AU2260300A - Protease inhibitors - II - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

u Name of Applicant: Actual Inventors: SmithKline Beecham Corporation CARR, Thomas Joseph DESJARLAIS, Renee Louis GALLAGHER, Timothy Francis HALBERT, Stacie Marie MASHITA, Dennis Shinji THOMPSON, Scott Kevin VEBER, Daniel Frank YEN, Jack Hwekwo Address for Service: DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Protease inhibitors II Invention Title: The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\PDB\2272479.081 21/3/00 PROTEASE INHIBITORS This application is a divisional application derived from Australian Patent Application No. 11180/97. the entire contents of which are incorporated herein by reference.

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

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

Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, et al., (1996) J.Biol.Chem. 271, 12517-12524; Drake, et al., (199 6 J.Biol.Chem. 271, 12511-12516; Bromme, et al., (1996) J.Biol.Chem. 271, 2126-2132.

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

SCathepsins function in the normal physiological process of protein degradation in 0o animals, including humans, in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease.

Thus, cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi.

trypsanoma brucei brucei and Crithidia fusiculata: as well as in schistosorruasis, 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 A 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, S" thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes 15 remodelling at discrete foci throughout life. These foci, or remodelling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.

Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight 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 a the osteoclast secretes proteolytic enzymes. The low pH of the compartment :06 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 pnase 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 cystene proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example.

Delaisse, et al., Biochem. 1980, 192, 365, disclose a series of protease inhibitors in a mouse bone organ culture system and suggest that inhibitors of cysteine proteases leupeptin, Z-Phe-Ala-CHN2) prevent bone resorption, while serine protease inhibitors were ineffective. Delaisse, et al., Biochem. Biophys. Res.

Commun., 1984, 125, 441, disclose that E-64 and leupeptin are also effective at preventing bone resorption in vivo, as measured by acute changes in serum calcium in rats on calcium deficient diets. 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, 18, and Everts, et al., 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, et al., Biochem. Biophys. Res. Commun., 1995, 206, 89 and Shi, et al., FEBS Lett., 1995, 357, 129 disclose that under normal conditions cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.

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

Several cvsteine protease inhibitors are known. Palmer. 1995) J. .ed.

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

See Palmer, id, and references cited therein.

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

International Patent Application No. PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-11 convertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479).

Azapeptides which are designed to deliver the azaamino acid to the active S* 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 senne proteases. In addition, J. Med. Chem., 1992, 35, 4279, discloses certain s*o azapeptide esters as cysteine protease inhibitors.

25 Antipain and leupeptin are described as reversible inhibitors of cysteine protease in McConnell et al., J. Med. Chem., 33, 86; and also have bc -n disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its Ssynthetic 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.4,749,79 2 and 4,638,010).

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

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

Thus, a structurally diverse variety of cysteine protease inhibitors have been identified. However, these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor :II: 15 solubility, and overly rapid plasma clearance. A need therefore exists for methods 0 of treating diseases caused by pathological levels of cysteine proteases, including cathepsins, especially cathepsin K, and for novel inhibitor compounds useful in such methods.

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

SUMMARY OF THE INVENTION An object of the present invention is to provide hydrazidyl, bis-hydrazidyl 25 and bis-aminomethyl carbonyl protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.

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

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

In yet another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.

In a particular aspect, the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix 15 degradation, such as osteoarthritis and rheumatoid arthritis.

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

O

O*

II

20

D-C-

Q

"wherein:

D=

R R 22 3 21 l R 2 R-B- 0 R 23

H

H

0 N 0 0 0 0 j 3~ 8

N

RN

N

H4- -1 0* *e

S

S

S

S

*.SS

S.

S

S S OeSS SS S 5 5

S

S. S 5* 05

S

R

~N

0 R L49- R 12 0 It R1 26 N, NC tjR 4 N' N A 113 '24 R R 0 S. &S

S

5555

S

R31

HH

0 ~OR 3 5 N-IS-R 3 6 H 1 0 M 6 R63 S S *5 S 0 *SOSS9 0 R42 R 51 N~ -R 39 N' N, R 5

R

41 so 'where: 0 N -r A absent, Bz x ;y 0 R B. *e 0

B

t S S S *5 S B *0 5 V. S B S

S

L C2-) 6 alkvI. Ar-CO.

6 alkvl, He[-CO- 6 alkv1, CH(R 6 6

)NR

6

OR

6 8

CH(R

6 6 )Ar, CH(R 66 )OAr'. INR 6 6

R

6 7 M so),; z x-Y see* J so.); T Ar, Het; V =C3-7cvcloalkyl; W -CN, -CE 3 -N02, -COR 7 -C02)R 6

-CONHR

6

-SO-,NHR

6 -NHSO2R 6

-NHCOR

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 *5B5 5*

S

S

provided that at least cwo of X. Y and Z are ,iteroato,-S 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; mn 0. 1. 2; n =I to 6; (D 0, 1, 2; Ar phenyl, napbthyl, optionally substituted by one or more of Ph-CO- 6 alkyl, H-et-C 0 6 alkyI, C 1 6 alkoxy, Ph-CO 0 6 alkoxv, HeE-CO.

6 alkoxy, OH, 1 6

NR

5 8

R

5 9 O(CH7) 1 I 6

NR

5 8

R

5 9 Ar'= phenyl or naphthyl, optionally substituted by one or more of Ph-CO 0 6 aikyl, Het-CO 0 6 alkyl, C 1 -a~koxy, Ph-CO 0 6 alkoxv.

:Het-C 0 6 aLkoxy, OH, (CH 2 I 6

NR

5 8

R

5 9

O(CH

2 1 _6NR 5 8

R

5 9 or halogen; H, C I 6alkyl, Ar-CO-6alkyl. Het-CO 0 6 alkyl;, RI= H, C 1-6alkyl;.

R2= C4-6alkyl, C4.6alkenyl, benzyl; R3= CI..6alkyl, Ar-CQ-6alkyl, Het-C 0 6 alkyI, R 5 CO_, R 5

R

5

R

5

NI-CO-;

R4= H, C 1-6alkyl, Ar-C0-6alkyl, Het-CO..6alkyl;, Ar-0-6alkyI, Het-CO- 6 alkyl; R6= H, C 1-6alkyl, CH 2

CF

3 Ar-CO-6alkyl, Het-CO- 6 alkyl; C 1-6alkyl, Ar-CO..6alklcy, Het-CO-6all;

R

8 H; C2-6 alkenyl; C2-6alkynyl; Het; Ar; C 1-6alkyl, optionally substituted by OR', SR', NR' 2

CO

2

R',

CO-)NR'

2

N(C=NH)NH

2 Het or Ar; R9= H. C 1-6aikyl, Ar-CO-6.a~kyI, Het-CO- 6 alkyl; RIO C 1-6alkyl, A-r-CQ..6alkyl, Het-CO-6alkyl; C 1-6alk 1l. Ar-C I 6 akNvI. He[-C 0 6 alkvI, or R 1 6 R17 R9- R 2= H, C I 6 alkyl, Ar-CO.

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

6 alkyl; R1 4

N-R

9 R 7 2 ,c R1 H, C I 6 alkyl, C 2 6 alkenyl, C 2 6 alkcynyl, Ar, Het, or

C

1 6 alkyl optionally substituted by OR 9

NR

9 2 9

CONR

9 2 N(C=NH)NII-, Het or Ar; R1 C 2 6 alkyl, C 2 6 a~kenyl, C 2 6 alkynyl, Ar, Het, or C2- 6 alky1 10optionally substituted by OR 9

SR

9 NR2 C0 2

R

9

CONR

9 2 N(C=NH)NH-, Het or Ar; R =1 H, C 1 -all, C 2 -6alkenyl, C 2 6 alkynyl, Ar, Het, or C 1

.I

a6aLkyl optionally substituted by OR 9

SR

9 NR2 C0 2

R

9

CONR

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

R

17

R

7 2 H, CL..6alkYl, RIO, RIOC(O)-, RIOC(S)-, RIO0C(O)-;

R

2 1

R

2 6 C5-6alkYl; C2-6alcenyI; CM.. icycloalkyl; T-C3..

6alkyl; V-CI-6alky1; T-C2..6alkenyl; T- (CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR 2 0 0R 2 0

,NR

20

R

2 7 or Ci 1-4alkyl; :20 R 27

R

2 8 C0,R 8 00 R8= C 1-6alkYl; C3-. 11 cycloalkyl; Ax, Het; T-C 1.6allcyl; T-(CH2)nCH(T)(CH2)n; optionally substituted by one or two halogens, SR 2 0 0R 2 0

,-NR

20

DR

7 3 C I -6alkyl; R0= R 2 2

R

2 3

R

24

R

2 5

R

73 H, C 14alky1, Ar-C 0 6 alkyl, Het-CO 0 6 alkyl;

R'

9 R2

H

R 33

H

0 )y 00 00 s C..0 0 0 *0 0 S0 SCk% f 0 0 P EtO2 C C Cbz-leucinyl-; or 4-pyridyl rnethyloxycarbonvileucinyl-, 4-irnidazole aceryl-leucinyl-, phenyl acetyileucinyl, NN-dimethyl-glycinyl leucinyl, 4-pyi-idyl acetylleucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonylleucinyl, acetyl-leucinyl. benizoyl-leucinyl, 4-phenoxybenzoyl-, 2- or 3- benzyloxybenzoyl-, biphenyl acetyl, alpha- isobutyi-biphentyl acetyl. Cbz-phenylaaMnyl. Cbznorieucinyl-, Cbz-norvaiinyl-. Cbz-glutamyl-, Cbz-epsilon- (t-butyi ester)-glutamyl; acetyl-leucinyl-, 6- or 8- quinoline carbonyl. biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; or 4- pyridylmethyloxycarbonylaminoacid-; aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-am-ino acid-, aryl CO-C 6 alkyloxy carbonyl-amino acid-, heteroarvi CO-C 6 alkyloxy carbonyl-arniino acid-, C I

C

6 alkyloxv carbonyl-amnino acid-; C I-C 6 alkyI carbonyl. aryl

*.CO-C

6 alkyI carbonyl, heteroaryl CO-C 6 a.Lkyl carbonyl, aryl CO-C 6 all carbonyl, heteroaryl CO-C 6 alkyI carbonyl, 1 5 C C a k l s l o y a y O C a k l s l o y h t r a y 15 CO-C 6 alkyl sulfonyl, aryl CO-C 6 alkyl sulfonyl, heteroaryl

CO-C

6 alkyl sulfonyl; R3 C 1 6 alkyl; R32 H

N

0 R3

H

0 3 0 0 0 0 o *0 si Me I, 0 o 0 OCH 2 Ph

*SS@

C

*SS*

CCC.

S

5.-C

C

0 %%O 2 0 weC 0, *V C 0 Cbz-leucinyl-; or 4-pyi-idyl methyloxycarbonylleucinyl-; 4-imi~dazole acetyl-leucinyl-, phenyl acrylleucinyl, NN-imethyl-glycinyl leucinyl, 4-pyridyl acetylleucinyl, 2-pyridyl sulfonyl-leucinyl, 4-pyridyl carbonylleucinvi. acervl-leucinyl, benzoyl-leucinyl. 4-phenoxybenzoyl-, 2- or 3- benzvioxybenzoyi-, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, Cbz-phenvlalarnnL. Cbznorieucinyl-, Cbz-norvalinyl-, Cbz-glutarnyl-, Cbz-epsilon- (t-butyl ester)-gluramyl; acetyl-leucinvi-, 6- or 8- quinoline carbonyl, biphenyl acetyl, alpha- isobutyl-biphenyl acetyl, acetyl, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-amino acid-; or 4- pyridylmethyloxycarbonylamninoacid-; aryl CO-Calkyloxy carbonyl-amiino acid-, heceroaryl CO-C 6 alkyloxy carbonyl-amino acid-, aryl CO-C 6 alkyloxy carlbonyl-ami no acid-, heteroaryl CO-C 6 alkyloxy carbonyl-amidno acid-, C 1 I

C

6 alkyloxy carbonyl-amnino acid-; C I-C 6 alkyI carbonyl. ar-yl

CO-C

6 alkyl carbonyl. heteroaryl CO-C 6 alkyl carbonyl, *aryl C0-C6a.LRyl carbonyl. heteroaryl COCakl abnl C I-C 6 alkyI sulfonyl, aryl CO-C 6 alkyI sulfonyl, heteroaryl 0

-C

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

CO-C

6 a~kyI sulfonyl; R3 OCH 2 Ar, OCH2C 1 -6alkyI, aryl substituted CO- 6 alkyl, heteroaryl substituted CO-6alkyI,4-imidazole methylene; 2-, or 4-pyridylmethylneneoxy; 4-pyridyl methylene, 2pyridyl sulfonyl, 4-pynidyl, aryl substituted CO- 6 alkyloxy, heteroaryl substituted CO- 6 alkyloxy; R3= C 1 6 alkyI, -CH 2 Ph, -CH2CH 2

CO

2

R

34 R4= C 1 6 aikyI; R5= Ar, HetAr; R6= Aryl, heteroaryl, pyridyl, isoquinolinyl;

R

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

CH

2

CO

2

R

3 4 R8= Cbz; C 1 6 alkyI or aryl substituted Cbz; C 1 6 alkyI -GO; benzoyl; C 1 6 alkyl or aryl substituted benzoyl; R9= R2H H3 0 m o 0 o r 0 R34 0 o 0 0 0* 0N 0W 0 S0 0 0

S:

*IN s *so 0 0SC2P E 2- C'I"ucny- 3-Nr...iylmtylxcrbn lecnl;4-mdzl aey-eciy@Shny crl lecnl NNdmty-lcnSlucnl -yiy crl 10 lecnl Syiy ufnl.ecnl -yiy abnl lecn* ac£iluiybnolluiy,4peoy bNzy- 2- or 3-bnyoyezv in yactl alpha- isobutyl-biphenvi aceivi. Cbz-phenvlalaninvl. Cbznorleucinyl-, Cbz-norvalinyl-, Cbz-gYlutarnvl-. Cbz-epsilon- (t-butvl ester)-glutamyl,. acetyl-leucinyl-, 6- or 8- quinoline carbonyl, biphenyl acetyl. alpha- isobutyl-biphenyl acetyl.

ace',yI, benzoyl, 2- or 3- benzyloxy benzoyl, 4-phenoxy benzoyl-, Cbz-arni'no acid-; or 4- pyridylmethyloxycarbonylarninoacid-; aryl CO-C 6 alkyloxy carbonyl-ainino acid-, heteroaryl CO-C 6 alkyloxy carbonyl-amnino acid-, arYl CO-C 6 alkcyloxy carbonyl-amnino acid-,heteroaryl

CO-C

6 alkyloxy carbonyl-amrino acid-, C 1-C 6 alkyloxy carbonyl-amnino acid-; C 1

-C

6 alkyl carbonyl, aryl COC.ly caboyl heeory OColcabnl *a C-C 6 alky carbonyl, heteroaryl C-C 6 alky carbonyl, 15 C I-C 6 alkyI sulfonyl, aryl CO-C 6 alkyI sulfonyl, heteroaryl CO-C~alkyl sulfonyl, arYl CO-C 6 alkyl sulfonyl, heteroaryl

CO-C

6 alkyl sulfonyl; R0= H and C 1 6 alkyI; R41= H and C 1 6 alkyl; R2= C 1 6 alkyI, aryl substituted C 1 6 alkyI and hetero aryl susiue C- 6 alkyl,; H when R 4 3 isC- 6 alkyl, aryl substituted C I- 6 alkyl; and heteroaryl substituted C 1- 6 alkyl; .0 R43- C 1 6 alkyl, aryl substituted C 1 6 alkyl and hetero aryl 0 substituted C 1- 6 alkyl,; H when R 42 is C 1 6 alkyl, aryl substituted C I- 6 alkyI;, and heteroaryl substituted C 1 6 alkyl; R4= CH(R 53

)NR

45

R

54

CH(R

5 5 )Ar, C 5 6 alkYl;

R

4 5 R6= R7= R 4 8 R9= R0= R1= H, C 1 6 alkyI, Ar-C 0 6 alkyl, Het-C 0 6 alkyI; R2= Ar, Het, CH(R 5 6 )Ar, CH(R 5 6 )OAr, N(R 5 6 )Ar, C 1 6 alkyl,

CH(R

5 6

)NR

4 6

R

57 RD- C 2 6 alkyl, Ar-CO 0 6 alkyl. Het-CO 0 6 aikyl.

R

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

R

5 4 R5 R 4 7

R

4 7

R

4 7

R

4 7 0C(O);

R

5 5 R5 R 5 8

R

59 H, C 1 alkyl, Ar-C 0 6 alkyl, Het-C 0 6alkyl; R6=6 R2= R3= R4= H, C I 6 alkYl, Ar-CO 0 6 alkYl, or Het-CO..

6 alky1; R6 C 1 I 6 alkYl, Ar, Het, CH(R 6 9 )Ar, CH(R 6 9 )OAr, N(R 6 9 )Ar,

CH(R

6 9

)NR

6 lR 7 0 R6= R9= R1= H, C 1 6alkYl, (CH 2 0 6

-C

3 6 cYcloalkyl, Ar-CO 0 6 alkyl, Het-COJ.6allcyl;

R

6 7 C I 6 aikyl, (CH 2 0 6

-C

3 6 cYcloalkyl, Ar-CO-.

6 alkyl, Het-C 0 6 alkyl; R 6 6 and R 6 7 may be combined to form 15 a 3-7 membered monocyclic or 7-10-membered bicyclic carbocyclic or heterocyclic ring, optionally substituted with 1-4 Of C I 6 alkyl, Ph-CO- 6 alkyl, Het-CO- 6 all, Cj..

6 alkoxy, Pb-C- 6 alkoxy, Het-COJ..alkoxy, OH, (CH 2 1 6

NR

5 8

R

59

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),

R

6 2 0C(O)NR 5 9

CH(R

7 1 and pharmaceutically acceptable salts thereof.

The compounds of Formula I are hydrazidyl, bis-hydrazidyl and bisaininomethyl carbonyl compounds having in common key structural features required of protease substrates, most particularly cathepsin K substrates. These structural features endow the present compounds with the appropriate molecular shape necessary to fit into the enzymatic active site, to bind to such-active site, and to react with a sulfhydryl group on the active site, thereby blocking the site and inhibiting enzymatic biological activity. Referring to Formula 1, such structural features include the central electrophiic carbonyl, a peptidyl or peptidonumetic molecular backbone on either side of the central carbonyl, a terminal carbobenzyloxy moiety Cbz-leucinvl). or a mimric thereof, on the backbone on one or both sides of the carbonyl. and optionally, an isobutyl side chain extending from the backbone on one or both sides of the carbonyl.

R~ Compounds of Formula I wherein D =R and Q Nz aR are preferred embodiments of the present invention. For the a: sake of convenience, such compounds are referred to herein after as compounds of Formula IL.

10 More preferred embodiments of the present invention include compounds of Formula [I wherein: X=S, Y=CH, and Z=-N; X=CH, Y=S, and Z=-N; X=N, Y=N, and Z=-S; 15 X=N, Y=N, and Z=O; and X=N, Y=N, and Z--N.

Preferably R I is H, methyl or isobutyl. Preferably

R

1 is isobutyl.

Preferably

R

2 is isobutyl or benzyl.

Preferably R 3 is R 5 particularly benzyloxycarbonyl.

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

Preferably W is CN, NHR 6

SR

6

CONHR

6 or C0 2

R

6 Suitably'R 6 is H, C 1 4alkyl, phenyl or benzyl. Typically, W is CQ2H, C02-CI..4alkyl, C0 2 -Ph, C0 2 CH-,Ph, CONH 2 7, NH 2 or SH.

L Ll LJlvvv UlgU ui rUILIUlil 11 dic PdIxucularly prelerreU: (2S, I S)-2-(benzvloxvcarbonyl)amiuno-N-[ '-(2-carboxythiazol-4-yI)-3'merhylbutyl]-4-methylpentanamide; (2S. I S )-2-(benzyloxycarbonyl)amino-N-[ I -(2-carboxamidothiazol-4-yI)-3Ymethylbutylj-4-methylpentanamide; (2S, I'S)-2-(benzyloxycarbonyl)amino-N-I 1'-(2-carboethoxythiazol-4-yI)-3'methylbucyl]-4-methylpentanamide; (2S, 1'S )-2-(benzyloxycarbonyl)arruno-N-f [1'-(2-cyanothiazol-4-yl)-3'-Mediylbutylj.

4-methylpentanamide; (2S.1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(2-(N'-benzylcarboxan-tido)thiazol-4yII-3'-methylburyll--methylpenanamide;' (2,1'S )-2-(benzyloxycarbonyl)amino-N-( 1 methylpropyl)carboxamnidolthazol-4-yI)I-3'-rnethylbutyll-4-methylpentanan-ide; (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-( phenylethyl)carboxamido]thiazoI-4-y1)]-3Y-methylbuty]-4methylpentanamide; (2S,1 'S)-2-(benzyloxycarbonyl)aniino-N- (1 -(4-carboethoxythiazol-2-yl)-3'methylbutyl]-4-methylpentanamide; (2S,1 'S)-2-(benzyloxycarbonyl)am-ino-N-[ 1 '-(4-carboxythiazol-2-yl)-3'methylbutyl]-4-methylpernanamide; (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-( 1 '-(4-carboerthoxythiadiazol-2-yl)-3'methylbutyl]-4-rnethylpentanamide; (2S.1 IS)-2-(benzyloxycarboriyl)am-ino-N-[ 1 '-(2-carbo-2,2,2-triflu orocthoxythiazol- 4-yl)-3'-methylbutyl]-4-methylpentanaxnide; (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 '-(4-carboethoxyoxadiazol-2-yl)-3'methylbutyl]-4-methylpentanamride; (2S,1 'S)-2-(benzyloxycarbonyl-L-leuc jnyl)kaino-N-[ (1'-(4-carbaethoxythiazol-2-yI)- 3'-methylbutyl]-4-methylpentanaxmde; (2S, 1 S)-2-(benzyloxycarbonyl)amino-N-( I '-(4-carboxamridooxadiazol-2-yI)-3'methylbutyl]-4-methylpentanamide; (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-( 1'-(2-carboethoxythiazol-4-yl)-3'methylbutyI- 3-phenyipropanamide; 2S benzvloxvcarbonv I LIeucInvI)amnoN[ 2 -carboethoxvthzoI-4-vj J'-methyl butv 114-methyipentanrde, (2S.1 IS)- 2 -(benzyloxvcarbonyl)arinoN-[1'-(5-mercapto- I 2 4 -oxadiazoj-3-vI)-3'mechylbutyi-4-methylpentanarde; (2S, I 2 -(benzvloxvcarbony)aninoN( 2 -mercaptothiazoI-4-yi)-3..

znethylpentanamide; (2S, I 2 -(benzyloxycarbonyl)arruno-.N-( 2 -benzyloxycarbonylthiazolI4-yi- 3 mnethyl buryI14-methylpentanamide;

I'S)-

2 (bezyIoxycarbonyl)amno -mthy1..N-[3methylI (2S, I'S)- 2 -(benzyloxycarbony)amno-4mety.N-[3*methyI 1 (2R, 1'S)-2-(benzyloxycarbnyl)amino-N-[ 1 -(4-carboethoxythiazol-2-yl)ethy1I -4methylpentanarnide; *000*(2R, I 'R)-2-(benzyloxycarbonyl)arnino..N- 1 4 -carboethoxythiazol-2-yI)ethyl j-4methylpentananide; and (2S, 1 S)-N-f -aiohao--l-'mtybty]2(ezlxcroy~nio 4 -methylpentanamide.

0. 0 Most particularly preferred compounds of Formula HI are: (2S.1 'S)-2-(benzyoxycarbonyl)aino-N- l'-(2-carboethoxythiazoi.4-yl)-3'rnethylbuty]J4methylpentanarade; (2S, I'S)-2-(benzyloxycarbonyl)amino-N-[ lI (4-carboethoxythiazol-2-yl)-3'methylburyl]-4-methylpentananiide; and 2S, 1 S)-2-(benzyloxycarbonyl-Lleucinyl)aniio-N-( 1 -(4-carboethoxythiazol-2-yl)- 3 -methylbutyl].4-methypenana-ide.

R 0 N C 14 R BR 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 In.

With respect to compounds of Formula EII: Preferably B is So .o N-N N-N N

H

0 i-Bu

H

More preferably B is or

R

*1 Preferably Rl 1 is R'R'-N Preferably R 12 and R 13 are H.

R

1 9 Preferably

R

1 4 is N-R R Preferably R 15

R

16

R

18 and R 19 are Cl.

6 alkyl.

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

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

NO

2

SR

9

OR

9

NR

9 or C 1-4alkyl.

Preferably R 17 and R 7 2 are RIOOC(O)-; and more preferably R 10 is Ar-Ci-4alkyl.

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

Preferably R 17 and R 7 2 are Cbz.

One particular embodiment of the invention of Formula III is a compound of Formula F: R'1 6 0 R 1 9

R

17 .H N .R 72 N N H H H X=Y 0

F

wherein X, Y, Z, R 16

R

17 R1 9 and R 7 2 are as described in Formula I.

Most particularly preferred compounds of Formula II are: (I -benzyloxycarbonylalmno)-3-methylbutyljthiazol-2-ylcarbonyl]N'.

(N-benzyloxycarbonyl-L-leucinyl)hydrazide; N-benzyloxycarbonyl-L-leucinyl-N'-benzyloxycarbonylL-leucinylLleucinylhydrazide; and (1 -benzyloxycarbonyl amino)-3-methylbutyl thiazol-4ylcarbonyIN' (N-benzyloxycarbonyl-L-leucinyl)hydrazde.

RP

21 1 R

NN

Compounds of Formula I wherein D O and Q

R

2 N R 00 24 are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula IV.

A more preferred embodiment of the present invention is a compound of Formula IV wherein R 21 and R 26 are selected from the group consisting of: N-Cbz-leucinyl. N-Cbz-gIycinyI, N-acery1-leucinyl. N-Cbz-alanyl, 0 00 and R 22

R

23

R

24 and R 25 are H.

Particularly preferred embodiments of Formula TV are: 2,2'-(N.N'-bis-cyclohexylacery)carbohydrazide; 2,2'-(N,N'-bis-4-methylpentanoyl)carbohydrazide; 2,2'(N,N'-bis-cyclopentylacety)carbohydrazide; 2.'(,'bsbnyoyaboygyiy~abhdaie 2,*(,N-i-en*oycroy: aaylcroydaie and 2,'(,'bsbnyoyabny--ecnlcroyrzd is a most preferred embodiment of Formula IV.

R-N

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

In more preferred compounds of For mua V, when R 3 0 -C -C6 ailkyl, R 30 is preferably Me or -CH 2

CH

2 Me 2 When R 3 3 -C 1

-C

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

CH

2 Me2. When R 3 4

=-C

1

-C

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

Even more preferred embodiments of Formula V include: bis-(Cbz-leucinyl)- I ,3-dianiino-propan-2-ole; bis- 1. .3 (4-phenoxy -be nzoylI)-diamilo-propan- 2 -onle; I -(Cbz-Ieucinvl)-arn-ino-3- acetvl-leucinvyl)-arnino-propan-2-one- I -(Cbz-leucinyl)-ami no-3-(Cbz-glutamyl-t-butyl ester)-amnino-propan-2-one: I -(Cbz-Ileuciny I)-amino-3-(Cbz-gl utamyl)-amino- propan- 2-one; bis- 1 .3-(Cbz- leuc inyl) -di amino-(S) -bucEanone 2-one; 1I-(Cbz-Ieucinyl)-amino-3 -(Cbz-phenyl aanyl)-amino-propan-2 -onle I (Cbz-leucinyl)- amnino- 3-(Cbz- norle ucinyl)- amino- propan -2-one; I -(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amin-o-propal-2-one; bis- 1 ,3-(Cbz-Ieucinyl)-diamino-5-methyl-(S)-hexan-2-ofle; I -(acetyl-leucinyl)-amino-3-(4-phenoxy-benzoyl)-amino-propan-2-one; 1 -(Cbz-homo-leucinyl)-amrino-(Cbz-leucinyl)-3-amrino-propan-2-one; I -(Cbz- leucinyl)- amino- 3-(acetyl-Ileucinyl)- amrino-propan- 2-one is a most particularly preferred embodiment of the present invention of Formula V.

355 0 R a Compounds of Formula Iween 00 I

C

I Mo~ re preferaby 3 P, Crpried ebdien ote preent, 3 00

CI

=Ph, ON .Ph may be optionally substituted with CI..6alkyl, C 1 6 alkoxy, halogens and cyano groups. When R 35 pyridine, R may be 2-pynidyl, 3-pynidyl.

or 4-pyridyl.

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

Compounds of Formula I wherein D=

H

0 0 N,

R

37 0 0 0 R

N--

3 6 Hi11 and Q= 0 are preferred :embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula VII.

More preferably, R 3 6 is selected from the group consisting of: 00 Me 0% 0 0 0 0 C ON CI;, and R 3 7 Me in the more preferred compounds of Formula VII.

Particularly preferred embodiments of Formula VII are: 1 -(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-pheny sulfonamido)propan-2-one; 1 -(Cbz-Ieucinyl)- amino-3-(tosyl-amino)-propan-2-one; Cbz-Ileuciivyl-ano3 -(4peo -hni sfoaio-rpn oe Il-(Cbz- eucinyl)arno-3(2di benzofuransulfonanmjdo)..propan2 -one; I -(Cbz-homo-leucinyi )-ar ino- 3 2 -dibenzofuransulfonamido)propan-2one, and I -(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one, and I -(Cbzleucinyl)-amnino-3-(2 -di be nzofuransulfonarr~ido)(S)bu tan2 -one are most particularly preferred embodiments of Formula VII.

38 1 H 0* R ~Compounds of Formula I wherein D R and Q R 4 N RR 3 are preferred embodiments of the present invention. For the sake of convenience, such compounds are referred to herein after as compounds of Formula yin.

A more preferred embodiment of Formula VM is when R 4 3 -is 2dibenzofuranyisulfonyl.

Particularly preferred embodiments of Formula Vlf are: (S)-Phenylmethyl [1 (benzyloxycarbony!eucinyl-anino]-2-oxopropyl.. 1 (benzyl)amino~carbonyl-3-methybutycrarate.

(S )-Phenylmethyl (I 3 2 -dibenzofuranylsulfonyl)axnino]-2.oxopropyll-..

(benzyl)aminolcarbonyl]-3-methylbutycarbamate (S)-Phenylmethyl [1 3 2 -dibenzofuranylsulfonyl)aniino-2-oxopropyl]-3-(4.

pyridinylmethy)ainolcarbony].3methybuty]crbate 1- 2 -dibenzofuranylsulfony I)aminolI-2-oxopropylI- 3-(4-pyridinvmethv 1) benzamide (S)-Phenylmethyl [I -[[[3-[(2-dibenzofuranylsulfonyl)amino j-2-oxopropyl- pyridinylmethyl)amninojcarbonylj-3-methylbutyljcarbamate (S )-Phenylmethyl fl[1 1l3-R(2-dibenzofuranylsulforiyl)arninol-2-oxopropyi j- I -(4-pyridinylmethyl)aniinolcarbonyll-3-methylbutyljcarbamate is a most particularly preferred embodiment of Formula Uin.

R 48

NNJ

of Formula IX wherein:D0 R an 51

N

4 4

R

8 4

.R

0 adR 1 aeH 0N' 0 so R44 ACH(R)Ar, HR 0 O5,NR 0 )r HR 1

)RR

R3= ethyl, i-Bu; R4= R 4 7

R

4 7

R

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

R

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

NR

5 8

R

59

O(CH

2 1 6

NR

5 8

R

5 9 8 R5 9 H, C 1 6 alkvl. Ar-CO.

6 alkyl; Het-CO 0 6 alkyl.

are more preferred embodiments of the present invention.

The following compounds of Formula IX are particularly preferred: 2-[N-(N-benzyloxycarbonyl-L-leucinyl)I-2'-[N'-( 4 phenoxyphenylsulfonyl)Jcarbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-alanyl)]-2'-[N-(N-benzyloxycarbonyi-L- Ieucinyl)Icarbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-rN'-(4-phenylbenzoyl)]carbohydrazide; 2- [N-(N-benzyloxycarbonyl-L-Ieucinyl)]-2'-[N'-( 4 methoxybenzoyl)]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-( 4 phenoxybenzoyl)]carbohydrazide; 2-(N-acetyl)-2'-[N'-(N-benzyloxycarbonyl-L-Ieucinyl)Icarbohydrazide; alanyl)]carbohydrazide; 2-(N-(N-acetyl-L-alanyl)]-2'- [N'-(N-benzyloxycarbonyl-Lleucinyl)]carbohydrazide; 2- [N-(N-benzyloxycarbonyl-L-Ieucinyl)]-2'- dimethylaminomethyl)benzoyl)]]carbohydrazide; 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-hydoxy-[ 3 4 morpholinomethyl)] ]benzoyl]carbohydrazide;:.

2- [N-(N-benzyloxycarbonyl-L-Ieucinyl)]-2'-(N'- Ndimethylarninomethyl)benzyloxylcarbonyl-L-leucinyllcarbohydrazide; 2-(N-benzoyI)-2'-[N'-(N-benzyoxycarbony-L-euciny)]cabohydrazide; 2- (N-(N-benzyloxycarbonyl-L-leucinyl)]-24[N'-[I3-(4morpholinomethyl)benzoyl]]carbohydrazide; 2- 3-benzyloxybenzoyl)]-2'-[N'-(N-benzyloxycarbonyl-Lfeucinyl))carbohydrazide;, 2-[N-(N-benzyloxycarbonyl-L-Ieucinyl)1-2-N'-4-[3-(N-N-dimethylailo)- I1propyloxv]benzoyl]Icarbohydrazide;, 28 leucinyl)Jcarbohydrazide; 2 N-(N-benzyloxycarbofl-Lleuciflyl) [3 pyridylmethoxy)belzoyI]Icarbohydazide; Ieucinyl)]carbohydrazide; 2-[N-(N-benzyIoxycarboflL-leucifl)fl 2 methoxy)benzoyIcarbohydrazide; 2-N(-ezlxcroy--eciy)-'-N-3bnyoy45 dimethoxy)benzoy1]carbohydrazide; ethoxy)benzoyl]carbohydrazide; 2-[N-(N-benzyioxycarbonylglycifl]- 2 '-[N'-(N-benzyloxycarboflyl-Leucinyl)Icarbohydrazide, 2-[N-(3-benzyoxybenflZY)I-2'- [N'-(N-benzyloxycarboflyl-Lprolinyl)Icarbohydrazide; *24[N-(N-benzyloxycarbonyI-L-Ieuciny)- 2 4 phenylphenylacecyl)]carbohydrazide; (2S--N(-ezlxbaol]2-N-Nbnyoyabnl2 aminobutyiyl)]carbohydrazide, phenylphenoxy)propiofyl]carbohydrazide; 2-N(-ezlxbnol12-N-4mtypnaol]abhdaie (2RS, 2'RS)-2,2'-[NN'-f[bis-[2-(4-pheflphe~flY) 4 methylpentanoylffllcarbohydrazide; (2'RS)-2-[N-(N-bcnzyloxycarbonyI-L-ieucilyl)] -2'-[N-2-(4-phenylphelyl)- 4 methylpentanoyl)]]carbohydrazide; (2'RS)-2-[N-(3-benzyoxybeflzoyl)I- 2'-[N'-[2-(4-phenylphelyl)-4methylpentanoyl)1]carbohydrazide; 2-(N-(S,-benzv loxvbenzovl)]-2'-fN-(N-benzylIoxycarbonyl-N-methyl-Lle ucinyl) Icarbohvdrazide; 2-[N-(3-benzvloxvbenzoyl)]-2'-[N'-[N-(2-pyridinylmethoxvcarbonyl)-Lle ucinyl lcarbohydrazide; -II[N-[3-(4-pyridylmethoxy)benzoyl]]-2'-IN'-IIN-(2-pyridinylmethoxycarbonyl)-Lleucinylilcarbohydrazide; (2RS)-2-[N-[2-(4-phenylphenyl)-4methylpentanoyl)]-2'-IN'-[N-(2pyridinylmethoxycarbonyl)-L-Ieucinyl] ]carbohydrazide; (N-(N-benzyloxycarbonyl-L-leucinyl)]-2'- [N'-(2-(4-phenylphenyl)-4methylpentanoyl)]Icarbohydrazide; 2)-(N-(N-benzyloxycarbonyl-L-Ieucinyl)]-2'-CN-(2-(4-phenylphenyl)-4methylpentanoyl)] Icarbohydrazide; 2-rN-(N-bezyloxycarbony1-L-leucinyl)I-2'- [N'-[N-(4-phenylphenyl)-N-(2methylpropyl)carbanioyl] ]carbohydrazide; 2.-[N-(3-benzyloxybenzoyl)]-2'-[N'-(N-methyl-L-leucinyl)carbohydrazide; 2- rN-a4-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-(N-methyl-Lleucinyl)]carbohydrazide.

165 Compounds of Formula I wherein D L-G and Q- R6 are preferred embodiments of the present invention. For the saki of convenience, such compounds are referred to herein after as compounds of Formula X.

With respect to Formula X: More preferably G is

S

N

S

More More is H. More preferably preferably preferably

CH

2

N

R

63 and R4are H and R 66 and R 69 are j-butyl.

