-3-N- (3- (2-pyridiP-phenyl-acetyl) -amino-propan-2-one) a) 1-N- (N- (4-phenoxy-phenyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridiD-phenyl-acetyl) -amino-propan-2-one) Following the procedure of example 15 (ac), except by substituting "4-phenoxyphenylcarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 593.2 (M + H +).

EXAMPLE 67 Preparation of 1-N- (N- (3-methoxy-2-quino-carbon-P-leuci-N-amino-3- N -3-, 2-pyridyl) -phenyl-acetyl) -amino -propan-2-one a) 1-N- (N- (3-methoxy-2-quinoline-carbonyl) -leucine-P-amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino- propan-2-one Following the procedure of example 15 (ac), except substituting "3-methoxy-2-quinolinecarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 581.2 (M + H + ).

EXAMPLE 68 Preparation of 1-N- (N-Cbz-leucinyl) amino-3-N- (3- (2-pyridyl- (phenyl acetyD-amino- (S) -butan-2-one a) Preparation of 1-N- (N-Cbz-leuci-N-Phenyl-3-N-.3- (2-pyridyl- (phenyl-acetyl-amino-S, -butan-2-one) Following the procedure of example 44 (ai), except substituting "Cbz-leucine and HBTU" with "2- (3-biphenyl) -4-methyl-pentanoic acid and thionyl chloride", the title compound was prepared: MS (ES +) 545.3 (M + H +).

EXAMPLE 69 Preparation of 1-N-f N- (4-fluorobenzoiP-leucinePamino-3-N- (3- (2-pyridyl- (phenyl) acetyl) -amino- (S) -butan-2-one a) 1-N-.N-Boc-leucinePamino-3-N- (3-.2-pyridyl- (phenyl acetyl, -a mino- (S) -butan-2-ol) Following the procedure of example 44 (ai), except substituting "Boc-leucine and HBTU" with "2- (3-biphenyl) -4-methyl-pentanoic acid and thionyl chloride", the title compound was prepared: MS (ES +) 513.2 (M + H +). b) 1-N-leucinyl) amino-3-N- (3- (2-pyridyl- (phenyl-acetyl) -amino- (S) -butan-2-ol) Following the procedure of example 1 ( b), except substituting with "1-N- (N-Boc-leucinyl) amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-ol" "1-N- (Boc-leucinyl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-ol", the title compound was prepared: MS (ES +) 413.1 (M + H +). c) 1-N- (N- (4-fluorobenzoiP-leucinePamino-3-N- (3- (2-pyridyl- (phenol-acetyl-amino- (S) -butan-2-one) the procedure of example 15 (bc), except substituting with "1-N- (leucinyl) amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) - butan-2-ol "the" leucinyl-amino-3-Ñ- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol ", and with" 4-fluorobenzoic acid "the" acid pentafluorobenzoic acid ", the title compound was prepared: MS (ES +) 533.3 (M + H +), 555.1 (M + Na +).

EXAMPLE 70 Preparation of 1-N- (N- (2-benzothiophene-carboniP-leuci-N-amino-3-N- (3-, 2-pyridyl- (phenyl-acetyl-amino- (S) -butan-2-one a) 1-N- (N- (2-benzothiophene-carboniP-leucinePamino-3-N -3- (2-pyridyl-Cphenyl acetyl) -amino- (S) -butan-2- Following the procedure of Example 79 (ac), except substituting "2-benzothiophenecarboxylic acid" with "4-fluorobenzoic acid", the title compound was prepared: MS (ES +) 571.2 (M + H +).

EXAMPLE 71 Preparation of 1-N- (N- (2-pyridyl-methyleneoxy-carboniP-leucineP-amino-3-N- (1-naphthalene sulfoniP-amino-propan-2-one a) 1-N- (N- (2-pyridyl-methylenedioxy-carboniP-leucyl-P-amino-3-N- (1-naphthalene sulfonyl) -amino-propan-2-one Following the procedure of example 14 (de), except substituting "2-pyridyl methyleneoxycarbonyl-leucine" with "Cbz-leucine", and with "1-naphthalene sulfonyl chloride" the "3- (2-pyridyl) phenyl acid" acetic acid and EDCT ", the title compound was prepared: MS (ES +) 527.2 (M + H +).

EXAMPLE 72 Preparation of 1-N- (N- (2-pyridyl-methyleneoxy-carboniP-leuciniP-amino-3-N- (1,3-dimethyl-5-chloro-pyrazolo-4-sulfoniP-amino -propan-2-one a) 1-N- (N- (2-pyridyl) -methylene-carbon-N, -leucine-P-amino-3-N- (1,3-dimethyl-5-chloro-pyrazolo- 4-sulfonyl) -amino-propan-2-one Following the procedure of Example 14 (de), except substituting "2-pyridyl methyleneoxycarbonyl-leucine" with "Cbz-leucine", and with "1, 3-, chloride" dimethyl-5-chloro-priazolo-4-sulfonyl "the" 3- (2-pyridyl) phenyl acetic acid and EDCl ", the title compound was prepared: MS (ES +) 530.2 (M + H +).

EXAMPLE 73 Preparation of 1-N- (N-.2-pyridyl-methyleneoxy-carbon-P-leucinyl) -amino-3-N-f-benzo-2,1,3-thiadiazolo-4-sulfoniP-amino-2-propanone) a) 1-N- (N- (2-pyridyl-methyleneoxy-carbon-P-leucyl-P-amino-3-N- (benzo-2,1, 3-thiazol-4) -sulfonyl) -amino-2-propanone) Following the procedure of Example 14 (de), except substituting "2-pyridyl methyleneoxy carbonyl-leucine" with "Cbz-leucine", and with "benzo-2-chloride, 1,3-thiadiazole-4-sulfonyl "the" 3- (2-pyridyl) phenyl acetic acid and EDCl ", the title compound was prepared: MS (ES +) 535.2 (M + H +).

