The discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.12.039

Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors

Full text of DOI:10.1016/j.bmcl.2010.12.039

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1248–1252
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The Discovery of furo[2,3-c]pyridine-based indanone oximes as potent
and selective B-Raf inhibitors
Alex J. Buckmelter a, Li Ren a, , Ellen R. Laird a, , Bryson Rast a, Greg Miknis a, Steve Wenglowsky a,
Stephen Schlachter a, Mike Welch a, Eugene Tarlton a, Jonas Grina a, Joseph Lyssikatos b,
Barbara J. Brandhuber a, Tony Morales a, Nikole Randolph a, Guy Vigers a, Matthew Martinson a,
Michele Callejo a
⇑
⇑
a Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States
b Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080-4990, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We
describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone
oximes as highly potent and selective inhibitors of B-Raf.
Received 18 October 2010
Revised 2 December 2010
Accepted 6 December 2010
Available online 10 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
B-Raf
Kinase
Cancer therapy
The Ras/Raf/MEK/ERK signal transduction pathway is critical to
the survival, growth, and proliferation of cells and has been impli-
cated in several human cancers. B-Raf is a serine-threonine kinase
in this pathway that has been shown to have a much higher basal
kinase activity relative to either of its isoforms (A-Raf or C-Raf),
and recently has been reported to be frequently mutated in various
human cancers. Activating B-Raf mutations, most notably V600E
(formerly termed V599E), have been identified in 66% of melanomas
and to lesser extents in many other cancers.1 The Raf kinase inhibitor
Bay43-9006(Sorafinib)hasbeenapprovedforthetreatmentofrenal
cell carcinoma. However, its lack of activity in tumors that express
mutant B-Raf, for example, melanoma, may arise because the princi-
pal mechanism of action is through inhibition of VEGFR rather than
Raf.2 The development of specific B-Raf inhibitors is therefore an
active area of investigation for cancer therapy.
At the outset of this work in 2003, X-ray crystal structures of
B-Raf were not available, although diverse inhibitor classes had
been reported (Fig. 1). The triaryl imidazoles represented by
L-779,4503 are compact structures that possess very few confor-
mations that could comprise the binding mode. A shape-based
virtual screen of our in-house compound collection using the ROCS
program4 yielded 270 hits, the most interesting of which came
from a library of imidazo[1,2-a]pyrazines5 depicted in Figure 2.
Subsequent screening confirmed compound 1a (Table 1) as a
1.4 l
M inhibitor.6 Because acylated and sulfonylated amines from
the library were not active (data not shown), we anticipated that
the aminomethylphenyl group was occupying a confined space.
Homology models of B-Raf were constructed on the basis of
sequence similarity to the Src and MAP kinase families,7 and con-
firmed that B-Raf possesses a small gatekeeper residue (Thr529),
which is indicative of sensitivity to aryl substituents.8 In order to dif-
ferentiate between the possible binding modes (Fig. 3), a small set of
analogs was synthesized (exemplified by compounds 1b and 1c,
Table 1). In order to enhance hydrophobic contact in the pocket
made accessible by the gatekeeper threonine (the ‘gatekeeper pock-
et’), the4-aminomethylgroupwasreplacedwith4-chloro, whichled
to a modest improvement in activity. Subsequent replacement of the
2-phenyl moiety with methyl was of little consequence. These data
enhanced our confidence in the preferred binding mode (Fig. 3a) and
enabled the initiation of lead optimization.
Concurrent with this work,10 we were investigating pyridinyl–
pyrazole oximes, and were aware that an appropriately positioned
oxime moiety, represented by SB-59088511 and GDC-0879
(Fig. 1),10 could impart both potency and Raf selectivity. Because
the 4-chlorophenyl group of 1b was modeled to reside in the same
region as the oxime moiety of GDC-0879, we opted to explore imi-
dazopyrazine oximes.
⇑
Corresponding authors.
