AU2260500A - Protease inhibitors - III - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

S

*SS

S

*5 Name of Applicant: Actual Inventors: 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 Address for Service: Invention Title: DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Protease inhibitors III The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPERPDB\2272481.082 22/3/0 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 0* 0 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, 20 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. Thb. 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 A1, 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 SOmatrix. 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 15 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 20 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 25 digest the protein matrix. In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, osteoblasts lay down a new protein matrix that is subsequently mineralized. In several disease states, such as osteoporosis and Paget's 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-CHN2) 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. Lerer, 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 al., J. Cell. Biochem., 1994, 56, 118, and Everts,

S**

et al., J. Cell. Physiol., 1992, 150. 221, also report a correlation between inhibition S15 of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol. Chem., S1994, 269, 1106, Inaoka, et al., Biochem. Biophys. Res. Commun., 1995, 206, 89 Sand 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.

20 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 25 disease. Cathepsin K levels have also been demonstrated to be elevatd 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 cvsteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, co-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 A1, and EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.

e International Patent Application No. PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl 15 ketones which inhibit the cysteine protease IL- 13 convertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479).

I 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 McConrnll 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).

C.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, etal., 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 *15 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 bis- 20 aminomethyl 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 25 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 15 degradation, such as osteoarthritis and rheumatoid arthritis.

0 DETAILED DESCRIPTION The present invention provides compounds of Formula I:

O

00 o

D--C--Q

I

goo: wherein:

D=

2 R R

R

2 R- B- O R

H

H

0 N 0 3 0 R" 0 0

S

0 *8*W *0 i 0 S 6 S. 6

S.

S

0~ 0 '3 0

R

4 3 4 R R N 0 0 4. O.L--G- 112 N C. 14 N R..

R N' 1~3 2 R R 2 0 *00 0 R31

H

0

R

37 (9OR 3 N-S-H 36 II H 11 HO 0 0 06 S. 0

S

S

R 42 52 "YN~

-R

39 N' N,

~R

41 1 50 R R 1 163

R

%vnere.

0

N

A absent.

z B 0 R 0*0 0*09 *at Sp

L=C--

6 alkyI, 5Lr-C 06 aLkyI, Het-CO- 6 alkyI. CH(R 6 6

).NR

6

R

6 8

CH(R

6 6 )Ar. CH(R 6 6

NR

66

R

6 7 .M S0'l; z j so-); T =Ar, Ret; V =C3-7cvcloalkyI; W -CE 3

-COR

7

-CO-,R

6

-CON-IP.

6

-SO

2

)NHR

6

-NHSO-,R

6

-N}{COR

7

-O-COR

6

-SR

6

NR'R

6

NR'(C=N}I)NHR

5 Cl, Br, 1, F; X 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 1, 2; n =I to 6; 1, 2; Ar =phenyl, naphthyl, optionally substituted by one or more of Ph-CO.6allcyl. Het-C-6allcyl, C I 6 allcoxy, Ph-C 0 6 alkoxy, Het-C 0 6 alkoxy, OH, (CH 2 1 6

NR

5 8

R

59

O(CH

2 1 I_6NR 58

R

5 9 ~s.Ar phenyl or naphthyl. optionally substituted by one or more of Ph-CO-6alkYl, Het-COj 6 alkyl, C 1 6 alcoxy, Ph-CO- 6 alkoxy, Het-C 0 6 alkoxy, OH, (CH 2 1

NR

58

R

59

*O(CH

2 1 6

NR

58

R

59 or halogen; R= H, C I -6alklcyl Ar-CO- 6 alkyl, Het-CO.

6 alkyl; R H, C1-6alklcy;

R

2 C4-6alkyl, C4-6alkenyl, bcnzyl;

R

3 Cl-6a1cyl. Ar-Co-6alkyl, Het-CO 0 6 alkyi, R 5 CO-, R 5 S0 2

R

5

R

5

NHCO-;

R4= H, C 1-6alkyl, Ar-CO-.6allcyl, Het-CO- 6 alkyl; Ar-o-6alkyl, Het-CO- 6 allky1; R6= H, C 1-6alkyl, CH 2

CF

3 Ar-CO-6alkyl, Het-CO 0 6 aky; R7= C I 6alkyl, Ar-C-alkyI, Het-CO- 6 alkyl; R8= H. C2-6 alkenyl; C2-6alkynyl; Het, Ar;, C 1-6alkyl, optionally substituted by OR', SR', NR' 2 C0 2

R',

CO

2

NR'

2

N(C=NH)NH

2 Het or Ar;

R

9 H, C 1-6alkyl, Ar-CO.

6 alkyl, Het-CO- 6 alkyl; RI C 1-6alkyi, Ar-CO 0 6 alkyl, Het-CO..6alkyI; 9 C I 6alkYl. A-r-C I 6 alkyl. Het-CO 0 6 aikvI, or R 1 6 R17 R9- R 2= H, C I 6 alkyl, Ar-CO.

6 alkyl, Het-CO- 6 akyl;

R

13 H, C I 6 alkyl, Ar-CO.

6 alkyl, Het-C 0 6 alkyl; R1 4 N-R 9 R 72 Ac;

R

15 H, C I 6 alkyI, C 2 6alkenyl, C 2 6 allcynyl, Ar, Het, or C 1 6aIcyl optionally substituted by OR 9 NR2

CONR

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

=C

2 6 alkyl, C 2 -alkenyl, C2-6alcyny1, Ar, Het, or C2..6all 10 optionally substituted by OR 9

SR

9

NR

9 2 C0 2

R

9

CONR

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

:RR

19 H, C I 6 alkyl, C 2 6 allcenyl, C 2 6 alkynyl, Ar, Het, or C 1 6alcyl optionally substituted by OR 9

SR

9

NR

9 2 C0 2

R

9

CONR

9 2 N(C=NH)NH-, Het or Ar; 15 R 17

R

72 H, C1-all RIO, RIOC(O)-, RIOC(S)-, RIO0C(O)-; R1= R 26 C5-6alcYI; C2..6allcenyl; C3-1 Icycloalkyl; T-C3..

6alkyl; V-C I -alky1; T-C2-6alcenyl; T- (CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR 20 0R 2 0

,NR

20

R

27 or C 1-4alkyl;-

R

2 7

R

2 8 C0, R 2 8 0C0;

R

2 8 C 1-6allcyl; C3- lcycloalkyl; Ar, Het; T-C I -6alcyl; T-(CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR 20

OR

20

NR

20

DR

7 3 C 1.6allcYl; R0= R 22

R

23

R

24

R

25

R

73 H, C I -alkyl, Ar-C 0 6 alkyl, Het-CO 0 6 alkyl;

R

2 9 R3

HH

o 0 r~ 0 0* 0 0 N 0. 0 Me 11- N S N Sa 00 0 0 0 0 0H 2 Ph t 2 C s Cbz-leucinyl-; or 4-pyridyl methyloxycarbonylleucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetylleucinyl, NN-dimethyl-glycinyl leucinyl, 4-pyridyl acryl- Ieucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonylleucinyl, acetyl-leucinyl, benzoyl-Ieucinyl, 4-phenoxybenzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, aipha- isobutvi-biphenvi acetyl. Cbz-phenvialanjnvl. Cbznorleucinyl-, Cbz-norvalinyl-. Cbz-glutamyI-. Cbz-epsiion- (t-buty] ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl. 2- or 3- benzyloxy benzoyl, 4 -phenoxy benzoyl-, Cbz-amino acid-; or 4- pyridymethyloxycarbonylamninoacid-; aryl CO-C 6 alkyloxy carbonyl-amino 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-; C I-C 6 alkyI carbonyl. aryl

CO-C

6 alkyl carbonyl, heteroaryl CO-C 6 a.Lky1 carbonyl, :aryl CO-C 6 alkyl carbonyl, heteroaryl CO-C 6 alkyI carbonyl, C I-C 6 all sulfonyl, aryl CO-C~alkyl sulfonyl, heteroarvi

CO-C

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

CO-C

6 alkyl sulfonyl; R3 C 1 6 alkyl;,

R

3 1 R2 H m R 33

H

0.

N.

N

00 0 Me N0 0

S-

s,' 0 0 OCH 2 Ph EtO 2 C s Cbz-Ieucinyl-; or 4-pyridyl methyloxycarbonylleucinyl-; 4-imidazole acetyl-leucinyl-, phenyl acetylleucinyl, NN-dimethyl-glycinyl leucinyl, 4-pyridyl acetylleucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonylleucinyl, acetyl-Ieucinyl, benzoyl-leucinyl. 4-phenoxybenzoyl-, 2- or 3- benzvloxybenzoyl-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, Cbz-phenvial mynl. Cbznorleucinyl-, Cbz-norvalinvl-. Cbz-glutamyJ-, Cbz-epsilon- (t-butyl ester)-gluramy1; acetyl-ieucinv-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyioxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; or 4- pyridylmethyloxycarbony..

amidnoacid-; aryl CO-C 6 alkyloxy carbonyl-arnino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-arnino acid-, aryl CO-C 6 aLkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 aikyloxy carbonyl-amino acid-, C 1

I-

:C

6 alkyloxy carbonyl-arrino acid-; C I-C 6 alkyl carbonyi, aryl

CO-C

6 alkyI carbonyl. heteroaryl CO-C 6 alkyI carbonyl, :aryl

CO-C

6 alkyl carbonyl, heteroaryl CO-C 6 alkyI carbonyl, 15 C I-C 6 aLkyI sulfonyl, aryl CO-C 6 alkyl sulfonyl, heteroaryl

CO-C

6 alky1 sulfonyl, aryl CO-C 6 alkyI sulfonyl, heteroaryl

CO-C

6 alkyI sulfonyl; R3 OCH 2 Ar, 0CH2C I.

6 alkyI, aryl substituted CO- 6 alkyl, heteroaryl substituted CO-6alkyI,4-irnidazole methylene; 2-, or 4-pyridylmethylneneoxy; 4-pyridyl methylene, 2pyridyl sulfonyl, 4-pyridyl, aryl substituted CO- 6 alkyloxy, heteroaryl substituted CO- 6 alkyloxy;

SR

3 3

CI-

6 alkyI, -CH 2 Ph, -CH 2

CH

2

CO

2

R

3 4

R

3 4 C 1 6 alkyI,

R

3 5 Ar, HetAr; R6= Aryl, heteroaryl, pyridyl, isoquinolinyl;

R

3 7

C

1 6 alkyl, -CH 2 Ph, -CH 2

CH

2

CO

2

R

3 4

R

3 8 Cbz; C 1 6 alkyl or aryl substituted Cbz; C 1 6 alkyl -CO; benzoyl; C 1 6 alkyI or aryl substituted benzoyi;

R

3 9 R 2

H

0

RN

00 0 a -O

S-

a a -C P EO2 Cb-lucnl- 2,3- o -priylmthloyaroal lC-eucinyl; 2-,iy oy-enl 4-pyridyl ehlxcarbonylleucinyl, aceryl-leucinyl, benzoyl-Ieucinyl, 4-phenoxybenzoyl-, 2- or 3- benzyloxybenzovi-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl. Cbz-phenviaJanny1l Cbznorleucinyl-, Cbz-norvalinyl-, Cbz-glutamvl Cbz-epsilon- (Fbutvl ester)-glutamyl, acetvl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyf acetyl, alpha- isobutyl-biphenyl aceryl, ace.yl. benzoyl, 2- or 3- benzyloxy benzoyl, 4 -phenoxy benzoyl-, Cbz-amiuno acid-; or 4- pyridylImethyloxycarbonylamninoacid-; aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-ami no acid-, t0 ar-yl CO-C 6 alkyloxy carbonyl-amrino acid-, heteroary I

CO-C

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

CO-C

6 alkyI carbonyl, heteroaryl CO-C 6 alkyl carbonyl.

aryl CO-C 6 alkyI carbonyl, heteroaryl CO-C 6 alkyI carbonyl, C 1-C 6 alkyl sulfonyl, ay OCaklsloyhtray

CO-C

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

CO-C

6 alkyI sulfonyl; R4 *n I-akl R1= H and C 1 I 6 alkyl; R42 H 6 l any stttd C 1- 6 alkyladhteoay 203 C 1 -6akyI, aryl substituted C 1 -alkyI and hetero aryl substituted C 1 I 6 alky1,; H when R 4 2 is C 1 6 alkyI, aryl substituted C I- 6 alkyI; and heteroaryl substituted C 1 6 alkyI; R4= CH(R 5 3

)NR

4 5

R

54

CH(R

55 )Ar, C 5 6 alkYl;

R

4 5

R

4 6

R

4 7

R

4 8 R9= R 5 0

R

5 1 H, C 1 _alkyI, Ar-CO.

6 alkyI, Het-CO 0 6 alkyI; R2= Ar. Het, CH(R 5 6 )Ar, CH(R 5 6 )OAr, N(R 5 6 )Ar, C 1 6 alkyI,

CH(R

5 6

)NR

4 6

R

5 7

C

2 6 alkyl, Ar-CO.

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

54

=R

5 7

R

4 7

R

4 7

R

4 7

R

4 7 0C(O);

R

55 R5 R 5 8 R9= H, C I 6 alkyl, Ar-C 0 6 alkyl, Het-C 0

R

60 =R6=R6=R6=R6=H,

C

1 6 alkyl, Ar-CO 0 6 alkyl, or Het-COJ.

6 alicYl;

R

6 5 C 1 6 a1kYl, Ar, Het, CH(R 6 9 )Ar, CH(R 6 9 )OAr, N(R 6 9 )Ar,

CH(R

6 9

)NR

6 lR 70 R6 6 R1= H, C 1

I..

6 alkYl, (CH2)0- 6

-C

3 6 cycoaIcy1, Mr-CO 6 alkyl, Het-CO- 6 all; :R6 I C 1 6alkYl, (CH 2 )0- 6

-C

3 .6cycloalkyl, Ar-CO- 6 a~kyl, Het-CO- 6 alkY1; R 6 6 and R 6 7 may be c~mbined to form .15 a 3 -7 membered monocyclic or 7- 10-membered bicyclic carbocyclic or heterocyclic ring, optionally substituted with 1-4 Of C 1 6alkyl, Ph-CO.

6 alkyl, Het-C4- 6 alkyl, C 1 I .6alkoxy, Ph-CO-j.6a11coxy, Het-COj.

6 alkoxy, OH, (CH 2 )l-6NR 5 8

R

5 9

O(CH

2 1 6

NR

5 8

R

5 9

R

6 8 R7 R 6 2

R

6 2

R

6 2

R

6 2 0C(O),

R

6 2 0C(O)NR 5 9

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 compounds 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 I, such structural features include the central electrophilic carbonyl, a peptidyl or peptidomiumetic molecular backbone on either side of the central carbonyl, a termninal ca-rbobenzyloxv. moietv Cbz-leuciny, or a rrimic thereof. on the backbone on one or both sides of the car-bonyl. and optionally, an isobutyi side chain extendincy from the backbone on one or both sides of the carbonyl.

R

Compounds of Formula I wherein D =R and Q= z .R are preferred embodiments of the present invention. For the foot sake of convenience, such compounds are refer-red to herein after as compounds of Formula

HI.

10 More preferred embodiments of the present invention include compounds of Formula 11 wherein: X=S Y=H n -N X=S, Y=SH, and Z-N; X=N, Y=N, and Z=-S; 15 X=N, Y=N, and Z0O; and X=N, Y=N, and Z=-N.

Preferably R I is H, methyl or isobutyl. Preferably

R

1 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 Suitably k 6 is H, CI-4alkyl, phenyl or benzyl. Typically, W is CO2H, CO2-CJ4akyl, C0 2 -Ph, CC) 2 CH-,Ph,

CONH

2 7, NH-, or SH.

t Hllvvl6tliviu L U L rI-UIlIId 11 WC parLICUIdrIV prelr-reu: (2S, I S)-2-(benzvloxvcarbonyl)amxuno-N-[ I'-(2-carboxythiazol-4-yI)-3'merhylbutylj-4-methylpentanaxnide; (2S, I'S)-2-(benzyloxycarbonyl)aniino-N-[ l -carboxamidothiazol-4-yl)-3, methylbutylj-4-methylpentanamride; (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ l -(2-carboethoxythiazol-4-yI)-3' methylbutyl]-4-methylpentanamide; (2S, I'S)-2-(benzyloxycarbonyl)amino-N-[ l 2 -cyanothiazoI-4-yi)-3'-methylbutyl].

4-methylpentanamide; (2S, 1 'S)-2-(benzyloxycarbonyl)arnino-N-[ I '-[2-(N'-benzylcarboxamnido)thiazol-4.

:ylI-3'-methylbutyl]-4-methylpentanamide; (2S, 1'S)-2-(benzyloxycarbonyl)amino-N-[ methylpropy)carboxaidoJthiazo--y1)-3-methybutyI]-4methypentnamde; I'S )-2-(benzyloxycarbonyl)amino-N-[ 1 '42- phenylethyI)carboxamido]diazo4-y1)-3'-rethybut4methypennamde; (2S, I'S )-2-(benzyloxycarbonyl)amnino-N.[ 1 '-(4--carboethoxythiazol-2-yl)-3 methylbutyll-4-methylpentanamide; (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 -(4-carboxthxEaiazol-2-y -3 mnethylbutyl]-4-methylpentanamide; 20(2S, 1 'S)-2-(benzyloxycarbonyi)aiino-N-( [1'-(4-carbo2,-ilroethoxythiaiazol-- 4-erylbucmehyuyl]-4-methylpentana; (2S,.1'S )-2-(bcnzyloxycarbonyl)amino-N-[ 1 '-(2-carboet2,2,2-rriuoethyiazol.

25y-3methylbutyl]-4-methylpeanarride; (2S,1 lS)-2-(benzyloxycarbonyl-Lanucijmno-N-[ -(4-carbo etyoxa iazol-2-y methylbutyl]-4-methylpntanamide; (2S,1 'S)-2-(benzyloxycarbonyl-L-einy-[l'aro[1-(4-carbooythiazol-2-yl 3 'methylbutyl-4-methylpentanamide; (2S,1 'S)-2-(benzyloxycarbonyl)arnino-N-[ 1 '-(2-carboethoxythiazol-4-yi)-3'methylbutylI- 3-phenyipropanarnide; (2S. I 2 -(benzYloxvcarbonYi-L-leucinviarrunoN[ l'-(-carboethoxvthiazol-4- (2S.1 IS)- 2 -(benzyoxvcarbony)rrnoN I 5 -mercapco-1I 2 4 -oxadiazo[-3Vi.)-3' methyi butyl J- 4 -rnethylpentananiide; (2S,1 3 2 -(benzvloxvcarbonyl)arnno-N-[ 2 -mercaptothiazoI.4-y1>-3- 2

S-

2 (benzyycronycarb o-N-(4-arboe(4oxytzl 2 )ehl methylpentanarnide; (2S, I')2(ezlxcroy~rin-- '-2bnyoyabnlhao--l-' mehluyl4mtypnaaie (2S, I'S)- 2 (benzyloxycabonyl)a ino-4-methylN[3 -mthyl phenoxycarbonylthiazol4-yl )butyljpentanamide; IlS)- 2 (benzyloxycarbonyl)mino-4-methyj-N-[3mtil (2R, IlS)- 2 -(benzyloxyc rbonyl)amino.N- 1 4 -carboethoxytffiazo12..yI)ethy1I.

4 methylpentanamide; (2R, I -(benzyloxycarbony)a~no-N- 4 -carboethoxythiazo2yl)etiyll4 rnethylpentanarnide; and (2S, I .amiinothiazoI-y 3'mebty]2-benz2yloy arbony).m 4 -methylpentanamide.

*Most particularly preferred co mpounds of Formula HI are: (2S. I'S)- 2 -(benzyoxycarbony)ano-N-[ Il-( 2 -carboethoxytiazo4yi)-3.

methylbuylI4mehylpntananidc; (2S, l'S)-2-(benzyloxycarbnyl)amino-N.[1 4 -carbotioxythiazol2-y)3..

mehluy]4mthletnnie and 2S, l'S) 2 (b nzyloxycaronyl-L-Ieuciflyl)aniino-N (1'-(4-carboethoxythazol.2-yl)- 3 '-methybul]mehyenaade.

R' 0 1 1 I N

R

1 4 Compounds of Formula I wherein D and Q R are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula III.

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

N

N

N N

H

0 i-Bu More preferably B is

S

N Ntr

H

or prY 0 i-Bu

R

16 Preferably

R

11 is R R -N Preferably R 12 and R 13 are H.

R

19 Preferably

R

14 is N-R

R

72 Preferably R 15

R

16

R

18 and R 19 are Cl-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 RIOOC(O)-; and more preferably R 10 is Ar-Ci-4alkyl.

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: R 16 0 R 19 R N N NR H v. H H X=Y a

F

wherein X, Y, Z, R 1 6

R

17

R

1 9 and R 72 are as described in Formula III.

Most particularly preferred compounds of Formula m are: (I 1benzyloxycarbonylamino)-3-methybuylltiazol.2.ylcarbonyl.N.

(N-benzyloxycarbonyl-L-leucinyl)hydrazide, iII:N-benzyloxycarbony-L-leucinyl-N'-benylcroy--ecnlL leucinylhydrazide; and (1 S)-N-[2-[(I-benzyloxycarbonylamino)-3-methylbutyl]thiuol..-ylcarbonyl]N.

(N-benzyloxycarbonyl-L-leucinyl)hydrazide.

R 2 21 R y* N N- Compounds of Formula I wherein D and Q

R

2 24 y R 0 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 rV wherein R 21 and R 26 are selected from the group consisting of: N-Cbz-leucinyl N-Cbz-glycinyl, N-acetyl-leucinyl. N-Cbz-alanyl, 0 0N 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; i 2,2'-(N,N'-bis-acetyl-L-leucinyl)carbohydrazide; 2,2'-(N,N'-bis-benzyloxycarbonyl-L-alanyl)carbohydrazide; and 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-[N'-(4-methylpetanoyl)carbohydrazide.

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

R

R-N

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 Fo*rmula V, when R 30 =C -C 6 ailyl. R 3 0 is preferably Me or -CH 2

CI

2 Me 2 When R 3 3 =C -C6 alkyl, R 33 is preferably -Pr, Bu, or -CH 2

CI

2 Me2. When R 34 =C I-C6 alkyl, R 34 is preferably -t-Bu.

Even more preferred embodiments of Formula V include: bis-(Cbz-leucinyl)- 1 ,3-dian-no-propan-2-one; bis- 1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one; I -(Cbz-leucinvl)-ajnjino-- acetvlI-Ieucinyl)-arnino-propan-2 -one*.

1 -(Cbz-Ieucinyl)-anino-3-(Cbz-L-lutamyl-t-buty estrii)-amiuno-propan- 2-one: I -(Cbz-leuciny I)-amnino-3 -(Cbz-glutamy )-amino-propan 2-one; bis- 1 .3 -(Cbz- leuc inyl) -diamino- -bu tanone 2-one; 1 -(Cbz-le ucinyl)-arnino-3 -(Cbz-phenyl alanyl)-amino-propan-2 -one; I (Cbz-le uc inyl)-amino- 3 -(Cbz- norle uc inyl)- amino- propan-2 -one; I -(Cbz-leucinyl)- amino- 3-(Cbz-norvalinyl)-ainino-propan-2-one; bis- 1, ,3-(Cbz-Ileuc inyl)-diamino-5 -methyl-(S)-hexan-2 -one; 1 -(acetyl-Ieucinyl)-amino-3-(4-phenoxy-benzoyl)-amrino-propan-2-one; 1 -(Cbz-homo-Ieucinyl)-amino-(Cbz-Ieucinyl)-3-amaino-propan-2-one; -(Cbz-leuc inyl)-amrino-3-(acetyl-Ileucinyl)-arnino-propan- 2-one is a most particularly preferred embodiment of the present invention of Formula V.

00 ascompounds of Formula IweenD n 00

III

Q re preferaby 3 P, C rpried ebdien ote preent, 3 00 cCI =Ph. CN Ph may be optionally substituted with CI..6alkyI, C 1 6alkoxy, halogens and cyano groups. When R 35 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)-phenyI sulfonamido)-propan -2 -one, bis-1I 3-(4-phenoxy-phenyl sulfonamido)-propan-2-one.

Compounds of Formula I wherein D=

H

0 N 3 370 0 R 36 N- s- R H"1 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 0 Me 0 0 0

ON

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

Particularly preferred embodiment's of Formula VUI are: 1 -(Cbz-Ieucinyl )-amiuno-3-(4-( 3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)propan-2-one; 1 -(Cbz-Ieucinyl)- am-ino-3-(tosyl-amino)-propan-2-one; I -i Cbz-eucinv)arno3((4phenoxpheni)-sulfonao-poa -n I -(Cbz-homo-Ieucinyi )-amrino-3 2 -dibenzofuransulfonanido-propan2.

0 ne. and I -(Cbz-leucinyl)-am~no3(2-dibenzofuransulfonanido)-(S)-butan-2-o 1-(Cbz-leuciny)ano3 ((4phenoxyphenysunrfd)oan-oone 1-Czluiy)aio3(-iezfiasloaio-rpn2oe and I -(Cbzleciy)aio3( d enournufnmd) S btn2-n are most particularly preferred embodiments of Formula VII.

H 0 R 40 *Compounds of Formula I wherein D =and

Q=-

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 VII is when R 4 3 -is 2- dibenzofuranylsulfonyl.

Particularly preferred embodiments of Formula VIII are: (S)-Phenylmethyl [1 3 -[benzyloxycarbonylleucinyl-arrino]..2-oxopropyl]-1- (benzy)amino~carbonyl3methylbullcb ae.

(S )-Phenylmethyl 3 2 -dibenzofuranylsulfonyl1amno..2oxopropyl] -3- (benzyl)armino~carbonyl]..3..methybutycarbmate (S)-Phenyimethyl (1 3 2 -dibenzofuranylsulfonyl)ahano..2oxopropyl..3(4.

pyridinylmethy)amino~carbony]-3methylbuty1]carbamate I- [U 3 2 -dibenzofuranylsulfony l)amiunol2-oxopropyl-3 -(4-pyridinvlrnethv1) benzarnide (S )-Phenylmethyl [I -[[U3-f(2-dibenzofuranylsulfonyl)arninol-2-oxopropyiJ- 1 pyridinylmethyl)an-inolcarbonylj-3-methylbutyijcarbamate.

(S )-Phenylmethyl (1 -1li3-[(2-dibenzofuranylsulfonyl)aminol-2-oxopropyl].

I -(4-pyridinylmethyl)amninojjcarbonylj-3-mehylbutyljcarbamate is a most particularly preferred embodiment of Formula VMI.

R 48' N J of Formula IC wherein:D0 R n

R

4 5

R

46 N' R 4 8 R 4 .R 0 adR 1 reH of isoneenentl sch, pondsylr referrdtoxy ei ftrasmpoulrndofz R44 ACH(R)AR, HR5O4 NR;Ar H(')RR 1 R3= ethyl, i-Bu; R4= R 4 7

R

4 7

R

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

R

5 7

R

4 7

R

4 7 0C(O); Ar phenyl or naphthyl, optionally substituted by one or more of Ph-CO 0 6aLkyl, Het-C 0 6 alkyl, C 1 -6aikoxy, Ph-CO 0 6 alkoxy, Het-CO- 6 alkoxy, OH, (CH 2 1 6

NR

5 8

R

5 9

O(CH

2 1 6

NR

5 8

R

5 9 8 R5 9 H, C 1- 6 alkyl. Ar-C 0 6 alkyl; Her-CO 0 6 alkvi.

are more preferred embodiments of the present invention.

The following compounds of Formula DC are particularly preferred: 2-[N-(N-benzyloxycarbonyl-L-leucinyl)J-2-[N-(4phenoxyphenylsulfonyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-alanyl)]-2'-[N-(N-benzyloxycarbo-ny[-L leucinyl)Icarbohydrazide; 2-N(-ezlxcroy--ecnl12-N-4peybnoljabhdaie 2-rN-(N-benzyloxycarbonyl-L-Ieucinyl)I-2'[N'-(4- :methoxybenzoyl)Icarbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4- :phenoxybenzoyl)]carbohydrazide;

S

2 -(N-acetyl)-2'-[N'-(N-benzyoxycarbonyl-L-leucinyl)]carbohydrazide; 2-fjN-(N-acetyl-L-leucinyl)]-2'- [N'-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide; 2-[N-(N-acetyl-L-alanyl)]-2'-[N'-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-Ieucinyl)I-2'- dimethylaminomethyl)benzoyl)]]carbohydrazide; ~:.2-[N-(N-benzyloxycarbanyl-L-leucinyl)]-2'-[N'-[4-hydroxy4[3-(4rnorpholinomethyl)] ]beazoyl]carbohydrazide;, 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4-(N,Ndimethylaminomethyl)benzyloxy]carbonyl-L-leucinyllcarbohydrazide; 2-(N-benzoyl)-2'-[N'-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide; 2- [N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-tN'-t3-(4morpholinomethyl)berizoyl]]carbohydrazide; 2-[N-(3-benzyloxybenzoyl)]-2'-(N'-(N-benzyloxycarbonyl-L- Ieucinyl)Icarbohydrazide; 2-N -ezixcro i ehlmn) I propyloxylbenzoylllcarbohydrazide; leucinyl)]carbohydrazide; 2 [N(NbenzyoxycarbonyI -L-IeuciflY)- 2 3 4 pyridylmethoxy)benzoyfl]carbohydrazide; 2- [N-(4-benzyloxybenzoyl N'-(N-benzyIoxycarbonyI-L- Ieucinyl)jcarbohydrazide; 2-N(-ezlxcroy--ecnl]2-N-3bayoy5 mechoxy)benzoyllcarbohydrazide; dimethoxy)benzoyIcarbohydrazide; 2- [N.(N-benzyoxycarbonyL-euciyl)]-2'-N-(3-b11zyloxy-5ethoxy)benzoyllcarbohydrazide; 2-(N-(N-benzyloxycarbonyglyciny1-2'-[N-(N-bezlZoxycarbofyl-L- .9 leucinyl) ]carbohydrazide; 15 2- [N-(3-benzyloxybenzoy)]-2'-[N'-(N-benlZoxycarboflL- 9999 prolinyl)Icarbohydrazide; 2- [N-(N-benzyloxycarbonyl-L-leucifl)]-2'-[N t 4 phenylphenylacetyl)]carbohydrazide; (2'S)-2-[N-(3-benzyloxybnzoy)-2-[N'-(N-bI1zyloxycarbonlI2aminobutyryl)]carbohydrazide;, 2,2'-[N,N'-[bis-(4-phenylphenylacetyl)]]carbohydrazide; (2'RS )-2-[N-(N4-benzyloxycarbonyl-L-leucifl)]-2'-[2-( 4 phenylphenoxy)propionyl]carbohydrazide; 2-N(-ezlxbnol]2-N-4-ehypnaol]abhdaie (2RS, 2'RS)-2.2-[NN'-[bis-[2-(4-.phenylphenyI)methylpentanoyl)]]]carbohydrazide; (2R)2[-NbnyoyabnlLluiy)-'['[-4peypey)4 methylpentanoyl)]]carbohydrazide; (2'RS)-2-[N-(3-bcnzyloxybenzoyl)]- 2'-[N-[2-(4-phenylpheflyl)-4methylpentanoyl)]]carbohydrazide; (-N-('S-benzv loxvbenizovI) ]-2'-(N'-(N-benz-vl.oxvcarbonvl-N-methvl-Lleucinyl)jcarbohydrazide:.

2-[N-(3-benzyloxybenzoyl)j-2-fN'-N-(2-pyridinylmethoxvcarbonyl)-L.

Ieucinyl]]carbohvdrazide; 2 4 -pyridylmethoxy)benzoyj]I-2'-(N'-IN-(2-pyridinylmethoxycarbonv leucinyll]carbohydrazide; (2RS)-2-[N-[2-(4-phenylphenyl)4-methylpentanoyl)J-2Z-[N'-[N-(2pyridinylmethoxycarbonyl)-L-Ieucinylj]carbohydrazide; [N-(N-benzyloxycarbonyl-L-Ieucinyl)J-2'- [N'-r2-(4-phenylphenyl)-4methylpentanoyl)]]carbohydrazide; [N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[2-(4-phenylphenyl)-4- ::::*methylpentanoyl)]]ca'rbohydrazide; 2- [N-(N-benzyloxycarbonyl-L-leucinyl)I-2 t [N'-N-(4-phenylphenyl)-N-(2- ***methylpropyl)carbamoyl]]carbohydrazide; 15 2- [N-(3-benzyloxybeazoyl)I-2'-(N'-(N-methyl-L-eucinyl)]carbohydrazide; 2- (N-(N-benzyloxycarbonyl-L-Ieucinyl)]-2'-[N'-(N-rnethyl-L.

leucinyl)Icarbohydrazide.

R 64 N N M R ~~Compounds of Formula I wherein D R n Q 6 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 N N S or More preferably R 6 3 and R4are H and R 6 6 and R 6 9 are i-butyl.

More preferably

R

65 is CH(R 69

)NR

6

IR

70 in whi ch R 69 is i-butyl and R 6 1 is H. More preferably R 7 0 is R 6 2 0C(O), in which R 6 2 is

H

2

CH

2

N

CH 2

N

2

N

Dee, De..

Doe.