R

65 is CH(R6 9

)NR

6 1 R 7 0, in which

R

6 9 is i-butyl and R 6 1

R

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

R

6 2 is N2 CH 2

H

2

N

Alternately,

R

6 5 is Ar or CH(R 6 9 )Ar, in which Ar in said R 6 5 group is 0 More preferably, L is CH(R66)NR6OR 6 8

CH(R

6 6 )Ar. NR 6 6

R

67

CH(R

6 6 )OAr',

R

66 is i-butyl and Ar in said L group is, Ar, or Het, in which ;01 N

N-S

N

W~e

N.

ii or or Het in said L group is 0* SS 5

S

S

g5SO 0 0 S 0S S

SS

0* 0 @0 0 S

SS

0 S0 2 More preferably L is NR 6 6

R

6 7 or CH(R 6 6

)R

6

GR

6 8 One particularly preferred embodiment is a compound of Formula G: 0 R6 H N R' 0 Ar x'-y a Gi Another particularly preferred embodiment is a compound of Formula H: R 60R 69 z H ~R 70

NH

R 6 x .y 0 0050 0 500S

S

0 0500 0 OSS0

S

0050 0@ 0@ S

S

000550 0 The following compounds of Formula X are most particularly preferred: -benzyioxvcarbonylamino)-3-methyibutyflthiazol-4viabnl-'(-hnxphniufnlhdaie (1 I -(N-benzyloxycarbony-L-leucinlanuno)-3me thy lbu tyllIrhiazol- 2 ylc arbony IlI-N-(N- benzy loxycarbon yl-L-le uc iny Ohydrazide (I -benzyloxycarbonylam-ino)-3-methylbutyllthiazol-4ylcarbonylj-N'-(4-phenylphenylacetyl)hydrazide; (1 I -benzyloxycarbonylamino)-3-methylbutyllthiazol-4ylcarbonyl]-N'-[3-(4-pryidinyhnethoxy)benzoyllhydrazide; N- (2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N'-(N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[N-(4-pyridinylniethoxycarbony)-L-leucifl]-N'-[2- 1,2,3-thiadiazol 4-yI)phenyl]thiazol-4.-ylcarbanyljhydrazide; N-[2-[3-(4..chlorophenylsulfonylmethyl)thien-2-yllthiazol-4-ylcarbonyl [N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; (IS ,2'RS 1-beazyloxycarbonylamino)-3-methylburyllthiazol-4ylcarbonyl]-N'-[2-(4-phenylphenylactyl)4-mthypeltaoyllhydrazide .:15 N-[2-(3-benzyloxypheny1)thiazo-4-ycarboflI-N'-[N-(2pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; (1 1 (4-phenylphenyl)-3-methylbutyl]thiazoI-4-ycarboflyl]-N'-[N- (4-pyridnymethoxycarbonyl)-L-leucinyl]hydazide; N-(2-(2-benzyloxyphenyl)thiazol-4-ycarbofl]-N'-iN-(4- .20 pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; N- [2-(N-rethy1-N-(4-phenylpheny)aminothiazo1-4-y1carbofl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; N-(N-benzyloxycarbony-L-euciny)-N'-2-(4-phelbelZ)thiazoI- 4 ylcarbonyl]hydrazide; N-f2-(4-phenylphenyibenzyl)thiazoI-4-ylcarbonyl]-N'-(N-(4pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; N-(N-benzyloxycarbonyl-L-Ieuciny1)-N'-[2-[N-(2-methylpropy1)-Nphenylaminolthiazol-4-ylcarbonyl]hydrazide; N- (N-(2-methylpropyl)-N-pheiylaminothiazol-4-ylcabofll-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyllhydrazide; N-(2-(2-benzyloxvphenvl thiazol-4-vlcarbonvl pyridinylmethoxycarbonyl)-L-leucinylhydrazide; 2 -benzyloxyphenyl)thiazo -4-ylcarbonyl]-N'-[N-(2pyridinylmethoxycarbonyl)-L-leucinylhydrazde N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N'-(2-( 2 benzyloxyphenyl)thiazol-4-ylcarbonylIhydrazide; 2- N-(2-methylpropyl)-N-phenylaminoNthiazo-4-ylcarbonyl]-N'-[N-(2pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; N-[2-[N-(2-methylpropyl)-N-phenylanothiazol4-ylcarbonyl-N'-N-(3pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide; and 2 -methoxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinylJhydrazide.

o D efinitions 15 The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are any covalently S*0 bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a *compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in .which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

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

Abbreviations and symbols commonly used in the peptide and chemical arns are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the [UPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). The term "amnino acid" as used herein refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

"Cl-6alkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any Cl-6alkyl group may be optionally substituted independently by one *or two halogens, SR', OR', N(R') 2

C(O)N(R')

2 carbamyl or C[-4alkyl. where R' is Cl-6alkyl. C 0 alkyl means that no alkyl group is present in the moiety. Thus, Ar- 15 C 0 alkyl is equivalent to Ar.

"C

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

"C

2 6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons 20 wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.

C2-6alkenyl includes ethylene, I-propene, 2-propene, 1 -butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.

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

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

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

NR

5 8

R

5 9

O(CH

2 )1- 6

NR

58

R

5 9 where R 58

R

59 H. C 1 6 aMkyI: Het-CO 0 6 aikyl, from C 1 4 a~kvl, OR'. SR', CF 3 NO02, CN. CO-)R, CON(RI) F, Cl, Br and 1.

As used herein "H-et" or "heterocyclic" represents a stable 5- to 7 -membered monocyclic or a stable 7- to 1O-membered bicyclic heterocyclic ring, w hich is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatorns selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatorns may optionally be oxidized, and the nitrogen heteroatom may optionaly be quatemnized, 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 heteroatom or carbon atom which results in C the creation of a stable structure, and may optionally be substituted with one or two moieties selected from Cj..4alcyl, OR', N(R') 2 SR', CF 3 N0 2 CN, CO 2

R',

F, Cl, Br and 1, where R' is Cj.6akyl. Examples of such heterocycles :include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2 -oxopiperidinyl, 2oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl.

pyrazolyl, pyrazolidinyl, iniidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, rhiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzirnidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiarnorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

"HetAr" or "heteroaryl" means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, pyridine, It wil be appreciated that the heterocyclic ring described when N Z includes thiazoles, oxazoles, triazoles, thiadiazole s, oxaiazolcs, isoxazoles, isothiazols, imidazojes, pyrazines, pyridazines, pyrimidines, unazines and tetrazines which are available by routine chemical synthesis and are stable. The single and double bonds in such heterocycles are arranged based upon the heteroatoms present so that the heterocycle is aromatic it is a heteroaryl group). The term heteroatom as applied herein refers to oxygen, nitrogen and sulfur. When the heteroaryl group comprises a five membered ring, W is preferably an electron withdrawing group, such as halogen, -CN, -CF 3 -NOi, -COR 7 -COi)R 6

CONHR

6

-SO

2

NHR

6 -NHSO,2R 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 dicyclohexylcarbodiirnide, DMAP is 2,6-dimethylarninopyridine. EDC refers to Nethyl-N'(dimcthylaminopropyl)-carbodiimride. HOBT refers to 1hydroxybenzotriazole, DMEF refers to dimethyl formamide, BOP refers to 0 benzotriazol- I -yloxy-cxis(dimethylamrino)phosphonium hexafluorophosphate, too DMA is dimethylaminopyridine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)- I,3-dithia-.4-diphosphetane-24-disulfide, NNLM is N-methylmorpholine, TFA 0. 15 refers to trifluoroacetic acid, TFAA refers to trifluoroacetic anhydride and THF refers to tetrahydrofuran. Jones reagent is a solution of chromium trioxide, water, and sulfuric acid well-known in the art.

.0 Methods of Preparauion Compounds of Formula 11 wherein X CH. Y 5 and Z N. and CO"R. CN. or CO.YR'R may be conveniently prepared by methods analog:ous to hose described in Scheme I.

6*06 09,6 0O a Scheme O R 1 0 R' N OH a HWC'1 N2 HjH 0 0 b O R'1

H

0 O R 1

N

S

0

DN

H

A

1

N

'S

A4\ 0 00 00 @0 0 0 0 *000 0 0 0000 0@ 00 0 *0 S @000 60 0 00 00 0 00 0 00 @0

S

H

2 N N O3E D"a 0 00..

0 0000 *000 0006

S

@000 0 @000

S

0000 0g 0 0 000600 0 0

RI

D~NI N 0 N

CN

0ORi D N N OFj

HI

S

z 1 a) i-BuOCOCI, NMM. CH 2

N

2 EtOAc, Et 2 O; b) HBr, AcOH, EtOAc. Et 2 O; c) H2NCSCO 2 Et.

EtOH:, d) NaOH, H 2 0, 11-F; e) t-BuOCOCI, NMM, NH 2 Ti-F or BOP, Et 3 N. RNH 2

CH

2

CA

2 f) TFM,. pyridine. CH 2

CJ

2 g) R'OH, Boc 2 O, Pyridine or R 4 OH, EDCI, CH 2

CJ

2 h) pipenidine, OMF: i) BOP. Et 3 N, D-CO 2 H, CH~CI 2 I1-Scheme--I is treated with isobutyl chloroforrnate and N-methylmorpholine in ethyl acetate to give a mixed anhydride which is treated with diazomethane in ether to provide 2-ceeI The diazoketone is halogenated using 30% HBr in acetic acid in ethyl acetate/ether solution to provide 3-Scheme I. This material is treated with ethyl thiooxamate in refluxing ethanol to give 4-Scheme 1. The thiazole carboxylic ester is saponified by treatment with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 5-Scheme 1. The carboxylic acid is treated with isobutyl chloroformate and Nmethylmorpholine, followed by gaseous ammonia to provide primary amide 6- Scheme 1 (R 3 The primary amide is treated with TFAA and pyridine in dichloromethane to provide 7-Scheme 1. Alternatively, 5-Scheme 1 can be convenrted to substituted amides, 6-Scheme 1, by treatment with alkyl amines (such as benzylamine, 2-phenylethylamine or isobutylarnine) and a peptide coupling reagent (such as BOP, EDC*HC/1-HOBT or N-methylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichloromethane or DMF). The carboxylic acid 5-Scheme 1 can be convenrted to carboxylic esters 8-Scheme I by treatment with a primary or secondary alcohol (such as 2,2,2-trifluoroethanol, 15 isobutyl alcohol, benzyl alcohol or phenol) and a dehydrating reagent (such as DCC/DMAP, EDCI or Boc20/pyridine) in an aprotic solvent (such as dichloromethane or ether). When R 2 9-fluorenylmethoxy, treatment of 4-Scheme 1. with piperidine in DMF gives 9-Scheme 1. Treatment of 9-Scheme 1 with a carboxylic acid (such as N-Cbz-L-phenylalanine or N-Cbz-L-leucinyl-L-leucine) and a peptide coupling reagent (such as BOP) in an aprotic solvent (such as dichloromethane) provides 10-Scheme 1.

Scheme IA S S SMe S R'HN S H.Na b H 2 N N NH2 2N NH 2 H 2 2

H

2 3 R' H Rr N NHR' RR'N

Y

NH

4 a) Mel, THF; b) R'NH2,, i-PrOH; c) Bromomethyl ketone, EtOH Compounds of Formula HI wherein X CH, Y S and Z N are prepared by methods analogous to those described in Scheme IA. I -Scheme L A is treated With iodomethane in an aprotic solvent (such as TI-f) to afford 2-Scheme I A, which is treated with a primary amine in a protic solvent (such as isopropanol) to give 3-Scheme IA. this material is then treated with a brornomethyl ketone in a protic solvent (such as ethanol) to provide 4-Schemne IA.

Scheme 2 BocH -11 OH BocHN--' NH b BocHN N2 0 0 S 'BocHN -CO 2 Et H 2 N -C 2 Et 4 *0 F11 0 R' D .aN D N.

H C0Et' C0 2

H

z i-BuOCOCl, NMM, NH 3 THF; b) Lawesson's reagent, THF; c) BrCH 2

COCO

2 Et, TFAA, Pyridine, CH 2 C1 2 d) TFA; e) DCO 2 H, EDC-HCl, HOBT, Et3,N, DMF; f) NaOH, H 2 0, THF Compous of Formula H wherein X Y =CH and Z N mybe conveniently prepared by methods analogous to those described in Scheme 2. 1 Scheme .2 is treated with isobutyl chlorofortnate, N-methylmorpholine and ammonia in THF to provide 2-Scheme 2. This material is converted to the thioaxnide, Scheme 2 by treatment with Lawesson's reagent in an aproric solvent (such as THF or toluene). 3-Scheme 2 is converted to the thiazole by condensation with a aketoester bearing a suitable leaving group for displacement by a sulfur nucleophile (CL Br. 1, OMs, O-p-Tos) in dichioromethane. 4-Scheme 2 is treated with TFA to provide 5-Scheme 2. This material is treated with a carboxylic acid (such as N-Cbz- L-leucine, N-Cbz-D-Ieucine or N-Cbz-L-leucinyl-L-Ieucine) and a peptide coupling reagent such as BOP. EDC*HCIII-HOBT or N-methylmorpholine/isobutyl chlorofot-mate) in an aprotic solvent (such as dichloromethane, DMF 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'

RHN N C0Et a BocR'N N N C0OEt b R R 2 N N N R 2 R 0 R R.

2 4 15 a) Boc-amino acid, EDC*HCI, 1-HOBT. DMF; b) TFA; c) R 5 OCOC1, i-Pr 2

NEE

Compounds of Formula II wherein X =5S, Y CH and Z =N may also be prepared by methods analogous to those described in Scheme 2A. 1-Scheme 2Ais treated with a tert-butoxycarbonyl-protected amino acid (such as N-tertbutoxycarbonyl-L-leucine) and a peptide coupling reagent such as BOP, EDC*HCII1-HOBT or N-methylmorpholine/ispbutyl chioroformate) in an aprotuc solvent (such as dichioromethane, DMF or THE) to yield 2-Scheme 2A. which is treated with trifluoroacetic acid to provide 3-cen A This material is treated with a chloroforrnate (such as 2-biphenylmethyl chloroformate, 2-benzylbenzyl chloroformate, 2-naphthylmethyl chioroformate or 2-phenoxybenzyl chioroformate) and a tertiary amine base (such as diisopropylethylarnine) in an aprotic solvent (such as methylene chloride) to provide 4-Scheme 2A.

Scheme 3

H

2 N)NyK~ a )ocN .I OMe b 1 0 0 1 2 BocHN NHNH 2 BocHN N N CO 2 Etd 0 0 -4 BocHN S e

H

2

NJ

*0

RI

H II i 'E2

NN

a) Boc, 2 O, Et 3 N. THF; b) hydrazine hydrate, MeOH; c) EtO 2 -CCOCl, Pyridine,

CH

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

CI

2 f) DCO 2

H,

EDC.HCIHOBT, Et 3 N, DMF Compounds of Formula 11 wheremiX and Y N, and Z S may be conveniently prepared by methods analogous to those described in $cheme 3. 1- Scheme 3 is treated with di-tert-butyl dicarbonate and triethylamine in THE to provide 2-Scern 3 This material is treated with hydrazine hydrate in methanol to provide 3-Schemne 3. The hydrazide is acylated by treatment with ethyl oxalyl chloride and pyridine in dichloromethane to provide 4-Scheme 3. This material is converted to the thiadiazole, 5-Scheme-3, by treatment with Lawesson's reagent in an aprotic solvent (such as THE or toluene). .5-Scheme 3 is treated with TEA to provide 6-Scheme 3. This material is treated with a carboxylic acid (such as N-Cbz- 43 L-Ieucine) and a peptide coupling reagrent (such as BOP, EDC-HCIII-HOBT or Nmethvlmorpholine/isoburvl chioroformate) in an aprotic solvent (such as dichioromethane. DMF or THE) to yield 7-Scheme 3.

Scheme 4

H

0

N-N

F310 RI b H 2 N j) C 2 Et D D)N 0E N-N H J >-O 4 0

R'

d

\CONH

2 H

I//

NN

a) SOCl 2 pyridine, Et 2 O, toluene; b) TEA, CH 2 C1 2 c) DCO 2 H, EDC*HCIIHOBT.

Et 3 N, DM4F; d) NH 3 EtOH Compounds of Formula HI wherein X and Y N, and Z 0, and W CO2Et or CONH2 may be conveniently prepared by methods analogous to those described in Scheme 4. 1 -Scheme 4 is treated with thionyl chloride and pyridine in ether, followed by refluxing in toluene to provide 2--hee4 The resultant oxadiazole is treated with TFA to provide 3-Schme. This material is treated with a carboxylic acid (such as N-Cbz-L-leucine) apd a peptide coupling reagent such as BOP, EDC*HCIl-HOBT or N-methylmorpholinelisobutyl chloroforrnate) in an aprotic solvent (such as dichiloromethane, DMIF or THF) to yield 4-Scfieme 4. The carboxylic ester is treated with ammonia in methanol to yield 5-Scheme 4.

Scheme o R 2

R

5 N C0 2

H

H

1 1

H

2 N .(CO 2 Me a N C 0 R2 O e 5 N N 2 Me

H

0

R

0 R2 0 b

HNHNH

2 0

RI

C

4 0 A 2

N-N

A

5

J~HKK>SH

0 R 1 a) EDC*HCIIHOBT, Et 3 N, DMF; b) H 2

NNH

2

H

2 0, MeOH; c) CSCI 2 Et 3 N, CHC1 3 Compounds of Formula 1I wherein X and Y N, and Z 0, and W SH may be conveniently prepared by methods analogous to those described in Scheme 1-Schene 5 and 2-Scheme 5 are treated with a peptide coupling reagent such as BOP. EDC*HClII-HOBT or N-methylmorpholine/isobutyl chioroformate) in an aprotic solvent (such as dichioromethane, DMF or THF) to yield 3-Scheme 5. This material is treated with hydrazine hydrate in methanol to provide 4-Scheme Treatment of 4-Scheme 5 with thiophosgene and triethylamine in chloroform provides 5-Scheme Scheme 6 0 R 1 D )N

H

0 1 0 R 1 Br a D N N H i S H

S

b 2 0 R 1 D0 N HN H L H -NH

S

ft S 4 t* o S S 0

L

obeI o o eo 5* 5 6* *5 55

I

a..

5 a) H2NCS 2

NH

4 EtOH; b) H2NCSNH 2 EtOH Compounds of Formula II wherein X CH, Y S and Z N, and W SH or NH2 may be conveniently prepared by methods analogous to those described in 10 Scheme 6. 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 D N Br H 0 O R 1 D N b H 0 2 0 R1 D k N N H N

SCO

2

H

a) Et 2 NO; b) H 2

NCH

2

CH(NH

2

)CO

2

H

Compounds of Formula II wherein X CH. Y N and Z N and W=C may be prepared by methods analogous to those described in Scheme 7. Treatment of 1- Scheme 7 with diethylamine N-oxide should provide 2-Scheme 7. Condensation of 2-Scheme 7 with a 2,3-diaminocarboxylic acid should then provide 3-Scheme 7, which may be 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 whereiri 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.

O o N

H

a) i. i-BuOCOC1, NMM, TH; ii. CH 2

N

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

H

2

NCSCO

2 Et, EtOH; d) R 6 3

NHNH

2 EtOH; e) R 6 5 C0 2 H, EDC9HCI, I-HOBT,

DMF.

Compounds wherein X CH, Y S and Z= N, are prepared by methods analogous to those described in Scheme 22. 1-Scheme 8 is treated with isobutyl chloroformate and N-methylmorpholine in ether to give a mixed anhydride which is treated with diazomethane in ether to provide 2-Schemrne. 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 47 47 Scheme 8. The thiazole carboxylic ester is created with a hydrazine (such as hydrazine monohvdrate or methyl hydrazine) in ethanol to yield 5-Scheme 8. This material is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as EDC*HCVI-I-OBT) in an aprotic solvent (such as DMF) to provide 6-Scheme 8.

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

Scheme 9

LCO

2 H a. LCONH 2 b LCSNH, ffi /d N CO Et 1 2 3N2 S SH J.,jViec N "JR 6 L N CONHNH 2 L

N

50

H

6 (J =CO, S02) a) i-BuOCOC1, NMM4, NH 3 THF; b) Lawesson's reagent, THF; c) i.

EtO 2

CCOCH

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

NNH

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

CH

2

CI

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

1 -Scheme 9 is converted to 2-Scheme 9 by treatment with isobutyl chloroformate. N-methylmorpholine and amnmonia in THF. 2- Scheme 9 is treated with Lawesson's reagent in THF to provide the thioamide 3-cee9 This material is converted to the thiazole by condensation with an a-ketoester followed by treatment with trifluoroacetic anhydride and pyridine in methylene chloride to afford 4-Scheme 21 which is converted to 5-cen by treatment with hydrazine monohydrate. This material is treated with a sulfonyl chloride (such as 4phenoxybenzenesulfonyl chloride) and pyridine in an aprotic solvent (such as dichioromethane) to provide 6-Schemne 9. Alternatively, 6-Scheme 9 may be prepared by treatment with a carboxylic acid (such as N-benzyloxycarbonyl-Lleucine, N-benzyloxycarbonyl-N-methyl.L..eucine, N-(2pynidinylmethoxycarbonyl)-L-leucine,. N-(3 -pyridinylmethoxycarbonyl )-L-leucine.

N-(4-pyridinylmethoxvcarbonyl)-L-leucine, 4-biphenylacetic acid, 3-(4pyndinylmethoxy)benzioc acid. or 4-methvl-2-(4-phenylphenyi)penranoic acid) and a peptide coupling reagent (such as EDC*HCII-HOBT) in an aprotlic Solvent (such as DMF).

R9 Compounds wherein B 0 R 1 are prepared by routine methods of peptide synthesis as illustrated for instance by Scheme Scheme R1 R 6

R

16 H2N C E a R "N N CO 2 Et H 0 R1 16 211 H H H H 0 R' 0 Rt' 5 0 4 a) EDC*HCI, HOBT, DMF; b) H 2 N1NH 2

*H

2 O. EtOH; c) R' 4 -B-CO2H, EDC*HCL, HOBT, DMFf Treatment of a mixture of I -ScherneL1 and 2-Schene -1 with a peptide coupling reagent (such as BOP or EDC-HCII1-HOBT) in an aprotic solvent (such as DMF or dichioromethane) provides 3-S~me 10. This material is treated with hydrazine hydrate in ethanol to yield 4-Sheme 10, which is treated with a carboxylic acid (such as N-Cbz-L-leucine) and a peptide coupling reagent (such as BOP or EDC.HCI/I-HOBT) in an aprotic solvent (such as DMF or dichioromethane) to provide 5-Scheme Compounds of Formula IV wherein R2 2

R

23

R

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

Scheme 11 R H 0 H

H

2 NHN NHNH 2

R

21 C0 2 H a N1 N N N 1 2 a) EDC.HCI, 1-HOBr, DMF Symmetric compounds of the Formula IX having RCO as the terminal substituerit on both sides are prepared by methods analogous to those described in 10 Scheme 11. Treatment of I1-Scheme I I with a carboxylic acid (such as 4biphenylacetic acid or 4 -methyl-2-(4-phenylpheny)enaoic acid) and a peptide coupling reagent (such as EDC-HCL'1-HOBT) in an aprotic solvent (such as DMF) provides 2-Scheme 11.

Nonsymmemrc compounds of the Formula IX, and compounds of Formula [V wherein R 22

R

2 3

R

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

Scheme 12

H

RACO

4 a 0 OHH2 b N-N

C

2 R 0 0 R "N A N N 2 de r 1 R N N' NNg o H 0 H H (F C0R 52 S 2

R

52 a) H NNH 2

H

2 MeOH; b) CICO PhMe; c) H NNH 2 HO Me- d) 4 9

CHEDHI

1 -HOBT, DMF; e) R 52 S0 2 C1 or R 52 COCI, pyddine, DMF; f)R 52 C0 2 C0R 52 g) R52C0NR 5 1

NH

2 Treatment of 1 -Schemne 12 with hydrazine hydrate in a protic solvent (such *as methanol or ethanol) provides 2-cee1 which is treated phosgene in toluene to afford 3-cem 2 This material is treated with hydrazine hydrate in a protic solvent (such as methanol or ethanol) to provide 4-Scheme.J12 Treatment of 4- Scheme 12 with a sulfonyl chloride (such as 4-phenoxyphenyisulfonyl chloride), an acid chloride (such as benzoyl chloride), or a carbamnoyl chloride (such as N-(2methylpropyl)-N-(4-phenylphenyl)carbanioyl chloride) and pyridine in DMF affords 5-cem-2 Alternatively, 5-Sckmn-IZ may be prepared by treatment of 4-Sherne12 with a carboxylic acid (such as N-benzyloxycarbonyl-L-alamine, Nbenzyloxycarbonyl-L-proline, N-benzyloxycarbonylglycine, benzyloxydarbonyl-2-aminobutyric acid, N-benzyloxycarbony-N-methyl-L-leucine, N-tert-butoxycarbonyl-N-methyl-L-leucine, N-acetyl-L-leucine, N:-acetyl-L-alanine, N-(2-pyridinylmethoxycarbonyl)-L-leucine, dimethylaininomethyl)benzyloxycarbonyl-L-leucine, 4-phenylbenzoic acid, 4methoxybenzioc acid, 4-phenoxybenzoic acid, 4-(NNdimethylaminomethyl)benzoic acid, 4-yrx--N(-opoioehllezi acid. 3-[N-(4-morpholinomethyl)Ilbenzoic acid, 2-benzyloxybenzoic acid, 3benzyloxybenzoic acid, 4-benzyloxybenzoic acid, 4-(3dimethvlaminomethvlpropoxv benzoic acid. 3-benzvloxy-5-me thoxvbenzoic acid.

3 -be nzylox y-4,5 -dime thoxy be nzoic acid. 3-benzyloxy-5-ethox ybenzoic acid, 3-(4pyrxdinylmethoxy)benzoic acid, 4-biphenviacetic acid, 2-(4p hen ylphenoxy)propionic acid or 4-methyl-2 4 -phenylphenyl)pentarioic acid) and a peptide coupling reagent such as BOP, EDC-HCI-HOBT or Nmethylmorpholine/isobutyl chloroformate) in an aprotic solvent (such as dichioromethane, DMF or TI-F). 5-Scheme- 12 may also be prepared by treatment of 4-Scheme 12 with an anhydride (such as acetic anhydride). Alterniatively, 3- Scheme 12 may be converted directly to 5-Scheme- I by treatment with a hydrazide (such as 4-methylpentanoyl hydrazide -or N.methyl-N-benzyloxycarbony-L.

leucinyl hydrazide).

Scheme 12A

R

R2 RCONHNH 2

R

2 1

CONHNHCH

2 R R21.11 H 0 H 0 H R21N). d1or R 2 1 R N N A'NHNH 2 deorfR1 Y N N N IN, X I I 0 0 H H 4 (RCH 2

R

23 j5 (X C0R 52

SO

2 R%2 a) L. PhCHO, EtOH; ii. BH3*THF; b) CI 2 CO, PhMe; c) H 2

NNH

2

H

2 0, MeOH; d) R52C0 2

H,

EDCQHCI, 1-HOBT, DMF; e) R 52 80 2 CI or RS 2 0CI, pyridine, DMF; R1) RC0 2 C0R 52 Nonsymmetric compounds of Formula rV, wherein R 2 3 H are prepared by methods analogous to those described in Scheme 12A. I1-Scheme 12A is treated with an aldehyde (such as benzaldehyde) in a protic solvent (such as ethanol) and the resulting irnine is treated with borane-TI{F complex to afford 2-Scheme 12A, which is subsequently treated with phosgene in toluene to afford 3-Scheme 12A.

This material is treated with hydrazine hydrate in a protic solvent (such as methanol or ethanol) to provide 4-Scheme 1 2A. Treatment of 4-Scheme 1 2A with a carboxylic acid (such as N-benzyloxycarbonyl-L-leucine) and a peptide coupling 52 reagent such as BOP. EDC*HCI-HOBT or N-methvlmorpholine/isobutvi chloroforinate) in an aprotic solvent (such as dichioromethane, DMF or THF) to yield 5-Scheme-I 12A.

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

Scheme 13 00 HN OH 0 0 0 a) HBTU, NMM, DNIF; b) Jones, acetone I ,3-Bis-am-ido propan-2-ones may be prepared by acylation of I ,3-diaminopropan-2-ol 1-Scheme 13 with a carboxylic acid 2-SchemC.13 or a mixture of 2 different carboxylic acids (2 and 3) in equimrolar amounts and a coupling reagent such as a dialkyl carbodiirnide such as DCC or EDCI or HBTU/ N-methyl morpholine, followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

Scee1 2 S6 so S. N 010 a) NMM, DMIF; b) Jones, acetone 1 ,3-Bis-sulfonamido propaniones may be prepared by sulfonylatfon *of 1,3diamino-propan-2-olI I-Scheme 14 with a sulfonyl chloride 2-Scheme 14 and a base such as N-methyl morpholine. followed by oxidation of the carbinol to a ketone with an oxidant such as Jones reagent.

Scheme 0. C

ON

MI NM2 0 OI solo Q 3 0 H N

C

o CC *r C

S

et

C

S CCC a) EDCI, HOBT, DMF; b) NMM. DMF, 3) Jones, acetone I -Amido-3-sulfonamido propanones may be prepared by acylation of 1,3diarino-propan-2-ol I-Scheme 15 with a carboxylic acid 2-Scheme 15 and a coupling reagent such as a carbodiinilde 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.

0 0 rY% .z K H CU. 2: R.N 2 0 me 3: FPP9 4: R.N 3 N 01

H

0 m .L s. f 00 6 0 M19C1 CIO's J: L 0 0 Ntg~YY K c; 0 Me I1-Amjido-3-sulfonarrtudo alkan-2-ones that are larger than propan-2-one, such as burtan-2-one or 5-methyl-hexan-2-one, can be prepared by converting an Nprotected peptide such as Cbz-leu-leu-OH 1 -Schemne 16 co its bromo methyl ketone 3-Scheme 16 via a cliazo 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 1,3-propandithiol gives the free amine 6-Schemne 16. Acylation or sulfonylation of the amine gives amnide or sulfonamide 7-cem 6 Finally, oxidation of the carbinol with an oxidant such as Jones gives the desired compounds.

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

~Scheme 17 HO-< a b Nr^%-rOT- p 0 0y.O

ON

23 N 'f 'TOG P NS PPh

N

0 0 a) NaN 3 MeOH, H 2 0; b) Tosyl chloo~de, triethylamine, CH 2

CI

2

C)

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

NH

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

SH,

MeOH, Et 3 N; g) Cbz-leucine HBTU, N-methyl morpholine, NMP; h) TFA, CH 2 Cl 2 Me 2 S; i) Jones reagent, acetone Azide opening of glycidol 1 -Scheme 17, followed by tosylation of the primary alcohol gave tosylate 2-Scheme 17, which was coupled to Eliman polymer 3-Scheme 17 as described by described in 1. Med. Chem. 1995, 38, 1427-1430 to produce polymer 4-Scheme 17, which was reacted with benzyl amine in toluene.

then washed extensively with various solvents. Then, the azide was reduced with 1.

3 -propanedithiol in MeOH, triethylamine, then was washed extensively with various solvents. Coupling of Cbz-leucine 6-Scheme 17 with the diamine 17 with equimolar amounts and a coupling reagent such as a dialkyl carbodiimide such as DCC or EDCI or HBTU/ N-methyl morpholine. Cleavage of the ether linkage to an alcohol was accomplished with trifluoroacetic acid -with various scavengers. Finally, oxidation of the carbinol to a ketone 7-Scheme 17 with an oxidant such as Jones reagent provided the desired final product.

Scheme 18 0 0 s. 0o 2 3 bk rd..

a) 4-pyridyl methyl amine, isopropanol, reflux; b) Cbz-leucine, HBTU, N-methyl morpholine, DMF; c) hydrazine, MeOH, reflux; d) 2dibenzofuransulfonyl chloride, N-methyl morpholine, DMF; e) Jones reagent, acetone ~N-(2.3-Epoxypropyl)phthalimide I-Scheme 18 (Aldrich) was reluxed with 20 an amine such as 4-pyridiyl methyl amine in isopropanol. The secondary amine 2- Scheme 18 was then acylated with an acylating agent such as Cbz leucine or a sulfonylating reagent such as 2-dibenzofuransulfonyl chloride and base such as Nmethyl morpholine in DMF. The phthalimid6 was then removed with hydrazine in MeOH and the resulting free amine was acylated with an acylating agent such as Cbz leucine or a sulfonylating reagent such as 2-diberizofuransulfonyl chloride and base such as N-methyl morpholine in DMF.

Compounds of Formula IX may conveniently be made using methods analogous to those in Schemes 19 and Compounds of Formula X may be conveniently made using methods analogous to those described in Schemes 2 1-27.

LN~ CO 2 Et a LNC ICO 2

H

I.

R 6 C2Meb 0 65 CQNR 64N 2 0

ES

N

0 0 0*

*C.

a) KOH, MeOH/H2O; b) R 6 6

NHNH

2 EtOH; c) EDCeHCl, l-HOBT, DMF Compounds wherein X CH, Y Z =N and R4*H, are prepared by methods analogous to those described in Scheme 19. Carboxylic ester 1 -Scheme 19 is treated with a hydroxide base (such as lithoum hydroxide, sodium hydroxide or potassium hydroxide) in methanol/water to provide 2-chm 19 -cee1 is treated with a hydrazine (such as methyihydrazine) in a protic solvent (such as ethanol) to give 4-Scheme 19. 2-cee1 and 4Scheme 19 are coupled by treatment with a peptide coupling reagent (such as EDC*HCI/I-HOBT) in an aprotic solvent (such as DMF) to provide 5-cem 9 Scheme EtO CCOCH Br abN 4 2 CO 2 Et Br N CO2Et 12 3 c or d e e Ar N CO 2 Et r N CONHNH 2 H 0 NAN 6 Ar -SN

H

a) Thiourea, EtOH; b) i. NaNO 2 16% aqueous HBr, ii. CuBr, 16% aqueous HiBr; :iii. HBr EtCH; c) ArB(OH) 2 Pd(PPh 3 4 CsF, DMIE; d) ArSnMe 3 Pd(PPh 3 4 PhMe; e) l- 2

NNH

2

*H

2 0, EtCH; e) R 65 C0 2 H, EDC*HC1, 1-HOBT,

DMIF.

Compounds wherein X S, Y CH, Z N and V 2-methoxyphenyl or 2benzyloxyphenyl, are prepared by methods analogous to those described in Scheme Ethyl bromopyruvate (1-Schemne 20) is treated with thiourea in refluxing ethanol to provide 2-cem 0 which is treated successively with sodium nitrite and copper bromide in 16% aqueous HBr, and the product was heated in ethanol with a catalytic amount of HBr to give 3-cem 0 Treatment of this material with an arylboronic acid (such as 2-benzyloxyphenylboronic acid), tetraks(triphenylphosphine)pauladium(o) and cesium fluoride in refluxing DNM Il provides 4-cem 0 Alternatively, 4-cen 0 may be prepared by treatment of 3-cee2 with an arylstannane (such as 2-trimethylstannylanisole) and tetrakisczriphenylphosphine)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-leucine,

N-(

2 -pyridinylmethoxycarbonyl).Lleucine, N-(3-pyridinylmethoxycarbonyl)-Lleucine or N-(4-pyridinylmethoxycarbonyl)-L-leucine) and a peptide coupling reagent (such as EDC.HCIII-HOBT) in an aprotic solvent (such as DMF) to provide 6-Schemne Scheme 21 RCOCI a RCONHR 64 b RCH 2

NHR

6 7 C RCH 2

NR

67

CSNH

2 d 12 3 4 66~6,~,L/'CO~t66 7 N CONHNH R6 R 6 N "0E R66R67NN 2 s H 0 6 6 7 N R R R NW'N

I

0 H a) R 67

NH

2 Py, CH 2

CI

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

CI

2 ii. NH 3 MeOH or 1. PhCONCS, CHC1 3 ii. K 2 C0 3 MeOH. H 2 0; d) EtO 2

CCOCH

2 Br, 10 EtOH; e) H 2

NNH

2 eH 2 0, EtOH; e) R 6 5 C0 2 H, EDC.HCl. l-HOBT, DM[F.

Compounds wherein X S, Y. CH, Z N and V NR 6 6

R

6 7 are prepared *Pooby methods analogous to those described in Scheme 21. An acid chloride C Scheme 21) is treated with a primary amine (such as 4-arninobiphenyl or aniline) and pyridine in an aprotic solvent (such as rnethylene chloride) to provide 2-Scherne ~JIL which is treated with lithium aluminum hydride in THF to afford 3-Scheme Treatment of 3-Shem 2 with thiophosgene and pyridine in methylene chloride.

followed by treanment with ammonia in methanol provides 4-cem 1 Alternatively, 4-cee2 may be prepared by treatment of 3-Scheme21 with benzoyl isothiocyanate, followed by treatment of the intermediate benzoyl thiourea with potassium carbonate in methanol/water. 4-cee2 is treated with hydrazine hydrate in ethanol to give 5-Scheme 21. Treatment of 5-Schemne 21 with a carboxylic acid (such as N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-(3pyridinylmethoxycarbonyl)-L-leucine or N-(4-pyridinylmethoxycarbonyl)-Lleucine) and a peptide coupling reagent (such as EDC*HCII-HOBT) in an aprotic solvent (such as DMF) affords 6-cee21 59 Scheme 22

H

2 NCSCO 2 Et a~ 1 H 2 N i CO 2 Et

H

N-N

C

N 'rCONHNH 2d

N-N

H

I

H

L N 6 N H 0 a) H 2

NNH,)*H

2 O, EtOH; b) LCO2)CO-,i-Bu, 200 0 C; c) H 2 NNH-b.H 2 0, EtOH; d)

R

6 5 C0 2 H, EDCeHCI, I1-HOBT, DMF Compounds wherein X and Y N, and Z NH, are prepared by methods analogous to those described in Scheme 26. 1 -Scheme 22 is treated with hydrazine hydrate in ethanol to give 2-Scheme 22, which is heated with a mixed anhydride to provide triazole I-cem 2 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-HCI- HOBT) in an aprotic solvent (such as DNM to provide 5-Scheme-22.

9 1 Scheme 23 o H R 69 SH 0 R 6 1 o H R 6 9 N N M' R 62 H 0 R 6 0 H R 6 9 L b or c H 0 2(M CO. S0 2 9.

9.

*9 9 R 660 H 1 65 BocNRw N N YR H 0 R0 H a 30. HR N< N 11 N R 6 S

Y~

9* 9 9 4R 5 a) TFA; b) R 62 C0 2 H, EDC*HCl, 1-HOBT, DMF; c) R 62 S0 2 Cl, i-pr 2 N~t Comnpouinds wherein X S, Y CH, Z N, L CH(R 66 )NR6OR 68 where

R

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

)NR

6 lR 70 where R 70 Boc or Cbz are prepared by methods analogous to those described in Scheme 27. 1bnccme23 is 10 treated with trifluoroacetic acid to provide 2-Scheme 23. This mnaterial is treated with a carboxylic acid (such as pryazinecarboxylic acid, isonicorinic acid, 4irnidazolylacetic acid or pipecolic acid) and a peptide coupling reagent (such as EDC*HCI/I-HOBT) in an aprotic solvent (such as DMF) to provide 3-Scheme 23.

3-cee2 may also be prepared by treatment of 2-Shme 23 with a sulfonyl chloride (such as 2-pyridinesulfonyl chloride) and a terticary amine base (such as diisopropylethylamine) in an aprotic solvent (such as methylene chloride).

Alternatively, treatment of 4Schme 2 with trifluoroacetic acid provides Scheme 23.

Scheme 24

OH

HN 4H BNN CONH

OH

aON NH 2

I

0 HoN H~~I I 00 OCM'Ph N N, 0 0 OCH,Pti a a 5 a) EDCI, DMF; b) 2-PhCH 2 OPhSO 2 C1, NMM, DMF; c) TFA, DCM; d) 4-pyridyl acetic acid, HBTU, NMM, DMF; e) Jones I .3-Diamino-propan-2-ol (or an N-alkyl substituted diaxnino-propanol) is coupled to a protected leucine analog (either Cbz- or Boc-) and another carboxylic 10 acid or sulfonyl chloride. Removal of the protective group, followed by acylation or sulfonylation, and oxidation of the alcohol provides the desired compounds.

a a *..aaa Scheme Cbz-NH C0 2

H

a Cbz-NH b Cbz-NH

N,,

0 OH Me NI e IH Y lNHCbz 0 0 Cbz-NH YN"

N~

0 d

S

S. S S. S *5 0*

S

0 S S. S

S

0 Me H ")"Ii Cbz-NH N 0 0 a) HBTU, NMM, DMF, allyl amine; b) mCPBA, DCM; c) MeNH 2 isopropanol, 5 C; d) Cbz-leucine, EDCI, DMF, e) Jones, acetone N-Allyl amine (or a N-alkyl-N-allyl amine) is coupled to a Cbz-amino acid (or sulfonylated with an aryl sulfonyl chloride), then the alkene is epoxidized with a peracid (or diniethyl diooxirane). The epoxide is opened with a subsituted amine, 10 then the amine is acylated or sulfonylated. Final oxidation gives the desired ketones.

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

OF

ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience).

Coupling methods to form amide bonds herein are generally well known to the art. The methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS. Springer-Verlag, Berlin, 1984; E.

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

Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted S side reactions. Such protective groups are described generally in Green, T.W, 15 PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley Sons, New York (1981). The term "amino protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art.

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

Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form S* inner salts or zwitterions which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing'the appropriate cation; or with an appropriate organic amine. Cations such as Li Na Mg++ and NH 4 4 are specific examples of cations present in pharmaceutically acceptable salts.

