Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor

Article abstract of DOI:10.1016/j.bmcl.2012.04.036

High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.

Full text of DOI:10.1016/j.bmcl.2012.04.036

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4163–4168
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class
of selective mTOR kinase inhibitor
⇑
M. Raymond V. Finlay , David Buttar, Susan E. Critchlow, Allan P. Dishington, Shaun M. Fillery,
Eric Fisher, Steve C. Glossop, Mark A. Graham, Trevor Johnson, Gillian M. Lamont, Simon Mutton,
Paula Perkins, Kurt G. Pike, Anthony M. Slater.
AstraZeneca, Oncology Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 February 2012
Revised 5 April 2012
Accepted 8 April 2012
Available online 13 April 2012
High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-
pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties
and selectivity over related kinases such as PI3Ka. Library preparation of related analogs allowed the
establishment of additional SAR understanding and in particular the requirement for a key hydrogen
bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replace-
ment of the indole functionality led to the identification of urea compounds such as 32 that show good
levels of mTOR inhibition in both enzyme and cellular assays.
Keywords:
Kinase
Enzyme
Inhibitor
mTOR
Ó 2012 Elsevier Ltd. All rights reserved.
Recently, both AstraZeneca1 and others2 have described studies
towards the identification of inhibitors of the mammalian target of
rapamycin (mTOR), a serine/threonine protein kinase that, due to
its regulation of cell growth, proliferation and survival, may offer
an attractive therapeutic target for tumor growth inhibition.2 We
now wish to disclose the discovery and development of a novel
morpholino-pyrimidine series that shows potent and selective
inhibition of mTOR in both an enzyme and cellular setting
Screening of the AstraZeneca compound collection against a re-
combinant mTOR enzyme assay identified a variety of active clus-
ters deemed worthy of further investigation. Whilst several of
these series offered start points with high potency, our attention
was attracted to compounds such as 1. The compounds displayed
at 10 lM, high levels of free drug in plasma (compound 2) and
minimal inhibition of the hERG ion channel in a whole cell assay
(compound 1).
Encouraged by the attractive profiles shown by these com-
pounds, we elected to prepare further analogs to explore ways to
further increase mTOR potency whilst retaining both selectivity
over PI3K and the favorable properties described above. We de-
signed two libraries of compounds to examine the effects of vary-
ing independently the sulfone (compounds such as 9, Scheme 1) or
the 2-pyridyl moiety (compounds such as 15, Scheme 2). The core
morpholino-pyrimidine moiety was judged to be optimal both
from initial SAR analysis and the precedent of other literature PIKK
inhibitors4 and initially no changes were planned in this region of
the molecule. To optimally interact with the hinge region of the
PIKK kinases, the combination of the weak morpholine oxygen
hydrogen bond acceptor and a relatively electron-deficient hetero-
cyclic system such as pyrimidine has been found to be preferred.
The bulk of the binding contribution is thought to come from a
tight fit of both the hydrophobic region of the morpholine and a
conserved lipophilic methionine residue on the protein. The elec-
tron deficient nature of the pyrimidine ring also appears to be
important for binding to PIKK enzymes.5
modest mTOR potency (e.g., 1 IC50 = 1.41 lM), leading to merely
average ligand efficiency3 (1 LE = 0.22), but a particularly interest-
ing observation was that 1 showed significantly lower affinity for
the structurally related enzyme PI3 kinase alpha (PI3K
a,
IC50 = 17.3 M). We reasoned that an mTOR kinase inhibitor dis-
l
playing selectivity over other PI3K and PIKK enzymes would be a
useful tool to understand the biology of the PI3 kinase/AKT path-
way, and this philosophy guided much of our subsequent thinking.
Intrigued by the selectivity of 1, we proceeded to further examine
the cellular potency, physical and pharmacokinetic properties of
the cluster. As can be seen from Table 1, compounds 1 and 2
showed oral exposure in the rat, no cytochrome P450 inhibition
Compounds of type 9 were prepared as described in Scheme 1.
