Discovery of GSK1070916, a potent and selective inhibitor of aurora B/C kinase

Article abstract of DOI:10.1021/jm901870q

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K_i* values of 0.38 ± 0.29 and 1.5 ± 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC₅₀ = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.

Full text of DOI:10.1021/jm901870q

J. Med. Chem. 2010, 53, 3973–4001 3973
DOI: 10.1021/jm901870q
Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase
,
Nicholas D. Adams,* Jerry L. Adams, Joelle L. Burgess, Amita M. Chaudhari, Robert A. Copeland, Carla A. Donatelli,
†
†
†
†
†
†
‡
David H. Drewry, Kelly E. Fisher, Toshihiro Hamajima, Mary Ann Hardwicke, William F. Huffman,
†
§
†
†
‡
Kristin K. Koretke-Brown, Zhihong V. Lai, Octerloney B. McDonald, Hiroko Nakamura, Ken A. Newlander,
†
‡
§
†
†
Catherine A. Oleykowski, Cynthia A. Parrish, Denis R. Patrick, Ramona Plant, Martha A. Sarpong, Kosuke Sasaki,
†
†
†
†
§
†
†
†
‡
†
Stanley J. Schmidt, Domingos J. Silva, David Sutton, Jun Tang, Christine S. Thompson, Peter J. Tummino,
†
†
Jamin C. Wang, Hong Xiang, Jingsong Yang, and Dashyant Dhanak
†
†
†
†
‡
Cancer Research, Oncology R&D, and Molecular Discovery Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville,
§
Pennsylvania 19426, and Tsukuba Research Laboratories, Japan
Received December 18, 2009
The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or
amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors
with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azain-
dole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the
series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to
significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive
inhibitor of Aurora B and C with K * values of 0.38 ( 0.29 and 1.5 ( 0.4 nM, respectively, and is >250-
i
fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an
extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical
compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results
in a potent antiproliferative effect (EC =7 nM). Intraperitoneal administration of 17k in mice bearing
5
0
human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon
cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed
to human clinical trials.
Introduction
overlapping functions and similar localization patterns to
1
9-22
Aurora B.
A number of small molecule inhibitors of Aurora kinases
The mammalian Aurora kinases (A, B, and C) are a family
of Ser/Thr protein kinases that play key roles in regulating cell
cycle progression through mitosis. Along with its cellular
a
binding partner TPX2 , Aurora A plays an essential role in
bipolar spindle assembly, including centrosome separation
3,23,24,25
have been progressed to clinical development.
1
-5
VX-680/
MK-0457 (1, Vertex/Merck) inhibits all three Aurora kinase
isoforms with approximately equal potency and was the first
2
6
6-8
inhibitor to show the potential for in vivo activity (Figure 1).
Examples of Aurora isoform selective agents include AZD-
and maturation.
kinase activity causes defects in centrosome separation, with
Small molecule inhibition of Aurora A
27
9
the formation of characteristic monopolar spindles. Aurora
1152 (2, AstraZeneca, Aurora B/C selective), MLN8054 (3,
2
8
Millenium, Aurora A selective), and most recently MK-5108
(Merck, Aurora A selective). Although it is not clear whether
B is a chromosomal passenger protein that functions together
with its binding partners INCENP, survivin, and borealin, to
ensure proper kinetochore-microtubule attachments.
29
1
0-13
inhibition of all three Aurora isoforms is necessary for optimal
antitumor efficacy, in cell culture most of the reported pan-
Aurora inhibitors induce an Aurora B inhibition phenotype, i.
e., chromosomal endoreduplication abnormalities. This obser-
vation suggests that Aurora B inhibition alone may be sufficient
for antitumor activity. In this report, we describe our efforts to
improve the activity and selectivity profile of a 7-azaindole-
based lead series culminating in the identification of GSK-
During mitosis, Aurora B is required for phosphorylation of
histone H3 at serine 10 prior to chromosome condensation
and plays a key role in chromosome segregation and
1
4-16
cytokinesis.
Inhibition of Aurora B kinase activity with
small molecules leads to failure in cytokinesis and abnormal
exit from mitosis, resulting in endoreduplication, polyploid
cells, and ultimately apoptosis.
restricted expression profile with low levels in most somatic
tissues and high levels in the testis, and although its function is
not as well understood, recent studies suggest that it has
1
7,18
Aurora C has a more
3
0
1
070916 (17k), a potent and selective ATP-competitive inhi-
bitor of Aurora B and C with >250-fold selectivity over
Aurora A.
Lead Profile. Screening of small molecules for Aurora kinase
inhibitors and subsequent SAR refinement identified compound
*
To whom correspondence should be addressed. Phone: 610-917-
1
2c as a lead with good Aurora B potency and selectivity over
6
2
018. Fax: 610-917-4157. E-mail: nicholas.d.adams@gsk.com.
a
Abbreviations: TPX2, target protein of Xenopus kinesin-like protein
; INCENP, inner centromere protein; DNAUC, dose normalized area
Aurora A (Figure 2). Although 12c also displayed potent
antiproliferative activity vs A549 lung cancer cells, other proper-
ties (activity vs non-Aurora kinases, high in vivo blood clearance
under the curve.
r
2
010 American Chemical Society
Published on Web 04/26/2010
pubs.acs.org/jmc

3
974 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
Figure 1. Structures and activities of lead Aurora inhibitors.
Figure 2. Biological profile and putative binding mode of inhibitor 12c in an Aurora B homology model.
in rodents, and potent CYP2C9 and CYP2D6 inhibition) were
pharmaceutically unattractive. A putative binding mode of
compound 12c in an Aurora B homology model is shown in
Figure 2. Compound 12c is proposed to reside in the ATP-
binding pocket with the azaindole interacting with the hinge
region and the phenylurea occupying a hydrophobic pocket
Recent reports highlighting the use of drug-target residence
time (i.e., dissociation half-life) as an additional parameter for
compound optimization prompted us to evaluate compounds
31
32,33
of interest for time dependence.
Accordingly, compound
12c was tested for time dependent inhibition against Aurora B/
INCENP with rapid dilution experiments and found to have a
short residence time (7.7 (0.8 min), indicating the formation of
(back pocket). Relative to Aurora B/INCENP, Aurora A/
3
4
TPX2 has a smaller and less accessible hydrophobic pocket
where the urea moiety is proposed to reside, and this structural
difference potentially explains the isoform selectivity of 12c and
a rapidly reversible, short-lived enzyme-inhibitor complex.
Aurora B/INCENP dissociation half-lives of <30 min were
34
also reported for clinical compounds 1 and 2.
7
related compounds. The pyrazole ring occupies the ATP sugar
Results and Discussion
pocket and the azaindole 2-position points toward the solvent
accessible surface. Guided by this putative binding mode, our
medicinal chemistry strategy consisted of exploring the SAR
around three main areas of the molecule, the pyrazole ring (R1),
the 2-position of the 7-azaindole ring (R2), and the phenylurea
Chemistry. The synthesis of derivatives 12a-o which
modify the pyrazole group (R1) commenced with the pre-
paration of pyrazoles 5a-c by reaction of 1-(4-nitrophe-
nyl)ethanone with N,N-dimethylformamide dimethylacetal,
followed by treatment with the appropriate hydrazine in
ethanol (Scheme 1). Bromination with N-bromosuccinimide
(R3), in a concerted effort to maintain Aurora B inhibitory
activity and address the shortcomings of the lead.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3975
a
Scheme 1. Synthesis of R1 Substituted Azaindole Derivatives
a
Reagents and conditions: (a) DMF DMA, DMF, 80 ꢀC; (b) hydrazine monohydrate or t-butylhydrazine hydrochloride, EtOH, 70 ꢀC; (c) NBS,
3
3
DMF, rt; (d) R1-Br, NaH, DMF, 0 ꢀC to rt; (e) bis(pinacolato)diboron, KOAc, PdCl
Zn, AcOH, rt; (g) PhNCO, pyr, rt; (h) Pd(PPh
2
(PPh
3
)
2
, 1,4-dioxane, 100 ꢀC; (f) Sn(0), 6N HCl, EtOH, 70 ꢀC or
3
)
4
, DMF, NaHCO
3
(aq), 100 ꢀC; (i) 12i: OsO
4
, NMO, t-BuOH, H
2
O, acetone, rt; 12j: 9-BBN, 6N NaOH,
Et, EDCI, DMAP, DMF, rt; 12o:
30% H (aq), THF, H
morpholine, CDI, DMF, rt .
2
O
2
2
O, 0 ꢀC to rt; (j) 12m: ethyl chloroformate, NH
4
OH, TEA, THF, 0 ꢀC to rt; 12n: NH
2
provided intermediate bromides 6a-c. Alkylation of pyra-
zole 6a under basic conditions provided regioisomeric mix-
tures which were readily separable by chromatographic
methods to give 7a-e. Bromides 7a-e were used as is or
converted to their corresponding boronates for the final
palladium catalyzed Suzuki cross-coupling step with their
azaindole counterparts. Synthesis of pyrazole bromides in-
corporating the phenylurea R3 group were prepared through
Sn(0) or Zn(0) mediated reduction of the nitrophenyl deri-
vatives 6a, 6c, or 7a-b to their corresponding anilines and
subsequent conversion to the phenylurea with phenyl iso-
cyanate. These intermediates were either used as is or con-
verted to their corresponding boronates for the subsequent
Suzuki cross-coupling reactions with the requisite azaindole
fragment.
amination reactions to provide amines 15i-n. With the pyra-
zole-azaindole core in place, the 4-nitrophenyl derivatives
15g-n were reduced to their corresponding anilines, depro-
tected under basic conditions, and capped with appropriate R3-
group, thereby providing target molecules 17c-u.
A synthesis of compounds 22a-c, where R2 is an amide
group, is outlined in Scheme 3. Regioselective bromination
of ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate 7-oxide
3
6
(18) provided bromide 19, which underwent Suzuki cou-
pling with boronate 8a. The Suzuki conditions also served to
hydrolyze the ester, providing acid 20 from which the amide
was installed via EDC or 1,1-carbonyldiimidazole mediated
couplings. The phenyl urea was introduced along the lines
described in Scheme 2 to provide the target compounds.
Derivatives which incorporate a substituted methyl-
amino moiety at R2 (28a-f) were prepared using 2-formyl
intermediate 24, synthesized by phenylsulfonyl-directed
metalation of 23 with LDA and trapping of the resulting
anion with DMF (Scheme 4). Reductive amination of
aldehydes 24 or 26 with an amine in the presence of sodium
triacetoxyborohydride afforded the desired aminomethyl
Synthesis of compounds 17a-u where R2 and R3 are
functionalized is outlined in Scheme 2. Sequential Suzuki cross-
coupling of 4-bromo-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo-
3
5
[
2,3-b]pyridine(13) with the appropriate phenyl boronic acids
followed by pyrazole boronic acid 8a provided intermediates
5a-h. Aldehyde intermediates 15a-d underwent reductive
1

3
976 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
a
Scheme 2. Synthesis of R2 and R3 Substituted Azaindole Derivatives
a
Reagents and conditions: (a) R2-Ph-B(OH)
2
, Pd(PPh
3
)
4
, DMF, NaHCO
3
(aq), 100 ꢀC; (b) 8a, Pd(PPh
3
)
4
, DMF, NaHCO
3
(aq), 100 ꢀC; (c) amine,
NaBH(OAc)
3
, THF, rt; (d) Sn(0), 6N HCl, EtOH, 70 ꢀC or Zn, AcOH, rt; then 6N NaOH (aq), MeOH, 70 ꢀC; (e) PhNCO or EtNCO, pyr, rt (or TEA,
. *Compounds 17a and 17b were prepared from 15e and 15f, respectively, through
THF, rt), or 4-nitrophenyl chloroformate, TEA, THF, rt, HNMe
2
reduction of the nitro group with palladium hydroxide/hydrogen, urea formation with PhNCO and subsequent deprotection of the phenylsulfonyl
group with 6N NaOH (aq); see the Experimental Section for details.
a
Scheme 3. Synthesis of R2 Amide Azaindole Derivatives
a
Reagents and conditions: (a) Me
0
4
NBr, (MeSO
2 2 3 4 2 3
) O, DME; (b) 8a, Pd(PPh ) , 2 M K CO (aq), dioxane, 100 ꢀC; (c) EDC or 1,1-carbonyldiimi-
0
dazole, NH
2
CH CH
2
2
R2 , DMF, rt; (d) Sn(0), 6N HCl, EtOH, 70 ꢀC; (e) PhNCO, pyr, rt.
intermediates, which were then converted to final com-
pounds 27a-f through a similar sequence described in
Scheme 2.
Biological Evaluation of Inhibitors. The ability of azain-
dole derivatives to inhibit Aurora B/INCENP and Aurora
A/TPX2 protein kinase activity was determined using a

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3977
a
Scheme 4. Synthesis of R2 Methylamino Azaindole Derivatives
a
000
Reagents and conditions: (a) (i) LDA, THF, hexanes, -78 ꢀC, (ii) DMF; (b) HNR , NaBH(OAc)
3
, CH
2
Cl :AcOH (4:1); (c) bis(pinacolato)diboron,
2
KOAc, PdCl (dppf) CH
2
2
Cl
2
3 4 3
, 1,4-dioxane, 90 ꢀC; (d) 10c, Pd(PPh ) , satd aq NaHCO , DMF, 100 ꢀC; (e) 6N NaOH, MeOH, 70 ꢀC.
3
LEADSeeker (Amersham Biosciences) scintillation proxi-
0,34
the identification of compounds with high Aurora B inhibi-
tory activity but with significant erosion in antiproliferative
activity. The attenuated cellular activity of alcohols 12g, 12j,
3
mity assay (SPA) format as previously described.
Com-
pounds were assayed for their antiproliferative activity
against the human lung cancer cell line A549 using Promega
and 12i is potentially due to their reduced cell permeability
-1
3
0,37
CellTiter-Glo reagents as previously described.
(artificial membrane permeability 27, 3, and 41 nm s ,
respectively) relative to 12c (artificial membrane permeabil-
We first investigated the regiochemical preference for the
pyrazole substituent (depicted as N1 and N2 in Table 1) while
maintaining the phenyl urea at R3. Transposition of the ethyl
group from the N1-position to the Ν2-position led to a 12-fold
decrease in Aurora B inhibitory activity and concomitant loss
in antiproliferative activity (cf. compound 12c vs 12b). Delet-
ing the ethyl group of 12c to give unsubstitued pyrazole 12a
resulted in ∼15-fold lower potency against Aurora B and a
concomitant loss in cellular potency. Initial structure-activity
relationship (SAR) studies also established that modification
of the phenyl urea, such as substituting the phenyl ring with
electron withdrawing and/or donating groups, replacement of
the phenyl group with alkyl groups, or replacement of the urea
moiety with amides, sulfonamides, or carbamates, did not lead
to substantial improvement in activity relative to 12c (data not
shown). Transposing the para-phenyl urea (12c) to the meta
position led to significant loss in Aurora B inhibitory potency,
presumably due to the para-substituent having a more favor-
able trajectory to access the hydrophobic back pocket region
adjacent to the ATP binding site. Taken together, these data
suggested that the enzyme preferred a bulky lipophilic para-R3
group albeit in combination with the unsubstituted azaindole
core (R2=H).
With the pyrazole N1-position identified as the preferred
position for Aurora B enzymatic and cellular activity, our
SAR efforts focused on exploring different pyrazole R1
substituents with a goal of further improving the cellular
potency of this series. On the basis of the putative binding
mode (vida supra), the pyrazole ring occupies the sugar
pocket region of the ATP-binding site. Therefore we incor-
porated polar hydrogen bond donating groups in an effort to
enhance potency. Indeed, incorporation of ethanol (12g),
propanol (12j), or 1,2-propanediol (12i) moieties resulted in
-1 38
ity =170 nm s ). Substitution of the pyrazole with various
substituted acetamides (compounds 12m-o) was also not
fruitful. Taken together, small R1-alkyl groups were the
substituents of choice during the course of further SAR
investigations.
Although an inhibitor bound Aurora B cocrystal structure
was not available during these investigations, our putative
binding mode revealed a solvent accessible area toward the
front pocket of the Aurora B ATP-binding pocket and could
potentially accommodate a wide variety of functionality
2
7
(vide supra). We reasoned that incorporation of an appro-
priately substituted aryl group adjacent to the presumed
hinge binding moiety would allow for access to the solvent
accessible area of the enzyme without interfering with hinge
binding and also enable modulation of physicochemical
properties. A number of such compounds were prepared
and evaluated in the A549 cell proliferation assay in the
presence and absence of 70% human serum in order to assess
the effect of inhibitor binding to serum proteins on their
antiproliferative activity (Table 2). A comparable 10-20-
fold decrease in cellular potency in the presence of 70%
human serum was noted for this set of derivatives (data not
shown). Incorporation of a 3-N-acetylaniline at R2 (17a) led
to a 20-fold attenuation in the in vitro Aurora B inhibitory
activity relative to unsubstituted azaindole 12c; surprisingly,
however, cellular activity was not diminished (Table 2). Com-
pound 17a has much slower Aurora B/INCENP dissoci-
ation half-life (320 ( 120 min) relative to 12c (7.7 (
0.8 min), and it is possible that its true potency is under-
estimated in our in vitro biochemical assay even with a
3
4
30 min enzyme-inhibitor preincubation. This could poten-
tially explain the level of cellular activity for compound 17a.

3
978 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
Table 1. Biochemical and Cellular Data for Substituted Pyrazole
Derivatives (R1)
17a, 17b, 17e) relative to 12c are not clear, but a potential
explanation is that the substituted phenyl group (R2) plays a
role in orienting the phenylurea in the lipophilic back pocket,
which is smaller and less accessible in Aurora A/TPX2. In
general, the presence of an R2-phenyl group containing a
7
basic amine (e.g., dimethylamine (17c-f,j-m), morpholine
(17h-i,r-u), or pyrrolidine (17g,n-q)) led to improved cel-
lular activity. Replacing the phenyl group with amides
(
22a-c) resulted in potent Aurora B inhibitors but modest
cellular potency. Aminomethyl derivatives 28a-f exhibited
reduced biochemical and cellular potency. No significant solu-
bility or cell permeability differences were noted that could
account for the attenuated activity of 28a-f. On the basis of
their improved potency in cells, R2-aryl groups containing a
basic amine were selected for further SAR investigations.
With the addition of aryl amines at the R2-position, we
reinvestigated phenyl urea SAR with the intention of identi-
fying groups that led to a reduction in overall molecular
weight and lipophilicity of the compounds. Furthermore,
taking into account the previously discussed SAR trends, we
postulated that various combinations of R2 and R3 groups
would affect the Aurora B potency and selectivity over
Aurora A. As such, R2 and R3 combination analogues were
prepared and evaluated in the biological assays (Table 3). A
majority of the hybrid derivatives were highly potent against
Aurora B and demonstrated excellent antiproliferative acti-
vity against A549 tumor cells. In fact, some compounds from
this set have in vitro Aurora B/INCENP IC s that are
5
0
similar to their EC s on cells, for example compound 17c.
5
0
Compound 17c also has a slow Aurora B/INCENP dissocia-
tion half-life (520 ( 110 min) and, as discussed above, it is
possible that its true potency is underestimated in our in vitro
biochemical assay even with a 30 min enzyme-inhibitor
3
4
preincubation.
Modulation in selectivity over Aurora A depending on the
R2/R3 combination was also noted. For example, replace-
ment of the phenylurea of 17c with an ethylurea (17j) resulted
in a modest improvement in Aurora B inhibitory activity and
an increase in selectivity over Aurora A from 3-fold to 42-
fold while maintaining excellent antiproliferative activity.
Selectivity was further improved to 252-fold through com-
bination of the R3-dimethylurea group with the R2-meta-
(dimethylaminomethyl)phenyl, providing 17k. The observed
selectivity may be attributed to the corresponding R2
group’s potential role in orienting the urea group in the disti-
nct lipophilicback pockets of AuroraB/INCENPand Aurora
7
A/TPX2. In addition to good selectivity over Aurora A, 17k
demonstrated excellent Aurora B inhibition (IC =5 nM)
5
0
and antiproliferative activity (A549 EC =7 nM). Transpo-
5
0
sition of the dimethylaminomethyl tail moiety to the para-
position (17m) led to retention in biochemical and cellular
activity (cf. 17k) and a slight diminution in Aurora B/A
selectivity, from 252- to 156-fold. In general, meta-dimethyl-
amino and morpholino tails were slightly favored over their
para counterparts with respect to Aurora B vs A selectivity,
regardless of the R3 group (cf. 17k vs 17m and 17s vs 17u) for
this set of derivatives.
a
NT = not tested.
Selectivity over a panel of non-Aurora kinases was as-
sessed for several of the compounds that showed potent in
vitro activity and/or selectivity over Aurora A (Figure 3).
Compound 12c demonstrated >70-fold selectivity against
this panel of kinases; however, when an aminoaryl group was
introduced at the azaindole 2-position (compound 17c),
significant activity against LCK, LYN, MET, and ROCK
Incorporation of a meta-dimethlyaminomethyl-phenyl R2
group (17c) resulted in a further improvement in antiproli-
ferative activity in A549 cells (EC =14 nM). Interestingly,
5
0
however, selectivity over Aurora A was diminished (cf. 12c,
15-fold vs 3-fold). Reasons for the diminished Aurora
A selectivity of compound 17c and related compounds (e.g.,
3

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3979
a
Table 2. Biochemical and Cellular Data for R2 Group Derivatives
a
NT = not tested.
was observed. Truncating the phenylurea moiety of com-
pound 17c to an ethylurea (compound 17j) resulted in signi-
ficant attenuation of these off-target activities, and even
further attenuation (>140-fold selectivity) was observed
with dimethylurea 17k. Compound 17k represented the best
combination of biochemical/cellular potency and selecti-
vity within this set of analogues and was thus selected for
further study.
compound 17k is a highly selective inhibitor of Aurora B and
C kinase.
We recently reported that compound 17k is a reversible,
ATP-competitive inhibitor of Aurora B/INCENP and
Aurora C/INCENP with K * values of 0.38 ( 0.29 and 1.5 (
i
0.4 nM, respectively, and is >250-fold selective over Aurora
3
4
A/TPX2, which had a K value of 490 ( 60 nM. The Ki*
i
values take into account the slow onset of inhibition and
define the true potency of 17k against the enzyme, as
Evaluation of 17k. The selectivity of 17k was further deter-
mined by measuring its ability to inhibit 328 unique human
protein and lipid kinases using either in vitro activity or binding
3
4
previously described. Remarkably, 17k exhibited >480
min and 270 ( 28 min dissociation half-lives in Aurora B/
INCENP and Aurora C/INCENP, respectively, resulting in
prolonged inhibition of kinase activity. The extremely slow
off-rate of compound 17k from Aurora B/INCENP is in
contrast to compounds 1 and 2, which display a dissociation
39
assays. Furthermore, we generated full dose-response ana-
lysis for a subset of 58 kinases to determine their IC50 values. In
addition to the Aurora kinases, only five kinases were identified
with IC50 values below 100 nM (Table 4), indicating that

3
980 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
Table 3. Biochemical and Cellular Data for R2 and R3 Group Combinations
Figure 3. Kinase selectivity comparison for compounds 12c, 17c,
1
7j, and 17k.
Table 4. Inhibitory Activity of 17k against Other Kinases
kinase
IC50 (nM)
AurA/TPX2
AurB/INCENP
AurC/INCENP
FLT1
1259
5
6.5
42
74
59
70
76
FLT4
TIE2
SIK
FGFR1
rate is that it may confer a selective advantage such as less
frequent dosing and perhaps greater tolerance over com-
pounds with shorter half-lives. This hypothesis will ulti-
mately be tested in clinical trials.
As we reported previously, compound 17k follows a one-step
Aurora B/INCENP binding model with an on rate of 0.022 (
-
1
-1
-1
0.004 μM
s , and an off rate of <0.0014 min , resulting in
34
a dissociation half-life of >480 min. To identify inhibitor
structural features that could potentially contribute to a long
residence time, Aurora B/INCENP dissociation rates were
determined for a number of azaindole derivatives with varying
R2 and R3 groups. Compound 12c, which lacks substitution of
the azaindole 2-position (R2), had a short dissociation rate of
<10 min (Table 5). Incorporation of a meta-(dimethyl-
aminomethyl)phenyl group onto the azaindole 2-position
in combination with a phenyl urea at R3 (17c) resulted in
a compound with a long dissociation half-life of 520 (
110 min. Truncating the phenyl urea of 17c to an ethyl (17j)
or dimethyl urea (17k) also provided compounds with long
Aurora B/INCENP dissociation half-lives of 200 and >480
min, respectively. Furthermore, acetamide 17a had a long
dissociation half-life, indicating that a basic amine at R2
is not necessary for the prolonged residence time on Aurora
B/INCENP. For this limited set of derivatives, these results
suggest that incorporation of a 2-aryl group on the azaindole
ring contributes to the long dissociation half-life. Although the
absence of a cocrystal structure makes it difficult to rationalize
inhibitor-enzyme interactions that could explain the long
dissociation half-life of these inhibitors, it is possible that
the back pocket may take time to undergo conformational
changes until it reaches a conformation accessible to compound
a
NT = not tested.
3
half-life of <30 min under the same conditions. The
potential measurable advantage of 17k’s long dissociation
4

