Title of Invention

PEPTIDIC COMPOUNDS

Abstract The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.
Full Text WO 2006/074501 PCT/AU2005/001444
1.
Peptidic Compounds
FIELD OF THE INVENTION
This invention relates to novel peptidic compounds, methods for preparing them and their use as antibiotics and in
the treatment of HTV infections.
5 BACKGROUND OF THE INVENTION
Bacteria and the bacterial infections that can be treated by antibiotics include, but are not limited to the following:
Staphylococcus aureus, (or "staph"), are bacteria commonly found on the skin and in the noses of healthy people,
(F)and are one of the most common causes of skin infections and can also cause serious and sometimes fatal
infections (such as bloodstream infections including toxic shock syndrome, impetigo, surgical wound infections.
10 infections of plastic implants, osteomyelitis and pneumonia).
Enterococci, which have been known as a cause of infective endocarditis for close to a century, more recently have
been recognized as a cause of nosocomial infection and "superinfection" inpatients receiving antimicrobial agents.
Other Gram positive bacteria that can be treated by antibiotics include staphylococcus epidermitis which causes
endocarditis, Clostridium difficile which causes diarrhea and pseudomembranous colitis, bacillus anthracis of
15 anthrax and streptococcus pneumoniae which causes pneumonia, meningitis, septicemia, and childhood otitis media
(or ear-ache). The family of streptococcus bacteria can also be divided into group A or Pyrogenes, which are
involved in blood poisoning, glomerularnephritis and fevers such as puerperal, scarlet and rheumatic fever. Group B
or streptococcus agalactiae cause neonatal meningitis and pneumonia.
Bacterial Resistance to Antibiotics
20 Bacterial Infections can occur while in hospital (noscomial), but an additional problem is the increase of infections
that are aquired while the person is in the community. A recent study (C ) identified the antimicrobial susceptibility
profile and resistance mechanisms of pretreatment MRSA isolates obtained from adult subjects participating in
recent clinical treatment trials of community respiratory infections. Out of 465 S. aureus isolates, 43 were identified
as MRSA. Antimicrobial susceptibility testing indicated susceptibility rates to: vancomycin (100%), gentamicin
25 (86%), clindamycin (39%), quinolones (49%), and erythromycin (12%)). All ciprofloxacin-resistant isolates had an
amino acid change in GyrA and GrIA. The results indicate that MRSA from adult subjects with community
respiratory infections have similar antimicrobial susceptibility profiles and resistance mechanisms as nosocomial
MRSA.
The pathogenic potential of Staphylococcus aureus in nosocomial and community -acquired infections is well known.
30 When penicillin was introduced in mid-1940s, S. aureus was almost 94% susceptible to this drug. Widespread
resistance to penicillin developed in the 1950s, followed by resistance to semi-synthetic penicillins in the 1960s and
1970s. Since then, strains of methicillin-resistant S. aureus and methicillin-resistant coagulase-neg. staphylococci
have spread worldwide. The prevalence of methicillin-resistant S. aureus varies geographically. In Argentina it
reaches nearly 50%. Methicillin resistance in staphylococci develops due to the additional, penicillin binding
35 protein PBP2a encoded by gene mecA and is a serious problem both for microbiologists and physicians( A). The

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2.
high prevalence of methicillin-resistant staphylococci compromises the use of semi-synthetic penicillins for clin.
treatments in many institutions, thus increasing the use of vancomycin (a glycopeptide). Until 1996, glycopeptides
were almost universally active against S. aureus but it was then that the first glycopeptide-intermediate S. aureus
(GISA) also known as VISA (vancomycin intermediately resistant S. aureus) was described and isolated in Japan,
5 followed by France and USA. Infections with Staphylococcus aureus with reduced susceptibility to vancomycin
continue to be reported, including 2 cases caused by S. aureus isolates with full resistance to vancomycin. (A) There
is also vancomycin-resistant S. aureus (VRSA) The worldwide increase in the incidence of S. aureus clinical isolates
with reduced susceptibility to vancomycin and teicoplanin means that glycopeptide resistance in S. aureus is
becoming an important clinical problem
10 The exact mechanisms involved have not been elucidated yet, although VISA is associated with increased wall
synthesis. Many VISA strains are characterized by increased cell wall biosynthesis and decreased crosslinking of
the peptide side chains, leading to accumulation of free D-alanyl-D-alanine termini in the peptidoglycan, which it
has been proposed can act as false target sites for vancomycin. (B)
The mechanism of vancomycin resistance in enterococcus is well defined and appears to be different to that of VISA.
15 Vancomycin resistance in enterococci, known as VRE or glycopeptide-resistant enterococci (GRE). exists as either
intrinsic resistance where isolates of Enterococcus gallinarum andE. casselifiavus/E. flavesccns demonstrate an
inherent, low-level resistance to vancomycin or by acquired resistance where Enterococci become resistant to
vancomycin by acquisition of genetic information from another organism. Most commonly, this resistance is seen in
E. faecium and E. faecalis, but also has been recognized in E. raffinosus, E. avium, E. durans, and several other
20 enterococcal species.
Several genes, including vanA, vanB, vanC, vanD, and vanE, contribute to resistance to vancomycin in enterococci.
E. faecium is the most frequently isolated species of VRE in hospitals and typically produces high vancomycin
(>128 g/ml) and teicoplanin (>16 (g/ml) minimum inhibitory concentrations (MICs). These isolates typically
contain vanA genes. The epidemiology of vancomycin-resistant Enterococcus faecium (VREF) in Europe is
25 characterized by a large community reservoir. In contrast, nosocomial outbreaks and infections (without a
community reservoir) characterize VREF in the United States. (G)
In vancomycin-susceptible enterococci, D-alanyl-D-alanine (formed by an endogenous D-alanine-D-alanine ligase)
is added to a tripeptide precursor to form a pentapeptide precursor. The D-AIa-D-Ala terminus is the target of
vancomycin; once vancomycin has bound, the use of this pentapeptide precursor for further cell-wall synthesis is
30 prevented. In the VanA phenotype, one of the proteins whose synthesis is induced by exposure of bacterial cells to
vancomycin is called VanA: VanA is a ligase and resembles the D-alanine-D-alanine ligase from Escherichia coli
and other organisms, including vancomycin-susceptible enterococci. VanA generates D-AIa-D-X, where X is
usually lactate; the formation of D-Iactate is due to the presence of VanH, a dehydrogenase encoded by vanll. The
depsipeptide moiety, D-Ala-D-Lac, is then added to a tripeptide precursor, resulting in a depsipentapeptide
35 precursor. Vancomycin does not bind to the D-Ala-D-Lac terminus, so this depsipentapeptide can be used in the
remaining steps of cell-wall synthesis. However, when the normal pentapeptide precursor ending in D-AIa-D-Ala is

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3.
also present, cells are not fully vancomycin resistant, despite the presence of D-Ala-D-Lac containing precursors.
This apparent problem is taken care of in large part by vanX, which encodes a dipeptidase, VanX, that cleaves D-
Ala-D-Ala, preventing its addition to the tripeptide precursor. Should any D-AIa-D-Ala escape cleavage and result
in a normal pentapeptide precursor, vanY encodes an ancillary or back-up function. That is, it codes for a
5 carboxypeptidase, VanY, which cleaves D-alanine andD-lactate from D-AIa-D-Ala and D-Ala-D-Lac termini,
res pectively, resulting in tetrapeptide precursors, to which vancomycin does not bind. The other genes involved in
the VanA resistance complex include vanR and vanS, whose encoded proteins are involved in sensing the presence
of extracellular vancomycin or its effect and signaling intracellularly to activate transcription of van! I, vanA, and
vanX. A final gene in the vanA cluster is vanZ, which encodes VanZ, the role of which is not known. (J)
10 VanR encoded by vanB in the variB gene cluster, is also a ligase that stimulates the formation of D-Ala-D-Lac. The
VanB phenotype is typically associated with moderate to high levels of vancomycin resistance but is without
resistance to teicoplanin. This is explained by the observation that vancomycin, but not teicoplanin, can induce the
synthesis of VanB and of VanHB and VanXB. However, because mutants resistant to teicoplanin can readily be
selected from VanB strains on tcicoplanin-containing agar, clinical resistance would likely occur among VanB
15 strains if teicoplanin were widely used. Most of the proteins encoded by the vanA gene cluster have homologues
encoded by the vanB gene cluster, except for VanZ. The vanB gene cluster has an additional gene, vanW, of
unknown function.
The acquired gene clusters associated with vanA and vanB are found in different genetic gurroundings. These
elements have in turn been found on both transferable and nontransferable plasmids, as well as on the chromosome
20 of the host strain. VanB type resistance was initially not found to be transferable, but at least in some instances, the
vanB gene cluster has been found on large (90 kb to 250 kb) chromosomally located transferable elements, More
recently, vanB has been found as part of plasmids. (I)
In addition to being found in different genetic surroundings, the vanA and vanB gene clusters have also been found
in a number of different bacterial species. vanA has been found in multiple enterococcal species as well as in
25 lactococci, Orskovia, and Arcanobacteria (H). The distribution of the vanB gene cluster seems somewhat more
restricted, having been found primarily inE. faecium andE. faecalis, although it has recently been found in
Streptococcus bovis (H).
The VanC phenotype (low-level resistance to vancomycin, susceptible to teicoplanin) is an inherent (naturally
occurring) property of E. gallinarum and E. casseliflavus. This property is not transferable and is related to the
30 presence of species-specific genes vanC-1 and vanC-2, respectively; a third possible species, E. flavescens and its
gene vanC-3, are so closely related to E. casseliflavus and vanC-2 that different names are probably not warranted.
These species appear to have two ligases: the cell-wall pentapeptide, at least in E. gallinarum, ends in a mix of D-
Ala-D-Ala and D-Ala-D-Ser. The genes vanC-1 andvanC-2 apparently lead to the formation ofD-Ala-D-Ser
containing cell-wall precursors, while D-AIa-D-Ala ligases, also present in these organisms, result in D-AIa-D-AIa.
35 The presence of both D-AIa-D-Ala and D-Ala-D-Ser precursors may explain why many isolates of these species test
susceptible to vancomycin and why even those isolates with decreased susceptibility display only low-level
resistance. (J)

WO 2006/074501 PCT/AU2005/001444
4.
VanD-type glycopeptide resistance has been recently described in an E. faecium isolate from the United States (I).
The organism was constitutively resistant to vancomycin (MIC > 64 g/ml) and to low levels (4 (g/ml) of
teicoplanin. Following polymerase chain reaction amplification with primers that amplify many D-AIa-D-Ala
ligases, a 605-bp fragment was identified whose deduced amino acid sequence showed 69% identity to VanA and
5 VanB and 43% identify to VanC.
Bacterial Resistance to Different classes of antibiotics.
As well as resistance to approved beta-lactam. glycopeptide antibiotics (including vancomycin, trade name
vancocin). and the macrolide-lincosamide-streptogramins (including quinupristin-dalfopristin. trade name
synercid)(D) various recent findings have also underlined the importance of biocide resistance as a clin. relevant
10 phenomenon. (D) Outbreaks of biocide-resistant organisms in hospitals have been described and the genetic
mechanism for resistance to quaternary ammonium compds. (QACs) in Staphylococcus aureus has now been
elucidated.
Some strains of MRS A which have intermediate resistance to glycopeptides were demonstrated to have decreased
susceptibility to some biocides including triclosan for which minimal bactericidal conens. (MBCs) increased from
15 0.002 to 3.12 mg 1-1. Biocide resistance amongst enterococci has also been demonstrated although there was no
clear correlation between biocide and antibiotic resistance. The exact mechanisms of resistance in these strains are
still being studied but it is clear that biocide resistance is an important clin. phenomenon.
Vancomycin is a cyclic compound. Disclosed herein by reference. WO 03/002545 teaches that 'peptoid
compounds' made from a peptide chain covalently linked in a cyclic form through a heterocyclic or aromatic ring
20 system have antibacterial activity. The reaction know to those skilled in the art variously as 'ring closing metathesis'.
'Gnibbs metathesis' or 'olefin metathesis' is taught in W 003/00254 to join the ends of the molecule which therefore
need to terminate in allyl groups (-CH2-CH=CH2 ) that react in that chemical processes described. The literature
(LBremner et al New J.Chem. 2002. 26, 1549-1551) teaches that cyclic compounds so made based on a
1,1 -binaphthyl scaffold linked in a ring through the 3,3 '-positions can have antibacterial activity. Further this
25 literature describes cyclic molecules made from 11'-binaphthyl linked through the 2.2' positions.
Additionally the prior art (J.Bremner et al Tetrahedron 2003, 59. 8741-8755) teaches that related cyclic compounds
(therein known as 'carbazole linked cyclic peptoids') can have antibacterial activity.
There is a need for new compounds which are useful in the treatment of bacterial infections, especially those caused
by vancomycin resistant organisms.
30 (A) Staphylococcus aureus with reduced susceptibility to vancomycin. Cosgrove, S. E.: Carroll. K. C :Perl. T. M.
Clinical Infectious Diseases (2004). 39(4), 539-545.
(B) Morphological and genetic differences in two isogenic Staphylococcus aureus strains with decreased
susceptibilities to vancomycin. Reipert. A: Ehlert. Kn: Kast. T: Bierbaum. G. . Antimicrobial Agents and
Chemotherapy (2003). 47(2), 568-576.

WO 2006/074501 PCT/AU2005/001444
5.
(C) Antimicrobial susceptibility and molecular characterization of community-acquired methicillin-resistant
Staphylococcus aureus. Aimer, L.S.: Shortridge, V.D.; Nilius, A.M.: Beyer, Jill M.; Soni, Niru B.; Bui. Mai H.;
Stone, G.G.;Flamm, R.K Diagnostic Microbiology'and Infectious Disease (2002), 43(3), 225-232.
(D) Methicillin-resistant, quinupristin-dalfopristin-resistant Staphylococcus aureus with reduced sensitivity to
5 glycopeptides. Werner, G.: Cuny. C ; Schmitz, F.-J.: Witte, W. Journal of Clinical Microbiology (2001),
39(10), 3586-3590.
(E ) Susceptibility of antibiotic-resistant cocci to biocides. Fraise, A. P. Society for Applied Microbiology
Symposium Series (2002), 31 (Antibiotic and Biocide Resistance in Bacteria).
(F) WWW.CDC.gov VISA/VRSA Vancomycin-Intermediate/Resistant Stapylococcus aureus
10 (G) Epidemic and nonepidemic multidrug-resistant Enterococcus faecium. Leavis HL, Willems RJL, Top J,
SpalburgE,Mascini EM,Fluit AC, et al. Emerg Infect Dis. 2003 Sept. Available from: URL:
http://www.cdc.gov/ncidod/EID/vol9no9/02-0383.htm
(H) Power EGM, Abdulla YH, Talsania HG, Spice W, Aalhithan S,French GL. vanA genes in vancomycin-resistant
clinical isolates of Oerskovia turbata and Arcanobacterium (Corynebacterium) haemolyticum. J Antimicrob
15 Chemother 1995:36:595-606.
(I) Perichon B, Reynolds P, Courvalin P. VanD-type glycopeptide-resistant Enterococcus faecium BM4339.
Antimicrob Agents Chemother 1997:41:2016-8.
(J) Diversity among Multidrug-Resistant Enterococci Barbara E. Murray, M.D. Emerg Infect Dis. 2003 Sept.
Available from: URL: http://www.cdc.gov/ncidod/EID/vol4nol/muiTay.htm
20 SUMMARY OF THE INVENTION

or pharmaceutically acceptable derivatives thereof, wherein:
25 Arl and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
fully reduced derivatives thereof:

WO 2006/074501 PCT/AU2005/001444
6.
Qi and Q2 are each independently selected from hydrogen, Ci.C12alkyl, C3.C6CYcloalkyL Q-C^alkyloxy,
nitro, halogen, hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group such
as carboxamide, sulphonamide or phosphoramide wherein each C1-C12alkyl, Ci-C^alkyloxy or
5 C3_ C6C gcycloalkyl is optionally substituted with hydroxyl, amino, carboxylic acid or a salt or ester thereof,
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide, sulphonamide or phosphoramide;
B is selected from-O-, -S-, -S(O)-, -S(O)2 -,NH-, and -JSKQ.Qalkyl)-:
Ri is selected from hydrogen, Ci.Ci2alkyl, Ci.C6alkylC3_c6cycIoalkyl. Ci.QalkylC 6-Cioaryl. C2.C6alkenyI,
10 C2.C6alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms, and when B
is -S-, -S(O)-, -S(O)2-, -NH- or -N(Ci.C 6alkyl)- then Ri may be hydroxyl;
V is a linker group selected from -0-,-0-L-C(O), -0-L-NR 6-, -C(O)-
,-NR5-,-S(O)-, -S(O)2-, -O-L-S(O)-, -S(O)2-L-C(O)-, -.S(O)2-L-NR6-,P(O)2O-;
wherein L is selected from Q.C^alkyl, C2C8alkenyl, C3.C6cycloalkyl, polyoxyalkylene having
15 from 2 to 6 carbon atoms, C6.Ci0aryl and Ci C6alkylC6..Cioaryl and wherein R6is selected from II,
Ci.C 12alkyl;
Ai and A2 are the same or different and are basic amino acid residues;
each of Si, S2 and S3 is either present or absent and is an independently selected amino acid residue;
T is present or absent and is selected from -C(O)R 8, -C(O)OR 8, -OR8, -NHR8,
20 NHOR 8, -NH-QaTyl-CO-R 8, -NH-QaTyl-CO-NHR 8, -NH-QaTyI-CONHOR 8, -NH-Qaryl-CONHOH, -
C(O)NHR8, -(NH)-SO2C6aryl, -(NH)COR8;
or T forms a carboxylate isostere, optionally substituted with R8, which replaces the carboxylic
acid group of the amino acid to which T is connected;
wherein R8 is selected from hydrogen, C1-C12alkyl, Ci_C6alkylC6.Cioaryl,
25 Ci.C6alkylC3-C6cycloalkyl, C2.C6alkenyl, and C2.C6alkynyl; and
wherein when T is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue mav be reduced to methvlene.

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7.
In a second aspect, ihere is provided a compound of formula II,

or pharmaceutically acceptable derivatives thereof, wherein:
Ati and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
5 fully reduced derivatives thereof;
Qi and Q2 are each independently selected from hydrogen, Q.C^alkyl, C3.C6cyclodkyl' Cr Ci2alkyloxy,
nitro, halogen, hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a snlt or ester thereof or n nitropen containing cronn such
as carboxamide, sulphonamide or phosphoramide wherein each Ci.Ci2alkyl, Ci-Ci2alkyloxy or
10 C3.C6Cycloalkyl is optionally substituted with hydroxyl, amino, carboxylic acid or a salt or ester thereof,
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide, sulphonamide or phosphoramide;
each of Vi and V2 is a linker group independently selected from -0-,-0-L-C(O), -0-L-NR 6-, -C'(O)-
,-NR6-,-S(O)-, -S(O)2-, -O-L-S(O)-, -S(O)2-L-C(O)-. -S(O)2-L-NR6-,P(O)2O-;
15 wherein L is selected from Q.C 12alkyl, C2.Csalkenyl, C3.C6cycloalkyl, polyoxyalkylene having from 2 to 6
carbon atoms, C6.Cioaryl and Ci.C6alkylC6.Ci0aryl and wherein R6is selected from II, Ci_Ci,alkyk
Ai and A^2 arc the same or different and are basic amino acid residues;
each of Si. S2, S3 and S, is either present or absent and is an independently selected amino acid residue:
Ti is either present or absent and is independently selected
20 from -C(O)R8, -C(O)OR8, -OR8, -NHR8. -NH()R8, -NH-C6ary 1-COR8, -NH-C6ary 1-CONHR8, -NH-C6aryl-
CONHOR8. -NH-C6aryl-CONHOH, -C(O)NHR8, -(NH)-SO2C6aryl, -(NH)COR 8;
or Ti forms a carboxylate isostere, optionally substituted with R8, which replaces the carboxylic
acid group of the amino acid to which TI is connected;
wherein R8 is selected from hydrogen, Ci_ Ci2alkyl, Ci.C6alkylC6_ Ci0aryl,
25 Ci.C6alkylC3.C6cycloalkyl, C2C6alkenyk and C2.C6alkynyk and

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8.
wherein when Tl is connected to the C-terminus of nn amino acid residue then the carbony] group
of the amino acid residue may be reduced to methylene;
T2 is either present or absent and is independent selected from -C(O)OR9, -OR9, -NHR9,
NHOR9, -NH-C6ary1-CO-R9, -NH-C6aryl-CO-NHR 9, -NH-C6aryl-CONHOR 9, -NH-C6aryl-CONHOH, -
5 C(O)NHR 8, -(NH)-SO2C6aryl, -(NH)COR 8;
or T2 forms a carboxylate isostere, optionally substituted with R9, which replaces the carboxylic
acid group of the amino acid to which T2 is connected;
wherein R9 is selected from hydrogen. Ci_C12alkyl, Ci.C6alkylC6.Ci0aryl,
Ci_C6alkylC 3.C6cycloalkyl, C2.C6alkenyI, and C2.C6alkynyl; and
10 wherein when T2 is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
In a third aspect, there is provided a compound of formula III,

or pharmaceutically acceptable derivatives thereof, wherein:
15 Aii and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
fully reduced derivatives thereof;
Q1 and Q2 are each independently selected from hydrogen, Ci_Ci2alkyl, C3C6cycloalkyl, Ci-Ci2alkyloxy,
nitro, halogen, hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group such
20 as carboxamide, sulphonamide or phosphoramide wherein each Ci.C'i2 ,alkyl, Ci-Ci2alkyloxy or
C3C6cycloaIkyl is optionally substituted with hydroxyl, amino, carboxylic acid or a salt or ester thereof,
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide, sulphonamide or phosphoramide;
B is selected from-0-, -S-, -S(O)-. -S(O)2-. -NH-. and -N(C 1AaIkVl)-;

WO 2006/074501 PCT/AU2005/001444
9.
Ri is selected from hydrogen, Ci.Ci2alkyl, Q.C 6alkylCa.Qcycloalkyl, Q.QalkylC 6.Cioaryl, C2C6alkenyl.
C2.C6alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms, and when B
is -S-, -S(O)-, -S(O)2-, -NH- or -N(Ci.C 6alkyl)- then R1 may be hydroxyl;
Vi is a linker group selected from selected from -0-, -O-L-C(O), -0-L-NR 5-, -C(O)-
5 -NR6-. -S(O)-, -S(0)2 -O-L-S(O)-,-S(O) 2-L-C(O)-, -S(O)2-L-NR6-, -P(O)2O-:
wherein L is selected from Ci_Ci2alkyl, C2.C'8alkenyl, C3C'6cycloalkyl, polyoxyalkylene having
from 2 to 6 carbon atoms, C6-Ci0 aryl and Ci.C6alkylC6.Ci0 aryl and wherein R6 is selected from H,
C1.C12 alkyl ; A 1 is a basic amino acid residue;
10 each of S1 and S2 is either present or absent and is an independently selected amino acid residue:
T is present or absent and is selected
from -C(O)R8, -C(O)OR8, -OR8, -NHR8, -NHOR8, -NH-C6aryl-COR8, -NH-C6aryl-CONHR8, -NH-C6aryl-
CONHOR8, -NH-C6aryl-CONHOH, -C(O)NIIR8, -(NII)-SO2C6aryl, -(NH)COR8;
or T forms a carboxylatc isostcrc, optionally substituted with R8, which replaces the carboxylic
15 acid group of the amino acid to which T is connected:
wherein R8is selected from hydrogen, C1.C12alky, QC 6alkylCg.Qoarvl,
Ci.C6alkylC3-C6cycloalkyl, C2.C6alkenyl, and C2.C6alknyl; and
wherein when T is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
20 In a fourth aspect, there is provided a compound of formula IV,

IV
or pharmaceutically acceptable derivatives thereof, wherein
R12 is an alkylaromatic or alkylpolyaromatic group optionally substituted with -OCi.6alkyl or-OC2.6alkenyl:
25 each B is an independently basic amino acid residue:
n = 1 or 2:

WO 2006/074501 PCT/AU2005/001444
10.
S1 is present or absent and is an independently selected amino acid residue;
Ti is selected
from -NHR13, -NHOR13. -NH-C6aryl-COR13. -NH-C6aryl-CONHR13. -NH-C6aryl-CONHOR13.

5 orTl forms a carboxylate isostere, optionally substituted withRI3. which replaces the oarboxylic acid
group of the amino acid to which T1 is connected:
wherein R13 is selected from hydrogen. Q.Qaalkyl. Q-QalkylC 6Aoaryl. C1-C6alkylC3-C6cycloalkyl,
C2.C6alkenyl, and C2.Cfalkynyl; and
wherein when T1 is connected to the C-terminus of an amino acid residue then the carbonyl group of the
10 amino acid residue may be reduced to methylene;
T2 is selected from -C(O)R14. -C(O)OR14. -OR14. -C(O)NHR14.
wherein R14 is selected from hydrogen. C1-C12alkyl, C1-C6alkylC6-C10aryl, C-C6alkylC3-C6cycloalkyl,
C2Qalkenyl. C2Qalkynyl. and CH2-fluorene;
wherein the optional substituent OfR12 and the side-chain of S1 may together fonn a -OC^alkvlene linking
15 group.
In a fifth aspect, there is a provided a compound of Example 2.
In a sixth aspect, there is provided a composition comprising a compound according to any one of the first to fifth
aspects, a salt or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically
acceptable carriers or adjuvants.
20 In a seventh aspect, there is provided a method of treating a bacterial infection in a mammal comprising
administering an effective amount of compound according to any one of the first to fifth aspects, a salt or a
pharmaceutically acceptable derivative thereof.
In an eighth aspect, there is provided a method for treatment or prophylaxis of HTV in a subject comprising
administering to said subject an effective amount of a compound according to any one of the first to fifth aspects, a
25 salt or a phannaceutically acceptable derivative thereof.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. shows a diagramatic representation of the antibacterial screening assay design using a 96-well microtitrc
plate.

WO 2006/074501 PCT/AU2005/001444
11.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the present invention provides a compound of formula I,

5 or pharmaceutically acceptable derivatives thereof, wherein:
Ar1 and Ar12 are each independently selected from an aromatic or heterocyclic ring system or
partially or fully reduced derivatives thereof;
Qi and Q2 are each independently selected from hydrogen, Q.C^alkyl, C'3.C6cycloalkyl, Ci-C 12alkyloxy,
nitro, halogen, hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt or ester thereof, sulphoni
10 acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group sucl
as carboxamide, sulphonamide or phosphoramide wherein each Ci.C'i2alkyl, C'r Ci2alkyloxy or
C3.C6cycloalkyl is optionally substituted with hydroxyl, amino, carboxylic acid or a salt or ester thereof,
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide, sulphonamide or phosphoramide;
15 B is selected from -O-, -S-, -S(O)-, -S(O)2 -, -NH-, and -NtQ.Qalkyl)-;
Ri is selected from hydrogen, Ci_Ci2alkyl, Ci_C6alkylC3_c6cycloalkyl, Ci C6alkylC'6.Cioaryl, C2.C6alkenyl,
C2.C6alkynyI, a polyoxyalkylene having from 2 to 6 carbon atoms, and when R
is -S-, -S(O)-, -S(O)2-, -NH- or -N(Ci.C 6alkyl)- then Ri may be hydroxyl;
V is a linker group selected from -O-,-
20 O-L-C(O), -0-L-NR 6-, -C(O)-, -NR6-, -S(O)-, -S(O)2-, -O-L-S(O)-, -S(O)2-L-C(O)-, -S(O),-L-NR6-,
P(O)2O-;
wherein L is selected from Ci.C^alkyl, C2-C8 alkenyl. C3C6cycloalkyl, polyoxyalk^lene having
from 2 to 6 carbon atoms, C6.Ci0aryl and Ci_C6alkylC6Ci0aryl and wherein R6is selected from H
Ci.C12alkyl;
25 Ai and A2 are the same or different and are basic amino acid residues;
each of Si. S2 and S3 is either present or absent and is an independently selected amino acid residue;

WO 2006/074501 PCT/AU2005/001444
12.
T is present or absent and is selected from -C(O)OR8, -OR8, -NHR8,
NHOR8 -NH-QaTyl-CO-R 8, -NH-C6aryl-CO-NHR8, -NH-Cearyl-CONHORs, -NH-C6aryl-CONHOH, -
C(O)NHR8 -(NH)-SO2C6aryl, -(NH)COR8:
or T forms a carboxylate isostere, optionally substituted with R8, which replaces the carboxylic
5 acid group of the amino acid to which T is connected;
wherein R8 is selected from hydrogen, Ci.C^alkyl, Ci_ C6alkylC'6.C10aryl,
Ci.C6aIlkylC3Cgcycloalkyl, C2.C'6alkenyl, and C2.C6alkynyl: and
wherein when T is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
10 Preferably, Ai and A2 are each independently selected from the group consisting of lysine, arginine and omithine.
More preferably A1 is selected from lysine and ornithine and A2 is selected from arginine.
Preferably, Si and S2 are absent.

15 wherein Q1, Q2 V, Si, Ai, Si, A2. S3, T, B and R1 are as defined above.
In a preferred embodiment, the compound of formula I is of formula la:

WO 2006/074501 PCT/AU2005/001444
13.

wherein Q1. Q2. V. S1. A1. S1, A2. S3. T. B and R1 are as defined above.
In a second aspect, there is provided a compound of formula n.
In a further preferred embodiment, the compound of formula I is of formula Ib:

or pharmaceutically acceptable derivatives thereof, wherein:
Ar1 and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
fully reduced derivatives thereof:
Q1 and Q2 are each independently selected from hydrogen. Q.C^alkyl. C3.C6cycloalkyl. Cr C12alkyloxy.
10 nitro, halogen, hydroxyl. amino. mono or dialkylamino. carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group such
as carboxamide, sulphonamide or phosphoramide wherein each Q.C 12alkyl, CrC 12alkyloxy or
C3.C6cycloalkyl is optionally substituted with hydroxyl. amino, carboxylic acid or a salt or ester thereof.
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
15 group such as carboxamide, sulphonamide or phosphoramide:
each OfV1 and V2 is a linker group independently selected from -O-.-O-L-C(O). -0-L-NR 6-. -C(O)-
. -NR6-. -S(O)-. -S(O)2-. -O-L-S(O)-. -S(O)2-L-C(O)-. -S(O)2-L-NR6, -P(O)2O-:

WO 2006/074501 PCT/AU2005/001444
14.
wherein L is selected from CLCi2 alkyl, C2-C8 alkenvl, C3C6cycloalkvl, polyoxyalkylene having from 2 to
6 carbon atoms, C6.Cioaryl and Ci.Ci6aIkylC6.Ci0aryl and wherein R6is selected from H, Ci.C'i2alkyl;
Ai and A2 are the same or different and are basic amino acid residues:
each of Si, S2, S3 and S4 is either present or absent and is an independently selected amino acid residue;
5 Ti is either present or absent and is independently selected
from -C(O)OR8, -OR8, -NHR8, -NHOR8, -NH-C6aryl-COR8, -NH-C6aryl-CONHR 8, -NH-C6aryl-CONHOR
8, -NH-Qaryl-CONHOH, -C(O)NHR8 , -(NH)-SO2C6aryl, -(NH)COR 8:
or T1 forms a carboxylate isostere, optionally substituted with R8, which replaces the carboxylic
acid group of the amino acid to which T1 is connected;
10 wherein R8 is selected from hydrogen, C1-C12alkyl, C1-C6ealkylC6.C10aryl,
Ci.C6alkylC3.C6cyloalkyl, C2.C'6alkenyl, and C2.C6alkynyl; and
wherein when Tl is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene;
T2 is either present or absent and is independently selected from -C(O)OR9, -OR9, -NHR9,
15 NHOR9, -NH-C6aryI-CO-R 9, -NH-C6aryl-CO-NHR 9, -NH-C6aryl-CONHOR 9, -NH-Qaryl-CONHOH, -
C(O)NHR -(NH)-SO C aryl-(NH)COR •
or T-2 forms a carboxylate isostere, optionally substituted with R9, which replaces the carboxylic
acid group of the amino acid to which T2 is connected;
wherein R9 is selected from hydrogen, Ci_Ci2alkyl, Ci_ C6alkylC6.Cioaryl,
20 Ci.C6alkylC3.C6cycloalkYl, C2.C6alkenyl, and C2_C6alkynyh and
wherein when T2 is connected to the C-lcrminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
Preferably, Ai and A2 are each independently selected from the group consisting of lysine, arginine and omithine.
Preferably, A1 and A2 are the same.
25 Preferably, Si, S2 S3 and S4 are absent.

WO 2006/074501 PCT/AU2005/001444
15.
In a third aspect, there is provided a compound of formula IE,

or pharmaceutically acceptable derivatives thereof, wherein:
Ari and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
5 fully reduced derivatives thereof;
Q1 and Q2 are each independently selected from hydrogen, Q.C^alkvl, C3.C6cycloalkyl, Ci-Ci2alkyloxy,
nitro, halogen, hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group such
as carboxamide, sulphonamide or phosphoramide wherein each Q.C12alkyl, CrC 12alkyloxy or
10 C3.C6cycloalkyl is optionally substituted with hydroxyl, amino, carboxylic acid or a salt or ester thereof,
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide, sulphonamide or phosphoramide;
B is selected from-O-, -S-, -S(O)-, -S(O)2 -NH-, and -N(C 1AaUCyD-;
R1 is selected from hydrogen, Q.C^alkyl, Ci.C'6alkylC3_ C6cycloalkyl, Ci.C6alkylC6-Cioaryl. C2.C6alkenyl,
15 C2.C6alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms, and when B
is -S-, -S(O)-, -S(O)2-,-NH- or -N(Ci.C 6alkyl)- then Ri may be hydroxyl;
Vi is a linker group selected from selected from -O-, -O-L-C(O), -0-L-NR 5-, -C(O)-
-NR6-, -S(O)-, -S(O)2,- -O-L-S(O)-;,-S(O) 2-L-C(O)-, -S(O)2-L-NR6-,P(O)2O-
wherein L is selected from Ci_Ci2alkyl, C2.C8ulkenyl, C3.C6cyeIoalkyl, polyoxyalkylene having
20 from 2 to 6 carbon atoms, C6-Ci0 aryl and C1.C6aIkyIC6-C10aryl and wherein R6 is selected from H,
Ci.C12alkyl;
A i is a is a basic amino acid residue;
each of Si and S2 is either present or absent and is an independently selected amino acid residue;
T is present or absent and is selected from -
25 C(O)OR8, -ORS. -NHR8. -NHOR8, -NH-C6aryl-COR 8, -NH-C6aryl-CONHR 8. -NH-C6ani-COWIOR 8. -NH
-C6anl-CONIIOH, -C(O)NHR 8, -(NH)-SO2C6aryl. -(NH)COR8;

WO 2006/074501 PCT7AU2005/001444
16.
or T forms a carboxylatc isostcrc, optionally substituted with R8, which replaces the carboxvlic
acid group of the amino acid to which T is connected;
wherein R8 is selected from hydrogen, CiCi2alkyl, Ci_C6alkylC Ci0aryl,
Ci.C6alkylC3.C6cycloalkyl, C2.C6alkenyl, and C2_C6alkynyk: and
5 wherein when T is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
Preferably. Ai is selected from lysine, arginine and omithine.
Tn a fourth aspect, there is provided a compound of formula IV,

10 IV
or pharmaceutically derivatives thereof, wherein
Ri2 is an alkylaromatic or alkylpolyaromatic group optionally substituted with -OCi_6alkyl or -OC2-6alkenyl:
each B is an independently selected basic amino acid residue;
n = 1 or 2:
15 Si is present or absent and is an independently selected amino acid residue:
Ti is selected
from -NHRi3, -NHORi3, -NH-C 6aryl-CORi 3, -NH-C 6aryl-CONHRi 3, -NH-C 6aryl-CONHORi 3,
-NH-Cgaryl-CONHOH. -(NH)-SO2C6aryl, -(NH)CORi 3or NH2 ;
or Ti forms a carboxylate isostere, optionally substituted with Ri, which replaces the carboxvlic acid group
20 of the amino acid to which T1 is connected:
wherein Ri3 is selected from hydrogen, Ci.C'^alkyl. Ci_C6alkylC6- Ci0aryl, Ci.C6alkTlC3.C6cycloallal,
C2.C6alkenyk and C2.C6alkynyk and

WO 2006/074501 PCT/AU2005/001444
17.
wherein when Ti is connected to the C-terminus of an amino acid residue then the carbonvl group of the
amino acid residue may be reduced to methylene;
T2 is selected from -C(O)Ri 4, -C(O)ORi 4, -ORi4, -C(0)NHR 14.
wherein R14 is selected from hydrogen, C1.C12alkyl, Ci.C6alkylC6.Cioaryl, Ci_C:alkylC3c6cycloalkyl,
5 C2.C6alkenyl, C2.C6alkynyl, and CH2-fluorene:
wherein the optional substituent OfRi2 and the side-chain of Si may together form a -OCi_6alkylene linking
group.
Preferably, R12 is selected from-CH 2-phenyl-OCH2 CH=CH2 and -CH^phenylanthracene. Preferably, Si is selected
from allylglycine. Preferably, T2 is -C(O)CH3 Preferably, TiisCH3O-. Preferably, R is arginine or lysine.
10 In a fifth aspect, there is provided a compound of Example 2.
Preferably the compound of Example 2 is selected from 69,70, 71, 72, 73, 74, 75, 76, 83, 32, 37, 65, 56, 118, 119,
120, 121, 132, 90, 134, 135, 136, 137, 139,140, 141, 159, 160, 163,164, 78, 81,88,87, 89, 165, 166, 167, and 168.
It would be understood by the person skilled in the art the peptide chain formed by Ihe combination of the amino
acid residues of the compounds of the present invention could be a peptide or a reverse peplide depending on the
15 nature of the linker group V: lor example, where the group V is of the form -O-L-C(O)- then the peplide will be a
peptide chain with its N-terminus bound to V whereas if the group V is of the form -0-L-NH- then the peptide will
be a reverse peptide chain with its C-terminus bound to V.
As is well known to those skilled in the art, the term carboxylate isostere includes any moiety capable of replacing
the carboxylate group of an amino acid. Suitable carboxylate isosteres include letrazole (ref: e.g JOC 1992.57,
20 202-209; .JAC'S 1998, 110,5875-5880 orTetLett, 1993,34, 1757-1760.), isoxazole, oxazole and thiazole.
As used herein, the term "halo" or "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine
(iodo).
As used herein, the term "alkyl" either used alone, having 1 to 12, preferably 1 to 8, more preferably 1 to 6, carbon
atoms, or in compound terms such as NH(alkyl) or N(alkyl)2 , refers to monovalent straight chain or branched
25 hydrocarbon groups having 1 to 12 carbon atoms, including their stereoisomeric forms if applicable. For example,
suitable alkvl groups include, but are not limited to methvl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,
pentyl, 2-melhylbutyl, 3-mefhylbutyl, n-hexyl, 2-, 3- or 4-mefhylpentyl, 2-ethylbutyl, n-hexyl, and 2-, 3-, 4-or
5-methylpentyl.
As used herein, the term "alkenyl" refers to straight chain or branched hydrocarbon groups having one or more
30 double bonds between carbon atoms. Suitable alkenyl groups include, but are not limited to efhenyl, propenyl,
isopropenyl. butenyl, pentenyl and hexenyl.

WO 2006/074501 PCT/AU2005/001444
18.
The term "nlkynyl" as used herein, refers to straight chain or branched hydrocarbon groups containing one or more
triple bonds. Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and
hexenyl.
The term "cycloalkyl" as used herein, refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but
5 are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "aryl" as used herein, refers to a C6)-Ci0 aromatic hydrocarbon group, for example phenyl or naphthyl.
The term "heterocyclc" when used alone or in compound words includes monocyclic, polycyclic, fused or
conjugated hydrocarbon residues, preferably C3.6,wherein one or more carbon atoms (and where appropriate,
hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic or aromatic residue.
10 Suitable heteroatoms include, O, N and S. Where two or more carbon atoms are replaced, this may be by two or
more of the same heteroatom or by different heteroatoms. Suitable examples of heterocyclic groups may include
pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, morpholino, indolinyl, indazolyl, quinolinyl, isoquinolinyl,
imidazolidinyl, pyrazolidinyl, thiomorpholino, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl
etc.
15 Each alkyl, alkenyl, alkynyl, cycloalkyl. aryl or heterocyclyl group may be optionally substituted with Cj-C6alkyl,
OH, OCr C6alkyl, halo, CN, NO2, CO2H, COzQ.Qalkyl, CONH2, CONII(Ci.C6alkyl), CON(Ci_C6alkyl)2,
trifluoromethyl, C6aryl, C3-C6VcycloalkyL hetrocyclyL NH2. NH(Ci_C6alkyl) or N(C1-C6alkyl)2 For example, an
optionally substituted aiyl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted
alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl. Futher, methyl substituents (Qalkyl) may
20 be substituted with an optionally sustitued aryl to form a benzyl substituent.
As used herein, the term "amino acid residue" refers to an amino acid which is bound by means of amide bonds or
suitable replacements thereof to one or more of the linker group V, other amino acid residues and the terminal group
T. The amino acid may be an -amino acid or a amino acid. A suitable replacement for the amide bond can be
any replacement that is known in the art as it is well known that where two amino acids or a combination of natural
25 and unnatural amino acids are joined together to form an amide bond between them the bond can be replaced by a
suitable link, which may be called a peptoid (discussion of this may be found inPM Fischer 'The design, synthesis
and application of stereochemical and directional peptide isosteres a critical review' Cun: Protein and Peptide
Science, 2003, 4(5), 339-356 and references therein). Examples of suitable replacements include, but are not limited
to:
30 reduced amide: ammo methylene: CH2NH: (Szelke. M, Leckie, B.: Hallet A.. Jones, D.M., Sueiras, J.;
Atrash.B.: Lever, A., Nature, 19821982, 299, 555-557.; Ambo A, Adachi T. Sasaki Y. Synthesis and opioid
activities of [D-Leu-8]Dynorphin(l-8) analogs containing a reduced peptide bond. psi(CH2-NH). Chem
Pharm Bull (Tokyo). 1995,43(9), 1547-50)

WO 2006/074501 PCT/AU2005/001444
19.
ether bond : CH2O: (Hedenstrom M, Yuan Z. Brickmann K, Carlsson .T, Ekholm K, Johansson B, Kreutz H.
Nilsson A, Sethson I, Kihlberg j. Conformations and receptor activity of desmopressin analogues, which
contain gamma-turn mimetics or a psi[CH(2)O] isostere. J Med Chem. 2002, 45(12), 2501-1 1)
hydroxy ethylene CHOHCH2- and ketomethylene COCH2: (Harbeson SL. Rich DH. Inhibition of
5 aminopeptidases by peptides containing ketomethylene and hydroxyethylene amide bond replacements. J
Med Chem. 1989, 32(6), 1378-92)
urea NHCONH: (Dales NA, Bohacek RS, Satyshur KA, Rich DH. Design and synthesis of unsymmetrical
peptidyl urea inhibitors of aspartic peptidases OrgLett. 2001, 3(15), 23 13-6)
The amino acid may be a L- or D- isomer and may have a naturally occurring side chain or a non-naturally
10 occurring side chain. The amino acid may also be further substituted in the -position or the -position with a
group selected
from-C r CI2alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -(CH2)nCORa, -(CH2)nRb, -PO,H, -(CH2)nheterocyclyl
or -(CH2)naryl where Ra is -OH. -NH2, -NHC'r C6alkyl, -OCr C'I2alkyl or -Cr Ci2alkyl and Rb
is -OH, -SIT, -SCr C6alkyl, -OCr Ci2alkyl, -C3-C6cycloalkyl, -C3-C6cycloalkenyl, -NH2, -NHCr C6)alkyl
15 or -NHC(C=NH)NH2, n is 0 or an integer from 1 lo 6 and where each alkyl, alkenyl, alkynyl, cycloalkyl.
cycloalkenyl, aryl or heterocvclvi group may be substituted with one or more groups selected
from -OH, -NH2, -NHCr C6)alkyl, -OCr CI3alkyl, -SH, -SCr C6alkyl, -CO2H, -CO2Cr C6alkyl, -CONH2
or -CONITCrQalkyl.
The term "-amino acid" as used herein, refers to a compound having an amino group and a carboxyl group in
20 which the amino group and the carboxyl group are separated by a single carbon atom, the oc-carbon atom. An
-amino acid includes naturally occurring and non-naturally occurring L-amino acids and their D-isomers and
derivatives thereof such as salts or derivatives where functional groups are protected by suitable protecting groups.
The -amino acid may also be further substituted in the -position with a group selected
from -C1. Ci2alkyl, -C2-Cl0alkenyl, -C2-C12alkynyl, -(CH2)nCORb -(CH2)nR2,-PO3H,-(CH2)nheterocyclyl
25 or -(CH2)naryl where Ri is -OH. -NH2, -NI-ICr Ci2alkyl, -OCr Ci2alkyl or Cr Ci2alkyl and R2
is -OH. -SH, -SCr C6alkyl. -OCr C12alkyl, -C3-C6cycloalkyl, -C3C6cycloalkenyl, -NH2, -NITC1 C3alkyl
or -NHC(C=NH)NH2,n is Oor an integer from 1 to 10 and where each alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected
from -OH, -NH2,-NHCr C6alkyl, -OC1 C12alkyl, -SH, -SCr C6alkyl, -CO2H, -CO2Cr C6alkyl, -CONH2
30 . or-CONHCi-C6alkyl.
As used herein, the term "-amino acid" refers to an amino acid that differs from an -amino acid in that there are
two (2) carbon atoms separating the carboxyl terminus and the amino terminus. As such, -amino acids with a
specific side chain can exist as the R or .S' enantiomers at either of the a (C2) carbon or the  (C3) carbon, resulting
in a total of 4 possible isomers for any given side chain. The side chains may be the same as those of naturally
35 occurring -amino acids or may be the side chains of non-naturally occurring amino acids.

WO 2006/074501 PCT/AU2005/001444
20.

Furthermore, the -amino acids may have mono-, di-, tri- or tetra-substitution at the C2 and C3 carbon atoms.
5 Mono-substitution may be at the C2 or C3 carbon atom. Di-substitution includes two substituents at the C2 carbon
atom, two substituents at the C3 carbon atom or one substitucnt at each of the C2 and C3 carbon atoms.
Tri-substitution includes two substituents at the C2 carbon atom and one substituent at the C3 carbon atom or two
substituents at the C3 carbon atom and one substituent at the C2 carbon atom. Tetra-substitution provides for two
substituents at the C2 carbon atom and two substituents at the C3 carbon atom. Suitable substituents
10 include -Cr Ci2alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -(CH2)nCORa, -(CH2)nRb, -PO3II, -(CI I2) 0heterocyclyl
or -(CH2)naryl where Ra is -OH, -NH2, -NHCr C6alkyl, -OCr Ci2alkyl or -Cr Ci2alkyl and Rb
is -OH. -SH, -SCr C6alkyl, -OCr Ci2alkyl, -C3-C6cycloalkyl, -C3-C6cycloalkenyl, -NH2, -NHCr C6alkyl
or -NHC(C=NH)NH2, n is Oor an integer from 1 to 6 and where each alkyl, alkenyl, alkynyl cycloalkyl,
cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected
15 from -OH. -NH2. -NHCr C6alkyl, -OCr C12alkyL -SH. -SCr C6alkyl, -CO2H. -CO2Cr C6alkyl, -CONH2
or -CONHCi-Cealkyl.
The term "non-naturally occurring amino acid" as used herein, refers to amino acids having a side chain that does
not occur in the naturally occurring L-oc-amino acids. Examples of non-natural amino acids and derivatives include,
but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3-hydroxy-5-phenylpentanoic acid,
20 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine,
4-amino-3-hydro\y-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids.
The term "basic amino acid" includes any amino acid having a side chain that can act as a base and generally
includes amino acids having a side chain bearing one or more nitrogen atoms. Included within the definition are the
naturally occurring basic L-amino acids lysine. arginine. and histidine and their D-isomers. Further included are the
25 L- and D- forms of ornithine: 2-.3- and 4- amidinophenylglycine: 2,3. and 4 amidinophenylalanine: 2-. 3- and
4-guanidinophenyiglycine: pyridylalanine: cysteic- and homocysteic acid-S-(aminoiminomethyl) amides: and
amidinopiperidinylalanine. Preferably, the side-chain comprises an amino group (NH2) or an amino group
substituted on the nitrogen atom with up to two substituents. Examples of optional substituents include Cr Ci2alkyl.

WO 2006/074501 PCT/AU2005/001444
21.
C3-C'7cycloalkyL C'6-C10aryL benzyl and suitable nitrogen protecting groups (see "Protective Groups in Organic
Synthesis" Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999). Preferably, the amino group
is capable of carrying a positive charge at physiological pH. In a preferred form of the invention, the side chain
comprises a substituent selected from a group consisting
5 of: -N(R |0)2, -N(R 1Q)-COR11, -NR|0CX=NR10)N(R 10)2, -C(=NR |0)N(R |0)2, -NR 10C(=O)N(R 10)2, -N=NC(=NR 10)N(R 10
.)2,NRI0NR10C(=O)NHN(R 10)2, -NR10C'C=NHN(R i0)2 wherein each R10 is independently selected from hydrogen
and CrCealkyl and Rl 1 is selected from hydrogen, hydroxy, Cr C12alkyl, Q-Cgalkoxy and NR10; and
3-8-membered N-containing heterocyclic group such as piperidinyl, pyrollodinyl, imidazolinyl, pyrazolidinyl or
piperazinyl, wherein the 3-8-membered N-containing heterocyclic group can be attached via a nitrogen or carbon
10 atom. Preferred substituents include optionally substituted guanidine [-NHC(=NH)NH2], amidino f-C(=NH)NH2],
ureido [-NHC(=O)NH 2], carbazono [-N=NC(=)NHNH 2], carbazido f-NHNHC(=( ))NHNH 2] and semicarbazido
[-NHC(=O)NHNH 2] and amino ([NH21.
The compounds of the present invention include binaphthyl derivatives. Substituted binaphthyl derivatives are
chiral compounds. The present invention encompassed both enantiomeric forms. Preferably, when the compound
15 of the present invention is a 2,2'-binapthyl derivative then the binapthyl group is in the S configuration.
The term "pharmaceutically acceptable derivative" may include any pharmaceutically acceptable salt, hydrate or
prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or
indirccuv) u corfipouriu of trie present invention or a priiiniictCcutiCuiry tictivc irictauOutc oi icSiuuc tucicui.
The salts of the compound of formulae (I) to (FV) are preferably pharmaceutically acceptable, but it will be
20 appreciated that nori-pharmaceutically acceptable salts also fall within the scope of the present invention, since these
are useful as intermediates in the preparation of pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable
inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobrornic acids,
or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic,
25 hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic,
methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic,
palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium,
potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine.
30 alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamme, choline or
amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts
and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of
Pharmaceutical salts"'P.H.StahL C.G.Wermuth , Sedition, 2002, Wiley-VCH.
Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide. such as methyl, ethyl.
35 propyl. and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate: and others.

WO 2006/074501 PCT/AU2005/001444
22.
The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the
compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for
example, compounds in which a free hydroxy group is converted into a group, such as an ester, carbonate or
carbamate, which is capable of being converted in vivo back to a hydroxy group. A prodrug may include
5 modifications of one or more of the functional groups of a compound of formula (1). In particular, compounds of
formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs
include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four)
amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid
groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids
10 commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine,
isodemosine, 3-methylhistidine, norvlin, bcta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,
homoserine, omithine and methioine sulfone. Prodrugs also include compounds wherein carbonates, carbamates,
amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl
carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds of the present invention (such
15 as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxy 1 of the compoundl.
It will also be recognised that the compounds of the first to fifth aspects may possess asymmetric centres and are
therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in
substantially pure isomeric form at one or more nsvmmetrir. centres ep greater than about 90% ee, such as about
95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may
20 be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
In a sixth aspect, there is provided a composition comprising a compound according to any one of the first to fifth
aspects, a salt or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically
acceptable carriers or adjuvants.
The compositions of the present invention may contain other therapeutic agents as described below, and may be
25 formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical
additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives,
stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
In a seventh aspect, there is provided a method of treating a bacterial infection in a mammal comprising
administering an effective amount of compound according to any one of the first to fifth aspects, a salt or a
30 pharmaceutically acceptable derivative thereof.
Yet another aspect of the present invention provides a use of a compound of the first to fifth aspects in the
preparation of a medicament for treating or preventing bacterial infection. They are particularly useful for treating
infections caused by Gram positive bacteria such as enterococcus faecium, Staphylococcus aureus, Staphylococcus
epidermis. Klebsiella pneumoniae. Streptococcus pneumoniae. including multi-resistant strains such as vaneomycin
35 resistant Staphylococcus aureus and methicillin-resistant Staphylococcus aureus.

WO 2006/074501 PCT/AU2005/001444
23.
Accordingly the invention provides the use of a compound of the first to fifth aspects for treatment or prophylaxis of
bacterial infections and provides method comprising of administering an suitable amount of a compound according
to one of the first to fifth aspects.
Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per
5 dosage. The dosage is preferably in the range of 1 g to 1 g per kg of body weight per dosage, such as is in the
range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage is in the range of 1 mg to
500 mg per kg of body weight per dosage. In another embodiment, the dosage is in the range of 1 mg to 250 mg per
kg of body weight per dosage. In yet another preferred embodiment, the dosage is in the range of 1 mg to 100 mg
per kg of body weight per dosage, such as up to 50 mg per kg of body weight per dosage In yet another
10 embodiment, the dosage is in the range of l|a,g to lmg per kg of body weight per dosage.
Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the
severity of the condition as well as the general age, health and weight of the subject.
The active ingredient may be administered in a single dose or a series of doses. While it is possible for the active
ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical
15 formulation.
This invention thus further provides pharmaceutical formulation comprising a compound of the invention or a
phannaceutically acceptable salt or derivative thereof together with one or more pharmaceuticallv acceptable
carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carriers(s) must be
"acceptable' in the sense of being compatible with other ingredients of the formulation and not deleterious to the
20 recipient thereof.
Pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal
or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for
administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant,
carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in
25 such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions,
emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal
administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the
present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats,
30 guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However,
the method can also be practiced in other species, such as avian species (e.g., chickens).
The subjects treated in the above method are mammals, including, but not limited to. cows, sheep, goats, horses.
dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a
human being, male or female.

WO 2006/074501 PCT/AU2005/001444
24.
As used herein, the term "effective amount" relates to an amount of compound which, when administered according
to a desired dosing regimen, provides the desired treatment of the bacterial infection or therapeutic activity, or
disease prevention. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously
over any one of these periods. A therapeutic, or treatment, effective amount is an amount of the compound which,
5 when administered according to a desired dosing regimen, is sufficient to at least partially attain the desired
therapeutic effect, or delay the onset of, or inhibit the progression of or halt or partially or fully reverse the onset or
progression of the bacterial infection. A prevention effective amount is an amount of compound which when
administered according to the desired dosing regimen is sufficient to at least partially prevent or delay the onset of a
particular disease or condition.
10 The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in
the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified
ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient
must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms "administration of and or "administering a" compound should be understood to mean providing a
15 compound of the invention to the individual in need of treatment.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be
presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. AU
methods include the step of bringing the active ingredient into association with the carrier which constitutes one or
more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately
20 bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then,
if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object
compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in
the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified
25 ingredients in the specified amounts.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This
suspension may be formulated according to the known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution
30 in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution
and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or
diglycendes. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The pharmaceutical composition and method of the present invention may further comprise other therapeuticallv
35 active compounds which are usually applied in the treatment of the above mentioned pathological conditions.
Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art.

WO 2006/074501 PCT7AU2005/001444
25.
according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically
to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able
to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
When other therapeutic agents are employed in combination with the compounds of the present invention they may
5 be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one
of ordinary skill in the art.
In addition to the antibacterial properties of compounds of the present invention, the present inventors have also
found that compounds of the present invention are also effective in treating HIV. Accordingly, in an eighth aspect
the present invention provides a method for treatment or prophylaxis of HTV in a subject comprising administering
10 to said subject an effective amount of a compound according to any one of the first to fourth aspects, a salt or a
pharmaceutically acceptable derivative thereof.
Preferably, the compound is selected from one or more of the following compounds of Example 2: 78, 81, 88, 89,
165, 166, 167, 168, 83. 119, 164, 163,158.
In order that the nature of the present invention may be more clearly understood, preferred forms thereof will now
15 be.described with reference to the following non-limiting examples.
EXPERIMENTAL
Compounds of Formulae (I) to (III) may be prepared using the methods depicted or described herein or known in the
art for the preparation of compounds of analogous structure. It will be understood that minor modifications to
methods described herein or known in the art may be required to synthesise particular compounds of Formula (1).
20 General synthetic procedures applicable to the synthesis of compounds may be found in standard references such as
Comprehensive Organic Transformations, R. C. Larock, 1989, VCH Publishers, Advanced Organic Chemistry, J.
March. 4th edition, 1992, Wiley InterScience, Amino Acid and Peptide Synthesis, J Jones, (Oxford Chemistry
Primers) 2nd edition 2002, Oxford university press. The practice of peptide synthesis, 2003, 2nd edition, M.
Bodansky and A. Bodansky, Springer-Verlag, New York and references therein. It will also be recognised that
25 certain reactive groups may require protection and deprotection during the synthetic process. Suitable protecting
and deprotecting methods for reactive functional groups are known in the art for example in Protective Groups in
Organic Synthesis, T. W. Greene & P. Wutz, John Wiley & Son, 3rdEdition, 1999.
Compounds of formula (I) as described above, may be prepared by reacting a compound of formula (A):

WO 2006/074501 PCT/AU2005/001444

5 B
wherein B, R1, Ar1, Ar2, V. Qi, Ch, Si, Ai, S2, A2, S3,. T are as defined in formula (I).
Conveniently the reaction between compounds formulae (A) and (B) is based upon forming an amide bond and may
be conducted using approaches routinely used in peplide synthesis. For example, the coupling reaction of an amine
with a carboxylic acid (X=OH) or an activated carbonyl carbon such as an acyl chloride , acyl azide , acyl-
10 succinimide or an anhydride (X= Cl, N3, O-succinimde, OC(O)R).
Compounds of the formula (A) may be conveniently prepared from an aromatic or heteroaromatic ring syslem
carrying any of;
desired subslituents
functional groups which may be converted into desired substituents using conventional approaches known to those
15 skilled in the art: or
appropriately activated positions on the nucleus of the ring system such that desired substituents may be placed on
the ring system using conventional approaches known to those skilled in the art.
In addition the ring system ATi-Ar2 includes a position that may be converted into the group BR1. This position may
be a functional group or may be an appropriately activated position on the ring to allow conversion into functional
20 groups using conventional approaches known to those skilled in the art. For example functional groups include
hydroxvl. amino and suitably protected derivatives of these. Examples of suitably activated positions include those
which may be alkylated or acylated such as phenoxide.
The compound of formula (B) can be prepared using any suitable approach readily ascertainable to those skilled in
the art. Preferably compound (B) can be formed by reactions of suitably protected amino acids in a suitable
25 sequence. In one preferred approach this is based upon formation of amide bonds and may be conducted using
approaches routinely used in peptide synthesis, for example, the reaction of an amine with an appropriately activated

WO 2006/074501 PCT/AU2005/001444
27.
carbonyl group. Preferably compound (B) may have a protecting group on the amino terminus of SI or S2 which is
removed once the group S1A1S2A2S3T has been formed to allow coupling of SI or Al to V of compound (A).
Those skilled in the art can readily determine the appropriate methodology to build the desired group (B).
Where appropriate , protecting groups may be used to mask certain positions on the compounds of formulae (A) and
5 (B) so as to avoid or limit unwanted side reactions.
Suitable aromatic or heteraromatic ring systems may be commercially available or be readily prepared from
commercially available ring systems or ring system precursors.
The compounds of the present invention may be prepared according to the general procedure of Scheme 1. Although
this process is illustrated using specific reagents and compounds, it will be appreciated by one of skill in the art that
10 suitable analogous reagents may be used to prepare analogous products, as depicted, for example, in scheme 1.
As would be understood by persons skilled in the art compounds of formulae II and III can be prepared by similar
methods (after appropriate modification) to those used to produce compounds of formula I.
Example 1 Preparation and Biological Activity of Compounds according to the Present Invention
General Synthetic Procedures
15 Protocol 1: Peptide Coupling
To a stirrod solution of an acid (1 cquiv.) and an amine (1 cquiv) in dry acctonitrilc or DMF (5 10 mis) was aeddd
EDCI (1.2 equiv.) and HObt (1.2 equiv.). If the amine was a HC1 salt then 1 equivalent of DIPEA was also added.
The reaction mixture was stirred overnight before the solvent was removed and the resultant residue subjected to
flash silica gel column chromatography (normally using 2%MeOH/DC'M as the eluant) to afford the desired
20 compound
Protocol 2: iV-Fmoc Deprotection
To a stirring solution of the Fmoc-protected peptide in dry acetonitrile (5-10 mis) was added piperidine (0.1 ml).
The resultant solution was then stirred at room temperature for 3 hours. The solvent was then removed and the
resultant residue subjected to flash silica gel chromatography using a short column (using 2%MeOH/DCM then
25 5%MeOH/DCM upon removal of Fmoc byproducts) to afford the desired compound.
Protocol 3: iV-Boc & PMC/PBF Deprotection
To a stirring solution of the protected peptide in DCM (2 mis) was added TFA (2 mis). The reaction mixture was
stirred at room temperature for three hours before the solvent was removed. After triturating twice more with DCM
(2 mis), the residue was taken up in DCM (2 ml) and treated with a HCl/ether solution (2 ml, IM), stirred for a
30 minute and evaporated to dryness. This treatment with HC1 was repeated twice more. For BOC-deprotection this is
the Final step, for PMC/PBF-deprotection the following is completed. The residue is taken up in DCM (or dry
MeOH if insoluble in DCM). precipitated by the addition of ether and the solid collected by centrifugation. This step
is repeated once more to remove the protecting group byproduct. The resultant solid is then dried to yield the desired
compound as its hydrochloride salt.

WO 2006/074501 PCT7AU2005/001444
28.
Protocol 4
To a stirring solution of the acid, alcohol, and triphenylphosphine in THF at 0oC under a nitrogen atmosphere was
added DIAD dropwise. The solution was allowed to warm to room temperature and stirred overnight. The solvent
was then removed in vacuo and the resulting residue purified by flash column chromatography over silica to yield
5 the desired product.
Protecting Groups

Gcnerai Notes
Melting point determinations were carried out on a Gallenkamp melting point apparatus. Chemical ionization (CI)
10 and electron impact (El) mass spectra were obtained on a Slmnadzu QP-5000 mass spectrometer by a direct
insertion technique with an electron beam energy of 70 eV. Electrospray (ES) miz mass spectra were obtained on a
VG Autospec spectrometer. High-resolution mass spectra (HRMS) were determined on a micromass QTof2
spectrometer using polyethylene glycol or polypropylene glycol as the internal standard. The miz values arc stated
with their peak intensity as a percentage in parentheses. Proton and carbon nuclear magnetic resonance (NMR)
15 spectra were obtained as specified on a Varian Mercury 300 MHz or Varian Inova 500 MHz spectrometer. Spectra
were recorded in the specified deuterated solvent, and referenced to the residual non-deuterated solvent signal.
Chemical shifts () in ppm were measured relative to the internal .standard. Multiplet (m) signals are reported from
the centre of the peak. Analytical thin layer chromatography (TLC) was carried out on Merck silica gel 60 F254 pre-
coated aluminium plates with a thickness of 0.2 mm. All column chromatography was performed under 'flash'
20 conditions on Merck silica gel 60 (230-400 mesh). Chromatography solvent mixtures were measured by volume. All
compounds were judged to be of greater than 95% purity based upon 'H NMR and TLC analysis. Starting materials
and reagents were purchased from Sigma-Aldrich Pty Ltd or Auspep Pty Ltd and were used as received.

WO 2006/074501 PCT/AU2005/001444
29.
General Synthetic Scheme (Example - Compound I)


WO 2006/074501 PCT/AU2005/001444
30.
Compounds of Formula I
Synthesis of Compound 1
Ki)

5 To a solution of 1,1'-binaphth-2.2'-diol (1 g. 3.49 mmol) in dry acetone (100 ml) was added anhydrous potassium
carbonate (5g). A solution of l-bromo-3-methylbutane (0.52 ml, 4.19 mmol) in acetone (30 ml) was added dropwise
over a 90 min period. The mixture was then heated at reflux for 3 hrs and left to sit overnight before being cooled
and filtered. The solid residue was then washed twice more with acetone (10 ml) before the combined organic
extracts were evaporated to dryness to yield a honey coloured oil. Subsequent flash column chromatography with
10 1:1 DCM/Hexane as the eluant affords the desired product l(i) as a yellow oil (705 mg, 57%). Rf = 0.64 (1:1
hexane/DCM). Starting diol was also recovered (357 mg, 36%) indicating the reaction had not gone to completion.
1H NMR (300 MHz, CDCl3)  0.61, d, J = 6.5 Hz, 3H; 0.65. d,J = 6.5 Hz, 3H; 1.32, m. 3H; 3.98, m, 2H; 4.95, s.
OH; 7.04, dist d, J - 7.8 Hz, IH; 7.25, m, 7H: 7.42. d,J= 9.1 Hz, IH; 7.84, d, J = 7.8 Hz, IH; 7.87, d,J = 8.7 Hz.
IH; 7.99, d, / = 9.0, Hz, IH.
15 l(ii)

To l(i) (532 mg, 1.49 mmol) in dry MeOH (25 ml) was added potassium carbonate (2.06 g, 14.9 mmol) and
bromoacetic acid (1.03 g, 7.45 mmol). The resultant solution was then heated at reflux for 8 hrs over which time a
white ppte had fallen out of solution. The reaction mixture was then evaporated to dryness and the residue dissolved
20 in water (50 ml). This was then washed with ether (3 x 30 ml) before the aqueous layer was acidified with 3M HC1.
This acidified solution was then extracted with DCM (3 x 30 ml) to yield a yellow solution. This yellow solution
was then dried (MgSO4) and evaporated to dryness to yield the product I(ii) as a yellow oil (325 mg. 53%). Starting
material was also recovered (135 mg, 25%) indicating the reaction had not gone to completion.
1H NMR (300MHz. CDC13)  0.54. d. J = 6.5 Hz. 3H: 0.64. d. / = 6.5 Hz. 3H: 1.19, m. IH: 1.30. m. 2H. 3.94. m.
25 IH: 4.13. m, IH: 4.57. ABq, J = 16.8 Hz, IH: 4.69. ABq, j = 16.8 Hz. IH; 7.26, m. 4H: 7.37. m. 3H: 7.48, d, j =

WO 2006/074501 PCT/AU2005/001444
31.
8.8 Hz. IH; 7.90. d. J = 8.2 Hz. 2H; 7.97. d, J = 8.8 Hz. IH: 8.00. d. J = 8.8. Hz. IH: 8.06. br s. COOH. MS (EI
+ve)414 (100%) [M+H]
l(iii)

5 This compound was prepared via Protocol 1. using BOC-(L)-leu-OH (600 mg, 2.59 mmol) and BzOH (0.41 ml, 4.0
mmol) to yield the desired product l(iii) as an off white solid (512 mg, 62%). Rf = 0.78 (5%MeOH/DCM), staining
with Mo dip.
1H NMR (300 MHz, CDC13)  0.91, d,J = 6.5 Hz, 6H: 1.44, m. 2H: 1.45, s, 9H: 1.66, m, IH: 4.36. m, IH: 5.08.
ABq, J = 12.3 Hz, IH: 5.17, ABq,j = 12.3 Hz, IH; 5.27. d, J = 8.4 Hz, NH: 7.31, m, 5H. MS (ES +ve) niz 322
10 (100%) [M+H]+.
1(iv)

To l(iii) (510 mg, 1.59mmol) dissolved in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at
room temperature for 1 hr. Ethyl acetate (15 ml) was then added and the solution washed with sat. sodium
15 bicarbonate solution until the washings were basic. The organic layer was then dried (MgSO4) and evaporated to
dryness to yield the desired product l(iv) as a colourless oil (172 mg, 49%). Rf = 0.37 (5% MeOH/DCM). staining
with Mo dip.
1H NMR (300 MHz, CDC13)  0.88. , J = 6.4 Hz. 3H; 0.90, , J = 6.4 Hz, 3H: 1.43, m, 2H: 1.54, m, IH; 1.72. m,
IH; 1.74, m,NH2; 3.48, m, IH: 5.12, s, 2IT: 7.32, m, 5H. MS (ES+ve)m/z 222 (100%) [M+H1 + .
This compound was prepared via Protocol 1 using l(iv) (160 mg. 0.723 mmol) and Fmoc-(D)-arg(Pmc)-OH (662.8
mg, 1.00 mmol) to yield the desired product l(v) as an off white solid (460 mg, 73%).
20 l(v)


WO 2006/074501 PCT/AU2005/001444
32.
1H NMR (300 MHz, CDC13)  0.81, ra, 6H; 1.21, s, 6H; 1.58, m. 5H: 1.67, m, 3H; 1.85, m, IH; 2.04, s, 3H; 2.49, m,
2H; 2.54, s, 3H: 2.58, s, 3H; 3.21, m, 2H: 4.04, m. IH; 4.23, m, 3H; 4.52. m. IH; 5.02, ABq, J = 12.3 Hz, IH; 5.08,
ABq,J = 12.3 Hz, IH; 6.22, br s, NH; 6.36, bs , NH; 7.25. m, 9H; 7.50, d, J = 7.3 Hz, 2H; 7.69, d,J = 7.3 Hz, 2H.
MS (ES +ve) m/z 888 (100%) [M+Na] + ; 866 (10) [M+H]+.
5 l(vi)

This compound was prepared via Protocol 2, using l(v) (450 mg, 0.520 mmol) to yield the desired product l(vi) as
an off white solid (244 mg. 73%). Rf = 0.07 (5% MeOH/DCM).
1H NMR (300 MHz, CDC13)  0.88, m, 6H; 1.28, s. 6H; 1.57, m, 5H; 1.77, m, 2H; 1.86, m, 2H; 2.08, s. 3H; 2.54. s.
10 3H; 2.58, s, 3H: 2.60, m, 2H; 3.14, m, 2H; 3.38, m, IH; 4.51, m, IH; 5.05, ABq, J = 12.3 Hz, IH; 5.13, ABq, J =
12.3 Hz, IH; 6.33, br s, NH; 6.38, br s, NH; 7.29, m, 5H; 7.78, d, J = 7.6 Hz, NH. MS (ES +ve) m/z 644 (100%)
[M+H].-
Kvii)

15 This compound was prepared via Protocol 1. using l(vi) (240 mg. 0.373 mmol) and Fmoc-(£>)-rys(BOC)-OH (187
mg, 0.4 mmol) to yield the desired product I(vii) as an off white solid (336 mg, 82%). Rf = 0.28 (5% MeOH/DCM).
1HNMR (300 MHz, CDC13) 8 0.83, m, 6H; 1.17, m,2H; 1.18, s,6H; 1.40, s,9H; 1.40, m, 2IT; 1.60, m, HH; 2.02, s,
3H; 2.51, m, 2H; 2.52, s, 3IT; 2.55. s, 3H; 3.02, m,2H; 3.18, m,2H; 3.91, m, IH; 4.18. m, 3H, 4.52, m, IH; 5.00, m,
2H; 6.48, br s, NH; 7.25, m. 9H; 7.43, d.J - 7.6 Hz. NH; 7.52, m, 2H; 7.69. d, J = 7.6 Hz. 2H. MS (ES +ve) m/z
20 1116 (80%) [M+Na] + 1094 (100) [M+H] +

WO 2006/074501 PCT/AU2005/001444
33.
l(viii)

This compound was prepared via Protocol 2, using l(vii) (330 mg, 0.302 mmol) to yield the desired product l(viii)
as an off white solid (239 mg, 91%). Rf = baseline (5% MeOH/ DCM).
5 1HNMR (300 MHz, CDC13)  0.82, d, J = 5.8 Hz, 3H; 0.84, d, J = 5.8 Hz, 3H; 1.23, m, 2H; 1.27, s, 6H; 1.38, s, 9H:
1.40, m,2H; 1.60, m, HH: 2.07, s, 3H: 2.52. s, 3H: 2.54. s, 3H; 2.58, m,2H; 3.01, m, 2H; 3.19, m,2H; 3.29, m, IH;
4.52, m. 2H: 4.92, m, NH; 5.03, ABq. J = 12.3 Hz, IH; 5.09, ABq, J = 12.3 Hz, IH; 6.39, br s, NH: 7.28, m, 5H:
7.58, d,J = 7.9 Hz, NH; 7.95. ,J = 7.3 Hz. NH. MS (ES +ve) m/z 872 (100%) |M+H]+.
l(ix)

This compound was prepared via Protocol 1. using I(ii) (50 mg, 0.121 mmol) and I(viii) (1 10 mg, 0.126 mmol) to
yield the product l(ix) as a white solid (1 14 mg, 74%). Rf = 0.16 (5% MeOH/ DCM).
1H NMR (300 MHz, CDC13)  0.46, d, J = 6.2 Hz, 3H; 0.52-, a, J = 6.2 Hz, 3H: 0.89, m. 911: 1.20, m, 511; 1.28. s,
6H; 1.39. m, 2H: 1.41, s. 9H; 1.70, m, 7H; 2.09, s, 3H; 2.55, s, 3H; 2.57, s, 3H; 2.61, m. 2H: 2.89, m. 2H: 3.10, m,
15 2H; 3.86. m, IH; 4.04, m, 2H: 4.48. m, 4H: 4.82. m,NH; 5.07, ABq, J = 12.6 Hz, IH; 5.16, ABq, J = 12.6 Hz, IH:
6.18, d, J = 7.0 Hz, NH: 6.29, br s, NH; 6.48. br s, NH: 7.20. m,4H: 7.31, m, 7H; 7.45, d, J = 9.1 Hz, 2H: 7.85, m,
2H; 7.95. m, 2H; 8.06, d.J= 8.8 Hz. NH. MS (ES +ve) m'z 1291 (70%) [M+Na|- 1268 (100) [M+H|-.

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Compound 1

This compound was prepared via Protocol 3, using l(ix) (104 nig, 0.082 mmol) to yield the desired compound I as a
white solid (78 mg, 98%).
5 1H NMR (300 MHz, CD3OD) 0.38, d, J = 6.2 Hz, 3H; 0.43. d, J= 6.2 Hz, 3H; 0.80, m, 9H; 1.07, m, 3H; 1.52, m.
1OH; 2.69, m, 2H; 3.05, m, 2H; 3.82, m, IH; 4.01, m, 2H; 4.35, m, 4H; 5.03, m, 2H; 6.94, m, 2H. 7.06, m, 211; 7.21,
m, 7H; 7.34. d, J = 9.1 Hz, IH; 7.42, d, J = 9.1 Hz, IH; 7.85, m, 4H. MS (F,S +ve) m/z 902 (10%) [M+II]+; 452
(100) [M+H]2+.
Synthesis of Compound 2
10 2(9

To BOC-(L)-val-OH (100 nig, 0.48 mmol) and potassium carbonate (160 mg, 1.16 mmol) in acetone (10 ml) was
added benzyl bromide (0.1 ml, 0.84 mmol). The resulting solution was healed at reflux overnight before being
cooled, filtered and evaporated to dryness. The resultant residue was then subjected to flash column ehromatography
15 over silica, using initially 1:1 hexane/DCM to remove benzyl bromide, then DCM to yield the product 2(i) as a
colourless oil (110 mg, 75%). Rf = 0.38 (DCM) staining with Mo dip.
1H NMR (300 MPIz, CDC13)  0.84, d,J = 7.0 Hz. 3H; 0.93, a, J = 7.0 Hz, 3H; 1.43, s, 9H: 2.14, m, III; 4.27, dd, J1
= 9.1 Hz. J2 =4.7 Hz, III; 5.05. obscured d,NH; 5.07, ABq, J= 12.3 Hz, III; 5.20, ARq, J= 12.3 Hz, TH: 7.34, m.
5H. MS (ES +ve) m/z 308 (60%) [MH-H]+ 208 (100) [M+H-Boc] +.

This compound was prepared via Protocol 3 using 2(i) (105 mg. 0.34 mmol) to give the product 2(ii) as an off white
solid (65 mg. 92%).
20 2(ii)

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1H NMR (300 MHz, CDCl3)  1.06, m 6H: 2.44, m, IH: 4.09, m, IH: 5.13, ARq, J - 12.0 Hz, IH: 5.26, ABq. J =
12.0 Hz, IH; 7.32. m, 5H; 8.51, br s,NH3-.
2(Si)

5 This compound was prepared via Protocol 1 using 2(M) (136 mg, 0.800 mmol) and Fmoc-(D)-arg(Pmc)-OH (530 mg,
0.800 mmol) to yield the desired product 2(iii) as an off white solid (659 mg, 97%). Rf = 0.40 (5% MeOHTDCM).
1H NMR (300 MHz, CDC13)  0.79, d, J = 7.0 Hz, 3H; 0.83, d, J =7.0 Hz, 3H; 1.23, s, 6H; 1.60, m, 2H; 1.68, m,
3H: 1.87, m, IH: 2.04, s, 3H: 2.11, m. IH: 2.52, m. 2H; 2.53, s. 3H; 2.56. s, 3H: 3.20, m, 2H; 4.05. m. IH: 4.25. m,
3H; 4.45, dd, J1 = 8.5 Hz, J2 = 5.6 Hz, IH: 5.00, ABq, J = 12.3 Hz, IH; 5.10, ABq, J = 12.3 Hz, IH; 6.27, m, NH;
10 7.21, rn, 2H; 7.26, m, 5H; 7.31, m, 2H: 7.50, a, J = 7.3 Hz, 2H; 7.69, d, J = 7.6 Hz, 211. MS (ES +ve) m/z 852
(100%) [M+H]+.
2(iv)

This compound was prepared via Protocol 2, using 2(iii) (604 mg, 0.709 mmol) to yield the desired product 2(iv) as
15 a colourless oil (361 mg, 81%). Rf= baseline (5% MeOH/DCM).
1H NMR (300 MHz, CDC13)  0.85, d, / = 7.0 Hz, 3H: 0.88, d, J = 7.0 Hz, 3H; 1.28, s, 6H: 1.53, m, 3H; 1.77. m.
3HZNH2:2.08. s. 3H: 2.17. m, IH: 2.53, s, 3H; 2.55, s, 3H: 2.59, m. 2H: 3.13, m, 2H; 3.38, m. IH: 4.40. dd. J1 = 8.5
Hz, J2 = 5.3 Hz, IH: 5.15, ABq. J = 12.3 Hz, IH: 5.15, ABq, J= 12.3 Hz, IH: 6.38, br s.NH: 7.30, m, 5H: 7.87, d,
J = 8.5 Hz, NH. MS (ES +ve) m/z 630 (100%) [M+H] + .

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36.

This compound was prepared via Protocol 1. using 2(iv) (350 mg, 0.556 mmol) and Fmoc-(Z3)-lys(BOC)-OH (260
mg, 0.555 mmol) to yield the desired product 2(v) as an off white solid (592mg, 99%). Rf = 0.25 (5% MeOH/DCM).
5 IH NMR (300 MHz, CDC13)  0.87, m, 6H; 1.21, s, 3H; 1.22, s, 3H; 1.41. m, 13H; 1.67, m, 4H; 1.75, m, 3H; 1.88,
m, III; 2.05, s, 3H; 2.18, m, IH; 2.52, m, 211; 2.54, s, 311; 2.57, s, 311; 3.03, m, 2H; 3.19, m, 211; 4.01, m, IH; 4.28,
m, 3H; 4.52, m, IH; 4.61, m, IH; 4.98, ABq, J= 12.3 Hz, IH; 5.04, m,NH; 5.12, ABq, J= 12.3 Hz, IH; 6.48, br m,
NH; 7.27, m, 7H; 7.33, m, 2H; 7.45, d, J = 8.2 Hz, NH; 7.55, m, 2H; 7.70, d, J = 7.0 Hz, 2H; 7.89, m, NH. MS (F.S
+ve) m/z 1080 (20%) [M+H]+; 559.8 (100) [M+H+K]2+.