E-mail addresses: li.ren@arraybiopharma.com (L. Ren), Ellen.Laird@arraybio
Table 1 shows SAR for selected imidazopyrazines. Introduction
of the indane–oxime moiety (compare 2b and 1a, 1b) led to a
pharma.com (E.R. Laird).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.039

A. J. Buckmelter et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1248–1252
1249
F
HO
N
N
F
F
H
N
O
Cl
O
N
O
HO
Cl
N
N
H
N
H
N
N
OH
HN
N
Bay 43-9006
(Sorafenib)
L-779,450
GDC-0879
B-Raf IC50 = 1 nM
B-Raf IC50 = 10 nM
B-Raf IC50 = 0.13 nM
Figure 1. Selected B-Raf inhibitors known at the outset of this work.
significant improvement in enzyme (V600E B-Raf) potency and
measurable inhibition of phospho-ERK production. Various substit-
uents (compounds 2a–2d) were tolerated at C2, consistent with our
presumedbinding mode. It is notable that analogsthat are capable of
an internal hydrogen bond to the C3 NH (i.e., compounds 2a and
2d)12 showed modest enhancement in enzyme potency, but consid-
erable improvement in the cellular assays. The internal hydrogen
bond may provide a conformational constraint to the desired bind-
ing mode, and may also mask polar surface area and improve cell
permeability.
Despite significant improvement in activity for this series, the
imidazopyrazines did not approach the level of inhibition attained
in the pyridinyl–pyrazole oxime series that was under investigation
simultaneously.10 We hypothesized that this could arise from a
number of contributing factors, including differences in conforma-
tional energetics, parameters relating to exposed and buried surface
area, and hydrogen-bonding capabilities. We determined from
conformational profiling at the 6-31G(d) level of theory13 that, while
theboundconformationofthepyridinyl–pyrazoletemplateliesvery
near its global minimum, the bound conformation of the imidazo-
pyrazines lies ca. 3.4 kcal/mol above the global minimum
conformer. In addition, relative to the corresponding pyridinyl–
pyrazoles, the total buried surface area for the imidazopyrazines is
significantly lower upon engagement by the active site, but the
fraction of polar surface area buried is higher (data not shown). This
suggests less Van der Waals contact coupled with a potentially
higher desolvation penalty.
a
b
R1
NH
We evaluated various electronic parameters for alternatives to
the imidazopyrazine. Calculation of partial atomic charges and
interaction potentials is often used as a measure of hydrogen-bond
N
N
accepting ability for inhibitors.14 Figure
4 illustrates these
R2
N
computed properties for several fused templates versus a simpli-
fied pyridinyl–pyrazole.
The imidazopyrazine template buries a substantial amount of
strongly polar surface area, owing to the significant charge density
at N1. On the other hand, the thieno[2,3-c]pyridines were predicted
to maintain the same overall geometry with improved hydrogen-
bond accepting capability for the hinge interaction, and thus
comprised our next targets.
Figure 2. (a) Selected virtual screening hit. The query triarylimidazole (L-779,450)
is shown in white, and a representative ROCS virtual screening hit is depicted in
magenta. (b) The generic imidazo[1,2-a]pyrazine template.
A number of thienopyridines were synthesized and representa-
tive examples are shown in Table 2. To our satisfaction, the thieno-
Table 1
Activity of imidazopyrazines
HO
NH2
N
Cl
NH
NH
NH
N
3
N
R
N
Ph
N
R
N
N
N
N
N
1
7
1a
1b-c
2a-2d
Compound
R
B-Rafa IC50 (nM)
pERKa IC50 (nM)
1a
1b
1c
Ph
Ph
Me
1400
570
1200
—
76,000
—
CO2Et
2a
2b
16
35
3100
Figure 3. Possible binding modes for compound 1b.9 (a) The preferred binding
mode, based on evaluation of HTS data (data not shown) and precedence in kinase
X-ray structures for halogenated aromatics in the gatekeeper pocket. The distance
between N7 and the hinge nitrogen is 2.8 Å. (b) Alternative binding mode;
disfavored owing to a nonoptimal hinge contact for N7 (over 3.7 Å) and N1 (over
3.8 Å). The sidechains of the hinge residues are undisplayed for clarity; the
sidechain of the gatekeeper (Thr529) is explicitly illustrated. Hydrogen-bonding
interactions are illustrated with dashed green lines.
Ph
19,000
N
2c
47
4
16,000
1400
O
2d
a
Biochemical and cellular IC50 values are an average of three experiments.

