Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents

Article abstract of DOI:10.1021/jm020587n

A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.

Full text of DOI:10.1021/jm020587n

J . Med. Chem. 2003, 46, 2973-2984
2973
Du a l P r otein F a r n esyltr a n sfer a se-Ger a n ylger a n yltr a n sfer a se-I In h ibitor s a s
P oten tia l Ca n cer Ch em oth er a p eu tic Agen ts
S. J ane deSolms,† Terrence M. Ciccarone,† Suzanne C. MacTough,† Anthony W. Shaw,† Carolyn A. Buser,‡
Michelle Ellis-Hutchings,‡ Christine Fernandes,‡ Kelly A. Hamilton,‡ Hans E. Huber,‡ Nancy E. Kohl,‡
Robert B. Lobell,‡ Ronald G. Robinson,‡ Nancy N. Tsou,# Eileen S. Walsh,‡ Samuel L. Graham,*,†
Lorena S. Beese, and J effrey S. Taylor
Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486,
Department of Molecular Design & Diversity, Merck Research Laboratories, Rahway, New J ersey 07065,
and Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710
Received December 27, 2002
A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of
protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I),
enzymes involved in the prenylation of Ras. The structure of the complex formed between one
of these compounds and FTase has been determined by X-ray crystallography. These compounds
are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo.
Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.
In tr od u ction
factor signals.4,5 Thus, inhibition of both FTase and
GGTase-I would be required to inhibit K-Ras-dependent
biology and a single molecule with dual inhibitory
properties could potentially be a useful chemotherapeu-
tic agent.
Previously6 we have demonstrated that imidazole-
methyl diaryl ethers are potent inhibitors of FTase with
a spectrum of activity vs GGTase-I. In particular, the
racemic compound 1 exhibited excellent activity in both
The ras oncogene product Ras p21 plays an important
role in controlling cell proliferation. Mutations in Ras
can lead to unregulated cell growth and are implicated
in 20-30% of all human tumors.1 Protein farnesyltrans-
ferase (FTase), a zinc metalloenzyme, catalyzes the
S-farnesylation of a cysteine residue in the C-terminal
tetrapeptide (CAAX) sequence of Ras. This prenylation
is an essential first step in the localization of Ras to
the plasma membrane, whereupon further post-trans-
lational modifications enable signal transduction and,
in the case of mutant Ras, uncontrolled cell growth.
Considerable effort has focused on the development
of selective FTase inhibitors as potential cancer chemo-
therapeutics.2 Early studies with these agents demon-
strated effective reversion of the transformed phenotype
of cells bearing an activating mutation in the Harvey
isoform of Ras (H-Ras). Altered cellular morphology and
growth inhibition occurred at compound doses that
coincided with blockade of H-Ras farnesylation. Inhibi-
tion of H-Ras farnesylation was achieved without af-
fecting the prenylation of geranylgeranylated proteins
such as Rap1A.3
The most frequently mutated form of Ras in human
cancers, however, is Ki-Ras4B (K-Ras). Ordinarily,
K-Ras appears to be almost exclusively farnesylated by
FTase in vivo. However, inhibition of FTase does not
lead to the accumulation of unprenylated K-Ras. In-
stead, K-Ras becomes geranylgeranylated by the closely
related enzyme protein geranylgeranyltransferase-I
(GGTase-I) in a reaction that is only a few-fold less
efficient than farnesylation. Geranylgeranylated K-Ras
appears to be fully competent for transducing growth
enzyme assays (FTase IC50 ) 2.9 nM, GGTase-I IC50
)
7.1 nM). In this paper, we describe modifications of 1
that provided extremely potent dual FTase/GGTase-I
inhibitors that have good activity in cell culture and can
inhibit the prenylation of K-Ras in vivo.
Ch em istr y
The syntheses of 1 and several analogues thereof are
described in Schemes 1-8. A convergent strategy was
used in which two comparably sized fragments were
joined by a nucleophilic aromatic substitution reaction
that formed the ether linkage.
The phenolic components for the syntheses were
prepared (Scheme 1) following a procedure described by
White7 for the synthesis of the analgesic meptazinol.
Thus, the enolate derived from N-methylazepinone 3a
was treated with the m-methoxybenzyne precursor 2 to
afford anisole 4a . Generation of the enolate from 4a and
reaction with several alkylating agents provided a
family of anisoles 4b-h . These compounds were re-
solved by chiral-phase chromatography and demethy-
lated with boron tribromide to obtain the corresponding
* To whom correspondence should be addressed. Address: Depart-
ment of Medicinal Chemistry, Merck Research Laboratories, WP14-2,
P.O. Box 4, West Point, PA 19486. Phone: (215) 652-6979. Fax: (215)
652-7310. E-mail: sam_graham@merck.com,
† Department of Medicinal Chemistry, Merck Research Laboratories.
‡ Department of Cancer Research, Merck Research Laboratories.
#
Department of Molecular Design and Diversity, Merck Research
Laboratories.
Duke University Medical Center.
10.1021/jm020587n CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/11/2003

2974 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Sch em e 1. Phenolic Intermediatesa
deSolms et al.
Sch em e 2. Preparation of N-Substituted Imidazole
Fragmenta
a
Reagents: (a) KMnO4, H2O/pyridine; (b) borane-THF, THF;
(c) Zn(CN)2, Pd[PPh3]4, DMF; (d) CBr4, PPh3, CH2Cl2; (e) imidazole,
DMF.
Sch em e 3. Preparation of C-Substituted Imidazole
Fragmenta
a
Reagents: (a) Zn, NiCl2(PPh3)2, BrCH2CH2Br, THF.
a
Reagents: (a) LiTMP; (b) R2X, LiTMP; (c) BBr3, CH2Cl2; (d)
Sch em e 4. Synthesis of Functionalized Analogues of
11a
LiAlH4, THF; (e) NBS, DMF.
phenols 5a -h . The absolute stereochemistry of (-)-5c
was determined to be S by X-ray crystallographic
analysis of the derived bromide 5l (see Supporting
Information). The stereochemistry ascribed to the other
resolved phenols was assumed from their optical rota-
tion and their relative mobility on chiral-phase chro-
matography and was supported by consistent patterns
of enzyme-inhibitory activity that were observed for the
diastereomers of the final compounds.
To prepare compounds without substitution on the
azepinone nitrogen, the benzyne chemistry and alkyla-
tion were carried out using N-trimethylsilylazepinone
3b, again following White’s precedent. The silyl group
cleaved spontaneously upon workup to provide, after
demethylation, the phenols 5i and 5j. Reduction of the
amide carbonyl of 4j with LiAlH4 and phenol demethy-
lation gave the amine 5k .
a
Reagents: (a) pyridine-SO3, DMSO, CH2Cl2; (b) 10, EtMgBr,
CH2Cl2; (c) Ac2O, pyr, DMF; (d) (CH3)2SO4, EtOAc; (e) CH3OH; (f)
NaOH, THF; (g) SOCl2; (h) NH3, CHCl3.
15. Treatment of 15 sequentially with thionyl chloride
and ammonia gave the amine 16.
An efficient, asymmetric synthesis of the aminated
fluorobenzonitrile intermediate 20 is shown in Scheme
5. Reaction of aldehyde 12 with lithiated imidazole 1711
provided direct access to the alcohol 15. To obtain
enantiomerically enriched 20, the use of diaryl ketones
in Ellman’s12 method for the asymmetric preparation
of amines was explored. Thus, the chiral sulfinylimines
(R)- and (S)-19 were prepared. Methyl Grignard reagent
addition to (R)-19 gave a 4:1 mixture of diastereomeric
sulfinamides from which the major diastereomer could
be purified by recrystallization. Cleavage of the sulfinyl
group gave the levorotatory amine (-)-20. On the basis
of crystallographic data described below, the levorota-
tory isomer can be assigned the S stereochemistry.
Using methyllithium instead of the Grignard gave the
opposite sense of stereoselection, with the same degree
of selectivity, leading to (+)-20. Since this was the first
example of diastereoselective transformation of a diaryl
ketone using Ellman’s method, the scope of this reaction
was further explored, as described elsewhere.13
2-Fluoro-4-imidazolylmethylbenzonitrile 98 was pre-
pared from 4-bromo-3-fluorotoluene via 4-bromomethyl-
2-fluorobenzonitrile9 (8) by a straightforward reaction
sequence, as described in Scheme 2. Since the benzylic
linkage to N-1 of the imidazole ring of 1 was perceived
as a potential site for metabolic N-dealkylation, the
regioisomeric fragment 11, with the benzyl group ap-
pended to C-5 of the imidazole, was prepared by Suzuki
coupling of 8 with 4-iodo-1-tritylimidazole10 (10).
Analogues of 11 with a higher degree of functional-
ization at the benzylic linker were prepared as shown
in Scheme 4. Swern oxidation of alcohol 7 gave the
aldehyde 12.6 Addition of the Grignard reagent derived
from 10-12 led to alcohol 13. After conversion of 13 to
the corresponding acetate, the imidazole nitrogen was
alkylated with dimethyl sulfate and the trityl group was
removed by methanolysis of the intermediate imidazo-
lium salt. The acetate was hydrolyzed to give alcohol

Transferase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2975
Ta ble 1. Azepinone Modifications of 1
Sch em e 5. Alternative, Asymmetric Synthesis of
Analogues of 16a
IC50, nM (n )a
compd
R1
R2
X
FTase
GGTase-I
(RS)-1
(R)-1
(S)-1
CH3
CH3
CH3
C2H5
C2H5
C2H5
H
H
C2H5
O
O
O
O
O
O
3.0 (2) 7.2 ( 0.6 (6)
5.3
1.4
61
25 (2)
5.8 (2)
560 ( 60 (4)
1200 (2)
20 (2)
(RS)-21 CH3
(RS)-22
(RS)-23
(RS)-24
H
H
H
41
1.3
100
1.9
C2H5 H, H
280 (2)
8.9
(RS)-25 C(CdO)CH3 C2H5 H, H
a
n ) number of determinations. For assays with n > 2, data
are reported as the mean ( SEM. If n is unreported, the data
represent a single determination. Standard errors in the enzyme
assays were typically less than (50% of the mean.
a
Reagents: (a) MnO2, CH2Cl2; (b) (R)- or (S)-tert-BuSONH2,
Ti(OEt)4, THF; (c) MeMgBr, THF, 0 °C; (d) MeOH, HCl.
Sch em e 6. Phenol Arylation with Benzonitrile 9a
Sch em e 7. Synthesis of 27 and 28a
a
Reagents: (a) KF/Al2O3, 18-crown-6, CH3CH; (b) Et3SiH, TFA;
(c) CH3O)2SO2, EtOAc; (d) MeOH.
Ta ble 2. 5-Substituted Imidazoles
a
Reagents: (a) KF/Al2O3, 18-crown-6, CH3CH; (b) CH3COCl,
Et3N, CH2Cl2.
The enantiomers of 1 were prepared (Scheme 6) by
reaction of each of the enantiomers of phenol 5c with
benzonitrile 9 in the presence of KF/alumina. Similarly,
reaction of 9 with racemic phenols 5a , 5i, and 5j gave
compounds 21-23. Also, azepane 24, derived from 5k ,
was further transformed by acetylation to 25. Com-
pounds prepared from 9 are shown in Table 1.
Arylation of phenol 5c with the tritylated imidazole
11 also occurred readily using KF/alumina to provide
intermediate 26 (Scheme 7). Detritylation of 26 with
TFA/ Et3SiH gave 27 (Table 2). Alternatively, methy-
lation of 26 and solvolysis of the resulting imidazolium
salt gave the N-1 methyl derivative 28.
Ether formation between the benzyl alcohol 15 and
racemic 5c gave the expected ether 29, which could be
further transformed to the amine 30 (Scheme 8). An
attempt at the direct formation of 30 by reaction of the
benzylic amine 16 with 5c led primarily to ketone 31,
an autoxidation product. This unexpected product was
converted via Grignard reaction to the tertiary alcohol
32 from which the amine 33 was prepared. Initially,
chiral phase chromatography was used to separate the
four stereoisomers of 33. Subsequently the more ef-
ficient assembly of these compounds was attained by
coupling enantiomerically enriched fragments 5c and
IC50, nM (n )a
compd
R1
R2
R3
FTase
GGTase-I
27
28
29
30
31
32
33
H
H
H
H
13
0.6
2.0
12
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
10 ( 1 (4)
17 (2)
OH
NH2
dO
OH
NH2
0.19
1800
1.2
8 (2)
10000
13 ( 5 (3)
5.1 ( 2.0 (3)
CH3
CH3
0.38
a
n ) number of determinations. For assays with n > 2, data
are reported as the mean ( SEM. If n is unreported, the data
represent a single experiment. Standard errors for enzyme assays
were typically less than (50% of the mean. Compounds were
tested as mixtures of all possible diastereomers.
20 under the standard KF/alumina conditions. Tables
2 and 3 summarize the compounds prepared using these
methods. Diaryl ether formation under the conditions
described above using enantiomerically enriched 20
with a variety of resolved phenols 5 gave the compounds
shown in Table 4. Only the most potent diastereomer,
resulting in each case from reaction of (S)-(-)-20 with
(-)-5,14 is reported in the Table.