Thus, base promoted condensation of amidine hydrochloride 3
with keto-ester 4 gave the pyrimidine intermediate 5. Treatment
with phosphorous oxychloride to give 6 followed by morpholine
displacement of the newly formed 4-chloropyrimidine delivered
benzyl chloride 7. This was then treated with a diverse set of thiols
⇑
Corresponding author.
E-mail address: ray.finlay@astrazeneca.com (M.R.V. Finlay).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.036

4164
M. Raymond V. Finlay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4163–4168
Table 1
Structures and in vitro activity for compounds 1 and 2
O
N
O
N
N
N
O
O
O O
S
N
S
N
N
1
2
Compounds
mTOR IC50
M)
PI3K
a
IC50
p-AKT IC50
M)
% Free
(rat)
hERG mean
CYP IC50
(
lM)
LogD pH=7.4
Rat Clp
(ml/min/Kg)
Rat
(
l
(lM)
(
l
IC50
(lM)
Bioavailability (%)
1
2
1.41
5.0
17.3
>1000
9.2
>30
—
28
>32
—
>10
>10
1.34
1.94
32
11
18
97
All IC50 measurements reported are the geometric mean of at least two measurements.
keto-ester 10 was cyclized with methylthioisourea under basic
conditions to give the pyrimidine 11. Displacement of the benzyl
chloride with the sodium salt of methane sulfinic acid gave the sul-
fone 12 that was then treated sequentially with phosphorous oxy-
chloride to provide 13 and then morpholine to give thioether 14.
Copper catalyzed cross coupling with a variety of boronic acids
employing Liebeskind’s6 conditions then gave access to the target
compounds 15.
The mTOR potency SAR for compounds of type 9 seemed very
flat, with little change in potency in most examples (Table 2, com-
pounds 16, 17 and 18). Alkyl, heterocyclic and substituted phenyl
sulfones with a range of lipophilicity all had similar mTOR enzyme
affinity, although this may have been as a consequence of the rel-
atively limited variety of functionalities that could easily be intro-
duced in a library fashion employing the chemistry described in
Scheme 1. Nevertheless, we were encouraged to see that, on the
O
H Cl
N
N
(a)
NH
NH2
O
O
Cl
Cl
N
N
N
Cl
O
3
7
4
5
(b)
Cl
O
N
N
N
(c)
Cl
N
N
N
6
(d)
O
N
O
N
whole, selectivity over PI3Ka was maintained.
In contrast, variation of substituents at the pyrimidine 2 posi-
tion provided compounds with higher mTOR potency relative to
our initial hit 1. Of particular interest was the 5-indole compound
197 (Table 3).
N
(e)
N
O
R
O
S
R
N
S
N
N
N
8
9
In addition to increased enzyme potency, the compound also
showed more potent inhibition of p-AKT in cells (serine 473 phos-
phorylation site). Indole 19 showed no affinity for the hERG ion
channel, modest lipophilicity (LogD = 2.06), high free fraction in
the rat (19.3%) and an acceptable cytochrome P450 inhibition pro-
Scheme 1. Synthesis of sulfone analogs of 1. Reagents and conditions: (a) NaH,
EtOH, reflux, 1 h, 38%; (b) POCl3, reflux, 1 h, 57%; (c) morpholine, DIPEA, THF, rt–
70 °C, 4 h, 86%; (d) RSH, NaOEt, MeCN, rt, 18 h, 15–30%; (e) oxone, EtOH, water, rt,
3–18 h, 5–65%.
file (most potent hit, 2C9 isoform IC50 = 5 lM). Aqueous solubility
OH
OH
O
O
was low, despite the modest LogD observed and we speculated
that this may be due to the presence of a hydrogen bond network
between the indole NH and sulfone oxygens in the crystal lattice.
We next examined the pharmacokinetic profile of 19 in the rat.
