AU2260400A - Protease inhibitors - IV - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

@000 0 *0 0 o 0 .000* Name of Applicant: Actual Inventors: Address for Service: Invention Title: SmithKline Beecham Corporation CARR, Thomas Joseph DESJARLAIS, Renee Louis GALLAGHER, Timothy Fra HALBERT, Stacie Marie YAMASHITA, Dennis Shinji THOMPSON, Scott Kevin incis VEBER, Daniel Frank YEN, Jack Hwekwo DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Protease inhibitors IV The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\PDM2272504.081 21/3/00 (11'ER llIIJ 11180-97 MAl 20 3 INIJ PROT'EASE INIlil'lTORS This application is a dlivisional application derived from Australian Patent Application No. 11180/97, the entire contents of which are incorporated herein by reference.

FIELD OF TlHE INVENTION This invention relates in general to hydrazidyl, bis-hydrazidyl and bis-amninomethyl carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteiIic protscases of the papain superfamily, yet more particularly 8f 10 compounds which inhibit cysteine proeases of the cathepsin K. Such compounds are :0 particularly useful for treating diseases in which cysteine proteases are implicated, especially 0000 diseases of excessive bone or cartilage loss, osteoporosis, periodlontitis, and arthritis.

o6 IBACKGROUND OF THE INVENTION 15 Cathepsins are a Ifamily of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, I-I, L, N and S have been described in the literature.

Recently, cathepsin K p 1 )olypep)tide 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 aloe expressed, purified, and characterized. Bossard, et al., (1996) J Biol.Chem.271, S 20 12517-12524; Drake, et al., (1996) J.Iiol.Chem. 271, 12511-12516; Bromme, et 0.00 al., (1996) J Biol. Chem. 271,2126-2132.

Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the S literature. The designation cathepsin K is considered to be thile 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 inll pathological conditions leading to disease.

Thus, cathepsins have been inmplicated as causative agents in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanonma cruzi, trypsanoma brucei brucei and Crithidia fusiculata: as well as in schistosormasis. malaria, tumor metastasis. metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See International Publication Number WO 94/04172, published on March 3, 1994. and references cited therein. See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P. gingivallis, called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.

Cathepsin K is believed to play a causative role in diseases of excessive bone or cartilage loss. Bone is composed of a protein matrix in which spindle- or plateshaped crystals of hydroxyapatite are incorporated. Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes 15 remodelling at discrete foci throughout life. These foci, or remodelling units, l 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 10 in rats on calcium deficient diets. Lerner, et al., J. Bone Min. Res., 1992, 7, 433, disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulated bone resorption in mouse calvariae. Other studies, such as by Delaisse, et al., Bone, 1987, 8, 305, Hill, et al., J. Cell. Biochem., 1994, 56, 118, and Everts, et at, J. Cell. Physiol., 1992, 150, 221, also report a correlation between inhibition 15 of cysteine protease activity and bone resorption. Tezuka, et al., J. Biol. Chem., 1994, 269, 1106, Inaoka, er al., Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al., FEBS Let., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.

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

Several cysteine protease inhibitors are known. Palmer, (1995) J. Med.

Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, a-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases.

See Palmer, id, and references cited therein.

U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease. Published International Patent Application No. WO 94/04172, and European Patent Application Nos. EP 0 525 S• 420 Al, EP 0 603 873 Al, and EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.

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

Azapeptides which are designed to deliver the azaamino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by 20 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.

25 Antipain and leupeptin are described as reversible inhibitors of cysteine 0 0 protease in McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. 201, 189, and Grinde, Biochem. Biophys. Acta,, 701, 328).

U.S. Patent No. 5,142,056 describes 1,3-diamido-propanones which inhibit HIV protease. 1,3-diamido-propanones have also been described as analgesic agents Patent Nos.4,749,792 and 4,638,010).

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

The synthesis of azatides (polyacylhydrazides) as peptide mimetics has 10 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 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

S

diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix S" 15 degradation, such as osteoarthritis and rheumatoid arthritis.

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

I

s.e 20 D C Q wherein:

D=

R R2 I 21

R

SN R 9 N

R

2 RB- O R23 H 1

H

H

0 N N 0 37 0

R

3 50 C) S-N- 11 H 0 00 0 0 00 0 .000 00 00 00 0 00 0 00 0 3~ 8 N44. RN N

RN

H 00 49 -G R R' 0 R' R 2oR2 ml p 1 3

R

2 0 0000 6 0000 0000 0 .000 0 .000 0 0009 0 *000 0 00 00 0 0 000000 0 ,R31

N

10

H

0 R 37

O

35 1-S- 36 HO0 0

R

3 .N 5 2 N R 39 N'

NJI

41 50 R R R 6 4 A. 6 R63 where: 0

N

Ra A absent,

B=

x=Y ,Y N 0

R'

0000 0 jOSO goOS 0 0 0000 00 S 00 0 geSO 0 00 0 00 0 0 0. 0 00 00 0 L C2.

6 alkyl, Ar-C 0 aikyl. Het-CO 6 alkyI, CH(R 6 6

)NR

6

GR

6 8

CH(R

6 6 )Ar, CH(R 6 6 )OAr'. NR 6 6

R

6 7 M S02 z x-:Y 3000 0 0030 0000 0 @010 0 15 0000 0 .000 J so); T =Ar, Ret; V =C3-7cYcloalky1; W -CN, -CF 3

-COR

7

-CO,R

6

-CONHR

6

_SO)N]HR

6

-NHSO-,R

6

-N-HCOR

7

-O-COR

6

-SR

6

NR'R

6

NR'(C=NH)NHR

5 Cl, Br, I, F; X =Y Z N, 0, S or CR 4 0 .306 0 gO 00 0 0 0.0000 0 0 provided that at least twko of X. Y and Z are heteroatoms and at least one of X. Y and Z is N. or one of X. Y and Z is C=N. C=C or N=N and the other two are CR 4 or N, provided that X. Y and Z together comprise at least two N; indicates a single or double bond in the five-membered heterocycle; m 0, 1, 2; n =I to 6; 0, 1, 2; Ar phenyl, naphthyl, optionally substituted by one or more of Ph-CO- 6 alkyl, Het-C 0 6 aikyl, C I.

6 alkoxy, Ph-C 0 6 alkoxv, Het-C 0 6 alkoxy, OH, (CHi) I 6

NR

58

R

5 9 O(CH2)) I _NR 5 8

R

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

NR

5 8

R

5 9

:O(CH

2 1 6

NR

5 8

R

5 9 or halogen; R' H, C1-6alkyl, Ar-Co-6alkyl, Het-CO-6alkyl; RI= H, C 1-6alkyl;

R

2 C4..6alkyl, C4..6alkenyl, benzyl;

R

3 C 1-6alkYl, Ar-CO-6alkyl, Het-C 0 6 alkyl, R 5 CO-, R 5 SO2-,

R

5

R

5

NHCO-;,

R

4 H, C 1-6alkyl, Ar-CO-alkyl, Het-C 0 6 alkyl; Ar-o-6alkyl, Het-CO- 6 alkyl; R6= H, C 1-alkyl, CH 2

CF

3 Ar-CO-6alkyl, Het-CO- 6 alkyl;, C 1-6alkyl, Ar-CO-6a1cy1, Het-C 0 6 alcyl; R8= H; C2-6 alkenyl; C2-6alkyflyl; Het; Ar; C 6alkyl, optionally substituted by OR', SR', NR.' 2

CO

2

R',

CO2NR' 2

N(C=NH)NH

2 Het or An; R9= H, C1-6alkyl, Ar-CO..

6 aLkyI, Het-CO-6alkyI; RIO C 1-6alkyI. Ar-C 0 6alkyl, Het-C 0 6 alkyl; U 1-6a~kvI. ArV-C 1 6alkyl. He[-C 0 6 alkvIL or R 12 H. C 1 6 alkvl, Ar-CO 0 6 alkvl, Het-CO 0 6 alkyI.

R 3= H, C I 6 alkvl. Ar-CO 0 6 alkyl, Het-Cq..

6 alkyl; R 19 R1 4 N-A R7, Ac;

R

15 H, C I 6 alcI, Cx1 6 alkenyl, C21 6 alkynyl, Ar, Het, or C 1 6 alkyl optionally substituted by OR 9

NR

9

CONR

9 2 N(C=NH)NH-, Het or Ar; R6= C 2 6 alkyl, C21 6 alkenyl, C21 6 alkynyl, Ar, Het, or C'x) 6 alkyl optionally substituted by OR 9

SR

9

NO

9 C02)R 9 4:00 CONR%-, N(C=NH)NH-, Het or Ar; @000 H, C 1 6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl, Ar, Het, or C 1 6 alkyl optionally substituted by OR 9

SR

9

NR

9 2 C0 2

R

9

CONR

9 2 N(C=NH)NH-, Het or Ar; 0.150: R 17 R2= H, C 1-6alkY1, R 10 R I R I R I 0C(O)-; 0 R 21

R

26 C5-6alkY1; C2-6alkenyl; CM- Icycloalkyl; T-C3- 6alkyl; V-C 1.6alcyl; T-C2-6alkcnyl; T- (CH2)nCH(T)(CH2)n; optionally substituted by one or *0 two halogens, SR 20 0R 20

,NR

20

R

27 or C 14alkyl; R7= R 2 8 C0, R 2 8 0C0;

R

2 8 Cl-6alkYl; C3- I Icycloalkyl; Ar; Het; T-C1-6aLky1; see: T-(CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, S R 20

OR

2 0

NR

20

R

73 C I -6alkyI; so R 2 0

R

2 2

R

2 3

R

2 4

R

2 5

R

73 H, C 1 4 alkyI, Ar-C 0 0: 6alkyl, Het-C 0 6 alkyl; R,9=

R

32 R3

H

0 09

S

*000 900@ 0 0000

S.

0 0 0000 0* S B S 0@ 0 S. S 0*

S.

0

S

'I 0 Me 'I 0 0 0 OCH 2 Ph

@SSS

S

0000 0 0500 0 EtO 2 c- 00:9 so

S

Cbz-Ieucinyl-;, or 4-pyridyl methyloxycarbonylleucinyl-; 4-.imidazole areryl-leucinyl-, phenyl acerylleuciyl, N N-dixnethyl-glycinyl leucinyl, 4-pyridyl acerylleucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonylleucinyl, acetvl-Ieucinyl, benzoyl-leucinyl, 4-phenoxybenzoyl-, 2- or 3- berizyloxybenzoyl-, biphenyl aceryl, Wdpba- isobui\ i-biphen,; ,cetyll. Cbz-phenvialamunvi. CbznorieujcmNxY C bz-glutamyk- Cbz-e psilontourv.; se iuani acetyl-leucinyi-, 6- or 8- quinoline carbonvi, bi.Dhenyl acetN 1 aipha- isobutvl-biphenyl acervl.

acevy1, benzovl, or 3- benzvloxy benzoyl, 4-phenoxy benzoyl-, Cbz-arnino acid-; or 4- pyridylmethyloxycarbonylaminoacid-; aryl CO-C 6 alkyloxy carbonyt-amino acid-.

heteroaryl CO-C 6 alkyloxy carbonyl-amino acid-, aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroarvi CO-C 6 alkcyloxy carbonyl-amrino acid-, C 1

C

6 alkvloxy carbonvi-amino acid-, C 1

-C

6 a.Lky carbonyl. ary I

CO-C

6 alkvl carbonyl, heteroaryl CO-C 6 aikyl carbonyl, aryl CO-C 6 alkvI carbonyl, heteroaryl CO-C 6 alkyI carbonyl, C I-C 6 alkyl sulfonyl, aryl CO-C 6 alkvI sulfonyl, heteroarvi

CO-C

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

CO-C

6 alkyl sulfonyl;

R

3 0 H, C 1 6 alkyl; R31 H 0 00 0 o 0-@ 0.

S

Oe*e 0 @600

S.

0 *0 0 000P @0 0 0 0 00 0 00 0 0* 0@ 0 S~a Me N, 0 0 0 OCH 2 Ph

N

/0 0

\\O

2 1 @000 0 0600 0000 0 0000 @000 0 @000

SO

@0 0 000000 0 Cbz-leucinyl-; or 4-pyridyl methyloxycarbonylleucinyl-. 4-imi~dazole acetyl-leucinyl-, phenyl acetylleucinyl, NN-dimethyl-giycinyl leucmnyl, 4-pyridyl acetylleucinyl, 2-pyridyl sulfonyl-leucinyl. 4-pyridyl carbonylleucinyl. acetvl-Ieuciyl, benzoyl-leucinyl, 4-phenoxybenzoyl-, 2- or 3- benzvloxybenizoyl-, biphenyl aceyl, aWrha- isooutvl-biphenyi a~etyl, Cbz-pnenylajaninvJ. C..i)znorleucinyi-, Cbz-nor-%alinvl-. Cbz-glucanl-, Cbz-epsilonit-butyi estern-glutamvl: acetyl-eucinvl-. 6- or S- quinoline carbonyl. biphenyl acetyl. alpha- isobutyi-biphenyi aceRAi.

acetyl, benzoyl, 2- or 3- benzyloxv benzovl, 4-phenoxy benzoyl-, Cbz-amiuno acid-; or 4- pyridylmethyloxycarbonvlarrunoacid-; aryl CO-C 6 alkyloxy carbonyl-amiio acid-, heteroaryl CO-C 6 alkyloxy carbonyl-arnino acid-, arvlI CO-C 6 alkyloxy carbonyl-axnino acid-, heteroaryi CO-C 6 alkyloxy carbonyl-am-ino acid-, C 1

I-

C

6 alkyloxy carbonyl-ami'no acid-, C I-C 6 alkyl carbonvi. aryvI

CO-C

6 aikyl carbonyl, heteroaryl CO-C 6 alkyl carbonyl, 000: arvi CO-C 6 alkyl carbonyl, heteroaryl CO-C 6 alkyl carbonyl, 4'0000: 15 C I-C 6 alkyl sulfonyl, aryl CO-C 6 alkyl sulfonyl, heteroaryl 0 0 -C-.Lky sulfonyl, aryl CO-C 6 alkyl sulfonyl, heteroaryl .00. :CO-C 6 alkyI sulfonyl; =:R3 OCH 2 Ar, OCH2C 1 -alkyi, aryl substituted CO- 6 alkyl, heteroaryl substituted CO- 6 alkyI,4-imnidazole methylene-, 2-, or 4-pyridylmethylneneoxy; 4-pyridyl methylene, 2- *see pyridyl sulfonyl, 4-pyridyl, aryl substituted CO- 6 alkyloxy, heteroarvi substituted CO- 6 alkyloxy; R33 Cj 6 alkyl, -CH2)Ph, -CH2)CH 2

CO

2

R

3 4 R4= C I-'alkyl;

R

3 5 Ar, HetAr;, 6o :io

R

3 6 Aryl, heteroaryl, pyridyl, isoquinolinyl; 0.0000:

R

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

CH

2

CO

2

R

3 4 o R 3 8 Cbz; C 1 6 alkyI or aryl substituted Cbz; C 1 6 alkyl benzoyl; C 1 6 alkyI or ar-yl substituted benzoyl;

R'

9 R32

N

o0 0

C

*000 0000 0eOe S S 0 e.g.

0* S S S S 0000 00 0 S S

C.

0 5* 0 0*

S.

0 0 on Me s% 0 0 OCH 2 Ph 0 0 DtO 2 CZ S3 0

C

0

S

0555

C.

*5 S

C

0 0CC S 0

S

Cbz-leucinyl-; or 4.-pyridyl methyloxycarbonylleucinyl-; 4-imiddazole acetyl-leucinyl-. phenyl acetylleucinyl. NN-dimethyl-glycinyl leucinyl, 4-pyridyl aretylleucinyl, 2-pyridyl sulfonyl-leucinyl. 4-pyridyl carbonylleucinyl. acetyl-leucinyl. benzoyl-leucinyl, 4-phenoxybenzoyl-, 2- or 3- benzyloxvbenzovl-, biphenyl acetyl, i[hj- jsobuvi-biphen~ ii. _Dz-9ne-,wiaianin. i: norleucin'ii-, Cbz-nonvalinv Cbzi-2LuaMvl-. Cbz-epsiIon- -butvl ester)-glutafl:l acet-Ideucinyl-, 6- or 3- quinoline ca-rbonyl. bi phenyl acetyl. alpha- I'sobutyl-biphenvi acervl.

ace.! benzoyl, 2- or 3- benzyloxy berizoyl. 4-phenoxy benzoyl-, Cbz-arn-ino acid-; or 4- pyndyimethyloxycarbonylarninoacid-; aryl CO-C 6 alkyloxy carbonyl-arnino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-ammno acid-, anY! CO-C 6 alkyloxy carbonyl-armino acid-,heteroaryl

CO-C

6 alkyloxy carbony I-amiuno acid-, C 1 I -C 6 aLkyloxy c arbonvl-armino acid-, C 1 I -C 6 aLkyI carbonyl, aryl

CO-C

6 alkyl carbonyl, heteroaryl CO-C 6 a.LkyI c arbonyl, aryl CO-C 6 alkYI carbonyl, heteroaryl CO-C~akyl carbonyl,

C

1 I -C 6 alky! sulfonyl. aryl CO-C 6 alkyI sulfonyl, heteroaryl

CO-C

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

CO-C

6 alkyI sulfonyl; R0= H and C I- 6 alkyI; R1= H and C 1 6 alkyI; R4- C I- 6 alkyl, aryl substituted C 1 6 alkyl and hetero, aryl *6000*substituted C 1 6 alkyl,; H when R 4 3 is C 1 6 alkyI, aryl substituted *C I 6 alkyl-, and heteroaryl substituted C 1 6 alkyl; C 1 6 alkyI, aryl substituted C 1 6 aLkyI and hetero, aryl substituted C 1 6 alkyI,; H when R 42 is C 1 6 alkyl, aryl substituted

C-

6 alkyI; and heteroaryl substituted C 1 6 alkyl; R44 CH(R 53

)NR

45

R

54

CH(R

55 )Ar, C 5 6 alkYl;

R

4 5 R6= R7= R 4 9 R9= R 5 0

R

5 1 H, C 1 6 alkyl, Ar-C 0 6 alkyl, Het-C 0 6 alkyI;

R

5 2 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 RD)= C2 6 alkyl, Ar-C 0 6 aikyvl. Het -CO 0 6 alkyl.

R

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

R

54 R7= R 4 7

R

4 7

R

4 7

R

4 7 0C(O);

R

5 5 R6= R 5 8

R

59 H, C I 6 alkyI, Ar-C 0 6 alkyl. Het-C 0 6alcyl; R0R 6 1=R6= R 6 3 =R4= H, C 1 6 alkyl, Ar-CO 0 6 alkyl, or Het-COJ.6aicyl; R6 C 1 6 aLkYl. Ar, Het, CH(R 6 9 )Ar, CH(R 6 9 )OAr, N(R 6 9 )Mr, HR9N lR0 R6 6 R 7 1 H, C I 6 alkYl, (CH 2 40 6

-C

3 6 cYcloalkyl, Ar-C 0 6 alkyl, Het-CO- 6 alcyl; R6 C 1 6 alkYI, (CH 2 40 6

-C

3 6 cYcloalkyl, Ar-CO.

6 alkyl, Het-CO- 6 alkyl; R 6 6 and R 67 may be combined to form a 3-7 membered monocyclic or 7- 10-membered bicycic .:..carbocyclic or heterocyclic ring, optionally substituted with :1-4 Of C 1 6 alkyl, Ph-CO- 6 alcYl, Het-COy6alkyl, C 1 6 alkoxy, 6a11cOXY, Het-CtO.

6 allcoxy, OH, (CH 2 1 6

NR

5 8

R

5 9

O(CH

2 1 6

NR

5 8

R

59

R

6 8

=R

7 0

R

6 2

R

6 2

R

6 2

R

6 2 0C(O), us..

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 *6 :.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 peptidomimetic molecular backbone on either side of the central carbonyl, a terminal ,:arbobenzviox- rmoletv Cbz-ieucinvii. or a -rruc thereof. or. t he backbone orn one or both sides of the carbonyl. and optionally, an Isobutyl side chain extendins: from the backbone on one or both sides of the carbonyi.

R

Compounds of Formula I wherein D R A and Q

R

N

R are preferred embodiments of the present invention. For the sake of convenience. such compounds are referred to herein after as compounds of Formula 11.

.00.10More preferred embodiments of the present invention include compounds of Formula H1 wherein: X=S S=H n -N X=S, Y=S, and Z=-N; X=N, Y=N, and Z=-S; X=N, Y=N, and Z-O;and X=N, Y=N, and Z--N.

*se Preferably R I is H, methyl or isobutyl. Preferably R I is isobutyl.

Preferably R 2 is isobutyl or benzyl.

Preferably R 3 is R 5 particularly benzyloxycarbonyl.

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

CPreferably W is CN, NHR 6

SR

6

CONHR

6 Or C0 2

R

6 Suitably R 6 is H, 0: 0 CI-alkyl, phenyl or benzyl. Typically, W is CO-)H, CO2-Cl 4 alkyl, C02-Ph, CO')- CH-,Ph, CONH-), NH-) or SH.

ILI LU IIUV 1114A U uptmuu U I FUL II I U I d I al C cU k UIalI I\ t p feTCU.

(2S. I S)-2-(benzvloxvcarbonvflamino-N-[ l -t2-carboxvthiazol-4-vl)mechyl bury] ]-4-methylpentanarrnide; CS, I'3S)(fnlYoxycarbonl~an-iiot NLi lu(-croxamidotuuuzoZl--vl)-3,methylburylj-4-rnethylpentanamride; (2S, I S )-2-(benzyloxycarbonyl)amrino-N-[ I '-(2-carboethoxythiazol-4-yI)-3'methylbutyl J-4-methylpentanarnide; (2S, I S)-2-(benzyloxycarbonyl)amino-N-[ 1 -(2-cyanorthiazol-4-yI)-3'-methylbutvlj- 4-methylpentanamride; (2S. 1 S)-2-(benzyloxycarbonyl)amino-N-[ I '-[2-(N'-benzylcarbaxaxnido)thiazol-4yIj-3'-merthylburyl]-4-methylpen~anarnide; (2S, F 2-(be azyloxycarbonyl) amino- 1 see* methylpropyl)carboxarnido]thiazol-4-yI)1-3'-methylbutyl]-4-methylpentanamride., Goes (2S, 1 'S)-2-(benzyloxycarbonyl)arniino-N-[ *ses 15 phenylethyl)carboxarnidolthiazol-4-y)]-3'-methylbuyl-4-methylpentanamide; IS)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(4-carboethoxythiazol-2-yl)-3'- *:methylbutyl]-4-methylpentananriide; I 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 -(4-carboxytiazol-2-yI)-3'- 5 methylbutyl]-4-methylpentanamide; (2S,1 IS)-2-(benzyloxycarbonyl)arnino-N-[ 1 '-(4-carboethoxythiadiazol-2-yI)-3'methylbutyl]-4-methylpentanamide; (2S, 1 S )-2-(benzyloxycarbonyl)arriino-N-[ 1 -(2-carbo-2,2,2-trifluoroethoxythiazolsees 4-yI)-3'-methylbutyl]-4-methylpentanamride; *so: (2S,1 'S)-2-(benzyloxycarbonyl)arnino-N-[ 1 -(4-carboethoxyoxadiazol-2-yi)-3'methylbutyl]-4.-methylpentananmide; 'S)-2-(bcnzyloxycarbonyl-L-Ieucinyl)amino-N-[ I '-(4-carboethoxythiazol-2-yI)- Go 3'-methylbucyl]-4-methylpentanamide; (2S, 1 S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(4-carboxamidooxadiazol-2-yI)-3'methylbutyl]-4-methylpentanamide; (2S, 1YS) 2-(be nzy lox ycarbonyl) arnino-N- [1 l-(2-carboethoxythiazol-4-yI)-3'methylbutyl]- 3-phenyipropanamide;, S. benzv-ioxvcarbonvli-L-ieucinvl ;arnno-N-[ >caiboethoxvthiazoj-- ~-mechviburvIJ4-methylpentanarr.ide: t'2S. I'S')-2-(benzyloxvcarbonyl )arruino-N-[ I -(5-mercapto- I 2 4 -oxadiazoI-S-vlI-S methylbutvl]-4-methylpentanari~de.

I'S 2 -(berlzvloxvcarbonvl)arrzmno-N-r 1 '-(2-mercaptothiazoI-4-v1)-3..

methyl butyij-4-merhylpentanaxnide; (2S) 2 -(berizy loxycarbonyl) amino- N-(4-c arboethoxythi azol 2 .v)me thy] -4methylpentanarnide; (2S, I S)- 2 -(benzvloxycarbonvl)arnino-N-[ l -(2-benzyloxycarbonylthiiazol-4.vly3' methyl bury]l1-4-methylpentanamide; (2S, I 2 -(benzyioxvcarbonyl)amrino-4methyl-N-[3'-methyl- 1 phenoxvcarbonylthiazo-4-vl)butyijpentanam..de; (2S.1 2 -(benzyloxycarbonyl)arnino-4-methyl-N[3.methyl. I a...methylpropyloxvcarbonyl)thiiazolb4-yllbutvllpentanarr-ude, 15 (2R. I'S)-2-(berzyloxycarbonyl)amino-N- 1 -(4-carboethoxythiazol-2-y1)ethy -4methylpentanarnide; (2R, I 'R)-2-(benzyloxvcarbonyl)amino-N-[ 1 '-(4-carboethoxythiazol-2-yl)ethylj-4methylpentanamide; and a. (2S, I .aminothiazo-4-yl)-3'-methylbuty1] -2-(benzyloxycarbony) anno- 4 -methylpentanarnide.

Most particularly preferred compounds of Formula II are: as(2S1 FS) 2-(be nzy loxycarbonyl) amino- N I '-(2-carboethoxythiazol-4-yI)-3'methylbutyl]-4-methylpentanarnxde; 1 S)-2 -(benzyloxycarbony) amino- N- l -(4-carboethoxythiazol-2-yI)-3'methylbutyII-4-.methylpentananmjde; and aI25.1 S)- 2 -(benzyloxycarbonyl-L-Ieucinyl)affino-N..[1 I-(4-carboethoxythiazol-2-yl)a a a 3 '-methylbutyll-4-methylpentananide.

R 0 N R14 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

S

N-N

H

yN 0 i-Bu

N--

N-N

N

N

S r ND/ -LN *0 *6S *6 0

S

S 0 0* a *6* 0 00i0 0** as N N

H

or 0 i-Bu More preferably B is Preferably

R

1 1 is R 1 7

NR

9

N

10 Preferably R 12 and R 13 are H.

R

1 9 Preferably

R

14 is N-R R 72 Preferably R 15

R

16

R

18 and R 19 are Ci.

6 alkyl.

More preferably R 15 and R 18 are C4_alkyl.

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 Cl-4alkyl.

Preferably R 17 and R 7 2 are RIOOC(O)-; and more preferably R 10 is Ar-Cl-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 parncular embodimeni of the .nvention of Formula III is a omDound of Formula F: R 1 6 0 R 19 R 17 H R 72 N I 'N N,9 H v. H H X==Y o

F

wherein X, Y, Z, R 1 6

R

17

R

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

Most particularly preferred compounds of Formula Ell are: (1 -benzyloxycarbonylaino)-3-methylbutylthiazl-2-ylcarbonylI-N'- (N-benzyloxvcarbonyl-L-leucinyl)hydrazide; N-benzloxcarbonyl-L-leucinyl-N'-benzyloxycarbonyl-L-euciflYLL- 10 leucinylhydrazide: and -benzyloxycarbonyarnino)-3-methylbul]thiazo14-lcarboYIl-N'- (N-benzyloxycarbonyl-L-leucinyl)hydrazide.

R 22

RR

24

R

2 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 nreferred embodiment of the present invention is a compound of Formula IV wherein R 2 1 and R 2 6 are selected from the group consisting of: N-Cbz-leucinyl, N-Cbz-giycinyL. N-acetylI-leucInyI. -Cbz-alanvi.

C 10C J0 and R 22

R

23

R

24 and R 25 are H.

Particularly preferred embodiments of Formula IV are: 2,2'-(NN-i-ez xcroy-Lluiy~abhdaie 2,2'-(N.N'-bis-cyclohexylacety1)carbohydrazide; 2.2- (N,N'-bis-4-methylpentanoyl)carbOhydrazide; 000: (N,N'-bis-cyclopentylacety)carbohydrazide; 2 ,2'-(N,N'-bis-benzyloxycarbonylglycinl)cabohydaide; .2'-(N,N'-bis-aceryl-L-leuciny)carbohydrazide; I'(,'bsbnzlxcroy--lay~abhdaie and mose preferred embodiment of Foe rulat ivenin.o h ak fcneine

C

Comound orfere Fomula s of wherein D, whe H and Qcl R3 Hs preferably Me or -CH 2

CH

2 Me2. When R 3 3 -C -C 6 alkyl, R 3 3 is preferably -Pr, Bu, or -CH 2

CH

2 Me 2 When R34- I -C 6 alkyl, R 34 is preferably -t-Bu.

Even more preferred embodiments of Formula V include: bis-(Cbz-leucinyl)- I ,3-diam-ino-propan-2-ofle; bis- 1.3 phenoxy -be nzovlI)-diamino-propal- 2 -one-, -t Cbz-ieucinyl -1-arruno-~-' acetv I-leucifl] -aim no-prolaf--_-one* 1 (b-luinl nuo3-Czlit-v--butvl ester -arilno-propan- 2-one.

I Cbz- leuc inyl )-arrno03-(Cbz- giutarnYI)-amflifo-propaf 2 -one.

bis- 1. .3 (Cbz- leuc iny1) -diamfl0- bu anle 2 -one; 1 -(Cbz-leucinyl)arun- -(b-hnilnl)an opoa oe bis- 1 ,3-(Cbz-leucinyl)-diarriflo-5-methyl-(S)-hexan- 2 -one; 1 -(Cbz -homo-lIe ucin y anino-(Cbz-leuc ifl) -3 amlo-propal- 2 -one: I -(Cbz-leucinvi)-amino-3-(acetyI-Ieucinyl)-am.1flo-propan- 2 -ofle is a most particularly preferred embodiment of the present invention of Formula V.

*see 00 :e0 Compounds of Formula I wherein D 0 and 00 000*15 Q- H 0 are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after 0000 as compounds of Formula VI.

00 :000: 00

CC,

haMoen peabl ya rupWe R 35 =Ph N o pyridine, eve m e prerbl -yrid or0pndl Most particularly preferred emnbodiments of Formula VI include: bis-1I,3-(4-(3-chloro-2-cyalo-pheloxY )-phenyl sulfonamido)-propan- 2 -one: bis-1I,3-(4-phenoxy-phenyl sulfonamido)-propal- 2 -ofle.

Compounds of Formula I wherein D

H

0 0 R R37 0 11 36 N R H 11 0 0@*W 0

*OOS

0060 0 0 0000 0O 0 0O S 0S00 00 0 0 0 0@ 0 0* S 0 S

OS

0 and Q= are pri embodiments of the present invention. For the sake of convenience, such 10 compounds are referred to herein after as compounds of Formula VII.

More preferably, R 36 is selected from the group consisting of: eferred ao_0 Me 0 *000 0000 0 0000 0 0000

S

0000 0 0500 00 00 0 0 050000 0 0 0aC 0 ONCI ;and R 37 Me in the more preferred compounds of 15 Formula VII.

ParticulAy preferred embodiments of Formula VII are: 1ICzluiy)a-in--4(-hoo2cyn-hnx)pey sulfonarnido)propan-2-one;, 1 -(Cbz-leucinyl)- amino- 3-(tosy -amino)-propa- 2 -ole.

I Cb-ecnj-r In- 4-Dhenoxy-p hen vi ,-sulfonarido j-propan- b-ecn~,arn- -one, I -(Cbz-leucinvl )-anhino-3- 2-dibenzofuransu Ifonamido)-propan-2-one: I -i Cbz-horno-Ieucinvl )-amino-3 -(2-dibenzofuransulfonarnido i-propan-2--one:. and Cbz-leucinyl )-amnino-3-(2 -di benzofuransul fonamido)-(S )-bucan-2 -one.

1 -(Cbz-leucinyl)-ami no-3 -((4-phenoxy-phenyl)-sulfonaniido)-propan-2 -one, l-(Cbz-leucinyl)-axnino-3-(2-dibenzofuransuifonamido)-propan-2-one, and 1-(Cbzleucinyl) -amino-3 -di benzofuransulfonamido)-(S) -butan-2 -one are most particularly preferred embodiments of Formula VII.

0 0 0 43 0R 00000N 0 H 0 Compounds of Formula I wherein D andQ 0 0 0R Se 0: '4 NR3 0 VI 0:e 0: N.

(S)-Penrey preferre(diboientuasf eprnt ~inveon. orothe ake o coenvnin sccopounds armethrefelrre hrnafter scmonso oml *0*@nlehl[-[[-(-iezfraysloy~niol2oorpl--4 *000 idin tv~mnlcroyl3mtyluylabmt I -f[[3-f'(2-dibenzofuranvlsulfonyl ,asmnoJ-2 -oxopropyl]- 3 4-pyridinylmeth'i) benzariide (S )-Phenylmethyl [1I -[[[3-f(2-dibenzofuranysulfonl)amino]-2-oxopropyl 3- 14-4pyridin y Ime thyl )amri nojcarbonylI 1- 3 -methvi bu tyllcarbamate.

(S)-Phenylmethyl [1 .f[3-[2-dibenzofuranysulfonyl)arninoJ-2-oxopropvi 3- I -(4-pyridinylmethyl)arninojcarbonyl-3-methylbutylicarbamnate is a most particularly preferred embodiment of Formula VIII.

R

~N

6..Compounds of Formula I wherein D 0 R 49and Q-- *0 0 51 N' i 0: Rare preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula IX.

Compounds of Formula IX wherein: R4 CH(R 5 3 )NHR-54

R

4 5

R

4 6

R

4 8

R

4 9

R

5 0 and R 5 1 are H;

R

4 7 is independently CH 3 benzyl, 2-pynidinylmethoxy, 4-dimethylaminobenzyl; J

R

5 2 Ar, CH(RIO)Ar, CH(RI 0 )OAr, N(RIO)Ar, CHRO)RR 1;

R

5 3 ethyl, i-Bu;

R

5 4

R

4 7

R

4 7

R

4 7 0C(O);

R

5 6 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 6a~kyI, Het-CO.

6 alkyl, Cj 6 alkoxy, Ph-CO 0 6 alkoxy, Het-CO 0 6 alkoxy. OH, (CH2)l 6

NR

5 8

R

5 9 1 6 N 8

R

9 R' H, C 1 6 aikvi. Ar-CO- 6 alkN I He[-CO 0 6 akvi-.

are more preferred embodiments of the present invention.

The following compounds of Formula IX are particularly preferred: -[N-(N-benzvloxvcarbonyi-L-leucinyl)I-2'-[N'-(4phenoxyphenylsulfonyl)Jcarbohydrazide; 2-IIN-(N-benzyloxycarbonyl-L-alanyl) J-2'-[N-(N-benzyloxycarbonyl-Lleucinvl)Jcarbohydrazide; 2.-[N-(N-benzyloxycarbonyl-L-leucinyl)I-2'-[,N-(4-phenylbenzoyl)jcarbohvdrazide: 2-N(-ezlxcrov-Lluiy)-'[N-4 methoxybenzoyl)jcarbohydra.zide; 2'-[N-(N-berizyloxycarbonyl-L-leucinyl)1-2'-(N'-(4phenoxvberizoyl)Jcarbohydrazide-; 2-(N-acetyl)-2'-[iN-(N-benzyloxycarbonyl-L-leucinyl)carbohydrazide; 15 2-[N-(N-acetyl-L-leucinyl)]-2-[N'-(N-benzyloxycarbonyl-Lalanyl)Icarbohydrazide; 0: 2-[N-(N-acetyl-L-alanyl)I-2'-[N'-(N-bezyloxycarbolyl-Lleucinyl)]carbohydrazide;, 2- [N-(N-benzyioxycarbony1-L-.Ieucinyl1-2'- [N'-114-(N,N- 0 20 dimethylarninomethyl)benzoyl)]]carbohydrazide; (N-(N-benzyloxycarbonyl-L-eucinyl)]-2'-[N'-4-hydroxy-1 3 4 morpholinomethyl)) ]benzoyllcarbahydrazide; 2-f N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N.Ndimethylamrinomethy I)berizyloxy]carbonyl-L-leucinyllcarbohydrazide; 25 2-(N-benzoyl)-2'- N t -(N-benzy 1ov-ycarbony1-L-1eucinyl)]carbohydrazide; ~:2-[N-(N-benzyloxycarbonyl-L- ieucinyI)1-2'-[N'-[3-(4morphoiinomethyl)benzoylflcarbohydrazide; 2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide;, 2- [N-(N-benzyloxycarbonyl-L-leucinyl)-2-fN'-[4-f 3-(N-N-dimethylamino)- I1propyloxvlbenzoyl] ]carbohydrazide- 2

N-(

2 -beflzvioxbenzo 1) 2 N (Nbenzy loxvcarbony

I-L

Ieucinyl) Icarbohydrazide; (~N-(NbenzIoxcarbofYi L-e uc y 1) 2 N-[ 3 4 pyrdylmethoxy)benzl]]Icarohydraide; 2-[N -ezlxbnzy)-'['(-enyoyabnlL Ieucinyl)]carbohydrazide; 2 -(N-(N-benzyIoxycarboflIL-eucinyl)]- 2 [N-(3-benzy1oxy-5merhoxy)benzl2Ofcabohydazide; 2-N(-ezlxcronlLluiy)- -benzyloxy- 4 dimethoxy)bnzoy1]carbhydraide; 0 2 -[N-(N-benzyloxycarbonyI-L-1eucinyI)l- 2 @000ethoxy)benzoyl]carbohydazide; o: leucinyl)]carbohydrazide; **prolinyl)]carbohydrazide, 2 -[N-(N-benzyloxycarboflY-L-eucinyl)]- 2 phenylphenylacetyl)Icabohydrzide; 20 aminobutyryl)lcarbohydrazide;, *2,2'-[NN-bs(-hnlhnlaey~labhdaie see: 2 'RS)-2[N(NbelzyloxycaronylL-Cucinyl1) 2 2 phenylphenoxy)propionlcarbohydrazde-; 00000S 25 (2RS, N'-[bis- [2-(4-phenylphefly1)- 4 methylpentaloyl)Ilcarbohydraide; (2R)2[-Nbezlxcroy Lluiy)-2'-[N'- (2-(4-phenylpheflyl)4 methylpentanolY))cabhydraide; (2ZRS)-2-EN-( 3-benzyloxybeflzoyl)I- 2'['[-4peypey)4 methylpefltaoly)flcaohydrazide-; -j-,--&enizvloxv-benzoavl N-benzv-Ioxv-carbonvI-N-rnethvi-Lle ucin vl) ]carbohvdrazide: [N z lx bno l] N -'-yiivm to vabnl)L leucinvi ]jjcarbohvdrazide, 3 (4-pyridylrnethoxy)benzoyl1I-2-[N-N-(2-pyrdiyimetoxycabofly1)-Lleucinyll J carbohydrazide; (2 RS)- N 2-4peypey14mtypn ol pyridinyimethoxycarbonyl)-L-leucI nyll] ]carbohydrazide; 2 [N-(N-benzyloxycarbonyl-L-leucinyl)I- 2 [2-(4-phenylphenyl)-4methylpentanoyl)]lcarbohydrazide; 2-fN-(N-benzyloxycarbonyI-L-leucinyl)]-2-iN'-(2-(4-phelphelyl)-4methylpentanoyl)]]jcarbohvdrazide; 2~N~Nbezyovcarbonvl-L- leucinyl)-2-[N- phelphel)-N- (2rnethylpropyl)carbamoylI] ]carbohydrazide; 15 2- [N-(3-benzyloxybenzoy)]-2-N-(N-mehyl-L-Cucil)]carbohydrazide; 00: 2- [N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(N-nethyi-L- Ieucinyl)]carbohydrazide.

NN MR 6 0000 63 00000 Compounds of Formula I wherein D an~d R 0000 0 20 aepeerdebdmnsothprsnineto.Frteskofcneine such compounds are referred to herein after as compounds of Formula X.

With respect to Formula X: ~:.More preferably G is 0 N N LS or

S

More preferably

R

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

More pre ferably

R

6 5 is CH(R69)NR 6 l R 7 in whic 6 sibuy n 6 is H. More preferably

R

7 0 is R 6 2 0C(O), in which

R

62 Is

H

2

CH

2

N

CH

2

N

2

N

*000 .06.

0* 0 0** 000 B. 0 *00 0 0 Alternately.

R

65 is IZ 0jo A, or CH(R 6 9 )Ar in which Ar in said R 6 5 group is

N

N

0

""O

More preferably, L is CH(R66)NR6OR 68

CH-(R

66 )Ar. NR 66

R

6 7

CH(R

6 6 )OAr', Ar, or Het, in which

R

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

N

7

N

N

N-S

501 W~e or or Het in said L group is

S

S0 0 *066 Onote particularly preferred embodiment is a compound of Formula R 6 Th6olwn opud fFruaXaems atclrypeefd 8:)N(-(-ezlxcroyamn)3mtybtltizl4 1-(N-benzvl oxycarbonyl-L-leucinvlam'no)-3methy lburyl Ithiazol- 2-vicarbonyl )-N'-(N-benzylox ycarbonyvlI-L -le uc inyI)hvdrazide: (I 1 -benzyloxvcarbonylamino)-3-methyI bury]lithiazol-4yI carbonylj-N'-(4-phenylphenylacetyl)hydrazide; (I -benzyloxycarbonylanino)-3-methylbutylllthiazol-4ylcarbonyl]-N'-[3-(4-pryidinylmetboxy)benzoyllhydrazide; N- (2-(2-chlorophenoxynethyl)thiazol-4-ylcarbonyfl-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[N-(4.-pyridinylmethoxycarbonyl)-L-leucinyll-N'-[2-(4-( 1.2 3-thiadiazol- 4-vI)phenyl]thiazol-4-ylcarbonyl]hydrazide; N- [2-[3-(4-chlorophenylsulfonylmethyl)thien-2-yI]thiazol-4-ylcarbonyl [N-(4-pyridinyhnethoxycarboriyl)-L-Ieucinyllhydrazide; (I 1 -benzyloxycarbonylanino)-3-methylbutyljthiazol-4ylcarbonyll-N'-(2'-(4-phenylphenylacetyl)-4-methylpentanoyllhydrazide, N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2pyridinylmethoxycarbonyl)-L-Ieucinyllhydrazide.

