AU2259100A - Protease inhibitors - I - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

a .e *1 a a a.

a a a.

Name of Applicant: Actual Inventors: Address for Service: SmithKline Beecham Corporation CARR, Thomas Joseph DESJARLAIS, Renee Louis GALLAGHER, Timothy Francis HALBERT, Stacie Marie MASHITA, Dennis Shinji THOMPSON, Scott Kevin VEBER, Daniel Frank YEN, Jack Hwekwo DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Invention Title: Protease inhibitors I The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\PDB\2272466.080 20/3/00 P:\OPER\PDB\II 180-97.DVI 20/3/00 PROTEASE INHIBITORS This application is a divisional application derived from Australian Patent Application No. 11180/97, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION This invention relates in general to hydrazidyl, bis-hydrazidyl and bis-aminomethyl carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, osteoporosis, periodontitis, and arthritis.

BACKGROUND OF THE INVENTION Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature.

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 characterized. Bossard, et al., (1996) J.Biol.Chem.271, 12517-12524; Drake, et al., (1996) J.Biol.Chem. 271, 12511-12516; Bromme, et al., (1996) J.Biol.Chem. 271, 2126-2132.

Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the literature. The designation cathepsin K is considered to be the more appropriate one.

Cathepsins function in the normal physiological process of protein degradation in animals, including humans, 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, including but not limited 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, amytrophy, 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 references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, 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 plateshaped crystals of hydroxyapatite are incorporated. Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 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 remodelling at discrete foci throughout life. These foci, or remodelling units, undergo a cycle consisting 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 sealing zone, followed by extensive membrane ruffling on their apical resorbing) surface. This creates an enclosed extracellular compartment 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 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 disease, the 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 bone and may result in increased fracture risk with minimal trauma.

Several published studies have demonstrated that inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem. 1980, 192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases leupeptin, Z-Phe-Ala-CHN 2 prevent bone resorption, while serine protease inhibitors were ineffective. 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 calcium deficient diets. Lerner, et aL, J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, et aL, Bone, 1987, 8, 305, Hill, et at, J. Cell. Biochem., 1994, 56, 118, and Everts, et at, J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol Chem., 1994, 269, 1106, Inaoka, et Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al, FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.

The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, 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 diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.

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 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 mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.

International Patent Application No. PCT/US94/08868 and and European Patent..

Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-13 convertase. Alkoxymethyl and i. mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479).

Azapeptides which are designed to deliver the azaamino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by Elmore et al., Biochem. 1968, 107, 103, Garker et al., Biochem. 1974, 139, 555, Gray et aL, Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et aL, J. Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases. In addition, J. Med. Chem., 1992, 35,4279, discloses certain azapeptide esters as cysteine protease inhibitors.

Antipain and leupeptin are described as reversible inhibitors of cysteine protease in McConnell 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 cysteine protease inhibitors (Barrett, Biochem. 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-diamido-propanones have also been described as analgesic agents Patent Nos.4,749,792 and 4,638,010).

Certain heterocyclic derivatives of amino acids have been disclosed in the art. For instance, Hamada, et al., PEPTIDE CHEMISTRY, 1983. Proceedings of the 21st Symposium on Peptide Chemistry (1984), and Boden, et al., Tet. Lett., 1994, 8271 (1994) disclose thiazole derivatives; and Borg, et al., 1995, 60, 3112, disclose oxadiazole and triazole derivatives.

The synthesis of azatides (polyacylhydrazides) as peptide mimetics has recently been disclosed by Han and Janda, J. Am. Chem. Soc. 1996, 118, 2539.

Thus, a structurally diverse variety of cysteine protease inhibitors have been identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance. A need therefore exists for methods of treating diseases caused by pathological levels of cysteine proteases, including cathepsins, especially cathepsin K, and for novel inhibitor compounds useful in such methods.

We have now discovered a novel class of hydrazidyl, bis-hydrazidyl and bisaminomethyl carbonyl compounds which are protease inhibitors, most particularly of cathepsin K.

SUMMARY OF THE INVENTION An object of the present invention is to provide hydrazidyl, bis-hydrazidyl and bis-aminomethyl 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 cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.

Accordingly, in the first aspect, this invention provides a compound according to Formula I.

In another aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.

In yet another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet 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 degradation, such as osteoarthritis and rheumatoid arthritis. DETAILED DESCRIPTION The present invention provides compounds of Formula I: 0

II

D--C-Q

wherein:

D=

R '22 3 2 Ra R N .R R R R 29 N R R B- O R H 0 0 R)

S-N'

0 0 R3 38 14 N R yN' H 0 R" 0 R 0 112 R, 0, 'C R 4 N'N R R~4 00 11 0 1 N-S- 36 10 0 R31

H

RI 51 N 52 41 50 R R N N

R

6 163

R

where: 0 NJk A absent, x=Y 0 R 1 L C2..6alkYl, Ar-C 0 6 a~kyl, Het-CO4 6 alcYl, CH(R 6 6

)NR

60 R68,

CH(R

6 6 )Mr, CH(R 6 6 )OAr' NR 6 6

R

6 7 M SO 2 'z J SO 2 T =Ar, Het; V =C3..7cYcloallcyl; W -CN, -CE 3

-NO

2

-COR

7 -C0 2

R

6 -coNHR 6

-SO

2

NHR

6

-NHSO

2

R

6

-NHCOR

7

-O-COR

6

-SR

6

NR'R

6

NR,(C=NH)NHJ(

5 Cl, Br, 1, F; X Y Z= N, 0, S or CR 4 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 CR 4 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 =I to 6; 1, 2; Ar phenyl, naphthyl, optionally substituted by one or more of Ph-CO-6alkyl. Het-C4- 6 alkyl, C 1 6 alkoxy, Ph-C 0 6 alkoxy, Het-CO- 6 alkoxy, OH, (CH 2 1

NR

58

R

5 9

O(CH

2 1 _6.NR 5 8

R

5 9 Ar' phenyl or naphthyl, optionally substituted by one or more of Ph-CO- 6 alcyl, Het-COj 6 a~kyl, C 1 6 alkoxy, Ph-CO- 6 alkoxy, Het-CO- 6 alkoxy, OH, (CH 2 1

_NR

58

R

59

O(CH

2 1 _6.NR 58

R

59 or halogen; H, ClI 6alkyl, Ar-CO- 6 alkyl, Het-CO.

6 alcyl; RI= H, C I-6alkyl; R2= C4..6alklcy, C4-6alkenyI, benzyl; R3= C 1-6alkyl. Ar-CO-6alkyI, Het-C 0 6 alkyl, R 5 CO-, R 5 S0 2

R

5

R

5

NHCO-;-

R4= H, C 1-6alkyl, Ar-CO..6alkyl. Het-CO- 6 alkyl; Ar-o-6alkyl, Het-COJ..alkyl; R6= H, C 1.6alkyI, CH 2

CF

3 Ar-CO_.alkyl, Het-CO- 6 alkyl; R7= C 1-6alkyl, Ar-CO..6alkyl, Het-CO- 6 alkyl;

R

8 H; C2-.6 alkenyl; C2-6a~kyny1; Het; Ar, C I 6alkyl, optionally substituted by OR', SR!, NR' 2

CO

2

R',

CO

2

NR'

2

N(C=NH)NH

2 Het or Ar; R9= H, CI-6alkyl, Ar-CO-acyl, Het-C4- 6 alkyl; RO= Ci I 6alkyl, Ar-CO-6.alkyl, Het-C 0 6aLcyl; CI.-6a~kYl, Ar-C I 6 alkyl, Het-C 0 6 alkyl, or

R

1 R17 R9- R 2= H, C I 6 alkyI, Ar-C 0 6 alkyl, Het-CO- 6 alkYI; R 13 H, C I 6 alkyl, Ar-CO- 6 afkyl, 1-et-C 0 6 alkYl; 4 N-R9 R72 RI NR ,Ac;

R

15 C I 6 alkyl, C2..6alkenyl, C2-6alcynyl, Ar, Het, or C 1 -alcyl optionally substituted by OR 9

NR

9 2

CONR

9 2 N(C=NH)NII-, Het or Ar; R 16 =C2-6alcyl, C 2 6 alkenyl, C2-6alcynyl, Ar, Het, or C2..6afkyl optionally substituted by OR 9

SR

9

NR

9 2 C0 2

R

9

CONR

9 2 N(C=NH)NH-, Het or Ar; R 1 H, C 16alkyl, C2.6alkenyl, C2-6alcynyl, Ar, Het, or C I.

6 alkyI optionally substituted by OR 9

SR

9

NR

9 2 C0 2

R

9

CONR

9 2 N(C=NH)NH-, Het or Ar;

R

1 7

R

7 2 H, CI-6alcYl, RIO, RIOC(O)-, RIOC(S)-, RIO0C(O)-; R1= R 26 C5-6alklcy; C2-6alkenyl; C3-1 Icycloalkyl; T-C3..

6alkyI; V-C1..6allcyl; T-C2-6alceny1; T- (CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR 20 0R 20 1

NR

20

R

27 or Cl1-alcyl;

R

2 7

R

28 C0, R 2 8 0C0;

R

28 CI..6alkYl; C3- 1 lcycloalcyl; Ar, Het; T-C I -6allcyl; T-(CH2)nCH(T)(C112)n; optionally substituted by one or two halogens, SR 20

OR

20

NR

20

R

73 C1..6allcYl; R0= R2= R 23

R

2 4

R

2 5

R

7 3 H, C 1-alcyl, Ar-C 0 6alkyl, Het-CO- 6 alkyl; R9=

R

32 0 R3 H yNN) 0 3 0 O~ 0 00 0N S1

I,

0 0 Me N 0

S

0 0 OCH 2 Ph

NC

S N 0 %0 So Cbz-leucinyl-; or 4-pyridyl methyloxycarbonylleucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetylleucinyl, NN-diinethyl-glycinyl leucinyl, 4-pyridyl acetyl- Ieucinyl. 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonylleucinyl, acetyl-leucinyl, benzoyl-leucinyl, 4-phenoxybenzoyi-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, Cbz-phenvilaaninyt. Cbznorleucinyl-, Cbz-norvalinyl-, Cbz-glutamyl-, Cbz-epsilon- (t-butyl ester)-glutarnyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, aipha- isobutyl- bipheryl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; or 4- pyridylmethyloxycarbonyl.

aminoacid-; aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-amidno acid-, aryl C 0

-C

6 alkyloxy carbony-anmtino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-amrino acid-, C 1 I C~alkyloxy carbonyl-amrino acid-; C 1 I -C 6 alkyl carbonyl, aryl

CO-C

6 alkyl carbonyl, heteroaryl CO-C 6 alkyI carbonyl, aryl CO-C 6 alkyl carbonyl, heteroaryl CO-C 6 a.lkyl carbonyl, C I-C 6 alkyl sulfonyl, aryl CO-C~alkyI sulfonyl, heteroaryl CO-C~alky1 sulfonyl, aryl CO-C 6 alkyI sulfonyl. heteroaryi

CO-C

6 alkyl sulfonyl;

R

30 C 1 6 alkyl;

R

3 1 R2

H

m F1 33

H

0 00 0 N 0 0 M eIs

O

0I 0 0

SS~

00 OCH2 0 h c Cbz-leucinyl-; or 4-pyridyl methyloxycarbonylleucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetylleucinyl, NN-dimethyl-glycinyl leucinyl, 4-pyridyl acetyl- Ieucinyl, 2-pyridyl sutfonyl-leucinyl, 4-pynidyl carbonylleucinyl, acetyl-leucmnyl, benzoyl-leucinyl, 4-phenoxybenzoyl-. 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, Cbz-phenylajaninyi. Cbznorleucinyl-, Cbz-nor-valinyl-. Cbz-glutamy!-, Cbz-eps ilon- (t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyi, 4 -phenoxy benzoyl-, Cbz-ami~no acid-; or 4- pyridylmethyloxycarbonyl.

axninoacid-; aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 alkyioxy carbonyl-amino acid-, aryl CO-C~alkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-amino acid-, C 1 I C~alkyloxy carbonyl-aniino acid-; C 1

-C

6 alky1 carbonyl, aryl

CO-C

6 alkyI carbonyl, heteroaryl CO-C~alkyl carbonyl, aryl CO-C 6 alkyI carbonyl, heteroaryl CO-C 6 alkyl carbonyl,

C

1 I -C~alky1 sulfonyl, aryl CO-C 6 alkyI sulfonyl, heteroaryl

CO-C

6 alkyI sulfonyl, aryl CO-C 6 alkyl sulfonyl, heteroaryl

CO-C

6 alkyI sulfonyl; R3 OCH 2 Ar, OCH2C 1 6 alkyi, aryl substituted CO- 6 alkyI, heteroaryl substituted CO-6alkyI,4-imidazole methylene; 2-, or 4 -pyridylmethylneneoxy; 4-pyridyl methylene, 2pyridyl sulfonyl, 4-pyridyl, aryl substituted

CO-

6 alkyloxy, heteroaryl substituted

CO-

6 alkyloxy; R3 C 1 -6alkyI, -CH 2 Ph, -CH 2

CH

2

CO

2

R

3 4 R3= C I- 6 alkyI; R3 Ar, HetAr; R3 Aryl, heteroaryl, pyridyl, isoquinolinyl;

R

3 7 C 1 6 alkyI, -CH 2 Ph, -CH 2

CH

2

CO

2

R

3 4 R8= Cbz; C I- 6 alkyI or aryl substituted Cbz; C 1 6 alkyl -CO; benzoyl; C 1 6 alkyl or aryl substituted benzoyl;

R

39 R N3H H m R0 0 0 R3 IIN Me N, <ON 0

S-

0 0 OCH2Ph E0 Cbz-leucinyl-; or 4-pyridyl methyloxycarbonylleucinyl-;, 4-imidazole acetyl-leucinyl-, phenyl acetylleucinyl, NN-diniethyl-glycinyl leucinyl, 4-pyridyl acetylleucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonylleucinyl, acetyl-leucinyl, benzoyl-Ieucinyl, 4-phenoxybenzoyl-, 2- or 3- benzyloxybenzoyi-, biphenyl acetyl, alpha- isobutyl-biphenvi acetvi, Cbz-phenylaianinyl, Cbznorleucinyl-, Cbz-riorvalinyl-, Cbz-glutarny], Cbz-epsilon- (t-butyl ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, ameyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4 -phenoxy benzoyl-, Cbz-ani-ino acid-; or 4- pyridylmethyloxycarbonyj.

am-inoacid-; aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-axnino acid-, aryl CO-C 6 alkyloxy carbonyl-amino acid-,heteroaryl

CO-C

6 alkyloxy carbonyl-amino acid-, C 1 I -C6aloxY carbonyl-amidno acid-; C I-C 6 alkyl carbonyl, aryl

CO-C

6 alkyI carbonyl, heteroaryl CO-C 6 alkyl carbonyl, aryl CO-C 6 alkyl carbonyl, heteroaryl CO-C 6 alkyl carbonyl, C I-C 6 a.Ll sulfonyl, aryl CO-C 6 alkyI sulfonyl, heteroaryl

CO-C

6 alkyI sulfonyl, aryl CO-C 6 alkyl sulfonyl, heteroaryl

CO-C

6 alkyI sulfonyl;

R

4 0 H and C 1 I -6alky1; R1= H and C I- 6 alkyl; R2= C I- 6 alkyl, aryl substituted C I- 6 alkyl and hetero aryl substituted CjI 6 alkyl,; H when R 4 3 is C 1 -6alkyl, aryl substituted C I- 6 alkyI; and heteroaryl substituted C I- 6 alkyI;_ R3= C 1 6 alkyl, aryl substituted C 1 6 alkyI and hetero aryl substituted C 1- 6 alkyl,; H when R 4 2 is C 1 6 aikyI, aryl substituted Cj- 6 alkyI; and heteroaryl substituted Cj- 6 alkyI; R4= CH(R 5 3

)NR

4 5

R

5 4

CH(R

5 5 )Ar, C 5 .6alky1;

R

4 5 R6= R7= R 4 8 R9= R0= R1= H, C 1 6 alkyl, Ar-C 0 6 alkyI, Het-COy'.

6 alkyl; R2= Ar, Het, CH(R 5 6 )Ar, CH(R 5 6 )OAr, N(R 56 )Ar, C 1 6 alkyl,

CH(R

5 6

)NR

4 6

R

5 7 R3= C 2 6 alkyl, Ar-C 0 6 alkyl. Het-CO 0 6 alkyl,

R

5 3 and R 4 5 may be connected to form a pyrrolidine or piperidine ring;

R

4 7

R

4 7

R

4 7

R

4 7 0C(O);

R

55 =5 R 58

=R

59 C I 6 alkyl, Ar-C 0 6 alkYl, Net-C 0 6 aikyl; R6 6 R6 R 6 3 R6 H, C I 6 alkyl, Ar-CO 0 6 alkYl, or Het-CO-.

6 alcYl; R6 C I 6allcYl, Ar, Het, CH(R 69 )Ar, CH(R 69 )OAr-, N(R 69 )Ar,

CH(R

69

)NR

6 lR 70 R6= R9= R1= H, C I..6allcYl, (CH 2 0 6

-C

3 6cYcloalcyl, Ar-C 0 6 allcyl, Het-CO- 6 alkyl; R7= C 1 6 allcyl, (CH 2 )0- 6

-C

3 6 cycloalkyl, Ar-CO- 6 alkyl, Het-CO- 6 all; R 66 and R 67 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 C 1 6allcyl, Ph-CO 6 alkyl, Het-CO 6 alcyl, Cj 1 6 alkoxy, Ph-CO..6alkoxy, Het-CO- 6 alkoxy, OH, (CH 2 1 6

NR

5 8

R

5 9

O(CH

2 1 6NR 5 8

R

59

R

6 8 R0= R 62

R

62

R

62

R

62 0C(O),

R

62 0C(O)NR 59

CH(R

71 and pharmaceutically acceptable salts thereof.

The compounds of Formula I are hydrazidyl, bis-hydrazidyl and bisaminomethyl carbonyl compounds having in common key structural features required of protease substrates, most particularly cathepsin K substrates. These structural features endow the present compo unds with the appropriate molecular shape necessary 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 1, such structural features include the central electrophilic carbonyl, a peptidyl or peptidomimetic molecular backbone on either side of the central carbonyl, a terminal carbobenzvloxy moiety Cbz-leucinvl), or a mim-ic thereof, on the backbone on one or both sides of the carbonyl, and optionally, an isobutyl side chain extending from the backbone on one or both sides of the carbonyl.

R

Compounds of Formula I wherein D R and Q R X *1W

N

R are preferred embodiments Of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula HI. More preferred embodiments of the present invention include compounds of Formula HI wherein: X=S, Y=CH, and Z=-N; X=CH, Y=S, and Z-N; X=N, Y=N, and Z=-S; X=N, Y=N, and Z0O; and X=N, Y=N, and Z=-N.

Preferably R I is H. methyl or isobutyl. Preferably R I is isobutyl.

Preferably

R

2 is isobutyl or benzyl.

Preferably

R

3 is R 5 particularly benzyloxycarbonyl.

Preferably A is a D- or L- amino acid or is absent, preferably A is absent.

Preferably W is CN, NHR 6

SR

6

CONHR

6 or C0 2

R

6 Suitibly

R

6 is H, C14alkyl, phenyl or benzyl. Typically, W is CO 2 H, CO2-C1alCYI, C0 2 -Ph, C0 2 CH-,Ph, CONH 2

NH

2 or SH.

18 &-,LVIIJVLLL 1 1r lllvuiUL u rumi1uid jit uePdrLICUldriy prelerreU; (2S, I'S)-2-(benzyloxycarbonyl)amiuno-N-( 1 -carboxythiazol-4-yl)-3'methylbutylj-4-methylpentanarride; (2S, I S)-2-(benzyloxycarbonyl)amrino-N-[ l'-(2-carboxarrudohiazo-4-yl)-3methylbutyl]-4-rnethylpentanamrjde; (2S, I S)-2-(benzyloxycarbonyl)amnino-N-f [1'-(2-carboethoxythiazol-yI)-3methylbutyll-4-methylpentanamide; (2S, I'S)-2-(berizyloxycarbonyl)amino-N-f [1 -(2-cyanothiazo1-4..yl)-3'-rnethylbutyIJ.

4-methylpentanainide; (2S, I 'S)-2-(benzyloxycarbonyl)amino-N-[ I '-[2-(N'-benzylcarboxarnido)thiazolA..

ylI-3'-methylbutyl]-4-methylpentananm de; (2S, 1 'S)-2-(benzyloxycarbonyl)amno-N-( 1 methylpropyl)carboxamido~tiazo-4-yl)1-3'-methylbuty1]..4.methypentaarde (2S, I 'S)-2-(berizyloxycarbonyl)amino-N-[ I phenyethy)carboxaidotiazo4-yl)I-3Y-methylbut]4meti~pnmde; (2S, 1 'S)-2-(benzyloxycarbonyl)animno-N-( I '-(4-carboethoxythiazol-2-yl)-3'methylbutyl]-4-methylpentanamride; (2S, I S)-2-(benzyloxycarbonyl)amino.N-[ I '-(4-carboxythiazol-2-yI)-3'methylbutyl]-4-methylpentanamide; (2S,1 IS)-2-(benzyloxycarbonyl)ammno-N-[ 1 '-(4-carboethoxythiadiazol-2-yl)-3'methylbutyll-4-methylpentanamide; (25.1 IS)-2-(benzyloxycarbonyl)amino-N-[ 1 -(2-carbo-2,2,2-trifluoroethoxythiazol- 4 -yI)-3Y-methylbutyl]-4-methylpentanamide; 2 S, I'S)-2-(benzyloxycarbonyl)axnino..N- lF-(4-carboethoxyoxadiazol-2-yl)-3'methylbutyl]..4-methylpentanamide; 2 S,lI'S)- 2 -(bcnzyloxycarbonyl-L-leucinyl)amno-N-[. I'-(4-carboethoxythiazol-2-yI)- 3 '-methylbutyl]-4-ncthylpentananide; (2S, 1 S)-2-(benzyloxycarbonyl)amino-N-[ 1 -(4-carboxamidooxadiazol-2-yl)-3'methylbutyl]-4-methylpentanarnide; (2S, 1 S)-2-(benzyloxycarbonyl)anmino-N [1 l-(2-carboethoxythiazol-4-yI)-3'methylbutyll- 3-phenyipropanarnide; (2S, I'S)- 2 -(benzyloxvcarbonyl.L-leucinyl)aridno-N-[ I 2 -carboethoxvthiazoI-4-v)- 3 '-methylbut1I-4methylpenanarnde; (2S. I'S 2 -(benzyloxycarbony)arnoN[ 5 -mercapto- I 2 4 -oxadiazo.3 -yl)-3' mehluy]4mthletnr~e (2S, I 2 -(benzvloxycarbony)amino-Na[j 2 -mercaptothiazol-4-yl)y3.

methylpentanamide; (2S.1 2 -(benzyloxycarbnyl)amino-N-( 2 -b 1Izyloxycarbonylt1~azo[4-yi).3 metybtl:-etypnaaie (2S,1 I'5)- 2 -(benzyloxycarbonyl)amino4methy..N[3 methyl- phenoxycarbonyhiazo4y)bul]tannde; (2S, VS 2 -(benzyloxycarbony)ano4mehyl.N.[3'-methyI1-[-2 (2R, I'S)- 2 -(benzyloxycarbonyl)amino-N..[ 4 -carb~et-hoxythiazoI2.y1)ethyl]A..

methylpentanamide; (2R, I 2 -(benzyloxycarbonyI)amno-.N-[ lU-( 4 carboethoxythiazo-2..yl)ethylJJ4 methylpentanamide; and (2S, 1 -aiohao--i-'mtybty]2(ezlxcroy)aio 4 -methylpentanarrude.

Most particularly preferred compounds of Formula HI are: (2S,1 'S)-2-(benzyloxycarbonyl)amio-N-[ l'-(2-carboethoxytJhiazoI-4yl)-3..

methybuty-4methylpenamde; (2S,1 2 -(benzyloxycarbonyl)amno-N-[ l'-(4-carboethoxythiazol-2yl)-3.

methylbuty]4methylpenaamide; and l'S)- 2 (benzyloxycarbonyl-L-eucinyl)amino-N [1 '-(4-carboethoxythiazol-2.yl)- 3 '-methybuy14methypenaaide.

'N R14 Compounds of Formula I wherein D R B and Q R 13 are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula M.

With respect to compounds of Formula III: Preferably B is or N-N N-N N

N

H

H

More preferably B is /7 or N N 0 i-Bu

R

1 6 Preferably Rll is R R'-N Preferably R 12 and R 13 are H.

R

1 9 Preferably R14 is N- R'R72 Preferably R 15

R

16

R

18 and R 19 are Ci-6alkyl.

More preferably R 15 and R 18 are C4-6alkyl.

Preferably Ar is phenyl optionally substituted by one or two groups chosen from halogen, CF 3

NO

2

SR

9

OR

9

NR

9 or Ci-4alkyl.

Preferably R 17 and R 7 2 are R 10 and more preferably Rl0 is Ar-Cl4alkyl.

Preferably, R 16 and R 19 are C4-6alkyl; more preferably, R 16 and R 19 are i-Bu.

Preferably R 17 and R 7 2 are Cbz.

One particular embodiment of the invention of Formula III is a compound of Formula F: 6 0 19 N A NN NR

R

7 2 H H H X=Y 0

F

wherein X, Y, Z, R 16 R 17

R

1 9 and R 7 2 are as described in Formula III.

Most particularly preferred compounds of Formula I are: (I -benzyloxycarbonylamino)-3-methybuty-tbazo2.ycarbolyJN.

(N-benzyloxycarbonyl-L-leuciny)hydrazide; N-benzyloxycarbonyl-L-leucinyl-N'-benzyloxycarbonyl-L- leucinyl-lleucinylhydrazide; and (1 1-benzyloxycarbonylamino)-3-methylbutyl]tthiazo14..ycarbonyI]-N.

(N-benzyloxycarbonyl-L-leucinyl)hydrazide.

R 2 Compounds of Formula I wherein D R and Q R N .N

YR

2 24 15~ are preferred embodiments of the present invention. For the sake of convenience, 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 R 21 and R 26 are selected from the group consisting of: N-Cbz-Ieucinyl, N-Cbz-glycinyl, N-acetyl-leucinyl. N-Cbz-alanyl, and R 22

R

23

R

24 and R 25 are H.

Particularly preferred embodiments of Formula IV are: 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-acecyl-L-Ieucinyl)carbohydrazide; 2,2'-(N,N'-bis-benzyloxycarbonyl-L-alanyl)carbohydrazide; and 2-(N-benzyloxycarbonyl-L-Ieucinyl)-2'-[N'-(4-methylpentanoyl)]carbohydrazide.

2,2'-(N,N'-bis-benzyloxycarbonyl-L-Ieucinyl)carbohydrazide is a most preferred embodiment of Formula IV.

Compounds of Formula I wherein D H and Q H are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula V.

In more preferred compounds of Formula V, when R 3 0 -C I -C 6 ailkyl, R 30 is preferably Me or -CH 2

CH

2 Me 2 When R 3 3

-C

6 ailkyl, R 3 3 is preferably -Pr, Bu, or -CH 2

CH

2 Me 2 When R 34

I-C

6 alkyl, R 3 4 is preferably -t-Bu.

Even more preferred embodiments of Formula V include: bis-(Cbz-leucinyl)- I ,3-diamino-propan-2-one; bis- 1 ,3-(4-phenoxy-benzoyl)-diamino-propan-2-one; I -(Cbz- leucinyl)-anmino-3 -(acetyl- leucinyl)-ari no-propan- 2-one; I -(Cbz-leucinyl )-arnino-3-(Cbz-glutamyl-t-butyl ester)-amnino-propan 2 -one, I -(Cbz- le uci1nyl)-amino-3 -(Cbz-gl utamyl)-amino- propan -2 -one; bis- 1 .3-(Cbz-Ieucinyl)-diamrino-(S)-butanone-2-one; 1 -(Cbz-Ieucinyl)-amnino-3 -(Cbz-phenylalanyl)-arrino-propan-2 -one; I -(Cbz-leucinyl)-amino-3-(Cbz-norleucinyl)-amino-propan-2-one; I -(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one; bis- 1 ,3 -(Cbz-Ieuc inyl)-diamino-5 -methyl-(S )-hexan-2 -one; I -(acetyl-Ieucinyl)-amnino-3-(4-phenoxy-benzoyl)-amino-propan-2-one; 1 -(Cbz-homo-Ieucinyl)-arnino-(Cbz-leucinyl)-3-am-ino-propan-2-one;, 1 -(Cbz-leucinyl)-amnino-3-(acetyl-leucinyl)-amino-propan-2-one is a most particularly preferred embodiment of the present invention of Formula V.: Compounds of Formula I wherein D 0 and

OR

Q. H 0 are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula VI.

0

IC,

More preferably, R 3 5 =Ph, ON or pyridine, even more preferably, R 3 0

CI

=Ph, CN Ph may be optionally substituted with CI-6alkyl, C 1 6alkoxy, halogens and cyano groups. When R 3 5 pyridine, R may be 2-pyridyl, 3-pyridyl, or 4-pyridyl.

Most particularly preferred embodiments of Formula VI include: bis-1I 3-(4-(3-chloro-2-cyano-phenoxy )-phenyl s ulfonamnido)-propan-2 -one; bis-1I,3-(4-phenoxy-phenyl sulfonamido)-propan-2-one.

Compounds of Formula I wherein D 0 H 0 N o'3R3 0 0 R

N--

3 6

H"I

and Q= 0 are preferred embodiments of the present invention. For the sake of convenience-, such compounds are referred to herein after as compounds of Formula VII.

More preferably, R 3 6 is selected from the group consisting of: 0 Me o, 0 0*' o 0

CN

CI ;and R 3 7 Me in the more preferred compounds of Formula VII.

Particularly preferred embodiments of Formula VII are: 1 -(Cbz-leucinyl)-amino-3-(4-( 3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)propan-2-one; 1-(Cbz-Ieucinyl)- amino-3-(tosyl-amino)-propan-2-one; Il-(Cbz- leucinylyamino-3 (2dibenzofuransulfonamddo)-propan- 2 -oe I-(Cbz- homo e uc-aino- 3no-(2di benzofurs u fo ndo)poa 2 -nand Il-(Cbz-leucinyl)aino-3(2..dibenzofuransulfonansdo)(S)-butan- 2 -o 1 -(Cbz-leucinyl)-amjzno-3 4 -phenoxy-pheny)-sulfonarmido)-propan- 2 -one, I (b-ecnl-mn--2dbnzfrnufnnio-rpn2oe and I -(Cbzlecnl-mn- (-ibnournufnmd)()btn2-n are most particularly preferred embodiments of Formula VII.

I c. Compounds of Formula I wherein D 0 H an R 4 R are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula

VII.

A more preferred embodiment of Formula VMI is when _R 4 3 is 2dibefizofuranylsulfonyl.

Particularly preferred embodiments of Formula VMI are: (S)-Phenylmethyl 3 -[enzyoxycarbonyl-!eucinyl.an-jnoJ-2-xopropyl..1- (benzyl)aninocarbonyl3methybulcb ae.

(S)-Phenylmethyl (1 3 2 -dibenzofuranylsulfonyllamino..2.oxopropylI-3 (bny~mnlabnl--ehluy~abmt (S)-Phenylmethyl [I 3 2 -dibenzofuranysulfonyl)arruno]2oxopropyl].3.(4.

pyridinylmethy)annocarbony3methylbuyl]carbmate 1- ff[ 3 2 -dibenzofuranylsulfonyl)amrinol -2-oxopropyl-3-(4-pyridinyrnethyl) benzamnide (S )-Pheriylmethyl [1-f [[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropy 1-1 pyridinyirnethyl )aminojcarbonyl ]-3-methylbutyllcarbanate.

(S)-Phenylmethyl [1 -[[[3-[(2-dibenzofuranylsulfonyl)arninol-2-oxopropyj..

1 -(4-pyridinylmethyl)aminojcarbonylj-3-methylbutyljcarbamate is a most particularly preferred embodiment of Formula Hin.

Compounds of Formula I wherein D 0 R 4 and Q=- 1 52 N N'NJ R are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula IX.

Compounds of Formula IX wherein: R4= CH(R 5 3

)NHR

5 4

R

4 5

R

46

R

4 8

R

4 9

R

50 and R 5 1 are H;

R

4 7 is independently CH 3 benzyl, 2-pyridinylmethoxy, 4-dimethylaniinobenzyi; J

R

5 2 Ar, CH(Rl( 0 )Ar, CH(R 1 0 )OAr, N(RIO)Ar, CH(RIO)NR"RI 1; R3= ethyl, i-Bu; R4= R 4 7

R

4 7

R

4 7 0C(O); R6= H, CH 3 i-Bu; R7= R 4 7

R

4 7 0C(O); Ar phenyl or naphthyl, optionally substituted by one or more of Ph-CO 0 6 alkyl, Het-C 0 6 alkyl, C 1 -6alkoxy, Ph-CO- 6 alkoxy, Het-Cj..

6 alkoxy, OHK (CH 2 I 6

NR

5 8

R

59

O(CH

2 1 6 6

NR

5 8

R

5 9

R

5 8

R

5 9 HI C 1 6 akYl, Ar-C 0 6 alkyl; Hec-C 0 6 alkvl.

are more preferred embodiments of the present invention.

The following compounds of Formula IX are particularly preferred: 2-[N-(N-benzyloxycarbonyl-.L.leucinyl)]-2.[N'-(4.

phenoxyphenylsulfonyl)Jcarbohydrazide; 2 -[N-(N-benzyloxycarbonyl-Lalanyl)]-2'-[N(N-e.yloxycarbny.L- Ieucinyl)Icarbohydrazide; 2-N(-ezlxcroy--ecnl]2-N-4peybnol]abhdaie 2-[N-(N-benzyloxycarbonyl-L-Ieucinyl)]-2.-[N'..(4methoxyberizoyl)]carbohydrazide; 2-[N-(N-bezyloxycarbony-L-leucinyl)I..2'-[N...(4 phenoxybeazoyl)]carbohydrazide; 2-(N-acetyl)-2'-[N- bnyoyabnlL-ecnl]abhdaie 2-[N-(N-acetyl-L-leucinyl)]-2'-[N'-(N-benzyloxycarbonyl.Lalanyl)]carbohydrazide; 2-[N-(N-acetyl-L-alanyl)]-2'- [N'-(N-benzyloxycarbonyl-L- 1eucinyl)Icarbohydrazide-, 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'[N'..[4.(NjNdimethylainomethyl)benzoyl)]carbohydaide; 2-(N-(N-benzyoxycabony-L-euciny)]2'(-4hydroxy(3..(4.

morpholinomethyl)]]benzoyl]carbohycirazide; 2-[N-(N-benzyoxycarbonyLeuciny)2'N[(,N-.

dimethylaminomethyl)benzyloxy]carbnybLleucinycbohydrazide; 2-Nbnol--N-Nbnyoyaroy--ecnl]abhdaie 2-[N-(N-bnzyoxycaony-Leuciny)2'N[3-(4morpholinomethyl)benzoyl]]carbohydzide; 2 -[N-(3-benzyoxybenzoy)]2'N(Nbezyoxycrbny-L- Ieucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyI)1-2'-N.. (4-[3-(N-N-dimethylamino)- 1 propyloxy]benzoyl] ]carbohydrazide; 2 -[N-(2-benzyloxybenzoyl)I-2'- (N'-(N-benzyloxycarboflyl-L- Ieucinyl)]carbohydrazide, 2- (N-(N-benzyloxycarbonyl-L-Ieuciflyl)I-2'-[N'-[3-(4pyridylmehoxy)benzoyl]carbohydlazide; 2-[N-(4-benzyloxybenzoyl)]-2'- N'-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide; 2- [N-(N-benzyloxycarbofl-L-leucinlY)I2'4[N'-(3 methoxy)benzoyl]carbohydrazide; 2-N(-ezlxcroy--ecnl12-N-3bnyoy45 dimethoxy)benzoyllcarbohydrazide; 2-[N-(N-benzyloxycarbony-L-IeucnyI)]-2'-N'-(3-benlZoxyethoxy)benzoyl]carbohydrazide; 2-[N-(N-benzyloxycarbonylglyciny)-2'-N-(N-bezloxycaboflILleucinyl)]carbohydrazide; 2-[N-(3-benzyloxybenzoy)-2'-N'-(N-benlZoxycarboflLprolinyl)]carbohydrazide; 2- [N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4phenylphenylacetyl)]carbohydrazide; [N-(3-benzyloxybenzy)]-2'-[N'-(N-beflzyoxycarbofl[ 2 aminobutyryl)]carbohydrazide; 2,2'-[N,N'-[bis-(4-phenyphenyacety)]]carbohydrazide; (2'RS)-2-[N-(N4-benzyloxycarbonyl-L-lucil)J-2'-[2-(4phenylphenoxy)propionyl]carbohydrazide, 2-N!3bnyoyezy)-'['(4mtypnaol]abhdaie (2RS, 2'RS)-2,2'-(NN'-bis-[2-(4-phenylphenyi)-4methylpentanoyl)]]]carbohydrazide; (2'RS)-2-[N-(N-benzyloxycarbonyl-L-Ieucinyl)] -2'-[N'-[2-(4-phenylphenyl)-4methylpenranoyl)]]carbohydrazide;, (2'RS)-2-(N-(3-bcnzyloxybenzoyl)I- 2'-(N'-[2-(4-phenylphelyl)-4rnethylpenanoyl)]]carbohydrazide; 2-(N-(3-benzvloxvbenzoyl)]-2'-[N-(N-benzvloxvcarbonvl-N-methv-Lleucinyl) Icarbohydrazide; 2-[N-(3-benzvloxvbenzoyl)I-2-[N'-[N-(2-pyridinylmethoxycarbonyl)-L leucinyl]Jcarbohydrazide, -(4-pyridylmethoxy)benzoyl] J-2'-[N'-fN-(2-pyridinylrnethoxycarbonyl leucinylllcarbohydrazide; (2RS)-2 -[N-[2-(4-phenylphenyl)-4-methylpeinanoyl)]-2'-N'-[N-(2pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide; 2--[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'- [N'-[2-(4-phenylphenyl)-4methylpentanoyl)]Jcarbohydrazide; 2- [N-(N-benzyloxycarbonyl-L-leucinyl)]-2Z-[N'-[2-(4-phenylphenyl)-4.

methylpentanoyl)Ilcarbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'- (N'-(N-(4-phenylphenyl)-N-(2methylpropyl)carbarnoyl]]carbohydrazide; 2-[N-(3-benzyloxybenzoy)]-2'-[N'-(N-methy-L-leuciny)]carbohydrazide; SS 2- [N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(N-methyl-L- Ieucinyl)Icarbohydrazide.

1N 6 Compounds of Formula I wherein D L--G and R are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula X.

With respect to Formula X: More preferably G is Sor More preferably

R

6 3 and R4are H and R 66 and R 69 are i-butyl.

More preferably

R

65 is CH(R 6 9

)NR

6

IR

7 0, in which R 6 9 is i-butyl and R 6 1 is H. More preferably

R

70 is R 6 2 0C(O), in which R 6 2 Is N2

CH

2

AN

I

CH 2

H

2

N

Alternately,

R

6 5 is 0 Ar or CH(R 6 9%M, in which Ar in said R 6 5 group is nr Morm prferably, L is CH(R66)NR6,R 6 8

CH(R

6 6 )Ar, NR 6 6

R

67

CH(R

66 )OAr', Ar, or Het, in which

R

6 6 is i-butyl and Ar in said L group is

A

N

N

N-

W~e 0 N'

N

0

N

or Het in said L group is More preferably L is NR 6 6

R

6 7 or CH(R 6 6

)R

60

R

6 8 One particularly preferred embodiment is a compound of Formula G:

H

A r X'y0

G

Another particularly preferred embodiment is a compound of Formula H-: The following compounds of Formula X are most Particularly preferred: (is -benzYloxycarbonylaino)3methybuyl]haoj- 4 Ylabnl-'(-hnxphniufnlhdaie (I 1-(N-enzyloxycarbonyl-L-eucinylamino).3 mehluy~hao--labnl-'(-ezlxcroy--ecnlhdaie (I 1 -benzyloxycarbonylalino)-3-methylbutyllthiazol.4ylcarbonyll-N'-(4.'phenylphenylacetyl)hydrazide; (I I -benzyloxycarbonylamino)-3-methylbutyllthiazolA..

ylcarbonyl]-N'-(3-(4-pryidinylmethoxy)bertzoylhydrazide; N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N-[N-(4.

pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[N-(4-pyridinylmethoxycarbonyl)-L-eucinyl-N'-2[4.(1I,2,3-thiadiazol- 4-yI)phenyl]thiazol-4-ylcarbonyl]hydrazide; N-[2-(3-(4-chlorophenyisulfonyhnethy)tien2y]tiiazol..-ylcaronyl].N- [N-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; (1 S,2RS)-N- 1 -benzyloxycarbonylamino)-3-methylburyllthiazolA..

ylabnl-'['(-hnlhnlctl--ehlemolhdaie N-[2-(3-benzyloxypherlylflhiazol-4-ylcarbonyl]-N'-[N-(2pyridinylmethoxycarbonyl)-L-Ieucinyl]hydrazide; (1 1-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonyl]-N-[N- (4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-methyl-N-(4-phenylpheny)aminothazol-4-ylcarbonyl]N'.[N.(4 pyridinylmethoxycarbonyl)-L-Ieucinyllhydrazide;- N-(N-beazyloxycarbonyl-L-leucinyl):-N'-[2-(4-phenylbenzyl)thiazol-4.

ylcarbonyllhydrazide; N-(2-(4-phenylphenylbenzyl)thiazol4-ylcarbonyl-N-[N.(4.

pyridinylmethoxycarbonyl)-L-leucinyl]hydrazid; N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N-(2-methylpropy)-Nphenylamino]thiazol-4-ylcarbonyl]hydrazide; N-2(-2mtylrp hnlann(hao--ycroy]N-N-(4pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; N-2-(2-benzyloxyphenyl)hiazol-4-ylcarbonylJ pyridinylmethoxycarbonyl)-L-leucinylJhydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-IN-(2pyridinylmethoxycarbonyl)-L-leucinyllhydrazide, N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N'-[2-(2benzyloxyphenyl)thiazol-4-ylcarbonyllhydrazide; N-2-N-(2-methylpropyl)-N-phenylaino]thiazol-4-ylcarbonyl]-N'-N-(2pyridinylmethoxycarbonyl)-L-leucinylJhydrazide; N-[2-[N-(2-methylpropyl)-N-phenylamino thiazol-4-ylcarbonyl-N'- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazidi; and N-12-(2-methoxyphenyl)thiazol-4-ylcarbonylJ-N'-[N-(4- PYridinylmethoxycarbonyl)-L-leucinyl]hydrazide.

