Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites

5710

J. Med. Chem. 2006, 49, 5710-5727

Structurally Simple, Potent, Plasmodium Selective Farnesyltransferase Inhibitors That Arrest

the Growth of Malaria Parasites

Matthew P. Glenn,^†Sung-Youn Chang,^†Carrie Horne´y,^§Kasey Rivas,^§Kohei Yokoyama,^‡Erin E. Pusateri,^†Steven Fletcher,^†

Christopher G. Cummings,^†Frederick S. Buckner,^§Prakash R. Pendyala,^#Debopam Chakrabarti,^#Sa¨ıd M. Sebti,^|

Michael Gelb,^‡Wesley C. Van Voorhis,^§and Andrew D. Hamilton*^,†

Department of Chemistry, Yale UniVersity, 225 Prospect Street, New HaVen, Connecticut 06511, Department of Biochemistry, Department of

Medicine, and Department of Chemistry and Biochemistry, UniVersity of Washington, Seattle, Washington 98195, 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, and Department of Molecular Biology and Microbiology, UniVersity of Central Florida, Orlando, Florida 32826

ReceiVed January 24, 2006

Third world nations require immediate access to inexpensive therapeutics to counter the high mortality

inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors,

designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies

based on this recently validated antimalarial target. This novel series of compounds represents the first

Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors

displaying excellent in vitro activity (IC₅₀< 1 nM) and toxicity to cultured parasites at low concentrations

(ED₅₀< 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.

Introduction

The clear need for new effective antimalarials is complicated

by the resource limitations of the countries most affected, with

the overwhelming majority of mortality (∼90%) confined to

the world’s most impoverished nations.^1,6In this setting, the

development of new antimalarial treatments must give critical

consideration to the economics of drug development and

delivery. In an effort to reduce development costs and accelerate

access to new antimalarials, recent attention has been directed

toward identifying antimalarial activity from agents developed

for the treatment of other diseases.^7-11

Malaria is an ancient, infectious disease that continues to

inflict suffering and death on a large scale. Current estimates

indicate that there are 300-500 million acute cases of malaria

each year, resulting in 1-3 million deaths.¹In the highest risk

group, African children under the age of 5, malaria claims a

young life every 40 s. Unfortunately, mortality from malaria

appears to be increasing and is almost certainly associated with

the increasing resistance of malaria parasites to available

drugs.^2-4

On recognizing the essential role of prenylation for cellular

function in lower eukaryotes,^7,12several groups have investigated

the antimalarial potential of inhibitors of protein farnesyltrans-

ferase (PFT^a),^8,13-16a recognized key target for the interception

of aberrant Ras activity common to many (∼30%) human

cancers.¹⁷Nallan et al. have recently surveyed a number of

mammalian-cell-optimized PFT inhibitors that are in clinical

and preclinical development, including those from Bristol-Myers

Squibb (BMS) (e.g., 1¹⁶and 2⁸) and from the Hamilton/Sebti

group (e.g., 3a and 3b),¹³for their abilities to inhibit Plasmodium

falciparum PFT (PfPFT^a) enzyme activity (as determined by

IC₅₀values) and to arrest the in vitro growth of the intraeryth-

rocytic forms of P. falciparum (as determined by ED₅₀values,

Figure 1).⁸The peptidomimetics from Hamilton et al. proved

to be potent inhibitors, with 3b presumably a prodrug of 3a,

facilitating cell entry of the inhibitor and becoming active upon

cleavage of the benzyl ester by cellular esterases. More potent

still were heterocylic derivatives from BMS, with the tetrahy-

droquinoline (THQ) scaffold (e.g., 2) being superior to the

benzodiazepine scaffold (e.g., 1). Recently, Schlitzer et al. have

reported potent inhibitors of PfPFT based on a benzophenone

scaffold, e.g., 4 (Figure 1).¹⁵

Malaria is caused by protozoal parasites of the genus

Plasmodium, of which four species are known to cause malaria

in humans: falciparum, ViVax, malariae, and oVale. The

parasites are transmitted through the bite of infected mosquitoes

of the genus Anopheles, and following an initial asymptomatic

localization and incubation in the liver, the parasites enter

circulating erythrocytes and consume hemoglobin and other

proteins within the cell. The protozoa replicate inside the blood

cells, ultimately inducing cytolysis and release of toxic metabolic

byproducts into the blood stream. The clinical symptoms of

malaria result exclusively from the erythrocytic stage and include

flulike symptoms, jaundice and anemia. Mortality is almost

exclusively attributable to infection by P. falciparum, which

produces specific proteins that embed into the cell membrane

of the infected erythrocyte. These cells bind to prevenous

capillaries, resulting in obstruction of blood vessels in many

areas of the body. Of significant concern is the increasing

discovery of P. falciparum resistance to existing drugs (chlo-

roquine, mefloquine, sulfadoxime/pyrimethamine),^4,5with strains

now reported that are resistant to all known antimalarial

therapies, potentially foreshadowing devastating consequences

if new treatments are not identified.

Treatment of P. falciparum infected cells with anticancer PFT

inhibitors induces a decrease in farnesylated proteins and

* To whom correspondence should be addressed. Phone: (203) 432-

5570. Fax: (203) 432-3221. E-mail: andrew.hamilton@yale.edu.

^†Yale University.

^aAbbreviations: 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.

^§Department of Medicine, University of Washington.

^‡Department of Chemistry and Biochemistry, University of Washington.

^#University of Central Florida.

^|University of South Florida.

Published on Web 08/25/2006

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5711

Figure 1. Protein farnesyltransferase (PFT) inhibitors and their activities against P. falciparum PFT (IC₅₀values represent the doses that inhibit

50% of the PfPFT enzyme activity) and P. falciparum growth (ED₅₀values represent the doses that inhibit 50% of P. falciparum growth).

Figure 2. Active site conformation of 12x (colored by atom type), as determined by flexible ligand docking (GOLD),¹⁹in the homology model

of the active site of Plasmodium PFT (red hydrophobic to blue hydrophilic). Values in parentheses refer to the corresponding residues of rat FTase

(PDB: 1JCR). FPP is shown in red.

associated lysis of the parasites.¹¹Animal studies recently

demonstrated that closely related derivatives of anticancer PFT

inhibitors cure malaria-infected mice. However, the delivery

costs (synthesis and administration) of drugs developed by

wealthy nations for the treatment of diseases such as cancer

may be prohibitively expensive for third-world nations, even

in the absence of the associated costs for research and develop-

ment. In this manuscript, we elaborate on our previous com-

munication¹⁴with an extensive SAR study of our series of PFT

inhibitors that have been developed specifically as novel

antimalarial agents, emphasizing simple molecular architecture

and straightforward chemical synthesis as prerequisites for

access to low cost treatment for the third world.

ferases I and II) that catalyze the transfer of prenyl groups from

farnesyl or geranylgeranyl pyrophosphate to the free thiol of a

cysteine residue within a tetrapeptide recognition sequence

(CaaX, a ) aliphatic amino acid, X often is M, S, A, or Q for

PFT) located at the carboxyl terminus of the substrate protein.¹⁸

The X-ray crystal structure of rat PFT complexed with the

selenotetrapeptide Ac-Cys-Val-Ile-Met(Se)-OH and a farnesyl-

pyrophosphate (FPP) analogue (1JCR) shows a heterodimeric

zinc metalloenzyme composed of a 48 kDa R-subunit and a 46

kDa â-subunit, with the tetrapeptide in an extended conformation

and coordinated to the catalytic zinc ion through the cysteine

thiol, in proximity to the FPP phosphonate. The sequences of

the two subunits of PfPFT were obtained from the PlasmoDB

database (gene loci: PFL2050w, R, and chr11.glm_528, â),^18,19

and aligned with the reported structure of rat PFT using the

program T-COFFEE.²⁰While PfPFT is found to be considerably

Results and Discussion

Design. PFT is one of three closely related heterodimeric zinc

metalloenzymes (protein farnesyl- and geranylgeranyltrans-

5712 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Glenn et al.

Scheme 1^a

^aReagents and conditions: (a) HBTU, DIPEA, DMF; (b) TFA; (c) LAH, THF; (d) alkylsulfonyl chloride (R²), TEA, DMF.

Table 1. SAR of R²Sulfonamide Substitutions

Scheme 2^a

^aReagents and conditions: (a) 4-fluorobenzonitrile, TEA, DMSO, 120

°C; (b) (1) 4-X-aniline (X ) Br, Ph) acetic acid, 3 Å molecular sieves,

MeOH, (2) NaCNBH₃; (c) LDA, NaH, 5-chloromethyl-1-methyl-1H-

imidazole‚HCl (16), THF, -78 °C; (d) NaH, alkyl bromide (R¹), DMF, 0

°C; (e) TFA; (f) sulfonyl chloride (R²), TEA, DMF; (g) alkyl bromide (R¹),

Cs₂CO₃, DMF.

PfPFT on the template crystal structure of rat PFT complexed

with the nonsubstrate tetrapeptide inhibitor CVFM and farnesyl-

pyrophosphate (FPP).²⁰The homology model (Figure 2) indi-

cates a large, open, and predominantly hydrophobic cavity for

the active site (∼20 × 20 × 20 Å³), with the phospholipid

binding partner (FPP) extending across the cavity base. The Zn

ion coordinates to three residues (Cys 661, Asp 659, and His

838), with a water molecule hydrogen-bonded between the

terminal phosphate of FPP and Asp 659 defining the limit of

the Zn binding domain. The remainder of the active site cavity

includes two well-defined hydrophobic pockets (Lys 149, Asn

317, Ser 150, Phe 151; Trp 456, Trp 452, Tyr 837) and a larger

hydrophilic domain formed by Arg 564 and three water

molecules participating in a hydrogen-bonded network between

Ser 449 and Gln 152.

Figure 3. 2D NOESY of deprotected 9 (X ) CN) in methanol-d₄

identifies the close spatial arrangement of protons about the imidazole

and aniline, confirming chemoselective alkylation of the aniline nitro-

gen. Strong cross-peaks are observed (highlighted in red) between the

methylene protons at c and the protons at g and b, while only a weak

cross-peak is observed between protons at c and the methylene at a.

different from rat PFT, being significantly larger in both the

R- (472 vs 379 residues) and â-subunits (621 vs 437), the

differences are mainly due to insertions in the PfPFT protein

sequence, and overall there is minimal difference in the residues

that form the active site. A homology model of the active site

of P. falciparum was generated by our collaborators at the

University of Washington by using the sequence alignment of

We envisaged accessing these four pockets from a simple

aliphatic tether. Application of a flexible scaffold offers several

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5713

Table 3. SAR of R²Substitutions with X ) CN

Table 2. SAR of X and R³Substitutions

^aInhibitor concentration required to decrease hypoxanthine incorporation

into parasites by 50%. ^b2-Methylbenzyl in place of benzyl (see Table 3, R¹).

advantages to the design of a new series of PFT inhibitors. A

simple acyclic scaffold may be obtained through a short

series of straightforward chemical transformations and may be

refractory to resistance arising from mutation of PfPFT.²⁰One

of the simplest of scaffolds conceivable, ethylenediamine,

affords an inexpensive, 4-fold substitutable flexible tether of

suitable size to project the appended diversity into the

active site pockets. Imidazole provides a convenient zinc

binding group, which has been consistently demonstrated to

confer activity in other series of inhibitors.¹³To maintain a

suitably lipophilic compound, extension from the amines has

been restricted to formation of anilines, sulfonamides, and

amides. Flexible ligand docking studies (GOLD)¹⁹of a series

of compounds incorporating this basic design demonstrate

complementarity to the active site of the homology model

(Figure 2).

Synthesis. PFT inhibitors were prepared as outlined in

Scheme 1, through a simple series of reductive amination, amide

coupling, reduction, and alkylation. This route is not effective

for the preparation of compounds bearing strong para electron-

withdrawing groups on the aniline. In these systems, the amide

coupling becomes increasingly difficult, and in the case of

4-cyanoaniline, the selective reduction of the amide also proves

to be problematic. Performing the reductive amination with

aniline derivatives (X ) Ph and Br) and Boc-glycinal, followed

by alkylation of the resulting aniline with chloromethyl-N-

methylimidazole (16) proved to be suitable for the formation

of the 4-bromo and 4-phenyl derivatives; however, reductive

amination with 4-cyanoaniline proceeded in poor yield (Scheme

2). For the nitrile system, excellent yields of aniline 8c can be

obtained via nucleophillic substitution of p-fluorobenzonitrile

with monoprotected ethylenediamine. Chemoselective alkylation

of aniline 8c, via double deprotonation with LDA and sub-

sequent alkylation at the anilide anion, proceeds smoothly in

THF with no evidence of alkylation of the carbamate (Figure

3). Finally, alkylation of the carbamate, deprotection, and

coupling to sulfonyl or acid chlorides furnish the desired series

of inhibitors.

Structure-Activity Relationships. An initial series of

inhibitors maintained the zinc binding imidazole and hydro-

phobic components (R¹) benzyl, X ) H) constant while

exploring a small focused diversity set (R², seven substitutions)

of sulfonamide substitutions predicted by docking studies

(GOLD)¹⁹to reasonably access the hydrophilic pocket. The

inhibition of PfPFT for these preliminary inhibitors was

determined at a single concentration (50 nM), using a scintil-

lation proximity assay with partially purified PfPFT¹²(Table

1). Four of the seven compounds inhibited PfPFT at 50 nM,

with one compound (1-methyl-1H-imidazole-4-sulfonamide, 7c)

demonstrating very promising inhibition (32% at 50 nM).

Elaboration of 7c, through incorporation of para-substituted

anilines (Br, CN, Ph, Scheme 2), induced at least a 2-fold

improvement in activity (compare 12a and 7c, Table 2).

Inspection of the docked conformations of 12a and 12c indicates

that the para position of the aniline can reasonably access a

hydrophilic domain formed by Ser 150, Asn 317, and Lys 149

at the limit of the mostly hydrophobic pocket occupied by the

aniline (Figure 1).

Modification of the zinc binding imidazole has previously

led to a significant impact on inhibitor potency in related

5714 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Table 4. SAR of R¹Substitutions with X ) CN

Glenn et al.

systems¹³and appears to be particularly important for effective

activity in whole cells. The homology model for PfPFT indicates

that small alkyl groups appended to the imidazole (3-methyl-

3H-imidazol-) might reasonably be accommodated, and the

corresponding methylimidazole inhibitors demonstrated signifi-

cantly improved activity (compare 12b to 12a, Table 2).

Inhibitor 12b, and related methylimidazole inhibitor 12d,

additionally demonstrated inhibition of the growth of parasites

in whole cells (3D7: ED₅₀< 1 µM), as monitored through

incorporation of tritium-labeled hypoxanthine (see Experimental

Section for details).

Having identified a potent inhibitor with good whole-cell

activity (12d), we revisited the series of sulfonamides, now

incorporating both methylimidazole and p-cyanoaniline (Table

3). Inclusion of 1-methyl-1H-imidazole-4-sulfonamide as the

R²substituent again conferred the best in vitro activity against

PfPFT (12d, 86% inhibition at 5 nM), with similar potency

observed for 2-pyridylsulfonamide (12g, 64% inhibition at 5

nM). Phenyl (12e), thiophene (12f), or quinoline (12h) sulfon-

amides were less active. Replacement of the sulfonamide by

small alkylamides (methyl (12j) and isopropyl (12k)), indicated

by docking studies to be able to access a hydrophobic cleft

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5715

that retained sp²-hybridized centers (propenyl (12l), methyl-

propenyl (12m), bromopropenyl (12n), and tert-butylacetamidyl

(12o)) provided inhibitors with reduced activity against PfPFT

and no inhibition against the growth of parasites in cells (>5000

nM). Introduction of cyclohexylmethyl (12q) as a close

comparison for benzyl provided activity similar to that of the

parent inhibitor 12d and offers slight improvement in whole-

cell activity (3D7, ED₅₀) 220 nM; K1, ED₅₀) 850 nM).

Incorporation of oxygen into the cyclohexyl ring to afford the

tetrahydropyran 12r is tolerated, while the similar piperidine

12s is inactive. Activity of the piperidine derivatives is recovered

with amides 12t-v, with larger amides conferring improved

activity. The large tert-butoxy carbamate derivative 12v provides

similar in vitro inhibition as the parent benzyl derivative 12d

but is significantly more toxic to erythrocytic parasite growth

(3D7, ED₅₀) 88 nM; K1, ED₅₀) 54 nM). The isoelectronic

inhibitor 12w is similarly active against both PfPFT and parasite

growth in whole cells.

Table 5. Comparison of Inhibitor Activity against Plasmodium

falciparum and Rat PFT

Incorporation of nitrogen in aryl substitutents (pyridine) is

tolerated for the ortho position, but not for the meta or para

position, and in all cases diminishes toxicity to parasites. A

similar trend is observed for methyl and cyano substitution, with

2-methylbenzyl derivative 12x providing excellent inhibition

against both PfPFT and parasite growth in cells. Condensation

of both 2-pyridyl (12aa) and 2-cyano derivatives with 1-methyl-

1H-imidazole-4-sulfonyl chloride was problematic, and the latter

was not prepared. Large R¹benzyl substituents (phenyl or

pyrrole) can be accommodated at the meta or para position with

a modest reduction of PfPFT inhibition. In both cases whole-

cell activity was better for the para-substituted compounds

(12ag, 12ai), with p-pyrrole 12ai displaying whole-cell activity

comparable to that of the unsubstituted benzyl system (12d).

The 4-phenylbenzyl derivative 12ag is approximately 4-fold less

active than the closely related pyrimidine 12w, despite their

similar structures, while the related 4-pyrrole inhibitor 12ai

displays intermediate activity.

Overall, minor structural modification of any of the four

ethylenediamine substituents has significant impact on PfPFT

activity, and generally good correlation between PfPFT inhibi-

tion and toxicity to cultured parasites is observed, supporting

PfPFT as the relevant target for the antimalarial activity. The

generally straightforward synthesis of these structurally simple

inhibitors facilitates rapid incorporation of diversity at any

position and should greatly ease elucidation of inhibitors with

“druglike” pharmacokinetics.