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3981
Table 5. Aurora B/INCENP Dissociation Half Life Values for Inhi-
bitors
Table 7. Intravenous Pharmacokinetic Profile of 17k in the Conscious
Mouse
a
1
2c
Aur B/INCENP 7.7 ( 0.8 320 ( 120 520 ( 110 200 ( 50 >480
1/2 (min)
17a
17c
17j
17k
dose
CL
(mL min kg
b
-1
DNAUC(0-¥)
V
(L kg
dss
-1
MRT
(h)
-1
-1
-1
-1
-1
(
mg kg
)
)
(ng h mL mg kg
3
345
)
)
b
b
0.8
b
t
2.0
49.4
0.3
a
b
n = 3. CL
b
was calculated using AUC0-t ; Vdss and MRT were
estimated using AUC0-t and AUMC0-t
.
Table 6. CYP450 IC50 Values (μM) for 17k in Human Liver Micro-
somes
1
A2
2C9
2C19
2D6
3A4
3A4
phenacetin diclofenac S-mephenytoin bufuralol nifedipine midazolam
>
33 38 81 12 15 activator
binding. Additional conformational change may then lock the
compound in the pocket, hence giving rise to the time depen-
dent inhibition. However, it is apparent that some other
undetermined factors also contribute to the time dependence
as certain back-pocket binders (e.g., 12c) do not show signi-
ficant time dependent inhibition.
Figure 4. Inhibition of pHH3 after treatment of advanced Colo205
tumors in mice with 17k.
To test for the potential of compound 17k to affect the
metabolism and or clearance of other coadministered agents
leading to clinical drug-drug interactions, IC s were gene-
xenograft in nude mice (Figure 5). Compound 17k was dosed
-1
5
0
daily (ip) at 75 or 100 mg kg for five days and for two cycles
rated against six CYP450 isozymes in human liver micro-
somes (Table 6). Compound 17k displayed IC50 values g12
μM against the panel of CYP450 isozymes, with the excep-
tion of the 3A4 (midazolam) for which it was an activator.
Our P450 inhibition assay in human liver microsomes was
performed using selective probe substrates, and product
formation was monitored by LC/MS/MS. The enzyme
activity in the presence of compound 17k was normalized
with the enzyme activity in the absence of compound and
expressed as a percentage of control activity. In the study
with CYP3A4 and midazolam, increased enzyme activity
was observed with increased inhibitor concentration
(
qdx5 ꢀ 2; doses indicated by arrows in Figure 5). In contrast to
the untreated control mice, complete regression (CR) of the
tumor was observed in all mice that received 17k at both dose
levels. Notably for the 100 mg kg dose, no tumor regrowth
was observed 51 days post the last dose. Further in vivo
characterization of 17k against solid human tumor xenografts
-1
37
and human leukemia has been reported.
Conclusion
In summary, lead optimization efforts of a 7-azaindole
series of kinase inhibitors led to the discovery of compound
17k, a potent, selective, long acting inhibitor of Aurora B/C
suitable for evaluation in cancer patients. Key to the advance-
ment of the series was the introduction of a 2-aryl group
containing a basic amine onto the azaindole, leading to
significantly improved cellular activity. The presence of a
2-aryl group also allowed for truncation of the phenylurea
R3 group, leading to compounds with dramatically improved
kinase selectivity without compromising Aurora B activity or
cellular potency. Compound 17k is a novel, highly potent, and
(>100% of control activity).
Treatment of a panel of human tumor cell lines with
compound 17k results in potent inhibition of histone H3
phosphorylation (pHH3) at serine 10, a substrate and mar-
3
7,40
ker of intracellular Aurora B activity.
In light of its on-
target in vitro potency in biochemical and cellular assays and
good overall kinase selectivity, 17k made an excellent candi-
date for in vivo pharmacodynamic and efficacy evaluation
using human tumor xenograft models in rodents. As a
prelude to these studies, 17k was evaluated for its intrave-
nous pharmacokinetic parameters in the conscious mouse
selective Aurora B and C/INCENP inhibitor (K *=0.38 (
0.29 and 1.5 ( 0.4 nM, respectively) that exhibits potent
antiproliferative activity in human tumor cell culture (A459
i
3
4
(
Table 7). Following single dose iv administration at 1 mg
-1
-
1
-1
37,40
kg , 17k showed blood clearance of 49.4 mL min kg
and a dose normalized area under the curve (0 - ¥) of
3
dog, and monkey have been reported elseware. Compound
lung cell EC =7 nM).
5
This activity was manifested in
0
vivoasmeasured by a dosedependent inhibition of histone H3
phosphorylation at serine 10, a hallmark of Aurora B inhibi-
tion, in human colon cancer tumors (Colo205) and tumor
regression in human leukemia (HL-60) mouse xenografts
following intraperitoneal administration. Isoform selectivity
of compound 17k may be attributed to the urea group (R3)
imparting unfavorable interactions with the smaller, less
accessible hydrophobic back pocket of Aurora A/TPX2
-
1
45 ng h mL mg kg . The iv PK profiles for 17k in rat,
-1
-1
3
4
1
1
acceptable formulations (pH 4).
7k also demonstrates >10 mg/mL solubility in clinically
4
1
In an in vivo pharmacodynamic study, compound 17k was
assessed for its capacity to inhibit the phosphorylation of
histone H3 (pHH3) at serine 10 in mice with advanced
subcutaneous Colo205 tumors. The study was designed to
measure the percent inhibition of pHH3 relative to control at
7
relative to that of Aurora B/INCENP. The extremely slow
dissociation half-life of compound 17k from Aurora B/IN-
CENP is a clear distinction from clinical compounds 1 and 2.
A structure based rationale for the time dependent inhibition
is difficult in absence of an inhibitor-enzyme cocrystal
structure. One possible explanation is that the back pocket
may take time to undergo conformational changes until it
reaches a conformation accessible to compound binding, and
additional conformational change may then lock the com-
pound in the pocket, hence giving rise to the time dependent
3
(
3
0 h post dose using a pHH3 ELISA. After intraperitoneal
ip) treatment of the mice with the indicated doses of 17k at
0 h, a robust dose-dependent pharmacodynamic response,
as measured by a decrease in phosphohistone H3 (serine 10),
was observed and is consistent with in vivo Aurora B
inhibition (Figure 4).
Compound 17k was also evaluated for in vivo efficacy against
human leukemia HL-60 tumors grown as a subcutaneous

3
982 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
Figure 5. Evaluation of 17k against advanced HL-60 (acute monocytic human leukemia) tumors in nude mice.
inhibition. Despite Aurora B being relatively short-lived in
4
4-Bromo-1-{[4-(methyloxy)phenyl]methyl}-3-(4-nitrophenyl)-
1H-pyrazole (7e). To a solution of 4-bromo-3-(4-nitrophenyl)-
2
cells prior to degradation, the >8 h half-life of compound
7k suggests thatit canstay bounduntil AuroraB isdegraded.
1
H-pyrazole (1.9 mmol) in N,N-dimethylformamide (5.0 mL)
was added sodium hydride as a 60% dispersion in mineral oil
2.1 mmol). After 40 min, p-methoxybenzylchloride (2.2 mmol)
1
This is the maximum inhibition one can ever achieve for
Aurora B. Furthermore, it is possible that the slow enzyme
off-rate of the compound may in fact extend the half-life of the
protein, although this has not yet been demonstrated.
Although the clinical relevance of a slow dissociation rate of
an enzyme-inhibitor complex remains to be seen, the long
residence time of 17k may prove advantageous by prolonged
inhibition of Aurora B in vivo, after it has been cleared from
(
was added and the resulting mixture was stirred for 1 h. The
reaction mixture was then poured into water (60 mL), and the
precipitate was filtered and rinsed with water (2 ꢀ 15 mL). The
brown solid was dried under vacuum to yield 97% of the title
þ
1
product (7e). MS m/z 388.2 [M þ H] . H NMR (DMSO-d
6
):
δ 8.33 (d, 2H, J=8.8 Hz), 8.27 (s, 1H), 8.11 (d, 2H, J=8.6 Hz),
7.32 (d, 2H, J=8.6 Hz), 6.94 (d, 2H, J=8.6 Hz), 5.33 (s, 2H), 3.74
(s, 3H).
3
2,33,34
systemic circulation.
human clinical trials is planned.
Evaluation of compound 17k in
1-{[4-(Methyloxy)phenyl]methyl}-3-(4-nitrophenyl)-4-(4,4,5,
-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8e). A
5
solution of 4-bromo-1-{[4-(methyloxy)phenyl]methyl}-3-(4-nitro-
phenyl)-1H-pyrazole (7e, 1.44 mmol), bis(pinacolato)diboron
(1.73 mmol), potassium acetate (4.33 mmol), and dichlorobis-
(triphenylphosphine)palladium(II) (0.072 mmol) in dioxane (7.0
Experimental Section
Chemistry. General Methods. Unless otherwise noted, start-
ing materials and reagents were purchased from commercial
sources and used without further purification. Air- or moisture-
sensitive reactions were carried out under a nitrogen atmo-
sphere. Anhydrous solvents were obtained from Sigma-
Aldrich. Microwave irradiation was carried out in a Personal
Chemistry Emrys Optimizer microwave. Flash chromatogra-
phy was performed using silica gel (EM Science, 230-400 mesh)
under standard techniques or using silica gel cartridges
˚
mL) was heated at 100 ꢀC for 4 h. Crushed and activated 3 A
molecular sieves and additional dichlorobis(triphenylphosphine)-
palladium(II) (0.036 mmol) were added to the reaction mixture,
which was heated at 100 ꢀC for 17 h. The reaction mixture was
cooled, filtered through celite, diluted with water (75 mL), and
extracted with (3 ꢀ 60 mL) ethyl acetate. The combined organic
layers were dried over sodium sulfate and were concentrated in
vacuo. Purification of the residue by reverse phase HPLC
(50-100% acetonitrile in water) and concentration in vacuo
(
RediSep normal phase disposable flash columns) on an Isco
CombiFlash. Reverse phase HPLC purification was conducted
on a Gilson HPLC (monitoring at a wavelength of 214 or
provided the title product (8e) as an orange solid (20%). MS m/z
þ 1
2
3
54 nm) with a YMC ODS-A C18 column (5 μm, 75 mm ꢀ
435.4 [M þ H] . H NMR (CDCl
3
):δ8.26 (d, 2H, J=8.9 Hz), 8.21
0 mm), eluting with 5-90% CH CN in H 0 with 0.1% TFA
(d, 2H, J=9.1 Hz), 7.75 (s, 1H), 7.28 (m, 2H), 6.92 (d, 2H, J=8.6
Hz), 5.31 (s, 2H), 3.83 (s, 3H), 1.33 (s, 12H).
3
2
1
unless otherwise noted. H NMR spectra were recorded on a
Bruker Avance 400 MHz spectrometer. Chemical shifts (δ) are
reported in ppm relative to an internal solvent reference.
Apparent peak multiplicities are described as s (singlet), br s
4-[1-{[4-(Methyloxy)phenyl]methyl}-3-(4-nitrophenyl)-1H-pyra-
zol-4-yl]-1H-pyrrolo[2,3-b]pyridine. A solution of 4-bromo-1H-
pyrrolo[2,3-b]pyridine (0.26 mmol), 1-{[4-(methyloxy)phenyl]-
methyl}-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)-1H-pyrazole (8e, 0.28 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (0.013 mmol) in 2 M aq
potassium carbonate (0.75 mL) and dioxane (0.75 mL) was
heated at 98 ꢀC for 19 h. The reaction mixture was cooled,
diluted with water (5 mL), and extracted with (3 ꢀ 5 mL) ethyl
acetate. The combined organic layers were dried over sodium
sulfate and were concentrated in vacuo. Purification of the
residue by silica gel chromatography (50-70% ethyl acetate/
hexanes) and concentration in vacuo provided the title product
as a yellow solid containing ∼20% triphenylphosphine oxide
(85% yield). The intermediate was used directly in the next
(
broad singlet), d (doublet), dd (doublet of doublets), t (triplet),
q (quartet), or m (multiplet). Coupling constants (J) are
reported in hertz (Hz) after the integration. LCMS analysis
was conducted on a Shimadzu 10Avp LC/UV and a PE Sciex
single quadruple MS using a Thermo Aquasil column (C18,
4
5
3
0 mm ꢀ 1 mm, 5 μ particle diameter) and a gradient of
-100% MeCN (0.018% TFA)/water (0.02% TFA) over
t
.2 min. The retention time (R ) is expressed in minutes at a
UV detection of 214 nm. All tested compounds were deter-
mined to be g95% purity by LCMS unless otherwise noted.
Elemental analyses were performed by Quantitative Techno-
logies Inc., Whitehouse, NJ.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3983
þ 1
step. MS m/z 426.2 [M þ H] . H NMR (DMSO-d
6
): δ 11.73 (s,
H), 8.34 (s, 1H), 8.16-8.14 (m, 3H), 7.62 (d, 2H, J=9.1 Hz),
.42 (m, 2H), 7.39 (m, 1H), 6.96 (d, 2H, J=8.8 Hz), 6.86 (d, 1H,
The residue was dissolved in pyridine (16 mL), phenylisocya-
nate (0.203 mL, 1.857 mmol) was added, and the reaction
mixture was stirred at room temperature under an atmosphere
of nitrogen for 2 h. The solution was purifed directly on a silica
gel column, eluting with 40-80% ethyl acetate in hexanes to
provide the title compound (10b, 0.37 g, 57%). MS m/z 385.3,
1
7
J=5.0 Hz), 6.12 (m, 1H), 5.41 (s, 2H), 3.75 (s, 3H).
-[3-(4-Nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyr-
4
idine. A solution of 4-[1-{[4-(methyloxy)phenyl]methyl}-3-(4-
nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (0.22
mmol) in trifluoroacetic acid (0.75 mL) was heated at 74 ꢀC
for 1.5 h. The reaction mixture was diluted with water (4 mL)
and extracted with (3 ꢀ 5 mL) ethyl acetate. The combined
organic layers were dried over sodium sulfate and were concen-
trated. Purification of the residue by reverse phase HPLC
þ
1
387.2 [M þ H] . H NMR (400 MHz, DMSO-d
6
) δ ppm
1.19-1.31 (3H, m), 4.05 (2H, q, J=7.33 Hz), 6.99 (1H, t, J=
7.33 Hz), 7.23-7.40 (4H, m), 7.48 (2H, d, J = 7.58 Hz),
7.58-7.69 (3H, m), 8.79 (1H, s), 8.95 (1H, s).
N-{4-[1-Ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-
0
5-yl]phenyl}-N -phenylurea (12b). A mixture of N-[4-(4-bromo-
0
(
5-85% acetonitrile in water with 0.1% TFA), neutralization
1-ethyl-1H-pyrazol-5-yl)phenyl]-N -phenylurea (10b, 0.135 g,
of the fractions, and extraction into ethyl acetate, drying over
sodium sulfate, and concentration in vacuo afforded the title
0.352 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-pyrrolo[2,3-b]pyridine (86 mg, 0.352 mmol), tetrakis-
(triphenylphosphine)palladium(0) (20.3 mg, 0.0176 mmol), an-
hydrous 1,4-dioxane (2 mL), and 2.0 M aq potassium carbonate
(2 mL) was stirred at 100 ꢀC in a sealed tube for 18 h. The
reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and the organic portion separated. The aq portion
was extracted with ethyl acetate (3 ꢀ 3 mL), and the combined
organic layers were dried over magnesium sulfate and concen-
trated in vacuo. Purification of the residue by reverse phase
HPLC provided the title compound (12b) as a white solid (73
þ
1
product as a yellow solid (64%). MS m/z 306.4 [M þ H] . H
NMR (DMSO-d ): δ 13.62 (s, 1H), 11.70 (s, 1H), 8.22-8.16 (m,
6
4
H), 7.64 (d, 2H, J=8.6 Hz), 7.39 (m, 1H), 6.88 (d, 1H, J=4.8
Hz), 6.10 (s, 1H).
-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline.
A mixture of 4-[3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo-
2,3-b]pyridine (0.13 mmol) and tin metal (0.67 mmol) in 6N aq
4
[
hydrochloric acid (0.75 mL) and ethanol (0.75 mL) was heated
at 70 ꢀC for 1 h. The reaction mixture was cooled and filtered
through celite, and the solution was poured into saturated aq
sodiumbicarbonate (60mL) and extracted with(3 ꢀ 50 mL) ethyl
acetate. The combined organic layers were dried over sodium
sulfate and concentrated in vacuo. The title product (yellow solid,
quantitative) was used without further purification in the next
þ
1
mg, 49%). MS m/z 423.2 [M þ H] . H NMR (400 MHz,
DMSO-d ) δ ppm 1.33 (3H, t, J=7.20 Hz), 4.07 (2H, q, J=7.16
6
Hz), 6.38 (1H, dd, J=3.54, 1.77 Hz), 6.59 (1H, d, J=5.05 Hz),
6.98 (1H, t, J=7.33 Hz), 7.22-7.34 (4H, m), 7.37-7.41 (1H, m),
7.46 (2H, d, J=7.58 Hz), 7.55 (2H, d, J=8.59 Hz), 7.91-8.05
(2H, m), 8.77 (1H, s), 8.92 (1H, s), 11.60 (1H, br s).
þ
step. MS m/z 276.2 [M þ H] .
0
N-Phenyl-N -{4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyra-
zol-3-yl]phenyl}urea (12a). To a solution of 4-[4-(1H-pyrrolo-
5-(4-Nitrophenyl)-1H-pyrazole (5a). A solution of 1-(4-nitro-
phenyl)ethanone (100 g, 605 mmol) and N,N-dimethylforma-
mide dimethyl acetal (86.5 g, 726 mmol) in N,N-dimethyl-
formamide (1000 mL) was stirred for 1 h at 80 ꢀC. The reaction
was concentrated, redissolved in ethanol, (1000 mL) and treated
with hydrazine monohydrate (100 mL, 1816 mmol). After the
reaction was stirred 2 h at 70 ꢀC, it was cooled to room
temperature and poured into ice-water (2000 mL). Solid pre-
cipitated out of the solution and was filtered, washed with water
(4 ꢀ 500 mL), and dried to provide the title product (5a) as a
[
2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.13 mmol) and
triethylamine (0.20 mmol) in tetrahydrofuran (1.5 mL) was
added phenyl isocyanate (0.13 mmol). After 14 h, the reaction
mixture was concentrated in vacuo, and the residue was purified
by reverse phase HPLC (10-90% acetonitrile to water with
0
.1% TFA) to provide a mixture of bis- and monourea adducts
(
∼2:1 ratio).
This mixture was dissolved in methanol (1.0 mL), treated with
N aq sodium hydroxide (0.01 mL), and heated at 70 ꢀC for
þ
1
6
yellow powder (98%). MS m/z 190.2 [M þ H] . H NMR (400
45 min. The resultant precipitate was filtered, rinsed with
methanol, and dried in vacuo. Formation of the hydrochloride
salt of the title product (12a) with 4 M HCl in dioxane gave a
MHz, CDCl ) δ ppm 9.04-9.29 (m, 1H), 8.34 (d, J=8.84 Hz,
3
2H), 8.12 (d, J=8.84 Hz, 2H), 7.78 (s, 1H).
4-Bromo-3-(4-nitrophenyl)-1H-pyrazole (6a). A solution of
5-(4-nitrophenyl)-1H-pyrazole (113 g, 595 mmol) in N,N-di-
methylformamide (1000 mL) was treated with N-bromosucci-
nimide (116 g, 654 mmol). The reaction was stirred for 30 min at
room temperature and was poured into ice-water (1000 mL).
Solid precipitated out of the solution and was filtered, washed
with water (4 ꢀ 500 mL), and dried to provide the title product
þ
1
yellow powder in 25% yield. MS m/z 395.0 [M þ H] . H NMR
(
DMSO-d ): δ 12.75 (s, 1H), 9.63 (s, 1H), 9.45 (s, 1H), 8.32
6
(
d, 1H, J=5.8 Hz), 8.24 (s, 1H), 7.65 (m, 1H), 7.48 (d, 2H, J=
8
.5 Hz), 7.46 (d, 2H, J=7.6 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.27
t, 2H, J=8.0 Hz), 7.16 (d, 1H, J=6.0 Hz), 6.96 (t, 1H, J=7.4
Hz), 6.56 (m, 1H).
-Bromo-1-ethyl-5-(4-nitrophenyl)-1H-pyrazole (7a). The crude
(
þ
4
(6a) as an off-white powder (90%). MS m/z 269.2 [M þ H] .
1
mixture of 4-bromo-1-ethyl-5-(4-nitrophenyl)-1H-pyrazole (minor)
and 4-bromo-1-ethyl-3-(4-nitrophenyl)-1H-pyrazole (major)
6
HNMR (400 MHz, DMSO-d ) δ ppm 8.16 (d, J=8.59 Hz, 2H),
8.20 (s, 1H), 8.34 (d, J=8.34 Hz, 2H), 13.70 (br s, 1H).
(
∼15 g) was purified by silica gel chromatography, eluting
4-Bromo-1-ethyl-3-(4-nitrophenyl)-1H-pyrazole (7b). A 0 ꢀC
solution of 4-bromo-3-(4-nitrophenyl)-1H-pyrazole (130 g, 485
mmol) in N,N-dimethylformamide (1000 mL) was slowly trea-
ted with sodium hydride (19 g, 485 mmol) and then iodoethane
(47 mL, 582 mmol). The reaction mixture was stirred for 30 min
at room temperature and then poured into ice-water (1000
mL). Solid was precipitated out of the solution and was collected
by filtration, washed with water (4 ꢀ 500 mL), and dried to
provide 4-bromo-1-ethyl-3-(4-nitrophenyl)-1H-pyrazole (7b) as
with 10% ethyl acetate in hexane to 20% ethyl acetate in hexane.
This provided 5.92 g of a 1:1 mixture of 4-bromo-1-ethyl-5-
(4-nitrophenyl)-1H-pyrazole (minor) and 4-bromo-1-ethyl-3-(4-
nitrophenyl)-1H-pyrazole (major). This mixture was separated by
reverse phase HPLC, eluting with acetonitrile and water (no
TFA). The desired fractions were concentrated to furnish the title
þ
1
compound (2.542 g). MS m/z 296.6 [M þ H] . H NMR (400
MHz, DMSO-d ) δ ppm 1.26 (3 H, t, J=7.20 Hz) 4.10 (2 H, d, J=
.33 Hz) 7.73-7.88 (3 H, m) 8.40 (2 H, d, J=8.84 Hz).
6
þ 1
7
a light-brown powder (94%). MS m/z 297.2 [M þ H] . H NMR
0
N-[4-(4-Bromo-1-ethyl-1H-pyrazol-5-yl)phenyl]-N -phenylurea
10b). A mixture of 4-bromo-1-ethyl-5-(4-nitrophenyl)-1H-pyr-
azole (7a, 0.5 g, 1.688 mmol), tin metal (1 g, 8.44 mmol), 6N
(400 MHz, DMSO-d ) δ ppm 1.43 (t, J=7.33 Hz, 3H), 4.22 (q,
6
(
J=7.33 Hz, 2H), 8.13 (d, J=8.84 Hz, 2H), 8.22 (s, 1H), 8.34 (d,
J=8.84 Hz, 2H).
hydrochloric acid (aq) (9 mL), and ethanol (9 mL) was stirred at
7
concentrated in vacuo, and the residue used directly in the next
reaction.
1-Ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)-1H-pyrazole (8a). A solution of 4-bromo-1-ethyl-
0 ꢀC for 4.75 h. The reaction mixture was filtered, the filtrate
0
0
0
0
3-(4-nitrophenyl)-1H-pyrazole (8 g, 27 mmol), 4,4,4 ,4 ,5,5,5 ,5 -
0
octamethyl-2,2 -bi-1,3,2-dioxaborolane (7.6 g, 30 mmol), potassium

3
984 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
acetate (8 g, 81 mmol), and bis(triphenylphosphine)palladium(II)
dichloride (758 mg, 1.08 mmol) in 1,4-dioxane (30 mL) was stirred
for 3 h at 100 ꢀC in a sealed tube. After cooling to room temperature,
the reaction mixture was diluted with ethyl acetate (200 mL), filtered
though a silica-gel plug, and concentrated. Purification of the
residue by reverse phase HPLC provided the title product (8a) as
isomer (5b) following bromination and NOE studies. MS m/z
1
190.0 (M - C(CH ) þ 2H). H NMR (400 MHz, DMSO-d ) δ
3
3
6
ppm 1.41 (9H, s), 6.25 (1H, d, J=1.52 Hz), 7.49 (1H, d, J=1.52
Hz), 7.70 (2H, app d, J=8.59 Hz), 8.28 (2H, app d, J=8.59 Hz).
4-Bromo-1-(1,1-dimethylethyl)-5-(4-nitrophenyl)-1H-pyrazole
(6b). To a solution of 1-(1,1-dimethylethyl)-5-(4-nitrophenyl)-
1H-pyrazole (5b, 1.77 g, 7.22 mmol) in dry N,N-dimethylforma-
mide (22 mL) was added N-bromosuccinimide (1.413 g, 7.94
mmol). The reaction mixture was stirred at room temperature
for 30 min and then poured into water. The white precipitate
that formed was collected and washed with water and then
hexanes to provide the title compound (6b, 2.176 g, 93%). MS
þ
1
a yellow powder (28%). MS m/z 344.2 [M þ H] . HNMR (400
MHz, DMSO-d ) δ ppm 1.29 (s, 12 H), 1.42 (t, J=7.20 Hz, 3 H),
.23 (q, J=7.16 Hz, 2 H), 8.11 (s, 1 H), 8.15-8.21 (m, 2 H), 8.26 (d,
J=9.09 Hz, 2 H).
-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo-
2,3-b]pyridine. 4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-
H-pyrrolo[2,3-b]pyridine. A solution of 1-ethyl-3-(4-nitro-
phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyra-
6
4
4
[
1
1
m/z 268.0, 270.0 [M - C(CH ) þ 2H]. H NMR (400 MHz,
3
3
DMSO-d ) δ ppm 1.38 (9H, s), 7.62-7.79 (3H, m), 8.35 (2H, d,
6
43
zole (2.6 g, 7.5 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine
J=8.59 Hz).
(
(
1.2 g, 6.3 mmol), and tetrakis(tripheylyphosphine)palladium(0)
291 mg, 0.25 mmol) in 1,4-dioxane (12 mL) and 2 M aq potassium
1-(1,1-Dimethylethyl)-5-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8d). In a sealed tube was
combined 4-bromo-1-(1,1-dimethylethyl)-5-(4-nitrophenyl)-1H-
pyrazole (6b, 2.08 g, 6.416 mmol), potassium acetate (1.89 g,
19.248mmol), bis(pinacolato)diboron (1.792 g, 7.058 mmol), and
bis(diphenylphosphino)palladium(II)dichloride (0.18 g, 0.257
mmol) followed by anhydrous 1,4-dioxane (64.16 mL). The
reaction mixture was stirred at 100 ꢀC for 16.5 h then cooled to
rt. The solution was diluted with EtOAc (5 mL) and washed with
water (ꢀ 1). The aqsolutionwas extractedwithethyl acetate(ꢀ 4)
carbonate (12 mL) was stirred for 18 h at 100 ꢀC in a sealed tube.
Upon cooling to room temperature, product precipitated out of
solution, which was filtered and dried to provide the title product
þ
1
as a light-yellow powder (80%). MS m/z 334.2 [M þ H] . H
NMR (400 MHz, DMSO-d ) δ ppm 1.51 (t, J=7.20 Hz, 3H), 4.31
q, J=7.33 Hz, 2H), 6.15 (dd, J=3.41, 1.89 Hz, 1H), 6.87 (d, J=
6
(
4
.80 Hz, 1H), 7.35-7.44 (m, 1H), 7.59-7.69 (m, 2H), 8.13-8.19
(
m, 2H), 8.25 (s, 1H), 11.72 (br s, 1H).
-[1-Ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-
aniline. A solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-
-yl]-1H-pyrrolo[2,3-b]pyridine (59 mmol) in glacial acetic acid
25 mL) was treated with zinc dust (41 mmol) and stirred for 1 h
4
2 4
and the combined organic layers dried (Na SO ), filtered, and
concentrated in vacuo. The residue was purified by reverse phase
HPLC to give the title compound (8d, 0.273 g, 11%). MS m/z
4
(
1
315.2 [M - C(CH
3
)
3
þ H]. H NMR (400 MHz, DMSO-d
6
) δ
at room temperature. The reaction was then filtered and con-
centrated in vacuo. The resultant residue was suspended in a 1:1
mixture of ethyl acetate (10 mL) and saturated aq sodium
bicarbonate (10 mL) and stirred 30 min. The organic layer was
separated, filtered, washed with brine (1 ꢀ 5 mL), dried over
sodium sulfate, and concentrated. Purification of the residue by
flash chromatography (80-100% ethyl acetate/hexanes) pro-
vided the title product as a white powder (85%). MS m/z 304.2
ppm 1.03 (9H, s), 1.30 (12H, s), 7.63-7.67 (3H, m), 8.23-8.27
(2H, m).
N-{4-[1-(1,1-Dimethylethyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-
0
yl)-1H-pyrazol-5-yl]phenyl}-N -phenylurea (12d). A mixture of
1-(1,1-dimethylethyl)-5-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8d, 0.103 g, 0.277 mmol),
4-bromo-1H-pyrrolo[2,3-b]pyridine (46 mg, 0.0.231 mmol), 1,4-
dioxane (2 mL), 2 M aq potassium carbonate (2 mL), and
tetrakis(triphenylphosphine)palladium(0) (26.7 mg, 0.028 mmol)
in a sealed tube was stirred at 100 ꢀC for 18 h. The solution
was cooled to rt, diluted with ethyl acetate, and washed with
water (ꢀ 1). The organic layer was separated, and the aqueous
portion was further extracted with ethyl acetate (ꢀ 3). The
þ
1
[
7
1
M þ H] . H NMR (400 MHz, DMSO-d
6
) δ ppm 1.46 (t, J=
.20 Hz, 3H), 4.20 (q, J=7.33 Hz, 2H), 5.14 (br s, 2H), 6.28 (br s,
H), 6.45 (d, J=8.59 Hz, 2H), 6.81 (d, J=5.05 Hz, 1H), 7.03 (d,
J=8.59 Hz, 2H), 7.38 (d, J=3.28 Hz, 1H), 8.02-8.12 (m, 2H),
1
1.67 (br s, 1H).
N-{4-[1-Ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-
4
combined organic solution was dried (MgSO ), filtered, and
0
3
-yl]phenyl}-N -phenylurea (12c). A solution of 4-[1-ethyl-4-(1H-
concentrated in vacuo. This residue was purified by reverse phase
HPLC to give the 0.100 g of 4-[1-(1,1-dimethylethyl)-5-(4-
nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine with
91% purity by LCMS (0.091 g, 91%). This 91% pure material
was used in the next reaction without further purification. MS
pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (2.2 mmol) in
pyridine (4 mL) was treated with phenyl isocyanate (2.4 mmol)
and stirred for 1 h at room temperature. The reaction mixture was
concentrated in vacuo, and purification of the residue by flash
chromatography (80-100% ethyl acetate/hexanes) provided the
þ
m/z 362.2 [M þ H] . A mixture of 4-[1-(1,1-dimethylethyl)-5-(4-
title product (12c) as a white powder (50%). MS m/z 424.2 [M þ
nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (∼0.100
g, 0.276 mmol), glacial acetic acid (15 mL), zinc dust (90.4 mg,
1.38 mmol), and ethanol (1.5 mL) was stirred at room tempera-
ture for 1.5 h. The reaction mixture was filtered through a fritted
funnel, concentrated in vacuo, and dried in vacuo. The residue
was dissolved in pyridine (2.75 mL) and phenylisocyanate (30 μL,
0.276 mmol) added. The reaction mixture was stirred at room
temperature overnight. The solution was concentrated in vacuo
andthe residue purifiedbyreversephaseHPLC tofurnishthe title
þ 1
6
H] . H NMR (400 MHz, DMSO-d ) δ ppm 1.49 (t, 3H), 4.25 (q,
J=7.24 Hz, 2H), 6.25 (dd, J=3.41, 1.89 Hz, 1H), 6.82 (d, J=5.05
Hz, 1H), 6.97 (t, J=7.33 Hz, 1H), 7.21-7.33 (m, 4H), 7.34-7.41
(
1
m,3H), 7.45(d, J=7.58Hz, 2H), 8.11 (d, J=5.05 Hz, 1H), 8.15(s,
H), 8.70 (d, J=11.62 Hz, 2H), 11.63 (br s, 1H).
-(1,1-Dimethylethyl)-5-(4-nitrophenyl)-1H-pyrazole (5b). To
a round bottomed flask equipped with a stir bar was added
-nitroacetophenone (2.21 g, 13.37 mmol), N,N-dimethylfor-
1
4
þ
mamide dimethyl acetal (2.13 mL, 16.04 mmol), and N,N-
dimethylformamide (33.4 mL). The reaction mixture was stirred
at 80 ꢀC under a reflux condenser for 1 h 20 min. The solution
was concentrated in vacuo, the residue taken up in ethanol,
treated with tert-butylhydrazine hydrochloride (5 g, 40.125
mmol), and the solution stirred at 70 ꢀC for 2.5 h under an
atmosphere of nitrogen. LCMS did not show complete con-
sumption of starting material so the reaction mixture was heated
for a further 5 h at 70 ꢀC. The reaction mixture was then cooled
to room temperature, poured into water, and the deep-yellow
precipitate that formed was collected, washed with water (ꢀ 3).
This precipitate (2.62 g, 80%) was determined to be the desired
compound (12d, 72 mg, 58%). MS m/z 451.2 [M þ H] . LCMS
1
purity 92%. H NMR (400 MHz, DMSO-d
6
) δ ppm 1.47 (9H, s),
6.40 (1H, d, J = 5.05 Hz), 6.59 (1H, dd, J = 3.41, 1.89 Hz),
7.50-7.72 (6H, m), 7.86 (1H, d, J=4.80 Hz), 7.95 (1H, s), 8.68
(4H, s), 8.77 (1H, s), 8.91 (1H, s), 11.60 (1H, br s).
1-(1,1-Dimethylethyl)-3-(4-nitrophenyl)-1H-pyrazole (5c). To
a round bottomed flask equipped with a stir bar was added
4-nitroacetophenone (2.21 g, 13.37 mmol), N,N-dimethylfor-
mamide dimethyl acetal (2.13 mL, 16.04 mmol), and N,N-
dimethylformamide (33.4 mL). The reaction mixture was stirred
at 80 ꢀC under reflux for 1 h 20 min. The solution was con-
centrated in vacuo, the residue taken up in ethanol, treated with