EXAMPLE 74 Preparation of 1-N- (N- (2-pyridyl-met8-lenoxy-carboniP-leucine-8) -amino-3-N- (3,5-dimethyl-isoxazolo-4-sulfon-P-amino-propan-2- ona a) 1-N- (N- (2-pyridyl-methylene-x-carbon-P-leucine-P-amino-3-N- (3,5-dimethyl-5-oxo-4-sulfonyl) -amino- propan-2-one Following the procedure of Example 14 (de), except substituting "2-pyridyl methyleneoxycarbonyl-leucine" with "Cbz-leucine", and with "3,5-dimethyl-isoxazolo-4-sulfonyl chloride" "the" 3- (2-pyridyl) phenyl acetic acid and EDCl ", the title compound was prepared: MS (ES +) 496.2 (M + H +).

EXAMPLE 75 Preparation of 1-N- (N- (4-trifluoromethyl benzoyl-P-leuciniP-amino-3-N- (3- (2-pyridiP-phenyl-acetyl-amino-propan-2-one) a) 1-N- (N- (4-trifluoromethyl benzoyl, -leucineP-amino-3-N- (3- (2-pyridiP-phenyl-acetyl-P-amino-propan-2-one) procedure of example 15 (ac), except substituting "4-phenoxy-phenyl carboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 569.1 (M + H +).

EXAMPLE 76 Preparation of 1-N- (N- (6-benzothiazolo-carbon-P-leuci-N-3-N-, 3-.2-pyridiP-phenyl-acetyl-amino-propan-2-one) a) 1-N- (N- (6-benzothiazolo-carbonyl) -leucine-P-amino-3-N- (3- (2-pyridiP-phenyl-acety-P-amino-propan-2-one) Following the procedure of example 15 (ac), except substituting "6-benzothiazole carboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 558.2 (M + H +).

EXAMPLE 77 Preparation of 1-N- (N- (6-quinolinecarbonyl) -leucineD-amino-3-N- (3- (2-pyridiP-phenyl-acety-P-amino-propan-2-one) a) 1-N- (N- (6-quinolyl) -carbonyl-P-leucyl-P-amino-3-N- (3- (2-pyridiP-phenyl-acetyl-amino-propan-2-one) Following the procedure of example 15 (ac), except substituting "6-quinolinecarboxylic acid" with "pentafluorobenzoic acid", the title compound was prepared: MS (ES +) 552.3 (M + H +).

EXAMPLE 78 Preparation of 1-N- (N- (4-fluoro-benzoiP-norleuciniP-amino-3-N- (3- (2-pyridiP-phenyl-acetyl-amino-propan-2-one) a) 1-N- (N- (4-fluoro-benzoyl) -norleuciniP-amino-3-N- (3- (2-pyridiP-phenyl-acety-P-amino-propan-2-one) Following the procedure of Example 15 ( ac), except substituting "1-N- (N-Cbz-norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol" (see example 27). ) "1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-ol", and with "4-fluorobenzoic acid "the" pentafluorobenzoic acid ", the title compound was prepared: MS (ES +) 519.2 (M + H +).

EXAMPLE 79 Preparation of 1-N- (N- (2-naphthyl-carboniP-norleuciniP-amino-3-N- (3- (2-pyridiP-phenyl-acety-P-amino-propan-2-one) a) 1-N- (N- (2-naphthyl-carboniP-norleuciniP-amino-3-N- (3- (2-pyridiP-phenyl acetiD-amino-propan-2-one) Following the procedure of Example 78, except by substituting "2-naphthyl carboxylic acid" with "4-fluorobenzoic acid", the title compound was prepared: MS (ES +) 551.2 (M + H +).

EXAMPLE 80 Preparation of 1-N- (N- (3,4-dimethoxy-benzoiP-norleuciniP-amino-3-N- (3- (2-pyridiP-phenyl) acetyl-amino-propan-2-one a) 1-N- (N- (3,4-dimethoxy-benzoyl-norleucine-P-amino-3-N- (3- (2-pyridiP-phenyl-acetyl-P-amino-propan-2 -one Following the procedure of Example 78, except substituting "3,4-dimethoxybenzoic acid" with "4-fluorobenzoic acid", the title compound was prepared: MS (ES +) 561.2 (M + H +), 1121.3 (2M + H +).

EXAMPLE 81 Preparation of 1-N- (N- (5-benzothiophene-carboniP-norleuciniP-amino-3-N- (3- (2-pyridiP-phenol) acetiP-amino-propan-2-one a) 1-N- (N- (5-benzothiophene-carbon-P-norleucine-P-amino-3-N- (3- (2-pyridiD-phenyl-acety-P-amino-propan-2-one) Following the procedure of Example 78, except substituting "5-thiophenecarboxylic acid" with "4-fluorobenzoic acid", prepared the title compound.

