Design and synthesis of a novel tyrosine kinase inhibitor template

Article abstract of DOI:10.1016/j.bmc.2009.03.046

We report the design and synthesis of an insulin receptor kinase family-targeted inhibitor template using the inhibitor conformation observed in an IGF1R/inhibitor co-crystal complex by application of a novel molecular design approach that we have recentl

Full text of DOI:10.1016/j.bmc.2009.03.046

Bioorganic & Medicinal Chemistry 17 (2009) 3308–3316
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design and synthesis of a novel tyrosine kinase inhibitor template
P. Jake Slavish a, Qin Jiang b, Xiaoli Cui b, Stephan W. Morris b,c, Thomas R. Webb a,
*
a Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, United States
b Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, United States
c Department of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the design and synthesis of an insulin receptor kinase family-targeted inhibitor template using
the inhibitor conformation observed in an IGF1R/inhibitor co-crystal complex by application of a novel
molecular design approach that we have recently published. The synthesis of the template involves a
one pot Opatz cyclization reaction that provides a versatile indole ester in good yields. We also developed
the required chemistry to elaborate this template with additional substituents and have used this chem-
istry to prepare some initial compounds that show selective inhibition of anaplastic lymphoma kinase
(ALK).
Received 15 January 2009
Revised 18 March 2009
Accepted 21 March 2009
Available online 27 March 2009
Keywords:
Anaplastic lymphoma kinase
ALK
Ó 2009 Elsevier Ltd. All rights reserved.
De novo ligand design
Kinase template synthesis
Insulin receptor kinase family
Inhibitor design
1. Introduction
inhibitor template as well as the synthesis of a partially elaborated
template and initial activity data.
Often the discovery of new lead structures for drug discovery
projects starts from active molecules (hits) that are found from
the screening of compound libraries using in vitro assays or cell-
based high-throughput screening. However, in some cases, it is
possible to design ‘hits’ if sufficient information is available. We
have recently published a detailed report on a novel and general
method for de novo protein ligand design that uses pharmaco-
phore-based geometry queries, or other similar information, to
search virtual hydrocarbon databases for rigid frameworks that
match the geometry of the query.1 These new frameworks can then
be used as starting points in the design of new structures that con-
tain the constrained pharmacophore interaction features.1 One of
the general applications of this design method makes use of a phar-
macophore query derived from the bound conformation of an
Using the general published approach,1 we searched a virtual
framework library (VFL) using the pharmacophore shown in Figure
1, which was derived from a co-crystal structure of a ligand bound
to the non-activated IGF1R kinase domain.2 We utilized a pharma-
cophore with all of the interaction features converted to hydropho-
bic for the initial search of the VFL, as previously described.1–3 This
search yielded a large number of polycyclic framework hits that
were then subjected to selection based on synthetic and medicinal
chemistry expertise. This led to the selection of framework hit 1a
(see Fig. 2) since it was a close match to four of the five features
and also had a synthetically attractive framework. We then tar-
geted the synthesis of compounds containing this core template
as a starting point for the design of selective inhibitors of relevant
oncogenic tyrosine kinases in the insulin receptor superfamily by
the stabilization of the inactive form of their kinase domains.
inhibitor, as observed in a protein-inhibitor crystal structure.2
A
specific application of this approach to the inactive form of an
oncogenic tyrosine kinase has previously been presented.3 The
development of new inhibitors of certain tyrosine kinases in the
insulin receptor superfamily is of great interest since compounds
that demonstrate an appropriate inhibition selectivity profile show
promise as potential drugs for the treatment of human malignan-
cies caused by specific gain-of-function oncogenic kinase muta-
tions.4–8 We report here details of the design of a novel kinase
2. Results
As outlined in our retrosynthetic plan (Fig. 3) the synthesis of
tetracyclic pyridone 1 can start with compounds such as ester 4/
5, which can be prepared from commercially available 2-iodoani-
line (or 5-chloro-2-iodoaniline, Scheme 1) by iodo-vinyl exchange
using phosphine-free, thermal Heck conditions9 in 86/92%
yield. Treatment of the resulting ester 4/5 with aldehyde 6 (made
from the commercially available ester)10 using modified Opatz
conditions11,12 provided the indole ester 7/8 in 73/68% yield.
* Corresponding author. Tel.: +1 901 595 3928; fax: +1 901 595 5715.
E-mail address: thomas.webb@stjude.org (T.R. Webb).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.03.046

P.J. Slavish et al. / Bioorg. Med. Chem. 17 (2009) 3308–3316
3309
Figure 1. A detailed view of the pharmacophore including measurements in angstroms derived from the bound conformation of a ligand/IGF1R kinase domain co-crystal
structure.2,3 This pharmacophore was used to search the virtual framework library. The colour coding is as follows: Green = aromatic (Aro); Purple = hydrogen-bond donor
(Don); Cyan = hydrogen-bond acceptor (Acc). The size of each sphere is to scale with the query that was used to search the VFL.1 The radius dimensions are as follows:
Aro = 1.2 Å; Don = 0.8 Å; Acc = 0.8 Å.
Pharmacophore
geometry searching
of large virtual
N
framework library
and hit ranking and
selection by
Hyd
Acc
N
H
Hyd
N
H
O
medicinal chemist
1b
1c
1a
Figure 2. The evolution of scaffold 1c from initial computational hit 1a. Abbreviations: Hyd = hydrogen-bond donor; Acc = hydrogen-bond acceptor.
NHR2
R2
R2
N
N
R1
Cl
R1
R1
N
H
N
H
N
H
R3
R3
N
N
O
O
1
R3
H
Cl
O
N
RO2C
Cl
CO2R
+
Cl
N
R1
R1
NH2
N
H
Cl
N
6
R3
Cl
Figure 3. The general retrosynthetic approach to scaffold 1.
Deprotection of the t-butyl ester, followed by amide coupling gave
indole amide 9/10 in 80/74% overall yield. We initially investigated
the direct base-catalyzed cyclization to form the seven-membered
lactam13,14 using 9/10 as a substrate, but the yield of the desired
cyclized product was quite low. However, we found that amide
reduction followed by base treatment yielded the tetracyclic pyri-

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P.J. Slavish et al. / Bioorg. Med. Chem. 17 (2009) 3308–3316
O
O
Cl
Cl
I
CO2t-Bu
i
ii
R'
NH2
R'
NH2
N
H
N
R'
4, R' = H
2, R' = H
3, R' = Cl
7, R' = H
5, R' = Cl
8, R' = Cl
Ph
N
O
Ph
N
H
N
NH
Cl
Cl
R'
Cl
v, vi
iii, iv
11a, R' = H
Ph
7, 8
12a, R' = Cl
N
N
N
R'
H
N
9, R' = H
NH
10, R' = Cl
R'
Cl
11b, R' = H
12b, R' = Cl
Scheme 1. The syntheses of the tetracyclic intermediates 11a/12a and 11b/12b. Reagents and conditions: (i) t-butyl acrylate, cat. Pd(OAc)2, NaHCO3, DMF; (ii) (a) 6, HOAc,
EtOH; (b) KCN, HOAc, EtOH; (iv) trifluoroacetic acid, DCM; (v) phenethylamine, HBTU, N-methyl morpholine, DMF; (vi) 1.0 M borane–THF complex, trifluoroborane–methyl
etherate, THF; (vii) triethylamine, DMF.
dines 11a/12a and 11b/12b in 34% and 24/21% yields, respectively,
over two steps. Acid-promoted cyclization of the amine15 failed to
provide the desired tetracyclic compound.
