Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

Article abstract of DOI:10.1016/j.bmcl.2010.01.135

We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of th

Full text of DOI:10.1016/j.bmcl.2010.01.135

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2321–2325
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)met-
hylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competi-
tive inhibitors of the mammalian target of rapamycin (mTOR)
a
a
a
a
a
Hwei-Ru Tsou a, , Gloria MacEwan , Gary Birnberg , George Grosu , Matthew G. Bursavich , Joel Bard ,
Natasja Brooijmans a, Lourdes Toral-Barza b, Irwin Hollander b, Tarek S. Mansour a,
Semiramis Ayral-Kaloustian a, Ker Yu b
*
a Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States
b Oncology Research, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones
as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since
phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed.
The SAR data showed the structural features necessary for subnanomolar inhibitory activity against
Received 22 December 2009
Revised 26 January 2010
Accepted 28 January 2010
Available online 2 February 2010
mTOR kinase as well as selectivity over PI3K
mTOR-related PI3K revealed the key hydrogen bonding interactions.
Ó 2010 Elsevier Ltd. All rights reserved.
a. An X-ray co-crystal structure of one inhibitor with the
c
Keywords:
mTOR
Kinase inhibitors
Anticancer agent
Phosphoinositide-3-kinase
Serine/threonine kinase
The mammalian target of rapamycin (mTOR) is a key compo-
nent of the phosphoinositide 3-kinase (PI3K) pathway that plays
an important role in regulating cell growth, metabolism and angi-
ogenesis.1,2 mTOR, the founding member of a family of unconven-
tionally high molecular mass serine/threonine protein kinases,3 is
frequently dysregulated in human malignancy,4–6 making it an
attractive target for cancer therapy.7 In fact, rapamycin analogs
such as CCI-779 (temsirolimus)8 and RAD001 (everolimus)9 have
been approved as first-in-class mTOR inhibitors for cancer therapy.
However, they are allosteric inhibitors, only inhibiting mTOR com-
plex 1 (mTORC1), but not mTOR complex 2 (mTORC2).10,11 The
selective mTORC1 inhibitors can elicit a complex negative feedback
mechanism, causing stimulation of PI3K/AKT signaling in some
tumors, thereby minimizing the anticancer effect of mTORC1
inhibition.5 Intensive efforts have been underway to discover
small-molecule ATP-competitive inhibitors of mTOR kinase as
anticancer agents that target both mTOR complexes.
better tolerated, with the opportunity to achieve a higher thera-
peutic index for enhanced clinical efficacy. The ATP binding sites
of mTOR and PI3Ks (specifically PI3K ) show a high sequence sim-
ilarity of 68%, making the search for selective mTOR inhibitors
more challenging. Nevertheless, quite a few selective mTOR inhib-
itors have been reported recently.14–24 Herein, we report the dis-
covery and optimization of a new series of potent and selective
mTOR inhibitors.
c
Through high-throughput screening, we identified the indole-
bearing 4,6-dihydroxybenzofuranone 1 as an early lead. Introduc-
ing a 4-phenyl substituent on the indole gave 2 with improved
mTOR potency and higher selectivity over PI3Ka. 7-Azaindole 3,
an analog of 1, did not have improved selectivity, but exhibited en-
hanced mTOR potency (Table 1). We anticipated that combining
the features of 2 and 3 would create analogs with higher mTOR po-
tency while maintaining selectivity. That was indeed what we ob-
served in 9a, with mTOR potency (IC50 = 0.46 nM) and selectivity
(137-fold) superior over 2 and 3. Since phenol is known for meta-
bolic liability via glucuronidation and sulfation of the phenolic OH
groups,25 we decided to eliminate one of the two OH groups. As
shown in Table 2, the 4-OH group (9b) is more important than
the 6-OH group (9c) for mTOR potency, selectivity and cellular
activity. Therefore, our analoging efforts were directed at the
4-hydroxybenzofuranones.
A majority of reported ATP-competitive inhibitors of mTOR are
not selective, but rather pan-PI3K/mTOR inhibitors.7,12,13 PI3K is lo-
cated upstream in the PI3K-AKT-mTOR signaling pathway. Relative
to pan-PI3K/mTOR inhibitors, selective mTOR inhibitors may be
* Corresponding author. Tel.: +1 845 602 4712; fax: +1 845 602 5561.