Alternately, R 65 is Ar or CH(R 6 9 )Ar, in which Ar in said R 6 5 group is

N

N

aoj0 More preferably, L is CH(R66)NR6(R 68

CH(R

66 )Ar, NR 66

R

67

CH(R

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

R

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

N

N

N

N

N-S

W~e IN 0"I or or Het in said L group is

S

C1 .60 S0 Go..

too.~ 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: o*

H

Se. 0 R'N I H

H

C ATher partoicualrfegdebdieti compound of Formula H r otpriual rfre: (I )NC. 0eny oy ab n la i o h lb tltizl4 vcroy]N -4p e oy h nlufnSh d aie (1 1 -(N-benzyloxycarbonyl-L-leucinvarino)-3methylbutyl Ithiazol-2-ycarbonyI-N-(N-benzyloxvcarbonyl-L-Ieucinyl)hvdrajde (IS 1-benzyloxycarbonylamnino)-3-methylbutyllthazol4 ylcarbonyl]-N'-(4-phenylphenylaceryl)hydrazide; (1 -benzyloxycarbonylarnino)-3-methylbutyllthiazol-4ylcarbonyljj-N'-[3-(4-pryidinylmethoxy)benzoyl]hydrazide; N-(2-(2-chlorophenoxymethyl)tbhiazolA4-ylcarbonyl]-N-N-(4.

pyridinylmethoxycarbonyl)-L-leucinyljhydrazide; N-[N-(4-pyridinyhnethoxycarbonyl)-L-leucinyl]-N'- [4-(1I,2,3-thiadiazol- 4-yI)phenyl]thiazol-4-ylcarbonyllhydrazide; [3-(4-chlorophenylsulfonyimethyl)tien-2-yl]thiazol-4-ycarbonyl] [N-(4-pyridinylmethoxycarbonyl)-L-leucinyljhydrazide; (I 1 -benzyloxycarbonylamino)-3-methylbucyllthiazolylcarbonyll-N'-[2'-(4-phenylphenylacetyl)-4-methylpentanoyllhydrazide; *15 N-(2-(3-beazyloxyphenyl)thiazol-4-ylcarbonyl-N'-jN-(2pyridinylmethoxycarbonyl)-L-leucinyljhydrazide; (1 1-(4-phenylphenyl)-3-niethylbutyl]thiazol-4-ylcarbonyl]-N'-[N- (4-pyridinylniethoxycarbonyl)-L-leucinyljhydrazide, N- (2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N- [2-(N-methyl-N-(4-phenylphenyl)aminolthiazol-4-yIcarbonyl-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-benzyloxycarbonyl-L-leucinyl)-N-[2-(4-phenylbenzyl)thiazol4ylcarbonyl~hydrazide; N- (2-(4-phenylphenylbenzyi)tiazol4-ylcarbanyl]-N-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-benzyloxycarbonyl-L-leucinyl)-N'- [2-[N-(2-methylpropyl)-Nphenylaminolthiazol-4-ylcarbonyljhydrazide; [N-(2-methylpropyl)-N-phenylaminoltbiazol-4-ylcarbonyl]-N'- N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-1 2 -(2-benzyloxphenyl)thiazol-4-vicarbonyl PYridinylmethoxycarbonyl)-L-leucinyl Jhydrazide; N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2pyridinylmethoxycarbonyl)-L-leucinyllhydrazide, N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N'-[ 2 benzyloxyphenyl)thiazol-4-ylcarbonylJhydrazide; N-12-[N-(2-methylpropyl)-N-phenylaminothiazo-4-ylcar bonyl]-N'-[N-(2pyridinylmethoxycarbonyl)-L-leucinylhydrazide; N-12-[N-(2-methylpropyl)-N-phenylaminolthiazol-4-ylcarbonyl]-N'-IN-(3pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; and N-12-( 2 -methoxyphenyl)thiazol-4-ylcarbonyl]-N'- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide.

Definrmitions 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 20 enantiomers and diasteromers, 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 racemic mixture may be separated using well-known techniques and an individual enantiorner 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.

"C I-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 carbamrnyl or Cl-4alkyl, where R' is Cl-6alkyl. C 0 alkyl means that no alkyl group is present in the moiety. Thus, Ar- 15 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 trans 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, Cl, Br, and I.

"Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or more of Ph-CO-6alkyl, Het-CO- 6 alkyl, C1-6alkoxy, Ph-CO-6alkoxy, Het-CO- 6alkoxy, OH, (CH 2 1 -6NR 58

R

59

O(CH

2 1 6

NR

5 8

R

5 9; where R 5 8

R

5 9 H, C 1 6 alkyl; Fiet-CO 0 6 alkyl. from CI-4alkv, OR'. SR', CF 3 CN, CO-,R" COW(R), F, Cl, Br and 1.

As used herein "H-et" 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 car-bon atoms and from one to three heteroatomns 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 quarernized, 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 in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C14~alkyl, OR', N(R') 2 SR', CF 3

NO

2 CN, CO 2

R,

F, Cl, Br and 1, where R' is CI-6alkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2 -oxopiperazinyl, 2 -oxopiperidinyl, 2- 15 oxopyrrolodinyl, 2 -oxoazepinyl, azepinyl, pyrrolyl, 4 -piperidonyl, pyrrolidinyl, pyrazo:yl pyrazolidinyl, zxmazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazoly4,. morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimnidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydiropyranyl, thienyl, 20 benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

"'HetAr" or "heteroary!' means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, pyridine:- It will be appreciated that the heterocyclic ring described when N =Z includes thiazoles, oxazoles, triazoles, thiadiazole§', oxadiazoles, isoxazoles, isothiazols, imidazoles, pyrazies, pyridazines, pyrinidines, 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 heteroatrms 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 -COiR 6

CONHR

6

-SO,)NHR

6 -NHSOiR 6

-NHCOR

7

-O-COR

6

-SR

6 or NRR 6 or a simiular 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-butyloxycarbonyl 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 dicyclohexylcarbodiin-Lde, DMAP is 2,6-dimethylaminopyridine, EDC refers to Nethyl-N'(dimethylaminopropyl)-carbodiirride. H-OBT refers to 1 hydroxybenzotriazole, DMF refers to dimethyl formnaxnide, BOP refers to :benzotrazol- 1 -yloxy-tris(dimethylaniino)phosphomium hexafluorophosphate, DMAP is dimethylaminopyridine, Lawesson's reagent is 2 ,4-bis(4-methoxyphenyl)- 15 1,3-dithiia-2,4-diphosphetane-2,4-disulfide, NMIM is N-methylmorpholine, TEA 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.

Mfethods of Preparation Compounds of Formula NI wherein X CH-. Y S and Z N. and W= C027R 7 CN, or CONR'R 7 may be conveniently prepared by methods analogous to those described in Scheme 1.

Scheme 1 O RI 0 AI D N IyOH a ~D Jy HI H N 0 0 b O R' 0 A' Hr H~~N CO 2 Et 0

S

2 -4 0 RI

D=

O A' 0 Ge..

C

a

N

D N

'S

0 R'

N

RI

H

2 N N 0E

S

0

RI

HI\

S

C

O R' HjN

S

O R'

HIN

'S

a) t-BuOCOCI. NMM. CH 2

N

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

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

CH

2

CI

2 f) TFMA, pyridine, CH 2 C3 2 g) R4OH, Boc 2 O, Pyridine or R 4 OH, EDCI, CH 2

CA

2 h) pipenidine, DMF; i) BOP. Et 3 N, D-CO 2 H, CH2CI2 1IScemeI. is treated with isobutyl chloroformate and N-methylmorpholine in ethyl acetate to give a mixed anhydride which is treated with diazornethane in ether to provide 2-cem 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 thiooxarnate 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 chioroformate and Nmethylmorpholine, followed by gaseous ammonia to provide primary amiude 6- Scheme I (R 3 The primary amide is treated with TFAA and pyridine in dichioromethane to provide 7-Scheme 1. Alternatively, 5-Scheme I can be converted to substituted amrides, 6-cee1 by treatment with ailkyl amines (such as benzylamine, 2-phenylethylamine or isobutylamine) and a peptide coupling reagent (such as BOP, EDC*HCI-HOBT or N-methylmorpholine/isobutyl chloroforrnate) in an aprotic solvent (such as dlichloromethane or DMEF). 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 DCCIDMIAP, EDCI orBoc2O/pyridine) in an aprotic solvent (such a dichioromethane or ether). When R 2 9-fluorenylmethoxy, treatment of 4-Scheme with piperidine in DMF gives 9-Sbheme Treatmnent 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 dichioromethane) provides 10-Scheme 1.

Scheme I A 000.

S S SMe S R'HN S 1111III HI *0 H N" 'N NH H 2N "LN oo H2NN

H

2 2 2 N 2 HN N NH

H

1Z 3 RI H c N SRR-- N Y NHR' S

NH

4 a) Mel, THff; b) 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 I A. 1 -Scheme IlA is treated with iodomethane in an aprotic solvent (such as THF) to afford 2-Scheme I A, which is treated with a primary amine in a protic solvent (such as isopropanol) to give 3-Scheme IA. this material is then treated with a bromomethyl ketone in a protic solvent (such as ethanol) to provide 4-Scheme IA.

Schemne-2 BocHN""~ O BocHN y N2 b BocHN )NrINH2 o 0 S C d* BocHN Kf& C 2 0t 'H2NI~.o E 4 0 Ft' 0 RI D N D NOE C0 2

H

a) i-BuOCOCl, NNM. NH 3 THF; b) Lawesson's reagent, THF; c) BrCH 2

COCO

2 Et, TFAA, Pyridine, CH 2

CI

2 d) TFA; e) DCO 2 H, EDC-HCl, HOBT, Et 3 N, DMIF; f) NaOH, H 2 0, THF 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 chioroformnate, N-methylmorpholine and ammonia in THfF to provide 2-Scheme 2. This material is converted to the thioarnide, L~ Scheme 2. by treatment with Lawesson's reagent in an aprotic solvent (such as TI-F or toluene). 3-Scheme 2 is converted to the thiazole by condensation with a aketoester bearing a suitable leaving group for displacement by a sulfur nucleophile (0l, Br. 1, OMS, O-p-Tos) in dichloromethane. 4-Scheme 2 is treated with TFA- to provide 5-Scheme 2. This material is treated with a carboxvlic acid (such as N-Cbz- L-leucine. N-Cbz-D-ieucine or N-Cbz-L-leucinyl-L-Ieuclne) and a peptide coupling reagent (such as BOP, EDC*HCL'1 -HOBT or N-methylmorpholine/isobutyl .chioroformate) in an aprotic solvent (such as dichloromethane, DM7F 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 2 R0

R'

NH CO 2 Et a BocR'N N -CO 2 Et b Ile R R' RHN C0 2 Et c 5 N N CO E N N

CO

2 E R R 0 R R S 4 a) Boc-amino acid, EDC*HCI, 1-HOBT. DMF; b) TFA; c) R 5 OCOCI. i-Pr 2

NEE

Compounds of Formula [H wherein X S, Y CH and Z =N may also be prepared by methods analogous to those described in Scheme 2A. I1-Scheme 2A is treated with a tert-butoxycarbonyi-protected amino acid (such as N-tertbutoxycarbonyl-L..leucine) and a peptide coupling reagent such as BOP, EDC.HCI -HOBT or N-methylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMOF or TF) to yield 2She2A, which is treated with trifluoroacetic acid to provide 3 b-chee-A. This material is treated with a chioroformate (such as 2-biphenylmetliyl chioroformate, 2-benzylbenzyl chloroformate, 2-naphthylmethyl chioroformate or 2-phenoxybenzyl chloroforrnate) and a tertiary amine base (such as diisopropylethylamine) in an aprotic solvent (such as methylene chloride) to provide 4-Scheme 2A.

Scheme 3 H2N y Oe a IN.BocHN )N(OMeb o 0 1 2 Hl d BocHN"'j NHNH 2 C I-BcNNN C0 2 Et 0 0 e 0*0 .0 e _f *0 I) CO 2 Et i -OE 0. :N m N D 004, D N 1

S\

H I) 'CO 2 Et a) BocO, Et 3 N, THF b) hydrazine hydrate, MeOH; c) EtO 2 CCOCl. Pyridine,

CH

2

CI

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

H,

EDC*HClIHOBT, Et 3 N, DMff Compounds of Formula HI whereini X and Y N, and Z S may be conveniently prepared by methods analogous to those described in. Scheme 3. L- Schme is treated with di-tert-butyl dicarbonate and triethylamnine in THF to provide 2Shrn 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 dichloromer~hane to provide 4-Schemne 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 3itraewthTFA to provide 6-Scheme 3. This material is treated with a carboxylic acid (such as N-Cbz- L-leucine) and a peptide coupling reagent (such as BOP. EDC*-HCL1-HOBT or Nmethylmorpholinelisoburvl chioroformate) in an aprotic solvent (such as dichioromethane, DMF or THE) to yield 7-Schemne 3.

Scheme4 BocHN rN N 'JC 2 Et BocHN \-COE0 H I C2E 0

N-N

2 .b

H

2 N 0 CZEt D)&N

GOE

0 RI H ,>CONH 2

N=

a) SOCI 2 pyridine, Et 2 O, toluene; b) TFA, CI- 2 C1 2 C) DCO 2 H, EDC*HCI/HOBT.

Et 3 N, DMF; d) NH 3 EtOH Compounds of Formula HI wherein X and Y N, and Z 0, and W= CO2Et or CONH2 may be conveniently prepared by methods analogous to those de-scribed in Scheme 4. 1-Scheme 4 is treated with thionyl chloride and pyridine in ether. followed by refluxing in toluene to provide 2-Schme The resultant oxadiazole is treated with TFA to provide 3-cere4 This material is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent such as BOP, EDC*HCI/1-HOBT or N-methylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane, DMff or THE) to yield 4-Scheme 4. The carboxylic ester is treated with ammonia in methanol to yield 5-Scheme 4.

Scheme o R 2 ~N )N C 2

H

H

H

2 N (Co 2 Me a 0 2

R

5 N N CO 2 Me

H

0 R b .B HIr H J N N NHNH 2 H II 0

R

C

o R2 N- H SH 0 R a) EDC*HCIHOBT, Et 3 N, DMF; b) H 2

NNH

2

*H

2 0 MeOH; c) CSCI 2 Et 3 N, CHCI 3 Compounds of Formula II wherein X and Y N, and Z 0, and W SH may be conveniently prepared by methods analogous to those described in Scheme 1-Scheme 5 and 2-Scheme 5 are treated with a peptide coupling reagent such as BOP, EDC*HCI-HOBT or N-methylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane, DMF or THF) to yield 3-Scheme 5. This material is treated with hydrazine hydrate in methanol to provide 4Scheme Treatment of 4Scheme 5 with thiophosgene and triethylamine in chloroform provides 5-Scheme Scheme 6 0 R' 0 R D NBr a N H H L j- SH

S

b b S0 R' H L )NH2

S

a. a a a a a a) H-)NCS 2 NH4+, EtCH; b) H-,NCSNH 2 EtOH Compounds of Formula 11 wherein X CH, Y S and Z N. and W Sf1 or NH2 may be conveniently prepared by methods analogous to those described in Scheme 6. Condensation of I1-Scheme 6 with anmonium dithiocarbamate in ethanol yielded 2-Scheme 6. Alternatively, 1 Shm can be condensed with thiourea in ethanol to give 3-Scheme 6.

0 0 1 a 1

I

D' NBr D N '0 I- I H 0 H 0 a o Ai D N N H N..

CO 2

H

a) Et 2 NO; b) H 2

NCH

2

CH(NH

2

)CO

2

H

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 convened to a variety of carboxylic acid derivatives using procedures previously described in other schemes.

Compounds of Formula II 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.

15 Scheme 8 4 _e_.LCO,H N 5 0 0 L C0Et S 1 2 3 _4 6R 3 L 7 N CONR6 NH 2 N R 0 H a) i. i-BuOCOC1, 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 C0 2 H, EDC*HC1, 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- Scheme 8. The thiazole carboxvlic ester is treated with a hydrazine (such as hydrazine monohvdrate or methyl hydrazine) in ethanol to yield 5-Scheme 8. This material is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as EDC*HC/l-HOBT) in an aprotic solvent (such as DMF) to provide 6-Scheme 8.

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

Scheme 9 LC0 2 H 2. LCONH 2 P0

LCN

2 9 N CO 2 Et A 12 3 4 L CONHNH 2 L H J

H

6 (J =CO. S02) a) i-BuOCOC1, NN4M, NH 3 THfF; b) Lawesson's reagent, THF; c) i.

2

CCOCH

2 Br; ii. TFAA, Py, CH 2 C1 2 d) H 2

NNH

2

*H

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

CI

2 f) R 6 5 C0 2 H, EDC*HC1, I-HOBT, DMF.

1 -Scheme2 is converted to 2-Scheme 9 by treatment with isobutyl chloroform-ate, N-methylmorpholine and ammonia in THEF 2-Scheme 9 is treated with Lawesson's reagent in THF to provide the thioanxide 3-cee9 This material is converted to the thiazole by condensation with an ct-ketoeste'r followed by treatment with trifluoroacetic anhydride and pyridine in mnethylene chloride to afford 4-Scheme 21 which is converted to 5-cen 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-eucine, N-(2pyridinylmethoxycarbonyl)-L-leucine, N-(3-pyridinylmethoxycarbonyl)-Lleucne N-(4-pyridinylmethoxycarbonvl)-L-leucine, 4-biphenylacetic acid, 3-(4pyridinylmethoxy)benzioc acid, or 4-methvl-2-(4-phenyiphenyl)pentanoic acid) and a peptide coupling reagent (such as EDC.HCJIl-HOBT) in an aprotic solvent (such as DMF).

9 Compounds wherein B 0 O R are prepared by routine methods of peptide synthesis as illustrated for instance by Scheme Scheme 6

R

15

R

16 RP CO H 2 NH +H2N CO 2 Et N CO 2 Et H A 1 S0

RIS

1 216 6 R' 6 0 H IJ' H I H b RP, N N CONHNH 2 RPn..N.N.&R 14 b NC O R' 5 H R's 0 4 a) EDC*HCI, HOBT, DMF; b) H 2

NNH

2

.H

2 0, EtOH; c) R1 4

-B-CO

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*HC1 -HOBT) in an aprotic solvent (such as DMF or dichioromethane) provides 3-Schme 10. This material is treated with hydrazine hydrate in ethanol to yield 4Scheme 10, which is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as BOP or EDC*HClI/I-HOBT) in an aprotic solvent (such as DMF or dichioromethane) to provide 5-Schere Compounds of Formula IV wherein R 22

R

23

R

2 4 are H. and R 2 1

R

26 are prepared by methods analogous to those described in Scheme 11.

Scheme 11 0 H 0 H

R

2 COH R N 21 HNHN NHNH, N N 0 H H 0 1 2 a) EDC.HC1, 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 10 Scheme 11. Treatment of 1-Scheme 11 with a carboxylic acid (such as 4biphenylacetic acid or 4 -methyl-2-(4-phenylphenyl)pentanoic acid) and a peptide coupling reagent (such as EDC.HC1/1-HOBT) in an aprotic solvent (such as DMF) provides 2-Scheme 11.

15 Nonsymmetric compounds of the Formula IX, and compounds of Formula TV wherein R 22

R

2 3

R

2 4 and R 2 5 are H, and R 2 1 R26, are prepared by methods analogous to those described in Scheme 12.

SS

Scheme 12

H

R"aR:0 R "CONHNH 2 b N-N c 9 02 R 20 12 Ig H 0 H 0 H R N N 'A H N H d e o rf R N N N 0 H 0 H H 4(F COR52 So0R52) H 2

'H

2 0, MeOH; b) C1 2 C0, PhMe: c) H 2

NNH

2

H

2 0, MeOH;d 4

C

2

.DHI

1-HOBT, DMF; e) R5S Ior R52CLXI, pyn. 5C CR2 g) R52CONR 5 1

NH

2 Treatment of I -Sherne 2 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-cem 2 This material is treated with hydrazine hydrate in a protic solvent (such as methanol or ethanol) to provide 4-Schme 12. Treatment of 4- Scheme 12 with a sulfonyl chloride (such as 4-phenoxyphenylsulfonyl chloride), an acid chloride (such as benzoyl chloride), or a carbamoyl chloride- (such as N-(2methylpropyl)-N-(4-phenylphenyl)carbamoyl chloride) and pyridine in DMF affords 5-cee 2 Alternatively, 5-cem-1 may be prepared by treatment of 4-Schme 12 with a carboxylic acid (such as N-benzyloxycarbonyl-L-alanine. Nbenzyloxycarbonyl-L-proline, N-benzyloxycarbonylglycine, benzyloxycarbonyl-2-arninobutyric acid, N-benzyloxycarbonyl-N-methyl-L-leucine, N-rert-butoxycarbonyl-N-methyl-L-leucmne, N-acetyl-L-leucine, N-acetyl-L-alanine, N-(2-pyridinylmethoxycarbonyl)-L-leucine, dimethylarninomethyl)benzyloxycarbonyl]-L-leucine, 4-phenylbenzoic acid, 4methoxybenzioc acid, 4-phenoxybenzoic acid, 4-(NNdimethylaminomethyl)benzoic acid, 4-hycroxy-3-[N-(4-morpholinomethyl)Ibenzoic acid, 3-[N-(4-morpholinomethyl)]benzoic acid, 2-benzyloxybenzoic acid, 3benzyloxybenzoic acid, 4-benzyloxybenzoic acid, 4-(3dime thvlarninomethvi~propox) )belzo ic acid. 3 -benzvloxv-5-methoxvbenzoic acid.

3 -benzyloxy-4.5-dirnethoxvbenzoic acid. 3 -benzvloxv-5-ethoxybenzoic: acid, 3-'4pyridinylmethoxy)benzoic acid, 4-biphenviacetic acid, 2-(4phenylphenoxy)propionic acid or 4 -methyl-2-(4-phenylphenyl)penranoic acid) and a peptide coupling reagent such as BOP, EDC*HCI -HOBT or Nmethylmorpholine/isobutyl chioroforinate) in an aprotic solvent (such as dlichioromethane, DMF or THF). 5-Schemne- 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-znethyl-N-benzyloxycarbony..Lleucinyl hydrazide).

Scheme 12A

R

2 0NHH a b C R21C*N:N2

R

2 1

CONHNHCH

2 R0 12

A

R 0 H d0or H 0 H R N NHNH2 e rf>R1 NN'

N.

0 o 0 H H

R

4 (RCH 2

R

23 I V C0R 52 So 2 R52 a) i. PhHO,( EtH ii. BH3-THF b) C2C"' PhMe; c) H 2 NNH 2 2 0, MeIOH; d) F152C 2

H,

EDC HCI, 1 -HOBT, DMF; e) R 52 S0 2 CI or R 5 2 COCi, pyridine, DMF; Q) R52C0 2

CR

52 Nonsymmetric compounds of Formula rV, wherein R 2 3 H are prepared by methods analogous to those described in Scheme 12A. I1-Schemne 12A is treated with an aldehyde (such as benzaldehyde) in a protic solvent (such as ethanol) and the resulting imine is treated with borane-THF complex to afford 2-Scheme 1 2A, 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 rea~ent (,such as BOP. EDC*HC1I-HOBT or N-methylmorpholine/isobut chloroformate) in an aprotic solvent (such as dichioromethane DMF or THE) to yield 5-Scheme-I 2A.

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

Scheme 13 0 o

H

0 0 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 I-Scheme 13 with a carboxylic acid 2-Schee 13. or a mixture of 2 different carboxylic acids (2 and 3) in equimolar amounts and a coupling reagent such as a dialkyl carbodilmide 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.

Scheme 14 So0Lb 8 0 0 0 2

SO:)

ON

HN

NN,

a) NMM, DMF; b) Jones, acetone 1,3-Bis-sulfonaido propanones may be prepared by sulfonylation of 1.3diamino-propan-2-ol 1-Scheme 14 with a sulfonyl chloride 2-Scheme 14 and a base such as N-methyl morpholine. followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

Scheme N21 0

S

0 3

OH

HN11-

NH

2 0 so** a.

C S

S

SS

SS 0 a.

6@r no ;r o o a) EDCI, HOBT, DMF; b) NMM. DMF. 3) Jones, acetone I -Amido-3-sulfonanido propanones may be prepared by acylation of 1,3dianino-propan-2-ol I -Scheme 15 with a carboxylic acid 2Sheme 15 and a coupling reagent such as a carbodiimide 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

SSSO

-OH

&b 3: R.Br 4: P.N 3 0 OM Co 0 OHM 6 0 me 0O s CIO'SJ X- 7 0 N, Oaovo

SO

Me I-Amido-3-sulfonarnjdo 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-Ieu-leu-OH- 1 -Schemne 16 to its bromo methyl ketone 3-Scheme 16 via a diazo methyl ketone 2-Scheme 16. Then, the bromide 3-Schemne 16 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-cem 6 Subsequent reduction of the azide with a reducing agent such as 1,3-propandithiol gives the free amine 6-Scheme 16. Acylartion or sulfontylation of the amine gives amide or sulfonamide 7-cem 6 Finally, oxidation of the carbinol with an oxidant such as Jones gives the desired compounds.

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

:Scheme 17 HO ~0 TFA.~~POIc CH. CeS 1i) Joe0egntctn 250 Azide~~~~ o0nn fgyio -cee1, olwdb oyaino h primary alohol gave osylate 2-cheme 17, h a ope oEia oye 3-Scme 17 drpas esbebydredin Med. C(H)Chem 1995 38H2H, 1427-u430e t produce polymer 4-Schemne 1I7 which was reacted with benzv I ami~ne intoluene, then washed extensively with various solvents. Then, the azide was reduced with 1 3 -propaneciithiol in MeOH, triethylaxnine, then was washed extensiveywt various solvents. Coupling of Cbz-leucine 6-Schemne 17 with the diarnine 17 with equimolar amounts and a coupling reagent such as a dialkyl carbodiinriide such as DCC or EDCI or H-BTh/ 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 00 2 3 so. N 0 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 rnorpholine, DMF; e) Jones reagent, acetone N-(2,3-Epoxypropyl)phthalimide I-Shee n18 (Aldrich) was reluxed with 0 an amine such as 4-pyridjyl 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 phthainici~ was then removed with hydrazine in MeOH and the resulting free amine was acylated with an acylating agent such as Cbz leucine or a sulfontylating 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 Compounds of Formula X may be conveniently made using methods analogous to those described in Schemes 2 1-27.

Scheme 19 ~C0Et a CQ 2

H

~N NH 4 a) KOH, MeOELIH2O; b) R 6 6

NHNH

2 EtOH; c) EDC*HC1, I -HOBT, DMIF :10 Compounds wherein X CH, Y= S, N and R4*H, are prepared by methods analogous to those described in Scheme 19. Carboxylic ester I -chme 19 is treated with a hydroxide base (such as lithoum hydroxide, sodium hydroxide or potassium hydroxide) in methanol/water to provide 2-Sheme 19. 3-Schme 19 is 9:0015 treated with a hydrazine (such as methylhydrazine) in a protic solvent (such as ethanol) to give 4-chm 19.2-She 1 and 4-cee1 are coupled by treatment with a peptide coupling reagent (such as EDCoHCU I-HOBT) in an aprotic .:solvent (such as DMEF) to provide SiScherne 1..

0.- Scheme Et 2 CCOCH Br a bN~' r 2 2H2 N N CO 2 Et Br N CO 2 Et 12 3 cod Ar N 4 ONEt r N CONHNH 2 4 sH 0 I I 0 H 6 a) Thiourea, EtOH; b) L. NaNO 2 16% aqueous HBr, ii. CuBr, 16% aqueous HBr; iii. HBr EtOH; c) ArB(OH) 2 Pd(PPh 3 4 CsF, DUE; d) ArSnMe 3 Pd(PPh 3 4 PhMe; e) H 2

NNH

2 eH 2 O, EtOH; e) R 65 C0 2 H, EDC.HCI, Il-HOBT,

DMF.

Compounds wherein X S, Y CH. Z N and V 2 -methoxyphenyl or 2- 0 benzyloxyphenyl, are prepared by methods analogous to those described in Scheme Ethyl bromopyruvate (1 -Scheme 20) is treated with thiourea in refluxing *ethanol to provide 2-cee 0 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 HBr to give 3-Shm 0 Treatment of this material with an arylboronic acid (such as 2-benzyloxyphenylboronic acid), tetrakis(triphenylphosphine)palladurn(O) and cesium fluoride in refluxing DMIE provides 4-cem-0 Alternatively, 4-c m 0 may be prepared by treatment of 3-cee2 with an aryistannane (such as 2 -trimethylstannylanisole) and tetrakis(triphenylphosphine)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-benzyloxycarbonyl-N-methyl..L-eucine,

N-(

2 -pyridinylmethoxycarboflyl)-L.eucjne,

N-(

3 -pyridinylmethoxycarbonyl)..L.

leucine or N-( 4 -pyridinylmethoxycarbonyl)>L.eucine) and a peptide coupling reagent (such as EDC*HCIII-HOBT) in an aprotic solvent (such as DMF) to provide 6-Schemne Scheme 21 RCOCI- a RCONHR~ 64 b3 RCH2NHR 6 7 c RCH2NR 67 CSNH d 12 3 4 R 66R 6 W.<INN C 2 Et R 66 67 'NN CONHNH 2 :R R N SH 0

H

7 a) R 67

NH

2 Py, CH 2 Cl 2 b) LiAIH 4 THF; c) i. CI 2 CS, Py, CH 2

CI

2 ii. NH 3 MeOH or 1. PhCONCS, CHCJ 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*HCI, 1-HOBT, DMF.

Compounds wherein X S, Y CHi, Z =N and V NR 66

R

67 are prepared by methods analogous to those described in Scheme 2 1. An acid chloride (L-z Scheme 21) is treated with a primary amine (such as 4-axmnobiphenyl or aniline) and pyridine in an aprotic solvent (such as miethylene chloride) to provide 2-Schme !1L which is treated with lithium aluminum-hydride in THF to afford 3-cem Treatment of 3-Shm 21 with thiophosgene and pyridine in methylene chloride, folowed by treanment with ammonia in methanol provides 4-Scheme 2 1.

Alternatively, 4-chm 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. 4-Schme 21 is treated with hydrazine hydrate in ethanol to give 5-Scheme 2 1. Treatment of 5-Scheme 21 with a carboxylic acid (such as N-(2-pyridinylmnethoxycarbonyl)-L-leucine, N-(3pyridinylmethoxycarbonyl)-L-leucine or N-(4-pynidinylmethoxycarbonyl)-Lleucine) and a peptide coupling reagent (such as EDC*HCII-HOBT) in an aprotic solvent (such as DMF affords 6-cee21 59 Scheme 22

H

2

NCSCO

2 Et a 1

H

2

NN

H,N COEt

H

I

b L- N CO Et C

N-N

H

N CONHNH 2 d

N-N

H

O H I H N-N H 0 p p a) H2NNH 2 *H20, EtOH; b) LCO2CO2i-Bu, 200 c) H 2

NNH

2

*H

2 0, EtOH; d)

R

6 5

CO

2 H, EDC*HCl, 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-Schcme 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*HC1/1- HOBT) in an aprotic solvent (such as DMF) to provide 5-Scheme 22.

-i 0 0# Scheme 23 0 H R6 1 1 61 H 0 R H R 69 'IN 61 borc H 0 U. S. U U U

S.

0 H R 6 S H 0 1 S(M CO, SO 2 R 560 H BOCNR' N H 0 R" 0 H a HNO _NYR' H 0 S U S. 4 a) TFA; b) R 62 C0 2 H, EDC*HCI, 1-HOBT, DMff; c) R 62 S0 2 C1, i-Pr 2 NEt Compo'inds wherein X =5S, Y CH, Z N, L CH(R 66 )NR6OR 68 where R8* Boc or Cbz, or R5= CH(R 69

)NR

6 lR 70 where R 70 Boc or Cbz are prepared by methods analogous to those described in Scheme 27. 1 -Scerne23 is treated with trifluoroacetic acid to provide 2-Scheme23. This-material is treated with a carboxylic: acid (such as pryazinecarboxylic acid, isonicotinic acid, 4imnidazolylacetic: acid or pipecolic acid) and a peptide coupling reagent (such as EDC*HCI/I-HQBT) in an aprotic solvent (such as DMF) to provide 3-Schem 2.

3-Sc~heme23 may also be prepared by treatment of 2-cee2 with a sulfonyl chloride (such as 2-pyridinesulfonyl chloride) and a tercicary amine base (such as diisopropylethylamine) in an aprotic solvent (such as methylene chloride).

Alternatively, treatment of 4-S m 2 3 with trifluoroacetic acid provides Scee 3 Scheme 24

OH

H2NHj, NH2 BAINI O'H a

OH

HoN

NH,

0 O CHSP 0 OS 0 O cH 2

P

d N OH 0 0 004 Pt' a) EDCI. DMF; b) 2-PhCH 2 OPhSO 2 CI, NMM, DMF; TFA, DCM; d) 4-pyridyl acetic acid, HBTU, NMM, DMF; e) Jones 1.

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 Cbz-NH C0 2

H

a b 0 H 0 ,N

C

Cbz-NH

OH

H""

Cbz-NH

YNN~

OH Med e Cbz-NH NHCbz 0 0 a a a.

a *n.

0 Me Cbz-NH Y I NHCbz 0 0 a) HBTU, NMM, DMIF, allyl amine; b) mCPBA, DCM; c) MeNH 2 isopropanol. C; d) Cbz-leucine, EDCI, DMIF; e) Jones, acetone N-Allyl amine (or a N-alkyl-N-allyl amine) is coupled to a Cbz-arnino acid (or sulfonylated with an aryl sulfonyl chloride), then the alkene is epoxidized with a peracid (or dixnethyl diooxurane). The epoxide is opened with a subsituted amine, then the amine is acylated or sulfonylated. Final oxidation gives the desired ketones.

