Design, Synthesis, and Biological Activity of 4-[(4-Cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as Potent and Selective Farnesyltransferase Inhibitors

Article abstract of DOI:10.1021/jm030434f

A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-

Full text of DOI:10.1021/jm030434f

612
J . Med. Chem. 2004, 47, 612-626
Design , Syn th esis, a n d Biologica l Activity of
4-[(4-Cya n o-2-a r ylben zyloxy)-(3-m eth yl-3H-im id a zol-4-yl)m eth yl]ben zon itr iles a s
P oten t a n d Selective F a r n esyltr a n sfer a se In h ibitor s
Le Wang,* Gary T. Wang, Xilu Wang, Yunsong Tong, Gerry Sullivan, David Park, Nicholas M. Leonard,†
Qun Li, J erry Cohen, Wen-Zhen Gu, Haiying Zhang, J oy L. Bauch, Clarissa G. J akob, Charles W. Hutchins,
Vincent S. Stoll, Kennan Marsh, Saul H. Rosenberg, Hing L. Sham, and Nan-Horng Lin
Globe Pharmaceutical R & D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101
Received September 3, 2003
A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles
have been synthesized as selective farnesyltransferase inhibitors using structure-based design.
X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed
our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I
binding site could be one possible reason to explain the improved selectivity for this new series
of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent
cellular activity (EC50 ) 3.5 nM) and outstanding pharmacokinetic profiles in dog (96%
bioavailable, 18.4 h oral t1/2, and 0.19 L/(h‚kg) plasma clearance).
Ch a r t 1
Mutated Ras proteins, found in over 30% of human
cancers, and particularly in 50% of colon and over 95%
of pancreatic cancers, are constitutively activated and
lead to uncontrolled cell division due to the loss of their
normal GTPase functions. Among several post-transla-
tional modifications, the S-farnesylation of the C-
terminal cysteine residue of Ras proteins catalyzed by
a zinc metalloenzyme farnesyltransferase (FTase) is the
critical step that enables the Ras proteins to participate
in the transduction of extracellular mitogenic signals
to the nucleus.1 It has been shown that inhibitors of
FTase can stop protein farnesylation and suppress the
growth of Ras-dependent tumor cells both in cell culture
and in rodents.2 Recently, there has been growing
evidence that Ras may not be the only substrate of
FTase associated with oncogenesis. RhoB, for example,
another member of the class of small GTPases that
regulates receptor trafficking, was proposed as a poten-
tial target for FTase inhibitor.3 There is also evidence
suggesting that CENP-E and CENP-F, centromere-
associated proteins, are the pertinent targets of FTase
inhibitors, since functional association of CENP-E with
microtubles seems to require farnesylation.4 While the
exact mechanism by which FTase inhibitors exert their
antitumor activity still remains controversial, FTase
inhibitors are promising agents in cancer therapy
because of their excellent efficacy and low systemic
toxicity in preclinical animal models.
FTase inhibitor design has evolved from early thiol-
containing peptidimimetics to recent non-thiol, non-
peptidic, and imidazole-containing chemical entities.
This is highlighted by the advancement of several potent
inhibitors, most of which have an imidazole moiety that
interacts with zinc in the FTase binding site, to clinical
* To whom correspondence should be addressed. Phone: (847) 935-
4952. Fax: (847) 935-5165. E-mail: le.wang@abbott.com.
† Summer student from Department of Chemistry at Illinois Wes-
leyan University. Currently a Ph.D. student in Department of Chem-
istry at University of California, Irvine.
trials (Chart 1).5 Compounds R115777, SCH66366, and
BMS-214662 are reported to be highly selective inhibi-
tors of FTase vs geranylgeranyltransferase-I (GGTase-
10.1021/jm030434f CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/06/2004

Benzonitriles as Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 613
Sch em e 1a
I), while L-778,123 is a dual inhibitor with an inhibitory
activity of 98 nM against GGTase-I.
In our continuing effort to identify novel FTase
inhibitors,6 compound A315493 was discovered to have
a strong inhibitory activity against FTase (IC50 ) 0.4
nM) with potent cellular activity (EC50 ) 8 nM). It
exhibits good pharmaockinetic properties in dog and
monkey.7 However, A315493 is a potent GGTase-I
inhibitor as well (IC50 ) 24 nM). It has been documented
that a far great number of proteins are post-transla-
tionally modified with geranylgeranyl groups while
about 50 mammalian proteins are the substrates of
FTase.8 Although inhibitors of GGTase-I have shown
in vivo efficacy,9 they are likely to cause severe, non-
specific side effects resulting from inhibition of other
critical cellular processes. Indeed, in a recently pub-
lished paper, Lobell and co-workers demonstrated that
using either a combination of an FTase inhibitor and a
GGTase inhibitor or a dual prenyltransferase inhibitor,
although eliciting a greater apoptotic response in vitro,
significantly shortened the duration of treatment in
mouse because of toxicity. They concluded that the
therapeutic benefit offered by inhibiting oncogenic Ki-
Ras through dual prenyltransferase inhibitor therapy
is then limited.10
a
Reagents and conditions: (a) n-BuLi, THF, -78 °C; (b) TESCl;
(c) t-BuLi, THF, -78 °C; (d) ArCHO; (e) HCl(aq); (f) LDA, THF,
-78 °C, then 4-CN-PhCHO.
To solve the selectivity issue with A315493, we took
a close look at R115777, a selective FTase inhibitor. It
is worthwhile to point out that both A315493 and
R115777 share quite a few common binding character-
istics. Both of them have an N-methylimidazole ring
that presumably interacts with the zinc ion in the
catalytic site of FTase. From a 3-D model, it appears
that the 5-cyano-2-pyridyl group of A315493 occupies
the same site as the N-methylquinolin-2-one of R115777.
The cyano group next to the 1-naphthyl of A315493 and
the 4-chlorophenyl group of R115777 point into the same
region. However, 1-naphthyl of A315493 and 3-chlo-
rophenyl of R115777 clearly bind differently in the
active site. We suspect that this binding difference may
contribute to the potent GGTase-I activity for A315493
in that both A315493 and R115777 have comparable
inhibitory activity against FTase. On the basis of the
analysis above, we decided to move the 1-naphthyl
group in the upper phenyl ring of A315493 to its lower
phenyl ring, leading to compounds with a general
structure 1 shown in Chart 1. In doing so, we hoped
that analogues of compound 1 would not have the
FTase/GGTase selectivity problem that was found for
A315493 yet still maintain potent enzymatic and cel-
lular activity and good pharmacokinetic properties. In
this report, the synthesis, SAR study, and pharmaco-
kinetic evaluation of the derivatives of compound 1 are
described.
Sch em e 2a
a
Reagents and conditions: (a) NBS, AIBN, CCl4; (b) Ag2O, 4a ,
CH2Cl2; (c) Pd(PPh3)4, ArB(OH)2, Na2CO3, toluene, H2O.
anobenzaldehyde to give alcohol 4h . Treatment of
4-chororpyridine 3d with LDA followed by addition of
4-cyanobenzaldehyde generated the alcohol 4i.
The synthesis of compounds 7-11 proceeded as shown
in Scheme 2. 2-Iodo-4-chlorotoluene 5 was brominated
with NBS and AIBN in CCl4 to give the corresponding
benzyl bromide, which then reacted with the alcohol 4a
to afford benzyl ether 6. Suzuki coupling between
various arylboronic acids and 6 provided compounds
7-11. The synthesis of compounds 15-19 and 22-30
is described in Scheme 3. Cyanation of 4-bromo-2-
aminotoluene 12 with Zn(CN)2 and Pd(PPh3)4 in DMF
followed by the treatment with NaNO2, HCl, and KI
afforded 4-cyano-2-iodotoluene 13. The preparation of
compounds 15-19 and 22-30 from 13 was conducted
in a manner similar to that of compounds 7-11. Scheme
4 details the preparation of compounds 33-36. Suzuki
coupling of 2-bromo-4-nitrotoluene 31 with 3-methoxy-
benzene boronic acid gave the biaryl compound 32 in
high yield. Bromination of 32 with NBS and AIBN in
CCl4 afforded the corresponding benzyl bromide, which
was coupled with the alcohol 4a to form benzyl ether
33. Reduction of the nitro group of 33 with SnCl2 and
HCl gave the corresponding amino compound 34. Reac-
Ch em istr y
The synthesis of secondary alcohols 4a -i is described
in Scheme 1. Thus, N-methylimidazole was sequentially
treated with n-BuLi and triethylsilyl chloride to afford
2-triethylsilyl N-methylimidazole 3a . Lithiation of 3a
with t-BuLi followed by addition of substituted benzal-
dehydes provided the alcohols 4a -f. Alcohol 4g was
prepared in a way similar to that of 4a starting from
the thiazole 2b. 2-Methyl-N-methylimidazole 3c was
lithiated with t-BuLi and then quenched with 4-cy-

614 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Wang et al.
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (a) Zn(CN)2, Pd(PPh3)4, DMF, 110
°C; (b) NaNO2, HCl, KI; (c) NBS, CCl4, AIBN; (d) Ag2O, CH2Cl2,
4a ; (i) Pd(PPh3)4, ArB(OH)2, Na2CO3, toluene, H2O.
Sch em e 4a
a
Reagents and conditions: (a) Pd(PPh3)4, Na2CO3, H2O, toluene,
3-CH3OPhB(OH)2; (b) NBS, CCl4, AIBN; (c) Ag2O, CH2Cl2, 4a ; (d)
LiOH, H2O; (e) SnCl2‚2H2O, HCl, MeOH, room temp; (f) NaNO2,
HCl, KI; (g) Zn(CN)2, Pd(PPh3)4, DMF; (h) DIBAL, toluene; (i)
PBr3, LiBr, DMF.
Sch em e 6a
a
Reagents and conditions: (a) Pd(PPh3)4, Na2CO3, H2O, toluene,
3-CH3OPhB(OH)2; (b) NBS, CCl4, AIBN; (c) Ag2O, CH2Cl2, 4a ; (d)
SnCl2, HCl, EtOH; (e) CH3SO2Cl, CH2Cl2, pyridine; (f) EDC, HOBt,
HO2CCH2N(CH3)2, DMF.
tion of 34 with either CH3SO2Cl or (CH3)2NCH2CO2H
generated the sulfonamide 35 or amide 36, respectively.
The synthesis of 39, 40, and 45 is depicted in Scheme
5. Compound 39 was prepared in a manner similar to
the synthesis of 33. Hydrolysis of 39 gave compound 40.
Aniline 42 was prepared by Suzuki coupling between
41 and 3-methoxybenzene boronic acid followed by
reduction with SnCl2 and HCl in methanol. Conversion
of aniline 42 to its corresponding iodo derivative with
NaNO2 in HCl followed by cyanation with Zn(CN)2 and
Pd(PPh3)4 in DMF gave the corresponding cyano com-
pound 43. Benzyl alcohol 44 was obtained from the
reaction of 43 with DIBAl in toluene. Treatment of 44
with PBr3 and LiBr in DMF provided the corresponding
benzyl bromide, which was then coupled with the
alcohol 4a to afford compound 45.
a
Reagents and conditions: (a) Pd(PPh3)4, ArB(OH)2, Na2CO3,
toluene, H2O; (b) NBS, CCl4, AIBN; (c) Ag2O, CH2Cl2, 4b-f and
4i; (d) NaH, DME, 4g,h .
Scheme 7 describes the preparation of compounds
60a -c, 61, and 62. Amino compound 58 was synthe-
sized in a manner similar to the preparation of com-
pound 34. Reaction of 58 with various arylsulfonyl
chlorides afforded sulfonamides 59a -d , which were
converted to the corresponding cyano derivatives 60a -d
with Zn(CN)2 and Pd(PPh3)4 in DMF. Reductive ami-
nation of 58 with 3,5-difluorobenzaldehyde followed by
cyanation gave compound 61. Similarly, amidation of
58 with benzoic chloride followed by cyanation gener-
ated compound 62.
Compounds 47-55 were prepared as shown in Scheme
6. Biaryl compounds 46a -c were synthesized by Suzuki
coupling of 4-cyano-2-iodotoluene 13 with the corre-
sponding arylboronic acids in excellent yields. Bromi-
nation of 46a -c with NBS and AIBN followed by the
coupling with various alcohols (4b-i) in the presence
of Ag2O gave compounds 47-55.
Compounds 64 and 65 were prepared as shown in
Scheme 8. Methoxy carbonylation of 4-cyano-2-iodo-
toluene 13 afforded 4-cyano-4-carbomethoxyltoluene,
which was converted to its corresponding benzyl bro-