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3985
tert-butylhydrazine hydrochloride (5 g, 40.125 mmol), and the
solution stirred at 70 ꢀC for 2.5 h under an atmosphere of
nitrogen. LCMS analysis did not show complete consumption
of starting material so the reaction mixture was heated for a
further 5 h at 70 ꢀC. The reaction mixture was then cooled to
room temperature and poured into water, and the deep-yellow
precipitate that formed was collected and washed with water (ꢀ
J=4.55 Hz), 7.48-7.59 (1H, m), 8.22 (1H, d, J=4.55 Hz), 11.65
(1H, br s).
N-[4-(4-Bromo-1H-pyrazol-3-yl)phenyl]-N -phenylurea (10a).
A heterogeneous mixture of 4-bromo-3-(4-nitrophenyl)-1H-
pyrazole (2.1 g, 7.83 mmol), elemental tin dust (4.65 g, 39.16
mmol), 6.0N aq HCl (30 mL), and absolute ethanol (30 mL) was
stirred at 70 ꢀC for 1 h. The solution was filtered through celite
and concentrated in vacuo. The residue was dissolved in anhy-
0
3
). This precipitate (2.62 g, 79.9%) was determined to be the
undesired isomer after bromination and NOE studies. The
filtrate was concentrated and a second crop of yellow preci-
pitate formed, containing the desired title compound (5c) as the
minor isomer (0.539 g, 16%). This material was used in the
next step without further purification. MS m/z 190.0 [(M -
drous pyridine (20 mL) and anhydrous CH Cl2 (10 mL).
2
Phenylisocyanate (0.86 mL, 7.83 mmol) was added dropwise
and the reaction mixture stirred at room temperature overnight.
Concentration in vacuo and purification by reverse phase
HPLC afforded the title compound as a white solid (10a, 1.6
þ 1
C(CH
-Bromo-1-(1,1-dimethylethyl)-3-(4-nitrophenyl)-1H-pyrazole
6c). To a solution of 1-(1,1-dimethylethyl)-3-(4-nitrophenyl)-
H-pyrazole (5c, 0.375 g, 1.529 mmol) in anhydrous N,N-
dimethylformamide (5 mL) was added N-bromosuccinimide
0.299 g, 1.68 mmol). The reaction mixture was stirred at room
3
)
3
þ 2H].
g, 57%). MS m/z 357.0 [M þ H] . H NMR (400 MHz, DMSO-
4
d ) δ ppm 6.91-7.04 (1H, m), 7.21-7.35 (2H, m), 7.40-7.51
6
(
1
(2H, m), 7.57 (2H, m, J=8.59 Hz), 7.71 (2H, m, J=8.59 Hz), 7.86
(1H, br s), 8.80 (1H, s), 8.91, (1H, br s), 13.29 (1H, br s).
N-{4-[4-Bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phe-
0
(
nyl}-N -phenylurea (10e). To a solution of N-[4-(4-bromo-1H-
0
temperature for 30 min and then poured into water. The white
precipitate that resulted was collected to furnish the title com-
pound (6c) as a white solid (0.48 g, 97%). MS m/z 268.0, 270.0
pyrazol-3-yl)phenyl]-N -phenylurea (10a, 0.1 g, 0.28 mmol) in
N,N-dimethylformamide (5 mL) cooled to -78 ꢀC was added
1 M potassium t-butoxide in THF (0.765 mL, 0.765 mmol)
slowly. The reaction mixture was stirred at -78 ꢀC for 10 min,
and then trifluoromethanesulfonic acid 2,2,2-trifluoroethylester
(60.34 mg, 0.26 mmol) was added. The reaction mixture was
stirred for 2 h at -78 ꢀC and then allowed to warm to room
temperature and stirred for a further 21 h. The reaction was
quenched by addition of saturated ammonium chloride (aq).
The solution was filtered and purified directly by reverse phase
HPLC to provide the title compound (10e) confirmed by NOE
[
M - C(CH ) þ 2H].
3
3
N-{4-[4-Bromo-1-(1,1-dimethylethyl)-1H-pyrazol-3-yl]phe-
0
nyl}-N -phenylurea (10d). A mixtureof 4-bromo-1-(1,1-dimethyl-
ethyl)-3-(4-nitrophenyl)-1H-pyrazole (6c, 48 mg, 0.148 mmol),
zinc dust (67.7 mg, 1.036 mmol), acetic acid (1 mL), and ethanol
(
1 mL) was stirred at room temperature for 5 h. The solution was
filtered and the filtrate concentrated in vacuo. This residue was
dissolved in anhydrous pyridine (2 mL), and phenylisocyanate
þ
1
(
17.8 μL, 0.163 mmol) was added. The reaction mixture was
studies (43 mg, 38%). MS m/z 439.2 [M þ H] . H NMR (400
stirred under an atmosphere of nitrogen for 1 h and 45 min. The
solution was concentrated in vacuo to a provide a crude sample
of the title compound (10d, 61 mg, quantitative), which was used
MHz, DMSO-d ) δ ppm 5.20 (2H, q, J=9.09 Hz), 6.92-7.03
6
(
(
1H, m), 7.29 (2H, t, J=7.96 Hz), 7.49 (2H, d, J=7.58 Hz), 7.58
2H, app d, J=8.59 Hz), 7.73 (2H, app d, J=8.59 Hz), 8.19 (1H,
in the next reaction without further purification. MS m/z 415.4
[
s), 9.05 (1H, s), 9.18 (1H, s).
0
þ
M þ H] .
N-Phenyl-N -{4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2,2,2-
trifluoroethyl)-1H-pyrazol-3-yl]phenyl}urea (12f). A mixture of
N-{4-[4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phe-
N-{4-[1-(1,1-Dimethylethyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-
0
yl)-1H-pyrazol-3-yl]phenyl}-N -phenylurea (12e). A mixture of
N-{4-[4-bromo-1-(1,1-dimethylethyl)-1H-pyrazol-3-yl]phenyl}-
0
nyl}-N -phenylurea (10e, 26 mg, 0.059 mmol), 4-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
0
N -phenylurea (10d, 61 mg, 0.148 mmol), 4-(4,4,5,5-tetramethyl-
1
,3,2-dioxaborolan-2-yl)-1H-indole (36 mg, 0.148 mmol), tetra-
(11, 14.5 mg, 0.059 mmol), tetrakis(triphenylphosphine)palla-
dium(0) (3.4 mg, 0.003 mmol), saturated sodium bicarbonate
kis(triphenylphosphine)palladium(0) (17.1 mg, 0.015 mmol),
anhydrous N,N-dimethylformamide (1.5 mL), and satd aq
sodium bicarbonate (0.44 mL) was stirred at 100 ꢀC in a sealed
tube for 5 h and 15 min. The reaction mixture was cooled to
room temperature, filtered, and concentrated in vacuo. The
residue was taken in ethyl acetate and purified by silica gel
chromatography, eluting with 20-100% ethyl acetate in hexane
followed by a second silica gel purification, eluting with
(
0.177 mL), and anhydrous DMF (1 mL) was stirred at 100 ꢀC in
a sealed tube for 4 h and cooled to rt. Filtration through a pad of
celite, concentration in vacuo, and reverse phase HPLC purifi-
cation furnished the title compound (12f) as a white solid (10 mg,
þ
1
35%). MS m/z 477.2 [M þ H] . LCMS purity 93%. H NMR
(400 MHz, DMSO-d ) δ ppm 5.15-5.39 (2H, m), 6.14-6.30
6
(1H, m), 6.84 (1H, d, J=4.80 Hz), 6.91-7.04 (1H, m), 7.17-7.53
90-100% ethyl acetate. Final purification by reverse phase
HPLC provided the title compound (12e) as a white solid
(9H, m), 8.14 (1H, d, J=4.80 Hz), 8.28 (1H, s), 8.68-8.79 (2H,
m), 11.71 (1H, br s).
N-{4-[4-Bromo-1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-
þ
1
(
4 mg, 6%). MS m/z 451.4 [M þ H] . H NMR (400 MHz,
DMSO-d ) δ ppm 1.47 (10H, s), 6.51 (1H, d, J=5.31 Hz), 6.75
1H, br s), 6.97 (1H, t, J=7.33 Hz), 7.26-7.35 (5H, m), 7.47 (2H,
d, J=7.58 Hz), 7.52-7.59 (3H, m), 7.99 (1H, d, J=5.56 Hz), 8.05
1H, s), 9.25 (1H, s), 9.49 (1H, s), 12.08 (1H, br s).
-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo-
2,3-b]pyridine (11). In a sealed tube was combined 4-bromo-1H-
pyrrolo[2,3-b]pyridine (92 mg, 0.47 mmol), potassium acetate
0
6
ethyl)-1H-pyrazol-3-yl]phenyl}-N -phenylurea (10f). To a solu-
0
(
tion of N-[4-(4-bromo-1H-pyrazol-3-yl)phenyl]-N -phenylurea
(10a, 1 g, 2.8 mmol) in dry DMF cooled to 0 ꢀC was added 1 M
potassium tert-butoxide in THF (11.2 mL, 11.2 mmol). The
reaction mixture was stirred for 15 min and then (2-bromo-
ethoxy)-tert-butyldimethylsilane (0.6 mL, 2.8 m,mol) was added
dropwise. The reaction mixture was stirred at 0 ꢀC for 30 min
and then at room temperature for 2 days. The reaction mixture
was quenched with aq ammonium chloride, extracted with ethyl
(
4
[
(
0.14 g, 1.40 mmol), bis(pinacolato)diboron (0.24 g, 0.93 mmol),
0
and 1,1 -bis(diphenylphosphino)ferrocenepalladium(II)dichlo-
ride dichloromethane complex (15.25 mg, 0.018 mmol) followed
by anhydrous 1,4-dioxane (3.11 mL). The reaction mixture was
stirred at 90 ꢀC for 18 h and then cooled to room temperature.
After dilution with ethyl acetate (5 mL) and filtration through a
pad of celite, the filtrate was concentrated in vacuo. The residue
was purified by reverse phase HPLC to provide the title product
acetate (ꢀ 3), and the combined organic layers dried (Na
2 4
SO )
and concentrated in vacuo. Purification by silica gel chromato-
graphy, eluting with 20-50% ethyl acetate in hexanes, afforded
the title product (10f, 0.806 g, 56%) and 39% recovered starting
þ 1
material. MS m/z 515.4 [M þ H] . H NMR (400 MHz, DMSO-
d ) δ ppm -0.08 (6H, s), 0.80 (9H, s), 3.93 (2H, t, J=4.67 Hz),
6
(
(
11) as a white solid (48 mg, 64%). MS m/z 302.2 [M -
4.21 (2H, t, J=5.05 Hz), 6.97-7.00 (1H, m), 7.28-7.31 (2H, m),
7.47 (2H, d, J=7.58 Hz), 7.54 (2H, d, J=8.59 Hz), 7.73 (2H, d,
J=8.59 Hz), 7.98 (1H, s), 8.72 (1H, s), 8.80 (1H, s).
1
CH
3
)
2
CC(CH
3
)
2
þ 2H]. H NMR (400 MHz, DMSO-d
6
) δ
ppm 1.35 (12H, s), 6.66 (1H, dd, J=3.28, 1.77 Hz), 7.29 (1H, d,

3
986 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
N-{4-[1-(2-Hydroxyethyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
0
(2H, d, J=6.06 Hz), 5.27-5.37 (2H, m), 6.07-6.25 (2H, m),
6.88 (1H, d, J=5.05 Hz), 7.38-7.46 (1H, m), 7.59-7.67 (2H,
m), 8.13-8.20 (4H, m), 8.23 (1H, s), 11.74 (2H, br s).
1H-pyrazol-3-yl]phenyl}-N -phenylurea (12g). A mixture of
N-{4-[4-bromo-1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-
0
0
ethyl)-1H-pyrazol-3-yl]phenyl}-N -phenylurea (10f, 0.775 g,
1.503 mmol), 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (11, 0.866 g,
N-Phenyl-N -{4-[1-(2-propen-1-yl)-4-(1H-pyrrolo[2,3-b]pyr-
idin-4-yl)-1H-pyrazol-3-yl]phenyl}urea (12h). A mixture of 4-[3-
(4-nitrophenyl)-1-(2-propen-1-yl)-1H-pyrazol-4-yl]-1H-pyrrolo-
[2,3-b]pyridine (0.5 g, 1.448 mmol), tin metal (0.895 g, 7.239
mmol), 6N aq hydrochloric acid (1 mL), and ethanol (5 mL) was
stirred at 70 ꢀC for 1 h, concentrated in vacuo, and the residue
taken up in ethyl acetate and washed with saturated sodium
bicarbonate (aq). The organic layer was dried (Na SO ), fil-
2
0
.25 mmol), tetrakis(triphenylphosphine)palladium (0.086 g,
.0759 mmol), saturated sodium bicarbonate (aq) (4.5 mL),
0
and N,N -dimethylformamide (15 mL) was heated at 100 ꢀC in
a sealed pressure vessel for 15.5 h. The reaction mixture was
cooled to room temperature, filtered through celite, and con-
centrated in vacuo. To the resulting residue was added 6N aq
sodium hydroxide (5 mL) and methanol (10 mL). The solution
was stirred at 70 ꢀC under a reflux condenser overnight. The
solution was concentrated in vacuo and the residue taken up in
ethyl acetate and purified by silica gel chromatography, eluting
with 20-50% ethyl acetate in hexane, followed by 1% methanol
in ethyl acetate. The product obtained was further purified by
2
4
tered, and concentrated in vacuo. The residue was dissolved in
pyridine (5 mL), and phenylisocyanate (0.174 mL, 1.593 mmol)
was added. The reaction mixture was stirred for 1 h and then
concentrated in vacuo, redissolved in ethyl acetate, filtered, and
the filtrate concentrated in vacuo. The residue was purified by
reverse phase HPLC to provide the title compound (12h, 0.342 g,
þ 1
54%). MS m/z 435.4 [M þ H] . H NMR (400 MHz, DMSO-d )
6
reverse phase HPLC to provide the title compound (12g, 0.345 g,
5
δ ppm 4.87 (2H, d, J=5.81 Hz), 5.25-5.38 (2H, m), 6.08-6.33
(2H, m), 6.83 (1H, d, J=4.80 Hz), 6.87-7.05 (6H, m), 7.33-7.43
(3H, m), 7.65-7.78 (1H, m), 8.03-8.21 (2H, m), 8.71-8.82 (2H,
m), 11.65 (1H, br s).
þ 1
2%). MS m/z 439.4 [M þ H] . H NMR (400 MHz, DMSO-d )
6
δ ppm 3.85 (2H, q, J=5.56 Hz), 4.26 (2H, t, J=5.56 Hz), 5.02
1H, t, J=5.31 Hz), 6.26 (1H, dd, J=3.41, 1.89 Hz), 6.82 (1H, d,
J=5.05 Hz), 6.92-7.03 (1H, m), 7.27-7.31 (4H, m), 7.37 (1H, s),
.38-7.41 (2H, m), 7.44 (2H, d, J=7.58 Hz), 8.11 (2H, t, J=2.53
Hz), 8.70 (1H, s), 8.67 (1H, s), 11.64 (1H, br s).
-Bromo-3-(4-nitrophenyl)-1-(2-propen-1-yl)-1H-pyrazole (7c).
(
N-{4-[1-(2,3-Dihydroxypropyl)-4-(1H-pyrrolo[2,3-b]pyridin-
0
7
4-yl)-1H-pyrazol-3-yl]phenyl}-N -phenylurea (12i). To a solution
0
of N-phenyl-N -{4-[1-(2-propen-1-yl)-4-(1H-pyrrolo[2,3-b]pyr-
4
idin-4-yl)-1H-pyrazol-3-yl]phenyl}urea (12i, 80 mg, 0.18 mmol)
in 5:1 acetone:water (1.2 mL) was added N-methylmorpholine
N-oxide (32.4 mg, 0.276 mmol) followed by a 2.5% solution of
osmium tetroxide in t-butanol (93.5 mg). The reaction mixture
was stirred at room temperature for 18 h. The reaction was
To a cooled (0 ꢀC) solution of 4-bromo-3-(4-nitrophenyl)-1H-
pyrazole (10 g, 37.3 mmol) in anhydrous N,N -dimethylforma-
0
mide (74.6 mL) was added sodium hydride, 60% dispersed in
mineral oil (1.492 g, 37.3 mmol). This was followed by slow
addition of allylbromide (3.87 mL, 44.76 mmol). The reaction
mixture was stirred at room temperature for 1 h and then poured
into an ice-water mixture (100 mL). The precipitate that formed
was collected, washed with water, and air-dried. The precipitate
was dissolved in dichloromethane and treated with hexane to
crash out the product. This product was collected by suction
filtration to provide the title compound (7c, 11.3 g, 98%). MS m/z
2 3
quenched with satd aq Na SO (1 mL), filtered through a pad of
celite (rinsing with ethyl acetate), and concentrated in vacuo.
The residue was purified by reverse phase HPLC to afford the
title compound as a white solid (12i, 12 mg, 14%). MS m/z 469.2
þ 1
[
3
M þ H] . H NMR (400 MHz, DMSO-d ) δ ppm 3.5 (2H, br s),
6
.96 (2H, m), 4.05-4.17 (1H, m), 4.35 (1H, dd, J=13.77, 3.66
Hz), 6.37 (1H, br s), 6.90 (1H, d, J=5.31 Hz), 6.97 (1H, t, J=7.33
Hz), 7.21-7.34 (4H, m), 7.36-7.56 (5H, m), 8.13-8.19 (2H, m),
þ
1
3
(
08.2 [M þ H] . H NMR (400 MHz, DMSO-d ) δ ppm 4.85
6
2H, d, J=5.81 Hz), 5.18-5.34 (2H, m), 6.07 (1H, m), 8.13 (2H,
app d, J=9.09 Hz), 8.19 (1H, s), 8.34 (2H, app d, J=8.84 Hz).
-(4-Nitrophenyl)-1-(2-propen-1-yl)-4-(4,4,5,5-tetramethyl-1,
,2-dioxaborolan-2-yl)-1H-pyrazole (8b). In a sealed tube was
8
.67-8.77 (2H, m).
-{3-(4-Nitrophenyl)-4-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]-
3
3
pyridin-4-yl]-1H-pyrazol-1-yl}-1-propanol. To a solution of 0.5
M 9-borabicyclo[3.3.1]nonane in THF (6.16 mL) cooled to 0 ꢀC
was added a solution of 4-[3-(4-nitrophenyl)-1-(2-propen-1-yl)-
3
combined 4-bromo-3-(4-nitrophenyl)-1-(2-propen-1-yl)-1H-pyr-
azole (7c, 5 g, 16.22 mmol), potassium acetate (4.778 g, 48.69
mmol), bis(pinacolato)diboron (4.532 g, 17.849 mmol), and bis-
1
(
H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
1 g, 2.06 mmol) in THF (14 mL). The reaction mixture was
(
diphenylphosphino)palladium(II)dichloride (0.4555 g, 0.649
stirred at room temperature under an inert atmosphere for 4.5 h
and then recooled to 0 ꢀC followed by quenching with water (1.7
mL). After 15 min of stirring at 0 ꢀC, 6N aq NaOH (1.24 mL)
was added dropwise, followed by 30% aq H O (0.865 mL). The
mmol), followed by anhydrous 1,4-dioxane (160 mL). The reac-
tion mixture was purged with nitrogen and then stirred at 100 ꢀC
for 18.75 h. The reaction mixture was filtered through celite,
concentrated in vacuo, and the residue purified by reverse phase
HPLC to provide the title compound (8b, 3.145 g, 55%). MS m/z
2
2
reaction mixture was stirred for 1.5 h at 0 ꢀC, neutralized with
6N aq HCl, and concentrated in vacuo. Water (10 mL) was
added to the residue and the solution extracted with EtOAc (3 ꢀ
þ
1
3
(
56.2 [M þ H] . H NMR (400 MHz, DMSO-d
12H, s), 4.86 (2H, d, J=5.81 Hz), 5.15-5.31 (2H, m), 6.07 (1H,
m), 8.09 (1H, s), 8.14-8.22 (2H, m), 8.23-8.32 (2H, m).
-[3-(4-Nitrophenyl)-1-(2-propen-1-yl)-1H-pyrazol-4-yl]-1H-
6
) δ ppm 1.29
1
5 mL), and the combined organic layers were dried over
magnesium sulfate and concentrated in vacuo to afford the title
compound (0.87 g, 84%). This material was used without
4
pyrrolo[2,3-b]pyridine. A mixture of 3-(4-nitrophenyl)-1-(2-pro-
pen-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole (8b, 2.05 g, 5.78 mmol), 4-bromo-1H-pyrrolo[2,3-b]-
pyridine (1.14 g, 5.78 mmol), tetrakis(triphenylphosphine)-
palladium (0.334 g, 0.289 mmol), 2 M potassium carbonate
þ
further purification. MS m/z 504.2 [M þ H] .
3
-[3-(4-Nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-
pyrazol-1-yl]-1-propanol. A solution of 3-{3-(4-nitrophenyl)-
-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyr-
4
azol-1-yl}-1-propanol (1.04 g, 2.06 mmol), 6N aq NaOH (1.03
mL), and methanol (10 mL) was heated at 70 ꢀC for 18 h. The
reaction mixture was concentrated in vacuo and purified by
silica gel chromatography (Analogix, 5% methanol/ethyl
acetate) to afford the title compound (0.653 g, 87%). MS m/
(
aq) (20 mL), and 1,4-dioxane (20 mL) was heated at 100 ꢀC in a
sealed pressure vessel overnight. The solution was cooled to
room temperature, the organic layer separated, and the aqu-
eous portion extracted with ethyl acetate. The combined
organic layers were filtered through a plug of celite and the
filtrate concentrated in vacuo. The residue was taken up in
ethyl acetate, and the product crashed out of solution. This
precipitate was purified by reverse phase HPLC to give the title
compound as a bright-yellow solid (0.905 g, 46%). MS m/z
þ
1
z 364.2 [M þ H] . H NMR (400 MHz, DMSO-d
6
) δ ppm
2.01-2.12 (2H, m), 3.42-3.52 (2H, m), 4.23 (2H, t, J=6.95
Hz), 4.66 (1H, t, J=5.18 Hz), 6.46 (1H, s), 6.70-6.84 (1H, m),
7.04 (1H, d, J=8.34 Hz), 7.28-7.35 (2H, m), 7.60 (2H, dd, J=
7.45, 1.89 Hz), 8.06 (1H, s), 11.59 (1H, br s).
þ
1
3
46.2 [M þ H] . H NMR (400 MHz, DMSO-d
6
) δ ppm 4.94