EXAMPLE 82 Preparation of 3-N-N-Cbz-leucine-P-amino-1-N- (phenyD5-methyl-hexan-2-one) a) Cbz-leu-leu-bromo methyl ketone Isobutyl chloroformate (1.37 ml, 10.58 mmol) was added dropwise to a solution of Cbz-leu-leu-OH (4.0 g, 10.58 mmol) and N-methylmorpholine (1.16). ml, 10.58 mmol) in THF (20 ml) at -40 ° C. The reaction was stirred for 15 minutes, then filtered and washed with ether. Dizomethane (mmoles from 5.9 g of 1-methyl-3-nitro-nitroso-guanidine and 18 ml of 40% KOH in 150 ml of ether) in ether (50 ml) was added and the reaction It was placed in a refrigerator overnight. 30% HBr / AcOH (7.0 ml) was added dropwise to the crude reaction mixture, and stirred for 5 minutes. The solution was washed with 15% aqueous citric acid, saturated aqueous sodium bicarbonate, and then with brine. The combined organic extracts were dried with magnesium sulfate, filtered and concentrated in vacuo to give a solid which was used in the next step without purification: MS (ES +) 455.4, 457.4 (M + H +), 477.3, 479.3 ( M + H +). b) (S) -3-N- (N-Cbz-leuciniP-amino-1-N- (phenyl) -5-methyl-hexan-2-one Cbz-Leu-LeuCH2Br was dissolved (0.1 g, 0.22 mmoles) in DMF (1.0 ml) and then potassium fluoride (0.02 g, 0.33 mmoles) and aniline (0.061 g, 0.66 mmoles) were added and the reaction mixture was stirred at room temperature overnight. EtOAc / H20, combined organic extracts were dried with magnesium sulfate, filtered, concentrated in vacuo and chromatographed to provide the title compound as a white solid (18 mg, 18%): MS (ES +) 468.4 (M + H +) The above specification and examples fully describe how to obtain and use the compounds of the present invention, however, the present invention is not limited to the particular embodiments described above, but includes all modifications thereof within scope The following references to journals, patents and other publications which are cited herein comprise the state of the art, and are hereby incorporated by reference in their entirety.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I: wherein: R1, R2 and R3 are independently selected from the group consisting of H, C6 alkyl, C3-1 cycloalkyl, C2_6 alkenyl, C2_6 alkynyl, Ar, Het, C alkyl. .6-Ar, C3-n-Ar cycloalkyl; C2-6-Ar alkenyl; C2-6 alkynyl-Ar; C1-6 alkyl-Het, C3- cycloalkyl. .-Het; C2_6-Het alkenyl; and C2-6-Het alkynyl; R4 is selected from the group consisting of N- (R6) -NHCH (C ^ -CO alkyl, N, N-R6- (C6 alkyl) -N (C1-6 alkyl) -CO, N- (Rd) -NHCH (C2-6 alkenyl) -CO-; N- (Rd) -NHCH (C2.6 alkynyl) -CO-; N- (R6) -NHCH (C1-6 alkyl-Ar) -CO-; N- (R6) -NHCH (C2-6-Ar alkenyl) -CO-; N- (R6) -NHCH (C2-6-Ar alkynyl) -CO-; N- (R6) - NHCH (C 1-6 alkyl-Het) -CO-; N- (R 6) -NHCH (C 2-6 alkenyl-Het) -CO-; N- (R 6) -NHCH (C 2-6 alkynyl-Het) -CO-, ArCO, Ar-C1-6-CO-alkyl, Ar-S02, Ar-C1-6-S02-alkyl, Het-CO, Het-C1-6-CO-alkyl, Het-S02, and Het -alkyl of C? -6-S02; R5 is selected from the group consisting of N-R7 amino acid, d-6-CO alkyl, C3-n-CO cycloalkyl, ArCO, Ar-C? -6- alkyl CO, Ar-S02, Ar-alkyl of C-? -6-S02; Het-CO, Het-alkyl of C? -6-CO; Het-S02, alkyl of C.-6; Ar-alkyl of Co- 6, Het-C0-6 alkyl, R6 and R7 are independently selected from the group consisting of Ar- (C? -6 alkyl) -0-CO, Ar-CO, Ar-S02, Het-CO, Het- S02, C1-6 alkyl-CO, Cr-S02 alkyl, alkenyl of C2-6-CO; C2-6-S02 alkenyl; C2-6 alkynyl-CO; C2-6 alkynyl-SO2; Ar-alkyl of C -? - 6-CO; Aralkyl of C1-6-SO2; C2-6-CO-alkenyl; C2-6-S02 ar-alkenyl; C2-6-CO alkynyl; C2-6-S02 ar-alkynyl; Het-alkyl of C.-6-CO, Het-alkenyl of C2-6-CO; Het-alkenyl of C2-6-S02; Het-alkynyl of C2-6-CO; and C2-6-S02 Het-alkynyl; and pharmaceutically acceptable salts, hydrates and solvates thereof.

2. The compound according to claim 1, further characterized in that R1, R2 and R3 are independently selected from the group consisting of methyl, isobutyl, phenyl, benzyl and isonicotinyl.

3. The compound according to claim 1, further characterized in that R1, R2 and R3 are H.

4. The compound according to claim 1, further characterized in that R4 is selected from the group consisting of N-R6- leucinyl, N-R6-norleucinyl, N-R6-norvalinyl, N-R6-isoleucinyl, N-R6-a-allyl-glycinyl, N-R6-a- (cyclopropylmethyl) -glycinyl, N-R6-β-fer- butyl-alaninyl, N-R6-homo-leucinyl, N, N-R6-methyl-leucinyl, 3-phenoxy-benzoyl, 4-phenoxy-benzoyl, 2-benzyloxy-benzoyl, 4-biphenyl-acetyl, 2- (4-biphenyl) ) -4-methyl-valeryl, 2- (3-biphenyl) -4-methyl-valeryl, 1- (3-biphenyl) -but-3-ene-1-carbonyl, 1- (3-biphenyl) -ethyl- 2- cyclopropane-1-carbonyl, 1- (3-biphenyl) -3-methyl-but-3-ene-1-carbonyl, 3- (2-pyridyl) -phenylacetyl, 3- (3-pyridyl) - phenylacetyl, 3-phenoxy-phenylsulfonyl, 4-phenoxy-phenylsulfonyl, 3- (4- (3-chloro-2-cyano-phenoxy) phenylsulfonyl and 8-quinoline sulfonyl

5. The compound according to claim 1, characterized also because N-R7-amin o acid is selected from the group consisting of N- (R7) -NHCH (C6 alkyl) -CO, N- (R7) -NHCH (C2 alkenyl. 6) -CO, N-R7-NHCH (C2.6 alkynyl) -CO, N- (R7) -NHCH (N- (R7) -NHCH alkyl (C2.