Though the cyclization was not regioselective, these com-
pounds were readily separable and we viewed the diversity of
these structures as an opportunity for our envisioned kinase inhib-
itory structure–activity studies on final compounds derived from
both of these two templates (Scheme 1, see Fig. 4).
Direct conversion of chlorides 11a/12a and 11b/12b to the cor-
responding pyridones, using the published acidic conditions
(HOAc,16 HCl17) and basic conditions (KOH/DMSO)18 failed to pro-
vide the desired products. For this reason, we chose to convert the
chloro intermediates to the corresponding ethers, which could
serve as a precursor to the pyridone (see Scheme 2). While sodium
methoxide (in methanol or toluene)19 under reflux conditions and
DMAP yielded only partial chloro to methoxy conversion, we found
that barium hydroxide (octahydrate) in the presence of excess
DMAP in refluxing methanol provided complete conversion to
ethers 13a/14a and 13b in 54/51% and 54% yield (Scheme 2).
Though barium hydroxide is used quite often as the base for Suzuki
couplings20,21 and as an ester saponification reagent,22,23 the afore-
mentioned exchange catalyzed by barium hydroxide appears
rather new. Ether 13a could readily be converted to pyridone 1,24
in a modest yield of 63% after recrystallization. Structural confir-
mation of pyridone 1 was achieved via X-ray crystal determination
(Fig. 5). Using Buchwald conditions, ether 14a was converted to its
Figure 4. A right-left stereoview of a low energy conformation of 1 (the methyl group on the pyridine is omitted for simplicity) with an overlay of the pharmacophore from
Figure 1 generated in MOE. The colour coding is as follows: Green = aromatic (Aro); Purple = hydrogen-bond donor (Don); Cyan = hydrogen-bond acceptor (Acc). The size of
each sphere is to scale with the query that was used to search the VFL.1 The radius dimensions are as follows: Aro = 1.2 Å; Don = 0.8 Å; Acc = 0.8 Å. Small green dots represent
centroids recognized by MOE. See Figure 1 for a detailed view of the pharmacophore.

P.J. Slavish et al. / Bioorg. Med. Chem. 17 (2009) 3308–3316
3311
Ph
Ph
N
O
N
ii
i
NH
NH
11a or 12a
N
NH
R'
O
1
13a
, R' = H
14a, R' = Cl
Ph
Ph
N
O
N
O
N
i
iii
11b
N
14a
NH
N
NH
15
N
13b
Scheme 2. The synthesis of pyridone or methoxy pyridine inhibitors. Reagents and conditions: (i) barium hydroxide (octahedrate), DMAP, CH3OH; (ii) 4 M HCl (aq), THF; (iii)
Pd2(dba)3, N-methyl-piperazine, X-PhosÒ, lithium hexamethyldisilazide, THF.
amino analogue 15. Using a synthetic approach similar to Scheme
1 we synthesized various aryl analogues (Scheme 3).
3. Discussion
With this initial set of compounds in hand, we investigated their
inhibitory effects on a set of kinases using in vitro enzymatic assays,
performed as previously reported.5 As can be seen (Table 1), depend-
ing on the position of the regioisomer and the substituents, we were
able to identify initial compounds with the desirable selectivity for
the oncogenic human anaplastic lymphoma kinase (ALK).5,25 For
example, compounds such as 24b, 25a and 26a showed selectivity
for ALK as compared to the highly homologous (and clinically rele-
vant due to the possibility of iatrogenic diabetes with its inhibition)
human insulin receptor kinase (IRK), exhibiting IC50s in the single-
digit micromolar range for ALK and greater than the highest com-
Figure 5. The single crystal X-ray structure of 1, which confirms our structural
assignment (see Supplementary data).
pound concentration tested (40
lM) for the IRK. We have previously
O
O
I
Br
I
Br
CO2t-Bu
i
ii
Br
NH2
NH2
N
H
N
16
18
Cl
R"
17
18
N
Br
O
R"
N
NH
N
H
Cl
23a-26a
I
iii, iv
Br
v, vi
R"
N
H
N
N
I
Cl
N
Br
OH
NH
23b-26b
19, 23 R" =
21, 25 R" =
Ph
Ph
20, 24 R" =
22, 26 R" =
NH
Ph
Scheme 3. Synthesis of aryl analogues. Reagents and conditions: (i) t-butyl acrylate, cat. Pd(OAc)2, NaHCO3, DMF; (ii) (a) 2-chloro-4-iodo-nicotinaldehyde, HOAc, EtOH; (b)
KCN, HOAc, EtOH; (iii) trifluoroacetic acid, DCM; (iv) amine, HBTU, N-methyl morpholine, DMF; (v) 1.0 M borane–THF complex, trifluoroborane–methyl etherate, THF; (vi)
triethylamine, DMF.

3312
P.J. Slavish et al. / Bioorg. Med. Chem. 17 (2009) 3308–3316
Table 1
vents: A: 0.1% formic acid in water, B: 0.1% formic acid in acetoni-
trile, detector types: PDA (210–400 nm) and ELSD.