Selectivity. Previously reported PFT inhibitors have shown

no selectivity for inhibition of parasitic over mammalian

farnesyltransferase or are highly selective inhibitors of the

mammalian enzyme.^7,8,12While inhibition of farnesyltransferase

has been demonstrated to have limited toxicity to mammalian

cells at concentrations required to elicit a therapeutic response,⁸

selective inhibition of parasitic farnesyltransferase may yet be

an essential goal in the development of safe and effective

antimalarial PFT inhibitors. To examine the selectivity of this

new series of PFT inhibitors, 12 compounds were chosen on

the basis of structural diversity and in vitro PfPFT activity and

their 50% inhibition concentrations (IC₅₀) against both PfPFT

and rat PFT were determined (Table 5). Eleven of the 12

compounds demonstrated selectivity for inhibition of PfPFT

over rat PFT, representing to our knowledge the first reported

series of Plasmodium-selective farnesyltransferase inhibitors.

Six inhibitors displayed better than 10-fold selectivity for

Plasmodium (12b-d, 12x, 12aa, 17), with inhibitors 12b and

12c displaying over 100-fold selectivity. Examination of low-

^aInhibitor concentration required to decrease farnesyltransferase activity

by 50%. ^bRatio of rat to Plasmodium falciparum PFT activity.

inaccessible to the larger sulfonamides, resulted in significantly

reduced activity (56% and 61% inhibition at 50 nM, respec-

tively). Good inhibition of the growth of parasites in whole cells

(3D7, K1) was observed with methyl-1H-imidazole-4-sulfon-

amide (12d, ED₅₀) 349 and 375 nM, respectively) and

dansylsulfonamide (12i, ED₅₀) 300 and 388 nM, respectively)

despite the lower PfPFT activity observed for 12i.

A broader series of substitutions was investigated for the R¹

hydrophobic pocket (∼20 compounds) while maintaining the

remaining three groups as previously optimized (Table 4).

Replacement of the benzyl substituent with small alkyl groups

5716 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Glenn et al.

Table 6. In Vitro, In Vivo, and Pharmacokinetic Properties of Selected PfPFT Inhibitors

^aInhibitor concentration required to reduce PfPFT activity by 50%. ^bInhibitor concentration required to reduce hypoxanthine incorporation into parasites

by 50%. ^cAverage results for three mice given 50 mg/kg po dose. ^dAverage results for three rats given 50 mg/kg po dose.

energy docked conformations (GOLD)¹⁹of 12b and 12c in our

homology model shows a consistent position of the para aniline

substituent in the pocket formed by Asn 317 and Phe 151,

corresponding to two (His 201 and Tyr 166, respectively) of

only three residues in the active site that differ between PfPFT

and rat PFT (PDB: 1JCR). Further work is being undertaken

to better elucidate the binding modes of this series of inhibitors,

but these preliminary observations provide tantalizing evidence

for the potential development of highly selective PfPFT inhibi-

tors through exploitation of the modest active site structural

differences of farnesyltransferase isoforms.

Pharmacokinetics. On the basis of their in vivo activity and

structural diversity, 11 PfPFT inhibitors were evaluated for

metabolism and absorption, and in 5 cases oral bioavailability

in mice or rats was examined (Table 6). Three of the 11

inhibitors are structurally divergent at the aniline (12d, 12b,

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5717

Figure 4. (A) Metabolism of 12d by rat liver microsomes. (B) Average plasma concentrations of inhibitors 12d, 12x, 12g, and 12v in three rats

or mice after oral gavage (dose: rats 12.5 mg, mice 1 mg).

12c, with X ) CN, Br, Ph, respectively). Seven represent

modifications of the hydrophobic binding substituent R¹, and

one inhibitor differs by the hydrophilic binding sulfonamide R²

(12g). For each of these inhibitors, the concentration required

to reduce PfPFT activity by 50% (IC₅₀) has also been determined

(Table 6).

junctional complexes. The apparent permeability of small

molecules across these membranes represents a well established

in vitro model of in vivo intestinal wall transport that has

demonstrated good correlation with intestinal absorption in

humans.^22,23The apparent permeability coefficients of a selection

of ethylenediamine PFT inhibitors were generally low (Table

6, (0.4-2.8) × 10^-6cm/s) but not unacceptably removed from

values typically observed for drugs that are fully absorbed in

humans (>1 × 10^-6cm/s).²³Sensitivity to structural modifica-

tion was observed, with three compounds (12q, 12aa, 12g) dis-

playing reasonable permeability coefficients (>1.5 × 10^-6cm/s).

Oral Bioavailability. Oral administration is the preferred

route of drug delivery but is essential when considering the

development of an effective antimalarial for use in the third

world. Oral administration of 12d, an inhibitor with both

moderate microsome stability and apparent permeability, in

saline (50 mg/kg in 90% saline, 3% ethanol, 7% Tween) to

rats with monitoring of inhibitor concentration in plasma over

5 h resulted in a peak inhibitor concentration (C_max) of 0.74

µM after 30 min (T_max), with an elimination half-life of 96 min

(t_1/2) (Table 6, Figure 4B). Similar inhibitor concentrations in

plasma were observed for 12x after oral dosing in mice (50

mg/kg), with a slightly elevated peak inhibitor concentration

(C_max) 1.05 µM, T_max) 40 min). On the basis of Caco-2

permeability and metabolism profiles similar to those of 12d

and 12x, 12g (Caco-2: 2.8 × 10^-6cm/s) was expected to

demonstrate improved oral bioavailability. However, oral

administration of 12g to mice identified extremely disappointing

concentrations of the inhibitor in plasma, with maximum peak

Metabolism. Liver microsomes provide a convenient model

of in vitro hepatic metabolism, allowing rapid initial assessment

of the relative metabolic stability of a series of inhibitors. On

treatment of 12d with rat or mouse liver microsomes, complete

metabolism was observed within 1 h (Figure 4A), with inhibitor

half-lives of 18 and 9 min, respectively (Table 6). Residual

metabolite mass spectrum ionization reflected only a minor

proportion of the initial ionization observed (<10%) and

corresponded principally to oxidation of the inhibitor (+O), and

oxidation with loss of the aniline imidazole (-R³+ O). Despite

the presence of the strong para electron-withdrawing group

(CN), a metabolism pathway may reasonably involve oxidation

of the aniline nitrogen, followed by N-dealkylation.²¹However,

the metabolism half-lives of inhibitors 12b and 12c, bearing

less electronegative para substitution (Br and Ph, respectively),

exhibit only relatively minor charges in stability, suggesting

that aniline oxidation may not be the primary site of metabolism.

The methylbenzyl inhibitor 12x displayed a metabolism

profile very similar to that of 12d, despite the additional benzylic

position, which may be expected to be readily oxidized. In

comparison, 12q, incorporating cyclohexylmethyl as the hydro-

phobic substituent in place of the benzyl, is metabolized

significantly more rapidly (t_1/2< 5 min). The related but larger

piperidine derivatives 12v and 12w are considerably more stable

(rat t_1/2) 60 and 40 min, respectively), which does not appear

to be directly related to the increased size of this substituent,

given the rapid metabolism of the very similar 4-phenyl- and

4-pyrrolebenzyl derivatives 12ag and 12ai (mouse t_1/2< 4 min).

Inhibitors 12v and 12w bearing isoelectronic R¹piperidine

substitution represent the most metabolically stable inhibitors

observed in this series, and in general, modification of the R¹

position has been found to have the greatest overall impact on

the rate of microsome metabolism. Efforts are ongoing to

identify the principal metabolic pathway operative for this series

of inhibitors.

concentrations and clearance rates (C_max) 0.31 µM, T_max

)

30, t_1/2) 16 min) significantly lower than those observed for

12d and 12x (Table 6). In comparison, 12v, which demonstrated

long half-life stability against liver microsome metabolism (rat

t_1/2) 60 min), had considerably improved inhibitor availability

in blood plasma after oral dosing in mice. An average

concentration of 12v in plasma ∼6-fold above the concentration

required to reduce parasite growth in erythrocytes by 50% (3D7,

ED₅₀) 88 nM; K1, ED₅₀) 54 nM) was maintained for the

duration of the experiment (5 h), with an average peak plasma

inhibitor concentration 30-fold over the ED₅₀observed within

40 min (Table 6, Figure 4B).

Absorption. Caco-2 cells cultured on a semipermeable

membrane form a highly functionalized epithelial barrier, with

remarkable similarity to small intestinal epithelial cells, including

high levels of brush border hydrolases and well-developed

Conclusion

In summary, new, simple acyclic PfPFT inhibitors have been

developed and their efficacy against PfPFT and reduction of

5718 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Glenn et al.

(232 µL, 0.6 M), MgCl₂(12.0 µL, 0.1 M), EDTA (0.8 µL, 0.5 M),

10× NADPH regenerating system (40.0 µL), glucose-6-phosphate

deghydrogenase (0.8 µL, 500 U/mL), Milli-Q water (267.8 µL),

and liver microsomes (10.0 µL, 20 mg/mL) were heated at 37 °C

for 10 min. To each reaction well was added inhibitor (200 µM,

2.0 µL) in DMSO. Control runs included standard compounds such

as propanolol and tetrahydroquinoline compounds. Reactions were

quenched with acetonitrile (75 µL) and internal standard at

designated time points, and the sample was immediately frozen

(-20 °C). Metabolites and unreacted inhibitor were quantified by

liquid chromatography/mass spectrometry.

parasite load in infected erythrocytes have been evaluated.

Compounds based on this readily accessible scaffold are found

to be highly active inhibitors of PfPFT, with IC₅₀values as low

as 0.5 nM identified from the initial diversity set (∼40

compounds). Effective translation of this activity into whole-

cell models of parasitemia is observed, with four compounds

requiring doses of less than 100 nM to reduce parasite

populations (3D7, K1) in erythrocytes by 50%. A preliminary

study of the pharmacokinetic profile of this series of inhibitors

identifies metabolism and absorption rates, as measured by

microsome metabolism and Caco-2 permeability, to be respon-

sive to minor structural modification. Relatively metabolically

stable (t_1/2≈ 60 min) inhibitors have been identified, in addition

to compounds with promising Caco-2 permeability. Further, oral

gavage of a microsome stable inhibitor to mice identified very

encouraging concentrations of inhibitor maintained in blood

plasma over 5 h. We are hopeful that elaboration of this series

will identity exceptionally potent inhibitors of PfPFT, with

suitable pharmacokinetic profiles to allow a drug candidate to

progress further. The structural simplicity that underlines the

design of these compounds should greatly facilitate third-world

nation access to any potential drug emergent from these novel

PFT inhibitors.

Ligand Docking Studies. Ligand energy minimization was

peformed with the CVFF force field in InsightII on an SGI O2.

Flexible ligand docking studies were subsequently performed with

GOLD, version 3.0,¹⁹on a Linux PC. Default GOLD parameters

were utilized with the following exceptions: (i) maximal ligand

flexibility was allowed; (ii) the affinity of nitrogen for zinc ion

was increased in the GOLD parameters file to better reflect the

ability of an imidazole ring to bind to the active site metal ion.

Each ligand was used to seed the genetic algorithm 10 times.

Chemistry: General Methods. ¹H and ¹³C NMR spectra were

recorded on Bruker AM 400 MHz and Bruker AM 500 MHz

spectrometers. Analysis and purification by reversed-phase HPLC

(rpHPLC) were performed using either Phenomenex 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 water/0.1% TFA

(A) and 10:1 acetonitrile/water (B) with 0.1% TFA. Product

fractions were always lyophilized to dryness. 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. Mass

determinations were performed using electrospray ionization on

either a Varian MAT-CH-5 (HRMS) or Waters Micromass ZQ

(LRMS). Solvents DMF, THF, and CH₂Cl₂were dried on an

Innovative Technology SPS-400 dry solvent system. Methanol,

TEA, and DMSO were dried over calcium hydride. Molecular

sieves were activated by heating to 300 °C under vacuum overnight.

General Procedure A (Alkylation of Carbamates). Sodium

hydride (60% dispersion, 1.5 equiv) was added in one portion to a

solution of the carbamate (1.0 equiv) dissolved in DMF (2 mL/

mmol) at 0 °C. The resulting suspension was stirred for 5 min before

addition of the alkyl halide (1.1 equiv), and stirring was then

continued for a further 10 min. The resulting solution was diluted

with EtOAc (20 mL/mmol) and washed consecutively with equal

portions of 1.0 M aqueous HCl, saturated NaHCO₃, and brine. The

organic phase was dried over magnesium sulfate, and the solvent

was removed under vacuum. The crude reaction product was

generally deprotected immediately by dissolving the crude material

in TFA (1 mL/mmol) and stirring for 10 min. After removal of the

TFA under reduced pressure, the resulting oil was purified by

rpHPLC to provide the product amine as the TFA salt.

General Procedure B (Alkylation of Sulfonamides). The

required alkyl bromide (1.1 equiv) was added in one portion to a

solution of the primary sulfonamide (1.0 equiv) and Cs₂CO₃(1.5

equiv) in DMF (5 mL/mmol), and the resulting solution was stirred

for 2 days at room temperature. Filtration and purification by

rpHPLC provided the desired compound as the TFA salt.

General Procedure C (Reaction of Amines with Sulfonyl or

Acid Chlorides). The required sulfonyl or acid chloride (1.2 equiv)

was added in one portion to a solution of the amine (1.0 equiv)

and dry TEA (5.0 equiv) in DMF (2 mL/mmol) at 0 °C. The mixture

was stirred for 10 min, diluted with acetonitrile, and purified directly

by rpHPLC to provide the desired sulfonamide as the TFA salt.

1-Trityl-1H-imidazole-4-carbaldehyde (13). Dry triethylamine

(12.6 mL, 90.0 mmol) was added dropwise over 2 h to a slurry of

(1,3)-H-imidazole-4-carbaldehyde (5.0 g, 52 mmol) and trityl

chloride (16.0 g, 57.0 mmol) in acetonitrile (170 mL). After

complete addition of the triethylamine, the resulting solution was

stirred overnight and then hexane (16.6 mL) and water (170 mL)

were added. After the mixture was stirred for an additional 30 min,

Experimental Section

Plasmodium Strains. The P. falciparum strains used in this study

were 3D7 (The Netherlands, sensitive), provided by Dr. Pradipsinh

Rathod from the University of Washington, and K1 (Thailand, ChQ-

R, Pyr-R), obtained from the MR4 unit of the American Type

Culture Collection (ATCC, Manassas, VA).

P. falciparum Culture. Strains of P. falciparum were sustained

in vitro on the basis of experimental techniques as described by

Trager and Jensen.²⁴Cultures were maintained in RPMI-1640

(Sigma, St. Louis, MO) with 2 mM L-glutamine, 25 mM HEPES,

33 mM NaHCO₃, 20 µg/mL gentamicin sulfate, and 20% (v/v) heat-

inactivated human plasma type A+ (RP-20P). Type A+ erythro-

cytes were obtained from lab donors, washed three times with

RPMI, resuspended in 50% RPMI, and stored at 4 °C. Parasites

were grown in 10 mL of a 2% hematocrit/RP-20P (v/v) in 50 mL

flasks under a 5% CO₂, 5% O₂, and 90% N₂atmosphere.

P. falciparum ED₅₀Determination. An amount of 1 µL of

PfPFT inhibitor dissolved in DMSO was added to each well of a

96-well plate followed by the addition of 200 µL of P. falciparum

culture at parasitemia and hematocrit of 0.5%. Plates were flushed

with 5% CO₂, 5% O₂, and 90% N₂and 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

â-scintillation counter. The background level detected with un-

infected erythrocytes was subtracted from the data. The ³H-

incorporation into infected RBCs with 1 µL of DMSO vehicle alone

represents 100% malaria growth. ED₅₀values were determined by

linear regression analysis of the plots of [³H]hypoxanthine incor-

poration versus concentration of compound.

PfPFT IC₅₀Determination. Assays for PfPFT activity were

performed with a PFT-specific scintillation assay (SPA) kit

(Amersham Biosciences, Piscataway, NJ) slightly modified from

that previously described.¹²An amount of 1 µM biotinylated lamin

B peptide substrate (biotin-YRASNRSCAIM) was used. The

concentration of [³H]farnesyl pyrophosphate (FPP) (3.7 MBq) was

increased beyond manufacturer’s recommendations to 1 µM. IC₅₀

values were calculated using linear regression analysis of the plots

of [³H]FPP prenylation versus concentration of compounds.

Microsome Metabolism. Liver microsome metabolism assays

were performed with female pooled microsomes from BD Bio-

sciences (20 mg/mL). Reaction wells containing phosphate buffer

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5719

the resulting solid was collected and dried overnight under vacuum

to provide the title compound as a white solid (16.8 g, 96%). H

for 1 h at room temperature, Na₂SO₄‚10H₂O (∼1.0 g) was added,

and the resulting suspension was stirred overnight. The mixture

was filtered and solvent removed under reduced pressure to afford

the title compound, which was purified by rpHPLC (230 mg, 63%).

LRMS calcd for C₁₉H₂₃N₄307.2, found 307.1. H NMR (400

MHz, MeOH-d₄): δ 8.61 (s, 1H), 7.33 (m, 5H), 7.19 (s, 1H), 7.15

(m, 2H), 7.01 (t, J ) 7.15 Hz, 1H), 6.82 (d, J ) 8.61 Hz, 2H),

4.53 (s, 2H), 4.15 (s, 2H), 3.62 (t, J ) 6.86 Hz, 2H), 3.15 (t, J )

6.83 Hz, 2H). ¹³C NMR (125 MHz, CDCl₃): δ 147.3, 138.0, 134.7,

131.6, 129.9, 129.5, 129.2, 128.8, 126.7, 118.2, 113.3, 53.7, 50.2,

48.0, 46.9.

