MXPA98003548A - Prote inhibitors - Google Patents

Abstract

The present invention provides compounds that inhibit proteases, including cathepsin K, pharmaceutical compositions of said compounds, and methods for treating diseases of excessive bone loss or excessive cartilage or matrix degradation, including osteoporosis, gingival disease including gingivitis and periodontitis; arthritis; specifically osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, as well as metabolic disease of the bones, which comprise inhibiting said bone loss or excessive degradation of cartilage or matrix by administering a compound of the present invention to a patient in need the same

Description

t, NH? PIPP gg P5 PRQTEASA C? MPq PE THE TNV? CIQM This invention relates in general to hydrazidyl »bis-h? Drazid inhibitors? lo and bis-ami ome ilcarbom'lo protease »particularly cysteine and serine protease inhibitors» very particularly compounds that inhibit cysteine proteases »very particularly still compounds that inhibit this protease from the papain super amyl» is not particularly still compounds that inhibit cysteine protease of the cathepsin family »very particularly compounds that inhibit cathepsin K. Said compounds are particularly useful for the treatment of diseases in which cysteine proteases are involved» especially diseases of excessive loss of bone and cartilage »For example» osteoporosis »periodontics and arthritis.

BACKGROUND OF THE INVENTION Cathepsins are a family of enzymes that are part of the papain superfamily of cysteine proteases. Cathepsins B. H »L» N and S have been described in the literature. Recently »the polypeptide cathepsin K and the cDNA encoding said polypeptide are described in the patent of E.U.A. No. 5 »501» 969 (referred to as cathepsin 0 herein). Cathepsin K has recently been expressed, encoded and characterized. Bossard M. J. et al (1996) J. Biol. Chem. 271 »12517-12524; DraKe F. H. and others (1996) J. Biol. Chem. 271, 12511-1251S. Bromme D. and others C199S) J. Biol. Chem. 271, 2126-2132. Cathepsin K has been denoted variously as cathepsin 0 or cathepsin 02 in the literature. The designation cathepsin K is considered to be 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, high levels of these enzymes in the body can result in pathological conditions that lead to disease. In this way, catheps have been implicated as causative agents of various pathological conditions, including but not limited to Pneumocystis carinii infections. Trypanosoma cruzi, Trypanosoma brucei brucei and Chytrid a fasicul ata; as well as in schistosomiasis »malaria» tumor metastasis »leukodystrophy» metatrophysiology »muscular dystrophy. amitrophy and the like. ease International Publication No. WO 94/04172 »published on March 3, 1994 and references cited therein. See also European Patent Application EP 0603 S76 Al, and references cited therein. Two bacterial cysteine proteases of P. gingi va11 is »called gingipains» have been implicated in the pathogenesis of gingivitis »Potempa J. et al. (1994) Perspecti es i Drugs Discovery and Desing. 2 »445-458. It is believed that catheps to K plays a causative role in diseases of excessive loss of bone or cartilage. The bone is composed of a protein matrix in which spindle-shaped crystals or hydroxyapati a-plate are incorporated. Type I collagen represents the main structural protein of bone comprising approximately 9054 protein matrix. The remaining 1054 matrix is composed of a number of non-collagen proteins, including osteocalci, proteoglycans, osteopon a, osteonectin. thrombospondin. fibronectin »and bone sialoprotein. Skeletal bone undergoes remodeling in discrete foci during life. These foci or remodeling units "go through a cycle consisting of a bone resorption phase followed by a bone replacement phase. Bone resorption is carried out by osteoclasts, which are ultinuclear cells of hematopoietic origin. The osteoclasts adhere to the surface of the bone and form a hermetic sealing zone followed by excessive membrane undulation on its apical (ie resorptive) surface. This creates an extracellular compartment enclosed on the surface of the bone that is acidified by proton pumps in the corrugated membrane, and in which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves the hydroxyapat a crystals on the bone surface "while the proteolytic enzyme digests the protein matrix. In this way a resorption or cavity gap is formed. At the end of this phase of the cycle, the osteoblasts tend on a new protein matrix that is subsequently mineralized. In various pathological states such as osteoporosis and Paget's disease the normal balance between bone resorption and formation is altered, and there is a net loss of bone at each site. Finally, this leads to weakening of the bone and can result in an increased factor risk with minimal trauma. Several published studies have shown that cysteine protease inhibitors are effective in the inhibition of bone resorption mediated by osteoclasts. and indicate an essential function for a cysteine protease in bone resorption. For example. Delaisse et al. Biochem J .. 19T0 »192. 365 describes a series of protease inhibitors in a mouse bone organ culture system and suggests that cysteine protease inhibitors (ie» leupeptin »Z-phe-Ala- CHN-.) Prevent bone resorption "while serine protease inhibitors are ineffective. Delaisse and other Biochem Biophys. Res. Commun .. 1984 »125. 441» discloses that E-64 and leupeptin are also effective in the prevention of bone resorption in vivo, as measured by acute changes in serum calcium in rats on calcium-efficient diets . Lerner and others J. Bone M e. Res .. 1992. 7, 433. describe that cystatin "an endogenous cysteine protease inhibitor" inhibits bone resorption stimulated by PTH in mouse calvariae. Other studies »such as those made by Delaisse and others Bone. 1987, 8. 305. Hill and others J. Cel 1. Biochem .. 1994. 56. 11B and Everts and others J. Cel 1. Physiol .. 1992. 150. 221 »also report a correlation between the inhibition of activity of cysteine protease and bone resorption. Tezuka et al., J. Biol. Chem .. 1994 »269» 1106. InaoKa and others Biochem. Biophys. Res. Commun. »1995. 206» B9 and Shi and other FEBS Lett. , 1995 »357. 129 describes that under normal conditions. cathepsin K »a cysteine protease. It is abundantly expressed in osteoclasts and may be the main 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. Therefore selective inhibition of cathepsin K can provide an effective treatment for excessive bone loss diseases, including, but not limited to osteoporosis, gingival diseases such as gingivitis and periodontitis. Paget's disease. hypercalcemia of malignancy, as well as metabolic bone disease. The levels of cathepsin K have also been shown to be elevated in osteoarthritic synovium chondroclastic. Thus »selective inhibition of cathepsin K may also be useful for treating diseases of excessive matrix or cartilage 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, the selective inhibition of cathepsin K may also be useful for the treatment of certain neoplastic diseases. Several cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem. 38. 3193 describe certain vines lsulfones that irreversibly inhibit cysteine protease. such as cathepsins B. L, S. 02 and cruzain. Other classes of compounds »such as aldehydes, nitriles. compounds of oteetocarboni lo. halogenometi 1 ketones. di azometi l ketones. ac loximeti leetonas »ethosulfonium keto salts and hemoxysuccinyl compounds have also been reported as inhibitors of cysteine proteases. See Palmer, id "and references cited therein. U.S. Patent No. 4,518,528 describes peptidyl-fluoromethyletheones as irreversible inhibitors of cysteine protease. The published International Patent Application No. WO 94/04172 and the European Patent Application No. EP 0 525 420 Alf EP 0 603873 Al and EP 0 611 756 A2 describe alkoxymethyl- and mercaptomethyletheones which inhibit the cysteine proteases cathepsins B. H and L. International Patent Application No. PCT / US94 / 08868 and European Patent Application No. EP 0623 592 Al disclose alkoxymethyl- and mercapto ethexones which inhibit the cysteine protease IL-1Q convertase. The alkoxymethyl- and mercaptomethanetones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT / GB91 / 01479). The azapépidos that are designed to supply the aza-a i oáci o to the active site of the other proteasas, and that possess a good residual group, are described in Elmore et al. Biochem. J., 196B, 107. 103 , Garker et al. Biochem. J., 1974, 139, 555, Gray et al. Tetrahedron, 1977, 33, 387, Gupton et al. J. Biol. Biochem., 1984, 259, 4279, Po ers et al. J. Biol. Chem., 1984. 259. 2488. and are known to inhibit cysteine proteases.In addition, J. Med. Chem .. 1992. 35. 4279. describe certain azapeptide esters as inhibitors of cysteine protease.The anti-ainine and leupeptin are describe as reversible inhibitors of cysteine protease in McConell et al. J. Med. Chem., 33. 86. " and they have also been described as serine protease inhibitors in Umeza a and other Met Enzymol 45. 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 Patent of E.U.A. No. 5,142,056 describes 1,3-diamido-propanones that inhibit HIV protease. The 1,3-dia gone propanones have also been described as analgesic agents (U.S. Patent No. 4,749,792 and 4,638,010). Some heterocyclic amino acid derivatives have been described in the art. For example. Ha ha and others.

PEPTIDE CHEMISTRY. 1983. Proceedings of the 2nd Symposium on Peptide Chemistry (1984). and Boden and others Tet. Lett .. 1994. 35. 8271 (1994) describe thiazole and Borg derivatives and others. 1995, 60 3112, describes oxadiazole and triazole derivatives. The synthesis of azathides (pol acyl hydrazides) as peptide mimetics have recently been described by Han and Janda, J. Am. Chem. Soc. 1996. 118, 2539. Thus, a structurally diverse variety of cysteine protease inhibitors is they have identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from several inconveniences. These inconveniences include lack of selectivity. citotorcicidad. Poor solubility and plasma clearance too fast. Therefore there is a need for methods to treat diseases caused by pathological levels of cysteine proteases. including cathepsins. especially cathepsin K and for novel inhibitory compounds useful in such methods. Now a novel class of hydrazidil has been discovered. bis-hydrazidi lo and bis-ami or ethyl carboni which are protease inhibitors, most particularly of cathepsin K.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide inhibitors of hydrazidyl protease, bis-hydrazidi lo and bis-aminomethylcarbonyl, particularly inhibitors of cysteine and cerin protease, very particularly cysteine protease inhibiting compounds, very particularly still compounds that inhibit cysteine proteases of the superfamily of papain, very particularly still compounds that inhibit cysteine proteases of the cathepsin family, very particularly still compounds that inhibit cathepsin K and that are useful for the treatment of diseases that can be therapeutically modified by altering the activity of said proteases. Accordingly, in the first aspect, the invention provides a compound according to formula I. In another aspect, the invention provides a pharmaceutical composition comprising a compound according to formula I and a pharmaceutically acceptable carrier or excipient carrier. In yet another aspect the invention provides a method for treating diseases in which the pathology can be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, very particularly cysteine proteases, very particularly still cysteine proteases of papain superfamily, very particularly. still the cysteine protease of the cathepsin family and very particularly still cathepsin K. In a particular aspect the compounds of this invention are especially useful for the treatment of diseases characterized by bone loss "such as osteoporosis and gingival diseases" such as gingivitis and periodontitis. or by excessive cartilage or matrix degradation »such as osteoarthritis and rheumatoid arthritis.

PE5 T IQ DgTALAADA The present invention provides compound of the formula i: I where: D = A R2. R1JB.

Q = where: A = absent.

R9 L = alk of Ca_ß. Ai-C0_a alkyl »Het-alkyl of Co .., CH (Rßß) RßoR **, CH (R *«) Ar, CH (R * «) OAr ', NRßßR ** -' M = C (O) , SO ...; 5 G = z x-? J = C (0). SO-j. ".T = Ar. Het; V = C-cycloalkyl; NHS0aR * »-NHCOR- ', -O-COR *, -SRβ, NR'R«, NR' (C = NH) NHRβ »Cl. Br, I, F» X = Y = Z = N. O, S ? CR- », provided that at least one of X» Y and Z are heterogeneous atoms and at least one of X. Y and Z is N. or one of X. Y »and Z is C = N» C ^ C or N = N and the other two are CR- "or N provided that X, Y and Z together comprise at least two N; - indicates a single bond or a double bond in the 5-membered heterocycle; m = o »?» 2; n = 1 to 6, * 0 = 0, l »2; Ar = phenyl »naphthyl» optionally substituted by one or more of Ph-C0_ß alkyl »Het-alkyl of a_m * C-alkoxy? 'Ph-alkox of o_ß, Het-al cox i of o_ß »OH. (CHX) _. Rß-'R "*»,? (CHa) a ._ (, NRßßRßß; Ar = phenyl. naphthyl. optionally substituted by one or more of Ph-alkyl of C0_ß »Het-al qui of Co_ß, C alco-alkoxy. Ph-alkoxy of C ^ .. Het-al coxy of C0_ß. OH, (CH ^) ^ ßNRß "Rßß., Or (CHa); t_NNRß *» RB * », or halogen, R '= H» Cx_ß alkyl, AR C0_ß alkyl, Het-alkylCo, Rx = H »C0_ß alkyl, R 2 = C 1 - β alkenyl of C" _ »benzyl, R * = C 1 - alkyl, C 1 - R - C 0 -, R - S - a - R - OC < 0 > -, RßNHCO- »R-" = H. alkyl of Ar-alkyl of Co ... Het-alkyl of C0_ß; β = Ar alkyl of Ct>, Het-alkyl of Co_ß R «= H, alkyl of C , .. ,, »CHacF3, AR-C0_ß alkyl, Het-C0_ß alkyl» R "7 = C 1 alkyl, C 1 alkyl, Co- * 'R' = H; alkenyl of Cs_ ?, C2_ß alkyl; Het; Ar; C-m alkyl> optionally substituted by OR '»SR', NR '.,' CO 'R'. CO- ^ NR'-JB. N (C = NH) NHa !, Het or Ar; R "= H.Ca._.sup.-alkyl. C.sub.1 -C.sub.-alkyl.Het.-C0_M alkyl; RAO - Cx_ß alkyl. Ar-alkyl of C0_ß, Het-alkyl of Rs-a- = H. Cx.sup.-β alkyl. At-C.sub.alkyl, ...,., Het.-alkyl of Co.sub.β, or R.sub.16 Ri'R »- ^ • * • RAat = H, Cx_ß alkyl. Ar-C0_ß alkyl »Het-alkyl of C0_ßí R ?.» = H. C ^ alkyl ,. At-alkyl of C ^.! Het-C0_ß alkyl; R19 R * - * = RiB = H, alkyl of C ^ .. alken that of Ca_ß? Ar, Het, or allo of optional x_ß being replaced by OR », NR» CONR, N (C = NH) NH-, Het or Ar; R3- * = alkyl Cx_ß, alkenyl Ca_ß, alquinils CSS-ß 'Ar' Het 'or x_m alkyl optionally substituted by OR', SR ', R' ', COAr' C0NR "a. N (C = NH) NH-, Het O Ar; Ra. * - H 'C alquilo alkyl, C al _ alkenyl, C9_Mt alkynyl, »Het' or optionally substituted Cx_ß alkyl by -substituted by OR ', SR », NR» », CO ^R», CONR * a, N (C = NH) NH-, Het or Ar; R? - - »a - H, alkyl of C, _ß, R3-0, R ^ -oCiS) -, RxoOC (0) -; R ** - RM = Cß-βalkyl, C2_-alkenyl, C ciclo-C ciclo-cycloalkyl, C T-C alquilo-alkyl, C V-C V-alkyl, C--C T-alkyl; t- (CH-a) "CH (T> (CH2) n, optionally substituted by one or two halogens» SR110 »0R * 0» NRaoRa or alkyl of, _ ^ »Ra-7 _. a« C0 »Rßß0C0 »Al of CA_ß» Cycloalkyl of C 3 - LA Ar; Het; T-C 1 alkyl; T- (CHa!) R? CH (T) (CHa) "; optionally substituted by one or two SR halogens ». 0R20» R ^ oR "3, Cx_ß alkyl, RZO = ñ22 = R *» _ RM - R2ß = T3 = H, alkyl of C .._ ^, A -what C Cbz-leucin lo; 2. 3-. or 4-pyridol metí loxicarboni 1-leucini lo-; 4-imidazole aceti 1-leucini lo. feni lacet 1-leucini lo, N.N-dimeti 1-gl cini leucinilo. 4-pyridylacety 1-leucine lo. 2-pyridyl sulfonyl-leucine lo. 4-pyridyl carboni l-leucin lo. acetil-leucini lo. benzoyl-leucini lo. 4, phenoxy-benzoyl-, 2-, or 3-, benzyl-benzoyl-. bifeni laceti lo. alpha-isobutyl-biphenylacetyl. Cbz-feni lalaninyl, Cbz-norleuci ilo-, Cbz-norval inyl-. Cbz-gluta i lo-. Cbz-epsi lo- (steth-butyl) -glutamyl; aceti l-leucin lo-. 6 or? -quinolin carbonyl. bifeni laceti the alpha-lo-bifem isobuti "1 acetyl, acetyl, benzo the 2- or 3-benz lox i 4-pheno benzoyl Cbz-ami i benzoilo- oácido-;.... 2-, 3- or. 4-piridilmeti loxicarbon 1-o- aminoác; arylalkyloxy of coal C0_Cß 1-aminoáci or heteroaryl alkyloxy C0_Cß carboni 1-aminoáci do ar l alkyloxy carbonyl C0_Cß to inoácido "heteroaryl alkyloxy C0_Cß carboni 1-amino acid" alkyloxy. of Cx_Cß carbonyl-amino "alkylcarbonyl C _Cß. aryl alkyl Co_Cß carbonyl. heteroaryl- alkyl C0_Cß carbonyl" alkylaryl of C0_Cß carbonyl, heteroaryl alkyl carbonyl oC, alkyl Cx_Cß sulfonyl "aryl alkyl C ^ C. sulfonyl, heteroaryl C 1 C. sulfonyl, aryl C 1 alkylsulfonyl, heteroaryl C 1 -C 3 sulphonyl alkyl, R 1 O 4 H, C 1 7 alkyl; Cbz-leucinyl; 2-. 3-. or 4-pyridol methyloxycarbonyl-leucinyl-; 4-imidazole acet 1-leucinyl. phenylacetyl-leucinyl. -dimeti 1-gl icin leucinilo. 4-piridi laceti 1-leucinil. 2-pyridyl sulfone 1-leucine lo. 4-piridil carboni 1-leucini lo, acetil-leucini lo. benzoi 1-leucini lo. 4. phenoxy-benzoyl-, 2-, or 3-. benc i lox i benzoi lo-. bifeni laceti the alpha-isobutyl-biphen laceti as "Cbz-fen lala ini him, Cbz-norleuci i LO-, Cbz-norval ILO-, Cbz-gl ta LO-, LO Cbz-Eps (this? -buti ' l ico) -gluta ilo; aceti l-leucini lo-. 6 or S-quinoline carbonyl. bifeni lacet lo. alpha-isobut lo-bifeni 1 acetyl. acet lo. benzoyl 2- »or 3- benzi lo i benzoi 1. 4-phenox benzo lo-. Cbz-ami oác do-; 2-. 3-. or 4-pyridylmethyl loxycarbonyl-amino acid-; Alkyloxy of C 1 C 1, carboni 1-a and o acid. Heteroaryl alkyloxy of Co_Cß carbonyl-amino acid. aryl C 1 -C 12 alkyloxycarbonyl-amino acid. hetero-alkyloxy of co-c * carbonyl-amino acid. Cx_Cβ alkyloxycarbonyl-amino acid. alkyl carbonyl of Cx_Cß. arylC ^ alkyl. carbonyl. heteroaryl C0_C.sub.-carbonyl alkyl, arylC.sub.1 -C.sub.C carbonyl.alkyl, heteroarylC.sub.C alkyl. carbom'lo. Cx_C? sulfonyl alkyl? aryl C0_C alkyl? sulfonyl "heteroaryl alkyl C ^ C ^ alkylsulfonyl" aryl alkyl sulfonyl Co_Cß "heteroaryl alkyl sulfonyl C0_Cß» RASB = OCH ^ Ar 'Cx_ß 0CH2 alkyl substituted aryl, substituted heteroaryl alkyl C0_ß "4-imidazole methylene; 2- »3-» or 4-pyridi Imet Inenoxy; 4-pyridyl methylene »2-pyridyl sulfonyl, 4-pyridyl» substituted alkyls of Co_β. heterocylating the substituted C0_β alkyloxy; Raa = alkyl of Cx_ß, -CH ^ Ph, -CH ^ CH ^ CO ^ R »- *; R "-» st H, Cx_ß alkyl, RS "= Ar, HetAr; R »« = Ar l .heteroaryl, pyridyl, isoquinol nyl; R »-7 = Cx_ß alkyl, -CH ^ Ph, -CHajCH ^ COaR» * »R3» ** = Cbz; Cx_ß alkyl "or ar substituted Cbz; Cx_ß alkyl -CO; benzoyl; Cx_ß alkyl or benzoyl or substituted alkyl; Cbz-leuci lo »2-» 3-, or 4-pyridol me i loxi carboni 1-leucinilo-; 4-imidazole acetyl-1-leucinyl, phenylacetyl-leucinyl »NfN-dimethyl-1-glycol, leucinyl, 4-pyridyl-lactin-1-leucinyl, 2-pyridyl-sulfonyl-leucine, 4-pyridyl-carbom-l-leucine,» acetyl- leucini lo, benzoyl-leucini lo., 4-phenoxy-benzoi 1-, 2-, or 3-, benzylox benzoi lo-, bifeni laceti lo, alpha-isobuti lobifeni laceti lo, Cbz-feni lalanin lo, Cbz- norleucini lo-, Cbz-norval ini lo-. Cbz-glutam lo-, Cbz-épsi lo- (esters-but-l ico) -glutamilo, aceti l-leucini lo-, 6 or B-quinolin carbonyl, bifeni laceti the »alpha-isobut lo-bipheni acetyl, acetyl» benzoyl 2-, or 3- benzyl loxibenzoi 1. 4-phenoxy benzoyl- Cbz-a noacid-; 2-. 3-, or 4-pyridi Imeti loxycarboni -amino-acetyl, aryloxy-carbonyl-aminoalkyloxylated alkyloxy, heteroaryl-CO 2 -carbonyl-amino acid alkyloxy, aryl-alkyloxy-carbonyl-amino acid, heteroaryl-alkyloxy-carbon-1-amino acid, alkyloxy-Cx_C-carbonyl-amino-acid, alkyl carbonyl of Cx_Cß, arylC1-carbonyl alkyl, heteroaryl C 1 -C 4 alkylcarbonyl, C 1 -C carbonyl aryl alkyl, C 1 -C carbonyl heteroaryl alkyl. C 1 -C 5 Sulfonyl alkyl, C 1 -C 5 Sulfonyl aryl, C 1 Sulfonyl heteroaryl, C 1 -C 5 Sulfonyl aryl, C 1 -C 5 Sulfonyl, C 1 -C 5 alkyl, C 1 -C 6 alkyl; -"to. - H and C 1 to R 2 - alkyl = substituted C 1 -C 5 alkyl and substituted C 1 -C 5 alkyl substituted steryl; H when R- * is substituted C _ ar alkyl; C.sup.-C-substituted heteroaryl alkyl of Cx.sup.β, R.sup.- »= C.sup.x.sup.-alkyl. substituted Cx_β alkyl substituted C 1 heteroaryl alkyl; H when R "** is substituted Cx_β alkyl substituted Cx_ß alkyl and substituted heteroaryl C de R alkyl = CH (Rβa) NR- 'βRβ- *, CH (RβB) Ar, Cß-β alkyl; - »ß _. R-» ß = R- »t _ -» »- ßo _ R =? - H, Cx_ß alkyl.

Ar-alkyl of C0_ß'Het-alkyl of R_sr -. r, Het, CH (RBB) AR, CH (RBβ) 0Ar, N (Rβ *) Ar, Cx_β alkyl, CH (Rβ *) NR - »* Rβ" 7; RBB = Ca_ß alkyl, A-alkyl Co_ß »Het-alkyl-co-« Rß3 and R "" can be contacted to form a pyrrolidine or piperidine ring; RB-> R .-- -. R - »^, R -» - C (0), R- ^ CtS), R- »7OC (0), RBB = RBβ = RB *» = RB »= H, Cx_ß alkyl, o_ß alkyl, Het-alkyl of C0_ß; R * BO - .X _ R «= ROS _ Rß-» - H (Cx_ß alkyl, C0_ß aralkyl or Hey-alkyl of o__? Rßß = Cx_ß alkyl, Ar, Het CH (R * ») Ar, CH (RB ») OAr N (R *») Ar, CH < Rß ») NR ** R" », 0? Rßß = Rß »= RT *. _ H, Cx_ß alkyl, (CHa) o_ß ~ cycloalkyl of Cm_, Ar-alkyl of C0_ # t Het-alkyl of C ,,.,; Rß-r _ Cx_ß alkyl »< CH _.) 0 __- cycloalkyl of C __. ß. Aralkyl of C0_ß »Het-alkyl of o_« R ** and Rß-T can be combined to form a bicyclic or heterocyclic carbocyclic ring of 7 to 10 members »optionally with 1-4 of Cx_ß alkyl» Ph -alkyl of o_ß »Het-alkyl of Co_m * alkoxy of Cx_ß» Ph-alkoxy of C0_ß, Het-alkoxy of Co_β »OH, (CHa) _.NRB *» RB », O (CH_) x_ MRBBRB»; R * B = R7 ° = R **, RBßC (0), RB * C (S), RB * OC (0), RBS * OC (O) NRB »CH (R7 * -) (CO) and pharmaceutically acceptable salts thereof. The compounds of the formula I are hydrazidyl compounds. bis-hydrazide it and bis-aminometi Icarbon which have in common key structural features required of protease substrates. very particularly cathepsin K substrates. These structural characteristics give the compounds herein the appropriate molecular form necessary to fit within the active enzyme site. to bind to said active site and to react with a solfinyl group on the active site, thus blocking the site and inhibiting enzymatic biological activity. Referring to formula I. said structural characteristics include electrophilic carbonyl! central ico, a peptidyl or a molecular peptide structure on either side of the central carbonyl, a terminal carbobenzyloxy moiety (eg Cbz-leucinyl). or an imitator thereof, on the base structure on one or both sides of the carbonyl and optionally an isopropyl side chain extending from the base structure on one or both sides of the carbonyl.

The compounds of the formula I wherein D = and Q = are preferred embodiments of the present invention. For convenience, said compounds are known herein as compounds of formula II. More preferred embodiments of the present invention include compounds of formula II wherein: X = S, Y = CH, and Z = N; X = CH, Y = S, Y Z = N; ? = N »Y = N, and Z = s; ? = N, Y = N, and Z = 0; and? = (VI,? = N, and Z = N. Preferably Rx is H, methyl or isobutyl.

Preferably R is isobutyl. Preferably R * is isobutyl or benzyl Preferably Ra is RBOC (0) -, particularly benzyloxycarbonyl 1o. Preferably A is D- or L-amino acid or is absent, preferably A is absent. Preferably W is CN »NHRß, SR * or CO-.R *». Suitably RB is H, C ^ -C ^ alkyl, phenyl or benzyl. Typically, W is C0_.H. C0 _, - al 1o of x_ ^. C0a-Ph. CO _.- CH_ _Ph, CONHa, NHa or SH. The following compounds of the formula II are particularly preferred: (2S-1 'S) -2- (benzyl-1-oxycarbonyl) amino-N-C1' - (2-carboxy ti azo1-4-i1) -3 'meti Ibuti 1] -4-methylpentanamide; (2S-1 'S) -2- (benzyl 1 oxycarbon 1) ami no-N-C1' - (2-carboxamyl doti azo1-4-1) -3fmeti Ibuti 1] -4-methyl Ipentanamide; < 2S-1'S) -2- (benzylcarboni 1) amino-N-Cl '- (2-carboethoxy thiazol-4-yl) -3'met lbutyl 13-4-methyl-Ipentanamide; (2 S-1 S) -2- (benzyloxycarboni 1) amino-N-Cl '- (2-c-anothiazol-4-1) -met Ipentanamide; (2S-1'S) -2- (benzyl and carbonyl) amino-N-Cl'-C2- (Nr-benzylcarboxylated) thiazole-4-yl) -3'methyl butyl 3-4-methyl Ipentanamide; < 2S-1'S > -2- (benz loxycarbonyl) amino-N-Cl'-C2-CN '- (3-methy1-prop 1) carboxam do.lthiazo1-4-i 1) -3'methyl 1 buty 11-4-methyl pentana gone; (2S-1'S) -2- (benzylcarboni 1) amino-N-Cl'-C2- (Nf- (2-phenylethyl) carboxamido) ti azol-4-yl) -3'methyl-butyl D- 4-methypentanamide; (2S-1'S) -2- (benzyloxycarbonyl) amino-N-Cl '- (4-carboethoxy thiazole-2-yl) -3'met l uti 12-4-methyl Ipentanamide; (2S-1S) -2- (benzyloxycarbon I) amino-N-Cl '- (4-carboxyl azol-2-yl) -3'methyl-l-butyl-3-4-methypentanamide; (2S-1'S) -2- < benz loxycarbon 1) amino-N-Cl '- (4-carboethoxy-yiazol-2-yl) -3'-methylbutyl D-4-methopentanamide; (2S-1 'S) -2- (benz 1 oxica boni 1) ami no-N-C1' - (2-carbo-2.2.2-trifluoroethoxy-aiazol-4-yl D-S'-methybutyl 1) - 4-meth Ipentanamide; (2S-1'S) -2- (benzylcarboni 1) to ino-N- l '- (4-carboe oxy thiazole-2-yl) -3'methylbutyl 3-4-methylpentanamide; (2S-1'S) -2- (benzyloxycarboni 1-L-leuci i 1) amino-N-Cl, - (4-carboethoxy-yiazol-2-yl) -3"methyl Ibuti 13-4-methyl-entanamide; 2S-1 'S) -2- (benzyloxycarbonyl 1) ami no-N-C1' - (4-carboxamidooxadizol-2-yl) -3tmethylbutyl 13-4-methypentanamide; (2S-1 * S ? -2- (benz 1 oxy carboni 1) ami non-N-Cl • - (2-carboethoxy-thiazol-4-yl) -3fmethylbutyl 13-3-methypentaneamy (2S-1 'S) -2 - (benzl 1-oxycarboni 1-Ll eucin l) ami no-N-Cl '- (2-carethoxy thiol-4-yl) -3'methylbutyl 13-4-methylpentanamide; (2S-1' S) -2- (benzyl 1 oxycarboni) ami no-N-Cl "- (5-merca, 2,4-oxadiazol-3-yl) -3'me I uti 13-4-methypentanamide; (2S-1 'S) -2- (benzyl 1 oxycarbon 1) amino-N-Cl' - (2-mercaptoti azo1 -4- 1) -3"methylbutyl-4-methylpentanamide; (2S) -2- (benzyloxycarbonyl) ami oN- (4-carboethoxy thiazol-2-yl) -methyl 1-4-methyl-1-phenane-ida (2S-1'S) -2- (benzyloxycarbon 1) amino-N-Cl f- (2-benzyl) loxi carboni l-ti azole-4-i 1) -3 'met 1 buti 13-4-methypentanamide; (2S-1'S) -2- (benzylocarbohydrate) nil) ami or-4-methyl-N-C3"-methyl-1" - (2-phenoxycarbonyl oxyl azol-4-yl) butyl-1-pentanamide; (2S-1'S) -2- (benzyl i carboni 1) amino-4-methyN-C3'-methi 1-1'-C2- (2-methy1propiox charcoal 1) azole -4-i1) but pentanam gives; (2R-1 'S) -2- (benzyloxycarboni 1) amino-N-Cl "- < 4-carboe oxy thiazo1-2-i 1) -ethyl 3-4-methylpentanamide» (2R-1 'R) -2- (benzyloxycarbonyl 1) ami no-N-C1' - (4-carboethoxy thiazo1-2-y1) -e il 3-4-methypentanamide; and < 2S.l "S ) -N-Cl "- < 2-aminotia? Ol-4i 1) -3'-meti lbuti 13-2- (benzyloxycarboni 1) ami o-4-meti Ipentanam da.

Very particularly the preferred compounds of formula II are: (2S. 1'S) -2- (benzylcarbonate 1) amino-N-C1 '- (2-carboethoxy thiazo1-4-1) -3'methyl-1-butyl 3-4-methyl Ipentanamide; (2S .1 'S) -2- (benzyl-1-oxycarbonyl-1) amino-N-Cl' - (2-carboethoxy-thiazol-2-1) -3'-methyl-3-4-methyl-Ipentanamide; and (2S-1'S) -2- (benzyloxycarbonyl-L-leucinyl) ami no-N-Cl '- (4-carboethoxy-azole-2-yl) -3'-methylbutyl 3-4-y-Ipentanamide.

The compounds of the formula I wherein D = R__B and Q = are preferred embodiments of the present invention. For purposes of convenience, said compounds are referred to hereafter as compounds of the formula III. With respect to the compounds of the formula III: Preferred B is Most preferably B is , 16 Preferably R a- is R ^ R »- Preferably Rils is Rxß are H. -A Preferably »R3- * is Preferably Rlβ »Rxß. R * - »and Rx» are alkyl of AC_. Most preferably RAB • "RXB are C ^ _ _alkyl Preferably Ar is phenyl optionally substituted by one or two selected halogen groups" CF 3"N0a" SR ".OR" »NR" or C alquilo .. alquiloalkyl, preferably R R "7 and R" 7 * are Rxo0C (0) -, and Rxo is most preferably Ar-alkyl of C _ ^. Preferably R and Rx "are alkyl of R, and very preferably RM and Rx" are i_- Bu. Preferably R * "7 and R" 7 * are Cbz A particular embodiment of the invention of the formula III is a compound of the formula F: F wherein X »Y» Z »Rxβ» R * - "7 and R-758 are as described in formula III.Very particularly» the preferred compounds of formula III are: (lS) -N-C4-C <l-benzyloxycarbonyl ami no) -3-me i 1-butyl 3-thiazol-2-ylcarbon l -N '- (N-benzyl loxycarboni 1-L-leuci il) idrazide; N-benzyloxycarbonni 1-L-leuci i l -N'-benz loxycarbon 1-L-leucine 1-L-leucine Ihydrazide »and (lS) -N- 2-C (l-benzylcarbonyl lamino) -3-me Ibu l 3thiazol-4-i Icarboni 1 - N '- (N-benzyloxycarboni 1-L-leuc ni 1) hydrazide.

A compound of the formula I where D = and Q = are preferred embodiments of the present invention. For convenience purposes, said compounds are refer later to compounds of formula IV. A more preferred embodiment of the present invention is a compound of formula IV wherein * and *? they are selected from the group consisting of: N-Cbz-leucine lo »N-Cbz-gl icinyl, N-aceti l-leucin lo, N-Cbz-alani lo. and R ». R * a and R * B are H. Particularly preferred embodiments of formula IV are: 2,2"- (N-N" -bis-benzyl? -carbon 1-L-leuc ni 1) carbohydrazide; 2,2t- (N-N'-bis-cyclohexy laceti 1> carbohydrazide; 2.2"- (NN, -bis-4-methylpentanoi 1) carbohydrazide; 2.2 '- (-N'-bis-cyclohexy 1aceti 1 ) carbohydrazide; 2,2 '- (N-N'-bis-benzyloxycarboni Igl icini 1) carbohydrazide; 2 * 2 * - (N-N'-bis-acet 1-L-leucine 1) carbohydrazide; 2f 2" - (N-N'-bis-benzyloxycarbon 1-L-alani 1) carbohydrazi a; 2f2f- (N-benzyloxycarboni 1-L-leucine 1) -2"N- (4-meth Ipentane I) carbohydrazide. 2» 2t- (- "-bis-benzyl 1 oxycarbonyl l-1-echinium 1) -carboh drazide is the most preferred modality of formula IV.

The compounds of the formula I wherein D = and Q = are preferred embodiments of the present invention. For purposes of convenience, said compounds are hereinafter referred to as compounds of the formula V. In more preferred compounds of the formula V. when R30 = Cx-Cß alkyl. R3 ° is preferably Me or -CHseCHaMe_ai.

When R3ß = Cx-Cß alkyl »R3a is preferably -Pr.-Bu. or -CH ^ CH ^ e ^. When Ra - * = Cx-Cß alkyl. R3 ** is preferably t-Bu. Even more preferred embodiments of formula V include: bis- (Cbz-leuci i l) -l, 3-diami o-propan-2-one; bis-l, 3- (4-phenoxy-benzoi 1) -diami-propan-2-one; 1- (Cbz-leucine 1) -amino-3- (acetyl-leucine 1) -amino-propan-2-one; l- (Cbz-leuc ni 1) -ami or -3- (Cbz-glutamyl-t-esterbutyl) -a ino-propan-2-one; 1- (Cbz-leucine 1) -ami or -3- (Cbz-gluta-il) -amino-propan-2-one; bis-l, 3- (Cbz-1 eucini 1) -diamino- (S) -butanone-2-one; 1- (Cbz-leucine 1) -ami or -3- (Cbz-phenylalan 1) -ami o-propan-2-one; 1- (Cbz-leuc ni 1) -amino-3- (Cbz-norleucini 1) -amino-propan-2-one; l- (Cbz-leuci i 1) -ami or-3- (Cbz-norval ini 1) -a i o-propan-2-one; bis-1, 3- (Cbz-leucine 1) -diamino-5-methyl-1- (S) -hexan-2-one; 1- (acet l-leucini 1) -amino-3- (4-phenoxy-benzoyl) -ami o-propan-2-one; l- (Cbz-homo-leucine 1) -amino- (Cbz-leucini 1) -3-ami o-propan-2-one »l- (Cbz-leucine 1) -amino-3- (acet l-leucini 1 ) -amino-propan-2-one is the particularly more preferred embodiment of the present invention of formula V.

The compounds of the formula I wherein D = Q = are preferred embodiments of the present invention. For purposes of convenience, said compounds will be referred to hereafter as compounds of the formula VI.

Most preferably, R3ß = Ph. or pi idina, very preferably still R3B = Ph. Ph can optionally be substituted by C _ß alkyl, Cx_β alkoxy. halogens and cyano groups. When R3B = pyridine »R can be 2-pyridyl. 3-pyridimethyl or 4-pyridinium Very particularly preferred embodiments of formula IV include: biß-1 -3- (4- (3-chloro-2-cyano-pheno) phen-1-sulfonam) propan- 2-one; bis-1 -3- (-phenoxy-phenyl sulphonamido) -propan-2-one; Compounds of the formula I wherein D = and Q = are preferred modalities of the present invention. For purposes of convenience, said compounds are hereinafter referred to as compounds of the formula VII. Most preferably »R03 * is selected from the group consisting of: more preferred compounds of the formula VII. Particularly preferred modalities of the formula VII are: l- (Cbz-leuc ni 1) -amino-3- (4- (3-chloro-2-cyano-phenoxy) pheni 1 s 1-phonamido) propan-2-one; 1- (Cbz-leucinyl) -a or -3- (tosyl-amino) -propan-2-one; l- (Cbz-leucine 1) -amino-3- ((4-phenoxy-phen-1) -sulfonam-do-propan-2-one; 1- (Cbz-1-eucy-il) -ami-3- (2- dibenzofuransulphonido) -propan-2-one; 1- (Cbz-homo-1-eucinyl) -amino-3- (2-di-benzofuransu1fonami-propan-2-one; and l- (Cbz-1-eucinyl) -a ino-3- (2-dibenzofuransulfonamido) - (S) -butan-2-one; l- (Cbz-leucine 1) -amino-3- ((4-phenoxy-phenyl) -sulfonamido-propan-2-one) 1- ( Cbz-1-eucinyl-amino-3- (2-dibenzofuransu-1-ammonido) -propan-2-one and l- (Cbz-leucine 1) -amino-3- (2-dibenzofuransulfonamido) - (S) -bu an-2-one they are the particularly preferred modalities of formula VII.

The compounds of formula I where D = and Q = > 42 R " are preferred embodiments of the present invention. For purposes of convenience, said compounds are hereinafter referred to as compounds of the formula VIII. A more preferred embodiment of formula VIII is when R ** a is 2-di benzonfurani 1 sulfonyl. Particularly preferred embodiments of formula VIII are: Cl-CCC3-Cbenzyloxycarbonyl l-leucine l-amino-3-2-oxopropy 13-1- (benzyl) amino3carboni 13-3-methyl-1-propylcarbamic acid (S) -phenylmethylcarbamate. Cl-CCC3-C (2-dibenzofrani lsulfoni 1) amino-2-oxopropy 13-3- (benzyl) amino3carbonyl-3-methyl-l-butyl-1-carbamic acid ester (S) -fem "methylmethyl Cl-CCC3-C (2) -dibezofurani Isulfonyl) amino-2-oxopropyl-1,3- (4-pyridinylmethyl) amino-carbon-3-methyl-butyl-3-carbamate ester of (S) -phenylmethyl, 1-C C3-C (2-dibenzofuran, lsulfo-1) amino -2-oxoprop 13-3- (4-pyridinylmethyl> benzamide Cl-C C C3-C (2-d enzofuran lysulfonyl) to ino3-2-oxoprop 13-1- (4-pyridine-1-methyl) amino-3-carbon-1 -3 -methi Ibuti 13-carbamate of (S) -phenylmethyl, C1-CCC3-C (2-di-benzofuranylsulfonyl) amino-3-oxopro-13-l- (4-pyridinylmethyl) amino-carboni 1 -3-methyl-1-butylcarbamate of (S) -phenylmethyl is a very particularly preferred embodiment of Formula VIII The compounds of Formula I wherein D = R51 1 52 R 's are preferred embodiments of the present invention. For purposes of convenience, said compounds are referred to hereafter as compounds of Formula IX. Compounds of Formula IX wherein: R **** = CH (RB3) NHRβ- "; R- »B, R-» «. R- »B, R- *», RBO and RBX are H; R - * "7 is independently CH 3, benzyl, 2-pyridinyl lmethox, 4-dimethyl aminobenzyl, J = C (0), R b» = A, CH (Ri 0) Ar, CH (Ra-) OAr N ( Ra- °) Ar, CH (R * °) NR "Ria-; RB! »= Ethyl, i-Bu; Rß- »_ R -» -, R - »- C (0), R -» -? OC (0); Rß * = H, CH3. i-Bu; Rß-- _ R- »t, R - * - > OC (0 »Ar = phenyl or naphthyl, optionally substituted by one or more of Ph-C0_ß alkyl» Het-C0_ß alkyl, Cx_ß alkoxy, pH-CQ alkoxy, Het-alkoxy of Co ... OH, ( CHat) x_ßNRBßRß », 0 (CHaj) x_ßNRßßRβ "; Rßß, ß »- H, Cx_ß alkoxy. Ar-C0_ßalkyl; Het-C0_ß alkyl "are more preferred embodiments of the present invention. The following compounds of Formula IX are particularly preferred. 2-CN- (N-benz loxycarboni 1-L-leucine 1) 3-l'-CN '- (4-phenoxyphen Isulfoni 1) carbohydrate? Ida; 2-CN- (N-benzyl? Icarbonyl-L-alanyl) 3-2'-CN- (N-benzyloxycarbonyl 1-L-leucine 1) 3-carbohydrazide; 2-CN- (N-benzyloxycarbonyl 1-L-leucine 1) 3-2t-CN '- (4-phenyl-1-benzoyl-1) 3-carbohydrazide »2-CN- (N-benzyloxycarbonyl 1-L-leucine 1) - 2'-CN '- (4-methoxy benzoyl) carbohydrazide; 2-CN- (N-benzyloxycarboni 1-L-leucine 1) 3-2'-CN '- (4-phenoxy benzoi 1) carbohydrazide; 2- (N-aceti 1) -2"-CN '- (N-benzyloxycarboni 1-L-leucine l) 3-carbohydrazide; 2-CN- (N-acetyl-L-leucine 1) -2" -CN'- (N-benzyloxycarbon 1-L-alanyl) carboidrazide; 2-CW- (N-acetyl-L-alani 1) -2"-CN" - (N-benzyloxycarboni 1-L-leucine 1) 3-carbohydrazide; 2-CN- (N-benzyloxycarbonyl-L-1euc nyl) 3-2'-CN'-C4- (N, N-di eti laminómeti 1) benzoyl) 3-carbohydrazide; 2-CN- (N-benzyloxycarboni 1-L-leucine 1) 3-2"-CN'-C4-hydroxy-C3- (4-morfol nomethyl) 33benzo 13carbo idrazide; 2-CN- (N-benzyloxycarbon i 1 -L-leucine 1) 3-2"-CN'-C4- (NN-dimeti laminomet 1) benc loxy 3carboni 1-L-leucine 1 carbohydrazide; 2- (N-benzo 1) -2'-CN '- (N-benzylcarbonyl 1-L-leucine 1) 3carbohydrazide; 2-CN- (N-benzyloxycarboni 1-L-leucinyl) 3-2'-CNt-C3- (4-morphonomethyl) benzoyl-1-carbohydrazide; 2-CN- (3-benzyloxybenzoi 1) 3-2'-CN '- (N-benzyloxycarbonyl-L-leucine 1) 3-carbohydrazide; 2-CN- (N-benzyloxycarboni 1-L-leucine 1) 3-2"-CN'-C4-C3- (NN-dimethylamino) -l-propy loxy-3-benzoyl-133-carbohydrazide; 2-CN- (2-benzyloxy-benzole) ) 3-2'-CN '- (N-benzyloxycarbon 1-L-leucine 1) 3-carbohydrazide; 2-CN- (N-benzyl-icarbonyl-L-leucinyl) 3-2'-CN'-C3- (4 -pyr di 1-methoxy) benzoyl-1-carbohydrazide; 2-CN- (4-benzyl-ibenzoi-1) 3-2'-CN '- (N-benzyloxycarbonyl-L-leucinyl) carbohydrazide; 2-CN- (N-benzyl? icarbonyl-L-leucine 1) 3-2"-CN '- (3-benzyloxy-5-methoxy) enzoyl-3-carbohydrate; 2-CN- (N-benzyl? -carbonyl-L-leucine 1) 3-2'-CN "- (3-benzyloxy-4,5-dirneto? I) benzoi-13-carbohydrazide; 2-CN- (N-benzyloxycarbonyl-) L-leucinyl) 3-2"-CN '- (3-benzyloxy-5-etho? I) benzoi-13-carbohydrazide» 2-CN- (N-benzyloxycarbonyl-1-icini-1) -2'-CNf- (N-benzyloxycarboni) L-leucine 1) 3-carbohydrazide; 2-CN- (3-benzyloxybenzoyl) 3-2'-CN, - (N-benzloxycarbon l-L-prol in 1) 3-carbohydrazide; 2-CN- (N-benzyloxycarbonyl L-L-leucine 1) 3-2r-CN '- (4-phenylephenylaceti 1) carbohydrazide; (2"S) -2-CN- (3-benzloxybenzole) -2 f-CN '- (N-benzylloxycarboni 1-2-aminobutyrrone 1) 3carbohydrazide; 2" 2"-CN, N" - Cbis- (4-fem * lfeni laceti 1) 3carbohydrazide; (2 'RS) -2-CN- (N-benzyl 1 ox i carboni 1-L-1 euc nil 3-2'-C2- < 4- feni Ifenox) propioni 1 carbohydrazide; 2-CN- (3-benzyl? ibenzoyl) 3-2'-CN '- (4- ei 1pentane I) carbohydrate; (2RS »2" RS) -2,2'- CN.N'-Cbis-C2- (4-phenylphenyl) -4-methyl-1-pentanoyl) 333-carbohydrate; < 2'RS) -2-CN- (N-benzyloxycarbonyl L-L-leuc i 1) -2'-CN'-C2- (4-phenyl-1-phenyl) -4-methylpentane 1) 3-carbohydrazide; (2'RS) -2-CN- (3-benz-loxibenzoyl) 3-2'-CN'-C2- (4-phenyl-l-phenyl-1) -4-met-pentanoi-1) 3-carbohydrazide; 2-CN- (3-benzyloyl benzoyl) -2"-CN '- (-benzyloxycarbonyl 1-N-methyl-L-leucinyl) 3-carbohydrazide; 2-CN- (3-benzyloxybenzoyl) 3-2, -CN'-CN- (2-pyridyl-1-methoxycarbonyl 1) -L-leucine-1-carbohydrazide; 2-CN-C3- (4-pyridylmethoxy) -benzo-3-2'-CN "-CN- (2 -piridini lmeto? i carboni 1) -L-leucine 133carbohydrazide »(2RS) -2-CN-C2- (4-phenylphenyl) -4-methylpentanoi 1) 33-2'-CN'-CN- (2-pyridini) 1-methoxy carboni 1) -L-leucine 1 3 -carbohydrazide; 2-CN- (N-benzylocarbonyl L-L-leucine 1) 3-2'-CNt-C2- (4-phen lfeni 1) -4-methyl Ipentanoi 1) 33carbohydraz; 2-CN- (N-benzyloxycarboni 1-L-leucim "1) 3-2'-CNt-C2- (4-fe i 1-phenyl) -4-methylopentanoi 1) 33carbohydrazide; 2-CN- (N-benzyl) loxycarboni L-leucine 1) -2'-CN "-CN- (4-phenyl Ifenyl) -N- (2-methylpropi 1) carbamoyl-3-carbohydrazide; 2-CN- (3-benzyloxy benzoyl) 3-2r-CN, - (N-methyl 1-L-leucine 1) 3-carbohydrazide; 2-CN- (N-benzyloxycarbonyl L-L-leucine 1) -2'-CN '- (N-methyl l-L-leucine 1) carbohydrazide. Compounds of Formula I where: R64 65 D = L-G- and? R63 are preferred embodiments of the present invention. For purposes of convenience, said compounds are referred to hereafter as compounds of Formula X. With respect to Formula X: Very preferably Q is Most preferably R * 3 and R1"- * are H and Rßß and" "are i-butyl, most preferably R * B is CH (Rβ») NR * a-R'70, wherein RB "is i-butyl and Rβ? - is H. Most preferably, R "70 is Rβ * oC (0), where RB is Alternatively, R * B is Ar or CH (R ** ») Ar, where Ar in said group R * B is Most preferably, L is CH (R * »*> NR *» ° RßB, CH (Rßß) Ar. NR ** Rß_. CH (R * B) OAr '. Ar »or Het, where R *** is i-buti lo and Ar in said group L is ? OR or Het in said group L is Most preferably L is NRßßRß'7 or CH (Rßß) Rß © Rß *. A particularly preferred embodiment is a compound of Formula G: Another particularly preferred embodiment is a compound of Formula H: The following compounds of formula X are very particularly preferred: (lS) -N- 2-C (l-benzyloxycarbon lami) -3-methylbutyl-13-thiazole-4-icarboni 13-N '- (4-phenoxypheni-sulfonium) 1) hydrazide; (ÍS) -N-C4-Cl- (N-benzyl 1 oxycarboni 1-Ll euci ni 1 ami no) -3-met l butyl ti azo1-2-i Icarbon 1 -N '- (-benz i loxi carboni 1-L- 1 eucini 1) hi draz i da; (1S) -N-C2-C (1-benzyloxycarbonyl-lamino) -3-ethylbutyl-1-thiazol-4-yl carbonyl-N '- (4-phenyl-1-phenyl-aceti-1) idrazide; (SS) -N-C2- (1-benzyl-1-oxocarbonyl-1-amino) -3-methyl-1-butyl-thiazol-4-yl-carbonyl 3-N'-C3- (4-pyridinyl-l-methoxy) -benzo-1-hydrazide; N-C2- (2-c 1 orophenoxymethi 1) thiazo1-4-i i carbon 13- '-CN- (4-? Iridini lmeto? Icarbonyl) -L-leucinyl hydrazide; N-CN- (4-pyridinium methoxycarboni 1> -L-leucine 13-N'-C2- C4- (1.2.3-ti adi azo1-4-l) pheny1 ti azo1-4- Icarboni 13 hydrazide; N- C2-C3- (4-chloropheni lsulfoni imeti l) thien-2-ii thiazol- -i Icarboni 1 -N "-CN- (4-pyri dini I ethoxycarboni 1) -L- leucine l hydrazide; (ÍS .2 ' RS 5-N-C2- (1-benzyl-1-oxy-carboni-1-amino) -3-methyl-1-butyl-1-thiazol-4-i-Icarboni-1-N "-C2 '(4-phenolyl-1-4-met) ipentanoi 1 hydrazide; N- 2- (3-benzyloxy-pheni 1) thiazole-4-icarbon 1 -N'-CN- (2-pyridinium methoxycarbonyl 1) -L-leucine 1 hydrazide; (lRS) -N- C2-Cl- (4-phenylphenyl) -3-methyl-util thiazole-4-i-1-carboni 13-N'-CN- (4-pyridine or lmetocarboxy) 1) -L-1 eucine 13-hydrazide; N-C2- ( 2-benzyloxypheni 1) thiazole-4-i Icarboni 13-N'-CN- (4-pyridine Imeto? I carboni 1) -L-leucine 13 -hydrazide; N-C2- N -methyl-N- (4-phenylphenyl) amino-3-thiazole 4-yl carbonyl-N'-CN- (4-pi-lime or lmeto-1-carbonyl) -L-leucine-13-hydrazide; N- (N-benzylocarboxy 1-L-leucine 1) -N'-C2- ( 4-phenylbenzyl 1) thiazole-4-icarboni 13hydrazide; N-C2 - (4-phenyl-l-phenyl-1-benzyl) -yl azo-1-4-Icarboni-13-N'-CN- (4-pyridinium-I-ethoxycarbonyl-1) -L-leucine-13-hydrazide; N- (-benz i lox i carboni l-L-leuc i 1) -N'-C2-CN- (2-methyl Iprop 1) -N-phen lamino-3-thiazole-4-ylcarboni-1-hydrazide; N-C2-CN- (2-methyl propi 1) -N-fe i lamino ti azo1-4-i Icarboni 13-N -CN- (4-pyridini lmetoxicarbom "1) -L-leucine 13-hydrazide; N-C2- (2-benz loxifeni 1) thiazol-4-i Icarboni l -N'-CN- (3-pyridinium-1-ethoxy-carboni-1) -L-leucine-13-hydrazide; N-C2- (2-benzyllo-ifeni-1) thiazole -4-i Icarboni 13-N'-CN- (2-pyridinium methoxycarboni 1) -L-leucine 13-hydrazide; N- (N-benzyloxycarboni 1-N-methyl-L-leucine 1) -N'-C2- (2 -benzyl loxifeni 1) thiazole-4-i Icarboni 13hydrazide; N-C2-CN- (2-methylpropi 1) -N-phenylamino thiazole-4-i 1carbon l -Nr-CN- (2-pyridinium methoxycarbonyl 1) - L-1eucine 13 hydrazide; N-C2-CN- (2-methyl-1-propyl) -N-phenylamino-3-thiazol-4-ylcarbonyl 3-N "-CN- (3-pyridyl or lmetocarbonyl) -L-leucine l 3-hydrazide; and N-C2- (2-metho-ifen l) thiazole-4-i-Icarboni 1-N'-CN- (4-pyridinium lmetocarboni 1) -L-leucine l 3-hydrazide. nEflNIC Q? S The present invention includes all hydrates, solvates. complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently linked compounds that release the active parent drug according to Formula I n v or v. If a chiral center or other form of an isomeric center is present in a compound of the present invention, all forms of said isomer or isomers, including enantiomers or diastereomers, are intended to be covered herein. The compounds of the invention which contain a chiral center can be used as a racemic mixture. an enantiomerically enriched mixture or a racemic mixture can be separated using well known techniques and a single enantiomer can be used alone. In cases where the compounds have unsaturated carbon-carbon double bonds. the cis (Z) and trans (E) isomers are within the scope of this invention. In cases where the compounds can be emitted in tautomeric forms, such as ketoenol tautomers, each tautomeric form is contemplated as being included within the invention either existing in equilibrium or predominantly in one form. The meaning of any substituent in any occurrence in Formula I or any Sub-phrase thereof is independent of its meaning, or the meaning of any other substituent. in any other occurrence "unless otherwise indicated. Abbreviations and symbols that are commonly used in the techniques of peptides and chemical compounds are used herein to describe the compounds of the present invention. In general. the abbreviations for amio acids follow the IUPAC-IUB Jo nt Commission on Biochemical Nomenclature. as described in Eur J. Biochem .. 15B.9 (1984). The term "ami oacid", as used in the present invention, refers to the D or L isomers of alanine, arginine. aßparagine Aspartic acid. cysteine, glutamine »glutamic acid. glycine, histidine, isoleucine, leucine, Usina, methionine, phenylalanine »proline, serine, threonine, tryptophan, tyrosine and valine. "Cx-6 alkyl", as applied in the present invention, includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl substituted and not substituted, and the simple aliphatic isomers thereof. Any Cx_ß alkyl group can be optionally substituted independently by one or two halogens, SR ', OR', N (R ') a. C (0) N (Rt) at, carbamyl or Cx_ ^ alkyl, wherein Rt is Cx_ß alkyl. Alkyl of C0 means that no alkyl group is present in the portion. Thus, Ai-alkyl of C0 equals Ar. "Cycloalkyl of C3_xx", as applied in the present invention »includes cyclopropane» cyclobutane »cyclopentane. cyclohexane. cycloheptane. cyclooctane, cyclononane. cyclodecane and cycloundecane substituted and not substituted. "Cz_ß alkenyl", as applied in the present invention, means an alkyl group of 2 to 6 carbon atoms, wherein a single carbon-carbon bond is replaced by a carbon-carbon double bond. Alkenyl of Ca_ß includes ethylene. 1-propene, 2-propene, 1-butene, 2-butene, ßob teno, and the different isomeric pentenes and hexenes. The cis and trans isomers are included. "Alkynyl of Ca_ß" means an alkyl group of 2 to 6 carbon atoms, wherein a single carbon-carbon bond is replaced by a carbon-carbon triple bond. Alquin that of a_ß includes acetylene, 1-propyne, 2-propyne, 1-bu no, 2-b tino, 3-buty or, and the simple isomers of pent not and hen ino. "Halogen" means F, Cl, Br and I. "Ar" or "aryl" means = phenyl or naphthyl, optionally substituted by one or more of Ph-alkyl of Het-alkyl of C0_ß, alco? I of Cx_ß, Ph- alco? i of C0_ß, Het-alco? i of Co_ß. OH, < CHse) _ßNRßBRB », 0 < CHa) x_ßNRB "R59; wherein RBB, RB" = H "C alquiloß alkyl" Het-C de_ß alkyl "of Cx-alkyl" 0 0Rf »N (R ') β, SR", CF;,. N0ß, CN, COaR ', CON (R), F, Cl, Br and I. As used in the present invention. "Het" or "heterocyclic" represents a stable monocyclic ring of 5 to 7 members, or a stable bicyclic heterocyclic ring of 7 to 10 members, which is saturated or unsaturated "and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, 0 and S "and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized" and the nitrogen heteroatom may optionally be quaternized. and including any cyclic group in which any of the heterocyclic rings defined above is fused with a benzene ring. The heterocyclic ring can be attached to any heteroatom or carbon atom, which results in the creation of a stable structure, and can be optionally substituted with one or more selected portions of C 1 -3 alkyl. ') a, SR'. CF, NOa, CN, COaR ', CON (R), F, Cl, Br and I, where R' is C.sub.4 alkyl Examples of said heterocycles include piperidinyl, piperazinyl, -o? opiperazini lo. 2-o? opiperid ni lo »2-o? opirrolodini lo» 2-oxoazepinilo »azepinilo» pyrrolilo »4-piperidonilo» pirrol idim'lo »pyrazole» »pyrazole idin lo» imidazolyl »pyridyl» pyrazinyl Or "azol idini lo." Or "azolinyl" or "azolyl" iso-azolyl "morpholinyl, thiazole dini lo-thiazolinyl" thiazolyl "quinucl idini lo. Indolyl, quinolinyl, isoquinolinyl" benzimidazolyl "benzopirani lo, benzo? Azol ilo» pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoyl, lolyl, sulfonyl, amorphoyl, thiamorphol, 1-sulfone and oxadiazole. "HetAr" or "heteroaryl" represents any heterocyclic moiety encompassed by the above definition of Het, which is of aromatic character, for example, pyridine. It will be appreciated that the heterocyclic ring described when N = includes thiazoles, oxazoles, triazoles, thiadiazoles, or? adiazoles, iso? azoles; sotiazoleß »imidazoles» pyrazines »pyridazines» pyrimidines »triazines and tetrazines» which are 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 (for example »is a heteroaryl group). The term "heteroatom", as applied in the present invention, refers to oxygen »nitrogen and sulfur. When the heteroaryl group comprises a five-membered ring, W is preferably an electron-separating group, such as halogen, -CN, -CF3, -N0a, -COR-7, -COaR-, -CONHR *, -S0ßrjNMr, β , -NHSOafR *, -NHC0R "7" -0-COR **, -SRβ or NR'R *, or an electron-withdrawing substituent similar to those known in the art Certain groups of radicals are abbreviated herein invention, t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyl or the carbonyl radical, Fmoc refers to the fluorenyl-lmetocarbonyl radical, Ph refers to the phenyl radical, and Cbz refers to the benzyl radical. icarboni 1. Certain reagents are abbreviated in the present invention DCC refers to dicycloherthecarbodiimide »DMAP is 2,6-dimethylaminopyridine, EDC refers to N-et 1-N" (dimethyl-a-inopropy1) -carbodiimide . HOBT refers to hdro? Ibenzotriazole, DMF refers to dimethyl formamide, BOP refers to he? Benzotriazole-1-i loxi-tris (dimethylamino) -phosphonium afluorophosphate. DMAP is dimethyl laminopyridine, Lawesson's reagent is 2,4-disulfur of 2,4-bis (4-methoxy-1) -l, 3-dithio-2,4-diphosphoethane, NMM is N-methylmorpholine, TFA refers to trifluoroacetic acid, TFAA refers to tri-luoroacetic anhydride and THF refers to tetrahydrofuran. Jones reagent is a trioxide solution of chromium, water and sulfuric acid, and is well known in the art.