*aa.

a a 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 ncorporated 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, 15 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+, 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.

This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered, isotonic, aqueous solution.

Examples of suitable diluents are normal isotonic saline solution, standard dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternately, these compounds may be encapsulated, tableted or prepared in a an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate 'preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water.

The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

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 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.

This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an 15 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.

20 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.

The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein.

Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about mg/kg.

No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.

Biological Assays The compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.

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

Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature.

Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product.

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 (Ki,app) were calculated according to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140): 9 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) 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).

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°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 e *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 30 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.

7 g/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 (87MEM1 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.

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 0 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 0 C. Excess buffer was aspirated, and the slices were air dried following a 10 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 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 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 S.In the following synthetic examples, temperature is in degrees Centigrade o 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 15 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. 'S)-2-(benzvloxvcarbonvl)amino-N- 1 '-(2-carboethoxvthiazol-4vl)- 3 '-methvlbutvll-4-methvlpentanamide a) N-benzyloxycarbonyl-L-leucinyl-L-leucinyl bromomethylketone l-Methyl-3-nitro- -nitrosoguanidine (5.9 g, 40.11 mmol) in ether (200 mL) o 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 -40C 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 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 -IHNMR (400 MHz, CDCI 3 57.34 (in, 5H), 6.51 I 5.15 I 5. 10 2H), 4.78 (im, I 4.20 (in, INH), 4.04 (dd, 2H), 1.63 (mn, 6H), 0.93 (mn, 12H).

b) (2S, 1 S)-2-(benzylox'ycarbonyl)anmino-N-[ I'-(2-carboethoxythiazol.4-yl)-3inethylbutyl]-4-inethylpentananiide The compound of Example I1(a) (2.0 g, 4.4 mmol) and ethyl thiooxainate (0.59 g. 4.4 mxnol) were refluxed in ethanol for 4 h. The solvent was evaporated and the residue chromatographed (silica gel, 2.5% inethanol/dichloromethane) to give the title compound as a white solid (1.46 IH NMR (400 MiHz, CDCI3) 8 7.32 (s, 1H), 7.21 (mn, 5N), 6.40 1H), 5.13 (dd, lH), 5.02 2H), 4.41 2H), 4.06 (in.

1H), 1.71 (in, 2H), 1.47 (in, 4H), 1.33 3H), 0.73 (mn, 12H).

Preparation of (2S.1 'S)-2-(benzyloxvcarbonyl)arnino-N-[ 1'-(2-carboxvthiazol-4-vl)- 3 '-iethylbutyl-4-methvlpentananide The compound of Example 1(c) (0.92 g, 1.88 rnmol) was stirred in tetrabydrofuran 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 dichloromethane. The combined organic extracts were evaporated in vacuo to give the title compound as a white solid (0.844 IHNMR (400 Mz, CDCl3) 87.40 I1H), 7.23 (in, 5H), 6.89 I1H), 5.22 IlH), 5.14 (dd, ILH), 5.02 2H), 4.15 (mn, 1H), 1.67 (mn, 2H), 1.44 (in, 4H), 0.81 (mn, 12H).

Preparation of (2S. 1'S)-2-(benzyloxycarbonyl~aiino-N-r 1'-(2-carboxaxnidothiazol- 4-yl3metb ylbmtyl1-4hlamde The compound of Example 2 (0.408 g, 0.88 rnmol) in tetrahydrofuran was cooled to -40'C and treated with N-inethylinorpholine 185 g, 1.85 rnmol, 0.2 mL) and isobutyl chloroformate 12 g, 0.88 rnrol, 0. 11 mnL). The mixture was stirred at -40*C for 15 minutes and then ammonia was bubbled through the solution for several minutes. The mixture was allowed to warm to room temperature and was then diluted with ethyl acetate and washed successively with I .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 chromatographecl (silica gel, 3% methanolldichloromethane) to give the title compound as a white solid (0.245 IH NMR (400 MIHz, CDCI3) 8 7.22 (in, 7.04 IlH), 6.40 (br s, I 5.51 (br s, I1H), 5.09 (mn, I 5.02 (dd, 4.07 (in, IH), 1.66-1.42 (in, 0.82 (mn, 12H).

Example 4 Preparation -of (2S. I'S )--2-(benzvloxvcarbonvl)amino-.N-f 1 -(2-cvanothiazol-4-vl)-3'iethvlbutyl I- 4 -methylpentanarride 15 The compound of Example 3 (0.185 g, 0.4 minol) was dissolved in dichloromethane, cooled to 0 0 C and treated with TFAA (0.093 g, 0.44 mmol, 0.06 mL) and pyridine (0.07 g, 0.88 minol, 0.07 mL). After 3 h, the mixture was poured into a solution of saturated aq~ueous 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 1 H NMvR (400 M4Hz, CDCl3) 8 7.44 IH), 7.29 (s, 6.51 (br d, 1H). 5.14 (Mn IH), 5.07 2H), 4.11 (in, lH), 1.78-1.41 (in, 6H), 0.83 (mn, 12H).

Example Preparation of 2 S.l'S)- 2 -(benzvloxycarbonylrpjno.N-l.f2(N'.

benzylcarboxainlidoithiazgl-4..vl1..3tmethvlbuw11l4methypntanmde To a solution of the compound of Ex ample 2 (0.12 g, 0.26 minol) in dichloromerthane under argon at room temperature is added benzylamnine (0.03 g, 0.29 inmol, 0.03 mL), BOP reagent 115 g, 0.26 inmol), and triethyl amine (0.026 g, 0.26 minol, 0.0.4 rnl-) which is allowed to stir for 16 h. The solut-ion 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 NMR (400 Mllz, CDCI3) 5 7.56 (br s, 1H), 7.33 (in, 10H), 6.48 (br d, IH), 5.15 (dd, IH), 5.03 2H), 4.63 2H), 4.12 (in, JH), 1.72-1.40 (mn, 6H), 0.85 (in, 12H).

Preparation of (2S. 1 S)-2-(benzyloxycarbonvl)amino-N-r 1 methvlpropvl )carboxarmidolthiazol-4-vll-3'-methylbutyll-4-methylpentanamide Following the procedure of Example 5, except substituting isobutylaniine for :benzylamine, the title compound was prepared (0.074 I H NMR (400 MIHz, CDCI3) 5 7.27 5H), 7.19 IN), 6.38 (br d. IH), 5.09 (mn, IH), 5.01 2H), 4.07 (mn, 1H), 3.20 (dd, 2H), 1.83 (in, IH), 1.69-1.40 (mn, 6H), 0.90 6H), 0.81 (mn, 12H).

*xrnl 7 Preparation of (2S. 1 'S)-2-(benzyloxycarbonylharrno-N-f 1 phenvlethylharboxamidolthiazol-4-yll-3'-rnethylbuyll-4-methvlpentananiide Following the procedure of Example 5, except substituting 2phenylethylamine for beazylaniine, the title compound was prepared (0.070 IH NMR (4.00 MIHz, CDC13) 8 7.30-7.11 (MI 1H), 6.35 (br d, 1H), 5.09 (mn, 1H), 5.01 2H), 4.05 (in, IN), 3.64 (mn, 2H), 2.87 2H), 1.69-1.40 (in, 6H), 0.80 (mn, 12H).S Example 8 Prearation of (2S. I'S)- 2 -(benzloxvcarbonvl)amino-Nf 4 -carbethoxvthiazol2 vi)-3'-rethvllbuvtll- 4 -methvlpentanamide a) N-ert-butoxycarbonyl-(L)-leucinamide To a solution of N-tert-butoxycarbonyl-(L)-leucine (Advanced Chemtech) g, 20.0 mmol in dry THF (100mL) at -40 0 C was added isobutyl chloroformate (2.7 g, 20.0 mmol) and N-methylmorphiline (4.2 g, 42 mmol). 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). IH NMR (400 MHz, CDCI3) 6 6.38 (br s, 1H), 5.79 (br s, 1I 5.04 (br d, 1I), 4.13 1H), 1.71-1.49 3H), 1.39 9H), 0.92 (dd, 6H).

S* b) N-tert-butoxycarbonyl-L-leucinethioamide 15 To a stirring solution of the compound of Example 8(a) (2.38 g, 10.35 mmol) in dry THF was added Lawessons reagent (2.51 g, 6.21 mmol) and the 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 I H NMR (400 MHz, CDCl3) 6 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).

0 04 c) (1S)-1 -(tert-butoxycarbonyl)amino-l1-( 4 -carboethoxythiazol-2-yl)-3methylbutane The compound of Example 8(b) (2.40 g, 9.76 mmol) was stirred in dry acetone (20 mL) under argon at -10C. Ethylbromopyruvate (2.12 g, 10.73 mmol, 1.35 mL) was added and stirred for 1 h at -10*C. The solution was poured into a well stirred mixture of chloroform and water and then saturated with sodium bicarbonate. The organic phase was separated and the aqueous layer 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 mmnol, mL) and pyridine (1.70 g, 21.47 rnmol, 1.75 rnL) in dichloromethane 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 chromnatographed (4% methanol/dichloromethane) to give the title compound as a tan solid (1.2 I H NMIR (400 MIHz, CDCI3) 8 7.98 I 5. 04 (br d, lH), 4.95 (mn, IH), 4.31 (q, 2H), 1.88 (in, IH), 1.63 (mn, 2H), 1.40 9H), 1.32 3H), 0.85 (dd, 6H).

d) (2S. 1 S)-2-(beazyloxycarbonyl)amino-N-( I -(4-carboethoxythiazol-2-yl)-3'methylbutyl]-4-methylpentanamide .~*The copon of Exml 8(c) g, 2.92 Yfliol) was dissolved in neat TEA (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 iniol) was dissolved in dichlorometbane with N-Cbz-L-Ieucine (0.394 g, 1.49 niol) BOP reagent (0.66 g, 1.49 inmol) and triethylammne (0.73 g, 7.2 inmol, 1.0 mL) 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 tidle compound as a white solid (0.396 IH NMR (400 MHz, CDCI3) 867.96 1H), 7.25 5H), 6.61 (br d, IH), 5.30 (mn, 1H), 5.09 (br d, IH), 5.01I 2H), 4.33 (q, 2H), 4. 10 (in, I1H), 1.90-1.58 (mn, 6H), 1.29 3H), 0.81 (dd, 12H).

Example 9 Preparation of (2S. 1 'S)-2-(benzvloxycarbonyflaniino-N-f 1 -(4-carboxythiazol-2-XDY 3'-iethylbutyll-4-methylpentanamide Following the procedure of Example 2, except substituting (2S,lI'S)-2- (benzyloxycarbonyl)arnino-N-[ 1 '-(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4inethylpentanamide for (2S, 1'S)-2-(benzyloxycarbonyl)amino-N-[ 1 carboxytiazol-4yl)-3-methylbutyl]4methylpentanamide, the title compound was prepared (0.301 I H NMR (400 MIHz, CDCl3) 8 8.06 LH), 7.24 (in, 5H), 7.11 1H), 5.30 (mn. 2H), 5.04 2H), 4.16 im. lH). 1.88-1.40 6H), 0.71 (dd.

12H).

Example Preparation of (2S. FS)- 2-(benzy foxvycarbonvl )arno-N- r carotoyhaizl2y)3-mtybil--ehlntnmd a) N-tert-butoxycarbonyl.L-.leucine 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 mimol) in THF mL) was added triethylamine (3.34 g, 33.0 mmol, 4.60 niL). 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), water, and saturated brine, then dried ~over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (8.02 g, IH N7vR (4.00 M[Hz, CDCl3) 8 4.88 111), 4.33-4.31 IH), 7.73 3H), 1.75-1.48 (in, 3H), 1.44 9H), 0.96 3H), 0.93 3H).

*Off b) N-tert-butoxycarbonyl..L-eucine hydrazide To a stirring solution of the compound of Example 10(a) (8.02 g, 32.7 mniol) in methanol (250 mL) was added hydrazine hydrate (16.38 g. 327 imol, 15.9 After stirring for 22 h at room temperature, the solution was a a*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 M41z, CDC13) 8 7.71 (br s, ILH), 4.99 2H), 4.12-4. 10 (in, I 3.94 (br s, 2H), 1.68-1.49 (in, 3H), 1.44 (s, 9H), 0.95 3H), 0.92 3H).

c) 2 2 -(benzyloxycarbonyl)armno-4.methylpentaoyl..N'.

carboethoxycarbonylhydrazide To a stirring solution of the compound of Example 10(b) (8.02 g, 32.7 mmrol) and pyridine (2.85 g, 36.0 ixol, 2.91 rnL) in dichloromethane (200 m.L) was added ethyl oxalyl chloride (4.91 g, 36.0 mmiol, 4.02 mL). After stirring at room temperature for 2 h, thye solution was washed with 1 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 MiHz, CDCI3) 8 9.32 (br s, 2H), 5.04 2H), 4.38 2H-), 4.28 (in, IH), 1.77-1.56 (in, 3H), 1.44 9H), 1.39 38), 0.96 3H), 0.94 (d, 3H).

d) (1 1-(terr-butoxycarbonyl)amino-lI-(4-carboethoxythiadiazol-2-yl)-3inethylbutane To a stirring solution of the compound of Example 10(c) (2.50 g, 7.24 inmol) in toluene (70 mL) was added Lawesson's reagent (1.46 g, 3.62 minol). 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, IH NMR (400 MHz, CDC13) 8 5.19 (in, 1H), 5.13 (d, 1H), 4.51 2H), 1.95 (mn, IH), 1.83-1.73 2H), 1.44 98), 1.00 38), 0.98 3H).

*20 e) (1 I1-amino-i -(4-carboerthoxythiadiazol-2-yl)-3-methylbutane bistrifluoroacetate salt To a stirring solution of the compound of Example 10(d) (1.75 g, 5.1 inmol) in dichloromethane (40 mL) was added TFA (10 inL). After stirring for 5 mini at room temperature, the solution was concentrated to give the title compound as an oily pale yellow solid (2.40 g, 100%). IH NMR (400 MHz, CDCI3) S89.83 (br s, 48), 5.20 (in, I 4.51 28), 2.07 (in, 2H), 1.70 (mn, 18H), 1.44 3H), 1 .00 (t, 38).

f) (2S, 1'S)-2-(benzyloxycarbonyi)amino-N4 1 '-(4-carboethoxythiadiazol-2-yl)-3'inethylbutyl]-4-methylpentanamide To a stirring solution of the compound of Example 10(e) (566.1 mg, 1.20 mmol), N-Cbz-L-leucine (250.5 mg, 1.32 mmnol), I -(3-dirnethylamlinopropyl)>' ethylcarbodiimide hydrochloride (253.3 mg. 1.32 rnmol) and I hydroxybenzotriazole (32.5 mg, 0.24 mmol) in 2.5 rnL of DMF was added triethylamine (243.1 mg, 2.40 mmol, 0.335 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 mg, 1

H

NMR (400 MHz, CDCI3) 5 7.35 5H), 6.77 1H), 5.49 (in, lH), 5.12 (dd, 2H), 4.51 2H), 4.20 (mn, lH), 1.97(m, IH), 1.88 (mn, IH), 1.66 (mn, 3H), 1.52 (mn, 1H), 1.45 3H), 0.97-0.92 (in, 12H).

Example I1I Prep~aration of (2S.l S)-2-(benzyloxvcarbonylhamino-N-rl1'-(2-carbo-2.2.2trifluoroethoxvthiazol-4..vh-3'-methylbutyl b4-methvlpenitanamnide The compound of Example 2 (0.200 g, 0.433 inmol), 1, 1, 1 trifluoroethanol (.052 g, 0.52 inmol, .04 mL), pyridine 1 and di-t-butyl dicarbonate 104 g, 0.477 inmol) 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 tidle compound as a white solid (.098 I H NMR (400 MHz, CDCl3) 867.50 I1H), 7.36 5H), 6.64 IlH), 5.22 (in, 2H), 5.09 2H), 4.73 (mn, 2H), 4.16 (mn, I H), 1.66-1.41 (mn, 6H), 0.87 (mn, 12H).

Example 12 Preparation of (2S. I S)-2-(benzvloxvcarbonvl)armino-N-f 1-(4carboethoxyoxadiazol-2-vl)-3 '-methylbutvll-4-methvlpentanamide a) (IS)-I -(terr-butoxycarbonyl)amino- I -(4-carboethoxyoxadiazol-2-yl)-3methylbutane 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, i:52 mL) in ether (15 mL) was added thionyl chloride (1.12 g, 9.41 mmol, 0.69 mL). After stirring at room temperature for 2 h, the solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in toluene and heated 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, CDCI3) 8 5.14 1H), 5.03 (hr d, 1H), 4.52 2H), 1.78-1.70 3H), 1.44 9H), 0.99 6H).

b) -amino-i -(4-carboethoxyoxadiazol-2-yl)-3-methylbutane Following the procedure of Example 10(e), except substituting I-(rertbutoxycarbonyl)amino- 1 -(4-carboethoxyoxadiazol-2-yl)-3-methylbutane for (I5)-I (tert-butoxycarbonyl)amino-1 -(4-carboethoxythiadiazol-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 LW), 1.44 3W), 1.00 (t, 6H).

c) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(4-carboethoxyoxadiazol-2-yl)-3'methyibutyl]-4-methylpentanamxde Following the procedure of Example 10(f), except substituting amino-I -(4-carboethoxyoxadiazol-2-yl)-3-methylbutane for (15)-I-amino-i carboethoxythiadiazol-2-yl)-3-methylbutane, the title compound was prepared (235 mg, 1 H NMR (400 MHz, CDCl3) 87.26 5H), 6.64 1W), 5.45-5.39 (m, 1H). 5.12 (in, 4.52 2H), 4.20 Min 1H), 1.81 2H), 1.68-1.64 (irn. 3H).

1.54-1.50 (in, 1H), 1.46 3H), 0.97-0.92 (in, 12H).

Example 13 Preparation of (2S. I'S 2 -(benZyloxvcarbonl.L- lucinv )ami~no-N-[ carboethoxvthjazol-2.yl)-3 -methvlbutyI l- 4 -methylpgntanarnide The compound of Example 8(c) (160.7 mg, 0.47 rnmol) was dissolved in neat TFA (1.0 m.L) and stirred for 15 minutes. The solution was diluted with methanol and evaporated to dryness. The residue was dissolved in DMF (2 ML) and to the resulting solution was added N-Cbz-L-leucinyl-L-leucine (194.0 mg, 0.52 mmol), I 3 -dimethylaminopropy)3.ethylcrodijrwde hydrochloride (99.0 mg, 0.52 inmol) and I1-hydroxybenzotriazole (13.0 mg, 0.094 mmol) and triethylamine (94.7 mng, 0.936 inmol, 0. 13 mL). After stirring at roomi temperature for 24 h, the :mixture was diluted with ethyl acetate and washed with water, saturated aqueous *.15 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 S 146 I H NI'%4R (400 M[Rz, CDC13) 6 8.04 111), 7.33 5H), 7.14 IH), 6.61 lH), 5.37 (in, 2H), 5.08 (in, 2H), 4.47 lH), 4.39 211), 4.18 (mn, 11H), 20 1.98 1.45 (mn, 9H), 1.38 3H1), 0.94 0.86 (in, 1811).

Preparation of 2 S. I'S)-2-4benzyloxycarbonylmarnoN..r'-(4-.

carboxanidooxadiazo2vyl)3eiethybu11-4m typntn de Ammonia was bubbled through a solution of the compound of Example 12 (96.8 mng, 0.2 mmol) in ethanol (2 mL) for 5. ini. After stirring an additional min, the solution was concentrated to give the title compound as a white solid (91.2 mng, IH NMR (400 Mlz, CDCI 3

/CD

3 OD) 6 7.29 511), 5.90 111), 5.30 111), 5.04 2H), 4.15 (mn, LH), 1.76 (mn, 2H), 1.59-1.43 (in, 411), 0.92-0.85 (mn, 1211).

Example Preparation of (2S.1 'S)-2-(benzvloxycarbonvl)amino-N-' I 2 -carboethoxthiazolvi)-3'-methvlbutvll-3-phenvlpropanaide a) N-(9-fluorenylmethoxycarbonyl)-L-leucinyl bromomethyl ketone Following the procedure of Example except substituting N-(9fluorenylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucinyl-Lleucine, the title compound was prepared (516 1 H NMR (400 MHz, CDCI3) 7.71 2H), 7.51 2H), 7.34 (dd, 2H), 7.22 (dd, 2H), 5.08 1H), 4.53 IlH), 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-yI)-I -(9-fluorenylmethoxycarbonyl)amino-3methylbutane Following the procedure of Example except substituting N-(9- 9.9 fluorenylmethoxycarbonyl)-L-leucinyl bromomethyl ketone for N- Benzyloxycarbonyl-L-leucinyl-L-leuciny bromomethylketone, the title compound was prepared (4.13 I H NMR (400 MHz, CDC13) 8 7.72 2H), 7.49 2H), 7.32 (dd, 2H), 7.22 (dd, 2H), 7.19 1K), 5.31 1K), 4.88 1H), 4.40 2H), 4.28 2H), 4.08 LH), 1.62-1.41 3H), 1.36 0.88 6H).

c) 1-amino-i -(2-carboethoxythiazol-4-y)-3-methylbutane The compound of Example 15(b) (0.5 1.1 nmol) was stirred in a piperidine/DMF solution for 10 minutes at roam 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)anino-N-( I'-(2-carboethoxythiazol-4-yl)-3methylbutyl]-3-phenylpropanamide Following the procedure of Example 5, except substituting (1S)-I-amino-I- (2-carboethoxythiazol-4-yl)-3-methylbutane for benzylamine, and N-Cbz-Lphenylalanine for (2S,1 'S)-2-(benzyloxycarbonyl)aino-N-[ 1 '-(2-carboxythiazol-4yl)- 3 '-iethylbutyl]-4-iethylpentanamide, the title compound was prepared 162 'H NMR (400 MHz, CDCI3) 8 7.27 5H). 7.11 1H). 7.04 m, 5H). 6.12 IH), 5.24 IH), 5. 10 5.01 2H), 4.37 2H). 4.21 IH), 2.91 2H), 1.62 3H), 1.37 3H), 0.81 6H).

Example 16 Preparation of (2S 1 'S)-2-(benzvloxvcarbonvl-L-eucinyl)azmno-N-f I carboethoxvthiazol4-J)-3 '-methvlbutvllA-4methlDentanamade Following the procedure of Example 5, except substituting 1-amino-I- 2 -carboethoxythiazol4-y)-3-methylbutae for benzylamine, and N-Cbz-L- Ieucinyl-L-leucine for (2S,I 'S)-2-(benzyloxycarbonyI)amino-N-[ carboxythiazol-4-yl)-3'-methybutylj4methylpennmd the title compound was prepared (0.098 IH NMR (400 M}Lz, CDC13) 5 7.39 IH). 7.25 6.87 IH), 6.49 1H), 5.30 IH), 5.16 4.99 2H), 4.36 2H), 4.31 IH), 4.09 1H), 1.74-1.38 9H), 1.32 3H), 0.80 Example 17 Preparation of (2S. I'S)-2-benzvioxycarbonyl)amiao-N-r '-(5-mercapto- 1.2.4oxadiazol-3-vl)-3'-methbutvll-4-methvenaid a) N-benzyloxycarbonyl-L-leucinyl-L-leucine methyl ester N-Cbz-L-leucine (Chemical Dynamics) (1.32 g, 4.97 rmol), L-Ieucine methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 miol), l-hydroxybenzotriazole (0.14 g. 1.0 mmol) and 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiijide hydrochloride (1.05 g, 5.47 mnol) were combined, dissolved in 25 mL of DMIF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 ni) and washed successively with water, 0. 1 N HC1, 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 1:3 ethyl acetate hexanes, to give the title compound as a white solid (1.28 g, IH NMR (400 MIz, CDCI3) 8 7.37-7.32 5H), 6.28 1f), 5.28 (m, 3H), 4.61-4.58 1f), 4.20 lH), 3.74 3H), 1.69-1.54 6H), 0.96-0.92 12H).

b) N-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide To as stirring solution of the compound of Example 17(a) (1.28 g, 3.26 mmol) in 25 mL of methanol was added hydrazine hydrate (1.63 g, 32.6 rnmol, 1.58 mL) and the solution was allowed to stir a t 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, CDC13) 6 8.05 (br s, 7.35-7.32 (mn, 5H), 6.67 (d, lH), 5.50 1H), 5.11 2H), 4.46 (in, 1H), 4.21 (in, 1H), 3.88 (br s, 2H), 1.64- 1.51 (mn, 6H), 0.92-0.88 (mn, 12H).

c) (2S, 1 S)-2-(benzyloxycarbonyl)amino-N- [1'-(5-rnercapto- 1 2 4 -oxaciiazol-3-yl)- 3 -methylbutyl]-4-methylpentanamide To a stirring solution of the compound of Example 17(b) (0.3 g, 0.76 minol) in 1.5 niL of chloroform was added triethylamine 155 g, 1.53 mmol, 0.213 niL) and thiophosgene (0.088 g, 0.76 nmmol, 0.058 mL). 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 (MgSO 4 filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 11I% methanol in dicb.Ioromethane, to give the title compound as a white solid (0.20 g, 6 IHNM(400 Mhz, CDCl3) 67.36(in, 6H), 6.85 1H), 5.37 IH), 5.14 (in, 3H), 4.24 (mn, 1H), 1.65-(m, 6H), 0.95- 0.87 (mn, 12H).

Example 18 Preparation of (2S. 1 'S)-2-(benzvloxycarbonvl)amino-N- F -(-mercaptothiazol.4yi)-3'-methvlburvll..4-methvlpentananide The compound of Example I1(a) 1.0 g, 2.2 mmol) and ammonium 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 whiite solid (0.58 g).

1 H NMR (400 MIHz, CDCI3) 6 7.24 (in, 5H), 7. 10 IlH), 6.33 I H) 6.00 (d, 1H), 5.11 2H), 4.94 (mn, 4.05 (in, IH), 1.49 (in, 6H), 0.78 (mn, 12H).

S. Example 19 Prep~aration of (25 )-2-(benzyloxvcarbonvl ~axino-N-(4-carboethoxythiazoI -2vI )methvl-4-methylpgntanamide a) 1 -(tert-butoxycarbonyl)am-ino-l1-(4-carboethoxythiazoi-2-yl)inethane .:15 Following the procedure of Example except substituting N-terrbutoxycarbonyiglycine for N-rert-butoxycarbonyl-(L)-leucine in step the title compound was prepared (1.9g, 58% overall). IH NMR (400 MHz, CDC13) 6 8.11 1H), 5.31 IH), 4.56 211), 4.43 2H), 1.45 9H), 1.42 3H).

'20 b) 2

S)-

2 -(benzyloxycarbonyl)anino-N(4.caroethoxytazo.2.yl)methyl.4 methylpentanamide Following the procedure of Example, 13, except substituting 1-(tertbutoxycarbonyl)amino.. 1 -(4-.caboethoxythiazo1-2-yl)methane for (15S)- I -(tertbutoxycarbonyl)ainino.. 1 4 -carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz- L-Ieucine for N-Cbz-L-leucinyl-L-leuciwe, the title compound was prepared 120g, MS 434.2.

Example Preparation of (2S. 1 'S)-2-(benzvloxvcarbonl)amino-N- I '-L2benzvloxvcarbonvlthiazol-4-vl)-3'-methlbutvI 1-4-methylentanaride The compound of Example 2 (0.105 0.22 rmol) was dissolved in dichloromethane and treated with l-(3-dinethylaminopropyl)-3-ethylcarbodiimide methiodide (0.062 0.22 miol) 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 IH NMR (400 MHz, CDCl3) 8 7.37 IH), 7.26 lOH), 6.50 lH) ,5.33 2H), 5.11 (q, 2H), 5.09 IH), 4.99 2H), 4.04 IH), 1.49 6H), 0.78 12H).

:.:::,Example 21 ,i Preparation of (2S.1 'S-2-benvloxcarbonl )amino-4-methyl-N-r3'-methl- D henox ycarbonylthi azol -4-l)buill ntananide Following the procedure of Example 20, except substituting phenol for benzyl alcohol, the title compound was prepared (0.075 I H NMR (400 NfHz, CDC13) 8 7.41 1H), 7.26 IOH). 6.49 1Hl) 5.20 IH), 5.04 IH), :i 5.00 2H), 4.08 11), 1.49 6H1), 0.82 (m 12H1).

Ex.Ale 22 iPrearation of (2S. 1'S-2-(benyloxcarbol)amin4--me-f mehy-'-f2- (2-methgroloxcaonylthiazo-yl-ullnanid Following the procedure of Example- 20, except substituting isobutyl alcohol for benzyl alcohol, the title compound wasprepared (0.075 IH NMR (400 MHz, CDC13) 8 7.25 6H), 6.50 1H) S. I I(q, 211), 5.09 IH), 4.99 2H), 4. 11 2H), 3.91 1H),2.02 1H), 1.70- 1.39 6H), 0.82 6H), 0.78 (m, 12H).

Example 23 Preparation of (2R. I'S)-2-(benzvloxycarbonyl)arpanoN[ 4 crotovha 2-il)ethyl l- 4 -methylpentanamide Following the procedure of Example 19, except substituting N-tenrbutoxycarbonyl-L-alanine for N-trn-buzoxycarbonylglycine in step and N-Cbz- D-leucine for N-Cbz-L-leucine in step the title compound was prepared as white solid (0.l135g, MS 448.2.

Example 24 Preparation of (2R. I R)-2-(benZyloxycarbonyl )anuno-N-r I 4 -carboethoxvhiaoj.

Y-I )ethyl l-methylntanamiude 9Following the procedure of Example 19, except substituting N-terrbutoxycarbonyl-D-alanine for N-terr-butoxycarbonylglycine in step and N-Cbz- D-leucine for N-Cbz-L-leucine in step the title compound was prepared as white solid 1 10g, MS 448.2.

Example Prep~aration of (2S. 1 I -(2-aminothiazol-4-vl)-3'-methylbu~iyl2- (benzvloxycarbonl)amino4methylpeftanamide To a stirring solution of the compound of Example I1(a) (0.85 g, 1.87 mmnol) in 4 m.L of ethanol was added thiourea 142 g, 1.87 mmol). The solution was allowed to stir at room temperature for 90 min. The solution was concentrated, the residue was dissolved in ethyl acetate and washed with saturated 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, IH NMR (400 MHz, CDCI3) 8 7.36 (in, 5H), 6.30 (in, 2H), 5.12 (in, 3H),"4.95-4.91 (in, 3H), 4.16 (in, IH), 1.63 (in, 4H), 1.49 (in, 2H), 0.93-0.89 (in, 12H-).

Example 26 Preparation of (1 1 -bernzvloxycarbonvlanmino)-3-methylbuv11thj l.l2.

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 mmnol) in ether (225 ml) is cooled to 0 0 C. 40% sodium hydroxide ii 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 rmol) was dissolved in THF (10 mL), cooled to -40 0 C, and 4-methylmorpholine (0.77 g, 7.6 mrnol, 0.83 mL) was added, followed by dropwise addition of isobutyl chloroforrnate (1.04 g, 7.6 rnmol, 0.98 After 15 nin, the solution was filtered into the previously prepared 0 0

C

~**:.solution of ethereal diazomethane. The resulting solution was allowed to stand at 0 S 'C for 23 h. HBr (30% in acetic acid) (45.2 mnrol, 9 mL) was added and the .S*.15 resulting solution was stirred at 0 *C for 5 rain, then washed sequentially with 0. 1 N HCI, saturated aqueous NaHCO 3 and saturated brine, then dried (MgSO 4 filtered and concentrated to give the tidle compound as a colorless oil (2.43 g, 94%).

b) I bayoyabnlmn-I-2crbehxtizl4y)3mtybtn A solution of the compound of Example 26(a) (1.57 g, 4.58 mmol) and ethyl thiooxamate (0.61 g, 4.58 mmol) in ethanol (10 mL) was heated at reflux for 4 h.

The solution was then cooled concentrated and the residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:4 ethyl acetatelhexanes, to give the title compound as a yellow oil (1.0 g, 'H NMR (400 M&z, CDC1 3 8 7.41 1H), 7.34-7.31 (in, 5H), 5.40 I 5. 10 I1H), 5.05 I1H), 4.98 1H), 4.48 2H), 1.80-1.76 (in, 2H), 1.57-1.53 (mn, IH), 1.44 3H), 0.95 3H), 0.93 3H).

0) 0IS)- I -benzvloxvcarbonvlamino- 1 -(2-hydrazlnocarbonvlthiazol-4-vl methylbutane A solution of the compound of Example 26(b) (0.30 g, 0.8 mmol) and hydrazine hydrate (0.40 g, 8.0 mmol, 0.39 rnL)in ethanol (8 m.L) was allowed to stir at room temperature for 2 h. The solution was then concentrated to yiel4 the title compound as a white foam (0.28 g, 'H NMR (400 MI-z, CDC1 3 5 8.29 IH), 7.37-7.35 (in, 5H), 5.18 1H), 5.09 (dd, 2H), 4.95 lH), 4.07 2H), 1.71 2H), 1.55 (in, IH), 0.96 314), 0.94 3H).

d) (1 I-benzyloxycarbonylamino)-3-methylbutyllthiazol-2-vlcarbonyil-N'- (N-benzyloxycarbonyl-L-leucinyl)hydrazide A solution of the compound of Example 26(c) (100 mg, 0:28 inmrol), N-Cbz- L-leucine (80.5 mng, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.2 mg, 0.30 rnmol) and 1-hydroxybenzotriazole (7.5 mg, 0.06 15 mmol) in DMF (0.6 minol) was allowed to stir at room temperature for 18 h. The 0 solution was diluted with ethyl acetate and washed successively with water, 0. 1 N saturated aqueous NaHCO3 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 110-1 12 *C.

