Potent, plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: Structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation

Article abstract of DOI:10.1021/jm800113p

New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaffold was varied in order to examine both the homology model of Plasmodium falciparum PFT (PfPFT) and our predicted inhibitor binding mode. We identified several PfPFT inhibitors (PfPFTIs) that are selective for PfPFT versus the mammalian isoform of the enzyme (up to 136-fold selectivity), that inhibit the malarial enzyme with IC₅₀ values down to 1 nM, and that block the growth of P. falciparum in infected whole cells (erythrocytes) with ED₅₀ values down to 55 nM. The structure-activity data for these second generation, ethylenediamine-inspired PFT inhibitors were rationalized by consideration of the X-ray crystal structure of mammalian PFT and the homology model of the malarial enzyme.

Full text of DOI:10.1021/jm800113p

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J. Med. Chem. 2008, 51, 5176–5197
Articles
Potent, Plasmodium-Selective Farnesyltransferase Inhibitors That Arrest the Growth of Malaria
Parasites: Structure-Activity Relationships of Ethylenediamine-Analogue Scaffolds and
Homology Model Validation
Steven Fletcher,† Christopher G. Cummings,† Kasey Rivas,‡ William P. Katt,† Carrie Horne´y,‡ Frederick S. Buckner,‡
Debopam Chakrabarti,# Sa¨ıd M. Sebti,| Michael H. Gelb,§ Wesley C. Van Voorhis,‡ and Andrew D. Hamilton*,†
Department of Chemistry, Yale UniVersity, 225 Prospect Street, New HaVen, Connecticut 06511, Department of Medicine and Department of
Chemistry and Biochemistry, UniVersity of Washington, Seattle, Washington 98195, Department of Molecular Biology and Microbiology,
UniVersity of Central Florida, Orlando, Florida 32826, and Department of Oncology and Department of Biochemistry and Molecular Biology,
H. Lee Moffitt Cancer Center and Research Institute, UniVersity of South Florida, Tampa, Florida 33612
ReceiVed February 3, 2008
New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series
of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study,
we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine
scaffold was varied in order to examine both the homology model of Plasmodium falciparum PFT (PfPFT)
and our predicted inhibitor binding mode. We identified several PfPFT inhibitors (PfPFTIs) that are selective
for PfPFT versus the mammalian isoform of the enzyme (up to 136-fold selectivity), that inhibit the malarial
enzyme with IC50 values down to 1 nM, and that block the growth of P. falciparum in infected whole cells
(erythrocytes) with ED50 values down to 55 nM. The structure-activity data for these second generation,
ethylenediamine-inspired PFT inhibitors were rationalized by consideration of the X-ray crystal structure of
mammalian PFT and the homology model of the malarial enzyme.
Introduction
antimalarial drugs, such as mefloquine and sulfadoxime/pyrimeth-
amine,6,7 and in those countries that are affected most seriously,
existing alternative chemotherapeutics are virtually unaffordable.
Of significant concern is the identification of multidrug resistant
strains of P. falciparum.5 The development of drug resistance
is not the only cause of the increasing spread of malaria. Other
factors also contribute to this worsening scenario, such as the
resistance of the Anopheles mosquito to the pesticide DDT, the
migration of refugee populations, and an ever-warming climate.8
The associated increase in malaria mortality has accelerated
research into new antimalarial drugs, to disrupt not only
conventional targets, such as heme polymerization, but also more
novel targets, such as the biochemical pathways of fatty acid
biosynthesis and mevalonate-independent isoprenoid biosyn-
thesis.5 We believe that exploitation of these alternative targets
will fast become essential, owing to the existence of multidrug
resistant strains of P. falciparum coupled with the observation
that the parasite readily mutates to develop resistance to new
drugs (designed for conventional targets).5 Since the economic
reality of the effective treatment of malaria is beyond the means
of Third World countries, where this disease is most prevalent,
this raises the need for inexpensive chemotherapeutics. Subse-
quently, while it is acknowledged that the majority of the cost
of a new therapeutic lies in its clinical trials, to minimize the
cost at the drug development stage and to expedite access to
new antimalarials, there has been considerable research into the
possible antimalarial activity of drugs designed for other diseases
in a so-called “piggy-back” approach.9–14
Malaria is an infectious disease, prevalent primarily in the
tropics and subtropics. With as many as 300-500 million cases
reported each year, malaria causes between 1 and 3 million
deaths annually, approximately 90% of which occur in Africa.1,2
Unfortunately, malaria mortality is increasing, especially in the
highest risk group, African children.3 There are a number of
likely reasons for this increase, the most important of which is
increased resistance of malaria parasites to existing drugs.4–6
There is now a general consensus that new antimalarials are
urgently needed.7
Transmitted by mosquitoes of the genus Anopheles, four
species of the protozoal parasite Plasmodium are known to cause
malaria in humans, namely falciparum, ViVax, malariae, and
oVale. Of these, P. falciparuma is the most virulent, and malaria
mortality is almost exclusively attributable to infection by this
species.1,7 Chloroquine, which is believed to disrupt heme
polymerization, is one of the cheapest and most widespread
drugs for malaria chemotherapy. However, P. falciparum has
developed considerable resistance to chloroquine and to other
* To whom correspondence should be addressed. Phone: (203) 432-5570.
Fax: (203) 432-3221. E-mail: andrew.hamilton@yale.edu.
†
Yale University.
Department of Medicine, University of Washington.
Department of Molecular Biology and Microbiology, University of
‡
#
Central Florida.
|
University of South Florida.
Department of Chemistry and Biochemistry, University of Washington.
§
a Abbreviations: PFT, protein farnesyltransferase; P. falciparum, Plas-
modium falciparum; PfPFT, P. falciparum protein farnesyltransferase; FPP,
farnesyl pyrophosphate; ED50, effective dose that inhibits 50% of P.
falciparum proliferation; IC50, inhibitor concentration that inhibits 50% of
PFT enzyme activity; rt, room temperature.
Mammalian protein farnesyltransferase (PFT) is a key target
for the antagonism of oncogenic Ras activity that is found in
around 30% of human cancers,15 and a number of protein
10.1021/jm800113p CCC: $40.75
2008 American Chemical Society
Published on Web 08/08/2008

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5177
Figure 1. The various scaffolds used in this study as alternatives to the ethylenediamine scaffold in 1.
farnesyltransferase inhibitors (PFTIs) have shown antitumor
activity, having progressed to phase II/III in clinical trials.16
PFT, a member of the prenyltransferase family, is one of three
closely related heterodimeric zinc metalloenzymes (the others
being the protein geranylgeranyltransferases I and II, PGGT-I
and PGGT-II, respectively) that are important post-translational
modification enzymes, catalyzing protein prenylation and sub-
sequent membrane association.17 PFT catalyzes the transfer of
a C15 isoprenoid (farnesyl) unit from farnesylpyrophosphate
(FPP) to the free thiol of a cysteine residue within a specific
CaaX tetrapeptide sequence, located at the C-terminus of the
substrate protein (e.g., RasGTPase), where a ) an aliphatic
amino acid and X (which contributes to substrate specificity)
) M, S, A, or Q. Chakrabarti et al. have identified prenylated
proteins and associated prenyltransferase activity in P. falci-
parum and confirmed the viability of P. falciparum protein
farnesyltransferase (PfPFT) as a new antimalarial target.9,18
Upon administration of mammalian-designed anticancer PFTIs
to P. falciparum-infected erythrocytes, a reduction in the cellular
levels of farnesylated proteins was observed coupled with lysis
of the parasites.13,18 More recently, Van Voorhis and co-workers
have identified two P. falciparum mutants, each with single
amino acid substitutions (Y837C19 and G612A20) in PfPFT that
map to the predicted inhibitor binding site, which show
resistance to tetrahydroquinoline (THQ)-based PfPFT inhibitors
both in vitro and in whole cells, further supporting PfPFT as
the target for antimalarial activity.19,20 We10,21–23 and others14
have successfully adopted this “piggy-back” approach with
several series of anticancer PFTIs and observed antimalarial
activity in every case.10,21–23 Notably, in animal studies we have
cured rats infected with malaria via oral dosing of our PFT-
targeted THQ-based inhibitors,24 while Schlitzer et al. have
cured mice infected with malaria by intraperitoneal injection
of their benzophenone-based PFTIs.14 The now-complete ge-
nome of P. falciparum indicates an apparent lack of PGGT-I,25
suggesting that no alternative protein prenylation can occur upon
PfPFT inhibition, which may explain the observation that PFTIs
have been found to be significantly more toxic to plasmodial
cells than to mammalian cells.13 Indeed, if PFTIs are to be
effective antimalarials, plasmodium selectivity may be required,
since the antiproliferative nature of PFTIs may preclude or at
least restrict their use in children and pregnant women, the main
target groups in malaria therapy.
Using the sequence alignment of PfPFT on the template
crystal structure of rat PFT complexed with the nonsubstrate
tetrapeptide inhibitor CVFM and the cosubstrate FPP, we have
developed a homology model of the active site of PfPFT.19,26
This model reveals a large (∼20 × 20 × 20 Å3), open, and
predominantly hydrophobic cavity, with FPP extending across
the cavity base, itself forming part of the binding surface for
the enzyme substrate. Further inspection of the active site
homology model indicates that there are four subpockets. In
the first, the Zn(II) ion is chelated by three residues (Cys661,
Asp659, His838), with a water molecule hydrogen-bonded
between the terminal phosphate of FPP and Asp659, defining
the limit of the Zn binding domain. Second and third are two
well-defined, predominantly hydrophobic subpockets (Lys149,
Asn317, Ser150, Phe151, where Asn317 and Ser150 form a
hydrophilic domain at the deepest point; and Trp456, Trp452,
Tyr837). The fourth subpocket is a larger hydrophilic domain
formed by Arg564 and three water molecules participating in a
hydrogen-bonded network between Ser449 and Gln152. We
have previously reported on a series of ethylenediamine-based
inhibitors that were predicted to allow simultaneous access to
the four subpockets within the PfPFT active site.26,27 Lead
inhibitors displayed excellent activity in vitro (IC50 < 1 nM)
and toxicity toward cultured parasites in whole cells (ED50
<
100 nM). Furthermore, these PFTIs represent the first antima-
larials to exhibit selectivity for plasmodial over mammalian PFT
(up to 145-fold selectivity). With such potent data and plas-
modium PFT-isoform selectivity already achieved, the main aim
of the present research was to investigate the validity of the
PfPFT active site homology model, as well as the initial docking
studies reported in our previous work,26,27 by introducing
alternative scaffolds with different rigidities/flexibilities and with
different nitrogen-nitrogen distances into our ethylenediamine-
based inhibitors. In turn, we hoped that our findings would assist
in future, potent PfPFT inhibitor design.
First, we illustrate the scaffold modifications that we chose
to investigate and then comment on their abilities to dock in

5178 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
Figure 2. Low energy docked conformations (GOLD28) of inhibitors loosely constrained to the predicted binding mode of 1a.26,27 Docked inhibitors
are colored by atom type and are overlaid by the predicted docking pose of 1a in yellow. Farnesylpyrophosphate (FPP) is shown in red. Hydrophobic
surface residues are colored red, hydrophilic residues and structural waters are blue, and the Zn2+ ion is pink: (A) 1a docked alone; (B) (()-6a
overlaid with 1a; (C) (()-9a overlaid with 1a.
the PfPFT active site homology model using the computer
modeling program GOLD.28 We describe the syntheses of these
novel inhibitors and then present in vitro PfPFT inhibition data,
as well as two sets of whole cell data of erythrocytes infected
with either the 3D7 (chloroquine-sensitive) or the K1 (chloro-
quine-resistant, pyrimethamine-resistant) strain of P. falciparum.
To conclude the manuscript, we utilize our computational and
experimental data to present quantitative structure-activity
relationship (QSAR) models of PfPFT and discuss their
implications.
cis- and (()-trans-1,2-diaminocyclobutanes and the (()-cis- and
(()-trans-1,2-diaminocyclopropanes were deemed too unstable
because of the “push-pull effect” and were not investigated.29
Computational docking experiments were performed using
the GOLD 3.1 software package.28 First, InsightII30 was used
to draw structures (R ) Bn), energy-minimize them and to
prepare our homology model of the active site of PfPFT for
use in GOLD. Novel ligands were assumed to maintain a similar
binding mode to that hypothesized for 1a;26,27 the two imidazole
rings and the cyanoaniline were loosely constrained to their
associated binding pockets for each compound (for full details,
see Experimental Methods). Visualization of GOLD low energy
docked poses was performed with InsightII. In all figures
presented (Figure 2 and Supporting Information Figures 1-8),
the binding site of PFT has been surfaced, in which the enzyme
cosubstrate farnesylpyrophosphate (FPP) forms part of that
binding surface.
The GOLD docking studies predicted that many of these
alternative scaffolds should not be as well tolerated as the parent
ethylenediamine scaffold in the active site of PfPFT (Figure 2
and Supporting Information Figures 1–8. As Supporting Infor-
mation Figure 1 illustrates, the 1,3-diaminopropyl scaffold
(inhibitor 2a) is accommodated well in the active site, although
the extra methylene appears to require the inhibitor to buckle
in order to allow all four N-substituents to reach their predicted
subpockets. We anticipated that inhibitors derived from this
scaffold may bind PfPFT well but not as potently as the parent
ethylenediamine-based inhibitors. As expected, docking of the
gem-dimethylethylenediamine-based inhibitor (Supporting In-
formation Figure 2, inhibitor 3a) illustrates that all four
subpockets can be reasonably accessed by the four N-derivatives
in much the same way as the parent ethylenediamine scaffold,
suggesting that these compounds may be potent inhibitors of
PfPFT. While the amide-based scaffolds (Supporting Informa-
tion Figure 3, inhibitor 4a) are also predicted to bind well, the
constraints we imposed in the GOLD docking experiments have
Design
Previous research identified that our most potent ethylene-
diamine-based inhibitors were functionalized as in 1 and where
varying the R group proved critical to inhibitor potency. As
reference compounds, we selected five derivatives of 1 with
the following R groups: a, R ) benzyl; b, R ) 2-methylbenzyl;
c, R ) thiophen-3-ylmethyl; d, R ) N-Boc-piperidin-4-
ylmethyl; e ) N-(2-pyrimidinyl)-piperidin-4-ylmethyl. The
ethylenediamine-alternative scaffolds selected to test both our
predicted inhibitor binding mode and the PfPFT active site
homology model are illustrated in Figure 1. These fall into three
categories with respect to their rigidities/flexibilities relative to
the ethylenediamine scaffold (1). The first category possesses
only 1,3-diaminopropane (2), which is acyclic and, with the
additional methylene group, more flexible than ethylenediamine.
The second category includes gem-dimethylethylenediamine (3),
2-aminoethanamide (4), and 3-aminopropanamide (5), which
are acyclic and more rigid than ethylenediamine. The third
category incorporates (()-cis-1,2-diaminocyclopentane (6) and
(()-trans-1,2-diaminocyclopentane (7), (()-cis-1,3-diaminocy-
clopentane (8) and (()-trans-1,3-diaminocyclopentane (9), and
(()-cis-1,4-diaminocyclohexane (10) and (()-trans-1,4-diami-
nocyclohexane (11), all of which are cyclic and more rigid than
ethylenediamine and exhibit gradually increasing distances
between the scaffold nitrogens. The corresponding rigid (()-

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5179
Scheme 1a
caused the increase in hydrophilicity of the core scaffold to be
ignored, which may lead to an erroneous result due to the
hydrophobic environment in which the inhibitor scaffold is
predicted to bind. The rigid cis-1,2- (Figure 2B inhibitor 6a),
trans-1,2- (Supporting Information Figure 4, inhibitor 7a), and
cis-1,3-diaminocyclopentyl scaffolds (Supporting Information
Figure 5, inhibitor 8a), and the cis-1,4-diaminocyclohexyl
(Supporting Information Figure 7, inhibitor 10a) scaffold do
not fit well in the active site because of their constrained
structures that prevent simultaneous access by all four N-
substituents into the four subpockets. These observations suggest
that compounds with these scaffolds may be poor inhibitors of
PfPFT. On the other hand, trans-1,3-diaminocyclopentyl-
(Figure 2C, inhibitor 9a) and trans-1,4-diaminocyclohexyl-
(Supporting Information Figure 6, inhibitor 11a) derivatives
appear to be reasonably well accommodated, so we predicted
these inhibitors may bind well to PfPFT. However, the increas-
ing scaffold nitrogen-nitrogen distance may prove detrimental
with bulkier R groups.
We hypothesized that if a structure with a diamino-based
scaffold (whose nitrogens have been functionalized with four
previously optimized groups) is loosely constrained to our
predicted binding mode and subsequently docks well in the
active site homology model, then that structure should bind well
experimentally. In turn, this should be reflected by potent
enzyme inhibition data. Conversely, structures that are predicted
to bind less well should be poorer inhibitors. By testing this
hypothesis over a range of different scaffolds that modulate the
inhibitors’ abilities to simultaneously access all four predicted
binding subpockets within the PfPFT active site, we should be
able to garner enough information to develop a quantitative
structure-activity relationship (QSAR) model and thereby
validate both our predicted inhibitor binding mode and the
homology model itself. It is our hope that this information will
assist in future PfPFT inhibitor design.
a (a) DHP, cat. PPTS, CH2Cl2, 0 °C f rt, 16 h, 85%; (b) H2, 10% Pd/C,
MeOH, rt, 1 h, 82%; (c) p-fluorobenzonitrile, DIPEA, DMSO, 120 °C, 24 h,
87%; (d) (1) NaH, DMF, 0 °C, 30 min; (2) 15, 0 °C f rt, 3 h, 81% (or
97% brsm); (e) p-TsOH·H2O, MeOH, rt, 1 h, 88%; (f) 19a-e, DIAD, PPh3,
THF, rt, 1 h, 61-98%.
Scheme 2a
Chemistry
1,3-Diaminopropane-Based Inhibitors (2a-e). These in-
hibitors were prepared as in Scheme 1. N-Carbobenzyloxy-3-
amino-1-propanol (12) was converted to its THP ether derivative
(with dihydropyan (DHP) and catalytic pyridinium p-toluene-
sulfonate (PPTS)), after which the Cbz protecting group was
removed under standard hydrogenolytic conditions (H2 and 10%
Pd/C) to furnish primary amine 13. Nucleophilic aromatic
substitution of 13 with p-fluorobenzonitrile, followed by N-
alkylation of secondary aniline 14 with 5-chloromethyl-1-
methyl-1H-imidazole ·HCl (15) under optimized conditions gave
tertiary aniline 16 in a yield of 81% (or 97% based on recovered
starting material (brsm)). Acid-catalyzed methanolysis of the
THP protecting group furnished primary alcohol 17, which was
coupled to the secondary sulfonamides 19a-e (prepared as
described in Schemes 2 and 3) under Mitsunobu conditions,
employing diisopropyl azodicarboxylate (DIAD)/triphenylphos-
phine (PPh3) as the redox system, to give PfPFT inhibitors 2a-e
in excellent yields. Due to the success of the Mitsunobu reaction
coupled with its convergent effect on the overall syntheses of
these 1,3-diaminopropane-based PfPFTIs, we designed syntheses
of the remaining PfPFTIs that also incorporated Mitsunobu as
the final step.
a (a) RNH2, DIPEA, CH3CN, 0 °C f rt, 16 h, 81-93%.
from 81% to 93% (Scheme 2). Due to the unavailability of N-(2-
pyrimidinyl)-4-aminomethylpiperidine and the need for the more
acidic sulfonamide 21 in the synthesis of 3-aminoethanamide
derivatives 5a and 5d as well as the trans-1,2-diaminocyclo-
pentyl derivatives 7a-e, sulfonamide 19e was prepared by a
different route (Scheme 3). Accordingly, treatment of 19a with
Boc2O led to the fully derivatized sulfonamide 20 in quantitative
yield. Subsequent hydrogenolysis of 20 furnished N-tert-
butoxycarbonyl-1-methyl-1H-imidazole-4-sulfonamide (21), whose
NH was expected to have a lower pKa than that of simple
N-alkyl secondary sulfonamides, such as 19a, whose pKa values
are just on the cusp (pKa ≈ 12) of acidic nucleophiles (NuH)
allowed in the Mistunobu reaction. The enhanced acidity of 21
was subsequently found to resolve troublesome Mitsunobu
reactions (see sections on the syntheses of 5a,d and 7a-e).
Additionally, compound 21 was successfully coupled to N-(2-
pyrimidinyl)-4-hydroxymethylpiperidine, giving 22, which, after
Boc deprotection with TFA, yielded sulfonamide 19e in an
excellent two-step yield of 92%.
Sulfonamides for Mitsunobu Reactions (19a-e, 21). The
secondary sulfonamides 19a-d required for the Mitsunobu
reactions (e.g., step f in Scheme 1) were prepared in simple
one-step procedures from 1-methyl-1H-imidazole-4-sulfonyl
chloride (18) and the respective primary amines in yields ranging