(1 RS [1-(4-phenylphenyl)-3-methylbutyllthiazol-4-ylcarbonyl]-N'- fN- (4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; N- [2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyll-N'-[N-(4- 20 pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N- [2-[N-methyl-N-(4-pbenylphenyl)aminothiazo-4-yabofl]-N'- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-(N-benzyloxycarbonyl-L-leucinyl)-N'-2-(4-phenybenzyI)thiazol-4ylcarbonyl]hydrazide; 25 N-(2-(4-phenylphenylbenzyl)thiazol-4-ylcarbonyll-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl~hydrazide; N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-[N-(2-methylpropyl)-Nphenylamino]thiazol-4-ylcarbonyl]hydrazide; N-(2-[N-(2-methylpropyl)-N-phenylaninothiazol-4-yIcarbonyl]-N'-[N-( 4 pyridinylmethoxvcarbonyl)-L-leucinyl]hydrazide; .V i -benz,,-Ioxxlphelen 1 thiazoi- -aon V1 i -VN- y .N j pyridinlmehoxvcarbonvl)-L-leucinvl hvdrazide N-f 2-(2-benzvloxyphenvl)hiazo-4-vicarbonvi]N-[N-(2..

pyndinylmethoxvcarbonvl)-L-ieucinvljhydrazide, N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N'-[2(x benzyloxyphenyl)thiazo-4-ylcarbonyl]hydrazide; 2 -methylpropyl)-N-phenylaniinojtiazol-4-vcarbonyl-N'-.N-(2 pyridinylmethoxvcarbonyl)-L-leucinyllhydrazide; 2 -methylpropyl)-N-phenylaniinothiazol-4.ylcarbonylJ-N- 3pyridinylmethoxvcarbonyl)-L-Ieucinylihydrazide; and N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonylj-N'[N-(4pyridinyhnethoxycarbonyl)-L-leucinyl]hydrazide.

Definitions The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently se* 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 0 enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chira center may be used as a racern" mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in 0009 0 which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) 25 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 000 i 30 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 chemiucal arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commnission on Biochemical Nomenclature as described in Eur.]. 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, glutarnine, glutarnic 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, neopenryl and hexyl and the simple aliphatic isomers thereof. Any Cl-6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R') 2

C(O)N(R')

2 carbamyl or C 1-alkyl. where R' is CI1 6alkyl. CoalkyI means that no alkyl group is present in the moiety. Thus, Ar- 15 Coalkyl is equivalent to Ar.

0 'C 3 1 icycloalkyl" as applied herein is meant to include substituted and *goesunsubstituted 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 20 wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.

C

2 6 alkenyl includes ethylene, I1-propene, 2-propene, I1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are .6666 included.

'C2..6alkynyl" means an alkyl group of 2 to 6 carbons wherein one carbon- 25 carbon single bond is replaced by a carbon-carbon triple bond. C 2 6 alky'yI *see includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.

0 "Halogen" means F, Cl, Br, and L.

"Ar" or "aryl" means phenyl or naphthyl, optionally substituted by one or 30 more of Ph-CO 0 6 alkyl, Het-C 0 6 alkyl, C 1 -6.alkoxy, Ph-C 0 6 alkoxy, Het-Co..

6 alkoxy, OH, (CH 2 1 6

NR

58

R

59 1- 6

NR

58

R

5 9 where R 58

R

5 9 H. C 1 6aikyI: Het-C 9 6 alkyI. from C; 4 ,aikvi. OR' .NiR'. SR', NO-i CN. COi)R.

CON(R'). F. Cl. Br and L.

As used herein "Het" or 'heterocyclic- represents a stable 5- to 7 -membered monocyclic or a stable 7- to lO-membered bicyclic heterocyclic ring, which isetr saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N. 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any 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 heceroatomn or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from Cj-4alkyl. OR', N(R') 2 SR., CF 3 CN, CO-,R', CON(R'), F, Cl, Br and 1, where R' is C I-6.alkyl. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl. 4-piperidonyl, pyrrolidinyl, g: pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, :.quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benziniidazolyl, benzopyranyl, so0 benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxacdiazolyl.

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

C...Y

It will be appreciated that the heterocyclic ring described when N Z includes thiazoles, ox.zoles, triazoles, thiadiazoles, oxadiazoles, isoxazoles, 09025 isothiazols, imidazoles, pyrazines, pyridazines, pynmidines. triazines and tetrazines which are available by routine chemical synthesis and are stable. The single and double bonds in such heterocycles are arranged based upon the heteroatoms present so that the heterocycle is aromatic it is a heteroaryl group). The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur. When the heteroaryl group comprises a five membered ring. W is preferably an electron withdrawing gyroup. such as halogen. -CN, -CF 3 -CORl?. -COi)R 6

CONHR

6 -SOiNHR 6 -NHS0,)R 6

-NHCOR

7

-O-COR

6

-SR

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

Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-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 dicyclohexylcarbodiimide, DMIAP is 2,6-dimethylaminopyridine, EDC refers to Ne thy!I- N'(dimethy IaminopropylI)-carbod iiflude. HOBT refers to 1 hydroxybenzotriazole, DMEF refers to dirnethyl formrnide, BOP refers to benzotriazol- I -yloxy-ruis(dimethylarniino)phosphonium hexafluorophosphate.

DMAP is dimethylaininopyridine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)- I .3-dithia-2,4-diphospheane-2,4-disulfide, NMM is N-rnethylmorpholine, TFA refers to trifluoroacetic acid. TFAA refers to trifluoroacetic anhydride and TI-F refers to tetrahydrofuran. Jones reagent is a solution of chromium trioxide, water, and sulfuric acid well-known in the art.

0 0 0 Methods of Preparation Compounds of Formula TI wherein X CH. Y S and Z N. and W CO'R' CN, or CONRR' may be conveniently prepared by methods analogous o Wose described in Scheme 1.

0 @009 0 *0S* 0000 9 9

S.

0 S S 9S*e S@ 0 S 9

S.

0 S0 S 0 0 0 00

S

*S.S

0009

OSSO

0 @5 95 9 0 0 Scheme I 0 RI 0 R1 DN OH a HW D N 2

HYH

0 0 b O R' D)LN JrBr

H

0 O R' D'NJ C2H

S

0 RI

NN

-4

D=

0 @000 00 000 000 0*0 0 0 *0 0

N

H

2 N COI 0 R' HI C02Et H

IS

I-Q

0 D N

H

0S@ 00000 0 0 0.0 O

RI

S

o Rt 1

N

D N 4 a) i-BuOCOCI, NMM. CH 2

N

2 EtOAc. Et 2 O: b) HBr, AcOH. EtOAc, Et 2 O; 0) H 2

NCSCO

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

CH

2

CI

2

Q

TFMA, pyridine, CH 2 0 2 g) R 4 OH, Boc 2 O, Pyridine or R4OH, EDOI, CH 2 CA 2 h) pipenidifle, DMF: i) BOP, Et 3 N, D-CO 2 H, CH2CI2 I -Scheme 1 is treated with isobutyl chioroformate and N- methylImorpho line in ethyl acetate to give a mixed anhydride which is treated with diazomethane in ether to provide 2-Scheme The diazoketone 'is halogenated using 30% HBr in acetic acid in ethyl acetate/ether solution to provide S-Schemne 1. This material :s treated with ethyl thioioxamate in refluxing ethanol to give 4-Scheme 1. The thiazole carboxylic ester is saponified by treatment with a hydroxide base 1such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid S-Scheme 1. The carboxvlic acid is treated with isobutyl chioroformate and Nmethylmorpholine, followed by gaseous ammonia to provide primary armide 6- Scheme I (R 3 The primary amide is treated with TFAA and pyridine in dichioromethane to provide 7-Scheme 1. Alterniatively, 5-Scheme 1 can be converted to substituted amnides, 6-Scheme-1, by treatment with alkyl amiunes (such as benzylamnine, 2-phenylethylamrine or isobutylam-iine) and a peptide coupling reagent (such as BOP, EDC*HCI/I-HOBT or N-methylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane or DMF). The carboxylic acid 5-Scheme 1 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, benlzyl alcohol or phenol) and a dehydrating reagent (such as DCC/DM1AP, EDCI or Boc2O/pyridine) in an aprotic solvent (such as dichioromethane or ether). When R 2 9-fluorenylniethoxy, treatment of 4-Scheme I with pipenidine in DMF gives 9-cereA Treatment of 9-Scheme I with a carboxylic acid (such as N-Cbz-L-phenylaanine or N-Cbz-L-leucinyl-L-leucine) 20 and a peptide coupling reagent (such as BOP) in an aprotic solvent (such as dichloromethane) provides 10-Scheme 1.

Scheme IA

C

0000 0S*O 0 0@U@ 0e 0 0 0000 S* 0 @0 0O 0 @6 0e *6 0 e.g.

C

e.g.

0000 0 0000

C

S S H2 N" N' H2

H

SMe S R'HN S H 2 N N 1 "NH 2 H 2 NNH 2 2 3 c

RR'N

0 0 a) Mel, TIH; b) i-PrOH; c) Bromomethyl ketone, EtOH Compounds of Formula 11 wherein X CH, Y S and Z N are prepared by methods analogous to those described I n Scheme I A. I -Scheme I A is treated with iodomethane in an aprotic solvent (such as THE) to afford 2-Scheme I A, which is treated with a primary amiane in a protic solvent (such as isopropanol) to 2ive 3-Scheme IA. this material is then treated with a bromomethyl ketone in a protic solvent (such as ethanol) to provide 4-Scheme

IA.

Schem 2 BocHN k.y O a BocHN >(NH b BocHN Iy NH 0 0

S

R'

RI

c d SBocHN r1 -CO 2 Et

H

2 N N~

CO

2 Et 04 0 RI 0

R'

iz a) i-BuOCOC1, NMM, NH 3 THF; b) Lawesson's reagent, THF; c) BrCH 2

COCO

2 Et, TFAA, Pyridine, CI- 2 C1 2 d) TFA; e) DCO- 2 H. EDCQHCI, HOBT, Et3N, DMIF; f) NaOH, H 2 0, THF Compounds of Formula 11 wherein X S, Y CH- and Z N may be conveniently prepared by methods analogous to those described in Scheme 2. _L Scem 2 is treated with isobutyl chioroformate, N-methylmorpholine and ammonia in Ti-F to provide 2-Scheme 2. This material is converted to the thioanide, L Scheme 2, by treatment with Lawesson's reagent in an aprotic solvent (such as THE or toluene). 3-Scheme-2 is converted to the thiazole by condensation with a ciketoester bearing a suitable leaving group for displacement by a sulfur nucleophile Cl. Br. 1. O.Ms. O-D-Tos) in dichioromethane. 4-Scheme 2 is treated wvith Tr-A io Drovide 5-Scheme 2. This material is treated with a carboxylic acid (such as N-Cbz- L-leucine. N-Cbz-D-ieucine or N-Cbz-L-leucinyl-L-leucine) and a peptide couroiing reag-ent such as BOP. EDC*HC/ -HOBT or N-methvlmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichloromethane, DMIF or TI-F) to Yield 6-Scheme 2. This material is saponified by treatment with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 7-Scheme 2.

Scheme 2A R0

R'

1 CO 2 Et a BocR'N N CEt b N S

N

21 R' R 0: HNIeN CO2Et c R 5 0 N-AVN CO 2 Et

HN'>

1 'N -/N '000: 2 S 0 R 2

R

0. 4 .00 *e 0: :0 15 a) Boc-anuno acid, EDC*HCI, 1-HOBT, DMF; b) TEA; c) R 5 OCOC1. i-Pr2NEt 0:S Compounds of Formula HI wherein X S, Y CH and Z N may also be prepared by methods analogous to those described in Scheme 2A. 1-Scheme 2Ais 8005treated with a ter-butoxycarbonyl-protected amiino acid (such as N-terr- 0 butoxycarbonyl-L-leucine) and a peptide coupling reagent such as BOP, EDC*HCIII-HQBT or N-methylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane, DMF or THlE) to yield 2-Scheme 2A, which is treated with trifluoroacetic acid to provide 3-Scheme 2A. This material is treated with a chloroformate (such as 2-biphenylmethyl chioroformate, 2-benzylbenzyl chloroformate, 2-naphthylmethyl chioroformate or 2-phenoxybenzyl chioroformate) S and a tertiary amrine base (such as diisopropylethylamine) in an aprotic solvent (such as methylene chloride) to provide 4-Scheme 2A.

Scheme 3 R' R'

H

2 N OMe a BocHN OMe b O 0 1 2 RI RI O BocHN NHNH 2 BocHN N C02Et d O

O

4 R R 1 S eS B ocHN COEt H 2 N C CO 2 Et N-N NN *0 eg00 00 00 0 H: HI- C0 2 Et

N-N

7 a) BocO, Et 3 N, THF; b) hydrazine hydrate, MeOH; c) EtO 2 CCOCl, Pyridine,

CH

2 Cl 2 d) Lawesson's reagent, toluene; e) TFA, CH 2 C1 2 f) DCO 2

H,

EDC*HC1/HOBT, Et 3 N, DMF goes 10 Compounds of Formula II wherein X and Y N, and Z S may be conveniently prepared by methods analogous to those described in Scheme 3. Scheme 3 is treated with di-rert-butyl dicarbonate and triethylamnine in THF to provide 2-Scheme-3. This material is treated with hydrazine hydrate in methanol to *provide 3-Scheme 3. The hydrazide is acylated by treatment with ethyl oxalyl chloride and pyridine in dichloromethane to provide 4-Scheme 3. This material is convenrted to the thiadiazole, 5-Scheme 3, by treatment with Lawesson's reagent in an aprotic solvent (such as THF or toluene). 5-Scheme 3 is treated with TFA to provide 6-Scheme 3. This material is treated with a carboxylic acid (such as N-Cbz- 43 L-Ieucine) and a peptide coupiing reagent isuch as BOP. EDCoHCI-HOBT or Nmethvlmi-nopholineiisobutyI chloroformate) in an aprotic sol vent (such as dichioromethane. DMF or THF) to yield 7-Schemne 3.

Scheme 4 BoH -y N CQ 2 Et BocHN LY C2E 0

N-N

b

H

2 N "r-O

E

NN

0 R C D N0 H I>C02Et

NN

0 OeeO a OeeS 0000

S

a a Sees 55 S 0 S S Sees a. S £0 S 00 0 00 S

SO

05 0 0055 0 0606 Ce..

0

S

Sees 0*50

C

*0*S 5e 60 0

S

000.5.

0 0

R

H >-CONH 2

NN

a) SOC1 2 pyridine, Et2, toluene; b) TFA, CH 2 Cl 2 c) DCO,H, EDC-HClIHOBT, Et 3 N, DMF; d) NH 3 EtOH Compounds of Formula II wherein X and Y N, and Z 0, and W- C02Et or CONH2 may be conveniently prepared by methods analogous to those described in Scheme 4. 1I-Schemne 4 is treated with thionyl chloride and pyridine in ether, followed by refluxing in toluene to provide 2-Scheme 4. The resultant 15 oxacilazole is treated with TFA to provide 3-Sbheme This rnaterial. is treated with a carboxylic acia (such as N-Cbz-L-leucine) and a peptide coiupling reagent such as BOP, EDC*HCL/1I-HOBT or N-methylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane, DMIF or THF) to yield 4-Scheme 4. The carboxylic ester is treated with ammonia in methanol to yield 5-Scheme 4.

schemg z 0 R2 Ho~ H2 IKC2Me a 1W R5A N C02Me 0 R1 b 0 R2 0~~HH 0 R'

C

MW

r

C

a a C C a a a a C a a a a a a a 0 R2 N- N N S S A A a) EDC-HCl/HOBT, Et3N,. DMR,~ b) H2NM22.H20, MeOH; c) CSC12, Et3N, CHC13 Compounds of Formula H wherein X and Y N, and Z 0, and W SH may be onveniently prepared by methods analogous to those described in Scheme 5. 1 -Scheme 5 and 2-Scheme 5 are treatd with a peptide coupling reagent such as BOP, EDC-HC1/1-HOBT or N-methylmorpholine/isobutyl chloroformate) in an 10 aprotic solvent (such as dichloromethane, DNIF or THF) to yield 3-Scheme 5 This material is treated with hydrazine hydrate in methanol to provide 4Scheme Treatment of 4-Scheme 5 with thiophosgene and trithylamine in chloroform provides 5-Scheme Scneme 6 0 R'

H

0 1 0 a

D

R'

N N SH

S

b 2 0 R' D N s N H

NH,

S

a) H-NCS 2 NH4 EtOH; b) H-NCSNH 2 EtOH 0

S

*500 0e 0 0*ee 0O 0

S

00 6 r .6 0 Compounds of Formula II wherein X CH, Y S and Z N, and W SH or NH2 may be conveniently prepared by methods analogous to those described in Scheme 6. Condensation of 1-Scheme 6 with ammonium dithiocarbamate in ethanol yielded 2-Scheme 6. Alternatively, 1-Scheme 6 can be condensed with thiourea in ethanol to give 3-Scheme 6.

Scheme 7 o R D N Br H 0 0 R H 0O H 0 0 *0@e 1 0 R D N N

SCOH

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 I- Scheme 7 with diethylamine N-oxide should provide 2-Scheme 7. Condensation of 2-Scheme 7 with a 2,3-diaminocarboxylic acid should then provide 3-Scheme 7, which may be converted to a variety of carboxylic acid derivatives using procedures previously described in other schemes.

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

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

Scheme 8 LCOH a T N 2 B L COEt 0 0 N 1 23 4 *R6 Ro.. 0 SRNN O RC e NH 0 H 0 20 a) i. i-BuOCOC1, NMM, THF; ii. CH 2 N2, Et 2 0; b) HBr, AcOH, Et 2 0; c)

H

2 NCSCO2Et, EtOH; d) R 6 3

NHNH

2 EtOH; e) R 6 5

CO

2 H, EDC.HC' I-HOBT,

DMF.

SCompounds wherein X CH, Y S and Z N, are prepared by methods 25 analogous to those described in Scheme 22. I-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- SIcheme S. The thiazole carboxviic ester !s x:a~ ith a hydrazine i such as hydrazine monohvdrate or methyl hydrazine) in ethanol to yield 5-Scheme S. 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 D.MF) 4; 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 WuH a LOH b LCSNH c d LC02 2 2N CO 2 Et 12 3 4 e or f 1 N2 CONHNH 2 N N N -J 0:05 0 H 004.

6 (J CO, S02) 15 a) i-BuOCOC1, NMM, NH 3 TI-F; b) Lawesson's reagent, THF; c) i.

EtO2)CCOCH 2 Br; ii. TFAA, Py, CH,7C1 2 d) H-)NNH,)H 2 O, EtOH; e) R 6 5 S502C1, PvCH2C 2

R

6 C0 2 H, EDC.HC1. 1-HOBT, DMF.

1-Schemne 9 is converted to 2-Scheme 9 by treatment with isobutyl chloroformate, N-methylmorpholine and ammonia in THE 2-Scheme 9 is treated with Lawesson's reagent in THE to provide the thioamide 3-Scheme This material is conve-.ted to the thiazole by condensation with an ct-ketoester followed by treatment with trifluoroacetic anhydride and pyridine in methylene chloride to afford 4-Scheme 21 whiich is converted to 5-Schemne9 by treatment with hydrazine monohydrate. This material is treated with a sulfonyl chloride (such as 4- ~:.phenoxybenzenesulfonyl 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-benzvloxycarbonyl-Lleucine. N-benzyloxycarbonyl-N-methyl-L-leucine, N-(2pvridinylmethoxycarbonyl)--leucine. S-pyridinvlmethoxvcarbonyl)-L-leucine.

N- (.4pyridinymethoxvcarbonfll)-L-leucife, 4-biphenylaceic acid. 3-(4pnridinylmethoxy)benzioc acid. or 4-methvl-2-(4-phef-lYphefyl)peflanoic acid) and a peptide coupling reagent (such as EDC.HCII-HOBT) in an aprotic solvent (such as DMF).

YN

I

Compounds wherein B R are prepared by routine methods of peptide synthesis as illustrated for instance by Scheme Scheme R81615 s R 16 aCO 2 Et R N CO 2 H H 2 N CO 2 Et N N

H

H 0 R 1 1 a sees b '6C N NH H 2 8K -p H% HN~.N IH BHK~ Rl,4 s ees R H 1 0 H@ 4 Oi 0 050 a) EDC*HCI, HOBT. DIF; b) H 2

NNH

2 H2O. EtOH; c) R1 4 -B-CO2H.

EDC*HCL. HOBT, DMF Treatnent of a mixture of -Scheme 10 and 2-Scheme 1 with a peptide coupling reagent (such as BOP or EDC.HCI-HOBT) in an aprotic solvent (such as DMF or dichioromethane) provides 3-Schgme LO. This material is treated with hydrazine hydrate in ethanol to yield 4-Scheme LO. which is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as BOP or EDC.HCl/1-HOBT) in an aprotic solvent (such as DMIF or dichioromethane) to provide 5-Scheme Compounds of Formula IV wherein R 23

R

24 are H. and R 2

R

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

Scheme 11 0 H 0 H 2 a 21I 1 2 CO,2H R" N N N RA H,NHN NHNH, N N 0 H H 0 1 2 a) EDC.HCI. 1-HOBT, DMF Symmetric compounds of the Formula IX having RCO as the terminal substituent on both sides are prepared by methods analogous to those described in Scheme 11. Treatment of 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*HCI/1-HOBT) in an aprotic solvent (such as DMF) provides 2-Scheme 11.

*oe 15 Nonsymmetric compounds of the Formula IX, and compounds of Formula IV wherein R 22

R

2 3

R

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

*S 0 *e.

*go* 0 -Scheme 12

H

R

4 00R R 4

CNHH

2 b N-N C ORRCOHH3 12 R" 0 g1 H 0H 0 H I AA IN RN, N NHNH 2 deo f R N N ,F 0 H0 H H 4 1 (F COP 52 So0 2

R

52 a) H 2

NNH

2

H

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

NNH

2

'H

2 O, MeOH; d) R 49 C0 2

H,EDC*HCI,

1 -HOBT, DMF; e) R 52 S0 2 C1 or R 5 2 000I, pyridine, DMF; f) R 5 2 C0 2 C0R 52 g) Rt 52 00NR 51

NH

2 ramn f- Shre1 ihhdazn yrt napoi ovn sc to Tffream of-Scheme 12.Timaealsttd with hydrazine hydrate in a proticsoen(uc .:solvent (such as methanol or ethanol) to provide 4-ShemeL2. Treatment of 4- 10 Scheme 12 with a sulfonyl chloride (such as 4-phenoxyphenysulfonyl chloride), an acid chloride (such as beazoyl chloride), or a carbainoyl chloride (such as -2 methyipropyl)-N-(4-phenylphnyl)cabanoyI chloride) and pyridine in DN{F affords 5-cee 2 Alternatively, 5-Scheme-12 may be prepared by treatment of 4-cee1 with a carboxylic acid (such as N-benzyloxycarbonyl-L-alanine.

N-

benzyloxycarbonyi-L-prohine, N-benzyloxycarbolylglycine, benzyloxycarbonyl-2-aminobutyric acid, N-benzyloxycarbol-Nmethy-L-leucine, N-tert-butoxycarbonyl-N-methy1-L-leucine, N-acetyl-L-leucine, N-acetyl-L-alanine, N-(2-pyridinylmethoxycarbony)-L-leuciflC. djmethylaminomethyl)benzyloxycaboly l]-L-leucine, 4-phenylbenzoic acid, 4- 0e rnethoxybenzioc acid, 4-phenoxybenzoic acid, 4-(N,N- 2 0 dimethylarninomethy l)benzoic acid, 4-yrx--N(-opoioehllezi acid. 3-IIN-(4-morpholinomethyl)helzoic acid, 2-benzyloxybenzoic acid, 3benzyloxybenzoic acid, 4-benzyloxybenzoic acid, 4-(3a ,methy iarmno meth,.1-propoxy *benzoic acia. 3--benzvioxv--r-nethoxvbenzolc: .az!U.

3-benzvloxv-4.5-dimethoxvbenzoic acid. 3-benzyioxy-5-ethoxyoenzoic acid. 34 pvridinyimrethoxv)benizoic acid, 4-biphenviacetic acid. 2-(4phenylphenoxv)propionic acid or 4-methyl-2 -4-phenvl1phenvhpentanoic acid) and a eptide coupling reagent such as BOP, EDC-HCI-HOBT or Nmechylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane, DMF or THF). 5-Scheme- 12 may also be prepared by treatment of 4-Scheme 12 with an anhydride (such as acetic anhydride). Alternatively, Scheme 12 may be converted directly to 5-Scheme- I by treatment with a hvdrazide (such as 4-methylpentanoyl hydrazide or N-methyl-N-benzyloxvcarbonvl-Lfeucinyl hydrazide).

Scheme 12A

R

R

21

CONHNH

2 a R 2 1

CONHNHCH

2 R b P N- H 0 H 0 H 0 21 1I 11 'J d, eor f R 21 'Y N N NHNH 2 N N X 0* II I I .0 R. 0 H H 4 (RCH 2 23 (XP C0R 5 2 So R 52 2= 2 a) i. PhOHO, EtOH; ii. BH3-THF; b) CI 2 CO, PhMe; c) H 2

NNH

2

'H

2 Q, MeOH; d) R 52 C00 2

H,

EDC-HCI, 1-HOBT, DMF; e) R 52 S0 2 C1 or R 5 2 COCI, pyridine, DMF; )R, 52 C 2 C0R 52 Nonsymmet-ic compounds of Formula WV, wherein R 2 3 H are prepared by methods analogous to those described in Scheme 12A. 1 -Scheme 12A is treated with an aldehyde (such as benzaldehyde) in a protic solvent (such as ethanol) and the resulting imnine is treated with borane-THF complex to afford 2-Scheme 12A, which is subsequently treated with phosgene in toluene to afford 3-Scheme 12A.

a:...: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 reagyent such as BOP. EDC-HCbU1-HOBT or N-meihyimorpholineuisobutvl chloroformate) in an aprotic solvent (such as dichioromethane. DIMF or THF) to vield 5-Scheme-1I2A.

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

Scheme 13 0 OH 0 0

OHH

HN~ 0~I.

100 a) HBTU, NMM. DMEF; b) Jones, acetone 1,3-Bis-axnido propan-2-ones may be prepared by acylation of 1,3-diamninopropan-2-ol I -chmeJ13 with a carboxylic acid 2.Scbhxne.13 or a mixture of 2 15 different carboxylic acids (2 and 3) in equimolar amounts and a coupling reagent such as a dialkyl carbodiimide such as DCC or EDCI or HBTU/ N-methyl 0o* morpholine, followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

Scee1 S0op a. b

H

N' NH2S~ a) 0 NNM M;b ons ctn 251,-iss..nrnd poaoe ma0epeae ysufnlto f1 SO..o-rpa-2o I OHre1 ihasloy hlrd -cen 4adabs such as N-methyl morpholine. followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

&oH 2 0 a-

OH

H 2 'j

H

0+0

H

2 0 NH

CH.

Scheme 0 OH K NH 0 N- N2 NI 0 P N

SO'C

CA 3 0. C a) EDCI. HOBT. DMF: b) NMM, DMF. 3) Jones, acetone We..

0 0000

S.

S

S. See.

S. 5 0 *0 0 0 I-Anido-3-sulfonamido propanones may be prepared by acylation of 1.3diamino-propan-2-ol I-Sch me 15 with a carboxylic acid -Scheme 15 and a coupling reagent such as a carbodimide 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 0 0 2: P-N 2 0 3: PW~ 4: RoN 2 0 0M 0

H~

0 O e S NK, 6 0 Me I I CIO'S- 7 0 0r SS= 0 Me I1-Amrido-3-sulforiarlldo alkan-2-ones that are larger than propan-2-one.

such as butan-2-one or 5-methy1-hexan-2-ofle, can be prepared by conveni~ng an Nprotected peptide such as Cbz-leu-leu-OH 1 -Scheme 16 to its bromo methyl ketone 3-Scheme 16 via a diazo methyl ketone 2-Schemne 16. Then. the bromide 3-Scheme 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-Scheme 16. Subsequent reduction of the azide with a reducing agent such as. 13-propandithiol gives the free amine 6-Scheme 16. Acylation or sulfonylation of the amine gives ami~de or sulfonamide 7-Schme 16. Finally, oxidation of the carbinol with an oxidant such as Jones gives the desired compounds.

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

Scheme 17 23 0050 a." 0 0 0.

501 0 'A'N @0 1* 7 a) NaN 3 MeOH, H 2 0; b) Tosyl chloride, triethylamine,

CH

2

CI

2 r' ease Ellinan dihydropyran resin PPTS, C1(CH 2 2 C1; d) PhCH2)NH2, toluene, degrees C; e) HATIJ, N-methyl morpholiie, NMP; f) HS(CH 2 3

SH.

MeOH, Et 3 N; g) Cbz-leucine HBTU, N-methyl morpholine, NMP; h) 00. :TFA,

CH-)CI

2 Me 2 S; i) Jones reagent, acetone Azide opening of glycidol I -Schemne 17, followed by tosylation of the primary alcohol gave tosylate 2-Scheme 17, which was coupled to Ellman polymer 3-Scheme 17 as described by described in]. Med. Chem. 1995, 38, 1427-1430 to produce polymer 4-Schemne I which wvas re-acted wvith benzx'i amiune in toiuerie.

then washed extensively with various solvents. Then, the azide was reduced wuch I .3-propanedithiol in MeOH, triethvlamine, then was washed extensively with various solvents. Coupling of Cbz-leucine 6-Scheme 17 with the diamnine 17 with equimolar amounts and a coupling reagent such as a dialkyl carbodiirnide such as DCC or EDCI or I-BTU/ N-methyl moi-pholine. Cleavage of the ether linkage to an alcohol was accomplished with trifluoroacetic acid with various scavengers. Finally, oxidation of the carbinol to a ketone 7-Scheme 17 with an oxidant such as Jones reagent provided the desired final product.

Scheme 18 0 0 0 H0 23 N0 006. 5 0 A 0 sees 0 e a) 4-pyridyl methyl amine, isopropanol, reflux; b) Cbz-leucine, HBTU, so** 15 N-methyl morpholine, DMF; c) hydrazine, MeOH, reflux;, d) 2- 0: dibenzofuransulfonyl chloride. N-methyl morpholine, DMF; e) Jones reagent, acetone N-(2.3-Epoxypropyl)phthalimide I -Scheme 18 (Aldrich) was reluxed with an amnine such as 4-pyridiyl methyl amnine in isopropanol. The secondary amine 2 0.Schem 18~ was then acylated with an acylaring agent such as Cbz leucine or a a sulfonylating reagent such as 2-dibenizofuransulfonyl chloride and base such as Nmethyl morphoLine in DMEF. The phithalimide was then removed with hydrazine in 006: MeOH and the resulting free amine was acylated with an acylating agent such as Cbz leucine or a sulfonylating reagent such as 2-dibenzofuransulfonyl chloride and 0:98 base such as N-methyl morpholine in DMIF.

0 Compounds of Formula LX may conveniently be made using methods analogous to those in Schemes 19 and Compounds of Formula X may be coniveniently made using methods analogous to those described in Schemes 2 1 -2 Scheme 19 3 ~COEt C02 L N 2 L N R 65CO 2 M b R 65 CONR 64NH 2 CH 0 L N *K R6 0 R' 600 0 00 s o a) KOH, MeOH/H20; b) R66NHN}I 2 EtOH; c) EDCeHCI 1-HOBT, DMF Compounds wherein X CH, Y Z N and R 4 H, are prepared by methods analogous to those described in Scheme 19. Carboxylic ester I1-Scheme 19 is treated with a hydroxide base (such as lithoumn hydroxide, sodium hydroxide or potassium hydroxide) in methanol/water to provide 2-Shme 19. 3-cee1 is 15 treated with a hydrazine (such as methylhydrazine) in a protic solvent (such as ethanol) to give 4-cem 9 2-Sceme 19 and 4-Schme 19 are coupled by treatment with a peptide coupling reagent (such as EDC'HCII1-HOBT) in an aprotic solvent (such as DMIF) to provide 5-Sh.me 19.

*00.

C

0003 *000 0 0000 000w Scheme EtO CCOCH Br S-1S7 2H2N N CO Et B rN =Et 12 3 cord e odAr ~N CO 2 Et A N CN H 2 4 SH 0 Ar NN R 6

N

0 H 6 a) Thiourea, EtOH; b) i. NaNO 2 16% aqueous H~r; ii. CuBr, 16% aqueous HBr; :iii. HBr EtOH; c) ArB(OH) 2 Pd(PPh 3 4 CsF, DM[E; d) ArSnMe 3 Pd(PPh 3 4 PhMe; e) H 2

NNH

2 oH 2 0, EtOH; e) R 6 5 CHECHI HBT Compounds wherein X S, Y CHI, Z N and V 2-methoxyphenyl or 2benzyloxyphenyl, are prepared by methods analogous to those described in Scheme Ethyl bromopyruvate (1 -Schemne 20~ is treated with thiourea in refluxing ethanol to provide 2Scem 2, 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-che.me 2. Treatment of this material with an arylbororiic acid (such as 2-benzyloxyphenylboronic acid), tetrakis(ti-iphenylphosphine)palladium(O) and cesium fluoride in refluxing DN{E provides 4-Schemne 20. Alternatively, 4-Scheme 20, may be prepared by treatment of.3S m 20 with an arylstannane (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-Ieucine, N-(2-pyridinvlmethoxycarbonvl)-L-leucine, N-(3-pyridinylmethoxvcarbonyl)-Lleucine or N-(4-pyridinylmethoxycarbonvl)-L-leucine) and a peptide coupling reagent (.such as EDC-HC1/1-HOBT') in an aprotic soivent such as DINIF) to Drovilde 6-Scheme Scheme 21 RCOCI a RCONHR 4 3 RCH2NR67 C RCH2 NR67CSNH2 S2 3 4 66OE1R6A7

CONHNH,

R R b KN R R NN 0 H i a) R67NH2 Py, CH2C12; b) LiIH4, THIF; 0) i- C1CS, Py, CH202Z ii. NH3' MeOH or I. PhCONCS, CHC13; ii. K2C3, MeOH, H20; d) Et02CCOC H2Br, EtOH; e) H2NNH2H20, EtOH; e) R65CO2H, EDC*HCl. I-HOBT, DMF Compounds wherein X S, Y CH, Z N and V NR6R7 are prepared by methods analogous to those described in Scheme 2 1. An acid chloride 1 Scheme 21) is treated with a primary amine (such as 4-aminobiphenyl or aniline) and pyridine in an aprotic solvent (such as methylene chloride) to provide 2-Scheme 2 1 which is treated with lithium aluminum hydride in THF to afford 3-Scherne Treatment of 3-Schempq 21 with thiophosgene and pyridine in methylene chloride, foMowed by treanmeat with ammonia in methanol provides 4-Scheme 2, Alternatively, 4-Scheme 21 may be prepared by treatment of 3-Scheme 21 with benzoyl isothiocyanate, followed by treatment of the intermediate benzoyl thiourea with potassium carbonate in methanol/water. 4-Scheme 21 is treated with hydrazine hydrate in ethanol to give 5-Scheme 21. Treatment of 5-Scheme 21 with a carboxylic acid (such as N-(2-pyridinyimethoxycarbonyl)--leucine, N-(3pyridinylmethoxvcarbonyl)--leucine or N-(4-pyridinylmethoxycarbonyl)-Lleucine) and a peptide coupling reagent (such as EDC-HCI/I-HOBT) in an aprotic solvent (such as DMIF) affords 6-Scheme 21.

59 Scheme 22

H

H,N-

I

a N b L CO 2 Et c

H

2

NCSCO

2 Et Et

H

2 N CO 2 Et N-N 1 2 H H O H I

I

L N CONHNH 2 L" N NN R N-N N-N H O 4 8 a) H-2NNH-*H20, EtOH: b) LCO2CO2i-Bu, 200 c) H2NNH2*H20, EtOH; d)

"R

6 5 CO2H, EDC*HCl, 1-HOBT, DMF S* Compounds wherein X and Y N, and Z NH, are prepared by methods 10 analogous to those described in Scheme 26. 1-Scheme 22 is treated with hydrazine hydrate in ethanol to give 2-Scheme 22. which is heated with a mixed anhydride to provide triazole 3-Scheme 22. This material is treated with hydrazine hydrate to provide 4-Scheme 22. which is treated with a carboxylic acid (such as Nbenzyloxycarbonyl-L-leucine) and a peptide coupling reagent (such as EDC*HCL/1- 15 HOBT) in an aprotic solvent (such as DMF) to provide 5-Scheme 22.

0 *o 0@ 0 Scheme 23 0 L

N

H R" N NBoc H 0 R 1 0 H

R

69 SN NHR H 0 0 L

N

H

H

R

6 9 N M'R6 61 0 R 0 s 0 5 S.

.S

6@

S

*5 S

S

0@

S

I (M CO. SO 2

R

6 0 H N 6 SocNRW S H 0 R 6 a H

OS

G

00* 0 S

SOS.

0*@4 0 4 a) TFA; b) R 6 2 C0 2 H, EDCHCI. I-HOBT, DMF; c) R 6 2 S0 2 Cl, i-Pr 2 NEt Compolinds wherein X S, Y CH, Z N, L CH(R 6 6 )NR6R 6 8 where

R

68 Boc or Cbz, or R65 CH(R 6 9

)NR

6 1

R

70 where R 7 0 Boc or Cbz are prepared by methods analogous to those described in Scheme 27. i-Scheme 23 is 10 treated with trifluoroacetic acid to provide 2-Scheme 23. This material is treated with a carboxylic acid (such as pryazinecarboxylic acid, isonicotinic acid, 4imidazolylacetic acid or pipecolic acid) and a peptide coupling reagent (such as EDC*HCVI-HQBT) in an aprotic solvent (such as DNF) to provide 3-Scheme 23.

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

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

Scheme 24

OH

BoNHCO H a N N H 0

OH

H H 0 0 OCHIPt,

OH

H2 N N. 0 0 0 C>CH 2pt 0000 00.

00 0 006 5 a) EDCI, DMF; b) 2-PhCH,7OPhSO-,Cl, NMM, DMF; c) TFA. DCM; d) 4-pyndvl acetic acid, HBTU, NMIM, DMF; e) Jones 1.3-Diarnino-propan-2-oI (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.

0000 0 000V @006 0 0000 0000 0 o.0.

.000 00 0. 0 0 0.0.06 6 Scheme H

O:CN

a SC bz -J H OH Me CbNH N NHCbz

OH

I

a Cbz-N NHUH ~lbz 0 0 a) HBTU, NMM, DMI, allyl arnine, b) mCPBA, DCM; c) MeNH2, isopropanol, C d) Cbz-leucine, EDCI, DMIiF; e) Jones, acetone N-Allyl amne (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 dimethyl diooxirane). The epoxide is opened with a subsituted an-ine, then the antine is acylated or sulfonylated. Final oxidation gives the desired ketones.

The starung materials used herein are commercially available arrno ac:is or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books. such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience Coupling methods to form amide bonds herein are generally well known to the art. The methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984: E.

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

Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted 0 side reactions. Such protective groups are described generally in Green, T.W.

PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley Sons, New :York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art.

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

20 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, .*00 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 25 treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carboate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li Na Ca Mg++ and NH4 are specific examples of cations present in pharmaceutically acceptable salts.

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

0 0

U.S.

S

S.

S

S S 6@ S

S.

6 *5 S *0

OS**

0 S5*S

S

@559 0

S

0.5O 0@ S. S 0

OSOSS*

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 15 sodium citrate.

Alternately, these compounds may be encapsulated, tableted or prepared in 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 20 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 I g per dosage 25 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, glycenn, gelatin or polyethylene glvcols 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 15 cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, Smalaria, 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, 20 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.

25 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 compnse 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 pneumocysris 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 0 dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, S 25 in a manner to maintain the concentration of drug in the plasma at a concentration

S

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 adrrnistered orally to ime patient. in a manner such that the concentration of drug is sufficient to inhibit bone resorpton 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% DMvSO.

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

25 Product fluorescence (excitation at 360 nM; emission at 460 nM) was monitored 0 0 "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 carred 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 I (Brandt et al., Biochemirsry, 1989. 28, 140): V VmA /[Ka(J I/Ki, app) +A] whr(I) tevlct f h ecinwt aialvlct mAi h where [A is the ocofceteration wiprdth maoimal vecim t, A is theinta 15 sconentrno rat aewt ihei constant ofb /a andhibistth concentrationorkb/ 1)dsiin charerico time-dependent inhibition, lte dtaio fridiia srtets was bee full0 anlz decgived (M 5 orin t eatioAd. nz l 2:a.AesM .Bo. 98 2020) Human Osteoclast Resorption Assay Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium by centrifugation (1000 rpm. 5 rin at The medium was aspirated and replaced with munne 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 "e*e medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.

S. S.i 15 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 20 x 10. 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 25 1.7g/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEMI diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at 37 0 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 olaced 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 0 C. The slices were then washed in cold water and incubated in cold acetate buffer fast red garnet for min at 4°C. Excess buffer was aspirated, and the slices were air dried following a 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.