1250
A. J. Buckmelter et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1248–1252
NH
NH
-0.61
NH
N
N
N
N
-0.65
q =
-0.71
N
N
-0.69
N
N
H
N
S
-0.65
-5.7
-0.53
-6.7
Δ
EH2O
=
-6.7
-6.6
Figure 4. Electronic properties for B-Raf templates. q = computed partial atomic charges labeled on potential hydrogen-bond accepting atoms; red labeling highlights the
atom of highest negative charge. ChelpG charges were computed for structures that were optimized using the 6-31G(d) basis set.
DEH2O is the computed interaction potential
with water as a general donor for the hinge-acceptor atom.15 Note that the thienopyridine template has a partial charge on the hinge-binding acceptor atom that closely
resembles that of the potent pyridinyl–pyrazole, and was hence the template of choice.
Table 2
pyridines did show significant improvements in both enzyme and
cellular potencies (compare 2a and 3a, 2b and 3e, and 2c and 3f).
Shortly after we began investigating this series, the first X-ray crys-
tal structures of imidazopyrazines and thienopyridines were
solved. Figure 5 illustrates the X-ray structure of 3a,16 and also re-
veals that the thienopyridines have additional hydrophobic
contacts to Ile463 of the P-loop, which probably also contributes
to the enhanced potency.
Representative thienopyridines
HO
N
NH
In spite of the improved activity of the thienopyridines, a draw-
back of this series was its propensity to inhibit multiple CYP P450s
at sub-micromolar concentrations, possibly via mechanisms
related to the well-known metabolic activation of thiophene
moieties.17 For example, IC50 values of 3a for CYP3A4, 2C19, and
1A2 were determined to be 50, 129, and 616 nM, respectively.
The inherent CYP liabilities of the thienopyridines suggested a
core change was necessary and we opted to address this issue by
substituting the sulfur with oxygen;18 several of the resulting
R
N
S
3a-3g
Compound
R
B-Rafa IC50 (nM)
pERKa IC50 (nM)
CO2Et
3a
3b
3
280
CONMe2
O
40
5800
3c
N
52
8200
N
H
Table 3
Representative furopyridines
3d
3e
H
Ph
32
3
7300
1500
N
HO
N
3f
3
170
140
O
3g
<2b
a
NH
R
Biochemical and cellular IC50 values are an average of three experiments.
IC50 value below the detection limit of the routine enzyme assay.
b
N
O
4a-4h
Compound
R
B-Rafa IC50 (nM)
pERKa IC50 nM
<2b
5
30
CO2Et
4a
4b
CONMe2
O
340
N
4c
2
40
N
H
4d
4e
3
2000
150
N
<2b
N
4f
<2b
<2b
960
365
4g
N
O
N
4h
0.2c
5
Figure 5. X-ray crystal structure of thienopyridine 3a bound to B-Raf. Hydrogen
bonds are depicted as dashed yellow lines, and include interactions with the
mainchain NH of Cys532 of the hinge sequence, and contacts between the oxime
OH and Glu501 and the oxime nitrogen with Lys483. Evaluation of Van der Waals
contacts reveals that the sulfur atom makes significant contact to the sidechain of
Ile463.
N
a
b
c
Biochemical and cellular IC50 values are an average of three experiments.
IC50 value below the detection limit of the routine enzyme assay.
The enzyme IC50 of 4h was determined in a more sensitive assay using a lower
concentration of the B-Raf protein.

A. J. Buckmelter et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1248–1252
1251
R4
HO
N
NH
R4 N C
N
OHC R3
+
N
R3
N
NH2
Sc(OTf)3
N
N
NH2
NH
Scheme 1. Preparation of imidazopyrazines.
CN
Br
i
ii, iii
Ar
Ar
N
N
N
O
O
TBSO
+
NH2
CO2Et
N
8
4d-h
9
i, iii, ii
i, ii
3a
3b and 3c
Scheme 4. Synthesis of 2-aryl and 2-heteroarylfuropyridines: (i) NaH, ArCH2OH,
DMF, À10 °C, 30 min; then 8, 60 °C, 16 h (35%); (ii) 5-bromo-2,3-dihydroinden-1-
one O-tert-butyldimethylsilyl oxime, Pd2(dba)3, XPhos, Cs2CO3, toluene, 110 °C,
(70%); (iii) TBAF, THF, (90%).
