Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.11.127

A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which displayed excellent PARP enzyme inhibition with IC₅₀ = 4 nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC₅₀ = 42 nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.

Full text of DOI:10.1016/j.bmcl.2009.11.127

Bioorganic & Medicinal Chemistry Letters 20 (2010) 488–492
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-car-
boxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors
,
*
Rita Scarpelli , Julia K. Boueres, Mauro Cerretani, Federica Ferrigno, Jesus M. Ontoria, Michael Rowley,
Carsten Schultz-Fademrecht, Carlo Toniatti, Philip Jones
IRBM—Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia 00040, Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as
inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the
identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which displayed
excellent PARP enzyme inhibition with IC50 = 4 nM, inhibited proliferation of cancer cell lines deficient
in BRCA-1 with CC50 = 42 nM and showed encouraging pharmacokinetic properties in rats compared to
the lead 6.
Received 29 September 2009
Revised 19 November 2009
Accepted 21 November 2009
Available online 1 December 2009
Keywords:
Poly(ADP-ribose) polymerase
PARP inhibitor
Ó 2009 Elsevier Ltd. All rights reserved.
2-Phenyl-2H-indazole-7-carboxamides
Poly(ADP-ribose) polymerases (PARPs) are cell signaling en-
zymes that catalyze the transfer of ADP-ribose units from nicotin-
amide adenine dinucleotide (NAD+) to itself plus a number of
2281 (3),11 MK-4827 (4)12 (Fig. 1), plus INO-100113 and BSI-
20114 both of whose structures have not been disclosed yet.
We have recently reported the identification of a novel class of
2-phenyl-2H-indazole-7-carboxamide PARPi, such as compounds 5
and 6 (Fig. 2), and the optimization to MK-4827 (4).12 These com-
pounds incorporate a nitrogen atom within the [6,5]-bicyclic het-
eroaromatic ring which locks the carboxamide group into the
desired conformation by an intramolecular hydrogen bond.
The lead compound 5 was a moderate PARP enzyme inhibitor,
with IC50 = 25 nM12 and its corresponding methylaminomethyl
analog 6 resulted in 5-fold improvement in enzyme activity
(IC50 = 5 nM) and inhibited the proliferation of BRCA-1 deficient
(BRCA1-) HeLa cells (CC50 = 500 nM), displaying good selectivity,
>10-fold, over the corresponding BRCA-1 wild type (BRCA1wt)
HeLa cells.
acceptor proteins (e.g., histones H1 and H2B, DNA polymerases
a
and b).1 PARP-1, the best characterized member of the PARP family
which currently comprises 18 members,2 is an abundant nuclear
DNA-binding enzyme implicated in cellular responses to DNA
damage. Upon formation of DNA single strand breaks, PARP cata-
lyzes the polymerization of NAD+ into long poly(ADP-ribose)
(PAR) polymers on various proteins, including PARP-1 itself. The
presence of the negatively charged polymers leads to a chromatin
relaxation, facilitating the access of DNA break repair proteins to
the site of damage.3
PARP inhibitors (PARPi) have been shown to enhance the cyto-
toxic effects of ionizing radiation and DNA-damaging chemother-
apy agents, such as methylating agents and topoisomerase I
inhibitors.4–6 Recent in vitro and in vivo evidence suggests that
PARPi could be used not only as chemo/radiotherapy sensitizers,
but also as single agents to selectively kill cancers defective in
DNA double strand break repair, specifically cancers with muta-
tions in the breast cancer-associated genes (BRCA-1 and BRCA-2).7
Most of the PARPi in development mimic the nicotinamide moi-
ety of NAD+. There are currently at least six PARPi in clinical trial
development,8 including: ABT-888 (1),9 AG-014699 (2),10 AZD-
H
O
N
CONH2
N
N
H
N
N
H
HN
F
H
O
1 ABT-888
2 AG-014699
NH
N
O
F
CONH2
NH
N
N
N
N
* Corresponding author. Tel.: +39 01071781233; fax: +39 0107170187.
E-mail address: rita.scarpelli@iit.it (R. Scarpelli).