Definitions The present invention includes 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 compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemrnic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

The meaning of any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.

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 "amino acid" as used herein refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

"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 Cl-4alkyl, where R' is CI-6alkyl. C 0 alkyl means that no alkyl group is present in the moiety. Thus, Ar-

C

0 alkyl is equivalent to Ar.

"C

3 -1 Icycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane.

!"C

2 _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, I -propene, 2-propene, I -butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trains isomers are included.

"C2-6alkynyl" means an alkyl group of 2 to 6 carbons wherein one carboncarbon single bond is replaced by a carbon-carbon triple bond. C 2 6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.

"Halogen" means F, C1, Br, and I.

"Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-CO-6alkyl, Het-C.O- 6 alkyl, C-6alkoxy, Ph-CO- 6 alkoxy, Het-CO.- 6alkoxy, OH, (CH 2 1 -6NR 58

R

5 9, O(CH 2 1 -6NR 5 8

R

5 9 where R 58

R

59 H. C- 6~Y Fe-CO 6alkyl, from C1_4alkyl, OR', SR', CF 3 CN. CO 9

R',

CON(R'), F, Cl, Br and 1.

As used herein "Het" or "heterocyclic" represents a stable 5- to 7 -membered monocyclic or a stable 7- to lO-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatorns selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatomn or carbon atom which results i the creation of a stable structure, and may optionally be substituted with one or two moieties selected from Cj-4alkyl, OR', N(R') 2 SR', CF 3 N0 2 CN, C0 2

R',

CON(R'), F, Cl, Br and 1, where R'is Cj-6alkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2 -oxopiperazinyl, 2 -oxopipenidinyl, 2oxopyrrolodinyl, 2 -oxoazepinyl, azepinyl, pyrrolyl, 4 -piperidanyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, itnidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzixnidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl. sulfoxide, thiamnorpholinyl sulfone, and oxadiazolyl.

"HetAr" or "heteroaryl" means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, pyridine.

It wil be appreciated that the heterocyclic ring described when N P includes thiazoles, oxazoles, triazoles, thiadiazoles, oxadiazoles, isoxazoles, isothiazols, imnidazoles, pyrazines, pyridazines, pyrimidines, triazines and tetrazines which are available by routine chemical synthesis and are stable. The single and double bonds in such heterocycles are arranged based upon the heteroatoms present so that the heterocycle is aromatic it is a heteroaryl group). The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur. When the heteroaryl group comprises a five membered ring, W is preferably an electron withdrawing group, such as halogen, -CN, -CF 3 -COR 7

-CO-,R

6

CONHR

6

-SO

2

NHR

6 -NHS0 2

R

6

-NHCOR

7

-O-COR

6

-SR

6 or NR'R 6 or a similar electron withdrawing substituent as known in the art.

Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxyca rbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical.

Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodimnide, DMAP is 2,6-dixnethylamninopyridine, EDC refers to Nethyl-N'(dimethylamninopropyl)-carbodiixniide. HOBT refers to 1 hydroxybenzotriazole, DMF refers to dirnethyl formamnide, BOP refers to benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, DMAP is dirnethylaniinopyridine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)l,3-dithia-2,4-diphosphetane-2,4.disulfide, NMIM is N-methylmorpholine, TFA refers to trifluoroacetic acid. TFAA refers to trifluoroacetic anhydride and THF refers to tetrahydrofuran. Jones reagent is a solution of chromium trioxide, water, and sulfuric acid well-known in the art.

Methods of Preparation Compounds of Formula II wherein X CH, Y S and Z N, and W C02R 7 CN, or CONR'R 7 may be conveniently prepared by methods analogous to those described in Scheme 1.

o *e s Scheme I 0 RI 0 R' H a 2 b HI HN 2 p 0 0 0 R 1 0 R 1 HI\ -C0 2 0t 0

S

0 R 1

'S

-4 0

RI

H

2 N N 02

'S

0

RI

D N C02N>

S

0 D N

H

D N

C

HI

'S

0 R 1

S

a) i-BuOCOCI, NMM, CH 2

N

2 EtOAc, Et 2 O; b) HBr, AcOH, EtOAc, Et 2 O; c) K NCSC0 2 Et.

EtOH; d) NaOH, H 2 0, THF; e) i-BuOCOCI, NMM, NH 2 THF or BOP, Et 3 N, RNHi 2

CH

2

CA

2

I

rFMA, pyridine, CH 2 CI2; g) R 4 OH, Boc 2 O, Pyridine or R 4 OH, EDCI, CH 2 Cl 2 h) piperidine, DMF; i) BOP, Et 3 N, D-CO 2 H. CH2C1 2 I Shm is treated with isobutyl chioroformate and N-methylmorpholine in ethyl acetate to give a mixed anhydride which is treated with diazomethane in ether to provide 2-Scheme 1. The diazoketone 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 treatment with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 5-Scheme 1. The carboxylic acid is treated with isobutyl chloroformate and Nmethylmorpholine, followed by gaseous ammonia to provide primary amide 6- Scheme 1 (R 3 The primary amide is treated with TFAA and pyridine in dichloromethane to provide 7-Scheme 1. Alternatively, 5-Scheme I can be converted to substituted amides, 6-Scheme 1, by treatment with alkyl amines (such as benzylamine, 2 -phenylethylamine or isobutylamine) and a peptide coupling reagent (such as BOP, EDC*HCl/I-HOBT or N-methylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichloromethane or DMF). The carboxylic acid 5-Scheme I can be converted to carboxylic esters 8-Scheme I by treatment with a primary or secondary alcohol (such as 2 2 2 -trifluoroethanol, isobutyl alcohol, benzyl alcohol or phenol) and a dehydrating reagent (such as DCC/DMAP, EDCI or Boc20/pyridine) in an aprotic solvent (such as dichloromethane or ether). When R 2 9-fluorenylmethoxy, treatment of 4-Scheme I with piperidine in DMF gives 9-Scheme 1. Treatment of 9-Scheme 1 with a carboxylic acid (such as N-Cbz-L-phenylalanine or N-Cbz-L-leucinyl-L-leucine) and a peptide coupling reagent (such as BOP) in an aprotic solvent (such as dichloromethane) provides 10-Scheme 1.

Scheme

IA

S S SMeS R'HN S a HI b H N NH H 2 N N NH b H NNH

H

2 3 R H C N I RR'N N NHR

NH

4 a) Mel, THF; b) R'NH 2 i-PrOH; c) Bromomethyl ketone, EtOH Compounds of Formula II wherein X CH, Y S and Z N are prepared by methods analogous to those described in Scheme IA. 1 -Schemne IlA is treated with iodomethane in an aprotic solvent (such as THF) to afford 2-Scheme IA, which is treated with a primary amine in a protic solvent (such as isopropanol) to give 3-Scheme lA. this material is then treated with a bromomethyl ketone in a protic solvent (such as ethanol) to provide 4-Scheme ILA.

Scheme 2 BocHN 1 OH BocHN b -1 BocHN )NKNY 0 0 S C d SBocHN C0 2 Et H 2 N 0E 4 0 R' 0 RI D D~N i -CO 2 Et D ~~C 2

H

Z

a) i-BuOCOC1, NM4M, NH 3 THE; b) Lawesson's reagent, THE; c) BrCH 2

COCO

2 Et, TFAA, Pyridine, CH 2 C1 2 d) TEA; e) DCO 2 H, EDC'HCl, HOBT, Et 3 N, DME; f) NaOH, H 2 0, THE Compounds of Formula HI wherein X S. Y CH and Z N-may be conveniently prepared by methods analogous to those described in Scheme 2.

Scheme 2 is treated with isobutyl chioroformate, N-methylmorpholine and ammonia in THF to provide 2-Scheme 2. This material is converted to the thioamide, 3- Scem by treatment with Lawesson's reagent in an aprotic solvent (such as THE or toluene). 3-Scheme 2, is converted to the thiazole by condensation with a axketoester 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 f-Scheme 2. This material is treated with a carboxYlic acid (such as -\-Cbz- L-leucine, N-Cbz-D-leucine or N-Cbz-L-leucinyl-Lleucine) and a peptide coupling reagent such as BOP, EDC*I-CL/I -HOBT or N-methylmorpholine/isobutyl chloroforinate in an aprotic solvent (such as dichioromethane, DMFT or TI-F) to yield 6-Scheme 2. This material is saponified by treatment with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 7-Scheme 2.

Scheme 2A R0

R'

RNCO Et a BocR'N N~0E b S R

R'

1 2 R'HN N 0E c R0 N"A NCOzEt :2 Y 2 R 0 R 4 a) Boc-amino acid, EDC*HCI, 1-HOBT, DMF; b) TFA; c) R 5 OCOCI, i-Pr 2 NEt Compounds of Formula 11 wherein X Y =CH and Z= N may also be prepared by methods analogous to those described in Scheme 2A. 1-Scheme 2Ais treated with a tert-butoxycarbonyi..prtected amino acid (such as N-terrbutoxycarbonyIL-eucine) and a peptide coupling reagent such as BOP, EDC.HC i/l-HOBT or N-ehlopoieiouy chioroformate) in an aprotic solvent (such as dichloromethane. DME or THF to yield 2-Sch eme 2A which is treated with trifluoroacetic: acid to provide 3-cem A This material is treated with a chloroformate (such as 2 -biphenylmethyl chioroformate, 2-benzylbenzyl chloroformate. 2 -naphthylmethyl chloroforinate or 2-phenoxybenzyl chloroformate) and a tertiary an-ine base (such as diisopropylethylarr~ine) in an aprotic solvent (such as methylene chloride) to provide 4 -Scheme 2A.

Scheme 3 H2 a BocHN y OMe b 0 0 1. 2

H

1 0 BocHN"f NHH 2 Y BocN""~f~OE AY 0 0 2 -4 BocHN )>Sj..CO 2 t

H

2 NilI sI) 0E N N H -C0 2 Et a) Boc 2 O, Et 3 N, THfF; b) hydrazine hydrate, MeOH; c) EtO 2 CCOCl, Pyridine,

CH

2 Cl 2 d) Lawesson's reagent, toluene; e) TFA. CH 2 Cl 2 f) DCO 2

H,

EDC*HCI/HOBT, Et 3 N, DMIF Compounds of Formula IU wherein X and Y N, and Z S may be conveniently prepared by methods analogouis to those described in Scheme 3. 1- .Shre3 is treated with di-terr-butyl dicarbonate and triethylamine in THF to provide 2-cen 3'This material is treated with hydrazine hydrate in methanol to provide 3-Schemne 3. The hydrazide is acylated by treatment with ethyl oxalyl chloride and pyridine in dichloromethane to provide 4-Scheme 3. This material is converted to the thiadiazole, 5-Scheme 3, by treatment with Lawesson's reagent in an aprotic solvent (such as THIF or toluene). 5-Schemne 3 is treated with TEA to provide 6-Schemne 3. This material is treated with a carboxylic acid (such as N-Cbz- 43 L-Ieucine) and a peptide coupling reagent such as BOP, EDCoHCL./1-HOBT or Nmethylmorpholine,'isobutyl chloroformate) in an aprotic solvent (such as dichioromethane, DMF or TI-F) to yield 7-Scheme 3.

Scheme 4 BocHN n N C 2 Et aoH O\ 0E H 0NN RI0

R

1 b

H

2 N' l i~-0 2 CN C0EtD H O\ >CO 2 Et

N-N

4 0 R' d H I>CONH 2 a) SOC1 2 pyridine, Et 2 O, toluene; b) TFA, CH 2 C1 2 c) DC0 2 H, EDC*HCIHOBT, Et 3 N, DMF; d) NH- 3 EtOH Compounds of Formula II wherein X and Y N, and Z= 0, and W CO2Et or CONH2 may be conveniently prepared by methods anialogous to those described in Scheme 4. 1 -Scheme 4 is treated with thionyl chloride and pyridine in ether, followed by refluxing in toluene to provide 2-cee4 The resultant oxadiazole is treated with TFA to provide I-cee4 This material is treated with a carboxylic acid (such as N-Cbz-L-leucie) and a peptide coupling reagent such as BOP. EDC*HCI-HOBT or N-methylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichloromethane, DMF or THF) to yield 4-Scheme 4. The carboxylic ester is treated with ammonia in methanol to yield 5-Scheme 4.

Scheme O R 2 N C02H

H

1

H

2 N CO 2 Me a 0 R 2 RA N N ,.CO 2 Me

H

0 Ri 2 0 R2 0 b RS IN NHNH2 O R 0 8'

C

O R 2

N-N

SH

RA N N S

S

O R' a) EDC*HC/HOBT, Et 3 N, DMF; b) H 2

NNH

2

*H

2 0, MeOH; c) CSCl 2 Et 3 N, CHC1 3 Compounds of Formula II wherein X and Y N, and Z= O0, and W SH may be conveniently prepared 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*HCl/1-HOBT or N-methylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMF or THIF) to yield 3-Scheme 5. This material is treated with hydrazine hydrate in methanol to provide 4-Scheme Treatment of 4-Scheme 5 with thiophosgene and triethylamine in chloroform provides 5-Scheme Scheme 6 0 R' 0 R 1 D N Br a NJ-- H H L\-S

S

1b 2

R'

H L \)-NH 2

S

a) H,)NCS 2 NH4+, EcOH; b) H-,NCSNH 2 EtOH Compounds of Formula HI wherein X CH, Y S and Z N, and W =SH or NH2 may be conveniently prepared by methods analogous to those described in Scheme 6. Condensation of I -Scheme 6 with ammonium dithiocarbarnate in ethanol yielded 2-Scheme 6. Alternatively,, Jjchme can be condensed with thiourea in ethanol to give 3-Scheme 6.

Scheme 7 DI& N5 Br a D D N5 b H 0 H 0 1 2.

o

R

1 H N 02 a) Et 2 NO; b) H 2 NCH 2 CH(NH 2

)CO

2

H

Scheme 8. The thiazole carboxvlic ester is treated with a hydrazine (such as hydrazine monohydrate or methyl hydrazine) in ethanol to yield 5-Schemne 8. Thi~s material is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as EDC*HCL/lI-H-OBT) in an aprotic solvent (such as DMF) to provide 6-Scheme 8.

Compounds wherein X S, Y CH and Z are prepared by methods analogous to those described in Scheme 9.

Scheme 9 LC2H a O LCONH 2 b I LCSNH 2 Cd L~J~Jr1 ~2 N L 2 C Q 2 Et 12 3 S -S H e orf 1,

CONHNN

N 2N

N

0 H 6 (J CO, S02) a) i-BuOCOC1, NM1M, NH 3 THF; b) Lawesson's reagent, THF; c) 1.

EtO 2

CCOCH

2 Br; ii.. TFAA, Py, CH 2 Cl 2 d) H 2

NNH

2 oH 2 0, EtOH; e) R 6 5 S0 2 C1, Py, CH 2

CI

2 f) R 6 5 C0 2 H, EDC*HCl, 1-HOBT, DMF.*: 1 -Sheme9 is converted to 2-Scheme 9 by treatment with isobutyl chloroformate, N-methylxnorpholine and ammonia in THE. 2-Scheme 9 is treated with Lawesson's reagent in TIF to provide the thioanude 3-cee9 This material is converted to the thiazole by condensation with an a-ketoester followed by treatment with trifluoroacetic anhydride and pyridine in methylene chloride to afford 4-Scheme 21 which is converted to 5-cee9 by treatment with hydrazine monohydrate. This material 'is treated with a sulfonyl chloride (such as 4phenoxybenzenesulfonyl chloride) and pyridine in an aprotic solvent (such as dichioromethane) to provide 6-Scheme 9. Alternatively, 6-Scheme 9 may be prepared by treatment with a carboxylic acid (such as N-benzyloxycarbonyl-Lleucine, N-benzyloxycarbonyl-N-methyl-L-leucine, N-(2- Compounds of Formula II wherein X CH, Y N and Z N and W=C may be prepared by methods analogous to those described in Scheme 7. Treatment of 1- Scheme 7 with diethylamine N-oxide should provide 2-Scheme 7. Condensation of 2-Scheme 7 with a 2,3-diaminocarboxylic acid should then provide 3-Scheme 7, which may be converted to a variety of carboxylic acid derivatives using procedures previously described in other schemes.

Compounds of Formula III may be generally prepared by methods common in the art of organic chemistry for coupling carboxylic acid derivatives to hydrazine.

Schemes 8, 9 and 10 are illustrative of a method to prepare compounds wherein B or E is a heterocycle. Compounds of Formula X may be conveniently prepared by methods analogous to those described in Schemes 8, 9 and 19-23.

Scheme 8 LCOH L N 2 CO Br L N COEt 0 0 L COEt 12 1 4 R 63 0 d e N L CONRNH 2

L

N

R

O H a) i. i-BuOCOC, NMM, THF; ii. CH 2

N

2 Et 2 0; b) HBr, AcOH, Et 2 0; c)

H

2

NCSCO

2 Et, EtOH; d) R 6 3

NHNH

2 EtOH; e) R 6 5

CO

2 H, EDCeHC1, 1-HOBT,

DMF.

Compounds wherein X CH, Y S and Z N, are prepared by methods analogous to those described in Scheme 22. 1-Scheme 8 is treated with isobutyl chloroformate and N-methylmorpholine in ether to give a mixed anhydride which is treated with diazomethane 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 material is treated with ethyl thiooxamate in refluxing ethanol to give 4 Compounds of Formula IV wherein R 22

R

23

R

2 4 are H, and R 2 1 R2 are prepared by methods analogous to those described in Scheme 11.

Scheme HI 0H 0 H 21C0H

R

2 1

R

2 1

H

2 NHN NHNH, C2 N N (NNy I I 0 H H 0 1 2 a) EDC.HCI, 1-HOBT, DMF Symmetric compounds of the Formula IX having RCO as the terminal substituent on both sides are prepared by methods analogous to those described in Scheme 11. Treatment of I1-Scheme 11 with a carboxylic acid (such as 4biphenylacetic acid or 4 -methyl-2-(4-phenylpheny)penaoic acid) and a peptide coupling reagent (such as EDC*HCIII-HOBT) in an aprotic solvent (such as DMF) provides 2-Scheme 11.

Nonsymmetric compounds of the Formula IX, and compounds of Formula IV wherein R 22

R

2 3

R

24 and R 2 5 are H, and R 2 1 R26, are prepared by methods analogous to those described in Scheme 12.

pyridinylmethoxycarbonyl)-L-leucine N-(3-pyridinylmethoxycarbonyl)-L-leucine N-(4-pyridinymethoxycarbonyl)-L-leucine, 4-biphenylacetic acid, 3-(4pyridinylmethoxy)benzioc acid, or 4-methyl-2-(4-phenylphenyl)pentanoic acid) and a peptide coupling reagent (such as EDC-HCJI1-HOBT) in an aprotic solvent (such as DMF).

Compounds wherein B A A are prepared by routine methods of peptide synthesis as illustrated for instance by Scheme Scheme RN, CO 2H

H

H

2 N CO 2 Et a R 1 6 I H R P1 N N CO 2 Et 0 R 1 R 6' 6 0 b_ CONHNH 2 HH1 P, c RP-1 N B- H Y H IH Y 0 R1 5 0 R's 0 a) EDC.HCI, HOBT, DMF; b) H 2

NNH

2

-H

2 0, EtOH; c) R1 4

-B-CQ

2

H,

EDC*HCL, HOBT, DMF Treatment of a mixture of I-Scheme 10 and 2-Scheme 10 with a peptide coupling reagent (such as BOP or EDC-HCI/1-HOBT) in an aprotic solvent (such as DMF or dichioromethane) provides 3-Scheme 10. This material is treated with hydrazine hydrate in ethanol to yield 4-Scheme 10, which is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as BOP or EDC-HCII-HOBT) in an aprotic solvent (such as DMF or dichloromethane) to provide 5-Scheme-10.

dimethylaminomethylpropoxy)benzoic acid, 3-benzyloxy-5-methoxybenzo'ic acid, 3 -be nzylox y-4,5 -dime thoxy benzoic acid, 3-benzyloxy-5-ethoxybenzoic acid, 3-(4pyridinylmethoxy)benzoic acid, 4-biphenyl acetic acid, 2-(4phenylphenoxy)propionic acid or 4-methyl-2-(4-phenylphenyl)pentanoic acid) and a peptide coupli ng reagent such as BOP, EDC*HCL/I -HOBT or Nmethylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane, DMF or THF). 5-Schme-12 may also be prepared by treatment of 4-Scheme 12 with an anhydride (such as acetic anhydride). Alternatively, 3- Scheme 12 may be converted directly to 5-Scheme- I by treatment with a hydrazide (such as 4-methylpentanoyl hydrazide or N-methyl-N-benzyloxycarbonyl-Lleucinyl hydrazide).

Scheme -12A ab N-N

R

1

CONHNH

2 R 1

CONHNHCH

2 R R- 21 0 1 2 H 0 H 0 H R2 d,eorf R21 N.)L N~ NHNH 0KR 0H H _4 (RCH 2

R

23 I (X C0R 5 2

SO

2 R52) a) i. PhOHO. EtOH; ii. BH3-THF; b) CI 2 CO, PhMe; c) H 2

NNH

2

'H

2 O, MeOH: d) R 52 C0 2

H,

tDC-HCI, I1-HOBT, DMF; e) R 5 2 S0 2 CI or R 52 COCI, pyridine, DMF; f)R5C0 2 C0R 5 2 Nonsyminetric compounds of Formula IV, wherein R 2 3 H are prepared by methods analogous to those described in Scheme 1 2A. I1-Scheme 1 2A -is treated with an aldehyde (such as benzaldehyde) in a protic solvent (such as ethanol) and the resulting imine is treated with borane-TI{F complex to afford 2-Scheme 12A, which is subsequently treated with phosgene in toluene to afford 3-Scheme 12A.

This material is treated with hydrazine hydrate in a protic solvent (such as methanol or ethanol) to provide 4-Scheme 12A. Treatment of 4-Scheme 12A with a carboxylic acid (such as N-benzyloxycarbonyl-L-leucine) and a peptide coupling 52 Scheme 12

H

R"CO 2A a ;IR "CONHNH2 b N-N c 1 2 2 19 H 0 H 0 H 0 H 0 H H 44 (F 00R 52 S0 2

F

52 a) H 2

NNH

2

H

2 0, MeOH; b) CI 2 CO, PhMe; c) H 2

NNH

2

*H

2 O, MeOH; d) R 49 C0 2

H,EDC-HCI,

1 -H0BT, DMF; e) R 52 S0 2 CI or R 5 2 COCI, pyridine, DMF; f) R52C0 2 C0R 52 g) R 5 kCONR 5

NH

2 Treatment of 1 -Scheme 12 with hydrazine hydrate in a protic: solvent (such as methanol or ethanol) provides 2-cem 2 which is treated phosgene in toluene to afford 3-cne 12. This material is treated with hydrazine hydrate in a protic solvent (such as methanol or ethanol) to provide 4Shme 2. Treatment of 4- Scee1 with a sulfonyl chloride (such as 4-phenoxyphenylsulfonyl chloride), an acid chloride (such as benzoyl chloride), or a carbarnoyl chloride (such as -2 methylpropyl)-N-(4-phenylphenyl)carbarnoyI chloride) and pyri dine in DMF affords 5-cem-2 Alternatively, 5Sherne-2- may be prepared by treatment of 4-Sceme 2 with a carboxylic acid (such as N-benzyloxycarbonyl-L-alanine, Nbenzyloxycarbonyl-L-proline, N-benzyloxycarbonyiglycine, benzyloxycarbonyl-2-aminobutyric acid, N-benzyloxycarbonyl-N4-methyl-L-leucine, N-trn.butoxycarbonyl-N-methyl-L-leucine, N-ar-etyl-L-leucine, N-acetyl-L-alanine, N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-[4-(NNdimethylaniinomethyl)benzyloxycarbonyl]-L-leucine, 4-phenylbenzoic acid, 4methoxybenzioc: acid, 4-phenoxybenzoic acid, 4-(NNdimethylaniinomethyl)benzoic acid, 4-hycroxy-3-[N-(4-morpholinomethyl)]benzoic acid, 3-[N-(4-morpholinomethyl)]benzoic acid, 2-benzyloxybenzoic acid, 3benzyloxybenzoic acid, 4-benzyloxybenzoic acid, 4-(3such as N-methyl morpholine, followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

Scheme 0 OH 0 N- 0 3

OH

HN

NN,

0 a) EDCI, HOBT, DMF; b) NMM, DMIF, 3) Jones, acetone I -Amnido-3-sulfonaxnido propanones may be prepared by acylation of 1,3diamino-propan-2-ol 1--Scheme 15 with a carboxylic acid 2-cee1 and a coupling reagent such as a carbodiiide, or HBTU/ N-methyl morpholine, followed by treatment with an appropriate 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.

Scheme 16 d 0 0

M

NSOP:

z ;As 6 0 ~CIOjIZ-I c~o~7 reagent such as BOP, EDC*HC/1-HOBT or N-mechylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMF or THF) to yield 5-Scheme-12A.

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

Scheme 13 a) HBTU, NMM, DMF; b) Jones, acetone 1,3-Bis-amido propan-2-ones may be prepared by acylation of 1,3-diaminopropan-2-ol 1-Scheme 13 with a carboxylic acid 2-Scheme 13 or a mixture of 2 different carboxylic acids (2 and 3) in equimolar amounts and a coupling reagent such as a dialkyl carbodiimide such as DCC or EDCI or HBTU/ N-methyl morpholine, followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

S2 0 'ab NIrTIIL Scheme 14 a a

OM

a) NMM, DMF; b) Jones, acetone 1,3-Bis-sulfonamido propanones may be prepared by sulfonylation of 1,3diaminopropan-2-ol 1-Scheme 14 with a sulfonyl chloride 2-Scheme 14 and a base 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 -propanedithiol in MeOH, triethylamine, then was washed extensively with various solvents. Coupling of Cbz-leucine 6-Scheme 17 with the diamine j-Scheme 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-Scheme 17 with an oxidant such as Jones reagent provided the desired final product.

Scheme 18 0 0 1 2 o o a C. d s- 0 a) 4-pyridyl methyl amine, isopropanol, reflux; b) Cbz-leucine, HBTU, N-methyl morpholine, DMF; c) hydrazine, MeOH, reflux; d) 2dibenzofuransulfonyl chloride, N-methyl morpholine, DMF; e) Jones reagent, acetone 0a V* N-(2,3-Epoxypropyl)phthalimide I-Scheme 18 (Aldrich) was reluxed with an amine such as 4-pyridiyl methyl amine in isopropanol. The secondary amine 2- Scheme 18 was then acylated with an acylating agent such as Cbz leucine or a sulfonylating reagent such as 2-dibenzofuransulfonyl chloride and base such as Nmethyl morpholine in DMF. The phthalimide was then removed with hydrazine in MeOH and the resulting free amine was acylated with an acylating agent such as Cbz 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 I -Amnido-3-sulfonamrido 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 Nprotected peptide such as Cbz-leu-leu-QH I-Scheme 16 to its bromo methyl ketone 3-Schemne 16 via a diazo methiyl ketone 2-Schemne 16. Then, the bromide 3 -ScheMe i~is displaced with sodium azide to give the corresponding azide 4-Scheme 16.

Reduction of the carbonyl with a reducing agent such as sodium borohydride gives alcohol 5-Schee 16. Subsequent reduction of the azide with a reducing agent such as 1.3-propandithiol gives the free amine 6-Scheme 16. Acylation or sulfontylation of the amine gives amiide or sulfonamide 7-Scheme 16. Finally, oxidation of the carbinol with an oxidant such as Jones gives the desired compounds.

Compounds of Formula VIII may be conveniently made using methods analogous to those in Schemes 17 and 18.

Scheme 17 HON<1 2 N(>-NrOTs 0 0 I2 3 PO0 0~(Oo d. 0 0 0 ON~ 4 6 a) NaN 3 MeOH, H 2 0; b) Tosyl chloride, triethylanune, CH 2 C1 2

C)

Eliman dihydropyran resin PPTS, CI(CH 2 2 CI; d) PhCH 2

NH

2 toluene, degrees C; e) HATU, N-methyl morpholine, NMP; f) HS(CH 2 3

SH,

MeOH, Et 3 N; g) Cbz-leucine HBTU, N-methyl morpholine, NMP; h) TFA, CH 2

CI

2 Me 2 S; i) Jones reagent, acetone Azide opening of glycidol I1-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 1. Med. Chem. 1995, 38, 1427-1430 to Scheme Et2CC2r a N b S> H2O 2

CCCH

2 BrN

CO

2 Et BzN CQ 2 Et 12 3 c or d S Ar' O 2 e Ar N CONHNH, N 2N 4 H 0 Ar N 'N i J -R 0 H a) Thiourea, EtOH; b) i. NaNO 2 16% aqueous HBr, ii. CuBr, 16% aqueous H-Br; iii. HBr EtCH; c) ArB(OH) 2 Pd(PPh 3 4 CsF, DM[E; d) ArSnMe 3 Pd(PPh 3 4 PhMe; e) H 2

NNH

2

*H

2 O, EtCH; e) R 6 5 C0 2 H, EDC*HCI, Il-HOBT,

DM[F.

Compounds wherein X S, Y CH, Z N and V 2-methoxyphenyl or 2benzyloxyphenyl, are prepared by methods analogous to those described in Scheme Ethyl bromopyruvate (I-Schme 2) is treated with thiourea in refluxing ethanol to provide 2She2, which is treated successively with sodium nitrite and copper bromide in 16% aqueous HBr. and the product was heated in ethanol with a catalytic amount of I{Br to give 3-cem 0 Treatment of this material with an arylboronic acid (such as 2-benzyloxyphenylboronic acid), tetrakis(triphenylphosphine)palladium(O) and cesium fluoride in refluxing DME provides 4-Scheme 20. Alternatively, 4-Schemne 20, may be prepared by treatment of 3Scem 2 with an arylstannane (such as 2-trimethylstannylanisole) and tetrakis(triphenylphosphie)palladium(o) 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-beazyloxycarbonyl-N-methyl-L-eucine,

N-(

2 -pyridinylmehoxycarbonyl)Lleucine, N-(3-pyridinylmethoxycarbony)-Lleucine or N-( 4 -pyridinylmethoxycarbonyl)-L-.leucine) and a peptide coupling Compounds of Formula X may be conveniently made using methods analogous to those described in Schemes 21-27.

Scheme' 19 N CO 2 Et a N 'CO 2

H

jS H 0 N N l. 6 0 R 6 a) KOH, MeOH/H20; b) R 6 6

NHNH

2 EtOH; c) EDCoHCI, I-HOBT, DMF Compounds wherein X CH, Y S5, Z N and R4 H, are prepared by methods analogous to those described in Scheme 19. Carboxylic ester I1-Scheme 19 is treated with a hydroxide base (such as lithoumn hydroxide, sodium hydroxide or potassium hydroxide) in methanol/water to provide k bchmme 1. 3-Scheme 19 is treated with a hydrazine (such as methylhydrazine) in a protic solvent (such as ethanol) to give 4-chm 19 2Scem 1 and 4-cee1 are coupled by treatment with a peptide coupling reagent (such as EDC*HCII-HOBT) in an aprotic solvent (such as DMF) to provide 5-Scheme 1.

Scheme 22

H

H

2 N N

IH

H2NCSCO2Et a L> N CO 2 Et c 1 2 2 H2N CO2Et

N-N

1 2 3 H H I I O H L-I N CONHNH, 2 L N ,N R" N-N N-N H O 4 a) H 2

NNH

2

*H

2 0, EtOH; b) LCO 2

CO

2 i-Bu, 200 OC; c) H 2

NNH

2

*H

2 0, EtOH; d)

R

6 5 C0 2 H, EDC*HCI, 1-HOBT, DMF Compounds wherein X and Y N, and Z NH, are prepared by methods analogous to those described in Scheme 26. 1-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-Scheme 22. This material is treated with hydrazine hydrate to provide 4-Scheme 22. which is treated with a carboxylic acid (such as Nbenzyloxycarbonyl-L-leucine) and a peptide coupling reagent (such as EDC*HCl/1- HOBT) in an aprotic solvent (such as DMF) to provide 5-Scheme 22.

reagent (such as EDC*HClI -HOBT) in an aprofic solvent (such as DMF) to provide 6-Scheme Scheme 21 RCOCI- a RCONHR64 b RCH 2

NHR

6 7 C~ RCH2NR 67 CSdH 12 3 4 R66 Re7''N C E 66 67 N14 CONHNH 2 SH 0 0 H 7 a) R 67

NH

2 Py, CH 2 Cl 2 b) LiAlH 4 THE; c) i. CI 2 CS, Py, CH 2

CI

2 I. NH 3 MeOH or 1. P1ICONCS, CHCI 3 ii. K 2 C0 3 MeOH, H 2 0; d) EtO 2

CCOCH

2 Br, EtOH; e) H 2

NNH

2 eH 2 0, EtOH; e) R 65 C0 2 H, EDC*HCl. l-HOBT, DMF.

Compounds wherein X S, Y CHI, Z N and V NR66,are prepared by methods analogous to those described in Scheme 2 1. An acid chloride (L- Scheme21. is treated with a pr-imary amine (such as 4-aniinobiphenyl or aniline) and pyridine in an aprotic solvent (such as methylene chloride) to provide 2-Schme 2L* which is treated with lithium aluminum h ydride in THE to afford 3-Scheme Treatment of 3-Schem!: 2[ with thiophosgene and pyridine in methylene chloride, followed by treanment with ammonia in methanol provides 4-cee Alternatively, 4Scem 2 may be prepared by treatment of 3-Schem21 with benzoyl isothiocyanate, followed by treatment of the intermediate benzoyl thiourea with potassium carbonate in methanol/water. -4Sheme1 is treated with hydrazine hydrate in ethanol to give 5Sceme2 Treatment of 5-Scheme 21 with a carboxylic acid (such as N-(2-pyridinylmethoxycarbonyl)-Lleucine, N-(3pyridinylmethoxycarbonyl)-L-leucine or N-(4-pyridinylmethoxycarbonyl)-Lleucine) and a peptide coupling reagent (such as EDC*HCL/1-HOBT) in an aprotic solvent (such as DMIF) affords 6-cene21 59 Scheme 24 0+H H2N

NHZ

SA.NH CO'H

OH

aH 8 o c N 0 b HoN 00 OCX, Phi

OM

H H 0 0 09OCH'Pt d N 0 OH H 0 AO 000Ht a) EDCI, DMF; b) 2-PhCH 2 OPhSO 2 CI, NMM, DMF; c) TFA. DCM; d) 4-pyridyl acetic acid, HBTU, NMM, DMF; e) Jones I .3-Diamino-propan-2-ol (or an N-alkyl substituted diamino-propanol) is coupled to a protected leucine analog (either Cbz- or Boc-) and another carboxylic acid or sulfonyl chloride. Removal of the protective group, followed by acylation or sulfonylation, and oxidation of the alcohol provides the desired compounds.

Scheme 23 H 0 R 6 0 L

N

I

H

H

RA

69 0 2 (M Co. S0 2 R 66 0 H BOCN 65 H 0 R 660 H HR )60 N' H 0 a) TEA; b) R 62 C0 2 H, EDC*HCI, 1-HOBT, DMIF; c) R 62 S0 2 C1, i-Pr 2 NEt Compoids wherein X S, Y CH, Z N, L CH(R 66

)NR

60

DR

68 where

R

68 Boc or Cbz, or R5= CH(R 69

)NR

6

IR

70 where R 70 Boc or Cbz are prepared by methods analogous to those described in Scheme 27. I-Scem 2 is treated with trifluoroacetic acid to provide 2Sheme 23. This material is treated with a carboxylic acid (such as pryazinecarboxylic: acid, isonicotinic acid, 4imidazolylacetic acid or pipecolic acid) and a peptide coupling reagent (such as EDC.PHCI/I-HOBT) in an aprotic solvent (such as DMF) to provide 3-Scheme 23.

3-Schme 23 may also be prepared by treatment of 2hme 2 with a sulfonyl chloride (such as 2-pyridinesulfonyl chloride) and a terticary amine base (such as diisopropylethylamine) in an aprotic solvent (such as methylene chloride).

Alternatively, treatment of 4-Schme 23 with trifluoroacetic acid provides Scheme 23.

The starting materials used herein are commercially available amino acids or are prepared by routine methods well known to those of ordinary skill in the an and can be found in standard reference books, such as the COMPENDIUM

OF

ORGANIC SYNTHETIC 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 PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984; E.

Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984. are generally illustrative of the technique and are incorporated herein by reference.

Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions. Such protective groups are described generally in Green, T.W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art.

Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.

Acid addition salts of the compounds of Formula I are prepared in a standard...

manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li Na+, Ca Mg and NH4+ are specific examples of cations present in pharmaceutically acceptable salts.

Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.

Scheme Cbz-NH C02H a H 0 Cbz-NH 0 Cbz-NH

OH

H

Cb-H N NHMe 0 d-- Mee NHCbz 0 0 Me- Cbz-NN HY NHCbz 0 0 a) HBTU, NMM, DMF, allyl amine; b) mCPBA, DCM; c) MeNH 2 isopropanol, C; d) Cbz-leucine, EDCI, DMF; e) Jones, acetone N-Allyl amine (or a N-ajkyl-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 subsituted amine, then the amine is acylated or sulfonylated. Final oxidation gives the desired ketones.

For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.

Utility of the Present Invention The compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.

The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, 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.

Metastatic neoplastic cells also typically express high levels-of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.

The present invention also provides methods of treatment of diseases 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 superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention. The present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K. which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof an inhibitor of cathepsin K, including a compound of the present invention. The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carnii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy,, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Pagers disease, hypercalcemia of malignancy, and metabolic bone disease.

This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of 'Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.

For acute therapy, parenteral administration of a compound of Formula I is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K. The compounds are administered 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 inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.

Human Osteoclast Resorption Assay Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37 0 C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm, 5 min at The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium, and incubated for 30 min on ice The cell suspension was mixed frequently.

The cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4 0 C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.

Sufficient magnetic beads (5 mononuclear cell), coated with goat antimouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated for min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the beadcoated cells to dislodge any trapped osteoclasts. This wash process was repeated x10. The bead-coated cells were discarded.

The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5x10 4 /mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEMI diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at 37"C for 30 min.

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 initiated by addition of enzyme to buffered solutions of inhibitor and substrate. Data analysis was conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors.

For those compounds whose progress curves were linear, apparent inhibition constants (Kiapp) were calculated according to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140): v VmA /[Ka(l I/Ki, app) +A] (1) where v is the velocity of the reaction with maximal velocity Vm A is the concentration of substrate with Michaelis constant of Ka, and I is the concentration of inhibitor.

For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give kobs according to equation 2: [AMC] vss t (vo vss) [I exp (-kobst) /kobs (2) where [AMC] is the concentration of product formed over time t, vo is the initial reaction velocity and vss is the final steady state rate. Values for kobs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (kobs inhibitor concentration or kobs describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61,201).

points were taken on a Thomas-Hoover melting point apparatus and are uncorrected.

All temperatures are reported in degrees Celsius.

.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 indicated, certain of the materials were purchased from the Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey, and Advanced Chemtech, Louisville, Kentucky.