The iv profile revealed that the compound possessed low plasma
(a)
(b)
N
N
O
Cl
Cl
N
S
N
S
O S O
10
11
12
clearance (3.8 mL/min/kg) and
a low volume of distribution
(c)
(0.4 L/kg). Oral dosing of 19 subsequently revealed a small AUC
and bioavailability of 3%. The fraction absorbed was also relatively
low at 0.03. We hypothesized that the low bioavailability could be
attributable to a lack of permeability or indeed transporter medi-
ated efflux, but MDCK testing revealed good permeability (A–B Papp
37 Â 10À6 cm/s) and minimal efflux potential (B–A Papp 34 Â 10À6
cm/s). We concluded therefore, that the aqueous solubility of
19 was limiting its absorption and oral bioavailability. A number
of other structure activity relationships also became apparent from
analysis of related analogs from the same library as 19. The pres-
ence of the free NH did seem to be crucial as methylation of this
moiety (to give 20) completely ablated mTOR activity. Interest-
ingly, not only was the presence of the NH required for activity,
but its position also appeared to be important. The 4-indole isomer
21 showed reduced mTOR enzyme potency and increased PI3
kinase alpha potency compared to 19. Although we did not have
O
O
Cl
N
N
N
(e)
(d)
N
N
N
S
N
R
N
S
O S O
O S O
O S O
15
14
13
Scheme 2. Synthesis of aryl analogs of 1. Reagents and conditions: (a) Meth-
ylisothiourea, Na2CO3, H2O, rt, 16 h, 92%; (b) MeSO2Na, MeCN/DMF (4:1, v/v),
100 °C, 1 h, 42%; (c) POCl3, reflux, 1 h, 83%; (d) excess, morpholine, DCM, rt, 18 h,
89%; (e) copper thiophene-2-carboxylate, Pd(PPh3)4, boronic acid, dioxane, 130 °C,
microwave, 45 min, 5–86%.
in a parallel synthesis fashion to provide a variety of sulfide prod-
ucts 8. These were then oxidized to give the final sulfone targets 9.
Scheme 2 depicts our synthetic approach to analogs of 1 bearing
modified substituents at the 2 position of the pyrimidine. Thus
access to X-ray crystal structures of either mTOR or PI3K
a to help
us rationalize these observations, we were able to construct a

M. Raymond V. Finlay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4163–4168
4165
Table 2
Structures, in vitro activity and selected data for compounds 16, 17 and 18
O
O
N
O
N
N
N
N
N
O
O
O
O
O O
S
N
S
N
S
N
N
N
N
F
N
16
17
N
18
Compounds
mTOR IC50
(
lM)
PI3K
a
IC50
(lM)
p-AKT IC50
(lM)
LogD (pH=7.4)
ClogP
16
17
18
1.38
1.54
3.16
7.6
36.7
>90
12.4
>30
>80
1.6
—
<0.5
1.02
À0.21
À1.41
All IC50 measurements reported are the geometric mean of at least two measurements.
Table 3
Structures, in vitro activity and selected data for compounds 19, 20 and 21
O
N
O
N
O
N
N
N
O
O
O
O
N
O
O
S
S
N
H
N
S
N
N
N
N
H
19
20
21
Compounds
mTOR IC50
M)
PI3K
a
IC50
p-AKT IC50
M)
% Free
(rat)
hERG mean
Solubility
(pH=7.4) (
LogD
pH=7.4
Rat Clp
(ml/min/Kg)
Rat
(
l
(lM)
(
l
IC50
(lM)
lM)
Bioavailability (%)
19
20
21
0.288
>100
1.46
26.3
>24
14.3
5.7
—
6.3
19.3
—
30.1
>32
—
>33
6.2
—
13
2.1
—
1.7
4
—
—
3
—
—
All IC50 measurements reported are the geometric mean of at least two measurements.