Biochemical evaluation of pyridone 1 and analogs (using the in vitro enzymatic kinase
assay previously described in the Supplementary data)5
ID
ALKa
IRK
IGF1R
JAK2
MET
5.2. X-ray crystallographic data
11a
11b
13a
13b
1
21.3
11.8
>40
>40
18.0
5.1
8.3
5.8
6.2
7.1
5
30.5
19.8
>40
>40
15.6
3.5
>40
11.9
11.1
>40
>40
>40
>40
24.7
12.6
>40
>40
11.8
4.5
33.5
>40
>40
>40
16.9
5.1
ND
ND
ND
ND
ND
ND
ND
26.1
12.4
>40
>40
19.7
5.5
>40
12.9
9.7
12.5
8.6
>40
>40
Crystallographic data (excluding structure factors) for the struc-
tures in this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication nos. CCDC
711726. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
15
23b
23a
24b
24a
25b
25a
26a
NDb
ND
ND
ND
ND
ND
5.3. (E)-tert-Butyl 3-(2-aminophenyl)acrylate (4)
>40
9.3
ND
To a solution of iodoaniline (5.5 g, 25.0 mmol), acrylate (3.8 mL,
26.2 mmol) and sodium bicarbonate (5.3 g, 62.4 mmol) in DMF
(8 mL) was added palladium acetate (0.3 g, 1.3 mmol) in one por-
tion. The resulting mixture was heated to 70 °C for 16 h. The mix-
ture was then diluted with EtOAc and filtered through Celite. After
concentrating under reduced pressure, crude product was purified
via column chromatography (EtOAc/hexanes, 10:90) to provide the
ester 4 (4.72 g, 86%) as a yellow solid. Mp 76–78 °C. 1H NMR
(CDCl3) d 7.75 (d, J = 15.8 Hz, 1H), 7.38 (dd, J = 7.8, 1.3 Hz, 1H),
7.17 (t, J = 7.5, 1.6 Hz, 1H), 6.78 (t, J = 7.6, 1.5 Hz, 1H), 6.72 (d,
J = 8.1 Hz, 1H), 6.32 (d, J = 15.8 Hz, 1H), 3.93 (br s, 2H), 1.56 (s,
9H). 13C NMR (CDCl3) d 166.7, 145.4, 139.1, 128.1, 120.2, 120.1,
118.9, 116.7, 80.5, 28.3. HRMS (ESI) m/z calcd for C13H18NO2
(M+1)+ 220.1338, found 220.1332.
a
All IC50 values (lM) are averages from triplicate assays.
Not determined.
b
observed that this degree of selectivity at the hit stage indicates that
these ‘hits’ may be converted into more potent and selective com-
pounds. The relative potency of regioisomers such as 25b versus
25a was unexpected and could be due to difference in the kinase do-
mainstructureof ALKversus IGF1R, X-ray crystalstructureof ALKre-
main unpublished at this time. The observed potencies are ‘hit-like’
and demonstrates the utility of our framework design method to
identify compounds that are suitable starting points for further opti-
mization into more potent selective inhibitors for additional itera-
tions of medicinal chemistry.
5.4. (E)-tert-Butyl 3-(2-amino-4-chlorophenyl)acrylate (5)
4. Conclusion
Compound 5 was prepared in a similar manner to conditions for
ester 2 to give ester 5 (92%) as a yellow solid. Mp 63–65 °C. 1H NMR
(400 MHz, CDCl3) d 7.55 (d, 1H, J = 15.8 Hz), 7.20 (d, 1H, J = 8.1 Hz),
6.63 (m, 2H), 6.18 (d, J = 15.8 Hz, 1H), 1.44 (s, 9H), 13C NMR
(100 MHz, CDCl3) d 166.4, 146.2, 137.9, 136.5, 129.2, 120.7,
119.1, 118.6, 116.1, 100.0, 80.7, 28.3. HRMS (ESI) m/z calcd for
C13H16NO2Cl (M+1)+ 253.08695, found 253.08688.
We report the details on the specific application of our recently
published ‘framework’ design1 of a new kinase inhibitor template
and the synthesis of the subject of this design, a novel tetracyclic
pyridone tyrosine kinase inhibitor template, which was accom-
plished in eight steps.26 This synthesis involves a one pot di-
ortho-substituted aldehyde condensation, followed by the cya-
nide-catalyzed cyclization, which gave the key indole intermediate
in >70% yield. In addition, we report the first example of barium
hydroxide-catalyzed chloro-to-methoxy pyridine conversion. Fi-
nally, we present initial structure–activity data showing that rep-
resentative examples of compounds based on these templates
demonstrate activity and initial selectivity for anaplastic lym-
phoma kinase (ALK), thus indicating that they are suitable starting
points for the development of more active ‘lead-like’ inhibitors
through the usual process of ‘hit-to-lead’ chemistry. A future ave-
nue of research will be the exploration of these templates for the
discovery of new therapeutic leads against oncogenic tyrosine ki-
nases in the insulin receptor superfamily such as ALK.5,25
5.5. tert-Butyl 2-(2-(2,4-dichloro-6-methylpyridin-3-yl)-1H-
indol-3-yl)acetate (7)
To a solution of amine 4 (1.4 g, 6.4 mmol) and aldehyde 6 (1.5 g,
7.7 mmol) in EtOH (5 mL) was added HOAc (0.6 mL, 10.2 mmol).
After 2 h, the solvent was removed under reduced pressure. The
resulting crude imine was treated with potassium cyanide (0.9 g,
14.1 mmol) and additional acetic acid (0.37 mL, 6.4 mmol). The
reaction mixture was heated to 70 °C stirred for 22 h. Once deemed
complete, the solvent was removed under reduced pressure. Crude
product was taken up in EtOAc and washed with satd aq NaHCO3
solution. The organic phase was dried over sodium sulfate, filtered
and concentrated under reduced pressure. The crude ester was
purified via column chromatography (EtOAc/hexanes, 20:80) to
furnish the indole ester 7 (1.84 g, 73%) as a yellow oil. 1H NMR
(CDCl3) d 7.90 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.1 Hz,
1H), 7.24 (s, 1H), 7.19 (m, 3H), 7.12 (t, J = 7.5 Hz, 1H), 3.43 (d,
J = 1.0 Hz, 2H), 2.54 (s, 3H), 1.48 (s, 9H). 13C NMR (CDCl3) d 170.2,
160.3, 152.4, 147.5, 136.2, 122.8, 127.5, 123.0, 120.1, 119.9,
111.1, 110.1, 80.7, 32.5, 27.9, 24.0. HRMS (ESI) m/z calcd for
C20H21N2O2Cl2 (M+1)+ 391.0980, found 391.0976.
5. Experimental
5.1. General remarks
All reactions were performed under an atmosphere of nitrogen.