This compound was prepared via Protocol 2, using 2(v) (350 mg, 0.324 mmol) to yield the desired product 2(vi) as
an off white solid (204 mg, 79%). Rf= baseline (5% MeOH/ DCM).
IH NMR (300 MHz, CDCl3)  0.82, , J = 6.7 Hz, 3H; 0.86, d, J = 6.7 Hz, 3H; 1.27, s, 6H; 1.30, m, 4H; 1.38, s. 9H;
15 1.52. m. 2H; 1.69, m, 2H: 1.76, dist t. 2H; 1.85. m, 2H; 2.07, s, 3H; 2.12, m, IH; 2.52, s. 3H; 2.54. s, 3H; 2.58. m.
2H; 3.01, m. 2H; 3.18. m. 2H: 3.30, m, IH; 4.46, m, IH; 4.61, m. NH; 5.02. ABq, J= 12.3 Hz, IH; 5.12. ABq. / =
12.3 Hz. IH; 6.40. br s. NH; 7.28. m. 5H; 7.52, d,J = 8.5 Hz, NH; 7.99. d,J= 7.0 Hz, NH. MS (ES +ve) m'z 858
(100%) [M+H]-.

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37.
2(vii)

This compound was prepared via Protocol 1. using I(ii) (92 mg, 0.222 mmol) and 2(vi) (190 mg, 0.222 mmol) to
yield the product 2(vii) as a white solid (180 mg, 65%). Rf = 0.1 1 (5% MeOH/DCM).
5 1H NMR (300 MHz, CDC13)  0.48, a, J = 6.4 Hz, 3H; 0.53, a, J = 6.4 Hz, 3H; 0.82, m, 2H; 0.87, t, J = 7.0 Hz, 6H:
1.18, m, 6H; 1.28, s, 6H; 1.41, s, 9H; 1.60, m, IH; 1.76, dist t, 2H; 1.85, m, IH; 2.08, s, 311; 2.20, m, IH; 2.54, s, 3H;
2.56, s, 3H; 2.58, m, 2H; 2.89. m, 2H; 3.14, m, 211; 3.87, m, IH: 4.06, m, 211; 4.45, m, 4H; 4.82, m, NH; 5.08, ABq,
./= 12.3 Hz, IH; 5.19, ABq,.J = 12.3 Hz, IH; 6.22, m, NH; 7.13, m, 2H; 7.25, m, 2H; 7.35, m, 8H: 7.46. d,J= 9.1
Hz, IH; 7.83, d, J = 7.6 Hz, IH; 7.85, d, J = 7.9 Hz, IH; 7.93, d, J = 8.8 Hz. IH; 7.94, d, J = 9.1 Hz, IH. MS (RS
10 +ve) nvz 1255 (100%) [M+HJ+.
Compound 2

This compound was prepared via Protocol 3. using 2(vii) (100 mg. 0.080 mmol) to yield the product 2 as a white
solid (49 mg, 64%).
15 1H NMR (300 MHz, CD3OD)  0.51. d, J = 6.5 Hz, 3H; 0.56, d, J = 6.5 Hz, 3H; 0.92, d, J = 6.7 Hz. 6H: 0.94. m.
Ill; 1.18, m, 3H: 1.61, m. 6H: 2.18, m, IH: 2.79. m, 211; 3.16, m, 211; 3.94, m. III: 4.10. m, 211; 4.48. m. 411; 5.13.
ABq, J = 12.3 Hz, IH: 5.20, ABq, / = 12.3 Hz, IH: 7.06, m, 2H: 7.20. dist t, 2H: 7.35, m, 7H: 7.46, a, J = 8.8 Hz.
IH: 7.55, d, J = 9.1 Hz. IH: 7.89, d, J = 7.9 Hz. IH: 7.91. d, J = 8.2 Hz. IH: 8.00. d. / = 9.1 Hz, 2H. MS (ES +ve)
m/z 888 (10%) [MH-H]+:445 (100) [M+2H]2+.

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Synthesis of Compound 3
3(0

To BOC-(L)-IIe-OH (200 mg, 0.86 mmol) and potassium carbonate (300 mg, 2.16 mmol) in acetone (20 ml) was
5 added benzyl bromide (0.2 ml, 1.72 mmol). The resulting solution was heated at reflux overnight before being
cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column chromatography over
silica, eluting first with 1:1 hexane/DCM to remove benzyl bromide, then with DCM. The product 3(i) was isolated
as a colourless oil (253 mg, 91%). Rf = 0.28 (DCM) using Mo stain.
1HNMR (300 MHz, CDC13)  0.88, m, 6H; 1.12, m, IH; 1.38, m, IH: 1.43, s, 9H; 1.86, m, IH; 4.31, m, IH: 5.05, m,
10 NIT; 5.10. ABq, 7 = 12.3 Hz, IH; 5.20, ABq, J = 12.3 Hz, IH; 7.33, m, 5H.
3(ii)

This compound was prepared via Protocol 3, using 3(i) (115 mg, 0.358 mmol) to yield the desired product 3(ii) as an
off white solid hydrochloride salt (80 mg, 87%).
15 1H NMR (300 MITz, CDC13) 0.90, t,J = 7.1 Hz, 3H; 1.03, d, J = 6.8 Hz, 3IT; 1.43, m, 2H; 2.16, m, IH; 4.14, m,
ITT; 5.13, ABq, J= 120 Hz, IH; 5.26, ABq,J = 12.0 Hz, IH; 7.33, m,5H, 8.62, br s, NH3+.
3(iu)

This compound was prepared via Protocol 1 using 3(ii) (173 mg, 0.778 mmol) and Fmoc-(D)-arg(Pmc)-OH (520 mg,
20 0.785 mmol) to yield the desired product 3(iii) as an off white solid (452 mg, 79%). Rf= 0.40 (5% MeOH/DCM).
1H NMR (300 MHz. CDC13)  0.75. m,6H; 1.11, m. IH; 1.23. s.6H; 1.30. m, IH; 1.60. m.2H: 1.70. distt. 2H; 1.86.
m. 2H; 1.99. m. IH; 2.05. s. 3H; 2.50, m, 2H; 2.53, s. 3H; 2.56. s. 3H; 3.20. m. 2H; 4.06, dist t. IH: 4.25. m. 3H:
4.50. dd. J1 = 8.3 Hz.J2 = 5.3 Hz. IH; 5.01. ABq. J = 12.0 Hz. IH; 5.12. ABq. j = 12.3 Hz. IH; 6.13. br s. NH:

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39.
6.27. s. NH; 7.19. dist t. 2H: 7.26. m. 5H: 7.33. dist t. 2H; 7.51. d.J = 7.5 Hz. 2H: 7.6. dist t. NH: 7.70, d, J = 7.8
Hz, 2H. MS (ES +ve) m/z 866 (100%) [M+H]+.
3(iv)

5 This compound was prepared via Protocol 2, using 3(iii) (540 mg, 0.623 mmol) to yield the desired product 3(iv) as
a white solid (338 mg, 84%). Rf= baseline (5% MeOH/DCM).
1H NMR (300 MHz, CDC13)  0.85, m, 6H: 1.13, m, IH; 1.28, s, 6H; 1.34, m, IH; 1.54, m, 3H: 1.66, m, IH; 1.77,
dist t, 2I-I; 1.90, m, IH; 2.08, s, 3H; 2.54, s, 3H; 2.56, s, 311: 2.60, dist t, 2H; 3.13, m, 2H; 3.37, m, III; 4.45. dd. J1 =
8.5 Hz. J2 = 5.3 Hz, IH; 5.04. ABq, J = 12.3 Hz, IH; 5.16, ABq, J = 12.3 Hz. IH: 6.31. hr s. Nil; 6.38, br s, NH:
10 7.30, m. 5H; 7.87, d.J = 8.5 Hz, NH. MS (ES +ve) m/z 644 (100%) [M+H|+.
3(v)

This compound was prepared via Protocol 1. using 3(iv) (300 mg, 0.466 mmol) and Fmoc-(£))-lys(BOC)-OH (218
mg, 0.465 mmol) to yield the desired product 3(v) as an off white solid (388 mg, 76%). Rf = 0.25 (5% MeOH/DCM).
15 1H NMR (300 MHz. CDC13) 0.83. m, 6H: 1.16, m. IH: 1.21, s. 3H; 1.22, s, 3H; 1.38. m. 4H: 1.40. s. 9H; 1.67. m.
8H: 1.92, m, 2H; 2.04. s, 3H: 2.52, m, 2H; 2.53, s, 3H: 2.56, s. 3H: 3.03. m, 2H: 3.18, m. 2H; 4.01, dist t. IH: 4.26,
m, 3H: 4.54. m.2H: 4.95. m.NH; 4.98, ABq.J= 12.3 Hz. IH; 5.13, ABq. J= 12.3 Hz, 1H: 6.20, br s. NH: 6.41. br
s. NH: 7.27, m, 9H: 7.54, m, 2H; 7.70. d, J =7.3 Hz, 2IT. MS (ES +ve) m/z 1116 (80%) [M+Na]+: 1094 (100)
[MH-H]+.

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40.
3(vi)

This compound was prepared via Protocol 2, using 3(v) (388 mg, 0.355 mmol) to yield the desired product 3(vi) as
an off white solid (268 mg. 87%). Rf = baseline (5% MeOH/DCM).
5 1H NMR (300 MMz, CDC13) 0.82, m, 6H; 1.15. m, IH; 1.26, s, 6H; 1.31, m, 2H; 1.37, m, 2H: 1.38, s, 9H; 1.51, m,
211; 1.71, m, 6IT. 1.86, m, 2H; 2.07, s, 3H; 2.52, s, 3H; 2.54, s, 3H: 2.59, m, 2H; 3.02, m, 2H; 3.18, m, 2H; 3.30. m,
IH; 4.51, m, IH; 4.58, m, IH; 4.93, m, NH; 5.01, ABq, / = 12.3 Hz, IH; 5.13, ABq, J = 12.3 Hz, IH; 6.39, br s,
NH; 7.28, m, 5H; 7.49, d, J= 8.5 Hz. NH; 7.98, d. J = 7.9 Hz. NH. MS (ES +ve) m/z 872 (100%) [M+H]+.
3(vii)

This compound was prepared wo Protocol ]. using l(ii) (119 mg, 0.287 mmol) and 3(vi) (250 mg, 0.287 mmol) to
yield the product 3(vii) as a white solid (171 mg, 47%). Rf = 0.07 (5% MeOH/DCM).
1H NMR (300 MHz, CDC13)  0.48, d, J = 6.4 Hz, 3H; 0.53, d, J = 6.4 Hz, 3H; 0.87, m. 7H; 0.96, m, IH; 1.20, m,
HH; 1.27, s, 6H; 1.41, s, 9H; 1.59, m, IH; 1.75, m, 2H; 1.84, m, IH; 1.92, m, IH; 2.08, s. 3H; 2.54, s, 3H; 2.56, s,
15 3H; 2.57. m. 2H; 2.88, m, 2IT; 3.11, m, 2H; 3.87. m, IH; 4.09, m, 2H; 4.49, m. 4H; 5.07. ABq. J = 12.3 Hz, IH;
5.19, ABq, J = 12.3 Hz, IH; 6.24, br s, NH; 7.31. m, 12H; 7.44, d. J = 9.1 Hz, IH; 7.84, m. 2H; 7.92, m. 2H. MS
(ES +ve) m/ z 1269 (100%) [M+H]+.


41.
Compound 3
This compound was prepared via Protocol 3, using 3(vii) (170 mg, 0.134 mmol) to yield the product 3 as a white
solid (127 mg, 97%).
5 1H NMR (300 MHz, CD3OD)  0.48, d, J = 6.2 Hz, 3H: 0.53, d, J = 6.2 Hz, 3H; 0.87, m, 7H; 0.96, m, IH; 1.17, m,
5H; 1.57, m, 8H; 1.79, m, IH; 1.91, m, IH; 2.81, m, 2H; 3.16, m, 2H; 3.92, m, IH; 4.10, m, IH; 4.19, m, IH; 4.43,
m, 411: 5.10, ABq,J = 12.3 Hz, III; 5.19, ABq, J = 12.3 Hz, III; 7.05, m, 2H: 7.16, m, 2H; 7.33, m, 711; 7.43, d,J
= 9.1 Hz, IH; 7.53, d, J = 9.1 Hz, IH; 7.85, m, 2H: 7.99, m, 211. MS (ES +vc) m'z 902 (10%) [M+H1+; 452.0 (100)
|M+2H|:+.
T[O Svnthosis of Conpound 4
4(i)

To BOC(L)-LeU-OH (250 mg, 1.08 mmol) and potassium carbonate (747 mg, 5.40 mmol) in acetone (50 ml) was
added 4-chlorobenzyl bromide (333 mg, 1.62 mmol). The resulting solution was heated at reflux overnight before
15 being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column
chromatography over silica, eluting with 1:4 hexane/DCM to first remove 4-chlorobenzyl bromide, then with DCM
to yield the product 4(i) as a colourless oil (366 mg. 95%). Rf = 0.55 (DCM) using Mo dip.
1H NMR (300 MHz, CDC13)  0.89, d, J = 6.4 Hz, 3H; 0.90, a, J = 6.4 Hz, 3H: 1.41, s, 911; 1.48. m, 2H; 1.64, m,
IH; 4.3 1. m, IH; 4.95. d,J = 8.2 Hz, NH; 5.06, ABq, J = 12.3 Hz, IH; 5.13. ABq. J = 12.3 Hz. IH; 7.25, ABq, J =
20 8.4 Hz, 2H; 7.30. ABq.J = 8.2 Hz, 2H. MS (ES +ve) m/z 356 (100%) [M+H]+.
4(0)


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42.
This compound was prepared via Protocol 4, using 4(i) (366 mg, 1.03 mmol) to yield the desired product 4(H) as a
colourless oil (235 mg, 89%).
1H NMR (300 MHz, CDC13)  0.88, d,J = 6.4 Hz, 3H; 0.91, d,J = 6.4 Hz, 3H; 1.43, m, IH; 1.55, m, IH; 1.56, m,
NH,: 1.74, m, IH: 3.48, m, IH; 5.09, s, 2IT. 7.27, ABq, J = 8.5 Hz, 2H; 7.32, ABq, J = 8.5 Hz, 2H. MS (ES +ve)
5 m/z 256 (100%) [M+H1+.
4(Hi)

This compound was prepared via Protocol I using 4(H) (235 mg, 0.919 mmol) and Fmoc-(£>)-arg(Pmc)-OH (609 mg,
0.919 mmol) to yield the desired product 4(Hi) as an off white solid (806 mg, 97%).
10 IH NMR (500 MHz, CDCl3)  0.79, dist d. 6H: 1.28, s, 6H; 1.65, m, 8H; 1.89, m, IH; 2.03, s, 3H; 2.49, m, 2H; 2.53,
s, 3H: 2.56, s, 3H: 3.23, m, 2H; 4.03, m, IH; 4.28, m, 3H; 4.51, m, IH; 4.96, ABq, J = 12.2 Hz, IH: 5.02, ABq, J =
12.2 Hz, IH; 6.42, br s, NH; 7.19, m, 6H; 7.31, dist t, 2H; 7.49, dist d, 2H; 7.54, d, / = 7.8 Hz, NH: 7.68, ABq, J =
7.8 Hz, 211. MS (ES +ve) m/z 900 (100%) [M+H]+.
4(iv)

This compound was prepared via Protocol 2, using 4(Hi) (798 mg, 0.887 mmol) to yield the desired product 4(iv) as
an off white solid (532 mg, 88%).
IH NMR (500 MHz. CDC13)  0.76, d, J = 6.1 Hz, 3H: 0.88, d, J = 6.1 Hz, 3H: 1.28. s. 6H: 1.57. m, 5HTNH2: 1.77.
m, 3H: 2.02, m, IH: 2.08, s, 3H: 2.53, s. 311: 2.55, s, 311; 2.59, m, 2H: 3.15, m, 2H; 3.41, m, IH: 4.49, m, IH: 5.01.
20 ABq, J = 12.2 Hz, IH: 5.07, ABq.J = 12.2 Hz. IH: 6.45, br s, NIT: 7.22. ABq. J = 8.5 Hz. 211: 7.26. ABq. J = 8.5
Hz. 2H: 7.83. A. J = 7.9 Hz, NH. MS (ES +ve) m/z 678 (100%) fM+H]+.

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43.
4(v)

This compound was prepared via Protocol 1. using 4(iv) (519 mg. 0.765 mmol) and Fmoc-(D)-lys(BOC)-OH (359
mg, 0.766 mmol) to yield the desired product 4(v) as an off white solid (785 mg, 91%).
5 IH NMR (500 MHz, CDC13) 0.82, d,J = 5.5 Hz, 3H: 0.84, d,J= 5.9 Hz, 3H; 1.19, br s, 6H: 1.39, s, 9H; 1.63, m,
14H; 2.02, s, 3H; 2.05, m, IH: 2.51, m, 2H: 2.52, s, 3H: 2.55. s, 3H: 3.02, m, 2H: 3.19, m, 2H: 3.94. m. IH; 4.14, m,
3H; 4.53, m, 2H: 4.95, m, 2H/NH; 6.47, br m, NH: 7.19, m, 4H: 7.32, m, 2H: 7.54, m, 4H: 7.69, m. 2H. MS (TRS +ve)
m/z 128 (100%) |M+H|+.
4(vi)

This compound was prepared via Protocol 2. using 4(v) (330 mg, 0.292 mmol) to yield the desired product 4(vi) as
an off white solid (236 mg, 89%).
1H NMR (500 MHz, CDC13)  0.85, d, J = 5.9 Hz, 3H: 0.87, d, J = 5.9 Hz, 3H: 1.29, s, 611: 1.48, s. 9H: 1.57, m,
14HZNH2: 2.09, s, 3H: 2.13, m, IH: 2.54, s, 3H: 2.56, s. 3H: 2.60, m, 2H: 3.04, m, 2H: 3.22, m, 2H: 3.35, m, III:
15 4.52, m. IH: 4.59, m, IH: 4.98, m, NH: 5.02, ABq, J = 12.2 Hz, III: 5.07, ABq, J = 12.2 Hz, IH: 6.45, br s, NH:
7.23, ABq, J = 8.5 Hz. 2H: 7.28, ABq, J = 8.5 Hz. 2H: 7.71, m, NH: 8.00. m. NH. MS (ES +ve) m/z 906 (100%)
[M+H]+.

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44.
4(vii)

This compound was prepared via Protocol 1. using l(ii) (105 mg, 0.254 mmol) and 4(vi) (230 mg, 0.254 mmol) to
yield the product -l(vii) as a white solid (144 mg, 44%).
5 IH NMR (500 MHz, CDC13)  0.46, d, J= 5.3 Hz. 3H; 0.52. d, J = 5.3 Hz, 3H; 0.79, m. 2H; 0.87, d, J = 5.9 Hz, 3H;
0.89.d J = 5.9 Hz, 3H; 0.94, m, IH; 1.19, m, 6I-I; 1.28, s, 6I-I: 1.29, m, 2H; 1.41, s, 9H; 1.64, m, 4H; 1.76, m, 211;
1.84. m, IH; 2.09. s, 3H; 2.54, s, 3H; 2.56, s, 3H; 2.58, m, 2H; 2.90, m, 2H; 3.15. m, 2H; 3.87, m, IH; 4.04, m, 2H;
4.41, m, 2H; 4.45, m, 3H; 4.82, m. NH; 5.04, ABq, J = 12.2 Hz, IH; 5.11, ABq, / = 12.2 Hz, IH; 6.19, a, J -6.8
Hz, NH; 6.29, hr s,NH; 7.26, m, HH; 7.44, d,/ = 9.1 Hz, IH; 7.83, d, J= 8.3 Hz, IH; 7.85, d,J = 8.3 Hz, IH; 7.93,
10 a,.7= 9.0 Hz, IH; 7.94, d, / = 8.9 Hz, IH. MS (ES +ve) m/z 1302 (60%) [M+H]+; 602 (100) [M+2H-BOC]2+.
Compound 4

This compound was prepared via Protocol 3, using 4(vii) (140 mg, 0.107 mmol) to yield the desired product 4 as a
white solid (101 mg, 93%).
15 IH NMR (500 MHz, CD3OD)  0.40, d.,J = 6.3 Hz. 3H; 0.45, d, / = 6.3 Hz, 3H: 0.78, d,J = 4.8 Hz, 3H; 0.83, d,J
= 4.8 Hz, 3H; 0.84, m, 2H; 1.05, m. 2H; 1.13. m, 2H; 1.53, m, 9H; 1.72, m, IH; 2.70, m, 2H; 3.06, m, 2H; 3.84, m,
IH; 4.03. m, 2H; 4.36. m. 4H; 5.02. s, 2H; 7.06. dist t. 2H; 7.18, m, 211; 7.33, m. 6H; 7.45, d .J = 9.3 Hz, IH; 7.54. d,
J = 8.8 Hz. IH; 7.88, d, J = 7.8 Hz. IH; 7.91. d, J = 8.3 Hz. IH; 8.00. dist t. 2H. MS (ES +ve) m/z 936 (15%)
[M+H];469 (100) [M+2H]2+.

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Synthesis of Compound 5
5(i)

To BOC(L)-Leu-OH (250 mg, 1.08 mmol) and potassium carbonate (747 mg, 5.40 mmol) in acetone (50 ml) was
5 added 4-nitrobenzyl bromide (350 mg, 1.62 mmol). The resulting solution was heated at reflux overnight before
being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column
chromatography over silica, eluting with 1:4 hexane/DCM to first remove 4-nitrobenzyl bromide, then with DCM to
yield the product 5(i) as a colourless oil.
1H NMR (500 MHz, CDCT3)  0.95, d, J = 6.8 Hz, 6H; 1.44, s, 9H; 1.53, m, IH: 1.63, m, IH: 1.71, m, IH; 4.38, m,
10 IH: 4.99, d, J = 8.3 Hz, NH: 5.27, s, 2H: 7.53, ABq, J = 8.3 Hz, 2H: 8.22, ABq, J = 8.3 Hz, 211. MS (El) m/z 265
(100%) [M-BOC1+.
5(ii)

To 5(i) (215 mg, 0.59 mmol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
15 temperature for 3 hrs. The solution was then diluted with DCM (5 ml) and washed with sat. sodium bicarbonate
solution until the washings were basic. The organic layer was then dried (MgS()^, filtered and evaporated to
dryness to yield the desired product 5(ii) as a white solid (131 mg, 84%).
IHNMR (500 MHz, CDC13)  0.93, a, J = 8.8 Hz., 3H: 0.95, d,J = 8.8 Hz, 3H; 1.50, m, IH; 1.62, m, IH: 1.54, m,
IH: 1.79, m, IH: 2.37, br s, NH2: 3.61, m, IH: 5.26. s, 2H: 7.54, ABq,J = 8.8 Hz, 2H: 8.22, ABq,J = 8.8 Hz, 2H.
20 MS (ES +ve) m/z 267 (100%) [M+H]+.

This compound was prepared via Protocol 1 using 5(ii) (130 mg, 0.488 mmol) and Fmoc-fDVarglPmcVOH (323 mg.
0.488 mmol) to yield the desired product 5(Hi) as a white solid (414 mg. 93%).
5(iii)

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IH NMR (500 MHz, CDC1,)  0.83, br s, 6H: 1.21, s, 6H: 1.61, m, 4H: 1.66, m, 3H; 1.75, m. 2H; 2 03, s, W: 2 49,
m, 2H: 2.53, s, 3H: 2.57, s, 3H; 3.23, m. 2H: 4.01, in, IH; 4.23, m,2H; 4.36, m, IH; 4.56, m, IH; 5.09, s, 2H: 6.45,
br s, NFL 7.17, m, 2H: 7.29, m, 5H (me NH): 7.48. ABq, J = 8.8 Hz, 2H: 7.66. m, 2H; 7.70, m, NH: 8.04. ABq,./ =
8.8 Hz, 2H. MS (ES +ve) m/z 911 (100%) [M+H]+.
5 5(iv)

This compound was prepared via Protocol 2, using 5(iii) (400 mg, 0.439 mmol) to yield the desired product 5(iv) as
an off white solid (210 mg. 69%).
ifi NMR (500 MHz. CDC13) 8 0.90, dist d, 6H; 1.28, s, 6H; 1.57, m. 4H; 1.65, m, 2H; 1.78, m, 3H; 2.07, s, 3H; 2.52,
10 s, 3H: 2.54, s, 3H; 2.59, m, 2H: 3.17, m. 2H; 3.49, m, IH; 4.53, m, IH: 5.20, s, 2H; 6.45. br s, NH; 7.47, ABq, J =
8.3 Hz. 2H; 7.90, d, J = 5.4 Hz, NH. 8.22, ABq, / = 8.3 Hz, 2H. 13C NMR (125 MHz, CDC13)  12.0, 17.3, 18.4.
21.2, 21.5, 22.6, 22.9, 24.8, 25.2. 26.6, 31.6, 32.6, 40.2, 50.7, 54.0, 65.2, 73.5, ii7.9, 123.6, 123.9, 128.2, 133.i,
134.6. 135.2. 142.7, 147.5. 153.5. 156.3. 172.4, 175.3. MS (ES +ve) m/z 689 (100%) [M+H]+.
5(vi)

The Fmoc-protected precursor to this compound was prepared via Protocol 4, using 5(iv) (200 mg, 0.290 mmol) and
Fmoc-(Z')-lys(BOC)-OH (136 mg, 0.290 mmol) to yield the Fmoc-protected derivative 5(v) as an off white solid.
The desired deprotected compound was prepared via Protocol 2, to yield the product 5(vi) as an off white solid (201
mg, 76%).
20 ill NMR (500 MHz, CDC13)  0.87, d. J = 5.8 Hz, 3H: 0.90, d, J = 5.8 Hz, 3H: 1.29, s, 6H: 1.40, s. 911: 1.60, m.
15H; 2.08, s, 3H: 2.54, s, 3H: 2.56. s, 3H; 2.60. m, 2H: 3.04. m, 2H: 3.23. m, 2H: 3.51, m. Ill: 4.58. m. 2H: 4.93. m.
NIT: 5.19. s, 2H: 6.44, br s. NH; 7.48. ABq,.J = 8.8 Hz, 2H; 7.77, m, NH: 8.01, m, NH; 8.16, ABq. J = 8.8 Hz. 211.
MS (ES +ve) mz917 (10%) [M+H|- 431.5 (100) [M+IT-C'4H8]+.

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47.
5(vii)

This compound was prepared via Protocol 1. using I(ii) (91 mg, 0.022 mmol) and 5(vi) (190 mg, 0.021 mmol) to
yield the product 5(vii) as a white solid (194 mg, 71%).
5 IH NMR (.500 MHz, CDC13)  0.46, d, J = 6.3 Hz, 3H; 0.51, a,J= 6.3 Hz, 3H; 0.89, a, J = 5.8 Hz, 3H; 0.90, m, 2H:
0.92. d, J = 5.8 Hz, 3I-I; 1.25, m, 4H; 1.26, s, 6H; 1.40. s, 9H: 1.56, m, 1OH: 1.83, m, III; 2.07, s, 311; 2.53, s, 311;
2.56. s. 3H: 2.58. m. 2H; 2.90, m. 2H; 3.15. m. 2H; 3.93. m. 311; 4.51. m,4H; 5.22. s, 2H; 6.20, d.J = 7.0 Hz, NH;
6.29, br s, NTT; 7.04, d,J = 13 Hz, TH; 7.06, a,,/ = 8.3 Hz, TH; 7.17, m, 2H; 7.31, t, J - 7.3 Hz. 2H; 7.-15, d, J = 9.3
Hz, IH; 7.53, d,J = 9.3 Hz, IH; 7.58, ABq, J = 8.8 Hz, 2H; 7.87, d, J = 8.3 Hz, IH; 7.89, d, J = 8.3 Hz. Ill; 7.99. d,
10 J= H.B Hz, IH; 8.00, d,J = 9.3 Hz, IH: 8.19, ABq, J= 8.8Hz, 2H. MS (ES +ve) nrz 1313 (100%) [M+H]+ .
Compound 5

This compound was prepared via Protocol 3, using 5(vii) (194 mg, 0.015 mmol) to yield an impure product.
Protocol 3 was repeated on 130 mg of this product to yield the desired product 5 as an off white solid (110 mg. 84%).
15 'H NMR (500 MHz, CD3OD)  0.38, a, J = 6.4 Hz. 3H: 0.44, d, J = 6.4 Hz, 3H; 0.80, a,./ = 5.5 Bz, 3H: 0.85, d.J
= 5.5 Hz. 3H: 0.90, m, 2H: 1.10, m, 4H: 1.56, m, 9H: 1.74, m, IH: 2.70. m, 2H; 3.06, m. 2H: 3.83. m, IH: 4.02. m.
211: 4.27. m. Ill: 4.36. ABq, J = 14.5 Hz, III; 4.40, m. Ill: 4.46, ABq,J = 14.5 Hz. IH: 5.26. s, 2H: 7.04, d,J = 7.3
Hz, IH; 7.06, a, J = 8.3 Hz. IH; 7.17, m, 2H: 7.31, t, J = 7.3 Hz, 2H; 7.45. d,J = 9.3 Hz, IH: 7.53, d, J = 9.3 Hz,
IH: 7.58, ABq, J= 8.8Hz. 2H; 7.87, d,J= 8.3 Hz, IH; 7.89, d,J - 8.3 Hz, III; 7.99, d,/ = 8.8 Hz. IH: 8.00. d,J =
20 9.3 Hz. IH: 8.19. ABq. J = 8.8 Hz. 2H. MS (ES +ve) m/ z 947 (10%) [M+Hl+: 474.5 (100) [M+2H]2-

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48.
Synthesis of Compound 6
6(i)

To BOC-(L)-leu-OH (250 mg, 1.08 mmol) and potassium carbonate (1.00 g. 7.24 mmol) in acetone (25 ml) was
5 added 2-chlorobenzyl bromide (0.16 ml, 1.22 mmol). The resulting solution was heated at reflux overnight before
being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column
chromatography over silica, eluting with 5% ethyl acetate^exane to first remove 2-chlorobenzyl bromide, then with
DCM to yield the product 6(i) as a white solid (370 mg. 96%).
IHNMR (500 MHz, CDC13) 0.92, d,.J = 6.3 Hz, 3H; 0.93, d, J = 6.3 Hz, 3H; 1.43, s,9H: 1.54, m, IH; 1.68, m,2H;
10 4.36, m, IH; 5.08, m, NH; 5.13, m, 2H; 7.22, m, IH; 7.27, m, 2H; 7.34, s, IH. MS (ES +ve) m/z 357 (100%)
[M+H]+;257 (70) [M+H-BOC]+.
6(H)

To 6(i) (360 mg, 1.01 mmol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
15 temperature for 3 hrs. The solution was then diluted with DCM (5 ml) and washed with sat. sodium bicarbonate
solution until the washings were basic. The organic layer was then dried (MgSO4), filtered and evaporated to
dryness to yield the desired product 6(ii) as a pale yellow oil (179 mg, 69%).
iH NMR (500 MHz. C'DCl3)  0.85, d, J = 6.8 Hz, 3H; 0.87, d, J = 6.8 Hz, 3H; 1.41, m, IH; 1.52, m, IH; 1.71, m,
IH; 2.41, br s NH2,; 3.50, m, IH; 5.05, s, 2H; 7.18, m, IH; 7.23, m, 2H; 7.28, s, IH. MS (ES +ve) nr/z 256.0 (100%)
20 [M+H]+.

This compound was prepared in two steps. The first step via Protocol 1. using 6(ii) (170 mg, 0.67 mmol) and Fmoc-
(D)-arg(Pmc)-OH (398 mg. 0.60 mmol) to yield the Fmoc protected precursor 6(Hi) as an off white foamy solid (529
6(iv)

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49.
mg, MS (ES +ve) m/z 900.0 (100%) [M+H]+). The desired product was then prepared via Protocol 2. using
precursor 6(iii) (230 mg, 0.26 mmol) to afford the product 6(iv) as a colourless oil (150mg, 85% two steps).
IH NMR (500 MHz, CDC13)  0.80, d, J = 6.4 Hz, 3H: 0.82. d,J = 6.4 Hz. 3H: 1.21, s. 6H; 1.51, m, 5H: 1.70, m.
3H; 2.01, s, 3H; 2.03, m, IH: 2.46, s, 3H: 2.48, s, 3H; 2.52, m, 2H: 3.08, m, 2IT: 3.36, m, IH; 4.42, m, IH; 4.95.
5 ABq,J = 12.3 Hz, IH; 5.01, ABq, J = 12.3 Hz, IH; 6.32, br s, NH; 7.15, m, 4H; 7.76, d, J = 6.8 Hz, NH. MS (ES
+ve) m/z 678.0 (100%) [M+H]+. HRMS for C33H48C1N5O6S, calculated 678.3092, found 678.3094.
6(v)

This compound was prepared via Protocol 1. using l(ii) (642 mg, 1.55 mmol) and (D)-Iys(BOC)-OMe (400 mg,
10 1.54 mmol) to yield the desired compound 6(v) as a off white sticky solid (898 mg, 89%). Rf = 0.53 (5%
MeOHTDCM).
IH NMR (500MHz, CDC13) 5 0.54, a, J = 6.4 Hz, 3H; 0.58, d,J= 6.4 Hz, 3H; 0.78, m, 2I-I: 1.00, m, IH; 1.22, m,
6H; 1.42, s, 9H; 2.91, m, 2H; 3.59, s, 3H; 3.95, m, IH; 4.06, m, IH; 4.29, m, III; 4.45, ABq, J = 14.3 Hz, IH; 4.51,
ABq, J = 14.3 Hz, IH; 4.64, br s, NH; 6.15, a, J = 8.5 Hz, NH; 7.17, m, 4H; 7.30, m, 3H; 7.46, d, / = 8.9 Hz, IH:
15 7.83, d, J = 7.5 Hz. IH; 7.84, d, J = 7.8 Hz, IH; 7.92, d. J = 10.2 Hz, IH; 7.94, d, J = 10.2 Hz, IH. MS (ES) m./z
657.1 (100%) [M+H]+: 557.1 (90) [M+H-BOC]+
6(vi)

To a solution of 6(v) (898 mg, 1.37 mmol) in THF (20 ml) was added a solution of LiORH 2O (1260 mg, 30.1 mmol)
20 in water (10 ml). The resultant solution was stirred at RT for 1 hr before diethyl ether (20 ml) was added and the
layer separated. The aqueous layer was extracted with sat. sodium bicarbonate solution and the aqueous extracts
combined then acidified to pH -2-3 using IM potassium bisulphate. The aqueous layer was then extracted with
DCM (3 x 20 ml). A TLC of the initial and final organic layers was completed and showed the product was in both
layers. As a result, all of the organic fractions were combined, dried (MgSO4) and evaporated to dryness to yield the
25 product 6(vi) as an off white foamy solid (854, 97%).

WO 2006/074501 PCT/AU2005/001444
50.
1H NMR (300 MHz, CDC13) 8 0.53. d, J = 6.3 Hz, 3H; 0.57, d, J = 6.3 Hz, 3H: 0.82, m, 2H; 1 24. m 5H: 1.40. m,
2H (obscured by BOC-CH3): 1.44, s, 9H; 2.92, m, 2H; 3.95, m, IH: 4.05, m, IH; 4.31, m, IH; 4.49, ABq, J = 14.6
Hz, IH: 4.57, ABq, J = 14.6 Hz, IH; 4.60, br s, NH (obscured by ABq): 6.15, m, NH: 7.19, m, 4H: 7.32, m, 3H:
7.44, d. J = 9.1 Hz, IH; 7.85, d,J= 8.0 Hz, IH; 7.86, d, J = 8.1 Hz, IH; 7.94, d, / = 9.0 Hz, IH; 7.96, d, J = 9.1 Hz,
5 IH. MS (ES+ve) 643.1 (100%) [M+H]+; 543.1 (30) [M+H-BOq>.
6(vii)

This compound was prepared via Protocol 1. using (J(vi) (122 mg, 0.186 mmol) and 6(iv) (145 mg, 0.199 mmol) to
yield 6(vii) as a white solid (198 mg, 82%).
10 IH NMR (500 MHz. CDC1,)  0.39. d. J = 6.5 Hz. 3H: 0.44. d. / = 6.5 Hz, 3H; 0.70, m, 2H; 0.80, d, J = 5.6 Hz, 3H;
0.82, d, J = 5.6 Hz, 3H; 0.89, m, IH; 1.12, m, 6H; 1.19, s, 6H: 1.29, m, 2H; 1.33, s, 9H; 1.55, m, 4H: 1.68, m, 2H:
1.71, m, IH; 2.00, s, 3H: 2.48, s, 3H; 2.48, s, 3H; 2.50, m, 2H; 2.82, m, 2H; 3.07, m, 2H; 3.79, m, IH; 3.96, m, 2H;
4.33, m. 2H; 4.44. m. 3H: 4.73. m. NH: 4.97. ABq, J = 12.7 Hz, IH; 5.03, ABq, / = 12.7 Hz, IH; 6.12, d, J= 6.9
Hz, NH; 6.22, br s. NH; 7.26. m. HH; 7.36, d, J = 9.1 Hz, IH; 7.75, d, J = 10.1 Hz, IH; 7.77, d. J = 8.7 Hz, III;
15 7.84, d.J = 8.7 Hz. IH; 7.86, d.J - 7.6 Hz, IH. MS (ES +ve) m/z 1301.9 (100%) [M+H]+: 602.6 (30) [M+2H-
BOC]>.

This compound was prepared via Protocol 3. using 6(vii) (180 mg, 0.138 mmol) to yield 6 as an off white solid (130
20 mg. 93%).
Compound 6
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51.
1H NMR (500 MHz, CD3OD) d 0.50, d, J = 6.3 Hz, 3H: 0.55. d. J = 6.3 Hz. 3H; 0.90. d. / = 4.8 Hz. 3H: 0.94. d. J
= 4.8 Hz, 3H; 0.95, m. 2H: 1.14, m, 2H: 1.23, m, 2H: 1.67, m, 1OH: 2.83, m, 2H: 3.18, m, 2H; 3.96, m. IH: 4.14, m,
2H: 4.36, m, IH; 4.48, m, 3H: 5.12, s, 2H; 7.05, d, J = 3.7 Hz, IH: 7.08, d, J = 3.5 Hz, IH: 7.17, dist t, 2H: 7.30. m,
5H: 7.38, s, IH: 7.45, d, J = 9.0 Hz, IH: 7.54, d, J = 9.0 Hz, IH: 7.88, d, J = 8.5 Hz, IH: 7.91, d. J = 8.5 Hz, IH:
7.99, a, J = 8.7 Hz, IH: 8.02, d, J= 8.5 Hz, IH. MS (ES +ve) m/z 935.7 (5%) [M+H]+;468.7 (100) [M+2H]2+.

To BOC-(L)-leu-OH (250 mg, 1.08 mmol) and potassium carbonate (1.00 g, 7.24 mmol) in acetone (25 ml) was
added 2-chlorobenzyl bromide (0.16 ml, 1.23 mmol). The resulting solution was heated at reflux overnight before
being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column
chromatographv over silica, eluting with 5% ethyl acetate/hexane to first remove 2-chlorobenzyl bromide, then with
DCM to yield the product 7(i) as a white solid (353 mg, 92%).
1HNMR (500 MHz, CDCl,)d0.92, d, / = 6.4 Hz, 3H: 0.93, d, J = 6.4 Hz, 3H: 1.43, s, 9H; 1.56, m, IH: 1.68, m,2H:
4.40, m. IH: 5.16, d, J = 8.4 Hz, NH: 5.22, ABq, J= 13.1 Hz, IH; 5.27, ABq, J = 13.1 Hz, IH; 7.25, m, 2H: 7.35, m,
IH; 7.42, m, IH. MS (ES +ve) m/z 356.1 (100%) [M+H]+: 256.0 (70) [M+H-BOC].

To 7(i) (350 mg, 0.984 mmol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
temperature for 3 hrs. The solution was then diluted with DCM (5 ml) and washed with sat. sodium bicarbonate
solution until the washings were basic. The organic layer was then dried (MgSO4), filtered and evaporated to
dryness to yield the desired product 7(ii) as a white solid (236 mg, 94%).
1H NMR (500 MHz, CDC13) d0.86, d, J = 6.8 Hz, 3H: 0.88, d,.J = 6.8 Hz, 3H: 1.45, m, IH: 1.57, m, IH: 1.74, m,
IH: 2.64, s. NH2: 3.54. m, IH: 5.20. s, 2H: 7.22. m. 2H: 7.35. m, 2H. MS (ES +ve) m/z 256.1 (100%) [M+H]+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared in two steps. The first step via Protocol 1. using 7(ii) (230 mg, 0.900 mmol) and
Fmoc-(D)-arg(Pmc)-OH (563 mg, 0.850 mmol) to yield the Fmoc protected precursor 7(iii) as a white foamy solid
(662 mg, MS (ES +ve) m/z 900 (100%) [M+H]+). The desired product was then prepared via Protocol 2, using the
precursor 7(iii) (200 mg, 0.22 mmol) to affordthe product 7(iv) as a white solid (135 mg, 66% two steps).
1H NMR (500 MHz, CDCl3) 5 0.81, d, / = 5.9 Hz, 3H: 0.83, d, J = 5.9 Hz, 3H: 1.21, s. 6H: 1.51, m, 5H: 1.71, m,
3H: 2.01, s, 3H: 2.01. m, IH: 2.47, s, 3H; 2.49, s, 3H: 2.53, m, 2H: 3.08, m, 2H: 3.33, m. IH: 4.46. m, IH: 5.10,
ABq, J = 12.9 Hz, IH: 5.15, ABq. J = 12.9 Hz. IIT: 6.34, br s, NH: 7.16, m, 2H: 7.30, m, 2H: 7.75, d, J = 7.8 Hz,
NH. MS (ES +ve) m/z 678.0 (100%) [M+H]+.

This compound was prepared via Protocol 1. using 6(vi) (111 mg, 0.169 mmol) and 7(iv) (130 mg, 0.179 mmol) to
yield 7(v) as a white solid (172 mg, 78%).
1H NMR (500 MHz. CDCl,) d 0.38, d, J = 6.2 Hz, 3H: 0.43. d, J = 6.6 Hz, 3H: 0.70, m, 2H: 0.81, d, J = 5.5 Hz. 3H:
0.82, d, J = 5.5 Hz, 3H: 0.89, m, IH: 1.12, m, 6H: 1.19, s. 6H: 1.29, m, 2H: 1.33, s, 9H: 1.58, m, 4H: 1.68. m, 2H:
1.71. m, IH: 2.00, s, 3H: 2.46. s, 3H: 2.48. s. 3H: 2.50, m, 2H: 2.81, m. 2H: 3.07, m. 2H: 3.78, m. IH: 3.96. m. 2H:
4.33, m. 2H: 4.46, m. 3H: 4.73, m, NH: 5.11, ABq, J = 12.7 Hz, IH: 5.19, ABq, J = 12.7 Hz, IH: 6.12. d. J= 7.3
Hz, NIT: 6.23. br s, NH: 7.26, m, HH: 7.36, d. J = 10.0 Hz, IH: 7.75, d,,/ = 8.0 Hz, IH: 7.77, d, J = 8.3 Hz, IH:
7.84, a. J = 9.0 Hz, IH: 7.85. d. J = 9.0 Hz. IH. MS (ES +ve) m z 1301.9 (100%) [M+H]+: 601.7 (60) [M+2H-
BOC]2+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 3, using 7(v) (160 mg, 0.123 mmol) to yield 7 as an off white solid (109
mg, 88%).
1H NMR (300 MHz, CD3OD) d0.51, d, J = 6.4 Hz, 3H; 0.56, d, J = 6.4 Hz, 3H; 0.90, d, J = 5.7 Hz, 3H: 0.95, d, J
= 5.7 Hz, 3H; 1.15, m, 2H; 1.25, m, 3H; 1.67, m, HH: 2.82, m, 2H; 3.16, m, 2H; 3.97, m, IH; 4.15, m, 2H; 4.34, m,
IH: 4.48, m, 3H; 5.21, ABq, J = 12.8 Hz, IH; 5.28, ABq,,/ = 12.8 Hz, IH: 7.05, a,./ = 4.5 Hz, IH; 7.08, d, J = 4.5
Hz, IH; 7.20, m,2H; 7.32, m,4H; 7.44, m,3H; 7.54, d, J=9.0 Hz, IH; 7.89, d, J= 8.1 Hz. IH; 7.91. d, J = 7.7 Hz,
IH; 8.01. d, J = 9.0 Hz, IH; 8.02, d. J = 9.0 Hz, IH. MS (ES +ve) m/z 935.7 (5%) [M+H]+; 468.7 (100) [M+2H]2+.

To BOC-(L)-leu-OH (250 mg, 1.08 mmol) and potassium carbonate (100 mg, 7.24 mmol) in acetone (25 ml) was
added 2,6-dichlorobenzyl bromide (266 mg, 1.50 mmol). The resulting solution was heated at reflux overnight
before being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column
chromatography over silica, eluting with 5% ethyl acetate/hexane to first remove 2,6-dichlorobenzyl bromide, then
with DCM to yield the product 8(i) as a white solid (383 mg. 91%).
1H NMR (500 MHz, CDCl3) d 0.85, d, J = 7.8 Hz, 6H; 1.37, s, 9H: 1.46, m. IH; 1.58, m, IH; 1.68, m, IH: 4.40, m,
IH: 5.99, d, J = 7.8 Hz, NH: 5.35, s, 2H: 7.18. dist t, IH: 7.27, d, J = 8.3 Hz, 2H. MS (ES +ve) m/z 333.2 (100%)
[M+H-C4H8]+: 289.9 (50) [M+H-BOC]+.


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To 8(i) (380 mg, 0.974 ramol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
temperature for 1 hr. The solution was then diluted with ethyl acetate (20 ml) and washed with sat. sodium
bicarbonate solution added until the washings were basic. The organic layer was then separated and the aqueous
layer extracted once more with ethyl acetate (10 ml). The combined organic layers were dried (MgSO^, filtered and
evaporated to dryness to yield the desired product 8(ii) as a white solid (275 mg, 97%).
1H NMR (500 MHz, CDCl3) d0.84, d, J = 7.0 Hz, 3H: 0.86, d, J = 8.0 Hz, 3H: 1.48, m, IH; 1.57, m, IH; 1.73, m,
IH; 3.58, m. IH: 3.76, s, NH2: 5.35. ABq, J = 11.8 Hz, IH: 5.38. ABq. J = 11.8 Hz. IH: 7.19. dist t. IH: 7.29, d..J
=7.9 Hz, 2H. MS (ES +ve) m/z 290 (100%) [M+H]+.

This compound was prepared in two steps. The first step via Protocol 1. using 8(11) (120 mg, 0.41 mmol) and Fmoc-
(D)-arg(Pbf)-OH (260 mg, 0.40 mnol) in yield the Finoc protected precursor 8(iii) as a white foamy solid (MS (ES
+ve) m/z 900 (100%) [M+H]+). This was then deprotected via Protocol 2 to afford the desired compound 8(iv) as a
white solid (178 mg, 64% two steps).

This compound was prepared via Protocol I. using 6(vi) (160 mg. 0.25 mmol) and 8(iv) (175 mg. 0.25 mmol) to
yield 8(v) as a white solid (231 mg. 69%).
1HNMR (300 MHz, CDC13) d 0.81, d, J =5.9 Hz, 3H: 0.83, d, J = 5.9 Hz, 3H: 1.21, s, 6H; 1.51,m, 5H: 1.71, m,
3H: 2.01, s, 3H: 2.02, m, IH: 2.47, s, 3H; 2.49, s, 3H: 2.53, m, 2H: 3.08, m, 2H: 3.33, m, IH: 4.46, m, IH: 5.10,
ABq. J = 12.9 Hz. IH: 5.15. ABq. / = 12.9 Hz. IH: 6.34, br s. NH: 7.16. m. 2H: 7.30, m. 2H: 7.75. d,.J = 7.8 Hz,
NH. MS (ES +ve) m/z 678 (100%) [M+H]+.

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1H NMR (300 MHz, CDCl3) d 0.46, d, J = 6.2 Hz, 3H: 0 52, d, J = 6.5 Hz, 3H; 0.79. m, 2H: 0.86. d, J = 6.7 Hz, 3H;
0.88, d, J = 6.7 Hz, 3H; 0.94, m. IH; 1.19, m, 6H; 1.41, s, 6H; 1.43, s, 9H; 1.64, m, 5H; 1.83, m, 2H; 2.07, s, 3H;
2.51. s. 3H; 2.58, s, 3H; 2.92, s, 2H; 3.08, m, 2H; 3.16, m, 2H; 3.88, m, IH; 4.05, m, 2H; 4.48, m, 5H; 4.86, m,NII;
5.37, ABq, J = 11.9 Hz, IH; 5.44, ABq, J = 11.9 Hz, IH; 6.20, d, J = 7.0 Hz, NH; 6.32, br s, NH; 7.25, m, 1OH;
7.47, d, J = 9.1 Hz, IH; 7.85, d, J = 7.9 Hz, 2H; 7.95, d, J = 9.4 Hz, IH; 7.98, d, J = 9.7 Hz, IH. MS (ES +ve) m/z
1322.3 (60%) [M+H] + ; 612.8 (100) [M+2H-BOC]2+.

This compound was prepared via Protocol 3, using 8(v) (185 mg, 0.138 mmol) to yield 8 as a white solid (78 mg,
98%).
1H NMR (300 MHz, CD3OD) d 0.50, d, / = 6.3 Hz, 3H; 0.56, a, J = 6.4 Hz. 3H; 0.87, d,./ = 5.2 Hz, 3H; 0.92, d, J
= 5.2 Hz, 3H; 0.99, m, 2H; 1.23, m, 4H; 1.66, m, IOH: 2.86, m, 2H; 3.19, m, 2H; 3.96, m, IH; 4.16, m, 2H; 4.49, m,
4H; 5.38, ABq, / = 11.7 Hz, IH; 5.44, ABq, J= 11.7 Hz, IH; 7.10. m, 2H; 7.17, m,2H; 7.32, m, 3H; 7.39, m, 2H;
7.46. d, J =9.0 Hz, IH; 7.57, d, J = 9.0 Hz, IH; 7.87, d, J =8.1 Hz, IH; 7.93, d, J= 8.1 Hz, IH; 7.99, d, J = 9.0 Hz,
IH; 8.04. d, J =9.0 Hz, IH. MS (ES +ve) m/z 969.8 (10%) [M+H]+; 485.7 (100) [M+2H]2+.

To BOC-(L)-LeU-OH (250 mg, 1.08 mmol) and potassium carbonate (747 mg, 5.40 mmol) in acetone (50 mL) was
added 4-methylbenzyl bromide (300 mg, 1.62 mmol). The resulting solution was heated at reflux overnight before
being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column
chromatography over silica, eluting with 1:4 hexane/DCM to first remove 4-chlorobenzyl bromide, then with DCM
to yield the product 9(i) as a colourless oil (340 mg. 94%).
1H NMR (300 MHz, CDCl3) d 0.91. d, J = 6.5 Hz. 3H; 0.92. d, J = 6.2 Hz. 3H; 1.43. s. 9H: 1.49. m, 2H; 1.66, m.
IH; 2.35, s. 3H; 4.35. m, IH; 4.95. d, J = 9.2 Hz, NH: 5.08, ABq, J= 12.3 Hz. IH; 5.14. ABq. J = 12.3 Hz. IH;

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56.
7.16, ABq, J = 7.9 Hz, 2H: 7.24, ABq, J - 7.9 Hz, 2H. MS (ES +ve) m/z 353.3 (100%) [M+H2O]+; 336.3 (90)
[M+H]+.

To 9(i) (340 mg, 1.01 mmol) in DC'M (2 mL) was added TFA (2 mL) and the resulting solution stirred at room
temperature for 3 hrs. The solution was then diluted with DC'M (5 mL) and washed with sat. sodium bicarbonate
solution until the washings were basic. The organic layer was then dried (MgSO4), filtered and evaporated to
dryness to yield the desired product 9(ii) as a white solid (215 mg, 90%).
1HNMR (300 MHZ, CDCl3) d 0.90, d, J = 6.5 Hz, 3H; 0.92, d, J = 6.7 Hz, 3H: 1.43, m, IH; 1.55, m, IHZNH2: 1.76,
m. IH: 2.35, s, 3H: 3.49, m, IH: 5.10, s. 2H: 7.18, ABq. J = 7.9 Hz, 2H; 7.25, ABq. J = 7.9 Hz, 2H. MS (ES +ve)
m/z 236.0 (100%) [M+H]+.

This compound was prepared via Protocol 1 using 9(ii) (215 mg, 0.914 mmol) and Fmoc-(D)-arg(Pmc)-OH (606 mg,
0.914 mmol) to yield the desired product 9(iii) as an off white solid (780 mg, 97%).
1H NMR. (500 MHz, CDCl3) d 0.78, m, 6H: 1.28, s, 6H: 1.61, m, 8H. 1.91, m, IH: 2.01, s, 3H; 2.26, s, 3H; 2.50, m,
2H; 2.54, s, 3H: 2.57, s, 3H; 3.23, m, 2H: 4.03, m, IH; 4.25, m, 3H; 4.52, m, IH: 4.97, ABq. J = 12.2 Hz, IH; 5.03.
ABq, J = 12.2 Hz, IH; 6.42. br s, NH; 7.06, ABq, J = 7.7, Hz, 2H: 7.13. ABq, J = 7.7, Hz, 2H: 7.17, m, 2H; 7.31,
dd, J1 =1.5 Hz, J2 = 7.5 Hz, 2H; 7.51. m, 2H: 7.68. d, J = 7.5 Hz, 2H. MS (ES +ve) m/z 658.1 (100%) [M+H-
Fmoc]+.


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This compound was prepared via Protocol 2, using 9(iii) (650 mg, 0.739 mmol) to yield the desired product 9(iv) as
a colourless oil (409 mg, 84%).
1HNMR (500 MHz, CDC13) d 0.86, d, J =5.9 Hz, 3H; 0.88, d, J = 5.4 Hz, 3H; 1.28, s, 6H: 1.58, m, 5HZNH2: 1.77,
m, 3H: 2.00, m, IH; 2.09, s, 3H: 2.31, s, 3H; 2.54, s, 3H; 2.56, s, 3H; 2.59, m, 2H; 3.15, m, 2H; 3.40, m, IH; 4.49, m,
IH; 5.01, ABq, J = 12.2 Hz, IH; 5.08, ABq, J = 12.2 Hz, IH; 6.42, br s, NH; 7.11, ABq. J = 8.0, Hz, 2H; 7.18,
ABq, .7 = 8.0, Hz, 2H; 7.81, d, J = 7.8 Hz. NH. MS (ES +ve) m/z 658.1 (100%) [M+H]+.

This compound was prepared via Protocol I. using 9(iv) (377 mg, 0.573 mmol) and Fmoc-(£>)-lys(BOC)-OH (268
mg, 0.573 mmol) to yield the desired product 9(v) as an off white solid (575 mg, 91%).
1HNMR (500 MHz. CDCl3) d0.82, m. 6H; 1.19, s, 6H; 1.39, s, 9H; 1.58, m, 13H; 2.02, s, 3H; 2.28, s, 3H; 2.49, m,
2H: 2.53, s, 3H: 2.55, s, 3H: 3.02, m, 2H; 3.19, m, 2H; 3.93, m. IH; 4.19, m, 2H: 4.25, m, IH; 4.53, m, 2H; 4.98, m,
2H; 6.23, m. NH; 6.50, br s.NH; 7.07, m, 2H; 7.1 1. m, 2H; 7.22, m, 2H; 7.33, m, 2H; 7.53, m, 2H; 7.68, m, 211. MS
(ES +ve) m/z 1108.3 (100%) [M+II]+.

This compound was prepared via Protocol 2, using 9(v) (290 mg, 0.262 mmol) to yield the desired product 9(vi) as
an off white solid (162 mg. 70%).
1H NMR (500 MHz. CDCl3) d 0.85. d, J = 6.3 Hz. 3H; 0.87, a, .7 = 6.3 Hz, 3H: 1.29. s, 6H; 1.40. s. 9H; 1.58, m,
10HZNH2; 1.78. dist t. 2H; 1.89. m. IH: 2.09. s, 3H: 2.32. s. 3H: 2.54. s, 3H: 2.56. s, 3H: 2.61. m, 2H: 3.05. m, 2H:
3.22. m, 2H; 3.36. m. IH; 4.54. m. 2H: 4.95. m. NH: 5.01. ABq. .7 = 12.2 Hz. IH: 5.07, ABq. J - 12.2 Hz. IH: 6.42.

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58.
br s, NH: 7.12, ABq, J = 7.8 Hz, 2H: 7.18. ABq. J = 7.8 Hz, 2H: 7.60, d, J = 7.3 Hz, NH: 8.00, d, J = 6.4 Hz. NH.
MS (ES +ve) m/z 886.3 (100%) [M+H]+.

This compound was prepared via Protocol 1. using I(ii) (75 mg, 0.181 mmol) and 9(vi) (160 mg, 0.181 mmol) to
yield the desired product 9(vii) as a white solid (193 mg, 83%).
1H NMR (500 MHz, CDCl3) d 0.47, d, J = 6.5 Hz, 3H; 0.53, d, J = 6.5 Hz, 3H: 0.78, m, IH; 0.87, d, J = 5.8 Hz, 3H;
0.89, d. J = 5.8 Hz, 3H: 0.91, m, IH: 1.22. m, 8H; 1.28, s, 6H; 1.42, s. 9H; 1.62, m, 3H; 1.76, dist t, 2H; 1.82, m, IH;
2.09, s, 3H: 2.33, s, 3H: 2.55, s, 3H; 2.57, s, 3H; 2.59, m, 2H; 2.91, m, 2H; 3.16, m, 2H; 3.88, m, IH; 4.05, m, 2H;
4.49, m, 4H; 4.84, m, NH; 5.04, ABq, J = 12.2 Hz, IH; 5.13, ABq, J = 12.2 Hz, IH; 6.19, d, J = 6.4 Hz, NH; 6.27,
s, NH; 7.22, m. HH; 7.46, d, J = 9.1 Hz, IH; 7.85, dist t, 2H; 7.94, dist t, 2H. MS (ES +ve) m/z 1282 (100%)
[M+H]+.

This compound was prepared via Protocol 3, using 9(vii) (107 mg, 0.083 mmol) to yield the product 9 as a white
solid (28 mg, 34%).
1H.NMR (.300 MHz, CD3OD) d 0.38, d, J = 6.2 Hz, 3H; 0.43. d, J = 6.2 Hz, 3H; 0.85. m, 8H; 1.07, m, 2H; 1.18. m,
2H: 1.59, m, 9H; 2.25. s, 3H; 2.74, m, 2H; 3.09, m, 2H; 3.90, m, IH; 4.06, m, 2H; 4.34, m, 3H; 4.40, ABq, J = 14.7
Hz. IH; 4.51. ABq. J = 14.7 Hz. IH: 4.99. ABq. J = 12.1 Hz, IH; 5.05, ABq. J = 12.1 Hz. IH: 6.99. d, J = 8.5Hz.
IH: 7.01. d, J= 8.5 Hz, IH: 7.09. d, J = 7.8 Hz. IH: 7.15, m, 4H: 7.27, m. 3H; 7.41, d, J = 9.0 Hz. IH; 7.49, dd, J1
= 9.1 Hz. J2 = 11.6 Hz. IH; 7.84, m. 2H; 7.95. m. 2H. MS (ES +ve) m/z 916 (5%) [M+II]+; 812 (10) [M+H-
pMeBzt: 459 (95) [M+2H]2+:407 (100) [M+2H-pMeBz]2+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using (R)-l(ii) (67 mg, 0.162 mmol) and l(viii) (140 mg, 0.161 mmol)
to yield the desired product 10(i) as a white solid (108 mg, 53%).
1H NMR (300 MHz, CDCl3) d0.51, d, J = 6.3 Hz, 3H: 0.56. d, J = 6.3 Hz, 3H; 0.84, d, J = 5.4 Hz, 3H; 0.86, m, 3H;
0.88, d, J = 5.4 Hz, 3H; 1.21, m, 6H; 1.25, s, 6H; 1.29, m, 2H; 1.43, s, 9H: 1.64, m, 4H; 1.76, m, 2H; 1.84, m, IH;
2.09, s, 3H; 2.52, s, 3H; 2.54, s, 3H: 2.58, m, 2H; 2.94, m, 2H; 3.11, m, 2H; 3.89, m. IH: 3.99, m, 2H; 4.35, m. IH;
4.37, ABq, J = 14.7 Hz, IH: 4.90, m, IH; 4.58, ABq, / = 14.7 Hz., IH; 4.90, m, NH; 5.04, ABq, J = 12.3 Hz, IH;
5.13, ABq, J = 12.3 Hz, IH: 6.10, br s NH; 6.19, br s, NH; 7.45, m, 12H; 7.44, d, J = 9.3 Hz, IH; 7.82, d, J = 8.3
Hz, IH: 7.84. d, J = 8.3 Hz, IH: 7.89, d, / = 8.8 Hz, IH: 7.94, d, J = 8.8 Hz, IH. MS (ES +ve) m/z 1268 (50%)
[M+H]+;585 (100) [M+2H-BOC]2+.

This compound was prepared via Protocol 3, using 10(i) (105 mg, 0.083 mmol) to yield an impure product. Protocol
3 was repeated on 80 mg of this product to yield 10 as an off white solid (58 mg, 82%).

1H NMR (300 MHz, CD3OD) d 0.41, d, J = 6.6 Hz, 3H; 0.46, d, J = 6.6 Hz, 3H: 0.78, d, J = 5.7 Hz. 3H: 0.83. d. J
= 5.7 Hz, 3H: 1.06. m, 6H: 1.38, m, IH: 1.53, m, 8H; 1.72, m. IH: 2.78, m. 2H; 3.05, m. 2H; 3.84. m, IH: 3.97, m.
IH; 4.02. m, IH: 4.25, m. IH; 4.35, m, 2H; 4.51, ABq, J = 15.0 Hz. IH: 5.00, ABq. J = 12.3 Hz. IH; 5.05. ABq,.J
= 12.388 Hz. IH; 6.96. d, J = 8.7 Hz, IH; 7.05. d, J = 8.4 Hz. IH: 7.13. m. 2H: 7.24. m. 7H; 7.38. d. J = 9.0 Hz. IH:

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7/15, d, J = 9.0Hz, IH; 7.80, d, J= 8.1 Hz, IH: 7.84 d, J =7.8 Hz, IH; 7.91, d, J = 9.0 Hz, IH; 7.96, d, J= 8.7 Hz,
IH. MS (ES +ve) m/z 902 (10%) [M+H]+; 452.0 (100) [M+H]2+.

To a solution of l,l'-t>iphen-2,2'-diol (0.21 g, 1.15 mmol) in dry acetone (25 ml) was added potassium carbonate
(1.62 g, 12.0 mmol). To the resulting suspension a solution of l-bromo-3-methylbutane (0.18 ml, 1.50 mmol) in dry
acetone (10 ml) was added portionwise over 90 minutes. The reaction mixture was then heated at reflux for 18 hours.
The cooled mixture was filtered and the solid residue was washed with acetone (2 x 20 ml). The combined filtrate
and washes were concentrated in vacua to yield the product ll(i) as a colourless oil (292 mg, 99%).

1H NMR (300 MHz, CDCl3) d 0.95, d, J =6.2 Hz, 6H; 1.71, m, 3H; 4.13, t,J =6.4 Hz, 2H: 7.25, m, 8H. MS (EI)
m/z 256 (30%) [M]+: 186 (100) [M-(CH2CH2CH(CH3)2)]+.

To a solution of ll(i) (0.29 g, 1.13 mmol) in methanol (20 ml) was added potassium carbonate (1.83 g, 13.2 mmol)
and bromoacetic acid (0.56 g, 4.03 mmol) and the resulting suspension was heated at reflux for 16 hours. The cooled
reaction mixture was concentrated in vacuo and the residue was dissolved in distilled water (100 ml) then washed
with ether (3 x 20 ml). The aqueous solution was acidified (10% HCl) and extracted with DCM (3 x 20 ml). The
combined organic layers were dried (MgSO4) and concentrated in vacuo to yield the title compound ll(ii) as a thick
colourless oil (111 mg, 30%).
1H NMR (300 MHz. CDCl3) d 0.77. d. J = 4.4 Hz, 6H: 1.45. m, 3H; 3.99, t, J =6.5 Hz, 2H: 4.62. s, 2H: 6.87, dd, J =
8.2. 0.9 Hz, IH; 7.08, m, 3H: 7.31. m, 4H. MS (ES +ve) m/z 353 (12%) [M+K] + : 337 (39) [M+Na]+: 332 (96)
[MH-NH4]:315 (100) [M+H]+;245 (38).

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol l. using (R)-Lysine(Boc)-methyl ester (0.10 g, 0.38 mmol) and ll(ii)
(0.11 g. 0.34 mmol) in anhydrous acetonitrile (10 ml) with EDCI (0.09 g. 0.45 mmol) and HObt (0.08 g. 0.58
mmol). Purification with 1-2% methanol:DCM gave product II(iii) as a pale yellow oil (179 mg, 93%).
1H NMR (300 MHz, CDCl3) d 0.76, dd, J = 6.4 Hz, 6H; 1.08, m, 2H; 1.43, m, 12H; 1.67, m, 2H; 3.00, m, 3H: 3.66,
s, 3H; 3.90, m, 3H: 4.44, m, 4H; 6.74, br d, J = 8.5 Hz, IH; 8.86, d, J = 7.9 Hz, IH; 7.03, m, 3H; 7.27, m, 4H. MS
(ES +ve) m/z 579 (11%) [M+Na]+:557 (100) [M+H]+;457 (29) [M-Boc+H]+;233 (88).

To a solution of Il(iii) (0.18 g, 0.32 mmol) in THRwater (4:1) (15 ml) was added lithium hydroxide (0.11 g, 2.60
mmol) and the resulting solution was stirred at 20 °C for 16 hours. The reaction mixture was diluted with water (5
ml), acidified with 10% HCl and extracted with DCM (4 x 10 ml). The combined organic layers were dried (MgSO4)
and concentrated in vacuo to give the product ll(iv) as a pale yellow oil (108 mg, 62%).

1H NMR (500 MHz, CDCl3) d 0.77, dd, J =6.3, 4.4 Hz. 6H; 1.13, m, 2H; 1.44, m, 14H; 1.75, br s, IH; 3.12, m, 2H:
3.94, m, 2H; 4.49, ABq, J= 14.6 Hz, 2H: 4.64, m, IH: 6.87, m, 2H; 6.99, m, 2H: 7.05, t, J =7.8 Hz, IH: 7.26, m,
4H. MS (ES +ve) m/z 543, (100%) [M+H]+:487 (46) [M+H-56]+:443 (46) [M+H-Boc]+.


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62.
This compound was prepared in two steps. The first step via Protocol 1, using l(iv) (1.12 g, 5.06 ramol) and Fmoc-
(D)-arg(Pbf)-OH (3.06 mg, 4.72 mmol) to yield the Fmoc protected precursor ll(v) as a white foamy solid (MS (ES
+ve) m/z 852 (100%) [M+H]+). This was then deprotected via Protocol 2 to afford the desired compound Il(vi) as a
yellow oil (1.54 g, 52% two steps).
MS (ES +ve) m/z 630 (100%) [M+H]+

This compound was prepared via Protocol 1. using Il(iv) (70 mg, 0.13 mmol) and ll(vi) (77 mg, 0.12 mmol) in
anhydrous acetonitrile with EDCI (40 mg, 0.21 mmol) and HObt (39 mg, 0.29 mmol). Purification with 1-2%
methanol:DCM gave product ll(vii) as a clear colourless oil (103 mg, 71%).
1H NMR (300 MHz, CDCl3) d 0.77, dd, J = 6.4, 1.8 Hz, 6H; 0.88, dd, / = 7.3, 7.3 Hz, 6H: 1.08, m, 2H: 1.43, m,
23H: 1.63, m, 5H; 1.83, m, IH; 2.05, s, 3H; 2.47, s, 3H; 2.54, s, 3H: 2.91, s, 2H; 3.00, m, 2H; 3.17, m, 2H; 3.93, m,
2H: 4.46. m, 5H; 4.85, m, IH; 5.14, ABq, J = 12.3 Hz, 2H; 6.15, br s, 2H: 6.79, m, 2H; 7.01, m, 3H; 7.28, m, 1OH:
7.61, br d, IH. MS (ES +ve) m/z 1153 (100%) [M+H]+; 527 (68); 288 (98).

This compound was prepared via Protocol 3, using Il(vii) (95 mg, 82 \gmmol) and TFAITIPSIH 2O (95:2.5:2.5) (2 ml).
Precipiation from methanol using ether (3 times) gave the product 11 as off-white crystals (67 mg, 93%).
1H NMR (300 MHz. CD3OD) d 0.78. dd. J = 6.4. 1.2 Hz. 6H; 0.91. dd. J = 14.4. 5.6 Hz. 6H; 1.25. m. 2H: 1.55. m.
14H; 2.89. m, 2H; 3.16, m, 2H: 3.96. m, 2H: 4.44. m, 5H: 5.14. ABq. J= 10.7 Hz. 2H: 7.02. m.4H: 7.23. m. 2H;
7.35. m. 7H. MS (ES +ve) m/z 802 (4%) [M+H]+;401 (100) [M+H]2.

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To BOC(L)-LcU-OH (300 mg, 1.30 mmol) and potassium carbonate (0.4 g, 2.90 mmol) in acetone (25 ml) was
added 4-bromo-l-methylbutane (0.2 ml, 1.60 mmol). The resulting solution was heated at reflux overnight before
being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column
chromatography over silica, eluting with DCM to yield the product 12(i) as a colourless oil (172 mg, 44%).
1HNMR (300 MHz, CDCl3) d 0.94, m, 12H; 1.44, s,9H; 1.55,m,4H; 1.70, m, 2H; 4.14, dt, J1 =6.8 Hz, J2 =2.0 Hz,
2H. 4.29, m, IH; 5.04, d, J = 8.3 Hz, NH. MS (ES +ve) m/z 302.1 (100%) [M+H]+; 246.1 (70) [M+H-ZBuf; 202.1
(70) [M+H-BOC]+.

To 12(i) (170 mg, 0.592 mmol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
temperature for 1 hr. The solution was then diluted with ethyl acetate (10 ml) and washed with sat. sodium
bicarbonate solution until the washings were basic. The organic layer was then dried (MgSO4), filtered and
evaporated to dryness to yield the desired product 12(ii) as a white solid (93 mg, 78%).
1H NMR (300 MHz, CDCl3) d 0.93, m, 12H: 1.43, m. IH: 1.55, m, 3H/NH2: 1.73, m, 2H: 3.45, dd, J1 - 8.2 Hz, J2 =
5.9 Hz, IH: 4.14, t, J = 6.9 Hz, 2H. MS (F.,S +ve) m/z 202.0 (100%) [M+H]+.

This compound was prepared via Protocol 1 using 12(ii) (90 mg, 0.481 mmol) and Fmoc-(D)-arg(Pmc)-OH (160 mg.
0.241 mmol) to yield the desired product 12(iii) as an off white solid (198 mg. 97%).

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1H NMR (300 MHz, CDCl3) d 0.84, m, 12H: 1.21, s,3H: 1.22, s, 3H; 1.47,m, 2H; 1.60, m,9H: 1.90, m, IH: 2.05, s,
3H; 2.51, m, 2H; 2.55, s, 3H; 2.58, s, 3H; 3.24, m, 2H; 4.05, m, 3H; 4.24, m, 3H: 4.47, m, IH: 6.26, br s, NH: 6.35.
d. J -8.0 Hz, NH; 6.40, br s, NH; 7.18, t, J = 7.4 Hz, 2H; 7.32, t, J = 7.5 Hz, 2H; 7.37, d. J = 7.7 Hz, NH: 7.51, d, J
=7.4 Hz, 2H; 7.69, d, J = 7.5 Hz, 2H. MS (ES +ve) m/z 846.0 (100%) [M+H]+.

This compound was prepared via Protocol 2, using 12(iii) (150 mg, 0.177mmol) to yield the desired product 12(iv)
as a colourless oil (101 mg, 91%).
1H NMR (300 MHz, CDCl3) d 0.92, m, 12H; 1.30, s, 6H: 1.52, m, 3H; 1.62, m, 4H/NH2: 1.80, m, 5H: 2.10, s, 3H;
2.55, s. 3H; 2.57, s, 3H: 2.62, t, J =6.7 Hz, 2H: 3.19, m, 2H: 3.40, m, IH: 4.11, m, 2H; 4.46, m. IH: 6.31, br s, NH;
6.38, br s, NH: 7.76, d, J =8.0 Hz, NH. MS (ES +ve) m/z 624.0 (100%) [M+H]+.
12(v)

This compound was prepared via Protocol 1. using 6(vi) (75 mg, 0.117 mmol) and 12(iv) (86 mg, 0.138 mmol) to
yield 12(v) as a light brown solid (122 mg, 84%).
1H NMR (300 MHz, CDCl3) d 0.47, d, J = 6.6Hz, 3H; 0.52, d, J = 6.6 Hz, 3H; 0.76, m, 2H; 0.91, m, 12H; 1.18, m,
6H: 1.27, s. 6H; 1.41, s, 9H: 1.53, m. 5H: 1.63, m, 5H: 1.77, m, 3H; 2.09, s, 3H; 2.55, s, 3H; 2.57, s, 3H; 2.60. m,
2H:2.92, m, 2H; 3.19, m,2H: 3.89, m, IH: 4.11, m, 4H; 4.43. m,4H; 4.84, m, NH: 6.19, d, J= 7.7 Hz, NH; 6.28. br
s. NIT: 7.26. m. 7H: 7.46. d, J = 9.2 Hz, IH; 7.84, d, J = 8.9 Hz. IH: 7.86, d, J = 8.8 Hz, IH: 7.93, d. J = 9.3 Hz, IH;
7.96. a. J = 9.5 Hz. IH. MS (ES +ve) m/z 1247.9 (40%) [M+H]+. 574.7 (TOO) [M+2H-BOC]2+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 3, using 12(v) (120 mg, 0.096 mmol) to yield 12 as an off white solid (84
mg, 92%).
1H NMR (300 MHz. CD3OD) d 0.52, d. / = 6.6 Hz. 3H; 0.57, d. / = 6.6 Hz. 3H: 0.91. m. 14H; 1.14, m. 2H;
1.26, m. 2H; 1.54, m. 5H; 1.65, m. 7H; 1.84, m. IH: 2.82. m. 2H; 3.18, m. 2H; 3.95. m. IH; 4.14. m. 4H; 4.36.
m. 2H: 4.46. ABq. / = 14.6 Hz. IH; 4.58. ABq. / = 14.6 Hz. IH: 7.07. dist t. 2H: 7.21. dist t. 2H; 7.34. dist t.
2H; 7.47, d. / = 9.3 Hz. IH; 7.56, d. / = 9.3 Hz. IH; 7.91, dist t. 2H; 8.03, dist t. 2H. MS (US +ve) m/z 882.0
(5%) [M+H]+; 441.6 (100) [M+2H]2+.

To BOC-(L)-Leu-OH (200 mg, 0.865 mmol) and potassium carbonate (400 mg, 2.89 mmol) in acetone (40 ml) was
added (2-bromoethyl)benzene (0.14 ml, 1 mmol). The resulting solution was heated at rellux overnight before being
cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column chromatography over
silica, eluting with 5% ethyl acetate/hexane to first remove (2-bromoethyi)benzene. then with DCM to yield the
product 13(i) as a colourless oil (235 mg, 81%).
1H NMR (500 MHz, CDCl3) d 0.86, d, J = 6.6 Hz, 3H; 0.88, d, J = 6.6 Hz, 3H: 1.42, s. 9H: 1.47, m, 2H; 1.54, m,
IH; 2.92, t, J = 7.0 Hz, 2H; 4.31, m, 3H; 5.04, d, / = 8.3 Hz, NH; 7.19, m, 3H. 7.26, m. 2H. MS (ES +ve) m/z
374.2 (80%) [M+K]+; 358.3 (100) [M+Na]+; 336.3 (10) [M+H]+; 236.2 (50) [M+H-BOC]+


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To 13(i) (230 rng, 0.686 mmol) dissolved in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at
room temperature for 2 hrs. Ethyl acetate (15 ml) was then added and the solution washed with sat. sodium
bicarbonate solution until the washing were basic. The organic layer was then dried (MgSO4) and evaporated to
dryness to yield the desired product 13(ii) as a yellow oil (140 mg, 87%).
1HNMR (500 MHz, CDCl3) d 0.87, a. J = 5.7 Hz, 3H; 0.89, a, J = 5.7 Hz, 3H: 1.35, m, IH; 1.48, m, IH: 1.69, m,
IH; 1.89, m,NH2: 2.94, t, J= 7.0 Hz, 2H; 3.42, dd, J1 = 8.3 Hz, J2 = 5.9 Hz, IH: 4.33, m,2H: 7.21, m, 3H; 7.28, m,
2H. MS (ES +ve) m/z 236.2 (100%) [M+H]+.

This compound was prepared in two steps. The first via Protocol 1, using using 13(Ii) (92 mg, 0.391 mmol) and
Fmoc-(D)-arg(Pmc)-OH (265 mg, 0.400 mmol) to yield the Fmoc protected precursor 13(ui) as a colourless oil (308
mg, 90% MS (ES +ve) m/z 880.2 (100%) [M+H]+). The desired product was then prepared via Protocol 2, using
13(Hi) (280 mg. 0.318 mmol) to afford the product 13(iv) as a colourless oil (123 mg, 59%).

1HNMR (300 MHz, CDCl3) d 0.85, d, J= 5.7 Hz, 3H; 0.86, d, J =5.9 Hz, 3H: 1.29, s, 6H: 1.53, m,4HTNH2: 1.78,
m, 5H: 2.09, s, 3H: 2.54, s, 3H: 2.56, s, 3H: 2.60, m, 2H: 2.91, t, J = 7.0 Hz, 2H; 3.17, m, 2H: 3.37, m, IH: 4.29, m,
2H: 4.43. m, IH: 6.33, br s, NH; 6.38. br s, NH: 7.22, m, 5H: 7.73, a, J - 8.0 Hz, NH. MS (ES +ve) m/z 658.0
(100%) [M+H]+: 554.1 (60) [M+H-EtPh]+.

This compound was prepared via Protocol 1. using 6(vi) (107 mg. 0.166 mmol) and 13(iv) (107 mg, 0.167 mmol) to
yield 13(v) as a white solid (118 mg, 55%).
1H NMR (300 MHz, CDCl3) d 0.46. d. J = 6.3 Hz. 3H; 0.51. d, J = 6.3 Hz. 3H: 0.77. m, 2H: 0.89. m, 6H: 1.19. m.
3H. 1.27. s. 6H: 1.41. s. 9H; 1.54, m, 5H; 1.76. m. 4H: 2.09. s. 3H: 2.54. s. 3H; 2.56. s. 3H: 2.61. m. 2H: 2.91. m.

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2H: 2.93. t. J = 7.1 Hz: 3.15, m. 2H: 3.87. m, IH: 4.04. m, 2H: 4.42, m.4H: 4.82. m, NH: 6.18. d. J= 7.1 Hz. NH;
6.28, br s, NH; 7.21. m. 12H; 7.43, a, J - 9.1 Hz, IH; 7.83, d, J =7.8 Hz, IH: 7.85, a, J = 7.8 Hz, IH: 7.92, d, J =
9.0 Hz. IH: 7.93. d, J= 8.9 Hz, IH. MS (ES+ve) m/z 1282.0 (80%) [M+H]+: 591.7 (100) [M+2H-BOC]2+.

This compound was prepared via Protocol 3, using 13(v) (110 mg, 0.086 mmol) to yield 13 as a white solid (80 mg,
96%).
1H NMR (300 MHz, CD3OD) d 0.50, d, J = 6.2 Hz, 3H: 0.55, d, J = 6.2 Hz, 3H: 0.85, d, J = 6.1 Hz, 3H; 0.89, d, J
= 6.1 Hz, 3H; 0.96, m, 2H: 1.16, m, 5H: 1.57, m, IOH: 1.81, m, IH; 2.80, m, 2H; 2.93, t, J - 6.7 Hz, 2H; 3.16, m,
2H; 3.94, m, IH; 4.14, m, 2H; 4.34, m, 2H; 5.45, ABq, J = 14.8 Hz, IH; 5.56, ABq, J = 14.8 Hz, IH; 7.04, a, J =
4.3 Hz, IH; 7.07, d, J =4.3 Hz, IH; 7.22, m, 9H; 7.45, d, J = 9.0 Hz, IH: 7.53, d, J = 9.0 Hz, IH; 7.88, d, J = 7.6
Hz, IH; 7.91, d, J = 7.3 Hz, IH: 7.99, d, J = 9.0 Hz, IH; 8.00, d. J = 9.0 Hz, IH. MS (ES +ve) m/z 915.9 (5%)
[M+H]+; 458.9 (100) [M+2H]2+.