6-Ar alkenyl) -CO, N - (R7) -NHCH (C2_6-Ar alkynyl) - CO, R7 -? - t-butyl-glutamyl, R7-glutamyl and N, N-R7- (C? -C6 alkyl) -leucynyl. The compound according to claim 1, further characterized in that R5 is selected from the group consisting of N-R7-leucinyl, N-R7-norleucinyl, N-R7-norvalinyl, N-R7-isoleucinyl, N-R7-a- allyl-glycinyl, N-R7-a- (cyclopropylmethyl) -glycinyl, N-R7-β-fer-butyl-alaninyl, N-R7-homo-leucinyl, N- (R7) -phenylalaninyl, acetyl, benzoyl, 3- phenoxy-benzoyl, 4-phenoxy-benzoyl, 2-benzyloxy-benzoyl, 3-benzyloxy-benzoyl, 4-benzyloxy-benzoyl, 2- (4-biphenyl) -4-methyl-valeryl, 2- (3-biphenyl) -4-methyl -valeryl, 1- (3-biphenyl) -but-3-ene-1-carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl, 1 - (3-biphenyl) -3-methyl-but-3-ene-1-carbonyl, 1- (3-biphenyl) -but-3-ene-1-carbonyl, 3- (2-pyridyl) -phenyl acetyl, 3- (3-pyridyl) -phenyl-acetyl, 4-biphenyl-acetyl, 3-biphenyl-acetyl, 3-biphenyl-sulphonyl, 4-cyano-phenyl-sulfonyl, 2-carboxyl-phenyl-sulfonyl, 2-carboxymethyl-phenyl-sulfonyl, -C-tetrazolo-phenyl sulfonyl, 1-naphthalene sulfonyl, 3-phenoxy-phenyl-sulfonyl, 4-phenoxy-phenyl-suifonyl, 3- (4- (3-chloro-2-cyano-phenoxy) -phenyl-sulfonyl, 4-biphenyl) sulfonyl, 2-dibenzofuran-sulfonyl, 8-quinoline carbonyl, 6-quinoline carbonyl, 2-pyridine carbonyl, 5- (2-pyridyl) -thiophene carbonyl, N-benzyl-4-piperidinyl carbonyl, 2-quinoline carbonyl, 2- pyridyl sulfonyl, 1,3-dimethyl-5-chloro-pyrazolo-4-sulfonyl, 3,5-dimethyl-isoxazolo-4-sulfonyl, benzo-2,1, 3-thiadiazolo-4-sulfonyl, fenii-sulfone-5 -thiophene-2-sulfonyl, 2-carboxymethyl thiophene-sulfonyl, 2,5-dichlorothiophene-3-sulfonyl and phenyl

7. The compound according to claim 1, further characterized in that R6 and R7 are independently selected from the group consisting of benzyloxycarbonyl, 2-pyridyl methyloxycarbonyl, 3-pyridyl methyloxycarbonyl, 4-pyridyl methyloxycarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, 4-phenoxy-benzoyl, 3-phenoxy-benzoyl, 2-phenoxy benzoyl, 2-chloro-benzoyl, 4-fluoro-benzoyl, 3,4-difluorobenzoyl, 4-trifluoromethyl benzoyl, 2-chlorobenzoyl, 4-carboxymethyl-benzoyl, 4-carboxyl-benzoyl, 2-pyridylcarbonyl, 3-pyridyl carbonyl, 4-pyridyl carbonyl, 2-quinoline carbonyl, 3-quinolino carbonyl, 4-quinolino carbonyl, 5-quinolino carbonyl, 6-quinolino carbonyl, 7-quinolino carbonyl, 8-quinolino carbonyl, 1-isoquinolino carbonyl, 3-isoquinolino carbonylo, 4-isoquinoline carbonyl, 5-isoquinoline carbonyl, 6-isoquinoline carbonyl, 7-isoquinoline carbonyl, 8-isoquinoline carbonyl, 1-benzothiophene carbonyl, 1-benzofurancarbonyl, 5-indole-carbonyl-sulphonyl, N-methyl- prolinyl, 2-quinoxaline-carbonyl, 5- (2,3-dihydrobenzofuran-carbonyl, 2-benzofuran-carbonyl, 2-be nzothiophene-carbonyl, N-morpholino-carbonyl, N-methyl-piperidino-carbonyl, N-pyrazolo-carbonyl, 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, 2-quinolino-sulfonyl, 3-quinolino-sulfonyl, -quinoline sulfonyl, 5-quinoline sulfonyl, 6-quinoline sulfonyl, 7-quinoline sulfonyl, 8-quinoline sulfonyl, 1-isoquinoline sulphonyl, 3-isoquinoline sulfonyl, 4-isoquinoline sulphonyl, 5-isoquinoline sulphonyl, 6-isoquinoline sulfonyl , 7-isoquinoline sulfonyl, 8-isoquinoline sulphonyl, acetyl, fra / 7S-4-propyl-cyclohexyl-carbonyl, cyclohexyl-carbonyl, 4-imidazole acetyl, 2-pyridyl-acetyl, 3-pyridyl-acetyl , 4-pyridyl acetyl and N-morpholino acetyl.

8. The compound according to claim 1, further characterized in that: R1 is H or C? _6 alkyl; R2 and R3 are H; R4 is N- (R6) -NHCH (C1-6 alkyl) -CO, N, N-R6- (C1-6 alkyl) -N (6-alkyl) -CO or Ar-alkyl of d-6- CO; R5 is N-R7-norvalinyl, Ar-alkyl of d-6-CO, Het-S02, Het-CO, ArCO, Ar-S02 or Ar-.

9. The compound according to claim 8, further characterized in that R4 is N-R6-leucinyl, N-R6-norleucinyl, N-R6-norvalinyl, N-R6-isoleucinyl, N-R6-a-allyl-gl Cinyl, N-R6-a- (cyclopropylmethyl) -glycinyl or N-Rd-L-β-ér-butyl-alaninyl.

10. The compound according to claim 8, further characterized in that N, N-R6- (alkyl of C.-6) -N (alkyl of C.-6.-CO is N, N-R6-methyl- leucinyl