O
3 AZD-2281
4 MK-4827
Present address: Department of Drug Discovery and Development, Italian
Institute of Technology, Via Morego, 30, 16163 Genoa, Italy.
Figure 1. Some PARP inhibitors currently in clinical trials.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.127

R. Scarpelli et al. / Bioorg. Med. Chem. Lett. 20 (2010) 488–492
489
Nicotinamide
binding site
Table 1 (continued)
H
N
Compd R1
R2
PARP-112 BRCA1-12 BRCA1wt12
Adenosine-ribose
binding site
Internal
H-bond
O
IC50
CC50
CC50
CONH2
H
N
(nM)a
(nM)a
(nM)a
7
N
2
N
4
N
O
O
HN
17
18
H
H
N
20
30
1400
5000
3000
N
H
5
6
PARP-1 IC50 = 25 nM
PARP-1 IC50 = 5 nM
O
BRCA1- CC50 = 500 nM
BRCA1wt CC50 = 5.6 µM
Rat Cl = 220 mL/min/Kg
>6000
N
N
N
H
O
Figure 2. Development of novel indazole PARP inhibitors.12
19
20
21
22
H
H
H
H
46
10
30
20
2600
3600
820
6700
8400
4300
6000
N
H
(+/-)
O
Herein we describe a further investigation on this series of PAR-
Pi, conducting an extensive SAR exploration around the indazole
scaffold, with the aim to find compounds with improved potency,
selectivity, cell-based activity and optimal pharmacokinetic pro-
file. Furthermore, we also report exploration of alternative groups
on the pendant phenyl ring, knowing that the major route of
metabolism of 6 in rats occurs through extra-hepatic oxidation
by CYP450 1A1 and 1A2 of the methylaminomethyl group.12
The SAR exploration started with the preparation of analogs bear-
ing alternative substituents at the meta- and para-positions of the
pendant phenyl ring, such as carboxamides and anilides (Table 1),
in the hope of picking up additional binding interactions in the aden-
N
H
N
N
O
O
N
H
1300
N
N
H
O
N
23
24
H
H
17
10
1200
920
5000
N
H
O
>20,000
N
H
NH
Table 1
SAR study around the pendant phenyl ring
N
N
25
26
27
28
H
H
H
H
25
18
22
65
8600
>20,000
>20,000
9400
CONH2
N
1
R
O
O
2
N
NH
R
N
>20,000
2300
Compd R1
R2
PARP-112 BRCA1-12 BRCA1wt12
O
IC50
CC50
CC50
H
(nM)a
(nM)a
(nM)a
N
N
H
6
7
H
H
5
500
5600
8900
N
H
NH
H
N
N
>20,000
>20,000
N
10
5400
O
O
O
a
H
N
Values are means of >2 experiments with standard deviations <30%.
N
8
9
H
H
20
38
3300
3000
8000
6400
H
N
N
osine-ribose binding pocket (Fig. 2). We intentionally excluded sub-
stitutionat the ortho-positionof thephenylring, based onpreviously
reported results,12 which demonstrated that functionalization adja-
centto theindazoleringsystemwasdetrimentalforactivity. Wealso
decided to focus our attention on studying the effect of polar groups
with a view to maintaining good physicochemical properties and
improve metabolic stability.
From this preliminary SAR exploration, we were pleased to
demonstrate a general tolerability of different substituents on the
pendant phenyl ring of the indazole scaffold, as reported in Table 1.