METHODS OF PREPARATION The compounds of Formula II, wherein X = CH. Y = S and Z = N y = CO ^ R "7 CN or CONR'R" 7. they can be conveniently prepared by methods analogous to those described in Scheme 1.

SCHEME l a) i-BuOCOCI »NMM, CHaNa, EtOAc, Eta?; b) HBr, AcOH, EtOAc, Eta.0 c) Hs-CSCO ^ Et, EtOH 5 d) NAOH, HaO, THF; e) i-BuOCOCI, NMM, NH.-, THF or BOP, Et3N, RNHa, CH ^ Cl-; f) TFAA, pyridine, CH ^ Clj ,,; g) R- "OH, BoC3-jO, pyridine or R3H, EDC1, CH ^ Cl ^; h) piperidine, DMFf i) BOP, Et3N, D-CO-jH, Compound 1 of Scheme 1 is treated with isobutyl oroformate and N-methyl 1-morpholine in ethyl acetate to give a mixed anhydride which is treated with diazomethane in ether to provide compound 2 of Scheme 1. Diazoketone is halogenated using 30 ° C HBr in acetic acid in sodium acetate solution. ethyl / ether to provide compound 3 of Scheme 1. This material is treated with ethyl thiooxatoethanol in refluxing ethanol to give compound 4 of Scheme 1. Carboxylic thiazole ether is saponified by treatment with a base of hydroxide (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to produce the carboxylic acid 5 of Scheme 1. Carboxylic acid is treated with isobutyl chloroformate and N-methyl orfolin, followed by gaseous ammonia to provide the primary amide 6 of scheme 1 (R3 = H) .The primary amide is treated with TFAA and pyridine in dichloromethane to provide compound 7 of Scheme 1. Alternatively, compound 5 of Scheme 1 can be converted to substituted amides, compound 6 of Scheme 1, by treatment with alkyl amines (such as benzylamine) 2-pheni leti lamina or isobutyl sheet) and a peptide coupling reagent (such as BOP, EDC-HC1 / 1-H0BT or N-methylmorphine / isobutyl chloroformate) in an aprotic solvent (such as dichloromethane or DMF). The carboxylic acid 5 of Scheme 1 can be converted to carbohydrate esters B of Scheme I by treatment with a primary or secondary alcohol (such as 2,2,2-trifluoroethanol, isobutyl alcohol, benzyl alcohol or phenol) and a dehydration reagent (such as DCC / DMAP, EDCl or Boc-.O / pyridine) in an aprotic solvent (such as dichloromethane or ether). When Ra = 9-fluoreni lmeto? I, treatment of compound 4 of Scheme I with pipiridine in DMF gives compound 9 of Scheme 1. Treatment of compound 9 of Scheme 1 with a carbo-ylic acid (such as N-Cbz) -L-feni lalani a or N-Cbz-1eucinyl-L-leucine) and a peptide coupling reagent (such as BOP) in an aprotic solvent (such as dichloromethane), provides compound 10 of Scheme 1.

SCHEME ÍA a) Mel, THF; b) R'NHa, i-PrOH; O Bromomethyl ketone, EtOH. The compounds of Formula II, wherein X = CH, Y = S and Z = N, are prepared by methods analogous to those described in Scheme IA. Compound 1 of Scheme IA is treated with iodomethane in an aprotic solvent (such as THF) to yield compound 2 of Scheme IA which is treated with a primary amine in a protic solvent (such as isopropanol) to give compound 3 of the Scheme ÍA. This material is then treated with a bromomethyl ketone in a protic solvent (such as ethanol) to provide compound 4 of Scheme IA.

SCHEME 2 BocHN a) i-BuOCOCI, NMM, NH .., »THF; b) Lawesson reagent, THF; c) BrCHa-COCO ^ Et, TFAA, Pyridine, CH ^ Cl. ,,; d) TFA; e) DCOaH, EDC-HC1, HOBT, Et3N, DMF; f) NaOH, Hg.0, THF. The compounds of formula II, wherein X = S, Y = CH and Z = N, can conveniently be prepared by methods analogous to those described in Scheme 2. Compound 1 of Scheme 2 is treated with isobutyl chloroformate, N- methylmorphol ina and ammonia in THF to provide compound 2 of Scheme 2. This material is converted to the thioamide, compound 3 of scheme 2, by treatment with Lawesson's reagent in an aprotic solvent (such as THF or toluene). Compound 3 of Scheme 2 is converted to the thiazole by condensation with an α-ketoester having a residual group suitable for displacement by a sulfur nucleophile (Cl, Br. I »OMs. 0- £ -Tos) in dichloromethane. Compound 4 of scheme 2 is treated with TFA to provide compound 5 of scheme 2. This material is treated with a carboxylic acid (such as N-Cbz-L-leucine, N-Cbz-D-leucine or N- Cbz-L-leuc nil-L-leuc a) and a peptide coupling reagent (such as BOP, EDC-HC1 / 1-H0BT or N-methyl Imorphol ina / isobutyl oroformate) in an aprotic solvent (such as such as dichloromethane, DMF or THF) to produce compound 6 of scheme 2. This material is hydrolyzed by treatment with a hydrogenated base (such as potassium hydroxide, sodium hydroxide or hydroxide). lithium) to produce the carboxylic acid 7 of scheme 2.

SCHEME 2A a) Boc-amino acid, EDC-HC1, 1-HOBT, DMF; b) TFA; c) RßOCOCl, i.-Pr.NEt. The compounds of the formula II, wherein X = S, Y = CH and Z = N, can also be prepared by methods analogous to those described in scheme 2A. Compound 1 of scheme 2A is treated with an amino acid protected with tert-butocarbonyl (such as N-butocarboxyl-1euc a) and a peptide coupling reagent (such as BOP, EDC-HC1 / 1 -H0BT or N-met lmorfol ina / isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMF or THF) to yield compound 2 of scheme 2A, which is treated with trifluoroacetic acid to provide compound 3 of scheme 2A . This material is treated with a chloroformate (such as 2-biphenyl methylochloroformate, 2-benzyl benzyl chloroformate, 2-naphthylmethyl chloroformate or 2-phenoxybenzyl chloroformate) and a tertiary amine base (as described in US Pat. sopropi leti lamina) in an aprotic solvent (such as methylene chloride) to provide compound 4 of scheme 2A.

ESQUE A 3 2 -. R5A A. W. NHNHs a) Boca0, Et3N, THF; b) hydrazine hydrate, MeOH; c) Et03CCOCl, Pyridine, CHaCl3; d) Lawesson reagent, toluene; e) TFA, CHa-Clg .; f) DCOaH.EDC-HCl / HOBT, Et3N, DMF.

The compounds of formula II, wherein X and Y = N and Z = S, can conveniently be prepared by methods analogous to those described in scheme 3. Compound 1 of scheme 3 is treated with di-butyl dicarbonate and triethylamine in THF to provide compound 2 of scheme 3. This material is treated with hydrazine hydrate in methanol to provide compound 3 of scheme 3. Hydrazine is acylated by treatment with ethylene chloride and pyridine in dichloromethane to provide compound 4 of scheme 3. This material becomes in thiadiazole »compound 5 of scheme 3, by treatment with Lawesson's reagent in an aprotic solvent (such as THF or toluene). Compound 5 of scheme 3 is treated with THF to provide compound 6 of scheme 3. This material is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as BOP, EDC-HC1 / 1-H0BT or N-methylmorpholyl isobutyl oroformate) in an aprotic solvent (such as dichloromethane, DMF or THF) to yield compound 7 of scheme 3.

SCHEME 4 BocHN] f a) SOCljg, pyridine, Etaa, toluene; b > TFA, CHaCla; c) DCOaH, EDC-HC1 / H0BT, EtaN, DMF; d) NH3, EtOH. The compounds of formula II, wherein X and Y = N and Z = 0 and W = COaEt or CONHa, can be conveniently prepared by methods analogous to those described in scheme 4. Compound 1 of scheme 4 is treated with chloride of thionyl and pyridine in ether, followed by reflux in toluene to provide compound 2 of scheme 4. The resulting oleate is treated with TFA to provide compound 3 of scheme 4. This material is treated with a carbohydrate acid. "lico" (such as N-Cbz-L-1euci a) and a peptide coupling reagent (such as BOP, EDC-HCl / l-HOBT or N-meti Imorfol a / isobutyl eloroformi) in an aprotic solvent ( such as dichloromethane, DMF or THF) to produce compound 4 of scheme 4. The carbo-yl ester is treated with ammonia in methanol to yield compound 5 of scheme 4.

SCHEME 5 s 0 K II) -8 a) EDC-HCl / HOBT, Et 3 N, DMF; b) HaNNHa-HaO, MeOH; C) CSCla, Et, fN, CHCl 3.

The compounds of formula II, wherein X and Y = N and Z = 0 and W = SH, can conveniently be prepared by methods analogous to those described in scheme 5. Compounds 1 and 5 of scheme 5 are treated with a reagent of peptide coupling (such as BOP, EDC-HC1 / 1-H0BT or N-ethylmorphine / isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMF or THF) to produce compound 3 of scheme 5. This material is treated with hydrazine hydrate in methanol to provide compound 4 of scheme 5. Treatment of compound 4 of scheme 5 with thiophosgene and triethylamine in chloroform provides compound 5 of scheme 5.

ESQ M G a) HaNCSaNHV, EtOH, "b> HaNCSNHa» EtOH.

The compounds of formula II, wherein X = CH »Y = S and Z = N and W = SH or NHa, can conveniently be prepared by methods analogous to those described in scheme 6. The condensation of compound 1 of scheme 6 with Ammonium thiocarbamate in ethanol yields compound 2 of scheme 6. Alternatively, compound 1 of scheme 6 can be condensed with thiourea in ethanol to give compound 3 of scheme 6.

SCHEME 7 a) EtaN0; b) HaNCHaCH (NHa) COaH.

The compounds of formula II, wherein X = CH, Y = N and Z = N and W = C »can be prepared by analogous methods to those described in scheme 7. Treatment of compound 1 of scheme 7 with N-or The diethyl sheet should provide compound 2 of scheme 7. The condensation of compound 2 of scheme 7 with 2,3-diaminocarbo acid? The compound should then provide compound 3 of scheme 7, which can be converted to various carbo-fatty acid derivatives using the procedures described above in other schemes. The compounds of the formula III can generally be prepared by methods known in the art of organic chemistry for coupling carbo-ioic acid derivatives with hydrazine. Schemes 8, 9 and 10 illustrate a method for preparing compounds, wherein B or E is a heterocyclic. The compounds of formula X can be conveniently prepared by methods analogous to those described in Schemes B. 9 and 19-23.

SCHEME 9 LCO, H «. L? ^ », -J" * ^? L C N C0-Et a) i. 1-BuOCOCl, NMM, THF; ii. CHANa, Eta0; b) HBr, AcOH, Eta0! c) HaNCSCOaEt, EtOH; d) R * »NHNHa, EtOH; e) R «ßCOaH, EDC-HC1, 1-HOBT, DMF.

The compounds where X = CH. Y = S and Z = N 'are prepared by methods analogous to those described in scheme 22. Compound 1 of scheme B is treated with isobutyl chloroformate and N-methylmorpholine in ether to give an anhydride which is treated with diazomethane in ether to provide compound 2 of Scheme B. Diazoketone is halogenated using 30% HBr in acetic acid in ether solution to provide compound 3 of Scheme 8. This material is treated with ethyl thioamide in ethanol a reflux to give compound 4 of scheme 8. The carbo-thiazole ester of thiazole is treated with a hydrazine (such as hydrazine onohydrate or methyl hydrazine) in ethanol to yield compound 5 of Scheme B. This material is treated with a carbohydrate ? ilico (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as EDC-HC1 / 1-H0BT) in an aprotic solvent (such as DMF) to provide compound 6 of scheme 8.

Compounds where X = S, Y = CH and Z = N, are prepared by methods analogous to those described in scheme 9.

SCHEME 9 6 (J = CO, S02) a) -BuOCOCl. NMM, HV, THF; b) Lawesson reagent, THF; c) i. EtOAcCOCHaBr; ii. TFAA, Py, CHaCla; d) HaNNHa-HaO, EtOH; e) R- «SOaCl» Py »CHaCla; f) RßßCOaH »EDC-HC1, 1-HOBT, DMF. Compound 1 of scheme 9 is converted to compound 2 of scheme 9 by treatment with isobutyl chloroformate »N-methylmorpholine and ammonia in THF. Compound 2 of scheme 9 is treated with Lawesson's reagent in THF to provide the thioamide 3 of scheme 9. This material is converted to thiazole by condensation with an α-keto ester followed by treatment with trifluoroacetic anhydride and pyridine in methylene chloride for producing compound 4 of scheme 21 which is converted to compound 5 of scheme 9 by treatment with hydrazine monohydrate. This material is treated with a sulfonyl chloride (such as 4-phene-ibenesulfonyl chloride) and pyridine in an aprotic solvent (such as dichloromethane) to provide compound 6 of scheme 9. Alternatively, compound 6 of scheme 9 can prepared by treatment with a carboxylic acid (such as N-benzylocarbon 1-L-leucine »N-benzyloxycarbon 1-N-methyl-1-L-leucine, N- (2-pyridi-ni Imeto? icarboni 1) -L-leucine, N- (3-pyridi "imetatocarbonyl) -L-leucine, N- (4-pyridine lmetocarboni 1) -L-leucine, 4-biphenacetic acid, 3-phenyl acid - (4-pyridinium Imeto?) Benzoic acid or 4-methyl-2- (4-phenylisphenyl) pentanoic acid) and a peptide coupling reagent (such as EDC-HC1 / 1-H0BT) in an aprotic solvent (such as DMF). R »N \ / \ / || | The compounds wherein B = 0 RAβ are prepared by routine methods of peptide synthesis, as illustrated for example in scheme 10.

SCHEME 10 a) EDC-HC1, HOBT, DMF; b) HaNNHa-HaO, EtOH; c) R ^ -B-COj-H, EDC-HCL, HOBT, DMF. Treatment of a mixture of compounds 1 and 2 of scheme 10 with a peptide coupling reagent (such as BOP or EDC-HCl / l-HOBT) in an aprotic solvent (such as DMF or dichloromethane) provides compound 3 of the scheme 10. This material is treated with hydrazine hydrate in ethanol to produce compound 4 of scheme 10, which is treated with a carboxylic acid (such as N-Cbz-L-1 eucine) and a peptide coupling reagent ( such as BOP or EDC-HC1 / 1-H0BT) in an aprotic solvent (such as DMF or dichloromethane) to provide compound 5 of scheme 10.

The compounds of the formula IV, wherein Raa, Raa, R * - * are H and R * "- = R * ßr are prepared by analogous methods to those described in scheme 11.

SCHEME 11 a) EDC-HC1, 1-HOBT, DMF, Symmetric compounds of formula IX having RCO as a terminal substituent on both sides, are prepared by methods analogous to those described in scheme 11. The treatment of compound 1 of scheme 11 with a carboxylic acid (such as 4-biphenylacetic acid or 4-methi 1-2- (4-phenyi-Ieni-1) pentanoic acid) and a peptide coupling reagent (such as EDC-HCl / 1-HOBT) in a aprotic solvent (such as DMF), provides compound 2 of scheme ll.

The non-symmetrical compounds of the formula IX, and the compounds of the formula IV, wherein Rza, R23, R * - »and R2B are H and Ra4- = R26, are prepared by methods analogous to those described in scheme 12.

SCHEME 12 H R CO-R > R CONHNH, -? // c > 9 (F = COR52, S09R52) a) HaNNHa-HaO, MeOHJ b) ClaCO »PhMe; c) HaNNHa-HaO, MeOH; d) R ** ßCOaH, EDC-HCl. 1-HOBT, DMF; e) Rß * SOaCl or RßseCOCl, pyridine, DMF; f) Rß5 »COaCORßsl; g) Rß *; CONRßa-NHa.

Treatment of Compound 1 of Scheme 12 with hydrazine hydrate in a protic solvent (such as methanol or ethanol) provides Compound 2 of Scheme 12, which is treated with phosgene in toluene to yield Compound 3 of Scheme 12. This material is treated with hydrazine hydrate in a protic solvent (such as methanol or ethanol) to provide Compound 4 of Scheme 12. The treatment of Compound 4 of Scheme 12 with a sulfonyl chloride (such as 4-phenoyl chloride) Isulfon lo), an acid chloride (such as benzoyl chloride), or a carbamoyl chloride (such as N- (2-methyl-1-propyl) - - (4-phen Ifeni 1) carbamoyl chloride) and pyridine in DMF produce the Compound 5 of Scheme 12. Alternatively, Compound 5 of Scheme 12 can be prepared by treating Compound 4 of Scheme 12 with a carbohydric acid (such as N-benzylocarbonyl-L-alanine, N-benzyl? icarbo il-L-proline, N-benzyl icarboni lgl icine, acid (S) -N-benzylcarbaryl 1-2-aminobutyric acid, N-benzyl icarbonyl 1-N-methyl 1-L -leucine, N-tei-buto? icarboni 1-N-meti 1-Ll eucine, N-acetyl-L-leucine, N-acet 1-L-alanine, N- (2-pyridinium-1-methocarboxy 1) -L -leucine, N-C4- (N, N-dimeti laminometi 1 >benzylocarbonyl 3-L-leucine, 4-phenylene-benzoic acid, 4-methoxy-benzoic acid, 4-phenoxy benzoic acid, 4- (N »N-dimethylaminomethyl) benzoic acid. 4-Hydroxyl-3-CN- (4-morfol nometi 1) benzoic acid, 3-CN- (4-morphyl inomethyl) Ubenzoic acid. 2-benzyl, benzoic acid, 3-benzyl-benzoic acid, 4-benzyl-benzoic acid, 4- (3-dimethylaminomethyl-lpropo-benzoic acid, 3-benzyl-5-methoxy acid) Ibenzoic acid, 3-benzyl-1, 4,5-dimethoxybenzoic acid, 3-benzyloxy-5-ethoxy benzoic acid, 3- (4-pyridinium Ito) benzoic acid, 4-biphenylacetic acid, 2- (4-phen-lphene? I) propionic or 4-methyl-2- (4-phenylephenyl) pentanoic acid) and a peptide coupling reagent (such as BOP, EDC-HCl / l-HOBT or N-me il orfolin / isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMF or THF). Compound 5 of Scheme 12 can also be prepared by treating Compound 4 of Scheme 12 with an anhydride (such as acetic anhydride). Alternatively, Compound 3 of Scheme 12 can be directly converted to Compound 5 of Scheme 1 by treatment with a hydrazide (such as 4-methylpentanoic acid 1 hydrazide or N-methyl-N-benzylocarbon l-L-leucine 1 hydrazide).

SCHEME 12A R21CONHNH2-? R21CONHNHCH2R a) i. PhCHO, EtOH; i i. BH3-THF; b) Cl aCO »PhMe c) HaNNHa-HaO, MeOH; d) Rß * COaH, EDC-HC1, 1-HOBT, DMF 5 e) RßzSOaCl or RßzCOCl, pyridine. DMF; f) Rßl! COaCORßíe.

The non-symmetric compounds of Formula IV. wherein Raa = H. are prepared by methods analogous to those described in scheme 12A. Compound 1 of Scheme 12A is treated with an aldehyde (such as benzaldehyde) in a protic solvent (such as ethanol). and the resulting imine is treated with borane-THF complex to produce Compound 2 of Scheme 12A which is subsequently treated with phosgene in toluene to produce Compound 3 of Scheme 12A. This material is treated with hydrazine hydrate in a protic solvent (such as methanol or ethanol) to provide Compound 4 of Scheme 12A. The treatment of Compound 4 of Scheme 12A with a carboxylic acid (such as N-benzylocarboni 1-L-leucine) and a peptide coupling reagent (such as BOP, EDC-HCl / l-HOBT or N-methyl) lmorfolia / isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMF or THF) yields Compound 5 of Scheme 12A.

The compounds of Formulas V-VII can conveniently be prepared by methods analogous to those described in Schemes 13 to 16.

SCHEME 3V3 a) HBTU. NMM. DMF; b) Jones reagent, acetone.

The 1,3-bis-amido propan-2-ones can be prepared by acylation of the 1,3-dia inopropan-2-ol 1 of Scheme 13 with a carboxylic acid 2 of Scheme 13 or a mixture of 2 different carboxylic acids (2 and 3) in equimolar amounts and a coupling reagent such as dialkyl carbod imide such as DCC or EDCl or HBTU / N-methyl orfolin. followed by oxidation of the carbinol to a ketone with an oxidant such as the Jones reagent.

SCHEME 14 a) NMM, DMF; b) Jones reagent, acetone, 1, 3-bis-sulfonamido propanones can be prepared by sulfonating the 1, 3-diamino-propan-2-ol 1 of Scheme 14 with a sulfonyl chloride 2 of Scheme 14 and a base such as N-methyl orfoli a. followed by oxidation of the carbinol to a ketone with an oxidant such as the Jones reagent.

SCHEME 15 a) EDCl. HOBT, DMF; b) NMM, DMF, 3) Jones reagent, acetone, The l-amido-3-sulfonamidopropanones can be prepared by acylation of the l, 3-amino-propan-2-ol 1 of Scheme 15 with a carboxylic acid 2 of Scheme 15 and a coupling reagent such as a carbodiimide or HBTU / N -methyl orfolone, followed by treatment with an appropriate sulfonyl chloride 3 of Scheme 15 and a base such as N-ethyl lmorphine. followed by oxidation of the carbinol to a ketone with an oxidant such as the Jones reagent.

SCHEME 16 The l-a-ido-3-sulfonamido alean-2-ones. which are larger than propan-2-one. such as butan-2-one or 5-methy1-he? an-2-one, can be prepared by converting an N-protected peptide such as Cbz-leu-leu-OH l from Scheme 16 into its bromine methyl ketone 3 of Scheme 16 by a diazo methyl ketone 2 of Scheme 16. Then, bromide 3 of Scheme 16 is displaced with sodium azide to give the corresponding azide 4 of Scheme 16. Reduction of the carbonyl with a reducing agent such as sodium borohydride. gives the alcohol 5 of Scheme 16. Subsequent reduction of the azide with a reducing agent such as 1,3-propanedithiol gives the free amine 6 of Scheme 16. The acylation or sulfonating of the amine gives the amide or sulfonamide 7 of the Scheme 16. Finally, the elimination of carbinol with an ingredient such as Jones's reagent gives the desired compounds.

The compounds of Formula VIII can conveniently be prepared using methods analogous to those of Schemes 17 and 18.

SCHEME 17 a) NaN3 »MeOH, Ha0; b) tosyl chloride »triethylamine, CHaCla; c) Ell an (3) dihydropyran resin, PPTS, Cl (CHa) aCi; d) PhCHaNHa, toluene, 80 ° C; e) HATU, N-methylmorpholine. NMP; f) HS (CHa) 3SH, MeOH, Et 3 N; g) Cbz-leucine (6). HBTU, N-ethylmorphol ina. NMP; h) TFA, CHaCla, MeaS; i) Jones reagent, acetone. The opening of the azide of glycidol 1 of the Scheme 17, followed by tosylation of the primary alcohol, gives tosylate 2 of Scheme 17, which was coupled to the Ellman polymer 3 of Scheme 17 »as described in J. Med. Chem. 1995» 38 »1427-1430 to produce the polymer 4 of Scheme 17, which was reacted with benzylamine in toluene and then washed haustily with various solvents. Then the azide was reduced with 3-propanedithiol in MeOH and triethylamine. and then thoroughly washed with various solvents. The coupling of Cbz-leucine 6 of Scheme 17 with diamine 5 of Scheme 17 with equimolar amounts and a coupling reagent such as dialkyl carbodi mide such as DCC or EDCl or HBTU / N-methylmorphol ina. The breaking of the ether bond with an alcohol was achieved with trifluoroacetic acid with several sweepers. Finally, the clearance of the carbinol in the ketone 7 of Scheme 17 with an ingredient such as Jones' reagent, allowed to obtain the desired final product.

SCHEME 19 a) 4-pyridyl methyl amine, isopropanol, at reflux; b) Cbz-leucine »HBTU» N-methylmorpholine, DMF; c) hydrazine, MeOH, at reflux; d) 2-di-benzofuransulfonyl chloride, N-methyl lmorphol ina, DMF; e) Jones reagent, acetone.

The N- (2 »3-epo? Ipropyl) ftal i imide l of Scheme IB (Aldrich) was refluxed with an amine such as 4-pyridyl methyl amine in isopropanol. The secondary amine 2 of Scheme 18 was then acylated with an acylating agent such as Cbz leucine or a sulfonating reagent such as 2-di-cyclophosphononyl chloride and a base such as N-methylmorpholine in DMF. The phthalimide was then removed with hydrazine in MeOH, and the resulting free amine was acylated with an acylating agent such as Cbz leucone or a sulfonylating reagent such as 2-dibenzofuransulfonyl chloride and a base such as N-ei. lmorfol ina in DMF. The compounds of Formula IX can conveniently be prepared using methods analogous to those of Schemes 19 and 20. The compounds of formula X can conveniently be prepared using methods analogous to those described in Schemes 21 to 27.

SCHEME 19 a) KOH. Me0H / H20; b) Rß * NHNHa. EtOH; C) EDC-HC1, 1-HOBT. DMF. The compounds wherein X = CH »Y = S» Z = N and R- = H »are prepared by methods analogous to those described in Scheme 19. The carbohydrate ether 1 of Scheme 19 is treated with a hydrogenated base (such as hydroxide of lithium »hydrogenated sodium or potassium hydroxide) in methanol / water to provide compound 2 of Scheme 19. Compound 3 of Scheme 19 is treated with a hydrazine (such as methy1 hydrazine) in a protic solvent (such as ethanol) to give Compound 4 of Scheme 19. Compounds 2 and 4 of Scheme 19 are coupled by treatment with a peptide coupling reagent (such as EDC- HCl / l-HOBT) in an aprotic solvent (such as DMF) to provide compound 5 of Scheme 19.

SCHEME 20 4. s a) Thiourea »EtOH; b) i. NaNO- .. HBr aqueous at 16%; ii. CuBr. HBr aqueous at 16X; iii. HBr (cat.) »EtOH; c) ArB (0H) a, PdíPPh.,).,.

CsF »DME; d) ArSnMe3 »Pd (PPh3) ^, PhMe; e) HaNNHa-Hao. EtOH; e) R CO-, H, EDC-HC1, HOBT, DMF.

Compounds wherein X = S, Y = CH, Z = N and V = 2-methoxyphenyl or 2-benzyloxygen are prepared by methods analogous to those described in scheme 20. Ethyl bromopyruvate (compound 1) of scheme 20) is treated with thiourea in refluxing ethanol to provide compound 2 of scheme 20, which is treated successively with sodium nitrite and copper (I) bromide in aqueous HBr at 16K, and the product is heated in ethanol with a catalytic amount of HBr to give compound 3 of scheme 20. The treatment of this material with an arylboronic acid (such as 2-benzyl? -arylboronic acid) »tetrakis (triphenyl Iosphine) pallet (0) and fluoride cesium in DME at reflux provides compound 4 of scheme 20. Alternately, compound 4 of scheme 20 can be prepared by treating compound 3 of scheme 20 with an arylstannane (such as 2-trimeti lestani lanisol) and tetrakis (triphenylphosphine). ) palladium (O) in toluene at reflux. Treatment of compound 4 of scheme 20 with hydrazine hydrate in ethanol provides compound 5 of scheme 20, which is treated with a carboxylic acid (such as N-benzyl? -carbonyl-N-methyl 1-L-leucine, N- (2-pyridinium methoxycarboni 1) -L-leucine, N- (3-pi ridini lmeto? icarboni 1) -Lucine or N- (4-pyridinium lmeto? -carbon 1) -L-leucine) and a peptide coupling reagent (such as EDC-HCl / l-HOBT) in an aprotic solvent (such as DMF) to provide compound 6 of scheme 20.

SCHEME 21 RCOCI RCONHR6 - ^ CH2NHRd7 - =? RCH2NR67CSNH2 - 1 2 2 4 s a) Rß- * NHa, Py, CHaCla; b) LiAlH ^, THF; c) i. ClaCS, Py, CHaCla; ii. NH3, MeOH or I. PhCONCS, CHC13; ii. KaC03, MeOH, Ha0; d) EtOaCCOCHaBr. EtOH ", e), EtOH, e) R * ßCOaH, EDC-HC1, 1-HOBT, DMF.

Compounds wherein X = S, Y = CH, Z = N and V = NR ** R «'7, are prepared by methods analogous to those described in scheme 21. An acid chloride (compound 1 of scheme 21) it is treated with a primary amine (such as 4-aminob-phenyl-1 or aniline) and pyridine in an aprotic solvent (such as methylene chloride) to provide compound 2 of scheme 21, which is treated with lithium-aluminum hydride in THF to produce compound 3 of scheme 25. Treatment of compound 3 of scheme 21 with thiophosgene and pyridine in methylene chloride, followed by treatment with ammonia in methanol, provides compound 4 of scheme 21. Alternatively, compound 4 of the scheme 21 can be prepared by treating compound 3 of scheme 21 with benzoyl isothiocyanate, followed by treatment of the intermediate benzoyl thiourea with potassium carbonate in methanol / water. Compound 4 of scheme 21 is treated with hydrazine hydrate in ethanol to give compound 5 of scheme 21. Treatment of compound 5 of scheme 21 with a carboxylic acid (such as N- (2-pyridinium lmetocarbonyl 1) - L-leucine, N- (3-pyridinium-1-methoxycarbom "1) -L-leucine or N- (4-pyridinium-lime-1-carbon-1) -L-leucine) and a peptide coupling reagent (such as EDC-HCl / l -HOBT) in an aprotic solvent (such as DMF), yields compound 6 of scheme 21.

SCHEME 22 L R65 N a) Ha. NHa.-H2O, EtOH; b) LCOaC02 ± -Bu, 200 ° c; c) Ha. Ha.-H3O, EtOH; d) R «ßCO.i? H. EDC-HC1. 1-HOBT. DMF.

The compounds where X and Y = N and Z = NH. are prepared by methods analogous to those described in scheme 26. Compound 1 of scheme 22 is treated with hydrazine hydrate in ethanol to give compound 2 of scheme 22, which is heated with a methyl anhydride to provide the thiazole 3 of scheme 22. This material is treated with hydrazine hydrate to provide compound 4 of scheme 22, which is treated with a carboxylic acid (such as N-benzylocarboxy 1-L-leucine) and a peptide coupling reagent (such as EDC-HCl / l-HOBT) in an aprotic solvent (such as DMF) to provide compound 5 of scheme 22. 3 (M = CO, S02) a) TFA; b) R «COaH. EDC-HC1. 1-HOBT, DMF; O RßjeSOaCl, v-Pr.?NEt.

The compounds where X = S, Y = CH »Z = N. L = CH (R **) RßoR * ß »where Rmm = Boc or Cbz or R« ß = CH (R ^ J R'-a- "'0, where R" 70 = Boc or Cbz »are prepared by methods analogous to those described in scheme 27. Compound 1 of scheme 23 is treated with trifluoroacetic acid to provide compound 2 of scheme 23. This material is treated with a carboxylic acid (such as pyrazinecarboxylic acid). isonicotinic acid »4-imidazole lactic acid or pipecolic acid) and a peptide coupling reagent (such as EDC-HCl / l-HOBT) in an aprotic solvent (such as DMF) to provide compound 3 of scheme 23. The compound 3 of scheme 23 can also be prepared by treating compound 2 of scheme 23 with a sulfonyl chloride (such as 2-pyridine sulfonyl chloride) and a tertiary amine base (such as diisopropyl leti sheet) in an aprotic solvent (such as methylene chloride.) Alternatively, the treatment of compound 4 of scheme 23 with trifluoroacetic acid pro see compound 5 of scheme 23.

SCHEME 24 a) EDCl, DMF; b) 2-PhCHa0PhS0aCl, NMM, DMF; c) TFA, DCM; d) 4-pyridylacetic acid, HBTU, NMM, DMF; e) Jones' reagent.

The l, 3-diamine or-propan-2-ol (or an N-alkyl substituted d-N-propanol) is coupled to a protected leucine analogue (Cbz- or Boc-) and another carboxylic acid or sulfonyl chloride. The removal of the protective group, followed by acylation or sulfonating, and oxidation of the alcohol, provides the desired compounds.

SCHEME 25 a) HBTU, NMM, DMF, allyl amine; b) mCPBA, DCM; c) MeNH,., isopropanol, 70 C; d) Cbz-leucine, EDCl »DMF; e) Jones reagent »acetone.

The N-allyl amine (or an N-alky1-N-alkylamine) is coupled to an innocuous Cbz-a (or sulfonized with an arylsulfonyl chloride), and then the alkene is epoxideized. with a peracid (or dimethyl dioo-irano). The epoxide is opened with a substituted amine and then the amine is acyl or sulfonyl ada. The final oration gives the desired ketones.

The starting materials used in the present invention are commercially available, or are prepared by routine methods well known to those skilled in the art, and can be found in common reference standards such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS. Vol. I-VI (published by Wi l e-Interscience). Coupling methods for forming amide bonds in the present invention are generally well known in the art. Peptide synthesis methods are generally described by Bodaneky and others. THE PRACTICE OF PEPTIDE SYNTHESIS »Springe - erlag. Berlin 19B4 *. E. Gross and J. Meienhofer. THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2a. ed. , Pierce Chemical Co .. RocKford, 111., 1984, are generally illustrative of the art, and are incorporated herein by reference. The synthesis methods that are used to prepare the compounds of this invention often use protecting groups to mask a reactive functional state or minimize inconvenient side reactions. Said protecting groups are generally described in Green, T.W., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley S Sons. New York (1981). The term "amino protecting groups" generally refers to the groups Boc, acetyl, benzoyl, Fmoc and Cbz "and derivatives thereof, as are known in the art. Methods of protection and deprotection, and the replacement of an amino group protecting group with another portion are well known in the art. The acid addition salts of the compounds of the formula I are prepared in a standard form in a suitable solvent from the original compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric. phosphoric »acetic» trifluoroacetic »maleic» succinic, methanesulfonic. Some of the compounds form internal salts or suteions which may be acceptable. The cationic salts are prepared by treating the original compound with an excess of an alkaline reagent such as a hydroxide. carbonate or alcó? ido "containing the appropriate cation; or with an appropriate organic amine. The cations such as Li *. Na *. K *. Ca * ~ *, Mg - * "* - and H ^ * are specific examples of cations present in pharmaceutically acceptable salts: halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates and sulfonates (such as mesylate), Examples of anions present in pharmaceutically acceptable salts This invention also provides a pharmaceutical composition comprising a compound according to formula I and a pharmaceutically acceptable carrier, diluent or excipient, Accordingly, the compounds of formula I can be used for The manufacture of a medicament The pharmaceutical compositions of the compounds of the formula I, prepared as described above, can be formulated as glyphosate solutions or powders for parenteral administration Powders can be reconstituted by the addition of a suitable diluent or other vehicle pharmaceutically acceptable before use.The liquid formulation can be a aqueous, isotonic and regulated in its pH. Examples of suitable diluents are normal isotonic saline, standard 5 * 4 saline solution in water, or sodium or ammonium acetate solution regulated at its pH. Said formulation is principal 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 convenient to add excipients such as polyvinylpyrrolidone, gelatin, hydrogel, acacia, polyethylene glycol, mannitol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds may be encapsulated, tabletted or prepared in an emulsion or syrup for oral administration. 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 sulphate di hydrate, terra alba, magnesium stearate or stearic acid, talc, pectin. acacia, agar or gelatin. Liquid vehicles include syrup, peanut oil »olive oil» saline solution and water. The vehicle may also include a sustained release material such as glyceryl monostearate or glyceryl distearate. alone or with a wax. The amount of solid vehicle varies but. preferably. it will be between about 20 mg to approximately 1 g per dose unit. Pharmaceutical preparations are made following conventional pharmacy techniques that include molded »mixing, granulation and compression» when necessary »for tablet forms; or grinding »mixing and filling for gelatin hard 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 orally, or it can be filled in 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 into a suppository.

UTILITY OF THE PRESENT INVENTION The compounds of the formula I are used as protease inhibitors "particularly as inhibitors of cysteine and serine proteases" more particularly as inhibitors of cysteine proteases. even more particularly as inhibitors of cysteine proteases of the papain superfamily »even more particularly as inhibitors of cysteine proteases of the cathepsin family. more particularly as inhibitors of cathepsin K. The present invention also provides compositions and formulations of such compounds "including compositions and pharmaceutical formulations of said compounds. The present compounds are useful for treating diseases in which cysteine proteases are implicated including infections by Pneumocystis cari ni i, Trypanoma cruzi. Trypanosoma brucei and Chrit dia fusiculata; as well as schistosomiasis »malaria» tumor metastasis »metachromatic leukodystrophy» muscular dystrophy, amitrophy; and especially diseases in which cathepsin K is involved, more particularly diseases of excessive loss of bone or cartilage, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; malignant hypercalcemia »and metabolic bone disease. Neoplastic metastatic cells also typically express high levels of protease enzymes! Policies that degrade the surrounding matrix "and certain tumors and metastatic neoplasms can be effectively treated with the compounds of this invention. The present invention also provides methods for treating diseases caused by pathological levels of proteases, particularly cysteine and serine protease, more particularly cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily »even more particularly cysteine proteasee of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, more particularly a human in need thereof, a compound of the present invention. The present invention provides especially methods for treating diseases caused by cathepsin K pathological conditions which methods comprise administering to an animal, particularly a mammal »more particularly a human in need thereof, a cathepsin K inhibitor» including a compound of the present invention. The present invention particularly provides methods for treating diseases in which cysteine proteases are involved, including Pneumocystis carinii infections. Trypanoma cruzi. Trypanosoma brucei and Chritidia fusiculata; as well as esquietoeomiasis »malaria» etástaeie tumoral »metachromatic leucodietrophy» muscular dystrophy, amitrophy; and especially diseases in which cathepsin K is involved, more particularly diseases of excessive loss of bone or cartilage, including osteoporosis. gingival disease including gingivitis and periodontitis »arthritis» more specifically »osteoarthritis and rheumatoid arthritis» Paget's disease »malignant hypercalcemia and metabolic bone disease. This invention further provides a method for treating osteoporosis or inhibiting bone loss, which comprises the internal administration to a patient of an effective amount of a compound of formula I alone or in combination with other bone resorption inhibitors. »Such as bisphosphonates (ie» alendronate) »hormone replacement therapy, antiestrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent such as bone morphogenic protein, hiproflavone, 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 5% enantioste compound in water or normal saline, or a similar formulation with suitable excipients, is more effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be from about 0.01 to approximately 100 mg / kg; preferably between 0.1 and 20 mg / kg, in order to maintain the concentration of the drug in the plasma at a concentration effective to inhibit cathepsin K. Compounds are administered one to four times a day at a level to achieve a total daily dose from about 0.4 to about 400 mg / kg / day. The precise amount of a novel compound that is therapeutically effective, and the route by which said compound is best administered, are easily determined by any expert in the art comparing the level of people in blood to the concentration required to have a therapeutic effect. The compounds of this invention can also be administered orally to the patient, such that the concentration of the drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as described in the present invention. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of from about 0 to about 50 mg / kg in a manner consistent with the patient's condition. Preferably, the oral dose would be from about 0.5 to about 20 mg / kg. No unacceptable toxicological effect would be expected when the compounds of the present invention are administered in accordance therewith.

PR EB 3I0 QSICAS The compounds of this invention can be tested in one of several biological tests to determine the concentration of the compound that is required to have a given pharmacological effect.

Determination of the catalytic activity proteo! cathepsin K test All cathepsin K tests were carried out with recombinant human enzyme. Normal test conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 M sodium acetate at pH 5.5 containing cysteine at 20 mM and EDTA at 5 mM . Substrate supply solutions were prepared at concentrations of 10 or 20 M in DMSO with a final substrate concentration of 20 μM in the tests. All tests contained 10X DMSO. By means of independent experiments, it was found that this level of DMSO had no effect on the activity of the enzyme or 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 Citofluor II from Perceptive Biosystems. Product development curves were obtained for 20 to 30 minutes after the formation of the AMC product.

Inhibition studies Potential inhibitors were evaluated using the curve-in-progress method. Tests were carried out in the presence of varying concentrations of the test compound. Reactions were initiated by the addition of enzyme to solutions regulated at their pH of inhibitor and substrate. The data analysis was carried out according to one of two procedures "depending on the appearance of the progress curves in the presence of inhibitors. For those compounds whose progression curves were linear, inhibition constants K < pß | S,) apparent in accordance with equation 1 (Brandt et al. »Biochemi tsry, 19B9, 28, 140): V = V," A / CK. (1 + 1 / KH, .., _ ,, + AD (1) where v is the velocity of the reaction with minimum velocity V. ,, A is the concentration of the substrate with Michael's constant ia of K, the concentration of the inhibitor. whose progress curves showed downward curvature characteristic of time-dependent inhibition, the individual co-data were analyzed to give Kßteß according to equation 2: L "AMC3 = v..t + (v0-v ..) Cl -e? p (-Kßt > .t)] / kob. (2) where CAMC3 is the concentration of the product formed with time t, v0 is the initial rate of reaction and v is the final velocity of the steady state. The kotoß values were then analyzed as a linear function of the concentration of the inhibitor to generate a second order apparent velocity constant (ks. / Inhibitor concentration). or kotom / CI3 that describes the time-dependent inhibition. A full discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol, Relat.Areas Mol. Biol. 19BS 61. 201).

Resorption test of human osteoclas oß Aliquots of osteoclast-derived cell suspensions were removed from storage in liquid nitrogen, heated rapidly to 37 ° C. and washed once 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. it was diluted 1: 3 in RPMI-1640 medium. and incubated for 30 minutes on ice. The cell suspension was mixed frequently. The cells were washed twice with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4 ° C) and then transferred to a 15 ml sterile centrifuge tube.

The number of mononuclear cells was enumerated in an improved Neubauer counting chamber. A sufficient number of magnetic spheres (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their storage bottle, and placed in 5 ml of fresh medium (this eliminates the preservative of toxic azide). The medium was removed by immobilizing the spheres on a magnet, and placed 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 spheron-coated cells were immobilized on a magnet, and the remaining cells (osteoclast-rich fraction) were decanted into a 50 ml sterile centrifuge tube. Fresh medium was added to the spider-coated cells to dislodge the trapped osteoclasts. This washing procedure was repeated 10 times. The spheres coated cells were discarded. Osteoclasts were enumerated in a counting chamber, using a large inner diameter disposable plastic pasteur pipette to charge the chamber with the sample.

The cells were transformed into pellets by centrifugation, and the density of the osteoclasts was adjusted to 1.5? 10-Vml in EMEM medium. supplemented with fetal calf serum at 10% and 1.7 g / liter of sodium bicarbonate. Aliquots of 3 ml were decanted from the cell suspension (by treatment) into 15 ml centrifuge tubes. These cells were traneformed into pellets by centrifugation. To each tube, 3 ml of the appropriate treatment was added (diluted to 50 μM in the EMEM medium). Appropriate vehicle controls were also included »a positive control (B7MEM I diluted to 100 μg / ml) and an isotope control (IgG2a diluted to 100 μg / ml). The tubes were incubated at 37 ° C for 30 minutes. 0.5 ml aliquots were seeded from sterile dentine cells in a 48-well plate and incubated at 37 ° C for 2 hours. Each treatment was performed in quadruplicate. The slices were washed in six hot PBS changes (0 ml / well in a 6-well plate), and then placed in fresh treatment or control, and incubated at 37 ° C for 48 hours. The sections were then washed in pH-regulated saline with phosphate and fixed in 2% glutaraldehyde (in sodium cacodylate at 0.2M) for 5 minutes, after which they were washed in water and incubated in water. pH regulator for 5 minutes at 37 ° C. The slices were then washed in cold water, and incubated in cold acetate acetate / red garnet buffer for 5 minutes at 4 ° C. The pH regulator was exhausted and the cuts were air-dried after washing in water.

The TRAP positive osteoclasts were enumerated by bright field microscopy. and then removed from the surface of the dentin by sound treatment. The volume of the cavities was determined using the confocal microscope and ILM21W from Nikon / Lasertec. gen rali ades Nuclear magnetic resonance spectra were recorded at 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDCl ^ is deuterterioch orm. DMSO-dβ is sulphonated from he? Adeuteriodimet 1 »and CD3OD is tetradeuterio ethanol. The chemical changes are reported in parts per million (d) from the tetramethyl if internal standard. The abbreviations for the NMR data are the following: s = single band »d = doublet. t = triplet »q = quartet» m = mul tipleto »dd = doublet of doublets» dt = doublet of triplets »app = apparent» br = wide. J indicates the NMR coupling constant measured in Hertz. Continuous infrared (IR) wave spectra were recorded on a Perkin-Elmer 6B3 infrared spectrometer and the Fourier transform infrared (FTIR) spectra were recorded on a Nicolet I pact 400 D infrared spectrometer. IR and FTIR were recorded in transmission mode, and band positions are reported in reverse wave numbers (cm- *). The mass spectra were taken on VG 70 FE instruments. PE Sy? API III or VG ZAB HF. using techniques of fast atom bombardment (FAB) or ionization by electrospray (ES). Elemental analyzes were obtained using a Perkin-Elmer elemental analyzer 240C. The melting points were measured in a Tho as-Hoover melting point determination apparatus and were not corrected. All temperatures were reported in degrees Celsios. Silica gel thin film plates were used 60 F-254 from E. Merck and from Analtech GF silica gel for thin layer chromatography. Flash and flash chromatography was carried out on silica gel Kieselgel 60 of E. Merck (230-400 mesh). Where indicated, some of the materials were purchased from Aldrich Chemical Co. »Milwaukee» Wisconsin. Chemical Dynamics Corp .. South Plainfield, New Jersey and Advanced Chemtech, Louisville, Kentuchy.

EJ M IQS In the following synthesis examples, the temperature is given in degrees centigrade < ° C). Unless otherwise indicated, all starting materials were obtained from commercial sources. Without further elaboration, it is clear that any expert in the art can, using the above description, utilize the present invention to the fullest extent. These examples are given to illustrate the invention, 9B and not to limit its scope. Reference is made to the indications, which are reserved for the inventors.

EXAMPLE 1 Preparation of (2S.l-S) -Z- (benzyloxycarbonyl) amino-N-Cl '- (2-carboethoxythiazo1-4-yl) -3t-p > eti1buti13-4-n, et? lPsntana. *. ida a) N-benzylcarbonyl l-L-leucine l-L-leucine 1 bromomethyl Iceone 1-methy1-3-nitro-l-ni troeoguanidine (5.9 g, 40.11 mmol) in ether (200 ml) is cooled to 0 ° C. Slowly add potassium hydroxide to 40%. and the diazomethane is collected in the ether solution for 30 minutes at 0 ° C. N-Cbz-L-leucinyl-L-leucine (Bachem) (4.0 g, 10.58 mmol) is stirred in tetrahydrofuran at -40 ° C. N-methyl lmorphol ina (1.07 g, 10.58 mmol) is added. 1.16 ml) and isobutyl chloroformate (1.45 g, 10.58 mmol, 1.38 ml). The mixture is stirred at -40 ° C for 15 minutes, and then filtered in a cold flask to remove the precipitated salts. To the filtered solution is added an evolution of the diazomethane solution previously prepared, and the mixture is allowed to stand at 0 ° C for 16 hours. An amount of 30% HBr in acetic acid is added at 0 ° C and the solution is subsequently washed successively with citric acid at 1.0N. saturated aqueous sodium bicarbonate (carefully), and brine. The solution is dried over sodium sulfate, filtered and evaporated to give the title compound as a white solid (4.10 g) XH NMR (400 MHz »CDC1.) Or 7.34 (m, 5H), 6.51 (d, 1H), 5.15 (d, 1H), 5.10 (S, 2H), 4.78 (m, 1H), 4.20 (m, 1H), 4.04 (dd, 2H), 1.63 (m, 6H), 0.93 (, 12H) . b) (2S, 1S) -2- (benzylcarboni 1) amino-N-Cl '- (2-carboetho-itiazol-4-l) -3'-methyl-l-butyl-13-4-methylpentanamide The compound of the example Ka) (2.0 g, 4.4 mmol) and ethyl thio? Amato (0.59 g »4.4 mmol) were refluxed in ethanol for 4 hours. The solvent was evaporated and the residue chromatographed (silica gel »methanol / dichloromethane at 2.5%) to give the title compound as a white solid (1.46 g). AH NMR (400 MHz, CDC1 ,,,) at 7.32 (s. 1H), 7.21 < m »5H)» 6.40 (d, 1H), 5.13 (dd, 1H). 5.02 (S, 2H). 4.41 (q, 2H), 4.06 (m, 1H), 1.71 (m, 2H), 1.47 (m, 4H), 1.33 (t, 3H), 0.73 (m, 12H).

E LO 2 Preparation of (ZS, l'S) -2- (benz loxycarboni 1) am no-N-Cl-- < 2- carboxythiazol-4-yl) -3'-met? Mbuti13 4-methypentanamide The compound of example 1 (c) (0.92 g »1.88 mmol) was stirred in tetrahydrofuran at 0 ° C with sodium hydroxide at 1.0N. After stirring for 1 hour, the solution was warmed with citric acid at 1.0N. and it was brought three times with dichloromethane. The combined organic extracts were evaporated in vacuo to give the title compound as a white solid (0.844 g). * H NMR (400 MHz, CDC1-,.) And 7.40 (s, 1H), 7.23 (m, 5H), 6.89 (d, 1H), 5.22 (d.1H), 5.14 (dd.1H), 5.02 ( S, 2H), 4.15 (m, 1H), 1.67 (m, 2H), 1.44 (m, 4H), 0.81 (m, 12H).

EXAMPLE 3 Preparation of < 2S.l'S) -Z- (benz loxycarbon 1) ami no-N-Cl '- (2- carboxart.idothiazol-4-i 1) -3'-met lbuti 13-4-methypentanamide The compound of Example 2 (0.408 g, 0.88 mmol) in tetrahydrofuran was cooled to -40 ° C, and treated with N-methyl lmorfolin (0.185 g, 1.B5 mmol, 0.2 ml) and isobutyl chloroformate (0.12 g). 0.88 mmol, 0.11 ml). The mixture was stirred at -40 ° C for 15 minutes, and then ammonia was bubbled through the solution for several minutes. The mixture was allowed to warm to room temperature, and was then diluted with ethyl acetate, and washed successively with 1 L citric acid. 5% aqueous sodium bicarbonate and brine. The organic solution was dried over magnesium sulfate, filtered and evaporated to a residue which was chromatographed (silica gel »methanol / 3% dichloromethane) to give the title compound as a white solid (0.245 g). AH NMR (400 MHz. CDC13) or 7.22 (m, 5H). 7.04 (s, 1H), 6.40 (br s, 1H). 5.51 (br. 1H), 5.09 (m.H.). 5.02 (dd, 2H), 4.07 (m, 1H). 1.66-1.42 (m, 6H), 0.82 (m, 12H).

E EMPIP Preparation of (ZS.l-S) -Z- (benzyloxycarboryl) amino-N-Cl '- (2-cyanothiazol-4-yl) -3t-methyl 1 but l 3-4-methylpentane »ida The compound of Example 3 (0.185 g, 0.4 mmol) was dissolved in dichloromethane, cooled to 0 ° C and treated with TFAA (0.093 g, 0.44 mmol, 0.06 mL) and pyridine (0.07 g, 0.88 mmol, 0.07 mL). . After 3 hours, the mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were washed with hydrochloric acid at 5% and brine, dried over magnesium sulfate, filtered and evaporated to an oil which was chromatographed (silica gel, ethyl acetate and sodium acetate). 40%) to give the title compound as a white solid (0.095 g). XH NMR (400 MHz, CDCl-j.) Or 1.AA (S, 1H), 7.29 (s, 5H>, 6.51 (br d, 1H), 5.14 (m, 1H), 5.07 (ß, 2H) , 4.11 (m, 1H), 1.78-1.41 (m, 6H), 0.83 (m, 12H).