2976 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
Sch em e 8. Phenol Arylation: Syntheses of 29-33a
deSolms et al.
minished potency slightly, the amino group in 30
appeared to improve affinity for FTase. However, com-
pound 30 was highly susceptible to air oxidation,
affording ketone 31. This ketone was several-hundred-
fold less active than 28 as an FTI or GGTI.
Encouraged by the potency of 29 and 30 but concerned
about their chemical and metabolic stability, we re-
placed the remaining benzylic hydrogen with a methyl
group to provide compounds 32 and 33 (Table 2),
initially prepared and evaluated as mixtures of four
diastereomers. The hydroxy compound (32) was com-
parable to 29 in potency but remained slightly less
active than the unsubstituted compound 28 as an
inhibitor of prenyltransferases. The methylated amino
compound 33 was similar in activity to 30, but again,
the amino group appeared to contribute slightly greater
affinity for FTase and GGTase-I compared to 28. The
properties of each of the four diastereomers of 33 (33a -
d ) are shown in Table 3. The stereoisomers vary in
FTase inhibitory potency over a 100-fold range, with the
stereoisomer resulting from the coupling of (S)-5c and
(-)-20 being an extremely potent inhibitor (60 pM).
GGTase-I activity was somewhat less sensitive to the
stereostructure of these inhibitors. The crystallographic
data presented below for 33a revealed that the levoro-
tatory fragment (-)-20 has the S configuration.
Table 4 illustrates the effect of the substituent at the
3-position of the azepinone ring on enzyme inhibition.
While all four diastereomers of these compounds were
prepared, data are provided only for the most potent
isomer, which invariably arose from coupling the levoro-
tatory enantiomers of 5 and 20. For all isomers of the
compounds in Table 4, the same pattern of inhibitory
potency as a function of stereochemistry was observed
as for the isomers of 33. Thus, with respect to the optical
rotation of the fragments 5 and 20, the rank order of
IC50 was (-)/(-) < (-)/(+) < (+)/(-) < (+)/(+).
For both enzymes the least potent inhibitor is 34,
which is unsubstituted at the 3-position of the azepi-
none. While the presence of a non-hydrogen substituent
on the azepinone ring is clearly beneficial in this series,
a profound relationship between substituent size or
hydrophobicity and activity is not obvious. For the
majority of substituents we explored, potency varied
only 2- to 4-fold.
a
Reagents: (a) KF/Al2O3, 18-crown-6, CH3CN; (b) MeMgBr,
THF; (c) SOCl2; (d) NH3, CHCl3.
Str u ctu r e-Activity Rela tion sh ip s
All compounds were assayed for their ability to inhibit
FTase and GGTase-I in vitro. As previously described,
compound 1 was a dual FTase-GGTase-I inhibitor of
good potency (Table 1). Resolution of this compound
revealed that the S enantiomer of 1 is a more potent
inhibitor of both FTase and GGTase-I in vitro (FTase
IC50 ) 1.4 nM, GGTase-I IC50 ) 5.8 nM) than (R)-1
(FTase IC50 ) 5.3 nM, GGTase-I IC50 ) 25 nM).
Compound (R,S)-21, which lacks the ethyl substituent
on the azepinone in 1, is 20- and 80-fold less potent than
(R,S)-1 as an FTI and GGTI, respectively. Compounds
22 and 23 demonstrate that the lactam N-methyl
substituent in 1 is not important for FTase activity,
although it may contribute slightly to GGTase-I activity.
The importance of the azepinone ethyl group to the
intrinsic potency of this family of inhibitors is under-
scored by the reduced potency of 22 in comparison to
23.
Converting the amide group in 23 to an amine in 24
resulted in a 100-fold loss of potency against FTase and
a more modest 14-fold reduction in GGTase-I inhibitory
activity. Most of this activity can be restored by acety-
lating the lactam nitrogen to give 25.
The data in Table 2 show the impact of changing the
position of substitution on the imidazole group from N-1
to C-5 in the context of the ethyl-substituted azepinone.
Compound (R,S)-27, a monosubstituted imidazole, was
2- to 4-fold less potent than (R,S)-1 as an FTI and GGTI.
Methylating N-1 of the imidazole gave a compound
((R,S)-28) that was equipotent to (R,S)-1. Hydroxylation
and amination of the benzylic carbon of 28 gave com-
pounds 29 and 30 (each prepared as a mixture of four
stereoisomers). Although the hydroxyl substituent di-
Str u ctu r e of a n In h ibitor -F Ta se Com p lex. A
crystal structure of human farnesyltransferase was
obtained with compound 33a bound in the active site,
and the data are represented graphically in Figure 1.
The compound, clearly possessing the S,S stereochem-
istry, occupies the space where the peptide substrate is
normally bound,15 while the binding of FPP is unaffected
by the inhibitor. The most striking features of the
complex are the direct ligation of the active site zinc
atom by N-3 of the imidazole and the close packing of
the isoprenoid and cyanophenyl hydrophobic surfaces.
The location of the cyano group in the vicinity of
Arg202â may provide an additional favorable polar
interaction within the complex. The central phenyl
group of 33a makes hydrophobic interactions with
Trp102, Trp106, Trp303, and Tyr361 of the â subunit,
as well as with the tail of the isoprenoid chain. The
aliphatic portion of the azepinone ring resides in a
predominantly hydrophobic pocket bounded by Ala151,

Transferase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2977
Ta ble 3. Diastereomers of 33
a
IC50
,
nM
GGTase-I
protein processing inhibition EC50, nM (n)b
compd
/
†
FTase
HDJ 2
Rap1a
K-Ras
33a
33b
33c
33d
S
S
R
R
S
R
S
R
0.06
1.5
0.36
7.6
3.6
4.5
13
54
2.1 ( 0.9 (3)
470 ( 20 (3)
720
340 ( 50 (3)
1900
11
6
140
230
120
3200
8000
a
b
Average of two determinations. Results of a single determination except for 33a , for which the average of n ) 3 determinations (
SEM is reported.
Ta ble 4. Effects of Azepinone Substitution on Activity
IC50, nM (n )a
GGTase-I
protein processing EC50, nM (n)b
compd
R
FTase
HDJ 2
Rap1a
K-Ras
34c
35d
36
H
CH3
C3H7
c-C3H5CH2
CF3CH2CH2
C4H9
11 (1)
92 (2)
0.41 (2)
0.46 (3)
0.3 (1)
30 (2)
26 (1)
0.9 (2)
1.5 (2)
3.1 (2)
4 (2)
3990 (1)
220 (2)
87 (2)
3730 (1)
100 (2)
2.9 (2)
2.1 (2)
2.5 (2)
1.4 (2)
0.81 (2)
37
220 (2)
38
0.19 (2)
0.12 (2)
0.18 (1)
47 (2)
207 ( 65 (4)
39
250 (2)
>1000 (1)
320 (2)
40
c-C3H5CH2CH2
11 (1)
1290 (1)
a
b
n ) number of determinations. Standard deviations for enzyme assays were typically (50% of the mean or less. Average of n
determinations. Replicate values typically differed less than 2-fold. c Assays run with a 1:1 mixture of compounds arising from the
asymmetric center on the azepinone ring. Processing assays were performed on a mixture of the four diastereomers of 35.
d
at the carbon bearing the primary amine (e.g., 33a and
33c), where the S configuration is preferred by 5- to
6-fold. In 33a , the (presumably protonated) amine is
near the phosphate group of FPP, although the distance
between the amine and nearest phosphate oxygen (N-O
separation of 4.3 Å) is too great to represent a contact
ion pair, such as had been observed in an FTase complex
with a peptidomimetic inhibitor (N-O separation of 2.7
Å).15 Well-ordered water molecules capable of mediating
a hydrogen-bonding interaction are also absent. How-
ever, it remains plausible that a solvent-separated ion
pair could contribute to binding, an interaction that
would be diminished upon inversion of configuration.
Changing the configuration of the asymmetric center
in the azepinone ring has an even larger effect on
binding affinity (20- to 25-fold) than is observed for the
F igu r e 1. Crystal structure of 33a (yellow) bound to hFTase.
primary amine-bearing carbon. If one assumes that the
The farnesyl hydrocarbon is shown in magenta. Two crystal-
ethyl and aryl groups in 33a and 33b occupy similar
lographically defined water molecules are shown near the
sites in the enzyme, then the azepinone carbonyl, which
is exposed to solvent in the complex of 33a , would
project toward Trp102 and Ser99 of the â subunit, while
the hydrocarbon segment is removed from its preferred
hydrophobic environment to one that is solvent-exposed.
Another interesting aspect of the SAR is the large loss
in potency that accrues upon reduction of the lactam of
23 to the amine 24. As noted above, the lactam carbonyl
in the crystal structure does not appear to make any
lactam carbonyl.
Trp102, and Ser99 of the â subunit, while the ethyl
group lies near Leu96 and Trp106. The lactam carbonyl
is solvent-exposed and interacts with a crystallographi-
cally well-defined water molecule.
An interesting feature of the structure-activity re-
lationships is the stereoselectivity in the binding of the
pairs of amino compounds differing only in configuration