Flash chromatography purifications employed Silica Gel 60 from
EMD Chemicals (particle size: 0.040–0.063 mm, 230–400 mesh
ASTM). Thin layer chromatography was performed on silica gel
with UV-254 indicator (250 lm thickness). All TLC visualizations
were conducted with UV light. Nuclear magnetic resonance exper-
iments were conducted using a 400 MHz II instrument (Bruker
Avance II). Microwave reactions were conducted using a Biotage
Initiator 60 (N = 100–300 W, H = 50–150 W, VH = 40–90 W). HPLC
analyses were accomplished using an UPLC/UV/ELSD/SQD (Single
5.6. tert-Butyl 2-(6-chloro-2-(2,4-dichloro-6-methylpyridin-3-
yl)-1H-indol-3-yl)acetate (8)
Compound 8 was prepared in a similar manner to the condi-
tions above for 4 to give 8 (68%) as a off-white solid. Mp 72–
Quadrapole Detector) with stationary phase: BEH C18, 1.7 lm, sol-

P.J. Slavish et al. / Bioorg. Med. Chem. 17 (2009) 3308–3316
3313
74 °C. 1H NMR (400 MHz, CDCl3) d 8.21 (s, 1H), 7.79 (d, J = 1.8 Hz,
1H), 7.20 (m, 3H), 3.36 (d, J = 3.3 Hz, 2H), 2.50 (s, 3H), 1.28 (s,
9H). 13C NMR (100 MHz, CDCl3) d 169.9, 160.6, 152.3, 147.5,
136.5, 129.0, 128.2, 126.3, 123.2, 121.1, 111.1, 110.3, 80.9, 32.4,
27.9, 24.0. HRMS (ESI) m/z calcd for C20H20N2O2Cl3 (M+1)+
425.0590, found 425.0571.
139.8, 139.4, 135.4, 134.7, 127.2, 126.3, 126.0, 122.8, 118.8,
116.7, 115.5, 110.3, 109.2, 53.5, 51.9, 34.7, 27.1, 23.6. HRMS (ESI)
m/z calcd for C24H23N3Cl (M+1)+ 388.1581, found 388.1589. 4-
Chloro pyridine 11b (0.12 g, 24%) was a yellow solid. Yield: 24%,
mp 155–156 °C. 1H NMR (CDCl3) d 8.92 (s, 1H), 7.52 (d, J = 7.8 Hz,
1H), 7.37 (d, J = 8.1 Hz, 1H), 7.19–7.00 (m, 7H), 6.8 (s, 1H), 3.86
(t, J = 7.7 Hz, 2H), 3.57 (t, J = 7.5 Hz, 2H), 3.09 (t, J = 5.4 Hz, 2H),
3.02 (t, J = 7.7 Hz, 2H), 2.45 (s, 3H). 13C NMR (CDCl3) d 160.6,
154.8, 147.0, 138.8, 135.4, 128.9, 127.2, 126.7, 123.2, 118.5,
116.1, 113.5, 110.6. 109.5, 54.2, 53.9, 34.7, 26.5, 23.9. HRMS (ESI)
m/z calcd for C20H21N2O2Cl2 (M+1)+ 388.1581, found 388.1563.
5.7. 2-(2-(2,4-Dichloro-6-methylpyridin-3-yl)-1H-indol-3-yl)-N-
phenethylacetamide (9)
A solution of indole ester 5 (1.7 g, 4.0 mmol) in dichlorometh-
ane (3 mL) was treated with trifluoroacetic acid (3.0 mL,
40.0 mmol). The solution stirred at rt for 1 h. The solvent was then
removed under reduced pressure. The crude acid was dissolved in
DMF, treated with 4-methylmorpoline (1.3 mL, 12.0 mmol) fol-
lowed by HBTU (2.3 g, 6.0 mmol) and phenethylamine (0.6 mL,
4.8 mmol) in one portion. After 1 h, the mixture was diluted with
EtOAc and washed with satd aq NaHCO3 solution, dried with so-
dium sulfate, filtered and concentrated under reduced pressure.
Crude product was purified via column chromatography (EtOAc/
hexanes, 1:1) to yield indole amide 9 (0.50 g, 80%) as an off-white
solid. Mp 165–167 °C. 1H NMR (CDCl3) d 8.02 (s, 1H), 7.54 (d,
J = 8.0 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H),
7.20–7.15 (m, 3H), 7.05–6.90 (m, 3H), 6.67 (d, J = 6.9 Hz, 2H),
5.62 (s, 1H), 3.47 (q, J = 17.5 Hz, 2H), 3.39–3.22 (m, 2H), 2.55–
2.48 (m, 5H). 13C NMR (CDCl3) d 170.2, 161.3, 152.5, 147.3, 138.3,
135.9, 128.6, 127.5, 126.2, 123.4, 120.6, 119.1, 111.4, 109.4, 40.3,
35.6, 32.6, 24.0. Anal. Calcd for C24H21Cl2N3O: C, 65.76; H, 4.83;
N, 9.59. Found: C, 65.22; H, 4.81; N, 9.39. HRMS (ESI) m/z calcd
for C24H22N3OCl2 (M+1)+ 438.1140, found 438.1144.
5.10. Compounds 12a and 12b
These compounds were prepared in a similar manner to the
above cyclization from amide 10 to give 2-chloro pyridine 12a
(34%) as an off-white solid. Mp 152–154 °C. 1H NMR (400 MHz,
CDCl3) d 9.02 (s, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.36 (d, 1H,
J = 8.4 Hz), 7.18–7.05 (m, 6H), 6.66 (s, 1H), 3.63 (t, J = 7.4 Hz,
2H), 3.52 (t, J = 5.6 Hz, 2H), 3.00–2.92 (m, 4H), 2.46 (s, 3H), 13C
NMR (100 MHz, CDCl3)
d 160.5, 155.0, 146.9, 138.7, 135.2,
128.7, 128.5, 128.0, 126.6, 126.3, 120.1, 119.6, 116.0, 113.2,
110.4, 109.5, 54.6, 53.9, 34.4, 26.6, 24.0, HRMS (ESI) m/z calcd
for C24H21Cl2N3 (M+1)+ 422.1191, found 422.1197. 4-Chloro pyri-
dine 12b (21%) was a yellow solid. Mp 175–177 °C. 1H NMR
(400 MHz, CDCl3) d 8.90 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.35 (d,
J = 1.6 Hz, 1H), 7.17–7.13 (m, 5H), 7.08 (dd, J = 8.4, 1.8 Hz, 1H),
6.79 (s, 1H), 3.86 (t, J = 7.6 Hz, 2H), 3.53 (t, J = 5.5 Hz, 2H), 3.05–
2.97 (m, 4H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3) d 161.6,
153.7, 140.2, 139.3, 135.3, 128.9, 128.3, 128.1, 126.5, 120.1,
119.7, 116.7, 115.7, 110.3, 108.7, 53.7, 51.8, 34.7, 26.8, 23.8.
HRMS (ESI) m/z calcd for C24H21Cl2N3 (M+1)+ 422.1191, found
422.1187.