Benzonitriles as Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 615
Sch em e 7a
less potent. It is necessary to point out that placing an
aryl group ortho to the cyano group of the lower benzene
ring resulted in significant loss in biological activities
(data not shown).
With this encouraging result, we started a systematic
SAR study that led to several interesting findings (Table
1). It appeared that the substitution pattern on the aryl
group is important for enzymatic and cellular activity,
especially when R ) Cl. The substituent at the 3-posi-
tion of the aryl group resulted in the best enzymatic
activity against FTase as shown by compounds 7-9.
When R ) CN, however, the difference in enzymatic
activity against FTase resulting from 3- and 4-substi-
tuted aryl groups became indistinguishable as demon-
strated by compounds 20, 24, 26, and 27. The cellular
activity is a different case. It is clear that compounds
with 3-substitued aryl groups exhibit much better
activity than those with 4-substituted aryl groups in the
whole-cell assay, demonstrated by compounds 19, 24,
26, and 27.
Although, with the exception of compound 25, differ-
ent substituents at the 3-position on the aryl group have
little effect on the enzymatic activity against FTase,
they show profound influence on the cellular activity
when R is either a chlorine or a cyano group. For
example, compound 11 bearing a 3-ethoxyphenyl shows
more than 80-fold improvement in cellular activity over
the 3-chlorophenyl. A similar observation was also noted
when R ) CN, as demonstrated by compounds 18 and
24. Compared to A315493, most of the compounds have
demonstrated better cellular activity when R ) CN. This
was another pleasant surprise for this new series of
FTase inhibitors.
a
Reagents and conditions: (a) NBS, CCl4, AIBN; (b) Ag2O,
CH2Cl2; (c) SnCl2‚2H2O, HCl, ethanol, room temp; (d) CH2Cl2, Py,
ArSO2Cl; (e) Zn(CN)2, Pd(PPh3)4, DMF, 80 °C; (f) NaCNH3, AcOH,
3,5-di-F-PhCHO; (g) PhCOCl, CH2Cl2, pyridine.
Among many factors that affect the activity of com-
pounds in the cell-based assay, a compound’s ability to
penetrate the cell membrane is certainly important.
Both compounds bearing a 3-methoxyphenyl (10, CLogP
) 4.17; 19, CLogP ) 2.93)11 show a reduction in
lipophilicity compared to compounds with 3-chlorophe-
nyl (8, CLogP ) 4.94; 18, CLogP ) 3.66), as suggested
by their ClogP values. Compound 26 (CLogP ) 2.93),
which is 14-fold more potent than compound 29 (CLogP
) 3.44) in the whole-cell assay, also has a lower CLogP
value. This reduced lipophilicity, which stems from the
introduction of both cyano and methoxy groups, may be
contributing to cellular activity via improved cell pen-
etration. It is worthwhile to point out that several
compounds exhibit cellular activity exceeding their
intrinsic activity against FTase. Though rare, this
phenomenon has been reported by other researchers.12
Chirality is important for activity as demonstrated
by compounds 20 and 21. The R enantiomer 20 is 60-
fold more potent than the corresponding S enantiomer
21 in the enzymatic assay against FTase. 21 is es-
sentially inactive in the whole-cell assay. Similar ob-
servations have also been documented in other FTase
inhibitor research programs.13
Sch em e 8a
a
Reagents and conditions: (a) Pd(dppf)2, CO, MeOH, Et3N; (b)
NBS, CCl4, AIBN; (c) Ag2O, CH2Cl2, 4a ; (d) LiOH, MeOH/H2O;
(e) EDC, HOBt, ArNH2.
mide with NBS and AIBN in CCl4 and coupled with the
alcohol 4a to produce benzyl ether 63. Compounds 64
and 65 were obtained from reaction of the acid, obtained
by hydrolysis of 63, with various arylamines.
Resu lts a n d Discu ssion
We first examined the effects of various aryl groups
on the activities of FTase and GGTase-I and the
inhibition of farnesylation of Ras protein in NIH3T3
cells (EC50). The results are summarized in Table 1. It
was gratifying to see that by moving the 1-naphthyl
group from the upper benzene ring of A315493 to the
lower benzene ring ortho to the benzyl ether, we have
successfully obtained a potent FTase inhibitor 16 with
a much improved selectivity profile compared to that
of A315493, although its cellular activity is somewhat
It is apparent that this new series of FTase inhibitors
has shown much better selectivity behavior, with inhibi-
tory activity against GGTase-I largely in the micromolar
range. Depending on the aryl groups, the improvements
in selectivity range from 30- to more than 410-fold
compared to that of A315493. Given their activities
against GGTase-I, it is unlikely for these compounds to

616 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Wang et al.
Ta ble 1. Structure-Activity Relationship of Substitution on the A-Ringa
compd
R
Ar
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
3-OMe-Ph
3-OEt-Ph
Ph
1-naphthyl
8-quinolinyl
3-Cl-Ph
3-OMe-Ph
3-OMe-Ph (R)
3-OMe-Ph (S)
3,4-OCH2O-Ph
3,4-OCF2O-Ph
3-OEt-Ph
FTase (nM)
GGTase (nM)
EC50 (nM)
7
8
9
Cl
Cl
Cl
Cl
8.9
0.80 (4)
4.8
0.91
1.1
1.3
0.94 (2)
5.2 (2)
0.87 (2)
0.75 (2)
0.35
21
0.87 (2)
1.1
0.69 (2)
0.19 (2)
0.96
1.2
0.84
1.1
0.98
1.1
40
35
11
13
83
1.6
1800
>1000
390
525 (2)
100
4.6
140
1400 (2)
>1000
2000
1700
3500
7600(2)
>10000 (2)
1300 (2)
4300 (2)
1800
>10000
3100
2000
2100 (2)
1800 (2)
2900
750
1100
10
11
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
33
34
35
36
39
40
45
Cl
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
NO2
NH2
14
15
5.2 (2)
0.75 (2)
0.14
>100
<1 (2)
9.1
0.19
1.0
7
13
5.1
>100
96
0.81
>100
>100
>100
>100
NDb
>100
3-CH2OCH3-Ph
4-OMe-Ph
4-OEt-Ph
4-OCF3-Ph
4-CH3-Ph
3,5-DiF-Ph
3-OMe-Ph
3-OMe-Ph
3-OMe-Ph
3-OMe-Ph
3-OMe-Ph
3-OMe-Ph
3-OMe-Ph
2200
1500
903
>10000
>10000
>10000
>10000
NDb
NHSO2CH3
NHCOCH2OMe
CO2Me
CO2H
CHO
NDb
a
b
All the compounds were assayed once unless indicated by the number of the replicates shown in parentheses. ND: not determined.
Ta ble 2. Structure-Activity Relationship of Substitution on
inhibit protein geranylgeranylation efficiently at the
concentration required for the inhibition of farnesyla-
tion.
the B-Ringa
Several other R groups attached to the A-ring were
also investigated as shown in Table 1. Only compounds
33 and 45, bearing a strongly electron-withdrawing
nitro and formyl group, respectively, show potent in-
trinsic activity against FTase. Although compound 33
exhibits potent cellular activity, it is less selective than
the rest of the compounds.
Once we optimized the substituents for the A-ring,
we moved our attention to the B-ring. The results are
listed in Table 2. It appears that the cyano group at the
R1 position is very important for cellular activity,
although both a chloride and a trifluoromethyl group,
bioisosteres of the cyano group, gave comparable enzy-
matic activity against FTase. Again, this may be a
reflection of the fact that the presence of a cyano group
lowers the lipophilicity of the compounds. Substitution
at the R2 position has significant effect on the selectivity
and cellular activity. Even a small group such as a
fluorine atom causes an increased GGTase-I activity and
a decreased cellular activity (compare compounds 18,
19, 48, and 49). This observation reinforced our suspi-
cion that the poor selectivity associated with A315493
originates from the location of the 1-naphthaly group.
However, a fluorine atom at the R3 position has little
effect on biological activity.
compd
R
R1 R2 R3 FTase (nM) GGTase (nM) EC50 (nM)
47
48
49
50
51
OMe Cl
OMe CN Cl
Cl
Cl
Cl
H
H
H
H
F
2.0
3300
170
630 (2)
1600
2100
17.7
130
36
3.3
>100
0.97
0.44
0.77
1.1
CN
CN
CF3
F
H
H
H
a
All the compounds were assayed once unless indicated by the
number of the replicates shown in parentheses.
The imidazole ring is a very important moiety of
FTase inhibitors, since its basic nitrogen has a strong
interaction with the zinc atom in the FTase catalytic
binding site. Different heterocycles such as 1,2-dimeth-
ylimidazole and 5-thiazole were examined as replace-
ments. The results are listed in Table 3. It seems that
N-methylimidazole-4-yl is the best for enzymatic and
cellular activity. Although the introduction of a methyl
group at the 2-position of the imidazole ring results in

Benzonitriles as Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 617
Ta ble 3. Structure-Activity Relationship of Aryl Heterocyclesa
a
b
All the compounds were assayed once. Not determined.
minimum change in the enzymatic activity, it has a
negative impact on the cellular activity. Using other
heterocycles yields significant losses in activity due to
their attenuated basicity or unfavorable bulk.
similarly poor results, which may arise from the benzylic
oxidation of the benzyl ether facilitated by these electron-
donating groups. On the other hand, when there is an
amide bond with the carbonyl group directly attached
to the A-ring and ortho to the benzyl ether, the benzylic
oxidation of the benzyl ether was suppressed because
of the strong electron-withdrawing nature of the car-
bonyl group, resulting in a much improved pharmaco-
kinetic behavior (low plasma clearance rate, long oral
half-life, and excellent oral bioavailablity) as demon-
strated by compound 64. It is worthwhile to note that
better pharmacokinetic profiles were observed for the
compounds bearing the fluorine-containing alkoxy groups
as demonstrated by compounds 22, 23, and 28, although
to a lesser extent. This probably results from the slower
dealkylation associated with fluorine-containing alkoxy
groups. The introduction of a methyl group at the
2-position of the imidazole ring proved to be detrimental
to the pharmacokinetic behavior because compound 56
shows a dramatic decrease in oral AUC and bioavail-
ablity compared to compound 22. Replacement of the
cyano group of the A-ring with a chlorine atom or
substitution of the hydrogen with a fluorine atom ortho
to the cyano group of the B-ring gives little change in
pharmacokinetic behavior.
Last, we explored the effect of a linker inserted
between the aryl group and the A-ring on biological
activity. The results are summarized in Table 4. In
general, the different linkers have little effect on the
enzymatic activity against FTase except for compound
62, which shows a decreased activity compared to its
retroinverted amide 64. However, the selectivity and
cellular activity may be significantly changed depending
on the linker inserted. For example, compounds 60a -c
bearing a sulfonamide linker show significant losses in
selectivity. This may be due to the fact that a NHSO2
bond adopts a cis configuration different from other
linkers, projecting the aryl groups to an area where a
better contact between the GGTase-I and the inhibitors
can be made. In addition, neither the NHSO2 bond nor
the NHCH2 bond is helpful for the cellular activity. Only
the amide linker in which the carbonyl group is attached
to the A-ring is well tolerated. Indeed, in addition to its
potent intrinsic activity against FTase, compound 64
exhibits an excellent selectivity over GGTase-I and a
strong cellular inhibition of Ras processing activity.
Pharmacokinetic studies of selected compounds were
conducted in dog. The results are listed in Table 5. It is
interesting to note that the electronic nature of the
substituents on the A-ring plays an important role in
the pharmacokinetics. Chlorine, an electron-withdraw-
ing group, provides a much better pharmacokinetic
profile for compound 18 compared to compound 19,
which has an electron-donating methoxy group. Other
electron-donating groups such as OEt and CH2OMe give
X-r a y Cr ysta llogr a p h y. To further elucidate the
binding mode of this new series of FTase inhibitors to
FTase catalytic binding site and answer the question
why this series of compounds possesses much better
selectivity than A315493, compound 19 was cocrystal-
lized with hydroxylfarnesyl phosphate (HFP) and FTase
for X-ray crystallographic determination. Figure 1 il-
lustrates the X-ray structure of 20, the more active
enantiomer of 19, bound to the FTase active site. As

618 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Ta ble 4. Structure-Activity Relationship of the Linker X-Ya
Wang et al.
a
b
All the compounds were assayed once. Nd: not determined. c Compound 65 was assayed twice.
expected, the imidazole shows a strong interaction with
the zinc ion with a distance of 2.3 Å. The B-ring is on
the top of the HFP iosprenoid. The nitrile nitrogen of
the B-ring is about 3.4 Å away from the side chain of
Arg202 in the â-subunit, the closest amino acid side
chain, making reasonable van der Waals contact. The
van der Waals nature of the interaction between the
cyano group and the protein may explain why the
replacement of the cyano group with either a chloride
or a trifluoromethyl group resulted in little change in
enzymatic activity against FTase. The cyano group of
the A-ring is in a pocket defined by lipophilic side chains
of amino acids Tyr36, Tyr93, Leu96, and Try106. Again,
strong van der Waals interaction between the nitrile
nitrogen and the amino acid side chains and main
chains was observed, explaining why either a chlorine
atom or a nitro group is tolerated. It is interesting to
point out that the 3-methoxyphenyl and the B-ring are
stacking on top of each other at a distance of 4.5 Å,
suggesting a strong π-π interaction.
Figure 2 shows the superimposed X-ray structures of
20 and A313326, a close analogue of A315493 (Chart 1)
bound to the FTase active binding site. It is clear that
compound 20 shares a lot of similarities with A313326
in the FTase binding site except the locations of the aryl
rings. For example, both compounds show the same
distances between the unsubstituted nitrogen of imi-
dazole and the zinc. The similar distances were also
observed in the X-ray cocrystal structures with FTase
for a couple of close analogues of compound 20.14 It is
noticeable that the A-ring of compound 20 and the
4-cyanobenzyl ethyl of A313326 are slightly shifted
because of the naphthalene ring, but making very
similar interaction with the 360’s loop. This supported
our initial hypothesis that the poor selectivity associated
with A313495 stems from the alteration of the inhibitor
binding mode caused by the location of the naphthalene
ring.
It is difficult to pinpoint the origin of the poor
selectivity associated with A313326 without X-ray co-
crystal structures of compound 20 and A313326 in the
GGTase-I active binding site. It should be noted, how-
ever, that Trp102 is not found in the GGTase-I active
binding site but is replaced by Ser 48.15 One possible
explanation would be that 3-methoxyphenyl group of
compound 20 may have a reduced interaction with Ser
48 in the GGTase-I active binding site compared to
1-naphthyl of A313326 because these two aryl groups
bind differently. Therefore, compound 20’s activity
against GGTase-I would be significantly reduced.
Con clu sion
A novel series of potent, selective FTase inhibitors,
the design of which is based on the 3-D model of
A315493, have been developed. X-ray crystallography
determination of 19 subsequently confirmed our initial
design. The decreased interaction between the aryl
groups and Ser 48 in GGTase-I active binding site could
be one possible reason to explain the selectivity for this
new series of FTase inhibitors. Medicinal chemistry
efforts revealed that among different substitutents at
the para positions of both A and B rings the cyano group