2978 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
deSolms et al.
important interactions with the enzyme but is solvent-
exposed, interacting with a nearby water molecule.
Perhaps an unfavorable interaction of the protonated
amine in the reduction product with Arg202â (N-N
distance of 4.7 Å) or insertion of the methylene group
from the former carbonyl into an aqueous environment
contributes to the loss of activity. The restoration of
activity upon acetylation suggests that the electrostatic
interaction may be of greater importance.
processing is not improved in the presence of an excess
of either a selective FTase or GGTase inhibitor. In
contrast, K-Ras processing inhibition by 33a (ratio of
224) was markedly enhanced by supplementation with
a GGTase inhibitor.
As reported elsewhere,18 compounds 33a and 38 were
evaluated in mice for antitumor efficacy and toxicity.
These studies were challenging because of the poor
pharmacokinetic properties of the compounds. They are
not orally bioavailable and have rapid apparent clear-
ance in mice. To observe substantial inhibition of K-Ras
processing, we resorted to infusion with Alzet osmotic
pumps at nominal doses approaching 2000 mpk. Despite
the enormous dose, plasma concentrations of about
3-10 µM were attained. Although at these doses both
33a and 38 could be shown to inhibit K-Ras prenylation
in vivo, attempts to demonstrate antitumor efficacy with
these compounds were complicated by severe toxicity.
Mice treated for 72 h with doses of inhibitors sufficient
to inhibit K-Ras processing showed signs of myelosup-
pression, became edematous, and suffered 100% mortal-
ity. These effects were also seen after treatment with a
selective inhibitor of GGTase-I alone. Although an
antitumor effect was observed following a 24 h treat-
ment with the dual inhibitors, it was no greater than
that achieved with a comparable dose (i.e., equipotent
for hDJ processing inhibition) of a pure FTase inhibitor
alone. On the basis of these observations, it is unlikely
that suppression of K-Ras function by inhibition of its
prenylation will be of clinical utility.
Mech a n ism of In h ibition of GGTa se-I
The crystallographic analysis of 33a in complex with
FTase defines the mechanism of inhibition as protein
substrate competitive, as is the case for many other
cyanobenzylimidazole-containing compounds.16 For GG-
Tase, we have previously reported that cyanobenzylimi-
dazoles can inhibit GGTase in competition with either
peptide or prenyl pyrophosphate substrates.17 To define
the mechanism of inhibition of GGTase-I by these diaryl
ethers, the IC50 for inhibition of GGTase-I by six of the
compounds in Table 4 was redetermined at three
concentrations of GGPP (see Experimental Section). The
slopes of the plots of log IC50 vs log [GGPP] for these
compounds varied from -0.28 to -0.03, indicating that
the compounds are not competitive, and possibly un-
competitive, vs GGPP. Thus, in common with the
mechanism of inhibition of FTase, and similar to some
of our earlier compounds,17 inhibition of GGTase by
competition with the peptide substrate is highly likely.
In h ibition of P r otein P r en yla tion
It should be noted that the high doses of dual
prenyltransferase inhibitors required to inhibit K-Ras
prenylation probably suffice to substantially block the
prenylation of all substrates of FTase and GGTase-I.
As suggested by the studies of Sun et al.,4 it remains
conceivable that in some settings lower doses of such
compounds may have beneficial effects by selective
inhibition of the prenylation of a subset of proteins.
We also determined the relationship of intrinsic
enzyme inhibitory potency to inhibition of protein pre-
nylation in cultured PSN-1 pancreatic carcinoma cells.18
As representative intracellular substrates, we used the
chaperone protein hDJ as an example of a purely
farnesylated substrate and the small GTPase Rap1a as
a specifically geranylgeranylated protein. The prenyla-
tion state of K-Ras, a substrate for both enzymes, was
also evaluated. For the diastereomers of 33, inhibition
of hDJ protein processing was rank-ordered correctly
by intrinsic enzyme inhibitory activity (Table 3). How-
ever, a quantitative correlation is absent. The relation-
ship between Rap1a processing and in vitro GGTase-I
inhibition is less apparent and may be obscured by the
relatively small range of GGTase-I inhibitory activities
displayed by this set of compounds. The compounds in
Table 4 were also evaluated in the processing assays.
Since there is significant variation in the chemical
constitution of these compounds, it is not surprising that
intrinsic enzyme inhibitory potency does not predict
potency in the processing assays. In particular, the most
hydrophobic compound (40) is significantly less potent
in cell culture than might have been predicted from its
enzyme inhibitory activities. Note that the apparent
anomaly in the processing activity of 35 is largely
attributable to the use of an equimolar mixture of the
four diastereomers of 35 in the processing assay while
the enzyme inhibitory data shown refer to the most
potent of the diastereomers.
Exp er im en ta l Section
All reagents and starting materials used in the syntheses
were purchased from Aldrich, Fisher, Fluka, Sigma, or Lan-
caster and used without purification. All solvents were pur-
chased from Fisher or Aldrich. Thin-layer chromatography
(TLC) was performed on E. Merck 60F-254 (0.25 mm) pre-
coated silica gel plates. Visualization of TLC plates was ac-
complished with UV light and/ or phosphomolybdic acid stain.
Flash chromatography was performed on E. Merck silica gel
60 (230-400 mesh) unless otherwise noted. Melting points
(mp) were determined on a Thomas-Hoover melting point
apparatus and are uncorrected. Preparative HPLC was per-
formed on a Waters DeltaPrep 4000 instrument using either
a C-18 Waters PrepPak column or a Vydac column for reverse
phase or on Chiral Technologies, Inc. Chiralcel OD or Chiral-
pak AD columns for chiral normal phase. Proton nuclear
magnetic resonance (1H NMR) spectra were obtained on a
Varian XL 300 or 400 spectrometer. Chemical shifts are
expressed in ppm relative to tetramethylsilane. Mass spectra
were obtained on a VG Micromass MM7035 spectrometer.
Elemental analyses were performed on a Perkin-Elmer 2400
analyzer, and results are within (0.4% of the theoretical value
unless indicated otherwise. Optical rotations were measured
with a Perkin-Elmer 241 polarimeter.
Several of these inhibitors were more efficient inhibi-
tors of K-Ras processing than 33a . The balance of FTase
and GGTase inhibition potency (ratio of EC50 values for
Rap1a to HDJ processing is 15) of 38 has been shown18
to be nearly ideal in that its EC50 for inhibition of K-Ras
3-(3-Meth oxyp h en yl)-1-m eth yla zep a n -2-on e (4a ).7 To
1.6 M n-BuLi in hexane (187.5 mL, 0.3 mol) at 0 °C was added
a solution of 2,2,6,6-tetramethylpiperidine (50.6 mL, 0.3 mol)
in anhydrous THF (300 mL) over 5 min under an Ar atmo-
sphere. N-Methylazepinone (3a , 38.2 g, 0.3 mol) in anhydrous

Transferase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2979
THF (60 mL) was added. After the reaction mixture was
stirred for 10 min, an additional portion of 1.6 M n-BuLi in
hexane (187.5 mL, 0.3 mol) was added. After the mixture was
stirred for 10 min, 2-chloroanisole (2, 42.8 g, 0.3 mol) was
added. After the mixture was stirred for 30 min, the reaction
was quenched with ice-H2O, and the mixture was stirred for
30 min and concentrated in vacuo. The residue was diluted
with EtOAc and washed with 5 N HCl (100 mL) and brine.
The organic layer was dried (MgSO4), concentrated, and
purified by silica gel chromatography (0.5% MeOH/CH2Cl2) to
6.74 (m, 2H), 6.64 (t, 1H, J ) 2 Hz), 6.35 (br s, 1H), 3.10-3.17
(m, 1H), 3.05 (s, 3H), 2.78-2.85 (m, 1H), 2.17-2.24 (m, 1H),
1.86-2.00 (m, 1H), 1.70-1.86 (m, 4H), 1.51-1.59 (m, 1H),
