SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.10.007

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.

Full text of DOI:10.1016/j.bmcl.2012.10.007

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7653–7658
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent
and selective Janus kinase 2 (JAK2) inhibitors
⇑
⇑
Timothy Forsyth, Patrick C. Kearney, Byung Gyu Kim , Henry W. B. Johnson , Naing Aay, Arlyn Arcalas,
David S. Brown, Vicky Chan, Jeff Chen, Hongwang Du, Sergey Epshteyn, Adam A. Galan, Tai P. Huynh,
Mohamed A. Ibrahim, Brian Kane, Elena S. Koltun, Grace Mann, Lisa E. Meyr, Matthew S. Lee,
Gary L. Lewis, Robin T. Noguchi, Michael Pack, Brian H. Ridgway, Xian Shi, Craig S. Takeuchi, Peiwen Zu,
James W. Leahy, John M. Nuss, Ron Aoyama, Stefan Engst, Steven B. Gendreau, Robert Kassees, Jia Li,
Shwu-Hwa Lin, Jean-Francois Martini, Thomas Stout, Philip Tong, John Woolfrey, Wentao Zhang,
Peiwen Yu
Exelixis, Department of Drug Discovery, 169 Harbor Way, South San Francisco, CA 94083, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2012
Revised 26 September 2012
Accepted 1 October 2012
Available online 16 October 2012
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective
JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of
hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors.
Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect
in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical
trials.
Keywords:
JAK1
Ó 2012 Elsevier Ltd. All rights reserved.
JAK2
JAK3
4-Aryl-2-aminoalkylpyrimidine
Janus kinase 2 nonreceptor tyrosine kinase, a member of the JAK
family of kinases (JAK1, JAK2, JAK3, and TYK2), has garnered a tre-
mendous amount of attention in recent years since the discovery of
a somatic mutation of the gene encoding JAK2 (JAK2V617F).1–5 The
V617F mutation occurs in the auto-inhibitory JH2 domain and is
thought to disrupt its negative regulatory function. This leads to
constitutive activation of JAK2, downstream signal transducer
and activators of transcription (STAT), and activation of gene tran-
scription. A frequent point mutation of JAK2 was identified in mye-
loproliferative disorders (MPDs) including polycythemia vera (PV),
essential thrombocythemia (ET), and primary myelofibrosis (PMF).
Recent approval of ruxolitinib6 (JAK1/2 inhibitor), developed by In-
cyte and Novartis, has clinically validated JAK2 for the treatment of
MPDs. Not surprisingly, several JAK2 selective inhibitors have been
developed and are currently being tested in clinical trials.7–14 Here-
in, we report our efforts in the identification and SAR exploration of
potent and selective JAK2 inhibitors.
our investigation (Fig. 1). Compound 1 displayed potent inhibitory
activity against JAK2 with >50-fold selectivity over JAK3 along with
no activity below 5000 nM against a broad in-house panel of ki-
nases. In addition, 1 possessed reasonable in vitro stability (62%
remained after exposure of 1 to mouse liver microsomes for
O
HN
N
O
Cl
N
N
H
N
H
1
Cl
High Throughput Screening (HTS) of our in-house compound li-
brary revealed hit 1 that was considered a good starting point for
JAK2 : 104 nM
JAK3 : >5000 nM
⇑
Corresponding authors.
E-mail addresses: byunggyu72kim@gmail.com (B.G. Kim), hjohnson@onyx.com
Figure 1. HTS hit 1.
(H.W.B. Johnson).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.007

7654
T. Forsyth et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7653–7658
Table 1
Optimization of the linker
O
N
O
O
N
HN
HN
HN
O
N
a, b
c
HN
N
O
Ar
N
Cl
N
N
H
6a-6f
N
H
Ar
N
N
H
O
Cl
2
7a-7c
N
Linker
Scheme 2. 17Reagents and conditions: (a) Et3N, N-Boc-amino-3-aniline, 1-butanol,
180 °C; HCl, MeOH; (b) DIEA, THF, arylbenzoyl chloride, 70 °C or DIEA, DMF, HATU,
arylbenzoic acid; (c) ArNH2, 1-butanol, 180 °C.