Examples In the following synthetic examples, temperature is in degrees Centigrade Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding 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 reserved to the inventors hereunder.

Example 1 Preparation of (2S.1'S)-2-(benzyloxycarbonyl)amino-N- 1'-(2-carboethoxvthiazol-4vl)-3'-methvlbutvll-4-methylpentanamide a) N-benzyloxycarbonyl-L-leucinyl-L-leucinyl bromomethylketone l-Methyl-3-nitro-l-nitrosoguanidine (5.9 g, 40.11 mmol) in ether (200 mL) is cooled to 0*C. 40% potassium hydroxide is added slowly and the diazomethane is allowed to collect in the ether solution for 30 minutes at 0*C.

N-Cbz-L-Leucinyl-L-Leucine (Bachem) (4.0 g, 10.58 mmol) is stirred in tetrahydrofuran at -40 0 C. N-methylmorpholine (1.07 g, 10.58 mmol, 1.16 mL) and isobutyl chloroformate (1.45 g, 10.58 mmol, 1.38 mL) are added. The mixture is stirred at -40*C for 15 minutes and then filtered into a cold flask to remove precipitated salts. To the filtered solution is added an excess of the previously prepared diazomethane solution and the mixture is allowed to stand at 0"C for 16 h.

An excess of 30% HBr in acetic acid is added at 0 C and the solution is then washed mL aliquots of the cells were seeded onto sterile dentine slices in a 48well plate and incubated at 37 0 C for 2 h. Each treatment was screened in quadruplicate. The slices were washed in six changes of warm PBS (10 mL well in a 6-well plate) and then placed into fresh treatment or control and incubated at 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 incubated in buffer for 5 min at 37*C. The slices were then washed in cold water and incubated in cold acetate buffer fast red garnet for min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.

The TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.

General Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDC13 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD30D is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s singlet, d doublet, t triplet, q quartet, m multiplet, dd doublet of doublets, dt doublet of triplets, app apparent, br broad. J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm- 1 Mass spectra were taken on either VG 70 FE, PE Syx API m, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting successively with L.ON citric acid, saturated aqueous sodium bicarbonate (carefully), and brine. The solution is dried over sodium sulfate, filtered, and evaporated to give the title compound as a white solid (4.10 IH NMR (400 MJ-z,CDCI 3 )567.34 (mn, 5H), 6.51 I 5.15 I1H), 5. 10 2H), 4.78 (in, I 4.20 (in, INH), 4.04 (dd, 2H), 1.63 (mn, 6H), 0.93 (in, 12H).

b) (2S, 1'S)-2-(benzyloxycarbonyl)amino-N-fI'-(2-carboethoxythiazol-4-yl)-3'inethylbutyl]-4-inethylpentanamide The compound of Example 1 (2.0 g, 4.4 mmol) and ethyl thiooxamate (0.59 g, 4.4 inmol) were refluxed in ethanol for 4 h. The solvent was evaporated and the residue chroinatographed (silica gel, 2.5% inethanolldichloromethane) to give the title compound as a white solid (1.46 IH NMR (400 MHz, CDCI3) 8 7.32 (s.

1H), 7.21 (mn, 5H), 6.40 IH), 5.13 (dci, IH), 5.02 2H), 4.41 2H), 4.06 (mn, IN), 1.71 (mn, 2H), 1.47 (in, 4H), 1.33 3H), 0.73 (mn, 12H).

Example 2 Preparation of (2S. 1'S)-2-4benzvloxycarbonyl'anmino-N-[ I'-(2-carboxythiazol-4-vl)- 3'-iethylbutyll-4-methylpentananmide The compound of Example 1(c) (0.92 g, 1.88 rnmol) was stirred in tetrahydrofuran at 0 0 C with 1LON sodium hydroxide. After stirring for 1 h, the solution was quenched with 1LON citric acid and extracted three times with dichloroinethane. The combined organic extracts were evaporated in vacuo to give the title compound as a white solid (0.844 IH NMR (400NMHz, CDCl3) 67.40 iH), 7.23 (in, 5H), 6.89 (di, 1H), 5.22 (ci; 1H), 5.14 (dci, 1H), 5.02 2H), 4.15 (in, 1H), 1.67 (mn, 2H), 1.44 (mn, 4H), 0.81 (in, 12H).

Example 3 Preparation of (2S. 1 S)-2-(benZyloxyca-bonyl)ainino-N-( I -(2-carboxaxnidothiazol- 4 -yl)-3'-iethylbutyll-4-nethylpgntanarnide The compound of Example 2 (0.408 g, 0.88 mrnol) in tetrahydrofuran was cooled to -40 0 C and treated with N-inethylmorpholine 185 g, 1. 85 iniol, 0.2 ml-) and isobutyl chloroformate 12 g, 0.88 ramol, 0. 11 rnI4. The mixture was stirred at -40'C for 15 minutes and then ammonia was bubbled through the solution for several minutes. The mixture was allowed to warmn to room temperature and was then diluted with ethyl acetate and washed successively with L ON citric acid, 5% aqueous sodium bicarbonate, and brine. The organic solution was dried over magnesium sulfate, filtered, and evaporated to a residue which was chromatographed (silica gel, 3% methanol/dichloroniethane) to give the title compound as a white solid (0.245 IH NMR(400NZvHz,CDCI3) 67.22(in, 7.04 IH), 6.40 (br s, 1H), 5.51 (br s, 1H), 5.09 (in, 1H), 5.02 (dd, 2H), 4.07 (in, 16-42(in, 6H), 0.82 (in, 12H).

Example 4 Preparation of (2S. 2 -(benzyloxvcarbonvl)amino-N..r I'-(2-cvanothiazo-4-yl)-3'methylbutyl M-methyllentanamide The compound of Example 3 (0.185 g, 0.4 mnmol) was dissolved in dichloroinethane, cooled to 0 0 C and treated with TFAA (0.093 g, 0.44 mxnol, 0.06 mL) and pyridine (0.07 g, 0.88 mmol, 0.07 mL). After 3 h, the mixture was poured into a solution of saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extracts were washed with 5% hydrochloric acid and brine, dried over magnesium sulfate, filtered, and evaporated to an oil which was chromatographed (silica gel, 40% ethyl acetate/hexane) to give the title compound as a white solid (0.095 I H Nlv R (400 MLRz, CDCl3) 8 7.44-(s, 1H), 7.29 (s, 51l.), 6.51 (br d, I1H), 5.14 (in, IlH), 5.07 2H), 4. 11 I1H), 1.78-1.41 (mn, 6H), 0.83 (mn, 12H).

Example Preparation of (25.1 'S)-2-(benzvloxycarbonyl)aniino.Nr 1 benzvlcarboxamidolthiazol1Avyll3'.methvlbulyll-4mieth1gntanmde To a solution of the compound of Example 2 (0.12 g, 0.26 rnmol) in dichloroinethane under argon at room temperature is added benzylaniine (0.03 g, 0.29 mmnol, 0.03 inL), BOP reagent 115 g, 0.26 rninol), and triethyl amine (0.026 74 ag, 0.26 minol, 0.04 rnL) which is allowed to stir for 16 h. The solution is washed with water, then brine and the organic layer is dried over magnesium sulfate, filtered, and evaporated to give a residue which was chromatographed (silica gel, ethyl acetate/hexane) to give the title compound as a white solid (0.065 IH NMvR (400 MHz, CDCI3) 6 7.56 (br s, 1H), 7.33 (in, 1OH), 6.48 (br d, 1H), 5.15 (dd, 1H), 5.03 2H), 4.63 2H), 4.12 (mn, lH), 1.72-1.40 (in, 6H), 0.85 (in, 12H).

Preparation of (2S.1 'S)-2-(benzvloxycarbony j'arnino-N-[I methyiproyl)carboxaxnidolthiazol-4-yll-3'-methylbutvll 4 nethylpefltalamlde Following the procedure of Example 5, except substituting isobutylainine for benzylannne, the title compound was prepared (0.074 IH NMR (400 MHz, CDC13) 8 7.27 5H), 7.19 IlH), 6.38 (br d, 1 5.09 (mn, I 5.01 2H), 4.07 (in, 1H), 3.20 (dd, 2H), 1.83 (in, IH), 1.69-1.40 (mn, 6H), 0.90 6H), 0.81 (mn, 12H).

Exampe Preparation-of (2S.1 'S)-2-(benzyloxvcarbonylhamino-N-[ 1 '42- rN'-(2phnltlabxr~otizl-l-'mfluyl4mtypnaai- Following the procedure of Example 5, except substituting 2phenylethylamine for benzylarnine, the title compound was prepared (0.070 IH NMR (4.00 MIHz, CDC13) 8 7.30-7.11 (in, I1H), 6.35 (br d, LH), 5.09 1H), 5.01 2H), 4.05 (in, 1H), 3.64 (mn, 2H1), 2.87 2H), 1.69-1.40 (mn, 6H1), 0.80 (in, 12H).

Example 8 Preparation of (2S. 1'S)-2-(benzyloxvcarbonvl)amjno..N[ 4 -carboethoxythiazol.2.

VI )-3'-methvlbucvl l 4 -methylpgntanarnide a) N-tert-butoxycarbony[-(L)-leucinamide To a solution of N-tert-butoxycarbonyl-(L)-leucine (Advanced Chemtech) g, 20.0 minol in dry THF (Il0OmL) at -40*C was added isobutyl chlorofornate (2.7 g, 20.0 minol) and N-methylmorphiline (4.2 g, 42 minol). After 15 minutes of stirring, ammonia was bubbled through the mixture for an additional 15 minutes, then warmed to room temperature and allowed to stir for 2 hours. Mixture filtered and filtrate concentrated in vacuo to yield title compound as a white solid (4.9 g, 19.7 mmol). I H NMvR (400 MHz, CDCI3) 6 6.38 (br s, IlH 5.79 (br s, I1H), 5.04 (br d, 1H), 4.13 (in, IH), 1.71-1.49 (in, 3H), 1.39 9H), 0.92 (dd, 6H). b) N-et-uoy:roylLlu.ntiomd To a stirring solution of the compound of Example 8(a) (2.38 g, 10.35 inmol) in dry THF was added Lawessons reagent (2.51 g, 6.21 inmol) and the mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the residue chromatographed (silica gel, methanoL/dichloromethane) to give the title compound as a white solid (2.3 1

H

NMvR (400 MIHz, CDC13) 8 8.54 (br s, IH), 7.97 (br s, lH), 5.28 (Ibr d, 1H), 4.52 (in, IH), 1.72-1.58 (mn, 3H), 1.40 9H), 0.92 6H).

c) 1-(tert-butoxycarbonyl)amji.. l-(4-carboethoxythiazol-2-y1)-3methylbutane The compound of Example 8(b) (2.40 g, 9.76 inmol) was stirred in dry acetone (20 mL) under argon at 10 0 C. Ethylbromopyruvate (2.12 g, 10.73 inmol, 1. 35 mL) was added and stirred for 1 h at -1I0 0 C. The solution was poured into a well stirred mixture of chloroform and water and then saturated with sodium bicarbonate. The organic phase was separated and the aqueous layer extracted with 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 minol, mL) and pyridine (1.70 g, 21.47 mmol, 1.75 mL) in dichioromethane for I h at Excess solvent was removed in vacuo and the residue was dissolved in dichioromethane. The solution was washed with saturated aqueous sodium bicarbonate and L ON KHS04 until pH 7. The solution was dried over sodium sulfate, filtered, and evaporated to an oil which was chromatographed (4% methanoL/dichioromethane) to give the title compound as a tan solid (1.2 IH NMR (400 MHz, CDCI3) 8 7.98 1H), 5.04 (br d, 1H), 4.95 (in, 1H), 4.31 (q, 2H), 1.88 1H), 1.63 (in, 2H), 1.40 9H), 1.32 3H), 0.85 (dd, 6H).

d) (2S, I'S )-2-(benzyloxycarbonyl)amino-N- [1'-(4-carboethoxythiazol-2-yI)-3'inethylbutyll-4-inethylpentanamide The compound of Example 8(c) (1 .0 g, 2.92 inmol) was dissolved in neat TFA (1.0 mL) and stirred for 15 minutes. The solution was diluted with methanol and evaporated in vacuo. A portion of the residue obtained (0.36 g, 1.49 inmol) was dissolved in dichioromethane with N-Cbz-L-leucine (0.394 g, 1.49 inmol) BOP reagent (0.66 g, 1.49 inmol) and triethylamine (0.73 g, 7.2 inmol, 1.0 inL) and stirred at room temperature for 16 h. The solution was washed with water, then brine and dried over magnesium sulfate, filtered, and evaporated to a residue which was chromatographed (silica gel, 40% ethyl acetate/hexane) to give the title compound as a white solid (0.396 I H NUR (400 MHz, CDCI3) 8 7.96 1H), 7.25 5H), 6.61 (br d, 111), 5.30 (in, 1H), 5.09 (hr d, 1H), 5.01 2H), 4.33 (q, 2H), 4.10 (in, 1H), 1.90-1.58 (in, 6H), 1.29 3H), 0.81 (dd, 12H).

Exmple Preparation of (25.1 'S')-2-(benzyloxycarbony I Iamino-N-f 1 '-(4-carboxvthiazol-2-1')- 3'-metylbutyll-4-methylpentanarnide Following the procedure of Example 2, except substituting (2S,1I'S)-2- (benzyloxycarbonyl)ainino-N-( I '-(4-carboethoxythiazol-2-yI)-3'-iethylbutyl]-4methylpentanamide for (25,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 carboxythiazol-4-yl)-3'-inethylbutyl]-4-methylpentananide, the title compound was prepared (0.301 I H NMR (400 M41z, CDC13) 588.06 lH), 7.24 (in, 5H), 7.11 I 5.30 (in, 5.04 2H), 4.16 (in, I 1.88-1.40 (in, 6H), 0.71 (dd, 12H).

Example Preparation of (2S.1 S)-2-(benzyloxycarbonyl )amino-N-f I carboethoxvthiadiazol-2-vI -methvlbutyl1-4-methvlpentanamjde a) N-tert-butoxycarbonyl-L-leucmne methyl ester To a stirring suspension of L-leucine methyl. ester hydrochloride (Aldrich) (6.00 g, 33.0 mmol) and di-tert-butyl dicarbonate (7.21 g, 33.0 mmol) in THfF mL) was added triethylamnine (3.34 g, 33.0 mnmol, 4.60 The mixture was allowed to stir at room temperature for 3 d. The mixture was diluted with ethyl acetate and washed with 1 N HCI (2 times), waler, and saturated brine, then dried over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (8.02 g, IH NMR (4.00 MIHz, CDCI3) 8 4.88 1H), 4.33-4.31 (in, IH), 7.73 3H), 1.75-1.48 (in, 3H). 1.44 9H), 0.96 3H), 0.93 3H).

b) N-tert-butoxycarbonyl-Lleucine hydrazide To a stirring solution of the compound of Example 10(a) (8.02 g, 32.7 inmol) in methanol (250 m.L) was added hydrazine hydrate (16.38 g, 327 inmol, 15.9 inL. After stirring for 22 h at roam temperature, the solution was concentrated and the residue was azeotroped with toluene to provide the title compound as a white foam (8.02 g, 100%). 1 H NMR (400 MIHz, CDCI3) 8 7.71 (br s, I 4.99 2H), 4.12-4. 10 (in, I1H), 3.94 (br s, 2H), 1. 68-1.49 (mn, 3 1.44 (s, 9H), 0.95 3H), 0.92 3H).

c) (2)N[-bnyoyabnlaio4mtypnaol-' carboethoxycarbonyuhydrazide To a stirring solution of the compound of Example 10(b) (8.02 g, 32.7 rmnol) and pyridine (2.85 g, 36.0 inmol, 2.91 mQL in dichioromethane (200 inL) was added ethyl oxalyl chloride (4.91 g, 36.0 inmol, 4.02 mL). After stirring at room temperature for 2 h, thye solution was washed with I N HCl, water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a white foam (9.84 g, IH NMR (400 MHz, CDC13) 6 9.32 (br s, 2H), 5.04 2H), 4.38 2H), 4.28 1H), 1.77-1.56 3H), 1.44 9H), 1.39 3H), 0.96 3H), 0.94 (d, 3H).

d) (1S)-1 -(tert-butoxycarbonyl)amino-1 -(4-carboethoxythiadiazol-2-yl)-3methylbutane To a stirring solution of the compound of Example 10(c) (2.50 g, 7.24 mmol) in toluene (70 mL) was added Lawesson's reagent (1.46 g, 3.62 mmol). The mixture was heated at reflux for 3 h. The solution was diluted with ether, washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated to leave a pale yellow oil. The crude material was purified by flash chromatography on 75 g of 230-400 mesh silica gel, eluting with 1:4 ethyl acetate/hexanes, to provide the title compound as a pale yellow solid (1.75 g, 1 H NMR (400 MHz, CDC13) 85.19 1H), 5.13 (d, 1H), 4.51 2H), 1.95 1H), 1.83-1.73 2H), 1.44 9H), 1.00 3H), 0.98 3H).

e) -amino- l-(4-carboethoxythiadiazol-2-yl)-3-methylbutane bistrifluoroacetate salt To a stirring solution of the compound of Example 10(d) (1.75 g, 5.1 mmol) in dichloromethane (40 mL) was added TFA (10 mL). After stirring for 5 min at room temperature, the solution was concentrated to give the title compound as an oily pale yellow solid (2.40 g, 100%). 1 H NMR (400 MHz, CDC13) 8 9.83 (br s, 4H), 5.20 1H), 4.51 2H), 2.07 2H), 1.70 1H), 1.44 1.00 (t, 3H).

f) (2S, l'S)-2-(benzyloxycarbonyl)amino-N-[ l'-(4-carboethoxythiadiazol-2-yl)-3'methylbutyl]-4-methylpentanamide To a stirring solution of the compound of Example 10(e) (566.1 mg, 1.20 mmnol), N-Cbz-L-leucine (250.5 mg, 1.32 minol), l-( 3 -dinethylaminopropyl).3 ethylcarbodlirnide hydrochloride (253.3 mg, 1.32 mmol) and Ihydroxybenzot-iazole (32.5 mg, 0.24 mmol) in 2.5 mL of DMF was added triethylamrine (243.1 mg, 2.40 mmnol, 0.335 mL). After stirring at room temperature for 3 d, the mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated to give a yellow oil. The cride material was purified by flash chromatography on 20 g of 230-400 mesh silica gel, eluting with 1:2 ethyl acetate/hexanes, to provide the title compound as a white solid (271 mng, 1'H NMvR (400 MHz, CDCI3) 8 7.35 6.77 IH), 5.49 (in, 1H), 5.12 (dd, 2H),a:o 4.51 2H), 4.20 (in, lH), 1.97(m, IH), 1.88 (in, IH), 1.66 (in, 3H), 1.52 (in, LU), 1.45 3H), 0.97-0.92 (mn, 12H). Example I I Prep~aration of (2S. I'S')-2-(benzyloxycarbonl)anino.N.rl1'-(2-carbo-2.2.2trifluoroethoxtiazol l3'tyb-4-mebutvl14methvlm'de The compound of Example 2 (0.200 g, 0.43 3 inmol), 1, 1, 1 trifluoroethanol (.052 g, 0.52 inmol, .04 inL), pyridine 1 inL), and di-t-butyl dicarbonate 104 g, 0.477 minol) were stirred in ethyl acetate at room temperature for 16 h. The solution was diluted with ethyl acetate and washed successively with hydrochloric acid, 10% aqueous sodium bicarbonate, and brine.-The organic layer was dried over magnesium sulfate, filtered, and evaporated to give a residue which was chroinatographed (silica gel, 20 ethyl acetate/hexane) to give the title compound as a white solid (.098 I H NMR (400 MIHz, CDCl3) 6 7.50 18), 7.36 5H), 6.64 1H), 5.22 (in, 5.09 2H), 4.73 (mn, 28), 4. 16 (mn, 18), 1.66-1.4 1 (mr, 6H), 0.87 (in, 12H).

Example 12 Preparation of (2S.1 'S)-2-(benzvloxvcarbonvl)amino-N-r carboethoxvoxadiazol-2-vfl-3'-methvlbutyl 1-4-methvlpentanamide a) (15)-I -(tert-butoxycarbonyl)amino- l .(4-carboethoxyoxadiazol-2-yl)-3.

methylbutane To a stirring solution of the compound of Example 10(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 mmol, 0.69 After stirring at room temperature for 2 h, the solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in toluene and heated 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 with* 1:4 ethyl acetate/hexanes, to give the title compund as a pale yellow oil (0.84 g, 1

H

NMR (400 MHz, CDCl3) 8 5.14 lH), 5.03 (br d, 1H), 4.52 2H), 1.78-1.70 3H), 1.44 9H), 0.99 6H).

b) 1-amino- 1-(4-carboethoxyoxadiazol-2-yl)-3-methylbutane Following the procedure of Example 10(e), except substituting I -(terbutoxycarbonyl)amino- 1-(4-carboethoxyoxadiazol-2-yl)-3-methylbutane for (1 I- (terr-butoxycarbonyl)amino. 1 -(4-carboethoxytbiadiazol-2-yl)-3-methylbutane, the title compound was prepared (582 mg, 100%). IH NMR (400 MHz, CDC13) 8 4.99 1H), 4.52 2H), 2.10-2.02 2H), 1.77-1.70 1H), 1.44 3H), 1.00 (t, 6H).

c) (25,1 'S)-2-(benzyloxycarbonyl)aino-N 1 -(4-carboethoxyoxadiazol-2-yl)-3'methylbutyl]-4-methylpentanamide Following the procedure of Example 10(f), except substituting (IS)-lamino- 1-(4-carboethoxyoxadiazol-2-yl)-3-methylbutane for (IS)-I-amino- 1-(4carboethoxythiadiazol-2-yl)-3-methylbutane, the title compound was prepared (235 mg, 1 H NMR (400 MHz, CDCI3) 8 7.26 5H), 6.64 1H), 5.45-5.39 (m, 5.12 (in, 3H), 4.52 2H), 4.20 (in, 1H), 1.81 (in, 1.68-1.64 (in, 3H), 1.54-1.50 (in, IH), 1.46 3H), 0.97-0.92 (in, 12H).

Example 13 Preparation of (2S. I'S)- 2 -(benzyloxvcarbonvI.L..eucny)~ilo-- 1 carboethoxvtiazol-2-yl '-methylbutyl l- 4 -inethvlpentanamide The compound of Example 8(c) (160.7 mg, 0.47 mmol) was dissolved in neat TFA (1.0 rnL) and stirred for 15 minutes. The solution was diluted with Methanol and evaporated to dryness. The residue was dissolved in DMF (2 m.L) and to the resulting solution was added N-Cbz-L-leucinyl-L-leucjne (194.0 ing, 0.52 mmol), 1-( 3 -dimethylaminopropy)-3-ethylcarboijinide hydrochloride (99.0 mng, 0.52 innol) and I -hydroxybenzotriazole (13.0 mng, 0.094 inmol) and triethylamine (94.7 mng. 0.936 mmol, 0. 13 mL). After stirring at room temperature for 24 h, the mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with ethyl acetate/hexanes, to provide the title compound (0.146 IH NMR (400 MHz, CDCl3) 8 8.04 IH), 7.33 (in, 5H), 7.14 11H), 6.61 1H), 5.37 (in, 5.08 (in, 2H), 4.47 (in, IH), 4.39 2H), 4.18 (in, 1H), 1.98 1.45 (in, 9H), 1.38 3H), 0.94 0.86 (mn, 18H).

Example 14 Preparation f 2S. 1 'S)-2-(benzyloxycarbonylarnino..N..r 1 carboxamidooyxadiazo2vl)3'methlbuy14-methy lpenarde Ammonia was bubbled through a solution of the compound of Example 12 (96.8 mng, 0.2 inmol) in ethanol (2 mL) for 5 irm. After stirring an additional min, the solution was concentrated to give the title compound as a white solid (91.2 ing, IH NMR (400 Mfz, CDC13gCD 3 OD) 8 7.29 5H), 5.90 1H), 5.30 1HI), 5.04 28), 4.15 (in, 18), 1.76 (in, 2H), 1.59-1.43 (in, 4H), 0.92-0.85 (in, 12H).

Example Preparation of (2S. I'S)-2-(benzvioxvcarbonvylamino-N-r I 2 -carboethoxvthiazol-4.

vy)-3'-methvlbutvlI-3-phenvlpropanamide a) N-(9-fluorenylmethoxycarbonyl)-L-leucinyl bromomethyl ketone Following the procedure of Example except substituting N-(9fluorenylmethoxycarbonyl)-L-Ieucine for N-benzyloxycarbonyl-L-leucinyl-Lleucine, the title compound was prepared (5.6 1 H NMR (400 MHz, CDCI3) 6 7.71 2H), 7.51 2H), 7.34 (dd, 2H), 7.22 (dd, 2H), 5.08 1H), 4.53 1H), 4.36 (dd, 2H), 4.13 (dd, 2H), 3.89 (dd, 2H), 1.62-1.41 3H), 0.88 6H).

b) (1S)-I -(2-carboethoxythiazol-4-yl)- 1 -(9-fluorenylmethoxycarbonyl)amino-3methylbutane Following the procedure of Example except substituting N-(9fluorenylmethoxycarbonyl)-L-leuciny bromomethyl ketone for N- Beazyloxycarbonyl-L-leucinyl-L-leuciny bromomethylketone, the title compound was prepared (4.13 1 H NvR (400 MHz, CDC13) 8 7.72 2H), 7.49 2H), 7.32 (dd, 2H), 7.22 (dd, 2H), 7.19 1H), 5.31 1H), 4.88 1H), 4.40 2H), 4.28 2H), 4.08 1H), 1.62-1.41 3H), 1.36 0.88 6H).

c) -amino-i -(2-carboethoxythiazol-4-yl)-3-methylbutane The compound of Example 15(b) (0.5 1.1 nmol) was stirred in a piperidine/DMF solution for 10 minutes at room temperature. The solvents were evaporated and the solid obtained was dried in vacuo to give the title compound (0.27 g).

d) (2S, 1'S)-2-(benzyloxycarbonyl)amino-N-[ 1!-(2-carboethoxythiazol-4-yl)-3'iethylbutyl]-3-phenylpropanamide Following the procedure of Example except substituting (1S)-I-amino-I- 2 -carboethoxythiazol-4.yl)-3-methylbutane for benzylamine, and N-Cbz-Lphenylalanine for (2S,1'S)-2-(benzyloxycarbonyl)amino-N-[ I'-(2-carboxythiazol4yl)-3'-methylbutyl-4-iethylpentanamide, the tide compound was prepared 162 1 H NMR (400 MI-z, CDCI3) 67.27 5H), 7.11 1H), 7.04 5H), 6.12 I 5.24 I 5.10 IH), 5.01 2H), 4.37 2H), 4.21 1 2.91 2H), 1.62 3H), 1.37 3H), 0.81 6H).

Example 16 Preparation of (2S.I IS)-2-(benzyloxvcarbonyl-L-leucinyl)amino-N-r1'-(2carboethoxvthiazo-4-l)-3'-methvlbutgy ]-4-methvlentanamide Following the procedure of Example 5, except substituting I-amino-l.I.

2 -carboethoxythiazok.4-yl)-3-methylbutane for benzylamine, and N-Cbz-Lleucinyl-L-leucine for (2S, I'S)-2-(benzyloxycarbonyl)arnino-N- carboxythazol-yl)-3'-methylbuty l]methypen ide the title compound was prepared (0.098 IH NMR (400 MHz, CDC13) 8 7.39 1H),7.25 6.87 1H), 6.49 18), 5.30 18), 5.16 4.99 2H), 4.36 2H), 4.31 18), 4.09 1H), 1.74-1.38 9H), 1.32 38), 0.80 Example 17 Preparation of (2S.I'S)-2-(benzloxycar~bonylanan-Nr rl'-(5-mercapto-1.2.4oxadiazol- 3 -y)-3'-methylbuty I-4-methvylentanamide a) N-benzyloxycarbonyl-L-eucinyl-L-leucine methyl ester N-Cbz-L-leucine (Chemical Dynamics) (1.32 g, 4.97 miol), L-leucine methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 miol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol) and l-( 3 -dimethylaminopropy)-3thylcarbodiie hydrochloride (1.05 g, 5.47 mmol) were combined, dissolved in 25 nL of DMF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed successively with water, 0. 1 N HCI, saturated aqeous NaHC03 and saturated brine, then dried (MgSO 4 filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:3 ethyl acetate hexanes, to give the title compound as a white solid (1.28 g.

H NMR (400 MHz, CDCI3) 6 7.37-7.32 58), 6.28 5.28 3H), 4.61-4.58 IH), 4.20 18), 3.74 31), 1.69-1.54 6H), 0.96-0.92 12H).

b) N-benzyloxycarbonyl-L-leucinyl-L-ieucinylhydrazide To as stirr-ing solution of the compound of Example 17(a) (1.28 g, 3.26 mrnol) in 25 m.L of methanol was added hydrazine hydrate (1.63 g, 32.6 mmol, 1.58 rnL) and the solution was allowed to stir at room temperature for 15 h. The solution was evaporated to dryness to give the title compound as a white solid (1.28 g, 100%). IH NMR (400 MHz, CDCI3) 8 8.05 (br s, IH), 7.35-7.32 (mn, 5H), 6.67 (d, 1H), 5.50 1H), 5.11 2H), 4.46 (mn, 1H), 4.21 (mn, 1H), 3.88 (br s, 2H), 1.64- 1.51 (in, 6H), 0.92-0.88 (in, 12H).

c) (2S, 1'S)-2-(benzyloxycarbonyl)amino-N- [1'-(5-mercapto- 1,2,4-oxadiazol-3-yl)- 3'-methylbutyl]-4-methylpentanamide To a stirring solution of the compound of Example 17(b) (0.3 g, 0.76 inmol) in 1.5 mL of chloroform was added triethylamrine (0.155 g, 1.53 nixol, 0.2 13 ML) and thiophosgene (0.088 g, 0.76 inmol, 0.058 niL). The solution was heated at reflux for 3 h, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 11I% methanol in dichioromethane, to give the title compound as a white solid (0.20 g, 6 IH NMR (400 MHz, CDCI3)8&7.36(in, 6H), 6.85 1H), 5.37 IH), 5.14 3H), 4.24 (mn, 1H), 1. 65 (in, 6H), 0.95- 0.87 (mn, 12H).I Example 18 Preparation of (2S. I'S )-2-(benzyloxvcarbonyl)amino-N-f 1 2 -mercaptothiazol-4vi)-3'-methylburvll-4-methylpentanaxnide The compound of Example I1(a) (1.0 g, 2.2 mmol) and anmmonium dithiocarbamate (0.25 2.2 mmol) were dissolved in ethanol and heated to 55 0

C

for 13 hours. The solvent was evaporated and the residue chromatographed (silica gel, 20% ethyl acetate/hexane) to give the title compound -as a white solid (0.58 g).

IH NMR (400 M&z, CDCl3) 8 7.24 (in, 5H), 7. 10 1H), 6.33 IH) 6.00 (d, 1H), 5.11 2H), 4.94 (mn, 1H), 4.05 (mn, IH), 1.49 (in, 6H1), 0.78 (in, 1211).

Preparation of (2S)-2-(benZyloxycarbonylhamino-N-(4-carboethoxvtiiiazol2.

yl)methyl-4-methvlpentananiide a) 1 -(tert-butoxycarbonyl)amino- 1 -(4-carbocthoxythiazol-2-yl)inethane Following the procedure of Example except substituting N-tertbutoxycarbonyiglycine for N-terr-butoxycarbonyl-(L)-leucine in step the title compound was prepared (1.9g, 58% overall). III NMR (400 MOz, CDC13) 8 8.11 1H), 5.31 1H), 4.56 2H1), 4.43 2H), 1.45 9H), 1.42 3H).

b) 2 S)-2-(benzyloxycarbonyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4inethylpentanamide Following the procedure of Example 13, except substituting 1-(tertbutoxycarbonyl)aniino.. 1 -(4-carboerthoxythiazol-2-yl)methane for (1 1 -(terrbutoxycarbonyi)amino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz- L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120g, MS 434.2.

Example Preparation of (2S.1'S)-2-(benzvloxvcarbonvI)amino-N-rl benzyloxvcarbonvlthiazol-4-vI')-3'-methvybutyll-4-methylefltanamide The compound of Example 2 (0.105 0.22 mmol) was dissolved in dichloromethane and treated with l-(3-dimethylaminopropyl)-3-ethylcarbodiinide methiodide (0.062 0.22 imol) and benzyl alcohol (0.03 mL, 0.22 mmol). The mixture was allowed to stir at room temperature for 4 hours and the solvents were evaporated and the residue obtained was cheromatographed( silica gel, 30% ethyl acetate/ hexane) to give the title compound as a white solid (0.04 1 H NMR (400 MHz, CDCl3) 87.37 lH), 7.26 1OH), 6.50 1H) 5.33 2H), 5.11 (q, 2H), 5.09 1H), 4.99 2H), 4.04 1H), 1.49 6H), 0.78 12H).

Example 21 Preparation of (25.1 'S)-2-(benzloxycarbony')ainino--4-methvl-N-f3'-methvl-1'-(2phenoxcarbonvlthiazol4-v)butyllpentanaide Following the procedure of Example 20, except substituting phenol for benzyl alcohol, the title compound was prepared (0.075 1 H NMR (400 MHz, CDC13) 8 7.41 1H), 7.26 lOH), 6.49 1H), 5.20 1H) 5.04 LH), 5.00 2H), 4.08 lH), 1.49 6H), 0.82 12H).

Exame 22 Preparation of (2S.1 'S)-2-(benzvloxvcarbonyl'amino-4-methyl-N-[3'-methyl-1'-r2- (2-methvlproloxycarbonllhiazol-4-yllbutylpentanaiide Following the procedure of Example 20, except substituting isobutyl alcohol for benzyl alcohol, the title compound was prepared (0.075 1 H NMR (400 MHz, CDC13) 8 7.25 6H), 6.50 IH) 5.11 2H), 5.09 4.99 2H), 4.11 2H), 3.91 1H),2.02 1H), 1.70- 1.39 6H), 0.82 6H), 0.78 (m, 12H).

Emple 23 Preparation of (2R. I S)- 2 -(benzyloxycArbonvI)a1jno-N..fl'-( 4 -cabothxy ja 0 p 2-vi )ethyl 1- 4 -methylpentanaxnide Following the procedure of Example 19, except substituting N-tertbutoxycarbonyl-L-alanine for N-rert-butoxycarbonylglycine in step and N-Cbz- D-leucjne for N-Cbz-L-leucjne in step the title compound was prepared as white solid 135g, MS 448.2.

Example 24 Preparation of (2R. V R)-24--benzyloxyc rny)mno-N.1

Y-(

4 -carboethoxvthiazol- 2-vi )ethyl1l-methlentanaide Following the procedure of Example 19, except substituting N-terrbutoxycarbonyl-D-alanine for N-tert-butoxycarbonylglycine in step and N-Cbz- D-leucine for N-Cbz-L-leucine in step the title compound was prepared as white solid (0.l11Og, MS 448.2.

Example Preparation f(2S. 1 2 -arrinothiazol-4yl)3'methylbuil.2.

(benzloxyc ronlanomtyftnad To a stirring solution of the compound of Example 1 85 g, 1. 87 inmol) in,4 mL of ethanol was added thiourea 142 g, 1.87 mrnol). The solution was allowed to stir at rom temperatmr for 90 min. The solution was concentrated, the residue was dissolved in ethyl acetate and washed with saturated aqeous NaHCO 3 and saturated brine, then dried (MgSO 4 filtered, and concentrated. 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, 1

H

NMR (400 M&Z, CDC13) 867.36 (in, 5H), 6.30 (in, 2H1), 5.12 (mn, 3H), 4.95-4.91 (mn, 3H1), 4.16 (mn, 1H), 1.63 (in, 4H), 1.49 (mn, 2H), 0.93-0.89 (mn, 12H1).

Example 26 Preparation of (IS I-benzyloxycarbonvlamino)-3-methylbuyllthzol-2.

ylcarbonyll-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide a) N-benzyloxycarbonyl-L-leucinyl bromornethyl ketone 1l-methyl-3-nitro-lI-nitrosoguanidine (6.65 g, 45.2 rnxol) in ether (225 ml-) is coaled to 0 0 C. 40% sodium hydroxide is added slowly and the diazomethane is allowed to collect in the ether solution for 30 minutes at 0 0 C. The ether solution is then decanted and left at 0 *C.

N-Cbz-L-leucine 10 g, 7.6 mmol) was dissolved in THF (10 mL), cooled to -40 0 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 miL). After 15 min, the solution was filtered into the previously prepared 0 0

C

solution of ethereal diazomethane. The resulting solution was allowed to stand at 0 'C for 23 h. HBr (30% in acetic acid) (45.2 inmol, 9 mL) was added and the resulting solution was stirred at 0 *C for 5 min, then washed sequentially with 0. 1 N HC1, saturated aqueous NaHCO 3 and saturated brine, then dried (MgSO4), filtered and concentrated to give the title compound as a colorless oil (2.43 g, 94%).

b) (1 1 -benzyloxycarbonylamino- 1 -(2-carboethoxythiazol-4-yl)-3-methylbutane A solution of the compound of Example 26(a) (1.57 g, 4.58 inmol) and ethyl thiooxamate (0.61 g, 4.58 mmol) in ethanol (10 mL) was heated at reflux for 4 h.

The solution was then coaled concentrated and the residue was purified by flash chromatography on 230-400 mesh silica gel; .eluting with 1:4 ethyl acetate/hexanes, to give the title compound as a yellow oil (1.0 g, 'H NMR (400 NE&,

CDCI

3 867.41 IH), 7.34-7.31 (in, 5H), 5-.40 (di, lH), 5.10 1H), 5.05 IH), 4.98 1H), 4.48 2H), 1.80-1.76 (in, 2H), 1.57-1.53 (in, 1H), 1.44 3H), 0.95 3H1), 0.93 (di, 3H).

c) (I 1 -benzyloxycarb~onylamin o-lI -(2-hydrazinocarbonylthiazol--y)-3.

methylbutane A solution of the compound of Example 26(b) (0.30 g, 0.8 mmol) and hydrazine hydrate (0.40 g, 8.0 mrnol, 0.39 mL) in ethanol (8 mL) was allowed to stir at room temperature for 2 h. The solution was then concentrated to yieI4 the title compound as a white foam (0.28 g, 'H NMR (400 M1Hz, CDC1 3 8 8.29 IH), 7.37-7.35 (in, 5Hf), 5.18 IH), 5.09 (dd, 2H), 4.95 1H), 4.07 2H), 1.71 2H), 1.55 (mn, IH), 0.96 3H), 0.94 3H).

d) (1 1-benzyloxycarbonylamino)-3-methylbutyl]thiazo12..ylcarbonyl]-N.

(N-benzyloxycarbonyl-L-leucinyl)hydrazide A solution of the compound of Example 26(c) (100 mg, 0:'28 inmol), N-Cbz- L-leucine (80.5 mng, 0.30 inmol), I-( 3 -dixnethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.2 mng, 0.30 inmol) and 1-hydroxybeazotriazole (7.5 mg, 0.06 inmol) in DMF (0.6 inmol) was allowed to stir at room temperature for 18 h. The solution was diluted with ethyl acetate and washed successively with water, 0. 1 N HCl, saturated aqueous NaHCO 3 and saturated brine, then dried (MgSO 4 filtered and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1: 1 ethyl acetate/hexanes, to provide the title compound as a white solid (111.4.mg, mp 110- 112 *C.

Example 27 Preparation of N-benzyloxycarbonvI7--leucinv-N'benloxycbnylLleucinyvl L-leucinylhydrazide a) N-benzyloxycarbonyl-L-1eucinyl-L-leucine methyl ester Following the procedure of Example 26(d), except L-leucine methyl ester hydrochloride for (1 S)-l1-benzyloxycarbonylanuno. 1-(2-hydrazinocarbonyithiazol- 4-yl)-3-methylbutane, the title compound was prepared as a white solid (1.28 g, 'H NMR (400 MIRz, CDCI3) 8 7.37-7.32 (mn, 5H), 6.28 1H), 5.28 (mn, 3H), 4.61-4.58 (mn, 1H), 4.20 (in, 1H), 3.74 3H1), 1.69-1.54 (in, 611), 0.96-0.92 (in, 12H).

b) N-benzyloxycarbonyl-L-Ieucinyl-L-leucinylhydrazide Following the procedure of Example 26(c), except substituting Nbenzyloxycarbonyl-L-leucinyl-L-leucine methyl ester for (I 1benzyloxycarbonylamino-l1-(2-carboethoxythiazol-4-yl)-3-methylbutane, the title compound was prepared as a white solid (1.28 g, 100%). H NMR (400 MHz, CDCl3) 5 8.05 (br s, IH), 7.35-7.32 (in, 5H), 6.67 111), 5.50 1H), 5.11 (s, 2H), 4.46 (mn, lH), 4.21 (mn, 1H), 3.88 (br s, 2H), 1.64-1.51 (mn, 6H), 0.92-0.88 (in, 12H).

c) N-benzyloxycarbonyl-L-leucinyl-N'-benzyloxycarbonyl-L-leucinyl-Lleucinylliydrazide Following the procedure of Example 26(d), except substituting Nbenzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide for (I 1benzyloxycarbonylamino- 1-(2-hydrazinocarbonylthiazol-4-yl)-3-methylbutane, the title compound was prepared as a white solid (0.059 MS 662.1 Example 28 Preparation of (1 S)-N-f2-f(I1-benzloxycarbonylamino)-3-metlbutyllthiazol-4vlcarbonyll-N'-(N-benzvloxycarbonl-L-leucinyl~hydrazide a) N-tert-butoxycarbonyl-(L)-leucinamide To a solution of N-tert-butoxycarbonyl-(L)-leucine (7.0g, 28. 1immol in dry THF (IlOOmL) at -4.0*C was added isobutyichioroformnate (3.8g, 28. 1Immol) and Nmethylmorphiline 59nimol). After 15 minutes of stirring, ammonia was bubbled through the mixture for an additional 15 minutes, then warmed to room temperature and allowed to stir for 2 hours. 'Mixture filtered and filtrate concentrated in vacuo to yield title compound as a white solid 28.Onunol).