1.39-1.50 (m, 1H), 0.74 (t, 3H, J ) 7.3 Hz).
(+)-3(R)-Ethyl-3-(3-hydroxyphenyl)-1-methylazepan-2-one (R-
(+)-5c) was prepared in a like manner. [R]D +46.9° (c 1, EtOH).
(3-(3-Eth yla zep a n -3-yl)p h en ol (5k ). Compound 4j (1.05
g, 4.24 mmol) in anhydrous THF (4.2 mL) was added to a
solution of LiAlH4 (0.193 g, 5.09 mmol) in anhydrous THF (4.2
mL), and the mixture was refluxed for 24 h. The solution was
cooled, quenched with H2O (0.18 mL), 15% NaOH (0.18 mL),
and H2O (0.54 mL), filtered, and concentrated. The residue
was purified using reverse-phase chromatography (95:5 to 5:95
H2O/CH3CN with 0.1% TFA, flow ) 65 mL/min), converted to
its free base using saturated NaHCO3 solution, extracted with
CH2Cl2 (3×), and dried (MgSO4) to give 0.316 g (32%) of 4k .
1H NMR (CDCl3): δ 7.25 (t, 1H, J ) 8 Hz), 6.90 (d, 1H, J )
7.8 Hz), 6.87 (t, 1H, J ) 2 Hz), 6.73 (dd, 1H, J ) 2, 8 Hz), 3.81
(s, 3H), 3.23 (d, 1H, J ) 14.2 Hz), 2.92-2.96 (m, 1H), 2.87 (d,
1H, J ) 14.2 Hz), 2.74-2.80 (m, 1H), 2.20-2.25 (m, 1H), 1.51-
1.76 (m, 7H), 0.60 (t, 3H, J ) 7.3 Hz).
A 1 M solution of BBr3 (2.56 mL, 2.56 mmol) in CH2Cl2 was
added to compound 4k (0.300 g, 0.1.28 mmol) dissolved in
anhydrous CH2Cl2 (10 mL) at -78 °C. After the mixture was
stirred for 20 h at room temperature, the reaction was
quenched with saturated NaHCO3 solution and the mixture
was extracted with CH2Cl2 (3×), dried (MgSO4), and concen-
trated to give 0.28 g (100%) of 5k . 1H NMR (CDCl3): δ 7.21 (t,
1H, J ) 8 Hz), 6.80 (d, 1H, J ) 8 Hz), 6.78 (s, 1H), 6.70 (d,
1H, J ) 8.2 Hz), 4.6 (v br s, 2H), 3.46 (d, 1H, J ) 14.6 Hz),
2.90-2.98 (m, 1H), 2.84 (d, 1H, J ) 14.2 Hz), 2.78-2.88 (m,
1H), 2.32-2.39 (m, 1H), 1.64-1.80 (m, 3H), 1.50-1.59 (m, 4H),
0.62 (t, 3H, J ) 7.2 Hz).
(-)-3(S)-Eth yl-3-(4-br om o-3-h yd r oxyp h en yl)-1-m eth y-
la zep a n -2-on e ((S)-(-)-5l). To a solution of (-)-5c (0.10 g,
0.404 mmol) in DMF (2 mL) was added dropwise a solution of
N-bromosuccinimide (0.10 g, 0.562 mmol) in DMF (2 mL) with
stirring under Ar at room temperature. After being stirred for
16 h, the reaction mixture was partitioned between CH2Cl2
and H2O. The organic layer was separated and washed with
H2O, aqueous saturated NaHCO3 solution, and brine. The
solution was dried (Na2SO4), filtered, and concentrated to
dryness to obtain 0.019 g of (-)-5l after silica gel chromatog-
raphy (EtOAc/hexane, 1:3) and crystallization from hexane/
EtOAc. The absolute stereochemistry of (-)-5l was determined
to be S by X-ray crystallography.
1
give 28.35 g (40%) of 4a . H NMR (CDCl3): δ 7.20-7.25 (m,
1H), 6.76-6.82 (m, 3H), 3.84-3.88 (m, 1H), 3.80 (s, 3H), 3.64-
3.71 (m, 1H), 3.22-3.29 (m, 1H), 3.02 (s, 3H), 1.98-2.06 (m,
3H), 1.77-1.86 (m, 1H), 1.65-1.76 (m, 1H), 1.50-1.59 (m, 1H).
Rep r esen ta tive P r oced u r e for th e Alk yla tion of Aze-
pan on e 4a: (+)-3(R)-Eth yl-3-(3-m eth oxyph en yl)-1-m eth yl-
a zep a n -2-on e ((R)-(+)-4c) a n d (-)-3(S)-Eth yl-3-(3-m eth -
oxyp h en yl)-1-m eth yla zep a n -2-on e ((S)-(-)-4c).7 To 1.6 M
n-BuLi in hexane (172 mL, 0.275 mol) at 0 °C was added a
solution of 2,2,6,6-tetramethylpiperidine (46.4 mL, 0.275 mol)
in anhydrous THF (450 mL) over 15 min under Ar. After the
reaction mixture was stirred for 15 min, compound 4a (31.32
g, 0.134 mol) was added and the mixture was stirred for 1 h
at 0 °C. Iodoethane (25.1 g, 0.161 mol) was added in one
portion, and the reaction mixture was allowed to warm to room
temperature and stirred overnight. The reaction was quenched
with ice-H2O, and the mixture was stirred for 30 min and
concentrated in vacuo. The residue was diluted with EtOAc
and washed with 5 N HCl (200 mL) and brine. The organic
layer was dried (MgSO4), concentrated, and purified on silica
gel (30-50% EtOAc/hexane) to give 10.6 g of 4c and 14.5 g of
recovered 4a (56% yield based on recovered starting material).
Racemic 4c was separated by HPLC on a ChiralPak AD
column eluting with 90:10 hexane/ethanol to give 5.37 g of (R)-
(+)-4c, [R]D +59.8° (c 1, CCl4), and 5.39 g of S-(-)-(-)-4c, [R]D
-60.8° (c 1, CCl4). 1H NMR (CDCl3): δ 7.21-7.27 (m, 1H),
6.67-6.78 (m, 3H), 3.80 (s, 3H), 3.05-3.12 (m, 1H), 3.05 (s,
3H), 2.76-2.84 (m, 1H), 2.17-2.24 (m, 1H), 1.82-1.94 (m, 2H),
1.49-1.57 (m, 1H), 1.37-1.68 (m, 1H), 0.75 (t, 3H, J ) 7 Hz).
3-(3-Meth oxyp h en yl)a zep a n -2-on e (4i).7 Azepinone (10.0
g, 88 mmol), triethylamine (14.8 mL, 106 mmol), and chlorot-
rimethylsilane (13.5 mL, 106 mmol) were dissolved in 60 mL
of toluene and refluxed under argon for 3 h. The mixture was
filtered, and the solvent was evaporated to provide N-trim-
ethylsilylazepinone (3b). The title compound was prepared
from this crude intermediate as described for the preparation
of 4a .
2-F lu or o-4-h yd r oxym eth ylben zon itr ile (7). 4-Bromo-3-
fluorotoluene (6, 40.0 g, 0.212 mol) was heated at 90 °C in H2O
(200 mL)-pyridine (200 mL) with mechanical stirring under
Ar. Potassium permanganate (KMnO4) (67 g, 0.424 mol) was
added portionwise over 3 h. [Warning: Solid KMnO4 must be
added to the hot reaction mixture.] After 4 h, an HPLC of a
filtered sample indicated 50% conversion to the acid. Ad-
ditional KMnO4 (50 g) was added portionwise with reaction
monitoring by HPLC until > 95% conversion was obtained.
The reaction mixture was filtered through Celite, and the filter
pad was washed with H2O, aqueous NaOH, and EtOH. The
filtrate was concentrated to a small volume and partitioned
between 3 N NaOH solution and diethyl ether. The aqueous
basic layer was separated, cooled in an ice-H2O bath, and
acidified slowly with 6 N HCl solution to precipitate 40.8 g
(88%) of 4-bromo-3-fluorobenzoic acid as a white solid, mp
2-Eth yl-3-(3-m eth oxyp h en yl)a zep a n -2-on e (4j). To 1.6
M n-BuLi in hexane (31.3 mL, 0.05 mol) at 0 °C was added a
solution of 2,2,6,6-tetramethylpiperidine (8.43 mL, 0.05 mol)
in anhydrous THF (100 mL) over 5 min under an Ar atmo-
sphere. N-Trimethylsilylazepinone (3b, 9.26 g, 0.05 mol) in
anhydrous THF (20 mL) was added. After the reaction mixture
was stirred for 10 min, an additional portion of 1.6M n-BuLi
in hexane (31.3 mL, 0.05 mol) was added. After the mixture
was stirred for 10 min, 2-chloroanisole 2 (6.34 g, 0.05 mol) was
added. After the mixture was stirred for 30 min, ethyl iodide
(3.90 mL, 48.7 mmol) was added. After 30 min, the reaction
was quenched with ice-H2O, and the mixture was stirred for
30 min and concentrated in vacuo. The residue was diluted
with EtOAc and washed with 5 N HCl (100 mL) and brine.
The organic layer was dried (MgSO4), concentrated, and
purified using silica gel chromatography (10-15% EtOAc/CH2-
Cl2) to give 4j.
1
190-192 °C. H NMR (CDCl3): δ 7.83 (dd, 1H, J ) 2, 9 Hz),
7.78 (dd, 1H, J ) 2, 8 Hz), 7.67-7.71 (m, 1H).
Rep r esen ta tive P r oced u r e for P h en ol Dem eth yla -
tion : (-)-3(S)-Eth yl-3-(3-h ydr oxyph en yl)-1-m eth ylazepan -
2-on e ((S)-(-)-5c). A 1 M solution of BBr3 (77.7 mL, 77.7
mmol) in CH2Cl2 (80 mL) was added to compound (S)-(-)-4c
(6.04 g, 25.9 mmol) dissolved in anhydrous CH2Cl2 (400 mL)
at 0 °C under N2. After 3.5 h, the reaction was quenched with
saturated aqueous NaHCO3 solution and the mixture was
extracted with CH2Cl2 (3×). The extract was dried (Na2SO4)
and concentrated to give 4.9 g (76%) of (S)-(-)-5c. [R]D -43.0°
(c 1, EtOH). 1H NMR (CDCl3): δ 7.19 (t, 1H, J ) 7.8 Hz), 6.68-
4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dis-
solved in THF (250 mL) with magnetic stirring under Ar in
an ice-H2O bath. The cloudy solution was treated dropwise
with borane-THF complex (1 M) (374 mL, 0.374 mol) over a
1 h period, maintaining the internal temperature at <10 °C.
The reaction mixture was left to warm to room temperature
overnight and then cooled in an ice-H2O bath and treated
dropwise with H2O (150 mL). The THF was removed on a
rotary evaporator, and the residue was partitioned between
EtOAc and H2O. The aqueous layer was extracted with EtOAc