5180 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
Scheme 3a
of products. However, alternative protection of the alcohol with
tert-butyldiphenylsilylchloride (TBDPSCl), employing imidazole
(Im) as base and nucleophilic catalyst, gave the desired
compound 25 in excellent yield. The zinc-binding imidazole
group was next installed by treatment of secondary aniline 25
with NaH at 0 °C followed by addition of 5-chloromethyl-1-
methyl-1H-imidazole·HCl (15) as before to furnish tertiary
aniline 26. Quantitative deprotection of the TBDPS group with
tetra-n-butylammonium fluoride (TBAF) was observed, and the
resultant primary alcohol was condensed with the five sulfona-
mides 19a-e under Mitsunobu conditions at 45 °C to afford
the final PfPFTIs 3a-e in 50-68% yields.
2-Aminoethanamide-Based Inhibitors (4a, 4d) and 3-Ami-
nopropanamide-Based Inhibitors (5a, 5d). Due to earlier
findings that incorporation of an amide bond into the inhibitor
scaffold is not tolerated,31 we decided to make just two
derivatives of each amide-containing scaffold, with a small (a,
R ) Bn) and a large (d, R ) N-Boc-piperidin-4-ylmethyl) R
group. The syntheses of these 2-aminoethanamide- (4a, 4d) and
3-aminopropanamide-based PfPFT inhibitors (5a, 5d) are
presented in Scheme 5 and are described in full in Supporting
Information.
a (a) Boc2O, cat. DMAP, THF, rt, 16 h, 99%; (b) H2, 10% Pd/C, EtOH,
rt, 16 h, 100%; (c) N-(2-pyrimidinyl)-4-hydroxymethylpiperidine, PPh3,
DIAD, THF, rt, 16 h; (d) TFA/CH2Cl2, 1:1, rt, 3 h, 92% (two steps).
(()-cis-1,2-Diaminocyclopentane-Based Inhibitors ((()-
6a-e) and (()-trans-1,2-Diaminocyclopentane-Based Inhibi-
tors ((()-7a-e). The (()-cis-1,2-diaminocyclopentyl-based
inhibitors (()-6a-e were furnished by following the synthetic
steps described in Scheme 6. Racemic (()-trans-2-benzyloxy-
cyclopentylamine ((()-36) was arylated with p-fluorobenzoni-
trile, using an excess of the aryl fluoride to compensate for
reduced reactivity due to steric hindrance. N-Alkylation of the
resultant secondary aniline (()-37 with 15 as before furnished
(()-38 in a moderate yield of 56% (or 89% brsm), which was
then smoothly debenzylated under optimized conditions (1 atm
of H2, catalyst 10% Pd/C, 0.5% concentrated HCl in EtOH (v/
v), 1 h) to furnish secondary alcohol (()-39. The proposed final
step in this synthesis, Mitsunobu reaction of (()-39 with the
secondary sulfonamides 19a-e, proved unsuccessful, leading
to elimination rather than substitution, presumably due to the
sterically encumbering tertiary amine and/or the low acidities
of the sulfonamides (pKa ≈ 12) that places them at the
uppermost limit of allowed nucleophiles for the Mitsunobu
reaction. However, even with the more acidic sulfonamide 21
(Scheme 3), we again observed only elimination. Likewise,
alternative, more powerful Mitsunobu redox systems such as
N,N,N′,N′-tetramethylazodicarboxamide (TMAD)/tri-n-butylphos-
phine (TBP) and cyanomethyl-tri-n-butylphosphorane (CMBP)
proved fruitless. We next considered the steric hindrance in the
desired transformation and found that Mitsunobu reaction of
(()-39 with diphenylphosphorylazide (DPPA), which involves
the smaller and linear azide ion as the nucleophile, was more
successful. These conditions led to a 3:2 inseparable mixture
of the azide (substitution) product (()-40a, wherein the usual
inversion of stereochemistry had occurred, and the alkene
(elimination) product (()-40b. Staudinger reduction of azide
(()-40a in the mixture led to the anticipated increase in polarity,
enabling facile separation from alkene (()-40b and furnishing
primary amine (()-41 in a yield of 56% for the two steps.
Subsequently, sulfonylation of (()-41 afforded secondary
sulfonamide (()-42 in good yield, which was then alkylated
with a series of bromides (or iodides) to give the (()-cis-1,2-
diaminocyclopentyl PfPFT inhibitors (()-6a-e in poor to good
yields. Importantly, for the two benzylic and thiophen-3-
ylmethyl bromides, this reaction had to be performed under
dilute (0.01 M) conditions to reduce the facile quaternization
Scheme 4a
a (a) p-fluorobenzonitrile, DIPEA, DMSO, 180 °C, 48 h, 40%; (b)
TBDPSCl, Im, DMF, 45 °C, 18 h, 90%; (c) (1) NaH, DMF, 0 °C, 30 min;
(2) 15, 0 °C f rt, 3 h, 53% (or 82% brsm); (d) TBAF, THF, 0 °C f rt,
2 h, 95%; (e) 19a-e, DIAD, PPh3, THF, 45 °C, 18 h, 50-68%.
gem-Dimethylethylenediamine-Based Inhibitors (3a-e).
The hindered gem-dimethylethylenediamine derivatives 3a-e
were furnished as shown in Scheme 4. Nucleophilic aromatic
substitution of 2-amino-2-methylpropan-1-ol (23) with p-
fluorobenzonitrile in a sealed vessel at 180 °C for 48 h afforded
24 in 40% yield. Attempted chemoselective benzylation of the
primary hydroxyl of 24 with NaH and BnBr led to a mixture

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5181
Scheme 5a
a (a) (1) 3-Methyl-3H-imidazole-4-carbaldehyde, AcOH, 4 Å molecular sieves, MeOH, rt, 1 h; (2) NaCNBH3, rt, 16 h, 63%; (b) benzyloxyacetyl chloride
(or 3-benzyloxypropanoyl chloride), pyridine, CH2Cl2, rt, 2 h, 87-94%; (c) Zn(CN)2, 10 mol % Pd(PPh3)4, cat. Zn(OAc)2, cat. Zn dust, DMF, 120 °C, 2 h,
85-89%; (d) H2, 10% Pd/C, 0.5% conc HCl (v/v), EtOH, rt, 90 min, 84-94%; (e) 19a or 19d, PPh3, DIAD, THF, rt, 1 h, 52% for 4a, or 20% for 4d; or
21, PPh3, DIAD, THF, rt, 1 h, 56% for 34; (f) TFA/CH2Cl2, 1:1, rt, 3 h, 97%; (g) RBr, Cs2CO3, DMF, rt, 16-36 h, 50-96%.
Scheme 6a
a (a) p-Fluorobenzonitrile, DIPEA, DMSO, 120 °C, 24 h, 87%; (b) (1) NaH, DMF, 0 °C, 30 min; (2) 15, 0 °C f rt, 3 h, 56% (or 89% brsm); (c) H2, 10%
Pd/C, 0.5% conc HCl, EtOH, rt, 1 h, 87%; (d) PPh3, DIAD, DPPA, THF, 0 °C f rt, 16 h; (e) (1) PPh3, THF, rt, 1 h; (2) H2O, 65 °C, 7 h, 56% (combined
yield for steps d and e); (f) 18, DIPEA, CH3CN, 0 °C f rt, 16 h, 75%; (g) RBr (or RI), Cs2CO3, DMF, rt, 16 h to 7 days, 22-81%.
of the Zn(II)-binding imidazole τ-nitrogen (Nτ-alkylation), a side
reaction that competed effectively with the desired sulfonamide
alkylation because of considerable steric hindrance around the
sulfonamide NH.
In order to prepare the corresponding trans analogues, (()-39
was reacted with p-nitrobenzoic acid under Mitsunobu conditions
(Scheme 7), which again led to an approximate 3:2 mixture of
ester (substitution product) and alkene (elimination product). No
attempt at purification was made at this stage, and LiOH ·H2O was
added directly to the reaction mixture. After 3 h, the ester hydrolysis
was complete. Purification of the reaction mixture gave the cis
product (()-43 in 39% yield for the two steps, whose inverted
1
stereochemistry was evident from the comparison of H NMR
spectra of (()-39 and (()-43. Again, the subsequent Mitsunobu
reaction with secondary sulfonamide 19a was unfruitful. However,
reaction with the alternative sulfonamide 21 was a success, likely
due to a combination of the increased acidity of 21 relative to the
other sulfonamides 19a-e and reduced steric hindrance in the
substitution step of the Mitsunobu reaction. Silica gel flash column
chromatography furnished (()-44 in approximately 90% purity,

5182 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
Scheme 7a
51 to give O-benzyl compound (()-52 (95%, two steps).
Mitusnobu conditions effected conversion of the hydroxyl of
(()-52 to the inverted azide whose reduction to primary amine
(()-53 was accomplished with PPh3 and water (Staudinger
reaction). Nucleophilic aromatic substitution of (()-53, followed
by N-alkylation as before gave tertiary aniline (()-54, which
was then subjected to optimized hydrogenolytic cleavage
conditions to furnish secondary alcohol (()-55 in a yield of
83%. Finally, coupling of (()-55 to the series of secondary
sulfonamides 19a-d with PPh3 and DIAD proceeded in poor
to good yields to afford the (()-trans-1,3-diaminocyclopentyl
PfPFT inhibitors (()-8a-d. Due to the limited solubility of
sulfonamide 19e and the already low yields for this final
Mitsunobu step, compound 8e had to be prepared in the same
manner as that used to prepare the trans-1,2-diaminocyclopen-
tane-based inhibitors. Specifically, (()-55 was coupled to
sulfonamide 21 under standard Mitsunobu conditions, after
which the Boc group was removed by TFA, and then the
resultant secondary sulfonamide was alkylated with N-(2-
pyrimidinyl)-4-iodomethylpiperidine, furnishing (()-8e. For the
syntheses of the (()-trans-1,3-diaminocyclopentyl PfPFT in-
hibitors (()-9a-e, the synthetic transformations were identical
from (()-57, as depicted in Scheme 8.
(()-cis-1,4-Diaminocyclohexyane-Based Inhibitors ((()-10a,
(()-10d) and (()-trans-1,4-Diaminocyclohexane-Based Inhibi-
tors ((()-11a, (()-11d). Scheme 9 illustrates the synthetic steps
pursued in order to furnish the (()-cis-1,4- ((()-10a, (()-10d)
and the (()-trans-1,4-diaminocyclohexyl ((()-11a, (()-11d)
PfPFT inhibitors, for which only the R ) Bn and R ) N-Boc-
piperidin-4-ylmethyl derivatives were prepared. (()-cis-1,4-
Diaminocyclohexane ((()-61) was mono-arylated with p-flu-
orobenzonitrile in 77% yield to give (()-62, which was then
sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl choride
(18) to furnish 63. Chemoselective alkylation of the sulfonamide
NH with benzyl bromide and N-Boc-4-bromomethylpiperidine
was accomplished without incident, affording (()-64a and (()-
64d, respectively. Finally, the secondary anilines were alkylated
with 15 to yield the target PfPFT inhibitors (()-10a and (()-
10d in moderate yields, where the mass balance was recovered
starting material. Starting from (()-trans-1-tert-butoxycarbo-
nylamino-4-aminocyclohexane ((()-65), the trans isomers (()-
11a and (()-11d were furnished in a similar fashion.
a (a) p-Nitrobenzoic acid, PPh3, DIAD, THF, rt, 16 h; (b) LiOH ·H2O,
THF/MeOH/H2O, 3:1:1, rt, 3 h, 39% (two steps); (c) 21, PPh3, DIAD, THF,
45 °C, 16 h; (d) TFA/CH2Cl2, 1:1, rt, 3 h, 63% (two steps); (e) RBr, Cs2CO3,
DMF, rt, 16 h to 7 days, 75-85%.
and subsequent removal of the Boc group with TFA, followed by
the usual purification, generated pure secondary sulfonamide (()-
45 in a yield of 63% for the two steps. Finally, alkylation of
sulfonamide (()-45 with the five bromides as before gave the final
(()-trans-1,2-diaminocyclopentyl PfPFT inhibitors (()-7a-e in
good yields.
(()-cis-1,3-Diaminocyclopentane-Based Inhibitors ((()-
8a-e) and (()-trans-1,3-Diaminocyclopentane-Based Inhibi-
tors ((()-9a-e). The 1,3-diaminocyclopentyl inhibitors (()-
8a-e and (()-9a-e were prepared as shown in Scheme 8. After
quantitative O-silylation of hepta-1,6-dien-4-ol (46) with TB-
DPSCl, the cyclopentane scaffold was constructed by treatment
with Grubbs’s catalyst to give 48. Subsequent oxidation with
m-CPBA in CH2Cl2 gave cis epoxide 49 and trans epoxide 50
in an approximate 1:1 ratio, in a combined yield of 84%.
Reductive opening of the epoxide ring of 49 with H2 and a range
of catalysts, including 10% Pd/C, Pd(OH)2, or PtO2, were all
attempted but were very slow even at pressures of up to 70 psi
of H2. Alternative treatment with LiAlH4 was successful,
furnishing racemic (()-51 in 93% yield. On the other hand,
while executing the reductive opening of the epoxide ring of
diastereomeric compound 50, LiAlH4 also caused the surprising
removal of the TBDPS protecting group to give (()-trans-
cyclopentane-1,3-diol ((()-56) in 84% yield. Nucleophilic
aromatic substitution test reactions of the primary amino
analogue of (()-51, specifically 1-tert-butyldiphenylsilyloxy-
2-aminocyclopentane, with p-fluorobenzonitrile, led to removal
of the silicon protecting group, presumably by the action of
liberated fluoride ion, and subsequent O-arylation. Therefore,
single re-silylation of (()-56 was not attempted; monobenzy-
lation of (()-56 under phase transfer conditions was instead
effected to give (()-57 in excellent yield.
Results and Discussion
Ethylenediamine-Based Inhibitors (1a-e). For comparison
with the 10 series of inhibitors in this study, we present a table
that includes previously published data on the corresponding
ethylenediamine-based inhibitors.26,27 Table 1 shows percentage
enzyme inhibition of PfPFT by compounds 1a-e at 50 and 5
nM inhibitor concentration. Also shown are ED50 data, which
are the required inhibitor concentration to inhibit 50% of the
growth of parasites (two strains of P. falciparum: 3D7 and K1)
in whole cells (erythrocytes), as determined through the
incorporation of tritium-labeled hypoxanthine (see Experimental
Methods for details). As indicated in Table 1, all inhibitors
exhibited potent inhibition of PfPFT in vitro (g74% inhibition
at 5 nM) and proved highly effective antimalarials in whole
cells (several ED50 values <100 nM).
1,3-Diaminopropane-Based Inhibitors (2a-e). By com-
parison of the percentage enzyme inhibition data for the 1,3-
diaminopropane-based inhibitors (Table 2) with the correspond-
ing data for the ethylenediamine scaffold derivatives (Table 1),
compounds 2a, 2b, and 2c were all much poorer inhibitors of
PfPFT. However, with the larger N-Boc-piperidin-4-ylmethyl
In order to keep the two syntheses, which were already being
conducted in tandem, as similar as possible, we executed a two-
step protecting group exchange on O-TBDPS derivative (()-

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5183
Scheme 8a
a (a) TBDPSCl, Im, THF, 45 °C, 16 h, 99%; (b) Grubbs’s first generation catalyst, CH2Cl2, rt, 3 days, 63%; (c) m-CPBA, CH2Cl2, 0 °C f rt, 16 h, 43%
(49), 41% (50); (d) LiAlH4, THF, 0 °C, 2 h, 93% ((()-51) or 84% ((()-56); (e) BnBr, NaH, DMF, 0 °C f rt, 16 h, 98%; (f) TBAF, THF, 0 °C f rt, 3 h,
97%; (g) PPh3, DIAD, DPPA, THF, rt, 16 h, 88% (from (()-52) or 92% (from (()-57); (h) (1) PPh3, THF, rt, 1 h; (2) H2O, 65 °C, 7 h, 94% ((()-53) or
97% ((()-58); (i) p-fluorobenzonitrile, DIPEA, DMSO, 120 °C, 2 d, 48 h, 99% (from (()-53) or 94% (from (()-58); (j) (1) NaH, DMF, 0 °C, 30 min; (2)
15, 0 °C f rt, 3 h, 52% ((()-54) or 47% ((()-59); (k) H2, 10% Pd/C, 0.5% conc HCl (v/v), EtOH, rt, 1 h, 83% ((()-55) or 85% ((()-60); (l) 19a-e, PPh3,
DIAD, THF, rt, 16 h, 32-79%; (m) (1) NaH, THF, 0 °C, 1 h; (2) BnBr, TBAI, 0 °C f rt, 16 h, 95%.
Scheme 9a
a (a) p-fluorobenzonitrile, DIPEA, DMSO, 120 °C, 48 h, 77% (for (()-62) or 89% (from (()-65); (b) 18, DIPEA, CH3CN, rt, 16 h, 76% (for (()-63) or
86% (for (()-66); (c) RBr, Cs2CO3, DMF, rt, 16 h to 3 days, 82-99%; (d) (1) NaH, DMF, 0 °C, 30 min; (2) 15, 0 °C f rt, 12 h, 61-69% (92-95% brsm);
(e) TFA/CH2Cl2, 1:1, rt, 30 min, 100%.
(2d) and N-(2-pyrimidinyl)-piperidin-4-ylmethyl derivatives
(2e), inhibition of the enzyme was almost the same as that for
the corresponding ethylenediamine derivatives (e.g., 2d, 73%
inhibition at 5 nM, vs 1d, 81% inhibition at 5 nM), suggesting
that the reduction in activity caused by the additional methylene
in the scaffold may have been offset by incorporating a large R
group. Indeed, compound 2d was an especially potent inhibitor
of PfPFT, with an IC50 of 1 nM (Table 7). ED50 data reflect the
variation in PfPFT inhibitor potency, supporting inhibition of
PfPFT as the target for antimalarial activity, with 2d proving
the most effective antimalarial of this series in whole cells (ED50
) 330 nM (3D7), 190 nM (K1)). A low energy docked
conformation of 2a overlaid with that of 1a (Supporting
Information Figure 1) suggested that the ethylenediamine-based
derivative should be a much better fit in the homology model
of the PfPFT active site and that 2a with its extra methylene
unit in the scaffold should be too long to bind as well as 1a,
requiring a degree of buckling of the scaffold to enable