5.8. 2-(6-Chloro-2-(2,4-dichloro-6-methylpyridin-3-yl)-1H-
indol-3-yl)-N-phenethylacetamide (10)
Compound 10 was prepared in a similar manner to above con-
ditions for 5 to give amide 10 (74%) as a transparent oil. 1H NMR
(400 MHz, CDCl3) d 9.25 (s, 1H), 7.47–7.42 (m, 2 H), 7.22 (s, 1H),
7.16 (dd, J = 8.4, 1.4 Hz, 1H), 7.11–7.01 (m, 3H), 6.76 (m, 2H),
5.65 (t, J = 5.6 Hz, 1H), 3.53–3.27 (m, 4H), 2.78 (s, 5H). 13C NMR
(100 MHz, CDCl3) d 170.2, 161.0, 152.1, 147.2, 138.2, 136.8,
129.4, 128.5, 128.4, 125.8, 123.4, 123.2, 121.3, 120.1, 111.6,
109.1, 40.5, 38.6, 35.4, 32.6, 24.0. HRMS (ESI) m/z calcd for
C24H20N3OCl3 (M+1)+ 472.0750, found 472.0758.
5.11. Compound 13a
2-Chloro pyridine (0.2 g, 0.4 mmol) and DMAP (0.4 g, 3.6 mmol)
was dissolved in methanolic barium hydroxide octahydrate solu-
tion (1.2 g, 7.2 mmol Ba(OH)2ꢀ8H2O, 8 mL methanol). The resulting
solution was heated to reflux for 16 h. The methanol was removed
under reduced pressure; the crude product was dissolved in EtOAc
and washed with water. The organic solution was dried with so-
dium sulfate, filtered, concentrated and purified via column chro-
matography (EtOAc/hexanes, 1:9) to yield ether 13a (0.07 g, 54%)
as a white solid. Mp 137–139 °C. 1H NMR (CDCl3) d 10.1 (s, 1H),
7.52 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.30–7.20 (m, 6H),
7.12 (t, J = 7.4 Hz, 1H), 6.48 (s, 1H), 4.18 (s, 3H), 3.64 (t, J = 7.8 Hz,
2H), 3.50 (t, J = 5.4 Hz, 2H), 3.12 (t, J = 5.3 Hz, 2H), 3.03 (t,
J = 7.8 Hz, 2H), 2.43 (s, 3H). 13C NMR (CDCl3) d 160.9, 158.7,
152.1, 139.3, 134.4, 128.6, 128.2, 126.5, 122.1, 118.1, 113.7,
110.3, 105.9, 100.9, 55.2, 53.8, 52.0, 34.7, 27.8, 24.1. Anal. Calcd
for C25H25N3O: C, 78.30; H, 6.57; N, 10.96. Found: C, 77.95; H,
6.62; N, 10.75.
5.9. Compounds 11a and 11b
A refluxing mixture of amide 9 (0.6 g, 1.3 mmol) and boron tri-
fluoride dimethyl etherate (0.2 mL, 2.2 mmol) in THF (3 mL) was
exposed to 1.0 M borane-THF complex (3.9 mL, 3.9 mmol in THF)
for 3 h. After this time, the reaction was cooled to 0 °C and
quenched with 4.5 N HCl (3 mL). The mixture was stirred for 1 h
and then at rt for 1 h. The mixture was then cooled to 0 °C and basi-
fied to pH 13 with solid KOH and extracted with CH2Cl2 (10 mL)
three times. The organic solution was dried (sodium sulfate), fil-
tered and concentrated to afford the amine, which was diluted in
DMF (5 mL) and treated triethylamine (0.2 mL, 1.3 mmol). The
reaction was heated to 70 ° C for 16 h, then quenched via the addi-
tion of water (5 mL) at rt. The aqueous layer was extracted with
EtOAc (5 mL). The organic layer was dried, filtered and concen-
trated under reduced pressure. The regioisomers were separated
via column chromatography (EtOAc/hexanes, 9:1 to 4:1) to afford
pure 2-chlroro pyridine 11a (0.17 g, 34%) as an off-white solid.
Mp 165–166 °C. 1H NMR (CDCl3) d 8.95 (s, 1H), 7.41 (d, J = 7.8 Hz,
1H), 7.31 (d, J = 8.1 Hz, 1H), 7.18–7.00 (m, 7H), 6.57 (s, 1H), 3.53
(t, J = 7.6 Hz, 2H), 3.46 (t, J = 5.6 Hz, 2H), 2.97 (t, J = 5.6, 2H), 2.86
(t, J = 7.6 Hz, 2H), 2.39 (s, 3H). 13C NMR (CDCl3) d 161.5, 154.0,
5.12. Compound 13b
This compound was prepared in a similar manner to the above
methoxy displacement to give ether 13b (51%) as an off-white so-
lid. Mp 80–82 °C. 1H NMR (CDCl3) d 9.75 (s, 1H), 7.51 (d, J = 7.8 Hz,
1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26–7.23 (m, 4H), 7.19 (t, J = 8.0 Hz,
2H), 7.10 (t, J = 7.0 Hz, 1H), 6.42 (s, 1H) 4.06 (s, 3H), 3.88 (t,
J = 7.8 Hz, 2H), 3.53 (t, J = 5.3 Hz, 2H), 3.12–3.08 (m, 4H), 2.48 (s,
3H). 13C NMR (CDCl3) d 140.6, 134.7, 129.0, 128.4, 128.1, 126.1,
122.1, 118.8, 118.4, 113.4, 110.3, 98.5, 56.0, 54.5, 50.9, 34.9, 29.7,
27.8, 24.8. HRMS (ESI) m/z calcd for C25H26N3O (M+1)+ 384.2076,
found 384.2069.

3314
P.J. Slavish et al. / Bioorg. Med. Chem. 17 (2009) 3308–3316
5.13. Compound 14a
J = 5.2 Hz, 1H), 7.83 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.28 (dd,
J = 8.6, 1.8 Hz, 1H), 7.24–7.18 (m, 2H), 3.36 (d, J = 4.6 Hz, 2H),
1.31 (s, 9H). 13C NMR (101 MHz, CDCl3) d 169.6, 151.7, 149.9,
134.6, 134.0, 133.2, 133.2, 129.4, 126.1, 123.1, 114.8, 113.5,
112.8, 108.8, 81.2, 32.5, 28.1. HRMS (ESI) m/z calcd for
C19H18N2O2ClBrI (M+1)+ 546.9285, found 546.9272.
This compound was prepared in a similar manner to the above
methoxy displacement to give ether 14a (54%) as a clear oil. 1H
NMR (400 MHz, CDCl3) d 9.98 (s, 1H), 7.28 (d, J = 1.8 Hz, 1H) 7.27
(d, J = 8.7 Hz, 1H), 7.18–7.07 (m, 7H), 6.96 (dd, J = 8.4, 1.8 Hz, 1H),
6.38 (s, 1H), 4.05 (s, 3H), 3.54 (t, J = 7.7 Hz, 2H), 3.37 (t, J = 5.2 Hz,
2H), 2.95–2.86 (m, 4H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) d
159.1, 156.8, 150.6, 137.4, 132.9, 127.0, 126.8, 125.9, 125.1,
124.7, 117.7, 117.1, 111.9, 108.4, 98.8, 53.4, 52.0, 50.2, 32.8, 25.8,
22.4. HRMS (ESI) m/z calcd for C25H25N3OCl (M+1)+ 418.1686,
found 418.1680.