E EMPLQ 5 Preparation of (ZS-lS) -2- (benzyloxycarboni lo) amnot-N-Cl - C2- (N-benzylcarboxamido) thiazole-4-i13-3'-methylbutyl3-4-ij lpe ami? To a solution of the compound of Example 2 (0.12 g, 0.26 mmol) in dichloromethane under argon at room temperature is added benzylamine (0.03 g, 0.29 mmol, 0.03 ml), BOP reagent (0.115 g, 0.26 mmol, and triethylamine (0.026 g. 0.26 mmol »0.04 ml) which was stirred for 16 hours, the solution was washed with water and then with brine and the organic layer was dried over magnesium eulfate, filtered and evaporated to give a residue which was chromatographed ( silica gel, ethyl acetate / water at 40%) to give the title compound as a white solid (0.065 g), AH NMR (400 MHz, CDC13) or 7.56 (br e, 1H), 7.33 (m 10H), 6.4B (1H), 5.15 (dd, 1H), 5.03 (s, 2H). 4.63 (d, 2H), 4.12 (m, 1H), 1.72-1.40 (m, 6H), 0.85 (m, 12H).

AXIS LO 5 Preparation of (2S.l'S) -2- (benzylcarbonyl) amino-N-Cl'-C2-CN- (3-methanepropyl) carboxamido3thiazole-4-i13-3 -methylbutyl 13-4- ipentanamide meti Following the procedure of example 5, e replacing benzylamine with isobutyl sheet, the title compound was prepared (0.074 g). X H NMR (400 MHz, CDC1, ") at 7.27 (s, 5H). 7.19 (S. 1H). 6.38 (rd.1H). 5.09 (.1H), 5.01 (8, 2H), 4.07 (m, 1H), 3.20 (dd, 2H), 1.83 (m, 1H), 1.69-1.40 (m, 6H), 0.90 (d.6H), 0.81 (m, 12H).

EXAMPLE 7 Preparation of (2S-lS) -Z- (benzyloxycarbon 1) for non-N-Cl'-C2-CN- (2-phen leti 1) carboxamido-3-thiazo-1-4-i13-3-methy1buti13-4- Ipentanamide Following the procedure of Example 5, except substituting benzyl for 2-phenol let, the title compound was prepared (0.070 g). ^ H NMR (40O MHz, CDC13) at 7.30-7.11 (m, 11H). 6.35 (br d »1H), 5.09 (m.H), 5.01 (s, 2H), 4.05 (m, 1H), 3.64 (m, 2H), 2.87 (t, 2H). 1.69-1.40 (m, 6H), 0.80 (m, 12H).

EXEMPL.Q 9 Preparation of (2S.l-S) -Z-benzyloxycarbon? 1) amino-N-Cl '- (4- carboethoxyt? Azo1-Z-i1) -3'-roeti-1-butyl 3-4-methylpipenamide a) N-tert-butoxycarbonyl- (L) -1eucineamide To a solution of N-tert-butoxycarbonyl- (L) -leucine (Advanced Chemtech) (5.0 g »20.0 mmol) in dry THF (100 g) mL) at -40 ° C was added isobutyl chloroformate (2.7 g, 20.0 mmoles) and N-raet lmorfi 1 ina (4.2 g, 42 mmoles). After 15 minutes of stirring, ammonia was bubbled through the mixture for an additional 15 minutes, then warmed to room temperature and allowed to stir for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound as a white solid (4.9 g, 19.7 mmol). NMR AH (400 MHz »CDC1..¡.) Or 6.38 (br s, 1H), 5.79 (br s, 1H), 5.04 < br d, 1H), 4.13 (m, 1H>, 1.71-1.49 (m, 3H), 1.39 (8, 9H), 0.92 (dd.6H). b) N-tert-butoxycarboni 1-L-leucintioa idß To a stirring solution of the compound of example 8 (a) (2.38 g »10.35 mmol) in dry THF was added Lawesson's reagent (2.51 g» 6.21 mmol) and the The mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the residue chromatographed (silica gel »2.5% methanol / dichloromethane) to give the title compound as a white solid (2.3 g). NMR AH (400 MHz. CDC1 ,,) or 8.54 (br. 8, 1H) »7.97 (br S. 1H). 5.28 (br di 1H) »4.52 (, 1H), 1.72-1.58 (m.3H), 1.40 (S» 9H), 0.92 (d, 6H). c) (lS) -l- (er-butoxycarbon I) ara-ol- (4-carboethoxy-thiazole-2-yl) -3-raeti-1-butane The compound of Example B (b) (2.40 g, 9.76 mmol) was stirred in dry acetone (20 L) under argon at -10 ° C. Ethyl bromopyruvate (2.12 g, 10.73 mmol, 1.35 mL) was added and stirred for 1 h at -10 ° C. The solution was poured into a well-stirred mixture of chloroform and water, and then saturated with sodium bicarbonate. The organic phase was separated and the aqueous layer was extracted with chloroform. The combined organic extracts were dried over MgSO ", filtered and evaporated to an oil. The oily residue was treated with TFAA (2.19 g »10.73 mmol, 1.5 mL) and pyridine (1.70 g, 21.47 mmol, 1.75 mL) in dichloromethane for 1 h at -20 ° C. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate and 1.0 N KHSO ^ to pH 7. The solution was dried over sodium sulfate, filtered and evaporated to an oil which was chromatographed (4% methanol / dichloromethane) to give the title compound as a tan solid (1.2 g). NMR ^ H (400 MHz, CDC13) or 7.98 (s, 1H), 5.04 (br d.1H), 4.95 (m, 1H), 4.31 (q, 2H), 1.88 (m, 1H), 1.63 (m, 3H), 1.40 (S, 9H), 1.32 (t, 3H) »0.85 (dd.6H). d) (2S.l "S) -2- (benzyloxycarboni 1) arai or N-Cl * - (4-carboetho-itiazol-2-i 1> -3, -meti Ibuti 13-4-methypentanamide The compound of example 8 (c) (1.0 g »2.92 mmol) was dissolved in pure TFA (1.0 L) and stirred for 15 minutes The solution was diluted with methanol and evaporated in vacuo A portion of the obtained residue (0.36 g. 1.49 mmoles) the dichloromethane was dissolved with N-Cbz-L-leuc a (0.394 g, 1.49 mmoles) »BOP reagent (0.66 g» 1.49 mmoles) and triethylamine (0.73 g, 7.2 mmoles »1.0 mL) and stirred at The solution was washed with water, then with brine and dried over magnesium sulphate, filtered and evaporated to a residue which was chromatographed (silica gel) at 40% ethyl acetate / he? anus) to give the title compound as a white solid (0.396 g) .H NMR (400 MHz, CDC13) or 7.96 (s, 1H), 7.25 (s, 5H), 6.61 (br d, 1H), 5.30 ( m, 1H), 5.09 (br d, 1H), 5.01 (S, 2H), 4.33 (q, 2H), 4.10 (m, 1H), 1.90-1.58 (m, 6H ), 1.29 (t, 3H), 0.81 (dd, 12H).

EXAMPLE 9 Preparation of (ZS.l-S) -2- < benzyloxycarbonyl) amino-N-Cl - (4-carboxythiazol-Z-yl) -3t-met-1-butyl-4-y-Ipentanamide The title compound was prepared following the procedure of Example 2 »but substituting with (2S» 1 S) -2- (benzyloxycarbon) ami oN-Cl '- (4-carboetho-thiazol-2-yl) -3t-methylbutyl-4-methyl-Ipentanamide (2S.l'S) -2- (benzyloxycarboni 1 >amino-N-Cl '- (2-carboxy-thiazol-4-yl) -3'-methybutyl 13-4-methylpentanamide (0.301 g) .H NMR (400 MHz, CDC1, -) or 8.06 (s) , 1H), 7.24 Sm, 5H), 7.11 (d, 1H), 5.30 (m, 2H), 5.04 (s, 2H) »4.16 (m, 1H)» l.BB-1.40 (m, 6H), 0.71 (dd, 12H).

EJ IQ 10 Preparation of < 2S, l'S) -2- (penei loxicarbon l) a? Rnno-N-Cl'- < 'carboethoxythiazole-Z-1) -3'-meti I ut 13-4-methypentanamide a) Methyl ester of IV-ter butoxycarboni 1-L-leucine To a stirred suspension of L-leucine methyl ester hydrochloride (Aldrich) (6.00 g, 33.0 mmol) and di-tert-butyl dicarbonate (7.21 g) »33.0 mmol) in THF (35 mL) was added triethylamine (3.34 g, 33.0 mmol, 4.60 mL). The mixture was allowed to stir at room temperature for 3 d. The mixture was diluted with ethyl acetate and washed with IN HCl (twice), water and saturated brine, and then dried over sodium sulfate, filtered and concentrated to give the title compound as a colorless oil ( 8.02 g »99%). NMR AH (400 MHz »CDC13)? 4.B8 (d »1H), 4.33-4.31 (m, 1H), 7.73 (s, 3H), 1.75-1.48 (m, 3H), 1.44 8s, 9H), 0.96 (d, 3H), 0.93 (d , 3H). b) N-tert-butoxycarbonyl hydrazide 1-L-leucine To a stirred solution of the compound of example 10 (a) (8.02 g, 32.7 mmol) in methanol (250 mL) was added hydrazine hydrate (16.38 g, 327 g). mmol, 15.9 mL). After stirring for 22 h at room temperature, the solution was concentrated and the residue was azeotroped with toluene to provide the title compound as a white foam (8.02 g, 100%). NMR * H (400 MHZ, CDC1,) or 7.71 (br S, 1H), 4.99 (d, 2H), 4.12-4.10 (m.H.), 3.94 (br S, 2H), 1.68-1.49 (m, 3H), 1.44 (8 »9H), 0.95 (d. 3H)» 0.92 (d »3H). c > (2S) -N-CZ- (benzyloxyl-yl) amino-4-methyl-1-entanoyl-3-N'-carboethoxycarbonylhydrazine To a stirred solution of the compound of the example < b) (8.02 g, 32.7 mmol) and pyridine (2.85 g, 36.0 mol, 2.91 mL) in dichloromethane (200 mL) was added ethyl chloride or lo (4.91 g, 36.0 mmol), 4.02 mL). . After stirring at room temperature for 2 h, the solution was washed with IN HCl HCl, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated to give the title compound. as a white foam (9.84 g, 87%). NMR AH (400 MHz, CDC1 ,,) or 9.32 (br s, 2H), 5.04 (d, 2H), 4.38 (q, 2H), 4.28 (m, 1H), 1.77-1.56 (m, 3H), 1.44 (s, 9H), 1.39) t, 3H), 0.96 (d, 3H), 0.94 (d, 3H). d) (SS) -1- (tert-butoxycarboni 1) amino-1- (4-carboethoxy-thiadiazol-2-yl) -3-methyl-butane To a stirred solution of the compound of example 10 (c) (2.50 g) »7.24 mmoles) in toluene (70 L) was added Lawesson's reagent (1.46 g, 3.62 mmoles). The mixture was refluxed for 3 h. The solution was diluted with ether, washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated to leave a light yellow oil. The crude material was purified by flash chromatography on 75 g of 230-400 mesh silica gel, eluting with 1: 4 ethyl acetate / hexanes to provide the title compound as a light yellow solid (1.75 g, 70%). %). H NMR (400 MHz »CDC13) or 5.19 8m. 1 HOUR). 5.13 (d, 1H) »4.51 (q, 2H), 1.95 (m, 1H), 1.83-1.73 (m, 2H). 1.44 (s, 9H) »1.00 (d.3H), 0.98 (d.3H). e) Salt of biß-tr luoroacetate of (lS) -l-araino-l- (4-carboethoxythiadiazo-2-yl) -3-methyl-1-utane To a stirred solution of the compound of example 10 (d) ( 1.75 g »5.1 mmol) in dichloromethane (40 mL) was added TFA (10 mL) After stirring for 5 min at room temperature, the solution was concentrated to give the title compound co or an oily light yellow solid (2.40 g). 100%). NMR (400 MHz, CDCl, r) and 9.83 (br s, 4H), 5.20 (m, 1H), 4.51 (q, 2H), 2.07 (m, 2H), 1.70 8m, 1H), 1.448t, 1H), 1.00 (t, 3H). ) < 2S.l'S) -Z- (benzyloxycarbonyl> amino-N-Cl * - (4-carboethoxy-adiazol-2-yl) -3"-methylbutyl 3-4-methylpentanamide To a stirring solution of the composition of Example 10 (e) (566.1 mg »1.20 mmol), N-Cbz-L-leucine (250.5 mg, 1.32 mmol), l- < 3-dimeti laminopropy 1) -3-eti Icarbod mida hydrochloride (253.3 mg, 1.32 mmol ) and 1-hydro? ibenzotriazole (32.5 mg, 0.24 mmoles) in 2.5 L DMF was added triethylamine (243.1 mg, 2.40 mmole? 0.335 L) .After stirring at room temperature for 3 d, the mixture was diluted with ethyl acetate. ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated to give a yellow oil.The crude material was purified by flash chromatography on 20 g of ethyl acetate gel. silica of 230-400 mesh »eluting with 1: 2 ethyl acetate / hexanes to provide the title compound as a white solid (271 mg, 46%). NMR JH (400 MHz, CDC13) or 7.35 (S, 5H), 6.77 (d.1H), 5.12 (dd, 2H), 4.51 (q.2H), 4.20 (m, 1H), 1.97 (m, 1H) , 1.88 ßm, 1H), 1.66 (m, 3H), 1.52 8m, 1H), 1.45 (t, 3H), 0.97-0.92 (m, 12H).

JEM LO 3.1 Preparation of (ZS, l'S) -Z- (benzyloxycarbonyl) ami or N-Cl - (2-carbo-2.2, Z-trifluoroethoxythiazo1-4-i1) -3-methy1buti13-4-methygpg tanamide The compound of Example 2 (0.200 g, 0.433 mmole), r 1.1.1 trifluoroethanol (0.52 g, 0.52 mmole ».04 L), pyridine (0.1 mL) and di-t-butyl dicarbonate (0.104 g, 0.477 mmole) were stirred in ethyl acetate at room temperature for 16 h. The solution was diluted with ethyl acetate and washed successively with 5% hydrochloric acid, 10% aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to give a residue which was chromatographed (silica gel, 20% ethyl acetate / hexanes) to give the title compound as a white solid (0.98 g) . NMR AH (400 MHZ, CDC13) or 7.50 (s, 1H), 7.36 (8.5H), 6.64 (d.1H), 5.22 (m, 2H), 5.09 (s, 2H), 4.73 (m, 2H) , 4.168m, H), 1.66-1.41 8m, 6H), 0.87 (m, 12H).

EXAMPLE 12 Preparation of (2S, 1 »S) -Z- < enci loxicarboni 1 > ami no-N-Cl '- (4- carboethoxyoxadiazo1-Z-i1) -3-methy1butyl-3-4-methylpentanamide a) (lS) -l- (tert-butoxycarbon 1) am non-l- (4-carboethoxy-oxadiazole-Z-1) -3-methyl-1-butane To a stirred solution of the compound of example 10 (c) (250 g, 7.24 mmol) and pyridine (1.49 g, 18.8 mmol, 1.52 mL) in ether (15 mL) were added thionyl chloride (1.12 g, 9.41 mmol, 0.69 mL). After stirring at room temperature for 2 h. the solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in toluene and heated to reflux. After 12 h, the solution was concentrated to leave a brown oil. The residue was purified by flash chromatography on 175 g of 230-400 mesh silica gel, eluting with 1: 4 ethyl acetate / hexanes to give the title compound as a light yellow oil (0.84 g, 35%). NMR ^ -H (400 MHz, CDC1,.,) Or 5.14 8m, 1H), 5.03 (br d, 1H), 4.52 (q, 2H), 1.78-1.70 (m, 3H), 1.44 88, 9H), 0.99 (d, 6H). b > (lS) -l-amino-1- (4-carboethoxyoxadiazol-Z-yl) -3-methyl-1-butane The title compound was prepared following the procedure of Example 10 (e), but substituting (1S) -1- ( ter-buto? i? arbon 1) amino-l- (4-carboetho? io? adiazol-2-l) -3-methylbutane (lS) -l- (tert-buto? -carboni 1) amino-l- ( 4-carboetho? -thiadiazol-2-y1) -3-met-1-butane (582 mg, 100%). NMR AH (400 MHz, CDC13) or 4.99 (t, 1H), 4.52 (q, 2H), 2.10-2.02 (m, 2H), 1.77-1.70 (m, 1H), 1.44 (t. 3H) »1.00 ( t »6H). c) (2Stl "S) -2- (benzyloxycarbonyl) am no-N-Cl * - (4-carboethoxyoxadiazol-2-yl) -3'-methy1butyl-4-methopentane The title compound was prepared following the procedure of example 10 (f), but substituting (1S) -1-amino-1- (4-carboetho-io? -adiazol-2? 1) -3-me-1-butane with (1S) -1-amino-1 - (4-carboetho-thiadiazol-2-yl) -3-methylbutane (235 mg »39%). NMR '• H (400 MHz» CDC13) at 7.26 (S, 5H), 6.64 (8, 1H) , 5.45-5.39 (m.1H), 5.12 (m.3H) »4.52 (q, 2H)» 4.20 (m.1H) »1.81 8m, 2H), 1.68-1.64 (m.3H), 1.54-1.50 (m. M. 1H), 1.46 (t, 3H), 0.97-0.92 (m, 12H).

AXIS LO JL3 Preparation of (2S.lS) -2- (benzyloxycarbon 1-L-leucine 1) amino-N-Cl • - (4-carboethoxy-azol-2-y1) -3 * me lbutil 3-4-methyl-Ipentanamide Compound of Example B (c) (160.7 mg, 0.47 mmol) was dissolved in pure TFA (1.0 mL) and stirred for 15 minutes. The solution was diluted with methanol and evaporated to dryness. The residue was dissolved in DMF (2 mL) and to the resulting solution was added N-Cbz-L-leucine 1-L-leucine (194.0 mg, 0.52 mmol), l- (3-d met laminopropy 1) hydrochloride. 3-eti Icarbodi imide (99.0 mg, 0.52 mmol) and 1-hydro? Ibenzotriazole (13.0 mg, 0.094 mmol) and triethylamine (94.7 mg, 0.936 mmol, 0.13 mL). After stirring at room temperature for 24 h, the mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography of 230-400 mesh, eluting with ethyl acetate / henias to provide the title compound (0.146 g). NMR AH (400 MHz, CDC13) or 8.04 (S, 1H), 7.33 (m, 5H), 7.14 (d, 1H), 6.61 (d, 1H), 5.37 (m, 2H), 5.08 (m, 2H) , 4.47 (m, 1H), 4.39 (q, 2H). 4.18 (m.H.), 1.98-1.45 (m.H8), 1.38 (t, 3H), 0.94-0.86 (m, 18H).

EXAMPLE A4 Preparation of (ZS, ltS) -Z- (benzyloxycarboni 1) amino-N-Cl, - < 4- carboxamidooxadiazol-2-1) -3'met Ibut 13-4-methylpentanamide Ammonia was bubbled through a solution of the compound of Example 12 (96.8 mg »0.2 mmol) in ethanol (2 mL) for 5 minutes. After stirring an additional 5 minutes, the solution was concentrated to give the title compound as a white solid (91.2 mg, 98%). XH NMR (400 MHz. CDC13 / CD30D) < 5 7.29 (S, 5H), 5,900 < d. 1 HOUR ) . 5.30 (t.1H). 5.04 (s.2H) »4.15 (m.H). 1.76 (m.2H), 1.59-1.43 (m, 4H). 0.92-0.85 (m.12H).

EXAMPLE 5 Preparation of (2S, l-S) -2- (benzyloxycarbonyl) amino-N-Cl '- <2-carboethoxyt azo1-4-1) -3'-me Ibut 13-3- in Ipropanam gives a) N- (9-Luorenylmethoxycarbonyl) -L-1-echin-1-bromomethyl ketone The title compound was prepared following the procedure of the example Ka), but replacing with N- (9-fluoreni Imeto? Icarbon 1) -L-leucine the N-benc lo? Icarboni lL-leucini 1-L-leucine (5.6 g). NMR AH (400 MHZ »CDC1, H) or 7.71 (d.2H), 7.51 (d, 2H), 7.34 (dd.2H). 7.22 (dd, 2H), 5.08 (d, 1H), 4.53 (m, 1H), 4.36 (dd, 2H), 4.13 (dd, 2H), 3.89 (dd, 2H), 1.62 - 1.41 (m, 3H) , O.88 (m, 6H). b) (lS) -l- (2-carboetho-itiazo1-4-yl) -1- < 9- Luoreni 1-methoxycarbon l) araino-3-methy1butane The title compound was prepared following the procedure of Example Kb), but replacing N- (9-fluoreni lmeto-icarboni 1) -L-leucini-1-bromomethyl ketone N-benz locarboni lL-leucini lL-leucine 1 bromomethyl ketone (4.13 g). NMR AH (400 MHZ, CDCl--) or 7.72 (d, 2H), 7.49 (d, 2H), 7.32 (dd, 2H). 7.22 (dd, 2H), 7.19 (s.1H), 5.31 (d, 1H). 4.88 (m, 1H), 4.40 (q, 2H), 4.28 (d, 2H), 4.08 (t, 1H), 1.62-1.41 (m, 3H) »O. BB (m 6H). c) (iS) -l-araino-l- (2-carboethoxythiazo1-4-i1) -3-methobutane The compound of example 15 (b) (0.5 g.ll llmoles) was stirred in a 5% solution. of p pen * di na / DMF for 10 minutes at room temperature. The solvents were evaporated and the solid obtained was dried under vacuum to give the title compound (0.27 g). d) (ZS »1 * S) -Z- (benzyloxycarboni 1> amino-N-Cl '- (2-ca oetox thiazo1-4-1) -3" -raeti1 ut l3-3- in 1propanamide was prepared the title compound following the procedure of Example 5 »but substituting benzylamine with (lS) -l-amino-1- (carboetho-thiazole-4-1) -3-methyl butane, with N-Cbz-L-pheni 1a1 ani na (2S, 1 'S) -2- (benz 1 o? I carboni 1) ami no-N-ci' - (2-carbo? It azol-4- 1) -3'-metí Ibuti 1 -4-met Ipentanamide (0.162 g). NMR AH (400 MHz, CDC13) or 7.27 (m, 5H), 7.11 (s, 1H) (8, 1H), 7.04 (m, 5H), 6.12 (d, 1H), 5.24 (d, 1H, 5.10 ( q, 1H), 5.01 (8, 2H), 4.37 (q, 2H), 4.21 (m, 1H), 2.91 (m, 2H), 1.62 (m, 3H), 1.37 (t, 3H, 0. Bl < m, 6H).

EXAMPLE 3.6 Preparation of (2S, 1S) -2- (benzyloxycarbon 1-L-leucine 1) am o- N-Cl - (2-carboethoxythiazo1-4-i1) -3'-methy1 but 1 3-4-methyl ipentamide The title compound was prepared following the procedure of Example 5. but substituting (iS) -l-amino-1- (2-carboetho-thiazole-4-yl) -3-methyl-Ibutane with benzylamine and with N -Cbz-L-leucine 1-L-leucine the (2S.l'S) -2- (benzyloxycarbon? 1) ami or N-Cl r- (2-carbo? Tiazol-4-1) -3'-methy lbuti 13-4-methypentamide (0.098 g). NMR "-h (400 MHz, CDC13) or 7.39 (s, 1H), 7.25 (m, 5H), 6.87 (d.1H), 5.30 (d, 1H), 5.16 (q, 1H), 4.99 (s, 2H), 4.36 (q, 2H), 4.31 (rn, 1H), 1.74 - 1.3B (m, 9H), 1.32 (t, 3H), 0.80 (m, 15H).

EXAMPLE 3.7 Preparation of < 2S.1 »S) -2- (benzyloxy carboni 1) ami or N-Cl '(5- mercapto-l, 2,4-oxa azo1-3-i 1) -3-methy 1buti 13-4-methy Ipentanamide a) Methyl ester of N-benzyl? -carbonyl-L-leucine 1- L-leucine N-Cbz-L-leucine (Chemical Dynamics) (1.32 g. 4.97 mmole) »Methyl ester hydrochloride of L-leucine (Aldrich) (0.99 g »5.47 mmoles)» 1-hydroxy benzotriazole (0.14 g, 1.0 mmol) and 1- (3-dimet laminopropy 1) -3-ethylcarbodimide hydrochloride (1.05 g »5.47 mmol) were combined, dissolved in 25 mL of DMF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed successively with water, 0.1N HCl, saturated NaHCO, saturated aqueous and then brine (MgSO), filtered and concentrated. The residue was purified by 230-400 mesh silica gel chromatography eluting with 1: 3 ethyl acetate / hexanes to give the title compound as a white solid (1.28 g, 66%). NMR (400 MHZ, CDC13) or 7.37-7.32 (m, 5H), 6.28 (d »1H). 5.28 (m, 3H> »4.61-4.58 (m, 1H), 4.20 <m, 1H), 3.74 (s, 3H), 1.69-1.54 (m.6H), OR.96-0.92 (m, 12H) ). b > N-benzyloxycarboni 1-L-leucine 1-L-1-eucinylhydrazide To a stirred solution of the compound of Example 17 (a) (1.28 g, 3.26 mmol) in 25 mL of methanol was added hydrazine hydrate (1.63 g, 32.6 mmol. »1.58 mL) and the solution was allowed to stir at room temperature for 15 h. The solution was evaporated to dryness to give the title compound as a white solid (1.28 g »100%). NMR ^ -H (400 MHZ »CDC13) or 8.05 (br S» 1H), 7.35-7.32 < m »5H)» 6.67 (d, 1H), 5.50 (d.1H) »5.11 (S, 2H >, 4.46 (m, 1H), 4.21 (m, 1H), 3.88 (br S, 2H), 1.64 -1.51 (m, 6H, O.92-0, BB (m, 12H). c) (ZS.1 * S) -Z- (enci 1o? icarboni 1) am no-N-Cl? - (5-mer-capto-l, 2,4-oxadiazo1-3-il) -3'- methi 1 but l 3-4-methyl Ipentanamide To a stirring solution of the compound of Example 17 (b) (0.4 g »0.76 mmol) in 1.5 mL of chloroform was added triethylamine (0.55 g, 1.53 mol, 0.213 mL) and tr Oxygen (0.088 g, 0.76 mmol, 0.058 mL). The solution was refluxed for 3 h and then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO 4), filtered and concentrated. The residue was purified by silica gel chromatography of 230-400 mesh, eluting with 11% methanol in dichloromethane to give the title compound as a white solid (0.20 g, 61%). NMR AH (400 MHz, CDC1 ,,,) or 7.36 (m, 6H), 6.85 (d, 1H), 5.37 (d, 1H), 5.14 (m, 3H), 4.24 (m, 1H), 1.65 (m , 6H), OR .95-0.B7 (m, 12H).

EXAMPLE IB Preparation of < 2S.l'S) -Z- (benzyl lox carbon 1) amino-N-Cl - (2-mercaptothiazol-4-yl) -3'-methy1butyl-4-methylpentanamide The compound of Example Ka) (1.0 g 2.2 mmole) and ammonium di thiocarbamate (0.25 g. 2.2 mmole) were dissolved in ethanol and heated at 55 ° C for 13 hours. The solvent was evaporated and the residue chromatographed (silica gel, 20% ethyl acetate / blood) to give the title compound as a white solid (0.58 g). NMR, (400 MHz, CDC1, ") or 7.24 (m, 5H), 7.10 (S, 1H). 6.33 (8. 1H), 6.00 (d.1H), 5.11 (q, 2H), 4.94 (m, 1H), 4.05 (m, 1H), 1.49 (m, 6H), 0.78 (m, 12H).

EXAMPLE 19 Preparation of (ZS) -Z- (benzloxycarbonyl) amino-N- (4-carboethoxythiazole-Z-1) methy1-4-methypentanamide a) l- (tert-butoxycarbonyl> amino-l- (4-carboethoxythiazo1-Z-yl) methane The title compound was prepared following the procedure of example 8 (a) -? (c) »but substituting N- T-buto? icarbonylglycine N-tert-buto? carboni l- (L) -leucine in step (a) d.9g »58% overall). NMR (400 MHz »CDC13) or B.ll (S» 1H), 5.31 (8, 1H), 4.56 (d, 2H), 4.43 (q, 2H), 1.45 (S. 9H). 1.42 (t »3H). b) (2S) -2- (benzloxycarboni 1) amino-N- (4-carboetho-i-thiazole-Z-1) methi 1-4-met-pentanamide The title compound was prepared following the procedure of example 13, but replacing with l- (tert-buto-icarboni 1> amino-l- (4-carboetho it azol-2-yl) methane the (1S) -l- (tert-butylcarboni 1) amino-1- ( 4-carboetho-i thiazol-2-1) -3-methylbutane, and with N-Cbz-L-leuci to N-Cbz-L-leucine 1-L-leucine (0.120 g, 32%, MS (MH * ): 434.2.

EXAMPLE 20 Preparation of (2S, 1 * S) -Z- (benzyloxycarbon I) amino-N-Cl '- (2-benzyloxycarbon 1-thiazole 3-4-i 1) -3'-methy Ibut 13-4-met Ipentanamide compound of Example 2 (0.105 g .. 0.22 mmole) was dissolved in dichloromethane and treated with l- < 3-dimet laminopropil) -3-eti Icarbodi imide (0.062 g .. 0.22 mmoles) and benzyl alcohol (0.03 g. »0.22 mmoles). The mixture was allowed to stir at room temperature for 4 hours, the solvents were evaporated and the residue obtained was chromatographed (silica gel, 30% ethyl acetate / water) to give the title compound as a white solid ( 0.04 g) H-NMR (400 MHz. CDC13) 07.37 (S. 1H), 7.26 (m.10H). 6.50 (d, 1H) »5.33 (s.2H). 5.11 (q.2H) »5.09 (m.1H). 4.99 (S. 2H). 4.04 (m.H.) 1.49 (m, 6H), 0.78 (m, 12H).

EXAMPLE Preparation of (ZS * l'S) -Z- < benzyloxycarboni1) amino-4-methy1-N-C3'-methi 1-1-- < Z- enox carbon l thiazole 3-4-i 1) -but 1 pentanamide The title compound was prepared following the procedure of Example 20 »but substituting the benzyl alcohol with phenol (0.075 g) XH NMR (400 MHz. CDC13) < S7.41 (s, 1H). 7.26 (m, 10H), 6.49 (d.1H), 5.20 (m, 1H). 5.04 (m, 1H), . 00 (s.2H), 4.08 (m, 1H), 1.49 (m, 6H), 0.82 (m, 12H).

EXAMPLE ti Preparation of (ZS.l'Si-Z-Cbenzyloxycarbonyl) aroino-4-methyl-N-C3-raeti 1-l'-C2- (2-methylProPi loxycarboni 13thiazo1-4- j 1)? M \ S 1 Jpe Tanarojda, The title compound was prepared following the procedure of Example 20. but substituting the benzyl alcohol with isobutyl alcohol (0.075 g) XH NMR (400 MHz, CDC13) 07.25 (m, 6H), 6.50 (d, 1H), 5.11 (q, 2H), 5.09 (m, 1H), 4.99 (S, 2H), 4.11 (d, 2H), 3.91 (m, 1H), 1.70-1.39 (m, 6H), 0.82 (d, 6H) , 0.78 (m, 12H).

EXAMPLE? 3 Preparation of (ZR.lS) -Z- (benzyloxycarbonyl) araino-N-cy '- (4- carboethoxy t azo1-Zi 1) ethyl 3-4-methylapentanamide The title compound was prepared as a white solid following the procedure of Example 19, but replacing N-te? -buto? icarboni 1-L-alani with N-tert-buto? icarboni Igl icine in step (a), and with N-Cbz-D-leucine the N-Cbz-L-leuc na in step (b> (0.135 g, 36%). MS (MH *): 448.2.

EXAMPLE 4 Preparation of < 2R, l'R) -Z- < benzyloxycarbonyl) amino-N-Cl - (4-carboethoxythiazole-Z-yl) etl13-4-methylapentanamide The title compound was prepared as a white solid following the procedure of Example 19, but substituting N-tert-buto carboni 1-d-alanine N-te? - buto? icarboni Iglic na in step (a), and with N-Cbz-D-leuc na N-Cbz-L-leucine in step (b) (0.110 g. 29%). MS (MH *): 448.2.

EXAMPLE 25 Preparation of < ZR-1'S) -N-Cl-- < 2-aminothiazo1-4-i1) -3'-meti Ibuti 1 -Z- (encyloxycarboni 1) ami o-4-meti Ipentanami a Thiourea (0.142 g, 1.87 mmol) was added to a stirred solution of the compound of the example Ka) (0.85 g, 1.87 mmol) in 4 L of ethanol. The solution was allowed to stir at room temperature for 90 min. The solution was concentrated, the residue was dissolved in ethyl acetate and washed with saturated NaHCOO, saturated aqueous, then dried (MgSO 4), filtered and concentrated. The residue was purified by silica gel chromatography of 230-400 mesh, eluting with 1: 1 ethyl acetate, to give the title compound as a white solid (0.64 g, 78%). . XH NMR (400 MHz, CDC1,) < S7.36 (m, 5H), 6.30 (m, 2H), 5.12 (m, 3H), 4.95-4.91 (m, 3H), 4.16 (ra, 1H), 1.63 (m, 4H), 1.49 (ra, 2H), 0.93-0.89 (m, 12H).

EXAMPLE 26? Preparation of (lS) -N-C4-C (l-benzyloxycarbonylamino) -3-met Ibuti 13thiazo1-2-i Icabom "13-N '- (N-benzloxycarbonyl 1-L-leucyl) hydrazide a) N-benzyloxycarboni 1-L-leucine 1 bromomethane Icetona l-Methyl-3-nitro-l-ni trosoguanidine (6.65 g, 45.2 mmol) in ether (225 mL) is cooled to 0 ° C. 40% sodium hydroxide is added slowly and the diazomethane is allowed to accumulate in the ether solution for 30 minutes at 0 ° C. The ether solution is then decanted and left at 0 ° C. N-Cbz-L-leucine (2.10 g 7.6 mmole) was dissolved in THF (10 mL) was cooled to -40 ° C, and 4-methylmorphine (0.77 g 7.6 mmol, 0.83 mL) was added, followed by the dropwise addition of isobutyl chloroformate (1.04 g, 7.6 mmol 0.98). mL). After 15 min, the solution was filtered in the previously prepared solution of ethereal diazomethane at 0 ° C. The resulting solution was allowed to stand at 0 ° C for 23 h. HBr (30% in acetic acid) (45.2 mmol, 9 mL) was added and the resulting solution was stirred at 0 ° C for 5 min, then sequentially washed with 0.1 N HCl, saturated aqueous NaHCO 3 and saturated brine, then dried (MgSO 4), filtered and concentrated to give the title compound as a colorless oil (2.43 g, 94%). b) (ÍS) -l-benzyl 1o-icarboni 1 amino-1- (2-carboetho-i-thiazol-4-yl) -3-methyl-1-butane A solution of the compound of example 26 (a) (1.57 g, 4. 58 mmol) and ethyl thiool (0.61 g »4.58 mmol) in ethanol (10 mL) was heated to reflux for 4 h. The solution was then cooled and concentrated and the residue was purified by chromatography by steaming on 230-400 mesh silica gel eluting with 1: 4 ethyl acetate / heme. to give the title compound as a yellow oil (1.0 g, 58%). NMR XH (400 MHz, CDC13) 7.41 (s. 1H) »7.34-7.31 (m, 5H). 5.40 (d. 1H) »5.10 (d, 1H)» 5.10 (d.1H) »5.05 (d, 1H), 4.98 (q.1H). 4.48 (q.2H) »1.80-1.76 (m, 2H), 1.57-1.53 (m, 1H), 1.44 (t.3H), 0.93 (d, 3H), 0.93 (d, 3H). c > (SS) -l-benzyl-1-oxycarbonyl-1-amino-1- (Z-hydrazinocarbo-ni 1-thiazol-4-yl) -3-methyl-1-butane A solution of the compound of Example 26 (b) (0.30 g, 0.8 mmol) Hydrazine hydrate (0.40 g, 8.0 mmoles »0.39 mL) in ethanol (8 mL) was allowed to stir at room temperature for 2 h. The solution was then concentrated to yield the title compound as a white foam (0.28 g, 98%). X H NMR (400 MHZ, CDC1-,) 08.29 (S, 1H), 7.37-7.35 (m, 5H). 5.18 (d.1H), 5.09 (dd, 2H), 4.95 (q, 1H), 4.07 (d, 2H), 1.71 (t, 2H), 1.55 (m, 1H), 0.96 (d, 3H). 0.94 (d, 3H). d) (lS) -N-C4-C (l-benzyloxycarbonyllamino) -3-methyl-1-butyl-1-triazole-Z-Icarboni 13-N, - < N-benzyloxycarbonyl L-L-leucine 1) hydrazide A solution of the compound of example 26 (c) (100 mg, 0. 28 mmoles) »N-Cbz-L-leucine (B0.5 mg, 0.30 mmol), l- (3-dimethylaminopropy 1) -3-ethyl-1-carbodiimide hydrochloride (58.2 mg, 0.30 mmol) and 1-hi Drox i enzotr azole (7.5 mg, 0.06 mmol) in DMF (0.6 mmol) was allowed to stir at room temperature for 18 h. The solution was diluted with ethyl acetate and washed successively with water, 0.1 N HCl, saturated aqueous NaHCO 3, and saturated brine, then dried (MgSO 4), filtered and concentrated. The residue was purified by silica gel chromatography on 230-400 mesh, eluting with ethyl acetate: to provide the title compound as a white solid (111.4 mg, 66%). ). mp 110-112 ° C.

EXAMPLE 27 Preparation of N-benzyloxycarbon 1- leucine 1-N'-benzyloxycarboni 1-L-leucinyl-L-leucinyl hydrazide a) N-benzyloxycarbonyl-L-leucine methyl ester L-leucine The title compound was prepared as a white solid following the procedure of example 26 (d), but replacing with L-leucine methyl ester hydrochloride (lS) -l-benz lo? icarbon lami ol- (2-idrozinocar oni 1 ti azo1-4-yl) -3-methyl butane (1.28 g, 66%). X H NMR (400 MHz, CDC1 ,,,) 67.37-7.32 (m, 5H). 6.28 (d, 1H), 5.2B (m, 3H), 4.61-4.58 (m, 1H), 4.20 (m.1H). 4.20 (m, 1H), 3.74 (s, 3H), 1.69-1.54 (m, 6H), 0.96-0.92 (m, 12H). b) N-benzyloxycarboni 1-L-leucine 1-L-1-echinium-1-hydrazide The title compound was prepared as a white solid following the procedure of example 26 (c), but substituting N-benzyl-methylcarbamate with methyl ester. L-leucine 1-L-leucine to (lS) -l-benzylocarboni lamino-l- (2-carboetho-thiazol-4-yl) -3-methyl butane (1.28 g, 100%). XH NMR (400 MHz, CDC13) «58.05 (r s, 1H), 7.35-7.32 < m, 5H), 6.67 (d, 1H), 5.50 (d.1H), 5.11 (S, 2H), 4.46 (m, 1H), 4.21 (m »1H), 3.88 (br s, 2H), 1.64- 1.51 (m, 6H), 0.92-0.88 (m.12H). c) N-benzyloxycarboni 1-L-leucine l-Nt-benzyloxycarbo-ni 1-L-leucine l-1-echinium 1-hydrazide The title compound was prepared as a white solid following the procedure of example 26 (d), but substituting with N-benz locarboni-L-leucine-L-leucine-Ihydrazide (lS) -l-benz-locarbonyl-1-yl-1- (2-hydrazinocarbonyl-thiazol-4-yl) -3-methyl-butane (0.059 g). MS (M + Na): 662.1.

EXAMPLE 3S Preparation of (1S) -N-C2-C (1-benzloxycarbonylamino) -3-methyl-1-butyl-13-thiazole-4-Icarbon 13-Nt- (N-benzyloxycarbonyl 1-L-leucine 1) hydrazide a) N-tert-buto-icarboni 1- (L) -1-eucinaraide To a solution of N-tert-butoxycarbon 1- (L) -1eucine (7.0 g, 28.1 mmol) in dry THF (100 mL) at -40 ° C isobutyl chloroformate (3.8 g, 2B.1 mmole) and N-methylmorpholine (6.0, 59 mmole) were added. After 15 minutes of stirring, ammonia was bubbled through the mixture for an additional 15 minutes, then warmed to room temperature and allowed to stir for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to yield the title compound as a white solid (6.5, 28.0 mmol). XH NMR (400 MH ?, CDC13) 6.38 (rs, 1H), 5.79 (brs. 1H), 5.04 (br d, 1H), 4.13 (m, 1H), 1.71-1.49 (m, 3H), 1.39 ( S, 9H), 0.92 (dd »6H). b > N-tert-butoxycarbon 1- (D-1eucythioamide) To a stirring solution of the compound of Example 26 (a) (6.5 »28.0 mmol) in dry THF was added Lawesson's reagent (6.8 g, 16.9 mmol) and the mixture was stirred at room temperature under argon overnight.The solvent was evaporated and the residue was chromatographed (silica gel »12% ethyl acetate / water) to give the title compound as a white solid (5.4 g, 77%). %) XH NMR (400 MHz, CDC13) 68.54 (br S, 1H), 7.97 (br 1H), 5.28 (br 1H), 4.52 (m, 1H), 1.72-1.58 (m, 3H). , 1.40 (s.9H), 0.92 (m, 6H). c) (lS) -l- (tert-butoxycarbon l) ami o-l- (4-carboethoxy-thiazole-Z-1) -3-methy1butane The compound of Example 26 <b) (5.4 g, 21.7 mmol) was stirred in dry acetone (100 mL) under argon at -10 ° C. Ethyl bromopyruvate (4.7 g, 23.9 mmol) was added and stirred for 1 h at -10 ° C. The solution was emptied into a well-stirred mixture of chloroform and water and then into a saturated solution of sodium bicarbonate. The organic phase was separated and the aqueous layer was extracted with chloroform. The combined organic extracts were dried over MgSO 4, filtered and concentrated to an oil. The oily residue was treated with TFAA (5.0 g, 23.9 mmol) and pyridine (3.8 g, 47.8 mmol) in dichloromethane for 1 h at -20 ° C. The excess solvent was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate and KHSO.sub.1 of l.ON to a pH of 7. The solution was dried over magnesium sulfate, filtered and concentrated to an oil which was chromatographed (silica gel, 7.5% ethyl acetate / year) to give the title compound as a tan solid (4.5g, 61%). XH NMR (400 MHZ, CDC13) 7.98 (s, 1H), 5.04 (br d, 1H), 4.95 (m, 1H), 4.31 (q, 2H), 1.88 (m, 1H), 1.63 (m. 2H), 1.40 (S. 9H), 1.32 (t, 3H). 0.85 (dd., 6H). d) < 1S) -I- (Benzylocarboni 1) amino-1- (4-carboetho-i-thiazol-2-yl) -3-methyl-butane The compound of example 26 (c) (0.250 g, 0.731 mmol) was dissolved in TFA (2 mL) and stirred at room temperature for 15 minutes, then diluted with methanol and concentrated in vacuo. The residue was dissolved in methylene chloride and treated with triethylamine (0.739 g »7.31 mmol) followed by benzyl chloroformate (1.2 g» 7.31 mmol). The solution was stirred at room temperature for 2 h and partitioned between ethyl acetate / water. The organic layer was washed with brine, combined, dried (MgSO 4) and concentrated to a residue which was chromatographed (silica gel, 15% ethyl acetate / water) to give the title compound as one oil (0.19B g, 72%). NMR ^ H (400MHz, CDC13) or 8.01 (s, 1H), 7. 32 (m, 5H), 5.51 (r d, 1H), 5.14 (m, 1H). 5.10 (S, 2H), 4.37 (q, 2H), 1.93 (m, 1H). 1.81-1.67 (m, 2H), 1.39 (t, 3H), 0.95 (m, 6H). e) (1S) -N-C2-C (1-benzyloxycarbonylamino) -3- me i luthi 13thiazo1-4-i Icarboni 13-Nt- (N-benzyloxycarboni 1-L-1-eucinyl) hydrazi a The compound of title following the procedure example 26 (c) -l (d), but substituting (lS) -l- (benzyloxycarbon 1) amino-1- (4-carboethoxy-yiazol-2-yl) -3-methyl 1 butane (lS) -l-benzylcarboni 1 amino- l- (2-carboethoxy-thiazol-4-yl) -3-methane in step (c). MS (MH *): 610.0.

EXAMPLE £ 9 Preparation of 2,2'- < N.N'-biß-benzyloxycarboni-1-L-leucinyl) carbohydrazide To an additive solution of N-Cbz-L-leucine (Chemical Dynamics Corp.) (2.94 g, ll.l mmoles) in 22 mL of DMF carbohydrazide (0.5 g, 5.6 mmol), 1- (3-dimethylaminopropy 1) -3-ethecarbodmida hydrochloride (2.13 g, ll.l mmoles) and 1-hydroxy benzotr azol (0.3 g, 2.2 mmol) were added. After stirring at room temperature for 22 h the solution was emptied into 500 mL of water. The precipitate was collected by vacuum filtration and washed with water (4 X 150 mL) and dichloromethane (4 X 150 mL) and then dried under vacuum to provide the title compound as a white solid (1.49 g, 46%). . MS (ESI): 607.1 (M + Na) *.

EXAMPLE 30 Preparation of 2.2t- (N »N'-bis-cyclohexyl-acetyl) carbo-drazide The title compound was prepared following the procedure of Example 29, but replacing N-Cbz-L-leucone with cyclohexylacetic acid (0.410 g, 73%) ). MS (ESI): 339.3 (M + H) *.

EXAMPLE 31 Preparation of 2tZ, - (N > N, -bis-4-methypentanoi 1) carbohydrazide The title compound was prepared as a white solid following the procedure of Example 29 »but replacing the N-Cbz with 4-metpentanoic acid -L-leucine (0.212 g »44%). MS (ESI): 287.3 (M + H) *.

Preparation of 2.2 - (N, N'-biß-2-cic1openti laceti 1) - carbohydrazide The title compound was prepared as a white solid following the procedure of Example 29 »but replacing N-Cbz-L with lactic cyclopentyl acid -leucine (0.345 g »67%). MS (ESI): 311.2 (M + H) *.

EXAMPLE 33 Preparation of 2 > Z * - < N.N'-biß-benzyloxycarboni lol icinyl) -? Erbphidraaside The title compound was prepared as a white solid following the procedure of Example 29, but substituting N-Cbz-gl-N-Cbz-L-leucine with N-Cbz-gl. (0.719 g, 91%). MS (ESI): 473.1 (M + H) *.

EXAMPLE 34 Preparation of 2 »2, - (N, N, -bis-acet-L-leucine 1) carbohydrazide The title compound was prepared as a white solid following the procedure of Example 29. but replacing with N-acetyl-1-L-leuc na N-Cbz-L-leuc na (0.153 g, 23%). MS (ESI): 401.3 (M + H) *.

EXAMPLE 35 Preparation of Z-Z'-C-N'-biß-benzyloxycarbonyl-L-ai anj i > gart? P "•? druide The title compound was prepared as a white solid following the procedure of Example 29» but substituting N-Cbz-L-alan with N-Cbz-L-leucine (0.762 g, 91% MS (ESI): 501.1 (M + H) *.

EXAMPLE 36 Preparation of 2- (N-benzyloxycarboni 1-L-leucinyl) -2'-CN - (4-methypentanoi 1) 3-carbohydrazide a) Methyl ester of N-benzyloxycarboni 1-L-leucine to a solution of leucine methyl ester hydrochloride (5.0 g, 27.5 mmoles) in 1,4-dioxane (50 mL) was added sodium carbonate (30.3 L, 2M in water) followed by benzyl chloroformate (4.69 g »27.5 mmol). The mixture was stirred at room temperature for 24 hours when it was partitioned between ethyl acetate and water. The organic layer was collected, dried (MgSO 4), filtered and concentrated to give the title compound as a colorless oil (7.67 g, 100%). H NMR (400 MHZ, CDCl, r) or 7.39 (m, 5H), 5.3B (d, 2H >;, 5.12 (S. 2H), 4.42 (m, 1H), 3.75 (S, 3H), 1.73-1.50 (m, 3H), 0.94 (m, 6H). b) N-benzylcarbonyl 1-Ll eucyyl hydrazide To a solution of the compound of example 36 (a) (7.67 g, 27.5 mmol) in methanol (40 mL) was added hydrazine monohydrate (13.5 g »270 mmol) . The solution was stirred at room temperature for 24 hours when it was partitioned between water and ethyl acetate. The organic layer was combined, dried (MgSO?), Filtered and concentrated to give the title compound as an off-white solid (7.67 g, 100%). X-NMR (400 MHz, CDC1,.)? 8.14 (S, 1H), 7.38 (m, 5H), 5.64 (d, 1H), 5.09 (dd, 2H), 4.20 (m, 1H). 3.81 (8, ür, 2H), 1.69-1.51 < m, 3H), 0.92 (dd, 6H). c) 1-Benzylloxycarbon 1 amino-3-methyl-1 - (i, 3,4-oxa-diazole-Z-1) butane A solution of the compound of example 36 (b) (1.0 g, 3. 58 mmol) in methylene chloride (12 mL) was added dropwise to a solution of 4-n-trophoniumchloroformate (0.361 g, 1. 79 mmol) in methylene chloride (8 mL) at 0 ° C. The solution was warmed to room temperature and stirred for one hour when it was partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaHCO 3, then combined, dried (MgSO 4), filtered and concentrated to a residue which was chromatographed (20% ethyl acetate / hexane) to give the title compound as a light yellow solid (0.322 g »59%). NMR XH (400MHZ »CDC1 ,,.) Or 9.18 (S» 1H). 7.38 (m, 5H), 5.13 (m, 3H), 4.79 (m, 1H), 1.71 (m, 3H), 0.9B (dd, 6H). d) 4-methypentanoyl-1-hydrazide The title compound was prepared as a white solid following the procedure of example 36 (b), but substituting ethyl isocaproate with benzylcarbonyl 1-L-leuc methyl ester neither (1.8 g, 100%). H NMR (400 MHz, CDC13) or 7.48 (S. br.H). 3.62 (s br.2H). 2.13 (t.2H), 1.51 (m.3H), 0.85 (d.6H). e) 2- (N-benzyloxycarboni 1-L-1eucini1) -Z * -CN, - (4-met Ipentanoi 1) carbohydrazide The compounds of example 36 (c) (0.100 g, 0.325 mmol) and of example 36 ( d) (0.042 g »0.325 mmol) were combined and dissolved in ethanol (1 mL). The solution was refluxed for 24 hours and then concentrated to a solid yellow residue which was washed with cold methylene chloride to yield the title compound as a white solid (0.053 g, 37%). MS (MH *): 436.2.

EXAMPLE 37 Preparation of bis- < Cbz-1eucin 1) -l, 3-diamino-propan-2-one Cbz-leucine (500 mg, 1.88 mmol), EDCl (558 mg, 1.88 mmol) were dissolved in DMF (4.0 mL) with 1,3-d amino-propan-2-ol (85 mg, 0.94 mmole) and Hun? g base (0.3 mL, 1.88 mmol) and stirred at RT overnight. The reaction was diluted with EtOAc (20 mL) and washed with water (2? 20 mL). The combined organics were dried with magnesium sulfate, filtered and concentrated in vacuo. The intermediate was then dissolved in acetone (4.0 mL) and added by Jones reagent drop (2.0 mL, 1.5 M) and the reaction was stirred at room temperature overnight. The Jones reagent run was then extracted with isopropanol (1.0 mL). then the reaction was diluted with EtOAc (20 mL) and was brought up with water (2? 20 mL) to remove the inorganic salts. The combined organic residues were dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel »2-5% MeOH / methylene chloride) to give the compound. of the title as a white solid (410 mg, 75%). MS (ES) M + H * = 583, M + Na * = 605.

EXAMPLE 3B Preparation of β-1,3- (4-enoxy-benzo-l) -d-amino-propan-2-one The title compound was prepared following the procedure of Example 37 »but substituting" 4-phenoxy-benzoic acid " the "Cbz-leucine": MS (ES) M + H * = 481, M + Na * = 503.

EXAMPLE 39 Preparation of l- (Cbz-leucyl) amino-3- (acetyl-1-echin-1) -amino-proparv-2-one The title compound was prepared following the procedure of Example 37, but substituting with "a mixture of N- Ac-leuci and Cbz-leuci to "the" Cbz-leuci na ": MSÍES) M + H *) = 491, M + Na * = 513.

EXAMPLE -O Preparation of l- (Cbz-1eucini1) -ami or -3- (Cbz-qlutamyl-t-but-1-yl) -amino-propan-2-one ester The title compound was prepared following the procedure of Example 37, but substituting "Cbz-leucine" with "a mixture of t-butyl ester of Cbz-glutamic acid and Cbz-leuc na": MS (ES) M + H * = 655.

EXAMPLE 4, Preparation of l- (Cbz-1eucini1) -amino-3- (Cbz-a1utami1) -amino-propan-2-one l- (Cbz-leucini 1) -amino-3- (Cbz-glutamyl-t-butyl ester) ico) -amino-propan-2-one (5 mg, 0.007 mmol) was dissolved in a solution of trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) »then stirred at RT for 2 h, the reaction was d luised with toluene (10 mL) and then concentrated in vacuo to provide the title compound: MS) M + H * = 599.

EXAMPLE 42 Preparation of biß-l »3- (Cbz-leucin l) -d am no- (S) -butanon-2-one a) Cbz-1eu-a1a-b omome i 1-ketone Chloroformate of sobutyl (1.46 mL, 11.3 mmolee) was added by dripping to a solution of Cbz-leu-ala-OH (4.0 g, 11.3 mmoles) and N-meti 1 -morphol (1.24 mL »11.3 mmol) in THF (40 mL) at -40 ° C. The reaction was stirred 15 minutes, then filtered and washed with ether. Diazomethane (40.1 mmoles of 5.9 g of 1-methyl 1-3-n tro- "throso-guanidi-a and 18 L of 40% KOH in 150 mL of ether) was added in ether (200 mL) and the reaction was placed in a refrigerator overnight, 30% HBr / AcOH (7 mL) was added dropwise to the crude reaction mixture and stirred for 5 minutes.The solution was washed with aqueous citric acid (50 rnL? 2), sodium bicarbonate saturated aqueous sodium (3? 150 mL) and then 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 purification MS (ES) M + H ** = 413 and 415, M + Na "= 435 and 437. b) Cbz-leu-leu-azi ome i 1-ketone Cbz-l eu-ala-bromomet 1 ketone (650 mg »1.6 mmol) was dissolved in DMF (7 mL), then sodium azide (122 mg, 1.9 mmol) was added. ) and potassium fluoride (137 mg, 2.36 mmol) and the reaction was stirred overnight. The reaction was partitioned between EtOAc and water, then the combined organic extracts were dried with magnesium sulfate, filtered, concentrated in vacuo and chromatographed (2-5% MeOH, methylene chloride, silica gel) provide the title compound as a white solid (330 mg »53%)» MS) M + Na ** = 398. c) Cbz-1eu-2-amino-4-azido-propan-3-o1 Cbz-leu-leu-azidomethyl 1-ketone (330 mg, 0.9 mmol) was dissolved in EtOH (5 mL) and sodium borohydride ( 100 mg, 2.65 mmol) at room temperature and the reaction was stirred for 15 minutes. The reaction was extracted 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, MS (ES) M + H ** = 378, M + Na * »= 400. d) Cbz-leu-2-amino-4-amino-? ropan-3-o1 Cbz-leu-2-am no-4-azido-propan-3-ol (300 mg, 0.8 mmol) was dissolved in MeOH ( 4 mL) and triethylamine (0.33 mL, 2.4 mmol), propan-l, 3-diol (0.35 mL, 3.82 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) M + H ** = 352. e) B s-lr3- (Cbz-1euc ni1) -diamino- (S) -butanon-2-o1 Cbz-leu-2-am o-4-amino-propan-3-ol (140 mg »0.4 mmol) and Cbz-l euc a (106 mg »0.4 mmoles) were dissolved in DMF (2 mL) and N-methyl morphine (0.08 mL, 0.8 mmol) and HBTU (151 mg, 0.4 mmol) and stirred overnight. The reaction was partitioned between EtOAc and water, the combined organic extracts were dried with magnesium sulfate, filtered and concentrated to give the title compound, MSI) M + H ** = 599, M + Na + = 621. f) Bis-1.3- (Cbz-leucinyl) -diamino- (S) -butanon-2-one Bis-l, 3- (Cbz-leucine 1) -diami or- (S) -butanon-2-ol (240 mg, 0.4 mmol) was dissolved in acetone (2 mL). Jones's 1.5 mL, 1.5 M) reagent was added dropwise and the reaction was stirred at room temperature overnight. The Jones reagent was then extracted with isopropanol (10 mL) and then the reaction was diluted with EtOAc (20 mL) and extracted with water (2? 20 mL) to remove the inorganic salts. The combined organic extracts were dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel »2-5% MeOH / methylene chloride) to give the title compound as a white solid (80%). mg 33%). MS ES) M-H ~ = 595.SDI.