Article
N-{4-[1-(3-Hydroxypropyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3987
extracts were dried over magnesium sulfate and concentrated
in vacuo. Purification of the residue by reverse phase HPLC
afforded the title compound as a white solid (12k, 8 mg, 11%).
0
1
(
1
H-pyrazol-3-yl]phenyl}-N -phenylurea (12j). A mixture of 3-[3-
4-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-
-yl]-1-propanol (0.653 g, 1.787 mmol), ethanol (10 mL), 6N aq
þ
1
MS m/z 479.4 [M þ H] . LCMS purity 92%. H NMR (400
hydrochloric acid (5 mL), and tin metal (1.06 g, 8.936 mmol) was
heated at 70 ꢀC for 1 h. The reaction mixture was cooled, filtered,
and neutralized with saturated sodium bicarbonate (aq) and
then concentrated in vacuo. The residue was dissolved in
pyridine (10 mL), and phenylisocyanate (0.216 mL, 1.977 mmol)
added. The reaction mixture was stirred at room temperature
for 16 h and then filtered. The filtrate was concentrated in vacuo,
and the residue was taken into DMSO and purified by reverse
phase HPLC. The desired fractions were concentrated in vacuo
MHz, DMSO-d ) δ ppm 1.64-1.89 (2H, m), 3.76-3.93 (2H, m),
6
4.14-4.36 (3H, m), 4.80-5.00 (1H, m), 5.22-5.40 (1H, m),
6.22-6.31 (1H, m), 6.58-6.70 (1H, m), 6.80-6.86 (1H, m),
6.91-7.02 (1H, m), 7.21-7.76 (7H, m), 8.02-8.21 (3H, m),
9.01-9.23 (2H, m), 11.74 (1H, br s).
1,1-Dimethylethyl [4-bromo-3-(4-nitrophenyl)-1H-pyrazol-1-
yl]acetate (7d). To a cooled (0 ꢀC) solution of 4-bromo-3-(4-
nitrophenyl)-1H-pyrazole (3 g, 11.12 mmol) in anhydrous DMF
(25 mL) was added 60% NaH in mineral oil portionwise (0.445
g, 11.12 mmol). This was followed by slow addition of 1,1-
dimethylethyl bromoacetate (1.98 mL, 13.43 mmol). The reac-
tion mixture was stirred for 1 h at room temperature and then
poured into an ice-water mixture (50 mL). The resulting
precipitate was collected by filtration and washed with water
(20 mL). The residue was dissolved in methylene chloride and
precipitated out with hexanes to furnish the title compound as a
to provide the title compound as a white solid (12j, 0.140 g,
1
þ 1
7%). MS m/z 453.2 [M þ H] . H NMR (400 MHz, DMSO-d )
6
δ ppm 2.03 (2H, quin, J=6.63 Hz), 3.49 (2H, q, J=6.15 Hz), 4.28
2H, t, J=7.07 Hz), 4.67 (1H, t, J=5.05 Hz), 6.25 (1H, dd, J=
(
3
7
8
.54, 1.77 Hz), 6.82 (1H, d, J=5.05 Hz), 6.98 (1H, q, J=7.58 Hz),
.25-7.31 (4H, m), 7.35-7.42 (3H, m), 7.44 (2H, d, J=7.58 Hz),
.08-8.18 (2H, m), 8.70 (1H, s), 8.67 (1H, s), 11.64 (1H, br s).
þ
1
1
-(Phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
white solid (7d, 3.5 g, 83%). MS m/z 382.0 [M þ H] . H NMR
2
4
1
-yl)-1H-pyrrolo[2,3-b]pyridine. In a sealed tube were combined
-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.87 g,
1.48 mmol), potassium acetate (3.38 g, 34.43 mmol), bis(pina-
(400 MHz, DMSO-d ) δ ppm 1.45 (9H, s), 5.08 (2H, s), 8.13 (2H,
6
m, J=8.84 Hz), 8.19 (1H, s), 8.35 (2H, m, J=8.84 Hz).
1,1-Dimethylethyl [3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (8c). In a
0
colato)diboron (3.50 g, 13.77 mmol), and 1,1 -bis(diphenyl-
phosphino)ferrocenepalladium(II)dichloride dichloromethane
complex (0.375 g, 0.46 mmol) followed by anhydrous 1,4-di-
oxane (115 mL). The reaction mixture was stirred at 100 ꢀC for
sealed tube were combined 1,1-dimethylethyl [4-bromo-3-(4-
nitrophenyl)-1H-pyrazol-1-yl]acetate (7d, 2.4 g, 6.28 mmol),
potassium acetate (1.849 g, 18.84 mmol), bis(pinacolato)di-
boron (1.754 g, 6.91 mmol), bis(triphenylphosphine)palladium-
(II) chloride (0.176 g, 0.25 mmol), and anhydrous dioxane (62.8
mL). The reaction mixture was stirred at 100 ꢀC in a sealed tube
for 18 h. After cooling to room temperature, the reaction
mixture was diluted with EtOAc (40 mL) and washed with
water (20 mL). The aqueous solution was then extracted with
EtOAc (2 ꢀ 10 mL) and the combined organic solutions dried
4
5 min and then cooled to room temperature. After dilution with
EtOAc (50 mL) and filtration through a pad of celite, the filtrate
was concentrated in vacuo. The residue was purified by silica gel
chromatography, eluting with 20-50% ethyl acetate/hexanes to
provide the title product as a white solid (4.06 g, 92%). MS m/z
þ
1
3
(
(
84.0 [M þ H] . H NMR (400 MHz, DMSO-d ) δ ppm 1.32
6
12H, s), 6.97 (1H, d, J=4.04 Hz), 7.48 (1H, d, J=4.80 Hz), 7.61
2H, t, J=7.71 Hz), 7.71 (1H, t, J=7.45 Hz), 7.98 (1H, d, J=4.04
2 4
(Na SO ), filtered, and concentrated in vacuo. The residue was
Hz), 8.05-8.15 (2H, m), 8.38 (1H, d, J=4.55 Hz).
N-{4-[4-Bromo-1-(tetrahydro-2-furanylmethyl)-1H-pyrazol-
purified by silica gel chromatography (10-30% ethyl acetate in
hexane) to yield the title compound as a white solid (8c, 1.2 g,
0
þ 1
3
-yl]phenyl}-N -phenylurea (10g). To a solution of N-[4-(4-bro-
0
44%). MS m/z 430.2 [M þ H] . H NMR (400 MHz, DMSO-d
6
)
mo-1H-pyrazol-3-yl)phenyl]-N -phenylurea (10a, 0.1 g, 0.28
mmol) in anhydrous DMF (6 mL) cooled to 0 ꢀC was added
1
δ ppm 1.45 (9H, s), 5.06 (2H, s), 8.05-8.10 (2H, m), 8.18 (1H, s),
8.25-8.30 (2H, m).
.0 M potassium tert-butoxide in THF (1.12 mL, 1.12 mmol)
[3-(4-Nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyr-
azol-1-yl]acetic acid. In a sealed tube was combined 1,1-di-
methylethyl [3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (0.272 g, 0.633
mmol), 4-bromo-7-azaindole (9, 0.104 g, 0.527 mmol), tetrakis-
(triphenylphosphine)palladium(0) (60.9 mg, 0.0527 mmol), 2.0
M aq potassium carbonate (3.25 mL), and 1,4-dioxane (3.25
mL). This mixture was stirred at 100 ꢀC for 15 h. The reaction
mixture was filtered through a pad of celite and concentrated in
vacuo. Purification by reverse phase HPLC afforded the title
dropwise. The reaction mixture was stirred for a further 15 min
before dropwise addition of tetrahydrofuryl bromide (31.82 uL,
0
ture overnight, followed by quenching with saturated aq NH Cl
.28 mmol). The reaction mixture was stirred at room tempera-
4
(
1 mL). The reaction mixture was diluted with water (3 mL) and
extracted with EtOAc (3 ꢀ 5 mL). The combined organic layers
were dried over magnesium sulfate and concentrated in vacuo.
The residue was purified by reverse phase HPLC to afford the
þ
1
title compound (10g, 65 mg, 53%). MS m/z 441.4 [M þ H] . H
NMR (400 MHz, DMSO-d ) δ ppm 1.60-1.97 (4H, m),
.60-3.82 (2H, m), 4.09-4.26 (3H, m), 6.94-7.03 (1H, m),
þ
6
product as a white solid (0.13 g, 68%). MS m/z 364.4 [M þ H] .
1
3
7
8
8
H NMR (400 MHz, DMSO-d ) δ ppm 4.51 (2H, s), 6.14 (1H,
6
.24-7.33 (2H, m), 7.47 (2H, d, J=7.58 Hz), 7.54 (2H, m, J=
.59 Hz), 7.73 (2H, m, J=8.59 Hz), 8.00 (1H, s), 8.82 (1 H, s),
.93 (1 H, s).
d, J=3.28 Hz), 6.86 (1H, d, J=5.05 Hz), 7.40 (1H, d, J=3.28
Hz), 7.50-7.73 (2H, m), 8.05 (1H, s), 8.10-8.22 (3H, m), 11.72
(1H, br s).
0
N-Phenyl-N -{4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(tetra-
hydro-2-furanylmethyl)-1H-pyrazol-3-yl]phenyl}urea (12k). A
mixture of N-{4-[4-bromo-1-(tetrahydro-2-furanylmethyl)-1H-
pyrazol-3-yl]phenyl}-N -phenylurea (65 mg, 0.147 mmol),
1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1H-pyrrolo[2,3-b]pyridine (92.9 mg, 0.162 mmol), DMF (1.5
[3-(4-{[(Phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo-
[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (12l). A hetero-
geneous mixture of [3-(4-nitrophenyl)-4-(1H-pyrrolo[2,3-
b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (0.387 g, 0.31.065
mmol), elemental tin dust (0.632 g, 5.325 mmol), 6.0N aq HCl
(5.3 mL), and absolute ethanol (5.3 mL) was stirred at 70 ꢀC for
1 h. The solution was filtered through celite and concentrated in
vacuo. The residue was dissolved in anhydrous pyridine (10 mL)
and phenylisocyanate (0.128 mL, 11.17 mmol) added dropwise.
The reaction mixture was stirred at room temperature for 4 h.
After concentration in vacuo, purification by reverse phase
HPLC afforded the title compound as a white solid (12l,
0
mL), saturated aq sodium bicarbonate (0.44 mL), and tetrakis-
(
triphenylphosphine)palladium(0) (8.5 mg, 0.007 mmol) in a
sealed tube was stirred at 100 ꢀC for 18 h. The solution was
cooled to rt, filtered through celite, and concentrated in vacuo.
The residue was dissolved in methanol (5 mL) and 6.0N aq
NaOH (1 mL) and stirred at 70 ꢀC for 6 h. The reaction mixture
was concentrated in vacuo, dissolved in water (10 mL), and
extracted with EtOAc (3 ꢀ 10 mL). The combined organic
þ
1
0.45 g, 93%). MS m/z 453.2 [M þ H] . H NMR (400 MHz,
DMSO-d ) δ ppm 5.09 (2H, s), 6.18-6.41 (1H, m), 6.80-7.04
6

3
988 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
(
5
1
2H, m), 7.19-7.34 (4H, m), 7.37-7.52 (5H, m), 8.19 (1H, d, J=
vacuum, taken up in ethyl acetate, washed with water, brine,
dried (Na SO ), filtered, and concentrated under vacuum.
Purification by flash chromatography on silica gel eluting with
.05 Hz), 8.25 (1H, s), 8.71 (1H, s), 8.77 (1H, s), 11.94 (1H, br s),
3.21 (1H, s).
2
4
2
-[3-(4-{[(Phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo-
2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetamide (12m). To a cooled
0 ꢀC) solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-
-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (12l,
5 mg, 0.166 mmol) in anhydrous THF (3.3 mL) was added
80% ethyl acetate in hexanes gave the product (14e, 0.67 g, 1.4
1
mmol, 64% yield) as a white solid. H NMR (400 MHz, CDCl
[
(
4
7
3
)
δ ppm 8.28 (d, J=5.30 Hz, 1H), 7.93 (d, J=7.33 Hz, 2H), 7.82 (s,
1H), 7.65 (d, J = 5.81 Hz, 2H), 7.54 (t, J = 7.45 Hz, 1H),
7.38-7.46 (m, 4H), 7.28 (d, J = 7.58 Hz, 1H), 6.60 (s, 1H),
þ
triethylamine (34.7 uL, 0.25 mmol) and ethylchloroformate (17.3
uL, 0.18 mmol). After 30 min at 0 ꢀC, ammonium hydroxide (50 μL)
was added and the reaction stirred at room temperature for 1 h.
Concentration in vacuo followed by reverse phase HPLC furnished
the title compound as a white solid (12m, 10 mg, 13%). MS m/z
2.24 (s, 3H). MS m/z 470.2 [M þ H] .
N-{3-[4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}acetamide (15e).
In a glass pressure tube was added N-{3-[4-bromo-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}acetamide (14e,
0.50 g, 1.0 mmol), 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 1.1 mmol),
tetrakis(triphenylphosphine)palladium(0) (70 mg, mmol), aq
satd sodium bicarbonate (4 mL), and dimethylformamide (16
mL). The reaction was purged with nitrogen and capped and
stirred at 100 ꢀC for 6 h. After cooling to room temperature, the
reaction was evaporated to dryness under vacuum, taken up in
ethyl acetate, filtered to remove insolubles, and concentrated
under vacuum. Purification of the residue by flash chromatog-
raphy on silica gel eluting with ethyl acetate gave the product
þ
1
4
52.4 [M þ H] . LCMS purity 94%. H NMR (400 MHz, DMSO-
d
6
) δ ppm 4.88 (2H, s), 6.25 (1H, dd, J=3.41, 1.64 Hz), 6.83 (1H, d,
J=5.05 Hz), 6.93 (1H, t, J=7.33 Hz), 7.23-7.32 (4H, m), 7.33-7.51
(
(
6H, m), 7.65 (1H, s), 8.03-8.20 (2H, m), 9.65-9.77 (2H, m), 11.65
1H, br s).
N-Ethyl-2-[3-(4-{[(phenylamino)carbonyl]amino}phenyl)-4-(1H-
pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetamide (12n). To
a solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-
-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid
12l, 75 mg, 0.166 mmol), EDCI (47.7 mg, 0.249 mmol), DMAP
4
(
(
1
30.4 mg, 0.249 mmol), and DMF (3.2 mL) at room temperature
(15e, 0.55 g, 0.91 mmol, 91% yield) as a yellow solid. H NMR
(400 MHz, DMSO-d ) δ ppm 10.09 (s, 1H), 8.33 (s, 1H), 8.31 (d,
was added a 2 M solution of ethylamine in THF (204 mL, 0.415
mmol). The reaction mixture was stirred for 3 days at room
temperature, concentrated in vacuo, taken up in DMSO, fil-
tered, and the filtrate concentrated and purified by reverse phase
HPLC to provide the title compound (12n, 32 mg, 40%). MS m/z
6
J=5.05 Hz, 1H), 8.14 (d, J=8.84 Hz, 2H), 7.90-7.92 (m, 2H),
7.85 (s, 1H), 7.73 (t, J=7.45 Hz, 1H), 7.53-7.65 (m, 5H), 7.38 (t,
J=7.83 Hz, 1H), 7.13 (d, J=7.58 Hz, 1H), 7.04 (d, J=5.05 Hz,
1H), 6.55 (s, 1H), 4.26 (q, J=7.24 Hz, 2H), 2.09 (s, 3H), 1.47 (t,
þ
1
þ
4
80.2 [M þ H] . H NMR (400 MHz, DMSO-d ) δ ppm 1.08
J=7.33 Hz, 3H). MS m/z 607.4 [M þ H] .
6
(
3H, s), 3.16 (2H, s), 4.89 (2H, s), 6.25 (1H, br s), 6.77-7.01 (3H,
N-(3-{4-[1-Ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-
1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}phenyl)acetamide
(17a). To a stirred solution of N-{3-[4-[1-ethyl-3-(4-nitro-
phenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]-
pyridin-2-yl]phenyl}acetamide (15e, 0.50 g, 0.8 mmol) in ethyl
acetate (30 mL) was added 20 wt % palladium hydroxide on
carbon (0.1 g). A balloon of hydrogen was attached, and the
reaction was stirred for 3 days. The reaction was filtered through
a pad of celite, rinsed with ethyl acetate, and evaporated to
m), 7.21-7.32 (3H, m), 7.34-7.49 (5H, m), 8.03-8.21 (2H, m),
8
.29-8.48 (1H, m), 9.49-9.73 (2H, m), 11.67 (1H, br s).
N-{4-[1-[2-(4-Morpholinyl)-2-oxoethyl]-4-(1H-pyrrolo[2,3-b]-
0
pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-N -phenylurea (12o). To a
solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-
-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid
12l, 75 mg, 0.166 mmol) in anhydrous N,N-dimethylformamide
4 mL) was added N,N-carbonyldiimidazole (32.2 mg, 0.20
4
(
(
mmol). The reaction mixture was stirred at room temperature
for 30 min, and then morpholine (43 uL, 0.50 mmol) was added.
The reaction mixture was stirred for a further 3 h. Concentraton
in vacuo and purification by reverse phase HPLC afforded the
title compound as a white solid (12o, 23 mg, 26%). MS m/z 522.4
dryness to give the product (0.48 g, 0.8 mmol, 100% yield) as an
1
off-white solid. H NMR (400 MHz, DMSO-d ) δ ppm 10.09 (s,
6
1H), 8.22 (d, J=5.05 Hz, 1H), 8.17 (s, 1H), 7.85-7.87 (m, 2H),
7.82 (s, 1H), 7.56-7.72 (m, 5H), 7.39 (t, J=7.96 Hz, 1H), 7.16 (d,
J=7.83 Hz, 1H), 7.01 (d, J=5.05 Hz, 1H), 6.90 (d, J=8.59 Hz,
2H), 6.54 (s, 1H), 6.47 (d, J=8.59 Hz, 2H), 5.23 (s, 2H), 4.15 (q,
J=7.16 Hz, 2H), 2.10 (s, 3H), 1.42 (t, J=7.20 Hz, 3H). MS m/z
þ
1
[
M þ H] . LCMS purity 94%. H NMR (400 MHz, DMSO-d
6
)
δ ppm 3.47-3.71 (8H, m), 5.18-5.34 (2H, m), 6.23 (1H, dd, J=
3
8
þ
.28, 1.77 Hz), 6.83 (1H, d, J=4.80 Hz), 6.97 -7.51 (7H, m),
.05-8.19 (2H, m), 8.68-8.83 (4H, m), 11.66 (1H, br s).
N -{4-[1-Ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-
577.4 [M þ H] .
To a stirred solution of N-{3-[4-[3-(4-aminophenyl)-1-ethyl-
1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-
2-yl]phenyl}acetamide (200 mg, 0.35 mmol) in THF (5 mL) was
added phenylisocyanate (45 uL, 0.41 mmol) and 1 drop of
triethylamine. The reaction was stirred at room temperature
for 18 h and evaporated to dryness under vacuum. The residue
was triturated with (1:1) ethyl ether/petroleum ether, filtered,
and dried under vacuum to give N-{3-[4-[1-ethyl-3-(4-{[(phenyl-
amino)carbonyl]amino}phenyl)-1H-pyrazol-4-yl]-1-(phenylsul-
fonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}acetamide (0.29 g,
0.42 mmol, 100% yield) as a pale-yellow solid. MS m/z 696.4
0
3-yl]phenyl}-N,N-dimethylurea (12p). A solution of 4-[1-ethyl-
4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (80 mg,
0.26 mmol) in pyridine (1 mL) was treated with dimethylcarba-
moyl chloride (26 μL, 0.29 mmol). The reaction stirred for 18 h
at room temperature and concentrated in vacuo. Purification of
the residue by reverse phase HPLC provided the title product
þ
1
(
12s) as a white powder (38%). MS m/z 375.0 [M þ H] . H
NMR (400 MHz, DMSO-d ) δ ppm 1.49 (t, J=7.33 Hz, 3H),
.92 (s, 6H), 4.26 (q, J=7.16 Hz, 2H), 6.40-6.52 (m, 1H), 6.97
d, J=5.56 Hz, 1H), 7.25 (d, J=8.84 Hz, 2H), 7.43 (d, J=8.59
6
2
(
þ
[M þ H] .
Hz, 2H), 7.55-7.61 (m, 1H), 8.22 (d, J=5.56 Hz, 1H), 8.30-8.37
To a stirred solution of N-{3-[4-[1-ethyl-3-(4-{[(phenylamino)-
carbonyl]amino}phenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-
1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}acetamide (0.25 g, 0.36
mmol) in methanol (5 mL) was added aq 6 N sodium hydroxide
(120 μL, 0.72 mmol). The reaction was refluxed for 8 h, cooled
to room temperature, and diluted with water (5 mL). The solid
which precipitated was filtered off and dried under vacuum.
(
m, 2H), 12.22 (br s, 1H).
N-{3-[4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-
2
4
-yl]phenyl}acetamide (14e). In a glass pressure tube was added
-bromo-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
(
2
1.0 g, 2.2 mmol), [3-(acetylamino)phenyl]boronic acid (0.39 g,
.2 mmol), tetrakis(triphenylphosphine)palladium(0) (125 mg,
mmol), aq satd sodium bicarbonate (5 mL), and dimethylfor-
mamide (20 mL). The reaction was purged with nitrogen,
capped, and stirred at 100 ꢀC for 16 h. After cooling to room
temperature, the reaction was evaporated to dryness under
Purification by reverse phase HPLC (10-90% CH
3
CN/
H O) gave the product (17a, 120 mg, 0.22 mmol, 60% yield)
2
1
as a white solid. H NMR (400 MHz, DMSO-d
(br s, 1H), 10.01 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 8.25 (s, 1H),
6
) δ ppm 12.19

Article
.10 (d, J=4.80 Hz, 1H), 8.00 (br s, 1H), 7.55 (dd, J=15.16, 7.83
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3989
8
dryness under vacuum. Purification of the residue by flash chro-
matography on silica gel (0-4% ethyl acetate in dichloromethane)
gave the product (14a, 0.72 g, 1.6 mmol, 77% yield) as a white solid.
Hz, 2H), 7.25-7.45 (m, 9H), 6.96 (t, J=7.07 Hz, 1H), 6.81 (d, J=
4
3
.55 Hz, 1H), 6.67 (br s, 1H), 4.28 (q, J=6.91 Hz, 2H), 2.07 (s,
H), 1.52 (t, J=7.20 Hz, 3H). MS m/z 556.4 [M þ H] . Anal.
þ
1
3
H NMR (400 MHz, CDCl ) δ ppm 10.13 (s, 1H), 8.32 (d, J=5.31
(
C
33
H
29
N
7
O 0.5H
3
2
O) C, H, N.
Hz, 1H), 8.06 (t, J=1.52 Hz, 1H), 8.03 (dt, J=7.58, 1.39 Hz, 1H),
7.91-7.97 (m, 2H), 7.89 (ddd, J=7.83, 1.52, 1.26 Hz, 1H), 7.69 (t,
J=7.71 Hz, 1H), 7.58 (t, J=6.82 Hz, 1H), 7.43 (d, J=5.31 Hz, 1H),
N-{4-[4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-
-yl]phenyl}acetamide (14f). The reaction used to prepare 14e
was repeated with [4-(acetylamino)phenyl]boronic acid to give
2
þ
7.46 (t, J=7.83 Hz, 2H), 6.67 (s, 1H). MS m/z 441.0 [M þ H] .
the product (14f, 0.63 g, 1.3 mmol, 61% yield) as a white solid.
4-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-(3-formyl-
phenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (15a). To a
sealed pressure tube were added 4-bromo-2-(3-formylphenyl)-1-
phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (0.7 g, 1.6 mmol),
3-(4-nitrophenyl)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)-1H-pyrazole (0.6 g, 1.7 mmol), N,N-dimethylform-
amide (15 mL), aq satd sodium bicarbonate (4 mL), and
tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol).
The reaction was purged with nitrogen, capped, and stirred at
100 ꢀC for 16 h. After cooling to room temperature, the reaction
was concentrated under vacuum, taken up in ethyl acetate,
washed with water, brine, dried (Na SO ), filtered, and evapo-
1
6
H NMR (400 MHz, DMSO-d ) δ ppm 10.17 (s, 1H), 8.24 (d, J=
5
5
.31 Hz, 1H), 7.79-7.81 (m, 2H), 7.66-7.73 (m, 3H), 7.61 (d, J=
.31 Hz, 1H), 7.54-7.58 (m, 4H), 6.72 (s, 1H), 2.11 (s, 3H). MS
þ
m/z 470.2 [M þ H] .
N-{4-[4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}acetamide (15f).
The reaction used to prepare 15e was repeated with N-{4-[4-
bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}-
acetamide to give the product (15f, 0.53 g, 0.87 mmol, 87%
1
yield) as a yellow solid. H NMR (400 MHz, DMSO-d
6
) δ ppm
1
8
8
0.13 (s, 1H), 8.32 (s, 1H), 8.29 (d, J=5.05 Hz, 1H), 8.13 (d, J=
.84 Hz, 2H), 7.81-7.83 (m, 2H), 7.70-7.73 (m, 1H), 7.66 (d, J=
.59 Hz, 2H), 7.57-7.61 (m, 2H), 7.53 (d, J=8.84 Hz, 2H), 7.38
2
4
rated to dryness under vacuum. Purification of the residue by
flash chromatography on silica gel (5-10% ethyl acetate in
dichloromethane) gave the product (15a, 0.75 g, 1.3 mmol, 81%
(
(
d, J=8.59 Hz, 2H), 7.05 (d, J=5.05 Hz, 1H), 6.48 (s, 1H), 4.26
q, J=7.33 Hz, 2H), 2.09 (s, 3H), 1.47 (t, J=7.20 Hz, 3H). MS m/
1
yield) as a yellow solid. H NMR (400 MHz, DMSO-d ) δ ppm
6
þ
z 607.4 [M þ H] .
10.09 (s, 1H), 8.35 (s, 1H), 8.34 (d, J=5.05 Hz, 1H), 8.14 (d, J=
8.84 Hz, 2H), 8.02 (d, J=7.58 Hz, 1H), 7.96 (s, 1H), 7.88 (s, 1H),
7.86 (d, J=1.26 Hz, 2H), 7.73 (q, J=7.49 Hz, 2H), 7.61 (t, J=
7.83 Hz, 2H), 7.54 (d, J=9.09 Hz, 2H), 7.07 (d, J=5.05 Hz, 1H),
N-(3-{4-[1-Ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-
H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}phenyl)acet-
1
amide. The nitro reduction reaction used to prepare 17a was
repeated with N-{4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-
yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}-
acetamide to give the product (0.25 g, 0.43 mmol, 52% yield) as
6
.72 (s, 1H), 4.26 (q, J=7.33 Hz, 2H), 1.47 (t, J=7.33 Hz, 3H).
þ
MS m/z 578.3 [M þ H] .
4
-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethyl-
aminomethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine
15i). To a stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-
pyrazol-4-yl]-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyrrolo-
2,3-b]pyridine (0.75 g, 1.3 mmol) in THF (20 mL) was added a
þ
an off-white solid. MS m/z 577.4 [M þ H] .
N-{4-[4-[1-Ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-
H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-
(
1
yl]phenyl}acetamide. To a stirred solution of N-{4-[4-[3-(4-
aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-
pyrrolo[2,3-b]pyridin-2-yl]phenyl}acetamide (170 mg, 0.30 mmol)
in THF (5 mL) was added phenylisocyanate (50 μL, 0.46 mmol)
and 1 drop of triethylamine. The reaction was stirred at room
temperature for 18 h and evaporated to dryness under vacuum.
The residue was triturated with (1:1) ethyl ether/petroleum
ether, filtered, and dried under vacuum to give the product
[
solution of 2 M dimethylamine in THF (1 mL, 2.0 mmol)
followed by sodium triacetoxyborohydride (0.4 g, 1.9 mmol).
The reaction was stirred at room temperature for 4 h and
concentrated to dryness under vacuum. The residue was taken
up in ethyl acetate, washed with aq 1N sodium carbonate, brine,
dried (Na SO ), filtered, and evaporated under vacuum. Puri-
2
4
fication of the residue by flash chromatography on silica gel
(
6
0.21 g, 0.30 mmol, 100% yield) as a pale-yellow solid. MS m/z
96.4 [M þ H] .
[
0-5% (5% ammonium hydroxide in methanol) in dichloro-
þ
methane] gave the product (15i, 0.69 g, 1.1 mmol, 87% yield) as a
N-(Phenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo-
2,3-b]pyridin-2-yl]phenyl}acetamide (17b). To a stirred solution
1
yellow solid. H NMR (400 MHz, DMSO-d ) δ ppm 8.34 (s,
6
[
of N-{4-[4-[1-ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-
1
7
2
7
3
H), 8.34 (d, J = 5.05 Hz, 1H), 8.13 (d, J = 8.84 Hz, 2H),
.86-7.88 (m, 2H), 7.74 (t, J=7.45 Hz, 1H), 7.61 (t, J=7.83 Hz,
H), 7.53 (d, J=8.84 Hz, 2H), 7.33-7.40 (m, 3H), 7.23 (s, 1H),
.11 (d, J=5.05 Hz, 1H), 6.43 (s, 1H), 4.26 (q, J=7.33 Hz, 2H),
1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-
2-yl]phenyl}acetamide (0.21 g, 0.30 mmol) in methanol (5 mL)
was added aq 6 N sodium hydroxide (110 uL, 0.72 mmol). The
reaction was refluxed for 8 h, cooled to room temperature, and
diluted with water (5 mL). The solid which precipitated was
filtered off and dried under vacuum to give the product (17b, 110
.42 (s, 2H), 2.18 (s, 6H), 1.47 (t, J=7.33 Hz, 3H). MS m/z 607.4
þ
[
M þ H] .
4
-[3-(4-Aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethyl-
1
aminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (16a). To a stir-
red solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-
-[3-(dimethylaminomethyl)phenyl]-1-phenylsulfonyl-1H-pyr-
mg, 0.20 mmol, 66% yield) as a white solid. H NMR (400 MHz,
DMSO-d
(
6
) δ ppm 12.07 (s, 1H), 10.06 (s, 1H), 8.71 (s, 1H), 8.67
s, 1H), 8.26 (s, 1H), 8.05 (d, J=5.05 Hz, 1H), 7.83 (d, J=8.59
Hz, 2H), 7.65 (d, J=8.59 Hz, 2H), 7.25-7.45 (m, 8H), 6.96 (t, J=
2
rolo[2,3-b]pyridine (0.69 g, 1.1 mmol) in acetic acid (20 mL) was
added portionwise zinc dust (0.52 g, 8.0 mmol) over 5 min. The
reaction was stirred at room temperature for 1 h, filtered
through a pad of celite, rinsed with acetic acid, and concentrated
to dryness under vacuum. The residue was re-evaporated several
times from methanol, followed by toluene to remove the excess
acetic acid, taken up in methanol (35 mL) and treated with aq
6N sodium hydroxide (1.5 mL). The reaction was stirred and
heated at 70 ꢀC for 8 h. After cooling to room temperature, the
reaction was concentrated under vacuum, triturated with cold
water, filtered, washed with water, and dried under vacuum to
give the crude product (16a, 0.49 g, 1.1 mmol, 100% yield) (87%
pure by LCMS) as a pale-orange solid, which was in the next
7
4
.33 Hz, 1H), 6.77 (d, J=5.05 Hz, 1H), 6.75 (d, J=1.77 Hz, 1H),
.27 (q, J=7.24 Hz, 2H), 2.07 (s, 3H), 1.52 (t, J=7.20 Hz, 3H).
þ
MS m/z 556.4 [M þ H] . Anal. (C33
29 7 2
H N O 0.5H O) C, H, N.
3
4
-Bromo-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyrrolo[2,
-b]pyridine (14a). To a glass pressure tube were added 4-bromo-
-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (1 g, 2.1 mmol),
-formylbenzeneboronic acid (0.32 g, 2.1 mmol), dimethylfor-
3
2
3
mamide (15 mL), aq satd sodium bicarbonate (5 mL), and
tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.1 mmol).
The reaction was purged with nitrogen, capped, and stirred at
1
00 ꢀC for 16 h. After cooling to room temperature, the reaction
was concentrated under vacuum, taken up in ethyl acetate, washed
with water, brine, dried (Na SO ), filtered, and evaporated to
þ
2
4
step without further purification. MS m/z 437.2 [M þ H] .