5.18. 2-(5-Bromo-2-(2-chloro-4-iodopyridin-3-yl)-1H-indol-3-
yl)-N-((S)-1-phenylethyl)acetamide (19)
Compound 19 was prepared in a similar manner to above con-
ditions for 5 to give amide 19 (68%) as a tan oil. 1H NMR (400 MHz,
CDCl3) d 8.50 (d, J = 9.9 Hz, 1H), 8.03 (dd, J = 5.2, 2.2 Hz, 1H), 7.75
(dd, J = 6.2, 5.4 Hz, 1H), 7.68 (dd, J = 8.8, 1.8 Hz, 1H), 7.33 (dt,
J = 8.6, 1.9 Hz, 1H), 7.24 (dd, J = 10.0, 1.2 Hz, 1H), 7.20–7.10 (m,
4H), 7.01 (m, 2H), 5.84 (d, J = 8.0 Hz, 1H), 4.99 (qn, J = 7.2 Hz, 1H),
3.46 (dd, J = 17.5, 5.5 Hz, 1H), 3.36 (dd, J = 17.5, 4.5 Hz, 1H), 1.25
(dd, J = 6.9, 5.0 Hz, 3H). 13C NMR (CDCl3) d 168.9, 151.4, 151.4,
150.4, 142.9, 142.8, 135.0, 133.3, 132.7, 127.3, 126.1, 122.3,
114.7, 114.0, 113.2, 108.1, 108.0, 49.0, 33.0, 21.8. HRMS (ESI) m/z
calcd for C23H19N3OClBrI (M+1)+ 593.9445, found 593.9445.
5.14. 3-Methyl-6-N-phenethyl-5,6,7,12-tetrahydroindolo[2,1-
d]pyrido[4,3-b]azepin-1(2H)-one (1)
To a solution of O-methyl pyridine (0.05 g, 140 lmol) in dioxane
(0.2 mL) was added 4 M HCl (aq). The mixture was heated to 65 °C
for 5 h. Crude product was purified via recrystallization (EtOAc/
hexanes) to afford pyridone 1 (32 mg, 63%) as a tan solid. Yield:
63%, mp 244 °C. 1H NMR (CDCl3) d 12.4 (s, 1H), 9.94 (s, 1H), 7.49
(d, J = 7.5 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.36–7.24 (m, 6H), 7.17
(t, J = 7.0 Hz, 1H), 7.09 (t, J = 7. 0 Hz, 1H), 5.85 (s, 1H), 3.65 (t,
J = 7.6 Hz, 2H), 3.51 (t, J = 4.8 Hz, 2H), 3.12 (t, J = 4.9 Hz, 2H), 3.08
(t, J = 7.6 Hz, 2 H), 2.30 (s, 3H). 13C NMR (CDCl3) d 165.7, 158.1,
140.9, 138.7, 133.7, 132.1, 128.8, 128.0, 126.7, 121.1, 118.5,
117.5, 111.2, 110.6, 100.4, 99.8, 55.4, 51.3, 34.8, 29.7, 26.9, 19.1.
5.19. 2-(5-Bromo-2-(2-chloro-4-iodopyridin-3-yl)-1H-indol-3-
yl)-N-(2-(4-hydroxyphenyl)ethyl) acetamide (20)
Compound 20 was prepared in a similar manner to above con-
ditions for 5 to give amide 20 (39%) as a brown oil. 1H NMR
(400 MHz, acetone) d 10.64 (s, 1H), 8.20 (br s, 1H) 8.15 (t,
J = 4.9 Hz, 1H), 8.04 (t, J = 4.9 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.47
(dd, J = 8.6, 4.4 Hz, 1H), 7.36 (m, 1H), 6.83 (m, 2H), 6.63 (m, 3H),
3.46 (t, J = 5.3 Hz, 2H), 3.31 (m, 2H), 2.58 (m, 2H). 13C NMR
(101 MHz, acetone) d 169.8, 156.7, 151.9, 150.9, 136.3, 136.0,
134.4, 134.3, 130.8, 130.6, 130.5, 126.1, 123.4, 116.1, 115.6,
114.3, 113.2, 109.3, 41.8, 35.7, 33.4. HRMS (ESI) m/z calcd for
C22H19N3O2ClBrI (M+1)+ 609.9394, found 609.9421.
5.15. Compound 15
A mixture of 14a (0.08 g, 0.2 mmol), dicyclohexyl(20,40,60-tri-
isopropylbiphenyl-2-yl)phosphine (X-PhosÒ, 6 mg, 0.01 mmol),
and Pd2(dba)3 (16 mg, 0.02 mmol) was treated with a solution of
N-methyl piperazine (0.03 mL, 0.2 mmol) in THF (1 mL). This solu-
tion was treated with LiHMDS (0.6 mL, 1 M in THF) in one portion.
The reaction was heated to 70 °C in a sealed tube overnight. The
reaction mixture was dissolved in EtOAc, washed with satd aq
NaHCO3 solution, dried over magnesium sulfate, filtered and con-
centrated under reduced pressure. Crude product was purified
via reverse phase HPLC. Ether 15 (11 mg, 10%) was a tan oil. 1H
NMR (400 MHz, CDCl3) d 10.4 (s, 1H), 8.25 (s, 1H), 7.30–7.25 (m,
6H), 6.96 (d, J = 1.9 Hz, 1H), 6.75 (dd, J = 8.6, 2.0 Hz, 1H), 4.05 (s,
3H), 3.57 (t, J = 7.8 Hz, 4H), 3.44 (t, J = 5.2 Hz, 4H), 3.12 (t,
J = 4.8 Hz, 4H), 3.00–2.92 (m, 5H), 2.32 (s, 3H), 2.24 (s, 3H). 13C
NMR (100 MHz, CDCl3) d 163.6, 160.2, 158.1, 150.8, 147.5, 139.4,
135.6, 128.8, 127.0, 126.1, 121.8, 117.9, 112.9, 110.9, 105.4,
100.5, 97.5, 54.8, 54.3, 53.3, 51.5, 50.0, 45.7, 33.7, 27.2, 23.8. HRMS
(ESI) m/z calcd for C30H35N5O (M+1)+ 482.2920, found 482.2912.
