CA2236111A1 - Protease inhibitors - Google Patents

Abstract

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

Description

W O 97/16433 PCT~US96/18000 -PROTEASE INE~BITORS

FIELD OF TH h~ INVENTION
This invention relates in general to hydrazidyl, bis-hydr~idyl and bis-S arninomethyl carbonyl protease inhibitors, particularly such inhibitors of cysteineand serine proteases, more particularly co~ oLnlds which inhibit cysteine proteases, even more particularly compounds wnich inhibit cysteine proteases of the papain su~lra llily, yet more particularly colllpoullds which inhibit cysteine proteases of the caLl~ farnily, most particularly co~ oullds which inhibit cathepsin K. Such 10 compounds are particularly useful for treating ~ e~cçc in which cysteine proteases are implicated, especially diseases of excessive bone or ca.tilage loss, e.g., osteoporosis, periodontitis, and a.ll~.ilis.

BACKGROUND OF THE INVENTION
Ca~ sills are a family of enzymes which are part of the papain ~ .f . r~.. ily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the lil~;Latul~. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O
therein). Cathepsin K has been recently expressed, purified, and char~teri7e~l Bossard, M. J., et al., (1996) J. BioL Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem.
271, 2126-2132.
Cathepsin K has been variously denoted as caLlle~sin O or cathepsin 02 in the liL~ldtule. The llesign~tion cathepsin K is considered to be the more a~plopliate one.
Cathepsins function in the normal physiological process of protein degradation in ~nim~l~, in-~luriing l~-n,-~-.c, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated as causative agents in various disease states, in- 1nfling but not lirnited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, arnytrophy, and the like. See International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and 5 references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingip~ins, have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.
Cathepsin K is believed to play a causative role in diseases of excessive bone or cartilage loss. Bone is composed of a protein matrix in which spindle- or plate-10 shaped crystals of hydroxyapatite are incorporated. Type I collagen represents themajor structural protein of bone comprising approximately 90% of the protein matrix. The rem:~ining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes 15 remodelling at discrete foci throughout life. These foci, or remodelling units, undergo a cycle concic1ing of a bone resorption phase followed by a phase of bone replacement.
Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight 20 sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface. This creates an enclosed extracellular conll)a, llllent on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes 25 digest the protein matrix. In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget's flice~ce, t'ne normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Ultimately, this leads to weakening of the 30 bone and may result in increased fracture risk with minim~l trauma.

W O 97/16433 PCT~US96/18000 -Several published studies have demonstrated that inhibitors of cysteine proteases are effective at inhibiting osteoclast-mp~ t~-~i bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem. J., 1980, 192, 365, disclose a series of protease inhibitors 5 in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CHN2) ~lc~ nt bone resorpuon, while serineprotease inhibitors were inPffective. Delaisse, et al., Biochem. Biophys. Res.
Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum calcium in rats on c~lcil7m ~lefi~ient diets. Lerner, et al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PI'Hstim~ te~l bone resorption in mouse calvariae. Other shl-liçc, such as by Delaisse, et al., Bone, 1987, ~, 305, Hill, et aL, J. Cell. Biochem., 1994, 56, 118, and Everts, et al., J. Cell. Physiol., 1992, 150, 221, also report a correlation b~.w~Q inhibition of cysteine protease activity and borie resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, l 106, Inaoka, et al., Biochem. Biophys. Res. Commun., l99S, 206, 89 and Shi, et al., FEBS Lett., 199~, 357, 129 disclose that under normal conditions c~th~pcin K, a cysteine ~lvtease, is abundantly expressed in osteocl~ctc and may be the major cysteine protease present in these cells.
The abundant selective ~ ion of cathepsin K in osteoclasts strongly suggests that this enzyme is essçnti~l for bone resorption. Thus, selective inhibition of caL}l~sill K may provide an effective tre~tm~nt for ~lic~o~ces of excessive bone loss, inclu-lin~, but not limited to, osteoporosis, gingival dice~ces such as gingivitis and periodontitis, Paget's flice~se~ hy~cr~alcemia of m~lign~n~ y, and metabolic bone disease. Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium. Thus, selective inhibition of cathepsin K
may also be useful for treating ~lice~ces of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and ,l.~ toid arthritis. l~çtz~ctz~tic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic ~lice~ses ,, 3 Several cysteine protease inhibitors are known. Palmer, (1995) J. Med Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, a-ketocarbonyl compounds, halomethyl 5 ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases.
See Palmer, id, and references cited therein.
U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease. Published International Patent Application No. WO 94/04172, and European Patent Application Nos. EP 0 525 420 Al, EP 0 603 873 Al, and EP 0 611 756 A2 describe alkoxymethyl and llle..;a~lolllethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.
Tnt~rn~tional Patent Application No. PCT/US94/08868 and and l~w~e~l Patent Application No. EP 0 623 592 Al describe aLko~ylllcLl-yl and lllc~ca~tomcLllyl k~ton~s which inhibit the ~;y~Lei1.e protease IL-1,13 convertase. AlkoAyll~,Lllyl and ",~ca~Loll~thyl ketones have also been ~l~s~ ribe~ as inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479).
Azapeptides which are decignç~ to deliver the ~7~rnino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by Elmore et al., Biochem. J., 1968, 107, 103, Garker et al., Biochem. J., 1974, 139, 555, Gray et al., Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. C*em., 1984, 259, 4279, Powers et al., J. Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases. In addition, J. Med Chem., 1992, 35, 4279, discloses certain az~ lide esters as ~;y~ c p~utease inhibitors.
~nti~in and ltu~ Lil1 are described as ~,v~l~ible inhibitors of cysteine protease in Mc~onn~ll et al., J. Med Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cy~Lei-lc protease inhibitors (Barrett, Biochem. J., 201, 189, and Grinde, Biochem. Biophys. Acta,, 701, 328).

U.S. Patent No. 5,142,056 describes 1,3-diamido-propanones which inhibit HIV protease. 1,3-diarrudo-propanones have also been described as analgesic agents (U.S. Patent Nos.4,749,792 and 4,638,010).
Certain heterocyclic derivatives of amino acids have been disclosed in the 5 art. For inCtQnCÇ, ~QmQ~lQ~ et al., pEprlDE CHEMISTRY, 1983. Procee~iin~c of the 21st Symposium on Peptide Ch~mictry (1984), and Boden, et al., Tet. Lett., 1994,35, 8271 (1994) disclose thiQ7ole de.ivalives; and Borg, et al., 199~, 60, 3112,disclose ox~1iQ7ole and tri~ole dcl;v~LivGs.
The synthesis of ~atides (poly~ylhydrazides) as peptide mim.otics has l~,cellLly been disclosed by Han and Janda, J. Am. Chem. Soc. 1996, 118, 2539.
Thus, a structurally diverse variety of cysteine protease inhibitors have been ntifi.o~l However; these known inhibitors are not considered suitable for use aslh~,.d~cutic agents in Qnim~lC, especi~lly hl-mQnc, because they suffer from various shortcomingc These shcllcolllings include lack of selectivity, cytotoxicity, poor 15 solubility, and overly rapid plasma cleal~ce. A need therefore exists for methods of treating diceQce~c caused by pathological levels of ~;y~lGi.le protPQces, including cQth~psinc, especially c~ p~i.. K, and for novel inhibitor cc.lllpoullds useful in such met_ods.
We have now discovered a novel class of hydrazidyl, bis-hydr~idyl and bis-20 alllillolll~,Lilyl c~ubollyl coll~poul~ds which _re protease inhibitors, most particularlyof c~fhlopcin K.

SUMM~RY OF THE INVENTION
An object of the present invention is to provide hydrazidyl, bis-hydrazidyl 25 and bis-arl~inolllGLllyl carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteineproteases of the papain ~ ,e- r~ ily, yet more particularly such compounds which- inhibit cysteine proteases of the cathepsin family, most particularly such compounds 30 which inhibit cathepsin K, and which are useful for treating ~lice~ces which may be therapeutically modified by altering the activity of such plotea es.

W O 97/16433 PCT~US96/18000-Accordingly, in the first aspect, this invention provides a compound according to Formula I.
In another aspect, this invention provides a pharrnaceutical composition comprising a compound according to Formula I and a pharm~.euti~ally acceptable 5 carrier, diluent or excipient.
In yet another aspect, this invention provides a method of treating diseases in which the disease pathology may be the,a~euLically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain ~upelr~llily, yet 10 more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix 15 degradation, such as osteo~LllliLis and rhPum~qtoid arthritis.

DETAILED DESCRIPTION
The present invention provides compounds of Formula I:

D C Q

whereln:
D =

R~A,N~ 23 R N
R2 ; R 'B; O R ;H

W O 97/1~433 PCT~US96/18000 -R350~5--N~ ~F

,~' R43 R48 H~f ~ 'If , 49 L~

Q=

, N~ ; ,C~ R14 ~ N - N ~ R26 R31 ~ II~OR35 ~N--~--R36 H ; H O ; O

42 Rsl R64 39 ~N,N~J,R5 ~N'N'M'R65 R4l R50 R63 where:
o ~ N
A = absent, R8 ~N~
S B = ~<. :~ ~ l 15 X--Y

L = C2 6alkyl, Ar-Co 6aL~cyl, Het-Co 6alkyl, CH(R66)NR60R68, CH(R66)Ar, CH(R66)0Ar', NR66R67;
M = C(O), S02;
G--~Z~
X--Y

J= C(O). S~2;
T = Ar, Het;
V = C3 7cycloaL~yl;
W = H, -CN, -CF3, -N02, -CoR7, -C02R6, -CONHR6 -S02NHR6, -NHS02R6, -NHCoR7, -0-COR6, -SR6, NR'R6, NR'(C=NH)NHR~, Cl, Br, I, F;
X=Y=Z=N, O, S orCR4, W O 97/16433 PCT~US96/18000 -provided that at least two of X, Y and Z are heteroatoms 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 CR4 or N, provided that X, Y and Z together comprise at least two N;
_ in~iC~t.oS a single or double bond in the five-membered heterocycle;
m=0, 1,2;
n= 1 to6;
~=0, 1,2;
Ar = phenyl, naphthyl, optionally ~ub~liLult;d by one or more of Ph-Co 6alkyl, Het-Co 6alkyl, Cl 6alkoxy, Ph-Co 6alkoxy, Het-Co 6alkoxy, OH, (CH2) 1 6NR58R59, O(CH2)1 6NR58RS9;
Ar' = phenyl or naphthyl, optionally substituted by one or more of Ph-Co 6aL~cyl, Het-Co 6alkyl, Cl_6aLkoxy, Ph-Co 6alkoxy, Het-Co 6alkoxy, OH, (CH2)1 6NR58R59, O(CH2)1 6NR58RS9,orhalogen;
R' = H, C1 6alkyl, Ar-Co_6aLkyl, Het-Co 6alkyl;
R1 = H, C1 6alkyl;
R2 = C4 6alkyl, C4 6alkenyl, benzyl;
R3 = C1 6alkyl, Ar-Co-6allcyl~ Het-Co 6alkyl, R5Co-, RSSO2-, R5OC(o)-, RSNHCO-;
R4 = H, C1 6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl;
R5 = Ar-0 6aL~cyl, Het-Co 6alkyl;
R6 = H, C1 6alkyl, CH2CF3, Ar-Co 6alkyl, Elet-Co 6alkyl;
R7 = C1 6aLkyl, Ar-Co 6alkyl, Het-Co 6alkyl;
R8 = H; C2 6 alkenyl; C2 6alkynyl; Het; Ar; C1 6alkyl, optionally substituted by OR', SR', NR'2, C02R', CO2NR'2, N(C--NH)NH2, Het or Ar;
R9 = H, C1 6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl;
R10 = C1 6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl;

W O 97/16433 PCT~US96/18000 -~1 1 = ~, ( l-6aL~yl~ Ar-Cl 6alkyl, Het-Co 6alkyl, or R'7R9--N l;
R12 = H, Cl 6aLkyl, Ar-Co 6alkyl, Het-Co 6alkyl;
R13 = H, Cl 6aLkyl, Ar-Co 6alkyl, Het-Co 6alkyl;
R1~ , R14= 1N--R9R'2 Ac;
Rl~ = H, Cl 6alkyl, C2_6alkenyl, C2 6alkynyl, Ar, Het, or Cl 6alkyl optionally substituted by OR9, NR92, CONR92, N(C----NH)NH-, Het or Ar;
R16 = C2 6alkyl, C2 6aL~cenyl, C2 6alkynyl, Ar, Het, or C2 6allyl optionally cllbstitllted by OR9, SR9, NR92, C02R9, CONR92, N(C=NH)NH-, Het or Ar;
Rl9 = H, Cl 6aLkyl, C2 6alkenyl, C2 6alkynyl, Ar, Het, or C
6alkyl optionally ~ub~liLuled by OR9, SR9, NR92, C02R9, CONR92, N(C_NH)NH-, Het or Ar;
R17 = R72 = H, Cl 6alkyl, R10, R10C(O)-~ R10C(S)-~ RlOoC(o)-;
R21 = R26 = C5 6alkyl; C2 6alkenyl; C3-1 lcycloalkyl; T-C3 6alkyl; v-cl-6alkyl; T-C2 6aLkenyl;
T- (CH2)nCH(T)(CH2)n; optionally ~"l.~lil"leA by one or two halogens, SR20, oR20,NR20R27 or Cl q.alkyl;
R27 = R28CO, R28OCO;
R28=C1 6alkyl;C3 1lcycloalkyl;Ar;Het;T-Cl 6alkyl;
T-(CH2)nCH(T)(CH2)n; optionally ~ul,~Lilult;d by one or two halogens, SR20, oR20, NR20R73, C1 6aL~cyl;
R20 = R22 = R23 = R24 = R25 = R73 = H, C14alkyl, Ar-Co 2~ 6alkyL Het-Co 6alkyl;

_ W O 97/16433 PCT~US96118000 -R29 =

R32~

~ R34 '"s~3~ '"s~
~ ~S~
O O O
"S~ EtO2C--~3 Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methylo~yc~'~..yl-leucinyl-; 4-imi~l~7QIe ~etyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dime~yl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-wridyl carbonyl-leucinyl, ~etyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzylo~yben~oyl-, biphenyl acetyl, PCT~US96/18000 -alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, C~z-norleucinyl-, Cbz-norvalinyl-, Cbz-glutarnyl-, Cbz-epsilon-(t-butyl ester)-glutarnyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, S acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-aminoacid-; aryl Co-C6alkyloxy carbonyl-amino acid-, heteroaryl Co-C6alkyloxy carbonyl-amino acid-, aryl Co-C6alkyloxy carbonyl-amino acid-, heteroaryl Co-C6alkyloxy carbonyl-amino acid-, Cl-C6alkyloxy carbonyl-amino acid-; Cl-C6alkyl carbonyl, aryl Co-C6alkyl carbonyl, heteroaryl Co-C6aL'cyl carbonyl, aryl Co-C6alkyl carbonyl, heteroaryl Co-C6alkyl carbonyl, 1~ Cl-C6alkyl sulfonyl, aryl Co-C6alkyl sulfonyl, heteroaryl Co-C6alkyl sulfonyl, aryl Co-C6alkyl sulfonyl, heteroaryl Co-C6alkyl sulfonyl;

R30 = -H, C1-6 alkyl;
-W O 97/16433 PCT~US96/18000 -R31 =

R32~ R

~ R34 ~"S~ '"s~
~S~
O ~ O O
~ ~OC3H2Ph EtO2C~

Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methylo~ycal'L,onyl-leucinyl-; ~imitl~7.ole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glycil-yl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzylo~yL~.~oyl-, biphenyl acetyl, PCT~US96/18000-alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-arnino acid-; 2-,3-, or 4- pyridylmethyl~ yca~bonyl-aminoacid-; aryl Co-C6alkyloxy carbonyl-amino acid-, heteroaryl Co-C6alkyloxy carbonyl-amino acid-, aryl Co-C6alkyloxy carbonyl-arnino acid-, heteroaryl Co-C6alkyloxy carbonyl-amino acid-, Cl-C6alkyloxy carbonyl-amino acid-; Cl-C6alkyl carbonyl, aryl Co-C6alkyl carbonyl, heteroaryl Co-C6alkyl carbonyl, aryl Co-C6alkyl carbonyl, heteroaryl Co-C6alkyl carbonyl, Cl-C6alkyl sulfonyl, aryl Co-C6alkyl sulfonyl, heteroaryl Co-C6alkyl sulfonyl, aryl Co-C6alkyl sulfonyl, heteroaryl Co-C6alkyl sulfonyl;
R32 = OCH2Ar, OCH2Cl 6alkyl, aryl substituted Co-6alkyl, heteroaryl substituted Co-6alkyl,4-imid~ole methylene; 2-, 3-, or 4-pyridylmethylneneoxy; 4-pyridyl methylene, 2-pyridyl sulfonyl, 4-pyridyl, aryl substituted Co-6alkyloxy, heteroaryl substituted Co-6alkyloxy;
R33 = C1-6alkYI. -CH2Ph, -cH2cH2co2R34;
R34 = -H, Cl -6alkyl;
R35 = Ar, HetAr;
R36 = Aryl, heteroaryl, pyridyl, isoquinolinyl;
R37= C1-6alkYI. -CH2Ph, -CH2CH2Co2R34;
R38 = Cbz; C1-6alkyl or aryl substituted Cbz; Cl-6alkyl -CO; benzoyl; Cl-6alkyl or aryl sl1bstit~~t.oA benzoyl;

PCT~US96/18000 ~

R39 =

R33 H~
~ R34 ~"S~ "S~3 ~S~ ~ Me ~ ~OCH2Ph EtO2C--~

Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methyloxycarbonyl-leucinyl-; 4-imid~7.ole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, ~pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzyl~yl~enzoyl-, biphenyl acetyl.

alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz-norleucinyl-, Cbz-norvalinyl-, Cbz-glutarnyl-, Cbz-epsilon-(t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-arnino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-arninoacid-; aryl Co-C6alkyloxy carbonyl-amino acid-, heteroaryl Co-C6alkyloxy carbonyl-arnino acid-, aryl Co-C6alkyloxy carbonyl-amino acid-,heteroaryl Co-C6alkyloxy carbonyl-arnino acid-, C 1 -C6alkyloxy carbonyl-arnino acid-; C1-C6alkyl carbonyl, aryl Co-C6alkyl carbonyl, heteroaryl Co-C6alkyl carbonyl, aryl Co-C6alkyl carbonyl, heteroaryl Co-C6alkyl carbonyl, Cl-C6alkyl sulfonyl, aryl Co-C6alkyl sulfonyl, heteroaryl Co-C6alkyl sulfonyl, aryl Co-C6alkyl sulfonyl, heteroaryl Co-C6alkyl sulfonyl;
R40 = H and Cl-6alkyl;
R41 = H and Cl-6alkyl;
R42 = C 1 -6alkyl, aryl substituted C 1 -6alkyl and hetero aryl substituted C1-6alkyl,; H when R43 is Cl-6alkyl, aryl substituted C1-6alkyl; and heteroaryl substituted C1-6alkyl;
R43 = Cl-6alkyl, aryl substituted C1-6alkyl and hetero aryl substituted Cl-6alkyl,; H when R42 is C1-6alkyl, aryl substituted C1-6alkyl; and heteroaryl substituted Cl-6alkyl;
R44 = CH(R53)NR45R54, CH(R55)Ar, Cs 6alkyl;
R45 = R46 = R47 = R48 = R49 = R50 = R5 1 = H, C 1 6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl;
R52 = Ar, Het, CH(R56)Ar, CH(R56)OAr, N(R56)Ar, Cl 6alkyl, CH(R56)NR46R57;

-W O 97/16433 PCT~US96/18000 -R~ = C2 6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl, RS3 and R45 may be conn~-ctrc~ to form a pyrrolidine or piperi~lin~ ring;
R54 = RS7 = R47, R47C(o), R47C(S), R47OC(o);
R55 = R56 = R58 = R59 = H, Cl_6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl;
R60 = R61 = R62 = R63 = R64 = H, Cl 6alkyl, Ar-Co 6alkyl, or Het-Co 6aL~cyl;
R65 = Cl_6alkyl, Ar, Het, CH(R69)Ar, CH(R69)OAr, N(R69)Ar, CH(R69)NR61R70;
R66 = R69 = R71 = H, Cl 6alkyl, (CH2)0-6-c3-6cY
Ar-Co 6alkyl, Het-Co 6alkyl;
R67 = Cl 6alkyl, (CH2)0 6-C3 6cycloalkyl, Ar-Co 6alkyl, Het-Co 6alkyl; R66 and R67 may be combined to form a 3-7 m~mh~red monocyclic or 7-10-membered bicyclic carbocyclic or heterocyclic ring, optionally substituted with 1~ of Cl 6alkyl, Ph-Co 6alkyl, Het-Co 6alkyl, Cl 6alkoxy, Ph-Co 6alkoxy, Het-Co 6alkoxy, OH, (CH2)1 6NRS8R59, O(CH2)1 6NR58RS9;
R68 = R70 = R62, R62C(o)~ R62C(S), R62OC(O), R62oC(o)NR59CH(R7 1 )(CO);
and ph~rm~reutir~lly acceptable salts thereof.
The cc ~ oullds of Formula I are hydrazidyl, bis-hydrazidyl and bis-aminomethyl c~ ollyl compounds having in common key structural features 25 required of ~rotease ~ub~Ll~L~s, most particularly c~thrpsin K substrates. These structural features endow the present compounds with the a~lu~liate molecular shape n.-cecc~ry to fit into the enzymatic active site, to bind to such active site, and to react with a sulfhydryl group on the active site, thereby blocking the site and inhibiting enzymatic biological activity. Referring to Formula I, such structural 30 features include the central electrophilic c~ln~--yl, a peptidyl or peptidomimetic molecular backbone on either side of the central carbonyl, a terminal carbobenzyloxy moiety (e.g., Cbz-leucinyl), or a rnimic thereof, on the backbone on one or both sides of the carbonyl, and optionally, an isobutyl side chain exten~1in~
from the backbone on one or both sides of the carbonyl.

R~A,N~
Compounds of Formula I wherein D = R2 and Q =

~W
~Z
Rl are preferred embo~lim~nt.s of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Forrnula II.
More preferred embo~ .. t~i of the present invention include compounds of Formula II wherein:
X=S, Y=CH, and ~--N;
X=CH, Y=S, and Z=N;
X=N, Y=N, and ~--S;
X=N, Y=N, and ~--O; and X=N, Y=N, and ~N.

Preferably R1 is H. methyl or isobutyl. Preferably R 1 is isobutyl.
Preferably R2 is isobutyl or benzyl.
Preferably R3 is R50C(o)-, particularly benzyloxycarbonyl.
Preferably A is a D- or L- amino acid or is absent, preferably A is absent.
Preferably W is CN, NHR6, SR6, CONHR6 or C02R6. Suitably R6 is H, Cl4alkyl, phenyl or benzyl. Typically, W is C02H, C02-C14aLkyl, C02-Ph, C02-CH2Ph, CONH2, NH2 or SH.

, PCT~US96/18000 -, LVlIVVVlll~ r.,V~ r-,rUll~ .)1 r~ U~ UG ~Ll~Ulany prClCll~a;
(2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(2-carboxythiazol~L-yl)-3'-methylbutyl]-4-methylpent~nz-mide;
(2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(2-carboxamidothiazol-4-yl)-3'-5 methylbutyl]-4-methylpent~n~mid~;
(2S ,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(2-carboethoxythi~ol-4-yl)-3'-- methylbutyl]-4-~ hyl~,e~ mi~
(2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[1 '-(2-cyanothiazol4-yl)-3'-methylbutyl]-4-methylp~nt~n~mid~;
(2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-[2-(N'-benzylcarboxamido)thiazol~-yl]-3'-methylbutyl]-4-methylpçnt~n~mide;
(2S ,1 'S)-2-(benzyl~ycalbollyl)amino-N-[ 1 '-[2-[N'-(3-methylpropyl)carboxamido]thi~ol-4-yl)]-3~-methylbutyl]-4-mcLhylL~ nt,"~mi~le;
(2S ,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-[2-[N'-(2-phenylethyl)carboxamido]thiazol-4-yl)]-3'-methylbutyl]-4-meLhyl~ mi~
(2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[1 '-(4-carboethoxythi~ol-2-yl)-3'-methylbutyl]-4-methylpe~tzm~mi~
(2S, I 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(4-carboxythiazol-2-yl)-3'-methylbutyl]-4-methyl~,en~n~."i~
(2S,l'S)-2-f~benzyloxycarbonyl)amino-N-[1'-(4-carboethoxythi~ 7ol-2-yl)-3'-methylbutyl]-4-lll,,lhy~ n~n~mi~e;
(2S, 1 'S)-2-(benzylo~ycallJo.lyl)amino-N-[ 1 '-(2-carbo-2,2,2-trifluoroethoxythiazol-4-yl)-3'-methylbutyl]-4-methyl~ l,ts~ mi.~
(2S, l'S)-2-(benzylo~y~albonyl)amino-N-[1'-(4-carboethoxyox~ ol-2-yl)-3'-25 methylbutyl]-4-methylpent~n~mi~
(2S ,1 'S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[ 1 '-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-methylp,~ mi~le;
(2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(4-carboxamidooxadiazol-2-yl)-3'-methylbutyl]-4-mc~hyl~cnf ~ mide -(2S ,1 'S)-2-(benzyloxycarbonyl)amino-N- [ 1 '-(2-carboethoxythiazol~-yl)-3 '-methylbutyl]-3-phenyl~lo~n~mi~

W O 97/16~33 PCTAJS96/18000-(2S, 1 'S)-2-(benzyloxycarbonyl-L-leucinyl)aIIuno-N-[ 1 '-(2-carboethoxythiazol4-yl)-3~-methylbutyl]-4-methylpellt~n~mi~le;
(2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(5-mercapto- 1 ,2,4-oxadiazol-3-yl)-3 '-methylbutyl]-4-methylpent~n~mi~
(2S, 1 'S)-2-(berlzylo~yc~ l,o,lyl)amino-N-[ 1 '-(2-mercaptothiazol-4-yl)-3'-methylbutyl]-4-methylpent~n~mi~ic;
(2S)-2-(benzylo-~yc~l,onyl)amino-N-(~-carboethoxythiazol-2-yl)methyl4-methylpent~n~mi~
(2S, 1 'S)-2-(benzylo~yc~l,ollyl)arruno-N-t 1 '-(2-benzyloxycarbonylthiazol-4-yl)-3'-10 methylbutyl] 4-methy~ mi~
(2S, 1 'S)-2-(benzyloxycarbonyl)arruno~-methyl-N-[3'-methyl- 1'-(2-phenoxycarbonylthi~ol-4-yl)butyl3pent~n~mi~le;
(2S, 1 'S)-2-(benzyloxycarbonyl)a~runo-4-methyl-N-[3'-methyl- 1'-[2-(2-methylpropyloxycarbonyl)thi~ol-4-yl]butyl~p~nt~n~mi~le;
(2R, 1 'S)-2-(benzylo~yc~l~ollyl)amino-N-[ 1 '-(4-carboethoxythiazol-2-yl)ethyl]-4-methylpc.~
(2R,l'R)-2-(benzylo~yc~hl,ullyl)amino-N-tl'-(4-carboethoxythiazol-2-yl)ethyl]-4-methyl~,.-t~.~;.",il1e; and (2S, 1 'S)-N-[ 1 '-(2-aminothiazol-4-yl)-3'-methylbutyl]-2-(benzyloxycarbonyl)amino-20 4-1ll~ yl~e~ mi~
Most par~icularly preferred compounds of Formula II are:
(2S, 1 'S)-2-(benzylo~ycalbonyl)amino-N-[ 1 '-(2-carboethoxythiazol-4-yl)-3'-methylbutyl]-4-methylpent~n~mi~e;
(2S, 1 'S)-2-(benzylo~yca bollyl)amino-N-[ 1 '-(4-carboethoxythiazol-2-yl)-3'-25 methylbutyl]-4-me;lhyl~.~ mide; and 2S, 1 'S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[ 1 '-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-m~Ll~yll~c~n~n~mi~

W O 97/16433 PCT~US96/18000 -1'~ 11 ,N~N,C~R14 Compounds of Formula I wherein D = R B and Q = l 13 - are preferred embodiments of the present invention. For the sake of convc.. iençe, such compounds are referred to herein after as compounds of Formula m.
With respect to compounds of Formula III:
Preferably B is N--N N--N ~¢N~ N N~ CN or N ~
O i-Bu More preferably B is ~ ~ or ~r ~ B~U .

Rt6 PreferablyRll iS R 7R9--10 Preferably R12 and R13 are H.
R'9 F'lcrG,ably R14 iS N_R9R72 Preferably R15, R16, R18 and R19 are Cl 6alkyl.
More preferably R15 and R18 are C4 6aLkyl.
Preferably Ar is phenyl optionally ~ul~liluled by one or two groups chosen from halogen, CF3, N02, SR9, oR9, NR9 or Cl4aL~cyl.
PlGre,al)ly R17 and R72 are RlOOC(O)-; and more preferably R10 is Ar-C14aLkyl.
Preferably, R16 and Rl9 are C4~alkyl; more ~.G~e,~bly, R16 and Rl9 are i-Bu.
P~Grt;ldbly R17 and R72 are Cbz.

W O 97/16433 PCT~US96/18000 -One particular embodiment of the invention of Formula III is a compound of Formula F:
R16 ~ Rl9 R17-- ~Z~J~ N~ ,R72 X~ i O
F
S wherein X, Y, Z, R16, R 17, Rl9 and R72 are as described in Formula III.
Most particularly ~l~,~lled coll~o~ ds of Forrnula m are:
( 1 S)-N-[4-[( 1 -benzyll~ycaLl,onylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N'-(N-benzylo~ycall,ollyl-L-leucinyl)hydrazide;
N-benzyloxycarbonyl-L-leucinyl-N'-benzylo~yc~lJollyl-L-leucinyl-L-leucinylhydrazide; and ( 1 S)-N-[2-[( 1 -benzyloxyca,l,onylamino)-3-methylbutyl]thiazol~-ylcarbonyl]-N'-(N-benzyloxycarbonyl -L-leucinyl)hydrazide .

R21 N~N, Compounds of Formula I wllel~1ill D = ~ R and Q =

N ~
1~ R24 o are preferred embodirnents of the present invention. For the sake of conveni~nce, such compounds are referred to herein after as compounds of Formula IV.
A more preferred embodiment of the present invention is a compound of Formula IV wherein R21 and R26 are sç~ctç~i from the group conci~tin~ of:
-W O 97/16433 PCTrUS96/18000 -N-Cbz-leucinyl, N-Cbz-glycinyl, N-acetyl-leucinyl, N-Cbz-alanyl, O ~ 0 and R22, R23, R24 and R25 are H.
Particularly preferred embo~lim~ntc of Formula IV are:
2,2'-(N,N'-bis-benzyloxycarbonyl-L-leucinyl)carbohy~d~ide;
2,2'-(N,N'-bis-cyclohexylacetyl)carbohydrazide;
2,2'-(N,N'-bis-4-methylpçnt~n~ yl)carbohydrazide;
2,2'-(N,N'-bis-cyclopentylacetyl)carbohydrazide;
10 2,2'-(N,N'-bis-benzyloxycarbonyl~;lyciyl)carbohyd.d~ide;
2,2'-(N,N'-bis-acetyl-L-leucinyl)carbohydrazide;
2,2'-(N,N'-bis-benzyl(~Ayc~l,ollyl-L-alanyl)carbohydrazide; and 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-tN'-(4-m~lhylpe-1-t~ yl)~carbohydrazide.

2,2'-(N,N'-bis-benzylo~yc~l,ol.yl-L-leucinyl)carbohydrazide is a most p.er~ d embodiment of Formula IV.

R29NJ\ --~,R3 Cc .ll~o~l.. ds of Formula I wherein D = H and Q = H
are ~.ef~ ,d embo-l;...e..1~ of the present invention. For the sake of convenience, 20 such co.l-poullds are referred to herein after as compounds of Formula V.
In more preferred compounds of Formula V, when R30=C 1 -C6 alkyl, R30 is preferably Me or -CH2CH2Me2. When R33=Cl-C6 alkyl, R33 is preferably -Pr, -Bu, or -CH2CH2Me2. When R34=Cl-C6 alkyl, R34 is preferably -t-Bu.
Even more preferred embo-lim~ t.c of Formula V include:

bis-(Cbz-leucinyl)- 1 ,3-diamino-propan-2-one;
bis- 1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one;

W O 97/16433 PCT~US96/18000-1 -(Cbz-leucinyl)-amino-3 -(acetyl-leucinyl)-amino-propan-2-one;
l-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-t-butyl ester)-amino-propan-2-one;
l -(Cbz-leucinyl)-amino-3-(Cbz-glutamyl)-amino-propan-2-one;
bis- 1 ,3-(Cbz-leucinyl)-diamino-(S)-butarlone-2-one;

5 l-(Cbz-leucinyl)-amino-3-(Cbz-phenylalanyl)-~mino-propan-2-one;
l-(Cbz-leucinyl)-amino-3-(Cbz-norleucinyl)-amino-propan-2-one;
1 -(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one;
bis- 1 ,3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one;
1 -(acetyl-leucinyl)-amino-3-(4-phenoxy-ben20yl)-amino-propan-2-one;
10 1-(Cbz-homo-leucinyl)-amino-(Cbz-leucinyl)-3-arnino-propan-2-one;
1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one is a most particularly preferred embodiment of the present invention of Formula V.

R35c~S--N~
Compounds of FormulaI wl~r~ D = ~ and . O
~S~OR3s Q= H O are preferred embo-lim~ntc of the present invention. For tne sake of conv~ni~rlre~ such compounds are referred to herein after as compounds of Formula VI.

~ Cl More preferably, R35 =Ph, CN or pyridine, even more preferably, R35 ~ Cl =Ph, CN . Ph may be optionally substituted with Cl 6aLkyl, Cl 6alkoxy, 20 halogens and cyano groups. When R35 = pyridine, R may be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

W O 97/16433 PCT~US96/18000 Most particularly preferred embodiments of Formula VI include:
bis-1,3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-one;

5 bis-1,3-(4-phenoxy-phenyl sulfonamido)-propan-2-one.

Compounds of Formula I wherein D =

~O~N~ f N~ R36 /~ and Q= ~ are preferred embo-1im~nt~ of the present invention. For the sake of convenience, such 10 compounds are referred to herein after as compounds of Formula VII.
More preferably, R36 is selected from the group consisting of:

O ~ ~Me /~ CN~
Cl ; and R37= Me in the more preferred compounds of 15 Formula VII.
Particularly preferred embodiments of Formula VII are:

l-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-one;
20 1-(Cbz-leucinyl)- amino-3-(tosyl-amino)-propan-2-one;

W O 97/16433 PCTrUS96/18000 -I -(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one;
1 -(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfon~mic~o)-propan-2-one;
l-(Cbz-homo-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one; and 1 -(Cbz-leucinyl)-arnino-3-(2-dibenzofuransulfon~mi-lo)-(S)-butan-2-one.

1 -(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfnn~miclo)-propan-2-one, l-(Cbz-leucinyl)-amino-3-(2--liben7ofuransulfonamido)-propan-2-one, and l-(Cbz-leucinyl)-arnino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one are most particularly preferred embo~lim~-nt.c of Formula VII.

N ~ ~
Compounds of Formula I wl.~,le;n D = ~ R and Q=

~,N~R39 R are preferred embo-limto.ntc of the present invention. For the sake of convenience, such cc ~ oullds are referred to herein after as co~ o~ ds of Forrnula vm.
A more preferred embodiment of Formula VIII is when R43 is 2-dibenz~r~ ylsulfonyl.
Particularly ~ler~ d emboc~;.,.e..lc of Formula VIII are:

(S)-Phe~ylll.clllyl [ 1-[[[3-[benzyloxycarbonyl-leucinyl-amino]-2-oxop~ yl]- 1-20 (benzyl)amino]carbonyl]-3-methylbutyl]carbamate.
(S)-Phenylmethyl [l-[[t3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(benzyl)amino]carbonyl] -3 -methylbutyl]carbamate (S)-Phenylmethyl [1-[[[3-[(2-dibenzofuranylsulfonyl)arnino]-2-oxopropyl]-3-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate 1 -[[r3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl) bçn7~mi~1~
(S)-Phenylmethyl [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxo~r ,pyl]-1-(4-pyridinylmethyl)arnino~carbonyl]-3-methylbutyl]carbamate.
(S)-Phenylmethyl [ 1 -[t[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)arnino]carbonyl]-3-methylbutyl]carbamate Is a most particularly preferred embodiment of Formula vm.

R44~N~N~
Compounds of Formula I wherein D = O R and Q=
R~l ~N 'N'J'R
R are preferred embod~lle~ of the present invention. For the sake of cc,nvenience, such colll~ol~nds are referred to herein after as colll~oullds of Formula ~.
Colll~oL-llds of Formula IX w R44 = CH(R53)NHR54;
R45 R46 R48, R49, R50 and R5 1 are H;
R47 is indepentltontly CH3, benzyl, 2-pyridinylmethoxy, 4-dimethylaminobenzyl;
J = C(O);
R52 = Ar, CH(R10)Ar, CH(R10)OAr, N(R10)Ar, CH(R10)NR"Rl l;
R53 = ethyl, i-Bu;
R54 = R47, R47C(o), R47OC(o);
R56 = H, CH3, i-Bu;
R57 = R47, R47OC(o);
25 Ar = phenyl or naphthyl, optionally substituted by one or more of Ph-Co 6aLkyl, Het-Co 6alkyl, Cl 6alkoxy, Ph-Co 6alkoxy, Het-Co 6alkoxy, OH, (CH2) 6NR58R59, O(CH2) 1 6NR58R59;

R58, R59 = H, Cl 6alkyl, Ar-Co 6alkyl; Het-Co 6alkyl, are more preferred embo-lim~nt.c of the present invention.

The following compounds of Formula IX are particularly preferred:
5 2-~N-(N-benzyloxycall,onyl-L-leucinyl)~-2'-[N'-(4-phenoxy~hc.lylsulfonyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-alanyl)]-2'-[N-(N-benzyloxyc~l,o..yl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4-phenylbenzoyl)]carbohydrazide;
10 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4-methoxybenzoyl)]carbohydrazide;
2-[N-(N-benzyloxycall,onyl-L-leucinyl)]-2'-[N'-(4-phenoAyl,enzoyl)]carbohydrazide;
2-(N-acetyl)-2'-[N'-(N-benzylo~yc~l,onyl-L-leucinyl)]carbohydrazide;
15 2-[N-(N-acetyl-L-leucinyl)]-2'-[N'-(N-benzyloxyc~ul,ollyl-L-alanyl)]carbohydrazide;
2-[N-(N-acetyl-L-alanyl)]-2'-[N'-(N-benzyloxy-;a,l.ol.yl-L-leucinyl)]carbohy~ ide;
2-[N-(N-benzyloxyc~l,ollyl-L-leucinyl)]-2'-[N'-[4-(N,N-20 di-l-~lllylaminomethyl)benzoyl)]]carbohydrazide;
2-[N-(N-benzyloxyca.bonyl-L-leucinyl)]-2'-tN'-[4-hydroxy-[3-(4-morpholinomethyl)]]bcn20yl]carbohydrazide;
2-[N-(N-benzyloxycall,o.lyl-L-leucinyl)]-2'-[N'-[4-(N,N-lhllclhylaminomethyl)benzyloxy]calbonyl-L-leucinyl]carbohydrazide;
2-(N-benzoyl)-2'-[N'-(N-benzyloxyc~ollyl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzyloAyc~l,onyl-L-leucinyl)]-2'-tN'-[3-(4-morpholinomethyl)benzoyl]]carbohydrazide;
2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
30 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-t4-[3-(N-N-dimethylamino)- 1-propyloxy]benzoyl]]carbohydrazide;

2-[N-(2-benzylo~yl,enzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzylo~yca,l,onyl-L-leucinyl)]-2'-[N'-[3-(4-pyridylmethoxy)benzoyl]]carbohydr~ide;
5 2-[N-(4-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzylo~yc~l,olly-l-L-leucinyl)]-2'-tN'-(3-benzyloxy-5-methoxy)benzoyl]carbohydrazide;
2-[N-(N-benzyloxyc~l,onyl-L-leucinyl)]-2'-[N'-(3-benzyloxy-4,5-10 ~lim~thoxy)be~zoyl]carbohydrazide;
2-[N-(N-benzylo~yc~l,onyl-L-leucinyl)]-2'-tN'-(3-benzyloxy-5-ethoxy)l,cnzoyl]carbohydrazide;
2-[N-(N-benzyloxyca;bonylglycinyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
15 2-[N-(3-benzylo~yl,enzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-prolinyl)]carbohydrazide;
2-tN-(N-benzylokyc~l,onyl-L-leucinyl)]-2'-[N'-(4-phenylphenylacetyl)]carbohydr~ide;
(2'S)-2-[N-(3-benzyloxybe~ yl)]-2'-[N'-(N-benzyloxycarbonyl-2-20 arninobutyryl)]carbohydrazide;
2,2'-[N,N'-[bis-(4-phellylphelly-lacetyl)]]carbohydrazide;
(2'RS)-2-[N-(N-benzylokyc~l,o.lyl-L-leucinyl?] -2'-[2-(4-phenylphenoxy)propionyl]carbohydrazide;
2-[N-(3-benzylo~ybe~oyl)]-2'-tN'-(4-methylpentanoyl)]carbohydrazide;
(2RS, 2'RS)-2,2'-[N,N'-tbis-[2-(4-phenylphenyl)4-methylpentanoyl)]]]carbohydrazide;
(2'RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)] -2'-[N'-[2-(4-phenylphe..yl)4-methylpentanoyl)]]carbohydrazide;
(2'RS)-2-[N-(3-benzyloxybenzoyl)]- 2'-[N'-t2-(4-phenylphenyl)-4-30 methylpentanoyl)]]carbohydrazide;

W O 97/16~33 PCT~US96/18000-2-tN-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)~carbohydrazide;
2-[N-(3-benzyloxybenzoyl)]-2'-[N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;
5 2-[N-[3-(4-pyridylmethoxy)benzoyl]]-2'-[N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;
(2RS)-2-[N-[2-(4-phenylphenyl)~-methylpentanoyl)]]-2'-[N'-[N-(2-pyridinylmetho~yc~l,ollyl)-L-leucinyl]]carbohydla~ide;

2-tN-(N-benzyloxycarbonyl-L-leucinyl)]-2'-tN'-[2-(4-phenylphenyl)~-10 methylpentanoyl)3]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-tN'-t2-(4-phellyl~henyl)4-methylpe,ltalloyl)]]carbohydrazide;
2-[N-(N-benzylokyc~l,onyl-L-leucinyl)]-2'-[N'-tN-(4-phenylphenyl)-N-(2-n~ llylpro~yl)carbamoyl]]carbohydr~ide;
1~ 2-[N-(3-benzylo~y~ell~oyl)]-2'-[N'-(N-methyl-L-leucinyl)]carbohydli1~ide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-tN'-(N-methyl-L-leucinyl)]carbohydrazide .

~N'N~ M'R65 Co"lpoullds of FormulaI wl.~ in D = L~ and Q= R
20 are preferred embo-lim~ntc of the present invention. For the sake of convenience, such compounds are referred to herein after as colll~ou,lds of Formula X.
With respect to Formula X:
More preferably G is 2~ yN> or S~~

More preferably R63 and R64 are H and R66 and R69 are i-butyl.
More preferably R65 is CH(R69)NR61R70, in which R69 is i-butyl and R
is H. More preferably R70 is R620C(O), in which R62 is a f H2 CH2 CH2 f H2 5 ~ N or ~3 Alternately, R65 is Ar or CH(R69)Ar, in which Ar in said R65 group is ,13 or ~ or ~N
~ .
More preferably, L is CH(R66)NR60R68, CH(R66)Ar, NR66R67, CH(R66)0Ar', Ar, or Het, in which R66 is i-butyl and Ar in said L group is 9, -W O 97/16433 PCTtUS96tl8000 -~ , or or Het in said L group is s ~Ç~ Ci S~r More preferably L is NR66R67 or CH(R66)R60R68 One particularly p~er~ll.,d embodiment is a compound of Formula G:

Ar X--Y ~

Another particularly preferred embodiment is a co~ ound of Formula H:
R66 ~ R69 R' ~ ~z~l~ ,N~ ,R'~

H

The following compounds of Formula X are most particularly preferred:

(lS)-N-[2-[(1-benzylo~yccubollylamino)-3-methylbutyl~thiazol4-20 ylcarbonyl]-N'-(4-phenoxyphenylsulfonyl)hydrazide;

W O 97/16~33 PCTAJS96/18000 -( lS)-N-t4-t 1-(N-benzyloxycarbonyl-L-leucinylarnino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;
( 1 S)-N-r2-[( 1 -benzyloxyc~l,ollylarnino)-3-methylbutyl]thi~ol4-ylcarbonyl]-N'-(4-ph~,.,ylphellylacetyl)hydr~ide;
( 1 S)-N-[2-[( 1 -benzyloxyc~ 1,onylarnino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[3-(4-pryidinylmethoxy)bellzoyl]hydrazide;
N-[2-(2-chlorophenoxymethyl)thiazol-4-ylc~b-,.lyl]-N'-[N-(4-pyridinylm~thoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-r2-[4-(1,2,3-thi~ ol-4-yl)phenyl]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[3-(4-chlo, ophel,ylsulfollyll"cthyl)thien-2-yi]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethl~yc~b~llyl)-L-leucinyl]hydrazide;
(lS,2'RS)-N-[2-[(1-benzylo~yc~ul,o"ylamino)-3-meLl,ylbl.Lyl]thiazol-4-ylcalbo"yl]-N'-[2'-(4-phenyl~h~ ylacetyl)~-meLllyl~llL~loyl]hydrazide;
N-[2-(3-benzyloxy~h~ .,yl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridi"yl"le~lo~y.,~l,onyl)-L-leucinyl]hydrazide;
( 1 RS)-N-[2-[ 1 -(4-phe,lyl~h~ llyl)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycall,o"yl)-L-leucinyl]hydr~ide;
N-[2-(2-benzylo~yph~,nyl)thiazol-4-ylc~lJonyl]-N'-[N-(4-pyridillyl,lletho~yc~l,o"yl)-L-leucinyl]hydr~ide;
N-[2-[N-methyl-N-(4-ph~l,yl~henyl)amino]thi~ol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-benzylo~ycalbol,yl-L-leucinyl)-N'-[2-(4-phenylbenzyl)thi~ol ~1-ylcarbonyl]hy~lr~
N-[2-(4-~h~l~yl~henylbenzyl)thiazol~ylc~ol~yl]-N'-[N-(4-pyridil~yll"ethoxyc~l,~",yl)-L-leucinyl]hydr~ide;
N-(N-benzylo~cycall,o,lyl-L-leucinyl)-N'-[2-[N-(2-methylpropyl)-N-phenylamino]thi~ol-4-ylc~l,~."yl]hydrazide;
- N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;

W O 97116433 PCT~US96/18000 ~
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-t2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridh,ylll.cil,oxycarbonyl)-L-leucinyl]hydrazide;
S N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N'-[2-(2-benzyl~ky~he.,yl)thiazol-4-ylcarbonyl]hydrazide;
N-f2-[N-(2-mell,,yl~ l)-N-phenylamino]thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxyc~l.onyl)-L-leucinyl]hydr~ide;
N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmetho~yc~ bonyl)-L-leucinyl]hydr~ide; and N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl] -N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydr~ide .

Definitions The prese~nt invention in~ dçs all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a co~ uu,~d of the present invention, all forms of such isomer or isomers, in~ lin~
enantiomers and diastereomers, are int~ntlecl to be covered herein. Inventive compounds co.~ ing a chiral center may be used as a racemic mixture, an enantiomerically erlrich~d mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which co~ uullds have unsaLuldtt;d carbon-carbon double bonds, both the cis (Z) 2~ and trans (E) isomers are within the scope of tnis invention. In cases wh~,.~,~
compounds may exist in t~ltom~ric forms, such as keto-enol t~lt-)m~rs, each tautomeric forrn is contemplated as being incln~.od within this invention whether existing in equilibrium or predomin~ntly in one form.
The m~ning of any subs~iluellt at any one oc-;ùll~nce in Formula I or any subformula thereof is independent of its m~ning, or any other substituent's mç~ning, at any other occurrence, unless specified otherwise.

W O 97/16433 PC~US96/18000 -Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical ~ Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). The term "arnino acid" as used herein refers to the D- or L- isomers of ~l~nine, arginine, asparagine, aspartic acid, cysteine, ghlt~mine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenyl~l~nin~, proline, serine, threonine, tryptophan, tyrosine and valine.
"Cl 6alkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl,pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any Cl 6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R')2, C(O)N(R')2, carbamyl or C 1 4alkyl, where R' is C1 6alkyl. Coalkyl means that no alkyl group is present in the moiety. Thus, Ar-Coalkyl is equivalent to Ar.
"C3 1 l cycloalkyl" as applied herein is meant to include substituted and lln~lbstit~lte-l cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane. -"C2 6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
C2 6alkenyl includes ethylene, l-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
"C2 6alkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2 6 alkynyl includes acetylene, l-propyne, 2-propyne, l-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
"Halogen" means F, Cl, Br, and I.
"Ar" or "aryl" means = phenyl or naphthyl, optionally substituted by one or more of Ph-Co 6alkyl, Het-Co 6alkyl, C 1 6alkoxy, Ph-Co 6alkoxy, Het-Co 6alkoxy, OH, (CH2)1 6NR58R59, O(CH2)1 6NR58R59; where R58, R59 = H, C

W O 97/16433 PCT~US96/18000 -6alkyl; Het-Co 6alkyl, from Cl4alkyl7 OR', N(R')2, SR', CF3, NO2, CN, CO2R', CON(R'), F, Cl, Br and I.
As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either 5 saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group concicting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be q~terni7ed and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The 10 heterocyclic ring may be attached at any hct~ atolll or carbon atom which results in the creation of a stable structure, and may optionally be subsLiluled with one or two moieties s~l~cte~1 from Cl~alkyl, OR', N(R')2, SR', CF3, N02, CN, C02R', CON(R'), F, Cl, Br and I, where R' is Cl 6allcyl. Examples of such heterocycles include piperidinyl, pi~~ yl, 2-oxopipel~zinyl, 2-oxopir~ri~inyl, 2-1~ oxopyrrolodinyl, 2-oxoa~ yl, az~pillyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyr~olyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, qninllcliflinyl, indolyl, quinolinyl, isoquinolinyl, beh~ 7olyl, benzo~y~ yl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahyd~ yl~yl, thienyl, 20 benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oY~ 7olyL
"HetAr" or "heteroaryl" means any heterocyclic moiety encomp~csed by the above definition of Het which is aromatic in character, e.g., pyridine.

It will be appreciated that the heterocyclic ring described when N = Z
includes thiazoles, oxazoles, triazoles, thi~ 7Oles, o~ 7oles~ isoxazoles, 2~ isothiazols, imidazoles, ~yl~ines, pyri-l~7in~s, pyrimidin~s, tri~7inlos and tetrazines which are available by routine chemical synthesis and are stable. The single anddouble bonds (i.e., ~) in such heterocycles are arranged based upon the heteroatoms present so that the heterocycle is aromatic (e.g., it is a heteroaryl group). The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur. When the 30 heteroaryl group comprises a five membered ring, W is preferably an electron CA 02236lll l998-04-28 W O 97/16433 PCT~US96/18000 -withdrawing group, such as halogen, -CN, -CF3, -NO2, -CoR7, -C02R6, -CONHR6, -S02NHR6, -NHS02R6, -NHCoR7, -O-COR6, -SR6 or NR'R6, or a similar electron withdrawing substituent as known in the art.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary 5 butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluole,lyllllethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxyc~l ollyl radical.
Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbo-liimi~iP. DMAP is 2,6-dhll~Lllylaminopyridine, EDC refers to N-10 ethyl-N'(dil,lt;lhylaminopropyl)-carbodiimide. HOBTrefers to 1-hyd~o~yl,~,,.zotriazole, DMF efers to dimethyl fG.~ llicle, BOP refers to benzotriazol-l-yloxy-tris(dimethylamino)phosphQni-lm hexafluorophosphate, DMAP is dimethylaminopyridine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-fli~lllfide, NMM is N-methylmorpholine, TFA
15 refers to trifluoroacetic acid, TFAA refers to trifluoroacetic anhydride and THF
refers to tetrahydrofuran. Jones reagent is a solution of Ch~'ullllU~ trioxide, water, and sulfuric acid well-known in the art.

Methods of Preparation Compounds of Formula II wherein X = CH, Y = S and Z = N, and W =
Co2R7 CN, or CoNR'R7 may be conveniently prepared by methods analogous to 5 those described in Scheme 1.