Benzonitriles as Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 619
Ta ble 5. Pharmacokinetic Evaluation of Selected Compounds in Dog
a
b
Unable to calculate. At least three animals were used for each dosing group (oral and iv, 5 mg/kg); the PK parameters reported here
were the averages of the animals. c Four animals used, cross-over fashion (oral and iv, 1 mg/kg, four different compounds were dosed
simultaneously); the PK parameters reported here were the averages of the animals.
is optimal, providing these compounds with potent
cellular activity. A wide range of aryl groups can be used
without compromising enzymatic or cellular activity and
selectivity. Pharmacokinetic studies in dog showed that
either 3-chlorophenyl or fluorine-containing alkoxyphe-
nyl groups are the aryl substiuents of choice and that

620 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Wang et al.
to - 78 °C again, and slowly treated with chlorotriethylsilane
(111 mL, 0.661 mol) via a cannula to keep the internal
temperature below -60 °C. The reaction mixture was gradu-
ally warmed to room temperature overnight. The solid was
removed by filtration under a stream of nitrogen, and the
filtrate was concentrated in vacuo. The resulting liquid was
purified with vacuum distillation to give 98 g of 1-methyl-2-
triethylsilanyl-1H-imidazole as a clear liquid (88%).
1-Methyl-2-triethylsilanyl-1H-imidazole (4.32 g, 22 mmol)
in 100 mL of anhydrous THF was cooled to -78 °C. To this
solution was added 1.7 M t-BuLi in hexane (14 mL, 24 mmol)
over 5 min. The solution was stirred at -78 °C for additional
1 h and treated dropwise with 4-cyanobenzaldehyde in 20 mL
of THF via a cannula. The solution was stirred at -78 °C for
3 h and treated with 20 mL of MeOH. After it warmed to room
temperature, the solution was treated with 50 mL of 10% HCl
and stirred overnight. The solution was neutralized to pH 7-8
using saturated aqueous NaHCO3, partitioned between EtOAc
and H2O, and extracted with additional EtOAc three times.
The combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography using 20:1 EtOAc/MeOH
to provide 2.52 g of 4-[hydroxy(3-methyl-3H-imidazol-4-yl)-
F igu r e 1. X-ray structure of 20 (green) bound to FTase active
site. The isoprenoid group of HFP is shown in blue. The zinc
ion is shown in purple.
1
methyl]benzonitrile 4a (59%). H NMR (CDCl3): δ 7.64-7.67
(dd, J ) 6.7, 2.3 Hz, 2H), 7.54-7.52 (dd, J ) 7.8, 0.7 Hz, 2H),
6.31 (s, 1H), 6.56 (s, 1H), 5.89 (s, 1H), 3.53 (s, 3H). MS/ESI
(+), m/z: 214 (M + H)+, 231 (M + NH4)+.
(4-Ch lor op h en yl)-(3-m et h yl-3H -im id a zol-4-yl)m et h a -
n ol (4b). Compound 4b was prepared in a similar manner as
described in the preparation of 4a from 1-methyl-2-triethyl-
silanyl-1H-imidazole. 1H NMR (DMSO-d6): δ 7.53 (s, 1H),
7.37-7.44 (m, 4H), 6.39 (s, 1H), 6.01 (d, J ) 5.09 Hz, 1H),
5.79 (d, J ) 4.4 Hz, 1H), 3.54 (s, 3H). MS/ESI (+), m/z: 223
(M + H)+, 240 (M + NH4)+.
(4-Tr iflu or om et h ylp h en yl)-(3-m et h yl-3H -im id a zol-4-
yl)m eth a n ol (4c). Compound 4c was prepared in a similar
manner as described in the preparation of 4a from 1-methyl-
2-triethylsilanyl-1H-imidazole. 1H NMR (DMSO-d6): δ 7.72-
7.75 (d, J ) 8.1 Hz, 2H), 7.60-7.62 (d, J ) 8.1 Hz, 2H), 7.55
(s, 1H), 6.40 (s, 1H), 6.11 (d, J ) 5.1 Hz, 1H), 5.90 (d, J ) 5.1
Hz, 1H), 3.55 (s, 3H). MS/ESI (+), m/z: 257 (M + H)+, 274 (M
+ NH4)+.
2-Ch lor o-4-[h yd r oxy(3-m eth yl-3H-im id a zol-4-yl)m eth -
yl]ben zon itr ile (4d ). Compound 4d was prepared in a similar
manner as described in the preparation of 4a from 1-methyl-
2-triethylsilanyl-1H-imidazole. 1H NMR (CDCl3): δ 7.50-7.54
(m, 1H), 7.28-7.39 (m, 2H), 7.28 (s, 1H), 6.72 (s, 1H), 5.95 (s,
1H), 3.55 (s, 3H). MS/ESI (+), m/z: 247 (M + H)+, 265 (M +
NH4)+.
(3-F lu or o-4-cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-yl)-
m eth a n ol (4e). Compound 4e was prepared in a similar
manner as described in the preparation of 4a from 1-methyl-
2-triethylsilanyl-1H-imidazole. 1H NMR (CDCl3): δ 7.60-7.64
(m, 1H), 7.28-7.39 (m, 2H), 7.28 (s, 1H), 6.72 (s, 1H), 5.95 (s,
1H), 3.55 (s, 3H). MS/ESI (+), m/z: 232 (M + H)+, 249 (M +
NH4)+.
(2-F lu or o-4-cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-yl)-
m eth a n ol (4f). Compound 4f was prepared in a similar
manner as described in the preparation of 4a from 1-methyl-
2-triethylsilanyl-1H-imidazole. 1H NMR (DMSO-d6): δ 7.77-
7.85 (m, 3H), 7.57 (s, 1H), 6.28 (s, 1H), 6.22 (d, J ) 5.8 Hz,
1H), 6.04 (d, J ) 5.2 Hz, 1H), 3.65 (s, 3H). MS/ESI (+), m/z:
232 (M + H)+, 249 (M + NH4)+.
F igu r e 2. Superimposed X-ray crystal structure of 20 (green)
and A313326 (white). The isoprenoid group of HFP is shown
in blue, and the zinc ion is shown in purple.
an amide bond is the linker of choice. Particularly, in
conjunction with its potent cellular activity and good
selectivity, compound 64 showed outstanding pharma-
cokinetic profiles as demonstrated by its long oral half-
life, good oral AUC value, and excellent oral bioavail-
ability.
Exp er im en ta l Section
All commercially available solvents and reagents were used
without further treatment as received unless otherwise noted.
DMF, DMA, methylene chloride, toluene, and THF were
commercial anhydrous solvents from Aldrich. FT-NMR spectra
were obtained on Bruker 250 MHz (62.5 MHz for 13C), 300
MHz (75 MHz for 13C), and 400 MHz (100 MHz for 13C)
spectrometers. Elemental analyses were performed by Rob-
ertson Microlit Laboratories, Inc., of Madison, NJ . Thin-layer
chromatography (TLC) was performed on Kiesegel 60 F254
plates (Merck) using reagent grade solvents. Flash chroma-
tography was performed on Merck silica gel 60 (230-400
mesh) using reagent grade solvents. All reactions were per-
formed under a nitrogen atmosphere.
Gen er a l P r oced u r e for P r ep a r a tion of th e Secon d a r y
Alcoh ols 4a -f. N-Methylimidazole 2 (46 mL, 0.577 mol) in
400 mL of anhydrous THF was cooled to -78 °C. To this
solution was slowly added 2.5 M n-BuLi in hexane (250 mL,
0.625 mol) via an addition funnel to maintain the internal
temperature below -60 °C. After the addition of n-BuLi was
complete, the solution was warmed to -10 °C briefly, cooled
(4-Cya n op h en yl)th ia zol-5-ylm eth a n ol (4g). Compound
4g was prepared in a similar manner as described in the
1
preparation of 4a from thiazole 2b. H NMR (CDCl3): δ 8.78
(s, 1H), 7.67-7.72 (m, 3H), 7.57 (d, J ) 8.1 Hz, 1H), 6.21 (s,
1H). MS/ESI (+), m/z: 217 (M + H)+.
(4-Cya n op h en yl)-(2,3-d im eth yl-3H-im id a zol-4-yl)m eth -
a n ol (4h ). Compound 4h was prepared in a similar manner
as described in the preparation of 4a from 2,3-dimethylimi-
dazole 3c. 1H NMR (DMSO-d6): δ 7.83 (d, J ) 8.1 Hz, 2H),
7.57 (d, J ) 8.1 Hz, 2H), 6.17 (s, 1H), 6.21 (s, 1H), 6.09 (d, J