E-mail addresses: tsouh@wyeth.com, tsouh10@gmail.com (H.-R. Tsou).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.135

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H.-R. Tsou et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2321–2325
Table 1
Early leads
N
Br
Br
N
Br
N
O
OH
O
i, ii
iii
N
N
N
X
N
R
A
H
O
OH
6
5
4
N
O
a
a
Compd
R
A
IC50 (nM)
IC50 (lM)
R
R
N
O
iv
LNCap
v
mTOR
PI3Ka
Selb
O
Y
1
2
3
H
Ph
H
CH
CH
N
800
33
42
1106
1478
77
1.4
45
1.7
na
1.4
6.5
N
N
N
7: R = Ar
8: R = NR1R2
9: R = Ar
10: R = NR1R2
a
Determinations were done in duplicate and repeat values agreed, on average,
with a mean twofold difference.
b
Selectivity = (IC50 PI3Ka)/(IC50 mTOR).
Scheme 1. Reagents and conditions: (i) NaH, DMF, then MeI, room temperature; (ii)
(CHO)n, Me2N HCl, n-BuOH, heat; (iii) hexamethylenetetramine, 66% propionic acid,
heat; (iv) for 7: ArB(OH)2, Pd(PPh3)4, Na2CO3, DME, heat, 36–68% yield; for 8:
NHR1R2, Pd2(dba)3, 20-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine,
K2HPO4, DME, heat, 38–80% yield; (v) substituted benzofuranone, EtOH, HCl, heat;
for 9, 49–82% yield; for 10, 32–75% yield.
Table 2
Hydroxyl and dihydroxyl analogs
X
O
O
O
Y
O
N
O
OH
N
N
a
a
Compd
X
Y
IC50 (nM)
IC50 (lM)
O
O
mTOR
PI3Ka
Selb
LNCap
i
iii
ii
9f
6
9a
9b
9c
OH
OH
H
OH
H
OH
0.46
3.45
19
63
89
219
137
25.8
11
0.077
0.2
1.8
N
N
N
N
12
a
11
Determinations were done in duplicate and repeat values agreed, on average,
with a mean twofold difference.
Scheme 2. Reagents and conditions: (i) methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzoate, PS-Pd(PPh3)4, Na2CO3, DME, heat, 75% yield; then MeOH,
2 N NaOH, room temperature, 80% yield; (ii) DMF, THF, N-Me-morpholine, i-
butylchloroformate, then add bridged morpholine, room temperature, 62% yield;
(iii) 4-OH-benzofuranone, EtOH, HCl, heat, 70% yield.
b
Selectivity = (IC50 PI3Ka)/(IC50 mTOR).
A key 4-bromo intermediate, 6, was synthesized from 4-bromo-
7-azaindole 426 via N-methylation and Mannich reaction, followed
by heating of 5 with hexamethylenetetramine.27 A variety of 4-
substituents were introduced via Suzuki or Buchwald coupling
conditions to yield 7 or 8, respectively. Subsequent coupling with
hydroxybenzofuranones in acidic ethanol yielded 9 and 10, respec-
tively, as depicted in Scheme 1. 4,6-Dihydroxybenzofuranone was
commercially available, but not 4-hydroxybenzofuranone, which
was prepared from 2,6-dihydroxyacetophenone.28 For 9f where
the benzamide boronic acid was not commercially available, the
4-benzamide was introduced via 4-benzoate followed by hydroly-
sis and then converting the resulting benzoic acid into amide as
shown in Scheme 2. The corresponding piperidine amide 10f was
prepared similarly (Scheme 3). Compared to 4-phenyl compound
9b, 4-benzamides 9d–h and 4-piperidine amides 10d–h were all
more potent in inhibiting both mTOR kinase and cellular prolifer-
ation, as shown in Table 3. LNCap, a PTEN deficient prostate cancer
cell line that showed hyperactive PI3K-AKT-mTOR signaling, was
used to evaluate our analogs as mTOR inhibitors. Benzamides
9d–h were slightly more potent than the corresponding piperidine
amides 10d–h, with IC50 values at or below 1 nM. Both benzamides
and piperidine amides showed excellent cellular activity with sin-
gle digit nM IC50 values. In terms of microsomal stability, 4,6-dihy-
droxy compounds 9a had reasonable microsomal stability in phase
I metabolism, but not in phase II metabolism, as expected. Unfor-
tunately there is no phase II metabolism data for the corresponding
4-hydroxy compound 9b. Nevertheless, both phase I and phase I/II
data were determined for a group of benzamides and piperidinyla-
O
O
N
O
O
N
N
O
N
N
O
iv
ii, iii
i
10f
6
N
N
15
14
Scheme 3. Reagents and conditions: (i) Pd2(dba)3, methyl isonipecotate, K2HPO4,
20-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, DME, heat, 66% yield;
(ii) 2 N NaOH, MeOH, 85% yield; (iii) N-Me-morpholine, i-butylchloroformate, THF,
then bridged morpholine, 60% yield; (iv) 4-OH-benzofuranone, EtOH, HCl, heat, 60%
yield.