5184 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
Table 1. Enzyme Inhibition and Whole Cell Data for
Ethylenediamine-Based Inhibitors 1a-ea
Table 2. Enzyme Inhibition and Whole Cell Data for
1,3-Diaminopropane-Based Inhibitors 2a-ea
a ND ) not determined because of limited stocks of PfPFT enzyme or
Plasmodium-infected whole cell cultures.
a ED50 ) effective dose of inhibitor required to decrease P. falciparum
growth (in infected erythrocytes) by 50%.
5a,d) (Figure 3) showed 0% enzyme inhibition at 50 nM and
were not studied further. Even though GOLD docking studies
suggested that these derivatives would be reasonably well
accommodated in the PfPFT active site (Supporting Information
Figure 3), we invoked several constraints that meant the increase
in hydrophilicity of the scaffold would be ignored. The scaffold-
binding region of the active site is hydrophobic, so it would be
expected that a compound with a polar component in the
scaffold, such as an amide bond, would be poorly tolerated. In
addition, the rigidity incurred upon inclusion of the planar amide
bond, which we hoped to offset by the addition of an extra
methylene in the scaffold (4 f 5), and the amide-induced
withdrawal of electrons from the p-cyanophenyl group (a moiety
that is known to contribute particular potency to our inhibitors27)
are two possible further reasons as to why these amide
derivatives showed no inhibition of PfPFT at 50 nM.
(()-cis- and (()-trans-1,2-Diaminocyclopentane-Based
Inhibitors ((()-6a-e and (()-7a-e). As Table 4 shows, the
(()-cis-1,2-diaminocyclopentyl-based derivatives (()-6a-e per-
formed very poorly indeed, with little or no inhibition of PfPFT
at 50 nM inhibitor concentration. Similarly, ED50 values were
disappointing; in most cases they were at least an order of
magnitude worse than their ethylenediamine-based parent
compounds. These results were expected, since docking studies
of (()-6a in the homology model of the enzyme active site
indicated that the constraint imposed by the cis 1,2-cyclic
scaffold meant that only one of the two functionalized scaffold
amines could project its appendages into its two predicted
binding subpockets (Figure 2B).
simultaneous access of the four N-appendages into the four
subpockets. This prediction appears to have been confirmed
experimentally, particularly in the case of the smaller R group
derivatives.
gem-Dimethylethylenediamine-Based Inhibitors (3a-e).
Discounting thiophene 3c, the gem-dimethylethylenediamine
scaffold derivatives (Table 3) were as potent, if not more so, as
the corresponding ethylenediamine compounds (e.g., 3a, 88%
inhibition, vs 1a, 86% inhibition at 5 nM; and 3e, 93%
inhibition, vs 1e, 74% inhibition at 5 nM). Especially potent
whole cell activity, such as ED50 ) 160 nM (3D7) and 55 nM
(K1) for 3a, parallels potent enzyme inhibition data in most
cases, again supporting PfPFT as the relevant target for
antimalarial activity. Indeed, 3a is one of our most potent,
ethylenediamine-inspired antimalarials to date, and the improved
whole cell activity relative to 1a (ED50 ) 349 nM (3D7) and
375 nM (K1)) may be a consequence of the increased hy-
drophobicity of the scaffold, facilitating cellular entry. GOLD
docking studies (Supporting Information Figure 2) suggested
that these gem-dimethylethylenediamine-based inhibitors should
be tolerated in the PfPFT active site as well as the parent
ethylenediamines, and this has been supported experimentally.
The reason for the increased potency of the gem-dimethyleth-
ylenediamine-based 3e in vitro may be due to additional
hydrophobic contacts between the extra methyls of the inhibitor
and the scaffold-binding region of the active site or to improved
contacts of the p-cyanoaniline as a direct consequence of the
Thorpe-Ingold effect32 or to a combination of both effects.
2-Aminoethanamide- and 3-Aminopropanamide-Based
Inhibitors (4a,d and 5a,d). All the amide derivatives (4a,d and
On the other hand, although the trans diastereoisomers (()-
7a-e (Table 4) did not perform better than the corresponding
ethylenediamine-based inhibitors (Table 1), they were more

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5185
Table 3. Enzyme Inhibition and Whole Cell Data for
gem-Dimethylethylenediamine-Based Inhibitors 3a-ea
(()-cis- and (()-trans-1,3-Diaminocyclopentane-Based
Inhibitors ((()-8a-e and (()-9a-e). As Table 5 shows, the
(()-cis-1,3-diaminocyclopentyl-based derivatives (()-8a-e were
not very active PfPFT inhibitors relative to the ethylenediamine
parent compounds 1a-e (Table 1). Nonetheless, these inhibitors
were more potent than the corresponding cis-1,2-diaminocy-
clopentyl derivatives (()-6a-e (Table 4) and approximately
as potent as the corresponding trans-1,2-diaminocyclopentyl-
based inhibitors (()-7a-e (Table 4). For example, compound
(()-8a exhibited 40% inhibition at 50 nM inhibitor concentra-
tion, compared with 0% for (()-6a and 42% for (()-7a. N-Boc-
piperidin-4-ylmethyl compound (()-8d was approximately as
active as (()-7d in terms of inhibition of PfPFT ((()-8d, 33%
inhibition at 5 nM, vs (()-7d, 41% inhibition at 5 nM) but even
more potent in whole cells with ED50 values of 300 nM (3D7)
and 125 nM (K1) for (()-8d compared with ED50 values of
2650 nM (3D7) and 600 nM (K1) for (()-7d. GOLD docking
studies correctly predicted that the cis-1,3-diaminocyclopentyl
scaffold would not facilitate binding as well as the ethylene-
diamine scaffold (Supporting Information Figure 5) and also
that simultaneous access to the four subpockets would be more
reasonable than with the isomeric but more sterically congested
cis-1,2-diaminocyclopentyls (compare Figure 2B and Supporting
Information Figure 5).
As was the case with the 1,2-cyclopentyl derivatives, the
trans-1,3-diaminocyclopentyl-derived inhibitors (()-9a-e were
more active (Table 5) than their analogous cis-1,3-diaminocy-
clopentyl diastereomers (()-8a-e. Especially noteworthy are
compounds (()-9a and (()-9d, which were approximately as
active as the corresponding ethylenediamine inhibitors: a, 93%
inhibition at 50 nM for (()-9a vs 98% for 1a; d, 86% inhibition
at 5 nM for (()-9d vs 81% for 1d. These potent enzyme
inhibition data are reflected in potent whole cell data, such as
ED50 ) 80 nM (K1) for (()-9d, making (()-9d one of our
most effective ethylenediamine-inspired antimalarials to date.
These experimental findings confirm the docking studies, which
suggested that the trans-1,3-diaminocyclopentyl scaffold would
allow access by all four N-substituents to each of the predicted
subpockets in a similar manner to the ethylenediamine scaffold
and were, therefore, predicted to be good inhibitors of PfPFT
(Figure 2C).
a ND ) not determined.
(()-cis and (()-trans-1,4-Diaminocyclohexane-Based
Inhibitors ((()-10a, (()-10d, (()-11a, and (()-11d). For the
cyclohexyl scaffold, we made only two derivatives of each
diastereoisomer, incorporating either the small benzyl group or
the larger N-Boc-piperidin-4-ylmethyl group; the percentage
enzyme inhibition data and whole cell ED50 data are shown in
Table 6. The cis-1,4-diaminocyclohexyl derivative (()-10a
exhibited limited inhibition of PfPFT (23% inhibition at 50 nM),
while the trans isomer (()-11a was more active (73% inhibition
at 50 nM). Both isomers were less potent than the parent
ethylenediamine-based inhibitor 1a, which was predicted by
GOLD docking studies. In the case of (()-10a, the cis
configuration of the scaffold appeared to render it difficult for
both the scaffold nitrogens to deliver their appendages into the
proposed binding pockets (Supporting Information Figure 6).
Conversely, in the case of (()-11a, the trans configuration was
predicted to facilitate simultaneous access to all four subpockets,
although the greater interscaffold nitrogen-nitrogen distance
appeared to be less optimal than for the parent inhibitor 1a
(Supporting Information Figure 7), possibly accounting for the
slightly worse percentage inhibition data. N-Boc-piperdin-4-
ylmethyl derivatives (()-10d and (()-11d demonstrated no
inhibitory activity against PfPFT, which is likely a consequence
Figure 3. 2-Aminoethanamide- (n ) 1) and 3-aminopropanamide- (n
) 2) based inhibitors.
active than their cis counterparts (()-6a–e (Table 4) at both 50
and 5 nM inhibitor concentration; the most potent trans
compound, (()-7d, displayed 41% enzyme inhibition at 5 nM
(cf. 81% for 1d and 3% for 6d). This improvement in activity
in the enzyme assay was also reflected in superior whole cell
activity, with (()-7d exhibiting an ED50 of 600 nM for K1 strain
(cf ED50 ) 1250 nM for (()-6d (K1)). These trends in the
experimental results (cis-1,2-diaminocyclopentane vs trans-1,2-
diaminocyclopentane vs ethylenediamine) appear to be mirrored
in the GOLD docking studies. While the trans-1,2-diaminocy-
clopentyl derivatives were predicted (Supporting Information
Figure 4) to be unable to simultaneously access all four
subpockets as effectively as the corresponding ethylenediamine-
based inhibitors, the trans derivatives ((()-7a-e) appeared to
exhibit better complementarity to the active site than did their
more sterically encumbered cis counterparts ((()-6a-6e).

5186 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
Table 4. Enzyme Inhibition and Whole Cell Data for (()-cis-1,2-Diaminocyclopentane-Based Inhibitors (()-6a-e and for
(()-trans-1,2-Diaminocyclopentane-Based Inhibitors (()-7a-e
of the large scaffold coupled with the bulky R group rendering
these inhibitors too big to access the active site.
percentage inhibition of PfPFT at 5 nM inhibitor concentration.
Given the often imprecise nature of percentage inhibition data
and the unavailability of multiple assay results for any given
compound, care was taken to ignore any model that suggested
an accuracy of greater than 90% (i.e., r2 or q2 > 0.9). The
corresponding theoretical data for the models were obtained as
follows. For the first QSAR model, docked poses of each ligand
constrained to our hypothesized binding mode were used for
descriptor calculations, and the resultant GOLD-Score values
were included as descriptors in the modeling. Nineteen samples
were randomly chosen as a training set, leaving nine samples
as a test set. Further details can be obtained by consulting the
Experimental Methods. As shown in Figure 4, the training set
has an r2 value of 0.86, suggesting there is very good correlation
between the observed inhibition and the predicted inhibition of
PfPFT at 5 nM inhibitor concentration. Indeed, a test set of the
QSAR model was found to have a q2 value of 0.81, suggesting
that this model may hold strong predictive power.
In order to further test our hypothesis regarding the proposed
binding mode of these molecules to PfPFT and of the homology
model itself, a second QSAR model was prepared. For this model,
descriptors were calculated on the basis of molecules that had been
energy minimized rather than docked, with the exception of GOLD-
Score derived values, which were still included but left unaltered.
Also, the training and testing sets were deliberately chosen to be
identical to those in the previous model rather than randomly
chosen. Other than this, all operations were identical between the
two models. The results of this second model are shown in Figure
5. While similar accuracy was achieved for the training set (r2 )
0.86), very little predictive power was seen with the test set (q2 )
0.37), suggesting that this model simply memorized, rather than
learned, data from the training set. Also, it suggests that there is
Selectivity. Previously reported PfPFT inhibitors have dem-
onstrated poor selectivity for parasitic PFT over mammalian
PFT or are highly selective for the mammalian enzyme.9,10,18
Although PFT inhibitors have demonstrated limited toxicities
to mammalian cells at concentrations required to effect a
therapeutic response,10 the antiproliferative nature of PFT
inhibitors may restrict their use by children and pregnant women,
two of the main target groups in malaria therapy. Hence, the
selective inhibition of parasitic PFT may prove mandatory in
order to realize safe and effective antimalarial PFT inhibitors.
We previously reported on the selectivity of our ethylenedi-
amine-based inhibitors for PfPFT over rat PFT; IC50 values
revealed several inhibitors with greater than 100-fold selectivity
for the parasitic PFT.27 The amino acid sequences of rat and
human PFT are 95% identical with complete sequence and
structural conservation around the active site.33 While the aim
of this research was not to design ever more Plasmodium-
selective PFT inhibitors, it is worth noting that modification to
the inhibitor scaffold has had no detrimental effect on PFT
selectivity. Specifically, for a series of the N-Boc-piperidin-4-
ylmethyl derivatives (selected as representative examples of
inhibitors bearing the alternative scaffolds) greater than 100-
fold selectivity for parasitic over mammalian PFT was observed
(Table 7). In particular, compound 3d represents one of our
most potent (PfPFT IC50 ) 1.1 nM) and most selective (136-
fold) PfPFT inhibitors.
QSAR Models. Quantitative structure-activity relationship
(QSAR) models were generated to help determine the validity
of both the proposed binding mode and the PfPFT active site
homology model itself. Experimental data selected were the

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5187
Table 5. Enzyme Inhibition and Whole Cell Data for (()-cis-1,3-Diaminocyclopentane-Based Inhibitors (()-8a–e and for
(()-trans-1,3-Diaminocyclopentane-Based Inhibitors (()-9a-ea
a ND ) not determined.
information content in the docked poses and thus that these docked
poses are reasonable. Taken together, these QSAR models inform
us that our hypothesis of the proposed binding mode is sound and
that the homology model is a good approximation of the active
site of PfPFT.
most potent (IC50 ≈ 1 nM) and the most selective for parasitic
PFT over mammalian PFT (up to 136-fold) currently reported
in the literature.
Considering cost involved and speed and ease of synthesis,
we conclude that the parent ethylenediamine-based inhibitors
reported previously26,27 are our best antimalarials of this series
thus far, and given the already high degree of selectivity over
the mammalian isoform of PFT, future research should now be
directed toward three goals. Inhibitor 1d is highly potent (IC50
) 1.2 nM), selective for parasitic over mammalian PFT (117-
fold), and exhibits very good whole cell activity (ED50 ) 88
nM (3D7), 54 nM (K1)). Therefore, we first suggest further work
is undertaken on this inhibitor to improve these ED50 values,
which may be achieved by substituting the 3-methyl-3H-
imidazole-4-sulfonyl group with the less basic and more
hydrophobic pyridine-2-sulfonyl group,27 for example. Second,
efforts should be made toward improving the limited metabolic
stability of 1d reported by us previously.26,27 We showed how
our inhibitors were quickly oxidized upon incubation with liver
microsomes, probably by cytochrome P450, followed by loss
of the aniline functionalized zinc-binding imidazole. It is likely
that cytochrome P450-mediated inhibitor oxidation is initiated
by loss of one electron of the aniline nitrogen lone pair, followed
by abstraction of a hydrogen radical from the activated meth-
ylene group between the aniline and imidazole, ultimately
leading to N-dealkylation of the imidazolylmethyl moiety. As
described in the manuscript by Seto et al.,34 aniline N-
dealkylation can only proceed when the aniline lone pair of
electrons is oxidizable and when there is at least one hydrogen
on the carbon directly attached to the aniline nitrogen. Thus,
improved inhibitor metabolic stability may be achieved by (a)
Conclusions
We have synthesized several series of novel antimalarials
incorporating a variety of scaffolds based on our previously
reported ethylenediamine-derived inhibitors of PfPFT. These
antimalarials were designed to allow exploration of the PfPFT
active site and therein assess the validity of our predicted
inhibitor binding mode and of the active site homology model
itself. In turn, it was hoped that this garnered information would,
in the near future, facilitate, and thereby accelerate, access to
increasingly more-potent PfPFT inhibitors. Low energy docked
conformations (GOLD), which were performed by loosely
constraining our inhibitors to the docking pose we predicted in
our previous publications,26,27 suggested which compounds
would inhibit PfPFT well and which would not. Broadly
speaking, biological evaluation of our compounds agreed with
the computational docking studies, and from these data we
developed two QSAR models that suggested the predicted
binding mode for our inhibitors is reasonable and that the
homology model we have used to design inhibitors is a good
approximation of the PfPFT active site. In addition, our first
QSAR model seems to have considerable predictive power and
with suitable biological validation could therefore be used to
design new inhibitors. Importantly, as well as proving particu-
larly cytotoxic to cultured parasites (ED50 < 100 nM), some of
our novel antimalarial PfPFTIs reported herein are among the

5188 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
Table 6. Enzyme Inhibition and Whole Cell Data for
(()-cis-1,4-Diaminocyclohexane-Based Inhibitors (()-10a and (()-10d
and (()-trans-1,4-Diaminocyclohexane-Based Inhibitors (()-11a and
(()-11d
Figure 5. QSAR model in which descriptors were calculated on the
basis of ligands that had been energy-minimized: (blue diamond)
training set, r2 ) 0.86; (pink square) test set, q2 ) 0.37.
Table 7. Comparative P. falciparum and Rat PFT Inhibition Data for a
Series of Inhibitors Where R ) N-Boc-piperidin-4-ylmethyl
Figure 4. QSAR model in which descriptors were calculated on the
basis of docked poses of ligands constrained to our hypothesized binding
mode: (blue diamond) training set, r2 ) 0.86; (pink square) test set, q2
) 0.81.
a Inhibitor concentration required to decrease P. falciparum or rat PFT
activity by 50%. ND ) not determined. b Ratio of rat to P. falciparum
PFT IC50 values.
reducing electron density on the aniline nitrogen through
incorporation of additional electron-withdrawing groups on the
cyanophenyl ring and/or (b) replacing the methylene unit
between the aniline nitrogen and the zinc-binding imidazole with
a gem-dimethyl unit. Finally, our third goal should be the
investigation of the activities of our antimalarials in drug-
resistant strains of P. falciparum PFT (such as the Y837C
strain19 that shows resistance to BMS-388891 and the G612A
strain20 that shows resistance to BMS-339941). This research
is essential not only to evaluate the potencies of our compounds
in such strains but also, after preparing similar QSAR models
for the mutant active sites as we did for the wild-type, to identify
structural modifications that we may undertake to restore
inhibitor potency where it may be needed. In this way, new
antimalarial PfPFTIs that are active against drug-resistant strains
of P. falciparum may be realized.
Experimental Methods
Ligand Docking Studies. Docking experiments were performed
using the GOLD version 3.128 software package. Ligands were
prepared for docking in InsightII.30 Each ligand was drawn as a
two-dimensional representation and converted to three dimensions.
Ligands were subsequently energy minimized with the cvff force
field. The homology model was also prepared for use in InsightII,
where each residue was protonated on the basis of calculated pKa
values at a pH of 7.4.
Ligands were constrained in the active site of PfPFT at three
points in order to maintain the binding mode hypothesized for lead