N
S
Br
Scheme 2. General synthesis of thienopyridines 3a–3c: (i) Pd2(dba)3, XPhos,
Cs2CO3, toluene, 110 °C, (75%); (ii) TFA, (89%); (iii) HNR1R2, Me3Al, (80%).
furo[2,3-c]pyridines19 are shown in Table 3. The first compound
synthesized was ethyl ester 4a, which was superior to both its
corresponding imidazopyrazine and thienopyridine analogs (2a
and 3a, respectively) in terms of enzyme and cellular potency. Fur-
thermore, furopyridine ester 4a exhibited a much improved P450
profile: IC50 values for CYP3A4, 2C19 and 1A2 were 8300, 1177
and >25,000 nM, respectively.
Table 4
ADME properties of selected furopyridine analogs
Compound
Hepat. Cla
Caco-2b
Pe ratio
Sol. @ pH 6.5
4c
4h
17
28
High
High
0.9
0.9
>1000
2
a
Rat hepatocyte clearance (ml/min/kg).
b
Caco-2 permeability classification: low (<2 Â 10À6 cm/s), medium (2–
8 Â 10À6 cm/s), high (>8 Â 10À6 cm/s).
Encouraged by these results and in an effort to improve the
chemical and metabolic stability of the series, we synthesized sev-
eral amides (represented by 4b and 4c) and found that secondary
amides were superior to tertiary amides. Amide 4c displayed im-
proved aqueous solubility (>1 mg/mL at pH 6.5), high caco-2 per-
meability, and low predicted clearance from human and rodent
hepatocytes. We also examined the placement of various aryl
and heteroaryl groups at the 2-position. Aryl derivatives (exempli-
fied by 4d) in general were less potent in cell assays, but heteroaryl
derivatives showed striking differences in cellular potency depend-
ing on substitution. For example, 3-pyridyl derivative 4f showed
improvement over 4d, but was inferior to 2-pyridyl derivative 4e.
As we had observed for the imidazopyrazines, superior cellular
activity appeared to correlate with the ability to form an internal
hydrogen bond, with concomitant masking of polar surface area.
When a second nitrogen atom was incorporated into the pyridine
ring system (exemplied by pyrimidine 4h), the result was an extre-
mely potent B-Raf inhibitor that exhibited a picomolar IC50 in the
V600E biochemical assay and corresponding low nanomolar inhi-
bition of pERK. Overall, we regarded the furopyridine series to be
superior to the thienopyridines and imidazopyrazines owing to
its clean P450 profile and potent in vitro activity.
Thienopyridine esters and amides (3a–3c) were synthesized
according to Scheme 2. Ethyl 3-aminothieno[2,3-c]pyridine-2-car-
boxylate21 was used in a Buchwald coupling with 5-bromo-2,3-
dihydro-1H-inden-1-one O-tert-butyldimethylsilyl oxime22 to
form the critical NH linkage. Silyl deprotection then afforded ester
3a directly. Amides 3b and 3c were prepared by treating the silyl
protected ester with preformed amino aluminates, followed by
removal of the sily protecting group.
For the 2-aryl- and 2-heteroarylthienopyridines (3e–3f), the
method of LaMattina and Taylor23 was used to construct the
requisite 2-arylthieno[2,3-c]pyridin-3-amine. Subsequent XPhos-
mediated palladium coupling with 5-bromo-2,3-dihydro-1H-
inden-1-one O-tert-butyldimethylsilyl oxime followed by silyl
deprotection afforded the desired 2-aryl thienopyridines. The 2-
keto derivatives (3g) were constructed via the Weinreb amide.19
The preparation of furopyridine esters and amides is outlined in
Scheme 3. Ethyl 3-hydroxyfuro[2,3-c]pyridine-2-carboxylate (6)
has been reported previously,24 however, in our hands the reported
alkylation of ethyl 3-hydroxyisonicotinate (5) with ethyl 2-bromo-
acetate was problematic in that we consistently observed large
amounts of byproduct resulting from alkylation on the pyridine
nitrogen. In order to avoid the undesired alkylation, this transfor-
mation was carried out under Mitsunobu conditions and the
desired product was isolated in consistently higher yields. Subse-
quent cyclization to 6 was accomplished in excellent yield using
NaH. The hydroxyl group was then converted to the corresponding
triflate and a Buchwald coupling afforded ester 7. Amides 4b and
The imidazopyrazine scaffold was rapidly constructed via a
3-component, 4+1 cyclization reaction20 involving an aldehyde,
2-aminopyrazine, and an isonitrile in the presence of scandium
triflate (Scheme 1). In most cases, the oximes were isolated as a mix-
ture of both the E- and the Z-isomer, with the E being the predomi-
nant form (>9:1 E/Z ratio). In several cases, we were able to
separate the E, Z isomers by column chromatography; the E isomers
were typically five-fold more active in both enzyme and cell assays.