11. The compound according to claim 8, further characterized in that R1 is H or Me; R4 is independently selected from the group consisting of N- (2-pyridylcarbonyl) -leucinyl, N- (8-quinoline carbonyl ) -leucinyl, N- (6-quinolinecarbonyl) -leucinyl, N- (4-imidazole acetyl) -leucinyl, N-benzoyl-leucinyl, N- (2-pyridyl sulfonyl) -leucinyl, N- (1-isoquinino-carbonyl) ) -leucynyl, N- (N-morpholino acetyl) -leucinyl, N- (N-methyl prolinyl) -leucinyl, N- (N, N-dimethyl glycyl) -leucinyl, N- (8-quinolino sulfonyl) - leucinyl, N-Cbz-leucinyl, N-pentafluorobenzoyl-leucinyl, N-2-naphthoyl-leuciniio, N-1-naphthoyl-leucinyl, N-4-fluorobenzoyl-leucinyl, N- (4-trifluoromethyl-benzoyl) -leucinyl, N-3,4-difluorobenzoyl-leucine, N-3,4-dimethoxy-benzoyl-leucinyl, N- ( 1-benzothiophene-carbonyl) -leucinyl, N- (2-benzothiazole-carbonyl) -leucinyl, N- (5-benzothiophene-carbonyl) -leucinyl, N- (6-benzothiophene-carbonyl) -leucine, N- (5- indole-carbonyl) -leucinyl, N- (urea-4-propyl cyclohexyl-carbonyl) -leucinyl, N- (2-quinoxaline-carbonyl) -leucinyl, N-5- (2,3, dihydrobenzofuran) -carbonyl) -leucinyl, N- (2-benzofuran-carbonyl) -Iucinyl, N- (N-methyl-2-indole-carbonyl) -leucinyl, N- (2-cyclo-benzoyl-carbonyl) -leucinyl, N- (4-phenoxy) phenylcarbonyl) -leucinyl, N- (3-methoxy-2-quinoline-carbonyl) -leucinyl, N- (2-pyridyl-methyleneoxy-carbonyl) -leucinyl, N- (cyclohexyl-carbonyl) -leucinyl, N-Cbz-norleucynyl , N- (2-naphthyl-carbonyl) -norleucinyl, N- (3,4, dimethoxy-benzoyl) -norleucinyl, N- (5-benzothiophene-carbonyl) -norieucinyl, N-Cbz-norvalinyl, N-Cbz-isoleucinyl , N-Cbz-allyl-glycinyl, N-Cbz-a-allyl-glycinyl, N-Cbz-N-methyl-leucinyl, N-Cbz-a- (cyclo-propylmethyl) -glycinyl, 2- (3-biphenyl) -4-methyl-valerate, 1- (3-biphenyl) -but-3-ene-1-carbonyl or 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl; R5 is selected from the group consisting of N-Cbz-norvalinyl, 3- (2-pyridyl) -phenyl-acetyl, 3- (3-pyridyl) -phenyl-acetyl, 3- (3-biphenyl) -3-methyl- but-3-ene-1 -carbonyl, 2- (3-biphenyl) -but-3-ene-1 -carbonyl, 2-pyridyl sulfonyl, 8-quinoline sulfonyl, 1,3-dimethyl-5-chloro-pyrazolo- 4-sulfonyl, 3,5-dimethyl-isoxazolo-4-sulfonyl, benzo-2,1, 3-thiadiazole-4-sulfonyl, 3-biphenyl-sulfonyl, 8-quinoline-carbonyl, 5- (2-pyridine) -thiophene- carbonyl, N-benzyl-4-piperidinyl carbonyl, 2-quinolino carbonyl, 2-pyridino-carbonyl, 4-phenoxy-phenyl-carbonyl, 2- (3-biphenyl) -3-methyl-valeryl, 2-carboxymethyl-phenyl- sulfonyl, 2-carboxy-phenyl-sulfonyl, 4-C-tetrazolo-phenyl-sulfonyl, 1-naphthalene-sulfonyl, 2-cyano-phenyl-sulfonyl or phenyl.

12. The compound according to claim 1, further characterized in that R1 is H or C alkyl; R2 and R3 are H; R4 is N- (R6) -NHCH (d-6-alkyl) -CO or Ar-C6-C6-alkyl; and R5 is Ar-alkyl of d-e-CO or Het-S02.

13. The compound according to claim 12, further characterized in that R4 is N- (R6) -NHCH (C.sub.6 -alkyl) -CO, N-R6-leucinyl or N-R6-norleucinyl.

14. The compound according to claim 12, further characterized in that R1 is H or Me; R4 is independently selected from the group consisting of N-Cbz-leucinyl, N-2-naphthoyl-leucinyl, 4-fluorobenzoyl-leucinyl, 3,4-dimethoxybenzoyl-leucinyl, (1-benzothiophene-carbonyl) -leucinyl, (2- quinoxaline-carbonyl) -leucinyl, 5- (2,3, dihydrobenzofuran) -carbonyl) -leucinyl, (2-benzofuran-carbonyl) -leucinyl, (2-naphthyl-carbonyl) -norleucinyl, (3,4, dimethoxy-benzoyl) ) -norleucine, (5-benzothiophene-carbonyl) -norleucinyl and 2- (3-biphenyl) -4-methyl-valeryl; and R5 is 3- (2-pyridyl) -phenyl acetyl or 2-pyridyl sulfonyl.