Figure 1. (a) Proposed binding mode of compound 19 in mTOR homology model. D835 from PI3K
c structure (1e7v) highlighted in red. Waters observed in PI3Kc crystal
structures that could influence binding interactions are displayed as red spheres. (b) Proposed binding mode of compound 22 in mTOR homology model.
homology model for the kinase domain ATP binding site of each
protein. These models were based on both the published sequences
of the proteins and the known crystal structure of the closely re-
acid residue, but this group appears too far away to make a produc-
tive interaction. In contrast, the mTOR homology model shows a
glutamic acid in the same position and due to the additional meth-
ylene spacer group now present, this residue can hydrogen bond
successfully with the indole NH group of 19 (see Fig. 1(a)), leading
to enhanced potency for mTOR. Analysis of two additional library
compounds compounds, 22 and 23 also revealed further SAR
understanding (Table 4).
lated PIKK enzyme PI3 kinasec.
8a, 8b Upon examination of the over-
layed homology models, it became apparent that there was a
subtle but important difference in the proteins in the vicinity of
where the indole NH of 19 was postulated to reside as highlighted
in Figure 1a.8c
In the homology model of PI3K
a
(and indeed the beta, gamma
Examination and comparison of the homology models and re-
and delta isoforms), the indole NH is oriented towards an aspartic
ported PI3Kc structures revealed the presence of water molecules

4166
M. Raymond V. Finlay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4163–4168
Table 4
Structures, in vitro activity and selected data for compounds 22, 23, 24 and 25
O
N
O
N
O
N
O
N
N
N
O
O
O
O
N
N
O
O
O O
S
S
N
N
S
S
N
N
N
OH
N
O
N
N
H
H
22
23
24
25
Compounds
mTOR IC50
M)
PI3K
a
IC50
p-AKT IC50
M)
% Free
(rat)
hERG mean
IC50 M)
Solubility
(pH=7.4) (
LogD
pH=7.4
Rat Clp
(ml/min/Kg)
Rat
(
l
(lM)
(
l
(
l
lM)
Bioavailability (%)
22
23
24
25
0.601
22.5
0.285
0.262
2.05
3.4
—
7.2
1.03
44.7
—
—
—
—
>32
>32
196
—
—
1.0
—
—
25
—
37
4
41
—
10
43
>300
1.06
0.98
—
48
1.9
All IC50 measurements reported are the geometric mean of at least two measurements.
Table 5
Structures, in vitro activity and selected data for compounds 26, 27 and 28
O
N
O
N
O
N
N
N
N
O
O
O
O
O O
S
S
S
N
N
N
N
N
N
H
H
H
26
27
28
Compounds
mTOR IC50
(
lM)
PI3K
a
IC50
p-AKT IC50
M)
% Free (Rat)
hERG Mean
Solubility
(pH=7.4) (
LogD
pH=7.4
Rat Clp
(ml/min/Kg)
Rat
(
lM)
(
l
IC50
(lM)
l
M)
Bioavailability (%)
26
27
28
0.303
0.385
0.252
22.95
5.3
>48
1.88
3.1
1.9
16.7
—
22.0
>32
—
>32
192
—
1.5
2.4
—
—
36
—
—
33
—
—
All IC50 measurements reported are the geometric mean of at least two measurements.
located between Y2225 and D2195. Both of these residues and the
These results highlight the subtleties of the interaction networks
that can be formed in this region of the protein and the limitations
of our initial homology modeling studies. Although 22, 24 and 25
did generally show improved PK profiles relative to 19 (possibly
driven by higher solubility), in addition to their reduced selectivity
profiles, these compounds also remained at around the micromolar
level of p-AKT inhibition in cells, and we thus elected to explore
other parts of the molecule to seek both additional potency and
selectivity. We had not yet attempted modification of the hinge-
binding morpholine motif and a number of morpoholines bearing
small substituents were readily accessible (Table 5).