00* *0 15 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 0 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 0 (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet unpact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm- 1 Mass spectra were taken on either VG 70 FE, PE Syx API I, 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 uncorrectec All temperatures are reported in degrees Celsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.

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

Examples In the following synthetic examples, temperature is in degrees Centigrade Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in iee "the art can, using the preceding description, utilize the present invention to its fullest a. 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. l'S)-2-(benzvloxvcarbonvl)amino-N-[ 1'-(2-carboethoxvthiazol- 4 20 vl)-3'-methvlbutyll-4-methylpentanamide a) N-benzyloxycarbonyl-L-leuciyl-L-leucinyl bromomethylketone l-Methyl-3-nitro-l-nitrosoguanidine (5.9 g, 40.11 mmol) in ether (200 mL) is cooled to 0°C. 40% potassium hydroxide is added slowly and the diazomethane is allowed to collect in the ether solution for 30 minutes at 0°C.

25 N-Cbz-L-Leucinyl-L-Leucine (Bachem) (4.0 g, 10.58 mmol) is stirred in tetrahydrofuran at -40"C. N-methylmorpholine (1.07 g, 10.58 mmol, 1.16 mL) and isobutyl 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, LON citric acid. saturated aqueous sodium bicarbonate (car-efullyj.

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 (400NMiz. CDCI3) 67.34 (in, 5H), 6.51 I 5.15 IlH), 5. 10 2H), 4.78 (in, IlH), 4.20 I 4.04 (dd, 2H), 1.63 (in, 6H), 0.93 (mn, 12H).

b) (2S, 1'S)-2-(benzylox'ycarbonyl)aflno-N-[ 1'-(2-carboethoxythiazol-4-vl)-3'methylburyl]-4-methylpentanamnide The compound of Example I1(a) (2.0 g, 4.4 inmol) 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 IH NMR (400 MIHz, CDCI3) 867.32 IH), 7.21 (mn, 5H), 6.40 Ii), 5.13 (dd, IH), 5.02 2H), 4.41 2H), 4.06 (in, lH), 1.71 (mn, 2H), 1.47 (in, 4H), 1.33 3H), 0.73 (mn, 12H).

Preparation of (2S. 1 S-2-(benzyloxycarbonylharino-N-fl1 -(2-carboxvthiazoI-4-yl)- 3'-methylbutyll-4-methlpentanan-ide 41 4 The compound of Example 1(c) (0.92 g, 1.88 inmol) was stirred in 0 0 20 tetrahydrofuran at 0 0 C with 1LON sodium hydroxide. After stirring for 1 h, the 41 solution was quenched with 1LON citric acid and extracted three times with 00*0dichioroinethane. The combined organic extracts were evaporated in vacuo to give the title compound as a white solid (0.844 IH NMR (400 MUz, CDC13) 6 7.40 ILH), 7.23 (mn, 5H), 6.89 I 5.22 I1H), 5.14 (dd, I1H), 5.02 2H), 4.15 (in, 1H), 1.67 (mn, 2H), 1.44 (mn, 4H), 0.81 (mn, 12H).

Example 3 Preparation of (2S. I S-2-(benzyloxycarbonv1~anino-N-rIl'-(2-carboxarnidothiazol- 4-yl)-3'-methylbutyll-4-methvlpentanarnide The compound of Example 2 (0.408 g, 0.88 inmol) in tetrahydrofuran was cooled to 4oaC and treated with N-methylinorpholine 185 1.85 inmol, 0.2 73 mnLi and isoburvil chloroforrnate 0.88 ramol. 0. 11 The miuxture 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 1LON citric acid, 5% aqueous sodium bicarbonate, and brine. The organic solution was dried over magnesium sulfate, filtered, and evaporated to a residue which was chromatographed (silica gel, 3% methanoL/dichloromethane) to give the title compound as a white solid (0.245 IH NMviR (400 MHz, CDCI3) 6 7.22 (in, 7.04 lH), 6.40 (br s, lE), 5.51 (br s, lH), 5.09 (in, 1H), 5.02 (dd. 2H), 4.07 IH), 1.66-1.42 (mn, 6H), 0.82 (mn, 12H).

Example 4 Preparation of (2S. 1'S)-2-(benzyloxycarbonvl)amino-N-r 1'4(2-cyanothiazol-4-vI 0....methylbutyll-4-methvlpentanamide The compound of Example 3 (0.185 g, 0.4 inmol) was dissolved in dichioromethane, cooled to 0 0 C and treated with TFAA (0.093 g, 0.44 mnrol, 0.06 rL) and pyridine (0.07 g, 0.88 mmol, 0.07 mL). After 3 h, the mixture was poured into a solution of saturated aqueous sodium bicarbonate and extracted with dichioromethane. The organic extracts were washed with 5% hydrochloric acid and brine, dried over magnesium sulfate, filtered, and evaporated to an oil which was *000* chroinatographed (silica gel, 40% ethyl acetate/hexane) to give the title compound *as a white solid (0.095 I H NMIR (400 Miflz, CDCl3) 5 7.44 ILH), 7.29 (s, 6.51 (br d, 1H), 5.14 (mn, lH), 5.07 2H), 4.11 (mn, IH), 1.78-1.41 (mn, 6H), 0.83 (mn, 12H).

.0:.25 Example Preparation of (2S.1 'S)-2-4benzyloxycarbonyl)anino-N-[ benzylcarboxamido'thiazol-4-vll-3'-methyI buil-4-methlpgntanamide To a solution of the compound of Example 2 (0.12 g, 0.26 mmol) in dichloromethane under argon at room temperature is added benzylamine (0.03 g., 0.29 inmol, 0.03 mL), BOP reagent 115 g, 0.26 inmol), and triethyl amine (0.026 g, 0.26 rnrol. 0.04 mrL) which is allowed to stir for 16 h. The solution is washed with water, then brine and the organic layer is dried over magnesium sulfate, filtered, and evaporated to give a residue which was chromatographed (silica gel.

ethyl acetate/hexane) to give the title compound as a white solid (0.065 1

H

NMR (400 MHz, CDC]3) 657.56 (br s, 11), 7.33 10H), 6.48 (br d, 1H), 5.15 (dd, 1W), 5.03 2H), 4.63 2H), 4.12 IH), 1.72-1.40 6H), 0.85 (m, 12H).

Example 6 Preparation of (2S. I'S)-2-(benzvioxvcarbonvl)anTino-N-f methvlpropvl)carboxamidolthiazol- 4 -vll-3'-methylbutvl-4-methylpentanamide Following the procedure of Example 5, except substituting isobutylamine for benzylamine, the title compound was prepared (0.074 1 H NMR (400 MHz, CDCI3) 5 7.27 5H), 7.19 1H), 6.38 (br d, 1H), 5.09 1H), 5.01 2H), 15 4.07 1H), 3.20 (dd, 2H), 1.83 1H), 1.69-1.40 6H), 0.90 6H), 0.81 12H).

0* S Example 7 Preparation of (2S.1 'S)-2-(benzvloxvcarbonl)amino-N-f henylethyl~carboxami dolthiazol-4-vll-3'-methylbutvll-4-methylwntanamide Following the procedure of Example 5, except substituting 2phenylethylamine for benzylamine, the title compound was prepared (0.070 IH NMR (400 MHz, CDC13) 8 7.30-7.11 11H), 6.35 (br d, 1H), 5.09 1H), 5.01 2H), 4.05 1H), 3.64 2H), 2.87 2H), 1.69-1.40 6H), 0.80 (m, 25 12H).

Example 8 Preparation of (2S. 1 S)-2-(benzvloxyca-rbonvl lamjino--\,-F -(4-carboethoxvthiazol- v me thv lbu tv I 4-methy Ipgntanamide a) N-tert-butoxycarbonyl-(L)-leucinamiide To a solution of N-rerr-butoxvcarbonyl-(L)-leucine (Advanced Chemtech) g, 20.0 rnmol in dry THF (IO0m.L) at -40'C was added isobutyl chloroformate (2.7 a, 20.0 mmol) and N-methylmorphiline (4.2 g, 42 inmol). After 15 minutes of stirring, amrmonia 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 imol). H N'M (400 MIHz, CDCl3) 8 6.3 8 (br s, I H 5.79 (br s, I 5.04 *:so(br d, lH), 4.13 (in, lH). 1.71-1.49 (mn, 3H), 1.39 9H), 0.92 (dd, 6H-).

b) N-rerr-butoxycarbonyl-L-leucinethioamide 15 To a stirring solution of the compound of Example 8(a) (2.38 g, 10.35 inmol) in dry THF was added Lawessons reagent (2.51 g, 6.21 minol) and the mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the residue chromatographed (silica gel, methanolldichloromethane) to give the title compound as a white solid (2.3 IH NMR (400 M]Hz, CDC13) 88.54 (br s, 1H), 7.97 (br s, IH), 5.28 (br d, 1H), 4.52 (in, 1H), 1.72-1.58 (mn, 3H), 1.40 9H), 0.92 6H).

c) (1 1-(rerr-butoxycarbonvl)arnino-l1-(4-.carboethoxyrhiazol-2-yI)-3inethylbutane The compound of Example 8(b) (2.40 g, 9.76 rnmol) was stirred in dry acetone (20 mL) under argon at -10 0 C. Ethylbromopyruvate (2.12 g, 10.73 rnol, 1.35 inL) 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 a, 10.73 rnrnol.

m.L and pyridine (1.70g-, 21.47 ramol, 1.75 rnL) in dichioromethane for I h at Excess solvent was removed in vacua and the residue was dissolved in dichioromethane. The solution was washed with saturated aqueous sodium bicarbonate and 1LON KHS04 until pH 7. The solution was dried over sodium sulfate, filtered, and evaporated to an oil which was chromatographed (4% methanol/dichloromethane) to give the title compound as a tan solid (1.2 IH NMvR (400 MHz, CDCI3) 6 7.98 IH), 5.04 (br d, IH), 4.95 IH), 4.31 (q, 2H), 1.88 (mn, IH), 1.63 (mn, 2H), 1.40 1.32 3H), 0.85 (dd. 6H).

d) (2S. 1'S)-2-(benzyloxycarbonyl)amilo-N-[ 1 -(4-carboethoxythiazol-2-yl)-3'methylbutyl]-4-methylpentanamide The compound of Example 8(c) (1.0 g, 2.92 inrol) was dissolved in neat TFA (1.0 inL) and stirred for 15 mainutes. The solution was diluted with methanol and evaporated in vacuo. A portion of the residue obtained (0.36 g, 1.49 mrnol) was 15 dissolved in dichioroinetbane with N-Cbz-L-leucine (0.394 g, 1.49 ininol) BOP reagent (0.66 g, 1.49 inmol) and triethylamine (0.73 g, 7.2 mrnol, 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 title compound as a white solid (0.396 IH NMvR (4.00 CDCI3) 8 7.96 1H), 7.25 5H), 6.61 (br di, IH), 5.30 (mn, 1H), 5.09 (br d, 1H), 5.01 2H), 4.33 (q, 2H), 4. 10 (mn, 1 1.90-1.58 (in, 6H), 1.29 3H), 0.81 (dci. 12H).

~::Example 9 do 25 Preparation of (2S. I'S)-2-(benzyloxycarbonyflanmino-N-[ 1'-(4-carboxthiazol-2-VI')- 3'-methvlbutyll-4-nethyleftanamihde Following the procedure of Example 2, except substituting (2S,1'S)-2- (benzyloxycarbonyl)amilo-N-[ (1 (4-carboethoxythiazol-2-y1)-3-ethylbutylIinethylpentanamide for (2S, 'S)-2-(benzyloxycarbonyl)arnino-N-( carboxythiazol-4-yl)-3'-methylbutyl-4-nethyIpeltalalde, the title compound was prepared (0.301 IH NMR (400 MHz, CDC13) 8 8.06 1H), 7.24 (mn, 5H), 7.11 I 5.30 (in. 5.04 is 2H). 4 .16 I 1.88-1.40~m 6H). 0. 71 (dd, 12H).

Example Preparation of (2S. I 2-('ben zy lox ycarbonvyl)ami no-N- f 1 carboethoxythiadiazol-2-vl -methvlbutyll-4-merhvlpentanarnude a) N-tert-butoxycarbonyl-L-le ucine methyl ester To a stirring suspension of L-leucine methyl ester hydrochloride (Aldrich) (6.00 g. 33.0 mmol) and di-tert-burvl dicarbonate (7.21 g, 33.0 mmnol) in THF nil-) was added triethylamine (3.34 g, 33.0 mmol, 4.60 rnL). 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 NMR (400 Mffz, CDCl3) 6 4.88 IH), 4.33-4.31 i (in, 1H), 7.73 3H), 1.75-1.48 (in. 3H), .1.44 9H), 0.96 3H), 0.93 3H).

b) N-rert-butoxycarbonyl-L-leucine hydrazide To a stirring solution of the compound of Example 10(a) (8.02 g, 32.7 rnmol) in methanol (250 niL) was added hydrazine hydrate (16.38 g, 327 Mmxol, 20 15.9 mL). After stirring for 22 h at room temperature, the solution was 0.200 sees. concentrated and the residue was azeotroped with toluene to provide the title compound as a white foam (8.02 g, 100%). 1 H NNIR (400 MlHz, CDCI3) 6 7.71 (br s, IH), 4.99 2H), 4.12-4. 10 (mn, lH), 3.94 (br s, 211), 1.68-1.49 (in, 3H), 1.44 (s, 9H), 0.95 3H), 0.92 3H).

0 so0a25 c) 2 2 -(benzyloxycarbonyl)amino-.4-methylpentaoy]..N' carboethoxycarbonylhydrazide To a stirring solution of the compound of Example 10(b) (8.02 g, 32.7 mxnol) and pyridine (2.85 g, 36.0 rnmol, 2.91 rnL) in dichloromethane (200 mL) was added ethyl oxalyl chloride (4.91 g, 36.0 minol. 4.02 inL. After stirring at room temperature for 2 h, thve solution was washed with I N HC1, water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate.

filtered, and concentrated to afford the title compound as a white foam (9.84 g, IH NMR (400 MHz, CDC13) 5 9.32 (br s. 2H), 5.04 2H). 4.38 2H).

4.28 1H), 1.77-1.56 3H), 1.44 9H), 1.39 3H), 0.96 3H), 0.94 (d.

3H).

d) (1S)-1 -(tert-butoxycarbonyl)amino-1 -(4-carboethoxythiadiazol-2-yl)-3methylbutane To a stirring solution of the compound of Example 10(c) (2.50 g, 7.24 mmol) in toluene (70 mL) was added Lawesson's reagent (1.46 g, 3.62 mmol). The mixture was heated at reflux for 3 h. The solution was diluted with ether, washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated to leave a pale yellow oil. The crude material was purified by flash chromatography on 75 g of 230-400 mesh silica gel, eluting with 1:4 ethyl acetate/hexanes, to provide the title compound as a pale yellow solid (1.75 g, 1 H NMR (400 MHz, CDC13) 8 5.19 1H), 5.13 (d, 1H), 4.51 2H), 1.95 1H), 1.83-1.73 2H), 1.44 9H), 1.00 3H), 0.98 3H).

20 e) (IS)-1-amino-l-(4-carboethoxythiadiazol-2-yl)-3-methylbutane bistrifluoroacetate salt To a stirring solution of the compound of Example 10(d) (1.75 g, 5.1 mmol) see in dichloromethane (40 mL) was added TFA (10 mL). After stirring for 5 min at room temperature, the solution was concentrated to give the title compound as an 25 oily pale yellow solid (2.40 g, 100%). 1 H NMR (400 MHz, CDC13) 8 7.83 (br s, 4H), 5.20 1H), 4.51 2H), 2.07 2H), 1.70 1H), 1.44 3H), 1.00 (t, 3H).

f) (2S,1'S)-2-(benzyloxycarbonyl)amino-N-[ '-(4-carboethoxythiadiazol-2-yl)-3'methylbutyl)-4-methylpentanamide a 9O90 9 0e*@

S

0 @000 6* 96 0 @0 0 0009 00 S 9 6

S.

0 69 S 09 66 0

S

0 *SS6

OOSS

O6OS 0 @9 9. 0 0 6@6S60 9 To a surrng, solution of thIe compound of Example l10 e) 566. 1 mg, 1.20 nimol), N-Cbz-L-leucine (250.5 mg, 1.32 rnmoi). I-(3-dimethylarrmnopropyl)-3echvlcarbodnimide hydrochloride (253.3 mg, 1.32 mmuol) and Ihydroxybenizotriazole (32.5 mg, 0.24 rnmol) in 2.5 niL of DMff was added ujiethvlarnine (243. 1 mg, 2.40 munol, 0.335 After stirring at room temperature for 3 d, the mixture was diuted 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.chromatograpby 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

Nl-vff (400 MHz, CDCl3) 5 7.35 5H), 6.77 IlH), 5.49 (in, I1H), 5.12 (dd, 2H), 4.51 2H), 4.20 (in, IH), 1.97(m, IH), 1.88 (in, 1H), 1.66 (in, 1.52 (in, 1H'), 1.45 3H), 0.97-0.92 (mn, 12H).

15 Example I1I Preparation of (2S. I S)-2-(benzvloxvcarbonyl)amino-N-[ 1 -(2-carbo-2.2.2trifluoroethoxythiazol-4-vl')-3'-mnethylbutyll-4-methylpefltalalide The compound of Example 2 (0.200 g, 0.433 rnmol), 1, 1, 1 trifluoroethanol 2 g, 0.52 inmol, .04 mL), pyridine 1 in.L), and di-t-butyl dicarbonate 104 20 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 chromatographed (silica gel, 20 ethyl acetate/hexane) to give the title 25 compound as a whi!. solid (.098 I H NMIR (400 MHz, CDCl3) 8 7.50 lH), 7.36 5H), 6.64 IH), 5.22 (in, 2H), 5.09 2H), 4.73 (mn, 2H), 4.16 (in, lH), 1.66-1.41 (in, 6H), 0.87 (in, 12H).

Example 1 Preparation of (2S. I S)-2-(benzvloxvcarbonvl)amifo-N-[ 1- (4carboethoxoxadiazol-2-v-3'methvl bujl 4-methvlluentananfLide a) (1S)-I -(ter-butoxycarbonyl)amino- I -(4-carboethoxyoxadiazol-2-yI)-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, 1.52 mL) in ether (15 ml) was added rhionyl chloride (1.12 g, 9.41 mrol, 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 tide compund as a pale yellow oil (0.84 g. 1 NMR (400 MHz, CDCI3) 65.14 1H), 5.03 (br d, 1H), 4.52 2H), 1.78-1.70 3H), 1.44 9H), 0.99 6H).

0 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 (tert-butoxycarbonyl)amino- 1-(4-carboethoxythiadiazol-2-yl)-3-methylbutane, the title compound was prepared (582 mg, 100%). 1 H NMR (400 MIz, CDC13) 64.99 1H), 4.52 2H), 2. 10-2.02 2H), 1.77-1.70 1H), 1.44 3H), 1.00 (t, 6H).

c) (2S,1'S)-2-(benzyloxycarbonyl)alo-N-[ 1'-(4-carboethoxyoxadiazol-2-yI)-3'methylbutyl]-4-methylpentanamide Following the procedure of Example 10(f). except substituting amino- I -(4-carboethoxyoxadiazol-2-y)-3-methylbutane for 1-amino-I carboethoxythiadiazol-2-yl)-3-methylbutane, the title compound was prepared (235 mg, IH NMR (400 MIz, CDC13) 6 7.26 5H) 6.64 IR), 5.45-5.39 (i, 1H). 5.12 tim. 3H), 4.52 2H, 4.20 IH), S I in. 1.68-1.64 (im. H.

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

Example 13 Preparation of (2S,1 'S)-2-(benzvloxvcarbonvl-L-leucinvl)amino-N-r carboethoxythiazol-2-yl )-3'-methylbutvyll -4-methylpentanamide The compound of Example 8(c) (160.7 mg, 0.47 mmol) was dissolved in neat TFA (1.0 mL) and stirred for 15 minutes. The solution was diluted with methanol and evaporated to dryness. The residue was dissolved in DMF (2 mL) and to the resulting solution was added N-Cbz-L-leucinyl-L-leucine (194.0 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiiide hydrochloride (99.0 mg, 0.52 mmol) and 1-hydroxybenzotriazole (13.0 mg, 0.094 mmol) and triethvlamine (94.7 mg, 0.936 mmol, 0.13 mL). After stirring at room temperature for 24 h. the 1 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 (0.146 1 H NMR (400 MHz, CDCI3) 6 8.04 1H), 7.33 5H), 7.14 1H), 6.61 1H), 5.37 (min, 2H), 5.08 2H), 4.47 1H), 4.39 2H), 4.18 1H), S 20 1.98 1.45 9H), 1.38 3H), 0.94 0.86 18H).

a 0 Example 14 *fe Preparation of (2S. 1'S)-2-(benzyloxvcarbonyvl)amnino-N-[ carboxamidooxadiazol-2-vl )-3'-methvibutyll-4-methvlpentanamide Ammonia was bubbled through a solution of the compound of Example 12 (96.8 mg, 0.2 mmol) in ethanol (2 mL) for 5 inm. After stirring an additional min, the solution was concentrated to give the title compound as a white solid (91.2 mg, 1 H NMR (400 MHz, CDCl3/CD 3 0D) 8 7.29 5H), 5.90 1H), 5.30 1H), 5.04 2H), 4.15 (in. 1H), 1.76 2H), 1.59-1.43 4H), 0.92-0.85 (inm, 12H).

Example Preparation of (2S. I'S)-2-(benzvloxvcarbonvly)aino-N-f '-(2-carboethoxvthiazol-4vy )-3-methvlburvll-3-phenvlpropan armde a) N-(9-fluorenlmethoxycarbonyl)-L-Ieucinyl bromomethyl ketone Following the procedure of Example except substituting N-(9fluorenylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucinyl-Lleucine, the title compound was prepared (5.6 1 H NMR (400 MHz, CDCI3) 7.71 2H), 7.51 2H), 7.34 (dd, 21), 7.22 (dd, 2H), 5.08 1H), 4.53 1H), 4.36 (dd, 2H), 4.13 (dd, 2H), 3.89 (dd, 2H), 1.62-1.41 3H), 0.88 6H).

b) (15)-i -(2-carboethoxythiazol-4-yl)- 1 fluorenylmethoxycarbonyl)amino-3methylbutane Following the procedure of Example except substituting N-(9fluorenylmethoxycarbonyl)-L-leuciny bromomethyl ketone for N- Berzyloxycarbonyl-L-leucinyl-L-leuciny bromomethylketone, the title compound .I was prepared (4.13 IH NMR (400 MHz, CDC13) 8 7.72 2H), 7.49 21), 7.32 (dd, 2H), 7.22 (dd, 2H), 7.19 1H), 5.31 1H), 4.88 1H), 4.40 2H), 4.28 2H), 4.08 11), 1.62-1.41 3H), 1.36 0.88 6H).

c) (1 -amino- 1-(2-carboethoxythiazol-4-yl)-3-iethylbutae The compound of Example 15(b) (0.5 1.1 nmol) was stirred in a piperidine/DMF solution for 10 minutes at room temperature. The solvents were evaporated and the solid obtained was dried in vacuo to give the title compound (0.27 g).

d) (25, 1'S)-2-(benzyloxycarbonyl)amino-N-[ 1'-(2-carboethoxythiazol-4-y)-3 iethylbutyl]-3-phenylpropanamide Following the procedure of Example 5, except substituting (1 I-amino- 1- (2-carboethoxythiazol-4-yl)-3-iethylbutane for benzylamine, and N-Cbz-Lphenylalanine for (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-t 1'-(2-carboxythiazol-4yl)-3'-methvlbutyl]-4-methylpentananide. the title compound was prepared 162 1HN-N NIR (400 .Mrz CDCI,,) 6 5H. 11 iH 7.C m. I 5.24 I 5. 10 IH), 5.01 2H). 4.37 2H), 4. -1I t m. I 2.91 2 H)2H. 1. 62 3 1. 37 Qt. 0. 8 1, 6H).

Example 16 Preparation of 12S. I'S)-2-(benzvloxycarbonvl-l-leucinvllarnio-- carboethoxylhiazol-e vl)-3'-methviburvl 1-4- methvlrwntanan-ide a 6000 06 4 6 0 .00.

.00.

0 0 0 Following the procedure of Example 5, except substituting 0 I-amino- I (-car~oethoxythiazol4-yl)-3-methylbutan for benylamine, and N-Cbz-Lleucinl-L-eucine for (2S, I'S)-2-(berzyloxycarbonyl)amin carboxythiaol4-y)-3'-methylbutyl methylpenanalide, the title compound was prepared (0.098 IH NMR (400 NfHz, CDC1) 5 7.39 IH).7.25 6.87 IH), 6.49 I 5.30 d, I 5.16 4.99 2H), 4.36 2H), 4.31 IH), 4.09 IH), 1.74-1.38 9H), 1.32 3H), 0.80 Example 17 Zaraion ot(2M. 2-(benzyloxycarbonyl aminoNlI-5mrat- 24 oxadiazol-3-yl)-3-methlbutyl methvientanamide r r a) N-benzyloxycarbonyl-L-leucinyl-L-leucine methyl ester 20 N-Cbz-L-leucine (Chemical Dynamics) (1.32 g, 4.97 mmol), L-leucine methyl ester hydrochlorde (Aldrich) (0.99 g, 5.47 mmol), 1-hydroxybenzotriazole 14 g, 1 .0 mmol) and 1 -(3-dimethylaminopropyl)-3-ethylcarbodiid hydrochloride (1 .05 g. 5.47 mmol) were combined, dissolved in 25 m.L of DNIF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate 25 (250 m.L) and washed successively with water, 0. 1 HCI, saturated aqeous NaHC03 and saturated brine, then dried (MgS04), filtered, and concentrated. The residue was purified by flash chromatograpy on 230-00 mesh silica gel, eluting with 1: 3 ethyl acetate hexanes, to give the title compound as a white solid 1 .8 C, IHi NMR (400 Mliz, CDC13) 5 7.37-7.32 (in, 5H), 6.28 1H), 5.28 (m.

3H), 4.61-4.58 1H), 4.20 IH), 3.74 3H), 1.69-1.54 6H), 0.96-0-92 b) N-benzyloxycarbonyll--eucinyl-L-leucinylhydrazide To as stirring solution of the compound of Example 17(a) 1 .2 8 g. 3.26 mmol) in 25 mL of methanol was added hydrazine hydrate (1.63 g, 32.6 mmol. 1.58 mL) and the solution was allowed to stir at room temperature for 15 h. The solution was evaporated to dryness to give the title compound as a white solid (1.28 g, 100%). 1 H NMR (400 MHz, CDCl3) 8 8.05 (br s, IH), 7.35-7.32 5H), 6.67 (d.

1H), 5.50 1H), 5.11 2H), 4.46 1H), 4.21 1H), 3.88 (br s, 2H), 1.64- 1.51 6H), 0.92-0.88 12H).

c) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1'-(5-mercapto-1,2,4-oxadiazol-3-yl)oa: 3'-methylbutyl]-4-methylpentanamide dTo a stirring solution of the compound of Example 17(b) (0.3 g, 0.76 mmol) in 1.5 mL of chloroform was added triethylamine (0.155 g, 1.53 mmol, 0.213 mL) 15 and thiophosgene (0.088 g, 0.76 mmol, 0.058 mL). The solution was heated at reflux for 3 h, then cooled to room temperature. The mixture was diluted with ethyl .0 acetate, washed with water and saturated brine, dried (MgS04), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 11% methanol in dichloromethane, to give the title 20 compound as a white solid (0.20 g, 1 H NMR (400 MHz, CDCl3) 87.36 (m, 6H), 6.85 1H), 5.37 IH), 5.14 3H), 4.24 1H), 1.65 6H), 0.95- 0.87 12H).

se0 00* E xamplI e IS Preparation of (2S. 1 'benzvloxvcarbonyVlar no-N-f I -2-mercqptothiazoI- %fl-Y-methylbuty I 14-methylpentananude The compound of Example I1(a) (1.0 g, 2.2 inmol) and ammoniumn Sdithiocarbamate (0.25 g,2.2 inmol) were dissolved in ethanol and heated to 55 0

C

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

I H NMR (400 M]-Lz, CDCI3) 5 7.24 (mn, 7. 10 1IH), 6.33 I1H) 6.00 (d, lH), 5.11 2H), 4.94 (in, lH), 4.05 (in. IH), 1.49 (mn, 6H), 0.78 (in, 12H).

Example 19 Preparation of (2S)-2-(benzyloxycarbonl)aiflo-N-(4-carboethoxythiazol-2yl)methyl-4-methvlpentanamide *ago a) 1 -(tert-butoxyc arbonyl) amino- 1 -(4-carboethoxythi azol-2 -yl)methane 15 Following the procedure of Example except substituting N-tertbutoxycarbonyiglycine for N-tert-butoxycarbonyl-(L)-leucine in step the title .se compound was prepared (1.9g, 58% overall). IH NMR (400 Mffz, CDCl3) 5 8.11 1H), 5.31 1H), 4.56 4.43 2H), 1.45 9H), 1.42 3H).

b) (2S)-2-(benzyloxycarboflyl)am-ino-N-(4-carboethoxythiazol-2-yl)iethyl 4 methylpentanamide Following the procedure of Example 13, except substituting 1-(tertbutoxycarbonyl)aniino- I -(4-carboethoxythiazol-2-yl)methane for (1 I -(tertbutoxycarbonyl)armno- 1-(4-carboethoxythiazo1-2-yl)-3-methylbutafle, and N-Cbz- L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared o 120g, MS 434.2.

Example Preparation of (2S. 1'S)-2-(benzvloxvcarbonvl)armino-N-f benzvloxvcarbonvlthiazol-4-vl)-3'-methyvlbuItyl 1-4-methylpentanamide The compound of Example 2 (0.105 0.22 mmol) was dissolved in dichloromethane and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiiride methiodide (0.062 0.22 mmol) and benzyl alcohol (0.03 mL, 0.22 mmol). The mixture was allowed to stir at room temperature for 4 hours and the solvents were evaporated and the residue obtained was cheromatographed silica gel, 30% ethyl acetate/ hexane) to give the title compound as a white solid (0.04 1 H NMR (400 MHz, CDCI3) 6 7.37 1H) 7.26 10H), 6.50 1H) 5.33 2H), 5.11 (q, 2H), 5.09 1H), 4.99 2H), 4.04 1 1.49 6H), 0.78 12H).

66: Example 21 Preparation of (2S, 1 'S)-2-(benzyloxycarbonyl)amiino-4-methvl-N-[3'-methyl-1'-(2- Dhenoxycarbonvlthiazol-4-vl)butvyllpentanaide Sb lFollowing the procedure of Example 20, except substituting phenol for benzyl alcohol, the title compound was prepared (0.075 1 H NMR (400 MHz, CDCl3) 8 7.41 1H), 7.26 10H), 6.49 1H), 5.20 1H), 5.04 lH) 5.00 2H), 4.08 1H), 1.49 6H), 0.82 12H).

Example 22 Preparation of (2S.1'S)-2-(benzyloxycarbonyl)axnino-4-methyl-N-[3'-methyl-1'-f2- (2-methylpropvloxycarbonvylthiazol-4-ylbutylpelntanamide Following the procedure of Example 20, except substituting isobutyl alcohol S 25 for benzyl alcohol, the title compound was prepared (0.075 1 H NMR (400 MHz, .e CDCl3) 8 7.25 6H), 6.50 1H) 5.11 2H), 5.09 IH), 4.99 2H), 4.11 2H), 3.91 1H)2.02 1H), 1.70- 1.39 6H), 0.82 6H1), 0.78 (m, 12H).

Example Preparation of (2R. 1S)-2- benz-vloxycarbonvl arnino-N-f I'- 4 -carboethOxvthiazol- 2-vt ethyll-4-methvtpenianamide Following the procedure of Example 19, except substituting N-terrbutoxycarbonyl-L-alanine for N-tert-butoxvcarbonylglycine in step and N-Cbz- D-leucine for N-Cbz-L-leucine in step the title compound was prepared as white solid (0.l135g, MIS 448.2.

Example 24 Preparation of (2R. I R)-2-(benzyloxvcarbonyl)amino-N'-r -(4-carboethoxythiazol- 2)-vt)ethyl 14-methylpentanaznide Following the procedure of Example 19, except substituting N-reenbutoxycaz-bonyl-D-alanine for N-tert-butoxycarbonvlglycine in step and N-Cbzsee" :0...:D-leucmne for N-Cbz-L-leucine in step the tit-le compound was prepared as white 0 0 15 solid (0.11 lOg, MIS 448.2.

Example Preparation of (2S. 1 1'-(2-anminothiazol-4-yfl-3'-methylbutylk-2- (bernzloxycarbonyl)amino-4-methylprntanamide To a stirring solution of the compound of Example 1(a) (0.85 g, 1.87 mmol) in 4 rnL of ethanol was added thiourea 142 g, 1.87 nmol). 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 NafHCO 3 and saturated brine, then dried (MgSO 4 filtered, and concentrated. The residue 25 was purified by fks-h chromatography on 230-400 mesh silica gel, eluting with 1:: Oe ethyl acetate/hexanes, to give the title compound as a white solid (0.64 g, 1

H

NMR (400 MIHz, CDCl3) 8 7.36 (in, 5H), 6.30 (mn, 2H) 5.12 (mn, 3H), 4.95-4.91 (in. 3H), 4.16 (in, 11-1), 1.63 (in, 4H), 1.49 (in. 2H), 0.93-0.89 (in, 12H).

Example 26 Preparation of (1 S)-N-[4-f(I1 benzyloxvcarbony'larrlfo)-3-meth lbuEvllthiazol-2vlicarbonvl-N'-(N-benzyoxvcarbofll-L-leucinl)hydrazide a) N-benzyloxycarbonyl-L-leuciflyl bromoniethyl ketone 1l-methyl-3-nitro-lI-nitrosoguanidine (6.65 g, 45.2 rnxol) in ether (225 mL) is cooled to 0 0 C. 40% sodium hydroxide is added slowly and the diazomethane is allowed to collect in the ether solution for 30 minutes at 0 0 C. The ether solution is then decanted and left at 0 'C.

N-Cbz-L-leucine 10 g, 7.6 nimol) was dissolved in THE (10 cooled to -40 and 4-methylmorpholine (0.77 g, 7.6 mniol, 0.83 was added, followed by dropwise addition of isobutyl chloroformate (1.04 g, 7.6 mrnol. 0.98 0:00 mnL). After 15 min, the solution was filtered into the previously prepared 0 'C a solution of ethereal diazomethane. The resulting solution was allowed to stand at 0 ego* C for 23 h. HBr (30% in acetic acid) (45.2 minol, 9 niL) was added and the :00: 15 resulting solution was stirred at 0 'C for 5 min, then washed sequentially with 0. 1 N ::boo HC1, saturated aqueous NaHCO3 and saturated brine, then dried (MNOW), filtered and concentrated to give the title compound as a colorless oil (2.43 g, 94%).

b) (l)lbnyoyabnlmn--2crbehxtizl4y)3mtybtn A solution of the compound of Example 26(a) (1.57 g, 4.58 mnmol) and ethyl thiooxamate (0.61 g, 4.58 inmol) in ethanol (10 mnL) 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 acetate/hexanes, to give the title compound as a yellow oil (1.0 g, 'H NMR (400 M&z, CDC1 3 8 7.41 1LH), 7.34-7.31 (in, 5H), 5.40 1 5. 10 1 5.05 IlH), as4.98 IH), 4.48 2H), 1.80-1.76 (mn, 2H), 1.57-1.53 (in, IH), 1.44 3H), 0.95 3H), 0.93 3H).

c) 1S)-l-benzvioxv-carbonvilan-no- i -t2-hvdrazinocarbon\ ILhuazoi-,-'. imethylbutane A solution of the compound of Example 26(b) (0.30 g. 0.8 rnmol) and hvdrazine hvdrate (0.40 g, 8.0 mmol, 0.39 m.L) in ethanol (8 mL) was allowed to stir at room temperature for 2 h. The solution was then concentrated to yiehq the title compound as a white foam (0.28 g, 1H NMR (400 MIHz, CDCI 3 6 8.29 IH), 7.37-7.35 (in, 5H), 5.18 IH), 5.09 (dd, 2H), 4.95 IN), 4.07 2H-), 1.71 2H), 1.55 (mn, lH), 0.96 0.94 3H).

d) (1 1-benzyloxycarbonylamino)-3-methvlburyl]thiazol-2-vlcarbonil-N'- (N-benzyloxycarbonyl-L-Ieucinyl)hydrazide A solution of the compound of Example 26(c) (100 mg, 0.28 inmnol), N-Cbz- L-leucine (80.5 mng, 0.30 inmol), 1-(3-diinethylaminopropyl)-3-ethylcarbodiiinide hydrochloride (58.2 mg, 0.30 inmol) and l-hydroxybenzotriazole (7.5 mg, 0.06 inrol) in DMF (0.6 mmol) was allowed to stir at room temperature for 18 h. The solution was diluted with ethyl acetate and washed successively with water, 0. 1 N HC1, saturated aqueous NaHCO 3 and saturated brine, then dried (MgSO 4 filtered and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1: 1 ethyl acetate/hexanes, to provide the title compound as a white solid (111.4 mg, mp 110-1 12 *C.

0.00.0Example 27 Preparation of N-benzyloxvcarbonyl-L-leucinyl-N'-benzyloxycarbonyl-L-leucinvl- L-leucinylhyd-razide 25 a) N-beazyloxycarbonyl-L-leucinyl-L-leucine methyl ester oi Following the procedure of Example 26(d), except L-leucine methyl ester hydrochloride for (1 1 -benzyloxycarbonylamiuno- 1 -(2-hydrazinocarbonyithiazol- 4-yl)-3-methylbutane, the title compound was prepared as a white solid (1.28 g' *H NMR (400 MiHz, CDCI3) 8 7.37-7.32 (in, 5H), 6.28 1H), 5.28 (in, 3H), 4.61-4.58 (in, IH), 4.20 IH), 3.74 3H), 1.69-1.54 (mn, 6H), 0.96-0.92 (mn, 12H).

b) N-ezixcroy--eciv--ecnlvrzd Following the procedure of Example 26(c). except substituting

N-

benzyloxycarbony1-L-leuc fllL-leucine methyl ester for (I1S)-lIbenzyloxycarboflylafllfo- 1- (2 -carboe thoxythia.zol-4-Yl)> 3 -methyl butanle, the title compound was prepared as a white solid (1.28 g, 100%). 'H NMR (400 vftz, CDCl3) 5 8.05 (br s, 1H), 7.35-7.32 (in. 5H), 6.67 IH), 5.50 1H), 5.11 (s, 4.46 (in, IR). 4.21 (mn, IR), 3.88 (br s, 2H), 1.64-1.51 (mn, 6H), 0.92-0.88 (in, 12H).

c) N-benzyloxycarboflvl-Lleucifli-NbenzyloxcaronylLleucinyl-L leucinyihydrazide Following the procedure of Example 26(d), except substituting N- .00, benzyloxycarbonyl-L-leucilY[L-leuciflyIhydainde for (I1S)- Ia 15 bezlxcroyaio -2hdaiocroytizl-l--ehluae the a title compound was prepared as a white solid (0.059 MS 662.1 Example 28 Preparation of (1 5)-N-f 2-f(1 I -xcrovamn)3mehluyltizl4 e 20 ylcarbonvl1-N'-(N-benzyloxycar -~l1eU in l~hvrrazide To a solution of N-tert-butoxycarbonl-l(L)-leucine (7.0g, 28. 1immol in dry THE (lOOniL) at -40*C was added isobutylchloroforflnate (3.8g, 28.Iminol) and Ninethylmorphiline 59mmol). After 15 minutes of stirring, ammonia was bubbled through the mixture for an additional 15 minutes, then warmed tc. 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.Oinmol).

'HNMR (400M1{z,

CDCI

3 5 6.38 (br s, 5.79 (br s, lH), 5.04 (br d, IH), 4.13 (mn, IH), 1.7 1-1.49 (mn, 3H), 1.39 9H), 0.92 (dd, 6H).

*S.a

S

S

S S U a. a S S

S

S

0O a.

0 S. 55 0 *5* 0

*OS*

S

S..