3
990 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
4-[3-(4-N-Phenylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
idine (17c). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-
1.7 mmol), 3-(4-nitrophenyl)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,
2-dioxaborolan-2-yl)-1H-pyrazole (8a, 0.65 g, 1.9 mmol), di-
methylformamide (20 mL), aq satd sodium bicarbonate (5 mL),
and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09
mmol). The reaction was purged with nitrogen, capped, and
stirred at 100 ꢀC for 16 h. After cooling to room temperature,
the reaction was concentrated under vacuum, taken up in ethyl
4
1
H-pyrrolo[2,3-b]pyridine (0.15 g, 0.34 mmol) in THF (5 mL)
was added phenyl isocyanate (45 μL, 0.41 mmol) and two drops
of triethylamine. The reaction was stirred at room temperature
for 1 h and concentrated to dryness under vacuum. The remain-
ing solid was triturated with (1:1) ethyl ether/petroleum ether,
filtered, and dried under vacuum. Purification of the residue by
2 4
acetate, washed with water, brine, dried (Na SO ), filtered, and
evaporated to dryness under vacuum. Purification of the residue
by flash chromatography on silica gel (4% ethyl acetate in
dichloromethane) gave the product (15b, 0.80 g, 1.35 mmol,
reverse phase HPLC (10-90% CH
gave the TFA salt which was basified with 1N aq sodium
carbonate, extracted with dichloromethane, dried (MgSO ),
3 2
CN/H O with 0.1% TFA)
þ
79% yield) as a yellow solid. MS m/z 592.4 [M þ H] .
4-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethyl-
aminomethyl)-6-methyl-phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,
3-b]pyridine (15j). To a stirred solution of 4-[3-(4-nitrophenyl)-
1-ethyl-1H-pyrazol-4-yl]-2-(3-formyl-6-methyl-phenyl)-1-phe-
nylsulfonyl-1H-pyrrolo[2,3-b]pyridine (0.80 g, 1.4 mmol) in
THF (30 mL) was added a solution of 2 M dimethylamine in
THF (1.35 mL, 2.7 mmol) followed by sodium triacetoxyboro-
hydride (0.5 g, 2.4 mmol). The reaction was stirred at room
temperature for 4 h and concentrated to dryness under vacuum.
The residue was taken up in ethyl acetate, washed with aq 1N
4
filtered, and evaporated to dryness under vacuum. The residue
was triturated with (1:1) ethyl ether/petroleum ether, filtered,
and dried under vacuum gave the product (17c, 83 mg, 0.15
1
mmol, 44% yield) as an off-white solid. H NMR (400 MHz,
DMSO-d
6
) δ ppm 12.15 (d, J=1.77 Hz, 1H), 8.75 (s, 1H), 8.71 (s,
H), 8.27 (s, 1H), 8.09 (d, J=5.05 Hz, 1H), 7.76-7.79 (m, 2H),
.39-7.46 (m, 5H), 7.31-7.36 (m, 2H), 7.25-7.29 (m, 3H), 6.96
1
7
(
t, J=7.33 Hz, 1H), 6.82 (d, J=5.05 Hz, 1H), 6.74 (d, J=2.02 Hz,
1
H), 4.28 (q, J=7.33 Hz, 2H), 3.45 (s, 2H), 2.18 (s, 6H), 1.52 (t,
þ
J = 7.20 Hz, 3H). MS m/z 556.4 [M þ H] . Anal. (C H -
2 4
sodium carbonate, brine, dried (Na SO ), filtered, and evaporated
3
4
33
N
7
O 1.0H
2
O) C, H, N.
-Bromo-4-methylbenzaldehyde. To a stirred solution of
-bromo-4-methylbenzyl alcohol (4.43 g, 22 mmol) in chloro-
under vacuum. Purification of the residue by flash chromatography
on silica gel [3% (5% ammonium hydroxide in methanol) in
dichloromethane] gave the product (15j, 0.70 g, 1.1 mmol, 83%
3
3
3
þ
form (100 mL) was added manganese dioxide (15 g, 172 mmol).
The reaction was stirred and refluxed (70 ꢀC oil bath) for 18 h,
cooled to room temperature, filtered through celite, rinsed with
chloroform, and concentrated to dryness under vacuum. Puri-
fication of the residue by flash chromatography on silica gel
yield) as a pale-yellow solid. MS m/z 621.6 [M þ H] .
4-[3-(4-Aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethyl-
aminomethyl)-6-methyl-phenyl]-1H-pyrrolo[2,3-b]pyridine (16b). To
a stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-
2-[3-(dimethylaminomethyl)-6-methyl-phenyl]-1-phenylsulfo-
nyl-1H-pyrrolo[2,3-b]pyridine (0.70 g, 1.1 mmol) in acetic acid (15
mL) was added portionwise zinc dust (0.32 g, 4.9 mmol) over 5 min.
The reaction was stirred at room temperature for 1 h, filtered
through a pad of celite, rinsed with acetic acid, and concentrated to
dryness under vacuum. The residue was re-evaporated several times
from methanol followed by toluene to remove the excess acetic acid,
taken up in methanol (25 mL), and treated with 6N aq sodium
hydroxide (1.5 mL). The reaction was stirred and heated at 70 ꢀCfor
8 h. After cooling to room temperature, the reaction was concen-
trated under vacuum, triturated with cold water, filtered, washed
with water, and dried under vacuum to give the crude product (16b,
0.49 g, 1.1 mmol, 100% yield) (74% pure by LCMS) as a pale-
(
6
10% ethyl acetate in hexanes) gave the product (3.0 g, 15 mmol,
1
8% yield) as a crystalline solid. H NMR (400 MHz, CDCl
ppm 9.94 (s, 1H), 8.06 (d, J=1.52 Hz, 1H), 7.74 (dd, J=7.83,
.52 Hz, 1H), 7.42 (d, J=7.83 Hz, 1H) 2.51 (s, 3H).
-Formyl-6-methyl-phenylboronate Pinacolato Ester. To a
3
) δ
1
3
glass pressure bottle were added 3-bromo-4-methylbenzalde-
hyde (3.0 g, 15 mmol), bis(pinacolato)diboron (4.5 g, 17.7
mmol), potassium acetate (4.5 g, 45.8 mmol), dichlorobis-
(
triphenylphosphine)palladium(II) (0.5 g, 0.7 mmol), and diox-
ane (50 mL). The reaction was purged with nitrogen, capped,
and stirred at 100 ꢀC for 8 h. The reaction was cooled to room
temperature and concentrated to dryness under vacuum. The
residue was taken up in ethyl acetate, filtered to remove insolu-
bles, and re-evaporated to dryness under vacuum. Purification of
the residue by flash chromatography on silica gel (25 to 100%
dichloromethane in hexanes) gave the product (2.76 g, 11.2 mmol,
þ
orange solid, which was used as is. MS m/z 451.4 [M þ H] .
4-[3-(4-N-Phenylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
4-yl]-2-[3-(dimethylaminomethyl)-6-methyl-phenyl]-1H-pyrrolo-
[2,3-b]pyridine (17d). To a stirred solution of 4-[3-(4-aminophenyl)-
1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)-6-methyl-phe-
nyl]-1H-pyrrolo[2,3-b]pyridine (16b, 250 mg, 0.55 mmol) in THF
(20 mL) was added phenyl isocyanate (73 uL, 0.67 mmol) and 2
drops of triethylamine. The reaction was stirred at room tempera-
ture for 18 h and concentrated to dryness under vacuum. The
remaining solid was triturated with (1:1) ethyl ether/petroleum ether,
filtered, and dried under vacuum. Purification of the residue by
7
4% yield) as an oil which solidified upon standing in the refrig-
1
erator. H NMR (400 MHz, CDCl ) δ ppm 10.01 (s, 1H), 8.27 (d,
3
J=2.02 Hz, 1H), 7.86 (dd, J=7.83, 1.77 Hz, 1H), 7.34 (d, J=7.83
Hz, 1H), 2.64 (s, 3H), 1.39 (s, 12H). MS m/z 246.4 [M þ H] .
þ
4-Bromo-2-(3-formyl-6-methyl-phenyl)-1-phenylsulfonyl-1H-
pyrrolo[2,3-b]pyridine (14b). To a glass pressure bottle were
added 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]-
pyridine (1.18 g, 2.5 mmol), 3-formyl-6-methyl-phenylboro-
nate pinacolato ester (0.71 g, 2.9 mmol), dimethylformamide
15 mL), aq satd sodium bicarbonate (5 mL), and tetrakis-
triphenylphosphine)palladium(0) (120 mg, 0.1 mmol). The
3 2
reverse phase HPLC (10-90% CH CN/0.1% TFA, H O) gave the
TFA salt, which was basified with 1N aq sodium carbonate,
extracted with (9:1) chloroform/isopropyl alcohol, dried (MgSO4),
filtered, and evaporated to dryness under vacuum. The residue was
triturated with (1:1) ethyl ether/petroleum ether, filtered, and dried
(
(
reaction was purged with nitrogen, capped, and stirred at
00 ꢀC for 16 h. After cooling to room temperature, the reaction
was concentrated under vacuum, taken up in ethyl acetate,
washed with water, brine, dried (Na SO ), filtered, and evapo-
1
under vacuum gave the product (17d, 70.6 mg, 0.12 mmol, 22%
1
yield) as a yellow solid. H NMR (400 MHz, DMSO-d ) δ ppm
6
2
4
11.85 (s, 1H), 8.78 (s, 1H), 8.73 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=5.05
Hz, 1H), 7.45 (d, J=7.83 Hz, 2H), 7.41 (d, J=8.59 Hz, 2H), 7.18 -
7.46 (m, 7H), 6.96 (t, J=7.20 Hz, 1H), 6.89(d, J=5.05 Hz, 1H), 6.25
(s, 1H), 4.25 (q, J=7.07 Hz, 2H), 3.36 (s, 2H), 2.29 (s, 3H), 2.13 (s,
rated to dryness under vacuum. Purification of the residue by
flash chromatography on silica gel (0-5% ethyl acetate in
dichloromethane) gave the product (14b, 0.77 g, 1.7 mmol,
þ
þ
6
7% yield) as a white solid. MS m/z 455.0 [M þ H] .
6H), 1.49 (t, J=7.33 Hz, 3H). MS m/z 570.4 [M þ H] . Anal.
4-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-(3-formyl-6-
35 7 2
(C35H N O 1.5H O) C, H, N.
3
methyl-phenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (15b).
To a glass pressure bottle were added 4-bromo-2-(3-formyl-6-
methyl-phenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (0.77 g,
4-Bromo-2-[4-(dimethylaminomethyl)phenyl]-1-phenylsulfo-
nyl-1H-pyrrolo[2,3-b]pyridine (14g). To a glass pressure tube were
added 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine

Article
1.2 g, 2.6 mmol), 4-[(N,N-dimethylamino)methyl]phenyl boronic
acid (0.7 g, 2.17 mmol), dimethylformamide (20 mL), aq satd
sodium bicarbonate (8 mL), and tetrakis(triphenylphosphine)palla-
dium(0) (125 mg, 0.11 mmol). The reaction was purged with
nitrogen, capped, and stirred at 100 ꢀC for 16 h. After cooling to
room temperature, the reaction was concentrated under vacuum,
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3991
(
reverse phase HPLC (10-90% CH
the TFA salt which was basified with 1N aq sodium carbonate,
extracted with dichloromethane, dried (MgSO ), filtered, and
3 2
CN/0.1% TFA, H O) gave
4
evaporated to dryness under vacuum. The residue was triturated
with (1:1) ethyl ether/petroleum ether, filtered, and dried under
vacuum to give the product (17e, 50 mg, 0.09 mmol, 20% yield)
1
taken up in ethyl acetate, washed with water, brine, dried (Na SO
2
4
),
as a white solid. H NMR (400 MHz, DMSO-d
6
) δ ppm 12.12
filtered, and evaporated to dryness under vacuum. Purification of
the residue by flash chromatography on silica gel (0-20% (5%
ammonium hydroxide in methanol) in ethyl acetate) gave the pro-
(br s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 8.08 (d, J=4.80
Hz, 1H), 7.83 (d, J=7.83 Hz, 2H), 7.26-7.45 (m, 10H), 6.97 (t,
J=7.33 Hz, 1H), 6.80 (d, J=5.05 Hz, 1H), 6.75 (s, 1H), 4.27 (q,
J=7.07 Hz, 2H), 3.39 (s, 3H), 2.15 (s, 6H), 1.52 (t, J=7.20 Hz,
1
duct (14g, 0.81 g, 1.7 mmol, 66% yield) as an off-white solid. H
þ
6
NMR (400 MHz, DMSO-d ) δ ppm 8.25 (d, J=5.31 Hz, 1H),
3H). MS m/z 556.4 [M þ H] .
7
.81-7.83 (m, 2H), 7.69 (t, J=6.82 Hz, 1H), 7.62 (d, J=5.31 Hz,
4-Bromo-5-methylbenzylalcohol. To a stirred solution of
4-bromo-5-methylbenzoic acid (5.0 g, 23 mmol) in THF (50
mL) at 0 ꢀC was added dropwise a solution of 1N borane
tetrahydrofuran complex in THF (34 mL, 34 mmol). The
reaction was allowed to warm to room temperature and stirred
for 18 h. The reaction was recooled to 0 ꢀC and slowly quenched
with water (10 mL). The reaction was allowed to warm to room
temperature and evaporated to dryness under vacuum. The
residue was taken up in ethyl acetate, washed with 1N aq sodium
1
H), 7.53-7.60 (m, 4H), 7.42 (d, J=8.08 Hz, 2H), 6.77 (s, 1H), 3.50
þ
(
s, 2H), 2.21 (s, 6H). MS m/z 470.0 [M þ H] .
4-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(dimethyl-
aminomethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine
(
(
15g). To a glass pressure tube were added 4-bromo-2-[4-
dimethylaminomethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo-
[
4
(
2,3-b]pyridine (14g, 0.5 g, 1.0 mmol), 3-(4-nitrophenyl)-1-ethyl-
-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
0.4 g, 1.1 mmol), dimethylformamide (16 mL), aq satd sodium
carbonate followed by brine, dried (MgSO ), filtered, and
4
evaporated to dryness to give the product (5.37 g, 26 mmol,
bicarbonate (4 mL), and tetrakis(triphenylphosphine)palla-
dium(0) (70 mg, 0.06 mmol). The reaction was purged with
nitrogen, capped, and stirred at 100 ꢀC for 8 h. After cooling
to room temperature, the reaction was concentrated under
vacuum, taken up in ethyl acetate, washed with water, brine,
1
100% yield) as a clear liquid. H NMR (400 MHz, CDCl ) δ
3
ppm 7.53 (d, J=8.08 Hz, 1H), 7.26 (d, J=1.77 Hz, 1H), 7.07 (dd,
J=8.08, 1.52 Hz, 1H), 4.65 (s, 2H), 2.42 (s, 3H).
4-Bromo-5-methylbenzaldehyde. To a stirred solution of
4-bromo-5-methylbenzyl alcohol (5.3 g, 26 mmol) in chloroform
(100 mL) was added manganese dioxide (18 g, 207 mmol). The
reaction was stirred and refluxed (70 ꢀC oil bath) for 18 h, cooled
to room temperature, filtered through celite, rinsed with chloro-
form, and concentrated to dryness under vacuum. Purification
of the residue by flash chromatography on silica gel (10% ethyl
2 4
dried (Na SO ), filtered, and evaporated to dryness under
vacuum. Purification of the residue by flash chromatography
on silica gel [2-6% (5% ammonium hydroxide in methanol) in
dichloromethane] gave the product (15g, 0.62 g, 1.0 mmol,
1
00% yield) as a yellow solid. H NMR (400 MHz, DMSO-
1
d6) δ ppm 8.34 (s, 1H), 8.30 (d, J=5.05 Hz, 1H), 8.14 (d, J=9.09
Hz, 2H), 7.82-7.84 (m, 2H), 7.72 (t, J=7.45 Hz, 1H), 7.59 (t, J=
acetate in hexanes) gave the product (3.53 g, 17.7 mmol, 68%
1
7
7
4
7
.83 Hz, 2H), 7.54 (d, J=8.84 Hz, 2H), 7.41 (d, J=8.08 Hz, 2H),
.36 (d, J=8.08 Hz, 2H), 7.05 (d, J=5.05 Hz, 1H), 6.54 (s, 1H),
.26 (q, J=7.33 Hz, 2 H), 3.47 (s, 2 H), 2.19 (s, 6 H), 1.47 (t, J=
yield) as a clear liquid. H NMR (400 MHz, CDCl -d) δ ppm
3
9
7
.98 (s, 1H), 7.75 (d, J=1.52 Hz, 1H), 7.73 (d, J=8.08 Hz, 1H),
.57 (dd, J=8.08, 1.52 Hz, 1H), 2.50 (s, 3H).
þ
.20 Hz, 3 H). MS m/z 607.6 [M þ H] .
4-Formyl-6-methyl-phenylboronate Pinacolato Ester. To a
4-[3-(4-Aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(dimethyl-
glass pressure bottle were added 4-bromo-5-methylbenzalde-
hyde (3.5 g, 17.5 mmol), bis(pinacolato)diboron (5.0 g, 19.6
mmol), potassium acetate (5.2 g, 53 mmol), dichlorobis-
(triphenylphosphine)palladium(II) (0.5 g, 0.7 mmol), and diox-
ane (50 mL). The reaction was purged with nitrogen, capped,
and stirred at 100 ꢀC for 8 h. The reaction was cooled to room
temperature and concentrated to dryness under vacuum. The
residue was taken up in ethyl acetate, filtered to remove inso-
lubles, and re-evaporated to dryness under vacuum. Purifi-
cation of the residue by flash chromatography on silica gel (25
to 100% dichloromethane in hexanes) gave the product (2.73 g,
aminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (16g). To a stir-
red solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-
2
-[4-(dimethylaminomethyl)phenyl]-1-phenylsulfonyl-1H-pyr-
rolo[2,3-b]pyridine (15g, 0.60 g, 1.0 mmol) in acetic acid (20 mL)
was added portionwise zinc dust (0.46 g, 7.0 mmol) over 5 min.
The reaction was stirred at room temperature for 1 h, filtered
through a pad of celite, rinsed with acetic acid, and concentrated
to dryness under vacuum. The residue was re-evaporated several
times from methanol, toluene to remove the excess acetic acid,
taken up in methanol (25 mL), and treated with 6N sodium
hydroxide (1.5 mL). The reaction was stirred and heated at 70 ꢀC
for 8 h. After cooling to room temperature, the reaction was
concentrated under vacuum and the residue was triturated with
cold water, filtered, washed with water, and dried under vacuum
1
11.1 mmol, 63% yield) as a clear oil. H NMR (400 MHz,
CDCl ) δ ppm 10.03 (s, 1H), 7.92 (d, J=7.83 Hz, 1H), 7.65-7.72
3
(m, 2H), 2.63 (s, 3H), 1.59 (s, 1H), 1.39 (s, 12H). MS m/z 246.4
þ
[M þ H] .
to give the product (16g, 0.39 g, 0.90 mmol, 90% yield) as a
4-Bromo-2-(4-formyl-6-methyl-phenyl)-1-phenylsulfonyl-1H-
pyrrolo[2,3-b]pyridine (14c). To a glass pressure bottle were
added 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyr-
idine (1.0 g, 2.1 mmol), 4-formyl-6-methyl-phenylboronate
pinacolato ester (0.6 g, 2.4 mmol), dimethylformamide (15 mL),
aq satd sodium bicarbonate (5 mL), and tetrakis(triphenyl-
phosphine)palladium(0) (120 mg, 0.1 mmol). The reaction was
purged with nitrogen, capped, and stirred at 100 ꢀC for 16 h.
After cooling to room temperature, the reaction was concen-
trated under vacuum, taken up in ethyl acetate, and washed with
water and brine. The organic layer was dried (Na SO ), filtered,
1
yellow solid. H NMR (400 MHz, DMSO-d
6
) δ ppm 12.09 (br s,
1
2
1
2
H), 8.20 (s, 1 H), 8.04 (d, J=5.05 Hz, 1H), 7.85 (d, J=8.34 Hz,
H), 7.35 (d, J=8.08 Hz, 2H), 7.08 (d, J=8.34 Hz, 2H), 6.81 (s,
H), 6.79 (d, J=5.05 Hz, 1H), 6.49 (d, J=8.59 Hz, 2H), 5.14 (s,
H), 4.23 (q, J=7.16 Hz, 2H), 3.41 (s, 2H), 2.16 (s, 6H), 1.49 (t,
þ
J=7.33 Hz, 3H). MS m/z 437.4 [M þ H] .
4-[3-(4-N-Phenylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
-yl]-2-[4-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
4
idine (17e). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[4-(dimethylaminomethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16g, 0.19 g, 0.44 mmol) in THF (10 mL)
was added phenyl isocyanate (71 uL, 0.65 mmol) and one drop
of triethylamine. The reaction was stirred at room temperature
for 1 h and concentrated to dryness under vacuum. The remain-
ing solid was triturated with (1:1) ethyl ether, petroleum ether,
filtered, and dried under vacuum. Purification of the residue by
2
4
and evaporated to dryness under vacuum. Purification of the
residue by flash chromatography on silica gel (0-2% ethyl
acetate in dichloromethane) gave the product (14c, 0.56 g, 1.2
1
mmol, 58% yield) as a white solid. H NMR (400 MHz, DMSO-
d
6
) δ ppm 10.11 (s, 1H), 8.29 (d, J=5.30 Hz, 1H), 7.84-7.92
(m, 4H), 7.68-7.73 (m, 2H), 7.66 (d, J = 5.31 Hz, 1H), 7.70