N-Benzyl-N-{2-[(3H-imidazol-4-ylmethyl)phenylamino]ethyl}-

benzenesulfonamide (7a, X ) H, R¹) Benzyl, R²) Phenyl-

sulfonyl, R³) H). Reaction of 7 was carried out according to

procedure C. Yield 71%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.71

(s, 1H), 7.79 (d, J ) 7.17 Hz, 2H), 7.61 (tt, J ) 1.17, 7.10 Hz,

1H), 7.54 (m, 2H), 7.24 (m, 5H), 7.05 (s, 1H), 7.13 (m, 2H), 6.93

(t, J ) 7.10 Hz, 1H), 6.79 (d, J ) 8.45 Hz, 2H), 4.31 (s, 2H), 4.18

(s, 2H), 3.54 (m, 2H), 3.19 (m, 2H). ¹³C NMR (125 MHz, CDCl₃):

δ 148.4, 138.3, 138.0, 135.0, 131.3, 130.9, 129.7, 129.4, 129.2,

128.8, 126.5, 119.8, 116.8, 113.8, 55.3, 51.8, 48.9, 46.7. HRMS

calcd for C₂₅H₂₆N₄O₂SH⁺447.1849, found 447.1840. Retention

time for analytical rpHPLC: condition I, 10.42; condition II, 13.10

min.

1

NMR (400 MHz, CDCl₃): δ 9.81 (s, 1H), 7.54 (s, 1H), 7.46 (s,

1H), 7.29 (m, 10H), 7.04 (m, 5H). ¹³C NMR (100 MHz, CDCl₃):

δ 186.9, 141.9, 141.2, 141.0, 130.0, 129.0, 128.9, 127.2, 76.7.

3-Methyl-3H-imidazole-4-carbaldehyde Trifluoromethane-

sulfonate (14). Methyl triflate (10.0 g, 60.1 mmol) was added

dropwise over 5 h to a solution of aldehyde 13 (13.5 g, 40.0 mmol)

in CH₂Cl₂(50 mL), and the resulting solution was stirred overnight

at room temperature. The volume of solvent was then reduced under

vacuum (∼30 mL), and hexane (40 mL) was added. Stirring was

continued for a further 30 min, at which time the crude solid of

3-methyl-1-trityl-1H-imidazole-4-carbaldehyde trifluoromethane-

sulfonate was collected and washed with hexane (3 × 25 mL). This

solid was immediately dissolved in 2:1 acetone/water (40 mL) and

stirred for 4 h at room temperature. The resulting suspension was

filtered, the solid washed with water (30 mL), and the supernatant

concentrated under vacuum, then lyophilized to afford the title

+

1

compound as a white solid (9.7 g, 93%). H NMR (400 MHz,

MeOH-d₄): δ 8.84 (s, 1H), 7.50 (s, 1H), 5.77 (s, 1H), 3.95 (s, 3H).

¹³C NMR (100 MHz, MeOH-d₄): δ 188.6, 148.4, 140.8, 135.3,

30.2.

(3-Methyl-3H-imidazol-4-yl)methanol (15). 3-Methyl-3H-imid-

azole-4-carbaldehyde (14) (4.0 g, 15 mmol) was suspended in THF

(10 mL), and the resulting solution was cooled to 0 °C. Lithium

aluminum hydride (300 mg, 32.0 mmol) was added portionwise

over 10 min, and the resulting suspension was stirred for a further

10 min. Excess hydride was quenched by the careful addition of

solid Na₂SO₄‚10H₂O (∼1 g) in small portions with vigorous stirring.

Additional THF was added as needed to prevent solidification of

the resulting slurry. The resulting suspension was stirred for a further

hour and then filtered to remove the sulfate salts, and the solvent

was removed under reduced pressure to provide the title alcohol

1-Methyl-1H-imidazole-4-sulfonic Acid Benzyl-{2-[(3H-imid-

azol-4-ylmethyl)phenylamino]ethyl}amide (7c, X ) H, R¹

)

Benzyl, R²) 4-Methyl-1H-imidazolesulfonyl, R³) H). Reaction

of 7 was carried out according to procedure C. Yield 62%. ¹H NMR

(400 MHz, MeOH-d₄): δ 8.74 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H),

7.28 (m, 5H), 7.22 (s, 1H), 7.04 (t, J ) 7.40 Hz, 2H), 6.64 (t, J )

7.30 Hz, 1H), 6.45 (d, J ) 8.02 Hz, 2H), 4.40 (s, 2H), 4.22 (s,

2H), 3.73 (m, 5H), 3.30 (obscured). ¹³C NMR (100 MHz, MeOH-

d₄): δ 148.6, 141.8, 138.3, 135.7, 133.5, 131.4, 130.7, 130.6, 130.2,

129.6, 127.0, 119.6, 118.4, 114.8, 55.2, 52.3, 46.8, 46.6, 34.7.

HRMS calcd for C₂₃H₂₆N₆O₂SH⁺451.1916, found 451.1908.

Retention time for analytical rpHPLC: condition I, 10.49; condition

II, 12.95 min.

1

(1.3 g, 80%). H NMR (400 MHz, MeOH-d₄): δ 7.57 (s, 1H),

6.89 (s, 1H), 4.58 (s, 2H), 372 (s, 3H). ¹³C NMR (100 MHz, MeOH-

d₄): δ 140.1, 132.7, 128.1, 31.9, 31.0.

5-Chloromethyl-1-methyl-1H-imidazole (16). DMF (1 drop)

was added to a slowly stirred solution of (3-methyl-3H-imidazol-

4-yl)methanol (15) (1.8 g, 16 mmol) dissolved in thionyl chloride

(12 mL). After 30 min the solvent was removed under reduced

pressure, and the resulting solid was triturated with diethyl ether

(20 mL). The resulting semisolid was dried overnight under vacuum

and used without further purification. ¹H NMR (400 MHz, MeOH-

d₄): δ 8.98 (s, 1H), 7.63 (s, 1H), 4.85 (s, 2H), 3.90 (s, 3H). ¹³C

NMR (100 MHz, MeOH-d₄): δ 138.3, 132.6, 120.5, 34.5, 33.9.

Benzyl-{[(3H-imidazol-4-ylmethyl)phenylcarbamoyl]methyl}-

carbamic Acid tert-Butyl Ester (6). HBTU (2.2 g, 5.8 mmol) was

added in one portion to a solution of (benzyl-tert-butoxycarbonyl-

amino)acetic acid²⁵(1.6 g, 5.8 mmol) and DIPEA (4.9 mL, 29

mmol) dissolved in DMF (300 mL), and the resulting solution was

stirred for 10 min before addition of (3H-imidazol-4-ylmethyl)-

phenylamine (5) (1.0 g, 5.8 mmol). The mixture was stirred at room

temperature for 1 h, after which the volume of solvent was reduced

(∼20 mL) under vacuum and the resulting residue dissolved in

EtOAc (500 mL) and washed successively with 1.0 M HCl (2 ×

200 mL), saturated NaHCO₃(2 × 200 mL), and brine (200 mL).

The organic layer was dried over magnesium sulfate, and the solvent

was removed under reduced pressure. Purification by flash column

chromatography (1:4 MeOH/EtOAc) provided the title compound

N-Benzyl-N-{2-[(3H-imidazol-4-ylmethyl)phenylamino]ethyl}-

C-p-tolylmethanesulfonamide (7d, X ) H, R¹) Benzyl, R²)

4-Methylbenzylsulfonyl, R³) H). Reaction of 7 was carried out

according to procedure C. Yield 71%. ¹H NMR (400 MHz, MeOH-

d₄): δ 8.61 (s, 1H), 7.39 (m, 5H), 7.32 (s, 1H), 7.23 (d, J ) 7.80

Hz, 2H), 7.19 (m, 2H), 7.05 (d, J ) 7.78 Hz, 2H), 6.87 (d, J )

8.58 Hz, 2H), 6.83 (t, J ) 7.33 Hz, 1H), 4.54 (s, 2H), 4.09 (s, 2H),

3.97 (s, 2H), 3.60 (t, J ) 6.96 Hz, 2H), 3.12 (t, J ) 6.95 Hz, 2H),

2.27 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ 148.4, 138.5,

135.7, 132.7, 132.6, 132.4, 131.8, 131.5, 131.2, 131.1, 130.5, 121.9,

118.6, 117.7, 114.9, 58.6, 55.4, 52.8, 47.7, 45.5, 21.6. HRMS calcd

for C₂₇H₃₀N₄O₂SH⁺475.2168, found 475.2154. Retention time for

analytical rpHPLC: condition I, 10.65; condition II, 13.39 min.

Naphthalene-2-sulfonic Acid Benzyl-{2-[(3H-imidazol-4-

ylmethyl)phenylamino]ethyl}amide (7e, X ) H, R¹) Benzyl,

R²) 2-Naphthylsulfonyl, R³) H). Reaction of 7 was carried

1

out according to procedure C. Yield 65%. H NMR (500 MHz,

MeOH-d₄): δ 8.30 (s, 1H), 7.89 (m, 5H), 7.52 (m, 2H), 7.42 (m,

4H), 7.26 (s, 1H), 7.21 (m, 3H), 6.85 (d, J ) 7.04 Hz, 2H), 6.79

(t, J ) 7.36 Hz, 1H), 4.57 (s, 2H), 4.39 (s, 2H), 3.71 (t, J ) 6.86

Hz, 2H), 3.27 (t, J ) 6.79 Hz, 2H). ¹³C NMR (125 MHz, MeOH-

d₄): δ 148.4, 135.9, 135.8, 134.3, 132.7, 131.4, 131.2, 131.1, 130.7,

130.2 (2C), 129.8, 129.2, 128.9, 128.3, 126.9, 124.5, 121.8, 118.5,

117.5, 52.9, 48.1, 46.7, 45.8. HRMS calcd for C₂₉H₂₈N₄O₂SH⁺

497.2006, found 497.1998. Retention time for analytical rpHPLC:

condition I, 10.71; condition II, 12.93 min.

+

(1.88 g, 77%). LRMS calcd for C₂₄H₂₉N₄O₃421.2, found 421.4.

NMR data were consistent with the proposed structure but

complicated by the presence of configurational isomers of the

carbamate and or amide. Full characterization is reported on the

deprotected and reduced products below.

N′-Benzyl-N-(3H-imidazol-4-ylmethyl)-N-phenylethane-1,2-

diamine (7). Carbamate 6 (500 mg, 1.20 mmol) was dissolved in

TFA/water (100:1, 25 mL) and the resulting solution stirred for 20

min. The solvent was removed under reduced pressure and the

residue triturated with ether and dried under vacuum. The resulting

viscous oil was dissolved in THF (50 mL), and LAH (190 mg,

5.00 mmol) was added in portions. After the mixture was stirred

Quinoline-8-sulfonic Acid Benzyl-{2-[(3H-imidazol-4-ylmethyl)-

phenylamino]ethyl}amide (7f, X ) H, R¹) Benzyl, R²

)

8-Quinolinesulfonyl, R³) H). Reaction of 7 was carried out

according to procedure C. Yield 70%. ¹H NMR (400 MHz, MeOH-

d₄): δ 8.79 (dd, J ) 1.45, 4.26 Hz, 1H), 8.63 (dd, J ) 1.38, 7.48

Hz, 1H), 8.39 (dd, J ) 1.75, 8.41 Hz, 1H), 8.32 (dd, J ) 1.36,

8.26, 1H), 8.21 (d, J ) 1.25 Hz, 1H), 7.77 (t, J ) 7.61 Hz, 1H),

7.57 (dd, J ) 4.29, 8.40 Hz, 1H), 7.43 (m, 5H), 7.20 (s, 1H), 6.99

5720 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Glenn et al.

(dd, J ) 7.38, 8.80 Hz, 2H), 6.61 (m, 3H), 4.32 (s, 2H), 4.21(s,

2H), 3.74 (t, J ) 5.53 Hz, 2H), 3.28 (t, J ) 5.52 Hz, 2H). ¹³C

NMR (100 MHz, MeOH-d₄): δ 155.5, 150.86, 146.8, 144.3, 143.1,

140.8, 140.5, 137.5, 136.7, 135.3, 133.5, 133.3, 133.0, 132.9, 132.7,

129.3, 126.7, 122.0, 119.9, 117.1, 54.8, 53.0, 52.0, 49.7. HRMS

calcd for C₂₈H₂₇N₅O₂SH⁺498.1964, found 498.1956. Retention

time for analytical rpHPLC: condition I, 10.62; condition II, 13.43

min.

1-Methyl-1H-imidazole-4-sulfonic Acid Benzyl-{2-[(4-bromo-

phenyl)-(3H-imidazol-4-ylmethyl)amino]ethyl}amide (12a, X )

Br, R¹) Benzyl, R²) 4-Methyl-1H-imidazolesulfonyl, R³)

H). Reaction of 10b was carried out according to procedure B.

Yield 65%. ¹H NMR (500 MHz, DMSO-d₆): δ 8.83 (s, 1H), 7.83

(s, 1H), 7.80 (s, 1H), 7.38 (m, 5H), 7.23 (s, 1H), 7.22 (d, J ) 9.01

Hz, 2H), 6.46 (d, J ) 9.05 Hz, 2H), 4.46 (s, 2H), 4.32 (s, 2H),

3.82 (s, 3H), 3.37 (m, 4H). ¹³C NMR (125 MHz, DMSO-d₆): δ

147.6, 141.5, 139.4, 138.0, 135.6, 133.1, 130.5, 129.9, 129.5, 129.3,

126.7, 118.2, 116.1, 110.8. HRMS calcd for C₂₃H₂₆BrN₆O₂S⁺

529.1021, found 529.1036. Retention time for analytical rpHPLC:

condition I, 13.36; condition II, 21.53 min.

5-Dimethylaminonaphthalene-1-sulfonic Acid Benzyl-{2-[(3H-

imidazol-4-ylmethyl)phenylamino]ethyl}amide (7g, X ) H, R¹

) Benzyl, R²) Dimethylaminonaphthalenesulfonyl, R³) H).

Reaction of 7 was carried out according to procedure C. Yield 63%.

¹H NMR (400 MHz, MeOH-d₄): δ 8.68 (dd, J ) 0.85, 8.51 Hz,

1H), 8.43 (dd, J ) 1. 20, 7.49 Hz, 1H), 8.16 (d, J ) 8. 69 Hz, 1H),

7.99 (d, J ) 1.37, 1H), 7.65 (dd, J ) 7.53, 8.51 Hz, 1H), 7.54 (dd,

J ) 7.70, 8.62, Hz, 1H), 7.53 (s, 1H), 7.36 (m, 5H), 7.26 (d, J )

7.67 Hz, 1H), 6.99 (dd, J ) 7.36, 8.78 Hz, 2H), 6.63 (t, J ) 7.30,

1H), 6.59 (d, J ) 7.96 Hz, 2H), 4.30 (s, 2H), 4.17 (s, 2H), 3.72 (t,

J ) 5.24 Hz, 2H), 3.24 (obscured), 2.83 (s, 6H). ¹³C NMR (100

MHz, MeOH-d₄): δ 154.3, 148.6, 143.3, 139.0, 135.0, 134.0, 133.1,

132.8, 131.6, 131.4, 131.3, 131.1, 130.9, 130.7, 130.6, 125.0, 120.0,

118.7, 117.6, 117.2, 115.1, 52.6, 51.0, 48.8, 47.4, 46.1. HRMS calcd

for C₃₁H₃₃N₅O₂SH⁺540.2428, found 540.2419. Retention time for

analytical rpHPLC: condition I, 10.70; condition II, 13.51 min.

[2-(4-Bromophenylamino)ethyl]carbamic Acid tert-Butyl Es-

ter (8b, X ) Br). A solution of 4-bromoaniline (6.5 g, 37 mmol),

(2-oxoethyl)carbamic acid tert-butyl ester (2.0 g, 12 mmol), and

acetic acid (790 µL, 12.4 mmol) in dry methanol (20 mL) with dry

3 Å molecular sieves (1.0 g) was stirred under nitrogen for 20 min.

Sodium cyanoborohydride (0.79 g, 12 mmol) was added in one

portion, and the resulting solution was stirred for a further hour

under nitrogen, at which time EtOAc (300 mL) was added and

the organic phase washed consecutively with 1.0 M aqueous HCl

(1 × 100 mL), saturated NaHCO₃(2 × 100 mL), and brine (1 ×

100 mL). The organic phase was dried over magnesium sulfate,

and the solvent was removed under vacuum to provide the title

compound as a viscous yellow oil (3.1 g, 79%) after flash column

chromatography (1:4 EtOAc/hexane). ¹H NMR (400 MHz,

CDCl₃): δ 7.14 (d, J ) 8.88 Hz, 2H), 6.38 (d, J ) 8.89 Hz, 2H),

4.88 (br s, 1H), 3.26 (br s, 2H), 3.09 (br t, J ) 5.94 Hz, 2H), 1.37

(s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 157.0, 147.5, 132.6, 114.6,

109.2, 80.1, 44.5, 40.3, 29.0.

{2-[(4-Bromophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]-

ethyl}carbamic Acid tert-Butyl Ester (9b-Me, X ) Br, R³)

Methyl). Lithium diisopropylamide (2.0 M, 4.9 mL, 9.8 mmol)

was added dropwise to a solution of 8b (1.01 g, 3.23 mmol) in dry

THF (40 mL) at -78 °C, and the resulting orange solution was

stirred for 1.5 h at -78 °C under nitrogen. In a separate flask sodium

hydride (60%, 194 mg, 4.85 mmol) was added to a solution of

5-chloromethyl-1-methyl-1H-imidazole‚HCl (594 mg, 3.55 mmol)

in dry THF (15 mL) at 0 °C. The suspension of sodium chloride

and imidazole was added to the dianion of 8b via cannula under

nitrogen, and the resulting solution was stirred for 1 h at -78 °C.

The reaction was quenched by addition of brine (1 mL), and THF

was evaporated. After dilution with EtOAc (200 mL), the organic

layer was washed consecutively with water (3 × 50 mL) and brine

(1 × 50 mL). The organic phase was dried over sodium sulfate,

and the solvent was removed under vacuum. Purification by flash

column chromatography (1:7:292 NH₄OH/MeOH/CH₂Cl₂) provided

the title compound as a white solid (600 mg, 98% yield based on

1

recovered starting material). H NMR (400 MHz, MeOH-d₄): δ

8.78 (s, 1H), 7.22 (d, J ) 9.01, Hz, 2H), 7.17 (s, 1H), 6.74 (d, J )

9.14 Hz, 2H), 4.58 (s, 2H), 3.79 (s, 3H), 3.40 (t, J ) 6.87 Hz, 2H),

3.14 (t, J ) 6.70 Hz, 2H), 1.32 (s, 9H). ¹³C NMR (125 MHz,

CDCl₃): δ 158.9, 148.5, 137.9, 134.0, 133.6, 119.6, 118.5, 111.5,

80.6, 51.9, 46.7, 39.1, 34.6, 29.1.