S

*SSS

5* *0 S

S

S

h) N-tert-buroxvcarbonv--L)-leucinethioamde, To a stirl-ine solution of the compound of Example 26(a) 28.0 Mmol Iin dry TI-F was added Lawesson's reagent (6.8g, 16.9 mm~ol) and the rrixture was stirred at room temperature under argon overnight. The solvent was evaporated and the residue chromatographed (silica gel, 12% ethyl acetate/hexane) to give the title compound as a white solid (5.4g, 'HNMR (400M4Hz, CDC 3 6 8.54 (br s, I 7.97 (br s, I 5.28 (br d, IlH), 4.52 (in, I 1. 72-1.58 (in, 3H), 1.40 9H), 0.92 (mn, 6H).

c) (1 1-(tert-butoxvcarbonvl)am-ino-l1-(4-carboethoxythiazol-2-yl)-3methylbutane The compound of Example 26(b) (5.4g, 21 .7 mmol) was stirred in dry acetone (lO0mL) under argon at -10 0 C. Ethylbromopyruvate (4.7g, 23.9rnrol) was added and stirred for lh at -10 0 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, 23.9mmol) and pyridine (3.8g, 47.8mxnol) in dichloromethane for Ilh at -20*C. Excess solvent 20 was removed in vacuo and the residue was dissolved in dichioroinethane. The solution was washed with saturated aqueous sodium bicarbonate and 1LON KHSO, until pH 7. The solution was dried over magnesium sulfate, filtered and concentrated to an oil which was chromatographed (silica gel. 7.5% ethyl acetate/hexane) to give the title compound as a tan solid (4.5g, 6 'HN4MR 25 (400MHz, CDCI 3 8 7.98 I 5.04 (br d, IlH), 4.95 (in, IlH), 4.31 2H), 1 8S (in. 1.63 (in, 2H), 1.40 9H),1.32 3H), 0.85 (dd, 6H).

d) (I 1 -(Benzyloxycarbonyl)amaino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane The compound of Example 26(c) (0.250g, 0.73 1 miol) was dissolved in TFA (2rnL) 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 Lriethylarnune (0.7392. -7.3 1Immol) followed by be nzyl chioroforinate (1.2g, 7.3 1imnol). 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 chroinatographed (silica gel, 15% ethyl acetate/hexane) to give the title compound as an oil 198g, 'HNMR (400MfHz, CDCI 3 5 8.01 IH), 7.32 (in, 5.51 (br d, 1H), 5.14 (in, 1H), 5. 10 2H), 4.37 2H), 1.93 (mn, IH), 1.81-1.67 (mn. 2H), 1.39 3H), 0.95 (mn, 6H).

e) (I bezlxcroy mn) -eh bt )tizl4 cabnvI (N-tbenzyloxycarbonylL-eucinyl)hvdrazide Following the procedure of Example except substituting (IS)-lI- (Benzyloxycarbonyl)amino-1I (4-carboethoxythiazo1-2-yl)-3-methylbutane for (IS)- I ::nyoyaroyaio 1-2crotoyhaol4y)3mtybtn in step the title compound was prepared. MS 6 10.0 To a stirring solution of N-Cbz-L-leucine (Chemical Dynamics Corp.) (2.94 g, 11. 1 mniol) in 22 mL of DMF was added carbohydrazide (0.5 g, 5.6 inmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.13 g, 11. 1 minol) and 1-hydroxybenzotriazole (0.3 g, 2.2 inrnol). After stirring at room temperature for 22 h, the solution was poured into 500 mL. of water. The precipitate was collected by vacuum filtration and washed with water (4 X 150 niL) and dichloromethane (4 25 X 150 niL), then dried ieinder vacuum to provide the title compound as a white Folid (1.49 g, MS(ESI): 607.1 Example Preparation of 2.2-(N.N-bis-cvclohexlacervl Icarbohydrazide Following the procedure of Example 29. except substituting cyclohexylacetic acid for N-Cbz-L-Ieucine, the title compound was prepared (0.4 g, MS(ESI): 339.3 Example 31 Preparation of 2.2'-(N.N'-bis-4-methvlpentanovl)carbohvdrazide Following the procedure of Example 29, except substituting 4methylpentanoic acid for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.212 g, MS(ESI): 287.3 Example 32 Preparation of 2 2 '-N.'-bis-2-cvcloentvlacetyl)carbohydrazde Following the procedure of Example 29, except substituting cyclopentylacetic acid for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.345 g, MS(ESI): 311.2 Example 33 Preparation of 2 2 '-(N.N'-bis-benzvloxvcarbonylglvcinyl)carbohydrazide 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, MS(ESI): 473.1 Example 34 Preparation of 22 -(N.N'-bis-acetv-L-leucinvl carbohycijde 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 0 153 g, MS(ESI): 401.3 Example Preparation of 2.2'-(NN'-bis- benzyloxvcarbonyl-L-alanvl)carbohydrazide Following the procedure of Example 29. except substituting N-Cbz-Lalanine for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.762 g, MS(ESI): 501.1 (M+H)Y.

Example 36 Preparation of 2-(N-benzloxvcarbonvl-L-leucinvl)-2'-rN-(4methylpprntanovylcarbohydrazide a) N-benizyloxycarbonyl-L-leucine methyl ester To a solution of leucine methyl ester hydrochloride (5.0 g, 27.5 rnmol) in woo: 1,4-dioxane (50 rnL) was added sodium carbonate (30.3 mL, 2M in water) followed by benzyl chloroforrnate (4.69 g, 27.5 mmol). The mixture stirred at room ese.

temperature for 24 hours when partitioned between ethyl acetate and water. The 00:0.

15 organic layer was collected, dried (MgSOJI, filtered and concentrated to give the tidle compound as a colorless oil (7.67 g, 100%). 'HNMR (400M&z, CDCI) 6 7.39 ev. 5H), 5.38 2H), 5.12 2H), 4.42 (mn, 111), 3.75 3H), 1.73 -15 i,3-) 0.94 (mn, 6H).

b) N-benzyloxycarbonyl-L-leucinyl hydrazide To a solution of the compound of Example 36(a) (7.67 g, 27.5 inrol) in methanol (40 rnL) was added hydrazine monohydrate (13.5 g, 270 rnxol). The solution was stirred at room temperature for 24 hours when partitioned between water and ethyl acetate. The organic layer was collected, dried (MgSO,). filtered :25 and concentrated to give the tidle compound as an off-white solid (7.67 g, 100%).

*woo*:'HNMIR (400M&, CDCI,) 868.14 LH), 7.38 (mn, 5H), 5.64 11H), 5.09 (dd, 2H), 4.20 (in, 1H), 3.81 (s br, 2H), 1.69 1.51 (mn. 3H), 0.92 (dd, 6H1).

c) 1 -benzyloxycarbonylamino-3-methyl- 1-(1 ,3 ,4-oxadiazol-2-onyl)butane A solution of the compound of Example 36(b) (1.0 g, 3.58 mmnol) in methylene chloride (l'-nmL) was added dropwise to a solution of 4nirrophenvichlorofor-nate (0.361 2, 1.79 mamoh in methylene ch-loride (S rnLi a-,

O

0 C. The solution warmed to room temperature and stirred for one hour when partitioned berween ethyl acetate and water. The organic layer was washed with aqueous NaI-{CO, then collected, dried (MgSOj), 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, I-INMvR (400MLHz, CDCI 1 6 9. 18 lH), 7.38 (in, 5H), 5.13 (mn, 4.79 1H), 1.71 (mn, 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%). IHNM (400MfHz. CDCI) 6 7.48 (s br.

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

e) 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-[N'-(4-methylpentanoyl)]carbohydrazaide .The compounds of Example 36(c) 100 g, 0.325 mmol) and Example 3 6(d) (0.042 g, 0.325 inmol) were combined and dissolved in ethanol (I The solution was brought to reflux for 24 hours then concentrated to a solid yellow residue which was washed with coal methylene chloride to yield the title compound as a white solid (0.053 g, MS 436.2.

6

S

Example 37 Preparation of bis-(Cbz-leucinl- I .3-diamino-propan-2-one Cbz-leucine (500 mg, 1.88 mmrol), EDCI (558 mg, 1.88 mmrol) was dissolved in DMEF (4.0 ml) with l,3-ciiamino-propan-2-ol (85 mg, 0.94 rnmol) and Hunig's base (0.3 ml, 1.88 mmol) and was stirred at RT overnight. The reaction was diluted with EtOAc (20 ml) and was extracted with water (2 x 20 ml). The combined organics were dried with magnesium sulfate, filtered, concentrated in 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 &:so reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 mil) to see: remove the inorganic salts. The combined organics were dried with magnesium "Was*sulfate, filtered, concentrated, and chrornatographed (silica gel, 2-5% MeOI methylene chloride) to give the title compound as a white solid (410 mg, 15 MS(ES) M+H'=583, M+Na=--605.

0. 0: Preparation of bis- 1.3 -(4-p2henoxy-benzoyl)-dianhino-propan-2 -one Following the procedure of Example 37, except substituting '4-phenoxy- 20 benzoic acid" for "Cbz-leucine", the title compound was prepared: MS(ES) *M+Wf=48 1, M+Na'=503.

Example 39 *PEparation of I -(Cbz-leucinyl)- arino- 3 -(acety -leuciny D- amino-propan- 2-one 25 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 Preparation of I -(Cbz-leucinvl -an-ino-3-(Cbz-2lutamnvl-t-butvI ester )-arrunop2ropan -2 -one Following the procedure of Example 37. except substituting "a mrixture of acid gamma t-butyl ester and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+H-=655.

Example 41 Preparation of I -(Cbz-leucinyl)-arnino-3-(Cbz-glutamnvl)-amino-propan-2 -one 1 -(Cbz-leucinyl )-amino-3-(Cbz-glutamyl-t-butyl es ter)- amino- propan- 2-one mg, 0.OO7mmoI) was dissolved in a solution of trifluoroacetic acid 0.5 ml) and Wes:methylene chloride (0.5 ml), then was stirrd at RT for 2 h, the reaction was dilutied with toluene (10 mnl), then was concentrated in vacuo to provide the title compound: MS(ES) M+H-=599.

Example 42 Preparation of bis- 1 .3-(Cbz- leucinyl)-di aring-(S-butanone-2 -one a) Cbz-leu-ala-bromo methyl ketone Isobutyl chloroforrnate (1.46 mal, 11.3 mmcl) was added dropwise to a '060Lb solution of Cbz-leu-ala-OH (4.0 g, 11.3 mmol) and N-methyl morpholine (1.24 nil, 11. 3 rnmol) in TI-lI (40 ml) at -40 degrees C. The reaction was stirred 15 in, then was filtered, and was washed with ether. Diazomnethane (40.1 mmol from 5.9 g of 1- methyl1-3 -nitro-nritroso-gu anidine and 18 ml of 40% KOH in 150 ml of ether) in ether (200 ml) was added and the reaction was placed in a refrigerator overnight.

'2B 30% HBr/ AcOH (7 nal) was added dropwise to the crude reaction mixture and was *:~:stirred 5 minutes. The solution was washed with aqueous citric acid (50 mlI x, 2), saturated aqueous sodium bicarbonate (3 x 150 ml), then brine (100 ml). The combined organics were dried with magnesium sulfate, filtered, and concentrated in vacuo to eive a solid which was used in the next step without purification. MS(ESj M+-=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 DMIF (7 ml), then sodium azide (122 mg, 1.9 mniol) and potassium fluoride (137 mg, 2.36 mmol) was added and the reaction was stirred overnight. The reaction was pa rtitioned between EtOAc and water, then the combined organic extracts were dried with magnesium sulfate, filtered, concentrated in vacuo, then chormatographed MeOH, rmethylene chloride, silica gel) to provide the title compound as a white solid (330 mag, MS(?ES) M+Na&=398.

c) Cbz-leu-2-amino-4-azido-propafl- 3 -oI Cbz-leu-leu-azido methyl ketone (330 mag, 0.9 namol) was dissolved in EtOH 15 (5 ml) and sodium borohydride (100 mg, 2.65 mmroi) 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) M+H= 378, M+Na*=400.

d) Cbz-leu-2-amino-4-an-info-propan- 3 -oI Cbz-leu-2-amino-4-azido-propan- 3 -ol (300 mg, 0.8 mmnol)was dissolved in MeOH (4 ml) and triethyl amnine (0.33 ml, 2.4 mnmol), propan-1,3-dithiol (0.35 ml.

3.82 namol) was added and the reaction was stirred overnight, concentrated in vacuo, then the white solid was washed with hexane providing the title compound 5 which was used in the next reaction without further purification, MS(ES) M+W-=352.

e) bis- I ,3-(Cbz-leucinyl)-diaxnino-(S)-butanone- 2 -ol Cbz-leu-2-wimino-4-axnino-propal- 3 -oI (140 mg, 0.4 mmol) and Cbz-leucifle (106 mg, 0.4 mnaol) were dissolved in DNIF (2 ml) and N-methyl morpholine (0.08 mi. 0.8 mmolj and I-IBTU (1l51 rn2, 0.4 rnrol) and was sir-red mvernlght. The reaction was partitioned between EtOAc and w;ater, the combined orL'anics werel dried with magnesium sulfate, filtered. concentrated to give the title compound.

MS(ES) M#WF=599, \M+Na+=62 1.

f) bis- 1, .3-(Cbz- leucinyl)-di amino-(S) -butanione -2 -one Bis-1I,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-ol (240 mng, 0.4 mxnol) was dissolved in acetone (2 ml). Jones reagent (0.5 1l, 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 mnl) to remove the inorganic salts. The 6:00 combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel. 2-5% MeOl-1 mnethylene chloride) to give the tide as a white solid (80 mg, 33 M4S(ES) M-HE=595.

Example 43 Preparation of I -(Cbz-leucinyl-amino-3-Cbz-henyalany)ano-&.propan-2one Following the procedure of Example 37. except substituting "a mixture of Cbz-phenylalanine and Cbz-Ieucine" for "Cbz-leucine", the title compound was .20 prepared MS(ES) 17. M+Na'=639.

Example 44 so.:Preparation of I -(Cbz-leuciny amino-3-(Cbz-noreucin1'-amino-proan.2 -one Following the procedure of Example 37, except substituting a mixture of Cbz-norleucine and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+H*=583, M+Na*=605.

Example Preparation of I -(Cz-1eucinvb)-arno3-Cbz-norvin~l-amino-propan- 2-one Following the procedure of Example 37, except substituting "a mixture of Cbz-norvaline and Cbz-leucine" for 'Cbz-leucine". the tide compound was prepared: MS(ES) M+W-=569, M+Na&=591.

Example 46 Preparation of bis-1I.3-(Cbz-Ileucinyl)-diarrnino-5-methyj-(S)-hexan-2 -one a) bis- 1, ,3-(Cbz- leucinyl) -diallfo- 5 -methy-(S)-hexal-2 -one Following the procedure of Example except substituting "Cbz-leuleu-OH-" for 'Cbz-leu-ala-OH" the title compound was prepared: MS(ES) 0:9 M+lf=-639.

Soo: age* Example 47 Preparation of I -(acetyl -Ieuc iny D- ami no- 3 -(4-p2henoxy-benzoy 1) amino- propan -2 e Exmle4 Prprto ofI-Czhm-ecn0-rin-Cb-ecnl-3aiopo~n2-n :0 Following the procedure of Example 37, except substituting "a mixture of N- Acm-leucine and -bnz-enzoci" for "Cbz-leucine", the title compound wasaed prepared: MS(ES)7 Mi-W=440.

6 0 9 0 Examle -49 Preparation of bis- I .3-(4-(3-chloro-2-cvano-phenoxv )-phenvlI sulfonamiudo )-propan- 2-one 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride (1.3 an. 4 ramol.

Mavbndge) was added to a solution of l,3-diaxmno-propan-2-ol 18 g, 2 rnmol) in DMfF (10 ml)! N-methyl morpholine (0.44 ml, 4 mxnol) and was stirred 3h at RT.

The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude bis- 1,3- 3-choro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-oI (0.28 g, 0.4 mmol) was then dissolved in acetone (1.0 ml) and Jones reagent (0.44 ml, 1.5 M) was added dropwise. and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 nil) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOI methylene chloride) to give the title compound as a white solid (90 mg, MS(ES) M+ Hf=67 1, M+Na*=693.

Example Preparation of bis- 1 .3-(4-phenoxy-phenyl sulfon amido) -propan-2 -one Following the procedure of Example 49, except substituting 4-phenoxya e phenyl sulfonyl chloride for 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M-W=551.

Example 5 1 Preparation of 1-Czluiv)aio3(-3clr--yn-hnx)pev sulfonarnido )-p2ropan-2 -one Cbz-Ieucine (660 rng, 2.5 mxnol), EDCI (480 mng, 2.5 mrnol), HOBT (340 mg, 2.5 mmol) was dissolved in DMFf (10 ml) with 1,3-diamino-propafl-2-ol (225 mg, 2.5 mnmol) and was stirred at RT overnight. N-methyl morpholine (0.41 ml., 3.75 mxnol) was added followed by 4-3-Chloro-2-cyalo-phefloxy)-phenyI sulfonyl chloride (820 mg, 2.5 mrnol, Maybridge) was added and the reaction was stirred 3h at RT. The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude *0:so 1 -(Cbz-leucinyl)-arnino-3-( 4 3-chloro-2-cyalo-phefloxy)pheflyI sulfonamido)propan-2-ol was then dissolved in acetone (5.0 ml) and Jones reagent (3.0 ml, OS 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 0* 15 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% MeOH/ methylene chloride), then the product was triturated from methylene chloride to give the title compound es% as a white solid (26 mg, MS(ES) M+ 627.

0 4 0 Example 52 GOO: Preparation f I -(Cbz-leucinvb- aino3(tosylamifo-roan 2 -ne Following the procedure of Example 5 1, except substituting tosyl chloride 0*@for 4-3Clr--yn-hnx)pey sulfonyl chloride, the title compound was prepared: MS(ES) M-W= -488.

Example 53 Preparation of I -(Cbz-leuci nyl )-arrno- 3 -(4-phenoxv-phe n vfl-su Ifonarnjdo i prop~an-2-one Following the procedure of Example 51, except substituting 4-phenoxvphenvl-sulfonvi chloride for 4 3 -Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M+H-=568, M+Na -=590.

Example 54 Prep aration of I (b-ecni-r~o3(-ibezfrnufnmd)DOan2 one Following the procedure of Example 5 1, except 2-dibenzofuransulfonvl chloride for 4 3 -Chloro-2-cvano-phenoxy)-phenyl sulfonyl chloride. the title compound was prepared: MS(ES) M+W=566, M+Na'=588 Exarple Prep~aration of -(Cbz-homo-leucinl)-amino3(2dibnzofuransulfonmdo)- *0 000 0000 00 #0 0 *Soo 15 Following the procedure of Example 5 1. except 2-dibenzofuransulfonyl chloride for 4 3 -Chloro-2-cvano-phenoxy)-phenyI sulfonyl chloride and Cbz- 20 homo-leucine for Cbz-leucine, the title compound was prepared: MS(ES) M+Na'=602.

0 0000 0 00 05 0 0 000000 0 0 Example 56 Preparation of I -(Cbz-leucinvf-amino-3-(2-dibnzofuransulfonarido)-(S'-buian-2:one a) I -(Cbz- leuci nyl)-amnino- 3 (2 -di benzofuransul fonamido)- utan -2 ol Cbz-leu-2-amino-4-arnino-propan-3-ol (150 mg, 0.42 mmol, as described in Example and 2-dibenzofuransulfonyl chloride were dissolved in DMF (2 nil) and N-methyl morphonline (0.09 ml, 0.84 mmol) and were 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.

00 1 -(Cbz-leucinyl)-amriino-3-(2-dibenzofuransulfonamido)-(S )-buta-2- -one ones le ucinyl)- amino- 3 -di be nzofuransulfonamido)- (S )-butan 2-ol1 (240 doe 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 mrl, 1.5 M) was :15 added dropwise and the reaction was stirred at RT overnight. The excess Jones so 0:reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted .00 with EtOAc (20 ml]) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOI methylene chloride) to for'o 20 give the title compound as a white solid (70 mg, MS(ES) M-W=578.

&*so 060 Exampie f Preparation of (S)-Phenylmethyl fI-f rf 3-[Benzvloxvcarbonv-i-eucinvl-amrino a) 2-hvdroxv-3-azido-propanol Sodium azide (1.7 g, 26 mmol) was added to a solution of glycidoi (Aldrich.

1.3 g, 17.5 mnrol) in MeOH (45 ml) and water (5 ml) and was heated to 65 degrees C for 4 h. The reaction was diluted with water (25 ml), extracted with EtOAc (2 x ml); the combined organic layers were extracted with water (2 x 50 then brine. (50 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel. 30 EtOAc! hexanes) to produce a white solid (1.3 7 g, MS(ES) M+H+=1 18.4.

900 1.40 b) 2 -hydrox y- 3-azido-propan-tcosy Iate Tosyl chloride (2.3 g, 12 mumol) was added to a solution of 2-hydroxy-3azido-propanol 1. 17 g, 10 mrnol) and u-iethyl amine (3.6 g, 36 mmol) in methylene achloride (50 ml) and was stirred at RT for 4h. The reaction was diluted with water :(20 ml), extracted with EtOAc (2 x. 50 ml); the combined organic layers were extracted with pH 7 buffer (2 x. 50 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 30 EtOAc/ hexanes) to produce a white solid (1.2 g, MS(ES) M+H+=272.2.

c) 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-azido-propaltosylate see* c) 2-Hydroxy-3-azido-propan-tosy late (1.2 g, 4.4 mmol) was added to a slurry 25 of Eliman dihydropyran polymer (cf. Scheme 1) (150 mg, 0.3 mmol) in 00 ClCI-2CH2C1 (25 ml), then pyridinium p-toluenesulfonate (0.84 g, 4.4 mmol) and was agitated at 80 degrees C by gentle bubbling with argon. The polymer was filtered, washed with DMIF (2 x 10 ml), then MeOH (20 ml), then methylene chloride (4 x 20 ml); [R 2105 cm- I Magic Angle Spinning I1H NMIR: d 8.0, 7.4, 5.0, 3.4.

d) -(Merrifield polymer-6- oxymethyiene-tetrahvdropyran-aceta)-3-azidopropan-N-benzyl-amine BenzyI amine (0.32 g, 3 mmol) was added to a slurry of 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyral-aceta-3-azido-propaltosylate (500 mg, I mmol) in N-methyl pyrolidinone (25 ail) and was and was agitated at degrees C by gentle bubbling with argon. The polymer was filtered, washed with DMF (2 x 10 mld), then MeOfi (20 ml), then methylene chloride (4 x 20 nil); JR 2-105cm-i1; Magic Angle Spinning I1H NMR: d 7.1, 4.7, 4.0, 3.8.

10 e) 2-(Merrifield polyiner-6-(oxymethylene-tetrahdopyral-aceta)-3-aido- 906 go: propan-N-benzyl-(Cbz-leucinyl)-amine Cbz-leucine (0.82 g, 3.0 mrnol) was added to a slurry of 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-azido-propa-N-benzyI -amine (120 mg, 0.22 mmol) in DMff (10 nml), diisopropyl ethyl amine (1.2 ml, 6 mmol) 15 and HATU (Perseptive Biosystems, 2.2 g, 6 mmol) and was shaken at room temperature overnight. The resin was filtered, washed with DM.F (3 x 10 ml). The above procedure was repeated, and the final resin washed with MeOH (2 x 20 ml), then methylene chloride (5 x 20 ml); JR 2105,1735, 1630 cm-i1;. Magic Angle Spinning I H NMR: d7.2, 4.7,4. 1.

f) 2-(Merrifield polymer-6-(oxymethyle ne-tetrahydropyran-acetal)- 3-aminlosee: propan-N-benzyl-(Cbz-ieucinyl)-amine Propanedithiol (0.5 ml. xx rnmoi) was added to a slurry of 2-(Merrifield polymer-6-(oxymethyiene-tetrahydropyran-acetal)-3-azido-propan-N-benzyi-(Cbzleucinyl)-amine (150 mg, 0.27 mrnol) in MeOH (5 ml) and triethylarnine (0.5 ml) and was gently rocked overnight. The resin was filtered, washed with MeOH (2 x ml), then with DMF (I x 10 ml), then with methylene chloride (5 x 20 ml), and was dried in a vacuum oven overnight; JR 1735, 1640, cm- 1 I Nlrrfed po.nr6 oxmehiene-rtrhdropyran-acetal Cbzleucinvl)-amino-propan-N-benzvl-(Cbz-1-eucinvl )-amine Cbz-leucine (0.82 a, 3.Omrnol) was added to a slumr 2-(Merrield polymner- 6-f oxymethylene-terrahvdropyran-acetal)-3-arniino-propan-N-benzyl-(Cbz-leuciny 1)amine (150 mg, 0.27 mmol) in N-methyl pyrollidinone (10 mnl), dilsopropyl ethyl amine (1.2 ml, 6 rnmol) and HBTU (2.2 g, 6 mmnol) and was shaken at room temperature overnight. The resin was filtered, washed with DML (3 x 10 ml). The above procedure was repeated, and the final resin washed with MeOH (2 x 10 ml), then methylene chloride (5 x 20 mil); Magic Angle Spinning I H NMR: d 7.6. 7.4, 5.1, 5.0, 3.4, 0.8.

h) 1 -IN-benzvl- 1 -Cbz-leucinvl-anuno-3-Cbz-leucinyl-ami no-propan-2-o 2-(Merrifield po Iy mer-6- (oxymethyle ne-terLrahydropyran -ace tal)- 3-(Cbz leucinvl)-amino-propan-N-benzyl-(Cbz-leucinyl)-amine (150 mg, 0.27 minol) was shaken as a slurry with 85:5: 10 TFAI 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/ methiene chloride) to produce a yellow solid (65 mg, MS(ES) M+H+=675.1.

20 i) 1 -N-benzyl- 1 -Cbz- leuc in yl-amino- 3- Cbz-leuc inyl-amino-propan- 2-one *0000*1 -N-benzyl- 1 -Cbz-leucinyl-amino-3-Cbz-leucinyl-amino-propan-2-o1 O mg, 0.96 rnmol) was dissolved in acetone (5 ml) and Jones reagent (2 ml,excess) was added dropwise at room temperature and the reaction was stirred overnight. The excess Jones reagent was then quenched with isopropanol (5 -lI) and the reaction was diluted with water (5 nil) and was extracted with EtOAc (2 x 20 nil). The go: combined organic layers were extracted with water (2 x 15 ml), then brine (10 mal), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce a yellow solid, which was chromatographed (silica gel, 50%EtOAcfHexanes to produce a white solid (16.8mg, MS(ES) 673. 1 Example 58 Preparation of (S)-Phenyimethyl flI-fr3-r(2-dibenzofuranvlsulfonvl)amrinol->, oxopropvl 1-3-(benzvl)amninolcarbonyll-3-methylbutvl icarbamate a) N-(2-hydroxy-3-N-benzylamino-propyl)phthalimide N-(2.3-Epoxypropyl)phthalimiide (Aldrich, 2.03 g, 10 rnmol) was reluxed with beazyl amine (1.07 g, 10 mmol) in isopropanol (15 ml) for 3h. The reaction was cooled to RT, then concentrated in vacuo producing a white gum, which was triturated with MeOH, then filtered producing a white solid (0.48 g, MS(ES) 311.

b) N-(2-hydroxy-3-(N-benzyl-2-dibezofuransulfonanide)-propyl)phthairnde strredN-(2-hydroxy-3-N-benzylamino-propyl)phthalimide (0.31 g, 1 mmol) was sirdwith 2-dibenzofuransulfonyl chloride (0.27 g, 1 mmol) in N-methyl morpholine (0.8 ml) and DMIF (5 ml) overnight. The reaction was diluted with 15 water (10 ml), extracted with EtOAc (Wx2 inl), the combined organic layers were :extracted with water (3 x 20 ml), then brine (20 ml), then were dried with 5 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-,-= 20 585 C) 2hdoy@Nbny0-ibnouaslfnmd)popl3aSn c) 2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide)-propylalnine iid (0.37 g, 0.69 mmol) was refluxed with hydrazine hydrate (0.34 g, 6.85 mmol) in MeOH (7 nil) for 1.5 h. The reaction was cooled RT, then was concentrated in vacuo. The resulting white solid was triturated with MeOH, then filtered to produce the desired product as a white solid (0.27 g, MS(ES) M+W*=41 1.

d) Cbz-Ieucinyl-(2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide))-propyl-3amine 2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide)-propyl-3-amine (0.2 g.

m-mol) was stirred with Cbz-leucine (0.13 g, 0.5 rnrnol) in N-methyl morpholine (0.6 ail) and IDMF (2 mal). then l-BTLU 0. 19 2. 0. 5 rnrol was added and the reaction was stirred overnight at RT. The reaction w'as diluted with water (10 mud.

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 mI), 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+W= 658, MS(ES) M+Na 680.

e) (S )-Phenylmethyl [1 [(2-dibenzofuralysulfolyl)aminl-2-oxopropyII -3- (benzvl)aminojcarbonvll-3-methylbutyllcarbamate Cbz-leucinvl-(2-hvdroxy-(N-benzyl-2-dibenzofuransulfonamflde))-propyI-3amine 16 g, 0.244 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml.

M) was added added and the reaction was stirred overnight. The excess Jones reagent was then quenched with isopropanol (1 ml) and the reaction was diluted with water (10 ml) and was extracted with EtOAc (2 x 20 ml). The combined organic layers were extracted with water (2 x 20 nil), then brine (20 ml), then were dried with magnesium sulfate, filtered, concentrated in vacua to produce a white solid, which was chromatographed (silica gel, 1: 1 EtOAc/ hexanes) to produce a white solid 14 g, MS(ES) M-WT654, MS(ES) M+C1*=690, MS(ES) M+HC0 2 700.

es0 0 000 sees

S

S

@000 *000 0000 0 0000 So 000000 0 Example 59 Preparation of (S)-Phenylmethvl [1 [3-[(2-dibenzofuranylsulfonyl)axninol-2oxopropyfll3-(4-2yridinylmethv1)aminolcarbonyll-3-methylbutyIlcarbamate Following the procedure of Example except substituting "4pyridyl methyl amine" for benzylamine" and, the title compound was prepared; MS(ES) M+W=-657.

110 Exampae Preparation of I -ff[3-12-dibenzofuranylsulfonvl )armnol-2-oxopropvll-3-(4pyridinvimetiivl) benzam-ide Following the procedure of Example except substituting "berizoic 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[I-I [f3 4(2-dibenzofuranyisulfonyvbamino] -2 oxopropyl- I -(4-pvridinylmethyl)aminolcarbonvll-3-methylbutvl carbamate 0:60 Following the procedure of Example except substituting "4- 690: pyridyl methyl amine" for benzylam-ine" and "Cbz-leucine and HBTU'" for "2dibenzofuransulfonyl chloride and "2-dibeazofuransulfonyl chloride "'for "Cz- :leucine and HBTU", the title compound was prepared; MS(ES) M+W=-657.

0S Preparation- of 2-fN-(N-benzyloxycarbonvl-L-leucinyl)1-2'-[N'-(4phenoxyphenylsulfonyl)lcarbohydrazide a) N-benzyloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester hydrochloride (2.0 g, 1 .Omrnol) in 1 ,4-dioxane (20 mL) was added Na 2

CO

3 (12.1 mil, 2M in water) followed by benzylchloroformate (1.96 g, 11.5 mniol). The mixture was stirred at room temperature for 4h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated to 25 yield the title compound as a colorless oil (3.1 g, 100%). IH NMR (40C MHRZ, 0 ODC 3 8 7.34 (in, 5H), 5.27 IH), 5.12 2H), 4.41 2H), 3.75 3H), 1.65 (in, 3H), 0.96 (in, 6H).

h) N-benzvloxvcarbonvi-L-ieucinvih-vcrazide To a stirring solution of the compound of Example 62(a) 1 g2, 11.0 mmrnoli in 15 raLL of methanol was added hvdrazide hydrate (5.9g.z 118 rnmolh. The solution was stirred at room temperature for 16h then concentrated to yield the tide compound as an off-white solid (3.1 g,100%). MS(ESI): 280.2 c) 1 -benzyloxvcarbonylamino-3-methyl- 1 ,3,4-oxadiazol-2-on-5vl)butane To a stirring solution of the compound of Example 62(b) (3.0 2, 10.8 mrnol) in toluene (50 m.L) was added phosgene (56 mL, 1.93M in toluene). The solution was heated at reflux for 4h then concentrated to yield the title compound as a pale Yellow foam (3.15 g, MS(ESI): 306.1 ;.-(N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide 15 To a stirring solution of the compound of Example 62(c) 147 g.0.482 mmol) in 2 rnL of methanol was added hydrazine hydrate (0.24 1 g,4.82 inmol).

:The solution was stirred at room temperature for 24h then concentrated and purified by column chromatography (silica gel, methanoi/dichloromethane) to yield the tidle compound as a white foam (0.097 g, MS(ESI): 338.2 e) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(4phenoxyphenylsulfonyl)]carbohydrazide To a stirring solution of the compound of Example 62(d) (0.097 g, 0.288 mnmol) in 2 m.L of DMF was added pyridine (0.046 g, 0.576 mmol) followed by 4phenoxyphenylsulfonylchioride 155 g, 0.576 mrnol). The solution was stirred at room temperature for 16h then partitioned between ethyl acetate and water. The *:Soo: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%).

Example 63 Preparation of 2-N(-ezlxcroy--lnl)-'f-NbnNIx'abn,] L-Ieucinyl)lcarbohvdrazide To a stirring solution of the compound of Example 62(d) 100 g, 0.297 rnol) in 2 mL of DMI was added N-benzyloxycarbonyl-L-alafline (0.070 g, 0.312 ramol), I -hydroxybenzotriazole (0.008 g, 0.059 mmol). and 1-(3dimethylamiinopropyl)-3-ethylcarbodiirflide hydrochloride (0.060 g, 0.312 numol).

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

*as: Example 64 :.Preparation of 2- rN-(N-bezloxycarbonyl-L-leucinvfll-2-rN'-(4phenylbenzoyl~lcarbohydrazide Following the procedure of Example 63, except substituting 4-phenylbenzoic acid for N-benzyloxycarbonyl-L-alafline, the title compound was prepared as a white solid (0.121 g, MS(ESI): 518.1 (M+H) 4 Eanl6 Preparation of 2-rN-4N-benzyloxyca~bonl-L-leucinfl)124-N'-( 4 methoxybenzoyl 'lcarbohydraz&d Following the procedure of Example 63, except substituting 4methoxybenzoic acid for N-benzyloxycarbonyl-L-alanifle the title compound was 2 .5 prepared as a white solid (0.057 g, MS(ESD: 472.1 Example 66 Preparation of 2-FN-(N-benzvloxvcarbonvl-L-Jeucinvl )1-2 -fN-4 4 2henoxybenzovl lcarbohxdrazide Following the procedure of Example 63. except substituting 4phenoxybenzoic acid for N-benzyloxvcarbonyl-L-alaniine the title compound was prepared as a white solid 102 g, 43 MS(ESI1): 5 34.1 Example 67 Preparation of 2)-(N-acetl)1-2-rN-(N-benzyloxvcarbonvl-Lleucinyl~carbohydrazide To the compound of Example 62(d) 100 g, 0.297 rnmol) was added acetic anhydride (0.303 2.97 mmol). The solution was stirred at room temperature for 16h then concentrated to an off-white solid which was washed with dichioromethane to yield the title compound as a white solid (0.086 g, 76%).

00':0b 15 MS(ESI): 380.1 .00 so Example 68 Preparation of 2-rN-(N-acetv1-L-euciny)1-2'-rN'-(N-benl~oxVcarboflyl-Lal any 1) carbohydrazide 20 a) 2-[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide .:::*Following the procedure of Example 62(a)-62(d), except substituting Lalanine ethyl ester hydrochloride for L-leucine methyl ester hydrochloride in step the title compound was prepared as a pale yellow foam 1 g, 3.8 mmol).

MS(ESI): 296.2 al any 1) carbohydrazide To a stirring solution of the compound of Example 63(d) 150g, 0.5O8mmol) in DMI (2mL) was added N-acetyl-L-leucine (0.092g, 0.534minol), Ihydroxvbenzotri azole (0.014g, 0. 102mmrol), and I -(3-dimethylamninopropyl)- 3 ethvlcarbodiride hydrochloride 102g, 0.534mnrnol). 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 p unified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as a white solid (0.028 g, MS(ESI): 451.1 Example 69 Prep~aration of 2-[N-(N-acetyl-L-alanylVI-2'-[N'-(N-benzvloxycarbovlL leucinvi) icarbohydrazide Following the procedure of Example 68(b), except substituting N-acetyl-Lalaniine for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-Lleucinyl )]carbohydrazide for 2- (N-(N-benzyloxycarbonyl-L-alanyl)jcarbohvdrazide.

the title compound was prepared as a white solid (0.050 g, MS(ESI): 473.1 Prelparation of 2-rN-(N-benzvloxvcarbonvl-L-leucinvl)1-2'-[N'-f4-(N.Ndimethylanminomethyl)benzovflhlcarbohydrazide a) methyl 4-(NN-dimethylamainomethyl)benzoate 20 Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 mmol) was added to a 000.0saturated solution of dirnethylamine in methanol. After stirring for 25 min, the solution was concentrated and the residue was partitioned between IN NaOH and @000 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 M1-z, CDCl 3 8 8.00 2H), 7.39 2H), 3.91 IH). 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-)O 1) and LiOH'H-,O (0.39 g, 9.3 rmcl) was added. The rrixture 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 reconcent-rated to vieid a whitie solid (1.6g 100%). IH NMR (400 M\1-z. CD 3 OD) 5 7.94 2H), 7.36 S'.64s, 214), 2.35 6H).

c. 2)-[N-(N-benzyoxvcarbonyl-L-leucinyI)J-2'-[N'-[4-(N,Ndimethylamrinomethyl)benzoyl)]]carbohydrazide Following the procedure of Example 68(b), except substituting dimethvlarninomethyl)benzoic acid lithium salt for N-acetyl-L-leucine and benzyloxvcarbonyl-L-leucinyl)]carbohyrazide for 2-[N-(N-benzyloxycarbonyl-Lalanvl)Jcarbohydrazide, the title compound was prepared as a pale yellow solid (0.050 g, MS(ESI): 499.1 Example 71 Preparation of 2-[N-(N-benzyloxycarbonyl-L.-Ieucinyfll-2'-[N'-F4-hvdroxv-f3-(4- 15 morpholinomethyl)llbenzoyllcarbohydrazide Following the procedure of Example 68(b), except substituting 4-hydroxy-3- (4-morpholinomethyl)benzoic acid for N-acetyl-L-Ieucine and benzyloxycarbonyl-L-leucinyl)Icarbohydrazide for 2-f N-(N-benzyloxycarbonyl-Lalanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.065 g, 20 MS(ESI): 557.0 Exmpe72 Prep~aration of 2-rN-(N-benzvioxvcarbonvl-L-leucinl)1-2'-F.N'-f4-(N.Ndi merhvlIamiunornethVl )benzylIoxvl]carbon v I-L-le ucinvl I carbohvdrazide a) ct-isocyanato-L-leucine methyl ester L-leucine methyl ester hydrochloride (25 g, 0. 14 mol) was dissolved in methylene chloride (450 niL), 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 18 mol, 92.7 niL) was -added slowly. After stirring at 0 *C for 2 b, 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 znL of ice. The aqueous layers were extracted with methylene &:Gochloride (450 niL) and the combined organic layers were washed with 1400 mL of so*:saturated brine and 900 niL of ice, then dried (MgSO 4 filtered and concentrated.

4 The residue was distilled (56-58 0.78 rmHg) to provide the title compound as a colorless liquid (20.4 g, 1 H NMR (250 MHz, CDCI 854.04 (dd. I 3.82 00 0 15 3H), 1.92-1.72 (in, I1-H), 1.69-1.62 (mn, 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 rnmol) in 25 mL of ether, cooled to 0 C, was added dropwise a 1 M solution of lithium eg* 20 aluminum hydride (8.4 mmol, 8.4 mL). After 5 min, the reaction was quenched by the addition of water (0.33 niL), 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, 25 IH NMR (250 MIHz, CDC1 3 8 7.32 2H), 7.28 2H), 4.68 2H), 3.41 2H), 2.22 6H).

c) N- -dimetLhylIamidnomethyl)be nzyloxycarbonyl leuc ine methyl ester A solution of the compound of Example 72(a) (1 .0 g, 5.8 mmol) and the compound of Example 7 2(b) in toluene (6 niL) was heated at reflux for 24 h. The solution was concentrated and the residue was purified by flash chromatography on g2 of 230-400 mesh s'ijca -gel, el uung2 with 5% methanoi nmhveecore.o provide the title compound a-s a pale yellow oil 1. 71 g2, 8717). I H NMNR (400 NIHlZ.

CDC13) 6 7.31 4H), 5. 13 1H), 5.10 2H), 4.41 IH). 3.74 3H). 3.43 2H), 2.24 6H), 1.70-1.62 (in, 2H), 1.52 (in. IH), 0.96 3H), 0.94 3H).

d) N- [4-(N,N-dimetEhyl aminome thy1) benzyloxyc abonyl leuci ne lithium salt Following the procedure of Example 70(b), except substituting diinethylamainomethyl)benzyloxycarbonyl]-L-leucine methyl ester for methyl 4- (N,N-dimethylaminomethyl)benzoate, the title compound was prepared as a white solid (1.57 1 H NMNR (400MIHz, CD 3 OD)567.35 (d,2H),7.30 2H) *5.06 (dd, 2H), 4. 10 (dd. I 3.48 2H), 2.23 6H). 1. 69-1.51 (in. 3 0. 94 (d.

3H), 0.93 3H).

se) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)I-2-[N'-4-(N,N- :0 15 dimethylaminomethyl)benzyloxylcarbonyl-L-leucinyllcarbohydrazide Following the procedure of Example 68(b), except substituting N-(14-(N,N- 0* dimethylaminomethyl)benzyloxycarbonyl]-L-leucine lithium salt for N-acetyl-Lleucine and 2- [N-(N-benzyloxycarbonyl-L-leucinyl)carbohydrazide for 2- benzyloxycarbonyl-L-alanyl)jcarbohydrazide, the title compound was prepared as a S 20 white solid (0.069 g, MS(ESI): 642.1 seep Example 73 Preparation of 2-(N-benzoyl)-2'-N 1-(N-benzyloxycarbonyl-Lleucinyl ~1carbohydrazide 2. 5 Following the procedure of Example 62(e) except substituting benzoyl chloride for 4-phenoxyphenylsulfonvichioride, the title compound was prepared as a white solid (6 1mg, 3 1 MS (ESI1): 442. 1 Example 7-4 Preparation of 2-fN-(N-benzvloxvcarbonvl-L-leucinvl)1-2'-FN'-f3-(4morpholinomethyl )benzoyll lcarbohvdrazide a) methyl 3-(4-morpholinomethyl)benzoate A solution of morpholine (0.836 g, 9.6 mrmol) and methyl 3- (bromomerthyl)benzoate in THE (5 m.L) and DMF (5 m.L) was stirred at 50 OC for 3h. The solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous Na.HCO 3 and brine then dried (MgSO 4 filtered and concentrated to yield a colorless oil (0.872 g, 3.721 mmol). I H NMR (400 MHz, CDCI 3 6 7.99 I 7.91 I 7.55 I H), 7.47 1H), 3.94 3H), 3.72 (in, 4H), 3.53 2H), 2.46 (in, 4H).