PCT~US96/18000 Scheme 1 O R1 o ~ R1 a ~ DJ~ N ~ N2 b O O

O R~ ~ D HN J~c~_C02Et O R~ ; o~3 D NH~ CO2H H2N~ C02Et \ S

\
~ \ i D tl ~CoNHR3~ ~ Rl 6 \ D H ~_~ CO2Et f \ tO
OR1 ~ Rl J~N1CN~ DH~ Co2R4 :Z 8 a) i-BuOCOCI, NMM, CH2N2, EtOAc, Et20; b) HBr, AcOH, EtOAc, Et20; c) H2NCSCO2Et,EtOH; d) NaOH, H20, THF; e) i-BuOCOCI, NMM, NH2, THF or BOP, Et3N, RNH2, CH2CI2; f) TFAA, pyridine, CH2CI2; 9) R40H, Boc20, Pyridine or R40H, EDCI, CH2CI2; h),, : " ,e, DMF;
- i) BOP, Et3N, D-C02H, CH2C12 l-Scheme 1 is treated with isobutyl chloroformate and N-methylmorpholine - in ethyl acetate to give a mixed anhydride which is treated with di~omPth~ne in S ether to provide 2-Scheme 1. The ~ .oketone is halogenated using 30% HBr in , acetic acid in ethyl acetate/ether solution to provide 3-Scheme 1. This material is treated with ethyl thiooxamate in refluxing ethanol to give 4-Scheme 1. The thiazole carboxylic ester is saponified by tre~tmPnt with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic 5 acid 5-Scheme 1. The carboxylic acid is treated with isobutyl chloroformate and N-methylmorpholine, followed by gaseous ammonia to provide primary amide 6-Scheme 1 (R3 = H). The primary amide is treated with TFAA and pyridine in dichlolv~ toprovide 7-Scheme 1. ~ ."~ ;vely, 5-Scheme 1 can be converted to sl7bstit~-t~A ~rnic1eS, 6-Scheme 1. by l~ f It with alkyl amines (such 10 as benzylamine, 2-phenylethylamine or isobutylamine) and a peptide coupling reagent (such as BOP, EDC-HCI/l-HOBT or N-methylmorpholinefisobutyl chloroformate) in an aprotic solvent (such as dichlolull~l'lA~-~ or DMF). The carboxylic acid 5-Scheme 1 can be converted to c~l3O~ylic esters 8-Scheme 1 by treatment with a primary or secondary alcohol (such as 2,2,2-trifluoroethanol, 15 isobutyl alcohol, benzyl alcohol or phenol) and a dehydlalillg reagent (such as DCC/DM~P, EDCI or Boc20/pyridine) in an aprotic solvent (such as dichlG.~JI 1l- 1h~ne or ether). When R2 = 9-fluc..~"lyh.l ,LIloxy~ t of 4-Scheme 1 with piperidine in DMF gives 9-Scheme 1. Tre~tm~nt of 9-Schem~. 1 with a carboxylic acid (such as N-Cbz-L-phenyl~l~nin~. or N-Cbz-L-leucinyl-L-leucine) 20 and a peptide coupling reagent (such as BOP) in an aprotic solvent (such as dichlorom-.th~n.o) provides 10-Scheme 1.

Scheme lA

H2N~ IN NH2 ~ H2NlN NH2 HzNlN NH2 R' H
C RR'N ~> N ~ NHR' S NH

a) MeI, THF; b) R NH2, i-PrOH; c) Bromomethyl ketone, EtOH

W O 97/16433 PC~AUS96/18000 Compounds of Formula II wherein X = CH, Y = S and Z = N are prepared by methods analogous to those ~scribed in Scheme lA. 1-Scheme lA is treated with iodoml-.th~ne in an aprotic solvent (such as THF) tO afford 2-Scheme lA, which is treated with a primary amine in a protic solvent (such as isopropanol) to 5 give 3-Scheme 1 A. this material is then treated with a bromomethyl ketone in a protic solvent (such as ethanol) to provide 4-Scheme lA.

Scheme 2 Rl R1 R1 BocHN ~ BocHN NH2 ' BocHN ~ NH2 O O S
;! ;~

BocHN ~ CO2Et ~ H2N _~--C02Et S~ ~ D HJ~ ~--C02H
Ç

a) i-BuOCOCl, NMM, NH3, THF; b) Lawesson's reagent, THF; c) BrCH2COCO2Et, TFAA, Pyridine, CH2CI2; d) TFA; e) DCO2H, EDC-HC1, HOBT, Et3N, DMF; f) NaOH, H2O, THF

Coll~ol"lds of Formula II wherein X = S, Y = CH and Z = N may be conveniently prepared by methods analogous to those described in Scheme 2. 1-Scheme 2 is treated with isobutyl chloroformate, N-methylmorpholine and al~ ,onia - 20 in THF to provide 2-Scheme 2. This m~teri~l is converted to the thioamide, 3-Scheme 2~ by tre~tm~nt with Lawesson's reagent in an aprotic solvent (such as THF
or toluene). 3-Scheme 2 is converted to the thiazole by condensation with a a-ketoester bearing a suitable leaving group for displacement by a sulfur nucleophile (Cl, Br, I, OMs, O-p-Tos) in dichloromethane. 4-Scheme 2 is treated with TFA to provide 5-Scheme 2. This material is treated with a carboxylic acid (such as N-Cbz-L-leucine. N-Cbz-D-leucine or N-Cbz-L-leucinyl-L-leucine) and a peptide couplingreagent ( such as BOP, EDC-HCl/l-HOBT or N-methylmorpholine/isobutyl 5 chloroformate? in an aprotic solvent (such as dichlorom~-~h~nç, DM~ or THF) toyield 6-Scheme 2. This material is saponified by tre~tm~nt with a hydroxide base(such as pot~sillm hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 7-Scheme 2.

Scheme 2A
R1 ~ Rl R'HN ~<~ C02Et a BocR'N ~R~ S ~~

O R~ R' ~ Rl R'HN ~N~<~ CO2Et C ~ Rs~~ N~JI'R' S~--;~ 4 1~ a) Boc-~mino acid, EDC-HCl, l-HOBT, DMF; b) TFA; c) R50COCl, i-Pr2NEt Co.l.~oul.ds of Formula II wh~rein X = S, Y = CH and Z = N may also be ,d by methods analogous to those desc~;ihe~i in Scheme 2A. l-Scheme 2A is treated witn a tert-buto~yc~bollyl-protected amino acid (such as N-tert-20 butoxycarbonyl-L-leucine) and a peptide coupling reagent ( such as BOP, EDC-HCl/1-HOBT or N-methylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichlol~ n~, DM~ or T~) to yield 2-Scheme 2A. which is treated with trifluoroacetic acid to provide 3-Scheme 2A. This m~ten~l is treated with a chloroformate (such as 2-biphenylmethyl chloroformate, 2-benzylbenzyl 25 chloroformate, 2-naphthylmethyl chloroformate or 2-phenoxybenzyl chloroformate) and a tertiary amine base (such as diisopl~,~ylethylamine) in an aprotic solvent (such as methylene chloride) to provide 4-Scheme 2A.

Scheme 3 Rl R1 OMe a 1 OMe b H2N 1~ -BocHN 1~ ~
O O

R1 R1 o BocHN ~ NHNH2 -BocHN ~ N CO2Et d O O
~ 4 BocHN ~ CO2Et ~ H2N~ CO2Et N--N N--N

DJ~ N J~l ~_ C02Et N--N
5 a) Boc20, Et3N, THF; b) llydld2iLIe hydrate, MeOH; c) EtO2CCOCl, Pyridine, CH2Cl2; d) Lawesson's reagent, toluene; e) TFA, CH2Cl2; f~ DCO2H, EDC-HCl/HOBT, Et3N, DMF

Compounds of Formula II wherein X and Y = N, and Z = S may be conveniently prepared by m~tho-ls analogous to those described in Scheme 3. 1-Scheme 3 is treated with di-tert-butyl dicarbonate and triethylamine in THF to provide 2-Scheme 3. This m~t~ri~l is treated with hydrazine hydrate in methanol to provide 3-Scheme 3. The hydrazide is acylated by treatment with ethyl oxalyl 15 chloride and pyridine in dichloromethane to provide 4-Scheme 3. This m~tPri~l is converted to the thi~Ai~7Qle, 5-Scheme 3. by tre~tm~nt with Lawesson's reagent in an aprotic solvent (such as THF or toluene). 5-Scheme 3 is treated with TFA to provide 6-Scheme 3. This material is treated with a carboxylic acid (such as N-Cbz-W O 97/16433 PCT~US96/18000 -L-leucine) and a peptide coupling reagent ( such as BOP, EDC-HC~Jl-HOBT or N-methylmorpholine/isobutyl chlolofo~ ate) in an aprotic solvent (such as dichlorom~oth~nt?, DMF or THF) to yield 7-Scheme 3.

Scheme 4 R1 o R1 BocHN ~ N CO2Et ~ BocHN ~ ,~ CO2Et O N--N

Rl o ~ R1 H2 N ~~ CO2Et ~ D H ~~ CO2Et O Rl D H ~ ,~ CONH2 --N

a) SOCl2, pyridine, Et2O, toluene; b) TFA, CH2Cl2; c) DCO2H, EDC-HCl/HOBT, Et3N, DMF; d) NH3, EtOH
Compounds of Formula II wherein X and Y = N, and Z = O, and W =
C02Et or CONH2 may be conveniently ~-e~ ,d by m~thntls analogous to those described in Scheme 4. 1-Scheme 4 is treated with thionyl chloride and pyridine in ether, followed by reflnxinp in toluene to provide 2-Scheme 4. The res--lt~nt 15 o~ ole is treated with TFA to provide 3-Schem~ 4. This m~t~ri~l is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent ( such as BOP, EDC-HCI/l-HOBT or N-methylmorpholine/isobutyl chlolurc~nate) in an aprotic solvent (such as dichlorometh~n~7 DMF or THF) to yield 4-Scheme 4. The carboxylic ester is treated with ammonia in methanol to yield 5-Scheme 4.

Scheme S

O R2 R1 a ~ R2 R5 N CO2HH2NlCO2Me ' R5l~Nln,N~,C02Me O

O R2 o R5ll Nl~N~J~NHNH2 c R5J~N~N~S~--SH

O Rl a) EDC-HCl/HOBT, Et3N, DMF; b) H2NNH2-H2O, MeOH; c) CSCI2, Et3N, CHCl3 s Compounds of Formula II wherein X and Y = N, and Z = O, and W = SH
may be conveniently plc~,d by methods analogous to those described in Scheme Scheme 5 and 2-Scheme 5 are treated with a peptide coupling reagent ( such as BOP, EDC-HCI/l-HOBT or N~ elllyllllorpholine/isobutyl chloroformate) in an 10 aprotic solvent (such as dichloromto.th~n~, DMF or THF) to yield 3-Scheme 5. This material is treated with hydrazine hydrate in methanol to provide 4-Scheme 5.
Tre~tm~nt of 4-Scheme ~ with thiophosgene and triethylamine in chloroform provides 5-Scheme 5.

W O 97/16433 PCT~US96tl8000-Scheme 6 O Rl ~ R
D HN Br a ~ DJ~ N ~ N~

\b 2 O Rl D HN ~ ~ ~> _ NH2 a)H2NCS2 NH4+,EtOH;b)H2NCS~nH2,EtOH

Compounds of Formula II wherein X = CH, Y = S and Z = N, and W = SH
or NH2 may be conveniently prepared by methods analogous to those described in 10 Scheme 6. Con-l~n.c~tion of l-Scheme 6 with ~mmonillm dithiocd.l,~l,ate in ethanol yielded 2-Scheme 6. ~It~.m~tively, l-Scheme 6 can be conAen.ced with thiourea in ethanol to give 3-Scheme 6.

Scheme 7 D I ~Br 3 D~N~O
H O H O

~ R, D N~N
H N ~,!J~

a) Et2NO; b) H2NCH2CH(NH2)C~2H

Compounds of Formula II wherein X = CH, Y = N and Z = N and W=C may be ~.c~alcd by methods analogous to those described in Scheme 7. Treatment of 1 Scheme 7 with diethylamine N-oxide should provide 2-Scheme 7. Concle~tion of 5 2-Scheme 7 with a 2,3-diaminocarboxylic acid should then provide ~-Scheme 7.
which may be converted to a variety of carboxylic acid derivatives using procedures previously described in other schf~m~s ..
Compounds of Formula III may be generally p.e~ed by methods common 10 in the art of organic chemistry for coupling carboxylic acid derivatives to hydrazine.
Schemes 8, g and 10 are illustrative of a method to prepare compounds wherein B or E is a heterocycle. Compounds of Formula X may be conveniently ~l~pa~.,d by methods analogous to those described in Schemes 8, 9 and 19-23.

Scheme 8 LCO2H a ~ ~N2 b ~ ~Br ~ L--CN~>--CO2Et L--~N~--CONR~~NH2 L--~N~ N R6s O H

a) i. i-BuOCOCl, NMM, THF; ii. CH2N2, Et20; b) HBr, AcOH, Et20; c) H2NCSCO2Et, EtOH; d) R63NHNH2, EtOH; e) R65Co2H, EDC-HCl, l-HOBT, DMF.

Compounds wh~ X = CH, Y = S and Z = N, are p.~pal~,d by methods analogous to those described in Scheme 22. l-Scheme 8 is treated with isobutyl - chloroformate and N-methylmorpholine in ether to give a mixed anhydride which is treated with diazom~th~ne in ether to provide 2-Scheme 8. The diazoketone is halogenated using 30% HBr in acetic acid in ether solution to provide 3-Scheme 8.
This m~t~ l is treated with ethyl thiooxamate in refluxing ethanol to give 4-Scheme 8. The thi~7ole carboxylic ester is treated with a hydr~ine (such as hydrazine monohydrate or methyl hydrazine) in ethanol to yield 5-Scheme 8. This m~to.Ti~l iS treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as EDC-HCI/1-HOBT) in an aprotic solvent (such as DMF) 5 to provide 6-Scheme 8.

Compounds wherein X = S, Y = CH and Z = N, are ~IG~ ,d by methods analogous to those tlescribe~l in Scheme 9.

Scheme 9 LCO2H ~ LCONH2 b ~ LCSNH2 ~ Ll~ CO2Et L~ CONHNH2 L~

6 (J = CO, S02) 15 a) i-BuOCOCl, NMM, NH3, THF; b) Lawesson's reagent, THF; c) i.
EtO2CCOCH2Br; ii. TFAA, Py, CH2C12; d) H2NNH2-H20, EtOH; e) R65S02Cl, Py, CH2Cl2; f) R65Co2H, EDC-HCl, 1-HOBT, DMF.

l-Scheme 9 is converted to 2-Scheme 9 by tre~tm~nt with isobutyl 20 chloroformate, N-methylmorpholine and ammonia in THF. 2-Scheme 9 is treated with Lawesson's reagent in THF to provide the thioarnide 3-Scheme 9. This m~teri~l iS converted to the thia_ole by co~densation with an oc-k~toest~r followed by l~ t with trifluoroacetic anhydride and pyridine in methylene chloride toafford 4-Scheme 21 which is converted to 5-Scheme 9 by LL~ with hydrazine 25 monohydrate. This material is treated with a sulfonyl chloride (such as 4-phenoxyben7~neslllfonyl chloride) and pyridine in an aprotic solvent (such as dichloromethane) to provide 6-Scheme 9. Alternatively, 6-Scheme 9 may be ple~ed by treatment with a carboxylic acid (such as N-benzyloxycarbonyl-L-leucine, N-benzyloxycarbonyl-N-methyl-L-leucine, N-(2-CA 02236lll l998-04-28 pyridinylmethoxycarbonyl)-L-leucine, N-(3-pyridinylmethoxycarbonyl)-L-leucine, N-(4-pyridinylmethoxycarbonyl)-L-leucine, 4-biphenylacetic acid, 3-(4-pyridinylmethoxy)benzioc acid, or 4-methyl-2-(4-phenylphenyl)pentanoic acid) and; a peptide coupling reagent (such as EDC-HCl/1-HOBT) in an aprotic solvent (such 5 as DMF) ,N~
Il 11~;
Compounds wherein B = ~ R are p-c~d by routine methods of peptide ~yllthejis as illustrated for inct~nre by Scheme 10 Scheme 10 RP~ l + NlCO Et ~ R15 R16 R16 o b RP~N~N~CONHNH 2 C RP~ ~H~H
O R15 o Rl5 o a) EDC-HCl, HOBT, DMF; b) H2NNH2-H20, EtOH; c) Rl4-B-Co2H, 15 EDC-HCL, HOBT, DMF
Trç~tm~nt of a ~ lule of l-Scheme 10 and 2-S~heme 10 with a peptide coupling reagent (such as BOP or EDC-HCI/l-HOBT) in an aprotic solvent (such as DMF or dichl~,~ol.-t;thane) provides 3-Scheme 10 This m~t~ l is treated with hyd.~ e hydrate in ethanol to yield 4-~SchemP 10 which is treated with a 20 carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as BOP or EDC-HCl/l-HOBT) in an aprotic solvent (such as DMF or - dichlorom~th~nP) to provide 5-Scheme lQ

, Compounds of Formula IV wherein R22, R23, R24 are H, and R21 = R~6 are prepared by methods analogous to those described in Scheme l l.

Scheme 1 1 O H O H
J~ + R21CO H- a ~R21 I JJ~ ,N
H2NHN NHNH2 ~ N N
O H H O

a) EDC.HCI, l-HOBT, DMF

SymmPtrif- compounds of the Formula IX having RCO as the termin~1 substituent on both sides are ~ d by methods analogous to those described in 10 Scheme l 1. Tl4 ~ t of l-Scheme 1 l with a carboxylic acid ~such as 4-biphenylacetic acid or 4-methyl-2-(4-phel,ylphGnyl)~ t.~loic acid) and a peptidecoupling reagent (such as EDC-HCl/1-HOBT) in an aprotic solvent (such as DMF) provides 2-Scheme l l.

Non~,y. .~ tric compounds of the Formula IX, and co~ vu~lds of Formula IV wherein R22, R23, R24 and R25 are H, and R2 1 ~ R26, are prepared by methods analogous to those described in Scheme 12.

, Scheme 12 R44Co2R a R44CoNHNH2 ~ c= O

;~ 3 ~,9 H O H O H
N NHNH2 . e or f ~ R~N~ J~ N
O H O H H
4 ~ (F = CoR52, So2R52) a) H2NNH2 H20, MeOH; b) C12CO, PhMe; c) H2NNH2-H20, MeOH; d) R49Co2H,EDC HCI, l-HOBT, DMF; e) R52S02CI or R52COCI, pyridine, DMF; f) R52Co2CoR52; 9) R52CoNR51NH2 S Tre~tmlont of l-Scheme 12 with llydlazine hydrate in a protic solvent (such as methanol or ethanol) provides 2-sch~ e 12. which is treated phosgene in toluene to afford 3-Scheme 12. This m~t~ri~l is treated with hydl~ine hydrate in a protic solvent (such as methanol or ethanol) to provide 4-Scheme 12. Tre~tment of 4-Scheme 12 with a sulfonyl chloride (such as 4-phenoxyphenylsulfonyl chloride), an acid chlori-l.o (such as benzoyl chloride), or a carbamoyl chloride (such as N-(2-lllc;~lylplopyl)-N-(4-phenylphenyl)carbamoyl chloride) and pyridine in DMF
affords 5-Scheme-12. ~Itern~tively, 5-Scheme-12 may be prepared by tre~tm~t of 4-Scheme 12 with a carboxylic acid (such as N-benzyloxyc~lJollyl-L-~I~nine7 N-benzyloxyc~l,onyl-L-proline, N-benzyloxycall,onylglycine, (S)-N-benzyloxycarbonyl-2-aminobutyric acid, N-benzyloxycarbonyl-N-methyl-L-le~lcine, N-tert-butoxy~;~bonyl-N-methyl-L-lellcinP7 N-acetyl-L-leucine, N-acetyl-L-~l~ninç, N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-t4-(N,N-dimethylaminomethyl)benzyloxycarbonyl]-L-Ie~cin~, 4-phenylbenzoic acid, 4-methoxybenzioc acid, 4-phenoxybenzoic acid, 4-(N,N-dimethylaminomethyl)benzoic acid, 4-hycroxy-3-[N-(4-morpholinomethyl)]benzoic , acid, 3-[N-(4-morpholinomethyl)]benzoic acid, 2-benzyloxybenzoic acid, 3-benzyloxybenzoic acid, 4-benzyloxybenzoic acid, 4-(3-W O 97/16433 PCT~US96/18000 -dimethylaminomethylpropoxy)benzoic acid, 3-benzyloxy-5-methoxybenzoic acid, 3-benzyloxy ~1,5-dimethoxybenzoic acid, 3-benzyloxy-5-ethoxybenzoic acid, 3-(4-pyridinylmethoxy)benzoic acid, 4-biphenylacetic acid, 2-(4-phenylphenoxy)propionic acid or 4-methyl-2-(4-phellylphenyl)pentanoic acid) and a S peptide coupling reagent ( such as BOP, EDC-HCl/l-HOBT or N-methylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichlorom~th~n~, DMF or THF). 5-Scheme-12 may also be plepa.~d by tre~tm.~nt of 4-Scheme 12 with an anhydride (such as acetic anhydride). .Alt.orn~tively, 3-Scheme 12 may be converted directly to 5-Scheme-l by tre~tm~nt with a hydra_ide 10 (such as 4-metllylpelltanoyl hydrazide or N-methyl-N-benzyloxycarbonyl-L-leucinyl hydrazide).

$cheme 12A

rR

R21 CO~ Jl INI 12 3R21 C~Jr~l ItJI ICH2R ~ 1 ~ O c H O H O H
NJ~NHNH d, e orf > R ~,N~
o ~ O H H
4 (RCH2 = R23) 5 (x = CoR52, So2R52) a) i. PhCHO, EtOH; ii. BH3-THF; b) C12CO, PhMe; c) H2NNH2-H20, MeOH; d) R52Co2H,EDC HCI, l-HOBT, DMF; e) R52SO2CI or R52COCI, pyridine, DMF; fl R52Co2CoR52 Non~y..~ ;c co~ oullds of ~;ormula IV, wherein R23 ;~ H are prepared by methods analogous to those described in Scheme 12A. l-Scheme 12A is treated 20 with an aldehyde (such as bçn7~kl~hyde) in a protic solvent (such as ethanol) and the rçs~llting imine is treated with borane-THF complex to afford 2-Scheme 12A~
which is subsequently treated with phosgene in toluene to afford 3-Scheme 12A.
This m~t~ l is treated with hydra_ine hydrate in a protic solvent (such as methanol or ethanol) to provide 4-Scheme 12A. Tre~rn~ont of 4-Scheme 12A with a 25 carboxylic acid (such as N-benzyloxycarbonyl-L-leucine) and a peptide coupling W O 97/16433 PCT~US96/18000-reagent ( such as BOP, EDC-HCI/l-HOBT or N-methylmolpholine/isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMF or THF) to - yield 5-Scheme-12A.

S Compounds of Formulae V-VII may be conveniently prepared by methods analogous to those described in Schemes 13-16.

Scheme 13 (9-- 2 o , b ~ ~ o o QH
H2N ~NH2 a) HBTU, NMM, DMF; b) Jones, acetone 1,3-Bis-amido propan-2-ones may be pre~d by acylation of 1,3-Ai~minc-propan-2-ol l-Scheme 13 with a carboxylic acid 2-Scheme 13 or a ~ ule of 2 15 dirfert,llt carboxylic acids (2 and 3) in equimolar amounts and a coupling reagent such as a diaL~cyl carboAiimiAe such as DCC or EDCI or HBTU/ N-methyl morpholin~, followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

Scheme 14 ~so2a ,~, ~ N~J~N~soJ3'~1 a a H2N~NH2 .
a) NMM, DMF; b) Jones, acetone 1,3-Bis-sulrul1alllido propanones may be prepared by sulfonylation of 1,3-diamino-propan-2-ol l-Scheme 14 with a sulfonyl chloride 2-Scheme 14 and a base such as N-methyl morpholine, followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

Scheme 15 [~~ H a ~OJ~N~N NH2 H2N~NH2 ~SO2CI
1 cl 3 NH~JI~HN ~
S o Cl a) EDCI, HOBT, DMF; b) NMM, DMF, 3) Jones, ~cet--n~

l-Amido-3-sulf~ n~mi~lo propanones may be prepared by acylation of 1,3-diamino-propan-2-ol l-Scheme 15 with a carboxylic acid 2-Scheme 15 and a coupling reagent such as a carbo~liimi-lç or HBTU/ N-methyl morpholine, followedby trç~tmlo.nt with an a~ ,pliate sulfonyl chloride 3-Scheme 15 and a base such as N-methyl morpholine, followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

~ Sch~ 16 O~N~¢N~OH a. b O~N~¢N~J~R
2: P~N2 ~ Me 3: R=Br _ 4: R=N3 [~f ~ H~ ~N~N, d O Me [~ 6 O Mll ~~oJ~
clo2s~ ~ ~3 ~ Me W O 97/16433 PCT~US96/18000 -l-Arnido-3-sulfonamido alkan-2-ones that are larger than propan-2-one, such as butan-2-one or 5-methyl-hexan-2-one, can be prepared by converting an N-protected peptide such as Cbz-leu-leu-OH l-Scheme 16 to its bromo methyl ketone 3-Scheme 16 via a diazo methyl ketone 2-Scheme 16. Then, the bromide 3-Scheme 16 is ~licpl,.red with sodium azide to give the corresponding azide 4-Scheme 16.- Reduction of the carbonyl with a re~ ~ing agent such as sodium borohydride gives alcohol ~5-Scheme 16. Subsequent reduction of the azide with a reducing agent such as 173-prop~n~fithiol gives the free amine 6-Scheme 16. Acylation or sulfonylation of the arnine gives amide or sulfon~mi fç 7-Scheme 16. Finally, oxidation of thecarbinol with an oxidant such as Jones gives the desired compounds.

Cc,n.pol nds of Formula VIII may be conveniently made using methods analogous to those in Schemes 17 and 18.
Scheme 17 HO~Io _ Na~OTos Po~3 c N~--~OTcs H2N~I NHPh po~ d, ~ po~~ 6 f, 9, h, i ~f o H J~ NH ~--~3 a) NaN3, MeOH, H2O; b) Tosyl chloride, triethylamine, CH2C12; c) Ellman dihy~ ylan resin (3), PPTS, Cl(CH2)2Cl; d) PhCH2NH2, toluene, 80 degrees C; e) HATU, N-methyl morpholine, NMP; f) HS(CH2)3SH, MeOH, Et3N; g) Cbz-leucine (6), HBTU, N-methyl morpholine, NMP; h) TFA, CH2C12, Me2S; i) Jones reagent, acetone Azide opening of glycidol 1 -Scheme 17. followed by tosylation of the primary alcohol gave tosylate 2-Scheme 17. which was coupled to Ellman polymer 3-Scheme 17 as described by described in J. Med Chem. l99S, 38, 1427-1430 to W O 97/16433 PCTAUS96/18000 ~

produce polymer 4-Scheme 17. which was reacted with benzyl amine in toluene, then washed extensively with various solvents. Then, the azide was reduced with 1,3-prop~ne-lithiol in MeOH, triethylamine, then was washed extensively with various solvents. Coupling of Cbz-leucine 6-Scheme 17 with the ~ minP 5-Scheme 5 17 with equimolar amounts and a coupling reagent such as a dialkyl carbodiimide such as DCC or EDCI or HBTU/ N-methyl morpholine. Cleavage of the ether linkage to an alcohol was accomplished with trifluoroacetic acid with various scavengers. Finally, oxidation of the carbinol to a ketone 7-Schem~ 17 with an oxidant such as Jones reagent provided the desired final product.
Scheme 18 O

~SO*~_~N~N~HN o~~3 a) 4-pyridyl methyl amine, isop~ allol, reflux; b) Cbz-le~l~inlo, HBTU, 15 N-methyl morpholine, DMF; c) hydrazine, MeOH, reflux; d) 2-dibenzofuransulfonyl chloride, N-methyl morpholine, DMF; e) Jones reagent, z~cetone N-(2,3-EpoAy~ yl)phth~limide 1-Scheme 18 (Aldrich) was reluxed with 20 an amine such as 4-pyridiyl methyl amine in iso~.lopanol. The secondary amine 2-Sch~orn~ 18 was then acylated with an acylating agent such as Cbz leucine or a sulfonylating reagent such as 2-dil~nzoruldll~ulfonyl chloride and base such as N-methyl morpholine in DMF. The phth~limi-lto. was then removed with hydrazine in MeOH and the resulting free amine was acylated with an acylating agent such as 25 Cbz leucine or a sulfonylating reagent such as 2-dibenzofuransulfonyl chloride and base such as N-methyl morpholine in DMF.

Compounds of Formula IX may conveniently be made using methods analogous to those in Schemes 19 and 20.

W O 97/16433 PCT~US96/18000 ~

Compounds of Formula X may be conveniently made using methods analogous to those described in Schemes 21-27.

Scheme 19 L--~N~--CO2EtL--~N~--CO2H
;~ N~H

R6sCO2Me ~R65CoNR64NH ~ R64 a) KOH, MeOH/H20; b) R66NHNH2, EtOH; c) EDC-HCl, l-HOBT, DMF
Compounds wherein X = CH, Y = S, Z = N and R4 . H, are ~lc~ d by methods analogous to those deseribed in Scheme 19. Carboxylic ester l-Scheme 19 is treated withl a hydroxide base (such as lithoum hydroxide, sodium hydroxide or pot~ccillm hydroxide) in methanol/water to provide 2-Scheme 19. 3-Scheme 19 is 15 treated with a hydrazine (such as methylhydrazine) in a protic solvent (such as ethanol) to give 4-Schem~ 19. 2-Scheme 19 and 4-Scheme 19 are coupled by L.e~l "~ t with a peptide coupling reagent (such as EDC-HCl/l-HOBT) in an aprotic solvent (such as DMF) to provide 5-Scheme 19.

Scheme 20 EtO2CCOCH2Br ~ l~--CO2Et Br~~CO2Et c or d ~ Ar~~~CONHNH

4 ~i S H o Ar~~ N ~ N J'' R65 O H

5 a) Thiourea, EtOH; b) i. NaNO2, 16% aqueous HBr; ii. CuBr, 16% aqueous HBr;
iii. HBr (cat.), EtOH; c) ArB(OH)2, Pd(PPh3)4, CsF, DME; d) ArSnMe3, Pd(PPh3)4, PhMe; e) H2NNHz-H2O, EtOH; e) R65Co2H, EDC-HCI, 1-HOBT, DMF.

Co,l,~ou"ds wherein X = S, Y = CH, Z = N and V = 2-methoxyphenyl or 2-benzylo~y~hel1yl, are prepared by method~ analogous to those described in Scheme20. Ethyl bromc,~y,uvale (1-Scheme 20) is treated with thiourea in refluxing ethanol to provide 2-Scheme 20~ which is treated ~ucces~ively with sodium nitrite and copper (I) bromide in 16% aqueous HBr, and the product was heated in ethanol15 with a catalytic amount of HBr to give 3-Scheme 20. Tle~ t of this m~t~ri~l with an arylboronic acid (such as 2-benzyloxyphênylboronic acid), tetrakis(triphenylphosphine)p~ m(0) and cesium fln~ ricle in ~t;flu~illg DME
provides 4-Scheme 20. ~ltern~tively, 4-Scheme 20. may be ~r~aled by L.~ t of ~-Scheme 20 with an aryl~t~nn~ne (such as 2-trimethylstannylanisole) and 20 tetrakis(triphenylphosphine)p~ -m(0) in refluxing toluene. Treatment of 4-Scheme 20 with hydrazine hydrate in ethanol provides 5-Scheme 20. which is treated with a carboxylic acid (such as N-benzyloxycarbonyl-N-methyl-L-leucine, N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-(3-pyridinylmethoxycarbonyl)-L-leucine or N-(4-pyridinylmethoxycarbonyl)-L-leucine) and a peptide coupling W O 97/16433 PCT~US96/18000 -reagent (such as EDC-HCl/l-HOBT) in an aprotic solvent (such as DMF) to provide 6-Scheme 20.
Scheme 21 S
RCOCI a ~ RCONHR64 b RCH2NHR67 ~ RCH2NR67CSNH2 R66R67 ~ ~ CO2Et 66 67 1 ~ ~ CONHNH

R66R6~Nl~ N ~ N J~ R6s a) R67NH2, Py, CH2C12; b) LiAlH4, THF; c) i. C12CS, Py, CH2Cl2; ii. NH3, MeOH or I. PhCONCS, CHC13; ii. K2CO3, MeOH, H2O; d) EtO2CCOCH2Br, EtOH; e) H2NNH2-H20, EtOH; e) R65Co2H, EDC-HCl, l-HOBT, DMF.

Compounds wherein X = S, Y = CH, Z = N and V = NR66R67, are ~par~d by methods analogous to those tiesrrihe-l in Schlom~- 21. An acid chloride (~
Scheme 21 ) is treated with a primary amine (such as 4-aminobiphenyl or aniline)15 and pyridine in an aprotic solvent (such as methylene chloride) to provide 2-Scheme ~L which is treated with lithium ~ minllm hydride in THF to afford 3-Scheme 25.
Tr~o~tm~nt of 3-Scheme 21 with thiophosgçnP and pyridine in methylene chloride, followed by ~ with ammonia in methanol provides 4-Scheme 21.
.~ltern~tively, 4-Schem~- 21 may be ~ie~arcd by tre~tm~nt of 3-Scheme 21 with 20 benzoyl isothiocyanate, followed by tre~tm~-nt of the intçrrn~ t~- benzoyl thiourea with pot~csillm carbonate in m~th~no]Jwater. 4-Scheme 21 is treated with hydr~ine hydrate in ethanol to give 5-Scheme 21. Tre~tm~nt of S-Scheme 21 with a carboxylic acid (such a N-(2-pyridinylmethoxycarbonyl)-L-le-lcine, N-(3-pyridinylmethoxycarbonyl)-L-leucine or N-(4-pyridinylmethoxycarbonyl)-L-25 leucine) and a peptide coupling reagent (such as EDC-HCl/1-HOBT) in an aprotic solvent (such as DMF) affords 6-Scheme 21.

W O 97/16433 PCT~US96/18000 -Scheme 22 H2N~ H
H2NCSC02Et ~ ~ b ~ L~ N ~ C02Et c H2N CO2Et N--N

L ~N~ CG~II INI 12 d, L_~N~'N'N~R65 N--N N--N H O

s a) H2NNH2-H2O, EtOH; b) LCO2CO2i-Bu, 200 ~C; c) H2NNH2-H2O, EtOH; d) R65Co2H, EDC-HCl, l-HOBT, DMF

Co~ ounds wherein X and Y = N, and Z = NH, are ~ d by methods 10 analogous to those described in Scheme 26 l-Scheme 22 is treated with hydrazine hydrate in ethanol to give 2-Scheme 22. which is heated with a mixed anhydride to provide triazole 3-Sch~m~ 22 This m~ter~l iS treated with hydrazine hydrate to provide 4-Scheme 22. which is treated with a carboxylic acid (such as N-benzyloxyc~ o.,yl-L-leucine) and a peptide coupling reagent (such as EDC-HCl/l-15 HOBT) in an aprotic solvent (such as DMF) to provide 5-Scheme 22 Scheme 23 O H R69 ~ H R69 Y~ 'N~NBoc a ~ ~N ~NHR6' S ~ N ~ N--M ~ R62 3 (M = CO, SO2) BocNRY~S~O ,N~R S a HRYN~N~O N,N~R~s a) TFA; b) R62CO2H, EDC-HCl, l-HOBT, DMF; c) R62S02Cl, i-Pr2NEt Compounds wh~ hl X = S, Y = CH, Z = N, L = CH(R66)NR60R68 where R68 ~ Boc or Cbz, or R65 = CH(R69)NR61R70 where R70 ~ Boc or Cbz are p.~a.t,d by methods analogous to those described in Scheme 27. l-Scheme 23 is 10 treated with trifluor~,acelic acid to provide 2-Scheme 23. This m~teri~l is treated with a carboxylic acid (such as pry~7inPc~lJo~ylic acid, isonicotinic acid, 4-imidazolylacetic acid or pipecolic acid) and a peptide coupling reagent (such asEDC-HCl/l-HOBT) in an aprotic solvent (such as DMl;) to provide 3-Scheme 23.
3-Scheme 23 may also be p.~a,~ed by tr~ of 2-Scheme 23 with a sulfonyl 15 chloride (such as 2-pyritiin~slllfonyl chloride) and a tertieary amine base (such as diisopropylethylamine) in an aprotic solvent (such as methylene chloride).
~ltern~tively, ~ nt of 4-Scheme 23 with trifluoroacetic acid provides 5-Scheme 23.
,, W O 97/16433 PCT~US96/18000 -Scheme 24 H ..
H2N NH2 ~i~N~NH2 BocN CO2H

N~J~HN ~ c N~N~ ~
O ~ ~ OCH2Ph O ~ ~ OCH2Ph ~ ~OCH Ph ~--~ ~ ~ fSt~

a) EDCI, DMF; b) 2-PhCH20PhS02Cl, NMM, DMF; c) TFA, DCM; d) ~pyridyl acetic acid, HBTU, NMM, DMF; e) Jones 1,3-Diamino-propan-2-ol (or an N-aL~yl ~ul~LiLuLed diamino-propanol) is coupled to a protected leucine analog (either Cbz- or Boc-) and another carboxylic 10 acid or sulfonyl chloride. Removal of the ~l~Le~;live group, followed by acylation or sulfonylation, and oxidation of the alcohol provides the desired compounds.

Scheme 25 Cbz-NH COzH Cbz-NH~ ~ ~ Cbz NH~f N~

~NHM~ N~N~N~ e C~ ~ Mc J--O O
a) BTU, NMM, DMF, allyl amine; b) mCPBA, DCM; c) MeNH2, isoplo~anol, 70 S C; d) Cbz-le~lein~, EDCI, DMF; e) Jones, ~etcn.o N-Allyl amine (or a N-alkyl-N-allyl amine) is coupled to a Cbz-amino acid (or sulfonylated with an aryl sulfonyl chloride), then the alkene is epoxidized with a peracid (or dimethyl diooxirane). The epoxide is opened with a ~ul~siluLed amine, 10 then the amine is acylated or sulfonylated. Final oxidation gives the desired ketones.

-The starting materials used herein are commercially available amino acids or are ~l~pal~,d by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF
ORGANIC SY~ 1~1 lC METHODS, Vol. I-VI (published by Wiley-Interscience).
Coupling methods to form amide bonds herein are generally well known to the art. The methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF ~;~lll>E SYNTHESIS, Springer-Verlag, -Berlin, 1984; E.
Gross and J. Meienhofer, THE ~llL~ES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE ~ E SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984. are generally illustrative of the technique and are inc~ u.aLed herein by reference.
Synthetic methods to prepare the co~ >o~llds of this invention frequently employ protective groups to mask a reactive functionality or ~ i7e unwanted side reactions. Such ~ Le~;live groups are described generally in Green, T.W;
PROTECTIVE GROUPS IN ORGANIC SY~ , John Wiley ~ Sons, New York (1981). The term "amino plot~ ;n~ groups" generally refers to the Boc, acetyl, bell~,oyl, Fmoc and Cbz groups and deliv~lives thereof as known to tne art.
Methods for ul~te.,lion and del,lolecLion, and repl~e..-~..t of an amino protecting group with another moiety are well known.
Acid addition salts of the compounds of Formula I are ~ al~,d in a standard manner in a s--it~hle solvent from the parent colll~oulld and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoro~etil~7 maleic, s~lccinic or mloth~n~ fonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are pl~al.,d by treating the parent colll~oulld with an excess of an ~Ik~lin~ reagent, such as ahydroxide, carbonate or ~lk~xitl.o, co~ ;r7ir~ the ap~>rù~liate cation; or with an ~.,yliate organic amine. Cations such as Li+, Na+, K+, Ca++, Mg++ and NH4+
are specific examples of cations present in ph~rm~~elltically acceptable salts.
~ es, sulfate, phosphate, alkanoates (such as acetate and trifluoroS~et~t~
ben70~t~s, and sulfonates (such as mesylate) are e~mples of anions present in ph~rm~elltically acceptable salts.

W O 97/16433 PCT~US96/18000 This invention also provides a pharm~el-tir~l composition which comprises a compound according to Formula I and a ph~rrn~reutic~lly acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in them~nnf~ re of a mPr~ m~nt ph~rm~-~el~tic~l compositions of the compounds of 5 Formula I prepared as hereinbefore described may be formlllAtrd as solutions or lyophilized powders for ~al ,l.t~.dl ~q-lminict~tion. Powders may be l~,COI-S~ t~cl by ~lrlitiQn of a suitable diluent or other ~ reuti~lly acceptable carrier prior touse. The liquid f~lrmnl~tion may be a buffered, isotonic, aqueous solution.
Exarnples of suitable ~ ntc are normal isotonic saline solution, standard 5%
10 dextrose in water or buffered sodium or ammonium acetate solution. Such forrn~ tion is especially suitable for ~a~ ldl ~dminictration~ but may also be used for oral ~lminictration or contained in a metered dose inhaler or nebulizer for incllffl~tion. It may be desirable to add excipients such as polyvillyl~yllolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mslnnitol, sodium chloride or 15 sodium citrate.
.Alt~-rn~t~ly, these co,ll~oullds may be enr~rc~ t~fl tableted or yl~ d in an emulsion or syrup for oral ~lmini~tr~tion. Ph~rm~reutir~lly acc~ldble solid or liquid carriers may be added to enh~n~~e or stabilize the colllyosilion, or to f~ilit~t~-of the colll~o~ ion. Solid carriers include starch, lactose, calcium 20 sulfate dihydrate, terra alba, m~gn~osillm stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water.
The carrier may also include a sllst~in~ release m~f~ri~l such as glyceryl monostearate or gly~,e~ ict~r~te, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage 25 unit. The ph~rm~relltir~l ylepA~ onc are made following the convçntion~l techniques Of rhA~ y involving millin~, mixin~, gr~n~ ting, and COlllyl~,S5illg,when nr~es~s~ y, for tablet forrns; or millin~, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the ~aldLion will be in the fo~n of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid30 foTmlllz~tiQn may be ~ minictered dhcclly p.o. or filled into a soft gelatin capsule.

6~

W O 97/16433 PCT~US96/18000 -For rectal ~(1minictration~ the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethyleneglycols and molded into a suppository.

Utility of the rr~3 ~lt Invention The co~ wlds of Formula I are useful as protease inhibltors, 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 .u~Glr~ullily, yet more particularly as inhibitors of ~;y~7leh~c proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful colll~osiLions and form~ tions of said compounds,inr-hlrlin~ ph~rm~relltir~l compositions and formulations of said colll~oullds.
The present co,ll~o~llds are useful for treating .lise~-cçs in which Uy~7lGillc proteases are implicated, inclu<lin~ infections by pnpnmr~cystis carinii, tryps~n~:~m~
cruzi, l ypsalloma brucei, and C~rithi~ fucirlll~t~: as well as in schictosomi~cic, m~l~ri~ tumor m~t~ct~cic, mlot~cl.,~llalic leukody~Ln~hy, mncc~ r dy~.L~ y, yLl~,phy; and especi~lly ~lice~ces in which cathepsin K is implicated, most particularly flice~ces of excessive bone or cartilage loss, including o~leoL,olu~is, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rh~llm~toid arthritis, Paget's disease; hyperc~k emi~ of m~lipn~n~y, and metabolic bone disease.
~t~ct~tic neoplastic cells also typically express high levels of proteolytic e-n~yllles that degrade the surrounding matrix, and certain tumors and mtot~ct:~ti~
neoplasias may be errc~,livcly treated with the compounds of this invention.
The present invention also provides methods of trÇ~tm~nt of ~licç~ces caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain ~ul,ç, r~...ily, yet more particularly cysteine proteases of the catl,~,~si,l farnily, which methods comprise a~lminictering to an animal, particularly a 30 m~mm~1, most particularly a human in need thereof a compound of the present invention. The present invention especially provides m~thorlc of t~e~t.~ t of diseases caused by pathological levels of cathepsin K. which methods comprise ~lmini.ct~ring to an animal, particularly a mzlmm~l, most particularly a human in need thereof an inhibitor of cathepsin K, inclllllin~ a compound of the present invention. The present invention particularly provides methods for treating diseases - S in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomi~ci.c, m~l~ri~ tumor mt~.t~ct~cic, m~t~h.vl,laLic leuko~ly~L~v~hy, muscular dystrophy, ~llyLluphy,, and especially fii~e~cçs in which cathepsin K is implicated, most particularly llice~ces of excessive bone or cartilage loss, inch~ ng osteo~3vlvsis; gingival disease including gingivitis and periocl- ntiti.c, arthritis, more speci~lr~lly, osteoarthritis and rht-llm~toid arthritis, Paget's ~ii.ce~ce, lly~Gl~ emi~
of m~lign~ncy, and metabolic bone ~lice~ce This invention further provides a method for treating os~eoporosis or inhibiting bone loss which comprices intern~ minictration to a patient of an effective amount of a col,,pvu,ld of Pormula I, alone or in co,llbination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone repl~ 1 therapy, anti-estrogens, or calcitonin. In addition, tre~tmPnt with a co~ uulld of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to inclGase bone mass.For acute LllGld~y, parenteral ~-lminictration of a compound of Formula I is preferred. An intld~nous infusion of the eolllpolllld in 5% dextrose in water ornormal saline, or a similar formulation with suitable excipients, is most effective, although an int~ sc~ bolus injection is also useful. Typically, the ~dl~,ntelal dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mglkg,in a lll~lnGI to m~int~in the conce.ll~dlion of drug in the plasma at a concentration effective to inhibit c~th~p~cin K. The col,l~o--nds are ~lmini.ct~red one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
The precise amount of an hlvelltivc~ compound which is therapeutir~lly effective, and the route by which such compound is best ~-lmini~tered, is readily determined by one of ordinary skill in the art by colll~alhlg the blood level of the agent to the concentration required to have a therapeutic effect.

The compounds of this invention may also be ~-iminictered orally to the patient, in a manner such that the concentration of drug is s-lfficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein.
Typically, a ph~rrn~ e~ti~l composition col-t~ining the compound is ~clmini~tçred S at an oral dose of ~.,L~eell about 0.1 to about 50 mg/kg in a manner c-)n~i~nt with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.
No unacceptable toxicological effects are expected when compounds of the present invention are ~clministered in accordance with the present invention.
Biological Assays The co,l,~oullds of this invention may be tested in one of several biological assays to ~lPte~ the concentration of compound which is required to have a given ph~rm~l~ological effect.
Determ;rsff~n of cathepsin K ~l ot~ lic catalytic activity All assays for cS~ sil~ K were carried out with human recombinant cll~;ylllc. Standard assay con-litions for the ~lel. "~ tion of lcinetic co.~ used a fluorogenic peptide substrate, typically Cbz-P_e-Arg-AMC, and were ~ietermin~ll in 100 mM Na acetate at pH 5.5 Cont~ininE 20 mM cysteine and S mM E~DTA. Stock ~ul~sLlale solutions were yl~,~arcd at concentrations of 10 or 20 mM in DMSO with 20 uM final ~u~ ate conrçntration in the assays. All assays cont~in~l 10% DMSO.
Independent e~cl.e- ;...~ . found that this level of DMSO had no effect on enzyme activity or kinetic cor~t~ntc. All assays were con~ ct~ at ambient te~ clature.
Product fluor~scçn~e (excitation at 360 nM; emission at 460 nM) was monitored with a ~e.ceptive Bio~y~lc~lls Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minlltes following formation of AMCproduct.

Inhibition studies Potential inhibitors were evaluated using the progress curve method. Assays were carried out in the presence of variable concentrations of test compound.
Reactions were initi~te~ by addition of enzyme to buffered solutions of inhibitor and - ~ substrate. Data analysis was con~ cl~l according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors.
For those colllpoullds whose progress curves were linear, a~palellt inhibition con~t~ntc (Ki,app) were c~ t~cl accu,-lhlg to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140):
v = VmA /rKa(l + I/~i, app) +Al (1) where v is the velocity of the reaction with m~xim~l velocity Vm, A is the 15 concentration of SUl~ alG with ~ich~ constant of Ka, and I is the concentration of inhibitor.
For those compounds whose progress curves showed dowl~w~ud ~,-UI VdLUlG
characteristic of time--lepen~ent inhibition, the data from individual sets was analyzed to give kob5 according to equation 2:
[AMC3 = v55 t + (vo - v55) [I - exp (-kobst)~ / kobs (2) where [AMC] is the concentration of product forrned over time t, vo is the initial 2~ reaction velocity and vSS is the final steady state rate. Values for kobs were then analyzed as a linear function of inhibitor concentration to gelle.dle an aL,~.,nt second order rate constant (kobs / inhibitor concellL aLion or kobs / [I]) ~les~ rihin~
the time-dependent inhibition. A complete discussion of this kinetic tre~tn-~nt has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 30 61, 2ûl).
-, W O 97/16433 PCT~US96/18000 Human O~ Resorption Assay Ali~uots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37~C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at 4~C). The m~ m was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 m~ um~
and incubated for 30 min on ice The cell suspension was mixed frequently.
The cells were washed x2 with cold RPMI-1640 by ce.,llirugation (1000 ~pm, 5 min at 4~C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enu~ ,.dt~d in an i~ v~cd Neuba-ler counting chamber.
S-lfficient m~.gn~tic beads (5 / monon-l~ le~r cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh mPrlillm (this washes away the toxic azide preservative). The m~nium was removedby immobilizing the 'oeads on a magnet and is replaced with fresh rn~-lillm The beads were mixed with the cells and tne ~ p~~.~ion was inrnb,.ttorl for 30 min on ice. The ~.US~l ~.ion was mixed frequently. The bead-coated cells wereirnmobilized on a magnet and the rem~ining cells (osteoclast-rich fraction) were~lec,.nt~-l into a sterile 50 nL cellL,iruge tube. Fresh medium was added to tne bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeatedxlO. The bead-coated cells were discarded.
The ost~ocl~ctc were enullle.ated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the ch~mher with the sample. The cells were pelleted by ce,lL,irugation and the density of osteoclasts adjusted to 1.5xlO4/mL in EMEM mf~inm, suppl~m~nt~ci with 10% fetal calf serum and 2~ 1.7gllitre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( pertre~tm.ont) were ~lec~nte~l into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the a~plo~liate tre~tm~nt was added (diluted to 50 uM in the EMEM m~ lm). Also included were ~lo~liate vehicle controls, a positive control (87MEMl diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/rnL). The tubes were incubate at 37~C for 30 min.

W O 97/16433 PCT~US96/18000 -0.5 rnL ali~uots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37~C for 2 h. Each tre~tmpnt was screened in quadruplicate. The slices were washed in six changes of warm PBS ( lO mL / well in a 6-well plate) and then placed into fresh tre~tmPnt or control and inc!lb~t~(l at 5 37~C for 48 h. The slices were then washed in phosphate buffered saline and fixed in 2~ glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and inrnb~t~A in buffer for 5 min at 37~C. The slices were then washed in cold water and incllb~t~d in cold acetate buffer / fast red garnet for 5 min at 4~C. Excess buffer was aspirated, and the slices were air dried following a 10 wash in water.
The TRAP positive osteoclasts were e.lulllelat~,d by bright-field rniclùscc,~y and were then removed from the surface of the dentine by sonication. Pit volumeswere dGtGlll~ cd using the Nikon/Lasertec ILM21W confocal microscope.

15 General Nuclear m~n~tir resonance spectra were recorded at either 2~0 or 400 MHz using, re~cc~ ,ly, a Bruker AM 250 or Bruker AC 400 specL.ulllet~ CDCl3 is deuteriochlolufollll, DMSO-d6 is he~ elltPriodilllG~lylsulfoxide, and CD30D is tetr~-lP,IltPriom~th~nol. Ch~miç~l shifts are reported in parts per million (d) 20 downfield from the internal standard tetramethylsilane. Abbreviations for NMRdata are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = mllltiplet, dd = doublet of doublets, dt = doublet of triplets, app = ~p~llt, br = broad. J
inr1ir~t.os the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and 2~ Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D
infrared spectlurl~t~,.. IR and FTIR spectra were recorded in tr~ncmiccion mode,and band positions are reported in inverse wavenumbers (cm~1). Mass spectra weretaken on either VG 70 FE, PE Syx API m, or VG ZAB HF instr~mP~tc, using fast atom bolllba~ nent (FAB) or electrospray (ES) ionization techniques. Flem~nt~l 30 analyses were obtained using a Perkin-Elmer 240C elemPnt~l analyzer. Melting points were taken on a Thomas-Hoover melting point ~aldtus and are uncorrected.
All lelll~e.dLur~s are reported in degrees C'~
Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.
Where inAir~tPA, certain of the m~teri~l~ were purchased from the Aldrich Chtomic~l Co., Milwaukee, Wisconsin, ~hemic~l Dynamics Corp.; South pl~inhe New Jersey, and Advanced ~h~mtech~ Louisville, KPnhlrlry Examples In the following ~yllLll~,tiC examples, Lelll~ dLulG is in degrees Centigrade (~C). Unless otherwise indicated, all of the starting m~teri~l~ were obtained from COl ,ne-~;ial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceAing description, utilize the present invention to its fullest extent. These Examples are given to illustrate the invention, not to limit its scope.
Reference is made to the claims for what is ,~se. ved to the inventors hereunder.