2980 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
deSolms et al.
(3 × 100 mL), and the organic layers were combined, washed
with brine, dried (Na2SO4), filtered, and concentrated to give
37.49 g (98%) of 4-bromo-3-fluorobenzyl alcohol as an oil that
pH of the mixture was adjusted to 8.5 with saturated NaHCO3
solution, and the product was extracted with CH2Cl2 (3×). The
combined organic layers were dried (MgSO4), concentrated,
and purified by silica gel chromatography (0-1% MeOH/CH2-
1
solidified on standing. H NMR (CDCl3): δ 7.52 (t, 1H, J ) 8
1
Hz), 7.16 (d, 1H, J ) 9 Hz), 7.02 (d, 1H, J ) 8 Hz), 4.67 (s,
Cl2) to yield 5.2 g (98%) of 13. H NMR (CDCl3): δ 7.70-7.80
2H), 1.47 (br s, 1H).
(m, 1H), 7.41 (s, 1H), 7.25-7.38 (m, 1H), 7.05-7.17 (m, 5H),
6.65 (s, 1H), 5.68 (d, 1H, J ) 7 Hz), 3.36 (d, 1H, J ) 7 Hz).
MS, m/z: (M + 1) 460.
4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dis-
solved in DMF (100 mL) and then placed under high vacuum
for 15 min. The solution was then purged with Ar for 15 min.
While purging continued, ZnCN (8 g, 0.068 mol) and the
catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The
reaction mixture was heated at 95 °C under Ar for 18 h and
then cooled to ambient temperature and added to H2O. The
mixture was extracted with EtOAc and then washed with 1
M HCl, H2O, and brine and dried (Na2SO4). Filtration and
concentration to dryness gave 11 g (75%) of 7 as a white solid
after chromatography (silica gel, 35% EtOAc/hexane). 1H NMR
(CDCl3): δ 7.61 (t, 1H, J ) 8 Hz), 7.23-7.29 (m, 2H), 4.80 (d,
2H, J ) 6 Hz), 1.93 (t, 1H, J ) 6 Hz).
2-F lu or o-4-im id a zol-1-ylm eth ylben zon itr ile (9). Com-
pound 7 (9.06 g, 0.06 mol), CBr4 (29.76 g, 0.09 mol), and Ph3P
(23.5 g, 0.09 mol) were combined in CH2Cl2 (250 mL) [exother-
mic reaction], and the mixture was stirred for 3 h at room
temperature. The reaction mixture was concentrated to dry-
ness, and the resulting crude bromide 88 was added to a
solution of imidazole (20.3 g, 0.30 mol) in DMF (250 mL). After
the mixture was stirred overnight at room temperature, the
DMF was removed in vacuo and the residue was partitioned
between EtOAc and H2O. The organic layer was separated,
washed with H2O (2×), and extracted with 1 N HCl solution.
The aqueous acidic layer was separated, neutralized with Na2-
CO3 solution, and extracted with CH2Cl2 (3×). The organics
were combined and dried (MgSO4). Filtration and concentra-
tion to dryness gave 6.09 g (51%) of 9. 1H NMR (CDCl3): δ
7.62 (dd, 1H, J ) 8.5, 9.5 Hz), 7.57 (s, 1H), 7.16 (s, 1H), 7.00
(d, 1H, J ) 8.5 Hz), 6.94 (d, 1H, J ) 9.5 Hz), 6.91 (s, 1H), 5.21
(s, 2H).
2-F lu or o-4-(1-t r it yl-1H -im id a zol-4-ylm et h yl)b en zon i-
tr ile (11). Zinc (0.301 g, 4.63 mmol) and dibromoethane (0.040
mL, 0.463 mmol) were stirred in anhydrous THF (2 mL) under
Ar for 1.5 h. A solution of 8 (0.546 g, 2.55 mmol) in anhydrous
THF (1 mL) was added dropwise, and the mixture was stirred
for 1 h. A mixture of 4-iodo-1-trityl-1H-imidazole (10)10 (0.808
g, 1.85 mmol) and NiCl2 (PPh3)2 (0.120 g, 0.183 mmol) was
added. After the mixture was stirred overnight under Ar, the
reaction was quenched with saturated NH4Cl (9 mL) and the
mixture was stirred for 2 h. The mixture was extracted with
CH2Cl2 (3×) and dried (MgSO4), and the solvents were
evaporated. Purification by silica gel chromatography (0.5%
MeOH/CH2Cl2 with NH4OH) gave 0.348 g (42%) of 11.
Acetic Acid (4-Cya n o-3-flu or op h en yl)(1-tr ityl-1H-im i-
d a zol-4-yl)m eth yl ester (14). Compound 13 (4.05 g, 8.81
mmol), pyridine (2.14 mL, 26.4 mmol), and Ac2O (12.5 mL, 132
mmol) were stirred in anhydrous DMF (650 mL) for 3 h under
Ar. The reaction mixture was concentrated in vacuo, diluted
with EtOAc (250 mL), washed with H2O (2×) and brine, dried
(MgSO4), and concentrated to give a quantitative yield of 14,
which was used without purification in the subsequent step.
2-F lu or o-4-[h yd r oxy(1-m eth yl-1H-im id a zol-5-yl)m eth -
yl]ben zon itr ile (15). Compound 14 (4.60 g, 8.81 mmol) was
treated with dimethyl sulfate (0.833 mL, 8.81 mmol) in EtOAc
(20 mL) and heated at 60 °C overnight under Ar. The reaction
mixture was concentrated in vacuo. The crude imidazolium
salt was dissolved in MeOH (30 mL) and refluxed for 1 h. The
solution was concentrated in vacuo, and the residue was
purified by silica gel chromatography (0.5-4% MeOH/CH2Cl2
with NH4OH) to give 0.838 g (35%) of acetic acid (4-cyano-3-
fluorophenyl)(3-methyl-3H-imidazol-4-yl)methyl ester. The es-
ter (1.26 g, 4.59 mmol) was treated with NaOH (5.5 mL, 5.5
mmol) in THF (15 mL) and H2O (25 mL) for 1 h at room
temperature. The solution was diluted with saturated aqueous
NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4),
and concentrated to give 0.97 g (91%) of 15. 1H NMR (CD3-
OD): δ 7.75 (t, 1H, J ) 8 Hz), 7.60 (s, 1H), 7.46 (d, 1H, J )
10.4 Hz), 7.39 (d, 1H, J ) 8 Hz), 6.57 (s, 1H), 5.98 (s, 1H),
3.64 (s, 3H).
Alter n a tive P r ep a r a tion of 15. A solution of 5-lithio-1-
methyl-2-(triethylsilyl)-1H-imidazole (17, 0.199 mol) in THF
(500 mL) was prepared at -78 °C as described by Molina.11
The cold solution of 17 was cannulated into a solution of 12
(27.0 g, 0.181 mol) in dry THF (200 mL) over 15 min at -78
°C. The cooling bath was removed, and the mixture was stirred
for 2 h while warming to room temperature. After cooling to 0
°C, the reaction mixture was quenched with saturated NH4Cl
solution. The mixture was acidified with 10% HCl, and the
THF was removed in vacuo. Solid NaHCO3 was added to make
the mixture basic, and this mixture was extracted with EtOAc
(3×). The organic layers were combined, washed with brine,
dried (MgSO4), filtered, and concentrated to dryness to give
28.5 g (68%) of crude 15, which was used without purification
in the preparation of 18.
2-Flu or o-4-[a m in o-(1-m eth yl-1H-im id a zol-5-yl)m eth yl]-
ben zon itr ile (16). Compound 15 (0.542 g, 2.31 mmol) was
dissolved in SOCl2 (15 mL), and the mixture was stirred at
room temperature for 2 h under Ar. The solution was concen-
trated in vacuo and coevaporated three times with CH2Cl2.
The solid was dissolved in CHCl3 (30 mL) and cooled to -78
°C. Gaseous NH3 was bubbled through the solution for 5 min,
and the mixture was stirred for 16 h while warming to room
temperature under Ar. After concentration to dryness and
chromatography (silica gel, 1-2% CH3OH/CH2Cl2 with NH3),
0.372 g (70%) of 16 was obtained. 1H NMR (CDCl3): δ 7.61 (t,
1H, J ) 7.9 Hz), 7.41 (s, 1H), 7.25-7.30 (m, 2H), 6.86 (s, 1H),
5.27 (s, 1H), 3.52 (s, 3H), 1.70 (br s, 2H). MS, m/ z: (M + 1)
231.
2-F lu or o-4-for m ylben zon itr ile (12). Compound 7 (10 g,
0.066 mol) and Et3N (32.3 mL, 0.231 mol) were dissolved in a
mixture of 100 mL of CH2Cl2 and 20 mL of DMSO. While being
stirred, the solution was treated dropwise with a solution of
pyridine-SO3 complex (31.5 g, 0.198 mol) in DMSO (70 mL),
maintaining the reaction mixture temperature between 5 and
10 °C. The reaction mixture was stirred at 5 °C for 1 h after
the addition and at ambient temperature for 1 h. The reaction
mixture was partitioned between CH2Cl2 and H2O. The organic
layer was separated, washed well with H2O and brine, and
dried (Na2SO4). Filtration and concentration gave 8.9 g (90%)
of 12 after purification by chromatography (silica gel, hexane/
EtOAc, 3:1). 1H NMR (CDCl3): δ 10.06 (d, 1H, J ) 2 Hz), 7.86
(dd, 1H, J ) 5, 8 Hz), 7.798 (dd, 1H, J ) 1, 8 Hz), 7.728 (dd,
1H, J ) 1, 8 Hz).
2-Flu or o-4-[h yd r oxy-(1-tr ityl-1H-im id a zol-4-yl)m eth yl]-
ben zon itr ile (13). To a solution of 4-iodo-1-trityl-1H-imida-
zole (10, 5.00 g, 11.5 mmol) in anhydrous CH2Cl2 (30 mL) was
added a 3.0 M solution of EtMgBr (6.58 mL, 19.7 mmol) with
stirring under Ar at room temperature. After 3 h, the reaction
mixture was cooled to -78 °C and a solution of 12 (1.73 g,
11.6 mmol) in CH2Cl2 (20 mL) was added dropwise. The
reaction mixture was allowed to warm to room temperature
over 2 h and quenched with saturated NH4Cl solution. The
2-Flu or o-4-(1-m eth yl-1H-im idazole-5-car bon yl)ben zon i-
tr ile (18). Crude alcohol 15 (28.5 g) was dissolved in CH2Cl2
(400 mL) and treated with MnO2 (100 g, 1.15 mol) at room
temperature. After 2 h, the reaction mixture was filtered
through Celite, and the filter cake was washed with CH2Cl2
and CH3CN. The filtrate was concentrated in vacuo, and the
residue was triturated with hexane/EtOAc to give 19.6 g of
18 (45% for two steps). 1H NMR (CDCl3): δ 7.77-7.81 (m, 1H),
7.70-7.73 (m, 2H), 7.67 (dd, 1H, J ) 1.3, 9 Hz), 7.59 (d, 1H, J
) 1 Hz), 4.03 (s, 3H). MS, m/z: (M + 1) 230.