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5189
compound 1a. A single atom of each imidazole and the cyanoaniline
were chosen and constrained to occupy a region of space within 1
Å of that occupied by the equivalent atoms of docked 1a. This
was performed using the substructure constraint functionality of
GOLD. A small spring constant was used as a penalty function
such that molecules could dock in alternative conformations, but
these would be discouraged. GOLD was allowed to configure the
optimal genetic algorithm settings for each ligand.
General Procedure C (Aniline Alkylation). Reaction of Second-
ary Anilines with 5-Chloromethyl-1-methyl-1H-imidazole·HCl
(15). The secondary aniline (1 equiv) was dissolved in DMF (0.07
M). Then the mixture was cooled to 0 °C. After 15 min, NaH (3
equiv) was added in one portion. After a further 15 min, 5-chlo-
romethyl-1-methyl-1H-imidazole·HCl27 (15) (1.1 equiv) was added
to the reaction mixture. The mixture was allowed to stir at 0 °C
for 2–3 h, when TLC indicated the reaction was complete or had
stalled. Upon quenching the reaction with brine (approximately 1
mL), the mixture was diluted with water and extracted with EtOAc
(×3). The EtOAc extractions were combined and washed with 5%
NaHCO3 (×3) and brine, dried (Na2SO4), filtered, and concentrated.
QSAR Modeling. Descriptors were calculated using the MOE
software package.35 RECON TAE and RAD descriptors36 were
calculated in addition to the standard assortment of 2D descriptors
in MOE. Additional descriptors included energy measurements with
the MMFF94x, Amber-99, and OPLS-AA force fields. Feature
selection and modeling were performed using the Analyze software
package.37 For further details, see Supporting Information.
Chemistry: General Methods. Solvents CH2Cl2, THF, CH3CN,
and DMF were dried on an Innovative Technology SPS-400 dry
solvent system. Anhydrous MeOH and DMSO were purchased from
Sigma-Aldrich and used directly from their Sure-Seal bottles.
Molecular sieves were activated by heating to 300 °C under vacuum
overnight. All reactions were performed under an atmosphere of
dry nitrogen in oven-dried glassware and were monitored for
completeness by thin-layer chromatography (TLC) using silica gel
(visualized by UV light or developed by treatment with KMnO4
stain or Hanessian’s stain). 1H and 13C NMR spectra were recorded
on Bruker AM 400 MHz and Bruker AM 500 MHz spectrometers
in either CDCl3, MeOH-d4 or DMSO-d6. Chemical shifts (δ) are
reported in parts per million after calibration to residual isotopic
solvent. Coupling constants (J) are reported in Hz. Mass spectrom-
etry (MS) was performed using electrospray ionization on either a
Varian MAT-CH-5 (HRMS) or a Waters Micromass ZQ (LRMS)
instrument. Before biological testing, target molecules (2a-e, 3a-e,
4a, 4d, 5a, 5d, 6a-e, 7a-e, 8a-e, 9a-e, 10a, 10d, 11a, 11d),
obtained as glassy films after silica gel flash column chromato-
graphic purification (eluent CH2Cl2/MeOH/NH4OH, 192:7:1), were
subjected to further purification by reversed-phase HPLC (rpHPLC).
Analysis and purification by rpHPLC were performed using either
Phenonenex Luna 5 µm C18 (2) 250 mm × 21 mm column run at
15 mL/min (preparative) or a Microsorb-MV 300 Å C18 250 mm
× 4.6 mm column run at 1 mL/min (analytical), using gradient
mixtures of (A) water with 0.1% TFA and (B) 10:1 acetonitrile/
water with 0.1% TFA. Appropriate product fractions were pooled
and lyophilized to dryness, affording the inhibitors as fluffy white
powders as their TFA salts. Inhibitor purity was confirmed by
analytical rpHPLC using linear gradients from 100% A to 100%
B, with changing solvent composition of either (I) 4.5% or (II)
1.5% per minute after an initial 2 min of 100% A. For reporting
HPLC data, percentage purity is given in parentheses after the
retention time for each condition.
[N-Benzyl-N-3-{(4-cyanophenyl)(3-methyl-3H-imidazol-4-
ylmethyl)amino}propyl]-1-methyl-1H-imidazole-4-sulfonamide (2a).
Primary alcohol 17 was coupled to secondary sulfonamide 19a on
a 0.106 mmol scale via general procedure A. The crude residue
was dry-loaded onto silica gel, then flash chromatographed (eluent
CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish 2a (51 mg, 96%): δH
(400 MHz, MeOH-d4) 1.71 (quin, J ) 7.0 Hz, 2H, CH2CH2CH2),
3.30-3.36 (obsc m, 4H, CH2CH2CH2), 3.83 (s, 3H, CH3(Im)), 3.89
(s, 3H, CH3(Im)), 4.34 (s, 2H, CH2Ph), 4.62 (s, 2H, CH2Im), 6.73
(d, J ) 8.8 Hz, 2H, 2 CH (Ar)), 7.14 (s, 1H, CH (Im)), 7.31-7.43
(m, 5H, 5 CH (Ph)), 7.50 (d, J ) 8.8 Hz, 2H, 2 CH (Ar)), 7.77 (s,
1H, CH (Im)), 7.84 (s, 1H, CH (Im)), 8.93 (s, 1H, CH (Im)); δC
(100 MHz, MeOH-d4) 27.4, 34.3, 34.4, 45.8, 48.6, 49.3, 54.7, 99.8,
113.8, 118.8, 121.0, 126.6, 128.9, 129.7, 129.9, 133.1, 134.7, 137.7,
138.7, 139.3, 141.4, 151.8; HRMS (ES+) calcd for [C26H29N7O2S
+ H] 504.2182, found 504.2198; HPLC (I) tR ) 15.69 min (100%),
(II), tR ) 27.81 min (100%).
[N-(2-Methylbenzyl)-N-3-{(4-cyanophenyl)(3-methyl-3H-imida-
zol-4-ylmethyl)amino}propyl]-1-methyl-1H-imidazole-4-sulfona-
mide (2b). Primary alcohol 17 was coupled to secondary sulfona-
mide 19b on a 0.137 mmol scale via general procedure A. The
crude residue was dry-loaded onto silica gel, then flash chromato-
graphed (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish 2b (64
mg, 90%): δH (400 MHz, MeOH-d4) 1.57 (quin, J ) 7.3 Hz, 2H,
CH2CH2CH2), 2.42 (s, 3H, CH3Ph), 3.21-3.27 (m, 4H, CH2-
CH2CH2), 3.85 (s, 3H, CH3(Im)), 3.88 (s, 3H, CH3(Im)), 4.33 (s,
2H, CH2Ph), 4.60 (s, 2H, CH2Im), 6.70 (d, J ) 8.8 Hz, 2H, 2 CH
(Ar)), 7.11 (s, 1H, CH (Im)), 7.14-7.26 (m, 3H, 3 CH (Ph)), 7.31
(br d, J ) 7.6 Hz, 1H, CH (Ph)), 7.49 (d, J ) 8.8 Hz, 2H, 2 CH
(Ar)), 7.78 (s, 1H, CH (Im)), 7.86 (s, 1H, CH (Im)), 8.93 (s, 1H,
CH (Im)); δC (100 MHz, MeOH-d4) 19.5, 27.8, 34.3, 34.4, 45.3,
48.0, 49.2, 53.5, 99.8, 113.8, 118.8, 121.0, 126.7, 127.1, 129.3,
131.2, 131.7, 133.0, 134.7, 135.6, 137.7, 138.7, 138.8, 141.4, 151.7;
HRMS (ES+) calcd for [C27H31N7O2S + H] 518.2338, found
518.2346; HPLC (I) tR ) 15.98 min (100%), (II) tR ) 28.75 min
(100%).
[N-(Thiophen-3-ylmethyl)-N-3-{(4-cyanophenyl)(3-methyl-3H-
imidazol-4-ylmethyl)amino}propyl]-1-methyl-1H-imidazole-4-sul-
fonamide (2c). Primary alcohol 17 was coupled to secondary
sulfonamide 19c on a 0.16 mmol scale via general procedure A.
The crude residue was dry-loaded onto silica gel, then flash
chromatographed (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give
2c (80 mg, 98%): δH (400 MHz, MeOH-d4) 1.78 (quin, J ) 7.2
Hz, 2H, CH2CH2CH2), 3.32-3.36 (obsc m, 2H, CH2CH2CH2NSO2),
3.37-3.41 (m, 2H, CH2CH2CH2NSO2), 3.83 (s, 3H, CH3(Im)), 3.91
(s, 3H, CH3(Im)), 4.36 (s, 2H, CH2thiophene), 4.68 (s, 2H, CH2Im),
6.79 (d, J ) 8.8 Hz, 2H, 2 CH (Ar)), 7.13 (dd, J ) 5.0, 1.2 Hz,
1H, CH (thiophene)), 7.18 (s, 1H, CH (Im)), 7.32-7.35 (m, 1H,
CH (thiophene)), 7.41 (dd, J ) 5.0, 2.8 Hz, 1H, CH (thiophene)),
7.53 (d, J ) 8.8 Hz, 2H, 2 CH (Ar)), 7.74 (s, 1H, CH (Im)), 7.83
(s, 1H, CH (Im)), 8.93 (s, 1H, CH (Im)); δC (100 MHz, MeOH-d4)
27.3, 34.3, 34.4, 45.4, 48.2, 49.3, 49.4, 99.8, 113.8, 118.9, 121.0,
125.1, 126.5, 127.5, 129.2, 133.1, 134.7, 137.7, 139.4, 139.4, 141.3,
151.8; HRMS (ES+) calcd for [C24H27N7O2S2 + H] 510.1746,
found 510.1761; HPLC (I) tR ) 15.12 min (100%), (II) tR ) 26.20
min (100%).
General Procedure A (Mitsunobu Reactions). Reaction of
Primary and Secondary Alcohols with Secondary Sulfonamides.
To a stirring solution of the alcohol (1 equiv) in THF (0.07 M)
(occasionally, sonication and a little warming (40 °C) was required
to achieve complete dissolution of the alcohol) was added the
secondary sulfonamide (2.5 equiv) and PPh3 (3 equiv). After the
mixture was stirred for 15 min at room temperature, DIAD (2.5
equiv) was added dropwise. For the acyclic, primary alcohols,
reactions were typically complete within 1 h; for the less reactive,
cyclic secondary alcohols and hindered primary alcohols, mixtures
were left stirring overnight (16 h). All solvent was removed in
vacuo.
General Procedure B (Sulfonamide Alkylations). Reaction of
Secondary Sulfonamides with Benzylic and Alkyl Bromides. To a
stirred solution of the secondary sulfonamide (1 equiv) in DMF
(0.01 M for benzylic bromide or 0.1 M for alkyl bromide) was
added Cs2CO3 (3 equiv). After 1 h, at room temperature, the
bromide (or iodide) alkylating agent (1.1 equiv) was added
dropwise. After 16 h, the reaction mixture was diluted with water
and extracted into EtOAc (×3). The EtOAc extractions were
combined and washed with 5% NaHCO3 (×3) and brine, dried
(Na2SO4), filtered, and concentrated.
[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-3-{(4-cyanophe-
nyl)(3-methyl-3H-imidazol-4-ylmethyl)amino}propyl]-1-methyl-

5190 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
1H-imidazole-4-sulfonamide (2d). Primary alcohol 17 was coupled
to secondary sulfonamide 19d on a 0.24 mmol scale via general
procedure A. The crude residue was dry-loaded onto silica gel, then
flash chromatographed (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to
afford 2d (132 mg, 90%): δH (400 MHz, MeOH-d4) 1.07 (qd, J )
12.3, 4.0 Hz, 2H, 2 CH (piperidinylmethyl)), 1.49 (s, 9H, C(CH3)3),
1.68-1.76 (m, 2H, 2 CH (piperidinylmethyl)), 1.79-1.90 (m, 1H,
CH (piperidinylmethyl)), 1.99 (quin, J ) 7.4 Hz, 2H, CH2CH2CH2),
2.64-2.80 (m, 2H, 2 CH (piperidinylmethyl)), 3.01 (d, J ) 7.6
Hz, 2H, 2 CH (piperidinylmethyl)), 3.29 (t, J ) 7.2 Hz, 2H,
CH2CH2CH2NSO2), 3.61 (t, J ) 7.2 Hz, 2H, CH2CH2CH2NSO2),
3.81 (s, 3H, CH3(Im)), 3.95 (s, 3H, CH3(Im)), 4.03-4.10 (m, 2H,
2 CH (piperidinylmethyl)), 4.87 (s, 2H, CH2Im), 6.96 (d, J ) 8.8
Hz, 2H, 2 CH (Ar)), 7.30 (s, 1H, CH (Im)), 7.58 (d, J ) 8.8 Hz,
2H, 2 CH (Ar)), 7.73 (s, 1H, CH (Im)), 7.79 (s, 1H, CH (Im)),
8.94 (s, 1H, CH (Im)); δC (100 MHz, MeOH-d4) 27.9, 28.7, 30.9,
34.2, 34.3, 36.5, 44.7 (br), 45.6, 48.9, 49.0, 56.3, 81.0, 100.0, 114.1,
119.0, 120.9, 126.5, 133.2, 134.8, 137.8, 139.3, 141.3, 151.9, 156.5;
HRMS (ES+) calcd for [C30H42N8O4S + H] 611.3128, found
611.3129; HPLC (I) tR ) 12.56 min (100%), (II) tR ) 18.92 min
(100%).
[N-{N-(2-Pyrimidinyl)-piperidin-4-ylmethyl}-N-3-{(4-cyanophe-
nyl)(3-methyl-3H-imidazol-4-ylmethyl)amino}propyl]-1-methyl-
1H-imidazole-4-sulfonamide (2e). Primary alcohol 17 was coupled
to secondary sulfonamide 19e on a 0.106 mmol scale via general
procedure A. The crude residue was dry-loaded onto silica gel, then
flash chromatographed (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to
yield 2e (38 mg, 61%): δH (400 MHz, MeOH-d4) 1.17 (qd, J )
12.2, 4.0 Hz, 2H, 2 CH (piperidinylmethyl)), 1.78-1.86 (m, 2H, 2
CH (piperidinylmethyl)), 1.94-2.04 (m, 3H, CH2CH2CH2, CH
(piperidinylmethyl)), 2.90-2.98 (m, 2H, 2 CH (piperidinylmethyl)),
3.04 (d, J ) 7.6 Hz, 2H, 2 CH (piperidinylmethyl)), 3.26-3.31
(m, 2H, CH2CH2CH2NSO2), 3.59-3.66 (m, 2H, CH2CH2-
CH2NSO2), 3.81 (s, 3H, CH3(Im)), 3.96 (s, 3H, CH3(Im)), 4.64-4.71
(m, 2H, 2 CH (piperidinylmethyl)), 4.88 (s, 2H, CH2Im), 6.66 (t,
J ) 5.1 Hz, 1H, CH (pyrimidine)), 6.97 (d, J ) 9.2 Hz, 2H, 2 CH
(Ar)), 7.31 (s, 1H, CH (Im)), 7.59 (d, J ) 9.2 Hz, 2H, 2 CH (Ar)),
7.73 (s, 1H, CH (Im)), 7.80 (s, 1H, CH (Im)), 8.38 (d, J ) 5.1 Hz,
2H, 2 CH (pyrimidine)), 8.95 (s, 1H, CH (Im)); δC (100 MHz,
MeOH-d4) 27.9, 30.9, 34.2, 34.3, 36.6, 45.2, 45.6, 49.1, 49.3, 56.3,
100.1, 110.6, 114.1, 119.0, 120.9, 126.5, 133.2, 134.8, 137.8, 139.3,
141.3, 151.9, 158.7, 160.7; HRMS (ES+) calcd for [C29H31N10O2S
+ H] 589.2822, found 589.2831; HPLC (I) tR ) 13.00 min (100%),
(II) tR ) 20.28 min (99.69%).
[N-Benzyl-N-{(4-cyanophenyl)(3-methyl-3H-imidazol-4-ylmet-
hyl)amino}-2,2-dimethylethyl]-1-methyl-1H-imidazole-4-sulfona-
mide (3a). The synthesis was as per general procedure A with
alcohol 27 on a 0.037 mmol scale and secondary sulfonamide 19a.
The mixture was heated to 45 °C for 18 h, reduced, and then dry-
loaded onto silica gel and purified by flash column chromatography
(eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give 3a (12 mg, 65%):
δH (400 MHz, CDCl3) 1.40 (s, 6H, C(CH3)2), 3.46 (s, 3H, CH3(Im)),
3.72 (s, 3H, CH3(Im)), 3.87 (s, 2H, CH2C(CH3)2), 4.47 (s, 2H,
CH2Ph), 4.70 (s, 2H, CH2Im), 6.58 (s, 1H, CH(Im)), 6.60 (d, J )
8.3 Hz, 2H, 2 CH (Ar)), 7.27-7.38 (m, 7H, 2 CH (Im), 5 CH (Ph)),
7.45 (d, J ) 8.3 Hz, 2H, 2 CH (Ar)), 7.47 (s, 1H, CH (Im)); δC
(125 MHz, CDCl3) 26.9, 31.8, 33.9, 47.1, 50.8, 59.3, 65.6, 99.3,
113.7, 120.0, 123.5, 126.7, 127.4, 127.7, 128.6, 129.0, 133.2, 138.4,
138.6, 139.4, 143.1, 151.6; HRMS (ES+) calcd for [C28H31N6O2S
+ H] 518.2343, found 518.2338; HPLC (I) tR ) 12.25 min
(99.66%), (II) tR ) 17.75 min (99.34%).
[N-(2-Methylbenzyl)-N-{(4-cyanophenyl)(3-methyl-3H-imidazol-
4-ylmethyl)amino}-2,2-dimethylethyl]-1-methyl-1H-imidazole-4-
sulfonamide (3b). The synthesis was as per general procedure A
with alcohol 27 on a 0.035 mmol scale and secondary sulfonamide
19b. The mixture was heated to 45 °C for 18 h, then reduced, and
dry-loaded onto silica gel and purified by flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give 3b (11
mg, 60%): δH (400 MHz, CDCl3) 1.40 (s, 6H, C(CH3)2), 2.23 (s,
3H, CH3Ph), 3.51 (s, 3H, CH3(Im)), 3.70 (s, 3H, CH3(Im)), 4.02
(s, 2H, CH2C(CH3)2), 4.56 (s, 2H, CH2Ph), 4.62 (s, 2H, CH2Im),
6.65 (s, 1H, CH (Im)), 6.72 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)),
7.10-7.39 (m, 6H, 2 CH (Im), 4 CH (Ar)), 7.45 (s, 1H, CH (Im)),
7.60 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CDCl3) 18.9,
26.5, 31.6, 33.6, 47.0, 47.3, 58.9, 65.2, 99.2, 113.6, 119.7, 123.6,
125.8, 126.5, 126.6, 127.0, 128.8, 130.0, 133.0, 133.6, 136.8, 138.2,
138.7, 142.5, 151.4; HRMS (ES+) calcd for [C28H33N7O2S + H]
532.2416, found 532.2452; HPLC (I) tR ) 12.80 min (95.01%),
(II) tR ) 19.70 min (95.06%).
[N-(Thiophen-3-ylmethyl)-N-{(4-cyanophenyl)(3-methyl-3H-imi-
dazol-4-ylmethyl)amino}-2,2-dimethylethyl]-1-methyl-1H-imidazole-
4-sulfonamide (3c). The synthesis was as per general procedure A
with alcohol 27 on a 0.088 mmol scale and secondary sulfonamide
19c. The mixture was heated to 45 °C for 18 h, reduced, and then
dry-loaded onto silica gel and purified by flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give 3c (25
mg, 55%): δH (400 MHz, CDCl3) 1.45 (s, 6H, C(CH3)2), 3.48 (s,
3H, CH3(Im)), 3.72 (s, 3H, CH3(Im)), 3.82 (s, 2H, CH2C(CH3)2),
4.46 (s, 2H, CH2thiophene), 4.67 (s, 2H, CH2Im), 6.61 (d, J ) 8.5
Hz, 2H, Ar), 6.64 (s, 1H, CH (Im)), 7.22-7.37 (m, 7H, 2 CH (Im),
2 CH (Ar), 3 CH (thiophene)), 7.45 (s, 1H, CH (Im)); δC (125
MHz, CDCl3) 26.9, 31.8, 33.9, 46.0, 46.9, 59.2, 65.3, 99.3, 113.7,
120.0, 122.9, 123.4, 126.0, 126.8, 128.1, 128.8, 133.2, 138.4, 138.5,
140.7, 143.2, 151.6; HRMS (ES+) calcd for [C25H29N7O2S2 + H]
524.1904, found 524.1902; HPLC (I) tR ) 12.56 min (100%), (II)
tR ) 18.70 min (100%).
[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-{(4-cyanophe-
nyl)(3-methyl-3H-imidazol-4-ylmethyl)amino}-2,2-dimethylethyl]-
1-methyl-1H-imidazole-4-sulfonamide (3d). The synthesis was as
per general procedure A with alcohol 27 on a 0.217 mmol scale
and secondary sulfonamide 19d. The mixture was heated to 45 °C
for 18 h, reduced, and then dry-loaded onto silica gel and purified
by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH,
192:7:1) to give 3d (68 mg, 50%): δH (400 MHz, CDCl3) 1.10
(qd, J ) 12.3, 4.0 Hz, 2H, 2 CH (piperidinylmethyl)), 1.39 (s, 6H,
C(CH3)2), 1.44 (s, 9H, C(CH3)3), 1.67-1.79 (m, 3H, 3 CH
(piperidinylmethyl)), 2.58-2.67 (m, 2H, 2 CH (piperidinylmethyl)),
3.28-3.36 (m, 2H, 2 CH (piperidinylmethyl)), 3.53 (s, 3H,
CH3(Im)), 3.72 (s, 3H, CH3(Im)), 3.85 (s, 2H, CH2(CH3)2),
4.05-4.15 (m, 2H, 2 CH (piperidinylmethyl)), 4.66 (s, 2H, CH2Im),
6.70 (s, 1H, CH (Im)), 6.92 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.35
(s, 1H, CH (Im)), 7.39 (s, 1H CH (Im)), 7.41 (s, 1H CH (Im)),
7.45 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CDCl3) 14.4,
27.3, 28.7, 29.9, 30.4, 32.1, 34.2, 38.3, 47.1, 52.5, 58.1, 64.8, 79.6,
100.0, 114.1, 120.1, 123.4, 129.4, 133.7, 138.5, 144.0, 152.1, 155.0,
171.4; HRMS (ES+) calcd for [C31H44N8O4S + H] 625.2765, found
625.2720; HPLC (I) tR ) 13.61 min (100%), (II) tR ) 21.80 (100%).
[N-{N-(2-Pyrimidinyl)-piperidin-4-ylmethyl}-N-{(4-cyanophenyl)(3-
methyl-3H-imidazol-4-ylmethyl)amino}-2,2-dimethylethyl]-1-meth-
yl-1H-imidazole-4-sulfonamide (3e). The synthesis was as per
general procedure A with alcohol 27 on a 0.037 mmol scale and
secondary sulfonamide 19e. The mixture was heated to 45 °C for
18 h, then dry-loaded onto silica gel and purified by flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to give 3e
(15 mg, 68% yield): δH (500 MHz, CDCl3) 1.17 (qd, J ) 12.2, 4.0
Hz, 2H, 2 CH (piperidinylmethyl)), 1.41 (s, 6H, C(CH3)2),
1.81-2.02 (m, 3H, 3 CH (piperidinylmethyl)), 2.79 (m, 2H, 2 CH
(piperidinylmethyl)), 3.33 (d, J ) 7.0 Hz, 2H, 2 CH (piperidinyl-
methyl)), 3.54 (s, 3H, CH3(Im)), 3.71 (s, 3H, CH3(Im)), 3.87 (m,
2H, CH2C(CH3)2), 4.68 (s, 2H, CH2Im), 4.73-4.79 (m, 2H, 2 CH
(piperidinylmethyl)), 6.42 (t, J ) 4.9 Hz, 1H, CH (pyrimidine)),
6.69 (s, 1H, CH (Im)), 6.91 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.35
(s, 1H, CH (Im)), 7.39 (s, 1H, CH (Im)), 7.42 (s, 1H, CH (Im)),
7.44 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 8.27 (d, J ) 4.9 Hz, 2H, 2
CH (pyrimidine)); δC (125 MHz, CDCl3) 27.4, 30.3, 32.1, 34.2,
38.6, 44.2, 47.1, 52.6, 58.3, 64.8, 99.9, 109.6, 114.1, 120.2, 123.5,
129.1, 133.7, 138.5, 139.0, 143.9, 152.1, 157.9, 161.8, 162.7; HRMS
(ES+) calcd for [C30H38N10O2S + H] 603.2969, found 603.2978;
HPLC (I) tR ) 13.62 min (100%), (II) tR ) 19.16 min (100%).
2-[Benzyl(1-methyl-1H-imidazole-4-sulfonyl)amino]-N-(4-cy-
anophenyl)-N-(3-methyl-3H-imidazol-4-ylmethyl)acetamide (4a).