15. The compound according to claim 1, further characterized in that it is selected from the group consisting of 1-N- (N- (2-pyridylcarbonyl) -leucinyl) -amino-3-N- ( 2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- (N- (8-quinolinecarbonyl) -leucinyl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- (N- (2-quinoline carbonyl) -leucyl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- (N- (4-imidazolo acetyl) -leucinyl) -amino-3-N- (3-biphenyl-sulfonyl) -amino-propan-2-one; 1-N- (N- (2-pyridyl-carbonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N-benzoyl-leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (2-pyridyl-suphonyl) -leucinyl) -amino-3-N- (8-quinolinocarbonyl) -amino-propan-2-one; 1-N- (N- (8-quinolinecarbonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (1-isoquinolino-carbonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (N-morpholino-acetyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (N-methyl prolinyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (N, N-dimethylglycinyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N- (8-quinolino sulfonyl) -leucinyl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-pentafluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl] -amino-propan-2-one; 1-N- (N-2-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-1-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-pyridyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-4-fluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-3,4-difluorobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-3,4-dimethoxybenzoyl-leucyl-1-yl) -3-N- (3- (2-pyridyl) -phene-1-acetyl) -amino-propan-2-one; 1-N- (N- (1-benzothiophene-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (5-indole-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -pheny] -acetyl) -amino-propan-2-one; 1-N- (N-Cbz-isoleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-norvalinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-α-allyl-glycinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-N-methyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-Cbz-a- (cyclopropyl) -methyl-glycoly) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan -2-ona; 1-N- (N-benzyloxycarbonyl-L-ß-yer-butylanine) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-carboxymethyl-phenyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (4-cyano-phenyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (8-quinolinecarbonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2- ona; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (3-pyridyl) -3-phenylethyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (2-pyridinocarbonyl) -amino-propan-2-one; 1-N- (2- (3-biphen-1) -4-methy1-valeryl) -amino-3-N- (5- (2-pyridino) -thiophene-carbonyl) -amino-propan- 2-one; 1-N- (2- (3-benzyl) -4-methyl-valeryl) -amino-3-N- (N-benzyl-4-piperidino-carbonyl) -amino- propan-2-one; 1-N- (2- (3-biphenyl) -4-methy1-valeryl) -amino-3-N- (2-quinoline-carbonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-vaaryl) -amino-3-N- (2-carboxyl-phenyl-sulfonyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (4-C-tetrazolo-phenyl-sulfonyl) -amino-propan-2- ona; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (2-pyridyl- (phenyl-acetyl) -amino- (S) -butan- 2-one; 1-N- (2- (3-biphenyl) -3-methyl-valeryl) -1-N-methyl-amino-3-N- (3- (2-pyridyl- (phenyl) acetyl) -amino -propan-2-one; 1-N- (N-2-pyridyl carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenyl-carbonyl) -amino-propan-2-one; 1-N- (N-8-quinoline-carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenyl-carbonyl) -amino-propan-2-one; 1-N- (N-2-quinoline-carbonyl-leucinyl) -amino-3-N- (4-phenoxy-phenylcarbonyl) -amino-propan-2-one; 1-N- (N- (Cbz-norvalinyl) -amino-3-N- (8-qui) nolino-sulfonyl) -amino-propan-2-one; 1-N- (8-quinolino-sulfonyl) -amino-3-N- (8-quinolino-sulfonyl) -amino-propan-2-one; -N- (2- (3-biphenyl) -3-methyl-valeryl) -amino-3-N- (8-quinolino-sulfonyl) -amino-propan-2-one; 1-N- (2- (3 -biphenyl) -3- methyl-valeryl) -amino-3-N- (2- (3-biphenyl) -3-methyl-valeryl) -amino-propan-2-one; 1-N- (N- (Cbz-norvanyl) -amino-3-N- (N- (Cbz-norvalinyl) -amino-propan-2-one; 1-N- (1 - (3-biphenyl) -but-3-ene-1 -carbonyl) -amino-3-N- (3- (2-pyridyl) -phenyl acet ii) -amino-propan-2-one; 1-N- (1 - (3-biphenyl) -but-3-ene-1 -carbonyl) -amino-3-N- (1- (3-biphenyl) -but-3-ene-1 -carbonyl) - propan-2-one; 1-N- (1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (2- (3-phenyl) -3-methyl-but-3-ene-1-carbonyl) -amino-3-N- (3- (2-pyridyl) -phenyl) acetyl) -amino-propan-2-one; 1-N- (1 - (3-biphenyl) -3-methyl-but-3-ene-1 -carbonyl) -amino-3-N- (1 - (3-biphenyl) -3-methyl-but-3 -neo-1 -carbonyl) -amino-propan-2-one; 1-N- (N- (trans-4-propylcyclohexylcarbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) phenyl acetyl) -amino-propan-2-one; 1-N- (N- (2-quinoxalino-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2- ona; 1-N- (N- (5- (2,3-dihydro-benzofuran) -carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (N- (N-methyl-2-indole-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (N- (cyclohexyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-chloro-benzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-benzofuran-carbonyl) -lucynyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (3-phenoxy-phenyl-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phene-1-acetyl) -amino-propan-2-one; 1-N- (N- (4-phenoxy-phenol-carbonyl) -leucyl] -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan -2-ona; 1-N- (N- (3-methoxy-2-quinoline-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (N-Cbz-Iuccinyl) -amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-one; 1-N- (N- (4-fluorobenzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl- (phenyl-acetyl) -amino- (S) -butan-2-one; 1-N- ( N- (2-benzothiophene-carbonyl) -Lucynyl) -amino-3-N- (3- (2-pyridyl- (phenyl-acetyl) -amino- (S) -butan-2-one; 1-N- (N- (2-pyridyl-methyleneoxycarbonyl) -leucinyl) -amino-3-N- (1-naphthalene sulfonyl) -amino-propan-2-one; 1-N- (N- (2 -pyridyl-methyleneoxycarbonyl) -leucynyl) -amino-3-N- (1,3-dimethyl-5-chloro-pyrrazolo-4-sulfonyl) -amino-propan -2-one; 1-N- (N- (2-pyridyl-methyleneoxy-carbonyl) -leucinyl) -amino-3-N- (benzo-2,1,3-thiadiazolo-4-sulfonyl) -amino-propan -2-one; 1-N- (N- (2-pyridyl-methyleneoxy-carbonyl) -leucinyl) -amino-3-N- (3,5-dimethyl-isoxazolo-4-sulfonyl) -amino-propan-2 -one; 1-N- (N- (4-trifluoromethyl-benzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; - (N- (6-benzothiazolo-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N - (6-quinolino-carbonyl) -leucinil ) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (4-fluoro-benzoyl) -norleucin-1) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (2-naphthyl-carbonyl) -nor-eucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (3,4-dithyloxy-benzoyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (N- (5-benzothiophene-carbonyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; and (S) -3-N- (N-Cbz-leucinyl) -amino-1-N- (phenyl) -5-methyl-hexan-2-one.

16. The compound according to claim 15, further characterized in that it is selected from the group consisting of 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl) acetyl) -amino-propan-2-one; 1-N- (N-2-naphthoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-4-flurobenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N-3,4-dimethoxybenzoyl-leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (1-benzothiophene-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (5-indolo-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (2-pyridyl-sulfonyl) -amino-propan-2-one; 1-N- ( 2- (3-biphenyl) -4-methyl-valeryl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N - (2-quinoxalino-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- (5 - (2,3-dihydro-benzofuran) -carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl] -amino-propan- 2-one; 1-N- (N- (2-benzofuran-carbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2 -one; 1-N- (N-Cbz-leucinyl) -amino-3-N- (3- (2-pyridyl) - (phenyl acetyl) -amino- (S) -butan-2-one; -N- (N- (2-benzothiophenecarbonyl) -leucinyl) -amino-3-N- (3- (2-pyridyl- (phenyl acetyl) -amino- (S) -butan-2-one; N- (N- (4-trifluoromethyl-benzoyl) -leucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1 -N- (N- (2-naphthyl-carbonyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-propan-2-one; 1-N- (N- ( 3,4-dimethoxy-benzoyl) -norleucinyl) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) -amino-pr opan-2-one; and 1-N- (N- (5-benzothiophene-carbonyl) -norleucine-1) -amino-3-N- (3- (2-pyridyl) -phenyl-acetyl) - amino-propan-2-one.

17. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

18. The pharmaceutical composition, further characterized in that it comprises a compound according to claim 16 and a pharmaceutically acceptable carrier, diluent or excipient.