5.20. 2-(5-Bromo-2-(2-chloro-4-iodopyridin-3-yl)-1H-indol-3-
yl)-N-(2,2-diphenylethyl)acetamide (21)
Compound 21 was prepared in a similar manner to above con-
ditions for 5 to give amide 21 (94%) as a clear oil. 1H NMR
(400 MHz, CDCl3) d 8.34 (s, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.70 (d,
J = 5.2 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.37 (dd, J = 8.6, 1.8 Hz,
1H), 7.25 (d, J = 8.6 Hz, 1H), 7.05–6.97 (m, 6H), 6.90–6.84 (m,
4H), 5.53 (t, J = 5.4 Hz, 1H), 3.82 (t, J = 7.6 Hz, 1H), 3.73 (t,
J = 6.7 Hz, 2H), 3.33 (d, J = 5.2 Hz, 2H). 13C NMR (101 MHz, CDCl3)
d 169.7, 151.4, 150.3, 141.5, 141.4, 135.1, 134.7, 133.0, 132.6,
128.8, 128.6, 128.0, 127.9, 126.8, 126.7, 122.1, 114.7, 114.1,
113.1, 107.8, 50.4, 43.6, 32.7. HRMS (ESI) m/z calcd for
C29H23N3OClBrI (M+1)+ 669.9758, found 669.9736.
5.16. (E)-tert-Butyl 3-(2-amino-4-bromophenyl)acrylate (17)
Compound 17 was prepared in a similar manner to conditions
for 2 to give ester 17 (92%) as yellow solid. Mp 63–65 °C. 1H
5.21. N-(2-(1H-Indol-3-yl)ethyl)-2-(5-bromo-2-(2-chloro-4-
iodopyridin-3-yl)-1H-indol-3-yl)acetamide (22)
NMR (400 MHz, CDCl3)
d 7.62 (d, J = 15.8 Hz, 1H), 7.48 (d,
J = 2.3 Hz, 1H), 7.23 (dd, J = 8.5, 2.2 Hz, 1H), 6.59 (d, J = 8.5 Hz,
1H), 6.29 (d, J = 15.7 Hz, 1H), 3.96 (s, 2H), 1.55 (s, 9H). 13C NMR
(101 MHz, CDCl3) d 166.2, 155.3, 144.3, 137.5, 133.4, 130.3,
121.9, 121.5, 118.2, 110.6, 80.8, 28.2. HRMS (ESI) m/z calcd for
C13H17NO2Br (M+1)+ 298.0443, found 298.0442.
Compound 22 was prepared in a similar manner to above con-
ditions for 5 to give amide 22 (58%) as a tan solid. Mp 240–242 °C.
1H NMR (400 MHz, DMSO) d 11.45 (s, 1H), 10.77 (s, 1H), 8.16 (d,
J = 5.2 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H) 7.94 (d, J = 1.9 Hz, 1H), 7.84
(t, J = 5.7 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H),
7.32 (d, J = 8.1 Hz, 1H), 7.30 (dd, J = 8.6, 2.0 Hz, 1H), 7.06–7.03 (m,
2H), 6.95 (dt, J = 7.5, 1.0 Hz, 1H), 3.30 (m, 5H), 2.72 (t, J = 7.5 Hz,
2H). 13C NMR (101 MHz, DMSO) d 169.1, 150.3, 149.9, 136.2,
134.9, 134.4, 133.3, 133.2, 129.5, 127.1, 124.2, 122.5, 122.4,
120.9, 118.2, 116.5, 113.3, 111.7, 111.4, 108.1, 31.9, 25.3, HRMS
(ESI) m/z calcd for C25H20N4OClBrI (M+1)+ 632.9554, found
632.9537.
5.17. tert-Butyl 2-(5-bromo-2-(2-chloro-4-iodopyridin-3-yl)-
1H-indol-3-yl)acetate (18)
Compound 18 was prepared in a similar manner to the condi-
tions above for 4 to give indole ester 18 (66%) as a yellow solid.
Mp 181–184 °C. 1H NMR (400 MHz, CDCl3) d 8.05 (s, 1H), 8.00 (d,

P.J. Slavish et al. / Bioorg. Med. Chem. 17 (2009) 3308–3316
3315
5.22. Compounds 23a/b
620.0198, found 620.0211. Compound 26a was a light brown solid
(30%). Mp 248–252 °C. 1H NMR (400 MHz, DMSO) d 10.99 (s, 1H),
10.81 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.69 (s, 1H), 7.56 (d,
J = 7.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H),
7.25 (d, J = 6.7 Hz, 1H), 7.17 (s, 1H), 7.06 (m, 2H), 6.95 (t,
J = 7.1 Hz, 1H), 3.64 (br s, 4H), 3.10 (br s, 2H), 3.06 (br s, 2H). 13C
NMR (101 MHz, DMSO) d 160.1, 147.9, 145.4, 136.1, 134.2, 129.2,
128.8, 127.1, 124.8, 122.9, 120.9, 120.6, 118.3, 114.8, 114.5,
113.3, 111.3, 111.3, 111.0, 110.39, 54.2, 53.1, 25.5, 23.1. HRMS
(ESI) m/z calcd for C25H21N4ClBr (M+1)+ 491.0638, found
491.0646. Compound 26b was a tan solid (5%). Mp 208–212 °C.
1H NMR (400 MHz, DMSO) d 10.76 (s, 2H), 7.75 (t, J = 4.3 Hz, 1H),
7.69 (br s, 1H), 7.63 (m, 1H), 7.44 (t, J = 4.7, 1H), 7.36 (dd, J = 8.3,
5.3 Hz, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 7.25 (m, 1H), 7.11 (br s,
1H), 7.05 (m, 1H), 6.96 (m, 1H), 3.80 (m, 2H), 3.60 (m, 2H), 3.08
(m, 4H). 13C NMR (101 MHz, DMSO) d 161.3, 144.2, 136.2, 134.3,
131.5, 129.4, 127.3, 127.0, 124.8, 122.5, 120.8, 118.5, 118.2,
116.9, 114.1, 113.3, 112.1, 111.3, 111.2, 104.9, 52.3, 51.3, 25.6,
23.6. HRMS (ESI) m/z calcd for C25H21N4BrI (M+1)+ 582.9994, found
583.0003.