'HNMR (400M&z, CDCI 3 8 6.38 (br s, 1H), 5.79 (br s, 1H1), 5.04 (br d, IH), 4.13 (in, 1H), 1.71-1.49 (mn, 3H), 1.39 9H), 0.92 (dd, 6H).

b) N-rert-butoxycarbonyl-(L)-leucinethioamide To a stirring solution of the compound of Example 26(a) 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 evaporated and the residue chromatographed (silica gel, 12% ethyl acetate/hexane) to give the title compound as a white solid (5.4g, 'HNMR (400MHz, CDCI 3 8 8.54 (br s, 1H), 7.97 (br s, 1H), 5.28 (br d, 1H), 4.52 1H), 1.72-1.58 3H), 1.40 9H), 0.92 6H).

c) -(tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3- methylbutane..

The compound of Example 26(b) (5.4g, 21.7 mmol) was stirred in dry acetone (100mL) under argon at -10 0 C. Ethylbromopyruvate (4.7g, 23.9mmol) was added and stirred for Ih at -10*C. The solution was poured into a well stirred mixture of chloroform and water and then into saturated sodium bicarbonate solution. The organic phase was separated and the aqueous layer extracted with chloroform. The combined organic extracts were dried over MgSO,, filtered and concentrated to an oil. The oily residue was treated with TFAA (5.0g, 23.9mmol) and pyridine (3.8g, 47.8mmol) in dichloromethane for lh at -20"C. Excess solvent was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate and 1.ON KHSO, until pH 7. The solution was dried over magnesium sulfate, filtered and concentrated to an oil which was chromatographed (silica gel, 7.5% ethyl acetate/hexane) to give the title compound as a tan solid (4.5g, 'HNMR (400MHz, CDCI,) 8 7.98 1H), 5.04 (br d, 1H), 4.95 1H), 4.31 2H), 1.88 1H), 1.63 2H), 1.40 9H),1.32 3H), 0.85 (dd, 6H).

d) (1 S)-1 -(Benzyloxycarbonyl)amino- 1-( 4 -carboethoxythiazol-2-yl)-3-methylbutane The compound of Example 26(c) (0.250g, 0.731 mmol) was dissolved in 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 triethylamnine 7 39g, 7.3 1Immol) followed by benzyl chloroformate (1 .2g, 7.3 Immol). The solution stirred at room temperature for 2h when paAition between ethyl acetate/watet. The organic layer was washed with brine, collected, dried (MgSO 4 and concentrated to a residue that was chromatographed (silica gel, 15% ethyl acetate/hexane) to give the title compound as an oil 198g, 'HNMR (400M4Hz, CDC 3 5 8.01 1H), 7.32 (in, 5.51 (br d, 1H), 5.14 (mn, IH), 5.10 2H), 4.37 2H), 1.93 (mn, lIH), 1.81-1.67 (mn, 2H), 1.39 3H), 0.95 (mn, 6H).

e) (1 1-benzyloxycarbonylamino)-3-methylbutyllthiazol-4-ylcarbonyl]-N.

(N-benzyloxycarbonyl-L-leucinyl)hydrazide Following the procedure of Example 26(c)-lI(d), except substituting I- (Benzyloxycarbonyl)arnino-1I-(4-carboethoxythiazol-2-yl)-3-inethylbutane for I -benzyloxycarbonylamino- 1-(2-carboethoxythiazol-4-yl)-3-inethylbutane in step the title compound was prepared. MS (MWT): 610.0 Example 29 Preparation of 2.2'-(N.N'-bis-benzyloxycarbonyl-L-Ieuciny~carbohydr-azide To a stirring solution of N-Cbz-L-leucine (Chemical Dynamics Corp.) (2.94 g, 11. 1 minol) in 22 uiL of DMF was added carbohydrazide (0.5 g, 5.6 inmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.13 g, 11. 1 nimol) and I-hydroxybenzot-iazole (0.3 g, 2.2 inmol). After stirring at room temperature for 22 h, the solution was poured into 500 mL of water. The precipitate was collected by vacuum filtration and washed with water (4 X 150 niL and dichloroinethane (4 X 150 inL), then dried under vacuum to provide the title compound as a white solid (1.49 g, MS(ESI): 607.1 Example Prep~aration of 2 2 '-(N.N'-bis-cyclohexylacetvl)carbohycjrazide Following the procedure of Example 29, except substituting cyclohexyl acetic acid for N-Cbz-L-leucjne, the title compound Was prepared (0.4 g, MS(ESI): 339.3 Example 31 Preparation of 2 2 '-(N.N'-bis-4-methylpentanoyl)c-arbohyd-jzidC Following the procedure of Example 29, except substituting 4methylpentanoic acid for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.2 12 g, MS(ESI): 287.3 Example 32 Prep~aration of 2.'(.'bs2ccoatlctl -royrzd Following the procedure of Example 29, except substituting cyclopentylacetic acid for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.345 g, MS(ESI): 311.2 Example 33 Preparation of 2 2 '-(N.N'-bis-benzyoxycarbongvc-inyl)chyrazde Following the procedure of Example 29, except substituting N-Cbz-Glycine for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.719 g, 91015). MS(ESI): 473.1 Example 34 Preparation of 2 2 '-(N.N'-bis-acey1li -euciny)caohyraid Following the procedure of Example 29, except substituting N-aceiyl-Lleucine for N-Cbz-L-leucine, the title compound was prepared as a white solid 153 g, MS(ESI): 401.3 Example Preparation of benzyloxycarbonvl-L-alanvl)carbohydrazide Following the procedure of Example 29, except substituting N-Cbz-Lalanine for N-Cbz-L-leucine, the tidle compound was prepared as a white solid (0.762 g, 9 MS(ESI): 501.1 Example 36 Preparation of 2-(N-benzvloxvcarbony-L-euciny)-2'-fN'-(4methylpentanoyhlcarbohydrazide a) N-benzyloxycarbonyl-L-leucine methyl ester To a solution of leucine methyl ester hydrochloride (5.0 g, 27.5 mmol) in 1 ,4-dioxane (50 rnL) 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 temperature for 24 hours when partitioned between ethyl acetate and water. The organic layer was collected, dried (MgSO 4 filtered and concentrated to give the title compound as a colorless oil (7.67 g, 100%). 'HNMR (400M&z, CDC 3 8 7.39 (in, 5H), 5.38 2H), 5.12 2H), 4.42 (mn, IH), 3.75 3H), 1.73 1.50 (in, 3H), 0.94 (in, 6H).

b) N-benzyloxycarbonyl-L-leucinyl hydrazide To a solution of the compound of Example 36(a) (7.67 g, 27.5 inmol) in methanol (40 mJL) was added hydrazine inonohydrate (13.5 g, 270 inmol). The solution was stirrd at room temperature for 24 hours when partitioned between water and ethyl acetate. The organic layer was collected, dried (MgSQ 4 filtered and concentrated to give the title compound as an off-white solid (7.67 g, 100%).

'HNMR (400MIHz, CDCI,) 8 8.14 1H), 7.38 (in, 5H), 5.64 IH), 5.09 (dd, 2H), 4.20 (in, 1H), 3.81 (s br, 2H), 1.69 1.51 (in, 3H), 0.92 (dd, 6H).

c) 1 -benzyloxycarbonylamino-3-inethyl- 1-(1 ,3,4-oxadiazol-2-onyl)butane A solution of the compound of Example 36(b) (1.0 g, 3.58 iniol) in methylene chloride (1 2mL) was added dropwise to a solution of 4niruophenylchloroformate (0.361 g, 1.79 mmol) in methylene chloride (8 mL) at 0°C. The solution warmed to room temperature and stirred for one hour when partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaHCO 3 then collected, dried (MgSO,), filtered and concentrated to a residue which was chromatographed (20% ethyl acetate/hexane) to give the title compound as a pale yellow solid (0.322 g, 'HNMR (400MHz, CDCI1) 6 9.18 1H), 7.38 5H), 5.13 3H), 4.79 1H), 1.71 3H), 0.98 (dd, 6H).

d) 4 -methylpentaneyl hydrazide Following the procedure of Example 36(b) except substituting ethyl isocaproate for benzyloxycarbonyl-L-leucinyl methyl ester, the title compound was prepared as a white solid (1.8 g, 100%). 'HNMR (400MHz, CDCI,) 6 7.48 (s br, 1H), 3.62 (s br, 2H), 2.13 2H), 1.51 3H), 0.85 6H).

e) 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-[N'-(4-methylpentanoyl)]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 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, MS 436.2.

Example 37 Prep~aration of bis-(Cbz-leucinvl)-lI.3-diamino-propan-2-one Cbz-leucine (500 mg, 1.88 mmol), EDCI (558 mg, 1.88 mmol) was dissolved in DMF (4.0 ml) with l,3-diamino-propan-2-ol (85 mg, 0.94 mmol) and Hunig's base (0.3 ml, 1.88 mmol) and was stirred at RT overnight. The reaction was diluted with EtOAc (20 ml) and was extracted with water (2 x 20 ml). The combined organics were dried with magnesium sulfate, filtered, concentrated in vacua. The intermediate was then dissolved in acetone (4.0 ml) and Jones reagent ml, 1.5 M) was added dropwise and the reaction was stirred at RT overnight.

The excess Jones reagent was then quenched with isopropanol (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 magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOI methylene chloride) to give the title compound as a white solid (410 mg, MS(ES) M+W=583, M+Na*--605.

Ex=Re 3 Preparation of bis- 1.3-(4-p2henoxy-benzol-diamuno-propan-2-one Following the procedure of Example 37, except substituting "4-phenoxybenzoic acid" for "Cbz-leucine", the tidle compound was prepared: MS(ES) M+W*=48 1, M+Na*=503.

Preparation of 1 -(Cbz-leucinyfl-amino-3-(aceyl-leucinfl-axniino-2ropan- 2 -one Following the procedure of Example 37, except substituting "a mixture of N- Ac-leucine and Cbz-leucine" for "Cbz-ieucine", the title compound was prepared: MS(ES) M-t-W=49 1, M+Na=5 13.

Example Preparation of 1 -(Cbz-leucinyl )-amino-3-(Cbz-2lutamvl-t-butyI ester)-arnino.

p2ropan- 2-one Following the procedure of Example 37, except substituting "a mixture of Cbz-glutamnic acid gamma t-butyl ester and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+W=655.

ExampLe_ 41 Preparation of 1-Czluiy)aio3(b-ltml-mn-rla--n 1 -(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-tbuty ester)-aino-propan2one mg, O.OO7mxnol) was dissolved in a solution of trifluoroacetic acid 0.5 ml) and methylene chloride (0.5 ml), then was stirred at RT for 2 h, the reaction was dilutied with toluene (10 ml) then was concentrated in vacuo to provide the title compound: MS(ES) M+ff=599. Example 42 Preparation of bis- 1 3 -(Cbz-leucinyl)-diamino-(S)-.butanone2one a) Cbz-leu-ala-bromo methyl ketone Isobutyl chloroforrnate (1.46 ml, 11.3 rmnol) was added dropwise to a solution of Cbz-leu-ala-OH (4.0 g, 11.3 inmol) and N-methyl morpholine (1.24 ml, 11.3 rnmol) in THF (40 ml) at -40 degrees C. The reaction was stirred 15 min, then was filtered, and was washed with ether. Diazomnethane (40.1 mnmol from 5.9 g of 1 -methyl-3-nitro-nitroso-guanidine and 18 ml of 40% KOH in 150 ml of ether) in ether (200 ml) was added and the reaction was placed in a refrigerator overnight.

30% HIBr/ AcOH (7 ml) was added dropwise to the crude reaction mixture and was stirred 5 minutes. The solution was washed with aqueous citric acid (50 ml x 2), saturated aqueous sodium bicarbonate (3 x 150 ml), then brine (100 ml). The combined organics were dried with magnesium sulfate, filtered, and concentrated in vacuo to give a solid which was used in the next step without purification, MS(ES) M+Hr=413 and 415, M+Na'=435 and 437.

b) Cbz-leu-leu-azido methyl ketone Cbz-leu-ala-bromo methyl ketone (650 mg, 1.6 mmol) was dissolved in DMFf (7 ml), then sodium azide (122 mg, 1.9 mmol) and potassium fluoride (137 mg, 2.36 mimol) was added and the reaction was stirred overnight. The reaction was partitioned between EtOAc and water, then the combined organic extracts were dried with magnesium sulfate, filtered, concentrated in vacuo, then chormatographed MeOH, methylene chloride, silica gel) to provide the title compound as a white solid (330 mg, MS(ES) M+Na*=398.

c) Cbz-leu-2-amiino-4-azido-propan- 3 -oI Cbz-leu-leu-azido methyl ketone (330 mg, 0.9 mmol) was dissolved in EtOH (5 mlJ) and sodium borohydride (100 mg, 2.65 mniol) was added at RT and the reaction was stifred for 15 minutes. The reaction was quenched with water (10 ml) and was extracted with EtOAc (25 ml). The combined organic extracts were dried with magnesium sulfate, filtered, concentrated to give the title compound without further purification, MS(ES) 378, M+Na*=400.

d) Cbz-leu-2-amino-4-amino-propa1- 3 -ol Cbz-leu-2-amino-4-azido-propan- 3 -ol (300 mg, 0.8 mmol)was dissolved in MeOH (4 ml) and triethyl arnine (0.33 ml, 2.4 mxnol), propan-1,3-ditbiol (0.35 ml, 3.82 mmol) was added and the reaction was stired overnight, concentrated in vacuo, then the white solid was washed with hexane providing the title compound which was used in the next reaction without further purification, MS(ES) M+H*=352.

e) bis- I ,3-(Cbz-leucinyl)-diamrino-(S)-butalone- 2 -ol Cbz-leu-2-amino-4-arniino-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 ml, 0.8 rnmol) and HBTU (151 mg, 0.4 minol) and was stirred overnight. The reaction was partitioned between EtOAc and water, the combined organics were dried with magnesium sulfate, filtered, concentrated to give the title compound, MS(ES) M+Wr=599, M+Na+=62 1.

f) bis- l, 3 -(Cbz-leucinyl)-diamino-(S)-.butanone-2one Bis- 1 3 -(Cbz-leucinyl)-cdiamino-(S)-butanone-2-oI (240 m'g, 0.4 mnnol) was dissolved in acetone (2 ml). Jones reagent (0.5 ral, 1.5 M) was added dropwise and the reaction was stirred at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc ml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/ methylene chloride) to give the title compound as a white solid (80 mg, 33 MS(ES) M-W*=595.

Exaple43 Preparation of -(Cbz-leucinyl )-ain- 3 (Cbz-1phenylaanyll-anino-1roan2one Following the procedure of Example 37, except substituting "a mixture of Cbz-phenylalanine and Cbz-leucine" for 'Cbz-leucine", the title compound was prepared MS(ES) M+W*=617, M-iNa*-639.

Example 44 Prepartion of 1-Czluitl-mn--(b-oluiy) n Following the procedure of Example 37, except substituting "a mixture of Cbz-norleucine and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+H*=583, M-sNa=-605.

100 Example Preparation of 1 -(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propa:2.one Following the procedure of Example 37, except substituting "a mixture of Cbz-norvaline and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+W=569, M+Na*=59 1.

Example 46 Preparation of bis- 1.3-(Cbz-leucinfl)-diamino-5-methvl-(S)-hexan-.2-one a) bis- 1, 3 -(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one Following the procedure of Example except substituting "Cbz-Ieuleu-OH" for "Cbz-leu-ala-OH" the title compound was prepared: MS(ES) M+W=-639.

Example 47 PReparation of 1 -(acetyl-leucinyfl-amino- 3-( 4 -p2henoxy-benzoyvh-amino-propan-2- Following the procedure of Example 37, except substituting "a mixture of N- Ac-leucine and 4-phenoxy-benzoic acid for "Cbz-leucine", the tidle compound was prepared: MS(ES) M+W-=440.

Example 48 PEparation of I -(Cbz-homo-leucinvl)-aniino-(Cbz-1eucinyfl-3-anino-propan-2 -one Following the procedure of Example 37, except substituting "a mixture Cbzhomo-leucine and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+H*=597, M+Na*=6 19.

Example 49 Preparation of bis- 1. 3 4 3 -chi oro- 2 -!qano-Vhen2N)L-phenXI sulfonamido).roa 2-one 4 3 -Chloro-2-cyano..phenoxyy-phenyl sulfonyl chloride (1.3 g, 4 mmol, Maybridge) was added to a solution of l, 3 -diamino-prpan.2oI 18 g, 2 mmol) in DMF (10 mnl)/ N-methyl morpholine (0.44 nil, 4 rnmol) and was stirred 3h at RT.

The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude bis- 1,3- 4 3 -chloro-2-cyano-phenoxy).phenyl sulfonamido)-propan-2ol (0.28 g, 0.4 mrmol) was then dissolved in acetone (1.0 nil) and Jones reagent (0.44 nil, 1.5 M) .was added dropwise, and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 nil), then the reaction was diluted with EtOAc (20 ml]) and was extracted with water (2x 20 nil) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chronlatographed (silica gel, 2-5% MeOHI methylene chloride) to give the title compound as a white solid (90 nmg, MS(ES) M+ W*=671, M+Na*=693.

Example Preparation of bis- l.

3 4 -phenoxy-phenyl sulforiamido)-propan..2-ne Following the procedure of Example 49, except sub stituting 4-phenoxyphenyl sulfonyl chloride for 4- 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride, the title compound was prepared: MS(ES) M-Wr=55 1.

Example 5 1 Preparation of 1 -(Cbz-leuc inyl) -amino- -chloro-2-cyano-phenoxy)-p~hen y sulfonamido)-propan-2-ofle Cbz-leucine (660 mg, 2.5 minol), EDCI (480 mg, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DMF (10 mld) with 1,3-diamino-propan-2-ol (225 mg, 2.5 mnmol) and was stirred at RT overnight. N-methyl morpholine (0.41 ml, 3.75 mmol) was added followed by 4-(3-Chloro-2-cyano-phefloxy)-phenyl sulfonyl chloride (820 mg, 2.5 mmol, Maybridge) was added and the reaction was stirred 3h at RT. The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude 1 (b-ecnl-mn--4(-clr--yn-hnx)pey sulfonamido)propan-2-ol was then dissolved in acetone (5.0 ml) and Jones reagent (3.0 ml, M) was added dropwise. and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 nml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromarographed (silica gel, 2-5% MeOHI methylene chloride), then the product was triturated from methylene chloride to give the title compound as a white solid (26 mg, MS(ES) M+ W=-627.

Exgle1L2 Preparation of I- -Cz-leucinfl)- amino-3-(tosyl-armino)-propan-- 2 -One Following the procedure of Example 51, except substituting tosyl chloride for 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M-H*-488.

Example 53 Preparation of (Cbz-Ieucinyl )-amino-3-((4-phenox-P-henvl)-sulfan~mdo) p2rop~an-2-one Following the procedure of Examnple 51, except substituting 4 -phenoxyphenyl-sulfonyl chloride for 4 3 -Chloro- 2 -cyano-phenoxy)-pheny sulfonyl chloride, the title compound was prepared: MS(E-S) M+Jf=568, M+Na'=590.

Example 54 :7Prep~aration of 11-Czlui.l-mn--2diezfrnu aio~zpn2 one Following the procedure of Example 51, except 2 -dibenzofuransulfonyl chloride for 4 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride, the title compound was prepared: MS(ES) M+W=566, M-i-N&=588 Example Preparation of I (b-ooluiy)-mn--(-iezfrnufnnid) D2rogan-2-one Following the procedure of Example 5 1, except 2-dibenzofuransulfonyl chloride for 4- 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride and Cbzhomo-leucine for Cbz-leucine, the title compound was prepared: MS(ES) M+Na*--602.

Example 56 Preparation of I -(Cbz-feucinl)-amino-3-(2dibenzofuransulfona-do)(S)-butn 2 a) 1 -(Cbz-leucinyl)-ainno-3-(2-dibenzofuransulfonamdo)-(S)-butan.2-oI Cbz-Ieu-2-amino-4-amino-propan-3-oI (150 mg, 0.42 rnmol, as described in Example and 2-dibenzofuransulfonyl chloride were dissolved in DMF (2 nil) and N-methyl morphonline (0.09 ml, 0.84 mmol) and were stired overnight.

The reaction was partitioned between EtOAc and water, the combined organics were dried with magnesium sulfate, filtered, concentrated to give the title compound, MS(ES) M+W=582, M+Na=6-<04.

b) I -(Cbz-leucinyl)-amino-3-(2 -dibenzofiransulfonaido)(S)-butan2 -one 1 -(Cbz-leucinyl)-amnino-3-(2-dibenzofuransulfonamdo)-(S)-utan..2 0 o (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction was stirred at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 nml), 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 magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOHW methylene chloride) to give the title compound as a white solid (70 mg, MS(ES) M-W*=578.

105 Example 57 Preparation of (S)-Phenvimethyl [1 -fr3-rBenzvloxycarbonl-leucinl-armjno-2.

oxopropyll- I -(benzyl )aminolcarbonyll-3-methylbutvllcarbamate a) 2-hydroxy-3-azido-propanol Sodium azide (1.7 g, 26 mmol) was added to a solution of glycidol (Aldrich, 1.3 g, 17.5 mmol) in MeOH (45 ml) and water (5 ml) and was heated to 65 degrees C for 4 h. The reaction was diluted with water (25 ml), extracted with EtOAc (2 x ml); the combined organic layers were extracted with water (2 x 50 ml), then brine (50 mnl), then were dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 30 EtOAc/ hexanes) to produce a white solid (1.37 g, MS(ES) M+H+=l 18.4.

b) 2-hydroxy-3-azido-propan-tosylate Tosyl chloride (2.3 g, 12 mmol) was added to a solution of 2-hydroxy-3azido-propanol 17 g, 10 mmol) and trietbyl amnine (3.6 g, 36 mmol) in methylene chloride (50 ml) and was stirred at RT for 4h. The reaction was diluted with water ml), extracted with EtOAc (2 x 50 nil); the combined organic layers were extracted with pH 7 buffer (2 x 50 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 30 EtOAc! hexanes) to produce a white solid (1.2 g, MS(ES) M+H+=272.2.

c) 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-azido-propantosylate C) 2-Hydroxy-3-azido-propan-tosylate (1.2 g, 4.4 mmol) was added to a slurry of Ellinan dihydropyran polymer (cf. Scheme 1) (150 mg, 0.3 mxnol) in CICH2CH2CI (25 ml), then pyridinium p-toluenesulfonate (0.84 g, 4.4 mmol) and was agitated 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-I1;. Magic Angle Spinning IlH NMR: d 8.0, 7.4, 5.0,3.4.

106 d) 2-(Merrifield polymer- 6 -(oxymethylene-tetrahydropyran-acetal>3 -azidopropan-N-benzyl-amrine Benzyl amine (0.32 g, 3 mxnol) was added to a slurry of 2-(Merrfield poye--oyehln-erhdoya-ctl--zd-rpntslt (500) mg, 1 mmol) in N-methyl pyrolidinone (25 ml) and was and was agitated at degrees C by gentle bubbling with argon. The polymer was filtered, washed with DMLF (2 x 10 ml), then MeOH (20 ml), then methylene chloride (4 x 20 ml); LR 2105cm-i1; Magic Angle Spinning I1H NMR: d 7.1, 4.7, 4.0, 3.8.

e) 2-(Merri-field poye--oyehln-erayrprnaea)3aio propan-N-benzyl-(Cbz-leucinyl)-amine Cbz-leucine (0.82 g, 3.0 mumol) was added to a slurry of 2-(Merrifield poye--oyehln-erhdoya-ctl--zd-rpnNbny-mn (120 mg, 0.22 mxnol) in DMF (10 ml), dilsopropyl ethyl amnine (1.2 ml, 6 mmol) and HATU (Perseptive Biosystems, 2.2 g, 6 rnmol) and was shaken at room temperature overnight. 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); JR 2 105,1735, 1630 cm-i1;. Magic Angle Spinning I H NMR: d 7.2, 4.7, 4. 1.

f) 2-(Merrifield polymer- 6 -(oxymethylene-tetahydropyranaceta).3.min,..

propan-N-benzyl.(Cbz-1eucinyl)-anwjne Propanedithiol (0.5 ml, xx mmnol) wa s added to a slurry of 2-(Merrifield poye-(xmtyeettaymya-ctl--zd-rpnNbny-Cz leucinyl)-amine (150 mg, 0.27 mnmol) in MCOH (5 ml) and tiiethylaniine (0.5 ml) and was gently rocked overnight. The resin was filtered, washed with MeOH (2 x ml), then with DMP (1 x 10 ml), then with methylene chloride (5 x 20 ml), and was dried in a vacuum oven overnight; JR 173 5, 1640, cm-1;.

g) 2-(Merrifield poIymer- 6 -(oxyme thyene tehydropyra ace a) 3 -(Cbzleucinyl)-annopropanNbnzyl(bzleucinyl)-amne Cbz-Ieucine (0.82 g, 3.Ommol) was added to a slurry 2 -(Merrifield polymer- 6 -(oxymethyentet rahyropyranea)3ano-petan-propnl( uciy) amine (150 mg, 0.27 nmnol) in N-methyl pyrollidinone (10 ml), diisopropyl ethyl amine (1.2 ml, 6 mnnol) and I-BTU (2.2 g, 6 mmol) and was shaken at room temperature overnight. The resin was filtered, washed with DMF (3 x 0o ni). The above procedure was repeated, and the final resin washed with MeOH (2 x 10 ml), then mnethylene chloride (5 x 20 ml); Magic Angle Spinning I H NMR: d 7.6, 7.4, 5.1, 5.0, 3.4, 0.8.

h) 1 -N-benzyl- IlCbz-leucinyl-amino-3-Cbz..leucinylano.propan 2 -oI 2-(Merrifield polymer- 6 -(oxymethylenetetrahydropanetal)3(bzlecnl-mn poa--ezl(b-ecnl-mn (150 mg, 0.27 mmol) was shaken as a slurry with 85:5: 10 TFA/ water/ mnethylene chloride (5 nil) for 4h at RT.

The solution was filtereed and the filtrate was concentrated in vacuo, then chromatographed (silica gel, 5% MeOHJ methiene chloride) to produce a yellow solid (65 mg, MS(ES) M+H+=675.lI.

i) 1 -N-benzyl- Il-Cbz-leucinylanino3Cbzleucinylmnopropan-2-ne 1-N-benzyl- l.Cbz-leucinyI-an-dno-3-Cbz.1euciny[ mio-propan2ol mg, 0.96 rnmol) was dissolved in acetone (5 inl) and Jones reagent (2 mI,excess) was added dropwise at room temperature and the reaction was stirred overnight. The excess Jones reagent was then quenched with isopropanol (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 nil), then brine (10 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce a yellow solid, which was chromatographed (silica gel, 5O%EtOAc/Hexanes to produce a white solid (l6.8mg, MS(ES) 673.1 Example 58 Preparation of (S)-Phenylmethyl 1 -rr3-r(2-dibenzofuranvlsulfon1)alno.2-.

oxoprol l]- 3 -(benzyl)anminolcarbonvll-3-methvlbutyllcarbanate a) N-( 2 -hydroxy-3-N-benzylamino.propyl)phthalirmde N-(2,3-Epoxypropyl)phthalimide (A ldrich, 2.03 g, 10 minol) was reluxed with beazyl amine (1.07 g, 10 mmol) in isopropanol (15 ml) for 3h. The reaction was cooled to RT, then concentrated in vacuo, producing a white gum, which was triturated with MeOH, then filtered producing a white solid (0.48 g, MS(ES) 311.

b) N-( 2 -hydroxy-3-(N-benzy1-2-dibenzofuransulfonamide)-propyl)phthalimide N-(2-hydroxy-3-N-benzylamino-propyl)phthalimide (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 (Wx2 ml), the combined organic layers were extracted with water (3 x 20 ml), then brine (20 ml), then were dried with, magnesium sulfate, filtered, concentrated in vacuo to produce an oil, which was chromatographed (silica gel, 30% EtOAc/ hexanes) to produce a white foam (0.37 g, MS(ES) M+W*=541, MS(ES) M+Na'=563, MS(ES- negative) M+HCO 2 585 c) 2 -hydroxy-(N-benzyl-2.dibenzofuransiulfonanide)-propy..3-an-mne N-2hdoy3(-ezl2dbnofrnufnmd)poy~hhlmd (0.37 g, 0.69 mmol) was refluxed with hydrazine hydrate (0.34 g, 6.85 mmol) in MeOH (7 ml) for 1.5 h. The reaction was cooled to RT, then was concentrated in vacuo. The resulting white solid was triturated with MeOH, then filtered to produce the desired product as a white solid (0.27 g, MS(ES) M+W*=41 1.

d) Cbz-leucinyl-(2-hydroxy-(N-benzyl2.dibenzofuransulfonamiide))propyl-3 amnine 2-yrx-Nbny--iezfrnufnnLd)poy--mn (0.2 g mmol) was stirred with Cbz-leucine 13 g, 0.5 nol) 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 mi), extracted with EtOAc (2x20 ml). A solid that was insoluble in both layers was filtered off. The combined organic layers were extracted with water (2 x 20 ml), then brine (20 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce a white solid, which was used in the next reaction without further purification; MS(ES) M+I= 658, MS(ES) M+Na'= 680.

e) (S)-Phenylmethyl 3 2 -dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3- (benzyl)amino]carbonyl]-3-methylbutyl]carbamate Cbz-leucinyl-(2-hydroxy-(N-benzyl-2-dbenzofuransulfonade))propyl3 adhine (0.16 g, 0.244 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, M) was added added and the reaction was stirred overnight. The excess Jones reagent was then quenched with isopropanol (1 ml) and the reaction was diluted.

with water (10 ml) and was extracted with EtOAc (2 x 20 ml). The combined organic layers were extracted with water (2 x 20 ml), then brine (20 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce a white solid, which was chromatographed (silica gel, 1:1 EtOAc/ hexanes) to produce a white solid (0.14 g, MS(ES) M-FT=654, MS(ES) M+C1*=690,

MS(ES)

M+HCO

2 700.

Example 59 Preparation of (S)-Phenvlmethvl l -1rr13-r(2-dibenzofuranvlsulfonvl)aminol-2 oxopropvll-3-(4-pvridinvlmethylaminolcarbonyl-3-methylbutvylcarbamate Following the procedure of Example except substituting "4pyridyl methyl amine" for benzylamine" and, the title compound was prepared; MS(ES) M+W=657.

Example Preparation of I -rff3- f(2-dibenzofuranylsulfonvl )aminoL-2-oxopropv!Lv3(4pyridinvlmethyl) benzamnide Following the proc:edure of Example except substituting "benzoic acid" for "Cbz-leucine", the title compound was prepared; MS(ES) M-I-=51 1, MS(ES) M+C]I=547.

Example 61 Preparation of (S)-Phenylmethyl I -[rf3-r(2-dibenzofuranysulfonl)aminol.2 oxopropyll- I 4 -pyridinylmethyl)aminolcarbonyll-3-methvlbuwllcarbam~ate Following the procedure of Example except substituting "4pyridyl methyl amine" for benzylamine" and "Cbz-leucine and HBTU" for "2dibenzofuransulfonyl chloride and "2-dibenzofuransulfonyl chloride for "Cbzleucine and HBTU", the title compound was prepared; MS(ES) M+W=-657.

Ekaiml 2 Preparation of 2-rN-(N-beazyloxycarbonyl-L-leucinylvk-2'-rN'-(4phenoxyphenylsulfonyfllcarbohydrazide a) N-benzyloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester hydrochloride (2.0 g, 1 l.Omniol) in 1,4-dioxane (20 mL) was added Na 2

CO

3 (12.1 ml, 2M in water) followed by benzylchloroformate (1.96 g, 1.5 inmol). The mixture was stirred at room temperature for 4h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated to yield the title compound as a colorless oil g, 100%). 1 H NMR (400 M&z,

CDCI

3 8 7.34 (in, 5H), 5.27 1H), 5.12 2H), 4.41 2H), 3.75 3H), 1.65 (in, 3H), 0.96 (mn, 6H).

b) N-benzyloxvcarbonvl-L-leucinylhydrazide To a stirring solution of the compound of Example 62(a) (3.1 g, 11.0 mmol) in 15 rnL of methanol was added hydrazide hydrate (5.9 118 mmol). The solution was stirred at room temperature for 1 6h then concentrated to yield the title compound as an off-white solid (3.1 g, 100%). MS(ESI): 280.2 c) (1 I -benzyloxycarbonyl amino- 3-methyl- 1 3 4 -oxadiazol -2-on-5 yl) butane To a stirring solution of the compound of Example 62(b) (3.0 g, 10.8 mmol) in toluene (50 rnL was added phosgene (56 m.L, 1.93M in toluene). The solution was'heated at reflux for 4h then concentrated to yield the title compound as a pale yellow foam (3.15 g, MS(ESI): 306.1 d) 2 -(N-(N-benzyloxycarbonyl-L-leucinyl)]carbohycirazide To a stirring solution of the compound of Example 62(c) 147 g, 0.482 mmol) in 2 mL of methanol was added hydrazine hydrate (0.24 1 g, 4.82 mmnol).

The solution was stirred at room temperature for 24h then concentrated and purified by column chromatography (silica gel, xnethanolldichloromethane) to yield the title compound as a white foam (0.097 g, MS(ESI): 338.2 e) 2 -[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4.

phenoxyphenylsuilfonyl)]carbohydrazide To a stirring solution of the compound of Example 62(d) (0.097 g, 0.288 mmol) in 2 m. of DMF was added pyridine (0.046 g, 0.576 mmol) followed by 4phenoxyphenylsulfonylchloride 155 g, 0.576 mmol). The solution was stirred at room temperature for 16h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated.

The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.052 g, 32%).

MS(ESI): 570.1 Example 63 Preparation of 2 N-(N-be nzvloxyc arbonvl-L- al any1) 2'-fN- (N-benzy loxyc arbonvlI L-leucinyl) icarbohydrazide To a stirring solution of the compound of Example 62(d) 100 g, 0.297 mnrnol) in 2 ml of DMF was added N-benzyloxycarbonyl-L-alamne (0.070 g, 0.312 mmol), 1 -hydroxybenzotriazole (0.008 g, 0.059 mmol), and 1-(3dimethylaminopropyl)-3-ethylcarbodiirnide hydrochloride (0.060 g, 0.312 mmol).

After stirring at room temperature for 16 h, the solution was poured into 150 mL of water. The precipitate was filtered and washed with water (150 mL) and dried under high vacuum to yield the title compound as a white solid (0.062 g, 39%).

MS(ESI): 543.1 Exmpe 6 Preparation of 2-[N-4N-benzyloxycar-bonyl-L-leucinyl)1-2'-rN'-(4phenylbenzoyl')lcarbohydrazide Following the procedure of Example 63, except substituting 4-phenylbenzoic acid for N-benzyloxycarbonyl-L-alanine. the title compound was prepared as a white solid 121 g, MS(ESI): 518.1 xpe6 Preparation of 2-fN-fN-benzloxvcarbonyl-L-leucinyl)1-2'-rN'-(4methoxybenzofllcar bohydrazide Following the procedure of Example 6 3, except substituting 4methoxybenzoic acid for N-benzyloxycarbonyli-L-alanine the title compound was prepared as a white solid (0.057 g, MS(ESI): 472.1 Example 66 Preparation of 24[N-(N-benzvloxycarbonyl-L-eucinvtl)1..2'.rN-(4phenoxybenzoyl )lcarbohydrazide Following the procedure of Example 63, except substituting 4phenoxybenzoic acid for N-benzyloxycarbonyl-L-alanine the title compound was prepared as a white solid 102 g, MS(ESI): 534.1 Example 67 Preparation of 2-(N-acetyl)-2'-fN'-(N-benzyloxvcarbonyl-L leucinyflicarbohydrazide To the compound of Example 62(d) 100 g, 0. 297 mniol) was added acetic anhydride (0.303 g, 2.97 minol). The solution was stirred at room temperature for 1 6h then concentrated to an off-white solid which was washed with dichloromethane to yield the title compound as a white solid (0.086 g, 76%).

MS(ESI): 380.1 Example 68 Preparation of 2- FN-(N-acetyl-L-leucinyl)1-24-N'-(N-benzloxycarbonyl.Lalanfllcarbohydrazide a) 2 -[N-(N-benzyloxyc.arbonyl-L-alanyl)]carbohydrazide Following the procedure of Example 62(a)-62(d), except substituting Lalanine ethyl ester hydrochloride for L-leucine methyl ester hydrochloride in step: the title compound was prepared as a pale yellow foam (1.1I g, 3.8 mmol).

MS(ESD: 296.2 b) 2 -[N-(N-acetyl-L.leucinyl)-2'[N'-(N..benzyloxycarbonyl-L alanyl)]carbohydrazide To a stirring solution of the compound of Example 63(d) 150g, O.508mxnol) in DMF (2rnL) was added N-acetyl-L-leucine (0-092g, 0.534mniol), 1hydroxybenzotriazole (0.014g, 0.1 O2mmol), and 1 -(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride 102g, 0.534mmol). After stirring at room temperature for 16h, the solution was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, methanolldichloromethane) to yield the title compound as a white solid (0.028 g, MS(ESI): 451.1 Exam ple 69 Preparation of 2-N(-cilLaay)-'-N-Nbny~yabnlL leucinyl) icarbohydrazide Following the procedure of Example 68(b), except substituting N-acetyl-Lalanine for N-acetyl-L-leucine and 2- rN-(N-benzyloxycarbonyl-Lleucinyl)Icarbohydrazide for 2 -[N-(N-benzyloxycarbonyl-L-aanyl)]carbohyrazde, the title compound was prepared as a white solid (0.050 g, MS(ESI): 473.1 Example Preparation of 2-[N-(N-benzvloxycarbonyl-L-Ieuciny)12'-rN'.r4.(N.N dimetbylaminomethyl~benzoyflhlcarbohydrzde a) methyl 4 -(NN-dimethylaminomethyl)benzoate Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 mmol) was added to a saturated solution of dimethylarnine in methanol. After stirring for 25 min, the solution was concentrated and the residue was partitioned between IN NaOH and ethyl acetate. The organic layer was washed with saturated brine, dired (MgSO 4 filtered, and concentrated to provide the title compound as a colorless liquid (1 .67 g, IH NMVR (250 MlHz, CDC1 3 6 8.00 2H), 7.39 2H), 3.91 3H), 3.47 2H), 2.25 6H).

b) 4 -(N,N-dimethylamiinomethyl)benzoic acid lithium salt The compound of Example 70(a) (1.67 g, 8.6 nunol) was dissolved in

THFIH

2 O 1) and LiOH*H 2 0 (0.39 g, 9.3 mnmol) was added. The mixture was stirred at room temperature for 0.5h, then taken to reflux for 1.5h. The mixture was 115 concentrated, red issolved in 25mL of water and reconcentrated to yield -a wh-ite solid (1.6 g, 100%). IH NMR (400 MfHz, CD 3 OD) 5 7.94 2H), 7.36 2H1), 3.64(s, 2H), 2.35 611).

c) 2- [N-(N-benzyloxycarbonyl-L-leucinyl)]-2'.[N'-f4-(N,Ndimethylaminonmethyl)berzoyl)I]carbohycfraide Following the procedure of Example 68(b), except substituting 4-(N,Ndimethylamlinomethyl)benzojc acid lithium salt for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbohyrazide for 2-(N-(N-beazyloxycarbonyl.L alanyl)]carbohydrazide, the title compound was prepared as a pale yellow solid (0.050 g, MS(ESI): 499.1 Example 71 Preparation of 2 -FN-(N-benzloxcarbonl-Lleucinym.2'-'r4hvdroxyr3-( 4 morpholinomethyl)llbenzoyllcarbohvlr-azide Following the procedure of Example 68(b), except substituting 4-hydroxy-3- (4-morpholinomethyl)benzoic acid for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.065 g, MS(ESI): 557.0 116 Example 72 Preparation of 2-[N-(N-benzyloxvcarbonyl-L-leucinyl)1-2-'-N'4-N.Ndimethvlaminomethyl)benzvloxvlcarbonvl-L-leucinvlcarbohvdrazide a) ca-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 OC, and pyridine (43.5 g, 0.55 mol, 44.5 mL) 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 mixture was poured into 1400 mL of 0.5 N Hcl and 900 mL of ice. The organic layer was washed with 1400 mL of 0.5 N Hcl and 900 mL of ice. The aqueous layers were extracted with methylene chloride (450 mL) and the combined organic layers were washed with 1400 mL of saturated brine and 900 mL of ice, then dried (MgSO 4 filtered and concentrated.