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5191
Compound 32 was coupled to secondary sulfonamide 19a as per
general procedure A on a 0.164 mmol scale. After workup, the
crude residue was purified by silica gel flash column chromatog-
raphy (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish 4a (43
mg, 52%): δH (500 MHz, CDCl3) 3.60 (s, 3H, CH3(Im)), 3.70 (s,
2H, CH2CO), 3.76 (s, 3H, CH3(Im)), 4.60 (s, 2H, CH2Ph), 4.85 (s,
2H, CH2Im), 6.59 (br s, 1H, CH (Im)), 6.95 (d, J ) 8.5 Hz, 2H, 2
CH (Ar)), 7.19-7.24 (m, 2H, 2 CH (Ph)), 7.27-7.31 (m, 3H, 3
CH (Ph)), 7.43 (br s, 1H, CH (Im)), 7.45 (s, 1H, CH (Im)), 7.46 (s,
1H, CH (Im)), 7.58 (d, J ) 8.5 Hz, 2H, 2 CH (Ar)); δC (125 MHz,
CDCl3) 31.7, 33.9, 41.5, 47.6, 51.6, 112.6, 117.6, 123.9, 126.1,
127.9, 128.5, 128.6, 129.3, 130.4, 133.6, 135.2, 138.9, 139.1, 140.1,
143.6, 167.1; HRMS (ES+) calcd for [C25H25N7O3S + H]
504.1818, found 504.1830; HPLC (I) tR ) 11.48 min (100%), (II)
tR ) 15.67 min (100%).
31.8, 33.9, 34.9, 35.1, 41.2, 43.4 (br), 46.0, 55.3, 79.4, 112.5, 117.7,
124.2, 126.5, 129.5, 130.3, 133.7, 138.7, 139.0, 139.5, 144.6, 154.7,
170.0; HRMS (ES+) calcd for [C30H40N8O5S + H] 625.2921, found
625.2923; HPLC (I) tR ) 12.74 min (98.83%), (II) tR ) 19.28 min
(99.47%).
(()-[N-Benzyl-N-{cis-2-[(4-cyanophenyl)(3-methyl-3H-imidazol-
4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imidazole-4-sulfona-
mide (6a). The synthesis was as per general procedure B with 42
and benzyl bromide on a 0.0273 mmol scale. The crude residue
was purified by silica gel flash column chromatography (eluent
CH2Cl2/MeOH/NH4OH, 192:7:1) to afford 6a (8 mg, 55%): δH (400
MHz, CDCl3) 1.37-1.50 (m, 1H, CH (cyclopentyl)), 1.84-1.96
(m, 2H, 2 CH (cyclopentyl)), 2.04-2.19 (m, 2H, 2 CH (cyclopen-
tyl)), 2.49-2.56 (m, 1H, CH (cyclopentyl)), 3.55 (s, 3H, CH3(Im)),
3.67 (s, 3H, CH3(Im)), 3.88 (d, J ) 16.4 Hz, 1H, CHaPh), 4.14
(m, 1H, CHN (cyclopentyl)), 4.20 (d, J ) 18.0 Hz, 1H, CHaIm),
4.25 (m, 1H, CHN (cyclopentyl)), 4.52 (d, J ) 16.4 Hz, 1H,
CHbPh), 4.75 (d, J ) 18.0 Hz, 1H, CHbIm), 6.52 (s, 1H, CH (Im)),
6.68 (d, J ) 9.2 Hz, 2H, 2 CH (Ar)), 6.97-7.01 (m, 2H, 2 CH
(Ph)), 7.15-7.20 (m, 3H, 3 CH (Ph)), 7.25 (s, 1H, CH (Im)), 7.37
(s, 1H, CH (Im)), 7.43 (d, J ) 9.2 Hz, 2H, 2 CH (Ar)), 7.47 (s,
1H, CH (Im)); δC (125 MHz, CDCl3) 21.1, 28.4, 28.6, 31.6, 33.9,
41.6, 52.3, 61.2, 61.8, 98.8, 113.2, 120.3, 124.7, 127.0, 127.4, 127.9,
128.3, 128.4, 133.2, 136.7, 137.8, 138.9, 140.6, 151.4; HRMS
(ES+) calcd for [C28H31N7O2S + H] 530.2338, found 530.2350;
HPLC (I) tR ) 12.73 min (100%), (II) tR ) 18.89 min (99.35%).
(()-[N-(2-Methylbenzyl)-N-{cis-2-[(4-cyanophenyl)(3-methyl-
3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imida-
zole-4-sulfonamide (6b). The synthesis was as per general procedure
B with 42 and 2-methylbenzyl bromide on a 0.116 mmol scale.
The crude residue was purified by silica gel flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford 6b (14
mg, 22%): δH (500 MHz, CDCl3) 1.38-1.48 (m, 1H, CH (cyclo-
pentyl)), 1.86-1.99 (m, 5H, CH3Ph, 2 CH (cyclopentyl)), 2.14-2.26
(m, 2H, 2 CH (cyclopentyl)), 2.67-2.76 (m, 1H, CH (cyclopentyl)),
3.59 (s, 3H, CH3(Im)), 3.62 (s, 3H, CH3(Im)), 4.05 (d, J ) 17.5
Hz, 1H, CHaPh), 4.09-4.15 (m, 1H, CHN (cyclopentyl)), 4.26 (m,
1H, CHN (cyclopentyl)), 4.31 (d, J ) 18.0 Hz, 1H, CHaIm), 4.42
(d, J ) 17.5 Hz, 1H, CHbPh), 4.90 (d, J ) 18.0 Hz, 1H, CHbIm),
6.55 (s, 1H, CH (Im)), 6.69 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)),
6.95-7.01 (m, 3H, 3 CH (Ph)), 7.07 (td, J ) 7.3, 1.5 Hz, 1H, CH
(Ph)), 7.16 (s, 1H, CH (Im)), 7.25 (s, 1H, CH (Im)), 7.43 (d, J )
9.0 Hz, 2H, 2 CH (Ar)), 7.45 (s, 1H, CH (Im)); δC (125 MHz,
CDCl3) 18.8, 21.2, 28.6, 28.7, 31.6, 33.8, 41.7, 50.6, 61.5, 62.2,
98.8, 112.9, 120.3, 124.5, 125.5, 126.9, 127.1, 127.3, 128.4, 130.2,
133.4, 134.2, 135.7, 137.8, 138.7, 140.8, 151.5; HRMS (ES+) calcd
for [C29H33N7O2S + H] 544.2495, found 544.2509; HPLC (I) tR )
12.77 min (100%), (II) tR ) 19.02 min (100%).
(()-[N-(Thiophen-3-ylmethyl)-N-{cis-2-[(4-cyanophenyl)(3-meth-
yl-3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imi-
dazole-4-sulfonamide (6c). The synthesis was as per general
procedure B with 42 and thiophen-3-ylmethyl bromide (prepared
by employing a standard bromination procedure of thiophen-3-
ylmethanol with PPh3Br2; the bromide darkened on standing at room
temperature, but 1H NMR of the material after 1 month suggested
no decomposition had occurred) on a 0.121 mmol scale. The crude
residue was purified by silica gel flash column chromatography
(eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford 6c (35 mg, 54%):
δH (500 MHz, CDCl3) 1.43-1.53 (m, 1H, CH (cyclopentyl)),
1.85-1.96 (m, 2H, 2 CH (cyclopentyl)), 2.04-2.13 (m, 2H, 2 CH
(cyclopentyl)), 2.41-2.50 (m, 1H, CH (cyclopentyl)), 3.57 (s, 3H,
CH3(Im)), 3.66 (s, 3H, CH3(Im)), 3.96 (d, J ) 16.5 Hz, 1H,
CHathiophene), 4.18 (m, 1H, CHN (cyclopentyl)), 4.27-4.34 (m,
2H, CHaIm, CHN (cyclopentyl)), 4.43 (d, J ) 16.5 Hz, 1H,
CHbthiophene), 4.74 (d, J ) 18.0 Hz, 1H, CHbIm), 6.53 (s, 1H,
CH (Im)), 6.70 (dd, J ) 5.0, 1.5 Hz, 1H, CH (thiophene)), 6.72 (d,
J ) 9.0 Hz, 2H, 2 CH (Ar)), 6.90-6.93 (m, 1H, CH (thiophene)),
7.11-7.13 (dd, J ) 5.0, 2.8 Hz, 1H, CH (thiophene)), 7.22 (s, 1H,
CH (Im)), 7.39 (s, 1H, CH (Im)), 7.43 (d, J ) 9.0 Hz, 2H, 2 CH
(Ar)), 7.44 (s, 1H, CH (Im)); δC (125 MHz, CDCl3) 21.0, 28.2,
28.3, 31.5, 33.9, 41.8, 47.4, 60.7, 61.8, 98.8, 113.2, 120.4, 123.0,
2-[(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)(1-methyl-1H-
imidazole-4-sulfonyl)amino]-N-(4-cyanophenyl)-N-(3-methyl-3H-
imidazol-4-ylmethyl)acetamide (4d). Compound 32 was coupled
to secondary sulfonamide 19d as per general procedure A on a
0.164 mmol scale. After workup, the crude residue was purified
by silica gel flash column chromatography (eluent CH2Cl2/MeOH/
NH4OH, 192:7:1) to furnish 4b (20 mg, 20%): δH (500 MHz,
CDCl3) 0.99 (m, 2H, 2 CH (piperidinylmethyl)), 1.44 (s, 9H,
C(CH3)3), 1.59-1.75 (m, 3H, 3 CH (piperidinylmethyl)), 2.54-2.68
(m, 2H, 2 CH (piperidinylmethyl)), 3.07-3.19 (m, 2H, 2 CH
(piperidinylmethyl)), 3.61 (s, 3H, CH3(Im)), 3.71 (s, 3H, CH3(Im)),
3.73-3.81 (m, 2H, CH2CO), 3.95-4.08 (m, 2H, CHCH2N (pip-
eridinylmethyl)), 4.81-4.94 (m, 2H, CH2Im), 6.59 (s, 1H, CH (Im)),
7.22 (d, J ) 8.5 Hz, 2H, 2 CH (Ar)), 7.33 (app s, 2H, 2 CH (Im)),
7.43 (s, 1H, CH (Im)), 7.69 (d, J ) 8.5 Hz, 2H, 2 CH (Ar)); δC
(125 MHz, CDCl3) 28.4, 29.6, 31.9, 34.0, 35.3, 41.7, 43.5 (br),
50.2, 55.1, 79.5, 112.8, 117.6, 123.6, 126.1, 129.7, 130.4, 133.9,
138.8, 139.1, 140.0, 143.8, 154.6, 167.5; HRMS (ES+) calcd for
[C29H38N8O5S + H] 611.2764, found 611.2769; HPLC (I) tR
12.44 min (99.53%), (II) tR ) 17.97 min (98.67%).
)
3-[Benzyl-(1-methyl-1H-imidazole-4-sulfonyl)amino]-N-(4-cy-
anophenyl)-N-(3-methyl-3H-imidazol-4-ylmethyl)propanamide (5a).
5a was prepared as per general procedure B with 35 and benzyl
bromide on a 0.0845 mmol scale. The crude residue was purified
by silica gel flash column chromatography (eluent CH2Cl2/MeOH/
NH4OH, 192:7:1) to give 5a (42 mg, 96%): δH (500 MHz, CDCl3)
2.12 (m, 2H, CH2CH2CO), 3.47 (t, J ) 7.3 Hz, 2H, CH2CH2CO),
3.53 (s, 3H, CH3(Im)), 3.72 (s, 3H, CH3(Im)), 4.31 (s, 2H, CH2Ph),
4.78 (s, 2H, CH2Im), 6.53 (s, 1H, CH (Im)), 6.68 (d, J ) 8.3 Hz,
2H, 2 CH (Ar)), 7.19-7.25 (m, 5H, 5 CH (Ph)), 7.37 (s, 1H, CH
(Im)), 7.38 (br s, 1H, CH (Im)), 7.41 (s, 1H, CH (Im)), 7.58 (d, J
) 8.3 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CDCl3) 31.7, 34.9, 35.2,
40.9, 45.3, 53.8, 112.3, 117.7, 124.2, 126.5, 127.7, 128.3, 128.4,
129.3, 129.7, 130.2, 133.6, 136.8, 138.9, 139.7, 144.5, 169.7; HRMS
(ES+) calcd for [C26H27N7O3S + H] 518.1974, found 518.1994;
HPLC (I) tR ) 11.82 min (98.91%), (II) tR ) 16.38 min (99.01%).
3-[(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)(1-methyl-1H-
imidazole-4-sulfonyl)amino]-N-(4-cyanophenyl)-N-(3-methyl-3H-
imidazol-4-ylmethyl)propanamide (5d). 5d was prepared as per
general procedure B with 35 and N-tert-butoxycarbonylpiperidin-
4-ylmethyl bromide (1.5 equiv) in DMF (0.1 M) on a 0.0986 mmol
scale. After the mixture was stirred at room temperature for 36 h,
byproduct began to form. So the reaction mixture was worked up
and then the crude residue was purified by silica gel flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give
5d (30 mg, 50% (73% brsm)): δH (500 MHz, CDCl3) 1.03 (qd, J
) 12.2, 4.0 Hz, 2H, 2 CH (piperidinylmethyl)), 1.43 (s, 9H,
C(CH3)3), 1.59 (br app d, J ) 12.2 Hz, 2H, 2 CH (piperidinylm-
ethyl)), 1.77 (m, 1H, CH (piperidinylmethyl)), 2.46 (m, 2H,
CH2CH2CO), 2.63 (m, 2H, 2 CH (piperidinylmethyl)), 2.92 (m,
2H, 2 CH (piperidinylmethyl)), 3.50 (m, 2H, 2 CH (piperidinyl-
methyl)), 3.59 (s, 3H, CH3(Im)), 3.71 (s, 3H, CH3(Im)), 4.05 (m,
2H, CHCH2N (piperidinylmethyl)), 4.90 (s, 2H, CH2Im), 6.61 (s,
1H, CH (Im)), 7.13 (d, J ) 8.0 Hz, 2H, 2 CH (Ar)), 7.32 (s, 1H,
CH (Im)), 7.33 (s, 1H, CH (Im)), 7.42 (s, 1H, CH (Im)), 7.68 (d,
J ) 8.3 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CDCl3) 28.4, 29.7,