Benzonitriles as Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 621
) 5.1 Hz, 1H), 5.83 (d, J ) 4.8 Hz, 1H), 3.43 (s, 3H), 2.23 (s,
3H). MS/ESI (+), m/z: 228 (M + H)+.
(m, 8H), 7.13-7.16 (m, 2H), 6.82 (s, 1H), 5.45 (s, 1H), 4.43 (d,
J ) 11.2 Hz, 1H), 4.33 (d, J ) 11.2 Hz, 1H), 3.30 (s, 3H). MS/
ESI, m/z: 449 (M + H)+. Anal. (C25H19Cl2N3O‚HCl‚1.15H2O)
C, H, N.
(4-Cya n op h en yl)-(4-ch lor op yr id in -3-yl)m eth a n ol (4i).
A solution of LDA, which was generated from diisopropylamine
(9.20 mL, 65.64 mmol) and n-BuLi (2.5 M in hexane, 27.0 mL,
67.5 mmol) in THF (100 mL) at -78 °C, was added to a
mixture of 4-chloropyridine (6.77 g, 59.63 mmol) in THF (15
mL) at -78 °C. The mixture was stirred at -78 °C for 1.5 h.
To this mixture at -78 °C was added a solution of 4-cyanobenz-
aldehyde (8.60 g, 65.58 mmol) in THF (50 mL). The reaction
mixture was stirred overnight while the temperature gradually
warmed to room temperature. Saturated NH4Cl solution was
added, and the mixture was extracted with ethyl acetate. The
combined extracts were washed with water and brine, dried
over MgSO4, and concentrated. The residue was purified on
silica gel, eluting with methylene chloride/methanol/NH4OH
(100:5:0.5, v/v/v) to give the title compound (12.04 g, 82.5%).
1H NMR (CDCl3): δ 8.74 (s, 1 H), 8.44 (d, J ) 5.43 Hz, 1 H),
7.66 (m, 2 H), 7.54 (m, 2 H), 7.31 (d, J ) 5.43 Hz, 1 H), 6.27
(d, J ) 3.05 Hz, 1 H), 2.98 (d, J ) 4.07 Hz, 1 H). MS (DCI/
NH3) m/z: 245, 247 (M + H)+.
5-[(4-C y a n o p h e n y l)-(5,4′-d i c h lo r o b i p h e n y l-2-y l-
m eth oxy)m eth yl]-1-m eth yl-1H-im id a zole (9). Compound
9 was prepared from compound 6 in a similar manner as
described for the preparation of compound 7. 1H NMR
(CDCl3): δ 7.63 (d, J ) 8.5 Hz, 2H), 7.40-7.18 (m, 11H), 6.81
(s, 1H), 5.45 (s, 1H), 4.45 (d, J ) 11.2 Hz, 1H), 4.33 (d, J )
11.2 Hz, 1H), 3.27 (s, 3H). MS/ESI, m/z: 449 (M + H)+. Anal.
(C25H19Cl2N3O‚HCl‚0.9H2O) C, H, N.
5-[(5-Ch lor o-3′-m et h oxyb ip h en yl-2-ylm et h oxy)-(4-cy-
a n op h en yl)m et h yl]-1-m et h yl-1H -im id a zole (10). Com-
pound 10 was prepared from compound 6 in a similar manner
as described for the preparation of compound 7. 1H NMR
(CDCl3): δ 7.61 (d, J ) 8.5 Hz, 2H), 7.41-7.28 (m, 7H), 6.92
(m, 1H), 6.80-6.85 (m, 2H), 6.76 (s, 1H), 5.43 (s, 1H), 4.46 (d,
J ) 11 Hz, 1H), 4.39 (d, J ) 11 Hz, 1H), 3.79 (s, 3H), 3.30 (s,
3H). MS/ESI, m/z: 444 (M + H)+. Anal. (C26H22ClN3O2‚1.4TFA)
C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of Ben zyl Br o-
m id e. A mixture of 2-chloro-4-iodotoluene (3.95 g, 15.6 mmol),
NBS (3.10 g, 17.2 mmol), and benzoyl peroxide (0.5 g, 2.1
mmol) in 100 mL of CCl4 was heated to reflux for 2 days. After
it cooled to room temperature, the solid was removed by
filtration. The filtrate was concentrated in vacuo, and the
residue was purified by flash chromatography using 25:1
hexanes/EtOAc to provide 3.24 g of 4-chloro-2-iodobenzyl
bromide. 1H NMR (CDCl3): δ 7.85 (d, J ) 2.0 Hz, 1H), 7.39
(m, 1H), 7.31 (m, 1H), 4.55 (s, 2H). MS/ESI (+), m/z: 332 (M
+ H)+.
Gen er a l P r oced u r e for P r ep a r a tion of Ben zyl Eth er .
A 100 mL round-bottom flask was charged with (4-cyanophe-
nyl)-(3-methyl-3H-imidazol-4-yl)methanol 4a (0.50 g, 2.34
mmol), 4-chloro-2-iodobenzyl bromide (1.16 g, 3.5 mmol), silver
oxide (1.60 g, 6.9 mmol), and 30 mL of methylene chloride.
The flask was wrapped by aluminum foil, and the reaction
mixture was stirred at room temperature for 12 h. The
insoluble material was filtered off through a pack of Celite,
and the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography using 100:5:0.3
EtOAc/MeOH/NH4OH to give 0.7 g of 5-[(4-chloro-2-iodoben-
zyloxy)-(4-cyanophenyl)methyl]-1-methyl-1H-imidazole 6 (70%).
1H NMR (CDCl3): δ 7.85 (s, 1H), 7.68-7.66 (m, 2H), 7.53 (d,
J ) 8.1 Hz, 2H), 7.47 (m, 1H), 7.34-7.32 (m, 2H), 6.95 (s, 1H),
5.65 (s, 1H), 4.52 (m, 2H), 3.41 (s, 3H). MS/ESI, m/z: 464 (M
+ H)+.
Gen er a l P r oced u r e for Su zu k i Cou p lin g to P r ep a r e
Dia r yl Com p ou n d s. A 50 mL round-bottom flask was
charged with 5-[(4-chloro-2-iodobenzyloxy)-(4-cyanophenyl)-
methyl]-1-methyl-1H-imidazole 6 (0.080 g, 0.177 mmol), 2-chlo-
rophenylboronic acid (0.055 g, 0.35 mmol), sodium carbonate
(0.042 g, 0.531 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (0.01 g, 0.0089 mmol). To the flask was added 3
mL of toluene, 3 mL of ethanol, and 1 mL of water. The
reaction mixture was heated to reflux for 12 h. After it cooled
to room temperature, the reaction mixture was partitioned
between EtOAc and water. The aqueous layer was extracted
with additional EtOAc, and the combined organic layers were
washed with brine, dried with MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by flash column
chromatography using 100:5:0.3 EtOAc/MeOH/NH4OH to give
5-[(5-Ch lor o-3′-e t h oxyb ip h e n yl-2-ylm e t h oxy)-(4-cy-
a n op h en yl)m et h yl]-1-m et h yl-1H -im id a zole (11). Com-
pound 11 was prepared from compound 6 in a similar manner
as described for the preparation of compound 7. 1H NMR
(CDCl3): δ 7.61 (d, J ) 8.5 Hz, 2H), 7.41-7.28 (m, 7H), 6.92
(m, 1H), 6.80-6.85 (m, 2H), 6.76 (s, 1H), 5.43 (s, 1H), 4.46 (d,
J ) 11 Hz, 1H), 4.39 (d, J ) 11 Hz, 1H), 4.04 (q, J ) 7.1 Hz,
2H), 3.30 (s, 3H), 1.47 (t, J ) 6.8 Hz, 3H). MS/ESI, m/z: 458
(M + H)+. Anal. (C26H22ClN3O2‚1.4TFA) C, H, N.
Gen er a l P r oced u r e for P a lla d iu m -Ca ta lyzed Cya n a -
tion of Ar yl Ha lid es (Br om id e or Iod id e). A mixture of
2-amino-4-iodotoluene (5.0 g, 21.4 mmol), Zn(CN)2 (1.51 g, 12.9
mmol), and Pd(PPh3)4 (1.24 g, 1.07 mmol) in 25 mL of DMF
was degassed via vacuum/nitrogen cycles. The reaction mix-
ture was heated at 80 °C for 2 h. After it cooled to room
temperature, the reaction mixture was partitioned between
H2O and EtOAc. The aqueous layer was extracted with
additional EtOAc, and the combined organic layers were
washed with brine, dried, filtered, and concentrated. The
residue was purified by flash column chromatography using
3:7 EtOAc/hexane to give 2.38 g of 2-amino-4-cyanotoluene
(84%).
2-Iod o-4-cya n otolu en e (13). 2-Amino-4-cyanotoluene (2.15
g, 16.3 mmol) in 20 mL of acetone was treated with 100 mL of
concentrated HCl at room temperature. The solution was
cooled to 0 °C and treated dropwise with NaNO2 (1.46 g, 21.4
mmol) dissolved in 10 mL of H2O. The solution was stirred at
0 °C for 2 h, then treated with KI (8.12 g, 48.9 mmol) in 20
mL of H2O. After 6 h, the solution was extracted with Et2O
several times. The combined ether layers were washed with
brine, dried, filtered, and concentrated. The residue was
purified by flash column chromatography using 1:9 EtOAc/
hexane to give 2.65 g of 2-iodo-4-cyanotoluene (70%). 1H NMR
(CDCl3): δ 8.08 (d, J ) 1.7 Hz, 1H), 75.2-7.55 (m, 2H), 7.32
(d, J ) 7.8 Hz, 1H), 2.50 (s, 3H). MS/ESI, m/z: 234 (M + H)+.
5-[(4-Cya n o-2-iodoben zyloxy)-(4-cya n oph en yl)m eth yl]-
1-m eth yl-1H-im id a zole (14). Compound 14 was prepared
from 2-iodo-4-cyanotoluene in a similar manner as described
1
for the preparation of compound 6. H NMR (CDCl3): δ 8.11
(d, J ) 1.7 Hz, 1H), 7.66-7.72 (m, 3H), 7.53-7.58 (m, 4H),
6.99 (s, 1H), 5.70 (s, 1H), 4.50-4.61 (m, 2H), 3.43 (s, 3H). MS/
ESI, m/z: 455 (M + H)+.
0.048
g of 5-[(4-cyanophenyl)-(5,2′-dichlorobiphenyl-2-yl-
methoxy)methyl]-1-methyl-1H-imidazole 7 (62%). 1H NMR
(CDCl3): δ 7.62-7.56 (m, 2H), 7.48-7.16 (m, 11H), 6.78 and
6.69 (s, 1H), 5.38 (s, 1H), 4.40-4.18 (m, 2H), 3.32 and 3.24 (s,
5-[(5-Cya n ob ip h en yl-2-ylm et h oxy)-(4-cya n op h en yl)-
m eth yl]-1-m eth yl-1H-im id a zole (15). Compound 15 was
prepared from compound 14 in a similar manner as described
for the preparation of compound 7. 1H NMR (DMSO-d6): δ
8.96 (s, 1H), 7.89 (m, 1H), 7.86 (d, J ) 8.05 Hz, 2H), 7.81 (d,
J ) 8.05 Hz, 1H), 7.73 (d, J ) 1.8 Hz, 1H), 7.48 (d, J ) 8.42
Hz, 2H), 7.42-7.44 (m, 3H), 7.33 (dd, J ) 6.6, 2.9 Hz, 2H),
7.23 (s, 1H), 5.94 (s, 1H), 4.62 (d, J ) 11.7 Hz, 1H), 4.47 (d, J
) 11.7 Hz, 1H), 3.63 (s, 3H). MS/ESI, m/z: 405 (M + H)+. Anal.
(C26H20N4O‚1.5 TFA) C, H, N.
3H) (two rotomers). MS/ESI, m/z: 449 (M + H)+. Anal. (C25H19
Cl2N3O‚HCl‚0.8H2O) C, H, N.
-
5-[(4-C y a n o p h e n y l)-(5,3′-d i c h lo r o b i p h e n y l-2-y l-
m eth oxy)m eth yl]-1-m eth yl-1H-im id a zole (8). Compound
8 was prepared from compound 6 in a similar manner as
described for the preparation of compound 7. 1H NMR
(CDCl3): δ 7.61 (d, J ) 6.8 Hz, 2H), 7.43 (s, 1H), 7.38-7.27