In particular, both carboxamide derivatives, 7–14 and anilide
derivatives, 15–24 proved to be tolerated, although both classes
of compounds generally displayed weaker activity than 6. With re-
gard to the carboxamides 7–14, a small set of different polar sub-
stituents was explored, including secondary and tertiary amides
bearing basic centers, such as Me2N, pyrrolidine, morpholine,
O
O
H
N
N
10
11
12
H
H
H
54
10
30
7600
3900
7300
>20,000
8700
O
N
H
N
O
O
N
>50,000
N
H
NH
N
13
14
H
22
40
>10,000
>20,000
>20,000
>20,000
O
NH
N
H
O
piperidine and 1,4-diazepane. These analogs displayed IC50
s
O
O
around 10–55 nM, although in cells they showed only micromolar
anti-proliferation activity in BRCA1- HeLa cells with a narrow
selectivity over BRCA1wt HeLa cells. Substitution at the para-posi-
tion was confirmed to be better tolerated than the isomeric meta-
position, as shown for the pair 13 and 14, whereby 14 displayed
N
N
15
16
H
H
15
10
1500
930
5000
2800
N
H
N
H

490
R. Scarpelli et al. / Bioorg. Med. Chem. Lett. 20 (2010) 488–492
2-fold weaker activity, IC50 = 40 nM, than the para-isomer 13,
IC50 = 22 nM.
activity and 32 displayed 2-fold improvement in anti-proliferation
activity against BRCA1- HeLa cells (CC50 = 200 nM), maintaining
17-fold selectivity against their BRCA-1 proficient HeLa
counterparts.
Although the anilides 15–24 showed similar enzymatic activity
to the carboxamides 7–14, only the anilides showed submicromo-
lar inhibitory activity against the proliferation of BRCA1- HeLa
cells, displaying modest selective cell growth inhibition. In partic-
ular, 21 and 24 while showing moderate enzymatic inhibition,
with IC50 = 30 and 10 nM, respectively, both demonstrated inhibi-
tion of the proliferation of the BRCA1- HeLa cells in the submi-
cromolar range. While the N-methylpiperidine 21 demonstrated
only 5-fold selective cytotoxicity for BRCA1- HeLa cells, the corre-
sponding azetidine 24 showed 20-fold selective cytotoxicity be-
tween BRCA-1 silenced and BRCA1wt cells. The (R)-N-methyl
piperidine 21 proved to have the preferential stereochemistry, as
enantiomer 22 displayed around 2-fold weaker activity. Unfortu-
nately, despite 24 showed good rat microsome stability
Turning attention to the indazole core, compounds bearing a
chlorine atom in the 3- and 4-position of the indazole ring, such
as 33 and 34, showed a loss of activity compared to the unsubsti-
tuted analog 6, with IC50 = 20, 180 and 5 nM, respectively. More-
over, it should be noted that, for compounds bearing Br or F
substituents at the 3- and 4-positions, we observed a tendency
for these compounds to undergo nucleophilic aromatic substitu-
tion. This fact could be exploited synthetically, and 40 and 41 were
prepared through methoxy displacement on the 4-fluoro substi-
tuted scaffold, followed by deprotection. Unfortunately, these
modifications were not tolerated. On the other hand, the isomeric
5-chloro substituted analog 35 although it maintained activity, lost
selectivity between BRCA1- and BRCA1wt HeLa cells, displaying
only a 4-fold window.
Similar observations were made with fluorine substitution
whereby the 4-substituted compound 36 (IC50 = 8 nM) was less ac-
tive than unsubstituted 6, as was the 6-fluoro substituted deriva-
tive 38 (IC50 = 20 nM). In contrast, 37, the 5-fluoro substituted
analog proved to be a very potent PARP enzyme inhibitor. In fact,
this structural change has led to 5-fold increase in enzymatic activ-
ity, IC50 = 1.4 nM, and double-digit anti-proliferation activity in the
BRCA1- HeLa cells (CC50 = 94 nM). This 5-fluoro analog displayed
nearly 20-fold selectivity against BRCA proficient cells
(CC50 = 1800 nM).
Having observed the beneficial effect of the 5-fluoro substitu-
tion, we decided to combine this structural feature with fluoro-
substituents in the ortho- and meta-positions of the pendant phe-
nyl ring (Table 2). The combination with the ortho-fluoro as in 42
proved to be ineffective for improving enzyme activity, IC50 = 6 nM,
although in comparison to 6 it showed modestly improved cellular
activity, CC50 = 230 nM. Instead, the meta-fluoro derivative 43
proved to be a very potent PARPi (IC50 = 2 nM), with excellent
anti-proliferation activity in BRCA1- cells and high selectivity over
BRCA-1 proficient HeLa cells, >50-fold. Unfortunately, these com-
pounds, showed poor rat PK profile due to the presence of the
highly unstable methylaminomethyl group, displaying clearance
value in large excess of rat liver blood flow.