Cl
ID Linker
JAK2
JAK3
(nM)
pStat1
(nM)
pStat3
(nM)
a
a
a
(nM)a
with 4-acetylphenylboronic acid to afford 2 (Scheme 1). Nucleo-
philic substitution of 2 with alkylamine or arylamine followed by
an amide coupling with2,6-dichlorobenzoyl chloride provided com-
pounds 3–6.
Having a derivative in hand with improved potency we next
turned our attention to modification of the aryl amide. Several ana-
logues were prepared with the 1,3-diaminophenyl linker using the
route shown in Scheme 2. In order to improve the solubility of this
series, modification of the lipophilic aryl amide was considered
critical (Table 2). Deletion of chloride substitution at the ortho po-
sition (6a and 6b) retained JAK2 biochemical potency with similar
selectivity against JAK3. Interestingly, simple aniline 6c retained
both biochemical activity and cellular activity. Removal of the aryl
N
H
N
H
1
3
4
104
>5,000
>980
8,138
n.d.
n.d.
n.d.
>980
5000
>30,000
>30,000
N
H
N
H
N
H
N
5000
5
6
12.6
>980
>980
763
505
n.d.
N
H
N
H
129.9
>30,000
N
H
N
N
H
amide also provided
a
significant increase in solubility
(Ksol = 233.8 M) compared to the aryl amide analogues in the ser-
l
ies. Encouraged by this result, additional analogues were synthe-
sized lacking the aryl amide. Meta piperidine substitution (7a)
displayed slightly improved biochemical and cellular potency com-
pared to 6c. The 3-morpholine analogue 7b provided a modest
improvement in both biochemical and cellular potency compared
to 7a. In addition, the 4-morpholine analogue 7c retained JAK2 po-
tency with similar selectivity against JAK3. The analogues 6a–6c
were prepared by nucleophilic substitution of 2 with N-Boc-ami-
no-3-aniline, followed by Boc deprotection and amide coupling
with either arylbenzoyl chloride or arylbenzoic acid (Scheme 2).
The analogues 7a–7c were synthesized by a nucleophilic substitu-
tion reaction of 2 with the appropriate aniline.
Subsequent modification involved the scaffold aminopyrimidine
core. Moving the nitrogen from C-3 to C-5 (9a) led to the complete
loss of JAK2 activity, presumably due to a weaker interaction with
the hinge region and/or a steric repulsion of the C-3 hydrogen and
thehydrogen ortho onthe morpholinoaniline moiety; a modification
which would force the two rings out of planarity. Fluoride substitu-
tion (9b) at C-5 maintained biochemical potency but suffered from a
significant loss of cellular potency. Analogue 9c with a methyl at C-5
had a similar potency profile to 7c but a significantly less desirable
n.d. = not determined.
a
Values reported are the average of at least two independent dose-response
curves.17
30 min) and acceptable drug-like properties (cLogP = 3.1, PSA 96 Å,
MW = 458). However, the poor cellular activity (IC50 = 8138 nM
(pStat1 in HEL92.1.7)) and solubility (Ksol = 6.5
moderate biochemical potency (IC50 = 104 nM) of
l
M), along with
1
required
improvement.
Rigidifying the linker between the aminopyrimidine and 2,6-
dichlorophenylamide was considered a viable method to potentially
improve the potency. We initiated our SAR studies by constructing
analogues that replaced the 1,3-propyldiamine with a different
functional group (Table 1). Both 1,3-cyclohexyldiamine 3 and azeti-
din-3-ylmethanamine 4 led to complete loss of JAK2 biochemical
activity. Gratifyingly, 1,3-phenylenediamine analogue 5 improved
not only JAK2 biochemical activity but also the cellular activity. Ana-
logue 6 containingthe 2,6-diaminopyridine displayed10-fold weak-
er JAK2 potency compared to 5. The analogues in Table 1 were
prepared by Suzuki coupling reaction15 of 2,4-dichloropyrimidine
O
O
O
HN
HN
HN
Cl
b,c
a
N
+
N
Cl
N
N
O
Cl
B(OH)2
N
N
Cl
Linker
3-6
Cl
2
Scheme 1. 17Reagents and conditions: (a) Et3N, Pd(dppf) Cl2ÁCH2Cl2, DME/H2O, 90 °C; (b) Linker, 1-butanol, 180 °C; (c) DIEA, THF, 2,6-dichlorobenzoyl chloride, 70 °C.