622 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Wang et al.
5-[(4-Cyan o-2-n aph th alen -1-yl-ben zyloxy)-(4-cyan oph e-
n yl)m eth yl]-1-m eth yl-1H-im id a zole (16). Compound 16
was prepared from compound 14 in a similar manner as
described for the preparation of compound 7. Compound 16
exists as a mixture of two rotatomers. 1H NMR (DMSO-d6): δ
8.94 (s, 0.5 H), 8.90 (s, 0.5 H), 8.00-8.04 (m, 3H), 7.87-7.91
(m, 1H), 7.75-7.78 (m, 2H), 7.51-7.67 (m, 4H), 7.28-7.44 (m,
4H), 7.14-7.24 (m, 2H), 7.08 (s, 0.5 H), 7.04 (s, 0.5H), 5.74 (s,
1H), 4.34 (dd, J ) 11.5, 1.4 Hz, 1H), 4.13 (dd, J ) 11.4, 6.6
Hz, 1H), 3.58 (s, 1.5H), 3.46 (s, 1.5H). MS/ESI, m/z: 455 (M +
H)+. Anal. (C30H22N4O‚0.4H2O) C, H, N.
(s, 3H), 1.42 (t, J ) 6.8 Hz, 3H). MS/ESI, m/z: 449 (M + H)+.
Anal. (C28H24N4O2‚HCl‚0.5H2O) C, H, N.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-3′-m eth oxym eth ylbip h en yl-3-ca r bon i-
tr ile (25). Compound 25 was prepared from compound 14 in
a similar manner as described for the preparation of compound
7. 1H NMR (HCl salt, DMSO-d6): δ 9.04 (s, 1H), 7.80-7.91
(m, 4H), 7.74 (d, J ) 1.7 Hz, 1H), 7.36-7.47 (m, 5H), 7.25-
7.27 (m, 3H), 5.95 (s, 1H), 4.61 (d, J ) 11.5 Hz, 1H), 4.41-
4.47 (m, 3H), 3.62 (s, 3H), 3.27 (s, 3H). MS/ESI, m/z: 449 (M
+ H)+. Anal. (C28H24N4O2‚HCl‚1.35H2O) C, H, N.
4-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-3-qu in olin -8-ylben zon itr ile (17). Com-
pound 17 was prepared from compound 14 in a similar manner
as described for the preparation of compound 7. 1H NMR
(DMSO-d6): δ 9.03 (s, 1 H), 8.75 (s, 1H), 8.47 (d, J ) 7.2 Hz,
1H), 8.09-8.11 (m, 1H), 7.94 (d, J ) 7.8 Hz, 1H), 7.68-7.75
(m, 5H), 7.57 (d, J ) 4.1 Hz, 1H), 7.28 (d, J ) 7.8 Hz, 1 H),
7.21 (d, J ) 7.5 Hz, 1H), 7.14 (s, 1H), 5.73 (s, 1H), 4.45 (d, J
) 11.5 Hz, 1H), 4.12 (d, J ) 11.4 Hz, 1H), 3.58 (s, 3H). MS/
ESI, m/z: 456 (M + H)+. Anal. (C29H21N5O‚1.8HCl) C, H, N.
3′-Ch lor o-6-[(4-cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-
yl)m et h oxym et h yl]b ip h en yl-3-ca r b on it r ile (18). Com-
pound 18 was prepared from compound 14 in a similar manner
as described for the preparation of compound 7. 1H NMR (HCl
salt, MeOH-d4): δ 8.92 (s, 1 H), 7.75-7.80 (m, 4H), 7.64 (s,
1H), 7.49 (d, J ) 8.1 Hz, 2H), 7.39-7.44 (m, 2H), 7.34 (s, 1H),
7.22-7.25 (m, 1H), 7.19 (s, 1 H), 7.21 (d, J ) 7.5 Hz, 1H), 7.14
(s, 1H), 5.87 (s, 1H), 4.65 (d, J ) 11.5 Hz, 1H), 4.53 (d, J )
11.5 Hz, 1H), 3.72 (s, 3H). MS/ESI, m/z: 439 (M + H)+. Anal.
(C26H19ClN4O‚HCl‚0.65H2O) C, H, N.
(R,S)-6-[(4-Cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-yl)-
m eth oxym eth yl]-3′-m eth oxybip h en yl-3-ca r bon itr ile (19).
Compound 19 was prepared from compound 14 in a similar
manner as described for the preparation of compound 7. 1H
NMR (CDCl3): δ 7.69-7.54 (m, 6H), 7.39-7.26 (m, 3H), 6.96
(m, 1H), 6.80-6.75 (m, 3H), 5.47 (s, 1H), 4.53 (d, J ) 12.2 Hz,
1H), 4.46 (d, J ) 12.2 Hz, 1H), 3.81 (s, 3H), 3.34 (s, 3H). MS/
ESI, m/z: 435 (M + H)+, 567 (M + Na)+. Anal. (C27H22N4O2‚
HCl‚H2O) C, H, N.
(R)-6-[(4-Cya n op h en yl)-(3-m et h yl-3H -im id a zol-4-yl)-
m eth oxym eth yl]-3′-m eth oxybip h en yl-3-ca r bon itr ile (20)
a n d (S)-6-[(4-Cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-yl)-
m eth oxym eth yl]-3′-m eth oxybip h en yl-3-ca r bon itr ile (21).
Compounds 20 and 21 were separated by preparative HPLC
using column Chiralcel (4.6 mm × 250 mm), eluting with 60:
40 hexane/ethanol.
3-Ben zo[1,3]d ioxol-5-yl-4-[(4-cya n op h en yl)-(3-m eth yl-
3H-im id a zol-4-yl)m eth oxym eth yl]ben zon itr ile (22). Com-
pound 22 was prepared from compound 14 in a similar manner
as described for the preparation of compound 7. 1H NMR
(CDCl3): δ 7.67-7.55 (m, 6H), 7.41 (d, J ) 8.1 Hz, 2H), 6.83
(m, 2H), 6.70-6.51 (m, 2H), 6.04 (s, 2H), 5.51 (s, 1H), 4.53 (d,
J ) 12.2 Hz, 1H), 4.46 (d, J ) 12.2 Hz, 1H), 3.38 (s, 3H). MS/
(DCI/NH3) m/z: 449 (M + H)+. Anal. (C27H20N4O3‚HCl‚0.8H2O)
C, H, N.
4-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m et h oxym et h yl]-3-(2,2-d iflu or ob en zo[1,3]d ioxol-5-yl)-
ben zon itr ile (23). Compound 23 was prepared from com-
pound 14 in a similar manner as described for the preparation
of compound 7. 1H NMR (CDCl3): δ 7.69-7.71 (m, 1H), 7.62-
7.66 (m, 3H), 7.54 (d, J ) 1.6 Hz, 1H), 7.46 (m, 1H), 7.41 (d, J
) 8.1 Hz, 2H), 7.10 (d, J ) 8.1 Hz, 1H), 6.99 (d, J ) 1.6 Hz,
1H), 6.94 (dd, J ) 8.1, 1.6 Hz, 1H), 6.88 (s, 1H), 5.52 (s, 1H),
4.50 (d, J ) 12.2 Hz, 1H), 4.41 (d, J ) 12.2 Hz, 1H), 3.33 (s,
3H). MS/(DCI/NH3) m/z: 485 (M + H)+. Anal. (C27H18F2N4O3)
C, H, N.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-3′-eth oxybip h en yl-3-ca r bon itr ile (24).
Compound 24 was prepared from compound 14 in a similar
manner as described for the preparation of compound 7. 1H
NMR (CDCl3): δ 7.69-7.54 (m, 6H), 7.39-7.27 (m, 3H), 6.94
(m, 1H), 6.80-6.75 (m, 3H), 5.47 (s, 1H), 4.53 (d, J ) 11.9 Hz,
1H), 4.46 (d, J ) 11.9 Hz, 1H), 4.02 (q, J ) 7.1 Hz, 2H), 3.36
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-4′-m eth oxybip h en yl-3-ca r bon itr ile (26).
Compound 26 was prepared from compound 14 in a similar
manner as described for the preparation of compound 7. 1H
NMR (HCl salt, DMSO-d6): δ 9.04 (s, 1H), 7.84-7.88 (m, 3H),
7.80 (d, J ) 7.7 Hz, 1H), 7.70 (d, J ) 1.8 Hz, 1H), 7.51 (d, J )
8.1 Hz, 2H), 7.24-7.27 (m, 3H), 6.95-6.98 (m, 2H), 5.96 (s,
1H), 4.62 (d, J ) 11.4 Hz, 1H), 4.47 (d, J ) 11.7 Hz, 1H), 3.81
(s, 3H), 3.65 (s, 3H). MS/ESI, m/z: 435 (M + H)+. Anal.
(C27H22N4O2) C, H, N.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-4′-eth oxybip h en yl-3-ca r bon itr ile (27).
Compound 27 was prepared from compound 14 in a similar
manner as described for the preparation of compound 7. 1H
NMR (HCl salt, DMSO-d6): δ 9.04 (s, 1H), 7.84-7.87 (m, 3H),
7.79 (d, J ) 8.1 Hz, 1H), 7.70 (d, J ) 1.5 Hz, 1H), 7.60-7.64
(m, 2H), 7.50 (d, J ) 8.1 Hz, 2H), 7.26 (s, 1H), 7.24 (d, J ) 8.4
Hz, 2H), 6.93-6.95 (m, 2H), 5.95 (s, 1H), 4.62 (d, J ) 11.4 Hz,
1H), 4.45 (d, J ) 11.4 Hz, 1H), 4.08 (q, J ) 7.0 Hz, 2H), 3.66
(s, 3H), 1.37 (t, J ) 7.0 Hz, 3H). MS/ESI, m/z: 449 (M + H)+.
Anal. (C28H24N4O2‚0.1H2O) C, H, N.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m et h oxym et h yl]-4′-t r iflu or om et h oxyb ip h en yl-3-ca r b o-
n itr ile (28). Compound 28 was prepared from compound 14
in a similar manner as described for the preparation of
compound 7. 1H NMR (HCl salt, DMSO-d6): δ 8.94 (s, 1H),
7.88-7.92 (m, 2H), 7.85 (d, J ) 8.1 Hz, 2H), 7.82 (d, J ) 8.1
Hz, 1H), 7.79 (d, J ) 1.8 Hz, 1H), 7.46-7.50 (m, 4H), 7.40 (d,
J ) 8.1 Hz, 2H), 7.30 (d, J ) 7.7 Hz, 1H), 7.20 (s, 1H), 5.93 (s,
1H), 4.60 (d, J ) 11.7 Hz, 1H), 4.41 (d, J ) 11.7 Hz, 1H), 3.64
(s, 3H). MS/ESI, m/z: 489 (M + H)+. Anal. (C27H19F3N4O2) C,
H, N.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-4′-m eth ylbip h en yl-3-ca r bon itr ile (29).
Compound 29 was prepared from compound 14 in a similar
manner as described for the preparation of compound 7. 1H
NMR (HCl salt, DMSO-d6): δ 9.00 (s, 1H), 7.85-7.87 (m, 3H),
7.79 (d, J ) 8.1 Hz, 1H), 7.70 (d, J ) 1.3 Hz, 1H), 7.49 (d, J )
8.1 Hz, 2H), 7.26 (s, 1H), 7.21-7.22 (m, 4H), 5.94 (s, 1H), 4.62
(d, J ) 11.7 Hz, 1H), 4.46 (d, J ) 11.7 Hz, 1H), 3.63 (s, 3H),
2.37 (s, 3H). MS/ESI, m/z: 419 (M + H)+. Anal. (C27H22N4O‚
1.4TFA) C, H, N.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-3′,5′-diflu or obiph en yl-3-car bon itr ile (30).
Compound 30 was prepared from compound 14 in a similar
manner as described for the preparation of compound 7. 1H
NMR (TFA salt, DMSO-d6): δ 8.99 (s, 1H), 7.91-7.93 (m, 1H),
7.86 (d, J ) 8.3 Hz, 2H), 7.29-7.32 (m, 2H), 7.86 (d, J ) 8.3
Hz, 2H), 7.29-7.32 (m, 1H), 7.27 (s, 1H), 7.13 (d, J ) 6.4 Hz,
2H), 5.96 (s, 1H), 4.65 (d, J ) 11.7 Hz, 1H), 4.48 (d, J ) 11.7
Hz, 1H), 3.64 (s, 3H). MS/ESI, m/z: 441 (M + H)+. Anal.
(C26H18F2N4O‚C2HF3O2‚0.9H2O) C, H, N.
3′-Meth oxy-2-m eth yl-5-n itr obip h en yl (32). Compound
32 was prepared via Suzuki coupling from compound 31 in a
similar manner as described for the preparation of compound
7. 1H NMR (CDCl3): δ 8.09-8.11 (m, 2H), 7.40-7.43 (m, 1H),
7.35 (d, J ) 8.1 Hz, 1H), 6.93-6.97 (m, 1H), 6.89 (d, J ) 7.46
Hz, 1H), 6.83-6.85 (m, 1H), 3.85 (s, 3H), 2.37 (s, 3H). MS/
(DCI) m/z: 244 (M + H)+.
4-[(3′-Meth oxy-5-n itr obip h en yl-2-ylm eth oxy)-(3-m eth -
yl-3H-im id a zol-4-yl)m eth yl]ben zon itr ile (33). Compound
33 was prepared from compound 32 in a similar manner as
described for the preparation of compound 6. 1H NMR