3
992 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
1
as a yellow solid. H NMR (400 MHz, DMSO-d
(
3
t, J=7.58 Hz, 1H), 7.60 (t, J=7.83 Hz, 2H), 6.81 (s, 1H), 2.35 (s,
H). MS m/z 455.0 [M þ H] .
6
) δ ppm 11.83
þ
(s, 1H), 8.76 (s, 1H), 8.71 (s, 1H), 8.20 (s, 1H), 8.12 (d, J=4.80
Hz, 1H), 7.46 (s, 1H), 7.45 (d, J=8.59 Hz, 2H), 7.40 (d, J=8.59
Hz, 2H), 7.33 (d, J=8.59 Hz, 2H), 7.28 (t, J=7.96 Hz, 2H), 7.21
(s, 1H), 7.18 (d, J=8.08 Hz, 1H), 6.97 (t, J=7.33 Hz, 1H), 6.88
(d, J=5.05 Hz, 1H), 6.28 (d, J=2.02 Hz, 1H), 4.25 (q, J=7.24
4-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-(4-formyl-
-methyl-phenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (15c).
6
To a glass pressure bottle were added 4-bromo-2-(4-formyl-6-
methyl-phenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (14c,
0.54 g, 1.1 mmol), 3-(4-nitrophenyl)-1-ethyl-4-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8a, 0.45 g, 1.3 mmol),
dimethylformamide (16 mL), aq satd sodium bicarbonate (4 mL),
and tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.056 mmol).
The reaction was purged with nitrogen, capped, and stirred at
Hz, 2H), 3.36 (s, 2H), 2.30 (s, 3H), 2.15 (s, 6H), 1.49 (t, J=7.20
Hz, 3H). MS m/z 570.4 [M þ H] . Anal. (C35
þ
35 7 2
H N O 0.75H O)
3
C, H, N.
4-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(N-pyrro-
lidinylmethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyr-
idine (15l). To a stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-
1H-pyrazol-4-yl]-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyr-
rolo[2,3-b]pyridine (15a, 1.0 g, 1.7 mmol) in THF (25 mL) was
added pyrrolidine (0.22 mL, 2.6 mmol) followed by sodium
triacetoxyborohydride (0.56 g, 2.6 mmol). The reaction was
stirred at room temperature for 4 h and concentrated to dryness
under vacuum. The residue was taken up in ethyl acetate and
washed with aq 1N sodium carbonate followed by brine. The
1
00 ꢀC for 8 h. After cooling to room temperature, the reaction
mixture was concentrated under vacuum, taken up in ethyl acetate,
and washed with water followed by brine. The organic layer was
dried (MgSO ), filtered, and evaporated to dryness under vacuum.
Purification of the residue by flash chromatography on silica
gel (5-10% ethyl acetate in dichloromethane) gave the product
(
4
15c, 0.41 g, 0.69 mmol, 63% yield) as a yellow solid. MS m/z 592.4
þ
[
M þ H] .
4
aminomethyl)-6-methyl-phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,
-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(dimethyl-
2 4
organic layer was dried (Na SO ), filtered, and evaporated
under vacuum to give the product (15l, 1.05 g, 1.66 mmol,
97% yield) as a yellow solid. MS m/z 633.6 [M þ H] .
þ
3
1
-b]pyridine (15k). To a stirred solution of 4-[3-(4-nitrophenyl)-
-ethyl-1H-pyrazol-4-yl]-2-(4-formyl-6-methyl-phenyl)-1-phenyl-
4-[3-(4-Aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(N-pyrro-
lidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (16d). To a stir-
red solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-
2-[3-(N-pyrrolidinylmethyl)phenyl]-1-phenylsulfonyl-1H-pyr-
rolo[2,3-b]pyridine (15l, 1.05 g, 1.66 mmol) in acetic acid
(40 mL) was added portionwise zinc dust (0.76 g, 11.6 mmol)
over 5 min. The reaction was stirred at room temperature for 1 h,
filtered through a pad of celite, rinsed with acetic acid, and
concentrated to dryness under vacuum. The residue was re-
evaporated several times from methanol followed by toluene to
remove the excess acetic acid. The residue was taken up in
methanol (35 mL), treated with 6N aq sodium hydroxide (1.5
mL), and heated at 70 ꢀC for 8 h. After cooling to room tem-
perature, the reaction was concentrated under vacuum and the
residue was triturated with cold water, filtered, washed with
water, and dried under vacuum. Purification of the residue by
flash chromatography on silica gel (10 to 20% methanol con-
taining 0.1% triethylamine in dichloromethane) gave the pro-
sulfonyl-1H-pyrrolo[2,3-b]pyridine (15c, 0.41 g, 0.69 mmol) in
THF (20 mL) was added a solution of 2 M dimethylamine in
THF (0.7 mL, 1.4 mmol) followed by sodium triacetoxyboro-
hydride (0.25 g, 1.1 mmol). The reaction was stirred at room
temperature for 18 h and concentrated to dryness under va-
cuum. The residue was taken up in ethyl acetate and washed
with aq 1N sodium carbonate followed by brine. The organic
layer was dried (Na SO ), filtered, and evaporated under vacu-
um. Purification of the residue by flash chromatography on
silica gel (97:3 dichloromethane/5% ammonium hydroxide in
methanol) gave the product (15k, 0.50 g, 0.69 mmol, 100% yield)
as a pale-yellow solid. MS m/z 621.6 [M þ H].
2
4
4-[3-(4-Aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(dimethyl-
aminomethyl)-6-methyl-phenyl]-1H-pyrrolo[2,3-b]pyridine (16c).
To a stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyra-
zol-4-yl]-2-[4-(dimethylaminomethyl)-6-methyl-phenyl]-1-phe-
nylsulfonyl-1H-pyrrolo[2,3-b]pyridine (15k, 0.50 g, 0.69 mmol)
in acetic acid (15 mL) was added portionwise zinc dust (0.32 g,
1
duct (16d, 0.48 g, 1.0 mmol, 62% yield) as a yellow solid. H
4
.9 mmol) over 5 min. The reaction was stirred at room
NMR (400 MHz, DMSO-d ) δ ppm 12.13 (s, 1H), 8.20 (s, 1H),
6
temperature for 1 h, filtered through a pad of celite, rinsed with
acetic acid, and concentrated to dryness under vacuum. The
residue was re-evaporated several times from methanol followed
by toluene to remove the excess acetic acid, taken up in methanol
8.06 (d, J=5.05 Hz, 1H), 7.87 (br s, 1H), 7.81 (d, J=7.58 Hz,
1H), 7.42 (t, J=7.58 Hz, 1H), 7.32 (d, J=7.58 Hz, 2H), 7.08 (d,
J=8.59 Hz, 2H), 6.81 (s, 1H), 6.80 (d, J=5.05 Hz, 2H), 6.49 (d,
J=8.59 Hz, 2H), 5.14 (br s, 2H), 4.23 (q, J=7.33 Hz, 2H), 3.74
(br s, 2H), 2.60 (br s, 4H), 1.76 (br s, 4H), 1.49 (t, J=7.20 Hz,
(
25 mL), and treated with 6N aq sodium hydroxide (1.5 mL).
þ
The reaction was stirred and heated at 70 ꢀC for 8 h. After
cooling to room temperature, the reaction was concentrated
under vacuum, triturated with cold water, filtered, washed with
water, and dried under vacuum to give the crude product (16c,
3H). MS m/z 463.4 [M þ H] .
4-[3-(4-N-Phenylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
4-yl]-2-[3-(N-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
idine (17g). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(N-pyrrolidinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16d, 200 mg, 0.43 mmol) in THF (10
mL) was added phenyl isocyanate (60 uL, 0.55 mmol). The
reaction was stirred at room temperature for 3 h and concen-
trated to dryness under vacuum. The remaining solid was
triturated with (1:1) ethyl ether/petroleum ether, filtered, and
dried under vacuum. Purification of the residue by reverse phase
0
.46 g, 1.0 mmol, 100% yield) (74% pure by LCMS) as a brown
þ
solid. MS m/z 451.4 [M þ H] .
4
-[3-(4-N-Phenylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
-yl]-2-[4-(dimethylaminomethyl)-6-methyl-phenyl]-1H-pyrrolo-
2,3-b]pyridine (17f). To a stirred solution of 4-[3-(4-aminophenyl)-
-ethyl-1H-pyrazol-4-yl]-2-[4-(dimethylaminomethyl)-6-methyl-
4
[
1
phenyl]-1H-pyrrolo[2,3-b]pyridine (16c, 200 mg, 0.44 mmol) in
THF (10 mL) was added phenyl isocyanate (58 uL, 0.53 mmol)
and 2 drops of triethylamine. The reaction was stirred at room
temperature for 4 h and concentrated to dryness under vacuum.
The remaining solid was triturated with (1:1) ethyl ether/petro-
leum ether, filtered, and dried under vacuum. Purification of the
3 2
HPLC (10-90% CH CN/0.1% TFA, H O) gave the TFA salt
which was basified with 1N aq sodium carbonate, extracted with
(9:1) chloroform/isopropyl alcohol, dried (MgSO ), filtered,
4
and evaporated to dryness under vacuum. Trituration of the
residue with (1:1) ethyl ether/petroleum ether, filtration, and
drying under vacuum gave the product (17g, 166 mg, 0.28 mmol,
residue by reverse phase HPLC (10-90% CH CN/0.1% TFA,
3
1
H
2
O) gave the TFA salt which was basified with 1N aq sodium
66% yield) as an off-white solid. H NMR (400 MHz, DMSO-
carbonate and extracted with (9:1) chloroform/isopropyl alco-
hol. The organic layer was dried (MgSO ), filtered, and evapo-
rated to dryness under vacuum. The residue was trituration with
1:1) ethyl ether/petroleum ether, filtered, and dried under
vacuum to give the product (17f, 57 mg, 0.10 mmol, 23% yield)
6
d ) δ ppm 12.14 (d, J=1.52 Hz, 1H), 8.74 (s, 1H), 8.70 (s, 1H),
4
8.26 (s, 1H), 8.10 (d, J = 4.80 Hz, 1H), 7.73-7.81 (m, 2H),
7.40-7.46 (m, 4H), 7.25-7.46 (m, 10H), 6.96 (t, J=7.33 Hz,
1H), 6.83 (d, J=5.05 Hz, 1H), 6.70 (d, J=2.02 Hz, 1H), 4.28 (q,
J=7.24 Hz, 2H), 3.63 (s, 2H), 2.47 (br s, 4H), 1.69 (br s, 4H), 1.52
(

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3993
þ
(
N O 1.0H O) C, H, N.
4
t, J=7.33 Hz, 3H). MS m/z 582.7 [M þ H] . Anal. (C36
H
35
-
aq satd sodium bicarbonate (5 mL), and tetrakis(triphenyl-
phosphine)palladium(0) (125 mg, 0.11 mmol). The reaction
was purged with nitrogen, capped, and stirred at 100 ꢀC for
16 h. After cooling to room temperature, the reaction was
concentrated under vacuum, taken up in ethyl acetate, and
washed with water followed by brine. The organic layer was
dried (Na SO ), filtered, and evaporated to dryness under
7
3
2
-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(N-morpho-
linylmethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine
15m). To a stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-
pyrazol-4-yl]-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyrrolo-
2,3-b]pyridine (15a, 1.0 g, 1.7 mmol) in THF (20 mL) was added
(
[
2
4
morpholine (0.35 mL, 4.0 mmol) followed by sodium triacetoxy-
borohydride (0.83 g, 3.9 mmol). The reaction was stirred at
room temperature for 3 days and concentrated to dryness under
vacuum. The residue was taken up in ethyl acetate, washed with
water, filtered free of a small amount of insolubles, dried
vacuum. Purification of the residue by flash chromatography
on silica gel (a gradient of 100:0 to 95:5 dichloromethane/5%
ammonium hydroxide in methanol) gave the product (14h, 1.13
1
g, 2.2 mmol, 84% yield) as a beige foam. H NMR (400 MHz,
DMSO-d ) δ ppm 8.25 (d, J=5.31 Hz, 1H), 7.80-7.83 (m, 2H),
6
(
Na SO ), filtered, and concentrated under vacuum. Purifica-
2
7.68 (t, J=7.45 Hz, 1H), 7.61 (d, J=5.31 Hz, 1H), 7.56-7.63 (m,
4H), 7.44 (d, J=8.08 Hz, 2H), 6.77 (s, 1H), 3.62 (t, J=4.42 Hz,
4
tion of the residue by flash chromatography on silica gel (a
gradient of 100:0 to 96:4 dichloromethane/5% ammonium
hydroxide in methanol) gave the product (15m, 0.94 g, 1.4
þ
4H), 3.57 (s, 2H), 2.42 (br s, 4H). MS m/z 512.2 [M þ H] .
4-[3-(4-Nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(N-morpho-
linylmethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine
(15h). To a sealed pressure tube were added 4-bromo-2-[4-(N-
morpholinylmethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]-
pyridine (14h, 0.5 g, 1.0 mmol), 3-(4-nitrophenyl)-1-ethyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.4 g,
1.1 mmol), dimethylformamide (16 mL), aq satd sodium bicar-
bonate (4 mL), and tetrakis(triphenylphosphine)palladium(0)
(70 mg, 0.06 mmol). The reaction was purged with nitrogen,
capped, and stirred at 100 ꢀC for 8 h. After cooling to room
temperature, the reaction was concentrated under vacuum,
taken up in ethyl acetate, and washed with water followed by
1
mmol, 85% yield) as a yellow solid. H NMR (400 MHz,
DMSO-d ) δ ppm 8.34 (s, 1H), 8.33 (d, J=5.05 Hz, 1H), 8.13
6
(
7
d, J=8.84 Hz, 2H), 7.84-7.87 (m, 2H), 7.74 (t, J=7.45 Hz, 1H),
.61 (t, J=7.83 Hz, 2H), 7.53 (d, J=8.84 Hz, 2H), 7.34-7.41 (m,
H), 7.27 (s, 1H), 7.10 (d, J=5.05 Hz, 1H), 6.45 (s, 1H), 4.26 (q,
3
J=7.33 Hz, 2H), 3.59 (t, J=4.29 Hz, 4H), 3.50 (s, 2H), 2.38 (br s,
4
þ
H), 1.47 (t, J=7.33 Hz, 3H). MS m/z 649.4 [M þ H] .
4-[3-(4-Aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(N-mor-
pholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (16e). To a
stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-
yl]-2-[3-(N-morpholinylmethyl)phenyl]-1-phenylsulfonyl-1H-
pyrrolo[2,3-b]pyridine (15m, 0.94 g, 1.4 mmol) in acetic acid
brine. The organic layer was dried (Na SO ), filtered, and
2 4
(
30 mL) was added portionwise zinc dust (0.7 g, 10.7 mmol)
over 5 min. The reaction was stirred at room temperature for
h, filtered through a pad of celite, rinsed with acetic acid, and
evaporated to dryness under vacuum. Purification of the residue
by flash chromatography on silica gel (98:2 dichloromethane/
5% ammonium hydroxide in methanol) gave the product (15h,
1
1
concentrated to dryness under vacuum. The residue was re-
evaporated several times from methanol followed by toluene
to remove the excess acetic acid, taken up in methanol (30 mL),
and treated with 6N aq sodium hydroxide (2.0 mL). The
reaction mixture was stirred and heated at 70 ꢀC for 8 h. After
cooling to room temperature, the reaction was concentrated
under vacuum, triturated with cold water, filtered, washed
with water, and dried under vacuum to give the crude product
0.64 g, 1.0 mmol, 99% yield) as a yellow solid. H NMR (400
MHz, DMSO-d ) δ ppm 8.33 (s, 1H), 8.30 (d, J=5.31 Hz, 1H),
6
8.14 (d, J=8.84 Hz, 2H), 7.82-7.84 (m, 2H), 7.72 (t, J=7.45 Hz,
1H), 7.57-7.63 (m, 2H), 7.54 (d, J=9.02 Hz, 2H), 7.43 (d, J=
8.08 Hz, 2H), 7.39 (d, J=8.34 Hz, 2H), 7.05 (d, J=5.05 Hz, 1H),
6.54 (s, 1H), 4.26 (q, J=4.26 Hz, 2H), 3.61 (t, J=4.55 Hz, 4H),
3.54 (s, 2H), 2.40 (br s, 4H), 1.47 (t, J=7.33 Hz, 4H). MS m/z
þ
649.2 [M þ H] .
(
16e, 0.73 g, 1.5 mmol, 100% yield) as a pale-yellow solid. MS
4-[3-(4-Aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(N-mor-
pholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (16h). To a
stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-
yl]-2-[4-(N-morpholinylmethyl)]-1-phenylsulfonyl-1H-pyrrolo-
[2,3-b]pyridine (15h, 0.64 g, 1.0 mmol) in acetic acid (20 mL) was
added portionwise zinc dust (0.4 g, 6.1 mmol) over 5 min. The
reaction was stirred at room temperature for 1 h, filtered
through a pad of celite, rinsed with acetic acid, and concentrated
to dryness under vacuum. The residue was re-evaporated several
times from methanol followed by toluene to remove the excess
acetic acid. The residue was taken up in methanol (25 mL) and
treated with aq 6N sodium hydroxide (1.5 mL). The reaction
mixture was stirred and heated at 70 ꢀC for 8 h. After cooling to
room temperature, the reaction was concentrated under vacu-
um, and the residue was triturated with cold water, filtered,
washed with water, and dried under vacuum to give the crude
þ
m/z 479.4 [M þ H] .
4-[3-(4-N-Phenylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
-yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
4
idine (17h). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16e, 150 mg, 0.31 mmol) in THF (5 mL)
was added phenyl isocyanate (41 μL, 0.37 mmol) and two drops
of triethylamine. The reaction was stirred at room temperature
for 1 h and concentrated to dryness under vacuum. The remain-
ing solid was triturated with (1:1) ethyl ether/petroleum ether,
filtered, and dried under vacuum. Purification of the residue by
3 2
reverse phase HPLC (10-90% CH CN/H O with 0.1% TFA)
gave the TFA salt which was basified with 1N aq sodium
carbonate, extracted with dichloromethane, dried (MgSO4),
filtered, and evaporated to dryness under vacuum. The residue
was triturated with (1:1) ethyl ether/petroleum ether, filtered,
and dried under vacuum to give the product (17h, 81 mg, 0.14
product (16h, 0.46 g, mmol, 0.96 mmol, 96% yield) as a yellow
1
solid. H NMR (400 MHz, DMSO-d ) δ ppm 12.09 (d, J=1.77
6
1
mmol, 44% yield) as an off-white solid. H NMR (400 MHz,
DMSO-d ) δ ppm 12.16 (d, J=1.52 Hz, 1H), 8.72 (s, 1H), 8.67 (s,
Hz, 1H), 8.20 (s, 1H), 8.05 (d, J=5.05 Hz, 1H), 7.85 (d, J=8.34
Hz, 2H), 7.37 (d, J=8.34 Hz, 2H), 7.08 (d, J=8.59 Hz, 2H), 6.80
(br s, 1H), 6.80 (d, J=4.80 Hz, 1H), 6.49 (d, J=8.34 Hz, 2H),
5.14 (s, 2H), 4.23 (q, J=7.24 Hz, 2H), 3.59 (t, J=4.42 Hz, 4H),
3.49 (s, 2H), 2.37 (br s, 4H), 1.49 (t, J=7.33 Hz, 3H). MS m/z
6
1
7
6
2
3
5
H), 8.27 (s, 1H), 8.10 (d, J=5.05 Hz, 1H), 7.74-7.82 (m, 2H),
.39-7.46 (m, 5H), 7.31-7.35 (m, 2H), 7.27 (t, J=7.83 Hz, 3H),
.96 (t, J=7.33 Hz, 1H), 6.82 (d, J=5.05 Hz, 1H), 6.73 (d, J=
.02 Hz, 1H), 4.28 (q, J=7.16 Hz, 2H), 3.58 (t, J=4.42 Hz, 4H),
þ
479.4 [M þ H] .
.50 (s, 2H), 2.38 (br s, 4H), 1.52 (t, J=7.33 Hz, 3H). MS m/z
98.6 [M þ H] . Anal. (C36
4-[3-(4-N-Phenylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
4-yl]-2-[4-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
idine (17i). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[4-(N-morpholinylmethyl)phenyl]-
1H-pyrrolo[2,3-b]pyridine (16h, 0.22 g, 0.46 mmol) in THF (15
mL) was added phenyl isocyanate (75 uL, 0.69 mmol) and one drop
of triethylamine. The reaction was stirred at room temperature for
þ
35 7 2
H N O 1.75H O) C, H, N.
3
4
-Bromo-2-[4-(N-morpholinylmethyl)phenyl]-1-phenylsulfo-
nyl-1H-pyrrolo[2,3-b]pyridine (14h). To a glass pressure tube
were added 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-
b]pyridine (13, 1.2 g, 2.6 mmol), 4-(N-morpholinylmethyl)ben-
zeneboronic acid (0.8 g, 2.6 mmol), dimethylformamide (20 mL),

3
994 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
1
off-white solid. H NMR (400 MHz, DMSO-d
1
h and concentrated to dryness under vacuum. Purification of the
6
) δ ppm 12.11 (br
residue by reverse phase HPLC (10-90% CH CN/H O) gave the
s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 8.06 (d, J=5.05 Hz, 1H), 7.83 (d,
J=8.08 Hz, 2H), 7.33-7.35 (m, 4H), 7.26 (d, J=8.59 Hz, 2H),
6.78 (d, J=5.05 Hz, 1H), 6.76 (s, 1H), 6.18 (t, J=5.56 Hz, 1H),
4.26 (q, J=7.24 Hz, 2H), 3.40 (s, 2H), 3.05-3.11 (m, 2H), 2.16 (s,
3
2
1
product (17i, 30 mg, 0.05 mmol, 11% yield) as a white solid. H
NMR (400 MHz, DMSO-d ) δ ppm 12.13 (br s, 1H), 8.80 (br s,
H), 8.75 (br s, 1H), 8.26 (s, 1H), 8.08 (d, J=5.05 Hz, 1H), 7.83 (d,
6
1
J=8.08 Hz, 2H), 7.25-7.46 (m, 10H), 6.93-7.00 (m, 1H), 6.81 (d,
J=5.05 Hz, 1H), 6.74 (s, 1H), 4.27 (q, J=7.16 Hz, 2H), 3.57 (br s,
6H), 1.51 (t, J=7.33 Hz, 3H), 1.04 (t, J=7.07 Hz, 3H). MS m/z
þ
508.4 [M þ H] . Anal. (C30
33 7 2
H N O 1.75H O) C, H, N.
3
4
H), 3.47 (s, 2H), 2.35 (br s, 4H), 1.52 (t, J=7.20 Hz, 3H). MS m/z
4-[3-(4-N,N-Dimethylcarbamylaminophenyl)-1-ethyl-1H-pyr-
azol-4-yl]-2-[4-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]-
pyridine (17m). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[4-(dimethylaminomethyl)phenyl]-
1H-pyrrolo[2,3-b]pyridine (16g, 0.45 g, 1.0 mmol) in THF (15
mL) was added p-nitrophenylchloroformate (0.23 g, 1.1 mmol).
After stirring for 1 h at room temperature, a solution of 2.0 M
dimethylamine in THF (8 mL, 16 mmol) was added. The
reaction was stirred an additional 1 h at room temperature
and then concentrated under vacuum. The residue which re-
mained was triturated with 0.5N aq sodium hydroxide, filtered,
washed with cold water, and dried under vacuum. Purification
of the residue by reverse phase HPLC (10-90% CH CN/H O
þ
598.4 [M þ H] . Anal. (C H N O 1.75H O) C, H, N.
3
6
35
7
3
2
4-[3-(4-N-Ethylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
4
idine (17j). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16a, 0.15 g, 0.34 mmol) in THF (5 mL)
was added ethyl isocyanate (55 uL, 0.70 mmol) and two drops of
triethylamine. The reaction was stirred at room temperature for
2
days and concentrated to dryness under vacuum. The remain-
ing solid was triturated with (1:1) ethyl ether/petroleum ether,
filtered, and dried under vacuum. Purification of the residue by
reverse phase HPLC (10-90% CH CN/H O with 0.1% TFA)
3
2
3
2
gave the TFA salt which was basified with 1N aq sodium
carbonate, extracted with dichloromethane, dried (MgSO ),
with 0.1% TFA) gave the TFA salt which was basified with 1N
aq sodium carbonate, extracted with dichloromethane, dried
(MgSO ), filtered, and evaporated to dryness under vacuum.
4
filtered, and evaporated to dryness under vacuum. Trituration
of the residue with (1:1) ethyl ether/petroleum ether, filtration,
and drying under vacuum gave the product (17j, 32 mg, 0.064
4
The residue was triturated with (1:1) ethyl ether/petroleum
ether, filtered, and dried under vacuum to give the product
1
1
(17m, 234 mg, 0.46 mmol, 46% yield) as a pale-yellow solid. H
mmol, 18% yield) as an off-white solid. H NMR (400 MHz,
DMSO-d
(
6
) δ ppm 12.17 (br s, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.09
d, J=4.80 Hz, 1H), 7.81-7.88 (m, 2H), 7.44 (t, J=7.58 Hz, 1H),
NMR (400 MHz, DMSO-d ) δ ppm 12.12 (d, J=1.52 Hz, 1H),
8.31 (s, 1H), 8.26 (s, 1H), 8.06 (d, J=4.80 Hz, 1H), 7.84 (d, J=
6
7
6
7
6
5
.30-7.37 (m, 3H), 7.24-7.30 (m, 2H), 6.80 (d, J=4.80 Hz, 1H),
.77 (s, 1H), 6.17 (t, J=5.43 Hz, 1H), 5.76 (s, 1H), 4.26 (q, J=
.07 Hz, 2H), 3.70 (br s, 2H), 3.05-3.13 (m, 2H), 2.35 (br s,
H), 1.51 (t, J=7.20 Hz, 3H), 1.03 (t, J=7.20 Hz, 3H). MS m/z
8.34 Hz, 2H), 7.42 (d, J=8.84 Hz, 2H), 7.35 (d, J=8.34 Hz, 2H),
7.28 (d, J=8.59 Hz, 2H), 6.78 (d, J=4.80 Hz, 1H), 6.78 (d, J=
2.27 Hz, 1H), 4.27 (q, J=7.33 Hz, 2H), 3.41 (s, 2H), 2.91 (s, 6H),
2.16 (s, 6H), 1.51 (t, J=7.20 Hz, 3H). MS m/z 508.4 [M þ H] .
þ
þ
08.4 [M þ H] .
4-[3-(4-N-Ethylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-4-
yl]-2-[3-(N-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
idine (17n). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(N-pyrrolidinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16d, 240 mg, 0.51 mmol) in THF (15
mL) was added ethyl isocyanate (110 μL, 1.4 mmol). The
reaction was stirred at room temperature for 4 days and con-
centrated to dryness under vacuum. The remaining solid was
triturated with (1:1) ethyl ether/petroleum ether, filtered, and
dried under vacuum. Purification of the residue by reverse phase
HPLC (10-90% CH CN/H O with 0.1% TFA) gave the TFA
4-[3-(4-N,N-Dimethylcarbamylaminophenyl)-1-ethyl-1H-pyr-
azol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]-
pyridine (17k). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16a, 0.45 g, 1.0 mmol) in tetrahydrofuran
(
15 mL) was added p-nitrophenylchloroformate (0.22 g, 1.1
mmol). After stirring for 1 h at room temperature, a solution of
.0 M dimethylamine in tetrahydrofuran (7 mL, 14 mmol) was
2
added. The reaction was stirred an additional 1 h at room
temperature and then concentrated under vacuum. The residue
which remained was triturated with aq sodium hydroxide, fil-
tered, washed with cold water, and dried under vacuum. Purifica-
tion of the residue by Gilson reverse phase HPLC afforded the
3
2
salt which was basified with 1N aq sodium carbonate, extracted
4
with (9:1) chloroform/isopropyl alcohol, dried (MgSO ), fil-
tered, and evaporated to dryness under vacuum. The residue
was triturated with (1:1) ethyl ether/petroleum ether, filtered,
title compound (17k, 235 mg, 0.46 mmol, 46% yield) as an off-
1
white solid. H NMR (400 MHz, DMSO-d
6
) δ ppm 12.14 (d, J=
and dried under vacuum to give the product (16n, 205 mg, 0.38
mmol, 73% yield) as an off-white solid. H NMR (400 MHz,
1
1
7
.8 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1 H), 8.07 (d, J=4.8 Hz, 1H),
.78 (d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.39
DMSO-d ) δ ppm 12.13 (d, J=1.52 Hz, 1H), 8.46 (s, 1H), 8.25 (s,
6
(
J=5.1 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 4.27 (q, J=7.3 Hz, 2H),
d, J=8.1 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.27 (dd, 1H), 6.79 (d,
1H), 8.07 (d, J=5.05 Hz, 1H), 7.73-7.81 (m, 2H), 7.38 (t, J=
7.58 Hz, 1H), 7.34 (d, J=8.59 Hz, 2H), 7.28 (d, J=7.07 Hz, 1H),
7.26 (d, J=8.59 Hz, 2H), 6.79 (d, J=4.80 Hz, 1H), 6.74 (d, J=
2.02 Hz, 1H), 6.10 (t, J=5.56 Hz, 1H), 4.26 (q, J=7.24 Hz, 2H),
3.63 (s, 2H), 3.09 (dd, J=7.07, 5.81 Hz, 2H), 2.47 (br s, 4H), 1.72
3
.43 (s, 2H), 2.91 (s, 6H), 2.18 (s, 6H), 1.51 (t, J=7.2 Hz, 3H). MS
þ
m/z 508.4 [M þ H] . Anal. (C30
33 7 2
H N O 1.0H O) C, H, N.
3
4-[3-(4-N-Ethylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-4-
yl]-2-[4-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
idine (17l). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[4-(dimethylaminomethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16g, 0.20 g, 0.46 mmol) in THF (5 mL)
was added ethyl isocyanate (75 uL, 0.95 mmol). The reaction
was stirred at room temperature for 2 days and concentrated to
dryness under vacuum. The remaining solid was triturated with
(br s, 4H), 1.51 (t, J=7.33 Hz, 3H), 1.04 (t, J=7.07 Hz, 3H). MS
þ
m/z 534.5 [M þ H] . Anal. (C H N O 1.5H O) C, H, N.
3
2
35
7
3
2
4-[3-(4-N,N-Dimethylcarbamylaminophenyl)-1-ethyl-1H-pyr-
azol-4-yl]-2-[3-(N-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]-
pyridine (17o). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(N-pyrrolidinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16d, 0.15 g, 0.32 mmol) in THF (10 mL)
was added p-nitrophenylchloroformate (75 mg, 0.37 mmol). The
reaction quickly became a suspension. After stirring for 1 h at
room temperature, a solution of 2.0 M dimethylamine in THF
(1.5 mL, 3 mmol) was added. The reaction was stirred an
additional 1 h at room temperature and then concentrated under
vacuum. The residue which remained was triturated with 0.5N
aq sodium hydroxide, filtered, washed with cold water, and
dried under vacuum. Purification of the residue by reverse phase
(
1:1) ethyl ether/petroleum ether, filtered, and dried under vacu-
um. Purification of the residue by reverse phase HPLC (10-
0% CH CN/H O with 0.1% TFA) gave the TFA salt which
was basified with 1N aq sodium carbonate, extracted with
dichloromethane, dried (MgSO ), filtered, and evaporated to
9
3
2
4
dryness under vacuum. The residue was triturated with (1:1)
ethyl ether/petroleum ether, filtered, and dried under vacuum
to give the product (17l, 115 mg, 0.23 mmol, 49% yield) as an