Linker = 1,3-propyldiamine,1,3-cyclohexyldiamine, azetidin-3-ylmethanamine, 1,3-phenyldiamine, 2,6-diaminopyridine.

T. Forsyth et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7653–7658
7655
Table 2
Table 3
SAR on the right-hand side
SAR on the pyrimidine ring
O
N
O
X
HN
HN
O
N
Y
R
N
N
H
R1
N
N
H
ID R1
JAK2
JAK3 (nM) pStat1
pStat3
(nM)
ID
X
Y
R
JAK2
JAK3
pStat1
(nM)a
pStat3
(nM)a
a
a
a
(nM)a
(nM)
(nM)a
(nM)a
7c
9a CH
9b
9c
N
CH
N
CH 5-F
CH 5-
CH3
CH 5-
CF3
CH 6-
CH3
H
H
3.6
>980
4.4
>980
>980
>980
104.5
974.7
795
n.d.
n.d.
447
O
Cl
Cl
>30,000
6486.7
608.9
N
H
N
N
5
12.6
>980
763
n.d.
5.1
Cl
O
9d
9e
N
N
39.6
>980
>980
2699.9
n.d.
n.d.
6a
6b
6.9
>980
>980
>30,000
>30,000
n.d.
n.d.
>980
>30,000
N
H
O
n.d. = not determined.
a
Values reported are the average of at least two independent dose-response
11.1
curves.17
N
H
6c
7a
H
12.8
6.5
1149.3
>980
1004.3
956.1
1971
1328
N
N
7b
4.2
3.6
>980
>980
615
591
795
O
7c 4-Morpholine
974.7
n.d. = not determined.
a
Values reported are the average of at least two independent dose-response
curves.17
selectivity profile against JAK3. Analogue 9d with trifluoromethyl at
C-5 demonstrated 10-fold weaker biochemical potency relative to
7c. Analogue 9e with 6-methyl was inactive against JAK2; a feature
that is not surprising as this substitution would likely disrupt hydro-
gen bonding with the kinase linker.
The synthesis of analogues in Table 3 started from the appropri-
ately substituted 2,4-dichlorpyrimidine or 4,6-dichloropyrimidine,
which was subjected to a Suzuki coupling reaction with 4-acetyl-
phenylboronic acid to produce 8 (Scheme 3). Nucleophilic substi-
tution of 8 with 4-morpholinoaniline in 1-butanol at 180 °C
afforded compounds 9a–9e. Despite our effort, modification of
the pyrimidine core did not result in an improvement in potency
over parent 7c.
Figure 2. Cocrystal structure of 7c/JAK2 solved at 1.9 Å resolution (PDB Code 4BBE).
7c exhibits an L-shape conformation in the kinase ATP binding pocket. Two
hydrogen bonds are formed between the aminopyrimidine ring and the linker
region of the kinase. The acetyl oxygen interacts with Asp994 (part of the DFG
motif) and Lys882. Residues in the active site of JAK2 that are different in JAK3 are
highlighted in yellow. Hydrogen bonding interations between 7c and JAK2 <3.3 Å
are indicated.
O
X
O
O
HN
HN
HN
Cl
N
b
a
Y
X
+
O
R
N
Cl
Y
Y
X
B(OH)2
R
R
X,Y =N or CH
N
N
H
N
Cl
8
9a-9e
Scheme 3. 17Reagents and conditions: (a) Et3N, Pd(dppf) Cl2ÁCH2Cl2, DME/H2O, 90 °C; (b) 4-morpholinoaniline, 1-butanol, 180 °C.

7656
T. Forsyth et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7653–7658
Table 4
Optimization of acetimide
ingly despite the high degree of homology between JAK2 and
JAK3, a >250-fold difference in selectivity was observed with 7c.