mides as shown in Table 3. Amides bearing bulky amines exhibited
more favorable phase II metabolic stability (9h > 9g > 9e; 10g,
10e > 10d) with exceptions of 10h bearing a hydroxyethylpiper-
azine and 9f and 10f bearing a 2,6-bridged morpholine.23 In micro-
somal stability studies, piperidinylamides appeared to be more
stable than the corresponding benzamides, presumably because
piperidine is more bulky and/or more polar than
ring. One exception lies in the pairs of 9h (benzamide) and 10h
a phenyl

H.-R. Tsou et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2321–2325
2323
Table 3
Benzamides and piperidylamides
O
R
O
R
OH
OH
O
O
N
N
O
O
N
N
N
B
A
M)a
Microsc
a
Compd
R
IC50 (nM)
IC50
(l
LNCap
mTOR
PI3Ka
Selb
I
I/II
9a
9b
0.46
3.45
63
89
137
25.8
0.077
0.2
20
22
2
—
9d
10d
A
B
0.55
0.67
36
30
65
46
0.004
0.001
—
>30
—
20
NMe2
9e
10e
A
B
0.5
1.4
49
63
97
45
0.001
<0.001
>30
>30
10
>30
N
N
N
O
O
N
9f
10f
A
B
0.56
2
57
52
103
26
0.008
0.001
6
>30
2
16
9g
10g
A
B
1
3.1
70
39
70
12
0.009
<0.001
28
>30
24
>30
OH
9h
10h
A
B
0.39
1.85
100
25
256
13
0.001
0.001
>30
>30
>30
14
N
N
a
b
c
Determinations were done in duplicate and repeat values agreed, on average, with a mean twofold difference.
Selectivity = (IC50 PI3K )/(IC50 mTOR).
Nude mouse microsomes T1/2 (min). Phase I: Substrate half-life (min) when incubated at 37 °C for 15 min with nude mouse microsomes (0.5 mg/mL protein) and NADPH
a
cofactor. Phase I/II: Substrate half-life (min) when incubated at 37 °C for 15 min with nude mouse microsomes (0.5 mg/mL protein), NADPH, and UDPGA cofactors.
Table 5
N-1 Substitution
(piperidinylamide), where 10h was less stable than 9h in phase II
metabolism.
The effect of the amide group position on mTOR activity was
also explored. It is clear from Table 4 that the amide substituent
is best situated at the para-position rather than the meta- or
ortho-position. As for substitution at N-1 of the azaindole, the
methyl analog 9h showed better mTOR potency and selectivity
than 13 which bears the larger ethyl group (Table 5). Aminometh-
ylpiperidine 17a and aminopiperidine 17b were prepared from the
corresponding BOC-protected intermediates 16, as shown in
Scheme 4. Amines 17a and 17b were much less potent mTOR
inhibitors than amides 10d and 10i (Table 6). The tertiary amide
10d exhibited higher cellular potency than the primary amide
OH
OH
N
O
N
O
O
N
R
N
a
a
Compd
R
IC50 (nM)
IC50 (lM)
LNCap
mTOR
PI3K
a
Selb
Table 4
9h
13
Me
Et
0.39
4.55
100
455
256
98
0.001
0.004
Effect of the position of substitution
O
N
a
Determinations were done in duplicate and repeat values agreed, on average,
with a mean twofold difference.
OH
O
b
Selectivity = (IC50 PI3Ka)/(IC50 mTOR).
O
10i. Other 4-substituted amines, 10j–m, which showed good mTOR
potency and cellular activity were also prepared (Table 7). Com-
pared to 4-morpholine 10j, analog 10k bearing a bulky 2,6-bridged
morpholine had enhanced mTOR activity (IC50 = 0.38 nM) and
selectivity (274-fold). However, analog 10l, bearing a 3,5-bridged
morpholine, was less selective than 10j, although the two
compounds were equipotent versus mTOR and in LNCap cells.