F.xample 1 r~aldLion of (2S.l'S)-2-(benzyloxycarbonyl)amino-N-rl'-(2-carboethoxythiazol~
yl)-3'-methylbutyl~-4-melllyl~ miAe a) N-benzylo~yc~ul,ollyl-L-leucinyl-L-leucinyl bromomethylketone l-Methyl-3-nitro-l-nitrosogll~nitlinP (5.9 g, 40.11 mmol) in ether (200 mL) is cooled to 0~C. 40% pot~il-m hydroxide is added slowly and the diazomP-th~nP- is allowed to collect in the ether solution for 30 minlltes at 0~C.
N-Cbz-L-Leucinyl-L-T ~ ine (Bachem) (4.0 g, 10.58 mmol) is stirred in tetrahydrofuran at -40~C. N-methylmorpholine (1.07 g, 10.58 mmol, 1.16 mL) and isobutyl chlol~folmaLe (1.45 g, 10.58 mmol, 1.38 mL) are added. The ll~i~Lule isstirred at -40~C for 15 minnt~s and then filtered into a cold flask to remove eA salts. To the filtered solution is added an excess of the previously ~,c~ed diazom~o-th~ne solution and the mixture is allowed to stand at 0~C for 16 h.
An excess of 30% ~r in acetic acid is added at 0~C and the solution is then washed snccçc~;iv~ly with l.ON citric acid, saturated aqueous sodium bicarbonate (carefully), and brine. The solution is dried over sodium sulfate, filtered, and ev~olaLed to give the title compound as a white solid (4.10 g). lH NMR (400 MHz, CDC13) o 7.34 (m, SH), 6.51 (d, lH), 5.15 (d, lH), 5.10 (s, 2H), 4.78 (m, lH), 4.20 (m, lH), 4.04 (dd, 2H), 1.63 (m, 6H), 0.93 (m, 12H).

b) (2S,l'S)-2-(benzyloxycarbonyl)arnino-N-[1'-(2-carboethoxythiazol4-yl)-3'-methylbutyl]4-m~yl~e~ m~
The compound of Example l(a) (2.0 g, 4.4 mmol) and ethyl thioox~m~tf 10 (0.59 g, 4.4 mmol) were refluxed in ethanol for 4 h. The solvent was evaporated and the residue chromatographed (silica gel, 2.5% m~oth~nol/dichlvlu~ ne) to give the title co~ vulld as a white solid (1.46 g). lH NMR (4vv MHz; CDC13) ~ 7.32 (s, lH), 7.21 (m, SH), 6.40 (d, lH), 5.13 (dd, lH), 5.02 (s, 2H), 4.41 (q, 2H), 4.06 (m, lH), 1.71 (m, 2H), 1.47 (m, 4H), 1.33 (t, 3H), 0.73 (m, 12H).
Fx~ ple 2 Plc~Lion of (2S.l'S)-2-(benzylo~yc~l,v"yl)amino-N-rl'-(2-carboxythiazol-4-yl)-3'-methylbuty-114-,1lclhyll.e.~ mide The compound of Example l(c) (0.92 g, 1.88 mmol) was stirred in 20 tetrahyLvru all at 0~C with l.ON sodium hydroxide. After stirring for 1 h, the solution was quenched with l.ON citric acid and extracted three times with dichlororn~th~n~. The combined organic extracts were evaporated in vacuo to givethe title compound as a white solid (0.844 g). lH NMR (400 MHz, CDC13) o 7.40 (s, lH), 7.23 (m, 5H), 6.89 (d, lH), 5.22 (d, lH), 5.14 (dd, lH), 5.02 (s, 2H), 4.15 25 (m, lH), 1.67 (m, 2H), 1.44 (m, 4H), 0.81 (m, 12H).

Example 3 F'1e~ Lion of (2S.1'S)-2-(benzyloxyc~l,ollyl)amino-N-r1'-(2-carboxamidothiazol-4-yl)-3'-methylbutyll4-methylpPnt~n~mi(le The compound of Example 2 (0.408 g, 0.88 mmol) in tetrahydl~,ru~ was cooled to 40~C and treated with N-methylmorpholine (0.185 g, 1.85 mmol, 0.2 W O 97/16433 PCT~US96/18000 mL) and isobutyl chloroformate (0.12 g, 0.88 mmol, 0.11 mL). The mixture was stirred at -40~C for lS minlltes and then ammonia was bubbled through the solution for several minlltes. The ~ UlG was allowed to warm to room le~ dture and was then diluted with ethyl acetate and washed snc-cescively with 1.0N citric acid, 5% aqueous sodium bicarbonate, and brine. The organic solution was dried over magnecillm sulfate, filtered, and eva~u,dled to a residue which was cl.~o",atogrArh~cl (silica gel, 3% methanol/dichlorom~-thAne) to give the title compound as a white solid (0.245 g). lH NMR (400 MHz, CDC13) o 7.22 (m, ~H), 7.04 (s, lH), 6.40 f~br s, lH), 5.51 f~br s, lH), ~.09 (m, lH), 5.02 (dd, 2H), 4.07 (m, lH), 1.66-1.42 (m, 6H), 0.82 (m, 12H).

Exan~le 4 P~ ~dlion of f2S~l'S~-2-fbenzylo~ycalbollyl)amino-N-rl'-(2-cyanothiazol~-yl)-3'-methylbutyll-4-1,wllyl~e.l-tAnamide The colll~ou~d of F.xample 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 h, the mixture was pouredinto a solution of Sdlu dled aqueous sodium bicarbonate and extracted with dichloromPth~n.o. The organic extracts were washed with 5% hydrochloric acid and20 brine, dried over m~ ci~ sulfate, filtered, and evd~o~led to an oil which waschromatographed (silica gel, 40% ethyl acetate/hexane) to give the title compound as a white solid (0.095 g). lH NMR (400 MHz, CDCl3) o 7.44 (s, lH), 7.29 (s, SH), 6.51 (br d, lH), 5.14 (m, lH), 5.07 (s, 2H), 4.11 (m, IH), 1.78-1.41 (m, 6H), 0.83 (m, 12H).
F.xample 5 ~dlion of (2S.1'$)-2-(benzyloxycarbonyl)amino-N-~l'-r2-(N'-l: ~n7ylcarboxamido)thiazol-4-yll-3~-methylbutyll-4-methylpent~n~mi~le To a solution of the compound of Example 2 (0.12 g, 0.26 mmol) in 30 dichlorom~th~ne under argon at room le~ eldlulc is added benzyla_ine (0.03 g,0.29 mmol, 0.03 mT~), BOP reagent (0.115 g, 0.26 mmol), and triethyl amine (0.026 g, 0.26 mmol, 0.04 rnL) which is allowed to stir for 16 h. The solu~ion is washed with water, then brine and the organic layer is dried over m~..e~ .... sulfate, filtered, and e~o,dt~;d to give a residue which was chromatographed (silica gel,40% ethyl acetate/hexane) to give the title col~lpound as a white solid (0.065 g). lH
NMR (400 MHz, CDC13) ~ 7.56 (br s, lH), 7.33 (m, lOH), 6.48 (br d, lH), 5.15 (dd, lH), 5.03 (s, 2H), 4.63 (d, 2H), 4.12 (m, lH), 1.72-1.40 (m, 6H), 0.85 (m, 12H).

Px~m~l?le 6 Preparation of (2S.l'S)-2-(benzylo~yc~bollyl)amino-N-rl'-r2-rN'-(3-yl)carboxamidolthiazol-4-yll-3~-methylbutyll-4-mel~ly~ t~ d~
Following the procedure of Example 5, except s~ g isobutylamine for benzylamine, the title compound was ~,~ed (0.074 g). lH NMR (400 MHz, CDC13) o 7.27 (s, SH), 7.19 (s, lH), 6.38 (br d, lH), S.09 (m, lH), ~.01 (s, 2H), 4.07 (m, lH), 3.20 (dd, 2H), 1.83 (m, lH), 1.69-1.40 (m, 6H), 0.90 (d, 6H), 0.81(m, 12H).

Ex~ml?le 7 P~ dlion of (2S.1 'S)-~-(ben;~yloxychll,ol,yl)amino-N-r 1 '-r2-rN'-(2-phenylethyl)carboxanudolthiazol-4-yll-3'-methylbutyll4-methyl~e Following the procedure of F.Y~mple S, except ~ubslillll;llg 2-phenylethyl~mine for benzylamine, the title compound was prepared (0.070 g). lH
NMR(400MHz,CDC13)~7.30-7.11 (m, llH),6.35(brd, lH),S.O9(m, lH),S.01 (s, 2H), 4.05 (m, lH), 3.64 (m, 2H), 2.87 (t, 2H), 1.69-1.40 (m, 6H), 0.80 (m, 12H).

W O 97/16433 PCT~US96/l8000 ~

F.X~nn~1~ 8 Pl~dLion of (2S.l'S)-2-(benzyloxycarbonyl)amino-N-rl'-(4-carboethoxythiazol-2-yl)-3'-methylbutylW-melllylpf n~ nli(le a) N-tert-butoxycarbonyl-(L)-leucin~mitl.o S To a solution of N-tert-butoxycarbonyl-(L)-leucine (Advanced ~hFl.llr~
(5.0 g, 20.0 mmol ) in dry THF (10OmT ) at 40~C was added isobutyl chloroformate(2.7 g, 20.0 mmol) and N-methylmorphiline (4.2 g,42 mmol). After 15 minllt~s of stirrin~, ~mmnni~ was bubbled through the ll~Llur~ for an additional 15 minl~t~s~
then warmed to room Itlll~cldlule and allowed to stir for 2 hours. Mixture filltered 10 and filtrate concentrated in vacuo to yield title colll~uulld as a white solid (4.9 g, 19.7 mrnol). lH NMR (400 MHz, CDC13) o 6.38 (br s, lH ), 5.79 (br s, lH), 5.04 (br d, lH), 4.13 (m, lH), 1.71-1.49 (m, 3H), 1.39 (s, 9H), 0.92 (dd, 6H).

b) N-tert-butu~yc~l,onyl-L-le~in~-thioamide To a stirring solution of the colllpou,ld of Example 8(a) (2.38 g, 10.35 mmol) in dry THF was added Lawessons reagent (2.51 g, 6.21 mmol) and the lulG was stirred at room IC~ dlU1C; under argon ov~rnight The solvent was ev~."aL~d and the residue chro,llalographed (silica gel, 2.5%
methanol/dichlor ~m~th~n~) to give the title cOlllLn~ d as a white solid (2.3 g). IH
20 NMR (400 MHz, CDC13) o 8.54 (br s, lH), 7.97 (br s, lH), 5.28 (br d, lH), 4.52 (m, lH), 1.72-1.58 (m, 3H), 1.40 (s, 9H), 0.92 (d, 6H).

c) ( lS)- l-(tert-butoxycarbonyl)arnino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane The colll~oulld of Example 8(b) (2.40 g, 9.76 mmol) was stirred in dry etonP (20 rnL) under argon at -10~C. Ethylbromc~yluvaLe~ (2.12 g, 10.73 mmol, 1.35 rnL) was added and stirred for 1 h at -10~C. The solution was poured into awell stirred rnixture of chloroform and water and then saturated with sodium bicarbonate. The organic phase was separated and the aqueous layer extracted with 30 chloroform. The combined organic extracts were dried over MgSO4, filtered, and evaporated to an oil. The oily residue was treated with TFAA (2.19 g, 10.73 mrnol, -1.5 mL) and pyridine (1.70 g, 21.47 mmol, 1.75 mL) in dichlorom~th~ne for 1 h at -20~C. Excess solvent was removed in vacuo and the residue was dissolved in dichloromf th~nf The solution was washed with s~tllr~tf -l aqueous sodium bicarbonate and 1.0N KHSO4 until pH 7. The solution was dried over sodium 5 sulfate, filtered, and evaporated to an oil which was chl.~ alographed (4%
methanol/dichloromf~th~nf ) to give the title co,~ ulld as a tan solid (1.2 g). IH
NMR (400 MHz, CDC13) o 7.98 (s, IH), 5.04 (br d, lH), 4.95 (m; lH), 4.31 (q, 2H), 1.88 (m, lH), 1.63 (m, 2H), 1.40 (s, 9H), 1.32 (t, 3H), 0.85 (dd, 6H).

d) (2S,l'S)-2-(benzylu"yc~l,onyl)amino-N-[1'-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-,lwll,yl~ mi~le-The compound of P.x~mple 8(c) (1.0 g, 2.92 mmol) was dissolved in neat TFA (1.0 mL) and stirred for 15 minlltf s The solution was diluted with mf th~nol and evaporated in vacuo. A portion of the residue obtained (0.36 g, 1.49 mmol) was dissolved in dichlc,,u.. ~lh~ne with N-Cbz-L-leucine (0.394 g, 1.49 mmol), BOP
reagent (0.66 g, 1.49 mmol), and triethyl~mine (0.73 g, 7.2 mmol, 1.0 mL) and stirred at room telll~c;ld~ule for 16 h. The solution was washed with water, then brine and dried over m~..f~ .... sulfate, filtered, and ~va~olaL~d to a residue which was chl~lllaL~graphed (silica gel, 40% ethyl acetate/hexane) to give the title co",~und as a white solid (0.396 g). lH NMR (400 MHz, CDC13) o 7.96 (s, lH), 7.25 (s, 5H), 6.61 (br d, lH), 5.30 (m, lH), 5.09 (br d, lH), 5.01 (s, 2H), 4.33 (q, 2H), 4.10 (m, lH), 1.90-1.58 (m, 6H), 1.29 (t, 3H), 0.81 (dd, 12H).

~xample 9 F~ dlion of (2S.l'S)-2-(benzyloxycarbonyl)amino-N-rl'-(4-carboxythiazol-2-yl)-3'-methylbutyll~-mGlhyli)f ~ .l ;ul~mi~1f~
Following the procedure of Example 2, except ~ub~ p (2S,l'S)-2-(benzylo~y~hl,onyl)amino-N-[ l '-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]~-m~lhyl~ .t~n~mi~l~ for (2S,1 'S)-2-(benzyloxycarbonyl)an~ino-N-[1 '-(2-carboxythiazol-4-yl)-3'-methylbutyl]-4-methyl~e.,~ mi~1f, the title compound wasprepared (0.301 g). IH NMR (400 MHz, CDC13) o 8.06 (s, lH), 7.24 (m, 5H), 7.11 W O 97/16433 PCT~US96/~8000 (d, lH), 5.30 (m, 2H), 5.04 (s, 2H), 4.16 (m, lH), 1.88-1.40 (m, 6H), 0.71 (dd, 12H).

Fx~ml?le 10 Preparation of (2S . I '$)-2-(benzylo~yc~l,onyl)amino-N-r 1 '-(4-carboetnoxyt'ni~Ai~7.ol-2-yl)-3'-,l~L'Ilyl~ lyll-4-lllGLllyll~ent~n~mi(1e a) N-tert-lJulo~yc~llollyl-L-leucine methyl ester To a stirring s~lcp~ncion of L-leucine methyl ester hydrocnloride (Aldrich) (6.00 g, 33.0 mmol) and di-tert-butyl dic~l~ollate (7.21 g, 33.0 mmol) in THF (35 mL) was added triethylamine (3.34 g, 33.0 mrnol, 4.60 mL). The llli~Lule was allowed to stir at room telll~eld~ ; for 3 d. The llliX.lUl~ was diluted with ethyl acetate and washed with 1 N HCl (2 times), water, and sa~ aLed brine, then driedover m~Enesillm sulfate, filtered and conc~l,Lldted to give the title compound as a colorless oil (8.02 g, 99%). 1H NMR (400 MHz, CDC13) ~i 4.88 (d, lH), 4.33-4.31 (m, lH), 7.73 (s, 3H), 1.75-1.48 (m, 3H), 1.44 (s, 9H), 0.96 (d, 3H), 0.93 (d, 3H).

b) N-tert-butoxycarbonyl-L-leucine hydrazide To a stirring solution of the compound of Example lO(a) (8.02 g, 32.7 mmol) in methanol (250 rnL) was added hy~ille hydrate (16.38 g, 327 mmol, 15.9 mL). After stirring for 22 h at room LGlll~GldLule, the solution was concentrated and the residue was azeotroped with toluene to provide the title compound as a white foam (8.02 g, 100%). IH NMR (400 MHz, CDC13) o 7.71 (br s, lH), 4.99 (d, 2H), 4.12-4.10 (m, lH), 3.94 (br s, 2H), 1.68-1.49 (m, 3H), 1.44 (s, 9H), 0.9~ (d, 3H), 0.92 (d, 3H).

c) (2S)-N-[2-(benzylo~yc~'vonyl)amino4-mGLllylpentanoyl]-N'-carboetho~,ycall,ollylhydrazide To a stirring solution of the compound of Example lO(b) (8.02 g, 32.7 mmol) and pyridine (2.85 g, 36.0 mmol, 2.91 mL) in dichlorometh~ne (200 mL) was added ethyl oxalyl chloride (4.91 g, 36.0 mmol, 4.02 mL). After stirring at room telllpel~LLIlG for 2 h, thye solution was washed with 1 N HCl, water, saturated aqueous sodium bicarbonate and saturated brine, then dried over m~g...~ ", sulfate, filtered, and concenLldLt;d to afford the title compound as a white foam (9.84 g, 87%). lH NMR (400 MHz, CDC13) ~ 9.32 (br s, 2H), 5.04 (d, 2H), 4.38 (q, 2H), 4.28 (m, lH), 1.77-1.56 (m, 3H), 1.44 (s, 9H), 1.39 (t, 3H), 0.96 (d, 3H), 0.94 (d, 3H)-d) (lS)-l-(tert-buto~y-;~bullyl)amino-1-(4-carboethoxythia~ 7ol-2-yl)-3 methylbutane To a stirring solution of the compound of Example lO(c) (2.50 g, 7.24 mmol) in toluene (70 mL) was added Ldwessoll's reagent (1.46 g, 3.62 mmol). The ~i~lulc; was heated at reflux for 3 h. The solution was diluted with ether, washed with salul~led aqueous sodium bicarbonate and saturated brine, then dried over magnf cium sulfate, filtered and co.-ccnLI~ted to leave a pale yellow oil. The crude mat~ri~l was purified by flash chromatography on 75 g of 230-400 mesh silica gel, eluting with 1:4 ethyl acetate/h~ n~s~ to provide the title compound as a pale yellow solid (1.75 g, 70%). IH NMR (400 MHz, CDC13) ~ 5.19 (m, lH), 5.13 (d, lH), 4.51 (q, 2H), 1.95 (m, lH), 1.83-1.73 (m, 2H), 1.44 (s, 9H), 1.00 (d, 3H), 0.98 (d, 3H).

e) (ls)-l-amino-l-(4-carboethoxyth~ 7ol-2-yl)-3-methylbutane bis-trifluoroacetate salt To a stirring solution of the compound of Example lO(d) (1.75 g, 5.1 rnmol) in dichloromethane (40 mL) was added TFA (10 rnL). After stirring for 5 min at room Lt~ dLule~ the solution was concentrated to give the title co"lpo.l"d as anoily pale yellow solid (2.40 g, 100%). lH NMR (400 MHz, CDC13) ~ 9.83 (br s, 4H), 5.20 (m, lH), 4.51 (q, 2H), 2.07 (m, 2H), 1.70 (m, lH), 1.44 (t, 3H), 1.00 (t, 3H).

f) (2S, l 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(4-carboethoxythia-lia7O1-2-yl)-3'-methylbutyl]-4-mell-yl~el-tan~rnide W O 97/16433 PCT~US96118000 ~

To a stirring solution of the colllpoulld of Example lO(e) (566.1 mg, 1.20 mmol), N-Cbz-L-leucine (250.5 mg, 1.32 rnmol), 1-(3-dimethylaminopropyl)-3-ethylcarbo-liimi~l~ hydrochloride (253.3 mg, 1.32 mmol) and I-hydroxybenzotriazole (32.5 mg, 0.24 mmol) in 2.5 mT of DMF was added S triethylamine (243.1 mg, 2.40 mmol, 0.335 mT) After sti~g at room ~lll~eldlfor 3 d, the llli~Lulc was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and saturated brme, then dried over m~nlocillm sulfate, filtered and cc-nrelltrated to give a yellow oil. The cride m~tf:ri~l was purified by flash chlol,lal~graphy on 20 g of 230-400 mesh silica gel, eluting with 1 :2 ethyl acetate/h~ nPs. to provide the title cwll~Juund as a white solid (271 mg, 46%). lH
NMR (400 MHz, CDC13) o 7.35 (s, SH), 6.77 (d, lH), 5.49 (m, lH), 5.12 (dd, 2H), 4.51 (q, 2H), 4.20 (m, lH), 1.97(m, lH), 1.88 (m, lH), 1.66 (m, 3H), 1.52 (m, lH), 1.45 (t, 3H), 0.97-0.92 (m, 12H).

~xaInple 11 P~ ~dlion of (2S.l'S)-2-(benzyloxy.;dlbollyl)amino-N-rl'-(2-carbo-2.2~2-iflll()roetho~ylllia;~ol-4-yl)-3~-methylbutyll4-methyl~ tA~A~
The colll~oul~d of Fx~n ple 2 (0.200 g, 0.433 mmol), 1,1,1 trifluoroethanol (.052 g, 0.52 mmol, .04 n~), pyridine (0.1 mL), and di-t-butyl dicarbonate (0.104 g, 0.477 mmol) were stirred in ethyl acetate at room telll~e.~lure for 16 h. Thesolution was diluted with ethyl acetate and washed succeccively with 5%
hydrochloric acid, 10% aqueous sodium bicarbonate, and brine. The organic layer was dried over m~.. f ~i.. sulfate, filtered, and evaporated to give a residue which was chromatographed (silica gel, 20 % ethyl acetate/hexane) to give the title com~oul,d as a white solid (.098 g). lH N~ (400 MHz, CDC13) o 7.50 (s, lH), 7.36 (s, SH), 6.64 (d, lH), 5.22 (m, 2H), 5.09 (s, 2H), 4.73 (m, 2H), 4.16 (m, lH), 1.66-1.41 (m, 6H), 0.87 (m, 12H).

- =

W O 97/16433 PCTAJS96/l8000-F.x~mple 12 ~a,alion of (2S.l'S)-2-(benzyloxycarbonyl)amino-N-rl'-(4-carboethoxyoxadiazol-2-yl)-3'-methylbutyll4-1llelhyl~ "~.-.icle a) ( 1 S)- 1 -(tert-butokycall,onyl)amino- 1 -(4-carboethoxyo~ 7O1-2-yl)-3-mel}lylbuL~-e To a stirring solution of the compound of Exarnple lO(c) (2.50 g, 7.24 mmol) and pyridine (1.49 g, 18.8 mmol, 1.52 mL) in ether (15 mL) was added thionyl chloride (1.12 g, 9.41 rnmol, 0.69 mL). After stirring at room l~;1U~;1dLU1t;
for 2 h, the solid was removed by filtration and the filtrate was conc;e~ aL~d. The residue was dissolved in toluene and heated at 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 witX 1:4 ethyl acetate/hexanes, to give the title compund as a pale yellow oil (0.84 g, 35%). lH
NMR (400 MHz, CDC13) o 5.14 (m, lH), 5.03 (br d, lH), 4.52 (q, 2H), 1.78-1.70 (m, 3H), 1.44 (s, 9H), 0.99 (d, 6H).

b) (lS)-1-amino-1-(4-carboethoxyoxadiazol-2-yl)-3-methylbutane Following the procedure of Flr~mrle lO(e), except sllb~ il.g (lS)-l-(tert-l~uto~ycalbollyl)arnino-l-(4-carboethoxyox~ c 1-2-yl)-3-methylbutane for (lS)-l-(tert-buto~yc~ubollyl)amino-1-(4-carboethoxythi~ 7~-1-2-yl)-3-methylbutane, the title compound was pl~al~,d (582 mg, 100%). lH NMR (400 MHz, CDCl3) o 4.99 (t, lH), 4.52 (q, 2H), 2.10-2.02 (m, 2H), 1.77-1.70 (m, lH), 1.44 (t, 3H), 1.00 (t, 6H).

c) (2S,1'S)-2-(benzylo~Lyc~l,onyl)amino-N-[1'-(4-carboethoxyox~ 7ol-2-yl)-3'-methylbutyl]~-mt:~lyl~ mide Following the procedure of Fx~mple lO(f), except ~ub~ .l;..g (lS)-1-~mino-l-(4-carboethoxyox~di~7ol-2-yl)-3-methylbutane for (lS)-l-amino-1-(4-carboethoxythi~ 7Ol-2-yl)-3-methylbutane, the title compound was prepared (235 mg, 39%). lH NMR (400 MHz, CDCl3) o 7.26 (s, 5H), 6.64 (s, lH), 5.45-5.39 (m, W o 97/16433 PCT~USg6/18000 ~

lH),5.12(m,3H),4.52(q,2H),4.20(m,lH),1.81(m,2H),1.68-1.64(m,3H), 1.54-l.50(m,lH),1.46 (t, 3H),0.97-0.92(m,12H).

F.x~nn~le 13 5 Plc~dtion of (2S.l'S)-2-(benzylo~yc~bol,yl-L-leucinyl)~mino-N-rl'-(4-ocL~lo~yllliazo~-2-yl)-3l-methylbutyll4-lllcLlly~ lt~ mi~le The compound of F.~zmple 8(c) (160.7 mg, 0.47 mmol) was dissolved in neat TFA (1.0 mL) and stirred for 15 minllt~s. The solution was diluted with m-o.th~nol and evaporated to dryness. The residue was dissolved in DMF (2 mL) and to the re.sllltin~ solution was added N-Cbz-L-leucinyl-L-leucine (194.0 mg, 0.52mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric:l~ (99.0 mg, 0.52 mmol) and l-hydro~yl,~,l~otliazole (13.0 mg~ 0.094 rnmol) and triethylamine(94.7 mg, 0.936 mmol, 0.13 mL). After stirring at room tell~ lulc for 24 h, the ll~LY.lulc was diluted with ethyl acetate and washed with water, saturated aqueous 15 sodium bicarbonate and saturated brine, then dried over m~e.~ . sulfate, filtered and cc.ncc-lLldlcd. The residue was purified by flash cl~c~lllaLography on 230 100 mesh silica gel, eluting with ethyl acetate/h~nPs, to provide the title compound(0.146 g). lH ~nMDR(400 ~DHz,CDC13)~ 8.04(s,lH),7.33(m,5H),7.14 (d, lH), 6.61 (d, lH), 5.37 (m, 2H), 5.08 (m, 2H), 4.47 (m, lH), 4.39(q,2H),4.18 (m, lH),1.98-1.45(m,9H),1.38 (t, 3H),0.94-0.86 (m, 18H).

F.x~mple 14 Pl~ ion of (2S.l'S)-2-(benzyl~Lye~bonyl)amino-N-rl'-(4-çarboxarnidoox~ 7ol-2-yl)-3~-methylbutyll~me~hyl~,e~ d~
,~Ammoni~ was bubbled through a solution of the co~ .oul,d of Example 12 (96.8 mg, 0.2 mmol) in ethanol (2 mL) for S inm. After stirring an additional S
min, the solution was concentl dted to give the title compound as a white solid (91.2 mg, 98%). lH N M R (400 M Hz,CDC13/CD30D)o7.29(s~SH),5.90 (d, lH), 5.30 (t, lH), 5.04 (s, 2H), 4.15 (m, lH), 1.76 (m, 2H), 1.59-1.43(m,4H),0.92-0.85 (m, 12H).

F.xample 15 ~aLion of (2S.l'S)-2-(benzylo~ycal1,onyl)amino-N-rl'-(2-carboethoxythiazol-4-yl)-3~-methylbutyll-3-phe~lyl~,lu~ m~
a) N-(9-fluorenylmethoxycarbonyl)-L-leucinyl bromnm~thyl ketone Following the procedure of Example l (a), except ~ubsl i ~ g N-(9-fluor.,.lyl.llellloxyca.l,ollyl)-L-leucine for N-benzyloxycarbonyl-L-leucinyl-L-leucine, the title compound was p epaL~d (5.6 g). lH NMR (400 MHz, CDC13) o 7.71 (d, 2H), 7.51 (d, 2H), 7.34 (dd, 2H), 7.22 (dd, 2H), 5.08 (d, lH), 4.53 (m, lH), 4.36 (dd, 2H), 4.13 (dd, 2H), 3.89 (dd, 2H), 1.62-1.41 (m, 3H), 0.88 (m, 6H).
b) ( 1 S)- 1 -(2-carboethoxythiazol4-yl)- 1 -(9-flu~lGllyll--t;lhoxyc~l~onyl)amino-3-methylbutane Following the procedure of Fx~mrle l(b), except ~ ul;l.g N-(9-fluo~ y~ oxyca~l~onyl)-L-leucinyl l~ cthyl ketone for N-Benzyloxyc~bonyl-L-leucmyl-L-leucinyl bromc.lll~Lllylk~ton~, the title col~ll,oulld was L)l~ d (4.13 g). lH NMR (400 MH[z, CDC13) ~i 7.72 (d, 2H), 7.49 (d, 2H), 7.32 (dd, 2H), 7.22 (dd, 2H), 7.19 (s, lH), 5.31 (d, lH), 4.88 (m, lH), 4.40 (q, 2H), 4.28 (d, 2H), 4.08 (t, lH), 1.62-1.41 (m, 3H), 1.36 (t,3H), 0.88 (m, 6H).

c) ( 1 S)- 1 -amino- 1 -(2-carboethoxythiazol-4-yl)-3-methylbutane The cc,~ oulld of Example l5(b) (0.5 g., 1.1 mmol) was stirred in a 5%
piperidine/DMF solution for 10 minlltes at room telll~el~Lur~. The solvents wereevaporated and the solid obtained was dried in vacuo to give the title compound (0.27 g).
d) (2S, l'S)-2-(benzylo~yc~l,onyl)amino-N-[ 1 '-(2-carboethoxythiazol~-yl)-3'-methylbutyl] -3 -phellyl~iolJ~ n ~ . . . i ~le Following the procedure of F.x~mp]e 5, except s~lb~ g (lS)-l-amino-l-(2-carboethoxythiazol~-yl)-3-methylbutane for benzylamine, and N-Cbz-L-phenyl~l~nine for (2S,l'S)-2-(benzylo~yc~bonyl)amino-N-[1'-(2-carboxythi~ol4-yl)-3'-methylbutyl]~-methyll,r,-~ mi~le, the title compound was prepared (0.162 W O 97/16433 PCT~US96/18000 -g). IH NMR (400 MHz, CDC13) o 7.27 (m, SH), 7.11 (s, lH), 7.04 (m, SH), 6.12 (d, lH), 5.24 (d, lH), 5.10 (q, lH), 5.01 (s, 2H), 4.37 (q, 2H), 4.21 (m, lH), 2.91 (m, 2H), 1.62 (m, 3H), 1.37 (t, 3H), 0.81 (m, 6H).

Fxample 16 Preparation of (2S.1'S)-2-(benzyloxyc~l,ollyl-L-leucinyl)amino-N-~1'-(2-.l~o~lhoxythi~7~nl-4-yl)-3~-methylbutyl~4-mellly~ )t~n~ e Following the procedure of Example 5, except sub~ (lS)-l-amino-l-(2-carboethoxythi~ol-4-yl)-3-methylbutane for benzylaTnine, and N-Cbz-L-leucinyl-L-leucine for (2S,l'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-carboxythiazol~yl)-3'-methylbutyl]-4-1lwlllylpe~ iC'ie7 the title compound was ~ed (0.098 g.). lH NMR (400 MHz, CDC13) o 7.39 (s, lH),-7.25 (m, SH), 6.87 (d, lH), 6.49 (d, lH), 5.30 (d, lH), 5.16 (q,lH), 4.99 (s, 2H), 4.36 (q, 2H), 4.31 (m, lH), 4.09 (m, lH), 1.74-1.38 (m, 9H), 1.32 (t, 3H), 0.80 (m, l5H).
F.xample 17 P~ lion of (2S.l'S)-2-(benzyloxycd,bollyl)amino-N-rl'-(S-mercapto-1.2.4-oxadi~ol-3-yl)-3~-methylbutyll4-me~lly~ m~
a) N-benzylo~yc~hl,ol~yl-L-leucinyl-L-leucine methyl ester N-Cbz-L-leucine (l~h~o.mic~l Dynamics) (1.32 g, 4.97 mmol), L-leucine methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 mmol), l-hydroxybenzotri~ole (0.14 g, 1.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 1.05 g, 5.47 mmol) were colllbined, dissolved in 25 mL of DMF and stirred at room telll~el~ture for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed succes~; vc;ly with water, 0.1 N HCl, saturated aqeous NaHCO3 and saturated brine, then dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, elutingwith 1:3 ethyl acetate h~.x~n~c, to give the title compound as a white solid (1.28 g, 66%). lH NMR (400 MHz, CDC13) o 7.37-7.32 (m, 5H), 6.28 (d, lH), 5.28 (m, 3H), 4.61-4.58 (m, lH), 4.20 (m, lH), 3.74 (s, 3H), 1.69-1.54 (m, 6H), 0.96-0.92(m, 12H).

b) N-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide To as stirring solution of the compound of Example 17(a) (1.28 g, 3.26 mmol) in 25 mT. of mf~th~n~l was added hydrazine hydrate (1.63 g, 32.6 mmol, 1.58 mL) and the solution was allowed to stir at room ~C~ dLulc for 15 h. The solution was eva~ aled to dryness to give the title compound as a white solid (1.28 g, 100%). lH NMR (400 MHz, CDCl3) ~ 8.05 (br s, lH), 7.35-7.32 (m, SH), 6.67 (d, lH), 5.50 (d, lH), 5.11 (s, 2H), 4.46 (m, lH), 4.21 (m, lH), 3.88 (br s, 2H), 1.64-1.51 (m, 6H), 0.92-0.88 (m, 12H).

c) (2S,l'S)-2-(benzylc,,,y~ ,ollyl)amino-N-[l'-(S-mercapto-1,2,4-ox~di~ol-3-yl) 3'-methylbutyl~4-mclllyl~?e~ ,I;.nslmi~l~
To a stirring solution of the compound of T;.x~mple 17(b) (0.3 g, 0.76 mmol) in 1.5 mT of chloroform was added triethylamine (0.155 g, 1.53 mmol, 0.213 mL) and thiophosgçn~ (0.088 g, 0.76 mmol, 0.058 mL). The solution was heated at reflux for 3 h, then cooled to room Lclll~e.dture. The llli;LlUl'C was diluted with ethyl acetate, washed with water and salulated brine, dried (MgSO4), filtered, and conce~ ated. The residue was purified by flash cl.. .,maLography on 230-400 meshsilica gel, eluting with 11% mtoth~n~l in dichlor~ n~, to give the title c~ und as a white solid (0.20 g, 61%). lH NMR (400 MHz, CDCl3) S 7.36 (m, 6H), 6.85 (d, lH), 5.37 (d, lH), 5.14 (m, 3H), 4.24 (m, lH), 1.65 (m, 6H), 0.95-0.87 (m, 12H).

W O 97/16433 PCT~US96/18000 -E~xample 18 P~ ~ion of (2S.l'S)-2-(benzyloxycall~ol"~l~arnino-N-rl'-(2-mell;a~Lc,Llliazol-4-yl)-3~-methylbutyll-4-methylpent~n~mide The compound of Example l (a) ( 1.0 g, 2.2 mmol) and ~mmo~ m S dithioca,b~-late (0.25 g., 2.2 mmol) were dissolved in ethanol and heated to 55~C
for 13 hours. The solvent was evaporated and the residue chromatographed (silicagel, 20% ethyl acetate/hexane) to give the title compound as a white solid (0.58 g).
lH NMR (400 MHz, CDC13) ~ 7.24 (m, 5H), 7.10 (s, lH), 6.33 (s, lH), 6.00 (d, lH), 5.11 (q, 2H), 4.94 (m, lH), 4.05 (m, lH), 1.49 (m, 6H), 0.78 (m, 12H).
Fx~ le 19 PlG~ ion of (2S)-2-(benzyloxyc~hl,ollyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4-lllGlllyl~e~ m a) 1 -(tert-butoxyc~bo..yl)amino- 1 -(4-carboethoxythiazol-2-yl)mt~th~n~
Following the procedure of F.x~mplt- 8(a)-8(c), except ~ul)slil.. l;.. ~ N-tert-~u~yc~l~onylglycine for N-tert-butu~Lyc~'L onyl-(L)-leucine in step (a), the title co..l~,u..d was ~lG~ d (1.9g, 58% overall). lH NMR (400 MHz, CDC13) o 8.11 (s, lH), 5.31 (s, lH), 4.56 (d, 2H), 4.43 (q, 2H), 1.45 (s, 9H), 1.42 (t, 3H).

b) (2S)-2-(benzylo~y~;~l,ollyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4-lllGL~lylll~l~t:lnz~m~
Following the procedure of Fx~mple 13, except ~ub~ 1-(tert-buLoxyc~h'L onyl)arnino- 1 -(4-carboethoxythiazol-2-yl)m~th~ne for ( 1 S)- 1 -(tert-buto~ycallJollyl)amino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-25 L-leucine for N-Cbz-L-leucinyl-L-le~cin~, the title c~ ou.ld was prepared (0.120g, 32%). MS (MH+): 434.2.

W O 97/16433 PCT~US96/18000 -Px~n~le 20 F'lc~a.alion of (2S.l'S)-2-(benzylo~yc~l,onyl)amino-N-rl'-(2-b~n7~ylo~Lyc~l~onylthi~ol-4-yl)-3~-methylbutyll-4-lllcLllyll~e~ am~
The compound of P~mple 2 (0.105 g., 0.22 mmol) was dissolved in 5 dichlorom~fh~n~ and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbo-liimi-le methiodide (0.062 g., 0.22 mmol) and benzyl alcohol (0.03 mL, 0.22 mmol). The ulc was allowed to stir at room telll~eldlulc for 4 hours and the solvents were evaporated and the residue obtained was cheromatographed ( silica gel, 30% ethylacetate/ hexane) to give the title co~ oulld as a white solid (0.04 g). lH NMR (400 MHz, CDC13) ~ 7.37 (s, lH), 7.26 (m, lOH), 6.50 (d, lH), 5.33 (s, 2H), 5.11 (q, 2H), 5.09 (m, lH), 4.99 (s, 2H), 4.04 (m, lH), 1.49 (m, 6H), 0.78 (m, 12H).

l~x~ le 21 ~ ,~dlion of (2S. 1 'S)-2-(benzyloxycarbonyl)amino4-methyl-N-r3'-methyl- 1'-(2-pheno~yc~l~ul~ylLlliazol4-yl)butyll~,e~ e Following the procedure of FY~mrle 20, except s~lh~ g phenol for benzyl alcohol, the title compound was plcpdl~,d (0.075 g). lH NMR (400 MHz, CDCl3) o 7.41 (s, lH), 7.26 (m, lOH), 6.49 (d, lH), 5.20 (m, lH), 5.04 (m, lH), 5.00 (s, 2H), 4.08 (m, lH), 1.49 (m, 6H), 0.82 (m, 12H).
Fx~nn~]?le 22 Pl~aldLion of (2S. 1 'S)-2-(benzyloxycarbonyl)arnino-4-methyl-N-r3'-methyl- 1 '-r2-(2-mGLhyl~lu~!yloxycarbonyl)thiazol4-yllbutyll~ le Following the procedure of Example 20, except ~ub~ isobutyl alcohol for benzyl alcohol, the title compound was prepared (0.075 g). lH NMR (400 MHz, CDC13) ~ 7.25 (m, 6H), 6.50 (d, lH), 5.11 (q, 2H), 5.09 (m, lH), 4.99 (s, 2H), 4.11 (d, 2H), 3.91 (m, lH),2.02 (m, lH), 1.70- 1.39 (m, 6H), 0.82 (d, 6H), 0.78 (m, 12H).

W O 97/16433 PCT~US96/18000 -~x~m,ple 23 Pre~aration of (2R~ 1 'S)-2-(benzyloxycarbonyl)aminQ-N-r 1 '-(4-carboethoxythia~ol-2-yl)ethyll-4-methylL,el-tan~n~ide Following the procedure of Example 19, except subs~ i.7g N-tert-butoxycarbonyl-L-alanine for N-tert-butoxycarbonylglycine in step (a), and N-Cbz-D-leucine for N-Cbz-L-leucine in step (b), the title compound was ~l~paled as white solid (0.135g, 36%). MS (MH+): 448.2.

F"~amrle 24 Ple~dtion of (2R.l'R)-2-(benzylo~yc~l,onyl)amino-N-rl'-(4-carboethoxvthia7ol-?-yl)ethyll~1-methylp~
Following the procedure of Example 19, except ~ub~ i.ig N-~e~-l,uLokycalL ol-yl-D-alanine for N-~ert-butoxycarbonylglycine in step (a), and N-Cbz-D-leucine for N-Cbz-L-leucine in step (b), the title compound was p,epa -,d as white solid (0. l lOg, 29%). MS (MH+): 448.2.

Fxample 25 nl ;on of (2S.1 ~s)-N-rl '-(2-aminothiazol-4-yl)-3'-methylbutyll-2-(ben7ylo~yc~1.onyl)amino-4-mGll,yl~e~lal~ami(l~
To a stirring solution of the compound of Fxample l(a) (0.85 g, 1.87 mmol) in 4 mL of ethanol was added thiourea (0.142 g, 1.87 mmol). The solution was allowed to stir at room telll~GldlulG for 90 _in. The solution was concelllldtGd, the residue was dissolved in ethyl acetate and washed with saturated aqeous NaHC03 and saturated brine, then dried (MgSO4), filtered, and concG~ dled. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1: 1 ethyl acetate/hexanes, to give the title compound as a white solid (0.64 g, 78%). IH
NMR (400 MHz, CDCl3) ~ 7.36 (m, SH), 6.30 (m, 2H), 5.12 (m, 3H), 4.95-4.91 (m, 3H), 4.16 (m, lH), 1.63 (m, 4H), 1.49 (m, 2H), 0.93-0.89 (m, 12H).

=

~xample 26 ~ alion of ( l S)-N-r4-r( l -benzyloxycarbonylamino)-3-methylbutyllthi~ol-2-ylc~l,onyll-N'-(N-benzyl~ yc~l,onyl-L-leucinyl)hydrazide a) N-benzyl~ycdll.onyl-L-leucinyl brom~ .yl ketone S l-methyl-3-nitro-l-nitrosogu~ni~1ine (6.65 g, 45.2 mmol) in ether (225 mL) is cooled to 0~C. 40% sodium hydroxide is added slowly and the r~i~7om.oth~n~ isallowed to collect in the ether solution for 30 minlltes at 0~C. The ether solution is then ~ nt~(l and left at 0 ~C.
N-Cbz-L-leucine (2.10 g, 7.6 mmol) was dissolved in THF (10 mL), cooled to -40 ~C, and 4-methylmorpholine (0.77 g, 7.6 mmol, 0.83 mL) was added, followed by dropwise addition of isobutyl chloroformate (1.04 g, 7.6 mmol, 0.98 mT ). After 15 min, the solution was filtered into the previously prepared 0 ~C
solution of ethereal ~ 7om~th~n~ The reslllting 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 resl~ltin~ solution was st~ITed at 0 ~C for 5 min, t_en washed sequentially with 0.1 N
HCl, salu.aL~d aqueous NaHCO3 and saturated brine, then dried (MgSO4), filtered and concentrated to give the title compound as a colorless oil (2.43 g, 94%).

b) ( 1 S)- 1 -benzyloxycarbonylamino- 1 -(2-carboethoxythiazol-4-yl)-3-methylbutane A solution of the co.ll~oulld of F~mrle 26(a) (1.57 g, 4.58 mmol) and ethyl thioo~c~m~te (0.61 g, 4.58 mmol) in ethanol (10 mL) was heated at reflux for 4 h.
The solution was then cooled, concelllldled and the residue was purified by flash cl~vlll~tography on 230-400 mesh silica gel, eluting with 1:4 ethyl acetate/hexanes, to give the title colll~oulld as a yellow oil (1.0 g, 58%). H NMR (400 MHz, CDC13) o 7.41 (s, lH), 7.34-7.31 (m, SH), 5.40 (d, lH), 5.10 (d, lH), 5.05 (d, lH), 4.98 (q, lH), 4.48 (q, 2H), 1.80-1.76 (m, 2H), 1.57-1.53 (m, lH), 1.44 (t, 3H), 0.95 (d, 3H), 0.93 (d, 3H).

W O 97/16433 PCT~US96/18000 ~

c) (lS)-l-benzyloxycarbonylamino-1-(2-hydrazinocarbonylthiazol-4-yl)-3-methylbutane A solution of the compound of Example 26(b) (0.30 g, 0.8 mmol) and llydldzille hydrate (0.40 g, 8.0 mmol, 0.39 rr-T ) in ethanol (8 mL) was allowed to stir at room IC1111J~,dLU1'C for 2 h. The solution was then concentrated to yiel~ the title compound as a white foam (0.28 g, 98%). H NMR (400 MHz, CDC13) â 8.29 (s, lH), 7.37-7.35 (m, 5H), 5.18 (d, lH), 5.09 (dd, 2H), 4.95 (q, lH), 4.07 (d, 2H), 1.71 (t, 2H), 1.55 (m, lH), 0.96 (d, 3H), 0.94 (d, 3H).

d) (lS)-N-[4-[(1-benzylo~yc~bollylamino)-3-1llcLllylbulyl]thi~ol-2-ylcarbonyl3-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide A solution of the compound of F.x~mrle 26(c) (100 mg, 0;28 mmol), N-Cbz-L-leucine (80.5 mg, 0.30 mmol), 1-(3-dilllGI~lylaminopropyl)-3-ethylcarbo-liimi-le hydrochloride (58.2 mg, 0.30 rnmol) and l-hydro~ybenzotl;azole (7.5 mg, 0.06 mmol) in DMF (0.6 mmol) was allowed to stir at room lem~eldll~lc for 18 h. The solution was diluted with ethyl acetate and washed succçs~i~cly with water, 0.1 N
HCl, sdLuld~ed aqueous NaHCO3 and ~dLuldted brine, then dried (MgSO4), filtered and con~e~ dtcd. The residue was purified by flash chromatography on 230400 mesh silica gel, eluting with 1: 1 ethyl acetate/h~Y~n~s, to provide the title compound as a white solid (111.4 mg, 66%). mp 110-112 ~C.

Fx~ml?le 27 Pl~ dLion of N-benzylo~ycall,o,lyl-L-leucinyl-N'-benzyloxyc~lJol,yl-L-leucinyl-T -leucinylhydrazide a) N-benzyloxyc~l,ol,yl-L-leucinyl-L-leucine methyl ester Following the procedure of Flr~mple 26(d), except L-leucine methyl ester hydrochloride for ( I S)- 1 -benzyloxycarbonylamino- 1 -(2-hydrazinoca,l,onylthiazol-4-yl)-3-methylbutane, the title compound was ~lepa.cd as a white solid (1.28 g, 66%). H NMR (400 MHz, CDC13) o 7.37-7.32 (m, SH), 6.28 (d, lH), 5.28 (m, 3H), 4.61-4.58 (m, lH), 4.20 (m, lH), 3.74 (s, 3H), 1.69-1.54 (m, 6H), 0.96-0.92(m, 12H).

, W O 97/16433 PCT~US96/18000 ~

b) N-benzylo~yc~l,~llyl-L-leucinyl-L-leucinylhydrazide Following the procedure of F~mple 26(c), except subsl ;~ g N-benzylo~yca~l~onyl-L-leucinyl-L-leucine methyl ester for (lS)-l-5 benzyloxycarbonylamino-1-(2-carboethoxythiazol4-yl)-3-methylbutane, the title compound was prepared as a white solid (1.28 g, 100%). H NMR (400 MHz, CDCl3) ~ 8.05 (br s, lH), 7.35-7.32 (m, SH), 6.67 (d, lH), 5.50 (d, lH), 5.11 (s, 2H), 4.46 (m, IH), 4.21 (m, lH), 3.88 (br s, 2H), 1.64-1.51 (m, 6H), 0.92-0.88 (m, 12H).

c) N-benzylo~yc~l,onyl-L-leucinyl-N'-benzyloxyc~lJollyl-L-leucinyl-L-leucinylhydrazide Following the procedure of Example 26(d), except sub~ g N-benzylo~yc~bo,lyl-L-leucinyl-L-leucinylhydrazide for (lS)-l-15 benzylo~yc~l,ollylamino-1-(2-llyd,d~illoc~l,ollylthiazol4-yl)-3-methylbutane, the title colllyou,Ld was prepared as a white solid (0.059 g). MS (M+Na'): 662.1 Example 28 hdLion of (lS)-N-r2-r(l-benzylo~yc~b~ vlamino)-3-methylbutyllthiazol~
20 ylcalbvllyll-N~-(N-benzylo~yc~bollyl-L-leucinvl)hydrazide a) N-tert-l,uLo~yc~l~o,lyl-(L)-l~urin~mi~le To a solution of N-tert-butoxycarbonyl-(L)-leucine (7.0g, 28. lmmol ) in dry THF(lOOmT) at -40~C was added isobutylchloroforrnate (3.8g, 28.1mmol) and N-lll~tllyl..lorphiline (6.0, S9mmol). After 15 minllt~s of stirrin~, a~ rol~ia was 25 bubbled through the Illi~lule for an additional 15 minntes, then warmed to room temperature and allowed to stir for 2 hours. Mixture filtered and filtrate ~ c-)n~ . ate~l in vacuo to yield title compound as a white solid (6.5, 28.0mmol).
IHNMR (400MHz, CDCl3) o 6.38 (br s, lH), 5.79 (br s, lH), 5.04 (br d, lH), 4.13 ~ (m, lH), 1.71-1.49 (m, 3H), 1.39 (s, 9H), 0.92 (dd, 6H).

W O 97/16433 PCT~US96/18000-b) N-tert-buto~yc~l~ollyl-(L)-leucinethioamide To a stirring solution of the compound of Example 26(a) (6.5, 28.0 mmol) in dry THF was added Lawesson's reagent (6.8g, 16.9 mmol) and the mixture was stirred at room temperature under argon overnight. The solvent was ev~l~olated and 5 the residue chromatographed (silica gel, 12% ethyl acetateAlexane) to give the title compound as a white solid (5.4g, 77%). 'HNMR (400MHz, CDCl3) o 8.54 (br s, lH), 7.97 (br s, lH), 5.28 (br d, lH), 4.52 (m, lH), 1.72-1.58 (m, 3H), 1.40 (s, 9H), 0.92 (m, 6H).

10 c) (15)-1-(tert-butoxyc~l,o,lyl)amino-1-(4-carboethoxythiazol-2-yl)-3-meLhyll~ukule The compound of Example 26(b) (5.4g, 21.7 mmol) was stirred in dry acetone (lOOmL) under argon at -10~C. Ethyl~ lu~yluv~Le (4.7g, 23.9mmol) was added and stirred for lh at -10~C. The solution was poured into a well stirred 15 l~ ul~, of chlo,~follll and water and then into salulaLed sodium bicarbonate solution. The organic phase was sei>~aled and the aqueous layer extracted with chloroform. The combined organic extracts were dried over MgS04, filtered and conrentrated to an oil. The oily residue was treated with TFAA (5.0g, 23.9mmol) and pyridine (3.8g, 47.8mrnol) in dichlorom~th~nl for lh at -20~C. Excess solvent 20 was removed in vacuo and the residue was dissolved in dichloromethane. The soll-tiorl was washed with saturated aqueous sodium bicarbonate and l.ON KHSO4 until pH 7. The solution was dried over m~gn~Sillm sulfate, filtered and concentlaled to an oil which was chromatographed (silica gel, 7.5% ethyl acetate/hexane) to give the title compound as a tan solid (4.5g, 61%). 'HNMR
25 (400MHz, CDCl3) ~ 7.98 (s, lH), 5.04 (br d, lH), 4.95 (m, lH), 4.31 (q, 2H), 1.88 (m, lH), 1.63 (m, 2H), 1.40 (s, 9H),1.32 (t, 3H), 0.85 (dd, 6H).

d) (1 S)- 1 -(Benzyloxycarbonyl)amino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane The compound of F~mI~le 26(c) (0.250g, 0.73 lmmol) was dissolved in 30 TFA (2mL) and stirred at room temperature for 15 minutes when diluted with methanol and concentrated in vacuo. The residue was dissolved in methylene chloride and treated with triethylamine (0.739g, 7.31rnmol) followed by benzyl chloroformate (1.2g, 7.3 lmmol). The solution stirred at room temperature for 2hwhen partition bCIV~ ethyl acetate/water. The organic layer was washed with brine, collected, dried (MgSO4) and c-)n-~lontr~te-l to a residue that was 5 cl~ullla~graphed (silica gel, 15% ethyl acetate/hexane) to give the title compound as an oil (0.198g, 72%). 'HNMR (400MHz, CDCl3) ~ 8.01 (s, lH), 7.32 (m, SH), 5.51 (br d, lH), 5.14 (m, lH), 5.10 (s, 2H), 4.37 (q, 2H), 1.93 (m; lH), 1.81-1.67 (m, 2H), 1.39 (t, 3H), 0.95 (m, 6H).

e) (1 S)-N-[2-t(1 -benzylo~yc~bollylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-(N-benzyloxyc~l,ul.yl-L-leucinyl)hydrazide Following the procedure of F.x~rnple 26(c)-l(d), except sul,~lil..li,-g (lS)-l-(Benzylo~yc~bonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane for (lS)-l-benzyloxycdll,uuylamino-1-(2-carboetho~yLlliazol-4-yl)-3-methylbutane in step (c), the title compound was ~l~alcd. MS (MH+): 610.0 F.x~rn]?l~ 29 F'l c~al dlion of 2.2 '-(N.N'-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide To a stirring solution of N-Cbz-L-leucine (Ch~ l Dynamics Corp.) (2.94 g, 11.1 mmol) in 22 mL of DMF was added carbohydrazide (0.5 g, 5.6 mmol), 1-(3-dimethyl~l,.nc~lu~yl)-3-ethylcarbc-liimi(le hydrûchloride (2.13 g, 11.1 mmol) and l-hydroxyben70tri~701e (0.3 g, 2.2 mmol). After stirring at room telll~el~Lul~ for 22 h, the solution was poured into 500 mL of water. The ~.~ci~iL~Le was coll~ct~l by vacuum filtration and washed with water (4 X 150 mL) and dichloromloth~ne (4 X 150 mL), then dried under vacuum to provide the title compound as a white solid (1.49 g, 46%). MS(ESI): 607.1 (M+Na)+.

W O 97/16433 PCT~US96/18000 Fxample 30 rre~?~dlion of 2.2'-(N.N'-bis-cyclohexylacetyl)carbohydr~7ir~
Following the procedure of Fx~mrle 29, except ~ukstit-lting cyclohexylacetic acid for N-Cbz-L-lellcine, the title compound was prepared (0 410 g, 73%). MS(ESI): 339.3 (M+H)+.

Fxan~le 31 P'r~ lion of 2.2'-(N.N'-bis-4-methylpentanoyl)carbohydrazide Following the procedure of Fx~mple 29, except sub~lil..li. g 4-10 lll~lhyl~e~ oic acid for N-Cbz-L-l~-urin~o, the title cc,~ olllld was ~lc~a,~d as a white solid (0.212 g, 44%). MS(ESI): 287.3 (M+H)+.

F~c~rnple 32 Pl~a.dlion of 2.2'-(N.N'-bis-2-cyclopentylacetyl)carbohydrazide Following the procedure of Exarnple 29, except sub~
cyclopentylacetic acid for N-Cbz-L-leue-in~, the title compound was ~ ~al~d as awhite solid (0.345 g, 67%). MS(ESI): 311.2 (M+H)+.