The residue was distilled (56-58 0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 1 H NMR (250 MHz, CDC1 3 84.04 (dd, 1H), 3.82 3H), 1.92-1.72 1H), 1.69-1.62 2H), 0.96 3H), 0.94 3H).

b) 4 -(N,N-dimethylamino)benzyl alcohol To a stirring solution of the compound of Example 70(a) (1.63 g, 8.4 mmol) in 25 mL of ether, cooled to 0 was added dropwise a 1 M solution of lithium aluminum hydride (8.4 mmol, 8.4 mL). After 5 min, the reaction was quenched by the addition of water (0.33 mL), 15% aqueous NaOH (0.33 mL) and water mL). The precipitate was removed by filtration, washed with ether 2 times and the filtrate was concentrated to provide the title compound as a colorless oil (1.36 g, 1 H NMR (250 MHz, CDCl 3 7.32 2H), 7.28 2H), 4.68 2H), 3.41 2H), 2.22 6H).

c) N-[ 4 -(N,N-dimethylaminomethyl)benzyloxycarbonyl]-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 117 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, 1IH NMR (400 MHz,

CDCI

3 8 7.3 1 4H), 5.13 I 5. 10 2H), 4.41 (in, IlH), 3.74 3.43 2H), 2.24 6H), 1.70-1.62 (in, 2H), 1.52 (in, IH), 0.96 3H), 0.94 3H-).

d) N-[ 4 -(N,N-dimethylaminomethyl)benzyloxycan,,onylI..Lleucine lithium salt Following the procedure of Example 70(b), except substituting dimethylainomethyl)benyloxycaronyl]-Lleucine methyl ester for methyl 4- .(N,N-dimethylaminomethyl)lbenzoate, the title compound was prepared as a white solid (1.57 g, IH NMR (4.00 MR{z, C'D 3 OD) 8 7.35 2H), 7.30 2H), 5.06 (dd, 2H), 4. 10 (dd, IH), 3.48 2H), 2.23 6H), 1.69-1.51 (in, 0.94 (d, 3H), 0.93 3H).

e) 2 -[N-(N-benzyoxycarbnylLeucinyl)..2-['[-NNdixethylaminorethyl)benzyloxyr onylLleucinylchy~drzd Following the procedure of Example 68(b), except substituting dimethylaminornethyl)benyloxycabonyl].Lleucine lithium salt for N-acetyl-Lleucine and 2 -[N-(N-benzyloxycarbonylLeucinyl)]carohyrade for 2-fIN-(Nbezyloxycarbonyl-L-alanyl)]cabohycfrazde, the title compound was prepared as a white solid 0 .069 g, MS(ESI): 642.1 Preparation Of 2 -(N-benzgyh -2'-[N'-(N-benzloxvcarbon1.L.

leucinylhicarbohydrazide Following the procedure of Example 62(e) except substituting benzoyl chloride for 4 phenoxyphenylsulfonylchide, the title compound was-prepared as a white solid (6 1mg, 3 1 MS(ESI): 442.1 Example 74 Preparation of 2-FN-(N-benzloxvcarbonyl-L-leucinyl)b2'-[N-r3-(4.

morpholinomethyl )benzoyvll1lcarbohydrazide a) methyl 3-(4-morpholinomethyl)benzoate A solution of morpholine (0.836 g, 9.6 mmol) and methyl 3- (bromomethyl)benzoate in THfF (5 niL) and DMvF (5 mL) was stirred at 50 OC for 3h. The solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous NaIHCO 3 and brine then dried (MgSO 4 filtered and concentrated to yield a colorless oil (0.872 g, 3.72 rnxol). IH NMR (400 MIHz, CDCl 3 8 7.99 1H), 7.91 1H), 7.55 Ifi), 7.47 IH), 3.94 3H), 3.72 (in, 4H), 3.53 2H), 2.46 (in, 4H).

b) 3-(4-morpholinomethyl)benzoic acid To a solution of the compound of Example 74(a) (0.872 g, 3.72 inmol) in THE (3 ml) and water (3 mL) was added lithium hydroxide monohydrate 171 g, 4.08 mniol). After stirring at room temperature for 3h, the solution was concentrated. The residue was redissolved in water (5 m.L) and 3N HCl was added and the solution was lyophilized to yield a yellow solid (0.822 g, 3.72 rnmol).

MS(ESI): 222.0 c) 2-{N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[3-(4morpholinomethyl)benzoyl]]carbohydrazide Following the procedure of Example 68(b), except substituting 3-(4morpholinoinethyl)benzoic acid for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbohydrazide 'for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.056 g, MS(ESI): 541.0 Example Preparation of 24[N-(3-benzvloxybenzoyl )1-2'-rN'-(N-benzyloxvg-arbonflL.

leucinyl )lcarbohydrazide a) methyl 3-benzyloxybenzoate To a suspension of NaH (0.395 g, 9.87 mmnol, 60% in mineral oil) in DM mL) was added methyl 3-hydroxybenzoate (1.0 g, 6.58 mniol). After stirring for 15 min at room temperature, benzyl bromide (1.1I g, 6.58 mxnol) was added.

After stirring at room temperature 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 bicarbonate, and brine, then dried (MgSO 4 filtered and concentrated to yield an off-white solid (1.013 g, 4.2 mmol). IH NMR (400 MIHz,

CDCI

3 8 7.67 (in, 2H), 7.48-7.34 (mn. 6H), 7.19 (mn, IN), 5.12 2H), 3.95 3H).

b) 3-benzyloxybenzoic acid To a solution of the compound of Example 75(a) (0.400 g, 1.65 rnmol) in THF (2 rnL and water (2 mL) was added lithium hydroxide monohydrate (0.076 g, 1.82 innol). After stirring at reflux for 5 h, the solution was partitioned between ethyl acetate and 3N HC1. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated to yield a white solid (0.355 g, 1.56 inmol). IH NIMR (400 MiHz, CD 3 OD) 8 7.58 (in, 2H), 7.36-7.24 (mn. 6H), 7. 10 (in, IiH), 5.04 2 3 -benzyloxybenzoyl1-2'-[N'-(N..benyoxycarbonyl.L leucinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting 3benzyloxybenzoic acid for N-acetyl-L-leucine and 2 -tjN-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide for 2 -(N-(N-benzyloxycarbonyl-L..alanyl)Icarbohydraide, the title compound was prepared as a white solid (0.062 g, MS(ESI): 548.1 Example 76 Preparation of 2-rN-(N-benzvloxvcarbonyl-L-leucinl)l-2-r lN'-r4-r3(N-N dimethylamino)- I -propvyloxylbenzoyl 1lcarbohydrazide a) methyl 4-[3-(N,N-dimethylamino)- 1-propyloxyjbenzoate To a solution of methyl 4-hydroxybenzoate (1.0 g, 6.58 mmol), 3dixnethylamino-1-propanol (1.01 g, 9.87 inmol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0 0 C in THF (20 mL) was added dropwise diisopropyl azodicarboxylate (1.99 g, 9.87 mmol). After stirring for 16 h at room temperature the solution was concentrated and the residue purified by column chromatography (silica: gel, methanolldichloromethane) to yield the title compound as an oily solid (1.25 g, 5:2 mmol). MS(ESI): 238.1 b) 4-[3-(N,N-dimethylamino)-l1-propyloxyjbenzoic acid Following the procedure of Example 74(b) except substituting methyl 4-[3- (N,N-dimethylaxnino)- 1 -propyloxylbenzoate for methyl 3-(4morpholinomethyl)benzoate, the title compound was prepared as a tan solid 17 g, 5.2 mmol). MS(ESI): 224.1 C) 2-N(-ezlxcroy--ecnl]-'['[-3(--dmtyain) 1 -propyloxylbenzoyl]]carbohydrazide Following the procedure of Example 68(b), except substituting 4-[3-(NNdimethylarmno)-1I-propyloxy]benzoic acid for N-acetyl-L-leucine and benzylo xycarbonyl-L-leucinyl)]carbohydrzide for 2-IIN-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the, title compound was prepared as a white solid (0.060 g, MS(ESI): 543.1 Example 77 Preparato o2-N-(2-benzyloxvbenzovl )1- 2 '-fN'-(N-benzvlxvabonyl.L.

leucinyl carbohydrazide Following the procedure of Example 68(b), except substituting 2benzyloxybenzoic acid for N-acetyl-L-leucine and 2 -fN.{N-benzyloxycarbonvl-L leucinyl)]carbohydrazide for 2-N(-ezlxcroy--lnllabhdaie title compound was prepared as a white solid (0.056 g, MS(ESI): 548.1 Example 78 Preparation of 2-rN-CN-benzyloxcarbonyLleuinl)12-4Nr 3 4 pvyridvlmethoxv)benzoyl ILcarbohydrazide a) methyl 4 -pyridinyimethoxybenzoate Following the procedure of Example 76(a) except substituting methyl 3hydroxybenzoate for methyl 4-.hydroxybenzoate and 4-pyridylcarbinol for 3diniethylamino-l-propanol, the title compound was prepared as a yellow solid (0.599 g, 2.5 rnmol). MS(ESI): 244.1 b) 4 -pyridinytmethoxybenzoic acid Following the procedure of Example 75(b) except substituting methyl 4pyridylmethoxybenzoate for methyl 3-benzyloxybenzoate the title compound was a prepared as a yellow solid (0.386 g, 1.69 inmol). IH NMIR (400 MHz, CD 3 OD) 8 8.54 2H), 7.64 (mn, 2H), 7.57 (mn, 2H), 7.4.0 (mn, 1K), 7.26 (mn, IH), 5.24 2H).

c) 2 -[N-(N-benzyloxycarbonyl-Lleucinyl)].2I[N'[3-(4.

pyridylmethoxy)benzoyl]]carbohydrzde Following the procedure of Example 68(b), except substituting 4pyridinylmethoxybenzoic acid for N-acetyl-L-leucine and bezlxcroy--euiy)croyrzd for 2 -[N-(N-benzyloxycarbonyl-Lalanyl)jcarbohydrazide, title compound was prepared as a white solid (0.219 g, MS(ESI): 549.1 Example '79 Preparation of 2-rN-(4-benzyloxybenzoyl)1-2'-N'-(N-benlZoxycarbol[Lleucinyl~lcarbohydrazide Following the procedure of Example 75(a)-75(c) except substituting methyl 4-hydroxybenzoate for methyl 3-hydroxybcnzoate in step the title compound was prepared as a white solid 160 g, MS(ESI): 548.1 Preparation of 2- fN-(N-benzyloxycarbonyl-L-leucinl)1- 2 methoxy)benzoyllcarbohydrazide a) methyl A suspension of methyl 3,5-dihydroxybenzoate (2.0 g, 11.9 minol), K 2 C0 3 (1.6 g, 11.9 mmol), and jodomethane (1.7 g, 11.9 mmol) in acetone (100 mL) was stirred at reflux. After stirring for three hours the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a white solid (0.813 g, 4.4 rnmol). 1 H NMR (400 MHz, CDCl 3 867.16 (in, INH), 7.12 (in, I1H), 6.61 I1H), 5.04 I1H), 3.91 3H) 3.82 3H).

b) methyl Following the procedure of Example 80(a) except substituting methyl 3for methyl 3,5-dihydroxybenzoate and benzyl bromide for iodomethane, the title compound was prepared as a tan oil (1.2 g, 4.4 mmol).

1H NMR (400 M&z, CDCl 3 867.45-7.31 (in 6H1), 7.24 lH), 6.76-(m, IN), 5.09 2H), 3.95 3H), 3.84 3H).

c) 3-benzyloxy-5.-methoxybenzoic acid Following the procedure of Example 75(b) except substituting methyl 3for methyl 3-benzyloxybenzoate, the title compound was prepared as an orange solid (1.14 g, 4.4 mmol). IHNvR (400 MI-z, CDCI 3 6 7.42-7.20 (in, 7H), 6.71 (in, IH), 5.05 2H), 3.80 3H).

d) 2-fjN-(N-benzyloxycarbonyl-L-leucinylyj..2'- rnethoxy)benzoyljjcarbohydrazide Following the procedure of Example 68(b), except substituting 3-benzyloxyacid for N-acetyl-L-leucine and 2 -fN-(N-benzyloxycarbonyl.L.

leucinyl)jcarbohydrazide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, title compound was prepared as a white solid (0.20 1 g, MS(ESI): 578.0 Example 81 Preparation of 2-rN-(N-benzyloxycarbonyl-L-leucinyl)1-24-N'.(3..benzyloxy-4.5 diinethoxy)benzoyllcarbohydrazide Following the procedure of Example 68(b), except substituting 3-benzyloxyacid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl- L-leucinyl)]carbohydrazide for 2-(N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid 155 g, MS(ESI): 607.9 Example 82 Preparation of 24[N-(N-benzyloxycarbonyl-L-leucinyi'ul-2'-[N'43-benzyloxy-5-: ethoxy~benzoyllcarbohydmaide Following the procedure of Example 80(a)-80(d) except substituting iodoethane for iodomethane in step the title compound was prepared as a white solid 162 g, MS(ESI): 592.3 ExaMpl1e 83 Preparation of 2-rN-(N-benzvloxycarbonvilycinyl 2 '-IN'-(N-benzvloxycarbon yl L-IeucinvlI lcarbohydrazide Following the procedure -of Example 68(b), except substituting Nbenzyloxycarbonylglycine for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl.

L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L.

alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.204 g, MS(ESI): 529.2 Exmle8 Preparation of 2-4N-(3-benzloxybenzovlll-2'-rN'-(N-benzylpxycarbonyl-L.

prolinylllcarbohydrazide a) 2-[N-(3-benzyloxybenzoyl)Icarbohydrazide Following the procedure of Example 62(b)-62(d) except substituting methyl 3-benzyloxybenzoate for N-benzyloxycarbonyl-L-leucine methyl ester in step the title compound was prepared as an off white solid (0.421 g, MS(ESI): 301.1 b) 2 -[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-Lprolinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting Nbenzyloxycarbonyl-L-proline for N-acetyl-L-leucine and benzyloxybenzoyl)Jcarbohydrazide for 2- [N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.2 19 g, MS(ESI): 532.0 Example Preparation of 2 -[N-(N-benzyloxycarbonyl-L-leucinvi phenvip~henviacetyl carbohydrazide Following the procedure of Example 68(b), except substituting 4biphenylacetic acid for N-acetyl-L-leucine and 2 -[N-(N-benzyloxycarbonyl.L leucinyl)]carbohydrazide for 2 -[N-(N-benzyloxycarbonyl-L..aanyl)carohydrazide, the title compound was prepared as a white solid (0.224 g, 71%) MS(ESI): 554.2 Example 86 Preparation of N(-ezlxbnovl)-'r'(-enyovabnl2 aminobutyrl)lcarbohydrazide Following the procedure of Example 68(b), except substituting benzyloxycarbonyl-2-aminobutyrc acid for N-acetyl-L-leucine and benzyloxybenzoyl)Icarbohydrazide for 2 -[N-(N-benzyloxycarbonyl-L alanyl)Jcarbohydrazide, the title compound was prepared as a white solid (0.244 g, MS(ESI): 520.3 Example 87 Preparation of 2 2 '-IN.N'-rbis-(4-p2henylphenyacety'l1cabhydrazide To a stirring solution of carbohydrazide (0.200 g, 2.22 rnmol) in DMF (12 mL.) was added 4-biphenylacetic acid (1.04 g, 4.89 mnmol), 1 -hydroxybenzotriazole (0.060 g, 0.444 mmol), and l-( 3 -dimethylaminopropyl)3ethylcarodiij 1 ide hydrochloride (0.937 g, 4.89 mmol). After stirring at room temperature for 16 h, the solution was poured into 150 mL. of water. The precipitate was filtered and washed with water (150 mil) and dried under high vacuum to yield the-title compound as a white solid (0.977 g, MS(ESI): 501.1 126 Example 88 Preparation of (2'RS)-2-[N-(N-benzloxycarbonl-L-leucinl)1-2 phenvlp~henoxv)p2ropionyl icarbohydrazide Following the procedure of Example 68(b), except substituting 2-(4phenylphenoxy)propionic acid for N-acetyl-L-leucine and 2-fjN-(Nbenzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L alanyl)Jcarbohydrazide, the title compound was prepared as a white solid 183 g, MS(ESI): 562.3 Example 89 reparation of 2-FN-(3-benzyloxybenzovl)1-2'-rN'-(4methylpentanoylhicarbohydrazide Following the procedure of Example 68(b), except substituting 4methylpentanoic acid for N-acetyl-L-leucine and benzyloxybenzoyl)Icarbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.079 g, MS(ESI): 399.3 Example Preparation of (2RS. 2'RS N.N'-rbis-f 2 4 -phenvlphenv methylpentanovl)1 lcarbohydrazide a) 4 -methy1-2-(4-phenylphenyl)pent.4-enoic acid To a stirring solution of diisopropylaxnine (0.537 g, 5.31 mmol) in THE (5.2 mL) at 0 *C was added n-butyllthium (2.1 niL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0 the mixture was Cooled to -78 0 C and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THE (2 niL) was added dropwise. After again warming to 0 'C and cooling to -78 0 C, 3-bromo-2methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at -78 'C for lh, the reaction was quenched with 2 ML of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCI) and extracted with ether (3 X 100 niL). The organic layers were combined, dried (MgSO 4 filtered and concentrated to yield a white solid (0.449 g, MS(ESI): 265.3 b) 4 -methyl-2-(4-phenylpheny)pentanoic acid To a stirring solution of the compound of Example 90(a) (0.449 g, 1.69 inmol) in ethyi acetate (25 mL) was added palladium on carbon (0.225 After stirring under a balloon of hydrogen for 16h, the mixture was filtered through Cqelite. The filtrate was concentrated to yield an off white solid (0.430 g, ,AMS(ESI): 267.4 c) 2RS, 21 RS)-2,2'-(NN'-[bis-2.(4-phenylphenyl).4 methylpentanoy)]]carbohydrazide Following the procedure of Example 87 except substituting 4-methyl-2-(4phenylphenyl)pentanoic acid for 4-biphenylacetic acid, the title compound was obtained, after purification by column chromatography (silica gel, methanol/dichloromethane), as a white solid (0.143 g, MS(ESI): 591.3 Example 91 Preparation of (2'RS )-2-rN-(N-benzyloxycarbonvl-L-leucinyl)1-2'-[N phenviphenyl )-4-methylpentanoyvl carbohydrazide Following the procedure of Example 68(b), except 4-methyl-2-(4phenylphenyl)pentanoic acid for N-acetyl-L-lIeucine and benzyloxycarbonyl-L-leucinyl)Jcarbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)Icarbohydrazide, the title compound was prepared as a white solid 111 g, MS(ESI): 588.1 Example 92 Preparation of (2'RS )-2-fN-(3-benzyloxybenzovl)1- 2'-FN'-F2-(4-phenyfiphenyl)-4.

methylpentanoyflhlcarbohydrazide Following the procedure of Example 68(b), except substituting 4-methyl-2- (4-phenylphenyl)pentanoic acid for N-acetyl-L-leucine and benzyloxybenzoyl)]carbohydrazide for 2- [N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid 195 g, MS(ESI): 551.1 Example 93 Preparation of 2-[N-(3-benzvloxvbenzoyl)1-2'-fN'-(N-benzyloxycarbonyl-N-methyl- L-leucinyl~lcarbohydrazide Following the procedure of Example 68(b), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine and 2- benzyloxybenzoyl)Jcarbohydrazide for 2-fN-(N-benzyloxycarbonyl-Lalanyl)]carbobycirazide, the title compound was prepared as a white solid (0.341 g, MS(ESI): 562.2 Example 94 Preparation of 2-[N-(3-benzyloxybenzovI)1-2'-rN'-rN-.(2- 1Pyridinylmethoxycarbonvi )-L-Ieucinyl llcarbohydrazide a) N-( 2 -pyridinylmethoxycarbonyl..L..eucine methyl ester Following the procedure of Example 72(c), except substituting 2pryidylcarbinol for 4-(N,N-dimethylamino)benzyl alcohol, the title compound was prepared as a brown oil (8.06 g, MS(ESD: 281.2 b) 2 2 -pyrdnyiylmethoxycarbonyl)-Lleucinylcarohydrazide Following the procedure of Example 62(b)-62(d) except substituting o pyridinylmethoxycarbonyl)-L-leucine methyl ester for L-leucine methyl ester in step the title compound was prepared as a pale yellow foam (0.598 g, 69%).

MS(ESI): 339.3 c) -benzyloxybenzoyl)I-2'- 2 -pyridinylmethoxycarbonyl)-L.

Ieucinylllcarbohydrazide Following the procedure of Example 68(b), except substituting 3benzyloxybenzoic acid for N-acetyl-L-leucine and pyridinylylmethoxycarbonyl)Lleucinylcbhydfrazide for benzyloxycarbonyl-L-alanyl)]carbohydaide. the title compound was prepared as a w;hite solid (0.057 g, MS(ESI): 549.2 Example Preparation of 2-rN-r3-(4-pyridylmethoxvybenzoyll2'rN'rN-(2.

pydnlehxcroy)Lluiylcroyrzd Following the procedure of Example 68(b), except substituting 3-(4pyridinylmethoxy)benzoic acid for N-acetyl-L-leucine and pyridinylylmethoxycarbonyl)Lleucinyl]carbhydrazide for benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a yellow solid (0.088 g, MS(ESI): 550.2 130 Example 96 Preparation of (2RS)-2-fN-r2-(4-p2henvlphenvl)-4-methlpntanol)1 1-2'-rN,-rN-(2pvridinylmethoxvcarbonvl )-L-leucinyvl lcarbohydrazide Following the procedure of Example 68(b), except 4-methyl-2-(4phenylphenyl)pentanoic acid for N-acetyl-L-leucine and pyridinylyknethoxycarbonyl)-L-leucinyllcarbohydrazide for benzyloxycarbonyl-L-alanyl)]carbohydrazide,. the title compound was prepared as a yellow solid (0.056 g, MS(ESI): 589.4 Example 97 Preparation of 2-rN-(N-benzyloxycarbonyl-L-leucinl)1-2'-rN'- r2-(4-phenYlphenyl 4-methylpsntanoyfli icarbohydrazide The title compound was prepared from the compound of Example 91 using HPLC (Sumipax OA-3 100,4.6 X 150 mm, 80/20 hexane/ethanol, 1.0 mi~min, retention time 5.9 muin).

Example 98 Preparation of 2-rN-(N-benzyloxycarbonyl-L-leucinvh1-2'-rN'-f2-(4-phenlphenyl)- 4-methylpent-anoylificarbohydrazide The tidle compound was prepared from the compound of Example 91 using HPLC (Sumipax OA-3 100,4.6 X 150 mm, 80/20 hexane/ethanol, 1.0 mn~min, retention time 8.1 muin).

Example 99 Preparation of 2-[N-(N-benzyloxvcarbonvl-L-leucinvl)1..2-N'-rN( 4 phenviphenvi )-N-(2-methylpropvl )carbamoyl 1 karbohydirazide To a stirring solution of phosgene (0.228 mL, 0.244 mnzol, 12.5% solution in benzene) was added dropwise a solution of N-(2-rnethylpropyl)- N-(4phenylphenyl)amine (0.050 g, 0.222 mmol) and triethylamine (0.025 g, 0.244 mmol) in dichloromethane (I After stirrng at room temperature for 15 min this solution was added dropwise to a solution of the compound of Example 1 (d) (0.083 g, 0.244 mmol) and triethylamine (0.025 g, 0.244 mrnol) in dichloromethane rnL) at room temperature. After stirring at room temperature for 48h, Nmethylmorpholine (0.022 g, 0.222 minol) 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 successively with water, aqueous saturated NaHCO 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, methanol/ dichloromethane) to yield the title compound as a yellow solid (0.023 g, 18%).

MS(ESI): 589.4 Example 100 Preparation of 2-[N-(3-benzyloxybenzofl1-2'-4N'-(N-methyl-L leucinvl'lcarbohydrazide 2-N(-ezlxbnol12-N-(-etbtxcroy--ehl leucinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting N-tertbutoxycarbonyl-N-methyl.Lleucine for N-acetyl-L-leucine and benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)Icarbohydrazide, the title compound was prepared as a white solid 183g, MS(ESI): 550.4 b) 2- -benzvloxybenzoyl) -2'-N'-(N-methyLeucifyl)]carbohydra7ide To a stirring solution of the compound of Example I100(a) 100 g, 0. 189 minol) in dich-loromethane (1 mL) was added trifluoroacetic acid (0.296 g, mmol). After stirring at room temperature for. 15 min, the solution was concentrated and the residue was purified by column chromatography (silica gel, methanolldichloromethane) to yield the title compound as a white solid (0.055 g, MS(ESI): 428.4 Example 101 Preparation of 2-rN-(N-benzyloxvcarboflyl-L-leucinfl)fk2'-rN'-(N-methyl-Lleucinyl')lcarbohydrazide Following the procedure of Example 1 00(a)- I100(b), except substituting 2 [N-(N-benzyloxycarbonyl-L-1eucinyl)]carbohydra.1de for 2-IIN-(3benzyloxybenzoyl)]carbohydrazide in step the tidle compound was prepared.

MS(ESI): 465.5 Example 102 Preparation of (1 S)-N-r24-1benzyloxvcarbonylaminoI-3-methylbulyllthiazo[- 4 ylcarbonyll-N'(4-phenoxyphenvlsulfoylfhydrazide a) N-benzyloxycarbonyl-L-leucinaniide To a stirring solution of N-benzyloxycarbonyl-L-leucine (4.6 g, 17.3 inmol) in THF, cooled to -40 0 C, was added N-methylxnorpholine (3.68 g, 36.4 rumol; ruL) and isobutyl chioroformate (2.37 g, 17.3 mmiol; 2.25 ruL). After stirring for rmin, ammonia was bubbled through the solution for 5 rmin. The solution was warmed to room temperature, evaporated, and the residue was dissolved in ethyl acetate, washed with 0. 1 N Hcl, and saturated -brine, then dried (MgSO4), filtered and evaporated to dryness to give the tidle compound as a white solid (4.58 g, 100%).

b) N-benzyloxycarbonyl-L-leucinethioamide A solution of the compound of Example 102(a) (4.58 g, 17.3 mmol) and Lawesson's reagent (4.21 g, 10.4 mmol) in THF was allowed to stir at room temperature for 16 h. The solution was concentrated and the residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:3 EtOAc/hexanes, to provide the title compound as a pale yellow solid (3.74 g, 77%).

c) (1S)-1 -benzyloxycarbonylamino-1 -(4-carboethoxythiazol-2-yl)-3methylbutane The compound of Example 102(b) (2.20 g, 7.83 mmol) was dissolved in acetone (35 mL), cooled to -10 OC, 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 saturated aqueous NaHCO 3 The aqueous layer was extracted with methylene chloride and the combined organic layers were washed with saturated brine, dried (MgSO 4 filtered and concentrated. The residue was dissolved in methylene chloride, cooled to -20 0 C, pyridine (1.36 g, 17.2 mmol, 1.39 mL) and trifluroracetic anhydride (1.81 g, 8.62 mmol, 1.22 mL) were added.

After stirring for 1 h, the solution was washed with saturated squeous NaHCO 3 and saturated brine, then dired (MgSO 4 filtered, and concentrated. Tge residue was purified by flash chromatography on 90 g of 230-400 mesh silica gel, eluting with 1:3Iethyl acetate/hexanes, to provide the title compound as a pale yellow oil (2.36 g, IH NMR (400 MHz, CDC1 3 5 8.08 1H), 7.38 5H), 5.42 3H), 5:23-5.07 3H), 4.42 2H), 2.01-1.62 3H), 1.41 3H), 0.99 6H).

d) (IS)-1 -benzyloxycarbonylamino- 1-(4-hydrazinocarbonylthiazol-2-yl)-3methylbutane The compound of Example 102(c) (2.16 g, 5.73 mmol) was dissolved in ethanol (60 mL) and hydrazine hydrate (2.87 g, 57.3 mmol, 2.8 mL). was added and the solution was heated at 75 oC for 1 h. The solution was cooled and evaporated to dryness to provide the title compound as a pale yellow foam (2.01 g, 1

H

NMR (400 MHz, CDCI 3 8 8.35 (bs, 1H), 8.03 1H), 7.37 5H), 5.29 1H), 134 5.14-5.09 (mn, 3H), 4.07 (bs, 2H), 1.92-1.82 (mn, 1H), 1.79-1.66 (in, 2H), 1.00 (d, 6H).

e) -benzyloxycarbonylamuno)-3-methylbutyllthiazol-4ylcarbonyl]-N'-(4-phenoxyphenylsulfonyl)hydrazide To a stirring solution of the compound of Example 102(d) (275 mg, 0.76 mmol) in dicioromethane at roam temperature is added pyridine (180 mg, 2.28 inmol, 0.2 mL) and 4-phenoxybenzenesuifonyl chloride (408 mg, 1.52 mmol). The reaction was stirred for 16 hours and the solvents were evaporated to a riesidue which was chromatographed (silica gel, 40% ethyl acetate in hexane) to give the title compound as a white solid (0.3 10 MS (ESD): 595.6 Example 103 Preparation of (1 I-(N-benzyloxycarbonyl-L-leucinylamino)-3methylbutyllthiazol-2:ylcarbonyll-N'-(N-benzyloxcarbonyvl-L-leucinl)hydrazide a) N-benzyloxycarbonyl-L-leucinyl-L-leucinyl bromomethylketone I -Methyl-3 -nitro- I1-nitrosoguanidine (5.9 g. 40.11 mmol) in ether (200 mL) is cooled to 0 0 C. 40% potassium hydroxide is added slowly and the diazomethane is allowed to collect in the ether solution for 30 minutes at 0 0

C.

N-benzyloxycarbonyl-L-Leucinyl-L-Leucine (Bachem) (4.0 g, 10.58 mmol) is stirred in tetrahydrofuran at N-methylmorpholine (1.07 g, 10.58 mmol, 1. 16 mL) and isobutyl chloroformate (1.45 g. 10.58 mmol, 1.38 mL) are added.

The mixture is stirred at -40*C for 15 minutes and then filtered into a cold flask to remove precipitated salts. To the filtered solution is added an excess of the previously prepared diazomethane solution and the mixture is allowed to stand at 0 0 C for 16 h. An excess of 30% HBr in acetic acid is added at 0 0 C and the solution is then washed successively with L ON citric acid, saturated aqueous sodium bicarbonate (carefully), and brine. The solution is dried over sodium sulfate, filtered, and evaporated to give the title compound as a white solid (4.10 IH NMR (400 MHz, CDCl 3) 8 7.34 (in, 5H), 6.5 1 I1H), 5.15 I1H), 5. 10 2H), 4.78 (in, 1H), 4.20 (in, IH), 4.04 (dd, 2H), 1.63 (in, 6H), 0.93 (in, 12H).

b) (2S, 1'S)- 2 -(benzyloxycarbony)arndloN 11'-(2 -carboethoxyt,azOI-4y' 3 methylbutyll-4-methylpentanarride 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 evaporated and the residue chromatographed (silica gel, 2.5% methanol/dichloromethane) to give the title compound as a white s olid (1.46 IH NR (400 MHz, CDCI 3 5 7.32 (s, lH), 7.21 511), 6.40(d, 1H), 5.13 (dd, IN), 5.02 2H), 4.41 2H), 4.06 (m, 1H), 1.71 211), 1.47 4H), 1.33 3H), 0.73 12H).

c) (2S,I 2 -(benzyloxycarbonyl)amino-N-[I 2 -hydrazinocarbonyltaizol-4yl)-3'-me thylbutyl i-4-methylpentanamide Following the procedure of Example 102(d), except substituting (2S,1 (benzyloxycarbonyl)aino-N-[ Il'-( 2 -carboethoxythiazoI-4yl)-3'-methylbutyl]-4methylpentanamide for (I5)-I -benzyloxycarbonylamino- Il-( 4 -carboethoxythiazol-2 yl)- 3 -methylbutane, the title compound was prepared. MS (ESI): 476.3 d) (1 -(N-benzyloxycarbonyl-L-leucinylano)- 3 methylbutyl tia2ylcarbonyl]-N'-(N-beny lo xylLle lh To a stirring solution of the compound of Example 103(c) (180 mg, 0.38 mmol) in dinethylformamide is added N-benzyloxycarbonyl-L-.eucine (Ill mg, 0.42 mnol), 1-(3-dimethylaninopropyl)-3-ethylcarbodi hydrochloride (80 mg, -0:42 mmol), and l-hydroxybenzotriazole (13 mg, 0.096 mmol). The reaction mixture is stirred for 16 hours at room temperature, filtered, and washed twice with water. The solvent was evaporated to give the title compound as a white solid.

(0.207 MS (ESI): 723.9 Example 104 Preparation of (H S)-N-[r2 1 -benzyl oxycarbonyl amino)- 3 -methylbuty I thi azol-4ylcarbonyI1-N'-(4-p2henylphenylacetyl)hydrazide Following the procedure of Example 103(d), except substituting benzyloxycarbonylamino- 1-(4-hydrazinocarbonylthiazol-2-yi)-3-methylbutane for (2S, 1 'S)-2-(benzyloxycarbonyl)amnino-N-[ I '-(2-hydrazinocarbonylthiazol-4-yi)-3' methylbutyl]-4-methylpentanainide, and 4-biphenylacetic acid for Nbenzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid.

MS (ESI 557.2 Example 105 Preparation of (1 S-N-r2-f(I1-benzyloxycarbonylarnino)-3-methvlbutyllthiazol-4ylcarbonyll-N'- [3-(4-pRaidinvlnethoxy)benzoyllhydrazide a) methyl 3-(4-pyridinyllnethoxy)benzoate To a stirring solution of methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol), 4pyridylcarbinol (1.1I g, 9.87 rnmol and triphenylphosphine (2.6 g, 9.87 mmol) in THF (25 niL) at 0 0 C was added diisopropyl azodicarboxylate (2.0 g, 9.87 mmol) dropwise. After stirring at room temperature for 16h, the solution was concentrated and purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.599 g, MS(ESI): 244.1 b) 3-(4-pyridinylmethoxy)benzoic acid To a stirring solution of the compound of Example 105(a) (0.599 g, 2.47 mmrol) in THFIH 2 O 1, 10 mL) was added lithium hydroxide monohydrate 113 g, 2.71 mmol). After stirring at reflux for 3.5h, 1. 1 eq of 1N HCl was added and the mixture poured into water. The mixture was extracted with ethyl acetate (2 X 100 nmL). The organic layers were combined, washed with brine, dried (MgSO 4 filtered and concentrated to yield the title compound as a yellow solid (0.386 g, 1 H NMR (400 MlHz, CD 3 OD) 8 8.54 2H), 7.64 (in, 2H), 7.57 (mn, 2H), 7.40 (mn, 1H), 7.26 (in, 1H), 5.24 2H).

c) (S)-N-[2-[(l-benzloxycarbonylaino)-3-methyibutyl]thiazol-4ylcarbonylJ-N'-[ 3 -(4-pryidinylmethoxy)benzoyl]hydrazide Following the procedure of Example 103(d), except substituting 1benzyloxycarbonylamino- 1l-( 4 -hydrazinocarbonylthiazol-2-yl)-3-methylbutane for (2S, I'S)- 2 -(benzyloxycarbonyl)amino-N-[1 '-(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanamide, and 3 4 -pyridinylmethoxy)benzoic acid for Nbenzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid.

MS (ESI): 574.2 Example 106 Preparation of N-f 2 -(2-chlorophenoxymethyl)thiazol-4-vlcarbonvl Pvridinvlmethoxycarbonyl)-L-leucinllhydrazide 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 0 C, and pyridine (43.5 g, 0.55 mol, 44.5 mL) 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 OC for 2 h, the mixture was poured into 0.5 N HCI (1400 mL) and ice (900 mL). The organic layer was washed with 0.5 N HCI (1400 mL) and ice (900 mL). The aqueous layers were extracted with methylene chloride (450 mL) and the combined organic layers were washed with saturated brine (1400 mnL) and ice (900 mL), then dried (MgSO 4 filtered and concentrated.

The.residue was distilled (56-58 0 C; 0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 1 H NMR (250 MHz, CDCI 3 8 4.04 (dd, 1H), 3.82 3H), 1.92-1.72 1H), 1.69-1.62 2H), 0.96 3H), 0.94 3H).

b) N-( 4 -pyridinylmethoxycarbonyl)-L-leucine methyl ester A solution of the compound of Example 106(a) (5.10 g, 29.8 mmol) and 4pyridylcarbinol (3.25 g, 29.8 mmol) in toluene (30 mL) was heated at reflux for 24 h. The solution was concentrated and the residue was purified by flash chromatography on 250 g of 230-400 mesh silica gel, eluting with 3:1 ethyl acetate/hexanes, to give the title compound (7.86 g, 1 H NMR (250 MHz, 138 CDC1 3 68.59 2H), 7.24 2H), 5.33 IH), 5.13 3H), 4.40 (dt, IH), 3.75 3H), 1.81-1.51 3H), 0.96 3H), 0.95 3H).

C) N-(4-pyridinylmethoxycarbonyl)-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 LiOHeH 2 0 (325 mg, 7.76 mmol). The mixture was stirred for 30 minutes and then concentrated. The residue was redissolved in water (10 mL) and 3 NHCI was added (2.6 mL). The solution was lyophilized to yield a white solid (2.015 g, 6.44 mmol). MS (ESI): 267.2 d) N-[2-(2-chlorophenoxymethyl)thiazol4-ylcarbonyl]hydraide Following the procedure of Example 102(d), except substituting ethyl 2-(2chlorophenoxynethyl)thiazole-4-carboxylate for (1 I -benzyloxycarbonylaminol-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared.

MS (ESD: 284.1 e) N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N'-N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting chorophenoxymethyl)thiazol-4ylcarbonyl]hydrazide for (2S,1 (benzyloxycarbonyl)amino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4-yl).3' methylbutyl]-4-methylpentanamide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 532.1 Examp l e 1 07 Preparation of N-rN-(4-12yridinlmethoxcarbonl)-L-leucinyl.N'-[2-f4-( 1.23thiadiazol-4-vl )phenyllthiazol-4-ylcarbonyl ihydrazide a) 2 3 -thiadiazol-4-yl)Ithiazol-4-ylcarbonyl~hydrazide Following the procedure of Example 102(d), except substituting ethyl 2-[4- (1 ,2, 3 -thiadiazol-4-yl)]thiazole.4-carboxylate for (I I -be zyloxycarbonyl amino-.

1 -(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 304.1 b) N-[N-(4-pyridinylmethoxycarbonyl)-L-eucinyl..N'[2.[4-(1I,2,3-thiadjazol- 4-yl)phenyllthiazol-4-ylcarbonyljhydrazide Following the procedure of Example 103(d), except substituting N-[2-74- (1 ,2,3-thiadiazol-4-y1)]thiazol-4-ylcarbonyl~hydrazide for (2S,1 (benzyloxycarbonyl)amio-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyll-4-methylpentanamide, and N-( 4 -pyridinylmethoxycarbonyl)-L-Ieucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 552.1 Example 108 Preparation of N-r2-I3-(4.-chlorophenylsulfonylmethflthien-2-yllthiazol-4ylabnl-'r-4prdnlehxcroylLluiylyrzd a N-(2-(3-(4-chlorophenylsulfonylmethyl)thien-2ylJtiiol..carbonylihydrazide Following the procedure of Example 102(d), except substituting chlorophenylsulfonylmethyl)thien.2yl]thiazole.4carboxylate for (15)-i benzyloxycarbonylamino- l-(4-carboethoxythiazol-2-yI)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 414.1 b) N- [2-[P3-(4-chlorophenylsulfonylmethyl)th-ien-2 -yl Ithiazol-4-ylcarbonl j [N-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 103(d), except substituting chlorophenylsulfonylmethyl)thien-2-ylthiazol-4-carbonyllhydrazide for (2S, I'S (benzyloxycarbonyl)amino-N-[ I -(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanamnide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyi-L-leucine, the title compound was prepared as a white.