Example 27 Preparation of N-benzyloxycarbonvl-L-leucinyvl-N'-benzyloxvcarbonyl-L-leucinvl- L-leucinylhydrazide a) N-benzyloxycarbonyl-L-leucinyl-L-leucine mhethyl ester Following the procedure of Example 26(d), except L-leucmne methyl ester hydrochloride for (1 1 -benzyloxycarbonylamino- 1 .(2-hydrazinocarbonylthiazol- 4-yl)-3-inethylbutane, the title compound was prepared as a white solid (1 .28 g, 'H NNM (400 Mffz, CDCI3) 5 7.37-7.32 (in, 5H), 6.28 IH), 5.28 (in, 3H), 4.61-4.58 (in, 1H), 4.20 (in, IH), 3.74 3H), 1.69-1.54 (in, 6H), 0.96-0.92 (in, 12H).

b) N-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide Following the procedure of Example 26(c). except substituting Nbenzyloxycarbonyl-L-leucinyl-L-leucine methyl ester for (IS)-1benzyloxycarbonylanino- 1 -(2-carboethoxythiazol-4-y)-3-methylbutane, the title compound was prepared as a white solid (1.28 g, 100%). 'H NMR (400 MHz, CDCI3) 5 8.05 (br s, IH), 7.35-7.32 5H), 6.67 lH), 5.50 1H), 5.11 (s, 2H), 4.46 11), 4.21 11), 3.88 (br s, 21), 1.64-1.51 6H), 0.92-0.88 (m, 12H).

N-benzyloxycarbonyl-L-leucinyl-N t -benzyloxycarbonyl-L-Ieucinyl-Lleucinylhydrazide Following the procedure of Example 26(d), except substituting Nbenzyloxycarbonyl-L-leucinyl-L-leucinyhydrazide for benzyloxycarbonylamino- 1 -(2-hydrazinocarbonylthiazol-4-y)-3-methylbutane, the title compound was prepared as a white solid (0.059 MS 662.1 Example 28 Preparation of (1 -benzyloxcarbonylamino)-3-methylbutyllthiazol4vlcarbonyll-N'-(N-benzyloxycarbonyl-L-leucinyhv drazide a) N-tert-butoxycarbonyl-(L)-leucinanide To a solution of N-tert-butoxycarbonyl-(L)-leucine (7.0g, 28. 1mmol in dry THF (IOOrnL) at -40*C was added isobutylcbloroformate (3.8g. 28.l1nmol) and Nmethylmorphiline 59mmol). 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.Ommol).

'HNMR (400MHz, CDCl) 5 6.38 (br s, 1H), 5.79 (br s, 11), 5.04 (br d, 11), 4.13 1H), 1.71-1.49 3H), 1.39 9H), 0.92 (dd, 6H).

b) N-rert- buroxvcarbonvl-(L )-Ieucinethioamjde To a stirring solution of the compound of Example 26(a) 28.0 mol) in dry TI-F was added Lawesson's reagent (6.8g, 16.9 mnmol) 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, 'HNM1R (400M1-z, CDCI,) 5 8.54 (br s, IN), 7.97 (br s, 1H), 5.28 (br d, 1H), 4.52 1H), 1.72-1.58 (mn, 1.40 9H-), 0.92 (in, 6H).

c) (I 1 -(tert-butox ycarbonyl) amino-. I -(4-.carboethoxythiazo[-2-y1>-3 inethylbutane *The compound of Example 26(b) (5.4g, 21.7 mrmol) was stirred in dry acetone (lO0m.L) under argon at -10 0 C. Ethyibromopyruvate 4 .7g, 23.9nunol) :0 :was added and stirred for I h at -10*C. The solution was poured into a well stirred 15 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 4 filtered and concentrated to an oil. The oily residue was treated with TFAA (5.0g. 23.9inmol) and pyridine (3.8g, 47.8mmol) in dichloromethane for Ilh 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 1LON KHSO 4 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. 6 'HNMR (400MIHz,

CDCI

3 6 7.98 1 5.04 (br d, I 4.95 (in, I 4.3 1 2H), 1.8 8 (in. IH), 1.63 (in, 2H), 1.4.0 9H), 1.32 3H), 0.85 (dd, 6H).

d) (1 I -(Benzyloxycarbonyl)amino- l-( 4 -carboethoxythiazo-2yl).3methylbutane The compound of Example 26(c) (0.250g, 0.73 1immol) was dissolIved in TFA (2m.L) and stirred at room temperature for 15 minutes when diluted with methanol and concentrated in vacuo. The residue was dissolved in methvlene chloride and treated with u-iethylaznine 7 39g, 7.3 1Immol) followed by benzyl chloroformate (l.2g, 7.3 imiol). The solution stirred at room temperature for 2h when partition between ethyl acetate/water. 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 (400M~z, CDC1 3 568.01 IN), 7.32 (in, 5.51 (br d, IN), 5.14 (in, 1H), 5. 10 2H), 4.37 2H), 1.93 (in, 1H), 1.8 1-1.67 (mn, 2H), 1.39 3H), 0.95 (mn, 6H).

e) (1 1-benzyloxycarbonylamino)-3-methylbutyllthiazol-4-ylcarbonyl]-N'- ;..*(N-benzyloxycarbonyl-L-Ieucinyl)hydrazide Foloin th.rcdr fEape2()I(decp usiuig( (Benzyloxycarbonyl)amino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane for (I S)- -benzyloxycarbonylamino- 1 -(2-carboethoxythiazol-4-yl)-3-methylbutane in step h title compound was prepared. MS (MW: 610.0 Preparation of 2.2'-(N.N'-bis-benzyloxvcarbonyl-L-leucinvl'carbohydrazide To a stirring solution of N-Cbz-L-leucine (Chemical Dynamics Corp.) (2.94 g, 11. 1 minol) in 22 mL of DMIF was added carbohydrazide (0.5 g, 5.6 inmol), i-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.13 11. 1 rnmoi) and 1-hydroxybenzotriazole (0.3 g, 2.2 rnmol). After stirring at room temperature for 22 h, the solution was poured into 500 rnL of water. The precipitate was collected by vacuum filtration and washed with water (4 X 150 rnL) and dichloromethane (4 X 150 niL, then dried under vacuum to provide the title compound as a white solid (1.49 g, MS(ESI): 607.1 Example Preparation of 2.2'-(N.N'-bis-cvclohexylacetvl )carbohydrazide Following the procedure of Example 29, except substituting cyclohexylacetic acid for N-Cbz-L-leucine, the, title compound was prepared (0.4 g, MS(ESI): 339.3 Example 31 Preparation of 2.'(-'bs4mtylnaolcroy~d 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 Exampgle 2 Preparation of 2.'(.'--s2cconyaeykroymd 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 Preparation of yoyabnvLyiy~atoy--zd 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, *:aso91%). MS(ESI): 473.1 Example 34' Preparation of 2.'(.'bsaey--euiy~a-bhdrzd Following the procedure of Example 29, except substituting N-acetyl-Lleucine for N-Cbz-L-leucine, the title compound was prepared as a white solid 153 g, MS(ESI): 401.3 Example Preparation of benZyl oxycarbony I- L- al any fcarbohvdrazide Following the procedure of Example 29, except substituting N-Cbz-Lalanine for N-Cbz-L-leucjne, the tidle compound was prepared as a white solid 762 g, 9 MS(ESI): 50 1. 1 Exmpe 3 Preparation of 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-[N'-(4methylpgrntanoyD~carbohydrazide 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 miL) 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,), filtered and concentrated to give the title compound as a colorless oil (7.67 g, 100%). 'HNMR (400M&z, CDCI 3 6 7.39 ese.

(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 mnmol) in methanol (40 mL) was added hydrazine monohydrate (13.5 g, 270 rnmol). The solution was stirred at room temperature for 24 hours when partitioned between water and ethyl acetate. The organic layer was collected, dried (MgSOj), filtered and concentrated to give the title compound as an off-white solid (7.67 g, 100%).

'HNMR (400M&z, CDC1,) 8 8.14 1H), 7.38 (mn, 5H), 5.64 1H), 5.09 (dd, 2H), 4.20 (in, 1H), 3.81 (s br, 2H), 1.69 1.51 (mn, 3H), 0.92 (dd, 6H).

c) 1 -benzyloxycarbonylamino-3-methyl-l1-(1 .3,4-oxadiazol-2-onyl)butane A solution of the compound of Example 36(b) (1.0 g, 3.58 inmol) in methylene chloride (12ml-) was added dropwise to a solution of 4nitrophenylchloroformate (0.361 g, 1.79 mmol) in methylene chloride nL) 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, then collected, dried 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, CDCI 3 5 9.18 1H), 7.38 5H), 5.13 3H), 4.79 1H), 1.71 3H), 0.98 (dd, 6H).

d) 4-methylpentanoyl 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, CDC1,) 5 7.48 (s br.

1H), 3.62 (s br, 2H), 2.13 2H), 1.51 3H), 0.85 6H).

15 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 20 as a white solid (0.053 g, MS 436.2.

oo° o al o• Example 37 Preparation of bis-(Cbz-leuc invl) 1 .3 -diamino-p2ropan -2 -one Cbz-leucine (500 mg, 1.88 nunol), EDCI (558 mg, 1.88 minol) was dissolved in DMF (4.0 m.1) with l,3-diamino-propan-2-ol (85 mg, 0.94 rnmol) and Hunig's base ml, 1.88 mniol) and was stirred at RT overnight. The reaction was diuted with EtOAc (20 ml) and was extracted with water (2 x 20 ml). The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo. 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 nml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chrornatographed (silica gel, 2-5% MeOHI imethylene chloride) to give the title compound as a white solid (410 mg, MS(ES) M+H*=583, M.Na*--605.

Exr* 38 Preparation of bis- 1.3-(4-phe noxy-benzoyl)-diaznino-propan-2-one Following the procedure of Example 37, except substituting "4-phenoxybenzoic acid" for "Cbz-leucine", the title compound was prepared: MS(ES) o M+W=48 1, M+Na*=503.

Prearation of 1 -(Cbz-leucinyl)-axnino-3-(acetyl-leucinyfl-amino-propan- 2 -one Following the procedure of Example 37, except substituting "a mixture of N- Ac-leucine and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+W*=491, M+Na*=5 13.

Example Prep ration of 1-(Cbz-Ieucinvli)-anmino-3-(Cbz.glutamvz-tbuty,ester)-amjnoprppan-2-one Following the procedure of Example 37, except substituting "a mixture of Cbz-glutaxnic 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 I (b-ecnl-mn--C--ltml-mn~rR--n 1 -(Cbz-leucinyl)-amino-3-( Cbz-glutamylz..butyl ester)-amino-propa..2-one mg, 0.OO7mrnol) 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 vacua to provide the title compound: *MS(ES) M+Wr=599.

Examp-le42 Preparation of bis- 1. 3-(Cbz-leucinvl)-dia-mino-(S )-butanone-2-one a) Cbz-leu-ala-bromo methyl ketone Isobutyl chloroformate (1.46 ml, 11.3 mmol) was added dropwise to a solution of Cz-leu-laOH (4.0 g, 11.3 mmol) and N-methyl morpholine (1.24 ml, 11. 3 mmrol) in THF (40 ml) at -40 degrees C. The reaction was stirred -15 min, then was filtered, and was washed with ether. Diazomethane (40.1 mmol from 5.9 g of 1 -methyl- 3 -itr-nitroso-guaidine and 18 m-l of 40% KOH in 150 ml of ether) in ether (200 ml) was added and the reaction was placed in a refrigerator overnight.

30% HBr/ 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 nil), then brine (100 nil). 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+If=-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 DMF (7 mil), then sodium azide (122 mg, 1.9 mrnol) and potassium fluoride (137 mg, 2.36 mmol) 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, rnethylene chloride, silica gel) to provide the title compound as a white solid (330 mg, MS(ES) M+Na*=398.

C) Cbz-leu-2-amino-4-azido-propal-3-ol Cbz-leu-leu-azido methyl ketone (330 mg, 0.9 mmol) was dissolved in EtOH (5 nil) and sodium borohydride (100 mg, 2.65 rnmol) was added at RT and the reaction was stirred 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-propal-3-oI Cbz-leu-2-amino-4-azido-propan-3-o1 (300 mg, 0.8 mxnol)was dissolved in, MeOH (4 ml) and triethyl amine (0.33 ml. 2.4 mmol), propan-1,3-dithiol (0.35 ml, 3.82 mmol) was added and the reaction was stirred 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+W=352.

e) bis- I ,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-ol Cbz-leu-2-amino-4-ainino-propan-3-ol (140 mg, 0.4 mmol) and Cbz-leucine (106 mg, 0.4 mmol) were dissolved in DMF (2 mlJ) and N-methyl morpholine (0.08 m. 0.8 rnmol) and 1{BTU (151 mg, 0.4 mmnol) and was stirred overnigyht. The reaction was partitioned between EtOAc and water, the combined orvanics were dried with magnesium sulfate, filtered, concentrated to give the title compound.

MS(ES) M+W=599, M+Na+=621.

f) bis- 1, 3 -(Cbz-leuciyl)-daino(S)bu rone-2 -ne Bis-1I, 3 -(Cbz-leucinyl)-diamino-(S).butanone.2ol (240 mg, 0.4 mrnol) 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 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-H*=595.

Example 43 Preparation of 1 -(Cbz-leucinvl )-amino- 3 -Cbz-1henylaanyl..a~~nno-roian.2.one 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=6 17, M+Na*-639.

Examle 44 OV :Preparation of I (b-ecnl-mn--Cznoiuiy)aiopoa--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+Fr=583, M+Na*=605.

Example Preparation of I (Cbz- le ucinl I)-amnino- 3-(Cbz -norval i nv 1)-amin o-pRopAj..2 -one Following the procedure of Example 37, except substituting "a ixture of Cbz-norvaline and Cbz-leucine' for "Cbz-leucine", the title compound was prepared: MS (ES) M+W=5 69, M+Na'=59 1.

Example 46 Preparation of bis- 1.3-(Cbz-leucinyfl-diamino-5-methyl4JS)-hexan..2-one a) bis- I .3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one Following the procedure of Example except substituting "Cbz-leu- Ieu-OH" for "Cbz-leu-ala-OH" the title compound was prepared: MS(ES) -+W639.

Example 47 15 Preparation of 1 -(acetl-leucinl)-amino-3-(4-phenoxy-benzoyl-aiino-roai.2 Following the procedure of Example 37, except substituting "a mixture of N- Ac-leucine and 4-phenoxy-benzoic acid for 'Cbz-leucine", the title compound was prepared: MS(ES) M+W-440.

Preparation of I -(Cbz-homo-leucinyfl-amino-(Cbz-leucinyfl-3-amino-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+W=597, M+Na*=619.

Exgmile 49 Preparation of bis- I 3 4 3 -chloro-2-cyanop1henoxv)-phenvl sulfonarmidopro 4 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride (1.3 g, 4 rnrol, Maybridge) was added to a solution of l,3-diamno-propan-2-ol 18 g, 2 nimol) in DMF (10 mlI)/ N-methyl morpholine (0.44 ml, 4 minol) and was stirred 3h at RT.

The reaction was partitioned between water and EtOAc and the combined organijcs were dried with magnesium sulfate, then concentrated in vacuo. The crude bis- 1,3- 4 3 -chloro-2-cyano-phenoxy)-phenyl sulfonanido)-propan-2.ol (0.28 g, 0.4 mmol) was then dissolved in acetone (1 .0 nml) and Jones reagent (0.44 ml, 1.5 M) was added dropwise, and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 nil), 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% MeOHI methylene chloride) to give the title compound as a white solid (90 mg, MS(ES) M+ H=67 1, M+Na'=693.

Example Prep~arationof bis- 1.

3 -(4-phenoxy-phenyl sulfonanido-propn -2-one Following the procedure of Example 49, except substituting 4-phenoxyphenyl sulfonyl chloride for 4- 3 -Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M-W*=55 1.

Example 51 Preparation of 1 -(Cbz-leucinyl )-arino-3-(4-(13-chloro-2-cyano-pheloX)-phelyl sulfonamido)-p2rop-al- _-onle Cbz-leucine (660 mng, 2.5 mrnol), EDCI (480 mg, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DWvf (10 nil) with l,3-diamino-propan-2-ol (225 mg, 2.5 mmol) and was stirred at RT overnight. N-methyl morpholine (0.41 ml, 3.75 nunol) was added followed by 4-(3-Chloro-2-cyalo-pheloxy)-phelyl sulfonyl chloride (820 mg, 2.5 mmol, Maybridge) was, added and the reaction was stirred 3 h at RT. The reaction was partitioned between water and EtOAc and the combined 10 organics were dried with magnesium sulfate, then concentrated in vacuo. The crude 1 -(b-ecnl-ndo3(-3clr--yn-hnx)pey sulfonamido)propan-2-ol was then dissolved in acetone (5.0 ml) and Jones reagent (3.0 Dal, 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 mil) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/ methylene chloride), then the product was triturated from methylene chloride to give the title compound as a white solid (26 mg, MS(ES) M+ IE-627.

Preparation of -(Cbz-leucinvi)- aning- 3-tosyl-amfilo)-propan- 2 ofle Following the procedure of Example 5 1, except substituting tosyl chloride for 4-(3-Chloro-2-cyano-phefloxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M-W-488.P Example 53 Preparation of I -(Cbz-ieucinl )-amino- 3 -((4phenox -phoynvL-sulfonarmdo) p2ropan-2--one Following the procedure of Example 51, except substituting 4-phenoxvphenyl -sulfonyl chloride for 4 3 -Chloro-2..CYano-phenoxy)yphenyl sulfonyl chloride, the title compound was prepared: MS(ES) M+H-=568, M+Na'=590.

Example 54 Prep~aration of l- -ecnl-mn--2d nouaslo d) a-2 one Following the procedure of Example 5 1, except 2 -dibenzofuransulfonyl chloride for 4 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride, the title copon wa rprdaSE) +=6,MN'-8 15 *xmj poeueo Example 55 1,ecpt..bnzfrnslo chloride for 4-3Coo2cao-hnx)pey sulfonyl chloride and Cbzhomo-leucine for Cbz-Ieucine, the title compound was prepared:

MS(ES)

M+Na'=602..

Example 56 Preparation of I- -Cbz-ieucinyl )-arnino-3-(2-dibenzofuransuI onarnjdo -bu~ian-2- Cbz-leu-2-aminoA4-anino..propan-3yoI (150 mng, 0.42 mmol, as described in Example and 2-dibcnzofuransulfonyl chloride were dissolved in DMF ni) and N-methyl morphonline (0.09 ml, 0.84 mmol) and were 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+W=582, M+Na*=604.

l-(Cbz-leuciny)aino3(2ibeofuanulfonaido)(S)-butan- 2 ol (240 :mg, 0.4 nimol) was dissolved in acetone (2 nil). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction was stirrd at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 nil), then the reaction was diuted a 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% MeOHI methylene chloride) to give the title compound as a white solid (70 mg, MS(ES) M-W*=578.

Example 57 Preparation of (S)-Phenyimethyl [1 -Ifr3-IBenzyloxvcarbonyl-leucinl-ainEL2 oxop~ropyll- I-(benzvl)aminolcarbonyll-3-methvlbutLy-lcarbamate 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 mnmol) in MeOfi (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 nfil), then brine (50 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo, and chrornatographed (silica gel, 30 EtOAc! hexanes) to produce a white solid (1.37 g, MS(ES) M+H+=1 18.4. 2 b) 2-hydroxy-3-azido-propan-tosylate* Toy chord (2.3 g, 12 mnmol) was added to a solution of 2-hydroxy-3- azido-propanol 17 g, 10 mmol) and triethyl amine (3.6 g, 36 mmol) in methylene chloride (50 ml) and was stirred at RT for 4h. The reaction was diluted with water mlg), 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 chroniatographed (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-tosy late (1.2 g, 4.4 mnmol) was added to a slurry of EIlman dihydropyran polymer (cf. Scheme 1) (150 mg, 0.3 nunol) in CICH2CH2Cl (25 ml), then pyridinium p-toluenesulfonate (0.84 g, 4.4 rnmol) 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- Magic Angle Spinning I1H NMR: d 8.0, 7.4, 5.0,3.4.

d) 2-(Memrfield POlYmer-6-(oxvmethyvIene-tetrahvdropyran-aceta)-3-aido.

propan-N-benzyl-am-ine Benzyl amine (0.32 g, 3 rnrnol) was added to a slurry of 2-(Memrfield polymer-6-(oxyrnethylene-tetrahydropyran-acetal)-3 -azido-propan-tosyl ate (500 mg, 1 mmol) in N-methyl pyrolidinone (25 nil) and was and was agitated at 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); JR 2105cm-I1; Magic Angle Spinning I H NMR: d 7.1, 3.8.

e) 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-azidopropan-N-benzyl-(Cbz-leucinyl)-amine e~e*Cbz-leucine (0.82 g, 3.0 mniol) was added to a slurry of 2- (Merrifield :(120 mg, 0.22 mmol) in DMIF (10 ml), diisopropyl ethyl amine (1.2 ml, 6 minol) and HATU (Perseprtive Biosysterns, 2.2 g, 6 mmol) 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 nml); IR 2 105,1735, 1630 cm-i1;. Magic Angle Spinning IH NMR: d 7.2, 4.7, 4. 1.

2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetaJ)-3-aminopropan-N-benzyl-(Cbz-leucinyl)-aniine Propanedithiol (0.5 ml, xx mnmol) was added to a slurry of 2-(Merrifield poye--oyehln-erhcrprnaea)3aioppnNbny-Cz leucinyl)-amine (150 mg, 0.27 nol) in MeOH (5 ml) and triethylamine (0.5 ml) and was gently rocked overnight. The resin was filtered, washed with MeOH (2 x ml), then with DMF (1 x 10 ml), then with methylene chloride (5 x 20 ml), and was dried in a vacuum oven overnight; IR 1735, 1640, cm- 1

I-.

')-(Merrifield polymer- 6 -(oxymethviene-teLrahvdropyranaceta)3(Cbzleucinyl)-amino-propanNbenzvyI(CbzileucinvI )-amine Cbz-leucjne (0.82 g, 3.Ommol) was added to a slurry 2-(Merrifield polymer- 6-oyehln-erhdoya-ctl--mn-rpnNbny-Czluiy) amine (150 mg, 0.27 mnmol) in N-methyl pyrollidinone (10 mil), diisopropyl ethyl amnine (1.2 ml, 6 rnmol) and HBTU (2.2 g, 6 mmol) 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 MeOI- (2 x 10 ml), then methylene chloride (5 x 20 ml); Magic Angle Spinning I H NMR: d 7.6, 7.4, 5.1, 5.0,3.4, 0.8.

I -N-benzyl- I -Czluiy aio3Czlecnla0o-rpn2o :2-(Merritield polymer- 6 -(oxymethylenetetrahydropyranetal)3.(bz lecnl-mn-rpnNbezl(b-ecnl-mn (150 mg, 0.27 mxnol) was shaken as a slurry with 85:5: 10 TFA/ water/ methylene chloride (5 ml) for 4h at RT.

The solution was filtereed and the filtrate was concentrated in vacuo, then chromatographed. (silica gel, 5% MeOH/ methlene chloride) to produce a yellow solid (65 mg, MS(ES) M+H+=675. 1.

i) I -N-benzyl- I Czluiy-mn--b-ecnlaiopoa--n 1 -N-benazyl- Il-Cbz-leucinyl-amino-3-Cbz-leucinyl amino-propan-2-oI mg, 0.96 mrnol) was dissolved in acetone (5 ml) and Jones reagent (2 ml,excess) was added dropwise at room temperature and the reaction was stfired overnight. The excess Jones reagent was then quenched with isopropanol (5 all) and the reaction was diluted with water (5 ml) and was extracted with EtOAc (2 x 20 ml). The combined organic layers were extracted with water (2 x 15 ml), then brine (10 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce a yellow solid, which was chromatographed (silica gel, 5O%EtOAcfHexanes to produce a white solid (16.8mg, MS(ES) 673. 1 Example 58 Preparation of (S )-Phenylmethvl f 1404r-I(2-dibenzofuranvlsulfonvl)anino.2 oxopropl ]l-3-(benzvflarmnolcarbony!1-3-methylbutvlcarbamate a) N-(2-hydroxy-3-N-benzylamino-propyl)phthalimide N-(2,3-Epoxypropyl)phthalimide (Aldrich, 2.03 g, 10 mnmo1) was reluxed with benzyl amine (1.07 g, 10 nimol) 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.

N-(2-hydroxy-3-(N-benzyl-2-dibenzofuransulfonamide)-propyl)phthainide N-(2-hydroxy-3-N-benzylamino-propyl)phthalimide (0.31 g, 1 ninol) 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-dibenzofuransulfonaniide)-propyl-3-arune N-(2-hydroxy-3-(N-benzyl-2-dibenzofuransulfonamide)-propyl)phthaliniide (0.37 g, 0.69 mmol) was refluxed with hydrazine hydrate (0.34 g, 6.85 mmfol) 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+H* 411I.

d) Cbz-leucinyl-(2-hydroxy-(N-benzyl-2-dibenzofuransulfonanide))-propyl-3an-Line 2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide)-propyl-3-amine (0.2 g.

mniol) was stirred with Cbz-leucine 13 g, 0.5 minol) in N-methyl morpholine (0.6 rnl) and DMF (2 mnl). then HBTUT 19 0.5 mmcol) was added and te reaction was stirred overnight at RT. The reaction was diluted with water (10 rid), 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 ma) 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-e-W 658, MS(ES) M+Na'= 680.

e) (S)-Phenylmethyl [1 2 -dibenzoftu-aflysulfoflyl)aminol..2.oxopropyl- 3 (benzyl)aminojcarbonyl]-3 -me thybuy] Icarbamate Cbzleucinyl-(2hydroxy(NN-enzyl2dibeofuransunrLfonan))popl- 3 amine 16 g, 0.244 mmol) was dissolved in acetone (2 nil). 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 n-d) and the reaction was diluted *with water (10 nil) and was extracted with EtOAc (2 x 20 mal). 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 14 g, MS(ES) M-Wr=654, MS(ES) M+CV*690,

MS(ES)

M+HCO

2 700.

Example 59 Preparation of (S-Phenylmethyl 1 3 -[(2-dibenzofuranyisulfonyl~aino.2.

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 1 T3-U(2-dibenzofuranylsulfonvl )aminol-2--oxopropvi *-344pyridinylmethyl) benzamide Following the procedure of Example except substituting "benzoic acid" for "Cbz-leucine", the title compound was prepared; MS(ES) M-W'=51 1, MS(ES) M+CI-=547.

Example 61 Preparation of (S)-Phenvlmethyl r 1-rrr3-r(2-dibenzofuranylsulfonyl)amno..2 oxopropvyll-l 4 -pvridinylmethyl)ainoarbonyl-3-methylbutyhlcarbamate *:Following the procedure of Example except substituting "4pyridyl methyl amine" for benzylarnine" and "Cbz-leucine and HBTU" for "2dibenzofuransulfonyl chloride and "2-dibenzofuransulfonyl chloride for "Cbz- :leucine and I{BTU", the title compound was prepared; MS(ES) M+W--657.

Exml 62 Preparation of 2-rN-(N-benzyloxycarbonl-L-leucinyll-2'-FN'-(4phenoxyphenylsulfonfllcarbohydrazide a) N-benzyloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester hydrochloride (2.0 g, I 1.Ommol) in 1,4-dioxane (20 m.L) was added Na 2

CO

3 (12.1 ml, 2M in water) followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture was stirred at room temperature for 4h then partitioned b~iween ethyl acetate and water. The organic layer was washed with brine, dried (MgSQ 4 filtered and concentrated to yield the tidle compound as a colorless oil (3.1 g, 100%). 1 H NMR (400 M&z,

CDCI

3 8 7.34 (mn, 5H), 5.27 IH), 5.12 211), 4.41 2H), 3.75 3H), 1.65 (in, 3H), 0.96 (mn, 6H).

b) N -benzyloxycarbon vI- L- leucIn ylhydrazide To a stirring solution of the compound of Example 62(a) 1 g, 11.0 mmol in 15 rnL of methanol was added hydrazide hydrate (5.9g 118 mmol). The solution was stirred at room temperature for 16h 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 1 3 4 -oxadiazo I- 2-on yl)butane To a stirring solution of the compound of Example 62(b) (3.0 g, 10.8 rnimol) in toluene (50 mL) 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- rN-(N-beyloxycarbonyl-L-leucinyl)]carbohydraide To a stirring solution of the compound of Example 62(c) 147 g,0.482 numol) in 2 inL of methanol was added hydrazine hydrate (0.24 1 g, 4.82 minol). The solution was stirred at room temperature for 24h then concentrated and purified by column chromatography (silica gel, methanolldichloromethane) to yield the title compound as a white foam (0.097 g, MS(ESI): 338.2 too* e) 2 -[N-(N-benzyloxycarbonyl-L-leucinyl1p2..[N'-(4- ~'.phenoxyphenylsulfonyl)]cabohydrazide a stirring solution of the compound of Example 62(d) (0.097 g, 0.288 mmol) in 2 m.L of DMF was added pyridine (0.046 g, 0.576 mmol) followed by 4phenoxyphenylsulfonylchloride 155 g, 0.576 mmnol). 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 benzyloxycarbonyl-L-alanvl )1-2'-[N-(N-benzvloxvcarbonyl- L-leucinyl)lcarbohydrazide To a stirring solution of the compound of Example 62(d) 100 g, 0.297 mrnol) in 2 mL of DMF was added N-benzyloxycarbonyl-L-alanine (0.070 g, 0.3 12 mmol), 1 -hydroxybenzorriazole (0.008 g, 0.059 rnrol), and 1 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.312 m.mol).

After stirring at room temperature for 16 h, :the solution was poured into 150O ml, of water. The precipitate was filtered and washed with water (150 mL) and dried **10 under high vacuum to yield the title compound as a white solid (0.062 g, 39%).

MS(ESI): 543.1 Preparation of 2- rN-CN-benzvloxycarbonyl-L-leucinvfll-2'-FN'-(4phenylbe nzoylhlcarbohydrazide Following the procedure of Example 63, except substituting 4-phenylbenzoic acid for N-benzyioxycarbonyl-L-alanine, the title compound was prepared as a white solid 121 g, MS(ESD): 518.1 ExmIle 6 Preparation of 2-rN-(N-benzyloxycarbonvl-L-leucinyl)1-2'-rN'-(4methoxybenzoyfllcarbohydrazide Following the procedure of Example 63, except substituting 4methoxybenzoic acid for N-benzyloxycarbonyl-L-alanine the tidle compound was prepared as a white solid (0.057 g, MS(ESI): 472.1 Example 66 Preparation of 2-IN-(N-benzvloxycarbonvl-L-leucinyl)1-2'-[N'-(4phenoxybenzovl carbohydrazide 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-benzyloxycarbonyl-Lleucinyl)carbohydrazide To the compound of Example 62(d) 100 g, 0.297 mmol) was added acetic anhydride (0.303 g, 2.97 mmol). The solution was stirred at room temperature for 16h 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- rN-(N-acetyl-L-leucinyl)1-2'-rN'-(N-benzvloxycarbonyl-Lal any 1) carbohydrazide a) 2- [N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide Following the procedure of Example 62(a)-62(d), except substituting Lalanline ethyl ester hydrochloride for L-leucine methyl ester hydrochloride in step the tidle compound was prepared as a pale yellow foam (1.1I g, 3.8 mmnol).

MS(ESI): 296.2 b) 2-[N-(N-acetyl-L-leucinyl)]-2'-[N'-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide To a stirring solution of the compound of Example 63(d) 150g, O.SO8rnmol) in DMF (2mL) was added N-acetyl-L-leucine (0.092g, O.534mmo1), 1hydroxvbenzotriazole (0.0 14g, 0. 102mmrol), and l-(3-dimethylarninopropyl)-3ethvlcarbodiimnide hydrochloride 102g, 0.5 34mmol). 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, methanoildichloromethane) to yield the title compound as a white solid (0.028 g, MS(ESI): 451.1 Example 69 Preparation of 2- rN-(N-acetyl-L-alanvl )1-2'-fN'-(N-benZyloxycarbonl-Lleucinyihlcarbohydrazide Following the procedure of Example 68(b), except substituting N-acetyl-L- ~.:alanine for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-L- :9:::leucinyl)jcarbohydrazide for 2 -[N-(N-benzyloxycarbonyl-L-alanyl)]carlohydrazde, the title compou ,nd was prepared as a white solid (0.050 g, MS(ESI): 473.1 Example Preparation of 2-rN-(N-benzvloxycarbonyl-L-leucinyl) i-2'-rN'-r4-(N.Ndimethylarainomethl)henzoyl)l]carbohydrazide a) methyl 4-(NN-dimetbylam-inomethyl)bcnzoate Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 mmxol) was added to a ~:.saturated solution of dimethylamine 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 NMR (250 MHz, CDCl 3 8 8.00 2H), 7.39 2H), 3.91 3H), 3.47 2M, 2.25 6H).