N′-Benzyl-N-(4-bromophenyl)-N-(3-methyl-3H-imidazol-4-yl-

methyl)ethane-1,2-diamine (11b, X ) Br, R¹) Benzyl, R³)

Methyl). Reaction of 9b-Me was carried out according to procedure

1

A. Yield 73%. H NMR (400 MHz, MeOH-d₄): δ 8.75 (s, 1H),

7.35 (s, 5H), 7.26 (d, J ) 9.02 Hz, 2H), 7.12 (s, 1H), 6.75 (d, J )

9.06 Hz, 2H), 4.57 (s, 2H), 4.14 (s, 2H), 3.74 (s, 3H), 3.60 (t, J )

7.11 Hz, 2H), 3.17 (t, J ) 7.20 Hz, 2H). ¹³C NMR (100 MHz,

MeOH-d₄): δ 147.5, 138.2, 133.9, 133.3, 132.7, 131.4, 131.2, 130.8,

119.8, 118.5, 113.5, 53.0, 48.5, 46.6, 45.3, 34.6.

{2-[(4-Bromophenyl)-(3H-imidazol-4-ylmethyl)amino]ethyl}-

carbamic Acid tert-Butyl Ester (9b-H, X ) Br, R³) H). A

solution of aniline 8b (0.50 g, 1.6 mmol) and 3H-imidazole-4-

carbaldehyde (0.30 g, 3.2 mmol) in dry methanol (5.0 mL) with

dry 3 Å molecular sieves (0.20 g) was stirred under nitrogen for

20 min. Sodium cyanoborohydride (0.20 g, 3.2 mmol) was added

in one portion, and the resulting solution was stirred overnight under

nitrogen at 50 °C. The resulting solution was diluted with EtOAc

(100 mL) and then washed consecutively with 1.0 M aqueous HCl

(1 × 100 mL), saturated NaHCO₃(2 × 100 mL), and brine (1 ×

100 mL). The organic phase was dried over magnesium sulfate,

and the solvent was removed under vacuum to provide the title

compound as a viscous yellow oil, which was purified by flash

1-Methyl-1H-imidazole-4-sulfonic Acid Benzyl-{2-[(4-bromo-

phenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

amide (12b, X ) Br, R¹) Benzyl, R²) 4-Methyl-1H-

imidazolesulfonyl, R³) Methyl). Reaction of 11b was carried

1

out according to procedure C. Yield 65%. H NMR (400 MHz,

MeOH-d₄): δ 8.71 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.23 (m,

5H), 7.17 (s, 1H), 7.07 (d, J ) 9.10 Hz, 2H), 6.30 (d, J ) 9.15 Hz,

2H), 4.33 (s, 2H), 4.16 (s, 2H), 3.69 (s, 3H), 3.21 (obscured, 4H).

¹³C NMR (100 MHz, MeOH-d₄): δ 147.8, 141.9, 139.6, 138.2,

135.9, 133.4, 133.0, 130.6, 130.2, 129.7, 127.1, 118.5, 116.4, 111.2,

55.3, 52.7, 46.7, 46.6, 34.7. HRMS calcd for C₂₄H₂₇BrN₆O₂SH⁺

543.1178, found 543.1186. Retention time for analytical rpHPLC:

condition I, 14.26; condition II, 29.12 min.

[2-(Biphenyl-4-ylamino)ethyl]carbamic Acid tert-Butyl Ester

(8a, X ) Ph). 8a was prepared as described for 8b. Yield 52%. ¹H

NMR (400 MHz, MeOH-d₄): δ 7.54-7.51 (m, 3H), 7.46 (d, J )

8.83 Hz, 2H), 7.35 (t, J ) 7.70 Hz, 2H), 7.21 (t, J ) 7.33 Hz, 1H),

6.96 (d, J ) 8.83 Hz, 2H), 6.78 (s, 1H), 4.52 (s, 2H), 3.58 (s, 3H),

3.41 (t, J ) 6.75 Hz, 2H), 3.17 (t, J ) 6.75 Hz, 2H), 1.41 (s, 9H).

¹³C NMR (100 MHz, MeOH-d₄): δ 159.1, 149.6, 142.8, 131.0,

129.8, 128.7, 127.1, 127.0, 114.2, 80.3, 44.8, 41.0, 28.9.

1

column chromatography (10:1 CH₂Cl₂/MeOH) (0.21 g, 33%). H

NMR (400 MHz, CDCl₃): δ 7.46 (s, 1H), 7.16 (d, J ) 9.02 Hz,

2H), 6.71 (s, 1H), 6.60 (d, J ) 9.04 Hz, 2H), 4.36 (s, 2H), 3.40 (t,

J ) 6.31 Hz, 2H), 3.21 (t, J ) 6.30 Hz, 2H), 1.35 (s, 9H). ¹³C

NMR (100 MHz, CDCl₃): δ 157.0, 147.7, 135.4, 132.2 (2C), 117.1,

115.0, 109.2, 80.0, 51.8, 48.6, 38.8, 28.7.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Bromophenyl)-

(3H-imidazol-4-ylmethyl)amino]ethyl}amide (10b, X ) Br, R²

) 4-Methyl-1H-imidazolesulfonyl, R³) H). Reaction of 9b-H

was carried out according to procedure C after deprotection of Boc

1

group with TFA. Yield 71%. H NMR (400 MHz, MeOH-d₄): δ

8.76 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 7.24 (d, J )

8.86 Hz, 2H), 6.63 (d, J ) 8.91 Hz, 2H), 4.59 (s, 2H), 3.65 (s,

3H), 3.48 (t, J ) 6.36 Hz, 2H), 3.08 (t, J ) 6.17 Hz, 2H). ¹³C

NMR (100 MHz, MeOH-d₄): δ 148.0, 141.6, 141.0, 135.8, 133.4,

133.3, 126.3, 118.5, 117.0, 111.5, 52.9, 44.7, 41.6, 34.7.

{2-[Biphenyl-4-yl-(3-methyl-3H-imidazol-4-ylmethyl)amino]-

ethyl}carbamic Acid tert-Butyl Ester (9a, X ) Ph, R³) Methyl).

1

9a was prepared as described for 9c. Yield 36%. H NMR (400

MHz, MeOH-d₄): δ 7.54-7.51 (m, 3H), 7.46 (d, J ) 8.83 Hz,

2H), 7.35 (t, J ) 7.70, 2H), 7.21 (t, J ) 7.33 Hz, 1H), 6.96 (d, J

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5721

) 8.83, 2H), 6.78 (s, 1H), 4.52 (s, 2H), 3.58 (s, 3H), 3.41 (t, J )

6.75 Hz, 2H), 3.17 (t, J ) 6.75, 2H). ¹³C NMR (100 MHz, MeOH-

d₄): δ 158.7, 149.3, 142.5, 140.1, 131.8, 131.7, 129.9, 128.8, 128.7,

127.3, 127.2, 115.4, 80.3, 50.7, 45.7, 38.9, 32.3, 29.0.

MeOH-d₄): δ 8.79 (s, 1H), 7.73 (s, 1H), 7.69(s, 1H), 7.32 (d, J )

9.07 Hz, 2H), 7.25 (m, 5H), 7.06 (s, 1H), 6.48 (d, J ) 8.90 Hz,

2H), 4.44 (s, 2H), 4.17 (s, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 3.35 (m,

2H), 3.27 (m, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.9,

141.9, 139.3, 138.2, 135.1, 133.1, 130.8, 130.2, 129.7, 127.2, 121.2,

119.5, 114.0, 100.6, 55.6, 51.5, 46.8, 45.3, 34.7, 34.6. HRMS calcd

for C₂₅H₂₈N₇O₂S⁺490.2025, found 490.2028. Retention time for

analytical rpHPLC: condition I, 12.77; condition II, 24.84 min.

N-Benzyl-N-{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-

ylmethyl)amino]ethyl}benzenesulfonamide (12e, X ) CN, R¹)

Benzyl, R²) Phenylsulfonyl, R³) Methyl). Reaction of 11d

N-Biphenyl-4-yl-N′-(2-methylbenzyl)-N-(3-methyl-3H-imid-

azol-4-ylmethyl)ethane-1,2-diamine (11a, X ) Phenyl, R¹

)

o-Methylbenzyl, R³) Methyl). Reaction of 9a was carried out

according to procedure A. Yield 43%. ¹H NMR (400 MHz, MeOH-

d₄): δ 8.87 (s, 1H), 7.57-7.54 (m, 4H), 7.43-7.37 (m, 4H), 7.32-

7.25 (m, 4H), 7.05 (d, J ) 8.8 Hz, 2H), 4.76 (s, 2H), 4.30 (s, 2H),

3.87 (s, 3H), 3.81 (t, J ) 7.3 Hz, 2H), 3.38 (t, J ) 7.3 Hz, 2H),

2.41 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ 147.3, 141.7,

138.8, 137.6, 134.1, 133.2, 132.2, 131.3, 130.8, 129.8, 129.1, 127.8,

127.7 127.3, 119.3, 116.8, 114.4, 49.8, 48.0, 46.2, 45.4, 34.3, 19.2.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[Biphenyl-4-yl-(3-

methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(2-methylbenzyl)-

amide (12c, X ) Phenyl, R¹) o-Methylbenzyl, R²) 1-Methyl-

1H-imidazolesulfonyl, R³) Methyl). Reaction of 11a was carried

1

was carried out according to procedure C. Yield 67%. H NMR

(500 MHz, MeOH-d₄): δ 8.78 (s, 1H), 7.81 (s, 1 H), 7.80 (s, 1 H),

7.60 (t, J ) 7.40 Hz, 1H), 7.54 (m, 2H), 7.33 (d, J ) 9.08 Hz,

2H), 7.22 (m, 5H), 7.03 (s, 1H), 6.50 (d, J ) 9.13 Hz, 2H), 4.40

(s, 2H), 4.18 (s, 2H), 3.72 (s, 3H), 3.33 (m, 2H), 3.15 (m, 2H). ¹³

C

NMR (125 MHz, MeOH-d₄): δ 151.8, 140.0, 138.2, 138.0, 135.1,

134.8, 133.1, 131.0, 130.8, 130.3, 129.8, 128.9, 119.5, 114.1, 101.4,

55.7, 51.5, 46.8, 45.4, 34.6. HRMS calcd for C₂₇H₂₇N₅O₂SH⁺

486.1958, found 486.1963. Retention time for analytical rpHPLC:

condition I, 13.35; condition II, 26.31 min.

1

out according to procedure C. Yield 44%. H NMR (400 MHz,

MeOH-d₄): δ 8.84 (s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.50 (d, J )

7.6 Hz, 2H), 7.39-7.20 (m, 9H), 7.16 (s, 1H), 6.52 (d, J ) 8.8 Hz,

2H), 4.41 (s, 2H), 4.28 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.29-

3.19 (m, 4H), 2.38 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ

147.6, 142.0, 141.5, 139.6, 138.6, 137.5, 135.0, 133.5, 132.2, 132.1,

132.0, 129.8, 129.7, 128.8, 127.4, 127.2, 126.8, 119.4, 114.6, 53.9,

51.4, 45.8, 44.9, 34.4, 34.2, 19.4. HRMS (ESI): m/z calcd for

C₃₁H₃₄N₆O₂SH⁺555.2542, found 555.2533. Retention time for

analytical rpHPLC: condition I, 14.62; condition II, 30.89 min.

[2-(4-Cyanophenylamino)ethyl]carbamic Acid tert-Butyl Ester

(8c, X ) CN). Freshly distilled TEA (8.9 mL, 90 mmol) was added

to a solution of (2-aminoethyl)carbamic acid tert-butyl ester (5.0

g, 30 mmol) and 4-fluorobenzonitrile (3.6 g, 30 mmol) in dry

DMSO (250 mL), and the resulting solution was heated to 120 °C

for 2 days. A distillation head and condenser were fitted to the

reaction vessel, and the volume of solvent was reduced to ∼20

mL under reduced pressure. The resulting solution was dissolved

in EtOAc (300 mL) and washed consecutively with 1.0 M aqueous

HCl (1 × 100 mL), saturated NaHCO₃(2 × 100 mL), and brine

(1 × 100 mL). The organic phase was dried over magnesium

sulfate, and the solvent was removed under vacuum to provide the

title compound as a yellow solid (7.0 g, 89%) after flash column

chromatography (1:1 EtOAc/hexane). ¹H NMR (400 MHz,

CDCl₃): δ 7.43 (d, J ) 8.64 Hz, 2H), 6.58 (d, J ) 8.62 Hz, 2H),

3.41 (br s, 2H), 3.29 (br t, J ) 5.67 Hz, 2H), 1.47 (s, 9H). ¹³C

NMR (100 MHz, CDCl₃): δ 156.3, 147.7, 134.1, 117.2, 112.5,

110.1, 79.6, 46.6, 40.5, 28.7.

Thiophene-2-sulfonic Acid Benzyl-{2-[(4-cyanophenyl)-(3-

methyl-3H-imidazol-4-ylmethyl)amino]ethyl}amide (12f, X )

CN, R¹) Benzyl, R²) 2-Thiophenesulfonyl, R³) Methyl).

Reaction of 11d was carried out according to procedure C. Yield

59%. ¹H NMR (500 MHz, MeOH-d₄): δ 8.79 (s, 1H), 7.79 (dd, J

) 1.17, 5.01 Hz, 1H), 7.61 (dd, J ) 1.19, 3.70 Hz, 1H), 7.34(d, J

) 8.97 Hz, 2H), 7.25 (m, 5H), 7.16 (dd, J ) 3.82, 4.97 Hz, 1H),

7.04 (s, 1H), 6.51 (d, J ) 8.98 Hz, 2H), 4.39 (s, 2H), 4.19 (s, 2H),

3.72 (s, 3H), 3.39 (m, 2H), 3.17 (m, 2H). ¹³C NMR (125 MHz,

MeOH-d₄): δ 151.8, 139.6, 138.2, 137.8, 135.1, 134.4, 134.3, 133.0,

130.8, 130.3, 129.9, 129.5, 121.1, 129.6, 114.1, 100.8, 55.9, 51.5,

47.1, 45.4, 34.6. HRMS calcd for C₂₅H₂₆N₅O₂S₂⁺492.1528, found

492.1515. Retention time for analytical rpHPLC: condition I, 13.91;

condition II, 22.82 min.

Pyridine-2-sulfonicAcidBenzyl-{2-[(4-cyanophenyl)-(3-methyl-

3H-imidazol-4-ylmethyl)amino]ethyl}amide (12g, X ) CN, R¹

) Benzyl, R²) 2-Pyridylsulfonyl, R³) Methyl). Reaction of

11d was carried out according to procedure C. Yield 57%. ¹H NMR

(400 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.66 (d, J ) 5.41 Hz, 1H),

8.00 (td, J ) 1.37, 7.73 Hz, 1H), 7.89 (d, J ) 7.78 Hz, 1H), 7.63

(dd, J ) 4.69, 7.57 Hz, 1H), 7.41 (d, J ) 8.82 Hz, 2H), 7.22 (m,

5H), 7.13 (s, 1H), 6.55 (d, J ) 8.96 Hz, 2H), 4.44 (s, 2H), 4.36 (s,

2H), 3.65 (s, 3H), 3.29 (m, 4H). ¹³C NMR (100 MHz, MeOH-d₄):

δ 157.1, 150.7, 150.3, 139.4, 137.0, 136.8, 133.7, 130.7, 128.9-

(2C), 128.2, 127.9, 122.8, 120.3, 118.0, 112.7, 98.1, 53.3, 49.4,

45.6, 44.0, 33.7. HRMS calcd for C₂₆H₂₇N₆O₂S⁺487.1916, found

487.1903. Retention time for analytical rpHPLC: condition I, 13.47;

condition II, 21.41 min.

Quinoline-8-sulfonic Acid Benzyl-{2-[(4-cyanophenyl)-(3-

methyl-3H-imidazol-4-ylmethyl)amino]ethyl}amide (12h, X )

CN, R¹) Benzyl, R²) 8-Quinolinesulfonyl, R³) Methyl).

Reaction of 11d was carried out according to procedure C. Yield

63%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.92 (dd, J ) 1.72, 4.20

Hz, 1H), 8.79 (s, 1H), 8.41 (dd, J ) 1.32, 7.39 Hz, 1H), 8.37 (dd,

J ) 1.67, 8.40 Hz, 1H), 8.15 (dd, J ) 1.19, 8.21 Hz, 1H), 7.64 (t,

J ) 7.67 Hz, 1H), 7.56 (dd, J ) 4.23, 8.35 Hz, 1H), 7.35 (d, J )

9.04 Hz, 2H), 7.18 (m, 5H), 7.06 (s, 1H), 6.57 (d, J ) 9.07 Hz,

2H), 4.46 (s, 2H), 4.40 (s, 2H), 3.74 (s,3H), 3.64 (m, 2H), 3.53 (m,

2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 152.9, 152.0, 145.5, 138.8,

138.6, 138.2, 135.8, 135.1, 134.8, 133.1, 131.1, 130.5, 130.1, 129.6,

127.2, 124.0, 121.2, 119.5, 114.1, 100.6, 55.5, 31.6, 47.3, 45.4,

34.6. HRMS calcd for C₃₀H₂₉N₆O₂S⁺537.2073, found 537.2073.

Retention time for analytical rpHPLC: condition I, 14.34; condition

II, 24.08 min.