Transferase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2981
N-[(4-Cya n o-3-flu or op h en yl)(1-m eth yl-1H-im id a zol-5-
yl)m eth ylen e]-2-m eth yl-[S(R)]-p r op a n esu lfin a m id e ((R)-
19). Compound 18 (2.56 g, 11.2 mmol), titanium(IV) ethoxide
(7.02 mL, 33.5 mmol), and commercially available (R)-(+)-2-
methyl-2-propanesulfinamide (1.35 g, 11.2 mmol) were dis-
solved in anhydrous THF (100 mL) and heated at 75 °C for 7
days. The solution was cooled, diluted with brine (100 mL),
and filtered through a Celite pad. The filter cake was washed
generously with EtOAc and H2O. The filtrate was separated,
dried (MgSO4), and purified on silica gel (0-3% MeOH/CH2-
7.56 (s, 1H), 7.39 (t, 1H, J ) 7.9 Hz), 7.19 (d, 1H, J ) 7.7 Hz),
7.13 (d, 1H, J ) 7.3 Hz), 7.03 (s, 1H), 7.00 (d, 1H, J ) 11 Hz),
5.43 (s, 2H), 4.11 (d, 1H, J ) 9.1 Hz), 3.85-3.93 (m, 1H), 3.30-
3.38 (m, 1H), 3.02 (s, 3H), 1.76-2.07 (m, 5H), 1.52-1.63 (m,
1H). MS, m/z: (M + 1) 401. Anal. (C24H25N4O2‚1.00HCl‚
0.65H2O‚0.20CH2Cl2) C, H, N.
4-Im idazol-1-ylm eth yl-2-[3-(2-oxoazepan -3-yl)ph en oxy]-
ben zon itr ile Hyd r och lor id e (22). 1H NMR (CD3OD): δ 9.02
(s, 1H), 7.78 (d, 1H, J ) 7.9 Hz), 7.61 (s, 1H), 7.55 (s, 1H),
7.40 (t, 1H, J ) 8.1 Hz), 7.20 (d, 1H, J ) 7.8 Hz), 7.15 (d, 1H,
J ) 7.7 Hz), 7.03 (s, 1H), 7.00 (s, 2H), 5.42 (s, 2H), 3.95-4.01
(m, 1H), 3.43-3.51 (m, 1H), 3.24-3.33 (m, 1H), 1.78-2.10 (m,
5H), 1.45-1.58 (m, 1H). MS, m/z: (M + 1) 387. Anal.
(C23H22N4O2‚1.00HCl‚0.40CH2Cl2) C, H, N.
2-[3-(3-Eth yl-2-oxoa zep a n -3-yl)p h en oxy]-4-im id a zol-1-
ylm eth ylben zon itr ile (23). 1H NMR (CD3OD): δ 8.98 (s, 1H),
7.82 (d, 1H, J ) 7.9 Hz), 7.58 (s, 2H), 7.47 (t, 1H, J ) 7.9 Hz),
7.22 (d, 1H, J ) 9 Hz), 7.15 (d, 1H, J ) 7.8 Hz), 7.01 (dd, 1H,
J ) 2.4,8.1 Hz), 6.93 (s, 1H), 6.91 (s, 1H), 5.46 (s, 2H), 2.88-
2.95 (m, 1H), 2.60-2.70 (m, 1H), 2.24-2.31 (m, 1H), 1.71-
1.96 (m, 5H), 1.59-1.67 (m, 1H), 1.37-1.48 (m, 1H), 0.78 (t,
3H, J ) 7.3 Hz). MS, m/z: (M + 1) 415. Anal. (C25H26N4O2‚
1.00HCl‚0.10H2O‚0.40CH2Cl2) C, H, N.
2-[3-(3-E t h yl-a zep a n -3-yl)p h en oxy]-4-im id a zol-1-ylm -
et h ylben zon it r ile Bish yd r och lor id e (24). Compounds 9
(0.113 g, 0.560 mmol) and 5k (0.123 g, 0.560 mmol) were
reacted under standard displacement conditions to give 0.045
g (16%) of compound 24. 1H NMR (CD3OD): δ 9.03 (s, 1H),
7.83 (d, 1H, J ) 7.9 Hz), 7.61 (s, 1H), 7.58 (s, 1H), 7.51 (t, 1H,
J ) 8 Hz), 7.30 (d, 1H, J ) 7.9 Hz), 7.19-7.22 (m, 2H), 7.08
(s, 1H), 7.01 (dd, 1H, J ) 2, 8 Hz), 5.50 (s, 2H), 3.80 (d, 1H, J
) 14.5 Hz), 3.36 (d, 1H, J ) 14.5 Hz), 3.12-3.35 (m, 2H), 2.35-
2.44 (m, 1H), 1.83-1.98 (m, 4H), 1.68-1.81 (m, 3H), 0.66 (t,
3H, J ) 7.5 Hz). MS, m/z: (M + 1) 401. Anal. (C25H28N4O1‚
2.00HCl‚0.10H2O‚0.45CH2Cl2) C, H, N.
2-[3-(1-Acetyl-3-eth yla zep a n -3-yl)p h en oxy]-4-im id a zol-
1-ylm eth ylben zon itr ile Hyd r och lor id e (25). Compound 24
(0.116 g, 0.184 mmol), Et3N (0.103 mL, 0.736 mmol), and acetyl
chloride (0.020 mL, 0.276 mmol) were dissolved in anhydrous
CH2Cl2 (5 mL). After 1 h, the reaction mixture was concen-
trated in vacuo and purified using reverse-phase chromatog-
raphy (95:5 to 5:95 H2O/CH3CN with 0.1% TFA, flow ) 65 mL/
min). The compound was converted to its free base using
saturated NaHCO3 solution, extracted with CH2Cl2 (3×), dried
(MgSO4), filtered, and treated with 1 N HCl ethereal solution
to give 0.036 g (41%) of compound 25. 1H NMR (CD3OD): δ
9.00 (s, 1H), 7.81 (d, 1H, J ) 8 Hz), 7.60 (s, 1H), 7.57 (s, 1H),
7.40 (t, 1H, J ) 7.9 Hz), 7.28 (d, 1H, J ) 8.2 Hz), 7.19 (d, 1H,
J ) 8 Hz), 6.93-6.96 (m, 2H), 5.45 (s, 2H), 3.92 (d, 1H, J )
14.2 Hz), 3.73 (d, 1H, J ) 14.2 Hz), 3.55-3.72 (m, 1H), 2.10-
2.20 (m, 1H), 2.07 (s, 3H), 1.65-1.87 (m, 8H), 0.57 (t, 3H, J )
7.4 Hz). MS, m/z: (M + 1) 443. Anal. (C27H30N4O2‚1.00HCl‚
0.35H2O‚0.40CH2Cl2) C, H, N.
1
Cl2) to give 2.94 g (79%) of (R)-19. H NMR (CDCl3): δ 7.70-
7.76 (m, 1H), 7.67 (s, 1H), 7.25-7.34 (m, 2H), 6.93 (s, 1H), 4.04
(s, 3H), 1.29 (s, 9H). MS, m/z: (M + 1) 333.
(S)-19 was identically prepared using (S)-(-)-2-methyl-2-
propanesulfinamide.
(S)-(-)- a n d (R)-(+)-4-[1-Am in o-1-(1-m eth yl-1H-im id a -
zol-5-yl)eth yl]-2-flu or oben zon itr ile Bish ydr och lor ide ((S)-
(-) a n d (R)-(+)-20). Compound (R)-19 (1.50 g, 4.51 mmol)
was dissolved in anhydrous THF (30 mL) at 0 °C, and a 3.0 M
solution of MeMgBr (4.50 mL, 13.5 mmol) in Et2O was added.
The reaction was quenched with aqueous NH4Cl solution, and
the mixture was diluted with saturated NaHCO3 solution and
extracted with CH2Cl2 (3×). The combined organic layers were
dried (MgSO4), filtered, and concentrated to give 1.57 g (99%)
of an 80:20 mixture of 1-((S)/(R))-N-[1-(4-cyano-3-fluorophenyl)-
1-(3-methyl-3H-imidazol-4-yl)ethyl]-2-methyl-[S(R)]-propane-
sulfinamides. Crystallization from 5% hexane in EtOAc gave
the 1-(S)-[S(R)] diastereomer (99% pure) as colorless needles,
1
mp 205-207 °C. H NMR (CDCl3): δ 7.63-7.65 (m, 1H), 7.46
(s, 1H), 7.36 (s, 1H), 7.15-7.17 (m, 2H), 3.75 (s, 1H), 3.08 (s,
3H), 2.08 (s, 3H), 1.28 (s, 9H). Anal. (C17H21N4OSF‚0.35H2O)
C, H, N.
To a solution of this product (0.880 g, 2.51 mmol) in MeOH
(50 mL) was added 50 mL of a 4 M HCl solution in dioxane,
and the mixture was stirred for 1 h at room temperature After
concentration and trituration with EtOAc, 0.47 g (59%) of (S)-
(-)-20 was obtained as the bis HCl salt. [R]D -111.6° (c 1,
EtOH). 1H NMR (CD3OD): δ 9.05 (s, 1H), 7.97 (dd, 1H, J ) 6,
8 Hz), 7.93 (d, 1H, J ) 1.5 Hz), 7.52 (dd, 1H, J ) 2, 10 Hz),
7.43 (dd, 1H, J ) 2, 8 Hz), 3.44 (s, 3H), 2.20 (s, 3H).
Similarly, (R)-(+)-20 ([R]D + 99.6° (c 1,EtOH)) was obtained
from (S)-19. These enantiomeric amines were readily sepa-
rated on an HPLC Chiracel OD column, eluting with 60:40
EtOH/hexane.
2-[3-(3-E t h yl-1-m et h yl-2-oxoa zep a n -3-yl)p h en oxy]-4-
im ida zol-1-ylm eth ylben zon itr ile Hyd r och lor id e (1). Com-
pound 9 (0.045 g, 0.222 mmol), 5c (0.055 g, 0.222 mmol), KF‚
Al2O3 (0.136 g), and 18-crown-6 (0.006 g, 0.023 mmol) were
refluxed in CH3CN (2.5 mL) under Ar for 48 h (subsequently
referred to as standard displacement conditions). The solution
was filtered, concentrated in vacuo, and purified using reverse-
phase chromatography (95:5 to 5:95 H2O/CH3CN with 0.1%
TFA, flow ) 65 mL/min). The compound was converted to the
free base using saturated NaHCO3 solution, extracted with
CH2Cl2 (3×), dried (MgSO4), and filtered. Addition of 1 N HCl
in Et2O gave the hydrochloride salt of racemic 1. 1H NMR (CD3-
OD): δ 9.01 (s, 1H), 7.83 (d, 1H, J ) 7.9 Hz), 7.59 (s, 2H), 7.44
(t, 1H, J ) 7.8 Hz), 7.05 (d, 1H, J ) 7.5 Hz), 6.99 (d, 1H, J )
6.5 Hz), 6.95 (s, 1H), 6.80 (s, 1H), 5.48 (s, 2H), 3.00 (s, 3H),
2.97-3.10 (m, 2H), 2.22-2.27 (m, 1H), 1.71-1.88 (m, 5H),
1.45-1.64 (m, 2H), 0.76 (t, 3H, J ) 7.1 Hz). MS, m/z: (M + 1)
429. Anal. (C26H28N4O2‚1.05HCl‚0.05H2O) C, H, N.
Compound (S)-1 was prepared from (-)-5c. [R]D -22.9° (c
1, EtOH). FAB MS, m/z: (M + 1) 429. Anal. (C26H28N4O2‚
1.50HCl‚1.25H2O) C, H, N.
2-[3-(3-E t h yl-1-m et h yl-2-oxoa zep a n -3-yl)p h en oxy]-4-
(1H-im idazol-5-ylm eth yl)ben zon itr ile Hydr och lor ide (27).
Compounds 11 (0.348 g, 0.784 mmol) and 5c (0.194 mg, 0.784
mmol) were reacted under standard displacement conditions
to give 0.30 g (57%) of 2-[3-(3-ethyl-1-methyl-2-oxoazepan-3-
yl)phenoxy]-4-(1-trityl-1H-imidazol-4-ylmethyl)benzonitrile (26).
Without purification, 26 (0.074 g, 0.110 mmol) was treated
with TFA (2.5 mL) and Et3SiH (0.140 mL, 0.882 mmol) in CH2-
Cl2 (5 mL) at room temperature for 1 h. The solvent was
evaporated and the residue was purified by reverse-phase
chromatography (95:5 to 5:95 H2O/CH3CN with 0.1% TFA, flow
1
) 65 mL/min) to give 0.024 g (47%) of 27. H NMR (CD3OD):
Compound (R)-1 was prepared from (+)-5c. [R]D +22.9° (c
1, EtOH). FAB MS, m/z: (M + 1) 429. Anal. (C26H28N4O2‚
1.00HCl‚1.95H2O) C, H, N.
By use of these standard displacement conditions, com-
pounds 21, 22, and 23 were prepared from 5a , 5i, and 5j,
respectively.
4-Im id a zol-1-ylm et h yl-2-[3-(1-m et h yl-2-oxoa zep a n -3-
yl)p h en oxy]ben zon itr ile Hyd r och lor id e (21). 1H NMR
(CD3OD): δ 9.04 (s, 1H), 7.79 (d, 1H, J ) 7.7 Hz), 7.62 (s, 1H),
δ 8.83 (s, 1H), 7.75 (d, 1H, J ) 7.8 Hz), 7.43 (t, 1H, J ) 7.6
Hz), 7.32 (s, 1H), 7.18 (d, 1H, J ) 7.9 Hz), 7.04 (d, 1H, J ) 7.7
Hz), 6.98 (d, 1H, J ) 7.2 Hz), 6.85 (s, 1H), 6.76 (s, 1H), 4.12 (s,
2H), 2.99 (s, 3H), 2.92-3.11 (m, 2H), 2.20-2.29 (m, 1H), 1.65-
1.92 (m, 5H), 1.40-1.65 (m, 2H), 0.74 (t, 3H, J ) 7.1 Hz). MS,
m/z: (M + 1) 429. Anal. (C26H29N4O2‚1.00HCl‚0.10H2O‚0.35CH2-
Cl2) C, H, N.
2-[3-(3-Eth yl-1-m eth yl-2-oxoa zep a n -3-yl)p h en oxy]-4-(1-
m eth yl-1H-im id a zol-5-ylm eth yl)ben zon itr ile Hyd r och lo-