0*06 b) 3-(4-morpholinomethyl)benzoic acid 60:900To a solution of the compound of Example 74(a) (0.872 g, 3.72 mmol) in 0 9 15 TI-F (3 mL) and water (3 mL) was added lithium hydroxide inonohydrate 171 g, 4.08 inxol). After stirring at room temperature for 3h, the solution was concentrated. The residue was redissolved in water (5 inL) and 3N HC1 was added and the solution was lyophilized to yield a yellow solid (0.822 g, 3.72 mimol).

:2:MS(ESI): 222.0 0:0C) 2- [N-(N-benzyloxycarbonyl-L-leucinyl)I-2'- morpholinomethyl)benzoyl] ]carbohydrazide Following the procedure of Example 68(b), except substituting 3-(4morpholinomethyl)benzoic acid for N-acetyl-L-leucine and *:Soo: 25 benzyloxycarbonyl-L-leucinyl)]carbohydraz-ide for 2-[N-(N-benzyloxycarb&,,yi-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.056 g, MSESI): 541.0 Example Preparation of 2-[N-(3-benzvloxybenzoyl)l-2'-[N'-(N-benzvloxvca-rbonv-Lleucinyl lcarbohvdrazide a) methyl 3-benlzvloxvbenzoate To a suspension of NaHf (0.395 g,9.87 mmol, 60% in mineral oil) in DIEFf inL) was added methyl 3-hydroxybenzoate (1 .0 g, 6.58 mmrol). After sdi-ring for 15 min at room temperature, beazy] bromide (1.1I 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 rnmol). lH NMR (400. MHz, 0066 CDCJ 3 587.67 (in, 2H). 7.48-7.34 (in. 6H), 7.19 (mn. IH), 5.12 2H), 3.95 3H).

3-benzyloxvbenzoic acid 15 To a solution of the compound of Example 75(a) (0.400 g, 1.65 inxnol) in :THY (2 m.L) and water (2 rnL) was added lithium hydroxide monohydrate (0.076 g," 1.82 rnxnol). After stirring at reflux for 5 h, the solution was partitioned between ethyl acetate and 3N HCI. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated to yield a white solid (0.355 g, 1.56 Mmnol). 1

H

NMR (400 MlHz, CD 3 OD) 8 7.58 (mn, 2H), 7.36-7.24 (mn. 6H), 7. 10 (in, IRH), 5.04 2 H).

c) 2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide 25 Following the procedure of Example except substituting 3benzyloxybenzoic acid for N-acetyl-L-leucine and 2-fjN-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide for 2 -[N-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.062 g, MS(ESI): 548. 1 Example 76 Preparation of 2-fN-(,N-benzvloxycarbonvl-L--leucInvl)1-2'-fN-f4-f3-{'N-Ndimethylarnino)-l1-propvloxvlbenzovl ]lcarbohvdrazide a) methvl 4-[3-(N,N-dirnethvlamino)- 1 -propyloxyjbenzoate To a solution of methyl 4-hydroxybeazoate (1.0 g, 6.58 mmol). 3dime thy]lamino- I-propanol (1.01 g, 9.87 mxnol), and triphenylphosphine (2.6 g, 9.87 mumol) at 0 0 C in THfF (20 rnL) was added dropwise dilsopropyl azodicarboxylate (1.99 g, 9.87 mmol). After stirring for 16 h at room temperature the solution was concentrated and the residue purified by column chromatography (silica gel, methanolldichloromethane) to yield the title compound as an oily solid (1.25 g, 5.2 minol). MS(ESI): 238.1 b) 4- [3-(N,N-dimethylaiino)- 1 -propyloxy]benzoic acid Following the procedure of Example 74(b) except substituting methyl 44[3- 15 (N,N-dimethylIamino)-1I-propyloxyjbenzoate for methyl 3-(4morpholinomethy)benzoate, the title compound was prepared as a tan solid (1.17 g, 9 5.2 mmol). MS(ESI): 224.1 c) 2- [N-(N-benzyloxycarbonyl-L-leucinyl)] -2'-[N'-[4-[3-(N-N-dimethylamino)l-propyloxylbenzoyl]]carbohydrazide Following the procedure of Example 68(b), except substituting a:..dimethylamino)-lI-propyioxy]benzoic acid for N-acetyl-L-leucine and 2-IIN-(Nbenzyloxycarbonyl-L-leucinyl)Icarbohydrazide for 2- (N-(N-Ibenzy loxycarbony l-Lalanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.060 g, 25 MS(1ESI): 543.1 Example 7?, Preparation of 2-[N-'2-benzvloxvbenzovl)l-2'.fN'- N-benzvloxv-ca-bonvl-Lleucinvi )lcarbohvdrazide Following the procedure of Example 68(b), except substituting 2benzyloxybenzoic acid for N-acetyl-L-Ieucine and 2-7N,-(N-benzyloxvcarbonvl-L Ieucinyl)jcarbohydrazide for 2-[iN-(N-benzyloxycarbony-L-alanyl)]carbohvdr-zjde title compound was prepared as a white solid (0.056 g, MS(ESI): 548. 1 Example 78 Preparation of 2-fN-(N-benzyloxycarbonv1-L-Ieucinyl)1-2'rNj3-(4see: pvyridylmethoxyvbenzoylilcarbohydrazide a) methyl 4-pyridinylmethoxybenzoate 4 Following the procedure of Example 76(a) except substituting methyl 3- 15 hvdroxybenizoate for methyl 4-hydiroxybeazoate and 4-pyridylcarbinol for 3diinethylamino-lI-propanol, the title compound was prepared as a yellow solid 6 (0.599 g, 2.5 mmol). MS(ESI): 244.1 b) 4-pyridinylmethoxybenzoic acid Following the procedure of Example 75(b) except substituting methyl 4pyridylmetboxybeozoate for methyl 3-benzyloxybenzoate the title compound was prepared as a yellow solid (0.386 g, 1.69 rmol). IH NMIR (400 NMz, CD 3 OD) 8 8.54 2H), 7.64 (mn, 2H). 7.57 2H), 7.40 IlH), 7.26 (in, IlH), 5.24 2H).

c) 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[3-(4pynidylinethoxy)benzoyl] ]carbohydrazide Following the procedure of Example 68(b), except substituting 4pyridinylmethoxybeazoic acid for N-acetyl-L-Ieucine and 2-[jN-(Nbenzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2- (N-(N-benzyloxycarbonvl-Lalanyl)]carbohydrazidc, title compound was prepared as a white solid (0.2 19 g.

677c). MS(ESI): 549.1 122 Example 79 Preparation of 2 -fN- 4 4-benzyloxybenzovl)-2fN(NbenzvI oxvcarbonv-Lleucinvi )lcarbohydrazide Following the procedure of Example 75(a)-75(c) except substituting methyl 4-hydroxybeiZOate for methyl 3-hydroxybenzoate in step the title compound was prepared as a white solid 160 g, MS(ESI): 548.1 Preparation of 2-N(-ezlxcroy--ecnl12-N-3bnyov5 methoxv )benzoyllcarbohydrazide C C*a) methyl A suspension of methyl 3,5-dihydroxybenzoate (2.0 g, 11.9 mmol), K)C0 3 g, 11.9 minol), and jodomethane (1.7 g, 11.9 minol) in acetone (100 nl) was 15 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). IH NMR (400 MHz, K. CDC1 3 a 7.16 (in, I 7.12 (in, I 6.61 (in, I 5.04 ILH), 3.91 3H) 3.82 3H).

b) methyl FoUowing the procedure of Example 80(a) except substituting methyl 3hydroxy-5-methoxybe2zoate for methyl 3,5-dihydroxybenzoate and benzyl bromide for iodomethane, the title compound was prepared as a tan oil (1.2 g, 4.4 inmol).

1 H NMIR (400 M~z, CDC1 3 a 7.45-7.31 (mn, 6H1), 7.24 1H), 6.76 (in, 111). 5.09 2H), 3.95 3H), 3.84 3H).

c) 3-benzyloxy-5-nethoxybeflzoic acid Following the procedure of Example 7 5(b) except substituting methyl 3for methyl 3-benzyloxybenzoate, the title compound w.as prepared as an oran~e solid I. i4 2, .4 mmnmol i. IH-NMR (400 MHz, CDC I ia 7.4 2 -7.2 0 (in. 7 6.7 1 (mn. I 5.05 2 3 80 d -fN-(N-bzyiox methoxy)benzoylcarbohydrazide Following the procedure of Example 68(b), except substituting 3-beazvloxyacid for N-acetyl-L-leucine and 2- rN-(N-benzyloxycarbony1-Lleucinyl)Icarbohydrazide for 2- [N-(N-benzyloxvcarbonv1-L-alanyl)carbohydrazide.

title compound was prepared as a white solid (0.20 1 g. MS(ESI):- 578.0 Example 81 Preparation of 2 -UN-(N-benzloxycarbonyl-L-leucinyl)1b2'-N'(3.benzvloxv.4 dimethoxv)benzoyl icarbohydrazide 15 Following the procedure of Example 68(b), except substituting 3-benzyloxyacid for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl- L-leucinyl)Jcarbohydrazide 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- [N-(N-benzyloxycarbonyl-L-leucinyl)1-2'-[N'-(3-benzvloxv.5ethoxy)benzoyl Icarbohydrazide 6' Following the procedure of Example 80(a)-80(d) except substituting jodoethane for iodomethane in step the title compound was prepared a white solid 162 g, MS(ESI): 592.3 (M+H) 4 124 Example 83 Preparation of 2-f.[-N-benzvloxvcarboyl(gVcinl)1-2fN-N-belloxV-carbonlVI- L-leucinyl )lcarbohvdrazide Following the procedure of Example 68(b), except substituting Nbeazyloxycarbonylglycine for N-aceryl-L-leucine and 2-[N-(N-benzyloxycarbonyl- L- leucinyl)jcarbohydrazide for 2- (N-(N-benzyloxycarbonyl-Lalanyl)Jcarbohydrazide, the title compound was prepared as a white solid (0.204 g 657%). MS(ESU: 529.2 Eape9 Preparation of 2-fN-(3-benzvloxybenzolYI-2-N'-(N-bezloxycarboflvi-Lp1rol invi) carbohydrazide see a) 2-[N-(3-benzyloxybeazoyl)]carbohydrazide 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(ESD): 301.1 b) 2-N(-ezlxbnol]2-N-NbnyoyabnlL 20 prolinyl)]carbohydrazide Following the procedure of Example except substituting Nbenzyloxycarbonyl-L-proline for N-acetyl-L-leucine and benzyloxybenzoyl)Icarbohydraz-ide for 2-[-(N-benzyoxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.2 19 g MS(ESI): 532.0 Example Preparation of 2-f N-(N-benzvloxvcarbonvl-L-leucinvl l-2'-fN'-14phenvlphenlacetyl Icarbohvdrazide Following the procedure of Example 68(b), except substituting 4biphenylacetic acid for N-acevl-L-leucine and 2-[N-(N-benzyloxycarbony-Lleucinyl)jcarbohvdrazide for 2 -rN-(N-benzyloxvcarbonyl--alanyl)]carbohydrade the title compound was prepared as a white solid (0.224 g, MS(ESI): 554.2 Example 86 Preparation of ('S)-2-MN-3-benloxbenzo-2'- N o bv aminobutvrvl)lcarbohdrazide Following the procedure of Example 68(b), except substituting befzyloxycarbonyl-2-aminobutyric acid for N-acetyl-L-leucine and 15 benzyloxybenzol)Icarbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.244 g.

MS(ESI): 520.3 0 0 0000 0* 0 0. S 0000 0 00S0 *0600 20 0.00 000* 00S* 25 0 Example 87 Preparation of fbis-(4ohenlphenvacetyl)lIcarbohydrazide To a stirring solution of carbohydrazide (0.200 g, 2.22 mnol) in DMF (12 mL) was added 4-biphenylacetic acid (1.04 g, 4.89 rnnol), Il-hydroxvbenzotriazole (0.060 g, 0.444 mnol), and l-( 3 -dimethylaninopropyl)-3-ethylcarbodiniide hydrochloride (0.937 g, 4.89 mmol). After stirring at room temperature for 16 h, the solution was poured into 150 nL 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, MS(ESI): 501.1 Example 88 Preparation of (2'RS)-2-rN-(N-benzloxcarboflvl-L-leucil)~-2'-[2-( 4p2henvlp~henoxv )propionvl lcarbohvdrazide Following thie procedure of Example 68(b), except substituting 2-(4phenylphenoxy)propionic acid for N-aceryl-L-leucine and benzvloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-beazyloxycarbonyl-Lalanyl)Jcarbohydrazide, the title compound was prepared as a white solid 183 g, MS(ESI): 562.3 Example 89 OLC Preparation of 2-[N-(3-benzyloxybenzovl)1h2'-FN'-(4- *seemethylpentanovi carbohydrazide Following the procedure of Example 68(b), except substituting 4methylpentanoic acid for N-acetyl-L-leucine and 15 berizyloxybenzoyl)Jcarbohydrazide for 2-[N-(N-benzyloxycarbonyl-L- :alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.079 g, 6 MS(ESI): 399.3 Example Preparation of (2RS. N.N-Fbis-f2-ij-penvlhenv 4 methylpentanovi Vt 1lcarbohydrazide a) 4 -methyl-2-(4-phenylphenyl)pent-4-enoic acid To a stirring solution of diisopropylarnine (0.537 g, 5.31 ramol) in THF (5.2 rnL) at 0 'C was added n-butyllthium (2.1 rnL, 5.22 mrnol, 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 THE (2 mL) was added dropwise. After again warming to 0 'C and coolling to -78 3-bromo-2rnethylpropene (0.485 a, 3.54 mrnol) was added to the mixture in one portion. After S stirring at -78 'C for lh, the reaction was quenched with 2 rnL of water then concentrated. The residue was redissolved in water and extracted with ether (100 we.. rnL). The aqueous layer was acidified (3N HCI) and extracted with ether (3 X 100 ml). The organic layers were combined, dried (MgSO 4 filtered and concentrated 15 to yield a white solid (0.449 g, MS(ESI): 265.3 0b) 4 -methyl-2-(4-phenylphenyl)pentanoic acid To a stirring solution of the compound of Example 90(a) (0.449 g, 1.69 mxnol) in ethyi acetate (25 m.L) was added palladium on carbon (0.225 After *0e0- 20 stirring under a balloon of hydrogen for 1 6h, the mixture was filtered through Celite. The filtrate was concentrated to yield an off white solid (0.430 g, MS(ESI): 267.4 c) 2RS, 2 'RS)-2,2'-[N.N'-bis-f2-(4-phenylphenyl)-4- 25 methylpentanr-yl)]]]carbohycirazide Following the procedure of Example 87 except substituting 4-methyl-2-(4phenylphenyl)pentanojc 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 9 1.

Preparation of (2'RS)-2-[N-(N-benzyloxycarbonvl-L-ieucinvl fl-2'- 4pheriviphenvi )-,4-methvlpentanoyvl1lcarbohvdra-zide Following the procedure of Example 68(b), except 4-methyl-2-(4phenylphenyl)pentanoic acid for N-aceryl-L-leucine and benzyloxycarbonyl-L-leucinyl)jcarbohydrazide for 2-[N-(N-benzyloxycarbonvl-Lalanyl)jcarbohydrazide, the title compound was prepared as a white solid 111 MS(ESI): 588.1 Example 92 Preparation of (2'RS)-2-rN-(3-benzyoxyberizovl)1- 2'-fN'-f2-(4-phenvlp1henIvl)-4methylpentanoyl ,1 karbohydrazide Following the procedure of Example 68(b), except substituting 4-methyl-2- (4-pbenylphenyl)pentanoic acid for N-acetyl-L-leucine and 15 benzyloxybenzoyl)]carbohydrazide for 2-ijN-(N-benzyloxycarbonyl-L- '.:alanyl)]carbohydrazide, the title compound was prepared as a white solid 195 g, MS(ESI): 551.1 ::::*Example 93 20 Preparation of 2-rN-(3-benzloxybenizoyl)1-2'-rN'-(N-benzyloxycarbonyl-N-methyl- L-leucinylhkarbohydrazide Following the procedure of Example 68(b), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine and benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L- 25 alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.34 1 g, 9 MS(ESI): 562.2 129 Example 94 Preparation of 2-fN-(3-benzvloxvbenzovfll-24-N'-[N-(2pyridinvlmethoxycarbonyl)-L-leucinyll1 carbohydra-zide a) N-(2-pyridinvlme thoxvcarbonyl)-L-leucine methyl ester Following the procedure of Example 72(c), except substituting 2pryidylcarbinol for N-di me thyl amino) benzylI alcohol, the title compound was prepared as a brown oil (8.06 g, MS(ESI): 281.2 b) 2-[N-(2-pyridinvlvlmethoxvcarbonvl)-L-leucinvllcarbohydrazide Following the procedure of Example 62(b)-62(d) except substituting N-(2- 0:0* pyridinv~methoxvcarbonyl)-L-leucine methyl ester for L-leucine methyl ester in step .600: the tite compound was prepared as a pale yel-low foam (0.598 g, 69%).

MS(ESI): 339.3 15 c) -benzyloxvbeazovl) [N'-[N-(2-pyridinylmethoxycarbonyD-Les Ieucinyl]]carbohydrazide Following the procedure of Example 68(b), except substituting 3benzyloxybeazoic acid for N-acetyl-L-leucine and 6~6* pyridinylylmethoxvcarbonvl)-L-leucinyl]carbohydrazide for 2-fjN-(Nbenzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a *Se6 white solid (0.057 g, MS(ESI): 549.2 Example Preparation of 2-fiN-[3-(4-pyridylmrethoxy)benzovlll-2'rN'-rN-(2- 2o 5 pyridinylmethoxycartbonv l)-L-leucinylllcarbohydrazide *:e0o Following the procedure of Example 68(b), except substituting 3-(4pyridinylmethoxy)benzoic acid for N-acetyl-L-leucine and pyridinylyhnethoxycarbonyl)-L-leucinyl]carbohydrazide for 2- benzyloxycarbonyl-L-alanyl))carbohydrazide, the title compound was prepared as a yellow solid (0.088 MS(ESI): 550.2 0:* 90060 too* see*.

*000 0000 estC *00 Example 96 Preparation of (2RS)-2-fN-f2-(4-phenylphenvl)-4-methvlpentanovl)1-2'-rN'4N-,:.

pyridinylmethoxycarbonyl )-L-leucinyl 1lcarbohvdrazide Following the procedure of Example 68(b), except 4-methvl-2-(4phenylphenyl)pentanoic acid for N-acetyl-L-leucine and 2-cjN-(2pyridinylylmethoxycarbonyl)-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-benzyloxycarbonyl-L-leucinv f2-(4-p2henvilphenv i)- 4-methylpentanovl )1lcarbohydrazide The title compound was prepared from the compound of Example 91 using HPLC (Sumipax. OA-3 100, 4.6 X 150 mm, 80/20 hexane/ethanol, 1.0 ml~min, retention time 5.9 min).

Example 98 Preparation of 2-[N-(N-benzyloxycarbonl-L-leucinyl)1-2'-fN'-f2-(4-phenylphenvl)- 4-methyvlpntanoyl)1 lcarbohydrazide The title compound was prepared from the compound of Example 91 using 1{PLC (Sumipax OA-3 100, 4.6 X 150 mm., 80/20 hexane/ethanol, 1.0 miin.

retention time 8.1 min).

00 0 Example 99 Preparation of 2-rN-(N-benzvloxvca-rbonvl-L-leucinvl')1-2'-.N'-(N-(4phenvlphenvl)-N-(2-methvlpropl y)carbarnovl icarbohydrazide To a stirring solution of phosgene (0.228 rnL, 0.244 mmol, 12.5% solution benzene) was added dropwise a solution of N-(2-merthylpropyl)- N-(4phenylphenyl)amine (0.050 g, 0.222 mmol) and triethylamine (0.025 g, 0.244 mmnol) in dichloromethane (I After stirring at room temperature for 15 mmu~ this s olution was added dropwise to a solution of the compound of Example I1(d) (0.083 0, 0.244 mmol) and triethylam-ine (0.025 a, 0.24-4 rnol) in dichioromethane (1 m.L) at room temperature. After stirring at room temperature for 48h, Nmethylmorpholine (0.022 g, 0.222 mmol) and DMIF (2 m.L) were added to the solution and heated at 50 'C for 16h. The solution was then diluted with ethyl acetate (5mL) and washed successively with water, aqueous saturated NaHCO 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The go 15 residue was purified by column chromatography (silica gel, methanol] :dichloromethane) to yield the title compound as a yellow solid (0.023 g, 18%).

MS(ESI): 589.4 Example 100 "ago*" 20 Preparation of 2-[N-(3-benzvloxybenzovl)l-2'-rN'-(N-methyl-Lleucinyl~icarbohydrazide a) 2-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-terr-butoxycarbonyl-N-methyl-Lleucinyl)Ijcarbohydrazide 0:0 Following the procedure of Example 68(b), except substituting N-tert- **Soo: 25 butoxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine and 2-[IN-(3- 0 benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lal any1) ]carbohydrazide. the title compound was prepared as a white solid 183 g, MS(ESI): 550.4 b 3-benzvloxv benzovl)]-2-N'-( N-methl-L-eucini ujcarbohvdrazide To a stri-ng solution of the compound of Example 100(a) 100 2, 0. 189 mmol) in dichioromethane (I mL) was added trifluoroacetc 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, metbanolldichloromethane) to yield the title compound as a white solid (0.055 g, MS(ESI): 428.4 Example 101 Preparation of 2-[N-(N-benzloxcarbonl-L-leucinl)1-2'-rN-(N-methvl-L- 0:0* leucinvyi Icarbohydrazide see: Following the procedure of Example 100(a)-100(b), except substituting 2- *N-(N-benzyoxycarbonyl-L-leucinyl)]carbohydrazide for benzyloxybenzoyl)]carbohydrazide in step the title compound was prepared.

a0 0 a: 15 MS(ESI): 465.5 *0 S Example 102 Preparation of -benzyloxycarbonvlamino)-3-methylbutyllthiazol-4- *lcarbonyll-N'-(4-phenoxyphenylsulfonvl)hydmzide a) N-benzyloxycarbonyl-L-leucinamide To a stirring solution of N-benzyloxycarbonyl-L-leucine (4.6 g, 17.3 mmol) *080 in THF, cooled to -40 was added N-methylnorpholine (3.68 g, 36.4 mmol; t.L) and isobutyl chloroformate (2.37 g, 17.3 mmol; 2.25 mL). After stirring for min, ammonia was bubbled through the solution for 5 min. The solution was 25 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-benzvloxycarbonyl-L-leucinethoanmde A solution of the compound of Example 102(a) (4.58 2, 17.3 mmoi) 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 10 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 methvlene i: chloride/water, then into saturated aqueous NaHC0 3 The aqueous layer was extracted with methylene chloride and the combined organic layers were washed 15 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 (MgSO 4 filtered, and concentrated. Tge residue was S 20 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) -b-nzyloxycarbonylamino- 1-(4-hydrazinocarbonylthiazol-2-yl)-3methylbutane The compound of Example 102(c) (2.16 g, 5.73 mmol) was dissolved in ethanol (60 mL) and hydrazine hydrate (2.87 g, 57.3 mmol, 2.8 mL) was added and the solution was heated at 75 oC for 1 h. The solution was cooled and evaporated to dryness to provide the title compound as a pale yellow foam (2.01 g. 1

H

NMR (400 MHz, CDC1 3 5 8.35 (bs, 1H), 8.03 1H), 7.37 5H), 5.29 1H).

514-5.09 4.07 (bs. 2HL 1.192- 1.82 tin. I 1T-.6tn H .0d 6H).

e) (I I -berizyloxvcarbonvlamino)-3-methylburvljthiazol-4vlc arbonyl ]-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 m.L) and 4-phenoxybenzenesulfonyl chloride (408 mg, 1.52 inmol). The reaction was stirred for 16 hours and the solvents were evaporated to a residue *:so 10 which was chromatographed (silica gel, 40% ethyl acetate in hexane) to give the Go*:title compound as a white solid (0.3 10 MS (ESD): 595.6 :Example 103 Preparation of (IS f4-f 1 -(N-benZvloxycarbonvl-L-leucinylamino)-3- 15 methvlburvllthiazol-2-ylcarbonvll-N'-(N-benzyloxvcarbonyl-L-leucinvl)hydrazide a) N-benzyloxycarbonyl-L-leucinyl-L-leucinyl bromomethylketone I -Methyl-3 -nitro- 1 -nlitrosoguanidine (5.9 g, 40.11 nol) in ether (200 niL) 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 rnmol) is stirred in tetrahydrofuran at -40'C. N-methytmorpholine (1.07 g, 10.58 rnmol.

1. 16 rnL and isobutyl chloroformate (1.45 g, 10.58 mmol, 1.38 niL) are added.

The mixture is stirred at -40*C for 15 minutes and then filtered into a cold flask to fee remove precipitated salts. To the filtered solution is added an excess of the previously prepared diazornethane solution and the mixture is allowed to '-tand 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 LO.N 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 'H NMR (400 MiHz. CDCl3) 5 7.34 5H), 6.5 1 I 5.15 IlH), 5. 10 2H), 4.78 (in, IH), 4.20 (in. 1H), 4.04 (dd, 2H), 1.63 (in, 6H), 0.93 (mn, 12H).

b 2S, I'S)-2--(benzvloxvca-rbonvl larni no-N-[ 2'-carboethoxvthuazol-4-vl methvl burvl 4-methyl pentcan amride The compound of Example 103(a) (2.0 g, 4.4 rnmol) and ethyl thiooxamate (0.59 g, 4.4 mnmol) were refluxed in ethanol for 4 h. The solvent was evaporated and the residue chromatographed (silica gel, 2.5% methanol/dichloromethane) to give the title compound as a white solid (1.46 'HINMR (400 MI-z, CDCI3)567.32 (s.

lH), 7.21 (mn, 5H), 6.40 IH), 5.13 (dd. 114), 5.02 2H), 4.41 214), 4.06 (in, IH), 1.71 (mn, 2H), 1.47 (mn, 4H), 1.33 3H4), 0.73 (mn, 12H).

C) (2S, 1 S)-2-(benzvloxycarbonyl)ami~no-N-[ 1 2 -hvdrazinocarbonvlcimazo -4 .0.00. yl)- 3'-ime thy] bu tvl j4-me thy Ipenananide :0 Following the procedure of Example 102(d), except substituting (2S, l'S)-2- (benzyloxycarbonyl)amino-N-[ 1 '-(2-carboethoxythiazol4-vl)-3'-methylbutyl 15 methylpentaiiaride for (I I -benzyloxycarbonylaniino- 1 -(4-carboethoxythiazol-2 v l)-3-methylbutane, the title compound was prepared. MS (ESD: 476.3 d) (15 I-(N-benzyloxycarbonyl-L-leucinylamino)-3- To a stirring solution of the compound of Example 103(c) (180 mg, 0.38 mmol) in dimethylforinamide is added N-benzyloxycarbonyl-L-leucine (I1 In g, sees0.42 mmol), l-(3-diinethylaminopropyl)-3-ethylcarbodilmide hydrochloride (80 mg, 0.42 inmol), and 1-hydroxybenzotriazole (13 mg, 0.096 iniol). The reaction mixture is stirred for 16 hours at room temperature, filtered, and washed twice with See 0: 25 water. The solvent was evaporated to give the title compound as a white solid.

(0.207 MS (ESI): 723.9 (M+H 4 Preparation of (1 S)-N-f 2-r( 1 benzvloxvcarboflvlamno)-3-methylbutHIthiazolv lcarbonyl I -N'(44-he nylphen y lacetv1) h\drazide Following the procedure of Example 103 except substituting (I S)-lIbenzyloxycarbonylafllflo- I-(4-hydraziflocarboflylthazo[-2y)3methylbutane for (2S,l 'S)-2-(benzyloxycarbolyl)aminfo-N-[ l'-(2-hydrazinocarboflylthiazol- 4 -yl methylbutyll4-methylpeltalallde, and 4-bipheriylacetic acid for Nbenzyloxycarboflyl-L-leucifle, the title compound was prepared as a white solid.

MS (ESI 557.2 Example 105 fee: Prep~aration of (1 S)-N-r2-r( I benzvloxvcarbonviamifo)3methylbutvflthiazol- 4 ole 0 6 vicarbonvil f3(4-12rvidinlfethoxy~beflzoy-Uhydrazide a) methyl 3-(4-pyridiny~methoxy)be1zoate 15 To a stirring solution of methyl 3-hydroxybeazoate (1.0 g, 6.58 rnmol), 4pyridylcarbinol g, 9.87 rnmol), and triphenylphosphifle (2.6 g, 9.87 mmol) in THF (25 m.L) at 0 0 C was added diisopropyl azodicarboxylate (2.0 g, 9.87 mrnol) dropwise. After stirring at room temperature for 16h, the solution was concentrated see* and purified by column chromatography (silica gel, ethyl acetate/hexane) to yield so: 20 the title compound as a white solid (0.599 g, MS(ESI): 244.1 6b) 3-(4-pyridinylflethoxy)beflzoic acid To a stirring solution of the compound of Example 105(a) (0.599 g, 2.47 *mmol) in THIFJH 2 O 10 mL) was added lithi um hydroxide monohydrate 113 g, 2.7 1 mrnol). After stirring at reflux for 3.5h, 1. 1 eq of IN HCl was added and the mixture poured into water. The mixture was extracted with ethyl acetate (2 X 100 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, IH NMR (400 M&z, CD 3 OD) 8 8.54 2H), 7.64 (mn, 2H), 7.57 (in, 2H), 7.40 1H). 7.26 (in, 1H), 5.24 2H).

c IS l-benizylox vc arbonylarruno j-3- methyl butv I)thi azo i-4ylcarbonil-N-[3i-4-prvi dinvlmethoxy)benzovljhvdrazide Following the procedure of Example 103(d), except substituting (lIS)- Ibenzvloxvcarbonvarnino- l-(4-hydrazinocarbonvlthiazol-2-vl)-3- methvlbutane for (2S.1 S)-2-(benzvloxvcarbonyl)amino-N-[ 1-(2-hydrazinocarbonylthiazol..4-vy)3'.

methylbutyl]-4-methylpentanamide, and 3-(4-pyridinylmethoxy)benzoic acid for Nbenzyloxycaz-bonvl-L-leucine, the title compound was prepared as a white solid.

MS (ESI): 574.2 Example Preparation of N-f 2-chlorop~henoxvrnethyl )thiazol-4-vlcarbonvl 1-N- 2vrdinylmethoxycarbonyl)-L-leucinyllhvdrazide t a) c-isocyanato-L-leucine methyl ester s C:L-leucine methyl ester hydrochloride (25 g, 0. 14 mol) was dissolved in I00 :15 methylene chloride (450 mL), cooled to 0 and pyridine (43.5 g, 0.55 mol, 414.5 mL) was added, then a 1. 93 M solution of phosgene in toluene 18 mol, 92.7 mL) 0. was added slowly. After stirring at 0 0 C for 2h, then mxture was poured into 0.5 N HCI (1400 mL) and ice (900 mL). The organic layer was washed with 0.5 N HCI (1400 mL) and ice (900 rnL). The aqueous layers were extracted with methylene 20 chloride (450 mL) and the combined organic layers were washed with saturated brine (1400 m.L) and ice (900 mL), then dried (MgSO 4 filtered and concentrated.

The residue was distilled (56-58 0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 1 H NNM (250 MHz, CDCl 3 8 4.0.4 (dd, I1H), 3.82 3H), 1.92-1.72 (in, IH), 1.69-1.62 (in, 0.96 3H), 0.94 3H).

N-(4-pynidinylmethoxycarbonyl)-L-leucine methyl ester A solution of the compound of Example 106(a) 10 g, 29.8 mmol) and 4pyridylcarbinol (3.25 g, 29.8 mrnol) in toluene (30 m.L) 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 1 H NMR (250 MiHz.

138

CDCI

3 6 8.59 2H). 7.24 2H), 5.33 id. 1H). 5.13 S. 3H), 4.40 cdt. 1H. 3.7; 3H), 1.81-1.51 Cm. 3H), 0.96 Cd, 3H), 0.95 Cd. 3H).

C) N-(4-pyridinylmethoxvcarbonyl)-L-leucine To a stirring solution the compound of Example 106(b) (1.98g, 7.06 mmol) in THF (7 mL) was added 7 rnL of water followed by LiOH9H 2 0 (325 mg, 7.76 nunol). The mixture was stirred for 30 minutes and then concentrated. The residue was redissolved in water (10 mL) and 3 NHCI was added (2.6 mnL). The solution was lyophilized to yield a white solid (2.015 g, 6.44 mmol). MS (ESI): 267.2 d) N-f2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyllhydrazide Following the procedure of Example 102(d), except substituting ethyl 2-(2chlorophenoxymethyl)thiazole-4-carboxylate for (IS)-lI-benzyloxycarbonylamino- 15 1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared.

MS (ESI): 284.1 (MiH) 4 e) N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting chlorophenoxymethyl)thiazol-4-ylcarbonyllhydrazide for (2S,1'S)-2- (benzyloxycarbonyl)amino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanarnide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white 25 solid. MS (ESI): 532.1 6:g00.

Example 107 Preparation of N-F.\-(4-pvridinlmethoxvcarbonb-L-leucinvl-N'-f2-f4-( 12.3thiadiazol-4-v! )phenvl lthiazol-4-vlcarbonvi lhvdrazide a) 2,3-thiadiazol-4-vl)]thiazol4-ylcarbonyljhvdrazide Following the procedure of Example 102(d), except substituting ethyl 2-[4- -thiadiazol-4-yl)]thiazole-4-carboxylate for (1 1 -benzyloxycarbonyl amino- I -(4-carboethoxythi azol -2 3 -methyl butane, the title compound was prepared as a white solid. MS (ES 304.1 b) N-[N-(4-pyridinylmethoxvcarbonyl)-L-leucinyl]-N'-[2-[4-(1I,2,3-thiadiazol- 4-vl)phenyllthiazol-4-vlcarbonvllhvdrazide Following the procedure of Example 103(d), except substituting N-f 2-[4- (1 ,2,3-thiadiazol-4-yl)Jthiazol-4-vlcarbonyllhydrazide for (25,1 15 (benzyloxycarbonyl)amino-N-[ I '-(2-hydrazinocarbonylthiazol-4-yI)-3'methylburyl]-4-methylpentanamide, and N-(4-pyridinylrnethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white ~.:solid. MS (ESI): 552.1 Example 108 20 Preparation of N- [3-(4-chlorophenylsulfonylmethybthien-2-yllthiazol-4lcarbonvll-N'- [N-(4-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide a) N-f 2- (3-(4-chlorophenylsulfonylmethyl)thien-2-yllthiazol-4fees carbonyllhydrazide Following the procedure of Example 102(d), except substituting 2-[13-(4chiorophenylsul fonylmethyl)thien-2-yllthiazole-4-carboxylate for (15)-i 00 S benzyloxycarbonylamino- 1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 414.1 b 4-chioropheflysulfoflnlfeth%,l Ithien-2-ljthiazol-4-y-carbonv-i 1-N [-(-pyn'dinvimethoxvcarbonv )--leucinyijhydrazide Following the procedure of Example 103(d). except subsutuung 3-A4chlorophenylsulfonylmethyl)thiefl2-y1th1zl--aC nyl]hydraide for (2S.1 S)-2- (benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3'methylburyll-4-methylpentanarnide, and N-(4-pyridiylmehoxycarbonyl)-L-leucine for N-beazyloxycarbonyl-L-leucine, the title compound was prepared as a white.

MS (ESI): 664.0 Example 109 Preparation of 1 -benzvloxvcarbonvlamino)-3-methlbutyllthiazol- 4-vlcarbonvll-N'-[2 '-(4-henlphenylacetvl)-4-methnv1Pltafllhydrazide a) 4-methyl-2-(4-phenylphenyl)pent- 4 -enoic acid To a stirring solution of diisopropylamine (0.537 g, 5.31 nmol) in TIF (5.2 rnL) at 0 "C was added n-butyllithium (2.1 mL. 5.22 mmol, 2.5M in hexane) QV dropwise. After stirring for 15 min at 0 C, 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 *C and cooling to -78 3-bromo-2rethylpropene (0.485 g, 3.54 mxnol) was added to the mixture in one portion. After stirring at -78 0 C for lh, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3 X 100 .*00 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, MS(ESI): 265.3 b) 4-methyI-2-(4-phenylphenyl)pentanoic acid To a stirring solution of the compound of Example 109(a) (0.449 g. 1.69 nmol) 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) (1I -benzvloxvcarbonviamnino)-3-rnethy Ibum Iv thi azo 1-4- %-Ic arbonvl]-N'- [2'-(4-pbenvl pheny Iacevi)-4- methl pe ntanoy hydraz ie Following the procedure of Example 101 except substituting IS)no-I -(4-hydrazinocarbonyI thiazol-2-yl)-3 -methyl butane for (2S, 1 S)-2-(benzvloxycarbonyl)axnino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-vI methylburyl]-4-methylpentanainide, and 4-methyl-2-(4-phenylphenyl )pentanoic acid for N-benzyloxvcarbonyl-L-leucine, the tite compound was prepared as a white solid. MS (ESI): 613.2 Example I110 see Preparation of N-r2-(3-benzyloxvphenvl)thiazol-4-vlcarbonvll-N'-FN-(2pvridinylmethoxycarbonyl)-L-eucinllhydrazide :0a) methyl 3-benzyloxybenzoate To a suspension of Na- (0.395 g, 9.87 mmol, 60% in mineral oil) in DMEF m.L) was added methyl 3-hydroxybenzoate (1.0 g, 6.58 mnxol). After stirring for 15 min at room temperature, benzyl bromide (1.1I g, 6.58 inmol) was added.

After stirring at room temperature for 3h, the solution was partitioned between ethyl Soso acetate and water. The organic layer was washed with water (2 X 75 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). IHNLR (400 MI-z, CDCl 3 8 7.67 (mn, 2H), 7.48-7.34 (in. 6H), 7.19 (in, IH), 5.12 2H), 3.95 3H).

3-benzyloxybenzamide To a suspension of ammonium hydrochloride (1 .070g, 0.02 mnmol) in 20 m-l of toluene at 50C, was slowloy added a 2M solution (10 m.L) of trimethylalurninium 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 1 10(a) (605 mng, 2.49 mnmol) in toluene was added a 0.67 M solution of MeAlCINH-, (I11 mL. 7.49 ramol) in toluene. The reaction rruxture was allowed to stir overniaht 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 Mg-SO 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-ylcarbonyllhydrazide Following the procedure of Example 102(b)- 102(d), except substituting 3benzyloxybenzarnide for N-benzyloxvcarbonyl-L-leucinarniide in step the title compound was prepared as a white solid. MS (ESI): 326.2 d) N-(2-pyridinylmerthoxycarbonyl)-L-Ieucine Followong the procedure of Example 106(a)- 106(c), except substituting 2pyi-idvlcarbinol for 4-pyridylcarbinol in step the title compound was prepared.

15 'H NMR (400 MI-z, CD 3 OD) 5 8.50 I 7.86 (dt, IlH), 7.51 I1H), 7.3 6 (dd, lH), 5.20 IH), 5.16 IH), 4.19 1H), 1.78-1.72 (in, 1H), 1.62 2H), 0.97 3H), 0.94 3H-).

N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2- .000. 20 pyridinyLmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 103(d), except substituting N-I[2-(3benzvloxyphenyl)thiazol-4-ylcarbonyllhydrazide for (2S,1 S)-2- (benzyloxycarbonyl)amino-N-[ l'-(2-hydrazinocarbonyltbiazol-4-yl)-3'methylbutyl]-4-miethylpentanam-ide, and N-(2-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title coanpound was prepared as -white solid (106 mg, 0. 184 minol). MS (ESI): 574.2 Example I II Preparation of (1 RS)-N-[2-f I-(-4-phenviphenvi )-3-methvlbutvf'lthiazol-4vlIcarbonvll-N'-rN-(4-pvridinvmethoxvcarbonv)-L-eucinv[Ihvdrazide a) N-[2-flI-(4-phenvlphenyl)-3-methylburyl]thiazol-4-ylcarbonvljhvdrazide Following the procedure of Example 102(a)- 102(d), except substituting 4methyl-2-(4-phenylphenyl)pentanoic acid for N-benlzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid. MS (ESI): 366.3 b) (1 1-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonvllj-N'-[N- 0:08(4-pyridinylmnethoxycar-bonvl )-L-leucinyl Ihydrazide Following the procedure of Example 103(d), except substituting N-[2 -[(1I-i4phenylphenyl)-3-methylbutyllthiazol-4-ylcarbonvl]hvdrazide for (2S, 1'S (benzyloxycarbonyl)amino-N-[ 1 '-(2-hydrazinocarbonylthiazol-4-yI)-3 15 methylburyl]-4-methylpentanamide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-Ieucine, the title compound was prepared as a white 0 solid. MS (ESI): 614.3 Example 112 Preparation of N-rF2-(2-benzyloxyphenyl)thiazol-4-vlcarbonyll-N'-[N-(4pvridinvlmethoxycarbonyl)-L-leucinyllhydrazide a) ethyl 2-amiinothiazole-4-carboxylate hydrobromnide To a stirring suspension of thiourea (6.0 g, 78.8 mniol) in ethanol (80 m.L) added ethyl bromopyruvate (15.4 g, 78.8 mnmol). The resulting solution was 25 heated at 45 *C 23 h. The solution was cooled at 0 *C for 24 h, and the cr,. 'als were collected by filtration and washed with cold ethanol to provide the title compound (15.8 g, IH NMR (400 MI-z, CD 3 OD) 8 7.70 IH), 4.41 (q, 2H), 1.38 3H).