EXAMPLE 43 Preparation of l- (Cbz-1eucini1) -amino-3- (Cbz-phenylala il) -amino-propan-2-one The title compound was prepared following the procedure of example 37. but substituting "Cbz-Ieucine" with "a mixture of Cbz-phenylalanine and Cbz-leucine" (70%): MSIES) M + H ** = 617, M + Na ** = 639.

EXAMPLE 44 Preparation of l- (Cbz-1-eucinyl) -aroi or -3- (Cbz-no 1euc i1) -amino-propan-2-one The title compound was prepared following the procedure of example 37. but substituting "Cbz-leucine" with "a mixture of Cbz-norleuc na and Cbz-leucine" MSÍES) M + H "= 583. M + Na ** = 605.

EXAMPLE 45 Preparation of l- (Cbz-1eucin 1) -amino-3- (Cbz-no-va1-inyl) -aminq-propan-2-one The title compound was prepared following the procedure of example 37. but substituting "Cbz-leucine" "with" a mixture of Cbz-norval ina and Cbz-l eucine ": MS (ES) M + H * = 569. M + Na ** = 591.

EXAMPLE 46 Preparation of bis-l »3- (Cbz-leuci 1) -d amino-5-meti 1- (S) - he? An -? - pna a) Bis-lt3- (Cbz-1eucini1> -diamino-5-methy1- (S) -hexan-Z-one The title compound was prepared following the procedure of example 42 (a) - (f), but substituting with "Cbz-leu-leu-OH" the "Cbz-l eu-ala-OH": MS (ES) M + H- = 639.

EXAMPLE 47 Preparation of l- (acetyl-1-eucinyl) -amino-3- (4-enoxy-benzoyl) -amino-propan-2-ff? A The title compound was prepared following the procedure of example 37 »but substituting" Cbz- " lucine "with" a mixture of N-Ac-leucine and 4-phenoxy-benzoic acid ": MSIS) M + H ~ = 440.

EXAMPLE 4B Preparation of l- (Cbz-homo-leucinyl) -am- (Cbz-leucinyl) -3-amino-propan-2-one The title compound was prepared following the procedure of example 37, but substituting "Cbz-leucine" "with" a mixture of Cbz-homo-leuci a and Cbz-leucine ": MSÍES) M + H *» = 597, M + Na- = 619.

EXAMPLE 49 Preparation of biß-1,3- (4- (3-chloro-2-cyano-phenoxy) -eni 1 -ulonamido) -propan-Z-one 4-chloro-2-cyano-phene chlorwas added i) -fermyl sulfonyl, 1.3 g, 4 mmole, Maybridge) to a solution of 1,3-diam non-propan-2-ol? 18 g. 2 mmole) in DMF (10 mL) / N-methyl morpholine (0.44 mL, 4 mmol) and stirred 3 h at room temperature. The reaction was partitioned between water and EtOAc and the combined organic extracts were dried with magnesium sulfate and then concentrated in vacuo. Bis-l, 3- (4- (3-chloro-2-c ano-phenoxy) -phen-1-sulfonamido) -propan-2-bl (0.28 g, 0.4 mmol) was then dissolved in acetone (1.0 mL) and Jones's reagent was added (0.44 mL, 1.5 M) and the reaction was stirred overnight at room temperature. The Jones excess reagent was then quenched with isopropanol (1.0 mL), then the reaction was diluted with EtOAc (20 mL) and extracted with water (2x 20 mL) to remove the inorganic salts. The combined organic extracts were dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel, 2-5% MeOH / methylene chlor to give the title compound as a white solid (90 mg, 34%). MS (ES) M + H ** = 671, M + Na ** = 693.

EXAMPLE 5Q Preparation of bis-l, 3- (4-phenoxy-phenyl-1-phonamido) -propan-2-one The title compound was prepared following the procedure of Example 49, but replacing 4- (3-chloro-2-cyano-pheno) chlor(i) -phenol sulfonyl with 4-phenoyl-phenyl sulfonyl chlor MS) M + H- = 551.

EXAMPLE 51 Preparation of l- (Cbz-leucinyl) -amino-3- (4- (3-chloro-Z-cyano-phenoxy) -phenyl-1-trifluoromido) -propan-Z-one Cbz-leucine (660 mg, 2.5 mmol), EDCl (480 mg, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DMF (10 mL) with 1, 3-diamino-propan-2-ol (225 mg, 2.5 mmol) and stirred at room temperature for the night. N-Methylmorphine (0.41 mL, 3.75 mmol) was added followed by 4- (3-chloro-2-cyano-phenoxy-1-phenyl-1-sulfonyl-B-20 mg, 2.5 mmol, Maybridge) and the reaction was stirred 3 h at room temperature. The reaction was partitioned between water and EtOAc and the combined organic extracts were dried with magnesium sulfate and then concentrated in vacuo. The crude l- (Cbz-leucine 1) -amino-3- (4- (3-chloro-2-cyano-pheno? I) -phen-1-sulfonamido) -propan-2-ol was afterwards dissolved in acetone (5.0 mL ) and was added by Jones reagent drop (3.0 L. 1.5 M) and the reaction was stirred overnight at room temperature. The Jones reagent run was then extracted with isopropanol (1.0 mL)., then the reaction was diluted with EtOAc (20 mL) and brought up with water (2? 20 mL) to remove the inorganic salts. The combined organic extracts were dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel »2-5% MeOH / methylene chloride), and then the product was ground from sodium chloride. I put wood to give the title compound as a white solid (26 mg, 2%), MS (ES) M + H * »= 627.

EXAMPLE 52 Preparation of l- (Cbz-leucinyl) -amino-3- (to-1-amino) -propan-2- The title compound was prepared following the procedure of Example 51, but substituting the chloride of 4- (3) with tosyl chloride. -chloro-2-cyano-pheno? i) -pheni-1-sulfonyl: MSI) MH- = 48B.

EXAMPLE 53 Preparation of l- (Cbz-leucine l) -aroino-3- ((4-enoxy-phenyl-1) -b-1-onamido) -ropan-2-one The title compound was prepared following the procedure of Example 51, but replacing 4-phenoxy-1-phenyl-1-sulfonium chloride 4-γ-3-chloro-2-c-ano-phenoyl) -phenyl sulfonyl chloride: MS) M + H ** = 568, M + Na ** = 590 EXAMPLE 54 Preparation of l- (Cbz-1eucini1) -amino-3- (Z-dibenzofuranßu1fonam do) -propan-Z-one The title compound was prepared following the procedure of Example 51, but substituting the chloride with 2-dibenzofuransulfonyl chloride of 4- (3-chloro-2-cyano-pheno?) -pheni! sulfonyl: MSES) M + H ~ = 566, M + Na- = 588.

EXAMPLE Si- Preparation of l- (Cbz-homo-leuc n 1) -amino-3- (2-d-benzofuransu-pheno-pheno) -propan-2-one The title compound was prepared following the procedure of Example 51, but substituting with 2-chloride. dibenzofuransulfonyl the chloride of 4- (3-chloro-2-cyano-pheno? i) -phen-1-sulfonyl) and with Cbz-homo-leucine the Cbz-leucine: MSIES) M + Na ** = 602.

EXAMPLE 56 Preparation of l- (Cbz-leucine 1) -amino-3- (2-di-benzofuransu-1-ammonido) - (S) -b-tan-2-one a) l- (Cbz-l euc i 1) -ami no-3-y 2-di benzofuransulfonami do) - (S) -butan-2-ol. Cbz-leu-2-am or -4-propan-3-ol (150 mg »0.42 mmol) were solved as described in Example 56 (a) - (d)) and 2-dibenzofuransulphonyl chloride in DMF (2 ml) and N-methylmorphine were 0.09 ml »0.84 mmol) and stirred overnight. The reaction was partitioned between ethyl acetate and water, the combined organic phases were dried with magnesium sulfate "filtered" and concentrated to give the title compound, EMÍES) M + H * = 5B2, M + Na * = 604 . b) 1-iCbz-leuci nl) -ami no-3- (2-di-enzafuransulfonamido) - (S) -butan-2-one l- (Cbz-leucini 1) -ami no-3-y 2 was dissolved -di benzofuran-sulfonamido) -iS) -butan-2-ol (240 mg, 0.4 mmol) in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction was stirred at RT overnight. The Jones reagent run was then titrated with isopropanol (1.0 ml); then the reaction was diluted with ethyl acetate (20 ml) and brought with water (20 ml) to remove the inorganic salts. The combined organic phases were dried with magnesium sulfate, filtered, concentrated and subjected to chromatography (silica gel »MeOH / methylene chloride 2-5%) to give the title compound as a white solid (70 mg , 29%). MS (ES) M-H * = 57S.

EXAMPLE 57 Preparation of (S) -Cl-C CC3-C-benzyloxycarbonyl-1-1euci, or 1-ami-3-2-oxopropyl-3-1-benzyl) amino-3-carbon l 3-3-methyl-1-butyl-13-phenylmethylcarbamate a) 2-Hydro-i-3-azido-propanol Sodium azide (1.7 g, 26 mmol) was added to a solution of glycidol (Aldrich, 1.3 g, 17.5 mmol) in MeOH (45 ml) and water (5 g). mi) and heated at 65 ° C for 4 hours. The reaction was diluted with water (25 ml), brought with EtOAc (2? 50 ml); the combined organic layers were extracted with water 22 x 50 ml). then with brine (50 ml), then dried over magnesium sulfate, filtered, concentrated in vacuo and chromatographed (silica gel, EtOAc / Heilum 30%) to give a white solid (1.37 g, 67%). %); MS (ES) M + H + = 118.4. b) Cough 2-hydro? i-3-azido-propane. Tousyl chloride (2.3 g) was added. 12 mmoles) was added to a solution of 2-hydro? I-3-azido-propanol (1.17 g, 10 mmol) and triethylamine (3.6 g, 36 mmol) in methylene chloride (50 ml), and stirred at RT for 4 h. hours. The reaction was diluted with water (20 ml). it was brought with EtOAc (2? 50 ml); The combined organic layers were brought with a buffer of pH 7 2? 50 ml), then dried over magnesium sulfate, filtered, concentrated in vacuo and subjected to silica gel chromatography. 30% EtOAc / kidney) to produce a white solid (1.2 g, 44%; MS (ES) M + H + = 272.2. c) 2-ímermer of Merrif? 'eld-6- < oxymethi len-tetrahydropyran-acetal) -3-azido-propan-tos lato. 2-Hydro-i-3-azido-propane tosylate (1.2 g, 4.4 mmol) was added to a suspension of Ellman's dihydropyran polymer (see (3)) (Scheme 1) (150 mg, 0.3 mmol) in C1CH2CH2C1 (25 ml), then pyridinium pyridinium sulfonate (0.84 g, 4.4 mmol) and stirred at 80 ° C by gentle bubbling with argon. The polymer was filtered, washed with DMF 2 2 X 10 mL), then with MeOH (20 mL), then methylene chloride (4 20 20 mL); IR 2105 cm-i; 1H RMN Magic Angle Spinning: d 8.0, 7.4, 5.0, 3.4. d) 2-ípolol number of Merrifield-6- (or? imeti len-tetrahydrop an-acetal) -3-azido-propan-N-benzyl sheet. Benzylamine (0.32 g, 3 mmol) was added to a suspension of 2- (Merrifield-6-ι-methyl-tetrahydropyran-acetal) -3-azido-propan-tosylate urea 500 mg. l mmoles) in N-methylpyrrolidinone (25 ml) and stirred at 80 ° C by gentle bubbling with argon. The polymer was filtered, washed with DMF (2? 10 ml>) then with MeOH (20 ml), then with methylene chloride (4 x 20 ml); IR 2105cm-1; 1 H NMR Magic Angle Spinning: d 7.1 , 4.7, 4.0, 3.8. e) 2- (Merr f eld-6- or? imet len-tetrah drop an-acetal polymer) -3-az do-pro? an-N-benz l- < Cbz-leucini 1) -amine. Was added Cbz-leucine (0.82 g, 3.0 mmol) to a suspension of 2-pol polymer of Merrif on -6-io? methy len-tetrahydropyran-acetal-3-azido-propan-N-benzylamin (120 mg, 0.22 mmol) in DMF (10 ml), diisopropyl leti lamina (1.2 ml, 6 mmol), and HATU (Persept? ve Biosystems, 2.2 g, 6 mmol) and stirred at room temperature overn. The resin was filtered, washed with DMF (3 x 10 mL). The above procedure was repeated, and the final resin was washed with MeOH (2? 20 mL), then with methylene chloride (5? 20 mL); IR 2105, 1735, 1630 cm-i; 1H NMR Magic Angle Spinning: d 7.2, 4.7, 4.1. f) 2-íPolmer number of Merrif eld-6- (o? imeti len-tetrahydropy ran-acetal-3-amino-propan-N-benzyl-Cbz-leucine 1) -amine. Propanodithiol (0.5 ml, mmoles) was added to a suspension of 2- (polymer of Merrifield-6- (or? Imeti len-tetrahydropyran-acetal-3-azido-pro? An-N-benzy 1-yCbz -leucini 1) -amine 150 mg, 0.27 mmol) in MeOH (5 mL) and triethylamine (0.5 mL), and stirred gently overn. The resin was filtered, washed with MeOH? 2? 20 mi). then with DMF (1? 10 ml), then with methylene chloride (5? 20 ml), and dried in a vacuum oven overn; IR 1735. 1640. cu-1. g) 2- (Polymer of Merrif eld-6- (or? imeti len-tetrahydropyran-acetal) -3- (Cbz-leucine 1) -amino-propan-N-benz 1-íCbz-leucini l> -amine Cbz-leucine (0.B2 g 3.0 mmole) was added to a suspension of 2- (Merrifield-6-i-methyl-tetrahydropyran-acetal) -3-amino-propan-N-benzyl polymer. -cCbz-leucim "1) -amine (150 mg, 0.27 mmol) in N-met lpirrol id nona (10 ml), di isopropy leti lami a (1.2 ml, 6 mmol) and HBTU (2.2 g, 6 mmol) and it was stirred at room temperature overn The resin was filtered, washed with DMF (3? 10 mL) The above procedure was repeated and the final resin was washed with MeOH (2? 10 mL), then with methylene chloride (5 x 20 mi), 1 H NMR Magic Angle Spinning: d 7.6, 7.4, 5.1, 5.0, 3.4 OB h) 1-N-Benzyl 1-1-Cbz-leucine l-ami or-3-Cbz-leuci i 1-amino-propan-2-? l. 2- (Merrifield-6-ι-methyl-tetrahydropyran-acetal) -3- (Cbz-leuc ni-1) -amino-propan-N-benzyl-1-ylbz-leucinyl) -amine polymer was stirred. 0.27 mmole) as a suspension with TFA / water / methylene chloride (5 ml), 85: 5: 10 »for 4 hours at RT. The solution was filtered and the filtrate was concentrated in vacuo; then chromatographed (silica gel, MeOH / methylene chloride, 5%) to yield a yellow solid (65 mg, 35%); MS (ES) M + H + = 675.1. i) 1-N-benzyl 1-1-Cbz-leucin l-am no-3-Cbz-leuc or 1-am not-propan-2-one. 1-N-benzyl-Cbz-leucinyl-am-3-Cbz-leucin 1-am or-propan-2-ol (65 mg, 0.96 mmol) was dissolved in acetone (5 mL) and added dropwise , Jones reagent (2 ml eεεε) at room temperature, and the reaction was stirred overn. The Jones reagent run was then quenched with isopropanol (5 ml) and the reaction was diluted with water (5 ral) and brought up with EtOAc x2 x 20 ml). The combined organic layers were washed with water (2? 15 ml), then with brine (10 ml), then dried with magnesium sulfate, filtered and concentrated in vacuo to yield a yellow solid, which was subjected to chromatography (silica gel, 50% EtOAc / hemeal) to yield a white solid (16.8 mg, 29%); EMÍES) M + H * = 673.1.

EXAMPLE 5B Preparation of (S) -Cl-CCC3-C2-dibenzofurani Isul onyl) amino3-2-oxopro i 13-3- (benz1) am no3carboni 13-3-methyl-1-butyl 1-carmethyl phenamide a) N- (2-hi ro? i-3-N-benc lamino-prop l) phtal mi a. N- (2,3-e? O? Ipropi 1) ftal imidaldidrich, 2.03 g, 10 mmol) was refluxed with benzylamine (1.07 g, 10 mmol) in isopropanol (15 mL) for 3 hours. The reaction was cooled to RT, then concentrated in vacuo to give a white gum which was triturated with MeOH, then filtered to yield a white solid (0.48 g, 15%); EMÍES) M + H * = 311. b) N- (2-Hydro? -3- (N-benzyl-1-2-di-benzofuransulfonamide) -prop 1) -ftal imi a. N- (2-hydro? I-3-N-benzylamine o-propy1) -phthalimide (0.31 g, 1 mmol) was stirred with 2-dibenzofuransulfonyl chloride (0.27 g, 1 mmol) in N-methylmorpholine? .8 mi) and DMF (5 mi) during the night. The reaction was diluted with water (10 ml), brought with ethyl acetate (20 ml), the combined organic layers were extracted with water (3 ml), then brine (20 ml), Then they were dried with magnesium sulfate, filtered and concentrated in vacuo to yield an oil, which was subjected to chromatography (silica gel, ethyl acetate / 30% strength) to produce a white foam (0.37). g, 69%); MS (ES) M + H * = 541, MS (ES) M + Na * = 563, MS (ES-negative) M + HC0 -.- = 585. c) 2-Hydro? i-1 -benzyl-2-d benzofuransulfonamide) -propi 1-3-ami a. N-2-Hydro? I-3-y-benzyl-1-2-dibenzofuransulfonamide) -propyl) -phthalide, 37 g, 0.69 mmol) was refluxed with hydrazine hydrate,? 34 g, 6.85 mmol) in MeOH (7 ml) for 1.5 hr. The reaction was cooled to RT. Then it was concentrated in vacuo. The resulting white solid was triturated with methanol, then filtered to yield the desired product as a white solid (0.27 g, 96%); MS (ES) M + H * = 411. d) Cbz-l euci ni 1- (2-hydro? -i N-benzyl 1-2-di benzofuran-sulfonamide)) propi 1-3-amine 2-hydro? i-í N-benz 1-2 was stirred -d benzofran-sulfonamide) -propi 1-3-amine (0.2 g, 0.5 mmol) with Cbz-leuc na (0.13 g, 0.5 mmol) in N-methylmorpholine (0.6 ml) and DMF (2 ml), then HBTU (0.19 g, 0.5 mmol) was added and the reaction was stirred overnight at RT. The reaction was diluted with water (10 rol), was brought up with ethyl acetate, 2 · 20 ml). A solid which was insoluble in both layers was filtered off. The combined organic layers were washed with water (20 ml), then with brine (20 ml), then dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid which was used. in the next reaction without further purification; MS (ES) M + H * = 658, MS) M + Na * = 680. e) S) -Cl- C3- I 2-dibenzofuran lsulfoni 1) am no3-2-o? opropi 13-3- (benzyl) amino3carboni 1 -3-methyl-1-butyl 1-carbamate phen-Imethyl Cbz-l euci ni l- (2-hydro? I- (-benci 1-2-dibenzofuransul fonamide)) -prop was dissolved. 1-3-amine (0.16 g, 0.244 mmol) in acetone (2 mL). Jones 0.5 ml reagent was added. 1.5 M) and the reaction was stirred overnight. The excess Jones reagent was quenched after with isopropanol (1 ml) and the reaction was diluted with water (10 ml) and extracted with ethyl acetate (2 × 20 ml). The combined organic layers were extracted with water (2x20 ml), then with brine (20 ml), then dried with magnesium sulfate, filtered and concentrated in vacuo to give a white solid which was subjected to chromatography (gel silica, ethyl acetate / hexane, 1: 1) to yield a white solid (0.14 g, 88%); EMÍES) M-H * = 65, MS (ES) M + C1 * = 690, EMÍES) M + HC0, ._ = 700.

EXAMPLE 59 Preparation of (S) -Cl-CCC3-C (2-dibenzofurani1ßu1foni1) amino3-2-oxopropyl -3- (4-pyridinylmethyl) amn3carboni1 -3-methyl-1but 13-phenylmethyl carbamate The title compound was prepared following the procedure of Example 5B (a) - (e), except that "benzylamino" is substituted with "4-pi ridi 1meti lamino"; EMÍES) M + H * = 657.

EXAMPLE 60 Preparation of l-CCC3-C (2-dibenzofurani 1ßu1foni 1) amino3-2-oxoproPi '1 3-3- (4-Pir i di ni iraeti l) benzamide The title compound was prepared following the procedure of Example 58 (a) - (e), which concept is substituted, "Cbz-leucine" with "benzoic acid"; MS (ES) M-H * = 551, M (ES) M + C1 ~ = 547.

EXAMPLE 61 Preparation of (S) -Cl-CCC3-C (Z-dibenzofuran 1ßu1fon 1) amino3-2-oxopropy 13- - 4-pyridinium-1-methyl-1-amino3carboni 13-3-methyl-1-butyl-1,3-phenylmethylcarbamate The title compound was prepared following the procedure of example 58 (a) - (e), ectocept that "benzylamine" is substituted with "4-pyridi Imeti lamina" and "2-dibenzofuransulfoni chloride" with "Cbz- leucine and HBTU ", and" Cbz-leucine and HBTU "with" 2-dibenzofuransulphonic chloride "; EMÍES) M + H * = 657.

EXAMPLE 62 Preparation of 2-CN-β-benz loxycarboni 1-L-leuc nyl) 3-2t-CN'- (4- enox in 1ßu1foni1) 3carbohi raz a a) Methyl ester of N-benz lo carboni 1-L-leucine To a stirred solution of L-leucine methyl ester hydrochloride (2.2 g, 11.0 mmol) in 1,4-dioane (20 ml), Na3CO3 (12.1 ml, 2M in water) was added, followed by benzyl chloroformate (1.96 g, 11.5 mmol). The mixture was stirred at room temperature for 4 hours, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated to yield the title compound as a colorless oil (3.1 g, 100%). H NMR (400 MHz, CDC13) or 7.34 (m, 5H), 5.27 (d, 1H), 5.12 (S. 2H), 4.41 (S, 2H), 3.75 (s, 3H), 1.65 (m, 3H) 0.96 (m, 6H). b) N-benzylcarbomethyl-luccinylhydrazine To a stirring solution of the compound of example 62a) 0.3.1g, 11.0mmol) in 15ml of methanol, hydrazine hydrate (5.9g, 118mmol) was added. ). The solution was stirred at room temperature for 16 hours, then concentrated to give the title compound as an off-white solid (3.1 g, 100%). MS (ESI): 2B0.2 (M + H *). c) (lS) -l-benzyl icarbo lamino-3-methyl-l- (l »3» 4-o? adiazol-2-on-5-yl) butane. To a stirred solution of the compound of Example 62 (b) (3.0 g, 10.8 mmol) in toluene (50 mL), phosgene (56 mL, 193M in toluene) was added. The solution was heated to reflux for 4 hours; it was then concentrated to yield the title compound as a light yellow foam (3.15 g, 96%). MS (ESI): 306.1 M + H) *. d) 2-CN-iN-benzylocarbon 1-L-leucine I) carbohydrazide To a stirring solution of the compound of example 62 (c) (0.147 g »0.482 mmoles) in 2 ml of methane! hydrazine hydrate (0.241 g »4.82 mmol). The solution was stirred at room temperature for 24 hours, then concentrated and purified by column chromatography (silica gel, methanol / dichloromethane) to give the title compound as a white foam (0.097 g, 60%). MS (ESI): 338.2 (M + H) *. e) 2-CN- (N-benzylcarbon l-L-leucine 1) -2t-CN '- (4-pheno? i-phen lysulfoni 1) 3carbohydrazide. To a stirred solution of the compound of example 62 (d) 0.049 g, 0.288 mmoles) in 2 ml of DMF, pyridine was added ≤0.46 g »0.576 mmole), followed by 4-phenoyl chloride Isulfoni it (0.155 g, 0.576 mmoles). The solution was stirred at room temperature for 16 hours, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate / liver) to give the title compound as a white solid (0.052 g, 32%). MS (ESI): 570.1 (M + H) *. 15B EXAMPLE 63 Preparation of 2-CN (N-benzyloxycarboni1-L-a1ani1) -2 * -CN-n-benzyl-1-oxycarbon 1-L-1-eucinyl) 3-carbohydrazide To an agitated solution of the compound of the example 62) (0.100 g, 0.297 mmol) in 2 ml of DMF, was added N-benzyl? -carbonyl-L-alanine (0.070 g, 0.312 mmol), l-hydro? Ibenzotriazole (0.008 g, 0.059 mmol). and l- (3-dimethylaminopropy 1) -3-ethylcarbodiimide hydrochloride .060 g. 0.312 mmoles). After stirring at room temperature for 16 hours, the solution was emptied into 150 ml of water. The precipitate was filtered and washed with water 150 mL) and dried under high vacuum to yield the title compound as a white solid, 0.062 g. 39%). EMÍESI): 543.1 ÍM + H) *.

EXAMPLE S Preparation of 2-CN- (N-benzyloxycarbonyl l-L-leucine 1) 3-2'-CN'- (4- in l-benzo-l) 3-carboh-drazide The title compound was prepared as a white solid, following the procedure of Example 63, except that N-benzylocarboni 1-L-alanine was substituted with 4-phenyl-1-benzoic acid, (0.121 g, 53%) . MS (ESI): 518.1 M + H) *.

EXAMPLE 65 Preparation of 2-CN-N-benzyloxycarbon l-L-leucine I) 3-Z'-CN'- (4-methoxybenzoi 1) 3carboh drazide The title compound was prepared as a white solid, following the procedure of Example 63, except that N-locarbonyl 1-L-alanine was substituted with 4-metho-ibenzoic acid (0.057 g, 27%). MS (ESI): 472.1 (M + H) * EXAMPLE 66 Preparation of 2-CN- (N-benzyloxycarboni 1-L-leucinyl) 3-Z'-CN'- (4-methoxybenzoi 1) 3carbohydrazide The title compound was prepared as a white solid, following the procedure of Example 63, except that N-benzene-1-L-alanine was substituted with 4-phenoxybenzoic acid (0.102 g, 43%). MS (ESI): 534.1 (M + H) *.

EXAMPLE 67 Preparation of 2- (N-acetyl) -2'-CN- (N-benzyloxycarbonyl-1-L-leucine I) 3-carbohydrazide To the compound of Example 62 (d) (O.100 g, 0.297 vials) was added acetic anhydride (? 303 g, 2.97 mmoles). The solution was stirred at room temperature for 16 hours, then concentrated to an off-white solid which was washed with dichloromethane to give the title compound as a white solid (0.086 g, 76%). EM ESI): 380.1 (M + H) *.

EXAMPLE 63 Preparation of 2-CN- (N-acetyl-1-L-leucine I) -2t-CN '- (N-benzyloxycarbon 1-L-a1ani1) 3-carbohydrazide a) 2-CN- (N-benzylocarboni 1-L-alan 1) carbohydrazide The title compound was prepared as a light yellow foam, following the procedure of Example 62 (a) -62id), e? The L-leucine methyl ester hydrochloride is substituted with L-alanine ethyl ester hydrochloride in step a) (1.1 g, 3.8 mmol). MS (ESI): 296.2 (M + H) *. b) 2-CN-α-acetyl-1-L-leucyl) 3-2 f-CN * - (-benzylocarbonate 1-L-alanyl) carbohydrazide To a stirred solution of the compound of Example 63 (d ) (0.15 g, 0.508 mmoles) in DMF (2 ml), N-acetyl-L-leucine was added? 0.92 g, 0.534 mmol), 1-hydro? I benzotriazole 0.014 g »0.102 mmol), and l- (3-dimethylaminopropy 1) -3-ethylcarbodiimide hydrochloride (0.102 g »0.534 mmol). After stirring at room temperature for 16 hours, the solution was diluted with ethyl acetate and washed successively with water, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried (MgSO ^). it was filtered and concentrated. The residue was purified by column chromatography (silica gel, methanol / dichloromethane) to give the title compound as a white solid (0.028 g, 12%). MS (ESI): 451.1 M + H) *.

EXAMPLE 69 Preparation of Z-CN- (N-acet 1-L-a1ani 1) 3-2'-CN '- (N-benzyloxycarbon 1-L-leucine 1) 3carbohydraz The title compound was prepared as a white solid following the procedure of Example 68 (b). except that N-acetyl-1-L-leucine is substituted with N-acetyl-1-L-alanine and 2-CN-N-benzylocarbonyl 1-L-alani 1) 3carbohydrazide with 2-CN-N-benzyl? icarbo 'l-leucini 1) 3-carbohydrazide; ÍO.050 g. 25%) EEM (ESI): 473.1 ÍM + Na) * EXAMPLE 70 Preparation of Z-CN- (N-benzyloxycarbon 1-L-leucine 1) 3-Z'-CN'-C4- (N-dimet laminomethyl 1) benzoyl) 33carboh drazide a) Methyl 4- (N-dimethylamiomethyl) benzoate Methyl 4-β-bromomethyl) benzoate (2.0 g.

B.73 mmoles) to a saturated solution of dimethylamine in methanol. After stirring for 25 minutes, the solution was concentrated and the residue was partitioned between IN NaOH and ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO 4), filtered and concentrated to provide the title compound as a colorless liquid (1.67 g, 99%). * -H NMR (250 MHz, CDC13) or 8.00 (d, 2H), 7.39 (d, 2H), 3.91 (S, 3H), 3.47 (d, 2H), 2.25 (8, 6H). b) Lithium salt of 4-iN, N-dimethylaminomethyl 1) benzoic acid The compound of Example 70 (a), 1.67 g, B.6 mmol) was dissolved in THF / HaO (1: 1), and Did you add LiOH-H2? (0.39 g, 9.3 mmol). The mixture was stirred at room temperature for 0.5 hour, then refluxed for 1.5 hours. The mixture was concentrated, redissolved in 25 ml of water and reconcentrated to yield a white solid (1.6 g, 100%). * H NMR (400 MHz, CD3OD) or 7.94 (d, 2H), 7.36 id, 2H), 3.64 (s, 2H) »2.35 (S. 6H). c) 2-CN-N N-benzyloxycarbon 1-Ll euci ni 1) 3-2'-CN'-C4- (N »N -direneti laminomethyl) 1) benzoi 1) 33carbohydrazide The title compound was prepared as a light yellow solid »following the procedure of Example 69 (b), e) replacing N-acetyl-1-L-leucine with the lithium salt of 4- (N» N-dimethylaminomethyl) 1 ) benzoic acid and 2-CN- (N-benzylocarbaryl 1-L-alanyl) carbohydrazide with 2-CN- (N-benzyl? -carbonyl-L-leucine 1) 3-carbohydrazide; (0.050 g, 17%), MS (ESI): 499.1 ÍM + H) *.

EXAMPLE 7 Preparation of 2-CN- (IM-benzyloxycarbonyl-1-L-1-echin-1) 3-2'-CN-C4-hydroxy-C3- (4-morfo1 nometi1) 33-benzoi-13-carbohydrazide The title compound was prepared as a white solid, following the procedure of Example 68 (b), except that N-acetyl-1-L-leucine is substi tuted with 4-hydroxy acid. i-3- (4-morphol and nomethyl) benzoic and 2-CN- < -benci lo? icarboni 1-L-alam "1) 3carbohydrazide with 2-CN- (N-benzyl? i-carboni lL-leucin 1) 3carbohydrazide (0.065 g, 26%) .MS (ESI): 557.0 (M + H) *.

EXAMPLE 73 Preparation of 2-CIM- (N-benzloxycarboni 1-L-leucine 1) 3-2'-CN'- C4- (-N-dimethylamino) benzylox carbon 1-L-leucinyl-3-carbqhldrazid§ a) L-leucine α-isocyanate methyl ester L-leucine methyl ester hydrochloride (25 g, 0.14 mole) was dissolved in methylene chloride (450 ml), cooled to 0 ° C, and pyridine was added (43.5 g »0.55 moles» 44.5 ml); then a 1.93 M solution of phosgene in toluene (0.18 mol »92.7 ml) was added slowly. After stirring at 0 ° C for 2 hours, the mixture was poured into 1400 ml of 0.5 N HCl and 900 ml of ice. The organic layer was washed with 1400 ml of 0.5 N HCl and 900 ml of ice. The aqueous layers were extracted with methylene chloride (450 ml) and the combined organic layers were washed with 1400 ml of saturated brine and 900 ml of ice, then dried (MgSO 4). it was filtered and concentrated. The residue was distilled (56-5B ° C, 0.7B mmHg) to provide the title compound as a colorless liquid (20.4 g, 86%). AH NMR (250 MHZ »CDC13) 54.04 (dd» 1H) »3.82 (S, 3H), 1.92-1.72 (m, 1H)» 1.69-1.62 (rn »2H), 0.96 (d.3H), 0.94 (d) , 3H). b) 4- (N-dimethylamino) benzyl alcohol To a stirred solution of the compound of the example 70 (a) (1.63 g, 8.4 mmol) in 25 ml of ether, cooled to 0 ° C. a 1 M solution of lithium aluminum hydride (8.4 mmol, 8.4 ml) was added dropwise. After 5 minutes, the reaction was quenched by the addition of water (0.33 ml). Aqueous 15% NaOH (0.33 ml) and water (1.0 ml). The precipitate was removed by filtration, washed with ether 2 times and the filtrate was concentrated to provide the title compound as a colorless oil (1.36 g, 9B%). NMR (250 MHz. CDC1.,) At 7.32 (d, 2H), 7.28 (d, 2H), 4.68 (S, 2H), 3.41 ís, 2H), 2.22 (S, 6H). c) N-C4-N-dimethyl laminomethyl ester 1) benzylcarbonyl 13-L-leucine. A solution of the compound from example 72 (a> = 1.0 g, 5.8 mmol) and the compound of example 72 (b) in toluene (6 ml) was heated to reflux for 24 hours.The solution was concentrated and the residue was concentrated. purified by flash chromatography on 60 g 230-400 mesh silica gel, eluting with 5% methanol in methylene chloride, to provide the title compound as a light yellow oil (1.71 g, 87%). aH NMR (400 MHz, CDC13) at 7.31 (s, 4H), 5.13 (d, 1H), 5.10 (8, 2H), 4.41, 1H), 3.74, 3H), 3.43 and 2H, and 2.24, respectively. s »6H), 1.70-1.62 m» 2H), 1.52 (m, 1H), 0.96 (d, 3H), O.94 (d, 3H). d) Lithium salt of N-C4- (N, N-dimethylaminomethyl) benzyl? -carboni 1 -L-leucine The title compound was prepared as a white solid, following the procedure of Example 70Cb), ecept that 4- is replaced < N »N-dimethyl laminomethyl 1) methyl benzoate with N-C4- (N, N-dimethylaminomethyl) 1-benzylcarbonyi 13-L-leucine methyl ester (1.57 g» 95%). H NMR (400 MHz, CD30D) or 7.35 (d, 2H), 7.30 (d, 2H), 5.06 (dd, 2H), 4.10 (dd.1H), 3.48 (S, 2H), 2.23 id. 6H). 1.69-1.51 μm, 3H), 0.94 (d.3H), 0.93 (d, 3H). e) 2-CN- (N-benzylocarbonyl L-L-leucine 1) 3-2'-CN'-C4-N, N-di-me laminomethyl 1) benzyl-3-carbonyl-L-leucine-13-carbohydrazide. The title compound was prepared as a white solid, following the procedure of Example 6B (b), except that N-acetyl-1-eucine was substituted with N-C4-N-N-dimethylaminomethyl 1) benzyl. icarboni 1 -L-leucine and 2-CN- (N-benzylcarbonyl-L-alanyl) 3-carbohi-drazide with 2-CN- (N-benzyloxycarbon 1-L-leucine 1) 3-carbohydrazide; (0.069 g, 18%). MS (ESI): 642.1 (M + H) *.

EXAMPLE 73 Preparation of Z- (N-benzoyl) -Z'-CN '- (N-benzyloxycarbonyl-1-L-leucine I) 3-carbohydrazide The title compound was prepared as a white solid, following the procedure of Example 62 (e), except that 4-phenoxyphenylsulfonyl chloride was substituted with benzoyl chloride (61 mg, 31%). MS (ESI): 442.1 (M + H) *.

EXAMPLE 74 Preparation of 2-CN-N-benzyloxycarbonyl-L-leucine 1) 3-2'-CN'- C3- (4-mor or inomethyl) benzoyl-33-carbonyl-araz a) Methyl 3- (4-morphonomethyl) benzoate A solution of morpholine (0.B36 g, 9.6 mmol) and methyl 3- (bromomethyl) benzoate in THF (5 ml) and DMF (5) was stirred. at 50 ° C for 3 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated to yield a colorless oil (0.872 g, 3.72 mmol). XH NMR (400 MHz »CDC1,") at 7.99 (8. 1H). 7.91 (d, 1H), 7.55 id, 1H), 7.47 ít, 1H), 3.94 ÍS, 3H), 3.72 (m, 4H). 3.53 SS »2H), 2.46 mm, 4H). b) 3-4-morphol i nometi 1) benzoic acid To a solution of the compound of example 74 (a) (0.872 g, 3.72 mmol) in THF (3 ml) and water (3 ml) was added lithium hydroxide monohydrate í? .171 g. 4.0B mmoles). After standing at room temperature for 3 hours, the solution was concentrated. The residue was redissolved in water (5 ral) and 3N HCl was added and the solution was lyophilized to yield a yellow solid (0.822 g »3.72 mmol). MS (ESI): 222.0 (M + H) *. c) 2-CN- (N-Benzyloxycarbon l-L-leucine 1) 3-2t-CN'-C3-γ4-morphol and nomethyl) benzoyl-3-carbohydrate. The title compound was prepared as a white solid "following the procedure of Example 68IB). This means that N-acetyl-1-L-leucine is substituted with 3- (4-morphonomethyl) benzoic acid and 2-CN-N-benz locarbonyl-L-alanyl) carbohydrate with 2- N- í-benc i lo? i carboni 1-L-leucine 1) 3carbohi drazide; í? .056 g, 20%). EM ÍESI): 541.0 ÍM + H) *.

EXAMPLE 75 Preparation of Z-CN- (3-benzyloxybenzo 1) 3-Z'-CN '- (N-benzloxycarbonyl 1-L-leucinyl) 3-carbohydraz a a) Methyl 3-benzyloxy enzoate To a suspension of NaH (0.395 g »9.87 mmol, 60% in mineral oil) in DMF (20 ml) was added methyl 3-hdro-benzoate (1.0 g, 6.58 g). mmoleß). After stirring for 15 minutes at room temperature, benzyl bromide (11 g (6.58 mmol) was added, after stirring at room temperature for 3 hours, the solution was partitioned between ethyl acetate and water. with water (2.75 ml), saturated aqueous sodium bicarbonate and brine, then dried (MgSO4). it was filtered and concentrated to yield an off-white solid io.013 g. 4.2 mmoles). X H NMR (400 MHz »CDC13) 57.67 (m, 2H), 7.48-7.34 (m» 6H) »7.19 (m, 1H), 5.12 ís, 2H). 3.95 ís »3H). b) 3-Benzyl benzoic acid To a solution of the compound of Example 75) (0.400 g »1.65 mmol) in THF (2 ml) and water (2 ml) was added lithium hydroxide monohydrate (0.076 g). »1.B2 mmoles). After stirring at reflux for 5 hours. the solution was partitioned between ethyl acetate and 3N HCl. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated to give a white solid (0.355 g, 1.56 mmol).

^ -H NMR (400 MHz, CD30D> or 1.58, m, 2H), 7.36-7.24 m, 6H), 7.10 (m, 1H>, 5.04 (S. 2H). c) 2-CN-3-benzyl-benzoyl) -2'-CN'-β-benzylcarbonyl 1-L-leucine 1) 3-carbohydrazide The title compound was prepared as a white solid, following the procedure of Example 68 (b), eεcept that N-acet 1-L-leucine is substituted with 3-benzyl-ibenzoic acid and 2-CN-NN-benzylocarbaryl 1-L-alanyl) carbohydrazide, with 2-CN-iN-benz lo? icarboni lL-leucini 1) 3-carbohydrazide; í? .062 g. 25%). EMESI): 54B.1 (M + H) *.

EXAMPLE 76 Preparation of 2-CN- (N-benzyloxycarboni 1-L-leucine I) 3-2'-CN'-C4-C3- (N-N-di and 1-amino) -l-prop-1-oxo-benzo-1-carbohydrate a) 4-C3- (N, N-dimethylamino) -l-propyloyl methylbenzoate To a solution of methyl 4-hydroxybenzoate (1.0 g, 6.58 mmol) »3-dimethylamino- 1-propanol (1.01 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0 ° C in THF (20 mL), was added, dropwise, diisopropyl azodicarbo-lactate (1.99 g, 9 g). .7 mmoles). After stirring for 16 hours at room temperature, the solution was concentrated and the residue was purified by silica gel column chromatography »methanol / dichloromethane to yield the title compound as an oily solid (1.25 g, 5.2 mmol). MS (ESI): 238.1 (M + H) *. b) 4-C3- (N, N-dimethylamino) -l-prop acid? the? benzoic acid The title compound was prepared as a tan solid, following the procedure of Example 74 (b), except that methyl 3- (4-morfol nomethyl) enzoate is substituted with 4- 3-y, N-dimethylamine. ) -l-propi lo? i methyl benzoate; (1.17 g, 5.2 mmol). MS (ESI): (M + H) *. c) 2-CN-1-benzylcarbonyl 1-Ll-nucyl) 3-2f-CN'-C4-C3-N-N-dimethylamino) -l-propyl-3-benzo-1-carbohydrazide The compound was prepared of the title as a white solid, following the procedure of example 68 (b). e) that N-acetyl-1-L-leucine is substituted with 4-C3- (N.N-dimethylamino) -l-propyloxybenzoic acid. and 2-CN- (N-benz locarbaryl 1-L-alanyl) 3-carbohydrazide with 2-CN-N-benz locarbonyl L-L-leucine 1) 3-carbohydrazide; (0.060 g, 21%). MS (ESI): 543.1 (M + H) *.

EXAMPLE 77 Preparation of Z-CN- (Z-benzylox benzo 1) 3-2-CN '- (N-benzyl-C-carboxy-1-L-1-echin-1) 3-carbohydrazide The title compound was prepared as a white solid, following the procedure of example 68 (b), except that N-acet 1-Ll eucine was substituted with 2-benzyl-ibenzoic acid and 2- N- β-benzylcarboni 1-L-alani 1) carbo-hydrazide, with 2-CN- (N-benz locarbonyl-L-leucine 1) 3-carbohydrazide (0.056 g, 23%). MS (ESI): 548.1 (M + H) *.

EXAMPLE 7B Preparation of 2-CN- (-benz lox carboni 1-L-leucinyl) 3-2t-CN'- C3- (4-pyridi-1-methoxy) benzoi133carbohydrazide a) Methyl 4-pyridinylmethoxybenzoate The title compound was prepared as a yellow solid, following the procedure of Example 76 (a), except that methyl 4-hydroxybenzoate was substituted with methyl 3-hydroxybenzoate and 3- dimethylamino-l-propanol with 4-pyridylcarbinol (0.599 g, 2.5 mmol). MS (ESI): 244.1 (M + H) *. b) 4-pyridinimethylbenzoic acid The title compound was prepared as a yellow solid, following the procedure of Example 75 (b), which is replaced by methyl 3-benzyloxybenzoate with Methyl 4-pyridyl methylbenzoate, 0.386 g, 1.69 mmoles). AH NMR 4400 MHZ »CD3OD) B B.54 d» 2H) »7.64 (m, 2H)» 7.57 m »2H), 7.40 (m.1H), 7.26 (m.1H), 5.24 ís, 2H). c) 2-CN-lN-benzylcarbonyl-L-leucine l) 3-2'-CN'-C3-β4-pyridylmetho-i) benzoylcarbohydrazide The title compound was prepared as a white solid, following the procedure of Example 68 (b), e) that N-acetyl-L-leucine is substituted with 4-pyridinylmethoxybenzoic acid and 2-CN- (N-benz locarbonyl-L-alanyl) carbohydrazide with 2-CN-1 -benci lo? icarboniLL-leucini 1) 3carbohydrazide (0.219 g, 67%). MS (ESI): 549.1 (M + H) *.

EXAMPLE 79 Preparation of Z-CN- (4-benzyl? Ibenzoyl) 3-Z »CN'benzyl? I-carbon 1-L-leucine 1) 3-carbohydrazide The title compound was prepared as a white solid, following the procedure of Example 75 (a) -75c). ecept that 3-hydroxybenzoic acid methyl ester is substituted with methyl 4-hydroxybenzoate (0.160 g, 49%). EM (ESI): 548.1 (M + H) *.

EXAMPLE 90 Preparation of 2-CN- (N-benzyloxycarbonyl 1-L-leucine 1) 3-2'-CN'- (3-benzyloxy-5-methoxy) benzoyl-1-carbohydrazide a) 3-Hydro? i-5-methoxybenzoate methyl. A suspension of methyl 3,5-dihydro-ibenzoate (2.0 g »11.9 mmol) was stirred at reflux. K3C03 (1.6 g, 11.9 mmol) and iodomethane (1.7 g, 11.9 mmol) in acetone (100 μl). After stirring for three hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a white colored solid (δ 813 g »4.4 mmol). * H NMR Í400 MHz »CDC13 or 7.16 ím, 1H), 7.12 < m, 1H), 6.61 (m, 1H) »5.04 SS» 1H) »3.91 (s, 3H) 3.82 (S.3H). b) methyl 3-Benc lo? i-5-meto? i benzoate. The title compound was prepared as a tan oil "following the procedure of Example 80 (a)» ect that methyl 3'-5-dihydro-ibenzoate is substituted with 3-hydro? I-5-methoxy -methylbenzoate "and iodomethane with benzyl bromide; (1.2 g, 4.4 mmoles). H NMR (400 MHz, CDC13) at 7.45-7.31 (m.6H), 7.24 (S, 1H), 6.76 (m, 1H), 5.09 s, 2H, 3.95 and 8 3H), 3.84 (8, 3H). c) Acid 3-benc lo? i-5-metobenzoic acid. The title compound was prepared as an orange solid, following the procedure of Example 75 (b), except that methyl 3-benzyloxybenzoate with 3-benzyl? I-5-methoxy was substituted. methyl benzoate. AHNMR Í400 MHz »CDC13) or 7. 42-7.20 (m, 7H), 6.71 (m, 1H); 5.05 ÍS, 2H), 3.80 (s, 3H > d) 2- N-1-N-benzyllocarbonyl 1-L-leucim "1) 3-2'-CN '- (3-benzyl] -5-metho) benzoyl-3-carbohydrazide The compound was prepared of the title as a white solid "following the procedure of example 68IB), e that replaces N-acet 1-Ll eucine with 3-benzyl-5-metho-ibenzoic acid and 2-CN-1 - benci locarbon 1-L-alan l) carbohydrazide with 2-CN- (N-benzylo car oni 1-L-leuci il) 3carbohydrazide; (0.201 g 59%). EMÍESI): 57B.0 ÍM + H ) *.

EXAMPLE 61 Preparation of 2-CN- (N-benzyloxycarbonyl 1-L-leucine 1) 3-2'-CN'- (3-benzyloxy-4,5-dimethoxy) benzoylcarbohydraz a The title compound was prepared as a white solid "following the procedure of example 68 (b)" except that N-acetyl-L-leucine is substituted with 3-benzyloxyl-4,5-dimethoxybenzoic acid and 2- CN- (-benzyl? -carbonyl 1-L-alanyl) 3-carbohydrazide with 2-CN-N-benzylcarbonyl-L-leucine 1) carb? Hydrazide; Í0.155 g, 43%). EMÍESI): 607.9 (M + H) *.

EXAMPLE 62 Preparation of Z-CN- (N-benzloxycarbon 1-L-leucine 1) 3-2'-CN '- (3-benzyloxy-5-ethoxy) benzoylcarbohydrazide The title compound was prepared as a white solid, following the procedure of Example BO (a) -80 (d). except that iodomethane is substituted with iodoethane in step (a). (0.162 g, 46%). MS (ESI): 592.3 (M + H) *.

EXAMPLE 93 Preparation of 2-CN-iN-benzyloxycarboni IQI icinyl) 3-2'-CN'-iN-benz lox carboni 1-L-leuc nil) 3carboh drazide The title compound was prepared as a white solid, following the procedure of Example 6BIB), except that N-acetyl-1-lucine is substituted with N-benzylcarboxylic acid and 2-CN-N-benzyl carbon. L-alanyl) 3-carbohydrazide with 2-CN-β-benzyloxcarbon l-leucine 1) 3-carbohydrazide; 00.204 g, 65%). EMÍESI): 529.2 (M + H) *.

EXAMPLE 94 Preparation of 2-CN-O-benzyl? Ibenzoyl) 3-2'-CN '- (N-benzylocarbon 1-L-prol or 1) 3carboh draz da a) 2-CN- (3-Benzyl? ibenzoi 1) carbohydrazide The title compound was prepared as an off-white solid, following the procedure of Example 62b) -62id). e) that N-benzylcarbonyl 1-L-leucine methyl ester is substituted with methyl 3-benzylbenzoate in step ib); í? .421 g »67%). MS (ESI) 301.1 (M + H) *. b) 2-CN-O-benzyl? ibenzoyl) 3-2 * -CN "- (N-benzyl? -carboni 1-L-prol ini 1) Dcarbohydrazide The title compound was prepared as a white solid »Following the procedure of Example 68 (b), except that N-acetyl-1-Llucine is substituted with N-benzyloxycarbon 1-L-proline and 2-CN-N-benzylocarbonyl 1-L-alanyl ) carbohi razi a with 2-CN- (3-benzyl? ibenzoi 1) -carbohydrazide »'(0.219 g» 62%) .MS (ESI): 532.0 (M + H) *.

EXAMPLE 95 Preparation of 2-CN- (N-benzyloxycarbon 1-L-leucine 1) -2'-CN'- (4-pheny1 in laceti 1) 3carbohydraz The title compound was prepared as white solid urx, following the procedure of Example 6B (b). except that N-acet-1-L-1-euc a is substituted with 4-biphenylacetic acid and 2-CN-N-benz locarbaryl 1-L-alani 1) -carbohydrazone. with 2-CN---benc lo? icarboni l-L-leucini 1) 3-carbohydrazine; (0.224 g, 71%). MS (ESI): 554.2 (M + H) *.

EXAMPLE 96 Preparation of (ZtS) -Z-CN- (3-benzyloxybenzoi1) 3-2'-CN * - (N-benzl-1-oxycarbon 1-Z-arainobutyri) 3-carboh drazide The title compound was prepared as a white solid "following the procedure of Example 6B (b)" except that N-acetyl-L-leucine is substituted with (S) -N-benzylcarbaryl acid 1-2-aminobut and 2-CN- (N-benzylocarboni 1-L-alani 1) carbohydrazide with 2-CN-3-benzyl ibenzoi I) 3-carbohydrazi a; í? .244 g »70%). MS (ESI): 520.3 (M + H) *.

EXAMPLE 87 Preparation of 2, Z'-CNiN | l-Cbiß-í4-feni eni laceti 1) 33- carbohydrate To a stirring solution of carbohydrazide (0.200 g »2.22 mmol) in DMF (12 mL), 4-biphenylacetic acid (1.04 g, 4.B9 mmol) was added. 1-hydroxy-benzotriazole (0.60 g, 0.444, min), and l- (3-dimethylaminopropyl) -3-ethylcarbodihydrochloride, 0.937 g, 4.B9 mmol). After stirring at room temperature for 16 hours, the solution was poured into 150 ml of water. The precipitate was filtered and washed with water (150 ml) and dried under high vacuum to yield the title compound as a white solid; (0.977 g, 92%). EMÍESI): 501.1 (M + H) *.

EXAMPLE BB Preparation of (2TRS) -Z-CN- (N-benzyloxycarbon 1-L-leucine l) - 2'-C2-i4-phene Ifeno? I) rop oni 1 carbohydraz The title compound was prepared as a white solid, following the procedure of Example 6B (b), except that N-acet l-L-leucine was substituted with 2- (4-17B) acid. feni lfeno? i) propionic »and 2-CN- (N-benz locarboni 1-L-alani 1) 3-carbohydrazide with 2-CN- (N-benzylocarboxy '1-L-leucim" 1) -carbohydrazide (0.183 g, 73%). MSIESI): 562.3 M + H) *.

EXAMPLE 99 Preparation of 2-CN- (3-benzyl-1-benzo-1) 3-2'-CN '- (4-methyl-1 -pentane-1) 3-carbohydraz The title compound was prepared as a white solid "following the procedure of Example 68 (b). except that N-acetyl-L-leucine is sub-substituted with 4-methylpantanoic acid "and 2-CN- (N-benzyloxycarbonyl 1-L-alani 1) 3-carbohydrazide with 2-CN- (3-benzyl) lo? iben? ol) carbohydrazide; (0.079 g, 30%). EMÍESI): 399.3 (M + H) *.

EXAMPLE 90 Preparation of (2RS, ZTRS) -Z, ZT-CN.N'-Cbiß-CZ- (4- enyl eni 1) -4-roe Ipentanoi 1) 33carbohydrazide a) 4-Met l-2- (4-phenylphenyl) pent-4-enoic acid. To a stirring solution of diisopropylamin (0.573 g »5.31 mmole) in THF (5.2 ml)» at 0 ° C »was added drop by drop» n-butyllithium (2.1 ml »5.22 mmol» 2.5 M in he? year). After stirring for 15 minutes at 0 ° C. The mixture was cooled to -78 ° C and a solution of 4-biphenic acid (80,500 g, 2.36 mmole) in THF (2 ml) was added dropwise.

After heating again at 0 ° C and cooling to -7B ° C. 3-bromo-2-methylpropane (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at -78 ° C for one hour, the reaction was extracted with 2 ml of water and then concentrated. The residue was redissolved with water and extracted with ether (100 ml). The aqueous layer was acidified (3N HCl) and extracted with ether (3 X 100 mL). The organic layers were combined, dried (MgSO 4), filtered and concentrated to give a white solid (0.449 g, 72%). MS (ESI): 265.3 (M + H) *. b) 4-Methyl 1-2- (4-phenyl-1-pheny1) pentanoic acid To a stirred solution of the compound of example 90 (a) (0.499 g »1.69 mmoles) in ethyl acetate (25 ml) was added palladium on carbon (0.225 g). After stirring under a hydrogen balloon for 16 hours, the mixture was filtered through celite. The filtrate was concentrated to yield an off-white solid (0.430 g, 95%) MS (ESI): 267.4 M + H) *.

Or 2RS.2'RS) 2,2'-CN.N'-CbiS-C2- (4-phenylphenyl) -4-methyl-pentanoyl) 333carbohydrazide The title compound was obtained, after purification by column chromatography silica, methanol / dicotene oromethane), as a white solid following the procedure of example 87, eεcept that sub-acid 4-biphenyl-1-acetic acid with 4-met 1-2- (4-phenyl-1-phenyl) pentanoic acid; 0.143 g, 33%). EMÍESI): 591.3 (M + H) *.

EXAMPLE 3 Preparation of (2 'RS) -2-CN- (N-benzylox carbon 1-L-l euc ni 1) 3- 2'-CN-C2- (4-pheny1phen1) -4methylpentane 1) 33carbohydrazide The title compound was prepared as a white solid, following the procedure of Example 68IB). e) that N-acetyl-L-leucine is substituted with 4-methyl-2-yl-4-phenyl-phenyl-1-pentanoic acid, and 2-CN-N-benzylcarbonyl-1-L-alanyl) -carbohydrazide with 2-N-acetyl-L-alanyl) -CN-í -benci what? charcoal L-L-leucinyl) 3-carbohydrazide; (O.11 g, 42%). EMÍESI): 588.1 (M + H) *.

EXAMPLE 3 Preparation of (2-RS) -2-CN- (3-benzyloxybenzo 1) 3-2 '- (4- in 1 in 1) -4-methylpentanoyl) 3carbohydraz The title compound was prepared as a white solid, following the procedure of Example 68 (B). except that N-acetyl-L-leuci a is substituted with 4-methyl 1-2- (4-phenyl-phenyl-1) pentanoic acid. and 2-CN- (N-benzylocarbaryl 1-L-alanyl) 3-carbohydraz a with 2-CN- (3-benzyloxyzo) 1) 3-carbohydrazide; (0.195 g, 53%), MS (ESI): 551.1 ÍM + H) *.