F.x~mE~l~ 33 20 P~ dli~m of 2.2'-(N.N'-bis-benzyloxyc~l~ ylglych~yl)carbohydr~ide Following the procedure of Example 29, except sub~tit--ting N-Cbz-Glycine for N-Cbz-L-leucine, the title compound was ~.epa ed as a white solid (0.719 g, 91%). MS(ESI): 473.1 (M+H)+.

Fx~nl~?le 34 udLion of 2.2'-(N.N'-bis-acetyl-L-leucinyl)carbohydr~ide Following the procedure of Example 29, except substihlting N-acetyl-L-leucine for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.153 g, 23%). MS(ESI): 401.3 (M+H)+.

Example 35 P~ ,~dLion of 2.2'-(N.N'-bis- benzyloxycarbonyl-L-alanyl~carbohydrazide Following the procedure of Example 29, except sub~ g N-Cbz-L-alanine for N-Cbz-L-leucine, the title co~ ound was prepared as a white solid (0.762 g, 91%). MS(ESI): 501.1 (M+Hj'.

E~xample 36 r~ ation of 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-rN~-(4-. . .1~l h .yl~l~ oyl)lcarbohydrazide a) N-benzyl~ yc~l,ollyl-L-leucine methyl ester To a solution of leucine methyl ester hydrochloride (5.0 g, 27.5 mmol) in 1,4-dioxane (50 mL) was added sodium carbonate (30.3 mL, 2M in water) followed by benzyl chloroformate (4.69 g, 27.5 mmol). The mixture stirred at room telll~ dlulc for 24 hours when partitioned between ethyl acetate and water. The organic layer was collected, dried (MgSO4), filtered and concentrated to give the title compound as a colorless oil (7.67 g, 100%). 'HNMR (400MHz, CDCl3) ~ 7.39 (m, SH), 5.38 (d, 2H), 5.12 (s, 2H), 4.42 (m, lH), 3.75 (s, 3H), 1.73 - 1.50 (m, 3H), 0.94 (m, 6H).

b) N-benzylokyc~l,onyl-L-leucinyl hydrazide To a solution of the compound of Example 36(a) (7.67 g, 27.5 mmol) in m~th~nol (40 mL) was added hyLd~i,le monohydrate (13.5 g, 270 mmol). The solution was stirred at room lelll~e,dture for 24 hours when partitioned betweenwater and ethyl acetate. The organic layer was coll~ct~-l, dried (MgSO4), filtered and concenL,a~d to give the title compound as an off-white solid (7.67 g, 100%).IHNMR (400MHz, CDCl3) ~ 8.14 (s, lH), 7.38 (m, SH), 5.64 (d, lH), 5.09 (dd, ~ 2H), 4.20 (m, lH), 3.81 (s br, 2H), 1.69 - 1.51 (m, 3H), 0.92 (dd, 6H).

c) l-benzyloxycarbonylamino-3-methyl-1-(1,3,4-o~ 7.Ql-2-onyl)butane A solution of the compound of Example 36(b) (1.0 g, 3.58 mmol) in methylene chloride ( 12mL) was added dropwise to a solution of 4-W O 97/16433 PCTnUS96/18000 -nitrophenylchlo;oformate (0.361 g, 1.79 mmol) in methylene cnloride (8 mL) at 0~C. The solution warmed to room tt;~ e.dLul~ and stirred for one hour when partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaHCO3 then collected, dried (MgSO~), filtered and conce~ dled to a S residue which was chromatographed (20% ethyl acetate/hexane) to give the title compound as a pale yellow solid (0.322 g, 59%). 'HNMR (400MHz, CDCl3) ~ 9.18 (s, lH), 7.38 (m, SH), 5.13 (m, 3H), 4.79 (m, lH), 1.71 (m, 3H), 0.98 (dd, 6H).

d) 4-melhyl~elltanoyl hydrazide Following the procedure of F.xample 36(b) except sub~ g ethyl isocaproate for benzyl~yc~'L onyl-L-leucinyl metnyl ester, the title compound was LJl~arcd as a white solid (1.8 g, 100%). 'HNMR (400MHz, CDCl3) o 7.48 (s br, lH), 3.62 (s br, 2H), 2.13 (t, 2H), 1.51 (m, 3H), 0.85 (d, 6H).

e) 2-(N-benzylo~yc~ul,ollyl-L-leucinyl)-2'-[N'-(4-1llelllylpelltalloyl)]carbohydrazide The compounds of Example 36(c) (0.100 g, 0.325 mmol) and Example 36(d) (0.042 g, 0.325 mmol) were combined and dissolved in ethanol (1 mL). The solution was brought to reflux for 24 hours tnen concenLldled to a solid yellow residue which was washed with cool methylene cnloride to yield the title compound as a white solid (0.053 g, 37%). MS (MH'): 436.2.

-W O 97/16433 PCT~US96/18000 F.x~mI?le 37 Plc~)aldlion of bis-(Cbz-leucinyl)-1.3-diamino-propan-2-one Cbz-leucine (500 mg, 1.88 mmol), EDCI (558 mg, 1.88 rnmol) was dissolved in DMF (4.0 ml) with 1,3-(1i~minQ-propan-2-ol (85 mg, 0.94 mmol) and 5 Hunig's base (0.3 ml, 1.88 rnmol) and was stirred at RT overni~ht The reactionwas diluted with EtOAc (20 ml) and was extracted with water (2 x 20 ml). The combined organics were dried with m~gnecillm sulfate, filtered, concentrated in vacuo. The int~rm~ t~ was then dissolved in acetone (4.0 rnl) and Jones reagent (2.0 ml, 1.5 M) was added dropwise and the reaction was stirred at RT overnight.10 The excess Jones reagent was then qllen~h~-l with iso~--,p~-ol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with m~ cil.."
sulfate, filtered, concell~ldlGd~ and chromatographed (silica gel, 2-5% MeOH/
methylene chloride) to give the title compound as a white solid (410 mg, 75%).
MS(ES) M+H+=583, M+Na+=605.

F.~carn~ple 38 ~ ~IJdl dlion of bis- 1.3 -(4-phenoxy-benzoyl)-diamino-propan-2-one Following the procedure of FY~mrle 37, except ~ub~l;l..l;..~ "4-phenoxy-benzoic acid" for "Cbz-leucine", the title compound was ~lG~aled: MS(ES) M+H+=481, M+Na+=503.

F.~carnple 39 F'r C~al dlion of 1 -(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-oneFollowing the procedure of Exarnple 37, except sllb~ "a llli~lUle of N-Ac-leucine and Cbz-leucine" for "Cbz-leucine", the title cc,~ oulld was ~lG~al.,d:
MS(ES) M+H+=491, M+Na+=513.

W O 97/16433 PCT~US96/18000 -P~ dldLion of l-(Cbz-leucinyl)-arnino-3-(Cbz-glllt~myl-t-butyl ester)-~mino-propan-2-one Following the procedure of Example 37, except sl~bstit-~ting "a ~ lUle of S Cbz-ghlt~mi~ acid gamma t-butyl ester and Cbz-leucine" for "Cbz-leucine", the title cu~ uulld was ~l~ar~d: MS(ES) M~H+=655.

mple 41 P~ ~dLion of l-(Cbz-leucinyl)-amino-3-(Cbz-~luL~u,lyl)-amino-propan-2-one 1-(Cbz-leucinyl)-amino-3-(Cbz-glulanl~l-t-butyl ester)-amino-propan-2-one (5 mg, 0.007mmol) was dissolved in a solution of trifluoroacetic acid ( 0.5 ml) and met_ylene chloric1t~ (0.5 ml), then was stirred at RT for 2 h, the reaction was dilutied with toluene (10 ml), then was concel~lldted in vacuo to provide the title compound:
MS(ES) M+H+=599.
Example 42 P~ ,~dlion of bis-l.3-(Cbz-leucinyl)-diamino-(S)-butanone-2-one a) Cbz-leu-ala-bromo methyl ketone Isobutyl chlc,lofullllate (1.46 ml, 11.3 mmol) was added dropwise to a solution of Cbz-leu-ala-OH (4.0 g, 11.3 mmol) and N-methyl morpholine (1.24 ml, 11.3 mmol) in THF (40 ml) at -40 degrees C. The reaction was stirred 15 min, then was filtered, and was washed with ether. Di~7.omP.th~n~. (40.1 mmol from 5.9 g of l-methyl-3-nitro-nitroso-gll~ni-line and 18 ml of 40% KOH in 150 ml of ether) inether (200 ml) was added and the reaction was placed in a refrigerator overnight30% HE.r/ AcOH (7 ml) was added dropwise to the crude reaction llu~Lule and was stirred 5 minllt~s The solution was washed with aqueous citric acid (50 ml x 2),~aLuldled aqueous sodium bicarbonate (3 x 150 ml), then brine (100 rnl). The combined organics were dried with m~pnesillm sulfate, filtered, and concentrated in vacuo to give a solid which was used in the next step without purifiç~tion, MS(l~S) M+H+=413 and 415, M+Na+=435 and 437.

b) Cbz-leu-leu-azido methyl ketone S Cbz-leu-ala-bromo methyl ketone (650 mg, 1.6 mmol) was dissolved in DMF (7 ml), then sodium azide (122 mg, 1.9 mmol) and pol~c~ .. fluoride (137 mg, 2.36 mmol) was added and the reaction was stirred ov~rnight The reaction waspartitioned between E~tOAc and water, then the combined organic e~ctr~-~tc were dried with m~n~cinm sulfate, filtered, concellLl~Led in vacuo, then chormatographed (2-5% MeOH, methylene chloride, silica gel) to provide the titlecolll~ nd as a white solid (330 mg, 53%), MS(ES) M+Na+=398.

c) Cbz-leu-2-amino-4-azido-propan-3-ol Cbz-leu-leu-azido methyl ketone (330 mg, 0.9 mmol) was dissolved in EtOH
(5 ml) and sodium bo uhydlide (100 mg, 2.65 mmol) was added at RT and the reaction was stirred for 15 minlltes The reaction was quenched with water (10 ml) and was extracted with EtOAc (25 ml). The combined organic extracts were dried with m~ .;l - . - - sulfate, filtered, conc e-ntr~te~l to give the title compound without further p-lrifi~tion, MS(ES) M+H+= 378, M+Na+-400.
d) Cbz-leu-2-~mino-4-amino-propan-3-ol Cbz-leu-2-amino-4-azido-propan-3-ol (300 mg, 0.8 mmol)was dissolved in MeOH (4 ml) and triethyl amine (0.33 ml, 2.4 mmol), propan-1,3-dithiol (0.35 ml,3.82 mmol) was added and the reaction was stirred ovçrnight conce~ al~d in vacuo, then the white solid was washed with hexane providing the title compound which was used in the next reaction without further pllrifi~tion~ MS(ES) M+H+=352.

e) bis-1,3-(Cbz-leucinyl)-~ mino-(S)-butanone-2-ol Cbz-leu-2-amino-4-amino-propan-3-ol (140 mg, 0.4 mmol) and Cbz-leucine (106 mg, 0.4 mmol) were dissolved in DMF (2 ml) and N-methyl morpholine (0.08 . 99 W O 97/16433 PCT~US96/18000 ~

ml, 0.8 mmol) and HBTU (151 mg, 0.4 mmol) and was stirred overnight. The reaction was partitioned be,t~,en EtOAc and water, the c~ mhin.ocl organics weredried with m~gnçeillm sulfate, filtered, cont~~nl~dt~d to give the title compound, MS(ES) M+H'-S99, M+Na+=621.
s f) bis-1,3-(Cbz-leucinyl)-diamino-(S)-but~n~ n~-2-one Bis-1,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-ol (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added dropwise and t_e reaction was stirred at RT overnight The excess Jones reagent was then 10 quench~d with iso~.~ol (1.0 ml), then the reaction was diluted with EtOAc (20ml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with m~gn~ lrn sulfate, filtered, concentrated, andchl~ alographed (silica gel, 2-5% MeOH/ methylene chloride) to give the title coll.~ou..d as a white solid (80 mg, 33 %). MS(ES) M-H'--595.
F,~ple 43 Prepar~fion of 1-(Cbz-leucinyl)-arnino-3-(Cbz-phenylalanyl)-amino-propan-2-one Following the procedure of FY~mrle 37, except sub~ .g "a ll~ LUlG of Cbz-phenyl~l~nin~ and Cbz-leucine" for "Cbz-leucine", the title coll,p~,und was ~lcpolGd (70%): MS(ES) M+EI+=617, M+Na~=639.

F.~cample 44 r~ lion of l-(Cbz-leucinyl)-arnino-3-(Cbz-norleucinyl)-amino-propan-2-one Following the procedure of Exarnple 37, e~cept subs~ -g " a llliX.~UlG of 25 Cbz-nl-rlç-lcinto and Cbz-leucine" for "Cbz-leucine", the title compound was e~alcd: MS(ES) M+H~=583, M+Na~-605.

W O 97/16433 PCT~US96/18000 Fxample 45 ion of 1-(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one Following the procedure of F.x~mpl.~ 37, except sub~ ;..g "a ~ LùlG of Cbz-norvaline and Cbz-leucine" for "Cbz-leucine", the title compound was 5prG~a.~d: MS(ES) M+H+=569, M+Na+--591.

FY~ ?le 46 P1~1J~ dLion of bis- 1 3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one a) bis- 1,3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one 10Following the procedure of ~;Y~mple 42(a)-(f), except sub~ g "Cbz-leu-leu-OH" for "Cbz-leu-ala-OH" the title compound was pl'Gl~,d: MS(ES) M+H+--639.

F.Y~ml?le 47 15~G~aldLion of 1-(acetyl-leucinyl)-amino-3-(4-phenoxy-benzoyl)-amino-propan-2-one Following the procedure of Example 37, except sub~ ; . . g "a l~ u~c of N-Ac-leucine and 4-phenoxy-benzoic acid " for "Cbz-leucine", the title compound was ~l~p~cd: MS(ES) M+H+=440.
F~rnFle 48 PlG~aldlion of l-(Cbz-homo-leucinyl)-~mino-(Cbz-leucinyl)-3-amino-propan-2-one Following the procedure of Example 37, except substihlting "a l~ we Cbz-homo-leucine and Cbz-leucine" for "Cbz-leucine", the title compound was prepared:
25MS(ES) M+H+=597, M+Na+=619.

W O 97/16433 PCT~US96/18000 ~.x~ ?le 49 p~lGp~udlion of bis-1~3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfon~mido)-propan-2-one 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride (1.3 g, 4 m~ol, S Maybridge) was added to a sollltion of 1,3-di~mino-propan-2-ol (0.18 g, 2 mmol) in DMF (10 ml)/ N-methyl morpholine (0.44 ml, 4 mmol) and was stirred 3h at RT.
The reaction was partitioned between water and EtOAc and the combined organics were dried with m~gn~illm sulfate, then con~ dled in vacuo. The crude bis-1,3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfon~mi~o)-propan-2-ol (0.28 g, 0.4 mmol) was then dissolved in acetone (1.0 ml) and Jones reagent (0.44 ml, 1.5 M) was added dropwise, and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isop.~ol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was e~ dcled with water (2x 20 ml) to remove the il~Glgall~C salts. The comhin~ organics were dried with m~ oci-lm sulfate, filtered, conc~nL,dLed, and chlwlldl(~,ld~hcd (silica gel, 2-5% MeOH/ methylene chloride) to give the title compound as a white solid (90 mg, 34%). MS(ES) M+ H~=671, M+Na'-693.

F.xarr~ple 50 ~lG~ ion of bis-1.3-(4-phenoxy-phenyl sulfonamido)-prûpan-2-one Following the plocedur, of F~amrle 49, except ~ub~ g 4-phenoxy-phenyl sulfonyl chloride for 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title compound was p c;~ ,d: MS(ES) M-H~=55 1.

F.x~m~ple 5 1 ~alionof l-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-one Cbz-leucine (660 mg, 2.5 mmol), EDCI (480 mg, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DMF (10 ml) with 1,3~ mino-propan-2-ol (225 mg, 2.5 mmol) and was stirred at RT ovPrnipht N-methyl morpholine (0.41 ml, 3.75 mmol) was added followed by ~(3-Chloro-2-cyano~ lo~y)-phenyl sulfonyl ~hlori~lç (820 mg, 2.5 mmol, Maybridge) was added and the reaction was stirred 3h at RT. The reaction was partitioned belwecl~ water and EtOAc and the combined organics were dried with m~ sulfate, then conc~ntldLcd in vacuo. The crude l-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-ol was then dissolved in ~qcetQn~o (5.0 rnl) and Jones reagent (3.0 ml, 1.5 M) was added dropwise, and t_e reaction was stirred overnight at RT. The excess Jones reagent was then quçn~h~d with isu~L~,panol (l.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 rnl) to remove the inorganic salts. The colllbi~ed organics were dried with m~g..Pcil..., sulfate, filtered, conce~.lldted, and chromaLogld~hed (silica gel, 2-5% MeOH/ methylene chloride), then the product was LLiluldtcd from methylene chl~ le to give the title cc,.ll~ol~lld as a white solid (26 mg, 2%). MS(ES) M+ H~=627.
Fxample 52 Plc~ dLion of l-(Cbz-leucinyl)- amino-3-(tosyl-amino)-propan-2-one Following the procedure of F.~mple 51, except sub,~ .l ;ng tosyl chloride for 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl çhlon~le, the title compound was prepared: MS(ES) M-H~=488.

p.~al~Lion of l-(cbz-leucinyl)-amino-3-((4-phenQxy-phenyl)-sulfon~mido) propan-2-one Following the procedure of F.x~mple 51, except sub~ 4-phenoxy-5 phenyl-sulfonyl chloride for 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M+H+=568, M+Na+=590. .

F.xample 54 P~ ,~dtion of l-(Cbz-leucinyl)-amino-3-(2-dibe~lzorul~lsulfonamic1--)-propan-2-10 one Following the procedure of Example 51, except 2-dibenzofuransulfonyl chloride for 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title cc ~ oulld was ~c~e;d: MS(ES) M+H+=566, M+Na+=588 15F.Y~mFle 55 P1G1~aliOn of l-(Cbz-homo-leucinyl)-~mino-3-(2-dibenzofuransulfon~micl..)-propan-2-one Following the procedure of Example 51, except 2-dibenzofuransulfonyl chloAde for 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride and Cbz-20 homo-leucine for Cbz-leucint~, the title compound was prepared: MS(ES) M+Na+=602.

Fx~ ?le 56 F~ ~dlion of l-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one a) 1-(Cbz-leucinyl)-amino-3-(2-dibenzorul~sulf ~n~mit1O)-(S)-butan-2-ol Cbz-leu-2-a~nino~-amino-propan-3-ol (150 mg, 0.42 mmol, as described in Example 56(a)-(d)) and 2-dibellzoru,dllsulfonyl chloride were dissolved in DMF (2 ml) and N-methyl morphonline (0.09 ml, 0.84 mmol) and were stirred ov~rnipht The reaction was partitioned bel~.~,en EtOAc and water, the combined organics were dried with m~gne~ m sulfate, filtered, concenll~ted to give the title compound, MS(ES) M+H~=582, M+Na~=604.

b) l-(Cbz-leucinyl)-amino-3-(2-dib~nzuru~ ulfon~mitlo)-(S)-butan-2-one 1-(Cbz-leucinyl)-amino-3-(2-~lih~n7ofuransulf n~mi-1o)-(S)-butan-2-ol (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was15 added dropwise and the reaction was stirred at RT overnight. The excess Jonesreagent was then qllerl~h~l with isop~ ol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with m~g.~il.... sulfate, filtered, concentrated, and cl~ulllalographed (silica gel, 2-5% MeOH/ methylene chloride) to give the title compound as a white solid (70 mg, 29%). MS(ES) M-H+=578.

Ex~ ple 57 Pl~y~dlion of (S)-Phenylmethyl rl-rrr3-lBenzylo~ycalbollyl-leucinyl-aminol-2-oxopropyll- 1 -~benzyl)aminolcarbonyll-3-methylbutyllcall,a.l.d~e a) 2-hydroxy-3-azido-propanol S 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 ml) and was heated to 65 degrees C for 4 h. The reaction was diluted with water (25 ml), extracted with EtOAc (2 x 50 ml); the col..hi,-~A organic layers were extracted with water (2 x 50 ml), then brine (50 ml), then were dried with ma~;"e;,iu", sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 30 % EtOAc/ hexanes) to produce a white solid (1.37 g, 67%); MS(ES) M+H+=118.4.

b) 2-hydroxy-3-azido-propan-tosylate Tosyl chloride (2.3 g, 12 mmol) was added to a solution of 2-hydroxy-3-azido-propanol (1.17 g, 10 mmol) and triethyl amine (3.6 g, 36 rnmol) in methylene chlori-le (SO rnl) and was stirred at RT for 4h. The reaction was diluted with water (20 ml), extracted with EtOAc (2 x 50 rnl); the combined organic layers were extracted with pH 7 buffer (2 x 50 rnl), then were dried with m~gnPcillm sulfate, filtered, conct;~ ed in vacuo, and chromatographed (silica gel, 30 % EtOAc/
hpx~n~s) to produce a white solid (1.2 g, 44%); MS(ES) M+H+=272.2.
c) 2-(l!~errifield polymer-6-(oxymethylene-tetrahydlu~y.dll-acetal)-3-azido-propan-tosylate c) 2-Hydroxy-3-azido-propan-tosylate (1.2 g, 4.4 mmol) was added to a slurry of Ellman dihydropyran polymer (cf. (3), Scheme 1) (150 mg, 0.3 mmol) in ClCH2CH2Cl (25 ml), then pyri~linillm p-tolllenPsulfonate (0.84 g, 4.4 mmol) andwas Z~git~tP.~ at 80 degrees C by gentle bubbling with argon. The polymer was filtered, washed with DMF (2 x 10 ml), then MeOH (20 ml), then methylene chloride (4 x 20 ml); IR 2105 cm-l;. Magic Angle Spinning lH NMR: d 8.0, 7.4, 5.0, 3.4.

W O 97/16433 PCT~US96/18000 d) 2-(Merrifield polymer-6-(oxymethylene-tetrahy&o~yldll-acetal)-3-azido-propan-N-benzyl-amine Benzyl amine (0.32 g, 3 mmol) was added to a slurry of 2~ rrifiel~
polymer-6-(oxymethylene-tetrahyLu~yl~l-acetal)-3-azido-propan-tosylate (500 S mg, 1 mmol) in N-methyl pyrolidinone (25 ml) and was and was ~git~t~d at 80 degrees C by gentle bubbling with argon. The polymer was filtered, washed with DMF (2 x 10 ml), then MeOH (20 ml), then methylene chloride (4 x 20 ml); IR
2105cm-1; Magic Angle Spinning lH NMR: d 7.1, 4.7, 4.0, 3.8.

e) 2-(Merrifi~l(1 polymer-6-(oxymethylene-tetrahydlu~y~ -acetal)-3-~ido-propan-N-benzyl-(Cbz-leucinyl)-amine Cbz-leucine (0.82 g, 3.0 mmol) was added to a slurry of 2-(Merrifi~l(l polymer-6-(oxymethylene-tetrahydl~y~dll-acetal)-3-~ido-propan-N-benzyl-amine (120 mg, 0.22 mmol) in DMF (10 rnl), diisopropyl ethyl amine (1.2 ml, 6 mmol) and HATU (F~ ive Bio~y~ s, 2.2 g, 6 mmol) and was shaken at room tc~ dlu,~ ov~rnight The resin was filtered, washed with DMF (3 x 10 ml). The above procedure was repeated, and the final resin washed with MeOH (2 x 20 ml), then methylene chloride (5 x 20 ml); IR 2105,1735, 1630 cm-1;. Magic Angle Spinning lH NMR: d 7.2, 4.7, 4.1.
f~ 2-(Merrifi~ld polymer-6-(oxymethylene-tetrahy&~u~yl~-acetal)-3-amino-propan-N-benzyl-(Cbz-leucinyl)-amine Prop~n~(1ithiol (0.5 ml, xx mmol) was added to a slurry of 2-(Merrifi~lcl polymer-6-(oxymethylene-tetrahy&u~yl~l-acetal)-3-azido-propan-N-benzyl-(Cbz-leucinyl)-amine (150 mg, û.27 mmol) in MeOH (S ml) and triethylamine (0.5 ml) and was gently rocked overnight The resin was filtered, washed with MeOH (2 x 20 ml), then with DMF (1 x 10 ml), then with methylene chloride (5 x 20 ml), andwas dried in a vacuum oven overnight; IR 1735, 1640, cm~l;.

W O 97/16433 PCT~US96/18000-g) 2-(Merrifielcl polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-(Cbz-leucinyl)-amino-propan-N-benzyl-(Cbz-leucinyl)-amine Cbz-leucine (0.82 g, 3.0mmol) was added to a slurry 2-(Merrifielt1 polymer-6-(oky~ hylene-tetrahydl u~y~ all-acetal)-3-amino-propan-N-benzyl-(Cbz-leucinyl)-amine (150 mg, 0.27 mmol) in N-methyl pyrollidinone (10 rnl), diisopropyl ethyl amine (1.2 ml, 6 mmol) and HBTU (2.2 g, 6 mmol) and was shaken at room Lelll~ldlulG ov.ornight The resin was filtered, washed wi~ DMF (3 x 10 ml). The above procedure was ic~eatcd, and the final resin washed with MeOH (2 x 10 ml), then methylene chloride (5 x 20 ml); Magic Angle Spinning lH NMR: d 7.6, 7.4, 5.1,5.0,3.4,0.8.

h) 1 -N-benzyl- 1 -Cbz-leucinyl-amino-3-Cbz-leucinyl-amino-propan-2-ol 2-(Merrifiekl polymer-6-(oxymethy1ene-tetrahy~h~yl~l-acetal)-3-(Cbz-leucinyl)-amino-propan-N-benzyl-(Cbz-leucinyl)-amine (150 mg, 0.27 mmol) was shaken as a slurry with 85:5: 10 TFA/ water/ methylene chloride (5 ml) for 4h at lRT.
The solution was filtereed and the filtrate was conce~llldt~d in vacuo, then chl.,lll~lo~r~rh~-l (silica gel, 5% MeOH/ mt-thl~n~ çhlnritle) to produce a yellow solid (65 mg, 35%); MS(ES) M+H+=675.1.

i) 1 -N-benzyl- 1 -Cbz-leucinyl-amino-3-Cbz-leucinyl-amino-propan-2-one 1-N-benzyl-1-Cbz-leucinyl-amino-3-Cbz-leucinyl-~mino-propan-2-ol (65 mg, 0.96 mmol) was dissolved in acetone (5 rnl) and Jones reagent (2 ml,excess) was added Lv~wise at room temperature and the reaction was stirred overnight. The excess Jones reagent was then qll~nchto~l with isv~lv~allol (5 ml) and the reaction was diluted with water (5 ml) and was extracted with EtOAc (2 x 20 ml). The combined organic layers were extracted with water (2 x 15 ml), then brine (10 rnl), then were dried with m~gnPsium sulfate, filtered, conc~ LIdled in vacuo to produce a yellow solid, which was ch~ alographed (silica gel, 50%EtOAc/Hexanes ) to produce a white solid (16.8mg, 29%); MS(ES) M+H+= 673.1 W O 97/16433 PCTrUS96/18000 F.xampleS8 P~G~)a1dl;On Of (S)-PhenY1m~thYI r l -rrr3-r(2-dibenzofuranylsulfonyl)aminol-2-oxopropyll-3-(benzyl)aminolc~l~onyll-3-methvlbutyllcarbamate a) N-(2-hydroxy-3-N-benzylamino-propyl)phth~limicle N-(2,3-Epo~Ly~u~yl)phth~limi~le tAldrich, 2.03 g, 10 mmol) was reluxed with benzyl arnine (1.07 g, 10 mmol) in iso~lupallol (15 ml) for 3h. The reaction was cooled to RT7 then concentldled in vacuo producing a white gum, which was triturated with MeOH, then filtered producing a white solid (0.48 g, 15%); MS(ES) M+H~= 311.
b) N-(2-hydroxy-3-(N-benzyl-2-dibel~zoruldllsulfor~mi~l~)-propyl)phth~lim N-(2-hydroxy-3-N-benzylamino-propyl)phth~limi(1P (0.31- g, 1 mmol) was stirred with 2-dibenzofuransulfonyl chloride (0.27 g, 1 mmol) in N-methyl morpholine (0.8 ml) and DMF (5 ml) overnight. The reaction was diluted with water (10 ml), extracted with EtOAc (2x20 ml), the combined organic layers were extracted with water (3 x 20 ml), then brine (20 ml), then were dried with m~g..~si..i.~ sulfate, filtered, collce~ dted in vacuo to produce an oil, which was chromatographed (silica gel, 30% EtOAc/ h~x~ntos) to produce a white foam (0.37 g, 69%); MS(ES) M+H~=541, MS(ES) M+Na'=563, MS(~S- negative) M+HC02-=

c) 2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide)-propyl-3-arnine N-(2-hydroxy-3-(N-benzyl-2-dibenzofuransulfonarnide)-propyl)phth~limi (0.37 g, 0.69 mmol) was refluxed with hydrazine hydrate (0.34 g, 6.85 mrnûl) in 25 MeOH (7 rnl) for 1.5 h. The reaction was cooled to RT, then was concentrated in vacuo. The resulting white solid was lliluldled with MeOH, then filtered to produce the desired product as a white solid (0.27 g, 96%); MS(ES) M+H~=411.
d) Cbz-leucinyl-(2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide))-propyl-3-~ amine 2-hydroxy-(N-benzyl-2-dibenzofuransulfon~mi-l~)-propyl-3-amine (0.2 g, 0.5 mrnol) was stirred with Cbz-leucine (0.13 g, 0.5 mrnol) in N-methyl morpholine (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 ml), extracted with EtOAc (2x20 rnl). A solid that was insoluble in both layers was filtered off. The colnhin~ organic layers were extracted with water (2 x 20 rnl), S then brine (20 ml), then were dried with magnlocil-m sulfate, filtered, concentrated in vacuo to produce a white solid, which was used in the next reaction without further p~rifi~tiQn; MS(ES) M+H+= 658, MS(ES) M+Na+= 680.
e) (S)-Phenyllllt;lllyl [l-[[[3-[(2-~liben7vru~ ylsulfonyl)amino]-2-oxopropyl]-3 (benzyl)amino]c~l,o,lyl3-3-methylbutyl]c~ ul,ate Cbz-leucinyl-(2-hydroxy-(N-benzyl-2-dibenzofuransulfonarnide))-propyl-3-amine (0.16 g, 0.244 mmol) was dissolved in acetone (2 rnl). Jones reagent (0.5 ml, 1.5 M) was added added and the reaction was stirred ov~rnight The excess Jones reagent was then qu~n~h~l wit_ isc,~lopanol (1 ml) and the reaction was diluted with water (10 ml) and was extracted with EtOAc (2 x 20 rnl). The combined organic layers were extracted with water (2 x 20 ml), then brine (20 ml), then were dried with magn~Si~lm sulfate, filtered, concenllaled in vacuo to produce a white solid, which was ch~ ographed (silica gel, 1: 1 EtOAc/ htoxan~s) to produce a white solid (0.14 g, 88%); MS(ES) M-H~=654, MS(ES) M+CI'--690, MS(ES) M+HCO2-= 700-FxarnI?le 59 Preparation of (S)-Phenylmethyl rl-rrr3-r(2-dibenzoful~ylsulfonyl)aminol-2-oxo~ropyll-3-(4-pyridil~yllllc;Lllyl)aminolca~ yll-3-methylbutyll~ ~te Following the procedure of Example 58(a)-(e), except sn~stit-ltin~ "4-25 pyridyl methyl amine" for " benzylamine" and, the title compound was ple~ ,d; MS(ES) M+H+=657.

W O 97/16433 PCT~US96/18000-F.x~nnple 60 Preparation of l-rrr3-r(2-dil,ellzoful~lylsulfonyl)amino~-2-oxopropyl~-3-(4-pyridinylmethyl) b~7~mide v Following the procedure of Example 58(a)-(e), except ~lb~ g "benzoic S acid" for "Cbz-leucine", the title co~ oul~d was prepared; MS(ES) M-H~--51 1, MS(ES) M+Cl_547.

F.x~n~le 61 P~ tion of (S)-rll~,JIyllllethyl rl-rrr3-r(2-dib~l~zorul~lylsulfonyl)aminol-2-oxopropyll-1-(4-pyridinylmethyl)aminolcarbonyll-3-methylbutyllcall,alllate Following the procedure of Example 58(a)-(e), except subslilulillg "4-pyridyl methyl amine" for " benzylamine" and "Cbz-leucine and BTU" for "2-dibenzofuransulfonyl chloride " and "2-dibenzof lr~ncl-lfonyl chl~ride " for "Cbz-leucine and HBTU", the title compound was pl' ~,d; MS(ES) M+H~=657.
Exarr~ 62 tion of 2-rN-(N-benzylokycarl,onyl-L-leucinyl)1-2'-rN'-(4-pheno~y~he.lylsulfonvl)lcarbohydrazide a) N-benzylo~yc~ul.ollyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester hydrochloride (2.0 g, 1 l.Ommol) in 1 ,4-dioxane (20 mL) was added Na2CO3 ( 12.1 ml, 2M in water) followed by benzylchloroformate ( 1.96 g, 11.5 mmol). The mixture was stirred atroom tell~e.~lule for 4h then partitioned bGlween ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concellllaled to yield the title compound as a colorless oil (3.1 g, 100%). lH NMR (400 MHz, CDC13) ~ 7.34 (m, 5H), 5.27 (d, lH), 5.12 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 1.65 - (m, 3H), 0.96 (m, 6H).

W O 97/16433 PCT~US96/18000-b) N-benzyloxycarbonyl-L-leucinylhydrazide To a stirring solution of the compound of l~xample 62(a) (3.1 g, 11.0 mmol) in 15 mL of m~th~nol was added hydr~ide hydrate (5.9 g, 118 mmol). The solution was stirred at room le~ dlulc; for 16h then concentrated to yield the title S compound as an off-white solid (3.1 g, 100%). MS(ESI): 280.2 (M+H)+.

c) (lS)-l-benzylo~ycalbullylamino-3-methyl-1-(1,3,4-ox~ 7ol-2-on yl)butane To a stirring solution of the compound of F.x~mrle 62(b) (3.0 g, 10.8 mmol) in toluene (50 mL) was added phosgene (56 mL, 1.93M in toluene). The solution was heated at reflux for 4h then c~-n~entrated to yield the title compound as a pale yellow foam (3.15 g, 96%). MS(ESI): 306.1 (M+H)+.

d) 2-[N-(N-benzyloxyc~l,ollyl-L-leucinyl)]carbohydr~ide To a stirring solution of the compound of F.x~rnple 62(c) (0.147 g, 0.482 mmol) in 2 mL of methanol was added hydr~ine hydrate (0.241 g, 4.82 mmol).
The sollltio~ was stirred at room Lell.~eldl~lre for 24h then concentrated and purified by column c~ atography (silica gel, methanol/dichloromt~th~n~-) to yield the title compound as a white foam (0.097 g, 60%). MS(ESI): 338.2 (M+H)+.
e) 2-[N-(N-benzylo~yc~l,onyl-L-leucinyl)]-2'-[N'-(4-phenoxyphenylsulfonyl)]carbohydr~ide To a stirring solution of the compound of Example 62(d) (0.097 g, 0.288 mmol) in 2 mL of DMF was added pyridine (0.046 g, 0.576 mmol) followed by 4-phenoxyphenylsulfonylchloride (0.15~ g, 0.576 mmol). The solution was stirred atroom telll~eldture for 16h then partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried (MgSO4), filtered and conct;llL,dted.The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.052 g, 32%).
MS(ESI): 570.1 (M+H)+.

E~xample 63 cpaldlion of 2-rN-(N-benzyloxycalbollyl-L-alanyl)l-2'-rN-(N-benzyloxycarbonyl-T -leucinyl)lcarbohydrazide To a stilTing solution of the compound of Example 62(d) (0.10û g, 0.297 mmol) in 2 mL of DMF was added N-benzyloxycarbonyl-L-ala~ine (0.070 g, 0.312 mmol), 1-hydroxybenzotriazole (0.008 g, 0.059 mmol), and 1-(3-li",~l~,yl~ ~minopropyl)-3-ethylcarbo~1iimi~l~ hydrochloride (0.060 g, 0.312 mmol).
After st}rring at room tt;~ ,ldlure for 16 h, the solution was poured into 150 mT. of water. The ~cci~iLdle was filtered and washed with water (150 mL) and dried under high Vd~;UUlll to yield the title compound as a white solid (0.062 g, 39%).
MS(ESI): 543.1 (M+H)+.

F.x~n~le 64 P~Gl)dl~tion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)l-2'-rN'-(4-phenylbenzoyl)lcarbohydldcide Following the procedure of F.x~mple 63, except ~ub~ g 4-phenylbenzoic acid for N-benzylo~yc~l u--yl-L-~l~nin~7 the title compound was ple~,d as a white solid (0.121 g, 53%). MS(ESI): 518.1 (M+H)+.

Fxam~l?le 65 ~ion of 2-rN-(N-benzylu~yc~bu"yl-L-leucinyl)l-2'-rN'-(4-methoxybenzoyl)lcarbohydrazide Following the procedure of Example 63, except ~ub~ -g 4-metho~ybenzoic acid for N-benzyloxycarbonyl-L-alanine the title compound was ~ ~ed as a white solid (0.057 g, 27%). MS(ESI): 472.1 (M+H)+.

W O 97/16433 PCT~US96/18000-F.x~m~l?le 66 PlG~aldtion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-rN'-(4-phenoxybenzoyl)lcarbohydrazide Following the procedure of F~r~mple 63, except substitllting 4-5 phenoxybenzoic acid for N-benzyloxycarbonyl-L-alanine the title compound was prepared as a white solid (0.102 g, 43%). MS(ESI): 534.1 (M+H)+.

Ex~m~ 67 P~ aLion of 2-(N-acetyl)-2'-rN'-(N-benzyloxycallJonvl-L-leucinyl)lcarbohydl dzide To the compound of Example 62(d) (0.100 g, 0.297 mmol) was added acetic anhydride (0.303 g, 2.97 mmol). The solution was stirred at room te~llpe~ , for 16h then concentldLt;d to an off-white solid which was washed with dichlorom~th~nto to yield the title compound as a white solid (0.086 g, 76%).
MS(ESI): 380.1 (M+H)+.

Example 68 P~ aLion of 2-rN-(N-acetyl-L-leucinyl)1-2'-rN'-(N-benzylo~yca bul-yl-L-Al~rlyl)lcarbohydrazide 20 a) 2-[N-(N-benzylo~Lyc~l,ollyl-L-alanyl)]carbohydrazide Following the procedure of Example 62(a)-62(d), except ~ul!,~ L-alanine ethyl ester hydrochloride for L-leucine methyl ester hydrochloride in step (a), the title compound was ~le~cd as a pale yellow foam (1.1 g, 3.8 mmol).
MS(ESI): 296.2 (M+H)+.
b) 2-[N-(N-acetyl-L-leucinyl)]-2'-[N'-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide To a stirring solution of the compound of F.~mple 63(d) (0.150g, 0.508mmol) in D~F (2rnL) was added N-acetyl-L-leucine (0.092g, 0.534mmol), 1-hydroxybenzotriazole (0.014g, 0.102mmol), and 1-(3-dimethylarninopropyl)-3-ethylcarbo-liimi(le hydrochloride (0.102g, 0.534mmol). After stirring at room CA 02236lll l998-04-28 tt;~ c~lu,e for 16h, the solution was diluted with ethyl acetate, washed su~cçC.~i vely with water, saluldled aqueous sodium bicarbonate, and brine. The organic layer was dried (MgSO4), filtered and concenl.al~d. The residue was purified by column chromatography (silica gel, m~th~n~>Vdichlorom~th~n~) to yield S the title compound as a white solid (0.028 g, 12%). MS(ESI): 451.1 (M+H)+.

lF,x~mrle~ 69 Plc~ ion of 2-rN-(N-acetyl-L-alanyl~1-2'-rN'-(N-benzyloxycarbonyl-L-leucinyl)lcarbohydrazide Following the procedure of Example 68(b), except substituting N-acetyl-L-alanine for N-acetyl-L-leucine and 2-tN-(N-benzylo~yc~l ~,nyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzylo~yc~lJo-lyl-L-alanyl)]carbohydrazide, the title compou'nd was p~ d as a white solid (0.050 g, 25%). MS(ESI): 473.1 (M+Na)+.
~x~n~rle 70 Pl~dlion of 2-rN-(N-benzylo~ycall oll,vl-L-leucinyl)1-2'-rN'-r4-(N~N-ylaminomethyl)benzoyl)llcarbohydrazide a) methyl 4-(N,N-dimethyl~minQm~thyl)ben70~
Methyl 4-(bromr)m~thyl)benzoate (2.0 g, 8.73 mmol) was added to a sdlulaled solution of dimethylamine in meth~nol After stirring for 25 min, the solution was conce"l,al~d and the residue was partitioned beL~n lN NaOH and ethyl acetate. The organic layer was washed with saturated brine, dired (MgSO4),filtered, and c~ nl-çntr~t~A to provide the title co"l~uu"d as a colorless liquid (1.67 g, 99%). lH NMR (250 MHz, CDC13) ~ 8.00 (d, 2H), 7.39 (d, 2H), 3.91 (s, 3H), 3.47 (d, 2H), 2.25 (s, 6H).

b) 4-(N,N-dimethylamino,l~ yl)benzQic acid lithium salt The compound of Fx~mple 70(a) ( 1.67 g, 8.6 rnmol) was dissolved in THF/H20 (1:1) and LiOH-H20 (0.39 g, 9.3 mmol) was added. The ~ Lule was stirred at room te~ eldlu~ for 0.5h, then taken to reflux for 1.5h. The mixture was concenL.dt~d, redissolved in 25mL of water and reconcentrated to yield a white solid (1.6 g, 100%). lH NMR (400 MHz, CD30D) ~ 7.94 (d, 2H), 7.36 (d, 2H), 3.64(s, 2H), 2.35 (s, 6H).

c) 2-[N-(N-benzylo~yc~bollyl-L-leucinyl)]-2'-[N'-[4-(N,N-di~ lhylarninomethyl)benzoyl)]]carbohydrazide Following the procedure of F.x~mple 68(b), except ~.ub~ g 4-(N,N-dimethylarninomethyl)benzoic acid lithium salt for N-acetyl-L-leucine and 2-[N-(N-benzyloxycall,onyl-L-leucinyl)]carbolly~dzide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title cc,~ ou.ld was prepared as a pale yellow solid(0.050g, 17%). MS(ESI): 499.1 (M+H)+.

Fxaml?le 71 ~lGy~dlion of 2-rN-fN-benzyloxycarbonyl-L-leucinyl~1-2'-rN'-r4-hy&~y-r3-(4-morpholinomethyl)llbenzoyllcarbohydrazide Following the procedure of Example 68(b), except s~lbstit~lting 4-hydroxy-3-(4-morpholinornPthyl)benzoic acid for N-acetyl-L-leucine and 2-[N-(N-benzyloxyc~bo.lyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohy&d~ide, the title compound was ~ ,d as a white solid (0.065 g, 26%). MS(ESI): 557.0 (M+H)+.

Fxatr~ple 72 ~c~alaLion of 2-rN-(N-benzylo~yc~l,ullyl-L-leucinyl)l-2'-rN'-r4-(N~N-~lim~thylamin~ t;Lllyl)benzyloxylcarbonyl-L-leucinyllcarbohydrazide a) a-isocyanato-L-leucine methyl ester L-leucine methyl ester hydrochloride (25 g, 0.14 mol) was dissolved in methylene chloride (450 mL), cooled to 0 ~C, and pyridine (43.5 g, 0.55 mol, 44.5 rnL) was added, 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 h, the ~ Lule was poured into 1400 mT . 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 mT . of ice. The aqueous layers were extracted with methylene chlori(le (450 mL) and the combined organic layers were washed with 1400 mT . ofsaturated brine and 900 rnL of ice, then dried (MgSO4), filtered and conce.llldted.
The residue was ~ tillerl (56-58 ~C; 0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 86%). lH NMR (250 MHz, CDCl3) ~ 4.04 (dd, lH), 3.82 (s, 3H), 1.92-1.72 (m, lH), 1.69-1.62 (m, 2H), 0.96 (d, 3H), 0.94 (d, 3H).

b) 4-(N,N-dimethylamino)benzyl alcohol To a stirring solution of the colll~oul.d of Example 70(a) (1.63 g, 8.4 mrnol) in 25 mL of ether, cooled to 0 ~C, was added dropwise a 1 M solution of lithium ~ .. ;.. " hydride (8.4 mmol, 8.4 mL). After 5 min, the reaction was q~l~nrh~A by the addition of water (0.33 mL), 15% aqueous NaOH (0.33 mL) and water (1.0 mL). The ~lGci~itate was removed by filtration, washed with ether 2 times and the filtrate was conce~lllaLed to provide the title compound as a colorless oil (1.36 g, 98%). lH NMR (250 MHz, CDC13) o 7.32 (d, 2H), 7.28 (d, 2H), 4.68 (s, 2H), 3.41 (s, 2H), 2.22 (s, 6H).

c) N-[4-(N,N-dimethylaminomethyl)benzylo~yc~bollyl]-L-leucine methyl ester A solution of the compound of Example 72(a) (1.0 g, 5.8 mmol) and the compound of Example 72(b) in toluene (6 mL) was heated at reflux for 24 h. The solution was concentrated and the residue was purified by flash chromatography on 60 g of 230-400 mesh silica gel, eluting with 5% methanol in methylene chloride, to provide the title compound as a pale yellow oil (1.71 g, 87%). lH NMR (400 MHz, CDC13) o 7.31 (s, 4H), 5.13 (d, lH), 5.10 (s, 2H), 4.41 (m, lH), 3.74 (s, 3H), 3.43 (s, 2H), 2.24 (s, 6H), 1.70-1.62 (m, 2H), 1.52 (m, lH), 0.96 (d, 3H), 0.94 (d, 3H).
s d) N-[4-(N,N-dimethylaminomethyl)benzyloxyc~bonyl]-L-leucine lithium salt Following the procedure of Example 70(b), except ~ul,~ ;..g N-t4-(N,N-dimethylaminomethyl)benzylo~yca l,onyl]-L-leucine methyl ester for methyl 4-(N,N-dimethylamino..~ yl)l)el-7O~, the title compound was prepared as a white solid (1.57 g, 95%). lH NMR (400 MHz, CD30D) ~ 7.3~ (d, 2H), 7.30 (d, 2H), 5.06 (dd, 2H), 4.10 (dd, lH), 3.48 (s, 2H), 2.23 (d, 6H), 1.69-1.51 (m, 3H), 0.94 (d, 3H), 0.93 (d, 3H).

e) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N,N-dimethylaminc,~ ,lhyl)benzyloxy]carbonyl-L-leucinyl]carbohydr~ide Following the procedure of Example 68(b), except sub~ g N-[4-(N,N-dimethylaminomethyl)benzyloxycarbonyl]-L-leucine lithium salt for N-acetyl-L-leucine and 2-[N-(N-benzyloxyc~l,ollyl-L-leucinyl)]carbohydr~ide for 2-[N-(N-benzylo~yc~l,onyl-L-alanyl)]carbohydr~ide, the title compound was prepared as a white solid (0.069g, 18%). MS(ESI): 642.1 (M+H)+.

Example 73 P~ ~dlion of 2-fN-benzoyl)-2'-rN'-(N-benzyloxycarbonyl-L-leucinyl)lcarbohydrazide Following the procedure of Example 62(e) except substit-lting benzoyl chloride for 4-phenoxyphenylsulfonylchloride, the title compound was prepared as a white solid (61mg, 31%). MS(ESI): 442.1 (M+H)+.

W O 97/16433 PCTAUS96/18000 ~

F.~m~1~ 74 .~ Plc~,~dlion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-rN'-r3-(4-mnTpholinomethyl)benzoylllcarbohydr~ide a) methyl 3-(4-morpholinomethyl)be~-~o~
A solution of morpholine (0.836 g, 9.6 mmol) and methyl 3-(bromolllGlllyl)benzoate in THF (5 mT,) and DMF (5 mL) was stilTed at 50 ~C for 3h. The solution was partitioned b~ lw~n ethyl acetate and water. The organic layer was washed S~1C CI~S~ G1Y with water, saLu~ted aqueous NaHCO3, and brine then dried (MgS04), filtered and conccnLl~LGd to yield a colorless oil (0.872 g, 3.72 mmol). lH NMR (400 MHz, CDCl3) o 7.99 (s, lH), 7.91 (d, lH), 7.55 (d, IH), 7.47 (t, lH), 3.94 (s, 3H), 3.72 (m, 4H), 3.53 (s, 2H), 2.46 (m, 4H).

b) 3-(4-morpholinom~thyl)benzoic acid To a solution of the compound of F~Yamrle 74(a) (0.872 g, 3.72 mmol) in THF (3 mL) and water (3 mL) was added lithium hydroxide monohydrate (0.171 g, 4.08 mmol). After stirring at room lGIll~eldlulG for 3h, the solution was concellllated. The residue was redissolved in water (5 mL) and 3N HCl was added and the solution was lyophili7~1 to yield a yellow solid (0.822 g, 3.72 mmol).
MS(ESI): 222.0 (M+H)+.

c) 2-tN-(N-benzylo"yca l~onyl-L-leucinyl)]-2'-[N'-[3-(4-morpholinomethyl)benzoyl]]carbohydrazide Following the procedure of Example 68(b), except sub~l i 1. .l ;. ,g 3_(4-morpholinomethyl)benzoic acid for N-acetyl-L-leucine and 2-[N-(N-25 benzylo"yc~l,onyl-L-leucinyl)]carbohydr~ide for 2-[N-(N-benzyloxyc~hl.oyl-L-alanyl)]carbohydr~ide, the title compound was ~lGpaled as a white solid (0.056 g, 20%). MS(ESI): 541.0 (M+H)+.

, E~xa~ple 75 e~alation of 2-rN-(3-benzyloxybenzoyl)l-2'-rN'-(N-benzyloxycarbonyl-L-leucinyl)lcarbohydrazide a) methyl 3-benzylo-Lybellzoate To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMF
(20 mL) was added methyl 3-hydro~yb~.70~l~ (1.0 g, 6.58 mmol). After stirri~g for 15 min at room te---p~,alu c;, benzyl bromide (1.1 g, 6.58 mmol) was added.
After stirring at room le..~e.dlur~ for 3h, the solution was partitioned between ethyl acetate and water. The organic layer was washed with water (2 X 75 mL), saturated aqueous sodium bic~bollale, and brine, then dried (MgSO4), filtered and concentrated to yield an off-white solid (1.013 g,4.2 mmol). lH NMR (400 MHz, CDC13) o7.67 (m, 2H), 7.48-7.34 (m. 6H), 7.19 (m, lH), 5.12 (s, 2H), 3.95 (s, 3H).

b) 3-benzyl~ybellzoic acid To a solution of the c(il.lpou~ld of F.Y~mple 75(a) (0.400 g, 1.65 mrnol) in THF (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.076 g, 1.82 mrnol). After stirring at reflux for 5 h, the solution was partitioned between ethyl acetate and 3N HCl. The organic layer was washed with brine, dried (MgSO4), filtered and concent at~d to yield a white solid (0.355 g, 1.56 mrnol). lH
NMR (400 MHz, CD30D) o 7.58 (m, 2H), 7.36-7.24 (m. 6H), 7.10 (m, lH), 5.04 (s, 2H).

c) 2-[N-(3-benzylo~ybenzoyl)]-2'-tN'-(N-benzylo~ycalbonyl-L-leucinyl)3carbohydrazide Following the procedure of Example 68(b), except substitl-ting 3-benzyloxybenzoic acid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-tN-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide,the title compound was ple~ ,d as a white solid (0.062 g, 25%). MS(ESI): 548.1 (M+H)+.

W O 97/16433 PCT~US96/18000 -Example 76 P1G~J~dLiOn of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-rN'-r4-r3-(N-N-dim~thy!~min-))- 1 -propyloxylbenzoylllcarbohydrazide a) methyl 4-t3-(N,N-dimethylamino)-l-propyloxy]benzoate To a solution of methyl 4-hydl~yl~c ~~oat~ (1.0 g, 6.58 mmol), 3-dimetnylamino-1-propanol (1.01 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.~7 mmol) at 0~C in THF (20 mL) was added dropwise diisopropyl azodicarboxylate (1.99 g, 9.87 mmol). After stirring for 16 h at room ~m~el~ulc the solution was concentrated and the residue purified by column chromatography (silica gel, methanol/dichlorom~th~ne) to yield the title colll~oulld as an oily solid (1.25 g, 5.2 mnol). MS(ESI): 238.1 (M+H)+.

b) 4-t3-(N,N-dimethylamino)- 1-propyloxy]benzoic acid Following the procedure of Fl~mple 74(b) except substitl-ting metnyl 4-[3-(N,N-dimethylamino)-l-propyloxy]bçn7O~te for methyl 3-(4-morpholinc,-llcLllyl)'L.~ o~r7 the title compound was prepared as a tan solid (1.17 g, 5.2 rnmol). MS(ESI): 224.1 (M+H)+.

c) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2~ -[4-[3-(N-N-dilllt;lhylamino) l-propyloxy]ben~,vyl]]carbohydra_ide Following the procedure of Example 68(b), except subs~ 4-[3-(N,N-dilll~,~ylarnino)- l-propyloxy]benzoic acid for N-acetyl-L-leucine and 2-[N-(N-benzylo~yc~l onyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was pl~ d as a white solid (0.060 g, 21%). MS(ESI): 543.1 (M+H)+.

, W O 97/16433 PCTrUS96/18000 ExaP~ ~dlion of 2-rN-(2-benzyloxybenzoyl)1-2'-rN'-(N-benzyloxycarbonyl-L-leucinyl)lcarbohydr~ide Following the procedure of F~y~mple 68(b), except sub~ .f il~g 2-5 benzyl~ylJell~oic acid for N-acetyl-L-leucine and 2-rN-(N-benzylo~yc~l,onyl-L-leucinyl)]carbohydrazide for 2-~N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide,title compound was ~l~pal'.,d as a white solid (0.056 g, 23%). MS(ESI): 548.1 (M+H)+.