This compound was prepared via Protocol 1. using BOC-(L)-IeU-OH (200 mg, 0.865 mmol) and benzylamine (0.1
ml, 0.916 mmol) to yield the desired product 14(i) as an off white solid (239 mg, 86%).
1H NMR (500 MHz, CDCl3) d 0.86, d, J = 6.8 Hz, 3H; 0.88, d, J = 6.8 Hz, 3H; 1.34, s, 9H: 1.53, m, 2H; 1.64, m,
IH: 4.30, m,3H; 5.57, d, J= 7.7 Hz, NH; 7.17, m,5H, 7.50, m,NH. MS (ES +ve) m/z 359.2 (100%) [M+K]+: 343.3
(20) [M+Na]+:321.3 (20) [M+H]+: 222.3 (40) [M+H-BOC]+.

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To 14(i) (230 mg, 0.719 mmol) dissolved in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at
room temperature for 2 hrs. Ethyl acetate (15 ml) was then added and the solution washed with sat. sodium
bicarbonate solution until the washing were basic. The organic layer was then dried (MgSO4) and evaporated to
dryness to yield the desired product 14(H) as a colourless oil (65 mg, 41%).
1H NMR (300 MHz, CDCl3) d 0.93, d, J = 5.6 Hz, 3H: 0.96, d, J = 5.6 Hz, 3H; 1.37, m, IH: 1.68, br s, NH2; 1.73,
m, 2H: 3.43, m, IH: 4.42, d, J = 5.8 Hz, 2H; 7.27, m, 2H: 7.32, m, 3H: 7.69, m, NH. MS (ES +ve) m/z 221.2 (100%)
[M+H]+

This compound was prepared in two steps. The first step via Protocol 1. using 14(ii) (60 mg, 0.272 mmol) and
Fmoc-(Z))-arg(Pmc)-OH (176 mg, 0.272 mmol) to yield the Fmoc protected precursor 14(Ui) as a white foamy solid
(156 mg, 67%. MS (ES +ve) m/z 851.2 (100%) [M+H]+). The desired product was then prepared via Protocol 2,
using 14(iii) (156 mg, 0.183 mmol) to afford the product 14(iv) as a white solid (85 mg, 74%).
1HNMR (300 MHz, CDCl3) d 0.83, m, 6H: 1.44, s, 9H: 1.62. m. 6HZNH2: 1.80. m, IH: 2.05. s, 3H: 2.43, s, 3H:2.51,
s, 3H: 2.90, s. 2H: 3.15, m, 2H: 3.62, m, IH; 4.25, m, 2H: 4.45, m. IH: 6.54. br s, NH: 7.14, m, 5H: 7.72, dd, J1=
7.8 Hz, J2 = 16.0 Hz, NH; 8.25, m, NH. MS (ES +ve) /m/z 29.0 (100%) [M+H]+.
14(v)


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This compound was prepared via Protocol 1. using 6(vi) (82 mg. 0.127mmol) and 14(iv)(80 mg, 0.127 mmol) to
yield 14(v) as a white solid (63 mg, 41%).
1H NMR (300 MHz, CDCl3) d 0.44, a, J= 6.5 Hz, 3H; 0.49, A. J = 6.5 Hz, 3H; 0.79, d, J = 6.3 Hz, 3H: 0.83, d,.J =
6.3 Hz, 3H; 0.85, m, 2H; 1.11, m, 4H; 1.26, m, 4H; 1.40, s, 6H: 1.43, s, 9H; 1.69, m, 5H; 1.95, m, IH; 2.04, s, 3H;
2.46, s, 3H; 2.52, s. 3H; 2.90, s, 2H; 2.93, m, 2H; 3.19, m, 2H; 3.80, m, IH; 4.13, m, 2H; 4.30, m, 5H; 4.49, m, IH;
5.05, m,NH; 5.04, ABq, J= 12.2 Hz, IH; 5.11, ABq, J = 12.2 Hz, IH; 6.19, d, J = 6.8 Hz, NH; 6.15, br s, NH; 6.46,
br s, NH; 7.10, m, 6H; 7.31, m, 5H; 7.71, m, 3H; 7.84, dist d, IH; 7.90, d, J =9.2 Hz, 2H. MS (ES +ve) m/z Y1S1B
(80%) [M+H]+; 577.4 (100) [M+2H-BOC]2+.

This compound was prepared via Protocol 3, using 14(v) (63mg, 0.050 mmol) to yield 14 as a white solid (40 mg,
82%).
1HNMR (500 MHz, CD3,OD) d 0.48, d, J= 6.5 Hz, 3H; 0.53, d, J= 6.5 Hz, 3H; 0.90, m, 8H; 1.17, m, 5H; 1.36, m,
IH; 1.53, m, 3H; 1.68, m, 6H; 1.81, m, IH; 2.77, m, 2H; 3.19, m, 2H; 3.87, m, IH; 4.00, m, IH; 4.10, m, IH; 4.21,
m, IH; 4.37, m, 3H; 4.44, ABq. J = 15.0 Hz, IH; 4.52, ABq, J = 15.0 Hz, IH; 7.06, dist I, 2H: 7.25, m, 7H; 7.34, m,
2H; 7.46, d, J = 9.5 Hz, 2H; 7.90, d, J= 9.0 Hz. 2H; 7.99. a, J = 8.8 Hz., IH; 8.02, d, J = 8.7 Hz, IH. MS (ES +ve)
m/z 901.0 (5%) [M+H]+;451.1 (100) [M+2H]2+.

To a stirring suspension of NaH (60% dispersion, 73 mg, 1.86 mmol) in dry THF (10 ml) was added dropwise (L)-
leucinol (0.2 ml. 1.55 mmol). The solution was then heated at reflux overnight before being cooled and water (1 ml)
added. After evaporation to near dryness the residue was taken up in DCM (20 ml) and extracted with IM HC1 (3 x
20 ml). The combined acid extracts were then basified with 2M KOH and back extracted with DCM (5 x 15 ml).
The combined organic extracts were then dried (MgSO4). filtered and evaporated to dryness to yield the desired
product 15(i) as a white solid (172 mg. 54%) of sufficient purity to use in the next step.

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1HNMR (300 MHz, CDCl3) d0.87; d, J = 5 4 Hz, 3H; 0 89, a, J = 5.4 Hz, 3H: 1.23, m, IH: 1.41, m, IH: 1.56, m,
IH: 2.42, br s, NH2:2.74, m, IH: 3.31, dABq, J1 = 10.7 Hz, J2= 6.2 Hz, IH; 3.55, dABq, J1 = 10.7 Hz,. J2 = 3.9 Hz,
IH: 3.76, ABq, J = 12.9. Hz, IH; 3.82, ABq, J = 12.9, Hz. IH: 7.32, m, 5H. MS (ES +ve) m/z 208 (100%) [M+H]+,

This compound was prepared in two steps. The initial coupling reaction via Protocol 1. using 15(i) (140 mg, 0.675
mmol) and Fmoc-(Z))-arg(Pbf)-OH (438 mg, 0.675 mmol) to yield the Fmoc protected precursor 15(ii) as an off
white foamy solid (MS (ES +ve) m/z 837.9 (25% [M+H]+; 419.8 (100) [M+2H]2+). This compound was then
deprotccted via Protocol 2. 15(u) (200 mg. 0.238 mmol) to afford a colourless oil 15(iii) (27mg, 18% two steps).
1H NMR (300 MHz, CDCl3) d 0.88, d, J - 6.5 Hz, 3H; 0.89, d. J = 6.5 Hz, 3H; 1.25, m, 2H: 1.44, s, 6H; 1.56, m,
3H; 1.70, m,2H; 2.02. brs,NH2; 2.08, s, 3H: 2.50, s, 3H; 2.57, s, 3H; 2.93, s, 2H; 3.15, m,2H: 3.40, m,2H: 3.63, m,
IH. 4.13, m. IH. 4.45, ABq, J - 12.1 Hz, IH, 4.50, ABq, / — 12.1 Hz, IH, 6.34, br s,NH: 7.29, rn, 5H. 7.39, d. J =
9.0 Hz. NH. MS (ES +ve) m/z 616.3 (100%) [M+H]+.

This compound was prepared via Protocol 1, using 6(vi) (58 mg, 0.090 mmol) and 15(iii) (53 mg. 0.086 mmol) to
yield 15(iv) as a white solid (53 mg, 50%).
1H NMR (500 MHz, CDCl3) d 0.49. d. J = 6.5 Hz, 3H; 0.53, a, J - 6.6 Hz. 3H; 0.79, m. 2H; 0.88. d, J = 6.6 Hz, 3H:
0.90. d. J = 6.7 Hz, 3H: 0.95, m, 2H; 1.21. m, 6H; 1.42, s, 6H; 1.44, s, 9H: 1.56, m. 5H: 1.83. m, IH: 2.07. s, 3H; 2.49. s. 3H: 2.56. s. 3H: 2.91. s, 2H: 2.93, m, 2H: 3.17. m. 2H; 3.41, dABq. J1 = 9.6 Hz. J2 = 5.2 Hz. IH: 3.45.
dABq . J1 = 9.6 Hz. J2 = 4.6 Hz. IH: 3.89, m, IH: 4.01, m. 2H; 4.17. m, IH: 4.46. m, 5H: 4.76. m, NH; 6.13, d. J =
6.8 Hz. NH: 6.17, br s, NH; 6.66. d. J = 8.4 Hz. NH: 7.14, m, 2H: 7.24. m, 4H: 7.30. m, 6H; 7.42. d. J = 9.0 Hz. IH;

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7.84 d. J = 8.4 Hz, IH: 7.86, d, J = 8.4 Hz, IH; 7.92. d, J = 8.8 Hz, IH: 7.93. d. J = 8.8 Hz. IH. MS (ES +ve) mfz
1240 (100%) [M+H]+: 832.4 (100) [M+H-BOC-phf-ibuf.

This compound was prepared via Protocol 3, using 15(iv) (50 mg, 0.040 mmol) to yield 15 as a white solid (32 mg,
83%).
1H NMR (500 MHz, CDCl3) d 0.51, d, / = 6.6 Hz, 3H; 0.56, d, J = 6.6 Hz, 3H; 0.90, a, J= 6.7 Hz, 3H; 0.92, m, 2H:
0.93, d, J = 6.7 Hz, 3H; 1.24, m, 4H; 1.64, m, 9H; 1.84, m, IH: 2.75, m, 2H; 3.17, m, 2H: 3.43, a, J = 7.4 Hz, 2H;
3.92. m, IH; 4.12, m, 2H; 4.29, m, IH: 4.49, m, 4H: 7.06. dist t, 2H; 7.21, m, 2H; 7.34, m, 7H; 7.47, d, J= 9.1 Hz,
IH: 7.54, d, J = 9.1 Hz, IH; 7.91, d, J = 8.8 Hz, IH; 7.92, d, J= 8.8 Hz, IH; 8.02, d, J = 9.3 Hz, 2H. MS (ES +ve)
m/z 888.3 (10%) [M+H]+;444.9 (100) [M+2H]2+.
Synthesis of Compound 16 & Compound 17

To a suspension of L-leucine (1.17 g, 8.92 mmol) and phthalic anhydride (1.26 g, 8.51 mmol) in toluene (25 ml) was
added triethylamine (0.11 ml, 0.79 mmol). The flask was fitted with a Dean-Stark water separator and a condenser
and heated at vigorous reflux for 3 hours. The cooled solution was concentrated in vacuo, suspended in 2.5% HCl
(50 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layers were extracted with sat. aqueous
sodium bicarbonate (3 x 25 ml), acidified with 10% HC1 and back-extracted with ethyl acetate (3 x 25 ml). The
organic layers were dried (MgSC^) and concentrated in vacua to give the product 16(i) as a white solid (2.12 g,
95%).
1H NMR (500 MHz. CDCl3) d 0.87. dd, J = 10.7. 6.6 Hz.. 6H: 1.44. m, IH; 1.89. m. IH: 2.30. m. IH; 4.93. dd. J =
11.3. 4.4 Hz, IH: 7.67. dd, J= 5.3. 2.8 Hz. 2H: 7.79, dd. J=5.3. 2.8 Hz. 2H; 11.23, br s. IH. MS (ES -ve) m/z 260
(100%) [M-H]+:216 (46) [M-COOH]+.

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To a solution of 16(i) (0.70, 2.69 mmol) in THF (15 ml) under a N2 atmosphere at 0 °C was added
dicvclohexylcarboddimide (0.76 g, 3.69 mmol). The resultant solution was stirred at 0 °C for 1 hour. To this was
added 2-amino-1-phenylethanol (0.45 g, 3.28 mmol) and the solution was stirred at 0 °C for 30 minutes then at room
temperature (-15 0C) for a further 16 hours. The reaction mixture was filtered to remove the byproduct DCU, then
concentrated in vacuo. The crude residue was subjected to flash silica column chromatography and elution with 50%
ethyl acetate: petroleum spirit gave the title compound 16(H) as a pale yellow oil (783 mg, 76%).
1H NMR (500 MHz, CDCl3) d 0.90, d, J = 6.8 Hz, 6H; 1.43, m, IH; 1.83, m, IH: 2.30, m, IH; 3.28, m, IH; 3.66, m,
IH; 4.82, m, IH; 4.87, m, IH; 6.73, br s, IH; 7.26, m, 5H; 7.73, m, 2H; 7.83, m, 2H. MS (ES +ve) m/z 381.0 (100%)
[M+H]+; 363.0 (39); 225 (45).

To a solution of chromium trioxide (0.45 g, 4.5 mmol) in water (10 ml) was slowly added concentrated H2SO4 (10
ml, 95%). The cooled solution was then added portionwise to a solution of 16(ii) (0.72 g, 1.9 mmol) in acetone (7.5
ml) (CAUTION: exothermic reaction). The resulting solution was stirred at room temperature for 16 hours. The
reaction mixture was rendered basic by addition of sat. aqueous sodium carbonate and the alkaline solution was
extracted with DCM (3 x 25 ml), brine was added to facilitate complete separation. The organic layers were
combined, dried (MgSO4) and concentrated in vacuo. The crude residue was subjected to flash silica column
chromatography, eluting with 20% ethyl acetate:petroleum spirit to yield the title compound 16(Hi) as a pale yellow
oil (231 mg. 34%).
1H NMR (500 MHz, CDCl3) d 1.02. dd, J= 18.0. 6.6 Hz, 6H: 1.66, m, IH; 2.25. m. IH: 2.60. m. IH; 5.64, dd, J =
10.9. 5.0 Hz, IH, 7.27. m, IH: 7.28, t, J =7.8 Hz, IH: 7.36, t, J =7.9 Hz, 2H: 7.56, d, J =7.4 Hz, 2H: 7.74. dd, J =
5.3, 2.9 Hz, 2H: 7.87, dd, J = 5.3. 2.9 Hz, 2H. MS (E.S +ve) m/z 361.0 (100%) [M+H].


WO 2006/074501 PCT/AU2005/001444
73.
To a solution of 16(Hi) (0.19 g, 0.53 mmol) in ethanol (10 ml) was added ethylenediamine (0.14 ml. 2.25 mmol) and
the resulting solution was heated at reflux for 5 hours. The cooled reaction mixture was diluted with ethyl acetate
(50 ml) then extracted with 1M HCT (3 x 25 ml). The combined aqueous extracts were rendered alkaline with
addition of 1 M NaOH then extracted with DCM (3x25 ml). The combined organic extracts were dried (MgSO4)
and concentrated in vacuo to give the product 16(iv) as pale yellow crystals (100 mg, 82%).
1HNMR (500 MHz, CDCl3) d 0.96, dd, J =6.2, 9.0 Hz, 6H; 1.73, m, 5H; 4.13, t, J= 7.2 Hz, IH: 7.24, s, IH; 7.31, t,
J=7.7. Hz, IH; 7.42, t, J= 7.8 Hz, 2H; 7.62, d, J =7.8 Hz, 2H. MS (ES +ve) m/z 231 (100%) [M+H]+.

This compound was prepared via Protocol 1. using 16(iv) (0.10 g, 0.43 mmol) and (/?)-Fmoc-argmine(PMC)-OH
(0.28 g. 0.42 mmol) in anhydrous acetonitrile (5 ml) with EDCI (0.11 g, 0.57 mmol) and HObt (0.07 g, 0.52 mmol).
Purification with 2% methanol-DCM gave the product 16(v) as a thick off-white oil (292 mg 79%)

1HNMR (500 MHz, CDCl3) d 0.88, m,6H: 1.23, d. J = 3.2 Hz, 6H; 1.66, m,6H; 1.77, m, 2H; 2.03, m, 4H; 2.53, m,
8H; 3.23, m, 2H; 4.02, br s, IH; 4.23, m. 4H; 5.24, m, 2H; 6.37, m, 4H; 7.10, s, IH; 7.26, m, 6H; 7.69, m, 3H; 7.67,
m, 2H. MS (ES +ve) m/z 874.9 (48%) [M+H]+;438 (74); 143 (100).

This compound was prepared via Protocol 2, using 16(v) (0.26 g, 0.30 mmol) and piperidine (0.1 ml, 1.01 mmol) in
anhydrous acetonitrile (8 ml). Purification with 2-10% methanol:DCM gave the product I6(vi) as a pale yellow
solid (189 mg, 98%).
1H NMR (500 MHz, CDCl3) d ; 0.94, dd. J = 12.3, 6.6 Hz, 6H; 1.28. s. 6H; 1.61. m. 4H; 1.79. m, 5H; 2.07, s. 3H;
2.13, br s, 2H: 2.52. s, 3H; 2.54, s. 3H; 2.58, m, 2H; 3.17. m. 2H; 3.48, m. IH; 5.23, ABquart., J =6.6 Hz, IH; 6.42,
br s. 3H; 7.18. s, IH; 7.27, m, IH; 7.35. t, J = 7.6 Hz. 2H; 7.55, d, J = 7.3 Hz. 2H: 8.08. br d. IH. MS (ES +ve) m z:
653 (100%) [M+H]+: 327 (41) [M+H]2+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1, 16(vi) (0.19 g, 0.29 mmol) and 6(vi) (0.19 0.29 mmol) in anhydrous
acetonitrile (7 ml) with EDCI (0.08 g, 0.42 mmol) and HObt (0.06 g, 0.41 mmol). Purification with 2%
methanokDCM gave product 16(vii) as an off-white solid (343 mg, 92%).
1HNMR (300 MHz, CDCl3) d 0.48, dd, J= 16.1, 6.4 Hz, 6H; 0.88, m, 2H; 0.95, m,7H; 1.17, m, 6H: 1.27, m. 7H:
1.41, s, 9H: 1.74, m, 8H: 2.06, s. 3H: 2.52, m, 8H; 2.81, m, 3H: 3.18, m, IH: 3.85. m, IH: 4.03. m. 2H: 4.41. m. 3H:
4.79, rn, IH: 5.25, m, IH: 6.15, m, IH; 6.29, br s, 2H; 7.32, m, 17H; 7.90, m, 4H. MS (ES +ve) m/z 1278 (47%)
[M+H]+; 1277 (56) [M]+; 639 (100) [M+H]+.
Compound 16 & Compound 17
These compounds were prepared via Protocol 3, 16(vii) (0.34 g,0.27 mmol) and TFA (2 ml, 27.0 mmol) in DCM (2
ml). Precipiation from methanol using ether (3 times) gave a mixture of two compounds that were separated by
preparative reverse-phase HPLC to give 16 as a white solid (73 mg, 25%) and 17 as an off-white solid (62 mg, 21%).

1H NMR (300 MHz, CD3OD) d 0.50. dd, J= 16.9, 6.6 Hz, 6H: 0.98, m, 9H; 1.21, m. 5H; 1.38, m, 4H; 1.69, m, 4H;
1.88. m, 2H: 2.73, m, 2H: 3.19, m, IH: 3.96, m. IH: 4.10, m, 2H: 4.45. ABquart. J = 14.6 Hz. 2H:5.22. m, IH: 7.05.
t. J = 6.6 Hz. 2H: 7.21, m, 2H: 7.43, m. 8H: 7.71, m, 2H; 8.00. m, 4H. MS (ES +ve) m/z 911 (16%) [MH-H]+-: 456
(100) [M+H]2+.

WO 2006/074501 PCT/AU2005/001444

1H NMR (300 MHz, CD3OD) d 0.50, dd, J= 12.4, 12.4 Hz, 6H: 0.96, m, 6H: 1.24, m, 2OH: 2.10, m, 2H; 3.15, m,
IH; 3.98, m, IH; 4.15, m, 2H; 4.46, m, 2H; 5.06, m, IH; 7.09, m, 3H; 7.40, m, 4H; 7.66, m, 4H; 7.92, m, 4H; 8.33,
m, 2H. MS (ES +ve) m/z 992 (38%) [M+H]+:496 (100) [M+H]2+.

A suspension of (2,3-epoxypro pyl)benzene (0.5 ml, 3.80 mmol) in concentrated ammonia solution (10 ml, 28%) was
placed in a Teflon tube with a 100 bar pressure cap, then heated in a microwave reactor at 110 0C for 30 minutes.
After cooling the mixture was extracted with DCM (3 x 15 ml), the organic layers combined, dried (MgSC^) and
concentrated in vacua to give the product 18(i) as colourless prisms (490 mg, 86%).
1H NMR (300 MIIz, CDCl3) d 2.01, br s, 3H; 2.59, m, IH, 2.73, d, J = 6.4 Hz, 2H: 2.78, m. IH; 3.72, m, IH: 7.22,
m, 5H. MS (ES +ve) m/z 152 (100%) [M+H]+: 134 (21); 117 (12).

This compound was prepared via Protocol 1. using 18(i) (0.84, 3.23 mmol) and 16(1) in acetonitrile (10 ml), with
EDCI (0.75 g, 3.94 mmol) and HObt (0.53 g, 3.97 mmol). Purification with 50% ethyl acetate:petroleum spirit gave
the product 18(ii) as a colourless oil (1.02 g, 80%).
1H NMR (300 MHz. CDCl3) d 0.88, dd, J = 6.4, 2.1 Hz. 6H: 1.43, m, IH: 1.81, m, IH: 2.30, m, IH; 2.67, m, 2H:
3.01. br s. IH: 3.07. m. IH: 3.44, m, IH: 3.86, m. IH: 4.84. dd. J = 11.4, 4.7 Hz. IH; : 6.74, br s. IH: 7.20, m. 5H;
7.69. m, 2H; 7.80. m. 2H. MS (ES +ve) m/z z433 (20%) [M+K]+:417 (51) [MtNa]+: 395 (100) [M+H]+.

WO 2006/074501 PCT/AU2005/001444

To a solution of chromium trioxide (0.51 g, 5.1 mmol) in water (10 ml) was slowly added concentrated H2SO4 (10
ml, 95%). The cooled solution was then added portionwise to a solution of 18(ii) (0.82 g, 2.1 mmol) in acetone (7.5
ml) (CAUTION: exothermic reaction). The resulting solution was stirred at room temperature for 16 hours. The
reaction mixture was rendered basic by addition of sat. aqueous sodium carbonate and the alkaline solution was
extracted with DCM (3 x 25 ml), brine was added to facilitate complete separation. The organic layers were
combined, dried (MgSO4) and concentrated in vacuo. The crude residue was subjected to Hash silica column
chromatography, elution with 25% ethyl acetate:petroleum spirit gave the product IS(iii) as a dark yellow oil (200
mg, 25%).
1H NMR (300 MHz, CDCl3) d 0.98, dd, J = 9.1, 6.4 Hz, 6H; 1.60, m, IH: 2.14, m, IH: 2.51, m. 1H; 3.92, s, 2H:
5.52, dd, J=5.0, 11.1 Hz, IH: 6.65, s, IH: 7.22, m, 5H; 7.72, dd, J=5.3, 3.2 Hz, 2H: 7.85, dd, J=5.6, 2.9 Hz, 2H.
MS (ES +ve) m/z 375 (100%) [M+H]+.

A solution of 18(iii) (0.20 g, 0.53 mmol) and ethylenediamine (0.20 ml, mmol) in ethanol (10 ml) was placed in a
Teflon tube with a 100 bar pressure cap, then heated in a microwave reactor at 100 °C for 20 minutes The cooled
reaction mixture was diluted with ethyl acetate (50 ml) then extracted with 5% HCl (4 x 25 ml). The combined
aqueous extracts were rendered alkaline with addition of 1 M NaOH then extracted with DCM (4 x 25 ml). The
organic extracts were dried (MgSO4) and concentrated in vacuo to give the product 18(iv) as a thick colourless oil
(111 mg, 81%).
1H NMR (300 MHz. CDCl3) d 0.89. m, 6H; 1.64, m, 5H: 3.95, s, 2H: 4.0, m, IH: 6.62. s. IH: 7.26, m. 5H. MS (ES
+ve)m/z 245 (83%) [M+H]+:228 (100) [M-NH2]+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 18(iv) (88 mg, 36 mmol) and (i?)-Fmoc-arginine(PMC)-OH (240
mg, 37 )nmol) in anhydrous acetonitrile (6 ml) with EDCI (95 mg, 50 mmol) and HObt (64 mg, 47 mmol).
Purification with 2% methanohDCM gave the product 18(v) as a pale yellow oil (302 mg, 94%).
1H NMR (300 MHz, CDCl3) d 0.82, d, J =6.4 Hz, 6H; 1.24, s, 6H; 1.72, m, 9H: 2.01, s, 3H: 2.54, m, 8H: 3.23, m,
2H; 3.81, s, 2H; 4.03, m, IH: 4.24, m, 3H: 5.14, q, J = 7.3 Hz, IH; 6.47, m, 5H: 7.21, m, 8H: 7.37, m, 2H: 7.49, d, J
= 7.3 Hz, 2H; 7.69, J = 13 Hz, 2H. MS (ES +ve) m/z 888.9, (78%) [M+H]+; 445.3 (100) [M+H]2+.

This compound was prepared via Protocol 2, using I8(v) (0.30 g, 0.34 mmol) and piperidine (0.15 ml, 1.51 mmol)
in anhydrous acetonitrile (7 ml). Purification with 2-10% methanol:DCM gave the product 18(vi) as a thick pale
yellow oil (222 mg, 97%).
1HNMR (300 MHz, CDCl3) d 0.88, dd. J = 6.4, 5.3 Hz, 6H; 1.28, s, 6H: 1.62, m, 9H: 2.08, s, 3H: 2.19, m, 2H: 2.53,
s, 3H; 2.55, s. 3H: 2.57, m, 2H: 3.14, m, 2H: 3.42, m, IH; 3.90, s, 2H: 5.09, q, J = 7.0 Hz, IH: 6.38, m, 3H: 6.59, s,
IH: 7.23, m, 5H: 8.00, br d. J = 8.5 Hz, IH.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 18(vi) (0.11 g, 0.16 mmol) and 6(vi) (0.10 g, 0.16 mmol) in
anhydrous acetonitrile (5 ml) with EDCI (0.04 g, 0.21 mmol) and HObt (0.03 g,0.24 mmol). Purification with 2-5%
methanol:DCM gave the product 18(vu) as an off-white solid (131 mg, 64%).
1H NMR (300 MHz, CDCl3) 6 0.46, dd, J= 18.25, 6.4 Hz, 6H; 0.78, m, 2H; 0.89, m, 8H; 1.18, m, 14H; 1.42, s, 9H;
1.64. m, 8H; 2.08. s, 3H; 2.58, m, IOH; 2.79, br s, III; 2.91, m, 2H; 3.19, m, IH; 3.92, m, 5H; 4.43, m. 3H; 4.79, m.
IH; 5.10, m, IH; 6.25, m, 3H; 7.27, m, 12H; 7.91, m,5H. MS (ES +ve) m/z 1291 (28%) [M+H]+;646 (67) [M+H]2+;
83 (100). HRMS (ES +ve) for C73H95N8OnS, calculated 1291.6841, found 1291.6835.

This compound was prepared via Protocol 3, using 18(vii) (132 mg, 0.10 mmol) and TFAITIPSIH 2O(95:2.5:2.5) (2
ml). Precipiation from methanol using ether (3 times) gave the product 18 as an off-white powder (57 mg, 62%).
1H NMR (300 MHz, CD3OD) d0.52. dd, J = 16.1, 6.4 Hz, 6H: 0.91, m, 8H; 1.19. m, 5H; 1.57, m, IOH: 2.78, m, 2H:
3.17, m, 2H; 3.30, m. 2H; 3.49. q, J =7.0 Hz, 2H; 4.04. m, 4H; 4.53, ABquart, J = 14.1 Hz. IH; 5.17. m. IH: 7.08.
m, 2H: 7.25, m, 9H; 7.49. dd, J = 17.3, 9.0 Hz, 2H: 7.89, m. 2H; 8.01. dd, J=9.1. 2.6 Hz, 2H. MS (ES +ve) m/z 925
(4%) [M+H]+; 463.5 (100) [M+H]2+.

WO 2006/074501 PCT/AU2005/001444

To Boc-(L)-Phe-OH (265 mg, 1.00 mmol) and potassium carbonate (691 mg, 5.0 mmol) in acetone (30 ml) was
added benzyl bromide (0.24 ml, 2.0 mmol). The resulting solution was healed at reflux overnight before being
cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash column chromatography over
silica, eluting with 5% ethyl acetate/hexane to first remove benzyl bromide, then with DCM to yield the product 19(i)
as a white solid (351 mg, 99%).
1H NMR (500 MHz, CDCl3) d 1.46, s, 9H; 3.12, m, 2H; 4.68, m. IH: 5.15, ABq, J = 12.3 Hz, IH: 5.16, m, NH:
5.19, ABq, J = 12.3 Hz, IH: 7.09, m, 2H; 7.25, m, 3H: 7.32, m, 2H; 7.36, m, 2H. MS (ES +ve) m/z 401.1 (40%)
[M+HCOOH] + : 378.1 (20) [M+Na]+: 356.1 (25) [M+H]+: 300.0 (60) [M+H-C+Hsf; 256.0(100) [M+H-BOC]

To 19(i) (346 mg, 0.973 mmol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
temperature for 3 hrs. The solution was then diluted with DCM (5 ml) and washed with sat. sodium bicarbonate
solution until the washings were basic. The organic layer was then dried (MgSO4), filtered and evaporated to
dryness to yield the desired product 19(ii) as a colourless oil (203 mg, 82%).
1H NMR (500 MHz, CDCl3) d 1.54, s, NH2: 2.78, dABq. J1 - 13.5 Hz,.J2 = 5.5 Hz, IH: 2.96, dABq. J1 = 13.5 Hz,
J2 = 7.5 Hz, IH: 3.65, m, IH: 5.00, ABq, J = 12.3 Hz, IH: 1.56, m, NH: 5.03, ABq, J = 12.3 Hz, IH: 7.02, d, J =
6.9 Hz. 2H: 7.15. m. 8H. MS (ES +ve) m/z 256. 1 (100%) [M+H]+.


WO 2006/074501 PCT/AU2005/001444
80.
This compound was prepared in two steps. The first step via Protocol 1. using 19(ii) (200 mg, 0.78 mmol) and
Fmoc-(D)-arg(Pmc)-OH (464 mg, 0.70 mmol) to yield the Fmoc protected precursor 19(iii) as a white foamy solid
(573 mg, MS (ES +ve) m/z 899.8 (100%) [M+H]+). This precursor (200 mg) was then deprotected via Protocol 2 to
afford the desired compound 19(iv) as a white solid (148 mg, 89% two steps).
1H NMR (500 MHz. CDCl3) d 1.32, s, 6H; 1.44, m, 2HTNH2: 1.66. m, 2H: 1.80, dist t. 2H: 2.12, s, 3H; 2.58, s, 3H:
2.60, s. 3H: 2.61, m, 2H: 3.12, m, 4H; 3.36, m, IH: 4.81, m, IH: 5.07, ABq, J = 12.2 Hz, IH; 5.15, ABq. J = 12.2
Hz, IH: 6.41, m, NH: 7.09, d, J = 6.6 Hz, 2H: 7.25, m, 5H: 7.32, m, 3H. 7.88, d, J = 6.8 Hz, NH. MS (ES +ve) m/z
677.9 (100%) [M+H]+.

This compound was prepared via Protocol 1. using 6(vi) (122 mg, 0.190 mmol) and 19(iv) (140 mg, 0.207 mmol) to
yield 19(v) as a white solid (197 mg, 71%).
1H NMR (300 MHz, CDCl3) d 0.48, d, / = 6.2 Hz, 3H; 0.54, d, / = 6.2 Hz, 3H; 0.78, m, 2H; 0.89, m, 2H; 1.20, m,
8H; 1.43, s, 9H; 1.58, m, IH: 1.78, dist t, 2H; 2.12, s, 3H; 2.60, s, 3H. 2.61, s, 3H; 2.62, m, 2H; 2.90, m, 3H; 3.06, m,
2H; 3.19, m, IH; 3.88, m, IH; 4.06, m, 2H; 4.37, m, IH; 4.39, ABq, J = 6.6 Hz, IH; 4.52, ABq, J= 6.6 Hz, IH:
4.86, m, 1H/NH; 5.10, ABq, J = 12.3 Hz, IH; 5.18, ABq, J = 12.3 Hz, IH; 6.19, d, J = 7.3 Hz, NH; 6.35, br s, NH:
7.22, m, 8H: 7.33, m, 9H; 7.45, d, J = 9.1 Hz, IH: 7.85, d, J = 8.2 Hz, IH; 7.88, d, J = 7.9 Hz, IH; 7.96. d, J = 8.7
Hz, 2H. MS (ES +vc) m/z 1301.8 (100%) [M+H]+.


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81.
This compound was prepared via Protocol 3. using 19(v) (195 mg. 0.148 mmol) yield 19 as an off white solid (128
mg, 85%).
1H NMR (300 MHz, CD,OD) d 0.46, d, J = 6.6 Hz, 3H; 0.52, d, J = 6.6 Hz, 3H; 0.92, m, 2H; 1.08, m, 2H; 1.20, m,
2H; 1.50, m, 5H; 2.76, m, 2H; 3.03, m, 3H; 3.15, m, IH; 3.88, m, IH; 4.06, m, 2H; 4.28, m, IH; 4.46, m, 2H; 4.69,
m, IH; 5.11, s, 2H; 7.13, m, 8H; 7.27, m, 8H; 7.41, d, J = 9.0 Hz, IH; 7.51, d, J = 9.1 Hz, IH; 7.85, m, 2H; 7.98,
dist t, 2H. MS (ES +ve) m/z 936 (10%) [M+H]+; 468.9 (100) [M+2H]2+

To 1-amino-l-cyclopentane carboxylic acid (100 mg, 0.774 mmol) in dry acetonitrile (10 ml) was added
tctramcthylammonium hydroxide pentahydrate (190 mg. 1.04 mmol) and the mixture stirred at room temperature
until the acid had dissolved. Boc anhydride (300 mg. 1.37 mmol) was then added and the resultant solution stirred
for four days. The solvent was then removed and the resultant residue partitioned between water and ether. T'he
aqueous layer was washed with an additional portion of ether and then acidified with solid citric acid to pH 3-4. The
aqueous layer was then back extracted with ethyle acetate (3x15ml), before being combionedm, dried (MgSO4),and
evaporated to dryness to yield 20(i) as a pale yellow oil (101 mg, 57%).
1H NMR (300 MHz, CDCl3) d 1.44, s, 9H; 1.78, m, 4H; 1.96, m, 2H; 2.29, m, 2H; 5.06, br s, NH; 10.19, br s,
COOH.

To 20(i) (120 mg, 0.523 mmol) and potassium carbonate (178 mg, 1.29 mmol) in acetone (25 ml) was added benzyl
bromide (0. 1 ml, 0.920 mmol). The resulting solution was heated at reflux overnight before being cooled, filtered
and evaporated to dryness. The resultant residue was subjected to flash column chromatography over silica, eluting
with 5% ethyl acetate/hexane to first remove benzyl bromide, then with DCM to yield the product 20(ii) as a
colourless oil that solidified to a white solid upon standing (173 mg, 96%).
1HNMR (500 MHz, CDC13) d 1.37.s,9H; 1.74, m,4H; 1.91,m,2H; 1.20. m. 2H; 5.08, br s,NH; 5.13. s, 2H; 7.30.
m. 5H. MS (ES +ve) m/z 320 (50%) [M+H]+; 220 (100) [M+H-BOC] + .

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82
To 2O(π) (170 mg, 0.532 mmol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
temperature for 90 mins. The solution was then diluted with ethyl acetate (5 ml) and washed with sat. sodium
bicarbonate solution until the washings were basic. The organic layer was then dried (MgSO4), filtered and
evaporated to dryness to yield the desired product 20(iii) as a pale yellow oil (102 mg, 87%).
1H NMR (500 MHz,'CDCl3) d 1.58, m, 2H; 1.67, s, NH2; 1.73, m, 2H; 1.84, m, 2H; 2.08, m, 2H; 5.12, s, 2H; 7.32,
m, 511. MS (ES +ve) m/z 219.9 (100%) [M+H]+.

This compound was prepared in two steps. The initial coupling via Protocol 1. using 20(iii) (100 mg, 0.456 mmol)
and Fmoc-(D)-arg(Pbf)-OH (296 mg, 0.456 mmol) to yield the Fmoc protected precursor 20(iv) as a white foamy
solid (MS (ES +ve) m/z 850 (100%) [MH-H]+). This precursor was then deprotected via Protocol 2 to afford the
desired compound 20(v) as a white solid (152 mg, 53% two steps).
1H NMR (500 MHz, CDCl3,) d 1.44, s, 6H; 1.46, m, 2H; 1.63, m, 2H; 1.76, 4HTNH2; 1.93, m, 2H; 2.07, s, 3H; 2.24,
m, 2H; 2.50, s, 3H; 2.58, s, 3H; 2.93, s, 2H; 3.20, m, 2H; 3.87, m, IH; 5.08, s, 2H; 6.37. br s, NIL 6.42, br s, NH;
7.28, m.5H; 7.52, s,NH; 7.75,m,NH. MS (ES +ve)m/z628 (100%) [M+H]+.

This compound was prepared via Protocol 1. using 6(vi) (100 mg, 0.155 mmol) and 20( v) (14 1 mg. 0.224 mmol) to
yield 20(vi) as a white solid (123 mg. 63%).

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1HNMR (500 MHz, CDCl3) d 0.47, d, J = 6.4 Hz, 3H; 0.52, d,J = 6.4 Hz, 3H; 0.78, m. 2H; 0.94. m, IH; 1.23. m.
7H; 1.42, s, 9H; 1.43, s, 3H; 1.44, s, 3H; 1.70, m, 4H; 1.96, m, 2H; 2.07, s, 3H; 2.11, m, IH; 2.25, m, IH; 2.50, s,
3H; 2.57, s, 3H; 2.91. s, 2H; 2.93, m, 2H; 3.07, m, 2H; 3.87. m, IH; 4.00, m, 2H; 4.37, m, 2H; 4.59, m, IH; 4.79, m,
NH; 5.07, s, 2H; 6.15, d, J = 6.9 Hz, NH; 6.25,brs,NH; 7.11, d,J=8.5Hz, IH; 7.15, d,J = 8.5Hz, IH; 7.26, m,
1OH; 7.43, a, J = 9.1 Hz, IH; 7.84, d,j= 8.4 Hz, IH; 7.85, d, J = 8.4 Hz, III; 7.93, d, J = 6.9 Hz, IH; 7.94, d, J =
9.0 Hz. IH. MS (ES +ve) m/z 1252 (100%) [M+H]+.

This compound was prepared via Protocol 3. using 20(vi) (110 mg, 0.088 mmol) to yield 20 as an off white solid
(83 mg, 97%).
TINMR (500 MHz, CD3OD) d0.51, d, J =6.5 Hz, 3H; 0.57, d, J =6.5 Hz, 3H; 0.95, m,2H; 1.14, m, 2H; 1.24, m,
2H; 1.42, m. IH; 1.57, m, 5H; 1.77, m, 4H; 1.98, m, 2H; 2.12, m, IH; 2.30, m, IH; 2.79, m, 2H; 3.08, m, 2H; 3.95,
m. IH; 4.14, m, 2H; 4.27, m, IH; 4.45, ABq, J = 14.7 Hz, IH; 4.55, ABq, J = 14.7 Hz, IH; 5.07, ABq,j - 12.3 Hz,
IH; 5.12, ABq,j = 12.3 Hz, IH; 7.06, tj = 9.3 Hz, 2H; 7.20, m, 2H; 7.34, m. 7H; 7.47, d, J = 8.9 Hz. IH; 7.55. d.
/ = 9.0 Hz, IH; 7.89, d, J = 8.3 Hz, IH; 7.92, d,J = 8.3 Hz, IH; 8.01, d,j= 8.9 Hz, IH; 8.02. d,j = 8.9 Hz. IH.
MS (ES +ve) m/z 900 (5%) [MH-H]+; 450.7 (100) [M+2H]2+.

To Boc-1-amino-l-cyclohexane carboxylic acid (168 mg, 0.69 mmol) and potassium carbonate (691 mg, 5.00 mmol)
in acetone (30 ml) was added benzyl bromide (0.17 ml, 1.40 mmol). The resulting solution was heated at reflux
overnight before being cooled, filtered and evaporated to dryness. The resultant residue was subjected to flash
column chromatography over silica, eluting with 5% ethyl acetate/hexane to first remove benzyl bromide, then with
DCM to yield the product 21(i) as a colourless oil (226 mg, 98%).

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1H NMR (500 MHz, CDCl3) d 1.28, m, IH; 1.38, s, 9H; 1.42, m,2H; 1.58, m, 3H; 1.82, m,2H; 1.98, m. 2H; 4.86, s,
NH; 5.12, s, 2H; 7.32, m. 5H. MS (ES +ve) M/z 379 (70%) [M+HCOOH] +; 356.1 (20) [M+Na]+; 334.1 (40) [M+H]+;
278.1 (100) [JVM-H-C4Hs]+; 234.0 (95) [M+H-BOC] +.

To 2l(i) (218 mg, 0.654 minol) in DCM (2 ml) was added TFA (2 ml) and the resulting solution stirred at room
temperature for 3 hrs. The solution was then diluted with DCM (5 ml) and washed with sat. sodium bicarbonate
solution until the washings were basic. The organic layer was then dried (MgSO4), filtered and evaporated to
dryness to yield the desired product 21(ii) as a pale yellow oil (121 mg, 79%).
]H NMR (500 MHz, CDCl3) d 1.39, m, 6H; 1.56, m, 2H; 1.72, s, NH,; 1.87, m, 2H; 5.06, s, 2H; 7.26, m, 5H. MS
(ES +ve) mz 234.0 (100%) [M+H]+.

This compound was prepared in two steps. The first step via Protocol 1. using 21(ii) (115 mg, 0.49 mmol) and
Fmoc-(D)-arg(Pmc)-OH (318 mg, 0.48 mmol) to yield the Fmoc protected precursor 21(IIi) as a while foamy solid
(402 mg, MS (ES +ve) m/z 877.9 (100%) [M+H] +). This precursor 21(iii) (200 mg) was then deprotected via
Protocol 2 to afford the desired compound 21(iv) as a white solid (141 mg, 87% two steps).
1H NMR (500 MHz, CDC13) d 1.30, s, 6H; 1.58, m, 10HZNH,; 1.79, dist t. 2H; 1.90, m,2H; 2.10, s, 3H; 2.57, s, 3H;
2.58, s. 3H; 2.62. m.2H; 3.14. m.4H; 3.44. m. IH; 5.06. ABq. j= 12.6 Hz, IH; 5.09, ABq,j = 12.6 Hz. IH; 6.41.
m.NH; 7.29, m,5II; 7.80, s.NH. MS (ES +vc) M/z 656.3 (100%) [M+H]+.

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This compound was prepared via Protocol 1. using 6(vi) (122 mg, 0.190 mmol) and 21(iv) (140 mg, 0.213 mmol) to
yield 21(v) as a white solid (163 mg, 67%).
1H NMR (300 MHz, CDCl3) d 0.49, d, j = 6.4 Hz, 3H; 0.54, d, j = 6.4 Hz, 3H; 0.78, m, 2H; 0.92, m, 2H; 1.20, m,
6H; 1.29, s, 6H; 1.44, s, 9H; 1.53, m, 2H; 1.77, m, 3H; 1.89, m, IH; 2.09, s, 3H; 2.55, s, 3H; 2.57, s, 3H. 2.59. m,
2H; 2.89, m, 2H; 3.09, m, 2H; 3.89, m. IH; 4.04, m, 2H; 4.36, ABq,j - 14.6 Hz, IH; 4.42, m, IH; 4.54, ABq, J =
14.6 Hz, IH; 4.80, m.NH; 5.06, s, 2H; 6.14, br sNH; 6.36. br s,NH; 7.26. m, 12H; 7.44. d../ - 9.1 Hz. IH; 7.84. d,
,j = 8.9 Hz, IH; 7.86, d,j = 7.9 Hz, IH; 7.92, d,j = 8.8 Hz, IH; 7.95, a,J = 7.6 Hz, IH. MS (ES +ve) mJz 1280.3
(100%) [M+H]+.

This compound was prepared via Protocol 3, using 21(v) (106 mg, 0.083 mmol) to yield 21 as an off white solid (35
mg, 43%).
1HNMR (300 MHz, CD,OD) d 0.50, 6,J= 6.4 Hz, 3H; 0.56, d,j=6.4Hz, 3H; 0.94, m, 2H; 1.18,m,3H; 1.57, m,
13H; 1.94. m, 5H; 2.78, m, 2H; 3.08, m, 2H; 3.93. m, IH; 4.12. m, 2H; 4.30. m, IH; 4.42, ABq.J = 14.6 Hz, IH;
4.54. ABq.J - 14.6 Hz, IH; 5.02, ABq. J = 12.3 Hz, IH; 5.09, ABq. J = 12.3 Hz, IH; 7.06, dist t. 2H; 7.20. dist t.
2H; 7.32. m, 7H; 7.44, d,J= 8.8 Hz, IH; 7.53, d, J=9.1 Hz, IH; 7.90, dist t, 2H; 8.00. d. J= 9.1 Hz. IH; 8.01, d,j
= 9.1 Hz. IH; 8.09. s,NH. MS (ES +ve) M/z 915.0 (10%) [M+H]+; 457.9 (100) [M+H]2+.

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To a solution of Lr-bina phth-2,2'-diol (4.89 g. 17.1 mmol) in dry acetone (40 ml) was added anhydrous potassium
carbonate (3g) under an N2 atmosphere. After stirring for an hour a solution of allyl bromide (1.55 ml, 17.9 mmol)
in acetone (20 ml) was added dropwise over a 2 hr period. The mixture was then heated at reflux overnight before
being cooled and filtered. The solid residue was then washed twice more with acetone (10 ml) before the combined
organic extracts were evaporated to dryness to yield a honey coloured oil. Subsequent flash column chromatography
with 1;3 DCM/Hexane as the eluant affords the desired product 22(i) as a yellow solid (1.905 g, 53%). Rf = 0.06
(1;1 hexane/DCM). The disubstituted product (4%) and starting material (7%) were also recovered.
iHNMR (300 MHz, CDCl3) δ 4.48, in, 2H, 5.00, m, 2H; 5.51, m, IH; 7.13, dist d,j= 8.3 Hz, IH; 7.28. m, 7H; 7.83,
m, 3H;7.92, (1. / =9.1 Hz, IH.

To 22(i) (1.91 g, 5.84 mmol) in dry MeOH (50 ml) was added potassium carbonate (8.1 g, 58.6 mmol) and
bromoacctic acid (4.05 g, 29.3 mmol). The colour of the solution changed from yellow to almost clear upon addition
of the bromoacetic acid. The solution was then heated at reflux for three hours over which time a white ppte had
fallen out of solution. The reaction mixture was then evaporated to dryness and the residue dissolved in water (50
ml). This was then washed with three 30 ml portions of ether before the aqueous layer was acidified with 3M HC'l.
This acidified solution was then extracted with three 30 ml portions of DCM to yield a yellow solution. This yellow
solution was then dried over MgSO4 before being evaporated to dryness to yield the product 22(ii) as a yellow
foamy solid (1.87 g. 83%).
1H NMR (300 MHz. CDCI,) d 4.48, m. 2H; 4.55, ABq, / = 16.7 Hz. IH; 4.67. ABq. / = 16.7 Hz. IH; 4.95, m. 2H;
5.65. m, IH; 7.13, app t, 2H; 7.24, m, 2H; 7.34, m, 3H; 7.42, d, / =9.1 Hz. IH; 7.87. d,j= 8.2 Hz, IH; 7.87, d, / =
8.2 Hz, IH; 7.96. d. / = 8.8 Hz, IH; 7.97, d,/= 8.8 Hz, IH. MS (ES +ve) M/Z 385.0 (90%) [M+H]+ ;402.0 (100)
[MfNH]+

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This compound was prepared via Protocol 1. using 22(H) (46 mg, 0.12 mmol) and l(viii) (110 mg, 0.12 mmol) to
yield the desired product 22(iu) as a white solid (124 mg, 84%). Rf= 0.16 (5% MeOHTDCM).
1H NMR (300 MHz, CDCl3) d 0.78, m, 2H; 0.87, d. J = 5.6 Hz, 3H; 0.89, d, J = 5.6 Hz, 3H; 0.97, m, IH; 1.20, m,
4H; 1.27, s, 6H; 1.39, m, 2H; 1.41, s, 9H; 1.63, m, 3H; 1.75, m, 3H; 2.08, s, 3H; 2.53, s, 3H; 2.56, s, 3H; 2.57, m,
2H; 2.88, m, 2H; 3.13, m, 2H; 4.09, m, IH; 4.47, m, 6H; 4.79, m, NH; 4.86, m, 2H; 5.08, ABq, j - 12.3 Hz, IH;
5.16, ABq, J = 12.3 Hz, IH; 5.63, m, IH; 6.24, m, NH; 7.10, dist d, IH; 7.16, dist d, TH; 7.32, m, IOH; 7.42, a,J =
9.3 Hz, IH; 7.85, dist t, 2H; 7.92, d, J =8.8 Hz, 2H. MS (ES +ve) m/z 1260 (100%) [M+Na] +; 1238 (80) [MH-H] + .

This compound was prepared via Protocol 3, using 22(Hi) (94 mg, 0.076 mmol) to yield the desired product 22 as a
white solid (62 mg, 86%).
1H NMR (300 MHz, CD,OD) d 0.88, d,J= 5.6 Hz, 3H; 0.93, a,J =5.6 Hz, 3H; 0.97, m. 2H; 1.15,m, IH; 1.66. m,
IOH; 2.79, m, 2H; 3.14, m, 2H; 4.14. m, IH; 4.35, m, IH; 4.46, m, 2H; 4.56, m, 3H; 4.93, m, 2H; 5.11, ABq, J =
12.3 Hz, IH; 5.17, ABq, j = 12.3 Hz, IH; 5.71, m, IH; 7.05, m, 2H; 7.20. dist t, 2H; 7.33. m, 7H; 7.46, d,j = 9.1
Hz. IH; 7.53. d,j= 9.1 Hz. IH; 7.90, dist t, 2H; 8.01, d,J = 9.1 Hz. 2H, MS (ES +ve) M/Z 43 l (100%) [M+2H]2+.

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Bromomethylcyclohexane (240 ml, 1.75 mmol) was added to a mixture of l,l'-binaphth-2,2'-diol (500 mg, 1.75
mmol). potassium carbonate (l.00g, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for 3 days,
and then cooled and concentrated in vacuo. The crude product was purified by flash chromatography with 1-10 %
ethyl acetate-petrol as eluent to give the product 23(i) as a viscous oil (400 mg, 60%).
1H NMR (500 MHz, CDCK) δ 1.51, m, 1OH; 2.44, m, 1H; 3.92, m, 2H; 7.06, d,j= 8.5 Hz, IH; 7.26, m, 8H; 7.44, d,
/ = 9.2 Hz, IH; 7.84, d,/=8.1 Hz, IH; 7.89, dd, /=6.2, 6.2 Hz, 2H; 8.02, d,/= 9.2 Hz, IH.

To 23(i) (400 mg, 1.05 mmol) in methanol (10 ml) was added potassium carbonate (1.50 g, 10.9 mmol) and
bromoacetic acid (900 mg, 6.48 mmol) and the mixture stirred at reflux for 2 days. The reaction mixture was cooled
down, methanol removed in vacuo, and the crude residue redissolved in water and acidified with IM HC1.
Extraction with ether, drying (Na,SO4) and concentration gave the crude product that was purified by flash
chromatography. Elution with chloroform gave unreacted 23(i) (25 %). Further elution with 2 % methanol-
chloroform gave 23(H) as a viscous oil (240 mg. 51.9 %).
1H NMR (500 MHz, CDCh) d 0.51, m, 2H; 0.83, m, 3H; 1.17, br t, 2H; 1.36, m, 4H; 3.71, m, IH; 3.79, m; 4.49,
ABq. / = 16.6, IH; 4.61, ABq. / = 16.6 Hz, IH; 7.18. m,4H; 7..30, m, 3H; 7.40, d,j= 9.3 Hz. IH; 7.82. d. / = 7.8
Hz, IH; 7.83. d,/= 7.8 Hz. IH; 7.91, d./ = 9.3 Hz. IH; 7.92. d. / = 9.3 Hz. IH. 9.25, br s. IH.


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To a solution of (S)-allylglycine (225 mg, 1.96 mmol) in benzyl alcohol (5 ml.) was added thionyl chloride (2 ml.)
and the resulting mixture was allowed to stir for 16 h before addition of diethyl ether (30 mL) and extraction with
water (3 x 30 mL). The aqueous layer was concentrated, diluted with 2M sodium bicarbonate (20 mL), and extracted
with DCM (3 x 30 mL). The combined organic fractions were dried and acidified with IM HCl/diethyl ether (2 mL)
and evaporated. The crude product dissolved in a minimal volume of MeOH and precipitated with diethyl ether to
yield the title compound 23(iii) as a white solid (322 mg, 1.34 mmol, 68%) Mp 186-191 °C.
1-1 NMR (300 MHz, Dp) d 2.55, m, 2H; 4.08. t,J = 5.4 Hz, IH; 5.11. m,4H; 5.51, m, IH; 7.28, m, 5H. MS (CI
+ve) nr'z 205 (25%) [M+H]+.

This compound was prepared via Protocol 1. using 23(Ui) (155 mg, 0.65 mmol) and (/?)-Fmoc-Arg(PMC)-OH (431
mg, 0.65 mmol) to afford 23 (iv) (280 mg, 0.33 mmol, 51% as a white solid Mp 78-740C.
1H NMR (300 MHz CDCl3) d 1.22, s, 6H; 1.58, m, 2H; 1.69, t, J = 6.3 Hz; 1.85, m, 2H; 2.05, s, 3H; 2.52, m, 4H;
2.54, s, 3H; 2.57, s, 3H; 3.20, m, 2H; 4.05, t, / = 7.2 Hz, IH; 4.24, m, 3H; 4.58, m, IH; 4.99, m, 4H; 5.61, m, IH;
5.68. m, IH; 6.33, m, 3H; 7.28, m, 9H; 7.51, d,j =7.5 Hz, 2H; 7.69, d, J =7.5 Hz, 2H. MS (ES +ve) m/z 850 (100%)
[M+H]+.

This compound was prepared via Protocol 2. using 23(iv) (278 mg. 0.33 mmol) to yield 32(v) as a cream semi-solid
(144 mg, 0.23 mmole, 70%). Mp 66-68°C.
'IT NMR (300 MHz. CDC13)8 1.29, s,6H; 1.54. m,2H; 1.68. m,4H; 1.78. t.J =7.2 Hz, 2H; 2.09, s, 3H; 2.55. s. 3H;
2.56, s, 3H; 2.61. t.J =6.9 Hz. 2H; 3.09, m. 2H; 3.16, m. 2H; 3.40. m, IH; 4.56, m. IH; 5.14, m. 4H; 5.63, s. IH;
6.33. m.2H; 7.32. m. 5H; 7.60. d, J=7.8Hz. IH; 7.85. d, J = 7.8 Hz, IH. MS (ES +ve) m/z 628 (100%) [M+H]+

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This compound was prepared via Protocol 1. using 23(v) (200 mg, 0.32 mmol) and (7?)-Fmoc-Lys(Boc)-OH (151
mg, 0.32 mmol) to afford 23(vi) as a white solid (202 mg, 0.19 mmol, 59%). Mp 116°C.
1H NMR (300 MHz, CDC13) d 1.41, s, 6H; 1.59, m, 2H; 1.67, m, 4H; 1.74, m, 2H; 1.95, m, 4H; 2.03, s, 3H; 2.50, m,
4H; 2.52, s, 3IT; 2.55, s. 3H; 3.05, m, 2H; 3.18, m, 2H; 3.98, m, IH; 4.20, m, 2H; 4.29, m, IH; 4.51, m, IH; 4.59, m,
IH; 5.03, m,4H; 5.64, m, IH; 6.25, m, 3H; 7.29, m, HIT; 7.45, m, IH; 7.55, d, J =7.8 Hz, 2H; 7.72, d,j=7.8Hz,
2H. MS (ES +ve) m/z 1078 (10%) fM+Hl+;288 (100).

This compound was prepared via Protocol 2, using 23(vi) (202 mg, 0.19 mmol) to yield 23(vii) as a cream oil (157
mg, O.18mmole, 93%).
1H NMR (300 MHz, CDCl3) d 1.31. s, 6H; 1.42, s, 9H; 1.58. m. 4H; 1.72. m. 4H; 1.80. t, J = 6.3 Hz; 1.89. m,
2H; 2.10, s, 3H; 2.15, m, 2H; 2.47, m, 2H; 2.56, s, 3H; 2.58, s, 3H; 2.62, m, 2H; 3.05, m. 2H; 3.22, m, 2H; 3.36. m. IH;
4.61. m, 2H; 5.09, m, 4H; 5.63, m, IH; 6.44, m. 3H; ; 7.32, m, 5H; 7.58, d. J = 7.2 Hz. IH; 8.00. d, J = 7.2 Hz. IH.
MS (ES +ve) m/z 856 (100%) [M+H]+.

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This compound was prepared via Protocol 1. from acid 23(ii) with the 23(vii) (80 mg, 94 (mmol). Purification by
radial chromatography (1-2% methanol-chloroform) gave the product 23(viii) (94 mg, 79%).
1H NMR (500 MHz, CDCl3) d 0.48, m, 2H; 0.85, m, 6H; 1.28, s, 6H; 1.41, s, 9H; 1.32, m, 12H; 1.76, br t, 3H; 2.09,
s, 3H; 2.55, s. 3H; 2.57, s, 3H; 2.56, m, 4H; 2.91, br s, 2H; 3.09. m. 2H; 3.67, m. IH; 3.81, m, IH; 4.12, m. III; 4.43,
ABq, J = 14.4 Hz, IH; 4.51, ABq, J = 14.4 Hz, IH; 4.41, m, IH; 4.60, m. IH; 4.84, b s, IH; 5.06, m, 2H; 5.09, ABq,
IH. J = 12.5; 5.18, ABq, IH. J = 12.5; 5.68, m, IH; 6.19, br d, J= 7.0 Hz, IH; 6.26, br s, 2H; 7.25, m, 7H; 7.43, IH,
d, J =9.0 Hz; 7.85, m, 2H; 7.95, A, J =9.0 Hz, 2H. MS (FS +ve) M/z 1278 (100%) [M+H] + .

This compound was prepared via Protocol 3, using 23(viii) (80 mg, 62.6 (mmol). Standard work-up gave the product
23 as a cream crvstalline solid (40 mg, 65%).
'II NMR (500 MHz, DMSO-d 6) d 0.57, m, 2H; 0.90. m, 3H; 1.33, m, HH; 2.39, br s. 3H; 2.49, br s, 3H; 2.65, m,
2H; 2.40, m, 4H; 3.76, m, IH; 3.87. m, IH; 4.20. m, 3H. 4.51, br s, 2H; 5.05. m, 4H; 5.70, m, IH; 6.92. d. J = 8.5
Hz, IH; 7.00, .1. J = 8.0 Hz, IH; 7.27. m, 1OH; 7.54. m. IH; 7.91, m. 2H. 8.02. m. 2H. MS (ES +ve) m/z 912 (45%)
[M+H]+; 457 (100) [M+2H]2+.

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Bromomethylcyelobutane (200 ml, 1.75 mmol) was added to a mixture of l,l'-bina phth-2,2'-diol (500 mg, 1.75
mmol), potassium carbonate (l.0Og, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for 18 h, and
then cooled down and concentrated in vacuo. The crude product was purified by flash chromatography with 1 -4%
ethyl acetate-petrol as eluent to give the product 24(i) as a viscous oil (300 mg, 49%).
1H NMR (500 MHz, CDCl3) d 1.52, m, 6H; 2.43, m, IH; 3.92, m, 2H; 4.95, s, IH; 7.06, d, J = 8.3 Hz, IH; 7.28, m,
6H; 7.43, a,j =8.8 Hz, IH; 7.84, d. J =7.8 Hz, IH; 7.88, d, J= 9.3 Hz, IH; 7.89, d, IH,j = 8.3 Hz; 8.00, a, J = 9.3
Hz, IH.

To 24(i) (300 mg, 0.85 mmol) in methanol (10 ml) was added potassium carbonate (1.00 g. 7.27 mmol) and
bromoacetic acid (560 mg, 4.03 mmol) and the mixture stirred at reflux for 2 days. The reaction mixture was cooled
down, methanol removed in vacuo, and the crude residue redissolved in water and acidified with IM HC1.
Extraction with ether, drying (Na2SO4) and concentration gave the crude product that was purified by flash
chromatography. Elution with 10% methanol;DCM gave the product 24(ii) as a viscous oil (200 mg, 57%).
1H NMR (500 MHz, CDC1?) d 1.43, m, 6H; 2.33, m, IH; 3.80, m, IH; 3.99, m, IH; 4.52, ABq, IH, j = 16.5 Hz;
4.69, ABq. IH,j = 16.5 Hz; 7.15, d,J = 8.5 Hz, 2H; 7.29, m, 5H; 7.43, d, J = 8.8 Hz, IH; 7.87, d, J = 7.0 Hz, 2H;
7.94, d. J = 8.5 Hz, IH; 7.96, d. J = 8.8 Hz, IH.

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This compound was prepared via Protocol 1, using 24(ii) and 23(viii) (110 mg, 117 mmol). Purification by radial
chromatography (1-3% methanol-DCM) gave the product 24(iii) (80 mg, 55%).
1H NMR (500 MHz, CDCl3) d 0.79, m, 2H; 0.94, m, IH; 1.28, s, 6H; 1.41, s, 9H; 1.38, m, 12H; 1.76, br t, 3H; 2.09,
s, 3H; 2.29, m, IH; 2.55, s, 3H; 2.57, s, 3H; 2.54, m,4H; 2.90, m, 2H; 3.08, m, 2H; 3.80, m, IH; 3.97, m, IH; 4.09,
br s. Ill; 4.41, ABq, J = 14.5 Hz, IH; 4.51, ABq, J = 14.5 Hz, IH; 4.42, m, IH; 4.59, m, IH; 4.84, br s, IH; 5.06, m,
2H; 5.12, ABq,j/= 12.5 Hz, IH; 5.18, ABq,j = 12.5 Hz, IH; 5.66, m, IH; 6.22, m, 3H; 7.25. m. 7H; 7.43, d, J = 8.8
Hz, III; 7.84, d, J = 8.3 Hz, IH; 7.86, d,J = 8.8 Hz, IH; 7.93, d, J = 9.3 Hz, IH; 7.94, d, J = 8.8 Hz. IH. MS (ES
+ve) m/z 1250 (100%) [M+H] +.

This compound was prepared via Protocol 3, using 24(iii) (70 mg, 55.98 mmol). Standard work-up gave the product
24 as a cream crystalline solid (35 mg, 65%).
1H NMR (300 MHz, DMSO-d 6) d 0.97, br s, IH; 1.15, br s, IH; 1.45, m, 1OH; 2.10, s, IH; 2.45, m, 5H; 2.66, br s.
IH; 3.07, br s, 3H; 3.99. m, 3H; 4.34, m, 4H; 5.09, m, 4H; 5.73. br s, IH; 6.03. m, 3H; 7.29, m, 8H; 7.57. m. 2H;
8.01. m.4H. 8.19. br s, IH; 8.41. br s, 2H. MS (ES +ve) M/z 884 (95%) [M+H]+; 443 (100) [M+2H]2+.

WO 2006/074501 PCT/AU2005/001444

l-Bromo-2-methylpropane (190 ml 1.75 mmol) was added to a mixture of l,l'-binaphth-2,2'-diol (500 mg. 1.75
mmol), potassium carbonate (l.0Og, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for 42 h, and
then cooled down and concentrated in vacno. The crude product was purified by flash chromatography with 1-4%
ethyl acetate-petrol as eluent to give the product 25(i) as a viscous oil (280 mg, 47%). Further elution with 10%
ethyl acetate-petrol gave unreacted diol (200 mg, 40%).
1HTNMR (300 MITz, CDC13) d 0.63, d,J =6.6 Hz, 3H; 0.66, d,J =6.6Hz, 3H; 1.77, m, IH; 3.75, m, 2H; 4.98, br s,
IH; 7.09, d,J = 8.4 Hz; 7.30, m, 6H; 7.44, d,J =9.3 Hz, IH; 7.87, d,j = 8.1 Hz, IH; 7.91, d, J = 8.4 Hz, 2H; 8.01, d,
J=9.0Hz, IH.

To 25(i) (280 mg, 0.82 mmol) in methanol (10 ml) was added potassium carbonate (500 mg, 3.63 mmol) and
bromoacetic acid (454 mg, 3.27 mmol) and the mixture stirred at reflux for 4 days. The reaction mixture was cooled
down, methanol removed in vacua, and the crude residue redissolved in water and acidified with IM HC1.
Extraction with ether, drying (Na2SO4) and concentration gave the crude product which was purified by flash
chromatography. Elution with 4% ethyl acetate;petrol gave unreacted 25(i) (150 mg, 54%). Further elution with
10% methanol;DCM gave the product 25(ii) (TOO mg, 31%).
1H NMR (500 MHz, CDC13) d 0.44, d, J = 6.5 Hz, 3H; 0.51, d,j = 7.0 Hz, 3H; 1.68, m, IH; 3.63, ABq, J = 7.0, 9.5
Hz. IH; 3.83, ABq, j= 6.5, 9.5 Hz, IH; 4.56, ABq,j = 17 Hz, IH; 4.71. ABq, / = 16 Hz. IH; 7.14. d, J = 8.0 Hz;
7.25, m. 2H, 7.35, m,4H; 7.45, d,J = 9.5 Hz, IH; 7.89, d. J = 8.5 Hz, 2H; 7.99, d. J = 8.5 Hz, 2H.

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95
This compound was prepared via Protocol 1. using 25(ii) with 23(viii). Purification by radial chromatography (1-4%
methnnol;DCM) gave the product 25(iii) (90 mg. 70%).
1H NMR (500 MHz, CDC13) d 0.43, d, J = 7.0 Hz, 3H; 0.49, a,j = 6.0 Hz, 3H, 0.77, m, 2H; 0.93, m, IH; 1.28, s, 6H;
1.41, s. 9H; 1.45, m,7H; 1.76, br t, 3H; 2.08, b s, 2H; 2.54, s, 3H; 2.56, s, 3H; 2.56, m,4H; 2.95, m, 2H; 3.13, m, IH;
3.60. m. IH; 3.81, m, IH; 4.07, br s, IH; 4.40, ABq, J = 14.5 Hz, IH; 4.50, ABq, J= 14.5 Hz, IH; 4.40, m, IH; 4.57,
m, IH; 4.83, b s, IH; 5.03, m, 2H; 5.09, ABq, J = 12.5 Hz; 5.18, ABq, J = 12.5 Hz; 5.63, m, 1; 6.20, m, 3H; 7.26, m,
7H; 7.43, a, J = 9.5 Hz, IH; 7.85, m, 2H; 7.94, a, J = 9.0 Hz, 2H. MS (ES +ve) 1260 (35%) [M+Nal]+; 1238 (15)
[M+H]+.

This compound was prepared via Protocol 3, using 25(Hi) (70 mg, 56.5 mmol) to give the product 25 as a cream
crystalline solid (30 rng, 56%).
1HNMR (500 MHz, CD,OD) d 0.52, d, J =6.2 Hz, 3H; 0.57, d, J =6.6 Hz, 3H; 0.87, m, 2H; 0.96, br s, IH; 1.13, m,
IH; 1.62. m, 4H; 1.28, m, 2H; 2.57, m, 2H; 2.79, br s. 2H; 3.15, br s, 2H; 3.70, m. IH; 3.91, m, IH; 4.14, b s. IH;
4.48, m. 4H; 4.89, br s, IH; 5.11, m. 2H; 5.15, ABq, IH, j = 12.5 Hz; 5.19. ABq. IH. J = 12.5 Hz; 5.74, m, IH; 7.09,
m. 2H; 7.22. m, 2H; 7.37, m. 7H; 7.47, d,J 8.5 Hz, IH; 7.54, d,,J=8.5 Hz, IH; 7.91. d,/ -7.7 Hz. 2H; 8.03, d,
7=8.5 Hz. 2H. MS (ES +ve) d72 (25%) [M+H] + ;437 (100) [M+2H]2+.

WO 2006/074501 PCT/AU2005/001444

96
Bromopentane (216 ml, 1.75 mmol) was added to a mixture of U'-bina phfh-2,2'-diol (500 mg, 1.75 mmol),
potassium carbonate (I,OOg, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for 18 h, and then
cooled and concentrated in vactio. The crude product was purified by flash chromatography with 1-4% ethyl
acetate;petrol as eluent to give the product 26(i) as a viscous oil (380 mg, 61%).
1H NMR (500 MHz, CDC13) d 0.66. t, J= 7 Hz, 3H; 0.96, m, 2H; 1.03. m, 2H; 1.43. m, 2H; 3.95, m, 2H; 4.94, s, IH;
7.05, d,J =8.5 Hz, IH; 7.28, m, 6H; 7.42, d,j= 9.0 Hz, IH; 7.83, d, J= 8.5 Hz; 7.87, d, J = 9.0 Hz, 2H; 7.98, d,j =
9.0 Hz. IH.

To 26(i) (280 mg, 0.82 mmol) in methanol (10 ml) was added potassium carbonate (500 mg, 3.63 mmol) and
bromoacetic acid (454 mg, 3.27 mmol) and the mixture stirred at reflux for 4 days. The reaction mixture was cooled
down, methanol removed in vacuo, and the crude residue redissolved in water and acidified with IM HC1.
Extraction with ether, drying (Na,SO4) and concentration gave the crude product that was purified by flash
chromatography. Elution with 4% ethyl acetate;petrol gave unreacted 26(i) (150 mg, 54%). Further elution with
10% methanol;DCM gave the desired compound 26(ii) as a viscous oil (100 mg, 31%).
IH NMR (500 MHz, CDCl3) d 0.53, t, /=7.5 Hz, 3H; 0.79, m, 4H; 1.35, m, 2H; 3.88, m, IH; 4.05, m, IH; 4.55, ABq.
J= 16.5 Hz, IH; 4.74. ABq, j= 16.5 Hz, IH; 7.14. dd,j = 8.5. 2.5 Hz, IH; 7.25. dd, j=5.5, 5.5 Hz, IH; 7.33. d. J =
9.5 Hz, IH; 7.36, m. 3H; 7.46, d.j =7.46 Hz, IH; 7.89. d,j = 8.0 Hz. IH; 7.98. d. J = 8.5 Hz, IH.

WO 2006/074501 PCT/AU2005/001444

This compound was prewed via Protocol 1. using 26(ii) with 23(viii) (80 mg, 94 mmol). Purification by radial
chromatography (1-4% mcthanol;DCM) gave the desired product 26(iii) (110 mg, 95%).
1H NMR (500 MHz, CDC13) d 0.54, d, J = 7.2 Hz, 3H; 0.83, m, 7H; 1.27, s, 6H; 1.41, s, 9H; 1.33, m, 8H; 1.76, br t,
3H; 2.08, br s, 3H; 2.54, s, 3H; 2.56, s, 3H; 2.53, m, 4H; 2.90, m, 2H; 3.06, m, 4H; 3.85, m. IH; 4.00, m. IH; 4.08,
br s, IH; 4.40. ABq. J = 14.5 Hz, IH; 4.52, ABq, J = 14.5 Hz, IH; 4.54, m, 2H; 4.85, br s, IH; 5.05, m, 2H; 5.15,
ABq, j= 12.0 Hz. IH; 5.17. ABq, J= 12.0 Hz, IH; 5.65. m. IH; 6.23, m. 3H; 7.11, d,j= 8.3 Hz, IH; 7.15, d,j=
8.3 Hz. IH; 7.26, m, 1OH; 7.44. d,j= 9.05 Hz; 7.85, m, 2H; 7.93, m, 211. MS (RS +ve) m/z 1252 (100%) [M+H]+.

This compound \vas prepared via Protocol 3, using 26(iii) (90 mg, 71.9 mmol). Standard work-up gave the product
26 as a white crystalline solid (45 mg. 65%).
MS (ES +ve) m/z 886 (70%) [M+H]+;444 (100) [M+H]2+

WO 2006/074501 PCT7AU2005/001444

l-Bromo-2,2-dimethylpropane (220 (J.1, 1.75 mmol) was added to a mixture of l,l'-binaphth-2,2'-diol (500 mg, 1.75
mmol). potassium carbonate (T.OOg. 7.27 mmol) and dimethylformamide (10 ml). The mixture was stirred at 80°C
for 7 days, and then cooled down and acidified with diluted hydrochloric acid. The mixture was diluted with water
and extracted with ether. The crude product was purified by flash chromatographv with 1-4% ethyl acetate;petrol as
eluent to give the product 27(i) as a viscous oil (80 mg, 13%).
1H NMR (500 MHz, CDC13) d 0.57, s, 9H; 3.57, m, 2H; 4.94, s, IH; 7.05, d. IH, j = 8.5 Hz; 7.17, m. 1H; 7.26, m,
2H; 7.35,m,4H; 7.81, d,J-8Hz, IH; 7.85, d,j =9 Hz, 2H; 7.95, d,j=9.5 Hz, IH.

To 27(i) (80 mg, 0.22 mmol) in methanol (10 ml) was added potassium carbonate (1.00 g, 7.27 mmol) and
bromoacetic acid (560 mg, 4.03 mmol) and the mixture stirred at reflux for 18h. The reaction mixture was cooled
down, methanol removed in vactio, and the crude residue redissolved in water and acidified with 1M HCI.
Extraction with ether, drying (Na2SO4) and concentration gave the crude product that was purified by flash
chromatographv. Rlution with 10% methanol;DCM gave the acid 27(ii) as a viscous oil (85 mg, 92%).
1H NMR (500 MHz, CDC13) d 0.50, s, 9H; 3.51, ABq, J= 8.0 Hz, IH; 3.66, ARq, J= 8.0 Hz, IH; 4.52. s. 2H; 7.20,
m. 4H; 7.32. m. 3H; 7.38. d, J = 9.0 Hz. IH; 7.85. d. J = 8.5 Hz. 2H; 7.93. m. 2H.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1, using 27(ii) and 23(viii) (82 mg, 96 jjmol) Purification by radial
chromatography (1-3% methanohDCM) gave the product 27(Hi) (73 mg, 61%).
1H NMR (300 MHz, CDC13) d 0.47, s,9H; 0.80, m,2H; 0.91, m,IH; 1.28, s, 6H; 1.41, s,9H; 1.40,m,6H; 1.77, brt,
3H; 2.08, s, 3H; 2.54, 4H; 3.11, m, 4H; 3.48, ABq, J = 8.1 Hz, IH; 3.72, ABq, J = 8.4 Hz, IH; 4.08, br s, IH; 4.49,
m, 4H; 4.84, br s, IH; 5.03, m, 2H; 5.09, ABq, j = 12.3 Hz, IH; 5.18, ABq, J = 12.3 Hz, IH; 5.66, m, IH; 6.13, d,J
= 7.2 Hz, IH; 6.30. br s, 2H; 7.27, m, 7H; 7.42, d, J = 9.0 Hz, IH; 7.85, m, 2H; 7.94, d, J = 8.7 Hz, 2H. MS (ES +ve)
m/z 1252 (20%) [M+H]+.

This compound was prepared via Protocol 3, using 27(iii) (60 mg, 47.9 mmol). Standard work-up gave the product
27 as a cream crystalline solid (30 mg, 65%).
1H NMR (300 MHz, CD3OD) d 0.52, br s, 9H; 1.05. m, 3H; 1.66, m, 6H; 2.52, m, 2H; 2.79, br s. 2H, 3.34, br s. 2H;
3.55, ABq, J = 8.1 Hz, IH; 3.79, ABq,J = 8.1 Hz, IH; 4.14, br s. IH; 4.42, m, 4H; 4.86, br s, IH; 5.11, m, 4H; 5.73,
m. IH; 7.31, 13H; 7.90. d,J = 8.1 Hz. 2H; 8.02, d, J = 8.4 Hz, 2H. MS (ES +ve) m/z 887 (20%) |M+H]+; 444 (100)
[M+2H]2+.

WO 2006/074501 PCT/AU2005/001444



100
2-Bromoethylbenzene (240 (m1, 1.75 mmol) was added to a mixture of l,l'-bina phth-2,2'-diol (500 mg, 1.75 mniol),
potassium carbonate (l.0Og, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for 18 h, and then
cooled down and filtered. The crude product was purified by flash chromatography with 1-4% ethyl acetate;petrol as
eluent to give the product 28(i) as viscous oil (250 mg, 37%)
1HT NMR (300 MHz, CDC13) d 2.69, m, 2H; 4.12, m, 2H; 4.90, s, IH; 6.76, m, 2H; 7.02, m, 4H; 7.26, m, 7H; 7.89, m,
4H.

To 28(i) (250 mg, 0.64 mmol) in methanol (10 ml) was added potassium carbonate (1.00 g. 7.27 mmol) and
bromoacctic acid (560 mg, 4.03 mmol) and the mixture stirred at reflux for 18h. The reaction mixture was cooled
down, methanol removed in vacuo, and the crude residue redissolved in water and acidified with IM MCI.
Extraction with ether, drying (Na2,SO4) and concentration gave the crude product that was purified by flash
chromatography. Elution with 10% methanol-DCM gave the acid 28(ii) as a viscous oil (257 mg, 89%).
1H NMR (500 MHz, CDCl3) d 2.62, m, 2H; 4.06, m, 2H; 4.15, m, 2H; 6.67, d, /= 7.5 Hz, 2H; 6.98, m, 3H. 7.15, m,
3H; 7.27, m, 2H; 7.34, m, 3H; 7.80. d, J= 8.5 Hz, IH; 7.89, m, 3H; 10.30. br s. IH.
WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 28(H) and l(viii) (100 mg, 115mmol). Purification by radial
chromatography (1-3% methanoLDCM) gave the product 28(iii) (83 mg, 56%).
1H NMR (300 MHz, CDC13d 0.75. m, 2H: 0.89, m, 6H; 1.26, s, 6H: 1.40, s, 9H; 1.60, m, 6H; 1.76, br t, 3H: 2.08, s,
3H; 2.62, m, 4H; 3.00, m, 4H: 4.05, m, 211; 4.31, m, 411; 4.54, m. IH: 4.80, m, IH; 5.09, ABq, J =12.6 Hz, IH; 5.17,
ABq, ./ = 12.6 Hz, III; 6.10, br d, J = 7.2 Hz. IH; 6.31. br s, 2H; 6.59, a, J =6.9 Hz, 2H; 6.99, m. IH; 7.22, m,911;
7.82, d../ = 8.1 Hz, IH; 7.90, m. 2H. MS (ES +vc) mz 1302 (100%) [M]+.

This compound was prepared via Protocol 3, using 28(Hi) (80 mg. 61.4 |imol). Standard work-up gave the product
28 as a cream crystalline solid (40 mg, 65%).
1H NMR (300 MHz, DMSO-d6) d 0.47, m, 6H; 1.12, m, 3IT; 1.47, m, 4H; 2.07, s. 1H; 2.41, m, IH; 2.49, br s, 3H;
2.66, m, IH; 2.66, m, IH: 3.04, m, IH: 3.55, m, 8H: 4.26, m, 4H: 5.03, m, 2H: 5.74, m, IH: 6.94, br d, j = 8.4 Hz,
IH: 7.02. br d. j= 8.4 Hz. IH: 7.30, m. 15H: 7.51, m, IH: 7.92, m, 2H; 8.02. m, 2H. MS (ES +vc) m'z 936 (100%)
[M] +

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 23(vii) (121 mg, 0.14 mmol) and l(ii) (58 mg, 0.14 mmol) to
afford 29(i) as a white solid (114 mg, 65%) Mp 90-94oC.
1H NMR (300 MHz, CDC13) d 0.46, d, J = 6.3 Hz, 3H; 0.52, d, J =.3 Hz, 3H; 0.79, m. 4H; 0.92, m, 2H; 1.12, m,
2H; 1.26, s, 6H; 1.41, s, 9H; 1.52, m, 4H; 1.76, t, J = 5.7 Hz, IH; 2.09, s, 3H; 2.49, m, 2H; 2.55, s, 3H; 2.56, s, 3H;
2.64. m, 2H; 2.92, m, 2H; 3.14, m, 2H; 3.95, m, 2H; 4.80, m, 5H; 5.05, m, 2H; 5.13, ABq, J = 12.3 Hz, 2H; 5.65. m,
IH; 6.18, d, j = 6.9 Hz, IH; 6.29, br s, 2H; 6.47, m, IH; 7.30, m, 13H; 7.90, m, 4H. MS (ES +ve) mz 1274 (100%)
[M+NH4].