Compound 18, a 4,6-dihydroxy analog of 10m (Table 7), was
slightly more potent (3-fold) than the 4-hydroxy compound 10m.
However, unlike the pair of 9a (4,6-dihydroxy) and 9b (4-hydroxy),
where 9a was more selective and more potent in cells than 9b, 18
N
N
a
a
Compd
Position
IC50 (nM)
PI3K
IC50 (lM)
LNCap
mTOR
a
Selb
9d
9i
9j
P-
m-
o-
0.55
18
180
36
369
5895
65
20.5
32.8
0.004
0.6
>60
a
Determinations were done in duplicate and repeat values agreed, on average,
with a mean twofold difference.
b
Selectivity = (IC50 PI3Ka)/(IC50 mTOR).

2324
H.-R. Tsou et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2321–2325
in Table 8. It is clear that 9k was quite potent (IC50 = 1.6 nM) and
O
selective for mTOR versus 23 other protein kinases.
(CH2)n
N
O-t-Bu
ii
(CH2)n NH2
O
Compound 18 was successfully co-crystallized with PI3Kc pro-
H
OH
tein, which was utilized as a surrogate for crystallography studies
based on its high similarity to mTOR at the ATP binding sites. The
X-ray structures (PDB code 3LJ3) and the predicted binding mode
with the mTOR homology model showed the 7-N forms a hydrogen
bond to Val2240 in the hinge region at the ATP binding site of the
protein (Fig. 1). This helps explain why the 7-azaindoles are more
potent mTOR inhibitors than the corresponding indoles. The 4-hy-
droxy group in the benzofuranone portion of 18 makes a hydrogen
bonding interaction with Lys2187. In addition, the 6-hydroxy
group forms a hydrogen bond to Asp2195 and the backbone-NH
of Phe2358. These hydrogen bond interactions may explain the
contribution of the 4- and 6-hydroxy groups to mTOR binding
affinity. It is clear that there is a lot of room to accommodate sub-
stituents at the C-4 position of the azaindole core, although the X-
ray structure does not reveal structural requirements for selectiv-
N
O
N
i
O
6
N
N
N
N
16
17
Scheme 4. Reagents and conditions: (i) 4-substituted piperidine, Pd2(dba)3,
K2HPO4, 20-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine, DME, heat,
43% yield; (ii) 4-OH-benzofuranone, EtOH, HCl, heat, 60% yield.
Table 6
Substitution on the piperidine ring
R
OH
O
ity for mTOR over PI3Ka.
In summary, we discovered a series of 4-substituted 7-azain-
doles as potent and selective mTOR inhibitors. Since phenolic OH
N
O
Table 8
Inhibitory activity of 9k against a panel of protein kinases
N
N
H
O
N
a
a
Compd
R
IC50 (nM)
IC50 (lM)
OH
O
LNCap
mTOR
PI3Ka
Selb
OH
10d
10i
C(O)NMe2
C(O)NH2
CH2NH2
0.63
0.72
17
38
29
60
41
9
0.001
0.01
O
17a
17b
155
119
0.075
0.24
N
N
9k
19
6
NH2
a
Kinase
mTOR
IC50 (nM)
Kinase
IC50 (nM)
Kinase
IC50 (lM)
Determinations were done in duplicate and repeat values agreed, on average,
with a mean twofold difference.
0.0016
0.016
50
50
27.7
5.9
50
35.5
9.7
VEGFR2
RSK1
PKA
50
45.9
50
6.5
50
10.6
50
SRC
ROCK1
PDFGR
MET
HCK
50
50
50
50
27.1
50
50
b
Selectivity = (IC50 PI3Ka)/(IC50 mTOR).
PI3K
PKC
P38
a
a
a
a
MK2
Table 7
LYN A
GSK3b
FGFR1
CDK2
ABL1
IKK
a
Effect of the amine substitution
GSK3
a
GCK
ERK2
CDK1
CK1
c
39.2
Aurora B
22.2
OH
OH
N
N
O
O
R
O
O
OH
N
N
N
18
N
Compd
R
IC50 (nM)a
IC50 (l
M)aLNCap
mTOR
PI3K
a
Selb
24
10j
10k
10l
2.2
53
0.005
0.002
0.002
N
N
N
N
O
O
O
N
0.38
2.1
104
19
274
9
10m
18
2.75
0.94
173
43
63
46
0.003
0.11
a
Determinations were done in duplicate and repeat values agreed, on average,
with a mean twofold difference.
b
Selectivity = (IC50 PI3Ka)/(IC50 mTOR).