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

THFJH

2 0 1) and LiOH*H 2 0O (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 concentrated. redissolved in 25rnL of water and reconcentrated to yield a white solid (1.6 g, 100%). IH NMR (400 I-iz. CD 3 OD) 5 7.94 2H). 7.36 2H). 3.64(s.

2H), 2.35 6H).

c) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)J-2'-[N'-[4-(N,Ndimethylaminomethyl)benzoyl)Jcarbohydrazide Following the procedure of Example 68(b), except substituting 4-(N,Ndimethylaminomethyl)beazoic acid lithium salt for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a pale yellow solid (0.050g, MS(ESI): 499.1 Example 71 :Preparation of 2-rN-(N-benzyloxycarbonyl-L-eucinvl)1-2'-rN'-f4-hvdroxy-r3-(4morpholinomethyl)lbenzoylkcarbohydrazide 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-L- :::*alanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.065'g" MS(ESI): 557.0 116 Example 72 Preparation of 2-fN-(N-benzvloxvcarbonvl-L-leucinyl)1-2-'-N4-(N.Ndimethvlaminomethyl)benzvloxvycarbonvl-L-leucinvlicarbohydrazide 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 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, 1H NMR (250 MHz, CDC1 3 5 4.04 (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 OC, 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, 1H NMR (250 MHz, CDC1 3 8 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 methanol in methylene chloride, to provide the title compound as a pale yellow oil (1.71 a, 1 H NMR (400 MHz.

CDCJ

3 67.31 4H), 5.13 IH), 5. 10 2H), 4.41 IH), 3.74 3H), 3.43 2H), 2.24 6H), 1.70-1.62 2H), 1.52 IH), 0.96 3H), 0.94 3H).

d) N-[4-(N.N-dimethylaminomethyl)benzyloxycarbonyl]-L-leucine lithium salt Following the procedure of Example 70(b), except substituting dimethylaminomethyl)benzyloxycarbonyl]-L-leucine methyl ester for methyl 4- (N,N-dimethylaminomethyl)benzoate, the title compound was prepared as a white solid (1.57 g, IH NMR (400 MHz, CD 3 OD) 67.35 2H), 7.30 2H), 5.06 (dd, 2H), 4.10 (dd, 1H), 3.48 2H), 2.23 6H), 1.69-1.51 3H), 0.94 (d, 3H), 0.93 3H).

to e) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(NNdimethylaminomethyl)benzyloxy]carbonyl--leucinyl]carbohydrazide Following the procedure of Example 68(b), except substituting dimethylaminomethyl)benzyloxycarbonyl--leucine lithium salt for N-acetyl-Lleucine and 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide for benzyloxycarbonyl-L-alanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.069 g. MS(ESI): 642.1 9*.

Example 73 Preparation of 2-(N-benzovl)-2'-[N'-(N-benzyloxycarbonLleucinvl)lcarbohydrazide Following the procedure of Example 62(e) except substituting benzoyl chloride for 4-phenoxyphenylsulfonylchloride, the title compound was prepared as a white solid (61mg, MS(ESI): 442.1 Example 74 Preparation of 2-[N-(N-benzvloxycarbonyl-L-leucinvl)1-2'- rnorpholinomethvi )benzovi llcarbohydrazide a) methyl 3-(4-morpholinornethyl)benzoate A solution of morpholine (0.836 g, 9.6 mmol) and methyl 3- (bromomethyl)benzoate in THF (5 mL) and DMF (5 mL) was stirred at 50 0 C for 3h. The solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous NaHCO 3 and brine then dried (MgSO 4 filtered and concentrated to yield a colorless oil (0.872 g, 3.72 mmol). I H NMR (400 M4Hz, CDC1 3 8 7.99 IlH), 7.91 I1H), 7.55 I-H), 7.47 1H), 3.94 311), 3.72 (in, 4H). 3.53 2H), 2.46 (in, 4H).

S.b) 3-(4-morpholinomethyl)benzoic acid To a solution of the compound of Example 74(a) (0.872 g, 3.72 mmol) in THF (3 mL) and water (3 rnL) was added lithium hydroxide inonohydrate 171 g, Be s 4.08 mniol). After stirring at room temperature for 3h, the solution was concentrated. The residue was redissolved in water (5 rnL) and 3N HCl was added and the solution was lyophilized to yield a yellow solid (0.822 g, 3.72 mmol).

MS(ESI): 222.0 c) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)I-2'-[N'-[3-(4morpholinoinethyl)benzoyl)Icarbohydrazide Following the procedure of Example 68(b), except substituting 3-(4inorpholinomethyl)benzoic acid for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbahydrazide 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 2-[N-(3-benzyloxvbenzol)1-2'-rN'-(N-benzyloxclarb~onllLleucinyl )lcarbohydrazide a) methyl 3-benzyloxybenzoate To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DM mL) was added methyl 3-hydroxybenzoate (1 .0 g, 6.58 mmol). After stirring for 15 min at room temperature, beazyl 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 niL), 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 M~fz,

CDCI

3 587.67 (mn, 2H), 7.48-7.34 (in. 6H), 7.19 (in, lH), 5.12 3.95 3H).

b) 3-benzyloxybenzoic acid To a solution of the compound of Example 75(a) (0.400 g, 1.65 mmol) in THE (2 niL) and water (2 m.L) was added lithium hydroxide monohydrate (0.076 g, 1.82 mmol). 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 mmnol). I H NMR (400 MGz, CD 3 OD) 8 7.58 (in, 2H), 7.36-7.24 (mn. 6H), 7. 10 (in, I1H), 5.04 2H).

c) 2 -[N-(3-benzyloxybenzoyl)].2..[N'-(N-benzyloxycarbonyl-L.

leucinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting 3benzyloxybenzoic acid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-Lleuc inyl)]caibohydrazide for 2 -[-(N-benzyloxycarbonylLalanyl)]crohydrazde, the title compound was prepared as a white solid (0.062 g, MS(ESI): 548.1 Example 76 Preparation of 2 -rN-(,N-benzyloxvcarbonyl-L-leucinvl)-2'-fN-[4-[34(N-Nd i methyl amino)- I -propy loxy I benzol I I c arbo hydrazide a) methyl 4-[3-(N,N-dimethylamino)- 1 -propyloxylbenzoate To a solution of methyl 4-hydroxybenzoate (1.0 g, 6.58 mmnol), 3dimethylamino- I-propanol (1.01 g, 9.87 rnol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0 0 C in TBfF (20 rnL) was added dropwise dilsopropyl azodicarboxylate (1.99 g, 9.87 minol). After stirring for 16 h at room temperature the solution was concentrated and the residue purified by column chromatography (silica gel, methanot/dichioromethane) to yield the tide compound as an oily solid (1.25 ga, 5.2 mmol). MS(ESI): 238.1 4- [3-(N,N-dimethylamino)-l1-propyloxylbeazoic acid a: Following the procedure of Example 74(b) except substituting methyl 4-[3- (N,N-dimethylamino)- 1 -propyloxylbenzoate for methyl 3-(4morpholinomethyi)benzoate, the title compound was prepared as a tan solid 17 g, 5.2 minol). MS(ESI): 224.1 c) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2-[N-[4-[3-(N-N-dimethylamino)- 1 -propyloxy]benzoyl]]carbohydrazide :::*Following the procedure of Example 68(b), except substituting a:...:dimethylamino)- 1 -propyloxylbenzoic 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 (0.060 g, MS(ESI): 543.1 Example 77 Preparation of 2-rN-(2-benzyloxybenzovl)1-2'-fN'-(N-benzvloxvcarbonyl-L leucinyl) carbohydrazide Following the procedure of Example 68(b), except substituting 2benzyloxybenzoic acid for N-acetyl-L-leucine and 2 -!jN-(N-benzyloxycarbonvl-L leucinyl)Icarbohydrazide for 2-[N-(N-benzyloxycarbonyl-L-alanyl)Icarbohydrazide, title compound was prepared as a white solid (0.056 g, MS(ESI): 548.1 Example 78 Preparation of 2-rN-(N-benzvloxycarbonyl-Lieuciny)12'-N*.r3-(4 pvri~dylmethoxv)benzoylflcarbohydrazide methyl 4-pyridinyimethoxybenzoate :Following the procedure of Example 76(a) except substituting methyl 3hydroxybenzoate for methyl 4-hydroxybenzoate and 4-pyridylcarbinol for 3dimethylamino-1I-propanol, the title compound was prepared as a yellow solid (0.599 g, 2.5 mmuol). MS(ESI): 244.1 b) 4-pyridinylmethoxybeazoic acid Following the procedure of Example 75(b) except substituting methyl. 4pyridylmethoxybenzoate for methyl 3-benzyloxybenzoate the title compound was prepared as a yellow solid (0.386 g, 1.69 mmol). 1 H NMR (400 MHz, CD 3 OD) 8 8.54 2H), 7.64 (mn, 2H), 7.57 2H), 7.40 (in, 1H), 7.26 (in, IH), 5.24 2H).

c) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(3-(4.

pyridylmethoxy)benzoyl]]carbohydrazide Following the procedure of Example 68(b), except substituting 4pyridinylmethoxybenzoic acid for N-acetyl-L-leucine and benzyloxycarbonyl-L-Ieucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbony

I-L-

alanyl)]carbohydrazide, title compound was prepared as a white solid (0.2 19 g," MS(ESI): 549.1 Example 79 Prep~aration of 2 -[N-(4benzloxybeflzoV)12rN'Nbeflz loxycarbonyl-L leucinyl)lcarbohydrazide Following the procedure of Example 75(a)-75(c) except substituting methyl 4-hydroxybeazoate for methyl 3-hydroxybenzoate in step the title compound was prepared as a white solid 160 g, MS(ESI): 548.1 Exmpe- Preparation of 2- [N-N-benzyloxycarbonyl[L-leucinlYF1>rN-(3-benlZYoxy-5 methoxy)benzoyllcarbohydrazide a) methyl :A suspension of methyl 3,5-dihydroxybenzoate (2.0 g, 11.9 minol), K 2 C0 3 g, 11 .9 mmol), and iodomethane (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 (0.8 13 g, 4.4 mmol). I H NMvff (400 MHz, CDC1 3 8 7.16 (in, I1H), 7.12 (mn, ILH), 6.61 (mn, 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 iodomnethane, the title compound was prepared as a tan oil (1.2 g, 4.4 mmol).

1H NMR (400 MHz, CDCI3) 8 7.45-7.31 6H), 7.24 IH), 6.76 (mn, lH), 5.09 2H), 3.95 3H), 3.84 3H).

c) 3-benzyloxy-5-mthoxybeflzoic 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 minol). 1 INMR (400.MI-z. CDC1 3 6 7.42-7.20 (in, 7H), 6.71 (mn. IH), 5.05 2H), 3.80 3H).

d) 2 -[N-(N-benzyloxyvcarbonyl-L-leucinyl)I-2'-['-(3--benzyloxv..5 methoxy)benzoyllcarbohydrazide Following the procedure of Example 68(b), except substituting 3-benzyloxyacid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide for 2- [N-(N-benzyloxycarbonyl-L-alanyl)carbohylrazide, 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-Ieucinyl 1-2'-rN'-(3-benzyloxy-4 .:dimethoxy)benzoylkcarbohydrazide Following the procedure of Example 68(b), except substituting 3-beazyloxyacid for N-acetyl-L-leucine and 2-IN-(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 2-rN-(N-benzyloxycarbonyl-L-leucinyfll-2'-rN'-(3-benzyloxv-5ethoxy)benzoyl Icarbohydrazide 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 Example 83 Preparation of 2-f[N-(N-benzyloxycarbonyIlvicinyl')1-2'-[N'-(N-benzvloxvcarbonvI L-leucinyl )lcarbohydrazide Following the procedure of Example 68(b), except substituting Nbeazyloxycarbonylglycine 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 (0.204 g, MS(ESI): 529.2 Eape8 Preparation of 2-rN-(3-benzyloxybenzoyl1-2'-rN'-(N-benzyloxycarbonvl-La) rolinyl)lcarbohydrazide 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'-IIN'-(N-benzyloxycarbonyl-Lprolinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting Nbenzyloxycarbonyl-L-prolie for N-acetyl-L-leucine and benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound-was prepared as a white solid (0.219 g, MS(ESI): 532.0 125 Example Preparation of 2-[N-4N-benzyloxycarbonyl -L-Ieuci-nvl phenvlp~henylacetvl) lcarbohydrazide Following the procedure of Example 68(b), except substituting 4biphenylacetic acid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-L.

leucinyl)Jcarbohydrazide for 2- rN-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.224 g, 7 MS(ESI): 554.2 Example 86 ::*:Preparation of (2S--N(-ezlxbnol12-N-Nbnyoyabnl2 aminobutryl )lcarbohydrazide Following the procedure of Example 68(b), except substituting CC:benzyloxycarbonyl-2-aminobutyric acid for N-acetyl-L-Ieucine and 15 benzyloxybenzoyl)jcarbohydrazide for 2-[N-(N-benzyloxycarbonyl-L.

alanyl)Jcarbohydrazide, the title compound was prepared as a white solid (0.244 g, MS(ESI): 520.3 (M+H) 4 Example 87 Preparation of 2 2 '-[N.N'-rbis-(4-p2henlphenvlacetyl'mlcarbohydraide To a stining solution of carbohydrazide (0.200 g, 2.22 rnrol) in DMIF (12.

mL) was added 4-biphenylacetic acid (1.04 g, 4.89 mmol), 1 -hydroxybeazotniazole (0.060 g, 0.444 mmol), and l-( 3 -dimethylaminopropyl)-3-ethylcarbodijrnide hydrochloride (0.937 g, 4.89 mmnol). 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 (0.977 g, MgESI): 501.1 Example 88 Preparation of ('RS )-2-[N-(N-benzyloxycarbonyl-L-leucinvl)1 -2 phenylpheoxv )propionyllcarbohvdrazide Following the procedure of Example 68(b), except substituting 2-(4phenylphenoxy)propionic acid for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)Jcarbohydrazide, the title compound was prepared as a white solid 183 g, MS(ESI): 562.3 Example-89 :Preparation of 2 -[N-(3-benZyloxybenzovl1-2'-[N'-(4methylpentanoyl)lcarbohydrazide Following the procedure of Example 68(b), except substituting 4rethylpentanoic acid for N-acetyl-L-leucine and 2-f[N-(3benzyloxybenzoyl)]carbohydrazide for 2- [N-(N-beazyloxycarbonyl-Lalanyl)Jcarbohydrazide, the title compound was prepared as a white solid (0.079 g, MS(ESI): 399.3 Example Preparation of Q2RS. 2'RS)-2,2-N.N'-bis-r2-(4-phenvlphenyl)-4methylpentanol)1 1 karbohydrazide a) 4-methyl-2-(4-phenylphenyl)pent-4-enoic acid To a stirring solution of diisopropylamine (0.537 g, 5.31 rnmol) in THfF (5.2 rnL) at 0 0 C was added n-butyllthium (2.1 mL, 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 THF (2 mL) was added dropwise. After again warming to 0 'C and coofling to -78 3-bromo-2methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at -78 'C for Ih, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 rL). The aqueous layer was acidified (3N HCI) and extracted with ether (3 X 100 mL). The organic layers were combined, dried NMgOW, filtered and concentrated to yield a white solid (0.449 g, MS(ESI): 265.3 b) 4-methyl-2-(4-phenylphenyl)pentanoic acid To a stirring solution of the compound of Example 90(a) (0.449 g, 1.69 rnmol) in ethyi acetate (25 mL) was added palladium on carbon (0.225 After stirring under a balloon of hydrogen for 16h, the mixture 'w as filtered Celite. The filtrate was concentrated to yield an off white solid (0.430 g, MS(ESI): 267.4 c) 2RS, 2'RS)-2,2'-jNN'-[bis-[2-(4-phenylphenyl)-4methylpentanoyl)]]]carbohydrazile 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, methanolldichloromethane), as a white solid 143 g, MS(ESI): 591.3 Example 91 Preparation of (2'RS)-2-[)I-(N-benzvloxycarboflyl-L-leucinvl)1-2'-[N'-f24(4phenylphenvi )-4-methylpentanoyvlcarbohydrazide Following the procedure of Example 68(b), except 4-methyl-2-(4phenylphenyl)penranoic acid for N-acetyl-L-Jeucine and benzyloxycarbonyl.L-leucinyl)]carbohydrazide for 2-[N-(N-benzyioxycarbonyl-Lalanyl)]carbohydrazide, the title compound:was prepared as a white solid 111 g, MS(ESI): 588.1 Example-92 Preparation of (2'RS )-2-[N-(3-benzyloxybezovl)1- 2'-rN'-r2-(4-p~henylIphenvl)-4methylpgntanoyl)llcarbohydrazide 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-rN-(3-benzyloxybenzovlW12'-[N'-(N-benzyloxycarbonvl-N-methyl- L-leucinyflklarbohydrazide Following the procedure of Example 68(b), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine and 24[N-(3benzyloxybenzoyl)]carbohydrazide for 2-CN-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.34 1 g, 9 MS(ESI): 562.2 Example 94 Preparation of 2-FN-(3-benzloxybenzoyl)1-2'-[N'-rN-(2pvyridinylmethoxycarbonyl )-L-leucinyvl carbohydrazide a) N-(2-pyridinylmetlioxycarbonyl)-L-leucine methyl ester Following the procedure of Example 72(c), except substituting 2pryidylcarbinol for 4-(N,N-dirnethylamino)benzyl alcohol, the title compound was prepared as a brown oil (8.06 g, MS(ESI): 281.2 b) 2- [N-(2-pyridinylylmethoxycarbonyl)-L-leucinyllcarbohydrazide Following the procedure of Example 62%b-62(d) except substituting N-(2pyridinylniethoxycarbonyl)-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 15 c) 2-[N-(3-benzyloxybenzoyl)]-2'-[N'-[-(2-pyridinylmethoxycarbonyl)-Lleucinyl]]carbohydrazide 0 Following the procedure of Example 68(b), except substituting 3benzyloxybenzoic acid for N-acetyl-L-leucine and *000 pyridinylylmethoxycarbonyl)-L-leucinyl]carbohydrazide for benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.057 g, MS(ESI): 549.2 Example Preparation of-2-rN-f3-(4-p2yridylmethoxy~henzoyll pyridinylmethoxycarbonyl)-L-leucinylllcarbohydrazide Following the procedure of Example 68(b), except substituting 3-(4pyridinylmethoxy)benzoic acid for N-acetyl-L-leucine and pyridinylylmethoxycarbony)-L-leucinyl~carbohydrazide 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-[N-[2-(4-phenylphenyl)-4-methvlpentanoyl) 11-2'-[N-rN-(2 pyridinvlmethoxycarbonyl)YL-leucinyl 1lcarbohvdrazide Following the procedure of Example 68(b), except 4-methyl-2-(4phenylphenyl)pentanoic acid for N-acetyl-L-Ieucine and pyridinylylmethoxycarbonyl)-L-leucinyljcarbohydrazide 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-FN-(N-benzyloxvcarbonyl-L-leucinvl)1-2'-rN'-r2-(4-phenylphenvl)- 4-methvlpentanovl)llcarbohydrazide The title compound was prepared from the compound of Example 91 using HPLC (Sumipax OA-3 100, 4.6 X 150 mun, 80/20 bexane/ethanol, 1.0 mUrnin, retention time 5.9 min).

Example 98 Preparation of 2- rN-(N-benzyloxycarbonyl-L-leucinyfl]-2'-rN4-2-(4-phenylphenfl)- 4-methylpentanoyl11carbohydrazide The title compound was prepared from the compound of Example 91 using HPLC (Sumipax OA-3100, 4.6 X 150 mm, 80120 hexane/ethanol, 1.0 ml~min, retention time 8.1 mini).

Example 99 Preparation of 2-[N-(N-benzvloxvcarbonyl-L-leucinvl)1-2- phen ylphenyl)-N-(2-methvlpropyl )carbarnoyl I Icarbohydrazide To a stirring solution of phosgene (0.228 m.L, 0.244 mmol, 12.5% solution in benzene) was added dropwise a solution of N-(2-methylpropyl)- N-(4phenylphenyl)amine (0.050 g, 0.222 imol) and triethylamine (0.025 g, 0.244 mrnmol) in dichloromethane (I mL). After stirring 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 triethylam-ine (0.025 g, 0.244 mrnol) in dichioromethane (1 mL) at room temperature. After stirring at room temperature for 48h, Nmethylmorpholine (0.022 g, 0.222 mmnol) and DMIF (2 m.L) were added to the .:::solution and heated at 50 'C for 16h. The solution was then diluted with ethyl j 15 acetate (5m.L) 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/ dichioromethane) to yield the title compound as a yellow solid (0.023 g, 18%).

MS(ESI): 589.4 Example 100 Preparation of 2-rN-(3-benzyloxybenzovfll-2'4[N'-(N-methyl-Lleucinvi')lcarbohydrazide a) 2-[N-(3-benzyioxybenzoyl)] -2'-[N'-(N-ter-butoxycarbonyl-N-methyl-Lleucinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting N-tertbutoxycarbonyl-N-metbyl-L-leucmne for N-acetyl-L-leucine and benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)Icarbohydrazide, the tidle compound was prepared as a white solid 183 g, MS(ESI): 550.4 132 b) -ezlxbnzv)-"['(-mtv--ecnl~crovrzd To a stirring solution of the compound of Example 100(a) 100 g, 0. 189 mmol) in dichloromethane (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.

methanolldichloromethafle) to yield the title~compound as a white solid (0.055 g, MS(ESI): 428.4 Example 101 Preparation of 2-[N-(N-benzyloxvcarbonl-kL-leuciflyl)l- fN'-(N-methvl-L.- :leucinyhilcarbohydrazide Following the procedure of Example 100(a)-l00(b), except substituting 2- [-(N-benzyloxycarbonyl-Lleuciyl)]carbohydazide for benzyloxybenzoyl)]carbohydrazide in step the title compound was prepared.

MS(ESD): 465.5 Example 102 Preparation of (1 S)-N-f 24[(1 benzyloxycarbonylarrino)-3-methylbuyllthiazo[ylcarbonyllkN'44phenoxypheylsulffol~lhydrazide a) N-benzyloxycarbonyl-L-leucilamihdC To a stirring solution of N-benzyloxycarbonyl-L-leucine (4.6 g, 17.3 mmol) in THF, cooled to -40 was added N-methylmorpholine (3.68 g, 36.4 rnmol; mL) and isobutyl chioroformate (2.37 g, 17.3 mmol; 2.25 mL). After stirring for min, ammonia was bubbled through the solution for 5 mini. The solution was warmed to room temperature. evaporated, and the residue was dissolved in ethyl acetate, washed with 0. 1 N Hcl, and saturated brine, then dried (MgSO 4 filtered and evaporated to dryness to give the title compound as a 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) (1 S)-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 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 NaHC0 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 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 (MgS0 4 filtered, and concentrated. Tge residue was purified by flash chromatography on 90 g of 230-400 mesh silica gel, eluting with 1:3 ethyl acetate/hexanes, to provide the title compound as a pale yellow oil (2.36 g, 1 H NMR (400 MHz, CDC1 3 8 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) (1 S)-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 °C for 1 h. The solution was cooled and evaporated to dryness to provide the title compound as a pale yellow foam (2.01 g, 1

H

NMR (400 MHz, CDC!3) 8 8.35 (bs, 1H), 8.03 1H), 7.37 5H), 5.29 1H).

134 14-5.09 3H), 4.07 (bs, 2H). 1.9.1-1.82 (in. 1H), 1.79-1.66 (in, 2Hf), 1.00 (d, 6H).

e) (I 1 -benzyloxycarbonylarnino)-3-methylbutyl]thiazol-4ylcarbonyl]I-N'-(4-phenoxyphenylsulfonyl)hydrazide To'a stirring solution of the compound of Example 102(d) (275 mg, 0.76 mmol) in dichioromethane at room temperature is added pyridine (180 mg, 2.28 mmol, 0.2 mL) and 4-phenoxybenzenesulfonyl chloride (408 mg, 1.52 mmol). The reaction was stirred for 16 hours and the solvents were evaporated to a residue 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 *~Prepratin ofExamp~le 103 Prprtino (1 S)-N-f4-r I -(N-benZyloxvcarbonyl-L-leucinylamino)-3methylbutyl 1thiazo1-2-ylcarbonvll-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide N-beazyloxycarbonyl-L-leucinyl-L-leucinyI bromomethylketone 1 -Methyl-3 -nitro- 1 -nitrosoguanicline (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 -40*C. N-methyhnorpholine (1.07 g, 10.58 mmol, 0:0-0:1. 16 mL) and isobutyl chioroformate (1.45;g, 10.58 mmol, 1.38 mL) are added.

The mixture is stirred at 40o 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 cilazomethane 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 MlHz, CDCl3) 8 7.34 (in, 5H), 6.5 1 I1H), 5.15 1iH), 5. 10 2H), 4.78 (in, IH), 4.20 (in, IN), 4.04 (dd. 2H), 1.63 (mn, 6H1), 0.93 (mn, 12H).

b) (2S, I'S)-2-(benzyloxycarbonyl)amino-N -(2-carboethoxythiazoI-4-vl)3' methylburylj-4-methylpentanamide The compound of Example 103(a) (2.0 g, 4.4 rmol) 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% methanolldichloromethane) to give the title compound as a white solid (1.46 1 H NMR (400 MHz, CDCI3) 5 7.32 (s.

IH), 7.21 5H), 6.40(d, IlH), 5.13 (dd, IH), 5.02 2H), 4.41 2H), 4.06 (i, 1I), 1.71 2H), 1.47 4H), 1.33 3H), 0.73 12H).

c) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4 yI)- 3 '-methylbutyl]-4-iethylpentanamide Following the procedure of Example 102(d), except substituting (2S,I'S)-2- (benzyloxycarbonyl)amino-N-[ 1 2 -carboethoxythiazol4-yl)-3'-ethylbutyl]-4methylpentananide for (1 I -benzyloxycarbonylamino- 1 -(4-carboethoxythiazol-2yl)-3-methylbutane, the title compound was prepared. MS (ESI): 476.3 d) (1 I-(N-benzyloxycarbonyl-L-leucinylamino)-3 methy Ibutyl i thiazol- 2-y lcarbonyl]]-N'-(N-benzyl oxyc aronyl--leuc iny l)hydrazide To a stirring solution of the compound of Example 103(c) (180 mg, 0.38 inmol) in dimethylformaiide is added N-benzyloxycarbonyl-L-leucine (111 mg, 04 9 0.4*0: 0.42 mmol), 1-(3-dimethylaininopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol), and 1-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 (1 S)-N-f2-f( I benzyloxycarbonlanino)-3-methylbutVIlthiazol-4vicarbonyl 1-N'-(4-p2henylphenylacetyl)hydrazide Following the procedure of Example 103(d), except substituting (I 1benzyloxycarbonylamnino- I .(4-hydrazinocarboflylthiazol-2-yl)-3-methylbutane for (2S,1 'S)-2-(benzyioxycarbonyl)arflino-N- [1 -(2-hydrazinocarboriylthiazol-4-yI)-3' methylbutyl]-4-methylpentanamide, 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 (15 r2-f 1 -benzyloxycarbonylamno)-3-methylbutyllhhiazoI-4vlcarbonyll-N'- r3-4-pryidinylmethoxy)benzoyllhydrazide a) methyl 3-(4-pyridinylimethoxy)benzoatC To a stirring solution of methyl 3-hydroxybeozoate (1 .0 g, 6.58 mmol), 4pyridylcarbinol 1 g, 9.87 inmol), and triphenylphosphine (2.6 g, 9.87 mnnol) in THF (25 mL) 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 20 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 rnmol) in THFIH 2 O 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 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a yellow solid (0.386 g, 1 H NMR (400 MHz, CD 3 OD) 8 8.54 2H), 7.64 (in, 2H), 7.57 (in, 2H), 7.40 (in, IH), 7.26 (in, 1H), 5.24 2H).

C) (I 1 -benzvloxycarbonylamino)-3-methvlbutvllthiazol-4ylcarbonyl] [3-(4-pryidinvlrnethoxy)benzoyljhydrazide Following the procedure of Examrple 103(d). except substituting (I1S)-I benzyloxycarbonylamrino- 1 -(4-hydrazinocarbonylthiazol-2-yl)-3-methylbutane for (2S,1 IS)-2 -(beazyloxycarbonyl)amnino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4-yl)-3methylbutyl]-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- r2-(2-chlorophenoxvmethyl'thiazol-4-vlcarbonyI 1-N'-rN-(4z :pyridinylmethoxycarbonyl '-L-leucinyllhydrazide a) ct-isocyanato-L-leucine methyl ester e:L-leucine methyl ester hydrochloride (25 g, 0. 14 mol) was dissolved in :15 methylene chloride (450 m1L), cooled to 0 and pyridine (43.5 g, 0.55 mol, 44.5 rnL) was added, then a 1.93 M solution of phosgene in toluene 18 mol, 92.7 inL) was added slowly. After stirring at 0 *C for 2 h, the mixture was poured into 0.5 N HCl (1400 mnL) and ice (900 mL). The organic layer was washed with 0.5 N HCl (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 mL) and ice (900 mL), then dried (MgSO4), filtered and concentrated.

The residue was distilled (56-58 0.78 mmJHg) to provide the title compound as a colorless liquid (20.4 g, 1 H NMR (250 Mz, CDCI 3 8 4.04 (dd, lH), 3.82 3H), 1.92-1.72 (in, 1H), 1.69-1.62 (in, 2H4), 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

CDCI

3 88.59 2H), 7.24 2H), 5.33 1H), 5.13 3H), 4.40 (dt. 1H), 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 THE (7 mL) was added 7 mL of water followed by LiOH@H 2 O (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 NHC1 was added (2.6 iL). The solution was lyophilized to yield a white solid (2.015 g, 6.44 mmol). MS (ESI): 267.2 d) N-[2-(2-chlorophenoxynethyl)thiazol-4-ylcarbonylhydrazide Following the procedure of Example 102(d), except substituting ethyl 2-(2- *i chlorophenoxynethyl)thiazole-4-carboxylate for (I 1 -benzyloxycarbonylamino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared.

MS (ESI): 284.1 e) N-(2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyll-N- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting chlorophenoxymethyl)thiazol4-ylcarbonyl]hydrazide for (2S,1'S)-2- (benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yI)-3'methylbutyl]-4-methylpentananide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 532.1 Exampe 107 Preparation of N-rN-(4-pyridinlmethoxcarbonl)-LleucinlNr2f4-(1.2.3thi adiazol -4-vi )phenyl lthiazol-4-ylcarbonvl ihydrazide a) N- .2,3-thiadiazol-4-yl)jthiazol-4-ylcarbonyllhydrazide Following the procedure of Example 102(d), except substituting ethyl 2-44- (1,2,3 -thiadiazol-4-yl)]thiazole-4-carboxylate for (I I -benzyloxycarbonylamino- I -(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-leucinyll-N'-[2{4(1 ,2,3-thi adiazol 4byl )phenyllthiazol-4-ylcarbonyllhydrazide :Following the procedure of Example 103(d), except substituting (1 .2,3-thiadiazol-4-yl)]thiazol-4-ylcarbonyljhydrazide for (2S, 1'S)-2- (benzyloxycarbonyl)amino-N-[ I '-(2-hydrazinocarbonylthiazol-4-yI)-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): 552.1 Example 108 Preparation of N- r2- (3-(4-.chlorophenylsulfonylmethflthien-2-yllthiazol.4ylcarbonyll-N'-[N-(4-pyridinylmethoxycarbonyh)-L-leucinvlmydrazide [3-(4-chlorophenylsulfonylmethyl)thien-2-yl]thiazol..carbonylihydrazide Following the procedure of Example 102(d), except substituting ch~oropheylsufonylmethyl)tien-2-yl]jhazole4-arboxylate for 1benzyloxycarbonylamino-l1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 414.1 b) N-II2-[3-(4-chlorophenyisulfonylmethyl)thiefl-2-vl] thiazol-4-yicarbonv I [N-(4-pyridinylmethoxycarbonyl)-L-leucinylhydrazide Following the procedure of Example 103(d), except substituting chlorophenylsulfonylmethyl)thien-2-yljthiiazol-4-carbonylhydrazide for (2S, I S (beazyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3methylbutylj-4-methylpentanaznide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-beazyloxycarbonyl-L-leucine, the title~compound was prepared as a white.