Given the increased potency observed with indole 19, we elected
to combine these modifications with this template, and were grati-
fied to see that potency and selectivity had been retained. Of note
also was the effect of these changes on the physicochemical and
pharmacokinetic properties of the compounds. In particular, indole
26 although having higher plasma clearance than the its des-methyl
matched pair, did now show improved oral bioavailability (33%). It is
tempting to speculate that this increased oral exposure could per-
haps be driven by the greater aqueous solubility of 26, resulting in
turn from the methyl group increasing the twist between the mor-
pholine and pyrimidine rings in 26 and thereby disrupting the effi-
water are predicted by the models to be conserved between PI3K
a
and mTOR. The benzyl alcohol in 22 could potentially bind to or dis-
place a water molecule leading to an increase in potency against
both enzymes as displayed in Figure 1b. This is indeed seen to be
the case for 22. In this binding mode it is believed that the benzyl
alcohol displaces a water interacting with Y2225 and the nature
of the interaction is postulated to require the presence of a hydro-
gen bond donor group. In contrast, methoxy ether 23, lacking the
ability to replace the hydrogen-bond donor water interaction and
possibly being too large to be accommodated in this pocket, shows
little affinity for either enzyme. It is assumed that compounds 22
and 23 form a different interaction network with the protein and
that both lack the required donor to interact with E2190, conse-
quently neither of these compounds shows selectivity for mTOR
over PI3Ka. Encouraged by the ability of our model systems to pre-
dict selectivity and potency, we next targeted benzimidazole com-
pound 24 for synthesis. We reasoned that this compound could
interact favorably with both E2190 and the water described above
and the hybridization of these two rationales would provide a both
potent and selective mTOR inhibitor. Compound 24 presents a
hydrogen bond acceptor to target the Y2225 water interaction as
proposed for compound 22. Although a different functionality to
compound 22, at the time we were interested in exploring the nat-
ure of the possible interaction networks that could target Y2225.
Whilst 24 did indeed show improved mTOR enzyme potency, it also
ciency of crystal packing in the solid state. The reduction in PI3K
a
potency for the bridged morpholine 28 is striking and similar obser-
vations have recently been made by other groups.9a Indole 27, whilst
still selective over PI3Ka, showed reduced selectivity compared to
displayed increased potency against PI3K
azaindole 25 also showed an increase in PI3K
to 19. Both compounds 24 and 25, introduce additional functional-
ity that weakens the H-bonding donor character of the indole NH.
a
. Related analogs such as
potency compared
its enantiomer 26. In a similar fashion to the findings described here,
the 5-(4-morpholin-4-ylpyrimidin-2-yl)-1H-indole motif has also
concurrently been identified by a number of groups9b–e as a potent
and selective mTOR inhibitory scaffold.
a

M. Raymond V. Finlay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4163–4168
4167
O
N
O
N
O
N
(a), (b)
(c)
N
N
O O
O
O
S
N
S
O
O
N
O
S
O
N
S
N
S
N
H
NH2
14
29
30
O
N
O
N
(d)
(e)
N
N
O O
O
O
S
F
S
N
O
N
O
O
N
N
N
N
H
H
H
31
32
Scheme 3. Synthesis of sulfonamide, amide and urea analogs of 19. Reagents and conditions: (a)[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid, copper
thiophene-2-carboxylate, Pd(PPh3)4, 1-4-dioxane, 101 °C, 2.5 h, 84%; (b) 4 M HCl in 1-4-dioxane, rt, 4 h, 84%; (c) MeSO2Cl, pyridine, rt, 2 h, 45%; (d) 1,2-oxazole-5-carboxylic
acid, HATU, Et3N, DMF, rt, 18 h, 30%; (e) 4-fluorophenylisocyanate, 1-4-dioxane, 70 °C, 69%.
Table 6
Structures, in vitro activity and selected data for compounds 30, 31 and 32
Compounds
mTOR IC50
M)
PI3K
a
IC50
p-AKT IC50
M)
% Free
(rat)
hERG
mean IC50
Solubility
(pH=7.4) (
LogD pH=7.4
Rat Clp
(ml/min/Kg)
Rat
(
l
(
lM)
(
l
(
lM)
lM)
bioavailability (%)
30
31
32
2.6
0.037
0.028
>100
>100
0.565
>20
5.1
0.087
>66
32
2.15
>29
>33
>100
11
—
0.77
0.85
1.74
>3.2
15
—
—
38
—
—
All IC50 measurements reported are the geometric mean of at least two measurements.