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3995
HPLC (10-90% CH
salt which was basified with 1N aq sodium carbonate, extracted
3
CN/H
2
O with 0.1% TFA) gave the TFA
1H), 6.54 (s, 1H), 4.26 (q, J=8.0 Hz, 2H), 3.64 (s, 2H), 2.47 (br s,
4H), 1.69-1.75 (m, 4H), 1.47 (t, J=8.0 Hz, 3H).
with dichloromethane, dried (MgSO
4
), filtered, and evaporated
[4-(1-Ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo-
[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (16f). To a
stirred solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-
yl]-1-(phenylsulfonyl)-2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine(15n, 308 mg, 0.49 mmol) in acetic acid (4 mL)
was added portionwise zinc dust (223 mg, 3.41 mmol) (exotherm
observed). The reaction was stirred at room temperature for 1 h,
filtered through a pad of celite, rinsed with acetic acid, and concentra-
ted to dryness under vacuum. The residue was re-evaporated several
times from methanol followed by toluene to remove the excess acetic
acid. Theresiduewas taken up in methanol (5 mL) and treated with
aq 6N sodium hydroxide (0.24 mL, 1.46 mmol). The reaction
mixture was stirred and heated at 70 ꢀC for 5 h. After cooling to
room temperature, the reaction was concentrated under vacuum,
triturated with cold water, filtered, washed with water, and dried
under vacuum to give the crude product (16f, 229 mg, 100% yield)
(92% pure by LCMS) as an orange solid. The material was used as
to dryness under vacuum. The residue was triturated with (1:1)
ethyl ether/petroleum ether, filtered, and dried under vacuum to
give the product (17o, 69 mg, 0.13 mmol, 40% yield) as a pale-
1
yellow solid. H NMR (400 MHz, DMSO-d
1
6
) δ ppm 12.15 (s,
H), 8.32 (s, 1H), 8.27 (s, 1H), 8.07 (d, J = 5.05 Hz, 1H),
7.74-7.81 (m, 2H), 7.43 (d, J=8.59 Hz, 2H), 7.38 (t, J=7.58
Hz, 1H), 7.27 (d, J=8.59 Hz, 3H), 6.79 (d, J=5.05 Hz, 1H), 6.76
(
(
d, J=1.77 Hz, 1H), 4.27 (q, J=7.24 Hz, 2H), 3.61 (s, 2H), 2.91
s, 6H), 2.45 (br s, 4H), 1.71 (br s, 4H), 1.51 (t, J=7.20 Hz, 3H).
þ
MS m/z 534.4 [M þ H] . Anal. (C H N O 1.25H O) C, H, N.
3
2
35
7
3
2
4
-[4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-
benzaldehyde (14d). To a glass pressure tube were added 4-bro-
mo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (13, 3.67
g, 7.93 mmol), 4-formylbenzeneboronic acid (1.19 g, 7.93 mmol),
N,N-dimethylformamide (60 mL), aq satd sodium bicarbonate
(
0
20 mL), and tetrakis(triphenylphosphine)palladium(0) (458 mg,
.40 mmol). The reaction was purged with nitrogen, sealed, and
þ
is in the subsequent reaction. MS m/z 463 [M þ H] .
0
stirred at 100 ꢀC overnight (20 h). After cooling to room tem-
perature, the reaction was diluted with water, brine, and ethyl
acetate. The aqueous layer was extracted with two portions of
ethyl acetate and the combined extracts were dried (Na SO ),
N-Ethyl-N -[4-(1-ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-
1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]urea (17p).
To a stirred solution of [4-(1-ethyl-4-{2-[4-(1-pyrrolidinylme-
thyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-
phenyl]amine (16f, 100 mg, 0.216 mmol) in THF (2 mL) was
added one drop of triethylamine followed by ethyl isocyanate
(20 μL, 0.259 mmol). The reaction was stirred at room tempera-
ture for 22 h and concentrated to dryness under vacuum. The
remaining solid taken up in DMSO and purified by reverse phase
HPLC (10-90% CH CN/H O with 0.1% TFA) to give the TFA
2
4
filtered, and evaporated to dryness under vacuum. Purification of
the residue by flash chromatography on silica gel (35% ethyl
acetate in hexanes) gave the product (14d, 2.64 g, 75% yield) as a
þ
1
yellow solid. MS m/z 441.2 [M þ H] . H NMR (DMSO-d
ppm 10.13 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz,
H), 7.89 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.72-7.65
m, 2H), 7.58 (app t, J=8.0 Hz, 2H), 6.96 (s, 2H).
-[4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsul-
6
) δ
2
(
3
2
salt which was basified with satd aq sodium bicarbonate and
extracted with three portions of dichloromethane. The combined
organics were dried (Na SO ), filtered, and evaporated to dryness
4
fonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde (15d). To a sealed
pressure tube were added 4-[4-bromo-1-(phenylsulfonyl)-1H-pyr-
rolo[2,3-b]pyridin-2-yl]benzaldehyde (14d, 2.64 g, 5.99 mmol), 3-(4-
nitrophenyl)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2
4
under vacuum to give the product (17p, 22 mg, 19% yield) as a
þ
1
yellow solid. MS m/z 534.4 [M þ H] . H NMR (DMSO-d ) δ
6
ppm 12.10 (s, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.06 (d, J=4.0 Hz,
2
-yl)-1H-pyrazole (2.05 g, 5.99 mmol), dimethylformamide (45
1H), 7.82 (d, J=8.0 Hz, 2H), 7.32-7.37 (m, 4H), 7.26 (d, J=8.0
Hz, 2H), 6.78 (d, J=4.0 Hz, 1H), 6.74 (s, 1H), 6.09 (bs, 1H), 4.26
(q, J=8.0 Hz, 2H), 3.59 (bs, 2H), 3.09 (m, 2H), 2.45 (app bs, 4H),
1.71 (app bs, 4H), 1.51 (t, J=8.0 Hz, 3H), 1.04 (t, J=8.0 Hz, 3H).
mL), aq satd sodium bicarbonate (15 mL), and tetrakis(tri-
phenylphosphine)palladium(0) (346 mg, 0.30 mmol). The reaction
was purged with nitrogen, capped, and stirred at 100 ꢀC overnight
0
(20 h). After cooling to room temperature, the reaction was
N -[4-(1-Ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyr-
concentrated under vacuum, taken up in ethyl acetate, and washed
with water and brine. The organic layer was dried (Na SO ), filtered,
and evaporated to dryness under vacuum. Purification of the residue
by flash chromatography on silica gel (50-55% ethyl acetate in
hexanes) gave the product (15d, 1.86 g, 1.3 mmol, 54% yield) as a
rolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethyl-
urea (17q). To a stirred suspension of [4-(1-ethyl-4-{2-[4-(1-
pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-
pyrazol-3-yl)phenyl]amine (16f, 130 mg, 0.281 mmol) in THF
(3 mL) was added p-nitrophenyl chloroformate (62 mg, 0.31
mmol), giving a yellow slurry. After 45 min, dimethylamine
(0.56 mL of a 2 M solution in THF, 1.12 mmol) was added. After
an additional 45 min, the reaction was diluted with ethyl acetate
and washed with three portions of 1N NaOH. The combined aq
layers were back-extracted with ethyl acetate, and the combined
2
4
þ 1
yellow solid. MS m/z 578.4 [M þ H] . H NMR (DMSO-d
6
) δ ppm
1
0.10 (s, 1H), 8.35 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.14 (d, J=8.0
Hz, 2H), 8.01 (d, J=8.0 Hz, 2H), 7.88 (app d, J=4.0 Hz, 2H),
.72-7.75 (m, 3H), 7.61 (app t, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz,
H), 7.07 (d, J=4.0 Hz, 1H), 6.76 (s, 1H), 4.27 (q, J=8.0 Hz, 2H),
.47 (t, J=8.0 Hz, 3H).
-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfo-
nyl)-2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine
15n). To a stirred solution of 4-[4-[1-ethyl-3-(4-nitrophenyl)-
7
2
1
extracts were dried (Na
ness under vacuum. The residue was purified by reverse phase
CN/0.1% TFA in H O) to give the TFA
2 4
SO ), filtered, and evaporated to dry-
4
HPLC (10-90% CH
3
2
(
salt which was basified with satd aq sodium bicarbonate,
extracted with three portions of dichloromethane, dried
1
2
H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-
-yl]benzaldehyde (15d, 300 mg, 0.52 mmol) in THF (5 mL) was
2 4
(Na SO ), filtered, and evaporated to dryness under vacuum
to give the product (17q, 62 mg, 39% yield) as a light-yellow
added pyrrolidine (148 mg, 2.1 mmol) followed by sodium
triacetoxyborohydride (441 mg, 2.1 mmol). The reaction was
stirred at room temperature for 20 h, quenched with water, and
diluted with ethyl acetate. The aqueous layer was extracted with
four portions of ethyl acetate and the combined extracts were
þ
1
solid. MS m/z 534.4 [M þ H] . H NMR (DMSO-d
) δ ppm
6
12.11 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.06 (d, J=4.0 Hz, 1H),
7.82 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0
Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.76 (s,
1H), 4.27 (q, J=8.0 Hz, 2H), 3.59 (bs, 2H), 2.91 (s, 6H), 2.44
(app bs, 4H), 1.71 (app bs, 4H), 1.51 (t, J=8.0 Hz, 3H). Anal.
dried (Na
ification of the residue by flash chromatography on silica gel
95:5 dichloromethane/5% ammonium hydroxide in methanol)
gave the product (15n, 308 mg, 93% yield) as a golden fluffy
2 4
SO ), filtered, and evaporated under vacuum. Pur-
(
35 7 2
(C32H N O 1.0H O) C, H, N.
3
4-[3-(4-N-Ethylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-4-
yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
idine (17r). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16e, 0.15 g, 0.31 mmol) in THF (5 mL)
þ
1
solid. MS m/z 633.4 [M þ H] . H NMR (400 MHz, DMSO-d
6
)
δ ppm 8.34 (s, 1 H), 8.30 (d, J=4.0 Hz, 1H), 8.11-8.17 (m, 2H),
.81-7.87 (m, 2H), 7.72 (t, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz,
H), 7.51-7.56 (m, 2H), 7.34-7.43 (m, 4H), 7.05 (d, J=4.0 Hz,
7
2

3
996 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
was added ethyl isocyanate (50 uL, 0.63 mmol) and two drops of
triethylamine. The reaction was stirred at room temperature for
2H), 2.37 (br s, 4H) 1.51 (t, J=7.33 Hz, 3H), 1.04 (t, J=7.07
Hz, 3H). MS m/z 550.4 [M þ H] . Anal. (C32
þ
H N O 1.5H O)
35 7 2
3
2
days and concentrated to dryness under vacuum. The remain-
C, H, N.
ing solid was triturated with (1:1) ethyl ether/petroleum ether,
filtered, and dried under vacuum. Purification of the residue by
reverse phase HPLC (10-90% CH CN/0.1% TFA in H O)
4-[3-(4-N,N-Dimethylcarbamylaminophenyl)-1-ethyl-1H-pyr-
azol-4-yl]-2-[4-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]-
pyridine (17u). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[4-(N-morpholinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16h, 105 mg, 0.22 mmol) in THF (2 mL)
was added p-nitrophenylchloroformate (50 mg, 0.25 mmol).
After stirring for 1 h at room temperature, a solution of 2.0 M
dimethylamine in THF (1.5 mL, 3 mmol) was added. The
reaction mixture was stirred an additional 1 h at room tempera-
ture and then concentrated under vacuum. The residue which
remained was triturated with 0.5N aq sodium hydroxide, fil-
tered, washed with cold water, and dried under vacuum. The
3
2
gave the TFA salt which was basified with 1N aq sodium
carbonate, extracted with dichloromethane, dried (MgSO4),
filtered, and evaporated to dryness under vacuum. The residue
was triturated with (1:1) ethyl ether/petroleum ether, filtered,
and dried under vacuum to give the product (17r, 71 mg, 0.13
1
mmol, 42% yield) as an off-white solid. H NMR (400 MHz,
DMSO-d
(
6
) δ ppm 12.15 (s, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 8.08
d, J=5.05 Hz, 1H), 7.74-7.81 (m, 2H), 7.40 (t, J=7.96 Hz, 1H),
7
6
7
7
.31-7.36 (m, 2H), 7.24-7.30 (m, 3H), 6.80 (d, J=5.05 Hz, 1H),
.73 (d, J=2.02 Hz, 1H), 6.11 (t, J=5.56 Hz, 1H), 4.26 (q, J=
.16 Hz, 2H), 3.59 (t, J=4.42 Hz, 4H), 3.51 (s, 2H), 3.09 (dd, J=
residue was purified by reverse phase HPLC (10-90% CH
2
3
CN/
H O). Trituration of the residue with (1:1) ethyl ether/petroleum
ether, filtration, and drying under vacuum gave the product
.07, 5.81 Hz, 2H), 2.39 (br s, 4H), 1.51 (t, J=7.33 Hz, 3H), 1.04
þ
1
(17u, 95 mg, 0.17 mmol, 78% yield) as an off-white solid. H
(
t, J = 7.07 Hz, 3H). MS m/z 550.6 [M þ H] . Anal.
(
C
32
H
-[3-(4-N,N-Dimethylcarbamylaminophenyl)-1-ethyl-1H-pyr-
35
N
7
O 1.0H
3
2
O) C, H, N.
6
NMR (400 MHz, DMSO-d ) δ ppm 12.12 (br s, 1H), 8.32 (s,
4
1H), 8.25 (s, 1H), 8.06 (d, J=4.80 Hz, 1H), 7.83 (d, J=8.08 Hz,
2H), 7.42 (d, J=8.59 Hz, 2H), 7.37 (d, J=8.08 Hz, 2H), 7.27 (d,
J=8.59 Hz, 2H), 6.79 (d, J=5.05 Hz, 1H), 6.76 (s, 1H), 4.26 (q,
J=7.24 Hz, 2H), 3.59 (br s, 4H), 3.48 (s, 2H), 2.91 (s, 6H), 2.37
azol-4-yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]-
pyridine (17s). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (0.41 g, 0.85 mmol) in THF (10 mL) was
added p-nitrophenylchloroformate (207 mg, 1.0 mmol). The
reaction mixture quickly became a suspension. After stirring
for 1 h at room temperature, a solution of 2.0 M dimethyl-
amine in THF (6.0 mL, 12 mmol) was added. The reac-
tion was stirred an additional 1 h at room temperature
and then concentrated under vacuum. The residue which
remained was triturated with 0.5N aq sodium hydroxide,
filtered, washed with cold water, and dried under vacuum.
Purification of the residue by reverse phase HPLC (10-
þ
(br s, 4H), 1.51 (t, J=7.20 Hz, 3H). MS m/z 550.4 [M þ H] .
Anal. (C H N O 0.5H O) C, H, N.
3
2
35
7
3
2
Ethyl 1H-Pyrrolo[2,3-b]pyridine-2-carboxylate 7-Oxide (18).
Compound 18 was prepared as described in WO2000044753.
H NMR (400 MHz, CDCl -d) δ ppm 8.40 (d, J=6.32 Hz, 1H),
3
6
1
3
7.80 (d, J=7.33 Hz, 1H), 7.28 (s, 1H), 7.17 (dd, J=8.08, 6.32 Hz,
1H), 4.45 (q, J=7.07 Hz, 2H), 1.44 (t, J=7.07 Hz, 3H). MS m/z
þ
207.0 [M þ H] .
Ethyl 4-Bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (19).
To a stirred solution of ethyl 1H-pyrrolo[2,3-b]pyridine-2-car-
boxylate 7-oxide (4.35 g, 21 mmol) and tetrabutylammonium-
bromide (4.90 g, 31.8 mmol) in 1,2-dimethoxyethane (50 mL) at
0 ꢀC was added portionwise over 5 min methanesulfonic anhy-
dride (7.4 g, 42.5 mmol). The reaction was allowed to warm to
room temperature and stirred for 18 h. The reaction was
evaporated to dryness under vacuum, neutralized with cold
0.5N aq sodium bicarbonate in water, filtered, rinsed with cold
9
0% CH CN/0.1% TFA in H O) gave the TFA salt which
3 2
was basified with 1N aq sodium carbonate, extracted
with dichloromethane, dried (MgSO ), filtered, and evapo-
4
rated to dryness under vacuum. The residue was triturated
with (1:1) ethyl ether/petroleum ether, filtered, and dried
under vacuum to give the product (17s, 204 mg, 0.37 mmol,
1
4
DMSO-d
3% yield) as an off-white solid. H NMR (400 MHz,
) δ ppm 12.15 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H),
6
water, and dried under vacuum to give the product (6.20 g,
1
8
3
1
4
.08 (d, J=5.05 Hz, 1H), 7.74-7.81 (m, 2H), 7.37-7.45 (m,
100%) as a white solid. H NMR (400 MHz, DMSO-d ) δ ppm
6
H), 7.26-7.29 (m, 3H), 6.80 (d, J=4.80 Hz, 1H), 6.74 (d, J=
.77 Hz, 1H), 4.27 (q, J=7.24 Hz, 2H), 3.59 (t, J=4.29 Hz,
H), 3.51 (s, 2H), 2.91 (s, 6H), 2.39 (br s, 4H), 1.51 (t, J=7.20
12.97 (br s, 1H), 8.28 (d, J=5.05 Hz, 1H), 7.48 (d, J=5.05 Hz,
1H), 7.05 (d, J=2.02 Hz, 1H), 4.36 (q, J=7.07 Hz, 2H), 1.35 (t,
þ
J=7.07 Hz, 3H). MS m/z 269.2 [M þ H] .
þ
Hz, 3H). MS m/z 550.4 [M þ H] . Anal. (C32
H
35
N
7
O
4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]-
pyridine-2-carboxylic Acid (20). A solution of ethyl 4-bromo-
1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3.31 mmol), 1-ethyl-
3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1H-pyrazole (3.97 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (0.17 mmol) in 2 M aq potassium carbonate
solution (12 mL) and N,N-dimethylformamide (12 mL) was
stirred at 100 ꢀC for 17 h. The reaction mixture was cooled and
saturated aq ammonium chloride solution (20 mL) was added,
and the product was extracted with ethyl acetate (3 ꢀ 20 mL).
The combined organic layers were dried over magnesium sulfate
and concentrated in vacuo. Precipitation from ethyl acetate
3
1
.0H
4-[3-(4-N-Ethylcarbamylaminophenyl)-1-ethyl-1H-pyrazol-
-yl]-2-[4-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyr-
2
O) C, H, N.
(
4
idine (17t). To a stirred solution of 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-2-[4-(N-morpholinylmethyl)phenyl]-1H-
pyrrolo[2,3-b]pyridine (16h, 0.18 g, 0.37 mmol) in THF (10 mL)
was added ethyl isocyanate (50 μL, 0.63 mmol) and two drops of
triethylamine. The reaction was stirred at room temperature for
2
4 h and concentrated to dryness under vacuum. The remaining
solid was triturated with (1:1) ethyl ether/petroleum ether,
filtered, and dried under vacuum. Purification of the residue
1
by reverse phase HPLC (10-90% CH
gave the TFA salt which was basified with 1N aq sodium
carbonate, extracted with dichloromethane, dried (MgSO ),
3
CN/0.1% TFA in H
2
O)
afforded the title compound (20) as a yellow solid (81%). H
NMR (400 MHz, DMSO-d ) δ ppm 11.68 (s, 1H), 8.29 (s, 1H),
6
4
8.17 (dd, J=6.82, 1.77 Hz, 3H), 7.66 (d, J=8.59 Hz, 2H), 7.29 (br
s, 1H), 6.80 (d, J=4.80 Hz, 1H), 6.53 (s, 1H), 4.32 (q, J=7.16 Hz,
filtered, and evaporated to dryness under vacuum. The residue
was triturated with (1:1) ethyl ether/petroleum ether, filtered,
and dried under vacuum to give the product (17t, 138 mg, 0.25
þ
2H), 1.51 (t, 3H). MS m/z 378.2 [M þ H] .
4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-N-[2-(4-morpho-
linyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (21a). A
solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-
pyrrolo[2,3-b]pyridine-2-carboxylic acid (20, 0.212 mmol) and
1
mmol, 68% yield) as a white solid. H NMR (400 MHz, DMSO-
d
8
4
2
3
6
) δ ppm 12.12 (d, J=1.52 Hz, 1H), 8.47 (s, 1H), 8.25 (s, 1H),
.06 (d, J=4.80 Hz, 1H), 7.83 (d, J=8.34 Hz, 2H), 7.31-7.39 (m,
H), 7.23-7.30 (m, 2H), 6.78 (d, J=5.05 Hz, 1H), 6.75 (d, J=
.02 Hz, 1H), 6.11 (t, J=5.56 Hz, 1H), 4.26 (q, J=7.33 Hz, 2H),
.59 (t, J=4.42 Hz, 4H), 3.48 (s, 2H), 3.09 (dd, J=7.20, 5.68 Hz,
0
1,1 -carbonyldiimidazole (0.25 mmol) in anhydrous N,N-di-
methylformamide (1 mL) under nitrogen at room temperature
was stirred for 30 min. 4-(2-Aminoethyl)-morpholine (0.64 mmol)

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3997
DMSO-d ) δ ppm 12.09 (br s, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.43
was added to the mixture, and the reaction was stirred for 16.5 h at
room temperature. The reaction mixture was concentrated in
vacuo. Purification of the residue by reverse phase HPLC
(10-90% MeCN/0.1% NH OH in H O) afforded the title com-
4 2
pound (21a) as a white solid (15%). H NMR (400 MHz, DMSO-
6
(t, J=5.56 Hz, 1H), 8.20 (d, J=5.05 Hz, 1H), 8.18 (s, 1H), 7.44
(d, J=7.83 Hz, 2H), 7.37 (d, J=8.70 Hz, 2H), 7.24-7.32 (m,
4H), 7.03 (s, 1H), 6.96 (t, J=7.33 Hz, 1H), 6.83 (d, J=4.80 Hz,
1H), 4.26 (q, J=7.24 Hz, 2H), 3.25-3.31 (m, 2H), 2.31 (t, J=
7.26 Hz, 10H), 2.09 (s, 3 H), 1.66 (quin, J=7.20 Hz, 2H), 1.51 (t,
1
d6) δ ppm 12.20 (s, 1H), 8.36 (t, J=5.81 Hz, 1H), 8.28 (s, 1H), 8.27
þ
(
d, J=5.00 Hz, 1H), 8.16 (d, J=8.84 Hz, 2H), 7.64 (d, J=8.84 Hz,
J=7.20 Hz, 3H). MS m/z 606.6 [M þ H] .
2
2
6
H), 6.95 (s, 1H), 6.89 (d, J=4.80 Hz, 1H), 4.33 (q, J=7.33 Hz,
H), 3.55 (t, J=4.55 Hz, 4H), 3.35-3.41 (m, 2H), 2.36-2.47 (m,
4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-N-[2-(4-meth-
yl-1-piperazinyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide
(21c). A solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-
yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (20, 0.331 mmol),
2-(4-methyl-piperazin-1-yl)-ethylamine (0.993 mmol), and N-(3-
þ
H), 1.53 (t, J=7.33 Hz, 3H). MS m/z 490.4 [M þ H] .
4
-[1-Ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-1H-
pyrazol-4-yl]-N-[2-(4-morpholinyl)ethyl]-1H-pyrrolo[2,3-b]pyri-
dine-2-carboxamide (22a). To a mixture of 4-[1-ethyl-3-(4-nitro-
phenyl)-1H-pyrazol-4-yl]-N-[2-(4-morpholinyl)ethyl]-1H-pyrrolo-
0
dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (0.397
mmol) in anhydrous N,N-dimethylformamide (1 mL) under
nitrogen was stirred for 17 h at room temperature. The reaction
was concentrated in vacuo, and the residue was purified by reverse
phase HPLC (MeCN/0.1% NH OH in H O) to afford the title
[
2,3-b]pyridine-2-carboxamide (21a, 0.033 mmol) in 6N hydro-
chloric acid solution (1 mL) and ethanol (1 mL) under nitrogen at
room temperature was added tin powder (0.164 mmol). The
reaction was stirred at 70 ꢀC for 1 h and then cooled to room
temperature. The mixture was filtered through celite, and the fil-
trate was concentrated in vacuo to give 4-[3-(4-aminophenyl)-1-
ethyl-1H-pyrazol-4-yl]-N-[2-(4-morpholinyl)ethyl]-1H-pyrrolo[2,
4
2
compound (21c) as a solid (20%). This compound was used
directly in the next reaction without NMR characterization. MS
þ
m/z 503.4 [M þ H] .
4
-[1-Ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-1H-
3-b]pyridine-2-carboxamide as the crude HCl salt. LCMS showed
pyrazol-4-yl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-1H-pyrrolo-
2,3-b]pyridine-2-carboxamide (22c). To a mixture of 4-[1-ethyl-
-(4-nitrophenyl)-1H-pyrazol-4-yl]-N-[2-(4-methyl-1-piperazinyl)-
þ
m/z 460.4 [M þ H] and 100% purity (UV214). To a solution of
[
3
this crude product (0.033 mmol theoretical) in anhydrous pyridine
(0.5 mL) under nitrogen at room temperature was added phenyl
ethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (21c, 0.066 mmol)
in 6N hydrochloric acid solution (1 mL) and ethanol (1 mL) under
nitrogen at room temperature was added tin powder (0.33 mmol).
The reaction was stirred at 70 ꢀC for 1 h and then cooled to room
temperature. The mixture was filtered through celite, and the filtrate
was concentrated in vacuo to give 4-[3-(4-aminophenyl)-1-ethyl-
isocyanate (0.036 mmol). The reaction was stirred at room
temperature for 30 min and then concentrated in vacuo. Purifica-
tion of the residue by reverse phase HPLC (MeCN/H O þ 0.1%
2
4
NH OH) provided the title compound (22a) as a white solid
1
(
58%). H NMR (400 MHz, DMSO-d ) δ ppm 12.10 (br s, 1H),
6
8.71 (s, 1H), 8.69 (s, 1H), 8.37 (t, J=5.68 Hz, 1H), 8.21 (d, J=5.05
1H-pyrazol-4-yl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-1H-pyrrolo-
Hz, 1H), 8.18(s, 1H), 7.44(d, J=7.58Hz, 2H), 7.38(d, J=8.59 Hz,
H), 7.23-7.32 (m, 4H), 7.04 (s, 1H), 6.96 (t, J=7.33 Hz, 1H), 6.83
d, J=4.80 Hz, 1H), 4.27 (q, J=7.33 Hz, 2H), 3.56 (t, J=4.55 Hz,
[
2,3-b]pyridine-2-carboxamide as the crude HCl salt. LCMS
2
(
þ
showed m/z 473.4 [M þ H] and 100% purity (UV214). To a
solution of this crude product (0.066 mmol theoretical) in anhy-
drous pyridine (0.5 mL) under nitrogen at room temperature was
added phenyl isocyanate (0.072 mmol). The reaction was stirred at
room temperature for 30 min and left to stand overnight. The
reaction mixture was concentrated in vacuo. Purification of the
residue by reverse phase HPLC (MeCN/H O þ 0.1% NH OH)
4
H), 3.37-3.43 (m, 2H), 2.36-2.48 (m, 6H), 1.51 (t, J=7.20 Hz,
þ
3H). MS m/z 579.6 [M þ H] .
4-[1-Ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-N-[3-(4-methyl-
-piperazinyl)propyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide
1
(21b). A solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-
yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (20, 0.265 mmol),
2
4
1
provided the title compound (22c) as a white solid (52%). H NMR
[
3-(4-methyl-1-piperazinyl)propyl]amine (0.795 mmol), and N-(3-
0
(400 MHz, DMSO-d
(
6
) δ ppm 12.11 (br s, 1H), 8.72 (br s, 1H), 8.70
s, 1H), 8.35 (t, J=5.56 Hz, 1H), 8.21 (d, J=4.80 Hz, 1H), 8.17 (s,
dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (0.318
mmol) in anhydrous N,N-dimethylformamide (1 mL) under
nitrogen was stirred at room temperature over the weekend.
LCMS showed that 41% of the starting material was still present.
The reaction was concentrated in vacuo and the residue was
1
H), 7.44 (d, J=7.83 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.22-7.34
(
m, 4H), 7.04 (s, 1H), 6.96 (t, J=7.60 Hz, 1H), 6.83 (d, J=4.80 Hz,
1
H), 4.27 (q, J=7.24 Hz, 2H), 3.35-3.44 (m, 4H), 2.22-2.48 (m,
þ
8H), 2.13 (s, 3H), 1.51 (t, J=7.33 Hz, 3H). MS m/z592.4 [M þ H] .
purified by reverse phase HPLC (5-75% MeCN/0.1% NH
4
OH
[
4-(4-Bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]amine. In a sealed
in H O, 15 min) to afford the title compound (21b) as a solid
(19%). This compound was used directly in the next reaction
2
tube, a mixture of 4-bromo-1-ethyl-3-(4-nitrophenyl)-1H-pyra-
zole (7b, 7.63 mmol) and tin powder (38.16 mmol) in 6N HCl (25
mL) and ethanol (25 mL) was stirred at 70 ꢀC for 1 h. The reaction
mixture was cooled to room temperature, filtered through celite,
and concentrated in vacuo. The residue was treated with ethyl
acetate (30 mL) and neutralized using saturated aq sodium
bicarbonate solution. The organic layer was dried over magne-
sium sulfate and concentrated in vacuo to give the title compound
þ
without NMR characterization. MS m/z 517.4 [M þ H] .
4
-[1-Ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-1H-
pyrazol-4-yl]-N-[3-(4-methyl-1-piperazinyl)propyl]-1H-pyrrolo-
2,3-b]pyridine-2-carboxamide (22b). To a mixture of 4-[1-ethyl-
-(4-nitrophenyl)-1H-pyrazol-4-yl]-N-[3-(4-methyl-1-piperazinyl)-
[
3
propyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (21b, 0.05
mmol) in 6N hydrochloric acid solution (1 mL) and ethanol
(
1 mL) under nitrogen at room temperature was added tin
as a solid. This crude product was used as is in the next reaction.
1
powder (0.25 mmol). The reaction was stirred at 70 ꢀC for 1 h
and then filtered through celite. The filtrate was concentrated in
vacuo to give 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-
N-[3-(4-methyl-1-piperazinyl)propyl]-1H-pyrrolo[2,3-b]pyri-
H NMR (400 MHz, DMSO-d ) δ ppm 7.98 (s, 1H), 7.48 (d, J=
6
8.59 Hz, 2H), 6.60 (d, J=8.34 Hz, 2H), 5.26 (s, 2H), 4.11 (q, J=
7.33 Hz, 2H), 1.38 (t, J=7.33 Hz, 3H). MS m/z 266.0 [M þ H] .
þ
0
N-[4-(4-Bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N -phenyl-
dine-2-carboxamide as the crude HCl salt. LCMS showed m/z
4
urea (10c). To a solution of [4-(4-bromo-1-ethyl-1H-pyrazol-3-
yl)phenyl]amine (7.63 mmol) in anhydrous pyridine (30 mL)
under nitrogen was added phenyl isocyanate (8.39 mmol). The
reaction was stirred at room temperature for 1 h and then
concentrated in vacuo. The residue was triturated with ethyl
þ
87.4 [M þ H] , and 100% purity (UV214). To a solution of this
crude product (0.05 mmol max) in anhydrous pyridine (0.5 mL)
under nitrogen at room temperature was added phenyl isocya-
nate (0.055 mmol). The reaction was stirred at room tempera-
ture for 30 min and left to stand overnight. The reaction mixture
was concentrated in vacuo. Purification of the residue by reverse
acetate to give the title compound (10c) as an off-white solid
1
(63% over 2 steps). H NMR (400 MHz, DMSO-d ) δ ppm 8.80
6
phase HPLC (MeCN/H
compound (22b) as a white solid (15%). H NMR (400 MHz,
2
O þ 0.1% NH
4
OH) provided the title
(s, 1H), 8.71 (s, 1H), 8.07 (s, 1H), 7.74 (m, J=8.59 Hz, 2H), 7.53
(m, J=8.59 Hz, 2H), 7.47 (d, J=7.58 Hz, 2H), 7.29 (t, J=7.96
1