Although a rationale for the excellent selectivity of 7c was not
readily apparent, our attention was turned to modifying the amide
of 7c. The cocrystal structure indicated that polar functionality
would likely be tolerated and consequently could serve to decrease
the lipophilicity of 7c. Thus, a focused library of amide compounds
was prepared from the corresponding aniline and a summary of
this data is provided in Table 4. From this study it was observed
O
N
HN
R
O
N
that analogues containing a heteroatom
well tolerated. For example, while -glycine analogue 10a dis-
played slightly weaker activity, -glycine analogue 10b improved
cellular activity threefold compared to 7c. Both -serine analogue
10c and -proline analogue 10d showed a similar improvement
in cellular activity although the selectivity against JAK3 was mod-
estly eroded. Surprisingly, the -pyroglutamic acid (10f) and 3-
substituted -pyrrolidine (10e) derivatives were completely inac-
tive in the cellular assay although they retained similar biochemi-
cal activity. Substitution of nitrogen on the -proline (10g–10h)
revealed a modest loss of both biochemical and cellular activity.
The synthesis of analogues 10a–10h is shown in Scheme 4.
Deacetylation of 7c in refluxing acid yielded the aniline, which
was then coupled with the N-Boc protected appropriate acid in
the presence of HATU followed by Boc deprotection to afford ana-
logues 10a–10d and 10f. Analogues 10e and 10g–10h were syn-
a or b to the amide were
N
N
H
L
D
ID
R
JAK2
JAK3
pStat1
(nM)a
pStat3
(nM)a
(nM)a
(nM)a
D
D
7c
Me
3.6
>980
974.7
795
D
10a
8.7
1.7
2.7
2.2
298.3
1052.5
1510
D
NH2
NH2
NH2
D
10b
10c
10d
306.8
159.8
214.2
327.7
621.7
386.4
452
OH
1391
695
HN
thesized via
a HATU coupling reaction of the aniline and
appropriate acid.
An X-ray cocrystal structure of 10d bound to the active site of
JAK2 indicated that a similar binding mode is observed for 7c
and 10d, however the amide of 10d is rotated to accommodate
the larger pyrrolidine ring (Fig. 3).
The desirable in vitro potency of 10d prompted further investi-
gation in a pharmacodynamic study.16 Analogue 10d was adminis-
tered orally to mice bearing HEL92.1.7 tumors and inhibition of
STAT phosphorylation was measured after 4 h. A significant inhibi-
tion of downstream markers pSTAT1 and pSTAT3 is observed at 30,
100, and 300 mg/kg resulting in an ED50 of 42 mg/kg (pSTAT1) and
210 mg/kg (pSTAT3) (Table 5).
10e
0.9
61.7
>30,000
n.d.
HN
O
10f
10g
10h
5.7
5.2
9.1
368.1
483.8
557.3
>30,000
745.7
n.d.
NH
1051
2166
N
1431.3
N
Further in vivo characterization of advanced acetamide ana-
logues indicated that 10d had a superior pharmacodynamic profile
and thus was evaluated in an efficacy experiment measuring
growth inhibition of HEL.92.1.7 xenograft tumors in mice (Fig. 4).
Derivative 10d demonstrated 60% and 70% inhibition when dosed
orally at 200 mg/kg and 300 mg/kg respectively twice a day for
14 days. Harvested tumors were also subjected to immunohisto-
chemical analysis of microvessel density (CD31), proliferation
(Ki67) and apoptosis (TUNEL). Dosing at 300 mg/kg bid provided
an 11.3-fold increase in apoptosis relative to vehicle control.
Pharmacokinetic data collected for 10d in mouse, rat, dog, and
monkey are summarized in Table 6. Generally, compound 10d
exhibited good oral absorption, and modest clearance and half life
across species.
n.d. = not determined.
a
Values reported are the average of at least two independent dose-response
curves.17
To facilitate optimization, an X-ray cocrystal structure of 7c
bound to the ATP binding site of JAK2 was obtained (Fig. 2). Hydro-
gen bonding interactions of 7c with JAK2 occurs with both the lin-
ker and salt bridge residues Asp994 and Lys882. The morpholino
group is solvent exposed and does not appear to make specific
interactions with the target, thereby providing an explanation for
the wide variety of functionality tolerated in this region. Surpris-
O
O
HN
R
HN
NH2
O
O
O
N
N
N
N
N
N
N
a
b or
b-c
N
N
H
N
N
H
N
H
7c
10c-10j
Scheme 4. 17Reagents and conditions: (a) 6 N HCl, MeOH, reflux; (b) RCO2H, Et3N, HATU, DMA; (c) HCl, 1,4-dioxane.