Although considerable progress had been made in going from
initial hit 1 to lead 26, a further increase in both enzyme and cel-
lular potency was seen as desirable. Consequently, building on
the SAR established from our studies up to this point we elected
to expand the range of compounds modified at the pyrimidine 2-
position. In particular, the previously described necessity for an
appropriately positioned hydrogen bond donor (compare 19 and
21, vide supra) led us to target structures that would potentially
maintain this important interaction whilst allowing us to further
diversify substitution on the 4-anilino substituent. Initially we tar-
geted a range of amides, sulfonamides and ureas, prepared as
shown in Scheme 3.
of the phenyl ring greatly reduced mTOR enzyme potency (data
not shown). We have described herein a high throughput screening
approach to identify ATP competitive mTOR kinase inhibitors.
Starting with a modestly potent hit compound, we have estab-
lished SAR that allowed us to improve target inhibition potency
in both biochemical and cellular screening assays. Since our group
first disclosed the [4-(4-morpholin-4-ylpyrimidin-2-yl)phenyl]ur-
ea motif in 2008,1b it is evident from the large number of subse-
quent publications exemplifying this pharmacophoric element2
that it is a privileged scaffold for mTOR inhibition. Work to further
optimize these lead compounds will be described in due course.
Thus aniline 29 was prepared in an analogous fashion to 15
employing copper catalysed cross coupling of thioether 14 and
4-BOC-aminophenyl boronic acid. Reaction with the appropriate
isocyanate, sulfonyl chloride or acid chloride then delivered the
urea, sulfonamide or amide derivatives respectively.
Interestingly, the amide examples such as 31 did provide
increased levels of enzyme potency, (Table 6) although levels of
cellular p-AKT inhibition remained around the five micromolar
level.
Acknowledgments
We acknowledge the excellent technical expertise of the follow-
ing scientists: Darren Jones, Sarah Kearney and Dr. Kin Tam. The
authors gratefully acknowledge useful and stimulating discussions
with Dr. Jason Kettle and Dr. Ed Griffen.
Supplementary data
The sulfonamide derivatives such as 30 generally showed low
levels of mTOR inhibition both in an enzyme and cell setting,
although interestingly 30 did show an attractive rat PK profile
(Table 6). In contrast, the urea derivatives such as 32 exhibited
higher mTOR enzyme potency and this was also translated into
increased p-AKT potency in cells. Pleasingly, the compounds also
Supplementary material contains detailed descriptions of the
biochemical and cellular assays employed. Supplementary data
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2012.04.036.
References and notes
retained selectivity against PI3Ka. It can be seen from Table 6 that
1. (a) Pike, K. G.; Finlay, M. R. V.; Fillery, S. M.; Dishington, A. P. PCT Int. Appl.
WO2007080382.; (b) Finlay, M. R. V.; Morris, J.; Pike, K. G. PCT Int. Appl.
WO2008023159.; (c) Menear, K. A.; Gomez, S.; Malagu, K.; Bailey, C.; Blackburn,
K.; Cockcroft, X.-L.; Ewen, S.; Fundo, A.; Le Gall, A.; Hermann, G.; Sebastian, L.;
Sunose, M.; Presnot, T.; Torode, E.; Hickson, I.; Martin, N. M. B.; Smith, G. C. M.;
Pike, K. G. Bioorg. Med. Chem. Lett. 2009, 19, 5898; (d) Malagu, K.; Duggan, H.;
the incorporation of the urea moiety also led to increased lipophil-
icity and reduced aqueous solubility and 32 was consequently not
taken forward for in vivo PK investigations. Reflecting the earlier
positional SAR observed for 19 and 21, altering the position of
the sulfonamide, amide or urea motif from the 4 to the 3 postion

4168
M. Raymond V. Finlay et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4163–4168
Menear, K.; Hummersone, M.; Gomez, S.; Bailey, C.; Edwards, P.; Drzewiecki, J.;
8. (a) Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann,
M. P.; Williams, R. L. Mol. Cell 2000, 4, 909; (b) Walker, E. H.; Perisic, O.; Ried, C.;
Stephens, L.; Williams, R. L. Nature 1999, 402, 313; (c) Figure 1 was generated
using PyMOL: DeLano, W.L. The PyMOL Molecular Graphics System (2002),
DeLano Scientific, San Carlos, CA, USA, http://www.pymol.org.