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

This invention also provides a pharmaceutical composition which comonses 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, Sgelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or 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 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

For rec:al adrmnistration, the compounds of this invention may aiso De combined with excipients such as cocoa butter. givcenn. 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, 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, 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 invent'on 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 *0 *0 0 0 .000 00 *9 0 0@ B 0 0- 0 *000 0 @000 0000 00 diseases caused bv Dathoiogicai levels of cathesin K. hich memoos comrnise adrrmnstering to an animal, particularly a mammal, most particulariy 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 cvsteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis. arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.

This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an 15 effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.

For acute therapy, parenteral administration of a compound of Formula I is preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective.

although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K. The compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.

The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.

The compounds of tnis invention may also acrrunistere~ oraii :o pauent. in a manner such that the concentration of drug is sufficient .o inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein.

Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0. 1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about mg/kg.

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

Biological Assays The compounds of this invention may be tested in one of several biologicaj 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 20 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO.

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

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

Inhibition studies Potential inhibitors were evaluated using the progress curve method. Assays were carried out in the presence of variable concentrations of test compound.

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

For those compounds whose progress curves were linear, apparent inhibition constants (Ki,app) were calculated according to equation 1 (Brandt et al., Biochemitsr', 1989. 28, 140): v VmA/[Ka(1 I/Ki, app) +A] (1) 0 where v is the velocity of the reaction with maximal velocity Vm A is the *o 15 concentration of substrate with Michaelis constant of Ka, and I is the concentration 0 of inhibitor.

For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give kobs according to equation 2: [AMC] Vss t (vO vss) [1 exp (-kobst)] /kobs (2) where [AMC] is the concentration of product formed over time t, vo is the initial 25 reaction velocity and vss is the final steady state rate. Values for kobs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (kobs inhibitor concentration or kobs describing the time-dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61.201).

Human Osteoclast Resorption Assay Aliquots of osteoclastoma-denved cell suspensions were removed from iiauid nitrogen storage, warmed rapidly at 37"C and washed xl in RPMI-1640 medium by centnfugation (1000 rpm. 5 min at 4 0 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 counung chamber.

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

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 (87MEM diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 um/mL). The tubes were incubate at 37 0 C for 30 min.

rnL aliuots of the cells were seeded onto stenle dentine slices in a -Swell plate and incubated at 37'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°C. The slices were then washed in cold water and incubated in cold acetate buffer fast red garnet for min at 4 0 C. Excess buffer was aspirated, and the slices were air dried following a 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.

S**

: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 tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) 20 downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s singlet, d doublet, t triplet, q quartet, m multiplet, dd doublet of doublets, dt doublet of triplets, app apparent, br broad. J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and 25 Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact -00 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers Mass spectra were taken on either VG 70 FE, PE Syx API m, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected.

All temperatures are reported in degrees Celsius.

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

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

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

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

An excess of 30% HBr in acetic acid is added at 0°C and the solution is then washed successively with L.ON citric acid, saturated aqueous sodium bicarbonate (carefully.

and brine. The solution is dried over sodium sulfate, filtered, and evaporated to give the title compound as a white solid (4.10 IH NMR (400 MIHz, CDCI 3 5 7.34 (in, 6.51 I1H), 5.15 I1H), 5. 10 2H), 4.78 (in, IlH), 4.20 (mn, IlH), 4.04 (dd, 2H), 1.63 (in, 6H), 0.93 (mn, 12H).

b) (2S, 1 S)-2-(benzylox'ycarbonyl)amino-N-[ 1'-(2-carboethoxythiazol-4-y)-3'.

methylbutyl]-4-methylpentanamide The compound of Example 1 (2.0 g, 4.4 minol) and ethyl thiooxamate (0.59 g, 4.4 innol) were refluxed in ethanol for 4 h. The solvent was evaporated and the residue chromatographed (silica gel, 2.5% inethanoL'dichloromethane) to give the title compound as a white solid (1.46 IH NMR (400 MfHz, CDCI3) 8 7.32 (s, 1W), 7.21 (mn, 5H), 6.40 1W), 5.13 (dd, lH), 5.02 2H), 4.41 2H), 4.06 (in, 1H), 1.71 (mn, 2H), 1.47 (mn, 4H), 1.33 3H), 0.73 (in, 12H).

Preparation of (2S.1 'S)-2-(benzyloxycarbonylanino-N-I 1 -(2-carboxythiazol-4-yl)- 3'-methylbutyli-4-methylpentananiide The compound of Example 1 (0.92 g, 1.88 iniol) was stirred in tetrahydrofuran at 0 0 C with L ON sodium hydroxide. After stirring for I h, the solution was quenched with 1LON citric acid and extracted three times with dichloromethane. The combined organic extracts were evaporated in vacuo to give the title compound as a white solid (0.844 I H NMIR (400 MIHz, CDCI3) 6 7.40 I1H), 7.23 (mn, 5H), 6.89 I1H), 5.22 I1H), 5.14 (dd, 1WH), 5.02 2H), 4.15 (in, 1W), 1.67 (in, 2H), 1.44 (in, 4H), 0.8 1 12W).

Example 3 Preparation of (2S. 1'S)-2-(benZyloxycarbonyflamino-N-rIl'-(2-carboxaynidothiazol- 4-fl)-3'-methylbutyll-4-methvl2entanaraide The compound of Example 2 (0.408 g, 0.88 mmol) in tetrahydrofuran was cooled to -40*C and treated with N-methylinorpboline 185 g, 1. 85 inrol, 0. 2 ml) and isobutvi chloroformate 12ga, 0.88 rnmol. 0. 11 rnL). The mixture was stirred at -40'C for 15 minutes and then ammonia was bubbled through the solution for several minutes. The mixture was allowed to warm to room temperature and was then diluted with ethyl acetate and washed successively with L ON citric acid, 5% aqueous sodium bicarbonate, and brine. The organic solution was dried over magnesium sulfate, filtered, and evaporated to a residue which was chroinatographed (silica gel, 3% methanolldichloromethane) to give the title compound as a white solid (0.245 IH NN{R (400 M~z, CDCI3) 6 7.22 (in, 7.04 lH), 6.40 (br s, 1H), 5.51 (br s, 1H), 5.09 (in, 1H), 5.02 (dd, 2H), 4.07 (in, IH), 1.66-1.42 (in, 6H), 0.82 (mn, 12H).

Example 4 Preparation of (2S. 1'S)-2-(benzvloxvcarbonvhamino-N-r 1'-(2-cvanothiazol-4-vl)-3'methylbutyll-4-methvlpentanainide 15 The compound of Example 3 (0.185 g, 0.4 mmol) was dissolved in .:dichioromethane, cooled to 0 0 C and treated with TFAA (0.093 g, 0.44 inmol, 0.06 mL) and pyridine (0.07 g, 0.88 inmol, 0.07 mL). After 3 h, the mixture was poured into a solution of saturated aqueous sodium bicarbonate and extracted with dichioroinethane. The organic extracts were washed with 5% hydrochloric acid and brine, dried over magnesium sulfate, filtered, and evaporated to an oil which was chromatographed (silica gel, 40% ethyl acetate/hexane) to give the title compound as a white solid (0.095 I H NNMI (400 MIHz, CDC13) 8 7.44 1W), 7.29 (s, 6.51 (br d, IH), 5.14 (mn, 1H), 5.07 2H), 4.11 (mn, IH), 1.78-1.41 (in, 6H), 0.83 (mn, 12H).

Example Preparation of (2S. 1'S)-2-(benzyloxycarbonylhamino-N-[ benzylcarboxamrido)thiazol-4-yll-3'inet-hlbuvl-4-methylpentanamide To a solution of the compound of Example 2 (0.12 g, 0.26 inrol) in dichioroinethane under argon at room temperature is added benzylamine (0.03 g, 0.29 inmol, 0.03 inL), BOP reagent 115 g, 0.26 mnol), and triethyl amnine (0.026 ag, 0.26 rnmol, 0.04 mL) which isallowed to stir for 16 h. The solution is washed with water, then brine and the organic layer is dried over magnesium sulfate, filtered, and evaporated to give a residue which was chromatographed. (silica gel, ethyl acetate/hexane) to give the title compound as a white solid (0.065 IH NMR (400 MHz, CDCI3) 587.56 (br s, IH), 7.33 (in, IlOH), 6.48 (br d, IlH), 5.15 (dd, 1H), 5.03 2H), 4.63 2H), 4.12 (in. 1W), 1.72-1.40 (in, 6H), 0.85 (mn, 12H).

Preparation of (25.1 'S)-2-(benZyloxycarbonl)amino-N-f 1 methylpropylhcarboxamidolthiazol-4-yl-3'-nethylbutylk 4 -nethyI~entalamide Following the procedure of Example 5, except substituting isobutylarnine for *.benzylamine, the title compound was prepared (0.074 I H NMR (400 MHz, CDC13)8S 7.27 5H). 7.19 1H), 6.38 (br d, 1H), 5.09 (in, 1W), 5.01 2H), 4.07 (mn, I 3.20 (dd, 2H), 1. 83 (mn, I 1. 69- 1.40 6H), 0. 90 6H), 0.8 1 12H).

0% 0Preparation of (2S.1 'S)-2-(b-enzyloxvcarbonvflamino-N-f 1J RhenylethylkarboxamidothazoA-yll3'-inethybutyll-4-nethyignftalanide Following the procedure of Example 5, except substituting 2phenylethylamine for benzylamine, the title compound was prepared (0.070 IH NMR (400 MHz, CDCl3) 8 7.30-7.11 .1 1IIW), 6.35 (br d, 1 5.09 IH), 5 .01 2H), 4.05 (in, 1W), 3.64 (mn, 2H), 2.87 2H), 1.69-1.40 (in, 6H), 0.80 (in, 12H). Example 8 Preparation of (2S. IS)-2-(benzv loxvycarbonyl)am-ino-N-r [I -4-carboethoxythiazol->v l)- 3 '-methvlbutvll-4-methylpentananide a) N-rerr-butoxycarbonyl-(L)-leucinamide To a solution of N-tert-butoxycarbonyl-(L)-leucine (Advanced Chemtech) g, 20.0 mmol in dry THF (10OrmL) at -40*C was added isobutyl chloroforrnate (2.7 g, 20.0 mmol) and N-merthylmorphiline (4.2 g, 42 mmol). After 15 minutes of stirring, ammonia was bubbled through the mixture for an additional 15 minutes, then warmed to room temperature and allowed to stir for 2 hours. Mixture filtered and filtrate concentrated in vacuo to yield title compound as a white solid (4.9 g, 19.7 mrnol). H NMR (400 MHz, CDCI3) 8 6.38 (br s, I1H 5.79 (br s, IlH), 5.04 (br d, IN), 4.13 (in, IH), 1.71-1.49 (mn, 3H), 1.39 9H), 0.92 (dd, 6H).

b) N-:ern-butoxycarbonyl-L-leucinethioamide oo: 15 To a stirring solution of the compound of Example 8(a) (2.38 g, 10.35 minol) in dry THF was added Lawessons reagent (2.51 g, 6.21 imol) and the mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the residue chromatographed (silica gel, methanol/dichloromethane) to give the title compound as a white solid (2.3 H 0 20 NMR (400 MfHz, CDC13) 8 8.54 (br s, IH), 7.97 (br s, lH), 5.28 (br d, 1H), 4.52 ILH), 1.72-1.58 (in, 3H), 1.40 9H), 0.92 6H).

9:00:c) 1-(terr-butoxycarbonyl)amino. 1-(4-carboethoxythiazol-2-yl)-3methylbutane The compound of Example 8(b) (2.40 g, 9.76 minol) was stirred in dry acetone (20 inL) under argon at -10*C. Ethyibromopyruvate (2.12 g, 10.73 mmol, 1. 35 inL) was added and stirred for 1 h at -I10 0 C. The solution was poured into a well stirred mixture of chloroform and water and then saturated with sodium bicarbonate. The organic phase was separated and the aqueous layer extracted with chloroform. The combined organic extracts were dried over MgSO4, filtered, and evaporated to an oil. The oily residue was treated with TFAA (2.19 g,10.73 minol, mL) and pyridine (1.70 g, 21.47 mmol, 1.75 mL) in dichioromethane for I h at 0 OC. Excess solvent was removed in vacuo and the residue was dissolved in clicioromethane. The solution was washed with saturated aqueous sodium bicarbonate and L.ON KHS04 until pH 7. The solution was dried over sodium sulfate, filtered, and evaporated to an oil which was chromatographed (4% methanol/dichloroinethane) to give the title compound as a tan solid (1.2 I H NMvR (400 MIHz, CDCI3) 8 7.98 lH), 5.04 (br d, IH), 4.95 1H), 4.31 (q, 2H), 1.88 (mn, 1H), 1.63 (mn, 2H), 1.40 9H), 1.32 3H), 0.85 (dd, 6H).

d) (2S, 1S )-2-(benzyloxycarbonyl)amino-N-[ 1 -(4-carboethoxythiazol-2-yl)-3'- ****methylbutyl]-4-methylpentanamide The compound of Example 8(c) (1.0 g, 2.92 mmol) was dissolved in neat oto.TFA (1.0 inL) and stirred for 15 minutes. The solution was diluted with methanol and evaporated in vacuo. A portion of the residue obtained (0.36 g, 1.49 inmol) was dissolved in dichioromethane with N-Cbz-L-leucine (0.394 g, 1.49 mmol) BOP reagent (0.66 g, 1.49 inmol) and tniethyiamine (0.73 g, 7.2 inmol, 1.0 mL) and stirred at room temperature for 16 b. The solution was washed with water, then brine and dried over magnesium sulfate, filtered, and evaporated to a residue which 0: 0.was chroinatographed (silica gel, 40% ethyl acetate/hexane) to give the title o.6o 20 compound as a white solid (0.396 IH NMR (400 MHz, CDCl3) 8 7.96 IH), 7.25 5H), 6.61 (br d, 1H), 5.30 (mn, 1H), 5.09 (br d, 1H), 5.0-1 2H), 4.33 (q, 0:2H), 4. 10 (in, 1H), 1.90-1.58 (in, 6H), 1.29 3H), 0.81 (dd, 12H).

Example 9 Preparation of (2S.1 'S)-2-(benzyloxycarbonyharino-N-I 1-(4-carboxvthiazol-2-U)- 3'-metylbutyll-4-methylyentananide Following the procedure of Example 2, except substituting (2S,1'S)-2- (benzyloxycarbonyl)aino-N-[ 1 '-(4-carboethoxythiazol-2-y)-3'-nethybutyI]- 4 methylpentanamide for (2S, 1 S)-2-(benzyloxycarbonyl)amino-N-[ carboxythiazol-4-yl)-3'-methylbutyl]-4-methylpentanamide, the title compound was prepared (0.301 'H NMR (400 MHz, CDC13) 5 8.06 1H), 7.24 (in, 5H), 7.11 I1H), 5.30 (in, 2 5.04 2 4.16 (rm. I 1. 8 8-1.40 (6n 0. 71 (dd.

12H).

Example Preparation of (2S.1 'S)-2-(benzvloxvcarbonv1 )amino-N-f 1 -44carboethoxythiadiazol-2-vl)-3 '-methvlburyll-4-rnethvlpentanamide a) N-tert-butoxycarbonyl-L-leucine methyl ester To a stirring suspension of L-leucine methyl ester hydrochloride (Aldrich) (6.00 g, 33.0 mmol) and di-tert-butyl dicarbonate (7.21 g, 33.0 mmol) in THE rnL) was added triethylamine (3.34 g, 33.0 mmol, 4.60 The mixture was allowed to stir at room temperature for 3 d. The mixture was diluted with ethyl acetate and washed with I 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 NMIR (400 MHz, CDCl3) 5 4.88 IH), 4.33-4.31 15 (in, IH), 7.73 3H), 1.75-1.48 (mn, 3H), 1.44 9H), 0.96 3H), 0.93 3H).

b) N-tert-butoxycarbonyl.L-leucine hydrazide To a stirring solution of the compound of Example 10(a) (8.02 g, 32.7 inmol) in methanol (250 niL) was added hydrazine hydrate (16.38 g, 327 rnmol, 15.9 niL). After stirring for 22 h at room temperature, the solution was concentrated and the residue was azeotroped with toluene to provide -the title compound as a white foam (8.02 g, 100%). IH NMR (400 M4Hz, CDCl3) 8 7.71 (br a s, I 4.99 2H), 4.12-4. 10 (mn, I1H), 3.94 (br s, 2H), 1.68-1.49 (in, 3H), 1.44 (s, 9H), 0.95 3H), 0.92 3H).

c) 2 S)-N-[2-(benzyloxycarbonyl)amino-4-methylpentanoyl].N'.

carboethoxycarbonylhydrazide To a stirring solution of the compound of Example 10(b) (8.02 g, 32.7 rnmol) and pyridine (2.85 g, 36.0 nimol, 2.91 niL) in dichloromethane (200 inL) was added ethyl oxalyl chloride (4.91 g, 36.0 inmol, 4.02 mL). After stirring at room temperature for 2 h, thye solution was washed with 1 N HC1, water, saturated aqueous sodium bicarbonate arnd saturated brine, then dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a white foam (9.84 g, 'H NMR (400 MHz, CDCI3) 5 9.32 (br s, 2H), 5.04 2H), 4.38 2H), 4.28 (in, 1H), 1.77-1.56 (in, 3H), 1.44 9H), 1.39 3H), 0.96 3H), 0.94 (d, 3H).

d) 1-(tert-butoxycarbonyl)arnino-l1-(4-carboethoxythiadiazol-2-yl)-3methylbutane To a stirring solution of the compound of Example 10(c) (2.50 g, 7.24 rnmol) in toluene (70 rnL) was added Lawesson's reagent (1.46 g, 3.62 inmol). 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 acetatelhexanes, to provide the title compound as a pale yellow solid (1.75 g, IH NMvR (400 MflHz, CDC13) 5 5.19 (mn, IH), 5.13 (d, lIH), 4.51 2H), 1.95 (mn, IH), 1.83-1.73 (mn, 2H), 1.44 9H), 1.00 3H), 0.98 3H).

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

f) (2S, l'S)-2-(benzyloxycarbonyl)amino-N-j '-(4-carboethoxythiadiazol-2-yl)-3'methylbutyl)-4-methylpentanamide To a stirring solution of the compound of Example 10(e) (566.1 mg, 1.20 minol), N-Cbz-L-leucine (250.5 Mg, 1.32 rninol), 1-(3-dimethvlaininopropyl)-3ethvlcarbodlimide hydrochloride (253.3 mg, 1.32 mrnol) and Ihydroxybenzotriazole (32.5 mg, 0.24 minol) in 2.5 mL of DMF was added triethylamine (243.1 mng, 2.40 mrnol, 0.3 35 rnL). After stirring at room temperature for 3 d, the mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated to give a yellow oil. The cride material was purified by flash chromatography on 20 g of 230-400 mesh silica gel, eluting with 1:2 ethyl acetate/hexanes, to provide the title compound as a white solid (271 mg, 1

H

NMvR (400 MiHz, CDC13) 587.35 5H), 6.77 IH), 5.49 (mn, IH), 5.12 (dd, 2H), 4.51 2H), 4.20 (in, IH), 1.97(m, 111), 1.88 (in, IH), 1.66 (in, 3H), 1.52 (mn, IH), 1.45 3H), 0.97-0.92 (in, 12H).

Example I1I Preparation of (2S. 1 'S)-2-(bernzvloxycarbonvhanuno-N-f 1 -(2-carbo-2.2.2trifluoroethoxythazol-4-.vl-3.-methylbutyll4inethloentanamide The compound of Example 2 (0.200 g, 0.433 minol), 1, 1, 1 trifluoroethanol (.052 g, 0.52 mmiol, .04 rnL), pyridine 1 inL), and di-t-butyl dicarbonate 104 g, 0.477 mmiol) were stirred in ethyl acetate at room temperature for 16 h. The solution was diluted with ethyl acetate and washed successively with hydrochloric acid, 10% aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give a residue which was chroinatographed (silica gel, 20 ethyl acetate/hexane) to give the title compound as a white solid (.098 I H NMIR (400 MIz, CDC13) 8 7.50 I1H), 7.36 5H), 6.64 1H), 5.22 (in, 2H), 5.09 2H), 4.73 (mn, 211), 4.16 (in, III), 1.66-1.41 (in, 6H), 0.87 (in, 12H).

Example..12 Preparation of (2S.1 S)-2-(benzyloxycarbonyI)aminfo-N-T 1 carboethoxyoxadiazol -2-vI)- 3 -methylbutyl 1-4-methylpentanamide a) 1-(terr-butoxycarbonyl)aifl-1-(4-carboethoxyoxadiazol-2-yI)-3methylbutane To a stirring solution of the compound of Example 10(c) (2.50 g, 7.24 minol) and pyridine (1.49 g, 18.8 mmol, 1.52 mL) in ether (15 rnL) was added thionyl chloride 12 g, 9.41 mxnol, 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 '6 acetate/hexanes, to give the title compund as a pale yellow oil (0.84 g, IH NMR (4.00 MIHz, CDCI3) 8 5.14 (in, 1H), 5.03 (br d, 1H), 4.52 2H), 1.78-1.70 '15 (in, 3H), 1.44 9H), 0.99 6H).

b) (I 1 -amino-i I (4-carboethoxyoxadiazo-2-y1)-3-methylbutale Following the procedure of Example 10(e), except substituting 1-(tertbutoxycarbonyl)amino- 1 -(4-carboethoxyoxadiazol-2-yl)-3-mfethylbutale for (1 I1- 00020 (tert-butoxycarbonyl)axnino- 1 (4-carboethoxythiadiazol-2-yl)-3-inethylbutane, the .oe~k. title compound was prepared (582 mg, 100%). IH NMR (400 MfHz, CDC13) 8 4.99 9:9t6 1H), 4.52 2H), 2. 10-2.02 (in, 2H), 1.77-1.70 (in, 1H), 1.44 3H), 1.00 (t, 6H).

c) (2S,1 'S)-2-(benzyloxycarbonyl)amino-N-( 1'-(4-carboethoxyoxadiazol-2-yl)- 3 methylbutyl]-4-methylpentanamide Following the procedure of Example 10(f), except substituting amino-i -(4-carboethoxyoxadiazol-2-yl)-3-nethylbutale for (1 I -amino-I1 carboethoxythiadiazol-2-yl)-3-methylbutane, the title compound was prepared (235 mrg, 1 H NMR (400 NMz, CDCl3) 8 7.26 5H), 6.64 1H), 5.45-5.39 (in, 1H). 5.12 (in, 3H), 4.52 2H), 4.20 1H), 1.81 (mn. 2H), 1.68-1.64 (in. 31-).

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

Example 13 Preparation of (2S. I'S)-2-(benzvloxycarbonvl-L-leucinyl)armino-N-r V -4 carboethoxythiazol-2-v1)-3'-rethvlbutyll1-4-methvlpntanaide The compound of Example 8(c) (160.7 mg, 0.47 romol) was dissolved in neat TFA (1.0 m.L) and stirred for 15 minutes. The solution was diluted with methanol and evaporated to dryness. The residue was dissolved in DMEF (2 m.L) and to the resulting solution was added N-Cbz-L-Ieucinyl-L-leucine (194.0 mg, 0.52 minol), I -(3-dimethylammnopropyl)-3-ethylcarbodiimide hydrochloride (99.0 ing, 0.52 mmol) and Il-hydroxybenzotriazole (13.0 mg, 0.094 mmol) and triethylamnine (94.7 mg, 0.936 mmol, 0. 13 mL). After stirring at room temperature for 24 h, the mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and saturated brine, then dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with ethyl acetate/hexanes, to provide the title compound 146 I H NUbR (400 M&z, CDCI3) 6 8.04 I 7.33 (in, 5H), 7.14 I1H), 6.61 1H), 5.37 (mn, 2H), 5.08 (mn, 2H), 4.47 (mn, IH), 4.39 2H), 4.18 (in, I1H), 1.98 1.45 (in, 9H), 1.38 3H), 0.94 0.86 (mn, 18H).

Exm* 14 4 Preparation of (2S.l'S)-2--(benzyloxycarbon-yl)amino-N-r1'-(4carboxainidooxadiazol-2-vI)-3'-methylbuyll-4-methylpentanarmide Ammonia was bubbled through a solution of the compound of Example 12 (96.8 mng, 0.2 minol) in ethanol (2 mnL) for 5 mrm. After stirring an additional min, the solution was concentrated to give the title compound as a white solid (91.2 mg, IH NMR (400 MIHz, CDC1g/CD 3 OD) 6 7.29 5H), 5.90 1H), 5.30 1H), 5.04 2H), 4.15 (in, 1H), 1.76 (mn, 2H), 1.59-1.43 (in, 4H), 0.92-0.85 (in, 12H).

Example Preparation of (2S. I 'S)-2-(benzvloxvcarbonvl)amino-N-f I '-(2-carboethoxvthiazol-4vl)-3'-methylbutyll-3-phenvlproanamide a) N-(9-fluorenylmethoxycarbonyl)-L-leucifyl 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) 8 7.71 2H), 7.51 2H), 7.34 (dd, 2H), 7.22 (dd, 2H), 5.08 1H), 4.53 lH), 4.36 (dd, 2H), 4.13 (dd, 2H), 3.89 (dd, 2H). 1.62-1.41 3H), 0.88 6H).

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

c) (1 -amino-i -(2-carboethoxythiazol-4-yl)-3-iethylbutane 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).

;1 d) (2S, 1'S)-2-(benzyloxycarbonyl)amino-N-[ 1'-(2-carboethoxythiazol-4-yl)-3'methylbutyl]-3-phenylpropanamide Following the procedure of Example 5, except substituting (1S)-I-amino-l- (2-carboethoxythiazol4-yl)-3-methylbutane for benzylamine, and N-Cbz-Lphenylalanine for (2S, 1'S)-2-(benzyloxycarbonyl)anino-N-[ I'-(2-carboxythiazol-4yl)-3'-methylbutyl]-4-methylpentanamide. the title compound was prepared 162 IH.NMvR (400 MI-z, CDC13) 867.27 (irn, 5H). 7.11 IH), 7.04 tin. 5H). 6.12 I 5.24 I1H), 5. 10 I1H), 5.01 2H), 4.37 (q 2H). 4.21 (in 1H), 2.91 (in. 2H), 1.62 (in, 3H), 1.37 3H), 0.81 (in, 6H-).

Example 16 Preparation of (2S. 1 S)-2-(benZyloxvcarbonvl-L-leucinyl)aniino-N-[ carboethoxvthiazol-4-vl)-3 -methvlbutyll-4-methylpgntanarn-ide Following the procedure of Example 5, except substituting (1 I1-amino-I -(2-carboethoxythiazol-4-yl)-3-methylbutane for benzylamine, and N-Cbz-L- Ieucinyl-L-leucine for (2S, 1 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 carboxythiazol-4-yl)-3'-methylbutyl-4-methylpentanamide, the title compound was prepared (0.098 I H NMR (400 M4Hz, CDC13) 8 7.39 I H),'7.25 (in. 96:: 6.87 18), 6.49 18), 5.30 IH), 5.16 4.99 2H), 4.36 2H), 14.31 (mn, LH), 4.09 (in, 1H), 1.74-1.38 (mn, 9H), 1.32 3H), 0.80 (mn, *0 0. Example 17 Preparation of (2S.1 'S)-2-(benzyloxvcarbonylhamino-N-f I '-5-mercapto- 1.2.4oxadiazol-3-vl)-3'-methvlbutvll-4-inethvlpentananide a) N-benzyloxycarbonyl-L-leucinyl-L-leucine methyl ester N-Cbz-L-leucine (Chemical Dynamics) (1.32 g, 4.97 mmol), L-leucine 0000 methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 iniol), 1-hydroxybenzotriazole 14 g, 1.0 inmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.47 mmxol) were combined, dissolved in 25 mL of DMIF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed successively with water, 0. 1 N HCl, saturated aqeous NaHCO3 and saturated brine, then dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:3 ethyl acetate hexanes, to give the title compound as a white solid (1.28 g, IH NMR (400 MI-z, CDCI3) 8 7.37-7.32 (mn, 5H), 6.28 18), 5.28 (in, 38), 4.61-4.58 (mn, 18), 4.20 (mn, IH), 3.74 3H), 1.69-1.54 (mn, 6H), 0.96-0.92 (mn, 12H).

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

c) (2S, 1 S)-2-(benzyloxycarbonyl)amino-N-f 1'-(5-inercapto- 1,2,4-oxadiazol-3-yI)- 3'-methylbutyl]-4-inethylpentanainide To a stirring solution of the compound of Example 17(b) (0.3 g, 0.76 minol) in 1.5 ruL of chloroform was added triethylanine 155 g, 1.53 inrol, 0.213 inL) *15 and thiophosgene (0.088 g, 0.76 minol, 0.058 mL). The solution was heated at reflux for 3 h, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO 4 filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 11I% methanol in dichioromethane, to give the title 20 compound as a white solid (0.20 g, IH NMR (400NMHz, CDC13) 87.36(in, 6H), 6.85 1H), 5.37 1H), 5.14 3H), 4.24 (mn, IH), 1.65 in, 6H), 0.95- 0.87 (mn, 12H).

Example 18 Preparation of (2S. 1 'S)-2-(benzvloxcarbonl)amino-N-f 1 -(2-mercaptothiazol-4vi)-3-methvlbutvl1-4-methvlpentanamide The compound of Example 1(a) (1.0 g, 2.2 rmol) and ammonium dithiocarbamate (0.25 2.2 imol) were dissolved in ethanol and heated to 55 0

C

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

IH NMR (400 MHz, CDCl3) 6 7.24 5H), 7.10 11), 6.33 IH) 6.00 (d, 1H), 5.11 2H), 4.94 (in, 1H), 4.05 I 1.49 6H), 0.78 12H).

Example 19 Preparation of (2S)-2-(benzvloxvcarbonyl)amino-N-(4-carboethoxiiazol-2.

v)methvl-4-methylentanamide 1 -(terr-butoxycarbonyl)amino- 1 -(4-carboetboxythiazol-2-yl)iethane Following the procedure of Example except substituting N-tertbutoxycarbonyiglycine for N-tert-butoxycarbonyl-(L)-leucine in step the title compound was prepared (1.9g, 58% overall). 1 H NMR (400 MHz, CDC13) 68.11 1H), 5.31 1H), 4.56 2H), 4.43 21), 1.45 9H), 1.42 3H).

b) (2S)-2-(benzyloxycarbonyl)amino-N-(4-carboethoxythiazol-2-yl)nethyl-4methylpentanamide Following the procedure of Example. 13, except substituting 1-(tertbutoxycarbonyl)amino- I -(4-carboethoxythiazol-2-yl)methane for (I5)-I -(terbutoxycarbonyl)amino 1 -(4-carboethoxythiazol-2-y)-3-methylbutane, and N-Cbz- L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120g, MS 434.2.

Example Preparation of (2S. 1 S)-2-(benzyloxycarboflyl)amiflo-N-i1 ben zy Ioxvcarbo ny Ithi azol -4-y methylIbutl- 1-4- methyl Vgntanarnide The compound of Example 2 (0.105 0.22 mmol) was dissolved in dichloromethane and treated with 1 -(3-dimethylaminopropyl)-3-ethylcarbodiride methiodide (0.062 0.22 mmol) and benzyl alcohol (0.03 mL, 0.22 mniol). 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 IHNM(400 MLHz, CDCI3) 6 7.37 IH), 7.26 (in, lOH), 6.50 LH), 5.33 211), 5.11 (q, 211), 5.09 (in, IH), 4.99 2H1), 4.04 (in, 111), 1.49 (mn, 611), 0.78 (in, 12H).

Preparation of (2S. 1'S)-2-(benzyloxycarbonylarriflo-4-mfeth vl-N-f3'-methyl- 1 15 p2henoxvcarbonlthiazol4-flbut~l~eftananllde Following the procedure of Example 20, except substituting phenol for benzyl alcohol, the title compound was prepared (0.075 I H NMR (400 MIHz, CDCl3) 867.41 I1H), 7.26 (mn, 1011), 6.49 111) 5.20 (mn, 111), 5.04 (mn, 111), 5.00 211), 4.08 (mn, 111), 1.49 (in, 611), 0.82 (in, 1211).

Preparation of (2S.1 'S)-2-(benzyloxycarbonyflamnfo4-ethyl-N-[ 3 '-metl (2-methylpropvloxycabofyltazol4-y1butyllcftanamide Following the procedure of Example 20, except substituting isobutyl alcohol for benzyl alcohol, the title compound was ,prepared (0.075 III NMR (400 MHz, CDCl3) 6 7.25 (mn, 6H1), 6.50 11H) 5. 11 2H1), 5.09 (mn, 111), 4.99 2H1), 4. 11 211), 3.91 (mn, 1H),2.02 (mn, 111), 1.70- 1.39 (in, 611), 0.82 611), 0.78 (in, 12H).

ExaMple 23 Preparation of (2R. I'S)-2-(benzvloxvcarbon-vl)arniino-N-r lg-Arbetoytia 2 -yI)ethvlI-4-methylggntanaide Following the procedure of Example 1 9, except substituting N-terrbutoxycarbonyl-L-alanine for N-rert-butoxycarbonylglycine in step and N-Cbz- D-leucine for N-Cbz-L-leucine in step the title compound was prepared as white solid 135g, MS 448.2.

Example 24 Preparation of f 2R. I 'R)-2-(benZyloxvcarbonyl)amjno-N-r I 4 -carboethoxythiazol.

2 -Xl)ethylIl4-methypgntananide Following the procedure of Example 19, except substituting N-tenrbutoxycarbonyl-D-alaaine for N-tert-butoxycarbonylglycine in step and N-Cbz- D-leucine for N-Cbz-L-leucjne in step the title compound was prepared as white solid 1 l0g, MS 448.2.

Example Preparation of (2S. '-(2-arninothiazol-4-vh)-3'-methvlbutylv2.

(benzyloxycarbonyl )aniino-4-methylpentanamide To a stirring solution of the compound of Example I1(a) (0.85 g, 1.87 rnmol) in 4 mL of ethanol was added thiourea 142 g, 1.87 mmol). The solution was allowed to stir at room temperature for 90 min. The solution was concentrated, the residue was dissolved in ethyl acetate and washed with saturated aqeous NaHCO 3 and saturated brine, then dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1: 1 ethyl acetate/hexanes, to give the title compound as a white solid (0.64 g, IH NMR (400 MJI~z, CDC13) 587.36 (in, 5H), 6.30 (mn 2H) 5.12 (in, 3H), 4.95-4-91 (in, 3H1), 4.16 111), 1.63 (in, 4H), 1.49 (in, 2H), 0.93-0.89 (in, 12H).

Example 26 Preparation of (1 S)-N-f4-f( I-benzyloxvcarbonvlamino)-3-methvlbutvllhiazol-2ylcarbonyll-N'-(N-benzvloxycarbonl-L-Ieucinvl)hydrazide a) N-bernzyloxycarbonyl-L-Ieucinyl bromomethyl ketone 1 -methyl-3 -nitro-lI-nitrosoguanidine (6.65 g, 45.2 mmol) in ether (225 rnL 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 minol) was dissolved in THfF (10 rnL), cooled to -40 and 4-methylmorpholine (0.77 g, 7.6 mmol, 0.83 mL) was added, .:::followed by dropwise addition of isobutyl cbloroforrnate (1.04 g, 7.6 mmol, 0.98 mL). After 15 min, the solution was filtered into the previously prepared 0 OC solution of ethereal diazoinethane. The resulting solution was allowed to stand at 0 0 C for 23 h. H~r (30% in acetic acid) (45.2 mmol, 9 mL) was added and the resulting solution was stirred at 0 *C for 5 min, then washed sequentially with 0. 1 N HCl, saturated aqueous NaHCO 3 and saturated brine, then dried (MgSO 4 filtered and concentrated to give the title compound as a colorless oil (2.43 g, 94%).

b) (I I -benzyloxycarbonylaino- 1 -(2-carboethoxythiazol-4-yl)-3-methylbutane *20 A solution of the compound of Example 26(a) (1.57 g, 4.58 mmol) and ethyl thiooxamate (0.61 g, 4.58 ramol) in ethanol (10 m.L) 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 Mfz, CDC1 3 8 7.41 I 7.34-7.3 1 (in, 5H), .40 1 5. 10 1 5.05 IlH), 4.98 lH), 4.48 2H), 1.80-1.76 (in, 2H), 1.57-1.53 (mn, IH), 1.44 3H), 0.95 3H), 0.93 3H).

c) (I 1 -benzvloxvcarbonvlamjino- I 2-hvdrazinocarbonvlthiazol-4-vl methylbutane A solution of the compound of Example 26(b) (0.30 g, 0.8 mmol) and hydrazine hydrate (0.40 g, 8.0 mmol, 0.39 mL) in ethanol (8 mnl) 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, 'H NMR (400 MJ-z, CDC1 3 6 8.29 IH), 7.37-7.35 (in, 5H), 5.18 1H), 5.09 (dd, 2H), 4.95 1H), 4.07 2H), 1.71 1.55 (in, IH), 0.96 3H), 0.94 3H).% d) (1 I-benzyloxycarbonylamnino)-3-methylbutyl]thiazol-2-ylcarbonylj-N'- *.e (N-benzyloxycarbonyl-L-leucinyl)hydrazide A solution of the compound of Examnple 26(c) (100 mg, 02'28 minol), N-Cbz- L-leucine (80.5 mng, 0.30 mxnol), I -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.2 mg, 0.30 imnol) and I-hydroxybenzotriazole (7.5 mg, 0.06 inmol) in DMF (0.6 minol) 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 NaHCO3 and saturated brine, then dried (MgSO 4 filtered and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1: 1 ethyl acetate/hexanes, to provide the title compound as a white solid (111.4 mg, mp 110- 112 *C.

Example 27 Preparation of N-benzyloxvcarbonyl-L-leuciny l-N'-benzyloxycarbonyl-L-leucinyl- L-leucinylhydrazide a) N-benzyloxycarbonyl-L-leucinyl-L-leucine mnethyl ester Following the procedure of Example 28(d), except L-leucine methyl ester hydrochloride for (1 1 -benzyloxycarbonylaznino- I -(2-hydrazinocarbonylthiazol- 4-yl)-3-methylbutane, the title compound was prepared as a white solid (1.28 g, 'H NMR (400 MHz, CDC13) 5 7.37-7.32 (mn, 5H), 6.28 IH), 5.28 (in, 3H), 4.61-4.58 (in, 1H), 4.20 (mn, IH), 3.74 3H), 1.69-1.54 (mn, 6H), 0.96-0.92 (mn, 12H).

b) N-benzyloxycarbonyl-L-leucinyl-L-leuc inylhydrazide Following the procedure of Example 26(c). except substituting Nbenzyloxycarbonyl-L-leucinyl--leucine methyl ester for (lS)-lbeazyloxycarbonylamino- 1 .(2-carboethoxythiazol-4-yl)-3-methylbutane, the title compound was prepared as a white solid (1.28 g, 100%). 'H NvR (400 MHz, CDCI3) 58.05 (br s, 1H), 7.35-7.32 5H), 6.67 lH), 5.50 LH), 5.11 (s, 2H), 4.46 IH), 4.21 IH), 3.88 (br s, 2H), 1.64-1.51 6H), 0.92-0.88 (m, 12H).

c) N-benzyloxycarbonylL-eucinylN'be zyloxycarboyl-L-euciyl-Lleucinyihydrazide Following the procedure of Example 26(d), except substituting Nbenzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide for (1 S)-lbenzyloxycarbonylamino- 1 -(2-hydrazinocarbonylthiazol-4-y1)-3-methylbutane, the title compound was prepared as a white solid (0.059 MS 662.1 i Example 28 Preparation of 2-f 1 -benzyloxycarbonylamno)-3-inethlbutylthiazoI- 4 vlcarbonyll-N'-(-benzoxycarbony--lCcily drazide a) N-tert-butoxycarbonyl-(L)-leucinam ide To a solution of N-tert-butoxycarbony1-(L)-leucine (7.0g, 28. 1inmol in dry THF (I0 OiL) at -40'C was added isobutylchloroforrate (3.8g, 28. 1mmol) and Nrethylmorphiline 59mmol). After 15 minutes of stirring, ammonia was bubbled through the mixture for an additiohal 15 minutes, then warmed to room temperature and allowed to stir for 2 hours. Mixture filtered and filtrate concentrated in vacuo to yield title compound as a white solid 28.Ommol).