T. Forsyth et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7653–7658
7657
Figure 3. (a) Cocrystal structure of 10d/JAK2 solved at 2.0 Å resolution (PDB Code 4BBF). A similar L-shaped binding mode is observed for 7c and 10d within the JAK2 active
site. Hydrogen bonding interations between 10d and JAK2 <3.1 Å are indicated. (b) Overlay of the cocrystal structures of 7c/JAK2 (grey) and 10d/JAK2 (orange). The amide of
10d is rotated to allow a hydrogen bond between the nitrogen and Asp994 of the DFG motif.
Table 5
In vivo phramcodynamics of 10d
Dose
Plasma/tumor Concentration (
l
M)a
% Inhibition pSTAT1/pSTAT3
Est. ED50 pSTAT1/pSTAT3 (mg/kg)
42/210
Est. IC50 pSTAT1/pSTAT3 (
lM)
30
100
300
0.83 0.45/2.00 1.02
5.35 1.15/240 6.43
20.23 8.77/62.4 62.38
41/9
72/40
88/55
1.39/13.0
a
Inhibition of STAT phosphorylation was measured 4 h after treating female nude mice (n = 4) implanted with HEL92.1.7 xenograft tumors. Plasma/tumor concentration
reported as the mean SD. Inhibition reported as the mean (n = 4) relative to vehicle. 10d was formulated in water +10 mM HCl.
Table 7
2250
2000
1750
1500
1250
1000
750
Kinase selectivity profile of 10da
Vehicle:1, 0 mg/kg, PO bid
100 mg/kg, PO bid
Kinase
IC50 (nM)
Kinase
IC50 (nM)
Kinase
IC50 (nM)
200 mg/kg, PO bid
JAK1
MLK1
FLT3
134.3
370.0
139.7
375.4
TYK2
PDGFRA
FLT4
348.3
546.7
554.5
313.8
c-KIT
PDGFRB
KDR
225.8
125.4
483.6
910.5
300 mg/kg, PO bid
IKKbeta
p70S6K
FLT1
a
Values reported are the average of at least two independent dose-response
curves. All assays were performed at ATP concentrations approximately equal to the
Km values of the respective enzymes.
500
250
0
JAK family members JAK1 and TYK2. Further in vitro evaluation
0
5
10
15
20
25
30
of 10d revealed that it demonstrated a desirable CYP (1A2, 2C9,
Days Post-Implantation
2D6, 3A4 P20
lM), hERG (16 lM), and P-glycoprotein inhibition
Figure 4. Inhibition of HEL.92.1.7 xenograft tumor growth by 10d. Experiment
involved twice daily administration of 10d to tumor-bearing nude mice over a
14 day period. Data represents mean tumor size SE (n = 10). Analogue 10d was
formulated in water +10 mM HCl.
(>20 M) profile.