Benzonitriles as Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 623
(CDCl3): δ 8.23 (dd, J ) 8.3, 2.5 Hz, 1H), 8.15 (d, J ) 2.4 Hz,
1H), 7.70 (d, J ) 8.5 Hz, 1H), 7.64 (d, J ) 8.4 Hz, 2H), 7.56 (s,
1H), 7.39 (d, J ) 8.1 Hz, 2H), 7.32 (d, J ) 7.8 Hz, 1H), 6.96
(dd, J ) 7.5, 2.4 Hz, 1H), 6.79-6.84 (m, 3H), 5.50 (s, 1H), 4.48-
4.60 (m, 2H), 3.82 (s, 3H), 3.35 (s, 3H). MS/(DCI) m/z: 455 (M
+ H)+. Anal. (C26H22N4O4‚HCl‚0.5H2O) C, H, N.
was extracted with EtOAc several times. The combined organic
layers were washed with brine, dried with Na2SO4, filtered,
and concentrated in vacuo to give 0.44 g of compound 40. H
NMR (TFA salt, DMSO-d6): δ 8.96 (s, 1H), 7.90 (dd, J ) 8.0,
1.7 Hz, 1H), 7.78 (d, J ) 8.4 Hz, 2H), 7.71 (d, J ) 1.6 Hz, 1H),
7.66 (d, J ) 8.1 Hz, 2H), 7.42 (d, J ) 8.1 Hz, 2H), 7.26 (t, J )
8.0 Hz, 1H), 7.18 (s, 1H), 6.90 (dd, J ) 8.3 1.4 Hz, 1H), 6.80-
6.81 (m, 2H), 5.88 (s, 1H), 4.56 (d, J ) 11.2 Hz, 1H), 4.41 (d,
J ) 11.5 Hz, 1H), 3.68 (s, 3H), 3.57 (s, 3H). MS/ESI, m/z: 454
(M + H)+. Anal. (C27H23N3O4‚0.9TFA) C, H, N.
1
4-[(5-Am in o-3′-m eth oxybiph en yl-2-ylm eth oxy)-(3-m eth -
yl-3H-im id a zol-4-yl)m eth yl]ben zon itr ile (34). A mixture
of compound 33 (1.0 g, 2.2 mmol) and SnCl2‚2H2O (1.98 g, 8.8
mmol) in 20 mL of EtOH and 10 mL of concentrated HCl was
stirred at room temperature overnight. The solution was
diluted with 100 mL of H2O, neutralized with 10% NaOH, and
extracted with EtOAc several times. The combined organic
layers were washed with H2O and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography using 100:4:0.4 EtOAc/
5-Am in o-3′-m eth oxybip h en yl-2-ca r boxylic Acid Meth -
yl Ester (42). A mixture of 2-chloro-4-nitrobenzoic acid methyl
ester (0.42 g, 2 mmol), 3-methoxyphenyl boronic acid (0.375
g, 2.4 mmol), Pd(PCy3)2Cl2 (0.074 g, 0.1 mmol), and Na2CO3
(0.64 g, 6 mmol) in 10 mL of toluene, 10 mL of dioxane, and 4
mL of EtOH was heated at reflux overnight. After the reaction
mixture was cooled to room temperature, it was partitioned
between H2O and EtOAc. The aqueous layer was extracted
with additional EtOAc. The combined organic layers were
washed with H2O and brine, dried with MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash
column chromatography using 10:90 EtOAc/hexane to give
0.58 g of 5-nitro-3′-methoxybiphenyl-2-carboxylic acid methyl
1
MeOH/NH4OH to give 0.78 g of compound 34 (84%). H NMR
(CDCl3): δ 7.57 (d, J ) 8.1 Hz, 2H), 7.38 (s, 1H), 7.23-7.28
(m, 1H), 7.19 (d, J ) 8.14 Hz, 1H), 6.85-6.90 (m, 3H), 6.66-
6.69 (m, 2H), 6.61 (d, J ) 2.3 Hz, 1H), 5.40 (s, 1H), 4.29-4.41
(m, 2H), 3.77 (s, 3H), 2.39 (s, 3H). MS/ESI, m/z: 425 (M +
H)+. Anal. (C26H24N4O2‚2HCl‚0.9H2O) C, H, N.
N-{6-[(4-Cya n op h en yl)-(3-m et h yl-3H -im id a zol-4-yl)-
m et h oxym et h yl]-3′-m et h oxyb ip h en yl-3-yl}m et h a n esu l-
fon a m id e (35). Compound 34 (64 mg, 0.15 mmol) in 5 mL of
CH2Cl2 was treated with CH3SO2Cl (17 mg, 0.15 mmol) and
Et3N (0.10 g, 0.6 mmol) at room temperature. The solution
was stirred overnight. The solvent was removed in vacuo, and
the residue was purified by flash column chromatography
using 100:4:0.4 EtOAc/MeOH/NH4OH to give 0.02 g of com-
pound 35 (27%). 1H NMR (CDCl3): δ 7.58-7.61 (m, 2H), 7.34-
7.43 (m, 4H), 7.24-7.31 (m, 3H), 7.10 (d, J ) 2.3 Hz, 1H), 6.91
(dd, J ) 8.3, 2.5 Hz, 1H), 6.80-6.85 (m, 2H), 6.74 (s, 1H), 5.44
(s, 1H), 4.38-4.49 (m, 2H), 3.79 (s, 3H), 3.32 (s, 3H), 3.06 (s,
3H). MS/ESI, m/z: 5.0 (M + H)+. Anal. (C27H26N4O4S‚TFA‚
0.7H2O) C, H, N.
1
ester. H NMR (CDCl3): δ 8.27 (dd, J ) 8.4, 2.3 Hz, 1H), 8.23
(d, J ) 2.4 Hz, 1H), 7.98 (dd, J ) 8.5, 0.7 Hz, 1H), 7.38-7.41
(m, 2H), 7.34-7.36 (m, 1H), 7.19-7.23 (m, 1H), 3.72 (s, 3H).
MS/ESI, m/z: 292 (M + H)+.
Compound 42 was prepared from 5-nitro-3′-methoxybiphe-
nyl-2-carboxylic acid methyl ester using SnCl2‚2H2O in a
similar manner described for the preparation of compound 34.
5-Cya n o-3′-m eth oxybip h en yl-2-ca r boxylic Acid Meth -
yl Ester (43). 5-Iodo-3′-methoxybiphenyl-2-carboxylic acid
methyl ester was prepared from compound 42 in a similar
manner as described in the preparation of compound 13. 1H
NMR (CDCl3): δ 7.75-7.76 (m, 2H), 7.51-7.54 (m, 1H), 7.26-
7.33 (m, 2H), 6.83-6.93 (m, 3H), 3.83 (s, 3H), 3.63 (s, 3H). MS/
ESI, m/z: 369 (M + H)+.
N-{6-[(4-Cya n op h en yl)-(3-m et h yl-3H -im id a zol-4-yl)-
m et h oxym et h yl]-3′-m et h oxyb ip h en yl-3-yl}-2-m et h oxy-
a ceta m id e (36). A mixture of compound 34 (60 mg, 0.14
mmol), methoxyacetic acid (15 mg, 0.17 mmol), HATU (66 mg,
0.17 mmol), and Et3N (34 mg, 0.34 mmol) in 5 mL of CH2Cl2
was stirred overnight. The solution was diluted with EtOAc,
washed with H2O and brine, dried with MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash
column chromatography using 100:4:0.4 EtOAc/MeOH/NH4-
Compound 43 was prepared using the general procedure of
cyanation of aryl iodides from 5-iodo-3′-methoxybiphenyl-2-
1
carboxylic acid methyl ester. H NMR (CDCl3): δ 7.85 (d, J )
8.5 Hz, 1H), 7.67-7.71 (m, 2H), 7.31-7.36 (m, 1H), 6.93-6.97
(m, 1H), 6.82-6.88 (m, 2H), 3.84 (s, 3H), 3.68 (s, 3H). MS/
ESI, m/z: 268 (M + H)+.
6-H yd r oxym e t h yl-3′-m e t h oxyb ip h e n yl-3-ca r b a ld e -
h yd e (44). Compound 43 (0.67 g, 2.51 mmol) in 20 mL of
toluene was treated with 1.5 M DIBAL in toluene (4.2 mL,
6.3 mmol) at -78 °C. The solution was stirred at -78 °C for 2
h and warmed to room temperature gradually. The reaction
mixture was treated with 10 mL of concentrated HCl and
partitioned between H2O and EtAOc. The aqueous layer was
extracted with additional EtOAc. The combined organic layers
were washed with H2O and brine, dried with MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
column chromatography using 30:70 EtOAc/hexane to give
0.59 g of 6-hydroxymethyl-3′-methoxybiphenyl-3-carbaldehyde
42 (95%). MS/(DCI) m/z: 243 (M + H)+.
4-[(5-For m yl-3′-m eth oxybiph en yl-2-ylm eth oxy)-(3-m eth -
yl-3H-im id a zol-4-yl)m eth yl]ben zon itr ile (45). A mixture
of compound 42 (0.61 g, 2.54 mmol), LiBr (0.254 g, 2.92 mmol)
in 5 mL of DMF was treated with PBr3 (0.25 mL, 2.63 mmol)
at 0 °C. The solution was stirred at 0 °C for 2 h, poured into
water, and extracted with EtOAc several times. The combined
organic layers were washed with H2O and brine, dried with
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography using 10:90 EtOAc/
hexane to give 0.63 g of 6-bromomethyl-3′-methoxybiphenyl-
3-carbaldehyde 42 (82%). 1H NMR (CDCl3): δ 10.05 (s, 1H),
7.63-7.90 (m, 3H), 7.37-7.42 (m, 1H), 6.95-7.03 (m, 3H), 4.47
(s, 2H), 3.87 (s, 3H). MS/(DCI) m/z: 306 (M + H)+.
1
OH to give 53 mg of compound 36 (77%). H NMR (CH3OH-
d4): δ 8.84 (s, 1H), 7.67-7.74 (m, 3H), 7.54 (d, J ) 2.0 Hz,
1H), 7.50 (d, J ) 8.1 Hz, 1H), 7.44 (d, J ) 8.1 Hz, 2H), 7.30 (t,
J ) 7.8 Hz, 1H), 7.09 (s, 1H), 6.95 (dd, J ) 8.5, 1.7 Hz, 1H),
6.83-6.87 (m, 2H), 5.75 (s, 1H), 4.48-4.59 (m, 2H), 4.04 (s,
2H), 3.79 (s, 3H), 3.65 (s, 3H), 3.48 (s, 3H). MS/ESI, m/z: 496
(M + H)+. Anal. (C29H28N4O4‚HCl‚H2O) C, H, N.
3′-Meth oxy-6-m eth ylbip h en yl-3-ca r boxylic Acid Meth -
yl Ester (38). Compound 38 was prepared via the Suzuki
coupling from compound 37 in a similar manner as described
for the preparation of compound 7. 1H NMR (CDCl3): δ 7.91-
7.93 (m, 2H), 7.31-7.36 (m, 2H), 6.85-6.93 (m, 3H), 3.90 (s,
3H), 3.84 (s, 3H), 2.32 (s, 3H). MS/(DCI) m/z: 257 (M + H)+.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-3′-m eth oxybip h en yl-3-ca r boxylic Acid
Meth yl Ester (39). Compound 39 was prepared from com-
pound 38 in a similar manner as described for the preparation
1
of compound 6. H NMR (CDCl3): δ 8.04 (dd, J ) 8.0, 1.9 Hz,
1H), 7.91 (d, J ) 1.7 Hz, 1H), 7.56-7.62 (m, 3H), 7.36-7.40
(m, 3H), 7.28 (d, J ) 7.8 Hz, 1H), 6.92 (d, J ) 7.8, 2.0 Hz, 1H),
6.81-6.85 (m, 2H), 6.77 (s, 1H), 5.46 (s, 1H), 4.46-4.67 (m,
2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.31 (s, 3H). MS/ESI, m/z: 468
(M + H)+. Anal. (C28H25N3O4‚0.5H2O) C, H, N.
6-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-3′-m eth oxybip h en yl-3-ca r boxylic Acid
(40). A mixture of compound 39 (0.58 g, 1.23 mmol) and LiOH
(59 mg, 2.46 mmol) in 10 mL of H2O and 5 mL of methanol
was stirred at room temperature for 2 days. The pH value of
the solution was adjusted to 6 using 1 M NaHSO4. The solution
A mixture of 6-bromomethyl-3′-methoxybiphenyl-3-carbal-
dehyde (0.23 g, 0.75 mmol), compound 4a (0.106 g, 0.5 mmol),
and Ag2O (0.34 g, 1.5 mmol) in 10 mL of CH2Cl2 was stirred
at room temperature overnight while the flask was covered
with aluminum foil. The solution was filtered through a pack

624 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Wang et al.
of Celite, and the filtrate was purified by flash column
chromatography using 100:5:0.5 EtOAc/methanol/NH4OH to
give 0.133 g of 45 (60%). 1H NMR (CDCl3): δ 10.05 (s, 1H),
7.88-7.92 (m, 2H), 7.80 (d, J ) 1.7 Hz, 1H), 7.68 (d, J ) 7.8
Hz, 1H), 7.62 (d, J ) 8.5 Hz, 2H), 7.50 (s, 1H), 7.38 (d, J ) 81.
Hz, 2H), 7.29-7.34 (m, 1H), 6.94 (dd, J ) 7.8, 2.0 Hz, 1H),
6.80-6.85 (m, 3H), 5.48 (s, 1H), 4.48-4.59 (m, 2H), 3.81 (s,
3H), 3.34 (s, 3H). MS/ESI, m/z: 438 (M + H)+. Anal.
(C27H23N3O3‚0.4 H2O) C, H, N.
3′-Ch lor o-6-[(4-cya n op h en yl)-(2,3-d im eth yl-3H-im id a -
zol-4-yl)m eth oxym eth yl]bip h en yl-3-ca r bon itr ile (52). A
mixture of compound 4h (0.113 g, 0.5 mmol) and 6-bromo-
methyl-3′-chlorobiphenyl-3-carbonitrile (0.153 g, 0.5 mmol),
which was prepared from compound 46a using the general
procedure for the preparation of benzyl bromide, in 5 mL of
DME was treated with 60% NaH in mineral oil (40 mg, 1
mmol) at 0 °C. The solution was stirred at room temperature
overnight, poured into H2O, and extracted with EtOAc several
times. The combined organic layers were washed with brine,
dried with MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography using
100:5:0.5 EtOAc/methanol/NH4OH to give 0.108 g of compound
3′-Ch lor o-6-m eth ylbip h en yl-3-ca r bon itr ile (46a ). Com-
pound 46a was prepared via Suzuki coupling from compound
13 in a similar manner as described for the preparation of
1
compound 7. H NMR (CDCl3): δ 7.54-7.57 (m, 1H), 7.49 (d,
1
J ) 1.7 Hz, 1H), 7.36-7.39 (m, 3H), 7.27-7.29 (m, 1H), 7.14-
7.18 (m, 1H), 2.31 (s, 3H). MS/ESI, m/z: 228 (M + H)+.
3′-Meth oxy-6-m eth ylbiph en yl-3-car bon itr ile (46b). Com-
pound 46b was prepared via Suzuki coupling from compound
13 in a similar manner as described for the preparation of
compound 7. 1H NMR (CDCl3): δ 7.52-7.55 (m, 2H), 7.33-
7.38 (m, 2H), 6.93 (dd, J ) 7.5, 2.7 Hz, 1H), 6.85 (m, 1H), 6.79-
6.80 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H). MS/ESI, m/z: 224 (M
+ H)+.
52 (48%). H NMR (CDCl3): δ 7.67-7.71 (m, 1H), 7.60-7.65
(m, 3H), 7.56 (d, J ) 1.7 Hz, 1H), 7.32-7.42 (m, 4H), 7.27-
7.28 (m, 1H), 7.11-7.14 (m, 1H), 6.70 (s, 1H), 5.43 (s, 1H),
4.39-4.53 (m, 2H), 3.19 (s, 3H), 2.33 (s, 3H). MS/ESI, m/z: 453
(M + H)+. Anal. (C27H21ClN4O‚HCl‚1.3H2O) C, H, N.
3-Ben zo[1,3]d ioxol-5-yl-4-[(4-cya n op h en yl)-(2,3-d im e-
th yl-3H-im id a zol-4-yl)m eth oxym eth yl]ben zon itr ile (53).
Compound 53 was prepared from compound 46c in a similar
1
manner as described for the preparation of compound 52. H
3-Ben zo[1,3]dioxol-5-yl-4-m eth ylben zon itr ile (46c). Com-
pound 46c was prepared via Suzuki coupling from compound
13 in a similar manner as described for the preparation of
NMR (CDCl3): δ 7.63-7.65 (m, 4H), 7.55 (s, 1H), 7.42 (d, J )
8.5 Hz, 1H), 6.84 (d, J ) 7.8 Hz, 1H), 6.66-6.71 (m, 3H), 6.03
(s, 2H), 5.45 (s, 1H), 4.43-4.56 (m, 2H), 3.22 (s, 3H), 2.34 (s,
3H). MS/ESI, m/z: 463 (M + H)+. Anal. (C28H22N4O3‚0.55H2O)
C, H, N.
1
compound 7. H NMR (CDCl3): δ 7.48-7.52 (m, 2H), 7.34 (d,
J ) 7.8 Hz, 1H), 6.88 (d, J ) 7.5 Hz, 1H), 6.70-6.75 (m, 2H),
6.02 (s, 2H), 2.32 (s, 3H). MS/ESI, m/z: 238 (M + H)+.
6-[(4-C h lo r o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m eth oxym eth yl]-3′-m eth oxybip h en yl-3-ca r bon itr ile (47).
Compound 47 was prepared from compound 46b in a similar
manner as described for the preparation of compound 6. 1H
NMR (HCl salt, MeOH-d4): δ 8.84 (s, 1H), 7.75-7.76 (m, 2H),
7.62 (s, 1H), 7.38-7.41 (m, 2H), 7.27-7.35 (m, 3H), 7.10 (s,
1H), 6.97-7.00 (m, 1H), 6.81-6.84 (m, 2H), 5.70 (s, 1H), 4.51-
4.63 (m, 2H), 3.79 (s, 3H), 3.69 (s, 3H). MS/ESI, m/z: 429 (M
+ H)+. Anal. (C26H22ClN3O2‚HCl‚0.9H2O) C, H, N.
3′-Ch lor o-6-[(4-cya n op h en yl)th ia zol-5-ylm eth oxym eth -
yl]bip h en yl-3-ca r bon itr ile (54). Compound 54 was prepared
from compound 46a in a similar manner as described for the
preparation of compound 52. 1H NMR (CDCl3): δ 8.80 (s, 1H),
7.63-7.71 (m, 5H), 7.56 (d, J ) 1.7 Hz, 1H), 7.43 (d, J ) 8.1
Hz, 2H), 7.27-7.39 (m, 3H), 7.10-7.13 (m, 1H), 5.86 (s, 1H),
4.39-4.49 (m, 2H). MS/ESI, m/z: 442 (M + H)+. Anal. (C25H16
ClN3OS‚0.5TFA) C, H, N.
-
3′-Ch lor o-6-[(4-ch lor op yr id in -3-yl)-(4-cya n op h en yl)-
m eth oxym eth yl]bip h en yl-3-ca r bon itr ile (55). Compound
55 was prepared from compound 46c in a similar manner as
described for the preparation of compound 52. 1H NMR
(CDCl3): δ 8.68 (s, 1H), 8.44-8.46 (m, 1H), 7.60-7.65 (m, 4H),
7.54 (s, 1H), 7.43 (d, J ) 8.1 Hz, 2H), 7.30-7.33 (m, 1H), 6.80
(d, J ) 8.1 Hz, 1H), 6.63-6.67 (m, 2H), 6.03 (s, 2H), 5.78 (s,
6-[(3-Ch lor o-4-cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-
yl)m et h oxym et h yl]-3′-m et h oxyb ip h en yl-3-ca r b on it r ile
(48). Compound 48 was prepared from compound 46b in a
similar manner as described for the preparation of compound
6. 1H NMR (CDCl3): δ 7.66-7.69 (m, 1H), 7.58-7.63 (m, 3H),
7.42 (d, J ) 8.5 Hz, 2H), 7.30-7.35 (m, 1H), 7.2 (dd, J ) 8.8,
1.7 Hz, 1H), 6.95 (dd, J ) 8.0, 2.2 Hz, 1H), 6.86 (s, 1H), 6.76-
6.81 (m, 2H), 5.43 (s, 1H), 4.44-4.57 (m, 2H), 3.81 (s, 3H), 3.29
(s, 3H). MS/ESI, m/z: 469 (M + H)+. Anal. (C27H21ClN4O2‚
0.55H2O) C, H, N.
1H), 4.49 (s, 2H). MS/ESI, m/z: 472 (M + H)+. Anal. (C28H18
ClN3O3‚2HCl‚0.6H2O) C, H, N.
-
4-[(4-Iod o-2-n itr oben zyloxy)-(3-m eth yl-3H-im id a zol-4-
yl)m eth yl]ben zon itr ile (57). Compound 57 was prepared
from compound 56 in a similar manner as described for the
preparation of compound 33. 1H NMR (CDCl3): δ 8.38 (d, J )
1.7 Hz, 1H), 7.97 (dd, J ) 8.1, 1.7 Hz, 1H), 7.69 (d, J ) 8.1 Hz,
2H), 7.45-7.51 (m, 4H), 6.89 (s, 1H), 5.67 (s, 1H), 4.76-4.92
(m, 2H), 3.43 (s, 3H). MS/(DCI) m/z: 475 (M + H)+.
3′-Ch lor o-6-[(4-cya n o-3-flu or op h en yl)-(3-m et h yl-3H -
im id a zol-4-yl)m et h oxym et h yl]b ip h en yl-3-ca r b on it r ile
(49). Compound 49 was prepared from compound 46a in a
similar manner as described for the preparation of compound
1
6. H NMR (HCl salt, MeOH-d4): δ 7.69-7.71 (m, 1H), 7.57-
4-[(2-Am in o-4-iod oben zyloxy)-(3-m eth yl-3H-im id a zol-
4-yl)m eth yl]ben zon itr ile (58). Compound 58 was prepared
from compound 57 in a similar manner as described for the
preparation of compound 34. 1H NMR (CDCl3): δ 7.66 (d, J )
8.5 Hz, 2H), 7.51 (s, 1H), 7.45 (d, J ) 8.1, Hz, 2H), 7.03-7.07
(m, 2H), 6.95 (s, 1H), 6.68 (d, J ) 7.5 Hz, 1H), 5.54 (s, 1H),
4.41-4.54 (m, 2H), 3.37 (s, 3H). MS/(DCI) m/z: 445 (M + H)+.
Th iop h en e-2-su lfon ic Acid {2-[(4-Cya n op h en yl)-(3-
m eth yl-3H-im ida zol-4-yl)m eth oxym eth yl]-5-iod op h en yl}-
a m id e (59a ). A mixture of compound 58 (0.10 g, 0.23 mmol),
thiophene-2-sulfonyl chloride (0.043 g, 0.24 mmol), and 0.2 mL
of pyridine in 5 mL of CH2Cl2 was stirred at room temperature
overnight. The solution was poured into water and extracted
with additional CH2Cl2. The combined organic layers were
washed with brine, dried with MgSO4, and concentrated. The
residue was purified by flash column chromatography using
100:5:0.5 EtOAc/methanol/NH4OH to give 0.110 g of compound
59a (81%). 1H NMR (CDCl3): δ 7.68-7.82 (m, 5H), 7.56 (dd, J
) 5.1, 1.4 Hz, 1H), 7.50 (dd, J ) 8.0, 1.5 Hz, 1H), 7.42-7.49
(m, 3H), 7.14 (s, 1H), 7.00-7.03 (m, 1H), 6.91 (d, J ) 9.1 Hz,
1H), 5.56 (s, 1H), 4.30-4.51 (m, 2H), 3.40 (s, 3H). MS/ESI,
m/z: 591 (M + H)+.
7.61 (m, 3H), 7.33-7.43 (m, 3H), 7.27 (d, J ) 3.8 Hz, 1H),
7.10-7.19 (m, 3H), 6.91 (s, 1H), 7.21-7.22 (m, 4H), 5.47 (s,
1H), 4.41-4.54 (m, 2H), 3.30 (s, 3H). MS/ESI, m/z: 457 (M +
H)+. Anal. (C26H18ClFN4O‚HCl‚0.7H2O) C, H, N.
3′-Ch lor o-6-[(4-cya n o-2-flu or op h en yl)-(3-m et h yl-3H -
im id a zol-4-yl)m et h oxym et h yl]b ip h en yl-3-ca r b on it r ile
(50). Compound 50 was prepared from compound 46a in a
similar manner as described for the preparation of compound
6. 1H NMR (CDCl3): δ 7.68-7.70 (m, 1H), 7.62 (d, J ) 8.1 Hz,
1H), 7.57-7.60 (m, 1H), 7.55 (s, 1H), 7.49 (d, J ) 7.5 Hz, 1H),
7.40-7.42 (m, 2H), 7.32-7.35-7.22 (m, 2H), 7.23-7.25 (m,
1H), 7.10 (d, J ) 7.5 Hz, 1H), 5.72 (s, 1H), 4.39-4.49 (m, 2H),
3.50 (s, 3H). MS/ESI, m/z: 456 (M + H)+. Anal. (C26H18ClFN4O‚
HCl‚0.7H2O) C, H, N.
3′-Ch lor o-6-[(3-m et h yl-3H -im id a zol-4-yl)-(4-t r iflu or o-
m et h ylp h en yl)m et h oxym et h yl]b ip h en yl-3-ca r b on it r ile
(51). Compound 51 was prepared from compound 45a in a
similar manner as described for the preparation of compound
6. 1H NMR (CDCl3): δ 7.56-7.70 (m, 5H), 7.26-7.41 (m, 6H),
7.12 (d, J ) 7.1 Hz, 1H), 6.83 (s, 1H), 5.50 (s, 1H), 4.40-4.62
(m, 2H), 3.34 (s, 3H). MS/ESI, m/z: 483 (M + H)+. Anal.
(C26H19ClF3N3O) C, H, N.