5192 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
124.5, 125.7, 127.5, 127.7, 128.2, 133.2, 137.9, 138.0, 138.8, 140.8,
151.5; HRMS (ES+) calcd for [C26H29N7O2S2 + H] 536.1902,
found 536.1915; HPLC (I) tR ) 11.08 min (100%), (II) tR ) 18.85
min (98.38%).
CH2Cl2/MeOH/NH4OH, 192:7:1) to afford 7a (10 mg, 85%): δH
(400 MHz, CDCl3) 1.19-1.29 (m, 1H, CH (cyclopentyl)), 1.54-1.64
(m, 2H, 2 CH (cyclopentyl)), 1.65-1.79 (m, 2H, 2 CH (cyclopen-
tyl)), 1.83-1.91 (m, 1H, CH (cyclopentyl)), 3.60 (s, 3H, CH3(Im)),
3.73 (s, 3H, CH3(Im)), 3.87 (m, 1H, CHN (cyclopentyl)), 4.04 (d,
J ) 16.4 Hz, 1H, CHaPh), 4.41 (d, J ) 17.8 Hz, 1H, CHaIm),
4.61-4.72 (m, 2H, CHbPh, CHN (cyclopentyl)), 4.80 (d, J ) 17.8
Hz, 1H, CHbIm), 6.33 (d, J ) 8.8 Hz, 2H, 2 CH (Ar)), 6.60 (s, 1H,
CH (Im)), 6.94-7.02 (m, 3H, 3 CH (Ph)), 7.20-7.25 (m, 4H, 2
CH (Ph), 2 CH (Ar)), 7.39 (s, 1H, CH (Im)), 7.47 (s, 1H, CH (Im)),
7.45 (s, 1H, CH (Im)); δC (125 MHz, CDCl3) 19.3, 24.1, 26.2,
32.1, 34.0, 39.6, 48.1, 60.0, 61.1, 98.6, 113.1, 120.3, 124.2, 127.0,
127.3 (2), 128.2, 128.6, 133.0, 137.1, 137.9, 139.0, 140.2, 151.2;
HRMS (ES+) calcd for [C28H31N7O2S + H] 530.2338, found
530.2353; HPLC (I) tR ) 12.98 min (98.35%), (II) tR ) 19.76 min
(98.05%).
(()-[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-{cis-2-[(4-
cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclopen-
tyl}]-1-methyl-1H-imidazole-4-sulfonamide (6d). The synthesis was
as per general procedure B with 42 and N-tert-butoxycarbonylpi-
peridin-4-ylmethyl iodide (prepared by Finkelstein transformation
on N-tert-butoxycarbonylpiperidin-4-ylmethyl bromide with sodium
iodide in acetone) (1.5 equiv) on a 0.116 mmol scale in DMF (0.1
M), and the mixture was stirred for 7 days at room temperature.
After the usual workup, the crude residue was purified by silica
gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH,
192:7:1) to yield 6d (60 mg, 81%): δH (500 MHz, CDCl3)
0.62-0.72 (m, 1H, CH (piperidinylmethyl)), 0.81-0.89 (m, 1H,
CH (piperidinylmethyl)), 1.24-1.31 (m, 2H, 2 CH (piperidinylm-
ethyl)), 1.41 (s, 9H, C(CH3)3), 1.42-1.61 (m, 3H, 2 CH (piperidi-
nylmethyl), CH (cyclopentyl)), 1.85-1.95 (m, 2H, 2 CH (cyclo-
pentyl)), 2.06-2.23 (m, 2H, 2 CH (cyclopentyl)), 2.25-2.35 (m,
1H, CH (piperidinylmethyl)), 2.38-2.49 (m, 1H, CH (cyclopentyl)),
2.73-2.81 (m, 1H, CH (piperidinylmethyl)), 2.86-2.99 (m, 1H,
CH (piperidinylmethyl)), 3.64 (s, 3H, CH3(Im)), 3.73 (s, 3H,
CH3(Im)), 3.81-3.97 (m, 2H, CHCH2N (piperidinylmethyl)), 4.13
(m, 1H, CHN (cyclopentyl)), 4.24 (m, 1H, CHN (cyclopentyl)),
4.57 (d, J ) 18.0 Hz, 1H, CHaIm), 5.06 (br d, J ) 18.0 Hz, 1H,
CHbIm), 6.56 (s, 1H, CH (Im)), 6.81 (d, J ) 9.0 Hz, 2H, 2 CH
(Ar)), 7.38 (s, 1H, CH (Im)), 7.41-7.46 (m, 4H, 2 CH (Im), 2 CH
(Ar)); δC (125 MHz, CDCl3) 20.9, 28.0, 28.2, 28.4, 29.9, 31.6, 34.0,
35.1, 42.3, 43.4 (br), 55.9, 61.8, 62.1, 79.4, 99.1, 113.3, 120.1,
124.1, 127.5, 128.0, 133.3, 138.0, 138.8, 141.4, 151.5, 154.6; HRMS
(ES+) calcd for [C32H44N8O4S + H] 637.3284, found 637.3288;
HPLC (I) tR ) 13.28 min (100%), (II) tR ) 20.60 min (100%).
(()-[N-{N-(2-Pyrimidinyl)-piperidin-4-ylmethyl}-N-{cis-2-[(4-cy-
anophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-
1-methyl-1H-imidazole-4-sulfonamide (6e). The synthesis was as
per general procedure B with 42 and N-(2-pyrimidinyl)-piperidin-
4-ylmethyl iodide (prepared by the reaction of PPh3Br2 on N-(2-
pyrimidinyl)-piperidin-4-ylmethanol to give N-(2-pyrimidinyl)-
piperidin-4-ylmethyl bromide, followed by Finkesltein halide
exchange with NaI) (1.5 equiv) on a 0.118 mmol scale in DMF
(0.1 M), and the mixture was stirred for 7 days at room temperature.
The crude residue was purified by silica gel flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish 6e (57
mg, 79%): δH (500 MHz, CDCl3) 0.76 (qd, J ) 12.5, 4.0 Hz, 1H,
CH (piperidinylmethyl)), 0.94 (qd, J ) 12.5, 4.0 Hz, 1H, CH
(piperidinylmethyl)), 1.35-1.41 (m, 1H, 1 CH (cyclopentyl)),
1.48-1.57 (m, 2H, 2 CH (piperidinylmethyl)), 1.68-1.77 (m, 1H,
CH (piperidinylmethyl)), 1.87-1.97 (m, 2H, 2 CH (cyclopentyl)),
2.09-2.20 (m, 2H, 2 CH (cyclopentyl)), 2.39 (td, J ) 12.5, 2.5
Hz, 1H, CH (piperidinylmethyl)), 2.44-2.52 (m, 2H, CH (cyclo-
pentyl), CH (piperidinylmethyl)), 2.80 (dd, J ) 14.5, 7.0 Hz, 1H,
CH (piperidinylmethyl)), 2.97 (dd, J ) 14.5, 7.5 Hz, 1H, CH
(piperidinylmethyl)), 3.66 (s, 3H, CH3(Im)), 3.73 (s, 3H, CH3(Im)),
4.17 (m, 1H, CHN (cyclopentyl)), 4.26 (m, 1H, CHN (cyclopentyl)),
4.53-4.63 (m, 3H, CHaIm, CHCH2N (piperidinylmethyl)), 5.02
(br d, J ) 17.5 Hz, 1H, CHbIm), 6.42 (t, J ) 4.9 Hz, 1H, CH
(pyrimidine), 6.59 (s, 1H, CH (Im)), 6.82 (d, J ) 9.5 Hz, 2H, 2
CH (Ar)), 7.38 (s, 1H, CH (Im)), 7.44-7.47 (m, 3H, CH (Im), 2
CH (Ar)), 7.49 (s, 1H, CH (Im)), 8.25 (d, J ) 4.9 Hz, 2H, 2 CH
(pyrimidine)); δC (125 MHz, CDCl3) 21.0, 28.1, 28.4, 29.8, 31.7,
34.0, 35.4, 42.3, 43.5, 55.7, 61.9, 62.7, 99.2, 109.4, 113.3, 120.1,
124.0, 127.0, 128.2, 133.4, 137.9, 138.7, 141.6, 151.5, 157.7, 161.4;
HRMS (ES+) calcd for [C31H38N10O2S + H] 615.2978, found
615.2999; HPLC (I) tR ) 13.12 min (99.94%), (II) tR ) 19.98 min
(99.39%).
(()-[N-(2-Methylbenzyl)-N-{trans-2-[(4-cyanophenyl)(3-methyl-
3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imida-
zole-4-sulfonamide (7b). The synthesis was as per general procedure
B with 45 and 2-methylbenzyl bromide on a 0.082 mmol scale.
The crude residue was purified by silica gel flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford 7b (37
mg, 83%): δH (500 MHz, CDCl3) 1.20-1.29 (m, 1H, CH (cyclo-
pentyl)), 1.55-1.66 (m, 2H, 2 CH (cyclopentyl)), 1.76-1.89 (m,
3H, 3 CH (cyclopentyl)), 2.21 (s, 3H, CH3Ph), 3.58 (s, 3H,
CH3(Im)), 3.76 (s, 3H, CH3(Im)), 3.90 (m, 1H, CHN (cyclopentyl)),
4.23 (d, J ) 16.0 Hz, 1H, CHaPh), 4.35 (d, J ) 18.0 Hz, 1H,
CHaIm), 4.57 (d, J ) 16.0 Hz, 1H, CHbPh), 4.62 (m, 1H, CHN
(cyclopentyl)), 4.75 (d, J ) 18.0 Hz, 1H, CHbIm), 6.40 (d, J ) 9.0
Hz, 2H, 2 CH (Ar)), 6.61 (s, 1H, CH (Im)), 6.83-6.97 (m, 3H, 3
CH (Ph)), 7.25-7.30 (m, 3H, 2 CH (Ar), CH (Ph)), 7.41 (s, 1H,
CH (Im)), 7.43 (s, 1H, CH (Im)), 7.50 (s, 1H, CH (Im)); δC (125
MHz, CDCl3) 19.2, 19.6, 24.2, 26.4, 31.9, 34.0, 39.5, 46.3, 59.1,
61.2, 98.6, 113.2, 120.4, 124.3, 125.7, 127.3, 128.0, 128.3, 128.4,
130.4, 133.1, 134.6, 135.5, 138.2, 139.0, 140.4, 151.4; HRMS
(ES+) calcd for [C29H33N7O2S + H] 544.2495, found 544.2501;
HPLC (I) tR ) 12.91 min (100%), (II) tR ) 19.69 min (99.61%).
(()-[N-(Thiophen-3-ylmethyl)-N-{trans-2-[(4-cyanophenyl)(3-
methyl-3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-
imidazole-4-sulfonamide (7c). The synthesis was as per general
procedure B with 45 and thiophen-3-ylmethyl bromide on a 0.0888
mmol scale. The crude residue was purified by silica gel flash
column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1)
to afford 7c (36 mg, 75%): δH (500 MHz, CDCl3) 1.27-1.35 (m,
1H, CH (cyclopentyl)), 1.57-1.69 (m, 3H, 3 CH (cyclopentyl)),
1.75-1.82 (m, 1H, CH (cyclopentyl)), 1.88-1.95 (m, 1H, CH
(cyclopentyl)), 3.56 (s, 3H, CH3(Im)), 3.71 (s, 3H, CH3(Im)), 4.02
(m, 1H, CHN (cyclopentyl)), 4.14 (d, J ) 16.0 Hz, 1H,
CHathiophene), 4.44 (d, J ) 18.0 Hz, 1H, CHaIm), 4.55 (d, J )
16.0 Hz, 1H, CHbthiophene), 4.63 (m, 1H, CHN (cyclopentyl)),
4.76 (d, J ) 18.0 Hz, 1H, CHbIm), 6.57 (d, J ) 9.0 Hz, 2H, 2 CH
(Ar)), 6.60 (s, 1H, CH (Im)), 6.92 (dd, J ) 5.3, 1.5 Hz, 1H, CH
(thiophene)), 6.97 (dd, J ) 5.3, 3.0 Hz, 1H, CH (thiophene)),
7.00-7.02 (m, 1H, CH (thiophene)), 7.30 (d, J ) 9.0 Hz, 2H, 2
CH (Ar)), 7.34 (s, 1H, CH (Im)), 7.41 (s, 1H, CH (Im)), 7.44 (s,
1H, CH (Im)); δC (125 MHz, CDCl3) 19.4, 24.7, 26.3, 31.8, 33.9,
39.8, 43.5, 60.0, 61.3, 98.8, 113.3, 120.3, 122.4, 124.1, 126.0, 127.2,
128.0, 128.2, 133.1, 138.2, 138.5, 138.9, 140.4, 151.4; HRMS
(ES+) calcd for [C26H29N7O2S2 + H] 536.1902, found 536.1912;
HPLC (I) tR ) 12.93 min (100%), (II) tR ) 19.55 min (100%).
(()-[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-{trans-2-
[(4-cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclo-
pentyl}]-1-methyl-1H-imidazole-4-sulfonamide (7d). The synthesis
was as per general procedure B with 45 and N-tert-butoxycarbo-
nylpiperidin-4-ylmethyl bromide (1.5 equiv) on a 0.0774 mmol scale
in DMF (0.1 M), and the mixture was stirred for 7 days at room
temperature. The crude residue was purified by silica gel flash
column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1)
to afford 7d (41 mg, 83%): δH (500 MHz, CDCl3) 1.00-1.09 (m,
1H, CH (piperidinylmethyl)), 1.24-1.35 (m, 2H, CH (cyclopentyl),
CH (piperidinylmethyl)), 1.37-1.46 (m, 11H, C(CH3)3, and 2 CH
(()-[N-Benzyl-N-{trans-2-[(4-cyanophenyl)(3-methyl-3H-imida-
zol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imidazole-4-sul-
fonamide (7a). The synthesis was as per general procedure B with
45 and benzyl bromide on a 0.0228 mmol scale. The crude residue
was purified by silica gel flash column chromatography (eluent

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5193
(piperidinylmethyl)), 1.51-1.65 (m, 5H, 3 CH (cyclopentyl), 2 CH
(piperidinylmethyl)), 2.00-2.08 (m, 2H, 2 CH (cyclopentyl)),
2.17-2.26 (m, 1H, CH (piperidinylmethyl)), 2.68-2.80 (m, 1H,
CH (piperidinylmethyl)), 3.23 (dd, J ) 15.0, 9.0 Hz, 1H, CH
(piperidinylmethyl)), 3.65 (s, 3H, CH3(Im)), 3.75 (s, 3H, CH3(Im)),
3.89-4.00 (m, 3H, CHCH2N (piperidinylmethyl), CHN (cyclo-
pentyl)), 4.63 (m, 1H, CHN (cyclopentyl)), 4.72 (d, J ) 18.0 Hz,
1H, CHaIm), 5.06 (d, J ) 18.0 Hz, 1H, CHbIm), 6.71 (s, 1H, CH
(Im)), 6.78 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.42 (s, 1H, CH (Im)),
7.46 (s, 1H, CH (Im)), 7.48 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.60
(s, 1H, CH (Im)); δC (125 MHz, CDCl3) 18.5, 23.0, 25.8, 28.4,
30.2, 32.0, 34.0, 36.8, 39.5, 43.7 (br), 49.6, 60.0, 61.5, 79.3, 99.5,
113.1, 119.9, 124.1, 127.7, 128.2, 133.6, 138.2, 139.0, 140.1, 151.6,
154.5; HRMS (ES+) calcd for [C32H44N8O4S + H] 637.3284, found
637.3292; HPLC (I) tR ) 13.45 min (100%), (II) tR ) 21.09 min
(100%).
(()-[N-{N-(2-Pyrimidinyl)-piperidin-4-ylmethyl}-N-{trans-2-[(4-
cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclopen-
tyl}]-1-methyl-1H-imidazole-4-sulfonamide (7e). The synthesis was
as per general procedure B with 45 and N-(2-pyrimidinyl)-piperidin-
4-ylmethyl bromide (1.5 equiv) on a 0.0799 mmol scale in DMF
(0.1 M), and the mixture was stirred for 7 days at room temperature.
The crude residue was purified by silica gel flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford 7e (38
mg, 78%): δH (500 MHz, CDCl3) 0.88 (qd, J ) 12.2, 4.0 Hz, 1H,
CH (piperidinylmethyl)), 1.01 (qd, J ) 12.3, 4.0 Hz, 1H, CH
(piperidinylmethyl)), 1.25-1.34 (m, 1H, 1 CH (cyclopentyl)),
1.38-1.48 (m, 2H, 2 CH (piperidinylmethyl)), 1.52-1.78 (m, 4H,
3 CH (cyclopentyl), CH (piperidinylmethyl)), 1.98-2.09 (m, 2H,
2 CH (cyclopentyl)), 2.28 (br t, J ) 12.0, 1H, CH (piperidinylm-
ethyl)), 2.40 (br t, J ) 12.0 Hz, 1H, CH (piperidinylmethyl)), 2.74
(dd, J ) 14.8, 6.0 Hz, 1H, CH (piperidinylmethyl)), 3.24 (dd, J )
14.8, 8.5 Hz, 1H, CH (piperidinylmethyl)), 3.61 (s, 3H, CH3(Im)),
3.74 (s, 3H, CH3(Im)), 3.97 (m, 1H, CHN (cyclopentyl)), 4.47-4.54
(m, 2H, CHCH2N (piperidinylmethyl)), 4.63 (m, 1H, CHN (cyclo-
pentyl)), 4.73 (d, J ) 17.5 Hz, 1H, CHaIm), 5.05 (d, J ) 17.5 Hz,
1H, CHbIm), 6.41 (t, J ) 4.9 Hz, 1H, CH (pyrimidine), 6.59 (s,
1H, CH (Im)), 6.78 (d, J ) 8.5 Hz, 2H, 2 CH (Ar)), 7.41 (s, 1H,
CH (Im)), 7.43-7.49 (m, 4H, 2 CH (Im), 2 CH (Ar)), 8.25 (d, J )
4.9 Hz, 2H, 2 CH (pyrimidine)); δC (125 MHz, CDCl3) 18.6, 23.1,
25.8, 29.9, 31.8, 33.9, 37.0, 39.5, 43.5, 49.7, 60.1, 61.6, 99.4, 109.3,
113.2, 119.9, 124.1, 128.2, 128.4, 133.6, 138.4, 138.9, 140.1, 151.8,
157.6, 161.3; HRMS (ES+) calcd for [C31H38N10O2S + H]
615.2978, found 615.2990; HPLC (I) tR ) 12.91 min (99.70%),
(II) tR ) 19.32 min (99.65%).
(()-[N-Benzyl-N-{cis-3-[(4-cyanophenyl)(3-methyl-3H-imidazol-
4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imidazole-4-sulfona-
mide (8a). The synthesis was as per general procedure A with
alcohol 55 and sulfonamide 19a on a 0.102 mmol scale. The crude
residue was purified by silica gel flash column chromatography
(eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish 8a (38 mg,
71%): δH (500 MHz, CDCl3) 1.45-1.55 (m, 1H, CH (cyclopentyl)),
1.62-1.86 (m, 4H, 4 CH (cyclopentyl)), 1.92-1.98 (m, 1H, CH
(cyclopentyl)), 3.42 (s, 3H, CH3(Im)), 3.65 (s, 3H, CH3(Im)),
4.02-4.17 (m, 4H, CH2Ph, 2 CHN (cyclopentyl)), 4.30 (d, J )
16.5 Hz, 1H, CHaIm), 4.41 (d, J ) 16.5 Hz, 1H, CHbIm), 6.52-6.58
(m, 3H, 2 CH (Ar), CH (Im)), 7.14-7.27 (m, 6H, 5 CH (Ph), CH
(Im)), 7.30 (d, J ) 8.5 Hz, 2H, 2 CH (Ar)), 7.33 (s, 1H, CH (Im)),
7.39 (s, 1H, CH (Im)); δC (125 MHz, CDCl3) 26.8, 28.0, 31.5,
33.6, 33.9, 41.6, 49.5, 56.4, 57.3, 99.2, 113.5, 120.0, 123.8, 127.1,
127.2, 127.3, 128.0, 128.4, 133.3, 138.2, 138.4, 138.9, 140.7, 151.9;
HRMS (ES+) calcd for [C28H31N7O2S + H] 530.2338, found
530.2357; HPLC (I) tR ) 12.28 min (100%), (II) tR ) 18.26 min
(100%).
pentyl)), 1.66-1.75 (m, 1H, CH (cyclopentyl)), 1.75-1.93 (m, 3H,
3 CH (cyclopentyl)), 2.03-2.08 (m, 1H, CH (cyclopentyl)), 2.26
(s, 3H, CH3Ph), 3.46 (s, 3H, CH3(Im)), 3.73 (s, 3H, CH3(Im)), 4.13
(m, 1H, CHN (cyclopentyl)), 4.17-4.24 (m, 3H, CH2Ph, CHN
(cyclopentyl)), 4.34 (d, J ) 16.5 Hz, 1H, CHaIm), 4.46 (d, J )
16.5 Hz, 1H, CHbIm), 6.60-6.64 (m, 3H, CH (Im), 2 CH (Ar)),
7.08-7.11 (m, 1H, CH (Ph)), 7.13-7.17 (m, 2H, 2 CH (Ph)), 7.28
(s, 1H, CH (Im)), 7.36-7.40 (m, 3H, 2 CH (Ar), CH (Im)),
7.41-7.44 (m, 1H, CH (Ph)), 7.45 (s, 1H, CH (Im)); δC (125 MHz,
CDCl3) 19.2, 26.9, 27.8, 31.5, 33.5, 34.0, 41.7, 47.4, 56.4, 57.2,
99.3, 113.5, 120.1, 123.9, 126.0, 127.2, 127.7, 128.0, 128.1, 130.2,
133.4, 135.2, 135.8, 138.3, 138.9, 140.7, 151.9; HRMS (ES+) calcd
for [C29H33N7O2S + H] 544.2495, found 544.2495; HPLC (I) tR )
12.41 min (98.55%), (II) tR ) 17.99 min (98.89%).
(()-[N-(Thiophen-3-ylmethyl)-N-{cis-3-[(4-cyanophenyl)(3-meth-
yl-3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imi-
dazole-4-sulfonamide (8c). The synthesis was as per general
procedure A with alcohol 55 and sulfonamide 19c on a 0.102 mmol
scale. The crude residue was purified by silica gel flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford
8c (43 mg, 79%): δH (500 MHz, CDCl3) 1.53-1.62 (m, 1H, CH
(cyclopentyl)), 1.74-1.86 (m, 3H, 3 CH (cyclopentyl)), 1.87-1.93
(m, 1H, CH (cyclopentyl)), 2.01-2.06 (m, 1H, CH (cyclopentyl)),
3.54 (s, 3H, CH3(Im)), 3.71 (s, 3H, CH3(Im)), 4.11-4.19 (m, 2H,
2 CHN (cyclopentyl)), 4.25 (AB quartet, J ) 17.8 Hz, 2H, CH2Ph),
4.37 (d, J ) 16.4 Hz, 1H, CHaIm), 4.45 (d, J ) 16.4 Hz, 1H,
CHbIm), 6.61-6.61 (m, 3H, 2 CH (Ar), CH (Im)), 7.04 (dd, J )
5.0, 1.2 Hz, 1H, CH (thiophene)), 7.05-7.07 (m, 1H, CH
(thiophene)), 7.22 (dd, J ) 5.0, 3.0 Hz, 1H, CH (thiophene)), 7.25
(s, 1H, CH (Im)), 7.38 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.41 (s,
1H, CH (Im)), 7.42 (s, 1H, CH (Im)); δC (125 MHz, CDCl3) 26.9,
28.1, 31.5, 33.6, 33.9, 41.8, 45.2, 56.5, 57.2, 99.3, 113.5, 120.0,
122.0, 123.7, 126.0, 127.2, 127.4, 128.1, 133.4, 138.3, 138.8, 139.7,
141.0, 152.0; HRMS (ES+) calcd for [C26H29N7O2S2 + H]
536.1902, found 536.1910; HPLC (I) tR ) 12.09 min (100%), (II)
tR ) 17.62 min (100%).
(()-[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-{cis-3-[(4-
cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclopen-
tyl}]-1-methyl-1H-imidazole-4-sulfonamide (8d). The synthesis was
as per general procedure A with alcohol 55 and sulfonamide 19d
on a 0.102 mmol scale. The crude residue was purified by silica
gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH,
192:7:1) to furnish 8d (40 mg, 62%): δH (500 MHz, CDCl3)
0.92-0.98 (m, 1H, CH (piperidinylmethyl)), 1.04 (qd, J ) 12.5,
4.0 Hz, 1 H, CH (piperidinylmethyl)), 1.45 (s, 9H, C(CH3)3),
1.65-1.77 (m, 3H, 2 CH (piperidinylmethyl), CH (cyclopentyl)),
1.79-1.91 (m, 4H, 3 CH (cyclopentyl), CH (piperidinylmethyl)),
1.94-2.06 (m, 2H, 2 CH (cyclopentyl)), 2.58-2.69 (m, 2H, 2 CH
(piperidinylmethyl)), 2.87-2.98 (m, 1H, CH (piperidinylmethyl)),
2.99-3.10 (m, 1H, CH (piperidinylmethyl)), 3.62 (s, 3H, CH3(Im)),
3.72 (s, 3H, CH3(Im)), 3.98 (m, 1H, CHN (cyclopentyl)), 4.03-4.14
(m, 2H, CHCH2N (piperidinylmethyl)), 4.18 (m, 1H, CHN (cyclo-
pentyl)), 4.42 (AB quartet, J ) 17.5 Hz, 2H, CH2Im), 6.67 (s, 1H,
CH (Im)), 6.69 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.20 (s, 1H, CH
(Im)), 7.39 (s, 1H, CH (Im)), 7.41 (d, J ) 9.0 Hz, 2 CH (Ar)),
7.44 (s, 1H, CH (Im)); δC (125 MHz, CDCl3) 26.9, 28.2, 28.4,
29.9, 31.6, 33.5, 33.9, 36.7, 41.9, 43.6 (br), 52.5, 56.3, 58.3, 79.3,
99.4, 113.6, 120.0, 123.7, 128.1, 128.3, 133.4, 138.3, 138.7, 140.7,
152.0, 154.7; HRMS (ES+) calcd for [C32H44N8O4S + H]
637.3284, found 637.3283; HPLC (I) tR ) 12.89 min (99.52%),
(II) tR ) 20.14 min (99.30%).
(()-[N-{N-(2-Pyrimidinyl)-piperidin-4-ylmethyl}-N-{cis-3-[(4-cy-
anophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-
1-methyl-1H-imidazole-4-sulfonamide (8e). The synthesis was as
per general procedure A with alcohol 55 (0.203 mmol, 1 equiv)
and sulfonamide 21 (1.5 equiv), with 2 equiv of PPh3 and 1.5 equiv
of DIAD. The crude residue was purified by silica gel flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish
(()-[N-tert-butoxycarbonyl-N-{cis-3-[(4-cyanophenyl)(3-methyl-
3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imida-
zole-4-sulfonamide as a white powder (108 mg, 99%): δH (500
(()-[N-(2-Methylbenzyl)-N-{cis-3-[(4-cyanophenyl)(3-methyl-
3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imida-
zole-4-sulfonamide (8b). The synthesis was as per general procedure
A with alcohol 55 and sulfonamide 19b on a 0.102 mmol scale.
The crude residue was purified by silica gel flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to yield 8b (36
mg, 65%): δH (500 MHz, CDCl3) 1.51-1.58 (m, 1H, CH (cyclo-