'HNMR (400MHz, CDCI) 8 6.38 (br s, lH), 5.79 (br s, 111), 5.04 (br d, 1H), 4.13 IH). 1.71-1.49 3H), 1.39 9H), 0.92 (dd, 6H).

b) N-tert-butoxycarbonyl-(L)-leucinethioamide To a stirring solution of the compound of Example 26(a) 28.0 mmol) in dry THF was added Lawesson's reagent (6.8g, 16.9 mmol) and the mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the residue chromatographed (silica gel, 12% ethyl acetate/hexane) to give the title compound as a white solid (5.4g, 'HNMR (400MHz, CDCI 3 6 8.54 (br s.

1H), 7.97 (br s, 1H), 5.28 (br d, 4.52 1H), 1.72-1.58 3H), 1.40 9H), 0.92 6H).

c) 1-(tert-butoxycarbonyl)amino- 1 -(4-carboethoxythiazol-2-yl)-3methylbutane The compound of Example 26(b) (5.4g, 21.7 mmol) was stirred in dry acetone (100mL) under argon at -10°C. Ethylbromopyruvate (4.7g, 23.9mmol) was added and stirred for lh at -10*C. The solution was poured into a well stirred mixture of chloroform and water and then into saturated sodium bicarbonate solution. The organic phase was separated and the aqueous layer extracted with chloroform. The combined organic extracts were dried over MgSO,, filtered and concentrated to an oil. The oily residue was treated with TFAA (5.0g, 23.9mmol) .and pyridine (3.8g, 47.8mmol) in dichloromethane for Ih at -20 0 C. Excess solvent was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate and 1.ON KHSO, until pH 7. The solution was dried over magnesium sulfate, filtered and concentrated to an oil which was chromatographed (silica gel, 7.5% ethyl acetate/hexane) to give the title compound as a tan solid (4.5g, 'HNMR (400MHz, CDC1,) 87.98 1H), 5.04 (br d, 1H), 4.95 1H), 4.31 2H), 1.88 1H), 1.63 2H), 1.40 9H),1.32 3H), 0.85 (dd, 6H).

d) (1 S)-1 -(Benzyloxycarbonyl)amino-1 -(4-carboethoxythiazol-2-yl)-3-methylbutane The compound of Example 26(c) (0.250g, 0.731mmol) was dissolved in TFA (2mL) and stirred at room temperature for 15 minutes when diluted with methanol and concentrated in vacuo. The residue was dissolved in methylene chloride and treated with triethylamine (0.

7 39g, 7.31lrmol) followed by beLNzvl chioroformate (1.2g, 7.3 immol). The solution stirred at room temperature for 2h when partition between ethyl acetate/water. The organic layer was washed with brine, collected, dried (MgSO 4 and concentrated to a residue that was chromatographed (silica gel, 15% ethyl acetate/hexane) to give the title compound as an oil 198g, 'HNMR (400MIHz, C~DCI) 8 8.01 IH), 7.32 (in, 5.51 (br d, IN), 5.14 (in, IN), 5. 10 2H), 4.37 2H), 1.93 (in, 1H), 1.8 1-1.67 (mn, 2H), 1.39 3H), 0.95 (mn, 6H).

10 e) (1 I-benzyloxycarbonylamino)-3-inethylbutyllthiazol-4-ylcarbonyl]-N- O~d. (N-benzyloxycarbonyl-L-leucinyl)hydrazide :Following the procedure of Example 26(c)-lI(d), except substituting (I S)-lI- (Benzyloxycarbonyl)amino-1I-(4-carboethoxythiazol-2-yl)-3-methylbutane for (iS)- 1 -benzyloxycarbonylamino- 1-(2-carboethoxythiazol-4-yl)-3-methylbutane in step the title compound was prepared. MS 610.0 Example 29 Preparation of 2.2'-(N.N'-bis-benzyloxvcarbonyl-L-leucinyhcarbohydrazide To a stirring solution of N-Cbz-L-leucine (Chemical Dynamics Corp.) (2.94 g, 11. 1 rnmol) in 22 rnL of DMIF was added carbohydrazide (0.5 g, 5.6 inmol), 1-(3dimethylanhinopropyl)-3-ethylcarbodiimide hydrochloride (2.13 g, 11. 1 inmol) and 1-hydroxybeazotriazole (0.3 g, 2.2 inmol)." After stirring at room temperature for 22 h, the solution was poured into 500 mL of water. The precipitate was collected by vacuum filtration and washed with water (4 X 150 niL and dichioroinethane (4 X 150 niL, then dried under vacuum to provide the title compound as a white solid (1.49 g, MS(ESI): 607.1 Example Preparation of 2.2'-(N.N'-bis-cvclohexvlacetyl )carbohvdrazide Following the procedure of Example 29, except substituting cyc lohexyl acetic acid for N-Cbz-L-leucine, the title compound was prepared (0.4 g, MS(ESI): 339.3 Example 31 Preparation of 2 2 t -bis-4-methvlpgntanoyl)carbohydraide Following the procedure of Example 29, except substituting 4methylpentanoic acid for N-Cbz-L-leucine, the title compound was prepared as a white solid (0.2 12 g, MS(ESI): 287.3 xample 3-2 Preparation of 2 2 1 -(N.N-bis-2-cyclopentylacetyi')carbohd&zde Following the procedure of Example 29, except substituting 2>cyclopentylacetic acid for N-Cbz-L-leucine, the ftde compound was prepared as a white solid (0.345 g, MS(ESI): 311.2 mpJefl Preparation of 2 2 -(N.N-bis-benzyloxcarbonllcinl)cohydraide 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, 9 MS(ESI): 473.1 Example 34 Preparation of 2 2 '-(N-N'-bis-acetyl.L-leucinyl-)a-ibohydrazide Following the procedure of Example 29, except substituting N-acetyl-Lleucine for N-Cbz-L-leucine, the tidle compound was prepared as a white solid 153 g, MS(ESI): 401.3 Example Preparation of benZyloxvcarbonyl-L-alanyI)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 762 g, 9 MS(ESI): 50 1. 1 Preparation of 2-(N-benzvloxycarbonyl-L-leucinvl)-2'-rN'-(4methylpgntanoyl~lcarbohydrazide a) N..benzyloxycarbonyl-L- leucine methyl ester To a solution of leucine methyl ester hydrochloride (5.0 g, 27.5 mxnol) in 1,4-dioxane (50 mL) was added sodium carbonate (30.3 mL, 2M in water) followed :by benzyl chloroformate (4.69 g, 27.5 mmol). The mixture stirred at room temperature for 24 hours when partitioned between ethyl acetate and water. The organic layer was collected, dried (MgSO.), filtered and concentrated to give the title compound as a colorless oil (7.67 g, 100%). 'HNMR (400M&z, CDCl 3 )567.39 (in, 511), 5.38 2H1), 5.12 2H), 4.42 (in, IH), 3.75 3H1), 1.73 1.50 (in, 3H1), 0.94 (in, 6H).

0 V 20 b) N-benzyloxycarbonyl-L-leucinyl hydrazide To a solution of the compound of Example 36(a) (7.67 g, -27.5 mmol) in methanol (40 mL) was added hydrazine monohydrate (13.5 g, 270 minol). The solution was stirrd at room temperature for 24 hours when partitioned between water and ethyl acetate. The organic layer was collected, dried (MgSO 4 filtered and concentrated to give the title compound as an off-white solid (7.67 g, 100%).

'HNMR (400M4Hz, CDCl 1 8 8.14 1H), 7.38 (mn, 511), 5.64 1H), 5.09 (dcl, 2H1), 4.20 (mn, I 3.81 (s br, 2H), 1.69 1.51 (mn, 311), 0.92 (dcl, 611).

c) 1 -benzyloxycarbonylamino- 3-methyl-i ,3,4-oxadiazol-2-onyl)butane A solution of the compound of Example 36(b) (1.0 g, 3.58 inxol) in mnethylene chloride (12inL) was added dropwise to a solution of 4rutrophenylchloroformate (0.361 g, 1.79 mmol) in methylene chloride (8 mL) at 0°C. The solution warmed to room temperature and stirred for one hour when partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaHCO, then collected, dried (MgSO,), filtered and concentrated to a residue which was chromatographed (20% ethyl acetate/hexane) to give the title compound as a pale yellow solid (0.322 g, 'HNMR (400MHz, CDCI 3 6 9.18 IH), 7.38 5H), 5.13 3H), 4.79 IH), 1.71 3H), 0.98 (dd, 6H).

d) 4-methylpentanoyl hydrazide Following the procedure of Example 36(b) except substituting ethyl 0 isocaproate for benzyloxycarbonyl-L-leucinyl methyl ester, the title compound was prepared as a white solid (1.8 g, 100%). 'HNMR (400MHz, CDC1) 5 7.48 (s br.

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

9.

e) 2-(N-benzyloxycarbonyl-L-leucinyl)-2'-[N'-(4-methylpentanoyl)]carbohydrazide The compounds of Example 36(c) (0.100 g, 0.325 mmol) and Example 36(d) (0.042 g, 0.325 mmol) were combined and dissolved in ethanol (1 mL). The solution was brought to reflux for 24 hours then concentrated to a solid yellow oe* residue which was washed with cool methylene chloride to yield the title compound as a white solid (0.053 g, MS 436.2.

Example 37 Preparation of bi s-(Cbz-leucinfl)- 1. 3-diamino-propan-2 -one Cbzideucine (500 mrg, 1.88 mrnol), EDCI (558 mg, 1.88 mmol) was dissolved in DMF (4.0 ml) with l,3-diammno-propan-2-oI (85 mg, 0.94 inmol) and Hung's base (0.3 ml, 1.88 nunol) and was stirred at RT overnight. The reaction was diuted with EtOAc (20 rLI) and was extracted with water (2 x 20 ml). The combined organics were dried with magnesium sulfate, filtered, concentrated in vacua. The intermediate was then dissolved in acetone (4.0 ml) and Jones reagent nil, 1.5 M) was added dropwise and the reaction was stirred at RT overnight.

The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 mil) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chrornatographed (silica gel, 2-5% MeQHI methylene chloride) to give the title compound as a white solid (410 mg, MS(ES) M+HW=583, M+Na=--605.

*too Preparation of bis- 1.3-(4-p2henoxy-benzyl)-diax-ino-propan-2-one Following the procedure of Example 37, except substituting "4-phenoxybenzoic acid" for "Cbz-leucine", the title compound was prepared: MS(ES) 0' M+W=48 1, M+Na*=503.

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

Example Preparation of -bz-leucinyl)-anmino-3-(Cbz-glutamvlrtbu!il ester)-arnino.

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

Example 41 Preparation of I -(b-ecnl-mn--Czgltml-run-rpn2-n 1 -(Cbz-Ieucinyl )-axino-3-(Cbz-glutarnyl-t-butyl ester)-amino-propan-2-one mg, 0.OO7mmoI) was dissolved in a solution of trifluoroacetic acid 0.5 ml) and methylene chloride (0.5 ml), then was stirred at RT for 2 h, the reaction was dilutied with toluene (10 ml), then was concentrated in vacuo to provide the title compound: :MS(ES) M+Fr=599.

Example 42 Preparation of bis-1I.3-(Cbz-leucinyfl-diamino-(S )-butanone-2-one a) Cbz-leu-ala-bromo methyl ketone 0% 0 Isobutyl chloroformate (1.46 ml, 11.3 mrmol) was added dropwise to a 20 solution of Cbz-leu-ala-OH (4.0 g, 11.3 mxnol) and N-methyl morpholine (1.24 ml, 11.3 mmol) in THF (40 ml) at -40 degrees C. The reaction was stirred 15 min, then was filtered, and was washed with ether. Diazomethane (40.1 rnnol from 5.9 g of l-methyl-3-nitro-nitroso-guanidine and 18 ail of 40% KOH in 150 ml of ether) in ether (200 ml) was added and the reaction was placed in a refrigerator overnight.

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

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

Cb-e--mn4azd-rpn3o *.:Cbz-leu-leu-azido methyl. ketone (330 mg, 0.9 mmol) was dissolved in EtOH (5 ml) and sodium borohydride (100 mg, 2.65 mmol) was added at RT and the reaction was stirred for 15 minutes. The reaction was quenched with water (10 ml) and was extracted with EtOAc (25 ml). The combined organic extracts were dried with magnesium sulfate, filtered, concentrated to give the title compound without :::.further purification, MS(ES) 378, M+Na*=400.

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

e) bis- I ,3-(Cbz-leucinyl)-diamino-(S)-butanone- 2 -ol Cbz-leu-2-axnino-4-amfino-propan- 3 -ol (140 mg, 0.4 minol) and Cbz-leucine (106 mg, 0.4 mmol) were dissolved in DMF (2 ml) and N-methyl morpholine (0.08 ml, 0.8 mrnol) and I-BTU (151 mg, 0.4 mmofl and was stirred overnjght. The reaction was partitioned between EtOAc and water, the combined ormanics were dried with magnesium sulfate, filtered, concentrated to give the title compound.

MS(ES) M-#fr=599, M+Na+=62 1.

f) bis- 1 3 -(Cbz-leucinyl)-diamino-(S)-butanone.2-one B is-I 3 -(Cbz-leucinyl)-diamnino-(S )-butanone-2-ol (240 mg, 0.4 mxnol) was dissolved in acetone (2 nil). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction was stirred at RT overnight. T7he excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc ml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOHI mnethylene chloride) to give the title compound as a white solid (80 mg, 33 MS(ES) M-W*=595.

Example 43 Preparation of 1 -(Cbz-leucinfl)-amino-3 -(Cbz-12henvlalanyl) alnpoan..2-one Following the procedure of Example 37, except substituting "a mixture of Cbz-phenylalanine and Cbz-leucine" for "Cbz-Ieucine", the title compound was prepared MS(ES) M+Wr=6 17, M+Na*-639.

'Preparation of I (b-ecnl-mn--(b-oluiy) n Following the procedure of Example 37, except substituting a mixture of Cbz-norleucine and Cbz-leucine" for "Cbz-leucine", the title compound was prepared: MS(ES) M+W*=583, M+Na*=605.

100 Example Preparation of 1 -(Cbz-leucinvl)-amrino-3-(Cbz-norvaI inyl )-arnino-pLO-pan -2 -one Following the procedure of Example 37, except substituting "a mixture of Cbz-norvaline and Cbz-leucine' for "Cbz-leucine", the title compound was prepared: MS(ES) M+W=569, M+Na*=591.

Example-46 Preparation of bis-1I.3-(Cbz-Ieucinyl)-diamino-5-methvl-(S)-hexan-2 -one a) bis- I ,3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one Following the procedure of Example except substituting "Cbz-leu- :9 9.leu-OH" for "Cbz-leu-ala-OH" the tidle compound was prepared: MS(ES) 99999*M+W=-639.

Exarnple 47 Preparation of 1 4aceryl-Ieucinfl)-arrino-3-(4-phenoxy-benzoyl)-amino-propan-2- Following the procedure of Example 37, except substituting "a mixture of N- Ac-leucine and 4-phenoxy-benzoic acid for "Cbz-leucine", the title compound was prepared: MS(ES) M+Wr=440.

Preparation of 1 -(Cbz-homo-leucinyfl-amino- (Cbz-leucinyfl-3-anmino-propan-2-one Following the procedure of Example 37, except substituting "a mixture Cbzhomo-leucine and Cbz-leucine" for "Cbz-leucine', the title compound was prepared: MS(ES) M+W=597, M+Na'=6 19.

Example 49 Preparation-of bis- 1.

3 4 3 -chloro-2-cvano-phenoxy)-phen-vI sulfonainjidn)-propan- 2-one 4 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride (1.3 g, 4 mxnol.

Maybridge) was added to a solution of l,3-diamnino-propan-2-ol 18 g, 2 Mmnol) in DMF (10 ml)/ N-methyl morpholine (0.44 ml, 4 mmol) and was stirred 3h at RT.

The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude bis- 1,3- 4 3 -chloro-2-cyano-phenoxy)..phenyl sulfonam-ido)-propan-2-ol (0.28 g, 0.4 .mmol) was then dissolved in acetone (1.0 ml) and Jones reagent (0.44 ml. 1.5 M) was added dropwise, and the reaction was stifred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ail) and was extracted with water (2x 20 mil) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOHI methylene chloride) to give the title compound as a white solid (90 mg, MS(ES) M+ H=67 1, M+Na'=693.

Example Preparation of bis- 1 .3-(4-phenoxy-p2henyl sulfonamidoJ-propan-2-one Following the procedure of Example 49, except substituting 4-phenoxyphenyl sulfonyl chloride for 4 3 -Chloro-2-cyano-phenoxy)-phen--yIsulfonyl chloride, the title compound was prepared: MS(ES) M-W*=55 1.

102 Example 5 1 Preparation of 1 -(Cbz-leucin l)-mn--4-r-hoo 2caopenU-2ey Cbz-leucine (660 mng, 2.5 inmrol), EDCI (480 nig, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DMIF (10 ml) with 1,3-diamino-propan-2-ol (225 mg, 2.5 mnrol) and was stirred at RT overnight. N-methyl morpholine (0.41 ml, 3.75 mniol) was added followed by 4-(3-Chloro-2-cyalo-phelOXY")-pheflyl 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 *1-(b-ecnl-nio3(-3clr--yn-hnx)pey sulfonamido)propan-2-ol was then dissolved in acetone (5.0 ml) and Jones reagent (3.0 ml, M) was added dropwise, and the reaction was stirred overnight at RT. The excess :Jones reagent was then quenched with isopropanol (1.0 mal), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOI methylene chloride), then the product was triturated from methylene chloride to give the title compound as a white solid (26 mg, MS(ES) M+ H--627.

Example 52 ~~~Preparation o -Cbleucin I- aino 3(tosvI n if)proan 2 e Following the procedure of Example 5 1, except substituting tosyl chloride for 4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride, the title compound was prepared: MS(ES) M-W*-488.

Example 53 Preparation of I -(Cbz-leucinyl )-amnino-3-((4-p2henoxv-phenyI~ufnd propan-2-one Following the procedure of Example 51. except substituting 4-phenoxyphenyl-sulfonyl chloride for 4 3 -Ch~oro-2-cyano-phenoxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M+Jf=568, M+Na'=590.

Example 54 Preparation of. 1-Czluiy)ann--2dbnouasloaio-r~n2 one Following the procedure of Example 5 1, except 2-dibenzofuransulfonyl chloride for 4 3 -Chloro-2-cyano..phenoxy)-phenyl sulfonyl chloride, the title compound was prepared: MS(ES) M+Wr=566, M+Na'=588 Example Preparation of -(Cbz-homo-eucinl)--aino-3-(2-dibenzofuransulfona.ido)p2rop~an-2-one Following the procedure of Example 5 1, except 2-dibeazofuransulfonyl chloride for 4 3 -Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride and Cbzhomo-leucine for Cbz-Ieucine, the title compound was prepared: MS(ES) M+Na'=602.

Example 56 Preparation ofI -(Cbz-leucinv! -arruno-3-(2-djbenzofuransulfonardo -(S)-buan- one~ a) I -(Cbz- leucinvl)-amino-S3- (2 -dibenzofurans ul fonamido)- )-butan-2 -ol Cbz-leu-2--amino-4-amnino-propan-3-oI (150 mg, 0.42 rnmol, as described in Example and 2-diberizofuransulfonyl chloride were dissolved in DIMF (2 ml) 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-F-f=582, M+Na&=604.

I -(Cbz-leucinyl)-am-ino-3-(2-dibenizofuransulfonamtido)-(S)-butan-2 -onle I- (Cbz- le uciny I)-arin o- 3 -djbenzofuransu Ifonamnido) bu tan-2 -ol1 (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was 15 added dropwise and the reaction was stirred at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 nil), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2x 20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/ methylene chloride) to 20 give the title compound as a white solid (70 mg, MS(ES) M-W=578.

C C C. C CC., C. C COCe CC*. C 0@C C I.e.

S

S

iC S C. 2~

C.

C

CCC.

C

CSC*

C

CCC.

C

.*CC

0 C C C p

C

C

S65e S C C S. C

C

CCC CC Example 57 Preparation of (S)-Phenylmethvl f I -fff3-rBenzvloxvcarbonyl-Ieucinyl-aminol-2oxoprop~yfl- 1 -(benzyl)arminolcarbonll-3-methvbuvllcarbamate a) 2-hydroxy-3-azido-propanol Sodium azide (1.7 g, 26 mmol) was added to a solution of glycidol (Aldrich, 1.3 g, 17.5 mmnol) in MeGH (45 ml) and water (5 ml) and was heated to 65 degrees C for 4 h. The reaction was diluted with water (25 nil), extracted with EtOAc (2 x nil); the combined organic layers were extracted with water (2 x 50 mld), then brine (50 ml), then were dried with magnes ium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 30 EtOAc/ hexanes) to produce a white solid (1.37 g, MS(ES) M+H+=1 18.4.

b) 2-hydroxy-3-azido-propan-tosylate .Tosyl chloride (2.3 g, 12 mmol) was added to a solution of 2-hydroxy-3azido-propanol 17 g, 10 mmol) and triethyl amine (3.6 g, 36 mnmol) in methylene chloride (50 ml) and was stirred at RT for 4h. The reaction was diluted with water ml), extracted with EtOAc (2 x 50 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-tetrahydropyrani-acetal)-3 -az.ido-propantosylate c) 2-Hydroxy- 3-azido-propan-tosy late (1.2 g, 4.4 mmol) was added to a slurry of Eliman dihydropyran polymer (cf. Scheme 1) (150 mg, 0.3 mimol) in ClCH2CH2CI (25 nil), then pyridinium p-toluenesulfonate (0.84 g. 4.4 mrnol) and was agitated at 80 degrees C by gentle bubbling with argon. The polymer was filtered, washed with DMF (2 x 10 mrl), then MeOW (20 ml), then methylene chloride (4 x 20 ml); IR 2105 cm-i1;. Magic Angle Spinning I1W NMR: d 8.0, 7.4, 5.0,3.4.

d) 2-(Memrfield Polymer-6-(oxymethylene-tetrahydropyran-acetal )-3-azidopropan-N-benzyl-amine Benzyl amine (0.32 g, 3 mmol) was added to a slurry of 2-(Memrfield polymer-6-(oxymethylene-tetrahydropyran-acetal)-3 -azido-propan-tosylate mg, 1 mmol) in N-methyl pyrolidinone (25 nil) and was and was agitated at degrees C by gentle bubbling with argon. The polymer was filtered, washed with DMF (2 x 10 ml), then MeOH (20 ml), then methylene chloride (4 x 20 ml); JR 2105cm-i1; Magic Angle Spinning I1H NMR:. d 7.1, 4.7, 4.0, 3.8.

e) 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetal)- 3-azidopropan-N-benzyl-(Cbz-leucinyl)-amine Cbz-leucine (0.82 g, 3.0 minol) was added to a slurry of 2-(Merrifield :polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-azido-propan-N-beazyl-amine (120 mg, 0.22 rnmol) in DMEF (10 ml), diisopropyl ethyl amine (1.2 ml, 6 rnmol) and HATU (Persepuive Biosystems, 2.2 g, 6 mmol) and was shaken at room temperature overnight. The resin was filtered, washed with DMOF (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 210b5,173 5, 1630 cm-i1;. Magic Angle Spinning I HNMIR: d 7.2, 4.7, 4. 1.

f) 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-aminopropan-N-benzyl-(Cbz-leucinyl)-amine Propanedithiol (0.5 ml, xx mmol) was added to a slurry of 2-(Merrifield polynier-6-(oxymethylene-tetrahydropyran-ac etal)-3-azido-propan-N-benzyl-(Cbzleucinyl)-amine (150 mg, 0.27 mmol) in MeOH (5 ml) and triethylaniine (0.5 ml) and was gently rocked overnight. The resin was filtered, washed with MeOH (2 x ml), then with DMF (1 x 10 ml), then with methylene chloride (5 x 20 mnl), and was dried in a vacuum oven overnight; JR 1735, 1640, cm- 1 '-(Merrfield polymer-6- .oxvme thylene -erudropy.ran-ace tal)y3 (Cbz leucinyl )-amino-propan -N-benzy l-(Cbz-leucinvl)-arrine Cbz-leucine (0.82 g, 3.Ornmol) was added to a slurry 2-(Merrifield polymer- 6-oyehln-erhdoya-ctl-3ann-rpnNbay-Czluiy) amine (150 mg, 0.27 mrnol) in N-methyl pyrollidinone (10 mil), diisopropyl ethyl amnine (1.2 ml, 6 mmol) and HBTU (2.2 g, 6 mmol) and was shaken at room temperature overnight. The resin was filtered, washed with DF (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 ml); Magic Angle Spinning 1I-H NMR: d 7.6, 7.4, 5.1, 5.0, 3.4, 0.8.

h) I -N-benzyl- 1 -Cbz-leucinyl-amino-3-Cbz-leucinyl-anno.propan2-o 2~-(Merrifid poye-6-(oxymethyeneterahydropyrancetal)..3.(Cz leucinyl)-amino-propan-N-benzy[-(Cbz-leucinyl) amine (150 mg, 0.27 mmol) was *15 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/ methlene chloride) to produce a yellow ~'*solid (65 mg, MS(ES) M+H+=675. 1.

20 1) 1 -N-beazyl- I -Cbz-leucinyl-amino-3-Cbz-leucinyl-amno.propan2-ne 1 -N-benzyl- 1 -Czluiy-ndo3Czluiy-mn-rpn2o mg, 0.96 mmol) was dissolved in acetone (5 ml) and Jones reagent (2 ml,excess) was added dropwise at room temperature and the reaction was stirrd overnight. The excess Jones reagent was then quenched with isopropanol (5 ml) and the reaction was diluted with water (5 ml) and was extracted with EtOAc (2 x 20 ml). The combined organic layers were extracted with water (2 x 15 ral), then brine (10 ml), then were dried with magnesium sulfate, filtered, concentrated in vacua 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)-Phenylmethvl r I -rr3-r(2-dibenzofuranylsulfonflamjno-2oxopropyl i-3-(benzvl)arninolcarbonvll-3-methylbutvllcarbamate a) N-(2-hydroxy-3-N-benzylamino-propyl)phthaliinide N-(2,3-Epoxypropyl)phthalimide (Aldrich, 2.03 g, 10 mmol) was reluxed with beazyl amine (1.07 g, 10 mmol) in isopropanol (15 mnl) for 3h. The reaction was cooled to RT, then concentrated in vacuo producing a white gum, which was triturated with MeOH, then filtered producing a white solid (0.48 g, MS(ES) 311.

N-(2-hydroxy-3-(N-benzyl-2-dibenzofuransulfonaniide)-propyl)phthaimide ::::*N-(2-hydroxy-3-N-benzylamino-propyl)phthalimide (0.31 g, 1 imnol) was stirred with 2-dibenzofuransulfonyl chloride (0.27 g, 1 minol) in N-methyl morpholie (0.8 ml) and DMF (5 ml) overnight. The reaction was diluted with water (10 extracted with EtOAc 2x.20 mal), the combined organic layers were extracted with water (3 x 20 ml), then brine (20 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce an oil, which was chroinatographed (silica gel, 30% EtOAc/ hexanes) to produce a white foam (Q.37 g, MS(ES) M+W=541, MS(ES) M+Na*=563, MS(ES- negative) M+HCO 2 585 2-yrx-N.ny--iezfrnufnmd)poy- .mn c) 2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide)-propylarmfle r~ (0.37 g, 0.69 minol) was refluxed with hydrazine hydrate (0.34 g, 6.85 nm.01o) in MeOH (7 ml) for 1.5 h. The reaction was cboled to RT, then was concentrated in vacuo. The resulting white solid was triturated with MeOH, then filtered to produce the desired product as a white solid (0.27 g, MS(ES) M+W*41 1.

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

mnmol) was stirred with Cbz-leucine 13 g, 0.5 mmol) in N-methyl morpholine 109 (0.6 rnrl) and DMIF (2 ml). then HBTU 0 19g-, 0.5 inmol) was added and the reaction was stirred overnight at RT. The reaction was diluted with water (10 ml).

extracted with EtOAc (2x20 ml). A solid that was insoluble in both layers was filtered off. The combined organic layers were extracted with water (2 x 20 ml), then brine (20 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce a white solid, which was used in the next reaction without further purification; MS(ES) M+W= 658, MS(ES) M+Na*= 680.

e) (S)-Phenylmethyl [1 [(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3 (benzyl)aminojcarbonyl]-3-methylbutyl]carbamate Cbz-leucinyl-(2-hydroxy-(N-benzyl-2-dibenzofuransulfonamide))-propyl.3 amine 16 g, 0.244 rnmol) 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 (I ml) and the reaction was diluted with water (10 ml) and was extracted with EtOAc (2 x. 20 ml). The combined 15 organic layers were extracted with water (2 x 20 ml), then brine (20 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo to produce a white 0 solid, which was chromatographed (silca gel, 1: 1 EtOAc/ hexanes) to produce a white solid 14 g, MS(ES) M-W=654, MS(ES) M+Cl*=690, MS(ES)

M+HCO

2 700.

Example 59 Preparation of (S)-Phenvlmethyl [1 -1f[3-[(2-dibenzofuranylsulfonyl)aniinoh-2- *Vo oxopropyll-3-(4-p2yrdinylmethvl)axninolcarbonyll-3-methylbutyllcarbamate Following the procedure of Example 58( except substituting "4pyridyl methyl amine" for benzylamine" and, fthe title compound was prepared; MS(ES) M+W=-657.

Example Preparation of I -f[f3- [(2-dibenzofuranylsulfonvl )aminol-2-oxoropvj1-3-(4pvyridinylmethyl) benzamide Following the procedure of Example except substituting "benzoic acid" for "Cbz-leucine", the title compound was prepared; MS(ES) M-W=5 1.

MS(ES) M+CI-=547.

Example 61 Preparation of (S)-Phenylmethyl rl1-rfF3-(2-dibenzofuranylsulfonvlDanmnol.2 oxoproly]- 1 4 -pvyidinylmethyl)ainocarbonyl1-3-methylbutyllcarbamate Following the procedure of Example except substituting "4- **~,*pyridyl methyl amine" for "benzylamnine" and "Cbz-leucine and HBTtJ" for "2dibenzofuransulfonyl chloride and "2-dibeazofuransulfonyl chloride for "Cbzleucine and HBTU". the title compound was prepared; MS(ES) M+W=-657.

Preparation of 2-rN-(N-benzyloxvcarbonyl-L-leucinyl)1-2'-rN'-4-.

phenoxyphenylsulfonvl)lcarbohydrazide a) N-benzyloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester hydrochloride (2.0 g, 1 I Ommol) in 1,4-dioxane (20 mL) was added Na 2

CO

3 (12.1 ml,-2M in water) followed by benzylchloroformate (1.96 g, 115 minol). The mixture was stirred at room temperature for 4h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated to yield the title compound as a colorless oil (3.1 g, 100%). IH NMR (400 M&L,

CDCI

3 867.34 (in, 5H), 5.27 5.12 2H), 4.41 2H), 3.75 3H), 1.65 (in, 3H), 0.96 (mn, 6H).

b) N -ben zyloxyc arbon v I-L -leuc in ylIhydrazi de To a stirring solution of the compound of Example 62(a) 1 a, 11.0 mmofl) in 15 mnL of methanol was added hydrazide hydrate (5.9 g, 118 mmol). The solution was stirred at room temperature for 16h then concentrated to Yield the tte compound as an off-white solid (3.1 g, 100%). MS(ESI): 280.2 c) (1 S)-l1-benzyloxycarbonylamino-3-methyl-l1-(1 3 4 yI)butane To a stirring solution of the compound of Example 62(b) (3.0 g, 10.8 rnlmol) in toluene (50 niL) was added phosgene (56 mL., 1.93M in toluene). T'he solution was heated at reflux for 4h then concentrated to yield the title compound as a pale yellow foam (3.15 g, MS(ESI): 306.1 d) 2 -(N-(N-benzyloxycarbony1-L-leucinyl)]carbohydrazide :15 To a stirring solution of the compound of Example 62(c) 147 g, 0.482 mmol) in 2 niL of methanol was added hydrazine hydrate (0.24 1 g, 4.82 minol).

The solution was stirred at room temperature for 24h then concentrated and purified by column chromatography (silica gel, methanolldichloromethane) to yield the title compound as a white foam (0.097 g, MS(ESI): 338.2 e) 2 -IIN-(N-beinzyloxycarbonyl..L.leucinyly[-2*.[N'-(4phenoxyphenylsulfonyl)]carbohydrazide To a stirring solution of the compound of Example 62(d) (0.097 g, 0.288 nimol) in 2 m.L of DMP was added pyridine (0.046 g, 0.576 nimol) followed by 4phenoxyphenylsulfonylctide 155 g, 0.576 rnmzol). The solution was stirred at room temperature for 16h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated.

The residue was purified by colun chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.052 g, 3 MS(ESI): 570.1 Example 63 Preparation of 2- fN-(N-benzvloUvCarbonvl -L-alanvl) I- N-N-benzv lox ycarbonl L-leucinyl)lcarbohydrazide To a stirring solution of the compound of Example 62(d) 100 g, 0.297 mm-ol) in 2 mL of DMF was added N-benzyloxycarbonyl-L-alanine (0.070 g, 0.312 mmol). Il-hydroxybenzotriazole (0-008 g, 0.059 mmol), and l-(3dimethylaminopropyl)-3-ethylcarbodiiinide hydrochloride (0.060 g, 0.312 mnaol).

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

MS(ESI): 543.1 Preparation of 2-[N-(N-benzyloxycarbonyl-L-leucinvfll-2'-I'N'-(4phenylbenzoyl)lcarbohydrazide Following the procedure of Example 63,_except substituting 4.-phenylbenzoic acid for N-benzyloxycarbonyl-L-alanine, the title compound was prepared as a white solid 121 g, MS(ESI): 518.1 Exmpl 6 Preparation of 2-[N-(N-benzloxvcarbonvl-L-leucinyl)1-2'-rN'-(4methoxybenzoyl')lcarbohydrazide Following the procedure of Example 63, except substituting 4methoxybenzoic acid for N-benzyloxycarbonyl-L-alanine the title compound was prepared as a white solid (0.057 g, MvS(ESI): 472.1 Example 66 Preparation of 2-f N-(N-benzvloxycarbonvl-L-Jeucinyl phenoxybenzoyl) lcarbohydrazide Following the procedure of Example 63, except substituting 4phenoxybenzoic acid for N-benzyloxycarbonyl-L-alarline the title compound was prepared as a white solid 102 g, MS(ESI): 534.1 Example 67 Preparation of 2-(N-acetyl)-2-rN'-(N-benvloxvcarbonl-L.

leucinyl)lcarbohydrazide To the compound of Example 62(d) 100 g, 0.297 rnmol) was added acetic anhydride (0.303 g, 2.97 rnmol). The solution was stirred at room temperature for 16h then concentrated to an off-white solid which was washed with 15 dichloromethane to yield the title compound as a white solid (0.086 g, 76%).

Example 68 Preparation of 2 -N-(N-aceyl-L-leucinyfll-2-N'-N-benzloxcarbonl.L alanyl~lcarbohydrazide a) 2- rN-(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 (1.1I g, 3.8 rnxol).

MS(ESI): 296.2 b) 2 -(N-(N-acety1-L-leucinyl)]-2'..[N'-(N- benzyloxycarbonyl.Lalanyl)]carbohydrazide To a stirring solution of the compound of Example 63(d) 150g, O.5O8rnmol) in DMF (2mL) was added N-acetyl-L-leucine (0.092g, 0.534mmol), 1 hydroxybenzotriazole (0.0 1 4g, 0. 1 2mmol), and 1 -(3-dimerthylaminopropyl)-3 ethvlcarbodiinude hydrochloride 102g, 0.5 34mmrol). After stirring at room temperature for 16h, the solution was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, methanoildichloromethane) to yield the title compound as a white solid (0.028 g, MS(ESI): 451.1 Example 69 Prep~aration of 2- rN-(N-acetyl-L-alanyl V1-2'-fN-(N-benzvloxycarbonlyl-L.

leucinvl) icarbohydrazide Following the procedure of Example 68(b), except substituting N-acetyl-Lalanine for N-acetyl-L-leucine and 2-[N-(N-benzyloxycarbonyl-L.

*leucinyl)]carbohydrazide for 2-[N(-ezlxcabn Laay)]abhdaie the title compound was prepared as a white solid (0.050 g, MS(ESI): 473.1 Example Preparation of 2 -fN-(N-benzyloxycarbonl-L-leuciny12-N'4-4N.N dimethylarninomethylbenzovl)llcarbohydrazjde a) methyl 4 -(NN-dimethylarninomethyl)benzoate 20 Methyl 4-(bromomethyl)benzoate (2.0 g, 8.73 rnmol) was added to a saturated solution of dimethylamine in methanol. After stirring for 25 mini, the solution was concentrated and the residue was partitioned between IN NaOH and ethyl acetate. The organic layer was washed with saturated brine, dired (MgSO 4 filtered, and concentrated to provide the title compound as a colorless liquid (1.67 g, IH NMR (250 M&z, CDCl 3 8 8.00 2H), 7.39 2H), 3.91 3H), 3.47 2H), 2.25 6H).

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

TH{FIH

2 0 1) and LiOH*H,)0 (0.39 g, 9.3 mmol) was added. The mixture was stirred at room temperature for 0.5h, then taken to reflux. for 1.5h. The mixture was concentrated, redissolved in 2"5rnL of water and reconcentrated to yield a white solid (1.6 g, 100%). 1 H NMR (400 Mfiz. CD 3 OD) 5 7.94 (di. 2H), 7.36 2H), 3.64(s, 2H), 2.35 6H).

c) 2- [N-(N-benzyloxycarbonyl-L-leucinyl)J-2'-[N'-[4-(N,Ndimethylaminomethyl )benzoyl)]Jjcat-bohydrazide Following the procedure of Example 68(b), except substituting 4-(N,Ndimethylaminornethyl)beazoic acid lithium salt for N-acetyl-L-leucine and 2[N-(Nbenzyloxycarbonyl-L-leucinyl)]carbohydriazide for 2-[N-(N-benzyloxycarbonyl-L alanyl)]carbohydrazide, the title compound was prepared as a pale yellow solid (0.050 g, MS(ESI): 499.1 Example 71 :Preparation of 2-rN-(N-benzyloxycarbonyl-L-Ieucinyl)1-2-rN-f4-hydrox-r3-(4- 15 morpholinomethvl)flbenzovflcarbohydr-azide 0 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)]carbohydrazide for 2- [N-(N-benzyloxycarbonyl-L- ::aa al any 1)]carbohydrazide, the title compound was prepared as a white solid (0.065 g 'a 20 MS(ESI): 557.0 Example 72 Preparation of 2-fN-(N-benzyloxycarbonvl-L-leucinvl)1-2'-fN'-4-(NNdimethvlaminomethyl)benzvloxy]carbonyl-L-leucinvlcarbohydrazide a) a-isocyanato-L-leucine methyl ester L-leucine methyl ester hydrochloride (25 g, 0.14 mol) was dissolved in methylene chloride (450 mL), cooled to 0 and pyridine (43.5 g, 0.55 mol, 44.5 mL) was added, then a 1.93 M solution of phosgene in toluene (0.18 mol, 92.7 mL) was added slowly. After stirring at 0 *C for 2 h, the mixture was poured into 1400 mL of 0.5 N Hcl and 900 mL of ice. The organic layer was washed with 1400 mL of 0.5 N Hcl and 900 mL of ice. The aqueous layers were extracted with methylene chloride (450 mL) and the combined organic layers were washed with 1400 mL of saturated brine and 900 mL of ice, then dried (MgSO 4 filtered and concentrated.