~xaml?le 78 Pl~a-~Lion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-rN'-r3-(4-pyri.lyhl~lhoxy)benzoylllcarbollylll ~ide a) methyl 4-pyridillyllllGLlloxybçn70~t~
Following the ~l~)ccdul~G of Example 76(a) except sub~ llti,,g methyl 3-hydro~yl~el~7o~t~ for methyl 4-hy~yberl7.0~t~ and 4-pyridylcarbinol for 3-dimethylamino-l-propanol, the title compound was ~lG~al~d as a yellow solid (0.599 g, 2.5 mmol). MS(ESI): 244.1 (M+H)+.

b) 4-pyridillylllleLllo~Lyl,~,~zoic acid Following the procedure of Example 75(b) except substitllting methyl 4-pyridyllllGlhoxyben7o~te for methyl 3-benzyloxybenzoate the title colll~ound wasprepared as a yellow solid (0.386 g, 1.69 mmol). lH NMR (400 MHz, CD30D) o 8.54 (d, 2H), 7.64 (m, 2H), 7.57 (m, 2H), 7.40 (m, lH), 7.26 (m, lH), 5.24 (s, 2H).

c) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[3-(4-pyridyLl,~,~oxy)benzoyl]]carbohy& a~ide Following the procedure of FY~mple 68(b), except ~ubs~ g 4-pyridinylmethoxybenzoic acid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, title co~ oulld was ~lG~ ,d as a white solid (0.219 g, 67%). MS(ESI): 549.1 (M+H)+.

W O 97/16433 PCTrUS96/18000-., Example 79 P~ aldlion of 2-rN-(4-benzyloxybeîlzoyl)1-2'-rN'-(N-benzyloxycarbonyl-L-leucinyl)lcarbohydra_ide S Following the procedure of ~xample 75(a)-75(c) except su'o.,l i ~ g methyl 4-hydroxyben7O~te for methyl 3-hy~o~y'LJe~.70~te in step (a), the title compoundwaspreparedasawhitesolid(0.160g,49%). MS(ESI): 548.1 (M+H)+.

Fxample 80 F're~,~dLion of 2-rN-(N-benzyloxvcarbonyl-L-leucinyl)1-2'-rN'-f3-benzyloxy-5-m~th-~xy)benzoyllcarbohydrazide a) methyl 3-hyd~ y-5-methokybellzoate A suspension of methyl 3,5-dihydroxy'~e~7o~te (2.0 g, 11.9 mmol), K2CO3 (1.6 g, 11.9 mmol), and iodometh~n~ (1.7 g, 11.9 mmol) in ~reton~(100 mL) was stirred at reflux. After stirring for three hours the ~ , was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4),filtered and concenL~dled. The residue was purified by column chromatography to yield the title compound as a white solid (0.813 g, 4.4 mmol). 1H NMR (400 MHz, CDCl3) o 7.16 (m, lH), 7.12 (m, lH), 6.61 (m, lH), 5.04 (s, lH), 3.91 (s, 3H) 3.82 (s, 3H).

b) methyl 3-benzyloxy-5-metho,~.yben7O~te Following the procedure of Fx~rnple 80(a) except substit~lting methyl 3-hydroxy-5-methoxyben7O~t~ for methyl 3,5-dihydroxyben7O~te and benzyl bromide 25 for iodo~ , the title compound was prepared as a tan oil (1.2 g, 4.4 mmol).
lH NMR (400 MHz, CDC13) o 7.45-7.31 (m, 6H), 7.24 (s, lH), 6.76 (m, lH), 5.09 (s, 2H), 3.95 (s, 3H), 3.84 (s, 3H).

c) 3-benzyloxy-5-methoxybenzoic acid Following tne procedure of Example 75(b) except substituting methyl 3-benzyloxy-5-methoxybenzoate for methyl 3-benzylo~ybellzoate, the title compound W O 97/16433 PCTAJS96/18000 ~

was prepared as an orange solid (1.14 g, 4.4 mrnol). lHNMR (400 MHz, CDC13) 7.42-7.20 (m, 7H), 6.71 (m, lH), 5.05 (s, 2H), 3.80 (s, 3H).

d) 2-rN-(N-benzyloxycarbonyl-L-leucinyl)]-2'-rN'-(3-benzyloxy-5-5 methoxy)benzoyl~carbohydrazide Following the procedure of Example 68(b), except sub~li l . .l i ~-~ 3-benzyloxy-5-metho~ybellzoic acid for N-acetyl-L-leucine and 2-[N-(N-benzylv~ycall,onyl-L-leucinyl)]carbohydr~ide for 2-rN-(N-benzylo~ycall,onyl-L-alanyl)]carbohydrazide,, f title compound was ~le~.,d as a white solid (0.201 g, 59%). MS(ESI): 578.0 10 (M+H)+.

Fx~nu?le 81 F'le~,aldLion of 2-rN-(N-benzyloxvcarbonyl-L-leucinyl)l-2'-rN'-~3-benzyloxy-4.5-~lim~thoxy)benzoyllcarbohydrazide Following the procedure of F.Y~mple 68(b), except sub~ ;.. g 3-benzyloxy-4,5--1im~tho~ybe~ ioc acid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydr~ide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title co~ oulld was prepared as a white solid (0.155 g, 43%). MS(ESI): 607.9 (M+H)+.
Ex~ny?le 82 ~alalion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-rN'-(3-benzyloxy-5-ethoxy)benzoyllcarbohydrazide Following the procedure of Example 80(a)-80(d) except substituting 25 io-loeth~n~ for iodo. ~ h~nP in step (a), the title compound was prepared as a white solid (0.162 g, 46%). MS(ESI): 592.3 (M+H)+.

W O 97/16433 PCTrUS96/18000 Ex~ e 83 F'lepalaLion of 2-rN-(N-benzylu~ycall,onylglycinyl)1-2'-~N'-(N-benzvlo~y~ lyl-L-leucinyl)lcarbohydrazide Following the procedure of F.xzlmrle 68(b), except substitllting N-5 benzyloxycarbonylglycine for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl- L-leucinyl)]carbohy~d~ide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a wh~te solid (0.204 g, 65%). MS(ESI): 529.2 (M+H)+.

Fx~m~ple 84 Pl~dLion of 2-rN-~3-benzyloxybenzoyl)1-2'-rN'-(N-benzyloxyc~l,ollyl-L-prolinyl)lcarbohydrazide a) 2-[N-(3-benzyloxybenzoyl)]carbohydrazide Following the procedure of F~r~mple 62(b)-62(d) except ~ub~ methyl 3-benzylo~ybr~ t~ for N-benzyloxycarbonyl-L-leucine methyl ester in step (b), the title cc,lll~oulld was p~ .,d as an off white solid (0.421 g, 67%). MS(l~SI):
301.1 (M+H)+.

b) 2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-prolinyl)]call.ollydld~ide Following the procedure of F.x~mple 68(b), except sub~liluli~-~ N-benzyloxycarbonyl-L-proline for N-acetyl-L-leucine and 2-[N-(3-benzylo~yl,e~c,yl)]carbohydrazide for 2-[N-(N-benzylo~yc~l,onyl-L-alanyl)]carbohy~dzide, the title compound was ~ ~ed as a white solid (0.219 g, 62%). MS(ESI): 532.0 (M+H)+.

-W O 97/16433 PCT~US96/18000 E~x~nlrle 85 PlGpaldtion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-rN'-(4-~he~ ,henylacetyl)lcarbohydr~ide Following the procedure of Example 68(b), except substitl-ting 4-5 biphenylacetic acid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycalLonyl-L-alanyl)]carbohydr~ide, the title compound was prepared as a white solid (0.224 g, 71%). MS(ESI): 554.2 (M+Na)+.

Fx~n~ple 86 P~ dLion of (2'S)-2-rN-(3-ben7~1Oxybenzoyl)l-2'-rN'-(N-benzyloxycarbonyl-2-~minobutyryl)lcarbohydldzide Following the procedure of F~mrle 68(b), ~xcept substitrlting (S)-N-benzyluxycalbonyl-2-aminobutyric acid for N-acetyl-L-leucine and 2-[N-(3-benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.244 g, 70%). MS(ESI): 520.3 (M+H)+.

Fx~rnple 87 Preparation of 2.2'-rN.N'-rbis-(4-phenylphenylacetyl)llcarbohydrazide To a stirring solution of carbohydrazide (0.200 g, 2.22 mrnol) in DMF (12 mL) was added 4-biphenylacetic acid (1.04 g, 4.89 rnmol), l-hydroxybenzotriazole(0.060 g, O.l l~l mmol), and 1-(3-dimethylarninopropyl)-3-ethylcarbodiimide hydrochloride (0.937 g, 4.89 mmol). After stirring at room te~ GldLulG for 16 h,the solution was poured into 150 mL of water. The pleci~ lt; was filtered and washed with water (150 mL) and dried under high va~;uulll to yield the title compound as a white solid (0.977 g, 92%). MS(ESI): 501.1 (M+Na)+.

W O 97/16433 PCT~US96/18000 F.xaTn~?le 88 ? Preparation of (2'RS)-2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-r2-(4-phGI~yll~henoxy)propionyllcarbohyd~ d~ide Following the procedure of Example 68(b), except ~ub~ 2-(4-5phenylphenoxy)propionic acid for N-acetyl-L-leucine and 2-[N-(N-benzyl~ycall,onyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycall,ullyl-L-alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.183 g, 73%). MS(ESI): 562.3 (M+H)+.

10Exarr~ 89 Pl~alion of 2-lN-(3-benzylo~LybGnzoyl)1-2'-rN'-(4-m.GIl~ entalloyl)~carbohydrazide Following the procedure of l~xample 68(b), except subsl i~ ~l i ..g 4-lllGl11yl~ent~loic acid for N-acetyl-L-leucine and 2-[N-(3-15 benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzylo~yc~l,o~yl-L-alanyl)]carbohydrazide, the title coll,~.,ulld was ~.c~,d as a white solid (0.079 g, 30%). MS(ESI): 399.3 (M+H)+.

W O 97/16433 PCT~US96/18000-Example 90 P,~paldlion of (2RS. 2'RS)-2~2'-rN~N'-rbis-r2-(4-phenylphenyl)-4-m~ elltanoyl)lllcarbohydrazide a) 4-methyl-2-(4-phenylphenyl)pent-4-enoic acid S To a stirnng solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0 ~C was added n-butyllithillm (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0 ~C, the ~ e was cooled to -78 ~C and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again walming to 0 ~C and coolling to -78 ~C, 3-bromo-2-lllcLllylpl~ene (0.485 g, 3.54 mmol) was added to the llli;ClUl~ in one portion. After stirring at -78 ~C for lh, the reaction was qu~nch~(1 with 2 mL of water then concentldl~d. The residue was redissolved in water and extracted with ether (100mT.). The aqueous layer was ~ci~lifiç-l (3N HCl) and extracted with ether (3 X 100 mT.). The organic layers were colllbilled, dried (MgS04), filtered and collcen~ ed to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)-.

b) 4-met_yl-2-(4-phe.lyl~hellyl)pe-rlt~nQic acid To a stirring solution of the compound of Fx~mrle 90(a) (0.449 g, 1.69 mmol) in ethyl acetate (25 rnL) was added p~ m on carbon (0.225 g). After 20 stirring under a balloon of hydrogen for 16h, the llliX.~Ule was filtered through Celite. The filtrate was conce~ led to yield an off white solid (0.430 g, 95%).
MS(ESI): 267.4 (M+H)-.

c) 2RS, 2'RS)-2,2'-[N,N'-[bis-[2-(4-phenyl~heliyl)-4-25 methylpentanoyl)]]]carbohydrazide Following the procedure of Fl~mrle 87 except sub~ g 4-methyl-2-(4-phenylphenyl)pentanoic acid for 4-biphenylacetic acid, the title compound was obtained, after pllrifi~tion by column chromatography (silica gel, methanol/dichloromethane), as a white solid (0.143 g, 33%). MS(ESI): 591.3 30 (M+H)+.

, W O 97/16433 PCTrUS96/18000-Example 91 Pl~dLion of (2'RS)-2-rN-(N-benzylo~ycall,onyl-L-leucinyl)l-2'-rN'-r2-(4-phenylphenyl)-4~ cLllylpelltalloyl)llcarbohydr~ide Following the procedure of Example 68(b), except 4-methyl-2-(4-5 phenylphenyl)pentanoic acid for N-acetyl-L-leucine and 2-tN-(N-benzyl~Ayc~ubollyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzylo~ycall,onyl-L-alanyl)]carbohyd.a~,ide, the title compound was ~l~alcd as a white solid (0.111 g, 42%). MS(ESI): 588.1 (M+H)+.

Example 92 P~ ion of f2'RS)-2-rN-(3-benzylo~yl,enzoyl)1- 2'-rN'-r2-(4-phenylphenyl)4-~lleLl~yll~cllL~o~l)llcarbohydr~ide Following the procedure of Example 68(b), except sub~ g ~methyl-2-(4-phellylphenyl)pçnt~noic acid for N-acetyl-L-leucine and 2-[N-(3-15 benzylol~yl,enz-~yl)]carbohydr~ide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydr~ide, the title colll~ouLld was prepared as a white solid (0.195 g, ~i3%). MS(ESI): 551.1 (M+H)+.

Example 93 20 rlc~a-a~ion of 2-rN-(3-benzvloxybenzoyl)1-2'-rN'-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)lcarbohydr~ide Following the procedure of Example 68(b), except sul,s~ li..g N-benzyloxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine and 2-[N-(3-benzyloxybenzoyl)]carbohydl~ide for 2-[N-(N-benzyl~xyc~l,onyl-L-25 alanyl)]carbohydr~ide, the title compound was ~ d as a white solid (0.341 g,91%). MS(ESI): 562.2 (M+H)+.
c Example 94 P~ ion of 2-rN-~3-ben~ylo~yl,enzoyl)1-2'-rN'-rN-(2-pyridinylmethoxycarbonyl)-L-leucinylllcarbohydrazide a) N-(2-pyridhlyl~ o~yc~l~onyl)-L-leucine methyl ester S Following the procedure of Example 72(c), except ~ub~ g 2-pryidylcarbinol for 4-(N,N-dhlletllylamino)benzyl alcohol, the title compound was ~l~dl~d as a brown oil (8.06 g, 89%). MS(ESI): 281.2 (M+H)+

b) 2-rN-(2-pyridinylylmethoxycarbonyl)-L-leucinyl]carbohydr~ide Following the procedure of Example 62(b)-62(d) except s~lb~ g N-(2-pyriLnyhllGlllo~yc~lJollyl)-L-leucine methyl ester for L-leucine methyl ester in step (b), the title colllpoulld was ~lcpaled as a pale yellow foam (0.598 g, 69%).
MS(ESI): 339.3 (M+H)+.

c) 2-~N-(3-benzyloxybenzoyl)]-2'-tN'-[N-(2-pyridinyimPtho~ycarbonyl)-L-leucinyl]]carbohydrazide Following the procedure of Exarnple 68(b), except :jub~ g 3-benzylo~yl,ellzoic acid for N-acetyl-L-leucine and 2-tN-(2-pyridhlylylllletho~ycalbonyl)-L-leucinyl]carbohydrazide for 2-tN-(N
benzyloxycarbonyl-L-alanyl)lcarbohydrazide, the title compound was ~ie~al~d as awhite solid (0.057 g, 33%). MS(ESI): 549.2 (M+H)+.

F~rnple 95 P~ aldlion of 2-rN-r3-(4-pyridylmethoxy)benzoylll-2'-rN'-rN-(2-pyridinylmethoxycarbonyl)-L-leucinylllcarbohydrazide Following the procedure of Fx~mple 68(b), except sub~Lilulillg 3-(4-pyridinylmethoxy)benzoic acid for N-acetyl-L-leucine and 2-[N-(2-pyridhlylyllllethoxycarbonyl)-L-leucinyl]carbohydrazide for 2-~N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as ayellow solid (0.088 g, 27%). MS(ESI): 550.2 (M+H)+.

W O 97/16433 PCT~US96/18000-~xample 96 c~dlion of (2Rs~-2-rN-r2-(4-phenylL~hc.,yl)-4-.l.cLllyl~enl~uloyl)ll-2~-rN~-rN-(2 pyridinylmethoxycarbonyl)-L-leucinylllcarbohydrazide Following the procedure of Fx~mple 68(b), exeept 4-methyl-2-(4-5 phenylphenyl)pent,.n- ie aeid for N-aeetyl-L-leueine and 2-[N-(2-pyriL--ylyhllethoxycaLI,ul.yl)-L-leucinyl]c~bollydrazide for 2-tN-(N-benzylo~ye~l,ol~l-L-alanyl)]edrbohydr~ide, the title eompound was ~ d as a yellow solid (0.056 g, 24%). MS(ESI): 589.4 (M+H)+.

10l~xample 97 Preparation of 2-rN-(N-benzyloxycarbonvl-L-leucinyl)~-2'-rN'-r2-(4-phenylphenyl)-4-llle~lylyentdnoyl)llcarbohydrazide The title compound was ~ alcd from the compound of Fx~mple 9l using HPLC (Sumipax OA-3100, 4.6 X 150 mm, 80/20 hexane/ethdnol, 1.0 mL/min, 15retention time = 5.9 min).

Fx~m,~le 98 PlG~,~dLion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)l-2'-rN'-r2-(4-~,h~"ylphenyl)-4-1ll~,Lhyl~ellL;Illoyl)llcarbohydrazide 20The title colll~oulld Wds ~lcpalcd from the compound of F.Y,.mple 9l using HPLC (Sumipax OA-3100, 4.6 X 150 mm, 80/20 hexane/ethanol, 1.0 mL/min, retention time = 8.1 min).

W O 97/16433 PCT~US96/18000 -Exarnple 99 P~e~ lion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-rN'-rN-(4-phenylphenyl)-N-(2-m~ yl~-upyl)carbamoylllcarbohydrazide To a stirring solution of phosgene (0.228 mL, 0.244 rnmol, 12.5% solution in benzene) was added dropwise a solution of N-(2-methylpropyl)- N-(4-phenylphenyl)arnine (0.050 g, 0.222 mmol) and triethylamine (0.025 g, 0.244 mmol) in dichloromethane (1 mL). After stirring at room te~ lalule for 15 min this solution was added dlu~wise to a solution of the co.llpoulld of Example l(d) (0.083 g, 0.244 mmol) and triethylamine (0.025 g, 0.244 mmol) in dichloromethane(1 mL) at room Lelll~ ~atule. After stirring at room telll~ aL~-lc; for 48h, N-methylmorpholine (0.022 g, O.~2 mmol) and DMF (2 mL) were added to the solution and heated at 50 ~C for 16h. The solution was then diluted with ethyl acetate (5mL) and washed sllccçs~ively with water, aqueous saturated NaHCO3, andbrine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by column clhulllaLography (silica gel, methanol/
dichlorom~th~n~) to yield the title colll~oul.d as a yellow solid (0.023 g, 18%).
MS(ESI): 589.4 (M+H)+.

F.x~ml?le 100 Preparation of 2-rN-(3-benzyloxybenzoyl)1-2'-rN'-fN-methyl-L-leucinyl)lcarbohydrazide a) 2-[N-(3-benzylu~yl,ellzoyl)]-2'-[N'-(N-tert-butoxycarbonyl-N-methyl-L-leucinyl)]carbohyL d~ide Following the procedure of F.Y~mrle 68(b), except substituting N-tert-butoxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine and 2-[N-(3-benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title colll~oulld was prepared as a white solid (0.183g, 69%). MS(ESI): 550.4 (M+Na)+.

W O 97/16433 PCT~US96/18000 -b) 2-[N-(3-benzylo~ybenzoyl)]-2~ -(N-methyl-L-leucinyl)]carbohydrazide To a stirring solution of the compound of Example lOO(a) (0.100 g, 0.189 mmol) in dichlororn~-th~n.o (1 mL) was added trifluoroacetic acid (0.296 g, 2.5 rnmol). After stirring at room te~ eldLul~, for 15 min, the solution was 5 concenL~led and the residue was purified by colurnn chromatography (silica gel, methanol/dichlo o...~ ne) to yield the title compound as a white solid (0.055 g,68%). MS(ESI): 428.4 (M+H)+.

Fxz~mI?le 101 Ple~aLion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)l-2'-rN'-(N-methyl-L-leucinyl)lc~l,ohydrazide Following the procedure of F.Y~mrle lOO(a)- lOO(b), except sub~LiluLillg 2-[N-(N-benzyloxyca,l,c"lyl-L-leucinyl)]carbohydrazide for 2-[N-(3-benzyloxybenzoyl)]c~bohycl~a~ide in step (a), the title co",~ou,ld was ~,epal~d.15 MS(ESI): 465.5 (M+H)+.

Fxample 102 Lion of (lS)-N-r2-r(l-benzyloxyc~l,ollylamino)-3-methylbutyllthiazol4-ylcall,u,lyll-N'-(4-phenoxyphenvlsulfonyl)hyd. ~zide 20 a) N-benzyloxycall~ollyl-L-le~ n~m~
To a stirring solution of N-benzylo~y~l,ollyl-L-leucine (4.6 g, 17.3 mmol) in THF, cooled to -40 ~C, was added N-methylmorpholine (3.68 g, 36.4 mmol; 4.0 mL) and isobutyl chlo,of~"l"ate (2.37 g, 17.3 mmol; 2.25 mL). After stirring for 15 min, ~mm~ni~ was bubbled through the solution for 5 min. The solution was 25 warmed to room telll~ ul~ t;v~o,~led, and the residue was dissolved in ethyl acetate, washed with 0.1 N Hcl, and saturated brine, then dried (MgSO4), filtered and ev~ laled to dryness to give the title compound as a white solid (4.58 g, 100%).

W O 97/16433 PCT~US96/18000 ~

b) N-benzyloxycarbonyl-L-le-lcin~thioarnide A solution of the compound of Example 102(a) (4.58 g, 17.3 rnmol) and Lawesson's reagent (4.21 g, 10.4 mmol) in T~F was allowed to stir at room ~elll~)~,.d~Ul~ for 16 h. The solution was conce.,Llaled and the residue was purified by flash ch~ alography on 230-400 mesh silica gel, eluting with 1 :3 EtOAc/h~ n~s, to provide the title co~ oulld as a pale yellow solid (3.74 g, 77%).

c) ( lS)- 1 -benzyloxycarbonylamino- 1 -(4-carboethoxythiazol-2-yl)-3-lllGLllyll,uL~e The compound of Fl~mrle 102(b) (2.20 g, 7.83 mmol) was dissolved in acetone (35 mL), cooled to -10 ~C, and ethyl bromopyruvate (1 68 g, 8.62 mmol, 1.08 mL) was added. After stirring for 1 h, the solution was poured into methylene chloride/water, then into s~t~lr~t~d aqueous NaHCO3. The aqueous layer was extracted with methylene chloride and the co~llbined organic layers were washed with sdLulal~d brine, dried (MgSO4), filtered and conce"llaled. The residue was dissolved in methylene chloncle, cooled to -20 ~ C, pyridine (1.36 g, 17.2 mmol,1.39 rnL) and Llinul~,lacetic anhydride (1.81 g, 8.62 rnmol, 1.22 mL) were added.
After stirring for 1 h, the solution was washed with saluldted squeous NaHCO3 and saturated brine, then dired (MgS04), filtered, and concentrated. Tge residue waspurified by flash chromatography on 90 g of 230-400 mesh silica gel, eluting with 1:3 ethyl acetate/hex~n~s, to provide the title colll~ound as a pale yellow oil (2.36 g, 80%). lH NMR (400 MHz, CDC13) o 8.08 (s, lH), 7.38 (m, SH), 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) (1 S)- 1 -benzyloxycarbonylamino- 1 -(4-hydrazinocarbonylthiazol-2-yl)-3-methylbutane The compound of F.x~mple 102(c) (2.16 g, 5.73 mmol) was dissolved in ethanol (60 rnL) and hydrazine hydrate (2.87 g, 57.3 rnmol, 2.8 mL) was added and the solution was heated at 75 ~C for 1 h. The solution was cooled and evaporated to dryness to provide the title compound as a pale yellow foam (2.01 g, 97%). lH
NMR (400 MHz, CDC13) o 8.35 (bs, lH), 8.03 (s, lH), 7.37 (m, SH), 5.29 (d, lH), W O 97/16433 PCT~US96/18000-5.14-5.09 (m, 3H), 4.07 (bs, 2H), 1.92-1.82 (m, lH), 1.79-1.66 (m, 2H), 1.00 (d,6H).

e) (lS)-N-t2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol4-ylcarbonyl]-N'-(4-phenoxyphenylsulfonyl)hydrazide To a stirring solution of the co~ oulld of Example 102(d) (275 mg, 0.76 mmol) in dichlorom.oth~n~ at room telll~clalulG is added pyridine (180 mg, 2.28 mmol, 0.2 mL) and 4-phenol~yl~c.~ os~llfonyl chloride (408 mg, 1.52 mmol). The reaction was stirred for 16 hours and the solvents were ev~oldted to a residue which was chromatographed (silica gel, 40% ethyl acetate in hexane) to give the title compound as a white solid (0.310 g). MS (ESI): 595.6 (M+H+).

Examrle 103 F'l cy~ ~lion of (1 S )-N- r4- r 1 -(N-benzyloxycarbonyl-L-leucinylamino)-3-m~thylbutyllthiazol-2-ylc~bollyll-N'-(N-benzylo~ycalbullyl-L-leucinyl)hydrazide a) N-benzylo~yc~l,onyl-L-leucinyl-L-leucinyl bromomethylketone l-Methyl-3-nitro-1-nitrosogu~ni-lin~ (5.9 g, 40.11 mmol) in ether (200 ml) is cooled to 0~C. 40% pot~ lm llydloxide is added slowly and the diazom~thane isallowed to collect in the ether solution for 30 minutes at 0~C.
N-benzyloxyc~l.o"yl-L-Leucinyl-L-T enCin~o (R~rhlom) (4.0 g, 10.58 mmol) is stirred in tetrahydrofuran at -40~C. N-lllclhyllllorpholine (1.07 g, 10.58 mmol, 1.16 mL) and isobutyl chlo,vfollllate (1.45 g, 10.58 mmol, 1.38 mL) are added.
The llli~lule is stirred at 40~C for 15 min~ltes and then filtered into a cold flask to remove precipit~te-l salts. To the filtered solution is added an excess of the previously ~rc~alcd fii~7om~th~ne solution and the ~ Lulc is allowed to stand at0~C for 16 h. An excess of 30% HBr in acetic acid is added at 0~C and the solution is then washed succfs~ivcly with l.ON citric acid, s~tllr~t~d aqueous sodium bicarbonate (carefully), and brine. The solution is dried over sodium sulfate, - filtered, and evaporated to give the title colll~ound as a white solid (4.10 g). lH
NMR (400 MHz, CDC13) ~ 7.34 (m, SH), 6.51 (d, lH), 5.15 (d, lH), 5.10 (s, 2H), 4.78 (m, lH), 4.20 (m, lH), 4.04 (dd, 2H), 1.63 (m, 6H), 0.93 (m, 12H).

b) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[1 '-(2-carboethoxythiazol4-yl)-3'-methylbutyl]~-meth-yl~e~ m~
The compound of Example 103(a) (2.0 g, 4.4 mmol) and ethyl thiooxamate (0.59 g, 4.4 mmol) were refluxed in ethanol for 4 h. The solvent was ev~c.-dted and the residue cl~ulllalographed (silica gel, 2.5% methanol/dichlorometh~ne) to give the title co~ oulld as a white solid (1.46 g). lH NMR (400 MHz; CDC13) o 7.32 (s, lH), 7.21 (m, SH), 6.40 (d, lH), 5.13 (dd, lH), 5.02 (s, 2H), 4.41 (q, 2H), 4.06 (m, lH), 1.71 (m, 2H), 1.47 (m, 4H), 1.33 (t, 3H), 0.73 (m, 12H).
c) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[1 '-(2-hydrazinocarbonylthiazol4-yl)-3'-methylbutyI]4-meL~yl~ t~n~mi~le Following the procedure of Example 102(d), except ~ul,sl il ~.l i rl~ (2S, l 'S)-2-(benzylo~ycall~onyl)anlino-N-[1'-(2-carboethoxythiazol4-yl)-3'-methylbutyl]-4-meLhyl~ mide for (lS)-l-benzylo~Lyca,bollylamino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was ~r~ed. MS (ESI): 476.3 (M+H+).

d) (1 S)-N-[4-t 1 -(N-benzyloxycarbonyl-L-leucinylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide To a stirring solution of the compound of Example 103(c) (180 mg, 0.38 mmol) in dimeLllylrv....~mi~1~ is added N-benzyloxycarbonyl-L-leucine (111 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbo~iimide hydrochloride (80 mg, 0.42 mmol), and l-hydroxybenzot~i~701e (13 mg, 0.096 rnmol). The reaction LIule is stirred for 16 hours at room L~ ,.dLult, filtered, and washed twice with 25 water. The solvent was ~v~ aLed to give the title compound as a white solid.
(0.207 g). MS (ESI): 723.9 (M+H+).

W O 97/16433 PCT~US96/18000 ;Example 104~lcpaldlion of (lS)-N-r2-r(1-benzyloxycarbonylamino)-3-methylbutyllthiazol-4-ylcarbonyll-N'-(4-phenvlphenylacetyl)hydrazide Following the procedure of F.x~mple 103(d), except sub~ ;..g (lS)-l-S benzyloxycarbonylamino-1-(4-hy~d;~ oca-l~u-lylLllidzol-2-yl)-3-methylbutane for (2S,l'S)-2-(benzyloxyc~ul,onyl)arnino-N-[1'-(2-hydr~7:ino~i~.bo,lylLlliazol~-yl)-3'-methylbutyl]4-lllGlhyl~ç~ mi~-p7 and 4-biphenylacetic acid for N-benzyloxyc~u1,vllyl-L-leucine, the title coll~vulld was ~rG~ ,d as a white solid.
MS (ESI ): 557.2 (M+H)+.

Fx~rn~l~ 105 P~ a.dtion of (lS)-N-r2-r(l-benzyloxycarbonylarnino)-3-methylbutyllthiazol4-ylcarbonyll-N'-r3-(4-pryidhlyllllethoxy)benzoyllhydrazide a) methyl 3-(4-pyridinyllmethoxy)ben7o~tP
To a stirring solution of methyl 3-hydroxybP~.~o;~e (1.0 g, 6.58 mmol), 4-pyridylcarbinol (1.1 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) inTHF (25 mT) at 0~C was added diisv~lv~yl ~7o~lic~rboxylate (2.0 g, 9.87 mmol) dlv~wise. After stirring at room ~elll~e~dture for 16h, the solution was concellL~dted and purified by column cl,lc,lllatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.599 g, 37%). MS(ESI): 244.1 (M+H)+.

b) 3-(4-pyridinyllmethoxy)benzoic acid To a stirring solution of the compound of Example lO5(a) (0.599 g, 2.47 mmol) in THF~H2O (1:1, 10 mL) was added lithium hydroxide monohydrate (0.113 g, 2.71 mmol). After stirring at reflux for 3.5h, 1.1 eq of lN HCl was added and the LulG poured into water. The lni~Lu~G was extracted with ethyl acetate (2 X 100 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concellLl~Led to yield the title compound as a yellow solid (0.386 g, 68%). lH NMR (400 MHz, CD30D) o 8.54 (d, 2H), 7.64 (m, 2H), 7.57 (m, 2H), 7.40 (m, lH), 7.26 (m, lH), 5.24 (s, 2H).

W O 97/16433 PCT~US96/18000 c) ( 1 S)-N-~2-~ benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[3-(4-pryidinylmethoxy)benzoyl]hydrazide Following the procedure of Example 103(d), except sub~ g (lS)-l-benzylo~ycal luollylamino- 1 -(4-hy dl azillocarbonylthiazol-2-yl)-3 -methylbutane for (2S,1'S)-2-(benzylo~yc~l~onyl)amino-N-[1'-(2-hyd~ oc~ o.lyll~iazol~-yl)-3~-methylbutyl]-4-mGLhylpe..~ mide, and 3-(4-pyridinylm~thoxy)benzoic aeid for N-benzyloxycarbonyl-L-leucine, the title eompound was plGpaled as a white solid.
MS (ESI): 574.2 (M+H)+.

Example 106 alion of N-r2-(2-chlorophenoxymethyl)thiazol4-ylcarbonyll-N'-rN-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide a) a-isocyanato-L-leucine methyl ester L-leucine methyl ester hydrochloride (25 g, 0.14 mol) was dissolved in methylene chloride (450 mL), cooled to 0 ~C, and pyridine (43.5 g, 0.55 mol, 44.5 rnL) was added, 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 h, the Il~i~ G was poured into 0.5 N
HCl ( 1400 mL) and ice (900 mL). The organic layer was washed with 0.5 N HCl (1400 mL) and ice (900 rnL). The aqueous layers were extracted with methylene chlnri~l~o (450 mT,) and the combined organic layers were washed with sdLuldled brine (1400 mL) and ice (900 mL), then dried (MgSO4), filtered and conce,l~ldted.
The residue was ~li.ctille~l (56-58 ~C; 0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 86%). lH NMR (250 MHz, CDCl3) ~ 4.04 (dd, lH), 3.82 (s, 3H), 1.92-1.72 (m, lH), 1.69-1.62 (m, 2H), 0.96 (d, 3H), 0.94 (d, 3H).
b) N-(4-pyridinylll.cthoxycarbonyl)-L-leucine methyl ester A solution of the colll~oulld of Example 106(a) (5.10 g, 29.8 mmol) and 4-pyridylcarbinol (3.25 g, 29.8 mmol) in toluene (3~) mL) was heated at reflux for 24 h. The solution was concelltlaLed and the residue was purified by fla h chromatography on 250 g of 230~00 mesh silica gel, eluting with 3:1 ethyl acetate/h~x~n~c, to give the title compound (7.86 g, 94%). lH NMR (250 MHz, W O 97/16433 PCT~US96/18000 CDCl3) o 8.59 (d, 2H), 7.24 (d, 2H), 5.33 (d, lH), 5.13 (s, 3H), 4.40 (dt, lH), 3.75 (s, 3H), 1.81-1.51 (m, 3H), 0.96 (d, 3H), 0.95 (d, 3H).

c) N-(4-pyridinylmethoxyc~l,ollyl)-L-leucine To a stirring solution the compound of Example 106(b) (1.98g, 7.06 mmol) in THF (7 mL) was added 7 mL of water followed by LiOH-H20 (325 mg, 7.76 mmol). The ~ Lur~; was stirred for 30 minlltes and then conr~e~ The residue was redissolved in water (10 mT) and 3 NHCl was added (2.6 mL). The solution was lyophilized to yield a white solid (2.015 g, 6.44 mmol). MS (ESI): 267.2 (M+H)+.

d) N-[2-(2-chlol~henoxymethyl)thi~7Ol~-ylcarbonyl]hydrazide Following the procedure of Example 102(d), except ~uL ~ .g ethyl 2-(2-chloropheno~Lyll,clllyl)thiazole-4-carboxylate for (1 S)- 1 -benzyloxyc~l,o"ylamino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was ple~ d.
MS (~SI): 284.1 (M+H)+.

e) N-[2-(2-chlc ,u~henoxymethyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmetho~yc~l,onyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except sub~ N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]hydrazide for (2S,l'S)-2-(benzyloxycarbonyl)amino-N-[ l '-(2-hydrazinoc~l,onyl~iazol-4-yl)-3'-methylbutyl]~..l~Lllyl~ mi-le, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxyca,bonyl-L-leurint-, the title compound was p,e~aled as a white 25 solid. MS (ESI): 532.1 (M+H)+.

W O 97/16433 PCT~US96/18000 Fx~ ?le 107 P~c~Lion of N-rN-(4-pyridinylmethoxycarbonyl)-L-leucinyll-N'-r2-~4-(1.2.3-thia~ 7~ 4-yl)phenyllthiazol-4-ylcarbonyllhydr~7i~
a) N-r2-[4-( 1 ,2,3-thi~ 7ol-4-yl)]thiazol-4-ylcarbonyl]hydrazide S Following the procedure of Example 102(d), except sub~ ,g ethyl 2-[4-(1,2,3-thi~ 7Ol~-yl)]thiazole-4-carboxylate for (lS)-1-benzyloxycarbonylamino-I-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title co~ oulld was prepared as a white solid. MS (ESI): 304.1 (M+H)+.

b) N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-t2-[4-(1,2,3-thi~
4-yl)phenyl]thiazol4-ylcarbonyl]hydrazide Following the procedure of Example 103(d), except sub~ ..f ;..g N-[2-[4-(1,2,3-thi~ 7Ol4-yl)]thiazol-4-ylcarbonyl]hydrazide for (2S,l'S)-2-(benzyloxycarbonyl)amino-N-[l '-(2-hydl~illocdlbollylLhiazol-4-yl)-3'-1~ methylbutyl]4-mellly~ n~lnid~7 and N-(4-pyridinylmethox.yc~l,onyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title colll~und was pl~l,aled as a w_ite solid. MS (ESI): 5~2.1 (M+H)+.

F.xample 108 Pl~alion of N-r2-~3-(4-chlorophenylsulf~llyhllethyl)thien-2-vllthiazol~-ylcarbonyll-N'-rN-(4-pyridinylmethoxyc~l,cl,yl~-L-leucinyllhydrazide a) N-~2-[3-(4-chlor~,~hel,ylsulfollyllllethyl)thien-2-yl]thi~ol-4-c~l,ollyl]hydr~ide Following the procedure of FY~mp]e 102(d), except sub~ 2-[3-(4-2~ chlol~henylsulrollyllllethyl)thien-2-yl]thi~7ole4-carboxylate for (lS)-l-benzylc~xyc~bonylarnino-1-(4-carboethoxythi~ol-2-yl)-3-methylbutane, the title compound was ~le~ d as a white solid. MS (ESI): 414.1 (M+H)+.

W O 97/16433 PCTrUS96/18000 ~

b) N-[2-[3-(4-chlorophenylsulrol,yll"ethyl)thien-2-yl]thiazol-4-ylcarbonyl]-N'-~N-(4-pyridinylll,GLho~yc~hbullyl)-L-leucinyl]hydr~ide Following the procedure of F~r~mple 103(d), except substit-lting N-[2-[3-(4-chlorophenylsulfol~yllllGLhy-l)thien-2-yl]thiazol4-c~bollyl]hydrazide for (2S,l'S)-2-5 (benzy-loxycarbonyl)amino-N-[ l '-(2-hy-lr~7inocz~ bollylll~iazol-4-yl)-3'-methylbutyl]-4-meLllyl~e~ m~ o7 and N-(4-pyridinylm~tho~ycarbonyl)-L-leucine for N-benzylo~yc~hl,onyl-L-leucin~, the title conl~uu~d was ~ Gd as a white .
MS (ESI): 664.0 (M+H)+.

Fxannple109 PlG~lion of (lS.2'RS)-N-r2-r(l-benzylo~yc~l~ullylamino)-3-methylbutyllthiazol-4-ylcarbonyll-N'-r2'-(4-phenylphenylacetyl)4-methylpentanoyllhydrazide a) 4-methyl-2-(4-ph~nyll)henyl)pent-4-enoic acid To a stirring solution of diiso~,u~ylamine (0.537 g, 5.31 mrnol) in T~; (5.2 ~) at 0 ~C was added n-butyllithillm (2.1 ~, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0 ~C, the llli~L-Ile was cooled to -78 ~C and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mT ) was added dropwise. After again W~ .llg to 0 ~C and coolling to -78 ~C, 3-bromo-2-meLl,yl~ ,n~ (0.485 g, 3.54 mmol) was added to the ll~ in one portion. After stirring at -78 ~C for lh, the reaction was qll~ncl~ l with 2 mL of water then concenl,dled. The residue was redissolved in water and extracted with ether (100mT ). The aqueous layer was acidified (3N HCI) and extracted with ether (3 X 100mT .). The organic layers were combined, dried (MgS04), filtered and concel-lldted to yield a white solid (0.449 g, 72%). MS(ESI)- 265.3 (M+H)-.
b) ~methyl-2-(4-phel,yl~henyl)pentanoic acid - To a stirring solution of the compound of Example lO9(a) (0.449 g, 1.69 mmol) in ethyl acetate (25 mT .) was added p~ lillm on carbon (0.225 g). After stirring under a balloon of hydrogen for 16h, 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)-.

W O 97/16433 PCT~US96/18000 c) (lS,2'RS)-N-t2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[2'-(4-phenylphenylacetyl)4-methylpentanoyl]hydrazide Following the procedure of Exarnple lOl(d), except subst~ ting (IS)-l-benzyloxycarbonylamino-1-(4-hydr~inoc~rbonylthiazol-2-yl)-3-methylbutane for (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[1 '-(2-hyd,dzinocarbonylthiazol-4-yl)-3'-methylbutyl]-4-lll~Lllylpc.~ mi~ and 4-methyl-2-(4-phenylphenyl)pçnt~noic acid for N-benzyloxyc~bol,yl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 613.2 (M+H)+.
~xample 110 r~ ~ aLiOn of N-r2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl~ -N'-l N-(2-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide a) methyl 3-benzyloxyb~n~os-tP
To a ~u~pellsion of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMIF
(20 rnL) was added methyl 3-hydro~yl,e-,70~te (1.0 g, 6.58 mrnol). After stirring for 15 min at room telll~,.atule, benzyl bromide (1.1 g, 6.58 mmol) was added.
After stirring at room tt~ aldLule for 3h, the solution was partitioned between ethyl acetate and water. The organic layer was washed with water (2 X 75 mL), salu,dled 20 aqueous sodium bicarbonate, and brine, then dried (MgSO4), filtered and concentrated to yield an off-white solid (1.013 g, 4.2 mmol). lH NMR (400 MHz, CDC13) o 7.67 (m, 2H), 7.48-7.34 (m. 6H), 7.19 (m, lH), 5.12 (s, 2H), 3.95 (s, 3H).

b) 3-benzyloxyl,~-7z~ . . .i~1e To a s~lspPncion of ammonium hydrochlori~ (1.070g, 0.02 mmol) in 20 mL
of toluene at 5~C, was slowloy added a 2M solution (10 mL) of trimethylal.. i.. il in toluene. After the addition was complete, the reaction mixture was allowed towarm at room le~ eldlulc; and was stirred for 2 hours until gas evolution has ceased.
To a stirring solution of the compound of Example l lO(a) (605 mg, 2.49 mmol) in toluene was added a 0.67 M solution of MeAlClNH2 (11 mL, 7.49 mmol) in toluene. The reaction llu~LulG was allowed to stir overnight at reflux. The reaction was qll.onch~d with 5% HCl, the organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated to afford the title colll~o~lld as a white solid (409 mg, 72%). MS (ESI): 228.1 (M+H)+.

c) N-[2-(3-benzylo~y~hel.yl)thiazol~-ylc~lJonyl]hydrazide Following the procedure of Example 102(b)-102(d), except sub~ uLillg 3-benzylo~ybe~ 1e for N-benzyloxyc~bollyl-L-leucin~mide in step (b), the title co,lllx~ul-d was prepared as a white solid. MS (ESI): 326.2 (M I H)+.

d) N-(2-pyridillyllllethoxycarbonyl)-L-leucine Followong the procedure of Flr~mrle 106(a)- 106(c), except sub~,l i I . .l; . .~ 2-pyridylcarbinol for 4-pyridylcarbinol in step (b), the title compound was pl'~p~d.
lH NMR (400 MHz, CD30D) ~ 8.50 (d, lH), 7.86 (dt, lH), 7.51 (d, lH), 7.36 (dd, lH), 5.20 (d, lH), 5.16 (d, lH), 4.19 (t, lH), 1.78-1.72 (m, lH), 1.62 (t, 2H), 0.97 (d, 3H), 0.94 (d, 3H).

e) N-[2-(3-benzylo~y~hellyl)thiazol-4-ylc~l,ollyl]-N'-[N-(2-pyridillyl - . ,rthokyc~lJonyl)-L-leucinyl]hydrazide Following the procedure of F.x~mple 103(d), except ~,ubsl i~ g N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]hydrazide for (2S,l'S)-2-(benzyloxycarbonyl)amino-N-[ l '-(2-hydrazinocarbonylthiazol-4-yl)-3'-methylbutyl]-4-lllt;~yl~e~-t~n~mi-1~7 and N-(2-pyridinylmethoxycarbonyl)-L-leucine 25 for N-benzylo~yc~l~ollyl-L-leucine, the title co~ ound was ~ ed as a white solid (106 mg, 0.184 mmol). MS (ESI): 574.2 (M+H)+.

E~xample 111 P~ a,dLion of (lRS)-N-r2-rl-(4-phenylphenvl)-3-methylbutyllthiazol4-ylcarbonyll -N'-rN-(4-pyridinylmethoxycarbonyl~-L-leucinyllhydrazide a) N-[2-tI-(4-phenylphenyl)-3-methylbutyllthiazol-4-ylcarbonyl3hydrazide Following the procedure of Example 102(a)-102(d), except s~lbstit lting 4-methyl-2-(4-phenylphenyl)pentanoic acid for N-benzylo~yc~lJol~yI-L-leucine in step (a), the title compound was prepared as a white solid. MS (ESI): 366.3 (M+H)+.

b) (lRS)-N-t2-tl-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylc~l,onyl]-N'-tN-(4-pyridinylmetho~yc~bol,yl)-L-leucinyl]hydrazide Following the procedure of F.x~mple 103(d), except sub~ ;..g N-[2-[1-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonyl]hydrazide for (2S,l'S)-2-(benzyloxycarbonyl)~rmirlo-N-[1 '-(2-hydrazinoc~l,ollylLlliazol-4-yl)-3'-methylbutyl]-4-m~thylpel-t~n~mi~1e, and N-(4-pyridinylmethoxycarbonyl)-L-leucinefor N-benzylo~yc~bollyl-L-leucin~, the title compound was ~le~cd as a white solid. MS (ESI): 614.3 (M+H)+.

F.xample 112 P~ a alion of N-r2-(2-benzylo~y~;~henyl)thiazol-4-ylc~lJollyll-N'-rN-(4-pyridhlyllllellloxycarbonyl)-L-leucinvllhydrazide a) ethyl 2-arninothiazole-4-carboxylate hydrobromide To a stirring suspension of thiourea (6.0 g, 78.8 mmol) in ethanol (80 mL) was added ethyl bromopyruvate (15.4 g, 78.8 mmol). The reslllting solution was heated at 45 ~C for 23 h. The solution was cooled at 0 ~C for 24 h, and the crystals were collected by filtration and washed with cold ethanol to provide the title co~ ou"d (15.8 g, 79%). lH NMR (400 MHz, CD30D) ~ 7.70 (s, lH), 4.41 (q, 2H), 1.38 (t, 3H).

W O 97/16433 PCT~US96/18000 -b) ethyl 2-bromothiazole-4-carboxylate To a stirring ~ peniion of the co~ oulld of F~x~mple 112(a) (12.15 g, 48 mmol) in 16% aqueous HBr (150 mL), cooled to 0 ~C, was added d lu~wis a solution of sodium nitrite (3.44 g, 49.8 mmol) in water (6 mL). After stirring for 35 S r~un, cûpper (I) bromide (7.83 g, 54.6 mmol) and 16% aqueous Br (60 rnL) were added and the ~ LulG was heated at 70 ~C for 1 h. The .~ U1G was filtered and the filtrate was saturated with NaCl then e~L,~Ied with ethyl acetate (2 X 170 mL).
The combined extracts were dried (MgS04), filtered and ~vdpûldled to dryness.
The residue was combined with comhin~-d with the solid collected in the first filtration, heated at reflux in ethanol (500 mL) for S rnin, then filtered. To the filtrate was added 1.5 mL of 48% aqueous HBr and the solution was heated at reflux for 16 h, then concenL~led. The residue was partitioned b~L'..~ll salu.dled aqueous NaHC03 and ethyl acetate. The organic layer was washed with s~ t~A brine, dried (MgS04), decolorized with charcoal, filtered and concentldled to provide the title compound as a pale yellow solid (7.46 g, 75%). MS (ESI): 236.0 (M+H)+.

c) 2-benzylo~yl,-u.llob~ le To a stirring 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 K2C03 (12.0 g, 86.7 mmol). After stirring at reflux for 4h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgS04), filtered and conce~ d~ The residue was purified by colllmn chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol). lHNMR (400 MHz, CDCl3) o 7.62 (m, lH),7.54 (m, 2H), 7.45 (m, 2H),7.37 (m, lH), 7.28 (m, lH),6.98 (m, lH), 6.91 (m, lH), 5.17 (s, 2H).

- d) 2-benzylo~y~h~l.ylboronic acid To a stirring solution of the compound of Example 112(c) (15.2 g, 57.8 mmol) in THF (100 mL) at -78~C was added dropwise n-BuLi (23.1 mL, 2.5M in hexane, 57.8 rnmol). The ~ u~e stirred at -78~C for 25 min when added via c~nnlll~tion to a stirring solution of triisopropylborate (54.4 g, 289 mmol) in THF

W O 97/16433 PCT~US96/18000 ~

(100 rnL) at -78~C. After walllling to room temperature and stirring for 3h, thell--~Lu~e was poured into 3N HCl (100 mL) and extracted with ethyl acetate (3 X
200mL). The organic layers were combined, washed succes~ively with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified by 5 column chromatography (silica gel, ethyl acetate~hexane) to yield the title colllpoulld as a pale yellow solid (6.9 g, 30.3 mmol). lHNMR (400 MHz, CDC13) 7.90 (d, lH), 7.42 (m, 6H), 7.07 (t, lH), 7.02 (d, lH), 6.05 (s, 2H), 5.16 (s, 2H).

e) ethyl 2-(2-benzyloxyphenyl)thiazole4-carboxylate To a stirring solution of the compound of Example 112(b) (4.0 g, 16.9 mmol), the co.n~ou..d of Example 72(d) (4.29 g, 18.8 mrnol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.57 mmol) in ~impthoxyethane (60 mT.) was added cesium fluoride (8.58 g, 56.5 mmol) and the mixture was heated at 85 ~C for 16 h. Tetrakis(triphenylphosphine)p~ m(0) (0.65 g, 057 mmol) was added and heating at 85 ~C was continllçc1 for 5 h. The ll~ LUl~ was dilutedwith water (60 mL) and extracted with ethyl acetate (2 X 120 rnL). The combined extracts were washed with sdluldLed aqueous NaHCO3 and sdLu,dted brine, dried (MgSO4), 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 h~nPc, to provide the tltle compound as a white solid (3.22 g, 56%). MS (ESI):
340.3 (M+H)+-f~ 2-(2-benzylo~y~hellyl)thi~ol-4-ylcarbonylhydrazide Following the procedure of Example 102(d), except sub~ . .l i . .g ethyl 2-(2-benzyloxyphenyl)thiazole4-carboxylate for (1 S)- 1 -benzyloxycarbonylamino- 1 -(4-carboethoxythi~ol-2-yl)-3-met'nylbutane, the title compound was prepared as a white solid. MS (ESI): 326.2 (M+H)+.

-g) N-[2-(2-benzyloxyphenyl)thi~ol-4-ylcal~ollyl~-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except subs~ g 2-(2-benzyloxyphenyl)thiazole4-ylcarbonylhydrazide for (2S,l'S)-2-S (benzyloxycarbonyl)amino-N-[1'-(2-hydrazinocarbonylthi~ol-4-yl)-3'-methylbutyl]-4-methylpent~n~mide, and N-(4-pyridinylmeth~yc~l,onyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 574.3 (M+H)+.