EXAMPLE 93 Preparation of 2-CIM- (3-benzylo-ibenzoyl) 3-2'-CN'-N-benzloxycarboni 1-N-met-1-L-leucinyl) 3-carbohydrazide The title compound was prepared as a white solid, following the procedure of example 68 (b), except that N-acetyl-1-L-leucine was replaced with N-benzylocarboni 1-N-methyl-1-L -leucine and 2-L "N- (N-benzylocarboxy 1-L-alani 1) 3carbohydrazine with 2-CN-O-benzyl? i benzoi 1) carbohydrazide (0.341 g, 91%), EM ( ESI): 562.2 (M + H) *.

EXAMPLE 94 Preparation of Z-CN- (3-benzyl-oxo-benzoyl) 3-2'-CN'-CN- (2-Pirid-l-methoxycarbon-1) -L-1-euci or 133-carbohydrazide a) Methyl ester of N-2-pyrid i 1-methocarbom '1) -L-leuc Na The title compound was prepared as a brown oil "following the procedure of Example 72c), which is it replaces alcohol 4- (NN-dimeti 1 ami no) benzyl 1 with 2-pyridylcarbinol; (B.06 g, 89%) »EMÍESI): 281.2 (M + H) *. b) 2-CN- (2-pyridin 1 i lmeto? icarbon 1) -L-leucini 1 carbohydrazide The title compound was prepared as a light yellow foam »following the procedure of the example 62 (b) -62 (d) »ecept that L-leucine methyl ester is substituted with N- (2-pyridinium lmeto-icarboni 1) -L-leucine methyl ester in step (b > 0.598 g »69%). MS (ESI): 339.3 M + H) *. c) 2-CN- (3-benz lo? ibenzoi 1) -2'-CNt-CN- (2-pyridine Imeto? i-carboni 1) -L-leuc ni 133carbohydrazide The title compound was prepared as a white color, following the procedure of Example 68 (b), e) that N-acetyl-L-leucine is substituted with 3-benzyl-ibenzoic acid. and 2-CN- (N-benz locarbaryl 1-L-alani l> 3-carbohydrazide with 2-CN- (2-pyridinylmethocarbonyl 1) -L-leucine! 3-carbohydrazide; (0.057 g, 33%) MS (ESI): 549.2 (M + H) *.

EXAMPLE 96 Preparation of 2-CN-C3- (4-pyridyl-1-methoxy) -benzoyl 133-Z'-CN'-CN- (2-iridinium-1-methoxycarbon-1) -L-1-eucine 133carbohydrate The title compound was prepared as a yellow solid, following the procedure of Example 68 (b), except that N-acet-L-leucone is substituted with 3- (4-pyridinylmethoxy) benzoic acid and 2-CN- ( N-benz lo? Carboni 1-alanyl) 3-carbohydrazide with 2-CN-2-pyridine lmeto? -carboni 1) -L-leucine? '1 carbohydrazide; (0.088 g, 27%), MS (ESI): 550.2 (M + H) *.

EXAMPLE 96 Preparation of (2RS) -Z-CN-C2- (4-phenyl-1-phenyl) -4-methyl-1- pentanoyl) 33-Z, -CN, -CN- (Z-pyridine-1-methoxycarbonyl) -L-leycinj 133? arfrQhidr3ZJda The title compound was prepared as a yellow solid, following the procedure of Example 6B (b), except that N-acetyl-L-leucine was substituted with 4-methyl-2- (4-phenyl-phenyl-1) pentanoic, and 2-CN- (N-benzyllox carboni 1-L-alanyl) 3carboh drazi da, with 2-CN- (2-pyridine Imeto? i carboni 1) -L-leucine? "13carbohydrazide; (0.056 g , 24%), EMÍESI): 5B9.4 ÍM + H) *.

EXAMPLE 97 Preparation of Z-CN- (N-benzyloxycarbonyl-1-L-1-echin-1) 3-Z'-CN'-C2- (4-enylphenyl) -4-roet Ipentanoi 1) 3 carbohydrate The title compound was prepared from the compound of Example 91, using HPLC (Sumipa? OA-3100, 4.6? 150 mm, 80/20 cells / ethanol, 1.0 ml / min, retention time = 5.9 minutes).

EXAMPLE 99 Preparation of 2-CN-IM-benzyloxycarboni 1-L-leucinyl) 3-2'-CN'-t2- 4-eni 1-phenyl 1) -4-methylpentanoi 1) 33carbohydraz The title compound was prepared from the compound of Example 91. using HPLC? Sumipa? OA-3100,4.6? 150 mm. 80/20 heine / ethanol, 1.0 ml / min. retention time = 8.1 mi utos).

EXAMPLE 99 Preparation of 2-CN-N-benzyloxycarboni 1 -leucine I) 3-2, -CN'-CN- (4-pheny1pheny1) -N- (2-methylpropy1) carbamoy1 3-carbohydrazide To a stirring solution of phosgene (0.228 ml, 0.244 mmol, 12.5% solution in benzene) was added dropwise »a solution of N-2-methyl Ipropi 1) -N-4-phenyl Ifeni 1) amine ( 0.050 g, 0.222 mmole) and triethylamine (0.025 g, 0.244 mmole) in dichloromethane (1 ml). After stirring at room temperature for 15 minutes, this solution was added, drop by drop, to a solution of the compound of Example 1 (d) (0.083 g, 0.244 mmol) and triethylamine (0.025 g, 0.244 mmol) in dichloromethane (1 ral) at room temperature. After stirring at room temperature for 48 hours, N-met lmorfoli a (0.022 g, 0.222 mmol) and DMF (2 mL) were added to the solution, and it was heated at 50 ° C for 16 hours. Then the solution was diluted with ethyl acetate (50 ml) and washed successively with water, saturated aqueous NaHCO3 and brine. The organic layer was dried (MgSO 4), filtered and concentrated. The residue was purified by silica gel column chromatography, methanol / dichloromethane) to afford the title compound as a yellow solid i0.023 g, 18%). MS (ESI): 589.4 (M + H) *.

EXAMPLE 100 Preparation of 2-CN- (3-benzyl) ibenzoi 1) 3-2'-CN '- (N-methyl-1-L-leucine 1) 3-carbohydrazide a) 2-CN- (3-benzyl? ibenzo 1) -2 'CN' - (N-tert-buto? -carbon 1-N-methyl-L-leucine 1) 3-carbohydrazide. The title compound was prepared as a white solid, following the procedure of Example 68 (b), except that N-acetyl-L-leucine was replaced with N-tert-butocarboxy 1-N-methyl-1. -Lucin, and 2-N- (-benzyl or 1-carboni 1-L-alani 1) 3-carbohydrazide with 2-CN-i3-benzyl-ibenzoi 1) 3-carbohydrazide; (0.183 g, 69%), EMÍESI): 550.4 (M + Na) *. b) 2-CN- (3-benzyl ibenzoyl) 3-2'-L "N '- (N-methyl-1-L-leucine 1) 3-carbohydrate? ida To a stirred solution of the compound of example 100 ( a) 0.100 g, 0.189 mmoles) in dichloromethane (81 ml), trifluoroacetic acid (0.296 g, 2.5 mmol) was added, after stirring at room temperature for 15 minutes the solution was concentrated and the residue was purified by chromatography on silica gel column, methanol / dichloromethane) to yield the title compound as a white solid (0.055 g, 68%): EMISSI): 428.4 (M + H) * EXAMPLE 101 Preparation of 2-CN- ( N-benzyloxycarboni1-L-1eucini1) 3-2'-CNf- (N-methyl-L-leuc nyl) 3-carbohydrazide The title compound was prepared following the procedure of example 100 (a) -OOOO), except that 2-CN- (3-benzyl) ibenzoi-1) 3-carbohydrazide is substituted with 2-CN-N-benzylcarbonyl. -leucini 1) carbohydrazide in step (a). EMiESI): 465.5 ÍM + H) *.

EXAMPLE IQ2 Preparation of (1S) -N-C2-C (l-benzyloxycarbonylamine) -3-met Ibuti 13thiazo1-4- Icarboni 13-N '- (4-phenoxypheni-1-ulul on l) hydrazide a) N-benz 1o-icarboni 1-L-leuci namide. To an agitated solution of N-benz locarbaryl 1-L-leucine (4-6 g, 17.3 mmol) in THF, cooled to -40 ° C »was added N-methyl Imofol (3.68 g, 36.5 mmol). 4.0 ml) and isobutyl chloroformate (2.37 g, 17.3 mmol, 2.25 ml). After stirring for 15 minutes, ammonia was bubbled through the solution for 5 minutes. The solution was warmed to room temperature; evaporated, and the residue was dissolved in ethyl acetate, washed with 0.1 N HCl, and saturated brine, then dried (MgSO 4), filtered and evaporated to dryness to give the title compound as a solid of color. white (4.58 g, 100%). b) N-benzylcarbonyl 1-L-leucineethamide A solution of the compound of Example 102 (a) (4.58 g, 17.3 mmol) and Lawesson reagent (4.21 g, 10.4 mmol) in THF was allowed to stir at room temperature during 16 hours. The solution was concentrated and the residue was purified by flash chromatography on 230-400 mesh of silica gel, eluting with 1: 3 EtOAc / water to provide the title compound as a pale yellow solid (3.74 g. , 77%). c) (IS) -l-benzylocarboxy 1-non-l- (4-carboetho-i-thiazol-2-yl) -3-methyl-1-butane The compound of example 102 (b) (2.20 g, 7.83 mmol) was dissolved in acetone (35 ml), cooled to -10 ° C and ethyl bromopyruvirate (1.68 g, 8.62 mmol, l.OB ml) was added.After stirring for 1 hour, the solution was poured in. in methylene chloride / water, then in saturated aqueous NaHCO3 solution, The aqueous layer was extracted with methylene fluoride and the combined organic layers were washed with a saturated saline solution, dried (MgSO4), filtered The residue was dissolved in methylene chloride, cooled to -20 ° C, pyridine (1.36 g, 17.2 mmol, 1.39 ml) and trifluoroacetic anhydride (1.81 g, 8.62 mmol, 1.22 ml) were added. stirring for 1 hour, the solution was washed with saturated aqueous solution of NaHCO 3 and saturated saline, then dried (MgSO 4), filtered and concentrated, the Tge residue was purified by chromatography. to immediate vaporisation of about 90 g of the title compound as a pale yellow oil (2.36 g, 80%. AHNMR (400MHz, CDCla) or 8.08 (s, 1H). 7.38 (m, 5H). 5.42 (S, 3H), 5.23-5.07 (m.3H), 4.42 (q.2H). 2.01-1.62 (m, 3H). 1.41 < t »3H)» 0.99 (d, 6H). d) (IS) -l-benzylocarbom "lamino-l-4-hydraz non-carboni 1 ti azo1-2-i 1) -3-methyl-1-butane The compound of example 102ÍO (2.16 g, 5.73 mmol) It was dissolved in ethanol (60 ml) and hydrazine hydrate (2.87 g, 57.3 mmol, 2.B ml) was added and the solution was heated at 75 ° C. for 1 hour.The solution was cooled and evaporated to dryness to provide the title compound as a pale yellow foam (2.01 g, 97%) .H NMR (400 MHz, CDC1 ,,,) or 8.35 (bS.lH). 8.03 IS, 1H), 7.37 (m, 5H), 5.29 id, 1H), 5.14-5.09 ím, 3H> »4.07 (bs, 2H), 1.92-1.82 (m.1H), 1.79-1.66 (m, 2H), 1.00 id, 6H) e) (IS) - N - C2 - C (1-benzylocarbonyl-lamino) -3-methybutylthiazole-4-Icarboni 13- N'-4-phenoyl-1-sulfonyl) hydrazide To a stirred solution of the compound of the example 102 (d) (275 mg, 0.76 mmol) in dichloromethane at room temperature add pyridine (180 mg, 2.28 mmol, 0.2 ml) and 4-phenoxybenzene foniyl chloride (408 mg, 1.52 mmol). The reaction was stirred for 16 hours and the solvents were evaporated to a residue which was subjected to chromatography (silica gel »40% ethyl acetate in henum) to give 1B9 title compound as a white solid (0.310 g). MS (ESI): 595.6 (M + H *).

EXAMPLE 103 Preparation of (IS) -N-Cl- (N-benzyloxycarboni 1-L-leucine sheet) - 3-met 1but l thiazole-2-i Icarboni 13-N '- (N-benzloxycarboni 1-L- 1euci il) hydraz a) N-benzylox carbon 1-L-leucine 1-Ll euc ni l romo-raeti Icetona. It is cooled to 0 ° C 1-meti 1-3-ni tro-l-nitrosoguanidine (5.9 g »40.11 mmol) in ether (200 ml). Potassium hydroxide is added slowly to 40% and the diazomethane is allowed to collect in the ether solution for 30 minutes at 0 ° C. N-Benzyloeicarbom "1-L-Leuci ni l-L-Leucine (Bachem) (4.0 g» 10.58 mmo1) is stirred in tetrahydrofuran at -40 ° C. N-methylmorpholyl a (1.07 g) is added.10.58 mmol. 1.16 ml) isobutyl chloroformate (1.45 g, 10.58 mmol, 1.3 B mi). The mixture is stirred at -40 ° C for 15 minutes and then filtered to a cold flask to remove the precipitated salts. An excess of the diazomethane solution prepared previously is added to the filtered solution and the mixture is allowed to stand at 0 ° C for 16 hours. 30% HBr in acetic acid at 0 ° C is added and the solution is then washed successively with 1% citric acid »saturated aqueous sodium bicarbonate (carefully)» and saline. The solution is dried over sodium sulfate, filtered and evaporated to give the title compound as a white solid (4.10 g). X NMR (400 MHz. CDC13) 6 7.34 (m, 5H), 6.51 id. 1H), 5.15 (d »1H), 5.10 <; S »2H)» 4.78, m, 1H), 4.20 (m, 1H), 4.04 (dd, 2H), 1.63 (m, 6H), 0.93 (m, 12H). b) 2S, 1S) -2-benzene locarboni 1) amino-N-Cl'-2-carboetho-itiazole-4-1) -3'-beti Ibuti l 3-4-methypentanamide. The compound of Example 103 (a) i2.0 g, 4.4 mmol) and ethyl thiooxamate i? .59 g. 4.4 mmol) were refluxed in ethane for 4 hours. The solvent was evaporated and the residue was subjected to chromatography (silica gel 2.5% methanol / dichloromethane) to give the title compound as a white solid (1.46 g). H NMR (400 MHZ, CDC13) or 7.32 (S, 1H), 7.21 (m, 5H), 6.40 (d, 1H), 5.13 (dd, 1H), 5.02 (s, 2H), 4.41 iq, 2H), 4.06 μm, 1H), 1.71 μm, 2H), 1.47 (m, 4H), 1.33 it, 3H), 0.73 μm. 12H). c) Y2S.1 'S) -2- (benzylocarbon 1) am non-N-Cl' (2-hydrazinocarboni 1 thiazol-4-yl) -3'methylbutyl 13-4-methylpentanamide. Following the procedure of example 102 (d). I mean the substitution of (2S, 1 'S) -2- (benzylocarboni 1 Jamino-N-Cl "- (2-carboetho-itiazol-4-yl) -3'-methylbut?' 13-4 -methylpentanamide by IS) -l-benz locarboni lami ol- (4-carboetho-thiazol-2-yl) -3-methyl butane, to the title compound was prepared. MSI): 476.3 (M + H *) d) (IS) -N- -4- l-í N-benzi 1 o? i carboni 1-Ll euci ni 1-am? no) -3- met Ibut 1 thiazol-2-Icarbon 13- N '-Ni-benzyl? i -carboni lL-leucini 1) hydrazide.

To the stirred solution of the compound of example I03 (c) (180 mg, 0.3B mmol) in dimethylformamide is added N-benzyl-icarbonyl-L-leucine (111 mg, 0.42 mmol) 1- (3-dimethylaminopropy) hydrochloride 1) -3-eti 1 carbod imide (BO mg »0.42 mmol), and l-hydro? Ibenzotriazole (13 mg, 0.096 mmol). The reaction mixture is stirred for 16 hours at room temperature, filtered and washed twice with water. The solvent was evaporated to give the title compound as a white solid. 0.207 g). MSI ESI): 723.9 ÍM + H *).

EXAMPLE 104 Preparation of (IS) -N-CZ-C (l-benzyloxycarbonyl lam no) -3-methyl-1-butyl-1-thiazol-4-i-1-carbonyl 13- '- (-phenyl-1-en-1-acetyl-1-hydrazide) Following the procedure of example 103 (d), except the substitution of (IS) -l-benzylocarbo "lappno-l- (4-hydrazinocarbonylthiazol-2-yl) -3-met-1 butane for (2S, 1S) -2- (benzylocarboni 1) ami no-N-Cl '- (2-hydrazi "nocarboni-thiazol-4-yl) -3'-methyl-1-butyl-3-4-methylpentanamide. and 4-bifen lacético acid by N-benci lo? icarboni 1-L-leuci na. The title compound was prepared as a white solid. MS (ESI): 557.2 (M + H *) EXAMPLE 105 Preparation of (IS-N-C2-Cl-benzyloxycarbonylamino) -3-methylbut lthiazol-4-ylcarboni 13-N "-C3- (4-pyridine lmethoxy) benzoi-13-hydrazide a) methyl 3- (4-pyridine Imethoxy) benzonate ) To a solution of methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol), 4-pyridylcarbonate (1.1 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) in THF (25 mL) at 0 ° C is added dropwise azod carboxy of di soprop (2.0 g, 9.87 mmol) After stirring at room temperature for 16 hours, the solution is concentrated and purified by silica gel column chromatography, ethyl acetate / hen ano) to produce the title compound as a white solid (0.599 g, 37%) MS (ESI): 244.1 M + H *) b) 3- (4-pi di i Imeto? benzoic acid) To a solution of the compound of example 105 (a) (0.599 g, 2.47 mmol) in THF / H.? 0 (i: i, 10 ml) is added lithium hydroxide monohydrate i0.113 g 2.71 mmol), then reflux is stirred for 3.5 hours, and 11 eq of IN HC are added. l and the mixture is poured into water. The mixture is extracted with ethyl acetate (2 X 100 mL). The organic layers are combined, washed with saline, dried (MgSO 4), filtered and concentrated to yield the title compound as a yellow solid (0.386 g, 58%). NMR (400 MHz, CD30D) at 8.54 (d, 2H), 7.64 (m, 2H), 7.57, 2H), 7.40, 1H), 7.26, 1H), 5.24 (2, 2H). c)? IS) -N-C2-Cyl-benzylcarbonylamino) -3-methylbutyl-13-thiazole-4-i-Icarboni 13-N'-C3 - (4-pridinyl-limeto) benzoyl-13-hydrazide Following the procedure of example 103id), e ect the substitution of i IS) -l-benzylocarboni lam no-l- (4-hydrazinocarbo-lthiazol-2-l) -3-met-1 butane by (2S, 1S) -2 -benzyl-1-carbon-1) amino-N-Cl '- (2-hydrazinocarbonyl-thiazol-4-yl) -3'-met-1-butyl-1-4-methylpentanamide and 3- (4-pyridinium-lime) ) benzoic by N-benci ls? icarbom "1-L-leucine, the title compound was prepared as a white solid MS (ESI): 574.2 (M + H) * EXAMPLE 106 Preparation of N-CZ- (Z-chlorophenoxymethyl) -iazol-4-ylcarbonyl 3- N "-CN- (4-Pyridinium-1-ethoxycarbonyl) -L-1-eucine 13 -hydrazide a) Methyl ester of α-isocyanate-L-leucine. Dissolve L-1eucine methyl ester hydrochloride (25 g, 0.14 mol) in methylene fluoride 8450 ml), cool to 0 ° C, and add pyridine (43.5 g, 0.55 mol, 44.5 ml) then slowly add a 1.93 M solution of phosgene in toluene 0.18 mol, 92.7 ml.) After stirring at 0 ° C for 2 hours, the mixture. ee pour in 0.5 N HCL (1400 mi) and ice (900 ml). The organic layer was washed with 0.5 N HCl (1400 ml) and ice (900 mi) The aqueous layers were extracted with methylene chloride or (450 ml) and the combined organic layers were washed with a saturated saline solution (1400 ml) and ice (900 ml), then dried (MgSO), filtered and they concentrated. The residue was distilled (56-58 ° C, 0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 86%). AH NMR (250 MHz, CDC1 ,,,) or 4.04 (dd, 1H), 3.82 (s, 3H), 1. 92-1.72 (m, 1H), 1.69-1.62 (m, 1H), 0.96 (d, 3H), 0.94 id, 3H). b) Methyl ester of N- (4-p? ridini Imeto? icarboni 1) -L-1eucine. A solution of the compound of Example 106 (a) (5.10 g, 29 B mmol) and 4-pyridylcarbinol (3.25 g, 29.8 mmol) in toluene (30 mL) was heated at reflux for 24 hours. The solution was concentrated and the residue was purified by flash chromatography on 250 g of 230-400 silica gel mesh, eluting with 3: 1 ethyl acetate / hexanes, to give the title compound (7.86). g, 94%. * H NMR (250 MHZ, CDC13) or 8.59 (d, 2H9, 7.24 id, 2H), 5.33 (d.1H) »5.13 (S. 3H), 4.40 (dt, 1H)» 3.75 (d. 8, 3H) »1.81-1.51 (m, 3H), 0.96 id, 3H), 0.95 id, 3H). c) N-4-pyridinium lmetocarboni 1) -L-leucine. To a solution of the compound of example 106 (b) (1.98 g, 7.06 mmol) is added 7 ml of water followed by LiOH-H30 (325 mg, 7.76 mmol). The mixture was stirred for 30 minutes and then concentrated. The residue was redissolved in water (10 ml) and 3 N HCl (2.6 ml) was added. The solution was lyophilized to produce a white solid (2.015 g, 6.44 mmol). MSÍESI): 267.2 ÍM + H) *. d) N-C22- (2-chlorophen-1-imeti-1) thiazo-1-4-Icarboni-13-hydrazide Following the procedure of example 102 (d), I ecused the substitution of 2- (2-chlorophene-1-imeti-1) t-azole. 4-ethylcarbamate by (IS) -l-benzylocarboni lami ol- (4-carboetho-thiazol-2-l) -3-methylbutane, the title compound MSIESI was prepared): 284.1 (M + H) *. e) N-C2- (2-C1-orophen-methyl) t-azo1-4-icarbon-1-N'-CN-4-pyridinium-lime-1-carbon-1) -L-leucine-1-hydrazide. Following the procedure of Example 103 (d), I substitute the substitution N-C2-2 2-c1 orophen im imet 1) thiazol-4-yl carbonyl 3h drazide for 2 2 S, S S) -2- (benzyl icarbonyl) amino -N-Cl '- (2-hydrazinocarboni-1-thiazol-4-yl) -3'-methylbuty 13-4 -methyl-pentanamide "and N- (4-pyridinyl-lmetocarbonyl) -L-leucine by N- benci lo? icarbom "1-L-leucine. the title compound was prepared as a white solid. MSiESI): 532.1 ÍM + H) *.

EXAMPLE + Q7 Preparation of N-CN-4-Pyridinium Imethylcarbonyl) -L-1euccinyl-N'-C2-C4- (l, Z.3-tidiazo1-4-i1) phenyl-1-thiazo-1-4-Icarboni-13-hydrazide a ) N-C2-C4- (1, 2,3-thiazol-4-yl) 3-thiazol-4-ylcarbonyl-3-hydrazide Following the procedure of Example 102 (d), e ept the substitution of 2-C4- (1) 2'-3-thiadiazol-4-yl) ethyl thiazole-4-carbohydrate by iIS) -l-benzylcarbonylamino-l-4-carboetho-1-thiazo-1-2-yl-3-methyl butane »The title compound was prepared as a white solid. MS (ESI): 304.1 (M + H) *. b) N-CN- (4-pyridinium-1-methocarbon) -L-leuc-n-N'-C2-C4. (Im2m3. Tuaduazik .4-yl) fem "13-thiazole-4-ylcarboni-13-hydrazide. Following the procedure of Example I03 (d), I e ect the substitution of N-C2-C4-I 1.2.3-thiadiazole-4- il) thiazol-4-ylcarbonyl hydrazide by (2S.l'S) -2- benzylcarbom'l) arai non-N-Cl '- (2-hi dra? i nocarboni 1 thiazo1-4- 1) -3'-methybutyl 1 -4-methylpentanamide "and N- (4-pyridinium lmetocarbonyl 1) -L-leucine by N-benzylcarbonyl 1-L-leucine. the title compound was prepared as a white solid. MS (ESI): 552.1 (M + H) *.

EXAMPLE 108 Preparation of N-C2-C3- (4-C1 oropheni Ißul onylmethyl) thien-2- 13-thiazo-1-4-icarboni 1 + -N "-CN- (4-pyridine-methoxycarbonyl) -L- 1eu? J i1 The present invention relates to a) N-C2- 3- (4-chlorophenylsulfonylmethyl) thien-2-ylthiazole-4-carbonylhydrazide 13. Following the procedure of example 102 (d), except for the substitution 2-C3- (4-) Chlorophenesulfonylmet 1> thien-2-yl thiazole-4-carboxylate by (IS) -l-benzyl locarboni lamino-l- (4-carboetho-thiazole-2-yl) -3-methyl butane The title compound was prepared as a white solid MS 8ESI): 414.1 (M + H) *. B) N- 2-C3- (4-chlorophenylsulfonylmethyl) thien-2-yl-thiazol-4-ylcarboml 3 -N'-CN- (4-pyridinylmethocarboni 1) -L-1eucini 1 hi drazi da Following the procedure of Example 103id), eject the substitution of N-C2-C3-Í4-chlorophenylsulfoni Imeti 1) 2-i 1 thiazole-4-carboni-1-hydrazide for 2S-1'S) -2- (benzylcarbonyl) am non-N-Cl '- (2-hydrazidecarbonyl tiolol-4-yl) -3' -metilbuti l + -4-meti ipentanam da and N- (4-pi i dini lmeto? icar boni 1) -L-1eucine by N-benzyl? -carboni 1-L-leucine »the title compound was prepared as a blank. MS (ESI): 664.0 ÍM + H) *.

EXAMPLE 109 Preparation of (IS, ZtRS) -N-CZ-Cyl-benzyloxycarbonylamino) -3-methylbut 13thiazo1-4-i Icarboni 13-Nr-CZ "- (4-pheny1 in laceti 1) -4- meti Ipentanoi 1 hydraz gives a) 4-methyl 1-2- <4-phenyl Ifenyl) pent-4-enoic acid To a solution of diisopropylamin 0.537 g, 5.31 mmol) in THF (5.2 ml) at 0 ° C was added by drip n-buti lithium (2.1 ml.t.22 mmol, 2.5 M in hexane) After stirring for 15 minutes at 0 ° C., the mixture was cooled to -78 ° C. and a solution of 4-bifem acid was added. Acetic acid (0.500 g, 2.36 mmol) in THF (2 ml) After heating to 0 ° C and cooling to -78 ° C, 3-bromo-2-meth-1-propene (0.485 g, 3.54 mmol) was added to the mixture. ) After stirring at -78 ° C for 1 hour, the reaction was extracted with 2 ml of water and then concentrated, the residue redissolved in water and extracted with ether (100 ml). The aqueous layer was acidified (3N HCl) and extracted with ether (3 X 100 mL). The organic layers were combined, dried (MgSO). ^) .They were filtered and concentrated to yield a white solid (0.449 g »72%). MS (ESI): 265.3 ÍM + H) -. b) 4-methyl 1-2-i4-fem "Ifenyl" pentanoic acid To a stirring solution of the compound of example 109 (a) (0.449 g, 1.69 mmol) in ethyl acetate (25 ml) was added palladium on carbon (0.225 g) After stirring under a balloon of hydrogen for 16 hours, the mixture was filtered through Cel te The filtrate was concentrated to yield an off-white solid 0.430 g »95%) MS (ESI): 267.4 ( M + H) -. C) i IS »2 'RS) -N- 2-C i-benzyl-1-oxycarbonyl-1-amino) -3-methylbutyl-3-thiazole-4-ylcarbom! 3-N'-C2 '(4-fem'lfeni laceti 1) -4-meti Ipentanoi 1 hydrazide Following the procedure of example 1 (t), except substitution of (IS) -l-benz locarboni lamino -l- (4-hydrazinocarbonyl thiazol-2-yl) -3-methyl-1-butane by (2S, 1 S) -2- (benzylcarbonyl 1) amino-N-Cl'-i2 -hydrazinocarbonyl thiazole-4- l) -3'-meti Ibuti 13-4-met Ipentanamide, and 4-met 1-2-y-phenyl-phenyl acid by N-benzyl? 1-L-leucine carboni, the title compound was prepared as a white solid. MS (ESI): 613.2 (M + H) *.

EXAMPLE 110 Preparation of N-CZ-3-benz loxifeni 1) thiazo1-4-i Icarboni 13-N'CN- (2-pyridinium-1-methoxycarbonyl) -L-1eucine-13-hydrazide a) Methyl 3-benzyl-1-benzoate To a solution of NaH (0.395 g 9.B7 mmol, 60% in mineral oil) in DMF (20 mL) was added methyl 3-hydroxybenzoate 1.0 g, 6.58 mmol). After stirring for 15 minutes at room temperature, benzyl bromide (1 g, . 5B mmol). After stirring at room temperature for 3 hours, the solution was partitioned between ethyl acetate and water. The organic layer was washed with water 2 X 75 mL), saturated aqueous sodium bicarbonate and saline, then dried (MgSO 4), filtered and concentrated to yield an off-white solid (1013 g, 4.2 mmol). AH NMR (400 MHz, CDC1.,.) And 7.67 (m, 2H). 7.48 7.34 (m, 6H), 7.19 (m, 1H) »5.12 is» 2H), 3.95 is, 3H). b) 3-benzyl? ibenzamide To a suspension of ammonium hydrochloride and 1.070 g. 0.02 mmol) in 20 ml of toluene at 5 ° C. A 2M solution (10 ml) of trimethylaluminum in toluene was slowly added. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours until gas evolution ceased. To a stirring solution of the compound of the example 110 (a) (605 mg »2.49 mmol) in toluene was added a solution of 0.67 M MeAlClNH ^ (11 mL» 7.49 mmol) in toluene. The reaction mixture was allowed to stir overnight at reflux. The reaction was quenched with 5% HCl. the organic layer was separated and the aqueous layer was extracted 3 times with ethyl acetate. The organic extracts were combined, dried over MgSO 4, filtered and concentrated to give the title compound as a white solid (409 mg, 72%). MS (ESI): 228.1 iM + H) *. c) N-C2-í3-benc lo? fen l) thiazo1-4- icarboni 1 h drazi da Following the procedure of example 102 (b) -102 (d). ect the substitution of 3-benc lo? i enzamide by N-benzyl? -carbon 1-L-leucinamide in step (b). the title compound was prepared as a white solid. MS íESI): 426.2 (M + H) *. d) N- (2-pyridine Imetocarboni 19-L-lucine Following the procedure of Example 106a) -106ic) »I exclude the substitution of 2-pyrid Icarbinol for 4-pyridylcarbinol in step <b). the title compound was prepared. H NMR 4 400 MHz, CD 3 OD) or 8.50 (d, 1 H), 7.8 G (dt 1 H), 7.51 (d »1 H). 7.36 (dd., 1H). 5.20 (d.1H), 5.16 (d, 1H), 4.19 ít. 1 HOUR). 1.78-1.72 (m, 1H). 1.62 (t, 2H). 0.97 (d.3H), 0.94 (d, 3H). e) N-C2-3-benci lo? feni 1) i azo1-4-i Icarboni l -N'-CN- (2-pyridinium Imetocarboni 1) -L-leucine "13hydrazide Following the procedure of example 103 (d), I exclude the substitution of N- C2- (3-benzyloxygen) 1) thiazole-4-ylcarbon l 3hi drazi gives by (2S.l'S) -2- (benzylocarboni 1) ami or N-Cl'-2-hydrazinocarboni lthiazole-4-yl ) -3'- methylbut? '13 -4-methyl-pentanamide and N- (2-pyridinylmethocarbaryl) -L-leucine by N-benzylcarbomyl-1-eucine. of the title as a white solid, 106 mg, 0.184 mmol), MD (ESI): 574.2, M + H) * EXAMPLE 111 Preparation of (lRS) -N-C2Cl- (4-phenyl-phenyl) -3-methyl-1-butyl 3-thiazo1- 4- l carbon l 3-N "-CN- (4-pyridinium-1-icarbon-l) -L-1-eucinyl-3-hydrazide a) N-C2-Cl-4-phenylphen l) -3-methylbutyl-3-thiazole-4-ylcarboni-1-hydrazide Following the procedure of Example 102a) -l02 (d), e ect the substitution of methyl-1-acid. 2- (4-fenifeni 1) pentanoic by N-benzyl carbon l-leucine in step (a), the title compound was prepared as a white solid. MS (ESI): 366.3 (M + H) *. b) (lRS) -N-C2-Cl-4-phenylphen l) -3-meltyl Ibut 13thiazol-4-ylcarboni 1-N'-CN-14-pyridine imethocarbaryl 1) - L-leucinyl hydrazide Following the procedure of example 103 (d), e ect the substitution of N-C2-Cl-4-fem'lfeni 1) -3-meltylbut 13thiazol-4-icarboni 13hydrazide by (2S, 1S) -2- (benzyl) carbonyl) ami no-N-Cl '- (2-h drazi nocarboni 1 thiazol-4-l) -3'-methylbutyl-4-methylpentane, and N-4-pyridine Imeto-i-carboni 1 ) -L-leucine by N-benzylocarbicari 1-L-leucine, the title compound was prepared as a white solid. MS (ESI): 614.3 (M + H) *.

EXAMPLE 2 Preparation of N-C2- (2-benzyloxypheni1) thiazole-4-i Icarboni 13-N'- CN- (4-pyridinylmethoxycarbon I) -L-1eucini1 hydrazide a) 2-aminothiazole-4-carbohydrate bromide To a stirred suspension of thiourea (6.1.0 g, 7B.8 mmol) in ethanol (80 ml) was added ethyl bromopyruvate (15.4 g, 78.8 mmol) . The resulting solution was heated at 45 ° C for 23 hours. The solution was cooled to 0 ° C for 24 hours and the crystals were collected by filtration and washed with cold ethanol to provide the title compound (15. B g, 79%). ^ H NMR (400 MHz, CD3OD) or 7.70 (s, 1H), 4.41 (q, 2H), 1.38 (t, 3H). b) Ethyl-2-bromo iazo1-4-carbo? i lato To a stirred suspension of the compound of example 112 (a) ≤2.15 g, 48 mmol) in aqueous HBr at 16% and 150 ml), cooled to 0 ° C, a solution of sodium nitrite (3.44 g, 49.8 mmol) in water (6 ml) was added dropwise. After stirring for 35 minutes, copper bromide (I) i 7.83 g, 54.6 rare) and aqueous HBr at 16% i60 ml) were added and the mixture was heated at 70 ° C for 1 hour. The mixture was filtered and the filtrate was saturated with NaCl then brought with ethyl acetate. 170 mi). The combined tracts were dried (MgSO 4), filtered and evaporated to dryness. The residue was combined with the solid collected in the first filtration, heated to reflux in ethanol (500 ml) for 5 minutes, and then filtered. To the filtrate was added 1.5 mL of aqueous HBr at 4B% and the solution was heated to reflux for 16 hours and then concentrated. The residue was separated between saturated aqueous NaHCO3 and ethyl acetate. The organic layer was washed with saturated saline solution, dried (MgSO ^), decolorized with charcoal, filtered and concentrated to provide the title compound as a pale yellow solid 77.46 g »75%), MS (ESI). ): 236.0 (M + H) *. c) 2-benzyl? -bromobenzene To a stirred solution of 2-bromophenol (10.0 g, 57.8 mmol), and benzyl bromide (9.9 g, 57.8 mmol) in acetone (150 mL) was added KaC03 (12.0 g, 86.7 mmol). After stirring at reflux for 4 h, the mixture was separated between ethyl acetate and water. The organic layer was washed with saline, dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate / heel) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol). * HRMN (400 MHz, CDC13) or 7.62 (m, 1H), 7.54 (m, 2H), 7.45, 2H), 7.37, 1H), 7.28 (m, 1H), 6.98, 1H), 6.91, , 1H), 5.17 (s, 2H). d > 2-benzyl-1-bisenic acid (To a solution of the compound of example 112c) (15.2 g »57.8 mmol) in THF (100 ml) at -78 ° C was added dropwise n-BuLi 2323.1 ml. 2.5M in the year, 57.8 mmol). The mixture was stirred at -78 ° C for 25 minutes when it was added via cannulas to a stirring solution of trisopropyl-1-borate (54.4 g, 289 mmol) in THF (100 mL) at -78 ° C. After warming to room temperature and stirring for 3 hours, the mixture was poured into 3N HCl (100 mL) and was brought up with ethyl acetate (3? 200 mL). The organic layers were combined, washed successively with water and saline, dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate) to yield the title compound as a pale yellow solid (6.9 g, 30.3 mmol). * HRMN (400 MHz, CDC13) 7.90 (d, 1H), 7.42 (m, 6H), 7.07 (t, 1H), 7.02 (d, 1H), 6.05 (s.2H), 5.16 (S, 2H). e) Eti l-2- (2-benci lo? ifeni 1) thiazole-4-carbo? lato To a stirred solution of the compound of example 112 (b) i4.0 g, 16.9 mmol), the compound of example 72 (d) (4.29 g, 18.8 mmol). tetrakisi trifen lfosf ina) palladium (O) (0.65 g, 0.57 mmol) in dimetho-ietane (60 mL) was added cesium fluoride (B.5B g »56.5 mmol) and the mixture was heated at 85 ° C for 16 hours . Tetrakisi trifeni Ifosphine) palladium (O) i? .65 g was added. 0.57 mmol) and the heating was continued for 5 hours at 85 ° C. The mixture was diluted with water (60 ml) and brought with ethyl acetate (2? 120 ml). The combined tracts were washed with saturated NaHCO 3, saturated aqueous and saturated saline. dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography on 180 g of 230-400 mesh silica gel, eluting with 15% ethyl acetate in children. to provide the title compound as a white solid (3.22 g, 56%). MS (ESI): 340.3 (M + H) *. f) 2- (2-benzyl? phen 1) thiazole-4-icarbonyl-1-idrazide Following the procedure of example 102 (d), I exclude the substitution of ethyl 2- (2-benzlo-ifeni 1) thiazole- 4- carboylate by (SS) -1-benzylcarbonyl 1 ami no-1- (-carboetho-thiazol-2-yl) -3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 326.2 (M + H) *. g) N-C2- (2-benzyloxypheni 1) thiazole-4-icarboni 1 -N'-CN- (4-pyridyl-limetocarbonyl) -L-leuc nihydrazide Following the procedure of Example I03 ( d), e ect the substitution of 2- (2-benc lo? ifeni 1) ti azo1-4-i Icarbom "1 hydrazed by (2S, l'S) -2- (benzylocarbon 1) amino-N -Cl'-2'-hydrazinocarboni-1-thiazol-4-yl) -3'-methyl-l-butyl-1-4-methyl-pentanamide "and N-i4-pyridinyl-methyl-1-carbonyl-1-L-leucine by N-benzylcarboni 1-L-leucine, the title compound was prepared as a white solid MSIESI): 574.3 iM + H) *.

EXAMPLE 1 + 3 Preparation of N-C2-CN-methy1-N- (4-phenylphenyl) amino3-thiazo1-4-lcarboni 1-N "-CN- (4-? Ir dini Imethoxylcarbonyl) -L-1euci-13-hydrazide a) N- (4-pheni Ifen 1) -2-methylpropionamide To a stirred solution of 4-ami bisphenol 1 (9.53 g, 56.3 mmol) and triet sheet (5.70 g, 56.3 mmol, 7.85 ral) in sodium chloride. methylene (60 ml), cooled to 0 ° C. isobutyryl chloride (6.0 g, 56.3 mmol), 5.90 ml) was added slowly. After stirring at 0 ° C for 1 hour, the mixture was diluted with methylene chloride (120 ml) and washed with IN NaOH and saturated saline, then dried (MgSO 4), filtered and concentrated. The residue was washed with ether and dried to provide the title compound as a pale yellow crystalline solid (9.83 g, 73%). ^ -HRMN (400 MHz, CDC13 / CD30D) or 7.58 (d, 2H), 7.50 (m, 4H). 7.40-7.25, m, 3H). 2.55-2.49 (m, 1H), 1.18 (d, 6H). b) N-i4-phen Ifenyl) -N- (2-methyl-1-propy1) amine To a stirring solution of lithium aluminum hydride i 58.6 mmol) in THF (58.6 mmol), cooled to 0 ° C a solution of the compound of example 73 (a) (9.35 g, 39.0 mmol) in THF il 70 ml) was added slowly over 10 minutes. After the addition was complete, the ice bath was removed and the solution was heated at 55 ° C for 30 minutes. The mixture was cooled to 0 ° C and water (2.22 ml) was added slowly, followed by 15% aqueous NaOH (2.22 ml) and water (6.67 ml). The precipitate was removed by filtration and washed with ether 4 times. The filtrate was evaporated to dryness to provide the title compound as a pale yellow solid (8.34 g, 97%). MS (ESI): 226.2 (M + H) *. c) N- (4-phenyl-1-phenyl) -N- (2-methyl-1-propy1) thiourea To a solution of thiophosgene 9.9 mg, 2.6 mmol, 198 uL) in methylene chloride (6.5 ml) , cooled to 0 ° C. a solution of the compound of example 73 (b) (540.7 mg, 2.0 mmol) in methylene chloride was added dropwise. After stirring for 2 hours, methanol saturated with ammonium (20 ml) was added and the solution was stirred at room temperature for 2 hours. The solution was concentrated and the residue was partitioned between ethyl acetate and IN HCl. The organic layer was washed with IN HCl twice. then with saturated saline solution. then MgSO4 was dried), filtered and concentrated. The residue was purified by flash chromatography on 10 g of 230-400 silica gel mesh, eluting with 1 * 3 ethyl acetate / henias, to provide the title compound as a pale yellow solid (470 mg , 83%). MS (ESI): 285.3 (M + H) *. d) Ethyl 2-CN-i4-phenylphenyl) -N-2 2-met-1-propy1) amino t-azole-4-carbo-ylate A solution of the compound of example ll3ic) (184.6 mg, 0.65 mmol) and bromopi uvate of ethyl ether (126.6 mg, 0.65 mmol, 81.5 uL) in ethanol (2.5 ml) was heated to reflux for 5 minutes, then concentrated. The residue was separated between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was washed with ethyl acetate and the combined organic layers were washed with saturated saline, dried (MgSO 4), filtered and concentrated. The residue was passed through a 230-400 mesh plug of silica gel, eluting with 12% ethyl acetate in the kidneys. to provide the title compound as a pale yellow oil (230 mg, 93%). MS (ESI): 381.4 (M + H) *. e) N-2-CN- (4-phenyl-1-phenyl) -N- (2-methyl-1-propyl-1) amino-3-azol-4-ylcarbonyl hydrazide Following the procedure of example 102), I exclude the substitution of 2- CN- (4-phenylphenyl-1) -N- (2-methyl-1-propyl-1) amino-3-thiazole-4-carboaldelate by (1S) -l-benzylcarbonyl 1-amino-1- (4-carboethoxy? itiazol-2-yl) -3-methylbutane, the title compound was prepared as a white solid. MS iESI): 367.3 ÍM + H) *. f) N-C2-CN-met? l-N-4-phenylpheni l) amino-3-thiazole-4-lcarbon l -N'-CN-4-pyridinium lmeto? icarboni 1) -L-leuc i 13hi drazide Following the procedure of Example 103id), e ect the substitution of N-C2-CN- (4-phen lfeni 1) -N-2-methyl-1-propyl) amino-3-thiazole -4-i Icarboni 1 hydrazide by (2S, l'S) -2-benzylocarboni 1) amino-N-Cl'-í 2-hydrazinocarboni 1 thiazol-4- 1) -3'-meti Ibuti 13-4- methypentanamide "and N- (4-pyridine Imethoxy-carboni 1) -L-leucine by N-benzylcarbonyl 1-L-leucine, the title compound was prepared as a white solid. MS (ESI): 615.3 i M + H) *.

EXAMPLE * Preparation of N-iN-benz locarbaryl 1-L-leucinyl) -N'-C2- (4-phenylbenzyl) thiazo-1-4-Icarbonyl hydrazide a) N-C2- (4-pheni Ibenci 1) thiazole-4-Icarboni 13-hydrazide Following the procedure of example 102 (a) -102 (d), eptcept the substitution of 4-bifeni lacetic acid for N-benzyl icarboni 1-L-leucine in step (a), the title compound was prepared as a white solid. MS (ESI): 310.3 (M + H) *. b) N- (N-benzylocarbonyl-L-leucine l) -N'-C2- (4-phenyl-1-benzyl) -3-azole-4-Icarbonyl-hydrazide Following the procedure of Example I03 (d), ecep the substitution of N-C2-β4-phenyl-l-benzyl) thiazole-4-ylcarbonyl-3-hydrazide for (2S, 1S) -2- (benzylcarbonyl) amino) -N-Cl '-i 2 -hydrazylcarbonate 1 thiazol-4-i 1) -3'-meti Ibuty 1 -4-methyl-1-phenynamide, the title compound was prepared as a white solid (20 mg, 0.035 mmol). MS ÍESI): 557.4 (M + H) *. :?or EXAMPLE 115 Preparation of N-CZ- (4-phen-1-phenyl-benz1) thiazo-1-4-Icarboni-13-Nt-CN- (4-pyridyl-methoxycarbonyl) -L-1-echin-1-hydrazide Following the procedure of Example I03 (d), except for the substitution of N-C2- (4-phenyl-1-benzyl) -thiazole-4-ylcarboni-13-hydrazide for (2S, 1S) -2- (benz-locarboni-1) amino -N-Cl'-y 2-hydrazi nocarboni 1 t azol-4-i 1) -3 '-methi Ibuti 1 -4-methyl-1-pentanamide, and N-4-pyridinylmethocarbaryl 1) -L-leucine N-benci what? carboni 1-L-leucine, the title compound was prepared as a yellow solid (30 mg, 0.053 mmol). MS (ESI): 55B.2 (M + H) *.

EXAMPLE 6 Preparation of N- (N-benzyloxycarboni 1-L-leuc nyl) -N "-C 2 -NC2-methyl iprop 1) -N-eni 1 amino3-thiazo-1-4-Icarboni 13-hydrazide a) N-C2-CN-pheni 1-Ni 2-methyl-1-propy1) amino3-thiazole-4-ylcarbonyl-3-hydrazide Following the procedure of example 113 (a) -113 (e), except for the substitution of aniline by 4-am nobifeni 1 in step (a) »the title compound was prepared as a pink orange solid (2776 mg» 0.950 mmol). MS (ESI): 291.3 (M + H) *. b) N-N-benzylcarbonyl-L-leucine 1) -N'-C2-CN-2-methy1prop-1-N-phenylamino-3-thiazole-4-ylcarboni-13-hydrazide Following the procedure of Example I03 (d) , e ect the substitution of N-C2-CN-pheni lN- (2-methylo-1-propyl) amino3t azol-4-i Icarbon lh drazi by (2S, l'S) -2-i benc lo? i carbon l) arai not-N-Cl '-i 2-h drazi nocarboni 1 thiazol-4-i 1) -3'-methybutyl 1 -4-methylpentanamide. The title compound was prepared as a white solid and 92 mg. 0.171 mmol). MS (ESI): 560.3 (M + Na) *.

EXAMPLE 13.7 Preparation of N-CZ-CN-α2-met Iprop 1) -N-phen 1 amino-3-thiazo-1-4-ylcarbonyl-N "-CN- (4-pyridinium-1-methoxycarbonyl) -L-1-euclide-13-hydrazide Following the procedure of example 113 (a) -ll3 (f), except for the substitution of aniline for 4-aminobipheni 1 in step (a), the title compound was prepared as a yellow solid .50 mg. 0.092 mmol). MS (ESI): 539.4 (M + H) *.

EXAMPLE I3, Preparation of N-CZ- (Z-benzyloxypheni 1) thiazo-1-4-Icarbonyl-N'-CN- (3-pyridinylmethoxycarbonyl) -L-1-echin-1-hydrazide Following the procedure of example 112 (a) -ll2 (g). except substituting N- (3-pyridinium lmethoxycarboni 1) -L-leucine for N- (4-pyridiniummethoxycarbonyl) -L-leucine in step ig). The title compound was prepared as a white solid i93. B mg. 53%). MS (ESI): 574.3 (M + H) *.

EXAMPLE 9 Preparation of N-C2- (Z-benzyloxypheni1) thiazole-4-ylcarbonyl 3-Nt-ClM- (2-pyridylmethoxycarbonyl) -L-1euccinyl hydrazide Following the procedure of example 112 (a) -112ig), I substitute N- (2-pyridinium lmeto? Icarbom'l) -L-leucine for N-i4-pyridinium Imethocarboni 1) -L-leucine in step ig). the title compound was prepared as a white solid (149.7 mg, 85%). MS (ESI): 574.4 (M + H) *.

EXAMPLE IZO Preparation of N- (N-benz loxycarboni 1-N-met 1-L-leucine I) -N "- CZ- (Z-benz loxifen 1) thiazo1-4-i Icarbon 1 Jhydrazide Following the procedure of the example H2 (a) -ll2 (g), I substitute N-benzylocarboni 1-N-methyl-1-L-leucine for N-4-pyridine Imeto-icarboni 1) -L -leucine in step (g), the title compound was prepared as a white solid i153.5 mg, 85%). MS (ESI): 609.3 (M + H) *.

EXAMPLE 121 Preparation of N-CZ-CN-α2-met lProPil) -N-phenylamino-3-thiazo-1-4-carbon-1-N "-CN-iZ-Pyridine Irohoxycarbon I) -L- 1 euci i 13 hydraz Following the procedure of example 113 (a) -113 (), except substituting aniline for 4-aminobipheni 1 in step (a) and N-2-pyridinium lmetocarbaryl 1) -L-leucine for N- (4) pyridine lmeto? icarboni 1) -L-leucine in step (f), the title compound was prepared as a white solid (40 mg). MS iESI): 539.4 ÍM + H) *.

EXAMPLE MZ Preparation of N-CZ-CN-iZ-methylPro il) -N-phen 1am no3 iazo1-4- i 1 carboni 13-N "-CN- (3-pyrid or 1-methoxycarboni 1) -L- 1euci i 13 hydraz da Following the procedure of example 113 (a) -ll3f), except for the substitution of aniline for 4-aminobiphenol in step IV) and N-3-pyridinium-Imethocarbonyl) -L-leucine for N- (4-pyridine) lmeto? icarboni 1) -L-leucine in step (f), the title compound was prepared as a white solid and 42 mg). MS ÍESI): 539.4 ÍM + H) *.

EXAMPLE 4 £ 3 Preparation of N-C2- (Z-methoxypheni1) thiazole-4- lcarboni 13-Nt-CN-i4-pyridi "1-methocarbaryl) -L-1eucine-13-hydrazide a) 2-trimeti lestan lanisola To a solution of n-BuLi (2.6 ml, 2.5 M in henian, 6.42 mmol) in diethyl ether (2.5 ml) at -78 ° C was added dropwise 2-bromoanisole (1.0 g) 5.35 mmol) in diethyl ether (2 ml). After stirring for 1 hour at -78 ° C. trisodium chloride was added dropwise (6.4 ml. lOM in THF, 6.42 mmol). The mixture was allowed to stir for 2 hours more while heating slowly to room temperature. The mixture was then washed with saturated aqueous NaHCO3. The aqueous layer was extracted with diethyl ether (1~50 mL) and the organic layers were combined, dried (MgSO ^), filtered and concentrated. The residue was purified by column chromatography (silica gel, ice) to yield the title compound as a colorless oil (1.11 g, 76%). AHRMN (400 MHz, CDC13) á 1.Al (d, 1H), 7.40 ít, 1H), 7.05 (t, 1H), 6.90 (d, 1H), 3.36 (S, 3H), 0.34 (S, 9H) . b) Ethyl 2- (2-tetraethylamine) thiazole-4-carboxylate A mixture of the compound of Example 112 (b) (0.250 g, 1.06 mmol), the compound of Example 83 ( a) 10.287 g, 1.06 mmol), and tetrakisitrifeni lphosphine) palladium (O) (0.037 g, 0.0318 mmol) in toluene (2 mL). The mixture was diluted with ethyl acetate and washed with water and saline. The organic layer was dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate / liver) to yield the title compound as a white solid (0.081 g, 29%). ^ HRMN (400 MHZ, CDC13) or 8.54 (d, 1H), 8.22 ís, 1H), 7.45 (t, 1H), 7.11 (t, 1H), 7.05 (d, 1H), 4.48 (q, 2H) » 4.04 (S, 3H), 1.46 (t, 3H). c) N-C2- (2-metho? ifeni 1) thiazole-4-icarboni 13-N'-CN- (4-pyridine lmeto? -carboni 1) -L-leucine 1 hydrazide Following the procedure of example 112 (f ) -ll2 (g), e ect the substitution of ethyl 2- (2-metho? ifenyl) thiazole-4-carbo? ylate for et l 2-í 2-benci lo? ifeni 1) thiazole-4-carbo? In step (f), the title compound was prepared as a white solid. MS (ESI): 498.3 (M + H) *. The above description fully describes how to make 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 the scope of the following claims. The various references to newspapers, patents and other publications cited herein comprise the state of the art and are incorporated by reference as if they were fully indicated.

EXAMPLE A? 4 Preparation of (2S, l'S) -N-Cl '- (4-carboetho-itiazo1-2-i 1) -3'- methybutyl 1 -4-methyl 1-2-iZ-phenol? icarboni 1) aminopentamide a) 22S, S S) -2- (tert-buto? i carbonyl) amino-N-Cl '- (4-carboeti lo? i ti azol-2-i 1) -3'-meti 1 util 3-4- Ipentanamide met. The compound of Example Bíc) (1.2 g, 3.5 mmol) was stirred at room temperature in net TFA (2.96 g, 26.0 mraol) for 15 minutes. The solution was concentrated in vacuo and redissolved in DMF (25 mL). Triethyl (0.779 g »7.7 mmol), BOC.Leu-OH (0.972 g, 3.9 mmol), 1-hydro? Ibenzotriazole (0.095 g, 0.7 mmol) and 1-i 3- hydrochloride were added to the stirring solution. dimeti laminopropi 1) -3-eti Icar oi imide i .750 g, 3.9 mmol). After stirring for 16 hours at room temperature, the solution was diluted with ethyl acetate and washed successively with water (X 100 ml), NaHCO 3, and saline. The organic layer was dried iMgSO ^), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate / liver) to yield the title compound as a white solid (1.15 g, 72%). MS (ESI): 456.2 (M + H) *. b) (2S, 1S) -N-4-carboetho-itiazol-2-yl) -3'-methylbutyl-13-methyl-1-2-phenyl-1-benzylcarbonyl) amino-pentanamide To a solution of phosgene ( 1.5 ml, 2.9 mmol, 1.93 M in toluene at 0 ° C was added 2-biphenmethoxide (0.486 g, 2.64 mmol) and d isopropyl leti lamina (0.375 g »2.9 mmol) The solution was allowed to stir at 0 ° C for 30 minutes. minutes, in a separate reaction vessel, after stirring at room temperature for 10 minutes, the compound of Example 124a) (0.150 g, 0.330 mmol) was dissolved in TFA, 0.2 ml), concentrated and redissolved in DMF. (3 mi) This solution was added to the solution of 2-bipheni I methanol followed by di isopropylella lamina i? 213 g. 1.65 mmol). After stirring at room temperature for 1 hour, the solution was diluted with ethyl acetate and washed successively with water and saline. The organic layer was dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography (silica gel »ethyl acetate / liver) to give the title compound as a white solid (0.138 g» 74%). MS (ESI): 566.3 (M + H) *.

EXAMPLE 125 Preparation of (ZS »l" S) -Z-C (2-benzyl) benzyloxycarbon 1) 3-araino-N-Cl "- (4-carboethoxythiazo1-Z-i1) -3" -raety1buti13-4-meth ipentanamide Following the procedure of Example 124 (b), except for the substitution of 2-benzylbenzyl alcohol by 2-biphenimethanol, the title compound was prepared as a white solid (0.123 g, 64%). MSíESI): 580.0 (M + H) *.

EXAMPLE 126 Preparation of (2S. L'S) -NC (l "- (4-carboethoxythiazo1-2-yl) -3'-methyl-1-butyl-3-4-methyl-1-ZC (Z-na t-tet-icarbon 1) 3 opentanamide Following the procedure of Example 124 (b), e ept the substitution of 2-naphthalenemethanol by 2-biphen-l-methanol »the title compound was prepared as a white solid (0.132 g, 74%). MS (ESI): 540.1 μM + H) *.