l
In summary, we have discovered a series of potent and selective
JAK2 inhibitors. Compound 10d shows good biochemical and cellu-
lar potency against JAK2 with good selectivity against the Janus
Kinase family as well as a broad kinase panel. It shows a favorable
pharmacokinetic profile and a dose-dependent pharmacodynamic
effect in HEL.92.1.7 cells. In addition, 10d induced moderate tumor
growth inhibition accompanied by increases in tumor cell apopto-
sis. Compound 10d was selected as a clinical candidate and
Analogue 10d was also evaluated against a selectivity panel of
118 kinases. Targets for which 10d exhibited IC50 <1000 nM are
displayed in Table 7. Overall 10d is a highly selective JAK2 inhibitor
displaying >50-fold selectivity against all kinases tested including
Table 6
Pharmacokinetic properties of 10d17,18
Species
Dose (mg/kg)
CL (mL/h/kg)
Vd (L/kg)
T1/2 (h)IV / PO
F (%)
Cmax
(lM)IV/PO
AUC/dose (lM h kg/mg) IV/PO
Mouse
Rat
Dog
10
5
3
4951.79
129.23
1397.5
1174.78
5.319
0.666
13.4
1.13/1.94
3.12/3.23
6.00/5.06
3.28/3.36
54.5
53.6
44.8
68.6
5.24/0.57
12.95/3.53
0.44/0.17
0.64/0.49
0.42/0.21
15.99/8.54
1.47/0.68
1.76/1.20
Cyno
3
6.739

7658
T. Forsyth et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7653–7658
9. Manshouri, T.; Quintas-Cardama, A.; Nussenzveig, R. H.; Gaikwad, A.; Estrov, Z.;
Prchal, J.; Cortes, J. E.; Kantarjian, H. M.; Verstovsek, S. Cancer Sci. 2008, 99,
1265.
10. Pissot-Soldermann, C.; Gerspacher, M.; Furet, P.; Gaul, C.; Holzer, P.; McCarthy,
C.; Radimerski, T.; Regnier, C. H.; Baffert, F.; Drueckes, P.; Tavares, G. A.;
Vangrevelinghe, E.; Blasco, F.; Ottaviani, G.; Ossola, F.; Scesa, J.; Reetz, J. Bioorg.
Med. Chem. Lett. 2010, 20, 2609.
advanced into human clinical trials where it was evaluated in pa-
tients with primary myelofibrosis, post-polycythemia vera, or
post-essential thrombocythemia myelofibrosis.19
Acknowledgments
11. Verstovsek, S. Clin. Cancer Res. 1988, 2010, 16.
12. Ioannidis, S.; Lamb, M. L.; Wang, T.; Almeida, L.; Block, M. H.; Davies, A. M.;
Peng, B.; Su, M.; Zhang, H.-J.; Hoffmann, E.; Rivard, C.; Green, I.; Howard, T.;
Pollard, H.; Read, J.; Alimzhanov, M.; Bebernitz, G.; Bell, K.; Ye, M.; Huszar, D.;
Zinda, M. J. Med. Chem. 2011, 54, 262.
13. William, A. D.; Lee, A. C.-H.; Blanchard, S.; Poulsen, A.; Teo, E. L.; Nagaraj, H.;
Tan, E.; Chen, D.; Williams, M.; Sun, E. T.; Goh, K. C.; Ong, W. C.; Goh, S. K.; Hart,
S.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. J. Med.
Chem. 2011, 54, 4638.
We greatly appreciate the contributions to the biochemical, cel-
lular, and pharmacokinetic data from members of Exelixis Genome
Biochemistry, New Lead Discovery, Molecular and Cellular Phar-
macology, Pharmacology, and Compound Repository Groups.
References and notes
14. Lim, J.; Taoka, B.; Otte, R. D.; Spencer, K.; Dinsmore, C. J.; Altman, M. D.; Chan,
G.; Rosenstein, C.; Sharma, S.; Su, H.-P.; Szewczak, A. A.; Xu, L.; Yin, H.; Zugay-
Murphy, J.; Marshall, C. G.; Young, J. R. J. Med. Chem. 2011, 54, 7334.
15. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
16. Paquette, R. P.; Sokol, L.; Shah, N. P.; Silver, R. T.; List, A. F.; Clary, D. O.; Bui, L,
A.; Talpaz, M. Abstract of Papers, 50th ASH Annual Meeting and Exposition, San
Francisco, CA, 2008; Abstract 2810.
17. Detailed experimentals and assay protocols for this manuscript are found in
the following patent application: Mann, G.; Naing, A.; Arlyn, A.; Brown, S. D.;
Chan, W. K. V.; Jeff, C.; Du, H.; Epshteyn, S.; Forsyth, T.; Galan, A. A.; Huyuh, T.
P.; Ibrahim, M. A.; Johnson, H. W. B.; Brian, K.; Kearney, P.; Kim, B. G.; Koltun,
E.; Leahy, J. W.; Lee, M. S.; Lewis, G. L.; Meyr, L. E.; Noguchi, R. T.; Pack, M.;
Ridgway, B. H.; Shi, X.; Woolfrey, J.; Zhou, P. WO 2007/089768, 2007.