HO
N
TBSO
N
COOEt
OH
NH
NH
OH
i, ii
iii, iv
v, vi
CONR1R2
CO2Et
CO2Et
N
N
N
O
O
O
N
6
7
4b-c
5
Scheme 3. Synthesis of amide furopyridines 4b–4c: (i) PPh3, DIAD, À10 °C, 30 min; then ethyl glycolate, À10 °C, 30 min; then 5, À10 °C to room temperature (76%); (ii) NaH,
THF, 0 °C to room temperature, then HOAc (84%); (iii) Tf2O, Py, DCM (90%); (iv) 5-amino-2,3-dihydroinden-1-one O-tert-butyldimethylsilyl oxime, Pd2(dba)3, XantPhos,
K3PO4, toluene, 110 °C, (70%); (v) NHR1R2, AlMe3, 0 °C, 30 min; then 7, (vi) TBAF, THF.

1252
A. J. Buckmelter et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1248–1252
3. Heimbrook, D. C.; Huber, H. E.; Stirdivant, S. M.; Patrick, D. R.; Claremon, D.;
Liverton, N.; Selnick, H.; Ahern, J.; Conroy, R.; Drakas, R.; Falconi, N.; Hancock,
P.; Robinson, R.; Smith, G.; Olif, A. American Association for Cancer Research,
New Orleans, Apr 1998; Poster #3793.
4c were generated by reacting 7 with preformed amino aluminates
followed by removal of the silyl protecting group.19
2-Aryl-3-amino furopyridines (9) were prepared from 3-bromo-
isonicotinonitrile 8 according to the procedure of LaMattina and
Taylor.23 The subsequent transformations to 4d–4h were similar
to the thienopyridine series and are highlighted in Scheme 4.
Being of interest due to its cellular activity, 4h was screened
against a panel of 25 non-RAF kinases at 1 lM. Satisfyingly, 4h
did not show greater than 50% inhibition against any of the
enzymes with the exception of casein kinase 1 delta.
4. ROCS: OpenEye Scientific Software: Santa Fe, NM. Virtual hits were comprised
of compounds from
a 50% sampling of our focused library collection
(approximately 200,000 virtual compounds) with a purely shape-matching
Tanimoto index of 0.85 or more.
5. Laird, E.; Topalov, G.; Lyssikatos, J. P.; Welch, M.; Grina, J.; Hansen, J.;
Newhouse, B. WO 2006125101.
6. For assay description see: Laird, E.; Lyssikatos, J.; Welch, M.; Grina, J.; Hansen,
J.; Newhouse, B.; Olivero, A.; Topolav, G. WO 2006/084015 A2, 2006.
7. The homology model was constructed using the program COMPOSER (Tripos
Associates, St. Louis MO). The X-ray coordinates of Lck in complex with PP2
(PDB accession code 1QPE) were chosen as the major template.
8. Noble, M. E. M.; Endicott, J. A.; Johnson, L. N. Science 2004, 303, 1800.
9. Binding modes were generated using the program GOLD (v2.2) Jones, G.;
Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.
10. Hansen, J. D.; Grina, J.; Newhouse, B.; Welch, M.; Topalov, G.; Littman, N.;
Callejo, M.; Gloor, S.; Martinson, M.; Laird, E.; Brandhuber, B. J.; Vigers, G.;
Morales, T.; Woessner, R.; Randolph, N.; Lyssikatos, J.; Olivero, O. Bioorg. Med.
Chem. Lett. 2008, 28, 4692.
11. Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.; Hird, A.
W.; King, F. D.; Lovell, P. K.; Naylor, A.; Reith, A. D.; Steadman, J. G.; Wilson, D.
M. Bioorg. Med. Chem. Lett. 2006, 16, 378.
12. The existence of an internal hydrogen bond was later confirmed by X-ray
crystallography. Vide infra.