2982 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
deSolms et al.
1
r id e (28). Dimethyl sulfate (0.014 mL, 0.149 mmol) and 26
(0.100 g, 0.149 mmol) were dissolved in EtOAc (10 mL) and
heated at 60 °C for 18 h under Ar. The reaction mixture was
concentrated in vacuo, triturated with Et2O, dissolved in
MeOH (15 mL), and refluxed for 1 h. The solution was
concentrated in vacuo and purified using reverse-phase chro-
matography (95:5 to 5:95 H2O/CH3CN with 0.1% TFA, flow )
65 mL/min). The compound was converted to its free base
using saturated NaHCO3 solution, extracted with CH2Cl2 (3×),
dried (MgSO4), filtered, and treated with 1 N HCl ethereal
solution to give 0.030 g (42%) of 28. 1H NMR (CD3OD): δ 8.86
(s, 1H), 7.77 (d, 1H, J ) 7.7 Hz), 7.44 (t, 1H, J ) 7.9 Hz), 7.23
(s, 1H), 7.18 (d, 1H, J ) 7.7 Hz), 7.04 (d, 1H, J ) 7.5 Hz), 6.99
(d, 1H, J ) 7.0 Hz), 6.88 (s, 1H), 6.76 (s, 1H), 4.15 (s, 2H),
3.73 (s, 3H), 2.99 (s, 3H), 2.95-3.11 (m, 2H), 2.20-2.29 (m,
1H), 1.65-1.91 (m, 5H), 1.44-1.62 (m, 2H), 0.74 (t, 3H, J )
7.1 Hz). MS, m/z: (M + 1) 443. HRMS calcd for C27H30N4O2
(M + 1)+: 443.2442, found 443.2431.
2-[3-(3-E t h yl-1-m et h yl-2-oxoa zep a n -3-yl)p h en oxy]-4-
[h yd r oxy-(1-m et h yl-1H -im id a zol-5-yl)m et h yl]b en zon i-
tr ile (29). Compounds 15 (0.162 g, 0.700 mmol) and 5c (0.173
g, 0.700 mmol) were reacted under standard displacement
conditions to give 0.118 g (36%) of compound 29. 1H NMR (CD3-
OD): δ 7.74 (d, 1H, J ) 8 Hz), 7.55 (s, 1H), 7.44 (t, 1H, J ) 8
Hz), 7.24 (d, 1H, 8 Hz), 7.00-7.05 (m, 3H), 6.83-6.84 (m, 1H),
6.51 (d, 1H, J ) 7.1 Hz), 5.86 (s, 1H), 3.58 (d, 3H, J ) 3.3 Hz),
2.99 (d, 3H, J ) 4 Hz), 2.90-3.08 (m, 2H), 2.20-2.28 (m, 1H),
1.68-1.89 (m, 5H), 1.51-1.60 (m, 1H), 1.40-1.50 (m, 1H), 0.74
(t, 3H, J ) 7.3 Hz). MS, m/z: (M + 1) 459. Anal. (C27H30N4O3‚
0.30CH2Cl2) C, H, N.
(56%) of 32. H NMR (CDCl3): δ 7.57 (d, 1H, J ) 8 Hz), 7.36
(t, 1H, J ) 7.8 Hz), 7.32 (s, 1H), 6.90-7.07 (m, 5H), 6.78 (s,
1H), 3.24 (s, 3H), 3.02 (s, 3H), 3.04-3.10 (m, 1H), 2.83-2.90
(m, 1H), 2.41-2.51 (m, 1H), 2.12-2.20 (m, 1H), 1.82 (s, 3H),
1.60-1.93 (m, 6H), 1.38-1.50 (m, 1H), 0.74 (t, 3H, J ) 7.2
Hz). HRMS calcd for C28H32N4O3 (M + 1)+: 473.2553, found
473.2600.
Mixtu r e of Dia ster eom er s of 2-[3-(3-Eth yl-1-m eth yl-2-
oxoa zep a n -3-yl)p h en oxy]-4-[1-a m in o-1-(1-m eth yl-1H-im i-
d a zol-5-yl)eth yl]ben zon itr ile (33). Compound 32 (0.099 g,
0.209 mmol) was dissolved in SOCl2 (5 mL), and the mixture
was stirred at room temperature for 2 h. The solution was
concentrated in vacuo and coevaporated with anhydrous CH2-
Cl2 (3×). The solid was dissolved in CHCl3 (5 mL) and cooled
to -78 °C. NH3(g) was bubbled through the solution, and the
mixture was stirred for 2 h while warming to room tempera-
ture under Ar. The solution was concentrated in vacuo and
purified using reverse-phase chromatography (95:5 to 5:95
H2O/CH3CN with 0.1% TFA, flow ) 65 mL/min). The com-
pound was converted to its free base using saturated NaHCO3
solution, extracted with CH2Cl2 (3×), dried (MgSO4), and
1
filtered to give 0.052 g (52%) of 33. H NMR (CD3OD): δ 7.72
(d, 1H, J ) 7.9 Hz), 7.48 (s, 1H), 7.40 (t, 1H, J ) 8.1 Hz), 7.22-
7.28 (m, 1H), 6.96-7.03 (m, 2H), 6.92 (d, 1H, J ) 8 Hz), 6.89
(s, 1H), 6.74-6.78 (m, 1H), 3.25 (s, 3H), 2.99 (s, 3H), 2.92-
3.08 (m, 2H), 2.18-2.27 (m, 1H), 1.66-1.89 (m, 5H), 1.73 (s,
3H), 1.55-1.65 (m, 1H), 1.40-1.53 (m, 1H), 0.74 (t, 3H, J )
7.3 Hz). MS, m/z: (M + 1) 472. Anal. (C28H33N5O2‚0.35EtOAc)
C, H, N.
All four diastereomers of 33 were independently prepared
using the standard displacement conditions described for
compound 1 using the resolved intermediates 5c and 20.
(S)-(-)-5c and (S)-(-)-20 gave 33a . 1H NMR (CD3OD): δ
7.72 (d, 1H, J ) 8 Hz), 7.52 (s, 1H), 7.40 (t, 1H, J ) 8 Hz),
7.24 (dd, 1H, J ) 1.5, 8 Hz), 6.98-7.01 (m, 2H), 6.93 (dd, 1H,
J ) 2, 8 Hz), 6.89 (d, 1H, J ) 1.5 Hz), 6.77 (s,1H), 3.26 (s,
3H), 2.99 (s, 3H), 2.92-3.08 (m, 2H), 2.21-2.27 (m, 1H), 1.66-
1.89 (m, 5H), 1.73 (s, 3H), 1.55-1.65 (m, 1H), 1.40-1.53 (m,
1H), 0.74 (t, 3H, J ) 7.3 Hz). MS, m/z: (M + 1) 472. Anal.
(C28H33N5O2‚0.70H2O) C, H, N.
4-[Am in o-(1-m et h yl-1H -im id a zol-5-yl)m et h yl]-2-[3-(3-
et h yl-1-m et h yl-2-oxoa zep a n -3-yl)p h en oxy]b en zon it r ile
(30). Compound 29 (0.093 g, 0.202 mmol) was dissolved in
SOCl2 (5 mL), and the mixture was stirred at room temper-
ature for 2 h under Ar. The solution was concentrated in vacuo
and coevaporated with CH2Cl2 (3×). The solid was dissolved
in CHCl3 (20 mL), and the solution was cooled to -78 °C. NH3-
(g) was bubbled through the solution, and the solution was
stirred for 16 h while warming to room temperature under
Ar. The solution was concentrated in vacuo and purified using
reverse-phase chromatography (95:5 to 5:95 H2O/CH3CN with
0.1% TFA, flow ) 65 mL/min). The compound was converted
to its free base using saturated NaHCO3 solution, extracted
with CH2Cl2 (3×), dried (MgSO4), filtered, and concentrated
(R)-(+)-5c and (S)-(-)-20 gave 33b. 1H NMR (CD3OD): δ
7.72 (d, 1H, J ) 8 Hz), 7.48 (s, 1H), 7.40 (t, 1H, J ) 8 Hz),
7.25 (dd, 1H, J ) 1.5, 8 Hz), 6.99-7.01 (m, 2H), 6.93 (dd, 1H,
J ) 2, 8 Hz), 6.89 (d, 1H, J ) 1.5 Hz), 6.75 (t, 1H, J ) 2 Hz),
3.25 (s, 3H), 2.99 (s, 3H), 2.92-3.08 (m, 2H), 2.21-2.27 (m,
1H), 1.66-1.89 (m, 5H), 1.73 (s, 3H), 1.55-1.65 (m, 1H), 1.40-
1.53 (m, 1H), 0.74 (t, 3H, J ) 7.3 Hz). MS, m/z: (M + 1) 472.
Anal. (C28H33N5O2) C, H, N.
(S)-(-)-5c and (R)-(+)-20 gave 33c. 1H NMR (CD3OD): δ
7.72 (d, 1H, J ) 8 Hz), 7.52 (s, 1H), 7.40 (t, 1H, J ) 8 Hz),
7.24 (dd, 1H, J ) 1.5, 8 Hz), 6.98-7.01 (m, 2H), 6.93 (dd, 1H,
J ) 2, 8 Hz), 6.89 (d, 1H, J ) 1.5 Hz), 6.77 (s,1H), 3.26 (s,
3H), 2.99 (s, 3H), 2.92-3.08 (m, 2H), 2.21-2.27 (m, 1H), 1.66-
1.89 (m, 5H), 1.73 (s, 3H), 1.55-1.65 (m, 1H), 1.40-1.53 (m,
1H), 0.74 (t, 3H, J ) 7.3 Hz). MS, m/z: (M + 1) 472. Anal.
(C28H33N5O2‚0.70H2O‚0.25H2O) C, H, N.
1
to give 0.031 g (34%) of 30. H NMR (CDCl3): δ 7.63 (t, 1H, J
) 7.7 Hz), 7.34-7.40 (m, 2H), 7.06-7.16 (m, 1H), 6.97-7.04
(m, 1H), 6.78-6.96 (m, 3H), 6.73 (s, 1H), 5.10 (s, 1H), 3.47 (s,
3H), 3.03 (s, 3H), 3.02-3.10 (m, 1H), 2.82-2.90 (m, 1H), 2.13-
2.22 (m, 1H), 1.67-1.95 (m, 7H), 1.53-1.62 (m, 1H), 1.39-
1.51 (m, 1H), 0.75 (t, 3H, J ) 7.1 Hz). MS, m/z: (M + 1) 458.
Anal. (C27H31N5O2‚0.35H2O) C, H, N.
2-[3-(3-Eth yl-1-m eth yl-2-oxoa zep a n -3-yl)p h en oxy]-4-(1-
m eth yl-1H-im id a zole-5-ca r bon yl)ben zon itr ile Tr iflu or o-
a ceta te (31). Compounds 16 (0.012 g, 0.052 mmol) and 5c
(0.014 g, 0.056 mmol) were reacted under standard displace-
ment conditions to give 0.010 g (33%) of compound 31, which
was isolated as the TFA salt after reverse-phase HPLC. 1H
NMR (CD3OD): δ 8.85 (s, 1H), 8.00 (s, 1H), 7.97 (d, 1H, J ) 8
Hz), 7.70 (dd, 1H, J ) 2, 8 Hz), 7.50 (t, 1H, J ) 8 Hz), 7.31 (s,
1H), 7.06-7.13 (m, 2H), 6.92 (s, 1H), 4.09 (s, 3H), 3.01 (s, 3H),
2.97-3.13 (m, 2H), 2.23-2.32 (m, 1H), 1.70-1.94 (m, 5H),
1.42-1.69 (m, 2H), 0.76 (t, 3H, J ) 7.3 Hz). MS, m/z: (M + 1)
457. HRMS calcd for C27H28N4O3 (M + 1)+: 457.2234, found
457.2232.
(R)-(+)-5c and (R)-(+)-20 gave 33d . 1H NMR (CD3OD): δ
7.72 (d, 1H, J ) 8 Hz), 7.49 (s, 1H), 7.40 (t, 1H, J ) 8 Hz),
7.24 (dd, 1H, J ) 1.5, 8 Hz), 6.98-7.01 (m, 2H), 6.93 (dd, 1H,
J ) 2, 8 Hz), 6.88 (d, 1H, J ) 1.5 Hz), 6.77 (t, 1H, J ) 2 Hz),
3.25 (s, 3H), 2.99 (s, 3H), 2.92-3.08 (m, 2H), 2.21-2.27 (m,
1H), 1.66-1.89 (m, 5H), 1.73 (s, 3H), 1.55-1.65 (m, 1H), 1.40-
1.53 (m, 1H), 0.74 (t, 3H, J ) 7.3 Hz). MS, m/z: (M + 1) 472.
Anal. (C28H33N5O2‚0.65H2O) C, H, N.
2-[3-(3-Eth yl-1-m eth yl-2-oxoa zep a n -3-yl)p h en oxy]-4-[1-
h yd r oxy-1-(1-m e t h yl-1H -im id a zol-5-yl)e t h yl]b e n zon i-
tr ile (32). To a solution of 31 (0.216 g, 0.473 mmol) in
anhydrous THF (10 mL) was added a 3.0 M solution of
MeMgBr (1.10 mL, 3.30 mmol) with stirring at room temper-
ature. The reaction was quenched with NH4Cl after 1 h and
the mixture was concentrated, diluted with EtOAc, washed
with saturated NaHCO3 solution, water, and brine, dried
(MgSO4), concentrated, and purified by silica gel chromatog-
raphy (1-3% MeOH/CH2Cl2 with NH4OH) to give 0.125 g
Except for compound 34, the final compounds listed in Table
4 were prepared by the standard displacement reaction of (S)-
(-)-20 with the requisite phenol (-)-5. Compound 34 was
obtained from (S)-(-)-20 and racemic 5b. Note that the
assignment of the absolute configuration14 of compounds 5
(except for 5c) was not rigorously determined but inferred to
be analogous to 5c based on their common levorotatory nature,
their consistent relative retention time upon chiral-phase
HPLC, and the rank order of enzyme inhibitory potency of the
diastereomers of 34-40 (data not shown).