MS (ESI): 664.0 Example 109 Preparation of (1 S.2'RS)-N-r2-[(I1-benzyloxycarbonylamino)-3-methylbutvllthiazol- 4-vlcarbonyll-N'-r2'-(4-phenylphenylacetyl)-4-methylpentnoyllhvdrazide a) 4-methyl-2-(4-phenylphenyl)pent-4-enoic acid ~:To a stirring solution of dilsopropylamine (0.537 g, 5.31 minol) in THF (5.2 m.L) at 0 'C was added n-butyllithiuxn (2.1 m.L. 5.22 mmol. 2.5M in hexane) dropwise. After stirring for 15 min at 0 the mixture was cooled to -78 *C and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0 0 C and coolling to -78 3-bromo-2methylpropene (0.485 g, 3.54 nunol) was added to the mixture in one portion. After stirring at -78 *C for Ilh, 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 HCl) and extracted with ether (3 X 100 The organic layers were combined, dried (MgSO 4 filtered and concentrated to yield a white solid (0.449 g, MS(ESI)6: 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 mimol) 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-methylbutyljthiazof-4vlcarbonyl]-N'-[2'-(4-phenylphenylacetyl)-4-methylpentanoyl]hydrazide Following the procedure of Example 101(d), except substituting (1S)-1benzyloxycarbonylamino- 1 -(4-hydrazinocarbonylthiazol-2-yl)-3-methylbutane for (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyll-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-12-(3-benzloxyphenvl)thiazol-4-lcarbonyll-N'-fN-(2pyridinvlmethoxvcarbonvl)-L-leucinvllhvdrazide a) methyl 3-benzyloxybenzoate 15 To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMF m.L) 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, CDCl 3 57.67 2H), 7.48-7.34 6H), 7.19 1H), 5.12 2H), 3.95 3H).

b) 3-benzyloxybenzamide To a suspension of ammonium hydrochloride (1.070g, 0.02 mmol) in 20 mL of toluene at 50C, 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 MeAlCINH- (11 mL, 7.49 mmol) in toluene. The reaction mixture was allowed to stir overnight at reflux. The reaction was quenched with 5% HCl, the organic layer was separated and the aqueous layer 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)thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 102(b)- 102(d), except substituting 3benzyloxybenzamide 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.

15 1 H NMR (400 MHz, CD 3 0D) 5 8.50 1H), 7.86 (dt, 1H), 7.51 1H), 7.36 (dd, IH), 5.20 1H), 5.16 1H), 4.19 1H), 1.78-1.72 1H), 1.62 2H), 0.97 3H), 0.94 3H).

e) N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2pyridinylmethoxycarbonyl)-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-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanamide, and N-(2-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid (106 mg, 0.184 mmol). MS (ESI): 574.2 Example I111 Preparation of (1 RS)-N-f 2-fl -(4-phenvlphenvl)-3-methvburvllthiazol-.4 vlcarbonyll-N'-UN-(4-12vridinvlmethoxycarbonyl)-L-leucinvllhydrazide a) N-f 2-fl -(4-phenylphenyl)-3-methylbutyIlthiazo1-4-ylcarbonyljhvdrazde 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 1-(4-phenylphenyl)-3-methylbutylthiazol-4-ylcarbonyl].N'.

N-

.(4-pyridinylmethoxycarbonyl)-L-leucinyljhydrazide :Following the procedure of Example 103(d), except substituting phenylphenyl)-3-methylburyllthiazol-4-ylcarbonyl Ihydrazide for (2S, IS (benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3'- 15 methylbutyl]-4-methylpentanamiide, and N-( 4 -pyridinylmethoxycarbonyl)-L-leucine for N-beazyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 614.3 Example 112 Preparation of N-r2-(2-benzloxyphenylthiazol-4-ylcarbonyll-N'4N-(4.

pRyidinvlmetlhoxycarbonyfl-L-leucinyll hydrazide ethyl 2-am-inothiazole-4-carboxylate hydrobromide To a stirring suspension of thiourea (6.0 g, 78.8 mnmol) in ethanol (80 m.L) was added ethyl bromopymuvate 15.4 g, 78.8 nimol). 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 MIz, 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 oC, 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 (MgS0 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 (MgS04), decolorized with charcoal, filtered and concentrated to provide the 15 title compound as a pale yellow solid (7.46 g, MS (ESI): 236.0 (M+H) 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 20 mmol). After stirring at reflux for 4h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography .See*: (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 6 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*C was added dropwise n-BuLi (23.1 mL, 2.5M in hexane, 57.8 mmol). The mixture stirred at -78*C for 25 min when added via cannulation to a stirring solution of triisopropylborate (54.4 g, 289 mmol) in THF (100 ml) at -78 0 C. After warming to room temperature and stirring for 3h. the miuxture was poured into 3N HCI (100 m.L) and extracted with ethyl acetate (3 X 200mL). The organic layers were combined, washed successively with water and brine, dried (MgSO 4 filt-tred and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a pale yellow solid (6.9 g, 30.3 mmol). lJ{NMRtif (400 MHz, CDCI 3 8 7.90 IH), 7.42 (in, 6H), 7.07 1H), 7.02 6.05 2H), 5.16 2H), e) ethyl 2-(2-benzyloxyphenyl)thiazole-4-carboxylate To a stirring solution of the compound of Example 112(b) (4.0 g, 16.9 **mmol), the compound of Example 72(d) (4.29 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.57 inmol) in dimethoxyethane (60 inL) was added cesium fluoride (8.58 g, 56.5 mmol) and the mixture was heated 85 0 C for 16 h. Tetrakis(triphenylphosphine)palladium(0) (0.65 gn. 057 mrnol) **15 was added and heating at 85 *C was continued for 5 h. The mixture was diluted with water (60 rnL) and extracted with ethyl acetate (2 X 120 mL). The combined extracts were washed with saturated aqueous NaHCO 3 and saturated brine, dried (MgOW, 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 (EST): 340.3 f) 2-(2-benzyloxyphenyl)thiazol-4..ylcarbonylhydrazide Following the procedure of Example:102(d), except substituting ethyl 2-(2benzyloxyphenyl)thiazole-4-carboxylate for -benzyloxycarbonylamino-l1-(4carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 326.2 N- 2-(2 -benzy1oxypheflyl)thiazol.-4-ylicarbolY I] pvndinylmethoxycarbonyl)-L-eucilyllhYdrazide Following the procedure of Example 103(d), except substituting benzyloxyphenyl)thazole-4-ylcabonylhydrazide for (2S, 1'S (benzyloxycarbonyl)amino-N-[ 1 -(2-hydraziflocarboflylthia.zol-yI 3' methylbutyl]-4-methylpeltalaaide, and N-(4-pyridiflylmethoxycabonyl)L-lucine for N-benzyloxycarbony1-L-leucine, the title compound was prepared as a white solid. MS (ESI): 574.3 Example 11 Preparation of N-[f2-[N ety -N(-hnlhnlaio Viao-- croy1N'vridinvlmethoxycarbonyl)L-ieuciflllhydr1iide N-(4-phenylphenyl)-2-methylpropionamde 9: To a stirring solution of 4-aminobiphenyl (9.53 g, 56.3 inmol) and triethylamine (5.70 g, 56.3 inmol, 7.85 mL) in methylene chloride (60 rnL), cooled to 0 was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0 *C for 1 h, the mixture was diluted with methylene chloride (120 rnL) 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 1{NMvR (400 MHz, CDC1 3

/CD

3 OD) 8 7.58 2H), 7.50 (in, 4H), 7.40-7.25 (in, 3H), 2.55-2.49 (mn, I 1. 18 6H).

b) N-(4-phenylphenyl)-N-(2-inethyl- 1'-propyl)amine To a stirring solution of lithium alumrinum hydride (58.6 imol) in THF (58.6 mmol), cooled to 0 0 C, was added slowly over 10 min a solution of the compound of Example 73(a) (9.35 g, 39.0 rnmol) in THF (170 inL). After the addition was complete, the ice bath was removed and the solution was heated at 0 C for 30 min. The mixture was cooled to 0 0 C and water (2.22 inL) was slowly added, followed by 15% aqueous NaOH (2.22 mL.) and water (6.67 The precipitate was removed by filtration and washed with ether 4 times. The filtrate 147 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 OC, 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 solution 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-[N-(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 S 20 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-l-propyl)amino]thiazol-4ylcarbonyl]hydrazide Following the procedure of Example 102(d), except substituting ethyl 2-[N- (4-phenylphenyl)-N-(2-methyl- -propyl)amino]thiazole-4-carboxylate for (1S)-1beazyloxycarbonylarnino-1I-(4-carboerthoxythiazol-2-yl 3 -methylbutane, the tide compound was prepared as a white solid. MS (ESI): 367.3 f) N- [N-methyl-N -(4-phenylphenyl)amninolthiazol-4-ylcarbonylj-N'-[N..(4pyridinylmethoxycarbonyl)-L-Ieucinyljhydrazide Following the procedure of Exampl e 103(d), except substituting phenylphenyl)-N-(2-methyl- 1 -propyl)aminojtbiazol-4-ylcarbonyljhydrazide for (2S,1'S )-2-(benzyloxycarbonyl)amino-N-[ I '-(2-hydrazinocarbonylthiazol-4-yl)-3*methylbutyll-4-methylpentanamide. and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-Ieucine, the title compound was prepared as a white solid. MS (ESI): 615.3 Exmple 11 K :Preparation of N-(N-benZyloxycarbonyl-L-leucinyl)-N'- [2-(4-phenylbenzyl)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 N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(4-phenylbcnzyl)thiazol-4ylcarbonyl]hydrazide Following the procedure of Example 103(d), except substituting phenylbenzyl)thiazol-4-ylcarbonyllhydrazide for (25,1 (beazyloxycarbonyl)amino-N-I 1'-(2-hydmaiinocarbonyltiazol-4-yl)-3'methylbutyl]-4-methylpentanamide, the title compound was prepared as a white solid (20 mg, 0.035 minol). MS (ESI): 557.4 (M+H) 4 149 Example 115 Preparation of N-f2-(4-phenvlphenvlbenzyl )thiazol-4-vlcarbonvl pvridinvlmethoxycarbonvl )-L-leucinyl lhvdrazide Following the procedure of Example 103(d), except substituting phenylbenzyl)tiazol4-ylcarbonyl]hydrazide *for (2S, 1 S)-2- (benzyloxycarbonyl)aiinoN- l'-(2-hydrazinocarbonylthiazol4-y).3methylbutyl]4-methylpernanaride, and N-( 4 -pyridinylmethoxycarbonyl)>Lleucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a yellow solid (30 mg, 0.053 mmol). MS (ESI): 558.2 Example 116 Preparation of N-(N-benzyloxvcarbonvl-Lleuciny 2 -IN-(2-methylpropvyl)-N phenylafinolthi-azO-ylcarbonyll1hydrazide N-[2-[N-phenyl-N-(2-methyl. I -propyl)amino]thiazol-4- :515 yicarbonyljhydrazide Following the procedure of Example I113(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-benzyloxycarbonylLleucinyl).N'-[2-[N-(2 -methylpropyl)-NphenylaminolthiazoI4-ylcarbonylhydrzid Following the procedure of Example 103(d), except substituting N-f 24Nphenyl-N-(2-methyl-l1-propyl)amino]thiazol-4-ylcarbonyllhydrazide for (2S,1'S (benzyloxycarbonyl)ammno-N-[ 1 -(2-hydrazinocarbonylthiazol4yi).3'methylbutl]-4-methylenamide, the title compound was prepared as a white solid (92 mg, 0. 17 1 mmol). MS (ESI): 560.3 Example 11 7 Preparation of N-42-rN-(2-methvlDropvl )-N-phenlaminolthiazol-4-vlcarbonv l-N'rN-(4-pvridinlmethoxcarbonvl )-L-Ieucinvllhvdrazide 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 mrol). MS (ESI): 539.4 Example 118 Preparation of N-f2-(2-benzloxyphenvl)thiazol-4-lcarbonvll-N-rN-(3pvridinvlmethoxvcarbonvl)-L-leucinvllhvdride 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-benzyloxyhenyl)thiazol-4-ylcarbonvl1-N'-rN-(2-.

pvridinvlmethoxvcarbonvl)-L-leucinvllhvdrazide Following the procedure of Example 112(a)-i 12(g), except substituting N- (2-pyridinylmethoxycarbonyl)-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 (M+H) 4 Exam~e. 120 Preparation of N-(N-benzyloxvcarbonyl-N-methvl-L-leucinywN'2-(2benzyloxyphenyl)thiazol-4-ylcarbonyllhydrazide 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-2-N-(2-methylpropyl-N-phenylaminolthiazol-4-vi rN-(2-vpyridinvlmethoxvcarbonvl)-L-leucinvllhydrazide Following the procedure of Example 113(a)-I 13(f), except substituting aniline for 4-aminobiphenyl in step and N-(2-pyridinylmethoxycarbonyl)-Lleucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (40 mg). MS (ESI): 539.4 Example 122 Preparation of N-2-rN-(2-methylpropyDl)-N-phenylaminolthiazol-4-ylcarbonyl [N-(3-pvridinvlImethoxcarbonyl)-L-leucinvllhydrazide 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-pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (42 mg). MS (ESI): 539.4 Example 123 Preparation of N-2-(2-methoxyphenvyl)thiazol-4-vlcarbonyll-N'-rN-(4pyridinylmethoxycarbonyl)-L-leucinyllhydra2;ide a) 2-trimethylstannylanisole To a stirring solution of n-BuLi (2.6 mL, 2.5M in hexane, 6.42 mmol) in Sdiethyl ether (2.5 mL) at -78C was added 2-bromoanisole (1.0 g, 5.35 mmol) in diethyl ether (2 mL) dropwise. After stirring for Ih at -78C, trimethyltin chloride (6.4 mL, 1.OM in THF, 6.42 mmol) 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 50rL) 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, lHNMR (400MHz, CDCl 3 )6 7.47 1H), 7.40 1H), 7.05 (t, 1H), 6.90 1H), 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%).

1 HNMR (400MHz, CDC1 3 5 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 15 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 **o 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 Preparation of (2S. 1 I -(4-carboethoxythiazol-2-v)-3'-methvlbuvl-4-MehVl- 2-(2-phenylbenzvloxvcarbonyl )aminop~entanamide a) (2S, 1 'S)-2-(tert-butoxycarbonyl)amnino-N-[ I -(4-carboethoxythiazol-2-yl)-3'.

methylbutyl]-4-methylpentanarnide The compound of Example 8(c)(1.2 g, 3.5 mmol) was stirred at room temperature in neat TEA (2.96 g, 26.0 mmol) for 15 min. The solution was the concentrated in vacuo and redissolved in DMIF (25 mL). To the stirring solution was added triethylamine (0.779 g, 7.7 rnrol), BOC-Leu-OH (0.972 g, 3.9 minol), l-hydroxybenzorriazole (0.095 g, 0.7 mnxol), and 1-(3-dirnethylanainopropyl)-3ethylcarbodjimride hydrochloride (0.750 g, 3.9 nunol). After stirring at room temperature for 16 hours, the solution was diluted with ethyl actate and washed 15 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 :2*white solid 15 g, MS(ESI): 456.2 b) (2S, 1 1 -(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-methyl-2-(2phenylbenzyloxycarbonyl)antinopentanamide To a stirring solution of phosgene (1.5 niL, 2.9 minol, 1 .93M in toluene) at 0 0 C was added 2-biphenylmethanol (0.486 g, 2.64 mmol) and diisopropylethylamine (0.375 g, 2.9 mmol). 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) (0.150;g, 0.330 rnol) dissolved in TFA niL) was concentrated and redissolved in DMEF (3 This solution was added to the 2-biphenylmethanol solution followed by diisopropylethylamine (0.2 13 g, 1.65 mmol). After stirring at room temperature for 1h, 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. 1 S)-2-1Y2-benzvl)benzyloxvcarbonvl)amino-N-r carboethoxvthiazol-2-yl )-3'-methylbutvl 14-methvlpentanamide Following the procedure of Example 124(b), except substituting 2benzylbenzyl alcohol for 2-biphenylmethanol, the title compound was prepared as a white solid 123 g, MS(ESI): 580.0 Example 126 Preparation of (2S. 1'-(4-carboethoxythiazol-2-l)-3'-methylbutvl-4methvl-2-f(2-naphthylmethoxycarbonvl)laninopentanamide 15 Following the procedure of Example 124(b), except substituting 2naphthalenemethanol for 2-biphenylmethanol, the title compound was prepared as a white solid (0.132 g, MS(ESI): 540.1 Examile 127 Preparation of 2S. 1 -(4-carboethoxythiazol-2-yi)-3'-methylbuyl-4methvl-2-f(3-phenoxvbenzyloxycarbonvylaminoentanamide Following the procedure of Example 124(b), except substituting 3phenoxybenzyl alcohol for biphenylnethanol, the title compound was prepared as a white solid (0.107 g, MS(ESI): 581.9 Example 128 Preparation of (2S. I'S)-2-(benzvloxvcarbonvl)armino-,N-[ l -f 2-(2benzyvguaniin y)thi azol 4-yl methlbuyl 4-me thy pen tan nde a) S-methyl dithiobiuret hvdroiodide salt To a stirring solution of dithiobiuret (5.0 g, 37 xniol) in THfF (75 miL) was added lodomethane (13.1 g, 92.5 mmol. 5.76 inl). After stirring at roam temperature for 22 h, the solution was diluted with 150 mL of toluene and allowed to stand at 0 'C for 3 h. The crystals were collected by filtration and washed with cold 2:1 toluene=TH, then dried in vacuc 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 mmol) was dissolved in isopropanol (80 mL) and benzylamine (1.77 g, 16.5 mmol, 1.8 mL) was added and 15 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 vacuo to provide the title compound as a white solid (2.59 g, 6 MS(ESI): 209.2 c) (2S, 1'S)-2-(benzyloxycarbonyl)arrnino-N-( I'-[2-(2-benzylguanidinyl)thiazol-4.

ylI-3'-methylbutyl]-4-methylpentanamide Following the procedure of Example except substituting 3benzylguanidinyl thiourea for ethyl thiooxainate, the title compound was prepared as a white solid (102 mg, MS(ESI): 565.1 Example 1 29 Preparation of (1 S)-N-f4-f I -(N-benzyloxycarbonlarno)-3-metylbu XItthlial yicarbonyil-N-methvl-.N'-(N-benzyloxycarbonl-L-eucinvf )hvdrazide 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 Preparation of (I S)-N--f4-f I bengyloxycarbony amino)- 3methylbutylj Ithi azol 2 v-carbonvi l-N'-(N-benzvloxycarbonyl-L-leucinyI)..N'-methyihvdrazide a) N-(N-benzyloxycarbonyl-L..leucinyl). N-methylhydrazide :..*Following the procedure of Example 26(c), except substituting N- .benzyloxycarbonyl-L-leucine methyl ester for (I I -benzyloxycarbonylamino- I1- *.15 2 -carboethoxythiazol-4-yly-3methylbutane and methyl hydrazine for hydrazine, the title compound was prepared.

b) (15)-l1-benzyloxycarbonylamzino-l1-( 2 -carboxythiazol-4-yl)-3-methylbutane The compound of Example 26(c)(0.57 1.5 mmol) was dissolved in .20 tetrahydrofuran and treated with an excess of L.ON sodium hydroxide. The mixture was allowed to stir for 4 hours, and was quenched with 1LON 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 Il-(N-benzyloxycarbonylamino)3methylbulthazol2ylcarbnyl] N'(-ezlxcroy--euiy)N-ehlyrzd Following the procedure of Example 28(e), except substituting

N-(N-

benzyloxycarbonylL..eucinyl)Nmethyhydrazde for 1- (benzyloxycarbonyl)amino. l-( 4 -carboethoxythiazol-2-yl)..3.methylbutane and (I S)- 1 -be nzyioxycarbony amino-. 1-(2-carboxythiazol-4-yly..3-methyibutane for Nbenzvloxycarbonyl-L-leucine, the title compound was prepared as a white solid.

MS (ESI): 624.2 Example 131 Preparation of benzy lox vc arbonyl -L-leucnyl) N'-N-benzvlox ycabonl.L leucinyl)-L-alayLhydrazide Following the procedure of Example 27(a)-27(c), except substituting Lalanine methyl ester for L-leucine methyl ester in step the title compound was prepared as a white solid (225 mg, MS(ESI): 598. 1 o:**Preparation of N-(N-benzyloxycarbonlLleucinyI-N'NenzyloxycarbonyI.Lleucinyflglycinvlhydrazide Following the procedure of Example 27(a)-27(c), except substituting glycine methyl ester for L-leucjne methyl ester in step the title compound was prepared as a white solid (307 mg, MS(ESI): 584.1 Example 1332:: Preparation of I -(N-benzvloxvcarbonylamino)-3-methvlbutyll. 1.3.4ethyl oxalamidrazonate a solution of ethyl thiooxamate (3.0 g, 22.6 mmol) in ethanol (50 mL) was added hydrazine hydrate 1. 13 g, 22.6 mmol, 1.09 rnL). The mixture was allowed to stir for 3 hours at room temperature, while venting through a scrubber of concentrated sodium hydroxide solution. The'§olution 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 -benzyloxvcarbonvlamino- 1 -(2-carboethoxv- I .3,4-triazol-5-vl)-S rnethylbutane N-benzyloxycarbonyl-L-leucine (0.535 g, 2.0 mxnol) was stirred in TI-IF at Ethyl chloroformate (0.23 mL, 2.4 mmol) and triethylarnine (0.25 C" 2.4 minol, 0.34 mL) were added. The compound of Example 10(a) (0.264 g, 2.0 mmol) was then added and the mixture was allowed to stir at room temperature overnight.

The solvents were evaporated and the residue was dissolved in xylenes and heated to 200 'C using a Dean-Stark apparatus. The. heating was stopped after 4 hours and the solution was evaporated to a residue which was chromatographed (silica gel, 40% ethyl acetate in hexane) to give the title compound as a white solid (0.498 g, 1 HNNMR(400 MHz, CDC 3 57.20 (5H) ,5.71 d, IH) ,5.04( s ,2H) 4.99 (dd IH) ,4.3 6q m 59 IH) ,II t,3 H)o,0.8 3 dd, 61-).

c) (I I -benzyloxycarbonylamino- 1 -(2-hydrazinoca-bonyl- 1 ,3,4-triazol-5-yi)-3methylbutane *Following the procedure of Example 26(c)-26(d), except substituting (I1S)- I benzyloxycarbonylamino- 1 -(2-carboethoxy- 1 ,3,4-triazol-5-yl)-3-methylbutane for (1S)-l -beazyloxycarbonylamino-l1-(2-carboethoxythiazol-4-yl)-3-methylbutane in step the title compound was prepared. MS (ESI): 594.5 Example 134 Preparation of (1 S)-N-(N-acetyl-L-leucinyfl-N'-r2-[ I-(N-benzyloxvcarbonylarnino)- 3-methylbutllthiazol-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 135 Preparation of (1 S)-IN-(N-benzyloxcarbonl-a]anyl 2- l bezixcab~ylmn)3mtybutvl lthiazol-4-ylcarbonvj ihydrazide Following the procedure of Example 28(a)-28(e), except substituting

N-

benzyloxycarbonyl-L..alamne 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 (IS )-N-(N-acetvl-L-alanyl I-CNbenzyloxyc rtonylmn)- 3 methylbutyl ithiazol -4-vicarbonyl ihvdrazide Following the procedure of Example 28(a)-28(e), except substituting

N-

acetylLaaine for Nber,oxcarboylL-lucine in step the title compound Preparation of (1 S'-N-(N-aceyl)..N'-f24 1 -(N-benzyloxycarbon lamino).3methvlbut'Ithiazol y~lcronyllhv-drzde 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 138 Preparation of (1 S)-N-f2-f -(N-benzvloxvcarbonvyLaMino)..3.methylbutyllthiazol4ylcarbonvlI-N'-N( 4 -griinletoxcro.1).L.eucinyllhvdazd Following the procedure of Example 28(a)-28(e), except substituting N-(4pyridinylmethoxycarbonyl)-Lleucine for N-benzyloxycarbonyl.L.leucine in step the title compound was prepared as a whi te solid (121 mg,

MS(ESI):

611.0 Example 139 Preparation of (IS)-N-r2-fl-(N-benzvloxycarbonvlaniino)-3-methvlbutvllthjazol-4ylcarbonyll-- N'-N-(2-pvyridinvlmethoxycarbonyl)-L-leucinyllhvdrazide Following the procedure of Example 28(a)-28(e), except substituting N-(2pyridinylmethoxycarbonyl)yL-leucine for N-beazyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (125 mg, MS (ESI): 611.2 Example 14 Preparation of( I r2-f F1 -(N-benzyloxycarbonl amino)- 3-methylbu lyI1 thiazol -4.

yicarbonvil- N-(N-Denzyloxvcarbonyl-N-methl-L-eucinyihvdrazijde 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 (I S)-N-[2-fI -(N-benZyloxycarbonyl-N-methylamino)-3- *6666 methylbutyllthiazol-4-ylcarbonyll-N'- rN-(4-pyridinylmethoxycarbonyl)-Llunyllhyz 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-pyi-idinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid (120 mg, 72%).

MS (ESI): 625.3 Example 142 Preparation of (I'S )-N-(N-benzvloxycarbonyl-L-leucinyl)-N-f2.flI-(Nbezlxcroy--ehlmio--ehlultiao--iabnd~~rzd Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step the title compound was prepared as a white solid (95 mg, MS (ESI): 624.3 Example 143 Preparation of (IS '-N-r2-r I-(N-benzvloxycarbonl-N-nethylamno)-3methylbutyllthiazol-4-yl icarbonvi- N'-(N-benzloxcarbonl-N-methl-L.

feucinyl)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 15 and N-benzyloxycarbonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid (129 mg, 59%).

MS (ESI): 683.3 Example 144 Preparation of (1 S)-N-[2-rl1-(N-methylamino-3-methylbu~iylthiazol4lca+.,bnyi.- N'-FN-(4-2vridinyvimethoxycarbonyl)-L-Ieucinvllhydraidea) (1 [1-(N-tert-butoxycarbonyl-N-methylaniino)-3methylbutylthiazolA.ylcarbonyl-N'-[N-(4-pyrdnyknethoxycabony)L-eucinyl~hydrazde Following the procedure of Example 28(a)-28(e), except substituting Ntert-butoxycarbonyl-Nmethyl-Lleucine for N, -er-butoxycarbonyl-L-leucine in step and N-( 4 -pyridinylmethoxycarbonyl-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-fI -(N-methylaino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide To a solution of the compound of Example 2 1(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 MgS04 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 (I 1 -(N-benzyloxcarbonylamino)-3-methylbutthiazol-4vlcarbonll-N '-N-(tert-butoxycarbo-nl)-L-leucinyllhydide Following the procedure of Example 28(a)-28(e), except substiniting N-tenbutoxycarbonyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title 15 compound was prepared as a white solid (293 mg, MS (ESI): 576.4 Example 146 Preparation of (1 I -(N-benzvloxycarbonvlamino)-3-methylbutlthiazol-4ylcarbonvll-N'- N-(tert-butoxvcarbonvl)-N-methyl-L-leucinvflhydrazide Following the procedure of Example 28(a)-28(e), except substituting N-rerbutoxycarbonyl-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 Example 147 Preparation of (I S)-N-f 2-fl -(N-benzyloxycarbonvlamino)-3-methylbutyllthiazol.4vlcarbonyi VN'-(N-methyl-L-leucinyl)hydrazide Following the procedure of Example 144(b), except substituting [1 -(N-benzyloxycarbonylamnino)-3-methylbutyllthiazol-4-ylcarbonyll-N'-[N-(tertbutoxycarbonyl)-N-methyl-L-leucinyllhydrazide for (1 1 -(N-tertbutoxycarbonyl-N-methylamino)-3-methylbutylthazol4-ylcarboflylI-N'-[N-(4pyridinylmethoxycarbonyl)-L-Ieucinyllhydrazide, the title compound was prepared as a white solid (40 mg, MS (ESI): 490.3 Example 148: Pr-eparation of (I S)-N-r2-f I -(N-benzyloxvcarbonvlamino)-3-met-hylbutyllthiazol-4- ylcarbonyl 1-N-(L-leucinyl Thydrazide Following the procedure of Example 144(b), except substituting [1 -(N-benzyloxycarbonylammio)-3-methylbutylthiazol-4-ylcarbol-N'-N-(tertbutoxycarbonyl)-L-leucinyllbydrazide for (1 1-(N-tert-butoxycarbonyl-Nmethylamino)-3-methylbutyl~thazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyllhydrazide, the title compound was prepared as a white solid (39 mg, 100%). MS (ESI): 476.4 ~20 Preparation of (1 1 (N-benzyloxycarbonylamino)-3-methylbutvl'Ithiazol- 4 vicarbonyl 1-N'-rN-(4-imnidazolylacetyl')-L-Ieucinvllhvdrazide Folowing the procedure of Example 28(e), except substituting (1S)-N-[2-I1- (N-benzyloxycarbonylamino)-3-methylbutyllthiazol-4-ylcarbonyl]-N'-(Lleucinyl)hydrazide for (15)-I -(benzyloxycarbonyl)anuino-l1-(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): Example 150 Preparation of (I 1 -(N-benzvloxvcarbonvl-N-methvlamin o -3.

methvlbul lthiazol-4-ylcarbonvl ]-N'-rN-.(3-pvyridinvlmethoxycarbonvl )-N-methyl- L-leucinyl ihydrazide a) N-methyl-L-leucine methyl ester N-methyl-L-leucine (1.3 g, 8.95 mmol) was dissolved in 4M HCI, 1,4dioxane (10 m.L) and methanol (10 The solution was stirred overnight at room temperature, then concentrated to afford the title compound as a white solid (100%).

MS 160.0 b) N-inethyl-N-(3-pyridinylxnethoxycarbonyl)-L-leucine methyl ester To a stirring solution of phosgene in toluene (5.63 rnL, 6.025 mmol) in methylene chloride (10 mL), cooled to 00(2, was added dropwise a solution of Nmethyl-L-leucine methyl ester (673 mg, 4.63 mmol) and pyridine 10 g, 0.97 rnL, :15 13.89 mmol) in methylene chloride (4 mL). The solution was stirred at OC for 2 hours. A solution of 3-pyridyl carbinol (0.56 g, 5.09 mrnol, 0.49 mL) was then added and the reaction mixture was stirred at room temperature for 5 hours. The 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 mg, 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-pyridinylnethoxycarbnyl).L-.leucine methyl ester (I 1benzyloxycarbonylaniino- 1-(2-hydrazinocarbonyltbiazol-4-yl)-3-methylbutane, the title compound was prepared as an orange solid (84 mg, 100%). MS (ESI): 281.3 d) (iS 1-(N-benzvloxcarbonyl-N-methiaino)-3-metvlbutvilthazol4 ylcarbonylI-N'-[N-(3-pyridinylmethoxycarbonv)-N-nethv1.L..1euciny1]hvdraide Following the procedure of Example. 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-Ieucine for N-tert-butoxycarbonyl-L-leucine in step and N-methyl-N-(3-pyridinvlmethoxycarbonyl)-L-leucine for Nbenzyloxycar-bonyl-L-leucine in step the title compound was prepared as a white solid (55 mng, MS (ESI): 639.4 Example 151 Preparation of (IS f2-fl1-(N-benzyloxycarbonyl-N-methylamino)-3methylbutyIlthiazol-4-ylcarbonyll-N'-rN-3-pyridinlmehoxycarbonI)-L.

leucinyilhydrazide Following the procedure of Example 28(a)-28(e), except substituting N- :benzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step *.15 and N-(3-pyridinvlmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid (31 mg, 34%).

