Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: Synthesis and activity

Article abstract of DOI:10.1016/j.bmcl.2005.03.049

A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC₅₀ values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC₅₀ values of 18 and 22 nM, respectively.

Full text of DOI:10.1016/j.bmcl.2005.03.049

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2918–2922
Benzimidazolones and indoles as non-thiol
farnesyltransferase inhibitors based on tipifarnib scaffold:
synthesis and activity
Qun Li,* Tongmei Li, Keith W. Woods, Wen-Zhen Gu, Jerry Cohen, Vincent S. Stoll,
Tomas Galicia, Charles Hutchins, David Frost, Saul H. Rosenberg and Hing L. Sham
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA
Received 18 February 2005; revised 8 March 2005; accepted 14 March 2005
Available online 21 April 2005
Abstract—A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and
indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC50
values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their
inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC50 values of 18 and 22 nM, respectively.
Ó 2005 Elsevier Ltd. All rights reserved.
Farnesyltransferase (FTase) inhibitors have been shown
to inhibit the growth of a variety of experimental human
xenograft models and to be effective for the treatment of
several cancers in recent clinical trials.1,2 By blocking the
prenylation of Ras proteins and other oncoprotein tar-
gets that play major roles in a number of intracellular
signaling pathways that control cell proliferation, FTase
inhibitors are generally believed to have reduced intrin-
sic toxicity as compared with conventional cytotoxic
agents. Among the several FTase inhibitors in Phase
III clinical trials, tipifarnib (R-115777, 1)3 is perhaps
the most potent and selective non-thiol FTase inhibi-
tor.2,4 In the preceding papers, we demonstrated that
the 2-quinolone core of 1 could be replaced by 4-quino-
lones and other heterocycles.5a We also detailed how the
scaffold of tipifarnib could be rearranged to give simpler
inhibitors of FTase while maintaining potency.5b,c In
this paper, we report on further efforts to utilize tipifar-
nib as a template in designing a novel class of FTase
inhibitors.
to the D-ring. Shrinkage of the A-ring to five-membered
heterocycles would not significantly alter the orientation
of the D-ring, while yielding a new template (as repre-
sented by 2) that has not previously been explored.4d
The benzimidazolone core in 2 is relatively easy to syn-
thesize and retains the carbonyl group of the parent
quinolone, which is important for activity (Fig. 1).
Our initial approach to the target molecules is illustrated
in Scheme 1. 2-Fluoronitrobenzene 3 was converted to
phenylaniline 4 in 97% yield by nucleophilic displace-
ment of the fluorine by 3-chloroaniline.7 Reduction of
the nitro group with SnCl2 followed by cyclization with
carbonyl-diimidazole gave benzimidazolone 5. Com-
pound 5 underwent Friedel–Crafts 4-chlorobenzoyla-
tion to produce two regioisomers 6 and 78 both of
which were converted to the final compounds 2a and
The X-ray structure of tipifarnib5a,6 in complex with
FTase revealed that the chlorophenyl group (C-ring) is
indispensable for the overall potent interaction of tipi-
farnib with the enzyme. By occupying the tryptophan-
rich hydrophobic pocket, the C-ring is nearly parallel
*
Figure 1. Modifications of tipifarnib (1) lead to novel inhibitors (2) of
FTase.
Corresponding author. Tel.: +1 847 937 7125; fax: +1 847 936
1550; e-mail: qun.li@abbott.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.049

Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2918–2922
2919
Scheme 2. Reagents and conditions: (a) (i) MeNH2, MeOH/H2O,
reflux, overnight, 98%; (ii) H2, 10% Pd–C, MeOH, rt, 30 min, 98%; (iii)
CDI, CH2Cl2, reflux, 3 h, 73%; (b) 4-halobenzoyl chloride (excess),
AlCl3, neat, 150 °C, overnight, 46–73%, 1:1 mixture of 5- and 6-
isomers; (c) Zn(CN)2, Pd(P(Ph)3)4, DMF, 80 °C, 3 h, 98%; (d)
ArB(OH)2, Cu(OAc)2, Et3N, CH2Cl2, rt, 3 days, 12–43%; (e) 1-
methyl-2-TES-imidazole, tert-BuLi, THF, À78 °C, 0.5 h, then 11,
À78 °C to rt, 4 h; (ii) MeOH, 10% HCl, rt, 0.5 h, 19–87%.
Scheme 1. Reagents and conditions: (a) 3-chloroaniline, KF, 180 °C,
44 h, 97%; (b) (i) SnCl2Æ2H2O, HCl, EtOH, 0 °C–rt, overnight, 97%; (ii)
CDI, CH2Cl2, reflux, 2 h, then EtOH, reflux, 2 h, 73%; (iii) MeI, NaH,
DMF, rt, 1 h, 94%; (c) 4-halobenzoyl chloride (excess), AlCl3, neat,
150 °C, overnight, 17–40% (6), 21% (7, X = Cl); (d) (i) 1-methyl-2-
TES-imidazole, tert-BuLi, THF, À78 °C, 0.5 h, then 6 or 7, À78 °C to
rt, 4 h; (ii) MeOH, 10% HCl, rt, 0.5 h, 62–87% (2), 42% (8); (e)
Zn(CN)2, Pd(P(Ph)3)4, DMF, 80 °C, 3 h, 71%.
8, respectively, by addition of 1-methyl-2-triethylsilyl-5-
imidazolyl lithium9 and subsequent removal of the tri-
ethylsilyl protecting group with HCl in methanol.
Repeating the same sequence with 4-iodobenzoyl chlo-
ride in place of the 4-chloro gave iodo analog 2b, which
was reacted with zinc cyanide catalyzed by tetrakis(tri-
phenylphosphine)palladium to furnish cyano analog 2c
in 71% yield.
Scheme 3. Reagents and conditions: (a) (i) 3-chlorobenzyl chloride,
NaH, DMF, rt, 1 h, 95%; (ii) 4-halobenzoyl chloride (excess), AlCl3,
neat, 100 °C, overnight, 31–34%; (b) 1-methyl-2-TES-imidazole, tert-
BuLi, THF, À78 °C, 0.5 h, then 12, À78 °C to rt, 4 h; (ii) MeOH, 10%
HCl, rt, 0.5 h, 85–94%; (c) Zn(CN)2, Pd(P(Ph)3)4, DMF, 80 °C, 3 h,
62%.
A more convergent synthetic approach that allows for
modifications of the C- and D-rings is shown in Scheme
2. Fluoronitrobenzene (3) was converted to N-methyl-
benzimidazolone 9 in a three-step sequence including
nucleophilic substitution by methylamine, hydrogena-
tion catalyzed by palladium on carbon and cyclization
with carbonyldiimidazole. Benzimidazolone 9 under-
went Friedel–Crafts reaction with 4-halobenzoyl chlo-
ride to provide compounds 10 as a 1:1 mixture of the
5-ketone and the 6-ketone in 46–73% yield. As before,
cyano analog 10c was prepared in 98% yield from the
iodo compound (10b). Without separation, 10, as a mix-
ture was reacted with arylboronic acids in the presence
of cupric acetate utilizing a condition developed by
Chan et al.10 to yield the desired ketones 11 in 12–43%
yield and the other regioisomers after chromatographic
separation. Addition of the imidazolyl lithium to ke-
tones 11 utilizing the same conditions used previously
for 2a furnished the final products.
The N-benzyl analogs (13) were prepared similarly from
9 by N-chlorobenzylation, Friedel–Crafts acylation and
subsequent addition of the imidazolyl lithium as
depicted in Scheme 3. Formation of cyano analog
13c was achieved in 62% yield from the corresponding
iodide (13b) with zinc cyanide in the presence of
Pd(PPh3)4.
The synthesis of the indole analogs (17) is illustrated in
Scheme 4. Reaction of Weinreb amide 1411 with 5-indo-
lyllithium12 provided ketone 15 in 43% yield. Ullmann
arylation of 15 with the aryliodides gave N-arylindole
16 in 27–30% yield. Addition of the imidazolyl lithium
as described previously furnished the desired com-
pounds 17 in 49–73% yield.
The compounds were evaluated for their inhibitory
activities against bovine FTase13 and cellular Ras pro-