MS (ESI): 664.0 Example 109 Preparation of (IS .2'RS [(1-benzyloxycarbonylamino)-3-methylbutyllthiazol- 4-ylcarbonyll-N'-r2'-(4-phenylphenylacetyl-4-metlpentanollhvdrazide a) 4-rnethyl-2-(4-phenylphenyl)pent4-enoic acid To a stirring solution of dilsopropylamine (0.537 g, 5.31 mmol) in THE (5.2 mL) at 0 0 C was added n-butyllithium (2.1 rnL, 5.22 minol, 2.5M in hexane) dropwise. After stirring for 15 min at 0 0 C, the mixture was cooled to -78 *C and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THE (2 mL) was added dropwise. After again warming to 0 *C and coolling to -78 3-bromo-2methylpropene (0.485 g, 3.54 mniol) was added to the mixture in one portion. After stirring at -78 *C for lh, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HQl and extracted with ether X 100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, MS(ESI): 265.3 (M+HY-.

b) 4-methyl-2-(4-phenylphenyl)pentanoic .acid To a stirring solution of the compound of Example 109(a) (0.449 g, 1.69 mmol) in ethyl acetate (25 mL) was added palladium on carbon (0.225 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, MS(ESI): 267.4 c) benzyloxycarbonylamino)-3-methylbutyl]thiazol-4ylcarbonylJ-N'-[2'-(4-phenylphenylacetyl)-4-methylpentanoyl]hydrazide Following the procedure of Example 101(d), except substituting (IS)-lbenzyloxycarbonylamino- I -(4-hydrazinocarbonylthiazol-2-yl)-3-methylbutane for (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-(1 '-(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanamide, and 4 -methyl- 2 -(4-phenylphenyl)pentanoic acid for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 613.2 Example 110 Preparation of N-2-(3-benzyloxyphenyvl)thiazol-4-vlcarbonyll-N'-rN-(2pyvridinlmethoxvcarbonl)-L-leucinllhvdrazide a) methyl 3-benzyloxybenzoate To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMF mL) was added methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol). After stirring for 15 min at room temperature, benzyl bromide (1.1 g, 6.58 mmol) was added.

After stirring at room temperature 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 bicarbonate, and brine, then dried (MgSO 4 filtered and concentrated to yield an off-white solid (1.013 g, 4.2 mmol). 1 H NMR (400 MHz,

CDCI

3 8 7.67 2H), 7.48-7.34 6H), 7.19 1H), 5.12-(s, 2H), 3.95 3H).

b) 3-benzyloxybenzamide To a suspension of ammonium hydrochloride (1.070g, 0.02 mmol) in 20 mL of toluene at 5oC, was slowloy added a 2M solution (10 mL) of trimethylaluminium in toluene. After the addition was complete, the reaction mixture was allowed to warm at room temperature and was stirred for 2 hours until gas evolution has ceased.

To a stirring solution of the compound of Example 110(a) (605 mg, 2.49 mmol) in toluene was added a 0.67 M solution of MeAICINH 2 (11 mL, 7.49 mmol) 142 in toluene. The reaction mixture was allowed to stir overnight at reflux. The reaction was quenched with 5% HCI, the organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO 4 filtered and concentrated to afford the title compound as a white solid (409 mg, MS (ESI): 228.1 c) N-[2-(3-benzyloxyphenyl)tbiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 102(b)- 102(d), except substituting 3benzyloxybeazarnide for N-benzyloxycarbonyl-L-leucinamide in step the title compound was prepared as a white solid. MS (ESI): 326.2 d) N-(2-pyridinylmethoxycarbonyl)-L-leucine Followong the procedure of Example 106(a)-106(c), except substituting 2pyridylcarbinol for 4-pyridylcarbinol in step the title compound was prepared.

1 H NMR (400 M&z, CD 3 OD) 8 8.50 I1H), 7.86 (dt, I 7.51 I 7.36 (dd, IH), 5.20 1H), 5.16 1H), 4.19 1H), 1.78-1.72 (in, IH), 1.62 2H), 0.97 3H), 0.94 3H).

e) N- [2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[IN-(2pyridinylnethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting benzyloxyphenyl)thiazol-4-ylcarbonyl] hydrazide for (2S, 1 (benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonyltbiazol-4-yl)-3'methylbutyl]-4-methylpentanamide, and N-(2-pyridinylmethoxycarbonyl)-L-Ieucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid (106 mg, 0. 184 rnmol). MS (ESI): 574.2 Example 1 I11 Preparation of (1 24 I -(4-phenviphenvi )-3-methvlbutyllthiazol-4y Icarbon yl fN-(4-pvyri din y Imethoxycarbon D- L-le uc i nyI hydrazide a) 1-(4-phenylphenyl).3-metlylbutyllthiazol-4-ylcarbonylhyrazde Following the procedure of Example 102(a)- 102(d), except substituting 4methyl-2-(4-phenylphenyl)pentanoic acid for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid. MS (ESI): 366.3 b) (1 4 -phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonyl].N..

[N-

(4-pyridinylmethoxycarbonyl)-L-leucinyljhydrazide Following the procedure of Example 103(d), except substituting 1-(4phenylphenyl)-3-methylburyllthiazol-4-ylcarbonyl]hydrazide for (2S,1 4 (benzyloxycarbonyl)amino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4-yl)-3ymethylbutyl-4--methylpentanamide, and N-( 4 -pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a- white solid. MS (ESI): 614.3 Example 112 Preparation of N-r2-(2-benzloxyphenl~thiazol-4-lcarbonl..N'.rN..(4 pyrdinylmethoxycarbonyh-L-leucinyllhydrazide ethyl 2-amidnothiazole-4-carboxylate hydrobromide To a stirring suspension of thiourea (6.0 g, 78.8 mmol) in ethanol (80 mnL) was added ethyl bromopyruvate (15.4 g, 78.8 minol). The resulting solution was heated at 45 0 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 compound (15.8 g, 1 H NMR (400 MHz, CD 3 OD) 8 7.70 IlH), 4.41 (q, 2H), 1.38 3H).

b) ethyl 2-bromothiazole-4-carboxylate To a stirring suspension of the compound of Example 112(a) (12.15 g, 48 mmol) in 16% aqueous HBr (150 mL), cooled to 0 was added drropwis a solution of sodium nitrite (3.44 g, 49.8 mmol) in water (6 mL). After stirring for min, copper bromide (7.83 g, 54.6 mmol) and 16% aqueous HBr (60 mL) were added and the mixture was heated at 70 °C for 1 h. The mixture was filtered and the filtrate was saturated with NaCI then extracted with ethyl acetate (2 X 170 mL).

The combined extracts were dried (MgSO 4 filtered and evaporated to dryness.

The residue was combined with combined with the solid collected in the first filtration, heated at reflux in ethanol (500 mL) for 5 min, 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 concentrated. The residue was partitioned between saturated aqueous NaHCO 3 and ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO4), decolorized with charcoal, filtered and concentrated to provide the title compound as a pale yellow solid (7.46 g, MS (ESI): 236.0 c) 2-benzyloxybromobenzene 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 K 2 C0 3 (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 (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol). 1HNMR (400 MHz, CDC1 3 8 7.62 1H), 7.54 2H), 7.45 (m, 2H), 7.37 1H), 7.28 1H), 6.98 1H), 6.91 1H), 5.17 2H).

d) 2-benzyloxyphenylboronic acid To a stirring solution of the compound of Example 112(c) (15.2 g, 57.8 mmol) in THF (100 mL) at -78 0 C was added dropwise n-BuLi (23.1 mL, 2.5M in hexane, 57.8 mmol). The mixture stirred at -78 0 C for 25 min when added via cannulation to a stirring solution of triisopropylborate (54.4 g, 289 mmol) in THF 145 (100 mnL) at -78-C. After warming to room temperature and stirring for 3h, the mixture was poured into 3N HCI (100 mL) and extracted with ethyl acetate (3 X 200miL). The organic layers were combined, washed successively with water and brine, dried (MgSO 4 filtered and concentrated. The residue was purified by colun chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a pale yellow solid (6.9 g, 30.3 mmol). IBNMIR (400 MHz, CDC1 3 7.90 IH), 7.42 (in, 6H), 7.07 1H), 7.02 IH), 6.05 2H), 5.16 2H).

e) ethyl 2 2 -benzyloxyphenyl)thiazole4-carboxylate To a stirring solution of the compound of Example 112(b) (4.0 g, 16.9 mmnol), the compound of Example 72(d) (4.29 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium(o) (0.65 g, 0.57 mmol) in dimnethoxyethane mL) was added cesium fluoride (8.58 g, 56.5 mmol) and the mixture was heated at 85 *C for 16 h. Tetrakis(triphenylphosphine)palladium(O) (0.65 g.057 mmnol) was added and heating at 85 0 C was continued for 5 h. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 X 120 mL). The combined extracts were washed with saturated aqueous NaHCO 3 and saturated brine, dried NMOW), 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 hexanes, to provide the title compound as a white solid (3.22 g, MS (ESD): 340.3 f) 2 2 -benzyloxyphenyl)thiazol-4-ylcarboiylhydrazide Following the procedure of Example 102(d), except substituting ethyl 24(2benzyloxyphenyl)thiazole-4-carboxylate for (1 1 -benzyloxycarbonylamino- I -4carboethoxythiazol-2-yl)-3-methybuae, the title compound was prepard as a white solid. MS (ESI): 326.2 g) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl-N'-[N-( 4 pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting 2-(2benzyloxyphenyl)thiazole-4-ylcarbonylhydrazide for (2S,1'S)-2- (benzyloxycarbonyl)amino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4-yl)- 3 methylbutyl]-4-methylpentanamide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 574.3 Example 113 Preparation of N-12-N-methyl-N-(4-phenvphevlaminolthiazol-4-carbon Il-N'rN-(4-pvridinylmethoxycarbonyl)-L-leucinyllhydrizide a) N-(4-phenylphenyl)-2-methylpropionamide To a stirring solution of 4-aminobiphenyl (9.53 g, 56.3 mmol) and triethylamine (5.70 g, 56.3 mmol, 7.85 mL) in methylene chloride (60 mL), cooled to 0 was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0 0 C for 1 h, the mixture was diluted with methylene chloride (120 mL) and washed with IN NaOH and saturated brine, then dreid (MgSO4), filtered and concentrated. The residue was washed with ether and dried to provide the title compound as a pale yellow crystalline solid (9.83 g, 1 HNMR (400 MHz, CDCl 3

/CD

3 0D) 8 7.58 21H), 7.50 4H), 7.40-7.25 3H), 2.55-2.49 (m, 1H), 1.18 6H).

b) N-(4-phenylphenyl)-N-(2-methyl- -propyl)amine To a stirring solution of lithium aluminum hydride (58.6 mmol) in THF (58.6 mmol), cooled to 0 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 *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 was evaporated to dryness to proveide the title compound as a pale yellow solid (8.34 g, MS (ESI): 226.2 (M+H) c) N-( 4 -phenylphenyl)-N-(2-methyl- I-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 was added dropwise a solution of the compound of Example 73(b) (540.7 mg, 2.0 mmol) in methylene chloride (1 mL).

After stirring for 2 h. ammonia-satruated methanol (20 mL) was added and the .olution was stirred at room temperatur for 2 h. The solution was concentrated and .the residue was partitioned between ethyl acetate and IN HCI. The organic layer was washed with IN HCI twice, then with saturated brine, then dried (MgSO 4 filtered and concentrated. The residue was purified by flash chromatography on 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, MS (ESI): 285.3 (M+H) d) ethyl 2 4 -phenylphenyl)-N-(2-methyl- 1-propyl)amino]thiazole-4carboxylate A solution of the compound of Example 113(c) (184.6 mg, 0.65 mmol) and ethyl bromopyruvate (126.6 mg, 0.65 mmol, 81.5 uL) in ethanol (2.5 mL) was heated at reflux fo 5 min, then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO 3 The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated brine, dried (MgSO 4 filtered and concentrated. The residue was passed through a plug of 230-400 mesh silica gel, eluting with 12% ethyl acetate in hexanes, to provide the title compound as a pale yellow oil (230 mg, MS (ESI): 381.4 (M+H) e) N-[2-[N-(4-phenylphenyl)-N-(2-methyl- -propyl)amino]thiazol-4ylcarbonyl]hydrazide Following the procedure of Example 102(d), except substituting ethyl 2-[N- 4 -phenylphenyl)-N-(2-methyl- 1-propyl)amino]thiazole-4-carboxylate for (1S)-1 benlzyloxycarbonyl amino- I -(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 367.3 f) N- [N-methyJ-N-(4-phenylphenyl)amiinolthiazol14-ylcarbonylJ-N-[N-(4pyridinylmethoxycarbonyl)-L-leucinyljhydrazide Following the procedure of Example 103(d), except substituting phenylphenyl)-N-(2-methyl- I -propyl)anuinolthiazol4-ylcarbonyllhydrazide for (2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3' methylbutyll-4-methylpentananiide. and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 615.3 Exmple 11 Preparation of N-(N-benzvloxycarbonyl-L-leucinyfl-N'-r2-(4-p2henylbenZyl)thiazol- 4-ylcarbonyllhydrazide a) N-[2-(4-phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 102(a)- 102(d), except substituting 4biphenylacetic acid for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid. MS (ESI): 310.3 b) N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(4-phenylbenzyl)thiazol-4ylcarbonyl]hydrazide Following the procedure of Example'103(d), except substituting phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide for (25,1 (benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanamide, the tidle compound was prepared-as a white solid (20 mg, 0.035 rnmol). MS (ESI): 557.4 ExaMpe 115 Preparation of N-r2-4-p2henylphenylbe-nzvl)thiazoIl-lc~tArbnLY,2-[N' pyridinylmethoxycarbon vl).L..eucinvl ihydrazide Following the procedure of Example 103(d), except substituting phenylbezyl)thizol4ycarbny]hydazide for (2S, I'S)-2- (beazyloxycarbonyl)amno-N..( I -(2-hydrazinocarbonylthiazol-4yl).3'.

methylbutyl]-4methylpentanamide, and N-( 4 -pyridinyhnethoxycarbonyl)-L.eucine for N-benzyloxycarbonyl-L-leucjne, the title compound was prepared as a yellow *solid (30 mg, 0.053 mmol). MS (ESI): 558.2 Example 116 Preparation of N-(N-benzyloxycarbonyl-Lleucinyl r2-fN-42- methy lropvl).N phenvlaminolthiazo]4.ylcarbonyl ihydrazide a) N-[2-(N-phenyl-N.(2-methyl-1-propyl)arnino]thiazol4.

ylcarbonyl]hydrazide Following the procedure of Example 113(a)- I 13(e), except substituting aniline for 4-aminobiphenyl in step the title compound was prepared as an orang-pink solid (276 mg, 0.950 mmol). MS (ESI): 291.3 b) N-(N-benzyoxycarbony[Leucinyl)-N*.[2.[N(2meylpropy)N phenylamino]thiazo14-ylcarbonyhyrai Following the procedure of Example 103(d), except substituting phenyl-N-(2-methyl- Il-propyl)amino]thiazoi-4.ylcarbonyllhydrazide for (2S,1 (benzyloxycarbonyl)amirn,.N-[ 1 -(2-hydrazinocarbonylthiazol4yl)-3'methylbuty]-4-methylenanmide, the title compound was prepared as a white solid (92 mg, 0. 17 1 mmol). MS (ESI): 560.3 Example 117 Preparation of N-r2-[N-(2-methvlpropvl)-N-phenlainolthiazol-4-lcabonvul.N..

[N-(4-pridinlmethoxcarbonl)-L-eucinyvlhycrazide Following the procedure of Example 113(a)-I 13(f), except substituting aniline for 4-aminobiphenyl in step the title compound was prepared as a yellow solid (50 mg, 0.092 mmol). MS (ESI): 539.4 Example 118 Preparation of N-r2-(2-benzyloxyphenyl thiazol-4-lcarbonvll-N- pvridinvlmethoxvcarbonyl-L-leucinvllhvdrazide Following the procedure of Example 112(a)-I 12(g), except substituting N- (3-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (93.8 mg, MS (ESI): 574.3 Example 119 Preparation of N-r2-(2-benyloxyhenylithiazol-4-ylcarbonyll-N'-rN-(2vridinylmethoxcarbonvl-L-leucinllhvdrazide Following the procedure of Example 112(a)-I 12(g), except substituting N- (2-pyridinylmethoxycaxbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (149.7 mg, MS (ESI): 574.4 Example 120 Preparation of N-(N-benzyloxycarbonyl-N-methyl-L-leucinyh-N'-2(2benzvloxyphenyl)thiazol-4-lcarbonyllhydrazide Following the procedure of Example 112(a)-I 12(g), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (153.5 mg, MS (ESI): 609.3 Example 121 Preparation of N- r2 -rN-(2-meth I propy I)-N-p2henvl Iaino thilazo 1-4- ylcarbo nylL1N- 2 -pvridinvlmethoxvcarbonl)-L-leucinllhvclrazide Following the procedure of Example 113(a)-Il 13(f), except substituting aniline for 4-anuinobiphenyl in step and N-(2-pyridinylxnethoxycarbonyl)-L leucine for N-( 4 -pyridinylniethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (40 mg). MS (ESI): 539.4 Example 122 Preparation of N-r 2 -rN-(2-methllpropl)-N-rphenlamnothiazol-4..vlcarbonI1..N'rN-( 3 -pyridinylmethoxycarbonyr)-L-eucinyllhydrazide Following the procedure of Example 113(a)-I 13(f), except substituting aniline for 4-aminobiphenyl in step and N-(3-pyridinylmethoxycarbonyl)-L..leucine for N-( 4 -pyridinylnmethoxycarbonyl)-L-leucine in step the tidle compound was prepared as a white solid (42 mg). MS (ESI): 539.4 Example 123 Preparation of N-r2-(2-niethoxyphenyl tiazol-4-lcarbonyli-N'- pyridinylmethoxycarbonyl)-L-Ieucinvllhvdrazide a) 2 -trimethylstannylanisole -To a stirring solution of n-BuLi (2.6 rnL, 2.5M in hexane, 6.42 mmol) in diethyl ether (2.5 mL) at -78C was added 2-bromoanisole (1.0 g, 5.35 mmol) in ,diethyl ether (2 mnL) dropwise. After stirring for lh at -78C, trirnethyltin chloride (6.4 m.L, 1 .OM in THF, 6.42 mrnol) was added dropwise. The mixture was allowed to stir an additional 2h while slowly warming to room temperature. The mixture was then washed with saturated aqueous NaHCO 3 The aqueous layer was extracted with diethyl ether (1 X 5OmL) and the organic layers were combined, dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (1.11 g, 1 fjNR (400MHz, CDC1 3 87.47 IH), 7.40 lH), 7.05 (t, I 6.90 I1H), 3.36 3H), 0.34 9H).

b) ethyl 2 -(2-methoxyphenyl)thiazole-4-carboxylate A mixture 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 tetrakis(triphenylphosphine)palladium(0) (0.037 g, 0.0318 mmol) in toluene (2 mL) was stirred at reflux for 16h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.081 g, 29%).

1HNMR (400MHz, CDC1 3 8 8.54 1H), 8.22 1H), 7.45 1H), 7.11 1H), 7.05 1H), 4.48 2H), 4.04 3H), 1.46 3H).

c) N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 112(f)-112(g), except substituting ethyl 2-(2-methoxyphenyl)thiazole-4-carboxylate for ethyl 2-(2benzyloxyphenyl)thiazole-4-carboxylate in step the title compound was prepared as a white solid. MS (ESI): 498.3 (M+H) The above description fully discloses how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Example 124 Prep~aration of (2S. I'S)-N-f I -(4-carboethoxthiazoL-2-yJ 3 '-meth lbuvI-4-methvI.

2 2 -phenvlbenzvloxycarbonvl )aminoetaa'de a) (2S, I 2 -(tert-butoxycarbonyl)arzino..N-[ I-(4-carboethoxythiazol-2-yly-3' methylbutylI-4-methylpentanamide The compound of Example 1.2 g, 3.5 mmol) was stirred at room temperature 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 stiring solution was added triethylamine (0.779 g, 7.7 mmol), BOC-Leu-OH (0.972 g, 3.9 mnmol), 1-hydroxybenzotriazole (0.095 g, 0.7 mnxol), and l-(3-dimethylaminopropyl)-3 ethylcarbodlinide hydrochloride (0.750 g, 3.9 mrnol). After stirring at room temperature for 16 hours, the solution was diluted with ethyl actate and washed successively with water (2 X 100 mL), NaHCO 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid 15 g, MS(ESI): 456.2 b) (2S, 1'S '(-abehxtiao--l-'mtybuyj4mty--2 phenylbenzyoxycarbonyl)ainiopenamde To a stirring solution of phosgene (1.5 mL, 2.9 rniol, 1.93M in toluene) at 0* C was added 2-biphenylmethanol (0.486 g, 2.64 mmol) and diiiopropylethylamine (0.375 g, 2.9 mxnol). The solution was allowed to stir at 0 0

C

for 30 min. In a separate reaction vessel, after stirring at room temperature for min, the compound of Example 124(a) 150 g, 0.330 mniol) dissolved in TFA mL) was concentrated and redissolved in DMF (3 mL). This solution was added to the 2 -biphenylmethanol solution followed by diisopropylethylamine (0.2 13 g, 1.65 mrnol). After stirring at room temperature for lh, the solution was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid 138 g, MS(ESI): 566.3 Example 125 Preparation of (2S. l'S )-2-I(2-benzvl)benzyloxycarbonvl)lamino-N-r 1 carboethoxythiazol-2-fl-3'-methvlbutllk4-methvlpentanamide Following the procedure of Example 124(b), except substituting 2benzylbenzyl alcohol for 2-biphenylxnethanol, the title compound was prepared as a white solid 123 g, MS(ESI): 580.0 Example 126 Preparation of (2S. 1 S)-N-f 1 -(4-carboethoxytiazol-2-yfl-3'-methylbutvll-4methyl-2-r(2-naphthylmethoxycarbonvhkniminopentanamjde Following the procedure of Example 124(b), except substituting 2naphthalenemethanol for 2-biphenylmethanol, the title compound was prepared as a white solid 132 g, MS(ESI): 540.1 Exmple127 Preparation of (2S. 1 l -(4-carboethoxythiazol-2-ylh-3'-methylbutyll-4methyl-2-[(3-phenoxybenzvloxycarbonylaminopentaamide Following the procedure of Example 124(b), except substituting 3phenoxybenzyl alcohol for biphenylniethanol, the title compound was prepared as a white solid 107 g, MS(ESI): 581.9 Example 128 Preparation of (2S.1 S 2 -(benzyloxvcarbonl)arnino-.N-r 1 -r2-(2benzylguan inl)thiazol4vyll3'-methylbutl l- 4 -methylpentananiide a) S-methyl dithiobiuret hydrolodide salt To a stirring solution of dithiobiuret (5.0 g, 37 mnmol) in TI-F (75 m.1) was added iodomethane (13.1 g, 92.5 mmol, 5.76 After stirring at room temperature for 22 h, the solution was diluted with 150 mL of tolu ene and allowed to stand at 0 *C for 3 h. The crystals were collected by filtration and washed with ,-,Cold 2:1 tolueneTHiF, then dried in vacua to give the title compound as a white solid (8.7 g, MS(ESI): 149.9 b) 3-benzylguanidinyl thiourea The compound of Example 128(b) 4 .35 g, 15.7 rnmol) was dissolved in isopropanol (80 mL) and benzylamine (1.77 g, 16.5 mrnol, 1.8 mL) was added and the mixture was heated at reflux for 16 h. The hot solution was filtered and the filtrate was cooled to 0 After 5 h, the solid was collected by filtration and washed twice with cold iospropanol, then dried in vacua to provide the title compound as a white solid (2.59 g, 61 MS(ESD: 209.2 c) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ I'-[2-(2-benzylguanidinyl)thiazol.4yij-3 '-methylbutyl]-4-methylpentanamide Following the procedure of Example except substituting 3benzylguanidinyl thiourea for ethyl thiooxamate, the title compound was prepared as a white solid (102 mg, MS(ESI): 565.1 Example 129 Preparation of(is -N-f4-f -(N-benzvoxvcarbonvlaino)-3-methvlbu l vIcarbonvi l-N-methv-N'-(N-benzvl oxvcarbonvl-L-Ieuc invl)hYdrazide Following the procedure of Example 26(a)-26(d), except substituting methyl hydrazine for hydrazine in step the title compound was prepared as a white solid. MS(ESI): 624.1 Example 13 Preparation of (I 1 -(N-benzyloxvcarbonvlamino-3-methybuylthiazol-2vcarbonyll-N'-(N-benzvloxycarbonI-L-Ieucinl)-N'methlhyci.azide a) N-(N-benzyloxycarbonyl-L-leucinyl) N-methylhydrazide Following the procedure of Example 26(c), except substituting Nbenzyloxycarbonyl-L-leucine methyl ester for I -benzyloxycarbonylamino- I 2 -carboethoxythiazol-4-yl)-3-methylbutane and methyl hydrazine for hydrazine, the title compound was prepared.

b) (1 I -benzyloxycarbonylamino- I -(2-carboxythiazol-4-y)-3-methylbutane The compound of Example 26(c)(0.57 1.5 mmol) was dissolved in tetrahydrofuran and treated with an excess of 1.ON sodium hydroxide. The mixture was allowed to stir for 4 hours, and was quenched with 1.ON citric acid. The solvent was evaporated and the aqueous layer extracted three times with dichloromethane. The organic layers were combined and evaporated to give the acid as a white foam (0.55 g, 100%).

c) (1 1-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol2.ylcarbonyl.

N'-(N-benzyloxycarnyl-L-leucinyl)-N'-lyrzd Following the procedure of Example 28(e), except substituting N-(Nbenzyloxycarbonyl-L-leucinyl)-N-methylhydrazide for 1- (benzyloxycarbonyl)axnino- 1 4 -carboethoxythiazol-2-yl)-3-methylbutane and I -benzyloxycarbonylaino 1 2 -carboxythiazol4-yl)-3-methylbutane for Nbeflzyloxycarbonyl-L.leucine, the title compound was prepared as a white solid.

MS (ESI): 624.2 Example 131 Preparation of N-N zlxcroy--ecny)NL-ezlx~~nlL leucinyl)-L-alanv~byd~azide Following the procedure of Example 27(a)-27(c), except substituting

L-

alanine methyl ester for L-leucjne methyl ester in step the title compound was ~prepared as a white solid (225 mg, MS(ESI): 598.1 Preparaion ofExample 132 a Prprto fN-(N-benzyloxycarbonyI.L-leucinyIl.N'-(N-,enzyloxycarbonv-L leucinyl )elvcinvlhydrazide Following the procedure of Example 27(a)-27(c), except substituting glycine methyl ester for L-leucine methyl ester in step the title compound was prepared as a white solid (307 mg, MS(ESI): 584.1 Example 133 Preparation of (1IS)-N-f2-F I-(N-benzyLoxvcarbonyamjno..3-.methylbu~iy V1.3.4a) ethyl oxalamidrazonate To a solution of ethyl thiooxamate (3.0 g, 22.6 mrmol) in ethanol (50 mL) was added hydrazine hydrate 1. 13 g, 22.6 mmol, 1.09 The mixture 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 16 hours and the ethanol was evaporated. The residue was boiled in dichioromethane in petroleum ether, filtered, and recrystallized to give the desired compound as a tan solid. (0.264 g, b) I-benzyloxycarbonvlamino-l1-(2-carboethoxy- 1,3,4-triazol-5-yl)-3methylbutane N-benzyloxycarbonyl-L-leucine (0.535 g, 2.0 minol) was stirred in TIF at Ethyl chloroformate (0.23 mL, 2.4 mrnol) and triethylaznine (0.25 g, 2.4 rnxnol, 0.34 m.L) were added. The compound of Example 10(a) (0.264 g, 2.0 inmol) was then added and the mixture was allowed to stir at room temperature overnight.

The solvents were evaporated and the residue was diissolved in xylenes and heated to 200 0 C using a Dean-Stark apparatus. The heating was stopped after 4 hours and the solution was evaporated to a residue which was chromnatographed (silica gel, 40% ethyl acetate in hexane) to give the title compound as a white solid (0.498 g, IHNMR(400 MHz, CDC 3 87.20(m, 5H), 5.71 IH), 5.04 2H), 4.99 (dd, IH), 4.36(q 1.8(m2H),l1.59(m lH), L.1( t, 3H) ,0.83( dd, 6H).

c) (1 I -benzyloxycarbonylamino- 1 -(2-hydrazinocarbonyl- 1,3 ,4-triazol-5-yl)-3methylbutane Following the procedure of Example 26(c)-26(d). except substituting (IlS)-lbenzyloxycarbonylamino- 1 -(2-carboethoxy- I ,3,4-triazol-5-yl)-3-methylbutane for (IS)-l1-benzyloxycarbonylamino-l1-(2-carboethoxythiazol-y)-3-methylbutane in step the title compound was prepared. MS (ESI): 594.5 Preparation of (1 S)-N-(N-acetv1-L-leucinyl)-N'-r2-I -(N-benzyloxvcarbonylarnino)- 3-methylbutyllthiazol-4-ylcarbonyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting Nacetyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (95 mg, MS(ESI): 518.0 ExaMple 1_35 Preparation of (I S)-N-(N-benzvloxycarbon lL- al anyl [2 Following the procedure of Example 28(a)-28(e), except substituting

N-

benzyloxycarbonyl-L-alanine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (129 mg, MS(ESI): 568.1 Example 136 Preparation of (1 S)-N-(N-acetvl-L-alanyl).N'r2..r 1-(N-benzvloxvcarbonvlanno)-3 Following the procedure of Example 28(a)-28(e), except substituting

N-

acetyl-L-alanine for N-benzyloxycarbonyl..L.leucine in step the title compound was prepared as a white solid (74 mg, MS(ESI): 498.1 (M-iNa)+.

Example 137 Preparation f I(I S)-N-(N-aceiyl)-N'.r2..r -(N-benzvloxycarbon~ylarmjno)-3- Following the procedure of Example 28(a)-28(e), except substituting acetic acid for N-benzyloxycarbonyl.L-.leucine in step the title compound was prepared as a white solid (87 mg, MS(ESI): 405.1 Example 38 Preparation of (1 -(N-benzvloxcrbonyla n)3-nethlbuyl lthiazol-4ylcarbonyllvN'- r-( 4 -tpvridnylmethoxcarboy-Lle illIhyrzde Following the procedure of Example 28(a)-28(e), except substituting N-(4pyridinylmethoxycarbonyl)-LIeucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (121 mg,

MS(ESI):

Example 139 Preparation of (1 S)-N-f2-rl1-(N-benzyloxycarbonylaminol-3-methylbutvllthjazoll-4 ylcarbonvi 1- N'-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting N-(2pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (125 mg, MS (ESI): Example 140 Preparation of (1 S)-N-r2-rl1-(N-benzyloxy-carbonylamino)-3-methylbuyllthiazoI-4vylcarbonyll- N'-(N-benzloxycarbonvl-N-methyl-L-leucinyhhydra7zide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (78 mg, MS (ESI): 624.3 Preparation of (1 S)-N-f2-r I-(N-benzyloxycarbonyl-N-methylamino)-3methylbutyllthiazol-4-ylcarbonyll-N'- rN-(4-pvridinvlmethoxvcarbonyfl-Llecnlhyrzd Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step and N-(2-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid (120 mg, 72%).

MIS (ESI): 625.3 Example 142 Preparation of (1 S)-N-(N-benzyloxycarbonyl.L-Ieucinyl 1-(Nbenzyloxycarbonyl-Nmethviaino)3methylbuiy lthiazol-4-ylcarbonvlb Fhyrazide Following the procedure of Example 28(a)-28(e), except substituting NbenzyloxycarbonyI-N-methypL-eucine for N-trn-butoxycarbonyl-L-leucine in step the title compound was prepared as a white solid (95 mg, MS (ESI): 624.3 Exampl e 143 Preparation of (I S)-N-r2-r I -(N-benzvloxycarbonyI-N-methyapano)..3 ,methylbutyllthiazol-4-,yllcarbonyl- N'-(N-benzyloxvcarbonyI-Nmethyl.L lenylbyydrzd Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methylLleucine for N-tert-butoxycarbonyl-L-leucine in step and N-benzyloxycarbonyl-N-methyl..L-eucine for N-bernzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid (129 mg, 59%).

MS (ESI): 683.3 Example 144 Preparation of (IS 1 ehlaio--etybilthao--lcroyl rN-(4-pvidinvlmethoxycarbonvI)-L..eucinyIhvdride a) I (-etbtxcroy--ehyaio--ehluy~zl4 Following the procedure of Example 28(a)-28(e), except substituting Ntert-butoxycarbonyl.N-.methyl..Lleucine for N-tert-butoxycarbonyl-L-leucine in step and N- 4-pyridixiylmethoxycarbonyl.L-leucine for N-benzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid. MS (ESI): 591.4 b) (1S)-N-[2-[-(N-methylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide To a solution of the compound of Example 21(a) in methylene chloride mL) was added trifluoroacetic acid (3 mL). After stirring one hour at room remperature the solution was concentrated and the residue was redissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over MgSO 4 and concentrated to afford the title compound as a white solid (259 mg, 68% for two steps). MS (ESI): 491.4 Example 145 Preparation of (1 S)-N-r2-f 1 -(N-benzvloxvcarbonvlanino)-3-methvlbutyllthiazol-4ylcarbonvll-N'-rN-(tert-butoxvcarbonvy -L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting N-tenbutoxycarbonyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (293 mg, MS (ESI): 576.4 Example 146 Preparation of (1 1 -(N-benzyloxvcarbonylariino)-3-methylbutyllthiazol-4ylcarbonvll-N'-rN-(tert-butoxcarbonyl)YN-methvl-L-leucinvllhydrazide Following the procedure of Example 28(a)-28(e). except substituting N-tertbutoxycarbonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (120 mg, MS (ESI): 590.3 Exampe 147 Preparation of (1 24[ 1 -(N-benzyloxycarbonylamino)-3-methylbutyllthiazo.4ylcarbonyll-N'-(N-methl-L-leucinl)hydrazide Following the procedure of Example 144(b), except substituting (I [1 -(N-benzyloxycarbonylaxnino)-3-methylbutyllthiazol-4-ylcarbonyl]-N'-[N-(terrbutoxycarbonyl)-N-methyl-L-leucinyljhydrazide for (1 1-(N-tertbutoxycarbonyl-N-methylamino)-3-methylbutyllthiazol-4-ylcarbonyl]-N-[N-(4pyridinylmethoxycarbonyl)-L-leucinyllhydirazide, the title compound was prepared as a White solid (40 mg, MS (ESI): 490.3 Example 148 Preparation of (I 1-(N-benzyloxvcarbonvlaffino)-3-methylbutyllthiazol-4- ylcarbonyll-N'-(L-leucinyl)hydrazide Following the procedure of Example 144(b), except substituting (I (1 -(N-benzyloxycarbonylaxnino)-3-rnethylbutyljthiazol-4-ylcarbonylj-N'-[N-(terbutoxycarbonyl)-L-leucinyl]hydrazide for (15S)-N- 1 -(N-tert-butoxycarbonyl-Nmethylamino)-3-methylbutyl~thazol-4-ylcarbonyl]-N'- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide, the title compound was prepared as a white solid (39 mrg, 100%). MS (ESI): 476.4 ExmJ2le1 Preparation of (1 S')-N-I2-r11-(N-benzyloxycarbonylamino)-3-methylbutylthiazo1-4ylcarbonvll-N'-FN-(4-irridazolylaceryl)-L-leucinyllhvdraide Folloiing the procedure of Example 28(e), except substituting (N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N'-(Lleucinyl)hydrazide for (I1S)- I -(benzyloxycarbonyl)amuno- 1 -(4-carboethoxythiazol- 2-yl)-3-methylbutane and 4-imidazoleacetic acid for N-benzyloxycarbonyl-Lleucine, the title compound was prepared as a white solid (50 mg, MS (ESI): 584.4 Example 150 Preparation of (1 1 .4N-benzvloxycarbonvl-N-methylarmino)-3methylbutiylthiazoI-4-ylcarbonyll-N4-N-(3-pridinylmethoxcarbony1)-N-methyI- L-leucinyl ihydrazide a) N-methyl-L-leucmne methyl ester N-methyl-L-leucine (1.3 g, 8.95 mmol) was dissolved in 4M HCl, 1,4dioxane (10 mL) and methanol (10 mQL. The solution was stirred overnight at room temperature, then concentrated to afford the title compound as a white solid (100%).

MS (ESD: 160.0 b) N-methyl-N-(3-pyridinylinethoxycarbonyl)-L-leucine methyl ester To a stirring solution of phosgene in toluene (5.63 mL, 6.025 minol) in methylene chloride (10 niL), cooled to OOC, was added dropwise a solution of Nmethyl-L-leucine methyl ester (673 mig, 4.63 mmol) and pyridine 10 g, 0.97 niL, 13.89 nimol) in methylene chloride (4 niL). The solution was stirred at 0"C for 2 hours. A solution of 3-pyridyl carbinol (0.56 g, 5.09 nimol, 0.49 niL) was then added and the reaction mixture was stirred at room temperature for 5 hours. Thbe solution was concentrated, redissolved in ethyl acetate, washed with water, dried (MgSO 4 filtered and concentrated. The crude residue was purified by column chromatography on silica gel methanol in methylene chloride) to afford the title compound as a yellow oil (88 mig, MS (ESI): 295.4 c) N-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucine Following the procedure of Example 130(b), except substituting N-methyl- N-(3-pyridinylxnethoxycarbonyl)-L-leucine methyl ester (1 1benzyloxycarbonylamino- 1-(2-hydrazinocarbonylthiazol-4-yl)-3-methylbutane, the title compound was prepared as an orange solid (84 mg, 100%). MS (ESI): 281.3 d) (IS -[1-(N-benzyloxycarbony1-Nmethyaino-3methvlbutyIIhazol-4 ylabnl-'[-3prdniehxcroy)Nmty--ecnlhvrzd Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L..eucine for N-tert-butoxycarbonyl-L..leucine in step and N-methyl-N-(3-pyridinylmethoxycarbonyl).L-.leucine for Nbenzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (55 mg, MS (ESI): 639.4 Example 151 Preparation of (I S)-N-r2-f I -(N-benzyloxycarbonyl-N-methvlanmano-3.

methylbutyllthiazol..4-vlcarbonyl l-N'-rN-(3-pvyridinylmethoxycarbonvl)L-.

leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L.leucine for N-tert-butoxycarbonyl-L-leucine in step and N-( 3 -pyridnylmethoxycarbonyl)..L-leucine for N-benzyloxycarbonyl-L.

leucine in step the title compound was prepared as a white solid (31 mg, 34%).