(Clint = 1.0 lL/min/mg), in vivo in rat PK this derivative suffered
from a lack of oral bioavailability (F = 1%). On the other hand, 21
displayed a good rat PK profile with low clearance in vivo
(Cl = 23 mL/min/kg) and good oral bioavailability (F = 47%). While,
the corresponding (S)-enantiomer 22 showed higher clearance in
rat (Cl = 42 mL /min/kg).
The two best fragments identified in the anilide series, piperi-
dine and azetidine groups, were selected and the corresponding
amide derivatives of compound 6 were prepared. Unfortunately,
these amides derivatives 25 and 26, resulted to be less active in
the cellular assays compared to 21 and 24. The same trend was ob-
served for the corresponding des-methylated amide analogs, 27
and 28.
We then moved our attention to study the effect of the intro-
duction of small substituents in different positions of the methy-
laminomethyl indazole series, specifically exploration on the
pendant phenyl ring and also the 3-, 4-, 5- and 6-positions of the
indazole core, with the aim to identify compounds with improved
potency and PK profile (Table 2).
First, we investigated different substituents in the meta-posi-
tion of the pendant phenyl ring, focusing on derivatives with di-
verse physicochemical properties, such as CF3, OMe, OH and F.
We were pleased to identify the fluorinated analog 32 which
showed similar potency in PARP enzyme assay compared to 6.
Moreover, the introduction of the fluoro group improved cellular
At this point, keeping in mind the encouraging potency and im-
proved PK properties of anilides 21 and 24, we were interested in
preparing the corresponding mono- and di-fluorinated analogs
(Table 3). Interestingly, both 44 and 45 were confirmed to show
improved activity compared to 21 and 24 both in enzyme and
cellular assays. Specifically, the 5-fluoro substitution gave a 2-fold
boost in activity with both compounds displaying anti-prolifera-
tion activity in BRCA1- HeLa cells with CC50 = 520 and 310 nM,
respectively. Although the N-methylated azetidine 46 showed sim-
ilar enzymatic activity compared to 45, this structural modification
resulted in lost of activity in the cellular assays and selectivity be-
tween BRCA1- and BRCA1wt HeLa cells.
Moreover, 44 showed also a good rat PK profile with low-mod-
erate clearance (Cl = 26 mL/min/kg) and good oral bioavailability
(F = 66%). Similar to azetidine 24, 45 when dosed in rats showed
low clearance (Cl = 13 mL/min/kg), but minimal oral bioavailability
(F = 3%).
As observed in the methylaminomethyl series, an interesting
additive effect of substitution at the meta-position of the pendant
phenyl ring was achieved and both di-fluorinated analogs 47 and
48 displayed improved properties compared to their mono-substi-
tuted counterparts, 44 and 45. The piperidine analog 47, although
only a modest PARPi (IC50 = 12 nM), displayed good cellular activ-
ity BRCA1- CC50 = 440 nM, while azetidine 48 was a potent PARP
enzyme inhibitor (IC50 = 4 nM) and showed double digit nanomo-
Table 2
SAR study around the indazole core and the pendant phenyl ring
Y
CONH2
N
3'
HN
N
5
5'
3
X
Compd
X
Y
PARP-1
BRCA1-
BRCA1wt
IC50 (nM)a
CC50 (nM)a
CC50 (nM)a
6
H
H
H
H
H
5
5
4
12
4
20
180
5
500
5600
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
30-CF3
30-OMe
30-OH
30-F
H
6200
1900
3400
200
5900
5200
260
>20,000
11,000
>10,000
3800
11,000
4300
1000
6300
1800
>10,000
>5000
5500
>20,000
4200
H
3-Cl
4-Cl
5-Cl
4-F
5-F
6-F
4,5-F
4-OMe
4-OH
5-F
5-F
H
H
H
H
H
H
H
H
8
2500
94
1.4
20
25
>1000
540
6
1600
2600
3400
>20,000
230
20-F
30-F
2
26
1500
a
Values are means of >2 experiments with standard deviations <30%.