2920
Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2918–2922
Table 1. Activity of benzimidazolone and indole farnesyltransferase
inhibitors13
Compd Ar
R2
n
IC50 (nM)
FTa GGTb
EC50 (nM)
Rasc
processing
2a
2b
2c
2d
2e
2f
Cl
0
0
0
0
0
0
0
0
16
11,000 26%d
1200 2%d
1800 18.1
Scheme 4. Reagents and conditions: (a) 5-Bromoindazole, KH/tert-
BuLi, ether, À78 °C, 10 min, then 16, À78 °C to rt, 1 h, 43%; (b) 3-
iodochlorobenzene, CuBr, Na2CO3, NMP, 170 °C, overnight, 27–30%;
(c) 1-methyl-2-TES-imidazole, tert-BuLi, THF, À78 °C, 0.5 h, then 16,
À78 °C to rt, 4 h; (ii) MeOH, 10% HCl, rt, 0.5 h, 49–73%.
I
24
CN
Cl
1.4
cessing in H-ras transformed cells.13 The results are
summarized in Table 1. Also included in Table 1 is the
selectivity data against type I geranylgeranyltransferase
(GGTase I), a closely related enzyme that is not
targeted.
6.7 >10,000 24%d
5.1 >10,000 NTe
CN
Cl
Compound 2a is a potent FTase inhibitor with an IC50
of 16 nM. This represents an approximately 20-fold
drop in activity as a result of the A-ring contraction of
tipifarnib. Please note that 2a lacks a tertiary amino
group as seen in 1. Because the hydroxy analog2c of
the tipifarnib is only 2-fold less active against FTase
than tipifarnib, the hydroxy analogs were used in this
study. Compared to 2a, activity is reduced ꢀ100-fold
for regioisomer 8, in which the tertiary carbon is at-
tached to C-6 of the benzimidazolone.
6.6
7500 22
2g
2h
CN
Cl
0.5 >10,000 47%d
150
NTe
NTe
2i
2j
CN
Cl
0
0
8
>10,000 0%d
Further modifications of the C- and D-rings were under-
taken in an attempt to improve the activity (Table 1).
Substituting iodine for the chlorine in the D-ring (2b)
is deleterious. On the other hand, the 4-cyanophenyl
analog (2c) demonstrates excellent activities in both
enzymatic and cellular assays, with IC50 and EC50 values
of 1.4 and 18.1 nM, respectively. The activity of 2c is
close to that of tipifarnib, exhibiting only 2-fold and
about 10-fold reduced potent against FTase and Ras
processing, respectively. These potency-enhancing ef-
fects of the cyanophenyl group have been known in
the literature14 as well as from our previous work.5,15
Although its role is not clear, the X-ray structure and
the modeling (Fig. 2) show that the D-ring cyano group
fits into a small pocket and accepts H-bonds from the
main chain NH of both Tyr361 and Phe360 of the b-
subunit.5a
21
2900 0%d
13a
13b
13c
17a
17b
Cl
I
1
150
71
NTe
NTe
NTe
NTe
1
CN
—
1
5.2
5600 51%d
—
36
NTe
13%f
Taking advantage of the convergent synthesis, several
compounds with various C-rings were prepared. Replac-
ing the 3-chloro with methoxyl (2d) or ethoxyl (2f)
groups imparted modest increases in activity against
FTase. Compound 2f also displays improved cellular po-
tency, with an EC50 of 22 nM. The bicyclic replacements
—
—
—
—
200
NTe
NTe
NTe
NTe
8
—
1100
(continued on next page)

Q. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2918–2922
2921
Table 1 (continued)
2a superimposes very well with tipifarnib, in which the
imidazole is interacting closely with the Zn2+ in the active
site. The A-ring extends out over the loop of residues
Asp359-Phe360 forming good van der Waals contact with
the loop. The C-ring is stacked against Trp106 and
Trp102 and the D-ring stacks along the hydroxy farnesyl-
pyrophosphate (HFP). The C- and D-rings also stack to-
gether forming a strong p/p interaction.
Compd
Ar
R2
n
IC50 (nM)
FTa GGTb
EC50 (nM)
Rasc
processing
1
Tipifarnibg
Lonafarnibg,16
0.65
8.3
1100
>10,000
1.6
100
a Bovine farnesyltransferase.
b Bovine geranylgeranyltransferase.
c In H-ras NIH-3T3 cells.
d Inhibition at 100 nM.
e Not tested.
f Inhibition at 1000 nM.
g Data from racemic mixtures.
In summary, a series of analogs of tipifarnib have been
synthesized as inhibitors of FTase by substituting benz-
imidazolone and indole for the 2-quinolone moiety of
tipifarnib. The novel benzimidazolones are potent and
selective inhibitors of FTase. The best compounds of
this series exhibits IC50 values close to those of tipifar-
nib. The current series demonstrate good cellular activ-
ity as measured by their Ras processing inhibitory
activity in NIH-3T3 cells. Even with the tertiary hydro-
xy group, rather than the known cellular potency-
enhancing amino group,2b compounds 2c and 2f display
EC50 values of 18 and 22 nM, respectively. These
encouraging results warrant further investigation in or-
der to optimize the desirable properties of these mole-
cules and to extend further in the achiral series as
described in our previous paper.5b
including the benzodioxolanes (2h,i) and the naphtha-
lene (2j) are less favorable. The most potent compound
in vitro in this series is 2g, which combines the 3-ethoxy-
phenyl and 4-cyanophenyl structural motifs. Compound
2g displays an IC50 of 0.5 nM, which is comparable to
that of tipifarnib (IC50 0.65 nM). Unfortunately, 2g
was found to have poor cellular activity in the Ras
processing assay. Compared with tipifarnib, the C-ring
attached to the benzimidazolones is tilted away from
the D-ring, resulting an altered conformation of which
may not be optimal. To compensate for this effect,
several compounds with a carbon inserted between the
A- and the C-rings were designed and synthesized. With
the exception of 13c, in general, the benzyl analogs (13)
display sharply reduced activity in comparison with the
phenyl analogs (2).
References and notes
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Figure 2. Stereo view of an overlay of a model of compound 2a (in green) over the X-ray crystal structure of tipifarnib (1)5 (in purple) in complex
with FTase in the active site. Zn2+ is in shown in gray and hydroxy farnesylpyrophosphate in blue.

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