{2-[(4-Cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]-

ethyl}carbamic Acid tert-Butyl Ester (9c, X ) CN, R³

)

Methyl). The title compound was prepared as described for 9b and

purified by flash column chromatography (1:7:292 NH₄OH/MeOH/

CH₂Cl₂, 85% yield based on recovered starting material). ¹H NMR

(500 MHz, MeOH-d₄): δ 8.82 (s, 1H), 7.42 (d, J ) 8.97 Hz, 2H),

7.15 (s, 1H), 6.88 (d, J ) 9.00 Hz, 2H), 4.70 (s, 2H), 3.82 (s, 3H),

3.51 (t, J ) 6.69 Hz, 2H), 3.20 (obscured t, J ) 6.70 Hz, 2H),

1.31 (s, 9H). ¹³C NMR (500 MHz, CDCl₃): δ 156.5, 151.4, 139.4,

134.0, 129.1, 127.2, 120.5, 112.9, 99.4, 80.0, 49.5, 44.9, 38.1, 32.1,

28.7.

4-[(2-Benzylaminoethyl)-(3-methyl-3H-imidazol-4-ylmethyl)-

amino]benzonitrile (11d, X ) CN, R¹) Benzyl, R³) Methyl).

Reaction of 9c was carried out according to procedure A. Yield

1

65%. H NMR (400 MHz, MeOH-d₄): δ 8.88 (s, 1H), 7.55 (d, J

) 8.73 Hz, 2H), 7.45 (s, 5H), 7.19 (s, 1H), 6.95 (d, J ) 8.87 Hz,

2H), 4.82 (s, 2H), 4.20 (s, 2H), 3.87 (s, 3H), 3.34 (br s, 2H), 3.24

(br s, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ. 151.7, 138.2, 134.2,

133.4, 132.5, 131.3, 131.1, 130.8, 122.0, 116.2, 114.6, 102.0, 53.2,

47.9, 46.0, 45.2, 34.7.

5-Dimethylaminonaphthalene-1-sulfonic Acid Benzyl-{2-[(4-

cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

amide (12i, X ) CN, R¹) Benzyl, R²) 5-Dimethylamino-

naphthalenesulfonyl, R³) Methyl). Reaction of 11d was carried

1-Methyl-1H-imidazole-4-sulfonic Acid Benzyl-{2-[(4-cyano-

phenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

amide (12d, X ) CN, R¹) Benzyl, R²) 4-Methyl-1H-

imidazolesulfonyl, R³) Methyl). Reaction of 11d was carried

1

out according to procedure C. Yield 64%. H NMR (400 MHz,

1

out according to procedure C. Yield 66%. H NMR (400 MHz,

MeOH-d₄): δ 8.78 (s, 1H), 8.58 (d, J ) 8.54 Hz, 1H), 8.28 (d, J

5722 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Glenn et al.

) 8.66 Hz, 1H), 8.09 (d, J ) 7.34 Hz, 1H), 7.53 (d, J ) 7.30 Hz,

1H), 7.49 (d, J ) 7.16 Hz, 1H), 7.32 (d, J ) 9.04 Hz, 2H), 7.23

(d, J ) 7.39 Hz, 1H), 7.18 (m, 5H), 6.99 (s, 1H), 6.48 (d, J ) 9.09

Hz, 2H), 4.41 (s, 2H), 4.37 (s, 2H), 3.71(s,3H), 3.32 (m, 4H), 2.82

(s, 6H). ¹³C NMR (100 MHz, MeOH-d₄): δ 153.5, 151.2, 138.2,

138.0, 136.1, 135.1, 133.5, 133.1, 132.2, 131.8, 131.1, 130.6, 130.2,

129.8, 129.7, 124.9, 121.2, 119.4, 117.1, 114.1, 100.9, 54.2, 50.7,

46.2, 45.7, 45.6, 34.6. HRMS calcd for C₃₃H₃₅N₆O₂S⁺579.2542,

found 579.2546. Retention time for analytical rpHPLC: condition

I, 14.67; condition II, 30.30 min.

N-Benzyl-N-{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-

ylmethyl)amino]ethyl}acetamide (12j, X ) CN, R¹) Benzyl,

R²) Acetyl, R³) Methyl). Reaction of 11d was carried out

according to procedure C. Yield 74%. ¹H NMR (400 MHz, MeOH-

d₄): δ 8.08 (s, 1H), 6.71 (d, J ) 9.08 Hz, 2H), 6.59 (br t, J ) 7.15

Hz, 2H), 6.54 (br t, J ) 7.32 Hz, 1H), 6.47 (br t, J ) 7.12 Hz,

2H), 6.40 (br s, 1H), 6.10 (d, J ) 9.11 Hz, 2H), 3.92 (s, 2H), 3.84

(s, 2H), 3.07 (s,3H), 2.77 (m, 2H), 2.52 (s, 2H). ¹³C NMR (100

MHz, MeOH-d₄): δ 172.5, 130.1, 136.2, 136.0, 132.9, 131.2, 128.3,

127.2, 126.4, 119.0, 117.2, 112.1, 98.5, 52.5, 43.2, 42.9, 32.5, 32.4,

19.9. HRMS calcd for C₂₃H₂₆N₅O⁺388.2137, found 388.2131.

Retention time for analytical rpHPLC: condition I, 12.74; condition

II, 18.88 min.

9H). ¹³C NMR (100 MHz, MeOH-d₄): δ 165.6, 151.3, 140.2, 135.0,

132.7, 122.7, 120.6, 114.3, 101.3, 52.7, 52.2, 45.6, 37.4, 34.5, 29.1,

28.8.

4-{(3-Methyl-3H-imidazol-4-ylmethyl)-[2-(2-pyrrol-1-ylethyl-

amino)ethyl]amino}benzonitrile (11p, X ) CN, R¹) Ethyl-

pyrrole, R³)Methyl). Reaction of 9c was carried out according

1

to procedure A. Yield 23%. H NMR (400 MHz, MeOH-d₄): δ

8.81 (s, 1H), 7.46 (d, J ) 8.97 Hz, 2H), 7.07 (s, 1H), 6.85 (d, J )

9.13 Hz, 2H), 6.68 (t, J ) 2.06 Hz, 2H), 6.02 (t, J ) 2.03 Hz, 2H),

4.69 (s, 2H), 4.21 (t, J ) 6.20 Hz, 2H), 3.79 (s, 3H), 3.71 (t, J )

7.52 Hz, 2H), 3.38 (t, J ) 6.22 Hz, 2H), 3.03 (t, J ) 7.50 Hz, 2H).

¹³C NMR (100 MHz, MeOH-d₄): δ 151.6, 138.4, 135.4, 133.0,

122.2, 120.9, 119.3, 114.7, 110.8, 101.9, 50.1, 47.9, 46.9, 46.0,

45.7, 34.6.

4-[[2-(Cyclohexylmethylamino)ethyl]-(3-methyl-3H-imidazol-

4-ylmethyl)amino]benzonitrile (11q, X ) CN, R¹) Cylohexyl-

methyl, R³) Methyl). Reaction of 9c was carried out according

1

to procedure A. Yield 59%. H NMR (400 MHz, MeOH-d₄): δ

8.84 (s, 1H), 7.48 (d, J ) 9.09 Hz, 2H), 7.14 (s, 1H), 6.91 (d, J )

9.13 Hz, 2H), 4.76 (s, 2H), 3.82 (s, 3H), 3.78 (t, J ) 7.45 Hz, 2H),

3.19 (obscured), 2.84 (d, J ) 6.96 Hz, 2H), 1.68 (m, 6H), 1.22 (m,

3H), 0.94 (m, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.7,

138.4, 135.4, 133.1, 121.0, 119.2, 114.6, 101.8, 55.8, 47.7, 46.0,

37.0, 34.6, 31.8, 27.4, 26.9.

N-Benzyl-N-{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-

ylmethyl)amino]ethyl}isobutyramide (12k, X ) CN, R¹

)

4-((3-Methyl-3H-imidazol-4-ylmethyl)-{2-[(tetrahydropyran-

4-ylmethyl)amino]ethyl}amino)benzonitrile (11r, X ) CN, R¹

) Tetrahydropyran-4-ylmethyl, R³) Methyl). Molecular sieves

were added to a solution of tetrahydropyran-4-carbaldehyde (25

mg, 0.22 mmol), 4-[(2-aminoethyl)-(3-methyl-3H-imidazol-4-yl-

methyl)amino]benzonitrile ditrifluoroacetic acid salt (0.11 g, 0.22

mmol), and acetic acid (13 µL, 0.23 mmol) in dry MeOH (2.0 mL),

and the reaction mixture was stirred at room temperature for 1 h.

NaCNBH₃(20 mg, 0.33 mmol) was then added in one portion,

and stirring continued for a further hour. Brine was added, and the

reaction was extracted into EtOAc. The organic layer was purified

by flash column chromatography (1:5:50 Et₃N/MeOH/CH₂Cl₂) to

Benzyl, R²) Isopropylcarbonyl, R³) Methyl). Reaction of 11d

1

was carried out according to procedure C. Yield 71%. H NMR

(400 MHz, MeOH-d₄): δ 8.09 (s, 1H), 6.70 (d, J ) 9.05 Hz, 2H),

6.61 (br t, J ) 7.21 Hz, 2H), 6.54 (br t, J ) 7.36 Hz, 1H), 6.45 (br

t, J ) 7.23 Hz, 2H), 6.39 (br s, 1H), 6.15 (d, J ) 9.05 Hz, 2H),

3.93 (s, 2H), 3.91 (s, 2H), 3.08 (s, 3H), 2.79 (m, 2H), 2.52 (s, 2H),

2.12 (m, 1H), 0.26 (d, J ) 6.60 Hz, 6H). ¹³C NMR (100 MHz,

MeOH-d₄): δ 178.4, 149.7, 136.1, 135.5, 132.5, 130.7, 127.7, 226.6,

125.6, 118.5, 111.5, 97.9, 30.9, 46.1, 42.8, 42.7, 32.0, 29.3, 17.6.

HRMS calcd for C₂₅H₃₀N₅O⁺416.2450, found 416.2436. Retention

time for analytical rpHPLC: condition I, 13.24; condition II, 20.24

min.

1

provide the title compound in 90% yield. H NMR (400 MHz,

4-[(2-Allylaminoethyl)-(3-methyl-3H-imidazol-4-ylmethyl)-

amino]benzonitrile (11l, X ) CN, R¹) Allyl, R³) Methyl).

Reaction of 9c was carried out according to procedure A. Yield

MeOH-d₄): δ 7.63 (s, 1H), 7.50 (d, J ) 9.05 Hz, 2H), 6.97 (d, J

) 9.05 Hz, 2H), 6.70 (s, 1H), 4.70 (s, 2H), 3.93 (dd, J ) 10.66,

3.98 Hz, 2H), 3.70-3.64 (m, 5H), 3.40 (dt, J ) 11.82, 1.64 Hz,

2H), 2.91 (t, J ) 7.47 Hz, 2H), 2.63 (d, J ) 6.89 Hz, 2H), 1.82 (m,

1H), 1.67 (dd, J ) 13.11, 1.89 Hz, 2H), 1.36 (t, J ) 7.28 Hz, 2H).

¹³C NMR (100 MHz, MeOH-d₄): δ 152.5, 140.3, 134.8, 129.6, 128.1,

121.3, 114.1, 99.6, 56.3, 53.8, 47.9, 46.9, 45.9, 35.6, 32.3, 32.2.

4-[[2-(2-Methylbenzylamino)ethyl]-(3-methyl-3H-imidazol-4-

ylmethyl)amino]benzonitrile (11x, X ) CN, R¹) o-Methylben-

zyl, R³) Methyl). Reaction of 9c was carried out according to

procedure A. Yield 62%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.91

(s, 1H), 7.56 (d, J ) 8.67 Hz, 2H), 7.45 (d, J ) 7.43 Hz, 2H),

7.34-7.26 (m, 3H), 7.20 (s, 1H), 7.00 (d, J ) 8.67 Hz, 2H), 4.86

(s, 2H), 4.32 (s, 2H), 3.93-3.89 (m, 5H), 3.43 (t, J ) 7.53 Hz,

2H), 2.44 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.3, 138.8,

138.0, 135.0, 132.7, 132.2, 131.3, 130.9, 130.8, 127.8, 120.6, 118.8,

114.3, 101.4, 50.0, 47.4, 45.6, 45.2, 34.2, 19.2.

1

65%. H NMR (400 MHz, MeOH-d₄): δ 8.92 (s, 1H), 7.56 (d, J

) 8.95 Hz, 2H), 7.22 (s, 1H), 7.00 (d, J ) 8.95 Hz, 2H), 5.97 (m,

1H), 5.53 (m, 1H), 5.36 (m, 1H), 4.81 (s, 2H), 3.91 (s, 3H), 3.84

(t, J ) 7.25 Hz, 2H), 3.72 (d, J ) 6.80 Hz, 2H), 3.31 (t, J ) 7.25 Hz,

2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.4, 137.9, 134.9, 129.1,

124.4, 118.8, 114.3, 101.4, 52.8, 51.2, 47.5, 45.7, 44.5, 37.4, 34.2.

4-[[2-(2-Methylallylamino)ethyl]-(3-methyl-3H-imidazol-4-yl-

methyl)amino]benzonitrile (11m, X ) CN, R¹) 2-Methylallyl,

R³) Methyl). Reaction of 9c was carried out according to

procedure A. Yield 60%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.93

(s, 1H), 7.56 (d, J ) 9.0 Hz, 2H), 7.22 (s, 1H), 7.00 (d, J ) 9.0

Hz, 2H), 5.20 (s, 1H), 5.1 (s, 1H), 4.86 (s, 2H), 3.92-3.89 (m,

5H), 3.68 (s, 2H), 3.31 (m, 2H), 1.88 (s, 3H). ¹³C NMR (100 MHz,

MeOH-d₄): δ 151.2, 137.9, 137.8, 134.9, 132.7, 120.6, 118.8, 118.1,

114.2, 101.3, 54.1, 47.3, 45.6, 44.8, 34.2, 20.7.

4-[[2-(3-Methylbenzylamino)ethyl]-(3-methyl-3H-imidazol-4-

ylmethyl)amino]benzonitrile (11y, X ) CN, R¹) m-Methyl-

benzyl, R³) Methyl). Reaction of 9c was carried out according

4-[[2-(2-Bromoallylamino)ethyl]-(3-methyl-3H-imidazol-4-yl-

methyl)amino]benzonitrile (11n, X ) CN, R¹) 2-Bromoallyl,

R³) Methyl). Reaction of 9c was carried out according to

procedure A. Yield 60%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.92

(s, 1H), 7.57 (d, J ) 9.0 Hz, 2H), 7.22 (s, 1H), 7.00 (d, J ) 9.0

Hz, 2H), 4.86 (s, 2H), 4.03 (d, J ) 2.5 Hz, 2H), 3.92-3.89 (m,

5H), 3.42 (t, J ) 7.2 Hz, 2H), 3.25 (t, J ) 2.5 Hz, 1H). ¹³C NMR

(100 MHz, MeOH-d₄): δ 151.2, 137.9, 135.0, 132.6, 126.5, 120.6,

118.8, 114.3, 114.2, 101.5, 47.3, 45.6, 44.4, 37.7, 34.2.

1

to procedure A. Yield 46%. H NMR (400 MHz, MeOH-d₄): δ

8.91 (s, 1H), 7.55 (d, J ) 8.99 Hz, 2H), 7.35-7.26 (m, 4H), 7.20

(s, 1H), 6.97 (d, J ) 8.99 Hz, 2H), 4.85 (s, 2H), 4.23 (s, 2H),

3.89-3.86 (m, 5H), 3.35 (t, J ) 7.40 Hz, 2H), 2.37 (s, 3H). ¹³C

NMR (100 MHz, MeOH-d₄): δ 151.2, 140.4, 138.0, 134.9, 132.7,

132.3, 131.6, 131.4, 130.2, 128.0, 120.6, 118.8, 114.3, 101.4, 52.7,

47.5, 45.6, 44.8, 34.2, 21.3.

N-tert-Butyl-2-{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-

4-[[2-(4-Methylbenzylamino)ethyl]-(3-methyl-3H-imidazol-4-

ylmethyl)amino]benzonitrile (11z, X ) CN, R¹) p-Methylben-

zyl, R³) Methyl). Reaction of 9c was carried out according to

procedure A. Yield 29%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.91

(s, 1H), 7.55 (d, J ) 8.85 Hz, 2H), 7.38 (d, J ) 7.84 Hz, 2H), 7.26

(d, J ) 7.84 Hz, 2H), 7.20 (s, 1H), 6.96 (d, J ) 8.85 Hz, 2H), 4.84

(s, 2H), 4.22 (s, 2H), 3.89-3.85 (m, 5H), 3.33 (t, J ) 7.22 Hz,

ylmethyl)amino]ethylamino}acetamide (11o, X ) CN, R¹

)

N-tert-Butylacetamido, R³) Methyl). Reaction of 9c was carried

1

out according to procedure A. Yield 52%. H NMR (400 MHz,

MeOH-d₄): δ 8.98 (s, 1H), 7.56 (d, J ) 9.01 Hz, 2H), 7.28 (s,

1H), 7.01 (d, J ) 9.01 Hz, 2H), 4.86 (s, 2H), 4.83 (s, 2H), 3.91 (s,

3H), 3.83 (t, J ) 7.13 Hz, 2H), 3.23 (t, J ) 7.13 Hz, 2H), 1.32 (s,

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5723

2H), 2.36 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.2, 141.1,

138.0, 134.9, 132.6, 131.0, 130.9, 129.3, 120.6, 118.8, 114.2, 101.4,

52.5, 47.5, 45.6, 44.6, 34.2, 21.2.

7.3 Hz, 2H), 7.40 (t, J ) 7.36 Hz, 1H), 7.22 (s, 1H), 6.99 (d, J )

9.06 Hz, 2H), 4.87 (s, 2H), 4.34 (s, 2H), 3.91 (m, 5H), 3.40 (t, J )

7.21 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.6, 144.3,

141.7, 138.4, 135.4, 133.0, 132.0, 131.7, 130.4, 129.4, 129.2, 128.4,

121.0, 119.3, 114.7, 101.9, 52.8, 47.9, 46.0, 45.2, 34.6.