MS (ESI): 625.4 Example 152 Preparation of (I S)-N-r2-flI-(N-benzloxycarbonlamino)-3-methylbuyllthiazol.4vicarbonyll--N'-[N-(3-pvridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting N-(3pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (63 rug, MS (ESI): 611.5 Example 153 Preparation of (1'S )-N-N-benzvloxycarbonl-L-leucil)-N'-( 1ben zyloxvcarbonvlI)-N'- f2 r[1 -me thvlaxnino)-3 -methvlbutyl I thi azol -4yicarbonvi 1-N-methvlhvdrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-Ieucine for N-tert-butoxycarbonyl-L-leucine in step and methyl hydrazine for hydrazine in step the tidle compound was prepared as a white solid (80 mg, MS (ESD): 660.4 Example 154 Preparation of (1 I -(N-benzyloxycarbonylamino')-3-methvlbutyllthiazol-4vilcarbonvil- N'-rN-(2-pvridinvlmethoxvcarbonvl)-N-methyl-L-leucinyllhvdrazide a) N-methyl-N-(2-pyridinylmethoxycarboflyl)-L-leucflC methyl ester *:N-(2-pyridinylmethoxycarbonyl)-L-leucine methyl ester (490 mg, 1.75 15 mnrol) was dissolved in THF (7.0 mL) and methyl iodide (0.435 mL, 6.99 Mmnol) was added. The reaction mixture was cooled to OOC 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 NaHCO3 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 2 -pyridinvlmetlhoxvcarbonv.i)Lieucine Following the procedure of Example 130(b), except substituting N-methyl-

N-(

2 -pyridinylmethoxycartbonyl).L-leucine methyl ester (I I1benzyloxycarbonylamjino-l (2-hdaio:abnltizo 4y)-3-et uae the title compound was prepared as a white solid (223 mg, 100%). MS (ESI): 281.3 c) (1 S)-N-[2-f(N-ezlxcroyann)3mthluylhaO4ycroyl N'[-2prdnlehxcroyl--ehlLluiyjyrzd Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methy-L-leucine for N-tert-butoxycarbonyl-L-leucine in step and N-ehlN(-yiiymtoyabnl--ecn for Nbenzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (50 rmg, MS (ESD: 639.5 Example 155 *Preparation of (1 S)-N-r2-f I -(N-benzvloxycarbonv-Nmethyamjno)-3 mehiuyihaQ--vcroylN N(-yrdnlehxgroy)-N-methvl- L-Ieucinyllhydrazide a) L-leucine tert-butyl ester isocyanate L-leucine tert-butyl ester hydrochloride (10. 185 g, 45.5 znmol) was dissolved in methylene chloride (100 mQL, cooled to 0 OC and pyridine (12.7 mL, 182.0 mmol) was added, then phosgene in benzene (47 ruL, 59.1 nio1). 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 exctracted with 100 ruL methylene chloride. The combined organic phases were washed with a mixture of saturated aqueous NaCl solution and crushed ice, dried over MgSO4, filtered and concentrated to afford the isocyanate as a yellow liquid (5.37 g, b) N-( 4 -pyri din ylme thoxvcarbonyl) le ucine tert-buryl ester The compound of Example 155(a) (3.05 g, 14.32 mmol) and 4-pyridvl carbinol (1.56 g, 14.32 mmol) were dissolved in toluene (80 rnL) and heated at reflux overnight. The solution was concentrated in vacua 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-pyridinylrnethoxycarbonyl)-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 comp ound wa prepard as a yellow liquid (2.038 g, 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 I -(N-tertpyridinylmethoxycarbonyl)-L-leucinyl]hydrazide, the title compound was prepared as a white solid (343 mg, 72% yield). MS (ESI): 281.3 (1 1 ezloyabnlN-ehlmn)--ehluyltizl4 ylabnl-'[-4prdnlehxcabnl--ehlLluiy~yrzd 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-methyl-N-(4-pyridinytrethoxycarbonyl)-L-eucine for Nbenzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (50 mg. MS (ESD): 639.5 Example 156 Prepraton f 2 2 -r.N'-Fbis-(N-aceyl-L-leuccinv)jcarbohdrid Following the procedure of Example 29, except substituting N-acetlLleucine for N-benzyloxycarbonyl-L-leucine, the tidle compound was Prepared as a pale yellow solid 153 g, MS(ESI): 401.3 Example 157 Preparation of benzvloxycarbonyl..Lleucinvl)l methylpgrntanovl) carbohydrazide a) N-benzyloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester (2.0 g, I11.0 mmol) in 1,4dioxane (20 ml-) was added aqueous Na 2

CQ

3 solution (12.1 mL. 2M in H-,O) followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture stirred at room ft. temperature for 4h then partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried (MgSO 4 filtered and concentrated to yield the title compound as a colorless oil 1 g, 100%). 1 -llMR (400MIHz, CDC1 3 5 7.34 (in, 5H), 5.27 IlH), 5.12 2H), 4.41 3.75 3H), 1.65 (in, 0.96 (mn, 6H).

b) N-(N-bnzyloxycarbonylLleucinyl)hy.rjz ft To a stirring solution of the compound of Example 157(a)-(3-.lIg, 1 1.Ormol) ft.. ftin methanol (15 mL) was added hydrazide hydrate (5.9 g, 11L8 inmol, 5.7 mnL). The ft.....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 4 c) l-benzyloxycarbonylamno3methy[ 1 3 4 To a stirring solution of the compound of Example 157(b) (3.0 g, 10.8 mmol) in toluene (50 ml) was added phosgene (56 rnL, 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)hvdrazide To a stirring solution of ethyl isocaproate (2.0 g, 13.8 mmol) in ethanol rnL) was added hydrazine monohydrate (6.9g, l38mmol, 6.7 rnL). 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%). 1 f{NMR (400MIHz, CDCl3) 8 7.48 (s-br, lH), 3.62 (s br, 2.13 2H), 1.51 (in, 3H), 0.85 6H).

e) 2-[N-(N-benzyoxycarbofl-leucinyl)]- 2 4 methylpentanoyl)Icarbohydrazide The compounds of Example 157(c) 100 g, 0.325 inmol) and Example 34(d) (0.042 g, 0.325 mmol) were combined and dissolved in ethanol (1 m1L). The solution was heated at reflux for 24 hours, then concentrated to a solid yellow residue which was washed with cool mnethylene chloride to yield the title compound as a white solid (0.053 g, MS(ESD: 436.2 Example 158 *Preparation of 2.'r.'ri-Nbnylxcroy--ehlL leucinyl)1 lcarbohydrazide Following the procedure of Example 29, except substituting Nbenzyloxycarbonyl-N-methyl-L-leucifle for substituting N-benzyloxycarboflyl-Lleucine, the title compound was prepared with purification bycolurn chromatography (silica gel, methanoldichlorom~ethafle) as a white foam (0.236 g, MS 613.2.

Example 159 Preparation of 2 -fN-(N-acetyl-L-leucinvl)1-2-rN'-(N-benzvloxvcarbonyl-L leucinyl)lcarbohydrazide) a) 2 -[N-(N-benzyloxycarbony-L-leuciny)]cabohyrazde To a stirring solution of the compound of Example 157(c) (3.15 g, 10.3 nunol) in methanol (2 m.L) was added hydrazine hydrate (5.0 g, 100 mmol, 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 eucinyl)]carbohydrazide To a stirring solution of the compound of Example 159(a) 100 g, 0.297 mmol), N-acetyl-L-leucine (0.054 g, 0.3 12 mniol) and l-hydroxybenzotriazole (0.008 g, 0.0594 mmol) in DMF (2mL) was added l-( 3 -dimethylaminopropyl)-3ethylcarbodijmjde hydrochloride (0.060 g, 0.312 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, methanol/dichloromethane) to yield the title compound as a white solid (0.052 g, MS(ESI): 493.1 Example160 Preparation of 2 2 '-rN.N'-rbis-[N-(4-pyrnvlehxcroy).

leucinyl)lllcarbohydrazidet Following the procedure of Example 29, except substituting N7(4pyridinylmethoxycarbony)-L-leucine for N-benzyloxycarbonyl-L-1eucine, the title compound was prepared as a white solid (199 mg, MS(ESI): 587.1 Example 161 Preparation of 2 2 N.N'-f bis -fN-(2 pri din y Imethox ycartony leucinyl11 carbohydrazide Following the procedure of Example 29, except substituting N-(2pyridinylmethoxycarbonyl)-Lleucine for N-benzyloxycarbonyl-L-leucine, the tide compound was prepared as a white solid (263 mg, 8 MS(ESI): 587.1 Example 162 Prep~aration of 2 -FN-(N-benzyloxymabonylL-.leucinyl)1-2'z- N--2- Ryridinlmethoxcarbonv-Lleucinvl~lc11cbhydfraide Following the procedure of Example 159(a)-I 159(b) except substituting N-(2ridyAmetIUyarbonuyl)..L-eucine lithium salt for N-acetyl-L-leucine in step the tidle compound was prepared as a white solid (0.040 g, MS(ESI): 586.3 4 .o Preparation of 2 -rN-(N-benzyloxycai-bonyliL..leucinyJ )1-2 -rN'-rN-(4- DrdinlmethoxcarbonflLeucinvfl]crbohydmzide Following the procedure of Example 159(a)- I 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(ESI): 586.3 Example 164 Preparation of 2-rN-(N-benzyoxycarbonvl-L.eucinyl)1 rN'-rN-(3pyridinylmethoxycarbony.L.IeucinvI'~1cabhv&raide Following thie procedure of Example 159(a)- I 59(b) except s ubstituting N-(3pyridinylmethoxycarbonyl)Lleucine 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'-fN.N'.-[bis-(N-benzyloxvcarbonyl-L-leucinylfll..(Nme thyl )carbohvdrazi de a) N-methyl-N-(N-benzyloxycarbonyl-L-leucinyl)hydrazide To a stirring solution of N-benzyloxycarbonyl-L-leucine methyl ester (2.2 g, 8.15 mmol) in methanol (4 rnL) was added methylhydrazine (3.7 g, 80 mmol).

After stirring at room temperature for 16 h, the solution was concentrated to yield the title compound as a yellow solid (2.14 g, 7.3 mrnmol). MS(ESI): 294.1 b) [bis-(N-benzyloxycarbonyl-L-leucinyl)I]-2-(N-methy)carbohydrazide The compound of Example 157(c) (0.250 g, 0.819 rnmol) and the compound 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, methanoildichloromethane) to yield the title compound as a white solid (0.060 g, MS(ESI): 599.1 Example 166 Preparation of 2.2'-[N.N'-[bis-rN-(3-pyridinylmethoxycarbonyl)-Lleucinyl)lllcarbohydrazide 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 Exampe 1.67 Preparation of I (N-benzv 1) [N.M-flis- N- ben zyl oxycarbonvi

-L-

leucinyl)llcArbohydrazide To a solution of the compound of Example 157(b) (1 g, 3.5 rnrol) in ethanol (30 niL) was added benzaidehyde-( 0.33 rnL, 3.2 mniol). The resulting mixture was heated at reflux for 4 h. The mixture was concentrated in Vacuo then purified by flash chromatography (silica gel, 10-50% EtOAc hexane) to yield the tide compound as a solid (0.31 g, MS(ESI): 368.0 b) N-ezlN-NbnyoyabnlLluiy~yrzd To a cooled solution of compound of Example 167(a) (0.24 g, 0.65 ramol) in THF (5 niL) was added borane tetrahydrofuran complex (0.65 rnL, 0.65 mmol: I M solution in THE). The resulting mixture was stirred at room temperature for 4 h then concentrated in vacuc and diluted with ethyl acetate, washed with water, saturated brine, dried (MgSO 4 filtered and concentrated in vacuc to give the tidle compound as a white solid (0.25 g, MS(ESD: 370.0 (M c) 1-benzyloxycarbonylamino.3.methyl 1 -(3-benzyl-1I,3,4-oxadiazol-2-on-5yI)butane Following the procedure of Example 157(c), except substituting N-benzyl- N'(-ezlxcroylLluiy~yrzd for N-(N-benzyloxycarbonyl-Lleucinyl)hydrazicle, the title compound was prepared as an oil (0.02 g, 83%).

MS(ESI): 396.0 4 d) 1-Nbny)2[-NbnyoyabnlLluiy)croyrzd Following the procedure of Example 159(a), except substituting 1 benzyloxycarbonylanmin-3methylI1 -(3-benzyl- 1 .3, 4 for l-benzyloxycarbonylamino.3-methyl. 1-(1 3 4 -oxadiazo-2-on-5..yl)butane in step the title compound was prepared as a solid (0.0 13 g, MS(ESI): 428.0 d) I-(N-berazyl)-2,2'-[NN'-[bis-(N-benzyloxcarbonv-L-eucinyl)]carbohyaide Following the procedure of Example 159(a)-159(b), except substituting Ibenzyloxycarbonylamino-3-methyl- I -(3-benzyl- 1, 3 4 for I -benzyloxycarbonylamino-3-methyl- 1-(1 ,3,4-oxadiazol-2-on-5-yl)butane in step the title compound was prepared as white solid (13 mg, MS(ESI): 675.0 Example 168 Preparation of 2-rN-(N-benzvloxcarbonl-L-leucinl)1-2-rN-(Nbenzvloxvcarbonyl-N-methvl--leucinvl)lcarbohydrazide Following the procedure of Example 159(a)-159(b) except substituting N- benzyloxycarbonyl-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 N-2-(1 -naphthyl)thiazol-4-lcarbonll-N'-IN-(4pvridinlmethoxvcarbonyl'-L-leucinvllhydrazide Following the procedure of Example 112(a)-I 12(g), except substituting 1naphthyl boronic acid for 2-benzyloxyphenyl boronic acid in step.(e), the title compound was prepared as a white solid (0.094 g, MS(ESI): 518.4 Example 170 Preparation of N-f2-(2-biheny)thiazol-4-ylcarbonvl1-N'rN(4pv-ndinylmethoxvcarbonyl -L-leucinvl hydrazide Following the procedure of Example 112(a)- I 2 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-benzyloxycarbonyl-N-methvl-L-eucinl)-N'-f2-[N-(2methylpropvyl)-N-phenlaminolthiazo-4-ylcarbonyl ihydrazide Following the procedure of Example 11I6(a)-Il 16(b), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-(4-pyrndinylmethoxycarbonyl leucine, in step the title compound was prepared as a white solid (40 mg, MS (ESI): 552.5 Exaple17 Preparation of N-rN-methvl-N-(2-pvr-idinylmethoxvcarbonyl)-L-leucinyll-N'-f2-rN- (2-methylp~rop~yl)-N-phenylaininolthiazol-4-ylIcarbonyllhydrazide :Following the procedure of Example I1I6(a)-Il 16(b), except. substituting Nmethyl-N-(2-pyridinylxnethoxycarbonyl)-L-leucine for N-(4pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared **15 as a white solid solid (70 mg, 7 1 MS (ESI): 553.4 *get Example 173 Preparation of N- [2-(2-benzyloxyphenyI~thiazol-4-ylcarbonyll-N'-(N-tertbutoxycarbonyl-L-leucinyl)hydrazide Following the procedure of Example 112(a)-Il 12(g), except substituting Ntert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucifle 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-tert-butoxycarbonyl-L-leucinyl)-N'-I2-rN-(2-methlproP~yfl-Nphenylarninolthiazol-4-ylcarbonyllhydr-azide Following the procedure of Example 11I6(a)-l except substituting Ntert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-eucifle in step the title compound was prepared as a white solid (740 mg, MS (ESI): 504.4 Example 175 Preparation of N-(N-tert-butoxycarbonylN-methylL-eucin)N2fN(methylpropal-N-phe nvlarmno lthiazol-4-ylcarbonyl lhydrazide Following the procedure of Example 116(a)-l I except substituting Ntert-butoxycarbonyl-N-me thy I-L-leuc ine for N-( 4 -pyn'dinylxnethoxycarbonyl leucine in step the title compound was prepared as a white solid (610 mg, 69%).

MS (ESI): 518.4 Example 176: Prearation of N-r2-(2-benzyloxyphenyI)thiazolI4ycaronyll-N'(Na) N- 2 2 -benzyloxyphenyl)thiazol-4-ylcarbonyl] -N'-(L-leucinyl)hydrazide Following the procedure of Example 144(b), except substituting 15 benzyloxypheny)tizol14ylcarbonyl-N'-(N-ert-butoxycarbonyL.

leucinyl)hydrazide for (1 [1-(N-tert-butoxycarbonyl-N-rnethylamno).3methylbutyl Ithiazol-4-ylcarbonyl]-N'- rN-(4-pyridinyhnethoxycarbonyl)-Lleucinyllhydrazide, the title compound was prepared as a white powder (0.766 g, MS(ESI): 439.3 b) N-f 2-(2-benzyloxyphenyl )thiazolA4-ylcarbonyl]-N-[N-(2-pyrazinylcarbonyl 9 leucinyllhydrazide Following the procedure of Example 116(b), except substituting benzyloxypheny)thiazol4ylcarbony]N'.(Lleucinyl)hydrazde for [Nphenyl-N-(2-methyl- 1 -propyl)arrino]thiazol-4-ylcarbonyllhydrazide and pyrazinecarboxylic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid 146 g, MS(ESI): 545.4 178 Example 177 Preparation of N-[2-(2-benzvloxvp~henyl)thiazol-4-vlcarbonyll-N'-(N-isonicotinovl- L-leucinvl )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 135 g, MS(ESD): 544.3 (M+H) t Example 178 Preparation of N-F2-(2-diberizofuranvl)thiazol-4.-ylcarbonyll-N'- N-(4pyridinylmethoxvcarbonyl )-L-leucinyllhydrazide ~:Following the procedure of Example 1 12(a)- I 12(g), except substituting 2bromodibenzofuran for 2-benzyloxybromobenzene in step the title compound was prepared as a white solid (0.079 g, MS(ESI): 558.3 Example 179 Preparation of N- r2-rN-(2-methylpropyvn-N-phenylanminolthiazol-4-ylcarbonl 1-N'- (N-pyrazinecarbonyl-L-leucinyl)hydrazide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-tert-butoxycarbonyl-L-leucinyl)-N'- [N-(2-methyipropyl)-Nphenylaminolthiazol-4-ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyll-N'-(N-terr-butoxycarbonyl-L-leucinyl)hydrazide--in step the title compound was prepared as a white solid (36 mg, MS (ESI): 510.4 ~Prlaration of N- [2-r-(2-methylgpmpyl)-N-phenvl-arrnolthiazol4ycarbonyll-N'- (N-methyl-N-1pyrazinecarbonyl-L-leucinyl~hydrazide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-terr-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2- (N-(2-methylpropyl)-Nphenylamlinolthiazol-4-ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-.L-leucinyl)hydrazide in step the title compound was prepared as a white solid (70 mg, MS (ESI): 524.4 179 Example 181 Preparation of N-(N-isonicotinoy1-Leucinl)N.f2f[N.(2-methvrop Vl)-N p2henyl amino Ithiazol -4-ylcarbonyl 1hydrazide Following the procedure of Example 176(a)-lI76(b), except substituting

N-

(N-tert-butoxycarbony[-Nmethyl.Lleucinyl).N'.[2- [N-(2-methylpropyl).N phenylamino~thiazoI-4ylcaronyljhydrazide for N-[2-(2-benzyloxypbenyl)thjazol 4-labnl-'(-etbtxyabnlLluiy~yrzd in step and isonicotinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (28 mug, MS (ESI): 509.4 *Example 182 Preparation of N(-snctny--ehlLtuiy)N-2[-2 :methylp~ropyl )-N-phenylaminothazoI.4lcarnyIlhydrazide :15 Following the procedure of Example 176(a)-i 176(b), except substituting N- (Nmty--erbtxcron Nmty--ecnl-'[2- methylpropyl)-Nphenyainojtifzo4ylcarbonyl]hydazide for N- benzyloxyphenyl)thiazol-4ylcarb-onylI..N'-(N-ter.pbutoxycarbonyl-j- Ieucinyl)hydrazide in step and isonicotinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (117 rmg, MS (ESI): 523.4 Example 183 Preparation of N-fN-(4-irmidazolylacetvl)-L-leucinyl rN-(2-methvlpropv)L -Np2henyl amino Ithi azol-4-yIc arbonyl lhydrazide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2- [N-(2-methylpropyl)-Nphenyl amino]thiazol-4-.ylcarbonyll]hydrazide for N-[ 2 -(2-benzyloxypheny)thiazo- 4-ylcarbanylj-N'-(N-terr-butoxycarbonyl-L-eucinyl)hydrazide in step and 4imidazolylacetic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (60 mg, IHNMR (400MIHz, CDC1 3 5 7.62-7.23 (in, 8H), 6.81 IH), 4.72-4.66 (in, lH), 3.75 IN), 3.55 2H), 1.96-1.93 (in, 2H), 1.76-1.54 (in, 0.96-0.84 (in, 12H).

Example 184 Preparation of N-[2-[N-(2-methyipropyl)-N-p2henylaminolthiazol-4-ylcarbonyl bN'- (N-p2icolinoyl-L-Ieucinyl)hydrazide Following the procedure of Example 176(a)-I 76(b), except substituting N- (N-tert-butoxycarbonyl-N-inethyl-L-leucinyl)-N'- [2-[N-(2-methylpropyl)-Nphenyl amino] thiazol-4-yicarbonyl] hydrazide for N- (2-(2-beazyloxyphenyl)thiazol- 4-ylcarbonylJ-Ni-(P4-ter-utoxyca1Tuony-L-eucmyfl~yIda i teu()cn picolinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (50 mug, MS (ESI): 509.5 Exml 185-V Preparation of N-[2-(2-benzyloxyphenylthiazol-4-ylcarbonyllrnethyI rN-(4pyridinylmethoxycarbonyl)-L-leucinamide a) 2-(2-benzyloxyphenykthiazole-4-carboxylic acid Following the procedure of Example 105(b), except substituting ethyl 2-(2benzyloxyphenyl)thiazole-4-carboxylate for methyl 3-(4pyridinyllmethoxy)benzoate, the title compound was prepared as a white solid (0.361 g, MS(ESI): 3*12.2 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-Leucinvl-L- Leucine, the title compound was prepared as a white solid (0.327 g, 73%).

MS(ESI): 388.2 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 15 g, MS(ESI): 373.3 d) 2-azido-1-[2-(2-benzyloxyphenyl)thiazol-4-yl]- I-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

o (400MHz, CDCI 3 88.41 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- l-[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 residue was purified by column chromatography (silica gel.

methano dichioromethane) to yield the title compound as a white solid (0.07 MS(ESI): 327.3 f) 1-[ 2 2 -benzyloxyphenyl)thiazol-4-yl) -hydroxy-2-(4pyridinylmethoxycaonyl -L-leucinylamino)ethane Following the procedure of Example 116(b), except substituting 2-amino-I 2 2 -benzyloxyphenyl)thiazol-4-yl]- 1 -hydroxyethane for N-[2-[N-phenyl-N-(2.

methyl- I -propyl)aminolthiazo -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 mmol) in dichloromethane (1 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, methano/dichloromethane) to yield the title compound as a pale yellow solid (0.0 17 g, MS(ESI): 573.4(M+H)+ Exgmple 186 Preparation of N-f 2 -rN-methvl-N-(2-methvylropyl amnolthiazol-4-ylcarbonyl fN-( 4 -yridinylmethoxcarbonyl)-L-leucinv1hvdrazide a) N-benzoyl-N'-methyl-N'(2-methylpopyl) To a stirring solution of N-methyliso'butylamine (3.21 g, 36.8 mnol, 4.45 mL) in 40 ml of CHC1 3 was added benzoyl 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%). lHNNR(400MHz, CDCl 3 2:1 mixture of rotamers) 8 7.86 2H), 7.60 IH). 7.50 2H), 3.90 2H), 3.44 (s, 3H), 3.41 2H), 3.27 3H), 2.35-2.32 1H), 2.13 LH), 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 (1 5 .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]thiazol-4-ylcarbonyl]..N'[N-(4 pyridinylmethoxycarbonyl)-L-leucinyl Ihydrazide Following the procedure of Example 113(d)-i 13(f), except substituting N- :methyl-N-(2-methylpropyl)thiourea for N-(4-phenylphenyl)-N-(2-methyl- 1- 15 propyl)thiourea in step the title compound was prepared as a white solid (202 mg, MS(ESI): 477.4 Example 187 Preparation of N-(N-methvl-N-picolinovl-L-leucinl)-N'-r2-fN-2-methlprol)-N phenylan-inolthiazol4-vlcarbonyllhydrazide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-methyl-N-tert-butoxycarbonyl-N-methyl-Lleucinyl).N'42 rethylpropyI)-N-phenylaminolthiazol-4.ycarbonyl]hydrazide for benzyloxypheny1)thiazol-4ylcarbonyl] ert-butoxycarbonyl-Lleucinyl)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-r2-(2-benzvloxyphenyl)thiazol-4-vlcarbonyl PN'-FN-'2pyridinesulfonvl)-L-1eucinyl lhydrazide a) 2-pyridinesulfonylchloiide Through a stirring solution of 2-mercaptopyridine (2.235 g, 20 nimol) in water (7.5 mnL) and concentrated HCI (26 mL) at 0 0(2 was bubbled Cl 2 After 75 rnL 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-(2-benzyloxyphenyl)ttiiazol-4-ylcarbonyll-N'-[N-(2-pyridinesulfonyl)-Lleucinyl]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, 0.571 rnmol) in dichloromethane (2 mL) was added N-methylmnorpholine (0.057 g, 0.571 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 100 g, 6 1 MS(ESI): 580.2 Preparation of N- F2-[N-(2-methylpropyfl-N-phenylaminolthiazol-4-ylcarbonyll-N'- FN-(2-pRiddinesulfonyl)-L-leucinyllhvdrazide Following the procedure of Example 188(b), except substituting N-(Lleucinyl)-N'- [2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4ylcarbonyllhydrazide 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(-ehyIpoy)Npey mn h r INi-mrethyLLN-(2 -pri dines ulfort l Ie uci nyl Ihydrazide Following the procedure of Example 188(b), except substituting

N-(N-

methyl-Lleucinyl)N'[2[N(2methypropyl)Nphenyanoiazoylcarbonyljhydrazide for N- 2 2 -benzyloxyphenyl)thiazol-4ylcarbonyll N' (jleucinyl)hydrazide, the title compound was prepared as an orange solid (53 mg, MS (ESI): 559.3 Example 191 Preparation of N-r2- rN-methlN(2methlpropvIj)anolthiazol-4vycarbonyll-N rN-( 3 -pvridinvlmethoxyvcarbonyl )-L-leucinvjlhydazjde 7I~ iecineFollowing the procedure of Example 186(a)- I86(c), except substituting N- 3 -pyridinylxnethoxycarbonyl).L.leucine for N-( 4 -pyridinylmethoxycarjbonyl)>L lecinein step the title compound was prepared as a white solid (138 mg, 66%).

MS (ESI): 477.4 Example 192 Preparation of N-2[-2mtylrpl--hnlmnihao--iabnl-' I N-methyl-N-(4- dmletov.~,v~lucinyl ihydrazide Following the procedure of Example 116(a)-i 16(b), except substituting

N-

methyl-N-(4-pyrdinylmethoxycarboIny)Lleucine for N-(4pyrldinylxnethoxycarbonyl)-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- r2- rN-(2-methvlpropvyl)-N-phenvlamrinolthiazol-4-vlcarbonvl 1-N'rN-methyl-N-(3-pyridinylmethoxycarbonvl )-L-leucinyllhydrazide Following the procedure of Example 116(a)- I 16(b), except substituting Nmethyl-N-(3-pyridinylmethoxycarbonyl)-L-leucine for N-(4pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid solid (50 mg, MS (BSD: 553.4 Example 194 Preparation of N-r2-(2-benzyloxyphenflthiazol-4-ylcarbonyll-N'-rN-methvl-N-(3pvyridinvlmethoxycarbonyfl-L-Ieucinyllhydrazide Following the procedure of Example 112(a)-I 12(g), except substituting N- :methyl-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 Preparation of N-rN-methyl-N-(4-pyridinylmethoxycarboflyl)-L-leucinll-N'-[2-( 1naphthyl'Ithiazol-4-vlcarbonyllhydrazide Following the procedure of Example 112(a)- I 12(g), except substituting 1naphthyl boromic acid for 2-benzyloxyphenyl boronic acid in step-(e) and N-methyl- N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pynidinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (0.072 g, 36%).

MS(ESD: 532.4 r4 EampIe 196 Preparation of N-2[.-bs--eh -Manoh 4ycroylN-N (4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 186(a)-186(c), except substituting N,Ndiisobutylamine for N-methylisobutylaxnine in step the title compound was prepared as a yellow solid (60 mg, MS (ESI): 519.5 Example 197 Preparation of N-(N-benzloxycarbony-L-leucinyl)-N'-f2.jN4b).2methylpropyl) )anolthiazol-4-ylcarbonyll hydrazide Following the procedure of Example 186(a)-1I86(c), except substituting

N,N-

diisobutylaznjne for N-methylisobutylarnine in step and N-benzyloxyca.jonyl.Lleucine for N-4prdnlehxcroy)--ecn in the final step, the title compound was prepared as a yellow solid (131 mg, MS (ESI): 518.4 Example 198 Preparation of N-F 2 -(4-mo~holino)thiazol.4.ylcarbonvI -N'-rN(4 pry-dinvlmethoxvcarbonyl )-L-Ieucinyllhydrazide :Following the procedure of Example 186(a)-i 186(c), except substituting 15 morpholine for N-methylisobutylamine in step the title compound was prepared as a white solid (45 mg, 3 1 MS (ESI): 477.3 Example 199 Preparation of N-r 2 -r 2 -(4:pyridinylmethoxy)p2henvl 'Aiazol-4-vlcarbonyll-N'N-(4pvnrdinylmethoxycarbonyl)-.Lleucinyjhvcfr-a-de a) 2 -methoxymethoxybromolezne To a stirring suspension of sodium hydride (1.2 g, 52.1 mnmol, p dispersion in mineral oil) in DMF (75 m.L) at 0 *C was added 2-bromophenol (6.0 g, 34.7 mmol) dropwise. After stirring for 20 min, broniomethyl methyl ether (4.3 g, 34.7 minol) was added. After stirring for 16 4i at room temperature, the mixture was poured into water (250 m.L) and extracted with hexane. The organic layer was washed with brine, 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 (4.0 g, IH4NflR (400M~z, CDCl 3 8 7.55 IH), 7.28 (t, IH), 7.16 1H), 6.91 1H), 5.25 2H), 3.54 3H-).

b) ethyl 2 -(2-methoxymethoxyphenyl)thiazole.4-carboxvare Following the procedure of Example 11I2(a)- I 12(b) and I1I2(d)-Il 12(e), except substituting 2-methoxymethoxybromobenzene for 2benzyloxybromobeazene in step the title compound was prepared. MS(ESI): 294.3 c) ethyl 2-(2-hydroxyphenyl)thiazole-4-carboxylate To a stir-ring solution of the compound of Example 199(b) (0.839 g, 2.86 mmnol) in ethanol (25 m1L) was added 10 drops of concentrated hydrochloric acid.

After stirring at reflux, for 2 h the solution was concentrated then redissolved in ~:ethyl acetate. The solution was washed successively with saturated sodium bicarbonate, and brine, dried (MgSO 4 filtered and concentrated to yield the title compound as a pale yellow solid (0.674 g, MS(ESI): 250.2 d)ehl*[-4prdlehxypeylhaoe-abxlt ty -4-pyridylmthoxy0.071 l0.653azole.-4-an rboxylpbshie(0e71g 0.653 mmol) in THEF (5 ml) at 0 0 C was added diisopropyl azodicarboxylate 132 g, 0.653 mnxol) dropwise. After stirring at room temperature for 16 h, the solution was concentrated and purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.1IOU g, 59%).

MS(ESI): 341.3 e) N- 2 2 4 -pyridinyixnethoxy)phenyl]thiazo14-ylcarbonyl]N'-[N(4.

pyridinylmethoxycarbonyl)-L-leuciny1]hydizide Following the procedure of Example I11 2 112(g), except substituting ethyl 2 2 -(4-pyridylmethoxy)phenyl]thiazole4-carboxylate for ethyl 2-(2benzyloxyphenyl)thiazole-4-cartboxylate in step the title compound was prepared as a white solid (146 mg, MS(ESI): 575.4 Example 200 Preparation of N-r2-(2-naphthl)thiazol-4-lcarbonvll-N'N(4 pvridinlmethoxvcarbonvl )-L-leucinvllhvdrazide Following the procedure of Example 112(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-r2-N.N(bis)-2-methylpropl)aminolthiazoI.4.ylcarbonyl

N-

methyl-N-(4-pyridinlmethoxycarbony)-L-leucinvl hvdrazide Following the procedure of Example 186(a)-I86(c), except substituting N,Ndilsobutylamine for N-methylisobutylamine in step and N-methyl-N-(4pyridinylmcthoxycarbonyl).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(M+H)+.

Example 202 Preparation of N-(N-benzvloxvcarbonvl-L-leucinl)-N'.r2-(4-momholino)thazo1-4-.

vlcarbonyllhydrazide Following the procedure of Example 186(a)- 186(c), except substituting morpholine for N-methylisobutylamine in step and N-benzyloxycarbonyl-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-1N-(4-pvyridinvlmethoxycarbonyl )-L-ieucinyI 1-N-f2 -4thiomorpholino)thiazol-4-ylcarbonyl ihydrazide Following the procedure of Example 186(a)- 186(c), except substituting thiomorpholine for N-methylisobutylanune in step the title compound was prepared as a white solid (35 mg, MS (ESI): 493.4 Preparation of N-CN-benzloxycarbonyl-L-Ieucinyl)-N'-r2-(4thiomo[Rholino'thiazo[-4-ylcarbonyllhydrazide Following the procedure of Example 186(a)- I 86(c), except substituting thiornorpholine for N-methylisobutylamine in step and N-ben~tyloxycarbonyl-L- :::.leucine for N-(4-pyridinylmethoxycarbonyl)-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-[2-(2.3-ethylenedioxv-4methoxyhenflthiazol4I..vcarbonvi rN-(4-pvridinylmethoxycarbonyl '-L-leucinyllhydrazide Following the procedure of Example 112(a)-i I except substituting 2,3ethylenedioxy-4methoxybromobenzene for 2-benzyloxybromobenzene in step the title compound was prepared as a white solid (31 mg, MS (ESI): 556.4 Example 206 Preparation of FN.N-(bis)-2-methlpcypl)anino1 thiazol-4-ylcarbonylI-N-

[N-

methyl-N-(3-pRyidinylmethoxycarbonfl-L-leucinyllhydrazide Following the procedure of Example 186(a)-186(c), except substituting N.Ndiisobutylamine for N-methylisobutylamine in step and N-methyl-N-(3pyridin'ylmethoxycarbonyl)-L-leucine for N-(4-pyridinylrnethoxycarbonyl)-Lleucine in the final step, the title compound was prepared as a yellow solid (30 mg, MS (ESI): 533.5 Example 207 Preparation of N- f 2 -(N-cyclopropylmethyl-N-propvl amino)thi zoI-4-Ylcaron vi N'-fN-(4-pvnidinlmethoxvcarbonvl).Lleucinyl lhydrazide Following the procedure of Example 186(a)- 1 86(c), except substituting Ncyclopropyixnethylpropylainine for N-methylisobutylamine in step the title compound was prepared as a yellow solid (60 mg, MS (ESI): 503.3 Preparation of N-rN-(4-pvyridinylmethoxvcarbonl).L..eucinvllvN'.r2.(8 guinolyl)thiazo]4vlcarbonyllhydrazide Following the procedure of Example 11 2(a)AI 12(g), except substituting 8bromoquinoline for 2-benzyloxybromobenzene in step the title compound was 15 prepared as a white solid (134 rug, MS (ESI): 519.3 *Preparation of N-Nmty--4pdiymtoyabnl--ecnl-'f-8 guinolvflthiazol-4-lcarbonyl1 hydrazide Following the procedure of Example I I12(a)-l except substituting 8bromoquinoline for 2 -benzyloxybromobenzene in step and N.-iethyl-N-(4pyridinylmethoxycarbonyl)-L-.leucine for N-(4-pyridinylmethoxycarbonyl)-L leucine in step the title compound was prepared as a white solid (53 mug, 22%).