This compound was prepared via Protocol 3, using 29(i) (114 mg, 0.091 mmol) to yield 29 as a highly hydroscopic
cream solid (48 mg, 55%).
1H NMR (500 MHz, CD3OD) d 0.47, d, J = 6.3 Hz. 3H; 0.53, d, J = 6.3 Hz, 3H; 0.96, m, 2H; 1.17, m, 2H; 1.24, m.
2H; 1.55, m, 4H; 1.71, m, 2H; 1.79, m, 2H; 2.55, m, 2H; 2.79, m, 2H; 3.14, m. 2H; 3.95, m. IH; 4.14. m. 2H; 4.35,
m. IH; 4.49, m. 3H; 5.1 1. m, 4H; 5.74, m. IH; 5.32. m, 13H; 7.96, m, 4H. MS (ES +ve) mz 886 (5%) [M]+2; 444
(100%).

WO 2006/074501 PCT/AU2005/001444
General Synthetic Scheme for Reverse-Peptide Compounds (Example - Compound 30)


WO 2006/074501 PCT/AU2005/001444

To l(i) (10.0 g, 28 mmol) in dry acetone (200 ml) was added potassium carbonate (20.0 g, 145 mmol),
chloroacetonitrile (3.0 ml, 47 mmol) and potassium iodide (2.50 g, 15 mmol). The resultant solution was heated at
reflux for 18 hrs and then cooled down and filtered. Acetone was removed and the residue redissolved in ethyl
acetate and water, and neutralized with IM HC1. Organic extract was separated and water phase extracted with more
ethyl acetate. Organic extracts were combined, dried (MgSO4) and concentrated. Purification by column
chromatography with 1-20% ethyl acetate/petrol gave the product 30(i) as a colourless viscous oil (10.0 g, 90%).
1H NMR (300 MHz, CDCl3) d 0.54, d, J =6.0 Hz, 3H; 0.60, d, J = 5.7 Hz, 3H; 1.25, m, 2H; 3.89, m. IH; 4.05, m,
IH; 7.22. m, 6H; 7.38, d, J = 9.0 Hz. IH; 7.40, d, j = 9.3 Hz, IH; 7.80, d,J = 7.5 Hz, 7.81: d, J = 8.1 Hz, IH, 7.90, d,
J = 9.0 Hz, III; 7.91, a, J = 9.3 Hz, IH.

A solution of 30(i) (10.00 g, 25 mmol) in dry ether (50 ml) was added dropwise to a suspension of lithium
aluminium hydride (3.00g, 79 mmol) in ether (30 ml) during 2 hrs with ice bath cooling, and then stirred for 18 hrs
at room temperature. Ether (100 ml) was added to the reaction mixture and then a potassium hydroxide solution in
water (20%) was added until a white precipitate separated on the bottom of the flask. Ether solution was filtered to
give the crude product that was purified by column chromatography to give the product 30(Ii) (8.05 g, 80%).
1H NMR (300 MHz, CDC13)'d 0.55, d, J = 6.3 Hz. 3H; 0.60, d, J = 6.3 Hz, 3H; 0.87 m, IH; 1.22, m. 4H; 2.64, br s,
2H; 3.95, m, 4H; 7.20. m, 4H; 7.31, m, 2H; 7.38. d. J = 8.7 Hz, IH; 7.41. d, J = 8.7 Hz. IH; 7.84, d, J = 8.1 Hz, 2H;
7.91.d.J=8.7 Hz, 2H.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 30(ii) (260 mg, 0.65 mmol) and (R)-Fmoc-Lys(Boc)-OH (305
mg, 0.65 mmol) to yield the desired product 30(iii) as an off white solid (310 mg, 56%).
1H NMR (300 MHz, CDC13) d 0.41, d. J= 6.0 Hz. 3H; 0.53, d, J =6.5 Hz, 3H; 1.27, m, MH; 1.44, s, 9H; 2.85, m,
2H; 3.35, m, 2H; 3.81, m, 2H; 4.03, m, 2H; 4.12, m, IH; 4.21, m, IH; 4.38, m, 2H; 4.53, m, IH; 5.38, br d, IH; 5.78,
brs, IH; 7.09, d, J = 8.5 Hz, IH: 7.25, m, IOH; 7.49, d, j = 9.0 Hz, IH; 7.58, d, J = 7.0 Hz, 2H; 7.73, d, j = 7.5 Hz,
2H; 7.85. d, j= 8.0 Hz, IH: 7.90, d, J = 7.5 Hz, IH; 7.94. d, j= 9.0 Hz, IH; 8.00, d, j = 9.0 Hz, IH. MS (ES +ve)
mz 849 (100%) [M+Na]+.

This compound was prepared via Protocol 2, using 30(iii) (310 mg, 0.365 mmol) to yield the desired product 30(iv)
as an off white solid (172 mg, 75%).
1H NMR (Soo MHZ. CDC13) d 0.58. 3H, dd, j = 6.3, 1.5 Hz; 0.65, 3H, dd, j = 6.6, 1.5 Hz; 1.51, m, 1 1H; 1.51. s. 9H;
2.93. m. IH; 3.17, m. 3H; 3.30. m, IH. 3.45, m, IH: 3.92, m, IH: 4.12, m, 3H; 4.79, br s, IH; 6.73, m, IH; 7.15. m,
IH; 7.25. m, 3H; 7.36, m. 2H; 7.48, m. 2H: 7.91, m. 2H; 7.99, m, 2H. MS (ES +ve) mz 628 (100%).

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol I. using 30(iv) (172 mg, 0.274 mmol) and (/?)-Fmoe-Arg(Pmc)-OH (182
mg, 0.274 mmol) to yield the desired product 30(v) as an off white solid (165 mg, 47%).
1H NMR (300 MHz, CDC13) d 0.41, d, J = 6.6 Hz, 3H; 0.52, d, j = 6.3 Hz, 3H; 1.25, s, 6H; 1.37, s, 9H; 1.30, m,
13H; 1.71, br t, 3H; 1.83, br s, IH; 2.07, s. 3H; 2.55. s. 3H; 2.59, s, 3H; 2.84, m, 3H; 3.19, m, 4H; 3.81, m. IH; 4.02,
m, 3H; 4.12, m, IH; 4.31, m, 3H; 4.84, br s, IH, NH; 6.22, m, 5H, NH; 7.21, m, 1OH; 7.48, m,4H; 7.70, d, J =7.5
Hz, 2H; 7.89, m,4H. MS (ES +ve) m'z 1272 (5%) [M+H]4

This compound was prepared via Protocol 2, using 30(v) (165 mg, 0.130 mmol) to yield the desired product 30(vi)
as an off white solid (100 mg, 73%).
1H NMR (300 MHz, CDC13) 5 0.41. d. j = 6.6 Hz, 3H; 0.53, d, J = 6.3 Hz. 3H; 1.28, s, 6H; 1.41, s, 9H; 1.36, m, 14
H; 1.77. br t, 3H; 2.10. s, 3H; 2.56. s, 3H; 2.58, s. 3H; 2.92, m, 2H; 3.20, m. 3H; 3.37. m. 211; 3.81. m. IH; 4.08, m,
4H; 4.84, br s, IH, NH; 6.22, m,5H, NH; 7.23, m. 6H; 7.38, d. J= 9.0 Hz, IH; 7.49, d, j = 9.0 Hz, IH; 7.96, m.4H.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 30(vi) (100 mg, 95 mmol) and (7?)-Fmoc-Leu- OH ( 34 mg, 95
mmol) to yield the desired product 30(vii) as an off white solid (120 mg, 91%).
1H NMR (300 MHz, CDC13) d 0.41, br d, J = 6.0 Hz, 3H; 0.51, br d, J = 6.3 Hz, 3H: 0.88, br d, j = 5.7 Hz, 3H; 0.90,
br d. j =5.7 Hz, 3H; 1.24, s, 6H; 1.39, s, 9H: 1.56, m, 23H; 2.06, s, 3H; 2.51, s, 3H: 2.54, s, 3H; 2.71, s, IH; 2.88, m,
2H; 3.11, m, 3H; 3.31, m, IH; 3.77, m. IH; 3.98, m, 2H. 4.11, m, IH; 4.27, m, 2H; 4.54, br s, IH, NIL 4.92, br s,
1H, NH; 6.35, m, 5H, NH: 7.26, m, 1OH; 7.55, m, 4H; 7.70, d, j = 7.2 Hz, 2H; 7.89, m,4H. MS (ES +ve) m z 1385
(15%) [M]+.

This compound was prepared via Protocol 2, using 30(vii) (120 mg, 87 mmol) to yield the desired product 30(viii) us
an off white solid (80 mg, 79%).
MS (ES +ve) m z 1163 (80%) [M]+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 30(viii) (50 mg, 43 (mmol) and phenylacetic acid (6 mg, 43 mmol)
to yield the desired product 30(ix) as a cream solid (50 mg, 91%).
1H NMR (300 MHz, CDC13) d 0.43. d, J = 6.0 Hz, 3H; 0.53, d, j = 6.3 Hz, 3H; 0.80, br d, 3H; 0.83, br d, 3H; 1.28, s,
6H; 1.26. m, 14H; 1.41, s, 9H; 1.77, br t, 3H; 2.09, s, 3H; 2.53, s, 3H; 2.55, s, 3H; 2.90, m, 3H; 3.13, m, 2H; 3.29, m,
IH; 3.50, m, 2H; 3.62. s. 2H; 3.81, m, IH; 3.99. m, 4H; 4.46, m, 2H; 4.86, br s, IH, 6.25, m, 5H; 7.24, m, 1IH, 7.89,
m,6H. MS (ES +vc) mz 1303 (75%) [Mn-Na]+.

This compound was prepared via Protocol 3, using 30(ix) (50 mg, 39 (mmol) to yield the desired product 30 as a
cream solid (20 mg, 56%).
1H NMR (300 MHz. CDC13) d 0.48. d.. j = 6.3 Hz. 3H; 0.57. d, J = 6.6 Hz. 3H; 0.88. br d, 311; 0.95. br d. 311; 1.19.
m. 6H; 1.58. m, 7H; 2.82, br s, 211; 3.27, m, 711; 3.65, m, 2H; 3.87, m. IH; 4.07, m.4H; 4.27, m, 2H; 4.54. br s, IH,
NH; 4.92. br s, IH, NH; 6.35, m. 5H, NH; 7.22, m, IOH; 7.55, m. 4H; 7.70. d. j= 7.2 Hz, 2H; 7.89, m, 4H. MS (ES
+ve) mz 915 (5%) [M]+, 458 (100) [M+2H]2+.

WO 2006/074501 PCT/AU2005/001444


WO 2006/074501 PCT/AU2005/001444

To Fmoc-(D)-Arg(Pmc)-OH (400 mg. 604 mmol) suspended in DCM was added SOCl2(2 ml) at 0°C. After
stirring for an hour the solvent was removed and the resultant residue resuspended in DCM and BzOH
(0.1 ml) added. The solution was then stirred overnight at 40°C before being evaporated to dryness. The
crude residue was then subjected to flash column chromatography over silica using 2%MeOH/DCM as
the eluant to afford the desired product 31(i) as a white solid (341 mg. 75%).
1H NMR (300 MHz. CDC13)  1.29. s, 6H; 1.51, m, 2H; 1.74. m, 4H; 2.H. s, 3H; 2.58, m, 8H; 3.13, m, 2H; 4.14. m,
IH. 4.34. m. 311; 5.H. s, 2H; 5.98. d. j = 9.2 Hz. NH; 6.16, br s. NH; 6.29. br s, NH; 7.30, m. 9H; 7.58. d, J = 7.5
Hz, 2H: 7.75, d, j =7.2 Hz. 2H.

This compound was prepared via Protocol 2, using 31(i) (341 mg, 0.463 mmol) to yield the desired product 3I(ii) as
a white solid (159 mg, 65%).
1H NMR (300 MHz, CDC13) d 1.27, s, 6H; 1.51,m,2H; 1.78, m,4H: 2.07, s, 3H; 2.52. m, 8H; 3H. m, 2H: 3.41, m,
IH: 5.07, s, 2H; 6.38. s, NH; 7.30, m, 5H.


WO 2006/074501 PCT/AU2005/001444
To a suspension of (S)-l.r-binapth~2.2'-diol (1 g. 3.5 mmol) and anhydrous potassium carbonate (2.4 g. 5
equiv) dissolved in acetone (25 ml). was added ethyl bromobutyrate (1.15 ml. 2.3 equivalents) under an
N2 atmosphere. The mixture was then heated at reflux for 24 hrs before being evaporated to dry ness and
the residue partitioned between ethyl acetate and water. The organic layer was then washed twice with
water before being dried and evaporated to dryness to yield an oil 31(iii) which was used in the next step
without further purification.
1H NMR (300 MHz. CDC13) d 1.17, t ,J = 7.2 Hz. 6H; 1.70, m, 4H, 1.85, m,4H; 3.98. m, 8H; 7.17. m, 4H; 7.30. m,
2H; 7.39. d, j = 8.8 Hz. 2H; 7.84, d, J = 8.0 Hz. 2H; 7.92. d, j = 8.8 Hz. 2H. MS (El) mz 514 (90%) [M]+; 400 (80);
115 (100).

To 31(iii) (598 me 152 mmnl) dissolved in THF (30 ml) was added a solution of LiOH (250 mg 10 5 mmol) in
water (20 ml), After stirring at RT for 4 hrs, diethyl ether was added and the layers separated. The aqueous layer was
then acidified with 1M HC1 before being extracted with diethyl ether (3 x 20ml). The combined organic extracts
were then dried (MgSO4) and evaporated to dryness to yield the product 31 (iv) as a white foamy solid (342 mg,
64%).
1H NMR (300 MHz, CDC13) d 1.65, m, 4H, 1.82, m, 4H; 3.93, m, 2H; 3.98, m, 2H; 7.15, m, 4H; 7.27, m, 2H; 7.35.
d, J = 9.1 Hz, 2H; 7.81, d, J = 8.2 Hz, 2H; 7.90, d, j= 8.8 Hz, 2H; H.84, br s. 1H. MS (El) mz 458 (50%) [M|+
372 (25) [M-CH2CH2CH2COOH]+; 286 (100) [M-2xCH2CH2CH2COOH] '.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via protocol 1. using 31(ii)(159 mg, 0.30 mmol) and 31(iv)(68.7 mg, 0.15 mmol) to
yield 31(v) as a white solid (124 mg, 59%).
1H NMR (300 MHz, CDC13) d 1.25, s, 12H; 1.34, m, 8H; 1.70, m, 12H; 2.06, s, 6H; 2.51, m, 16H; 3.05, m, 4H; 3.75,
m, 2H; 3.96, m, 2H; 4.34, m, 2H; 5.04, s, 4H; 6.H, br s, NH; 6.22, br s, NH; 6.42, d,J = 7.2 Hz; NH; 7.06, d,J =
8.5 Hz, 2H; 7.15, dist t, 2H; 7.25, m, 12H; 7.32, d, J = 9. lHz; 2H; 7.79, d, J = 8.2 Hz, 2H; 7.85, d, J = 8.0 Hz, 2H.
MS (ES +ve) m/z 742.7 (100%) [M+H]+2.

This compound was prepared via Protocol 3. using 31(v) (124 mg. 0.089 mmol) to yield 3 1 as a white solid (65.9
mg. 73%).

WO 2006/074501 PCT/AU2005/001444
1H NMR (300 MHz. CD3OD) d 1.58, m,4H; 1.70. m, 6H; 1.85. m.2H; 1.95. m, 4H; 3.12. m.4H; 3.98. m.4H; 4.38.
m, 2H; 5.08, s, 4H; 7.06, m, 2H; 7.15, m, 2H; 7.25, m, 12H; 7.42, m. 2H; 7.83, m. 2H; 7.95, m, 2H. MS (ES +ve)
m/z 951.2 (10%) [M+Hl+;476.8 (100) [M+H]2+.

mmol) to yield the desired product 32(i) as an off white solid (90 mg, 87%). Rf = 0.44 (5% MeOH/DCM).
1H NMR (300 MHz. CDC13) d 1.18, m, 4H; 1.40, m, 4H; 1.43, s, 18H; 1.69, m, 12M; 3.01, m. 4H; 3.73, s, 6H; 3.87,
m, 2H; 4.15, m, 2H; 4.47. m, 2H; 4.53, m, NH; 5.62. a, j = 8.2 Hz, NH; 7.19, m, 2H; 7.22, m, 2H; 7.35, m. 2H; 7.45,
d, j =9.1 Hz. 2H; 7.91. d.J = 8.2 Hz, 2H; 7.99. d, J = 8.8 Hz, 2H. MS (E,S +ve) m/z 981.5 (30%) [M+K]'; 968.6
(100) [M+Na]+; 943.6 (10) [M+H]+.


WO 2006/074501 PCT/AU2005/001444
This compound was prepared via Protocol 3, using 32(1) (88 mg, 0 093 mmol) to yield the desired product 32 as an
off white solid (50 mg, 76%).
1H NMR (300 MHz, CD3OD) d 1.39, m, 4H; 1.67, m, 12H; 1.96, m,4H; 2.89, m,4H; 3.35, s, 6H; 4.02, m,4H, 4.30,
m, 2H; 7.02, dist d; J = 8.0 Hz, 2H; 7.17, m, 2H; 7.29, m, 2H; 7.52, m, 2H; 7.87, m, 2H; 7.98, m. 2H. MS (ES +ve)
m/z 743.3 (10%) [M+H]+; 372.6 (100) [M+2H]2+.

This compound was prepared via Protocol 1, using (D)-arg(Pmc)-OMe (40 mg, 0.088 mmol) and 31(iv) (20 mg,
0.044 mmol) to yield 33(i) as a white solid (18 mg, 31%).
1H NMR (300 MHz, CDCl3) d 1.28, s, 12H; 1.43, m, 4H; 1.77. m, 12H; 1.86, m, 4H; 2.09. s, 6H; 2.52. s, 6H; 2.55. s.
6H; 2,59, m, 2H; 3.12, m, 4H; 3.65, s, 6H; 3.84, m, 2H; 4.01, m, 2H; 4.37. m, 2H; 6.20, br s, NH; 6.42. m, NFL; 7.02.
dist d, NIT; 7.09, d, j = 8.3 Hz, 2H; 7.19, dist t, 2H; 7.30, dist t, 2H; 7.39, d, J = 9.1 Hz, 2H; 7.85, m, 2H; 7.92, d. J
= 9.1 Hz, 2H; 7.97, d,NH; 7.99, d,NH.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 3, using 33(i) (20 mg, 0.015 mmol) to yield 33 as a white solid (9 mg,
64%).
1H NMR (300 MHz, CD3OD) d 1.34, m, IOH. 1.61,m, 6H; 2.93, m, 4H; 3.46, s, 6H; 3.62, m, 2H; 3.75, m, 2H; 4.05,
m, 2H; 6.53, m, 2H; 6.74, m, 4H; 7.16. d, j = 8.8 Hz, 2H; 7.42, d. J = 7.7 Hz, 2H; 7.57, d, j = 8.3 Hz, 2H. MS (E.S
IVC) m/z.' 401 (100% ) [M]2H]2+ .

To 32(i) (200 mg, 0.212 mmol) dissolved in THF (20 ml), was added a solution of LiOH (75 mg. 3.14 mmol) in
water (10 ml). After stirring at RT for 90 minutes, ethyl acetate was added and the layers separated. The aqueous
layer was then acidified with a dilute potassium bisulphate solution. This was then extracted with DCM (3 x 20ml)
and the combined organic extracts then dried and evaporated to dryness to yield the product 34(i) as a white foamy
solid (178mg, 92%).

WO 2006/074501 PCT/AU2005/001444
1H NMR (300 MHz, CDCl3) d 1.24, m, 4H; 1.40, s, 18H; 1.44, m,4H; 1 76, m, 12H; 3.00, m,4H; 3.77, m. 2H; 4.09.
m, 2H; 4.46, m, 2H; 4.85, m, NH; 6.29, m, NH; 7.16, m, 2H; 7.21, m, 2H; 7.28, m, 2H; 7.30, d, j = 9.0 Hz, 2H;
7.84, d, J = 7.8 Hz, 2H; 7.87. d, J = 8.7 Hz, 2H. MS (ES +ve) m/z 937.2 (15%) [M+Na]+; 915.2 (15) [M+H]+. MS
(ES -ve) m/z 913.1 (100%) [M-H]".

This compound was prepared via Protocol 4, using 34(i) (120 mg, 0.131 mmol), triphcnyl phosphinc (73 mg, 0.278
mmol), DIAD (0.055 ml. 0.275 mmol) and BzOH (0.05 ml. 0.275 mmol). The BOC- protected intermediate 34(ii)
eluted at the same time as a reaction by product, and so this material was then deprotected via protocol 3 to yield the
desired product 34 as a pale yellow hydrochloride salt (101 mg, 80%).
1H NMR (300 MHz, CDC13) d 1.32, m, 4H; 1.68, m, 1OH; 1.79, m, 2H; 1.93. m, 4H; 2.82, m, 4H; 3.97, m. 4H; 4.33,
m,2H; 5.H, ABq, j= 12.3 Hz, 4H; 7.01, dist d, j = 8.5 Hz, 2H; 7.14, app t. 2H; 7.31, m, 14H; 7.48, m, 2H; 7.62. m,
2H; 7.85, d, j = 7.9 Hz, 2H; 7.94, d, J = 8.8 Hz, 2H. MS (ES +ve) m/z 895.5 (10%) [M+H] + ; 825.4 (40) [M-lys]+;
448.7 (100) [M+2H]2+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 4, using 34(i) (60 mg, 0.066 mmol), triphenylphosphine (73 mg, 278
mmol). DIAD (0.055 ml, 0.275 mmol) and 1-naphthalene methanol (45 mg, 0.0.28 mmol). The BOC- protected
intermediate 35(i) eluted at the same time as a reaction by product, and so this material was then deprotected via
Protocol 3 to yield the desired product 35 as a pale yellow hydrochloride salt (58 mg, 83%).
1H NMR (500 MHz, CDC13) d 1.10, m, 4H; 1.40, m, 4H; 1.51, m, 4H; 1.63, m, 4H; 1.76, m, 4H; 2.58, m, 4H; 3.73.
m, 2H; 3.80, m, 2H; 4.19, m, 2H; 6.90. dist t, 2H; 7.00, t, J = 7.1 Hz. 2H; 7.13, dist t, 2H; 7.30, m, 4H; 7.37, m, 6H;
7.38, m, 8H, 7.84, d, j = 8.0 Hz; 2H. MS (ES +ve) m/z 995.5 (10%) [M+H)+; 825.4 (40) [M-lys]+; 448.7 (100)
[M+2H]2+.


WO 2006/074501 PCT/AU2005/001444
The crude PMC protected precursor 36(i) was prepared via Protocol I using 34(0 (120 mg. 0.131 mmol) and 2-
pyridyl carbinol (0.026 ml) to yield an impure light brown solid. This was then deprotected via protocol 3 to yield
36 as an off white solid (68 mg, 54%).
1H NMR. (300 MHz, CD3OD) d 1.41, m, 4H; 1.65, m, 8H; 1.95, m, 4H; 2.87, m, 4H; 3.97, m 4H; 4.31, m, 2H; 5.41,
ABq, J = 14.4 Hz, 2H; 5.52, ABq, j = 14.4 Hz, 2H; 6.96, dist d, 2H; 7.14, dist t, 2H; 7.26, dist t, 2H; 7.46, dist d,
2H; 7.83. d, j = 7.9 Hz, 2H; 7.92, m, 4H; 8.00, dist d, 2H; 8.47, dist t 2H, 8.76. br d, 2H. MS (ES +ve) m/z .AA9.A
(100%) [M+2H]2+.

To 33(i) (200 mg, 0.2 mmol) dissolved in THF (20 ml), was added a solution of LiOH (75 mg, 3.1 mmol) in water
(10 ml). After stirring at RT for 90 minutes, ethyl acetate was added and the layers separated. The aqueous layer was
then acidified with a dilute potassium bisulphate solution. This was then extracted with DCM (3 x 20ml) and the
combined organic extracts then dried and evaporated to dryness to yield the product 37(i) as a white foamy solid
(145 mg, 88%). The protected precursor was prepared via Protocol 1 using 37(i) (60 mg, 0.046 mmol) and 2-
pyridyl carbinol (0.02 ml) to yield 37(ii) as an impure light brown solid (MS (ES +ve) m/z 1485.5 (10%) [M+H]+.
743.3 (20) |M+H]2+). This was then deprotected via Protocol 3 to yield 37 as an off white solid (28 mg, 64%).
1H NMR (300 MHz, CD3OD) d 1.69, m. 1OH; 2.00, m,6H; 3.20, m,4H; 4.00, m,4H; 4.39. m, 2H; 5.44, ABq, J=
14.9 Hz. 2H; 5.53, ABq, j = 14.9 Hz, 2H; 6.99, m, 2H. 7.16. m. 2IT. 7.28, m. 2H; 7.50, m. 2H; 7.94, m, 8H. 8.47, m.
2H; 8.78. m, 2H. MS (ES +ve) m/z All. 5 (100%) [M+2H]2+.

WO 2006/074501 PCT/AU2005/001444

To a suspension of (/?)-1,1'-bina pth-2,2'-ol (1 g, 3.5 mmol) and anhydrous potassium carbonate (2.4 g, 5 equiv)
dissolved in acetone (25 ml), was added ethyl bromobutyrate (1.15 ml, 2.3 equivalents) under an N2 atmosphere.
The mixture was then heated at reflux for 4 days before being evaporated to dry ness and the residue partitioned
between ethyl acetate and water. The organic layer was then washed twice with water before being dried and
evaporated to dryness. The crude residue was subjected to Hash column chromatography to yield the desired
compound 38(i) (1.05 g, 68%).
1H NMR (300 MHz, CDC13)  1.15, t, j = 7.2 Hz, 6H; 1.70. m, 4H, 1.86, m, 4H; 3.98. m, 8H; 7.16, m, 4H; 7.27, m,
2H; 7.38, d, J - 9.1 Hz, 2H; 7.82, d,J = 8.2 Hz, 2H; 7.90, d, j - 9.1 Hz, 2H.

To 38(i) (1.0 g. 1.94 mmol) dissolved in THF (30 ml), was added a solution of LiOH (300 mg, 12.5 mmol) in water
(20 ml). After stirring at RT overnight, diethyl ether was added and the layers separated. The aqueous layer was then
acidified with a dilute HC1 solution. This was then extracted with diethyl ether (3 x 20ml), the combined organic
extracts were then dried and evaporated to dryness to yield 38(ii) as a white foamy solid (646 mg, 89%).
1H NMR (300 MHz. CDC13)  1.71. m.4H. 1.90.m.4H; 3.91, m, 2H; 3.99. m, 2H; 7.H, dist a, J = 8.3 Hz, 2H; 7.18,
m. 2H; 7.27. m. 2H; 7.37, d. J = 8.8 Hz. 2H; 7.83, d, J = 8.0 Hz. 2H; 7.90. d. J = 8.8 Hz, 2H; 9.34. bs s. COOH.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 1. using 31(H) (125 mg, 0.236 mmol) and 38(ii) (45 mg, 0.098 mmol) to
yield 38(iii) as a white solid (123 mg, 86%).
1H NMR (300 MHz, CDC13)  1.25, s, 12H; 1.34, m,4H; 1.70, m, 16H; 2.06, s, 6H; 2.51, m, 16H; 3.04, m, 4H; 3.79,
m. 2H; 3.96. m. 2H; 4.37. m, 2H; 5.04. s. 4H; 6.05. br s. NH; 6.21. br s. NH; 7.06. d.j = 8.5 Hz. 2H; 7.15. dist t. 2H;
7.25, m. 12H; 7.32, d, J = 9.1 Hz; 2H; 7.79, d, j = 7.9 Hz, 2H; 7.87. d, j = 9.1 Hz, 2H. MS (ES +ve) m/z 1483.4
(10%) [M+H]+; 742.4 (20) [M+H]2+.

This compound was prepared via Protocol 3, using 38(Hi) (120 mg. 0.081 mmol) to yield 38 as a white solid (71 mg.
86%).

WO 2006/074501 PCT/AU2005/001444
1H NMR (300 MHz. CD3OD)  1.56. m. 4H; 1.67. m. 6H; 1.83. m. 2H; 1.93. m. 4H; 3.12. m. 4H; 3.93, m. 2H; 4.02.
m, 2H; 4.34. m. 2H; 5.07, ABq, J = 12.3 Hz, 2H; 5.12, ABq, j = 12.3 Hz, 2H; 7.00, m. 2H; 7.12. m, 2H; 7.27. m,
12H; 7.46, m, 2H; 7.83, d, J = 7.9 Hz. 2H; 7.93, d. J = 9.1 Hz, 2H. MS (ES +ve) m/z 476.5 (100%) [M+H]2+.

To 34 (20 mg, 0.021 mmol) in DCM (2 ml) was added triethylamine (0.09 ml) and N,N'-bis(tert-butoxvcarbonyl)-
N"-triflyl guanadine (25 mg, 0.062 mmol) under N2,. The solution was allowed to stir overnight before being
evaporated to dryness. The resultant residue was then subjected to flash column chromatography (over silica), using
2% MeOH/DCM as the eluant to yield the desired compound 39(i) as a pale yellow oil (23 mg, 79%).
1H NMR (300 MHz, CDC13)  1.18, m,4H; 1.48,m,4OH; 1.59, m,4H; 1.70, m, 8H; 3.27, m, 4H; 3.82. m, 2H; 4.09,
m, 2H; 4.45, m, 2H; 5.15, ABq, J = 12.3 Hz, 4H. 5.54, d, J = 8.2 Hz, NH; 7.16, dist d, / = 8.2 Hz, 2H; 7.24, m, 2H;
7.31, m, HH; 7.49, m, IH; 7.62, m, 2H; 7.87, d, J = 7.9 Hz, 2H; 7.94, d, J = 9.1 Hz, 2H; 8.28, m.NH. MS (ES +ve)
m/z 1401.7 (40%) [M+Na]+; 1379 (100) [M+H] +.+

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 3, using 39(i) (20 mg, 0.014 mmol) to yield the desired product 39 as a
light brown solid (15 mg, 86%).
1H NMR (300 MHz, CDCI3)  1.18. m,4H; 1.48, m,4OH; 1.59, m,4H; 1.70, m, 8H; 3.27. m, 4H; 3.82, m, 2H; 4.09,
m 2H; 4.45, m, 2H; 5.15,ABq, j = ]2.3 Hz, 4H; 5.54,d, j = 8.2 Hz, NH; 7.16; dist d,j =8.2 Hz; 2H; 7.24; m; 2H;
7.31. m, HH; 7.49, m, IH; 7.62, m, 2H; 7.87, d, J= 7.9 Hz, 2H 7.94, d, j = 9.1 Hz, 2H; 8.28, m. NH. MS (ES +ve)
m/z 490.5 (60%) [M+2HT] 452.4 (100) [M+H-Ph]2+ ;414.5(80) [M+2H-2Ph]2+.


WO 2006/074501 PCT/AU2005/001444
To 35 (47 mg, 0.044 mmol) in DCM (2 ml) was added triethylamine (0.19 ml) and N,N'-bis(tert-butoxycarbonyl)-
N"-triflylguanadmc (53 mg, 0.13 mmol) under N2. The solution was allowed to stir overnight before being
evaporated to dryness. The resultant residue was then subjected to flash column chromatography (over silica),
eluting with 2%MeOH/DCM to yield the desired compound 40(i) as an off white solid (40 mg, 61%).
1HNMR (300 MHz, CDC13)  1.01,m,2H; 1.32, m,2H; 1.48,m,44H; 1.54, m,4H; 1.70, m, 8H; 3.14. m,4H; 3.73,
m, 2H; 4.00, m, 2H; 4.42, m, 2H; 5.51, d, J = 7.9 Hz. NH; 5.61, ABq, J = 12.3 Hz, 4H; 7.12, dist d, J = 7.9 Hz. 2H;
7.26, m, 6H; 7.53, m, 8H; 7.80, m, 4H; 7.88, m, 4H; 7.97, dist d, J = 7.9 Hz, 2H; 8.24, m, NH. MS (ES +ve) m/z
1501.8 (10%) [M+Na]+; 1479.7 (10) [M+H]+; 740.5 (20) [M+2H]+.

This compound was prepared via Protocol 3, using 40(i) (38 mg, 0.026 mmol) to yield the desired product 40 as a
light brown solid (18 mg, 61%).
1H NMR (300 MHz, CDCl3)  1.32, m,6H; 1.62, m, I OH; 1.92, m,4H; 2.95, m,2H; 3.10, m,2H; 3.97, m,4H; 4.30,
m, 2H; 5.57, m, 4H; 7.02, m, 2H; 7.17, m, 2H 7.229, m, 2H; 7.50, m, 1OH; 7.88, m, 1OH. MS (ES +ve) m/z 540.4
(20%) [M+2H]+; 477.3 (95) [M+H-nap] 2+; 414.4 (100) [M+H-2nap]2+.

WO 2006/074501 PCT/AU2005/001444

To a suspension of 3-aminobenzoic acid (1.03 g mg, 7.52 mmol) in MeOH (80 ml) at 0 °C was added dropwise
thionyl chloride (5 ml). The resulting solution was allowed to stir for 16 h before the solvent was removed by
evaporation and the product precipitated with diethyl ether. The diethyl ether was removed by evaporation to yield
the title compound 4I(i) as a white solid (1.38 g, 98%). Mp 176-178 °C.
1H NMR (300 MHz, D2O)  3.66, s, 3H; 7.37, m, IH. 7.42, m, IH. 7.71, m, IH; 7.75. dt, J = 1.8. 3.3, 7.2 Hz, IH.
MS (CI) m/z 152 (100%) [M]+.

This compound was prepared via Protocol 1. from 41(i) (220 mg. 2.27 mmol) and (i?)-Fmoc-Lys(Boc)-OH (578 mg.
1.27 mmol) to afford 41(ii) as a white solid (277 mg. 36%). Mp 96-98°C.

WO 2006/074501 PCT/AU2005/001444
1H NMR. (300 MHz, CDC13)  1.42, s, 9H; 1.60, m. 2H; 1.78. m, 2H; 3.08. m, 2H; 3.86. s, 3H; 4.17, t. J= 6.9 Hz,
IH; 4.36. d, j = 6.9 Hz, 2H; 4.63, m, IH; 6.03, d, J= 8.1 Hz, 2H; 7.26, m,2H; 7.36, m,2H; 7.56, d, 7 = 7.2, Hz, 2H;
7.72, d., j = 7.8 Hz, 2H; 7.77, m, IH; 7.88, d, J = 8.1 Hz, IH; 8.17, s, IH; 9.15, s, IH. MS (ES +ve) m/z 610 (100%)
[M+Na]+; 588 (70) [M+H]+.

This compound was prepared via Protocol 2, from 41(H) (555 mg, 0.95 mmol) to yield 41(iii) as a colourless viscous
oil (285 mg, 82%).
1H NMR (300 MHz, CDC13)  1.43, s, 9H; 1.65, m, 4H; 2.08, m, 2H; 3.19, m, 2H; 3.69, m, IH; 3.91, s, 3H; 5.H, m,
IH; 7.36. m. IH; 7.51, N; j = 7.8 Hz, IH; 7.84, t, J = 1.8 Hz, IH; 8.04, m, IH. MS (HS +ve) m/z 264 (100%) [M-
Boc+H]+

This compound was prepared via Protocol 1. from 22(H) (288 mg, 0.75 mmol) and 41 (Hi) (275 mg, 0.75 mmol) to
afford 41 (iv) as a white foam (434 mg, 79%). Mp 70oC.
1H NMR (300 MHz, CDC13)  1.04, m, 2H; 1.44. s, 9H; 1.62, m, 2H; 2.96, m, 2H; 3.87, s, 3H; 4.55, m, 5H; 4.94, m,
2H; 5.69. m, IH; 6.45, d, J = 8.1 Hz, IH; 7.85, m, 8H; 7.91, m, 7H; 9.08, s, IH. MS (RS +ve) m/z 732 (50%)
[M+H]+; 35I (100).

This compound was prepared via Protocol 3, from 41(iv) (56 mg. 0.077 mmol) to yield 4 1 as a highly hydroscopic
cream solid (38 mg. 74%).

WO 2006/074501 PCT/AU2005/001444
1H NMR (300 MHz, CD,OD)  1.30, m, 2H; 1.67, m, 2H; 2.76, m, 2H; 3.93, s, 3H; 4.59, in, 5H; 4.90, m, 2H; 5.71,
m. IH; 7.06, m, 2H; 7.34, m, 8H; 7.75, m, 2H; 7.92, m, 2H; 8.02, m, 2H. MS (ES +ve) mz 632 (100%) [M|+.

To a solution of'41(iv) (370 mg, 0.51 mmol) in THF/water, 3;1 (8 ml) was added lithium hydroxide nionohydrate
(43 mg. 0.51 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with
water (30 ml) and the THF was removed by evaporation before the remaining aqueous layer was washed with
diethyl ether (40 ml) to remove unreacted starting material. The aqueous phase was acidified with dilute potassium
bisult'ate and the resulting precipitate was extracted with DCM (3 x 40 ml). The combined DCM fractions were
dried and evaporated to yield the title compound 42(i) as a white solid (350 mg, 96%). Mp 86-9OoC.
1H NMR (300 MHz, CDC13)  1.15, m, 2H; 1.49, s, 9H; 1.65. m, 2H; 3.03, m, 2H; 4.59, m, 5H; 5.01, m, 2H; 5.71, m,
IH; 6.63, d, J = 9.0 Hz, IH; 7.34, m, 8H, 7.97, in, 7H. 9.26, s, IH, 9.70, br s, IH. MS (ES +vc) mz 740 (100%)
[M+Na]+; 718 (20) [M+H]+.

To a solution of 42(i) (40 mg, 0.056 mmol) in acetone (2 ml) was added K2CO3 (17 mg, 0.12 mmol) and benzyl
bromide (21 mg, 0.12 mmol). The resulting suspension was allowed to stir for 16 h before concentration and
purification by flash column chromatography (5% MeOH/DCM) to yield the title compound 42(ii) as a while solid
(36 mg, 80%). Mp 145-152OC.
1H NMR (300 MHz, CDC13)  1.05. m. 2H; 1.42. s, 9H; 1.52, m, 2H; 3.00, m, 2H; 4.50, m, 5H; 4.87, m, 2H; 5.30. s,
2H; 5.68. m, IH; 6.27, d, j = 8.4 Hz, IH; 7.30, m, HH; 7.90. m. 7H; 8.63, s. IH. MS (ES +ve) mz 808 (30%)
[M+H]+; 414 (100%).

WO 2006/074501 PCT/AU2005/001444




This compound was prepared via Protocol 3, from 42(ii) (35 mg, 0.043 mmol) to yield 42 as a highly hydroscopic
cream solid (30 mg, 93%).
1H NMR (500 MHz, CDOD) , m, 2H; 1.59; m, 2H; 2.68, m, 2H; 4.46, m, 5H;**** ,m, 2H; 5.27, s, 2H; 5.58,
m. IH; 7.28, m, HH; 7.80, m. 7H; 8.25, s. IH. MS (ES +ve) m'z 750 (35%) [M+K] +; 360 (100%).

This compound was prepared via Protocol I. from 42(i) (91 mg, 0.127 mmol) and 0-benzylhydroxylamine (20 mg,
1.27 mmol) to afford 43(i) as a white solid (82 mg, 78%). Mp 141-144oC.
1H NMR (300 MHz, CDCl3)  1.06, m, 2H; 1.43, s, 9H; 1.54, m, 2H; 2.93, m, 2H; 4.30, m, IH; 4.54, m, 4H; 4.66, t,
j -5.1 Hz, IH; 4.95, m, 4H; 5.66, m, IH; 6.41, d, j =7.5 Hz, IH. 7.31, m, 1OH; 7.88, m. 2H; 7.97, m, 2H; 9.14, s,
JH. MS (ES +ve) mz 823 (100%) [MH-H] + .

This compound was prepared via Protocol 3, from 43(i) (73 mg, 0.089 mmol) to yield 43 as a hydroscopic white
solid (67 mg, 99%).
1H NMR (500 MHz. CD3OD)  1.15. m, 2H; 1.62, m, 2H; 3.23. m, 2H; 3.90. m. IH; 4.46. m, 6H; 4.90. m. 2H; 5.63,
m. IH; 7.50. m. 2OH. MS (ES +ve) mz 723 (20%) [M]+; 360 (100%).

WO 2006/074501 PCT/AU2005/001444

To a solution of 41 (32 mg, 0.048 mmol) in DCM (3 ml) was added N l-tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methyl propanamide (28 mg, 0.072 mmol), triethylamine (7.3 mg,
0.072 mmol). The resulting solution was allowed to stir for 16 h under a nitrogen atmosphere. The solvent was
evaporated and the crude product was purified by flash column chromatography (15;1, DCM/MeOH) to yield the
title compound 44(i) as a white solid (41 mg, 98%). Mp 74-76°C.
lH NMR (300 MHz, CDC13)  1.14, m, 2H; 1.46, s, 9H; 1.51, s, 9H; 1.65, m, 2H; 3.26, m, 2H; 3.91, s, 3H; 4.34, m,
IH; 4.48. m, 2H; 4.57, d, J = 3.3 Hz, 2H; 4.67, m, 2H; 5.59, m, IH; 6.34, d. j= 8.4 Hz, IH; 7.26. m, 8H; 7.77, m,
7H; 8.27. br s, IH; 8.55, s, HI. MS (ES +ve) mz 896 (100%) [M+Na]+; 875 (95%) [M+H]+.

This compound was prepared via Protocol 3, from 44(i) (49 mg, 0.056 mmol) to yield 44 as a cream solid (32 mg,
0.045 mmol, 80%). Mp 124-126°C.
1H NMR (300 MHz, CD3OD)  1.17, m, 2H; 1.63, m, 2H; 3.01, m. 2H; 3.92, s. 3H; 4.52, m, 5H; 4.97, m, 2H; 5.73,
m, IH; 7.07, m, 2H; ; 7.32, m, 9H; 7.90, m, 4H; 8.28, s, IH. MS (ES +ve) mz 698 (25%) [M+Na]+; 413 (100%).


WO 2006/074501 PCT/AU2005/001444
To a solution of 42 (20 me, 0.027 mmol) in DCM (2 ml) was added N l-tert-
buloxycarbo\amido(trifluoromethylsulfonylimino)methyl propanamide (16 mg, 0.041 mmol). and triethylamine (4
mg, 0.041 mmol). The resulting solution was allowed to stir for 16 h under N2. The solvent was evaporated and the
crude product was purified by Hash column chromatography (15;1, DCM/MeOH) to yield the title compound 45(i)
as a white solid (15 mg, 58%). Mp 122-126°C.
1H NMR (300 MHZ, CDC13)  1.15, m,2H; 1.46, s,9H; 1.50, s,9H; 1.63, m, 2H; 3.25, m, 2H; 4.32, m, IH; 4.45, m,
2H; 4.56. m, 2H; 4.85, m, 2H; 5.37, s, 2H; 5.56, m, IH; 6.31, d, j= 8.1 Hz, IH; 7.32, m, 8H; 7.85, m, 7H; 8.26, br s,
IH; 8.41, s, IH. MS (ES +ve) m'z 950 (100%) [M+H]+.

This compound was prepared via Protocol 3, from 450) (15 mg, 0.016 mmol) to yield 45 as a highly hydroscopic
cream solid (6 mg, 48%).
1H NMR (500 MHz, CD3OD)  1.08, m, 2H; 1.54, m, 2H; 2.92, m, 2H; 4.28, dd, J= 5.0, 7.0 Hz, IH; 4.47, m, 4H;
4.80, m, 2H; 5.27, s, 2H; 5.59, m, IH; 7.25, m, 13H; 7.79, m, 7H; 8.22, s, IH. MS (ES +ve) m z 750 (100%) [M]+

To a solution of 43 (51 mg, 0.067 mmol) in DCM (3 ml) was added M-tert-butoxycarboxamido(trifluorometh-
ylsulfonylimino)methyl propanamide (39 mg, 0.10 mmol), and triethylamine (0.1 ml). The resulting solution was
allowed to stir for 16 hr under N2. The solvent was evaporated and the crude product was purified by flash column
chromatography (15;1, DCM/MeOH) to yield the title compound 46(i) as a white solid (58 mg, 90%). Mp H2°C.
1H NMR (300 MHz, CDCl3)  1.10,m.2H; 1.44,s, 9H; 1.50, s, 9H; 1.65, m, 2H; 3.23, m, 2H; 4.25, m. IH; 4.51. m.
4H; 4.89. m. 2H; 5.00, s, 2H; 5.63, m. IH; 6.34. d, J =7.5 Hz. IH; 7.31, m, I6H; 7.90, m. 4H; 8.25, br s. IH; 9.05. s,
IH. MS (ES +ve)mz 987 (100%) [M+Na]+; 965 (90%) [M+H]+.

WO 2006/074501 PCT/AU2005/001444

This compound was prepared via Protocol 3, from 46(i) (16 mg, 0.017 mmol) to yield 46 as a cream solid (7 mg,
51%). Mp 142 °C.
1H NMR (300 MHz, CD3OD)  1.20, m, 2H; 1.66, m, 2H; 3.04. m, 2H; 3.97, m, IH; 4.49, m, 6H; 4.96. m, 2H; 5.60,
m, IH; 7.33, m, 16H; 7.95, m, 4H. MS (ES +ve) m'z 765 (20%) [M]+; 102 (100).

To a solution of 43(i) (28 mg. 0.034 mmol) in THF (3 ml) was added palladium on activated carbon (15 mg). The
resulting mixture was flushed with hydrogen gas and allowed to stir for 16 h. The mixture was filtered through celite
and evaporated to dryness. This intermediate product was then subjected to the Protocol 3 to yield the title
compound 47 as a white solid (16 mg, 70%). Mp H6°C.
1H NMR (500 MHz, CD3OD)  0.76, m, 3H; 1.35, m, 4H, 1.67, m, 2H. 3.66, m, 2H; 3.88, m, 2H; 4.08, m, IH; 4.56.
m, 2H; 7.30, m, 9H; 7.89, m, 5H. MS (ES +ve) mz 636 (50%) [M]+; 623 (100).

To a solution of 46(i) (39 mg. 0.040 mmol) in THF (3 ml) was added palladium on activated carbon. The resulting
mixture was flushed with hydrogen gas and allowed to stir for 16 h. The mixture was filtered through celite and

WO 2006/074501 PCT/AU2005/001444
evaporated to dryness. This intermediate product was then subjected to Protocol 3 to yield the title compound 48 as
a white solid (24 mg. 84%). Mp I58-16OoC.
1H NMR (300 MHz, CD3OD) 0.51, t, J = 7.2 Hz, 3H; 1.17. m, 2H; 1.40. m.2H; 1.62, m.2H; 3.03, m. 2H; 3.92. m,
2H; 4.09, m, IH; 4.45, ABq, 7= 14.1 Hz, 2H; 7.24, m, 9H; 7.95, m, 5H; 9.96, br s, IH. MS (ES +ve) mz 677 (100%)
[M]+.
ACTIVITY
Antibacterial assay method for Staphylococcus aureus (ATCC 6538P) and Enterococcusfaecium
Bacterial strains;
Staphylococcus aureus (ATCC 6538P)
Enterococcus faecium
VRE strains; #243 E.faecium van B ST17 #449 E.faecium van B ST17
#820 E.faecium van A ST 17 #987 E.faccium van B ST39
The S. aureus assay is performed in the PC2 lab and the E. faecium assay is performed in the PC3 lab.
Compound preparation;
Compounds are accurateiy weighed out (between approx. i-2mg) and dissolved in either 10% methanol/water (v\v)
or 100%DMSO to a final stock concentration of 5mg/ml.
Compounds are then diluted 1/10 in H2O to a test cone of 500ug/ml ready for immediate use, or storage at -20°C.
Starter culture;
Grow up an o/n starter culture of Staphylococcus aureus and each VRE strain by diluting previous culture (stored at
4°C) 1/1000 into ~ 50mls Luna Broth (LB) for S. aureus or Enterococossel Broth (EB) for the VRE strains.
Incubate o/n at 37°C + shaking.
*A glycerol stock (0.6mls bacterial culture, 0.3mls glycerol) of each strain is kept at -80°C if needed.
Assay set up;
In a 96weli round bottom plate add 50ul LB / well for the S. aureus plate and add 50ul EB / well for the VRE plates.
Add 50ul of compound dilution (500ug/ml test cone) to each of three top row wells (ie; tested in triplicate) and
dilute lin 2 from the top row to the bottom row.
After the compound dilution, add to each well 50ul of a 1/1000 dilution of the appropriate overnight bacterial
culture, either S. aureus or the different VRE strains.
Plates are incubated at 37°C on a slowly rotating plate incubator.
test concentrations are (in ug/ml) 125. 62.5. 31.25. 15.6. 7.8, 3.9. 1.9. 0.98

WO 2006/074501 PCT/AU2005/001444
• final DMSO concentration in the first row of wells of the assay is 2.5%
Vancomycin is included in the assay (in triplicate) at a starting test concentration of 5ug/nil for S. aureus
and 125ug/ml for the VRE strains
Reading results of assay;
After incubation for 24hrs the plates are removed and read. Inhibition of bacterial growth is indicated by lack of
bacterial pellet or a clear well. In the VRE plates bacterial growth is indicated by black coloured media (EB) as well
as a bacterial pellet.
Untreated control wells are included in the assay to check they all contain bacterial pellets. Uninoculated untreated
control wells are included to check they all contain clear medium.
The plates are analysed for MIC and the results tabulated.
Antibacterial assay results for Staphylococcus aureus (ATCC 6538P) and Enterococcusfaecium
Activity for Compounds was determined in the assays described. The minimum inhibitory concentration (mg/ml)
was determined to be in a given range if at least two of three values fell within that range.
MIC of the compound in the range of less than 0.98 (mg/ml) is designated in the table by ++++
MIC of the compound in the range of greater than or equal to 0.99 (jig/ml) and less than or equal to 15.6
(mg/ml) is designated in the table by +++
— MIC of the compound in the range of greater than or equal to 15.7 (mg/ml) and less than or equal 62.5 (mg/ml)
is designated in the table by ++
SUBSTITUTE SHEET (RULE 26) RO/AU
MIC of the compound in the range of greater than or equal to 62.6 (mg/ml) is designated in the table by +


WO 2006/074501 PCT/AU2005/001444

SUBSTITUTE SHEET (RULE 26) RO/AU

WO 2006/074501 PCT/AU2005/001444
134.

Antibacterial assay methods for Staphylococcus aureus Mu50 (ATCC 700699), Methicillin-Rcsistant
Sraphyiococcus aureus (ATCC 43300), muiti-Drug;-Resistant Siaphyiocuccus epidermidis (ATCC 700562)
Compounds
The compounds were stored at room temperature in the dark prior to use. Each compound was solubilized in DMSO
to a final concentration of 40 mg/mL. The stock material was diluted to a concentration equivalent to two times the
final in-well high test concentration (100 mg/mL for all experimental compounds) in Mueller Hinton 11 broth.
Precipitation was observed in the wells at 100 and 50mg/mL with all eight compounds. Vancomycin and oxacillin
were obtained from Sigma Aldrich Chemical Company and were used as positive and/or negative control
compounds in the reported assays at high test concentrations of 100, 25 and 100 mg/mL respectively.
Bacterial Strains
The bacterial strains employed in these assays were obtained from the American Type Culture Collection (ATCC).
All of the bacterial strains were propagated as recommended by the ATCC. Each strain was stored as a frozen
glycerol stock at -80cC and a 10 mL loop of the frozen stocks was used to inoculate each culture for these assays.
The strains with their classification and properties are listed in the table below.

SUBSTITUTE SHEET (RULE 26) RO/AU

WO 2006/074501 PCT/AU2005/001444
135.

MIC Determination
The susceptibility of the above microorganisms to the test compounds was evaluated by determining the MIC of
each compound using micro-broth dilution analysis according to the methods recommended by the NCCLS. All
microbial strains were obtained from American Type Culture Collections (ATCC) and cultured according to the
suppliers recommendations. Evaluation of the susceptibility of each organism against the test compounds included a
positive control antibiotics Vancomycin and Oxacillin. For each organism, a standardized inoculum was prepared by
direct suspension of freshly plated colonies in Mueller Hinton II broth to an optical density 625 nm (OD62s) of 0.1
(equivalent b a 0.5 McFarland standard). The suspended inoculum was diluted to a concentration of approximately
1 x 106 colony forming units per milliliter (CFU/mL) and 100 mL placed into triplicate wells of a 96-well plate
containing 100 mL of test compound serially diluted 2-fold in Mueller Hinton II broth. One hundred microliters of
the inoculum was also added to triplicate wells containing 100 mL of two-fold serial dilutions of a positive control
antibiotic and to wells containing 100 mL of media only. This dilution scheme yielded final concentrations for each
microbial organism estimated to be 5 x 105 CFU/mL (verified by colony quantification on appropriate agar plates,
data is not presented). Test compound concentrations ranged from a high-test of 1:2 (TOO mg/mL)) to a low test of
1:2048 (0.1 mg/mL) using a two-fold dilution scheme. The plates were incubated for 24 hours at 37°C. and the
microbial growth at each concentration of compound was determined by measuring the optical density at 625 nm on
a Molecular Devices SpectraMax Plus-384 plate reader. The MIC for each compound was determined as the lowest
compound dilution that completely inhibited microbial growth.
Antibacterial assay results for Staphylococcus aureus Mu50 (ATCC 700699), Methicillin-Resistant
Staphylococcus aureus (ATCC 43300), Multi-Drug-Resistant Staphylococcus epidermidis (ATCC 700562)
Microsoft Excel 2003 was used to analyze and graph the data, and the MIC (minimal inhibitory concentration) was
determined from the resulting data. The MIC is defined as the lowest concentration of compound that completely
inhibited bacterial.
Activity for Compounds was determined in the assays described. The minimum inhibitory concentration (mg/p)
was determined to be in a given range if at least two of three values fell within that range.
MIC of the compound in the range of less than 0.98 (mg/ml) is designated in the table by ++++
MIC of the compound in the range of greater than or equal to 0.99 (mg/ml) and less than or equal to 15.6
(mg/ml) is designated in the table by +++
MIC of the compound in the range of greater than or equal to 15.7 (mg/ml) and less than or equal 62.5 (mg/ml)
is designated in the table by ++
SUBSTITUTE SHEET (RULE 26) RO/AU

WO 2006/074501 PCT/AU2005/001444
136.
MIC of the compound in the range of greater than or equal to 62.6 (mg/ml) is designated in the table by +

Example 2: Preparation and Biological Activity of Further Compounds according to the Present Invention
General Notes
Melting point determinations were carried out on a Gallenkamp melting point apparatus. Chemical ionization (CI
and electron impact (EI) mass spectra were obtained on a Shimadzu QP-5000 mass spectrometer by a direct
insertion technique with an electron beam energy of 70 eV. Electrospray (ES) mass spectra were obtained on a VG
Autospcc spectrometer. High-resolution mass spectra (FIRMS) were determined on a micromass QTof2
spectrometer using polyethylene glycol or polypropylene glycol as the internal standard. The m:z values are stated
with their peak intensity as a percentage in parentheses. Optical rotations were measured using a Jasco polarimeter
with a 10 mm path length. Proton and carbon nuclear magnetic resonance (NMR) spectra were obtained as specified
on a Varian Mercury 300 MHz or Varian Inova 500 MHz spectrometer. Spectra were recorded in the specified
deutcrated solvent, and referenced to the residual non-deuterated solvent signal. Chemical shiftsδ) in ppm were
measured relative to the internal standard. Where samples exhibited (E) and (Z) isomers the chemical shifts are
separated by (/). In general the two forms could not be separated by flash chromatography. Multiplet (m) signals are
reported from the centre of the peak. Proton and carbon assignments were determined through the interpretation of
two dimentional spectra (COSY. gHSQC and gHMBC). Analytical thin layer chromatography (TLC) was carried
out on Merck silica gel 60 F254 pre-coated aluminium plates with a thickness of 0.2 mm. All column
chromatography was performed under 'flash' conditions on Merck silica gel 60 (230-400 mesh). Chromatography
solvent mixtures were measured by volume. Organic solvent extracts were dried with anhydrous magnesium sulfate.
and the solvent removed under reduced pressure with a Buchi rotary evaporator. Solvents were purified and dried
SUBSTITUTE SHEET (RULE 26) RO/AU

WO 2006/074501 PCT/AU2005/001444
137.
based upon standard techniques. 12° All compounds were judged to be of greater than 95% purity based upon 1H
NMR and TLC analysis. Starting materials and reagents were purchased from Sigma-Aldrich Pty Ltd or Auspep Pty
Ltd and were used as received. The Grubbs' first generation catalyst used was specifically benzylidene
bis(tricyclohexylphosphene)dichlororuthenium.
Proton and carbon NMR spectra for all compounds were assigned using the numbering systems illustrated below.
Cyclic peptoids were named using the IUPAC "superatom" convention, in which the aromatic ring is considered
equivalent to, and sequentially numbered like all other atoms in the macrocycle.121

General Synthetic Procedures
N-Boc and Pmc Deprotection (Procedu re A)
The Af-Boc or Pmc protected amine was stirred for 3 h in 1:1 DCM/TFA (10 mL) solution at RT. The solvent was
removed under reduced pressure, and the residue was resuspended in a minimal volume of methanol. The solution
was then treated with an excess of IM MCI/ether solution and the solvent evaporated. The crude product was
purified by precipitation from DCM and/or MeOH by addition of diethyl ether.
Peptide Coupling (Procedu re B)
To a solution of the acid (1 equiv.) in DMF or CH3CN (10 mL) at room temperature was added HOBt (1.1 equiv.),
EDCT (1 equiv.) and the amine (1.2 equiv.). If the amine was a hydrochloride salt, DIPEA (1 equiv.) was also added.
The mixture was allowed to stir for 16 h before dilution with EtOAc (30 mL) and washing with water (30 mL) and
brine (30 mL). The organic fraction was dried (MgSO4) and further purified by column chromatography if required.
N-Fmoc Deprotection (Procedure C)
The Fmoc protected amine was stirred in 1% piperidine/acetonitrile (10 mL) for 3 h at RT. The solvent was removed
under reduced pressure and the crude product was purified by flash column chromatography (15:1. DCM/MeOR) to
yield the free amine.

WO 2006/074501 PCT/AU2005/001444
138.
Macrocyclization by Olefin Metathesis (ProcedureD)
To a solution of the precursor tripeptide (1 equiv.) in DCM (to 0.004 M) was added Grubbs' first generation catalyst
(15 mol%) and the resulting solution was heated at reflux for 48 h before the solvent was removed by evaporation
and the product isolated by flash column chromatography (15:1, DCM/MeOH) to yield the corresponding
macrocycle.
Experimental
Ethyl (2S)-2-acetamido-3-(4-alIyloxyphenyI)propanoate (15)
To a solution of ethyl (2S>2-acetamido-3-(4-hydroxyphenyl)
propanoatc monohydrate 13 (2.69 g, 9.98 mmol) and anhydrous K2CO3 (2.75 g, 20.0 mmol) in
DMF (15 mL) was added allyl bromide (2.42 g. 19.96 mmol). The resulting mixture was
allowed to stir for 16 h under nitrogen before the reaction was quenched with water (30 mL) and
extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with
water (5 x 50 mL), dried and the solvent was evaporated to yield the title compound (2.91 g,
9.98 mmol, 100%) as a white solid, which had spectral data in agreement with that reported. 122
[ab25+23.1 (c. O.LEtOH). Mp 69-7O°C (lit. 69.5°C)122 1HNMR (CDC13 300 MHz): 6 7.02 (d, J = 8.4 Hz, 211.
ArH2' and ArH6'): 6.83 (d, J = 8.8 Hz, 2H, ArH3' and ArH5'): 6.14 (d, J = 8.0 Hz, IH, NH); 6.06 (m. IH, H2");
5.31 (m. 2H H3"): 4.81 (dd, J = 13.5, 6.0 Hz, IH, H2): 4.50 (d, / = 5.1 Hz, 2H, HI"); 4.16 (dd, J = 13.9, 6.7 Hz, 2H,
OCH2CH3); 3.04 (m, 2H, H3); 1.98 (s, 3H, NCOCH3); 1.25 (x.J = 1.2 Hz, 3H, OCH2CH3). Mass Spectrum (Cl, +ve)
mJz 292 (100%) [MH+].HRMS calcd for C16H22NO4 292.1549, found 292.1559.

(2S)-2-Acetamido-3-(4-allyloxyphenyl)propanoicacid (16)
To a solution of 15 (2.90 g, 9.98 mmol) in THP/water, (3:1, 80 mL) was added lithium
hydroxide monohvdrate (838 mg, 20.0 mmol) and the resulting suspension was allowed to stir
for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by
evaporation. The aqueous layer was extracted with DCM (40 mL) to remove unreacted starting
material. The aqueous phase was acidified with 10% HC1 and the resulting precipitate was
extracted with DCM (3 x 40 mL). The combined organic fractions were dried and evaporated to
yield the title compound (2.62 g, 9.98 mmol. 100%) as white needles, which had spectral data in
agreement with that reported. 122 Mp 170-172°C (lit. 200°C)122 1H NMR (D6 acetone, 300 MHz): d 7.09 (s, IH, NH):
7.04 (d..j = 8.4 Hz. 2H. ArH2' and ArH6'); 6.73 (d. / = 8.4 Hz, 2H. Arffi'and ArH5'); 5.94 (m. IH, H2"); 5.27 (dd
J = 1.3 Hz, 17.3 Hz, IH. H3a"); 5.10 (ddj= 1.3, 10.5 Hz, IH. H3b" );4.52 (m, IH, H2); 4.41 (d j=5.5 Hz. 2H.
H1"): 2.98 (dd,j =5.7, 14.1 Hz, 2H, H3a). 2.79 (dd../ =8.1. 14.1 Hz. 2H, H3b): 1.75 (s. 3H. NCOCH3). Mass
Spectrum (C1 +ve) m/z 264 (100%) [MH+]. HRMS calcd for CHH18NO4 264.1236, found 264.1246.


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139.
Methyl (2S)-2-amino-4-pentenoatc hydrochloride (18)
To a susp ension of (25)-2-nmino-4-pentanoic acid 17(200 mg. 1.74 mmol) in MeOH (6 mL) at
OoC was added dropwise thionyl chloride (1 mL). The resulting solution was allowed to stir for
16 h before the solvent was removed by evaporation and the product crystallized with ether. The
ether was removed by evaporation to yield the title compound (287 mg. 1.74 mmol. 100°o) as a white solid, which
had spectral data in agreement with that reported. 82-Mp 172-174 °C (lit. 174-176 oC)82- 1H NMR (CDCI ,.300 MHz): 6
8.74 (bs, 3H. NH3+); 5.88 (m. IH. H4): 5.32 (d. J = 16.8 Hz. IH. H5a); 5.25 (d. J = 10.2 Hz. IH H5b);4.29 (t.j -
5.1Hz. IH. H2): 3.81 (s. 3H OCH ,): 2.86 (t j = 5.7 Hz. 2H. H3). Mass Spectrum (ES. +ve) mz 130 (100%) [M1]-
HRMS calcd for C6Hi2NO2 130.0868. found 130.0876.
Methyl (2S,5/?)-2-allyl-3-aza-9-(^ert-butoxycarboxainido)-5-(9£f-9-fluorenyIinethyloxycarboxainido)-4-
oxononanoate (19)

The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 18 (186 mg, 1.62 mmol) and (2R)-6-tert-
butoxycarboxamido-2-(917-9-fluorenylmethyloxy
carboxamido)hexanoic acid (633 mg, 1.35 mmol) to afford 19 (733 mg,
1.27 mmol, 94%) as a cream solid. Mp 117-120°C. 1HNMR(CDCl 3,
300 MHz): d 7.76 (d, J = 7.6 Hz, 2H. ArHl" and ArH8"); 7.59 (d, j =
7.6 Hz, 2H, ArH4" and ArH5"); 7.39 (t,j -7.6 Hz, 2H, ArH3" and
ArH6"): 7.31 (dd, J = 9.0, 7.2, 1.2 Hz, 2H, ArH2" and ArHT); 6.75 (d, J = 7.2 Hz, IH, NH); 5.65 (m, IH, H2');
5.07 (m, 2H, H3'); 4.65 (m, 2H, H2 and NH); 4.38 (d, J = 6.7 Hz, 2H, OCH2-W); 4.21 (m, 2H, H5 and H9"); 3.71
(s, 3H, OCH3); 3.10 (d, J =6.3 Hz, 2H. H9); 2.52 (m, 2H, H1'); 1.85 (m, 2H, H8); 1.66 (m, 2H, H7); 1.39 (m 2H,
H7); 1.43 (s, 9H, C(CH3)3).Mass Spectrum (ES, +ve) m/z 579.9 (80%) [MH+], 479.9 (100%) [MH+ (less Boc)].
HRMS calcd for C32H42N3O7 580.3023, found 580.3041.
Methyl (2S,5/.)-2-allyl-5-amino-3-aza-9-(ter/-butoxycarboxamido)-4-oxononanoatc (20)


The title compound was synthesized using the general iV-Fmoc deprotection procedure
(Procedure C), from 19 (715 mg, 1.23 mmol) to yield 20 (436 mg, 1.22 mmole, 99%) as
a cream oil, and is in agreement with the literature.78 1H NMR (CDCI,,300 MHz):  7.75
(d, J = 8.0 Hz, IH, NH): 5.70 (m. IH. H2'): 5.13 (m, 2H, H.3'); 4.80 (bs, IH, NH); 4.64
(m. IH. H2); 3.74 (s. 3H. OCH3); 3.38 (dd. / = 4.6, 7.6 Hz, IH. H5); 3.12 (d, J =6.3 Hz.
2H, H9); 2.57 (m, 2R H1'); 1.61 (m, 8H, H6, H7, H8 and NH2); 1.44 (s. 9H, C(CH3)3).
Mass Spectrum (ES. +ve) m'z 358.5 (70%) [MH+1, 258.4 (100%) [MH+ (less Boc)].
HRMS calcd for C17H32N3O5 358.2342. found 358.2334.

WO 2006/074501 PCT/AU2005/001444
140.
Methyl (2S,5/.,8S)-2-allyl-8-(4-alIyloxybenZyl)-3,6,9-triaZa-5-(4-[tert-butoxycarboxamido]butyI)-4,7,10-
trioxoundecanoate (21)
The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 20 (440 mg, 1.20 mmol) and 16 (270 mg, 1.03
mmol) to afford 21 (424 mg, 0.70 mmol, 69%) as a white solid. Mp 149-
15O°C. 1H NMR (CDC13,3OO MHz); d 7.20 (d, J= 8.0 Hz, IH, NH); 7.1 1 (d,
J - 8.4 Hz, 2H, ArH2"' and ArH6"'); 6.84 (d, J = 8.4 Hz, 2H, ArH3'" and
ArH5'"); 6.67 (d, J =8.0 Hz, IH, NH); 6.48 (d, J =7.2 Hz, IH, NH); 6.04 (m,
IH, H2""); 5.67 (m, IH, H2'): 5.41 (dd,./= 1.3, 17.3 Hz, IH, H3a'"); 5.28
(dd, J = 1.3, 10.5 Hz, IH. H3b""); 5.10 (m. 2H. H3'); 4.75 (t,J -5.9 Hz. IH.
H2); 4.60 (m, IH, H8); 4.50 (d, J =5.5 Hz, 2H, HI""); 4.42 (dd, j= 7.6, 13.1
Hz, IH, H5); 3.71 (s, 3H, OCH3); 2.97 (m, 4H, H4" and ArCH2); 2.52 (m, 2H,
HI'); 1.97 (s, 3H, Hll); 1.44 (s, 9H, C(CH3)3); 1.34 (m, 6H, HI", H2" and H3"). Mass Spectrum (ES, +ve) n/z
603.4 (40%) [MH+], 503.4 (100%) [MH+ (less Boc)]. HRMS calcd for C3|H47N4O8 603.3394. found 603.3389.
(7S,10R,135,4£:/Z)-13-Acetainido-8,II-diaza-10-(4-[tert-butoxycarboxainido1butyI)-7-mcthoxycarbonyI-2-oxa-
9,12-dioxo-l(l,4)phenylenacycIotetradecaphane-4-ene (22)

metathesis (Procedure D), from 21 (277 mg, 0.46 mmol) to yield 22 (199 mg,
0.35 mmol, 75%) as a brown solid. Mp 178-I8O°C. 1H NMR (CDC13 300
MHz): d 8.08 (m, 2H, NH); 7.07 (m, 2H, ArH); 6.71 (m, 2H, ArH); 5.63 (m,
2H. H4 and H5); 4.48 (m, 4H, H7, H13 and 113); 4.13 (m, 2H, NH and H1O);
3.60 (m. 3H. OCH3); 2.79 (bs, 4H, H4' and H14); 2.38 (m, 2H, H6); 1.80 (m.
3H, NCOCH3): 1.10 (m, 6H, HI', H2' and H3'): 1.26 (s. 9H, C(CH3)3)..
Mass Spectrum (ES, +ve) /HZ 575.3 (20%) [MH+1, 475.3 (100%) [MH! (less
Boc)]. HRMS calcd for C29H43N4O8 575.3081, found 575.3091.

(7S,10R,13S,4£:/Z)-13-Acetamido-10-(4-aininobutyl)-8,ll-diaza-7-inethoxycarbonyl-2-oxa-9,12-dioxo-
l(I,4)phenyIenacyclotetradecaphane-4-ene hydrochloride (12)
The title compound was synthesized using the general X-Boc deprotection
procedure (Procedure A), from 22 (49 mg, 0.084 mmol) to yield 12 (17 mg,
0.033 mmol. 49%) as a highly hydroscopic yellow solid. lH NMR (CD3OD
300 MHz): d 7.10 (m. 3H, ArH and NH): 6.85 (bs. IH. NH): 6.71 (d. J - 7.5
Hz. 2H, ArH): 5.75 (m. 2H. H4 and H5); 4.39 (m, 5H. H3. H7. H1O and H13):
3.68 (s. 3H. OCH3); 2.85 (m. 4H. H6 and H4'): 2.52 (m. 2H. H14); 1.93 (s. 3H.
NCOCH3); 1.50 (m. 6H. HI'. H2' and H3'). 13C NMR (CD3OD 75 MHz): d


WO 2006/074501 PCT/AU2005/001444
141.
173.5, C9; 173.1, 7-CO; 173.0, 13-NCO: 172.6, C12; 157.7, 1-ArCl: 132.4, l-ArCH2 and l-ArCH6: 131.1, C4;
129.6, C5; 129.3, l-ArC4: 116.8, l-ArCH3 and l-ArCH5: 70.0, C3; 57.9, C13; 54.9, CIO: 53.5, C41; 53.0, OCH3;
40.7, C7; 38.2, C14; 32.1, Cl': 31.7, C6: 28.0, C31; 23.5, NCOCH3; 22.6, C2'. Mass Spectrum (ES, +ve) m/z 475.3
. (100%) [M+].HRMS calcd for C,4H,SN4O5475.2557, found 475.2534.
Methyl (2S4>S)-2-all>l-3-aza-9-(tert-butoxycarboxamido)-5-(9fIr-9-fluorenyIniethyloxycarboxami(lo)-4-
oxononanoatc (23)
To a solution of 18 (430 mg, 2.61 mmol) and (2S)-6-tert-
buto\7carho\amido-2-(9H-9-fluorenylmethyloxy)carhoxamido
hexanoic acid (1.22 g, 2.61 mmol) in DCM (10 mL) was added EDCI
(500 mg, 2.61 mmol) and a catalytic quantity of DMAP. The resulting
mixture was allowed to stir at RT for 16 h. The reaction was diluted with
DCM (25 mL), then the organic layer was washed with brine (2 x 25 mL)
and water (2x25 mL) and dried, before being concentrated. The crude
product was purified by flash column chromatography (25:1 DCM/
MeOH) to afford the title compound (1.31 g, 2.27 mmol, 87%) as a
cream coloured solid. Mp 123-126oC. 1H NMR (CDC13 300 MHz):  7.76 (d,J = 7.6 Hz, 2H, ArHl" and ArHS");
7.59 (d, J=7.6 Hz, 2H, ArH4" andArHS"); 7.40 (t, J =7.6 Hz, 2H, ArH3" andArH6"): 7.31 (ddd, J = 9.0, 7.2, 1.2
Hz, 2H, A rH2 and ArH7"); 6.46 (bs, IH NH ) 5.64 (m,IH, H2 ); 5.44 (s, IH,NH); 5.10 (m,2H,H3'); 4.65 (m
IH, H2): 4.39 (d, J= 7.2 Hz, 2H. OCHrH9"): 4.22 (m, IH, H5): 4.17 (bs, IH, H9"); 3.74 (s, 3H, OCH3); 3.11 (m,
2H, H9); 2.55 (m, 2H, HI'): 1.85 (m, 2H, H7); 1.65 (m, 2H, H6): 1.50 (m 2H, H8); 1.44 (s, 9H, C(CH3),).Mass
Spectrum (ES, +ve) m/z 580.5 (10%) [MH+], 130.5 (100%) [MH+ (less allylgly)]. HRMS calcd for C32H42N3O7
580.3023, found 580.3025.
Methyl (2S,5S)-2-alIyl-5-amino-3-aza-9-(tei^-butoxycarboxamido)-4-oxononanoate (24)

The title compound was synthesized using the general Af-Fmoc deprotection procedure
(Procedure C), from 23 (1.27 g, 2.19 mmol) to yield 24 (778 mg, 2.18 mmole, 100%) as
a cream oil. 1H NMR (CDC13 300 MHz):  7.81 (d, J = 8.0 Hz, IH, NH): 5.69 (m, IH,
H2'): 5.11 (m, 2H, H3'): 4.76 (bs, IH, NH): 4.67 (m, IH, H2): 3.75 (s, 3H, OCH3): 3.39
(dd, 7 =4.6, 7.6 Hz, IH, H5); 3.12 (d, J =6.3 Hz, 2H, H9): 2.54 (m, 2H, HI'); 1.52 (m,
8H, H6, H7, H8 and NH,): 1.44 (s, 9H, C(CH3)3). 13C NMR (CDC13,75 MHz):  174.8,
C4; 172.1, Cl: 156.0,NCO 2; 132.2, C2'; 118.9, C3': 78.9, C(CH3)3:54.8, C5: 52.2, C2:
51.1, OCH,; 40.0, C9; 36.4, CT; 34.4, C6: 29.7, C8: 28.3, C(CH3)3; 22.6, C7. Mass Spectrum (ES, +ve) m/z 358.5
(85%) [MH+]. 258.4 (100%) [MH+ (less Boc)l. HRMS calcd for C17H32N3O5 358.2342, found 358.2339.


WO 2006/074501 PCT/AU2005/001444
142.
Methyl (2S,5S,8S)-2-aIlyI-8-(4-alhIox,vbenzyl)-3,6,9-triaza-5-(4-[fert-butoxycarboxamido]buty1)-4,7,10-
trioxoundecanoate (25)
To a solution of 24 (782 mg, 2.19 mmol) and 16 (576 mg, 2.19 mmol) in
DCM (10 mL) was added EDCI (420 mg, 2.19 mmol) and a catalytic
quantity of DMAP. The resulting mixture was allowed to stir at RT for 16 h.
The reaction was diluted with DCM (25 mL) and the organic layer was
washed with brine (2 x 25 mL) and water (2 x 25 mL) and dried, before
being concentrated by evaporation. The crude product was purified by flash
column chromatography (25:1 DCM/ MeOH) to afford the title compound
(664 mg, 1.10 mmol, 50%) as a 1:1 mixture of 2 epimers, as a white solid.
Mp 112-1 14oC. 1H NMR (CDCl3,300 MHz):  7.09 (m, 2H, ArH2'" and
ArH6'"); 6.91 (d, / = 8 Hz, IH, NH); 6.82 (m, 2H, ArH3"' and ArH5'"); 6.69 (d, J = 8.0 Hz, IH, NH); 6.55 (bs, IH,
NH); 6.03 (m, IH, HI""); 5.68 (m, IH, H2'): 5.25 (m, 4H, H3' and 113""): 4.96 (bs, IH, H2): 4.86 (bs, IH, H8):
4.67 (m, 2H, H2""); 4.48 (dd, / = 3.0, 8.4 Hz, IH, H5); 3.74/3.71 (s, 3H, OCH,); 3.04 (m, 4H, H4" and ArCH,);
2.51 (m, 2H, HI'); 1.98/1.96 (s, 3H, HI1); 1.79 (s, 2H, H2"); 1.60 (s, 2H, H1"); 1.43 (s, 9H, C(CH,),); 1.28 (s, 2H,
H3"). Mass Spectrum (ES, +ve) m/z 603.4 (35%) [MH+], 503.4 (100%) [MH+ (less Boc)]. HRMS calcd for
C31H47N4O8 603.3394, found 603.3397.
(7S,10S,135,4£/2;)-13-Acetamido-8,ll-diaza-10-(4-[tert-butoxvcarboxaniido]butyl)-7-mcthoxycarbonyl-2-oxa-
9,12-dioxo-l(l,4)phenylenacyclotetradecaphane-4-enc (26)

The title compound was prepared using the general procedure for olefin
metathesis (Procedure D) using 25 (311 mg, 0.52 mmol) to yield 26 as a
mixture of epimers and E/Ziosomers (228 mg, 0.40 mmol, 76%) as a brown
solid. Mp 196-201oC. 1H NMR (CDCT3,300 MHz): 7.54 (m, 2H, NH); 7.34
(bs, IH, NH); 7.06 (m, 2H, ArH); 6.81/6.73 (d, J= 8.0 Hz, 2H, ArH); 5.66 (d,
J= 16.4 Hz, IH, m-trans): 5.55 (m, IH, H5); 4.90 (m, 2H, H7 and HI3); 4.64
(m, 3H, H2 and H1O); 3.80/3.77 (s, 3H, OCH,); 3.10 (m, 4H, H6 and H4');
2.70 (m, 2H, H14); 2.10 (s, 3H, NCOCHg); 1.51 (m, 6H, HI', H2' and H3');
1.44/1.40 (s, 9H, C(CH3)3).Mass Spectrum (ES, +ve) m/z575.3 (25%) [MH+],
475.3 (40%) [MH+ (less Boc)]. HRMS calcd for C29H43N4O8 575.3081, found


WO 2006/074501 PCT/AU2005/001444
143.
(7S,lOS,13S,4₤Z)-13-Acetamido-lO-(4-aminobutyl)-8,ll"diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-
I(I,4)j)henyIenacyclotetradecaphane-4-ene hydrochloride (27)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A) using 26 (220 mg, 0.380 mmol) to yield 27 as a
mixture of epimers and E/Z iosomers (152 mg, 0.300 mmol, 79%) as a highly
hydroscopic yellow solid. 1H NMR (CD3OD, 300 MHz): d 8.19 (d, J = 8.4 Hz,
1H, NH); 6.98/6.92 (d, J = 8.0 Hz, 2H, ArH); 6.74/6.64 (d, J = 8.0 Hz, 2H,
ArH); 5.57 (d, J = 16.0 Hz, 2H, H4-trans); 5.39 (m, 1H, H5); 4.53 (m, 4H, H7,
H13 and H2); 4.21 (m, 1H, H10); 3.93 (bs, 1H, NH); 3.63/3.60 (s, 3H, OCH,);
2.76 (m. 6H, H6, H4' and H14); 1.99/1.89 (s, 3H, NCOCH3); 1.64 (m, 2H, H2'); 1.51 (bs, 2H, H3'); 1.22 (m, 2H,
HI'). 13CNMR(CD 3OD 75 MHz):  174.5, C9; 173.3, 7-CO; 173.1, 13-NCO; 172.5, C12; 157.7, 1-ArC1 131.4, 1-
ArCH2 and l-ArCH6; 131.1, C4: 129.5, C5; 129.1, l-ArC4; 116.4, l-ArCH3 and l-ArCH5; 66.9, C3; 57.7, C13;
53.9, CIO; 53.1, C4'; 53.0, OCH3;40.5, C7; 38.1, C14; 32.0, Cl'; 31.8, C6; 28.0, C3'; 23.5, NCOCH3; 22.5, C2'.
Mass Spectrum (ES, +ve) m/z 475.4 (100%) [M+]. HRMS calcd for C24H35N4O6 475.2557, found 475.2581.
Methyi (2S,5/.)-2-alIyI-3-aza-5-(9 ff-9-fluorenylmethyloxycarboxamido)-8-l(2,2,5,7,8-pentamethy 1-3.4-
dihydro-2ff-6-chromenyIsulfonyI)guanidino]-4-oxooctanoate(28)

The title compound was synthesised using the general peptide coupling,
procedure (Procedure B), from 18 (287 mg, 1.74 mmol) and (2tf)-2-(9H-9-
fluorenylmethyloxycarboxarnido)-8-[(2,2,5,7,8- pentamethyl-3,4-dihydro-
2#-6-chromenylsulfonyi)guanidino]pentanoic acid (961 mg, 1.45 mmol) to
afford 28 (1.01 g, 1.31 mmol, 90%) as a brown solid. Mp 96-100°C. lH
NMR (CDC13,300 MHz): S 7.70 (d, J =7.5 Hz, 2H, ArHl" and ArH8");
7.52 (d, J =7.2 Hz, 2H, ArH4" and ArH5"); 7.35 (bs, IH, NH): 7.33 (dd, J
= 7.2, 7.2 Hz, 2H, ArH3" and ArH6"); 7.20 (t, J= 7.2 Hz, 2H, ArH2" and
ArH7"); 6.35 (s, 2H, NH); 6.26 (bs, 2H, NH); 5.62 (m, IH, H2'): 5.03 (d, J= 18.0 Hz, IH, H3a'): 4.98 (d,J = 10.2
Hz. IH. H3b'); 4.53 (dd, J =7.2, 12.9 Hz, IH, H2); 4.27 (d, J= 6.6 Hz, 2H, OCH2-TO"): 4.10 (m, 2H, H5 and H9"):
3.63 (s, 3H, OCH,); 3.23 (m, 2H, H8); 2.57 (s, 3H, 7"'-CH 3); 2.54 (s, 3H, 5"'-CH ,); 2.49 (m, 4H, HI' and H4"');
2.06 (s.3H, 8"'-CH3); 1.88 (m, 2H, H7); 1.71 (t, J = 6.6 Hz, 2H, H3""); 1.61 (m, 2H, H6); 1.24 (s, 6H, 2 x 2"'-CH 3).
Mass Spectrum (ES, +ve) n/z 77A (100%) [MH+]. HRMS calcd for C4]H52N5O8S 774.3537, found 774.3559.