4-((3-Methyl-3H-imidazol-4-ylmethyl)-{2-[(pyridin-2-ylmethyl)-

amino]ethyl}amino)benzonitrile (11aa, X ) CN, R¹) 2-Pyridyl,

R³) Methyl). Reaction of 9c was carried out according to

procedure A. Yield 57%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.95

(s, 1H), 8.64 (d, J ) 4.73 Hz, 1H), 7.89 (dt, J ) 7.74, 1.68 Hz,

1H), 7.59 (d, J ) 8.99 Hz, 2H), 7.45 (d, J ) 7.83 Hz, 1H), 7.44

(dd, J ) 7.36, 5.07 Hz, 1H), 7.26 (s, 1H), 7.03 (d, J ) 9.04 Hz,

2H), 4.90 (s, 2H), 4.48 (s, 2H), 3.98 (t, J ) 7.20 Hz, 2H), 3.93 (s,

3H), 3.45 (t, J ) 7.18 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄):

δ 152.7, 151.7, 150.9, 139.4, 138.4, 135.4, 133.1, 125.5, 124.6,

121.0, 119.2, 114.8, 101.9, 52.4, 48.8, 47.9, 46.1, 34.7.

4-((3-Methyl-3H-imidazol-4-ylmethyl)-{2-[(pyridin-3-ylmethyl)-

amino]ethyl}amino)benzonitrile (11ab, X ) CN, R¹) 3-Pyridyl,

R³) Methyl). Reaction of 9c was carried out according to

procedure A. Yield 64%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.92

(br s, 2H), 8.82 (d, J ) 5.36 Hz, 1H), 8.47 (d, J ) 6.41 Hz, 1H),

7.90 (dd, J ) 7.92, 5.45 Hz, 1H), 7.57 (d, J ) 9.00 Hz, 2H), 7.23

(s, 1H), 7.02 (d, J ) 9.02 Hz, 2H), 4.89 (s, 2H), 4.48 (s, 2H), 3.95

(t, J ) 7.17 Hz, 2H), 3.92 (s, 3H), 3.49 (t, J ) 7.12 Hz, 2H). ¹³C

NMR (100 MHz, MeOH-d₄): δ 151.7, 148.3, 147.7, 145.6, 138.3,

135.4, 133.1, 132.0, 127.7, 121.0, 119.1, 114.7, 101.8, 49.7, 47.9,

46.0, 45.9, 34.6.

4-((3-Methyl-3H-imidazol-4-ylmethyl)-{2-[(pyridin-4-ylmethyl)-

amino]ethyl}amino)benzonitrile (11ac, X ) CN, R¹) 4-Pyridyl,

R³) Methyl). Reaction of 9c was carried out according to

procedure A. Yield 60%. ¹H NMR (400 MHz, MeOH-d₄): δ 8.94

(s, 1H), 8.83 (d, J ) 6.14 Hz, 2H), 7.96 (d, J ) 6.33 Hz, 2H), 7.58

(d, J ) 8.93 Hz, 2H), 7.24 (s, 1H), 7.03 (d, J ) 9.00 Hz, 2H), 4.88

(s, 2H), 4.54 (s, 2H), 3.97 (t, J ) 7.13 Hz, 2H), 3.92 (s, 3H), 3.50

(t, J ) 7.39 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.6,

148.9, 147.4, 138.4, 135.4, 133.1, 128.0, 121.0, 119.2, 114.7, 101.8,

51.4, 47.9, 46.2, 46.0, 34.6.

4-{(3-Methyl-3H-imidazol-4-ylmethyl)-[2-(3-pyrrol-1-ylbenzyl-

amino)ethyl]amino}benzonitrile (11ah, X ) CN, R¹) 3-Pyrrole-

benzyl, R³) Methyl). Reaction of 9c was carried out according

1

to procedure A. Yield 62%. H NMR (400 MHz, MeOH-d₄): δ

8.82 (s, 1H), 7.59 (s, 1H), 7.46 (m, 4H), 7.28 (d, J ) 7.43 Hz,

1H), 7.15 (t, J ) 2.26 Hz, 2H), 7.12 (s, 1H), 6.89 (d, J ) 9.07 Hz,

2H), 6.23 (t, J ) 2.23 Hz, 2H), 4.76 (s, 2H), 4.25 (s, 2H), 3.81

(obscured), 3.80 (s, 3H), 3.31 (t, J ) 7.56 Hz, 2H). ¹³C NMR (100

MHz, MeOH-d₄): δ 151.6, 143.1, 138.4, 135.4, 134.5, 133.1, 132.1,

128.1, 122.5, 122.2, 120.9, 120.3, 119.2, 114.7, 112.4, 101.9, 52.8,

47.9, 46.1, 45.3, 34.6.

4-{(3-Methyl-3H-imidazol-4-ylmethyl)-[2-(4-pyrrol-1-ylbenzyl-

amino)ethyl]amino}benzonitrile (11ai, X ) CN, R¹) 4-Pyrrole-

benzyl, R³) Methyl). Reaction of 9c was carried out according

1

to procedure A. Yield 58%. H NMR (400 MHz, MeOH-d₄): δ

8.81 (s, 1H), 7.48 (m, 5H), 7.45 (s, 1H), 7.14 (t, J ) 2.16 Hz, 2H),

6.88 (d, J ) 9.10 Hz, 2H), 6.21 (t, J ) 2.17 Hz, 2H), 4.75 (s, 2H),

4.20 (s, 2H), 3.80 (m, 5H), 3.28 (t, J ) 7.20 Hz, 2H). ¹³C NMR

(100 MHz, MeOH-d₄): δ 151.6, 138.4, 135.4, 133.1, 129.4, 121.5,

121.0, 120.3, 119.2, 114.7, 112.5, 111.4, 101.8, 52.5, 47.9, 46.0,

45.2, 34.6.

1-Methyl-1H-imidazole-4-sulfonic Acid Allyl-{2-[(4-cyano-

phenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

amide (12l, X ) CN, R¹) Allyl, R²) 4-Methyl-1H-imidazole-

sulfonyl, R³) Methyl). Reaction of 11l was carried out according

1

to procedure C. Yield 68%. H NMR (400 MHz, MeOH-d₄): δ

8.81 (s, 1H), 7.67 (s, 1H), 7.63(s, 1H), 7.45 (d, J ) 9.15 Hz, 2H),

7.21 (s, 1H), 6.86 (d, J ) 9.18 Hz, 2H), 5.60 (m, 1H), 5.05 (m,

2H), 4.73 (s, 2H), 3.80 (s, 3H), 3.68 (m, 5H), 3.57 (m, 2H), 3.28

(m, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 152.2, 141.9, 139.7,

138.2, 135.2, 133.2, 133.3, 127.0, 122.4, 121.2, 119.7, 114.4, 100.8,

54.0, 31.4, 46.0, 41.8, 34.7, 34.6. HRMS calcd for C₂₁H₂₆N₇O₂S⁺

440.1869, found 440.1855. Retention time for analytical rpHPLC:

condition I, 12.31; condition II, 17.86 min.

4-[[2-(3-Cyanobenzylamino)ethyl]-(3-methyl-3H-imidazol-4-

ylmethyl)amino]benzonitrile (11ad, X ) CN, R¹) m-Cyano-

benzyl, R³) Methyl). Reaction of 9c was carried out according

1

to procedure A. Yield 49%. H NMR (400 MHz, MeOH-d₄): δ

8.91 (s, 1H), 7.90 (s, 1H), 7.85-7.81 (m, 2H), 7.64 (t, J ) 7.80

Hz, 1H), 7.56 (d, J ) 8.77 Hz, 2H), 7.21 (s, 1H), 6.99 (d, J ) 8.77

Hz, 2H), 4.86 (s, 2H), 4.35 (s, 2H), 3.93-3.90 (m, 5H), 3.41 (t, J

) 7.27 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.6, 138.4,

136.3, 135.4, 135.2, 134.8, 134.6, 133.1, 131.8, 121.0, 119.4, 119.2,

114.7, 114.6, 114.3, 101.8, 52.1, 47.9, 46.1, 45.6, 34.6.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(2-methylallyl)-

amide (12m, X ) CN, R¹) 2-Methylallyl, R²) 1-Methyl-1H-

imidazolesulfonyl, R³) Methyl). Reaction of 11m was carried

1

out according to procedure C. Yield 71%. H NMR (400 MHz,

MeOH-d₄): δ 8.91 (s, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.53 (d, J )

9.03 Hz, 2H), 7.29 (s, 1H), 6.95 (d, J ) 9.03 Hz, 2H), 4.79 (s,

2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.73-3.69 (m, 4H), 3.36 (t, J )

3.95 Hz, 2H), 1.69 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ

151.7, 142.6, 141.4, 139.2, 137.9, 134.8, 132.8, 126.6, 120.8, 119.3,

114.0, 100.4, 57.3, 50.8, 46.0, 45.2, 34.3, 34.3, 34.2, 20.0. HRMS

(ESI): m/z calcd for C₂₂H₂₇N₇O₂SH⁺454.2025, found 454.2013.

Retention time for analytical rpHPLC: condition I, 14.29; condition

II, 18.51 min.

4-[[2-(4-Cyanobenzylamino)ethyl]-(3-methyl-3H-imidazol-4-

ylmethyl)amino]benzonitrile (11ae, X ) CN, R¹) p-Cyano-

benzyl, R³) Methyl). Reaction of 9c was carried out according

1

to procedure A. Yield 35%. H NMR (400 MHz, MeOH-d₄): δ

8.91 (s, 1H), 7.82 (d, J ) 8.19 Hz, 2H), 7.70 (d, J ) 8.19 Hz, 2H),

7.56 (d, J ) 8.88 Hz, 2H), 7.21 (s, 2H), 6.99 (d, J ) 8.88 Hz, 2H),

4.86 (s, 2H), 4.37 (s, 2H), 3.92-3.90 (m, 5H), 3.41 (t, J ) 7.33

Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.2, 138.0, 137.7,

135.0, 134.0, 132.6, 132.0, 120.6, 119.0, 118.8, 114.6, 114.2, 101.4,

52.0, 47.4, 45.6, 45.3, 34.2.

1-Methyl-1H-imidazole-4-sulfonic Acid (2-Bromoallyl)-{2-[(4-

cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

amide (12n, X ) CN, R¹) 2-Bromoallyl, R²) 1-Methyl-1H-

imidazolesulfonyl, R³) Methyl). Reaction of 11n was carried

4-[{2-[(Biphenyl-3-ylmethyl)amino]ethyl}-(3-methyl-3H-imid-

azol-4-ylmethyl)amino]benzonitrile (11af, X ) CN, R¹) 3-Phen-

ylbenzyl, R³) Methyl). Reaction of 9c was carried out according

1

out according to procedure C. Yield 67%. H NMR (400 MHz,

1

to procedure A. Yield 58%. H NMR (400 MHz, MeOH-d₄): δ

MeOH-d₄): δ 8.90 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.55 (d, J )

9.03 Hz, 2H), 7.32 (s, 1H), 7.00 (d, J ) 9.03 Hz, 2H), 4.85 (s,

2H), 4.07 (d, J ) 2.42 Hz, 2H), 3.91 (s, 3H), 3.82 (t, J ) 6.75 Hz,

2H), 3.77 (s, 3H), 3.55 (t, J ) 6.75 Hz, 2H), 2.64 (t, J ) 2.42 Hz,

1H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.9, 141.3, 138.6, 137.8,

134.8, 133.0, 127.1, 120.8, 119.3, 114.1, 100.4, 78.2, 75.3, 50.5,

46.0, 45.6, 39.3, 34.3, 34.3 HRMS (ESI): m/z calcd for C₂₁H₂₄-

BrN₇O₂SH⁺518.0974, found 518.0980. Retention time for analyt-

ical rpHPLC: condition I, 10.70; condition II, 16.36 min.

N-tert-Butyl-2-[{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-

4-ylmethyl)amino]ethyl}-(1-methyl-1H-imidazole-4-sulfonyl)-

amino]acetamide (12o, X ) CN, R¹) N-tert-Butylacetamido,

R²) 1-Methyl-1H-imidazolesulfonyl, R³)Methyl). Reaction of

8.82 (s, 1H), 7.72 (s, 1H), 7.63 (d, J ) 7.60 Hz, 1H), 7.56 (d, J )

7.19 Hz, 2H), 7.45 (m, 6H), 7.29 (t, J ) 7.24 Hz, 1H), 7.11 (s,

1H), 6.89 (d, J ) 9.04 Hz, 2H), 4.76 (s, 2H), 4.23 (s, 2H), 3.82 (t,

J ) 7.33 Hz, 2H), 3.80 (s, 3H), 3.32 (t, J ) 7.23 Hz, 2H). ¹³C

NMR (100 MHz, MeOH-d₄): δ 151.6, 143.9, 141.8, 138.4, 135.4,

133.5, 133.1, 131.3, 130.4, 130.3, 130.1, 129.6, 129.3, 128.4, 121.0,

119.2, 114.7, 101.7, 53.1, 47.9, 46.0, 45.2, 34.6.

4-[{2-[(Biphenyl-4-ylmethyl)amino]ethyl}-(3-methyl-3H-imid-

azol-4-ylmethyl)amino]benzonitrile (11ag, X ) CN, R¹) 4-Phen-

ylbenzyl, R³) Methyl). Reaction of 9c was carried out according

1

to procedure A. Yield 64%. H NMR (400 MHz, MeOH-d₄): δ

8.91 (s, 1H), 7.73 (d, J ) 8.26 Hz, 2H), 7.59 (m, 6H), 7.47 (t, J )

5724 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Glenn et al.

11o was carried out according to procedure C. Yield 83%. ¹H NMR

(400 MHz, MeOH-d₄): δ 8.94 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H),

7.52 (d, J ) 8.95 Hz, 2H), 7.29 (s, 1H), 6.92 (d, J ) 8.95 Hz, 2H),

4.82 (s, 4H), 3.91 (s, 3H), 3.74 (s, 3H), 3.65 (t, J ) 6.23 Hz, 2H),

3.21 (t, J ) 6.23 Hz, 2H), 1.32 (s, 9H). ¹³C NMR (100 MHz,

MeOH-d₄): δ 165.6, 151.7, 141.1, 140.5, 140.0, 134.8, 133.0, 125.8,

123.1, 120.8, 113.9, 100.3, 52.7, 52.2, 51.5, 46.0, 41.3, 34.5, 34.3,

28.7. HRMS calcd for C₂₄H₃₂N₈O₃SH⁺513.2396, found 513.2392.

Retention time for analytical rpHPLC: condition I, 12.14; condition

II, 17.82 min.

126.9, 120.8, 118.9, 114.0, 100.3, 56.5, 51.2, 51.1, 48.2, 45.3, 44.7,

34.4, 34.3, 27.6. HRMS (ESI): m/z calcd for C₂₄H₃₂N₈O₂SH⁺

497.2447, found 497.2444. Retention time for analytical rpHPLC:

condition I, 11.33; condition II, 18.l2 min.

1-Methyl-1H-imidazole-4-sulfonic Acid (1-Acetylpiperidin-4-

ylmethyl)-{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)-

amino]ethyl}amide (12t, X ) CN, R¹) 1-Acetylpiperidin-4-

ylmethyl, R²) 1-Methyl-1H-imidazolesulfonyl, R³) Methyl).

To a solution of 1-methyl-1H-imidazole-4-sulfonic acid {2-[(4-

cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

piperidin-4-ylmethylamide CF₃CO₂H salt (12s) (37 mg, 0.061

mmol) and TEA (51 µL, 0.37 mmol) in DMF (0.30 mL) at 0 °C

was added acetic anhydride (7.0 µL, 0.070 mmol). The mixture

was stirred at 0 °C for 10 min, then diluted with acetonitrile and

purified directly by rpHPLC to provide the title compound. Yield

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(2-pyrrol-1-yl-

ethyl)amide (12p, X ) CN, R¹) 2-Pyrrol-1-ylethylsulfonyl, R²

) 4-methyl-1H-imidazole, R³) Methyl). Reaction of 11p was

1

carried out according to procedure C. Yield 71%. H NMR (400

1

MHz, MeOH-d₄): δ 8.79 (s, 1H), 7.69 (s, 1 H), 7.67 (s, 1 H), 7.42

(d, J ) 9.09 Hz, 2H), 7.01 (s, 1H), 6.78 (d, J ) 9.11 Hz, 2H), 6.59

(d, J ) 1.95, 3.57 Hz, 2H), 5.89 (d, J ) 2.12 Hz, 2H), 4.90 (s,

2H), 4.02 (t, J ) 5.37 Hz, 2H), 3.78 (s, 3H), 3.69 (s, 3H), 3.45 (t,

J ) 5.63 Hz, 2H), 3.12 (m, 2H), 3.02 (m, 2H). ¹³C NMR (100

MHz, MeOH-d₄): δ 150.9, 140.9, 138.3, 137.1, 134.1, 132.2, 126.1,

121.4, 120.1, 118.5, 113.1, 108.6, 99.6, 52.6, 50.3, 50.2, 49.9, 44.6,

33.6, 33.5. HRMS calcd for C₂₄H₂₉N₈O₂S⁺493.2129, found

493.2122. Retention time for analytical rpHPLC: condition I, 11.26;

condition II, 14.39 min.