19. The use of a compound according to claim 1, for the manufacture of a medicament for inhibiting a protease in a patient, wherein the protease is selected from the group consisting of a cysteine protease and a serine protease.

20. The use of a compound according to claim 16, for the manufacture of a medicament for inhibiting a protease in a patient, wherein the protease is selected from the group consisting of a cysteine protease and a serine protease.

21. The use according to claim 19, wherein said protease is a cysteine protease.

22. - The use according to claim 20, wherein said protease is a cysteine protease.

23. The use according to claim 21, wherein said cysteine protease is cathepsin K.

24.- The use according to claim 22, wherein said cysteine protease is cathepsin K.

25.- The use of a compound according to claim 1, for the manufacture of a medicament for treating a disease characterized by bone loss in a patient.

26. The use according to claim 25, wherein said disease is osteoporosis.

27. The use according to claim 25, wherein said disease is periodontitis.

28. The use according to claim 25, wherein said disease is gingivitis.

29. The use of a compound according to claim 1, for the manufacture of a medicament for treating a disease characterized by excessive degradation of cartilage or matrix in a patient.

30. The use according to claim 29, wherein said disease is osteoarthritis.

31. The use according to claim 29, wherein said disease is rheumatoid arthritis.

32. The use of a compound according to claim 16, for the manufacture of a medicament for treating a disease characterized by bone loss in a patient.

33. The use according to claim 32, wherein said disease is osteoporosis.

34. The use according to claim 32, wherein said disease is periodontitis.

35.- The use according to claim 32, wherein said disease is gingivitis.

36 = The use of a compound according to claim 16, for the manufacture of a medicament for treating a disease characterized by excessive degradation of cartilage or matrix in a patient.

37. The use according to claim 36, wherein said disease is osteoarthritis.

38.- The use according to claim 36, wherein said disease is rheumatoid arthritis.

39.- A compound of formula II: wherein: R1, R2 and R3 are independently selected from the group consisting of H, C-β alkyl, C3-11 cycloalkyl, C2_6 ainyl, C2_6 alkynyl) Ar, Het, C6-6 alkyl Ar, cycloalkyl of C -? Ar; C2-6-Ar alkenyl; C2-6 alkynyl-Ar; C? -6-Het alkyl, C3-n-Het cycloalkyl; C2-6-Het alkenyl; and C2-β-Het alkynyl; R 4 is selected from the group consisting of N- (R 6) -NHCH (C 1-6 alkyl) -CO, N, N-R 6- (C 1-6 alkyl) -N (C 1-6 alkyl) -CO, N- (R6) -NHCH (C2-6 alkenyl) -CO-; N- (R6) -NHCH (C2-6 alkynyl) -CO-; N- (R6) -NHCH (C1-6alkyl-Ar) -CO-; N- (R6) -NHCH (C2-6-Ar alkenyl) -CO-; N- (R6) -NHCH (C2-6 alkynyl-Ar) -CO-; N- (R8) -NHCH (C1-6 alkyl-Het) -CO-; N- (R6) -NHCH (C2-6 alkenyl-Het) -CO-; N- (R6) -NHCH (C2-6-Het alkynyl) -CO-; ArCO, Ar-alkyl of d-6-CO, Ar-S02 > Ar-alkyl of C? -6-S02; Het-CO; Het-alkyl of C.-6-CO; Het-S02, and Het-alkyl of d.6-S02; R5 is selected from the group consisting of N-R7 amino acid, d-6-CO alkyl, cycloalkyl of C3.n-CO; ArCO, Ar-alkyl of d-6-CO, Ar-SO2, Ar-alkyl of C1-d-S02; Het-CO, Het-alkyl of C6-CO; Het-S02, alkyl of d.6; Ar-alkyl of Co-6, Het-alkyl of Co-6; R6 and R7 are independently selected from the group consisting of Ar- (C1-6 alkyl) -0-CO, Ar-CO, Ar-S02; Het-CO, Het-S02, Cr6-CO alkyl, C6-S02 alkyl; C2-6-CO alkenyl; C2-6-S02 alkenyl; C2-6 alkynyl-CO; C2-6-S02 alkynyl; Ar-Cr6-CO alkyl; Ar-alkyl of C.-6-S02; C2-6-CO-alkenyl; C2-6-S02 ar-alkenyl; C2-6-CO alkynyl; C2-6-S02 ar-alkynyl; Het-alkyl of d-6-CO, Het-alkenyl of C2-6-CO; Het-alkenyl of C2-6-S02; Het-alkynyl of C2-6-CO; and C2-6-S02 Het-alkynyl; and pharmaceutically acceptable salts, hydrates and solvates thereof.

40.- The compound according to claim 39, further characterized in that R1, R2 and R3 are independently selected from the group consisting of methyl, isobutyl, phenyl, benzyl, and sonicotinyl.

41. The compound according to claim 39, further characterized in that R1, R2 and R3 are H.

42. The compound according to claim 39, further characterized in that R4 is selected from the group consisting of N-R6- leucinyl, N-R6-norleucinyl, N-Rd-norvalinyl, N-R6-isoleucinyl, N-R6-a-allyl-glycinyl, N-Rd-a- (cyclopropylmethyl) -glycyl, N-R6- ß-fer-butyl-alanyl, N-R6-homo-leucinyl, N, N-Rd-methyl-leucinyl, 3-phenoxy-benzoyl, 4-phenoxy-benzoyl, 2-benzyloxy-benzoyl, 4-biphenyl acetyl, 2- (4-biphenyl) -4-methyl-varyl, 2- (3-biphenyl) -4-methyl-valeryl, 1- (3-biphenyl) -but-3-ene-1-carbonyl, 1 - (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl, 1- (3-biphenyl) -3-methyl-but-3-ene-1-carbonyl, 3- (2-pyridyl) -phenylacetyl, 3- (3-pyridyl) -phenylacetyl, 3-phenoxy-phenylsulfonyl, 4-phenoxy-phenylsulfonyl, 3- (4- (3-chloro-2-cyano-phenoxy) phenylsulfonyl and 8-quinoline sulfonyl.