EXAMPLE 127 Preparation of (ZS. L "S) -NC (l '- (4-carboethoxythiazo1-Z-i1) -3'-methyl-1-butyl-3-4-methyl-1-Z-cy-3-phenoxybenz-loxycarbon I) 3am nopentanam da Following the procedure of Example I24 (b) »except the substitution of 3-phenoxybenzyl alcohol for 2-bipheni-methanol» the title compound was prepared as a white solid (0.107 g, 56%). MS (ESI): 581.9 ÍM + H) *.

EXAMPLE * 29 Preparation of (ZS. LtS) -2- (benz lox carbonyl) am no-N-Cl "-CZ- (Z-benzy1guanidini1) thiazo1-4-i1 -3" -methi but l -4-meth ipentanamide a) Salt of S-methyl dithiobiuret hydroiodide To a stirring solution of dithioburet (5.0 g, 37 mmol) in THF (75 ml) was added iodomethane (13.1 g »92.5 mmol, 5.76 ml). After stirring at room temperature for 22 hours, the solution was diluted with 150 ml of toluene and allowed to stand at 0 ° C for 3 hours. The crystals were collected by filtration and washed with cold toluene / THF 2: 1, then dried in vacuo to give the title compound as a white solid (8.7 g, 85%). MS ESI): 149.9 (M + H) *. b) 3-benzylguanidinium thiurea The compound of Example 128 (b) (4.35 g, 15.7 mmol) was dissolved in isopropanol (80 ml) and benzylamine (1.77 g, 16.5 mmol, 1.8 ml) was added and the mixture was mixed. heated to reflux for 16 hours. The hot solution was filtered and the filtrate was cooled to 0 ° C. After 5 hours, the solid was collected by filtration and washed twice with cold isopropanol, then dried under vacuum to provide the title compound as a white solid (2.59 g, 61%). MS (ESI): 209.2 (M + H) *. c) (2S, 1S) -2-benzylcarbonyl) ami no-N-Cl'-C2- (2-benzylguanidini 1) thiazole-4? "133'-methylbut? '13-4 -methyl- pentanamide Following the procedure of Example (b), e ect the substitution of thiourea of 3-benz-1-guanine "dini 1 for ethyl thiool", the title compound was prepared as a white solid (102 mg, 79%). MS (ESI): 565.1 (M + H) *.

EXAMPLE 129 Preparation of (l "S) -N-C4-Cl- (N-benzloxycarboni 1 amino-3-methyl Ibut 13-thiazo-1-2-icarboni-1-N-methy1-N" - (N-benzylcarbonyl) -Lu euc nil) hydrazide Following the procedure of Example 26 (a) -26 (d), e ject the ßubstitution of methyl hydrazine by hydrazine in pa (c), the title compound was prepared as a white solid. MSÍESI): 624.1 (M + H) *.

EXAMPLE 130 Preparation of (1 S) -N-C4-Cl- (N-benzylcarboxylamino-3-methyl-1-butyl-1-azol-Z-Icarboni 13-N "- (N-benzyl-1-oxycarbonyl 1-L-leMcinyl). -ffle il id zjda, a) N- (N-benzylocarboni 1-L-leucine 1) -N-methylhydrazide Following the procedure of Example 26 (c), e ect the substitution of methyl ester of N-benzylocarboxy 1-L -leucine by iSS) -l-benzyl? -carbonyl-amino-l-2-carboetho-itiazol-4-yl) -3-methyl butane and methyl hydrazine by hydrazine, the title compound was prepared. b) iSS) -l-benzylcarboni lami ol-12-carbo i-thiazol-4-yl) -3-methyl-1-butane The compound of Example 26 (c) (0.57 g, 1.5 mmol) was dissolved in tetrahydrofuran and treated with an acidic sodium hydroxide solution. The mixture was allowed to stir for 4 hours, and was extracted with l.ON citric acid. The solvent was evaporated and the aqueous layer was extracted three times with dichloromethane. The organic layers were combined and evaporated to give the acid as a white foam (? 55 g, 100%). c) (lS) -N-C4-Cl-iN-benzyl-icarbonylamino) -3-methyl-1-yl-3-thiazole-2-ylcarbonyl-3-N '- (-benzylcarbonyl-L-leucine 1) -N'- methy1 hydrazide Following the procedure of Example 28 (e), I e ect the substitution of N- (N-benz lo carboni lL-leuc i 1> -N-raet lhydrazide for (lS) -l- (benzyl) icarboni 1) amino-l- (4-carboetho-itiazol-2-y1) -3-methyl butane and (1S) -1-benzyl 1o-icarboni 1ami no-1-i 2-carbo? i thiazo1-4 -i 1) -3-methyl-1-butane by N-benzyloxycarboni 1-L-leucine, the title compound was prepared as a white solid. MS (ESI): 624.2 (M + H) *.

EXAMPLE 3.33, Preparation of N- (N-benzyloxycarboni 1-L-leucine 1) -Nt- (N-benz loxycarboni 1-L-leucine I) -L-a1ani1-hydrazide Following the procedure of Example 27 (a) -27 (c), except for the substitution of L-alanine methyl ester with L-leucine methyl ester in page (a), the title compound was prepared as a white solid ( 225 mg »42%). MS (ESI): 598.1 ÍM + H) *.

EXAMPLE 132 Preparation of N- (N-benzyloxycarbonyl-1-L-1-echin-1) -N '- (N-benzyl-1-oxycarbonyl 1-L-leucine 1) to the icini 1 idrazide Following the procedure of Example 27 (a) -27 (c), except for the substitution of glycine methyl ester by L-leucine methyl ester in step (a), the title compound was prepared as a white solid (307 mg , 42%). MS (ESI): 584.1 (M + H) *.

EXAMPLE 133 Preparation of (lS) -N-CZ-Cl- (N-benzyloxycarbonyl-1-amino) -3-methyl-1 -but 13-1.3.4-triazo1-5-i -carboni 1 -N '- (N-benzyloxycarboni-1-L-) 1eucini1) hydrazide a) Ethyl Oxalamidrazone To a solution of ethyl thio? amata (3.0 g, 22.6 mmol) in ethanol (50 mL) was added hydrazine hydrate (1.13 g, 22.6 mmol, 1.09 mL). The mixture was allowed to stir for 3 hours at room temperature, while ventilating through a scavenger of concentrated sodium hydroxide solution. The solution was allowed to stand for 16 hours and the ethanol was evaporated. The residue was cleaned in 30% dichloromethane in petroleum ether, filtered and recrystallized to give the desired compound as a brown solid. 0.264 g, 9%). b) iSS) -l-benzylcarboni lamino-1-y 2-carboetho? i-1.3.4-triazol-5-yl) -3-methyl-1-butane. N-benzyloxycarboni 1-L-1-eucine (0.535 g 2.0 mmol) was stirred in THF at 5 ° C. Ethyl chloroformate (0.23 mL, 2.4 mmol) and triethylamine (0.25 g, 2.4 mmol, 0.34 mL) were added. The compound of Example 10 (a) (0.264 g, 2.0 mmol) was then added and the mixture was allowed to stir at room temperature overnight. The solvents were evaporated and the residue was dissolved in logs and heated to 200 ° C using a Dean-Stark apparatus. The heating was stopped after 4 hours and the solution was evaporated to a residue which was subjected to chromatography (silica gel »40% ethyl acetate in henum) to give the title compound as a white solid (0.498 g, 69%). AH NMR (400 MHZ, CDC13) or 7.20 (m, 5H), 5.71 id, 1H), 5.04 (S, 2H), 4.99 (dd, 1H), 4.36 (q, 2H), 1.8 (m, 2H). 1.59 ím. 1 HOUR) . 1.31 (t 3H), 0.83 idd. 6H). c) i1S) -l-benzylcarboni lamino-l- (2-hydrazinocarboni 1-l, 3,4-triazol-5-1) -3-methobutane. Following the procedure of Example 26 (c) -26id). I mean the substitution of (lS) -l-benzylcarboni lamino-l- (2-carboetho-i-1.3 »4-triazol-5-l) -3-methyl-butane by (1S) -1-benzyl locarboni lamino-l-2-carboetho-thiazole-4-yl) -3-methyl-1-butane in step (c), the title compound was prepared. MSÍESI): 594.5 ÍM + H) *.

EXAMPLE 134 Preparation of (lS) -N- (N-acetyl-L-leucinyl) -N "-C2-Cl- (N-benz-loxycarbonyl-lamino) -3-methyl-1-butyl thiazo-4-i Ica boni 13hjdrQZÍda Following the procedure of Example 2B (a) -28ie), except for the substitution of N-acetyl-L-leucine for N-benzylocarbonyl 1-L-leucine in step ee), the title compound was prepared as a white solid 95 mg, 67%). MSiESI): 518.0 (M + H) *.

EXAMPLE A Preparation of (lS) -IM- (N-benzyloxycarboni 1-L-alani 1) -N'-C2-Cl- (N-benzyloxycarboni lamino) -3-methy1buty13thiazo1-4- Icarbon 1 hydrazide Following the procedure of Example 28 (a) -28 (e) »except for the substitution of N-benzyloxycarbon 1-L-to-amino by N-benzylcarbonyl 1-L-leucine in step (e) The title compound was prepared as a white solid (129 mg, 82%). MS (ESI): 568. 1 ÍM + H) *.

EXAMPLE 3.36 Preparation of (lS) -N- (N-acetyl-L-alan l) -N'-CZ-Cl- (N-benz-1-oxocarbonyl-1-a) -3-methyl-1-t-1-thiazo-1-4-icarboni 3-hydrazide Following the procedure of Example 2B (a) -28e), I e ected the substitution of N-acetyl-1-L-amino by N-benzylcarbaryl-1-L-leucine in the step ie) »the title compound was prepared as a white solid (74 mg »57%). MS (ESI): 498.1 (M + H) *. EXAMPLE +37 Preparation of (lS) -N- (N-acetyl) -N'-CZ-Cl- (N-benzloxycarbonyllamino) -3-methyl-1-butylthiazo-1-4- and 1-carbon-13-hydrazide Following the procedure of Example 28 (a) -28 (e), except for the substitution of acetic acid for N-benzylocarbonyl 1-L-leucine in step (e), the title compound was prepared as a white solid Í87 mg »78%). MS (ESI): 405.1 ÍM + H) *.

EXAMPLE 139 Preparation of (lS) -N-CZ-Cl- (-benzyloxycarbon-1-amino) -3-methyl-Ibuti-1-thiazo-1-4-Icarboni-1-N'-CN- (4-pyridinyl-methoxycarbonyl) -L-1-eucine-13-hydrazide Following the procedure of Example 28 (a) -28 (e). except the subst tution of N-4-pyridinium lmeto-icarboni 1) -L-1-eucine by N-benzylcarbonyl 1-L-leucine in step te) »the title compound was prepared as a white solid. mg »72%). MS (ESI): 611.0 Í + H) *.

EXAMPLE 3.39 Preparation of (1S) -N-CZ-Cl-1-benzyloxycarbonyl 1-amino) -3- eti Ibuti 13thiazo-1-4-Icarboni 13-N'-CN- (2-pyridine Imethoxycarbon I) -L-1-eucine 13hydrazide Following the procedure of Example 2B (a) -2B (e). ect the substitution of N-2 2-pyridine "Imeto icarboni 1) -L-1 eucine by N-benz locarboni 1-L-leucine in step i.e., the title compound was prepared as a solid white, 125 mg, 65%). MS (ESI): 611.2 (M + H) *.

EXAMPLE 10 Preparation of (lS) -N-CZ-Cl-1-benzloxycarbon 1-amino) -3-methyl Ibut 13thiazo-1-4-Icarbon 1-N '- (N-benzloxycarbonyl 1-N-methyl 1-L- Leucine 1) Hydrazide Following the procedure of Example 28 (a) -28 (e), except for the substitution of N-benzylocarboni 1-N-methyl-1-L-1 eucine for N-benzylcarbonyl-1-eucine in the step (e), the title compound was prepared as a white Aeolide (0.5 mg, 50%). MS iESI): 624.3 ÍM + H) *.

EXAMPLE 1 1 Preparation of (IS) -N-C2-Cl- (N-benzyloxycarboni 1-N-methylamino) -3-RETHYLBUTYL-TIAZO-1-4-Icarbon 13-N "-CN- (4-pyridine Imethoxycarbon I) -L-1eucine 13hydrazide Following the procedure of Example 28a) -28ie), except for the substitution of N-benzyl? I carboni 1-N-methyl-1-L-1 eucine for N-tert-butocarbaryl-1-L-leucine in paeo ( a) and N- (2-pyridinium-1-metho-carboni-1) -L-leucine by N-benzylcarbonyl-L-leucine in paeo (e), the title compound was prepared as a white solid, 120 mg, 72%). MS iESI): 625.3 ÍM + H) *. 22B EXAMPLE 14? Preparation of (l "S) -N-iN-benzyloxycarboni-1-L-1-echin-1) -Nt-C2-Cl- (-benz-lo -carbonyl-N-methylam-no) -3-methyl-buty-1-azo-1-4-icarboni-13-hydrazide Following the procedure of Example 28 (a) -2? Íe), do I substitute N-benzylo? 1-N-methyl-1-L-leucine carbon by N-tert-buto-icarbonyl-L-leucine in step (a), the title compound was prepared as a white solid (95 mg, 74%). MS (ESI): 624.3 (M + H) *.

EXAMPLE 3 Preparation of (1S) -N-CZ-Cl- (-benz-loxycarboni 1-N-methylamino) -3-methyl-1-buti-13-thiazo-1-4-carbonyl-1"N" - (N-benzyloxycarbon 1-N-methyl-1) L-1eucine? Hydrazide Following the procedure of Example 28 (a) -28íe), except for the substitution of N-benzylo? 1-N-methyl-1-L-1eucine carbon by N-tert-buto-icarboni 1-L-leucine in step (a) and I -benzyl-icarboni 1-N-met-1-L-leucine by N-benzyl lo-carbonate 1-L-leucine in step e), the title compound was prepared as a white solid (129 mg, 59%). MS (ESI): 683.3 (M + H) *.

EXAMPLE 3 * M Preparation of (lS) -N-C2-Cl- (-methylamino) -3-methyl-1-butyl thiazo-4-icarbon I 3-N "-CN- (4-pyridin-1-methoxycarbonyl) -L-1-euci 13-draz da a) (lS) -N-C2-Cl- (N-tert-butoxycarbonyl-N-methylamino) -3-methylbutyl-13-thiazole-4-ylcarbonyl-L-N -'-CN-4-pyridine Imetocarbaryl 1) -L-leucine 1 hydrazide Following the procedure of Example 28 (a) -28e) »did the substitution of N-tert-buto? carboni lN-meti 1-L-leucine by N-tert-buto-icarboni 1-L-leucine in passage) and N-4-pyridinium lmetocarbaryl 1-L-leucine by N-benzylcarboni 1- L-leucine in step (e). the compound was prepared as a white solid. MS (ESI): 591.4 (M + H) *. b) (lS) -N-C2-Cl- (N-Methylamino) -3-ethoxybutyl thiazole-4-ylcarbonyl-N'-CN-i 4-pyridine lmetocarbonyl 1) -L-leucine 1 hydrazine A Solution of the compound of Example 21 (a) in methylene chloride (10 mL) was added trifluoroacetic acid (3 mL). After stirring for one hour at room temperature, the solution was concentrated and the residue was dissolved in methylene chloride. it was washed with saturated aqueous sodium bicarbonate, dried over M SO ^ and concentrated to provide the title compound as a white solid (259 mg, 68% for the two steps EM and ESI): 491.4 (M + H ) * EXAMPLE 45 Preparation of (lS) -N-CZ-Cl- (N-Benzyloxycarbonyl 1amino) -3-methyl Ibuti 13t azo1-4-Icarbon 1 -N'CN-i ter-butoxycarboni 1) -L- 1 eucin 1 hydrazine Following the procedure of Example 28a) -28e), etept that N-tert-buto-1-carbon 1-L-leucine was used in place of N-benzylcarbonyl 1-L eucine in Step (e). ), the title compound was prepared as a white solid (293 mg, 74%) MS (ESI). 576.4 (M + H) *.

EXAMPLE 146 Preparation of (lS) -N-CZ-Cl- (N-Benz-loxycarbonyl-lamino) -3-methyl butyl thiazo-1-4-Icarboni 13-N "-CN- (tert-butoxycarbon i> -N-methyl) -L-1eucini13hydrazine Following the procedure of Example 2B (a) -28 (e) »except that N-tert-buto i carboni 1-N-methyl-L-leucine was used in place of N-benzylcarbonyl-L-leucine in step ee) »the title compound was prepared as a white solid (120 mg, B7%) MS (ESI). 590.3 (M + H) *.

EXAMPLE 147 Preparation of (lS) -N-CZ-Cl- (IM-Benzyloxycarbonyl-1-amino) -3-methyl-1-butyl-thiazo-1-4-Icarbon 13-N '- (N-methyl-1-L-1-echin-1-hydrazine Following the procedure of Example 144 (B). except that (lS) -N-C2-Cl- (N-benzyl-icarbonyl-l-amino) -3-methyl-Ibuti-13-thiazol-4-ylcarboni 13-N'-CN-te > -buto? Icarbo-ni 1) -N-raeti lL-leucine 13-hydrazide in place of (lS) -N-C2-Cl- (N-tert-buto? I carbom'l-N-methyl amino) -3-meti l -butyl 3-t-azol-4-i -carbonyl-3-N'-CN'-CN- (4-pyridinium-1-methylcarbonyl) -L-leucine-13-hydra-zide. The title compound was prepared as a white solid, 40 mg. 80%) MS (ESI). 490.3 (M + H) *.

EXAMPLE 148 Preparation of (lS) -N-CZ-Cl- (N-Benzloxycarbon-1-amino) -3-ethyl-but-thiazo-1-4-Icarboni 13-N'-iL-1 euci or 1-hydrazine Following the procedure of Example 144ib), except that (lS) -N-C2-Cl-N-benzyloxycarbonyl-amino) -3-methyl-Ibuti-13-thiazol-4-ylcarbonyl-3-N'-CN-tert-buto was used? icarbo-ni 1) -L-leucine 13-hydrazide instead of (lS) -N- 2-Cl- (N-te? -buto? icarbo-ni 1-N-methylamino) -3-methyl-1-butyl-thiazole -4- icarboni 13-N'-CN'-CN-4 4-pyridinylmethocarbonyl) -Luci nor 13-hydrazide, the title compound was prepared as a white solid (39 rag, 100%) MS (ESI). 746.4 (M + H) *.

Preparation of (lS) -N-CZ-Cl- (N-Benzyloxycarbonylamino) -3-methylbutyl 3-thiazo-1-4carbon 13-N "-CN- (4-imidazo1 and 1acet) -L- 1euc nj l ^ idrazi na Following the procedure of Example 2B (e), eεcept that ilS) -N-C2-Cl-β-benzylcarbonylamino) -3-methyl-l-butyl-1-thiazol-4-Icarboni-1-N'-CL was used -leucini 1) hydrazide instead of ilS) -l-benzylocarboni 1) amino) -l- (carboetho-itiazol-2-yl) -3-methylbutane and 4-imidazoleacetic acid instead of N - benzylocarbom "1-L-leucine, the title compound was prepared as a white solid (50 mg, 47%). EM iESI) 584.4 M + H) *.

EXAMPLE 160 Preparation of (lS) -N-CZ-Cl- (N-Benzyloxycarbon 1-N-methylamino) -3-methy1buty13thiazo1-4-i1carboni13-N'-CN- (3-pyridinylmethoxycarbonyl) -N-roet 1 -L-1eucine 1 hydrazide a) Ester N-methyl 1-L-leucinemethyl N-methyl-1-L-leucine (1.3 g, 8.95 mmol) was dissolved in 4M HCl, 1,4-dioxide (10 mL) and methanol (10 mL). The solution was stirred overnight at room temperature, then concentrated to provide the title compound as a white solid (100%). MS (ESI): 160.0 (M + H) *. b) Ester N- (3-pyridinium lmeto? icarboni 1) -L-leucine-methylic.

To an agitated solution of phosgene in toluene. { 5.63 mL, 6.025 mmol) in methylene chloride (10 mL), cooled to 0 ° C, was added dropwise a solution of N-methyl-1-eucine-methylene ester (673 mg, 463 mmol) and pyridine. (1.10 g, 0.97 mL, 13.89 mmol) in methylene iodide (4 mL). The solution was stirred at 0 ° C for 2 hr. A solution of 3-p-ridyl-carbinol (0.58 g, 5.09 mmol, 0.49 mL) was then added and the reaction mixture was stirred at room temperature for 5 hours. The solution was concentrated, dissolved again in ethyl acetate, washed with water, dried (MgSO 4), filtered and concentrated. The crude residue was purified by column chromatography on silica gel (6% methanol in methylene chloride) to provide the title compound as a yellow oil (88 mg, 7%) MS (ESI): 295.4 (M + H) *. c) N-Meti 1- (3-pyridinium lmetocarbaryl 1) -L-leucine Following the procedure of Example 144IB), eεcept that Eßter-N-methyl-NO-pyridinium lmetoα-carboni was used. ) -L-leucine methyl in place of (lS) -l-benzylcarboni 1-amino-l-2-hydrazcarbonyl-1-thiazol-4-l) -3-methyl-1-butane was prepared the title compound as an orange solid (84 mg, 100%) MS (ESI). 281.3 ÍM + H) *. d) iS) -N-C2-Cl-N-Benzylocarbonyl-N-methylamino) -N-methyl-L-leucine 13-hydrazide.

Following the procedure of Example 28 (a) -28 (e) »e that N-benzylocarboni 1-N-methyl-1-L-leucine was used in place of N-tert-buto-icarboni 1-Ll eucine in Step ia), and N-meti 1-N-i3-pridini Imeto? icarboni 1) -L-leucine instead of N-benzylocarboni 1-L-leucine in Step (e), was prepared the title compound as a white solid (55 mg »38%) MS (ESI). 639.4 (M + H) *.

EXAMPLE 151 Preparation of (lS) -N-CZ-Cl- (N-Benzylcarbonyl) -3- eti 1but l tTazo1-4- Icarboni 1 -N'CN- (3-pyridinylreetoxicarbon l) -L-1eucini1 hydrazine Following the procedure of Example Z8 (a) -28 (e). Note that N-benzylcarbonyl 1-N-methyl-1-L-leucine was used instead of N-te -butylcarbonyl 1-L-leucine in Step (a), and N- (3) -pyridine Imeto? icarboni 1) -L-leucine instead of N-benzyl? -carboni 1-Llucine in Step (e). The title compound was prepared as a white solid (31 mg, 34%) MS (ESI). 625.4 (M + H) *.

EXAMPLE 15? Preparation of (lS) -N-C2-Cl- (N-Benzyloxycarbonylamino) -3- eti-1-butyl thiazo-1-4-Icarboni 1 -N "CN- (3-pyridine or 1-methoxycarbonyl-1) -L-l-eucinyl-1-drazine Following the procedure of Example 28 (a) -28 (e), except that ae used N-3-pyridinium lmetocarboni 1) -L-leucine instead of N-benzylcarbon l-leucine in Step ( e), the title compound was prepared as a white solid (63 mg, 42%) MS (ESI). 611.5 (M + H) *.

EXAMPLE 153 Preparation of (lS) -N-C2-Cl- (N-Benzyloxycarbon-1-amino) -3-met-1-ut-thiazo-1-4-ylcarbon-13-N-CN- (3-pyridinium-methoxycarbonyl) -L-1-eucine-13-hydrazide Following the procedure of Example 28 (a) -281), except that N-benzyloxycarbonyl-N-methyl-1-L-leucine was used in place of N-tert-butocarbonyl-L-leucine in Step a), and methyl hydrazine in place of hydrazine in Step 1e), the title compound was prepared as a white solid (80 mg, 70%) MS (ESI). 660.4 (M + H) *.

EXAMPLE 154 Preparation of (1S) -N-CZ-Cl- (N-Benz-loxycarboni-1-arnino) -3-methyl-1-butyl-3-thiazo-1-4-Icarboni 13-N'-CN- (2-iridin-1-methocarbon 1) -N-met 1-L-leucine 13-hydrazide a) Ester N-Meti 1-N-í 2-pi ridi ni lmeto? icarboni 1) -L-l eucine methyl. N-2-pyridinium lmetocarbaryl 1) -L-leucine-methyl ester (490 mg, 1.75 mmol) was dissolved in THF (7.0 mL) and methyl iodide (0.435 mL, 6.99 mmol) was added. Sodium hydride dispersion (236 mg, 2.62 mmol) was cautiously added and the sußpeneion was stirred for 5 hours at room temperature. Ethyl acetate was then added, followed by water dropwise. The solution was concentrated in vacuo and the oily residue was partitioned between ether and water. The organic layer was washed with saturated aqueous NaHCO 3 and the combined aqueous extracts were acidified to pH 3 with citric acid. The product was brought up with ethyl acetate, the ethanol was washed with water, 5% aqueous sodium thiosulfate and water, dried (MgSO 4), filtered and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate / water 3: 1) to give a yellow oil (235 mg, 46%). EM ÍESI): 295.4 (M + H) *. b) N-Methyl-N- (2-pyridinium lmetocarbaryl 1) -L-leucine Following the procedure of Example 130ib), except that N-methyl-N- (2-pi-ridinyl-methocarbonyl) ester was used. ) -L-leucine methyl instead of (1S) -1-benzyl? Icarbo-ylamino-l- < 2-hydrazinocarbonyl thiazole-4-1) -3-rnethylbutane »the title compound was prepared as a white solid (223 mg, 100%) EM iESI). 281.3 ÍM + H) *. c) (IS) -N-C2-Cl-iN-Benzyl-1-icarbonyl-amino) -3-methyl-1-butyl-1-4-i-carbonyl-1-N'-CN-i2-pyridinium-1-methoxy carbonyl) -N-methyl-L-leucine 13-hydrazide Following the procedure of Example 2Bla) -28e), except that N-benzyl-1-carbon-1-N-raeti-L-leucine ester was used instead of N-ter-buto icarboniLL-leucine in Step (a) and N-methy1-N- (2-pyridinium lmeto-icarboni 1) -L-leucine. in place of N-benzyl? i-carboni 1-L-leucine in Step (e), the title compound was prepared as a white solid (50 mg, 44%) MS iESI). 639.5 (M + H) *.

EXAMPLE 155 Preparation of (IS) -N- Z-Cl-1-Benzylox carboni 1-N-methylamino) -3-methy1buty13thiazo1-4-i1carboni13-N'-CN- (4-pyridinium-methoxycarbonyl) -N-methyl-1 L-1eucinyl-3-hydrazide a) Ester Isocyanate Ester hydrochloride (10185 g, 45.5 mmol) was dissolved in methylene chloride (100 mL), cooled to 0 ° C and pyridine (12.7 mL, 182.0 mraole) was added, then phosgene in benzene ( 47 mL, 59.1 mmol). The solution was stirred at 0 ° C for 2 hours. The reaction mixture was washed twice with 300 mL of aqueous HCl at 0.5 M. Each aqueous layer was brought with 100 mL of methylene chloride. The combined organic phases were washed with a mixture of saturated aqueous NaCl ice solution, dried over MgSO 4, filtered and concentrated to provide the isocyanate as a yellow liquid (5.37 g, 55%). (b) Ester N- (4-pyridinium lmeto? -carboni 1) -L-leucine-tert-butyl co. The compound of Example 155 (a) (3.05 g, 14.32 branch!) And 4-pyridyl carbinol (1.56 g, 14.32 mmol) was dissolved in toluene (BO mi) and heated to reflux overnight. The solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate / water 3: 1) to provide the title compound as a colorless oil (2945 g, 64%). MS (ESI): 323.4 iM + H) *. c) Ester N-Meti l- (4-pyridinium-1-methocarbyl-1-L-leucine-tert-butyl ester Following the procedure of Example 154a), eεcept that N-4-pyridinium-1-methylcarbonyl ester was used. ) -L-leucine-tert-butyl ico instead of N-2-pyridyl ester-1-methocarbaryl 1) -L-leucine-tert-methyl ester, the title compound was prepared as a yellow liquid. .038 g, 6B% yield.) EM ÍESI): 337.5 ÍM + H) *. id) N-Met l-N- < 4-pyridine Imeto? Icarbon 1) -L-leucine Following the procedure of Example 144b), except that N- (4-pyridinium lmeto? -carboni 1) -L-1eucine-tert-butyl ester was used instead of ester (IS) -N- 2-C1-l-tert-buto-i-carboni lN-meti lamí "no) -3-methybutyl-13-thiazole-4-i-Icarboni 13-N'-CN- (4-pyridinium) lmeto? icarboni 1) -L-leucine 1 hydrazine, the title compound was prepared as a white solid and 343 mg of 72%) MS (ESI): 2B1.3 (M + H) *. (e) iiS) -N-C2-Cl-iN-Benzylcarbaryl 1-N-methylamino) -3-methylbutyl-3-thiazo1-4-i -carbonyl-3-N'-CN-4-pyridinium-lime-1-carbon-1) -N-methyl-L-1-hydrazine Following the procedure in Examples 28) and 28 (e). I mean that N-benz locarboni 1-N-roet lL-leucine was used for N-tert-buto-icarboni-L-leucine in Step (a) and N-methyl-1-N-4-pyridinium-1-methyl-icarbom "L) -L-leucine for N-benzyl? i-carboni-L-leucine in paddo.) The title compound was prepared as a white solid {50 mg of 44%.) MS (ESI): 639.5 (M + H) *.

EXAMPLE 156 Preparation of 2.Z "-CN.N-Cbiß- (N-Aceti1-L- leuginjl pj? Arbphidrazine) Following the procedure of Example 29. etept that N-acetyl-L-leucine was used for N-benzylocarbaryl-L-leucine. the title compound was prepared as a yellow solid (0.153 mg of 23%). MS (ESI): 401.3 (M + H) *.

EXAMPLE 15 Preparation of 2-CN (N-Benzyloxycarbon 1-L-leucine 1) -2'-CN '- (4-methyl pentane I) 3-carbohydraz a) Ester N-Benci lo? icarboni 1-L-leucine-methyl ico To a solution of methyl L-leucine ester (2.0 g, 11.9 mmol) in 1,4-dio? an 820 ml) was added an aqueous solution from a ^ Oa (12.1 ml, 2 M in H ^ O) followed by benzyl chloroform to (1.96 g, 11.5 mmol). The mixture was stirred at room temperature for 4 hours and then partitioned between ethyl acetate and water. The organic layer was washed with saturated saline, dried (MgSO ^), filtered and concentrated to provide the title compound as a colorless oil (3.1 g, 100%). * NMR (400 MHz, CDC1, ") or 7.34 (m, 5H), 5.27 id, 1H), 5.12 is, 2H), 4.41 (s, 2H), 3.75 (S, 3H), 1. 65 (m, 3H), 0.96 (m, 6H). b) N- (N-Benzylocarboxyl-L-leucine 1) hirazine To a solution of Example 157 (a) Í3.1 g, 11.0 mmoles) in methanol (16 ml) was added hydrazine hydrate. Í5.9 g. 118 mmoles 5.7 mi). The solution was stirred at room temperature for 16 hours and then concentrated to provide the title compound as a whitish ßolid (3.1 g, 100%). MS (ESI): 280.2 (M + H) *. c) l-Benzylocarbom "lamino-3-methyll- (1, 3,4-o? adiazol-2-on-5-yl) butane To a solution of Example 157 (b) (3.0 g, 10.8 mmoles) in toluene (50 ml) was added phosgene (56 g, 1.93 M in toluene). The solution was heated under reflux for 4 hours and then concentrated to provide the title compound as a yellow foam solid (3.15). g, 96%). MS (ESI): 306.1 (M + H) *. d) N-iMeti Ipentanoi 1) drazi na To a stirring solution of ethyl isocaproate 22.0 g »13.8 mmoles) in ethanol 2525 ml) was added hydrazine monohydrate (6.9 g, 13B mmoles, 6-7 ml) . After stirring at room temperature for 48 hours, the solution was concentrated to provide the title compound as a white solid. (l.B g, 100%). * NMR (400 MHz, CDC1 ,,) or 7.48 (s br, 1H), 3.62 (S br, 2H). 2.13 ít 2H). 1.51 (m, 3H), 0.85 id. 6H). e) 2-CN-1-Benzylcarbonyl L-leucine 1) 3-2'-CN'-i4-methypentanoi 1) carbohydrazine Compounds of Example I57 (c) (0.100 g »0.325 mmol) were combined and Example 34 (d) (0.042 g »0.325 mmole) and dissolved in ethanol (1 ml). The solution was heated at reflux for 4 hours, then concentrated to a .42 solid yellow residue which was washed with methylene chloride cold log to provide the title compound as a white solid (0.053 g, 37%) MS (ESI): 436.2 (M + H) *.

EXAMPLE 159 Preparation of Z.Zf-CN.Nf-Cbiß- (N-Benzyloxycarbom'1-N-methy1-L-1-eucinyl) 33carbohydrate Following the procedure of Example 29. except that N-benzylcarbonyl-N-methyl-L-leucine was used in place of N-benzyloxycarbonyl-L-leucine, the title compound was prepared by purification with column chromatography (gel silica »methanol / dichloromethane) as a white foam (0.236 g, 23%). MS (ESI): 613.2.

EXAMPLE 159 Preparation of Z-CN- (N-Acetyl-1-L-leucine I) -Z "-CN'-N-benzylcarbonyl 1-L-leucyl) carbohydrazine a) 2CN-iN-Benzylocarboni 1-L-leucim'l) 3carbohydrazine To a stirred solution the compound of Example 157 (c) (3.15 g, 10.3 min) in methanol (2 ml) was added hydrate of hydrazine (5.0 g, 100 mmol, 4.8 ml). After stirring at room temperature for 24 hours, the solution was concentrated to provide the title compound as a pale yellow foam (3471 g, 100%). MS (ESI): 338.2 M + H) *. b) 2-CN- (N-AcetylLL-leuc ni 1) -2'-CN'-i-benzylcarbonyl-L-leucine 1) 3-carbohydrazine To a solution in the stirring of the compound of Example 159 (a) ? 100 g, 0.297 mmoles), N-acetyl-L-leuc na i? 0.54 g, 0.312 mmoles) and 1-hydro? Benzotriazole (0.008 g, 0.0594 mmol) in DMF (2 mL) was added with 1. (3-dimethylaminopropyl) -3-ethylcarboylimide hydrochloride (0.060 g, 0.312 mmol). After stirring at room temperature for 16 hours, the solution was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO), filtered and concentrated. The residue was purified by column chromatography (silica gel, methanol / dichloromethane) to provide the title compound as a white solid (0.052 g, 36%). MS (ESI): 493.1 (M + H) *.

EXAMPLE 160 Preparation of 2.2"-CN.N" -Cbiß-CN- (4-Pyridine-1-methoxycarbonyl) -L-leucine I) 333 -carbohydrazine Following the procedure of Example 29, except that N- (4-pyridinylmethocarbaryl) -L-leucine was used instead of N-benzylocarboni 1) -L-leucine, the title compound was prepared as a yellow liquid (199 mg, 64%). MS (ESI): 587.1 (M + H) *.

EXAMPLE 161 Preparation of 2.2-CN.N "-Cbiß-CN- (2-Pyridine-1-methoxycarbonyl) -L-leucine 1) 333 -carbohydrazine Following the procedure of Example 29. Did you think N-2-p r dini Imeto was used? carboni 1) -L-leucine instead of N-benz locarbaryl 1) -L-leucine, the title compound was prepared as a liquid araarillo i263 mg, 81%). EM ÍESI): 587.1 ÍM + H) *.

EXAMPLE 16? Preparation of Z-CN- (-Benzy lox carbonyl) -L-leucine 1) 3-2'-CN'- CN- (Z-pyridiniummethoxycarbonyl) -L-1eucini1) 33carbohydrazine Following the procedure of Examples 159 (a) - 159 (b), eεcept that N- (2-pyridi or lmeto-icarboni 1) -L-leucine-l iti salt was used instead of N-acetyl -L-leucine in Step ib), the title compound was prepared as a yellow liquid ≤0.040 mg. 15%). EMISI): 5B6.3 (M + H) *.

EXAMPLE 163 Preparation of 2-CN- (N-Benzyloxycarboni 1) -L-1-eucin 1) 3-2'-CN'- CN- (4-Pyridinium-1-methoxycarbon-1) -L-1-echin-1) 33 -carboh-drazine Following the procedure of Examples 159 (a) -1591b), eεcept that N- (4-pyridinium-Imeto-icarboni-1) -L-leucine-l-thio salt was used in place of N-acetyl-L-leucine in Step (b). the title compound was prepared as a yellow liquid (0.045 mg of 17%). MS (ESI): 586.3 iM + H) *.

EXAMPLE 164 Preparation of 2-CN- (N-Benzyloxycarboni 1) -L-1eucini1) -2'-CN'- CN- (3-Pyridinium-1-methoxycarbon 1) -L-leucine 1) 33 -carbohydrazine Following the procedure of Examples 159 (a) -159 (b) 'except that N- (3-pyridinium lmeto? -carboni 1) -L-leucine-1 itium salt was used in place of N-acetyl-L-leucine in Step (b). the title compound was prepared as a yellow liquid 0.084 mg. 32%). EM i ESI): 586.3 ÍM + H) *.

EXAMPLE 165 Preparation of 2.2"-CN.N" -Cbiß- (N-Benzyloxycarbon 1-L-leucine 1) 33-2- (N-methyl) carboidrazide a) N-Meti 1-N-iN-Benzylcarbonyl-L-leucine l) hydrazide To a solution of N-benzylcarbonyl-L-leucine-methyl ester (2.2 g, 8.15 mmol) in methanol (4 mL) he added methihydrazine i3.7 g. 80 mmoles). After stirring at room temperature for 16 hours, the solution was concentrated to yield the title compound as a yellow solid (2.15 g, 7.3 mmol) MS (ESI): 294.1 (M + H) *. b) 2,2'-CN.N'-Cbis- (N-Benzylocarbon l-L-leucine 1) 33-2- (N-methyl-1) carbohydrazide. Compound of Example 157c) i0.250 g »0.B19 mmoles) and the compound of Example 165a) i0.240 g» 0.819 mmoles were combined). it was dissolved in ethanol and refluxed for 24 hours. The solution was concentrated and the residue was purified by column chromatography (silica gel, methanol / dichloromethane) to yield the title compound as a white solid (0.060 g, 12%) MS (ESI): 599.1 (M + H) *.

EXAMPLE 166 Preparation of 2.2tCN.N "Cbiß-CN- (3-pyridinium-1-methoxycarbonyl) -L- 1euc i1 33carbo idrazide Following the procedure of Example 29, except that N- (3-pyridinium-l-methoxycarbonyl-1) -L-leucine was used in place of N-benzyloxycarbonyl-L-leucine, the title compound was prepared as white solid urx (157 mg, 48 mg). %) EM (ESI): 587.0 (M + H) *.

EXAMPLE 167 Preparation of 1- (N-Benzyl-2 * 2 * CN.N'-Cbiß-N-benz loxycarboni 1 -L-leucine 1) 33 carboh draz da a) N-Benz 1 ideno '-i N-benzylocarbom "L-1euci ni 1) hydrazide To a solution of the compound of Example 157 (b) (lg 3.5 mmolee) in ethanol (30 mL) was added benzaldehyde (0.33 mL), 3.2 min.) The resulting mixture was heated at reflux for 4 hours, the mixture was concentrated in vacuo and then purified by vapor chromatography (silica gel, 10-50% EtOAc / he? ano) to yield the title compound as a solid (0.31 g, 23%) MS (ESI): 368.0 (M + H) *. b) N-Benz 1-N "'- (N-Benzylcarbonyl-L-leucine 1) hydrazide To a solution of the compound of Example 167 (a), ≤24 g, 0.65 mmole) in THF i5 mL) the borane-tetrahydrofuran complex was added (0.65 mL, 0.65 mmol, solution to IM in THF). The resulting mixture was stirred at room temperature for 4 hours and then concentrated in vacuo and diluted in ethyl acetate, it was washed with water, saturated saline, dried (MgSO ^), filtered and concentrated in vacuo to give the title compound as a white solid 0.25 g, 89%) .MS (ESI) : 370.0 ÍM + H) *. c) 1-Benzylocarbom "lamino-3-methyl-l-3-benzyl-l, 3,4-o? adiazol-2-on-5-yl) butane.

Following the procedure of Example 157 (c), eεcept that N-benz 1-N "-i N-benz locarbonyl-L-leucine 1) hydrazide was used instead of N- (N-benzyl)? icarboni lL-leucini 1) -hydrazide. the title compound was prepared as an oil (0.02 g, 83%) MS (ESI): 396.0 (M + H) *. d) 1- (N-Benzyl) -2-CN- (N-benzylcarbonyl-L-leucine 1) carbohydrate Following the procedure of Example 159 (a), why was 1-benzyl used? icarboni lamí "o-3-meti 1-1-i 3-bencil-1.3.4-o? adiazol-2-on-5-i 1) butane instead of 1-ben-ci lo? i carbonil ami no- 3-methy1I-yl.3,4-o? Adiazol-2-on-5-yl) butane in Step (a), the title compound was prepared as a solid of 10.0 g, 62%) EM ÍESI): 428.0 iM + H) *. e) 1- (N-Benzyl) -2,2'-N, N'-Cbis-iN-benzylcarbonyl L-L-leucine 1) 33-carbohydrazide. Following the procedure of Example 159 (a) -159 (b) »ecept that 1-benzyl locarbonyl lamyl-3-methyloxy-3-benzyl-1,3,3 was used -o? adiazole-2-on-5-i 1) butane in place of 1-benzyl? i-carbonylamino-3-methi ll-ll.3 »4-o? adiazole-2-on-5-i 1) -butane in Step (a), the title compound was prepared as a solid (13 mg, 86%). EMISI): 675.0 .Im + H) *.

EXAMPLE 16B Preparation of 2-CN-1-Benzyl loxycarboni 1-L-leucine 1) 3-2'CN '- (N-benzyloxycarbonyl-N-me i 1-L-leucinyl) carbohydrazide Following the procedure of Example 159 (a) -l59ib), except that N-benzyloxycarboni lamino-N-methyl-L-leucine was used in place of N-acetyl-acetyl-leucine in Step ib), it was prepared the title compound as a solid? 141 g, 53%) EMIESI): 599.4 (M + H) *.

EXAMPLE 169 Preparation of N-CZ-naphthyl) thiazo1-4-i Icarbon 13-N'-CN- (4 pjridi or 1-methoxycarbon 1) -L-1eucine 13-hydrazide Following the procedure of Example 112 (a) -ll2 »g) except that 1-α-idonane-1-boronic acid was used in place of 2-benzyl-1-thienic acid in Step i), the title compound was prepared as a solid. 094 g, 58%). (ESI): 518.4 (M + H) *.

EXAMPLE 170 Preparation of N-C2- (2-bigeni1) thiazo1-4-i Icarboni 13-N "N- (4-pyridinium-1-methoxycarbonyl) -L-1-echinium-13-hydrazide Following the procedure of Example 112 (a) -ll2 (g), except that 2-bifen-1-boronic acid was used in place of 2-benzyloxybenzoic acid in Step e), the title compound was prepared as a solid (0.100 g »43%). (ESI): 544.3 (M + H) *.

EXAMPLE 171 Preparation of N- (N-Benz loxycarboni 1-N-methyl-L-leucine 1) -N'- C2-CN- (Z-methylpropi1) -N-phenylamino3-thiazo1-4-i1carboni13- hydride Following the procedure of Example 116 (a) -li6IB), except that N-benzylocarboxy-N-methyl-L-leucine was used in place of N-4-pyridinium lmetocarbaryl 1) -L-leucine in El Paso ib), the title compound was prepared as a solid (40 mg, %) MS (ESI): 552.5 (M + H) *.

EXAMPLE 172 Preparation of N-CN-methy1-N- (2-pyridine-1-methoxycarbonyl) -L-1-echinium-13N'-CZ-CN- (Z-methylpropyl) -N-phenylamino-3-thiazo-1-4-Icarbonyl-3-draz Following the procedure of Example 116 (a) -ll6 (b), eεcept that N-meth i N- (2-pyridinium methoxycarbonyl) -L-1eucine was used in place of N- (4-pi) di or Imeto icarboni 1) -L-leucine in Step ib), the title compound was prepared as a solid Í70 mg, 71%) EM ÍESI): 553.4 iM + H) *.

EXAMPLE 173 Preparation of N-C2- (2-Benzylo-ifenyl) thiazo-1-4-Icarbonyl 3-N'- (-ter-butoxycarboni i-L-1eucini 1) hydrazide Following the procedure of Example I12 (a) -112 (g), ecept that N-ter-buto was used? carboni l-L-leucine instead of l \ l- < 4-p-i r ~ i di ni Imeto? carboni 1) -L-leucine in Step ig), the title compound was prepared as a solid (1.015 g, 94%) MS (ESI): 539.1 (M + H > EXAMPLE 174 Preparation of N-N-tert-butoxycarbonyl-L-leucine l-N'-CZ-CN-tZ-met Iprop 1) -N-pheny1-amino-3-thiazo-1-4-Icarboni-13-hydrazide Following the procedure of Example 116 (a) -116í). except that N-tert-butocarboni-L-leucine was used in place of N- (4-? iridini lmeto? -carboni 1) -L-leucine in Step ib), the title compound was prepared as a solid 740 mg, 85%) EM ÍESI): 504.4 (M + H) *.

EXAMPLE 175 Preparation of N- (N-tert-butoxycarbon 1-N-me 1-L-1 eucine 1-N "- CZ-CN- (Z-methylpropyl) -N-phenylane no3-thiazo-1-4-i1-carphenylpihydrase, Following the procedure of Example I16 (a) -116í b), .52 ect that N-tert-buto-icarboni 1-N-methyl-L-leucine was used in place of N-14-pyridinium-Imethocarbon I) -L-leucine in Step ib), the title compound was prepared as a solid (610 mg, 69%) MS (ESI): 518.4 (M + H) *.

EJEHPLO 176 Preparation of N-C2- (2-Benzyloxypheni 1) thiazo1-4-i Icarboni 13-N'- (N-pyrazincarbonyl-L-leucinyl) hydrazide a) N-C2- (2-Benzylocarboni 1) thiazole-4-icarboni 13-N '- (L-1 euci ni 1) hydrazide Following the procedure of Example 144b), ecept that N was used. -C2- (2-benzyl? Ifeni 1) thiazole-4-i Icarboni 13-l \ l »- (N-ter-buto? Carboni lL-leucini 1) hydrazide instead of ilS) -N-C2-Cl -I N-ter-buto? Charcoal 1-N-meti lamethyl) -3-methylbutyl 13-thiazole-4-Icarboni 13-N'-CN-4-pyridinium-limetocarboni 1) -L-leuci-1-hydrazide, the compound of the title as a white powder (0.766 g, 93%) MS i ESI): 439.3 M + H) *. b) N-C2-y2-Benzylcarbon 1) thiazole-4-ylcarboni 1-N'-N'-CN-y 2-pyrazine Icarbonyl) -L-leuci i 1) idrazide Following the procedure of Example 116 (b), e) that N-C2- (2-benzylo-ifeni 1) thiazole-4-i Icarboni 13- N '- (L-leucine) hydrazide was used instead of N-C2-CN-pheny 1-N-2-methyl-1-propyl) amino-3-thiazole-4-ylcarboni-13-hydrazide and pyrazin-carbo-yl acid instead of N- < 4-piridini Imeto? i carboni 1) -L-leucine »the title compound was prepared as a white solid (0.146 mg» 94%) MS (ESI): 545.4 (M + H) *.

EXAMPLE 177 Preparation of N-C2- (Z-Benzl oxypheni1) thiazole-4- lcarbon 13-Nt- (n-ißonicotino 1-L-leucine 1) idrazide Following the procedure of Example I76a) -176ib) »ect that isonicotinic acid was used in place of pyrazincarboni acid 1) in Step ib)» the title compound was prepared as a white solid (0.135 g »87%). (ESI): 544.3 (M + H) *.

EXAMPLE 179 Preparation of N-cz- (2-Dibenzofuran l) thiazo1-4-i1carbonin1-N? R- CN- (4-Pridine 1methylcarboni 1) -L-1eucine 1 hydrazide Following the procedure of Example 112 (a) -ll2ig) »ecept that 2-bromod benzofuran was used in place of 2-benzyl? bromobenzene in Step id) »the title compound was prepared as a white solid (0.079 g, 49%) MS (ESI): 55B.3 (M + H) * EXAMPLE 179 Preparation of N-C2-CN-iZ-MethylPropi1) -N-phenylamino3-thiazo1-4- i 1-carbon-1-Nt- (-P-Irazincarboni 1-L-leucine 1) hydrazide Following the procedure of Example 176 (a) -l76ib), eεcept that N-tert-buto-icarboni-L-leucine 1) -N'-C2-CN- (2-met Ipropi 1) - -phenylamino-thiazole was used -4-icarboni-13-hydrazide in place of N-C2- (2-benzyl-1-phenyl) -i-azol-4-Icarboni-1-N '- (N-tert-buto-icarbonyl-L-leucine 1) hydrazide in Step (a), the title compound was prepared as a white solid (36 mg, 27%) MS (ESI): 510.4 (M + H) *.

EXAMPLE 190 Preparation of N-C2-CN- (Z-Meti Ipropyl) -N-phenylamino-3-thiazo1-4- and Icarbon 13-Ny- (N-methy1-N-Pirazincarbom "1-L-1-eucin 1) hydrazide Following the procedure of Example 176 (a) -l76i b), eεcept that N-tei-buto-icarbon lL-leucini 1) -N'-C2-CN-i 2-methyl-1-propyl) -N- was used phenylamino thiazole-4-i Icarboni 13hi draz-da in place of N-C2-i2-benzyl? ifeni 1) thiazole-4-i -carbonyl-N'-n-te-buto-icarboni 1-L-leucini 1) hydrazide in Step (a), the title compound was prepared as a white solid (70 mg, 72%) MS (ESI): 524.4 (M + H) *.

EXAMPLE 181 Preparation of IM-iN-Ißon with oil-L-leucinyl-N'-CS-Cmethylprop l) -N-phenyl-1-ane-3-azol-4-Icarbonyl-3-hydrazide Following the procedure of Example 176 (a) -176 (b), eεcept that N-N-tert-buto-icarboni 1-N-methyl-L-leucine 1) -N'-C2-CN-i2- was used meti Ipropi 1) -N-phenylami-3-thiazol-4-ylcarbonyl-3-hydrazide in place of N-C2- (2-benzyloe-1) thiazole-4-i-1-carboni 13-N'- < N-ter -buto? icarboni 1-L-leucinil) hydrazide in Step ia), and isonicotic acid in place of pyrazincarboxylic acid in Step ib), the title compound was prepared as a white solid (2B mg, 22% ) MS (ESI): 509.4 M + H) *.

EXAMPLE 1BZ Preparation of N- (N-Isonicotinoi 1-L-leucine 1) -N'-C2-CN- (2-methyl-Iprop-1) -N-phenyl-1-amino-3-amino-1-4-Icarboni-13-hydrazide Following the procedure of Example 176 (a) -l76ib), eεcept that Nf -methyl-1-N-tert-buto-1-carbon 1-N-met-L-leucine 1) -N'-C2-CN- was used 2-meti Ipropi 1) -N-phenylamino-3-thiazole-4-y-Icarboni-13-hydrazide instead of N-C2-Y 2-benzylo-ifeni 1) thiazole-4-i Icarboni 13-N'-iN-tert-buto icarboniLL-leucini 1) hydrazide in Step a), and isonicotic acid in place of pyrazinecarboyl acid in Step (b), the title compound was prepared as a white solid (117 mg, 93%). (ESI): 523.4 ÍM + H) - EXAMPLE 1B3 Preparation of N-CN- (4-Im dazol laceti 1) -L-1eucini13-N "-C2-CN- (Z-raeti Ipropi 1) -N-pheny1-amino3-thiazo-1-4-Icarbon-1-hydrazide Following the procedure of Example 176 (a) -176 (b), eεcept that N-yN-tei-buto-icarbonyl-N-methyl-L-leucine 1) - '- 2-CN-i 2 was used meti 1 propi 1) -N-feni 1 ami no 1i azo1-4-i 1 cay-boni l 3-hydrazide instead of N-C2-Í 2-benci lo? ifeni 1) thiazole-4-i 1-carboni 13-N '- (N-tert-buto i carboni lL-leucini l) h drazide in Step (a), and imidazole ethoacetic acid in place of pyrazincarboxylic acid in Step (b), the compound of title as a white solid (60 mg, 53%) * H NMR (400 MHz, CDC13) OR 7.62-7.23 (m, 8H), 6.81 (S, 1H), 4.72-4.66 im, 1H), 3.75 (d, 1H), 3.55 (d »1H)» 3.55 id, 2H), 1.96-1.93 im. 2H). 1.76-1.54 ím. 3H), 0.96-0.84, m, 12H).

EXAMPLE 194 Preparation of N-C2-CN- (Z-Methylpropi1) -N-phenylamino3-thiazo-4-icarboni 13-N '- (N-P CQ1 inoi 1-L-l euc nyl) idrazide Follg the procedure of Example 176 (a) -176 (b), eεcept that N- (N-te -buto? I carboni 1-N-met 1-Ll euci ni 1) -N'-C2- was used CN-2-met-1-propyl 1) -N-phenylamino-3-thiazole-4-ylcarbonyl-1-hydrazide instead of N-C2-t2-benzyl-ifenyl) thiazol-4-yl-carboni 1 -N '- (- terborate icarbonyl-L-leucine 1) hydrazide in Step (a), and picolinic acid in place of pyrazincarboxylic acid in Step (b). the title compound was prepared as a white ßol 50 mg. 44%) MS (ESI): 509.5 iM + H) *.

Preparation of N-C2- (Z-Benzyloxypheni 1) thiazo1-4- Icarbonyl 3methi-CN- (4-pyridinium-methoxycarbonyl) -L-1-eucinam a a) 2-β2-Benz-loxyphene-1-thiazole-4-carbohydrate acid Follg the procedure of Example 105 (b), e) that ethyl 2- (2-benzyl-1-in-1) thiazole-4-carbo was used? methyl γ-3-pyridyl-limeto) benzoate, the title compound was prepared as a white solid (0.361 g, 90%).

(ESI): 312.2 (M + H) * b) 2- (2-Benzyl) phen-1-thiazole-4- (1-bromomethyl-1-ketone. Follg the procedure of Example 103 (a), eεcept that 2- (2-benzyl-1-thienyl-1-thiazole-4-carboalicylic acid was used in place of N-benzylocarboxy 1-L-Leucini 1- L-Leucine "the title compound was prepared as a white solid (0.327 g, 73%). EMÍESI): 38B.2 (M + H) *. c) 2- (2-Benzyl? ifem "l) thiazole-4-yl-azidomethyl-1-ketone. A solution of the compound of Example 25B was stirred. 185b), i0.319 g, 0.822 mmole), sodium-azide (0.064 g 0.987 mmole), and potassium fluoride (0.072 g, 1.23 mmole) in DMF (6 raL). at room temperature for 16 hours. The solution was then diluted with ethyl acetate and washed successively with water, saturated aqueous sodium acid carbonate and saline. The organic layer was dried (MgSO ^) »it was filtered and concentrated. The residue was purified by silica gel column chromatography »ethyl acetate / liver» to yield the title compound as a white solid (0.087 g »30%). MS (ESI): 373.3 (M + Na) *. d) 2-Azido-l-C2-l2-Benci lo? ifen 1) thiazole-4-i 13-1-hydro? Ethane. To a stirring solution of the compound of Example lb5 (0.087 g, 0.249 mmol) in THF (1 mL) at 0 ° C, sodium borohydrate was added slowly (0.031 g, 0.820 mmol). After 20 minutes the mixture was diluted with ethyl acetate and washed with water and then with saline. The organic layer was dried (MgSO 4), filtered and concentrated to yield the compound as a white solid (0.084 g 96%). * HRMN (400 MHz. CDC1> or 8.41 (m. 1H), 7.50 m.m., 2H), 7.38 (m, 4H). 7.11 ím, 3H), 5.31 ÍS. 2H), 5.08 (t.1H), 3.69 (m.2H), 3.58 (s b, 1H). e) 2-Amino-l-C2-t2-Benzyl-1-yl) thiazol-1-yl-1-hydroxy-ethane. To a stirring solution of the compound of Example 185), 0.084 g, 0.239 mmol) in methanol (2 mL) was added stannous hydrochloride (0.108 g, 0.478 mmol). After stirring at room temperature for 16 hours, the mixture was diluted with ethyl acetate and washed successively with water, saturated aqueous NaHC03 and saline. The organic layer was dried (MgSO ^). it was filtered and concentrated. The residue was purified by column chromatography (silica gel, methanol / dichloromethane) to give the title compound as a white solid (0.07 g, 96%). MS (ESI): 327.3 M + H) *. f) l-C2-i2-Benzylifeni 1) thiazole-4-i 13-l-hydro i-2-i4-pyridinium-Imethocarbonyl-L-leucine-lamino-ethane. Follg the procedure of Example 116 (b), eεcept that 2-amino-1-C2-22-benc was used? lo? ifem "1) -thiazol-4-yl 3-1-hydro-iethene in place of N-C2-CN-phenyl 1-N-2-methyl-1-propyl) amino-3-thiazole-4-ylcarboni-1-hydrazide The title compound was prepared as a white solid (0.075 g, 57%).