The residue was distilled (56-58 C-0.78 mmHg) to provide the title compound as a colorless liquid (20.4 g, 1 H NMR (250 MHz, CDC1 3 8 4.04 (dd, 1H), 3.82 15 3H), 1.92-1.72 1H), 1.69-1.62 2H), 0.96 3H), 0.94 3H).

b) 4-(N,N-dimethylamino)benzyl alcohol To a stirring solution of the compound of Example 70(a) (1.63 g, 8.4 mmol) in 25 mL of ether, cooled to 0 was added dropwise a 1 M solution of lithium aluminum hydride (8.4 mmol, 8.4 mL). After 5 min, the reaction was quenched by the addition of water (0.33 mL), 15% aqueous NaOH (0.33 mL) and water mL). The precipitate was removed by filtration, washed with ether 2 times and the filtrate was concentrated to provide the title compound as a colorless oil (1.36 g, 1 H NMR (250 MHz, CDC13) 8 7.32 2H), 7.28 2H), 4.68 2H), 3.41 2H), 2.22 6H).

c) N-[4-(N,N-dimethylaminomethyl)benzyloxycarbonyl]-L-leucine methyl ester A solution of the compound of Example 72(a) (1.0 g, 5.8 mmol) and the compound of Example 72(b) in toluene (6 mL) was heated at reflux for 24 h. The solution was concentrated and the residue was purified by flash chromatography on 117 a of 230-400 mesh silica gel, eluting with 517% methanol in methylene chloride, to provide the title compound as a pale yellow oil (1.71 g, 1 H NMR (400 MHz.

CDCI

3 87.31 4H), 5.13 1H), 5.10 2H), 4.41 1H), 3.74 3H). 3.43 2H), 2.24 6H), 1.70-1.62 2H), 1.52 111), 0.96 3H), 0.94 3H).

d) N-[4-(N,N-dimethylaminomethyl)benzyloxycarbny].L-leucine lithium salt Following the procedure of Example 70(b), except substituting dimethylaminomethyl)benzyloxycarbonyl]-L..eucine methyl ester for methyl 4- (NN-dimethylaminomethyl)benzoate, the title compound was prepared as a white solid (1.57 g, 1 H NMR (400 MHz, CD 3 OD) 5 7.35 2H), 7.30 2H), 5.06 (dd, 2H), 4.10 (dd, 3.48 2H), 2.23 6H), 1.69-1.51 3H), 0.94 (d, 3H), 0.93 3H).

e) 2- [N-(N-benzyloxycarbonyl-L-leucinyl). dimethylainomethyl)benzyloxycarbonylleucinyllchyade Following the procedure of Example 68(b), except substituting N-[4-(NNdimethylaminomethyl)benzyloxycarbonyl-Lleucine lithium salt for N-acetyl-Lleucine and 2 -[N-(N-benzyloxycarbonyl-L-leucinyl)Icarbohyd-zde for benzyloxycarbonyl-L-alanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.069 g, MS(ESI): 642.1 Exampir, 73 Preparation of 2 -(N-benzovl)-2'-rN'-(N-benzyloxvcarbonvlL leucinyl)lcarbohydrazide Following the procedure of Example 62(e) except substituting benzoyl chloride for 4-phenoxyphenysulfonylchloride, the title compound was prepared as a white solid (61mg, 3 MS(ESI): 442.1 Example 74 Preparation of 2-rN-(N-benzvloxvcarbonyl-L-Ieucinvl) morpholinomethyl )benzoyvl carbohydrazide a) methyl 3-(4-morpholinomethyl)benzoate A solution of morpholine (0.836 g, 9.6 inmol) and mnethyl 3- (bromomethyl)benzoate in TI-IF (5 mL) and DMF (5 ml) was stirred at 50 0 C for 3h. The solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated aqueous NaHCO 3 and brine then dried (MgSO 4 filtered and concentrated to yield a colorless oil (0.872 g, 3.72 nunol). I H NMR (400 M[Hz, CDC1 3 8 7.99 IlH), 7.91 I 7.55 INH), 7.47 IH), 3.94 3H), 3.72 (in, 4H), 3.53 2H), 2.46 (mn, 4H).

b) 3-(4-morpholinomethyl)benzoic acid To a solution of the compound of Example 74(a) (0.872 g, 3.72 mmol) in THE (3 mnL) and water (3 mL) was added lithium hydroxide monohydrate 17 1 g, minol). After stirring at room temperature for 3h, the solution was concentrated. The residue was redissolved in water (5 mL) and 3N HCI was added and the solution was lyophilized to yield a yellow solid (0.822 g, 3.72 mmol).

MS(ESI): 222.0 C) 2-[N-(N-benzyloxycarbonyl-L-leucinyl))-2'-[N4-3-(4morpholinomethyl)benzoyl]]carbohydrazide Following the procedure of Example 68(b), except substituting 3-(4rnorpholinomethyl)benzoic acid for N-acetyl-L-leucine and benzyloxycarboiiyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.056 g, MS(ESI): 541.0 119 Example Preparation of 2 -(N4(3-benzloxybenzoyl )1-2 benzvloxvcaronvl leucinyil icarbohydrazide a) methyl 3 -benzyloxvbenzoate To a suspension of NaI- (0.395 g, 9.87 rnmol, 60% in mineral oil) in DIMF znL) was added methyl 3-hydroxybeazoate 1 0 g, 6.58 mmol). After stirring for 15 min at room temperature, benzyl bromide (I.1I g, 6.58 mniol) 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 mmrol). IH NMiR(400 MIHz,

CDCI

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

3-benzyloxybenzoic acid 15 To a solution of the compound of Example 75(a) 0 4 0 0 g, 1.65 mmol) in TI-IF (2 m.L) and water (2 rnL) was added lithium hydroxide monohydrate (0.076 g, 1.82 mmol). After stirring at reflux for 5 h, the solution was partitioned between ethyl acetate and 3N HCI. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated to yield a white solid (0.355 g, 1.56 minol). I H 20 NMR (400 NMHz, CD 3 OD) 587.58 (in, 2H), 7.36-7.24 (in. 6H), 7. 10 (in, IlH), 5.04 2ff). c) 2 -(-(3-benzyloxybezoy)..2'-.[N'-(N-benzyloxycarbonylL.

Ieucinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting 3benzyloxybenzoic acid for N-acetyl-L-leucine and 2 -[-(N-benzyloxycarbonyl.L leucinyl)]carbohycirazide for 2-N(-ezlxcroy--lnllabhdaie the title compound was prepared as a white solid (0.062 g, MS(ESI): 548.1 Example 76 Preparation of 2-f N-(iN-benzvloxycarbonyl-L-leucinyl)1-2-r'4 f~f3-(N-N.

dirnethvlami~no)-lI-propyloxvlbenzovll1lcarbohvdrazide a) methyl 4-[3-(N,N-dimethylarnino)- 1 -propyloxyjbenzoate To a solution of methyl 4-hydroxybenzoate (1 .0 g, 6.58 inmol), 3dimethylamino-1-propanol (1.01 g, 9.87 minol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0 0 C in THEF (20 mL) 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, methanoldichloromethane) to yield the title compound as an oily solid (1.25 a, 5.2 **:mxnol). MS(ESI): 238.1 b) 4-[3-(N.N-dimethylamino)-1I-propyloxyjbenzoic acid S. Following the procedure of Example 74(b) except substituting methyl 4-(3- (N,N-dimethylamino)- 1 -propyloxylbenzoate for methyl 3-(4morpholinomethyl)benzoate, the title compound was prepared as a tan solid 17 g, 5.2 mmol). MS(ESI): 224.1 1 -propyloxy]benzoyl]]carbohydrazide Following the procedure of Example 68(b), except substituting 9:555:dimethylamino)- 1 -propyloxy]benzoic acid for N-acetyl-L-leucine and 2-IjN-(Nbenzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the. title compound was prepared as a white solid (0.060 g, 2 1 MS(ESI): 543.1 Example 77 Preparation of 2-N(-ez])yezy)-'-N-NbnyoyabniL leucinyl carbohydrazide Following the procedure of Example 68(b), except substituting 2benzyloxybenzoic acid for N-aceryl-L-leucine and 2 -[N-(N-benzyloxvcarbonyp-L.

leucinyl)jcarbohydrazjde for 2 -[N-(N-benzyloxycarbony1-L-alanyl)Ica.Ibohydrazide, title compound was prepared as a white solid (0.056 g, MS(ESI): 548.1 Example 78 :.,eeePreparation of 2-rN-(N-benzloxcarbonl-L-Ieucinvi)1..2i-N'.r3-( 4 -0.6*0pyridylmethoxy)benzovlllcarbohydrazide methyl 4 -pyridinylmetboxybenzoate Following the ptocedure of Example 76(a) except substituting methyl 3hydroxybeazoate for methyl 4-hydroxybenzoate and 4-pyridylcarbinol for 3dirnethylamino-1I-propanol, the title compound was prepared as a yellow solid (0.599 g, 2.5 mmol). MS(ESI): 244.1 b) 4 -pyridinylmethioxybenzoic acid .20 Following the procedure of Example 75(b) except substituting methyl 4- *pyridylmethoxybeazoate for methyl 3-benzyloxybenzoate the ti "tle, compound was prepared as a yellow solid (0.386 g. 1.69 inmol). !H.NMR-(400 MHz, CD 3 OD) 8 8.54 2H), 7.64 (mn. 2H), 7.57 (mn, 2H), 7.40 (in, I1-H), 7.26 IH), 5.24 2H).

c) 2- (N-(N-benzyloxycarbony-L-leuciyl)..2'-[N'.(3(4.

pyridylmethoxy)benzoyl]]carbohydrazide Following the procedure of Example 68(b), except substituting 4pyridinylmethoxybenzoic acid for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, title compound was prepared as a white solid (0.2 19 g MS(ESI): 549.1 Example 79 Preparation of 2-N(-ezlxbnol12-N-NbnvoyabnlL leucinyl)Icarbohydrazide Following the procedure of Example 75(a)-75(c) except substituting methyl 4-hydroxybeflzoate for methyl 3-hydroxybenzoate in step the title compound was prepared as a white solid 160 g, MS(ESI): 548.1 9 10 Preparation of 2-rN(N-benzyloxycarbonyl-L-leucinl)1%2-rN-(3-benzloxy-5- 9**9 methoxy)benzoyllcarbohydrazide methyl A suspension of methyl 3,5-dihydroxybenzoate (2.0 g, 11.9 mmol), K 2 C0 3 g, 11.9 mmol), and jodomethane (1.7 g, 11.9 mmol) in acetone (100 mL) was stirred at reflux. After stirring for three hours the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a white solid (0.8 13 g, 4.4 mmol). I H NMIR (400 M1Hz, a...CDCI 3 8 7.16 (in, I 7.12 (in, I 6.61 (in, I1H), 5.04 1lH), 3.91 3H) 3.82 b) methyl Following the procedure of Example 80(a) except substituting methyl 3for methyl 3.5-dihydroxybenzoate and benzyl brom-ide for iodoinethane, the title compound was prepared as a tan oil (1.2 g, 4.4 inmol).

1H NMIR (400 IHz, CDC1 3 5 7.45-7.31 (in, 6H), 7.24 1H), 6.76 (in, IH), 5.09 2H), 3.95 3H), 3.84 3H).

C) 3-benzyloxy-5-methoxybenzoic acid Following the procedure of Example 75(b) except substituting methyl 3for methyl 3-benzyloxybenzoate, the title compound Example Preparation of 2-[N-(N-benzyloxycarbonyl -L-leucinvl phenyiphenvlaceryl carbohydrazide Following the procedure of Example 68(b), except substituting 4biphenylacetic acid for N-acetyl-L-leucine and 2 -[N-(N-benzyloxycarbonyp.L.

leucinyl)jcarbohydrazide for 2 -[N-(N-benzyloxycarbonyI-L-alanyl)]carbohydrazide, the title compound was prepared as a white solid (0.224 g, 71%) MS(ESI):- 554.2 Example 86 :.ePrep~aration of (2S--N(-ezlxyezy *'f'(-hnzyoyabnl2 aminobulyryl )lcarbohydrazide Following the procedure of Example 68(b), except substituting berlzyloxycarbonyl-2-aminobutyic acid for N-acetyl-L-leucine and 15 benzyloxybenzoyl)Jcarbohydrazide for 2 -[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.244 g, MS(ESI): 520.3 Example 87 20 Preparatioxn of N .i-...ey~hnlciy~laboyrzd To a stirring solution of carbohydrazide (0.200 g, 2.22 rnmol) in DMF (12 m.l) was added 4-biphenylacetic acid (1.04 g, 4.89 minol), I1-hydroxybenzotniazole (0.060 g, 0.444 mniol), and l-( 3 -dimethylaninopropy)-3-ethycarboiiide hydrochloride (0.937 g, 4.89 mmol). After stirring at room temperature for 16 h, the solution was poured into 150 mL of water. The precipitate was filtered and washed with water (150 mL) and dried under high vacuum to yield the title compound as a white solid (0.977 g, MS(ESI): 501.1 126 Example 88 Preparation of (2'RS )-2-rN-(N-benzyloxycarbonvl-L-leucinv!)1-2 -r2-(4p2henylphenoxy)p2ropionvllcarbohydrazide Following the procedure of Example 68(b), except substituting 2-(4phenylphenoxy)propionic acid for N-acetyl-L-leucine and benzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-L alanyl)]carbohydrazide, the title compound was prepared as a white solid 183 g, MS(ESI): 562.3 Example 89 V~o P'reparation of 2-rN-(3-benzyloxybenzoyl)1-2'-[N'-(4methylpentanofllcarbohydrazide Following the procedure of Example 68(b), except substituting 4- S. methylpentanoic acid for N-acetyl-L-leucine and 15 benzyloxybenzoyl)jcarbobydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid (0.079 g, MS(ESI): 399.3 see* &of* Example Preparation of Q2RS. 2 'RS)-2.2'-fN.N'-Fbis-f2-(4-phenvIpheny1)-4.

methylpentanovl )lilcarbohydrazide a) 4 -methyl-2-(4-phenylphenyl)pent.4-enoic acid To a stirring solution of dilsopropylamine (0.53 7 g, 5.31 rnmol) in THE (5.2 mL) at 0 'C was added n-butyllithium (2.1 mL. 5.22 mrnol, 2.5M in hexane) dropwise. After stirring for 15 min at 0 0 C, the mixture was cooled to -78 0 C and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 niL) was added dropwise. After again warming to 0 'C and coolling to -78 0 C, 3-bromo-2methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After 0 0. stirring at -78 0 C for I h, the reaction was quenched with 2 mL of water then 0 concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCI) and extracted with ether (3 X 100 0. 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 b) 4 -methyl-2-(4-phenylphenyl)pentanoic acid To a stirring solution of the compound of Example 90(a) (0.449 g, 1.69 mmol) in ethyi acetate (25 miL) was added palladium on carbon (0.225 After 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 (9.430 g, .o MS(ESI): 267.4 C) 2RS, 2'RS)-2,2'-[NN-[bis-[2-(4-phenylphenyl).4 rnethylpentanoyl)]]]carbohycdrazde Following the procedure of Example 87 except substituting 4-methyl-2-(4phenylphenyl)pentanoic acid for 4-biphenylacetic acid, the title compound was obtained, after purification by column chromatography (silica gel, methanol/dichloromethane), as a white solid 143 g, MS(ESI): 591.3 (M-iH) 4 Exampe 91 Preparation of (2'RS)-2-[N-(N-benzyloxycarbonyl-L-leuinl)-2- N2-( 4 phenvllhenyl )-4-methylpentanoyl) I carbohydrazide Following the procedure of Example 68(b), except 4-methyl-2-(4phenylphenyl)pentanoic acid for N-aceryl-L-leucine and 2-IIN-(Nbenzyloxycarbonyl-L-leucinyl)]carbohydrazide for 2-IIN-(N-benzyloxycarbonyl-L.

alanyl)]carbohydrazide, the title compound was prepared as a white solid 111 g, MS(ESI): 588.1 Example 92 Preparation of (2'RS)-2-fN-(3-benzyioxybenzoyl)l- 2 '-rN'-[2-(4-phenvlphenyl methvlpentanoyl lcarbohydrazide Following the procedure of Example 68(b), except substituting 4-methyl-2- (4-phenylphenyl)pentanoic acid for N-acetyl-L-leucine and 15 benzyloxybenzoyl)]carbohydrazide for 2-fjN-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid 195 g, MS(ESI): 551.1 Example 93 Preparation of 2-[N-(3-benzyloxvbenzoyl)1-2'-FN'-(N-benzyLoxycarbonyl-N-methyl- L-Ieucinfllcarbohydrazide 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-Lalanyl)]carbohydrazide, the title compoundwas prepared as a white solid (0.341 g, 9 MS(ESI): 562.2 Example 94 Preparation of 2-[N-(3-benzyloxybenzov1)1.2rN'-rN(2- D2yridinylmethoxycarbonvl )-L-leucinvl lcarbohydrazide a) N-( 2 -pyidinylmethioxycarbonyl)-L-leucjne methyl ester Following the procedure of Example 72(c), except substituting 2pryidylcarbinol for 4 (N,N-dimethyl amizno) benzyl alcohol, the title compound was prepared as a brown oil (8.06 g, MS(ESI): 281.2 b) 2-N(-yiiyymtoyabnl--ecnlcroyrzd Following the procedure of Example 62(b)-62(d) except substituting N-(2pyridinylmethoxycarbonyl)-L-eucine methyl ester for L-leucine methyl ester in step the title compound was prepared as a pale yellow foam (0.598 g, 69%).

MS(ESI): 339.3 (M-iH)t.

c) -benzyloxybenzoyl) 2 -pyridinylmethoxycarbonyl)-L.

leucinyl] ]carbohydrazide Following the procedure of Example 68(b), except substituting 3benzyloxybenzoic acid for N-acetyl-L-leucine and pynidinylylmethoxycarbony)L-eucinyl~carbohydrazide for 2- benzyloxycarbonyl-L-alanyl)Icarbohydrazide, the title compound was prepared as a white solid (0.057 g, MS(ESI): 549.2 Example Preparation of 2-rN-3-(4-pyridylmethoxymenzoylll2'.rN'-j.(2pyvridinylmethoxycarbonyl)-L~eucinlllcrohvdraide Following the procedure of Example 68(b), except substituting 3-(4pyridinylmethoxy)benzoic acid for N-acetyl-L-leucine and pyiiyymtoyabnl--ecnlcroyrzd for 2- bezlxcroy--lnllabhdaie the title compound was prepared as a yellow solid (0.088 g, MS(ESI): 550.2 Example 96 Preparation of (2RS )-2-rN-r2-(4-p2henylphenyl )-4methlpentanoyl )11-2 NJ N-(2 pvridinylmethoxycarbonvl )-L-leucinyvl carbohydrazide Following the procedure of Example 68(b), except 4-methyl-2-(4phenylphenyl)pentanoic acid for N-acetyl-L-Jeucine and pyridinylylmethoxycarbonyl)-L-leucinyljcarbohydrazide for benzyloxycarbonyl-L-alanyl)]carbohydrazide, the title compound was prepared as a yellow solid (0.056 g, MS(ESI): 589.4 Example 97 Prep~aration of 2-rN-(N-benZyloxycarbonyl-L-leucinl)1-2'-rN'-[2-(4-phenylphenl 4-methvlperitanoyl )llcarbohydrazide .*~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~mm, retention time 5.9 min).

Example 98 Preparation of 2- fN-(N-benzyloxvcarbonyl-L-Ieucinyl'1 -2'-rN'-f2-(4-phenvlphenvl)- 4-methylpentanoyl~llcarbohydrazide 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~mixi, *:aaaretention time 8.1 min).

Example 99 Preparation of 2-fN-(N-benzvloxvcarbonyl-L-leucinvl)1-2'-rN'-fN-(4phenylp~henyl)-N-(2-methy1lpropl y)carbamovl lcarbohydrazide To a stirring solution of phosgene (0.228 maL, 0.244 mmol, 12.5% solution in benzene) was added dropwise a solution of N-(2-methylpropyl)- N-(4phenylphenyl)amine (0.050 g, 0.222 mmol) and triethylamine (0.025 g, 0.244 mmol) in dichloromethane (1 mL). After stirring at roam temperature for 15 tni this solution was added dropwise to a solution of the compound of Example 1 (d) (0.083 g, 0.244 mmol) and triethylamine (0.025 g, 0.244 mmol) in dichioromethane (1 mL) at room temperature. After stirring at room temperature for 48h, Nmethylmorpholine (0.022 g, 0.222 mmol) and DMIF (2 mL) were added to the solution and heated at 50 0 C for 16h. The solution was then diluted with ethyl :::.acetate (5miL) and washed successively with water, aqueous saturated NaH-C0 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The 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 20 Preparation of 2-rN-(3-benzyloxybenzovl'1-2'-rN'-(N-methyl-Lleucinyflicarbohydrazide a) 2-(N-(3-benzyloxybenzoyl)]-2'- [N'-(N-:ert-butoxycarbonyl-N-methyl-Lleucinyl)]carbohydrazide Following the procedure of Example 68(b), except substituting N-tertbutoxycarbonyl-N-methyl-L-leucine for N-acptyl-L-leucine and benzyloxybenzoyl)]carbohydrazide for 2-[N-(N-benzyloxycarbonyl-Lalanyl)]carbohydrazide, the title compound was prepared as a white solid 183g, MS(ESI): 550.4 (M+Na) 4 b) 2-[-3-ezlx ezv1] N-N-eh ecnl croyrzd To a stirring solution of the compound of Example 1 00(a) 100 g, 0. 189 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (0.296 g, mmol). After stirring at room temperature for 15 mmii, the solution was concentrated and the residue was purified by colufm chromatography (silica gel, methanol/dichloromethale) to yield the title compound as a white solid (0.055 g, MS(ESI): 428.4 Example.101 Preparation of 2-[N-(N-benzyloxvcarbonyl-L-leucinVI)1-2-fN'-(N-methVI-Lleucinylmcarbohydrazide Following the procedure of Example I100(a)- I100(b), except substituting 2- [N(-ezlxcroy--luiy)croyrzd for benzyloxybenzoyl)]carbohydrazide in step the title compound was prepared.

MS(ESI): 465.5 Preparation of (1 I benzyloxycarbonvlamino)-3-methlbuylthiazoIylcarbonyll-N'-44-phenoxyphelulfoylhydrazide a) N-benzyloxycarbonyl-L-leucflamihde To a stirring solution of N-benzyloxycarbonyl-L-1eucifle 6 g, 17.3 mmol) in THIF, cooled to -40 0 C, was added N-methyhnorpholine (3.68 g, 36.4 mmol; rnL) and isobutyl chloroformate (2.37 g, 17.3 mimol; 2.25 mL). After stirring for min, ammonia was bubbled through the solution for 5 min. The solution was warmed to room temperature, evaporated, and the residue was dissolved in ethyl acetate, washed with 0. 1 N Hcl, and saturated brine, then dried (MgSO4), filtered and evaporated to dryness to give the title compound as a white solid (4.58 g, 100%).

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

c) -benzyloxycarbonylamino- -(4-carboethoxythiazol-2-yl)-3methylbutane The compound of Example 102(b) (2.20 g, 7.83 mmol) was dissolved in acetone (35 mL), cooled to -10 and ethyl bromopyruvate (1.68 g, 8.62 mmol, 1.08 mL) was added. After stirring for 1 h, the solution was poured into methylene chloride/water, then into saturated aqueous NaHCO 3 The aqueous layer was i 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 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 5 8.08 1H), 7.38 5H), 5.42 3H), 5.23-5.07 3H), 4.42 2H), 2.01-1.62 3H), 1.41 3H), 0.99 6H).

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

H

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

5.14-5.09 3H), 4.07 (bs, 2H). 1.92-1.82 (in. I 1. 79-1.66 (m,1 2H), 1.00 (d, 6H).

e) (I 1 -benzyloxycarbonylaino)-3-methylbutyljthiazol-4ylcarbonyl]I-N'-(4-phenoxyphenylsulfonyl)hydrazide To a stirring solution of the compound of Example 102(d) (275 mg, 0.76 inmol) in dichioromethane at room temperature is added pyridine (180 mg, 2.28 mimol, 0.2 mL) and 4-phenoxybenzenesulfonyl chloride (408 mg, 1.52 mmol). The reaction was stirred for 16 hours and the solvents were evaporated to a residue which was chromatographed (silica gel, 40% ethyl acetate in hexane) to give the title compound as a white solid (0.310 MS (ESD): 595.6 :~".Example 103 Preparation of (1 5)-N-IA- rl1-(N-benZyloxvcarbonyl-L-leucinyLa-nino)-3- **15 methvlbutyl ltliiazol-2-ylcarbonvll-N'-(N-benzyloxvcarbonyl-L-leucinyl)hvdrazide a) N-benzyloxycarbonyl-L-leucinyl-L-leucinyl bromomethylketone 1 -Methyl-3- nitro- 1 -nitrosoguanidine (5.9 g, 40.11 nunol) in ether (200 mL) is cooled to 0 0 C. 40% potassium hydroxide is added slowly and the diazomethane is allowed to collect in the ether solution for 30 minutes at 0 0

C.

N-benzyloxycarbonyl-L-Leucinyl-L-Leucine (Bachem) (4.0 g, 10.58 mnmol) is stirred in tetrahydrofuran at -40*C. N-metbylniorpholine (l.07 g, 10.58 mamol, 1. 16 mL) and isobutyl chloroformate (1.45 g, 10.58 mnmol, 1.38 niL) are added.

The mixture is stirred at -40'C for 15 minutes and then filtered into a cold flask to remove precipitated salts. To the filtered solution is added an excess of the previously prepared diazomethane solution and the mixture is allowed to stand at 0 0 C for 16 h. An excess of 30% HBr in acetic acid is added at 0 0 C and the solution is then washed successively with 1LON citric acid, saturated aqueous sodium bicarbonate (carefully), and brine. The solution is dried over sodium sulfate, filtered, and evaporated to give the title compound as a white solid (4.10 IH NMR (400 MiHz, CDC13) 8 7.34 (in, 5H), 6.51 IN), 5.15 1H), 5. 10 2H), 4.78 (in, IH), 4.20 (in, 1H), 4.04 (dd, 2H), 1.63.(m, 6H), 0.93 (mn, 12H).

b) (2S,1 IS)-2-(benzyloxlvcarbonyl)an-pnoN4[ I 2 -carboethoxvthiazo1..-vyly3'methyl bury] J-4-methylpentanamnide The compound of Example 103(a) (2.0 g, 4.4 m-mol) and ethyl thiooxarnate (0.59 g, 4.4 mmol) were refluxed in ethanol for 4 h. The solvent was evaporated and the residue chromatographed (silica gel, 2.5% methanol/dichloromethane) to give the title compound as a white solid (1.46 ~IH NMR (400 MIHz, CDCI3) 5 7.32 (s, IH), 7.21 (in, 5H1), 6.40 INH), 5.13 (dd, I 5.02 2H), 4.41 2H), 4.06 (in, IN), 1.71 (in, 2H), 1.47 (in, 4H), 1.33 3H), 0.73 (mn, 12H).

c) (2S. 1 'S)-2-(benzyloxycarbonyl)amno.N..[ I 2 -hydrazin ocarbonylthiazolA4 6666yl)- 3 '-methylbutylIA4-methylpentanarmjde 6:*oFollowing the procedure of Example 102(d), except substituting (2S,1'S)-2- 0. 90 (benzV~yloyronyln~hvamn-NMrl '/(2-arbethxytiazo-,l-'mthlu 0 6 15 methylpentanainide for (IlS)-lI-benzyloxycarbonylaino1(4carothoxythil-) 0990 yl)-3-methylbutane, the title compound was prepared. MS (ESI): 476.3 6660 *666d) (1 1-(N-benzyloxycarbonyl-L..leucinylamjino)-3 666me thy lbu tyl ]tIao 2yIabnl-N-(-ezlxcroyL-u ilhdaie 6 20 To a stirring solution of the compound of Example 103(c) (180 mng, 0.3 8 mmol) in dimethylformanide is added N-benzyloxycarbonyl-L-leucine (111 mg, 00 00.42 minol), 1-( 3 -dimethylaminopropyl)-3..ethylcarlbodimde hydrochloride (80 mg, 0.42 rnmol), and Il-hydroxybenzotriazole 13 mg, 0.096 minol). The reaction mixture is stirred for 16 hours at room temperature, filtered, and washed twice with water. The solvent was evaporated to give the title compound as a white solid.

(0.207 MS (ESI): 723.9 136 Example 104 Preparation of (1 S)-N-r2-[IY .benzyloxvcarbonvlarnino )-3-methylburvl lthiazol-4vicarbonvi 1-N'-(4-phenylphenylacetvl)hydrazide Following the procedure of Example 103(d), except substituting (IlS)-lbenzyloxycarbonylamnino- I .(4-hydrazilnocarbonylthi azol-2 -yI)-3 -methyl butane for (2S, I 'S)-2-(benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3' methylbutyl]-4-methylpentanamide, and 4-biphenylacetic: acid for Nbenzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid.

'MS (ESI 557.2 Example 105 Preparation of (1 1-benzvloxycarbonlarino)-3-methylbuyllthiazol-4vlcarbonyll-N'- r3-(4-prvidinvlmethoxy)benzovllhydrazide a) methyl 3-(4-pyridinyllmethoxy)benzoate 15 To a stirring solution of methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol), 4pyridylcarbinol 1 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) in THF (25 mL) at 0 0 C was added diisopropyl azodicarboxylate (2.0 g, 9.87 rnxol) dropwise. After stirring at room temperature for 16h, the solution was concentrated 0% and purified by column chromatography (silica gel, ethyl a cetate/hexane) to yield the tidle compound as a white solid (0.599 g, MS(ESI): 244.1 (M+H) 4 b) 3-(4-pyridinylimethoxy)bcnzoic acid To a stirring solution of the compound of Example 105(a) (0.599 g, 2.47 mmol) in THFIH 2 O 10 mL) was added lithium hydroxide monohydrate 113 g, 2.71 mnmol). After stirring at reflux for 3.5h, 1.1 eq of 1N HCl was added and the mixture poured into water. The mixture was extracted with ethyl acetate (2 X 100 niL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a yellow solid (0.386 g, 1 H NMR (400 M&z, CD 3 OD) 8 8.54 2H), 7.64 (in, 2H), 7.57 (mn, 2H), 7.40 (mn, I 7.26 (in, IlH), 5.24 2H).

C) (I 1 -benzvloxvcarbonvlamino )-3-methylbutvljthiazol-4ylcarbonyll [3-(4-pryidinvlme thoxy)benzovlj]jhydrazide Following the procedure of Example 103(d), except substituting (IlS)-1benzyloxycarbonylamino-1I-(4-hydrazinocarbonylthiazol-2-yl)-3 -methylbutane for (2S, 1 'S)-2-(benzyloxycarbonyl)am-ino-N-[ I -(2-hydrazinocarbonylthiazol-4-yl)-3methylburyl]-4-methylpentanamijde, and 3-(4-pyridinylmethoxy)be oic acid for Nbenzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid.

MS (ESD: 574.2 Example 106 Preparation of N- f2-(2-chlorop~henoxvmethvl )thiazol-4-ylcarbonyll1-N'-rN-(4pvridinvlmethoxvcarbonvl '-L-leucinyllhydrazide a) cz-isocyanato-L-leucine methyl ester **.L-leucine methyl ester hydrochloride (25 g, 0. 14 mol) was dissolved in *~15 met~hylene chloride (450 mL), cooled to 0 C, and pyridine (43.5 g, 0.55 mol, 44.5 was added, then a 1. 93 M solution of phosgene in toluene 18 mol, 92.7 ml) was added slowly. After stirring at 0 'C for 2 h, the mixture was poured into 0.5 N HCl (1400 mL) and ice (900 rnL). The organic layer was washed with 0.5 N HCl (1400 mL) and ice (900 The aqueous layers were extracted with methylene chloride (450 mL) and the combined organic layers were washed with saturated brine (1400 rnL) and ice (900 then dried (MgSO 4 filtered and concentrated.

The residue was distilled (56-58 0.78 mmr.Hg) to provide the title compound as a colorless liquid (20.4 g, IH NM (250 NMz, CDCI 3 8 4.04 (dd, 1H), 3.82 3H), 1.92-1.72 (mn, LH), 1.69-1.62 (in, 2H), 0.96 3H), 0.94 3H).

t b) N-(4-pyridinylmethoxycarbonyl)-L-leucine methyl ester A solution of the compound of Example 106(a) 10 g, 29.8 inmol) and 4pyridylcarbinol (3.25 g, 29.8 inmol) in toluene (30 mL.) was heated at reflux for 24 h. The solution was concentrated and the residue was purified by flash chromatography on 250 g of 230-400 mesh silica gel, eluting with 3:1 ethyl acetate/hexanes, to give the title compound (7.86 g, 1 H NMR (250 MI~z, CDCl 3 5 8.59 2H), 7.24 2H), 5.33 1H), 5.13 3H), 4.40 (dt. IH). 3.75 3H), 1.81-1.51 (in, 3H), 0.96 3H), 0.95 3H).

C) N-(4-pyridinylmethoxycarbonyl)-L-leucine To a stirring solution the compound of Example 106(b) (1.98g, 7.06 mmol) in THF (7 mL) was added 7 ml, of water followed by LiOH*H 2 0 (325 mg, 7.76 inmol). The mixture was stirred for 30 minutes and then concentr ated. The residue was redissolved in water (10 mL) and 3 N HCI was added (2.6 mL). The solution was lyophilized to yield a white solid (2.0 15 g, 6.4.4 inmol). MS (ESI): 267.2 d) N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]hydrazide Following the procedure of Example 102(d), except substituting ethyl 2-(2- 15 chlorophenoxymethyl)thiazole-4-carboxylate for (I1S)- I -benzyloxycarbonylarnino- 15 1 -(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared.

MS (ESI): 284.1 e) N- [2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N'- rN-(4pyridinylxnethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting chlorophenoxymethyl)thiazol-4-ylcarbonyl]hydrazide for (2S, (benzyloxycarbonyl)amino-N-[ (1-(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanamide, and N-(4 -pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 532.1 ExampLit 107 Preparation of N-rN-(4-pyridinylmethoxycarbonyl)-L-leucinvil-N'-f2:L4-Li.2 3thiadiazoi--4-vl)phenyl]thiazol-4-ylcarbonyllhydrazide a) N-[2-(4-(1,2,3-thiadiazol-4-yl)jthiazol-4-ylcarbonyllhydrazide Following the procedure of Example 102(d), except substituting eth.vl 2-[4- 1,2,3 -thiadiazol thiazole-4-carboxyl ate for (IS)-l-benzyloxycarbonylanlino- 1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 304.1 b) N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N'-[2-[4-(1,2,3-thiacLiazol- 4-yl)phenyllthiazol-4-ylcarbonyllhydrazide Following the procedure of Example 103(d), except substituting (1,2,3-thiadiazol-4-yl)lthiazol-4-ylcarbonyllhydrazide for (2SI'S)-2- (benzyloxycarbonyl)amino-N- C l'-(2-hydrazinocarbonylthiazol-4-yi)-3'methylbutyll-4-methylpentanamide, and N-(4-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 552.1 Example 108 Preparation of N-f2-13--(4-chlorophenylsulfonylme-thyl)thien-2-yllthiazol-4ylcarbonyll-N'-rN-(4-Ryridinylmethoxycarbonyl)-L-Leucinyllhydrazide a) N-[2-[3-(4-chlorophenylsulfonylmethyl)thien-2-yl]thiazol-4carbonyl]hydrazide Following the procedure of Example 102(d), except substituting cWorophenylsulfonylmethyl)thien-2-yllthiazole-4-carboxylate for (IS)-lbenzyloxycarbonylamino-l-(4-carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 414.1 b) N-[2 3-(4-chlorophenylsulfonylmethyl)tLhien-2-yl Ithiazol-4-vlcarbonyl j-N- [N-(4-pynidinvlmethoxycarbonyl)-L-leucinyljhyd razide Following the procedure of Example 103(d), except subsutuuing chlorophenylsulfonylmethyl)thien-2-yljthiazol-4-carbonyljhydrazide for 1,S (benzyloxycarbonyl)amino-N-C [1-(2-hydrazinocarbonyltbiazol-4-yI)-3'methylbutyll-4-methylpentanamiide, and N-(4-pyidinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white.

MS (ESI): 664.0 Example 109 Preparation of (IS .2'RS)-N-r2-r( I-benzyloxycarbonylamino)-3-methvlbutyl ithiazol- 4-vicarbonvi 1-N'-r2'-(4-phenylphenylacetyl)-4-methylpetanovlihydrazide 0 4-methyl-2-(4-phenylphenyl)pent-4-enoic acid 0 To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 m.L) at 0 *C was added n-butyllithium (2.1 m.L, 5.22 mniol, 2.5M in hexane) dropwise. After stirring for 15 min at 0 the mixture was cooled to -78 OC and a '00.0,solution of 4-biphenylacetic acid (0.500 g, 2.36 mrnol) in THF (2 mL) was added dropwise. After again warmning to 0 0 C and coolling to -78 3-bromo-2methyipropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at -78 'C for I h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 The aqueous layer was acidified (3N HCl) and extracted with ether (3 X 100 0:640:mL). The organic layers were combined, dried (MgSO 4 filtered and concentrated to yield a white solid (0.449 g, MS(ESI)b: 265.3 b) 4-methyl-2-(4-phenylphenyl)pentanoic acid To a stirring solution of the compound of Example 109(a) (0.4 49 g, 1.69 mmiol) in ethyl acetate (25 rnL) was added palladium on carbon (0.225 After stirrng 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) (1 -benzyloxycarbonylamino)-3-methlbutylt~azol.4 vlcarbonyl [2'-(4-phenylphenYlacervlI)-4- methylpentanoyl hyfrazide Following the procedure of Example 101(d), except substituting (IS)-lbenzyloxycarbonylanino- 1-( 4 -hydrazinocarbonylthiazol-2-yl)-3-methylbutane for (2S, 'S)-2-(benzyloxycarbonyl)amino-N- l'-(2-hydrazinocarbonylthiazol-4y).3'methylbutyl]-4-methylpentanamide, and 4 -methyl- 2 4 -phenylphenyl)pentanoic acid for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 613.2 Example 110 S. Preparation of N- r2-(3-benzvloxyheny1 )thiazol-4-vlcarbonvl rN-(2- Sotopvridinylmethoxycarbonyl)-L-leucinyllhydraLzide methyl 3-benzyloxybenzoate .:15 To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMF (20 mL) was added methyl 3-hydroxybenzoate (1.0 g, 6.58 rnmol). After stirring for 15 min at room temperature, beazyl bromide (1.1I g, 6.58 mniol) 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 saturated aqueous sodium bicarbonate, and brine, then dried (MgSO 4 filtered and *concentrated to yield an off-white solid (1.013 g, 4.2 minol). IH NM.R (400 MHz, CDC1 3 567.67 2H), 7.48-7.34 (in. 6H), 7.19 (in, IH), 5.12 2H), 3.95 3H).

b) 3-beazyloxybenzamide To a suspension of ammnonium hydrochloride (1.070g, 0.02 iniol) in 20 mL of toluene at 50C, was slowloy added a 2M solution (10 mL) of trimethylaluminium in toluene. After the addition was complete, the reaction mixture was allowed to warm at room temperature and was stirred for 2 hours until gas evolution has ceased.