WO 2006/074501 PCT/AU2005/001444
144.
Methyl (2S^i.)-2-aUyl-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyI-3,4-dihydro-2i T -6-
chromenyIsulfonyl)guanidino]-4-oxooctanoate (29)
The title compound was synthesized, using the general N-Fmoc deprotection
procedure (Procedure C), from 28 (717 mg, 0.93 mmol) to yield 29 (407 mg,
0.74 mmol, 80%) as a cream oil, and is in agreement with the literature.so 'H
NMR (CDC13,300 MHz): 5 7.87 (d, J = 8.1 Hz, 1H, NH); 6.36 (bs, 3H, NH);
5.68 (m, 1H, H2'); 5.10 (m, 2H, H3'); 4.52 (dd, /= 6.9,12.9 Hz, IH, H2); 3.71
(s, 3H, OCH3); 3.42 (m IH, H5); 3.19 (dd, J= 6.9,11.1 Hz, 2H, H8); 2.62 (t, J =
6.9 Hz, 2H, H4"); 2.56 (s, 3H, 7"-CH3); 2.54 (s, 3H, 5"-CH3); 2.49 (m, 2H, HI');
2.10 (s, 3H, 8"-CH3); 1.80 (t, J = 6.9 Hz, 2H, H2"); 1.74 (m, 2H, H7); 1.58 (m,
2H, H6); 1.30 (s, 6H, 2 x 2"-CH3).Mass Spectrum (ES, +ve) m/z 552 (100%) [MH+]. HRMS calcd for C26H4,N5O6S
552.2856, found 552.2839.
Methyl (2SAR,8S)-2-allyl-8-(4-alIyloxybenzyI)-3,6,9-triaza-5-(1 {2,2,5,7,8-pentamethyl-3,4-dihydro-2Jfir-6-
chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate (30)

The title compound was synthesised using the general peptide coupling
procedure (Procedure B) using 29 (387 mg, 0.70 mmol) and 16 (153 mg, 0.58
mmol) to afford 30 (336 mg,0.42 mmol, 73%) as a ligh brown solid Mp 172-
176°C. 1H NMR (CDC13> 500 MHz):  7.75 (d, J = 7.5 Hz, IH, NH); 7.11 (d, J -
8.7 Hz, 2H, ArH2"" and ArH6""); 6.78 (d, J= 8.4 Hz, 2H, ArH3"" and
ArH5""); 6.36 (bs, 2H, NH); 6.18 (bs, 1H, NH); 5.98 (m, IH, H2'""); 5.69 (m,
IH, H2'); 5.36 (dd, J = 1.5, 17.4 Hz, IH, H3a'""); 5.24 (dd,J= 1.5, 10.5 Hz, IH,
H3b""'); 5.08 (d, J = 15.6 Hz, IH, H3a'); 5.04 (d, J = 8.4 Hz, IH, H3b'); 4.48 (m,
2H, H2 and H5); 4.42 (d, J = 4.8 Hz, IH, HI""'); 4.29 (m, IH, H8); 3.69 (s, 3H,
OCH,); 3.05 (m, 2H, H3"); 2.99 (m, 2H, ArCH2); 2.63 (t, J= 6.9 Hz, 2H, H4'"); 2.59 (s, 311, 7"'-CH ,); 2.57 (s, 3H,
5"'-CH,);2.54(m, 2H, HI'); 2.09 (s, 3H, 8"'-CH3); 1.93 (s, 3H, HI1); 1.80(t,/6.6 Hz, 2H, H3'"); 1.51 (m,4H,
HI" and H2"); 1.30 (s, 6H, 2 x 2"'-CH 3). Mass Spectrum (ES, +ve) m/z 797 (100%) [MH+1. HRMS calcd for
C4OH,-N6O9S 797.3908, found 797.3913.


WO 2006/074501 PCT/AU2005/001444
145.
(7S,10i?,13S,4£7Z)-13-Acetamido-8,ll-diaza-10-c3[{2,2,5,7,8-pentamethyl-3,4-dihydro-2fl r-6-
chromenyIsuIfonyl}guanidino]propyI)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
l(l,4)phenyIenacyclotetradecaphane-4-ene (31)
The title compound was prepared using the general procedure for olefin
metathesis (Procedure D). from 30 (104 mg, 0.13 mmol) to yield 3 1 (103 nig,
0.13 mmol, 100%) as a grey solid. Mp 172-1750C. 1H NMR (CDC'1,,300 MHz):
 7.04 (m, 2H, ArH); 6.72 (m, 2H, ArH); 6.37 (bs, IH, NH); 5.45 (m, H4 and
H5); 4.79 (m, 2H, 113); 4.57 (m, 3H, H7, H1O and HI3); 3.63 (s, 3H, OCH3);
2.97 (m, 4H, H3' and H6); 2.54 (m, 1OH, H14, 7"-CH3, 5"-CH3 and H4"); 2.06
(s, 3H, 8"-CH3); 1.90 (s, 3H, NCOCH ,); 1.76 (m, 2H, HI'); 1-48 (m, 2H, H3");
1.27 (s, 6H, 2 x 2"-CH3). Mass Spectrum (ES, -ve) m/z 767 (100%) [MH+].
HRMS calcd for C38H53N6O9S 769.3595, found 769.3558.
(7S,10/-,13S,4£:/Z)-13-Acetamido-8,ll-diaza-10-(3-[guanidino]propyl)-7-methoxycarbonyI-2-oxa-9,12-dioxo-
I(l,4)phenylenacyclotctradecaphane-4-ene (32)

The title compound was synthesized using the general iV-Boc deprotection
procedure (Procedure A), from 31 (60 mg, 0.078 mmol) to yield 32 (38 mg, 0.071
mmol, 91%) as a white solid. Mp 218-224 0C. 1H NMR (CD,OD 300 MHz): d
7.10 (m, 2H, ArH); 6.79 (m, 2H, ArH); 5.70 (m, IH, H5); 5.51 (in, IH, H4); 4.44
(m, 5H, H3, H7, H1O and H13); 3.69 (m, 3H, OCH3); 3.10 (m, 2H, 113'); 2.94 (m,
2H. H14); 2.49 (m, 2H, H6); 1.94 (s, 3H, NCOCH ,); 1.71 (m, 2H, HI'); 1-33 (in,
2H, H2'). 13C NMR (CD3OD 75 MHz):  173.6, COOCH 3; 173.5, CI1: 173.1, C9;
172.4, NCOCH3; 158.4. CN3; 157.4, l-ArC4: 131.5. C4; 129.5. C5; 129.1. I-
ArCH2 and l-ArCH6; 129.0, 1-ArCl: 116.5, l-ArCH3 and l-ArCH5; 66.9, C3; 57.5, C7; 56.2, CIO; 54.3, CIO;
53.6, C3'; 52.5, OCH3;42.1, C6; 38.7, C14; 35.3, NCOCH3; 26.6, Cl'; 22.7, C21. Mass Spectrum (ES, +ve) w/z 503
(100%) [M+].HRMS calcd for C24H35N6O6 503.2618, found 503.2626.
Methyl (2S,55)-2-alIyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-
dihydro-2H-6-chromenyIsuIfonyI)guanidino]-4-oxooctanoatc(33)


The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 18 (287 mg, 1.74 mmol) and (25)-2-(9H-9-
fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-
2H-6-chromenylsulfonyl)guanidino]pentanoic acid (961 mg, 1.45 mmol) to
afford 33 (936 mg, 1.21 mmol, 83%) as a brown solid. Mp 90-94 oC. 1H
NMR (CDC13,300 MHz): 5 7.71 (d, J = 7.5 Hz, 2H, ArHl" and ArH8");
7.54 (d, J = 7.0 Hz, 2H, ArH4" and ArH5"); 7.39 (bs, IH, NH) 7.34 (t. J =
7.5 Hz, 2H, ArH3" and ArH6"); 7.22 (t, J = 7.5 Hz, 2H, ArH2" and
ArHT); 6.34 (bs, IH, NH); 6.12 (d,J = 7.5 Hz IH, NH): 5.65 (m. IH. H2'): 5.03 (d, J= 17.0 Hz. IH. H.V): 4.98 (d.

WO 2006/074501 PCT/AU2005/001444
146.
7= 10.0 Hz, IH, H3b'): 4.54 (m, IH, H2): 4.36 (m, IH, H5); 4.29 (d,J= 7.2 Hz, 2H, OCH2-HS*"): 4.11 (m. IH.
H9"): 3.65 (s, 3H, OCH,): 3.25 (m, 2H, H8 ); 2.58 (s, 3H, 7"'-CH,); 2.55 (s, 3H, 5"'-CH 3); 2.48 (m, 4H, HI' and
H4'"): 2.07 (s, 3H, 8"'-CH3): 1.93 (m, 2H, H6): 1.73 (t, J = 6.5 Hz, 2H, H3"1); 1.60 (m, 2H, H7); 1.26 (s, 6H, 2 x
2"'-CH,). Mass Spectrum (ES, +ve) n/z 774 (20%) [MH+], 130 (100%) [allylGly]. HRMS calcd for C4,H53N5O8S
774.3537, found 774.3517.
Methyl (2S,5S)-2-alIyI-5-amino-3-aza-8-[(2,2p,7,8-Pcntamcthyl-3,4-dihydro-2ff-6-
chromcnylsuIfonyl)guanidino]-4-oxooctanoate(34)
The title compound was synthesized using the general N-Fmoc deprotection
procedure (Procedure C), from 33 (749 mg, 0.97 mmol) to yield 34 (259 mg,
0.47 mmol, 48%) as a cream oil, which had spectral data in agreement with that
reported.80 1H NMR (CDCI3,300 MHz):  7.86 (d, J = 8.1 Hz, IH, NH); 6.33 (bs,
3H, NH); 5.66 (m, IH, H2'); 5.09 (m, 2H, H3'); 4.54 (m, 1H, H2); 3.73 (s, 3H,
OCH3); 3.43 (m, IH, H5); 3.20 (m, 2H, H8); 2.63 (t, J = 6.9 Hz, 2H, H4"); 2.57
(s, 3H, 7"-CH3); 2.55 (s, 3H, 5"-CH3); 2.50 (m, 2H, HI'); 2.10 (s, 311, 8"-CH3);
1.80 (m, 4H, H7 and H3"); 1.60 (m, 2H, H6); 1.30 (s, 6H, 2 x 2"-CH3). Mass
Spectrum (ES, +ve) m/z 552 (100%) [MH+]. HRMS calcd for C20H42N5O6S 552.2856, found 552.2856.
Methyl (2S,SS,8S)-2-allyI-8-(4-allyIoxybenzyI)-3,6,9-triaza-5-([ {2,2,5,7,8-|)entamethyl-3,4-dihydro-2i-6-
chromcnylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate (35)

The title compound was synthesized using the general peptide coupling
procedure (Procedure B), from 34 (236 mg, 0.43 mmol) and 16 (95 mg, 0.36
mmol) to afford 35 (207 mg, 0.25 mmol, 72%) as a light brown solid. Mp 99-
104°C. 1H NMR (CDCI3,500 MHz):  7.77 (d, J = 7.8 Hz, IH, NH). 7.69 (bs,
IH, NH); 7.14 (d, J = 7.5 Hz, IH, NH); 7.04 (d, J = 8.4 Hz, 2H, ArH2"" and
ArH6""); 6.74 (d, J = 8.4Hz, 2H, ArH3"" and ArH5""); 6.41 (bs, 2H, NH): 6.01
(m, IH, H2"'"); 5.70 (m, 1H,H2');5.37 (dd,J= 1.5, 17.4 Hz, lH,H3a'": 5.25
(dd, J = 1.5,10.5 Hz, IH, H3b""'); 5.07 (d, J = 15.3 Hz, IH, H3a'); 5.03 (d, J =
9.3 Hz, IH, H3b'); 4.74 (m, IH, H2); 4.64 (bs, IH, H5); 4.56 (dd, J = 6.9, 13.5
Hz, 2I-I, H8); 4.44 (d,J= 5.4Hz, 2H, HI""); 3.68 (s, 3H, OCH3); 3.17 (d, J =4.5 Hz, 2H, H3"): 2.95 (m, 211,
ArCH2): 2.59 (t, J = 6.3 Hz, 2H, H4""): 2.55 (s, 3H, 7"'-CH 3): 2.53 (s, 3H, 5"'-CH 3); 2.50 (m, 2H, HI'): 2.08 (s, 3H,
8"'-CH,): 1.88 (s, 3H, HI1): 1.78 (t,J= 6.3 Hz, 2H, H3'"): 1.72 (m, 2H, H7): 1.55 (m, 2H, H6): 1.29 (s, 6H, 2 x
2"'-CH ,). Mass Spectrum (ES, +ve) m/z 191 (100%) [MH+]. HRMS calcd for C40H57N6O9S 797.3908, found
797.3890.


WO 2006/074501 PCT/AU2005/001444
147.
(7S,1 CS,l3S,4E/Z)-i3-Acetamido-S,l 1 -diaza-1 O(3-t{2,2,S,7,S-pentamethyl-3,4Kliliydro-2H-6-
chromenyIsuIfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
1 (l,4)phenyle rcacyclotetradecaphane-4-ene (36)
The title compound was prepared using the general procedure for olefin
metathesis (Procedure D), from 35 (127 mg, 0.16 mmol) to yield 36 (117 mg,
0.15 mmol, 95%) as a grey solid. Mp 224-228 °C. tH NMR (CDC1, 300 MHz): 
6.97 (m, 2H, ArH); 6.71 (m, 2H, ArH); 6.41 (bs, IH, NH); 5.50 (m, H4 and H5);
4.57 (bs, 5H, H3, H7, H1O and H13); 3.67 (s, 3H, OCH,); 3.16 (m, 2H, H3'):
2.56 (m, I OH, H14, 7"-CH _,, 5"-CH, and H4"): 2.08 (s, 3H, 8"-CH ,); 1.78 (s, 3H,
NCOCHa); 1.52 (m, 2H, HI'): 1.35 (m, 2H, H3"); 1.30 (s, 6H, 2 x 2"-CH,).
Mass Spectrum (ES, +ve) m/z 769 (100%) [MH+]. HRMS calcd for
C3SH,,N6O9S 769.3595, found 769.3574.
(7S,10S,13S,4E/Z)-13-Acetamido-8,ll-diaza-10-(3-[guanidinolpropyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
l(l,4)phcnyTenacyclotetradecaphane-4-ene hydrochloride(37)

The title compound was synthesized using the general iV-Boc deprotection
procedure (Procedure A), from 36 (91 mg, 0.12 mmol) to yield 37 as a white
solid (38 mg, 0.071, 59%). Mp 218-220 oC. 1M NMR (CD,OD, 300 MHz):  7.05
(m, 2H, ArH); 6.74 (m, 2H, ArH); 5.80 (m, IH, H5); 5.55 (m, IH, H4); 4.51 (m,
5H, H3, H7, H1O and H13); 3.68 (m, 3H, OCH,); 3.18 (m, 2H, H3'); 2.84 (m, 2H,
H14): 2.49 (m, 2H, H6); 1.99 (s, 3H, NCOCH ,); 1.76 (m, 2H, HI'); 1-64 (m, 2H,
H2'). 13C NMR (CD3OD 75 MHz):  173.5, COOCH3; 173.3, CI1; 173.2, C9:
172.2, NCOCH,; 158.9, CN,; 157.8, l-ArC4; 131.5, C4; 129.9, C5; 129.1, l-ArCH2 and l-ArCH6; 129.0, 1-ArCl;
H6.2. l-ArCH3 and l-ArCH5: 66.8. C3: 57.6. C7; 56.0, CIO; 54.1, CIO; 53.6, C3'; 52.9, OCH3;42.0, C6; 38.0,
C14; 35.3, NCOCH3;26.2, C1; 22.6, C2'. Mass Spectmm (ES, +ve)m/z 503 (100%) [M+].HRMS calcd for
C24H35N6O6 503.2618, found 503.2603.
Methyl (2R)-2-amino-4-pentenoate hydrochloride (38)

To a suspension of (27?)-2-amino-4-pentenoic acid (200 mg, 1.74 mmol) in methanol (6 mL) at
CPC was added dropwise thionyl chloride (1 mL). The resulting solution was allowed to stir for
16 h before the solvent was removed by evaporation and the product crystallized with diethyl
ether. The diethyl ether was removed by evaporation to yield the title compound (287 mg, 1.74 mmol, 100%) as a
white solid which had spectral data in agreement with that reported. 123 Mp 135-14O°C. 1H NMR (CDCl3.300 MHz):
 8.70 (bs. 3H, NH3+); 5.89 (m, IH, H4); 5.32 (d, J = 17.3 Hz, IH, H5a); 5.24 (d, J = 10.1 Hz, IH, H5b); 4.31 (m, IH,
H2): 3.81 (s. 3H, OCH,); 2.87 (t, J= 6.3 Hz, 2H, H3). Mass Spectrum (ES. +ve) m/z 130 (100%) [M+]. HRMS calcd
forC6Hi2NO2 130.0868, found 130.0870.


WO 2006/074501 PCT/AU2005/001444
148.
Methyl (2/_j5R)-2-,allyl-3-aza-5-(9J I -9-fhiorenyImethyloxycarboxainido)-8-[ (2,2,5,7,8-pentaiiiethyl-3..4-
dihydro-2ff-6-chromenylsuIfonyI)guanidino]-4-oxooctanoate(39)
The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 38 (287 mg, 1.74 mmol) and (2R)-2-(9H-9-
fluorenylmetiiyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-
2/j-6-chromenyIsulfonyl)guanidino]pentanoic acid (961 mg, 1.45 mmol) to
afford 39 (1.01 g, 1.31 mmol, 90%) as a brown solid. Mp 96-98oC. 1H
NMR (CDC13 500 MHz): 5 7.70 (d, J= 7.5 Hz, 2H, ArHl" and ArH8");
7.53 (d, J=5.0 Hz, 2H, ArH4" and ArH5"); 7.40 (d, J-4.5 Hz, IH, NH);
7.34 (t J =7.5 Hz, 2H, ArH3" and ArH6"); 7.22 (t, J =7.5 Hz, 2H, ArH2"
and ArH7"); 6.34 (s, 2H, NH); 6.12 (bs, 2H, NH); 5.64 (m, IH, H2'); 5.03 (d,,/= 17.0 Hz, IH, H3a'); 4.98 (d,J =
10.0 Hz, IH, H3b'); 4.53 (m, IH, H2); 4.36 (dd, J= 8.5, 12.5 Hz, IH, H5); 4.29 (d, .7=7.0 Hz, 2H, 9"-CH2);4.10
(m, IH, H9"); 3.65 (s, 3H, OCH,);3.28 (m, 2H, H8); 3.22 (bs, IH, NH); 2.58 (s, 3H, 7"'-CH ,);2.55 (s, 311, 5"'-
CH,): 2.47 (m, 4H, HI' and H4'"); 2.07 (s, 3H, 8"'-CH ,); 1.91 (m, 2H, H7); 1.73 (t, J =6.5 Hz, 2H, H3'"); 1.60 (m,
2H, H6); 1.25 (s, 6H, 2 x 2"'-CH 3). Mass Spectrum (ES, +ve) m/z77A (100%) [MH+].HRMS calcd for
C41H52N5OSS 774.3537, found 774.3524.
Methyl (2fi,51 )-2-aIlyl-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2fl r-6-
chiomenyisultonyl)guandinoj-4-oxooctanoate (4u

The title compound was synthesized using the general Af-Fmoc deprotection
procedure (Procedure C), from 39 (693 mg, 0.900 mmol) to yield 40 (387 mg,
0.0700 mmole, 78%) as a cream oil. 1H NMR (CDC13,300 MHz):  7.87 (d, J =
7.5 Hz, IH, NH); 6.35 (bs, 3H, NH); 5.67 (m, IH, H2'); 5.09 (d, J = 16.2 Hz,
IH, H3a'); 5.09 (d, J= 12.0 Hz, IH, H3b'); 4.54 (m, IH, H2); 3.72 (s, 3H,
OCH3); 3.42 (m IH, H5); 3.19 (d, J = 5.4 Hz, 2H, H8); 2.56 (s, 3H, 7"-CH _,);
2.54 (s, 3H, 5"-CH3); 2.51 (m, 2H, HI'); 2.10 (s, 3H, 8"-CH3); 2.05 (bs, 2H,
H7); 1.80 (t, j = 6.3 Hz, 2H, H2"); 1.57 (m, 2H, H6); 1.30 (s, 6H, 2 x 2"-CH 3).
Mass Spectmm (ES, +ve) n/z 552.1 (40%) [MM +1,243.0 (100%) [MH+leSS allylGly], HRMS calcd for
C26H42N5O6S 552.2856, found 552.2829.


WO 2006/074501 PCT/AU2005/001444
149.
Methyl (2/_,5/.,8S)-2-ally!-8-(4-allyloxybenzyl)-3,6,9-triaza-5-([ {2,2,5,7,8-pentamethyI-3,4-dihydro-2H-6-
chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate (41)
The title compound was synthesised using the general peptide coupling
procedure (Procedure B) using 40 (387 mg, 0.700 mmol) and 16 (153 mg, 0.580
mmol) to afford 41 (297 mg, 0.37 mmol, 64%) as a light brown solid. Mp 217-
22O°C. IHNMR (CDC13 500MHz): 87.22 (bs, IH, NH); 7.10 (d,J =8.0Hz, 2H,
ArH2"" and ArH6""); 6.88 (bs, III, NH); 6.82 (d, 7 = 8.5 Hz, 2H, ArH3"" and
ArH5""): 6.31 (d, 7 = 7.0 Hz, IH, NH); 6.17 (bs, IH, NH); 6.01 (m, IH, H2"");
5.69 (m, IH, H2'); 5.38 (d, J = 17.0 Hz, IH, H3a""); 5.26 (d, J = 10 Hz, IH,
H3b""); 5.11 (d,J= 17.0 Hz, IH, H3a'); 5.08 (d, J= 10.5 Hz, IH, H3b'); 4.56
(m, IH, H2); 4.99 (m, 3H, H5 and HI""); 4.43 (d, 7 = 7.5 Hz, IH, H8); 3.71 (s,
3H, OCH3); 3.15 (bs, 2H, H3"); 3.00 (m, 2H, ArCH2); 2.63 (t, 7 = 6.5 Hz, 2H, H4'"); 2.59 (s, 3H, 7"'-CH 3); 2.57 (s,
3H, 5"'-CH,);2.51 (m,2H,Hl'); 2.11 (s, 3H, 8"'-CH:,); 1.97 (s, 3H, HI1); 1.80 (t, 7 6.5 Hz, 2H, EB1"); 1.58(s,6H,
2 x 2"'-CH3); 1.30 (s, 4H, HI" and H2"). Mass Spectrum (ES, +ve) Viz 797.4 (100%) [MH+], HRMS calcd for
C40H,7N6O9S 797.3908, found 797.3915.
(7i?,10i?,13S,4£!fZ)-13-Acetamido-8,H-diaza-10-(3-imino[{2,2,5,7,8-pentamethyl-3,4-dihydro-2J 9-6-
chromenyIsulfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
l(l,4)phenyIenacyclotetradecaphane-4-enc (42)

The title compound was prepared using the general procedure for olefin
metathesis (Procedure D), from 41 (170 mg, 0.210 mmol) to yield 42 (160 mg,
0.210 mmol, 99%) as a grey solid. Mp 205-207OC. W NMR (CD,OD,300 MHz):
5 8.05 (m, 2H, NH); 7.02 (m, 2H, ArH); 6.72 (m, 2H, ArH); 6.48 (bs, IH, NH);
5.75 (m, 2H, NH); 5.42 (m, H4 and H5); 4.62 (bs, 2H, H3); 4.30 (m, 3H, H7,
H1O and H13); 3.66 (s, 3H, OCH3); 2.90 (m, 4H, H3' and H14); 2.60 (m, 6H,
5"-CH3 and 7"-CH3): 2.55 (m, 2H, H4"); 2.00 (s, 3H, 8"-CH3); 1.75 (s, 3H,
NCOCH3); 1.55 (m, 2H, HI'); 1.34 (bs, 2H, EB"); 1.27 (s, 6H, 2 x 2"-CH3).
Mass Spectrum (ES, -ve) nvz 769.5 (85%) [M+l. HRMS calcd for C3SH53N6O9S


WO 2006/074501 PCT/AU2005/001444
150.
(7R. 10,. 13S. 4 -Z-l-Acetamido-8, l-diaza-10( 3-[guanidino]propyl -7-methoxycarbonyl-2-oxa-9.12-dioxo-
I(l,4)phenylenacyclotetradecaphane-4-ene hydrochloride (43)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 42 (108 mg, 0.140 mmol) to yield 43 (25 mg,
0.049 mmol, 35%) as a white solid. Mp 170-176°C. H NMR (CD3OD 300 MHz):
5 7.08 (m, 2H, ArH); 6.76 (m, 2H, ArH); 5.90 (m, IH, H5); 5.54 (m, IH, H4);
4.45 (m, 5H, H3, H7, H1O) and HI3); 3.69 (m, 3H, OCH3); 3.07 (m, 2H, H3');
2.92 (m, 2H, H14); 2.49 (m, 2H, H6); 1.94 (s, 3H, NCOCH 3); 1.65 (m, 2H, HI1);
1.33 (m, 2H, H2'). 13C NMR (CD3OD,75 MHz):  173.8, COOCH3; 173.5, CH;
173.2, C9; 172.6, NCOCH3; 158.4, CN3; 157.2, l-ArC4; 131.4, C4; 130.6, C5; 129.7, l-ArCH2 and l-ArCH6;
129.3, 1-ArCl; 115.9, l-ArCH3 and l-ArCH5; 67.3, C3; 57.2, C7; 54.0, CIO; 53.7, C13; 53.2, C3'; 52.9, OCH3;
42.0, C6; 37.9, C14; 35.2, NCOCH3; 26.1, Cl'; 22.6, C2'. Mass Spectrum (ES, +ve) m/z 503 (35%) [M+], HRMS
calcd for C24H35N6O6 503.2618, found 503.2644.
Methyl (2RR,5S)-2-allyl-3-aza-5-(9H7-9-fluorenylmethyloxycarboxamido)-8-[ (2,2,5,7,8-pentamethyI-3,4-
dihydro-277-6-criromenylsuIfonyl)guanidino]-4-oxooctanoate (44)
The title compound was synthesized using the general peptide coupling
prnraHnm (Prnra-Hurn R) fmm "?8 (787 mo, 1 74 mrnnl) and (?S)-?-(9H-Q-
fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-
2H-6-chromenylsulfonyl)guanidino] pentanoic acid (961 mg, 1.45 mmol) to
afford 44 (1.00 g, 1.29 mmol, 89%) as a brown foam. Mp 90-92°C. 1H
NMR (CDC1, 300 MHz):  7.70 (d, J = 7.6 Hz, 2H, ArHl" and ArH8");
7.51 (d,.7=7.6 Hz, 2H, ArH4" and ArH5"); 7.33 (t, J=7.2 Hz, 2H, ArH3"
andArH6"); 7.20 (t, 7=7.2 Hz, 2H, ArH2" and ArH7"); 6.42 (d,J=7.6
Hz, IH, NH); 6.34 (s, IH, NH); 6.20 (bs, IH, NH); 5.61 (m, IH, H2'); 5.02 (d, J = 18.1 Hz, IH, H3a'); 4.97 (d, J =
10.5 Hz, IH, H3b'); 4.53 (dd. J =7.6. 13.1 Hz, IH, H2); 4.26 (d, J =7.2 Hz, 3H, H5 and 9"-CH2);4.06 (t, J = 7.2 Hz.
IH, H9"); 3.63 (s, 3H, OCH,); 3.23 (bs, 2H, H8 ); 2.57 (s, 3H, 7"'-CH 3); 2.54 (s, 3H, 5"'-CH 3); 2.47 (m, 4H, HI'
and H4"'); 2.07 (s, 3H, 8"'-CH 3); 1.88 (m, 2H, H6); 1.70 (t, J =6.7 Hz, 2H, H3"1); 1.60 (m, 2H, H7); 1.23 (s. 611, 2
x2"'-CH3).Mass Spectrum (ES, +ve)m/z774 (12%) [MH+], 130(100%) [allylGly]. HRMS calcd for GnH52N5O5S
774.3537, found 774.3536.



WO 2006/074501 PCT/AU2005/001444
151.
Mcthyl(2/.5S)-2-aIIyl-5-amino-3-aza-8-[(2^,5,7,8-])cntamcthyl-3,4-dihydro-2H-6-
chromenylsulfonyl)guanidino]-4-oxooctanoate(45)
The title compound was synthesized using the general N-Fmoc deprotection
procedure (Procedure C), from 44 (788 mg, 1.01 mmol) to yield 45 (552 mg,
1.00 mmole, 99%) as a cream oil. 1H NMR (CDC13,300 MHz):  7.86 (d, J = 7.5
Hz, 1H, NH); 6.33 (bs, 3H, NH); 5.69 (m, 1H, H2'); 5.12 (d, J = 16.8 Hz, III,
H3a'); 5.11 (d, 7= 10.8 Hz, 1H, H3b'); 4.53 (dd, J = 7.2,12.9 Hz, IH, H2); 3.71
(s, 3H, OCH3); 3.41 (d, J = 7.2 Hz, IH, H5); 3.19 (m, 2H, H8); 2.57 (m, 211,
HI'); 2.57 (s, 3H, 7"-CH3); 2.55 (s, 3H, 5"-CH3); 2.10 (s, 3H, 8"-CH3); 180 (m,
4H, H7 and H3"); 1.58 (m, 2H, H6); 1.30 (s, 6H, 2 x 2"-CH3). Mass Spectrum
(ES, +ve) m/z 552.1 (50%) [MH+], 162.7 (100%). HRMS calcd for C36H42N5O6S 552.2856, found 552.2834.
Methyl (2/_,5S,8S)-2-allyl-8-(4-alIyloxybenzyI)-3,6,9-triaza-5-([ {2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-
chromenylsulfonyl} guanidino]propyl)-4,7,10-trioxoundecanoate (46)
The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 45 (513 mg, 0.930 mmol) and 16 (204 mg, 0.78
mmol) to afford 46 (496 mg, 0.622 mmol, 80%) as a light brown solid. Mp 98-
102°C. lH NMR (CDCI3.500 MHz): 5 7.71 (d, J = 7.0 Hz, IH, NH); 7.40 (d, J =
7.0 Hz, IH, NH); 7.06 (d, J= 8.5 Hz, 2H, ArH2"" and ArH6""); 6.99 (bs, IH,
NH); 6.76 (d, / = 9.0 Hz, 2H, ArH3"" and ArH5""); 6.38 (bs, 2H, NH); 6.20 (bs,
IH, NH); 6.02 (m, IH, H2""'); 5.69 (m, IH, H2'); 5.38 (dd, J = 1.5, 17.0 Hz, IH,
H3a'""); 5.25 (dd, / = 1.0,11.0 Hz, IH, H3b'""); 5.09 (d, /= 17.5 Hz, IH, H3a');
5.06 (d, J = 10.5 Hz, IH, H3b'); 4.66 (m, IH, H2); 4.55 (m, 2H, H5 and 118);
4.45 (d. J= 5.5 Hz, 2H, HI""); 3.67 (s, 3H, OCH3); 3.20 (d, J =4.5 Hz, 2H, 113"): 2.97 (m, 2H, ArCH2); 2.61 (t, J
-6.0 Hz, 2H,H4'"); 2.57 (s, 3H, 7"'-CH ,); 2.55 (s, 3H, 5"'-CH ,);2.53 (m, 2H, HI'); 2.09 (s, 3H, 8"'-CH3); 1.88 (s,
3H, HI 1); 1.79 (t, J =7.0 Hz, 2H, H3"'); 1.74 (m, 2H, H7); 1.57 (m, 2H, H6); 1.30 (s, 6H, 2 x 2"'-CH ,). Mass
Spectrum (ES, +ve) m/z 819 (100%) [MNa+]. HRMS calcd for C4OH57N6O9S 797.3908, found 797.3873.



WO 2006/074501 PCT/AU2005/001444
152.
(7/_ ,10 S, 13 S .4£7Z)-13-Acetamido-8,ll-diaza-10-(3 -imino[ {2,2,5.7,8-pentamethy 1-3,4-dihydro-2H-6-
chromenyIsuIfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
l(l,4)phenvIenacyclotetradecaphane-4-ene (47)
The title compound was prepared using the general procedure for olefin
metathesis (Procedure D), from 46 (262 mg, 0.330 mmol) to yield 47 (217 mg,
0.280 mmol, 86%) as a grey solid. Mp 174-176oC. 'H NMR (DMSO, 500 MHz):
 8.10 (m, 2H, NH); 7.06 (m, 2H, ArH): 6.73 (m, 2H, ArH): 6.44 (bs, IH, NH);
5.70 (m, 2H, NH); 5.40 (m, H4 and H5); 4.62 (bs, 2H, H3); 4.28 (m, 3H, H7,
H1O and HI3); 3.55 (s, 3H. OCH,); 3.00 (m, 2H, H3'); 2.80 (m, 2H, HI4); 2.44
(m, 6H, 5"-CH,and 7"'-CH 3)'2.55 (m, 2H, H4"); 2.00 (s, 3H, 8"-CH3); 1.73 (s,
3H, NCOCH3); 1.51 (m, 2H, HI1); 1.35 (bs, 2H, H3"); 1.23 (s, 6H, 2 x 2"-CTI,).
Mass Spectrum (ES, -We) m/Z 767 (65%) [MH+]. HRMS calcd for C38H53N6O9S
769.3595, found 769.3630.
(7i?,10S,13S,4£/Z)-13-Acctamido-8,11-diaza-10-(3-[guanidino]pro|)yl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
l(I,4)phenylenacyclotetradecaphane-4-ene hydrochloride (48)
The title compound was synthesized using the general iV-Boc deprotection
proced (procedor a)from 47 (129 mg 0.16 mmol) to yield 48 as a white
solid (71 mg, 0.14 mmol, 86%). Mp 134-138oC. 1H NMR (CD3OD, 300 MHz): 
7.10 (m, 2H, ArH): 6.78 (m, 2H, ArH); 5.85 (m, IH, H5); 5.46 (m, IH, H4V. 4.43
(m, 5H, H3, H7, H1O and H13): 3.69 (m, 3H, OCII3); 3.30 (m, 2H, H3'); 2.95 (m,
211,1114); 2.53 (m, 2H, H6); 1.94 (s, 3H, NCOCH,); 1.80 (m, 2H, HI'): 1.62 (m,
2H, H2'). 13C NMR (CD3OD,75 MHz): 5 174.0, COOCH3; 173.6, CI1: 173.3, C9:
173.0, NCOCH,; 158.4, CN3: 157.2, l-ArC4; 131.3, C4; 130.6, C5; 129.7, l-ArCH2 and l-ArCH6: 129.5, 1-ArCl:
115.8. l-ArCH3 and l-ArCH5: 67.7, C3; 57.8, C7: 54.9, CIO: 54.0, CIO: 53.2, C3'; 52.9, OCH3;42.0, C6: 37.7,
C14: 33.2,NCOCH,; 26.5, Cl': 22.3, C2'. Mass Spectrum (ES, +ve) n/z 503.4 (100%) [M+]. HRMS calcd for
C24H35N6O6 503.2618, found 503.2666.
Methyl (2fi)-2-amino-(4-hydroxyphenyl)-2-propanoate hydrochloride (50)
To a solution of (2/?)-2-amino-3-(4-hydroxyphenyi)propanoic acid 49 (1.07 g, 5.9 mmol) in
anhydrous MeOH (10 mL) at 0°C was added dropwise thionyl chloride (2 mL). The resulting
mixture was allowed to stir for 16 h before the solvent was removed by evaporation to yield the
title compound (1.36 g, 5.9 mmol, 100%) as a white solid, which had spectral data in agreement
with that reported.124 [23 -27.7 (c. 0.1, EtOH). (lit. []D24 -27.1 (c. 2.0, MeOH)124 MP I76°C (lit.
134-136°C)124 1H NMR (CD3OD, 300 MHz):  7.05 (d, J = 8.4 Hz, 2H, ArH2' and ArH6'). 6.82 (d.
J = 8.4 Hz, 2H, ArI-13' and ArH5'): 4.13 (t, J = 6.9 Hz, IH, H2), 3.83 (s, 3H, OCTI,): 3.22 (dd. J = 6.0. 14.4 Hz. IH,
3HaV.3.12 (dd, .7 = 6.9, 14.7 Hz, IH, 3Hb).Mass Spectrum (CI. +ve) m/z 196(100%) [M4].HRMS calcd for
C10Hi4NO, 196.0974, found 196.0985.




WO 2006/074501 PCT/AU2005/001444
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Methyl (2R)-2-acetamido-3-(4-hydroxyphenyI)propanoate (51)
A solution of the HC1 salt 50 (1.09 g, 6.02 mmol) in water (3 mL) was cooled to OC before the addition of 5M
sodium acetate solution (35 mL) and a small amount of ice. Acetic anhydride (10 mL) was added
and the resulting precipitate was collected by vacuum filtration and dried to yield the title
compound (1.09 g, 4.58 mmol, 76%) as a white solid, which had spectral data in agreement with
that reported,124 []D25-27.2 (c. 0.1, EtOH) (lit. [ct]D25-26.6 (c. 0.1, MeOH) 124Mp 132-133°C (lit.
134-135.50C)124 iHNMR (CDCl3,300 MHz): 86.94 (d, J = 8.4 Hz, 2H. ArH2' and ArH6'). 6.75 (d,
./ = 8.4 Hz, 2H, ArH3' and ArH5'); 4.77 (m, IH, H2); 3.71 (s, 3H, OCII,); 3.04 (dd, J = 5.7, 14.1
Hz, IH, 3Ha); 2.95 (dd, J-6.6, 14.1 Hz, IH, 3Hb); 1.96 (s, 3H,NCOCH3). Mass Spectrum (CI,+ve) w z 238 (100%)
[MH+].HRMS calcd for C12H|6N,O4 238.107933, found 238.108226.
Methyl (2fi)-2-acetamido-3-(4-allyloxyphenyI)i)ropanoate(52)
To a solution of 51 (989 mg, 4.17 mmol), and anhydrous K-,CO, (1.15 g, 8.34 mmol) inDMF
(10 mL) was added allyl bromide (1.01 g, 8.34 mmol) and the resulting mixture was allowed to
stir for 16 h under a nitrogen atmosphere. The reaction was quenched with water (30 mL),
extracted with ethyl acetate (3 x 30 mL), and the combined organics were washed with water (5
x 20 mL) before drying. The solvent was evaporated to yield the title compound (985 mg, 3.56
mmol, 85%) as a pale yellow solid. []D25 -24.2 (c. 0.1, EtOH). Mp 9CPC. 1H NMR (CDC13 300
MHz): 5 6.97 (d, j = 8.7 Hz, 2H, ArH2' and ArH6'); 6.80 (d, J = 8.7 Hz, 2H, ArH.V and ArH5'):
6.09 (d. J=7.8Hz, IH, NH); 6.01 (m, IH, H2"); 5.37 (dd,J = 1.8, 17.4Hz, IH, H3a"); 5.25 (dd,J= 1.8, 10.5 Hz,
IH, H3,,"); 4.80 (m, IH, H2); 4.47 (d,J = 5.5 Hz, 2H, HI"); 3.68 (s, 3H, OCH3); 3.04 (m, 2H, H3); 1.99 (s, 311,
NCOCH,). Mass Spectrum (CI, +ve) m/z 278 (100%) [MH+]. HRMS (El) calcd for C13H10NO4 277.131408, found
277.130309.
(2/?)-2-Acetamido-3-(4-AUyloxyphenyl)propanoic acid (53)
To a solution of 52 (900 mg, 3.25 mmol) in THF/water, 3.1 (10 mL) was added lithium
hydroxide monohydrate (273 mg, 6.5 mmol), and the resulting suspension was allowed to stir for
16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed in vacuo.
The aqueous layer was extracted with diethyl ether (40 mL) to remove unreacted starting
material. The aqueous phase was acidified with 10% HC1 and the resulting precipitate was
extracted with DCM (3 x 40 mL). The combined DCM fractions were dried and evaporated to
yield the title compound (750 mg, 2.85 mmol, 88%) as a white solid, []D23* -23.2 (c. 0.1, EtOH). Mp 750C. IH NMR
(D6 acetone, 300 MHz): 5 7.27 (d, J =7.8 Hz, IH, NH): 7.17 (d, J - 8.7 Hz, 2H, ArH2' and ArH6'); 6.86 (d, J = 8.7
Hz. 2H, ArH3'andArH5'): 6.06 (m, IH, H2"): 5.4O (dd/= 1.5 Hz, 17.5 Hz, IH, H.V'): 5.23 (dd, J= 1.5, 10.5 Hz,
IH, H3b" ): 4.67 (dd, J= 5.1, 8.1, 10.5 Hz IH, H2): 4.53 (d,J= 5.1 Hz, 2H, HI"): 3.11 (dd,J=5.4, 14.1 Hz, IH,
3Ha):2.93 (dd,J= 8.1, 14.1. IH. 3Hb): 1.89 (s, 3H, NCOCH3). Mass Spectrum (CI, +ve) m/z 264 (100%1 [MH+].
HRMS calcd for C14Hi8NO4 264.123583, found 264.123770.




WO 2006/074501 PCT/AU2005/001444
154.
Meth.v!(2S5S,8R)-2-aIly!-8-(4-aIlyIoxybenzyl)-3,6,9-triaza-5-([{2,2,5,7,8-pentamcthyl-3,4-d!hydro-2flr-6-
chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate (54)
The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 34 (654 mg, 1.19 mmol) and 53 (260 mg, 0.99
mmol) to afford 54 (683 mg, 0.86 mmol, 87%) as a light brown solid. Mp 200-
204°C. 1HNMR(CDCl3,300MHz):87.10(d,J=8.4Hz,2H, ArH2"" and
ArH6""); 6.90 (d, J = 4.8 Hz, 1H, NH); 6.57 (d, J = 8.4 Hz, 2H, ArH3"" and
ArH5""); 6.34 (d, J = 7.5 Hz, 1H, NH); 6.19 (bs, 2H, NH); 6.00 (m, IH, H2.....):
5.70 (m, IH, H2'); 5.37 (dd, J = 1.8,17.1 Hz, IH, H3a'""); 5.26 (dd, J = 1.8,
10.5 Hz, IH, H3b'""); 5.11 (d, J = 12.0 Hz, IH, H3a'); 5.03 (d, J = 10.0 Hz, IH,
H3b'); 4.49 (m, 5H, H2, H5, H8 and HI'""); 3.70 (s, 3H, OCH3); 3.16 (m, 2H,
H3"); 2.99 (m, 2H, ArCH,); 2.63(t, J =6.3 Hz, 2H, H4'"); 2.59 (s, 3H, 7"'-CH 3); 2.57 (s, 3H, 5"'-CH 3); 2.54 (m, 2H,
HI'): 2.11 (s, 3H, 8'"-CH3); 1.96 (s, 3H, HI1); 1.80 (t, J =6.3 Hz, 2H, H3"'); 1.72 (m, 2H, H7); 1.58 (m, 2H, H6);
1.30 (s. 6H, 2 x 2"'-CH 3).Mass Spectrum (ES, +ve) m/z 191 (40%) [MH+], 106 (100%). HRMS calcd for
C40H,.N6O9S 797.3908, found 797.3926.
(7S,10S,13/?,4£/Z)-13-Acetamido-8,H-diiiza-10-(3-[{2,2,5,7,8-i)entamethyl-3,4-dihydro-2H-6-
chromcnylsuIfonyl}guanidino]propyI)-7-methoxycarbonyl-2-oxa-9,12-dioxo-
lfl,4)phenyIenacyclotetradecaphane-4-ene (55)
The title compound was prepared using the general procedure for olefin
metathesis (Procedure D), from 54 (366 mg, 0.46 mmol) to yield 55 (307 mg,
0.40 mmol, 87%) as a grey solid. Mp 186-19O°C. IH NMR (DMSO 500 MHz):
5 8.17 (m, 3H, NH); 7.02 (m, 2H, ArH): 6.75 (m, 2H, ArH); 6.41 (bs, IH, NH):
5.75 (m, IH H5); 5.45 (m, IH, H4); 4.42 (m, 5H, H3, H7, H1O and HI3); 3.69 (s,
3H, OCH,): 3.06 (m, 2H, H3'); 2.62 (m, 2H, H4"): 2.56 (in, 8H, H14, 7"-CH3,
and 5"-CH3); 2.08 (s, 3H, 8"-CH3): 1.85 (s, 311, NCOCH,): 1.60 (m, 2H, HI1):
1.40 (m, 2H, H3"); 1.26 (s, 6H, 2 x 2"-CH3). Mass Spectrum (ES, +ve) m>z 769
(40%) [MH+], 106 (100%). HRMS calcd for C3SH5JN6O9S 769.3595, found 769.3600.
(7S,10S,13iR,4£'/Z)-13-Acetamido-8,l 1 -diaza-10-(3-[aimno{imino}methylamino]propyl)-7-methoxycarbonyl-2-
oxa-9,12-dioxo-l(l,4)phcny!enacyclotetradecaphane-4-ene (56)
The title compound was synthesized using the general TV-Boc deprotection
procedure (Procedure A), from 55 (128 mg, 0.17 mmol) to yield 56 as a highly
hydroscopic solid (29 mg, 0.058 mmol. 34%). 1H NMR (CD3OD. 300 MHz): 
8.19 (m, 3RNH); 7.63 (bs. IH, NH): 7.05 (m, 2H, ArH): 6.67 (m, 2H, ArH):
5.78 (m, IH, H5): 5.25 (m, IH, H4): 4.43 (m, 5H, H3, H7, HK) and H13): 3.58
(m. 3H, OCH3): 3.06 (m, 2H, H3'): 2.85 (m, 2H, H14); 2.51 (m, 2H, H6): 1.77 (s,
3H. NCOCH3): 1.65 (m, 2H. HI1): 1.37 (m, 2H. H2'). "C NMIR (CD3OD 75




WO 2006/074501 PCT/AU2005/001444
155.
MHz): 5 171.3. COOCH,: 171.6. CI1: 171.3. C9: 169.4. NCOCH3; 156.8, CN3; 155.8, l-ArC4-. 130.2. C4; 128.8.
C5: 128.2, l-ArCH2 and l-ArCH6; 127.9, 1-ArCl; 114.9, l-ArCH3 and l-ArCH5; 67.1, C3: 55.2, C7; 54.7, CIO:
52.9, CIO: 51.8, C3': 51.6, OCH3:42.0, C6: 36.9, C14: 33.9, NCOCH,; 29.0, CI1; 22.4, C2\ Mass Spectrum (ES,
+ve) m/z 503 (30%) [M+], 102 (100%). HRMS calcd for C24H35N6O6 503.2618, found 503.2638.
Methyl (2S)-(4-hydroxyphenyl)-2-/ert-butoxycarboxamido propanoate (58)
To a solution of (25)-2-amino-3-(4-hydroxyphenyl)propanoic acid 57 (5.23 g, 28.9 mmol) in
anliydrous MeOH (20 mL) at OC was added dropwise thionyl chloride (2 rnL). The resulting
mixture was allowed to stir for 40 h before the solvent was removed by evaporation and the
resulting hydrochloride salt was dissolved in DMF (15 mL). To this solution was added di-
ferf-butyl-dicarbonate (9.44 g, 43.3 mmol) and the reaction mixture was allowed to reach RT
whilst stirring. After 16 h the reaction was quenched with water (30 mL) and extracted with
EtOAc (3 x 30 mL). The combined organic fractions were washed with water (5 x 20 mL), dried and evaporated.
The crude product was purified by flash column chromatography (25: 1. DCM/MeOH) to yield the title compound
(1.32 g, 4.48 mmol, 16%) as a yellow oil, which had spectral data in agreement with that reported. l25 'H NMR
(CDCU, 300 MHz):  6.95 (d, J = 8.4 Hz, 2H, ArH2' and ArH6'): 6.73 (d, J = 8.4 Hz. 2H. ArH3' and ArH5'): 6.51
(bs, OH): 5.05 (d, ,7 = 8.4 Hz, IH, NH); 4.53 (m, IH, H2), 3.71 (s, 3H, OCH3);2.99 (m, 2FI, H3): 1.42 (s, 9H,
C(CH3)3). Mass Spectrum (CI, +ve) m/z 196 (100%) [MH+ (less Boc)]. HRMS calcd for Ci6II2:NO5 296.1498,
found 296.1503.
Methyl (2S)-3-(4-allyloxyphen\I)-2-ter/-butoxycarboxamidopropanoate (59)
To a solution of 58 (1.3O g, 4.39 mmol) in DMF (15 mL) under an N-, atmosphere was
added K-,CO3 (L21g, 8.79 mmol) and the resulting suspension was allowed to stir for 20
min before the addition of allyl bromide (0.76 mL, 8.79 mmol). The reaction mixture was
allowed to stir for 16 h before quenching with water (40 mL) and extracting with EtOAc (3
x 4OmL). The combined organic fractions were washed with water (4 x 40 mL), dried and
evaporated to yield the title compound (1.21 g, 3.35 mmol, 76%) as a clear solid, which hacl
spectral data in agreement with that reported. 126Mp 142-144°C (lit. 145°C)120 IH NMR
(CDC13, 300 MHz): 87.03 (d, J= 8.8 Hz, 2H, ArH2' and ArH6'V. 6.84 (d, /= 8.4 Hz, 2H, ArH3' and ArH5'): 6.04
(m. IH. H2"): 5.34 (m, 2H, H3"); 4.97 (d, J = 8.0 Hz, III, NH); 4.50 (m, 3H, HI" and H2): 3.70 (s, 3H, OCH3);
3.02 (m. 2H, H3): 1.42 (s, 9H, C(CH3)3). Mass Spectrum (CI, +ve) m/z 320 (100%) [MH+], HRMS calcd for
CrH,4N2O4 320.1736, found 320.1714.



WO 2006/074501 PCT/AU2005/001444
156.
Methyl (2S)-2-(4-allyloxyphenyl)-2-aminopropanoate hydrochloride (60)
To a solution of 59 (1.10 g, 3.28 mmol) in DCM (5 mL) was added TFA (5 mL) dropwise.
After stirring for 16 h the solvent was removed by evaporation and the resulting trifluoroacetate
salt was resuspended in methanol (2 mL) and treated with IM HCl/diethyl ether (2 mL). The
solution was stirred for 5 min before the solvent was evaporated to yield the crude
hydrochloride salt. The crude product was purified by precipitation (DCM/diethyl ether) to give
the title compound (889 mg, 3.28 mmol, 100%) as a white solid. Mp 216-22OoC. H NMR
(CD3OD, 300 MHz): 5 7.16 (d, J = 8.4 Hz, 2H, ArH2' and ArH6'); 6.93 (d, J = 8.8 Hz, 2H, ArH3' and ArH5'); 6.05
(m, IH, H2"); 5.38 (dd, J = 17.3, 1.7 Hz, IH, H3a"); 5.24 (dd, J= 11.8, 1.3 Hz, IH, H3b"); 4.54 (m. 2H, HI"); 4.26
(m, IH, H2); 3.81 (s, 3H, OCH3); 3.14 (m, 2H, H3). 13C NMR (CD3OD, 75 MHz):  170.3, Cl; 159.6, ArC4'; 139.6,
C2"; 131.4, ArCH2'and ArCH6'; 127.0, ArCl; 117.4, C3"; 116.2, ArCH3'and ArCH5'; 69.7, Cl"; 55.3, C2; 53.6,
OCH,; 36.6, C3. Mass Spectrum (Cl, +ve) m/z 236 (90%) |M+]. FIRMS calcd for C,,H18NO, 236.1287, found
. 236.1276.
Methyl (2S,5/.)-2-(4-allyIo\ybenzyl)-3-aza-9-(tert-butoxycarboxa raido)-5-(9i 1-9-
f!uorenylmethylcarboxamido)-4-oxononanoate (61)
The title compound was synthesized using the general peptide
(2/?)-6-tert-butoxycarboxamido-2-[(9/J-9-
fluorenylmethyloxy)carboxamido]hexanoic acid (291 mg, 0.62 mmol)
to afford 61 (317 mg, 0.47 mmol, 75%) as a pale yellow solid. Mp
114-116°C. 'H NMR (CDCb, 300 MHz): 5 7.74 (d, J = 7.6 Hz, 2H,
Arm1" and ArH8"'); 7.57 (d, J = 6.3 Hz, 2H, ArH4'" and AiHS"");
7.38 (t, J = 7.2 Hz, 2H, ArH3'" and ArH6"'); 7.28 (t, J = 7.6 Hz, 2H,
ArH2"' and ArHT"); 6.99 (d, J = 7.6 Hz, 2H, ArH2' and A1H6'); 6.82
(d, J = 7.2 Hz, IH, NH): 6.76 (d, J = 8.0 Hz, 2H, ArH3' and ArH5'); 5.97 (m, IH, H2"); 5.67 (d, J = 7.2 Hz, IH,
NI-I); 5.34 (d, J = 16.8 Hz, IH, H3a"); 5.23 (d, J = 10.5 Hz, IH, H3b"); 4.81 (d,./= 5.8 Hz, IH, H2); 4.70 (t, J= 5.9
Hz, IH. H5); 4.36 (m, 3H, OCH2 and OCH2-EK"'); 4.19 (m, 2H, HI"); 3.68 (s, 3H, OCH?): 3.05 (m, 4H, H9 and
ArCH2): 1.73 (m, 2IT, H6); 1.56 (m, 2H, H7); 1.42 (s, 9H C(CH,),); 1.24 (m, 2H. H8). Mass Spectrum (ES, +ve) iirz
708.4 (100%) [MNa+].HRMS calcd for C3t>H4SN,O8686.3439, found 686.3441.



WO 2006/074501 PCT/AU2005/001444
157.
Methyl (2S,5RJ)-2-(4-alIyloxybenzyl)-5-amlno-3-aza-9-(tert-butoxycarboxamido)-4-oxononanoate (62)
The title compound was synthesized using the general iV-Fmoc deprotection
procedure (Procedure C), from 61 (198 mg, 0.290 mmol) to yield 62 (131 mg,
0.280 mmole, 97%) as a cream oil. & NMR (CDC13 300 MHz):  7.63 (d, J =
8.4 Hz, IH, NH): 7.04 (d,./ = 8.4 Hz, 2H, ArH2' and ArH6'); 6.83 (d,./ = 8.4 Hz,
2H, ArH3' and ArH5'); 6.05 (m, IH, H2"); 5.40 (dd, J = 1.7. 17.3 Hz, IH, H3a");
5.28 (dd, J - 1.7, 11.8 Hz, IH, H3b"); 4.78 (m, IH, H2); 4.66 (bs, IH, NH); 4.50
(m, 2H, HI"): 3.71 (s, 3H, OCH3); 3.32 (dd, J = 4.2, 7.6 Hz, IH, H5): 2.61 (m,
4H, ArCH2 and H8); 1.52 (m, 6H, H6, H7 and H8); 1.43 (s, 9H, C(CH,K). Mass
Spectrum (ES, +ve) m'x 464.3 (100%) [MH4]. HRMS calcd for C;4H,SN,O6
464.2761, found 464.2749.
Methyl (2S,5R,8S)-2,8-di(4-allyIoxybenzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamidolbutyIH,7,10-
trioxoundecanoate (63)
The title compound was synthesized using the general peptide coupling
procedure (Procedure B), from 62 (220 mg, 0.600 mmol) and 16 (132 mg,
0.500 mmol )to yield 63 (130 mg 0.180 mmol 37% )as a whitesolid . Mp
185-186°C. 1H NMR (CDC13 300 MHz):  7.36 (d,J= 7.6 Hz, 2H, NH); 7.08
(d,J= 8.4 Hz, 2H, ArH2' and ArH6'); 7.02 (d, J = 8.4 Hz, 2H, ArH2"" and
Ai'H6""); 6.82 (d,J= 8.4 Hz, 4H, ArH3\ ArH5', ArH3"" and ArH5""); 6.63
(d, J= 7.2 Hz, IH, NH); 6.02 (m, 2H, H2" and 112""); 5.34 (m, 4H, H3" and
H3""); 4.78 (m, 2H, H2 and H8); 4.60 (m, IH, H5); 4.47 (m, 4H, HI" and
HI""); 3.67 (s, 3H, OCH3); 2.97 (m, 6H, Ar'-CH 2, Ar""-CH2 and H41");
1.93 (s, 3H, HI1); 1.43 (s, 9H, C(CH3)3); 1.19 (m, 6H, HI"', H21" and H3'").
Mass Spectrum (ES, +ve) m/z 709.3 (100%) [MH+]. HRMS calcd for
C3SH52N4O9709.3813, found 709.3793.



WO 2006/074501 PCT/AU2005/001444
158.
(10S,13R,16S,4£/Z)-16-Acetaniido-II,14-(Iiaza-13-([ter/-butoxycarboxami(lo]butyl)-10-methoxycarbonyl-2,7-
dioxa-12,15-(lioxo-l(I,4),8(4,l)-(liphenyIenecyclohepta(Iecaphane-4-ene (64)
The title compound was prepared using the general procedure for olefin
metathesis (Procedure D), from 63 (56 mg, 0.079 mmol) to yield 64 (22 mg,
0.032 mmol, 41%) as a brown solid. Mp 190-194°C. IINMR (CDC13 300 MHz):
86.96 (m, 8H, ArH); 5.93 (m, 2H, H4 andH5); 4.18 (m, IH, H1O); 4.83 (m, IH,
H16 );4.5 6 (m 4H,H? ami H6);4.1? (m, 1HJHIS); 3.74 (S, 3H, OCH ,): 3.28 (m,
2H, H4'); 2.84 (m, 4H, H9 and HI 7); 1.97 (s, 3H, NCOCH,); 1.25 (s, 9H,
C(CH,),): 1.40 (m, 6H, HI', H2' andH3'). Mass Spectrum (ES, -ve)m/z 125A
(100%) [MH++ formate], 681 (85%) [MH+l.HRMS calcd for C36H49N4O9
681.3500, found 681.3521.
(10S,13/?,16S,4EZ)-16-Acctamido-13-(4-aminobutyl)-ll,14-diaza-10-methoxycarbonyl-2,7-dioxa-12,15-dioxo-
I(l,4).8(4,l)-diphenylenecyclohei)tadecaphane-4-ene (65)
The title compound was synthesized using the general JV-Boe deprotection
procedure (Procedure A), from 64 (22 mg, 0.038 mmol) to yield 65 (20 mg, 0.034
mg, 89%) as a yellow solid. Mp >260°C. 'H NMR (CD,OD 300 MHz):  8.06 (m,
3H, NH): 7.07 (m, 4H, ArH); 6.78 (m, 4H, ArH): 5.95 (m, 2H, H4 and H5); 4.66
(hs, 4H, H3 and H6); 4.56 (m, IH, H1O); 4.40 (m, IH, HI6); 4.1 1 (m, IH, HI3):
3.75 (m. 3H, OCH_,); 2.90 (m. 6H. H9. HI7 and H4'): 1.92 (s. 3H.NCOCH ,):
1.45 (m. 4H. HI' and H2'); 0.90 (m. 2H. H3'). 13C NMR (CD3OD. 75 MHz): 6
171.1. C12: 170.3. NCOCH 3: 169.9. 10-CO. 169.4. C15: 157.3. 1-ArCl: 157.13.
8-ArCk 130.9. 8-ArC4: 130.5. 8-ArCH2 and 8-ArCH6: 130.1. l-ArCH2 and l-ArCH6: 128.8. C4: 128.4. C5: 126.3.
l-ArCH4: 115.5. 8-ArCH3 and 8-ArCH5: 114.4. l-ArCH3 and l-ArCH5: 68.6. C3: 67.9. C6: 54.8. CI6: 52.6. C13:
52.4. OCH 3". 52.2. CIO: 39.5. C4': 38.0. C9': 35.8. C17: 34.9. CI': 32.0. C31: 26.5. 16-NCOCH 3: 23.3. C2 Mass
Spectrum (ES. -ve) mz 581.6 (100%) [M+].HRMS calcd for C3]H4]N,O7 581.2975. found 581.2980.



WO 2006/074501 PCT7AU2005/001444
159.
Methyl (2S,5S)-2-(4-allyloxybenzyl)-3-aza-9-(fcr^butoxycatboxaniido)-5-(9/7-9-
fluorenyImethylcarboxamido)-4-oxononanoate (66)
The title compound was synthesized using the general peptide coupling
procedure (Procedure B), from 60 (200 mg, 0.74 mmol) and (2S)-6-tert-
hutoxycarboxamido-2- [/9H-9-
fluorenylmethyioxy)carboxamido]hexanoic acid (291 mg, 0.62 mmol)
to afford 66 (328 mg, 0.48 mmol, 77%) as a pale yellow solid. Mp 52-
54°C. iH NMR (CDC1, 300 MHz): 5 7.75 (d, J = 7.5 Hz, 2H, ArHT
andArH8'"); 7.59 (d,7 =6.9 Hz, 2H, ArH4'" and ArH5'"); 7.39 (t, 7 =
7.5 Hz, 2H, ArH3'" and ArH6'"); 7.30 (dd, 7 = 1.2, 7.5 Hz, 2R ArH2'"
and ArH7'"); 6.98 (d, 7 = 8.4 Hz, 2H, ArH2' and ArH6'); 6.77 (d, 7 =
8.7 Hz, 2H, ArH3' and ArH5'); 6.58 (d, 7 = 7.2 Hz, IH, NH); 5.98 (m,
IH, H2"); 5.56 (d, 7 =6.9 Hz, IH, NH); 5.35 (dd,7 = 1.5, 17.1 Hz, IH,
H3a"); 5.24 (dd,J= 1.5, 10.8 Hz, IH, H3,,"): 4.81 (dd,7=6.0, 13.8 Hz, IH, H2); 4.70 (t, /= 5.1 Hz, IH, H5); 4.40
(m, 4H, HI" and OCH2-H9'"); 4.20 (d, 7 = 7.2 Hz, 2H, HI"); 3.70 (s, 3H, OCH3): 3.04 (m, 4H, H9 and ArCH2);
1.80 (m, 2H, H6); 1.64 (m, 2H, H7); 1.43 (s, 9H C(CH3)3); 1.35 (m, 2H, H8). Mass Spectrum (F.S, +ve) m/z 686.4
(10%), 708.4 (100%) [MNa+]. HRMS calcd for C39H48N3O8 686.3441, found 686.3454.
Methyl (2S,5/?)-2-(4-alIyloxybenzyl)-3-aza-5-(9H-9-fluorcnylmethylcarboxamIdo)-4-oxo-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2£T-6-chromenyIsulfonyl)guanidino]nonanoate(67)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 60 (200 mg, 0.74 mmol)
and(27?)-2-(9H-9-riuorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2/7-6-
chromenylsulfonyl)guanidino]pentanoic acid (411 mg, 0.62 mmol)
to afford 67 (386 mg, 0.44 mmol, 71%) as a pale yellow solid. Mp
86«C. 'HNMR (CDC1, 300 MHz): 5 7.70 (d, 7 =7.5 Hz, 2H,
ArHF" and ArH8"'); 7.52 (d, 7= 8.7 Hz, 2H, ArH4'" and
ArH5'")-. 7.33 (dd, 7=7.8,7.8 Hz, 2H,ArH3'" and ArH6'"); 7.19
(m, 2H, ArH2'" and ArH7'"); 6.90 (d,J= 8.1 Hz, 2H, ArH2' and
ArH6'); 6.68 (d, 7=8.1 Hz, 2H, ArH3' and ArH5'): 6.32 (bs, 2H, NH): 6.15 (d,7 = 8.1 Hz, IH,NH); 5.91 (m, IH,
. H2"); 5.29 (d, 7= 17.4, IH, H3a"); 5.18 (d, / = 10.5 Hz, IH, H3b"): 4.71 (dd,7 =7.8, 13.5 Hz, IH, H2); 4.26 (m, 5H,
HI", OCiL-H" and H5): 4.06 (m, IH, H9'"); 3.62 (s, 3H, OCH3); 3.17 (m, 2I-L H8): 2.98 (m, 2H, ArCH,); 2.58 (s,
3H, 7""-CH3); 2.56 (m, 2H, H4""); 2.55 (s, 3H, 5""-CH3); 2.06 (s, 3H, 8""-CH3); 1.71 (t,7 =6.6 Hz, 2H, H311");
1.60 (m, 2H, H6): 1.48 (m, 2H, H7); 1.24 (s, 6H. 2 \ 2""-CH3). Mass Spectrum (ES, +ve) m X 880 (100%), [MH^.
HRMS calcd for C4SH58N5O9S 880.3955, found 880.3944.



WO 2006/074501 PCT/AU2005/001444
160.
Methyl (2S,5S)-2-(4-alIyloxybenzyl)-3-aza-5-(9/f-9-fluorenyImethylcarboxamido)-4-oxo-8-[(2,2^,7,8-
pentamethyI-3,4-dihydro-2H-6-chromenylsuIfonyI)guanidino]nonanoate(67)
The title compound was synthesized using the general peptide
coupling procedure (Procedure B), from 60 (200 mg, 0.74 mmol)
and(25)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-
[(2,2,5,7,8pentamethyl-3,4-dihydro-2/7-6-
chromenylsulfonyl)guanidino]pentanoic acid (411 mg, 0.62 mmol)
to afford 67 (460 mg, 0.52 mmol, 84%) as a pale yellow solid. Mp
88-90°C. 'H NMR (CDC13,300 MHz):  7.70 (d,J = 7.8 Hz, 2H,
ArHl'" and ArH8"'); 7.53 (d,J = 6.6 Hz, 2H, ArH4'" and
ArH5"'); 7.33 (m, 2H, ArH3"' and ArH6"'); 7.18 (m, 2H, AiH 2'"
and ArH7"'); 6.98 (d,J = 8.1 Hz, 2H, ArH2' and ArH6'); 6.70 (d,
J=8.1 Hz, 2H, ArH3' and ArH5'); 6.34 (bs, 2H, NH); 6.13 (bs, IH ,NH); 5.93 (m, IH, H2"); 5.30 (dd,/ = 1.5,
17.1, IH. H3a"); 5.19 (d,J= 1.5, 10.5 Hz, IH, H3b"V. 4.68 (m, IH. H2); 4.30 (m. 5H, HI", OCHrH9"'and H5);
4.08 (m, IH, H9'"); 3.60 (s, 3H, OCH3); 3.21 (m, 2H, H8); 2.97 (m, 2H, ArCH2); 2.58 (s, 3H, 7""-CH3); 2.56 (m,
2H, H4""); 2.54 (s, 3H, 5""-CH3): 2.07 (s, 3H, 8""-CH,): 1.84 (m, 2H, H6); 1.72 (t,J - 6.9 Hz, 2H, H3""); 1.55 (m,
2H, H7): 1.25 (s, 6H, 2 x 2""-CH3). Mass Spectrum (ES, +ve) m/z 880 (30%), 902 (100%) [MNa+]. HRMS calcd for
C48H58N2S 880.3955, found 880.3943.
Methyl (2S,5R)-2-aIIyI-3-aza-5-(9fi -9-fluorenylmethyIoxycarboxainido)-8-(guanidino)-4-oxooctanoate
hydrochloride (69)
The title compound was synthesized using the general iV-Boc deprotection
procedure (Procedure A), from 28(81 mg, 0.105 mmol) giving 69 as a
highly hydroscopic solid (43 mg, 0.079 mmol, 75%). Mp 203-208 "C. 'II
NMR (CD3OD 300 MHz):  7.88 (m, 2H, ArHl" and ArH8"); 7.62 (m, 2H,
ArH4" andArHS"); 7.36 (m, 4H, ArH3" and ArH6" and ArH2" and
ArH7"); 5.72 (m. III, H2'): 5.06 (m, 2H, H3); 4.46 (dd, J = 5.4, 8.4 Hz, IH,
H2); 4.39 (d,./ = 6.3 Hz, 2H, OCH7-HT); 4.31 (m, IH, H5); 4.19 (m, IH,
H9"): 3.68 (s, 3H, OCH3); 3.17 (bs, 2H, H8): 2.51 (m, Hz, 2H, HI'); 1.79 (m, 2H, H7): 1.64 (m, 211, H6). "C NMR
(CD3OD 75 MHz): 5 174.1,C4; 172.9, CT. 158.4. 5-NCO2; 146.3, ArC8a" andArC9a"; 142.4, ArC4a and ArC4b;
134.1.C2': 129.1, ArCH3" and ArCH6": 128.0, ArCH2" and ArCH7": 126.6, ArCH4" and ArCH5": 120.8,
ArCHl" and ./\rCH8"; 118.9, C3': 67.9, CH2-C9": 55.8, C9"; 53.4, C2; 52.8, OCH3;51.1, C5: 42.0, C8: 36.8, CT;
30.5, H7: 26.3, H6. Mass Spectrum (ES, +ve) m/z 508 (100%) [M+] HRMS calcd for C2-H34N5O 508.2526, found
508.2570.



WO 2006/074501 PCT/AU2005/001444
161.
Methyl (2SpS)-2-aIlyl-3-aza-5-(9H-9-fluorenyImethyloxycarboxamido)-8-(guanidino)-4-oxooctanoate
hydrochloride (70)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A) using 33 (81 mg, 0.105 mmol) giving 70 (27 mg,
0.05 mmol, 47%) as a highly hydroscopic solid. Mp 176-182°C. 1H NMR
(CD3OD,500 MHz):  7.79 (d, J = 7.5 Hz, 2H, ArH1" and ArH8"); 7.62
(m, 2H, ArH4" and ArH5"); 7.34 (m, 4H, ArH3" and ArH6" and ArII2"
and ArH7"); 5.77 (m, 1H, H2'); 5.10 (m, 2H, H3'); 4.46 (dd, J =6.0, 8.1
Hz, 1H, H2); 4.34 (d, J = 7.2 Hz, 2H, OCH2-H9"); 4.32 (m, IH, 115): 4.19
(m, IH, H9"); 3.69 (s, 3H, OCH3); 3.20 (m, 2H, H8); 2.52 (m, 2H, HI'); 1.83 (m, 2H, H7); 1.68 (m, 2H, H6). 13C
NMR (CD3OD,75 MHz):  174.4, C4; 173.2, Cl; 158.4, CN3; 158.3, 5-NCO,; 144.2, ArC8a" and ArC9a"; 142.4,
ArC4a" and ArC4b"; 134.1, C2'; 129.1, ArCH3" and ArCH6"; 128.7, ArCH2" and ArCHT; 126.7, ArCH4" and
ArCH5": 120.9, ArCHl" and ArCH8"; 119.0, C3'; 67.9, CH2-C9"; 55.6, C9"; 53.5, C2; 52.8. OCH,:48.1, C5; 42.0,
C8: 36.6, Cl'; 30.3, H7; 26.2, H6. Mass Spectrum (ES, +ve) n/z 508 (100%) [M+], HRMS calcd for C37H34N5O3
508.2560, found 508.2574.
Methyl (2R,5/ )-2-alIyI-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-(guanidino)-4-oxooctanoate
hydrochloride (71)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 39 (80 mg, 0.10 mmol) to yield 71 as a
highly hydroscopic white solid (45 mg, 0.083 mmol, 80%). 1H NMR
(CD3OD, 500 MHz):  7.61 (d, J = 7.5 Hz, 2H, ArHl" and ArH8"); 7.47 (d,
J = 8.5 Hz, 2H, ArH4" and ArH5"); 7.20 (t, J = 7.5 Hz, 2H, ArH3" and
ArH6"); 7.12 (t, J = 7.5 Hz, 2H, ArH2" and ArH7"); 5.58 (m, IH, H2'):
4.93 (d, J = 17.0 Hz, IH, H3a'); 4.87 (d, J = 10.0 Hz, IH, H3b'); 428 (dd. J
= 6.0, 8.0 Hz, IH, H2);4.20 (d, J= 7.0 Hz, 2H, OCH2-H9"); 4.03 (t, J=7.0Hz, IH, H5); 3.99 (t, J=7.0 Hz, IH,
H9"): 3.51 (s, 3H, OCH3); 3.01 (bs, 2H, H8); 2.34 (m, 2H, HI'); 1.64 (bs, 2H, H7); 1.47 (bs, 2H, H6). 13C NMR
(CD3OD,75MHz):  174.1. C4; 173.1, Cl; 158.4, CN3: 158.2, 5-NCO2; 145.1, ArC8a" and ArC9a"; 142.4, ArC4a
andArC4b: 133.9, C2'; 128.6, ArCH3" and ArCH6"; 128.0, ArCH2" and ArCHT; 126.0, ArCH4" and ArCH5";
120.8, ArCHl" and ArCH8"; 118.8, C3; 67.9, CH,-C9"; 55.6, C9": 53.6, C2: 52.7, OCH3;49.3, C5: 42.1, C8; 36.7,
Cl': 30.4, C7; 26.2, C6. Mass Spectrum (ES, +ve) m/z 508 (45%) [M+]. HRMS calcd for C37H34N5O5 508.2560,
found 508.2592.



WO 2006/074501 PCT/AU2005/001444
162.
Methyl (2/?,5S)-2-alIyI-3-aza-5-(9ff-9-fluorenylmethyloxycarboxamido)-8-(guanidino)-4-oxooctanoate
hydrochloride (72)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A) using 44 (94 mg, 0.12 mmol) to yield 72 as a
highly hydroscopic white solid (33 mg, 0.061 mmol, 51%). 1H NMR
(CD3OD,300 MHz): 5 7.79 (d, J = 7.5 Hz, 2H, ArH1" and ArH8"); 7.65
(m, 2H, ArH4" and ArH5"); 7.39 (t, J= 7.2 Hz, 2H, ArH3" and ArH6").
7.30 (t, J = 7.2 Hz, 2H, ArH2" and ArH7"); 5.72 (m, 1H, H2'); 5.09 (d, J =
16.5 Hz, 1H, H3a'); 5.04 (d, J = 9.6 Hz, 1H, H3b'); 4.46 (dd, J = 5.7, 8.4
Hz, IH, H2); 4.40 (d, 7= 6.3 Hz, 2H, 0CHrH9"); 4.22 (t, J =6.6 Hz, IH, H5); 4.16 (m, IH, H9"); 3.69 (s, 3H,
OCH3); 3.17 (t, J = 6.6 Hz, 2H, H8); 2.51 (m, 2H, HI'); 1.80 (m, 2H, H7); 1.62 (m, 2H, H6). 13C NMR (CD3OD 75
MHz): 5 174.0, C4; 172.9, Cl; 158.4, CN3; 158.2, 5-NCO2; 145.1, ArC8a" andArC9a"; 142.4, ArC4a" and ArC4b";
134.1. C2'; 128.7, ArCH3" andArCH6"; 128.0, ArCH2" andArCH7"; 126.0, ArCH4" andArCHS"; 120.8,
ArCHl" and ArcH8"; 118.9, C3'; 67.9, CH2-C9"; 55.8. C9"; 53.4, C2; 52.8, OCH3,;49.3, C5; 42.0, C8; 36.8, Cl';
30.5, C7; 26.3, C6. Mass Spectrum (ES, +ve) m/z 508 (25%) [M+], 179 (100%) [Sodium allylglycinamide"). HRMS
calcd for C27H34N5C5 508.2560, found 508.2555.
Methyl (2S,5R)-2-(4-allyloxybenzyI)-9-ainino-3-aza-5-(9H-9-fluorenyImcthyloxycarboxamido)-4-
oxononanoate hydrochloride (73)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 61 (132 mg, 0.19 mmol) to
yield 73 (92 mg, 0.15 mmol, 79%) as a white solid. Mp 162-17OoC. 1H
NMR (CD3OD 300 MHz): 5 8.02 (d, J = 8.0 Hz, IH, NH); 7.79 (d, J=
7.6 Hz, 2H, ArHl'" and ArH8'"); 7.64 (t, J = 8.4 Hz, 2H, ArH4'" and
ArH5'"); 7.38 (t, J= 7.2 Hz, 2H, ArH3"' and ArH6"'); 7.29 (m, 2H,
ArH2"' and ArH7'"); 7.04 (d, J = 8.4 Hz, 2H, ArH2' and ArH6'); 6.73
(d, J= 8.4 Hz, 2H, ArH3' and ArH5'); 5.94 (m, IH, H2"); 5.28 (d, J=
17.3 Hz, IH, H3a"); 5.16 (d, J= 10.5 Hz, IH, H3b"); 4.62 (dt, J = 5.0, 8.8 Hz, IH, H5); 4.33 (m, 4H, HI" andOCH,-
H9"'); 4.19(t, J=6.7Hz, IH, H9"'); 4.07 (dd, J= 5.1, 8.0 Hz, IH, H2); 3.70 (s, 3H, OCH,); 3.11 (m, 2H, H9); 2.90
(m. 2H, ArCH2); 1.60 (m, 4H. H6 and H7); 1.33 (m. 2H, H8). 13C NMR (CD3OD, 75 MHz):  174.2. C4; 173.2, Cl;
158.1, NCO2; 145.1, ArC4; 145.0, ArC8a'" and ArC9a'"; 142.4, ArC4a'" andArC4b'": 134.7, C2"; 131.1, ArCH2'
andArCH6'; 129.8, ArCH.3" andArCH6'"; 128.7, ArCH2"' and ArCH7": 128.7, ArCHl'" and ArCH8'"; 128.1,
ArCII4"' andArCH5"'; 120.8, ArCT: 117.3, C3': 115.6, ArCRT and ArCH5': 69.6. CHrC9'": 68.0, Cl"; 56.1,
C5; 55.2, C2: 55.1, OCH,;52.8, C9'"; 40.5. C9; 37.3, ArCH,; 32.6, C6; 28.1. C8; 23.6. C7. Mass Spectrum (ES.
+ve) m/z 586.3 (100%) [M+]. HRMS calcd for C34H40N3O6 586.2917, found 586.2935.