Transferase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 2983
Ta ble 5. Data and Refinement Statistics: HFTase + FPP +
2-[3-(1-Meth yl-2-oxoa zep a n -3(R,S)-yl)p h en oxy]-4-[1(S)-
a m in o-1-(1-m et h yl-1H -im id a zol-5-yl)et h yl]b en zon it r ile
Bistr iflu or oa ceta te (34). H NMR (CD3OD): δ 8.47 (d, 1H,
J ) 8 Hz), 7.86 (t, 1H, J ) 8 Hz), 7.55-7.60 (m, 1H,), 7.40 (q,
1H, J ) 8 Hz), 7.01-7.18 (m, 5H), 4.09-4.14 (m, 1H), 3.86-
3.95 (m, 1H), 3.35-3.45 (m, 1H), 3.37 (d, 3H, J ) 9 Hz), 3.00
(d, 3H, J ) 10.5 Hz), 2.01 (d, 3H, J ) 13.5 Hz), 1.80-2.00 (m,
5H), 1.49-1.62 (m, 1H). MS, m/z: (M + 1) 444. Anal.
(C26H31N5O2‚2.15CF3CO2H‚0.25H2O) C, H, N.
33a
1
resolution, Å
total reflections
unique reflections
37-2.0
278 618
75 205
7.8 (34.1)a
14.4 (2.3)a
94.7 (82.4)a
17.9
R
sym, %
average I/σ
completeness F > 0σ(F), %
R
R
work, %
free, %
20.8
2-[3-(1,3-Dim eth yl-2-oxoazepan -3(S)-yl)ph en oxy]-4-[1(S)-
a m in o-1-(1-m et h yl-1H -im id a zol-5-yl)et h yl]b en zon it r ile
number of residues
710
1
number of solvent molecules
average B factor, Å2
rmsd bond angle, deg
rmsd bond length, Å
690
21.9
1.17
0.006
Bistr iflu or oa ceta te (35). H NMR (CD3OD): δ 8.53 (s, 1H),
7.88 (d, 1H, J ) 8.2 Hz), 7.55 (s, 1H), 7.46 (t, 1H, J ) 8 Hz),
7.26 (dd, 1H, J ) 1.6, 8 Hz), 7.09 (d, 1H, J ) 7.7 Hz), 7.02 (d,
1H, J ) 1.5 Hz), 6.99 (dd, 1H, J ) 1.6, 8 Hz), 6.79 (s, 1H),
3.42 (s, 3H), 3.02 (s, 3H), 2.97-3.06 (m, 2H), 2.27-2.34 (m,
1H), 1.97 (s, 3H), 1.75-1.89 (m, 3H), 1.58-1.68 (m, 1H), 1.42-
1.53 (m, 1H), 1.34 (s, 3H). HRMS calcd for C27H31N5O2 (M +
1)+: 458.2551, found 458.2576.
a
Highest resolution bin.
In h ibition Assa ys. Inhibition of FTase is reported as an
IC50, the concentration of compound required to inhibit 50%
of the recombinant human FTase-catalyzed incorporation of
[3H]FPP into recombinant Ras-CVIM (a fusion protein that
consists of part yeast Ras1 sequence and part human Ras
sequence with the CaaX box of K-Ras). For details of the
method, see refs 19 and 20.
For GGTase-I, the IC50 is the concentration of compound
required to inhibit 50% of the human GGTase-I-catalyzed
incorporation of [3H]GGPP into a biotinylated peptide corre-
sponding to the C-terminus of human K-Ras. For the qualita-
tive determination of competition between inhibitors and
geranylgeranyl pyrophosphate (GGPP), IC50 values were de-
termined at 20, 100, and 500 nM GGPP. The following slopes
of the plots of IC50 vs [GGPP] were observed: 33a , -0.09; 35,
-0.28; 36, -0.19; 37, -0.03; 38, -0.09; 39, -0.19. Slopes of
<0 indicate that binding is not competitive with GGPP and
are consistent with uncompetitive binding. Details of these
assays are found in ref 17.
Cell-Ba sed Assa ys. To determine the potential of these
compounds to exhibit dual FTase/GGTase-I inhibition in vivo
and to consequently inhibit the prenylation of K-Ras, selected
compounds were tested in PSN-1 pancreatic tumor cells as
described by Lobell et al.18 Briefly, tumor cells were treated
for 24 h with inhibitors. The cell lysates were subjected to
SDS-PAGE and Western blot using antibodies specific for
hDJ 2, Rap1a, or K-Ras. Unprocessed and prenylated proteins
were distinguished by virtue of their different electrophoretic
mobilities.
An im a l Stu d ies. As described in detail in ref 18, nude mice
bearing PSN-1 tumor xenografts were treated with compounds
33a and 38 by constant infusion for 24-72 h using implanted
Alzet osmotic pumps. Doses ranged from 240 to 1920 mpk/
day, which afforded plasma levels of 2-15 uM.
Cr ysta llogr a p h y Meth od s. Human farnesyltransferase
was concentrated to 10 mg/mL and combined with FPP and
inhibitor dissolved in 25 mM DMSO in a 1:3:1.5 molar ratio.
Diffraction quality crystals were grown using the hanging drop
vapor diffusion method from a mother liquor of 200-400 mM
ammonium acetate and 12-14% PEG 8K, pH 5.3-5.5, at 17
°C. Diffraction data were collected at cryogenic temperature
using an R-axis IV image plate (Molecular Structure Corpora-
tion) mounted on a Rigaku RU-200 rotating anode X-ray source
with double mirror optics. Data were reduced using DENZO
and SCALEPACK.21 The space group of the crystals was
determined to be P61 with cell dimensions a ) b ) 178.4 Å
and c ) 64.6 Å. Phases were obtained by molecular replace-
ment with human farnesyltransferase, PDB accesssion number
1J CQ.22 Model building proceeded using the program O,23 and
the coordinates were refined using the program CNS.24 Dif-
fraction data and final refinement statistics are summarized
in Table 5. Coordinates have been deposited in the Protein
Data Bank with accession number 1MZC.
2-[3-(3(S)-P r op yl-1-m eth yl-2-oxoa zep a n -3-yl)p h en oxy]-
4-[1(S)-a m in o-1-(1-m et h yl-1H -im id a zol-5-yl)et h yl]b en -
zon itr ile Bistr iflu or oa ceta te (36). 1H NMR (CD3OD):
δ
8.56 (s, 1H), 7.86 (d, 1H, J ) 8 Hz), 7.57 (d, 1H, J ) 1.3 Hz),
7.44 (t, 1H, J ) 8 Hz), 7.22 (dd, 1H, J ) 1.7, 8 Hz), 7.09 (d,
1H, J ) 1.6 Hz), 7.07 (d, 1H, J ) 7.7 Hz), 6.97 (dd, 1H, J )
2.4, 8 Hz), 6.78 (t, 1H, J ) 2 Hz), 3.44 (s, 3H), 3.00 (s, 3H),
2.96-3.10 (m, 2H), 2.24-3.02 (m, 1H), 1.97 (s, 3H), 1.84-1.949
(m, 2H), 1.64-1.78 (m, 3H), 1.46-1.64 (m, 2H), 1.20-1.33 (m,
1H), 1.05-1.16 (m, 1H), 0.82 (t, 3H, J ) 7.3 Hz). HRMS calcd
for C27H31N5O2 (M + 1)+: 486.2864, found 486.2870.
2-[3-(3(R)-Cyclop r op ylm eth yl-1-m eth yl-2-oxoa zep a n -3-
yl)p h en oxy]-4-[1(S)-a m in o-1-(1-m eth yl-1H-im id a zol-5-yl)-
eth yl]ben zon itr ile (37). 1H NMR (CD3OD): δ 7.72 (d, 1H, J
) 8 Hz), 7.49 (s, 1H), 7.38 (t, 1H, J ) 8 Hz), 7.25 (dd, 1H, J )
1.6, 8 Hz), 7.03 (d, 1H, J ) 8 Hz), 6.98 (d, 1H, J ) 1.3 Hz),
6.91-6.94 (m, 2H), 6.81 (t, 1H, J ) 2 Hz), 3.26 (s, 3H), 3.01 (s,
3H), 2.92-3.07 (m, 2H), 2.39-2.46 (m, 1H), 1.97 (s, 3H), 1.84-
1.95 (m, 2H), 1.73 (s, 3H), 1.68-1.83 (m, 2H), 1.55-1.67 (m,
2H), 1.40-1.53 (m, 1H), 0.67-0.78 (m, 1H), 0.17-0.31 (m, 1H),
-0.18 to -0.26 (m, 1H), -0.29 to -0.36 (m, 1H). MS, m/z: (M
+ 1) 498. Anal. (C30H35N5O2‚0.40H2O) C, H, N.
2-[3-(1-Meth yl-2-oxo-3-(R)-(3,3,3-tr iflu or opr opyl)azepan -
3-yl)p h en oxy]-4-[1(S)-a m in o-1-(1-m eth yl-1H-im id a zol-5-
yl)eth yl]ben zon itr ile (38). 1H NMR (CD3OD): δ 7.75 (d, 1H,
J ) 8.2 Hz), 7.66 (s, 1H), 7.46 (t, 1H, J ) 8 Hz), 7.22 (dd, 1H,
J ) 1.6, 8 Hz), 7.09 (s, 1H), 7.05 (d, 1H, J ) 7.5 Hz), 6.96-
7.09 (m, 2H), 6.83 (s, 1H), 3.30 (s, 3H), 3.01 (s, 3H), 2.96-3.09
(m, 2H), 2.24-2.36 (m, 2H), 1.99-2.08 (m, 1H), 1.74-1.94 (m,
5H), 1.77 (s, 3H), 1.58-1.66 (m, 1H), 1.41-1.53 (m, 1H). MS,
m/z: (M + 1) 540. Anal. (C29H32N5O2F2‚0.65H2O) C, H, N.
2-[3-(3(S)-n -Bu tyl-1-m eth yl-2-oxoazepan -3-yl)ph en oxy]-
4-[1(S)-a m in o-1-(1-m et h yl-1H -im id a zol-5-yl)et h yl]b en -
zon itr ile Bistr iflu or oa ceta te (39). 1H NMR (CD3OD):
δ
8.61 (s, 1H), 7.88 (d, 1H, J ) 8 Hz), 7.60 (d, 1H, J ) 1.53 Hz),
7.43 (t, 1H, J ) 8 Hz), 7.24 (dd, 1H, J ) 1.7, 8 Hz), 7.12 (d,
1H, J ) 1.7 Hz), 7.06 (d, 1H, J ) 8.6 Hz), 6.95 (dd, 1H, J )
1.6, 7.5 Hz), 6.79 (t, 1H, J ) 2 Hz), 3.44 (s, 3H), 3.00 (s, 3H),
2.96-3.09 (m, 2H), 2.23-3.00 (m, 1H), 1.98 (s, 3H), 1.82-1.96
(m, 2H), 1.67-1.77 (m, 3H), 1.47-1.62 (m, 2H), 1.17-1.27 (m,
3H), 1.07-1.17 (m, 1H), 0.84 (t, 3H, J ) 7.3 Hz). MS, m/z: (M
+ 1) 500. Anal. (C30H39N5O2‚2.50CF3CO2H‚1.0H2O) C, H, N.
2-[3-(3(R)-Cyclop r op ylet h yl-1-m et h yl-2-oxoa zep a n -3-
yl)p h en oxy]-4-[1(S)-a m in o-1-(1-m eth yl-1H-im id a zol-5-yl)-
eth yl]ben zon itr ile Bistr iflu or oa ceta te (40). 1H NMR (CD3-
OD): δ 8.55 (s, 1H), 7.86 (d, 1H, J ) 8 Hz), 7.57 (d, 1H, J )
1.1 Hz), 7.43 (t, 1H, J ) 8 Hz), 7.22 (dd, 1H, J ) 1.8, 8 Hz),
7.11 (d, 1H, J ) 1.8 Hz), 7.06 (d, 1H, J ) 8 Hz), 6.95 (dd, 1H,
J ) 2.3, 7.5 Hz), 6.78 (t, 1H, J ) 1.8 Hz), 3.44 (s, 3H), 2.99 (s,
3H), 2.90-3.09 (m, 2H), 2.21-2.28 (m, 1H), 1.97 (s, 3H), 1.78-
1.93 (m, 4H), 1.68-1.78 (m, 1H), 1.43-1.62 (m, 2H), 1.12-
1.22 (m, 1H), 0.95 -1.05 (m, 1H), 0.49-0.59 (m, 1H), 0.30-
0.37 (m, 2H), -0.05 to 0.05 (m, 2H), -0.04 to -0.10 (m, 2H).
Su p p or tin g In for m a tion Ava ila ble: Details from the
crystallographic structure determination of 5l. This material
is available free of charge via the Internet at http://pubs.
acs.org.
HRMS calcd for
512.2991.
C
31H39N5O2 (M + 1)+: 512.3020, found

2984 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
deSolms et al.
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Oliff, A. I. Design and in Vivo Analysis of Potent Non-Thiol
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