To a stirring solution of the compound of Example 1 10(a) (605 mng, 2.49 inmol) in toluene was added a 0.67 M solution of MeAlIlNH,2 (1 I nL, 7.49 mnmol) in toluene. The reaction mixture was allowed to stir overnight at reflux. The reaction was quenched with 5% HC1, the organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO 4 filtered and concentrated to afford the title compound as a white solid (409 mg, MS (ESI): 228.1 c) N-[2-(3-benzyloxyphenyl)thiazol-.4-ylcarbonyl]hydrazide Following the procedure of Example 102(b)- 102(d), except substituting 3benzyloxybenzaxnide for N-benzyloxycarbonyl-L-leucinamide in step the title compound was prepared as a white solid. MS (ESI): 326.2 d) N-(2-pyridinylmethoxycarbonyl)-L-leucine *..*Followong the procedure of Example 106(a)- 106(c), except substituting 2pyridylcarbinol for 4-pyridylcarbinol in step the title compound was prepared.

IH NMR (400 MHz, CD 3 OD) 8 8.50 1H), 7.86 (dt, 1H), 7.51 1H), 7.36 (dd, 5.20 111), 5.16 1H), 4.19 IH), 1.78-1.72 (in, 1H), 1.62 2H), 0.97 3H), 0.94 3H).

e) N-[2-(3-benzyloxyphenyl)tbiazol-4-ylcarbonyl]-N'-jN-(2pyridinylinethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting benzyloxyheny)tiaol4-ylcarbnyl]hyic-ide for (2S,1 (benzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4-yl)-3'methylbutyl]-4.-methylpentanamide, and N-(2-pyridinylinethoxycarbonyl)-L-Ieucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid (106 mg, 0. 184 inmol). MS (ESI): 574.2 Example Ill Preparation of (1 RS)-N-f 2-fl -(4-p2henvilphenvl)-3-methylbuvlthiazo..4.

a) I-( 4 -phenylphenyl)-3-methylbutyllthiazoM--ylcarbonyljhvdraide Following the procedure of Example 102(a)- 102(d), except substituting 4methyl-2-(4-phenylphenyl)pentanoic acid for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid. MS (ESI): 366.3 b) (1 1-( 4 -phenylphenyI)-3-methylbutyl ithiazol-4-ylcarbonylj (4-pyridinyhnethoxycarbonyl )-L-leucinyllhydrazide Following the procedure of Example 103(d), except substituting 0phenylph'eny)3methylbutyl]hiaol-4ylcarbnyl]hydraide for (2S,1'S :(bcnzyloxycarbonyl)amino-N-[ 1 -(2-hydrazinocarbonylthiazol-4yl).3'- .:15 methylbutyl]-4-rnethylpentanarmide, and N-( 4 -pyridinylniethoxycarbonyl)-Lleucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 614.3 Example 112 Prep~aration of N- f2-(2-beflzyloxylhenlthiazol..4Vlcarbonyll1N'-r N-(4pvridinylmethoxycarbonyh-L-leucinyllhydrazide.

ethyl 2 -amiinothiazole-4-carboxylate hydrobromide To a stir-ring suspension of thiourea (6.0 g, 78.8 mnmol) in ethanol (80 mL) was added ethyl bromopyruvate (15.4 g, 78.8 mmol). The resulting solution was heated at 45 *C for 23 h. The solution was cc~oled at 0 0 C for 24 h, and the crystals were collected by filtration and washed with cold ethanol to provide the title compound (15.8 g, 1 H NMR (400 MHz, CD 3 OD) 6 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 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 (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the tide compound as a colorless oil (15.2 g, 57.8 mmol). 1 HNMR (400 MHz, CDCl 3 6 7.62 1H), 7.54 2H), 7.45 (m, 2H), 7.37 1H), 7.28 1H), 6.98 IH), 6.91 IH), 5.17 2H).

d) 2-benzyloxyphenylboronic acid To a stirring solution of the compound of Example 112(c) (15.2 g, 57.8 mmol) in THF (100 mL) at -78°C was added dropwise n-BuLi (23.1 mL, 2.5M in hexane, 57.8 mmol). The mixture stirred at -78 0 C for 25 min when added via cannulation to a stirring solution of triisopropylborate (54.4 g, 289 mmol) in THF (100 rnL) at -78'C. After warming to room temperature and stirring for 3h, the mixture was poured into 3N HCI (100 rnL) and extracted with ethyl acetate (3 X 200mL). The organic layers were combined, washed successively with water and brine, dried (MgSO 4 filt-,red and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a pale yellow solid (6.9 g, 30.3 rnmol). I1-INMR (400 MHz, CDCI 3 6 7.90 1HI), 7.42 (in, 6H), 7.07 1H), 7.02 1H), 6.05 2H), 5.16 2H).

e) ethyl 2-(2-benzyloxyphenyl)thiazole-4carboxylate To a stirring solution of the compound of Example 112(b) 4 .0 g, 16.9 mmol), the compound of Example 72(d) (4.29 g, 18.8 minol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.57 mmol) in dimethoxyethane mL) was added cesium fluoride (8.58 g, 56.5 mmol) and the mixture was heated 85 *C for 16 h. Tetrakis(triphenylphosphine)palladium(0) (0.65 g, 057 mmol) .:15 was added and heating at 85 0 C was continued for 5 h. The mixture was diluted with water (60 rnL) and extracted with ethyl acetate (2 X 120 mL). The combined extracts were washed with saturated aqueous NaHCO 3 and saturated brine, dried (MgSO 4 filtered and concentrated. The residue was purified by flash chromatography on 180 g of 230-400 mesh silica gel, eluting with 15% ethyl acetate in hexanes, to provide the title compound as a white solid (3.22 g, MS (ESD): 340.3 f) 2-(2-benzyloxyphenyl)thiazol-4-ylcarbonylhydrazide Following the procedure of Example 102(d), except substituting ethyl 2-(2benzyloxyphenyl)thiazole-4-carboxylate for (1 1 -benzyloxycarbonylamino- 14-4carboethoxythiazol-2-yl)-3-methylbutane, the title compound was prepared as a white solid. MS (ESI): 326.2 g) N- -benzyloxyphefl)thiazol-4-ylcarboflyl pyridinylmethoxycarboflyl)-L-leuciflYIhYdrzide Following the procedure of Example I103(d), except substituting 2-(2benzyloxyphenyl)thazoleA4yIcabonylhydrazide for (2S, iS (benzyloxycarbonyl)aliflo-N[ 1 '-(2-hydraiocarboflylthiazol-yl)- 3 methylbutyl-4-methylpefltalalide, and N-(4-pyfldiylethoxyca11)ofyl)L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid. MS (ESI): 574.3 Example 113 *Preparation of N-2f-ehlN(-hnl~ey~riotizl4ycroylN [N(4-pyridinylrnethoxycarbonyl)LeucinvllhvclIazide N-(4-phenylphenyl)-2-methylpropiona11de :To a stirring solution of 4-aminobiphenyl (9.53 g, 56.3 mmol) and triethylamine (5.70 g, 56.3 mmol, 7.85 mL) in methylene chloride (60 rnL), cooled to 0 0 C, was added slowly isobutyryl chloride (6.0 g, 56.3 mmol, 5.90 mL). After stirring at 0 0 C for I h, the mixture was diluted with methylene chloride (120 mL) and washed with IN NaOH and saturated brine, then dreid (MgSO4), filtered and concentrated. The residue was washed with ether and dried to provide the title compound as a pale yellow crystalline solid (9.83 g, IHNMR (400 MHz,

CDCI

3

/CD

3 OD) 867.58 2H), 7.50 (mn, 411), 7.40-7.25 (in, 3H); 2.55-2.49 (in, IH), 1.18 6H).

b) N-(4-phenylphenyl)-N-(2-mfethyl- 1 propyl)anhine To a stirring solution of lithium alumainum hydride (58.6 inmol) in TBFf (58.6 imol), cooled to 0 0 C, was added slowly over 10 min a solution of the compound of Example 73(a) (9.35 g, 39.0 mnmol) in TIF (170 mL). After the addition was complete, the ice bath was removed and the solution was heated at 0 C for 30 min. The mixture was cooled to 0 0 C and water (2.22 mL) was slowly added, followed by 15% aqueous NaOl- (2.22 mL) and water (6.67 The precipitate was removed by filtration and washed with ether 4 times. The filtrate 147 was evaporated to dryness to proveide the title compound as a pale yellow solid (8.34 g, MS (ESI): 226.2 (M+H) c) N-(4-phenylphenyl)-N-(2-methyl-1 -propyl)thiourea To a stirring solution of thiophosgene (98.9 mg, 2.6 mmol, 198 uL) in methylene chloride (6.5 mL), cooled to 0 was added dropwise a solution of the compound of Example 73(b) (540.7 mg, 2.0 nmmol) in methylene chloride (1 mL).

After stirring for 2 h. ammonia-satruated methanol (20 mL) was added and the solution was stirred at room temperatur for 2 h. The solution was concentrated and the residue was partitioned between ethyl acetate and IN HC1. The organic layer was washed with IN HCI twice, then with saturated brine, then dried (MgSO 4 filtered and concentrated. The residue was purified by flash chromatography on g of 230-400 mesh silica gel, eluting with 1:3 ethyl acetate/hexanes, to provide the title compound as a pale yellow solid (470 mg, MS (ESI): 285.3 (M+H) d) ethyl 2-[N-(4-phenylphenyl)-N-(2-methyl- -propyl)amino]thiazole-4carboxylate A solution of the compound of Example 113(c) (184.6 mg, 0.65 mmol) and ethyl bromopyruvate (126.6 mg, 0.65 mmol, 81.5 uL) in ethanol (2.5 mL) was heated at reflux fo 5 min, then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO 3 The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated brine, dried (MgSO 4 filtered and concentrated. The residue was passed through a plug of 230-400 mesh silica gel, eluting with 12% ethyl acetate in hexanes, to provide the title compound as a pale yellow oil (230 mg, MS (ESI): 381.4 (M+H) e) N-[2-[N-(4-phenylphenyl)-N-(2-methyl- -propyl)amino]thiazol-4ylcarbonyl]hydrazide Following the procedure of Example 102(d), except substituting ethyl 2-[N- (4-phenylphenyl)-N-(2-methyl-1 -propyl)amino]thiazole-4-carboxylate for 1- 148 benzyloxycarbonylamiuno- 1-(4-carboethoxythiazol-2-yl)-3-methylbutane, the titde compound was prepared as a white solid. MS (ESI): 367.3 f) N- [2 me thy] -N -(4-phenylphenyl)amino Ithiazol-4-ylcarbonyl (4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide Following the procedure of Example 103(d), except substituting phenylphenyl)-N-(2-methyl- 1 -propyl)amin olthiazol-4-ylcarbonyllhydrazide for (2S,l 'S )-2-(benzyloxycarbonyl)amino-N-( I -(2-hydrazinocarbonyltbhiazol-4-yl)-3methylbutyl]-4-methylpentanamide. and N-(4-pyridinylinethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-Ieucine, the title compound was prepared as a white solid. MS (ESI): 615.3 .:Preparation of N-(N-benZyloxycarbonyl-L-leucinyl)-N'-f2-(4-p2henylbenzyl)thiazol- 4-ylcarbonyllhydrazide a) N-[2-(4-phenylbenzyl)thiazol-4-ylcarbonyllhydrazide Following the procedure of Example 102(a)- 102(d), except substituting 4biphenylacetic acid for N-benzyloxycarbanyl-L-leucine in step the title compound was prepared as a white solid. MS (ESI): 310.3 b) N-(N-benzyloxycarbonyl-L-leucinyl)-N'-[2-(4-phenylbepzl)thiazol-4ylcarbonyl]hydrazide Following the procedure of Example 103(d), except substituting N-112-(4phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide for (2S, 1'S)-2- (benzyloxycarbonyl)aniino-N-[ 1 -(2-hydra~nocarbonylthiazol-4-yl)-3'methylbutyl]-4-methylpentanamide. the title compound was prepared as a white solid (20 mg, 0.035'nimol). MS (ESI): 557.4 Example 11 Preparation of N-r 2 -'4-phenyvlhenvbenzv)thizol4ylcarbonvl-NrN-( 4 pyridinvlmethoxycarbonyl)-Lleucmnyl lhydrazide Following the procedure of Example 103(d), except substituting phenylbzyl)thizol-ylcarbnyljhydraide for (2S, I (benzyloxycarbonyl)amino-N..( I'-(2-hydrazinocarbonylthiazol-4yly3methylbutyl]-4-rethypentaamde, and N-( 4 -pyridinylmethoxycarbonyl)-L-.leucine for N-benzyloxycarbonyl-L..Ieucine, the title compound was prepared as a yellow solid (30 mg, 0.053 mmnol). MS (ESI): 558.2 Example 116 Preparation of N-(N benzvloxycarbonyl..Lleucinvl).N I. r2-rN-(2-methvlpronvl)-N.

phenylaninolt-hiazol4vylcarlonyl hydrazide N-[2-[N-phenyl-N-(2-methyl.. 1 -propyl)aniino]thiazol-4ylcarbonyllhydrazide Following the procedure of Example I113(a)- I 13(e), except substituting aniline for 4-aminobiphenyl in step the title compound was prepared as an orang-pink solid (276 mg, 0.950 inmol). MS (ESI): 291.3 b) N-(N-benzyloxycarbonylLleucinyl)-N'.12 -methylpropyl)-N- Following the procedure of Example 103(d), except substituting N-f 2-[Nphenyl-N-(2-methyl- l-propyl)aminolthiazol-4-ylcarbonyl]hyrazde for (2S,'S (bcnzyloxycarbonyl)amJno-N..( 1 -(2-hydrazinocarbonylthiazol-.yl).3'.

methylbutyl]4-methylpenamde, the tide compound was prepared as a white solid (92 mg, 0. 171 mmol). MS (ESI): 560.3 Example 117 Preparation of N-r2-rN-'2-methvlprovl )-N-phenvlamrnolthiazol-4-vlcarbonll-N'- [N-(4-pvyidinlmethoxvcarbonvl)-L-leucinlVlhydrazide Following the procedure of Example 113(a)-I 13(f), except substituting aniline for 4-aminobiphenyl in step the title compound was prepared as a yellow solid (50 mg, 0.092 mmol). MS (ESI): 539.4 Example 118 Preparation of N-r2-(2-benzvyoxyphenylthiazol-4-ylcarbonvyl-N'-fN-(3pyridinvlmethoxvcarbonvl)-L-leucinll hvdrazide Following the procedure of Example 112(a)-i 12(g), except substituting N- (3-pyridinyliethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (93.8 mg, MS (ESI): 574.3 Example 119 Preparation of N-r2-(2-benzyloxyphenylthiazol4-lcarbonyvl-N'-rN-(2pvridinvlmethoxvcarbonyl)-l-ieucinvllhvdrazide Following the procedure of Example 112(a)-I 12(g), except substituting N- (2-pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylnethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (149.7 mg, MS (ESI): 574.4 Example 120 Preparation of N-(N-benzyloxycarbonyl-N-methyl-L-eucinyl)-N'-i2-(2benzyloxvphenyflthiazol-4-lcarbonllhydrazide Following the procedure of Example 112(a)- I 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 609.3 Example 121 Preparation of N-r2-N-(2-methvlpropvl)-N-phenlinolthiol-vlcarbonvl fN-(2-pvridinlmethoxycarbonvl)-L-leucinvllhydrazide Following the procedure of Example 1 13(a)-I 13(f), except substituting aniline for 4-aminobiphenyl in step and N-(2-pyridinyimethoxycarbonyl).L.

leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (40 mg). MS (ESI): 539.4 Example 122 Preparation of N-r2-rN-(2-methvlrovl)-N-henvlaminolthiazol-4-ylcarbonyll-N'rN-(3 -vridinylmethoxvcarbonl)-L-leucinvlhydrazide Following the procedure of Example I 13(a)-'I 13(f), except substituting aniline for 4-aminobiphenyl in step and N-(3-pyridinylmethoxycarbonyl)-Lleucine for N-( 4 -pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid (42 mg). MS (ESI): 539.4 Example 123 Preparation of N-r2-(2-methoxhenyl thiazol4-lcarbonvl.N'N-(4pvridinylmethoxvcarbonyl)-L-leucinvlIhvdrazide a) 2-trimethylstannylanisole To a stirring solution of n-BuLi (2.6 rL, 2.5M in hexane, 6.42 mmol) in diethyl ether (2.5 mL) at -78C was added 2-bromoanisole (1.0 g, 5.35 nmol) in diethyl ether (2 mL) dropwise. After stirring for lh at -78C, timethyltin chloride (6.4 mL, 1.OM in THF, 6.42 mmol) was added dropwise. The mixture was allowed to stir an additional 2h while slowly warming to room temperature. The mixture was then washed with saturated aqueous NaHCO 3 The aqueous layer was extracted with diethyl ether (1 X 5OmL) and the organic layers were combined, dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (1.11 g, 1 -IFNMR (40MHz, CDC1 3 87.47 1H), 7.40 lH), 7.05 (t, lH), 6.90 IH), 3.36 3H), 0.34 9H).

152 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 purifiedy column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.081 g, 29%).

1 HNMR (400MHz, CDC1 3 5 8.54 1H), 8.22 1H), 7.45 1H), 7.11 1H), 7.05 1H), 4.48 2H), 4.04 3H), 1.46 3H).

c) N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide 15 Following the procedure of Example 112(0-112(g), except substituting ethyl 2-(2-methoxyphenyl)thiazole-4-carboxylate for ethyl 2-(2- ~benzyloxyphenyl)thiazole-4-carboxylate in step the title compound was prepared as a white solid. MS (ESI): 498.3 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 and are incorporated herein by reference as though fully set forth.

Exa-mple 1 24 Preparation of (2S. I S)-N-r I -(4-carboethoxythiazol-2-vl )-3'-methvlburvll-4-methvl- 2-(2-phenylbenzyloxvcarbonyl )aminopentanamide a) (2S, 1 'S)-2-(tert-butoxycarbonyl)amrino-N-[ 1'-(4-carboethoxythiazol-2-yl)-3'methylbutyl]-4-methylpentanamide The compound of Example 8(c)(1.2 g, 3.5 minol) was stirred at room temperature in neat TFA (2.96 g, 26.0 mmol) for 15 min. The solution was the concentrated in vacuo and redissolved in DMEF (25 mL). To the stirring solution was added triethylamine (0.779 g, 7.7 mxnol), BOC-Leu-OH (0.972 g, 3.9 mmol), l-hydroxybenzotriazole (0.095 g, 0.7 mniol), and 1-(3-dimethylaminopropyl)-3ethylcarbodintride hydrochloride (0.750 g, 3.9 mrnol). After stirring at room temperature for 16 hours, the solution was diluted with ethyl actate and washed successively with water (2 X 100 mL), NaHCO 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid 15 g, MS(ESI): 456.2 b) (2S, 1 1 -(4-carboethoxythiazol-2-yl)-3'-methylbutyl]-4-methyl-2-(2e. 20 phenylbenzyloxycarbonyl)aminopentanarnide To a stirring solution of phosgene (1.5 m.L, 2.9 rnmol, 1.93M i toluene) at OCwas added 2-biphenylmethanol (0.486 g, 2.64 rnmol) and diisopropylethylamnine (0.375 g, 2.9 mmol). The solution was allowed to stir at 0 0

C

for 30 min. In a separate reaction vessel, after stirring at roam temperature for mini, the compound of Example 124(a) 150 g, .330 rnmol) dissolved in TFA mL) was concentrated and redissolved in DMOF (3 mL). This solution was added to the 2-biphenylmethanol solution followed by diisopropylethylamine (0.213 g, 1.65 mmol). After stir-ring at room temperature for 1 h, 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 geehlacetate/hexane) to -il h tie compound as a white solid 138 g, MS(ESI): 566.3 Example 125 Preparation of (2S. I 'S)-2-[(2-benzvl)benzyloxcarbonl)lamTino-N-r 1 carboethoxythiazol-2-yl )-3'-metybutv11-4-methylpentanarmide Following the procedure of Example 124(b), except substituting 2benzylbenzyl alcohol for 2-biphenylmethanol, the title compound was prepared as a white solid 123 g, MS(ESI): 580.0 Example 126 Preparation of (2S. 1 1 '-(4-carboethoxythiazol-2-yl)-3'-methvlbutvll-4- 9*.methyl-2-f(2-naphthvlmethoxycarbonylhlaminopentanamide .15 Following die procedure of Example 124(b), except substituting 2naphthalenemethanol for 2-biphenylmethanol, the title compound was prepared as a white solid 132 g, MS(ESI): 540.1 Preparation of (2S. I'S)-N-F1l'(4-carboethoxythiazol-2-yl)-3'-methylbutylI-4methyl-2- r(3-phenoxybenzyloxycarbonylvminopentananide 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): 58 1. 9 Example 128 Preparation of (2S. I S)-2-(benzvloxvcarbonflamjno-N-[f 2-(2benzylguanidinyl)thiazol-4vll-3'-methlbuvl14-mehylpentanamjde a) S-methyl dithiobiuret hydroiodide salt To a stirring solution of dithiobiuret (5.0 g, 37 mrnol) in TI-F (75 mL) was added iodomethane (13.1 g, 92.5 mmol, 5.76 ml). After stirring at room temperature for 22 h, the solution was diluted with 150 m.L of toluene and allowed to stand at 0 *C for 3 h. The crystals were collected by filtration and washed with -cold 2:1 tolueneljTF, then dried in vacuo to give the title compound as a white solid (8.7 g, MS(ESI): 149.9 b) 3-beazylguanidinyl thiourea The compound of Examiple 128(b) (4.35 g, 15.7 mmol) was dissolved in :isopropanol (80 m.L) and benzylamine (1.77 g, 16.5 mmol, 1.8 m.L) was added and 15 the mixture was heated at reflux for 16 h. The hot solution was filtered and the filtrate was cooled to 0 After 5 h, the solid was collected by filtration and washed twice with cold iospropanol, then dried in vacuo to provide the title compound as a white solid (2.59 g, 61 MS(ESI): 209.2 20 0) (2S, lFS)-2-(benzyloxycarbonyl)amino-N-( 1 '-[2-(2-benzylguanidinyl)thiazol-4ylJ -3 '-methylbutyll-4-methylpentanamide Following the procedure of Example except substituting 3benzylguanidinyl thiourea for ethyl thiooxamate, the title compound was prepared as a white solid (102 mg, MS(ESi): 565.1 Example 129 Preparation of 1 1 -(N-benzloxvcarbonlamino)-3-methvlbut vicarbonvy 1-N-methl-N'-(N-benzvloxvcaarbonl-L-leucinvllhvdrazide Following the procedure of Example 26(a)-26(d), except substituting methyl hydrazine for hydrazine in step the title compound was prepared as a white solid. MS(ESI): 624.1 ExamRle 130 Preparation of (I S)-N-4-4 I -(N-benzyloxcarbonylamino)-3-methvlbutllthiazolq.

vcarbonvll-N'-(N-benzvloxvcarbonvl-L-leucinl)-N'-methylhvdrazide a) N-(N-benzyloxycarbonyl-L-leucinyl)-N-miethylhyrazide Following the procedure of Example 26(c), except substituting Nbenzyloxycarbonyl-L-leucine methyl ester for (1 I -benzyloxycarbonylamino. 1- (2-carboethoxythiazol-4-yl)-3-methylbutane and methyl hydrazine for hydrazine, the title compound was prepared.

b) (1 1 -benzyloxycarbonylamino- 1 -(2-carboxythiazol-4-yI)-3-methylbutane The compound of Example 26(c)(0.57 1.5 mmol) was dissolved in too* 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) (1S)-N-(4-[I-(N-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]- N'-(N-benzyloxycarbonyl-L-leucinyl)-N'-methylhyclajde Following the procedure of Example 28(e), except substituting N-(Nbenzyloxycarbonyl-L-eucinyl)-N-methylhydrazide for (IS)-l- (benzyloxycarbonyl)amino- I -(4-carboethoxythiazol-2-yl)-3-methylbutane and (1 S)- I -benzyloxycarbonylamino- 1 -(2-carboxythiazol-4-yI)- 3-methylbutane for Nbenzvloxycarbonyl-L-leucine, the title compound was prepared as a white solid.

MS (ESI): 624.2 Example 131 Preparation of N-(N-benzvloxycarbonyl-L-leucinyl-N'-(N..benzyloxycarbonv-L.

leucinyl)-L-al any] hydrazide Following the procedure of Example 27(a)-27(c), except substituting Lalanine methyl ester for L-leucine methyl ester in step the title compound was .prepared as a white solid (225.mg, MS(ESI): 598.1 Example 132 Preparation of N-(N-benzyloxycarbonyI-L-leucinyl)-N'..(N..benzvloxcaronyIL.

leucinvi )lycinvlhydrazide :Following the procedure of Example 27(a)-27(c), except substituting glycine methyl ester for L-leucine methyl ester in step the title compound was prepared as a white solid (307 mg, MS(ESI): 584.1 (M+H) 4 Example 133 Preparation of (I S)-N-r2-r I -N-benzyloxycarbonylanino)-3-methvlbutyll- 1.3.4triazol-5-ylcarbonyll-N'-4N--benzyloxycarbtnyl[L..eucinyl~hydrazide a) ethyl oxalainidrazonate To a solution of ethyl thiooxarnate (3.0 g, 22.6 rnmol) in ethanol (50 mL) was added hydrazine hydrate 1. 13 g, 22.6 mmol, 1.09 rnL. The mixture was allowed to stir for 3 hours at room temperature, while venting through a scrubber of concentrated sodium hydroxide solution. The golution was allowed to stand for 16 hours and the ethanol was evaporated. The residue was boiled in dichioromethane in petroleum ether, filtered, and recrystallized to give the desired compound as a tan solid. (0.264 g, b) (I I -benzvloxvcarbonvlamino- 1 -(2-carboethoxv- I_ .3.4-triazol-5-yi)-3methylbutane N-benzyloxycarbonyl-L-leucine (0.535 g, 2.0 minol) was stirred in THE at Ethyl chloroformate (0.23 rnL, 2.4 mmol) and triethylarnine (0.25 g,2.4 mmol. 0.34 miL) were added. The compound of Example 10(a) (0.264 g, 2.0 mmol) was then added and the mixture was allowed to stir at room temperature overnight.

The solvents were evaporated and the residue was dissolved in xylenes and heated to 200 *C using a Dean-Stark apparatus. The heating was stopped after 4 hours and the solution was evaporated to a residue which was chromatographed (silica gel, 40% ethyl acetate in hexane) to give the title compound as a white solid (0.498 g, 1 HNMR(400 MI-z, CDCl3) 87.20 (mn, 5H), 5.71 LH), 5.04(s 2H), 4.99 dd, lH), 4.36 (q 1.8 1.59 m. lH), 131 t M 3) ,0.83( dd, 6H).

c) (15)-l1-benzyloxycarbonylamino-l1-(2-hydrazinocarbonyl- 1,3 ,4-triazol-5-yl methylbutane Following the procedure of Example 26(c)-26(d), except substituting (I1S)-I benzyloxycarbonylamino- 1 -(2-carboethoxy- I ,3,4-triazol-5-yl)-3-methylbutane for (1 S)-l1-benzyloxycarbonylamino-l1-(2-carboethoxythiazol-4-yl)-3-methylbutane in step the title compound was prepared. MS (ESI): 594.5 Example 134 Preparation of (1 S)-N-(N-acetyl-L-leucinvl)-N'-[2-f I -(N-benzyloxvcarbonylarnino)- 3-methylbutyllthiazol-4-ylcarbonyllhydrazide Following the procedure of Example except substituting Nacetyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (95 mg, MS(ESI): 518.0 159 Example 135 Preparation of0 S)-N-(N-benzyloxycarbonyl-L -alany f benzyloxvcarbonvli no).3methlburyl lthiazol-4-vlcarbonvl hydrazide Following the procedure of Example 28(a)-28(e), except substituting

N-

benzyloxycarbonylLlaamne for N-benzyloxycarbonyl-L-Ieucine in step the title compound was prepared as a white solid (129 mg, MS(ESI): 568.1 Example 136 Preparation of(S)-N-(N-acetv1-L-alanvl)-N42.. 1 ~-(N-benzyloxvcarboAnylano.- 3 *methvlbuylthiazo1.4vcaronvllhvdrazide 0 Following the procedure of Example 28(a)-28(e), except substituting

N-

acetyl-L-alanine for N-benzyloxycarbonyl.L.leucine in step the title compound was prepared as a white solid (74 mg, MS(ESJ): 498.1 Example 137 fee*Preparation of (1 S)-N-(N-acetvl)..N'r2flI-(N-benzlovcarbonyapano).3- FoHowing the procedure of Example 28(a)-28(e), except substituting acetic acid for N-benzyloxycarbnyl-L-eucine in step the title compound was prepared as a white solid (87 mg, MS(ESI): 405.1 Example 138 Preparationof (IS rL-(N-benzvloxycarbonylaino..3-mth1~utyllthiazol-4y~carbonvI-1- N -(-~rdnlehxcroy)Lluiylyrzd Following the procedure of Example 28(a)-28(e), except substituting N-(4pyfldinylmethoxycarbOnyl).L-leucine for N-benzyloxycarbonyl-L..1eucine in step the title compound was prepared as a white solid (121 mg,

MS(ESI):

611 .0 Example 139 Preparation of (1 S)-N-r2-rl1-(N-benzvloxycarbonylamino)-3-methvlbutvl ithiazol -4vlcarbonyfl- N'-[N-(2-pvridinylmethoxycarbonyl)-L-leucinvilhvdrazide Following the procedure of Example 28(a)-28(e), except substituting N-(2pyridinyhnethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (125 mg, MS (ESI): 611.2 Example 140 Preparation of (1 1 -(N-benzyloxycarbonylamuno)-3-methylbutvlkthiazo1-4ylcarbonvl- N'-(N-benzyloxycarbonl-N-methl-L-leucinl~hvdazde ***.Following the procedure of Example 28(a)-28(e), except substituting N- *.:benzyloxycarbonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-L-Ieucine in step the tidle compound was prepared as a white solid (78 mg, MS (ESI): 624.3 Eamnple41 Preparation of (I 1-(N-benzyloxycarbonyl-N-methylamino)-3methylbutyllthiazol-4-ylcarbonylI-' -N(-yiiymtoyabonyl) Lleucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step and N-(2-pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid (120 mg, 72%).

MS (ESD): 625.3 Example 14? Preparation of (I 'S)-N-(N-benzyloxvcarbonyl-L-leucinl)..N-r2r 1-(Nbenzyloxycarbonyl-N-methylamjno-3-methylbuiJ lthiazol-4-vlIca-rbonvl ihydrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-tert-butoxycarbonyl-L-leucine in step the title compound was prepared as a white solid (95 mg, MS (ESI): 624.3 Example 143 Preparation of (I S)-N-r 24 1 -(N-ben vloxycarbonvl-N-methvlamino)-3methylbutyllthiazol-4.vl karbonyl- N'-(N-benzvloxycarbonyl-N-methyl-Ll1eucinyl )hydrazide :Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyi-L-leucine for N-tert-butoxycarbony1.L-leucine in step and N-benzyloxycarbonyl-N-methyI-L-leucine for N-benzyloxycarbonyl-Lleucine in step the title compound was prepared as a white solid (129 mg, 59%).

MS (ESI): 683.3 Example 144 Preparation of (IS 1-(N-methvlamino)-3-methylbutyllthiazol-4vlcarbonylla 14N-fN(4--1wfdinlymethoxyca-rbofnyUILPI1inllhydrazide.

a) (1 [I-(N-tert-butoxycarbony-N-methylanlino)-3methylbutylIthiazolA..

ylabnl-'[-4prdnlehxcroy)Lluiy~yrzd Following the procedure of Example 28(a)-28(e), except substituting Nrerr-butoxycarbonyl-N-methyl-Lleucine for N-tert-butoxycarbonyl-L-leucine in step and N-( 4 -pyridinylmethoxycarbonyl-L.eucine for N-benzyloxycarbonyt-Lleucine in step the title compound was prepared as a white solid. MS (ESI): 591.4 b) I ,N-merhylarniflo)-3-methylbuy1]thiazo-4-ylcarboflul-N'-iN-(4pyridinylmethoxycarbonyl)--leucinyl Ihydrazide To a solution of the compound of Example 21(a) in methylene chloride mL) was added trifluoroacetic acid (3 mL). After stirring one hour at room remperature the solution was concentrated and the residue was redissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over MgSO 4 and concentrated to afford the title compound as a white solid (259 mg, 68% for two steps). MS (ESI): 491.4 Example 145 Preparation of (I I -(N-benzyloxycarbonvlamino')-3-methvlbuvl thiazol-4- Slcarbonvll-N'-fN-(:ert-butoxvcarbonvl)-L-leucinvllhydrazide Following the procedure of Example 28(a)-28(e), except substituting N-renbutoxycarbonyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (293 mg, MS (ESI): 576.4 Ex ame 146 Preparation of (I 1 (Nbenzloxycarbonvlaino')-3-methylbutyllthiazolA ylcarbonyll-N'-r-(tert-butoxcarbonl)-N-mehvl--leucin llbdrazide Following the procedure of Example 28(a)-28(e), except substituting N-tertbutoxycarbonyl-N-methyl-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (120 mg, MS (ESI): 590.3 Example 147 Preparation of (I S)-N-f 2-fl -(N-benzyloxycarbonylarnino)-3-methylbutyllthiazol -4vicarbonvi 1-N'-(N-methyl-L-leucinyl)hydrazide Following the procedure of Example 144(b), except substituting (IlS)-N-[2- [1 -(N-benzyloxycarbonylarnino)-3-methylbutyljthiazol-4-ylcarbonylj-N'-[N-(rerbutoxycarbonyl)-N-methyl-L-leucinyl]hydrazide for (I 1 -(N-tentbutoxycarbonyl-N-methylamino)-3-methylbutyllthiazol-4-ylcarbonyl-N-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide, the title compound was prepared as a white solid (40 mg, MS (ESI): 490.3 ****Example 148 Preparation of (1 I-(N-benzyloxycarbonylarxnino')-3-methylbutyllthiazol-4- :ylcarbonyll-N'-(L-leucinl~hydrazide Following the procedure of Example 144(b), except substituting [1 -(N-benzyloxycarbonylammno)-3-methylbutyl]thiazol-4-ylcarbonyll-N'-[N-(tertbutoxycarbonyl)-L-Ieucinyllhydrazide for (1 [2-ri -(N-tert-butoxycarbonyl-Nmethylamino)-3-methylbutyl]thiazol-4-ylcarbonyll-N'-[N-(4- 6% 0 pyridinylmethoxycarbonyl)-L-Ieucinyllhydrazide, the title compound was prepared S..0.

as a white solid (39 mg, 100%). MS (ESI): 476.4 Preparation of (1 24[ 1 -(N-benzyloxycarbonylamino)-3-methylbutvllthiazol- 4 vlcarbonyll-N'- FN-(4-imidazolylacetvl)-L-leucinyllhydrazide Following the procedure of Example 28(e), except substituting (I S)-N-[2-I1- (N-benzyloxycarbonylamino)-3-methylbutyl]6biazol-4-ylcarbonyl]-N'-(Lleucinyl)hydrazide for (1 1 -(benzyloxycarbonyl)amino- 1 -(4-carboethoxythiazol- 2-yl)-3-methylbutane and 4-imidazoleacetic acid for N-benzyloxycarbonyl-Lleucine, the title compound was prepared as a white solid (50 mg, MS (ESI): Example 150 Preparation of (iS I 1-4'N-benzvloxycarbonyl-N-methylamino)-3methylbutyl lthiazol-4-ylcarbonyl 1-N'-[N-(3-pvridinylmethoxycarbonyl)-N-methyl- L-leucinyl ihydrazide a) N-methyl-L-leucine methyl ester N-methyl-L-leucine (1.3 g, 8.95 mmnol) was dissolved in 4M HCI, 1,4dioxane (10 mL) and methanol (10 mL). 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-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucine methyl ester To a stirring solution of phosgene in toluene (5.63 mL, 6.025 rnrol) in :methylene chloride (10 mL), cooled to 0"C, was added dropwise a solution of N- :methyl-L-leucine methyl ester (673 mg, 4.63 rnmol) and pyridine 10 g, 0.97 ML, 13.89 minol) in methylene chloride (4 mL). The solution was stirred at 0OC for 2 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 temperature for 5 hours. The solution was concentrated, redissolved in ethyl acetate, washed with water, dried (MgSO 4 filtered and concentrated. The crude residue was purified by column chromatography on silica gel methanol in methylene chloride) to afford the title P. compound as a yellow oil (88 mg, MS (ESI): 295.4 c) N-methyl-N-(3-pyridinylmethoxycarbonyl)-L-leucine FoUowing the procedure of Example 130(b), except substituting N-methyl- N-(3-pyridinylmethoxycarbonyl)-L-leucine methyl ester (I 1benzyloxycarbonylamino- 1-(2-hydrazinocarbonyltbiazol-4-yl)-3-methylbutane, the title compound was prepared as an orange solid (84 mg, 100%). MS (ESI): 281.3 d) (1 I -(N-benzyloxycarbonyl-N-rnethylamrino)-3-methvlbutyljthiazo-4ylcarbonyl] [N-(3-pyridinylmethoxycarbonyl)-N-rnethvl-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting Nberizy lox ycarbonyl -N-methyl e uci ne for N-tert-butoxycarbonyl-L-leucine in step and N-methyl-N-(3-pyridinvlmethoxycarbonyl)-L-leucine for Nbenzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (55 mg, MS (ESI): 639.4 Example 151 Preparation of (I S)-N-f 2-flI -(N-benzyloxvcarbonvl-N-methvlantino)-3- ~:methylbutvllthiazol-4-ylcarbonvl 1-N-rN-(3-pyridinylmethoxycarbonfl)-L.