MS (ESI): 575.4 (M + H) *. g) N-C2- (2-Benz lo? ifen l) thiazole-4-Icarboni 13methi N- (4-pyridinium lmeto? -carboni 1) -L-leucinamide To a stirred solution of the compound of Example 185 (f) 0075 g. 0.131 mmol) in dichloromethane (1 mL) was added MnOj, i? 300 g. 3.45 mmoles). After stirring at room temperature for 24 hours, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography, methanol / dichloromethane) to afford the title compound as a pale yellow solid (0.017 g, 23%): 573.4 (M + H) *.

EXAMPLE 196 Preparation of N-C2-CN-Meti1-N- (Z-met lPropi1) amino3-thiazo-1-4-ylcarbonyl-N "-CN- (4-pyridinium-1-methoxycarbonyl) -L-1-eucine-13-hydrazide a) N-Benzoi 1-N'-methyl l-N '- (2-met lpropi 1) thiourea. To a stirred solution of N-meti 1 isobuti sheet Í3.21 g, 36.8 mmoles, 4.45 mL) in 40 mL of CHC13 was added benzoyl isothiocyanate i6.0 g, 36.8 mmol, 4.95 mL). After stirring for 45 minutes, the solution was concentrated to yield the title compound as a pale yellow solid (9.22 g, 100%). AHRMN (400MHz, CDC1 ,,; 2: 1 mixture of rotamers) or 7.86 (d, 2H), 7.60 (t, 1H), 7.50 (t, 2H), 3.90 id, 2H), 3.44 ÍS, 3H), 3.41 (d, 2H), 3.27 (s, 3H), 2.35-2.32 (m.1H), 2.13 (m.1H). 1.06 id, 6H), 0.90 id, 6H). b) N-meti 1-N-i 2-meti 1propi 1) tioruea. A compound of Example 186) was suspended (9.22 g. 36. 8 mmol) in 80 mL of methanol / water at 1: 1 and solid potassium carbonate (15.27 g, 110 mmol) was added. The mixture was heated at reflux for 48 hours, then cooled and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2X). The combined organic layers were washed with saturated saline, dried (MgSO ^), filtered and concentrated to provide the title compound as a pale yellow crystalline solid .4.82 g. 89%). EMÍESI): 147.0 ÍM + H) *. c) N-C2-CN-Met 1-N-2 2-methyl-1-propy1) amy no3-thiazole-4-i-Icarbom '13-N'-CN- (4-pi ridini lmeto-icarboni 1) -L-leucine 13hi drazi da. Following the procedure of Example 113 (d) -ll3 (f), etept that N-meti l-N-2-met Ipropi 1) thiourea was used instead of N- (4-pheni Ifeni 1) -N-2 2-methi 1-1-propi 1) thiourea in Step id), the title compound was prepared as a white solid (202 mg, 97%). MS (ESI): 477.4 (M + H) *.

EXAMPLE 197 Preparation of N- (N-Meti1-N-pico1 non-1-L-leucine 1) -N'-CN- (2-methyl Iprop 1) -N-phenyl-1-amino-3-aiazole-4-Icarboni-1-hydrazide Following the procedure of Example 176 (a) -l76 (b), eεcept that N-α-methi 1-N-tert-buto-icarboni 1-N-meti 1-L-leucini 1) -N 'was used -C2-CN-i 2-met lpropi 1) -N-phenylamino-3-thiazole-4-y-Icar-boni 13-hydrazide instead of N-C2- (2-benzylo-ifeni 1) -thiazole-4-i Icarboni 1 - N'-iN-tert-buto-icarboni-L-leucine 1) -hydrazide in Step (a), and picolinic acid pyrazincarboxylic acid in Step ib), the title compound was prepared as a white solid (30). mg, 41%). MS (ESI): 523.5 (M + H) *.

EXAMPLE 199 Preparation of N-C2- (Z-Benzyloxy-phenyl) -iazole-4-i -carboni 13-N'-CN- (Z-pyridin-sulfonyl-1) -L-leucine-13-hydrazide. a) Sulfonium chloride of Z-pyridine. Through a stirring solution of (2.235 g, 20 mmol) in water (7.5 mL) and concentrated HCl (26 mL) to OßC was bubbled Cl.t. After 30 minutes »75 mL of ice water were added and extracted with cold ether (2 X 75 mL). The organic layers were combined and washed successively with 10% aqueous NaHCO, and cold saline. The organic layer was dried (MgSO 4), filtered and concentrated to yield the title compound as a clear oil (3.1 g, 87%). b) N-C2- (2-Benzyloxypheni 1) thiazole-4-icarbon l 3-N'-CN- (2-pyridinesulfoni 1) -L-leucine 1 hydrazide. To a stirred solution of the compound of Example 176a) 0.125 g »0.2B5 mmoles) and the compound of Example lbBia) (0.101 g» 0.571 mmoles) in dichloromethane (2 mL) was added N-methylmorpholine (0.057 g » 0.571 mmoles). After stirring at room temperature for 10 minutes, the solution was diluted with ethyl acetate and washed successively with water and saline. The organic layer was dried (MgSO ^) »it was filtered and concentrated. The residue was purified by column chromatography (silica gel »ethyl acetate / hexane) to give the title compound as a pale yellow solid (0.100 g, 61%). MS (ESI): 580.2 M + H) *.

EXAMPLE 189 Preparation of N-C2-CN-i2-Methylpro-yl) -N-phenylamino-3-thiazo-1-4-Icarboni 13-N'-CN-i 2-Pyridin-sulfonyl 1) -L-1-echinium-13-hydrazide Following the procedure of Example IBB), e that N-iL-leucine 1) -N'-C2-CN- (2-methyl-1-propyl) -N-phenyl-1-amino-3-aiazole-4-ylcarbonyl-3-hydrazide was used instead of N-C2- (2-benzyl-phenyl) thiazole-4-iicarbom 1-N '- (-leuccinyl) hydrazide, the title compound was prepared as an orange solid (56 mg, 48%). EMÍESI): 545.3 (M + H) *.

EXAMPLE 190 Preparation of N-CZ-CN- (2-Met Ipropyl) -N-phenyl-1-aminopiazole-1-carbonyl-N > -CN-meti1-N- (Z-Piridinsu1foni1) -L- 1eucini13hydrazide Following the procedure of Example I88 (b), eεcept that N-N N-methyl 1-Ll euci ni 1) -N'-C2-CN- (2-haloethylpipe) -N-phenylarai o-thiazole was used. 4-i Icarbon 1 hi-drazide instead of N-C2-Y 2-benc lo? Ifeni 1) ti azole-4-i-Icarbonyl 3-N '- (L-leucine 1) hydra-zide, the compound of title as an orange solid (53 mg, 40%). MS (ESI): 559.3 (M + H) *.

EXAMPLE 3,91 Preparation of N-CZ-CN-Met l-N-iZ-met lpropyl) amino-3-thiazo-1-4-Icarbonyl 3- "-CN-i 3-P ridi or 1-methoxycarboni 1) -L-leup i 1 hydras? Following the procedure of Example 186 (a) -l86íc), except that N- (3-pyridinium Imeto-icarboni 1) -L-leucine was used in place of N-4-? Iridin lmeto-icarboni 1) -L -leucine in El Paso (c), the title compound was prepared as a white solid (138 mg, 66%). EMiESI): 477.4 (M + H) *.

EXAMPLE 192 Preparation of N-CZ-CN-iZ-Meti-loropyl) -N-phenylane-3-thiazole-4-ylcarboni 13-N'-3N-methi 1-N- (4-pyridinium-1-ethoxycarbon-1) -L-leupini 13 , hi razi a Following the procedure of Example 116 (a) -ll6 (b), except that N-methiN- (4-pyridinium-1-methoxycarbonyl) -L-1-eucine was used in place of N- (4-pyrimethoxymethoxycarboni) 1) -L-leucine in Step (b), the title compound was prepared as a white solid (74 mg, 41%). MS (ESI): 553.4 (M + H) *.

EXAMPLE 193 Preparation of N-CZ-CN-iZ-Meti Ipropyl) -N-phenyl amino-3-thiazo-1-4-ylcarbonyl-N'-CN-methyl 1-N-i3-Pyridinium-1-methocarboni 1) -L-1-ee-1-hydrazide Following the procedure of Example 116 (a) -116 (b), eεcept that N-methyl 1-N- (3-pyridine Imethoxy-carboni 1) -L-leucine was used in place of N-4-pyridine lmeth icarboni 1) -L-leucine in Step ib), the title compound was prepared as a white solid (50 mg, 38%). EMÍESI): 553.4 ÍM + H) *.

EXAMPLE 194 Preparation of N-CZ- (Z-Benzyloxifem "1) thiazo1-4-i Icarbonyl 3-N'-CN-methy1-N- (3-pyridinium methoxycarboni 1) -L-1eucine 13hydrazide Following the procedure of Example 112 (a) -112 (g), except that N-meti 1-N- (4-? Iridini Imeto? I-carboni 1) -L-leucine was used instead of N- (4-) pyridi "Imeto? icarbonil) -L-leucine in Step (g), the title compound was prepared as a white solid (0.028 g, 15%) MS (ESI): 5B8.4 M + H) *.

EXAMPLE 195 Preparation of N-CN-Meti1-N- (4-pyridine-1-ethoxycarbon-1) -L-1-echin-1-N'CZ- (l-naft-1) thiazo-1-4-Icarbon-13-hydrazide Following the procedure of Example 112 (a) -112ig) », it was used 1-naphthyl boronic acid instead of 2-benzyl-1-boronic acid in Step (e) and N-methyl-1N- ( 4-pyridinium lmeto? Icarboni 1) -L-leucine in place of N- (4-pyridinium lmetoxy-carboni 1) -L-leucine in Step (g), the title compound was prepared as a white solid (0.072 g 36%). MS (ESI): 532.4 (M + H) *.

EXAMPLE 196 Preparation of N-C2-CN.N- (biß) -2-Methylpropi1) amino3-thiazo-1-4-ylcarbonyl 3-N'-CN- (4-pyridinylmetho-icarpon-1) -L-1-echin-1-hydrazide Following the procedure of Example I86 (a) -l86 (c), ecept that NN-diisobutylamine was used in place of N-methyl isobutylamine in Step (a), the title compound was prepared as a yellow solid (60 mg, 39%). MS (ESI): 519.5 (M + H) *.

EXAMPLE 197 Preparation of N- (N-Benzylocarboni 1-L-leucine I) -N'C2-N- (biß) -2-roethylpropi1) amino3-thiazo-1-4-Icarboni-13-hydrazide Following the procedure of Example I86 (a) -186 (c), eεcept that N, N-di isobutylamine was used in place of N-methyl 1 sobutylamine in Step (a) and N-benzylcarbony L-leucine in place of N- (4-pyridinium-Imethocarboni 1) ~ L-leucine in the final step, the title compound was prepared as a yellow solid (131 mg, 69%). MS (ESI) "519.4 (M + H) *.

EXAMPLE 19B Preparation of N-C2- (4-Morfo1ino) thiazole-4-Icarbon 13-N'CN- (4-pyridinylmethoxycarbonyl) -L-1eucine-1-hydrazide Following the procedure of Example lb6 (a) -l86 (c). except that morpholine was used in place of N-meti Isobuti lamina in Step (a), the title compound was prepared as a white solid (45 mg, 31%). MS (ESI): 477.3 (M + H) *.

EXAMPLE 199 Preparation of N-C2- (4-Pyridinium lmetoxy) fem'13thiazo1-4- i 1carbon 13- "CN- (4-pyridinium-1-methoxycarbonyl-1) -L-leucine-1-hydrazide a) 2-Methoxymetho-? bromobenzene To a stirred suspension of sodium hydride (1.2 g, 52.1 mmol, 60% dispersion in 60% mineral oil) in DMF (75 ml) At 0 ° C, dropwise 2 was added dropwise. -bromophenol (6.0 g, 34.7 mmol). After stirring for 20 minutes, 1-methyl bromomethyl ether (4.3 g, 34.7 mmol) was added. After stirring for 16 hours at room temperature, the water mixture was poured (250 ral) and drained with water. The organic layer was washed with saline, dried (MgSO 4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to give the title compound as a colorless oil (4.0 g, 53%). ^ -RMN (400MHz, CDC13) or 7.55 (d, 1H), 7.2B (t.1H). 7.16 id. 1H) »6.91 it, 1H). 5.25 i S, 2H), 3.54 i s, 3H). b) Ethyl 2-ethyl 2-methyl-4-ethyl-4-carboxylic acid Following the procedure of Example 112 (a) -112ib) and 112 (d) -112), e that 2-metho-imethoxybromobenzene was used. in place of 2-benzyl? -bromobenzene in Step id), the title compound was prepared. EMiESI): 294.3 (M + H) *. c) 2-i2-Hydro? ifeni l9tiazole-4carbo? ethyl acetate To a stirring solution of the compound of Example 199b) (0.839 g, 2.86 mmol) in ethanol (25 ml) was added 10 drops of concentrated hydrochloric acid. After stirring at reflux for 2 hours, the solution was concentrated and then dissolved in ethyl acetate. The solution was washed successively with saturated sodium bicarbonate and saline, dried (MgSO 4), filtered and concentrated to yield the title compound as a pale yellow solid i674 g. 95%). EMÍESI): 250.2 ÍM + H) *. d) ethyl 2-C2-y4-pyridylmetho) i) pheny1-thiazole-4-carbohydrate To a stirred solution the compound of Example 199ÍO Í0.125g. 0.502 mmol), 4- ir iridi Icarbinol O0.071 g, 0.653 mmol) and triphenylphosphine (0.171 g, 0.653 mmol) in THF (5 mL) at 0 ° C was added dropwise to diisopropyl azodicarbo i lato (0.132). g, 0.653 mmol). After stirring at room temperature for 16 hours, the solution was concentrated and purified by column chromatography (silica gel »ethyl acetate / water) to yield the title compound as a white solid? 100 g. . 59%). e) N-2-C2-β4-pyridine imetho? i) phenyl-1-thiazole-4-ylcarbon 13-N'N-l4-pyridinium-1-methyl-1-carboni 1) -L-leucine-1-hydrazide Following the procedure of Example 112 (f) -ll2 (g), eεcept that 2-C2-4-pyridi Imeto i i) phenyl-1-thiazole-4-carbo-ylate-ethyl 2-i2-benz lo? Ifeni 1) thiazole- 4-carbohydrate ethyl 2-2 2-benzylo? Ifeni 1) thiazole-4-carbo? ethyl acetate in Step (f) »the title compound was prepared as a white solid (146 mg, 83%). MS (ESI): 575.4 (M + H) *.

EXAMPLE 200 Preparation of N-C2- (Z-Nafl) thiazo1-4-i1 carboni 13-Nt-CN-4-pyridinylraeto-icarboni 1) -L-1eucine 1 hydrazide Following the procedure of Example 112 (a) -ll2 (g), eεcept that 2-naphthyl-Iboronic acid was used in place of 2-benzyl-ifhenyl-boronic acid in Step (e), the title compound was prepared as a white solid (226 mg »75%). EM (ESI): 518.4 iM + H) *.

EXAMPLE 201 Preparation of N-CZ-N.N- (bis) -Z-Meti lpropi 1) aroino-thiazole-4- i 1 -carboni 1 -N > CN-meti 1-N- (4-pir in 1methoxycarbon 1) -L- 1 euc i ni l 3hi drazi da Following the procedure of Example 186 (a) -lB6 (c), except that NN-di isobutylam was used in place of N-methyl isobutyl in Step (a), and N-met lN- (4-pyridinium) -meto icarboni 1) -L-leucine instead of N-i4-pyridine Imethoxy-carboni 1) -L-leucine in the final step, the title compound was prepared as a yellow solid i30 mg »25%). EM iESI): 533.3 (M + H) *.

EXAMPLE 202 Preparation of N- (N-Benzylocarbon 1-L-leucinyl > -Nt-C2- (4-morfo1ino) thiazo-1-4-Icarboni-13-hydrazide Following the procedure of Example 186 (a) -lB6 (c) »ecept that morpholine was used in place of N-methyl isobutyl laminate in Step (a), and N-benz? loxicarboni L-L-leucine instead of N-Í4-pyridinium lmetocaricaryl 1) -L-leucine in the final step, the title compound was prepared as a white solid (115 mg). 67%). EM iESI): 576.4 ÍM + H) *.

EXAMPLE 203 Preparation of N- ^ N- (4-Pyridine Imetocarbonyl) -L-1eucine13-N "- C2- (4-thiomorphl-1-yl) thiazol-4-ylcarboni-13-hydrazide Following the procedure of Example 186 (a) -l86 (c), eεcept that thiomorpholine was used in place of N-methyl isobutylamine in Step ia), the title compound was prepared as a white solid. %). EM iESI): 493.4 (M + H) *.

EXAMPLE 204 Preparation of N- (N-Benzyloxycarboni 1-L-leucinyl) -N "-C2- (4-thiomorphino) thiazo-1-4-i1carboni-13-hydrazide Following the procedure of Example 186 (a) -186c) 'except that thiomorpholine was used in place of N-methyl Isobutylamine in Step (a), and N-benzyloxycarbom'1-L-leucine instead of N-4-pyridyl "lmeto? Icarboni 1) -L-leucine in the final step" The title compound was prepared as a white solid (20 mg, 20%). MS (ESI): 492.3 (M + H) * .

EXAMPLE 205 Preparation of N-CZ- (Z-3-Ethylene-dioxy-4-methoxypheni) thiazo-1-4-i1carboni-13-N'-CN- (4-pyridinium-1-methoxycarbonyl) -L- l ^ Cinj13-hydrazide Following the procedure of Example 112 (a) -112 (g), ecept that 2,3-eti-lenedio-y-4-metho-ibromobenzene was used in place of 2-benzyl? bromobenzene in Paβ (d), the title compound was prepared as a white solid (31 mg, 26%). MS (ESI): 556.4 M + H) *.

EXAMPLE 206 Preparation of N-C2-CN.N- (biß) -2-Methylpropi1) amino3-thiazo-1-4-ylcarbonyl-Nt-CN-methy1-N- (3-pyridinium-1-methoxycarbonyl) -L-1-echinium-13-hydraz Following the procedure of Example 186 (a) -lB6 (c), except that NN-di isobutylam was used in place of N-met l isobutyl in Step (a), and N-meti 1-N-y 3 pyridinyl-methoxycarbonyl) -L-leucine instead of N- (4-pyridinium lmeto? i-carboni 1) -L-leucine in the final step, the title compound was prepared as a yellow solid (30 mg, %). MS (ESI): 533.5 (M + H) *.

EXAMPLE Q7 Preparation of N-C2- (N-cycloQPropi1meti1-N-propylamine) thiazo1-4- Icarboni 13- N * CN- (4-pyridiniummethoxycarbonyl) -L-1eucini1 hydrz? Fla Following the procedure of Example 186a) -86c), except substituting N-methyl isobutylamine for cyclopropylmethylpropam in step a), the title compound was prepared as a yellow solid (60 mg, 23% MS (ESI) : 503.3 (M + H) *.

EXAMPLE 208 Preparation of N-CN- (4-P rid or Imeto? Icarbonyl> -L-1eucini13-N'- CZ- (B-qui ol 1) t azo1-4- Icarboni 13 hydrazide Following the procedure of example Il2 (l) -ll2 (g) »ecept by substituting 2-beni lo? Ibromobenzene for 8-bromoquinol ina in step id), the title compound was prepared as a white solid. %). EMESI): 519.3 iM + H) *.

EXAMPLE 209 Preparation of N-CN-methy1- N- (4-pyridinium-methoxycarbonyl) -L-leucinyl 3-N "-C2- (B-guino-1-yl) thiazo-1-4-I -carbonyl-hydrazide Following the procedure of example 112 (a) -112 (g), except substituting 2-benzi lo? I romobenzene for β-bromoquinol ina in step id) and N-4-pyridinylmethocarbaryl 1) -L-leucine for N -methyl-N-4-pyridinylmethocarboni 1) -L-leucine in step (g), the title compound was prepared as a white solid (53 mg, 22%). EMISI): 533.3 (M + H) *.

EXAMPLE 210 Preparation of 1-N- (N-Cbz-1euc ni1) -amino-3-N- (4-bi eni-1-sulfonyl) -amino-propan-2-one a) 4-biphenyl sulfonyl chloride 4-biphenyl sulfonic acid (2.4 g, 10 mmol) was heated at 100 ° C with phosphorus pentachloride (2.1 g, 10 mmol) overnight. The reaction was cooled to room temperature, dissolved with water, filtered and washed with water. The solid was then triturated with EtOAc-ether and the beige solid was used in the next reaction without further purification. b) 1-N- (N-Cbz-leucine 1) -amino-3-N- (4-bipheni-1-sulfonyl) -amino-propan-2-one Following the procedure of Example 51 (a), except substituting "Chloride of 4- (3-Chloro-2-cyano-phenoxy) -phenyl-1-sulfonyl" by "4-biphenyl-sulfonyl chloride", the title compound was prepared: MS) MH * = 550.

EXAMPLE 21 Preparation of 1-N- (N-Cbz-Ieuc ni1) -am no-3 N- (3-biphenol-sylfcnil > -aminQ-prppqn-Z-pna a) 3-bipheni-1-sulfonyl chloride 3-biphenyl bromide (9.3 g, 40 mmol) was dissolved in THF (40 mL) and a Grignard reagent was prepared in a normal manner with magnesium powder (1.2 g, 50 mmol). The reaction was cannulated in a solution of sulphoryl chloride (10.5 g, 6.4 ml, 80 mmol) in henias (25 ml) and was stirred at room temperature for 2 hours. The reaction was quenched with ice-water, treated with ether, dried with magnesium sulfate, filtered, concentrated and used in the next reaction without further purification. b) 1-N-1-Cbz-leucinyl) -amino-3-N- (3-bipheni-1-sulfoni 1) -amino-propane-2-one Following the procedure of Example 51ia). ecept by substituting "4-i3-chloro-2-cyano-phenoyl" i) -phenyl-1-sulfonyl chloride "for" 3-biphenyl-sulfonyl chloride ", the title compound was prepared: EMI) MH * = 550 .

EXAMPLE 1Z Preparation of l-N- (N-Cbz-leucine 1) -amino-3-N- (2-benzyl-1-oxy-1-sulfonyl-1) -amino-propan-2-one a) 2-benzyl lo? i-phenyl-sulfonyl chloride Following the procedure of example 211 (a), e replacing "3-biphenyl bromide" with "2-benzyl bromide lo? i-fe i lo" , the title compound was prepared and used in the next step without further purification. b) lN- (N-Cbz-leucine 1) -am no-3-N-2-benzi lo? i-phenyl-1-sulfonyl) -amino-propan-2-one Following the procedure of example 51 (a), ecept by substituting "4-l3-chloro-2-cyano-pheno? i) -phenyl-1-sulfonyl chloride" for "2-benzyl-phenyl chloride", the title compound was prepared: EMÍES) M + H * = 581, M + Na * = 604, 2M + Na * = 1185.

EXAMPLE 13 Preparation of l-N- (N-Cbz-1euc i 1) -amino-3-N- (4-ene-1-phen-1-sulfonyl) -areino-propan-Z-one a) 4-Phenoyl chloride? i-phenyl-sulfonyl Following the procedure of Example 21l (a), e replacing "3-biphenyl bromide" with "4-phenoyl phenyl bromide", the title compound was prepared and was used in the following step without further purification. b) 1-N-iN-Cbz-leuci i 1) -amino-3-N-3,4-pheno? -fem'l-ßulfonyl) -ami o-propan-2-one Following the procedure of example 51 (a), e replacing "4- (3-chloro-2-cyano-pheno? i) -phenyl chloride sulfonyl "by" 4-phenoyl-i-phenyl-sulfonyl chloride ", the title compound was prepared: EMÍES) M + H * = 568, M + Na * = 590.

EXAMPLE 214 Preparation of 1-N- (N-Cbz-Leucini1) -amino-3-N- (2-di-benzofuran-1-sulfonyl) -amino-propan-2-one. a) 4-phenoxy-phenyl-1-sulfonyl chloride Following the procedure of Example 210 < a), e replacing "4-bipheni-1-sulfonic acid" with "2-di-benzofuran-sulphonic acid", the title compound was prepared and used in the next step without further purification. b) l-N- (N-Cbz-leuci i 1) -am not-3-N-2-di-benzofransulphonyl) -amino-propan-2-one. Following the procedure of example 51ia). ecept by substituting 4- (3-chloro-2-cyano-phenoxy) -phenyl-1-sulfonyl chloride for "4-ene-phenyl sulfonyl chloride", the title compound was prepared: E iES) M + H * = 566, M + Na * = 5B8.

EXAMPLE 215 Preparation of lN- (N-Cbz-leucine 1) -am no-3-N- (3,4-d-methoxy-phenyl-β-onyl) -amino-propan-2-one Following the procedure of Example 51, except substituting "4-l3-Chloro-2-cyano-phenoyl chloride") -fem "l-sulfonyl" by "3,4-dimetho-i-phenyl-1-sulfonyl chloride", the title compound was prepared: EMÍES) M + H * = 536, M + NH * = 553.

EXAMPLE 216 Preparation of 1-N- (N-Cbz-Ieuc n 1) areino-3-N- (2,5-dichlorothiophene-3-βulonyl) -amino-propan-Z-one Following the procedure of Example 51, except substituting "4-β 3-C1-oro-2-cyano-phenoyl chloride") -eni-1-sulfonyl "by" 2,5-dichlorothiophene-3-sulfonyl chloride ", the title compound was prepared: EMÍ ES) M + NH - »* = 567.2M + H * = 1101.

EXAMPLE 217 Preparation of 1-N- (N-Cbz-Ieuc i1) am no-3-N- (phenyl-sulfone-5-t-ofene-2-βulon-1) -amy-propan-2-one Following the procedure of Example 51, except substituting "4-f3-Chloro-2-cyano-pheno? i) -phenyl-1-sulfonyl chloride" for "phenyl-sulphona-5-thiophene-2-sulfonyl chloride", the compound of The title was prepared: MS (ES) M + H * = 622.

EXAMPLE 219 Preparation of 1-N- (N-Cbz-Ieuc ni1) -am no-3-N- (B-guino-1-naphonyl) -amino-propan-2-one. Following the procedure of Example 51, e replacing "4- (3-Chloro-2-cyano-phenoxy) -phenyl-1-sulfonyl chloride" with "8-quinoline sulfonyl chloride", the title compound was prepared: MS (ES) M + H * = 527.

EXAMPLE 219 Preparation of l-N- (N-Cbz-leucinyl) -am-3-N- (Z-Pyr-di-sulfon-1) -aroino-propan-2-one. Following the procedure of example 51, e replacing "4- (3-chloro-2-cyano-pheno?) -phenyl-1-sulfonyl chloride" with "2-pyridyl sulfonyl chloride" as described in J. Org. Chem. 1989. 54, 392), the title compound was prepared: MS (ES) M + H * = 477, M + Na * = 499 ..

EXAMPLE 220 Preparation of 1-N- (N-Cbz-Ieucin 1) -amino-3-N- (Z-Pyr-di-1-sulfonyl) -am not-propan-Z-one. a) 1-N-1 -Cbz-leucinyl) -amino-3-N-4-phenoyl and -phenyl-sulfoni 1) -ami o-propan-2-ol 1, 3-Diamino propan-2-ol (6.75g, 75 mmol was dissolved in DMF (100ML) and Cbz-leucine (20g, 75.5 mmol), HOBT-hydratedlg, 81.5 mmol) and EDCl 1515.5g were added, 81.2 mmoles). The reaction was stirred overnight at room temperature. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether (50 ml) and MeOH (30 ml) were added. An IN-solution of hydrochloric acid in ether (1 M, 30 mL) was added and a white gum formed and washed several times with ether. MeOH-acetone was added and heated until the gum became a white solid. The white solid was dissolved in DMF (25 ml) DIEA (5 ml), then 4-phenoyl and phenyl a sulfonyl chloride was added. The reaction was stirred for 2 hours, concentrated in vacuo, then chromatographed (silica gel, 1: 1 EtOAc: hemen) to provide the desired product as a white solid. b) Leucinyl-amino-3-N- (4-phenoxy phenyl sulfone 1) -am or-propan-2-ol 1-N- (Cbz-1-eucinyl) -amino-3-N- (4-phenoxy) -fe i 1-sulfoni 1) -amino-propan-2-oll.Og, 1.8 mmol) was dissolved in EtOHOO ml), then 10% Pd / C i0.22g) was added followed by followed by hydrochloric acid at 6N ( 2.5 ml), and the reaction was stirred under a balloon of hydrogen gas for 4 hours at room temperature. The reaction mixture was filtered, concentrated and azeotropically treated with toluene to provide a white crystal which was used in the next reaction without further purification. c) lN-y-4-pi 1-acetyl-leucine 1) -amino-3-N- (4-pheno-i-phenyl-1-sulfonyl) -amino-propan-2-ol Leucine l-amino-3 -N- (4-phenoxy phenyl sulfon 1) -amino-pro-an-2-ol (0.36 g, 0.76 mmol) was dissolved in DMF (5 mL), then NMM (0.45 mL, 4 mmol) was added. followed by 4-pyridyl acetic acid (0.13g, 0.75 mmoles) and HBTU (0.29g, 0.76 mmoles) and the reaction was stirred overnight at room temperature, the reaction mixture was concentrated in vacuo, then chromatographed (silica gel 5% MeOH: methylene chloride) to provide the desired product as a white solid (90 mg MS (ES): M + H * = 555. d) 1-N-iN-4-pyridi laceti l-leucin 1) -amino-3-N-i4- 2B1 pheno? i-pheni 1-sulfoni 1) -ami o-propan-2-one. 1-Ni N-4-pyridyl-1-acetyl-1-eucinyl) -amino-3-N-4-phenoyl-1-eulphoni 1) -amino-propan-2-ol (45 mg »0.08 mmolee) was dissolved in acetone (5 ml), then hydrochloric acid was added to IN (2 ral). The reaction was concentrated in vacuo, then redissolved in acetone. The reagent Jones .l.5. several drops) was added and the reaction mixture was stirred for 6 hours at room temperature. Isopropanol i? 5 ml) was added and the reaction mixture was concentrated in vacuo. The reaction was dissolved with a pH 7 regulator and then extracted with EtOAc. dried over magnesium sulfate »filtered, concentrated in vacuo, then chromatographed (silica gel 5% MeOH-methylene chloride) to provide the desired product as a white solid (27 mg, 50%): MS (ES): M + H * = 553.

EXAMPLE 221 Preparation of 1-N- (N-Z-Pyrid-1-sulfon-l-leucinyl) -amino-3-N- (4-phenoxy-phenyl-1-yul-onyl) -amino-propan-2-one Following the procedure of example 220a) -id), except substituting "4-pyridyl-1-acetic acid and HBTU" for "2-pyridyl-sulfonyl chloride" (as described in J. Org. Chem. 1989, 54, 392), the title compound was prepared: EMIS) M + H * = 475, M + Na * = 497, 2M + Na * = 1171.

Preparation of l-N- (-morpholino-carboni 1-1eucinyl) -amino-3-N- (- enox-phenyl-l-sulfonyl) -ami o-propan-2-one Following the procedure of Example 220 (a) -id), except substituting "4-pyridyl acetic acid and HBTU" for "N-morpholino-carbonyl chloride", the title compound was prepared: MS (ES) M + H ** = 547, M + Na * = 569, 2M + Na * = 115.

EXAMPLE 223 Preparation of l-N- (N-4-pyrid 1-carbonyl-1-eucin 1) -amino-3-N- (4-phenoxyphen-1-ßul-oni-1) -amy-propan-2-one Following the procedure of Example 220 (a) -id), except substituting "4-pyridyl acetic acid" for "pyridyl-1-carboalkyl acid", the title compound was prepared: MS (ES) M + H »= 539 EXAMPLE 2Z4 Preparation of l-N- (N-4-1eucini1) -a ino-3-N- (4-phenoxy-phenyl-p-ylfpn l) -iffii? P-propan -? - o? A Following the procedure of Example 220 (a) -id), except substituting "4-pyridyl acetic acid and HBTU" for "acetyl chloride", the title compound was prepared: EMÍES) M + H ** = 476, M + Na * = 498, 2M + Na * = 973.

EXAMPLE 225 Preparation of l-N- (N-4-imidazo-1-acetyl-1-echin-1) -aroino-3-N-i4-enox-phenyl-1-sulfonyl 1) -am-propan-2-one Following the procedure of example 220a) -id), except by substituting "4-pyridyl acetic acid" for "acetic acid", the title compound was prepared: EMÍES) M + H * '= 542.

EXAMPLE ZZ6 Preparation of l-N- (N-4-carboxymethyl-1-benzo-1-eucinyl) -am-3-N- (4-enoxy-fer> il-ßu1foni 1) -ami or -propan-Z-one Following the procedure of Example 220 (a) -id), except substituting "4-pyridyl acetic acid" for "4-carbo-imethyl benzyl acid", the title compound was prepared: EMiES) M + H "= 596, M + Na * = 618. 2M + Na * = 1213.

EXAMPLE 227 Preparation of l-N- (N- (N-dimethy1-glycine) -1eucini1) -amino-3- N- (4-phenoxy-eni-1-ulsul-1) -am no-propan-2-one Following the procedure of example 220 (a) - (d). except by substituting "4-pyridyl acetic acid" for "N.N-dimethyl glycine", the title compound was prepared: MS (ES) M + H ** = 519.

EXAMPLE 22B Preparation of 1-N- (N-B-q no1 i a-β-sulfonamide-leuc n l) -amino-3-N- (4-enoxy-eni 1-sul on 1) -amino-propan-2-one Following the procedure of Example 220 (a) -id) "except substituting" 4-pyridyl acetic acid and HBTU "for "quinoline sulfonyl chloride" "the title compound was prepared: EMiES) M + H- = 625.

EXAMPLE ZZ9 Preparation of 1-N- (N-Cbz-Ieuc n 1) -am no-3-N- (B-guino-1-na-carbonyl) -am not-propan-Z-one 1. 3-diami or propan-2-ol (6-75 g »75 mmol) was dissolved in DMF (100 ml) and Cbz-leucine (20 g» 75.5 mmol), HOBT-hydrate (11 g, 81.5 mmoles) »and EDCl (15.5 g) was added 81. 2 mmol). The reaction was stirred overnight at room temperature. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether (50 ml) and MeOH (30 ml) were added. A solution of IN hydrochloric acid in ether was added (1 M. 30 ml) and a white gum formed which was washed several times with ether. MeOH-acetone was added and heated until the gum became a white solid. The white solid Í0.44 g, 1.1 mmol) was dissolved in DMF (3 ml) and NMM (0.33 ml »0.3 mmols)» and then 8-quinoline carboxylic acid (0.17 g, 1.0 mmol), and HBTU (0.3 g, 1.0 mmol) were added. and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel, 7: 2 EtOAc: heroin). Then the solid was dissolved in acetone (5 ml), then hydrochloric acid was added at 1 ml). The reaction was concentrated in vacuo, then dissolved in acetone. The reagent Jones (1.5 M »some drops) was added and the reaction mixture was stirred for 6 hours at room temperature. Isopropanol (0.5 ml) was added and the reaction mixture was concentrated in vacuo. The reaction was dissolved with a pH 7 regulator and then extracted with EtOAc »dried with magnesium sulfate, filtered» vacuum concentrated »then chromatographed (silica gel» 5% MeOH-methylene chloride) to obtain the indicated product as a white solid (23 mg »41%): MS (ES): M + H * = 491.

EXAMPLE 230 Preparation of l-N- (-Cbz-leuc nyl) -amino-3-N- (6-guinoline-carbonyl) -amino-propan-2-one Following the procedure of example 229 »ept replacing" carbohydric 8-quinoline acid "with" 6-quinolinocarboxylic acid ", the title compound was prepared: MS (ES): M + H * = 491.

EXAMPLE 231 Preparation of 1-N-i -Cbz-leuci-yl) -amino-3-N- (Z- (4-b-phen-1) -methyl-1-propanamide-Z-one Following the procedure of Example 229. e replacing "carboxylic acid" -quinoline "with" 2-isobutyl 1-4-bifem'l acetic acid ", the title compound was prepared: MSI) M + H * = 586 M + Na * = 60B. 2M + Na * = 1193.

EXAMPLE 232 Preparation of 1-N- (N-Cbz-Ieuci i1) -amino-3-N- (N 4 -Pyr-di-methyleneneoxycarbonyl-leucine D-araino-propan-Z-one) Following the procedure of Example 229 »except substituting" 8-carboxyl-carboxylic acid "for" 4-pyridylmethyl-1-carbonyl-leucine ", the title compound was prepared: MS (ES) M + H * = 584 .

EXAMPLE 233 Preparation of l-N- (-Cbz-leucinyl) -amino-3-N- (benzoi 1) -amino-propan-2-one Following the procedure of Example 229. e replacing "carbohydric 8-quinoline acid and HBTU" with "benzoyl chloride", the title compound was prepared: MS (ES) M + H * = 440, M + H * = 440, M + Na * = 462, 2M + Na * = 901. 2T7 EXAMPLE Q 34 Preparation of l-N- (-Cbz-leucinyl) -amino-3-N- (2,4-diroeti-3-ß-sulfonyl) -am not-propan-Z-one Following the procedure of example 51. e? Cepto? Substituting "4- (3-chloro-2-cyano-pheno? I) -phenyl-1-sulfonyl chloride" for "2,4-dimet l-3-sulfonyl chloride", the composed of the title was prepared: MSiES) M + H * = 494.

EXAMPLE 235 Preparation of l-N- (-Cbz-leucinyl) -amino-3-N- (1,3-dimeti-1-5-chloro-pyrazoa-4-β-sulfonyl) 1 -amino-propan-2-one Following the procedure of Example 51, e replacing "4- (3-chloro-2-cyano-pheno-i) -phenyl-1-sulfonyl chloride" with "1,3-dimeti-1-5-chloro-pyrazole chloride ! e-4-sulfonyl. " the title compound was prepared: MSiES) M + H * = 494.

EXAMPLE 236 Preparation of l-N- (N-4-Pyrid 1-meneoeneoxycarboni-1-eucinyl) -amino-3-N- (4-enoxy-phenyl-1-b sulfonyl) -ap.-amino-propan-2-one Following the procedure of example 213ía). I elect replacing "Cbz-leucine" with "4-pyridyl-methylene-leucine" and "carbonyl". the title compound was prepared: MSIES) M + H * = 569.

EJEMf > Q 37 Preparation of l-N- (N-3-Pyrid 1-methyloneoxy carbon 1-1eucine 1) - amino-3-N- (4-phenoxy-phen-1-sulfonyl) -amino-propan-Z-one Following the procedure of Example 2l3 (a > except substituting "Cbz-leucine" for "3-? Iridi l-meti leneo? I carbonil leucina", the title compound was prepared: MSiES) M + H * = 569.

EXAMPLE 238 Preparation of l-N- (N-2-Pyr-di-1-met-leneoxy-carboni-1-leucinyl) - a -3-N- (- enoxy-phen-1-sulfonyl) -arene-propan-2-one Following the procedure of Example 2l3 (a). except by substituting "Cbz-leucine" for "2-pyridyl-methyl-lene-1-carbonyl-leucine" »the title compound was prepared: MS (ES) M + H * = 569.

EXAMPLE 239 Preparation of l-N- (N-4-carboxy-benzoi 1-leucine 1) -amino-3-N-i4-enoxy-eni-1-ß-sulfon 1) -am no-propan-2-one lN- (N-4-carbo? i -benzo l-leucini 1) -amino-3-N- (4-pheno? i-pheni 1-sulfoni 1) -amino-propan-2-one (0.105 g, 0.176 2B9 mmoles) was dissolved in MeOH (5 ml) and water (ml), then LiOH-hydrate fl 5 mg was added. 0.35 mmoles) and the reaction was stirred for 1 h at room temperature. The reaction was diluted with water »acidified with hydrochloric acid at 6N (1 mL), then with EtOAc (2 → 10 mL). The combined organics were dried with magnesium sulfate, filtered, concentrated, chromatographed on silica gel, 50: 50: 1 EtOAc: hexanes: AcOH) to obtain the desired product as a white solid, 35.6 mg, 35%) : MS i ES) M + H * = 5B2, M + Na * = 604.

EXAMPLE 240 Preparation of 1-N- (N-Me-N-Cbz-Ieuc i1) -amino-3-N- (4-phenoxy- in 1-ß-sulfonyl) -am not-propan-2-one Following the procedure of example 213 (a), except substituting "Cbz-leucine" for "N-Me-N-Cbz-leucine", the title compound was prepared MSI M + H * = 5B2, M + Na * = 604 , 2M + Na * = 1185.

EXAMPLE 241 Preparation of l-N- (4-enoxi-enzoyl) -aroino-3-N- (4-phenoxy-phen-1-onul) -am or -propan-Z-one Following the procedure of Example 2l3a), e replacing "Cbz-leucine" with "4-phenoxybenzoic acid", the title compound was prepared: MS (ES M + H * = 517, M + Na * = 539, 2M + Na * = 1055.

EXAMPLE 242 Preparation of l-N- (3-phenoxy-benzo-1) -amy-3-N- (4-phenoxy-1-ßul-oni-1) -amino-propan-2-one Following the procedure of example 213 (a), except substituting "Cbz-leuc Ina" for "3-phenoxybenzoic acid", the title compound was prepared: MS (ES M + H * = 517, M + Na * = 539 , 2M + Na * = 1055.

EXAMPLE 43 Preparation of l-N- (4-f-enoxyl-benzoyl-1) -amyl or -3 N- (4-phenoxy-pyl-p-1 and p-1) -amjnp-propqn-2-Qna Following the procedure of Example 213 (a), except by substituting "Cbz-leucine" for "4-phenoylbenzoic acid", the title compound was prepared-MSiES M + H * = 517. M + Na * = 539. 2M + Na * = 515.

EXAMPLE 244 Preparation of l-N- (4-bipheni 1-ace i 1) -amino-3-N- (4-pheno? I-eni 1-ß-sulfon 1) -amino-propan-2-one Following the procedure of example 213ía). ecept by substituting "Cbz-leucine" for "4-biphenyl-1-acetic acid" »the title compound was prepared-MSiES M + H * = 515» M + Na * = 537 »2M + Na * = 1051.

EXAMPLE 245 Preparation of l-N- (Z-benzyloxy-benzoyl) -amino-3-N- (4-phenoxy-phenyl-1-sulfon-1) -am not-propan-Z-one Following the procedure of example 213 (a). ecept by substituting "" Cbz-leuci to "for" a do-2-benzyloxy-benzoic acid "" the title compound was prepared-MS (ES M + H * = 531 »M + Na * = 553» 2M + Na * = 10B3.

EXAMPLE 246 Preparation of 1-N-β-Cbz-leucinyl) -am-3-N- (4-benzyl-1-oxo-1-benzoyl) -ami or -propan-2-one Following the procedure of example 229. ecept by substituting "acid-B-quinol ina-carbo? Il co" for "acid-4-benzyl lo? -benzoic acid", the title compound was prepared: MS (ES M + H * = 546. M + Na * = 56B, 2M + Na * = 1113.

EXAMPLE 247 Preparation of l-N- (2- (4-biphenyl) -4-methyl-1-pentamido) -3-N- (4-enoxy-phen-1-b sulfonyl) -amino-p-opan-Z-one Following the procedure of Example 213 < to). ecept by substituting "Cbz-leucine" for "acid-2- (4-biphenyl) -4-metril-pentanoic". the title compound was prepared: MSiES) M + H * = 571, M + Na * = 593.

EXAMPLE 249 Preparation of lN- (Z- (3-bi eni1) -4-methi1-pentamido) -3-N- (4-phenoxy-eni 1-ulsul-1) -amino-propan-Z-one a) Acetate of 3-bromo-phene-1-methyl 3-bromo-phenyl-acetic acid, 2.15 g, 10 mmol) was dissolved in ether, then treated with a diazomethane solution until a yellow color persisted. The reaction was then quenched with an AcOH concentrate in vacuo and used in the next reaction without further purification. b) 3-biphenyl methyl acetate, 3-bromo-phenyl methyl acetate, 2.29 g. 10 mmol) was dissolved in toluene (30 ml). Then, phenylboronic acid (1.46 g, 12 mmol) was added followed by aqueous sodium carbonate (2M, 4.24 ml, 40 mmol) and tetrakisi triphenyl phosphine) palladium (0.35 g, 0.3 mmol) and refluxed throughout the night. The reaction was cooled to room temperature »diluted with saturated ammonium chloride, and extracted with EtOAc (2? 10 mL). The combined organics were dried with magnesium sulfate. filtered. Concentrates and chromatographed (silica gel »5% EtOAc: hemen) to provide the desired product as a white solid (1.93 g, 84%): MSiES): M + H * O 263. c) 3-biphenyl acetic acid Ester 3-Biphenyl acetyl methyl was dissolved in MeOH (40 ml) and water (6 ml) »after LiOH-hydrate (0.7 g» 16.8 mmol) was added and the reaction was stirred for 2 hours at room temperature. The reaction was diluted with water »acidified with hydrochloric acid to 6N (1 mL)» then with EtOAc (2 → 10 mL). The combined organics were dried with magnesium sulfate, filtered and concentrated to obtain the desired product as a white solid (1.66 g, 93%): - »- H NMR: d: 7.6-7.25 (m, 9H). 3.7 s, 2H). d) 3-i4-bifem '1) -4-met l-pent-4-enoic acid. nBuLi (3.26 mL, 1.6 M in years) was added dropwise to a solution of diisopropyl amino (0.74 ral, 5.3 mmol) in THF (6 mL) at 0 ° C. The reaction was stirred for 15 minutes, then cooled to -7 ° C. 3-biphenyl acetic acid (0.5 g, 2.35 mmoles) was dissolved in THF (2 ml) and added dropwise to the LDA solution. The reaction was heated to 0 ° C »stirred 40 minutes» then cooled to -78 ° C. Isobutenyl bromide (0.475 g, 3.52 mmol) was added and the reaction was stirred for 1 hour. Water (2 ml) was added and the THF was removed under vacuum. The reaction was dissolved with water, acidified with 6N hydrochloric acid. then with EtOAc (2? 10 mL). The combined organics were dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel 5% MeOH: methylene chloride) to obtain the desired product as a white solid (1668 g, 93%): 1H NMR: d : 7.6-7.3 (m, 9H), 4.75 id, 2H), 3.87 i, 1H), 2.87 Id, 1H), 2.50 id, 1H). 1.70 ÍS.3H). e) 3i4-biphenyl) -4-methyl-1-pentanoic acid. 3- (4-biphenol) -4-methyl-pent-4-enoic acid (0.5 g, 1.B7 mmoles) was dissolved in EtOAc (25 ml). After ße added 10% Pd / C (60 mg) and the reaction was stirred for 2.5 hours under a balloon of hydrogen gas. The reaction was filtered, concentrated in vacuo, then dissolved in 1: 5 EtOAc: EtOH (15 mL). Subsequently, 10% Pd / C (BO mg) was added and the reaction was stirred under a balloon of hydrogen gas overnight. The reaction was filtered, concentrated in vacuo, and chromatographed (silica gel, 5% MeOH: methylene chloride) to obtain the desired product as a white solid (1.66 g, 93%): * H NMR: d: 7.6- 7.3 (m, 9H). 3.7 (t, 1H), 2.07-1.95 (m. 1H >;, 1.8-1.7 (m, 1H), 1.6-1.45 im, 1H). f) lN-l2- (3-biphenyl) -4-methyl-pentamido) -3-N- (4-pheno? i-phenyl-1-sulfonyl) amino) propan-2-one Following the procedure of Example 213 ), e replacing "Cbz-leucine" with "3-l4-bifeni 1) -4-ethyl-pentanoic acid, the title compound was prepared: MSI) M + H * 0 = 571, M + Na * = 593 EXAMPLE 249 Preparation of l-N-3-biphenyl-acetyl 1) -amino-3-N- (4-phenoxyphene-1-sulfonyl) -am-propan-2-one Following the procedure of Example 213fa), except substituting "Cbz-leucine" for "3-biphenyl acetic acid", the title compound was prepared: MSiES) M + H * = 515, M + Na * = 537.2M + Na * = 1051 EXAMPLE 250 Preparation of l-N- (N-4-Pyrid-1-acetyl-1-leucine-1) -amino-3-N- (2-ß-sulfon-l) -amino-propan-Z-one a) 1-N-iN-Boc-leucine 1) -amino-3-N-2-benzi lo? i phenyl-sulfoni 1) -amino-propan-2-ol l, 3-diamino-propan-2-ol (3.375 g, 375.5 mmol) was dissolved in DMF (60 ml). Then HOBT-hydrate (5.5 g, 40.7 mmol) was added, followed by Boc-L-leucine (9.34 g, 37.5 mmol) and EDCl (7.77 g, 40.7 mmol). The reaction was stirred for 4 hours, then it was diluted with DMF to form a supply solution of a total volume of 100 ml (0.375 mmoles / ml). The supply solution (IB mi, 6.75 mmol) was treated with NMM (0.89 ml 7.2B mmoles), then with 2-benzyl? I chloride of phenyl sulfonyl (1.9 g, 6.72 mmol). The reaction was stirred an additional 2 hours, then it was diluted with water, extracted with EtOAc, dried with magnesium sulfate, filtered and concentrated and chromatographed (silica gel, 20% EtOAc: heroines): MS (ES) M + H * = 550. b) 1-Ni leucine 1) -amino-3-N- (2-benz lo? -feni 1 -β-sulfonyl) -amino-propan-2-ol iN- (Boc-leucinyl) -amino -3-N- (2-benzi lo? I phenyl sulfonyl) -amino-propan-2-o1 (0.7 g, 1.3 mmoles) was dissolved in i: 1TFA: DCM (50 ml) and was stirred for 2 hours at room temperature ambient, concentrated in vacuo and used in the next reaction without further purification: MS (en) M + H * = 450. c) lN- (N-4-pyridi 1 aceti 1-leucim "1) -amino-3-N - (2-benzi lo? I-phenyl l-ßulfom "1) -amino-propan-2-one Following the procedure of example 220 (b) -ic). This substi tutes "N-leuci i 1-amino-3-N-i4-phenoyl and phenyl sulfoni 1) -amino-propan-2-ol" by "1-N-leucine l-amino-3-N - (2-benzyl? I phenyl sulfonyl) -ami no-propan-2-ol ". the title compound was prepared: MS) M + H * = 567.

EXAMPLE 251 Preparation of l-N- (N-4-pi idyl carboni 1-leucinyl) -amino-3-N- (2-benxy-1-o-y-pheni-1-yu-1-yl) -amino-propan-2-one Following the procedure of example 250 (a) -íc). ecept by substituting "4-pyridyl acetic acid" for "4-pyridylcarboxylic acid" "the title compound was prepared: MS (ES) M + H * = 553.

EXAMPLE 252 Preparation of l-N- (N-4-imi azol acetyl-leucine 1) -am non-3-N-i2-benzyloxy-phenyl-β-sulfonyl) -am no-propan-2-one Following the procedure of Example 250 (a) - (c), e substitue "4-pyridyl-acetic acid" by "4-imidazolacetyl acid". the title compound was prepared: MSI) M + H * = 556.

EXAMPLE 253 Preparation of 1-N- (N- (-N-dimeti 1 gl ic 1) -1eucini1) -amino-3- N- (Z-benz-1-oxy-phen-1-sulfonyl) -am no-propan-2- ona Following the procedure of example 250 (a) - (c). except by substituting "4-pyridyl-acetic acid" for "N.N-dimethyl glycine", the title compound was prepared: MSI) M + H * = 533.

EXAMPLE 254 Preparation of lHM- (N- (-methyl-prolyl-leucinyl) -amino-3-N- (2-benzyloxy-phen-1-βul-oni-1) -amino-propan-2-one Following the procedure of example 250 (a) -íc). ecept by substituting "4-pyridinyl acetic acid" for "N-methyl proline", the title compound was prepared: MS (ES) M + H * = 559.

EXAMPLE 255 Preparation of l-N-N- (N- (N-methyl PiPeridi-4-carbonyl) -leucinyl) -amino-3-N- (2-benzyloxy-phenyl-1-sulfonyl) -amino-propan-2-grm Following the procedure of example 250ía) - (c). except by substituting "4-pyridyl acetic acid" for "N-methyl-piperidine-4-carbohydrate acid", the title compound was prepared: MS (ES) M + H * = 573.

EXAMPLE Z56 Preparation of l-N- (N- (N-methyl Piperidine-4-carbon l) -leucine l) -a ino-3-N- (Z-ibenzo uran-ß-sulfonyl) -amino-propan-Z-one Following the procedure of example 250 (a) -íc). I substitute "4-pyridyl acetic acid" for "N-methyl-1-pipen" di-na-4-carboalionic acid "and" 2-benzyl chloride and sulfonyl chloride "for" 2-dibenzofuran chloride " sulfonyl ", the title compound was prepared: MS (ES) M + H * = 557.

EXAMPLE 257 Preparation of l-N- (N- (-methyl prolyl) -1aucini1) -amino-3-N- (Z-ibenzofuran-βul oni 1) -aroino-propan-Z-one Following the procedure of Example 250 (a) -c1), we substitute "4-pyridyl acetic acid" for "N-methyl proline" and "2-benzyl chloride" or "sulfonyl" for "2-benzyl chloride". -dibenzofuran sulfonyl ", the title compound was prepared: MSI) M + H * 543.

EXAMPLE 25B Preparation of N- (N- (NN-dimethyl-1-cl cl) -1-echin-1) -amino-3-N- (Z-dibenzofuran-β-oneyl) -amino-propan-Z-one Following the procedure of Example 250 (a ) -ic), I substitute replacing "4-pyridyl acetic acid" with "NN-dimeti 1 glycine" and "2-benzyl chloride and 1-phenylsulfonyl chloride" with "2-dibenzofuran-sulfonyl chloride", the compueßto of the title η prepared: MS (ES) M + H * = 517.

EXAMPLE 259 Preparation of l-N-iN-4- m acetic acid-leucine l) -amino-3-N- (2-dibenzofuran-ßu1foni 1) -amino-ropan-2-a Following the procedure of example 250 (a) -tc). e) substituting "4-pyridyl acetic acid" for "4-imidazole acetic acid" and "2-benzyl phenyl sulfonyl chloride" for "2-di benzofuran-eulfonyl chloride", the title compound was prepared : MSíES) M + H * = 526.

EXAMPLE 260 Preparation of l-N- (N-4-pyrid 1 carboni 1-1euc n l) -amino-3-N- (2-dibenzofuran-ßu1 oni 1) -amino-propan-2-one Following the procedure of Example 250a) -ic), I substitute "4-pyridyl acetic acid" for "4-pyridylcarboxylic acid" and "2-benzyl-phenyl sulfonyl chloride" for benzofuran-sulfone "the title compound was prepared: MSiES) M + H * = 537.

EXAMPLE 261 Preparation of 1-N- (N 4-Pyridyl-acetyl-1-eucyl) -am-3-N 2 -dibenzofuran-β-1-yl) -am-no-propan-2-one Following the procedure of example 250 (a) - (c), substituting "2-benzyl-phenyl sulfonyl chloride" "2-di-benzofran sulfonyl chloride" the title compound was prepared: MS (ES) ) M + H * = 551.

EXAMPLE 262 Preparation of l-N- (N-4-imidazo-1-acr-1-yl-leucinyl) -amino-3-N- (2-dibenzofuran-1-phosphono) -amino-propan-Z-one Following the procedure of example 250 (a) - (c). I substitute "4-pyridyl acetic acid" for "4-imidazole-acrylic acid" and "2-benzyl-phenyl sulfonyl chloride" for "2-di-benzofuran-sulphonyl chloride" as the title compound. was prepared: MS (ES) M + H * = 552.

EXAMPLE 263 Preparation of l-N- (N-Pyrazole-carbonyl-1-echin-1) -amino-3-N- (2-dibenzofuran-sulfone 1) -amino-propan-one Following the procedure of example 250 (a) -ic). I mean replacing "4-p? p" dil acetic acid "with" pyrazole carbo? lico "and" 2-benzyl chloride and phenyl sulfonyl chloride "by" 2-di benzofuran sulfonyl chloride "the title compound was prepared: MSIS) + H * = 538.