85%. H NMR (400 MHz, MeOH-d₄): δ 8.91 (s, 1H), 7.77 (S,

1H), 7.75 (s, 1H), 7.56 (d, J ) 9.06 Hz, 2H), 7.27 (s, 1H), 7.01 (d,

J ) 9.06 Hz, 2H), 4.87 (s, 2H), 4.41 (d, J ) 13.27 Hz, 1H), 3.91

(s, 3H), 3.88-3.81 (m, 3H), 3.78 (s, 3H), 3.42 (t, J ) 7.18 Hz,

2H), 3.02-2.94 (m, 3H), 2.51 (dt, J ) 2.26, 12.64 Hz, 1H), 2.07

(s, 3H), 1.79-1.67 (m, 3H), 1.06 (m, 2H). ¹³C NMR (100 MHz,

MeOH-d₄): δ 171.4, 151.8, 141.4, 138.9, 137.9, 134.9, 133.0, 126.8,

120.8, 119.1, 114.0, 100.4, 57.1, 51.2, 45.4, 42.5, 36.5, 34.3, 34.3,

31.3, 30.6, 21.2. HRMS (ESI): m/z calcd for C₂₆H₃₄N₈O₃SH⁺

539.2553, found 539.2544. Retention time for analytical rpHPLC:

condition I, 12.42; condition II, 21.08 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}cyclohexylmeth-

ylamide (12q, X ) CN, R¹) Cylohexylmethyl, R²) 4-Methyl-

1H-imidazolesulfonyl, R³) Methyl). Reaction of 11q was carried

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(1-isobutyryl-

piperidin-4-ylmethyl)amide (12u, X ) CN, R¹) 1-Isobutyryl-

piperidin-4-ylmethyl, R²) 1-Methyl-1H-imidazolesulfonyl, R³

) Methyl). Acylation with isobutyric anhydride following the same

procedure as described above provided the title compound in 73%

1

out according to procedure C. Yield 75%. H NMR (400 MHz,

MeOH-d₄): δ 8.82 (s, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.47 (d, J )

9.04 Hz, 2H), 7.21 (s, 1H), 6.91 (d, J ) 9.14 Hz, 2H), 4.78 (s,

2H), 3.82 (s, 3H), 3.69 (m, 5H), 3.30 (m, 2H), 2.82 (d, J ) 7.32

Hz, 2H), 1.57 (m, 5H), 1.34(m, 1H), 1.05(m, 3H), 0.76 (m, 2H).

¹³C NMR (100 MHz, MeOH-d₄): δ 152.2, 141.7, 139.5, 138.3,

135.3, 133.4, 127.0, 121.2, 119-61 114.3, 100.8, 58.6, 51.61 48.4,

45.8, 38.4, 34.7, 32.3, 27.9, 27.3. HRMS calcd for C₂₅H₃₄N₇O₂S⁺

496.2495, found 496.2497. Retention time for analytical rpHPLC:

condition I, 14.92; condition II, 27.55 min.

1

yield. H NMR (400 MHz, MeOH-d₄): δ 8.91 (s, 1H), 7.76 (s,

1H), 7.75 (s, 1H), 7.57 (d, J ) 8.99 Hz, 2H), 7.29 (s, 1H), 7.01 (d,

J ) 8.99 Hz, 2H), 4.86 (s, 2H), 4.45 (d, J ) 12.09 Hz, 1H), 4.00

(d, J ) 13.70 Hz, 1H), 3.91 (s, 3H), 3.83-3.78 (m, 5H), 3.44 (m,

2H), 3.01-2.89 (m, 4H), 2.50 (t, J ) 11.62 Hz, 1H), 1.78-1.68

(m, 3H), 1.14-0.95 (m, 8H). ¹³C NMR (100 MHz, MeOH-d₄): δ

177.7, 151.8, 141.4, 138.8, 137.9, 134.9, 132.9, 126.8, 120.8, 119.1,

114.0, 100.4, 57.1, 51.2, 46.5, 45.4, 42.8, 36.7, 34.3, 31.8, 31.1,

30.7, 19.9, 19.7. HRMS (ESI): m/z calcd for C₂₈H₃₈N₈O₃SH⁺

567.2866, found 567.2840. Retention time for analytical rpHPLC:

condition I, 12.76; condition II, 22.13 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}(tetrahydropyran-

4-ylmethyl)amide (12r, X ) CN, R¹) Tetrahydropyran-4-

ylmethyl, R²) 1-Methyl-1H-imidazolesulfonyl, R³) Methyl).

Reaction of 11r was carried out according to procedure C. Yield

4-{[{2-[(4-Cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)-

amino]ethyl}(1-methyl-1H-imidazole-4-sulfonyl)amino]methyl}-

piperidine-1-carboxylic Acid tert-Butyl Ester (12v, X ) CN, R¹

) Methylpiperidine-1-carboxylic Acid tert-Butyl Ester, R²)

1-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 10c

1

67%. H NMR (400 MHz, MeOH-d₄): δ 8.91 (s, 1H), 7.77 (s,

1H), 7.76 (s, 1H), 7.56 (d, J ) 8.95 Hz, 2H), 7.27 (s, 1H), 7.01 (d,

J ) 8.95 Hz, 2H), 4.87 (s, 2H), 3.91 (s, 3H), 3.89-3.80 (m, 4H),

3.78 (s, 3H), 3.41 (t, J ) 7.11 Hz, 2H), 3.26 (t, J ) 10.99 Hz, 2H),

2.99 (d, J ) 7.30 Hz, 2H), 1.73 (m, 1H), 1.58 (d, J ) 13.02 Hz,

2H), 1.19 (m, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.7,

141.4, 138.9, 137.9, 134.9, 132.9, 126.8, 120.8, 119.1, 114.0, 100.4,

68.5, 57.5, 51.1, 48.1, 45.4, 35.5, 34.3, 34.2, 31.7. HRMS (ESI):

m/z calcd for C₂₄H₃₁N₇O₃SH⁺498.2287. found 498.2287. Retention

time for analytical rpHPLC: condition I, 10.97; condition II, 19.75

min.

1

was carried out according to procedure B. Yield 47%. H NMR

(400 MHz, MeOH-d₄): δ 8.90 (s, 1H), 7.76 (s, 1H), 7.75 (s, 1H),

7.58 (d, J ) 9.07 Hz, 2H), 7.29 (s, 1H), 7.01 (d, J ) 9.07 Hz, 2H),

4.87 (s, 2H), 3.99 (d, J ) 13.22 Hz, 2H), 3.82-3.78 (m, 5H), 3.42

(t, J ) 6.99 Hz, 2H), 2.97 (d, J ) 6.85 Hz, 2H), 2.61 (br s, 2H),

1.65-1.62 (m, 3H), 1.44 (s, 9H), 1.01 (m, 2H). ¹³C NMR (100

MHz, MeOH-d₄): δ 156.5, 151.8, 141.4, 138.9, 137.8, 134.9, 133.0,

126.8, 120.8, 119.1, 114.0, 100.4, 81.0, 57.3, 51.2 48.2, 45.4, 36.5,

34.3, 34.2, 30.8, 28.7. HRMS (ESI): m/z calcd for C₂₉H₄₀N₈O₄SH⁺

597.2971, found 597.2974. Retention time for analytical rpHPLC:

condition I, 13.25; condition II, 24.68 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}(1-pyrimidin-2-

ylpiperidin-4-ylmethyl)amide (12w, X ) CN, R¹) 1-Pyrimidin-

2-ylpiperidin-4-ylmethyl, R²) 1-Methyl-1H-imidazolesulfonyl,

R³) Methyl). To a solution of 1-methyl-1H-imidazole-4-sulfonic

acid {2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]-

ethyl}piperidin-4-ylmethylamide CF₃CO₂H salt (12s) (35 mg, 0.057

mmol) in THF (600 µL) at 0 °C was added LDA (2.0 M, 71 µL,

0.14 mmol), and the resulting solution was stirred for 1 h.

2-Chloropyrimidine (6.5 mg, 0.057 mmol) was then added, and the

mixture was stirred overnight. The mixture was diluted with EtOAc

and washed with brine. The organic phase was dried over magne-

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}piperidin-4-yl-

methylamide (12s, X ) CN, R¹) Piperidin-4-ylmethyl, R²)

1-Methyl-1H-imidazolesulfonyl, R³) Methyl). 4-{[{2-[(4-Cyano-

phenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(1-methyl-

1H-imidazole-4-sulfonyl)amino]methyl}piperidine-1-carboxylic acid

tert-butyl ester (0.15 g, 0.25 mmol) was dissolved in TFA (2.0 mL)

and the solution stirred at room temperature for 15 min. The solvent

was removed under reduced pressure, and the crude product was

purified by rpHPLC to provide the title compound. Yield 94%. ¹H

NMR (400 MHz, MeOH-d₄): δ 8.91 (s, 1H), 7.78 (s, 1H), 7.77 (s,

1H), 7.55 (d, J ) 9.02 Hz, 2H), 7.23 (s, 1H), 7.02 (d, J ) 9.02 Hz,

2H), 4.87 (s, 2H), 3.91 (s, 3H), 3.82 (t, J ) 7.51 Hz, 2H), 3.78 (s,

3H), 3.42-3.34 (m, 4H), 3.08 (d, J ) 7.12 Hz, 2H), 2.86 (dt, J )

2.31, 11.46 Hz, 2H), 1.93-1.84 (m, 3H), 1.39 (m, 2H). ¹³C NMR

(100 MHz, MeOH-d₄): δ 151.7, 141.5, 138.6, 137.8, 134.9, 132.9,

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5725

sium sulfate, and solvent was removed under reduced pressure. The

residue was purified by rpHPLC. Yield 46%. ¹H NMR (400 MHz,

MeOH-d₄): δ 8.91 (s, 1H), 8.36 (d, J ) 4.89 Hz, 2H), 7.77 (s,

1H), 7.75 (s, 1H), 7.57 (d, J ) 8.90 Hz, 2H), 7.28 (s, 1H), 7.02 (d,

J ) 8.97 Hz, 2H), 6.66 (t, J ) 4.92 Hz, 1H), 4.88 (s, 2H), 4.59 (d,

J ) 13.33 Hz, 2H), 3.92 (s, 3H), 3.83 (t, J ) 7.05 Hz, 2H), 3.78

(s, 3H), 3.44 (t, J ) 7.05 Hz, 2H), 3.01 (d, J ) 7.16 Hz, 2H), 2.88

(t, J ) 11.76 Hz, 2H), 1.85-1.80 (m, 3H), 1.14 (m, 2H). ¹³C NMR

(100 MHz, MeOH-d₄): δ 160.3, 158.7, 151.8, 141.4, 138.9, 137.9,

134.9, 133.0, 126.8, 120.8, 119.1, 114.0, 110.6, 100.4, 57.3, 51.2,

48.3, 45.4, 45.2, 36.6, 34.4, 34.3, 30.5. HRMS (ESI): m/z calcd

for C₂₈H₃₄N₁₀O₂SH⁺575.2665, found 575.2661. Retention time for

analytical rpHPLC: condition I, 12.94; condition II, 19.66 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(2-methylben-

zyl)amide (12x, X ) CN, R¹) 2-Methylbenzyl, R²) 4-Methyl-

1H-imidazolesulfonyl, R³) Methyl). Reaction of 11x was carried

C₂₄H₂₇N₈O₂S⁺491.1978, found 491.1970. Retention time for

analytical rpHPLC: condition I, 11.13; condition II, 14.43 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}pyridin-3-yl-

methylamide (12ab, X ) CN, R¹) 3-Pyridylmethyl, R²

)

4-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 11ab

1

was carried out according to procedure C. Yield 63%. H NMR

(400 MHz, MeOH-d₄): δ 8.90 (s, 1H), 8.62 (s, 1H), 8.56 (d, J )

6.49 Hz, 1H), 8.15 (d, J ) 8.01 Hz, 1H), 7.84 (s, 2H), 7.62 (dd, J

) 5.26, 7.87 Hz, 1H), 7.47 (d, J ) 9.05 Hz, 2H), 7.17 (s, 1H),

6.74 (d, J ) 9.11 Hz, 2H), 4.69 (s, 2H), 4.48 (s, 2H), 3.88 (s, 3H),

3.82 (s, 3H), 3.66 (m, 2H), 3.50 (m, 2H). ¹³C NMR (100 MHz,

MeOH-d₄): δ 151.8, 147.4, 146.9, 142.9, 142.2, 138.9, 138.3, 137.3,

135.2, 133.0, 127.7, 127.0, 121.1, 119.4, 114.1, 100.8, 52.6, 51.1,

48.1, 45.6, 34.8, 34.6. HRMS calcd for C₂₄H₂₇N₈O₂S⁺491.1978,

found 491.1969. Retention time for analytical rpHPLC: condition

I, 11.21; condition II, 14.84 min.

1

out according to procedure C. Yield 83%. H NMR (400 MHz,

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}pyridin-4-yl-

MeOH-d₄): δ 8.87 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.38 (d, J )

8.91 Hz, 2H), 7.30-7.17 (m, 4H), 7.10 (s, 1H), 6.48 (d, J ) 8.91

Hz, 2H), 4.40 (s, 2H), 4.25 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.29

(br s, 4H), 2.34 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.5,

141.6, 139.8, 138.2, 137.8, 134.9, 134.7, 132.6, 132.2, 132.1, 129.8,

127.2, 127.0, 120.8, 119.0, 113.5, 100.0, 54.0, 51.0, 45.6, 44.6,

34.4, 34.2, 19.3. HRMS (ESI): m/z calcd for C₂₆H₂₉N₇O₂SH⁺

504.2182, found 504.2177. Retention time for analytical rpHPLC:

condition I, 14.68; condition II, 22.48 min.

methylamide (12ac, X ) CN, R¹) 4-Pyridylmethyl, R²

)

4-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 11ac

1

was carried out according to procedure C. Yield 71%. H NMR

(400 MHz, MeOH-d₄): δ 8.79 (s, 1H), 8.43 (d, J ) 6.11 Hz, 1H),

7.73 (d, J ) 6.58 Hz, 1H), 7.49 (s, 1H), 7.48 (s, 1H), 7.37 (d, J )

9.04 Hz, 2H), 7.08 (s, 1H), 6.65 (d, J ) 9.01 Hz, 2H), 4.59 (s,

2H), 4.38 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.57 (t, J ) 6.60 Hz,

2H), 3.39 (t, J ) 6.65 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄):

δ 151.8, 148.5, 142.2, 138.9, 138.3, 135.2, 133.1, 127.7, 126.2,

126.1, 121.1, 119.5, 114.1, 100.9, 54.5, 51.0, 48.3, 45.5, 34.8, 34.6.

HRMS calcd for C₂₄H₂₇N₈O₂S⁺491.1978, found 491.2003. Reten-

tion time for analytical rpHPLC: condition I, 11.13; condition II,

14.43 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(3-methylben-

zyl)amide-m-toluene (12y, X ) CN, R¹) 3-Methylbenzyl, R²)

1-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 11y

1

was carried out according to procedure C. Yield 87%. H NMR

(400 MHz, MeOH-d₄): δ 8.88 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H),

7.39 (d, J ) 9.07 Hz, 2H), 7.22 (t, J ) 7.71 Hz, 1H), 7.14-7.11

(m, 4H), 6.56 (d, J ) 9.07 Hz, 2H), 4.52 (s, 2H), 4.21 (s, 2H),

3.82 (s, 3H), 3.80 (s, 3H), 3.47 (t, J ) 6.86 Hz, 2H), 3.35 (t, J )

6.86 Hz, 2H), 2.28 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ

151.9, 141.9, 140.2, 139.3, 138.2, 138.0, 135.1, 133.1, 131.4, 130.4,

130.1, 127.9, 127.2, 121.3, 119.5, 114.0, 100.5, 55.7, 51.5, 46.8,

45.4, 34.8, 34.6, 21.9. HRMS (ESI): m/z calcd for C₂₆H₂₉N₇O₂-

SH⁺504.2182, found 504.2186. Retention time for analytical

rpHPLC: condition I, 14.78; condition II, 20.99 min.

1-Methyl-1H-imidazole-4-sulfonic Acid (3-Cyanobenzyl)-{2-

[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

amidemcyanobenzyl (12ad, X ) CN, R¹) 3-Cyanobenzyl, R²

) 1-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of

1

11ad was carried out according to procedure C. Yield 67%. H

NMR (400 MHz, MeOH-d₄): δ 8.88 (s, 1H), 7.82 (s, 1H), 7.80 (s,

1H), 7.64-7.60 (m, 3H), 7.48 (d, J ) 7.93 Hz, 1H), 7.44 (d, J )

8.95 Hz, 2H), 7.16 (s, 1H), 6.67 (d, J ) 8.95 Hz, 2H), 4.61 (s,

2H), 4.34 (s, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.57 (t, J ) 6.67 Hz,

2H), 3.44 (t, J ) 6.67 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄):

δ 151.4, 141.7, 139.9, 138.7, 137.8, 134.7, 133.5, 132.8, 132.7,

130.9, 127.1, 120.8, 119.4, 119.0, 113.6, 113.5, 100.4, 54.4, 50.8,

47.3, 45.2, 34.4, 34.3. ΗRMS (ESI): m/z calcd for C₂₆H₂₆N₈O₂-

SH⁺515.1978, found 515.1971. Retention time for analytical

rpHPLC: condition I, 13.78; condition II, 18.94 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(4-methylben-

zyl)amide (12z, X ) CN, R¹) 4-Methylbenzyl, R²) 1-Methyl-

1H-imidazolesulfonyl, R³) Methyl). Reaction of 11z was carried

1

out according to procedure C. Yield 74%. H NMR (400 MHz,

MeOH-d₄): δ 8.88 (d, J ) 0.82 Hz, 1H), 7.81 (d, J ) 1.02 Hz,

1H), 7.78 (d, J ) 1.22 Hz, 1H), 7.38 (d, J ) 9.04 Hz, 2H), 7.20

(d, J ) 8.02 Hz, 2H), 7.15 (d, J ) 1.29 Hz, 1H), 7.12 (d, J ) 7.87

Hz, 2H), 6.54 (d, J ) 9.07 Hz, 2H), 4.56 (s, 2H), 4.19 (s, 2H),

3.83 (s, 3H), 3.80 (s, 3H), 3.43 (t, J ) 7.45 Hz, 2H), 3.34 (t, J )

7.45 Hz, 2H), 2.33 (s, 3H). ¹³C NMR (100 MHz, MeOH-d₄): δ

151.5, 141.5, 139.3, 138.8, 137.8, 134.6, 132.8, 130.4, 126.8, 120.8,

119.1, 113.5, 100.0, 55.1, 51.0, 46.4, 45.1, 34.3, 34.2, 21.2. HRMS

(ESI): m/z calcd for C₂₆H₂₉N₇O₂SH⁺504.2182, found 504.2184.

Retention time for analytical rpHPLC: condition I, 14.92; condition

II, 21.40 min.