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

MS (ESI): 625.4 Example 152 Preparation of (1 S)-N-r2-f 1 -(N-benzyloxycarbonylamino)-3-methlbuyllthiazol.4.

vicarbonyll- N'-FN-(3-pvridinylmethoxycarbonfl)-L-leucinyllhydrazide Following the procedure of Example 28(a)-28(e), except substituting N-(3pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (63 mg, MS (ESI): 611.5 Example 153 Prep~aration of (1 S )-N-(N-benzyloxycarbolL-leucinl)-N'-( 1ben ZyloxvycarbonvlI)- f2- 41 -methyl arino)-3 -mthVlbutllIthi azo 1-4yicarbonvi 1-N-merlivlhvdrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leuciflC for N-tert-butoxycarbonyl-L-leucine in step and methyl hydrazine for hydrazine in step the title compound was prepared as a white solid (80 mg, MS (ESI): 660.4 10 Example 154 Preparation of (1 I -4N-Denzloxycarbonylamino)-3-methylbulylthiazol-4ylcarbonyll- N'fN-(2-pyidinylmethoxycaroflyl)N-mthyl-L-leucinyllhydraide N-methyl-N-(2-pyridinylmethoxycarboflyl)-Lleucine methyl ester N-(2-pyridinylmethoxycarboflyl)-L-leucine methyl ester (490 mg, 1.75 mmol) was dissolved in THF (7.0 mL) and methyl iodide (0.43 5 mL, 6.99 mmol) 9**t was added. The reaction mixture was cooled to 0 0 C in a flask protected from moisture. Sodium hydride dispersion (236 mg, 2.62 mmol) was added cautiously and the suspension was stirred for 5 hours at room temperature. Ethyl acetate was then added, followed by water, dropwise. The solution was concentrated in vacuo, and the oily residue partitioned between ether and water. The organic layer was :washed with saturated aqueous NaHCO3 and the combined aqueous extracts 9 acidified to pH 3 with citric acid. The product was extracted with ethyl acetate, the extract was washed with water, 5% aqueous sodium thiosulfate and water, dried (MgSO 4 filtered and concentrated. The crude product was purified by column chromatography on silca gel (ethyl acetate/ hexane, 3: 1) to give a yellow oil (235 mg, MS (ESI): 295.4 b) N-methyl -N-(2-pyridinylmethoxvcarbonvyl>Lleucine Following the procedure of Example 130(b), except substituting N-methvl-

N-(

2 -pyridinylmethoxycarbonylyL-leucin-e methyl ester (I I1benzyloxycarbonylarznano-l-( 2 -hydrazinocarbonylthiazol 4-yl) -3-me thyl butane, the title compound was prepared as a white solid (223 mg, 100%). MS (ESI): 281.3 c) (I l-(N-benzyloxycarbonylamino)-3-methylbutyllthiazol-4.ylcarbonylI- N'[-2prdnlehxcroyl--ehlLluiylyrzd Following the procedure of Example 28(a)-28(e), except substituting N- SbenzloxycarbonylNmethyl-Lleucine for N-tert-butoxycarbonyl-L-leucine in step and N-methyl-N-(2-pyridinyimethoxycarbonyl).Lleucine for N- Does benzyloxycarbonyl-L-leucine in step the title compound was prepared as a white solid (50 mg, MS (ESI): 639.5 Example 155 Preparation of (1S)-N-r2-rl-(N-benzvloxycarbonyiNmethvlmno)-3 methylbutyl thiazol-4-ylcarbonyl rN-(4-pyridinvlrnethoxycarbonvl)-N..methvl L-leucinyllhydrazide a) L-leucine tert-butyl ester isocyanate L-leucine tent-butyl ester hydrochloride 10. 185 g, 45.5 mmol) was dissolved in methylene chloride (100 cooled to 0 O'C and pyridine (12.7 m.L, 182.0 mmol) was added, then phosgene in benzene (47 rnL, 59.1 mmol). The solution was stirred at 0 OC for 2 hours. The reaction mixture was washed two tines with 300 mL. of cold 0.5 M aqueous HCI. Each aqueous layer was exctracted with 100 mL methylene chloride. The combined organic phases were was-hed with a mixture of saturated aqueous NaCl solution and crushed ice, dried over MgSO 4 filtered and concentrated to afford the isocyanate as a yellow liquid (5.37 g, b) N-(4-pyridinYlmethoxycarbonyl)-L-leucine tert-butyl ester The compound of Example 155(a) (3.05 g, 14.32 rnmol) and 4-pyridyl carbinol (1.56 g, 14.32 mmol) were dissolved in toluene (80 ML) and heated at reflux overnight. The solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/ hexane, 3: 1) to afford the title compound as a colorless oil (2.945 g, MS (ES 323.4 c) N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine terr-butyl ester Following the procedure of Example 154(a), except substituting N-(4pyridinylmethoxycarbonyl)-L-leucine tert-butyl ester for N-(2- *~**pyridinylmethoxycarbonyl)-L-leucine methyl ester, the title compound was prepared as a yellow liquid (2.038 g, 68% yield). MS (ESI): 337.5 d) N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine Following the procedure of Example 144(b), except substituting N-methyl- N-(4-pyridinylmethoxycarbonyl)-L-leucine tert-butyl ester for (15S)-N- 1 -(N-ternbutoxycarbonyl-N-methylamino)-3-methylbutyllthiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide, the title compound was prepared as a white solid (343 mg, 72% yield). MS (ESI): 281.3 e) (1 1-(N-benzyloxycarbonyl-N-m ethylamino)-3-methylbutylthiazol-4ylcarbonyl]-N'-[N-(4-pyridinylmethoxycarbonyl)-N-methyl-L-leucinyl]hydrazide Following the procedure of Example 28(a)-28(e), except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine f4~ N-ter-butoxycarbonyl-L-leucine in step and N-methyl-N-(4-pyridinylmethoxycarbonyl)-L-leucine for Nbenzyloxycarbanyl-L-leucine in step the tidle compound was prepared as a white solid (50 mg, MS (ESD): 639.5 Exajmple156 Preparation of 2 2 fN.N'-[bis-(N-acetv-L-leuccinvl1carbohydrazide Following the procedure of Example 29, except substituting N-acetvl-Lleucine for N-benzyloxycarbonyl-L-leucine. the title compound was prepared as a pale yellow solid 0 153 g, MS(ESI): 401.3 Example 157 Preparation of 2 -rN-(N-benzvloxvcarbonyl.L-leucinvl)1.2'.rN'-(4.

rnethylpgntan~ol carb.ohvcfraide a) N-benzyloxycarbonyl-L-leucine methyl ester To a stirring solution of L-leucine methyl ester (2.0 g, 11.0 mmol) in 1,4dioxane (20 mL) was added aqueous Na 2

CO

3 solution (12.1 m.L, 2M in H 2 :.followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture stirred at room 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 1g, 100%). IEH4N{R (400MRz,

CDCI

3 5 7.34 (in, 5H1), 5.27 IH), 5.12 2H), 4.41 2H), 3.75 3H), 1.65 (in, 3H1), 0.96 (mn, 611).

b) N-(N-benzyoxycarbonylLleucinyl)hyaid To a stirring solution of the compound of Example 1 g, 1 1.Ominol) in methanol (15 mL) was added hydrazide hydrate (5.9 g, IL8 minol, 5.7 mL). The solution stirred at room temperature for 16 h then concentrated to yield the title compound as an off-white solid (3.1 g, 100%). MS(ESI): 280.2 c) l-benzyloxycarbonylamn>.3methyl. 1-(1,3 4 To a stirring solution of the compound of Example 157(b) (3.0 g, 10.8 iniol) in toluene (50 ml) 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 15 g, MS(ESI): 306.1 170 d) N-(4-methylpentanoyl)hdazide To a stirring solution of ethyl isocaproate (2.0 g, 13.8 mmol) in ethanol mL) was added hydrazine monohydrate (6.9g, 138rmCol, 6.7 rnL). After stirring at room temperature for 48 h, the solution was concentrated to yield the title compound as a white solid. (1.8 g, 100%). IHNM.R (400MHz, CDC13) 567.48 (s br, 111), 3.62 (s br, 2H), 2.13 2H), 1.51 (in, 3H), 0.85 6H).

e) 2 -[N-(NbenzyloxycarbofylLleucinyl)] 2 4 methylpentafloyl)]carbohydrzde The compounds of Example 157(c) 100 g, 0.325 mmol) and Example 34(d) (0.042 g, 0.325 inmol) were combined and dissolved in ethanol (1 mL). 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 Preparation of [N.N'-rbis(NbnZyoxc )onyl-Nethyl-L leucinyl~llcarbohydrazide Following the procedure of Example 29, except substituting

N-

benzyloxycarbonl-lN-methylLleucIie for substituting N-benzyloxycarbonyl-Lleucine, the title compound was prepared with purification byclIn chromatography (silica gel, methanoL/dichlorom~ethane) as a white foam (0.236 g, MS 613.2.

171 Example 159 Preparation of 2-fN-(N-acetvl-L-leucinyl)1-2'-rN-(N-benzvloxycarbonviL leucinyl)lcarbohydrazide a) 2-[N-(N-benzyloxycarbonylbL-leucinyl)]carbohydrazide To a stirring solution of the compound of Example 157(c) (3.15 g, 10.3 mmol) in methanol (2 m.L) was added hydrazine hydrate (5.0 g, 100 inrol, 4.8 mL).

After stirring at room temperature for 24 h, the solution was concentrated to yield the title compound as a pale yellow foam (3.471 g, 100%). MS(ESI): 338.2 leucinyl)Icarbohydrazide a stirring solution of the compound of Example 159(a) 100 g, 0.297 mrnol), N-acetyl-L-leucine (0.054 g, 0.312 mniol) and 1-hydroxybenzotriazole 15 (0.008 g, 0.0594 mmol) in DMF (2mL) was added l-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0.060 g, 0.3 12 mmnol). After stirring at room temperature for 16 h, the solution was poured into water and extracted with ethyl acetate. The organic layer was dried (MgS0 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, methanolldichloromethane) to yield the tidle compound as a white solid (0.052 g, MS(ESI): 493.1 Example 160 Preparation of FN-(4-pvridinylmethoxycarbonyl)-LlIeucinyl')lllcarbohydrazidet Following the procedure of Example 29, except substituting N-(4pyridinyhnethoxycarbonyl)yL-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid (199 mg, MS(ESI): 587.1 Example 161 Prep~aration of 2.2'-[N.N'-fbis-rN-(2-pyridinvimethoxycarbonvl)-Lleucinyl)lllcarbohydrazide Following the procedure of Example 29, except substituting N-(2pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucjne, the title compound was prepared as a white solid (263 mg, 8 MS(ESI): 587.1 Example 162 Preparation of 2-f N-N-benzyloxycarbonyl-L-Ieucinyl)1-2'-IN'-4N-(2pvyridinylmethoxycarbonyl )-L-leucinyl~llcarbohydrazide Following the procedure of Example 159(a)-159(b) except substituting N-(2pynidinylmethoxycarbonyl)-L-leucine lithium salt for N-acetyl-L-leucine in step the title compound was prepared as a white solid (0.040 g, MS(ESI): 586.3 *Preparation of 2-rN-(N-benzydoxvcabony-L-euciny)1v2'-N'rN-(4.

pyridinylmethoxycarbonyfl-L-Ieucinvflhlcarbohydrazide 0% Following the procedure of Example 159(a)-i 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 2-[N-CN-benzyloxycarbonyl-L-leucinvfll N'4[N-(3pyridinylmethoxycarbonyfl-L-leucinyl'llcarbohydrazide Following the procedure of Example 159(a)- 159(b) except substituting N-(3pyridinylmethoxycarbonyl)-L-Ieucine lithium salt for N-acetyl-L-leucine in step the title compound was prepared as a white solid (0.084 g, MS(ESI): 586.3 173 Example 165 Preparation of 2,2'-rN.N'-[bis-(N-benzyloxycarbonyl-L-leucinyl)1b2-(N methyl)carbohydrazide a) N-methyl-N-KN-benzyloxycarbonyl-L-leucinyl)hydrazide To a stirring solution of N-benzyloxycarbonyl-L-leucine methyl ester (2.2 g, 8.15 mrnol) in methanol (4 ruL) was added methylhydrazine (3.7 g, 80 minol).

After stirring at room temperature for 16 h, the solution was concentrated to yield the title compound as a yellow solid (2.14 g, 7.3 mmol). MS(ESI): 294.1 b) 2.2 [bis-(N-benzyloxycarbonyl-L-leucinyl)fl-2-(N-methyl )carbohydrazide The compound of Example 157(c) (0.250 g, 0.819 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 :column chromatography (silica gel, methanol/dichloromethane) to yield the title 15 compound as a white solid (0.060 g, MS(ESI): 599.1 Example 166 Preparation of 2.2-N.N'-Fbis-rN-(3-pvridinvlxnethoxycarbonyl)-Lleucinyl)lllcarbohydrazide Following the procedure of Example 29 except substituting N-(3pyridinylmethoxycarbonyl)-L-leucine for N-benzyloxycarbonyl-L-leucine, the title compound was prepared as a white solid (157 mg, MS(ESI): 587.0 Example 167 Preparation of I -(N-benzyl)-2.2'- N.N-Ibis-(N-benZyloxycarbonyl-Lleucinyl)llcarbohydrazide a) N-benzylidene-N'-(N-benzyloxycarbonyl-L-leucinyl)hydrazide To a solution of the compound of Examnple 157(b) (1 g, 3.5 mmol) in ethanol (30 rnL) was added benzaldehyde 0.33 m.L, 3.2 mnmol). The resulting mixture was heated at reflux for 4 h. The mixture was concentrated in vacuo then purified by flash chromatography (silica g el, 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-leucinyl)hydrazide To a cooled solution of compound of Example 167(a) (0.24 g, 0.65 ramol) in THF (5 mL) was added borane tetrahydrofuran complex (0.65 mL, 0.65 mmol; IM solution in TifF). 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 (MgSO4), filtered and concentrated in vacuo to give the title compound as a white solid (0.25 g, MS(ESI): 370.0 c) 1 -benzyloxycarbonylamino-3-methyl-l1-(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-Lleucinyl)hydrazide, the title compound was prepared as an oil (0.02 g, 83%).

MS(ESI): 396.0 d) 1 -(N-benzyl)-2-rN-(N-benzyloxycarbonyl-L-ieucinyl)carbohydrazide Following the procedure of Example 159(a), except substituting Ibenzyloxycarbonylamino-.3-methyl- 1-(3-benzyl- 1,3,4-oxadiazol-2-on-5-yl)butane for 1 -benzyloxycarbonylamino-3-methyl-l1-(1 ,3,4-oxadiazol-2-on-5-yl)butane in step the title compound was prepared as a solid (0.013 g, MS(ESI): 428.0 d) I-(N-benzyl)-2,2'-[N,N'-[bis-(N-benzyloxvcarbonyl-L-leuciiy)] ]carbohvdrazide Following the procedure of Example 159(a)-159(b), except substituting 1benzyloxycarbonylamino-3-methyl- 1-(3-benzyl- 1,3, 4 for I -benzyloxycarbonylamino-3-methyl- 1 ,3,4-oxadiazol-2-on-5-yl)butane in step the title compound was prepared as white solid (13 mg, MS(ESI): 675.0 Example 168 Preparation of 2-rN-(N-benzloxvcarbonl-L-leucinvl)1-2-N'-(Nbenzyloxvcarbonl-N-methvl-L-leucinvl)lcarbohvdrazide Following the procedure of Example 159(a)-59(b) except substituting 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 Example 169 Preparation of I-naphthl)thiazol-4-ylcarbonil-N'-[N-(4a. Dvridinvlmethoxvcarbonvl)-L-leucinyllhydrazide Following the procedure of Example 112(a)-I 12(g), except substituting 1naphthyl boronic acid for 2-benzyloxyphenyl boronic acid in step.(e), the title compound was prepared as a white solid (0.094 g, MS(ESI): 518.4 Example 170 Preparation of N-f2-(2-biphenyl)thiazol-4-lcarbonyll-N'-rN-(4pvridinylmethoxycarbonl)-L-1eucinyllhydrazide Following the procedure of Example 1 12(a)-I 12(g), except substituting 2biphenylboronic acid for 2-benzyloxyphenyl boronic acid in step the title compound was prepared as a white solid 100 g, MS(ESI): 544.3 (M+H) 4 Example 171 Preparation of N-(N-benzloxvcarbonvl-N-methvl-L-leucinvl)N-f2-rN-(2methvlpropl) N- henvlamino thiazol-4-vlcarboflvllhvdraide Following the procedure of Example 116(a)-Il except substituting Nbenzyloxycarbonyl-N-methyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (40 mg, MS (ESI): 552.5 Example 172 Preparation of NFN-methv-N-(2-pvridiflylmethoxyVcaboflv)-L-leuCiflal-N424N- 0 (2-methvyprovl)-N-Dhenylaminolthiazol-4-ylcarboflllhydrazide Following the procedure of Example 116(a)-i 16(b), except substituting Nmethyl-N-(2-pyridinymethoxycarbony)-L-leucine for N-(4pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid solid (70 mg, 7 MS (ESI): 553.4 Examle 173 Preparation of N-[2-(2-benzlox~henl)thiazol-4-lcarb butoxvcarbonyl-L-leucinl)hydrazide Following the procedure of Example 112(a)-i 12(g), except substituting Ntert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in istep the title compound was prepared as a white solid (1.015 g, 94%).

MS(ESI): 539.1 Example 174 Preparation of N-(N-tert-butoxvcarbonyl-L-leucin)N'2-N(2mthylprpyl)N phenylaminolthiazol-4-ylcarbonyllhYdrazide Following the procedure of Example 116(a)-I 16(b), except substituting Ntert-butoxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-1eucine in step the title compound was prepared as a white solid (740 mg, MS (ESI): 504.4 Example 175 Preparation of N-(N-tert-butoxycarbonyl-N-methyl-L-eucinyl methvlpropyl) -N-p2henyl amiuno I thi azol -4-ylcarbon yI] hydrazide Following the procedure of Example 1 16(a)-l I except substituting Nter-r-butoxycarbonyl-N-methyl-L-leucine for N-(4-pyridinylxnethoxycarbonyl leucine in step the tidle compound was prepared as a white sol id (6 10 mg, 69%).

MS (ESI): 518.4 Example 176 :0,00, Preparation of N-r2-(2-benzvloxyphenvl)thiazol-4-lcarbonllN'-(N- 0 pvraz inecarbonyl-L-leucinyl )hydrazide a) N- 2 2 -benzyloxyphenyl)thiazolA4-ylcarbonyl]-N'-(L-leucinyl)hydrazide 0* Following the procedure of Example 144(b), except substituting .00 15 benzyloxyphenyl)thiazol.4-ylcarbonyl-N'-(N-tert-butoxycarbonyl-L leucinyl)hydrazide for (1 [1-(N-tert-butoxycarbonyl-N-methylamino)-3leucinylihydrazide, the title compound was prepared as a white powder (0.766 g, MS(ESI): 439.3 (M+HY+.

b) N-( 2 2 -benzyloxyphenyl)thiazol-4ylcarbonyl]-N.[N.(2-pyrwznylcarbonyl).L 00 o leucinylihydrazide Following the procedure of Example 11I6(b), except substituting benzyloxypheny)thizolI4-ylcarbonyl]-N.(L.leucinyl)hydaide for N- [Nphenyl-N-(2-methyl- 1 -propyl)aminolthiazol-4-ylcarbonyl]hydrazide and pyrazinecarboxylic acid for N-(4-pyridinyLmethoxycarbonyl)-L-leucine, the title compound was prepared as a white solid 146 g, MS(ESI): 545.4 (M+HY+.

178 Example 1 -7 Preparation of N-f2-(2-benzvloxvphenvl )thiazol-4-vlIcarbonvfLLN'-(-joncoinvl L-leucinvl')hvdrazide Following the procedure of Example 176(a)- I 76(b), except substituting isonicotinic acid for pyrazinecarboxylic acid in step the tide compound was prepared as a white solid (0.135 g, MS(ESI): 544.3 Example 178 Preparation of N-f 2-(2-dibenzofuranyl)thiazol-4-vlcarbonvll-N-FN-(4pyridinyimethoxvcarbonyl)-L-leucinyllhyvdraide *oo Following the procedure of Example 112(a)-1 12(g), except substituting 2 ae* bromodibenzofuran for 2-benzvloxybromobenzene in step the tide compound was prepared as a white solid (0.079 g, MS(ESI): 558.3 to* 25 Preparatiota of N- [2-rN-(2-methylpropvl)-N-phenlaninolthiazol--vlcarbonl 1-N'- 0(N-mehlv -2razinecarbonecin leucraide~hdaz Following the procedure of Example 176(a)- 176(b), except substituting N- (N-terr-butoxycarbonyl-N-hL-leucayl)-N'-[2- [N-(2-rnethy propyl)-Nthiazol1-4-yIc arbonyI Ihydrazide for N-(2-(2-benzyloxyphenyl)thiazol- 4-ylcarbonyl-N'-(N-ter-butoxycarbonyl-L-leucinyl)hydrazide in step the title compound was prepared as a white solid (36 mg, MIS 510.4 Example 1 81 Prteparation of N-t-.''isonicotinovl-L-leucinvl f-N 2-merhvlProvlI)-Nphenvainnolthiazol -4-vicarbonyl I hydrazide Following the procedure of Example 1 76(a)- 176(b), except substituting N- (N-rert-butoxvcarbonvl-N-methyl-L-leucinyl)-N'-[2 -(N-(2-methvlpropyl)-Nphen yl amrino] th-iazol v I carbon yl Ihydrazide for N-[2-(I-benzy Ioxyphenvl)tLhiazol- 4-vlcarbonyl I-N'-(N-tert-butoxycarbonyl-L-leucinvl )hvdrazide in step and isonicotinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (28 mg, MS (ESI): 509.4 Examnpl 8 2 Ocoee,.Prparation of N-(,N-isonicotinovl-N-methvl-L-leucinyl)-N'-I2-[N-(2- 15 methvlpropl~y)-N-phenylarninolthiazol-4-vlcarbonyllhydrazide Following the procedure of Example 176(a)-1I76(b), except substituting N- (N-methyl-N-tert-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2- merthylpropyl)-N-phenylaiinojthiazol-4-ylcarbonyljhydrazide for benzyloxyphenyl)thiazol-4-ylcarbonyl]-N'-(N-tert-butoxycarbonyl-Lleucinyl)hvdrazide in step and isonicotinic acid for pyrazinecarboxylic aicd in 0* 20 step the title compound was prepared as a white solid (117 mg, MS Se*: (ESI): 523.4 Example 18 83 Preparation of N- [N-44-i ridazolvlace rv ucinll -N-[-rN-(2-methvlIprop-i i-N- _phenylarminolthiazol-4-vlcarboflvllhydrazide Following the procedure of Example 176(a)-l176(b), except substituting N- (N-tern-bucoxycarbonyl-N~methyl-L-leuciflyl)-N' 2 2 -methlproPYl)-Nphe nylamino] Jthiazol -4-ylcarbonyQ h ydrazide for N- [2-(2-benzvloxvphenyl )thiazol 4-v lcarbonylI-N'-(N-rerr-butoxycarbonyl-L-leucinyl)hvdrazide in step and 4imiudazolylacetic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (60 mg, IHNfR (400MfHz. CDClI) 67.62--7.213 (in, 8H). 6.81 lH), 4.72-4.66 (in, IH), 3.75 IH), 3.55 2H). 1.96-1.93 (m.

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

goo* 9P (N-p2icolinovl-L-leucinvl)hvydrazide Following the procedure of Example 176(a)-i 176(b), except substituting N- (N-tert-butoxycarbony-N-nethy-L-leucifl)lY' 2 [N-(2-methylpropyl)-Nphenylamino]thiazol-4-ylcarbonyl]hydrazide for N-[2-(2-benzyloxyphenyl)thiazolabnl-'-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 Exampe18 Pr*mto ofN[.(-ezlxpey~hao--labnlmty rN-(4pyridinylmethoxycarbonyl)-L-leuciflaride a) 2-(2-benzyloxyphenylthazole-4-carboxyhc acid Following the procedure of Example 105(b), except substituting ethyl benzyloxyphenyl)thiazole-4-carboxylate for methyl 3-(4pyridinyllxnethoxy)benzoate, the title compound was prepared as a white solid (0.361 g, MS(ESI): 312.2 b) 2-(2-benzyloxyphenyl)thiazol-4-yl bromomethyl ketone Following the procedure of Example 103(a), except substituting 2-(2benzyloxyphenylthiazole-4-carboxylic acid for N-benzyloxycarbonyl-L-Leucinyl-L- Leucine, the title compound was prepared as a white solid (0.327 g, 73%).

MS(ESI): 388.2 c) 2-(2-benzyloxyphenyl)thiazol-4-yl azidomethyl ketone A solution of the compound of Example 185(b), (0.319 g, 0.822 mmol), sodium azide (0.064 g. 0.987 mmol), and potassium fluoride (0.072 g, 1.23 mmol) in DMF (6 mL) was stirred at room temperature for 16 h. The solution was then diluted with ethyl acetate and washed successively with water, saturated aqueous sodium hydrogen carbonate, and brine. The organic layer was dried (MgSO 4 :filtered and concentrated. The residue was purified by column chromatography *00 (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (0.087 15 g, MS(ESI): 373.3 d) 2-azido-1-[2-(2-benzyloxyphenyl)thiazol-4-yl]- 1-hydroxyethane To a stirring solution of the compound of Example 185(c) (0.087 g, 0.249 mmol) in THF (1 mL) at 0*C, was added sodium borohydride (0.031 g, 0.820 mmol) slowly. After 20 min the mixture was diluted with ethyl acetate and washed with water then brine. The organic layer was dried (MgSO 4 filtered and concentrated to yield the title compound as a white solid (0.084 g, 1

HNMR

(400MHz, CDC1 3 8 8.41 1H), 7.50 2H), 7.38 4H), 7.11 3H), 5.31 2H), 5.08 1H), 3.69 2H), 3.58 (s b, 1H).

e) 2-amino- 1-[2-(2-benzyloxyphenyl)thiazol-4-yl]-1 -hydroxyethane To a stirring solution of the compound of Example 185(d) (0.084 g, 0.239 mmol) in methanol (2 mL) was added stannous chloride dihydrate (0.108 g, 0.478 mmol). After stirring at room temperature for 16 h, the mixture was diluted with ethyl acetate and washed successively with water, saturated aqueous NaHCO 3 and brine. The organic layer was dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography (silica gel, methanol/dichloromethane) to yield the tide compound as a white solid (0.07 MS(ESI): 327.3 f) 1- [2-(2-benzyloxyphenyl)thiazol-4-yl]-lI-hydroxy-2-(4pyridinylmethoxycarbonyl-L-leucinylamino)ethane Following the procedure of Example I116(b), except substituting 2-amino- I [2-(2-benzyloxyphenyl)thiazol-4-ylj- I -hydroxyetbane for [N-phenyl-N-(2methyl- I -propyl)aminolthiazol-4-ylcarbonyl]hydrazide, the title compound was prepared as a white solid (0.075 g, MS(ESI): 575.4 g) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyljmethyI :::*pyridinylmethoxycarbonyl)-L-leucinamide .:To a stirring solution of the compound of Example 185(f) (0.075 g, 0. 131 15 rnmol) in dichloromethane (1 mL) was added MnO 2 (0.300 g, 3.45 mmol). After stirring at roam temperature for 24 h, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as a pale yellow solid (0.0 17 g, MS(ESD: 573.4 (M+H) t Preparation of N-r2-[N-methyl-N-(2-methvlpropvl)aminolthiazol-4-vlcarbonyll-N'rN-(4-pyridinylmethoxycarbonyfl-L-leucinyllhvdrazide a) N-benzoyl-N'-methyl-N'-(2-methylpropyl)thiourea To a stirring solution of N-methylisobutylamine (3.21 g, 36.8 mmol. 4.45 ML) in 40 mL of CHC1 3 was added benzoyl isothiocyanate (6.0 g, 36.8 mmol, 4.95 ML). After stirring for 45 min, the solution was concentrated to yield the title compound as a pale yellow solid (9.22 g, 100%). 1 fH 4M4 (400M&z, CDC1 3 2:1 mixture of rotamers) 8 7.86 2H), 7.60 1H), 7.50 2H), 3.90 2H), 3.44 (s, 3H), 3.41 2H), 3.27 2.35-2.32 (in, IH), 2.13 (in, IH), 1.06 6H), 0.90 6H).

b) N- methyl (2 -methylpropyl) thiourea The compound of Example 186(a) (9.22 g, 36.8 mmol) was suspended in mL of 1: 1 methanol/water and solid potassium carbonate (15.27 g, 110 mmol) was added. The mixture was heated at reflux for 48 h, then cooled and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated brine, dried (MgSO4), filtered and concentrated to provide the title compound as a pale yellow crystalline solid (4.82 g, MS(ESI): 147.0 c) N-2[-ehlN(-ehlrpl mn~hao--labnl-'[N-(4pyridinylmethoxycarbonyl)-L-leucinyll hydrazide Following the procedure of Example 11I3(d)-i I except substituting N- 15methyl-N-(2-methylpropyl)thiourea for N-(4-phenylphenyl)-N-(2-methyl- I1propyl)thiourea in step the title compound was prepared as a white solid (202 mg, MS(ESI): 477.4 (M+H) t Example 187 Preparation of N-(N-methyl-N-picolinovl-L-leucinvl)-N'-[2-rN-(2-methvlpropyl)-Nphenylaminolthiazol-4-ylcarbonyllhydraide Following the procedure of Example 176(a)- 176(b), except substituting N- (N-methyl-N-rn-butoxycarbonyl-N-methyl-L-leucinyl)-N'-[2-[N-(2methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide for N- benzyloxyphenyl)thiazol-4-ylcarbonyl] -N'-(N-tert-butoxycarbonyl-L- Ieucinyl)hydrazide in step and picolinic acid for pyrazinecarboxylic aicd in step the title compound was prepared as a white solid (30 mg, 41 MS (ESI): 523.5 Example 188 Preparation of N- r2-(2-benzyloxyphenyl )thiazol-4-ylcarbonvl 1-N'-FN-(2pvyridinesulfonvl)-L-leucinyllhydrazide a) 2-pyridinesulfonyichliide Through a stirring solution of 2-rnercaptopyri dine (2.235 g, 20 rniol) in water (7.5 mL) and concentrated HCI (26 mnL) at 0 *C was bubbled C1 2 After 75 rnL of ice water was added and extracted with cold ether (2 X The organic layers were combined and washed successively with cold 10% aqueous NaHCO 3 and cold brine. The organic layer was dried (MgSO 4 filtered and concentrated to yield the tidle compound as a clear oil. (3.1 g, 87%).

b) N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N-[N-(2-pyridinesulfonyl)-Lleucinyl]hydrazide :To a stirring solution of the compound of Example 176(a) 125 g, 0.285 mmol), and the compound of Example 188(a) 101 g, 0.571 mmol) in dichloromethane (2 mJL) 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 tidle compound as a pale yeUow solid (0.100 g, 6 MS(ESI): 580.2 Preparation of N-[2-[N-(2-methylpropvl)-N-phenylaminolthiazol-4-ylcarbonylI-N'- [N-(2-pvridinesulfonyfl-L-leucinyllhydr-azide Following the procedure of Example 188(b), except substituting N-(Lleucinyl)-N'- [2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4ylcarbonyllhydrazide for N- [2-(2-benzyloxyphenyl)thiazol-4-ylcarbonylj-N'-(Lleucinyl)hydrazide, the title compound was prepared as an orange solid (56 mng, MIS (ESI): 545.3 185 Example 190 Preparation of N-[2-fN-(2-methylpropyl)-N-phenlainothiazol4vlcgarbonyl]L-N fN-methvl-N-(2-pyridinesulfonyl )-L-Ieucinvllhydrazide Following the procedure of Example 188(b), except substituting N-(Nmethyl-L-leucinyl)-N'.(2- (N-(2-methylpropyl)-N-phenylarninothjazo.-..

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-r2- [N-methyl-N-(2-methylpropvyl)anhinolthiazo1A-ylcarb 0 oyf 1-N'rN-(3-pyridinvlmethoxycarbonyl )-L-leucinyllhydrazide Following the procedure of Example 186(a)-186(c), except substituting N- 3 -pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylxnethoxycarbonyl)-L.

: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-[ 2 -iN-(2-methlropyl)-N-henlamjnolthiazo1-4.ylcarbonvil-N'.

rN-methyI.N-4p2ydinylmethoxycarbonyl).L.leuciflyllhydazde Following the procedure of Example 1 16(a)- I 16(b), except substituting Nmethyl-N-( 4 -pyridinylmethoxycarjyonyl)-L-eucine for N-(4- -pyridinylmethoxycarbonyl)-L-leucine in step the title compound was prepared as a white solid solid (74 mg, 4 MS (ESI): 553.4 186 Example 193 Preparation of N- r2- [N-(2-methvlp-ropl)-N-1hellamiolthiazoAl-ycarbonli-N'- F,-ehlN(-2rdnlehxcroy)Lluiylyrzd Following the procedure of Example 11I6(a)- I 16(b), except substituting Nmethyl-N-(3-pyridinylmethoxycarbofl)-L-leucine for N-(4pyridinylimethoxycarbonyl)-L-leucflC in step the title compound was prepared as a white solid solid (50 mg, MS (ESD): 553.4 Example 194 Preparation-of N-[2-(2-benzyloxyphenylthiazol-4-ylcarboll-N-r-methyl-N-(3pyrndinlmethoxycarboflyl)-L-eucinllhydrazide Following the procedure of Example 11 2(a)-l I except substituting Nmethyl-N-(4-pyridinylmethoxycarbol).L-leucine for N-(4- :pyridinylmethoxycarbonyl)-L-leucifle in step the title compound was prepared as a white solid (0.028 g, MS(ESI): 588.4 Example 195 Preparation of N-Nmty--41yrdnlehxcronl 1naphthyl)thiazol-4-vlcarboflyllhyd3Z Following the procedure of Example 11I2(a)- I 12(g), except substituting I napbthyl boronic acid for 2-benzyloxypheflyl boronic acid in step7(e) and N-methyl- N-(4-pyridinylmethoxycarbonyl)-L-lucilC for N-(4-pyridinylmethoxycarbonyl)-Lleucine in step the title compound was prepared as a white solid (0.072 g, 36%).

MS(ESI): 532.4 Exm~le29 Preparation f Nf2-4N. -(i)2mtypoy~mnltizl4ycroylN-N (4-pyridinylrnethoxycabtnfl)-L-Cuciflyllhydrazide Following the procedure of Example 186(a)-186(c), except substituting N,Ndiisobutylamine for N-methylisobutylalhifle in step the tidle compound was prepared as a yellow solid (60 mg, MS (ESI): 519.5 Example 197 Preparation of N-(N-benzyloxycarbonvl-L-leucinyl [N.N-(bis methylpropvl )aminolthiazol-4-ylcarbonvl hvdrazide Following the procedure of Example 186(a)-186(c), except substituting N,Ndilsobutylamine for N-methylisobutylainine in step and N-benzyloxycarbonyi-L.

leucine for N-(4-pyridinylmetboxycarbonyl)-L-leucine in the final step, the title compound was prepared as a yellow solid (131 mg, MS (ESI): 518.4 Example 198 Preparation of N-f2-(4-morholiiothiazol.4-.lcarbonyll-N'-[N-(4pv2ridinvlmethoxycarbovl )-L-leucinyllhydrazide Following the procedure of Example 186(a)- 186(c), except substituting rnorpholine for N-methylisobutylarnine in step the title compound was prepared as a white solid (45 mg, 3 MS (ESI): 477.3 0**4 Example 199 Preparation of N-r2-[2-(4-pvyridinylmethoxy~phenyllthiazol-4ylcarbonvyi..N'. pyrid inylmethoxycarbonvl'-L-leucinyllhydrazide a) 2 -methoxymethoxybromobenzene To a stirring suspension of sodium hydride (1.2 g, 52.1 mmol, ~0 dispersion in mineral oil) in DMIF (75 mL) at 0 0 C was added 2-bromophenol (6.0 g, 34.7 mmol) dropwise. After stirring for 20 min, bromomethyl methyl ether (4.3 g, 34.7 mmol) was added. After stirring for 16."h at room temperature, the mixture was poured into water (250 mL) 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, IHNMR (400MlHz, CDCl 3 8 7.55 1H), 7.28 (t, 1H), 7.16 1H), 6.91 IH), 5.25 3.54 3H).

b) ethyl 2-(2-methoxymethoxyphenyl)thiazole4-carbOXVlate Following the procedure of Example 1 12(a)-1I12(b) and 11 I 12(e), except substituting 2-methoxymethoxybromobenzene for 2benzyloxybromobeazene in step the title compound was prepared. MS(ESI): 294.3 c) ethyl 2-(2-hydroxyphenyl)thiazole-4-carboxylate To a stirring solution of the compound of Example 199(b) (0.839 g, 2.86 mmol) 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 bicarbonate, and brine, dried NMgOW, filtered and concentrated to yield the title compound as a pale yellow solid (0.674 g, MS(ESI): 250.2 d) ethyl 2- (2-(4-pyridylmethoxy)phenyl]thiazole-4-carboxylate To a stirring solution of the compound of Example 199(c) 125 g, 0.502 mmol), 4-pyridylcarbinol (0.071 g, 0.653 tumol), and triphenylphosphine 171 g, 0.653 mrnol) in THF (5 ml-) at 0 0 C was added diisopropyl azodicarboxylate 132 g, 0.653 mmol) dropwise. After stirring at room temperature for 16 h, the solution was concentrated and purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid 100 g, 59%).

MS(ESI): 341.3 e) N-[2-[2-(4-pyridinylxnethoxy)phenyl]thiazol-4-ylcarbonyl]-N'-[N-(4pyridinylmethoxycarbnyl)-L-leucinyljhydlazide Following the procedure of Example 1 12(f)-1 12(g), except substituting ethyl 2-12-(4-pyidylmethoxy)phenyl]tbhiazole-4-carboxylate for ethyl 2-(2benzyloxyphenyl)thiazole.-4-carboxylate in step the title compound was prepared as a white solid (146 mg, MS(ESI): 575.4 Example 200 Preparation of N-r2-(2-naphthyl)thiazol-4-ylcarbonvll-N'-fN-( 4 pyridinylmethoxycarbonyl)-L-1eucinvllhydrazide Following the procedure of Example I112(a)-l except substituting 2naphthylboronic acid for 2-benzyloxyphenyl boronic acid in step the title compound was prepared as a white solid (226 mg, MS (ESI): 518.4 Example 201 Preparation of N-f2-rN.N-(bis)-2-methlprol')ainolthiazoI-4-ylcarbonyll-N'- rNmethyl-N-(4-pvridinlmethoxcarbonfl-L-eucinlhydrazide Following the procedure of Example 186(a)- 186(c), except substituting N,Ndilsobutylamine for N-methylisobutylaxnine in step and N-methyl-N-(4- .:pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L- 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-benzloxvcarbonyl-L-leucinyl)-N'- f2-(4-morpholino'ahiazol-4vlcarbonyllhydrazide Following the procedure of Example 186(a)- 186(c), except substituting morpholine for N-methylisobutylamine in step and N-benzyloxycarbonyl-Lleucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in the final step, the title compound was prepared as a white solid (115 mg, MS (ESI): 576.4 Example 203 Preparation-of N-rN -(4-pyridinyimethoxycarbonyl )-L-leucinvl 2-(4thiomorpholino)thiazol-4-vlcarbonvllhvdirazide Following the procedure of Example 186(a)- 186(c), except substituting thiomorpholine for N-methylisobutylaxnine in step the title compound was prepared as a white solid (35 mg, MS (ESI): 493.4 Preparation of N-(N-benzyloxycarbonyl-L-leucinvl)rN'- r2-(4thiomorpholino)thiazol-4-vlcarbonyllhydrazide Following the procedure of Example 186(a)-i 186(c), except substituting thiomorpholine for N-methylisobutyiamine in step and N-bentyloxycarbonyl-L- :leucine for N-(4-pyridinylmethoxycarbonyl)-L-ieucine 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-ethvlenedioxy-4-methoxyphenvhthiazol-4-vlcarbonyl 1-N'rN-(4-pyridinylmethoxycarbonyl )-L-leucinyllhydrazide Following the procedure of Example 112(a)- I 12(g), except substituting 2,3ethylenedioxy-4-methoxybromobenzene for 2-benzyloxybromobenzene in step the title compound was prepared as a white solid (31 mg, MS (ESI): 556.4 Example 206 Preparation of N-r2- [N.N-(bis)-2-methvlpropyl)aminolthiazol-4-vlcarbonyll [Nmethyl-N-(3-pyridinylmethoxycarbonyl)-L-leucinyllhydrazide Following the procedure of Example 186(a)- 186(c), except substituting NNdiisobutylamine for N-methyiisobutylamine in step and N-methyl-N-(3pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-Lleucine in the final step, the title compound was prepared as a yellow solid (30 mg, MS (ESI): 533.5 Example 207 Preparation of N- f2-(N-cyclopropvylmethyl-N-propvylam-ino)thiazol-4-ylcarbonyl 1- N'-IN-(4-pyridinylmethoxycarbonyl)-L-leucinvllhydrazide Following the procedure of Example 186(a)- 186(c), except substituting Ncyclopropylmethylpropylamine for N-methylisobutylamine in step the title compound was prepared as a yellow solid (60 mg, MS 0E1): 503.3 Example 208 Preparation of N- rN-(4-pyridinylmethoxycarbonyl)-L-leucinyll-N'- gQuinolyl)thiazol-4-ylcarbonyll hydrazide Following the procedure of Example 11I2(a)- I 12(g), except substituting 8bromoquinoline for 2-benzyloxybromobenzene in step the title compound was 15 prepared as a white solid (134 mg, MS (ESI): 519.3 Exml 209.