43.- The compound according to claim 39, further characterized by the fact that N- R7-amino acid is selected from the group consisting of N- (R7) -NHCH (alkyl of d.6) -CO, N- (R7) -NHCH (C2-6 alkenyl) -CO, N-R7-NHCH ( C2-6 alkynyl) -CO, N- (R7) -NHCH (d6-Ar alkyl) -CO, N- (R7) -NHCH (C2.6-Ar alkenyl) -CO, N- ( R7) -NHCH (C2-6-Ar alkynyl) -CO, R7-γ-t-butyl-glutamyl, R7-glutamyl and N, N-R7- (CrC6 alkyl) -leucynyl.

44. The compound according to claim 39, further characterized in that R5 is selected from the group consisting of N-R7-leucinyl, N-R7-norleucinyl, N-R7-norvalinyl, N-R7-isoleucinyl, N-R7-a - allyl-glycine, N-R7-a- (cyclopropylmethyl) -glycinyl, N-R7-β-ér-butyl-alaninyl, N-R7-homo-leucinyl, N- (R7) -phenylalaninyl, acetyl, benzoyl, -phenoxy-benzoyl, 4-phenoxy-benzoyl, 2-benzyloxy-benzoyl, 3-benzyloxy-benzoyl, 4-benzyloxy-benzoyl, 2- (4-biphenyl) -4-methyl-valeryl, 2- (3-biphenyl) ) -4-methyl-valeryl, 1- (3-biphenyl) -but-3-ene-1-carbonyl, 1- (3-biphenyl) -ethyl-2-cyclopropane-1-carbonyl, 1- (3-biphenyl) ) - 3-methyl-but-3-ene-1-carbonyl, 1- (3-biphenyl) -but-3-ene-1-carbonyl, 3- (2-pyridyl) -phenyl-acetyl, 3- (3- pyridyl) -phenyl acetyl, 4-biphenyl-acetyl, 3-biphenyl-acetyl, 3-biphenyl-sulfonyl, 4-cyano-phenyl-sulfonyl, 2-carboxyl-phenyl-sulfonyl, 2-carboxymethyl-phenyl-sulfonyl, 4-C-tetrazolo-phenyl-sulfonyl , 1-naphthalene sulfonyl, 3-phenoxy-phenyl sulfonyl, 4-phenoxy-phenyl lphonyl, 3- (4- (3-chloro-2-cyano-phenoxy) -phenyl-sulfonyl, 4-biphenyl-sulfonyl, 2-dibenzofuran-sulfonyl, 8-quinoline-carbonyl, 6-quinoline-carbonyl, 2-pyridine-carbonyl, 5- (2-pyridyl) -thiophene carbonyl, N-benzyl-4-piperidinyl carbonyl, 2-quinolino carbonyl, 2-pyridyl sulfonyl, 1,3-dimethyl-5-chloro-pyrazolo-4-sulfonyl, 3,5- dimethyl-isoxazolo-4-sulfonyl, benzo-2,1, 3-thiadiazolo-4-sulfonyl, phenyl-sulfone-5-thiophene-2-sulfonyl, 2-carboxymethyl thiophene-sulfonyl, 2,5-dichlorothiophene-3-sulfonyl and phenyl.

The compound according to claim 39, further characterized in that Rd and R7 are independently selected from the group consisting of benzyloxycarbonyl, 2-pyridyl methyloxycarbonyl, 3-pyridyl methyloxycarbonyl, 4-pyridyl methyloxycarbonyl, benzoyl, 1-naphthoyl, -naphthoyl, 4-phenoxy-benzoyl, 3-phenoxy-benzoyl, 2-phenoxy-benzoyl, 2-chloro-benzoyl, 4-fluoro-benzoyl, 3,4-difluoro-benzoyl, 4-trifluoromethyl-benzoyl, 2-chloro-benzoyl, 4-carboxymethyl-benzoyl, 4-carboxyl-benzoyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-quinolinecarbonyl, 3-quinolinecarbonyl, 4-quinolinocarbonyl, 5-quinolinecarbonyl, 6-quinoline carbonyl, 7-quinoline carbonyl, 8-quinoline carbonyl, 1-isoquinoline carbonyl, 3-isoquinoline carbonyl, 4-isoquinoline carbonyl, 5-isoquinoline carbonyl, 6-isoquinoline carbonyl, 7-isoquinoline carbonyl, 8-isoquinoline carbonyl, -benzothiophene carbonyl, 1-benzofurancarbonyl, 5-indole-carbonyl-sulfonyl, N-methyl-prolinyl, 2-quinoxaline-carbonyl, 5- (2,3-dihydrobenzofuran-carbonyl, 2-benzofuran-carbonyl, 2-benzothiophene-carbonyl , N-morpholino-carbonyl, N-methyl-piperidino-carbonyl, N-pyrazolo-carbonyl, 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, 2-quinolino-sulfonyl, 3-quinolino-sulfonyl, 4-quinolino-sulfonyl , 5-quinolino sulfonyl, 6-quinolino sulfonyl, 7-quinolino sulfonyl, 8-quinolino sulfonyl, 1-isoquinolino sulfonyl, 3-isoquinoli non-sulfonyl, 4-isoquinoline sulfonyl, 5-isoquinoline sulphonyl, 6-isoquinoline sulphonyl, 7-isoquinoline sulfonyl, 8-isoquinoline sulphonyl, acetyl, isopropyl-4-propyl-cyclohexylcarbonyl, cyclohexylcarbonyl, 4-imidazole acetyl, -pyridyl acetyl, 3-pyridyl acetyl, 4-pyridyl acetyl and N-morpholino acetyl.

46. The use of the compound according to any of claims 1 to 16, for the manufacture of a medicament for use in the inhibition of a protease selected from the group consisting of a cysteine protease and a serine protease.

47. - The use according to claim 46, wherein said protease is a cysteine protease.

48. The use according to claim 47, wherein said cysteine protease is cathepsin K.

49. The use of the compound according to any of claims 1 to 16, for the manufacture of a medicament for use in the treatment of a disease characterized by bone loss.

50.- The use according to claim 49, wherein said disease is osteoporosis.

51. The use according to claim 49, wherein said disease is periodontitis.

52. The use according to claim 49, wherein said disease is gingivitis.

53. The use of a compound according to any of claims 1 to 16, for the manufacture of a medicament for use in the treatment of a disease characterized by excessive degradation of cartilage or matrix.

54. The use according to claim 53, wherein said disease is osteoarthritis. 55.- The use according to claim 53, wherein said disease is rheumatoid arthritis.