5194 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
MHz, CDCl3) 1.37 (s, 9H, C(CH3)3), 1.90-1.96 (m, 1H, CH
(cyclopentyl)), 1.98-2.06 (m, 1H, CH (cyclopentyl)), 2.09-2.17
(m, 1H, CH (cyclopentyl)), 2.25-2.41 (m, 3H, 3 CH (cyclopentyl)),
3.66 (s, 3H, CH3(Im)), 3.76 (s, 3H, CH3(Im)), 4.28 (m, 1H, CHN
(cyclopentyl)), 4.50 (AB quartet, J ) 17.5 Hz, 2H, CH2Im), 4.95
(m, 1H, CHN (cyclopentyl)), 6.72-6.79 (m, 3H, CH (Im) 2 CH
(Ar)), 7.41-7.50 (m, 4H, 2 CH (Im), 2 CH (Ar)), 7.59 (s, 1H, CH
(Im)); δC (125 MHz, CDCl3) 27.5, 27.7, 28.1, 31.3, 32.7, 33.9,
41.1, 56.1, 57.5, 83.8, 98.5, 113.1, 120.1, 124.9, 127.6, 128.3, 133.2,
138.0, 138.4, 140.0, 150.6, 152.0; HRMS (ES+) calcd for
[C26H33N7O4S + H] 540.2393, found 540.2391. The material (108
mg, 0.201 mmol) was redissolved in a 1:1 mixture of CH2Cl2/TFA (7
mL). After the mixture was stirred for 3 h at room temperature, TLC
indicated the reaction was complete, and so all solvent was removed
in vacuo. The residue was dry-loaded onto silica gel and purified by
flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:
1) to give (()-[N-{cis-3-[(4-cyanophenyl)(3-methyl-3H-imidazol-4-
ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imidazole-4-sulfona-
mide as a glassy film (88 mg, 96%): δH (500 MHz, MeOH-d4)
1.55-1.61 (m, 1H, CH (cyclopentyl)), 1.64-1.72 (m, 2H, 2 CH
(cyclopentyl)), 1.81-1.89 (m, 1H, CH (cyclopentyl)), 1.93-1.99 (m,
1H, CH (cyclopentyl)), 2.08-2.13 (m, 1H, CH (cyclopentyl)), 3.56
(m, 1H, CHNHSO2), 3.69 (s, 3H, CH3(Im)), 3.75 (s, 3H, CH3(Im)),
4.26 (m, 1H, CHN (cyclopentyl)), 4.46 (AB quartet, J ) 18.0 Hz,
2H, CH2Im), 6.57 (s, 1H, CH (Im)), 6.68 (d, J ) 9.3 Hz, 2H, 2 CH
(Ar)), 7.41 (d, J ) 9.3 Hz, 2H, 2 CH (Ar)), 7.47 (s, 1H, CH (Im)),
7.50 (s, 1H, CH (Im)), 7.52 (s, 1H, CH (Im)); δC (125 MHz, CDCl3)
26.3, 30.3, 30.5, 32.9, 35.7, 40.6, 51.7, 56.8, 97.5, 112.7, 119.5, 123.9,
125.7, 128.5, 132.7, 137.5, 138.9, 139.2, 151.7; HRMS (ES+) calcd
for [C21H25N7O2S + H] 440.1869, found 440.1881. Finally, (()-[N-
{cis-3-[(4-cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cy-
clopentyl}]-1-methyl-1H-imidazole-4-sulfonamide (0.096 mmol) and
N-(2-pyrimidinyl)-4-iodomethylpiperidine (1.5 equiv) were reacted
together as per general procedure B in DMF (0.1 M), and the mixture
was stirred for 3 days at room temperature. After the usual workup,
the crude residue was purified by silica gel flash column chromatog-
raphy (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to yield the title
compound 8e (50 mg, 85%): δH (500 MHz, CDCl3) 1.04 (qd, J )
12.3, 4.0 Hz, 1H, CH (piperidinylmethyl)), 1.11 (qd, J ) 12.3, 4.0
Hz, 1H, CH (piperidinylmethyl)), 1.65-1.72 (m, 1H, 1 CH (cyclo-
pentyl)), 1.78-2.09 (m, 8H, 5 CH (cyclopentyl), 3 CH (piperidinyl-
methyl)), 2.77-2.85 (m, 2H, 2 CH (piperidinylmethyl)), 2.95 (dd, J
) 14.5, 7.0 Hz, 1H, CH (piperidinylmethyl)), 3.07 (dd, J ) 14.5, 7.5
Hz, 1H, CH (piperidinylmethyl)), 3.59 (s, 3H, CH3(Im)), 3.72 (s, 3H,
CH3(Im)), 4.04 (m, 1H, CHN (cyclopentyl)), 4.18 (m, 1H, CHN
(cyclopentyl)), 4.43 (AB quartet, J ) 17.5 Hz, 2H, CH2Im), 4.73-4.80
(m, 2H, CHCH2N (piperidinylmethyl)), 6.44 (t, J ) 4.8 Hz, 1H, CH
(pyrimidine), 6.67 (s, 1H, CH (Im)), 6.69 (d, J ) 9.0 Hz, 2H, 2 CH
(Ar)), 7.20 (s, 1H, CH (Im)), 7.39 (s, 1H, CH (Im)), 7.40-7.44 (m,
3H, CH (Im), 2 CH (Ar)) 8.28 (d, J ) 4.8 Hz, 2H, 2 CH (pyrimidine));
δC (125 MHz, CDCl3) 26.9, 28.3, 29.9, 31.6, 33.5, 33.9, 37.1, 41.9,
43.7, 52.6, 56.3, 58.3, 99.6, 109.4, 113.6, 120.0, 123.7, 128.2, 128.3,
133.5, 138.4, 138.7, 140.9, 152.1, 157.7, 161.5; HRMS (ES+) calcd
for [C31H38N10O2S + H] 615.2978, found 615.3008; HPLC (I) tR )
12.56 min (99.21%), (II) tR ) 19.15 min (99.37%).
(Im)); δC (125 MHz, CDCl3) 29.0, 29.1, 30.9, 31.6, 33.9, 41.7,
48.1, 56.9, 57.9, 99.1, 113.3, 120.1, 123.7, 127.1, 127.3, 127.9,
128.2, 128.5, 133.3, 138.2, 138.3, 138.9, 140.5, 151.8; HRMS
(ES+) calcd for [C28H31N7O2S + H] 530.2338, found 530.2349;
HPLC (I) tR ) 12.21 min (100%), (II) tR ) 18.09 min (99.84%).
(()-[N-(2-Methylbenzyl)-N-{trans-3-[(4-cyanophenyl)(3-methyl-
3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imida-
zole-4-sulfonamide (9b). The synthesis was as per general procedure
A with alcohol 60 and sulfonamide 19b on a 0.136 mmol scale.
The crude residue was purified by silica gel flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give 9b (36
mg, 49%): δH (500 MHz, CDCl3) 1.37-1.53 (m, 2H, 2 CH
(cyclopentyl)), 1.78-1.85 (m, 1H, CH (cyclopentyl)), 1.86-1.92
(m, 2H, 2 CH (cyclopentyl)), 1.97-2.02 (m, 1H, CH (cyclopentyl)),
2.32 (s, 3H, CH3Ph), 3.63 (s, 3H, CH3(Im)), 3.69 (s, 3H, CH3(Im)),
4.17 (m, 1H, CHN (cyclopentyl)), 4.27-4.31 (m, 3H, CH2Ph,
CHaIm), 4.44 (d, J ) 16.5 Hz, 1H, CHbIm), 4.58 (m, 1H, CHN
(cyclopentyl)), 6.53 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 6.61 (s, 1H,
CH (Im)), 7.12-7.15 (m, 1H, CH (Ph)), 7.16-7.22 (m, 2H, 2 CH
(Ph)), 7.28 (s, 1H, CH (Im)), 7.34-7.37 (m, 3H, 2 CH (Ar), CH
(Im)), 7.44 (s, 1H, CH (Im)), 7.48-7.51 (m, 1H, CH (Ph)); δC
(125 MHz, CDCl3) 19.3, 28.9, 29.0, 31.5, 31.6, 33.9, 41.8, 45.9,
57.0, 57.9, 99.2, 113.3, 120.1, 123.8, 126.1, 127.1, 127.4, 128.0,
128.2, 130.1, 133.4, 134.9, 135.8, 138.3, 138.9, 140.4, 151.8; HRMS
(ES+) calcd for [C29H33N7O2S + H] 544.2495, found 544.2503;
HPLC (I) tR ) 12.34 min (98.09%), (II) tR ) 18.02 min (98.07%).
(()-[N-(Thiophen-3-ylmethyl)-N-{trans-3-[(4-cyanophenyl)(3-
methyl-3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-
imidazole-4-sulfonamide (9c). The synthesis was as per general
procedure A with alcohol 60 and sulfonamide 19c on a 0.136 mmol
scale. The crude residue was purified by silica gel flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish
9c (47 mg, 65%): δH (500 MHz, CDCl3) 1.40-1.48 (m, 1H, CH
(cyclopentyl)), 1.58-1.67 (m, 1H, CH (cyclopentyl)), 1.77-1.83
(m, 1H, CH (cyclopentyl)), 1.86-1.92 (m, 2H, 2 CH (cyclopentyl)),
2.00-2.06 (m, 1H, CH (cyclopentyl)), 3.62 (s, 3H, CH3(Im)), 3.68
(s, 3H, CH3(Im)), 4.25 (m, 1H, CHN (cyclopentyl)), 4.31 (s, 2H,
CH2thiophene), 4.32 (d, J ) 16.5 Hz, 1H, CHaIm), 4.46 (d, J )
16.5 Hz, 1H, CHbIm), 4.52 (m, 1H, CHN (cyclopentyl)), 6.58 (d,
J ) 9.1 Hz, 2H, 2 CH (Ar)), 6.61 (s, 1H, CH (Im)), 7.09 (dd, J )
5.0, 1.2 Hz, 1H, CH (thiophene)), 7.12-7.14 (m, 1H, CH
(thiophene)), 7.26 (s, 1H, CH (Im)), 7.28 (dd, J ) 5.0, 3.0 Hz, 1H,
CH (thiophene)), 7.35 (s, 1H, CH (Im)), 7.37 (d, J ) 9.1 Hz, 2H,
2 CH (Ar)), 7.43 (s, 1H, CH (Im)); δC (125 MHz, CDCl3) 29.0,
29.1, 31.6, 31.8, 33.9, 41.8, 43.9, 57.0, 57.9, 99.2, 113.3, 120.1,
122.1, 123.7, 126.0, 127.2, 128.0, 128.1, 133.4, 138.3, 138.8, 139.6,
140.6, 151.8; HRMS (ES+) calcd for [C26H29N7O2S2 + H]
536.1902, found 536.1911; HPLC (I) tR ) 12.05 min (98.16%),
(II) tR ) 17.43 min (98.44%).
(()-[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-{trans-3-
[(4-cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclo-
pentyl}]-1-methyl-1H-imidazole-4-sulfonamide (9d). The synthesis
was as per general procedure A with alcohol 60 and sulfonamide
19d on a 0.136 mmol scale. The crude residue was purified by
silica gel flash column chromatography (eluent CH2Cl2/MeOH/
NH4OH, 192:7:1) to afford 9d (27 mg, 32%): δH (500 MHz, CDCl3)
1.00-1.13 (m, 2H, 2 CH (piperidinylmethyl)), 1.40-1.52 (s, 11H,
C(CH3)3, CH (piperidinylmethyl), CH (cyclopentyl)), 1.56-1.65
(m, 1H, CH (cyclopentyl)), 1.70-1.84 (m, 3H, 2 CH (piperidinyl-
methyl), CH (cyclopentyl)), 1.87-2.01 (m, 2H, 2 CH (cyclopentyl)),
2.12-2.19 (m, 1H, CH (cyclopentyl)), 2.61-2.75 (m, 3H, 3 CH
(piperidinylmethyl)), 3.02-3.11 (m, 1H, CH (piperidinylmethyl)),
3.67 (s, 3H, CH3(Im)), 3.68 (s, 3H, CH3(Im)), 4.04-4.19 (m, 2H,
CHCH2N (piperidinylmethyl)), 4.31-4.37 (m, 3H, CH2Im, CHN
(cyclopentyl)), 4.42 (m, 1H, CHN (cyclopentyl)), 6.62 (s, 1H, CH
(Im)), 6.66 (d, J ) 9.3 Hz, 2H, 2 CH (Ar)), 7.24 (s, 1H, CH (Im)),
7.25 (s, 1H, CH (Im)), 7.41 (d, J ) 9.3 Hz, 2H, 2 CH (Ar)), 7.47
(s, 1H, CH (Im)); δC (125 MHz, CDCl3) 28.4, 29.0, 29.8, 30.2,
31.4, 33.9, 34.1, 36.9, 41.1, 43.7 (br), 49.9, 56.2, 58.7, 79.7, 100.7,
113.2, 118.6, 119.5, 124.7, 132.4, 133.8, 136.0, 138.1, 139.2, 150.9,
(()-[N-Benzyl-N-{trans-3-[(4-cyanophenyl)(3-methyl-3H-imida-
zol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imidazole-4-sul-
fonamide (9a). The synthesis was as per general procedure A with
alcohol 60 and sulfonamide 19a on a 0.102 mmol scale. The crude
residue was purified by silica gel flash column chromatography
(eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish 9a (29 mg,
54%): δH (500 MHz, CDCl3) 1.31-1.39 (m, 1H, CH (cyclopentyl)),
1.46-1.54 (m, 1H, CH (cyclopentyl)), 1.69-1.76 (m, 1H, CH
(cyclopentyl)), 1.76-1.84 (m, 2H, 2 CH (cyclopentyl)), 1.91-1.97
(m, 1H, CH (cyclopentyl)), 3.56 (s, 3H, CH3(Im)), 3.63 (s, 3H,
CH3(Im)), 4.14 (m, 1H, CHN (cyclopentyl)), 4.24 (s, 2H, CH2Ph),
4.26 (d, J ) 16.8 Hz, 1H, CHaIm), 4.43 (d, J ) 16.8 Hz, 1H,
CHbIm), 4.49 (m, 1H, CHN (cyclopentyl)), 6.48 (d, J ) 9.0 Hz,
2H, 2 CH (Ar)), 6.54 (s, 1H, CH (Im)), 7.20-7.23 (m, 2H, CH
(Ph), CH (Im)), 7.25-7.31 (m, 5H, 2 CH (Ar), 2 CH (Ph), CH
(Im)), 7.32-7.36 (m, 2H, CH (Im), CH (Ph)), 7.38 (s, 1H, CH

Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5195
154.9; HRMS (ES+) calcd for [C32H44N8O4S + H] 637.3284, found
637.3293; HPLC (I) tR ) 12.97 min (98.72%), (II) tR ) 20.52 min
(99.01%).
(()-[N-Benzyl-N-{cis-4-[(4-cyanophenyl)(3-methyl-3H-imidazol-
4-ylmethyl)amino]cyclohexyl}] 1-methyl-1H-imidazole-4-sulfona-
mide (10a). The synthesis was as per general procedure C with
64a on a 0.149 mmol scale. After workup, the crude residue was
dry-loaded onto silica gel, then purified by flash column chroma-
tography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford 10a
(52 mg, 65% (or 92% brsm)): δH (400 MHz, CDCl3) 1.55-1.67
(m, 8H, 2 NCH2CH2N), 3.35 (s, 3H, CH3(Im)), 3.65 (m, 1H, CHN
(cyclohexyl)), 3.73 (s, 3H, CH3(Im)), 3.77 (m, 1H, CHN (cyclo-
pentyl)), 4.17 (s, 2H, CH2Ph), 4.43 (s, 2H, CH2Im), 6.58 (s, 1H,
CH (Im)), 6.67 (d, J ) 9.0 Hz, 2H, CH (Ar)), 7.23-7.44 (m, 10H,
CH (Im), 5 CH (Ph), 2 CH (Ar), 2 CH (Im)); δC (125 MHz, CDCl3)
27.0, 27.2, 31.1, 33.7, 42.3, 48.9, 52.1, 56.3, 94.9, 97.5, 101.0,
116.5, 119.5, 123.6, 126.9, 127.2, 128.0, 128.3, 132.9, 138.6, 138.7,
140.9, 151.6; HPLC (I) tR ) 12.59 min (96.06%), (II) tR ) 18.98
min (95.85%); HRMS (ES+) calcd for [C29H33N7O2S + H]
544.2507, found 544.2495.
(()-[N-{N-(2-Pyrimidinyl)-piperidin-4-ylmethyl}-N-{trans-3-[(4-
cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclopen-
tyl}]-1-methyl-1H-imidazole-4-sulfonamide (9e). The synthesis was
as per general procedure A with alcohol 60 (0.203 mmol, 1 equiv)
and sulfonamide 21 (1.5 equiv), with 2 equiv of PPh3 and 1.5 equiv
of DIAD. The crude residue was purified by silica gel flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to furnish
(()-[N-tert-butoxycarbonyl-N-{2-trans-[(4-cyanophenyl)(3-methyl-
3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imida-
zole-4-sulfonamide as a white powder (90 mg, 83%): δH (500 MHz,
CDCl3) 1.42 (s, 9H, C(CH3)3), 1.51-1.61 (m, 1H, CH (cyclopen-
tyl)), 1.92-1.99 (m, 1H, CH (cyclopentyl)), 2.09-2.18 (m, 2H, 2
CH (cyclopentyl)), 2.20-2.28 (m, 1H, CH (cyclopentyl)), 2.43-2.49
(m, 1H, 1 CH (cyclopentyl)), 3.65 (s, 3H, CH3(Im)), 3.76 (s, 3H,
CH3(Im)), 4.38 (AB quartet, J ) 17.0 Hz, 2H, CH2Im), 4.72 (m,
1H, CHN (cyclopentyl)), 5.03 (m, 1H, CHN (cyclopentyl)),
6.72-6.77 (m, 3H, CH (Im), 2 CH (Ar)), 7.41 (d, J ) 9.0 Hz, 2H,
2 CH (Ar)), 7.45 (s, 1H, CH (Im)), 7.51 (s, 1H, CH (Im)), 7.52 (s,
1H, CH (Im)); δC (125 MHz, CDCl3) 28.1, 30.0, 30.8, 31.6, 32.2,
34.0, 41.4, 56.4, 57.7, 84.3, 98.8, 113.3, 120.2, 125.0, 127.6, 128.0,
133.3, 138.5, 139.1, 140.1, 150.5, 152.2; HRMS (ES+) calcd for
[C26H33N7O4S + H] 540.2393, found 540.2396. The material (85
mg, 0.158 mmol) was redissolved in a 1:1 mixture of CH2Cl2/TFA
(5 mL). After the mixture was stirred for 3 h at room temperature,
TLC indicated the reaction was complete, and so all solvent was
removed in vacuo. The residue was dry-loaded onto silica gel and
purified by flash column chromatography (eluent CH2Cl2/MeOH/
NH4OH, 92:7:1) to give (()-[N-{2-trans-[(4-cyanophenyl)(3-meth-
yl-3H-imidazol-4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-im-
idazole-4-sulfonamide as a glassy film (68 mg, 99%): δH (500 MHz,
CDCl3) 1.39-1.47 (m, 1H, CH (cyclopentyl)), 1.57-1.70 (m, 2H,
2 CH (cyclopentyl)), 1.90-2.06 (m, 3H, 3 CH (cyclopentyl)), 3.58
(s, 3H, CH3(Im)), 3.68 (s, 3H, CH3(Im)), 3.78 (m, 1H, CHNHSO2),
4.27 (s, 2H, CH2Im), 4.40 (m, 1H, CHN (cyclopentyl)), 6.56 (s,
1H, CH (Im)), 6.61 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.20 (s, 1H,
CH (Im)), 7.28 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.40 (s, 1H, CH
(Im)), 7.43 (s, 1H, CH (Im)), 7.47 (s, 1H, CH (Im)); δC (125 MHz,
CDCl3) 27.9, 31.6, 32.7, 34.0, 35.7, 42.6, 53.0, 57.2, 98.6, 113.4,
120.2, 123.9, 127.6, 128.2, 133.2, 138.3, 139.0, 140.5, 151.9; HRMS
(ES+) calcd for [C21H25N7O2S + H] 440.1869, found 440.1882.
Finally, (()-[N-{trans-3-[(4-cyanophenyl)(3-methyl-3H-imidazol-
4-ylmethyl)amino]cyclopentyl}]-1-methyl-1H-imidazole-4-sulfona-
mide (0.095 mmol) and N-(2-pyrimidinyl)-piperidin-4-ylmethyl
iodide (1.5 equiv) were reacted together as per general procedure
B in DMF (0.1 M), and the mixture was stirred for 3 days at room
temperature. After the usual workup, the crude residue was purified
by silica gel flash column chromatography (eluent CH2Cl2/MeOH/
NH4OH, 92:7:1) to yield the title compound 9e (49 mg, 85%): δH
(500 MHz, CDCl3) 1.08-1.19 (m, 2H, 2 CH (piperidinylmethyl)),
1.41-1.51 (m, 1H, 1 CH (cyclopentyl)), 1.57-1.65 (m, 1H, CH
(cyclopentyl)), 1.69-1.93 (m, 3H, 2 CH (piperidinylmethyl), CH
(cyclopentyl)), 1.97-2.02 (m, 1H, CH (cyclopentyl)), 2.04-2.15
(m, 2H, 2 CH (cyclopentyl)), 2.74 (dd, J ) 14.8, 8.1 Hz, 1H, CH
(piperidinylmethyl)), 2.80-2.87 (m, 2H, 2 CH (piperidinylmethyl)),
2.97 (dd, J ) 14.5, 7.5 Hz, 1H, CH (piperidinylmethyl)), 3.08 (dd,
J ) 14.8, 6.8 Hz, 1H, CH (piperidinylmethyl)), 3.67 (s, 3H, CH3),
3.68 (s, 3H, CH3), 4.29-4.39 (m, 3H, CHN (cyclopentyl), CH2Im),
4.45 (m, 1H, CHN (cyclopentyl)), 4.76-4.81 (m, 2H, CHCH2N
(piperidinylmethyl)), 6.43 (t, J ) 4.8 Hz, 1H, CH (pyrimidine),
6.60 (s, 1H, CH (Im)), 6.65 (d, J ) 9.0 Hz, 2H, 2 CH (Ar)), 7.26
(m, 2H, 2 CH (Im)), 7.38 (d, J ) 8.9 Hz, 2H, 2 CH (Ar)), 7.41 (s,
1H, CH (Im)), 8.28 (d, J ) 4.8 Hz, 2H, 2 CH (pyrimidine)); δC
(125 MHz, CDCl3) 26.6, 29.5, 29.9, 31.0, 31.7, 33.9, 37.4, 41.8,
43.8, 50.4, 57.7, 58.6, 99.2, 109.4, 113.3, 120.0, 123.8, 127.8, 128.3,
133.1, 138.4, 138.8, 139.8, 151.7, 157.8, 161.5; HRMS (ES+) calcd
for [C31H38N10O2S + H] 615.2978, found 615.2959; HPLC (I) tR
) 12.59 min (100%), (II) tR ) 19.17 min (100%).
(()-[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-{cis-4-[(4-
cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclohexyl}]-
1-methyl-1H-imidazole-4-sulfonamide (10d). The synthesis was as
per general procedure C with 64d on a 0.108 mmol scale. After
workup, the crude residue was dry-loaded onto silica gel, then
purified by flash column chromatography (eluent CH2Cl2/MeOH/
NH4OH, 192:7:1) to furnish 10d (48 mg, 69% (or 94% brsm)): δH
(400 MHz, CDCl3) 0.94-1.03 (m, 2H, 2 CH (piperidinylmethyl)),
1.46 (s, 9H, C(CH3)3), 1.56-1.85 (m, 9H, 2 NCH2CH2N (cyclo-
hexyl), CH (piperidinylmethyl)), 2.00-2.10 (m, 2H, 2 CH (pip-
eridinylmethyl)), 2.58-2.70 (m, 2H, 2 CH (piperidinylmethyl)),
2.87-3.01 (m, 2H, 2 CH (piperidinylmethyl)), 3.49 (s, 3H, CH3Im),
3.63 (m, 1H, CHN (cyclohexyl)), 3.72 (s, 3H, CH3(Im)), 3.81 (m,
1 H, CHN (cyclohexyl)), 4.03-4.16 (m, 2H, 2 CH (piperidinyl-
methyl)), 4.48 (s, 2H, CH2Im), 6.66 (s, 1H, CH (Im)), 6.78 (d, J )
9.0 Hz, 2H, 2 CH (Ar)), 7.32 (s, 1H, CH (Im)), 7.37 (s, 1H, CH
(Im)), 7.39 (s, 1H, CH (Im)), 7.45 (d, J ) 9.0 Hz, 2H, CH(Ar));
δC (125 MHz, CDCl3) 27.9, 28.2, 28.7, 29.7, 30.3, 31.7, 34.2, 36.9,
43.6, 51.3, 52.1, 58.3, 79.6, 101.9, 117.5, 119.9, 124.0, 127.8, 129.0,
133.5, 138.6, 139.0, 141.5, 152.4, 155.0; HRMS (ES+) calcd for
[C33H46N8O4S + H] 651.3420, found 651.3455; HPLC (I) tR
13.42 min (100%), (II) tR ) 21.42 min (100%).
)
(()-[N-Benzyl-N-{trans-4-[(4-cyanophenyl)(3-methyl-3H-imida-
zol-4-ylmethyl)amino]cyclohexyl}]-1-methyl-1H-imidazole-4-sul-
fonamide (11a). Compound 66 was benzylated on the sulfonamide
NH as per general procedure B on a 0.139 mmol scale with benzyl
bromide. The sample was purified by silica gel flash column
chromatography (eluent CH2Cl2/MeOH/NH4OH, 292:7:1 1:2) to
furnish (()-[N-benzyl-N-{trans-4-(4-cyanophenylamino)cyclohexyl}]-
1-methyl-1H-imidazole-4-sulfonamide as a colorless film (61 mg,
98%): δH (500 MHz, CDCl3) 1.17 (qd, J ) 12.5, 3.0 Hz, 2H, 2
CH (cyclohexyl)), 1.41 (qd, J ) 12.5, 3.0 Hz, 2H, 2 CH
(cyclohexyl)), 1.76-1.82 (m, 2H, 2 CH (cyclohexyl)), 1.96-2.02
(m, 2H, 2 CH (cyclohexyl)), 3.02 (tt, J ) 11.0, 3.5 Hz, 1H,
CHNSO2), 3.69 (s, 3H, CH3(Im)), 3.91 (tt, J ) 12.5 Hz, 3.5 Hz,
1H, CHNHAr), 4.43 (s, 2H, CH2Ph), 6.42 (d, J ) 8.0 Hz, 2H, 2
CH (Ar)), 7.21-7.32 (m, 5H, 5 CH (Ph)), 7.33 (s, 1H, CH (Im)),
7.39 (d, J ) 8.0 Hz, 2H, 2 CH (Ar)), 7.44 (s, 1H, CH (Im)); δC
(125 MHz, CDCl3) 30.0, 32.2, 33.9, 47.8, 50.6, 57.7, 98.3, 112.4,
120.4, 123.8, 127.2, 127.5, 128.3, 133.5, 138.8, 138.9, 141.2, 150.2;
HRMS (ES+) calcd for [C24H27N5O2S + H] 450.1964, found
450.1972. The secondary aniline NH was then alkylated with
imidazole 15 as per general procedure C on a 0.107 mmol scale,
but the mixture was allowed to stir for 12 h, with the temperature
gradually warming from 0 °C to room temperature, after which
time the reaction appeared to have stalled. After usual workup, the
crude residue was purified by silica gel flash column chromatog-
raphy (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give the title
compound 11a (38 mg, 65% (or 97% brsm)): δH (500 MHz, CDCl3)
1.41-1.53 (m, 4H, 4 CH (cyclohexyl)), 1.80-1.86 (m, 4H, 4 CH
(cyclohexyl)), 3.55 (m, 1H, CHNSO2), 3.61 (s, 3H, CH3(Im)), 3.71
(s, 3H, CH3(Im)), 3.95 (m, 1H, CHNAr), 4.29 (s, 2H, CH2Im), 4.42
(s, 2H, CH2Ph), 6.59 (d, J ) 9.5 Hz, 2H, 2 CH (Ar)), 6.62 (br s,
1H, CH (Im)), 7.24-7.44 (m, 10H, 5 CH (Ph), 2 CH (Ar), 3 CH

5196 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Fletcher et al.
(Im)); δC (125 MHz, CDCl3) 29.1, 30.4, 31.6, 33.9, 40.7, 47.6,
56.3, 57.5, 98.9, 112.9, 120.1, 123.7, 127.3, 127.4, 128.1, 127.9,
128.3, 133.4, 138.2, 138.6, 138.8, 141.2, 151.2; HRMS (ES+) calcd
for [C29H33N7O2S + H] 544.2495, found 544.2502; HPLC (I) tR )
11.97 (100%), (II) tR ) 17.04 (99.37%).
Plates were flushed with 5% CO2, 5% O2, and 90% N2 and then
incubated at 37 °C for 48 h. [8-3H]Hypoxanthine (0.3 µCi, 20 Ci/
mmol, American Radiolabeled Chemicals) in 30 µL of RP-20P was
added to cultures and incubated for an additional 24 h. Cells were
harvested onto filter mats by a Multiharvester (Skatron, Sunnyvale,
CA), and the radioactivity incorporated into the parasites was
counted on a ꢀ-scintillation counter. The background level detected
with uninfected erythrocytes was subtracted from the data. The 3H-
incorporation into infected RBCs with 1 µL of DMSO vehicle alone
represents 100% malaria growth. ED50 values were determined by
(()-[N-(N-tert-Butoxycarbonylpiperidin-4-ylmethyl)-N-{trans-4-
[(4-cyanophenyl)(3-methyl-3H-imidazol-4-ylmethyl)amino]cyclo-
hexyl}]-1-methyl-1H-imidazole-4-sulfonamide (11d). Compound 66
was alkylated on the sulfonamide NH as per general procedure B
on a 0.139 mmol scale and with N-tert-butoxycarbonyl-4-bromom-
ethylpiperidine in DMF (0.1 M). After 4 days, the reaction was
worked up, then purified by silica gel flash column chromatography
(eluent CH2Cl2/MeOH/NH4OH, 292:7:1) to furnish the (()-[N-(N-
tert-butoxycarbonylpiperidin-4-ylmethyl)-N-{4-(4-trans-cyanophe-
nylamino)cyclohexyl}]-1-methyl-1H-imidazole-4-sulfonamide as a
colorless film (77 mg, 100%): δH (500 MHz, CDCl3) 1.07 (qd, J
) 12.3, 4.3 Hz, 2H, 2 CH (piperidinylmethyl)), 1.25 (qd, J ) 12.3,
3.0 Hz, 2H, 2 CH (cyclohexyl)), 1.44 (s, 9H, C(CH3)3), 1.56 (qd,
J ) 12.2, 3.0 Hz, 2H, 2 CH (cyclohexyl)), 1.72-1.79 (m, 2H, 2
CH (cyclohexyl)), 1.81-1.92 (m, 3H, 3 CH (piperidinylmethyl)),
2.07-2.13 (m, 2H, 2 CH (cyclohexyl)), 2.61-2.71 (m, 2H, 2 CH
(piperidinylmethyl)), 3.01-3.08 (m, 2H, 2 CH (piperidinylmethyl),
3.18 (tt, J ) 11.5, 3.5 Hz, 1H, CHNSO2), 3.73 (s, 3H, CH3(Im)),
3.77 (qd, J ) 12.0, 3.5 Hz, 1H, CHNH), 4.06-4.15 (m, 2H, 2 CH
(piperidinylmethyl)), 6.50 (d, J ) 8.8 Hz, 2H, 2 CH (Ar)), 7.36 (d,
J ) 8.8 Hz, 2H, 2 CH (Ar)), 7.39 (s, 1H, CH (Im)), 7.44 (s, 1H,
CH (Im)); δC (125 MHz, CDCl3) 28.4, 30.0, 30.2, 32.2, 33.9, 36.9,
43.4 (br), 50.2, 50.7, 57.7, 78.6, 98.3, 112.4, 120.4, 123.6, 134.6,
139.8, 141.0, 150.2, 154.7; HRMS (ES+) calcd for [C28H40N6O4S
+ H] 557.2910, found 557.2931. The secondary aniline NH was
then alkylated with imidazole 15 as per general procedure C on a
0.0937 mmol scale, but the mixture was allowed to stir for 12 h,
with the temperature gradually warming from 0 °C to room
temperature. After usual workup, the crude residue was purified
by silica gel flash column chromatography (eluent CH2Cl2/MeOH/
NH4OH, 192:7:1) to furnish the target molecule 11d (37 mg, 61%
(or 95% brsm)): δH (500 MHz, CDCl3) 1.07 (qd, J ) 12.3, 4.3 Hz,
2H, 2 CH (piperidinylmethyl)), 1.44 (s, 9H, C(CH3)3), 1.51-1.61
(m, 4H, 4 CH (cyclohexyl)), 1.72-1.80 (m, 2H, 2 CH (cyclohexyl)),
1.82-1.95 (m, 5H, 3 CH (piperidinylmethyl), 2 CH (cyclohexyl)),
2.60-2.71 (m, 2H, 2 CH (piperidinylmethyl)), 2.97-3.03 (m, 2H,
2 CH (piperidinylmethyl)), 3.63 (s, 3H, CH3(Im)), 3.68 (m, 1H,
CHNSO2), 3.72 (s, 3H, CH3(Im)), 3.80 (m, 1H, CHNAr), 4.05-4.17
(m, 2H, 2 CH (piperidinylmethyl)), 4.36 (s, 2H, CH2Im), 6.63-6.69
(m, 3H, 2 CH (Ar), CH (Im)), 7.37 (s, 1H, Im), 7.40 (d, J ) 9.0
Hz, 2H, 2 CH (Ar)), 7.42 (s, 1H, CH (Im)), 7.45 (br s, 1H, CH
(Im)); δC (125 MHz, CDCl3) 28.2, 29.1, 30.0, 30.5 (br), 31.8, 33.9,
36.8, 40.8, 43.4 (br), 50.0, 56.4, 57.5, 79.5, 99.1, 113.0, 120.1,
123.5, 127.9, 128.2, 133.5, 138.3, 138.9, 140.9, 151.2, 154.7; HRMS
(ES+) calcd for [C33H46N8O4S + H] 651.3441, found 651.3446;
HPLC (I) tR ) 13.18 (100%), (II) tR ) 20.66 (99.92%).
3
linear regression analysis of the plots of H-hypoxanthine incor-
poration versus concentration of compound.
PfPFT and Rat PFT IC50 Determination. The PFT assay used
to determine the IC50 values (inhibitor concentration that causes
50% enzyme inhibition) of the compounds is based on a PFT [3H]
scintillation proximity assay (SPA) (TRKQ7010 Amersham Bio-
sciences Corp., Piscataway, NJ). Assays were carried out in assay
buffer (pH 7.5, 50 mM HEPES, 30 mM MgCl2, 20 mM KCl, 5
mM DTT, 0.01% Triton X-100), 1 µm human lamin-B carboxy-
terminus sequence peptide (biotin-YRASNRSCAIM), and 1 µCi
[3H]farnesylpyrophosphate (Amersham specific activity 15-20 Ci/
mM) in a total volume of 50 µL which included 1 µL of PfPFT
inhibitor solution in DMSO and 5 µL of partially purified PfPFT.17
Assays in the absence of PfPFT inhibitor and PfPFT were included
as positive and negative controls, respectively. Reaction mixtures
were incubated at 37 °C for 60 min and terminated by addition of
70 µL of assay STOP solution and 5 µL of SPA beads. The assay
mixture was incubated at room temperature for 30 min. The assay
was counted on a plate Chameleon 425-104 multilabel counter
(Hidex Oy Turku, Finland). IC50 values were calculated using linear
regression analysis of the plots of the amount of radioprenylation
versus the concentration of compound. For ratPFT IC50 determi-
nation, 0.01 µm human lamin-B carboxy-terminus sequence peptide
(biotin-YRASNRSCAIM) was used. The assay was incubated at
37 °C for 15 min; otherwise, experimental conditions were the same
as for PfPFT IC50 determination.
Acknowledgment. Financial support for this work was
provided by the Medicines for Malaria Venture (MMV) and
the National Institutes of Health (Grants CA67771 and AI54384).
We thank David Floyd, Lou Lombardo, and David Williams
from Bristol-Myers Squibb for helpful suggestions.
Supporting Information Available: GOLD low energy docked
pictures of compounds 2a-5a, 7a, 8a, 10a, and 11a, experimental
procedures and full characterizations of compounds 14-64d, and
HPLC traces of two independent conditions for all target molecules
(2a-9e, 10a, 10d, 11a, 11d). This material is available free of
charge via the Internet at http://pubs.acs.org.
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