MS (ESI): 625.4 Example 152 P~reparation of (1S)-N-f2-I I-(N-benzylxycarboylaino-3mthylbuyl1thioI4- ,.ycarbonyll- N'f-3RbiymtoyabnD--ecn-jyrzd Following the procedure of Example 28(a)-28(e), except substituting N-(3pyridimylnlethoxycarbonyl)-Lleucine for N-benzyloxycarbonyl-L..leucine in step the title compound was prepared as a white solid (63 mg, MS (ESI): 611.5 (M+H) 4 Example 153 Preparation of (I'S )-N-(N-benzvioxycarbonyl-L-leuciflI)-N'-( 1ben zyloxycarbonv!)-N- f2-[ 1 -(N-methvl amino)-3 -methylbutyl Ithiazol-4yicarbonvi l-N'-methvlhydrazide Following the procedure of Example, 28(a)-28(e), except substitut~ing Nbenzyloxycarbanyl-N-methyl-L-leuicifle for N-tert-butoxycarbonyl-L-leucine in step and methyl hydrazine for hydrazine in step the title compound was prepared as a white solid (80 mg, MS (ESI): 660.4 Example 154 Preparation of (1 24 1 -(N-benzyloxycarbonylaniino)-3-methvlbutyllthiazol-4vicarbonvil- N'-FN-(2-pvridinylmethoxycarbonyl)-N-nhethv-L-leucinvllhvdrazide a) N-methyl-N-(2-pyridinyimethoxycarbolyl)-L-leucifle methyl ester N-(2-pyridinylmethoxycarbonyl)-L-leucine methyl ester (490 mng, 1.75 rninol) was dissolved in THF (7.0 mL) and methyl iodide (0.435 mL, 6.99 mrnol) was added. The reaction mixture was cooled to 0"C in a flask protected from moisture. Sodium hydride dispersion (236 mg, 2.62 mmol) was added cautiously and the suspension was stirred for 5 hours at room temperature. Ethyl acetate was then added, followed by water, dropwise. The solution was concentrated in vacuo, and the oily residue partitioned between ether and water. The organic layer was washed with saturated aqueous Na1HCO 3 and the combined aqueous extracts acidified to pH 3 with citric acid. The product was extracted with ethyl acetate, the extract was washed with water, 5% aqueous -sodium thiosulfate and water, dried (MgSO 4 filtered and concentrated. The crude product was purified by column chromatography on silca gel (ethyl acetate/ hexane, 3: 1) to give a yellow oil (235 mg, MS (ESI): 295.4 b) N-methyl-N-(2-pyridinylmethoxycarbonyl)-Leucine Following the procedure of Example 130(b), except substituting N-methyl-

N-(

2 -pyridinylmethoxycarbonyl)-L-leucine methyl ester benzyloxycarbonylaninol-( 2 -hydrazinocarbonylthiazol4-yl).3.methylbutane the title compound was prepared as a white solid (223 mg, 100%). MS (ESI): 281.3 c) (1 l-(N-benzylox ycarbonylamino)-3-methylbutyllthiazo1Aylcabol]- 2 -pyridinylmethoxycarbonyl)-N-methyl-L-leucinyl]hydrazide -Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-ter-butoxycarbonyl-L-leucine in step and N-methyl-N-(2-pyridinylmethoxycaronyi)-L-eucine for NbenzyloxycarbonylLleucine in step the title compound was prepared as a white solid (50 rg, MS (ESI): 639.5 Example 155 Preparation of (1S)-N-r2-1 -(N-benzyloxvcarbonvl-N-methylamino)-3methlbutyllthiazol-4-vlcarbonvyl-N'-f(41.idiflylmethoxcarbovl)-N-methvl- L-leucinllhdrazide a) L-leucine tert-butyl ester isocyanate L-leucine tert-butyl ester hydrochloride (10.185 g, 45.5 rmol) was Yssolved in methylene chloride (100 rnL), cooled to 0 OC and pyridine (12.7 ruL, 182.0 mmol) was added, then phosgene in benzene (47 mL, 59.1 mmol). The solution was stirred at 0 OC for 2 hours. The reaction mixture was washed two times with 300 mL of cold 0.5 M aqueous HCI. Each aqueous layer was exctacted with 100 mL methylene chloride. The combined organic phases were washed with a mixture of saturated aqueous NaCI solution and crushed ice, dried over MgSO 4 filtered and concentrated to afford the isocyanate as a yellow liquid (5.37 g, 168 b) N-( 4 -pyridinylmethoxycarbonyl)-L-leucine tert-butyl ester The compound of Example 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 overnight. The solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/ hexane, 3:1) to afford the title compound as a colorless oil (2.945 g, MS (ESI): 323.4 c) N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine tert-butyl ester Following the procedure of Example 154(a), except substituting N-(4pyridinylmethoxycarbonyl)-L-leucine tert-butyl ester for N-(2pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a yellow liquid (2.038 g, 68% yield). MS (ESI): 337.5 d) N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine Following the procedure of Example 144(b), except substituting N-methyl- N-(4-pyridinylmethoxycarbonyl)-L-leucine tert-butyl ester for I -(N-tertbutoxycarbonyl-N-methylamino)-3-methylbutyl]thiazol4-ylcarbonyl-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide, the title compound was prepared as a white solid (343 mg, 72% yield). MS (ESI): 281.3 e) -(N-benzyloxycarbonyl-N-methylamino)-3-methylbutyl]thjazol-4ylcarbonyl]-N'-rN-(4-pyridinylmethoxycarbnyl)-N-methyl-L-leucinyl]hydrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step and N-methyI-N-(4-pyridinylmethoxycarbonyl)-L-leucine for N- benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (50 mg, MS (ESI): 639.5 169 Example 156 Preparation off 2 'r.'Fis-(N-acIQlLlecUCflL carbohydrazide Following the procedure of Example 29, except substituting N-acetyl-L.

leucine for N-benzyloxycarbonylLleucine, the title compound was prepared as a pale yellow solid 153 g, MS(ESI): 401.3 Example 157 Preparation of 2 -fN N-benzoxcaonlLleucinl)l2-[N( 4 methylpentanoyl) icarbohydrazide a) N-benzyloxycarbonylLleucine methyl ester To a stirring solution of L-leucine methyl ester (2.0 g, 11.0 mmol) in 1,4dioxane (20 mL) was added aqueous Na 2

CO

3 solution (12.1 mL, 2M in H 2 0) followed by beflzylchloroforrnate (1.96 g, 11.5 mmol). The mixture stirred at room temperature for 4h then partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried (MgS 04), filtered and concentrated to yield the title compound as a colorless oil 1 g, 100%). 1 HNMR.fl (4'3OMHz,

CDCI

3 8 7.34 (in, 5H), 5.27 1H), 5.12 2H), 4.41 28), 3.75 3H), 1.65 (mn, 3H), 0.96 (mn, 6H).

b) N-NbnyoyabnlLluiy~yrzd To a stirring solution of the compound of Example 157(a) 3 .l1g, I11.Oinmol) in_;methanol (15 inL) was added hydrazide hydrate (5.9 g, 118 inmol, 5.7 mL). The solution stirred at room temperature for 16 h then concentrated to yield the title compound as an off-white solid (3.1 g, 100%). MS(ESI): 280.2 c) 1-ezloyabo1ain--ety 3 4 To a stirring solution of the compound of Example 157(b) (3.0 g, 10.8 inmol) in toluene (50 inL) was added phosgene (56 mL, 1 .93M in toluene). The solution was heated at reflux for 4h, then concentrated to yield the title compound as a pale yellow foam (3.15 g, MS(ESI): 306.1 d) N-(4-methylpentanoyl)hydrazide To a stirring solution of ethyl isocaproate (2.0 g, 13.8 mxnol) in ethanol mL) was added hydrazine monohydrate (6.9g, 1 38mmol, 6.7 mL). After stirring at room temperature for 48 h, the solution was concentrated to yield the title compound as a white solid. (1.8 g, 100%). IHNMR (400MHz, CDCl3) 5 7.48 (s br, LH), 3.62 (s br, 2H), 2.13 2H), 1.51 3H), 0.85 6H).

e) 2-N(-ezlxcroy--ecnl]2-N-4 methylpentanoyl)]cabohydrazide The compounds of Example 157(c) 100 g, 0.325 mmol) and Example 34(d) (0.042 g, 0.325 mmnol) were combined and dissolved in ethanol (1 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, MS(ESD): 436.2 Example 158 Preparation of 2.'r.'ri-NhRyIj~cr- 1--ehlL leucinyU)llcarbohydrazide Following the procedure of Example 29, except substituting

N-

benzyloxycarbonyl-N-methyl-L-leucine for substituting N-benzyloxycarbonyl-Lleucine, the title compound was prepared with purification by-column chromatography (silica gel, methanol/dichloromethafle) as a white foam (0.236 g, MS 613.2.

Example 159 Preparation of 2-FN-(N-acetyl-L-leucinvl )l-2'-[N'-(N-benzyloxvcarbonvl.Lleucinvl)lcarbohydrazide a) 2 -[N-(N-benzyloxycarbonylLeucinyl)]carbohydrazjde To a stirring solution of the compound of Example 157(c) (3.15 g, 10.3 mmol) in methanol (2 mL) was added hydrazine hydrate (5.0 g, 100 mxnol, 4.8 mL).

After stirring at room temperature for 24 h, the solution was concentrated to yield the title compound as a pale yellow foam (3.471 g, 100%). MS(ESI): 338.2 b) 2-N(-ctlLluiy)-'-N-NbnyoyabnlL leucinyl)Icarbohydrazide To a stirring solution of the compound of Example 159(a) (0'.100 g, 0.297 mmol), N-acetyl-L-Ieucine (0.054 g, 0.312 mmol) and 1 -hydroxybenzotriazole (0-008 g, 0.0594 mmol) in DMF (2mL) was added l-( 3 -dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0.060 g, 0.3 12 mmol). After stirring at room temperature for 16 h, the solution was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, methanolldichloromethane) to yield the title compound as a white solid (0.052 g, MS(ESI): 493.1 Example 160 Reparation of IN.N'-Lbis- fN-(4-pvridinylmethoxycarbonyl)yL.

leucinvl)111carIohvdrazide Following the procedure of Example 29, except substituting pyridinylrnethoxycarbonyl).L-leucine for N-benzyloxycarbonyl-Lleucine, the title compound was prepared as a white solid (199 mng, MS(ESI): 587.1 Example 161 Preparation of 2.2'-[N.N'-fbis-[N-(2-pvridinlmethoxcarbonyl)L.

leucinvl)lllcarbohydrazide Following the procedure of Example 29, except substituting N-(2pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine. the title compound was prepared as a white solid (263 mg, MS(ESI): 587.1 Example 162 Preparation of 2-fN-(N-benzvyoxcarbonvl--leucinviy-2 r'-jN-N(2 pvridinvlmethoxycarbonyl )-L-leucinll Icarbohydrazide Following the procedure of Example 159(a)-159(b) except substituting N-(2pyridinylmethoxycarbonyl)-Lleucine lithium salt for N-acetyl-L-leucine in step the title compound was prepared as a white solid (0.040 g, MS(ESI): 586.3 Example 163 Preparation of 2 -rN-(N-benzvloxcarbonyl--leucinyl)1.2'jN'jN-(4 pyridinylmethoxcarn nvl)L-leucinl)l Following the procedure of Example 159(a)-59(b) except substituting N-(4pyridinylmethoxycarbonyl)-L-leucine lithium salt for N-acetyl-L-leucine in step the title compound was prepared as a white solid (0.045 g, MS(ESD: 586.3 Example 164 Preparation of 2 -rN-N-benzloxycarbony-l--.eucinl)l pyridinvlmethoxycarbonvl)-L-leuciny llarbohydzide Following the procedure of Example. 159(a)- 159(b) except substituting N-(3pyridinylmethoxycarbonyl)-L-leucine lithium salt for N-acetyl-L-leucine in step the title compound was prepared as a white solid (0.084 g, MS(ESI): 586.3 Example 165 Preparation of 2 2 -[NN-fbis-(N-benzloxcarbonyLeuIny)1.2.(Nmethyl )carbohydrazide a) N-methy1-N(N-benzyloxycarbonyI-Leucinyl)hydraide To a stirring solution of N-benzyloxycarbonyl-L-leucine methyl ester (2.2 ga 8.15 mrnol) in methanol (4 m.L) was added methylhydrazine (3.7 g, 80 mmnol).

After stirring at room temperature for 16 hi, the solution was concentrated to yield the title compound as a yellow solid (2.14 g, 7.3 mxnol). MS(ESI): 294.1 b) zlxcroy--ecny)12(-ehlcroyrzd The compound of Example 157(c) (0.250 g, 0.819 mmol) and the compound 0 of Example 165(a) (0.240 g. 0.8 19 mmol) were combined, dissolved in ethanol and heated at reflux for 24 h. The solution was concentrated and the residue purified by column chromatography (silica gel, methanolldichloromethane) to yield the title compound as a white solid (0.060 g, MS(ESI): 599.1 Example 166 Preparation of rN.N'-[bis-FN-(3-pridinvlmethoxycarbonyl).Lleucinyflfllicarbohydrazide Following the procedure of Example 29 except substituting N-(3pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid (157 mg, MS(ESI): 587.0 Example 167 Preparation of I -(N-benzfl)-2.2'-FN.N'-[bis-(N-benzvloxcarbonlL.

leucinyl)llcarbohydrazide a) N-benzylidene-N'-(N-benzyloxycarbonyl-L..leucinyl)hydrazjde To a solution of the compound of Example 157(b) (1 g, 3.5 mmol) in ethanol (30 mL) was added benzaldehyde 0.33 mL, 3.2 mmol). The resulting mixture was heated at reflux for 4 h. The mixture was concentrated in vacuc then purified by flash chromatography (silica gel, 10-50% EtOAc hexane) to yield the title compound as a solid (0.31 g, MS(ESI): 368.0 b) N-benzyl-N'-CN-benzyloxycarbonyl-L-euciny1)hydrazide To a cooled solution of compound of Example 167(a) (0.24 g, 0.65 minol) in THF (5 mL) was added borane tetrahydrofuran complex (0.65 mL, 0.65 mmol; I M solution in THF). The resulting mixture was stirred at room temperature for 4 h then concentrated in vacuo and diluted with ethyl acetate, washed with water, saturated brine, dried (MgSO 4 filtered and concentrated in vacuo to give the title compound as a white solid (0.25 g, MS(ESD: 370.0 c) 1 -benzyloxycarbonylamino-3-methyl-l1-(3-benzyl-l ,3,4-oxadiazol-2-on-5yl)butane Following the procedure of Example 157(c), except substituting N-benzyl- N'-(N-benzyloxycarbonyl-L-Ieucinyl)hydrazide for N-(N-benzyloxycarbonyl-L- Ieucinyl)hydrazide, the title compound was prepared as an oil (0.02 g, 83%).

MS(ESI): 396.0 d) 1-Nbny)2[-NbnyoyabnlLluiy)croyrzd Following the procedure of Example 159(a), except substituting Ibenzyloxycarbonylamino-3-metiyl- 1 -(3-benzyl- 1,3,4-oxadiazol-2-on-5-yl)butane for 1 -benzyloxycarbonylamino-3-methyl. 1-(1 ,3,4-oxadiazol-2-on-5-yl)butane in step the title compound was prepared as a solid (0.013 g, MS(ESI): 428.0 d) 1 (-ezl-,'[,'fl-Nbnyoxcroy--ecnl]croyrzd Following the procedure of Example 159(a)-159(b), except substituting Ibenzyloxycarbonylamjnc.-3-methyl- I -(3-benzyl- 1 3 4 -oxadiazol-2-on-5 -yl)butane for 1 -benzyloxycarbonylaniino-3-methyl- 1 4 -oxadiazol-2 -on -5-yl) butane in step the title compound was prepared as white solid (13 mg, MS(ESI): 675.0 Example 168 :Prep~aration of 2- rN-(N-benzyloxycarbonyl-L-Ieucinvl

FN'-(N-

benZyloxycarbonyl-N-methyI-L-leucinv1)lcarbohydrazide Following the procedure of Example 159(a)-1I59(b) except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine in step the title compound was prepared as a white solid (0.141 g, MS(ESI): 599.4 Example 169 Preparation of 1-naphthyl)thiazol-4ylcarbonyll-N'-rN-(4pyrdinvlmethoxycarbonyh)-L-1eucinyllhydrazide Following the procedure of Example 1 12(a)- I 12(g), except substituting 1 nAphthyI boronic acid for 2-benzyloxyphenyl boronic acid in step the title compound was prepared as a white solid (0.094 g, MS(ESI): 518.4 Example 170 Preparation of N-[2-(2-bipDhenyl)thiazoI-4vycarbonyl1-N'-rN-(4pyridinylmethoxycarbonyl)-L-leucinyllhydiide Following the procedure of Example 1 12(a)- I 12(g), except substituting 2biphenylboronic acid for 2-benzyloxyphenyl boronic acid in step the title compound was prepared as a white solid 100 g, MS(ESI): 544.3 176 Example 171 Preparation of N-(N-benzvloxvcarbonl-N-methl-L-leucinl)-N'-[2-[N-(2methylpropvl)-N-phenylaminolthiazol-4-vlcarbonyllhydrazide Following the procedure of Example 116(a)-I 16(b), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (40 mg, MS 552.5 Example 172 Preparation of N-fN-methl-N-(2-pridinlmethoxycarbonvl)-L-leucinyll-N-[2- N- (2-methvlpropyl)-N-phenylaminolthiazol-4-ylcarbonllhydrazide Following the procedure of Example 116(a)- 16(b), except substituting Nmethyl-N-(2-pyridinylIethoxycarbonyl)-L-leucine for N-(4pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid solid (70 mg, 7 MS 553.4 Example 173 Preparation of N-I2-(2-benzloxphenylthiazol-4-ylcarboyll-N'-(N-rertbutoxycarbonvl-L-leucinyl hvdrazide Following the procedure of Example 112(a)-I 12(g), except substituting Ntert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (1.015 g, 94%).

MS(ESI): 539.1 Example 174 Preparation of N-(N-rerr-butoxycarbonyl-L-leucinyl)-N'-[2-[N-(2-methylroyl)-Nphenylaminolthiazol-4-vlcarbonyllhvdrazide Following the procedure of Example 116(a)-I 16(b), except substituting Ntert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in' step the title compound was prepared as a white solid (740 mg, MS 504.4 (MiH)+.

Example 175 Preparation of N-(N-tert-butoxycarbonl-N-methv..L.eucinyl methylpropv1)-Nphenylamjnolthiazo1.4.ylcabony1 ihydrazide Following the procedure of Example I116(a)-Il 16(b), except substituting Ntert-butoxycarbonyl-Nmethyl..L-leucine for N-( 4 -pyridinylmethoxycarbonyl).L.

leucine in step the title compound was prepared as a white solid (6 10 mg, 69%).

MS (ESI): 518.4 -Example 176 PrepaLration of N-f 2 -(2-benzyloxyphenvI)thiazol..4vylcaibnvI1Ns(Npvyrazinecarbnyl-L-leucinyl ~hydrazide a) N-2(-ezlxpey~hao--lcroy]N-Lluiy~yrzd Following the procedure of Example 144(b), except substituting benzyloxyphenyl)thiazol4ylcarbonyI]-NI(N..te,.t.butoxycarbonlIL- Ieucinyl)hydrazide for (1 1 -(N-tert-butoxycarbonyl-N-methylamio).3 mehluyjhao--labnl-'[-4prdnlehxcroy)L leucinyl]hydrazide, the title compound was prepared as a white powder (0.766 g, MS(ESI): 439.3 b) N-2(-ezlxpey~hao--laroy]N-N(-yaiycroy)L leucinyllhydrazide Following the procedure of Example 116(b), except substituting benzyloxypheny)thiazo1-ylcarbonyl1]N-(L-eucinyl)hydrazide for N-f 2-[Nphenyl-N-(2-methyl- 1 -propyl)axmo) hiazoIA4-ylcarbonyl]hydrazide and pyrazinecarboxylic acid for N-( 4 -pyridinylmethoxycarbonyl).Lleucine, the title compound was prepared as a white solid 146 g, MS(ESI): 545.4 Example 177 Preparation of N-r2-(2-benzyloxyvphenyl)thiazol-4-ylcarbon11 'N4N.isoiqaio1.

L-leucinyl')hydrazide Following the procedure of Example 176(a)- I 76(b), except substituting isonicotinic acid for pyrazinecarboxylic acid in step the title compound was prepared as a white solid (0.135 g, MS(ESI): 544.3 (M+H) t Example 178 Preparation of N-r2-(2-dbenzofuranflthiazol4-ylcarbonyll-N'-rN-(4pvyridinylmethoxycarbonyfl-L-leucinyllhydraide Following the procedure of Example 112(a)- I 12(g), except substituting 2bromodibenzofuran for 2-benzyloxybromobenzene in step the& title compound was prepared as a white solid (0.079 g, M4S(ESI): 558.3 Example 179 Preparation of N-r2-rN-(2-methylpropvyl)-N-p2henylaminoltiazol-ylcarbonyl 1-N'- (N-p2yrazinecarbonyl-L-leucinylhvdrazide Following the procedure of Example 176(a)-i 176(b), except substituting N- (N-tert-butoxycarbonyl-L-leucinyl)-N'-[2- [N-(2-methylpropyi)-Nphenylaminolthiazol-4ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol- 4 -ylcarbonyl]-N'-(N-tert-butoxycarbonylLleucinyl)hydrazde in step the title compound was prepared as a white solid (36 mg, MS (ESI): 510.4 Exw26 18 Preparation of N-[ 2 -[N-(2-methvypRoyl'-NiphenvlanminolthiazoI4vycarbonyllvN'.

(N-methyl-N-pyrainecarbonyl-L-leucinvI)hdaide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-terr-butoxycarbonyl-N-methyl-L-eucinyl).N'-.[2-[N-(2-methylpropyl)-Nphenylamino]thiazol.4.ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol- 4 -ylcarbonyl]-N-(N-ter-butoxycarbony[Leucinyl)hyrazde in step the title compound was prepared as a white solid (70 mg, MS (ESI): 524.4 Example 181 Preparation of N-IN-isonicotinoy-L-L..eucinyl 2 -fN-(2-methvlpropvi p2henylaminolthjazol-4vlcarbonyl hy-drazide Following the procedure of Example 176(a)- 176(b), except substituting

N-

(N-tert-butoxycarbony.NmethylLleucinyl)-N'[ 2 (N-(2-methylpropyl)-N phnlriotizl4ycroy~yrzd for N-2.2bpyoyhnltizl 4-labnl-'(-etbtxyabnlLluiy~ymd in step and isonicotinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (28 mg, MS (ESI): 509.4 Example 182 Preparation of N-(N-is nicotinov[NmethylLleucinyl-N-f -r( 2 methylpropy )-N-phen laminoltiazoI-4vIcarnyllhydraide Following the procedure of Example 176(a)- I 76(b), except substituting

N-

(N.ely--etbtxcroy--ehlLluiy)N-2[-2 mehlrpl--hnlmiotizl4ycroy~yrzd for N- benzyloxypheny)tiazoI4ycaronylNtNte.t-butoxycarbofyl-L leucinyl)hydrazide in step and isonicotinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (117 mg,

MS

(ESI): 523.4 o Example 183 Preparation of N-[N-(4-irnidazolvlacetvl)-L-leucinyl 1-N'-[2-fN-(2-methylpropvl)-N.

p2henylarninolthiazol-4-ylcarbonyllhydrazide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2- [N-(2-methylpropyl)-Nphenylaininolthiazol-4-ylcarbonyllhydrazide for N-[2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyl]-N'.-(N-terr-butoxycarbonyl-L-leucinyl)hydrazide in step and 4imidazolylacetic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (60 mg, 'HNMR (400MiHz, CDCl 3 8 7.62-7.23 (in, 8H), 6.81 IH), 4.72-4.66 (mn, 1H), 3.75 1H), 3.55 2H), 1.96-1.93 (mn, 2H), 1.76-1.54 (mn, 3H), 0.96-0.84 (mn, 12H).

Example 184 Preparation of N4-f2-rN-(2-methylpropfl)-N-phenylaminolthiazol-4-vlcarbonyll-N'- (N-p2icolinoyl-L-leucinyl)hydrazide Following the procedure of Example 176(a)-i 76(b), except substituting N- (N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2-[N-(2-methylpropyl)-Nphenyl amino]jthiazol-4-ylcarbonylj hydrazide for N-[2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyl]-N'-(N-tern-butoxycarbonyl-L-leucinyl)hydrazide in step and picolinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (50 mug, MS (ESI): 509.5 Preparation of N-r2-(2-benzyloxyphenyluthiazol-4-ylcarbonyllmethyI pyridinylinethoxycarbonyl)-L-leucinaniide a) 2-(2-benzyloxyphenylthiazole-4-carboxylic acid Following the procedure of Example 105(b), except substituting ethyl 2-(2benzyloxyphenyl)thiazole-4-carboxylate for methyl 3-(4pyridinyUinethoxy)benzoate, the title compound was prepared as a white solid (0.361 g, MS(ESI): 312.2 b) 2-(2-benzyloxyphenyl)thiazol-4-yl bromomethyl ketone Following the procedure of Example 103(a), except substituting 2-(2benzyloxyphenylthiazole-4-carboxylic acid for N-benzyloxycarbonyl-L-Leucinyl-L- Leucine, the title compound was prepared as a white solid (0.327 g, 73%).

MS(ESI): 388.2 (M+H) c) 2-(2-benzyloxyphenyl)thiazol-4-yl azidomethyl ketone A solution of the compound of Example 185(b), (0.319 g, 0.822 mmol), _.sodium azide (0.064 g. 0.987 mmol), and potassium fluoride (0.072 g, 1.23 mmol) in DMF (6 mL) was stirred at room temperature for 16 h. The solution was then diluted with ethyl acetate and washed successively with water, saturated aqueous sodium hydrogen carbonate, and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.087 g, MS(ESI): 373.3 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 mL) at 0"C, was added sodium borohydride (0.031 g, 0.820 mmol) slowly. After 20 min the mixture was diluted with ethyl acetate and washed with water then brine. The organic layer was dried (MgSO 4 filtered and concentrated to yield the title compound as a white solid (0.084 g, 1

HNMR

(400MHz, CDC1 3 8.41 1H), 7.50 2H), 7.38 4H), 7.11 3H), 5.31 2H), 5.08 1H), 3.69 2H), 3.58 (s b, 1H).

e) 2-amino-1-[ 2 -(2-benzyloxyphenyl)thiazol-4-yl]-1 -hydroxyethane To a stirring solution of the compound of Example 185(d) (0.084 g, 0.239 mmol) in methanol (2 mL) was added stannous chloride dihydrate (0.108 g, 0.478 mmol). After stirring at room temperature for 16 h, the mixture was diluted with ethyl acetate and washed successively with water, saturated aqueous NaHCO 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The 182 residue was purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as a white solid (0.07 MS(ESI): 327.3 (M4H)+.

f) 1-[2-(2-benzyloxyphenyl)thiazol-4-ylj-l -hydroxy-2-(4pyridinylmethoxycarbonyl-L-leucinylamino)ethane Following the procedure of Example -116(b), except substituting 2 -amino- I [2-(2-benzyloxyphenyl)thiazol4-yll- I -hydroxyethane for N-[2-[N-phenyl-N-(2methyl-I -propyl)aninolthiazol-4-ylcarbonyl]hydrazide, the title compound was prepared as a white solid (0.075 g, MS(ESI): 575.4 g) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]methyl pyridinylmethoxycarbonyl)-L-leucinamide To a stirring solution of the compound of Example 185(f) (0.075 g, 0.131 rmol) in dichloromethane (I mL) was added MnO 2 (0.300 g, 3.45 mmol). After stirring at room temperature for 24 h, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as a pale yellow solid (0.0 17 g, MS(ESI): 573.4 Exa=I~e 186 Preparation of N-f2--methyl-N-(2-methyl~ro~yl)aminolth azol-4-ylcarbonyll-N'rN-(4-pyridinlmethoxvcarbonyl-l-leucinyllhvdrazide a) N-benzoyl-N'-methyl-N'.(2-methylpopyl)thiourea To a stirring solution of N-methylisobutylanine (3.21 g, 36.8 mmol. 4.45 mL) in 40 rL of CHC1 3 was Added beuzoyl isothiocyanate (6.0 g, 36.8 mmol, 4.95 mL). After stirring for 45 min, the solution was concentrated to yield the title compound as a pale yellow solid (9.22 g, 100%). IHNMR (400MHz, CDC1 3 2:1 mixture of rotamers) 857.86 2H), 7.60 lH), 7.50 2H), 3.90 2H), 3.44 (s, 31-1), 3.41 2H), 3.27 3H), 2.35-2.32 1H), 2.13 1H), 1.06 6H), 0.90 6H).

b) N-merhyl-N-(2-methylpropyl)thiourea The compound of Example 186(a) (9.22 g, 36.8 mmol) was Suspended in mL of 1:1 methanol/water and solid potassium carbonate (15.27 g, 110 mmol) was added. The mixture was heated at reflux for 48 h, then cooled and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated brine, dried (MgSO 4 filtered and concentrated to provide the title compound as a pale yellow -crystalline solid (4.82 g, MS(ESI): 147.0 c) N-[2-N-methyl-N-(2-methylpropyl)amino]t -l]N pyridinylmethoxycarbonyl)--leucinyl hydrazide Following the procedure of Example 113(d)- 13(0, except substituting Nmethyl-N-(2-methylpropyl)thiourea for N-(4-phenylphenyl)-N-(2-methyl- 1propyl)thiourea in step the title compound was prepared as a white solid (202 mg, MS(ESI): 477.4 Example 187 Preparation of N-(N-methyI-N-picolinoy-Lieucinyl )-N'-2.rN-(2methylpropvI)-Nphenylaminolthiazol-4-vlcarbonyllhvdrazide Following the procedure of Example 176(a)-i 76(b), except substituting N- (N-methyl-N-tert-butoxycarbonyl-N-methyl-L methylpropyl)-N-phenylamino]thiazol-4- yl ]hydrazide for benzyloxypheny)tfiazolAylcarbonylN'(Nebutoxycarony1L leucinyl)hydrazide in step and picolinic acid for pyrazinecarboxylic aicd in Step the title compound was prepared as a white solid (30 mg, MS (ESI): 523.5 Example 188 Preparation of N-F2-(2-benzloxphenvl)thiazol4vlcarbonyll-N.rN-(2.

pvyridinesulfonyl)-L-1eucinyllhydrazide a) 2-pyridinesulfonylchloride Through a stiuring solution of 2-mercaptopyridine (2.235 g, 20 mxnol) in water (7.5 mL) and concentrated HCI (26 mL) at 0 *C was bubbled Cl 2 After 75 mL of ice water was added and extracted with cold ether (2 X The organic layers were combined and washed successively with cold 10% aqueous NaHCO 3 and cold brine. The organic layer was dried (MgSO 4 filtered and concentrated to yield the title compound as a clear oil. (3.1 g, 87%).

b) N-2(-ezlxpey~bizl4ycabnl-'[-2prdnsloy)L leucinyl~hydrazide To a stirring solution of the compound of Example 176(a) 125 g, 0.285 mmol), and the compound of Example 188(a) 10 1 g, 0.57 1 mmol) in dichloromethane (2 mL) was added N-methylmorpholine (0.057 g, 0.57 1 mmol).

After stirring at room temperature for 10 min the solution was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried .(MgSO 4 filtered and concentrated. 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, 6 MS(ESI): 580.2 Eample-189 Preparation of N-r 2 -[N-(2-methylpropyfl..N-phenylamianolthiazol-4.vlcarbonyll.N..

rN-(2-pvridinesulfonyl)-L-eucinlhydrazide Following the procedure of Example 188(b), except substituting N-(Lleucinyl)-N'- 2 -[N-(2-methylpropyl)-N-phenylamino]thiazol-4.

ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol.4-ylcarbonyl].N'-(Lleucinyl)hydrazide, the title compound was prepared as an orange solid (56 mg, MS (ESI): 545.3 Example 190 Preparation of N-r2-rN-(2-methvlpropl y)-N-phenylaxniinolthiazol.4vcabon 11-N- FN-methyl-N:(2--pvndinesulfonyl )-L-leucinyllhydrazide Following the procedure of Example 188(b), except substituting

N-(N-

methyl-L-leucinyl).N'[2. N-(2-methypropy)-Nphenylainojt~azo..4 ylcarbonyllhydrazide for N-[ 2 2 -benzyloxyphenyl)thiazol4.ylcarbonylJN-IL leucinyl)hydrazide, the title compound was prepared as an orange solid (53 mg, MS (ESI): 559.3 Example 191 >Preparation of N- F 2 -fNmethl[N(2-methylpropyl)amnolthiazoL-4-ylcarbonyl

I-N'-

3 -pyridinylmethoxycarbov )-L-leucinyilhy-drazide Following the procedure of Example 186(a)-I 186(c), except substituting

N-

3 -pyridinylinethoxycarbonyl).Lleucine for N-( 4 -pyrnylethoxycaronyl).L.

leucine in step the title compound was prepared as a white solid (138 mg, 66%).

MS (ESI): 477.4 Example 192 Preparation of N- r2- rN-( 2 -methyljpropyvr-N..phenylainolthiazoiL-4lcarbonvl 1-N'rNmty--4pdi~ehxcabnl--ecnlhdrzd Following the procedure of Example 1 16(a)- I 16(b), except substituting

N-

niiethyl-N-(4-pyridinylmethoxycalryonyl)Lleucine for pyridinylmethoxycarbonyl)-L..leucine in step the title compound was prepared as a white solid solid (74 mg, 4 1 MS (ESI): 553.4 Example 193 Preparation of N-(2-methvl propyl)-N-phenvlIamino]thiazol -4-lcarbonvlI-NrN-methvl-N-(3-pridinlmethoxycarbonyl)-L-leucinvl hydrazide Following the procedure of Example 116(a)-I 16(b), except substituting Nmethyl-N-(3-pyridinymethoxycarbonyl)-L-leucifl for N-(4pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid solid (50 mg, MS (ESI): 553.4 Examle 194 Preparation of N-[2-(2-benzloxypheny l)thiazo l-4-vlarbolll-N'-rN-methyl-N-(3pvridinylmethoxvcarbonyl)-L-leucinyllhydrazide Following the procedure of Example 112(a)-I 12(g), except substituting Nmethyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-(4pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (0.028 g, MS(ESI): 588.4 Example 195 Preparation of N-rN-methyl-N-(4-pyridinlmethoxcarbonyl)-L-leucinyll-N'-r2 1naphthl)thiazol-4-lcarbonvllbydazide Following the procedure of Example 112(a)-I 12(g), except substituting 1naphthyl boronic acid for 2-benzyloxyphenyl boronic acid in step and N-methyl- N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (0.072 g, 36%).

MS(ESI): 532.4 Example -196 Preparation of N-[2-rN.N-(bis)-2-methylpropv1'aminothiazolA-ylcarbonyl1-N-rN- (4-pvridinylmethoxycarbonl)-L-leucinyllhydrazide Following the procedure of Example 186(a)-186(c), except substituting N,Ndiisobutylamine for N-methylisobutylanine in step the title compound was prepared as a yellow solid (60 mg, MS (ESI): 519.5 187 Examl 200 Preparation of N-r2-(2-naphthyl)thiazoI-vycarbonvI pvyridinylmethoxycarbonyl)-L..leucinyl ihydrazide Following the procedure of Example 1 12(a)- I 12(g), except substituting 2naphthylboronic acid for 2-benzyloxyphenyl boronic acid in step the title compound was prepared as a white solid (226 mg, MS (ESI): 518.4 Example 201 Preparation of N-2 N-bs--ehlrplainolhiazol-4-,lcarbonvj rNmethyl-N-( 4 -pyridinylmethoxycnl).L-eucinlIhydjzjde Following the procedure of Example 186(a)-i 186(c), except substituting N,Ndiisobutylamine for N-methylisobutylamine in step and N-niethyl-N-(4.

pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in the final step, the title compound was prepared as a yellow solid (30 mg, MS (ESI): 533.3 Preparation of N-(N-benzyloxycarbon L.leucinyl)-N'. [2-(4-rnorpholino')thiazolvlcarbonylihydrazide Following the procedure of Example 186(a)- 186(c), except substituting morpholine for N-methylisobutylamine in step and N-bcnzyloxycarbonyl-Lleucine for N-( 4 -pyridinylmethoxycarbonyl)-L-leucine in the final step, the title compound was prepared as a white solid (115 mg, MS (ESI): 576.4 Example 203 Preparation of N-[N-(4-pvyridinylmethoxycarbonyl)-L-leucinvl 1-N'-r2-(4thiomorpholino)thiaZo1-4vlcarbonyl Ihydrazide Following the procedure of Example 186(a)-i 186(c), except substituting thiomorpholine for N-methylisobutylamine in step the title compound was prepared as a white solid (35 mg, MS (ESI): 493.4 Example 204 Preparation of N-(N-benzyloxycarbonl-L-leucinl..N'-2-(4.

thiomorpholino'~thiazol-4-ylcarbonvllhydrazide Following the procedure of Example 186(a)- 186(c), except substituting thiomorpholine for N-methylisobutylamine in step and N-bentyloxycarbonyl-L.

leucine for N-(4-pyridinylrnethoxycarbonyl)-L-leucine in the final step, the title compound was prepared as a white solid (20 mg, MS (ESI): 492.3 Example 205 Preparation of N-r2-(2.3-ethylenedioxy-4-methoxyphenyl)thiazoI4.vlcarbonyllN'.

fN-(4-pyridinylmethoxycarbonvh)-L-leucinyllhydrazide Following the procedure of Example I112(a)- I 12(g), except substituting 2,3ethylenedioxy-4-methoxybromobenzene for 2-benzyloxybromobenzene in step the title compound was prepared as a white solid (31 mg, MS (ESD: 556.4 Example- 206 Preparation of N-f2-fN.N-(bis)-2-methylpropyl~aminolthiazol.4..vcaronyllN'INmethyl-N-(3-nyridinylmethoxycarbonyl)-L-leucinyllhydrazide- Following the procedure of Example 186(a)- 186(c), except substituting N.Ndiisobutylamine for N-methylisobutylamine in step and N-methyl-N-(3pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in the final step, the title compound was prepared as a yellow solid (30 mg, MS (ESD): 533.5 Example 207 Preparation of N- r 2 (N-c clopropymethl Npropvl amino) tffiazoA..IcArbonv 1rN-( 4 -pyridinvlrnethoxvycarbonyl).L..leucinvl lhydrazide Following the procedure of Example 186(a)- I 86(c), except substituting Ncyclopropylmethylpropylaine for N-methylisobutylamine in step the title compound was prepared as a yellow solid (60 mg, MS (ESI): 503.3 Example 208 Preparation of N [N-(4-pyridinylmethoxycarbonvi)L-.l.eucinyl 1-N- guinolyl)thiazol-4vlcarbonyllhydrazide Following the procedure of Example 112(a)- I 12(g), except substituting 8- bromoquinoline for 2 -benzyloxybromobenzene in step the title compound was prepared as a white solid (134 mg, MS (ESI): 519.3 Preparation of N- FN-methyl-N-(4-1pvridinylmethoxycarbnyl)L-leucinvil-N'-f2-(8- Following the procedure of Example I112(a)-i I except substituting 8bromoquinoline for 2 -benzyloxybromobenzene in step and N-methyl-N-(4pyridinylmethoxycarbonyl)Lleucine for N-(4-pyridinylmethoxycarbonyl).L leucine in step the title compound was prepared as a white solid (53 mg, 22%).

MS (ESI): 533.3 Example 2 Preparation of I -N-(N-Cbz-leucinyl)-amino-3-7N-(4-biphenyl-sulfonyl)-arunoprop~an-2-one a) 4-biphenyl sulfonyl chloride 4-Biphenyl sulfonic acid (2.4 g, 10 mmol) was heated to 100 C with phosphorus pentachloride (2.1 g, 10 mmol) overnight. The reaction was cooled to RT, diluted with water, filtered and washed with water. The solid was then triturated with EtOAc-ether and the beige solid was used in the next reaction without further purification.

b) 1 -N-(N-Cbz-leucinyl)-arnino-3-N-(4-biphenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example 5 except substituting "4-biphenyl sulfonyl chloride" for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M-W*=550.

Example 211 Preparation of 1 N-Cbz-leucinyl)-armino-3-N-(3-biphenyl-sulfonyl)-aminop2ropan-2-one a) 3-biphenyl-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 magnesium powder (1.2 g, mmol). The reaction was cannulated into a solution of sulfuryl chloride (10.5 g, 6.4 ml, 80 minol) in hexanes (25 ml) and was strirred at RT for 2h. The reaction was quenched with ice-water, extracted with ether, dried with magnesium sulfate, filtered, concentrated, and was used in the next reaction without fturther purification.

b) 1 N-Cbz-leucinyl)-amino-3-N-(3-biphenyl-sulfoniyl)-aniino-propan-2-one Following the procedure of Example 51 except substituting "3-biphenyl sulfonyl chloride" for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M-W=550.

193 Example 212 Preparation of-I N-Cbz-Ieucinvl )-amidno-3-N-(2-benzyloxv-Dhenvi-sulfonyay am-ino-propan-2-one a) 2 -benzyloxy-phenyl-sulfonyl chloride Following the procedure of Example 211 except substituting "2benzyloxy-phenyl bromide for "3-biphenyl bromide", the title compound was prepared and was used in the next step without further purification.

b) 1 N-Cbz-leucinyl)-amino-3-N-(2-benzyloxyphenyi.sulfony)aiopropan.

2-one Following the procedure of Example 51 except substituting "2benzyloxy phenyl sulfonyl chloride for 4 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) 581, M+Na*= 604, 2M+Na*= 1185.

Example 213 Preparation of 1 N-Cbz-eucinl)-anino-3-N-(4-phenoxy-p2henyl-sulfonyl)arriino-prop~an-2-one a) 4-phenoxy-phenyl-sulfonyl chloride Following the procedure of Example 211 except substituting "4-phenoxy phenyl bromide for "3-biphenyl bromide", the title compound was prepared and was used in the next step without further purification.

b) 1 N-Cbz-leucinyl)-amino-3-N-(4-phenoxypheny-sulfonyl)amopropan.2 one Following the procedure of Example 51I(a), except substituting "4-phenoxyphenyl-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) 568, M+Na*= 590.

Example 214 Preparation of I N-Cbz-ieucinyl)-amino-3-N-(2-dibenzofuiran-sulfonvtL arninop2ropan-2-one a) 4-phenoxy-phenyl-sulfonyl chloride Following the procedure of Example 210 except substituting "2dibenzofuran-sulfonic acid" for "4-biphenyl-sulfonic acid", the title compound was prepared and was used in the next step without further purification.

b) I N-Cbz-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonyl)-amnopropan-.2.

one Following the procedure of Example 5 1 except substituting "4-phenoxy.

phenyl sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) 566, M+Na*= 588.

Example 215 Preparation of 1 N-Cbz-leucinyl)-arnino-3-N-(3.4..dimethox-Vphenyl- sulfonyi)amino-propan-2-one Following the procedure of Example 5 1, except substituting "3,4dimethoxy-phenyl-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+W='536,

M+NH

4 553.