18. Mouse PK data: 10d was administered at 10 mg/kg PO or IV as a solution in
water to female athymic nude mice (n = 3). Rat PK data: 10d was administered
at 5 mg/kg PO or IV as a solution in 5% EtOH 45% PEG400/Water + HCl to female
CD Rats (n = 3). Dog and cyno PK data: 10d was administered at 3 mg/kg PO or
IV as a solution in 5% EtOH 45% PEG400/Water + HCl to either male beagle dogs
or male cynos (n = 3).
1. Rane, S. G.; Reddy, E. P. Oncogene 2000, 19, 5662.
2. Levine, R. L.; Wadleigh, M.; Cools, J.; Ebert, B. L.; Wernig, G.; Huntly, B. P.;
Boggon, T. J.; Wlodarsaka, I.; Clark, J. J.; Moore, S.; Adelsperger, J.; Koo, S.; Lee, J.
C.; Gabriel, S.; Mercher, T.; D’Andrea, A.; Frohling, S.; Dohner, K.; Marynen, P.;
Vandenberghe, P.; Mesa, R. A.; Tefferi, A.; Griffin, J. D.; Eck, M. J.; Sellers, W. R.;
Meyerson, M.; Golub, T. R.; Lee, S. J.; Gilliland, D. G. Cancer Cell 2005, 7, 387.
3. Baxter, E. J.; Scott, L. M.; Campbell, P. J.; East, C.; Fourouclas, N.; Swanton, S.;
Vassiliou, G. S.; Bench, A. J.; Boyd, E. M.; Curtin, N.; Scott, M. A.; Erber, W. N.;
Green, A. R. Lancet 2005, 365, 1054.
4. James, C.; Ugo, V.; Le Couedic, J. P.; Staerk, J.; Delhommeau, F.; Lacout, C.;
Garcon, L.; Raslova, H.; Berger, R.; Bennacaur-Griscelli, A.; Villeval, J. L.;
Constantinescu, S. N.; Casadevall, N.; Vainchenker, W. Nature 2005, 434, 1144.
5. Kralovics, R.; Passamonti, F.; Buser, A. S.; Teo, S.-S.; Tiedt, R.; Passweg, J. R.;
Tichelli, A.; Cazzola, M.; Skoda, R. C. N. Engl. J. Med. 2005, 352, 1779.
6. Verstovsek, S.; Mesa, R. A.; Gotlib, J.; Levy, R. S.; Gupta, V.; DiPersio, J. F.;
Catalano, J. V.; Deininger, M.; Miller, C.; Silver, R. T.; Talpaz, M.; Winton, E. F.;
Harvey, J. H., Jr.; Arcasoy, M. O.; Hexner, E.; Lyons, R. M.; Paquette, R.; Raza, A.;
Vaddi, K.; Erickson-Viitanen, S.; Koumenis, I. L.; Sun, W.; Sandor, V.; Kantarjian,
H. M. N. Engl. J. Med. 2012, 366, 799.
19. Shah, N. P.; Olszynski, L. S.; Verstovsek, S.; Hoffman, R.; List, A. F.; Cortes-
Franco, J.; Kantarjian, H. M.; Gillman, D. G.; Clary, D. O.; Bui, L. A.; Wadleigh, M.
Abstract of Papers, 50th ASH Annual Meeting and Exposition, San Francisco, CA,
2008; Abstract 98.
7. Thompson, J. E.; Cubbon, R. M.; Cummings, R. T.; Wicker, L. S.; Frankshun, R.;
Cunningham, B. R.; Cameron, P. M.; Meinke, P. T.; Liverton, N.; Weng, Y.;
DeMartino, J. A. Bioorg. Med. Chem. Lett. 2002, 12, 1219.
8. Hexner, E. O.; Serdikoff, C.; Jan, M.; Swider, C. R.; Robinson, C.; Yang, S.; Angeles,
T.; Emerson, S. G.; Carroll, M.; Ruggeri, B.; Dobrzanski, P. Blood 2008, 111, 5663.