WO 2006/074501 PCT/AU2005/001444
163.
Methyl (2S,5S)-2-(4-aIlyIoxybenzyl)-9-amino-3-aza-5-(9H-9-fluorenylmethyIoxycarboxamido)-4-
oxononanoate hydrochloride (74)
The title compound was synthesized using the general N-Boc deprotection procedure (Procedure A), from 66 (73 mg,
0.106 mmol) to yield 74 (48 mg, 0.07 mmol, 68%) as a white solid. Mp
160-168°C. 1HNMR(CD3OD, 300 MHz):  7.79 (d, J = 7.2 Hz, 2H,
ArHl"' and ArH8"'); 7.65 (d, J= 7.2 Hz, 2H, ArH4"' and ArH5'"):
7.39 (t, J = 7.2 Hz, 2H, ArH3'" and ArH6'"); 7.29 (t, J = 7.2 Hz, 211,
ArH2'" and ArH7'"); 7.07 (d, J = 8.4 Hz, 2H, ArH2' and ArH6'); 6.77
(d, J = 8.4 Hz, 2H, ArH3' and ArH5'); 5.96 (m, 1H, H2"); 5.29 (dd, J =
1.2,18.3 Hz, 1H, H3a"); 5.16 (dd, J= 1.2, 10.5 Hz, 1H, H3b"); 4.63 (m,
1H, H5); 4.37 (m, 4H, HI' andOCH2-H9'"); 4.20 (m, 1H, H9'"); 4.09
(m, IH,H2): 3.67 (s, 3H, OCH3): 3.00 (m, 2H, H9); 2.90 (m, 2H, ArCH2): 1.65 (m, 4H, H6 and H7); 1.39 (m, 2H,
H8).13C NMR (CD3OD, 125 MHz):  174.4, C4; 173.3, Cl; 158.1, NCO2: 145.2, ArC4'; 145.0, ArC8a'" and
ArC9a'"; 142.4, ArC4a'" andArC4b"'; 134.7, C2"; 131.2, ArCH2' andArCH 6'; 129.8, ArCH3"1 andArCH 6'";
128.8, ArCH2'" andArCH7"'; 128.1, ArCHl"' andArCHR"'; 126.2, ArCH4'" andArCH5"1; 120.9, ArCl'-. 117.4,
C3': 115.6, ArCH3 and ArCH5'; 69.6, CH2-C9"'; 68.0, Cl"; 55.9, C5; 55.2, C2; 55.1, OCH3;52.8, C9"'; 40.4, C9:
37.3, ArCH2; 32.4, C6: 27.9, C8: 23.6, C7. Mass Spectrum (ES, +ve) mπ. 586.7 (100%) [M+l. HRMS calcd for
C34H4flN3O6 586.2917, found 586.2925.
Methyl (2S,5i-2-(4-allyloxybenzyl)-3-aza-S-(9fl r-941uorenylmethylcarboxamido)-8-guanidino-4-
oxononanoate hydrochloride (75)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 67 (62 mg, 0.068 mmol) to
yield 75 (35 mg, 0.054 mmol, 79%) as a white solid. Mp 158-162"C. 1H
NMR (CD3OD 300 MHz):  7.78 (d, J = 7.5 Hz, 2H, ArHl'" and
ArH8"'); 7.64 (d, J= 8.1 Hz, 2H, ArH4"' and ArH5'"); 7.38 (t, J= 6.9
Hz, 2H, ArH3'" and ArH6'"); 7.37 (m, 2H, ArH2"' and ArH7"); 7.04
(d, J = 8.4 Hz, 2H, ARH2' and ArH6'); 6.72 (d, J = 8.4 Hz, 2H, ArH3'
and ArH5'); 5.92 (m, 1H, H2"); 5.28 (d, J = 17.1, 1H, H3a"); 5.16 (d. J
= 10.8 Hz, IK H3b"): 4.61 (dd, J= 5.1, 9.0 Hz, IH, H2); 4.32 (m, 4H, HI" and OCH2-Hr'): 4.18 (m, IH, H5);
4.09 (m. IH. H9'"); 3.69 (s, 3H, OCH3): 3.09 (m. 2H. H8): 2.91 (m, 2H. ArCH2V. 1.62 (m. 2H. H6): 1.51 (m. 2H,
H7). 13C NMR (CD,OD,75 MHz):  172.0, C4; 171.8, Cl 156.8, CN3: 156.6. ArC4': 155.9, NCO2; 143.8. ArC8a"'
and ArC9a"': 140.8. ArC4a'" and ArC4b'": 135.5, C2": 130.1, ArCl': 129.6, ArCHT' and ArCH5"': 127.7.
ArCH2'" andArCH": 127.2, ArCHl"' and ArCH8"': 125.4, ArCK3" andArCH6'": 120.2, ArCH2' and ArCH6':
117.3. C3": 114.3. ArCH3' and ArCH5": 68.0. Cl": 65.8, CH2-C9"': 59.3. C9'": 54.0, C5: 52.0. OCH,: 46.7, C2:



WO 2006/074501 PCT7AU2005/001444
164.
40.3, C8: 36.1, ArCH2: 29.1, C6; 24.9, Cl. Mass Spectrum (ES, +ve) m/z 614.6 (100%) [M+l. FIRMS calcd for
C34H40N5O6 614.2979, found 614.3007.
Methyl (2S55)-2-(4-allyloxybenzyI)-3-aza-5-(9H-9-fluorenylmethyIcarboxamido)-8-guanidino-4-
oxononanoate hydrochloridc (76)
The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 68 (93 mg, 0.10 mmol) to
yield 76 (54 mg, 0.083 mmol, 83%) as a white solid. Mp 170-175C 1H
NMR (CD3OD 300 MHz):  7.90 (d, J = 7.2 Hz, 2H, ArHl"' and
ArH8'"); 7.75 (m, 2H, ArH4"' and ArH5'"); 7.38 (m, 4H, ArH3'",
ArH6"', ArH2"' and ArHT"); 7.14 (d, J= 8.1 Hz, 2H, ArH2' and
ArH6'); 6.82 (d, J= 8.1 Hz, 2H, ArH3' and ArH5'); 5.98 (m, IH, H2"):
5.34 (d, 7 = 17.1, lH,H3a");5.21 (d,J= 10.8Hz, 1H,H3b");4.46 (m,
2H, H2 and H5); 4.26 (m, 4H, HI" and OCHj-ro"'); 4.08 (m, IH, H9'"): 3.59 (s, 3H, OCH,): 3.12 (m, 2H, H8);
2.94 (m, 2H, ArCH2); 1.69 (m, 2H. H6); 1.52 (m, 2H, H7). 13C NMR (CD,OD,75 MHz):  171.9, C4; 171.8, Cl
157.0, CN3; 156.6, ArC4': 155.9, NCO2: 143.9, ArC8a'" and ArC9a"': 140.7, ArC4a"' and ArC4b"'; 133.8, C2";
130.1, ArCl': 129.0, ArCH4"" andArCHS'"; 127.7, ArCH2'" andArCH7'"; 127.1, ArCHl"' and ArCI-18'"; 125.4,
ArCH3"' andArCH6"'; 120.1, ArCH2' andArCH6'; 117.3, C3"; 114.4,ArCH3' andArCH5'; 68.1, Cl"; 65.7,
CH2-C9'"; 59.3, C9'"; 53.9, C5; 51.8, OCH,:46.7, C2; 40.3, C8; 35.7, ArCH2;29.0, C6; 25.1, C7. Mass Spectrum
(ES, +ve) m/z 614.8 (100%) [M+]. HRMS calcd for C34H40-,N5O6 614.2979, found 614.2972.
Methyl (2S,5R,8S)-2-alIyI-8-(4-allyloxyphenyl)-5-(4-aminobutyl)-3,6,9-triaza-4,7,10-trloxoundecanoatc
hydrochloride (77)
The title compound was synthesized using the general iV-Boc deprotection
procedure (Procedure A), from 21 (64 mg, 0.11 mmol) to yield 77 (22 mg,
0.041 mmol, 37%) as a cream highly hydroscopic solid. 1H NMR (CD,OD,
500 MHz):  7.15 (d, J = 8.0 Hz, 2H, ArH2'" and ArH6"'); 6.87 (d, J = 8.0
Hz, 2H, ArH3'" and ArH5'"); 6.05 (m, IH, H2""); 5.73 (m, IH, H2'); 5.39 (d, J=
17.0Hz, lH,H3"");5.24(d, J= 10.5 Hz, 1H, H3""); 5.08 (d, J= 17.0Hz,
IH, H3'); 5.04 (d, J = 10.0 Hz, IH, H3'); 4.52 (d, J= 5.5 Hz, 2H, HI"): 4.44
(m, 2H, H2 and H5); 4.15 (d, J = 6.5 Hz, IH, H8); 3.69 (s, 3H, OCH,): 2.92
(m, 2H. HI'): 2.83 (bs, 2H, H4"); 2.54 (m, 2H, ArCH2): 1.93 (s, 3H, MH): 1.74 (bs, 2H, HI"): 1.50 (bs, 2H, H2"):
1.00 (bs, 2H, H3"). "C NMR (CD3OD 75 MHz):  174.3, C7: 173.7, Cl: 173.2, C4; 173.1, CIO: 158.8, ArC4"':
134.8. C2': 134.5, C2"": 131.3, ArCH2'" andArCH 6'": 129.9, ArCT": 118.4, C3': 117.5, C3"": 115.8. ArCH3"'
andArCH5"': 69.8, Cl"": 57.6, C5: 54.2, OCH,: 53.8. C8: 52.7, C2; 40.3, C4'; 37.4, ArCHy. 36.4, CT: 31.7, Cl":
28.0, C3": 23.5, CI1; 22.4. C2". Mass Spectrum (ES. +ve) m/z 503.7 (100%) [M+]. HRMS calcd for C26H39N4O6
503.2870. found 503.2881.



WO 2006/074501 PCT/AU2005/001444
165.
Methyl (2S5S,8S)-8-acetamido-2-alIyI-9-(4-aIlyloxyphen\l)-5-(4-aininobutyl)-3,6-diaza-4,7-(lioxononanoate
hydrochloride (78)
The title compound was synthesized using the general procedure (Procedure
A), by deprotection of 25 (104 mg, 0.170 mmol) to yield 78 as a l: l mixture
of epimers (55 mg, 0.10 mmol, 60%) as a highly hydroscopic yellow solid.
Mp 150-154°C. 1H NMR (CD3OD, 300 MHz):  7.14 (d, J = 8.0 Hz, 2H,
ArH2'" and ArH6"'); 6.84 (t, J = 8.0 Hz, 2H, ArH3'" and ArH5'"); 6.03 (m,
1H, H2""); 5.76 (m, 1H, H2'); 5.37 (d, J= 17.3 Hz, 1H, H3a""); 5.22 (d, J =
9.7 Hz, 1H, H3b""); 5.10 (m, 2H, H3'); 4.53 (m, 5H, H2, H5, H8 and HI"");
3.69/3.67 (s, 3H, OCH3); 2.87 (m, 4H, HI" and H4"); 2.54 (m, 2H, ArCH2);
1.93/1.91 (s, 3H, HI1); 1.50 (s, 6H, H1", H2" andH3"). 13C NMR (CD3OD,75 MHz):  173.7/173.6, C7; 173.4, Cl;
173.1, C4; 173.0/172.9, CIO; 158.7, ArCH4"'; 134.8, C2'; 134.3/134.0, C2""; 131.2/131.1, ArCH2"' and ArCH6"';
130.2/130.1, ArCl'"; 118.8/118.5, C3'; 117.4/117.3, C3""; 115.7/115.6, ArCH3"' andArCH5"'; 69.8/69.7, Cl"";
57.2, C5; 54.0, OCH3: 53.8/53.7, C8; 52.8/52.7, C2; 40.6/40.5, C4'; 37.8/37.7, ArCH2; 36.6/36.5, CH; 31.9, Cl";
28.0, C3"; 23.4, CI1; 22.5, C2". Mass Spectrum (ES, +ve) m/z 503.3 (100%) |M+]. HRMS calcd for C2fiH39N4O6
503.2870, found 503.2894.
Methyl (2/?,5/_,8S)-2-alIyl-8-(4-alIyloxybenzyl)-3,6,9-triaza-5-(3-[guanidino)-4,7,10-oxoundecarK)ale
hyurochioride (79)
The title compound was synthesized using the general iV-Boc deprotection
procedure (Procedure A), from 41 (48 mg, 0.60 mmol) to yield 79 as a highly
hydroscopic solid (32 mg, 0.060 mmol, 100%). 1H NMR (CD3OD, 300 MHz): 
7.15 (d, J = 8.4 Hz, 2H, ArH2'" and ArH6'"); 6.86 (d, J = 8.7 Hz, 2H, ArH3'"
and ArC5'"); 6.04 (m, IH, H2""): 5.77 (m, IH, H2'); 5.38 (dd, J= 1.5, 17.4 Hz,
IH, H3a""); 5.23 (dd, J = 1.2, 10.5 Hz, IH, H3b""); 5.09 (dd, J = 1.2, 16.8 Hz,
IH, H3a'); 5.06 (d, J= 10.6 Hz, IH, H3b'); 4.50 (m, 4H, H2"" and H2); 4.39
(dd, J= 5.7, 8.1 Hz, IH, H5); 4.26 (dd, J = 4.5, 8.7 Hz, IH, H8); 3.68 (s, 3H, OCH3); 3.07 (t, J -1.2 Hz, 2H, H3");
2.94 (m, 2H, ArCH2); 2.54 (m, 2H, HI'); 1.95 (s, 3H, HI1); 1.62 (m, 2H, HI"); 1.32 (m, 2H, H2"). "C NMR
(CD3OD,75 MHz):  173.7, C4; 173.6, CI1; 173.4, Cl; 172.9, C7; 158.8, ArC4'"; 158.4, CN3; 134.8, C2""; 134.3.
C2'; 131.2, ArCl'"; 130.0, ArCH2"' andArOto'"; 118.6, C3'; 117.4, C3""; 115.7, ArCH3'" and ArCH5'";69.8,
Cl""; 57.2, C2; 53.8, C5: 53.8, C8: 52.8, OCH3; 50.1, C3"; 37.7, ArCH2; 36.5, Cl'; 29.7, C2"; 22.9, CI1: 22.3, Cl".
Mass Spectrum (ES, +ve) n/z 531.5 (80%) [M+]. HRMS calcd for C26H39N6O6531.2931, found 531.2936.



WO 2006/074501 PCT/AU2005/001444
166.
Methyl (2/.,5S,8S)-2-allyI-8-(4-allyIoxybenzyl)-3,6,9-triaza-5-(3-fguanidino)-4,7 1O-oxoundecanoate
hydrochloride (80)
The tide compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 46 (87 mg, 0.11 mmol) to yield 80 as a highly
hydroscopic solid (35 mg, 0.062 mmol, 56%). 1HNMR (CD3OD,300 MHz): 
7.16 (d, J = 8.5 Hz, 2H, ArH2'" and ArH6"'); 6.83 (d, J= 8.0 Hz, 2H, ArH3'"
and ArH5"'); 6.04 (m, 1H, H2""); 5.74 (m, 1H, H2'); 5.38 (dd, J=1.5, 17.5 Hz,
1H, H3a""); 5.23 (dd, J = 1.0,10.5 Hz, 1H, H3b""); 5.12 (d, J = 17.0 Hz, IH,
H3a'); 5.08 (d, J= 10.5 Hz, IH, H3b'); 4.50 (d, J= 5.0 Hz, 2H, HI""); 4.43 (m,
H2, H5 and H8); 3.71 (s, 3H, OCH3); 2.97 (t, J = 7.5 Hz, 2H, H3"); 2.94 (m, 2H,
ArCH2): 2.52 (m, 2H, H1'); 1.93 (s, 3H, CH3, HI1); 1.78 (m, 2H, HI"); 1.61 (m, 2H, H2"). 13C NMR (CD3OD, 75
MHz):  173.9, C4; 173.4, CI1; 173.1, Cl; 172.9, C7; 158.8, ArC4'"; 158.4, CN3; 134.8, C2""; 134.1, C2'; 131.1,
ArCl'"; 130.2, ArCH2'" and ArCH6"'; 118.9, C3'; 117.2,C3""; 115.6, ArCH3'" and ArCH5'";69.7, Cl""; 56.9,
C2; 53.8, C5; 53.6, C8; 52.8, OCH3; 50.1, C3"; 37.7, ArCH2; 36.9, Cl'; 26.1, C2"; 22.5, CI1; 20.7, Cl". Mass
Spectrum (ES, +ve.) m/z 531.1 (85%) [M+].HRMS calcd for C26H39N6O6 531.2931, found 531.2952.
Methyl (2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(3-[guanidino]pro])\l)-4,7,10-oxoundlecanoate
hydrochloride (81)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 36 (63 mg, 0.079 mmol) to yield 81 as a highly
hydroscopic solid (38 mg, 0.036 mmol, 85%). 1H NMR (CD3OD,300 MHz): 
7.13 (d, J = 8.7 Hz, 2H, ArH2"' and ArH6"'); 6.82 (d, J= 8.7 Hz, 2H, ArH3'"
and ArH5'"); 6.03 (m, 1H,H2""); 5.77 (m, 1H,H2'); 5.36(dd, J= 1.5, 17.4Hz,
IH, H3a""); 5.22 (dd, J= 1.5,10.5 Hz, IH, H3b""); 5.13 (d, J = 18.3 Hz, IH,
H3a'); 5.08 (d, J = 9.6 Hz, IH, H3b'); 4.49 (m, 3H, HI"" and H5); 4.40 (m, 2H,
H2 and H8); 3.69 (s,3H,OCH3); 3.18 (m,2H,H3"); 3.02 (dd, J = 5.7, 13.8 Hz, IH, ArCHH); 2.82 (dd,J =9.0, 14.1
Hz, IH. ArCHH); 2.51 (m, 2H, HI'); 1.92 (s, 3H, Hll); 1.83 (m, 2H, HI"); 1.64 (m, 2H, H2"). 13C NMR (CD3OD,
75 MHz):  173.9, C4; 173.5, CI1; 173.4, Cl; 173.2, C7: 158.8, ArC4"'; 158.4, CN3; 134.9, C2""; 134.2, C2';
131.2. ArCl'"; 130.3, ArCH2"' and ArCH6'"; 117.4, C3': 116.2,C3""; 115.6, ArCH3'" and ArCH5'"; 69.7, Cl"";
56.6, C2; 53.8, C5; 53.6, C8; 52.8, OCH3;50.1, C3"; 36.6, ArCH,: 36.5, Cl': 30.3, C2"; 23.0, CI1; 22.5, Cl". Mass
Spectrum (ES, +ve) m/z 531.1 (100%) [M+].HRMS calcd for C36H39N6O6 531.2931, found 531.2916.



WO 2006/074501 PCT/AU2005/001444
167.
Methyl (2S,5J?,8S)-2-allyI-8.,(4-allyloxybenzyl)-3,6,9-triaza-5-(3-[guanidino]propyl)-l,7,10-oxoundecanoate
hydrochloride (82)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 30 (70 mg, 0.088 mmol) to yield 82 as a highly
hydroscopic solid (37 mg, 0.065 mmol, 74%). 1HNMR (CD3OD, 300 MHz): 
7.12 (d, J = 7.5 Hz, 2H, ArH2"' and ArH6"'); 6.83 (d, J=7.5 Hz, 2H, ArH3"
and ArC5"'); 6.01 (m, 1H, H2""); 5.69 (m, 1H, H2'); 5.35 (d, J = 17.4 Hz, IH.
H3a""); 5.19 (d, J= 9.9Hz, 1H, H3b""); 5.09 (m, 2H, H3'); 4.47 (m, 2H, H2"");
4.40 (m, 2H, H2 and H5); 4.16 (m, 1H, H8); 3.65 (s, 3H, OCH3); 3.3 1 (m, 2H,
H3"); 2.95 (m, 2H, ArCH2); 2.50 (m, 2H, H1'); 1.92 (s, 3H, HI 1); 1 74 (m, 2H,
H1"); 1.23 (m, 2H, H2"). 13C NMR (CD3OD,75 MHz):  174.0, C4; 173.4, CI1; 172.9, Cl; 169.0, C7; 158.8,
ArC4"': 158.2, CN3 134.7, C2"": 134.3, C2': 131.2, ArCl"'; 129.8, ArCH2'" and ArCH6"'; 118.4, C3'; 117.4,
C3""; 115.7, ArCH3'" and ArCH5'"; 69.8, Cl""; 57.7, C2; 54.0, C5; 53.7, C8; 52.8, OCH,; 50.1, C3"; 37.5, ArCH,;
36.4, Cl'; 29.5, C2"; 24.0, CI1; 22.3, Cl". Mass Spectrum (ES, +ve) n/z 531 (100%) [M+].HRMS calcd for
C26H39N6O6 531.2931, found 531.2939.
Methyl (2S,5R,8S)-2,8-di(4-aIlyloxybenzyl)-5-(4-aminobutyl)-3,6,9-triaza-4,7,10-trioxoundecanoate
hydrochloride (83)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 63 (33 mg, 0.051 mmol) to yield 83 (18 mg,
0.028 mmol. 55%) as a yellow solid. Mp 186-190oC. 1H NMR (CD3OD, 500
MHz): 87.50 (bs, IH, NH); 7.41 (m, 4H, ArH): 7.17 (m, 4H, ArH): 6.38 (m,
2H, H2" and H2'"); 5.64 (m, 4H, H3" and H3""); 4.83 (m, 6H, H2,H8,
H 1" and HI""); 4.51 (m, IH, H5); 3.70 (s, 3H, OCH,); 3.28 (m, 611, H4"
Ar'-CH 2 and Ar""-CH,); 2.27 (s, 3H, M1l); 1.87 (m, 4H, H1" and H3");
1.33 (m, 2H, H2"). 13C NMR (CD,OD 125 MHz):  173.9, C7; 173.7, C4:
173.1, Cl; 172.0, CIO; 158.5, ArC4"" and ArC4'; 134.7, C2" and C2"":
131.3, ArCH2' andArCH6'; 131.1. ArCH2"" and ArCH6""; 130.0, ArCl""; 129.8, ArCl': 117.8, C3": 117.5,
C3""; 115.8, ArCH3' andArCHS'; 115.6, ArCH3"" and ArCHS""; 70.0, Cl"; 69.8, Cl'""; 57.2, C2; 55.2, C5:
53.8, OCH3: 52.4, C8: 40.7, C4"': 37.4, Ar'-CH,; 37.1, Ar""-CH,; 31.7, Cl'"; 27.9, C.V"; 23.2, CI1: 22.2, C2'".
Mass Spectrum (ES, +ve) m/z 609.7 (100%) [M+]. HRMS calcd for C33H45N4O7 609.3288. found 609.330 1.



WO 2006/074501 PCT/AU2005/001444
168.
Methyl (2S,52?,8S)-2-aIlyI-8-(4-aIlyloxybenzyl)-3,6,9-triaza-5-(4[{iV,iV-di-tert-
butoxycarbonyl}guanidino]butyl)-4,7,10-trioxoundecanoate (84)
To a solution of 21 (56 mg, 0.093 mmol) inDCM (2 mL) was added TFA (2
mL) and the resulting mixture was allowed to stir for 3 h. The solvent was
concentrated and the intermediate trifluoroacetate salt was precipitated by
addition of diethyl ether and collected as a solid by vacuum filtration. To this
solid was added N-teH-
butoxycarboxamido(trifluoromethylsulfonylirnino)methyl propanamide (65
mg, 0.17 mmol), triethylamine (0.2 mL) and DCM (2 mL). The resulting
solution was allowed to stir for 16 h under N2. The solvent was evaporated
and the crude product was purified by flash column chromatography (15:1,
DCM/ MeOIT) to yield the title compound as a 1:1 mixture of epimers (70 mg, 0.093 mmole, 100%) as an
orange/yellow solid. Mp 112-1140C. 1H NMR (CDCI 3,sooMHZ): 5 S.3I (bs, IH, NH); 7.20 (d,./ = 8.01 Iz, III,
NH); 7.08 (m, 2H, ArH2'" and ArH6"'); 6.94 (d, J= 7.6 Hz, IH, NH); 6.84 (m, 2H, ArH3"' and ArH5'"); 6.72 (d, J
= 7.2 Hz, IH, NH): 6.60 (d. J = 7.6 Hz, IH, NH); 6.02 (m, IH, H2""); 5.65 (m, IH, H2'); 5.38 (d, J = 17.3 Hz, IH,
H3a""): 5.26 (d, J= 10.5 Hz, IH, H3b""); 5.11 (m, 2H, H3'); 4.52 (m, 5H, H2, H5, H8 and H2""); 3.74/3.70 (s, 3H,
OCH3); 3.32 (d, J= 6-7 Hz. 2H, H4"); 2-95 (m, 2H, ArCH2); 2.50 (m, 2H, HI'); 1.97/1 96 (s, 3H, HI1); 1.37 (m,
6H,H1", H2" andH3"); 1.49 (s, 18H, 2 x C(CH,)3). Mass Spectrum (ES, +ve) m/z745.4 (100%) [MH+].HRMS
calcd for C37H57N6Oi0 745.4136, found 745.4138.
Methy!(2S5S,8S)-2-aIlyl-8-(4-aIlyloxybenzyl)-3,6,9-triaza-5-(4[{iV^-dW^-
butoxycarbonyl}guanidino]butyl)-4,7,10-trioxoundecanoate (85)
To a solution of 25 (41 mg, 0.081 mmol) in DCM (2 mL) was added N-tert-
butoxycarboxamido (trifluoromethylsulfonylimino)methyl propanamide (35
mg, 0.089 mmol), triethylamine (0.1 mL). The resulting solution was allowed
to stir for 16 h under N2. The solvent was evaporated and the crude product
was purified by flash column chromatography (15:1, DCM/ MeOH) to yield
the title compound as a 1:1 mixture of epimers (45 mg, 0.060 mmole, 74%) ns
an orange/yellow solid. Mp 114-1 18oC. 1H NMR (CDCI, 300 MHz):  8.26
(bs, IH, NH): 7.08 (t, J = 8.4 Hz, 2H, ArH2'" and ArH6'"): 6.97 (m, IH, NH):
6.83 (t, J = 8.4 Hz, 2H, ArH3'" and ArH5"'): 6.73 (d, J = 8.0 Hz, IH, NH):
6.57 (t. J= 9.3 Hz, IH, NH): 6.03 (m, IH, H2""). 5.66 (m, IH, H2'); 5.39 (d,
J= 17.3 Hz, IH, H3a""): 5.26 (d, J = 10.1 Hz. IH, H3b""); 5.10 (m, 2H, H3'V. 4.51 (m, 5H, H2. H5, H8 and HI""):
3.74/3.71 (s, 3H, OCH,): 3.33 (bs, 2H, H4"): 2.96 (m, 2H, HI'): 2.52 (m, 2H, ArCH,): 1.97 (s, 3H, HI1); 1.47 (m,
6H,H1". H2" andH3");1.49 (s, 18H. C(CTIs),). Mass Spectrum (ES, +ve) m/z 745.2 (100%) [MH+l.HRMS calcd
for C3-H57N6O|0 745.4136. found 745.4105.



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(7S, 1OS ,13S,4£/Z)-13-Acetamido-8,ll-diaza-10-(4-[ (i V^V-di-tert-butox\'carbonyl \ guanidino]butyl)-7-
methoxycarbonyl-2-oxa-9, 12-dioxo-l(l,4)phen\ienacyclotetradecaphane-4-ene (86)
To a solution of 26 (75 mg, 0.15 mmol) in DCM (2 mL) was added N-tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methyl propanamide (115
mg, 0.29 mmol), triethylamine (0.1 mL) and DCM (2 mL). The resulting
solution was allowed to stir for 16 h under N2. The solvent was evaporated and
the crude product was purified by flash column chromatography (15:1,
DCM/MeOH) to yield 86 as a 1:1 mixture of epimers (96 mg, 0.13 mmole,
87%) as an orange/yellow solid. Mp 104-102°C. 1H NMR (CDCl.,300 MHz):
 8.26 (m, IH, NH); 6.89 (m, 4H, ArH ); 5.63 (m, 2H, H4 andH5); 4.65 (m,
5H, H2, H7, H1O and H13); 3.79/3.78 (s, 3H, OCH3); 3.30 (m, 2H, H4'); 2.92
(m, 2H, H6); 2.67 (m, 2H, H14); 2.09/2.07 (s, 3H, NCOCH,); 1.55 (m, 6H, HI', H2' andH3'); 1.49/1.48 (s, 18H,
C(CHs):,). Mass Spectrum (ES, +ve) m/z IMA (100%) [MH+]. HRMS calcd for C35H53N6O10 717.3823, found
717.3806.
Methyi (2S,5R,8S) -2-allyl-9-(4-aIlyloxybenzyl)-5-(4-[guani(lino]butyI)-3,6,9-triaza-4,7,10-trioxoundecanoate
hydrochloride (87)
The title compound was synthesized using the general Af-Boc deprotection
procedure (Procedure A), from 84 (71 mg, 0.095 mmol) to yield 87 (43 mg,
0.074mmol, 78%) as a yellow hydroscopic solid. 1H NMR (CD3OD 300
MHz): 5 8.20 (m, 2H, NHx 2); 7.15 (d, J = 8.4Hz, 2H, ArH2'" and ArH6'");
6.87 (d, J = 8.4 Hz, 2H, ArH3"' and ArH5'"); 6.03 (m, IH, H2""); 5.73 (m,
IH, H2'); 5.39 (d, J= 17.3 Hz, IH, H3a""); 5.24 (d, J= 10.5 Hz, IH, H3b"");
5.12 (d, J = 6.0Hz, IH,H3a');5.05 (d, J=9.9Hz, lH,H3b'); 4.45 (m. 4H.
H2, H5 and H1""); 4.17 (dd, J = 4.0, 8.7 Hz, IH, H8); 3.72 (s, 3H, OCH3).
2.99(m,4H,Hl' and H4");2.53 (m, 2H, ArCH2); 1.94(s,3H,Hl 1). 1.59 (m,
4H, H2" andH3"); 1.00 (m, 2H, HI"). "C NMR (CD3OD75 MHz):  174.3, C4; 174.0, C11 173.3, CL 173.2, C7;
159.0, ArC4"'; 158.5, CN,; 134.9, C2""; 134.5, C2': 131.4, ArCl"'; 130.4, ArCTLT" andArCH6"'; 118.6, C3';
117.5, C3""; 115.9, ArCH3"' andArCH5'"; 69.8, Cl"": 57.5, C2; 54.3, C5; 53.8, C8; 52.7, OCHy.42.1, C4": 37.5,
ArCH2: 36.4, Cl'; 31.9, C2"; 29.2, C3"; 23.6, CTh 22.4, Cl". Mass Spectrum (ES, +ve) viz 545.4 (100%) |M+].
HRMS calcd for C2-HuN6O6 545.3088, found 545.3073.



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170.
Methyl (2S,5S,8S)-2-aIlyl-9-(4-allvIoxyphenyl)-5-(4-[guani(lino]but\I)-3,6,9-triaza-4,7,10,,trioxoun(lecanoate
hydrochloride (88)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 85 (40 mg, 0.054 mmol) to. yield 88 (11 mg,
0.019 mmol, 35%) as a highly hydroscopic yellow solid. 'H NMR (CD3OD,
300 MHz): 57.10 (bs, 2H, ArH2"' andArH6"'); 6.79 (bs, 2H, ArEB"' and
ArH5'"); 6.00 (m, IH, H2""); 5.72 (m, IH, H21); 5.16 (m, 4H, H3"" and TO');
4.40 (m, 5H, H2, H5, H8 and HI""); 3.65 (s, 3H, OCH,); 3.00 (m, 4H, HI'
and H4"); 2.49 (bs, 2H, ArCH2); 1.87 (s, 3H, HI 1); 1.36 (m, 6H, HI", H2"
andH3"). !3C NMR (CD,OD 75 MHz): 5 174.2, C4; 174.1, CI1; 173.6, Cl;
173.2,C7; 159.4, ArC4'"; 158.4, CN3; 134.6, C2""; 134.2, C2'; 131.2,
ArCT": 130.3, ArCH2"' andArCH6"'; 119.6, C3'; 118.2, C3""; 116.3, ArCH3"' andArCHS'"; 70.0, CT"; 57.4,
C2; 54.4, C5; 53.9, C8; 52.4, OCH,; 42.2, C4"; 37.6, ArCH2; 36.6, Cl'; 32.5, C2"; 29.5, C3"; 23.6, CI1; 22.8, Cl".
Mass Spectrum (ES, +ve) m/z 545.3 (100%) |M+]. HRMS calcd for C27H41N6O6 545.3088, found 545.3066.
(7S,10S,13S,4£/Z)-13-Acctainido-10-(4-[guanidino]but\I)-8,ll-diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-
l(l,4)phenylenacycIotetradecaphane-4-ene hydrochloride (89)
procedure (Procedure A), from 86 (86 mg, 0.12 mmol) to yield 89 (50 mg,
0.097 mmol, 81%) as a highly hydroscopic yellow solid. 1H NMR (CD,OD_
500 MHz):  10.34 (bs, IH, NH); .42 (m, 211, Aril); 7.08 (m, 2H, Aiil); 5.97
(m, 2H, H4 and H5); 4.80 (m, 5H, H2, H7, H1O and HI 3); 3.65 (s, 311, OCH,);
3.32 (m, 211, H4'); 3.09 (m, 2H, H6); 2.42 (m, 2H, HI4); 2.10 (s, 3H,
NCOCHj); 2.04 (m, 2H, H3'); 1.86 (m, 2H, III'); 1.50 (m, 2H, H2'). 13C NMR
(CD,OD, 125 MHz):  173.3/173.2, C9; 172.7/173.6, 7-CO; 172.5, 13-NCO;
169.4, C12; 158.5/158.4, 1-ArCl; 131.4/131.3, l-ArCH2 and l-ArCH6; 131.0,
C4; 129.3, C5; 129.0, l-ArC4; 116.5, l-ArCH3 and l-ArCH5; 67.0, C3; 58.2, C7; 57.5, C13; 57.4, CIO; 53.9, OCH?;
42.1, C4'; 33.9, C14; 29.0, C6; 23.5, C3'; 22.7, Cl'; 22.5, NCOCH,;22.5, C2'. Mass Spectrum (ES, +ve)m/z 517.4
(100%) [M+|. HRMS calcd for C25H37N6O6 517.2775, found 517.2765.
(S)-2-Amino-3-(4-iodophenyl)propanoic acid (92)
To a solution (,S)-2-amino-3-phenylpropanoic acid 91 (4.01 g, 24.3 mmol) in acetic acid (22 mL) was
added sulfuric acid (2.9 mL, 5.14 mmol), iodine (2.47 g, 4.7 mmol) and sodium iodate (1.02 g, 5.14
mmol). The mixture was heated to 7CPC and allowed to stir at this temperature for 16 h before an
additional portion of sodium iodate (1.02 g. 5.14 mmol) was added. The reaction was left for a further
2 h before being concentrated, dissolved in methanol (20 mL) and treated with NaOH (60 mL). The
mixture was left to precipitate out of the basic solution overnight and the resulting solid was filtered by vacuum
filtration to yield the title compound (7.07 g, 24.3 mmol, 100%) as a pink solid, which had spectral data in




WO 2006/074501 PCT/AU2005/001444
171.
agreement with that reported.03 [ocID21 -10.6 (c. 0.3. HC1). Mp 258-26OoC (lit. 261-262°C)93 1H NMR (CD3OD, 300
MHz): 87.71 (d, J = 8.4 Hz, 2H, ArH2' and ArH6'); 7.10 (d, J = 8.4Hz, 2H, ArH3' and ArH5'): 4.26 (dd, J=6.3.
7.2Hz, H2); 3.26 (dd, J=5.4, 14.1 Hz, IH, H3a): 3.04 (dd, J=7.2, 14.4 Hz, IH, H3b).Mass Spectrum (CI.+ve)m/z
279 (100%), 292 (70%) [MH+].HRMS calcd for C9INO2 291.9834 found 291.9568.
Methyl (2S)-2-amino-3-(4-iodophenyI)propanoate hydrochloride (93)
To a solution of 92 (2.00 g, 6.87 mmol) in MeOH (10 mL) at CPC was added thionyl chloride (2
mL) and the resulting solution was allowed to stir for 16 h whilst equilibrating to RT. The reaction
was evaporated to dryness in vacuo to yield the title compound (2.25 g, 6.80 mmol, 99%) as a
white solid, which had spectral data in agreement with that reported. 93 [a]D21 -9.3 (c. 0.15, HC1).
Mp 195-1980C (lit. 199.5-200.50Cp 1H NMR (CD3ODr 300 MHz):  7.72 (d, J - 8.4 Hz, 211,
ArH2' and ArH6'); 7.06 (d, J= 8.4 Hz, 2H, ArH3' and ArH5'); 4.33 (dd, J = 6.3, 6.9 Hz, IH, H2): 3.80 (s, 3H,
OCH3K 3.23 (dd, J= 6.6, 14.4 Hz, IH, H3a); 3.15 (dd, J= 7.2, 14.4 Hz, IH, H3b). Mass Spectrum (ES, +ve) m/z 306
(100%) [M+].HRMS calcd for C10H13INO2 305.9986 found 305.9980.
Methyl (2S)-2-acetamido-3-(4-iodophcnyI)propanoate (94)
To a solution or 93 (2.25 g, 6.80 mmol) in 10% ITC1 (10 mL) at OC was added 4M sodium acetate
(115 mL) and the resulting reaction was allowed to stir whilst equilibrating to O'C. Acetic
anhydride (50 ml) was added and the reaction allowed to proced with vigorous stiring. After 1h
the product was collected by vacuum filtration, dissolved in ethyl acetate (30 mL) and washed with
2M sodium bicarbonate (2 x 30 mL). The organic layer was dried and evaporated to yield the title
compound (1.31 g, 3.79 mmol, 56%) as a white solid. Mp 118-12O0C. []D27 +93.8 (c. 0.1, CHC3,). 1H NMR (CDC13,
300 MHz): 7.61 (d, J =8.4 Hz, 2H, ArH2' and ArH6'); 6.84 (d, J- SA Hz, 2H, ArH3' and ArH5'); 5.92 (d, J-
7.2 Hz, IH, NH); 4.87 (m, IH, H2); 3.73 (s, 3H, OCH,); 3.11 (dd, J=6.0, 13.8, Hz, IH, II3a);3.03 (dd, J=5.4,
13.8 Hz, IH, H3b); 1.99 (s, 3H, NCOCH3). Mass Spectrum (CI, +ve) m/z 348 (100%) [MH+]. HRMS calcd for
C 12H15N031 348.0097, found 348.0104.
Methyl (2S)-2-acetamido-3-(4-trimethylstannyIphenyl)propanoate (95)
A solution of 94 (590 mg, 1.7 mmol), hexamethyldistannane (781 mg, 2.38 mmol), palladium
acetate (20 mg, 0.085 mmol), and triphenylphosphine (45 mg, 0.17 mmol) in toluene (7 mL) was
[lushed with nitrogen for 15 minutes and then heated at 100°C for 30 min under N,. The brown
mixture was filtered through a short pad of silica, diluted with diethyl ether (40 mL) and washed
twice vvith water -Tne organic layer was dried and evaporated to yield the title compound (497 mg,
1.29 mmol, 76%) as a clear oil. [a]D27 +13.7 (c. 0.3. CHC1,). W NMR (CDC13 300 MHz): 5 7.41 (d, J =7.5 Hz, 2H.
ArH2' and ArH6'): 7.07 (d, J= 7.8 Hz, 2H, ArH3' and ArH5'): 6.25 (d, J = 7.8 Hz, IH, NH): 4.87 (m, IH H2): 3.72
(s, 3H. OCH3);3.12 (dd, J=5.7, 14.1 Hz. IH. H3a):3.04 (dd, J = 6.0, 13.9 Hz, IH. H3b): 1.98 (s, 3H, NCOCH3);
0.27 (t. J = 27.6 Hz, 9H, Sn(CH3)3). Mass Spectrum (CI, +ve) m/z 386 (50%) [MH+1, 382 (10%) [MH+] (Sn 112). 85
(100%). HRMS calcd for C15H24NO3Sn (Sn 112) 382.075357 found 382.075603.




WO 2006/074501 PCT/AU2005/001444
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Methyl (2S)-2-acetamido-3-(4-[9-anthracenyl]phenyl)-propanoate (96)
A solution of 95 (192 mg, 0.50 mmol), 9-bromoanthracene (141 mg, 0.55 mmol), palladium
acetate (6mg, 0.025 mmol), and tri-o-tolylphosphine (15 mg, 0.05 mmol) in DMF (2 mL)
was Hushed with N, for 15 min then heated to 7CPC and allowed to stir for 16 h. The
reaction was diluted with diethyl ether (20 mL) and washed with water (5 x 20 mL), dried
and evaporated. The crude product was purified by flash column chromatography (15%
EtOAc/hexane then 5% MeOH/DCM) to yield the title compound (133 mg, 0.33 mmol,
67%) as an orange oil. []D27 +66.9 (c. 0.1, CHC13). 1H NMR (CDCl3,300MHz):  8.48 (s,
IH, ArHIO"); 8.03 (dd, J=0.9, 8.7 Hz, 2H, ArH3" and ArH6"); 7.63 (dd, J-0.6, 9.0 Hz, 2H, ArH8" and ArHl");
7.45 (m, 2H, ArH4" and ArH5"); 7.36 (m, 6H, ArH2" and ArH7", 4 x ArH'): 5.40 (d, J =7.8 Hz, IH, NH); 5.04 (m,
IH, H2); 3.79 (s, 3H, OCH3); 3.32 (dd, J =5.7, 13.8 Hz, IH, H3a); 3.25 (dd, J -6.3, 13.8 Hz, IH, H3b); 2.08 (s, 3H,
COCH3). Mass Spectrum (CL +ve) mJz 398 (100%) [MH+]. HRMS calcd for C6H23NO3 397.1678, found 397.1675.
Methyl (2S)-2-acetamido-3-(4-[9-phenanthrenyl]phenyl)proi)anoate(98)
A solution of 95 (259 mg, 0.67 mmol), 9-bromophenanthrene (190 mg, 0.74 mmol),
palladium acetate (8 ing, 0.034 mmol), and tri-o-tolylphosphine (20 mg, 0.067 mmol) in
DMF (2 ml ) was filched with N- for 15 min then hented tn 70oC and allowed to stir for 16
h. The reaction was diluted with diethyl ether (20 mL) and washed with water (5x 20 mL),
dried and evaporated. The crude product was purified by flash column chromatography
(15% EtOAc/hexane then 5% MeOH/DCM) to yield the title compound (157 mg, 0.40
mmol, 59%) as a clear oil. []D27 +94.6 (c. 0.1, CTIC1,). 1H NMR (CDCl3,300 MHz):  8.77
(d, / = 9.0 Hz, IH, ArH4"); 8.71 (d, J = 8.1 Hz, IH, ArH3"); 7.89 (m, 2H, ArHl" and ArHIO"); 7.61 (m, 5H, ArH7",
ArH6", ArH5", ArH2" and ArHl"); 7.48 (d, J = 8.4Hz, 2H, ArH2' andArH6'); 7.26 (d, J = 8.1 Hz, 2H, ArlLT and
ArH5'): 6.25 (d, J= 7.5 Hz, IH, NH); 5.00 (m, IH, H2); 3.79 (s, 3H, OCH3); 3.30 (dd, J= 5.7, 13.8 Hz, IH, H3.T;
3.20 (dd, J = 6.0, 13.8 Hz, IH, H3b); 2.05 (s, 3H, COCH,). Mass Spectrum (CI, +ve) ni'z 398 (100%) [MH+], HRMS
(El) calcd for C,6H,3NO3 397.1678, found 397.1680.
(2S)-2-Acetamido-3-(4-[9-anthracenyI]phenyl) propanoic acid (97)
To a solution of 96 (80 mg, 0.20 mmol) in THF/water, 2:1 (3 mL) was added lithium
hydroxide monohydrate (17 mg, 0.40 mmol) and the resulting suspension was allowed to
stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was
removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove
unreacted starting material. The aqueous phase was acidified with 10% HC1 and the
resulting precipitate was extracted with DCM (3 x 40 mL). The combined organics were
dried and evaporated to yield the title compound (69 mg, 0.18 mmol, 90%) as a white solid.
Mp 76oC. [cx]D30 +29.7 (c. 0.1, EtOH). IH NMR (CDC1,, 300 MHz): 5 8.47 (s, IH, ArHIO"): .02 (d, J = 8.4 Hz. 211.
ArH3" and ArH6"): 7.59 (d, J= 8.7 Hz. 2H, ArH8" and ArHl"): 7.45 (m. 2H. ArH4" and ArII5"): 7.35 (m. 6H.




WO 2006/074501 PCT/AU2005/001444
173.
ArH2" and ArH7", 4 x ArH'): 6.27 (d,J= 6.6 Hz, IH, NH): 5.00 (m, IR H2): 3.39 (dd, J= 4.8, 12.9 Hz, IR H3a):
3.26 (dd, J = 6.3, 14.4 Hz, IH H3b); 2.07 (s, 3H, COCH,). Mass Spectrum (ES, +ve) m/z 383 (70%) [MH+], HRMS
calcd for C25H22NO3 384.1600, found 384.1610.
(2S)-2-Acetamido-3-(4-[9-phenanthrenyI]phenyl)propanoic acid (99)
To a solution of 98 (124 mg, 0.31 mmol) in THF/water, 2:1 (9 mL) was added lithium
hydroxide monohydrate (26 mg, 0.62 mmol) and the resulting suspension was allowed to
stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was
removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove
unreacted starting material. The aqueous phase was acidified with 10% HC1 and the
resulting precipitate was extracted with DCM (3 x 40 mL). The combined organics were
dried and evaporated to yield the title compound (65 mg, 0.17 mmol, 55%) as a white solid.
Mp 128-132°C. [+36.8(c.O.1.EtOHD.1HNMR(CD3OD 300 MHz): 8.71 (d, J = 8.1
Hz, IH. ArH4"): .66 (d, J= 8.4 Hz, IR ArH3"); 7.79 (s, IH ArHl"); 7.76 (s, IH ArHIO"); 7.51 (m, 5H ArH7",
ArH6", ArH5", ArH2" and ArHl"): 7.32 (m, 2H, Ar'H); 4.76 (dd, J = 5.1, 9.0 Hz, IR H2); 3.29 (dd, J=4.8, 13.5
Hz, IH. H3a); 3.03 (dd, J = 8.7, 13.5 Hz, IH, H3b); 1.95 (s, 3H, COCH3). Mass Spectrum (ES, +ve) m/z 384 (50%,)
[MR], HRMS calcd for C25H22SO3, 384.1600, found 384.1628.
(2'-Allyloxy-[l,r]-(S)-binaphthalen-2-yloxy)-acctic acid (101)
To a solution of l,l'-(5)-binapthol (1.00 g, 3.50 mmol) and K2CO3 (600 mg, 4.35
mmol) in acetone (12 mL) was added dropwise, allyl bromide (0.26 mL, 3.68 mmol).
The resulting mixture was heated at reflux with stirring for 16 h before being filtered.
concentrated and dissolved in anhydrous MeOIT (40 mL). To this solution was added
K2CO-. (2.4 g, 17.4 mmol) and bromoacetic acid (1.21 g, 8.75 mmol). This mixture was heated at reflux for a further
3 h before evaporation to dryness and dissolution in water (50 mL). The aqueous layer was then washed with diethyl
ether (3 x 30 mL) before acidification with 3M MCI. The acidified solution was extracted with DCM, dried before
being evaporated to dryness to yield the title compound (825 mg, 2.15 mmol, 61%) as a viscous yellow oil. 1H NMR
(CDC1, 300 MHz):  7.96 (m, 2H, ArH); 7.86 (m, 2H, ArH): 7.26 (m, 8H, ArH): 5.66 (m, IH, H2"): 4.94 (m, 2H
H3"): 4.61 (ABq, J = 16.8 Hz, 2H, CH2-COOH): 4.48 (m, 2R HI"). Mass Spectrum (CI, +ve) m/z 339 (40%) [-
COOH], 385 (100%) [MH+]. HRMS calcd for C25H31O4 385.143984, found 385.142526.
(2'-Benzyloxy-[l,r]-(S)-binaphthalen-2-yIoxy)-acetic acid (102)
To a solution of l,l'-GS>binapthol (500 mg. 1.75 mmol) and K2CO3 (300 mg. 2.18
mmol) in acetone (6 mL) was added dropwise, benzyl bromide (0.21 mL, 1.75 mmol).
The resulting mixture was heated at reflux with stirring for 16 h before being filtered,
concentrated and dissolved in anhydrous MeOH (5 mL). To this solution was added
K2CO3 (2.4 g, 17.4 mmol) and bromoacetic acid (740 g, 5.25 mmol). This mixture was
heated at reflux for a further 3 h before evaporation to dryness and dissolution in water (50 mL). The aqueous layer
was then washed with diethyl ether (3 x 30 mL) before acidification with 3M HCT. The acidified solution was




WO 2006/074501 PCT/AU2005/001444
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extracted with DCM, dried before being evaporated to dryness to yield the title compound (218 mg, 0.50 mmol,
29%) as a viscous yellow oil. 1H NMR (CDC1, 300 MHz):  10.30 (bs, IH, COOH); 7.85 (m, 4H, ArH): 7.16 (m,
13H, ArH): 4.99 (ABq,J = 12.6Hz, 2H, CH,-COOH): 4.48 (ABq, J= 17.1 Hz, 2H, HI"). Mass Spectrum (CI. +ve)
m/z435 (100%) [MH+].HRMS calcd for C29H23O4 435.159634, found 435.158151.
(2'-Methyloxy-[l,l']-(S)-binaphthalen-2-yloxy)-acetic acid (103)
To a solution of l,l'-(S)-binapthol (500 mg, 1.75 mmol) and K2CO3 (300 mg, 2.18
mmol) in acetone (6 mL) was added dropwise, methyl iodide (0.11 mL, 1.75 mmol).
The resulting mixture was heated at reflux with stirring for 16 h before being filtered,
concentrated and dissolved in anhydrous MeOH (5 mL). To this solution was added
K,CO3 (2.4 g, 17.4 mmol) and bromoacetic acid (740 g, 5.25 mmol). This mixture was
heated at reflux for a further 3 h before evaporation to dryness and dissolution in water (50 mL). The aqueous layer
was then washed with diethyl ether (3 x 30 mL) before acidification with 3M HC1. The acidified solution was
extracted with DCM, and dried before being evaporated to dryness to yield the title compound (236 mg, 0.66 mmol,
38%) as a viscous yellow oil. 'H NMR (CDC1, 300 MHz):  10.22, COOH: 7.84 (m, 4H, ArH): 7.22 (m, 8H, ArH):
4 9 (ABq,J - 16.8 Hz, 2H, CH2-COOH): 3.65 (s, 3H, OCH,). Mass Spectrum (CI, +ve) m/z 359 (100%) [MH+].
HRMS (El) calcd for C23H18O4 358.120509, found 358.120418.
(2'-(3-Phenylallyloxy)-fl,ri-(S)-binaphthalen-2-ylox\)-acetic acid (104)
To a solution of l,l'-(S>binapthol (500 mg, 1.75 mmol) and K2CO3 (300 mg, 2.18
mmol) in acetone (6 mL) was added dropwise, cinnamyl bromide (362 mg, 1.84 mmol).
The resulting mixture was heated at reflux with stirring for 16 h before being filtered,
concentrated and dissolved in anhydrous MeOH (5 mL). To this solution was added
K2CO, (2.4 g, 17.4 mmol) and bromoacetic acid (740 g, 5.25 mmol). This mixture was
heated at reflux for a further 3 h before evaporation to dryness and dissolution in water
(50 mL). The aqueous layer was then washed with diethyl ether (3 x 30 mL) before
acidification with 3M HC1. The acidified solution was extracted with DCM. dried, then evaporated to dryness to
yield the title compound (544 mg, 1.18 mmol, 67%) as a viscous yellow oil. iH NMR (CDC1, 300 MHz):  10.20,
. COOH: 7.84 (m, 4H, ArH): 7.29 (m, 4H, ArH): 7.09 (m, 8H, ArH): 6.12 (d, J = 15.9 Hz, IH, H3"): 5.90 (dt, J = 5.7,
15.9 Hz. IH, H2"): 5.58 (m, 2H, HI"); 4.49 (ABq, 7 = 16.8 Hz, 2H, CH2-COOH). Mass Spectrum (CI, +ve) nrz 117
(100%). 461 (50%) [MH+], HRMS calcd for C31H,4O4 460.167460, found 460.167568.
[2'-(3-Methylbutoxy-[l,I']-(S)-binaphthalen-2-yloxy]-acetic acid (105)
To a solution of l,l'-(5)-binapthol (500 mg, 1.75 mmol) and K2CO3 (300 mg, 2.18
mmol) in acetone (6 mL) was added dropwise, l-bromo-3-methylbutane (0.22 mL, 1.75
mmol). The resulting mixture heated at reflux with stirring for 16 h before being filtered,
concentrated and dissolved in anhydrous MeOH (5 mL). To this solution was added
K-CO3 (2.4 g, 17.4 mmol) and bromoacetic acid (740 g, 5.25 mmol). This mixture was
heated at reflux for a further 3 h before evaporation to dryness and dissolution in water (50 mL). The aqueous layer




WO 2006/074501 PCT/AU2005/001444
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was then washed with diethyl ether (3 x 30 mL) before acidification with 3M HC1. The acidified solution was
extracted with DCM, dried before being evaporated to dryness to yield the title compound (604 mg, 1.46 mmol,
83%) as a viscous yellow oil. 1H NMR (CDC13 300 MHz):  9.93, COOH; 7.95 (m, 4H, ArH); 7.40 (m, 8H, ArH);
4.65 (m, 2H, CH2-COOH); 4.09 (m, 2H, HI"); 1.38 (m, 2H, H2"); 1.26 (m, IH, H3"); 0.71 (d, J =6.3 Hz, 3H,
H4a"); 0.61 (d, J=6.3 Hz, 3H,H4b"). Mass Spectrum (CI, +ve)m/z 415 (100%) [MH+].HRMS calcd for C27H27O4
415.1090, found 415.1913.
(2'-(3-Phenylpropyloxy)-[l,l']-(S)-binaphthalen-2-yloxy)-acetic acid (107)
To a solution 104 (213 mg, 0.46 mmol) in THF (15 mL) was added palladium on
activated carbon (5 mol%). The resulting mixture was allowed to stir for 16 h under a
hydrogen atmosphere (balloon) before being filtered and evaporated to dryness to yield
the title compound (188 mg, 0.4 mmol, 87%) as a viscous yellow oil. 1H NMR (CDC13,
300 MHz):  7.97 (m, 4H, ArH); 7.24 (m, 1 IH, ArH); 6.68 (m, 2H, ArH); 4.6 5 AB q,J
= 16.8 Hz, 2H, CH2-COOH); 3.96 (m, 2H, HI"); 2.09 (m, 2H, H3"); 1.69 (m, 2H, H2").
Mass Spectrum (CI, +ve) m/z 463 (100%) [MH+]. HRMS calcd for C3iH27O4 463.1909,
found 463.1915.
Benzyl (2S)-2-amino-4-pentenoate hydrochloride (108)
To a solution of (28)-2-amino -4-pentenoic acid 17 (255mg ,1.96 mmol) in benzy|
alcohol (5 mL) was added thionyl chloride (2 mL) and the resulting mixture was
allowed to stir for 16 h before addition of diethyl ether (30 mL) and extraction with
water (3 x 30 mL). The aqueous layer was concentrated, diluted with 2M sodium
bicarbonate (20 mL), and extracted with DCM (3 x 30 mL). The combined organic fractions were dried and
acidified with IM HCl/diethyl ether (2 mL) and evaporated. The crude product dissolved in a minimal volume of
MeOH and precipitated with diethyl ether to yield the title compound (322 mg, 1.34 mmol, 68%) as a white solid.
[]D2o-40.6 (c. 0.1, H2O). Mp 186-191°C. 1H NMR (D2O,SOO MHZ):  7.28 (m, 5H, ArH); 5.51 (m, 1H, H4); 5.11
(m, 4H. H5 and ArCH2): 4.08 (t, J = 5.4 Hz, IH, H2); 2.55 (m, 2H, H3). Mass Spectrum (CI, +ve) m/z 205 (25%)
[MH+]. HRMS calcd for C12H16NO2 206.1181, found 206.1169.
Benzyl (2S,5/.)-2-aUyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxo-8-(2,2,5,7,8-pentamethyl-3.4-
dihvdro-2£T-6-chromenyIsulfonyl)guanidino]octanoate (.109)
The title compound was synthesised using the general peptide
coupling procedure (Procedure B), from 108 (155 mg, 0.65 mmol)
and(27?)-2-(9H-9-lluorenylmethylo\ycarboxamido)-8-[(2,2,5,7,8-
pentamethyl-3,4-dihydro-2if-6-
chromenylsulfonyl)guanidine]pentanoic acid (43 1 mg, 0.65 mmol)
to afford 109 (280 mg. 0.33 mmol, 51%) as a white solid. Mp 78-
74°C. W NMR (CDC1, 300 MHz):  7.69 (d, J= 7.5 Hz. 2H.




WO 2006/074501 PCT/AU2005/001444
176.
ArHl" and ArH8"); 7.51 (d, J = 7.5 Hz, 2H, ArH4" and ArH5"); 7.28 (m, 9H, ArH); 6.33 (m, 3R NH); 5.68 (m, IH,
H2'); 5.61 (m, IH, NH); 4.99 (m, 4H, ArCH2 andH3'); 4.58 (m, IH, H2); 4.24 (m, 3H, 0CHrH9"and H5); 4.05 (t,
J =7.2 Hz, IH, H9"); 3.20 (m, 2H, H8); 2.57 (s, 3H, 7"'-CH 3); 2.54 (s, 3H, 5"'-CH 3); 2.52 (m, 4H, H3'" and HI');
2.05 (s, 3H, 8"'-CH3); 1.85 (m, 2H, H6); 1.69 (t, J =6.3 Hz, H4"'); 1.58 (m, 2H, H7); 1.22 (s, 6H, 2 \ 2"'-CH3).
Mass Spectrum (ES, +ve) m/z 850 (100%) [MH+], HRMS calcd for C47H56N5OgS 850.3850, found 850.3855.
Benzyl (2S,5/-)-2-allyI-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2i 7-6-
chronienylsulfonamido)guanidino]-4-oxooctanoate (110)
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 109 (278 mg, 0.33 mmol) to
yield 110 (144 mg, 0.23 mmole, 70%) as a cream semi-solid. Mp 66-
680C. iH NMR (CDC13 300 MHz):  7.85 (d, J = 7.8 Hz, IH, NH); 7.60 '
(d, J = 7.8 Hz, IH, NH); 7.32 (m, 5H, ArH); 6.33 (m, 2H, NH2); 5.63 (s,
IH, H2'); 5.14 (m, 4H, ArCH2 and H31); 4.56 (m, IH, H2); 3.40 (m, IH,
H5); 3.16 (m, 2H, H8); 3.09 (m, 2H, III'); 2.61 (t, J= 6.9 Hz, 2H, 114");
2.56 (s, 3H, 7"-CH3);2.55 (s, 3H, 5"-CH,);2.09 (s, 3H, 8"-CII3); 1.78 (t,
J =7.2 Hz, 2I-I, H3"); 1.68 (m, 4H, H6 and NH2); 1.54 (m, 2H, H7); 1.29 (s, 6H, 2 x 2"-CH3). Mass Spectrum (ES,
+ve) m/z 628 (100%) [MH+].HRMS calcd for C32H46N5O6S 628.3169, found 628.3157.
Benzyl (2S,5/f,8i?)-2-aUyl-3,6-diaza-12-(tert-butoxycarboxamido)-8-(9ff-9-fluorenylmethyIoxycarboxamido)-
5-([ {2,2,5,7,8-pentamethyl-3,4-dihydro-2ii -6-chromenylsulfonamido}guanidino]propyI)-l,7dioxododecanoate
The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 110 (200
mg, 0.32 mmol) and (2/?)-6-to/t-hutoxycarbo\amido-2-
(9H-9-fluorenylmethyloxycarboxamido)hexanoic acid (151
mg, 0.32 mmol) to afford 111 (202 mg, 0.19 mmol, 59%)
as a white solid. Mp 116"C. 'H NMR (CDC1, 300 MHz): 
7.72 (d, J= 7.8 Hz, 2H, ArHl"" and ArH8""); 7.55 (d, J =
7.8 Hz, 2H, ArH4"" and ArH5""); 7.45 (m, IH, NH); 7.29
(m, HH, ArH); 6.25 (m, 3H, NH); 5.64 (m, IH, H2'); 5.03
(m, 4H, ArCH2,H3'); 4.59 (m, IH, H2); 4.51 (m, IH, H5);
4.29 (in, IH, H8); 4.20 (m, 2H, OCHj-ro""); 3.98 (m, IH. H9""); 3.18 (m. 2H, H3"); 3.05 (m, 2H, H12): 2.55 (s,
3H, 7"'-CH3); 2.52 (s, 3H, 5"'-CH 3):2.50 (m, 4H. H4'" and HI'): 2.03 (s, 3H, 8"'-CH3): 1.95 (m, 4H, HI" and H9);
1.74 (m, 2H. H3"1): 1.67 (m, 4H. H2" and H1O); 1.59 (m, 2H, HI1); 1.41 (s, 6H, 2 x 2"'-CH ,). Mass Spectmm (ES,
+ve) m'z 1078 (10%) [MH+]: 288 (100%). HRMS calcd for C58H.fiN7On S 1078.5324, found 1078.5333.



WO 2006/074501 PCT/AU2005/001444
177.
Benzyl (25.5jR,8/.)-2-all\i-8-amino-3,6-diaza-12-(tert-butoxycarboxamido)-5-([{2,2,5,7,8-pentamethyI-3,4-
dihydro~2/7-6-chromenylsulfonamido}guanidino]propvl)-4,7dioxododecanoate (112)
The title compound was synthesized using the general A'-Fmoc
deprotection procedure (Procedure C), from 111 (202 mg, 0.19
mmol) to yield 112 (157 mg, 0.18 mmole. 93%) as a cream oil.
'H NMR (CDC13 300 MHz):  8.00 (d, J= 7.2 Hz, IH, NH);
7.58 (d, J= 7.2 Hz, IH, NH): 7.32 (m, 5H, ArH); 6.44 (m, 3H,
NH); 5.63 (m, IH, H2'); 5.09 (m, 4H, ArCH2 and H3'); 4.61 (m,
2H, H2 and H5); 3.36 (m, IH, H8); 3.22 (m, 2H, H3"): 3.05 (m,
2H, H12): 2.62 (m, 2H, H4'"); 2.58 (s, 3H, 7"'-CH 3); 2.56 (s,
3H, 5"'-CH 3); 2.47 (m, 2H, HI'); 2.15 (m, 2H, HI"); 2.10 (s,
3H, 8"'-CH 3); 1.89 (m, 2H, H9); 1.80 (t, 7 = 6.3 Hz, H3'"); 1.72
(m, 4H,H2" andHIO); 1.58 (m, 4H, Fill andNH2): 1.42 (s, 9H, C(CH,)3); 1.31 (s, 6H, 2 x 2"'-CH 3). Mass
Spectrum (ES, +ve) tn'z 856 (100%) [MH+].HRMS calcd for C13H66N7O9S 856.4643, found 856.4655.
Methyi (2S,5iR)-2-(4-aIlyloxybenzyl)-5-aniino-3-aza-8-[(2,2,5,7,8-pentainethyI-3,4-dihydro-2Ji -6-
chromenyI.suIfonyl)guanidino]-4-oxononanoate (113)
The title compound was synthesized using the general N-Fmoc
deprotection procedure (Procedure C), from 67 (295 mg, 0.32
mmol) to yield 113 (145 mg, 0.21 mmol, 66%) as a cream oil. 1H
NMR (CDCipOO MHz):  7.83 (d, J= 7.5 Hz, IH, NH); 7.04 (d.
J = 8.4 Hz, 2H, ArH2' and ArH6'); 6.81 (d, J= 8.4 Hz, 2M ,
ArH3' and ArH5'); 6.37 (bs, 2H, NH); 6.01 (m, IH. H2"); 5.30
(m, 2H, H3"); 4.68 (dd, J= 7.5, 13.2 Hz, IH, H2); 4.47 (m, 2H,
HI"); 4.22 (m, IH, H5); 3.67 (s, 3H, OCH3): 3.07 (m, 4H, H8 and
ArCH2);2.61 (t, J = 6.6 Hz, 2H, H4'"); 2.56 (s, 3H, 7"'-CH ,)•.
2.54 (s. 3H, 5"'-CH ,); 2.10 (s, 3H, 8"'-CH ,); 1.87 (m, 2H, NH2); 1.79 (m, 2H, H3'"); 1.68 (m, 2H, H6); 1.50 (m, 2H,
H7); 1.29 (s, 6H, 2 x 2"'-CH ,). Mass Spectrum (ES, +ve) n/z 658 (100%) fMH+l. HRMS calcd for C33H4gN5O2S
658.3274 found 658.3282.



WO 2006/074501 PCT7AU2005/001444
178.
Methyl (2S,5S,8S)-2-aIlyl-8-(4.[9-anthrecenyl]benzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido| butyl)-
4,7,10-trioxoundecanoate (114)
The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 24 (35 mg, 0.098 mmol) and 97 (20 mg, 0.052
mmol) to afford the title compound (22 mg, 0.030 mmol, 59%) as a cream
solid. Mp 128°C. 1HNMR (CDC'1,,300 MHz):  8.49 (s, IH, ArHIO""); 8.04
(d, 7-8.7 Hz, 2H, ArH2'" and ArH6'"); 7.64 (d, 7 = 8.4 Hz, 2H, ArH3'" and
ArH5"'); 7.38 (m, 8H, ArH""); 6.72 (d, J= 7.2 Hz, IH, NH); 6.48 (d, J=7.2
Hz, IH, NH); 6.37 (bs, IH, NH): 5.59 (m, IH, H2'); 5.06 (m, 2H, H3'); 4.82
(m, IH, H8); 4.60 (dd, J= 6.9, 14.1 Hz. IH, H2); 4.45 (m, IH, H5); 3.73 (s,
3H, OCH3); 3.24 (m, 2H, ArCH2); 3.08 (m, 2H, H4"); 2.47 (m, 2H, HI'); 2.07
(s, 3H, HI 1); 1.93 (m, 2H, HI"); 1.68 (m, 2H, H3"); 1.50 (m, 2H, H2"); 1.44
(s, 9H, C(CHa)3). Mass Spectrum (ES, +ve) mJz 745 (50%) [MNa+1, 723 (20%)
[MH+1, 623 (100%) [M less Boc], HRMS calcd for C44H.19N4O7 745.3601, found 745.3590.
Methyl (2S,5S,8S)-2-allyl-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyI)-4,7,10-trioxo-8-(4-[9-
phenanthrenyl]benzyl)undecanoate (115)
The title compound was synthesised using the general peptide coupling
procedure (Procedure B), from 24 (28 mg, 0.078 mmol) and 99 (15 mg, 0.039
mmol) to afford 115 (14 mg, 0.019 mmol, 50%) as a cream solid. Mp 132-
134oC. 1H NMR (CDC13 300 MHz): 5 8.76 (d, J = 8.1 Hz, IH, ArH4""): .71
(d, / = 8.4 Hz, IH, ArH3""); 7.88 (m, 2H, ArHl"" and ArHIO""); 7.60 (m,
5H, ArHT"', ArH6'"\ ArH5"", ArH2"" and ArHl""); 7.45 (d, J =7.8 Hz, 2H,
ArH2'" andArH6'"); 7.33 (d, J = 7.8 Hz, 2H, ArH3"' and ArH5'"); 7.10 (d, J
= 8.4 Hz, IH, NH); 6.94 (d, J = 8.7 Hz, III, NH): 6.74 (d, J = 8.1 Hz, III,
NH); 5.61 (m, IH, H2'); 5.06 (m, 2H, H3'); 4.90 (m. IH, H8); 4.57 (m, 2H,
H2 andH5); 3.72 (s, 3H, OCH3); 3.20 (m, 2H, ArCH2): 3.08 (m, 2H, H4");
2.47 (m, 2H, HI1); 2.04 (s, 3H, HI1); 1.92 (m, 2H, HI"): 1.68 (m, 2H, H3");
1.48 (m. 2H, H2"); 1.42 (s, 9H, C(CH,)3). Mass Spectrum (ES, +ve) m/z 745 (60%) [MNa]; 723 (20%) [MH']. 623
(100%) [M less Boc]. HRMS calcd for C4:HMN4O7 723.3758. found 723.3767.



WO 2006/074501 PCT/AU2005/001444
179.
Methyl (2S,5R)-2-alIyIoxybenzyI-8-(2-[2'-alIyIoxy-{I,I'}-(S)-binaphthalen-2-yIoxy])-3,6-diaza-5-([{2,2,5,7,8-
pentamcthyl-S^-dihydro^ff- 6-chromenylsulfonyIlguanidinolpropyO^^-dioxooctanoate C116)
The title compound was synthesised using the general peptide
coupling procedure (Procedure B), from 113 (81 mg, 0.1 1 mmol) and
101 (49 mg, 0.13 mmol) to afford 116 (70 mg, 0.065 mmol, 59%) as a
white solid. Mp lio°C. WNMR (CDC1, 300 MHz):  7.88 (m, 4H,
ArH); 7.75 (d, J= 8.4 Hz, IH. NH); 7.22, (m, 8H, Aril); 6.99 (d, J =
8.7 Hz, 2H, ArH2' and ArH6'); 6.79 (d, J= 8.7 Hz, 2H, ArH3' and
ArH5'); 6.31 (d, J = 8.1 Hz, IH, NH); 6.15 (bs, 2H, NH); 5.98 (m, IH,
H2"); 5.77 (bs, IH, NH); 5.63 (m, IH, H2""); 5.35 (dd, J= 1.5, 18.9
Hz, IH, H3an); 5.23 (dd, J= 1.5, 10.5 Hz, IH, H3b"); 4.88 (m, 2Hj
H3""); 4.64 (m, IH, H2); 4.40 (m, 6H, HI", HI"" and H8); 4.13 (m,
IH, H5); 3.61 (s, 3H, OCH3); 2.91 (m, 4H, ArCH2 and H3"'); 2.60 (s, 3H, 7""-CH3); 2.78 (s, 3H, 5""-CH3); 2.54 (m,
2H, H4""); 2.10 (s, 3H, 8""-CH3); 1.75 (t, J = 6.6 Hz, 2H, H3""); 1.36 (m, 2H, H2'"); 1.26 (s, 6H, 2 x 2""-CH,);
0.84 (m, 2H, HI'"). Mass Spectrum (ES, +ve) m/z 1024 (100%) [MH+1. HRMS calcd for C58H66N5O10S 1024.4530,
found 1024.4513.
Methyi (2S,5R)-2-allyloxybenzyI-3,6-diaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2ii -6-
chromenylsulfonyl}guanidino]propyl)-4,7-dioxo-8-(2-[2'-{3-phenyl-aIIyloxy}-{l,l'}-(S)-binaphthalen-2-
yloxy])octanoate (117)
The title compound was synthesised using the general peptide
coupling procedure (Procedure B), from 113 (64 mg, 0.09
mmol) and 104 (42 mg, 0.09 mmol) to afford 117 (61 mg,
0.055 mmol, 62%) as a cream solid. Mp 1000C. 'H NMR
(CDCl3,300 MHz):  7.90 (m, 4H, ArH); 7.76 (d, J = 8.1 Hz,
IH, NH); 7.46 (d,7= 9.0 Hz, IH, NH); 7.17, (m, 13H, ArH);
6.99 (d, J= 8.4 Hz, 2H, ArH2' and ArH6'); 6.79 (d, J= 8.4
Hz, 2H, ArH3' and ArH5'); 6.39 (d, /= 8.1 Hz, IH, NH);
6.13 (m, 2H, H2"" and 113""); 5.98 (m, IH, 112"); 5.30 (m,
2H, H3"V. 4.64 (m, IH, H2); 4.39 (m, 6H, HI", HI"" and H8); 4.15 (m, IH, H5); 3.60 (s, 3H, OCH3V. 2.95 (m, 4H.
ArC'H-, and H3"'); 2.60 (s, 3H, 7""-CH3); 2.58 (s, 3H, 5""-CH3); 2.52 (m, 2H, H4""); 2.10 (s, 3H, 8""-CH,); 1.74 (t,
J =6.1 Hz, 2H, H3""); 1.36 (m, 2H, H2'"); 1.25 (s, 6H, 2 x 2""-CH3);0.85 (m, 2H, HI"'). Mass Spectrum (ES. +ve)
nvz 1100(100%) [MH+]. HRMS calcd for C64H70N5O|0S 1100.4843, found 1100.4833.



WO 2006/074501 PCT/AU2005/001444
180.
Methyl (2S,5S,8S)-2-allyI-5-(4-aminobutyI)-8-(4-[9-anthrecenyl]bcnzyl)-3,6,9-triaza-5-butylamino-4,7,10-
trioxoundecanoatc hydrochloridc(HS)
The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A), from 114 (20 mg, 0.028 mmol) to yield 118 (13 mg,
0.017 mmol, 61%) as a light yellow solid. Mp 194-202°C. 'H NMR (CD3OD,
300 MHz): 5 8.53 (s, 1H, ArHIO""); 8.26 (m, 3H, exchanging NH's); 8.06 (d,
J = 8.1 Hz, 2H, ArH2"' and ArH6'"); 7.64 (d, J = 9.0 Hz, 2H, ArH3"' and
ArH5"'); 7.38 (m, 8H, ArH""); 5.68 (m, 1H, H2'); 5.02 (m, 2H, H3'): 4.67
(m, 1H, H8); 4.45 (m, 2H, H2 and H5); 3.69 (s, 3H, OCH3); 2.93 (m, 4H, H4"
and ArCH2); 2.44 (m, 2H, HI'); 2.00 (s, 3H, Hll); 1.69 (m, 4H, H1" and
H3"); 1.50 (m, 2H, H2"). 13C NMR (CD3OD 75 MHz):  174.4, C7: 173.7,
Cl; 173.6, C4; 173.5, C10; 138.7, ArC4'"; 137.8, ArCl'"; 137.7, ArC9"";
134.1, C2': 132.9, ArCH2'" and ArCH6"'; 132.4, ArC4a"" and ArClOa""; 131.5, ArC8a"" andArC9a"": 130.4,
ArCH4"" and ArCH5""; 130.1, ArCH3'" and ArCH5'"; 129.5, ArCHIO""-. 127.7, ArCH8"" and ArCHl"": 126.5,
ArCII2"" and ArCII7""; 126.2, ArCIB"" and ArCII6""; 118.8, C3'; 56.7, C5; 53.8, OCH,; 53.6, C8: 52.7, C2: 40.5,
C4": 38.6, ArCH2; 36.6, Cl'; 32.8, Cl"; 28.1, C3"; 23.4, CI1; 22.4, C2". Mass Spectrum (ES, +ve) m z 623 (100%)
[M+], FIRMS calcd for C37H43N4O5 623.3233, found 623.3215.
Methy! (2S,5S,8S)-2-alIyl-5-(4-aminobutyl)-3,6,9-triaza-5-butylamino-4,7,10-trioxo-8-(4-[9-
[phenanthrenyl]benzyl)undecanoate hydrochloride (119)
The title compound was synthesized using the general iV-Boc deprotection
procedure (Procedure A), from 115 (24 mg, 0.033 mmol) to yield 119(15 mg,
0.023 mmol, 69%) as a light yellow solid. Mp 198°C. 1H NMR (CD3OD, 300
MHz):  8.84 (d, J=7.8 Hz, 1H, ArH4""); 8.78 (d, J = 8.1 Hz, IH, ArH5""):
.30 (d, J = 7.2Hz, IH, exchanging NH); 8.15 (d, J= 8.1 Hz, IH, exchanging
NH); 7.90 (m, 2H, ArHl"" and ArHIO""); 7.60 (m, 5H, ArH7"', ArH6"",
ArH5"', ArH2"" and ArHl""); 7.45 (d, J = 8.4 Hz, 2H, ArH2'" and ArH6'");
7.40 (d, J= 8.7 Hz, 2H, ArH3"' and ArH5'"); 5.68 (m, IH, H2'); 4.98 (m, 2H,
H3'); 4.61 (m, IH, H8); 4.40 (m, 2H, H2 and H5); 3.67 (s, 3H, OCH3): 2.93 (t,
J= 7.5 Hz. 2H, H4"): 2.40 (m, 2H. HI'): 1.99 (s, 3H, HI 1); 1.83 (m, 4H, HI"
and ArCH2); 1.69 (m, 2H, H3"); 1.49 (m, 2H, H2"). ). "C NMR (CD3OD,75 MHz):  173.7, C7: 173.6, Cl: 173.5,
C4: 173.4, CIO: 140.7, ArC4'": 139.8, ArCl'"; 137.5, ArC9"": 134.0, C2': 133.0, ArC8a"": 132.3, ArC4b"": 132.0,
ArC4a"": 131.3, ArCH2"' and ArCH6"': 131.2, ArClOa"": 130.3, ArCH3"' andArCHS"': 129.7, ArCHl""L 128.5,
ArCH7"": 128.0. ArCH6"": 127.9. ArCHl"": 127.8. ArCH5"": 127.7, ArCHIO"": 127.6, ArCH2"": 124.2, ArC4"":
124.1, ArCH3"": 118.8, C3': 56.7. C5: 53.7. OCH,: 53.6, C8: 52.7, C2: 40.5, C4": 38.5, ArCH2: 36.5, CT: 32.8.
Cl": 28.0, C3": 23.3, CI1: 22.4, C2". Mass Spectrum (ES, +ve) m/z 623 (100%) [M+].HRMS calcd for C3-H43N4O5
623.3233. found 623.3262.



WO 2006/074501 PCT/AU2005/001444
181.
Methyl (2S,5i?)-2-aIlyloxybenzyl-8-(2-[2'-aIhloxy-{l,1'}-(5)-binaphthalen-2-yIoxv])-3,6-diaza-5-(3-
[guanidino)-4,7-dioxooctanoate hvdrochloride (120)
The title compound was synthesized using the general iV-Boc
deprotection procedure (Procedure A) using 116 (70 mg, 0.068 mmol)
to yield 120 (31 mg, 0.039 mmol, 58%) as a cream solid. Mp 104-
110°C. 1H NMR (CD3OD 500 MHz):  7.62 (m, 4H, ArH); 6.95, (m,
8H, ArH); 6.82 (d, J = 7.0 Hz, 2H, ArH2' and ArH6'); 6.58 (d, J =
7.0 Hz, 2H, ArH3' and ArH5'; 5.74 (m, 1H, BE"); 5.40 (m, IH,
H2'""); 5.09 (d, J = 17.0 Hz, IH, H3a"); 4.93 (d, J = 10.0 Hz, III,
H3b"); 4.62 (m, 2H, H3'""); 4.37 (m, IH, H2); 4.18 (m, 6H, HI",
HI..... and H8); 3.98 (m, IH. H5); 3.36 (s, 3H. OC'H,); 2.75 (m, 4H, ArCH2 and H3'"; 1.40 (m. 2H, HI'"); 0.68 (m,
2H, H2'"). "C NMR (CD3OD, 125 MHz):  173.1, Cl; 172.3, C7; 170.5, C4; 158.8, CN3; 158.2, ArC; 155.1, ArC;
153.8. ArC; 134.9, ArC4'; 134.8, ArC; 134.7, C2"; 134.7, C2""; 131.3, ArCH; 131.2, ArCH; 130.8, ArCH; 130.7,
ArCH; 130.5, ArCH2' and ArCH6'; 130.0, ArCH; 129.1, ArCH; 129.1, ArC; 129.1, ArC; 127.5, ArCH; 127.4,
ArCH; 126.4, ArCT; 125.7, ArCH; 125.2, ArCH; 124.8, ArC; 121.6, ArCH; 120.1, ArCH; 117.5, C3"; 117.0, C3.....;
116.1, ArC; 115.6, ArCRT and ArCH5'; 70.7, C8; 69.6, Cl"; 69.2, Cl""; 55.0, C2; 52.8, OCH3; 52.6, C5; 41.6,
C3'"; 37.4, ArCH2; 30.4, Cl'"; 25.6, C2'". Mass Spectrum (ES, +ve) m/z 758 (100%) |M+]. HRMS calcd for
C44H42M5O7 759.3632. found 759.3555.
Methyl (2S,5fi)-2-aHyIoxybenzyI-3,6-diaza-8-(2-[2'-hydroxy-{l,l'}-(S)-binaphthalen-2-yloxy])-5-(3-
[guanidino]propyl)-4,7-dioxooctanoatc (121)
The title compound was synthesized using the general iV-Doc
deprotection procedure (Procedure A) using 117 (58 mg, 0.053 mmol)
to yield 121 (28 mg, 0.037 mmol, 70%) as a cream solid. Mp 132°C.
1H NMR (CD3OD 500 MHz):  7.91 (m, 4H, ArH); 7.20, (m, 8H,
ArH); 7.06 (d, J = 8.4 Hz, 2H, ArH2' and ArH6'); 6.83 (d, .7-8.4 Hz.
2H, ArH3' and ArH5'); 6.01 (m, IH, H2"); 5.29 (m, 2H, H3"); 4.62
(m, 2H, H8); 4.55 (dd, J = 4.5,9.6 Hz, IH, H2); 4.46 (m, 2H, HI");
4.22 (dd, J = 5.4, 8.7 Hz,lH, H5); 3.67 (s, 3H, OCH3); 3.00 (m, 4H,
ArCH2 and H3'"); 1.58 (m, 2H, HI'"); 1.06 (m, 2H, H2"'). "C NMR
(CD,OD, 125 MHz):  173.2, Cl: 172.7, C7; 171.0, C4; 159.5, CN3
159.1,ArC: 158.4, ArC: 153.7, ArC4'; 135.4, ArC: 135.3,ArC; 134.9, C2"; 132.5,ArCH; 131.5,ArCH; 131.4,
ArCH: 131.2, ArCH; 130.6, ArCH2' and ArCH6'; 130.3, ArCH; 130.1, ArCH: 129.2, ArCH: 128.2, ArCH; 127.7.
ArCH: 127.4, ArCH; 126.4, ArCT; 125.3, ArC; 124.1, ArC: 121.1, ArC; 119.6, ArC: 117.5, C3": 116.7, ArCH;
115.9, ArCH; 115.8. ArCRT and ArCH5'; 69.7, C8; 69.0. Cl": 55.2, C2; 53.1, OCH3: 52.8, C5; 42.0, C3"'; 37.4,
ArCH2; 30.1, C1": 25.5. C2'". Mass Spectrum (ES, +ve) m/z 718 (100%) [M+]. HRMS calcd for C41H44N5O7
718.3241. found 718.3209.