Figure 1. Predicted binding mode of 18 with mTOR based on co-crystallization
with PI3K . Close-up of interactions of 18 with the mTOR binding site. Hydrogen
bonds are shown with black dashed lines and residue numbers are indicated for
hydrogen bonding partners.
(4,6-dihydroxy) was less selective and less potent (by 37-fold) in
cells, compared to 10m (4-hydroxy). One compound 9k was eval-
uated for its ability to inhibit a panel of protein kinases, as shown
c

H.-R. Tsou et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2321–2325
2325
12. Maira, S.-M.; Staffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.;
Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.; Fabbro, D.; Gabriel,
D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; Garcia-Echeverria, C. Mol.
Cancer Ther. 2008, 7, 1851.
groups pose metabolic liability, one of the two hydroxyl groups
was selectively removed. Lead optimization generated subnanom-
olar, ATP-competitive mTOR kinase inhibitors with low nanomolar
13. Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.; Box, G.;
Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.; Friedman, L. S.; Hayes,
A.; Hancox, T. C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.;
Patel, S.; Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.; Salphati, N.
C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S.
J. J. Med. Chem. 2008, 51, 5522.
cellular activity. An X-ray structure of our inhibitor with PI3Kc re-
vealed the important hydrogen bonding interactions, which sug-
gested the basis for the high mTOR potency of this new series of
inhibitors.
14. Feldman, M. E.; Apsel, B.; Uotila, A.; Loewith, R.; Knight, Z. A.; Ruggero, D.;
Shokat, K. M. PLoS Biol. 2009, 7, 371.
Acknowledgments
15. Garcia-Martinez, J. M.; Moran, J.; Clarke, R. G.; Gray, A.; Cosulich, S. C.; Chresta,
C. M.; Alessi, D. R. Biochem. J. 2009, 421, 29.
The authors thank Dr. Zheng Wang and Mr. Iwan Gunawan for
scaling up key intermediates, and for Ms. Angela Bretz for nude
mouse microsome stability assays. We thank Drs. Arie Zask and
Jeremy I. Levin for useful discussions. We also thank Dr. Robert
Abraham for program support. We are grateful to members of
the Wyeth Chemical Technologies group for analytical support.
16. Thoreen, C. C.; Kang, S. A.; chang, J. W.; Liu, Q.; Zhang, J.; Gao, Y.; Reichling, L. J.;
Sim, T.; Sabatini, D. M.; Gray, N. S. J. Biol. Chem. 2009, 284, 8023.
17. Yu, K.; Toral-Barza, L.; Shi, C.; Zhang, W.-G.; Lucas, J.; Shor, B.; Kim, J.;
Verheijen, J.; Curran, K.; Malwitz, D. J.; Cole, D. C.; Ellingboe, J.; Ayral-
Kaloustian, S.; Mansour, T. S.; Gibbons, J. J.; Abraham, R. T.; Nowak, P.; Zask, A.
Cancer Res. 2009, 69, 6232.
18. Zask, A.; Verheijen, J. C.; Curran, K.; Kaplan, J.; Richard, D. J.; Nowak, P.;
Malwitz, D. J.; Brooijmans, N.; Bard, J.; Svenson, K.; Lucas, J.; Toral-Barza, L.;
Zhang, W.-G.; Hollander, I.; Gibbons, J. J.; Abraham, R. T.; Ayral-Kaloustian, S.;
Mansour, T. S.; Yu, K. J. Med. Chem. 2009, 52, 5013.
19. Menear, K. A.; Gomez, S.; Malagu, K.; Bailey, C.; Blakburn, K.; Cockroft, X.-L.;
Ewen, S.; Fundo, A.; Le Gall, A.; Hermann, G.; Sebastian, L.; Sunose, M.; Presnot,
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21. Nowak, P.; Cole, D. C.; Brooijmans, N.; Bursavich, M. G.; Curran, K. J.;
Ellingboe, J. W.; Gibbons, J. J.; Hollander, I.; Hu, Y.; Kaplan, J.; Malwitz, D.
J.; Toral-Barza, L.; Verheijen, J. C.; Zask, A.; Zhang, W.-G.; Yu, K. J. Med.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.01.135.
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