1-Methyl-1H-imidazole-4-sulfonic Acid (4-Cyanobenzyl)-{2-

[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-

amide (12ae, X ) CN, R¹) 4-Cyanobenzyl, R²) 1-Methyl-

1H-imidazolesulfonyl, R³) Methyl). Reaction of 11ae was carried

1

out according to procedure C. Yield 60%. H NMR (400 MHz,

MeOH-d₄): δ 8.88 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.61 (d, J )

8.22 Hz, 2H), 7.48 (d, J ) 8.22 Hz, 2H), 7.42 (d, J ) 9.01 Hz,

2H), 7.15 (s, 1H), 6.64 (d, J ) 9.01 Hz, 2H), 4.63 (s, 2H), 4.35 (s,

2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.57 (t, J ) 6.72 H, 2H), 3.42 (t,

J ) 6.72 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.3, 143.7,

141.7, 138.5, 137.8, 134.6, 133.5, 130.8, 127.1, 120.8, 119.4, 119.0,

113.6, 112.9, 100.2, 54.9, 50.8, 47.5, 45.2, 34.4, 34.2. HRMS

(ESI): m/z calcd for C₂₆H₂₆N₈O₂SH⁺515.1978, found 515.1970.

Retention time for analytical rpHPLC: condition I, 13.84; condition

II, 18.91 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}pyridin-2-yl-

methylamide (12aa, X ) CN, R¹) 2-Pyridylmethyl, R²

)

4-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 11aa

1

was carried out according to procedure C. Yield 62%. H NMR

1-Methyl-1H-imidazole-4-sulfonic Acid Biphenyl-3-ylmethyl-

{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]-

ethyl}amide (12af, X ) CN, R¹) Biphenyl-3-ylmethyl, R²)

4-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 11af

(400 MHz, MeOH-d₄): δ 8.91 (s, 1H), 8.53 (d, J ) 5.17 Hz, 1H),

7.97 (td, J ) 1.52, 7.77 Hz, 1H), 7.83 (s, 1 H), 7.81 (s, 1 H), 7.64

(d, J ) 7.91 Hz, 1H), 7.48 (d, J ) 9.10 Hz, 2H), 7.47 (obscured,

1H), 7.21 (s, 1H), 6.80 (d, J ) 9.11 Hz, 2H), 4.73 (s, 2H), 4.55

(s, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.66 (m, 2H), 3.54 (m, 2H).

¹³C NMR (100 MHz, MeOH-d₄): δ 155.9, 150.6, 147.1, 140.6,

140.1, 137.6, 136.8, 133.8, 131.8, 126.1, 124.9, 124.3, 119.8, 118.0,

112.8, 99.3, 54.1, 49.5, 46.6, 44.2, 33.4, 33.2. HRMS calcd for

1

was carried out according to procedure C. Yield 69%. H NMR

(400 MHz, MeOH-d₄): δ 8.71 (s, 1H), 7.72 (s, 2H), 7.50 (m, 4H),

7.38 (m, 2H), 7.31 (m, 2H), 7.23 (d, J ) 7.72 Hz, 1H), 7.20 (d, J

) 9.04 Hz, 2H), 7.03 (s, 1H), 6.48 (d, J ) 9.09 Hz, 2H), 4.40 (s,

2H), 4.26 (s, 2H), 3.70 (s, 3H), 3.63 (s, 3H), 3.39 (m, 2H), 3.34

5726 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19

Glenn et al.

(m, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.8, 143.1, 142.0,

141.9, 139.4, 138.8, 138.1, 135.0, 133.0, 130.9, 130.5, 129.8, 129.3,

129.2, 128.3, 128.1, 127.3, 121.2, 119.4, 113.9, 100.5, 55.7, 51.5,

47.1, 45.4, 34.8, 34.5. HRMS calcd for C₃₁H₃₂N₇O₂S⁺566.2338,

found 566.2321. Retention time for analytical rpHPLC: condition

I, 14.51; condition II, 24.77 min.

C₂₃H₂₇N₇O₂S⁺544.1130, found 544.1145. Retention time for

analytical rpHPLC: condition I, 11.21; condition II, 14.74 min.

Acknowledgment. This work was supported by the Medi-

cines for Malaria Venture (MMV) and NIH Grants AI054384,

AI056641 and CA67771. Sung-Youn Chang thanks the Post-

doctoral Fellowship Program of Korea Science & Engineering

Foundation (KOSEF). We thank David Floyd, Lou Lombardo,

and David Williams from Bristol-Myers Squibb for helpful

suggestions.

1-Methyl-1H-imidazole-4-sulfonic Acid Biphenyl-4-ylmethyl-

{2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-ylmethyl)amino]-

ethyl}amide (12ag, X ) CN, R¹) Biphenyl-4-ylmethyl, R²)

4-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 11ag

1

was carried out according to procedure C. Yield 74%. H NMR

(500 MHz, MeOH-d₄): δ 8.77 (s, 1H), 7.80 (s, 1 H), 7.77 (s, 1 H),

7.58 (dd, J ) 1.28, 8.50 Hz, 2H), 7.56 (d, J ) 8.23 Hz, 2H), 7.44

(t, J ) 7.47 Hz, 2H), 7.37 (d, J ) 8.21 Hz, 2H), 7.36 (tt, J ) 1.14,

7.38 Hz, 1H), 7.29 (d, J ) 9.05 Hz, 2H), 7.12 (s, 1H), 6.53 (d, J

) 9.10 Hz, 2H), 4.54 (s, 2H), 4.26 (s, 2H), 3.78 (s, 3H), 3.76 (s,

3H), 3.48 (m, 2H), 3.38 (m, 2H). ¹³C NMR (125 MHz, MeOH-

d₄): δ 149.1, 139.9, 139.2, 139.0, 136.5, 135.4, 134.3, 132.3, 130.4,

128.7, 127.8, 126.4, 125.8, 125.5, 124.6, 118.4, 116.7, 111.2, 97.8,

52.8, 48.8, 44.4, 42.8, 32.0, 31.8. HRMS calcd for C₃₁H₃₂N₇O₂S⁺

566.2338, found 566.2358. Retention time for analytical rpHPLC:

condition I, 15.69; condition II, 30.13 min.

Supporting Information Available: HPLC retention times,

purity, and HRMS data. This material is available free of charge

via the Internet at http://pubs.acs.org.

References

(1) Sachs, J.; Malaney, P. The economic and social burden of malaria.

Nature 2002, 415, 680-685.

(2) Olliaro, P. L.; Bloland, P. B. Clinical and public health implications

of antimalarial drug resistance. Antimalar. Chemother. 2001, 65-83.

(3) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. New antimalarial

drugs. Angew. Chem., Int. Ed. 2003, 42, 5274-5293.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}-(4-pyrrol-1-yl-

benzyl)amide (12ai, X ) CN, R¹) 4-Pyrrol-1-ylbenzyl, R²)

4-methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 11ai

(4) May, J.; Meyer, C. G. Chemoresistance in falciparum malaria. Trends

Parasitol. 2003, 19, 432-435.

(5) Ridley, R. G. Medical need, scientific opportunity and the drive for

antimalarial drugs. Nature 2002, 415, 686-693.

1

was carried out according to procedure C. Yield 54%. H NMR

(6) Rosenthal, P. J. Antimalarial drug discovery: old and new approaches.

J. Exp. Biol. 2003, 206, 3735-3744.

(400 MHz, MeOH-d₄): δ 8.72(s, 1H), 7.74 (m, 4H), 7.49 (s, 1H),

7.32 (m, 4H), 7.13 (s, 1H), 7.06 (s, 1H), 6.52 (m, 3H), 6.24 (t, J )

2.54 Hz, 2H), 4.49 (s, 2H), 4.12 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H),

3.40 (m, 2H), 3.32 (m, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ

151.4, 144.4, 138.4, 136.7, 135.3, 133.9, 129.5, 127.5, 121.2, 121.0,

120.2, 119.2, 114.7, 112.4, 111.4, 101.8, 52.5, 51.4, 47.7, 46.2,

34.7, 34.5. HRMS calcd for C₂₉H₃₁N₈O₂S⁺555.2285, found

555.2292. Retention time for analytical rpHPLC: condition I, 13.21;

condition II, 20.55 min.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Cyanophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}amide (10c, X

) CN, R²) 1-Methyl-1H-imidazolesulfonyl, R³) Methyl).

Reaction of 9c was carried out according to procedure C after

deprotection of Boc group. Yield 82%. ¹H NMR (400 MHz, MeOH-

d₄): δ 8.89 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.52 (d, J ) 9.02

Hz, 2H), 7.24 (s, 1H), 6.91 (d, J ) 9.02 Hz, 2H), 4.83 (s, 2H),

3.90 (s, 3H), 3.75 (s, 3H), 3.66 (t, J ) 6.31 Hz, 2H), 3.21 (t, J )

6.31 Hz, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 151.8, 141.2,

140.4, 137.7, 130.0, 125.9, 120.9, 119.1, 114.0, 100.2, 51.5, 46.0

41.2 34.4, 34.3.

N-(4-Bromophenyl)-N-(3-methyl-3H-imidazol-4-ylmethyl)-N′-

pyridin-2-ylmethylethane-1,2-diamine (18, X ) Br, R¹) 2-Py-

ridylmethyl, R³) Methyl). Reaction of 9b was carried out

according to procedure A. Yield 52%. ¹H NMR (400 MHz, MeOH-

d₄): δ 8.78 (s, 1H), 8.46 (d, J ) 4.86 Hz, 1H), 7.73 (dt, J ) 7.70,

1.63 Hz, 1H), 7.31 (d, J ) 7.83 Hz, 1H), 7.28 (dd, J ) 5.03, 7.55

Hz, 1H), 7.25 (d, J ) 9.07 Hz, 2H), 7.14 (s, 1H), 6.78 (d, J ) 9.00

Hz, 2H), 4.59 (s, 2H), 4.30 (s, 2H), 3.74 (s, 3H), 3.66 (t, J ) 7.06

Hz, 2H), 3.22 (t, J ) 7.10 Hz, 2H). ¹³C NMR (100 MHz, MeOH-

d₄): δ 151.3, 149.5, 146.2, 137.9, 136.7, 132.4, 132.0, 124.1, 123.2,

118.3, 117.3, 112.1, 50.9, 47.1, 45.4, 44.2, 33.0.

(7) Chakrabarti, D.; Azam, T.; DelVecchio, C.; Qiu, L.; Park, Y.-I.; Allen,

C. M. Protein prenyl transferase activities of Plasmodium falciparum.

Mol. Biochem. Parasitol. 1998, 94, 175-184.

(8) Nallan, L.; Bauer, K. D.; Bendale, P.; Rivas, K.; Yokoyama, K.;

Horne´y, C. P.; Pendyala, P. R.; Floyd, D.; Lombardo, L. J.; Williams,

D. K.; Hamilton, A.; Sebti, S.; Windsor, W. T.; Weber, P. C.;

Buckner, F. S.; Chakrabarti, D.; Gelb, M. H.; Van Voorhis, W. C.

Protein farnesyltransferase inhibitors exhibit potent antimalarial

activity. J. Med. Chem. 2005, 48, 3704-3713.

(9) Clough, B.; Wilson, R. J. M. Antibiotics and plasmoidal plastid

organelle. Antimalar. Chemother. 2001, 265-286.

(10) Loyevsky, M.; Gordeuk, V. R. Iron chelators. Antimalar. Chemother.

2001, 307-324.

(11) Gelb, M. H.; Van Voorhis, W. C.; Buckner, F. S.; Yokoyama, K.;

Eastman, R.; Carpenter, E. P.; Panethymitaki, C.; Brown, K. A.;

Smith, D. F. Protein farnesyl and N-myristoyl transferases: piggy-

back medicinal chemistry targets for the development of antitrypan-

osomatid and antimalarial therapeutics. Mol. Biochem. Parasitol.

2003, 126, 155-163.

(12) Chakrabarti, D.; Da Silva, T.; Barger, J.; Paquette, S.; Patel, H.;

Patterson, S.; Allen, C. M. Protein farnesyltransferase and protein

prenylation in Plasmodium falciparum. J. Biol. Chem. 2002, 277,

42066-42073.

(13) (a) Ohkanda, J.; Lockman, J. W.; Yokoyama, K.; Gelb, M. H.; Croft,

S. L.; Kendrick, H.; Harrell, M. I.; Feagin, J. E.; Blaskovich, M. A.;

Sebti, S. M.; Hamilton, A. D. Peptidomimetic inhibitors of protein

farnesyltransferase show potent antimalarial activity. Bioorg. Med.

Chem. Lett. 2001, 11, 761-764. (b) Ohkanda, J.; Knowles, D. B.;

Blaskovich, M. A.; Sebti, S. M.; Hamilton, A. D. Inhibitors of protein

farnesyltransferase as novel anticancer agents. Curr. Top. Med. Chem.

2002, 2, 303-323.

(14) Glenn, M. P.; Chang, S. Y.; Hucke, O.; Verlinde, C. L.; Rivas, K.;

Horne´y, C.; Yokoyama, K.; Buckner, F. S.; Pendyala, P. R.;

Chakrabarti, D.; Gelb, M.; Van Voorhis, W. C.; Sebti, S. M.;

Hamilton, A. D. Structurally simple farnesyltransferase inhibitors

arrest the growth of malaria parasites. Angew. Chem., Int. Ed. 2005,

44, 4903-4906.

1-Methyl-1H-imidazole-4-sulfonic Acid {2-[(4-Bromophenyl)-

(3-methyl-3H-imidazol-4-ylmethyl)amino]ethyl}pyridin-2-yl-

(15) Wiesner, J.; Kettler, K.; Sakowski, J.; Ortmann, R.; Katzin, A. M.;

Kimura, E. A.; Silber, K.; Klebe, G.; Jomaa, H.; Schlitzer, M.

Farnesyltransferase inhibitors inhibit the growth of malaria parasites

in vitro and in vivo. Angew. Chem., Int. Ed. 2004, 43, 251-254.

(16) Hunt, J. T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.; Cho,

Y.; Chong, S.; Chao, S.; Gullo-Brown, J.; Guo, P.; Kim, S. H.; Lee,

F. Y.; Leftheris, K.; Miller, A.; Mitt, T.; Patel, M.; Penhallow, B.

A.; Ricca, C.; Rose, W. C.; Schmidt, R.; Slusarchyk, W. A.; Vite,

G.; Manne, V. Discovery of (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-

imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-

benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with

potent preclinical antitumor activity. J. Med. Chem. 2000, 43, 3587-

3595.

methylamide (17, X ) Br, R¹) 2-Pyridylmethyl, R²

)

4-Methyl-1H-imidazolesulfonyl, R³) Methyl). Reaction of 18

1

was carried out according to procedure C. Yield 24%. H NMR

(400 MHz, MeOH-d₄): δ 8.75 (s, 1H), 8.42 (d, J ) 5.18 Hz, 1H),

7.88 (td, J ) 1.69, 7.76 Hz, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.54

(d, J ) 7. 93 Hz, 1H), 7.39 (dd, J ) 5.23, 7.51 Hz, 1H), 7.15 (d,

J ) 9.11 Hz, 2H), 7.12 (s, 1H), 6.53 (d, J ) 9.14 Hz, 2H), 4.49 (s,

2H), 4.43 (s, 2H), 3.75 (s, 3H), 3.68 (s, 3H), 3.41 (m, 2H), 3.35

(m, 2H). ¹³C NMR (100 MHz, MeOH-d₄): δ 157.3, 148.2, 147.9,

142.0, 141.7, 139.1, 138.0, 133.7, 133.5, 127.5, 126.3, 125.7, 119.7,

116.9, 111.7, 55.3, 51.3, 48.1, 45.8, 34.8, 34.6. HRMS calcd for

Farnesyltransferase Inhibitors

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 19 5727

(17) Sebti, S. M.; Hamilton, A. D. Farnesyltransferase and geranylgeranyl-

transferase I inhibitors and cancer therapy: lessons from mechanism

and bench-to-bedside translational studies. Oncogene 2000, 19,

6584-6593.

(18) Strickland, C. L.; Windsor, W. T.; Syto, R.; Wang, L.; Bond, R.;

Wu, Z.; Schwartz, J.; Le, H. V.; Beese, L. S.; Weber, P. C. Crystal

Structure of farnesyl protein transferase complexed with a CaaX

peptide and farnesyl diphosphate analog. Biochemistry 1998, 37,

16601-16611.

(19) Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R.

Development and validation of a genetic algorithm for flexible

docking. J. Mol. Biol. 1997, 267, 727-748.

catalyzed by cytochrome P450 2B1. J. Biol. Chem. 1993, 268, 9986-

9997.

(22) Irvine, J. D.; Takahashi, L.; Lockhart, K.; Cheong, J.; Tolan, J. W.;

Selick, H. E.; Grove, J. R. MDCK (Madin-Darby canine kidney)

cells: a tool for membrane permeability screening. J. Pharm. Sci.

1999, 88, 28-33.

(23) Artursson, P.; Karlsson, J. Correlation between oral drug absorption

in humans and apparent drug permeability coefficients in human

intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Commun.

1991, 175, 880-885.

(24) Trager, W.; Jensen, J. B. Human malaria parasites in continuous

culture. Science 1976, 193, 673-675.

(20) Eastman, R. T.; White, J.; Hucke, O.; Bauer, K.; Yokoyama, K.;

Nallan, L.; Chakrabarti, D.; Verlinde, C. L.; Gelb, M. H.; Rathod,

P. K.; Van Voorhis, W. C. Resistance to a protein farnesyltransferase

inhibitor in Plasmodium falciparum. J. Biol. Chem. 2005, 280,

13554-13559.

(25) Van der Veken, P.; Senten, K.; Kertesz, I.; De Meester, I.; Lambeir,

A.-M.; Maes, M. B.; Scharpe, S.; Haemers, A.; Augustyns, K. Fluoro-

olefins as peptidomimetic inhibitors of dipeptidyl peptidases. J. Med.

Chem. 2005, 48, 1768-1780.

(21) Seto, Y.; Guengerich, F. P. Partitioning between N-dealkylation

and N-oxygenation in the oxidation of N,N-dialkylarylamines

JM060081V

Article Doi

Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites

DOI: 10.1021/jm060081v

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jm060081v

Full text of DOI:10.1021/jm060081v

Products guided by the article

R&D Labs maybe for 865788-36-9

Relevant to this article

Hot Product