WO 2006/074501 PCT/AU2005/001444
182.
Benzyl (2S,5/.,8/?)-2-aIlyl-ll-(2-[2'-alIyloxy-;1,l'}-(S)-binaphthalen-2-yloxy])-3.6,9-tna7.a-8-(tert-
butoxycarboxamidobutyI)-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2fT-6-
chromenvlsulfonyl} guanidino]propyl)-4,7,10-trioxoundecanoate (122)
The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112 (63
mg, 0.073 mmol) and 101 (28 mg, 0.073 mmol) to afford
122 (71 mg, 0.058 mmol, 79%) as a white solid. Mp 72-
74oC. 1H NMR (CDC1, 300 MHz):  7.93 (m, 2H, ArH);
7.85 (m, 2H, ArH); 7.27 (m, 13H, ArH); 6.20 (m, 2H,
NH):5.63 (m, 2H, H2' and H2""); 5.13 (ABq,J= 12.3
Hz, 2H, PhCH2O); 4.94 (m, 6H, HI 1, H3' and H3"");
4.50 (m, 4H, HI"", H2 andH5); 4.06 (m, IH, H8); 3.08
(m, 2H, H3"); 2.89 (m, 2H, H4""); 2.57 (m, 2H, H4'");
2.55 (s. 3H, 7"'-CH ,): 2.53 (s, 3H, 5"'-CH ,): 2.49 (m, 2H, HI'); 2.08 (s. 3H, 8"'-CH ,); 1.75 (t, J = 6.3 Hz, H3"');
1.52 (m, 2H, HI"); 1.40 (s, 9H, C(CH3)3); 1.34 (m, 2H, HI""); 1.27 (s, 6H, 2 x 2"'-CH ,); 1.21 (m, 2H, H3""); 0.95
(m, 2H, H2"); 0.77 (m, 2H, H2""). Mass Spectrum (ES, +ve) m/z Mil (10%) [MH+], 1172 (100%). HRMS calcd
forC6RH84N7O12S 1222.5899, found 1222.5889.
Benzyi (2S,5/_,5/?,iiS)-2-aiiyI-ii-(4-aIIyioxybenzyi)-3,6,9,12-teiraaza-8-(4-[^ii-buixycarboxamido]butyl)-5-
([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonamido}guanidmo]propyl)-4,7,10,13-
tetraoxotetradecanoate (123)
The title compound was synthesised using the general peptide
coupling procedure (Procedure B), from 112 (60 mg, 0.069
mmol) and 16 (18 mg, 0.068 mmol) to afford the 123 (65 mg,
0.058 mmol, 85%) as a white solid. Mp 94-102oC. 1H NMR
(CDC13 300 MHz): 7.76 (bs, IH, NH); 7.54 (bs, 1H, NH);
7.41 (bs, IH, NH); 7.31 (m, 5H, ArH); 7.09 (d, J= 8.7 Hz, 2H,
ArH2"" and ArH6""); 6.77 (d, J = 8.4 Hz, 2H, ArH3"" and
ArH5""); 6.39 (bs, 3H, 3 x NH's); 6.02 (m, IH, H2""); 5.70
(m, IH, H2'); 5.39 (dd,J = 1.5, 17.1 Hz, IH, H3a""); 5.26
(dd, J = 1.2, 10.5 Hz, IH, H3b""); 5.06 (m, 2H, H3'); 5.05 (m,
2H, PhCH,O); 4.65 (dd, J = 6.9, 13.5 Hz, IH, M1l); 4.57 (dd, J = 8.1, 13.5 Hz, IH, H2); 4.50 (m, IH, H5); 4.45 (d,
J = 5.4 Hz, 2H, HI""): 4.41 (m, IH, H8); 4.14 (bs, IH, NH); 3.15 (m, 2H, 113"); 2.92 (m, 4H, H4"" and H-CH ,);
2.58 (m, 4H, HI' and H4'"); 2.53 (s, 3H, 7"'-CH 3); 2.52 (s, 3H, 5"'-CH ,); 2.08 (s, 3H, H14): 1.94 (m, 4H, HI" and
HI""); 1.84 (s. 3IT, 8"'-CH 3); 1.78 (m. 2H, H3'"); 1.69 (m, 4IT, H2" andH2""): 1.55 (m. 2H, 113""); 1.40 (s, 9IT,
C(CHs)3); 1.30 (s, 6H, 2 x 2"'-CH ,). Mass Spectrum (ES, +ve) m/z 1101 (30%) [MH+]:288 (100%). HRMS calcd
for C5-H51N8Oi2S 1101.5695, found 1101.5731.



WO 2006/074501 PCT/AU2005/001444
183.
Benzyl (2S,5/.,8 R)-2-aiiyI-3,6,9-trias5a-li-(2-[2'-benzyIoxy-{l,I'}-(S)-binaphtha!en-2-yIoxy])-8-(/er/-
butoxycarboxanndobutyl)-5-(3-[{2,2£,7,8-pentamethyl-3,4-dihydro-2H-6-
chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate (124)
The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112 (58
mg, 0.067 mmol) and 102 (29 mg, 0.067 mmol) to afford
124 (61 mg, 0.048 mmol. 71%) as a white solid. Mp 114-
119oC. 1H NMR (CDC13,3OO MHz):  7.90 (m, 4H, ArH);
7.26 (m, 18H, ArH): 6.80 (d, J =6.9 Hz, IH, NH); 6.23
(m, 3H, NH); 5.65 (m, IH, H2'); 5.07 (m, 6H, HI1,
PhCH2O-ester and H3'); 4.81 (m, IH, H2); 4.60 (m, IH,
H5): 4.40 (m, 2H, HI 1): 4.08 (m, IH, H8); 3.01 (m, 2H,
H3"V. 2.89 (m, 2H, H4""); 2.59 (m, 2H, 114'"); 2.57 (s,
3H, 7"'-CH 3): 2.54 (s, 3H, 5"'-CH ,); 2.50 (m, 2H, HI'); 2.08 (s, 3H, 8"'-CH 3); 1.75 (t, J = 6.6 Hz, H3"'); 1.52 (m,
2H, HI"); 1.41 (s, 9H, C(CH3)3); 1.35 (m. 2H, HI"" and H3""); 1.27 (s. 6H. 2 x 2"'-CH ,); 1.15 (m, 4H, 112" and
H2""). Mass Spectrum (ES, +ve) m/z 1272 (100%) [MH+]. HRMS calcd for C72H86N7O12S 1272.6055, found
1272.6061.
Benzyl (2S,5R,8JR)-2-allyl-3,6,9-triaza-8-(tert-butoxycarboxamidobutyI)-ll-(2-[2'-methoxy-{l,1'}-(S)-
binaphthaIen-2-yloxy])-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2ff-6-chromenylsuIfonyl}}guanidinolpropyl)-
4,7,10-trioxoundecanoate (125)
The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112 (55
mg, 0.064 rnmol) and 103 (23 mg, 0.064 mmol) to afford
125 (51 mg, 0.042 mmol, 66%) as a white solid. Mp
104oC. 1H NMR (CDCl3 300 MHz):  7.91 (m. 4H, ArH);
7.30 (m, 13H, ArH); 6.23 (m, 3H, NH); 5.63 (m, IH,
H2'); 5.10 (m, 4H, PhCH2O and H3'); 4.80 (m, IH, H2);
4.58 (m, 2H, HI1); 4.41 (m, IH, H5); 4.11 (m, IH, H8);
3.71 (s, 3H, OCH3); 3.09 (m, 2H, H3"); 2.89 (m, 2H,
H4""); 2.56 (m, 2H, H4'"); 2.54 (s. 3H. 7"'-CH 3); 2.5 1 (s,
3H, 5'"-CH 3); 2.48 {m, 2H, HI'); 2.07 (s, 3H, 8"'-CH 3); 1.86 (m, 2H, HI"); 1.75 (t, J =5.7 Hz, H3'"): 1.56 (m, 2H,
HI""): 1.41 (s, 9H, C(CH3)3); 1.34 (m, 4H, HI"" and H3""); 1.27 (s, 6H, 2 x 2"'-CH 3): 1.54 (m, 4H, H2" and H2"").
Mass Spectrum (ES, +ve) m/z 1196 (30%) [MH+]. 346 (100%). HRMS calcd for C66H82N7O12S 1196.5742, found
1196.5757.



WO 2006/074501 PCT/AU2005/001444
184.
Benzyl (25,5i,8/)-2-allyI-3,6,9-triaza-8-(^rt-butoxycarboxainidobutyI)-5-(3-[{2,2,5,7 8-pentamethyl-3,4-
dihydro-2flr-6-chromenylsulfonyI}guanidino]propyl)-ll-(2 ,,[2'-{3-phenyIallyloxy}-[l,r]-(S)-binaphthalen-2-
vloxvl)-4,7,10-trioxoundecanoate (126)


The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112 (63
mg, 0.073 mmol) and 104 (34 mg, 0.073 mmol) to afford
126 (64 mg, 0.049 mmol, 67%) as a white solid. Mp 110-
112°C. 1H NMR (CDC13, 300 MHz):  7.91 (m, 4H, ArH)
7.28 (m, 18H, ArH): 6.22 (m, 3H. NH): 6.11 (d,J = 16.2
Hz, IH, H3'""); 5.91 (dt, J=5.1, 16.2 Hz, IH, H2'"");
5.64 (m, IH, H2'); 5.10 (m, 6H, PhCH2O,Hl'"" and
H3'); 4.81 (m, IH, H2); 4.67 (m, 2H, HI1): 4.59 (dd, J =
7.5, 12.9 Hz, IH, H5); 4.09 (m, IH, H8): 3.05 (m, 2H,
H3"); 2.88 (m, 2H. H4""): 2.56 (m, 2H, H4'"): 2.56 (s, 3H, 7'"-CH 3); 2.53 (s, 3H, 5"'-CH 3): 2.49 (m, 2H, HI'); 2.08 (s, 3H, 8"'-CH 3); 1.74 (m, 2H, H3'"); 1.55 (m, 4H, HI" and HI""); 1.41 (s, 9H, C(CH3)3); 1.32 (m, 2H, H3"");
1.26 (s, 6H, 2 x 2"'-CH 3); 1.15 (m, 411. H2" and H2""). Mass Spectrum (ES, +ve) vi'z 1298 (5%) [MII+], 1172
(100%). FIRMS calcd for C74H88N7Oi2S 1298.6212, found 1298.6185.
Benzyl (2S,5R,8/?)-2-alIyl-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl)-5-(3-[{2,2,5,7,8-pentamethyl-3,4-
dihydro-2ff-6-chromenylsulfonyl}guanidino]propyl)-ll-(2-[2'-{3-phenylpropyloxy}-[I,l']"(S)-binaphthalen-2-
20 yloxy])-4,7,10-trioxoundecanoate (127)


The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112 (124
mg, 0.14 mmol) and 107 (68 mg, 0.14 mmol) to afford
127 (146 mg, 0.1 1 mmol, 80%) as a white solid. Mp 92-
98"C. 1H NMR (CDC13 300 MHz): 7.90 (m, 4H, ArH):
7.23 (m, 18H, ArH): 6.68 (d, J = 9.0 Hz, IH, NH): 6.27
(bs, IH, NH); 6.21 (d, j = 7.2 Hz, IH, NH); 5.65 (m, IH,
H2'); 5.12 (ABq,J= 12.3 Hz, 2H, PhCH2O); 5.03 (m, 2H,
H3'): 4.55 (m, 2H, H5 and H2); 4.40 (ABq,/ = 14.4 Hz,
2H, HIl): 4.07 (m, IH, H8): 3.85 (m, 2H, HI'""): 3.08
(m, 2H, H3"): 2.90 (m, 4H, H4"" andH3'""); 2.58 (m, 2H, H4"'): 2.55 (s, 3H, 7"'-CH 3): 2.53 (s, 3H, 5"'-CH ,): 2.47
(m. 2H. HI'): 2.08 (s, 3H, 8"'-CH 3): 1.99 (m, 2H, HI1): 1.74 (t, J = 6.6 Hz, 2H, H3'"): 1.62 (m, 2H, H2'""): 1.40 (s,
9H. C(CHj)3): 1.23 (s, 6H, 2 x 2"'-CH 3): 1.14 (m, 2H, H3""): 0.95 (m, 2H, H2"): 0.77 (m, 2H, H2""). Mass
Spectrum (ES.+ve) mz 1321 (100%) [MNH4+]. HRMS calcd for C74H9()N7Oi2S 1300.6368, found 1300.6356.

WO 2006/074501 PCT/AU2005/001444
185.
Benzyl (2S,5R,8/.)-2-allyl-3,6,9-triaza-8-(terf-butox\xarboxamidobutyl-ll-(2-[2'-(3-methylbutoxy)-{l,1'}-(S)-
binaphthaIen-2-yloxy])-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2fl r-6-chromenyIsulfonyI}guanidino]propyI)-
4,7,10-trioxoundecanoate (128)


The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112 (121
mg, 0.14 mmol) and 105 (58 mg, 0.14 mmol) to afford
128 (114 mg, 0.091 mmol, 65%) as a white solid. Mp 90-
940C. 1H NMR (CDC13 300 MHz):  7.90 (m, 4H, ArH);
7.30 (m, 13H, ArH); 6.47 (m, IH, NH); 6.29 (bs, 2H,
NH); 6.18 (d, J= 6.9 Hz, IH, NH); 5.65 (m, IH, H2');
5.13 (ABq, J = 12.3 Hz, 2H, PhCH2O); 5.05 (m, 2H, H3');
4.80 (m, 5H, H2, H5, H8 and H1 1); 3.95 (m, 2H, HI'"");
3.14 (m, 2H, H3"); 2.92 (m, 2H, H4""); 2.64 (m, 2H,
H4"'): 2.56 (s, 3H, 7"'-CH 3); 2.55 (s, 3H, 5"'-CH 3); 2.49 (m, 2H, HI'); 2.09 (s, 3H, 8"'-CH3); 1.76 (t, J =5.7 Hz,
H3"'): 1.52 (m, 4H, HI" and HI""); 1.41 (s, 9H, C(CH3)3); 1.26 (s, 6H, 2 x 2"'-CH 3); 1.12 (m, 2H, H3'""); 0.92 (m,
2H, H2""); 0.79 (m, 4H, H3"" and H2"); 0.52 (d, J =6.3 Hz, 3H, H4a'""); 0.46 (d, J =6.3 Hz, 3H, H4b'""). Mass
Spectrum (ES, +ve) m/z 1274(100%) [MNH4+] .HRMS calcd for C70H 90N7O12S 1252.6368, found 1252.6388.
Benzyl (2S,5R,8i.,llS)-2-aIlyl-ll-(4-[9-anthracenyl]benzyl)-3,6,9,12-tetraaza-8-(4-[tert-
butoxycarboxamido]butyI)-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6- chromcnylsulfonyl}guanidino]propyl)-4,7,10,13-tetraoxotetradecanoatc (129)


The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112
(40 mg, 0.045 mmol) and 97 (17 mg, 0.045 mmol) to
afford 129 (20 mg, 0.016 mmol, 36%) as a white solid.
Mp 108-1 100C. 1H NMR (CDC13, 300 MHz):  8.48 (s,
IH, ArHIO'""); 8.03 (m, 2H, ArH); 7.58 (m, 2H,
ArH); 7.44 (m, 2H, ArH): 7.30 (m, HH, ArH); 6.82
(bs, IH, NH): 6.36 (bs, 2H,n 2 x NII' s); 5.77 (m, IH,
H2'); 5.12 (m,4H, H3' and PhCH2O): 4.85 (m, IH.
HI1); 4.59 (m, IH, H2): 4.44 (m, IH, H5); 4.31 (m,
IH, H8); 3.19 (m. 2H. 11-CH2): 2.95 (m. 4H, H4"" and H3"): 2.56 (s, 3H, 7"'-CH3 ); 2.54 (s, 3H, 5"'-CH 3): 2.52 (m,
4H, H4'" and H1'): 2.06 (s, 3H, 8"'-CH 3): 1.97 (m, 2H, H3""): 1.94 (s, 3H, H14): 1.74 (m. 4H, HI" and HI""): 1.71
(m, 2H. H3'"): 1.62 (m, 2H. H2"): 1.38 (m, 2H. H2""): 1.36 (s, 9H, C(CH3)3): 1.23 (s, 6H, 2 x 2"'-CH 3). Mass
Spectrum (ES. +ve) m/z 1221 (10%) [MH+]:282 (100%). HRMS calcd for C68H85N8O11S 1221.6059. found
35 1221.6089.

WO 2006/074501 PCT7AU2005/001444
186.
Benzyl (2S,5R,8/1lS)-2-allyl-3,6,9,12-tetraaza-8-(4-[^rt-butoxycarboxaniido]butyl)-5-([{2,2,5,7,8-
pentamethyI-3,4-dihydro-2ff-6-chromenylsulfonyl}guanidino]propyl)-4,7,10,13-tetraoxo-ll-(4-[9-
phenanthrenyl]benzyl)tetradecanoate (130)


The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 112
(38 mg, 0.044 mmol) and 99 (16 mg, 0.042 mmol) to
afford 130 (41 mg, 0.034 mmol, 80%) as a white solid.
Mp 108°C. 1HNMR (CDCl3,300 MHz):  8.72 (m,
2H, ArH): 7.58 (m, 16H, ArH): 6.40 (bs, 2H, NH):
5.71 (m, IH, H2'); 5.13 (m, 2H, PhCH2O); 5.03 (m,
2H, H3'); 4.83 (m, IH, HI1): 4.60 (m, IH, H2); 4.59
(m, IH, H5); 4.29 (m, IH, H8): 3.12 (m, 2H, H-CH2);
2.94 (m, 4H, H4"" and H3"): 2.56 (s, 3H, 7"'-CH 3;
2.54 (s, 3H, 5"'-CH 3); 2.53 (m, 4H, H4"' and HI'); 2.07 (s, 3H, 8"'-CH 3); 1.91 (s, 3H, H14): 1.82 (m, 4H, HI" and
15 HI""): 1.72 (t, J = 6.6 Hz, 2H, H3'"): 1.62 (m, 4H, H2" andH3""); 1.39 (m, 2H, H2""); 1.34 (s, 9H, C(CH3)3); 1.23
(s, 6H. 2 x 2"'-CH 3). Mass Spectrum (ES, +ve) m/z 1221 (100%) [MH+]. HRMS calcd for C68H85N8OnS 1221.6059,
found 1221.6045.
Benzyl (2S,5/?,8R)-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl)-5-(3-[{2,2,5,7,8-pentamethyi-3,4-dihydro-2fr-
6-chromenyIsuIfonyI}guanidino]propyl)-4,7,10-trioxo-2-propyl-ll-(2-[2'-3-(propyloxy)-{l,l'}-(S)-
20 binaphthalen-2-yloxy])undecanoate (131)


To a solution of 122 (170 mg, 0.145 mmol) in THF (5
mL) was added palladium on activated carbon. The
reaction vessel was degassed under vacuum and regassed
with hydrogen before being allowed to stir for 13 h. The
solution was filtered, evaporated to dryness and dissolved
in acetone (5 mL). To this solution was added K2CO3 (39
mg, 0.28 mmol) and benzyl bromide (24 mg, 0.14 mmol).
After a further 13 h the reaction was concentrated by
vacuum and the product isolated by flash column
chromatography (5% MeOH/ DCM) to yield 131 (127
mg, 0.10 mmol, 71%) as a white solid. Mp 118-123°C. 1H NMR (CDC13,300 MHz):  7.90 (m, 4H, ArH): 7.30 (m,
13H, ArH): 6.26 (bs, 2H, NH): 6.20 (d, J =7.2 Hz, IH, NH): 5.13 (ABq,J= 12.6 Hz, 2H, PhCH2O): 4.50 (m, 2H,
H2 and H5) 4.43 (m, 2H, HI 1): 3.99 (m. IH, H8): 3.69 (m, 2H, HI'""): 3.13 (m, 2H, H3"): 2.91 (m, 2H, H4""):
2.60 (m, 2H, H4'"): 2.56 (s, 3H, 7"'-CH 3): 2.54 (s, 3H, 5"'-CH 3): 2.08 (s, 3H, 8"'-CH ,): 1.90 (m. 2H, HI'): 1.88 (m,
35 2H. H2'""): 1.76 (m. 2H, H3'"): 1.58 (m, 2H, H2""): 1.41 (s, 9H, C(CH3)3): 1.38 (m, 4H, HI" and HI""): 1.34 (m,
2H. H2'): 1.27 (s. 6H. 2 x 2"'-CH 3): 1.20 (m, 2H, 112"): 0.87 (t, J= 6.9 Hz. 3H, H3'""): 0.43 _t. J = 7.2 Hz, 3H.

WO 2006/074501 PCT/AU2005/001444
187.
H3'). Mass Spectrum (ES, +ve) m/z 1226 (100%) [MH+]. HRMS calcd for C68H88N7O12S 1226.6212. found
1226.6240.
Benzyl (2S,5/.,8«)-2-allyl-ll-(2-[2'-alIyloxy-[l,r)-(S)-binaphthalen-2-yIoxy])-3,6,9-triaza-8-(butylamino)-5-
(3-guanidinopropyI)-4,7,10-trioxoundecanoate dihydrochloride (132)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 122 (65
mg, 0.055 mmol) to yield 132 (29 mg, 0.034 mmol, 62%)
as a highly hydroscopic cream solid.1H NMR (CD3OD
300 MHz):  8.04 (d, J = 6.0 Hz, IH, ArH): .01 (d, J =
6.0 Hz, IH, ArH): 7.93 (s, IH, ArH): 7.90 (s, IH, ArH):
7.55 (d, J= 9.3 Hz, IH, ArH): 7.48 (d, J= 9.3 Hz, IH,
ArH): 7.35 (m, 7H, ArH); 7.23 (m, 2H, ArH); 7.07 (m, IH, ArH); 7.05 (m, IH, ArH); 5.73 (m, 2H, H2' and H2"");
5.16 (ABq,J = 3.6 Hz, 2H,PhCH2O); 5.01 (m, 4H, H3'; andH3""): 4.55 (m, 6H, H2, H5, HI1 and HI""); 4.13 (m,
IH, H8); 3.13 (m, 2H, H3"); 2.77 (m, 2H, H4'"); 2.54 (ddd, J =5.4, 14.4, 24.3 Hz, 2H, HI'); 1.77 (m, 2H, HI");
15 1.62 (m, 2H, HI"'); 1.52 (m, 2H, H3'"); 1.44 (m, 2H, H2"); 0.95 (m, 2H, H2'"). C NMR (CD3OD. 75 MHz): 5
173.8. C4; 173.2, C2; 172.5, C7; 170.9, C1O: 158.5, CN3; 155.4, ArC; 154.1, ArC; 137.1, ArC; 135.1. C2'; 135.1,
C2"": 135.0, ArC; 134.2, ArC; 131.4, ArCH; 131.0, ArCH; 130.8, ArCH; 130.8, ArCH: 129.6. ArC; 129.4, ArC;
129.3, ArCH: 129.3, ArCH; 129.2, ArCH; 127.6, ArCH; 127.6, ArCH; 126.4, ArCH; 126.0, ArCH; 125.3, ArCH:
124.9, ArCH; 21.6, ArCH; 120.5, ArC; 119.1, ArC: 117.0, C3'; 116.9, C3""; 116.0, ArCH: 70.9, CI1: 69.2, C1"";
20 68.1. ArCH2: 53.9, C5; 53.7, C2; 53.6, C8; 41.9, C3"; 40.4, C4'": 36.7, Cl'; 32.2, Cl"; 30.3, Cl"'; 27.8, C2"; 26.2,
C2'"; 23.2, C3'". Mass Spectrum (ES, +ve) m/z 856 (100%) [M2+]. HRMS calcd for C49H58N7O7 856.4398, found
856.4367.
Benzyl (2S,5/.,8R,llS)-2-alIy1-ll-(4-aIlyIoxybenzy])-8-(4-aminoburyI)-3,6,9,12-tetraaza-5-(3-
[guanidino]propyl)-4,7,10,13-tetraoxotetradecanoate hydrochloride (133)


The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 123 (65 mg, 0.059
mmol) to yield 133 (39 mg, 0.048 mmol, 82%) as a cream
solid. Mp 108°C. 1H NMR (CDC13,300 MHz):  7.35 (m, 5H,
ArH); 7.16 (d, J= 8.7 Hz, 2H, ArH2"' and ArH6"'); 687 (d, J
= 8.7 Hz, 2H, ArH3'" and ArH5"'); 6.02 (m, IH, H2'"); 5.78
(m, 1H, H2'); 5.39 (dd, J= 1.8, 17.1 Hz, 1H, H3a'""); 524 (dd.
J= 1.8,10.5 Hz, IH, H3b'""); 5.10 (m, 4H, H3' and PhCH2O):
4.52 (m, 2H, HI""'); 4.39 (m, 2H, H13 and H2); 4.24 (dd, J =
4.8, 9.0 Hz, IH, H5): 3.98 (dd,J = 3.9, 9.9 Hz, IH, H8): 3.16 (m, 2H, H3"): 2.94 (m, 2H, H-CH2); 2.84 (m, 2H,
35 H4'"); 2.55 (m, 2H, HI'); 1.94 (s, 3H, H14): 1.87 (m. 2H, HI"): 1.73 (m, 2H, HI"'): 1.54 (m. 4H. H2" and H2'"):
1.03 (m. 2H, H3"'). 13C NMR (CDC13 75 MHz):  175.4. Cl: 174.4, C4; 174.2, C7: 172.5, CIO: 159.0. C13: 158.5.

WO 2006/074501 PCT/AU2005/001444
188.
NCO: 137.2, ArC4""; 134.9, C2'"": 134.3, C2'; 131.5, ArC; 130.0, ArCH2"" and ArCH6""; 129.6, ArCH: 129.4,
ArCH; 129.4, ArCH; 128.5, ArCl"; 119.0, C3'; 117.6, C3""'; 115.9, ArCH3"' and ArCH5"': 69.8, Cl'"": 67.9,
CH2-ester); 57.8, CI1; 55.3, C5; 54.8, C8: 54.0, C2; 41.9, C3"; 40.3, C4"': 37.4, H-CH2; 36.5, CT; 31.2, Cl"'; 29.5:
C2"; 28.0, C21"; 26.5, C14; 23.8, C3"'; 22.5, Cl". Mass Spectrum (ES, +ve) mJz 735 2 [M2+] (70%), 368 (100%).
5 HRMS calcd for C38H55N8O7 735.4194, found 735.4200.
Benzyl (2S,5/?,8/.)-2-allyl-3,6,9-triaza-ll-(2-[2'-benzyIoxy-{l,l'}-(S)-binaphthalen-2-yIoxy])-8-(butylaniino)-5-
(3-guanidinopropvl)-4,7,10-trioxoundecanoate dihydrochloride (134)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 124 (50
mg, 0.039 mmol) to yield 134 (29 mg, 0.030 mmol, 76%)
as a cream solid. Mp 116-1 18°C. 1H NMR (CD3OD, 300
MHz):  7.70 (m, 4H, ArH); 6.91 (m, 18H, ArH); 5.54
(m, IH, H2'); 4.89 (m, 6H, PhCHO,Hl"" and H3'):
4.49 (m, IH, H2); 4.30 (m, IH, H5); 4.23 (m, 2H, HI 1);
4.05 (m, IH, H8); 3.21 (m, 2H, H3"); 2.95 (m, 2H, H4'");
2.50 (m, 2H, HI'); 1.62 (m, 2H.H1"); 1.43 (m, 4H, HI"' and H3'"); 1.15 (m, 2H, H2"); 0.89 (m, 2H, H2'"). 13C
NMR (CD3OD, 75 MHz):  173.6. C4: 173.4, C2; 172.4, C7; 171.1, CIO; 158.2, CN3; 154.3, ArC; 154.1, ArC;
153.4, ArC; 142.1, ArC; 141.8, ArC; 140.8, ArC; 136.8, ArCH; 135.9, ArCH; 135.2, C2'; 132.6, ArC; 13 1.1, ArCH;
130.6, ArCH; 130.1, ArCH; 129.7, ArC; 129.6, ArC; 129.5, ArCH; 129.3, ArCH; 129.2, ArCH; 129.1, ArCH; 128.8,
20 ArCH; 127.4, ArCH; 126.9, ArCH; 126.7, ArCH; 126.3, ArCH; 125.5, ArCH; 125.1, ArCH; 120.6, ArCH: 120.2,
ArCH; 119.2, ArC; 116.6, C3'; 68.7, CI1; 68.7, Cl""; 68.0, ArCH2;54.0, C5; 53.9, C2; 53.6, C8; 41.8, C3"; 40.4,
C4"'; 36.5, Cl'; 31.9, Cl"; 30.0, Cl1"'; 27.6, C2"; 26.1, C2'"; 23.2, C3"' Mass Spectrum (ES, +ve) m/z 906 (100%)
[M2+]. HRMS calcd for C53H60N7O7 906.4554, found 906.4544.
Benzyl (2S,51,8R)-2-allyl-3,6,9-triaza-8-(butylamino)-5-(3-guanidinopropyl)-ll-(2-[2'-methyloxy-(l,l')-(S)-
25 binaphthalen-2-yloxy])-4,7,10-trioxoundecanoate dihydrochloride (135)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 125 (45
mg, 0.037 mmol) to yield 135 (24 mg, 0.027 mmol, 72%)
as a highly hydroscopic cream solid. 1H NMR (CD3OD
300 MHz):  7.76 (m, 4H, ArH): 7.03 (m, 13H, ArH);
5.56 (m, IH, H2'); 4.94 (m, 4H, PhCH2O andH3'): 4.31
(m, 4H, H2, H5 and HI1); 4.03 (m, IH, H8): 3.56 (s, 3H.
OCH3); 2.98 (m, 2H, H3"); 2.64 (m, 2H, H4'"); 2.36 (m, 2H, HI'); 1.42(m, 4H, HI" and HI1"); 0.99 (m, 2H, H2"):
0.78 (m. 2H, H2"'). 13C NMR (CD3OD,75 MHz):  173.7, C4; 173.1, C2; 172.4, C7; 170.8, C1O; 158.4, CN3: 156.2,
35 ArC; 153.8 ArC: 136.9, ArC; 135.0. ArC: 134.8, C2'; 134.1, ArCH: 131.2, ArC; 131.0. ArCH; 130.9, ArCH; 130.5,
ArC; 129.5, ArCH; 129.3, ArCH; 129.2, ArCH: 129.2. ArC: 129.1. ArCH: 127.6. ArC; 127.5. ArCH: 126.1, ArCH:

WO 2006/074501 PCT/AU2005/001444
189.
125.7, ArCH; 125.2, ArCH; 124.7, ArCH; 121.4, ArC; 119.5, ArCH; 119.2, C3'; 116.0, ArCH: 115.3, ArCH: 69.1,
CI1; 68.0, ArCH2; 57.2, OCH3; 54.0, C5; 53.6, C2: 53.6, C8: 41.9, C3"; 40.5, C4"'; 36.6, CT; 32.2, Cl": 30.1, Cl"':
27.7, C2"; 26.2, CT"; 23.1. C3"\ Mass Spectrum (ES, +ve) m/z 830 (100%) [M2+]. HRMS calcd for C47H56N7O7
830.4241, found 830.4219.
5 Benzyl (2S,5/?,8R)-2-allyI-3,6,9-triaza-8-(butyIamino)-5-(3-guanidinopropyl)-lI-(2-[2'-hydroxy-{l,I'}-(S)-
binaphthalen-2-yloxy])-4,7,10-trioxoundecanoatc dihydrochloride (136)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 126 (50
mg, 0.038 mmol) to yield 136 (35 mg, 0.036 mmol, 96%)
as a highly hydroscopic cream solid. 1H NMR (CD3OD
300 MHz):  7.62 (m, 4H, ArH); 6.90 (m, 13H, ArH);
5.44 (m, IH, H2'); 4.82 (m, 4H, PhCH2O and H3'); 4.40
(m, IH, H5); 4.31 (m, 2H, HI1); 4.21 (m, IH, H2); 3.96
(m, IH, H8); 2.86 (m, 2H, H3"); 2.54 (m, 2H, H4'"); 2.26 (m, 2H, HI'); 1.54 (m, 2H, HI"); 1.34 (m, 4H, H31" and
15 HI"'); 1.05 (m, 2H, H2"); 0.79 (m, 2H, H2'"). 13C NMR (CD3OD 75 MHz):  173.6, C4; 173.4, C2; 172.4, C7;
171.1, CIO; 158.2, CN3; 154.0, ArC; 153.3, ArC; 136.7, ArC; 135.2, ArC; 135.0, C2'; 133.9, ArCH; 13 1.0, ArCH;
130.8, ArC; 130.6, ArCH; 130.0, ArCH; 129.4, ArCH; 129.2, ArCH; 129.1, ArCH; 128.1, ArC; 127.8, ArCH; 127.5,
ArC; 127.3, ArC; 126.2, ArCH; 125.5, ArCH; 125. 1. ArCH; 124.1, ArCH; 120.5, ArC; 119.5, ArCH; 119.2, C3';
116.5, ArCH; 115.5, ArCH; 68.6, CI1;67.9, ArCH2;54.0, C5; 53.9, C2; 53.5, C8;41.7, C3"; 40.3, C41"; 36.4, CT;
20 32.0, Cl"; 30.0, Cl"'; 27.6, C2"; 26.0, C2'"; 23.2, C3"' Mass Spectrum (ES, +ve) m/z 888 (5%) [M2+], 831 (100%).
HRMS calcd for C46H54N7O7 816.4085, found 816.4086.
Benzyl (2S,5/?,8/.)-2-aIIyl-3,6,9-triaza-8-(butylamino)-5-(3-guanidinopropyl)- 4,7,10-trioxo-ll-(2-[2'-(3-
phcnylpropyloxy)-{l,l'}-(S)-binaphthalcn-2-yIoxy])-undecanoate dihydrochloride (137)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 127
(146 mg, 0.1 1 mmol) to yield 137 (91 mg, 0.090 mmol,
82%) as a highly hydroscopic cream solid. 1H NMR
(CD3OD,500 MHz):  7.95 (m, 4H, ArH); 7.15 (m, 18H,
ArH); 5.73 (m, IH, H2'); 5.10 (m, 4H, H3' and PhCH2O);
4.47 (m, IH, H5); 4.35 (m, 2H, HI 1); 4.17 (m. IH. H2);
4.08 (m, IH, H8); 3.86 (m, 2H, HI""); 3.13 (m: 2H. H3'):
2.80 (m, 2H, H2""); 2.52 (m, 2H, H4'"); 2.10 (m, 2H,
HI'); 1.61 (m, 4H, H3"" and HI"); 1.49 (m, 4H, H3' and HI"'); 1.12 (m, 2H, H2"); 0.96 (m, 2H, H2'"). 13C NMR
(CD3OD, 125 MHz):  173.8, C4; 173.1, C2; 172.4, C7; 170.7, ClO; 158.5, CN3; 155.6, ArC; 154.0, ArC; 142.7,
35 ArC; 137.0. C2'; 135.2, ArCH; 135.0, ArCH; 134.4, ArC; 134.1. ArCH; 131.3. ArC; 130.9. ArC; 130.6, ArCH;
l29.6 ArCH: 129.3, ArCH; 129.3, ArCH; 129.2 ArCH: 129.2, ArCH- 129.0 ArC'H: 127. 9 ArC; 127.6 ArCH;

WO 2006/074501 PCT/AU2005/001444
190.
126.5, ArCH; 126.4, ArC: 125.9, ArC: 125.3, ArCH: 124.8, ArCH: 121.7, ArCH: 120.9, ArCH: 120.3, ArC; 119.1,
C3'; 116.7. ArCH: 116.0, ArCH; 69.3, CI1; 69.2, ArCH2; 68.0, Cl"": 54.1, C5; 53.6, C2; 53.5. C8; 41.9, C3": 40.3,
C4"'; 36.6, Cl'; 32.5, Cl"; 32.2, Cl"'; 32.1, C3""; 30.1, C2""; 27.7, C2"; 26.2, C2"'; 23.1, C3"'. Mass Spectrum
(ES, +ve) m/z 934 (5%) [M2+],468 (100%). HRMS calcd for C55H64N7O7 934.4867, found 934.4844.
5 Benzyl (2S,5JR,8/?)-2-allyl-3,6,9-triaza-8-(butyIamino)-5-(3-guanidinopropyl)-ll-(2-[2'-(3-mcthIbutoxy)-
{l,rM>S)-binaphthaIen-2-yIoxy])- 4,7,10-trioxoundecanoate dihydrochloride (138)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 128
(114 mg, 0.091 mmol) to yield 138 (48 mg, 0.050 mmol,
55%) as a highly hydroscopic cream solid. 1H NMR
(CD3OD,500 MHz):  7.968 (m, 4H, ArH): 5.32 (m, 13H,
ArH); 5.74 (m, IH, H2'); 5.11 (m, 4H, PhCH2O and H3');
4.49 (m, 3H, H5 and H1); 4.35 (m, IH, H2): 4.14 (m,
2H, HI""): 3.95 (m, IH, H8): 3.14 (m, 2H, H3"); 2.79 (m, 2H, H4"); 2.55 (m, 211 HI'): 1.79 (m, 2H, HI"): 1.71 (m,
15 2H, H3'"); 1.55 (m. 4H, H2"" and HI"'); 1.24 (m, 2H, H3""); 1.17 (m, 2H, H2"); 0.96 (m, 2H, H2'"); 0.53 (d, J =
6.3 Hz, 3H, H4a""); 0.47 (d, J= 6.3 Hz, 3H, H4b""). 13C NMR (CD,OD 125 MHz):  173.9, C4; 173.2, C2; 172.5,
C7; 170.9, ClO; 158.5, CN3; 155.9, ArC; 154.0, ArC; 137.1, C2'; 135.2, ArC: 135.0, ArC; 134.3, ArCII; 134.2,
ArCH; 131.4, ArC; 129.6, ArCH; 129.6, ArCH; 129.4, ArCH; 129.3, ArC; 129.1, ArCH; 128.2, ArC; 128.0, ArC;
127.6, ArCH; 127.5, ArCH; 126.4, ArCH; 126.0, ArCH; 125.2, ArC; 124.8, ArCH; 121.8, ArCH; 120.5, ArCH;
20 119.1, C3'; 117.0, ArCH; 116.0, ArCH; 69.0, ArCH2; 68.0, CI1; 65.2, Cl"": 54.2, C5; 53.7, C2; 53.6, C8; 41.9, C3";
40.4, C4'"; 39.3, C2""; 36.7, Cl'; 32.2, Cl"; 30.1, C2"; 27.7, C2'"; 26.2, C3'"; 25.6, C3""; 22.8, C4a""; 22.6, C4b"".
Mass Spectrum (ES, +ve) m/z 886 (5%) [M2+],444 (100%). HRMS calcd for C5IH64N7O7 886.4867, found 886.4869.
Benzyl (2S,5fi,8/?,llS)-2-alIyl-8-(4-aminobutyl)-ll-(4-[9-anthracenyl]benzyl)-3,6,9,12-tetraaza-5-(3-
guanidinopropyl)-4,7,10,13-tetraoxotetradecanoate


(139)
The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 129 (20
mg, 0.016 mmol) to yield 139 (13 mg, 0.014mmol, 88%)
as a white solid. Mp 218-220°C. 1H NMR (CD3OD, 300
MHz): 7.68 (m, 17H, ArH); 5.77 (m, 1H.H2'); 5.15 (m,
4H, H3' and PhCH2O); 4.82 (m, 1H, H1 1); 4.42 (m. IH.
H2); 4.25 (m, 1H, H5); 4.07 (m, 1H, H8); 3.18 (m. 2H,
11-CH2); 2.88 (m, 4H, H4"" and H3"); 2.55 (m, 2H, H1'):
1.95 (s. 3H. H14): 1.85 (m. 2H. Hl"): 1.65 (m. 2H, H;l"'): 1.53 (m, 2H, H2"): 0.94 (m. 2H. H2'"). 13C NMR
35 (CD3OD 75 MHz):  175.2, C13: 174.4, Cl: 174.2, C4: 174.1, ClO: 172.5. C7: 158.6, CN3: 140.0, ArC: 139.9. ArC:
138.1. ArC: 137.4, ArC: 133.2, ArC: 134.3, C2': 131.5, ArC: 131.3, ArCH: 130.1. ArCH: 129.2. ArC: 128.1. ArC:

WO 2006/074501 PCT/AU2005/001444
191.
127.9. ArCH: 127.6, ArCH: 127.5, ArCH: 126.6, ArCH: 125.9, ArCH: 125.8, ArCH: 125.6, ArCH; 124.2, ArCH;
119.1. C3'; 68.1, CH2-ester; 57.9, Cll; 55.3, C8: 54.7, C5; 54.2, C2; 42.1, C3"; 40.3. C4"'; 38.1, H-CH2; 36.7, Cl';
31.4, Cl": 29.4, Cl"'; 27.3, C14; 26.5, C2": 23.6, C3"'; 22.5, C2"\ (Mass Spectrum (ES, +ve) m/z 855 (50%)
[M2+];428 (100%). HRMS calcd for C49H59N8O6 855.4558, found 855.4539.
5 Benzyl (2S,5R,8R,IIS)-2-aIlyl-8-(4-aminobutyl)-3,6,9,12-tetraaza-5-(3-guanidinopropyI)-4,7,10,13-tetraoxo-
ll-(4-[9-nhenanthre pyl]benzvl)tetradecanoate (140)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 130 (42
mg, 0.034 mmol) to yield 140 (25 mg, 0.027 mmol, 79%)
as a white solid. Mp 215-22O°C. 1H NMR (CD3OD 300
MHz):  8.82 (m, 2H, ArH); 7.60 (m, 16H, ArH); 5.81 (m,
IH, H2'); 5.15 (m, 4H, PhCH2O and H3'); 4.58 (m, IH,
HI1); 4.43 (m, IH, H2); 4.35 (dd, J = 4.8, 9.0 Hz, IH,
H5); 4.17 (dd, J =4.8, 9.6 Hz, IH, H8); 3.17 (m, 4H,
H4"" and H3"); 2.72 (m, 2H, H-ArCH,); 2.59 (m, IH,
HI'): 1.96 (s, 3H, H14); 1.80 (m, 4H, HI" and HI"');
1.65 (m, 2H, H3'"); 1.51 (m, 2H, H2"); 1.22 (m, 2H, H2"'). 13C NMR (CD3OD 75 MHz):  175.2, C13; 174.4, Cl:
174.2, C4; I74.l,ClO; 172.5, C7: 158.6, CN3; 140.7, ArC; 139.6, ArC, 137.4, ArC, 137.2, AiC, 134.3, C2', 132.9,
ArC; 132.1, ArC: 131.3, ArCH; 130.5, ArCH: 129.7, ArC: 129.6, ArC: 129.4, ArCH: 129.4, ArCH: 128.5, ArCH;
20 128.1, ArCH; 127.9, ArCH; 127.8, ArCH: 127.6, ArCH; 124.2, ArCH; 123.7, ArCH; 12.4, ArCH; 122.1, ArCH;
121.8, ArCH; 119.0, C3'; 68.0, CH2-ester; 57.7, CII; 55.2, C8; 54.7, C5; 54.0, C2; 42.0, C3"; 40.1, C4"'; 38.1, 11-
CH2;36.6, Cl'; 31.3, Cl": 29.6, Cl'"; 27.8, C14; 26.4, C2"; 23.8, C3"'; 22.6, C2"'. Mass Spectrum (ES, +ve) m/z
855 (30%) (M2+],428 (100%). HRMS calcd for C'49H59N8O6 855.4558, found 855.4528.
Benzyl (2S,5fi,8fi)- 3,6,9-triaza-8-(4-aminobutyI)-5-(3-guanidinopropyI)-4,7,10-trioxo-2-propyl-ll-(2-[2'-3-
25 (propyloxy)-{l,l')-(S)-binaphthalen-2-yloxy])undecanoate (141)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 131
(115 mg, 0.094 mmol) to yield 141 (75 mg, 0.080 mmol,
85%) as a highly hydroscopic white solid. 1H NMR
(CD3OD500 MHz)  7.95 (m, 4H, ArH): 7.30 (m, 13H,
ArH); 5.11 (m, 2H, PhCH2O): 4.58 (m, 2H, HII); 4.39
(m. IH, H5): 4.15 (m. IH, H2); 4.89 (m, IH, H8); 3.68
(m, 2H, HI""); 3.17 (m, 2H, H3"): 2.55 (m, 2H, H4"'); 2.07 (m, 4H, HI' and H2""): 1.38 (m, 6H, HI", H3'" and
HI'"): 1.34 (m, 2H. H2'); 1.13 (m. 2H, H2'"); 1.08 (m, 2H, H2"): 0.89 (m, 3H, H3""): 0.50 (m, 3H. H3'). 13C NMR
35 (CD3OD 125 MHz)  173.9, C4; 173.3, C2; 173.1, C7; 170.8, ClO: 158.4, CN3 155.8. ArC: 153.9. ArC; 142.6, ArC;
137.1. ArC: 135.1. ArCH: 135.1. ArCH: 131.3, ArC: 130.9,ArC: 130.6, ArC: 129.6. ArCH: 129.3,ArCH; 129.3.

WO 2006/074501 PCT/AU2005/001444
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ArCH: 129.1, ArC: 128.2, ArC; 127.6, ArCH: 127.4, ArCH; 126.3, ArCII; 125.9, ArCII: 125.2, ArCH: 124.8,
ArCH: 11.7, ArCH: 120.4, ArCH: 116.8, ArCH; 116.0, ArCH; 72.1, Cl""; 69.2, CII; 67.9, ArCH2: 54.1, C5: 53.7,
C2: 53.6, C8: 41.9, C3"; 40.4, C4"'; 34.3, CT; 32.2, Cl": 30.1, Cl"'; 27.7, C2": 26.2, C2""; 23.7, C2"': 23.1, C3"':
20.0, C2'; 13.9, C3': 10.8, C3"". Mass Spectrum (ES, +ve) iv/z 860 (30%) [M2+],431 (100%). HRMS calcd for
5 C49H62N7O7 860.4711, found 860.4730.
Methyl 3-amino-benzoate hydrochloride (143)


To a suspension of 3-aminohenzoic acid (1.03 gmg, 7.52 mmol) in McOH (80 mL) at
O0C was added dropvvise thionyl chloride (5 mL). The resulting solution was allowed
to stir for 16 h before the solvent was removed by evaporation and the product
10 precipitated with diethyl ether. The diethyl ether was removed by evaporation to yield the title compound (1.38 g,
7.38 mmol, 98%) as a white solid. Mp 176-1780C. 1H NMR (D20 ,300 MHz):  7.75 (dt, J = 1.8, 3.3, 7.2 Hz, 1H,
ArH); 7.71 (m, IH, ArH); 7.42 (m, IH, ArH): 7.37 (m,lH, ArH); 3.66 (s, 3H, OCH3). Mass Spectrum (Cl) m/z 152
(100%) [M+]. HRMS calcd for C8H10NO2 152.0712, found 152.0698.
Methyl (3'R)-3-(1 -aza-6-tert-butoxycarboxamido-3'-[9H-9-f urorepylmethoxycarboxamido]-2-
15 oxohexyl)benzoatc (144)


The title compound was synthesised using the general peptide
coupling procedurc (Procedurc B)-2-(from 143 (220 mg,2.27mmol)
and (i?)-5-(ferf-butoxycarboxamido)-2-(9H-9-
fluorenylmethyloxycarboxamido)pentanoic acid (578 mg, 1.27
mmol) to afford 144 (277 mg, mmol, 36%) as a white solid. Mp
96-980C. 1HNMR (CDC13, 300 MHz):  9.15 (s, IH, ArH): .17 (s,
IH, NH); 7.88 (d, J = 8.1 Hz, IH, ArH); 7.77 (m, IH, ArH); 7.72 (d, J = 7.8 Hz, 2H, ArHl" and ArH8"); 7.56 (d, J
= 7.2, Hz, 2H, ArH4" andArH5"); 7.36 (m, 2H, ArH3" andArH6"); 7.26 (m, 2H, ArH2" and ArH7"): 6.03 (d. J =
8.1 Hz, 2H,NH); 4.63 (m, IH, H3'); 4.36 (d,J = 6.9Hz, 2H, OCH2-W); 4.17 (t, J=6.9Hz, IH, H9"); 3.86 (s, 3H,
25 OCH3): 3.08 (m, 2H, H6'); 1.78 (m, 2H, H4'): 1.60 (m, 2H, H5'); 1.42 (s, 9H, (CH3)3). Mass Spectrum (ES, +ve)
m/z 610 (100%) [MNa+], 588 (70%) [MH+], HRMS calcd for C33H,SN3O7 588.2710, found 588.2726.
Methyl (3/-)-3-(3'-amino-l-aza-6-/ert-butoxycarboxamido-2-oxohexyl)benzoate (145)

The title compound was synthesized using the general Af-Fmoc deprotection
procedure (Procedure C), from 144 (555 mg, 0.95 mmol) to yield 145 (285 mg,
0.78 mmole, 82%) as a clourless viscous oil. 1H NMR (CDC13 300 MHz):  8.04
(m, IH, ArH); 7.84 (t, J = 1.8 Hz, IH, ArH); 7.51 (t, J =7.8 Hz, IH, ArH): 7.36 (m,
IH, ArH): 5.1 1 (m, IH, NH): 3.91 (s, 3H, OCH3); 3.69 (m, IH, H3'): 3.19 (m. 2H,
H6'); 2.08 (m. 2H, H4'); 1.65 (m. 4H, H5' and NH2): 1.43 (s, 9H, (CH3)3). HRMS calcd for Cl8H28N3O5 366.2029.
found 366.2051.

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Methyl (3/?)-3-(6-(2-[2'-allvIoxy-{l,l'}-(S)-binaphthalen-2-yIoxy])-l,4-diaza-3-[(3-teri;-
butoxycarboxamido)propyll-2,5-dioxohexyl)benzoate (146)


The title compound was synthesised using the general peptide
coupling procedure (Procedure B), from 101 (288 mg, 0.75 mmol)
and 145 (275 mg, 0.75 mmol) to afford 146 (434 mg, O59 mmol,
79%) as a white foam. Mp 70°C. lHNMR (CDC13, soo MHZ): 
9.08 (s, IH. ArH); 7.91 (m, 7H, ArH); 7.85 (m, 8H, ArH); 6.45 (d. J= 8.1 Hz, IH, NH); 5.69 (m, IH, H2"'); 4.94
(m, 2H, H3'"); 4.55 (m, 5H, H6\ HI"' and H3'); 3.87 (s, 3H, C)CH3); 2.96 (m, 2H, H3"); 1.62 (m, 2H, HI"); 1.44 (s,
9H, (CH3)3); 1-04 (m, 2H, H2")". Mass Spectrum (ES, +ve) m/z 732 (50%) [MH+], 351 (100%). HRMS calcd for
10 C43H46N3O8 732.3285, found 732.33 16.
(3/?)-3-(6-(2-[2'-allyloxy-{l,l'}-(S)-binaphthalen-2-yloxy])-l,4-diaza-3-[(3-tert-butoxycarboxamido)propyI]-
2,5-dioxohexyl)bcnzoic acid (147)

To a solution of 146 (370 mg, 0.51 mmol) in THF/water, 3:1 (8mL) was added lithium hydroxide monohydrate (43

mg, 0.5 1 mmol) and the resulting suspension was allowed to
stir for 16 h. The reaction mixture was diluted with water (30
mL) and the THF was removed by evaporation before the
remainine aqueous layer was wased with diethyl ether (40 mL)
to remove unreacted starting material. The aqueous phase was
acidified with dilute potassium bisulfate and the resulting
20 precipitate was extracted withDCM (3 x 40 mL). The
combined DCM fractions were dried and evaporated to yield the title compound (350 mg. 0.49 mmol, 96%) as a
white solid. Mp 86-900C. 1HNMR (CDC13 300 MHz):  9.70 (bs, IH, COOH); 9.26 (s. IH, ArH): 7.97 (m, 711,
ArH): 7.34 (m, 8H, ArH); 6.63 (d, J = 9.0 Hz, IH, NH); 5.71 (m, IH, H2"'); 5.01 (m, 2H, H3"'); 4.59 (m, 5H, H6Hl'" and H3'): 3.03 (m, 2H, H3"); 1.65 (m, 2H, Hl"): 1.49 (s, 9H, (CH3)3); 1.15 (m, 2H, H2"). Mass Spectrum (ES.
25 +ve)m/z 740 (100%) [MNa+],718 (20%) [MH+].HRMS calcd for C42H44N3O8 718.3128, found 718.3152.
Benzyl (3jR)-3-(6-(2-[2'-alIyloxy-{l,l'}-(S)-binaphthalen-2-yloxy])-l,4-diaza-3-[(3-tert-
butoxycarboxamido)propyl]-2,5-dioxohexyl)benzoate (148)


To a solution of 147 (40 mg, 0.056 mmol) in acetone (2 mL)
was added K2CO3 (17 mg, 0.12 mmol) and benzyl bromide
(21 mg, 0.12 mmol). The resulting suspension was allowed
to stir for 16 h before concentration and purification by flash
column chromatography (5%) MeOH/DCM) to yield the title compound (36 mg, 0.045 mmol, 80%) as a white solid.
Mp 145-1520C. 1H NMR (CDCl3,300 MHz):  8.63 (s. IH, ArH): 7.90 (m, 7H, ArH): 7.30 (m. 1IH, ArH): 6.27 (d,
35 J = 8.4 Hz, IH, NH): 5.68 (m. IH. H2'"): 5.30 (s. 2H, ArCH2); 4.87 (m, 2H. H3"'); 4.50 (m. 5H, H6'. HI"' and

WO 2006/074501 PCT/AU2005/001444
194.
EB'): 3.00 (.m, 2H, H3"); 1.52 (m, 2H, HI"); 1.42 (s, 9H, (CH3)3); 1.05 (m, 2H, H2"). Mass Spectrum (ES, +ve) m/z
808 (30%) [MH+]:414 (100%). HRMS calcd for C49H50N3O8 808.3598, found 808.3634.
AHyI(3i?)-3-(6-(2-[2'-aIlyloxy-{I,l'}-(S)-binaphthalcn-2-yloxy])-l,4-diaza-3-[(3-tert-
butoxycarboxamido)propyl]-2,5-dioxohexyl)beiizoate (149)


To a solution of 147 (43 mg, 0.060 mmol) in acetone (2 mL)
was added K2CO3 (18 mg, 0.12 mmol) and allyl bromide (0.1
inL, 0.12 mmol). The resulting suspension was allowed to stir
for 16 h before concentration and purification by flash column
chromatography (5% MeOHTDCM) to yield the title
10 compound (36 mg, 0.047 mmol, 79%) as a white solid. Mp 142-1500C. 1H NMR (CDC13 300 MHz):  8.75 (s, IH,
ArH); 7.90 (m, 7H, ArH); 7.29 (m, 8H, ArH); 6.32 (d, J =8.4 Hz, IH, NH); 6.02 (m, IH, CH-ester); 5.65 (m, IH,
H2'"); 5.39 (dd,J= 1.5, 17.4Hz, IH, H3a-ester). 5.27 (dd,J= 1.5, 10.5 Hz, IH, H3b-ester); 4.89 (m, 2H, H3"');
4.81 (m, 2H, Hl-ester): 4.55 (ABq,J = 14.7 Hz, 2H, H6'); 4.52 (m, 2H, H1'"); 4.23 (m, IH, H3'); 3.00 (m, 2H, H3");
1.91 (m. 2H. HI"): 1.44 (s. 9H, (CH3)3): 1.01 (m, 2H, H2"). Mass Spectrum (ES, +ve) m/z 758 (10%) [MH+]:444
15 (100%). HRMS calcd for C45H47N3O8Na 780.3261, found 780.3290.
(3i?)-3-(6-(2-[2'-allyloxy-{1,1'}-(S)-binaphthalen-2-yloxy])-l,4-diaza-3-|(3-terNbutoxycarboxainido)propyI ]-
2_5-dioxohexy1)- Af-benzyloxybenzamide (150)


The title compound was synthesised using the general
peptide coupling procedure (Procedure B), from 147 (91
mg, 0.127 mmol) and 0-benzylhydroxylaminc (20 mg,
1.27 mmol) to afford 150 (82 mg, O.lOOmmol, 78%) as a
white solid. Mp 141-1440C. 1H NMR (CDC13 300 MHz):
 9.14 (s. IH, ArH): 7.97 (m, 2H, ArH): 7.88 (m, 2H, ArH); 7.31 (m, 1OH. ArH); 6.41 (d, J =7.5 Hz, IH, NH); 5.66
(m, IH. H2"'): 4.95 (m, 4H, H3'" and ArCH2):4.66 (t,J = 5.1 Hz, IH, NH); 4.54 (m, 4H, H6', HI"'); 4.30 (m, IH,
25 H3'); 2.93 (m, 2H, H3"): 1.54 (m. 2H, Hl"); 1.43 (s, 9H, (CH3)3); 1.06 (m, 2H, H2"). Mass Spectnun (ES, +ve) m/z
823 (100%) [MH+].HRMS calcd for C49H51N4O8 823.3707, found 823.3726.
Methyl (31.)-3-(6-(2-[2'-allyloxy-{l,l'}-(S)-binaphthalen-2-yIoxy])-L4-diaza-3-(3[{di-tert-
butoxycarbonyI}guanidino]propyl)-2,5-dioxohexyl)benzoate (151)


To a solution of 155 (32 mg, 0.048 mmol) in DCM (3 mL) was
added Nl-tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methyl
propanamide (28 mg, 0.072 mmol), triethylamine (7.3 mg, 0.072
mmol). The resulting solution was allowed to stir for 16 h under a
nitrogen atmosphere. The solvent was evaporated and the crude
product was purified by flash column chromatography (15:1.
DCM/MeOH) to yield the title compound (41 mg, 0.047 mmole, 98%) as a white solid. Mp 74-76 0C. 1H NMR

WO 2006/074501 PCT/AU2005/001444
195.
(CDCl3 300 MHz):  8.55 (s, IH, ArH); 8.27 (bs, III, NII); 7.77 (m, 7H, ArH); 7.26 (m, 8H, ArH); 6.34 (d, J = 8.4
Hz, IH, NH); 5.59 (m, IH, H2'"); 4.67 (m, 2H, H3'"); 4.57 (d, J = 3.3 Hz, 2H, Hl'"): 4.48 (m, 2H, C6'): 4.34 (m,
IH, H3'): 3.91 (s, 3H, OCH3); 3.26 (m, 2H, H3"); 1.65 (m, 2H, HI"): 1.51 (s, 9H, (CH3)3); 1.46 (s, 9H, (CH,),);
1.14 (m, 2H, H2"). Mass Spectrum (ES, +ve) m/z 896 (100%) [MNa+], 875 (95%) [MH+]. HRMS calcd for
5 C49H56N5O10 874.4027, found 874.4043.
Benzyl (3R)-3-(6-(2-[2'-alIyloxy-{I,I'}-(S)-binaphthalen-2-yloxy])-l,4-diaza-3-(3[{di-tert-
butoxycarbonyl}guanidino]propyl)-2,5-dioxohexyl)benzoate (152)


To a solution of 157 (20 mg, 0.027 mmol) in DCM (2 mL)
was added Nl-tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methyl
propanamide (16 mg, 0.041 mmol), and triethylamine (4 mg,
0.041 mmol). The resulting solution was allowed to stir for
16 h under N2. The solvent was evaporated and the crude
product was purified by flash column chromatography (15:1,
15 DCM/MeOH) to yield the title compound (15 mg, 0.016 mmole, 58%) as a white solid. Mp 122-1260C. 1H NMR
(CDC13 300 MHz):  8.41 (s, III, ArH); 8.26 (bs, IH, NH); 7.85 (m, 7H, ArH); 7.32 (m, 8H, ArH); 6.31 (d, J = 8.1
Hz, IH, NH); 5.56 (m, IH, H2'"); 5.37 (s, 2H, ArCH2);4.85 (m, 2H, H3'"); 4.56 (m, 2H, HI'"); 4.45 (m, 2IT, H6');
4.32 (m, IH, H3'); 3.25 (m, 2H, H3"); 1.63 (m, 2H, HI"); 1.50 (s, 9H, (CH3)3); 1.46 (s, 9H, (CH3)3); 1.15 (m, 2H,
H2"). Mass Spectrum (ES, +ve) m/z 950 (100%) [MH+].HRMS calcd for C55IT60N5Oi0 950.4340, found 950.4339.
20 Allyl(3R)-3-(6-(2-[2'-alIyloxy-{l,I'}-(S)-binaphthalen-2-yloxy])-l,4-diaza-3-(3[{di-tert-
butoxycarbonyl}2guandino]pronyl)-2,5-dioxohexyl)benzoate (153)


To a solution of 159 (25 mg, 0.036 mmol) in DCM (2 mL) was
added N1 -tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methyl
propanamide (21 mg, 0.054 mmol), and triethylamine (0.1
mL). The resulting solution was allowed to stir for 1.6 h under
N2. The solvent was evaporated and the crude product was
purified by flash column chromatography (15:1, DCM/MeOH)
to yield the title compound (3 1 mg, 0.034 mmole, 97%) as a white solid. Mp 700C. 1H NMR (CDC13 300 MHz):
30  8.57 (s, IH, ArH): .26 (bs, IH, NH); 7.88 (m, 7H, ArH); 7.28 (m, 8H, ArH): 6.34 (d, J = 8.1 Hz, IH, NH): 6.03
(m, IH. CH-ester): 5.58 (m, IH, H2'"); 5.40 (dd, J = 1.5, 17.1 Hz. IH, H3a-ester): 5.28 (dd, J = 1.5. 10.5 Hz, IH,
H3b-ester); 4.85 (m, 4H, Hl-ester and H3'"); 4.50 (m, 4H. H6' and HI'"); 4.34 (m. IH, H3'): 3.26 (m, 2H. H3"):
1.62 (m, 2H, HI"): 1.50 (s, 9H, (CH3)3): 1.46 (s, 9H, (CH3)3): 1.10 (m, 2H, H2"). Mass Spectrum (ES. +ve) m/z 900
(10%) [MH+], 700 (100%). HRMS calcd for C5iH58N5O10 900.4184. found 900.4179.

WO 2006/074501 PCI7AU2005/001444
196.
(3jR)-3-(6-(2-[2'-alIyloxy-{l,l'}-(S)-binaphthalen-2-yloxy])-l,4-diaza-3-(3[{di-tert-
butoxycarbonyl}guanidino]propyl)-2,5-dioxohexyI)-A^-benzyIoxybenzamide (154)


To a solution of 161 (51 mg, 0.067 mmol) in DCM (3
mL) was added Nl-tert-
butoxycarboxamido(trifluoromcth-
ylsulfonylimino)methyl propanamide (39 mg, 0.10
mmol), and triethylamine (0.1 mL). The resulting
solution was allowed to stir for 16 hr under N2. The
solvent was evaporated and the crude product was
10 purified by flash column chromatography (15:1, DCM/MeOH) to yield the title compound (58 mg, 0.060 mmole,
90%) as a white solid. Mp 1120C. 1H NMR (CDCl3,3OO MHz): 5 9.05 (s, IH, ArH): .25 (bs, IH, NH): 7.90 (m, 4H,
ArH); 7.31 (m, 16H, ArH); 6.34 (d, J= 7.5 Hz, IH, NH); 5.63 (m, IH, H2"'): 5.00 (s, 2H, ArCH2, 4.89 (m, 2H,
H3"'): 4.51 (m, 4H, H6' and Hl"'); 4.25 (m, IH, H3'); 3.23 (m, 2H, H3"); 1.65 (m, 2H, HI"); 1.50 (s, 9H, (CH3)3);
1.44 (s, 9H, (CH3)3); 1.10 (m, 2H, H2"). Mass Spectrum (ES, +ve) m/z 987 (100%) [MNa+], 965 (90%) [MH+].
15 FIRMS calcd for C55H61N6O10 965.4449, found 965.4422.
Methyl (3iR)-3-(6-(2-[2'-alIyIoxy-{l ,1 '}-(S)-binaphthafen-2-yloxy])-3-(3-aminopropyl)-l ,4-diaza-2,5-
dioxohexyl)benzoate hydrochloride(155)


The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 146 (56 mg, 0.077
mmol) to yield 155 (38 mg, 0.057 mmol, 74%) as a highly
hydroscopic cream solid. 1H NMR (CD3OD 300 MHz):  8.02
(m, 2H, ArH); 7.92 (m, 2H, ArH); 7.75 (m, 2H, ArH); 7.34 (m,
8H, ArH); 7.06 (m, 2H, ArH); 5.71 (m, IH, H2'"); 4.90 (m, 2H, H3"'); 4.59 (m, 5H, H6', HI"' and H3'): 3.93 (s,
3FI, OCH3); 2.76 (m, 2H, H3"); 1.67 (m, 2H, HI"); 1.30 (m, 2H, H2"). 13C NMR (CD3OD,75 MHz):  170.9, I-CO:
170.6, C5': 168.1, C2'; 155.4, ArC; 154.1, ArC; 139.8, C21"; 138.0, ArC; 135.1, ArC; 134.9, ArC: 132.1, ArCH:
131.5, ArC: 131.3, ArC: 131.0, ArCH: 130.8, ArCH: 130.2, ArCH; 129.3, ArC: 129.2, ArCH: 127.6, ArCH: 127.3,
ArCH: 127.1, ArCH; 126.4, ArCH; 126.3, ArCH; 126.0, ArCH; 125.5, ArCH; 125.3, ArCH; 124.8, ArCH; 122.1,
ArC; 121.8, ArC: 117.0, C3"1; 117.0, ArCH; 116.2, ArCH: 70.9, CT"; 67.4, C61: 53.LH31: 52.6, OCH,:40.1, C3":
30.3, C2"; 24.5, CT. Mass Spectrum (ES, +ve) m/z 632 (100%) [M+]. HRMS calcd for C3SH38N,O6 632.2761,
found 632.2777.

WO 2006/074501 PCT/AU2005/001444
197.
Methyl (3/0-3-(6-(2-[2'-aUylovy-{l,l'}-(S)-binaphthalen-2-yloxy])-l,4-(liaza-3-(3-guanidylpropyl)-2^-
dioxohexyl)benzoate hydrochloride (156)


The title compound was synthesized using the general iV-Boc
deprotection procedure (Procedure A), from 151 (49 mg, 0.056
mmol) to yieid i56 (32 M 045 mmol 8o%-, as acream soiid,
Mp 124-1260C. 1HNMR (CD3OD,300 MHz):  8.28 (s, IH,
ArH); 7.90 (m, 4H, ArH); 7.32 (m, 9H, ArH); 7.07 (m, 2H, ArH);
5.73 (m, IH, H2"'); 4.97 (m, 2H, H3'"); 4.52 (m, 5H, H6', HI'" and H3'); 3.92 (s, 3H, OCH3): 3.01 (m, 2H, H3");
1.63 (m, 2H, HI"); 1.17 (m, 2H, H2"). 13C NMR (CD3OD 75 MHz): . 171.0, 1-CO; 170.4, C5'; 168.0, C2'; 158,A,
CN3: 155.4, ArC; 154.2,ArC; 140.0, C2"'; 138.8, ArC; 135.1, ArC; 135.0, ArC; 132.0. ArCH: 131.3, ArC: 131.1,
ArC; 131.0, ArCH; 130.7, ArCH; 130.2, ArCH; 129.4, ArC; 129.3, ArCH; 127.7, ArCH; 127.6, ArCH; 126.4,
ArCH; 126.3, ArCH; 126.1, ArCH; 126.0, ArCH; 125.9, ArCH; 125.4, ArCH; 125.4, ArCH: 122.0, ArC; 121.9,
ArC; 117.2, C3"'; 117.0, ArCH; 116.4, ArCH; 70.8, Cl'"; 69.4, C6'; 53.5, H3'; 52.9, OCH3;41.8, C3"; 30.6, C2";
25.8, Cl". Mass Spectrum (ES, +ve) m/z 698 (25%) [MNa+],413 (100%). HRMS calcd for C39H40N5O6 674.2979,
found 674.2979.
Benzyl (3JR)-3-(6-(2-[2'-allyloxy-{l,l}-(S)-binaphthaIen-2-yIoxyl)-3-(3-aminopropyl)-l,4-diaza-2,5-
dioxohexyl)benzoate hvdrochloride (157)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 148 (35
mg, 0.043 mmol) to yield 157 (30 mg, 0.040 mmol, 93%) as
a highly hydroscopic cream solid. 1H NMR (CD3OD,SOO
MHz):  8.25 (s, IH, ArH); 7.80 (m, 7H, ArH); 7.28 (m, 1IH, ArH); 5.58 (m, IH, H2"'); 5.27 (s, 2H, ArCH2);4.79
(m, 2H, H3'"): 4.46 (m, 5H, H6', HI'" and H3'); 2.68 (m, 2H, H3"); 1.59 (m, 2H, HI"); 1.22 (m, 2H, H2"). "C
NMR (CD3OD, 125 MHz): . 171.2, 1-CO; 169.8, C5'; 167.2, C2'; 153.9, ArC: 152.8, ArC: 137.2, C2'"; 136.4, ArC:
133.7, ArC: 133.6. ArC: 133.1, ArCH: 131.0, ArCH; 129.2, ArC; 129.0, ArC; 128.4, ArCH; 128.2, ArCH; 128.0,
ArCH: 127.0, ArCH: 126.8, ArCH; 126.6, ArCJH: 126.4, ArCH; 125.2, ArCH: 126.0, ArCH: 125.6, ArCH; 125.2,
ArCH; 124.4, ArCH: 123.9, ArCH: 123.0, ArC: 122.8, ArC; 121.0, ArCH: 120.8, ArCH; 119.5, ArC; 117.2, ArC;
116.2. C3"': 115.0. ArCH: 112.3. ArCH: 70.2, Cl"': 67.7, C6': 51.2, C3'; 40.4, C3"; 32.8, C2": 23.0, Cl". Mass
Spectrum (ES, +ve) nv'z 750 (35%) [MK+], 360 (100%). HRMS calcd for C44H42N3O6 708.3074. found 708.3062.

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198.
Benzyl (3«)-3-(6-(2-[2'-aIhloxy-{l,l'}-(S)-binaphthaIen-2-yloxy])-1,4-diaza-3-(3-«uanidylpropyl)-2,5-
dioxohexyl)benzoate hydrochloride (158)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 152 (15
mg, 0.016 mmol) to yield 158 (6 mg, 0.0076 mmol, 48%) as
a highly hydroscopic cream solid. 1H NMR (CD3OD, 500
MHz):  8.22 (s, IH, ArH); 7.79 (m, 7H, ArH); 7.25 (m,
13H, ArH); 5.59 (m, IH, H2"'); 5.27 (s, 2H, ArCH2);4.80
(m, 2H, H.V"); 4.47 (m, 4H, HI'" and H6'): 4.28 (dd, J =5.0, 7.0 Hz, IH, H3'); 2.92 (m, 2H, H3"); 1.54 (m, 2H,
HI"): 1.08 (m, 2H, H2"). 13C NMR (CDC13 125 MHz): 5 169.8, 1-CCX 168.9, C5': 166.4, C2': 153.4, ArC; 152.7,
ArC; 137.5, C2'"; 136.2, ArC: 133.4, ArC; 133.3, ArC; 133.2, ArCH; 131.4, ArC; 131.2, ArC: 130.5, ArCH; 130.4,
ArCH: 129.7, ArCH; 129.4, ArC; 128.8, ArCH: 128.5, ArCH; 128.7, ArCH: 128.4, ArCH: 126.9, ArCH; 126.8,
ArCH: 126.2, ArCH; 125.9, ArCH; 125.6, ArCH: 124.8, ArCH; 124.6, ArCH; 124.5, ArCH; 121.7, ArCH; 121.2,
ArC; 120.9, ArC; 119.6, ArC; 116.9, C3"'; 116.5, ArCH; 114.7, ArCH; 70.2, CT"; 68.5, C6'; 66.9, ArCH2; 52.8,
C3'; 40.3, C3"; 29.8, C2": 25.3, Cl". Mass Spectrum (ES, +ve) m/z 750 (100%) [M+]. HRMS calcd for C4JH44N5O6
750.3292, found 750.3273.
AIIyl(3i?)-3-(6-(2-T2'-allyloxy-l,l'}-(S)-binanhthalen-2-vloxyl)-3-(3-aininopropyl)-l.4-dia2a-2,5-
dioxohexyl)benzoate hydrochloride (159)


The title compound was synthesized using the general N-Boc
deprotection procedure (Procedure A), from 149 (8mg, 0.011
mmol) to yield 159 (7 mg, 0.010 mmol, 92%) as a highly
hydroscopic cream solid. 1H NMR (CDCl3 300 MHz):  8.20
(s, IH, ArH): 7.89 (m, 7H, ArH); 7.26 (m, 8H, ArH); 6.02 (m,
IH, CH-ester); 5.62 (m, IH, H2'"); 5.34 (dd, J= 1.5, 15.5 Hz, IH, H3a-ester); 5.20 (dd, J = 1.5, 10.5 Hz, IH, H3b-
ester); 4.83 (m, 2H, H3'"); 4.81 (m, 2H, Hl-ester); 4.50 (m, 5H, H6\ H3' and HI'"); 2.68 (m, 2H, H3"); 1.59 (m,
2IT, HI"): 1.12 (m, 2H, H2"). "C NMR (CDC1, 75 MHz):  169.5, 1-CO: 169.2, C5'; 166.0, C2'; 154.2, ArC; 152.6,
ArC; 138.4, ArC; 133.9, C2-ester; 133.8, C2'": 133.7, ArC; 132.5, ArC; 131.2, ArC: 130.9, ArCH: 130.4, ArCH;
129.9, ArC; 129.7, ArC: 129.6, ArCH; 128.9, ArCH; 128.4, ArCH; 128.2, ArCH; 126.9, ArCH: 126.0, ArCH; 125.8,
ArCH: 125.4, ArCH: 125.3, ArCH: 124.6, ArCH: 124.5, ArCH: 124.0, ArCH; 120.8, ArC; 119.8, ArC; 118.5, C3-
ester; 116.8, CT": 116.1, ArCH: 114.9, ArCH: 70.7, Cl-ester, 68.7, Cl"': 66.4, C6'; 52.2, C3'; 39.3, C3": 28.6,
C2"; 26.2. CT". Mass Spectrum (ES, +ve) m/z 698 (30%) [MK+], 123 (100%). HRMS calcd for C40,H40N3O6
658.2917, found 658.2918.

WO 2006/074501 PCT/AU2005/001444
199.
AIlyl(3R)-3-(6-(2-[2'-allyIoxy-{I,l'}-(S)-binaphthalcn-2-yloxy])-l,4-diaza-3-(3-guanidinopropyl)-2,5-
dioxohexyl)benzoate hydrochloride (160)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 153 (40 mg,
0.044 mmol) to yield 160 (11 mg, 0.015 mmol, 34%) as a
highly hydroscopic cream solid. 1HNMR (CD3OD, 500
MHz):  8.38 (s, 1H, ArH); 7.99 (t, J= 7.5 Hz, 2H, ArH);
7.88 (t, J= 7.5, 2H, ArH); 7.76 (t, J= 8.0 Hz, 2H, ArH);
7.52 (d, J = 9.0 Hz, IH, ArH); 7.45 (d, J = 9.0, IH, ArH); 7.40 (t, J = 8.0 Hz, III, ArH); 7.3 1 (dd, J = 7.0, 14.5 Hz,
2H, ArH); 7.19 (t, J = 7.0 Hz, 2H, ArH); 7.07 (m, 2H, ArH); 6.82 (d, J = 8.0 Hz. IH, NH): 6.04 (m, IH, CH-ester);
5.70 (m, IH, H2'"); 5.30 (m, 2H, H3-ester); 4.92 (m, 2H, H3"'); 4.53 (m, 6H, H6\ Hl-ester and HI'"); 4.43 (m, IH,
H3'): 3.04 (m, 2H, H3"): 1.68 (m, 2H, HI"); 1.20 (m, 2H, H2"). 13C NMR (CD3OD 125 MHz): . 171.0, 1-CO;
167.3, C2'; 158.4, CN3; 155.3, ArC: 154.0, ArC; 139.9, ArC; 135.1. C2-ester; 135.0, C2'"; 134.8, ArC: 131.9, ArC;
130.9, ArCH; 130.9, ArC; 130.8, ArC; 130.1, ArCH; 129.2, ArCH; 129.1, ArCH; 127.6, ArCH; 127.5, ArCH; 126.3,
ArCH. 126.2, ArC: 125.8, ArCH; 125.7, ArCH; 125.7, ArCH; 125.3, ArCH; 124.9, ArCH; 122.2, ArC; 122.1,
ArCH; 121.8, ArCH; 120.4, ArC; 118.6, C3-ester; 117.1,C3'"; 117.0,ArCH; 116.1, ArCH: 72.4, Cl-ester; 70.9,
Cl"; 69.4, C6'; 66.7, ArCH2; 53.5, C3'; 41.8, C3"; 30.4, C2"; 25.6, Cl". Mass Spectrum (ES, +ve) m/z 700 (100%)
(M+]. HRMS calcd for C41H42N5O6 700.3135, found 700.3129.
(3/?)-3-(6-(2-[2'-allyloxy-{l,l'}-(S)-binaphthalen-2-yloxy])-3-[(3-aminopropyl]-1,4-diaza-2,5-dioxohexyl)- N-
bcnzy loxybenzamidehydrochloride(161)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 150 (73
mg, 0.089 mmol) to yield 161 (67 mg, 0.088 mmol, 99%)
as a hydroscopic white solid. 1H NMR (CD3OD,soo
MHz):   7.50 (m, 2OH. ArH); 5.63 (m, IH, H2'"): 4.90 (m, 2H, H3'"); 4.46 (m, 6H, H6', HI'" and ArCH2); 3.90
(m, IH, H3'); 3.23 (m, 2H, H3"); 1.62 (m, 2H, HI"); 1.15 (m, 2H. H2"). "C NMR (CD3OD,75 MHz):  170.7, 1-
CO: 170.5, C5'; 167.7, C2'; 155.4, ArC: 154.0, ArC; 139.9, C2'"; 137.3, ArC; 135.1, ArC: 134.9, ArC; 134.8,
ArCH; 134.1, ArC; 131.6, ArC; 131.0, ArCH: 130.9, ArCH: 130.8, ArCH: 130.6. ArCH; 130.4. ArCH: 130.2,
ArCH: 129.6, ArCH; 129.5, ArCH: 129.3, ArCH: 129.2, ArCH: 127.8, ArCH: 127.6, ArCH: 126.8, ArCH: 125.6.
ArCH; 125.2, ArCH; 123.8, ArC; 121.9,ArC: 120.6,ArCH; 120.2, ArCH: 118.8,ArCH: 118.4, ArCH: 117.4, C3"';
116.6. ArC: 79.2, CT"; 71.0, ArCH2;69.5, C6'; 53.2, C3': 40.0, C3"; 30.3, C2": 24.5, Cl". Mass Spectrum (ES,
+ve) m/z 723 (20%) [M+], 360 (100%). HRMS caled for C44H43N4O6 723.3183, found 723.3137.