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

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

The residue was combined with combined with the solid collected in the first filtration, heated at reflux in ethanol (500 mL) for 5 min, then filtered. To the filtrate was added 1.5 mL of 48% aqueous HBr and the solution was heated at reflux for 16 h, then concentrated. The residue was partitioned between saturated aqueous NaHCO 3 and ethyl acetate. The organic layer was washed with saturated brine.

dried (MgSO4), decolorized with charcoal, filtered and concentrated to provide the 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

CO

3 (12.0 g, 86.7 o** 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 (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol). 1HNMR (400 MHz, CDC1 3 8 7.62 1H), 7.54 2H), 7.45 (m, 25 2H), 7.37 1H), 7.28 1H), 6.98 1H), 6.91 1H), 5.17 2H).

d) 2-benzyloxyphenylboronic acid To a stirring solution of the compound of Example 112(c) (15.2 g, 57.8 mmol) in THF (100 mL) at -78 0 C was added dropwise n-BuLi (23.1 mL, 2.5M in hexane, 57.8 mmol). The mixture stirred at -78°C for 25 min when added via cannulation to a stirring solution of triisopropylborate (54.4 g, 289 mmol) in THF 145 (100 raLi at -78'C. After xar=2n to room temperature and stirring for S3h. the mixture was poured into 3N HCL 100 rnL) and extracted with ethyl acetate (3 X 2-00rnL). The organic layers were combined, washed successively With water and brine, dried (M-RSO 4 filt-ered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the tide compound as a pale yellow solid (6.9 g, 30.3 mmnol). I HNMR (400 MI-Lz, CDCl 3 6 7.90 IH), 7.42 (in, 6H), 7.07 IH), 7.02 IH), 6.05 2H). 5.16 2H).

e) ethyl 2 (2 -benzy loxypheny1) thiazole -4-carboxy late To a stirring solution of the compound of Example 112(b) (4.0 g, 16.9 mmol), the compound of Example 72(d) (4.29g ,18.8 mmol), &Doe tetrakis(triphenylphosphine )palladium(0) (0.65 g, 0.57 inmol) in dimethoxvethane rnL) was added cesium fluoride (8.58 g, 56.5 mmol) and the mixture was heated at 85 'C for 16 h. Tertrakcis(triphenylphosphifle)palladium(O) (0.65 g, 057 mmol) 15 was added and heating at 85 0 C was continued for 5 h. The mixture was diluted C: with water (60 mnL) and extracted with ethyl acetate (2 X 120 The combined extracts were washed with saturated aqueous NaHCO 3 and saturated brine, dried (MgSO 4 filtered and concentrated. The residue was purified by flash chromatography on 180 g of 230-400 mesh silica gel, eluting with 15% ethyl acetate 0:0 20 in hexanes. to provide the title compound as a white solid (3.22 g, MS (ESI): 340.3 f) 2-(2-benzyloxyphenyl)thiazol-4-ylcar~oflhydrazide .Do:*Following the procedure of Example 102(d), except substituting ethyl 2-(2benzyloxyphenyl)thiazole4-c arboxyl ate for (I1S)- I -benzyloxycai -oonylamino- 1 carboethoxythiazol-2-yl)-3-methylbutale, the title compound was prepared as a white solid. MS (ESI): 326.2 g N-[2.(2-benzvloxypflenl hthiazol -4-ylc arbon ylL]N4-Ni 4 pvfldinylme thoxycarboflyl)-LI e ucil I hvdazide Following the procedure of Example 103(d), except substituting 24benzyloxypheflyl)thizole-4-ylcabonvlhY&raide for (2S,1IS)-2- (benzyloxycarboflvl)alfllfo-N-[l 2-hydra.zifocarbonylthiaol4vl mehluy]4mtypnaarie and N-(4-pyridinylmethoxycarbolY).Lleucine for N-benzyloxycarbofyl-Lleucine, the title compound was prepared as a white solid. MS (ESI): 574.3 Example 113 6eSPeparation of N- [2-rNmty--4peypev~ni :)tha lycabn-N' see* -2yridinylmethoxycarboflyl)Leucinllhydizide a) N-(4-phenylphelyl)-2-met1ylpropionamide :To a stirring solution of 4-amiunobiphelyl (9.53 g, 56.3 mmol) and 15 triethylamifle (5.70 g, 56.3 mmol. 7.85 mL) in methylene chloride (60 niL), cooled to 0 was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0 0 C for 1 h, the mixture was diluted with methylene chloride (120 m.L) 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, IHNMR (400 MU-z, CDC1 3 /CD3OD) 8 7.58 2H), 7.50 (mn, 4H), 7.40-7.25 (in, 3H), 2.55-2.49 (mn, IH), 1.18 6H).

N-4-peypey)N(-ehl-propyl)amnlfe To a stirring solution of lithium aluminum hydride (58.6 inmol) ia TI-F (58.6 imol), cooled to 0 was added slowly over 10 min a solution of the compound of Example 73(a) (9.35 g, 39.0 inmol) in THF (170 mL). After the addition was complete, the ice bath was removed and the solution was heated at *C for 30 min. The mixture was cooled to 0 *C and water (2.22 mL) was slowly added, followed by 15% aqueous NaOH (2.22 niL) and water (6.67 mL). The precipitate was removed by filtration and washed with ether 4 times. The filtrate was evaporated to drylness to proveide the bie compound a.3 a. pae yeijow sculd (8.34 g, MS 226.2 C) N-(4-phenylphenyl)-N-(2)-methyl-lI -propyl)thiourea To a stirring solution of thiophosgene (98.9 mg, 2.6 mmol, 198 uL) in methylene chloride (6.5 mL), cooled to 0 was added dropwise a solution of the compound of Example 73(b) (540.7 mg, 2.0 mnmol) in met~hylene chloride (1 mL).

After stirring for 2 h. anmmonia- satru ated 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 HCl. 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 gof 230-400 mesh silica gel, eluting with 1:3 ethyl acetate/hexanes, to provide the :title compound as a pale yellow solid (470 mg, MIS (ESI): 285.3 d) ethyl 2- [N-(4-phenylphenyl)-N-(2-methyl- 1 -propyl)axnino]thiazole-4a carboxylate A solution of the compound of Example 11 3(c) (184.6 mg, 0.65 mnmol) and ethyl bromopyruvate (126.6 mg, 0.65 mmol, 81.5 uL) in ethanol (2.5 m1L) was heated at reflux fo 5 min. then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaiHCO 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 compnund as a pale yellow oil (230 mg, MS (ESI): 381.4 e) [N-(4-phenylphenyl)-N-(2-methyl- I -propyl)amino]thiazolylcarbonyljhydrazide Following the procedure of Example 102(d), except substituting ethyl 2-[N- (4-phenylphenyl)-N-(2-methyl- I -propyl)arninolthiazole-4-carboxylate for (I I 148 benizvloxvcarbonvlarnuno- 1-i4-carboeLhoxv .tbuazol->y' l -3 -methylbutarie, (he tide compound was prepared as a white solid. MS (ESI): 367.3 f) N-[2-[.Nmethy1-N-(4-phenylphenyl)anlthiazol4-YlcarboflvlJ-N'- N-(4pyridinylmethoxvcarbonyl)-L-leucinyljhydrazide Following the procedure of Example 103(d), except substituting phenylphenyl)-N-(2-rnethyl- 1-propyl)aninolthiazol-4-ylcarbofljhydrazide for (2S, 1'S)-2-(benzyloxycarboflyl)afllfo-N- [1'-(2-hydrazinocarbonylthiazol-4-yl)-3' methylburyll-4-metbylpentanalflide. and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucifle, the title compound was prepared as a white solid. MS (ESI): 615.3 Exml01 Prprto of..*ezlxcr~ny--ecnl-'f-4-hnlezltizl b reaain N(N-benzylox carbnvl-L-leucinyl')-N'-2-(4-phylzlbthaflZ-4th~- 15 4-vicaronvl Tyddrazid Following the procedure of Example 102()30(d), except substituting 4phenylaetic acid fzor -benzxcarbony l-L-lucine in S1ste) ()-tetil mehluy]4mtypnaaie the itl compound was prepared as a white sld S(S) 1. MH 4 i 2 g .35mo) I EI) 5. MH+ 149 ExampLe 115 Preparation of N-f 2 i(4-12henylphenyibenzvl)thiazol-4-vlcarbonviL N'-N-4pvridinylmerhoxycarbonvl )-L-leucinvl hvdrazide Following the procedure of Example 103(d). except substituting phenvibezvl)thiazol-4ylcarbnyjhydrazide for (2S, I'S)-2- (benzyloxvcarbonyl)arinoN- I '-(2-hydrazinocarbonylthiazol-4yl).3methylbutyl]-4-methylpentanawide, and N-( 4 -pyridinylmethoxycarbonyl)-L-eucine for N -benzyloxycarbonyi-L-Ieucine, the title compound was prepared as a yellow solid (30 mg, 0.053 inmol). MS (ESI): 558.2 Example 116 UPrep~aration of N-(N-benzvloxycarbonlLeucinv)N'42f[N 2-methvlropvi-Nphenylamrinolthiazo-4-vlcarbonyI lhvdrazide N- [N-phenyl-N-(2-methyl- I -propyl)arnino]thiazol-4- 15 ylcarbonyljhydrazide Following the procedure of Example 113(a)- I 13(e), except substituting aniline for 4-aminobiphenyl in step the title compound was prepared as an orang-pinc solid (276 mg, 0.950 mmol). MS 291.3 20 b) N-(N-benzyloxycarbonyl-LleucinyI)..N'[2..[N-(2methylpropyl)-N S....phenyl amino] thiazol.4..ylcarbonyI) hydrazide :*eeFollowing the procedure of Example 103(d), except substituting phenyl-N-(2-methyl-lI-propyl)aminolthiazol-4-ylcarbonyllhydrazde for 2- (benzyloxycarbonyl)amino-N..( I '-(2-hydrazinocarbonylthiazol4.yl)-3'.

methylbutyl]-4- methylpentanamide, the title compound was prepared as a white 0:00 @00*e* solid (92 mg, 0. 17 1 mmol). MS 560.3 Example IIV Preparation of N-f2-fN-(2-methylpropvfl-N-phenylarninolthiazol-4-vlcarbonvll-N.

fN-(4-pyridinlmethoxvcarbonvl)-L-leucinllhvdrazide 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 rnmol). MS (ESI): 539.4 Example 118 Preparation of N-f2-(2-benzvloxvhenvl)thiazol-4-vlcarbonyvll-N'- 3pvridinvlmethoxvcarbonl)-L-leucinllhdrazide Following the procedure of Example 112(a)-I 12(g), except substituting N- (3-pyridinylmethoxvcarbonyl)-L-leucine for N-(4-pyridinylmethoxvcarbonvl leucine in step the title compound was prepared as a white solid (93.8 mg, MS (ESI): 574.3 ese Example 119 Preparation of N-f2-(2-benzyloxyphenl)thiazol-4-ylcarbonyfl-N'-fN-(2pidi nvImethoxvcarbonvl)-L-leucinvllhvdrazide Following the procedure of Example 112(a)- I 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 0*OS Example 120 Preparation of N-(N-benzyloxycaronyl-N-methyl-L-leucinyl)-N'-[2-(2benzaloxvphenyl~thiazol-4-lcarbonvllhydrazide Following the procedure of Example 1 12(a)-112(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 1 1' Preparation of N-2f-2mtv~o~l--2evar~otizl4vcro-.I-' FN-(2-pvnidinvlmethoxycarbonvl-L-leucilIlhvdrazide Following the procedure of Example 1 13(a)- I 13(f), except substitutin2 aniline for 4-aninobipbenyl in step and N-(2-pyridinvlmethoxvcarbonyl)-Lleucine for N-(4-pyridinylmethoxycarboflyl)-L-eucifle in step the title compound was prepared as a white solid (40 mg). MS (ESI): 539.4 Example 122 Preparation of N-r2-rN-(2-methylpropyl).N-Phefylaminnoithiazol- 4 -Vlcabolfl-N'- *:so N-(3-p2vridinlmethoxcarbofl)-L-leucill hvdrazide so*: Following the procedure of Example I113(a)-Il 13(f), except substituting aniline for 4-aminobiphenyl in step and N-(3-pyridinylmethoxvcarbonyl)-Lleucine for N-(4-pyridinylmethoxycarboflyl)-L-leucifle in step the title 15 compound was prepared as a white solid (42 mg). MS (ESI): 539.4 Example 123 Preparation of N- r2-(2-methoxyphenyl)thiazol-4-lcaboflyll pyridinylmethoxycarbonvl)-L-leucinyllhydrazide a) 2-timuerhylstannylanisole To a stirring solution of n-BuLi (2.6 mnL, 2.5M in hexane, 6.42 mnmol) in diethyl ether (2.5 ml) at -78C was added 2-brornoanisole (1.0 g, 5.35 inmol) in diethyl ether (2 mnL) dropwise. After stirring for 1h at -78C, trimethyltin chloride (6.4 mnL, 1 OM in THF, 6.42 minol) was added dropwise. The mixture was allowed to sti an additional 2h while slowly warming to room temperature. The r-ixture e~eee:was then washed with saturated aqueous NaHCO3. The aqueous layer was extracted with diethyl ether (1 X 5OmL) and the organic layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil 11 g, 1 HNMR (400M1{zCDCI3) 6 7.47 I 7.40 7.05 (t.

IH), 6.90 IH), 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, CDCI 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).

iC) 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-(2- 0 benzyloxyphenyl)thiazole-4-carboxylate in step the title compound was prepared as a white solid. MS (ESI): 498.3 (M+H) 20 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 25 and are incorrorated herein by reference as though fully set forth.

Example 124' Preparation of (2S. I S)-N4 I 4 -carboethoxvthiazol-2-vh)-3-methl-burvl.-..meh\,i- 2-(2-Dhenvlbenzvloxvcarbonvl )aminopentanan-ide a) (2S, I 'S)-2-(tert-butoxycarbonvl)amiino-N-r 1'-(4-carboethoxythiazol-2-vly3-' methyl burvi I-4-rnethylpentanamide The compound of Example 8(c)(1.2 g, 3.5 mxnol) was stirred at room temperature in neat TFA (2.96 g, 26.0 mmnol) for 15 min. The solution was the concentrated in vacuo and redissolved in DMF (25 mL). To the stirring solution was added triethylainine (0.779 g, 7.7 mmol), BOC-Leu-OH (0.972 g, 3.9 mamofl, 4:60 1-hvdroxybenzot-iazole (0.095 g, 0.7 mmol), and I-( 3 -dirnethylaminopropyl)-3I- 04b *006ethvlcarbodiimide hydrochloride (0.750 g. 3.9 mmol). After stirring at room temperature for 16 hours, the solution was diluted with ethyl actate and washed successively with water (2 X 100 mnL), NaHCO 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (1.15 g, MS(ESI): 456.2 b) (2S, 1 1 4 -carboethoxythiazol-2-yl)-3-methylbutyl]-4-methyl.2(2.

ag& 20 phenylbenzyloxycarbonyl)aminopentanarniide To a stirring solution of phosgene (1.5 mL. 2.9 mmol. 1.93M in toluene) at a 0 0 OC was added 2-biphenylmethanol (0.486 g, 2.6.4 mniol) and diisopropylethylamine (0.375 g, 2.9 minol). The solution was allowed to stir at 0 0

T

06:6 for 30 min. In a separate reaction vessel, after stirring at room temperature for in, the compound of Example 124(a) 150 g, 0.330 nimol) dissolved in TFA m.L) was concentrated and redissolved in DMIF (3 mL). This solution was addaed to the 2-biphenylmethanol solution followed by diisopropylethylamine (0.2 13 g, 1.65 minol). After stirring at room temperature for lh, the solution was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column 154 chromatography (silica gel. ethyl acetate/-hexane) to vield the title compound is a whIite solid 138 g, MvS(ESI): 566.3 (MIv+H)I.

Example 125 Preparation of (2S. 1 ezlxcronllmn-- c arboe thoxvthi azol y h- 3'-methvlIbutvl 1-4- met hylpen tanamide Following the procedure of Example 124(b), except substituting 2benzylbenzyl alcohol for 2-biphenylmethalol, the title compound was prepared as a white solid 123 g, MS(ESI): 580.0 Example 126 Preparation of (2S. 1 l -(4carboethoxvthiazol-2-Vl)-3'-methylbutlbll 4 methyl-2-[(2-naphthvlmethoxcarbofll'larninopentanamide 15 Following the procedure of Example 124(b), except substituting 2- :naphthalenemethanol for 2-biphenylmethanol, the title compound was prepared as a a white solid 132 g, MS(ESI): 540.1 #So 20 Preparation of (2S. l'(-ab>toyhao-2v)3-ehluyl4 methyl-2-[(3-2henoxybenzyloxycarbonlV'u ptnaa~fOl inde Following the procedure of Example 124(b), except substituting 3phenoxybenzyl alcohol for biphenylmethanol, the title compound was prepared as a white solid 107 g, MS(ESI): 581.9 Example 128 Preparation of (2S.1'S)-2-(benzvloxvcarbonl)arino-N-f l'-12-(2benzvlguanidinvylthiazol-4-vl -3'-methvlbutvil-4-methlpentanamde a) S-methvl dithiobiuret hvdroiodide salt To a stirring solution of dithiobiuret (5.0 g, 37 mmol) in THF (75 mL) was added iodomethane (13.1 g, 92.5 mmol, 5.76 mi). After stirring at room 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 tolueneTHF, then dried in vacuo to give the title compound as a white solid (8.7 g, MS(ESI): 149.9 900 *so: 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 S0 washed twice with cold iospropanol, then dried in vacuo to provide the title compound as a white solid (2.59 g, MS(ESI): 209.2 c) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-[2-(2-benzylguanidinyl)thiazol-4ylJ-3'-methylburyl]-4-methylpentanamide Following the procedure of Example except substituting 3benzylguanidinyl thiourea for ethyl thiooxamate, the title compound was prepared as a white solid (102 mg, MS(ESI): 565. 1 Exaarpe 129 Preparation of (1 S)-N-[4-flI -(N-benz'Ioxvcarbonviarmino)-3-methvlbutvlthiazolvlcarbon vll-N-methv-N'-(N-benzvioxycarbonv-L-leucinvl)hydrazide Following the procedure of Example 26(a)-26(d), except substituting methvl hydrazine for hydrazine in step the title compound was prepared as a white solid. MS(ESI): 624.1 Example 130 Preparation of (I S)-N-4-4 1 -(N-benzvloxvcarbonvlamino)-3-methvlbuvllthiazol-2vlcarbonvll-N'-(N-benzvloxvcarbonvl-L-leucinyl)-N-methlhydrazide a) N-(N-berzyloxycarbonyl-L-leucinyl)-N-methylhydrazide Following the procedure of Example 26(c), except substituting Nbenzyloxycarbonyl-L-leucine methyl ester for (IS)-I -benzyloxycarbonylamino-1i 15 (2-carboethoxythiazol4-y)-3-methylbutane and methyl hydrazine for hydrazine.

0: the title compound was prepared.

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

c) I-(N-benzyloxycarbonylamino)-3-methylbuyllthiazol-2-ylcarbonyl]- N'-(N-benzyloxycarbonyl-L-leucinyl)-N'-methylydrazide Following the procedure of Example 28(e), except substituting N-(Nbenzyloxycarbonyl-L-leucinyl)-N-methylhydrazide for (IS)-l- (benzvloxycarbonyl) amino- 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane and (IS)- 1 -benzvloxvcarbonylamino- 1-(2-carboxvthiazol-4-yv )-3-methvlbutane for Nbenzvloxvcarbonvl-L-leucine, the title compound was prepared as a whlite solid.

NIS (ESI': 624.2 .Example 131 Preparation of N-(N-benzvloxycarbonyl-L-leucinyb-N-(N-bezloxycarbolyl-Lleucinyl)-L-alanylhydrazide Following the procedure of Example 27(a)-27(c), except substituting Lalanline methyl ester for L-leucine methyl ester in step the title compound was prepared as a white solid (225 mg, MS(ESI): 598. 1 Example 132 Preparation of N-(N-benzvloxycarbonyI-L-euciny)-N'-(N-bezyoxVcarboflyl-Lleucinyl)glycinylhydrazide mthylFollowing the procedure of Example 27(a)-27(c), except substituting glycine mt* ester for L-leucine methyl ester in step the title compound was prepared 0: as a white solid (307 mg, MS(ESI): 584.1 Example 133 of (1 I (N-benzy Ioxycarbon lanino)- 3-me th lbutY I 1.3.4a) ethyl oxalarnidrazonate To 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 ml). The mixture was allowed to stir for 3 hours at room temperature, while venting through a scrubber of concentrated sodium hydroxide solution. The solution was allowed to stand for 16 hours and the ethanol was evaporated. The residue was boiled in dichiloromethane in petroleum ether, filtered, and recrystalized to give the desired compound as a tan solid. (0.264 g, b (1Si-l -benzvloxvcarbonyliarmno- l-(2-carboethox- I .3.4-rnazol-5-viimethylbutane N-benzvloxvcarbonvl-L-eucine (0.535 g, 2.0 mxnol) was stirred in THF at Ethyl chloroformate (0.23 mL, 2.4 mmol) and triethylarnine (0.25 g, 2.4 rnnol, 0.34 mL) were added. The compound of Example 10(a) (0.264 g, 2.0 nmol) 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 H NMR (400 MHz. CDCl3)67.20 5H) ,5.71 1H), 5.04(s, 2H) 0000 4.99 d IH) 4.36 q2H) ,1.8m 2H) 1.59 H) ,1.31 t, 3H) 0.83 dd .6H).

c) (1 1 -beazyloxycarbonylamino- 1 -(2-hydrazinocarbonyl- 1,3,4-triazol-5-y)-3methylbutane Following the procedure of Example 26(c)-26(d), except substituting benzyloxycarbonylamino- 1-(2-carboethoxy- 1,3,4-triazol-5-yl)-3-methylbutane for (IS)-l -benzyloxycarbonylamino- 1 -(2-carboethoxythiazol-4-yl)-3-methylbutane in step the title compound was prepared. MS(ESD: 594.5 Example 134 Preparation of S)-N-(N-acetyl-L-leucinvl)-N'-r2-f 1 -(N-benzyloxvcarbonlanino)- 3-methylburyllthiazol-vlcarbonllhydrazide Following the procedure of Example 28(a)-28(e), except substitu'-ng Nacetyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (95 mg, MS(ESI): 518.0 159 Example 135 Preparation of (I N-benzvloxvcarbonvl-L-aJanv)yNJ-2d 1 beflzyloxvcarbonylam nop-3-methylbutvllthiazol-.4..vlcarbonvl ihydrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxvcarbonyl-L.aJanne for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (129 mg, MS(ESI): 568.1 Example 136 Preparation of (1 S)-N-(N-acervl-L-alanyl)-N'-[2-r 1-(N-benzylo-xvycarbonyarnjno).3methyl bury] Ithiazol -4-y IcarbonylI yrzd Following the procedure of Example 28(a)-28(e), except substituting Nacetyl-L-aianine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (74 mg, MS(ESD: 498.1 Example 137 Pmrparation of (I S)-N-(N-acetyl)-N'-r2-r I-(N-benzvloxycarbo-nylaminop)-3mehluylhao--ycroylyrzd Following the procedure of Example 28(a)-28(e), except substituting acetic 20 acid for N-benzyloxycarbonyl..Lleucine in step the title compound was prepared as a white solid (87 mg, MS(ESI): 405.1 Example 138 Preparation of (1 r I -(N-benzyioxycarbonylamino)-3-methylbutyIlth iazol-4ylcaronylb-N'-rN-(4-2fidinylmethoxycarnvl)L..leuciny1hvy-dazide 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 white solid (121 mg, MS(ESI): 611.0 Example 139 Preparation of (1 5)-N-f 2-ri -(N-benzvloxycarbonylaxnino)-3-methylbutyllthiazol-4- %,Icarbonyll- N'-fN-(2-pyridinvlmethoxvcarbonyl)-L-leucinyllhvdrazide Following the procedure of Example 28(a)-28(e). except substituting N-(2pyridinylmethoxycarbonyl)-L-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 Prep~aration of (1 I -(N-benzyloxycarbonylarino)-3-methvlbuvllthiazol-4vlcarbonyll- N'-(N-benzyloxvcarbonyl-N-methyl-L-leucinyl)hydrazide Following the procedure of Example 28(a)-28(e), except substituting N- ****benzyloxycarbonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step 15 the title compound was prepared as a white solid (78 mg, MS (ESI): 624.3 Preparation of (I S)-N-f 2-flI -(N-benzyloxycarbonyl-N- methyl amino)-3 methylbutylthiazol-4vlcarbonll-N'-rN-(4-yridilmethoxycarbonl)-Lleucinyllhydr-azide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L- leucine for N-trn-butoxycarbonyl-L-leucine in step and N-(2-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-Lleucine in step thf- title compound was prepared as a white solid (120 mg, 72%).

S 25 MS (ESID: 625.3 (IMs-1D+.

Exme142 Preparation of (1 S)-N-(N-benzyioxvcarbonvl-L-leucinvl)-N'-r2-r 1-(NbenzyloxvcarbonvyI- N-methy Iarru no)- 3 -methy Ibutyl Ithi azol -4--vicarbonv ihydrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonvl-L-leucine in step the title compound was prepared as a white solid (95 mg, MS (ESI): 624.3 Example 143 Preparation of I-(N-benzyloxvcarbonyl-N-methvlamino)-3- 00 0*0: methylbuiyllthiazol-4-yllcarbonyl- N'-(N-benzvloxycarbonyl-N-methvl-L- 0.0.

leucinyl)hydrazide Following the procedure of Example 28(a)-28(e), except substituting N- "6 15 benzyloxycarbonyl-N-rnethyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step so* 1 and N-benzyloxycarbonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-L- 0: leucine 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-r2-f 1 -(N-methylarnino)-3-methylburvllthiazol-4-ylcarbonyll- N'-[N-(4-p2yrdinvlmethoxycarbonyl)-L-leucinyllhydrazide a) (1 1-(N-tert-butoxycarbonyl-N-methylamino)-3-methylbutyl]thiazol-4- *ylcarbonyl pyridinylmethoxyc ar bony)-L-euc inyl ]hydrazide Following the procedure of Example 28(a)-28(e), except substituting Nterr-butoxycarbonyl-N-methyl-L-leucine for N- tert-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 bi (1S)-N-[21 -(N-meth\laITInfl- -mehvbuyl]tha~-larbfl]lbN4N~ -l pyndinymehoxvcarbonl)-L-leucinyl]hydrazide To a solution of the compound of Example 21(a) in methvlene chloride ml) was added trifluoroacetic acid (3 mL). After stirring one hour at room remperarure the solution was concentrated and the residue was redissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to afford the title compound as a white solid (259 mg, 68% for two steps). MS (ESI): 491.4 Example 145 Preparation of (1 S)-N-r2-f 1 -(Nbenzy loxcarbonvlarin)- 3-methvlbuyl Ithiazol-4vlcarbonvll-N'- N-(terr-butoxcarbonvyl--leucillh drazide Following the procedure of Example 28(a)-28(e), except substituting N-tenbutoxycarbonyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (293 mg, MS (ESI): 576.4 Example 146 Preparation of (1 I -N-benzyloxycarbonylarif&)-3-methlbutyllthiazol- 4 ylcarbonll-N' -butoxc arbon Ledr Following the procedure of Example 28(a)-28(e), except substituting N-ten- 0eoO butoxycarbonyl-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 1- Example 147 Preparation of (I S)-N-[2-fl 1-(N -benzy loxycarbonyiaflO methy Ibuty I Ihiazol -4- \'Icarbonyll-N'-(N-methyI-L-leucilvl)hydrazide Following the procedure of Example 144(b), except substituting (IS)-N-f 2- (1 -(N-benzyloxycarboflylarnflo)- 3-methylbutyl Jthazol-4-vlcarbonyl]-N'- [N-Uterrbutoxycarbonyl)-N-methyl-L-leucillhydrazide for (iS -(N-tertbutoxyc arbonyl methylamino)- 3-methy lbutyl]tiazol- 4 -y Icarboly I N- 4 pyridinylmethoxycarbonyl)-L-leucillhydrazide, the title compound was prepared as a white solid (40 mg, MS (ESI): 490.3 Example 148 ~Preparation of (I S)-N-f 24 1 -(N-benzyloxycarbonylamino)-3-methlburvllthia-zol- 4 ylcarbonyll-N'-(L-leucinyl)hydrazide 00: Following the procedure of Example 144(b), except substituting 15 (1 -(-ezlxcabnlaio-3-etybtl hao--labnl]-' N(er 0@ so0:butoxycarbonyl)-L-leucinyl]hydrazide for (1 1-(N-tert-butoxycarbonyl-Nmethylamino)-3-methylbutyl~thiazol-4-ylcarbonl]lN4-N-(4pyridinylmethoxycarbonl)-L-leuciflhydrazide, the tidle compound was prepared as a white solid (39 mag, 100%). MS (ESI): 476.4 Example 149 Preparation of (1 S)-N-f2-f I -(N-benzyioxycarbonylamino)-3-methvlbutyllthiazol- 4 vlcarbonyll-N'-[N-(4-irmidazolylacetyl)-L-leuciyllhydrazide :Folilowing the procedure of Example 28(e), except substituting 0:00: 25 (Nbnyoyabnlmn)3m tyluy~hao4ycroy]N-L leucinyl)hydrazide for (1I 1 -(benzyloxycarbonyl)aniflo- 1 -(4-carboethoxythiazol- 2-yl)-3-methylbutane and 4- imidazole acetic acid for N-benzyloxycarbolyl-Lleucine, the title compound was prepared as a white solid (50 mg, MS (ESI): 584.4 Example 150 Preparation of (1 S)-N-12-t 1 L(N-benzvoxycarbonflV-N-methlarrhlo)- 3 methvlbutylhthiazol-4-vlcarbolvl-1N'-FN-3-pvridilm~fethoxvcarbonyl)N-meth~ll- L-leucinvl lhydrazide a) N-methyl-L-leucine methyl ester N-methyl-L-Ieucine (1.3 g, 8.95 rnxol) was dissolved in 4M HCl, 1,4dioxane (10 mL) and methanol (10 mnL). The solution was stirred overnight at room temperature, then concentrated to afford the title compound as a white solid (100%).

MS (ESI): 160.0 b) N-metbyl-N-(3-pyridinylinethoxycarbonyl)-L-leucine methyl ester To a stirring solution of phosgene in toluene (5.63 mL, 6.025 mmol) in :0000methylene chloride (10 mL), cooled to 0"C, was added dropwise a solution of Nmethyl-L-Ieucine methyl ester (673 mg, 4.63 tumol) and pyridine 10 g, 0.97 rnL, 15 13.89 mmol) in methylene chloride (4 mL). The solution was stirred at 0"C for 2 o hours. A solution of 3-pyridyl carbinol (0.56 g, 5.09 mmol, 0.49 mL) was then added and the reaction mixture was stirred at room temperatur for 5 hours. The solution was concentrated, redissolved in ethyl acetate, washed with water, dried (MgSO4), 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-pyridinylmethoxycarboflyl)-L-eucine :0 Following the pro~cedure of Example 130(b), except substituting N-methyl- N-(3-pyridinyhnethoxycarbonyl)-L-lCucine methyl ester (I S)-l- 0benzyloxycarbonylamino-l 1 znoabnlhazl4y)3mehluae the title compound was prepared as an orange solid (84 mg, 100%). MS (ESI): 281.3 d(I S 1 -4N-benzvloxvcarbonvl-N-rme chyiamino -S-methyibutvljchi azoly Ic arbonyl (3 pridinvl methoxycarbon vl0-N- methyl L-leuc in vlJhydrazide Following the procedure of Example 28(a)-28(e). except substituting Nbenzvloxvcarbonyl-N-me.hvl-L-leucine for N-tert-butoxvcarbonyl-L-leucine in step and N-merthyl- N-(3-pyridinvlmethoxycarbonyl)-L-leucine for Nbenzyloxycarbonvi-L-leucine in step the title compound was prepared as a whlite solid (55 mg, MS (ESI): 639.4 Example 151 Preparation of (I I -(N-benzyloxycarbony I-N-me thy larino)- 3- 0:0* methylbutvllthiazol-4-ylcarbonyll-N'-rN-(3-pvyridinylmethoxvcarbonyl)-Lleucinylihydrazide 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-(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 20 Preparation of (I I benzy loxycarbony Iamnino)- 3 -methylbury I thiazo 1-4vicarbonyll- N'-rN-(3-pvridinylmethoxycarbonvl)-L-leucinvllhydrazide Following the procedure of Example 28(a)-28(e), except substituting N-(3pyridinylmethoxvcarbonyl)-L-Ieucine for N-benzvloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (63 mg, MS (ESI): 611.5 Examle 153 Preparation of 'S)-N-(N-benzvloxvcarbonvl-L-leucinvl-N'-( benzvloxvcarbonl)-N-r 2 (Nmethlamino)-3-methvlbutvlthiazol-4vlcarbonvyll-N'-methylhvydrazide Following the procedure of Example 28(a)-28(e) except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-rert-butoxycarbonyl-L-leucine in step and methyl hydrazine for hydrazine in step the title compound was prepared as a white solid (80 mg, MS (ESI): 660.4 Example 154 *Preparation of (IS)-N-f2-fl-lN-benaioxvcarbonvlamino)-3-methylbutvlthiazol- *vlcarbonvll- N'-fN-(2-opvridinvlmnethoxvycarbonyvl)-N-methyl-L-leucinvllhydrazide a) N-methyl-N-(2-pyridinylmethoxycarbonyl)-L-leucine methyl ester N-(2-pyridinylmethoxycarbonyl)-L-leucine methyl ester (490 mg, 1.75 mmol) was dissolved in THF (7.0 mL) and methyl iodide (0.435 mL, 6.99 mmol) was added. The reaction 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, 20 and the oily residue partitioned between ether and water. The organic layer was washed with saturated aqueous NaHC03 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 (MgSO4), filtered and concentrated. The crude product was purified by column 25 chromatography on silca gel (ethyl acetate/ hexane, 3:1) to give a yellow oil (235 mg, MS (ESI): 295.4 bi N-methy 1-N-t2l-pv-ridinvlme rhoxvcarbonvfl--L-ieucine Following the procedure of Example 130(b), except substitutin2 N-methvl- N-('2-p'ridi nvlmethoxvcarbonyl)-L-leucine methyl ester HIS)- I1benzvlIoxvcarbonylarnjno-lI-(2-hydrazinocarbonylthiazol-4-vl)- 3 )-methvlbutane, the tide compound was prepared as a white solid (223 mg, 100%). MS (ESI): 281.3 c) (1 I-(.N-benzyloxvcarbonylamrino)-3-methvlbutyllthiazol-4-v Icarbonvll- N'-[N-(2-pyri dinylmethoxvcarbonyl)-N-methyl-L-leucinyljhvdrazide Following the procedure of Example 28(a)-28(e), except substitutine Nbenzvloxvcarbonyl-N-methyl-L-leucine for N-tert-butoxvcarbonvl-L-leucine in step *060 and N-methyl-N-(2-pyridinylmethoxvcarbonyl )-L-leucine for N- 00:: benzvloxvcarbonyl-L-leucine in step the title compound was prepared as a white 0. 0 solid (50 mg, MS (ESD: 639.5 .00 0 Example 155 aPreparation of (I S)-N-f2-r I -(N-benzvloxvc arbonyl -N-methyl amino)- 3methvlbutvllthiazol.4lcarbonylN'rN(4pyridinvlmethoxvcaronvl).N-methvl Get L-leucinyl 1hydrazide a) L-leucine teri-butyl ester isocyanate L-leucine tert-butvl ester hydrochloride (10. 185 g, 45.5 mmol) was a...dissolved in methylene chloride (100 cooled to 0 C and pyridine (12.7 rnL, 182.0 mnmol) was added, then phosgene in benzene (47 mL, 59.1 mmol). The solution was stirred at 0 OC for 2 hours. The reaction mixture was washed two times with 300 mL of cold 0.5 M aqueous HCL. Each aqueous layer was exctracted with 100 mL methylene chloride. The combined organic phases were washed with a mixture of saturated aqueous NaCi solution and crushed ice, dried over MgS 04, filtered and concentrated to afford the isocyanate as a yellow liquid (5.37 b) iN-(4-pyndinvmethoxvcarbonyl)-L-leucife rerr-butyl ester The compound of Example 155(a) (3.05 g, 14.32 mmol) and 4-pridvl carbinol (1.56 g, 14.32 mmol) were dissolved in toluene (80 mL) and heated at reflux overnight. The solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/ hexane, 3: 1) to afford the title compound as a colorless oil (2.945 g, MS (ESI): 323.4 c) N-methyl-N(4-pyridinylmethoxycarbonyl)--leucine tert-butyl ester Following the procedure of Example 154(a), except substituting N-(4pyridinylmethoxycarbonyl)-L-leucine rerr-butyl ester for N-(2pvridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a yellow liquid (2.038 g, 68% yield). MS (ESI): 337.5 d) N-methyl-N-(4-pyridnylmehoxycarbony)- Following the procedure of Example 144(b), except substituting N-methyl- N-(4-pyridinylmethoxycarbonyl)-L-leucine terr-butyl ester for (1 Il-(N-tertbutoxycarbonyl-N-methylamino)-3-methylbutylithiazOl 4 ylcarboflYlI-N'-[N.( 4 pyridinylmethoxycarbonyl)-L-leucinylhydrazide, the title compound was prepared as a white solid (343 mg, 72% yield). MS (ESI): 281.3 e) (1S)-N-12-[I -(N-benzyloxycarbonyl-N-methylamino)-3-methylbutyl]thiazol- 4 ylcarbonyl]-N'- [N-(4-pyridinylmethoxycarbonyl)-N-methyl--leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting N- 0:0.0: 25 benzyloxycarbonyl-N-methy l-L-leucine for N-rert-butoxycarbonyl-L-leucine in step and N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leuCine for Nbenzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (50 mg, MS 639.5 169 Example 1 56 Preparation of 2 .2'-F-N.N'-[bis-(N-acetvl-L-leuccinvl)llcarbohvdrazide Following the procedure of Example 29, except substituin2 -N-acervl-Lleucine for N-benzvloxvcarbonyl-L-leucine, the title compound was prepared as a pale yellow solid 153 g, MS(ESI): 401.3 Example 157 Preparation of 2-fN-(N-benzyloxycarbonvl-L-leucinvl)1-2'-rN-(4metvlpntanovl )Icarbohvdrazide a) N-benzvloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester (2.0 g, I11.0 mrnol) in 1,4dioxane (20 mnL) was added aqueous Na-)C0 3 solution (12.1 m.L, 2M in H-,)O off*followed by benzylchloroforrnate (1.96 g, 11.5 mmol). The mixture stirred at room S temperature for 4h then partitioned between ethyl acetate and water. The organic 15 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 HNNM (400M1Iz,

:CDCI

3 6 7.34 (mn, 5H), 5.27 (d;IlH), 5.12 2H), 4.41 2H), 3.75 3H), 1.65 (mn, 3H), 0.96 (in, 6H).

b) N-(N-beazyloxycarbonyl-L-leucinyl)hydrazide S...To a stirring solution of the compound of Examnple 157(a) 1g, 1 1.Onmol) in methanol (15 mnL) was added hydrazide hydrate (5.9 g, I L8 mmol, 5.7 The solution stirred at room temperature for 16 h then concentrated to yield the title compound as an off-white solid (3.1 g, 100%). MS(ESI): 280.2 c) 1 -benzyloxycarbonylanuno-3-methyl-l1-(1,3 .4-oxadiazol-2-on-5-yl)butane 0 To a stirring solution of the compound of Example 157(b) (3.0 g, 10.8 mmol) in toluene (50 m.L) was added phosgene (56 mL, 1.93M in toluene). The solution was heated at reflux for 4h, then concentrated to yield the title compound as a pale yellow foam (3.15 g. MS(ESI): 306.1

S

es..

*0*O

S

0 0@S@ 0O 5 0 0 0 0

S@

S

S@ 0 S *0 0 0@@S

S

0000 5 00*e

S

OOS@

S

0O@e d) N-4-methylpentanoyli)hvdrzide To a stin-ing solution of ethyl soarte(2.0 2. 13.8 mmol in ethanol m-Lj was added hydrazine monohydrate (6.9g. 138mnmol, 6.7 rnL). After stirringz at room temperature for 48 h, the solution was concentrated to yield the title compound as a white solid. (1.8 g, 100%). 1 1{NMR (400MIHz. CDCl3) 6 7.48 's br.

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

e 2-[N-(N-benzyloxycarbonylLeucinyl)] 2 4

N-(

4 methylpentanoyl)]carbohyd-razide The compounds of Example 157(c) 100 g, 0.325 mmol) and Example 34(d) (0.042 g, 0.325 mmol) were combined anid dissolved in ethanol (I mnL). The solution was heated at reflux for 24 hours, then concentrated to a solid yellow residue which was washed with cool methylene chloride to yield the title compound as a white solid (0.053 g, MS(ESD): 436.2 Preparatio~n of 2.'r.'ri-Nhnylxcroy--ehlL leucinyl)llcarbohydrazide Following the procedure of Example 29. except substituting

N-

20 benzyloxycarboflyl-N-metylL-leucine for substituting N-benzyloxycarboflyl-Lleucine. the title compound was prepared with purification by column chromatography (silica gel, methanoL/dichloromethane) as a white foam (0.236 'g.

MIS 613.2.

0 0000 U S @0 0 000005 0 Example 159 Preparation of 2-fN-(N-acetrvl-L-leucinvl-2'-fN-(N-benzvloxvcarbon-vl,-Lleucin VI) carbohydrazide a) 2- [N-(N-benzyloxycarbonvl-L-leucinyl )Jcarbohvdrazide To a stirring solution of the compound of Example 157(c) (3.15 g, 10.3 mmol) in methanol (2 mL) was added hydrazine hydrate (5.0 g, 100 mmol, 4.8 rnL).