R. Scarpelli et al. / Bioorg. Med. Chem. Lett. 20 (2010) 488–492
491
Table 3
An efficient procedure was developed which allowed Rapid
Analog Synthesis to be performed via a regioselective N-(2)-aryla-
tion of 51 under microwave assisted SNAr conditions (Scheme 1),15
using the appropriate activated fluorophenyl derivative in DMF in
presence of K2CO3. This procedure allowed us to rapidly introduce
versatile substituents (e.g., CO2R, NO2, CHO and CN) on the para-
position of the phenyl ring. Further chemical manipulations (e.g.,
basic hydrolysis/amide coupling, reduction/amide coupling and
reductive amination for CO2R, NO2, and CHO, respectively) allowed
us to synthesize the required derivatives 53. Alternatively, alde-
hyde 50 was treated with the appropriate substituted aniline in
EtOH at reflux to give the corresponding imine 54 which was con-
verted to the bicyclic indazole system by treatment with NaN3 in
DMF at elevated temperature.12 The corresponding carboxamides
56 were obtained by treatment of 55 with a 7 M methanolic NH3
solution at reflux in a sealed tube. This alternative procedure al-
lowed us to overcome the limitation of the microwave assisted
SNAr when using doubly substituted fluorophenyl derivatives. To-
gether these two synthetic routes allowed us to explore the effect
of different substituents in all the possible positions of the indazole
scaffold.
In conclusion, we have extensively explored the SAR on the
indazole scaffold and the pendant phenyl ring and we have identi-
fied compound 48 which was shown to be a potent PARP enzyme
inhibitor with IC50 = 4 nM, inhibiting the proliferation of the a
BRCA1- HeLa cells in the double-digit nanomolar range,
CC50 = 42 nM, displaying good selectivity over the corresponding
BRCA1wt HeLa cells. We also demonstrated the feasibility to over-
come the oxidative metabolic issue encountered with 6 as demon-
strated with 48 that displayed low clearance in rats.
SAR study around the indazole core and the pendant phenyl ring
CONH2
Y
N
N
R
X
Compd
X
Y
R
PARP-1
BRCA1-
BRCA1wt
IC50 (nM)a EC50 (nM)a EC50 (nM)a
O
21
24
44
H
H
F
H
H
H
30
10
16
820
920
520
4300
N
H
N
N
O
>20,000
2700
N
NH
H
O
N
H
O
45
46
F
F
H
H
5
6
310
720
5900
2600
N
NH
N
H
O
N
H
O
47
F
F
12
440
1800
N
H
N
O
O
48
49
F
F
F
F
4
6
42
650
N
NH
H
480
1600
N
H
N
a
Values are means of >2 experiments with standard deviations <30%.
Acknowledgments
lar activity against BRCA1- HeLa cells (CC50 = 42 nM) and 15-fold
selectivity. As expected, the N-methylated azetidine 49 showed
the same trend observed for compound 46.
The authors thank Claudia Giomini and Monica Bisbocci for bio-
logical screening and Fabrizio Fiore for routine PK studies.
Moreover, compounds 47 and 48 when dosed in vivo showed
similar rat PK profile to 44 and 45. In particular, 48, which showed
to be more potent and selective than 47, showed a low clearance
(Cl = 14 mL/min/kg) although being poorly oral bioavailable
(F = 2%).
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N
CONH2
CO2CH3
Z
Ref.12,
X = H; Z = NO2;
N
2
a)
N
EWG
NH
CHO
X
X
X
50: X = H, F, Cl
51
52: EWG = CO2R, NO2,
Z = NO2, F
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b)
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N
CO2CH3
Z
N
R1
N
Ar
X
X
54
53: R1 = CONHR2, NHCOR3
CH2NR4R5
c)
CO2CH3
CONH2
N
Y
R1
Y
R1
d)
N
N
N
X
X
55
56: R1 = CONHR2, NHCOR3
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over two steps); (d) NH3, MeOH, 60 °C, sealed tube, quantitative.

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