MS (ESI): 533.3 Example 2 Preparation of I -N-(N-Cbz-leucinyl )-amino-3-N-(4-biphenyl-sulfonyl )-amjno.

propan-2-one a) 4-biphenyl sulfonyl chloride 4-Biphenyl sulfonic acid (2.4 g, l0,mmol) was heated to 100 C with phosphorus pentachloride (2.1 g, 10 mimol) 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)-anino-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)-phenyl sulfonyl chloride", 15 the title compound was prepared: MS(ES) *Preparation of 1 N-Cbz-leucinyl)-amino-3-N-(3-biphenyl-sulfonyl)-amiinop2ropan-2-one 6% 0 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 rnmol) 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 further purification.

b) 1 N-Cbz-leucinyl)-amnino-3-N-(3-biphenyl-sulfonyl)-amino-propan-2 -one Following the procedure of Example 5 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-Ieucinyl)-amino-3-N-(2-benzyloxv-phenyl-sulfonvl)amino-propan-2-one a) 2-benzyloxy-phenyl-sulfonyl chloride Following the procedure of Example 2 11 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 -ecnl-mn--N(-ezlx-hnisufnl-mn-rpn 2-one Following the procedure of Example 51I(a), except substituting "2benzyloxy phenyl sulfonyl chloride for 4 3 -Chloro-2-cyano-phenoxy)-pheny *sulfonyl chloride", the title compound was prepared: MS(ES) 581, M+Na'= 604,2M+Na*= 1185.

Example 213 Preparation of 1 N-Cbz-eucinl)-amino-3-N-(4-phenoxv-phenyl-sulfonvl)amino-prop~an-2-one a) 4-phenoxy-phenyl-sulfonyl chloride Following the procedure of Example 211I(a), 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-phenoxy-phenyl.sulfonyl).amnopropan-2.

one Following the procedure of Example 5 except substituting "4-phenoxyphenyl-sulfonyl chloride for -Chloro-2-.cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M+W= 568, M+Na'= 590.

Example 214 Preparation of 1 N-Cbz-Ieucinyl )-amino-3-N-(2-dibenzofuran-sulfonyl )-aminop2rop~an-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)-amnino-propan-2one Following the procedure of Example 51(a), except substituting "4-phenoxy phenyl sulfonyl chloride for '4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+W= 566, M+Na*= 588.

Exmple 215 Preparation of 1 N-Cbz-Ieucinfl)-amino-3-N-(3 .4-dimethoxv-phenvl- sulfonyl)ano-propan-2-one Following the procedure of Example 5 1, except substituting "3,4diinethoxy-phenyl-sulfonyl chloride for "4-(3-Cbloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+Wr= 536, M+NHL*= 553.

Preparation of 1 N-Cbz-leucinyl)-amino-3-N-(2.5-dichlorothiophene-3sulfonyl)-amnoprpn-2-one Following the procedure of Example 5 1, except substituting dichiorothiophene-3-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M+NH 4 567, 2M+W'= 110 1.

Example 2 17 Preparation of I N-b-ecni-mn---1hev-u ln--tipee2 sulfonvi iprpa-2-one Following the procedure of Example 5 1, except substituting phenyl sulfone-5-tijophene-2-sulfonyl chloride for 4 3 -Chloro- 2 -cyano-phenoxyy.

phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+If= 622.

Preparation of 1 N-Cbz-leucinyI)-arnino-3-N-(8:quinolIneufnI)ai prolpan-2-one Following the procedure of Example 51, except substituting 8 -quinolinesulfonyl chloride for 4 -(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) 527.

*15. Example 219 *Preparation of I N-Cbz-leucinl)-arnhino-3-N-(2pvndyl-sulfonyl )-arrunop~ropan-2-one Following the procedure of Example 51, 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+I-C= 477, M+ Na+ 499.

Example 220 Prep~aration of 1-N-C N-Cbz-ieucinvl )-amino-3-N-(2-pvyridyl-siulfonYl )-an'jno.

prop~an-2-one a) l-N-(N-Cbzeuciny)anino3N(4..phenoxy.phenyl.sufonyl)Thnno-proparn- 2 01 1,3-Diamino propan-2-oI (6.75 g, 75 rnmol) was dissolved in DMF (l(Omrrl) and Cbz-leucine (20g, 75.5 mnrol), HOBT-hydrate (1 I g, 81.5 mmol), and EDCI (I15.5g, 81.2 mxnol) were added. The reaction was stirred overnight at RT. A portion of the reaction mixture (30 ml) was concentrated in vacua, then ether ml) and MeOH (30 ml) were added. A IN solution of hydrochloric acid in ether was added (I M, 30 ml) and a white gumi 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 DMFf (25 ml) and DIEA (Srnl), then 4phenoxy phenyl sulfonyl chloride was added. The reaction was stirred for 2h, .15 concentrated in vacua, then chromatographed (silica gel, 1: 1 EtOAc: hexanes) to provide the desired product as a white solid.

b) .ecnlaio3N(-hnx hey ufnl-mn-rpn2 b) LNb-eucinyl)-amino-3N..(4..phenoxy-phenyl sulfonyl)-amino-propan- 2-al (1.0g, 1.8 mmol) was dissolved in EtOH (30 rol), then 10% Pd/C (0.22g) was added followed by 6N hydrochloric acid (2.5 nil), and the reactiory 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).anmino-3-N(4-phenoxyphenyl.sulfonyl).

amino-propan-2-ol Leucinyl-amino.3N(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 nimol) was added followed by 4-pyridyl acetic acid 13g, 0.75 mmol) and HBTU (0.29g, 0.76 irnol) and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then chrornatographed (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 acetyI-1euciny1)-aniino-3-N-(4..phenoxy-phenyl..sulfonyl)amino-propan-2-one I N4prdlaey-ecnlamo---4phnx-hnlsloy)amino-propan-2-ol (45 mrg, 0.08 mmol) was dissolved in acetone (5mil), then IN hydrochloric acid (2 mld) 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 :0:0 ~buffer and then was extracted with EtOAc, dried with magnesium sulfate, filtered, 0000 concentrated in vacuo, then chromatographed (silica gel, 5% MeOH-methylene 0* 15 chloride) to give the desired product as a white solid (27 mg, MS(ES): M+H+ 553.

Example 221 Preparation of I N- 2 -pvyridyl-sulfonyl-leucinyl)an-ino-3.N-(4-henov.

phenyl-sulfonlY..amino-p2ropan.2.one Following the procedure of Example except substituting "2- :pyridyl-sulfonyl chloride" (as described in J. Org. Chem. 1989, 54, 392) for "4pyridyl-acetic acid and HBTU", the title compound was prepared: MS(ES) M+I-U= 475, M+ Na+ 497, 2M+ Na+ 117 1.

Example 222 Preparation o-f -N-tN-morpholino-carbonyl-. eucinyl)-amino-3-N-(4p1henoxv..

p-henyl-sulfonvn...amiuno-.propan.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+ 569, 2M+ Na+ 1115.

Example 223 Preparation of 1 -N-(-N-4-pyridyl-carbonyl-leucinyl )-ami~no-3-N-(4-phenoxyp2henvil-sulfonvi )-amiino- 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+FE= 539.

Example 224 Preparation of I N-acetyl-Ieucinyl')-amaino-3-N-(4-phenoxy-phenvl-sulfonyl)aniino-prop~an-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 1 N-im-idazole aceryl-leucinyl)-amino-3-N-(4-p2henoxy-phenylsulfonyvh- mn-rpn-2-one Following the procedure of Example except substituting .20 "imidazole acetic acid" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) 542.

ExampJe226 Preparation of Il-N-( N-4-carboxymethyl benzoyl-leucinyl)-anino-3-N-(4-phenoxyphenyl-sulfonyfl-amino-propan-2-one 't 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 Il-N-( N-(N.N-dimethyl jzyiy)luiy)afio3N(zhnx phe nyl -su Ifonyl)-am no propa 2-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+W= 519.

Example 228 Preparation of I N- qunln slfnmd ecinl-aio -Ia~oy p2henyI-sulfonv!L?-aminoptropa..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) 625.

0 000 0 000* 00 0 0000 00 0 0* 00 00 0 0* 0 0000 0 0000 0000 00 0 000000 0 200 Example 229 Preparation of I N-Cbz-leucinvl)-anino-3-N-(8-guinoine-carbonl)-anjnoprolpan-2-one 1,3-Diamino propan-2-ol (6.75 g, 75 minol) was dissolved in DMP (lO0mI) and Cbz-leucine (20g, 75.5 minol), HOBT-hydrate (I I 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 DMIF (3 ml) and NMM (0.33na1. 0.3 0000*mmol). then 8-quinoline carboxylic acid 17g, 1.0 nimol), and HBTU 38g, go 0.1 mol) were added and the reaction was stirred at RT overnight. The reaction 15 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 mijxture eec. was concentrated in vacua. The reaction was diluted with pH 7 buffer and then was extracted with EtOAc, dried with magnesium sulfate,'filtered, concentrated in vacuo, then chromatographed (silca gel, 5% MeOH-methylene chloride) to give the C:...:desired product as a white solid (23 mg, MS(ES): M+H 4 491.

Preparation of N-Cbz-leucinyfl-amirno-3-N-(6-guinoline-carbonyl)-anmino- Following the procedure of Example 229, except substituting "6-quinolinecarboxylic acid" for '8-quinoline carboxylic acid the title compound was prepared: MS(ES) M 49 1.

Example 231 Preparation of 1 N-Cbz-1eucinyI)-arnino-3-N-(2-(4-biphenvI)-4methv..

p2ropanarnide)-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) 586, M+ Na+ 608, 2M+ Na+ 1193.

Example 232 Preparation o1-N-( N-Cbz-Ieucinyl)-arnino-3-N-(

N-

4 -pyridyl-methyleneoxy carbonvl-leucinvl)-amino-prop~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) 584.

Example 233 Preparation of I N-Cbz-leucinyl )-amino-3-N-(benzoyl'-)nn-poan-2-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+FE= 440, M+ Na+ 462, 2M+ Na+ 901.

Example 234 *.PReparation of 1 N-Cbz-eucinv1)-amino-3-N-(2.4-dimethyl3sulfonyl)-amino Following the procedure of Example 5 1, except substituting "2,4-dimethyl- 3-sulfonyl chloride" for 4 -(3-Ch~oro-2-cyano.phenoxy)-pienyI sulfonyl chloride", the title compound was prepared: MS(ES) M 494.

202 Example 235 Preparation of I N-(N-Cbz-leucinyl')-anhino-3-N-( 1.3--di methvl-5-chloro- pyrazole- 4-sulfonyl)-amino-propan-2-ofle Following the procedure of Example 51, except substituting 1,3-dimethyl-.

5-chloro- pyrazole-4-sulfonyl chloride" for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) 494.

Example 236 Preparation of 1 -N-(N=4:.pyrdyI-rethleleoxy carbonvl-leucinyvh-arrino-3-N-(4p2henoxy-phenl-sulfonl)-amlifo-pro~afl- 2 -ofl :Following the procedure of Example 213(a), except substituting "4-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) M+Wr= 569.

Exmple 237 Preparation of N-3-pvridyl-methyleneoxy carbonyl-Ieucinfl)-amino-3-N-( 4 ~phenoxy-phenyl-sulfony')-arruno-popaf- 2 Ofl 6% Following the procedure of Example 213(a), except substituting "3-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) M+Wr= 569.

EamRe 238 Preparation of I N--~~y-ehlnoycronlluiy)ain---4 phenoxy-phenyl-sulfonyI)-amnino-propal- 2 -ofle Following the procedure of Example 213(a), except substituting "2-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucmne", the title compound was prepared: MS(ES) M+Wr= 569.

203 Example 239 Preparation of I N-4-carboxv-benzovl-leucinvl )-amino-3-N-(4-phenoxvphenvl-sulfonvl )-amino-propan-2-one I -N-(4-carboxy methyl-benzoyl-leucinyl )-amrino- 3 4 -phenoxy.phenyl.

sulfonyl)-amino-propan-2-one 105g, 0. 176 mol) was dissolved in MeOH (5 ml) and water (I ml), then LiOH-hydrate (15 mg, 0.35 mnrol) was added and the reaction was stirred at RT for Ilh. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml), 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 1 N-Me-N-Cbz-leucinvl )-amniino- 3 -N-(4-p2henoxy-p2henvlsulfonyfi-amino-.propan-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) M+W= 582, M+ Na+ =604, 2M+ Na+ 1185.

Example 241 Preparation of I 4-henoxy benzoi)-amino-3-N(4-phenoxy.pheny[. sulfonvi)- Following the procedure of Example 2 13(a), except "4-phenoxy benzoic acid "for Cbz-Ieucine", the title compound was prepared: MS(ES) 517, M+ Na 539, 2M+Na+ =1055.

204 Example 242 Preparation of I -N-(3-phenoxv-benzovl )-amino-3-N-(4-phenoxy-p2henvl- sulfonyl ari no-12rop~an-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+W= 517, M+ Na+ 539,,2M+ Na+ 1055.

Exampl43 Preparation of I -N-(4-phenoxy benzofl)-anino-3-N-(4-phenoxy-phenvl- sulfonvi amino-p2rop~an-2-one **Following the procedure of Example 213(a), except "4-phenoxy benzoic acid "for Cbz-leucine", the title compound was prepared: MS(ES) M+W= 517, Mi Na+ 539. 2M+ Na+ 1055, M-H+ 515.

Example 24 Preparation of 1 -N-(4-biphenyl acetyfl-amino-3-N-(4-phenoxy-p2henyl-sulfonvl)amino-Rropan-2-one Following the procedure of Example 213(a), except "4-biphenyl acetic acid "for" Cbz-Ieucine", the title compound was prepared: MS(ES) Mi-W= 515, M+ Na+=537, 2Mi- Na+ 105 1.

Preparation of 1 -N-(2-benzyloxy benzofl)-an-ino-3-N-(4-phenoxy-phenylsulfonyl)-arnino-Rropan-2-one Following the procedure of Example 2 13(a), except "2-benzyloxy- benzoic acid "for Cbz-leucine the title compound was prepared: MS (ES)M 5 31, Mi. Na+ 553, 2Mi. Na+ 1083.

205 Example 246 Preparation of I N-Cbz-leucinyl )-amino-3-N-(4-benzvloxy-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+ 1 113.

Example 247 Preparation of 1 -N-(2-(4-biphenvl )-4-rnethvl-pentaxnido)-3-N-(4-p2henoxv-p2henvl sulfonyl)-amino-propan-2-one Following the procedure of Example 2 13(a), except 2-(4-biphenyl)-4methyl-pentanoic acid for Cbz-leucine", the tidle compound was p repared: MS(ES) M-t-lH= 57 1, M+ Na+ 593.

Eample 248 Preparation of I -N-(2-(3-biphenvl )-4-methvl-pentarrudo)-3-N-(4-phenoxy-phenvlsul fonvi )-amrino-propan- 2-one a) 3-bromo-phenyl methyl acetate 3-Bromo phenyl acetic acid (2.15g, 10 mmol) 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 mmnol) was dissolved in toluene (30 ml). Then, phenyl boromc acid (1 .46g, 12 imol) was added followed by aqueous sodium carbonate (2M, 4.24 ml, 40 inmol), then tetrkis(triphenylphosphine) palladium (0.35g, 0.3 inmol) and was refluxed overnight. The reaction was cooled to RT, diluted with saturated amnmonium 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 15 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 Ihh. Water (2 ml) was added and the THF was removed in vacuo. The reaction was 20 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, 1H), 2.50 (dd, 1H), 1.70 3H).

207 e) 3'-(4-biphenyl)-4-methyl-penranoic acid 3-(4-Biphenyl)-4-methvl-pent-4-enoic acid 1.87 mnmol) was dissolved in EtOAc (25 rnl). 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 ral). 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 yacuo, and chromatographed (silica gel, 5% MeOH: methyl ene chloride) to give the desired product as a white solid (1 .66 g, 93 I1H NMIR: d: 7.6-7.3 (mn, 9H), 3.7 I1H), 2.07-1.95 (in, I1-H), 1.8-1.7 (in, IH), 1.6-1.45 (in, 1H).

l-N-( 2 3 -biphenyl)-4methylpentaido)-3-N-.(4-phenoxy-phenyl-sulfonyi).

amino-propan-2-one Following the procedure of Example 2 13(a), except 3-(4-biphenyl)-4- .*methyl-pentanoic acid for Cbz-Ieucine", the title compound was prepared: MS(ES) 571, M+ Na+ 593.

Example 249 Preparation of I -bip~henyl acetyl-armino-3-N-(4-phenoxy-phenyl-sulfonyl aminopropa-2-one Following the procedure of Example 213(a), except "3-biphenyl acetic acid for" Cbz-leucine", the title compound was prepared: MS(ES) M+H= 515, M+ Na+ 537, 2M+ NaI= 105 1.

208 Example 250 Preparation of 1 N-4-pyridyl, acetvl-leucinyl)-amino-3-N-(2-benzvoxv- phenvi sul fonyl)-ami no-12ropan-2 -one a) 1 -N-(N-Boc-leucinyl)-amrino-3-N-(2-beazyloxy phenyl-sulfonyl)-arnino-propan.

2-ol l,3-Diamino-propan-2-ol (3.375g, 37.5 mimol) was dissolved in DMF ml). Then HOBT-hydrate was added (5.5g, 40.7 rmmol), followed by Boc-L-leucine (9.34g, 37.5 mmol) and EDGI (7.77g, 40.7 mmol). T'he reaction was stirred for 4h, then diluted with DMF to make a stock solution of a total volume of 100 ml (0.375 mmol/ml). The stock solution (18 ml, 6.75 inmol) was treated with NMM (0.89 ml, 7.28 mmol), then 2-benzyloxy phenyl sulfonyl chiloride (1 .9g, 6.72 mrnol). The reaction was stir-red 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)-aniino-propan-2-oI 1I -N-(Boc-leucinyl)-arnino-3-N-(2-benzyloxy phenyl sulfonyl)-arninopropan-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 too. 20 without further purification: MS (ES) M +Wr 450.

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

209 ExampLe 25 1 Preparation of I N-4-pyridyl carbonyl-leucinvb)-amino-3-N-(2-benzloxv.

phenyl-sulfonl-aninop1ropan2one Following the procedure of Example except substituting "4pyridyl carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) 553.

Example 252 Preparation of N-4-imidazole acetic-leucinyvh-anino-3-N-(2-benzvloxvphenyl-sulfonyl)-arnino-propan-2-one Following the procedure of Example except substituting '4- ::~,*:imnidazole, acid" for "4-pyridyl-acetic acid the title compound was prepared: MS(ES) M+Wr= 556.

15 Example 253 @0Preparation of I N.N-dimethyl-glycvl) -leucinvl)-anmino-3-N-(2-benzyloxy.

p2henyl-sulfonyl)-arnino-p2rop~an-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 254 Preparation of N-(N-methyl roll-leucinfl-anino-3-N-(2-benzyloxvphenyl-sulfonyh)-arrino-propan.2one Following the procedure of Example except substituting "Nmethyl proline" for "4-pyridyl acetic acid the title compound was prepared: MS (ES) M 559.

Example 255 Prepxaration of I N-(N-methvl pipridine-4-carbonyl )-leucinyl)-amino-3-N-(2ben-zyloxy-phenv-sulfonl)amino-propan-2-one 210 Following the procedure of Example except substituting "Nmethyl-pipericiine-4-carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) 573.

Example 256 Preparation of 1 N-(N-methyl piperidine-4-cabnfl-leucinl)-amino-3-N-(2dibenzofuran--sulfonyl-amino-propan-2-oflC Following the procedure of Example except substituting "Nmethyl-piperidine-4-carboxylic acid" for "4-pyridyl acetic acid and "2- :10 dibenzofuran sulfonyl chloride" for "2-beazyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M+H7= 557.

:Example 257 Preparation of 1 N-(N-methyl prolfl)-leucinyl)-arnino-3-N-(2-dibenizofuransulfonyl)-axnino-propan-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 543.

Preparation of I N.N-dimethyl 2lycfl-Ieucinyl)-amino-3-N-(-_(2dibenzofuran-sulfonyfl-ain-p an-2-one Following the procedure of Example except substituting N,Ndimethyl glycine for "4-pyridyl acetic acid and "2-dibenzofuran-sulfoflyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) 517.

Example 259 Preparation of N-4-imiudazole acei-ec y)-mn-3 -2-ibnoua sul fon yi)-amino- propan-2 -one Following the procedure- of Example except substituting imidazole acetic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 526.

Example 26 Preparation of N-4-pyridyl cabny luiy)aio- N( d ezfrn sul fonyl )-amino-propan-2-one Following the procedure of Example except substituting "4- *.:pyridyl 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 1 N-4-pvriddl aceyl-leucinl)-anino-3-N2-dibenzofuran..

sul fonyl)-amnino-propan 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) M 55 1.

Example 262 Pemparaton of 1 N4-imidazole-acrll-euciny)-ano3N(2dibnzofuransulfonyI)-amuino-propan-2one Following the procedure of Example 2 except substituting "4im-iidazole-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) 552.

212 Example 263, Preparation of I N-pyrazole-carbonyI-Ieucinyl)-araflo-3-N-(2-dibenzofuran sulfonyl)-arnino-propan-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) M+W= 538.

Example 264 10 Preparation of N-benzoyl-leucinyl)-amino-3-N-(8-guilolile-sulfonyl)-aminop2ropan-2-one Following the procedure of Example except substituting "benzoic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M 497.

Example 265 *Preparation of I N-.-iloobnolluinl-mn---8gioie sulfonyfl-amn rpn-2-one Following the procedure of Example except substituting difluoro-benzoic acid" for "4-pyridyl acetic acid and "8-quinolmie sulfonic acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) Ms-W= 535.

Example 266 Preparation of I N-2.5-difluoro-phenyl acejyl -leucinyfl-amino-3-N-(quinoline-sulfonyl)-ainino-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 suiphonyl chloride" the title compound was prepared: MS(ES) 547.

213 Example 267 Preparation of I N-p2henvl acetvl-leucinyl)-amino-3-N-(8-guinoline-sulfonyl)ami no-prop~an-2-one Following the procedure of Example except substituting "phenyl acetic acid" for "4-pyridyl acetic acid and "8-quinoiine sulfonic acid" for "2benzyloxy phenyl suiphonyl chloride" the title compound was pre pared: MS(ES)-M +HW= 511.

Example 268 Prep~aration of I N-4-pvyridyl acetyl-leucinfl)-amino-3-N-(8-guinoline-0:: sul fonyl)-amino-propan-2 -one 00 Following the procedure of Example except substituting "4pyridyl acetic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 5 12.

Exmple269 Preparation of I N-4-pyridyl carbonyl-Ieucinyl)-arnino-3-N-(8-guinoline- 20 sulfonyl)- rio-rpn-2-one Following the procedure of Example except substituting "4pynidyl 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+W= 498.

214 Example 270 Preparation of I N-4-imidazole acetyl-leucinyl)-amino-3-N-(8-guinolinesulfonvi )-arnino-prolpan-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 sulphonyl chloride" the title compound was prepared: MS(ES) M+W= 501.

Example271 Preparation of I N-3-phenyl propionyl-leucinvl)-amnino-3-N-(8-guinolinesulfonyl)-aniino-p1ropan-2-one a.:.~Following the procedure of Example except substituting "hydrocinnarnic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl. sulphonyl chloride" the title compound was prepared: MS(ES) 525.

Preparation of bis-N.N'-( N-4-pydvyl methyleneoxy carbonyl-Jeuciny)- 1.3-' diamino-propan-2-one 20 Following the procedure of Example 37, except substituting "4-pyridyl- *methyleneoxycrbnyl-eucinyl for "Cbz-leucine" the title compound was prepared: MS(ES) M+W= 585.

Exmple273 Preparation of bis-N.N'-( N-3-Ryd-dyl methyleneoxy-carbonyl-leucinyfl- 1.3diamino-propan-2-one Following the procedure of Example 37, except substituting "3-pyridylmethyieneoxy..carbonyl-leucinyl for "Cbz-leucine" the title compound was prepared: MS(ES) 585.

Example 274 Preparation of- bis-N.N'-( N-2-pyridyl rnethyleneoxy carbonyd-lucinvl)-l.

di arino-p2ERgpa-2-one Following the procedure of Example 37, except substituting "2-pyridylmethyleneoxy-carbonyi-leucinyl for "Cbz-leucine, the title compound was prepared: MS(ES) M+W= 585.

Example 275 Preparation of I N-b-ecnl-mn---(-e~IUbnolg~o 12ropan-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 546.

Example 276 Preparation of I N-b-ecnl-mn---3-ezlx-ezy)ai6 propan-2-one Following the procedure of Example 229, except "3-benzyloxy beazoic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M 546.

Example 277 Preparation-of N-Cbz-leuci ny-l-arino3N(4biphenI..ace~iy) )am'ino-.

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

216 Example 278 Preparation of I N-Cbz-leucinvl )-arnino-3-N-( 2 -carboxvmethvI-thiophene-3 sulfonyl) aiopoan-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-H'=540.

Exam~le279 Preparation of I N-Cbz-leucinvl)-ami no-3-N-methvl-N-( N-Cbz-leucinvl)axino-p2ropan-2-one a) N-(Cbz-leucinyl)-amino-propene N-Cbz-leucine (3.0g, 1 1.3 mnmol) was dissolved in DMF (50 ml), then NMM 12.4 mxnol) was added, followed by allyl amine (0.65g, 0.85 mmol), and HBTU (4.3g, 11.3 mmol) and the reaction was stirred overnight at RT. The reaction was diluted with water, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 40% EtOAc: hexanes): MS(ES) M+Wr= 305.

b) N-(Cbz-leucinyl)-amino..propene oxide N-(Cbz-leucinyl)-amino-propene (2.95g, 9.7 mmol) was dissolved in muethylene chloride (100 ml), then mCPBA (5.0g, 29.1 mnmol) was added and the reaction was stirrd overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 50% EtOAc: hexanes).

c) 1 -N-(Cbz-leucinyl)-amino..3.Nmethy1.amopropan.2.oI N-(Cbz-leucinyl)-amino-propene oxide (400 mg, 1.25 mxnol) was dissolved in isopropanol (5 mil), then aqueous methyl amnine (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-leucinvl)-arnino-3-N-methvl-N-i N-CZbz-leucinyl)-arnino-propan-.> one Following the procedure of Example 229(a), except substituting "1I -N-(Cbzleucinyl)-an-Lino-3-N-rnethyl-amino-propan-2-oI for 8 -quinoline carboxylic acid ",the title compound was prepared: MS(ES) M 597.

Example 280 Preparation of Il-N-( N-Cbz-Ieucinvl)-amino-3-N-methvl-N-( N-4-pvyridlmethyloxy-carbonyl-leucinyl )-amino-propan-2-one Following the procedure of Example except substituting "4- Pyridyl-methyleneoxy-carbonyl leucine for "Cbz-leucine" in the title **.compound was prepared: MS(ES) 598.

Example 281 Preparation of I N-Cbz-leucinvI)-arnino-3-N-methyl-N-(2-dibenzofuransul fonv y)-amino-prop~an- 2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for "Cbz-leucine and HBTU" in the tidle compound was prepared: MS(ES) M+Wr=580, M+ Na+ 602.

Example 282 Preparation of I1-N- methyl- I- N-Cbz-leucinyl-amino-3- N-(2-dibenzofuransulfonyl)-amnoprpn-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 I methyl- I N-Cbz-leucinfl)-amino-3- N-(2-dibenzofuransulfonvi )-amino-propan- 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-Ieucine in step the title compound was prepared: MS(ES) M+W=580.

Exml 284 :10 Preparation of 1 -N-(2-dibenzofuran sulfonyl)-N-methyfl- amino-3Nm(N-4-p2yridyl methyleneoxv carbonvl-leucinyl)-amino-propan-2-one pyidylFollowing the procedure of Example except substituting "4- *:dy methyl amine" for "allyl amine" and "2-dibenzoftiran sulfonyl chloride" for "N-Cbz-leucine" in step and N-4-pyridyl methyleneoxy carbonyl -leucinyl for 'N-Cbz-Ieucine and HBTU in step the title compound was prepared: MS(ES) M+H=58 1.

Example 285 Preparation-of N-Cbz-leucinfl-amino-3-N-( 4-pydvl-methvlene)-3N-( N- 20 Cbz-leucinfl-amino-propan-2-one Following the procedure of Example except substituting "4pyridyl. methyl amine for "methyl amin6" the title compound was prepared: MS(ES) M+W= 674.

-l28 Preparation of I -N-(Cbz-leucinyl)-amino-3-N-(4-pyidyl-methylene)-3N-( 2 dibenzofuran sulfonyfl-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+W*=657.

219 Example 287 Preparation of 1 -N-(Cbz-leucinvl )-arnino-3-N-(4-pvyridyl-methylene dibenzofuran sulfonvi )-amn-propn-2-one Following the procedure of Example except substituting"2 dibenzofuran sulfonyl chloride "Cbz-leucine and HBTU" in step the title compound was prepared: MS(ES) M+W=657.

Example 288 Preparation of I -N-(4-biphenyl aceryl)-amino-3-N-(4-pvyridyl-methvlene)-3N-( N- Cbz-leucinyl')-amino-p2ropan-2-one Following the procedure of Example except substituting "4biphenyl acetic acid for "Cbz-leucine in step "4-pyridyl methyl amine "for methyl amine", the title compound was prepared: MS(ES) M+W*=62 1.

Example 289 650*Preparation of 1 -N-(4-phenoxy-benzofl)-amino-3-N-(4-pvyridyl-methylene)-3N-( N- Cbz-leucinfl)-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) M+W* 623.

00 Example 290 Preparation of 1 -N-(2-dibenzofuran-sulfonyfl)-aino-3-N-(4-pvridvl-methylene)- 3N-( N-Cbz-leucinyl)-aTmino-propan-2-one Folowing the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for "Cbz-leucine and HBTU" in step "4-pyridyl methyl amine" for "methyl amine", the title compound was prepared: MS(ES) 657.

220 Example 291 Preparation of I N-3prdlmtveex-abnlluiv )ano-3-Nmethvi-N..(2-dibenzofuran-su fonyI)-arr-ino-propan- 2 -onle Following the procedure of Example except substituting "Nmethyl-N-allyl amine for "allyl amine" in and "3-pyridyl-methyleneoxvcarbonyl-leucine" for "Cbz-leucine" in step the title compound was prepared: MS(ES) M+W= 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 0..06,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.

too.

Claims (17)

1. A compound of Formula VII wherein: H 0 N 0 0 0 HH1_ 3 6 0rf-

4. 9 4S* 9 .9 9 0 .9 .9 .9

9. 9 *9 9. 9 9 .99. 9. 9. 9 9 9 9 9 9 9990 *9 9 9 9. V111 wherein: R 34 is -H or C 1 6 alkyl; R3 6 is aryl, heteroaryl, pyridyl, or isoquinolinyl; R 37 is C 1 6 alkyl, -CH 2 Ph, or -CH 2 CHICO 2 )R 34 and pharmaceutically acceptable salts, hydrates and solvates thereof. A compound according to Claim 1 wherein R" 6 is selected from the group consisting 0-0 )a I0 a Me 3. A compound according to Claim 1 wherein R 37 of said compound is Me. 4. A compound according to Claim 2 selected from the group consisting of: 1 -(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-pheloxy)Phenyl sulfonamido)-propan-2-one; 1 -(Cbz-leucinyl)-amino-3-(tosyl-amino)-propan-2-ole; P:kOPER\PDB\1\I 80-97.DV4 22/3100 1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)propan-2-one; 1 -(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one; 1-(Cbz-homo-leucinyl)-amino-3-(2-dibenzofuransulfonamido)propan-2-one; and I -(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one. A compound according to Claim 4 known as 1-(Cbz-leucinyl)-amino-3-((4-phenoxy- phenyl)-sulfonamido)-propan-2-one. 6. A compound according to Claim 4 known as 1-(Cbz-leucinyl)-amino-3-(2- dibenzofuransulfonamido)-(S)-butan-2-one. 7. A compound according to Claim 4 known as 1-(Cbz-leucinyl)-amino-3-(2- dibenzofuransulfonamido)-propan-2-one. 8. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. 9. 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.

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

11. 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

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

13. A method according to Claim 11 wherein said disease is periodontitis. PAOPERPDB\II 180-97.DV4 271300 0 0 0* S. *0 S S S SS0* 0 SO SS

14. A method according to Claim 11 wherein said disease is gingivitis. 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.

16. A method according to Claim 15 wherein said disease is osteoarthritis.

17. A method according to Claim 15 wherein said disease is rheumatoid arthritis.

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

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

21. A use according to Claim 20 wherein said disease is osteoporosis.

22. A use according to Claim 20 wherein said disease is periodontitis.

23. A use according to Claim 20 wherein said disease is gingivitis.

24. 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. A use according to Claim 24 wherein said disease is osteoarthritis. *0 OS. S 5.55 S .55, S. 5 S *555 S. S 5e 55 S. SS'& S 45 0 S .55. 4 SO S 5* SS P:\OPER\PDB\I I 180-97.DV4. 27/3/003

26. A use according to Claim 24 wherein said disease is rheumatoid arthritis. 225