EXAMPLE 264 Preparation of l-N- (N-benzoi 1-1euc n l) -am no-3-N- (9-gu no1ina-ßulfonyl) -amino-propan-2-one Following the procedure of Example 250 (a) -ic), I substitute "4-pyridyl acetic acid" for "benzoic acid" and "benzyl chloride" and "phenyl sulfonyl" for "acid" 8-quinoline sulfonic acid "The title compound was prepared: MSIES) M + H * = 497.

EXAMPLE 265 Preparation of l-N- (N-2,5-difluoro-benzo l-leuc i 1) -amino-3-N- (9-guinol ina-ß-sulfon 1) -amino-propan-2-one Following the procedure of example 250 (a) - (c). ecept by substituting "4-pyridyl acetic acid" for "difluoro-benzoic acid" and "benzyl chloride" and "sulfonyl chloride" for "B-quinoline sulfonic acid" the title compound was prepared: MSiES) M + H * = 535.

EXAMPLE 266 Preparation of l-N- (N-2.5 di-luoro-phenyl-acetyl-leucinyl) -am-3-N- (B-guino-1-n-sulfon-l) -amino-propan-Z-one Following the procedure of example 250 (a) -ic). e) substituting "4-pyridyl acetic acid" for "2.5-difluoro-phenyl acetic acid" and "2-benzyloxy phenyl sulfonyl chloride" for "8-quinoline sulphonic acid" the title compound was prepared: MSiES) M + H * = 547.

EXAMPLE 267 Preparation of l-N- (N-pheny1-acetyl-leucine-1) -amino-3-N- (B-gui or na-ßulfoni 1) -aroino-propan-2-one Following the procedure of example 250 (a) -te), I substitute "4-pyridyl acetic acid" for "phenyl acetic acid" and "2-benzyl chloride and phenyl sulfonyl chloride" for "8-quinoline sulfonic acid" the title compound was prepared: MSI) M + H * = 511.

EXAMPLE 26S Preparation of l-N- (N-4-pyrid-1-acetyl-leucinyl) -amino-3-N- (8-guinol-na-ß-sulfonyl) -amy-propan-2-one Following the procedure of example 250 (a) - (c). I elect replacing "4-pyridyl acetic acid" with "4-pyridyl acetic acid" and "2-benzyl chloride and phenyl sulfonyl" with "B-quinoline sulfonic acid" The title compound was prepared: MS (ES) M + H * = 512.

EXAMPLE 269 Preparation of l-N- (N-4-pyridi1 carboni 1-1eucini 1) -am non-3-N- (9-guinol ina-ßulfonyl) -amino-propan-2-one Following the procedure of Example 250 (a) - (c), I educto substituting "4-pyridyl acetic acid" for "4-pyridylcarboxylic acid" and "2-benzyl-phenyl sulfonyl chloride" for " 8-quinol-naphonic acid "The title compound was prepared: MSI) M + H * = 49B.

EXAMPLE 270 Preparation of l-N- (N-4- ro dazo1 acet 1-leucine 1) -amino-3-N- (B-guinol ina-ßulfoni 1) -amino-propan-2-one Following the procedure of example 250ia) - (c). e) substituting "4-pyridyl acetic acid" for "acetyl 4-imi dazoic acid" and "2-benzyl" and phenyl sulfonyl chloride "for" 8-quinoline sulfonic acid "the title compound was prepared: MSI) M + H * = 501.

EXAMPLE 271 Preparation of l-N- (N-3-pheny1propionyl-leucinyl) -araino-3-N-iB-guinol na-ßul on l) -am no-propan-2-one Following the procedure of example 250 (a) - (c). e) substituting "4-pyridyl acetic acid" for "hydrocyanic acid" and "2-benzyl chloride and phenyl sulfonyl" for "B-quinoline sulfonic acid" the title compound was prepared: MS (ES) M + H * = 525.

EXAMPLE 272 Preparation of biß-N, N '- (N-4-pyrid 1 methyleneoxy carbon 1- 1 euccin 1) -l »3-diami no-propan-Z-one Following the procedure of Example 37, except substituting "Cbz-leucine" for "4-pyridyl-1-methyloxy-carbonyl-leucinyl" "the title compound was prepared: MSI) M + H * = 5B5.

EXAMPLE 273 Preparation of biß-NtN '- (N-3-Pyrid? ~ 1-roethyleneoxycarbonyl-1-eucinyl) -i.3-diamino-propan-2-one Following the procedure of Example 37 »e replacing" Cbz-leuc na "with" 3-p? Ridi 1-met leno? I-carboni 1- leucinil "» the title compound was prepared: MSiES) M + H * = 585.

EXAMPLE 74 ^ Preparation of biß-N.N "- (N-2-Pyridy1 raeti leneoxy carbon 1- 1eucini 1) -1.3-diamino-propan-2-one Following the procedure of Example 37 »except substituting" Cbz-leucine "for" 2-pyridyl-1-methyl-i-carboni-leucine "" the title compound was prepared: MSiES) M + H * = 5B5.

EXAMPLE 275 Preparation of 1-N-yN-Cbz-leucine 1) -amino-3-N-i2-benzi lo? I-benzoi 1) -amino-propan-2-one Following the procedure of example 229. e replacing "8-quinol a-carboyl acid" with 2-benzyl-i-benzoic acid, the title compound was prepared: MSiES) M + H * = 546.

EXAMPLE 276 Preparation of 1-N- (-Cbz-leuc nyl) -aroino-3-N- (3-benzyl-1-oxo-benzoyl-1) -amino-propan-2-one Following the procedure of Example 229, except substituting "B-quinoline carboxylic acid" for "3- benzyl? -benzoic acid", the title compound was prepared: MS) M + H * = 546.

EXAMPLE 277 Preparation of 1-N- (N-Cbz-1-eucinyl) -am-3-N- (4-biphenyl-i-1) -amino-propan-2-one Following the procedure of Example 229, e replacing "8-quinoline carboxyl co" with "4-biphenyl acetic acid", the title compound was prepared: MS) M + H * = 530.

EXAMPLE 279 Preparation of l-N- (N-Cbz-1euc i 1) -amino-3-N- (2-carboxymethyl-thiofene-3-β-sulfonyl 1) -am not-propan-Z-one Following the procedure of example 51, we e xept replacing "4- (3-chloro-2-cyano-pheno? I) -phen-1-sulfonyl" chloride with "2-carbo? Imeti-1-thiophene-3-sulfon", the title compound was prepared: MSiES) M + H * = 540.

EXAMPLE 279 Preparation of l-N- (N-Cbz-leuci-yl) -amino-3-N-me i1-N-i -Cbz-1euci ni 1) -amino-propan-2-one a) N-i Cbz-l euc i nil) -amino-propene N-Cbz-leucine (3.0 g, 11.3 mmol was dissolved in DMF (50 ml), then NMM (1.3 g »12.4 mmol) was added followed by allylamine (0.65 g, 0.85 mmol) and HBTU (4.3 g, 11.3 mmol) and the reaction was stirred overnight at room temperature. The reaction was released with water, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated and chromatographed (silica gel, 40% EtOAc: heroines): MS) M + H * = 305. b) O nido of N-i Cbz-leuc i ni l) -amino-propene N-iCbz-l euci ni 1) -amino-propene. { 2.95 g, 9.7 mmol) was dissolved in methylene chloride (100 μl), then mCPBA (5.0 g, 29.1 mmol) was added and the reaction was stirred overnight. The reaction was diluted with saturated sodium bicarbonate, washed with EtOAc, dried over magnesium sulfate, filtered, concentrated and chromatographed (silica gel 50% EtOAc: yellow). c) 1-N-i Cbz-leucine 1) -amino-3-N-methyl-1-amino-propan-2-ol O-amino acid of N-βCbz-leucine 1) -ara no-propene < 400 mg »1.25 mmol) was dissolved in isopropanol (5 ml)» then aqueous methylamine (2 ml) was added and the reaction was heated to 70 ° C in a sealed container for 2 hours. The reaction mixture was concentrated in vacuo and used in the next reaction without further purification. d) lN- (N-Cbz-l euc inyl) -amino-3-N-methyl-N- (N-Cbz-leucine 1) -amino-propan-2-one Following the procedure of Example 229a) »e? I substitute "carbohydric B-quinoline acid" for "lN-iCbz-l euci nil) -ami or-3-N-meti 1-ami no-propan-2-ol" »the title compound was prepared: MSI ) M + H * = 597.

EXAMPLE 280 Preparation of 1-N- (N-Cbz-Ieucin-1) -amino-3-met ^ - - (- - pyr-di-met ^ ^^ or ^ -carboni ^ - ^ euc ^ ^ n ^^ ^) -amino-propan-Z-one Following the procedure of example 279 (a) -id), we substitute "Cbz-leucine" for "4-pyridyl-1-methyl-1-carbonyl-leucine" in (d). the title compound was prepared: MSÍS) M + H * = 598.

EXAMPLE 291 Preparation of l-N- (N-? Bz-1eucini 1) -aroino-3-N-roeti1-N- (2-dibenzo-uransulfon 1) -amino-propan-2-one Following the procedure of example 279 (a) -id). ecept by replacing "Cbz-leucine and HBTU" sn < d) by "2-di benzofuran sulfonyl chloride". the title compound was prepared: MS (ES) M + H * = 5B0. M + Na * = 602.

EXAMPLE 292 Preparation of l-N-met 1-l-N- (N-Cbz-1euc ni1) -amino-3-N- (2-dibenzofuranßulfon 1) -ami o-propan-2-one Following the procedure of example 279 (a) - (d). I deduce "Cbz-leucine and HBTU" in (a), by "2-dibenzofuran sulfonyl chloride". the title compound was prepared: MS) M + H * = 580.

Preparation of 1-N methy1-l-N- (N- € bz-leucine1) -am -3-N- (Z- i enzofuran-βul oni 1) -amino-propan-2-one Following the procedure of example 279 (a) -id). ecept by substituting "N-Cbz-leucine" for "2-di-benzofuran sulfonyl chloride" in step (a) and substituting "Cbz-leucine" for "4-pyridyl methane leneo" and "carboni l-leucine" in the step id), the title compound was prepared: MS (ES) M + H * = 580.

EXAMPLE ZB4 Preparation of l-N- (Z-dibenzo-uran-sulfonyl) -N-methy1) -amino-3N- (-4-pyridyl-1-methyl-oxy-carbon-1-eicyl) -amino-propan-Z-one Following the procedure of example 279 (a) - (d), e substituting "allyl amine" for "4-pyridyl methyl amine" and substituting "N-Cbz-leucine" for "2-dibenzofuran sulfonyl chloride" in step (a) and substituting "N-Cbz-leucine and HBTU" for "N-4-pyridyl methylene? i carboni 1-leucinyl" in step id), the title compound was prepared: MSiES) M + H * = 5B1.

EXAMPLE 285 Preparation of 1-N- (N-Cbz-Ieucin 1) -am no-3-N- (4-pyridine-1-ether) -3N- (N-Cbz-1-eucine 1) -amino-propan-2 -one Following the procedure of Example 279a) -id) e replacing "methyl amine" with "4-pyridyl methyl amine", the title compound was prepared: M i ES) M + H * = 674.

EXAMPLE 286 Preparation of l-N- (Cbz-leucine 1) -amino-3-N- (4-pyridyl-methyl-1-ene) -3N- (2-dibenzofuran-sulfoni-1) -amino-propan-2-one Following the procedure of example 2B4 (a) - (d), e replacing "Cbz-leuci e and HBTU" with "2-dibenzofuran sulfonyl chloride" in step id), the title compound was prepared: MSI) M + H * = 657.

EXAMPLE 297 Preparation of l-N- (Cbz-1euc i 1) -amino-3-N- (4-pyridyl-roetheyl) -3N- (Z-benzofran sulfonyl 1) -amino-propan-Z-one Following the procedure of example 2B4 (a) - < d). ecept by substituting "Cbz-leucine and HBTU" for "2-dibenzofuran sulfonyl chloride" in step id), the title compound was prepared: MSI ES) M + H * = 657.

EXAMPLE 299 Preparation of l-N- (4-bifem "1-acetyl) -amino-3-N- (4-pyridyl-methylene) -3N- (N-Cbz-1-eucin-1) -aroino-propan-2-one Following the procedure of example 279 (a) - (d), eceptic substituting "Cbz-leucine" for "4-biphenyl-acetic acid" in step (a), and substituting "methyl amine" for "4-pyridyl" methyl amine ", the title compound was prepared: MSiES) M + H * = 621.

EXAMPLE 299 Preparation of lN- (4-phenoxy-benzoyl) -amino-3-N- (4-pyridi-1-methylene) -3-N- (N-Cbz-1-echin-1) -am-no-propan-2-one Following the procedure of example 279a) - (d), e replacing "Cbz-leucine" with "4-phenoxy-benzoic acid" in step (a), and substituting "methyl amine" for "4-pyridyl-methyl-amine" ", the title compound was prepared: MSÍES) M + H * = 623.

EXAMPLE 290 Preparation of l-N- (Z-di-benzofuran-ß-sulfon-l) -amino-3-N- (4-pyridi-1-methyl-1-ene) -3N- (N-Cbz-1-echin-1) -amino-propan-Z-one Following the procedure of example 279 (a) -id), except substituting "Cbz-l euci ne and HBTU" for "2-dibenzofuran sulfonyl chloride" in step (a), and substituting "methyl amine" for "4- pyridyl rnethyl amine ", the title compound was prepared: MSiES) M + H * = 657.

EXAMPLE 291 Preparation of l-N-iN-3-pyr-di-1-methylen-1-carbon-1-leucinyl) -amino-3-N-methyl-1-N-i 2-dibenzofuran-β-1-one-1-amino-propan-2-one Following the procedure of example 279ía) -ítí), e substituting "alil amina" for "N-meti 1-N-al i 1 amina" in ía), and substituting "Cbz-leucina" for "3-pi idyl-raethylene? i-carboni 1-leucine ", in step id), the title compound was prepared: MSI) M + H * = 581. The above specifications and examples describe broadly how to obtain and use the compounds of this invention. However, this is not limited to the particular modalities described above, but includes all modifications to those methods within the scope of the following indications. All the references of newspapers, patents and other publications that are cited here include the state of the art and are included here as a reference of what is established here.

Claims (72)

1. NOVELTY OF THE INVENTION CLAIMS 1.- A compound according to formula I e: D = Q = A = außente » L = Cx alkyl? t Ar-C0_ß alkyl. Het-alkyl of C, ^ ,. CH (Rß * »> NRßoR *» * »CHÍR **) Ar, CH (Rß *) OAr '» NRß * R * "i M = CiO)» SO-; G = z X-Y J = CÍO) »S0a; T = Ar, Het; V = cycloalkyl of C3_ ?; w = H »- CN. -CF, »- O-g, -CO ^ R., -CONHR *. -S02NHRß, -NHSO ^ R *, -NHSOa.Rß, -NHCOR-7, -O-COR *, -SRβ, NR'R *, NR '(= NH> NHRβ, Cl, Br, I, F! X = Y = Z = N, O, S or CR-4 »provided that at least one of X, Y and Z are heterogeneous atoms and at least one of X» Y and Z is N. or one of XY and Z is C = N C = C or N = N and the other two are CR- "or N provided that X" Y and Z together comprise at least two N "- indicates a single bond or a double bond in the 5-membered heterocycle; 0.1.2, n = 6; 0 = 0 »1» 2; Ar = phenol »naphthyl» optionally substituted by one or more of Ph-C 1 alkyl ... Het-C 1 alkyl; i of C __ß »Ph-alco? i of C0_ ß» Het-alco? i of Co_ß »OH» i CH, -) 1_ßNRßßRß *.? (CHss); t_ßNRß "Rß *"; Ar = phenyl »naphthyl 'optionally substituted by one or more of Ph-C0_ß alkyl» Het-alkyl of C0_ß »alcox of Cx_ß. Ph-alco? I of C0_ß, Het-alco? I of C0_ß, OH. (CHa) x_ßNRB "Rß", or (CHae) x_ßNRßßRB ", or halogen, R '= H, C 1 alkyl, C 1 C 1 alkyl, C 1 β Het alkyl, R x = H. Co 2 alkyl = C.sub.4.beta.-benzyl, C.sub.3 -C.sub.4 alkynyl, R.sub.3 -C.sub.be alkyl, C.sub.1 -C.sub.1 alkyl, C.sub.H.sub.H alkyl- »RBCO-» RBS02- »RISOC (0) -» RBNHCO-; R- * = H, C ^^ alkyl, Ar-C ^ alkyl »Het-C0_ßalkyl, Rß = Ar C 1 -alkyl- Het-C 0 -alkyl, R * = H. C 1 -alkyl» CHaCF 3, AR-alkylC0_ß »Het-alkyl of C0_ß; 7 = Cx_ß alkyl, Ar-C0_ß alkyl, Het-C0_ß alkyl, R * = H, C2_ß alkenyl, Ca_3 alkynyl, Het; _ß, optionally substituted by OR ', SR', NR'Z, COa.R ', CO-zNR'-2, NIC = NH) NH--, Het or Ar; R "= H, Cx_ß alkyl; alkyl of Co_.Het-alkyl of C0_ß; R o = Cx_m alkyl: C0_ß alkyl, C0_βHet-alkyl, R = H Cx_ß alkyl, Cx_ß. , 16 R17R9-N Ri * = H, Cx_ß alkyl. Ar-C0_ß alkyl, Het-C0_ß alkyl; R 9 - H »C alquiloß alkyl» Ar-C 0 β alkyl. Het-C0_ß alkyl; * = R '« R14 = - -R9R7Z > Ac; Rs-ß = H, Cx_β alkyl, C alm r Ar alkenyl, Het, or C _ alkyl optionally substituted by OR *, NR *, CONR, NíC = NH) NH-, Het or Ar; R ** 5 = alkyl of -j .., alkenyl of C2_ß, alkynyl of Cj ,,. ,,,, Ar, Het, or alkyl of Ca_ß, optionally substituted by OR », SR», R »^» C02R » , CONR »to» NíC = NH) NH-, Het or Ar; Rx »= H, Cx_ß alkyl. alkenyl of x_t alkynyl of c_ «« Ar »Het» or Cx_ß alkyl »optionally substituted by OR» »SR» »NR» ^, CO ^ R », CONR» a ?. N (C = NH) NH-, Het or Ar; R ^ = R "" * = H 'alkyl of Cx_ß, R o, R oC (S) ~, Rlo0C (0) -; R * = Ra * = C__ß alkyl »alkenyl of Ca_ß. C: cycloalkyl; T-alkyl of Ca ..! V-alkyl of Cx_ß. T-alkenyl of Ca_ ?; t- < CH-a) "CH (T) (CHa)"; optionally substituted by one or two halogens. SRao, 0R * °, R ^ R- "or alkyl of C,; R *" 7 = R »BC0, Ra »0C0; Raß = C 1 alkyl, cycloalkyl of Ca x, Ar; Het; T-C 1 alkyl; T- (CHa) "CH (T) (CHa)"; optionally substituted by one or two halogens SR ", OR * 0, NRoseR" 73, Cx_ß alkyl, R * 0 = R "= RM = R" ** = R2B = R "" * = H. al lo of Cx_ ^ »Ar-C0_ß alkyl» Het-C0_ß alkyl; Cbz-leucini lo; 2- »3-, or 4-pyridol meti lo? Icarboni l-leucini lo-; 4-imidazole aceti l-leucini lo »phenylacetyl-leucinyl» N.N- dimeti 1-gl icini 1 leucin lo. 4-pyridi lacetil-leucini lo. 2-pyridi lsulfoni l-leucin lo »4-pyrid icarboni l-leucini lo. aceti 1- leucinil. benzoi l-leucini lo. 4. feno? I-benzo 1-. 2-, or 3-, benci lo? I benzo lo-, bifeni laceti lo »alpha-isobutyl-bifeni laceti lo, Cbz- eni lalanini lo. Cbz-norleucinyl-, Cbz-norval inyl-, Cbz-glutami lo-. Cbz-épsi lon- (this? -butyl) -glutamyl; aceti l-leucini lo-. 6 or 8-quinoline carbonyl. bifeni laceti lo »alpha-isobuti lo-bifeni laceti lo. acetyl. benzoyl 2-. or 3- benzi lo? i benzoi 1. 4-pheno? i benzo lo- »Cbz-amino acid-; 2- »3-» or 4-pyridylmethi locarbonyl-amino acid-arylalkyl? I of C0_Cß carbonyl-amino acid »heteroarylalkyl? Of Co_Cß carbonyl-amino acid» ari lalqui lo? I of C0_C? carbonyl-amino acid »heteroarylalkyl lo? i of Co_.Ce carbonyl-amino acid» alkyl? i of C _C? carbonyl-ami o acid »alkylcarbonyl of Cx_ Cß» arylalkyl of C0_C? carbonyl »heteroarylalkyl of C0_C? carbonyl. ari lalqui 1 of C ^ C. carbonyl »C0_C.sub.-carbonyl heteroaryl» C.sub.Cm.sulfonyl-alkyl »C0-C-sulphonyl-arylalkyl» Cs-Csulfonyl-heteroarylalkyl »Cs-sulfonyl-aralkylsulfonyl» Cs-Csulfonyl-heteroarylalkyl »R3 = -H. Cx_) alkyl ß; Ra = Cbz-leucinyl; 2- »3-» or 4-pyridol methi lo-icarbonyl-leucinyl-; 4-imidazole acetyl-1-leucinyl »fem 'laceti l-leucini lo» NN-dimeti 1-glycome "leucinyl" 4-pyridine laceti-leucine lo »2-pyridyl sulfone l-leucine lo» 4-pyridine Icarboni -leucini lo »aceti l-leucini lo» benzoyl-leucini lo »4» pheo? i-ben? oil-, 2- »o 3-» benci lo i benzo i lo-. bifeni lacetilo., alpha-isobuti lo-bifeni laceti lo. Cbz-f eni lalam'ni lo. Cbz-norleucinilo-. Cbz-norval inilo- »Cbz-gl tami lo-, Cbz-épß lo-íester-butyl) -glutamilo; aceti l-leucini lo-» 6 or 8-quinoline carbonyl. bifeni laceti lo. alpha-isobutyl lo-bi in 1-acetyl »acetyl, benzoyl, 2-, or 3- benzyl, benzoyl, 4-phenoyl, benzoyl-, Cbz-amino acid-; 2-, 3-, or 4-pyridylmethyl lo? Icarbonyl-amino acid-; ari lalqu lo? i of C0_Cß carbonyl-amino acid, heteroarylalkyl? of CQ ^ C ^ carbonyl-amino acid, arylalkyl of Q ^ C ^ carbonyl-amino acid, heteroaryl layl of C0_Cβ carbonyl-amino acid, alkyl? Cx_Cß carbonyl-ami ocido, Cx_ Cß alkylcarbonyl, C0_C arylalkyl? carbonyl, heteroarylalkyl of C0_Cm carbonyl, ari lalqui 1 of C0_C? carboni or, heteroarylalkyl of Co_.Ce carbonyl, alkyl of C 1 -C sulfone, arylalkyl of Co-Csulfonyl, heteroarylalkyl of Co_.Ce sulfonyl, arylalkyl of Co_.Ce sulfonyl, heteroarylalkyl of C0_Cβ sulfonyl, R3a = OCH_, Ar » 0CH2 substituted aryl Cx_ßalkyl, substituted alkyl heteroaryl of C0_β »4-imidazole methylene; 2-, 3-, or 4-pyridi Imeti Inenoxy; 4-pyridyl methyl wood »2-pip" dil sulfonyl, 4-pyridyl, unsubstituted aryl, C0-lower alkoxy, substituted heteroaryl, C0-β-alkyl, R33 = C-alkyl, -CHaPh, -CHaCHaCOaR3- "; R3- * = H, alkyl of Cx_e »R3β = Ar, HetAr, R3β = Ari 1. heteroaryl, pyridyl» isoquinolinyl »R3" "= alkyl of Cx_ß, -CHaPh, -CHaCHaCO_.R3-"; R3"= Cbz; Cx_ß alkyl or substituted aryl, Cbz; Cx_ß alkyl -CO; benzoyl; Cx_e alkyl or lo-substituted benzoyl ary; R3 »= Cbz-leucini lo; 2. 3-. or 4-pyridol methi locarboni 1-leucim "lo-; 4-imidazol aceti l-leucini lo» fe 'laceti 1-leucinilo., NN-dimeti 1-gl icini leucinilo., 4-piridilacet l-leucini lo. -pyridyl sulfoni l-leucini, 4-pyridyl, Icarboni, l-leucine, acetyl-leucine, benzoyl-leucine, 4-phenoxy-benzoyl-, 2-, 3-, benzyl, i-enzoyl- bifeni laceti lo, alpha-isobuti lo-bifeni laceti lo, Cbz-feni lalanini lo, Cbz-norleuci ilo-, Cbz-norval inyl-, Cbz-glutami lo-, Cbz-epsi lo-ister-butyl ico) -glutamyl; aceti l-leucini lo-, 6 or 8-quinolin carbonyl, bifeni laceti lo, alpha-sobuti lo-bifeni 1 acetyl, acetyl, benzoyl 2-, or 3- benzi lo? benzoi 1. 4-phenoxy benzoyl- Cbz-amino acid-, 2-, 3-, or 4-pyridi Imeti lo? Icarbonyl-amino acid-; arylalkyl? I of the carbonyl-amino acid, heteroarylalkyl? Of Co-carbon l-amino acid, arylalkyl? i of C0_Cß carbonyl-amino acid, heteroaryl-alkyl of carbonyl-amino acid, alkyl-1 of Cx_Cß carbonyl-amino acid, alkylcarbonyl of Cx_Cß »C 1 -C 14 carbonyl arylalkyl» C 1 -C 15 carbonyl heteroaryl »C 1 -C carbonyl arylalkyl» C 1 -C 14 carbonyl heteroaryl »C 1 -C 5 sulfonic alkyl» C 1 -C 5 sulfonyl arylalkyl »C 1 -C 5 arylalkyl sulfonyl »heteroarylalkyl of CQ_C? sulfonyl. R-40 = H and Cx_ß alkyl; R *** = H and C x β alkyl; R "* 3 = substituted alkyl aryl and substituted C 1 -heteroalkyl alkyl"; H when R ** 3 is substituted C 1 -C 1 aryl "substituted C 1 -alkyl" heteroacyl substituted C 1+ "R" 3 = alkyl of C _ β "substituted Cx_β alkyl substituted Cx_β heteroaryl alkyl; H when R- * 3 is C 1 -C 4 alkyl substituted C 1 -C 5 alkyl and C 1 → R 4 alkyl substituted heteroaryl = CH 2 RB 3) NR- * BRB- *, CH (RBB) Ar, C 1 -C 3 alkyl- " R ** ß = R- * "= R ** ß = Rβ = Rm = H» Cx_alkyl »Ai-C0_ß alkyl» Het-alkyl 0_?; RBSE = Ar »Het, CH (RB«) AR. CHIRB «) OAr, NíRB *) Ar. Cx_ß alkyl »CHiRBB) NR" »*" RB'7; R B = Ca_ß alkyl »Ar-C0_ß alkyl» Het-alkyl of Co-β »Rß3 and R ** ß can be contacted to form a pyrrolidine or piperidine ring; RB'4 = RB "* = -.t, R ^ -C (0), R-» 7CÍS) R * »'OC (0); RBB = RβB = RBB = RB» = H, Cx_ß alkyl » O-alkyl-Het-alkyl-R * ° = Rma. RM - = R-> R < M _ H, alkyl of C_e »Ar-alkyl of C0_e or Hey-alkyl of Co_ß» Rßß = alkyl of x_e »Ar, Het, CH_R» ») Ar» CH_R »») OAr, NiR * ») Ar, CH (R_») NR_a-R "7 °; R ** = R «» = -? = H, Cx_ß alkyl »(CHa) 0_ß-cycloalkyl of C ^ _? , Aralkyl of C0_ß »Het-alkyl of C0_ß; Rß'r = C alquiloß alkyl (CHaf) 0_ß ~ c cloalqui C deß? A-C0_ß alkyl »Het-alkyl of Co_ß; Rßß and Rβ "* can be combined to form a 7 to 10-membered bicyclic or heterocyclic carbocyclic ring" optionally with 1-4 Cx_ß alkyl »Ph-C0_e 'Het-alkyl C0_ß» alkyl Cx_e »Ph-alco? Of 0_?, Het-alco? I of Co_ß. OH» < CHa &xgrot; x_ßNRBßRßß »0 (CH _.) X_ßNRßaRB»; R * ß = Ro _ Rß_, RßaC (0), R * 3C (S), Rß3GC <0), R * 3OCiO) NRB »CHi 7) ICO) → and pharmaceutically acceptable salts thereof 2.- A compound in accordance with the rei indication 1 »further characterized because: 3. - A compound according to the rei indication 2 »further characterized because A is Leu. 4. A compound according to claim 2 »further characterized in that it is CN» NHR *. SR * »CONHR * or CO-.R *. 5. - A compound according to the rei indication 2. further characterized in that Rx is H. methyl or isobutyl. 6. A compound according to claim 2. further characterized in that R3 is RBOC (0) -. 7. A compound in accordance with the claim 2. selected from the group consisting of: (2S-1'S) -2-benzyl-icarbom'l) ami non-N-Cl * -i 2-carboxy ti azo1-4-i 1) -3'methylbuti 13-4-methyl Ipentanamide; 2S-1'S) -2- (benzyl Toxicarboni 1) amino-N-Cl'-i2-carboamy or azole-4-yl) -3'methyl-13-4-methylpentanamide; (2S-1'S) -2-Ib benz lo? Icarbo il) ami no-N-Cl '- (2-carboetho-itiazol-4-y1) -3'methi Ibuti 1 -4-methyl-Ipenta-namide; (2S-1'S) -2-benzylocarboxy "1) ami no-N-Cl '-i 2-cyano-thiazol-4-yl) -methylpentanamide; 2S-1'S) -2-ibencylcarbohydrate; nil) amino-N-Cl'-C2-iN'-benc? " 1-carboxamido) thiazol-4-i 1) -3'methylbutyl 3-4-methyl-Ipentanamide; (2S-1'S) -2- (benz lox carbo-n 1) ami non-N-Cl '-C2- N' - (3-methyl-1-propy1) carbo amido3ti azo1-4-i 1) -3 ' meti lbuti 13-4-meti 1 pentanamide; (2S-1'S) -2- (benz lox i-carbonyl) amino-N-Cl'-C2-iN'-2-pheni leti 1) carboxamido) thiazol-4-1) - 3 'meti Ibuti 13-4- Ipentanamide methylation; (2S-1'S) -2-ibenz 1-o -carboni 1) amino-N-Cl'-4-carboethoxythiazol-2-yl) -3'methyl-1-butyl-1-4-methyl-Ipentanamide; i2S-1'S) -2-benzylocarboni 1) -amino-N-Cl '- (4-carbo? i thiazole-2-yl) -3'methi Ibuti 13-4-methypentanamide; 2S-1'S) -2-ibenz lo? Icarboni 1) amino-N-Cl'-4-carbo-etho-thiazole-2-yl) -3'met Ibuti 13-4-methyl Ipentanamide; (2S-1'S) -2-benzylcarbonyl) ami no-N-Cl '- (2-carbo-2, 2,2-trif luoro-etho-thiazol-4-yl 3-3'-methylbuti 13-4 -meti ipentanamida; í2S-l'S) -2-í benci lo? carboni 1) ami no-N-Cl '-. { 4-carboetho-thiazo-1-2-l) -3 '-methyl-Ibuti-4-methyl-entanamide; (2S-1'S) -2- (benz 1-o? I carboni 1-Ll euc nil) ami no-N-Cl '- (4-carboetho? I ti azol -2-i 1) -3'meti Ibuti 13 -4-meti Ipentanam da; (2S-1'S) -2- (benzyl-icarbo-ni 1) amino-N-Cl'-4-carboxamidooxadizol-2- 1) -3'methi Ibuti 1 -4-methyl-Ipentanaroide; (2S-1'S) -2- (benzylocarboni 1) ami not-N-Cl '- (2-carboetho- t azo1-4-i 1) -3'methylbutyl 13-3-methylantpenamide; (2S-1'S) -2- (benzylocarboni-L-leuc ni l) ami oN-Cl'-i 2-carboethoxythiazole-4-l) -3'me i 1 bu ti 13-4 -r.?e lpentanamide; (2S-1'S) -2-benzyl 1 or icarbonyl 1) amino-N-Cl '- (5-mercapto-1,2,4-oα-adiazol-3-yl) -3'methi Ibuti 1 - 4-met Ipentanamide; 2S-1'S) -2- (benzylocarbonyl) ami non-N-Cl'-i 2-mercaptoti azo1-4-i 1) -3'methi Ibuti 1 -4-met-Ipentanamide; i 2S) -2-i benci lo? car oni 1) -amino-N-4-carboetho itiazol-2-i 1) -methyl 1-4 -methylpentanamide; i2S-l'S) -2-í benc lo? carboni 1) am -no-N-Cl'-i2-benzyloxycarboni-thia? ol-4-l) -3'methyl-1-buty-13-4-methyl-Ipentanamide; i 2S-1'S) -2- (benzyl? -carbonyl) ami or-4-meti lN-C3'-meti 1-1 '- (2-pheno? carboni 1 to? i ti azo1-4-i 1) buti l 3pentanamide; 2S-1'S) -2-i-benzylcarbonyl) amino-4-methyl-N-C3'-methy1'1-C2-C2-methyl-1-piperazylcarbonyl 1) thiazol-4-yl) util 3-pentanamide; (2R-1'S) -2-benzylcarbonyl 1) amino-N-Cl'-4-carboetho-thiazole-2-yl) -eti 13-4 -methylpentanamide; (2R-1R) -2-ibenci lo? Icarbo-ni l) ami o -N-Cl '- (4-carboetho-thiazole-2- 1) -et l -4-met lpen-tanamide; and 22S, l'S) -N-Cl '- (2-aminothiazol-4-yl-3'-methyl-but-ω-l-2-benzyl-i-carbon 1) ami-4-methyl-Ipentanamide. 8. A compound according to claim 1, further characterized in that: 9. - A compound in accordance with the claim 8, characterized 10. - A compound according to claim 9, further characterized in that R * is R'6 R, 7R9- ^ and R12 and R * and R4-3 are H. 11. A compound according to claim 8 »further characterized in that E is absent. 12. A compound according to claim B, further characterized in that R + + is R "< ^ N-R9R72 13. - A compound according to claim 8, further characterized in that R a or R 9 are i-Bu. 14. A compound according to the rei indication 8 »which is: 15. - A compound according to claim 8, further characterized in that R * "7 or R-73 is R * - ° OC (0) - 16. A compound according to the rei indication 8, selected from the group consisting of of: (1S) -N-C4-C (l-benzylocarboni lami o) -3-met Ibuti 13ti azo1-2-i Icarbon l 3-N '- (N-benz lo icarboni lL-leuc ni 1 ) hydrazide, N-benzyl icarbonnil-L-leucini l-N'-benz lo? icarbonyl-Ll euci-nil-L-leucini Ihidrazide; and (lS) -N-C2-Ci 1 -benz lo? icarbom "l- amino) -3-methylobuti 1 ti azo1-4-i Icarboni 13-N '- (N-benzyloyl-carbonyl-L-leucine 1) hydrazide. 17. A compound according to claim 1, further characterized in that 18. - A compound according to claim 17, further characterized in that R3a- and R3 * are selected from the group consisting of: N-Cbz-leucini lo, N-Cbz-gl icini lo, N-aceti l-leucini lo, N-Cbz-alani lo. 19. - A compound according to the rei indication 17"selected cell group consisting of: 2,2 '- (N-N'-bis-benzylocarboxy 1-L-leucyl) carbohydrazide; 2, 2' -i N-N'-bis-c ic1 ohe? i 1 aceti 1) carbohydrate; 2, 2 '- (N-N'-bis-4-methypentane 1) carbohydrazide; 2,2'-N- N'-bis-ciclo-he? I laceti 1) carbohydrate, 2,2'-iN-N'-bis-benzyloxy carboni 1-glycine 1) carbohydrate, 2,2 '- (N-N'- bis-acetyl-L-leucine 1) -carbohydrazide; 2,2'-i-N'-bis-benzylocarboni 1-L-alani 1) -carbohydrazide; and 2- i -benz lox carboni lL-leucini 1 ) -2'CN- (4-meti Ipentanoi 1) carbohi drazi da 20.- A compound according to claim 1, characterized also because 21. - A compound according to claim 20, further characterized in that R3 ° is selected from the group consisting of -Me and -CHaCHaMea. 22. A compound according to the rei indication 20, further characterized in that R33 is selected from the group consisting of -Pr > -Bu and -CHaCHaMea. 23. A compound according to claim 1, further characterized in that R3-4 is -t-Bu. 24. A compound according to claim 20, selected from the group consisting of: bis-1Cbz-leucini l) -l, 3-diamino-propan-2-one; bi s-1, 3-i 4-phenoxy-benzoi 1) -diami o-propan-2-one; l- (Cbz-l euci n l) -amino-3- (aceti l-leucini 1) -amino-propan-2-one; 1- (Cbz-leucine 1) -amino-3- (Cbz-glutami 1-t-ether-butyl) -amino-propan-2-one; 1- (Cbz-leucinyl) -amino-3- (Cbz-glutami 1) -amino-propan-2-one; Bis-1.3- (Cbz-leucine 1) -diamino-S) -butanone-2-one; l- (Cbz-l euci ni 1) -amino-3-lCb? -pheni lalani l) -amino-propan-2-one; 1-iCbz-leucine 1) -amino-3- (Cbz-norleucini 1) -amino-propan-2-one; 1-tCbz-leucine 1) -amino-3-iCbz-norval ini 1) -amino-propan-2-one; bis-1, 3-iCbz-leucine 1) -diamino-5-met-1-y S) -hexan-2-one; 1-iaceti l-leucini 1) -amino-3-l4-pheno i-benzo l) -amino-propan-2-one; and 1-iCbz-homo-leucini 1) -amino-iCbz-leuc ni 1) -3-amino-propan-2-one. 25. A compound according to claim 24. known as l- (Cbz-leucine 1) -amino-3- (aceti-1-leucim "1) -amino-propan-2-one. according to claim 1. further characterized in that: 27. - A compound according to the rei indication 26, further characterized by: R3B is selected from the group consisting of Ph, or pyridine. 28. A compound according to claim 27, known as is-l, 3- (4-3 3-chloro-2-cyano-pheno? I) fem "1 sulfonamido) propan-2-one. A compound according to claim 27, known as bi sl, 3-i4-phenoxy-phenyl-su-fonamido) -propan-2-one 30. A compound according to claim 1, further characterized in that: 31. - A compound according to claim 30 »further characterized in that R3 * is selected from the group consisting of: O or Cl 32. - A compound according to claim 30, further characterized in that R3"7 of said compound is Me. 33.- A compound according to claim 31, selected from the group consisting of: 1- (Cbz-leucine 1) - amino-3- (4-3 3-chloro-2-cyano-pheno? i) pheny1-suphonamido) propan-2-one; 1- (Cbz-1 euci ni 1) -ami no-3- (tosylamino) -propan-2-one; 1-bz-l euc nyl) -ami no-3-i (4-pheno? I-fem '1) -sulfonamido-propan-2-one; 1- (Cbz-leuc i!) -amino-3- (2-dibenzofuran-8-sulfonamido) -propan-2-one; 1-íCbz-homo-leuc ni 1) - amino-3- (2-dibenzofuransulfonamino-propan-2-one; and l- (Cbz-leucinyl) -a ino-3- (2-dibenzofuransulfonamido) - (S) - bu-an-2-one 34.- A compound according to claim 33, known as l- (Cbz-leucinyl) -amino-3- ((4-phenoxy-phenyl) -sulphonido-propan-2-one. 35. A compound according to claim 33, known as l- (Cbz-leucinyl) -amino-3- (2-di-benzofuransulfone) or -propan-2-one. claim 33, known as l- (Cbz-leucinyl) -amino-3- (2-di-enzofuransulfonamido) - (S) -bu an-2-one 37. A compound according to claim 1, further characterized why: 38. - A compound according to claim 37, further characterized in that R * 3 is 2-dibenzof urani lsul fon i lo. 39.- A compound according to claim 38, selected from the group consisting of: [1- [[[3-C benzyloxy carbonyl-leucine 1 -ami no] -2-oxopropyl] -1- (benzyl) amino ] carbonyl] -3-methylbutyl] carbamate of (S) -phenylmethyl, C1-CC3- i2-di benzofurani 1sulfoni 1) amino-2-o? opropi 13-3-benz 1) amino3carbon 13-3-met Ibuti 1 carbamate of iS) -phenimethyl, Cl-C3-C (2-d bezofura i lsul fon l) ami no3-2-o? Opropi 13-3- (4-pyridini lmeti 1) ami o3carbom "l 3-3 -methi-1-buty-13-carbamate of (S) -fem'lmeti lo, l- CC3-C (2-di enzo-furani Isulfoni 1) amino3-2-o? opropi 13-3-í4-pyridim "Imeti 1) - benzamide, C1-CCC3-C2-dibenzofurani isulfoni 1) amino3-2-o? o-propi 1 -1- i 4-p ridi n lmeti 1) amino carbon 1 -3-meti Ibut l 3-carbaraate of IS) -fen lmeti lo. 40.- A compound according to claim 39, known as C1-CCC3-CÍ2-dibenzofurani Isulfo 1) amino3-2-oxopropi 1-l- (4-pyridini-1-methyl) amino-3-carbon-13-3-methyl-l-butyl-1-carbamate of iS) -fe "lmethyl 41. A compound according to claim 39, known as C1-CCC3-CÍ2-benzoi loxycarboni 1-1 euci ni l-ami o3-2-o? oprop 13-1-i benzyl) -amino-3-carbonyl 3-3-methyl-l-butyl-13-carbamate (S-phenyl) -methyl, 42. A compound according to claim 1, further characterized by: 43. - A compound according to claim 42, further characterized in that: R-4- = CH (RB3) NHRB- *; R- * B, R-**, R- »ß, R-» ß, RBO and RBX are H; R * '- * is independently CH 3, benc lo, 2-pi r di or 1 methoxy, 4-dimethyl aminobenzyl; J = C (0); Rzz = Ar, CH (Ra-) Ar, CH (RAO) 0Ar, N (R o) Ar, CHIRa-) NR ', Ra-: L; RB3 = ethyl, i-Bu; RB- * = R - »" 7, R- »7Ci0), R- * 7OIO); RB * = H, CH- ,, i-Bu; R81" 7 = R * »" ", R47OC (0) ¡ Ar = phenyl or naphthyl, optionally substituted by one or more of Ph-alkyl of C0_ < _ »Het-alkyl of C0_ß 'alkoxy of _ & , pH-alkoxy of C0_e »Het-al COX i of Co_« »OH» iCHa) A_eNRBßRß ", 0 (CH:) 3__ eNRBBRB"; RBB »RB» = H »C 1 -alkyl, C-aryl-C'-alkyl» Het-alkyl-Co-β. 44.- A compound according to claim 42 »selected from the group consisting of: 2-CN- (N-benzyl? Icarbom 'lL-leucine 1) 3-l'-CN' - (4-phenoxy in 1-eulphoni 1) 3-carbohydrazide; 2-CN- (N-benzlocarbaryl 1-L-alan 1) 3-2'-CN-1-benz locarboni 1-L-l euc nor 1) carbo-hydrazide; 2-CN-N-benzyllocarbonyl L-L-leucine 1) 3-2'-CN '- (4-phenyl Ibenzoi 1) 3-carbohydrazide; 2-CN- (N-benzylocarboni 1-L-leucine 1) 3-2 '-CN' - (4-methobenzoyl) 3carbohi drazi da; 2-CN-tN-benzylocarboni 1-L-l euc i ni 1) 3-2'-CN '- (4-phene ibenzoi 1) -carbohydrazide; 2- (N-acet 1) -2'-CN'-N-benzyloxycarbonyl L-L-leucine 1) 3-carbohydrazide; 2-CN-α-acetyl-1-L-l-euc nor 1) 3-2'-CN'-N-benzylocarbonyl 1-L-alan 1) 3-carbohydrazide; 2-CN- (N-acetyl-1-L-alani 1) 3-2 '-CN'-i N-benzylocarbonyl 1-L-leuc ni 1) carbohydraz; 2-CN-i-benzyloyl carboni 1-L-leuc ni l) 3-2'-CN'-C4-N-N-dimethyl laminomet 1) benzo l) 3-carbohydrazide; 2-CN- NN-benz lo? Icarboni l-L-leucini 1) 3-2'-CN'-C4-hydro? I-C3-4 4-morphol i nometi 1) 33-benzoi-1 carbohydrazide; 2-CN-1 N-benzyl-1-oxy-carboni-L-leuc ni 1) -2'-CN'-C4- (N, -dimeti 1 ami-omethyl) -benzyl-1-yl-3-carbonyl 1-Ll-euci-1-carbohydrazide; 2- (N-benzoyl-1) -2'-CN'-iN-benzylcarbon l-L-leucine 1) carbohydrazide; 2-CN- (N-benzyloxycarbonyl L-L-leucine 1) 3-2'-CN'-C3- (4-morphon-o-methyl-1) enzoi-133-carbohydrazide; 2-CN-3 3-benzyloyl benzo 1) -2'-CN '- (N-benzylocarbonyl L-L-leucine 1) carbohydrazide; 2-CN- (N-benzyl? Icarboni l-L-leucini 1) 3-2'-CN'-C4-C3- (N-N-dimeti 1-ami o) -l-propyl lo? 3-benzoyl-33-carbohydrazide; 2-CN- (2-benzyl-1-o? Ibenzoi 1) 3-2'-CN '- (N-benzylcarbonyl-L-L-leucine 1) 3-carbohydrazide; 2-CN-N-benzylocarbon l-L-leucine 1) -2'-CN'-C3- (4-pyridylmethoxy) benzoylcarbohydraz; 2-CN-i4-benzyl? I-benzoyl 1) -2'-CN'-i-benz locarbonyl L-L-leucine 1) 3-carbohydrazide; 2- N-N-benzylocarbonyl L-L-leucine 1) 3-2'-CN '- (3-benzyl? I-5-methoxy) benzoyl 3carbohi drazi da; 2- N-1 -benz 1-o? I carboni l-L-leuci i 1) 3-2'-CN '- (3-benzyl? I-4,5-dimetho i) -benzoi-13-carbohydrazide; 2-CN- (N-benzylocarboni 1-L-leuci-nyl) 3-2'-CN '- (3-benzyl? I-5-etho?) Benzoi-13-carbohydrazide; 2-CN-iN-benzylocarboni 1 gl icim "1) -2'-CN'-tN-benzyloxycarbonyl-L-leucine 1) 3-carbohydrazide; 2-CN-3-benzyl-i-benzoyl 1 ) 3-2 '-CN'-iN-benzyllocarboni 1-L-prol i ni 1) carbo-h-drazide; 2-CN- (N-benzylcarbonyl-L-leucine 1) 3-2'- CN '- (4-pheni Ifeni laceti 1) 3carbohydrazide; (2'S) -2-CN-3-benzyloxy-benzoi 1) 3-2' -CN'-íN-benzylocarboni 1-2-aminobutyr 1 ) -carbohydrazide; 2 »2'-CN.N'-Cb s- (4- eni Ifen 1 acetyl) carbohydrazide; (2 'RS) -2-CN- (N-benzyloxycarboni L-leucine) ) 3-2'-C2- (4-phenylenedi) propioni 13carbohydrazide; 2-CN- (3-benzyl-o? Ibenzoi l) 3-2'-CN '- (4-metpentane 1) 3carboh? Drazide; 22RS »2'RS) -2.2'-CN »N'-Cbis-C2-44-femlfenyl) -4-methylpentanoi 1) 333carbohydrazide; i 2'RS) -2-CN-i N-benzyl loxicarboni lL-leucini 1) -2'-CN'-C2- (4-phenyi ifeni 1) -4-methylopentanoi 1) 33carbohydraz da; i 2 'RS) -2- N-io 3 -benzyl? ibenzo ) -2'-CN'-C2-γ4-pheny1-lfeni 1) -4-methyl-1-pentanoi-1) 3-carbohydrazide; 2-CN-i3-benz-lo-ibenzoi 1) -2'-CN '- (N -benc loxicarbom "1-N-methyl l-L-leucine l) 3carboh drazide; 2-CN-í 3-benci lo? benzoi 1) 3-2'-CN'-CN- (2-pyridine Imetocarbaryl 1) -L-leucine 133carbohydrazide; -2-CN-C3-pyridyl-4-pyridyl) benzoic acid 1 -3- 2'-CN'-CN- (2-pyridylimethylcarbonyl) -L-leucine l 33 -carbohydrazide; (2RS) -2-CN-C2- (4-phenylpheni-1) -4-tneti Ipentanoi 1) 33-2'-CN'-CN- (2-pyridine lmetocarbon 1) -L-leucine 133carbohydrazide; 2-CN- (N-benzyl? Icarbom 'lL-leucine 1) 3-2'-CN'-C2- (4-pheni Ifeni 1) -4-me i Ipentanoi 1) 33carboh drazide »2-CN- ( -benc loxycarboni l-leucine 1) 3-2'-CN'-C2- (4-phenyl Ifeni 1) -4-methyl Ipentanoi 1) 33-carbohydrazide; 2-CN-N N-benzyloxy carboni 1-L-l euci ni 1) 3-2'-CN'-CN- < 4-Pheni Ifeni 1) -N-i2-methyl Ipropyl) carbamoyl 133carbohydrazide »2-CN- (3-benzyl? Ibenzoyl) -2 '-CN'-i-methyl-L-leucine 1) 3-carbohydrazide; 2-CN-iN-benci lo? carboni l-L-leucini l) 3-2 '-CN'-i -meti 1-L-l euci i l) 3carbohi drazi da. 45.- A compound according to claim 1 »further characterized in that: 46. - A compound according to claim 45 »further characterized in that G is: 47. - A compound according to claim 45 »further characterized in that R3 is H and R * -4 is H. 48.- A compound according to claim 45» further characterized in that Rßß is i-butyl and R * »ee i -buti what. 49.- A compound according to claim 45 »further characterized in that RßB is CHÍRß») NRßi-R70. 50.- A compound according to claim 49 »further characterized in that Rβ» is i-butyl. 51.- A compound according to claim 50 »further characterized in that R? X is H. 52.- A compound according to claim 49. further characterized in that R" 70 is R * 30Ci0). Wherein R * 3 is 53. - A compound according to claim 45, further characterized in that R65 is Ar or CH (R69) Ar, wherein Ar in said group R65 is 54. - A compound according to claim 45, further characterized in that L is CH (R *) NR'R6, CH (R <) Ar, NR * R5, CH (R *) 0Ar ', Ar, or Het. 55. A compound according to claim 54, further characterized in that RA is i-butyl. 56. A compound according to claim 45, further characterized in that L is CHi Rßß) NRßoRβ ", CH. {R **) Ar, NR ** R *» "7, CHiRββ) 0Ar". Ar, or Het, where Ar in said group L is 57. - A compound according to claim 54, further characterized in that L is Het, wherein said Het is 58. - A compound according to claim 54, further characterized in that L is NRßßR * "" 7. 59. A compound according to claim 54, further characterized in that L is CH1 R * »ß) RßoRβ. 60.- A compound according to claim 45, which is: 61. - A compound according to claim 45, which is: 62. - A compound according to claim 45 »selected from the group consisting of: ilS) -N-2-Cyl-benzylocarbonyl lamethyl-3-methyl-1-butyl thiazole-4-icarboni 13-N ' -i4-pheno? ife i 1sulfoni 1) hydrazide; i 1S) -N-C4-C1- (N-benzylocarboniLL-leucini lami no) -3-methyl-l-butyl-1-thiazol-2-ylcarbo-N ' -i N-benzylcarbonyl 1-Lluccinyl) hydrazide; (1S) -N-C2-Cyl-benzylcarbonylamino) -3-methyl Ibuti-13-thiazole-4-yl-1-carbonyl 13-N'-yl- phenylphenylacetyl) hydrazide; (1S) -N-C2-C (1-benzylcarbonylamino) -3-methylbutyl-thiazole-4-icarbonyl 3-N'-C3-> 4-pyridinium-limeto) benzoate 1 hydrazide; N-C2-i2-chlorophene? I-methyl) ti azo1-4-i Icarboni 1-N'-CN-i4-pyridinium lmetocarbonyl I) -L-leucine 1 hydrazide; N-CN-4-pyridine l-methoxycarboni 1) -L-leucine? "13-N'-C2-C4- (l, 2,3-thiadiazol-4-yl) phenyl thia? ol-4- i -carbonyl-3-hydrazine» N-C2-C3- ( 4-Cl oropheni-1-sulfonylmethyl) -thien-2-yl-thiazol-4-ylcarbonyl-3-N'-CN- (4-pyridinium-1-methoxy-carbo- "1) -L-1-eukin-1-hihydrazide; (lS, 2'RS ) -N-C2-C (l-benzyloxycarbon-nor-lamino) -3-methyl-l-butyl-13-azo1-4-iicarbom "13-N'-C2 'I-4-phenyl-1-phenyl-lactide 1) -4-met-Ipentanoi-13-hydrazide; N-C2-3-benzyl-1-o-ifeni 1) thiazole-4-lcarbon 13-N'-CN- (2-pyridinium-Imetho-icarbo-nil) -L-leuci "1-drazda; ilRS) - N-C2-Cl-i4-phenylfen l) -3-methyl-1-butyl thiazole-4-icarbon l 3-N'-CN- (4-pyridyl-ilme or? -carboni 1) -L-leucine 1-hydrazide » N-C2- (2-benzyloinif) 1-thiazole-4-i Icarboni 13-N'-CN- (4-pyridinium-methoxycarboxy) -L-leucine 13-hydrazide; N-C2-CN-meti-NN- (4-fem'lfeni l) amino3-thiazol-4-icarbon 1-N'-CN-4-pyridinylmethoxycarboni 1) -L-leucine 13-hydrazide; N- (N-benzylcarboxy-1-leucine) ) -N'-C2- (4- eni Ibencil) thiazol-4-ylcarbonyl-3-hydrazide; N-C2-I4-phenyl-1-phenyl-benzyl-1-t-azole -4-i-Icarboni-13-N'-CN- (4-pyridine-1-methoxycarbonyl) -L-l-eucy-il-hydroquinone; N-1-N-benzyllocarbonyl 1-L-leucine 1) -N'-C 2 -CN- (2-methylpro-yl) -N-phenylamino-3-thiazole-4-ylcarbonyl hydrazide; N-C2-CN-Y 2-methy1propi 1) -N-fem "lamino-3-thiazole-4-ylcarboni 1-N'-CN-4-pyridinium lmetocarboni 1) -L-leucine 1 hydrazide; N- C2-22-benzyl if en en en l) thiazole-4-i Icarboni 13-N'-CN- (3-p ridi "Imeto icarboni 1) -L-leucinyl 3hi drazide; N-C2-t2-benzylloene 1) thiazole-4-icarboni 13-N'-CN-i2-pyridylimethylcarboni 1) -L-leucine 13-hydrazide; N-N-benzyl 1-o? -carbonyl 1-N-methyl-L-leucine 1 > -N'-C2-i2-benzyloxypheni l > -thiazole-4-i Icarboni 13-hydrazide; N-C2-CN-2 2-methy1propy 1) -N-phenylamino3-thiazo1-4-Icarboni 13-N'-CN-2 2-pyridine Imethoxy-carboni 1) -L-leucine 13-hydrazide; N-C2-CN- (2-raeti lpropi 1) -N-phen lamí no3t azo1-4-i Icarboni 13-N '-CN-3 3-pyridi di no lmeto carboni 1) -L-leucine 13-hydrazide; and N-C2-γ2-metho-ife i 1) thiazole-4-i-Icarboni 13-N'-CN-4-pyridinium lmetocarboni 1) -L-1 euci ni 13hi draz i da. 63.- A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, diluent or excipient. 64.- The use of an effective amount of a compound according to claim 1, for preparing a composition for inhibiting a cysteine protease in a patient in need thereof. 65.- The use according to the rei indication 64, further characterized in that said cysteine protease is cathepsin K. 66.- The use of an effective amount of a compound according to claim 1. to prepare a composition for treating a disease such as bone loss in a patient who needs it. 67. The use according to claim 66, further characterized in that said disease is osteoporosis. 68.- The use according to claim G6 * further characterized because said disease is periodontitis. 69. - The application according to claim 66"further characterized because said disease is gingivitis. 70. The use of an effective amount of a compound according to claim 1 to prepare a composition for treating a disease such as the eroding degradation of cartilage or matrix in a patient in need thereof. 71. The use according to claim 70 »further characterized in that said disease is osteoarthritis. 72. The nail according to claim 70, further characterized in that said disease is rheumatoid arthritis.