Example 216 Preparation of 1 N-Cbz-leucinyl)-arino-3-N-(2-5-dichlorothiohene-3 sulfonyl)- mn-poa-2-one Following the procedure of Example 5 1, except substituting dichlorothiophene-3-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+NH4*= 567, 2M+W*= 110 1.

Example 217 Prep~aration of I sulfonyl)-ami*-prpan2-one Following the procedure of Example 51, except substituting phenyl sulfone-5-thiophene-2-sulfonyl chloride for 4 -(3-Chloro-2-cyano-phenoxyyphenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+W= 622.

Example 218 Prearaionof I N-Cbz-leucinyl )-amino-3-N-(8:quinoline-sulfonyi )-aminopropan-2-one Following the procedure of Example 51, except substituting "8-quinolinesulfonyl chloride for 4 -(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M+HW= 527.

Example 219 Preparation of 1 N-Cbz-leucinv)-anino-3-N-(2-pyvdvlsulfonvI )-amino- 12ropan-2-one Following the procedure of Example 5 1, except substituting 2-pyridylsulfonyl chloride" (as described in J. Org. Chem. 1989, 54, 392) for "4-(3-Chloro- 2 -cyano-phenoxy)..phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+Wr= 477, M+ Na+ 499.

Example 220 Preparation of I N-Cbz-Ieucinyl)-amino-3-N-(2-pvyridvl-sulfonvL)-aminop2rop~an-2-one a) I -N-(N-Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sufony)-anino-propan-2ol 1,3-Diamino propan-2-oI (6.75 g, 75 mmnol) was dissolved in DMF (loom]l) and Cbz-leucine (20g, 75.5 minol), HOBT-hydrate (I1Ig, 81.5 mmol), and EDCI (1 5.5g, 81.2 mmol) were added. The reaction wa s stirred overnight at RT. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether ml) and MeOH (30 nml) were added. A IN solution of hydrochloric acid in ether was added (I M, 30 ml) and a white gum formed, which was washed several times with ether. MeOH-acetone were added and heated until the gum became a white solid. The white solid was dissolved in DMF (25 ml) and DIEA then 4phenoxy phenyl sulfonyl chloride was added. The reaction was stirred for 2h, concentrated in vacuo, then chromratographed (silica gel, 1: 1 EtOAc: hexanes) to provide the desired product as a white solid.

b) Leucinyl-amino- 3-N-(4-plienoxy phenyl sulfonyl)-amino-propan-2-ol 1 -N-(Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenylsulfonyl).amino-propan.

2-ol (1.0g, 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 mixture was filtered, concentrated, and azeotroped with toluene to provide a white glass which was used in the next reaction without further purification.

c) 1 -N-(N-4-pyridyl acetyl-leucinyl)-amino-3-N-(4.phenoxy..phenyi-silfonyl)amino-propan-2-ol Leucinyl-axnino-3-N-(4-phenoxy phenyl sulfonyl)-amino-propan-2-ol (0.36 g, 0.76 mmol) was dissolved in DMF (5 ml), then NMM (0.45 ml, 4 mmol) was added followed by 4-pyridyl acetic acid 13g, 0.75 rnmol) and HBTU (0.29g, 0.76 mmol) and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel, 5%MeOH: methylene chloride) to provide the desired product as a white solid (90 mg, MS(ES): M+H+ 555.

d) 1 -N-(N-4-pyridyl acetyl-leucinyI)-amino-3-N-(4.phenoxy-phenyl..sulfonyl)y amino-propan-2-one I -N(--yiy-ctlluiy)aio3N(-hnx-hnlsloy) amino-propan-2-ol (45 mg, 0.08 rnmol) was dissolved in acetone then 1IN hydrochloric acid (2 ml) was added. The reaction was concentrated in vacuo, then redissolved in acetone. Jones reagent (1.5 M. several drops) was added and the reaction mixture was stirred for 6h at RT. Isopropanol (0.5 nil) was added and the reaction mixtur was concentrated in vacuo. The reaction was diluted with pH 7 buffer and then was extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated in vacua, then chromatographed (silica gel, 5% MeOH-methylene chloride) to give the desired product as a white solid (27 mg, MS(ES):

M+H

4 553.

Preparation of I N- 2 -pyridy-sulfonl-eucinl) -amino 3N(4-2.henoxv..

phenvl-sulfonvl)-anino-proan.2-.one Following the procedure of Example except substituting "2pyridyl-sulfonyl chloride" (as described in 1. Org. Chem. 1989, S4, 392) for "4pyridyl-acetic acid and HBTU", the title compound was prepared: MS(ES) M+W*= 4 75, M+ Na 497, 2M+ Na+ 117 1.

Example 222 Preparation of -N-(N-morpholino-carbonI-eucinl)-a-jno-3-N(4-henoxy.

phenyl-sulfony)-amlnoIropa-2-one Following the procedure of Example except substituting Nmorpholino-carbonyl chloride" for "4-pyridyl acetic acid and HBTU the title compound was prepared: MS(ES) M 547, M+ Na 4 569, 2M+ Na 4 1115.

198 Example 223 Preparation of I N-4-pvyridyl-carbonyl-leucinyfl-anino-3-N-(4-phenoxvphenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example except substituting 4pyridyl-carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) M 539.

Example 224 Preparation of 1 N-acetvl-leucinfl)-amino-3-N-(4-p2henoxy-phenvl-sulfonvl)amino-propan- 2-one Following the procedure of Example except substituting "acetyl chloride" for "4-pyridyl-acetic acid and HBTU", the title compound was prepared: MS(ES) M 476, M+ Na+ 498, 2M+ Na+ 973.

Example 225 Preparation of I N-imidazole acetyl-leucinyl)-amino-3-N-(4-p2henoxy-phenylsulfonyl)-amino-p2ropan-2-one Following the procedure of Example except substituting 'imidazole acetic acid" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) 542.

Example226 Preparation of I1-N-( N-4-carboxymethyl benzoyl-Ieucinyl)-axnino-3-N-(4-phenoxyp2henyl-sulfonvh)-anmino-proan-2-one Following the procedure of Example except substituting "4carboxymethyl benzoic acid" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) M 596, M+ Na+ 618, 2M+ Na+ 1213.

Example 227 Preparation of I N-(N.N-dimethvl glycinvi )-Ieucinvl )-amino-3-N-(4-phenoxv.phenyl-su Ifonyl)-amino-1prolpa.-.-one Following the procedure of Example except substituting

"N,N-

dimethyl glycine" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) M+FF= 519.

Example 228 Prep~aration of I -unln-sloaielucnl-mn--N(-~eov -p:1henyl-sulfony)-amino-propan.2.one Following the procedure of Example except substituting "8quinoline sulfonyl chloride" for "4-pyridyl-acetic acid and HBTU", the title compound was prepared: MS(ES) M 625.

200 Example 229 Preparation of N-Cbz-leucinvl)-amino-3-N-(8-quinoline-carbonyl)-aminopropan-2-one 1,3-Diamino propan-2-ol (6.75 g, 75 mmol) was dissolved in DMF (100ml) and Cbz-leucine (20g, 75.5 mmol), HOBT-hydrate (1 g, 81.5 mmol), and EDCI (15.5g, 81.2 mmol) was added. The reaction was stirred overnight at RT. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether (50 ml) and MeOH (30 ml) were added. A IN 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-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-quinoline carboxylic acid (0.17g, 1.0 mmol), and HBTU (0.38g, mmol) were added and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel, 7:2 EtOAc: hexanes). The solid was then dissolved in acetone (5ml), then IN hydrochloric acid (2 ml) was added. The reaction was concentrated in vacuo, then redissolved in acetone. Jones reagent (1.5 M, several drops) was added and the reaction mixture was stirred for 6h at RT. Isopropanol (0.5 ml) was added and the reaction mixture was concentrated in vacuo. The reaction was diluted with pH 7 buffer and then was extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated in vacuo, then chromatographed (silica gel, 5% MeOH-methylene chloride) to give the desired product as a white solid (23 mg, MS(ES): M+H 491.

Example 230 Preparation of N-Cbz-leucinyl)-amino-3-N-(6-quinoline-carbonvl)-aminopropan-2-one Following the procedure of Example 229, except substituting "6-quinolinecarboxylic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M 491.

Example 23 1 Preparation of 1 N-Cbz-Ieucinvl )-amino-3-N-(2-(4-biphenyi)-4-mehy..

propanarnide)-propan-2-one Following the procedure of Example 229, except substituting "2-isobutyl-4biphenyl acetic acid "for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M 586, M+i Na+ 608, 2M+ Na+ 1193.

Example232 Preparation of I N-Cbz-leucinyl)-aniino-3-N-( N-4-pvyridyl-methyleneoxy 'carbonyl-leucinvl)-amino-1prop~an-2-one Following the procedure of Example 229, except substituting "4-pyridyl methyleneoxy carbonyl leucine" for "8-quinoline-carboxylic acid"', the title compound was prepared: MS(ES) M+Wr= 584. Example 233 Preparation of 1 N-Cbz-leucinyvD-amino-3-N-(berizovylanio)oan2-one Following the procedure of Example 229, except substituting "benzoyl chloride" for "8-quinoline carboxylic acid and HBTU", the title compound was prepared: MS(ES) M 440, M-i Na+ 462, 2M+ Na+ 90 1.

Example 234 Preparation of 1 N-Cbz-leuciny)-aino-3-N-(2.4-dimethy-3sufonyl),amnoppn2-onefl Following the procedure of Example 5 1, except substituting "2,4-dimethyl- 3-sulfonyl chloride" for 4 -(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the tidle compound was prepared: MS(ES) 494.

202 Example 23 Preparation of 1 -N-(N-Cbz- leucin 1) -aminlo- 1 .3 -dimethy 1-5 -c hloro- pyrazole- 4-sulfonvi '-amino-propan -2 -one Following the procedure of Example 5 1, except substituting 1,3-dimethyl- 5-chioro- pyrazole-4-sulfonyl chloride" for "4-(3-Chloro-2-cyaflo-phefloxy)-phenyl sulfonyl chloride", the title compound was prepared: MS (ES) M +IH* 494.

Example 2316 Preparation of 1 -N-(N-4-pyridvl-methyeleoxy carbonyl-leucinyl'i-axnino-3-N-(4phenoxy-phenyl-sulfonyl)-amiflo-1Pro~l.

2 2of Following the procedure of Example 2 13(a), except substituting "4-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) 569.

Examle 237 Preparation of I N-3-prdvl-methleleoxy carbonyl-leucinyl)-amino-3-N-( 4 phenoxy-phenyl-sulfonyl)-arnino-prolaf- 2 -one Following the procedure of Example 213(a), except substituting "3-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) 569.

ExampLe-238 Preparation -of I N2pyrdylm.tleneoxy-carbonylleucinyl)-amno 3

N(-

4 phenoxvl-phenyl-sulfonyl)-amfiflo-Mpran- 2 -ofe Following the procedure of Example 2 13(a), except substituting "2-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucine', the title compounrd was prepared: MS(ES) 569.

203 Example 239 Preparation of 1 N-4-carboxy-benzovI-ieucinyl)-amino-3-N(4-phenoxvphenvi-sulfonvi )-amiino-p2rop~an-2-one I -N-(4-carboxy methyl-benzoyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl.

sulfonyl)-amino-propan-2-one 105g, 0. 176 mmol) was dissolved in MeOH (5 all) and water (1 then LiOH-hydrate (15 mg, 0.35 rnmol) was added and the reaction was stirred at RT for lh. The reaction was diluted with water, acidified with 6N hydrochloric acid (I nil), then with EtOAc (2 x 10 nil). The combined Organics were dried with magnesium sulfate, filtered, concentrated, chromatographed (silica gel, 50:-50:1 EtOAc: hexanes: AcOH) to give the desired product as a white solid (35.6 mg, MS(ES) 582, M+ Na+ 604.

Example 240 Preparation of I N-Me-N-Cbz-leucin1)-amjn -3-N44-phenoxy-phenvI.L sulfonyl')-amino-prop~an-2-one Following the procedure of Example 2 13(a), except "N-Me-N-Cbz-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) 582, M+ Na+ =604, 2M+ Na+ 1185.

Example 241 Preparation of 4-p-henoxy benzofl-amino-3-N-(4-phenoxy-phenyl. sulfonvi)amino-propan-2-one Following the procedure of Example 2 13(a), except "4-phenoxy benzoic acid" for Cbz-leucine", the title compound was prepared: MS(ES) M 517, M+ Na+ 539, 2M+ Na+ 1055.

204 Example 242 Preparation of 1 -N-(3-p2henoxv-benzovl)-arino-3-N-(4-p2henoxv-phenv.. sulfonyi)arnino-p2ropan-2-one Following the procedure of Example 213(a), except "3-phenoxy benzoic acid for "Cbz-leucine", the title compound was prepared: MS(ES) M 517, Mi- Nai- 539,.2M+ Nai- 1055.

Preparation of 1 -N-(4.-phenoxy benzol)-anmino-3-N-(4-phenoxy-p2henyl- sulfonyi)arnino-propan-2-one Following the procedure of Example 2 13(a), except "4-phenoxy benzoic acid for Cbz-leucine", the title compound was prepared: MS(ES) 517, Mi- Nai- 539, 2M+ Nai- 1055, M-Hi- 515.

Exaple24 Preparation of I -N-(4-biphenyl acetyfl-anuno-3-N-(4-phenoxy-phenyl-sulfonvl)arnino-propan-2-one Following the procedure of Example 2 13(a), except "4-biphenyl acetic acid "for" Cbz-leucine", the title compound was prepared: MS(ES) M+WH= 515, Mi- Nai-=537, 2M+ Nai-= 105 1.

Preparation of 1 -N-(2-benzvloxy benzofl)-axnino-3-N-(4-phenoxy-phenylsulfonyfl-arnino-propan-2-one Following the procedure of Example 213(a), except "2-benzyloxy- benzoic acid for Cbz-leucine", the title compound was prepared: MS(ES) M 53 1, Mi- Nai- 553, 2Mi- Nai- 1083.

Example 246 Preparation of I N-Cbz-IeucinyI)-amino-3-N-(4-benzyloxy-benzoyl)-aminopropan-2-one Following the procedure of Example 229, except substituting "4-benzyloxybenzoic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS (ES) M 546, M+ Na+ 568, 2M+ Na+ 1113.

Example 247 Preparation of 1 -N-(2-(4-biphenyl)--methl-entaido-3-N-(4phenox..phenvl.

sulfonyl)-axnino-p2ropan-2-one Following the procedure of Example 2 13(a), except 2-(4-biphenyl)-4methyl-pentanoic acid for Cbz-leucine", the title compound was prepared: MS(ES) M 57 1, M+ Na+ 593.

Exmple 248 Preparation of I -N-(2-(3-biphenvl)-4-methyl-pentaniido)-3-N-(4-phenoxy-phenylsulfonvi )-am-ino-p2ropan-2-one a) 3-bromo-phenyl methyl acetate 3-Bromo phenyl acetic acid (2.15g, 10 mmnol) was dissolved in ether, then was treated with a solution of diazomethane until the yellow color persisted. The reaction was then quenched with AcOH, concentrated in vacuo and was used in the next reaction without further purification.

b) 3-biphenyl methyl acetate 3-bromo-phenyl methyl acetate (2.29g, 10 mxnol) was dissolved in toluene (30 ml). Then, phenyl boronic acid (I -46g, 12 mmol) was added followed by aqueous sodium carbonate (2M, 4.24 ml, 40 mniol), then tetrakis(triphenylphosphine) palladium (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 magnesium sulfate, filtered, concentrated, and chromatographed (silica 206 gel, 5% EtOAc: hexanes) to provide the desired product as a white solid (1.93g, MS(ES): 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 stirred at RT for 2h. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml), then with EtOAc (2 x 10 ml). The combined organics were dried with magnesium sulfate, filtered, and concentrated to give the desired product as a white solid (1.66 g, 1H NMR: d: 7.6-7.25 9H), 3.7 2H) d) 3-(4-biphenyl)-4-methyl-pent-4-enoic acid nBuLi (3.26 ml, 1.6 M in hexanes) 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 minutes, then was cooled to -78 C. 3-Biphenyl acetic acid (0.5g, 2.35 mmol) wasa dissolved in THF (2 ml) and was added dropwise to the LDA solution.

The reaction was warmed to 0 C, stirred 40 minutes, then cooled to -78 C.

Isobutenyl bromide (0.475g, 3.52 mmol) was added and the reaction was stirred for Ih. 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 combined organics were dried with magnesium sulfate, filtered, concentrated, chromatographed (silica gel, 5% MeOH: methylene chloride) to give the desired product as a white solid (1.66 g, 1H NMR: d: 7.6-7.3 9H), 4.75 2H), 3.87 1H), 2.87 (dd, IH), 2.50 (dd, 1H), 1.70 3H).

e) 3-(4-biphenyl)-4-methyl-pentanoic acid 3 iphenylI)-4-me thyl -pen t-4-enoic acid (0.5g, 1.87 riuol) was dissolved in EtOAc (25 nil). 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, concentrated in vacuo, then was redissolved in 1:5 EtOAc: EtOH (15 nil). Then, 10% Pd/C mg) was added and the reaction was stirred under a balloon of hydrogen gas overnight. The reaction was filtered, concentrated in vacuo, and chromatographed (silica gel, 5% MeOH: methylene chloride) to give the desired product as a white solid (1.66 g, lH NNM: d: 7.6-7.3 (in, 9H), 3.7 IH), 2.07-1.95 (mn, 1H), 1.8-1.7 (in, IH), 1.6-1.45 (in, IH).

f) I -N-(2-(3-biphenyl)-4-methyl-pentamido)-3-N-(4-phenoxy-phenyl-sulfonyl)> arnino-propan-2-one Following the procedure of Example 213(a), except 3-(4-biphenyl)-4methyl-pentanoic acid for Cbz-leucine", the title compound was prepared: MS(ES) M-i-H= 57 1, M+ Na+ 593.

Example 249 Preparation of 1 -N-(3-biphenyl acetyl)-amino-3-N-(4-1henoxy-p2henyl-sulfonyl)arruno-propan-2-one Following the procedure of Example 213(a), except "3-biphenyl acetic acid "for" Cbz-leucine"., the title compound was prepared: MS(ES) 515, M+ Na+=537, 2M+ Na+ 105 1.

208 Example 250 Preparation of N-4-pyridyl acervl-leucinyl)-amino-3-N-(2-benzvloxv- p2henyisulfonvl)-amino-p2ropan-2-one a) I -N-(N-Boc-leucinyl)-amino-3-N-(2-beazyloxy phenyl-sulfonyl)-amino-propan.

2-ol 1,3-Diam-ino-propan-2-al (3.375g, 37.5 mfmol) was dissolved in DMF nil). Then HOBT-hydrate was added (5.5g, 40.7 mmol), followed by Boc-L-Ieucine (9.34g, 37.5 mmol) and EDCI (7.77g, 40.7 mmol). The reaction was stir-red for 4h, then diluted with DMF to make a stock solution of a total volume of 100 ml (0.375 mrnol/ml). The stock solution (18 ml, 6.75 mmol) was treated with NMM (0.89 MI.

7.28 mnxol), 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 magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 20% EtOAc: hexanes): MS(ES) 550.

b) 1 -N-(leucinyl)-amino-3-N-(2-benzyloxy-phenyl-sulfonyl)-amino-propan-2-oI 1 -N-(Boc-leucinyl)-amino-3-N-(2-benzyloxy phenyl sulfonyl)-aminopropan-2-ol (0.7g, 1.3 mmol) was dissolved in 1: 1 TFA: DCM (50 ml) and was stirred at RT for 2h, concentrated in vacuo and was used in the following reaction without further purification: MS(ES) 450.

c) 1 -N-(N-4-pyridyl acetyl-leucinyl)-amino-3-N-(2-benzyloxy-phenyl-sulfonyl)axnino-propan-2-one Following the procedure of Example except substituting 1-Nleucinyl-amino-3-N-(2-benzyloxy phenyl sulfonyl)-amino-propan-2-ol" for N-leucinyl-amino-3-N-(4-phenoxy phenyl sulfonyl)-amnino-propan-2-ol the title compound was prepared: MS(ES) 567.

209 Example 251 Preparation of 1 N-4-pvyridyl carbonyl-leucinyl)-anmino-3-N-(2-benzvloxvphenvi -sulfonvl)-amino-propan-2-one Following the procedure of Example except substituting "4pyridyl carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) M+HT= 553.

Example 252 Preparation of I N-4-imidazole acetic-leucinvl-amno-3-N-(2-benzyloxyp2henyl-sulfonyl)-amino-p~ropan-2-one Following the procedure of Example except substituting imidazole acid" for "4-pyridyl-acetic acid the title compound was prepared: MS(ES) M+W-r 556.

Example 253 Preparation of I N.N-dimethyl glycyl) -leucinl)-anino-3-N-(2-benzyloxyp2henyl-sulfonyl)-amino-propan-2-one Following the procedure of Example except substituting "N,Ndimethyl glycine" for "4-pyridyl -acetic acid the title compound was prepared: MS(ES) 533.

Example Preparation of I N-(N-methyl proll-leucinl)-amino-3-N-(2-benzyloxyphenyl-sulfonyl)-amnino-propan-2-one Following the procedure of Example except substituting "Nmethyl proline" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) 559.

Example 255 Preparation of I N-(N-methyl ipridine-4-carbonyl )-leucinvl)-amino-3-N-(2benzyloxy-p2henvI.sufonl)amin-propan-2-one 210 Following the procedure of Example except substituting "Nmethyl-piperidine-4-carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) M+If= 573.

ExaMple 256 Preparation of 1 N-(N-methyl p2iperidine-4-carbonyl)-leucinyl)-amino-3-N-(2dibenzofuran-sulfonyl)-anino-proan-2-oflC Following the procedure of Example except substituting "Nmethyl-piperidine-4-carboxylic acid" for "4-pyridyl acetic acid and "2dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M 557.

Example 257 Preparation of I N-(N-methyl prolyfl-leucinyl)-axnino-3-N-(2-dibenzofuransulfonyl)-anmuno-p2ropan-2-one Following the procedure of Example except substituting Nmethyl proline for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M+W= 543.

Preparation of I N.N-dimethyl glycyfl-leucinyl)-amino-3-N-(-( 2 dibenzofuran-sulfonyl)-anmino-propan-2-one Following the procedure of Example except substituting NNdimethyl glycne for "4-pyridyl acetic acid and "2-dibenzofuran-sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) 517.

Example 259 Preparation of 1 N-4-imidazole acetic- leuci nyl)-armino-3-N-(2-di benzofuran sulfonyl)- mn-rpn-2-one Following the procedure of Example except substituting "4imidazole 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+W= 526.

Example 260 Prep~aration of N-4-pvridyl carbonyl-leucinl)-amino-3-N-(2-diben ofuran..

sulfonyl)-amino-propan-2-one Following the procedure of Example except substituting "4pyridyl carboxlic acid" for "4-pyridyl acetic acid'" and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M+W= 537.

Example 261 Preparation -of I N-4-pyrddvl acetl-leucinyl)-aniino-3-N2-dibenzofuransulfonyl)-arxnino-p2ropan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 55 1.

Example 262 Preparation of I N- 4 -imidazole-ac~lyI-leucinyI-amino3-N(2-dibnzofuransulfonyh)-arnino-propan.2-one Following the procedure of Example except substituting "4imidazole-acryic 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+W= 552.

212 Example 263 Preparation of 1 N-pvrazole-c arbony I- leucin nvl)-amino- 3-N-(2 -dibe nzo furan sulfonyl)-amino-p2ropan-2-one Following the procedure of Example except substituting "pyrazole carboxylic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 538.

Example26 Prep~aration of 1 N-benzoyl-leucinyvh-aniino-3-N-(8-guinoline-sulfonyl)-arainoprolpan-2-one Following the procedure of Example except substituting "benzoic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M 497.

Example 265 Preparation of I N-2.5-difluoro--benzoyl-leucinyl)-amino-3-N-(8-guinolilesulfonyl)- mn-rpn-2-one Following -the procedure of Example except substituting difluoro-benzoic acid" for "4-pyridyl acetic acid and "8-quiaoline sulfomc acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 535.

Example 266 Preparation of Il-N-( N-2.5-difluoro-phenyl acetyl -leucinyl)-amino-3-N-(8quinoline-sulfonyl)-amino-propan-2-one Following the procedure of Example except substituting difluoro- phenyl acetic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl sulphonyl chloride" the tidle compound was prepared: MS(ES) 547.

213 Example 267 Preparation of 1 N-12henvl acetyl- leuc inyl) -amino- 3-N-(8-guinoli ne-sul fonyl)amino-p2ropan-2-one Following the procedure of Example except substituting "phenyl acetic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M 511.

Example 268 :0: Pre paration of I N-4-p2yridyl acety-leucinfl)-amino-3-N-(8-guinolinesulfonyfl-arnino-propan-2-one Following the procedure of Example except substituting "4pyridyl 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 512.

Example 269 Preparation of I N-4-p2yridyl carbonyl-leucinvl)-armino-3-N-(8-quinolinesulfonyfl- mn rpn-2-one Following the procedure of Example except substituting "4pyridyl carboxylic acid" for '4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M+H 4 498.

214 Example 270 Preparation of I N-4-imidazole acetl-leucinyl)-amino-3-N-(8-guinolinesulfonyl)-amino-propan-2-one Following the procedure of Example except substituting "4imidazole acetyl acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 501.

Exarpj22 Preparation of I N-3-phenyl propionyl-leucinyl')-amino-3-N-(8-guinolinesulfonyl)-arnino-propan-2-one Following the procedure of Example except substituting "hydrocinnamic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 525.

Exmple 22 Preparation of bis-N.N'-( N-4-pvdvl methyleneoxv carbonyi-leucinvl)- 1.3diamino-propan-2-one Following the procedure of Example 37, except substituting "4-pyridylmethylenoxycrbnyl-leucinyl for "Cbz-leucine, the title compound was prepared: MS(ES) M+W= 585.

Ex=Vie273 Preparation of bis-N.N'-( N-3-pyridyl methyleneoxy-carbonyl-leucinfl)- 1.3dianmino-prop an-2-one Following the procedure of Example 37, except substituting "3-pyridylmethyleneoxycaronyl-leucinyl for "Cbz-leucine" the title compound was prepared: MS(ES) 585.

ExampLe 274 Preparation of bis-N.N'-( N-2-pyridyl methyleneoxy carbonvl-leucinvl)- 1.3diamnino-propan-2-one Following the proc edure of Example 37, except substituting "2-pyridylmethyleneoxy-carbonyn-eucinyl for "Cbz-leucine" the title compound was prepared: MS(ES) M+W= 585.

Example 275 Preparation of 1 N-Cbz-leucinyl )-amino-3-N-(2-benzvloxy-benzoylI-arninopropan-2-one Following the procedure of Example 229, except 2-benzyloxy-benzoic acid" for "8-quinoline-carboxylic acid the title compound was prepared: MS(ES) M -iHW= 546.

Ea~e2 Preparation of I N-b-ecnl-rio3N(-ezlx-ezy)aio propan-2-one Following the procedure of Example 229, except "3-benzyloxy benzoic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) 546.

Example 277 Prpaaton of 1 N-Cbz-eucinyl)-aino-3-N-(4biphenyl-acetyl)-aino>.

Following the procedure of Example 229, except "4-biphenyl acetic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M +HW= 530.

216 Example 278 Preparation of I N-Cbz-Ieucinyl)-amino-3-N-(2-carboxymethyl-thiophene-3sulfonvi '-amino-p2ropan-2-one Following the procedure of Example 5 1, except substituting "2carboxymethyl thiophene-3-sulfonyl for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M-HW=540.

Example 279 Preparation of I N-Cbz-leucinfl)-amin'6-3-N-methvl-N-( N-Cbz-leucinvl arnino-propan-2-one a) N-(Cbz-leucinyl)-amino-propene IN-Cbz-leucine (3.0g, 11.3 inmol) was dissolved in DMF (50 ml), then NMM (1.3g, 12.4 minol) was added, followed by allyl amine (0.65g, 0.85 mmol), and HBTU (4.3g, 11.3 mmol) and the reaction was stifred overnight at RT. The reaction was diluted with water, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 40% EtOAc: hexanes): MS(ES) 305.

b) N-(Cbz-leucinyl)-amino-propene oxide N-(Cbz-leucinyl)-amino-propene (2.95g, 9.7 mmol) was dissolved in.

methylene chloride (100 nil), then mCPBA (5.0g, 29.1 mmnol) was added and the reaction was stirred overnight. The reaction was diluted with satuirated aqueous sodium bicarbonate, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chrornatographed (silica gel, 50% EtOAc: hexanes).

c) 1-N-(Cbz-leucinyl).amino-3-N-methyl-amino-propan-2.o N-(Cbz-leucinyl)-amino-propene oxide (400 mg, 1.25 mmnol) was dissolved in isopropanol (5 mld), then aqueous methyl amine (2 ml) was added and the reaction was heated to 70 C in a sealed bomb for 2h. The reaction mixture was concentrated in vacuo and was used in the next reaction without further purification.

217 d) I N-Cbz-leucinyl)-amino-3-N-methyl-N-( N-Cbz-leuciny)-arnino-propan.2..

one Following the procedure of Example 229(a), except substituting "Il-N-(Cbzleucinyl)-amino-3-N-methyl-amino-propan-2-oI for "8-quinoline carboxylic acid ",the title compound was prepared: MS(ES) M 597.

Example 280 Preparation of 1 N-Cbz-leucinvl )-amino-3-N-rnethvl-N-( N-4-pyridylmethyloxy-carbonyl-leucinyl)-amino-propan-2-one Following the procedure of Example except substituting '4yridyl- methyleneoxy-carbonyl leucine for "Cbz-Ieucine" in the title compound was prepared: MS(jES) 598.

Examp~le 281 Preparation of I N-Cbz-eucinyl-amino-3-N-methyl-N4(2-dibenzofuransulfonyl)-ainino-p2rop~an-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for "Cbz-leucine and HBTU" in the title compound was prepared: MS(ES) M+W*=580, M+ Na+ 602.

Example 282 Preparation of I methyl- I- N-Cbz-leucinyl-amino-3- N-(2-dibenzofuransulfonyl)- mn-rpn-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride "for "Cbz-leucine and HBTU" in the title compound was prepared: MS(ES) M+W*=580 218 Example 283 Preparation of I1-N- methyl- I N-Cbz-leucinyl)-arnino-3- N-(2-dibenzofurans ulfonfl)-amino-p1ropan-2 -one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride" for 'N-Cbz-leucine" in step and "4-pyridyl methyleneoxy carbonyl-leucine for "Cbz-leucine in step the title compound was prepared: MS(ES) M+W=580.

Example 284 Preparation of I -N-(2-dibenzofuran sulfonvl'-N-methyD- arnino-3N-(N-4-pvrddvlmethyleneoxy carbonyl-Ieucinyl)- mn-rpn- 2 -ofle Following the procedure of Example except substituting "4pyridyl methyl amine" for "allyl amine" and "2-dibenzofuran sulfonyl chloride" for "N-Cbz-leucine" in step and N-4-pyridyl methyleneoxy carbonyl -leucinyl for "N-Cbz-leucine and HBTU in step the title compound was prepared: MS(ES) M+W*=58 1.

Example 285 Preparation of I N-Cbz-leucinyl)-amino-3-N-( 4-p_)ridyl-methylene)-3N-( N- Cbz-leucinyfl-amino-propan-2-one Following the procedure of Example except substituting "4pyridyl methyl amine for "methyl amine" the title compound was prepared: MS(ES) M+W= 674.

Ea l 8 Preparation of 1 -N-(Cbz-leucinyl)-aTino-3-N-(4-pvrijdyl-methylene)-3N-( 2 dibenzofuran sulfonyfl-arnino-propan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride "Cbz-leucine and HBTU" in step the title compound was prepared: MS(ES) M+W*=657.

Example 287 Preparation of I -N-(Cbz-Ieucinyl)-arnino-3-N-(4-pyridyl-methvlene)-3N-(2.

dibenzofuran sulfonyl)-amino-propan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride "Cbz-leucine and HBTU' in step the title compound was prepared: MS(ES) M+H*=657.

Example 288 Preparation of 1 -N-(4-bip~henvl acetyl)-amino-3-N-(4-p2yridyl-methylene)-3N-(

N-

,,Cbz-Ieucinyl)-amino-propan-2-one Following the procedure of Example except substituting "4bipeny acticaci or Cb-leucine "in step "4-pyridyl methyl aie "for methyl amine, the title compound was prepared: MS(ES) M+W*=62 1.

Example 289 Preparation of 1 -N-(4-1phenoxv-benzoyl)-aino-3-N-(4-pridvl-methvlene)-3N-(

N-

Cbz-leucinyl)-amino-propan-2-one Following the procedure of Example except substituting "4phenoxy benzoic acid for "Cbz-leucine in step "4-pyridyl methyl amine for "methyl amine", the title compound was prepared: MS(ES) 623.

Example 290 Preparation of 1 -N-(2-dibenzofuran-sulfonyfl-aniino-3-N-(4-pvrddvl-methylene)- 3N-( N-Cbz-leucinyfl-anmino-propan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for "Cbz-leucine and I{BTU" in step "4-pyridyl methyl amine" for "methyl amine", the title compound was prepared: MS(ES) 657.

220 Example 291 Preparation of N-3-pyridyl-methyleneoxy-carbonyl-leucinyl)-amino-3-Nmethvl-N-(2-dibenzofuran-sulfonyl)-amino-propan- 2 -one Following the procedure of Example except substituting "Nmethyl-N-allyl amine for "allyl amine" in and "3-pyridyl-methyleneoxycarbonyl-leucine" for "Cbz-leucine" in step the title compound was prepared: MS(ES) M+H= 581.

The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims (17)

1. A compound according to Formula V: R 30 R2N-IC-- N-'R3 H II U H V wherein: R' 9 is N, 0 0 R 33 N 0 =34 0 0 0 222 0 0 Me Sp- 0 00 0 0 EtO OCH Ph Et2 s Cbz-leucinyl-; or 4-pyridyl methiyloxycarbonyl-leucinyl-; 4-imnidazole acetyl- leucinyl-, phentyl acetyl-leucinyL, N,N-dimethiyl-glycinyl leucinyl, 4-pyridyl acetyl- leucnyL, 2-pyridyl sulfonyl-leucinyL, 4-pyridyl c-arbonyl-leucinyL, acetyl-leucinyL, benzoy-leucinyL, 4-phienoxi-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyL, Cbz-phenylalaninyL, Cbz-norleucinyl-, Cbz- norvalinyl-, Cbz-glutamyl-, Cbz-epsflon-(t-butyl ester)-glutamyl; acetyl-leucinyl-,

6- or 8- quinoline carbonyl, biphenyl acetyL alpha- isobutyl-biphenyl acetyl, acetyL ****benzoyL, 2- or 3- benzylox.y beuzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; or 4- pyridylmnethiyloxycarbonyl-aminoacid-; aryl C 0 -C 6 alkyloxy carbonyl-amino acid-, heteroa ryl C 0 -C 6 alkyloxy carbonyl-amino acid-,aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroaryl C%-C 6 alkyloxy carbonyl-amino acid-, Cl-C 6 alkyloxy carbonyl-amino acid-; C 1 -C~a~kyl abnL, atyl CO-C 6 alkyl carbonyL, heteroaryl CO-C 6 akycabyl aryl CO--C 6 alkyl carbonyL, heteroaryl CO-C 6 alcyl carbonylC I-C 6 alkyl sulfonyL, aryl CO-C 6 alkyl sulfonyL, heteroaryl CO-C 6 alkyl sulfonyL, aryl CO-C 6 alkyl sulfonyL, or heteroaryl CO-C 6 alkyl sulfonyl; R 30 is -H Or C 1 6 alkyl;, R 3 1 is R32 H H 0 I)C m? R 33 H 0 0 o 3 0 0 0 I:0. 00 0 0 N.. 0 0 Me 0 0 0 00 OCH 2 P1 t2C Cbz-leucinyl-; or 4-pyridyl methyloxycarbonyl-leuc-inyl-; 4-imidazole acetyl- leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glycinyl leucinyL 4-pyridyl acetyl- leucinyL, 2-pyriclyl sulfonyl-leucinyL, 4-pyridyl carbonyl-leucmyL, acetyl-leucinyl, benzoyl-leucinyL, 4-phenoxy-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyL, alpha- isobutyl-biphenyl acet yL Cbz-phenylalaninyL, Cbz-norleucinyl-, Cbz- norvalinyl-, Cbz-glutarnyl-, Cbz-epsflon-(t-butyl ester)-glutamyl acetyl-leucinyl-, 6- or 8- quinoline carbonvi, biphenyl acetyL, alpha- isobutyl-biphenyl acetyL, acetyL, benzoyL, 2- or 3- benz-vioxy benzoyL, 4-phenoxy betizoyl-, Cbz-amino acid-; or 4- pyriclyhnethiyloxy carbonyl-aminoacid-; aryl CO-C 6 alkyloxy carbonyl-amino 224 acid-, heteroaryl CO-C 6 alkyloxy carbonyl-amino acid-,aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-amino acid-, C 1 C 6 alkyloxy carbonyl-amino acid-; Cl-C 6 alkyI carbonyl, aryl CO-C 6 all carbonyL, heteroaryl CO-C 6 alkyl carbonyl, aryl CO-C 6 alkyl carbonyl eteroaryl C 0 -C 6 alkyl carbonyl, Cl-C 6 alkyI sulfonyl, aryl CO-C 6 alkyl sulfonyl, heteroaryl C 0 -C 6 alkyl sulfonyL, aryl CO-C 6 alkyIl sulfontyl, substituted heteroaryl CO-C 6 alkyl sulfonyL R 32 is OCH 2 Ar, OCH2Cp 6 alkyl, aryl substituted CO- 6 alcyl heteroaryl substituted CO- 6 alkyl,4-imnidazole methylene; or 4- pyridylmethylneneoxy; 4-pyridyl methylene, 2-pyridyl sulfonyl, 4-pyridyl, aryl. Co- 6 alkyloxy, or heteroaqIl substituted CO- 6 alkyloxy, R 3 3 is Cl- 6 alkyI, -CH 2 Ph, -CH 2 CH 2 CO 2 R 34 R 3 4 is -H or CI- 6 alkvll; misO0, 1, or 2; and pharmaceutically acceptable salts, hydrates and solvates thereof. 2. A compound according to Claim 1 wherein WR' 3 is selected from the group consisting of -Me and -CH 2 i2Me 2 3. A compound according to Claim I or 2 wherein R 33 is selected from the group consisting of -Pr, -Bu, and -CH CH Me. A compound according to .any one of claims I to 3 wherein R 34 is -t-Bu. A compound according to Claim 1 selected from the group consisting of: bis-(Cbz-leucinyl)- 1,3-ciamino-propan-2-one; his- 1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one; 1-Czluiy)aio3(ctlluiy)aiopoa--n- 1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-t-buty ester)-amino-propan-2-one; 1-(Cbz-Ieuciny)-amino-3-(Cbz-glutamyl)-amilo-propan- 2 -ofle; bis- 1,3-(Cbz-leucinyl)-diaimino-(S)-butanone-2-one;, 1-(Cbz-leucinyl)-amino-3-(Cbz-phenylalany)-amno-propan- 2 -ofle; 1-(Cbz-Ieuciny)-amino-3-(Cbz-norleucinyl)-amino-propal- 2 -ole, l-(Cbz-1eucinyI)-arnino-3 -(Cbz-norvainy)-amino-propal- 2 -ofle; 225 P:\OPER\PDB\11180-97.DVI 20/3/00 bis-l,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. 6. A compound according to Claim 5 known as 1-(Cbz-leucinyl)-amino-3-(acetyl- leucinyl)-amino-propan-2-one.

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

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

9. A method according to Claim 8 wherein said cysteine protease is cathepsin K.

10. 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.

11. A method according to Claim 10 wherein said disease is osteoporosis.

12. A method according to Claim 10 wherein said disease is periodontitis.

13. A method according to Claim 10 wherein said disease is gingivitis.

14. 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. P:\OPER\PDB\I 180-97.DVI -20/3/00 A method according to Claim 14 wherein said disease is osteoarthritis.

16. A method according to Claim 14 wherein said disease is rheumatoid arthritis.

17. Use of a compound according to Claim 1 in the manufacture of a medicament for inhibiting a cysteine protease.

18. A use according to Claim 17 wherein the cysteine protease is cathepsin K. S* 19. Use of a compound according to Claim 1 in the manufacture of a medicament for treating a disease characterized by bone loss. A use according to Claim 19 wherein the disease is osteoporosis.

21. A use according to Claim 19 wherein the disease is periodontitis.

22. A use according to Claim 19 wherein the disease is gingivitis.

23. Use of a compound according to Claim 1 in the manufacture of a medicament for treating a disease characterized by excessive cartilage or matrix degradation.

24. A use according to Claim 23 wherein the disease is osteoarthritis. A use according to Claim 23 wherein the disease is rheumatoid arthritis.