FY~ le113 r~aldlion of N-r2-rN-methyl-N-(4-~hellyl~ ellyl)aminolthiazol~ylcarbonyll-N'-rN-~4-pvridillylllleL~lo~yc~l~o~yl)-L-leucinyllhydr~
a) N-(4-~h~,~lyl~h~.lyl)-2-1lwlllyl~lupion~Tnid~
To a stirring solution of 4-~arnjnobiphenyl (9.53 g, 56.3 rnmol) and triethylamine (5.70 g, 56.3 mmol, 7.85 mL) in methylene chloride (60 mL), cooledto 0 ~C, was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). Afterstirring at 0 ~C for 1 h, the lr..~lulc was diluted with methylene chloride (120 mL) and washed with lN NaOH and sdtuldted brine, then dreid (MgSO4), filtered and concelllldtcd. The residue was washed with ether and dried to provide the title compo~llld as a pale yellow crystalline solid (9.83 g, 73%). lHNMR (400 MHz, CDC13/CD30D) o 7.58 (d, 2H), 7 50 (m, 4H), 7.40-7.25 (m, 3H), 2.55-2.49 (m, lH), 1.18 (d, 6H).

b) N-(4-~henyl~henyl)-N-(2-methyl- 1 -propyl)amine To a stirring solution of lithium ~ ---- hydride (58.6 mmol) in THF
(58.6 mmol), cooled to 0 ~C, was added slowly over 10 min a solution of the compound of Example 73(a) (9.35 g, 39.0 mmol) in THF (170 mL). After the addition was complete, the ice bath was removed and the solution was heated at 55 ~C for 30 min. The mixture was cooled to 0 ~C and water (2.22 mL) was slowly added, 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 W O 97/16433 PCT~US96/18000 was evaporated to dryness to proveide the title compound as a pale yellow solid (8.34 g, 97%). MS (ESI): 226.2 (M+H)+.

c) N-(4-phenylphenyl)-N-(2-metnyl- 1 -propyl)thiourea To a stirring solution of thiophosgene (98.9 mg, 2.6 mmol, 198 uL) in methylene chloride (6.5 mL), cooled to 0 ~C, was added dropwise a solution of tne co~ ou,ld of Example 73(b) (540.7 mg, 2.0 mmol) in metnylene chloride (1 mL).
After stirring for 2 h. ~mmo~ -satlualed m~th~nQl (20 mL) was added and the solution was stirred at room lempelalul for 2 h. The solution was concel.LIdLcd and the residue was partitioned between ethyl acetate and lN HCl. The organic layer was washed with lN HCl twice, then with saLuldLed brine, then dried (MgSO4), filtered and concellLldled The residue was purified by flash chr~ dLc,graphy on 10 g of 230-400 mesh silica gel, eluting with 1:3 ethyl acetate/hexanes, to provide the title compound as a pale yellow solid (470 mg, 83%). MS (ESI): 285.3 (M+H)+.
d) ethyl 2-tN-(4-phenylphenyl)-N-(2-methyl-1-propyl)amino]thiazole-4-carboxylate A solution of the compound of Fx~mrle 113(c) (184.6 mg, 0.65 mmol) and ethyl bromo~y,.~vdte (126.6 mg, 0.65 mrnol, 81.5 uL) in ethanol (2.5 mL) was heated at reflux fo 5 min' tnen concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was extracted withethyl acetate and the combined organic layers were washed with saturated brine, dried (MgSO4), filtered and concentrated. The residue was passed t'nrough a plugof 230-400 mesh silica gel, eluting with 12% ethyl acetate in hexanes, to provide the title compound as a pale yellow oil (230 mg, 93%). MS (ESI): 381.4 (M+H)~.

e) N-t2-tN-(4-phe,nyl~henyl)-N-(2-methyl-l-propyl)amino]thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 102(d), except substitllting ethyl 2-~N-(4-phenylphenyl)-N-(2-methyl- 1 -propyl)amino]thiazole~-carboxylate for (1 S)- 1 -_ W O 97/16433 PCTAJS96tl8000-benzyloxyc~l,ollylarnino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the titlecompound was prepared as a white solid. MS (ESI): 367.3 (M+H)+.

f) N-[2-[N-methyl-N-(4-phenylphenyl)amino]thiazol-4-ylcarbonyl]-N~-[N-(4-5 pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of FY~mrle 103(d), except subsli~ irl~ N-[2-[N-(4-phenylphenyl)-N-(2-methyl-1-propyl)amino]thiazol4-ylcarbonyljhydrazide for (2s~l~s)-2-(benzylo~y~ yl)amino-N-[l~-(2-llydl~7il~oc~ ollylll~iazol-4-yl)-3~-methylbutyl]-4-lllGIllyl~ t~ mi(l~, and N-(4-pyridinylmtothoxycall,onyl)-L-leucine 10 for N-benzyloxycarbonyl-L-leucine, the title collll~ou..d was pl~G~alGd as a white solid. MS (ESI): 615.3 (M+H)+.

F.xample 114 Pl~paldlion of N-(N-benzyloxycarbonyl-l,-leucinyl)-N'-r2-(4-phenylbenzyl)thi~ol- 4-ylcarbonyllhydrazide a) N-[2-(4-phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide Following the procedure of FY~mple 102(a)-102(d), except ~ub~ 4-biphenylacetic acid for N-benzyloxycarbonyl-L-leucine in step (a), the title co...youlld was p,~alGd as a white solid. MS (ESI): 310.3 (M+H)+.
b) N-(N-benzylor~yc~hl,onyl-L-leucinyl)-N'-[2-(4-phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 103(d), except sub~ g N-[2-(4-phenylbenzyl)thiazol-4-ylc~l.oliyl]hydr~ide for (2S,l'S)-2-25 (benzylo~ycall,onyl)amino-N-[1'-(2-hydrazinocarbonylthiazol-4-yl)-3'-methylbutyl]-4-mGLhyll.e~ mi~le7 the title co~ oulld was prepared as a white - solid (20 mg, 0.035 mrnol). MS (ESI): 557.4 (M+H)+.

Example 115 P1G~dldLiOn of N-r2-(4-phenylphenylbenzyl)thiazol~-ylcarbonyl~-N'-rN-(4-pyridinylmetho~yc~l~oll~l)-L-leucinyllhydrazide Following the procedure of Example 103(d), except substituting N-[2-(4-S phenylbenzyl)thiazol-4-ylc~l,ollyl]hydrazide for (2S,l'S)-2-(benzyloxycarbonyl)amino-N-[l '-(2-hydl~inocarbonylthiazol4-yl)-3'-methylbutyl]-4-melhyl~ mi~, and N-(4-pyriLllyl"~ellloxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title co,ll~ound was ~ a~d as a yellow solid (30 mg, 0.053 mmol). MS (ESI): 558.2 (M+H)+.
Example 116 P~ ion of N-(N-benzyloxycarbonyl-L-leuchlvl)-N'-r2-rN-(2-methylpropyl)-N-phenylamino~thiazol-4-ylcarbonyllhydrazide a) N-[2-[N-phenyl-N-(2-methyl- 1 -propyl)amino]thiazol-4-15 ylc~l,ol.yllhydrazide Following the procedure of Example 113(a)-113(e), except subs~ .g aniline for 4-aminobiphenyl in step (a), the title compound was prepared as an orang-pink solid (276 mg, 0.950 mmol). MS (ESI): 291.3 (M+H)~.

20 b) N-(N-benzylo~yc~hl,onyl-L-leucinyl)-N'-t2-[N-(2-metllyll~lo~yl)-N-phenyl~rnino]thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 103(d), except subctitllting ) N-12-[N-phenyl-N-(2-methyl- l-propyl)amino]thiazol~-ylcarbonyl]hydr~ide for (2S,1 'S)-2-(benzylo~yc~bonyl)amino-N-[1'-(2-l,yd,~ oç~rbonylthi~ol~-yl)-3~-25 methylbutyl]~-methylpe~t~n~mide7 the title compound was prepared as a white solid (92 mg, 0.171 mmol). MS (ESI): 560.3 (M+Na)+.

F.Xamplel17 Plc~dLion of N-r2-rN-(2-methylpropyl)-N-phenylaminolthiazol-4-ylcarbonyll-N'-rN-(4-pyridinylmetho~yc~l~ollyl)-L-leucinyllhydrazide - Following the procedure of Example 113(a)-113(f), except subct~ ting S aniline for 4-aminobiphenyl in step (a), the title compound was ~r~a,~,d as a yellow solid (50 mg, 0.092 mmol). MS (ESI): 539.4 (M+H)+.

E~xample 118 PlGp~ation of N-r2-(2-benzylo~ylJhenyl)thi~ol-4-ylcarbonyll-N'-rN-(3-pyridhlyllllethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Exarnple 112(a)- 112(g), except ~uL ~ g N-(3-pyridinylmethokye~l,ûllyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (93.8 mg, 53%). MS (ESI): 574.3 (M+H)+.
Ex~n~?le 119 Pl~paldLion of N-r2-(2-benzyloxyphenyl)thiazol~ylcarbonyll-N'-rN-(2-pyridillyll,leth.,,~yca,bonyl)-L-leucinyllhydr~7~
Following the procedure of Example 112(a)-112(g), except ~.lb~ .l ;"g N-(2-pyridinylm~-tho~y.,~l,ullyl)-L-leucine for N-(4-pyridinylmetho~ycall,onyl)-L-leucine in step (g), the title colll~oulld was prepared as a white solid (149.7 mg, 85%). MS (ESI): 574.4 (M+H)+.

Example 120 Pl~ ion of N-(N-benzyloxycalbGIlyl-N-methyl-L-leucinyl)-N'-r2-(2-benzyloxyphenyl)thiazol~-ylcarbonyllhydrazide - Following the procedure of Example 112(a)-112(g), except sub~ ul il~g N-benzyloxycarbonyl-N-methyl-L-leucine for N-(4-pyridinylmethoxyca,l,ollyl)-L-~ leucine in step (g), the title compound was prepared as a white solid (153.5 mg, 85%). MS (ESI): 609.3 (M+H)+.

W O 97116433 PCTrUS96/18000-Fxample 121 Ple~ ion of N-r2-rN-(2-methylpropyl)-N-phenylaminolthiazol~-ylca,bollyll-N'-rN-(2-pyridinylmetho~yc~l,ollyl)-L-leucinyllhydr~ide Following the procedure of Example 113(a)-113(f), except substituting S aniline for 4-aminobiphenyl in step (a) and N-(2-pyridhlyLllethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (f), the title compound was prepared as a white solid (40 mg). MS (ESI): 539.4 (M+H~+.

F.xample 122 10 P~ .~dLion of N-r2-rN-(2-methylpropyl)-N-phenylaminolthiazol-4-ylcall,onyl~-N'-rN-~3-pyridhlyllllGLllo~y~;all,ollyl)-L-leucinyllhydrazide Following the procedure of Fx~mple 113(a)-113(f), except ~I.s~ ;n~
aniline for 4-aminobiphenyl in step (a) and N-(3-pyridinylm~thoxycarbonyl)-L-leucine for N-(4-pyridinylm~thoxycarbonyl)-L-leucine in step (f), the title compound was ~lGpa~ed as a white solid (42 mg). MS (ESI): 539.4 (M+H)+.

F.xample 123 P~ alalion of N-r2-(2-methoxyphenyl)thiazol-4-ylcall,olly1l-N'-rN-(4-pyriclinylmethoxycarbonyl)-L-leucinyllhydrazide 20 a) 2-trimethylstannylanisole To a stirring solution of n-BuLi (2.6 mL, 2.5M in h.ox~n~, 6.42 mmol) in diethyl ether (2.5 mL) at -78C was added 2-bromo~nicole (1.0 g, 5.35 mmol) in diethyl ether (2 mL) dropwise. After stirring for lh at -78C, trimethyltin chloride (6.4 mL, l.OM in THF, 6.42 rnmol) was added dropwise. The ..li~lulG was allowed to stir an ~ ition~l 2h while slowly warming to room te~ eldLulG. The llli~LulG
was then washed with saturated aqueous NaHCO3. The aqueous layer was extracted with diethyl ether (1 X 50mL) and the organic layers were coll.bi.~ed,dried (MgSO4), filtered and concenlldted. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (1.11 g, 76%). lHNMR (400MHz, CDCl3) o 7.47 (d, lH), 7.40 (t, lH), 7.05 (t, lH), 6.90 (d, lH), 3.36 (s, 3H), 0.34 (s, 9H).

W O 97/16433 PCTrUS96/18000-b) ethyl 2-(2-methoxyphenyl)thi~ole~-carboxylate A ll~ UlG of the compound of Example 112(b) (0.250 g, 1.06 mmol), the compound of Example 83(a) (0.287 g, 1.06 mmol), and S tetrakis(triphenylphosphine)p~ m(0) (0.037 g, 0.0318 mmol) in toluene (2 mL)was stirred at reflux for 16h. The ~ e was diluted with ethyl acetate and washedwith water and brine. The organic layer was dried (MgSO4), filtered and concentl~lt;d. The residue was purified by column chl."llalography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.081 g, 29%).
1HNMR (400MHz, CDC13) o 8.54 (d, lH), 8.22 (s, lH), 7.45 (t, lH), 7.11 (t, lH), 7.05 (d, lH), 4.48 (q, 2H), 4.04 (s, 3H), 1.46 (t, 3H).

c) N-[2-(2-metho~y~hel,yl)thi~ol-4-ylcarbonyl]-N'-tN-(4-pyridinylmethoxyc~ul,onyl)-L-leucinyl]hydrazid Following the procedure of F.x~mple 112(f)-112(g), except substit~lting ethyl 2-(2-methoxyphenyl)thiazole-4-carboxylate for ethyl 2-(2-benzyloxyphenyl)thi~ole-4-carboxylate in step (f), the title compound was ~lGp~das a white solid. MS (ESI): 498.3 (M+H)+.

The above ~lescrirtion fully ~ closes how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embo~lim~nt~ described hereinabove, but in~ des all modifications thereof within the scope of the following claims. The various references to joumals, patents and other publications which are cited herein compri~e the state of the art and are incorporated herein by reference as though fully set forth.

W O 97/16433 PCT~US96/18000 -Ex~n~le 124 rle~ ion of (2S. 1 ~s)-N-r 1 '-(~carboethoxythiazol-2-yl)-3'-methylbutyl~-4-methyl-2-(2-phenylbenzyloxycarbonyl)amino~e.~t~,~a, . ,itl~

5 a) (2S, l'S)-2-(tert-butoxycarbonyl)amino-N-[I'-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-m~ y~ n~ m~
The compound of F.lr~mrle 8(c)(1.2 g, 3.5 mmol) was stirrèd at room te~ eldtulG in neat TFA (2.96 g, 26.0 mmol) for 15 min. The solution was the concentrated in vacuo and redissolved in DMF (25 mL). To the stirring solution was added triethylamine (0.779 g, 7.7 mmol), BOC-Leu-OH (0.972 g, 3.9 mmol), l-hydroxybenzotriazole (0.095 g, 0.7 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.750 g, 3.9 mmol). After stirring at room t~ lalule for 16 hours, the solution was diluted with ethyl actate and washed succe~ively with water (2 X 100 mL), NaHCO3, and brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by column chlc,lllatography (silica gel, ethyl acetate/hexane) to yield the title colll~ou.ld as a white solid (1.15 g, 72%). MS(~SI): 456.2 (M+H)+.

b) (2S,l'S)-N-[1'-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-methyl-2-(2-phenylbenzylo~yca bonyl)aminop~ mi~le To a stirring solution of phosgene ( 1.5 rnL, 2.9 mmol, 1 .93M in toluene) at 0~C was added 2-biphenylm~th~nol (0.486 g, 2.64 mmol) and diisopropylethylamine (0.375 g, 2.9 mmol). The solution was allowed to stir at 0~C
for 30 min. In a se~alate reaction vessel, after stirring at room telll~ ul~ for 10 min, the compound of F~mrle 124(a) (0.150 g, 0.330 mmol) dissolved in TFA (2.0 mL) was concentrated and redissolved in DMF (3 mL). This solution was added to the 2-bi~h-,.-yll~ethanol solution followed by diisopropylethylamine (0.213 g, 1.65 mmol). After stirring at room te~pe.dluie for lh, the solution was diluted with ethyl acetate and washed surces~ively with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by colurnn W O 97/16433 PCT~US96/18000-ch.o..lalography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.138 g, 74%). MS(ESI): 566.3 (M+H)+.

FY~m~?le 125 5 rlt~dtion of (2S~ l'S)-2-r(2-benzyl)benzyloxycarbonyl)lamino-N-rl'-(4-carboethoxythiazol-2-yl)-3'-methylbutyll-4-mell~yly~ ".icle Following the procedure of Fx~mrle 124(b), except ~UlJ~ 2-benzylbenzyl alcohol for 2-biphenylmloth~nol, the title compound was p.~pa,~,d as a white solid (0.123 g, 64%). MS(ESI): 580.0 (M+H)+.

~ ml?le 126 P~dlionoff2s~ l'S)-N-rl'-(4-carboethoxythiazol-2-yl)-3'-methylbutyll~-methyl-2-r(2-naphthylmeth~yc~l~onyl)~aminupel ~l~n~rnj-1e Following the procedure of F~mrle 124(b), except sub~ g 2-n~phth~lPn~.~.rll.~n~l for 2-biphenyllllethanol, the title compound was p.G~,d as a white solid (0.132 g, 74%). MS(ESI): 540.1 (M+H)+.

Ex~mI?le 127 20 P~ ion of (2S. l 'S)-N-r l '-(4-carboethoxythiazol-2-yl)-3'-methylbutyll~-m.othyl-2-r(3-pheno~ybGllzylo~yc~hl,onyl)laminol,G-~1~ mi(le Following the procedure of Example 124(b), except subsfitllting 3-phenu~yl,ell~yl alcohol for biphellyl . . .~lh~nol, the title compound was p.G~aled as a white solid (0.107 g, 56%). MS(ESI): 581.9 (M+H)+.

~ 155 Example 128 Ple~aliQn of (2S.l'S)-2-(benzyloxycarbonyl)amino-N-rl'-r2-(2-benzylguanidinyl)thiazol-4-yll-3'-methylbutyll~-,1lcLllyl~.en~ ~n~mi~le a) S-methyl dithiobiuret hydroiodide salt To a stirring solution of dithiobiuret (5.0 g, 37 rnmol) in THF (75 rnL) was added ioclom~th~nt-- (13.1 g, 92.5 mmol, 5.76 ml). After stirring at room le-ll~elaLul~ for 22 h, the solution was diluted with 150 mL of toluene and allowed to stand at 0 ~C for 3 h. The crystals were collected by filtration and washed with cold 2: 1 toluene/THF, then dried in vacuo to give the title compound as a whitesolid (8.7 g, 85%). MS(ESI): 149.9 (M+H)+.

b) 3-benzylgu~nirlinyl thiourea The compound of Example 128(b) (4.35 g, 15.7 mmol) was dissolved in isc.~r~allol (80 mL) and benzylarnine (1.77 g, 16.5 mmol, 1.8 rnL) was added and15 the mixture was heated at reflux for 16 h. The hot solution was filtered and the filtrate was cooled to 0 ~C. After 5 h, the solid was collected by filtration and washed twice with cold io~lu~lol, then dried in vacuo to provide the title compound as a white solid (2.59 g, 61%) MS(ESI): 209.2 (M+H)+.

c) (2S,1 'S)-2-(benzylo~yc~hl,ollyl)amino-N-[1 '-[2-(2-benzylguanidinyl)thiazol~-yl]-3'-methylbutyl~-methylpent~n~mi~le Following the procedure of Example (b), except sub~l i I . .l i llg 3 benzylguanidinyl thiourea for ethyl thiooxamate, the title compound was preparedas a white solid (102 mg, 79%). MS(ESI): 565.1 (M+H)+.

W O 97/16433 PCT~US96/18000-Fxample 129 P1G~J~dLiOn of (lS)-N-r4-rl-(N-benzyloxycarbonylamino)-3-methylbutyllthiazol-2-ylcarbonyl~-N-methyl-N'-(N-benzylo~Lyc~ubollyl-L-leucinyl)hydr~ide Following the procedure of Fx~mrle 26(a)-26(d), except snhstit-lti~.-g methyl 5 hy~d~ille for hyLd~ c in step (c), the title compound was prepared as a white solid. MS(ESI): 624.1 (M+H)+.

FY~rnrle 130 Plc~ ion of ( l S)-N-r4-r l -(N-benzyloxyc~l,onylamino)-3-methylbutyllthi~ol-2-10 ylcarbonyll-N'-(N-benzylo~yc~ yl-L-leucinyl)-N'-methylhydrazide a) N-(N-benzylo~y~;a,l,onyl-L-leucinyl)-N-methylhydr~ide Following the procedure of Example 26(c), except ~ iI, . l i . .g N-benzylox.yc~l,onyl-L-leucine methyl ester for (lS)-l-benzyloxyc~l,ollylamino-l-15 (2-carboethoxythi~ol-4-yl)-3-methylbutane and methyl hydr~ine for hydr~ine, the title compound was p,.,~a,~,d.

b) (lS)-1-benzyloxyc~l,o.lyl~mino-1-(2-carboxythi~ol-4-yl)-3-methylbutane The c<nll~oulld of Example 26(c)(0.57 g., 1.5 mmol) was dissolved in 20 tetrahydn~ru,~l and treated with an excess of l.ON sodium hydroxide. The l~ UlC
was allowed to stir for 4 hours, and was quenched with l.ON citric acid. The solvent was evaporated and the aqueous layer extracted three times with dichlo,c,..l~ n~ The organic layers were co"lbhled and evaporated to give the acid as a white foam (0.55 g, 100%).
c) (lS)-N-[4-[1-(N-benzyloxyc~l,onylamino)-3-methylbutyl]thi~ol-2-ylcarbonyl]-N ' -(N-benzyloxycarbonyl-L-leucinyl)-N'-methylhydr~ide Following the procedure of F.x~mple 28(e), except ~.ub~ N-(N-benzyloxycarbonyl-L-leucinyl)-N-methylhydrazide for (lS)-l-(benzyloxycarbonyl)amino- 1 -(4-carboethoxythi~ol-2-yl)-3 -methylbutane and (1 S )-l-benzylo~yc~bollylarnino-1-(2-carboxythiazol-4-yl)-3-methylbutane for N-W O 97/16433 PCT~US96/18000 benzylv~ycalbvllyl-L-l~ucin~, the title compound was ~l~al~d as a white solid.
MS (ESI): 624.2 (M+H)+.

F.x~rr~ 131 S P~ation of N-(N-benzyloxvc~bollyl-L-leucinyl)-N'-(N-benzylo~yc~l~onyl-L-leucinyl)-L-alanylhydr~ide r Following the procedure of Example 27(a)-27(c), except ~ubs~ g L-alanine methyl ester for L-leucine methyl ester in step (a), the title compound was ~lcp~-,d as a white solid (225 mg, 42%). MS(ESI): 598.1 (M+H)+.
Example 132 P~ al aLion of N-(N-benzylo~yc~ l,onyl-L-leucinyl)-N'-(N-benzyloxycarbonyl-L-inyl)glycinylhydrazide Following the procedure of Example 27(a)-27(c), except subs~ l;, .g glycine methyl ester for L-leucine methyl ester in step (a), the title co.ll~oulld was pr~ ed as a white solid (307 mg, 42%). MS(ESI): 584.1 (M+H)+.

Fx:~m~I?le 133 Pl~aldlion of (lS)-N-r2-rl-(N-benzyloxycalbullylarnino)-3-methylbutyll-1.3.4-tri~7nl-s-ylcarbonyll-N~-(N-benzyloxycarbonyl-L-leucinyl)hydrazide a) ethyl o}~ mi~r~onate To a solution of ethyl thionY~m~t~ (3.0 g, 22.6 mmol) in ethanol (50 rnL) was added hydrazine hydrate ( 1.13 g, 22.6 mmol, 1.09 mL). The l~ ; was allowed to stir for 3 hours at room temperature, while venting through a scrubber of concentrated sodium hydroxide solution. The solution was allowed to stand for 16hours and the ethanol was ev~vld~ed. The residue was boiled in 30%
dichlorom~th~ne in petroleum ether, filtered, and recryst~lli7~1 to give the desired compound as a tan solid. (0.264 g, 9%).

W O 97/16~33 PCT~US96/18000 -b) (1 S)- 1 -benzyloxycarbonylamino- 1 -(2-carboethoxy- 1,3,4-triazol-5-yl)-3-methylbutane N-benzyloxycarbonyl-L-leucine (0.535 g, 2.0 mmol) was stirred in THF at -5 ~C. Ethyl chloroformate (0.23 rnL, 2.4 mmol) and triethylamine (0.25 g, 2.4 mmol, 0.34 mL) were added. The compound of Fx~mple lO(a) (0.264 g, 2.0 mmol) was then added and the ~ UlG was allowed to stir at room Le~ dlul~, overnight.
The solvents were ev~olal~d and the residue was dissolved in xyienes and heated to 200 ~C using a Dean-Stark a~Lus. The heating was stopped after 4 hours and the solution was ev~uldled to a residue which was chromatographed (silica gel, 40% ethyl acetate in hexane) to give the title compound as a white solid (0.498 g, 69%). 1H NMR (400 MHz, CDCl3) ~ 7.20 (m, SH), 5.71 ( d, lH), 5.04 ( s, 2H), 4.99(dd, lH),4.36(q,2H), 1.8(m,2H), l.S9(m, lH), 1.31 (t,3H),0.83( dd, 6H).

c) (lS)-1-benzylo~yc~l.ollylamino-1-(2-hydr~7inoc~rbonyl-1,3,4-triazol-5-yl)-3-methylbutane Following the procedure of F.Y~mple 26(c)-26(d), except sub~ ;..g (lS)-1-benzylo~yc~bollylamino- 1 -(2-carboethoxy- 1,3,4-triazol-5-yl)-3-methylbutane for (1 S)- 1 -benzyloxycarbonylamino- 1 -(2-carboethoxythiazol-4-yl)-3-methylbutane in step (c), the title c<~ oulld was ~lG~ed. MS (ESI): 594.5 (M+H)+.

~x~ 134 Preparation of (1 S)-N-(N-acetyl-L-leucinyl)-N'-r2-r l -(N-benzyloxycarbonylamino)-3-methylbutyllthiazol~-ylcarbonyllhydrazide Following the procedure of Example 28(a)-28(e), except sllb~ g N-acetyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title compound was plepa, d as a white solid (95 mg, 67%). MS(ESI): 518.0 (M+H)+.

W O 97/16433 PCT~US96/18000 ~xample 135 Preparation of (1 S)-N-(N-benzyloxyc~l,~nyl-L-alanyl)-N'-r2-r 1 -(N-ben7,ylo~yc&1,onylamino)-3-methylbutyllthiazol-4-ylcarbonyllhydrazide Following the procedure of F.xample. 28(a)-28(e), except sul~ g N-5 benzyloxycarbonyl-L-alanine for N-benzylo~ye&l~o--yl-L-leucine in step (e), the title compound was prepared as a white solid (129 mg, 82%). MS(ESI): 568.1 (M+H)+.

Fx~mrle 136 10 Plc~al~Lion of (lS)-N-(N-acetyl-L-alanyl)-N'-r2-rl-tN-benzyloxycarbonylamino)-3-methylbutyllthiazol-4-ylcall.onyllhydrazide Following the pluced-l~G of Example 28(a)-28(e), except srlb~ g N-acetyl-L-alanine for N-benzyloxyca,l,ol,yl-L-leucine in step (e), the title compound was ~,G~al~,d as a white solid (74 mg, 57%). MS(ESI): 498.1 (M+Na)+.
F.xarnple 137 P~ lion of (lS)-N-(N-acetyl)-N'-r2-rl-(~-benzyloxycarbonylamino)-3-mPtl~ylbutyllthiazol~ylc~bollyllhydrazide Following the procedure of F~campl~ 28(a)-28(e), except sub~ ulillg acetic 20 acid for N-benzyloxyc&bonyl-L-leucine in step (e), the title compound was ,ulG~cd as a white solid (87 mg, 78%). MS(ESI): 405.1 (M+H)+.

Example 138 PlG~ lioll of (lS)-N-r2-rl-~N-benzylo~yc~bonylamino)-3-metlurlbutyllthia7ol 4-25 ylr~- 1,ollyll-N'-rN-(4-pyri~ ,ylllletho~ycalbonyl)-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except sub~l;l..~;..g N-(4-pyridinylmPthnxycarbonyl)-L-leucine for N-benzylo~yc&l,ollyl-L-leucine in step (e), the title compound was ,u~palcd as a white solid (121 mg, 72%). MS(ESI):
611.0 (M+H)+.

_ W O 97/16433 PCT~US96/18000 Fx~n~ple 139 Pl~dlion of (lS)-N-r2-rl-(N-benzyloxyc~l,ollylarnino)-3-methylbutyllthiazol~-ylc~l,ollyll- N'-rN-(2-pyridinylmetho~yc~b~JIlyl)-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substitllting N-(2-S pyridinylmetho~yc~bol~yl)-L-leucine for N-benzylo~Lyc~l~onyl-L-leucine in step(e), the title compound was pl~a,ed as a white solid (125 mg, 65%). MS (ESI):
61 1.2 (M+H)+.

Ex~mple 140 10 Pl~dLion of (lS)-N-r2-rl-(N-benzylo~y-;~l.ol,ylamino)-3-methylbutyllthiazol-4-ylc~l,ollyll- N'-(N-benzylo~yc~l,onyl-N-methyl-L-leucinyl)hydrazide Following the procedure of F~mple 28(a)-28(e), except substitl-ting N-benzylo~yc~lJonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title compound was p,~al ,d as a white solid (78 mg, 50%). MS (ESI):
624.3 (M+H)+.

Fx~rnple 141 P~ tion of (lS)-N-r2-rl-(N-benzylo~cyc~1,ollyl-N-methylamino)-3-m.o,thylbutyllthiazol-4-ylcarbonyll-N'-rN-(4-pyridinylmethoxycarbonyl)-L-20 leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except sub~l il ~.l i ,-g N-benzylo~yc~l,onyl-N-methyl-L-leucine for N-tert-butoxyc~bollyl-L-leucine in step(a) and N-(2-pyridinylmetho~yc~bollyl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title c~ oulld was prepared as a white solid (120 mg, 72%).
25 MS (ESI): 625.3 (M+H)+.

W O 97/16433 PCT~US96/18000 -Example 142 P1G~dliOn of (l'S)-N-(N-benzyloxyc~bo,lyl-L-leucinyl)-N'-r2-rl-(N-benzylo~yca,bonyl-N-methylamino)-3-methylbutyllthiazol-4-ylc~l,ol,yllhydrazide Following the procedure of Fx~mple 28(a)-28(e), except ~ub~ .l i . .g N-S benzyloxyc~bollyl-N-methyl-L-leucine for N-tert-buto~yc~l~ollyl-L-leucine in step (a), the title compound was prepared as a white solid (95 mg, 74%). MS (ESI):
624.3 (M+H)+.

Ex~ ?le 143 10 rlc~dtion of (lS)-N-r2-rl-(N-benzylo~yc;all,onyl-N-methylamino)-3-mtot~ butyllthi~7~ 1-4-yllcarbonyl- N'-(N-ben7~10~yc~ubol,yl-N-methyl-L-leucinyl)hydrazide Following the procedure of Example 28(a)-28(e), except s-lb~ N-benzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step15 (a) and N-benzyloxyc~bol,yl-N-methyl-L-leucine for N-benzyl~yc~bonyl-L-leucine in step (e), the title compound was prepared as a white solid (129 mg, 59%).
MS (ESI): 683.3 (M+H)+.

~.x~ ?le 144 20 I~ ~dlion of ( 1 S)-N-r2-r 1 -(N-methylamino)-3-methylbutyllthiazol~-ylcarbonyll-N'-rN-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide a) (lS)-N-t2-[l-(N-tert-buto~y~;~l,ollyl-N-methylamino)-3-methylbutyl~thia_ol-4-ylc~ul,o,,yl]-N'-tN-(4-pyridinylmeth~yc~l,onyl)-L-leucinyl]hydrazide Following the procedure of Example 28(a)-28(e), except ~ul,~l; 1. .l i .,g N--25 tert-butoxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine instep (a) and N-(4-pyridinylm~thoxycarbonyl-L-leucine for N-benzylo~yc~l,onyl-L-leucine in step (e), the title compound was p,epaled as a white solid. MS (ESI):591.4 (M+H)+.

W O 97/16433 PCT~US96/18000 -b) (1 S)-N-[2-[1-(N-methylamino)-3-methylbutyl]thiazol~-ylc~bollyl]-N'-[N-(4-pyridinylmethoxyc~l,onyl)-L-leucinyl]hydr~ide To a solution of the compound of F.x~mple 21(a) in methylene chloride (10 mL) was added trifluoroacetic acid (3 mL). After stirring one hour at room S r~ e,dlu,~ the solution was concentrated and the residue was redissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried overMgSO4 and conce~ ted to afford the title compound as a white solid (259 mg, 68% fortwo steps). MS (ESI): 491.4 (M+H)+.

F.xan~le 145 r-~ a~iOn of (1 S)-N-r2-r 1 -(N-benzylo~yca-13u-lylamino)-3-methylbutyllthiazol~-ylca l~onyll-N'-rN-(tert-butoxyc~l,ol~yl)-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except sub~ g N-tert-butoxyc~l,ol.yl-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title compound was p,~ d as a white solid (293 mg, 74%). MS (ESI): 576.4 (M+H)+.

Fx~ le 146 P~ Lion of ( l S)-N-r2-r l -(N-benzyloxycarbonylamino)-3-methylbutyllthiazol~
20 ylc~bo--yll-N'-rN-(tert-buto~yc~bo--yl)-N-methyl-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except s~ N-tert-buto~Lyc~ul,o..yl-N-methyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title co"~und was ~l~a.ed as a white solid (120 mg, 87%). MS (ESI): 590.3 (M+H)+.

F,xam~l?le 147 PlG~aldlion of (lS)-N-r2-rl-(N-benzyloxycarbonylamino)-3-methylbutvllthiazol-4-ylcarbonyll-N'-(N-metllyl-L-leucinyl)hydr~ide Following the procedure of Example 144(b), except ~ (lS)-N-~2-5 [1-(N-benzyloxycarbonylarnino)-3-methylbutyl]thiazol4-ylc~l,onyl]-N'-[N-(tert-buloAycalbollyl)-N-methyl-L-leucinyl]hydrazide for (lS)-N-[2-[1-(N-tert-butoxycarbonyl-N-methylamino)-3-methylbutyl]thi~ol4-ylcarbonyl]-N'-[N-(4-pyridil,yllllethoAyc~l,onyl)-L-leucinyl]hydrazide, the title compound was prepar~d as a white solid (40 mg, 80%). MS (ESI): 490.3 (M+H)+.
Example 148 rlGL)dl ,lLion of (1 S)-N-r2-r 1 -(N-benzyl-~yc~bonylamino)-3-methylbutyllthiazol-4-ylcarbonyl~-N'-(L-leucinyl)hydrazide Following the pl~.ce~lurc of RY~mple 144(b), except sub~ (lS)-N-[2-15 [1-(N-benzyloAy~ onylamino)-3-methylbutyl]thi~ol4-ylcarbonyl]-N'-rN-(te~-butoxycarbonyl)-L-leucinyl]hydla~ide for (1 S)-N-[2-[1 -(N-tert-butoxycarbonyl-N-methylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoAy-;a,l,onyl)-L-leucinyl]hydr~ide, the title co~ol",d was ~ alcd as a white solid (39 mg, 100%). MS (ESI): 476.4 (M+H)+.
Fx~mI?le 149 ~lc~ ion of (lS~-N-r2-rl-(N-benzyloxycarbonylamino)-3-methylbutyllthiazol~-ylcarbonyll-N'-rN-(4-imidazolylacetyl)-L-leucinyllhydrazide Following the procedure of Example 28(e), except s~lba~ (lS)-N-[2-[1-2~ (N-benzyl~Ayc~bollylamino)-3-methylbutyl]thi~ol-4-ylc~l,onyl]-N'-(L-leucinyl)hydrazide for (1 S)- 1 -(benzyloAy~bol-yl)arnino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane and 4-imid~oleacetic acid for N-benzyloAycall,onyl-L-leurin~, the title compound was plep~cd as a white solid (~0 mg, 47%). MS (ESI):584.4 (M+H)+.

F~ ?le 150 rl~aldl.ion of (lS)-N-r2-rl-(N-benzyloxycarbonyl-N-methylamino~-3-,m~tl~lbutyllthiazol~-ylca,l,ollyll-N~-rN-(3-pyridillyln~Lho~yc~hbol~yl)-N-meth L-leu~inyllhydrazide 5 a) N-methyl-L-leucine methyl ester N-methyl-L-leucine (1.3 g, 8.95 mmol) was dissolved in 4M HCl, 1,4-dioxane (10 mL) and m~th~nol (10 mL). The solution was stirred overnight at roomLC~1)G1dLU1C~, then concenLl~L~d to afford the title compound as a white solid (100%).
MS (ESI): 160.0 (M+H)+.
b) N-methyl-N-(3-pyridinylmetho~yc~l,ol,yl)-L-leucine methyl ester To a stirring solution of phosgene in toluene (5.63 mL, 6.025 mmol) in methylene chloride (10 mT,), cooled to 0~C, was added dropwise a solution of N-methyl-L-leucine methyl ester (673 mg, 4.63 mmol) and pyridine (1.10 g, 0.97 mL,13.89 mmol) in methylene chloritle (4 mL). The solution was stirred at 0~C for 2hours. A solution of 3-pyridyl carbinol (0.56 g, 5.09 mmol, 0.49 mL) was then added and the reaction 11~~ WaS stirred at room te~ Lul~ for S hours. The solution was conce.,Ll,lt~;d, redissolved in ethyl acetate, washed with water, dried (MgSO4), filtered and co~ l The crude residue was purified by column 20 chrom~tography on silica gel (6% methanol in methylene chloride) to afford the title compound as a yellow oil (88 mg, 7%). MS (ESI): 295.4 (M+H)+.

c) N-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucine Following the pluce.lul~ of Example 130(b), except ~ul,~ N-methyl-25 N-(3-pyridinylm~tho~cyc~bonyl)-L-leucine methyl ester (lS)-l-benzylu~y~l,ollylamino- 1 -(2-l,y&~ loc~l,o,lylLhi~ol-4-yl)-3-methylbutane, the - title colll~ound was p ~alcd as an orange solid (84 mg, 100%). MS (ESI): 281.3 (M+H)+-~ , , CA 02236lll l998-04-28 PCTnUS96/18000 -d) (lS)-N-[2-[1-(N-benzyloxycarbonyl-N-methyl~mino)-3-methylbutyl~thia_ol~-ylc~bollyl~-N~-[N-(3-pyridillyll,lGlllo~yc~a~onyl)-N-methyl-L-leucinyl~hydra-ideFollowing the procedure of Fx~mrle 28(a)-28(e), except ~ubslil..li,-g N-benzylo~yc~lJonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step5 (a) and N-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucine for N-benzylu~yc~L onyl-L-leucine in step (e), the title compound was prepared as a white solid (5~ mg, 38%). MS (ESI): 639.4 (M+H)+.

I~x~nlple 151 10 Pl~dlion of (lS)-N-r2-rl-(N-benzyloxycalbonyl-N-methylamino)-3-mt-tl1ylbutyllthia~ol 1-ylc~l,ol.yl~-N'-rN-(3-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except sub~ N-benzyloxycarbonyl-N-methyl-L-leucine for N-ter~-butoxycarbonyl-L-leucine in step15 (a) and N-(3-pyridinylmetho,-yc~bonyl)-L-leucine for N-benzylo~yca l,onyl-L-leucine in step (e), the title compound was prepared as a white solid (31 mg, 34%).
MS (ESI): 625.4 (M+H)+.

F.xarnple 152 20 F~G~lion of (lS)-N-r2-rl-(N-ben_yloxycarbonylamino)-3-methylbutyl~thi~7ol~-ylcarbonyll- N'-rN-(3-pyridinylmetho~y~a~bollyl)-L-leucinyllhydrazide Following the procedure of Fx~mple 28(a)-28(e), except ~ub.~ i..g N-(3-pyridillyllllctho~yc~l,ollyl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title compound was ~cp~d as a white solid (63 mg, 42%). MS (ESI):
611.5 (M+H)+.

W O 97/16433 PCT~US96/18000-F.x~rru?le 153 E'lc~&-dlion of (l'S)-N-(N-benzyloxycarbonyl-L-leucinyl)-N'-(l-benzylo~yc~l,o,-yl)-N'-r2-r 1 -(N-methylamino)-3-methylbutyllthiazol-4-ylcarbonyll -N'-methylhydrazide Following the procedure of Example 28(a)-28(e), except s-lhsl;l.. l;.lg N-benzylo~yc~bollyl-N-methyl-L-leucine for N-te~t-buto~Lyc~l,ol.yl-L-leucine in step (a) and methyl l~&~ine for lly~lldzi~e in step (e), the title compound was prepared as a white solid (80 mg, 70%). MS (ESI): 660.4 (M+Na)+.

F~xample 154 Ple~dlion of (lS)-N-r2-rl-(N-benzyloxyc~bonylarnino)-3-methylbutyllthiazol~-ylcarbonyll- N'-rN-(2-pyridinylmethoxyc~bollyl)-N-methyl-L-leucinyllhydrazide a) N-methyl-N-(2-pyridinylmeth~ yc~hbonyl)-L-leucine methyl ester N-(2-pyridinylmethoxyc~bGllyl)-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. The reaction ~ UI~ was cooled to 0~C in a flask protected from moisture. Sodium hydride dispersion (236 mg, 2.62 mmol) was added cautiously and the ~spe-~ion was stirred for 5 hours at room IGIll~eldlulG. Ethyl acetate was then added, followed by water, dropwise. The solution was conce~ dl~d in vacuo, and the oily residue partitioned between ether and water. The organic layer was washed with saluia~d aqueous NaHCO3 and the combined aqueous extracts ~ci~lifilod to pH 3 with citric acid. The product was extr~ct~l with ethyl acetate, the extract was washed with water, 5% aqueous sodium thiosulfate and water, dried (MgSO4), filtered and concel.L,dlt:d. The crude product was purified by column clll~"l,atugraphy on silca gel (ethyl acetate/ hexane, 3: 1) to give a yellow oil (235 mg, 46%). MS (ESV: 295.4 (M+H)+.

W O 97/16433 PCT~US96/18000 b) N-methyl-N-(2-pyridinylmethoxycarbonyl)-L-leucine Following the procedure of Fx~mple I30(b), except sub~ g N-methyl-N-(2-pyridinylmethoxyc~l,ollyl)-L-leucine methyl ester (lS)-l-benzylokyc~l,onyl~mino-1-(2-hydrazinocarbonylthiazol~-yl)-3-methylbutane, the title compound was ~r~al~d as a white solid (223 mg, 100%). MS (ESI): 281.3 (M+H)+.

c) (1 S)-N-[2-[1 -(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[N-(2-pyrid~,ylll~lho~yc~l,onyl)-N-methyl-L-leucinyl]hydrazide Following the procedure of F.x~mpl~ 28(a)-28(e), except subs~ g N-benzyloxycallJonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step (a) and N-methyl-N-(2-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title co~ )ound was ~l~,pa,.,d as a white solid (50 mg, 44%). MS (ESI): 639.5 (M+H) 1.
Example 155 P~ Lion of (lS)-N-r2-rl-(N-benzyloxycarbonyl-N-methyl~mino)-3-mto,tllylbutyllthiazol-4-ylcallJo"yll-N'-rN-(4-pyridinylm~tho~yc~lJollyl)-N-methyl-T .-leucinyllhydrazide a) L-leucine tert-butyl ester isocyanate L-leucine tert-butyl ester hydrochloride (10.185 g, 45.5 mmol) was dissolved in methylene chloride (100 mL), cooled to 0 ~C and pyridine (12.7 mL, 182.0 mmol) was added, then phosgene in benzene (47 mL, 59.1 rnmol). The solution was stirred at 0 ~C for 2 hours. The reaction mi~ ; was washed two times with 300 mL of cold 0.5 M aqueous HCl. E~ach aqueous layer was exctracted with 100 mL methylene chloride. The combined organic phases were washed with a mixture of saturated aqueous NaCl solution and crushed ice, dried over MgSO4, filtered and concentrated to afford the isocyanate as a yellow liquid (5.37 g, 55%).

, W O 97/16433 PCT~US96/18000 b) N-(4-pyridillyl,,~lht-~yc~bonyl)-L-leucine tert-butyl ester The compound of l~xample 155(a) (3.05 g, 14.32 mmol) and 4-pyridyl carbinol (1.56 g, 14.32 mmol) were dissolved in toluene (80 mL) and heated at reflux ov,o-rnight The solution was con~cl.l, aLed in vacuo and the residue was 5 purified by column chromatography on silica gel (ethyl acetate/ hexane, 3: 1) to afford the title compound as a colorless oil (2.945 g, 64%). MS (ESI): 323.4 (M+H)+.

c) N-methyl-N-(4-pyridinylmpthoxycarbonyl)-L-leucine tert-butyl ester Following the procedure of Example 154(a), except ~,ub~,lil~.li.. g N-(4-pyri.lhlyll,lt;Lhoxycarbonyl)-L-leucine tert-butyl ester for N-(2-pyridillyllneLhoxyc~1~ollyl)-L-leucine methyl ester, the title compound was ~ d as a yellow liquid (2.038 g, 68% yield). MS (ESI): 337.5 (M+H)+.

15 d) N-methyl-N-(4-pyridinylmetho~yc~b~,llyl)-L-leucine Following the procedure of Example 144(b), except ~ulr~lilulillg N-methyl-N-(4-pyridinylmetho~ycalbollyl)-L-leucine tert-butyl ester for (lS)-N-~2-[1-(N-tert-buLu~yc~bo~yl-N-methyl~mino)-3-methylbutyl]thiazol4-ylcarbonyl]-N'-[N-(4-pyridinyl...- II.c)xy~a-boryl)-L-leucinyl]hydrazide, the title compound was ~le~,d as a white solid (343 mg, 72% yield). MS (ESI): 281.3 (M+H)+.

e) (1 S)-N-[2-[1 -(N-benzyloxycarbonyl-N-methylamino)-3-methylbutyl]thiazol4-ylcarbonyl]-N'-[N-(4-pyridillyl..,fthQxycarbonyl)-N-methyl-L-leucinyl]hydrazide Following the procedure of Example 28(a)-28(e), except Sub~lilulillg N-25 benzylokyc~l,onyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step (a) and N-methyl-N-(4-pyridinylmethu~yc~bol1yl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step (e), the title compound was pl~aled as a white solid (50 mg, 44%). MS (ESI): 639.5 (M+H)+.

Example 156 Plc~dlion of ~.2'-lN.N'-rbis-(N-acetyl-L-leuccinyl)llcarbohydrazide Following the procedure of Example 29, except sub~LiLuLing N-acetyl-L-leucine for N-benzyloxycarbonyl-L-leucine, the title co~ oll,.d was prepared as a pale yellow solid (0.153 g, 23%). MS(ESI): 401.3 (M+H)+.

F.x,~ le 157 ~aldlion of 2-rN-(N-benzyloxycdlllullyl-L-leucinyl)l-2'-rN'-(4-".- l h yl~e..ldl,oyl)lcarbohydr~ide a) N-benzyloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester (2.0 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added aqueous Na2C03 solution (12.1 mL, 2M in H20) followed by benzylchlorofo----~Le ( 1.96 g, 11.5 mmol). The mixture stirred at room telllp.~ldlulc for 4h then partitioned bel~een ethyl acetate and water. The organic layer was washed with sa~uldled brine, dried (MgS04), filtered and concentrated to yield the title compound as a colorless oil (3. lg, 100%). lHNMR (400MHz, CDC13) o 7.34 (m, SH), 5.27 (d, lH), 5.12 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 1.65 (m, 3H), 0.96 (m, 6H).

b) N-(N-benzyloxycarbonyl-L-leucinyl)hydrazide To a stirring solution of the compound of Exarnple 157(a) (3. lg, 11 .Ommol) in methanol (15 mL) was added hydrazide hydrate (5.9 g, 118 mmol, 5.7 mT.), The solution stirred at room IGlll~,ldlulG for 16 h then concellLldlGd to yield the title compound as an off-white solid (3.1 g, 100%). MS(ESI): 280.2 (M+H)+.
c) 1-benzyloxycarbonylamino-3-methyl-1-(1,3~4-ox~ 7ol-2-on-s-yl)butane To a stirring solution of the compound of Example 157(b) (3.0 g, 10.8 mmol) in toluene (50 mL) was added phosgene (56 mL, 1.93M in toluene). The solution was heated at reflux for 4h, then concellLlaLed to yield the title compound as a pale yellow foarn (3.15 g, 96%). MS(ESI): 306.1 (M+H)+.

d) N-(4-methyll,en~loyl)hydr~ide To a stirnng solution of ethyl isocaproate (2.0 g, 13.8 mmol) in ethanol (25 mL) was added hydrazine monohydrate (6.9g, 138mmol, 6.7 mL). After stirring at room ~ eldtulc for 48 h, the solution was co~e..l . dled to yield the title S co~ ound as a white solid. (1.8 g, 100%). lHNMR (400MHz, CDC13) o 7.48 (s br, lH), 3.62 (s br, 2H), 2.13 (t, 2H), 1.51 (m, 3H), 0.85 (d, 6H) e) 2-[N-(N-benzyloxycall,onyl-L-leucinyl)]-2'-[N'-(4-me~ yll~e~ yl)]carbohydrazide The compounds of F.l~mple 157(c) (0.100 g, 0.325 mmol) and Example 34(d) (0.042 g, 0.325 mmol) were combined and dissolved in ethanol (1 InT .). The solution was heated at reflux for 24 hours, then concentrated to a solid yellow residue which was washed with cool methylene chloride to yield the title compound as a white solid (0.053 g, 37%). MS(ESI): 436.2 (M+H)+.
F~mll?le 158 PlG~,a.dlion of 2.2'-rN.N'-rbis-(N-benzylo~yc~ yl-N-methyl-L-leucillyl)llcarbohydrazide Following the procedure of_xample 29, except ~ubs~ g N-benzylokyc~l,o,lyl-N-methyl-L-leucine for sub~ g N-benzylo,~yc~l,ollyl-L-le.ncine7 the title compound was ~lc~cd with purification by column chromatography (silica gel, methanol/dichlolo~ ne) as a white foam (0.236 g, 23%). MS (MH+): 613.2.

W O 97/16433 PCT~US96/18000 F~n~le 159 P c;~ alion of 2-rN-(N-acetyl-L-leucinyl)1-2'-1N'-(N-benzyloxycarbonyl-L-lçucinyl)lcarbohydrazide ) a) 2-[N-(N-benzylo~yc~l)onyl-L-leucinyl)]carbohydrazide To a stirring solution of the compound of F.x~mplP 157(c) (3.15 g, 10.3 mmol) in m~.th~no] (2 mT) was added hydrazine hydrate (5.0 g, 100 mmol, 4.8 mL).After stirring at room lt;~ Lule for 24 h, the solution was concentrated to yield the title c~,lll~oulld as a pale yellow foam (3.471 g, 100%). MS(ESI): 338.2 (M+H)~.
b) 2-[N-(N-acetyl-L-leucinyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)3carbohydrazide To a stirring solution of the compound of P~mple 159(a) (0.100 g, 0.297 mmol), N-acetyl-L-leucine (0.054 g, 0.312 mrnol) and l-hydroxybenzotriazole (0.008 g, 0.0594 mmol) in DMF (2mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.312 mmol). After stirring at room te.ll~lalul~; for 16 h, the solution was poured into water and çxtr~ett~d with ethyl acetate. The organic layer was dried (MgSO4), filtered and conce..L,alt;d. The residue was purified by column chromatography (silica gel, 20 m~th~nol/dichlor~mtoth~nlo) to yield the title compound as a white solid (0.052 g, 36%). MS(ESI): 493.1 (M+H)+.

F.xample 160 r~ dtion of 2.2'-rN.N'-rbis-rN-(4-pyridinylmetho~yc~l,onyl)-L-25 leucinyl)lllcarbohydrazide Following the procedure of Example 29, except ~ub~liluLing N-(4-pyridillyl~ lloxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-l.~ in~, the title compound was ~l~pal~,d as a white solid (199 mg, 64%). MS(ESI): 587.1 (M+H)+.

W O 97/16433 PCT~US96118000 F.xample 161 rle~a~ion of 2.2'-rN.N'-rbis-rN-(2-pyridinylmethoxycarbonyl)-L-leucinyl)lllcarbohydrazide Following the procedure of Fy~mple 29, except ~ubslil.~li..g N-(2-S pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxyca,l,ollyl-L-leurin~, the title compound was LJlc~dAc;d as a white solid (263 mg, 81%). MS(ESI): 587.1 (M+H)+.

F.xample 162 rlGp~alion of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-2'-~N'-rN-(2-10 pyridinylmethoxycarbonyl)-L-leucinyl)llcarbohydrazide Following the procedure of Example l59(a)-l59(b) except s-l~stil~ltin~ N-(2-pyridinylm~tho~yc~b~ yl)-L-leucine lithium salt for N-acetyl-L-leucine in step (b), the title compound was prepared as a white solid (0.040 g, 15%). MS(ESI): 586.3 (M~H)+.
FY~m~le 163 Pl~t,~dLion of 2-rN-(N-benzylo~yca,l,ol,yl-L-leucinyl)1-2'-rN'-1~-(4-pyridillyllll~lllohy~dA bonyl)-L-leucinyl)llcarbohydrazide Following the procedure of Example l59(a)-159(b) except subs~ g N-(4-20 pyridinylm~thoxyca l,ollyl)-L-leucine lithium salt for N-acetyl-L-leucine in step (b), the title compound was prepared as a white solid (0.045 g, 17%). MS(ESI): 586.3(M+H)+.

Fx~m.I?le 164 F'lG~aldLion of 2-rN-(N-benzylo~ycall,u"yl-L-leucinyl)1-2'-rN'-rN-(3-pyridinyl,lwLl,oxycarbonyl)-L-leucinyl)llcarbohydrazide A Following the procedure of Example 159(a)-l59(b) except sub~ lg N-(3-pyridinylmethoxycarbonyl)-L-leucine lithium salt for N-acetyl-L-leucine in step (b), the title compound was ~lc~a~,d as a white solid (0.084 g, 32%). MS(ESI): 586.3 30 (M+H)+.

W O 97/16433 PCT~US96/18000-Exan~le 165 ~lPreparation of 2~2'-rN~N'-rbis-(N-benzyloxycarbonyl-L-leucinyl)ll-2-(N-methyl)carbohydrazide a) N-methyl-N-(N-benzyloxycarbonyl-L-leucinyl)hydrazide To a stirring solution of N-benzylo~y-,~l,o.lyl-L-leucine methyl ester (2.2 g, 8.15 mmol) in meth~n~l (4 mL) was added methylhydrazine (3.7 g, 80 mmol).
After stirring at room Lell~ dlulc for 16 h, the solution was concèntrated to yield the title compound as a yellow solid (2.14 g, 7.3 mmol). MS(ESI): 294.1 (M+H)+.

b) 2,2'-[N,N'-[bis-(N-benzylo~ycall,ûnyl-L-leucinyl)]]-2-(N-methyl)carbohydrazide The compound of Fx~mrle 157(c) (0.250 g, 0.819 mmol) and the compound of Exarnple 165(a) (0.240 g, 0.819 mmol) were comhin~A, dissolved in ethanol andheated at reflux for 24 h. The solution was concentlaled and the residue purified by column cll,u~"alography (silica gel, methanoVdichlorom~th~ne) to yield the titlecompound as a white solid (0.060 g, 12%). MS(ESI): 599.1 (M+H)+.

F.xample 166 P~ lion of 2.2'-rN.N'-rbis-rN-(3-pyridinylmethoxycarbonyl)-L-leucinyl)lllcarbohydrazide Following the procedure of Fx~mple 29, except substit~lting N-(3-pyridillyllllc~loxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-lçncin~, the title compound was ~leparcd as a white solid (157 mg, 48%). MS(l~SI): 587.0 (M+H)+.