After stirring at room temperature for 24 h, the solution was concentrated to yield the title compound as a pale yellow foam (3.47 1 g, 100%). MS(ESI): 338.2 b) 2-[,N-(N-acetyl-L-leuciny1)]-2'-(N'-(N-beazvloxycarbonyl-Lleucinyl)jcarbohydrazide To a stirring solution of the compound of Example 159(a) 100 g,0.297 rnmol), N-acetyl-L-leucine (0.054 g, 0.3 12 mmol) and 1-hydroxybenzotriazole 15 (0.008 g, 0.0594 mmol) in DMF (2mL) was added l-(3-dimethylamrinopropyl)-3- 0: ethylcarbodixide hydrochloride (0.060 g, 0.3 12 mmol). After stirring at room temperature for 16 h, the solution was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, znethanolldichloromethane) to yield the title compound as a white solid (0.052 g, 0* MS(ESI): 493.1 Example 16 Preparation of 2.2'-rN.N'-rbis- [N-(4-p-ndinvlmethoxvcarbonvL -L- 2* 5 leucinyl~fllcarbohydrazide Following the procedure of Example 29, except substituting N-(4pyridinylrnethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid (199 mg, MS(ESI): 587.1 Example 161 Preparation of 2.2'-fN.N'-fbis-fN-(2-Drdinvim thxvca leucinvl)I1 karbohydrazide Following the procedure of Example 29, except substituting N-(2pyridinylmethoxycarbonyl)-L-leucine for N-benzvloxycarbonyl-L-leucine the title compound was prepared as a white solid (263 mg, MS(ESI): 587.1 Example 162 Preparation of 2-rN-(N-benzyloxcarbonyl-L-leucinll)1-2'-rN'-rN-(2vridinlmethoxvcarbonvl )-L-leucinl)llcarbohvdrazide Following the procedure of Example 159(a)-159(b) except substituting N-(2- 0:60 pyridinylmethoxycarbonyl)-L-leucine lithium salt for N-aceyl-L-leucine in step the title compound was prepared as a white solid (0.040 g, MS(ESI): 586.3 iExample 163 Preparation of 2-fN-(N-benzyloxcarbonvl-L-leucinyl)-2-rN-[N-(4pvridinylmethoxcarbonvl)-L-leucinvl)llcarbohydrazide Following the procedure of Example 159(a)- 159(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 -[N-(N-benzvloxycarbonyl-L-leucinyl)-2'-(N'-fN-( 3 pyridinylmethoxycarbonyl)-L-leucinvl)llcarbohydrazide Following the procedure of Example 159(a)-i 59(b) except substituting N-(3pyridinylmethoxycarbonyl)-L-leucine lithium salt for N-acetyl-L-leucine in step the title compound was prepared as a white solid (0.084 g, MS(ESI): 586.3 Example 165 Preparation of 2.2'-fN.N -fbis-( N-benzvloxv-carbonvl-L-leucinvl )11-2-(Nmethyl )carbohydrazide a) N-methyl-N-(N-benzvloxvcarbonyl-L-leucinyl)hvdrazide To a stirring solution of N-benzyloxycarbonvl-L-leucine methyl ester (2.2 a, 8.15 rnmol) in methanol (4 rn1L) was added methylhydrazine (3.7ga, 80 rnmol).

After stirring at room temperature for 16 h, the solution was concentrated to vield the tidle compound as a yellow solid (2.14 g, 7.3 mmol). MS(ESI): 294. 1 b) 2-,2"-[,N.N'-[bis-(N-benlzyloxycarbonyl-L-leucinyl)]]-2-(N-methyl)carbohydrazide The compound of Example 157(c) (0.250 g, 0.8 19 mmol) 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, ego: counchoaoraphy (silica gel, methanol/dichioromethane) to yield the tidle coum choao 15 compound as a white solid (0.060 g, MS(ESI): 599.1 go. Example 166 Preparation of 2.2'-[N.N'-rbis-[N-(3-pvridinylmethoxycarbonl)L leucinviDlllcarbohydrazide Following the procedure of Example 29 except substituting N-(3pyridinylinethoxycarbonyl)-L-leucine for N-beazyloxycarbonyl-L-leucine, the tidle compound was prepared as a white solid (157 mg, MS(ESI): 587.0 *see 6:9 Example 167 Preparation of I -(N-benzvl)-2.2'-,N.N'-bis-(-benz'loxvcarbonvl-Lleucinvl)llcarbohydrazide a) N-benzvlidene-N'-(N-benzyloxvcarbonyl-L-leucinyl)hdrazide To a solution of the compound of Example 157(b) (1 g, 3.5 mmol) in ethanol (30 mL) was added benzaldehyde (0.33 niL, 3.2 mmol). 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 title compound as a solid (0.31 g, MS(ESI): 368.0 b) N-benzyl-N'-(N-benzyloxycarbonyl-L-leuciny)hydrazide To a cooled solution of compound of Example 167(a) (0.24 g, 0.65 mmol) in THF (5 rL) was added borane tetrahydrofuran complex (0.65 mL, 0.65 mmol. LM see* solution in THF). 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 (MgS04), filtered and concentrated in vacua to give the title compound as a white solid (0.25 g, MS(ESI): 370.0(M+H)+.

c) 1-benzyloxycarbonylamino-3-methyl- l-(3-benzyl-1 ,3,4-oxadiazol-2-on-5yl)butane Following the procedure of Example 157(c), except substituting N-benzyl- N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide for N-(N-benzyloxycarbonyl-L- 0600 leucinyl)hydrazide, the title compound was prepared as an oil (0.02 g, 83%).

MS(ESI): 396.0 see**: d) l-(N-benzyl)-2- [N-(N-benzyloxycarbonyl-L-leucinyl)Icarbohydrazide Following the procedure of Example 159(a), except substituting 1benzyloxycarbonylarnino-3-methyl- 1 -(3-benzyl- 1,3 ,4-oxadiazol-2-on-5-yl)butane for 1 -benzyloxycarbonylaminno-3-methyl- 1-(1 ,3,4-oxadiazol-2-on-5-yl)butane in step the title compound was prepared as a solid (0.013 g, MS(ESI): 428.0 (M+H) 4 d' 1 -(N-benzv )-2,2'-[N.,N'-(bis-(N-benzvloxcarboly-L-leucifYl)I]carbohvdrazide Following the procedure of Example 159(a)-159(b). except substituting 1benzyloxycarbonylamino-3-methyl- 1-(3-benzyl- I,3,4-oxadiazol-2-on-5-vl)butane for I -benzyloxycarbonylanino-3-methyl- 1-(1 ,3,4-oxadiazol-2-on-5-vl1)butane in step the title compound was prepared as white solid (13 mg, MS(ESI): 675.0 Example 168 Preparation of 2-fN-(N-benzvloxvcaronvl-L-leucinlyl-2'-FN-(Nbenzvloxvcarbonvl-N- methvl-L-leucinvl)lcarbohvdrazide Following the procedure of Example 159(a)-159(b) except subsbruting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-acetyl-L-leucine in step the title compound was prepared as a white solid 141 g, MS(ESI): 599.4 *0 S ::Example 169 Preparation of N-r2-(I -naphthvl)thiazol-4-ylcarbonll-N'-rN-(4pvridinvlmethoxycarbonvl)-L-leucinllhydrazide Following the procedure of Example 112(a)-I 12(g), except substituting 1naphthyl boronic acid for 2-benzyloxyphenyl boronic acid in step the title compound was prepared as a white solid (0.094 g, MS(ESI): 518.4 0000 Example 170 2O Preparation of N-,2-(2-bihenyl)thiazol-4-lcarbonfl-N'-FN-(4yvridinylmethoxvcarbonyl)-L-leucinyllhydrazide Following the procedure of Example 112(a)-i 12(g), except substituting 2biphenylboronic acid for 2-benzyloxyphenyl boronic acid in step the title compound was prepared as a white solid 100 g, MS(ESI): 544.3 Example 171 Preparation of N(Nbenzvloxvcarbonl-N-mechA,-1eucinv1 Nf mehylproyl)-N-henyl Tinothiazol4-lc Following the procedure of Example 116(a)-I 16(b), except substituting

N-

benzyoxycarbonyl-N-methyl-Lleucine for N-(4-pyridinylmethoxycarbonyI)-Lleucine in step the title compound was prepared as a white solid (40 mg, MS (ESI): 552.5 Example 172 Preparation of N--methl-N-(2-rid lmethox )-L-leucinvl-N'-2-N- (2-me th 1rol)-N-henlaminol l crnIy d Following the procedure of Example 116(a)-i 16(b), except substituting

N-

methyl-N-(2-pyridinylmethoxycarbonyl)Lleucine for N-(4ee. pyridinylmethoxycarbonyl)-l-leucine in step the title compound was prepared as a white solid solid (70 mg, MS (ESI): 553.4 6@ S Examle 173 Preparation of N- 2-(2-bzylohhenylhi0l-vlcab NN-r butoxvcarbonvl-Lleucinv I)hvdrazide Following the procedure of Example 112(a)-1 12(g), except substituting

N-

tert-butoxycarbonyl-L-leucine for N-(4-pyridinyhlethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (1.015 g, 94%).

MS(ESI): 539.1 Exampi' 174 P re p a ra tio n o f N N-t ert- b ut o xy c a r o n y L- l e u ci nyl) -N N (2 m eth y o y phenylaminolhiazol-4-vlcabonlIlhvdrazid Following the procedure of Example 116(a)-I 16(b), except substituting

N-

tert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)le lucine in step the title compound was prepared as a white solid (740 mg,

MS

(ESI): 504.4 Example 175 Preparation of N-(N-rert-butoxvcarbonvl-N-mehv-L-Ieucinvl methylpropvl)-N-phenylaino lthiazol-4-vlcarbonvl lhydrazide Following the procedure of Example 1 16(a)- I 16(b), except substitutine Nterr-bu toxycarbon yl -N-me thylI-L-Ie ucine for N-(4-pyridinylmethoxvcarbonyl leucine in step the tide compound was prepared as a white solid (610 mg, 697h.

MS (ESI): 518.4 Example 176 Preparation of N-f 2-(2-benzyloxyphenylhthiazol-4-ylcarbonyll-N'-(Npvyrazinecarbonvl-L-leucinvl)hydrazide a) N-[2 -(2-benzyl oxyphenyl)thiazol-4-ylcarbonyll-N-(L-eucinyl)hydrazide :0...:Following the procedure of Example 144(b), except substituting N-112-(2benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-(N-ter-butoxycarbonyl-Lleucinyl)hydrazide for (1 I1 -(N-tert-butoxycarbonyl-N-methylam-ino)-3a' 0 methylbutyl]thiazol-4-ylcarbonyl]-N'-fjN-(4-pyridinylmethoxycarbonyl)-L- .00. 0 :0 leucinyllhydrazide, the title compound was prepared as a white powder (0.766 g, MS(ESI): 439.3 b) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(2-pyrazinylcarbonyl)-L- 0.0000 leucinyllhydrazide 0 Following the procedure of Example I116(b), except substituting was:benzyloxyphenyl)thiazol-4-ylcarbonyl ]-N'-(L-leucinyl)hydrazide for N- [Nphenyl-N-(2-methyl- 1 -propyl)amino]thiazol-4-ylcarbonyllhydrazide and pyrazinecarboxylic acid for N-(4-pyridinylmethoxycarbonyl)-L-leucine, the tidle 0 0*0 0 a compound was prepared as a white solid 146 g, MS(ESI): 545.4 Example 1 7 Preparation of N-r2-(2-benzvioxvphenvl)thiazoi-4-vilcarbonvflI-N'-('N-isonicoinov- L-leucinyl hvdazide Following the procedure of Example 176(a)- I except substituting isoaicotinic acid for pyrazinecarboxylic acid in step the title compound was prepared as a white solid 135 g, MS(!ESI): 544.3 Example 178 Preparation of N-f 2-(2-dibenzofuranyl)thiazol-4-ylcarbonvi 1-N'-fN-(4pyridinylmethoxycarbonyfl-L-leucinvllhvdrazide Following the procedure of Example 1 12(a)- I 12(g), except substituting 2a:**06 so*: bromodibenzofuran for 2-benzyloxybromobenzene in step the title compound 0.0.

was prepared as a white solid (0.079 g, MS(ESI): 558.3 15 Ex&ample 179 .Preparation of N- r2- methylpropy I-N-phenyl amino Ithiazol-4-ylcarbony I 1-N'a' 0 (N-pyrazinecarbonyl-L-leucinyl~hydrazide Following the procedure of Example 176(a)-l176(b), except substituting N- (N-terr-butoxycarbonyl-L-leucinyl)-N'- [N-(2-methylpropyl)-Na 20 phenylaminolthiazol-4-ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyll-N'-(N-tert-butoxycarbonyl-L-leucinyl)hydrazide in step the title compound was prepared as a white solid (36 mg, MS (ESI): 510.4 Exaple18 2 f Preparation of N-f2-fN-(2-methylpropyl)-N-phenvlaminolthiazol-4-vlcarbonyll-N'- (N-methyl-N-pyrazinecarbonyl-L-leucinyflhdrazide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-tert-butoxycarbonyl-N-methyl-L-Ieucinyl)-N'- (2-[N-(2-methylpropyl)-Nphenylamino]thiazol-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 Example 181 Preparation of N-(N-isonicotinovl-L-leucinyl )-N'-F-rN-(2-methvlp2ropl2 phenyl amino I hiazol -4-vicarbon yl I hydrazide Following the procedure of Example 176(a)-176(b), except substituting N- (N-tert-butoxycarbonyl-N-methyl-L-leuciflyl)-N'- [N-(2-methylpropyl)-Nphenvlan-linojthiazol-4-ylcarbonyl]hydrazide for N- [2-(2-benzvloxypbenvl )thiazol- 4-vlcarbonyl]-N'-(N-tert-butoxycarbonyl-L-eucinyl)hydrazide in step and isoni counic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (28 mg, MS (ESI): 509.4 0:0 00g. Example 182 Preparation of N-(N-isonicotinovl-N-methyl-L-leucinyl)-N'- f2- rN-(2methvlproply)-N-p2henlaminotiazol-4-Vlcarboflvllhydrazide ~E 15 Following the procedure of Example 176(a)-i 176(b), except substituting N- (N-methyl-N-terr-butoxycarbonyl-N-methyl-L-leuciflyl)-N'-(2-[N-(2- 0: methylpropyl)-N-phenylamino]thiazol-4-ylcarbonylhydazide for benzyloxyphenyl)thiazol-4-ylcarbonyll-N'-(N-tert-butoxycarboflyl-L- Ieucinyl)hydrazide in step and isonicotinic acid for pyrazinecarboxylic aicd in *seeg 20 step the title compound was prepared as a white solid (117 mg, MS ggge (ESI): 523.4 Example 1 83 Preparation of N-(4-iniidazolvlacervl)-L-leucinvl 1-N'-f2-[N-(2-methvlpropvl _phenylarrinolthiazol-4-ylcarbonyl lhvdrazide Following the procedure of Example 176(a)- I 76(b), except substituting N- (N-tert-butoxycarbonyl-N-nethyl-L-leucirnyl)-N'- 2- [N-(2-merthylpropyl)-Nphenyl amino] Jhiazol-4-ylcarbonyll hydrazide for N- [2-(2-benzyloxyphenyl)thiazol- 4-labnl-'(-etbtxyabnlLluiy~yrzd in step and 4imriidazolylacetic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (60 mg, IHNTVIR (400MIHz, CDC1 3 5 7.62-7.23 (in, 8H), 6.81 1H), 4.72-4.66 (mn, IH), 3.75 1H), 3.55 2H), 1.96-1.93 (in.

2H), 1.76-1.54 (mn, 3H), 0.96-0.84 (mn, 12H).

Preparation of N- r2-fN-(2-methylpropyl-N-phenyamnnolthiazol-4-vlcarbonvll1-N'- (N-p2icolinoyl-L-leucinyl)hvdaieExml 8 *es* 0Following the procedure of Example 176(a)- I 76(b), except substituting N- (N-terr-butoxycarbonyl-N-methyl-L-leuciflyl)-N'-f 2 [N-(2-methylpropyl)-N.

phenylaminolthiazol-4-ylcarbonyl]hydrazide for N- (2-(2-benzyloxyphenyl)thiazollabnl-'-Ntr-uoycroy--eciy~yrzd in step and picolinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (50 mg, MS (ESI): 509.5 0::reparation o N2-(2-benzyloxy~hevl)thiazol4lcarbol~lmethyI rN-(4pyridinyimethoxycarbonyl)-L-leucinamide a) 2-(2-benzyloxyphenylthiazole4-carboxyhc 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 (0.36 1 g, MS(ESI): 312.2 b) -2(-benzvl-ox \'phenvi thiazol-4'-vl bromornethyl ke-tonie Following the procedure of Example 103(a). except substituting 2 berizvloxvphenvlthiazole-4-carboxylc acid for N-benzvloxycarbonvlI-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 nimol), sodium azide (0.064 g. 0.987 nimol), and potassium fluoride (0.072 g, 1.23 numol) 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 0:96 sodium hydrogen carbonate, and brine. The organic layer was dried (MLYSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.087 g, MS(ESI): 373.3 d) 2-azido- I 2-(2-beazyloxyphenyl)thiazol-4-yl]- 1 -hydlroxyethane To a stirring solution of the compound of Example 185(c) (0.087 g, 0.249 mmol) in TI{F (1 mL) at 0 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 *see 0**60, 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, 1I-IYMR (400MHz, CDC1 3 8 8.41 (in, IlH), 7.50 (in, 2H), 7.38 (in. 4H), 7.11 (mn, 3H), 5.31 2H), 5.08 1H), 3.69 (in, 2H), 3.58 (s b, I H).

e) 2-amino- 1 2-(2-benzyloxyphenyl)th~iazol-4-yl]- I -hydroxyethane To a stirring solution of the compound of Example 185(d) (0.084 g, 0.239 mmol) in methanol (2 m:L) was added stannous chloride dihydrate 108 g, 0.478 inmol). After stirring at room temperature for 16 h, the mixture was diluted with ethyl acetate and washed successively with water, saturated aqueous NaH-C0 3 and brine. The org2anic laver was dried 00g6O 4 filtered and concentrated. The 182 residue was purified by column chromatography isilica gel.

methanol/dichjoromethane) to yield the title compound as a white solid (0.07 967c). MS(ESI): 327.3 f) 1 -[2-(2-benzyloxyphenyl)thiazol-4-ylJ- I-hydroxy-2-(4pyridinylmethoxycarbonyl-L-leucinylamino)ethane Following the procedure of Example 116(b), except substituting 2-amino-I- [2-(2-benzyloxyphenyl)thiazol-4-ylj- I -hydroxyethane for N-[2-[N-phenyl-N-(2methyl- 1 -propyl)amino]thiazol-4-ylcarbonylJhydrazide, the title compound was prepared as a white solid (0.075 g, MS(ESI): 575.4 900 so: g) N-[2-(2-benzloxyphenyl)thiazo4-ylcarbonyl]methyl pyridinylrethoxycarbonyl)-L-leucinamjde To a stirring solution of the compound of Example 185(f) (0.075 a, 0. 131 nmol) in dichioromethane (I mL) was added MnO 2 (0.300 g, 3.45 mmol). After stirring at room temperature for 24 h, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as a pale yellow solid (0.017 g, MS(ESI): 573.4 (M+H)t Example 186 Preparation of N-f2-[N-methl-N-(2-methylpropl')aminolthiazol-4-vlcarbonyl [N-(4-pvridinvlmethoxycarbonyl'-L-leucinvlhvdrazide a) N-benzoyl-N'-methyl-N'-(2-methylpropyl)thiourea To a stirring solution of N-methylisobutylamine (3.21 g, 36.8 mnol, 4.45 mrL) in 40 m.L of CHC1 3 was added benzoyl isothiocyanate (6.0 g, 36.8 mmol. 4.95 After stirring for 45 min, the solution was concentrated to yield the title compound as a pale yellow solid (9.22 g, 100%). IHNMR (400M Hz. CDC1 3 2:1 mixture of rotamers) 8 7.86 2H), 7.60 LH), 7.50 2H), 3.90 2H), 3.44 (s, 3H), 3.41 2H), 3.27 3H), 2.35-2.32 1H), 2.13 1H), 1.06 6H). 0.90 6H).

b) N-methvl-N-(-methylpropyl)thiourea The compound of Example 186(a) (9.22 g 36.8 mmol) was suspended in 8O rnL of 1:1 methanolwater and solid potassium carbonate (15.27 g 110 mmol) was added. The mixture was heated at reflux for 48 h, then cooled and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated brine, dried (MgSO 4 filtered and concentrated to provide the title compound as a pale yellow crystalline solid (4.82 g, MS(ESI): 147.0 c) N-2-[N-methyl-N-(2-methylpropyl)aminolthiazol-4-ycarbonvl-N'-[N-(4pyridinvlmethoxycarbonyl)-L-leuciny I hydrazide Following the procedure of Example 113(d)-I 13(f), except substituting Nmethyl-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 Se0 so mg, MS(ESI): 477.4 S. S *0 O Example 187 Preparation of N-(N-methvl-N-picolinol-L-leucinl)-N-r2-fN-(2-methylpropl)-N- 20 phenvlarninolthiazol-4-vlcarbonllhydrazide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-methyl-N-ert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2-N-(2methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide for benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-(N-ter-butoxcarbonyl-L- 25 leucinyl)hydrazide in step and picolinic acid for pyrazinecarboxylic alc.i in step 0:000: the title compound was prepared as a white solid (30 mg, MS (ESI): 523.5 Example 188 Preparation of N-r2-(2-benzvloxvphenvl)thiazol-4-vicarbonvfl-N'-fN-(2pyridinesulfonv)-L-leucinvllhdrazide a) 2-pyridinesulfonylchloride Through a stirring solution of 2-mercaptopyridine (2.235 g, 20 mrnmol) in water (7.5 mL) and concentrated HCI (26 mL) at 0 'C was bubbled Cl 2 After 75 mL of ice water was added and extracted with cold ether (2 X The organic layers were combined and washed successively with cold 10% aqueous NaHCO 3 and cold brine. The organic layer was dried (MgSO 4 filtered and concentrated to yield the title compound as a clear oil. (3.1 g, 87%).

0:9 b) N-[2-(2-benzyloxvphenyl)thiazol-4-ylcarbonyl-N'-[ N-(2-pyridinesulfonyl)-Lleucinylihydrazide To a stirring solution of the compound of Example 176(a) (0.125 g, 0.285 15 mmol), and the compound of Example 188(a) (0.101 g, 0.571 mmol) in dichloromethane (2 mL) was added N-methylmorpholine (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 (0.100 g, MS(ESI): 580.2 Example 189 Preparation of N-[2-fN-(2-methlpropvlY-N-phenviamiinothiazol-4-vlcarbonvll-N'rN-(2-pyridinesulfonvyl)-L-leucinvllhvdrazide Following the procedure of Example 188(b), except substituting N-(Lleucinyl)-N'-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N-(Lleucinyl)hydrazide, the title compound was prepared as an orange solid (56 mg, MS (ESI): 545.3 Example 190 Preparation of N-r2-fN-(2-methvlpropl y)-N-phenylarminolthiazol-4-,vlcarbonI 1-N'f-N-methyl-N-(2-pvr-idinesulfonvl '-L-leucinvl ihydrazide Following the procedure of Example 188(b), except substituting -N rnethyl-L-leucinyl)-N'-[2-[N-(2-methylpropyl )-N-phenylamino]thiazol...b ylcarbonyllhydrazide for N- [2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl leucinyl)hydrazide, the title compound was prepared as an orange solid (53 mg, MS (ESI): 559.3 Example 191 Preparation of N-2f-ehlN(-eblrly~mnlhao--labni-' 0:00 rN-(3-pvyridinvlmethoxycarbonvl )-L-leucinvllhvdrazide Following the procedure of Example 186(a)- 186(c), except substituting N- 3 -pyrnylnethoxycarbonyl)-Lleucine for N-(4-pyridinylmethoxycarbonyl 15 leucine in step the title compound was prepared as a white solid (138 mg, 66%).

MS (ESI): 477.4 Example 192 Preparation of N-r2- [N-(2-methvlpropyl)-N-phenylarnhnolthiazol-4vylcarbonyll .0::Following the procedure of Example 116(a)-I 16(b), except substituting Nmethyl-N-(4-pyridinylmethoxycarbonyl).Lleucjne for N-(4pyridinyhnethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid solid (74 mg, 4 1 MS 553.4 186 Example 193 Preparation of N-2-N--metho )-peyantNzi4vcbn,-N Following the procedure of Example 16(a)-I 16(b), except substituting

N-

methyl-N-(3-pydinylmetboxycaronyl)-Lleucine for N-(4pyridinylmetboxycarbonyl)-L-leucine in step the title compound was prepared as a white solid solid (50 mg, MS (ESI): 553.4 Example 194 Preparation of N-2-(2-benzxyphenv~thiazol-4-vlcarb prvridinvlmethoxvcarbonl)--leuinvllhvaide 0000 Following the procedure of Example 112(a)-I 12(g), except substituting

N-

methyl-N-(4-pyridiny ethoxycarbonyl)-le for N-(4pyridinylnethoxycarbonyl)--leucine in step the title compound was prepared as a white solid (0.028 g, MS(ESI): 588.4 iExample 195 Preparation of N- -methI-N- vridinvlmethoxvcaboyjl -1naphthl)thiazol-4-v caronllhvdrazide Following the procedure of Example 112(a)-1 12(g), except substituting

I-

naphthyl boronic acid for 2-benzyloxyphenyl boronic acid in step and N-methyl- N-(4-pyridinylmethoxycarbonyl)-Lleucife for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (0.072 g, 36%).

MS(EST): 532.4 .:,..iExamp1096 Preparation of N-[2-N.N-(bis2-mthgm~vl~arrnolth (4-pvridinylmethoxycarbonl)lYL-eucinyllhvdrazide Following the procedure of Example 186(a)- 186(c), except substituting

NN-

diisobutylamine for N-methylisobutylamine in step the title compound was prepared as a yellow solid (60 mg, MS (ESI): 519.5 Example 197 Preparation of N-(N-benzvloxycarbonvl-L-leucinyl)-N'-f2-fNN-(bis)-2methvlpropvl arrinolthiazol-4-vlcarbonvllhvdrazide Following the procedure of Example 186(a)-1I86(c), except substituting N.Ndiisobutylamine for N-methylisobutylamine in step and N-benzyloxvcarbonvl-L.

leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in the final step, the title compound was prepared as a yellow solid (131 mg, MS (ESI): 518.4 Example 198 0:*4Preparation of N-[2-(4-morpholino)thiazol-4-vlcarbonyll1-N'- N-(4- *000 pvyridinvlmethoxycarborivl)-L-leucinvllhvdrazide :Following the procedure of Example 186(a)-1I86(c), except substituting morphoiine for N-methylisobutylan-iine in step the title compound was prepared .as a white solid (45 mg, 3 MS (ESI): 477.3 Example 199 Prep~aration of N-f2-r2-(4-pvyridinvlmethoxy)p2henyllthiazol-4-vlcarbonvll-N- pvyridinylmethoxycarbonvh)-L-leucinyllhydrazide a) 2-methoxyinethoxybromobeazene To a stirring suspension of sodium hydride (1.2 g, 52.1 mmol, dispersion in mineral oil) in DM1F (75 rnL) at 0 0 C was added 2-bromophenol (6.0 g.

34.7 mmol) dropwise. After stirring for 20 mmii, bromomethyl methyl ether (4.3 g, M 34.7 mmol) was added. After stirring for 16 h at room temperature, the r-,xture 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, 1 flNMR (400M1I~z, CDCl 3 8 7.55 I1H), 7.28 (t, lH), 7.16 lH), 6.91 lH), 5.25 2H), 3.54 3H).

b) ethyl 2-42 -methoxymethoxyphen yl) thiazole -4-c arboxv late Following the procedure of Example 1 12(a)- I 12(b) and 1 12(d)- I 12(e), except substituting 2?-methoxymethoxybromobenzene for 2benzy lox ybromo benzene in step the title compound was prepared. IMS(ESI):- 294.3 c) ethyl 2-(2-hydroxyphenyl)thiazole-4-carboxylate To a stirring solution of the compound of Example 199(b) (0.839 a, 2.86 mrnol) in ethanol (25 ml) 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 see sets bicarbonate, and brine, dried (MgSO4), filtered and concentrated to yield the title compound as a pale yellow solid (0.674 g, MS(ESI): 250.2 15 d) ethyl 2-[2-(4-pyridylmethoxy)phenyljthiazole-4-carboxylate :To a stirring solution of the compound of Example 199(c) 125 g, 0.502 0 rnxol), 4-pyridylcarbinol (0.071 g, 0.653 minol), and triphenylphosphine 171 g, 0.653 minol) in THF (5 mL) at 0 0 C was added diisopropyl azodicarboxylate 132 *gotg, 0.653 rnmol) dropwise. After stirring at room temperature for 16 h, the solution *see 20 was concentrated and purified by column chromatography (silica gel, ethyl S acetate/hexane) to yield the title compound as a white solid 100 g, 59%).

MS(ESI): 341.3 0:*o e) N-[2-[2-(4-pyridinylmethoxy)phenyl]thiazol-4-ylcarbonyl]-N'-[N-(4pyridinyhnethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 112(f)- I112(g), except substituting ethyl 2-[2-(4-pyridylmethoxy)phenyl~thiazole-4-carboxylate for ethyl 2-(2benzyloxyphenylI)thi azole-4-c arboxyl ate in step the title compound was prepared as a white solid (146 mg, MS(ESI): 575.4 Example Preparation of N-r2-(2-naphthvl)thiazol-4-vlcarbonvll-N'-[N- 4pvridinvlmethoxvca-rbonyP)-L-leucinyI 1hydrazide Following the procedure of Example I112(a)- I 12(g), except substituting 2naphthylboronic acid for 2-benzyloxyphenyl boronic acid in step the tite compound was prepared as a white solid (226 mg, MS (ESI): 518.4 (M Example 201 Preparation of N-r2-rN.N-(bis)-2-methvlpropl)ainolhiazol-4-vlcarbonvI 1-N'-rNmethvI-N-(4-pyridinylmethoxycarbonl)-L-leucinlVhydrazide 0:08 Following the procedure of Example 186(a)- 186(c), except sbtuin Ngo: diisoburvlanune for N-methylisobutylamine in step and N-methvl-N-(4- 0.0.0 pyridinylmethoxvcarbonyl)-L-leucine for N-(4-pyridinylinethoxycarbonyl)-L- 0S 15 leucine in the final step, the title compound was prepared as a yellow solid (30 mg, MS (ESI): 533.3 Example 202 Preparation of N-(N-benzyloxycarbonyl-L-leucinyl)-N'- [2-(4-morpholino)thiazol-4ylcarbonyllhydrazide 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 O 25 0.1 Example 203 Preparation of N-fN-(4-rpvnidinylmethoxycarbonv)-L-leucill 1-N-r2- 4thiomorpholino)thiazol-4-vlcarbonyl ihydrazide Following the procedure of Example 186(a)- 186(c), except substituting rhiomorpholine for N-methylisobutylamine in step the title compound was prepared as a white solid (35 mg, MS (ESI): 493.4 Example 204 Preparation of N-(N-benzloxycarbonyl-L-leucinyl)-N'-r2-(4thiomoapholino')thiazol-4-vlcarbonyllhydrazide Following the procedure of Example 186(a)-i 186(c), except substituting thiomorpholine 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 (20 mg, MS (ESI): 492.3 Preparation of N-r2-(2.3-ethylenedioxy4-methoxyphenyl)thiazol-4-lcarbonll-N'- [N-(4-pyridinylmethoxycarbonyl )-L-leucinyllhydrazide Following the procedure of Example 112(a)- I 12(g), except substituting 2,3e 20 ethylenedioxy-4-methoxybromobeizene for 2-benzyloxybromobenzene in step the title compound was prepared as a white solid (31 mg, MS (ESI): 556.4 0 Example 206 25 Preparation of N-I2-[N.N-(bis)-2-methpropy)aninothiazol-4-1carbol1-N'-[N- :60e:methyl-N-(3-pyidinylmethoxcarbonyI-L-eucinlhydrazide Following the procedure of Example 186(a)-186(c), except substituting NNdiisoburyiamine for N-methylisobutylamine in step and N-methyl-N-(3pyridinylmethoxycarbonyi)-L-leucine for N-(4-pyridinyimethoxycarbonyi)-Lleucine in the final step, the title compound was prepared as a yellow solid (30 mg.

MIS (ESI): 533.5 Example 207 Preparation of N-f2-(N-cvcloproplmethv-N-propyarmno)thiazol-4-vlcarbonvl- N'-[N-(4-pvridinvlmethoxvcarbonl)-L-leucinllhydrazide Following the procedure of Example 186(a)-i 86(c), except substituting Ncyclopropylmethylpropylamine for N-methylisobutylamine in step the title compound was prepared as a yellow solid (60 mg, MS (ESI): 503.3 Example 208 Preparation of N-[N-(4-pvridinlmethoxcarbonvl')-L-Ieucinvll-N'-2-(8quinolvl)thiazol-y-vlcarbonvllhvdrazide Following the procedure of Example 112(a)-I 12(g), except substituting 8- .bromoquinoline for 2-benzyloxybrorobenzene in step the title compound was 15 prepared as a white solid (134 mg, MS(ESI): 519.3(M+H)+.

0. 0:Example 209 .e 0: Preparation of N-rN-methyl-N-(4-pvridinvlmethoxcarbonyl)-L-Ieucinyll-N-r2-(8quinolvl)thiazol-4-vlcarbonvflhydrazide Following the procedure of Example 112(a)-I 12(g), except substituting 8bronoquinoline for 2-benzyloxybromobenzene in step and N-methyl-N-(4pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (53 mg, 22%).

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

b) 1 -N(-Czl ciy)aio3-N(-ibny-ufnl-ru -rpn-2-n 000: Following the procedure of Example 5 except substituting "4-biphenyl sulfonyl chloride' for "4-(3-Chloro-2-cyalo-phenoxy)-phenvl sulfonyl chloride", the title compound was prepared: MS(ES) M-H=550.

Examle2 11 0Preparation of I N-b-ecnl-mn---3-ihnlsloy)aio p2ropan-2-one a) 3-biphenyl-sulfonyl chloride 3-Biphenyl bromide (9.3 g, 40 mmol) was dissolved in TIT (40 nil) and a 0:00 Grignard reagent was prepared in standard fashion with magnesium powder (1.2 g, mniol). The reaction was cannulated into a solution of sulfuryl chloride (10.5 g, 6.4 ml, 80 mmol) in hexanes (25 ml) and was strirred at RT for 2h. The reaction S...was quenched with ice-water, extracted with ether, dried with magnesir-,n sulfate, 0 25 filtered, concentrated, and was used in the next reaction without further purification.

Following the procedure of Example 51(a), except substituting '3-biphenyl sulfonyl chloride" for '4-(3-Chloro-2-cyano-pheloxy)-phenyl sulfonyl chloride'.

the title compound was prepared: MS(ES) M-H7=550.

Example 212 Preparation of I N-Cbz-leucinvl )-arniino-3-N-(2--benzvloxv-phenvl-sulioivI I ar~opropan-2-one a) 2-benzvloxv-phenvl-sulfonyl chloride Following the procedure of Example 211I(a), except substituting '2benzyloxy-phenyl bromide for "3-biphenyl bromide", the title compound was prepared and was used in the next step without further purification.

b) 1 N-Cbz-leucinyl) -amino- 3-N- beazyloxy -phe nvl-sul fonyl)-amino-pro pan 2-one Following the procedure of Example 5 except substituting "2- 00*: benzyloxy phenyl sulfonyl chloride "for "4-(3-Chloro-2-cyano-phenoxy)-phenvl sulfonyl chloride", the title compound was prepared: MS(ES) M+If= 58 1, M+Na'= 604. 2M+Na'= 1185.

Exaple21 Prpaato ofI--S-b-ecnl-mn---41hnx-hnisloy) b) Prprtio-N-( N-Cbz-leucinin 3-N(4phno--(-phenox-enl- ulf aion-ppn Following the procedure of Example 521(a), except substituting "4-phenoxyphloen rmd"fr"-ihnlboie, the title compound was prepared and)MH- 6,M+a=50 Example 214 Preparation of N-Cbz-Ieucinvl)-amino-3-N-(2-dibenzofuran-sulfol)-air~nopropan-2-one a) 4-phenoxy-pbenyl-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) N-Cbzleucinyl)-amino-3-N-(2-dibenzofuran-ulfoyl)-amifo-propaf-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+H= 566, M+Na*= 588.

Example 215 Preparation of N-Cbz-1eucin1-amino-3-N-(3.4-dimethoxy-phefly- sulfonyl)armno-an-2-one Following the procedure of Example 51, except substituting "3,4dimethoxy-phenyl-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-pheny sulfonyl chloride", the title compound was prepared: MS(ES) M+W= 536, M+NHf*= 553.

Example 216 Preparation of N-rlbz-Ieucinvl)-amino-3-N-(2.5-dichlorotiophene-3- .S o 25 sulfonvl)-amino-rop;mn-2-one Following the procedure of Example 51, except substituting dichlorothiophene-3-sulfonyl chloride for -Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+NH4= 567, 2M+W= 1101.

Example 217 Preparation of I N-Cbz-leucinvl)-arnino-3-N- sulfonyl )-amino-p2ropan-2-one Following the procedure of Example 5 1, except substitutincg phenyi 5sulfone-5-thiophene-2-sulfonvl chloride for "4-(3-Chloro-2-cyano-phenoxy)phenyl sulfonyl chloride", the title compound was prepared: MS(ES) 622.

Example 218 Preparation of 1 N-Cbz-leucinyl)-amino-3-N-(8-Quinoline-sulfonvl)-arrninoprop~an-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.

Example 219 Preparation of 1 N-Cbz-leucinvl )-amino-3-N-(2-pvridvl-sulfonyl )-amino- 12oSan2-n Following the procedure of Example 51, except substituting '2-pyridylsulfonyl chloride" (as described in I Org. Chem. 1989, 54, 392) for "4-(3-Chloro- 2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: M 477, M+ Na+ 499.

196 Example 220 Preparation of I N-Cbz-leucinvl )-arnino-3-N-(2-p2vrdvl-sulfonvl )-arrunopropan-2 -one a) l-N-(N-Cbz-leucinv l)-ami'no-3-N-(4-phenoxy-phenyl-sulfonyl)-an-ino-propan-2ol 1,3-Diamino propan-2-ol (6.75 g, 75 mxnol) was dissolved in DMLF (lO0mI) and Cbz-leucine (20g, 75.5 mmol), HOBT-hydrate (1 I g, 81.5 mmol), and EDGI (15.5g, 81.2 mmol) were added. The reaction was stirred overnight at RT. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether ml) and MeOH (30 nil) were added. A IN solution of hydrochloric acid in ether was added (I M, 30 ml) and a white gum formed, which was washed several times with ether. MeOH-acetone were added and heated until the gum became a white see: solid. The white solid was dissolved in DMF (25 ml) and DLEA then 4phenoxy phenyl sulfonyl chloride was added. The reaction was stirred for 2h, concentrated in vacuo, then chromatographed (silica gel, 1: 1 EtOAc: hexanes) to provide the desired product as a white solid.

b) Leucinyl-amrino-3 -N-(4-phenoxy phenyl sulfonyl)-amidno-propan-2-ol 1 -N-(Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amino-propanego.. 20 2-ol (1.0g, 1.8 nmol) was dissolved in EtOH (30 ml), then 10% Pd/C (0.22g) was added followed by 6N hydrochloric acid (2.5 mld), and the reaction was stirred under a baloon of hydrogen gas for 4h at RT. The reaction mixture was filtered, concentrated, and azeotroped with toluene to provide a white glass which was used in the next reaction without further purification.

c) 1 -N-(N-4-pyridyl acetyl-leucinyl)-amrino-3-N-(4-phenoxy-phenyl-sulfonyl)amino-propan-2-ol Leucinyl-amino-3-N-(4-phenoxy phenyl sulfonyl)-amino-propan-2-ol (0.36 g, 0.76 mmol) was dissolved in DMIF (5 then NMIM (0.45 ml, 4 mmol) was added followed by 4-pyridyl acetic acid 13g, 0.75 mmol) and HBTTJ (0.29g, 0.76 mnmol) and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel. 5%cMeOH: meihvlene chloride) to provide the desired product as a white solid (90 mg. MS(ES): N4+H+ .555.

d) I -N-(N-4-pyridvl acetvl-leucinyl)-amino-3-N-(4-phenoxy-phenvl-sulfonyl 1amino-propan-2-one 1 -N-(N-4-pyridyl-acetyl-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl amino-propan-2-ol (45 mg, 0.08 mxnol) was dissolved in acetone (5mil), then IN hydrochloric acid (2 m-l) was added. The reaction was concentrated in vacuo, then redissolved in acetone. Jones reagent (1.5 M, several drops) was added and the reaction miuxture 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 see: buffer and then was extracted with EtOAc, dried with magnesium sulfate. filtered.

0....concentrated in vacuo, then chromatographed (silica gel, 5% MeOH-methylene 15 chloride) to give the desired product as a white solid (27 mug, MS(ES): .000: =553.