3
998 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
Hz, 2H), 6.98 (t, J=7.33 Hz, 1H), 4.16 (q, J=7.33 Hz, 2H), 1.40
(
solution (0.29 mmol) in methanol (1 mL) was stirred at 70 ꢀC for
1 h. The reaction was cooled to room temperature and concen-
trated in vacuo. Purification of the residue by reverse phase
þ
t, J=7.20 Hz, 3H). MS m/z 385.0 [M þ H] .
4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-car-
baldehyde (24). n-Butyllithium (2.5 M in hexanes, 3.56 mmol) was
added dropwise to a solution of diisopropylamine (3.56 mmol) in
anhydrous THF (5 mL) at -78 ꢀC under nitrogen. The reaction
was stirred for 30 min at -78 ꢀC, and then a solution of 4-bromo-
HPLC (10-90% MeCN/0.1% NH
title compound as a white solid (24%). H NMR (400 MHz,
DMSO-d ) δ ppm 11.54 (s, 1H), 8.77 (br s, 1H), 8.74 (br s, 1H),
4 2
OH in H O) provided the
1
6
8.13 (s, 1H), 8.04 (d, J=4.80 Hz, 1H), 7.45 (d, J=8.08 Hz, 2H),
7.37 (d, J=8.59 Hz, 2H), 7.24-7.31 (m, 4H), 6.96 (t, J=7.33 Hz,
1H), 6.79 (d, J=5.05 Hz, 1H), 6.05 (d, J=1.01 Hz, 1H), 4.25 (q,
J=7.33 Hz, 2H), 3.46 (s, 2H), 2.12 (s, 6H), 1.49 (t, J=7.20 Hz,
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.97 mmol) in an-
hydrous THF (1 mL) was added dropwise by syringe. The
resulting reaction was stirred at -78 ꢀC for 2 h and then a solution
of N,N-dimethylformamide (11.88 mmol) in THF (1 mL) was
added dropwise by syringe. The reaction was stirred at -78 ꢀC for
þ
3H). MS m/z 480.4 [M þ H] .
2-({[4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-
methyl}amino)ethanol (25b). A solution of 4-bromo-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (24, 0.55
mmol), ethanolamine (1.1 mmol), and sodium triacetoxyboro-
hydride (1.1 mmol) in dichloromethane (4 mL) and acetic acid
(1 mL) under nitrogen was stirred at room temperature for 30
min. The reaction was quenched with 1N sodium hydroxide
solution (5 mL) and extracted with ethyl acetate (3 ꢀ 5 mL). The
combined organic layers were washed with brine (5 mL), dried
over magnesium sulfate, and concentrated in vacuo to provide
crude product as the title compound (25b). This crude product
was used as is in the next reaction without further characteriza-
2
h and then quenched with saturated aq ammonium chloride
solution (10 mL). The mixture was extracted with ethyl acetate
(
2 ꢀ 20 mL), and the combined organic layers were dried over
magnesium sulfate and concentrated in vacuo. Purification of the
residue by silica gel chromatography (Analogix IF280, 70-100%
CH Cl /hexanes) afforded the title compound (24) as a white solid
2
2
1
(
(
7
6
66%). H NMR (400 MHz, DMSO-d ) δ ppm 10.45 (s, 1H), 8.45
d, J=5.30 Hz, 1H), 8.24 (d, J=8.34 Hz, 2H), 7.72-7.90 (m, 2H),
þ
.59-7.72 (m, 2H), 7.46 (s, 1H). MS m/z 365.0 [M þ H] .
{
[4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-
methyl}dimethylamine (25a). A solution of 4-bromo-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (24, 0.55
mmol), dimethylamine (1.1 mmol, 2 M solution in tetrahydro-
furan), and sodium triacetoxyborohydride (1.1 mmol) in di-
chloromethane (4 mL) and acetic acid (1 mL) under nitrogen
was stirred at room temperature for 30 min. The reaction was
quenched with 1N sodium hydroxide solution (5 mL) and
extracted with ethyl acetate (3 ꢀ 5 mL). The combined organic
layers were washed with brine (5 mL), dried over magnesium
sulfate, and concentrated in vacuo. Purification of the residue
by silica gel chromatography (Analogix IF280, 0-10% MeOH/
þ
tion. MS m/z 409.2 [M þ H] .
N-(4-{1-Ethyl-4-[2-{[(2-hydroxyethyl)amino]methyl}-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-
0
N -phenylurea (27b). A suspension of 2-({[4-bromo-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}amino)ethanol
(25b, 0.55 mmol), bis(pinacolato)diboron (0.66 mmol), potas-
0
sium acetate (1.64 mmol), and dichloro[1,1 -bis(diphenylphos-
phino)ferrocene]palladium(II) dichloromethane adduct (0.02
mmol) in anhydrous 1,4-dioxane (3 mL) was stirred at 90 ꢀC
for 16 h. The reaction was cooled to room temperature, filtered
through celite, washed with dioxane, and concentrated in vacuo
CH
terial and the title product (25a) as a solid (46%). H NMR
400 MHz, DMSO-d ) δ ppm 7.43-7.50 (m, 2H), 7.33-7.40 (m,
2 2 4
Cl with 10% NH OH) afforded recovered starting ma-
1
þ
to give the boronic ester. LCMS showed [M þ H] =375.2 for
(
6
the boronic acid because the ester cleaves to the acid due to the
presence of TFA in the LCMS mobile phase. A solution of this
crude boronic ester (0.55 mmol), N-[4-(4-bromo-1-ethyl-1H-
1
H), 6.84 (t, J=7.71 Hz, 1H), 6.71-6.77 (m, 2H), 6.66-6.70
(
3
m, 1H), 5.88 (br s, 1H), 3.16 (br s, 2H), 1.52 (s, 6H). MS m/z
94.2 [M þ H] .
þ
0
pyrazol-3-yl)phenyl]-N -phenylurea (10c, 0.46 mmol), and
N-(4-{4-[2-[(Dimethylamino)methyl]-1-(phenylsulfonyl)-1H-
tetrakis(triphenylphosphine)palladium(0) (0.02 mmol) in
saturated aq sodium bicarbonate solution (1.37 mmol) and
N,N-dimethylformamide (5 mL) was stirred at 100 ꢀC for 5 h.
The reaction mixture was cooled to room temperature, and
water (10 mL) and ethyl acetate (10 mL) were added. The
layers were separated, and the organic layer was washed with
brine (10 mL), dried over magnesium sulfate, and concen-
trated in vacuo. Purification of the residue by reverse phase
0
pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N -
phenylurea (27a). A suspension of {[4-bromo-1-(phenylsul-
fonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}dimethylamine (25a,
0
.25 mmol), bis(pinacolato)diboron (0.30 mmol), potassium acet-
0
ate (0.76 mmol), and dichloro[1,1 -bis(diphenylphosphino)ferro-
cene]palladium(II) dichloromethane adduct (0.01 mmol) in anhy-
drous 1,4-dioxane (2 mL) was stirred at 90 ꢀC for 16 h. The
reaction was cooled to room temperature, filtered through celite,
washed with dioxane, and concentrated in vacuo to give the
HPLC (10-90% MeCN/H
2
O þ 0.1% NH
4
OH) provided
the title compound (27b, 52%). This product was used in the
next reaction without further characterization. MS m/z 636.4
þ
boronic ester. LCMS showed [M þ H] =359.2 for the boronic
þ
acid because the ester cleaves to the acid due to the presence of
TFA in the LCMS solvent mixture. A solution of this crude
boronic ester (0.25 mmol), N-[4-(4-bromo-1-ethyl-1H-pyrazol-3-
[M þ H] .
N-{4-[1-Ethyl-4-(2-{[(2-hydroxyethyl)amino]methyl}-1H-pyr-
0
rolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-N -phenylurea
(28b). A solution of N-(4-{1-ethyl-4-[2-{[(2-hydroxyethyl)amino]-
methyl}-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyr-
0
yl)phenyl]-N -phenylurea (10c, 0.21 mmol), and tetrakis-
(triphenylphosphine) palladium(0) (0.01 mmol) in saturated aq
0
sodium bicarbonate solution (0.64 mmol, assume 1 M solution)
and N,N-dimethylformamide (2 mL) was stirred at 100 ꢀC for 17 h.
The reaction mixture was cooled to room temperature, and water
azol-3-yl}phenyl)-N -phenylurea (27b, 0.24 mmol) and 6N sodi-
um hydroxide solution (0.71 mmol) in methanol (1 mL) was
stirred at 70 ꢀC for 1 h. The reaction was cooled to room tem-
perature and concentrated in vacuo. Purification of the residue
(5 mL) and ethyl acetate (5 mL) were added. The layers were
separated and the organic layer was washed with brine (5 mL),
dried over magnesium sulfate, and concentrated in vacuo. Purifi-
cation of the residue by reverse phase HPLC (10-90% MeCN/
by reverse phase HPLC (10-90% MeCN/0.1% NH
OH in
4
H
2
O) provided the title compound (28b) as a tan solid (14%).
1
6
H NMR (400 MHz, DMSO-d ) δ ppm 11.48 (s, 1H), 8.75 (br s,
H
2
O þ 0.1% NH
4
OH) provided the title compound (27a, 45%).
1H), 8.73 (br s, 1H), 8.12 (s, 1H), 8.01 (d, J=4.80 Hz, 1H), 7.45
(d, J=7.58 Hz, 2H), 7.37 (d, J=8.84 Hz, 2H), 7.21-7.32 (m,
4H), 6.96 (t, J=7.07 Hz, 1H), 6.75 (d, J=5.05 Hz, 1H), 6.16 (s,
1H), 4.45 (t, J=5.43 Hz, 1H), 4.25 (q, J=7.49 Hz, 2H), 3.79 (s,
2H), 3.44 (q, J=5.56 Hz, 3H), 2.08 (br s, 1H), 1.49 (t, J=7.20 Hz,
This product was 100% pure by LCMS and was used without
further characterization. MS m/z 620.6 [M þ H] .
þ
N-[4-(4-{2-[(Dimethylamino)methyl]-1H-pyrrolo[2,3-b]pyr-
0
idin-4-yl}-1-ethyl-1H-pyrazol-3-yl)phenyl]-N -phenylurea (28a).
A solution of N-(4-{4-[2-[(dimethylamino)methyl]-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-
þ
3H). MS m/z 496.4 [M þ H] .
N-(4-{4-[2-Formyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyr-
0
0
yl}phenyl)-N -phenylurea (0.1 mmol) and 6N sodium hydroxide
idin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N -phenylurea (26). A

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 3999
suspension of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri-
dine-2-carbaldehyde (24, 1.31 mmol), bis(pinacolato)diboron
reaction was quenched with 1N sodium hydroxide solution
(5 mL) and extracted with ethyl acetate (3 ꢀ 5 mL). The
combined organic layers were washed with brine (5 mL), dried
over magnesium sulfate, and concentrated in vacuo. Purifica-
tion of the residue by silica gel chromatography (Analogix
IF280, 25-80% ethyl acetate/hexanes) afforded recovered
0
(1.57 mmol), potassium acetate (3.92 mmol), and dichloro[1,1 -
bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane
adduct (0.05 mmol) in anhydrous 1,4-dioxane (13 mL) was stirred
at 90 ꢀC for 18 h. The reaction was cooled to room temperature
and quenched with saturated aq ammonium chloride solution (10
mL). The mixture was extracted with ethyl acetate (2 ꢀ 20 mL),
and the combined organic layers were dried over magnesium
sulfate and concentrated in vacuo to give 1-(phenylsulfonyl)-
starting material and the title product (25c) as a solid (34%).
1
6
H NMR (400 MHz, DMSO-d ) δ ppm 8.20 (s, 1H), 8.18 (dd, J=
3.28, 1.77 Hz, 2H), 7.73 (t, J=7.45 Hz, 1H), 7.62 (t, J=7.83 Hz,
2H), 7.57 (d, J=5.31 Hz, 1H), 6.77 (s, 1H), 4.25 (d, J=5.31 Hz,
2H), 3.05 (s, 3H), 3.01-3.08 (m, 2H), 2.62-2.69 (m, 1H). MS m/
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]-
þ
pyridine-2-carbaldehyde as the crude product. MS m/z 330.2 [M þ
z 472.2 [M þ H] .
þ
H] for boronic acid because the ester cleaves to the acid due to the
N-(4-{1-Ethyl-4-[2-({[2-(methylsulfonyl)ethyl]amino}methyl)-
-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-
yl}phenyl)-N -phenylurea (27d). To a suspension of N-{[4-bro-
mo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}-
1
presence of TFA in the LCMS mobile phase. A solution of this
crude 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.33 mmol),
0
0
2
-(methylsulfonyl)ethanamine (25c, 0.23 mmol), bis(pinaco-
lato)diboron (0.28 mmol), potassium acetate (0.69 mmol), and
N-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N -phenylurea
(
1.21 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.06
0
dichloro[1,1 -bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (0.01 mmol) in anhydrous 1,4-dioxane
mmol) in saturated aq sodium bicarbonate solution (3.63 mmol,
assume 1 M solution) and N,N-dimethylformamide (6 mL) was
stirred at 100 ꢀC for 17 h. The reaction mixture was cooled to
room temperature, and water (5 mL) and ethyl acetate (10 mL) were
added. The layers were separated, and the organic layer was washed
with brine (10 mL), dried over magnesium sulfate, and concentrated
in vacuo. Purification of the residue by silica gel chromatography
(
2 mL) was stirred at 90 ꢀC for 16 h. The reaction was cooled to
room temperature, filtered through celite, washed with dioxane,
and concentrated in vacuo to give the boronic ester. LCMS
þ
showed [M þ H] =437.4 for the boronic acid because the ester
cleaves to the acid due to the presence of TFA in the LCMS
mobile pahase. A solution of this crude boronic ester (0.23
(
Analogix IF280, 15-100% ethyl acetate/hexanes) afforded the title
þ
0
mmol), N-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N -phenyl-
product (26, 21%). MS m/z 591.4 [M þ H] .
urea (10c, 0.19 mmol), and tetrakis(triphenylphosphine)palla-
dium(0) (0.01 mmol) in saturated aq sodium bicarbonate solu-
tion (0.58 mmol, assume 1 M solution) and N,N-dimethylform-
amide (2 mL) was stirred at 100 ꢀC for 17 h. The reaction mixture
was cooled to room temperature, and water (5 mL) and ethyl
acetate (10 mL) were added. The layers were separated and
the organic layer was washed with brine (10 mL), dried
over magnesium sulfate, and concentrated in vacuo. Purifica-
tion of the residue by reverse phase HPLC (10-90% MeCN/
N-(4-{4-[2-({[2-(Dimethylamino)ethyl]amino}methyl)-1-(phenyl-
sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}-
0
phenyl)-N -phenylurea (27c). A solution of N-(4-{4-[2-formyl-
1
-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-
0
pyrazol-3-yl}phenyl)-N -phenylurea (26, 0.1 mmol), (2-aminoethyl)-
dimethylamine (0.2 mmol), and sodium triacetoxyborohydride (0.2
mmol) in dichloromethane (1 mL) and acetic acid (0.25 mL) under
nitrogen was stirred at room temperature for 30 min. The reaction
was quenched with 1N sodium hydroxide solution (5 mL) and
extracted with ethyl acetate (3 ꢀ 5 mL). The combined organic
layers were washed with brine (5 mL), dried over magnesium sulfate,
and concentrated in vacuo to give the title compound as the crude
product (27c). This crude product was used as is without NMR
H
2
O þ 0.1% NH
4
OH) provided the title compound (27d, 46%),
which was used as is without NMR characterization. MS m/z
698.4 [M þ H] .
þ
N-(4-{1-Ethyl-4-[2-({[2-(methylsulfonyl)ethyl]amino}methyl)-
0
þ
characterization in the next reaction. MS m/z 663.4 [M þ H] .
1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N -phe-
nylurea (28d). A solution of N-(4-{1-ethyl-4-[2-({[2-(methyl-
sulfonyl)ethyl]amino}methyl)-1-(phenylsulfonyl)-1H-pyrrolo-
LCMS purity 93%.
N-(4-{4-[2-({[2-(Dimethylamino)ethyl]amino}methyl)-1H-
0
0
pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N -
phenylurea (28c). To a solution of N-(4-{4-[2-({[2-(dimethyl-
amino)ethyl]amino}methyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,
[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N -phenylurea (27d,
0.09 mmol) and 6N sodium hydroxide solution (0.27 mmol) in
methanol (1 mL) was stirred at 70 ꢀC for 1 h. The reaction was
cooled to room temperature and concentrated in vacuo. Purifica-
tion of the residue by reverse phase HPLC (10-90% MeCN/0.1%
0
3
-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N -phenyl-
urea (27c, 0.1 mmol) and 6N sodium hydroxide solution (0.3
mmol) in methanol (1 mL) was stirred at 70 ꢀC for 1 h. The
reaction was cooled to room temperature and concentrated in
vacuo. Purification of the residue by reverse phase HPLC
NH
OH in H
O) provided the title compound (28d) as a tan solid
4
2
1
(28%). H NMR (400 MHz, DMSO-d
) δ ppm 11.49 (s, 1H), 8.79
6
(br s, 1H), 8.77 (br s, 1H), 8.12 (s, 1H), 8.02 (d, J=5.05 Hz, 1H),
7.45 (d, J=8.08 Hz, 2H), 7.38 (d, J=8.36 Hz, 2H), 7.24-7.32 (m,
4H), 6.96(t, J=7.45Hz, 1H), 6.76(d, J=5.05Hz, 1H), 6.19(s, 1H),
4.25 (q, J=7.33 Hz, 2H), 3.80 (br s, 2H), 3.22 (t, J=6.44 Hz, 2H),
3.00 (s, 3H), 2.84-2.90 (m, 2H), 2.37 (br s, 1H), 1.49 (t, J=7.20 Hz,
(
2
MeCN/0.1% TFA in H O) provided the desired product. The
product from purification was neutralized using saturated aq
sodium bicarbonate solution. The product was extracted with
ethyl acetate (2 ꢀ 10 mL). The organic layers were combined,
dried over magnesium sulfate, and concentrated in vacuo to give
þ
3H). MS m/z 558.4 [M þ H] .
1
the title compound as a white solid (28c, 5%). H NMR (400
N-(4-{1-Ethyl-4-[2-({[2-(4-morpholinyl)ethyl]amino}methyl)-
1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-
MHz, DMSO-d
H), 8.04 (d, J=4.80 Hz, 1H), 7.45 (d, J=8.08 Hz, 2H), 7.37 (d,
6
) δ ppm 11.54 (s, 1H), 8.86 (br s, 2H), 8.13 (s,
0
1
3-yl}phenyl)-N -phenylurea (27e). A solution of N-(4-{4-[2-for-
myl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-
J=8.59 Hz, 2H), 7.21-7.34 (m, 4H), 6.92-6.99 (m, 1H), 6.79 (d,
J=4.80 Hz, 1H), 6.06 (s, 1H), 4.25 (q, J=6.74 Hz, 2H), 3.55 (s,
0
1H-pyrazol-3-yl}phenyl)-N -phenylurea (26, 0.1 mmol), 4-(2-
2
7
H), 2.29-2.43 (m, 5H), 2.24 (s, 3H), 2.09 (s, 3H), 1.49 (t, J=
aminoethyl)-morpholine (0.2 mmol), and sodium triacetoxy-
borohydride (0.2 mmol) in dichloromethane (1 mL) and acetic
acid (0.25 mL) under nitrogen was stirred at room temperature
for 30 min. The reaction was quenched with 1N sodium hydro-
xide solution (5 mL) and extracted with ethyl acetate (3 ꢀ 5 mL).
The combined organic layers were washed with brine (5 mL),
dried over magnesium sulfate, and concentrated in vacuo to
give the title compound (27e) as the crude product. MS m/z
þ
.20 Hz, 3H). MS m/z 523.4 [M þ H] .
N-{[4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-
methyl}-2-(methylsulfonyl)ethanamine (25c). A solution of
-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-car-
4
baldehyde (24, 0.685 mmol), 2-aminoethylmethylsulfone hydro-
chloride (1.37 mmol), and sodium triacetoxyborohydride (1.37
mmol) in dichloromethane (4 mL) and acetic acid (1 mL) under
nitrogen was stirred at room temperature for 30 min. The
þ
705.6 [M þ H] .

4
000 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10
Adams et al.
N-(4-{1-Ethyl-4-[2-({[2-(4-morpholinyl)ethyl]amino}methyl)-
0
MHz, DMSO-d
6
) δ ppm 11.43 (br s, 1H), 8.87 (br s, 2H), 8.10 (s,
1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N -phe-
nylurea (28e). A solution of N-(4-{1-ethyl-4-[2-({[2-(4-mor-
1H), 8.01 (d, J=4.80 Hz, 1H), 7.45 (d, J=7.58 Hz, 2H), 7.38 (d,
J=8.34 Hz, 2H), 7.23-7.31 (m, 4H), 6.96 (t, J=7.45 Hz, 1H),
6.76 (d, J=4.55 Hz, 1H), 6.11 (s, 1H), 4.24 (q, J=7.16 Hz, 2H),
3.74 (br s, 2H), 2.09-2.47 (m, 13H), 2.08 (s, 3H), 1.51-1.60 (m,
pholinyl)ethyl]amino}methyl)-1-(phenylsulfonyl)-1H-pyrrolo-
0
[
(
2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N -phenylurea
27e, 0.1 mmol) and 6N sodium hydroxide solution (0.3 mmol)
þ
2H), 1.49 (t, J=7.33 Hz, 3H). MS m/z 592.4 [M þ H] .
in methanol (1 mL) was stirred at 70 ꢀC for 1 h. The reaction was
cooled and concentrated in vacuo. Purification of the residue by
Biology. Biochemical Characterization of Aurora Inhibitors.
Experimental details describing the (1) in vitro Aurora B/IN-
CENP, Aurora C/INCENP and Aurora A/TPX2 inhibition as-
says for IC50 determination, (2) determination of dissociation rates
of 12c, 17a, 17c, 17j, and 17k from human Aurora B/INCENP by
rapid dilution, and (3) Aurora B/INCENP, Aurora C/INCENP,
reverse phase HPLC (MeCN/0.1% TFA in H
subsequent purification by reverse phase HPLC (MeCN/0.1%
NH O) provided the title compound (28e) as a white
OH in H1
solid (10%). H NMR (400 MHz, DMSO-d ) δ ppm 11.50 (s,
H), 8.91 (br s, 2H), 8.11 (s, 1H), 8.02 (d, J=4.80 Hz, 1H), 7.45
d, J=7.83 Hz, 2H), 7.37 (d, J=8.59 Hz, 2H), 7.23-7.30 (m,
2
O) followed by
4
2
6
1
(
4
1
4
and Aurora A/TPX2 K
* determination of 17k by progress curve
i
30,34
analysis are described in separate publications.
H), 6.95 (t, J=7.20 Hz, 1H), 6.76 (d, J=5.05 Hz, 1H), 6.10 (s,
Tissue Culture and in Vivo Studies. Details of the cellular
proliferation (A549 cells) and in vivo pharmacodynamic and
efficacy in tumor xenograft studies are described in a separate
H), 4.24 (q, J=7.07 Hz, 2H), 3.77 (br s, 2H), 3.52 (t, J=4.42 Hz,
H), 2.68 (dt, J=3.73, 1.80 Hz, 1H), 2.17-2.40 (m, 8H), 1.49 (t,
3
7
þ
publication.
J=7.33 Hz, 3H). MS m/z 565.4 [M þ H] .
N-{[4-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-
methyl}-3-(4-methyl-1-piperazinyl)-1-propanamine (25d). A so-
lution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri-
dine-2-carbaldehyde (24, 0.55 mmol), 1-(3-aminopropyl)-4-
methylpiperazine (1.1 mmol), and sodium triacetoxyborohy-
dride (1.1 mmol) in dichloromethane (4 mL) and acetic acid
Supporting Information Available: Liquid chromatography-
mass spectrometry purities and retention times for all tested
compounds. Full combustion analysis results for 17a-d, 17f-i,
1
7k-l, 17n-o, and 17q-u. Statistical limits for biological data
in Tables 1-3. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
1 mL) under nitrogen was stirred at room temperature for 30
min. The reaction was quenched with 1N sodium hydroxide
solution (5 mL) and extracted with ethyl acetate (3 ꢀ 5 mL). The
combined organic layers were washed with brine (5 mL), dried
over magnesium sulfate, and concentrated in vacuo. Purifica-
tion of the residue by silica gel chromatography (Analogix
IF280, 0-10% MeOH/CH Cl with 10% NH OH) afforded
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þ
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(
(
0.02 mmol) in saturated aq sodium bicarbonate solution
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N -phenylurea (28f). A solution of N-(4-{1-ethyl-4-[2-({[3-(4-
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0
1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N -phe-
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(
compound (28f) as a light-brown solid (42%). H NMR (400
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Article
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