Preparation of N- rN-methyl-N-(4-pvridinylmethoxycarbonyfl-L-leucinyl f2-(8guinolflthliazol-4-ylcarbonyllhydrazide Following the procedure of Example 1 12(a)- I 12(g), except substituting 8bromoquinoline for 2-benzyloxybrornobenzene in step and N--methyl-N-(4pyridinylmethoxycarbonyl)-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L- leucine in step the title compound was prepared as a white solid (53 mg, 22%).

MS (ESI): 533.3 192 Example 210 Preparation of 1 -N-(N-Cbz-Ieucinvl)-amjno- 3 -N-(4-biphenyl -sul fonvl D-aminoprop~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 inmol) 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) I -N-(N-Cbz-leucinyl)-arnino-3-N-(4-bipbenyl-sulfonyl)-amino-propan-2 -one Following the procedure of Example 5 except substituting "4-biphenyl sulfonyl chloride" for '4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M-Wr=550.

Preparation of 1 N-Cbz-Ieucinyl)-amino-3-N-(3-biphenyl-sulfonyl)-aminop2ropan-2-one a) 3-biphenyl-sulfonyl chloride :.20 3-Biphenyl bromide (9.3 g, 40 mmol) was dissolved in THF (40 nml) and a Grignard reagent was prepared in standard fashion with magnesium powder (1.2 g, mmol). The reaction was cannulated into a solution of sulfuryl chloride (10.5 g, 6.4 ml, 80 mmol) in hexanes (25 ml) and was strirred at RT for 2h. The reaction was quenched with ice-water, extracted with ether, dried with magnesium sulfate, filtered, concentrated, and was used in the next reaction without further purification.

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

193 Example 212 Preparation of I N-Cbz-leucinvi)-amino-3-N-(2-benzvloxv-phenvi-sulfony)amino-propan-2 -one a) 2-benzyloxy-phenyi-sulfonyl chloride Following the procedure of Example 211 except substituting '2benzyloxy-phenyl bromide for "3-biphenyl bromide", the title compound was prepared and was used in the next step without further purification.

b) 1 N-Cbz-Ieucinyl)-amino-3-N-(2-benzyloxy-phenyl-sulfonyl)-amiino-propan- 2-one Following the procedure of Example 51 except substituting *ezlx phny sufoy chloride "fr"4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+W= 58 1, M+Na*= 604,2M+Na'= 1185.

Example 2 13 Prep~aration of I N-Cbz-leucinyl)-axnino-3-N-(4-phenoxy-phenvl-sulfonyl)amino-propan-2-one a) 4-phenoxy-phenyi-sulfonyl chloride Following the procedure of Example 211 except substituting "4-phenoxy Sphenyl brom-ide for "3-biphenyl bromide", the title compound was prepared and .3

C

was used in the next step without further purification.

b) 1 N-Cbz-leucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-anino-propan-2one Following the procedure of Example 5 1 except substituting "4-phenoxyphenyl-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M+W= 568, M+Na'= 590.

194 Example 2 14 Prep~aration of I N-Cbz-leucinyl)-amino-3-N-(2-dibenzofuran-sulfonvl)-aminopropan-2-one a) 4-phenoxy-phenyl-sulfonyl chloride Following the procedure of Example 2 10 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) 1 N-Cbz-leucinyl)-amino-3-N-(2-dibenzofuran-sulfony)-am-ino-propan-2one phnylFollowing the procedure of Example 5 except substituting "4-phenoxy phny sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M+Wr= 566, M+Na*= 588.

*15Exml21 Preparation of I N-Cbz-leucinyl)-amino-3-N-(3 .4-dirnethoxv-phenvl- sulfonyi)arrino-Rropan-2-one Following the procedure of Example 51, except substituting "3,4- """9dimethoxy-phenyl-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M+Wr= 536, M+NH4*= 553.

Example 216 Preparation of 1 N-Cbz-leucinyl)-amino-3-N-(2.5-dichlorothiophene-3sulfonyl)- iio-rpn-2-one Following the procedure of Example 51, except substituting dicblorothiophene-3-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M+NH 4 567, 2M+W'= 110 1.

Example 217 Preparation of I N-Cbz-leucinyl) -arnino- 3-N-(phenvl -su Ifone-5 hiophene -2 sulfonvi )-armino-propan-2-one Following the procedure of Example 5 1, except substituting phenyl sulfone-5-thiophene-2-sulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)phenyl sulfonyl chloride", the title compound was prepared: MS(ES) 622.

Example 218 Preparation of N-Cbz-leucinvl)-amino-3-N-(8-Quinoline-sulfonl)-aminoprop~an-2-one Following the procedure of Example 5 1, except substituting "8-quinolinesulfonyl chloride for "4-(3-Chloro-2-cyano-phenoxy)-pheny sulfonyl chloride", ~.the title compound was prepared: MS(ES) 527.

Example 219 Preparation of 1 N-Cbz-leuciny I)-amino- 3-N-(2-pvriddvl-sul fonvl) -aminopgRpan-2-one Following the procedure of Example 5 1, except substituting "2-pyridyl- 0% 0sulfonyl 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: MS(ES) 477, M+ Na+ 499.

Example 220 Preparation of I N-Cbz-leucinyl )-arnino-3-N-(2-pvridvl-sulfonyl )-amrnoprop~an-2 -one a) I -N-(N-Cbz-1eucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonyl)-amlno-propan-2.

ol 1,3-Diamino propan-2-ol (6.75 g, 75 niiol) was dissolved in DMIF (lO0mI) and Cbz-leucine (20g, 75.5 rnmol), HOBT-hydrate (1 Ig, 81.5 mmol), and EDGI (I15.5g, 81.2 mmnol) were added. The reacti on was stirred overnight at RT. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether m.l) and MeOH (30 ml) were added. A IN solution of hydrochiloric acid in ether was added (I M, 30 ml) and a white gum formed, which was washed several times with ether. MeOH-acetone were added and heated until the gum became a white solid. The white solid was dissolved in DMF (25 ml) and DIEA (Srnl), then 4phenoxy phenyl sulfonyl chloride was added. The reaction was stirred for 2h, concentrated in vacuo, then chromnatographed (silica gel, 1: 1 EtOAc: hexanes) to provide the desired product as a white solid.

b) Lecn*aio3N(-hnx hey ufnl-mn-rpn2 b) LNb-eucinyl)-amino-3-N-(4-phenoxy-pheny sulfonyl)-amino-propan- 2-ol (I1.0g, 1.8 mmol) was dissolved in EtOH (30 ml), then 10% Pd/C (0.22g) was ~added followed -by 6N hydrochloric acid (2.5 ml), and the reaction -was stirred under a baloon of hydrogen gas for 4h at RT. The reaction mixture was filtered, concentrated, and azeotroped with toluene to provide a white glass which was used in the next reaction without further purification.

c) 1 -N-(N-4-pyridyl acetyl-leucinyl)-anuno-3-N-(4-phenoxy-phenyl-sulfonyl)amino-propan-2-ol Leucinyl-amino-3-N-(4-phenoxy phenyl sulfonyl)-arnino-propan-2-ol (0.36 g, 0.76 mnmol) was dissolved in DMF (5 ml), then NMM (0.45 ml, 4 mmol) was added followed by 4.-pyridyl acetic acid (0.13g, 0.75 rnmol) and HBTU (0.29g, 0.76 rnmol) and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then chromatographed (silica gel. 5%MeOH: methylene chloride) Co provide the desired product as a white solid (90 mg, MS(ES): M-.H+ 555.

d) 1 -N-(N-4-pyridyl acetyl -le uciny1) -amino- 3-N- (4-phenoxy -phenyl -sul fonyl)axino-propan-2-one 1 -N-(N-4-pyridyl-acetyl-Ieucinyl)-amino-3-N-(4-phenoxy-phenyl-sulfonylyamnino-propan-2-ol (45 mg, 0.08 mmol) was dissolved in acetone (5mI), 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 see.reaction mixture was concentrated in vacuo. The reaction was diluted with pH- 7 buffer and then was extracted with EtOAc. dried with magnesium sulfate, filtered, concentrated in vacuo, then chromatographed (silica gel, 5% MeQH-rnethylene chloride) to give the desired product as a white solid (27 mg, MS(ES): =553.

Example 221 Preparation of I N-2-pvyridvl-sulfonvl-leucinyl)-an-ino-3-N-(4-p2henoxyp2henyl-sulfonvh)-amino-propan-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 HBTU", the title compound was prepared: MS(ES) M+W= 475, M+ Na+ 497, 2M+ Na+ 117 1.

Example 222 Preparation of I -N-(N-morpholino-carbonyl-leucinvh)-axnino-3-N-(4-phenoxvphenyl-sulfonyl)-amino-propan-2-one Following the procedure of Example except substituting Nmorphotino-carbonyl chloride" for "4-pyridyl acetic acid and HBTU", the title compound was prepared: MS(ES) M 547, M+ Na+ 569, 2M+ Na+ 1115.

198 Example 223 Preparation of 1 N-4-pyridvi-carbonVI-Ieucinl)-arinfo-3-N-(4-heloxVphenyl-sulfonyl)-anino-ropa- 2 -oflC Following the procedure of Example except substituting 4pyridyl-carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) M 539.

EampJe 24 Preparation of 1 N-acetyl-leucinyl')-alnino- 3-N-(4-p2henoxy-phenyl-sulfonvl)amno-popa-2-one Following the procedure of Example except substituting "acetyl chloride" for "4-pyridyl-acetic acid and HBTU", the title compound was prepared: 9.:MS(ES) M 476, M+ Na+ 498, 2M+ Na+ 973.

Example 225 .9.9 Preparation of 1 N-iniidazole acetyl-leucinl)-amino-3-N-(4-phenoxV-P2helylsulfonyvh-amino-propan-2-one Following the procedure of Example except substituting "imidazole acetic acid" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) M+W= 542.

Prep~aration of I N-4-carboxymethyl benzoy1-eucinv1)a-ino-3-N-( 4 -pheloxyphenyl-sulfonyl')-amino -propan-2-one Following the procedure of Example except substituting "4carboxymethyl benzoic acid" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) M 596, M+ Na+ 618, 2M+ Na+ 1213.

Example 227 Preparation of I N-(N.N-dimethyl glycinyl)-leucinvl)-arniino-3-N-('4_Lhenoxv phenyli-sulI fonv 1) -ami no-prop~an-2 -one Following the procedure of Example except substituting 'N,Ndimethyl glycine" for "4-pyridyl acetic acid", the title compound was prepared: MS(ES) M+W= 519.

Example 228 Preparation of I N-8-guinoline-sulfonamide-leucinvI)-anino-3-N-(4phEenoxv.

p2henyl-sulfonyl)-ammno-p2ropan-2-one *Following the procedure of Example except substituting 8 quinoline sulfonyl chloride" for "4-pyridyl -acetic acid and HBTU", the title :compound was prepared: MS(ES) M+W= 625.

200 Example 229 Preparation of I N-Cbz-leucinyl )-amino-3-N-(8-gtlinoline-carbonyl)-anminoprop~an-2-one l,3-Diamino propan-2-ol (6.75 g, 75 mmol) was dissolved in DMLF (lO0jm]) and Cbz-leucine (20g, 75.5 ininol), HOBT-hydrate (11Ig, 81.5 mmol), and EDCI (1 5.5g, 81.2 mmol) was added. The reaction was stirred overnight at RT. A portion of the reaction mixture (30 ml) was concentrated in vacuo, then ether (50 ml) and MeOH (30 ml) were added. A IN solution of hydrochloric acid in ether was added (1 M, 30 ml) and a white gum formed, which was washed several times with ether.

MeOH-acetone were added and heated until the gum became a white solid. The white solid (0.44g, 1. 1 mmol) was dissolved in DMIF (3 ml) and NMM (0.33m1, 0.3 rnmol). then 8-quinoiine carboxylic acid 17g, 1.0 mmol), and HBTU 38g, mmol) were added and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then chromatographed (siica gel, 7:2 EtOAc: hexanes). The solid was then dissolved in acetone then IN hydrochloric acid 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 andthe 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 99 vacuo. then chromatographed (silca gel, 5% MeOH-methylen-e chloride) to give the *9V 0.

desired product as a white solid (23 mng, 4 1 MS(ES): M+H+ 49 1.

Preparation of N-Cbz-leucinyl)-arniio-3-N-(6 -quinoline-carbonvl)-aniflo- Following the procedure of Example 229, except substituting "6-quinolinecarboxylic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M 49 1.

Example 23 1 Preparation of I N-Cbz-leucinvl )-arnino-3-N-(2-(4-biphenyl )-4-methylprop~anamide)-propan-2-one Following the procedure of Example 229, except substituting "2-isobutyl-4biphenyl acetic acid for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M 586, M+ Na+ 608, 2M+ Na+ -1193.

-Preparation of I N-Cbz-leucinyl)-axnino-3-N-( N-4-pvyridyi-methvleneoxy carbonyl-leucinvl)-aznino-propan-2-one Following the procedure of Example 229, except substituting '4-pyridyl 0 methyleneoxy carbonyl leucine" for "8-quinoline-carboxylic acid"', the title :compound was prepared: MS(ES) M+Wr= 584.

Example 233 Preparation of 1 N-Cbz-leucinyl )-amino-3-N-(benzoyl )-amno-p2rop~an-2-one Following the procedure of Example 229, except substituting "beazoyl chloride" for '8-quinoline carboxylic acid and HBTU', the title compound was prepared: MS(ES) M 440, M+ Na+ 462, 2M+ Na+ 90 1.

"'Prep rati n ofExample 234 Preartio o N-Cbz-leucinyl)-amino)-3-N-(2.4-dimethvl-3-sulfonyl)yamino- Following the procedure of Example 5 1, except substituting "2,4-dimethyl- 3-sulfonyl chloride" for "4-(3-Chloro-2-cyanq-phenoxy)-phenyI sulfonyl chloride", the title compound was prepared: MS(ES) M 494.

202 Preparation of 1 -N-(N-Cbz-1 eucinl)-.ahiflo- 3 -N-(1I 3-dimethyl-5-chloro- pyrazole- 4-sulfonyl')-amino-propal-2-ofle Following the procedure of Example 5 1, except substituting 1 3-dimnethyl- 5-chloro- pyrazole-4-sulfonyl chloride" for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M+W= 494.

Preparation-of 1 -N-(N-4-12yridy-methVleneoxy carbonyl-leucinyvh-amlino-3-N-( 4 10 phenoxy-phenyl-sulfonyla n-O~f 2 -one Following the procedure of Example 213(a), except substituting "4-pyridylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the tidle compound was prepared: MS(ES) M+W= 569.

EMl 3 Preparation of N-3-vddyl-methyleleoxy carbonyl-leucinvl')-alTino-3-N-( 4 phenoxy-phenyl-sulfonyl)-amino-pro~l 2 2ofl Following the procedure of Example 213(a), except substituting "3-pyridylmethyleneoxy carbonyl-leucine" for Cbz-Ieucine", the title compound was *20 prepared: MS(ES) M+W= 569.

0~ Preparation of N--ydimtyeex-aboy-ecnl-ni-- 4 12henoxy-phenl-sulfonyl)aliOpO-f 2 Ol Following the procedure of Example 2 13(a), except substituting "2-pynidylmethyleneoxy carbonyl-leucine" for Cbz-leucine", the title compound was prepared: MS(ES) 569.

Example 239 Preparation of I N-4-carboxv-benzovl-leucinvl)-amino-3-N-(4-phenoxv- Dhenvl-sulfonvl )-amino-prop~an-2-one I -N-(4-carboxy methyl- benzoyl-leucinyl)-amrino-3-N-(4-phenoxy-phenyl.

sulfonyl)-amino-propan-2-one 105g, 0. 176 mmol) was dissolved in MeOH (5 mJd) and water (1 mld), then LiQH-hydrate (15 mg, 0.35 mmol) was added and the reaction was stirred at RT for lh. 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, 50:50:1 EtOAc: hexanes: AcOli) to give the desired product as a white olid (35.6 mg, MS(ES) 582, M+ Na+ 604. E~xample 24 Preparation-of 1 N-Me-N-Cbz-!eucinl)-amino-3-N-(4phenoxy-1phenvIsulfonvl)-axnino-propan-2-one Following the procedure of Example 2 13(a), except "N-Me-N-Cbz-leucine" *for" Cbz-leucine", the title compound was prepared: MS(ES) 582, M+ Na+ =60492M+ Na+= 1185.

Example 241 Preparation of 4-phenoxy benzoyl-amino-3-N-(4-p2henoxv -phenyl- sulfonyl)- arnuno-p2ropan-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, M+ Na+ 539, 2M+ Na+ 1055.t Example 242 Preparation of 1 -N-(3-phenoxv-benzoyl )-arino-3-N-(4-p2henoxv-p2henyl- sulfonvi amino-p2ropan-2-one Following the procedure of Example 213(a), except "3-phenoxy benzoic acid "for Cbz-leucine", the title compound was prepared: MS(ES) M+W= 517, M+ Na+ 539,-2M+ Na+ 1055.

Example 243 Preparation of 1 -N-(4-p2henoxy benzovl)-amino-3-N-(4-p2henoxy-phenyl- sulfonvi anopoan-2-one Fo~owing the procedure of Example 213(a), except "4-phenoxy benzoic acid for Cbz-Ieucine", the title compound was prepared: MS(ES) M+Wr= 517, M+ Na+ 539, 2M+ Na+ 1055, M-H+ 515.

Example 244 2"Preparation of I -N-(4-biphenyl acetvl)-amino-3-N-(4-phenoxy-p2henyl-sulfonvl)arruno-propan-2-one Following the procedure of Example 213(a), except "4-biphenyl acetic acid "for" Cbz-leucine", the title compound was prepared: MS(ES) 515, M+ Na+ 537, 2M-s-Na+= 1051.

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

Example 246 Preparation of 1 N-Cbz- leucinvl )-ami no- 3-N-(4-benzyloxy-benzoyl amnop2rop~an-2-one Following the procedure of Example 229, except substituting "4-benzyloxybenzoic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) 546, M+d Na+ 568, 2M+ Na+ 1113.

Example 247 Preparation of I -N-(2-(4-biphenvl )-4-methvl-pentamido)-3-N-(4-p2henoxy-p2henvl sulfonfl)-axnino-propan-2-one Following the procedure of Example 213(a), except 2-(4-biphenyl)-4methyl-pentanoic acid for Cbz-leucine", the title compound was prepared:* MS(ES) M+W= 571, M+ Na+ 593.

Preparation of l-N-(2-(3-biphenyl)-4-methvl-pentamido)-3-N-(4-p2henoxv-p2henvlsulfonyl)-amino-propan-2-one a) 3-bromo-phenyl methyl acetate 3-Bromo phenyl acetic acid (2.15g, 10 mmol) was dissolved in ether, then was treated with a solution of diazomethane until the yellow color persisted. The reaction was then quenched with AcOH, concentrated in vacuo and Was used in the next reaction without further purification.:.* b) 3-biphenyl methyl acetate 3-bromo-phenyl methyl acetate (2.29g, 10 mnmol) was dissolved in toluene (30 ml). Then, phenyl boromc acid (1 .46g, 12 mmol) was added followed by aqueous sodium carbonate (2M, 4.24 ml, 40 mniol), then tetrakis(triphenylphosphine) palladium (0.35g, 0.3 mmol) and was refluxed overnight. The reaction was cooled to RT, diluted with saturated ammonium chloride, then extracted with EtOAc 2 x 10 ml). The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica 206 gel, 5% EtOAc: hexanes) to provide the desired product as a white solid (1.93g, MS(ES): 263.

c) 3-biphenyl acetic acid 3-Biphenyl acetyl methyl ester was dissolved in MeOH (40 ml) and water (6 ml), then LiOH-hydrate (0.7g, 16.8 mmol) was added, and the reaction was stirred at RT for 2h. The reaction was diluted with water, acidified with 6N hydrochloric acid (1 ml), then with EtOAc (2 x 10 ml). The combined organics were dried with magnesium sulfate, filtered, and concentrated to give the desired product as a white solid (1.66 g, 1H NMR: d: 7.6-7.25 9H), 3.7 2H)

S

d) 3-(4-biphenyl)-4-methyl-pent-4-enoic acid nBuLi (3.26 ml, 1.6 M in hexanes) was added dropwise to a solution of diisopropyl amine (0.74 ml, 5.3 mmol) in THF (6 ml) at 0 C. The reaction was stirred for 15 minutes, then was cooled to -78 C. 3-Biphenyl acetic acid (0.5g, 2.35 mmol) wasa dissolved in THF (2 ml) and was added dropwise to the LDA solution.

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

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

207 e) 3-(4-biphenyl)-4-methvl-pentanoic acid 3 Bipheny I)-4-methvl -pen t-4-e noic acid (0.5g, 1.87 minol) was dissolved in EtOAc (25 ml). Then, 10% Pd/C (60 mng) 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: mnethylene chloride) to give the desired product as a white -solid (1.66 g, IH NNM: d: 7.6-7.3 (in, 9H), 3.7 IH), 2.07-1.95 (in, IH), 1.8-1.7 (mn, IH), 1.6-1.45 (mn, 1H).

f) I -N-(2-(3-biphenyl)-4-inethyl-pentamido)-3-N-(4-phenoxy-pbenyl-sulfonyl)- :::.amino-propan-2-one 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 I -N-(3-biphenyl acetyfl-arnino-3-N-(4-p2henoxy-p2henyl-sulfonyl)amino-propan-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+ Na+ 537, 2M+ Na+ 105 1.

208 Example 250 Preparation of 1 N-4-pyridvl acetyl-leucinvl')-arnino-3-N-(2-benzvloxv-phenvisulfonyl)-amino-p2ropan-2-one a) 1 -N-(N-Boc-leucinyl)-amino-3-N-(2-beazyloxy phenyl-sulfonyl )-arnino-propan- 2-ol 1,3-Diam-ino-propan-2-ol (3.375g, 37.5 mmol) was dissolved in DMF ml). Then HOBT-hydrate was added (5.5g, 40.7 mmol), followed by Boc-L-leucine (9.34g, 37.5 mmol) and EDCI (7.77g, 40.7 mmol). The reaction was stirred for 4h, then diluted with DMF to make a stock solution of a total volume of 100 MI (0.375 mmolml). The stock solution (18 ml, 6.75 mmol) was treated with NMM (0.89 ml, 7.28 mmol), then 2-benzyloxy phenyl sulfonyl chloride (1.9g, 6.72 mxnol). The *..*reaction was stirred an additional 2h, then was diluted with water, extracted with .EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed .:(silica gel, 20% EtOAc: hexanes): MS(ES) 550.

b) *--Iuiy)aio3N(-ezlxypey-ufnl-mn-rpn2 b) 1 leucinyl)-amino-3 -N-(2-benzyloxyphenylsulfonyl)-amino-n2o propan-2-ol (0.7g, 1.3 mmol) was dissolved in 1: 1 TFA: DCM (50 ml) and was stirred at RT for 2h, concentrated in vacuo and was used in the following reaction without further purification: MS(ES) M+W= 450.

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

209 Example 251 Preparation of I N-4-pvyridyl carbonyl-Ieucinyl)-amino-3-N-(2-benzvloxvphenvi -sulfonvi )-amino-p2ropan-2-one Following the procedure of Example except substituting "4pynidyl carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) 553.

Example 252 Preparation of N-4-irrudazole, acetic- leucinyl)-arnino- 3-N-(2 -benzyloxvYp2henyl-sul fonyl)-amino-propan-2 -one Following the procedure of Example except substituting "4 imidazole acid" for "4-pyridyl-acetic acid the title compound was prepared: MS(ES) 556.

15 Example 253 Preparation of I N.N-dimethyl glycyl) leuciny amino- benzv loxy p2henyl-sulfonyl)-arnino-propan-2-one Following the procedure of Example except substituting "N,Ndimethyl glycine" for "4-pyridyl -acetic acid the title compound was prepared: MS(ES) M+W= 533.

Example 254 Preparation of 1 N-(N-methyl p2rolyl-leucinyl)-arniino-3-N-(2-benzyloxvp2henyl-sulfonyl)-amino-propan-2-one 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 Preparation of I N-(N-methyl pipgridine-4-carbony leucinylI)- amino- 3-N benzyloxy-phenyl-sulfonyl)-arnino-p2ropan-2-one 210 Following the procedure of Example except substituting "Nmethyl-piperidine-4-carboxylic acid" for "4-pyridyl acetic acid the title compound was prepared: MS(ES) M+lf= 573.

Example 256 Preparation of I N-(N-methvl piperidine-4-carbonyl)-leucinyl)-amino- 3-N-(2dibenzofuran.sulfonl).armno-prop2a- 2 -olC Following the procedure of Example except substituting methyl-piperidine-4-carboxylic acid" for '4-pyridyl acetic acid and "2dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M +HW 557.

Preparation of 1 N-(N-methyl p2rolyl)-leucinfl)-amino-3-N-(2-dibelzofuralsulfonyl)-aniino-p2ropan-2-one Following the procedure of Example except substituting N- Z"methyl proline for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl. suiphonyl chloride" the title compound was prepared: MS(ES) 543.

Preparation of I N.N-dimethyl icyl)-leucinyl)-amrino-3-N-(-( 2 dibenzofuran-sulfonyl)-anmino-propan-2-one Following the procedure of Example except substituting N,Ndimethyl glycine for "4-pyridyl acetic acid and "2-dibenzofuran-sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+W= 517.

Example 259 Preparation of N-4-imidazole acetic eucin yl)-arriino-3- N-(2-di benzofuran sulfonvi )-arnino-p2ropan-2-one Following the procedure- of Example except substituting '4irnidazole acetic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 526.

Example 26 Preparation of N-4-pyridyl c arbonvl-leucinyl)- amino- 3-N-(2-di benzofuran- Following the procedure of Example except substituting "4pyridyl carboxlic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 537.

Example 261 Preparation of 1 N-4-pvridyl acetyl-leucinyl)-armino-3-N2-dibenzofuransul fonfl)-armino-p2ropan 2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride" for "2-benzyloxy phenyl sulphonyl chloride" the tatle compound was prepared: MS(ES) M 55 1.

Example 262 Preparation of 1 N-4-imidazole-acryl-leucinyl)-amiuno-3-N-(2-dibenzofuransulfonyl)-amino-propan-2-one Following the procedure of Example except substituting "4irnidazole-acryic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for '2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+I-f= 552.

Example 263 Preparation of 1 N-pyrazole-carboflyl-leuciyl)niflo- 3

-N-

2 -dibelzofuransulIfonvl)-ainino-propan-2-one Following the procedure of Example except substituting "pyrazole carboxylic acid" for "4-pyridyl acetic acid and "2-dibenzofuran sulfonyl chloride" for "2-beazyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) 538.

Example 264 Preparation of I N-benzoyl-leucilyl)-amiffo-3-N-8-guioliC-sulfofll)-aminfop2rop~an-2-one Following the procedure of Example except substituting :~."benzoic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES)M 497.

Preparation of I N-2.5difuorobenzoyleucinylailo-3N-(8-iuiolilesulfonyh)-amnopr n-2-one Following the procedure of Example except substituting 'adifluoro-benzoic acid" for "4-pyridyl acetic acid and "8-quindlie sulfonic acid" for "2-benzyloxy phenyl. suiphonyl, chloride" the title compound was prepared: MS(ES) MiWr= 535.

Exampl e 266 Preparation of I N-2.5-difluoro-phenyl acetyl -leucinyl)-amino-3-N-(Sguinoline-sulfony)- nioprpf- 2 -oflC Following the procedure of Example except substituting difluoro- phenyl acetic acid" for '4-pyridyl acetic acid and "8-quinoline sulfomic acid" for "2-benzyloxy phenyl suiphonyl chloride" the title compound was prepared: MS (ES) M 547.

Example 267 Prep~aration of I N-phenyl acetvl-Ieucinvl)-amino-3-N-(8-guinoline-sulfonvl)ami nc-propan-2-one Following the procedure of Example except substituting "phenyl acetic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for "2benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M 511.

Example 268 ::Preparation of I N-4-pvridyl acetvl-Ieucinyl)-amino-3-N-(8-guinolinesulfonyl)-amino-propan-2-one Following the procedure of Example except substituting "4pyridyl acetic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" for 15 "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) 512.

Preparation of 1 N-4-pyridyl carbonyl-leucinyl)-amino-3-N-(8-guinolinesulfonyl)-amino-propa-2-one pyridylFollowing the procedure of Example except substituting prdlcarboxylic acid" for "4-pyridyl acetic acid and "8-quinoline sulfonic acid" 'for "2-beazyloxy phenyl suiphonyl chloride" the title compound was prepared: MS(ES) M+W= 498.

214 Example 270 Preparation of N-4-Imidazole acetyl-leucinyl)-amino-3-N-(8-guinolinesulfonvi )-amino-p2rop~an-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+W= 501.

Exmple 271 Preparation of Il-N-( N-3-phenyl p2ropionyl-leucinvl)-amino-3-N-(8-gQuinolinesulfonyl)-ainino-propan-2-one Following the procedure of Example except substituting :"hydrocinnaniic 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= 525.

Exmll 27 Prep~aration of bis-N.N'-( N-4-p2yrdl methvleneoxy carbonvl-leucinyfl- 1.3diaming-propan-2-one Following the procedure of Example 37, except substituting "4-pyridylmethyleneoxy-carbonyl-leucinyl for "Cbz-leucine" the title compound was prepared: MS(ES) M+lf= 585.

Example 273 Prep~aration of bis-N.N'-( N-3-pRyddyl methyleneoxy-carbonyl-leucinyl)- 1.3dianiino-propan-2-one Following the procedure of Example 37, except substituting "3-pyridylmethyleneoxy-carbonyl-leucinyl for "Cbz-leucine" the title compound was prepared: MS(ES) 585.

Example 274 Preparation of N-2-pyridyl methyleneoxy carbonvl-leuciL)-.3 di amino-popari -2 -one Following the procedure of Example 37, except substituting "2-pvi-idylrnethvleneoxy-carbonyl-leucinyl for "Cbz-leucine ",the titde compound was prepared: MS(ES) M+W= 585.

Example 275 Preparation of 1 N-b-ecnl-mn---2-e~lx-ezy)aio 10 -propan-2-one Following the procedure of Example 229, except 2 -benzyloxy-benzoic acid" 8 -quinoline-carboxylic acid the title compound was prepared: MS(ES) M 546.

Example 276 Prep2aration of I N-b-ecnl-mn---3-ezlx-ezy)aio prop~an-2-one Following the procedure of Example 229, except '3-benzyloxy benzoic acid" for "8-quinoline carboxylic acid ,the title compound was prepared: MS(ES) M+1r= 546.

Example 277 Preparation of N-Cbz- leuci nyl)- aino-3-N-(4-bipheny Iacey)-mno- Following the procedure of Example 229, except "4-biphenyl acetic acid" for "8-quinoline carboxylic acid the title compound was prepared: MS(ES) M 530.

216 Example 278 Preparation of 1 N-Cbz-leucinvl )-ami no-3-N(2 -carboxvmethvl-thiophene-3 sulfonyl)-amino-p2ropan-2-one Following the procedure of Example 5 1, except substituting "2carboxymethyl thiophene-3-sulfonyl for "4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride", the title compound was prepared: MS(ES) M-H'=540.

Example 279 Preparation of I N-Cbz-leucinvl)-arino-3-N-methvl-N-( N-Cbz-leucinyl)amino-p2rop~an-2-one a) N-(Cbz-leucinyl)-amino-propene ~*'*N-Cbz-leucine (3.0g, 11.3 minol) was dissolved in DMF (50 ml), then NNM (1.3g, 12.4 mmol) was added, followed by allyl amine (0.65g, 0.85 inmol), 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, 9 filtered, concentrated, and chromnatographed (silica gel, 40% EtOAc: hexanes): MS(ES) M+Wr= 305.

b) N-(Cbz-leucinyl)-amino-propene oxide N-(Cbz-Ieucinyl)-amino-propene (2.95g, 9.7 mmol) was dissolved in methylene chloride (100 then mCPBA (5.0g, 29. [rnxno13 was added and the reaction was stirred overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 50% EtOAc: hexanes).

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

217 d) I N-Cbz-leucinyl)-amiuno-3-N-methvl-N-( N--Cbz-leucinvl)-arrino-propan--:.

one Following the procedure of Example 2 29(a), except substituting "1 -N-(Cbzleucinyl)-am-ino-3-N-rnethyl-amnino-propan-2-oI for '8-quinoline carboxylic acid ,the title compound was prepared: MS(ES) 597.

Example 280 Preparation of N-Cbz-leucinyl)-arrino-3-N-methyl-N-( N-4-pyridvl-1 methyloxy-carbon yl-leucinyl)-amino-propan- 2-one Following the procedure of Example except substituting "4pyridyl-methyleneoxy-carbonyl leucine "for "Cbz-leucine" in the title compound was prepared: MS(ES) M+H 598.

Example 281 15 Preparation of N-Cbz-leucinl)-axniino-3-N-methyl-N-(2-dibenzofuransul fonyl)-ami no-propan- 2-one *0 Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for "Cbz-leucine and HBTU" in the title OLO compound was prepared: MS(ES) M+W*=580, M+ Na-I 602.

Example 282 Preparation of I1-N- methyl- I- N-Cbz-leucinyl)-amino-3- N-(2-dibenzofuransu~lfonyl)-am-ino-12ropan-2-one Following the procedure of Example except substituting "2dibeazofuran sulfonyl chloride "'for "Cbz-leyicine and HBTU"' in the title compound was prepared: MS(ES) M+W=580 218 Example 283 Preparation of I1-N- methyl- I N-Cbz-leucinyl)-ainino-3- N-(2-dibenzofuransulfonyvb-amino-p2ropan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride" for "N-Cbz-leucine" in step and "4-pyridyl methyleneoxy carbonyl-leucine for "Cbz-leucine in step the title compound was prepared: MS(ES) M+W=580.

Example 284 Preparation of 1 -N-(2-dibenzofuran sulfonvi '-N-methyl)- armino-3N-(N-4-pvyridyl methyleneoxv carbonvl-leucinyl)-anino-propal- 2 -one too.Following the procedure of Example except substituting "4pyridyl methyl amine" for "allyl amine" and "2-dibenzofuran sulfonyl chloride" for :"N-Cbz-leucine" in step and N-4-pyridyl methyleneoxy carbonyl -leucinyl for "N-Cbz-leucine and HBTU in step the title compound was prepared: MS(ES) M+If=58 1.

Example 285 Preparation-of I N-Cbz-leucinyl)-aniino-3-N-( 4-pRdvl-methvlene)-3N-( N- Cbz-leucinyl)-anmino-propan-2-one Following the procedure of Example except substituting "4- *pyridyl methyl amine "for "methyl. amine, the title compound was prepared: MS(ES) 674.

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

Example 287 Preparation of 1 -N-(Cbz-leucinyl)-amnino-3-N-(4-pvridvl-methylene)-3N-(2dibenzofuran sulfonvl)-amnino-propan-2-one* Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride "Cbz-leucine and HBTU" in step the title compound was prepared: MS(ES) M+HW=657.

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

Example 289 Preparation of 1 -N-(4-phenoxy-benzoyvb-amino-3-N-(4-pyridyl-methylene)-3N-'

N-

Cbz-leucinvl)-aniino-propan-2 -one Following the procedure of Example except substituting "4- 0000 phenoxy benzoic acid for "Cbz-leucne in step "4-pyridyl methyl amine "for .0.0 20 "methyl amine", the title compound was prepared: MS(ES) M+H= 623.

Example 290 Preparation of 1 -N-(2-dibenzofuran-su lfonyfl-araino-3-N-(4-pyridyl-methylene)- 3N-( N-Cbz-leucinyl)-arrino -propan-2-one Following the procedure of Example except substituting "2dibenzofuran sulfonyl chloride for "Cbz-leucine and HBTU" in step "4-pyridyl methyl amine" for "methyl amine", the title compound was prepared: MS(ES) M+W= 657.

220

Claims (19)

1. 2. A compound according to Claim 1 wherein: 0 ICI ON R 3 5 is selected fromn the group consisting of Ph, or pyridine.
2. 3. A compound according to Claim 2 known as bis-1,3-(4-(3-chloro-2-cyano-phenoxy)- phenyl sulfonamido)-propan-2-one.
3. 4. A compound according to Claim 2 know as bis-l ,3.-(4-phenoxy-phenyl sulfonamido)- propan-2-one. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. P:\OPER\PDB\1180-97.DV3 21/3/00 9 @9 9* 99
4. 6. 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.
5. 7. A method according to Claim 6 wherein said cysteine protease is cathepsin K.
6. 8. 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.
7. 9. A method according to Claim 8 wherein said disease is osteoporosis.
8. 10. A method according to Claim 8 wherein said disease is periodontitis.
9. 11. A method according to Claim 8 wherein said disease is gingivitis.
10. 12. 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.
11. 13. A method according to Claim 12 wherein said disease is osteoarthritis.
12. 14. A method according to Claim 12 wherein said disease is rheumatoid arthritis. Use of a compound according to Claim 1 in the manufacture of a medicament for inhibiting a cysteine protease.
13. 16. A use according to Claim 15 wherein said cysteine protease is cathepsin K.
14. 17. Use of a compound according to Claim 1 in the manufacture of a medicament for *90*0 a 9 9 9999 @9 223 P:\OPER\PDB\1 1180-97.DV3 27/3/00 treating a disease characterized by bone loss.
15. 18. A use according to Claim 17 wherein said disease is osteoporosis.
16. 19. A use according to Claim 17 wherein said disease is periodontitis. A use according to Claim 17 wherein said disease is gingivitis.
17. 21. 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.
18. 22. A use according to Claim 21 wherein said disease is osteoarthritis.
19. 23. A use according to Claim 21 wherein said disease is rheumatoid arthritis. g S. S S S. S S S S* S S* *r S. V. S. S S *SVS S