Exml 22 Preparation of I N- 2-pvridyl -sul fony I-le ucinl1) -arnino- 3-N-(4-p2henoxY- @So 20 phe nyI-s ulfonyl)- amino- prop an 2-one Following the procedure of Example except substituting "2pyridyl-sulfonyl chloride" (as described in J. Org. Chem. 1989, 54, 392) for "4pyridyl-acetic acid and 1{BTU the title compound was prepared: MS (ES) M +If= 475, M+ Na 497, 2M+ Na+ 117 1.

o Example 222 5 Preparation of I -N-(N-morpholino-carbonvl-leucinvn)-aino-.3..N-(4p1henoxv..

phenyl-sulfonfl-armino-p2ropan-2-one Following the procedure of Example except substituting INmorpholino-carbonyl chloride" for "4-pynidyl acetic acid and HBTU-". the title compound was prepared: MS(ES) M 547. M+ Na+ 569, 2M+ Na+ 1115.

198 Example 223 Preparation of I -N4( N-4- pyrd I -carbony I -e uc i ny1)-aminlo- 3-N-( 4 -heloxv pheny I-sulfony D-arntino-propal- 2 -onle Following the procedure of Example except substituting 4pyridyl-carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) M-4U= 539.

Example 224 Preparation of I N-acety!-leucinyl )-amino-3-N-(4-phenox-phenl-sLlfonfl)amio-popa-2-one see: Fol-lowing the procedure of Example except Substituting "acetyl 0000 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 :0 0 Preparation of I Njimidazole aceyI-leucinyl)-aino-3-N-(4-Dheloxy-phenV[sulfonyvb-amn rpn-2-oflt Following the procedure of Example except substituting "imidazole acetic acid" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) M+H= 542.

Example 226 Preparation of I N-4-carboxymethyl benzov1-leucinyl)-am ino-3-N-( 4 -12henoxy- 2 5 p2henyl-sulfonfl)-arino-pRmpal-2-ofle *sees: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 22- Preparation of I N-(NN-dimethvl glvcinvl -])-leucin\'l -arn-ino-S-N- 4 -phnoxv phenyl -s ulfon ami no-p2roan-2 -one Following the procedure of Example except substicng dimethyl glycine' for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) 519.

Example 228 Preparation of I -Ni N8qioiesloaielucnl-mn---4peo, phenyl-sulfonyl)-armno..propan.2-one Following the procedure of Example except substituting "8quinoline sulfonyl. chloride" for "4-pyridvl -acetic acid and HiBTU", the title 0see :0..:compound was prepared: MS(ES) M+W= 625.

200 Example 229 Preparation of N-Cbz-leucinvl)-amino-3-N-(8-quinoline-carbonv)-aminopropan-2-one 1,3-Diamino propan- 2 -ol (6.75 g, 75 mmol) was dissolved in DMF (100ml) and Cbz-leucine (20g, 75.5 mmol), HOBT-hydrate (1 g, 81.5 mmol), and EDCI (15.5g, 81.2 mmol) was added. The reaction was stirred overnight at RT. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether (50 ml) and MeOH (30 ml) were added. A IN solution of hydrochloric acid in ether was added (1 M, 30 ml) and a white gum formed, which was washed several times with ether.

MeOH-acetone were added and heated until the gum became a white solid. The white solid (0.44g, 1.1 mmol) was dissolved in DMF (3 ml) and NMM (0.33ml, 0.3 mmol), then 8-quinoline carboxylic acid (0.17g, 1.0 mmol), and HBTU (0.38g, mmol) were added and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel, 7:2 EtOAc: 15 hexanes). The solid was then dissolved in acetone (5ml), then IN hydrochloric acid (2 ml) was added. The reaction was concentrated in vacuo, then redissolved in *acetone. Jones reagent (1.5 M, several drops) was added and the reaction mixture was stirred for 6h at RT. Isopropanol (0.5 ml) was added and the reaction mixture was concentrated in vacuo. The reaction was diluted with pH 7 buffer and then was 20 extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated in •vacuo, then chromatographed (silica gel, 5% MeOH-methylene chloride) to give the desired product as a white solid (23 mg, MS(ES): M+H 491.

Example 230 25 Preparation of N-Cbz-leucinyl)-amino-3-N-(6-quinoline-carbonyl)-aminopropan-2-one Following the procedure of Example 229, except substituting "6-quinolinecarboxylic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M+H= 491.

Example 23 1 Preparation of 1 N-Cbz-leucinyl)-amino-3-N-(2-(4-biphenvl )-4-methvlpropanarnide )-propai- 2 -one Following the procedure of Example 229. except substituting "2-isobutvl-4biphenyl acetic acid "for "8-quinoline carboxylic acid the tidle compound was prepared: MS(ES) M 5 86, Na+ 608, 2M+ Na+ 1193.

Example 232 Preparation of 1 N-Cbz-Ieucinyl)-aniino-3-N-( N-4-pvyridyi-methyleneoxv carbonyl-leucinyl)-amino-propan-2-ofle Following the procedure of Example 229, except substituting "4-pyridvl methyleneoxy carbonyl leucine" for "8-quinoline-carboxylic acid the tidle compound was prepared: MS(ES) M+W= 584.

*00 15 Example 23 *Preparation of 1 N-Cbz-leucinyl)-aino-3-N-(benzovetl)- ufny)nino-on Following the procedure of Example 22, except substituting "beazomyl- 2 -unlchloride for "noiecarolic dand phBTU", theni copondl walrie" th il oudwsprepared: MS(ES) Mlf 44, ar= 4 94.Na 91 202 Example 235 Prep~aration of 1 -N-(N-Cbz-1 -ucinyl)-arliflo-3- N( I .3-dimnethyl-5-chloro- pyrazole-, 4-sulfonvi)-amino-propan-2-ofle Following the procedure of Example 5 1, except substituting 1,3-dimethvl- 5-chloro- pyrazole-4-sulfonyl chloride" for "4-(3-Chloro-2-cyaflo-phefloxy)-pheflyl sulfonyl chloride', the title compound was prepared: MS(ES) 494.

Example 236 Preparation of 1 -N-(N-4-pyridyl-methylefleoxy carbonvl-Ieucinvl)-amino-3-N-( 4 :06 10 phenoxv-1phenyl-sulfonyl)-amiflo-2ro~an- 2 -ofle **~~:Following the procedure of Example 2 13(a), except substituting "4-pyr-idylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) M+W= 569.

15Exml23 6 Preparation of 1 N-3-pvridyl-methyleneoxy carbonyl-leucinyl)-armno-3-N-( 4 p2henoxy-Rhenyl-sulfonyU -xnn-pr an- 2 -ofle Following the procedure of Example 213(a), except substituting "3-pynidyl- 0066methyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was 20 prepared: MS(ES) M+W= 569.

0. Example 238 *:Preparation of I N--ydlmtyeex-abnlluiy)ann---4 Following the procedure of Example 213(a), except substituting "2-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) M+Wf= 569.

203 Example 239 Preparation of I N-4-carboxv-benzo--]-eucinvl )-aino-3-N- 4-phenoxvphenyl-sulfonv)-amino-propan-2-one I -N-(4-carboxy methyl-benzoyl-leuciny)-aino-3-N-(4-phenoxv-phenv sulfonyl)-amino-propan-2-one 105g, 0. 176 rmol) was dissolved in MeOH (5 ml) and water (1 ml), then LiOH-bydrate (15 mg, 0.35 mmol) was added and the reaction was stirred at RT for Ih. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml), then with EtOAc (2 x 10 ml). The combined organics were dried with magnesium sulfate, filtered, concentrated, chromarographed (silica gel. 50:50:1 EtOAc: hexanes: AcOH) to give the desired ego: product as a white solid (35.6 mg, MS(ES) M+H1-= 582, M+ Na+ 604.

0 0Example 240 Preparation of N-Me-N-Cbz-leucinvl)-aino-3-N-(4-phenoxwphenv sulfonyl)-amino-propan-2-one Following the procedure of Example 213(a), except "N-Me-N-Cbz-leucine for Cbz-leucine", the title compound was prepared: MS(ES) M+Wr= 582, M+ Na+ 604, 2M+ Na+ 1185.

Example 241 Preparation of 4-phenoxv benzovl)-amino-3-N-(4-phenoxv-phen;- sulfonvi)amino-propan-2-one Following the procedure of Example 213(a), except "4-phenoxy benzoic acid for Cbz-leucine", the title compound was prepared: MS(ES) 517.

25 M+ Na+ 539, 2M+ Na+ 1055.

204 Example 242 Preparation of 1 -N-(3-phenoxv-benzoyl )-amino-3-N-(4-p~henoxv-tphenvl- sulfonvi arnino-propan-2-one Following the procedure of Example 2 13(a), except "3-pherioxy benzoic acid for Cbz-leucine", the title compound was prepared: MS(ES) 517, M+ Na+ 539, 2M+ Na+ 1055.

Eampie243 Preparation of 1 -N-(4-phenoxy benizoyl )-amino-3-N-(4-phenoxv-phenvl- sulfonvi arnino-2ropan 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 +HV 5 1 7.

M+ Na+ 539, 2M+ Na+ 1055, M-H+ 515.

*15Exml24 Prep~aration of 1 -N-(4-biphenyl acetyl)-amino-3-N-(4-phenoxy-p2henyl-sulfonyl arnino-propan-2-one Following the procedure of Example 213(a), except "4-biphenyl acetic acid move "for "Cbz-leucine", the title compound was prepared: MS(ES) M+W= 515, M+ Na+ 537, 2M+ Na+ 105 1.

Preparation of I -N-(2-benzyloxy benzoyl')-amino-3-N-(4-phenoxv-phenvlsulfonyh- rio-rpn-2-one 25 Following the procedure of Example 213(a), except "2-benzyloxy- benzoic acid for" Cbz-leucine", the title compound was prepared: MS(ES) M 53 1, M+ Na+ 553, 2M+ Na+ 1083.

205 Example 246 Preparation of Il-N-( N-Cbz-leucinyl)-aino-3-N-(4-benzyloxv-benzovl)-armno- 2ropan-2 -one Following the procedure of Example 229, except substituting '4-benzyloxvacid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M +lf= 546, M+ Na+ 568, 2M+ Na+ 1113.

Example-247 Preparation of I -N-(2-(4-biphenyl )-4--methyl-pentaxido)-3-N-(4-phenoxv-phenyl sulfonvl)-amino-p2ropan-2-one 9:00 Following the procedure of Example 213(a), except 2-(4-biphenyl)-4methyl-pentanoic acid for "Cbz-leucine", the title compound was prepared: :7MS(ES) M 57 1. M+ Na+ 593.

2..a Exml04 Preparation of 1 -N-(2-(3-biphenvl)-4-methvl-pntanudo)-3-N-(4-phenoxv-phenvlsulfonvi )-amnino-propan-2-one a) 3-bromo-phenyl methyl acetate 0 3-Bromo phenyl acetic acid (2.15g, 10 mmol) was dissolved in ether, then 20 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 mimol) was dissolved in toluene &:ate. 25 (30 ml). Then, phenyl boromc acid (1.46g, 12 minol) was added followed by aqueous sodium carbonate (2M, 4.24 ml, 40 mmol), then tetrakis(triphenylphosphine) palladium (0.35g, 0.3 mmol) and was refluxed overnight. The reaction was cooled to RT, diluted with saturated amnionium 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 06 10 solid (1.66 g, 1H NMR: d: 7.6-7.25 9H), 3.7 2H) *o 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 lh. Water (2 ml) was added and the THF was removed in vacuo. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml), then with EtOAc (2 x 10 ml). The 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) -4-biohenvl-)-4-methvl-pentanoic acid 3-44-13iphenvh'-4-methy -pen t-4-e noic acid (0.52, 1.87 mmnol) was dissolved in EtOAc (25 nil). Then. 10% Pd/C (60 mg) was added and the reaction was stirred for 2.5 h under a balloon of hydrogen gas. The reaction was filtered, concentrated in vacuo, then was redissolved in 1:5 EtOAc: EtOH (15 ml). Then, 10% Pd/C mg) was added and the reaction was stirred under a balloon of hydrogen gas overnight. The reaction was filtered, concentrated in vacuo, and chromatographed (silica gel, 5% MeOH: methylene chloride) to give the desired product as a white solid (1.66 g, IH NMIR: d: 7.6-7.3 (in, 9H), 3.7 IH), 2.07-1.95 (in. IH).

1.8-1.7 (in, lH), 1.6-1.45 (in. IH).

0:60 I 1-N-(2-(3-biphenvl)-4-methy1-pentarido)-3-N-(4-phenoxy-phenl-sulfoDnl amnino- propan- 2-one 15 Following the procedure of Example 213(a), except 3-(4-biphenyl)-4methyl-pentanoic acid for Cbz-Ieucine", the title compound was prepared: MS(ES) M 57 1, M+ Na+ 593.

::*Example 249 Preparation-of 1 -bip~henvl, acetvl)-arnino-3-N-(4-p2henoxy-phenvl-sulfonVI')amino-p2ropan-2-one Following the procedure of Example 2 13(a), except "3-biphenyl acetic acid "for" Cbz-leucine", the title compound was prepared: MS(ES) M+W= 515, M+ 537, 2M+ Na+ 105 1.

208 Example 250 Preparation of I N-4-pvridvl acetvl-leucinvl)-anmno-3'-N-(2-benzvloxv- phenvlsulfonyl)-arnino-2ropan-2-one a) I -N.(N-Boc -leucinyl) -amnino- 3-N-(2 -beloxy phenyl-sulfonyl)-arnno-propan- 2-ol 1,3-Diamrino-propan-2-ol (3.375g, 37.5 mxnol) was dissolved in DMFf mnl). Then I-OBT-hydrate was added (5.5g, 40.7 mmol), followed by Boc-L-leucine (9.34g, 37.5 rnrol) and EDCI (7.77g, 40.7 mmol). The reaction was stirred for 4h, then diluted with DMF to make a stock solution of a total volume of 100 mJd (0.375 mmol./mI). The stock solution (18 ml, 6.75 mniol) was treated with NMM (0.89 m.1, Woo:7.28 inmol), then 2-benzyloxy phenyl sulfonyl chloride (1.9g, 6.72 mmol). The reaction was stirred an additional 2h, then was diluted with water, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 20% EtOAc: hexanes): MS(ES) M 550.

b) 1 -N-(leucinyl)-amino-3-N-(2-benzyloxy-phenyl-sufonyl)-amilo-propal-2-oI I -N-(Boc-leucinyl)-arnino-3-N-(2-benzyloxy phenyl sulfonyl)-aminopropan-2-ol (0.7g, 1.3 mmol) was dissolved in 1: 1 TFA: DCM (50 mld) and was ov* stirred at RT for 2h, concentrated in vacuo and was used in the following reaction 0000 20 without further purification: MS(ES) M+W= 450.

c) 1 -N-(N-4-pyridyl acetyl-Ieucinyl)-amino-3-N-(2-benzyloxy-phenyl-sulfonyl)amino-propan-2-one Following the procedure of Example except substituting 1-N- %woo: 25 leucinyl-amino-3-N-(2-benzyloxy phenyl sulfonyl)-amino-propan-2-ol" for N-leucinyl-amino-3-N-(4-phenoxy phenyl sulfonyl)-amino-propan-2-ol the title compound was prepared: MS(ES) 567.

Example Preparation of 1 N-4-pyridyl-carbonvi-leucinvi )-arnino-3'-N-(2-berizvloxvphenvi-sulfonvi)-amnino-p2ropan-2-one Following the procedure of Example except substituting '4pyridvl carboxylic acid" for "4-pvridvl acetic acid the title compound was prepared: MS(ES) M+lf= 553.

Example 252 Preparation of 1 N-4-inmidazole acefic-Ileuciny I)-aznino- 3-N-(2 -benzy loxvphenyl -sul fony h- amino-p2rop1an 2-one Following the procedure of Example except substituting "4- Go*: imidazole acid" for 4- pyrid I -acetic acid the title compound was prepared: %see** MS(ES) M-4f= 556.

P1 prtino Example 253 Prprto ofI-N-( N.N-dimethyl glvcfl) -leucinyl)-amino-3-N-(2-benzvloxy- Zphenyl-sulfonfl)-amino -propan-2-one Following the procedure of Example except substituting "N,Ndimethyl glycine" for "4-pyridvi -acetic acid the title compound was prepared: 20 MS(ES) 533.

Exaple 54 Preparation of N-(N-methyl prolvl-leucinyl)-anmino-3-N-(2-benzyloxvp2henyl-sulfonyl)-arnino-propan-2 -one :25 Following the procedure of Example except substituting "Nmethyl proline" for '4-pyridyl acetic acid the title compound was prepared: MS(ES) M+W= 559.

Example 255 Prep~aration of I N-(N-methyl pipridine-4-c arbony )-leuc iny h- amino- 3-N-(2 benzy lox y-phenv I- sul fony -ami no-1propan- 2-one 210 Followin the procedure of Example 250(a-.c, except substituting 'Nmethyl -pi peri dine -4-carboxylic acid" for "4-pyridvl acetic acid the tite compound was prepared: IMS(ES) 573.

Example 256 Preparation of 1 N-(N-methvl p2iperidine-4-carbonyl')-leucinyl)-ainino- 3-N-(2dibenzofuran-sulfonyl)-amino-propal- 2 -one Following the procedure of Example except substituting "Nmethyl-piper-idine-4-carboxylic acid" for "4-pyridyl acetic acid and "2dibenzofuran sulfonyl chloride" for '2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+HF 557.

:Example 257 Preparation of 1 N-(N-methvl prolyl)leucinl)-amino-3-N-(2-dibenzofuraflsulfonyl)-ario-rpn-2-one Following the procedure of Example except substituting Nmethyl proline for "4-pyridyl acetic acid and "2-diberizofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the tidle compound was prepared: MIS(ES) M 543.

6 ExaMple 258 Preparation of N.N-dimethyl galycyfl-leucinyl)-amino-3-N-(-( 2 dibenzofuran-sulfonyl)-ami no-propan-2 -one Following the procedure of Example except substituting N,N- ':00 2 5 dimethyl glycine for "4-pyridyl acetic acid and "2-dibenzofuran-suiioflyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+W= 517.

Example 259 Preparation of I N-4-irnidazole acetic -leuc invi)-arru no- 3- N-(2-di benzofuran sulfonvfl-amino-propan- 2-one Following the procedur! of Example except substituting "4imidazole 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 I-N-C N-4-pyridyl carbonvl-leucinyl)-arnino-3-N-(2-dibenzofuransulfonvi )-amino-propan-2-one Following the procedure of Example except substituting '4pyridyl carboxlic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was 15 prepared: MS(ES) M+f-r= 537.

Example 261 Preparation of 1-N-C N-4-pvridyl acetyl-leucinyl)-axnino-3-N2-dibenzofuransulfonyl)-anino-projpan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride" for "2-beazyloxy phenyl suiphonyl chloride' the tidle compound was prepared: MS(ES) M 55 1.

Example 262 Preparation of 1-N N-4-imidazole-acrlyl-leucinyl)-amino-3-N-(2-dibenz~furaP: sulfonyfl-amino-propan-2-one Following the procedure of Example except substituting "4imidazole-acryic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the tidle compound was prepared: MS(ES) 552.

Example 263 Preparation of 1 N-pvyrazole-carbonyl-leucinfl)-amino-3-N-(2-dibenzofura-nsulfonyl)-arnino-prop~an-2-one Following the procedure of Example except substituting "pyrazole carboxylic acid" for "4-pyridyl acetic acid "and "2-dibenzofuran sulfonvi chloride" for '2-beazyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M+W= 538.

Example 264 Preparation of N-benzoyl-leucinyl)-antino-3-N-(8-guinoline-sulfonyl)-amjLnopropan-2-one "See* Following the procedure of Example except substituting 00: "benzoic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for '2beazyloxy phenyl suiphonyl chloride" the tidle compound was prepared: MS(ES) M 497.

Preparation of I N-2.5-difluoro-benzoyl-leucinyl)-amino-3-N-(8-guinolinesulfonyl)-amio-rpn-2-one Following the procedure of Example except substituting difluoro-beazoic 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= 535.

25 Example 266 Preparation of A N-2.5-difluoro-phenyl acetyl -leucinyl)-ar-runo-3-N-(8quinoline-sulfonyl)- mn-rpn-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) M 547.

213 Example 267 Preparation of I N-phenyl acetrvl-Ieucinvl)-arruno-3-N-(8-uilolile-sulfolvl amino-pro~an -2 -one Following the procedure of Example except substituting "phenvi acetic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2beazvloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M lFr= 511.

Example 268 Preparation of N-4-pvridvl ace~yl-leuc inyl)- amino- 3 -N-(8-quinolinesu I fonvi )-amino-prop~an- 2 -one Following the procedure of Example except substituting "4pyridyl acetic acid" for "4-pyridyl acetic acid and "8-quinotine sulfonic acid" for 0 15 "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) oe 0:M+H=512.

Example 269 0*0 Preparation of N-4-pvyridyl carbonyl-leucinyl)-amino-3-N-(8-guifloliflesulfonyl)-amino-p2ropan-2-one Following the procedure of Example except substituting "4pyridyl carboxylic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: 000 *0 MS(ES) M+W= 498.

2 14 Example 270 Preparation of N-4-imidazole acervl-leucinvl)-arruino-3-N-(8-guinoiinesulfonvi )-arruno-propan- 2 -one Following the procedure of Example except substituting "4imridazole acetyl acid" for "4-pyridyl acetic acid "and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl suiphonyl chloride' the title compound was prepared: MS(ES) M+Wr= 501.

Exam~le271 go 10 Preparation of 1 N-3-phenyl p2ropionvl-Ieucinyl)-aznino-3-N-(8-guinolinesulfonyll-ario-r n-2-one Following the procedure of Example except substituting "hvdrocinnamic acid" for "4-pyridyl acetic acid and "8-quinolirie sulfonic acid" for IS benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 5 Preparation of bis-N.N'-( N-4-1pvrdvl methyleneoxy carbonyl-leucinyfl)-1.3- *006 diamino-propan-2-one Following the procedure of Example 37, except substituting "4-pyridylmethyleneoxy-carbonyl-leucinyl for "Cbz-leucine' the title compound was so".

prepared: MS(ES) 585.

Example 273 2 5 Preparation of bis-N.N'-( N-3-pyrdvl methyleneoxy-carbonyl-leucinvl)- 1.3diamnino-propan-2-one Following the procedure of Example 37, except substituting "3-pyridylmethyleneoxycarony1-leucinyl for "Cbz-leucine" the title compound was prepared: MS(ES) M+W= 585.

2 Example 271 Preparation of bis-N.N'- N-2-pyridyl methyleneoxv carbondj-euciny- diamino-pran4 -2-one Following the procedure of Example 37. except substitutingc, "I-pvridvlmethyleneoxy-carbonyl-leucinyl for "Cbz-leucine ",the title compound was prepared: MS(ES) M+W= 585.

Example 275 Preparation of I N-Cbz-leucinyl)-amrino-3-N-(2-benzvloxvenzoyl)aminopropan-2-one Following the procedure of Example 229, except 2-benzyloxy-benzoic acid' for "8-quinoline-carboxylic acid the tide compound was prepared: MS(ES) NI +H0546 M 546 15Example 276 :Preparation of I N-Cbz-leucinvl)-aino-3-N-(-bienlxcy.nl),amno.

prgan-2on Following the procedure of Example 229, except "3-bpenylx bceni-cid a'for '8-quinoline carboxylic acid the tie compound was prepared: MS(ES) 2 54.

216 Example 278 Preparation of 1 N-Cbz-leucinvl )-arnino-3-N-( 2-carboxvrnethyl-thiophene-3sulfonyl)-amino-propan-2-one Following the procedure of Example 5 1, except substituting "2carboxymethyl thiophene-3-sulfonyl for '4-(3-Chloro-2-cyano-phenoxy)-phenvI sulfonyl chloride", the title compound was prepared: MS(ES) M-H'=540.

Example 279 Preparation of 1 N-Cbz-leucinyl )-arrino-3-N-methyl-N-( N-Cbz-leucinyl amino-p2ropan-2-one a) N-(Cbz-leucinyl)-amino-propene :N-Cbz-leucine (3.0g, 11.3 mnmol) was dissolved in DMF (50 ml), then NVM 12.4 mniol) was added, followed by allyl amine (0.65g, 0.85 mamol), 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, :0 *:filtered, concentrated, and chromatographed (silica gel, 40% EtOAc: hexanes): MS(ES) M+Wr= 305.

b) N-(Cbz-leucinyl)-amino-propene oxide 20 N-(Cbz-leucinyl)-amino-propene (2.95g, 9.7 mmol) was dissolved in methylene chloride (100 ml), then mCPBA (5.0g, 29.1 rMMol) was added and the reaction was stirred overnight. The reaction was diluted with saturated aqueous 0 sodium bicarbonate, extracted with EtOAc, dried with magnesium sulfate, filtered, ::concentrated, and chromatographed (silica gel, 50% EtOAc: hexanes).

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

d) N-Cbz-leucinvib-arrino-3-.N-meihvli-N-, N-Cbz-leucinvl .)-anlno-proparn-2one Following the procedure of Example 229(a), except substituting "Il-N-i'Cbzleucinvl)-amrino-3-N-rnethyl-ami no-propan-2-ol for 8 -quinoline carboxylic acid ,the ritle compound was prepared: MS(ES) N4+H-l= 597.

Example 280 Preparation of N-Cbz-leucinvl)-amjno-3-N-methvl-N-( N-4-pvyridylmethvloxy-c arbonylI- leuci nv I)-amin o-1rop~an- 2-one Following the procedure of Example except substituting '4pyridyi-methyleneoxv-c arbonyl leucine for "Cbz-leucine" in the title 0:0 090 compound was prepared: MS(ES) 598.

:Example 281 :15 Preparation of N-Cbz-leucinfl)-arrino-3-N-methyl-N-(2-dibenzofuransulfonyl)-amino-p2ropan-2-one 5 Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for 'Cbz-leucine and HBTU" in the tidle compound was prepared: MS(ES) M+W=580, M+ Na+ 602.

Example 282 ~Preparation of I1-N- methyl- I- N-Cbz-leucinyl)-amino-3- N-(2-dibenzofuransulfonyl)-arnino-propan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for "Cbz-leucine and HBTU" in the tidle 5 compound was prepared: MS(ES) M+1-V=580 218 Example 283 Preparation of I methyl- I N-Cbz-leucinvl)-amino-3- N-(2-dibenzofuransulfonvl)-amino-propan-2-one Following the procedure of Example except substituting 2 dibenzofuran 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.

Example 284 Preparation of 1 -N-(2-dibenzofuran sulfonvl)-N-methyl)- arnino-3N-(N-4-pyridvl methyleneoxy carbonvl-Ieucinyl)-amino-propan- 2 -ofle Following the procedure of Example except substituting "4yridvl methyl amine" for "allyl amine" and "2-dibenzofurani sulfonyl chloride" for :"N-Cbz-leucine" in step and N-4-pyridyl methyleneoxy carbonyl -leucinyl for e 15 "N-Cbz-leucine and HBU" in step the title compound was prepared: MS(ES) M+H'=58 1.

Exaple28 *Preparation of I N-Cbz-Ieucinvl)-armno-3-N-( 4-pyrdyl-methylene)-3N-( N- 20 Cbz- le uciny D-an-ino-propan-2 -one Following the procedure of Example except substituting "4pyridyl methyl amine for "methyl amine" the title compound was prepared: MS(ES) 674.

Preparation of I -N-(Cbz-leucinyl)-amino-3-N-(4-pyyri-methylefle)- 3

N-(

2 dibenzofuran sulfonyh)-amino-propan-2 -one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride "Cbz-leucine and 1{BTU" in step the title compound was prepared: MS(ES) M+H'=657.

Example 287 Preparation of I -N-(Cbz-leucinvl -arrno-3-N-(4-pyrndy-methylene dibenzofuran sulfonx'I -amino-propan-2-one Following the procedure of Example except substituting'dibenzofuran sulfonyl chloride "Cbz-leucine and 1-BTLJ" in step the Litle compound was prepared: MS(ES) M+H .=657.

Example 288 Preparation of I -N-(4-biphenyl acetvl)-amino-3-N-(4-pvyridvl-methylene)-3N-( N- Cbz-leucinvl)-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 amaine", the title compound was prepared: MS(ES) M+W=62 1.

15 Example 289 Preparation of I -N-(4-p2henoxv-benzoyl )-amyino-3-N-(4-pvyridyl-methylene N- Cbz- leuciny I)-amino-propan- 2-one Following the procedure of Example except substituting "4- 0***phenoxy benzoic acid for "Cbz-Ieucine in step "4-pyridyl methyl amine "for "methyl amine", the title compound was prepared: MS(ES) M+W= 623.

Example 290 Preparation of 1 -N-(2-dibenzofuran-sulfonyl)-amino-3-N-(4-pvyridyl-methlene)- 3N-( N-Cbz-leuciny)- amnino-p2ropan- 2-one Following the procedure of Example except substituting "2- 0 dibenzofturan sulfonyl chloride for "Cbz-leucine and HIBTU" in step "4-pyridvi methyl amine" for "methyl amine", the title compound was prepared: MS(ES) 657.

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

The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein 15 comprise the state of the art and are incorporated herein by reference as though fully set forth.

e...e 221

Claims (20)

1. A compound according to Formula VIII: R 43 0 R4 R38 N C" N 3 R N if 4 R H 0 R 40 R 4 wherein: mnis 0, 1, 2; R 32 is OCH 2 Akr, OCH2C 1 6 alkyI, aryl substituted C 0 6 alkyI, heteroaryl substituted C 0 6 aIlcyI,4-imnidazole methylene; or 4- *0.:p)Tidylmethylneneoxy,

4-pyridyl methytene, 2-pyridyl sulfonyl, 4-pyridyl, .:aryl C 0 6 alkyloxy, or heteroaryl substituted C 0 6 alkyloxy, R 33 is C 1 6 alkyI, -CH 2 Ph. -CH 2 CH 2 CO 2 R 34 *R 3 4 is -Hj, C 1 6 alkyl; R 38 is Cbz; CI- 6 alkyl or aryl substituted Cbz; CI- 6 alkyl -GO; benzoyl; C 1 6 alkyl or aryl sub)stituted benzoyl:, 222 R3' 9 is FZ2 H R 2 N m 0 s~ N 0S1 R 33 H 0 ~34 0 0 0 rNi Me -s '0 S N d'o 9 0 0 OCH 2 Ph Et 2 s Cbz-leucinyl-; or 4-pyridvi. meiyloxycarbonyl-leuciyl-; 4-imidazole acetyl-leucinyl-, phenyl acetyl-leucinyl, N,N-dimethyl-glyciflyl leucinyl, 4-pyridyl acetyl-leucinyl, 2-pyridyl sutfonyl-leucinyl, 4-pyridyl carbonyl-leucinyL, acetyl-leucinyL, benzoyl-leucinyl, 4-phenoxy-benzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyL, alpha- isobutyl-biphenyl acetyl, Cbz-phenylalaninyl, Cbz-norleucinyl-, Cbz-norvalinyl-, Cbz-glutamy1-, Cbz- 223 epsilon-(t-butyl ester)-glutamyl:, aceryl-leucinyl-, 6- or 8- quinoline carbonyl, biphenvi acetyl. alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl 4-phenoxy benzoyl-, Cbz-ammio acid-; or 4- pN.TidyfI-nethylo~xvcrbonlY-amifloacid-; aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroar I C-C~alkyloxy carbonyl-amino acid-, aryl Cij-C 6 alkyloxy carbonyl-amino acid-,heteroaryl Cij-C 6 alkyloxy carbonyl-amnino acid-, C 1 C 6 alkyloxy carbonyl-amino acid-; Cl-C 6 alkyI carbonyl, aryl CO-C 6 alkyl carbonyl, heteroaryl CO-C 6 alkyl carbonyl, aryl C 0 -C 6 alkyl carbonyl, heteroaryl CO-C 6 alkyI carbonyl, C 1 -C 6 alkyl sulfontyl, aryl CO-C 6 alkyI sulfonyL, heteroaryl CO-C 6 alkyl sulfonyl, aryl CO-C 6 alky1 sulfonyl, or heteroaryi C 0 -C~akvl sulfonyl;- R 40 is H or Cl- 6 a1kvIl; R 4 1 is H or C 1 6 alkNI: R 42 is C 1 6 alkyl, arNvi substituted C 1 6 alkyt or heteroaryl substituted C 1 6 alkyl; provided that R 42 is H when R 4 is C 1 6 alkyl, aryl substituted C 1 alkl, or hecteroaryl substituted C I- 6 alkyl; R4 is Cl- 6 akyl; artyl substituted CI- 6 alkyl, or hetero aryl substituted C 1 -Oakyl; provided that R 43 is H when R 4 2 is CI- 6 alkyl, any substituted Cj- or heteroaryl substituted CI- 6 alkl and pharmaceutically acceptable salts, hydrates, and solvates thereof. 2. A compound according to Claim 1 wherein R 43 is 2-dibenzofuranylsulfonyl. 3. A compound according to Claim 2 selected from the group consisting of: (S)-phenylmethyl 1.1[[3-[benzloxycarbonyleuciylY-amlhI-2-oxopropyll- I- *(benzy1)aminolrcarbonyli-3'-methylbut ,lcarbamate; (S)-phenylmethyl [1-[[[3-[(2-dibenzofuranylsufoflyl)aflifoI-2-oxopropylI- 3 (benzyl)aminoicarbonyll-3-mehylbutyllcarbatfate; (S)-pheiiykmethyl [1-[[[3-[(2-dibenzofralyisulfoflyl)aminoOF2-oxopropy]- 3 4 pyidinyhnethyl)aminolcarbonl-3-methylbutyllcarbamate; 1-[3[2dbnouaysloy~mnl2oorpl--4prdnlehl benzamide; (S)-phenylmethyl 1-f[[3-[(2-dibenzofuranysufolyl)alinoI-2-oxopropylF- 1-(4- pyridinyhnethyl)aminolcarbonylll-3-methylbutyllcarbamate; 224 1-N-(N-b ecnI-mn---4bpenisloy)a iopoa--n' N-Cbzleucilyl)amllo-3N(-bpeyi-suYfonyl)su'nponyla1-on N-Cbz-leucinl)-amflnol 3 3.-dienz oxy-phefylYIsufonyl)-amilo-propal2ofe; N-Cbz-IeuciflI)-ainin- 3 N-(3,4-iehx-hnl sufnl-rio-rpn2o N-b-ecnl-mn-'--25dclrthohn--ufnl-mn-rpn2oe one; N-b-ecnl-mn---8qiofn-ufnl-mn-rpn2oe N-b-ccn!)aio3N(-yiy-ufnl-mn-rpn2oe N--,viyaey-euiy)aio3N(-heoyhnls oy)amino propan-2 one; N--yiy-ufniluini-mn---4peoy phenyl-sufofl)-amin1fl propan-2-one: 1--Nmopoio-..n -ecny)aino3N(-peoy phenyl-sulfonyl)-aminofl ~~~~propan-2-one; pey-uff~)a~l propan-2-one-, N-ctlluiy)aio3N(-hnxypey-ufnl-mn-rpn2oe N-imidazole actlluiy)aio3N(-hnx-hnlsloy)ain-rpn 2-one; N-4-carboxym ethyl bezy-ecnl-mn---4phn~ypey-ufnl-nio propan-2-one; N-(N,N-dimethy-l glcnl-ecnl-mn---4-hnx-hnlsloy)aio propan-2-one;, I N--untn-ufnmd-ecnl-mno3N(-hnx-hnisloy)aio propan-2-one; N-b-ecni-mn---gqiofn-abnt-mn-rpn2oe N-b-ecnl-mn---6qiofn-abnl-mn-rpn2oe -ccni-mn---(-4bpey)4mty-poaaie-rpn2oe N-Cbz-1eucinY)-amno- 3 N( N-4-pyridyl-methyleleoxy carbonyl-leuciyl)-amflo- propan-2-one; N-b-ecnl-mn---bezy)a-n-rpn2oe 225 I-N-(N-4-1)ridI*-111etIeleo.\Y carbonl-euciflYi)-am ino-3-N-(4-pheno-pliey-sufoflI)' amino-propan-2-one'. N-3-pyridy-mediIe'eoxy cabnlluiy)aio3N(-hnx-hnl sulfonyI)-amino-propafl- 2 -ofle- sulfonyI)-amino-propafl-2-ofle- N---roybnoiluinl-mn---4peoy phenyl-sulforiyl)-amilo- propan-2-one; N-eNCzluiy)aio3N(-hnx-hnt sulfonyl)-amidno-propafl- 2 one; 4-phenoxy benzov1)-amino-3-N-(4-pheloxy-phenl sutfonyl)-amino-propafl 2 0fle, I--3peoybnol-mio3N(-hnx-hnl sulfonyl)-amino-propafl- 2 -ofle; 1-N-(4-biphenyl actI-mn---4peoypenisloy)a-n-rpn2oe I-N-(2-benzyloxyv benzovI )-amino-'3-N-(4-pheloxy-phenl sulfonyl)-amiflo-propafl- 2 0le, N-b-ecni-mn---4bnyoybnol-mn-rpn2oe 2-one; pro*.-2-one N-4-pyridyl arboni-euciny)-amno-3-N2-bezyloxy phenyl-sulfonyl)-amio- propan-2-one; N-4-pyridyzle catnic-euciny)-amno-3N(2benzyloy- phenyl-sulfony)-aflfo- propan-2-one;, N-4-dizl cy leuciny)-amo-3-N-(2-beIOXYphe-ufnyl-lfloy)ai 9' *.propan-2-one; N-methyl lyecyl)amn-N(2bzyo- phntsloy)aio propan-2-one; N-(N-methyl piroldeinI-ammnl-eci)aio-3-N-(2-belIOYpenzyloxyifonylal- sutfonyl)-amino-propafl2-ofe; N-(N-methyl prtl-ecnt-mn---2dbnoua-ufnt-mn-rpn2 one; 226 N,N-dimethyl 91C')luill-tfi----(-iezfrnsloy)aio propan-2-one;. N-ezy-ec y),lito3N(-uioleslotl-mn- N-2, 5-difluoro-phenyl acetyl -luiil-mn---8qioesloy)aio propan-2-one; N-plieniyl iey-eiiii-ii~o3N(-unoicsloy)aiiop-pn2oe N-4-pyridyl acetvlIeucfi lI)-ainino-3-N(8(u~fiotiesulonyl)a11iiopro1an 2 one; N-4-pyTidyl ca-oy-ecnl-iio3N(-uiofi-ufnl-mn-rpn2 one; N-4-inidazole ac~ilu~y)a-io3N(-lhiti-ufnl-nn-rpn2oe bis-N,N'-( N-4-pyiridyl inelliveneoxy carbonyl-leuciflyl)- 1 ,3-diarnino-propan-2-one; bis-N,N'-( N-3-pyridyl ,neihyleIeieoxy-caboyl-euciilI)-1I,3-diatnino-Ipropani-2-one; bis-N,N'-( N-2-pyriclyl iethyleneoxy carbonyl-leucinyl)- 1 ,3-diatnino-propan-2-one; N-Cbz-leuciiiyl)-am iiiio-3-N-(3-beizyloxy-belzoyl)-amilo-propa- 2 -onle; *goo N-Cbz-Ieuciniyl)-am ii---2ci-oyuttl-iolee3 sulfonyl)-aminio-propan- 2-one; N-Cbz-Ieucinyl)-aiiiio-3-N-flitI1ylN-( N-Cbz-1eucinyl)-amno-propal- 2 -oflC; N-Cbz-leuciniyI)-aiino-3-N-itiethyl-N-( N-4-1pxTidyI-mediyloxy-carbonyl-eucinyl)- amlino-proIpdn-2-11C (-b-eciv)aiio--Nietyl-N-(-ieizfrn sulfonyl)-amino-)ropaf- 2 one; 1-N- methyl-I- N-Cbz-Ieucinyl)-ainiflo-3- N-(2-dibetizofuran- sulfonyl)-amino-propafl- 2-one; N-Cbz-Ieuciy)-iiinio-3-N-( 4-p~yridyl-mediylene)-3N-( N-Cbz-leucinyl)-anfo- propan-2-one; Os* :1-N-(4-biphenyl icetl)-,~iniio-3-N-(4-Iyridyl-teihylciie)-3N-( N-Cbz-leucinyl)-atinfo- propan-2-one; and 1-N-(4-phienoxy-beizo),)-aIll inio-3-N-(4-pyriidyl-niiethylene)-3N-( N-Cbz-Ieucinyl)-aminto- propan-2-one. -T P:\OPER\PDB\I 1180-97.DV2 2113/00 4. A compound according to Claim 3 known (S)-phenylmethyl[1-[[[3-[( 2 dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3- methylbutyl]carbamate. A compound according to Claim 3 known as (S)-phenylmethyl[1-[[[3- [benzyloxycarbonyl-leucinyl-amino]-2-oxopropyl]-1-(benzyl)amino]carbonyl]-3- methylbutyl]carbamate.

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

7. 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.

8. A method according to Claim 7 wherein said cysteine protease is cathepsin K. *o

9. 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. A method according to Claim 9 wherein said disease is osteoporosis.

10. A method according to Claim 9 wherein said disease is osteoporosdontitis.

11. A method according to Claim 9 wherein said disease is periodontitis.

12. A method according to Claim 9 wherein said disease is gingivitis.

13. 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. 228 P:\OPER\PDB\ I 180-97.DV2 27/3/00 goes see* see& so** 0O 1 0* S 1. S S e S OS.. 0**O S *S e 0* S SO

14. A method according to Claim 13 wherein said disease is osteoarthritis. A method according to Claim 13 wherein said disease is rheumatoid arthritis.

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

17. A use according to Claim 16 wherein said cysteine protease is cathepsin K.

18. Use of a compound according to Claim 1 in the manufacture of a medicament for treating a disease characterized by bone loss.

19. A use according to Claim 18 wherein said disease is osteoporosis.

20. A use according to Claim 18 wherein said disease is periodontitis.

21. A use according to Claim 18 wherein said disease is gingivitis.

22. 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.

23. A use according to Claim 22 wherein said disease is osteoarthritis.

24. A use according to Claim 22 wherein said disease is rheumatoid arthritis. 229