13. Gaussian98, Revision A.11. Frisch, M.J. et al. Gaussian Inc. Pittsburgh PA.
14. (a) Murray, J. S.; Ranganathan, S.; Politzer, P. J. Org. Chem. 1991, 56, 3734; (b)
Chan, A. W. E.; Golec, J. M. C. Bioorg. Med. Chem. 1996, 4, 1673; (c) McClure, K.
F.; Abramov, Y. A.; Laird, E. R.; Barberia, J. T.; Cai, W.; Carty, T. J.; Cortina, S. R.;
Danley, D. E.; Dipesa, A. J.; Donahue, K. M.; Dombroski, M. A.; Elliott, N. C.;
Gabel, C. A.; Han, S.; Hynes, T. R.; LeMotte, P. K.; Mansour, M. N.; Marr, E. S.;
Letavic, M. A.; Pandit, J.; Ripin, D. B.; Sweeney, F. J.; Tan, D.; Tao, Y. J. Med. Chem.
2005, 48, 5728.
The in vitro ADME and pharmacokinetic profiles of furopyri-
dines 4c and 4h were determined. Although 4c and 4h were found
to be intrinsically stable in plasma and in liver hepatocytes, and
were highly permeable without efflux (Table 4), both compounds
were rapidly cleared from the plasma compartment when dosed
in rats (data not shown). The in vivo/in vitro disconnection can
be partially explained by the poor stability of 4h in rat microsomes
(CLpred = 50 ml/min/kg). Degradation of the oxime moiety to the
corresponding ketone was hypothesized and can occur via well-
known CYP mediated processes as well as in the presence of stom-
ach acid.25 This possibility led to a significant effort toward the
identification of indazole-based B-raf inhibitors, which we describe
in the following paper.26
Via virtual and high-throughput screening we discovered an
imidazopyrazine template as a lead structure for inhibition of
B-Raf. X-ray crystal structures confirmed the expected binding
mode, and consideration of binding orientation and electronic
properties enabled optimization to thienopyridines as a more po-
tent second-generation lead. Optimization of the thienopyridines
to remove the inherent CYP liabilities eventually led us to the
highly potent furopyridines, of which several potent and selective
B-RAF inhibitors have been identified. In the following paper, we
describe further evolution of the series geared toward enhanced
pharmacokinetic properties.
15. Interaction potentials were the averaged energy for
a water molecule
interacting with the hinge acceptor of the inhibitor as computed via Monte
Carlo simulation using the OPLS potential function and the TIP4P water model:
(a) Jorgensen, W. L.; Tirado-Rives, J. J. Am. Chem. Soc. 1988, 110, 1657; (b)
Jorgensen, W. L.; Blake, J. F.; Buckner, K. Chem. Phys. 1989, 129, 193.
16. Coordinates for the B-Raf crystal structure have been deposited in the PDB:
accession code 3PSB.
17. Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell, J.
P. Chem. Res. Toxicol. 2002, 15, 269.
18. Calculation of partial atomic charges for the furopyridine template resulted in
À0.67 for the pyridyl nitrogen.
19. Miknis, G.; Lyssikatos, J. P.; Laird, E.; Tarlton, E.; Buckmelter, A. J.; Ren, L.; Rast,
B.; Schlachter, S. T.; Wenglowsky, S. M. US 2007049603.
Acknowledgment
20. (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661; (b) Blackburn, C.; Guan,
B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39, 3635; (c)
Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234.
21. Beugelmans, R.; Bois-Choussy, M.; Boudet, B. Tetrahedron 1983, 39, 4153.
22. 5-Bromo-2,3-dihydro-1H-inden-1-one O-tert-butyldimethylsilyl oxime was
synthesized in 99% yield by heating 5-bromo-2,3-dihydro-1H-inden-1-one
and NH2OTBS in the presence of a catalytic amount of TsOH.
The authors thank Susan Rhodes, Jennifer Otten, and Michelle
Livingston for Caco, P450, and solubility determinations. The
authors also thank Drs. Joachim Rudolph and Stefan Gradl for
critical review of the manuscript and helpful suggestions.
23. LaMattina, J. L.; Taylor, R. L. J. Org. Chem. 1981, 46, 4179.
24. Morita, H.; Shiotani, S. J. Heterocycl. Chem. 1986, 23, 549.
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