9. (a) Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.;
Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Yu, K. J. Med.
Chem. 2009, 52, 7942; (b) Nowak, P.; Cole, D. C.; Brooijmans, N.; Bursavich, M.
G.; Curran, K. J.; Ellingboe, J. W.; Gibbons, J. J.; Hollander, I.; Hu, Y. B.; Kaplan, J.;
Malwitz, D. J.; Toral-Barza, L.; Verheijen, J. C.; Zask, A.; Zhang, W.-G.; Yu, K. J.
Med. Chem. 2009, 52, 7081; (c) Verheijen, J. C.; Yu, K.; Toral-Barza, L.; Hollander,
I.; Zask, A. Bioorg. Med. Chem. Lett. 2010, 20, 375; (d) Castanedo, G.; Goldsmith,
R.; Gunzner, J.; Heffron, T.; Malesky, K.; Mathieu, S.; Olivero, A.; Sutherlin, D. P.;
Tsui, V.; Wang, S.; Weismann, C.; Zhu, B.-Y.; Dotson, J.; Folkes, A.; Shuttleworth,
S.; Oxenford, S.; Hancox, T.; Bayliss, T. PCT Int. Appl. WO2007127183.; (e)
Bergeron, P.; Cohen, F.; Estrada, A.; Koehler, M. F. T.; Lau, K. H. L.; Cuong, L.;
Lyssikatos, J. P.; Ortwine, D. F.; Pei, Z.; Zhao, X. PCT Int. Appl. WO2010014939.
Leroux, F.; Quesada, M. J.; Hermann, G.; Maine, S.; Molyneaux, C.-A.; Le Gall, A.;
Pullen, J.; Hickson, I.; Smith, L.; Maguire, S.; Martin, N.; Smith, G.; Pass, M. Bioorg.
Med. Chem. Lett. 2009, 19, 5950.
2. (a) Richard, D. J.; Verheijen, J. C.; Zask, A. Curr. Opin. Drug Discov. 2010, 13, 428;
(b) Roychowdhury, A.; Sharma, R.; Kumar, S. Future Med. Chem. 2010, 2, 1577; (c)
Zask, A.; Verheijen, J. C.; Richard, D. J. Expert Opin. Ther. Patents 2011, 7, 1109; (d)
Fasolo, A.; Sessa, C. Expert Opin. Invest. Drugs 2011, 20, 381; (e) Garcia-
Echeverria, C. Bioorg. Med. Chem. Lett. 2010, 20, 4308.
3. Hopkins, A. L.; Groom, C. R.; Alexander, A. Drug Discovery Today 2004, 9, 430.
4. Workman, P.; Clarke, P. A.; Raynaud, F. I.; van Montfort, R. L. M. Cancer Res. 2010,
70, 2146.
5. Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M.
P.; Williams, R. L. Mol. Cell 2000, 6, 909.
6. Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
7. 1H NMR data for compound 16: (400 MHz, DMSO, 30 °C) d 3.24 (3H, s), 3.74 (8H,
s), 4.49 (2H, s), 6.53–6.56 (1H, m), 6.80 (1H, s), 7.37–7.40 (1H, m), 7.44 (1H, d),
8.16 (1H, dd), 8.61 (1H, s), 11.22 (1H, s).