W O 97/16433 PCT~US96/18000 ~

Ex~m~ple 167 4 P~ lion of 1-(N-benzyl)-2.2'-lN.N'-rbis-(N-benzyloxycarbonyl-L-leucinyl)llcarbohydrazide a) N-benzylidene-N'-(N-benzylo~ycalbu-lyl-L-leucinyl)hydrazide To a solution of the compound of F;.x~mrle 157(b) (1 g, 3.5 mmol) in ethanol (30 mL) was added ben7~1-1ehyde ( 0.33 mL, 3.2 mmol). The resulting llu~lulc; was heated at reflux for 4 h. The l~ lule was con~çntr~tul in vacuo then purified by flash chromatography (silica gel, 10-50% EtOAc / hexane) to yield the title co.~ou--d as a solid (0.31 g, 23%). MS(ESI): 368.0 (M+H)+.
b) N-benzyl-N'-(N-benzyl~yc~l,onyl-L-leucinyl)hydrazide To a cooled solution of compound of Example 167(a) (0.24 g, 0.65 mrnol) in THF (5 mL) was added borane tetral-ydlvruldn complex (0.65 mL, 0.65 mmol; lM
solution in THF). The rçsulting ll~IUle was stirred at room Lt;111~e;1dLU1C; for 4 h then COnCcllLLdLed in vacuo and diluted with ethyl acetate, washed with water, s~hlr~tP~ brine, dried (MgSO4), filtered and concentrated in vacuo to give the title co~ cJulld as a white solid (0.25 g, 89%). MS(ESI): 370.0 (M+H)+.

c) l-benzylo~yc~bollylamino-3-methyl-1-(3-benzyl-1,3,4-ox~ ol-2-on-5-yl)butane Following the procedure of Example 157(c), except subs! i L~ N-benzyl-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide for N-(N-benzyloxycarbonyl-L-leucinyl)hydl~ide, the title compound was prepared as an oil (0.02 g, 83%).
MS(ESI): 396.0 (M+H)+.
d) l-(N-benzyl)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)lcarbohydrazide ~ Following the procedure of Fx~mrle 159(a), except subsLi~uLi.lg 1-benzylo~y~;~l,onylamino-3-methyl-1-(3-benzyl-1,3,4-ox~ ol-2-on-5-yl)butane for 1-benzylo~yca,l,onylamino-3-methyl-1-(1,3,4-QX~ ol-2-on-5-yl)butane in step (a), the title compound was prepared as a solid (0.013 g, 62%). MS(ESI):
428.0 (M+H)+.

W O 97/16433 PCT~US96/18000 d) l-(N-benzyl)-2,2'-rN,N'-[bis-(N-benzylo~yc~bonyl-L-leucinyl)]]carbohydrazide Following the procedure of Example l59(a)-l59(b), except subslil..li..~ 1-benz,yloxycarbonylarnino-3-methyl-1-(3-benzyl-1,3,4-ox~Ai~7.ol-2-on-S-yl)butane S for l-benzyloxycarbonylarnino-3-methyl-1-(1 ,3,4-ox~ 7.ol-2-on-S-yl)butane in step (a), the title compound was ~lcpalcd as white solid (13 mg, 86%). MS(ESI):
675.0 (M+H)+.

~.x~ ?le 168 ~lGp~Lion of 2-rN-(N-benzylo~yc~bonyl-L-leucinyl)l-2'-rN'-(N
benzyloxycalbonyl-N-methyl-L-leucinyl)lcarbohydrazide Following the procedure of Fx~mple l59(a)-159(b) except~ ~Ub~ N-benzyloxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine in step (b), the title colll~oL~I~d was pl~alcd as a white solid (0.141 g, 53%). MS(ESI): 599.4 (M+H)+.

Fxample 169 Ple~ ion of N-r2-( 1 -naphthyl)thiazol-4-ylcarbonyl~-N'-rN-(4-pyridinylmethoxvcarbonyl)-L-leucinyllhydrazide Following the procedure of Exarnple 112(a)-1 12(g), except ~~~b~
naphthyl boronic acid for 2-benzyloxyphenyl boronic acid in step (e), the title ~ compound was yl~alcd as a white solid (0.094 g, 58%). MS(ESI): 518.4 (M+H)+.

~xarnple 170 25 P~c~ tion of N-r2-(2-biphenvl)thiazol 4-ylcarbonyll-N'-rN-(4-pyridhlyl.~ l.o~y~l,ollyl)-L-leucinyllhydr~ide Following the procedure of F.Y~mple 112(a)-1 12(g), except ~ub~ ..1 i..g 2-biphenylboronic acid for 2-benzyloxyphenyl boronic acid in step (e), the title compound was prepared as a white solid (0.100 g, 43%). MS(ESI): 544.3 (M+H)+.

-W O 97/16433 PCTrUS96/18000 Pxample 171 Pl ~a~ ation of N-fN-benzyloxycarbonyl-N-methyl-L-leucinyl)-N'- r2- rN-(2-m~ ,yl)-N-phenylaminolthiazol-4-ylcarbonyl~hydrazide Following the procedure of Example 116(a)-116fb), except ~- .I,tt,~ ;llg N-S benzyloxycarbonyl-N-methyl-L-leucine for N-(4-pyridinylmetho~yc~l,onyl)-L-leucine in step f~b), the title compound was prepared as a white solid (40 mg, 25%).
MS (ESI): 552.5 (M+H)+.

F.Y~ le 172 10 Plc~,~dlion of N-rN-methyl-N-(2-pyridinylmethokyc~l,onyl)-L-leucinyll-N'-r2-rN-(2-methylpropyl)-N-phenylaminolthiazol-4-ylc~l,ol,yllhydr~ide Following the procedure of F.x~mrle 116(a)-116(b), except s~lb~ N-methyl-N-(2-pyridinylmetho~ycall,,onyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step f~b), the title compound was L-l~al~d as a white solid solid (70 mg, 71%). MS f~ESI): 553.4 (M+H)+.

Fx~ml?le 173 PlG~a.~Lion of N-~2-(2-benzylo~yl,hel~yl)thiazol-4-ylcarbonyll-N'-fN-tert-buLo~yc~l~tonyl-L-leucinyl)hydrazide Following the procedure of Example 112(a)-112(g), except ~ g N-tert-bulo~yc~lJollyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was ~ al~d as a white solid (1.015 g, 94%).
MS(ESI): S39.1 (M+H)+.

Ex~rr~le 174 ~lG~Lion of N-(N-tert-butoxycarbonyl-L-leucinyl)-N'-r2-rN-(2-meLhyl~u~Jyl)-N-phenylaminolthiazol-4-ylc~hbonyllhydrazide Following the procedure of Example 116(a)- 116(b), except sul~ N-tert-butoxycarbonyl-L-leucine for N-(4-pyridhlyll,~Llloxycarbonyl)-L-léucine in step (b), the title compound was prepared as a white solid (740 mg, 85%). MS
(ESI): 504.4 (M+H)+.

W O 97/16433 PCT~US96/18000 l~xample 175 rlc~a, dtion of N-(N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-r2-rN-(2-m~.thylpropyl)-N-phenylaminolthiazol-4-ylcarbonyllhvdrazide Following the procedure of Example 116(a)-116(b), except substit-ltin,~ N-tert-bul~,xyc~Lbonyl-N-methyl-L-leucine for N-(4-pyridinylmeth~"~yc~hl,onyl)-L-leucine in step f~b), the title compound was ~a,ed as a white solid (610 mg, 69%).
MS (ESI): 518.4 (M+H)+.

F~mI?le 176 )a-aLion of N-r2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyll-N'-fN-pyrazinec~l,onyl-L-leucinyl)hydrazide a) N-[2-(2-benzyloxyphenyl)thi~ol-4-ylcarbonyl]-N'-(L-leucinyl)hydrazide Following the procedure of F.x~mrl~ 144(b), except sllbs~ N-[2-(2-benzyloxyphenyl)thi~ol4-ylcarbonyl]-N'-(N-tert-butoxyc~l,onyl-L-leucinyl)hydrazide for (ls)-N-[2-tl-(N-tert-butoxycarbonyl-N-methylamino)-3 methylbutyl]thi~7ol4-ylca 1~onyl]-N~-[N-(4-pyridinylm~oth~xyc~l~onyl)-L-leucinyl]hydr~ide, the title compound was p,b~ed as a white powder (0.766 g, 93%). MSfESI): 439.3 (M+H)+.
b) N-[2-(2-benzyloxyphenyl)thiazol~-ylcarbonyl]-N'-[N-(2-pyrazinylcarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 116(b), except sllhstitufin~ N-[2-(2-benzyl~ ~y~h~llyl)thiazol-4-ylcarbonyl]-N'-(L-leucinyl)hydldzide for N-[2-rN-phenyl-N-(2-methyl-1-propyl)amino]thiazol-4-ylcarbonyl]hydrazide and pyr~7.in~rboxylic acid for N-(4-pyridinylmetho~yc~lJollyl)-L-l~llcine~ the titlecolll~oul.d was ~lepared as a white solid (0.146 g, 94%). MS(ESI): 545.4 (M+H)+.

W O 97/16433 PCT~US96/18000 Example 177 Pl~palalion of N-r2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyll-N'-(N-isonicotinoyl-T -l~ucinyl)hydrazide Following the procedure of Example 176(a)-176(b), except substi~tinf~
S isonicotinic acid for pyr~7inloç~rboxylic acid in step (b), the title compound was p~ ,d as a white solid (0.135 g, 87%). MS(ESI): 544.3 (M+H)+.

E~ ?le 178 Plc~dlion of N-r2-(2-dibenzoruldllyl)thiazol-4-ylcarbonyll-N'-rN-(4-10 pyridillyllllcthoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Fx~mple 112(a)-112(g), except sub~ 2-bromodibPn7Qfuran for 2-benzylo~yl,lu,l,obenzene in step (d), the- title compound was prepared as a white solid (0.079 g, 49%). MS(ESI): 558.3 (M+H)+.

F~rn~l?le 179 Preparation of N-r2-rN-(2-melllyll,lu~yl)-N-phenylaminolthiazol-4-ylc~l,ullyll-N'-(N-pyr~7in.oc~, bonyl-L-leucinyl)hydrazide Following the procedure of Example 176(a)-176(b), except sub~lil..li.-g N-(N-tert-butoxyc~ul,ûnyl-L-leucinyl)-N'-t2-[N-(2-methylpropyl)-N-20 phenylamino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(2-benzyloxy~,hG.lyl)thiazol-4-ylcarbonyl]-N'-(N-tert-butoxyc~l,onyl-L-leucinyl)hydrazide in step (a), the title compound was prepared as a white solid (36 mg, 27%). MS (ESI): 510.4 (M[+H)+.

Fx~ ?le 180 25 P1G~dliOn of N-r2-rN-(2-1lleLllyl~lu~Jyl)-N-phenylaminolthiazol-4-ylc~lJollyll-N'-(N-methyl-N-pyrazinec~l,ollyl-L-leucinyl)hydrazide - Following the procedure of Example 176(a)-176(b), except substituting N-(N-tert-but~xyc~lJonyl-N-methyl-L-leucinyl)-N'-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol-30 4-ylc~bollyl]-N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step (a), the title compound was prepared as a white solid (70 mg, 72%). MS (ESI): 524.4 (M+H)+.

W O 97/16433 PCT~US96/18000 Exam,l?le 181 Preparation of N-(N-is- nicotinoyl-L-leucinyl)-N~-r2-rN-(2-mel~ly~ Jyl~-N
phenylaminolthia~;ol-4-ylcarbonyllhydrazide Following the procedure of F.~r~mple 176(a)-176(b), except substi~lltin~ N-(N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-r2-[N-(2-met~l~lu~yl)-N-phenylamino]thiazol4-ylcarbonyl]hydra~ide for N-[2-(2-benzyloxyphenyl)thi~ol-4-ylcarbonyl]-N'-(N-tert-buto~Lyc~l,ollyl-L-leucinyl)hydrazide in step (a) and isonicotinic acid for pyr~.in~ç~rboxylic aicd in step (b), the title compound was prepared as a white solid (28 mg,22%). MS ~ES~: 509.4(M +H)+.

Example 182 E'le~ Lion of N-(N-isonicotinoyl-N-methyl-L-leucinyl)-N'-r2-rN-(2-melllylyro~yl)-N-phenylaminolthiazol-4-ylcarbonyllhydrazide Following the procedure of Fx~mrle 176(a)-176(b), except ~ s~ lir,g N-(N-methyl-N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2-rN-(2-melhylplv~yl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide for N-r2-(2-benzyloxyphenyl)thiazol4-ylcarbonyl] -N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and isonicotinic acid for pyr~.in~c~rboxylic aicd in 20 step (b), the title co-l-L,u~llld was prepared as a white solid (117 mg,93%). M S
~ESI): 523.4(M +H)+.

W O 97/16433 PCT~US96/18000 F.xample 183 P~G~a~dliOn of N-rN-(4-imill~7olylacetyl)-L-leucinyll-N'-r2-rN-(2-melllyl~lu~yl)-N-phenylaminolthiazol-4-ylcarbonyllhydrazide Following the procedure of Example 176(a)-176(b), except ~bs~ g N-5 (N-tert-butukyc~bonyl-N-methyl-L-leucinyl)-N'-[2-[N-(2-~ yl~lu~yl)-N-phenylamino3thiazol4-ylcarbonyl]hydrazide for N-[2-(2-benzylo~y~h~,llyl)thia 4-ylc~bollyl]-N'-(N-te~-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and 4-imi~l~7t 1ylacetic acid for pyr~7inloc~rboxylic aicd in step (b), the title compound was ple~a cd as a white solid (60 mg, 53%). lHNMR (400MHz, CDC13) ~ 7.62-7.23 (m, 8H), 6.81 (s, lH), 4.72-4.66 (m, lH), 3.75 (d, lH), 3.55 (d, 2H), 1.96-1.93 (m, 2H), 1.76-1.54 (m, 3H), 0.96-0.84 (m, 12H).

F.x~ml?le 184 ~lc;~a~lion of N-r2-rN-(2-m~lhyl~lo~yl)-N-phenylarninolthiazol4-ylcallJollyll-N'-(N-picolinoyl-L-leucinyl)hydrazide Following the procedure of Example 176(a)-176(b), except sub~ g N-(N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-t2-[N-(2-m~ yl~lu~yl)-N-phenylamino]thiazol-4-ylc~l,ollyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol-4-ylca.bollyl]-N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step (a) and picolinic acid for pyr~7in-oc~rboxylic aicd in step (b), the title compound was pl~a~ed as a white solid (50 mg,44%). MS (ESI): 509.5 (M+H)+.

Ex~m~?le 185 ~l~a ~Lion of N-r2-(2-benzyloxyphenyl)thiazol~-ylc~l,ollyllmethyl ~N-(4-pyridinylmethoxyc~l,ollyl)-L-leucinzlmi~le a) 2-(2-benzyloxyphenyl~liazole~-c~hl,oxylic acid Following the procedure of FY~mrle lO~(b), except sub~ g ethyl 2-(2-benzyloxyphenyl)thiazole-4-carboxylate for methyl 3-(4-pyridinyllmethoxy)bçn7O~te7 the title compound was prepared as a white solid (0.361 g, 90%). MS(ESI): 312.2 (M+H)+.

W O 97/16433 PCTAUS96/18000 ~

b) 2-(2-benzyloxyphenyl)thi~ol~-yl bromom~thyl ketone Following the procedure of Example 103(a), except substituting 2-(2-benzyloxyphenyl~iazole-4-carboxylic acid for N-benzyloxycarbonyl-L-Leucinyl-L-T~.ucin~, the title compound was prepared as a white solid (0.327 g, 73%).
5 MS(ESI): 388.2 (M+H)+.

c) 2-(2-benzyloxyphenyl)thiazol4-yl z~7i(1Om~thyl ketone A solution of the co~l.pou--d of Example 185(b), (0.319 g, 0.822 mmol), sodium azide (0.064 g. 0.987 rnmol), and pot~c~ m fluon-le (0.072 g, 1.23 mmol) 10 in DMF (6 mL) was stirred at room tel--~e.dLul~; for 16 h. The solution was then diluted with ethyl acetate and washed succçc~ively with water, saturated aqueoussodium hydrogen carbonate, and brine. The organic layer was dri-ed (MgSO4), filtered and concenL aLc;d. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.087 g, 30%). MS(ESI): 373.3 (M+Na)+. ~

d) 2-azido- 1 -[2-(2-benzyloxyphenyl)thiazol-4-yl]- 1 -hydroxyethane To a stirring solution of the compound of Example 185(c) (0.087 g, 0.249 mmol) in THF (1 mT) at 0~C, was added sodium borohydride (0.031 g, 0.820 20 mmol) slowly. After 20 min the ~ ul~; was diluted with ethyl acetate and washed with water then brine. The organic layer was dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (0.084 g, 96%). lHNMR
(400MHz, CDCl3) ~i 8.41 (m, lH), 7.50 (m~ 2H), 7.38 (m, 4H), 7.11 (m, 3H), 5.31 (s, 2H), 5.08 (t, lH), 3.69 (m, 2H), 3.58 (s b, lH).
e) 2-amino- 1 -[2-(2-benzyloxyphenyl)thiazol-4-yl]- 1 -hydlu~ye~lane To a stirring solution of the compound of Example 185(d) (0.084 g, 0.239 mmol) in m~th~nol (2 mL) was added stannous chloride dihydrate (0.108 g, 0.478 mrnol). After stirring at room temperature for 16 h, the mixture was diluted with 30 ethyl acetate and washed successively with water, sal,~ ;d aqueous NaHC03, and brine. The organic layer was dried (MgSO4), filtered and concentrated. The W O 97/16433 PCT~US96/18000 residue was purified by column chromatography (silica gel, m~th~n~l/dichlorom~th~nf~) to yield the title compound as a white solid (0.07 Sg, 96%). MS(ESI): 327.3 (M+H)+.

f) 1-r2-(2-benzyloxyphenyl)thiazol-4-yl]-1-hydroxy-2-(4-pyri~ lylmeLhoxycarbonyl-L-leucinylamino)ethane Following the procedure of FY~mple 116(b), except subsl ;~ u~ 2-arnino-1-[2-(2-benzyloxyphenyl)thiazol-4-yl]-1-hyd-o~yGLhane for N-[2-[N-phenyl-N-(2-methyl-l-propyl)amino]thiazol-4-ylcarbonyl]hydrazide, the title compound was ~lG~d as a white solid (0.075 g, 57%). MS(ESV: 575.4 (M+H)~.

g) N-[2-(2-benzyloxyphenyl)thiazol-4-ylc~l,ol.yl]methyl tN-(~
pyriL.-ylll,~,lho~yc~L~onyl)-L le-lcin~mi~
To a stirring solution of the compound of Fx~mr)le 185(f) (0.075 g, 0.131 mmol) in dichlorom~-th~nf, (1 mL) was added MnO2 (0.300 g, 3.45 mmol). After stirring at room ~G~ e~aLulG for 24 h, the ~ lurG was filtered and the filtrate was conr~ . ;.tf ~l The residue was purified by column chromatography (silica gel, m~th~nol/dichlorom~th~nP) to yield the title compound as a pale yellow solid (0.017 g, 23%). MS(ESI): 573.4 (M+H)+.
~x~ml?le 186 Pl~aLiOn of N-r2-rN-methyl-N-(2-melhyl~ yl)aminolthiazol-4-ylc~l,ollyll-N'-rN-(4-pyri~lhlyll,lcLllo~yc~l~ollyl)-L-leucilnyllhydrazide a) N-benzoyl-N'-methyl-N'-(2-methylpropyl)thiourea To a stirring solution of N-methylisobutylamine (3.21 g, 36.8 mrnol,4.45 mL) in 40 mL of CHC13 was added benzoyl isothiocyanate (6.0 g, 36.8 mmol,4.95 mL). After stirring for 45 min, the solution was con~nt.,.t~l to yield the titlecompound as a pale yellow solid (9.22 g, 100%). lHNMR (400MHz, CDC13; 2: 1 mi~Lul~ of rot~l.ers) ;~ 7.86 (d, 2H), 7.60 (t, lH), 7.50 (t, 2H), 3.90 (d, 2H),3.44 (s, 3H),3.41 (d, 2H), 3.27 (s, 3H), 2.35-2.32 (m, lH), 2.13 (m, lH), 1.06 (d, 6H), 0.90 ~ (d, 6H).

W O 97/16433 PCT~US96/18000 b) N-methyl-N-(2-meLhyll,rc~yl)thiourea The compound of Example 186(a) (9.22 g, 36.8 mmol) was sllspe~ d in 80 mL of 1:1 methanol/water and solid pot~csium carbonate (15.27 g, 110 mmol) was S added. The ~ ule was heated at reflux for 48 h, then cooled and pa~Ltitioned bc;L~,c.l ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2X). The combined organic layers were washed with saturated brine, dried (MgSO4), filtered and conce~ aL~d to provide the title compound as a pale yellowcrystalline solid (4.82 g, 89%). MS(ESI): 147.0 (M+H)+.

c) N-[2-[N-methyl-N-(2-methyl~ yl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 113(d)-113(f), except sl-bs~ i..g N-methyl-N-(2-methylpropyl)thiourea for N-(4-phellylphel-yl)-N-(2-methyl-1-15 propyl)thiourea in step (d), the title compound was ~l~ed as a white solid (202mg, 97%). MS(ESI): 477.4 (M+H)+.

Example 187 P~ c,Lion of N-(N-methyl-N-picolinoyl-L-leucinyl)-N'-r2-rN-(2-.l-~lllyl~.vpyl)-N-20 phenyl~minolthiazol4-ylcarbonyllhydrazide Following the procedure of F.x~mple 176(a)-176(b), except ~ N-(N-methyl-N-tert-buto~yc~l,vllyl-N-methyl-L-leucinyl)-N'-t2-[N-(2-llyl~l~yl)-N-phenylamino]thiazol4-ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol4-ylc&ll,onyl]-N'-(N-tert-buto~yc~lJollyl-L-25 leucinyl)hydl~zide in step (a) and picolinic acid for pyr~7in~c~rboxylic aicd in step (b), the title compound was prepared as a white solid (30 mg, 41%). MS (ESI):
523.5 (M+H)+.

W O 97/16433 PCT~US96/18000 Example 188 Pl~a~alion of N-r2-(2-benzylo~yphellyl)thiazol ~1-ylcarbonyll-N'-rN-(2-pyri-lin~sulfonyl)-L-leucinyllhydrazide a) 2-pyri~lin~sl~lfonylchloride S Through a stirring solution of 2-mc~ o~ylidine (2.235 g, 20 m nol) in water (7.5 mT.) and concentrated HCl (26 rnL) at 0 ~C was bubbled C12. After 30min, 75 mL of ice water was added and extracted with cold ether (2 X 75mL).
The organic layers were coll-bL~ed and washed succçe~ively with cold 10% aqueousNaHCO3, and cold brine. The organic layer was dried (MgSO4), filte;ed and conc~ ated to yield the title compound as a clear oil. (3.1 g, 87%).

b) N-[2-(2-benzyloxyphenyl)thiazol~ylcarbonyl]-N~-[N-(2-pyr~ n~osll1fonyl)-L
leucinyl]hydrazide To a stirring solution of the compound of Example 176(a) (0.125 g, 0.285 mmol), and the co~l,you~d of Example 188(a) (0.101 g, 0.571 mmol) in dichlorom~th~n~ (2 mL) was added N-~llcL'Ilyllllorpholine (0.057 g, 0.571 mmol).After stirring at room telll~eLaLulc; for 10 min the solution was diluted with ethyl acetate and washed ~ cçssi ~ely with water and brine. The organic layer was dried (MgSO4), filtered and concentlat~d. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a pale yellow solid (0.100 g, 61%). MS(ESI): 580.2 (M+H)+.

Fx~n~le 189 Pl~paldlion of N-r2-rN-(2-methvlpropyl)-N-phenylaminolthiazol-4-ylcalbollyl]-N'-rN-(2-pyri-iin~slllfonyl)-L-leucinyllhydrazide Following the procedure of Example 188(b), except substitnting N-(L-leucinyl)-N'-t2-tN-(2-methylpropyl)-N-phenylamino]thiazol-4-ylc~bo~yl]hydrazide for N-~2-(2-benzylo~y~henyl)thiazol~-ylcarbonyi]-N'-(L-leucinyl)hydrazide, the title compound WdS pl~a,~d as an orange solid (56 mg, 48%). MS (ESI): 545.3 (M+H)+.

Fx~mple 190 r~ J~dlion of N-r2-rN-(2-methylpropyl)-N-phenylaminolthiazol~-ylcarbonyl~-N'-rN-methyl-N-(2-pyri~lirl~sulfonvl)-L-leucinyllhydrazide Following the procedure of Example 188(b), except sub~ l i..g N-(N-5 methyl-L-leucinyl)-N'-~2-[N-(2-1lwlllyl~,o~yl)-N-phenylamino]thiazol-4-ylcarbonyl]hydr~ide for N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-(L-leucinyl)hydrazide, the title compound was prepared as an orange solid (53 mg, 40%). MS (ESI): 559.3 (M+H)+.

10Example 191 P~G,~aldtion of N-r2-rN-methyl-N-(2-meLllyl~)l~yl)arninolthiazol-4-ylcarbonyll-N'-rN-(3-pyridinylme~ho~yca.l,ollyl)-L-leucinyllhydrazide Following the procedure of Exarnple 186(a?-186(c), except sub~Li~ g N-(3-pyridinylm.othoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-15leucine in step (c), the title compound was prepared as a white solid (138 mg, 66%).
MS (ESI): 477.4 (M+H)+.

Fx~mI?le 192 P.~a.~lion of N-r2-rN-(2-methylpropyl)-N-phenylarninolthiazol-4-ylcarbonyll-N'-20 rN-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Flr~mple 116(a)-116(b), except ~ ii-g N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridh~yl~ ,Llloxycarbonyl)-L-leucine in step (b), the title coll~oLIlld was prepared as a white solid solid (74 mg, 41%). MS (ESI): 553.4 (M+H)+.

W O 97/16433 PCT~US96/18000 F.x~ le 193 P~ udlion of N-r2-rN-(2-methylpropyl)-N-phenylaminolthiazol-4-ylcarbonyll-N'-rN-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of F.x~mplto 116(a)-1 16(b), except sub~.lil~.l;..g N-5 methyl-N-(3-pyridillyl . . .~thoxycalbollyl)-L-leucine for N-(4-pyri-lhlyl..~f Ihoxyc~ul~yl)-L-leucine in step (b), the title colll~oul.d was ~r~cd as a white solid solid (50 mg, 38%). MS (ESI): 553.4 (M+H)~.

F.~ ple 194 10 rl~alion of N-r2-(2-benzyloxy~henyl)thiazol-4-ylcarbonyll-N'-lN-methyl-N-(3-pyri-lhlyllllcllloxycarbonyl)-L-leucinyllhydrazide Following the ~loce-lul~, of Example 112(a)-1 12(g), except ~.ulr.li~ g N-methyl-N-(~pyridinylm~tho~ycall~onyl)-L-leucine for N-(4-pyri~lillyl.nto~hoxycarbonyl)-L-leucine in step (g), the title colu~o-u.d was prepared as a white solid (0.028 g, 15%). MS(LSI): 588.4 (M+H)+.

F~Yslm,l?le 195 rlG~dlion of N-rN-methyl-N-(4-pyridiLyllll~Llloxycarbonyll-L-leucinyll-N'-r2-(1-naphthyl)thiazol-4-ylca l,o,lyllhydrazide Following the procedure of Example 112(a)-1 12(g), except s~lb~ i.. g 1-naphthyl boronic acid for 2-benzyloxyphenyl boronic acid in step (e) and N-methyl-N-(4-pyri lhlyL~LLoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title co~ oulld was plcpal~,d as a white solid (0.072 g, 36%).
MS(ESI): 532.4 (M+H)+.
Fx~m~l?le 196 Pl~l,~dlion of N-r2-rN~N-~bis)-2-mcLhyl~ yl)aminolthi~ol-4-ylc~lJollyll-N'-rN-(4-pyridinylmetho~yc~b~ yl)-L-leucinyllhydr~ide - Following the procedure of F.x~mple 1 86(a)- 1 86(c), except sub~LiLuLillg N,N-30 diisobutylamine for N-methylisobutylamine in step (a), the title compound was .~,par~d as a yellow solid (60 mg, 39%). MS (ESI): 519.5 (M+H)+.

.

W O 97/16433 PCT~US96/18000 E,xample 197 P~ ion of N-(N-benzyloxycarbonyl-L-leucinyl)-N'-r2-rN.N-(bis)-2-m~ ylyro~)yl)aminolthiazol-4-ylcarbonyllhydrazide Following the procedure of F.x~mple 186(a)-186(c), except ~ub~ li..g N,N-diisobutylamine for N-methylisobutylamine in step (a) and N-benzyloxycarbonyl-L-leucine for N-(4-pyridhlyl,l.t;Llloxycarbonyl)-L-leucine in the finai step, the title cc,lll~oulld was prepared as a yellow solid (131 mg, 69%). MS (ESI): 518.4 (M+H)+.
Fx~ 198 r~ dlion of N-r2-(4-morpholino)thiazol~ylc~l,o"yll-N'-rN-(4-pyridil,yl"lelllo~yc~l,o"yl)-L-leucinyllhydrazide Following the procedure of FY~mple 186(a)-186(c), except subsli~ g 15 morpholine for N-methylisobutylamine in step (a), the title c~ ld was ~ d as a white solid (45 mg, 31 %). MS (ESI): 477.3 (M+H)+.

F.xample 199 alaLion of N-r2-r2-(4-pyridinylmethoxy)phenyllthiazol-4-ylcarbonyll-N'-rN-(4-pyri-lh,yl,l,~,Lhoxyc~l,ollyl)-L-leucinyllhydrazide a) 2-methoxymethu~yl,l."nobenzene To a stirring ~us~ ;on of sodium hydride (1.2 g, 52.1 mmol, 60%
dispersion in mineral oil) in DMF (7~ mL) at 0 ~C was added 2-bromophenol (6.0 g, 34.7 mmol) dropwise. After stirring for 20 min, bromomethyl methyl ether (4.3 g,34.7 mmol) was added. After stirring for 16 h at room temperature, the ~ ule waspoured into water (250 mL) and extracted with hexane. The organic layer was washed with brine, dried (MgSO4), filtered and concen~ ed. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (4.0 g, 53%). lHNMR (400MHz, CDCl3) ~ 7.55 (d, lH), 7.28 (t, lH), 7.16 (d, lH), 6.91 (t, lH), 5.25 (s, 2H), 3.54 (s, 3H).

W O 97/16433 PCT~US96/18000 b) ethyl 2-(2-methoxymethoxyphenyl)thiazole-4-carboxylate . Following the procedure of Example 112(a)-112(b) and 112(d)-112(e), except sub~ 2-metho~ylll~;illo,Lyl,l~,lllobenzene for 2-benzylo~y1,rolllobenzene in step (d), the title compound was ~ al~,d. MS(LSI):
294.3 (M+H)+.

c) ethyl 2-(2-hy~Loxy~henyl)thiazole-4-carboxylate To a stirring solution of the co~ ou..d of Example 199(b) (0.839 g, 2.86 mmol) in ethanol (25 mL) was added 10 drops of conce~ dLt;d hydrochloric acid.
10 After stirring at reflux for 2 h the solution was conce lllated then redissolved in ethyl acetate. The solution was washed succescively with sdluldled sodium bicarbonate, and brine, dried (MgSO4), filtered and conc~ .dt~d rO yield the title co~ ou"d as a pale yellow solid (0.674 g, 95%). MS(ESI): 250.2 (M+H)+.

d) ethyl2-t2-(4-pyridyl.. ~ oxy)phenyl3thi~7Ole-4-carboxylate To a stirring solution of the compound of Example l99(c) (0.125 g, 0.502 mmol), 4-pyridylcarbinol (0.071 g, 0.653 mmol), and triphenylrhosphinP (0.171 g,0.653 mmol) in THF (5 mL) at 0~C was added diiso~r~,~yl ~7orlic~ o~ylate (0.132 g, 0.653 mmol) dropwise. After stirring at room telllpeldLulc for 16 h, the solution 20 was concellL.dted and purified by column cluulllatography (silica gel, ethyl acetate/hexane) to yield the title colll~ouLId as a white solid (0.100 g, 59%).
MS(ESI): 341.3 (M+H)+.

e) N-[2-[2-(4-pyridinylmethoxy)phenyl]thiazol-4-ylc~hbollyl]-N'-[N-(4-25 pyridhlyl . . .~ cycarbonyl)-L-leucinyl]hydrazide Following the procedure of Ex~mrle 112(f)-112(g), except sub~ .l;..g ethyl 2-[2-(4-pyridylm.-fhoxy)phenyl]thiazole-4-carboxylate for ethyl 2-(2-benzyloxyphenyl)thiazole-4-carboxylate in step (f), the title compound was prepared as a white solid (146 mg, 83%). MS(ESI): 575.4 (M+H)+.

F.xample 200 Preparation of N-r2-(2-naphthyl)thiazol4-ylcall,vl.yll-N'-rN-(4-pyridinylmeth~xycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 112(a)-112(g), except substitllting 2-5 naphthylboronic acid for 2-benzyloxyphenyl boronic acid in step (e), the title co~ ound was pr~a.~,d as a white solid (226 mg, 75%). MS (ESI): 518.4 (M+H)+.

Fxarnple 201 I~lGy~alion of N-r2-rN.N-(bis)-2-mclhyl~,lo~yl)aminol~hi~7- 1-4-ylcarbonyl~-N'-rN-m~.ti ~yl-N-(4-pyridi-lyh..c;~loxycarbonyl)-L-leucinyllhydrazide Following the procedure of F.x~mrle 186(a)-186(c), except sub~liL~ N,N-diisobutylamine for N-methylisobutylamine in step (a) and N-methyl-N-(4-pyri~lh,yllllctlloxy~a,bonyl)-L-leucine for N-(4-pyridhlyll-lclllo~yc~bol.yl)-L-15 leucine in the final step, the title compound was prepared as a yellow solid (30 mg,25%). MS (ESI): 533.3 (M+H)+.

Example 202 r~ alion of N-(N-benzylo~Lyc~lJonyl-L-leucinyl)-N'-r2-(4-molpholino)thiazol4-20 ylcarbonyllhydrazide Following the ~,wedu.G of F.x~mple 186(a)-186(c), except sub~ li..g morpholine for N-methylisobutylamine in step (a) and N-benzyloxycarbonyl-L-leucine for N-(4-pyridil,yl...~th.-~yc~bonyl)-L-leucine in the final step, the title compound was prepared as a white solid (115 mg, 67%). MS (ESI): 576.4 25 (M+H)+-FxamI?le 203 Preparation of N-rN-(4-pyridinylmethoxycarbonyl)-L-leucinyll-N'-r2-(4-thiomorpholino)thiazol~-ylc~hbollyllhydrazide Following tne procedure of Example 186(a)- 186(c), except sub~ g S thiomorpholine for N-methylisobutylalrune in step (a), the title compound was prepared as a white solid (35 mg, 20%). MS (ESI): 493.4 (M+H)+.

Rxaml?le 204 Preparation of N-(N-benzvloAyc&~ lyl-L-leucinyl)-N'-r2-(4-10 thiomorpholino)thiazol~-vlc~bol,yllhydrazide Following the procedure of Example 186(a)- 186(c), except subsl i ~ i "~
tniomorpholine for N-methylisobutylarnine in step (a) and N-beniyloAyc~bollyl-L-leucine for N-(~pyri~linyl...~Li.~.~y~ yl)-L-leucine in the final step, the title compound was ~l~cd as a white solid (20 mg, 20%). MS (ESI): 492.3 (M+H)+.
F.xamrle 205 ion of N-r2-(2.3-ethylenedioxy4-methoxyphenyl)thiazol4-ylcarbonyll-N'-rN-(4-pyridinylmetnoxyc~l,ollyl)-L-leucinyllhydrazide Following the procedure of Example 112(a)-112(g), except ~.ub .LiLuLillg 2,3-20 ethylenedioxy4-metho~yL,rolllobellze-le for 2-benzyloAyblulllob~ e in step (d), the title compound was prepared as a white solid (31 mg, 26%). MS (ESI): 556.4 (M+H)+.

F.x~mI71e 206 25 PIG~a.dlion of N-r2-rN~N-(bis)-2-meLIlyl~ro~yl)arninolthiazol4-ylcarbonyll-N'-rN-mt-.thyl-~-(3-pyridillyllllGLhoxycarbonyl)-L-leucinyllhydrazide ~ Following the procedure of Fx~mple 186(a)-186(c), except sllbsti~lting N,N-diisobutyl~mine for N-methylisobutyla_ine in step (a) and N-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-30 leucine in the final step, the title compound was prepared as a yellow solid (30 mg, 30%). MS (E;SI): 533.5 (M+H)+.

W O 97/16433 PCT~US96/18000 Example 207 ~l~a,d~ion of N-r2-(N-cyclopropylmethyl-N-propylarnino)thiazol-4-ylcalbu~lyll-N'-rN-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide S Following the procedure of Example 186(a)-186(c), except ~-lb~ uli~g N-cyclopropylmt;lhyl~io~ylamine for N-methylisobutylamine in step (a), the title compound was pr~,paled as a yellow solid (60 mg, 23%). MS (ESI): 503.3 (M+H)+.

Example 208 Pl ~ dLion of N- rN-(4-pyridinylmethoxycarbonyl)-L-leucinyll -N'- r2-(8-~uinolyl~thiazol-4-ylc~l,onyllhydrazide Following the procedure of Example 112(a)- 112(g), except sub~ .1 i ~ .g 8-bromoq-linolin~ for 2-benzyloxyl"~",lobel,~ne in step (d), the title compound was p,~ed as a white solid (134 mg, 56%). MS (ESI): 519.3 (M+H)+.

E~x~mple 209 ~dlion of N-rN-methyl-N-(4-pyridinylmethoxyc~l,Gnyl)-L-leucinyll-N'-r2-(8-quinolyl)thiazol~-ylcarbonyllhydrazide Following the procedure of F.x~mple 112(a)-112(g), except substit--tin~ 8-bromoquinoline for 2-benzylo~yb,~",obenzene in step (d) and N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (g), the title compound was prepared as a white solid (53 mg, 22%).
MS (ESI): 533.3 (M+H)+.

F.xample 210 ~pa,alion of 1-N-(N-Cbz-leucinyl)-amino-3-N-(~biphenyl-sulfonyl)-amino-propan-2-one a) 4-biphenyl sulfonyl chloride 4-Biphenyl sulfonic acid (2.4 g, 10 mmol) was heated to 100 C with phosphorus perlt~ hloride (2.1 g, 10 mmol) overnight. The reaction was cooled toRT, diluted with water, filtered and washed with water. The solid was then LlilulaL~d with EtOAc-ether and the beige solid was used in the next reaction without further purifi~tion b) 1-N-(N-Cbz-leucinyl)-amino-3-N-(4-bi~hel~yl-sulfonyl)-amino-propan-2-one Following the procedure of Example 51(a), except subs~ "4-biphenyl sulfonyl chloride" for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M-H+=550.
Example 2 11 rl~alion of l-N-( N-Cbz-leucinyl)-amino-3-N-(3-biphenyl-sulfonyl)-amino-propan-2-one a) 3-biplle~lyl-sulfonyl chloride 3-Biphenyl bromide (9.3 g, 40 mmol) was dissolved in THF (40 ml) and a Grignard reagent was prepared in standard fashion with m~gnt~ m powder (1.2 g, 50 mmol). The reaction was c~nnul~t~d into a solution of sulfuryl chloride (10.5 g, 6.4 ml, 80 mmol) in hexanes (2~ ml) and was strirred at RT for 2h. The reaction was 4~ 'h~od with ice-water, extracted with ether, dried with m~gn~ lm sulfate, filtered, concel~l,a~d, and was used in the next reaction without further pllrifit~tion b) l-N-( N-Cbz-leucinyl)-amino-3-N-(3-biphenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 51(a), except sub~ g "3-biphenyl sulfonyl chloride" for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chlori~le",the title compound was prepared: MS(ES) M-H'=550.

W O 97/16433 PCT~US96/18000 F.~ample 212 ;pa~tion of l-N-( N-Cbz-leucinyl)-~mino-3-N-(2-benzyloxy-phenyl-sulfonyl)- A
aminf)-propall-2-one 5 a) 2-benzyloxy-phenyl-sulfonyl chloride Following the procedure of Example 211(a), except subsl il..l ;..g "2-benzyloxy-phenyl brornide " for "3-biphenyl bromide", the title compound was ~ d and was used in the next step without further pllrific ~tion.

10 b) l-N-( N-Cbz-leucinyl)-arnino-3-N-(2-benzyloxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Exarnple 51(a), except subsl il~.l i, .g "2-benzyloxy phenyl sulfonyl chloride " for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl c~hloride", the title compound was ~-ep~cd: MS(ES) M+H~= 581, M+Na~=
604, 2M+Na+= 1185.

F.x~mple 213 P~ tion of l-N-( N-Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-~mino-prop~n-2-one 20 a) 4-phenoxy-phenyl-sulfonyl chloride Following the procedure of Example 211(a), except substitllting "4-phenoxy phenyl bromide " for "3-biphenyl bromide", the title compound was prepared and was used in the next step without further pllrific~tion.

25 b) l-N-( N-Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 51 (a), except subs~ g "4-phenoxy-phenyl-sulfonyl chloride " for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was p,~Gd: MS(ES) M+H+= 568, M+Na+--590.

W O 97/16433 PCT~US96/18000 Ex~nlple 214 Plc~ ion of l-N-( N-Cbz-leucinyl)-am~no-3-N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one a) 4-phenoxy-phenyl-sulfonyl chloride Following the procedure of F.x~mple 210 (a), except sub~ g "2-dibenzoru~ -sulfonic acid" for "4-biphenyl-sulfonic acid", the title compound was prepared and was used in the next step without further purific ~tion b) l-N-( N-Cbz-leucinyl)-arnino-3-N-(2-~iben7ofuran-sulfonyl)-am-ino-propan-2 one Following the procedure of F.x~mple 51(a), except substitlltin~ "4-phenoxy phenyl sulfonyl chlori~ " for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was ~r~u~d: MS(ES) M+H+= 566, M+Na+- 588 Fx~m~ 215 ~cyaldlion of l-N-( N-Cbz-leucinyl)-amino-3-N-(3.~dimethoxy-phenyl- sulfonyl)-5lmino-propan-2-one Following the procedure of Example 51, except ~.h~ lg ~3,4 tlim.othoxy-phenyl-5ulfonyl chlQri~le " for "4-(3-Chloro-2-cyano-phenoxy)-phenylsulfonyl chloride", the title compound was pl~,~ed: MS(ES) M+H+- 536, M+NH4+--553.

Fx~m~l?le 216 P'lc~aliQn of l-N-( N-Cbz-leucinyl)-amino-3-N-(2~5-dichlorothiophene-3-sulfonyl)-~mino-propan-2-one Following the procedure of Example 51, except sub~l i 1. .l i. .g "2,5-dichlorothiophene-3-sulfonyl chloride " for "4-(3-Chloro-2-cyano-phenoxy)-phenylsulfonyl chloride", the title compound was prepared: MS(ES) M+NH4+--567, 2M+H+= 1101.

Fx~ml?le 2 17 P~ atiQn of 1-N-( N-Cbz-leucinyl)-~mino-3-N-(phenyl-sulfone-5-thiophene-2-lfonyl)-a~.uno-propan-2-one Following the procedure of Example 51, except subsl il..~ ;..g " phenyl S sulfone-5-thiophene-2-sulfonyl chloride " for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was ~cpal~,d: MS(ES) M+H~= 622.

Fxam,ple 218 Preparation of l-N-( N-Cbz-leucinyl)-arnino-3-N-(8-quinoline-sulfonyl)-amino-10 propan-2-on~
Following the procedure of Example 51, except ~llb~ "8-q~inolinf -sulfonyl chloride " for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride",the title cu~ oulld was prepared: MS(ES) M+H'- 527.

F.xample 219 Lion of 1-N-( N-Cbz-leucinyl~-arnino-3-N-(2-pyridyl-sulfonyl~-amino-propan-2-one Following the procedure of F.lr~mple ~1, except ~ulJ~l;l..l;i-g "2-pyridyl-sulfonyl chloride" (as described in J. Org. Chem. 1989, 54, 392) for "4-(3-Chloro-20 2-cyano-phenoxy)-phenyl sulfonyl chloride", the title co~l,pou"d was ~ a,~,d:MS(ES) M+H'= 477, M+ Na+ = 499.

-W O 97/16433 PCT~US96/18000 F,x~m~le 220 - P~ ~dlion of l-N-( N-Cbz-leucinyl)-amino-3-N-(2-pyridyl-sulfonyl)-amino-propan-2-one a) l-N-(N-Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-S ol 1,3-Diamino propan-2-ol (6.75 g, 75 mmol) was dissolved in DMl~ (lOOrnl) and Cbz-leucine (20g, 75.5 mmol), HOBT-hydrate (1 lg, 81.5 rnmol), and EDCI
( 1 S.Sg, 81.2 rnmol) were added. The reaction was stirred overnight at RT. A
portion of the reaction ~ , (30 ml) was concentrated in vacuo, then ether (50 10 ml) and MeOH (30 ml) were added. A lN solution of hydrochloric acid in ether was added ( 1 M, 30 ml) and a white gum formed, which was washed several times with ether. MeOH-~eton~ were added and heated until the gum became a white solid. The white solid was dissolved in DMF (25 ml) and DIEA (Sml), then 4-phenoxy phenyl sulfonyl chloride was added. The reaction was stirred for 2h, 15 c~ eJ~ erl in vacuo, then clollla~ographed (silica gel, 1:1 EtOAc: hexanes) to provide the desired product as a white solid.

b) Leucinyl-amino-3-N-(4-phenoxy phenyl sulfonyl)-a~nino-propan-2-ol 1 -N-(Cbz-leucinyl)-arnino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-ol (l.Og, 1.8 mmol) was dissolved in EtOH (30 ml), then 10% Pd/C (0.22g) was added followed by 6N hydrochloric acid (2.5 ml), and the reaction was stirred under a baloon of hydrogen gas for 4h at RT. The reaction ll~h~Lul~ was filtered, conc~l.t.,.l~l and azeotroped with toluene to provide a white glass which was used in the next reaction without further pllrific~tion~
c) 1-N-(N-4-pyridyl acetyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-- amino-propan-2-ol Leucinyl-amino-3-N-(4-phenoxy phenyl sulfonyl)-amino-propan-2-ol (0.36 g, 0.76 mmol) was dissolved in DMF (S ml), then Nh~M (0.45 ml, 4 mmol) was added followed by 4-pyridyl acetic acid (0.13g, 0.75 mmol) and BTU (0.29g, 0.76 mmol) and the reaction was stirred at RT overnight The reaction llU~lUlC; was ~ , , W O 97/16433 PCT~US96/18000 conce~ ed 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.

S d) 1-N-(N~-pyridyl acetyl-leucinyl)-arnino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-one 1 -N-(N-4-pyridyl-acetyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-ol (45 mg, 0.08 mmol) was dissolved in ~retone (Srnl), then lN
l~y~chloric acid (2 ml) was added. The reaction was collcelltldled in vacuo, then 10 redissolved in acetone. Jones reagent (1.5 M, several drops) was added and the reaction mixture was stirred for 6h at RT. Isopl~anol (0.5 ml) was added and thereaction lll.xLùlt; was conce.-lld~d in vacuo. The reaction was diluted with pH 7 buffer and then was extracted with EtOAc, dried with m~gn~ m sulfate, filtered, concentrated in vacuo, then chromatographed (silica gel, 5% MeOH-methylene 15 chloride) to give the desired product as a white solid (27 mg, 50%): MS(ES):
M+H+ = 553.

Ex~ ple 221 ~ tion of l-N-( N-2-pyridvl-sulfonyl-leucinyl)-amino-3-N-(4-phenoxy-20 phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 220(a)-(d), except sub~ g "2-pyridyl-sulfonyl chloride" (as described in J. Org. Chem. 1989, 54,392) for "4-pyridyl-acetic acid and HBTU", the title compound was ~le~ar~d: MS(ES) M+H+=
475, M+ Naf = 497, 2M+ Na+ = 1171.
F,xarr~le 222 rlev~alion of 1-N-(N-morpholino-carbonyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 220(a)-(d), except ~ubslil~.li..g " N-30 morpholino-carbonyl chloride" for "4-pyridyl acetic acid and HBTU", the title compound was prepared: MS(ES) M+H~= 547, M+ Na+ = 569, 2M+ Na+ = 1115.

_ FY~mple 223 Pl~pal~aLion of l-N-( N-4-pyridyl-c~l,onyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-one S Following the procedure of Example 220(a)-(d), except substitllting " 4-pyridyl-carboxylic acid" for "4-pyridyl acetic acid ", the title compound was d: MS(ES) M+H+= 539.

Example 224 rl~,p&l~lion of 1-N-( N-acetyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-~mino-propan-2-one Following the pl~cedLI-~ of Example 220(a)-(d), except sul)~ g "acetyl chloride" for "4-pyridyl-acetic acid and HBTU", the title compound was p.Gpa.~,d:
MS(ES) M+H+= 476, M+ Na+ = 498, 2M+ Na+ = 973.
Exaem~ple 225 r~p~lion of 1-N-( N-imi-1~7ole acetyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-,~nlfonyl)-amino-propan-2-one Following the procedure of Example 220(a)-(d), except ~uI,~lil..li..g 20 "imi~1~7O1e acetic acid" for "4-pyridyl acetic acid", the title compound was prepared:
MS(ES) M+H+= 542.

F.~m~le 226 ~lep~dlion of l-N-( N-4-carboxymethyl benzoyl-leucinyl)-amino-3-N-(4-phenoxy-25 phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 220(a)-(d), except ~ub~lil..l;..g "4-- carboxymethyl benzoic acid" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) M+EI~= 596, M+ Na+ = 618, 2M+ Na+ = 1213.

~mple 227 P,~dtion of l-N-( N-(N.N-dimethyl ~lycinyl)-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-~mino-propan-2-one Following the procedure of Example 220(a)-(d), except substit-lting "N,N-5 ~ ,~yl glycine" for "4-pyridyl acetic acid", the title colll~oulld was ylGp~ed:
MS(ES) M+H'--519.

F,~ ple 228 P~eydlalion of l-N-( N-8-quinoline-sulfonamide-leucinyl)-amino-3-N-(4-phen 10 ~h~nyl-sulfonyl)-~mino-propan-2-one Following the procedure of Example 220(a)-(d), except sul)sLiluLillg "8-quinoline sulfonyl chloride" for "4-pyridyl-acetic acid and HBTU", the title compound was prepared: MS(ES) M+Ht- 625.

-W O 97/16433 PCT~US96/18000 Exarnple 229 P'~ dtion of 1-N-( N-Cbz-leucinyl)-amino-3-N-(8-quinoline-c~hl,ollyl)-amino-propan-2-one 1,3-Di~rnino propan-2-ol (6.75 g, 75 mmol) was dissolved in DMF (lOOml) S and Cbz-leucine (20g, 75.5 mmol), HOBT-hydrate (1 lg, 81.5 mmol), and EDCI
(15.Sg, 81.2 mmol) was added. The reaction was stirred overnight at RT. A portion of the reaction l~ Lu,G (30 ml) was conr~..l.dl~d in vacuo, then ether (50 ml) and MeOH (30 ml) were added. A lN solution of hydrochloric acid in ether was added (1 M, 30 ml) and a white gum formed, which was washed several times with ether.
10 MeOH-acetone were added and heated until the gum became a white solid. The white solid (0.44g, 1.1 mmol) was dissolved in DMF (3 ml) and NMM (0.33ml, 0.3 mmol), then 8-q-linoline carboxylic acid (0.17g, 1.0 mmol), and ~BTU (0.38g, 1.0mmol) were added and the reaction was stirred at RT overni~ht The reaction ure was concenlldtc~d in vacuo, then chlu,l,dlographed (silica gel, 7:2 EtOAc:
15 hex~nt-s). The solid was then dissolved in acetone (Sml), then lN hydrochloric acid (2 ml) was added. The reaction was concen~ #d in vacuo, then redissolved in acetone. Jones reagent (1.5 M, several drops) was added and the reaction l~lurt;was stirred for 6h at RT. Is~,u~anol (0.5 ml) was added and the reaction ~
was conce~ ~d in vacuo. The reaction was diluted with pH 7 buffer and tnen was 20 extracted witn EtOAc, dried witn m~gne~ m sulfate, filtered, conr~~ e~l in vacuo, then chromatographed (silica gel, 5% MeOH-methylene chloride) to give thedesired product as a white solid (23 mg, 41%): MS(ES): M+H+ = 491.

F,x~nn~le 230 25 P.e~ation of 1-N-( N-Cbz-leucinyl)-amino-3-N-(6-quinoline-c,~l,o"yl)-amino-propan-2-one - Following the procedure of Example 229, except subsfit--ting "6-quinoline-carboxylic acid" for "8-quinoline carboxylic acid ", the title compound was prepared: MS(ES) M+H~= 491.

~ xample 231 Pl~e~ lion of 1-N-( N-Cbz-leucinyl)-amino-3-N-(2-(4-biphenyl)-4-methyl-prop~n~micle)-propan-2-one Following the procedure of F.x~mrl~ 229, except sub~ l ing "2-isobutyl-4-S biphenyl acetic acid " for "8-quinoline carboxylic acid ", the title compound was ~cpalcid: MS(ES) M+H+= 586, M+ Na+ = 608, 2M+ Na+ = 1193.

F.Y~n~I?Ie 232 P~ep~lion of l-N-( N-Cbz-leucinyl)-arnino-3-N-( N4-pyridyl-methyleneoxy 10 ~ ul~yl-leucinyl)-amino-propan-2-one Following the procedure of F~mple 229, except substituting "4-pyridyl methyleneoxy carbonyl leucine" for "8-quinoline-carboxylic acid ", the title compound was prepared: MS(l~S) M+H+--584.