WO 2006/074501 PCT/AU2005/001444
200.
(3R)-3-(6-(2-[2'-allyIoxy-{l,l'} ..(S)-binaphthaIen-2-yloxy])-l,4-diaza-3-[(3-guanidinopropyI]-2,5-(dioxohexyl)-
iV-benzyIoxybenzamidehydrochloride(162)


The title compound was synthesized using the general N-
Boc deprotection procedure (Procedure A), from 154 (16
mg, 0.017 mmol) to yield 162 (7 mg, 0.0087 mmol, 51%)
as a cream solid. Mp 142°C. 1H NMR (CD3OD, 300
MHz):  7.95 (m, 4H, ArH); 7.33 (m, 16H, ArH); V, 5.60
(m, IH. H2'"); 4.96 (m, 2H, H3"'): 4.49 (m, 6H, H6', H1" and ArCH2); 3.97 (m, IH, H3'): 3.04 (m, 2H, H3"); 1.66
(m,2H,Hl"); 1.20 (m, 2H, H2"). 13CNMR (CD3OD,75 MHz):  172.6, 1-CO; 171.1, C5'; 167.7, C2'; 158.4, CN3;
155.4, ArC; 154.0, ArC; 139.8, C2"'; 136.8, ArC; 135.1, ArC; 135.0, ArC; 134.9, ArCH; 134.0, ArC; 131.4, ArC;
130.9, ArCH; 130.9, ArCH; 130.8, ArCH; 130.4, ArCH; 130.2, ArCH; 130.0, ArCH; 129.7, ArCH; 129.5, ArCH;
129.3, ArCH; 129.2, ArCH; 127.6, ArCH; 127.5, ArCH; 126.4, ArCH; 125.9, ArCH; 124.6, ArC; 123.8, ArC; 121.9,
ArC; 120.4, ArCH; 120.3, ArCH; 118.8, ArCH; 118.0, ArCH; 117.0, C3'"; 116.2, ArC; 79.2, Cl"'; 71.0, ArCH2;
69.4, C6'; 53.6, C3'; 41.8, C3"; 30.5, C2"; 25.7, Cl". Mass Spectrum (ES, +ve) m/z765 (20%) [M+], 102 (100%).
HRMS calcd for C45H45N6O6 765.3401, found 765.3375.
(3R)-(3-(3-aininopropyl)-l,4-diaza-7-oxa-2,5-dioxohexyl-3-(6-(2-I2'-propyloxy-{l,l'}-(S)-binaphthalen-2-
yloxy-N-hydroxybenzamide hydrochloride (163)



To a solution of 150 (28 mg, 0.034 mmol) in THF (3 mL) was
added palladium on activated carbon (15 mg). The resulting
mixture was flushed with hydrogen gas and allowed to stir for 16
h. The mixture was filtered through celite and evaporated to
dryness. This intermediate product was then subjected to the
general acid deprotection procedure (Procedure A) to yield the title compound (16 mg, 0.024 mmole, 70%) as a
white solid. Mp 1160C. 1H NMR (CD3OD,500 MHz):  7.89 (m, 5H, ArH); 7.30 (m, 9H, ArH); 4.56 (m, 2H, H6');
4.08 (m, IH, H3'); 3.88 (m, 2H, HI"'); 3.66 (m, 2H, H3"); 1.67 (m, 2H, HI"); 1.35 (m, 4H, H2" and IT2"'); 0.76 (m,
3H, H3'"). "CNMR (CD3OD, 125 MHz):  170.9, 1-CO; 170.7, C5'; 166.3, C2'; 155.9, ArC; 154.1, ArC; 139.7,
ArC; 135.3, ArCH; 135.1, ArCH; 131.0, ArC; 130.9, ArCH; 130.7, ArCH; 130.5, ArCH; 130.4, ArC; 130.2, ArC;
130.1, ArCH; 129.5, ArCH; 129.3, ArCH; 129.1, ArCH: 127.5, ArCH; 126.9, ArCH: 126.4, ArCH; 125.9, ArCH:
125.6, ArCH; 125.3, ArC; 124.7; ArC; 124.5, ArC; 117.0, ArCH; 116.9, ArCH; 116.2, ArC: 72.1, C6': 69.5, CT";
53.1, C3'; 40.0, C3"; 30.4, C2": 24.8, C2'": 23.7, Cl"; 10.5, C3"\ Mass Spectrum (ES, +ve) m/z 636 (50%) [M+],
623 (100%). HRMS calcd for C37H39N4O6 635.2870, found 635.2863.

WO 2006/074501 PCT/AU2005/001444
201.
(3/.)-(l,4-diaza-3-(3-guanidinopropyI)-7-oxa-2,5-dioxohexyl-3-(6-(2-[2'-propvloxy-{l,l'}-(S)-binaphthalen-2-
yloxy])- N-hydroxybenzamide hydrochloride (164)


To a solution of 154 (39 mg. 0.040 mmol) in THF (3 mL) was
added palladium on activated carbon. The resulting mixture was
flushed with hydrogen gas and allowed to stir for 16 h. The
mixture was filtered through celite and evaporated to dryness.
This intermediate product was then subjected to the general acid
deprotection procedure (Procedure A) to yield the title compound (24 mg. 0.034 mmole. 84%) as a white solid. Mp
158-1600C. 1H NMR (CD3OD,300 MHz): 9.96 (hs, Hi OH): 7.95 (m. 5H. ArH): 7.24 (m. 9H. ArH): 4.45 (AB q. J
= 14.1 Hz. 2H. H6'). 4.09 (m. IH. H3'): 3.92 (m. 2H. HI'"): 3.03 (m. 2H. H3"): 1.62 (m. 2H. HI"): 1.40 (m. 2H.
H2'"): 1.17 (m, 2H. H2"); 0.51 (t. J =7.2 Hz. 3H. H3"'). 13C NMR (CDCl 3 75 MHz):  170.9. 1-CO: 170.8. C5':
170.8. C2'; 158.5. CN3; 155.9. ArC: 154.0, ArC; 139.9. ArC; 135.2. ArCH: 135.1. ArCH: 131.5. ArC: 131.0. ArC:
130.9. ArCH: 130.7. ArCH: 130.2. ArC; 130.1. ArC; 129.3. ArCH: 129.1. ArCH: 127.6. ArCH: 127.5. ArCH; 126.4.
ArCH: 125.9. ArCH: 125.3. ArCH; 124.7. ArCH; 124.4, ArCH: 124.2. ArCH: 123.6. ArC: 122.0. ArC; 120.3. ArC:
116.9. ArCH: 116.2. ArCH: 72.1. C6'; 69.4. CT"; 52.5. C3'; 41.9. C3"; 30.5. C2"; 25.7. C2'"; 23.7. Cl"; 10.5.
C3'". Mass Spectrum (ES. +ve) m/z 677 (100%) [M+].HRMS caled for C38H41N6O6 677.3088. found 677.3130.
Methyl (2S)-3-(4-hydroxyphenyl)-2-methoxycarboxamidopropanoate (170)


To a solution of methyl (2S)-2-ainmo-3-(4-hydroxyphenyl)propanoate hydrochloride (189 mg.
0.82 mmol) and sodium bicarbonate (210 mg. 2.5 mniol) in THF (3 mL) and water (3 mL) at
OPC was added methyl chloroformate (86 mg. 0.9 mmol) and the resulting mixture was allowed
to stir for 3 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL)
and DCM (2 x 30 mL), The combined organic fractions were dried and evaporated to dryness to
yield the title compound (195 mg, 0.77 mmol. 94%) as a clear oil. which had spectral data in agreement with that
reported. 127 1H NMR (CDCl 3 300 MHz):  6.95 (d. J = 8.7 Hz. 2H. ArH2' and ArH6): 6.73 (d. J = 8.4 Hz. 2H.
ArH3' and ArH5'): 5.31 (d. J = 8.4 Hz. IH. NH); 4.59 (m. IH. H2): 3.71 (s. 311. CH3 NCOOCH 3): 3.65 (s. 3H.
OCH 3): 3.01 (m. 2H. C3). Mass Spectrum (ES. +ve) m/z 254 (100%) [MH+]. HRMS calcd for C 12H16N O5 254.1029.
found 254.1036.
Methyl (2S)-3-(4-aliyloxyphenyl)-2-methoxyearboxamidopropanoate (171)


To a solution of 170(195 mg. 0.77 mmol) in DMF (6 mL) was added K2CO3 (213 mg. 1.54
mmol) and the resulting mixture was allowed to stir at RT under N2 for 20 min before the
addition of ally) bromide (0.14 mL. 1.54 mmol). After 16 h the reaction was quenched with
water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic fractions were
washed with water (5 x 30 mL) and brine (30 mL). The remaining organic fractions were
white solid. Mp 145-146 °C. 1H NMR (CDCl 3 300 MHz):  7.02 (d. J= 8.7 Hz. ArH2' and
ArH6'): 6.83 (d. J= 8.4 Hz. ArH3' and ArH5'): 6.04 (m. IH. H2"): 5.40 (dd. = 1.5. 17.1 Hz. IH. H3a"): 5.27 (dd.

WO 2006/074501 PCT/AU2005/001444
202.
J = 1.2. 10.5 Hz, IH, H3b"). 5.18 (d, J = 7.5 Hz, NH); 4.60 (m, IH, FI2); 4.50 (d, J = 5.1 Hz, 2H, HI"); 3.71 (s, 3H,
NCOOCH 3): 3.66 (s, 3H, OCH,): 3.03 (m, 2H, C3). Mass Spectrum (ES, +ve) m z [MH+]. HRMS calcd for
C15HT,NO5 294.1342, found 294.1346.
(2S)-3-(4-AIlyloxyphenyI)-2-methoxycarboxamidopropanoic acid (172)


To a solution of 171 (220 mg, 0.75 mmol) in THF/water (3:1, 10 mL) was added lithium
hydroxide (63 mg, 1.50 mmol) and the resulting suspension was allowed to stir for 16 h. The
reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation in
vacua. The aqueous layer was washed with DCM (30 mL) to remove unreacted starting
material. The pH of the aqueous phase was adjusted to pH 3 with 10% HCl and the resulting
precipitate was extracted with DCM (3 x 40 mL). The combined organic fractions were dried,
and evaporated to dryness to yield the title compound (186 mg, 0.67 mmol, 89%) as a white
solid. Mp 170-172°C. 1HNMR (CDCl3 300 MHz):  9.39 (bs, IH, COOH); 7.07 (d, J = 8.7 Hz, ArH2' and ArH6');
6.84 (d. J = 8.4Hz, ArH3' and ArH5'); 6.03 (m, IH. H2"): 5.39 (dd, J = 1.2, 17.1 Hz, IH, FI3a"); 5.27 (dd, J = 1.2,
10.5 Hz, IH, H3b"); 4.62 (dd, J = 6.0, 13.2 Hz IH, H2); 4.50 (d, J = 5.4 Hz, Cl"); 3.65 (s, 3H, NCOOCH 3); 3.0K (m,
2H, H3). Mass Spectrum (CI, +ve) m/z 280 (50%) [MH+],220 (100%) [MH+less methoxycarbonate] HRMS calcd
for C14H17NO5 279. 1107, found 279. 1114.
Methyl (2S)-2-benzyIoxycarboxamido-4-pentenoate (173)


To a solution of methyl (25)-2-amino-4- propenoate hydrochloride (422 mg, 2.56 mmol)
and NaHCO3 (645 mg, 7.68 mmol) in THF/water (3 mL/3 mL, 1:1) was added benzyl
chlorofomiate (482 mg, 2.82 mmol) and the mixture was allowed to stir for 16 h. The
reaction was quenched with 3% IIC1 (20 mL) and extracted with DCM (3 x 20 mL).
dried and concentrated to give the title compound (676 mg, 2.56 mmol, 100%) as a clear oil, which had spectral data
in agreement with that reported. 128 [D+ 9.1 (c. 0.15 in CHC13) (lit. [D20 + 6.4 (c. 1.05 in MeOH)) 128 1H NMR
(CDCl3.300 MHz):  7.33 (m, 5H, ArH); 5.69 (m, IH, H4); 5.56 (d, J = 7.8 Hz, IH, NH); 5.12 (m, 4H, ArCH2, C5);
4.47 (m. IH, H2); 3.72 (s, 3FI, OCH3);2.54 (m, 2H, H3). Mass Spectrum (CI, +ve) m/z 264 (20%) [MH+], 113
(100%). FIRMS calcd for Ci4HigNO4 264.12358, found 264.12421.
Methyl (2S,4£/Z)-2-bcnyloxycarboxamido-6-phenyl-4-hexenoatc (174)

10 a solution of 173 (181 mg, 0.69 mmol) mDCM (13.8 mL) was added alylbenzene
(163 mg, 1.38 mmol) and Grubbs' first generation catalyst (28 mg, 0.0345 mmol). The
mixture was heated at reflux for 16 h. The solvent was removed and the crude product
purified by flash column chromatography (4:1, hexane/EtOAc) to yield the title
compound as a 1:1 ratio mixture of E and Z isomers (103 mg. 0.29 mmol, 42%) as a
brown oil. 1H NMR (CDCl3 300 MHz):  7.26 (m. 1OH. ArH): 5.72 (m, IH. H4); 5.42
(m. 2FI. NH and H5): 5.13 (s, 2H, ArCH2O); 5.50 (m, IH. H2): 3.74/3.71 (s, 3H, OCH3 [E & Z]: 3.39/3.34 (d, J =
7.5, 6.6 Hz, 2H, H6): 2.54 (m, 2H. H3). Mass Spectrum (CI, +ve) m/z 354 (20%) [MH+], 263 (100%). HRMS calcd
for C21H24NO4 354.17053, found 354.17077.

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Methyl (2S)-2-amino-6-phenylhexanoatc (175)


To a solution of 174 (118 mg, 0.33 mmol) in THF (30 mL) was added palladium on activated
carbon (62 mg, 0.029 mmol). The flask was evacuated and twice filled with H2 gas before stirring
at RT for 16 h. The reaction mixture was filtered through celite and evaporated to dryness to yield
the title compound (73 mg, 0.33 mmol, 100%) as a light brown oil. 1H NMR (CDCl3,300 MHz):
 7.21 (m, 5H, ArH); 3.71 (m, 6H, OCH3, NH2 and H2); 2.60 (m, 2H, H6); 1.62 (m, 6H, H3, H4
and H5). Mass Spectrum (CI, +ve) m/z 222 (30%) [MH+], 113 (100%). HRMS calcd for Ci3H20NO2
222.14940, found 222.14934.
Methyl (2S,5S)-3-aza-2-benzyl-9-(tert-butoxycarboxamdo)-5-(9H-9-fluorenyImethyloxycarboxamido)-4-
oxononanoate (176)


The title compound was synthesized using the general coupling procedure
(Procedure B) from (lS)-2-phenyl-l-methoxycarbonylethylarnmoniurn
chloride (300 mg, 1.39 mmol) and (2S>6-£er?-butoxycarboxamido-2-(9i H-
9-fluorenylmethyloxy)carboxamido hexanoic acid (769 mg, 1.64 mmol) to
afford 176 (848 mg, 1.35 mmol, 97%) as a white solid. Mp 87-90°C. 1H
NMR (CDCl3,300 MHz):  7.75 (d, J =7.2 Hz, 2H, ArHl" and ArH8);
7.58 (d, J = 7.2 Hz. 2H, ArH4" and ArH5"); 7.39 (t, J =7.2 Hz, 2H, ArH3"
and ArH6); 7.30 (t, J = 6.9 Hz, 2H, ArH2" and ArH7"); 7.21 (m, 2H,
ArH3' and ArH5'); 7.07 (m, IH, ArH4'); 6.61 (d, J =7.2 Hz, IH, NH); 5.56 (d, J= 8.4 Hz, IH, NH); 4.85 (dd, J =
6.3, 14.1 Hz, IH, H2); 5.69 (bs, IH, NH); 4.36 (m, 2H, OCH2W); 4.19 (m, 2H, H5 and H9"); 3.69 (s, 3H, OCH3);
3.09 (m, 2H, m-CEb); 3.04 (m, 2H, H9); 1.77 (m, 2H, H7); 1.63 (m, 2H, H6); 1.42 (s, 911, C(CHj)3); 1.33 (m, 2H,
H8). Mass Spectrum (ES, +ve) m/z 630 (10%) [MH+], 104(100%). HRMS caled for C36H44N3O7 630.3179, found
630.3189.
Methyl (2S,5S)-3-aza-9-(tert-butoxycarboxamido)-5-(9£f-9-fluorenyImethyIoxycarboxamido)-4-oxo-3-(4'-


phenylbutyl)nonanoate (177)
The title compound was synthesized using the general coupling procedure
(Procedure B) from 175 (63 mg, 0.29 mmol) and (2S)-6-tert-
butoxvearboxamido-2-(9/f-9-fluorcnvImcthyloxy)carboxamido hexanoic
acid (113 mg, 0.24 mmol) to afford 177 (138 mg, 0.21 mmol, 86%) as a
clear oil. 1HNMR (CDCl3,300 MHz):  7.73 (d, J =7.2 Hz, 2H, ArHI'"
and ArH8'"); 7.57 (d, J= 5.4 Hz, 2H, ArH4'" and ArH5'"); 7.37 (t, J= 7.8
Hz, 2H, ArH3"' and ArH6""); 7.19 (m. 7H. ArH2", ArHT". ArHl",
ArH2", ArH3", ArH4", ArH5" and ArH6); 6.80 (d, J=7.2 Hz. IH, NH);
5.71 (d, J=7.8 Hz. IH, NH); 4.78 (bs, IH, NH); 4.55 (m, IH, H2); 4.37 (d.
J = 6.9 Hz. 2H. OCH2-W); 4.20 (m, 2H, H5 and H9'"); 3.69 (s. 3H.
OCH3); 3.07 (m, 2H. H9); 2.53 (t, J= 7.8 Hz, 2H. H4'): 1.84 (m. 2H, H7); 1.62 (m. 2H. H6); 1.42 (s. 9H, C(CHj) 3);

WO 2006/074501 PCT/AU2005/001444
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1.36 (m, 2H, H8); 1.26 (m. 4H, H2' and H3'). Mass Spectrum (ES, +ve) m/z 673 (100%) [MH+]. HRMS caled for
C39H50N3O7 672.3649, found 672.3624.
Methyl (2S,5S)-5-amino-3-aza-2-benzyl-9-(tert-butoxycarboxamido)-4-oxononanoate (178)


The title compound was synthesized using the general N-Fmoc deprotecting
procedure (Procedure C) from 176 (836 mg, 1.33 mmol) to afford 178 (142 mg,
0.35 mmol, 26%) as a clear oil. 1H NMR (CDCL3 300 MHz):  7.66 (d, J= 7.8 Hz,
IH, NH); 7.22 (m, 3H, ArH3\ ArH4' and ArH5'); 7.10 (m, 2H, ArH2' and ArH6');
4.83 (m, IH, H2); 4.60 (bs, IH, NH); 3.69 (s, 3H, OCH,); 3.29 (dd, J =4.5, 7.5 Hz,
IH, H5); 3.08 (m, 2H, H2-CH2): 3.06 (m, 2H, H9); 1.67 (m, 2H, H7); 1.46 (m, 2H,
H6); 1.41 (s, 9H, C(CH3)3): 1.24 (m. 2H, H8). Mass Spectrum (ES, +ve) m/z 409
(100%) [MH+],
Methyl (2S,5S)-2-amino-3-aza-9-(tert-butoxycarboxamido)-4-oxo-2-(4-phenylbutyl)nonanoate (179)


The title compound was synthesized using the general N-Fmoc deprotecting
procedure (Procedure C) from 177 (138 mg, 0.21 mmol) to afford 179 (78 mg, 0.17
mmol, 8 1%) as a light brown oil. 1H NMR (CDCl3, 300 MHz):  7.67 (d, J = 8.1 Hz,
IH, NH); 7.22 (m, 5H, ArH); 4.56 (m, 2H, H2 and H5); 3.72 (s, 3H, OCH3); 3.11
(m, 2H, H9); 2.60 (t, J = 7.5 Hz, 2H, H4'); 1.83 (m, 2H, H7); 1.66 (m, 6H, HI', H2'
and H3'); 1.44 (s, 9H, C(CH3);.): 1.29 (m, 2H, H8); 0.86 (m, 2H, H6). Mass
Spectrum (ES, +ve) m/z 450 (100%) [MH+].HRMS calcd for C24H40N3O5 450.2968,
found 450.2950.
Methyl (2S,55,8S)-8-(4-aIIyloxybenzyl)-3,6,9-triaza-2-benzyl-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-
trioxoundecanoate (180)


The title compound was synthesized using the general peptide coupling
procedure (Procedure B) from 16 (76 mg, 0.29 mmol) and 178 (142 mg, 0.35
mmol) to afford 180 (135 mg, 0.21 mmol, 72%) as an off-white solid. Mp
122-126°C. 1HNMR (CDCl3 300 MHz): 7.24 (m, 3H, ArHT, ArH4' and
ArH5'): 7.12 (m, 2H, ArH2' and ArH6'); 7.05 (d, J = 8.7 Hz, 2H, ArH2"' and
ArH6'"; 6.79 (d,J = 8.4 Hz. IH, ArH3"' and ArH5'": 6.50 (d. J = 6.9 Hz, IH.
NH); 6.01 (m, IH, H2""): 5.37 (dd, J = 1.5. 17.1 Hz, IH, H3a""); 5.25, J = 1.2,
10.5 Hz, IH, H3b""): 4.87 (bs, IH, NH): 4.79 (m. IH, H2); 4.68 (m, IH, H5):
4.45 (d, J =5.1 Hz, 2H, HI""): 4.43 (m, IH. H8): 3.69 (s, 3H, OCH3): 3.06 (m,

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411, 2-CH, and 8-CH2); 2.93 (m, 2H, H4"); 1.95 (s, 3H, HI1); 1.75 (m, 2H, H2"); 1.55 (m, 2H, HI"); 1.32 (s, 9H,
C(CHj)3); 1.26 (m. 2H, H3"). Mass Spectrum (ES, +ve) m/z 653 (10%) [MH+]; 104 (100%). HRMS caled for
C35H45N4O8Na 675.3370, found 675.3358.
Methyl (2S,5S,8S)-2-aIlyl-8-(4-alIyIoxybenzyI)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-II-oxa-4,7,10-
trioxododecanoate (181)


The title compound was synthesized using the general peptide coupling
procedure (Procedure B) from 24 (340 mg, 0.95 mmol) and 172 (148 mg,
0.53 mmol) to afford 181 (264 mg, 0.43 mmol, 81%) as an off-white solid.
Mp90-91°C. 1HNMR (CDC13 300 MHz): 57.08 (d, J=9.0Hz, 2H, ArH2"'
and ArH6'"): 7.00 (d, J= 7.5 Hz, IH, NH): 6.81 (d, J= 8.7 Hz, 2H, ArH3'"
and ArH5'"); 6.03 (m, IH, H2""); 5.63 (m, IH, H2'); 5.39 (dd, J = 1.5, 17.1
Hz, IH, H3a""); 5.27 (dd J = 1.5, 10.8 Hz, IH, H3b""): 5.12 (m, 2H, H3');
4.93 (bs, IH, NH); 4.61 (m, IH, H2); 4.51 (m, 2H, H5 and H8); 4.49 (d, / =
5.1 Hz, 2H, HI""); 3.74 (s, 3H, NCOOCH3); 3.62 (s. 3H. OCH,); 3.00 (m,
4H, H4" and ArCH2); 2.51 (m, 2H, HI'); 1.80 (m, 2H, H2"); 1.60 (m, 2H, HI"); 1.43 (s, 9H, C(CHs)3); 1.28 (m, 2H,
H3"). Mass Spectrum (ES,+ve) m/z 619 (60%) [MH+];641 (100%) [M++Na]. HRMS calcd for C31H46N4O4Na
641.3162, found 641.3184.
Methyl (2S,5S,8S)-8-(4-aIlyloxybenzyl)-3,6,9-triaza-5-(4-pert-butoxycarboxamido]butyI)-4,7,10-trioxo-2-(4-
phenylbutyl)undccanoatc (182)


The title compound was synthesized using the general peptide coupling
procedure (Procedure B) from 16 (37 mg, 0.14 mmol) and 179 (78 mg. 0.17
mmol) to afford 182 (72 mg, 0.10 mmol, 74%) as an off-white solid. Mp 112-
117°C. 1H NMR (CDCl3 300 MHz): 5 7.20 (m, 5H, ArH); 7.09 (d, J = 8.4 Hz,
2H, ArH2"" and ArH6""); 6.82 (d, J= 8.7 Hz, 2H, ArH3"" and ArH5""); 6.45
(m, 2H, NH); 6.09 (m, IH, NH); 6.02 (m, IH, H2'''); 5.39 (dd, J= 1.5, 17.1 Hz1
IH, H3a'''); 5.27 (dd, J 1.5, 10.5 Hz, IH, H3b'""); 4.79 (bs, IH, NH); 4.60 (m,
IH, H2); 4.48 (m, 3H, H5 and HI'''); 4.35 (m, IH, H8); 3.72 (s, 3H, OCH3);
3.02 (m, 4H, H4'", 8-CH2); 2.60 (t, J = 8.1 Hz, 2H, H4'); 1.97 (s, 3H, HID;
1.84 (m, 2H, H2"'); 1.66 (m, 6H, HI', H2' and H3'); 1.43 (s, 9H, C(CH3)3);
1.32 (m, 4H, HI'" and H3). Mass Spectrum (ES, +ve) m/z 695 (100%) [MH+].
HRMS calcd for C38H55N4O8 695.4020. found 695.4008.

WO 2006/074501 PCT/AU2005/001444
206.
Methyl (2S,SS,8S)-8-(4-aIIyIoxybenzyl)-3,6,9-triaza-2-benzyl-5-(4[{di-ter/-butoxycarbonyl}guanidino]butyl)-
4,7,10-trioxoundecanoate (183)


To a solution of 180 (125 mg. 1.19 mmol) in DCM (2 mL) was added TFA (2
mL) and the resulting mixture was allowed to stir for 3 h. The solvent was
removed by evaporation and the oily intermediate was precipitated by the
addition of diethyl ether (5 mL) which was decanted and the solid product was
dried in vacua. T o the salt was added Nl-tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide(82
mgg., 6).2211 mmmooll)),, trriieetthhyyllanmmiinnee (00.11 mLL)) and DCCMM (33 mL)).. Three ressuullttiinngg
solution was allowed to stir for 16 h under N2.The solvent was removed by
evaporation in vacuo, and the crude product was purified by flash
chromatography (20:1. DCM/ MeOH) to yield the title compound (177 mg. 0.21 mmol. 100%) as an off white solid.
M p 228 °C. 1H NMR (CDCl3 300 MHz): 5 7.26 (m, 3H. ArH3', ArH4' and ArH5'): 7.08 (m. 4H. ArH2\ ArH6ArH2'' and ArH6'"): 6.81 (d. J= 8.7 Hz. 2H. ArH3'" and ArH5'"): 6.46 (t. J = 8.4 Hz. 2H. NH); 6.21 (d. J = 7.8
Hz. IH. NH): 6.00 (m. 1H. H2""): 5.37 (dd. J=1.2. 16.8 Hz. IH. H3a""): 5.26 (dd, J=1.5. 10.8 Hz. IH. H3b""):
4.78 (m. IH. H2): 4.61 (m. IH. H5): 4.47 (d. J = 5.4 Hz. 2H, HI""): 4.32 (m. IH. H8); 3.71 (s. 3H. OCH3); 3.31 (m.
2H. 2-CH2);3.08 (m. 2H. 8-CH2): 2.97 (d. J = 6.9 Hz. 2H. H4"): 1.98 (s. 3H. II 11): 1.76 (m. 2H. H2"): 1.52 (m. 2H.
HI"); 1.48 (s. 18H. C(CHa) ,); 1.25 (m. 2H. H3"). Mass Spectrum (ES. +ve) m/z 795 (20%) [MH+|; 104 (100%).
HRMS calcd for C41H50N6O10 795.4293, found 795.4310.
Methyl (2S,5S,8S)-8-(4-allyIoxybenzyl)-3,6,9-triaza-2-benzyl-5-(4-guanidinobutyl)-4,7,10-trioxoundecanoate
hydrochloride (165)


The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A) from 183 (157 mg, 0.20 mmol) to yield 165 (93 mg.
0.15 mmol, 74%) as a white solid. Mp 175-179°C. 1H NMR (CD3OD 300 MHz):
 7.20 (m, 5H, ArH'); 7.11 (d, J = 8.1 Hz, 2H, ArH2'" and ArH6"'); 6.78 (d. J =
8.4 Hz, 2H, ArH3"' and ArH5"'; 6.01 (m, IH, H2""); 5.35 (dd, J= 1.2. 16.8 Hz.
IH,H3a""); 5.20, /= 1.5,10.8 Hz, IH, H3b""); 4.60 (dd, J = 5.7, 8.1 Hz. IH.
H2); 4.45 (m, IH, H5); 4.47 (d, J = 5.4 Hz, 2H, HI""); 4.34 (dd, J = 4.8. 8.4 Hz.
IH, H8); 3.65 (s, 3H, OCH3); 3.05 (m, 4H, 2-CH2 and 8-CH2); 2.77 (m. 2H.
H4"); 1.90 (s, 3H, H11); 1.73 (m, 2H, H2"); 1.56 (m, 2H, HI"); 1.37 (m. 2H.
H3"). 13C NMR (CD3OD,75 MHz): 5 173.6. C7: 173.4. C4; 173.3. C2: 173.0. CIO: 158.7. CN3: 158.4. ArC4"':
137.8. ArCH2' and .ArCH6; 134.8. C2"": 131.0. .ArCH2'" and ArC6'"; 130.3. ArCl'"; 130.1. ArCH4: 129.4.
ArCl': 127.8. .ArCH3' and ArCH5': 117.2. C3""; 115.6. .ArCH3'" and ArCH5'"; 69.7 Cl"": 56.6. C2: 55.2. C5:
54.0. OCH3; 52.7. C8: 42.2. C4": 38.3. 2-CH2; 37.8. 8-CH2: 32.6. Cl"; 28.2. C3"; 23.6. CH: 22.5. CT. Mass
Spectnim (ES. +ve) m/z 596 (100%) [MH +]. HRMS calcd for C31H43N6O6 595.3244. found 595.3225.

WO 2006/074501 PCT/AU2005/001444
207.

Methyl (2S,S,8S)-2-alIyl-8-(4-allyIoxybenzYl)-3,6,9-triaza-5-(4-{[di-tert-butoxycarbonyllguanidino}butyI)-ll-
oxa-4,7,10-trioxododecanoate(184)
To a solution of 181 (250 mg, 0.40 mmol) in DCM (3 mL) was added TFA
(3 mL) and the resulting mixture was allowed to stir for 3 h. The solvent was
removed by evaporation in vacuo, and the oily intermediate was precipitated
by the addition of diethyl ether (5 mL) which was decanted and the solid
product was dried in vacuo. To the remaining salt was added Nl-tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methyl propanamide (172
mg, 0.44 mmol), triethylamine (0.5 mL) and DCM (3 mL). The resulting
solution was allowed to stir for 16 h under N2. The solvent was removed and
the crude product was purified by flash chromatography (20: 1. DCM/MeOH)
to yield the title compound (309 mg, 0.40 mmol, 100%) as an off white oil. 1H NMR (CDC13, 300 MHz):  8.33 (bs,
IH, NH); 7.08 (d, J= 8.7 Hz, 2H, ArH2'" and ArH6"'); 6.83 (d, J= 8.7 Hz, 2H, ArH3'" and ArH5'"); 6.69(t. J=6
Hz, 2H, NH); 6.03 (m, IH, H2""); 5.67 (m, IH, H2'); 5.40 (dd, J = 1.2, 17.1 Hz, IH, H3a"")-. 5.33 (d, J =7.8 Hz, IH,
NH); 5.27 (m, J = 1.5, 10.5 Hz, IH, H3,,""); 5.12 (m, 2H, H3'); 4.57 (m, IH, H2); 4.50 (d, J=5.1 Hz, 2H, HI"");
4.40 (m, 2H, H5 and H8): 3.74 (s, 3H, H12). 3.62 (s, 3H, OCH3); 3.35 (t, J = 6.0 Hz, 2H, H4"); 2.99 (m, 2H,
ArCH2); 2.52 (m, 2H, HI'): 1.83 (m, 2H, H2"); 1.57 (m, 2H, HI"); 1.48 (s, 18H, C(CEb)3); 1.32 (m, 2H, H3"). Mass
Spectrum (E S, +vc) m/z 761 (100%) [MH+] HRMS calcd for C37H37N6On 761.4085. found 761.4067.
Methyl (25,5S,8S)-2-alIyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-{guanidmoJbutyl)-11-oxo-4,7,10-
trioxododecanoate hydrochloride (166)


The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A) from 184 (290 mg, 0.38 mmol) to yield 166 (171
mg, 0.29 mmol, 76%) as a highly hydroscopic white solid. 1H NMR (CD3OD,
300 MHz): 5 8.24 (d, J = 7.2 Hz, IH, NH); 8.09 (d, J = 7.8 Hz, IH, NH);
7.13 (d, J = 8.7 Hz, 2H, ArH2"' and ArH6"); 6.82 (d, J= 8.7 Hz, 2H,
ArH3'" and ArH5"'); 6.03 (m, IH, H2""); 5.77 (m, IH, H2'); 5.37 (dd, J =
1.8, 17.4 Hz, IH, H3a""); 5.22 (dd, 7= 1.5, 10.5 Hz, IH, H3b""); 511 (m, 2H,
H3'); 4.50 (d, J = 5.1 Hz, 2H, HI""); 4.42 (m, 2H, H5 and H8); 4.31 (dd, J =
5.4, 9.0 Hz, IH, H2); 3.70 (s, 3H, H12); 3.58 (s, 3H, OCH3); 3.17 (t, J =6.9
Hz, 2H, H4"); 2.91 (m, 2H, ArCH2); 2.52 (m, 2H, H1'); 1.82 (m, 2H. H2").
1.62 (m, 2H, HI"); 1.43 (m, 2H, BB"). 13C NMR (CD3OD 75 MHz): 5 174.0, C7; 173.6, CT; 172.9, C4: 158.5, CN3:
158.2. ArC4"': 158.2, C12; 134.7, C2'; 133.9, C2""; 131.1, ArCH2"' and ArCH6"'; 130.3, ArCl"': 118.9, C3':
117.3.C3""; 114.5, ArCH3'" and ArCH5"': 69.6, CT"": 57.9, C8: 54.2, C5: 53.6, C2: 52.8, OCH,: 42.3, C12: 38.2,
C4": 36.6. ArCH,: 32.7, Cl': 29.2, CT": 23.6, C3"; 15.5. C2". Mass Spectrum (ES. +ve) m/z 658 (100%) [MH+leSs
Cl-]. HRMS caled for C27H41N6O7 561.3037, found 561 .3016.

WO 2006/074501 PCT/AU2005/001444
208.
Methyl (2S,5S,S,8S)-8-(4-aIlyloxybenzyl)-3,6,9-triaza-5-(4[{di-tert-butoxycarbonyl}guanidino]butyl)-4,7,10-
trioxo-2-(4-phenylbutyI)undecanoate (185)


To a solution of 182 (40 mg, 0.058 mmol) in DCM (2 mL) was added TFA (2
mL) and the resulting mixture was allowed to stir for 3 h. The solvent was
removed and the oily intermediate was solidified upon the addition of diethyl
ether (5 mL) which was decanted and the solid product was dried in vacua. To
the remaining salt was added Nl-tert-
butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (34
mg, 0.086 mmol), triethylamine (0.1 mL) and DCM (2 mL). The resulting
solution was allowed to stir for 16 h under N2. The solvent was removed and
the crude product was purified by flash chromatography (20:1, DCM/MeOH)
10 yield the title compound (46 mg, 0.054 mmol, 95%) as an off white solid.
Mp 1980C. 1H NMR (CDC13 300 MHz): 5 7.20 (m, 5H, ArHV. 7.08 (d, J = 8.4 Hz, 2H, ArH2"" and ArH6""; 6.81 (d,
J = 8.4 Hz, 2H, ArH3"" and ArH5""); 6.71 (d, J = 7.8 Hz, IH, NH); 6.45 (d, J = 7.8 Hz, IH, NH); 6.02 (m, IH,
H2'""): 5.38 (dd, J - 1.5, 17.4 Hz, IH, H3a'''); 5.26 (dd, J 1.2, 10.5 Hz, IH, H3b'''); 4.65 (m, IH, H2); 4.47 (d, J =
5.1 Hz. 2H, HI'""); 4.40 (m, 2H, H5 and H8): 3.97 (s, IH, NH); 3.71 (s, 3H, OCH3); 3.37 (bs, 2H,H4'"); 2.98 (m,
2H, 8-CH,);2.59(t, J = 7.8Hz, 2H, H4'); 1.96 (s, 3H, Cl 1): 1.84 (m, 2H, H2'"); 1.63 (m, 6H, HI', H2'and H3');
1.49 (s, 18H, C(CHj)3); 1.36 (m, 4H, Hl'"and H3). Mass Spectrum (ES, +ve) m/z 837 (100%) [MM+]. HRMS calcd
for C44H65N6Oi0 837.4762, found 837.4744.
Methyl (2S,5S,8S)-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-guanidinobutyl)-4,7,10-trioxo-2-(4-
phenylbutyl)undecanoate hydrochloride (167)


The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A) from 185 (40 mg, 0.048 mmol) to yield 167 (18 mg,
0.026 mmol, 56%) as a white solid. Mp 180-188°C. 1H NMR (CD3OD, 300
MHz) 8 8.23 (d, J = 7.2 Hz, IH, NH); 8.08 (d, J = 7.2 Hz, IH, NH); 7.15 (m,
7H, ArH); 6.81 (d, J = 8.7 Hz, 2H, ArH3"" and ArH5""); 6.02 (m, IH, H2''');
5.36 (dd, J = 1.5,17.1 Hz, lH,H3a'"");5.21 (dd, J= 1.5, 10.5 Hz, IH, H3b'''):
4.49 (m, 3H, H2 and HI'""); 4.36 (m, 2H, H5 and H8); 3.68 (s, 3H. OCH3);
3.16 (m, 2H, H4'"); 2.92 (m, 2H, 8-CH2); 2.60 (t, J=7.2 Hz, 2H, H4'); 1.91 (s,
3H, HI 1); 1.82 (m, 2H, H2'"); 1.61 (m, 8H, HI', H2', H3' and HI"'); 1 42 (m,
2H,H3). 13C NMR (CD3OD,75 MHz): 5 174.1, C7; 173.9, C4; 174.4, Cl:
159.0, C10; 158.6, CN3; 143.5, ArC4""; 135.0, ArC1"; 131.2, C2'""; 130.4.
ArCT": 129.4, ArCH2"" and ArCH6""; 129.3. ArCH3" and ArCH5";126.8, ArCH4": 117.4, C3'''; 115.7.
ArCH3"" and ArCH5"": 69.7. Cl''': 56.6, C5: 53.9, C2; 53.7, OCH3; 52.7. C8: 42.3, C4'": 37.9. 8-CH2: 36.6. C4':
32.7. Cl': 32.2, C3'; 32.1. Cl"'; 29.2, C3'"; 26.4, CI1: 23.6, C2": 22.4, C2'". Mass Spectrum (ES. +ve) m/z 638
(100%) [M+].HRMS calcd for C34H49N6O65 637.3714. found 637.3745.

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Di-tert-butyl N-3-butenyliminodicarboxyIate (186)


To a solution of di-tert-butyliminodicarboxylate (868 mg, 4 mmol), cesium carbonate (2.61 g, 8
mmol), and lithium iodide (28 mg, 0.2 mmol) in 2-butanone (20 mL) was added 4-bromobutene
(812 mg, 6mmol) and the mixture was heated at reflux for 48 h. The reaction was allowed to
cool and was quenched with brine (40 mL) and extracted with diethyl ether (3 x 20 mL). The
combined organic fractions were washed with brine (30 mL), dried, and evaporated to yield the
title compound (1.01 g, 3.7 mmol, 93%) as a light brown oil. 1H NMR (CDC13 300 MHz):  5.77
(m, IH, H3); 5.04 (m, 2H, H4); 3.62 (dd, J= 6.0, 8.7 Hz, 2H, HI); 2.30 (in, 2H, H2): 1.51 (s, 18H, 2 x (CH3)3).
Mass Spectrum (ES, +ve) m/z 310 (55%) [MK+],294 (30%) [MNa+],272 (40%) [MH+].IIRMS calcd for
Ci4H26NO4 272.1862, found 272.1848.
tert-Butyl iV-3-butenylcarbamate (187)


To a solution of 186 (708 mg, 2.60 mmol) in DCM (20 mL) was added trifluoroacetic acid (593
mg, 5.20 mmol) and the mixture was allowed to stir for 5 min before being quenched with 2M
NaOH (25 mL) and extracted with DCM (3 x 20 mL). The combined organic fractions were
dried, and concentrated to yield the title compound (429 mg, 2.50 mmol, 96%) as a light brown oil, which had
spectral data in agreement with that reported, 104 1HNMR (CDC13,300 MHZ):  5.75 (m, IH, H3); 5.08 (m, 2H, H4);
4.59 (bs, IH, NH): 3.20 (dd, J =6.3, 12.6 Hz, 2H, HI); 2.24 (dd, J =6.9, 12.6 Hz, 2H, H2); 1.44 (s, 9H, (CHj)3).
Mass Spectrum (ES, +ve) m/z 116 (100%) [MH+IeSS 56 (Boc rearrangement].
Methyl (2S,4BJ/Z)-2-(benzyloxycarboxamido)-7-(tert-butoxycarboxamhlo)-4-heptenoate (188)


To a solution of 187 (220 mg, 1.29 mmol) in DCM (13 mL) was added 173 (169 mg,
0.64 mmol) and Grubbs' first generation catalyst (53 mg, 0.064 mmol). The mixture
was heated at reflux under N2 for 16 h. The solvent was removed and the crude
product purified by flash column chromatography (6.1, hexane/EtOAc) to yield the
title compound (180 mg, 0.44 mmol, 69%) as a brown oil as a 1:1 mixture of E and Z
isomers. []0 24 - 34.6 (c. 0.3 in EtOH). 1H NMR (CDCl3 300 MHz):  7.35 (m, 5H,
ArH): 5.43 (m, 3H, H4, H5, NH); 5.11/5.10 (s, 2H, OCH2Ph[E and Z]): 4.61 (bs, IH, NH); 4.43 (m, IH, H2);
3.75/3.72 (s, 3H, OCH3[E and Z]); 3.11 (m, 2H, H7); 2.47 (m, 2H, H3);. 2.17 (m, 2H, H6); 1.43 (s, 9H, (CH3)3).
Mass Spectrum (ES, +ve) m/z 429 (100%) [MNa+],407 (20%) [MH+].IIRMS calcd for C2iH31N2O6407.2182,
found 407.2171.
Methyl (2S)-2-amino-7-(/ert-butoxycarboxamido)-1-heptanoate (189)


To a solution of 188 (25 mg, 0.061 mmol) in THF (4 mL) was added palladium on
activated carbon (13 mg, 0.0061 mmol) The reaction vessel was evacuated. flushed
with H2 and allowed to stir for 16 h. The resulting crude product was filtered
through celite and evaporated to yield the title compound (15 mg. 0.055 mmol, 90
%) as a clear oil. []D24+ 9.6 (c. 0.1 in EtOH). 1H NMR (CDCl3 300 MHz): 4.55

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(bs, IH, NH); 3.72 (s, 3H, OCH3); 3.44 (t, J = 6.0 Hz, IH, H2); 3.10 (m, 2H, H7); 1.86 (m, 4H, H3, H4); 1.44 (s, 9H,
(CH3)3)-. 1.37 (m, 4H, H5, H6). Mass Spectrum (ES, +ve) m/z 275 (90%) [MH+]; 219 (100%). HRMS calcd for
C13H27N2O4 275.1971, found 275.1967.
(2S)-2,7-Diaminohentanoic acid dihvdrochloride (193)


A solution of 189 (16 mg, 0.058 mmol) in 1OM HCl (3 mL) was allowed to stir for 48 h.
The product was isolated by evaporation and dried over P2O5 to yield the title compound
(14 mg, 0.058 mmol, 100%) as a hydroscopic white solid, which had spectral data in
agreement with that reported, 106 []D22 + 10.9 (c. 0.1 in HC1) (Lit. []D23+14.4)106 1H
NMR (D20 ,300 MHz):  3.90 (t, J= 6.3 Hz, IH, H2); 2.83 (t, J=7.5 Hz, 2H, H7); 1.81
(m, 2H, H3); 1.64 (m, 2H, H5); 1.52 (m, 2H, H6); 1.30 (m, 2H, H4). Mass Spectrum (ES, +ve) m/z 161 (100%)
|M2+].HRMS calcd for C7H17N2O2 161.1290, found 161.1294.
Methyl (2S,5S)-5-(4-allyIoxybenzyl)-3,6-diaza-2-(5-[fert-butoxycarboxamido]pentyl)-4,7-dioxooctanoate (190)


The title compound was synthesized using the general peptide coupling procedure
(Procedure B) from 16 (53 mg, 0.20 mmol) and 189 (65 mg, 0.24 mmol) to afford 190
(103 mg, 0.20 mmol, 100%) as an off-white solid. Mp 96-103°C. 1H NMR (CDC13
300 MHz):  7.11 (d, J = 8.7 Hz, 2H, ArH2" and ArH6"); 6.82 (d, J = 8.7 Hz, 2H,
ArH3" and ArH5"); 6.50 (d, J= 7.8 Hz, iH, NH); 6.03 (m, IH, H2''); 5.39 (dd, J =
1.8, 17.4 Hz, IH, H3a"'); 5.26 (dd, J= 1.8, 9.3 Hz, IH, H3b"'); 4.66 (m, 2H, H2 and
H5); 4.48 (m, 2H, HI"'); 3.69 (s, 3H, OCH3); 2.98 (m, 4H, H5' and ArCH2); 1.96 (s,
3H, H8); 1.75 (m, 2H, HI'); 1.64 (m, 2H, H3'); 1.43 (s, 9H, C(CH3)3); 1.26 (m, 4H,
H2' and H4'). Mass Spectrum (ES, +ve) m/z 520 (100%) [MH+]. HRMS calcd for C27H41N3O7 542.2842, found
542.2855.
(2S.5S)-5-(4-AIlvloxvbenzvl)-3,6-diaza-2-(5-ltert-butoxvcarboxamidolpentyl)-4.7-dioxooctanoicacid (191)


To a solution of 190 (70 mg, 0.13 mmol) in THF/water, 3:1 (8mL) was added lithium
hydroxide monohydrate (11 mg, 0.26 mmol) and the resulting suspension was allowed
to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was
removed by evaporation. The aqueous layer was extracted with DCM (40 mL) to
remove unreacted starting material. The aqueous phase was acidified with 10% HC1
and the resulting precipitate was extracted with DCM (3 x 40 mL). The combined
organic fractions were dried and evaporated to yield the title compound (39 mg. 0.08
mmol, 62%) as a clear oil. 1H NMR (CDCl3 300 MHz):  7.09 (d, J= 8.7 Hz, 2H,
ArH2" and ArH6"): 6.82 (d, J= 8.7 Hz, 2H, ArH3" and ArH5"); 6.05 (m, IH. H2"'V. 5.39(dd. J= 1.8, 17.4Hz, IH.
H3a"'): 5.25 (dd, J = 1.8, 9.3 Hz, IH, H3b"'): 4.63 (t, J= 6.9 Hz. IH. H2): 4.47 (m. 3H, HI'" and H5): 3.05 (m. 4H,
H5' and ArCH,); 1.95 (s, 3H, H8): 1.84 (m, 2H, HI'): 1.69 (m. 2H, H3'): 1.44 (s, 9H. C(CHj)3): 1.28 (m. 4H. H2'
and H4').

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Methvl (2S,5S,8S)-2-allyI-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[tert-butox.vcarboxamido]pentyl)-4,7,10-
trioxoundecanoate (192)
The title compound was synthesized using the general peptide coupling procedure (Procedure B) from 18(14 mg.


0.084 mmol) and 191 (35 mg, 0.07 mmol) to afford 192 (31 mg, 0.048
mmol, 69%) as an off-white solid. Mp 130-136°C. 1H NMR (CDCl3 300
MHz):  7.07 (d, / = 8.7 Hz, 2H, ArH2"' and ArH6'"); 6.80 (d, J = 8.7 Hz,
2H,ArH3'" and ArH5"');6.59 (d, J=8.1 Hz, 1H, NH); 6.49 (d, J = 7.2 Hz,
1H, NH); 6.43 (d, J = 7.5 Hgz, 1H, NH); 6.02 (m, 1H, H2""); 5.67 (m, IH,
H2'); 5.39 (dd, J= 1.5,17.4 Hz, IH, H3a""); 5.26 (dd, 1.5,10.5 Hz, IH,
H3b""); 5.10 (m, 2H, H3'); 4.70 (m, 1H, H2); 4.58 (m, 1H, H5); 4.48 (m,
2H, HI""); 4.41 (m, 1H, H8); 3.73 (s, 3H, OCH3); 3.04 (m, 2H, H5"); 2.98
(t, J = 6.0 Hz, 2H, ArCH2); 2.53 (m, 2H, H1'); 1.96 (s, 3H, H1 1); 1.76 (m,
2H, HI"): 1.58 (m, 2H, H3"): 1.43 (s, 9H, C(CH,)3); 1.28 (m, 4H, H2" and H4"). Mass Spectrum (ES, +ve) m/z 639
(100%) [MNa+],617 (10%) [MH+],517 (95%) [MH+ less Boc]. HRMS calcd for C32H48Na 639.3370, found
639.3371.
Methyl (2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[{di-tert-butoxycarbonyl}guanidinolpentyI)-
4,7,10-trioxoundecanoate (195)


To a solution of 192 (20 mg, 0.032 mmol) in DCM (2 mL) was added
TFA (2 mL) and the resulting mixture was allowed to stir for 3 h. The
solvent was removed and the oily intermediate was solidified upon the
addition of diethyl ether (5 mL) which was decanted and the solid
product was dried in vacuo. To the remaining salt was added Nl-tert-
butoxycarboxamido(trifluoromemylsulfonylimino)methylpropanarnide
(34 mg, 0.086 mmol), triethylamine (0.1 mL) and DCM (2 mL). The
resulting solution was allowed to stir for 16 h under N2. The solvent was
removed and the crude product was purified by flash chromatography
(20:1. DCM/MeOH) to yield the title compound (23 mg, 0.030 mmol, 95%) as a clear oil. 1H NMR (CDCl3 300
MHz): 5 8.31 (bs, IH, NH): 7.08 (d, J = 8.7 Hz, 2H, ArH2'" and ArH6"'): 6.82 (d, J= 8.7 Hz, 2H, ArII3"' and
ArH5"'): 6.72 (d, J= 8.1 Hz, IH, NH): 6.60 (d, J = 7.5 Hz, IH, NH): 6.41 (d, J= 7.8 Hz, IH, NH): 6.03 (m, IH,
H2""): 5.65 (m, IH, H2'): 5.40 (dd. J= 1.5, 17.1 Hz, IH, H3a""): 5.27 (dd, 1.5, 10.5 Hz, IH, H3b""): 5.11 (m, 2H,
H31); 4.66 (m, IH. H2): 4.57 (m, IH, H5): 4.49 (m, 2H, HI""): 4.38 (m, IH, H8): 3.74 (s, 3H, OCH3): 3.34 (m, 2H,
H5"): 2.98 (m, 2H, ArCH2): 2.52 (m, 2H, HI'): 1.97 (s, 3H, HI1): 1.80 (m, 2H, HI"): 1.70 (m, 2H, H3"): 1.49 (s.
18H, C(CHj)3): 1.32 (m, 4H. H2" and H4"). Mass Spectrum (ES, +ve) m/z 759 (100%) [MH+]. HRMS caled for
C38H59NgO10 759.4293. found 759.4272.

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Methyl (2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5'(4-guanidinopentyl)-4,7,10-trioxoundecanoate
hydrochloride (168)


The title compound was synthesized using the general N-Boc deprotection
procedure (Procedure A) from 195 (20 mg, 0.026 mmol) to yield 168 (10 mg,
0.017 mmol, 65%) as a white hydroscopic solid. 1H NMR (CDCl3,300 MHz):
 7.13 (d, J = 8.4 Hz, 2H, ArH2"' and ArH6"'); 6.82 (d, J = 8.4 Hz, 2H,
ArH3'" and ArH5'"); 6.03 (m, IH, H2""); 5.76 (m, IH, H2'); 5.37 (dd, J=
1.5, 17.1 Hz, IH, H3a""); 5.22 (dd, 1.5, 10.5 Hz, IH, H3b""); 5.10 (m, 2H,
H3'); 4.50 (m, 2H, HI""): 4.38 (m, 3H, H2, H5 and H8); 3.69 (s, 3H, OCH3);
3.15 (m, 2H,H5"); 2.92 (m, 2H, ArCH2); 2.51 (m, 2H, HI'); 1.90 (s, 3H,
H11): L78 (i, 2H,H 1"); 1.58 (i, 2H H.3'); L38 (ni, 4H; H 2 and J14 "), 13C
NMR (CDCl3,75 MHz):  174.1, C7; 173.8, Cl; 173.3, C4; 168.9, CIO; 159.0, CN3; 158.6, ArC4'"; 134.4, C2';
131.4. C2""; 131.2, ArCH2'" and ArCH6'"; 130.4, ArCT"; 118.9, C3'; 117.4, C3""; 115.7, ArCH3'" and ArCH5'";
69.8, Cl""; 56.5, C5; 54.1, OCH3; 53.6, C8; 52.7, C2; 42.2, C5"; 37.9, ArCH2; 36.7, Cl'; 33.1, Cl"; 29.6, C4"; 27.1,
C3"; 26.0, CI1; 22.3, C2". Mass Spectrum (ES, +ve) m/z 559 (100%) [M+]. HRMS caled for C28H43N6O6 559.3244,
found 559.3226.
Antibacterial Screening Methodology for Compounds of Example 2
Bacterial Strain
■ All assays used the Staphylococcus aureus strain ATCC 6538P.
Assays described in Chapter 5 additionally used the vancomycin-resistant enterococci and vancomycin-
sensitive enterococci strains E/243, E/449, E/820 and E/487.
Culture Media
■ Mueller-Hinton Broth Medium (MHB): MHB (Oxoid CM405) was prepared with final concentrations of
1 g/mL MgCl2 and 2 g/mL CaCl2. Culture medium was pre-warmed for approximately 2-3 h at 37°C
before use.
■ Mueller-Hinton Agar Medium (MHA): MHB containing 1.5% Agar (Merck Agar 1.01614).
Maintenance of Bacteria
■ From a thawed cryovial, the bacteria was streaked onto MHA and the plate incubated overnight at 37°C.
■ From this plate, 10 cryovials were prepared by looping several colonies into 0.5 mL of 20% glycerol
solution. The cryovials were immediately stored at -140°C.
Preparation of Seed Cultures
■ A cryovial was removed from -14O°C storage and thawed at room temperature.

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■ An MHA plate was streaked with a loopful of bacterial suspension and incubated overnight at 37°C to
create a parent plate (Pl).
■ A daughter plate (Dl) was streaked from the parent plate and incubated overnight at 37°C. The parent plate
was stored at 4°C.
■ A loop of colony from the daughter plate was used to innoculate a 125 mL flask containing 20 mL of MHB
containing 25 g/mL CaCl2.2H2O and 12.5 g/mL MgCl2.6H2O.
■ The flask was shaken at 260 rpm for 18 h at 37°C on an orbital incubator shaker.
■ The parent plate (PI) was reused within 9 days to generate another daughter plate (D2), which was used to
inoculate a broth culture.
■ Parent plates were used twice (to generate Dl and D2 plates) before a new one was prepared from the
previously thawed cryovial. The second parent plate (P2) was used to generate two additional daughter
plates using the procedure outlined above before being discarded.
■ Cryovials were used twice to prepare parent plates (P1 and P2) before being discarded.
Preparation of Standardized Inocula for Assays
■ A 1/10 dilution of seed cultures was prepared by adding 250 L of the cultures to 2,250 L of MHB in a
disposable cuvette.
■ The OD650 was read and multiplied by a factor of 10 to calculate the optical density of the undiluted culture.
■ The required dilution factor for the preparation of standardized inocula was calculated by dividing the
observed OD650 by the standard OD650 (previously determined as an OD650 of 4.75 from optimization
studies).
■ A 1 OmL sample of standardized inocula was prepared as illustrated by the following example:
Sample calculation:
OD650 = 0.492 (1/10 dilution)
10 x 0.492 = 4.92
as; 4.75/4.92 =0.97
■ Add 0.97 mL of S. aureus seed culture to 9.03 mL of MHB as the first dilution.
■ Sufficient volumes of the final inoculum cultures were prepared in pre-warmed MHB (37°C) by diluting
the standardized cultures to the required final concentration (S. aureus required a 10s dilution).
Assay Procedure (for 96-well Microtitre Plates)
■ To each well of the 96-well microtitre plate was added 50 L of liquid medium.

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= The peptoid compounds to be tested were dissolved in a 50% MeOHZH2O solution to give a concentration
of 1 mg/mL
■ 50 mL of test solution was added in triplicate to the top row of the microtitre plate (2 peptoid samples were
tested per plate). A vancomycin control set (triplicate) and a compound negative control set (triplicate)
were also included on each plate (Figure 1).
■ The inoculated culture medium was incubated at 37°C for 30 min, with shaking at 1301pm.
■ Using a multichannel pipette, the contents of the first row were mixed before 50 mL was transferred to the
second row. The pipette tips were changed and the process repeated by 50 mL of the mixed broth solutions
in the second row being transferred to the third row. This process was repeated until the last row contained
either the diluted test compound or a control (vancomycin or compound-negative). 50 mL was discarded
from this final row so that each well contained 50 mL of liquid medium.
■ Using a multistepper pipette, 50 mL of the inoculum was added to each well of the plate except for the last
row in the compound-negative control set, which received 50 mL of liquid broth.
■ The plates were incubated at 37°C for 18 h, with shaking at 100 rpm in an environment of approximately
90% humidity.
■ The results were recorded as the highest dilution of iesi compound that prevenied bacterial growth (MIC).
Antibacterial Testing of compounds of Example 2
Introduction
The specific testing procedures and protocols are outlined in the section "Antibacterial Screening Methodology for
the Compounds of Example 2". The antibacterial testing was performed on a vancomycin-susceptible strain of S.
aureus, and compounds that showed promising activity were subsequently tested against a variety of vancomycin
resistant and vancomycin sensitive enterococcal strains (Enterococcusfaeciw h) (see Chapter 5).
Antibacterial Testing Results
The antibacterial activity results are measured by minimum inhibitory concentration (MIC), which is the lowest
concentration of compound necessary to prevent bacterial growth. The activities ranged from MIC 7.8 mg/mL for
compound 75 to MIC > 125 mg/mL (inactive) for a number of compounds. Some testing was done in the earlier
stages of the project at higher concentration ranges up to 500 mg/mL, while later testing was performed with an
upper limit of 125 mg/mL. For consistency, activity values greater than 125 mg/mL have been designated inactive,
whilst an activity of 125 mg/mL is considered weakly active. Vancomycin was used as the standard/control and
typically had an MIC range of 1.25-2.5 mg/mL. The antibacterial testing results for S. aureus are tabulated in Table 1.

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Table 1: Tabulated antibacterial testing results on S. aureus

Antibacterial Testing of Linear Cationic Peptides of Example 2
Introduction
The antibacterial testing was performed using the same protocols as those used previously described in the section
"Antibacterial Testing of compounds of Example 2", using a vancomycin-susceptible strain of S. aureus, and an
additional three strains of vancomycin-sensitive or partially sensitive enterococci (£/243 , £/449 and £/987:
vancomycin MIC 1.95, 62.5 and faecium strain (£/320: vancomycin MIC >125 mg/mL).

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Antibacterial Testing Results
The testing results again are measured by minimum inhibitory concentration (MIC), on a scale from 0.98 mg/mL to
125 mg/mL. Vancomycin was used as the standard/control. The antibacterial testing results for the linear cationic
peptides are described in Tables 2 and 3
Table 2


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Table 3

Testing of Compounds of Example 2 Against the HIV Integrase Enzyme
HIV Integrase Initial Screening Results
Compounds synthesized in Example 2 were additionally included in a random database screening strategy against
the HTV integrase enzyme.
The compounds that were chosen to be tested against HIV integrase were 78. 81. 88 and 89 and the results are
represented in Table 4.
Table 4

These results represent promising hits as the compounds are significantly different in structure from previously
known HTV integrase inhibitors. These results formed a preliminary set of structure activity relationships (SAR's)
with regard to the stereochemistry of the amino acid residues and the length and functionality of the basic side-chain

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Testing Against the HIV Integrase Enzyme
The results for the screening of the four target molecules 165-168 against the HTV integrase enzyme yielded some
encouraging results which supported the proposed mechanism of binding in the active binding trench of the HTV
integrase enzyme. The testing procedure for the four target compounds differed from the original screening
protocols employed. The original screening measured inhibition against the 3' processing function of the enzyme at
the fixed concentration of 50 mg/mL, whereas the four target molecules were tested in an assay adapted from a
literature procedure.107 which measures inhibition against the 3' strand transfer function of the enzyme. This allows
a result to be obtained as an inhibition constant (IC50) concentration which is the standard measurement of
inhibition within the literature. Along with the four target molecules. 88 was also re-tested in the 3' strand transfer
assay to determine the IC50 for direct comparison with the literature. The results for the testing of the four target
molecules and the re-testing of 88 against HIV integrase are summarized in Table 5.
Table 5


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Table 5 Cont.

After these compounds and the computer modelling studies had become established all compounds that were sent
for screening in the antibacterial assay were then also cross tested for their ability to inhibit the HIV integrase
enzyme. Several compounds are active with moderate levels of inhibition and compound 163, one of the
hydroxamic acid binaphthyl derivatives, appears to be almost as active as the original lead 88, and is again
structurally unique with the large hydrophobic binaphthyl moiety. The results of these compounds are summarized
in Table 6.

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Table 6

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be
understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not
the exclusion of any other element, integer or step, or group of elements, integers or steps.

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All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents.
acts, materials, devices, articles or the like which has been included in the present specification is solely for the
purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these
matters form part of the prior art base or were common general knowledge in the field relevant to the present
invention as it existed anywhere before the priority date of each claim of this application.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the
invention as shown in the specific embodiments without departing from the spirit or scope of the invention as
broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not
restrictive.

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REFERENCES
(1) Dineen, P.; Homan, W. P.; Grafe, W.R. Annals of Surgery 1976, 184, 717-22.
(2) Neu, H. C. Science 1992, 257, 1064-72.
(3) Nicolaou, K. C ; Boddy, C. N. C. Sci. Am. 2001, 284, 54-61.
(4) Noble, W. C ; Virani, Z.; Cree, R. G. A. FEMS Microbiol. Lett. 1992, 93, 195-8.
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CLAIMS
1. A compound of formula I.

or pharmaceutically acceptable derivatives thereof, wherein:
Ati and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
fully reduced derivatives thereof:
Q1 and Q2 are each independently selected from hydrogen. Ci_Ci2 alkyl. C3C6cycloalkyl. Ci-Ci 2alkyloxy.
nitro. halogen, hydroxvl. amino. mono or dialkylamino. carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group such
as carboxamide. sulphonamide or phosphoramide wherein each Ci.C alkyl. C1-C12alkyloxy or
C3.C6Cycloalkyl is optionally substituted with hydroxvl. amino. carboxylic acid or a salt or ester thereof
sulphonic acid or a salt or ester thereof phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide. sulphonamide or phosphoramide:
Bis selected from-O-. -S-. -S(O)-. -S(O),-. -NH-. and-N(Ci.C 6alky))-;
R1 is selected from hydrogen. Q.C 12alkyl. C1.C6alkylC3.C6cycloalkyl. C1.C6alkylC6-C1 Oaryl. C2C6alkenyl.
C2C6alkynyl. a polyoxyalkylene having from 2 to 6 carbon atoms, and when B
is -S-. -S(O)-. -S(O)2-.-NH- or-N(C 1AaUCyl)- then R1may be hydroxyl:
V is a linker group selected from -()-.-
O-L-C(O). -0-L-NR 6-. -C(O)-. -NR 6-. -S(O)-. -S(O)2-. -0-L-S(O)-. -S(O)2-L-C(O)-. -S(O)2-L-NR 6-.
P(O)2O-:
wherein L is selected from C1-C12alkyI. C2C8 alkcnyl. C3- C6cycloalkyl. polyoxyalkylene having
from 2 to 6 carbon atoms. C6-C10aryl and C1.C6alkylC6.C10aryl and wherein R6 is selected from H.
C1-Ci2BHCyI:
A1 and A2 are the same or different and are basic amino acid residues:
each of S1- S2 and S3 is either present or absent and is an independently selected amino acid residue:

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T is present or absent and is selected from -C(O)OR8, -OR8, -NHR8,
NHOR8, -NH-Qaryl-CO-Rg, -NH-C6aryl-CO-NHR8, -NH-Qaryl-CONHORs, -NH-Qaryl-CONHOR -
C(O)NHR8, -(NH)-SO2C6aryl, -(NH)COR8:
or T forms a carboxylate isostere, optionally substituted with R8, which replaces the carboxylic acid group
of the amino acid to which T is connected;
wherein R8 is selected from hydrogen, Ci.C^alkyl, Ci.C6alkylC6.Cioaryl,
Ci.C6alkylC3C6cycloalkyl, C2-C6alkenyl, and C2_C6alkynyl; and
wherein when T is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
2. A compound according to claim 1 wherein Ai and A2 are each independently selected from the group
consisting of lysine, arginine and omithine.
3. A compound according to claim 2 wherein A1 is selected from lysine and ornithine and A2 is selected from
arginine.
4. A compound according to any one of claims I to 3 wherein Si and S2are absent.
5. A compound according to any one of claims 1 to 4 wherein the compound of formula I is of formula la.


WO 2006/074501 PCT/AU2005/001444
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7. A compound of formula II,
6. A compound according to any one of claims 1 to 4 wherein the compound of formula I is of formula Ib.

or pharmaceutically acceptable derivatives thereof, wherein:
Ati and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
fully reduced derivatives thereof.
Qi and Q2 are each independently selected from hydrogen, CcCi2alkyl, C3-C6cycloalkyl, Ci-Ci2alkyloxy,
nitro, halogen, hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group such
as carboxamide, sulphonamide or phosphoramide wherein each Ci_Ci2alkyl, Ci-C12alkyloxy or
C3.C6Cycloalkyl is optionally substituted with hydroxyl, amino, carboxylic acid or a salt or ester thereof,
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide, sulphonamide or phosphoramide:
each of Vi and V2 is a linker group independently selected from -O-.-O-L-C(O), -0-L-NR 6-, -C(O)- -NE6-, -S(O)-, -S(O)2-, -O-L-S(O)-, -S(O)2-L-C(O)-, -S(O)2-L-NR6-. -P(O)2O-;
wherein L is selected from Ci_Ci2 alkyl, C2Csalkenyl, C3C6cycloalkyl, polyoxyalkylene having from 2 to
6 carbon atoms. C6.C10aryl and Ci.Ci6alkylC6-Ci0aryl and wherein R6 is selected from H. Ci.Ci2alkyl:

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Ai and A2 are the same or different and are basic amino acid residues;
each of S1 S2, S3 and S4 is either present or absent and is an independently selected amino acid residue:
T 1 is either present or absent and is independently selected
from -C(O)OR8, -OR8, -NHR8, -NHOR8, -NH-C6aryl-COR8, -NH-C6aryl-CONHR8, -NH-C6aryl-CONHOR
8, -NH-Qaryl-CONHOH, -C(O)NHR8, -(MH)-SO2C6aryl, -(NH)COR8;
or T1 forms a carboxylate isostere, optionally substituted with R8, which replaces the carboxylic
acid group of the amino acid to which T1 is connected;
wherein R8 is selected from hydrogen, C1-C12alkyl, C1-QaHCyIC6.C10aTyI.
Ci.C6alkylCa.C6Cycloalkyl, C2.C6alkenyl, and C2C6alkynyl; and
wherein when T1 is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene;
T2, is either present or absent and is independently selected from -C(O)OR9, -OR9, -NHR9.
NT 1OR9, -NII-C6aryl-CO-R 9, -NH-C 6aryl-CO-NHR 9, -NH-C 6aryl-CONHOR 9, -NH-C 6aryl-CONHOH, -
C(O)NHR 8, -(NH)-SO2C6aryl, -(NH)COR8;
or T2 forms a carboxylate isostere, optionally substituted with R9, which replaces the carboxylic
acid group of the amino acid to which T2 is connected
wherein R9 is selected from hydrogen, C1.C12alkyl,Ci-CgalkylC6-Qoaryl,
CiAalkylCsAcycloalkyl, C2.C6alkenyl, and C2.C6alkynyl; and
wherein when T2 is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
8. A compound according to claim 7 wherein A 1 and A2 are each independently selected from the group
consisting of lysine, arginine and ornithine.
9. A compound according to claim 7 or claim 8 wherein A1 and A2 are the same.
10. A compound according to any one of claims 7 to 9 wherein S1, S2, S3 and S4 are absent.

WO 2006/074501 PCT/AU2005/001444
232.
11. A compound of formula IE,

or pharmaceutically acceptable derivatives thereof, wherein:
Ati and Ar2 are each independently selected from an aromatic or heterocyclic ring system or partially or
fully reduced derivatives thereof;
Qi and Q2arc each independently selected from hydrogen, Ci_C12alkyl, C3C6cycloalkyl, Ci-Ci2alkyloxy,
nitro, halogen, hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt or ester thereof, sulphonic
acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing group such
as carboxamide, sulphonamide or phosphoramide wherein each Ci-C12alkyl, C1 Ci2alkyloxy or
C3.C6cycioalkyl is optionally substituted with hydroxyl, amino, carboxylic acid or a salt or ester thereof,
sulphonic acid or a salt or ester thereof, phosphoric acid or a salt or ester thereof, or a nitrogen containing
group such as carboxamide, sulphonamide or phosphoramide;
B is selected from-O, -S-, -S(O)-, -S(O)2-, -NH-, and -N(C1alkVl)-;
R1 is selected from hydrogen, C1.C12alkyl, C1AalkylC 3Acycloalkyl, QAalkylCgAoaryl, C2.C6alkenyl,
C2.C6alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms, and when B
is -S-, -S(O)-, -S(O)2-, -NH- or -N(C1Aalkyl)- then Ri may be hydroxyl;
V1 is a linker group selected from selected from-O-, -O-L-C(O), -0-L-NR6-, -C(O)-
-NR6-, -S(O)-: -S(O)2-,-O-T,-S(O)-;,-S(O)2-L-C(O)-: -S(O)2-L-NR6-, P(O)2O-
wherein L is selected from C1.C12alkyl, C2.C8alkenyl, C3.C6cycloalkyl, polyoxyalkylene having
from 2 to 6 carbon atoms, C6.Ci0 aryl and CiAalkylC 6Aoaryl and wherein R5 is selected from H1
C C12alkyl;
A1 is a is a basic amino acid residue;
each Of S1 and S2 is either present or absent and is an independently selected amino acid residue;

WO 2006/074501 PCT/AU2005/001444
233.
T is present or absent and is selected from -
C(O)OR8. -OR8. -NHR8. -NHOR8. -NH-C6aryI-COR8. -NH-C6aryl-CONHR8. -NH-C6aryl-CONHOR8. -NH
-C6aryl-CONHOH, -C(O)NHR8. -(NH)-SO2C6aryl, -(NH)COR8:
or T forms a carboxylate isostere. optionally substituted with R8. which replaces the carboxylic
acid group of the amino acid to which T is connected:
wherein R8 is selected from hydrogen. C1.C12alkyl, Ci.C6alkylC6-Ci0aryl
Ci.C6alkylC3.C6cycloalkyl. C2.C6alkenyl. and C2.C6alkynyl: and
wherein when T is connected to the C-terminus of an amino acid residue then the carbonyl group
of the amino acid residue may be reduced to methylene.
12. A compound according to claim 11 wherein A1 is selected from lysine, arginine and omithine.
13. A compound of formula IV.



or pharmaceutically acceptable derivatives thereof, wherein
Ri2 is an alkylaromatic or alkylpolyaromatic group optionally substituted with -OCi^alkyl or -OC2-6alkenyl:
each B is a basic amino acid residue;
n = 1 or 2;
Si is present or absent and is an independently selected amino acid residue;
Ti is selected
from -NHRi3. -NHOR13. -NH-C6aryl-COR13,. -NH-C6aryl-CONHR13. -NH-C6aryl-CONHORi3.

-NH-Qary 1-CONHOH. -(NH)-SO2C6aryL -(NH)CORi3 or
or T1 forms a carboxylate isostere. optionally substituted with Ri3. which replaces the carboxylic acid
group of the amino acid to which T1 is connected;

WO 2006/074501 PCT/AU2005/001444
234.
wherein R13 is selected from hydrogen, C1.C12alkyl, C1.C6alkylCgAoaryl, Ci.C6alkylC3.C6cycloalkyl,
C2C6alkenyl. and C2c6alkynyl and
wherein when Ti is connected to the C-terminus of an amino acid residue then the carbonyl group of the
amino acid residue may be reduced to methylene;
T2 is .selected from -C(O)R14, -C(O)OR14, -OR14, -C(O)NHR14,.
wherein R14 is selected from hydrogen, Q.C^alkyl, Ci.C6alkylCg.Cioaryl, Q.CgalkylQ.Cecycloalkyl,
C2.C6alkenyl, C2.C6alkyny1, and CH2-fluorene;
wherein the optional substituent of R12 and the side-chain of S1 may together form a -OC^alkylene linking
group.
14. A compound according to claim 13 wherein R12 is selected from-CH2-phenyl-OCH2CH=CH2 and -CH2-
phenylanthracene.
15. A compound according to claim 13 or 14 wherein S1 is selected from allylglycine.
16. A compound according to any one of claims 13 to 15 wherein T2is-C(O)CH3.
17. A compound according to any one of claims 13 to 16 wherein T 1 is CH3O-.
18. A compound according to any one of claims 13 to 17 wherein B is lysine or arginine.
19. A compound of Example 2.
20. A compound according to claim 19 wherein the compound of Example 2 is selected from 69, 70, 71, 72, 73,
74, 75, 76, 83, 32, 37, 65, 56, 118, 119, 120, 121, 132, 90, 134, 135, 136, 137, 139, 140. 141, 159, 160, 163,
164, 78, 81, 88, 87, 89, 165, 166, 167. and 168.
21. A composition comprising a compound according to any one of claims 1 to 20, a salt or a pharrnaceutically
acceptable derivative thereof together with one or more pharmaceutically acceptable carriers or adjuvants.
22. A method of treating a bacterial infection in a mammal comprising administering an effective amount of
compound according to any one of claims 1 to 20, a salt or a pharmaceutically acceptable derivative thereof.
23. Use of a compound according to any one of claims 1 to 20 in the preparation of a medicament for treating
or preventing bacterial infection.
24. A method for treatment or prophylaxis of HIV in a subject comprising administering to said subject an
effective amount of a compound according to any one of claims 1 to 20. a salt or a pharmaceutically
acceptable derivative thereof.
25. A method according to claim 24 wherein the compound is selected from one or more of the following
compounds of Example 2: 78, 81, 88, 89, 165, 166, 167, 168, 83, 119, 164, 163, 158.


The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.

Documents:

02719-kolnp-2007-abstract.pdf

02719-kolnp-2007-claims.pdf

02719-kolnp-2007-correspondence others.pdf

02719-kolnp-2007-description complete.pdf

02719-kolnp-2007-drawings.pdf

02719-kolnp-2007-form 1.pdf

02719-kolnp-2007-form 3.pdf

02719-kolnp-2007-form 5.pdf

02719-kolnp-2007-international publication.pdf

02719-kolnp-2007-international search report.pdf

2689-KOLNP-2006-(21-05-2012)-CORRESPONDENCE.pdf

2689-KOLNP-2006-(21-05-2012)-OTHERS.pdf

2719-KOLNP-2007-(18-05-2012)-ABSTRACT.pdf

2719-KOLNP-2007-(18-05-2012)-AMANDED CLAIMS.pdf

2719-KOLNP-2007-(18-05-2012)-DESCRIPTION (COMPLETE).pdf

2719-KOLNP-2007-(18-05-2012)-DRAWINGS.pdf

2719-KOLNP-2007-(18-05-2012)-EXAMINATION REPORT REPLY RECEIVED.pdf

2719-KOLNP-2007-(18-05-2012)-FORM-1.pdf

2719-KOLNP-2007-(18-05-2012)-FORM-13.pdf

2719-KOLNP-2007-(18-05-2012)-FORM-2.pdf

2719-KOLNP-2007-(18-05-2012)-FORM-3.pdf

2719-KOLNP-2007-(18-05-2012)-OTHERS.pdf

2719-KOLNP-2007-(18-05-2012)-PETITION UNDER RULE 137-1.pdf

2719-KOLNP-2007-(18-05-2012)-PETITION UNDER RULE 137.pdf

2719-KOLNP-2007-(21-05-2012)-CORRESPONDENCE.pdf

2719-KOLNP-2007-(21-05-2012)-OTHERS.pdf

2719-KOLNP-2007-ASSIGNMENT.pdf

2719-KOLNP-2007-CORRESPONDENCE OTHERS-1.1.pdf

2719-KOLNP-2007-CORRESPONDENCE.pdf

2719-KOLNP-2007-EXAMINATION REPORT.pdf

2719-KOLNP-2007-FORM 13.pdf

2719-KOLNP-2007-FORM 18 1.1.pdf

2719-kolnp-2007-form 18.pdf

2719-KOLNP-2007-FORM 3-1.1.pdf

2719-KOLNP-2007-FORM 3.pdf

2719-KOLNP-2007-FORM 5.pdf

2719-KOLNP-2007-GPA.pdf

2719-KOLNP-2007-GRANTED-ABSTRACT.pdf

2719-KOLNP-2007-GRANTED-CLAIMS.pdf

2719-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

2719-KOLNP-2007-GRANTED-DRAWINGS.pdf

2719-KOLNP-2007-GRANTED-FORM 1.pdf

2719-KOLNP-2007-GRANTED-FORM 2.pdf

2719-KOLNP-2007-GRANTED-SPECIFICATION.pdf

2719-KOLNP-2007-INTERNATIONAL PUBLICATION.pdf

2719-KOLNP-2007-INTERNATIONAL SEARCH REPORT.pdf

2719-KOLNP-2007-OTHERS.pdf

2719-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

2719-KOLNP-2007-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

abstract-02719-kolnp-2007.jpg


Patent Number 254080
Indian Patent Application Number 2719/KOLNP/2007
PG Journal Number 38/2012
Publication Date 21-Sep-2012
Grant Date 18-Sep-2012
Date of Filing 23-Jul-2007
Name of Patentee UNIVERSITY OF WOLLONGONG
Applicant Address NORTHFIELDS AVENUE, WOLLONGONG, NEW SOUTH WALES
Inventors:
# Inventor's Name Inventor's Address
1 BREMNER JOHN BARNARD 38 THE PARKWAY, BALGOWNIE, NEW SOUTH WALES 2519
2 BRKIC ZINKA 1/25 GLADSTONE AVE, WOLLONGONG, NEW SOUTH WALES 2500
3 COATES JONATHAN ALAN VICTOR 9A HUTCHISON AVE, BEAUMARIS, VICTORIA 3193
4 DALTON NEAL KEVIN 5 DEAN STREET, CARINGBAH, NEW SOUTH WALES 2229
5 DEADMAN JOHN 114 KAY STREET, CARLTON, VICTORIA 3053
6 KELLER PAUL ANTHONY 11 MICHAEL CRESCENT, KIAMA, NEW SOUTH WALES 2533
7 MORGAN JODY 28 ARUNTA DRIVE, THIRROUL, NEW SOUTH WALES 2515
8 PYNE STEPHEN GEOFFREY 5 RAVENWOOD PLACE, MT KEIRA, NEW SOUTH WALES 2500
9 RHODES DAVID IAN 15 MYRTLE STREET, HEIDELBERG HEIGHTS, VICTORIA 3081
10 ROBERTSON MARK JAMES 3/2 GREY STREET, KEIRAVILLE, NEW SOUTH WALES 2500
11 BOYLE TIMOTHY PATRICK 4 TEATREE PLACE, KIRRAWEE, NEW SOUTH WALES 2232
PCT International Classification Number C07C 277/00
PCT International Application Number PCT/AU05/001444
PCT International Filing date 2005-09-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2005900134 2005-01-13 Australia