Benzonitriles as Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 625
1
Th iop h en e-2-su lfon ic Acid {5-Cya n o-2-[(4-cya n op h e-
n yl)-(3-m eth yl-3H-im idazol-4-yl)m eth oxym eth yl]ph en yl}-
a m id e (60a ). Compound 60a was prepared from compound
59a using the general procedure of cyanation of aryl halides
(bromide or iodide). 1H NMR (CDCl3): δ 7.69-7.73 (m, 3H),
7.69 (s, 1H), 7.58 (dd, J ) 5.1, 1.4 Hz, 1H), 7.42-7.47 (m, 4H),
7.31 (s, 1H), 7.26-7.28 (m, 1H), 7.01-7.06 (m, 2H), 5.58 (s,
1H), 4.42-4.59 (m, 2H), 3.37 (s, 3H). MS/ESI, m/z: 489 (M +
H)+. Anal. (C24H19N5O3S2‚1.28TFA‚0.4H2O) C, H, N.
N-{5-Cya n o-2-[(4-cya n oph en yl)-(3-m eth yl-3H-im id a zol-
4-yl)m et h oxym et h yl]p h en yl}-4-m et h ylb en zen esu lfon a -
m id e (60b). Compound 60b was prepared from compound 59b
in a similar manner as described for the preparation of
compound 60a . 1H NMR (CDCl3): δ 7.69-7.72 (m, 3H), 7.50-
7.53 (m, 3H), 7.46 (d, J ) 7.8 Hz, 2H), 7.37 (dd, J ) 7.8, 1.4
Hz, 1H), 7.19-7.24 (m, 3H), 7.00 (s, 1H), 5.55 (s, 1H), 4.34-
4.51 (m, 2H), 3.36 (s, 3H), 2.39 (s, 3H). MS/ESI, m/z: 498 (M
+ H)+. Anal. (C27H23N5O3S‚HCl‚1.6H2O) C, H, N.
aryl iodide. H NMR (CDCl3): δ 9.25 (s, 1H), 8.75 (d, J ) 1.7
Hz, 1H), 7.69 (d, J ) 6.8 Hz, 2H), 7.56-7.63 (m, 3H), 7.40-
7.45 (m, 6H), 7.23 (d, J ) 7.8 Hz, 1H), 7.00 (s, 1H), 5.64 (s,
1H), 4.68-4.81 (m, 2H), 3.33 (s, 3H). MS/ESI, m/z: 548 (M +
H)+. Anal. (C27H21N5O2‚0.5H2O) C, H, N.
5-Cya n o-2-[(4-cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-
yl)m eth oxym eth yl]ben zoic Acid Meth yl Ester (63). A
mixture of 3-iodo-4-methylbenzonitrile (13) (2.92 g, 12.01
mmol), Pd(dppf)Cl2 (0.33 g, 0.45 mmol), triethylamine (2.5 g,
24 mmol), and 40 mL of MeOH in an autoclave was charged
with carbon monoxide to 450 psi. The autoclave was heated
at 120 °C for 20 h. After cooling to room temperature, the
reaction mixture was filtered and concentrated in vacuo. The
residue was purified by flash chromatography, eluting with
15:85 EtOAc/hexane to give 1.33 g of 5-cyano-2-methylbenzoic
1
acid methyl ester as a white solid (62%). H NMR (CDCl3): δ
8.21 (d, J ) 1.7 Hz, 1H), 7.66 (dd, J ) 8.0, 1.9 Hz, 1H), 7.37
(d, J ) 7.8 Hz, 1H), 3.93 (s, 3H), 2.68 (s, 3H). MS (DCI/NH3)
m/z: 193 (M + NH4)+.
Na p h th a len e-1-su lfon ic Acid {5-Cya n o-2-[(4-cya n op h e-
n yl)-(3-m eth yl-3H-im idazol-4-yl)m eth oxym eth yl]ph en yl}-
a m id e (60c). Compound 60c was prepared from compound
59c in a similar manner as described for the preparation of
Compound 63 was prepared from 5-cyano-2-methylbenzoic
acid methyl ester in a similar manner as described for the
preparation of compound 6. H NMR (CDCl3): δ 8.28 (s, 1H),
7.89 (d, J ) 8.1 Hz, 1H), 7.83 (d, J ) 8.1 Hz, 1H), 7.69 (d, J )
8.4 Hz, 2H), 7.54 (d, J ) 8.1 Hz, 2H), 7.48 (s, 1H), 6.89 (s,
1H), 5.72 (s, 1H), 5.01 (m, 2H), 3.89 (s, 3H), 3.45 (s, 3H). MS
(DCI/NH3) m/z: 387 (M + H)+.
1
1
compound 60a . H NMR (CDCl3): δ 8.43 (d, J ) 8.8 Hz, 1H),
8.23 (d, J ) 7.5 Hz, 1H), 8.08 (d, J ) 8.5 Hz, 1H), 7.95 (d, J )
8.1 Hz, 1H), 7.70 (d, J ) 8.5 Hz, 2H), 7.47-7.63 (m, 7H), 7.30
(dd, J ) 7.8, 1.4 Hz, 1H), 7.13 (d, J ) 7.8 Hz, 1H), 6.94 (s,
1H), 5.48 (s, 1H), 4.25-4.45 (m, 2H), 3.35 (s, 3H). MS/ESI,
m/z: 533 (M + H)+. Anal. (C30H23N5O3S‚HCl‚0.5H2O) C, H,
N.
5-Cya n o-2-[(4-cya n op h en yl)-(3-m eth yl-3H-im id a zol-4-
yl)m eth oxym eth yl]-N-p h en ylben za m id e (64). A solution
of 5-cyano-2-[(4-cyanophenyl)-(3-methyl-3H-imidazol-4-yl)-
methoxymethyl]benzoic acid methyl ester (63) (0.426 g, 1.10
mmol) in THF/methanol (12 mL/4 mL) at 0 °C was treated
with a solution of LiOH‚H2O (0.139 g, 3.30 mmol) in water (1
mL), warmed to room temperature, stirred for about 18 h, and
concentrated. The residue was dissolved in water, adjusted to
pH 5 with 1 N HCl, and extracted three times with dichlo-
romethane. The combined organic phases were dried (MgSO4),
filtered, and concentrated to provide 0.349 g of 5-cyano-2-[(4-
cyanophenyl)-(3-methyl-3H-imidazol-4-yl)methoxymethyl]ben-
zoic acid hydrochloride that was used directly without further
purification (78%). 1H NMR (CDCl3): δ 9.11 (br s, 1H), 7.87
(d, J ) 8.1 Hz, 1H), 7.81-7.79 (m, 2H), 7.70 (d, J ) 8.4 Hz,
2H), 7.54 (d, J ) 7.8 Hz, 2H), 7.35 (s, 1H), 5.77 (s, 1H), 5.07
(m, 2H), 3.37 (s, 3H).
A mixture of of 5-cyano-2-[(4-cyanophenyl)-(3-methyl-3H-
imidazol-4-yl)methoxymethyl]benzoic acid hydrochloride (25.0
mg, 0.0611 mmol), aniline (8.5 mg, 0.0917 mmol), EDC (17.6
mg, 0.0917 mmol), HOBT (12.4 mg, 0.0917), and diisopropyl-
ethylamine (24 mg, 0.183 mmol) in DMF (1.5 mL) was stirred
at room temperature for 24 h. The solution was poured into
water and extracted with EtOAc three times. The combined
organic layers were washed with saturated NaHCO3 and brine,
dried (MgSO4), filtered, and concentrated. The residue was
purified by flash column chromatography, eluting with ethyl
acetate/methanol/NH4OH (10:0.2:0.02 to 10:1:0.1) to provide
4-[(4-C y a n o p h e n y l)-(3-m e t h y l-3H -im id a zo l-4-y l)-
m et h oxym et h yl]-3-(3,5-d iflu or ob en zyla m in o)b en zon i-
tr ile (61). A mixture of compound 58 (0.150 g, 0.34 mmol),
3,5-difluorobenzaldehyde (0.096 g, 0.68 mmol), acetic acid
(0.122 g, 2.054 mmol), and NaBH(OAc)3 (0.432 g, 2.04 mmol)
in 10 mL of 1,2-dichloroethane was stirred overnight. The
reaction mixture was partitioned between water and EtOAc.
The aqueous layer was extracted with additional EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated. The residue was purified by flash
column chromatography using 100:5:0.5 EtOAc/methanol/NH4-
OH to give 0.100
g of 4-[[2-(3,5-difluorobenzylamino)-4-
iodobenzyloxy]-(3-methyl-3H-imidazol-4-yl)methyl]benzoni-
trile (52%). 1H NMR (CDCl3): δ 7.62 (d, J ) 8.5 Hz, 2H), 7.37-
7.44 (m, 3H), 7.06 (dd, J ) 7.8, 1.4 Hz, 1H), 6.98 (s, 1H), 6.89
(d, J ) 1.7 Hz, 1H), 6.69-6.78 (m, 4H), 5.55 (s, 1H), 4.98 (d, J
) 5.4 Hz, 1H), 4.45-4.63 (m, 2H), 4.30 (d, J ) 5.8 Hz, 2H),
3.29 (s, 3H). MS/ESI, m/z: 571 (M + H)+.
Compound 61 was prepared from 4-[[2-(3,5-difluoroben-
zylamino)-4-iodobenzyloxy]-(3-methyl-3H-imidazol-4-yl)meth-
yl]benzonitrile using the general procedure for the cyanation
1
of aryl iodide. H NMR (HCl salt, MeOH-d4): δ 8.93 (s, 1H),
7.79-7.81 (m, 2H), 7.66 (d, J ) 8.1 Hz, 2H), 7.36 (s, 1H), 7.30
(d, J ) 7.8 Hz, 1H), 6.82-6.98 (m, 4H), 6.73 (s, 1H), 5.97 (s,
1H), 4.74 (s, 2H), 4.44 (s, 2H), 3.74 (s, 3H). MS/ESI, m/z: 458
(M + H)+. Anal. (C27H21F2N5O‚1.5TFA) C, H, N.
1
13.0 mg of the desired product as an off-white solid (48%). H
NMR (CDCl3): δ 8.38 (s, 1H), 7.89 (s, 1H), 7.74 (dd, J ) 8.1,
1.6 Hz, 1H), 7.62 (d, J ) 7.8 Hz, 1H), 7.50-7.55 (m, 4H), 7.43
(d, J ) 8.1 Hz, 2H), 7.34-7.37 (m, 3H), 7.19 (t, J ) 7.5 Hz,
1H), 6.79 (s, 1H), 7.09-7.08 (m, 1H), 6.69 (s, 1H), 5.62 (s, 1H),
4.79-4.89 (m, 2H), 3.34 (s, 3H). MS ESI, m/z 448 (M + H)+.
Anal. (C27H21N5O2‚0.5H2O) C, H, N.
N -(3-Ch lor op h e n yl)-5-cya n o-2-[(4-cya n op h e n yl)-(3-
m eth yl-3H-im idazol-4-yl)m eth oxym eth yl]ben zam ide (65).
Compound 65 was prepared in a similar manner as described
for the preparation of compound 64 from compound 63. 1H
NMR (CDCl3): δ 8.70 (s, 1H), 7.81 (s, 1H), 7.66 (d, J ) 8.1 Hz,
1H), 7.57 (s, 1H), 7.54 (d, J ) 8.1 Hz, 1H), 7.50 (d, J ) 8.4 Hz,
2H), 7.36 (d, J ) 8.4 Hz, 2H), 7.29-7.26 (m, 1H), 7.21-7.18
(m, 2H), 7.09-7.08 (m, 1H), 6.69 (s, 1H), 5.55 (s, 1H), 4.76-
4.86 (m, 2H), 3.28 (s, 3H). MS ESI, m/z 482.0 (M + H)+. Anal.
(C27H20ClN5O2‚1.45TFA) C, H, N.
N-{5-Cya n o-2-[(4-cya n op h en yl)-(3-m eth yl-3H-im id a zol-
4-yl)m eth oxym eth yl]p h en yl}ben za m id e (62). A mixture
of compound 58 (0.10 g, 0.23 mmol), benzoyl chloride (0.042
g, 0.30 mmol), and Et3N (0.040 g, 0.38 mmol) in 3 mL of CH2-
Cl2 was stirred overnight. The reaction mixture was parti-
tioned between H2O and EtOAc. The aqueous layer was
extracted with additional EtOAc. The combined organic layers
were washed with brine, dried, and concentrated in vacuo. The
residue was purified by flash column chromatography using
100:3:0.3 EtOAc/methanol/NH4OH to give 0.073 g of N-{2-[(4-
cyanophenyl)-(3-methyl-3H-imidazol-4-yl)methoxymethyl]-5-
iodophenyl}benzamide (58%). 1H NMR (CDCl3): δ 9.08 (s, 1H),
8.77 (d, J ) 1.7 Hz, 1H), 7.69 (d, J ) 7.1 Hz, 2H), 7.57-7.61
(m, 3H), 7.39-7.49 (m, 6H), 6.99 (s, 1H), 6.84 (d, J ) 7.8 Hz,
1H), 5.61 (s, 1H), 4.58-4.72 (m, 2H), 3.32 (s, 3H). MS/ESI,
m/z: 548 (M + H)+.
Compound 62 was prepared from N-{2-[(4-cyanophenyl)-(3-
methyl-3H-imida zol-4-yl)methoxymethyl]-5-iodophenyl}-
benzamide using the general procedure for the cyanation of
In Vitr o En zym e Assa ys. The in vitro activity of com-
pounds inhibiting FTase or GGTase-I was determined by using
scintillation proximity assay (SPA) technology.16 Briefly, the