F.~m~l?le 233 P~ dlion of 1-N-( N-Cbz-leucinyl)-arnino-3-N-(benzoyl)-amino-propan-2-one Following the procedure of F~x~mrle 229, except subs~ g "bel~uyl chloride" for "8-quinoline carboxylic acid and HBTU", the title compound was plG~Gd: MS(ES) M+H+--440, M+ Na+ = 462, 2M+ Na+ = 901.
F~ample 234 P1GYa~aIiOn of 1-N-( N-Cbz-leucinyl)-amino-3-N-(2.4-dimetllyl-3-sulfonyl)-~mino propan-2-one Following the procedure of F.Y~mple 51, except sul,s~ "2,4-dimethyl-25 3-sulfonyl chloride" for "~(3-Chloro-2-cyano-phenoxy)-phenyl sulfonylchloride", the title coll,~oulld was ~Gpa~d: MS(ES) M+H~= 494.

Fx~mE\le 235 PlG~,~alion of l-N-(N-Cbz-leucinyl)-amino-3-N-(1.3-dimethyl-5-chloro- pyrazole-4-sulfonyl~-~mino-propan-2-one Following the procedure of F.Y~mrle 51, except sub~l il . .1 i . .g " 1,3-dimetnyl-S S-cnloro- pyrazole~-sulfonyl cnloride" for "4-(3-Cnloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title cc,lllpoulld was ~r~al~,d: MS(ES) M+H+= 494.

F.Y~m~ 236 I'l.,p~alion of l-N-(N4-pyridyl-methyleneoxy ca~ yl-leucinyl)-~mino-3-N-(4-10 phenoxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of F.Y~mrle 213(a), except substituting "4-pyridyl-methyleneoxy c~l,o.lyl-leucine" for " Cbz-leucine", the title comFound was pl.,~ d: MS(ES) M+H~= 569.

FY5~rrU?1~ 237 alalion of l-N-( N-3-pyridyl-methyleneoxy c~l,ul,yl-leucinyl)-aminû-3-N-(4-phenoxy-phenyl-sulfonyl)-~mino-propan-2-one Following the procedure of Example 213(a), except ~.ub~ g "3-pyridyl-methyleneoxy carbonyl-leucine" for " Cbz-leucine", the title cûlll~oulld was prepared: MS(ES) M+H~= 569.

Fx~mple 238 Lion of l-N-( N-2-pyridyl-methyleneoxy-carbonyl-leucinyl)-aminû-3-N-(4-phenûxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of F~mple 213(a), except ~.ub~ g "2-pyridyl-methyleneoxy carbonyl-leucine" for " Cbz-leucine", the title compound was - plepal~d: MS(ES) M+H~= 569.

-Fx~nlple 239 rlG~ dtion of l-N-( N-4-carboxv-benzoyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-~mino-propan-2-one l-N-(4-carboxy methyl-benzoyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-one (0 lOSg, 0.176 mmol) was dissolved in MeOH (5 m1) and water (1 1), then LiOH-hydrate (15 mg, 0 35 mmol) was added and the reaction was stirred at RT for lh The reaction was diluted with water, ~ lifi~,lwith 6N hydrochloric acid (1 ml), then with EtOAc (2 x 10 ml) The combined organics were dried with m~gn~cillm sulfate, filtered, conce~ dled, cLc,.,.alographed (silica gel, 50:50:1 EtOAc: hf~Y5-n~S: AcOH) to give the desired product as a white solid (35 6 mg, 35%): MS(ES) M+H~= 582, M+ Na+ = 604 Fx~ ple 240 dlion of 1-N-( N-Me-N-Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenyl-s~llfQnyl)-~mino-propan-2-one Following ~e procedure of Example 213(a), except "N-Me-N-Cbz-leucine"
for " Cbz-leucine", the title compound WdSpl~pdl~,d: MS(ES) M+H~= 582, M+ Na+
= 604, 2M+ Na+ = 1185.

Fx~n~ 241 Pl~paldlion of l-N-( 4-phenoxy benzoyl)-amino-3-N-(4-phenoxy-phenyl- sulfonyl)-~mino-propan-2-one Following the procedure of Fx~mple 213(a), except "4-phenoxy benzoic acid " for " Cbz-leucine", the title cc,--lpou..d was ~lct,~ed: MS(ES) M+H~= 517, M+ Na+ = 539, 2M+ Na+ = 1055.

W O 97/16433 PCT~US96/18000 rx-ample 242 aldlion of 1-N-(3-phenoxy-benzoyl)-amino-3-N-(4-phenoxy-phenyl- sulfonyl)-~mino-propan-2-one Following the procedure of Example 213(a), except "3-phenoxy benzoic S acid " for " Cbz-leucine", the title co,l,~ou,ld was ~ ~ed: MS(ES) M+EI+= 517, M+ Na+ = 539, 2M+ Na+ = 1055.

F.x~ le 243 Plel~aldLion of l-N-~4-phenoxy bt;-l~oyl)-amino-3-N-(4-phenoxy-phenyl- sulfonvl)-10 ~mino-propan-2-one Following the procedure of Fl~mpl~ 213(a), except "4-phenoxy benzoic acid " for " Cbz-leucine", the title compound was p,~a.ed: MS(ES) M+E~= 517, M+ Na+ = 539, 2M+ Na+ = 1055, M-H+ = 515.

Fx:~rnl?le 244 F~ e~ aLion of 1 -N-(4-bi~henyl acetyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl) ~minl -propan-2-one Following the procedure of Example 213(a), except "4-biyhenyl acetic acid " for " Cbz-leucine", the title compound was ~ ~ed: MS(ES) M+H+--515, M+
Na+ = 537, 2M+ Na+ = 1051.

Fx~Tru?le 245 Plcy~udlion of l-N-(2-benzyloxy benzoyl)-amino-3-N-(4-phenoxy-phenyl-~lllfonyl)-amino-propan-2-one Following the procedure of Fx~mple 213(a), except "2-benzyloxy- benzoic acid " for " Cbz-leucine", the title compound was ~l~,yalcd: MS(ES) M+H+= 531, - M+ Na+ = 553, 2M+ Na+ = 1083.

Example 246 P~ ~aLion of l-N-( N-Cbz-leucinyl)-amino-3-N-(4-benzyloxy-benzoyl)-amino-propan-2-one Following the procedure of Example 229, except sub~ .g "4-benzyloxy-S benzoic acid" for "8-quinoline carboxylic acid ", the title com~oulld was p.~ed:
MS(ES) M+H~= 546, M+ Na+ = 568, 2M+ Na+ = 1113.

F.xample 247 ~1G~dliOn 0~1 -N-(2-(4-bi~heI~YI)-4-methY1-~ 1O)-3-N-(4-PhenOXY-PhenVI-10 ~ for~yl)-~mino-propan-2-one Following the procedure of Example 213(a), except 2-(4-biphenyl)-4-methyl-pent~noic acid " for " Cbz-leucine", the title co~ou-ld was prepared:
MS(ES) M+H~= 571, M+ Na+ = 593.

Fx~ ?le 248 plelJ~ation of l-N-(2-(3-bi~h~llyl)-4-methyl-~~nlAIl~idQ)-3-N-(~phenoxy-phenyl-sl-lfonyl)-~mino-propan-2-one a) 3-bromo-phenyl methyl acetate 3-Bromo phenyl acetic acid (2.15g, 10 mrnol) was dissolved in ether, then was treated with a solution of diazometh~n~ until the yellow color per.ci~t~tl The reaction was then q~l~nch~d with AcOH, concentrated in vacuo and was used in thenext reaction without further pllrific~tion.
b) 3-biphenyl methyl acetate 3-bromo-phenyl methyl acetate (2.29g, 10 mrnol) was dissolved in toluene (30 ml). Then, phenyl boronic acid (1.46g, 12 mmol) was added followed by aqueous sodium c~l,onate (2M, 4.24 ml, 40 mmol), then tetrakis(triphenylphosphine) p~ (0.35g, 0.3 mmol) and was refluxed overnight The reaction was cooled to RT, diluted with saturated ammonium chloride, then extracted with EtOAc ( 2 x 10 ml). The combined organics were dried with m~nesium sulfate, filtered, concentrated, and chromatographed (silica -W O 97/16433 PCT~US96/18000 gel, 5% EtOAc: hexanes) to provide the desired product as a white solid (1.93g, 84%): MS(ES): M+H'- 263.

c) 3-biphenyl acetic acid 3-Biphenyl acetyl methyl ester was dissolved in MeOH (40 ml) and water (6 ml), then LiOH-hydrate (0.7g, 16.8 mmol) was added, and the reaction was stirredat RT for 2h. The reaction was diluted with water, ~ci~1ifiPd with 6N hydrochloric acid (1 ml), then with EtOAc (2 x 10 ml). The combined organics were dried with m~gn.o,~ m sulfate, filtered, and concenL,aLed to give the desired product as a white solid (1.66 g, 93%): lH NMR: d: 7.6-7.25 (m, 9H), 3.7 (s, 2H) d) 3-(4-bi~hc"yl)4-methyl-pent4-enoic acid nBuLi (3.26 ml, 1.6 M in h~Y~n~s) was added dropwise to a solution of diisopropyl amine (0.74 ml, 5.3 mmol) in THF (6 ml) at 0 C. The reaction was stirred for 15 minut~s, then was cooled to -78 C. 3-Biphenyl acetic acid (0 5g, 2.35 rnmol) wasa dissolved in THF (2 ml) and was added dropwise to the LDA solution.
The reaction was warmed to 0 C, stirred 40 minllt~s, then cooled to -78 C.
Iso~uLellyl bromide (0.475g, 3.52 mmol) was added and the re~tion was stirred for lh. Water (2 ml) was added and the THF was removed in vacuo. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml), then with EtOAc (2 x 10 ml). The comhin~-l organics were dried with m~gn~cillm sulfate, filtered, con~e~ , chromatographed (silica gel, 5% MeOH: methylene chloride) to give the desired product as a white solid (1.66 g, 93%): lH NMR: d: 7.6-7.3 (m, 9H), 4.75 (d, 2H), 3.87 (t, lH), 2.87 (dd, lH), 2.50 (dd, lH), 1.70 (s, 3H).

W O 97/16433 PCT~US96/18000 e) 3-(4-biphenyl)4-methyl-pentanoic acid 3-(4-Biphenyl)~-methyl-pent~-enoic acid (0.5g, 1.87 mmol) was dissolved in EtOAc (25 ml). Then, 10% Pd/C (60 mg) was added and the reaction was stirred for 2.5 h under a balloon of hydrogen gas. The reaction was filtered, concel~L,dled in vacuo, then was redissolved in 1:5 EtOAc: EtOH (15 ml). Then, 10% Pd/C (80 mg) was added and the reaction was stirred under a balloon of hydrogen gas overnight. The reaction was filtered, conce~ dl~d in vacuo, and chromatographed (silica gel, 5% MeOH: methylene chloride) to give the desired product as a whitesolid (1.66 g, 93%): lH NMR: d: 7.6-7.3 (m, 9H), 3.7 (t, lH), 2.07-1.95 (m, lH),1.8-1.7 (m, lH), 1.6-1.45 (m, lH).

f) l -N-(2-(3-biphenyl)4-methyl-~ . . .ido)-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 213(a), except 3-(~biph~,~yl)-4-methyl-pentanoic acid " for " Cbz-leucine", the title compound was ~ ,d:
MS(ES) M+H+= 571, M+ Na+ = 593.

F.x~n~l?le 249 ~ dlion of 1-N-(3-l~i~,l.el.yl acetyl)-~mino-3-N-(4-phenoxy-phenyl-sulfonyl)-slmino-propan-2-one Following the procedure of Example 213(a), except "3-biphenyl acetic acid " for " Cbz-leucine", the title com~ .ld was prepared: MS(ES) M+H+= 515, M+
Na+ = 537, 2M+ Na+ = 1051.

R~ le 250 - P~p~hdtion of l-N-( N~pyridyl acetyl-leucinyl)-arnino-3-N-(2-benzyloxy- phenyl-sulfonyl)-arnino-propan-2-one a) l-N-(N-Boc-leucinyl)-amino-3-N-(2-benzyloxy phenyl-sulfonyl)-amino-propan-5 2-ol 1,3-Diamino-propan-2-ol (3.375g, 37.5 rnmol) was dissolved in DMF (60 ml). Then HOBT-hydrate was added (5.Sg,40.7 mmol), followed by Boc-L-leucine (9.34g,37.5 mmol) and EDCI (7.77g, 40.7 mmol). The reaction was stirred for 4h, then diluted with DMF to make a stock solution of a total volume of 100 ml (0.375 mmol/ml). The stock solution (18 ml, 6.75 mmol) was treated with NMM (0.89 ml, 7.28 mmol), then 2-benzyloxy phenyl sulfonyl chloride (1.9g, 6.72 mmol). The reaction was stirred an additional 2h, then was diluted with water, extracted with EtOAc, dried with m~n~ m sulfate, filtered, concenl,dl~d, and chromatographed (silica gel, 20% EtOAc: hexanes): MS(ES) M+H'--550.
b) l-N-(leucinyl)-amino-3-N-(2-benzyloxy-phenyl-sulfonyl)-arnino-propan-2-ol l-N-(Boc-leucinyl)-amino-3-N-(2-benzyloxy phenyl sulfonyl)-amino-propan-2-ol (0.7g, 1.3 mmol) was dissolved in 1: 1 TFA: DCM (50 ml) and was stirred at RT for 2h, conr~ tr-l in vacuo and was used in the following reaction20 withoutfurtherpllrifiration MS(ES)M+H~=450.

c) l-N-(N-4-pyridyl acetyl-leucinyl)-amino-3-N-(2-benzyloxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 220(b)-(c), except sub~ ulillg " l-N-25 leucinyl-amino-3-N-(2-benzyloxy phenyl sulfonyl)-amino-propan-2-ol"
for " N-leucinyl-amino-3-N-(4-phenoxy phenyl sulfonyl)-amino-propan-2-ol ", the - title co~ oulld was pr~a,~d: MS(ES) M+H~= 567.

W O 97/16433 PCT~US96/18000 F.xample 251 Preparation of l-N-( N 4-pyridyl carbonyl-leucinyl~-amino-3-N-(2-benzyloxy-~h~nyl-sulfonyl)-amino-propan-2-one Following the procedure of FYample 250(a)-(c), except sllbstit-lting "4-5 pyridyl carboxylic acid" for "4-pyridyl acetic acid ", the title compound was a.Gd: MS(ES) M+H+= 553.

Example 252 F'~lion of 1-N-f N-4-imifla7~ le acetic-leucinyl)-amino-3-N-(2-benzyloxy-10 phenyl-sulfonyl)-amin--propan-2-one Following the procedure of Example 250(a)-(c), except substituting "4-imi~ ole acid" for "4-pyridyl-acetic acid ", the title co~ oulld was ~lG~ed:
MS(ES) M+H+--556.

FYam~ple 253 r~e~!~dtion of 1-N-( N-( N.N-dhll~ yl glycyl) -leucinyl)-amino-3-N-(2-benzyloxy-pheIlyl-sulfonyl)-amino-propan-2-one Following the procedure of F~mrle 250(a)-(c), except sub~ "N,N-dimethyl glycine" for "4-pyridyl-acetic acid ", the title compound was prepared:MS(ES) M+H+--533.

P.xample 254 Preparation of l-N-( N-(N-methyl prolyl-leucinyl)-am~ ino-3-N-(2-benzyloxy-phenyl-sulfonyl)-amino-propan-2-one Following the procedure of Fxample 250(a)-(c), except sub~ "N-methyl proline" for "4-pyridyl acetic acid ", the title compound was ~lG~hGd:
MS(ES) M+H+= 559.

Fx~mple 255 PIGyalalion of l-N-( N-(N-methyl piperidine-4-carbonyl)-leucinyl)-amino-3-N-(2-benzyloxv-phtorlyl-sulfonyl)-amino-propan-2-one W O 97/16433 PCT~US96/18000 Following the procedure of Example 250(a)-(c), except sub~ "N-- methyl-piperidine-4-carboxylic acid" for "4-pyridyl acetic acid ", the title compound was ~lcp~,d: MS(ES) M+H+= 573.

F.x~ ?le 256 plG~alalion of l-N-( N-(N-methyl piperidine-4-carbonyl)-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-arnino-propan-2-one Following the procedure of F.lr~mrle 250(a)-(c), except sl~b~ "N-methyl-piperidine-4-carboxylic acid" for "4-pyridyl acetic acid " and "2-dibe~ rulclll sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" thetitle coll.~oulld was ~ ,d: MS(ES) M +H+= 557.

l~xample 257 P~ lion of l-N-( N-(N-methyl prolyl)-leucinyl)-amino-3-N-(2-dibenGorulcul-sl-lfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except ~ " N-methyl proline " for "4-pyridyl acetic acid " and "2-dibenzofuran sulfonyl chloride"
for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared:
MS(ES) M+H+= 543.
~x~n~?le 258 Plcp~cLLion of l-N-( N-( N.N-dimethyl glycyl)-leucinyl)-amino-3-N-(-(2-dibçn70furan-sulfonyl)-arnino-propan-2-one Following the procedure of Example 250(a)-(c), except sllb~ g N,N-dhl~ hyl glycine " for "4-pyridyl acetic acid " and "2-dibenzofuran-sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title co~ oulld was pa.~,d: MS(ES) M+H'- 517.

,xample 259 Pl~)al~Lion of l-N-( N-4-imi-1~7~1e acetic-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-~mino-propan-2-one Following the procedure of Fx~mrle 250(a)-(c), except substitllting "4-5 imit1~7ole acetic acid" for "4-pyridyl acetic acid " and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+Hi- 526.

F.xample 260 10 rlcya~LiQn of l-N-( N-4-pyridyl carbonyl-leucinvl)-~mino-3-N-~2-dibenzofuran-lfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except substitlltin~ "4-pyridyl carboxlic acid" for "4-pyridyl acetic acid " and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title colllpoulld was 15 ~ .,d: MS(ES) M+H~= 537.

F.xarnple 261 Pl~dLion of l-N-( N~pyridyl acetyl-leucinyl)-amino-3-N2-dibenzofur~n-sulfonyl)-~mino-propan-2-one Following the procedure of FY~mpl~ 250(a)-(c), except sub~lil.. l;.~g "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chlori(l~" thetitle compound was L)l~ed: MS(ES) M+H~= 551.

~xarnple 262 25 rl~y~alion of l-N-( N-4-imidazole-acrylyl-leucinyl)-~mino-3-N-(2-dibenzofuran lfonyl)-amino-prol2~n-2-one Following the procedure of Fx~mple 250(a)-(c), except ~ub~l il ul i..~ "4-irnidazole-acryic acid" for "4-pyridyl acetic acid " and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was 30 ~ ~.,d: MS(ES) M +H~= 552.

W O 97/16433 PCT~US96/18000 Exarnple 263 - Plcyald~ion of 1-N-( N-pyrazole-carbonyl-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except sllb~ "lil,g "pyrazole c~1,o~Lylic acid" for "4-pyridyl acetic acid " and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was a cd: MS(ES) M+EI~= 538.

F.~n~le 264 Plcp~dLion of 1 -N-( N-b~ z~yl-leucinyl)-amino-3-N-(8-quinoline-sulfonyl)-arnino-propan-2-one Following the procedure of F.Y~mple 250(a)-(c), except subsl i ~
"benzoic acid" for "4-pyridyl acetic acid " and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl sulphonyl chlt ridt~" the title compound was ~lc~ d: MS(ES) M
+H+--497.

Fx~mple 265 Plc~dlion of l-N-( N-2.5-1linuol~-benzoyl-leucinyl)-amino-3-N-~8-quinoline-sulfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except substituting "2,5-difluoro-benzoic acid" for "4-pyridyl acetic acid " and "8-quinoline sulfonic acid"
for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared:
MS(ES) M+H~= 535.

F.xample 266 Plcy~dlion of l-N-( N-2.5-difluoro-phenyl acetyl -leucinvl)-amino-3-N-(8-- quinoline-sulfonyl)-arnino-propan-2-one Following the procedure of Example 250(a)-(c), except substituting "2,5-difluoro- phenyl acetic acid" for "4-pyridyl acetic acid " and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared:
MS(ES) M+H+= 547.

W O 97/16433 PCT~US96/18000 Ex~rr~le 267 Plc~L,a,alion of l-N-( N-phenyl acetyl-leucinyl)-amino-3-N-(8-quinoline-sulfonyl)-~mino-prQpan-2-one Following the procedure of Exarnple 250(a)-(c), except sub~ "phenyl acetic acid" for "4-pyridyl acetic acid " and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M
+H+=Sll.

F~rn]?le 268 r~ a.alion of 1-N-( N-4-pyridyl acetyl-leucinyl)-amino-3-N-(8-quinoline-~nlfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except sulJ~ uLillg "4-pyridyl acetic acid" for "4-pyridyl acetic acid " and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was ~.Gpalcd: MS(ES) M+H~= 512.

F~am,Fle 269 P~ Lion of l-N-( N-4-pyridyl carbonyl-leucinyl)-amino-3-N-(8-quin~,line-snlfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except sub~ g "4-pyridyl carboxylic acid" for "4-pyridyl acetic acid " and "8-quinoline sulfonic acid"
for "2-benzyloxy phenyl sulphonyl chloride" the title compound was ~lcpalc,d:
MS(ES) M+H~= 498.

W O 97/16433 PCT~US96/18000 FY~ ?le 270 Plc~ alion of l-N-( N~irnida2:ole acetyl-leucinyl)-amino-3-N-(8-~uinoline-sulfonyl)-arnino-propan-2-one Following the procedure of Example 250(a)-(c) except substi~ltin~ "4-S imi~l~7ole acetyl acid" for "4-pyridyl acetic acid " and "8-quinolin~ sulfonic acid"
for "2-benzyloxy phenyl slllrh~nyl chloricle" the title compound was ~ d:
MS(ES) M+EI+= 501.

_xample 271 10 F'rep~dlion of l-N-( N-3-phenyI propionyl-leucinyl)-amino-3-N-(8-quinoline-sulfonyl)-amino-propan-2-one Following the procedure of Fx~mrle 250(a)-(c) except sub~lil..l;.-g "hydrocinn~rnic acid" for "4-pyridyl acetic acid " and "8-q-1inolinP suIfonic acid" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was ~ d: MS(ES) M+H~= 525.

FY~n~le 272 Plc~J~alion of bis-N~N'-( N~-pyridyl methyleneoxy carbonyl-leucinyl)-1.3-tli~mino-propan-2-one Following the procedure of Example 37 except sub~titllting "4-pyridyl-methyleneoxy-c~l.onyl-leucinyl " for "Cbz-leucine ", the title compound was tl?aled: MS(ES) M+H+- 585.

F.x~mrle 273 F'~ ion of bis-N~N'-( N-3-pyridyl methyleneoxy-carbonyl-leucinyl)- 1.3-~i~mino-propan-2-one - Following the procedure of F.x~rnrle 37 except sub~ lir.g "3-pyridyl-methyleneoxy-c~l,on5rl-leucinyl " for "Cbz-leucine ", the title compound was p,cpaled: MS(ES) M+H'--585.

W O 97/16433 PCTAJS9~/18000 Fxample ~74 aLion of bis-N~N'-( N-2-pyridyl methyleneoxy carbonyl-leucinyl)- 1.3-mino-propan-2-one Following the procedure of Example 37, except substihlting "2-pyridyl-S methyleneoxy-carbonyl-leucinyl " for "Cbz-leucine ", the title compound was prepared: MS(ES) M+H+= 585.

F.x~ ?le 275 Fle~alalion of l-N-( N-Cbz-leucinyl)-amino-3-N-(2-benzyloxy-benzoyl)-amino-10 propan-2-one Following the procedure of F.~mple 229, except 2-benzyloxy-benzoic acid"
for "8-quinoline-carboxylic acid ", the title colllpc,ulld was ~i~al~,d: MS(ES) M
+H+= 546.

F.~m~le 276 r~alion of l-N-( N-Cbz-leucinyl)-amino-3-N-(3-benzyloxy-bellzc~yl)-amino-propan-2-one Following the procedure of F.Y~mp1e 229, except "3-benzyloxy benzoic acid" for "8-quinoline carboxylic acid ", the title compound was pl~&.-,d: MS(ES) M+H~= 546.

F.~ ?le 277 rl~aLion of l-N-( N-Cbz-leucinvl)-arnino-3-N-(4-biphenvl-acetyl)-arnino-~ropan-2-one Following the procedure of FY~mple 229, except "4-biyhel~yl acetic acid"
for "8-quinoline carboxylic acid ", the title compound was ~r~ d: MS(ES) M
+H+--530.

W O 97/16433 PCT~US96/18000 F.x~ le 278 lion of l-N-( N-Cbz-leucinyl)-amino-3-N-(2-carboxymethyl-thiophene-3-sulfonyl)-arnino-propan-2-one Following the procedure of Exarnple 51, except sub~ ..l;"~ "2-carboxymethyl thiophene-3-sulfonyl " for "~(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title co~ ou~d was ~ )a ed: MS(ES) M-H'-540.

F.xan~?le 279 PlG~,~dtion of l-N-( N-Cbz-leucinyl)-arnino-3-N-methyl-N-( N-Cbz-leucinyl)-amino-propan-2-one a) N-(Cbz-leucinyl)-arnino-propene N-Cbz-leucine (3.0g, 11.3 rnmol) was dissolved in DMF (50 ml), then NMM
(1.3g, 12.4 rnmol) was added, followed by allyl amine (0.65g, 0.85 mmol), and HBTU (4.3g, 11.3 mmol) and the reaction was stirred overnight at RT. The reaction was diluted with water, extracted with EtOAc, dried with m~nt~cillm sulfate, filtered, conce~ ted, and ch- ,lnatographed (silica gel, 40% EtOAc: h~x~nec):
MS(ES) M+EI~= 305.

b) N-(Cbz-leucinyl)-amino-propene oxide N-(Cbz-leucinyl)-amino-propene (2.95g, 9.7 mmol) was dissolved in methylene chloride (100 ml), then mCPBA (5.0g, 29.1 mrnol) was added and the reaction was stirred overnight. The reaction was diluted with sahlrate~ aqueous sodium bicarbonate, extracted with EtOAc, dried with m~gn~cillm sulfate, filtered, con~e.~ ed, and ch~ al~7graphed (silica gel, 50% EtOAc: hexanes).
c) l-N-(Cbz-leucinyl)-amino-3-N-methyl-amino-propan-2-ol - N-(Cbz-leucinyl)-amino-propene oxide (400 mg, 1.25 mmol) was dissolved in isopropanol (5 ml), then aqueous methyl arnine (2 ml) was added and the reaction was heated to 70 C in a sealed bomb for 2h. The reaction ~ ule was concentrated in vacuo and was used in the next reaction without further pllrifi~tion.

W O 97/16433 PCT~US96/18000 d) 1-N-( N-Cbz-leucinyl)-amino-3-N-methyl-N-( N-Cbz-leucinyl)-amino-propan-2-one Following the procedure of Example 229(a), except sub~liLulillg " l-N-(Cbz-leucinyl)-amino-3-N-methyl-~mino-propan-2-ol " for "8-quinoline carboxylic acid S ", the title compound was p,G~aled: MS(~S) M+H+= 597.

Fx~ le 280 r~ dlion of 1-N-( N-Cbz-leucinyl)-amino-3-N-methyl-N-( N4-pyridyl-rn~tllyloxy-c~ l~o~lyl-leucinyl)-amino-propan-2-one Following the procedure of Example 279(a)-(d), except s-lbs~ ;"g ~4-pyridyl-methyleneoxy-c~l,ol,yl leucine " for "Cbz-leucine" in (d), the title compound was pl~epa~cd: MS(ES) M+H+--598.

Ex~ ?le 281 15 rl~c~ ion of 1-N-( N-Cbz-leucinyl)-amino-3-N-methvl-N-(2-dibenzofu~
~nlfonyl)-amino-l?ropan-2-one Following the procedure of Example 279(a)-(d), except sub~ u~ g "2-dibenzofuran sulfonyl chlori~ " for "Cbz-leucine and HBTU" in (d), the title compound was ~lGp~,d: MS(ES) M+H+--580, M+ Na+ = 602.
~ x~rnple 282 P~ ion of l-N- methyl-1- N-( N-Cbz-leucinyl)-amino-3- N-(2-dibenzofuran-snlfonyl)-amino-propan-2-one Following the procedure of Example 279(a)-(d~, except substitnting "2-25 ~ ell~oru~l sulfonyl chloride " for "Cbz-leucine and HBTU" in (a), the title co~ ound was ~r~cd: MS(ES) M+H+=580 W O 97/16433 PCT~US96/18000 F~ample 283 - Ple~a~dLion of 1-N- methyl-l N-( N-Cbz-leucinyl)-amino-3- N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one Following the procedure of Example 279(a)-(d), except sub~l iL. ~1 i..~ "2-5 dibenzofuran sulfonyl chloride" for "N-Cbz-leucine" in step (a) and "4-pyridylmethyleneoxy c~l,ollyl-leucine " for "Cbz-leucine " in step (d), the title compound was ~lepal~d: MS(ES) M+H'--580.

F.~n~@le 284 10 PlGyaldtion of l-N-(2-dibenzofuran sulfonyl)-N-methyl)- ~mino-3N-(N4-pyrid m.othyleneoxv c~l~onyl-leucinyl)-amino-propan-2-one Following the procedure of Example 279(a)-(d), except slih~ 4 pyridyl methyl amine" for "allyl amine" and "2-dibellzoru,~l sulfonyl chloride" for "N-Cbz-leucine" in step (a) and " N4-pyridyl methyleneoxy carbonyl -leucinyl " for 15 "N-Cbz-leucine and HBTU " in step (d), the title co~ oulld was p~ued: MS(ES) M+H+=581.

E~xample 285 Pl~p~tion of l-N-( N-Cbz-leucinyl)-amino-3-N-( 4-pyridyl-methylene)-3N-( N-Cbz-leucinyl)-amino-propan-2-one Following the procedure of Example 279(a)-(d), except s~bsl i 1~
pyridyl methyl amine " for "methyl amine", the title compound was ~,epa~cd:
MS(ES) M+H+= 674.

F.scample 286 tion of 1-N-(Cbz-leucinyl)-amino-3-N-(4-pyridyl-methylene)-3N-(2-- dibenzofuran sulfonyl)-amino-propan-2-one Following the procedure of Example 284(a)-(d), except ~ub~ .t;~lg "2-dibel~oru,an sulfonyl chloride "Cbz-leucine and HBTU" in step (d), the title compound was prepared: MS(ES) M+H+-657.

W O 97/16433 PCT~US96/18000 Example 287 Ple~,)alaLion of l-N-(Cbz-leucinyl)-amino-3-N-(4-pyridyl-methylene)-3N-(2-~ihenzofu~an sulfonyl)-amino-propan-2-one Following the procedure of Fx~mrle 284(a)-(d), except ~Ubsli~Ulillg "2-S dibcl~zoruld n sulfonyl chloride "Cbz-leucine and HBTU" in step (d), the title cum~ound was prepared: MS(ES) M+EI+=657.

Fx~m~le 288 P~J~aLion of 1-N-(4-biphenyl acetyl)-amino-3-N-(4-pyridyl-methylene)-3N-( N-10 Cbz-leucinyl)-amino-propan-2-one Following the procedure of Example 279(a)-(d), except ~--b~ l;..g "4-biphenyl acetic acid " for "Cbz-leucine " in step (a), "4-pyridyl methyl amine " for "methyl amine", the title compound was ~lc~,d: MS(ES) M+H~=621.

F~ample 289 P~ dtion of l-N-(4-phenoxy-benzoyl)-amino-3-N-(4-pyridyl-methylene)-3N-( N-Cbz-leucinyl)-~mino-propan-2-one Following the procedure of Example 279(a)-(d), except ~ub~ "4-phenoxy benzoic acid " for "Cbz-leucine " in step (a), "4-pyridyl methyl amine " for 20 "methyl arnine", the title compound was ~lGp~d: MS(ES) M+H+= 623.

Example 290 P~ ~pal dlion of 1 -N-(2-dibenzofuran-sulfonyl)-arnino-3-N-(4-pyridyl-methylene)-3N-( N-Cbz-leucinyl)-amino-propan-2-one Following the procedure of Example 279(a)-(d), except ~ul,~l i ~.. 1 i i-g "2-dibenzofuran sulfonyl chloride " for "Cbz-leucine and HBTU" in step (a), "4-pyridyl methyl amine" for "methyl amine", the title co~ oulld was prepared: MS(ES) M+H~= 657.

W O 97/16433 PCTrUS96/18000 Example 29 1 - P~ Lion of l-N-( N-3-pyridyl-methyleneoxy-c~l~ullyl-leucinyl)-amino-3-N-m~,thyl-N-(2-dibenzofuran-sulfonyl)-amino-propan-2-one Following the procedure of Fx~mple 279(a)-(d), except ~ub~ .l i . ,g "N-S methyl-N-allyl amine " for "alIyl amine" in (a), and "3-pyridyl-methyleneoxy-c~l,onyl-leucine" for "Cbz-leucine" in step (d), the title compound was L,i~ar(,d:
MS(ES) M+H'--581.

The above specifi~ ~tion and F~r~mplPs fully disclose how to make and use the cc,~ oullds of the present invention. However, the present invention is not limited to the particular embo~ c clesc~ibecl hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publi~tion.c which are cited herein 15 c-)mpri~e the state of the art and are incorporated herein by reference as though fully set forth.

Claims (72)

We claim:

1. A compound according to Formula I:

wherein:

;

Q=
; ;

;

; ;

; ; ;

where:
A = absent, ;

;
B= , L = C2-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl,CH(R66)NR60R68, CH(R66)Ar,CH(R66)OAr', NR66R67;
M = C(O), SO2;

J = C(0), S02;
T = Ar, Het;
V = C3-7cycloalkyl;
W = H,-CN, -CF3, -N02, -C0R7, -C02R6, -C0NHR6, -S02NHR6, -NHS02R6, -NHC0R7, -0-C0R6, -SR6, NR'R6, NR'(C=NH)NHR5, C1, Br, I, F;
X=Y=Z=N,0,S or CR4, provided that at least two of X, Y and Z are heteroatoms 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 CR4 or N, provided that X, Y and Z together comprise at least two N;
_ indicates a single or double bond in the five-membered heterocycle;
m=0,1,2;
n= 1 to 6;
~= 0,1,2;
Ar = phenyl, naphthyl, optionally substituted by one or more of Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, 0H, (CH2)1 6NR58R59, 0(CH2)1-6NR58R59;
Ar' = phenyl or naphthyl, optionally substituted by one or more of Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, 0H,(CH2)1-6NR58R59, 0(CH2)1-6NR58R59,or halogen;
R' = H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R1 = H, C1-6alkyl;
R2 = C4-6alkyl, C4-6alkenyl, benzyl;

R3 = C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, R5C0-, R5S02-, R50C(0)-, R5NHC0-;
R4 = H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R5 = Ar-0-6alkyl, Het-C0-6alkyl;
R6 = H, C1-6alkyl, CH2CF3, Ar-C0-6alkyl Het-C0-6alkyl;
R7 = C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R8 = H; C2-6alkenyl; C2-6alkynyl; Het; Ar; C1-6alkyl, optionally substituted by 0R', SR', NR'2, C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R9 = H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R10 = C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R11 = H, C1-6alkyl, Ar-C1-6alkyl, Het-C0-6alkyl, or R12 = H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R13 = H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;

R15 = H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ar, Het, or C1-6alkyl optionally substituted by 0R9, NR92, C0NR92, N(C=NH)NH-, Het or Ar;
R16 = C2-6alkyl, C2-6alkenyl, C2-6alkynyl, Ar, Het, or C2-6alkyl optionally substituted by 0R9, SR9, NR92, C02R9, C0NR92, N(C=NH)NH-, Het or Ar;
R19 = H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ar, Het, or C1-6alkyl optionally substituted by 0R9, SR9, NR92, C02R9, C0NR92, N(C=NH)NH-, Het or Ar;
R17 = R72 = H, C1-6alkyl, R10, R10C(0), R10C(S) R100C(0);

R21 = R26 = C5-6alkyl; C2-6alkenyl; C3-11cycloalkyl; T-C3-6alkyl; V-C1-6alkyl; T-C2-6alkenyl;
T-(CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR20, 0R20,NR20R27 or C1-4alkyl;
R27 = R28C0, R280C0;
R28 = C1-6alkyl; C3-11cycloalkyl; Ar; Het; T-C1-6alkyl;
T-(CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR20, 0R20, NR20R73, C1-6alkyl;
R20 = R22 = R23 = R24 = R25 = R73 = H, C1-4alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R29 =

Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methyloxycarbonyl-leucinyl-;
4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-aminoacid-;
aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, C1-C6alkyloxy carbonyl-amino acid-; C1-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, C1-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl, alyl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl;

R30 = -H, C1-6alkyl;
R31 =

Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methyloxycarbonyl-leucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-aminoacid-; aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, C1-C6alkyloxy carbonyl-amino acid-; C1-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, C1-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, substituted heteroaryl C0-C6alkyl sulfonyl;
R32 = 0CH2Ar, 0CH2C1-6alkyl, aryl substituted C0-6alkyl, heteroaryl substituted C0-6alkyl,4-imidazole methylene; 2-, 3-,or 4-pyridylmethylneneoxy; 4-pyridyl methylene, 2-pyridyl sulfonyl, 4-pyridyl, aryl C0-6alkyloxy, heteroaryl substituted C0-6alkyloxy;
R33 = C1-6alkyl. -CH2Ph, -CH2CH2C02R34;

R34 = -H, C1-6alkyl;
R35 = Ar, HetAr;
R36 = Aryl, heteroaryl, pyridyl, isoquinolinyl;
R37= C1-6alkyl, -CH2Ph, -CH2CH2C02R34;
R38 = Cbz; C1-6alkyl or aryl substituted Cbz; C1-6alkyl -C0; benzoyl; C1-6alkyl or aryl substituted benzoyl;
R39 =

Cbz-leucinyl-; 2-, 3-, or 4-pyridyl methyloxycarbonyl-leucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonyl-leucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon-(t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; 2-,3-, or 4- pyridylmethyloxycarbonyl-aminoacid-; aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, aryl C0-C6alkyloxy carbonyl-amino acid-, heteroaryl C0-C6alkyloxy carbonyl-amino acid-, C1-C6alkyloxy carbonyl-amino acid-; C1-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, aryl C0-C6alkyl carbonyl, heteroaryl C0-C6alkyl carbonyl, C1-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl, aryl C0-C6alkyl sulfonyl, heteroaryl C0-C6alkyl sulfonyl;
R40 = H and C1-6alkyl;
R41 = H and C1-6alkyl;
R42 = C1-6alkyl, aryl substituted C1-6alkyl and hetero aryl substituted C1-6alkyl,; H when R43 is C1-6alkyl, aryl substituted C1-6alkyl; and heteroaryl substituted C1-6alkyl;

R43 = C1-6alkyl, aryl substituted C1-6alkyl and hetero aryl substituted C1-6alkyl,; H when R42 is C1-6alkyl, aryl substituted C1-6alkyl; and heteroaryl substituted C1-6alkyl;
R44 = CH(R53)NR45R54, CH(R55)Ar, C5-6alkyl;
R45 = R46 = R47 = R48 = R49 = R50 = R51 = H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R52 = Ar, Het, CH(R56)Ar, CH(R56)OAr, N(R56)Ar, C1-6alkyl, CH(R56)NR46R57;
R53 = C2-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, R53 and R45 may be connected to form a pyrrolidine or piperidine ring;
R54 = R57 = R47, R47C(O), R47C(S), R47OC(O);
R55 = R56 = R58 = R59 = H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl;

R60 = R61 = R62 = R63 = R64 = H, C1-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl;
R65 = C1-6alkyl, Ar, Het, CH(R69)Ar, CH(R69)OAr, N(R69)Ar, CH(R69)NR61R70;
R66 = R69 = R71 = H, C1-6alkyl, (CH2)0-6-C3-6cycloalkyl, Ar-C0-6alkyl, Het-C0-6alkyl;
R67 = C1-6alkyl, (CH2)0-6-C3-6cycloalkyl, Ar-C0-6alkyl, Het-C0-6alkyl; R66 and R67 may be combined to form a 3-7 membered monocyclic or 7- 10-membered bicyclic carbocyclic or heterocyclic ring, optionally substituted with 1-4 of C1-6alkyl, Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, OH, (CH2)1-6NR58R59, O(CH2)16NR58R59; R68 = R70 = R62, R62C(O), R62C(S), R62OC(O), R62OC(O)NR59CH(R71)(CO);

and pharmaceutically acceptable salts thereof.

2. A compound according to Claim 1 wherein:

and

3. A compound according to Claim 2 wherein A is Leu.

4. A compound according to Claim 2 wherein W is CN, NHR6, SR6, CONHR6 or CO2R6.

5. A compound according to Claim 2 wherein R1 is H, methyl or isobutyl.

6. A compound according to Claim 2 wherein R3 is R5OC(O)-.

7. A compound according to Claim 2 selected from the group consisting of:(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-carboxythiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-carboxamidothiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide;
2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-carboethoxythiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-cyanothiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-[2-(N'-benzylcarboxamido)thiazol-4-yl]-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-[2-[N'-(3-methylpropyl)carboxamido]thiazol-4-yl)]-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-[2-[N'-(2-phenylethyl)carboxamido]thiazol-4-yl)]-3'-methylbutyl]-4-methylpentanamide;

(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(4-carboxythiazol-2-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(4-carboethoxythiadiazol-2-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-carbo-2,2,2-trifluoroethoxythiazol-4-yl)-3'-methylbutyl]4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(4-carboethoxyoxadiazol-2-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1'-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(4-carboxamidooxadiazol-2-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-carboethoxythiazol-4-yl)-3'-methylbutyl]-3-phenylpropanamide;
(2S,1'S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1'-(2-carboethoxythiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(5-mercapto-1,2,4-oxadiazol-3-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-mercaptothiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S)-2-(benzyloxycarbonyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(2-benzyloxycarbonylthiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3'-methyl-1'-(2-phenoxycarbonylthiazol-4-yl)butyl]pentanamide;
(2S,1'S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3'-methyl-1'-[2-(2-methylpropyloxycarbonyl)thiazol-4-yl]butyl]pentanamide;

(2R,1'S)-2-(benzyloxycarbonyl)amino-N-[1'-(4-carboethoxythiazol-2-yl)ethyl]-4-methylpentanamide;
(2R,1'R)-2-(benzyloxycarbonyl)amino-N-[1'-(4-carboethoxythiazol-2-yl)ethyl]-4-methylpentanamide; and (2S,1'S)-N-[1'-(2-aminothiazol-4-yl)-3'-methylbutyl]-2-(benzyloxycarbonyl)amino- 4-methylpentanamide.

8. A compound according to Claim 1 wherein:

D = and Q =

9. A compound according to Claim 8 wherein B is , or

10. A compound according to Claim 9 wherein R11 is and R12 and R13 are H.

11. A compound according to Claim 8 wherein E is absent.

12. A compound according to Claim 8 in which R14 is

13. A compound according to Claim 8 in which R16 or R19 are i-Bu.

14. A compound according to Claim 8 which is:

15. A compound according to Claim 8 wherein R17 or R72 is R10OC(O)-.

16. A compound according to Claim 8 selected from the group consisting of:(1S)-N-[4-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;
N-benzyloxycarbonyl-L-leucinyl-N'-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide; and (1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide.

17. A compound according to Claim 1 wherein:

and

18. A compound according to Claim 17 wherein:
R21 and R26 are selected from the group consisting of:
N-Cbz-leucinyl, N-Cbz-glycinyl, N-acetyl-leucinyl, N-Cbz-alanyl, R22 = R23 = R24= R25 = H.

19. A compound according to Claim 17 selected from the group consisting of:2,2'-(N,N'-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;
2,2'-(N,N'-bis-cyclohexylacetyl)carbohydrazide;
2,2'-(N,N'-bis-4-methylpentanoyl)carbohydrazide;
2,2'-(N,N'-bis-cyclopentylacetyl)carbohydrazide;
2,2'-(N,N'-bis-benzyloxycarbonylglycinyl)carbohydrazide;
2,2'-(N,N'-bis-acetyl-L-leucinyl)carbohydrazide;
2,2'-(N,N'-bis-benzyloxycarbonyl-L-alanyl)carbohydrazide; and 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-[N'-(4-methylpentanoyl)]carbohydrazide.

20. A compound according to Claim 1 wherein:

D= and Q= .

21. A compound according to Claim 20 wherein R30 is selected from the group consisting of -Me and -CH2CH2Me2.

22. A compound according to Claim 20 wherein R33 is selected from the group consisting of -Pr, -Bu, and -CH2CH2Me2.

23. A compound according to Claim 1 wherein R34 is -t-Bu.

24. A compound according to Claim 20 selected from the group consisting of:
bis-(Cbz-leucinyl)-1,3-diamino-propan-2-one;
bis-1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one;
1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one;
1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-t-butyl ester)-amino-propan-2-one;
1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl)-amino-propan-2-one;
bis-1,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-one;

1-(Cbz-leucinyl)-amino-3-(Cbz-phenylalanyl)-amino-propan-2-one;
1-(Cbz-leucinyl)-amino-3-(Cbz-norleucinyl)-amino-propan-2-one;
1-(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one;
bis-1,3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one;
1-(acetyl-leucinyl)-amino-3-(4-phenoxy-benzoyl)-amino-propan-2-one; and 1-(Cbz-homo-leucinyl)-amino-(Cbz-leucinyl)-3-amino-propan-2-one.

25. A compound according to Claim 24 known as 1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one.

26. A compound according to Claim 1 wherein:

and

27. A compound according to Claim 26 wherein:

R35 is selected from the group consisting of Ph, or pyridine.

28. A compound according to Claim 27 known as bis-1,3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-one.

29. A compound according to Claim 27 known bis-1,3-(4-phenoxy-phenyl sulfonamido)-propan-2-one.

30. A compound of Claim 1 wherein:

and

31. A compound according to Claim 30 wherein R36 is selected from the group consisting of:

32. A compound according to Claim 30 wherein R37 of said compound is Me.

33. A compound according to Claim 31 selected from the group consisting of:
1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)phenyl sulfonamido)-propan-2-one;
1-(Cbz-leucinyl)- amino-3-(tosyl-amino)-propan-2-one;
1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)propan-2-one;
1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;
1-(Cbz-homo-leucinyl)-amino-3-(2-dibenzofuransulfonamido)propan-2-one; and 1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one.

34. A compound according to Claim 33 known as 1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one.

35. A compound according to Claim 33 known as 1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one.

36. A compound according to Claim 33 known as 1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one.

37. A compound according to Claim 1 wherein:

and Q=

38. A compound according to claim 37 wherein R43 is 2-dibenzofuranylsulfonyl.

39. A compound according to Claim 38 selected from the group consisting of:
(S)-phenylmethyl [1-[[[3-[benzyloxycarbonyl-leucinyl-amino]-2-oxopropyl]-1-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;
(S)-Phenylmethyl [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;
(S)-Phenylmethyl [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;
1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl) benzamide; and (S)-Phenylmethyl [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate.

40. A compound according to Claim 39 known (S)-phenylmethyl [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate.

41. A compound according to Claim 39 known as (S)-phenylmethyl [1-[[[3-[benzyloxycarbonyl-leucinyl-amino]-2-oxopropyl]-1-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate.

42. A compound according to Claim 1 wherein:

.
and Q=

43. A compound according to Claim 42 wherein:
R44 = CH(R53)NHR54;
R45, R46 R48, R49, R50 and R51 are H;
R47 is independently CH3, benzyl, 2-pyridinylmethoxy, 4-dimethylaminobenzyl;
J = C(O);
R52 = Ar, CH(R10)Ar, CH(R10)OAr, N(R10)Ar, CH(R10)NR"R11;
R53 = ethyl, i-Bu;
R54 = R47, R47C(O), R47OC(O);
R56 = H, CH3, i-Bu;
R57 = R47, R47OC(O);
Ar = phenyl or naphthyl, optionally substituted by one or more of Ph-C0-6alkyl, Het-C0-6alkyl, C1-6alkoxy, Ph-C0-6alkoxy, Het-C0-6alkoxy, OH, (CH2)1-6NR58R59, O(CH2)1-6NR58R59;
R58,R59 = H, C1-6alkyl, Ar-C0-6alkyl; Het-C0-6alkyl.

44. A compound according to Claim 42 selected from the group consisting of:
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4-phenoxyphenylsulfonyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-alanyl)]-2'-[N-(N-benzyloxycarbonyl-L-leucinyl) carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4-phenylbenzoyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4-methoxybenzoyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4-phenoxybenzoyl)]carbohydrazide;
2-(N-acetyl)-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(N-acetyl-L-leucinyl)]-2'-[N'-(N-benzyloxycarbonyl-L-alanyl)]
carbohydrazide;
2-[N-(N-acetyl-L-alanyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N,N-dimethylaminomethyl)benzoyl)]]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-hydroxy-[3-(4-morpholinomethyl)]]benzoyl]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N,N-dimethylaminomethyl)benzyloxy]carbonyl-L-leucinyl]carbohydrazide;
2-(N-benzoyl)-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[3-(4-morpholinomethyl)benzoyl]]carbohydrazide;
2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-[3-(N-N-dimethylamino)-1-propyloxy]benzoyl]]carbohydrazide;
2-[N-(2-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;

2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[3-(4-pyridylmethoxy)benzoyl]]carbohydrazide;
2-[N-(4-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(3-benzyloxy-5-methoxy)benzoyl]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(3-benzyloxy-4,5-dimethoxy)benzoyl]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(3-benzyloxy-5-ethoxy)benzoyl]carbohydrazide;
2-[N-(N-benzyloxycarbonylglycinyl)]-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;
2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-L-prolinyl)]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)] -2'-[N'-(4-phenylphenylacetyl)]carbohydrazide;
(2'S)-2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-2-aminobutyryl)]carbohydrazide;
2,2'-[N,N'-[bis-(4-phenylphenylacetyl)]]carbohydrazide;
(2'RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[2-(4-phenylphenoxy)propionyl]carbohydrazide;
2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(4-methylpentanoyl)]carbohydrazide;
(2RS, 2'RS)-2,2'-[N,N'-[bis-[2-(4-phenylphenyl)4-methylpentanoyl)]]]carbohydrazide;
(2'RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;
(2'RS)-2-[N-(3-benzyloxybenzoyl)]- 2'-[N'-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;
2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)]carbohydrazide;

2-[N-(3-benzyloxybenzoyl)]-2'-[N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;
2-[N-]3-(4-pyridylmethoxy)benzoyl]]-2'-tN'-tN-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;
(2RS)-2-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]-2'-[N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;
2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[N-(4-phenylphenyl)-N-(2-methylpropyl)carbamoyl]]carbohydrazide;
2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-methyl-L-leucinyl)]carbohydrazide; and 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(N-methyl-L-leucinyl)]carbohydrazide.

45. A compound according to Claim 1 wherein:

.
D=L~G~ and Q=

46. A compound according to Claim 45 wherein G is:

; .

47. A compound according to Claim 45 wherein R63 is H and R64 is H.

48. A compound according to Claim 45 wherein R66 is i-butyl and R69 is i-butyl.

49. A compound according to Claim 45 wherein R65 is CH(R69)NR61R70.

50. A compound according to Claim 49 wherein R69 is i-butyl.

51. A compound according to Claim 50 wherein R61 is H.

52. A compound according to Claim 49 wherein R70 is R62OC(O), in which R62 is , , , .
or

53. A compound according to Claim 45 wherein R65 is Ar or CH(R69)Ar, in which Ar in said R65 group is ; ;

.

54. A compound according to Claim 45 wherein L is CH(R4)NR'R6, CH(R4)Ar, NR4R5, CH(R4)OAr', Ar, or Het.

55. A compound according to Claim 54 wherein R4 is i-butyl.

56. A compound according to Claim 45 wherein L is CH(R66)NR60R68 CH(R66)Ar, NR66R67, CH(R66)OAr', Ar, or Het, in which Ar in said L group is , , , , , , or ;

or

57. A compound according to Claim 54 wherein L is Het, in which said Het is

58. A compound according to Claim 54 wherein L is NR66R67.

59. A compound according to Claim 54 wherein L is CH(R66)R60R68.

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:
(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-(4-phenoxyphenylsulfonyl)hydrazide;
(1S)-N-[4-[1-(N-benzyloxycarbonyl-L-leucinylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;
(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-(4-phenylphenylacetyl)hydrazide;
(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[3-(4-pryidinylmethoxy)benzoyl]hydrazide;
N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-[4-(1,2,3-thiadiazol-4-yl)phenyl]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[3-(4-chlorophenylsulfonylmethyl)thien-2-yl]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
(1S,2'RS)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[2'-(4-phenylphenylacetyl)-4-methylpentanoyl]hydrazide;

N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydraide;
(1RS)-N-[2-[1-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-methyl-N-(4-phenylphenyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(4-phenylbenzyl)thizol-4-yicarbonyl]hydrazide;
N-[2-(4-phenylphenylbenzyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N'-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]hydrazide;
N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N'-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; and N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide.

63. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

64. A method of inhibiting a cysteine protease comprising adminsistering to a patient in need thereof an effective amount of a compound according to Claim 1.

65. A method according to Claim 64 wherein said cysteine protease is cathepsin K.

66. A method of treating a disease characterized by bone loss comprising inhibiting said bone loss by administering to a patient in need thereof an effective amount of a compound according to Claim 1.

67. A method according to Claim 66 wherein said disease is osteoporosis.

68. A method according to Claim 66 wherein said disease is periodontitis.

69. A method according to Claim 66 wherein said disease is gingivitis.

70. A method of treating a disease characterized by excessive cartilage or matrix degradation comprising inhibiting said excessive cartilage or matrix degradation by administering to a patient in need thereof an effective amount of a compound according to Claim 1.

71. A method according to Claim 70 wherein said disease is osteoarthritis.

72. A method according to Claim 70 wherein said disease is rheumatoid arthritis.