These compounds were prepared in a similar manner to the
above cyclization from amide 10 except the cyclization step was
heated to 170 °C for 1 h using microwave heating (absorbance:
normal) to provide 23a (11%) as a tan solid. Mp 142–146 °C. 1H
NMR (400 MHz, CDCl3) d 9.00 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 7.51
(s, 1H), 7.29–7.22 (m, 7H), 6.68 (d, J = 5.7 Hz, 1H), 4.96 (q,
J = 6.8 Hz, 1H), 3.49 (t, J = 5.5 Hz, 2H), 2.93 (dt, J = 16.7, 5.7 Hz,
1H), 2.72 (dt, J = 16.7, 5.4 Hz, 1H), 1.67 (d, J = 6.9 Hz, 3H), 13C
NMR (101 MHz, CDCl3) d 159.8, 147.0, 144.2, 139.6, 132.5, 128.4,
127.8, 127.4, 126.6, 125.9, 125.2, 120.4, 114.7, 113.7, 111.5,
111.1, 110.0, 58.2, 47.6, 26.4, 17.4. HRMS (ESI) m/z calcd for
C23H20N3BrCl (M+1)+ 452.0529, found 452.0509. Compound 23b
was a tan oil (7%). 1H NMR (400 MHz, CDCl3) d 8.38 (s, 1H), 7.61
(d, J = 4.9 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.23 (m, 8H), 5.83 (q,
J = 6.9 Hz, 1H), 3.40 (ddd, J = 14.5, 6.5, 4.4 Hz, 1H), 3.18 (ddd,
J = 14.3, 8.2, 3.6 Hz, 1H), 2.78 (ddd, J = 16.7, 6.2, 3.7 Hz, 1H), 2.46
(ddd, J = 16.7, 8.2, 4.3 Hz, 1H), 1.61 (d, J = 6.9 Hz, 3H), 13C NMR
(101 MHz, CDCl3) d 160.9, 143.0, 140.7, 132.3, 129.0, 128.9,
127.3, 126.9, 126.6, 126.1, 125.0, 120.7, 114.7, 114.4, 111.6,
111.0, 100.9, 54.5, 45.1, 25.9, 15.5, HRMS (ESI) m/z calcd for
C23H20N3BrI (M+1)+ 543.9885, found 543.9873.
Acknowledgements
We would like to thank Antonio DePasquale and Arnold L.
Rheingold of the Department of Chemistry at the University of Cal-
ifornia, San Diego for the X-ray structure determination of 8a. This
work was supported in part by NCI grant CA69129 (S.W.M.), Cancer
center CORE grant CA1765, and by the American Lebanese Syrian
Associated Charities (ALSAC), St. Jude Children’s Research Hospital.
5.23. Compounds 24a/b through 26a/b
These compounds were prepared in a similar manner to the
above cyclization from amide 10. Compound 24a was a tan solid
(22%). Mp 217–219 °C. 1H NMR (400 MHz, acetone) d 10.29 (s,
1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.95 (d, J = 5.6 Hz, 1H), 7.66 (d,
J = 1.9 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.28 (dd, J = 8.6, 1.9 Hz,
1H), 7.07 (d, J = 5.7 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.65 (d,
J = 8.5 Hz, 2H), 3.65 (m, 4H), 3.12 (t, J = 5.8 Hz, 2H), 2.91 (t,
J = 7.7 Hz, 2H). 13C NMR (101 MHz, acetone) d 217.5, 214.9, 213.8,
212.7, 212.3, 206.1, 206.1, 161.3, 156.8, 149.1, 146.3, 135.3,
130.7, 130.7, 130.4, 130.2, 126.2, 121.8, 116.4, 116.1, 116.0,
113.8, 112.5, 111.3, 55.6, 55.2, 33.9, 26.8. HRMS (ESI) m/z calcd
for C23H20N3OBrCl (M+1)+ 468.0478, found 468.0469. Compound
24b was a brown solid (10%). Mp 208–212 °C. 1H NMR (400 MHz,
DMSO) d 10.80 (s, 1H), 9.17 (s, 1H), 7.76 (d, J = 4.9 Hz, 1H), 7.73
(d, J = 1.7 Hz, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H),
7.30 (dd, J = 8.6, 1.9 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.64 (d,
J = 8.4 Hz, 2H), 3.72 (t, J = 7.7 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 3.08
(t, J = 5.6 Hz, 2H), 2.85 (t, J = 7.7 Hz, 2H). 13C NMR (101 MHz,
DMSO) d 161.2, 155.5, 144.2, 134.2, 131.5, 129.8, 129.5, 129.4,
127.1, 124.8, 120.8, 117.1, 115.0, 114.1, 113.3, 111.1, 104.9, 52.5,
33.1, 25.5. HRMS (ESI) m/z calcd for C23H20N3OBrI (M+1)+
559.9835, found 559.9857. Compound 25a was an off-white solid
(24%). Mp 112–114 °C. 1H NMR (400 MHz, acetone) d 10.13 (s,
1H), 7.99 (d, J = 5.6 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.28 (dd,
J = 8.6, 0.4 Hz, 1H), 7.13 (dd, J = 8.6, 1.9 Hz, 1H), 7.00 (dd, J = 7.6,
1.6 Hz, 5H), 6.89 (t, J = 1.8 Hz, 1H), 6.87 (dd, J = 5.8, 1.4 Hz, 3H),
6.84 (t, J = 1.5 Hz, 1H), 6.83 (t, J = 3.0 Hz, 1H), 4.18 (d, J = 8.6,
6.9 Hz, 1H), 4.09 (d, J = 3.9 Hz, 2H), 3.48 (t, J = 5.8 Hz, 2H), 2.57
(d, J = 5.8 Hz, 2H).13C NMR (101 MHz, acetone) d 161.1, 149.2,
146.3, 143.5, 135.3, 130.4, 129.9, 128.9, 128.9, 127.1, 125.9,
121.9, 117.4, 116.6, 113.6, 112.1, 112.1, 58.8, 57.2, 50.6, 26.4,
HRMS (ESI) m/z calcd for C29H24N3ClBr (M+1)+ 528.0842, found
528.0848. Compound 25b was a tan oil (3%). 1H NMR (400 MHz,
CDCl3) d 8.23 (s, 1H), 7.60 (d, J = 4.9 Hz, 1H), 7.35 (d, J = 1.7 Hz,
1H), 7.29 (d, J = 5.0 Hz, 1H), 7.23 (dd, J = 8.6, 1.8 Hz, 1H), 7.19 (s,
2H), 7.14 (d, J = 8.5 Hz, 1H), 6.96 (m, 10H), 4.25 (m, 3H), 3.37 (t,
J = 5.7 Hz, 2H), 2.40 (t, J = 5.7 Hz, 2H). 13C NMR (101 MHz, CDCl3)
d 161.3, 144.1, 142.9, 133.3, 129.8, 129.7, 128.2, 128.1, 128.1,
126.2, 125.9, 121.9, 117.8, 115.9, 112.3, 111.8, 102.3, 57.4, 54.6,
49.9, 25.8. HRMS (ESI) m/z calcd for C29H24N3BrI (M+1)+
Supplementary data
Supplementary data (all additional experimental details includ-
ing methods for the kinase inhibition determination, NMR spectra
and HPLC purity data) associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.03.046.
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