626 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Wang et al.
P.; Ewing, P.; Alder, J .; Mitten, M.; Leal, J .; Marsh, K.; Bauch,
J .; Hoffman, D. J .; Sebti, S. M.; Rosenberg, S. H. Second-
Generation Peptidomimetic Inhibitors of Protein Farnesyltrans-
ferase Demonstrating Improved Cellular Potency and Significant
in Vivo Efficacy. J . Med. Chem. 1999, 42, 3701-3710. (c) Henry,
K. J .; Wasicak, J .; Tasker, A. S.; Cohen, J .; Ewing, P.; Mitten,
M.; Larsen, J . L.; Kalvin, D. M.; Swenson, R.; Ng, S.-C.; Saeed,
S.; Cherian, S.; Sham, H. L.; Rosenberg, S. H. Discovery of a
Series of Cyclohexylethylamine-Containing Protein Farnesyl-
transferase Inhibitors Exhibiting Potent Cellular Activity. J .
Med. Chem. 1999, 42, 4844-4852.
assays were performed with recombinant human FTase or
purified bovine brain FTase or GGTase-I [3H]-FPP (NEN) and
a biotin conjugated K-ras (B) decapeptide (KKSKTKCVIM) in
50 mM Hepes, 30 mM MgCl2, 20 mM KCl, 5 mM DDT, 0.01%
Triton X-100, pH 7.0. After 30 min of incubation, stop/
streptandin coated bead reagent was added and the counts
associated with the beads were determined using a Packard
TopCount scintillation plate reader (Packard).
Ra s P r ocessin g Assa y. Western blot assay was performed
to determine the activity of compounds in blocking Ras post-
translational processing in intact cells.16 The processed and
unprocessed Ras proteins were separated by gel electrophore-
sis and immunoblotted with a Pan-Ras antibody (Transduction
Laboratories, Lexington, KY) and quantified by densitometry
using an image analysis program Image-Pro Plus (Media
Cybernetics, Silver Spring, MD).
(7) Wang, W.; et al. Manuscript in preparation.
(8) Sun, J .; Qian, Y.; Hamilton, A. D.; Sebti, S. M. Both farnesyl-
transferase and geranylgeranyltransferase
I inhibitors are
required for inhibition of oncogenic K-Ras prenylation but each
alone is sufficient to suppress human tumor growth in nude
mouse xenografts. Oncogene 1998, 16 1467-1473.
(9) Cox, A. D.; Der, C. J . Farnesyltransferase inhibitors and cancer
treament: targeting simply Ras? Biochim. Biophys. Acta Rev.
1997, 1333, F51-F71.
(10) Lobell, R. B.; Omer, C. A.; Abrams, M. T.; Bhimnathwala, H.
G.; Brucker, M. J .; Buser, C. A.; Davide, J . P.; deSolms, S. J .;
Dinsmore, C. J .; Ellis-Huntchings, M. S.; Kral, A. M.; Liu, D.;
Lumma, W. C.; Machotka, S. V.; Rands, E.; Williams, T. M.;
Graham, S. L.; Hartman, G. D.; Oliff, A. I.; Heimbrook, D. C.;
Kohl, N. F. Evaluation of Farnesyl:Protein Transferase and
Geranylgeranyl:Protein Transferase Inhibitor Combinations in
Preclinical Models. Cancer Res. 2001, 61, 8758-8768.
(11) ClogP values were calculated using software ChemDraw Ultra
developed by CambridgeSoft. Com.
(12) Bell, I. M.; Gallicchio, S. N.; Abrams, M.; Beshore, D. C.; Buser,
C. A.; Culberson, J . C.; Davide, J .; Ellis-Hutchings, M.; Christine
Fernandes, C.; Gibbs, J . B.; Graham, S. L.; Hartman, G. D.;
Heimbrook, D. C.; Homnick, C. F.; Huff, J . R.; Kassahun, K.;
Koblan, K. S.; Kohl, N. E.; Lobell, R. B.; J Lynch, J . J ., J r.; Miller,
P. A.; Omer, C. A.; Rodrigues, A. D.; Walsh, E. S.; Williams, T.
M. Design and Biological Activity of (S)-4-(5-{[1-(3-Chloroben-
zyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)ben-
zonitrile, a 3-Aminopyrrolidinone Farnesyltransferase Inhibitor
with Excellent Cell Potency,. J . Med. Chem. 2001, 44, 2933-
2949.
(13) Williams, T. M.; Bergman, J . M.; Brashear, K.; Breslin, M. J .;
Dinsmore, C. J .; Hutchinson, J . H.; MacTough, S. C.; Stump, C.
A.; Wei, D. D.; Zartman, C. B.; Bogusky, M. J .; Culberson, J . C.;
Buser-Doepner, C.; Davide, J .; Greenberg, I. B.; Hamilton, K.
A.; Koblan, K. S.; Kohl, N. E.; Liu, D.; Lobell, R. B.; Mosser, S.
D.; O’Neill, T. J .; Rands, E.; Schaber, M. D.; Wilson, F.;
Senderak, E.; Motzel, S. L.; Gibbs, J . B.; Graham, S. L.;
Heimbrook, D. C.; Hartman, G. D.; Oliff, A. I.; Huff, J . R.
N-Arylpiperazinone Inhibitors of Farnesyltransferase: Discovery
and Biological Activity. J . Med. Chem. 1999, 42, 3779-3784.
(14) (a) Tong, Y.; Lin, N.-H.; Wang, L.; Hasvold, L.; Wang, W.;
Leonard, N.; Li, T.; Li, Q.; Cohen, J .; Gu, W.-Z.; Zhang, H.; Stoll,
V.; Bauch, J .; Marsh, K.; Rosenberg, S. H.; Sham, H. L. Discovery
of potent imidazole and cyanophenyl containing farnesyltrans-
ferase inhibitors with improved oral bioavailability. Bioorg. Med.
Chem. Lett. 2003, 13, 1571-1574. (b) Gu, W.-Z.; J oseph, I.;
Wang, Y.-C.; Frost, D.; Sullivan, G.; Wang, L.; Lin, N.-H.; Stoll,
V.; Anderson, M.; Kroeger, P.; Marsh, M.; Ng, S.; Rosenberg, S.
H.; Sham, H. L.; Zhang, Z. The effect of A-409100, a potent and
highly selective farnesyl transferase inhibitor in vitro and in
vivo. Cancer Res., submitted.
Ackn owledgm en t. We gratefully acknowledge Struc-
tural Chemistry Department of Abbott Pharmaceutical
Discover (Department 0418) for collecting NMR and
mass data. We express our appreciation to Dr. Michael
D. Wendt for proofreading this manuscript. For crystal
structure analysis, data were collected at beamline 17-
ID in the facilities of the Industrial Macromolecular
Crystallography Association Collaborative Access Team
(IMCA-CAT) at the Advanced Photon Source. These
facilities are supported by the companies of the Indus-
trial Macromolecular Crystallography Association.
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