Design, synthesis and biological evaluation of new tryptamine and tetrahydro-β-carboline-based selective inhibitors of CDK4

Article abstract of DOI:10.1016/j.bmc.2008.07.002

We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-tryptamine and (biphenylcarbonyl)-tetrahydro-β-carboline compounds related to the natural product fascaplysin, as novel inhibitors of CDK4/cyclin D1. We show all these molecules, prepared using the Suzuki-Miyaura reaction, being selective inhibitors of CDK4 over CDK2. The most active compounds have a CDK4 IC₅₀ in the range 9-11 μM, three of them containing the para-biphenyl plus para-substituents supporting the existence of a π-stacking pocket within the active site of CDK4.

Full text of DOI:10.1016/j.bmc.2008.07.002

Bioorganic & Medicinal Chemistry 16 (2008) 7728–7739
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and biological evaluation of new tryptamine
and tetrahydro-b-carboline-based selective inhibitors of CDK4
Paul R. Jenkins a, ,§, James Wilson a,§, Daniel Emmerson a, ,§, Marcos D. Garcia a,à,§, Matthew R. Smith a,§
,
*
Stephen J. Gray a,§, Robert G. Britton a,§, Sachin Mahale b,–, Bhabatosh Chaudhuri b,–
a Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
b School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-
tryptamine and (biphenylcarbonyl)-tetrahydro-b-carboline compounds related to the natural product
fascaplysin, as novel inhibitors of CDK4/cyclin D1. We show all these molecules, prepared using the
Suzuki–Miyaura reaction, being selective inhibitors of CDK4 over CDK2. The most active compounds have
Received 16 April 2008
Revised 24 June 2008
Accepted 2 July 2008
Available online 8 July 2008
a CDK4 IC50 in the range 9–11
supporting the existence of a
l
M, three of them containing the para-biphenyl plus para-substituents
-stacking pocket within the active site of CDK4.
Ó 2008 Published by Elsevier Ltd.
p
This paper is dedicated to the memory of
Prof. Yoshihiko Ito of Kyoto University,
Japan.
Keywords:
CDK4 inhibitors
Suzuki–Miyaura reaction
Anti-cancer
Fascaplysin
1. Introduction
R'
The development of new inhibitors of the cyclin-dependent ki-
nases is an ongoing area of research in the anti-cancer field.1 The
importance of the development of new inhibitors could be exem-
plified by the recent validation of CDK4/cyclinD1 as an anti-cancer
drug target in MCF-7 breast cancer cells.2
The natural pigment fascaplysin (1, Fig. 1) was first isolated
from the marine sponge Fascaplysinopsis Bergquist sp.3 in 1988
and has a range of interesting properties.4–6 It inhibits the growth
of several organisms including Staphylococcus aureus, Escherichia
coli, Candida albicans and Saccharomyces cerevisiae, it is capable of
suppressing the proliferation of mouse leukaemia cells and is a
potent inhibitor of cyclin-dependant kinase 4 (CDK4), causing cell
cycle arrest at the G1 phase of the cell cycle in both normal and
tumour cell lines.7 Fascaplysin (1) itself has limited potential as
N
R
O
N
H
Cl-
Type I compounds
N
2 R = Me, R' = p-Ph
Target compounds: R = H, Me; R' = Ar
R'
N
H
O
Fascaplysin 1
N
O
N
H
Type II Target compounds: R' = Ar
Figure. 1. Fascaplysin 1 and type I/II target compounds.
* Corresponding author.
an anti-cancer drug due to its toxic side effects, these are thought
to arise largely from the ability of its planar structure to intercalate
into the structure of DNA.8
We have previously reported a systematic study on the synthe-
sis and biological activity of non-planar analogues of fascaplysin.9
To devise a potent, non-toxic (non-planar) CDK4 inhibitor based
E-mail addresses: kin@leicester.ac.uk (P.R. Jenkins), mdgarcia@udc.es (M.D.
Garcia), bchaudhuri@dmu.ac.uk (B. Chaudhuri).
Present address: Department of Chemistry, Imperial College, London, UK.
Present address: Departamento de Química Fundamental, Universidade da
à
Coruña, campus da Zapateira, A Coruña, 15071, Spain (M.D.G.).
§
Tel.: +44 (0) 116 252 2124; fax: +44 (0) 116 252 3789.
Tel.: +44 (0) 116 250 7280; fax: +44 (0) 116 257 7284.
–
0968-0896/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2008.07.002

P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
7729
Suzuki–Miyaura coupling reaction as the key step as exemplified
in Scheme 1 in the retro-synthetic analysis of compound 2. Hence,
a library of analogues of type I/II bearing substitution on the termi-
nal phenyl ring of the biphenyl system, differing groups on the
chain nitrogen and alterations to the tryptamine backbone struc-
ture, were efficiently synthesised using this strategy (Schemes 2,
3 and Fig. 3).
The Suzuki–Miyaura reaction is now a well-established proce-
dure for the coupling of sp2 centres.12–14 An aromatic halide, of-
ten an aromatic bromide, is coupled to an aromatic boronic acid
using Pd0 as a catalyst. The reaction is easily applicable to a
wide range of substrates and generally proceeds in high yield,
side products, and starting materials being easily separated by
flash column chromatography. Even though the Suzuki–Miyaura
reaction on indole substrates has been reported,15 the closest
example to the chemistry described in this paper is the conver-
sion of a tryptamine sulfonamide to a biphenyl structure.16 The
results shown below further illustrate the versatility of this
cross-coupling methodology for the synthesis of unsubstituted
indole compounds.
Figure. 2. Compound 2 docked with the CDK4 homology model.9b
on fascaplysin (1), we designed a series of tryptamine-based ana-
logues of type I (Fig. 1).9a,9b Moreover, a series of related tetrahy-
dro-b-carbolines of type II (Fig. 1), that have less conformational
freedom, were synthesised.9b The most active compound reported
in these series was biphenyl-4-carboxylic acid [2-(1H-indol-3-yl)-
Tryptamine (3) and N-x-methyl tryptamine (4) ( Scheme 2)
were reacted with the corresponding o/m/p-benzoyl chlorides to
produce key intermediates 5a–f in moderate to good yields. Two
series of type I para-biphenyl derivatives (6a–k) in which the ter-
minal aromatic ring contained different substituents in the 4-posi-
tion were prepared by Suzuki–Miyaura coupling of 5a and 5d
with a range of 4-substituted boronic acids in yields of 42–65%
(Scheme 1).
ethyl]-methyl-amide (2, Fig. 1), which has an IC50 of 6
lM for the
inhibition of CDK4/cyclin D1 and 521
lM for the inhibition of
CDK2/cyclin A.10
These results, coupled with in silico studies using our homology
model of CDK4 postulated the existence of a strong -stacking
The biphenyl derivatives were also synthesised in the 1,2 form
(ortho-biphenyl) by reaction of key intermediate 5c with the
appropriate phenylboronic acid to provide the series 8a–e (Scheme
1). One example of 1,3-derivative (meta-biphenyl) was produced
from the intermediate 5b to give 7 (Scheme 1). As compound 7
was found to have a significantly lower IC50 value than compounds
in the ortho/para-biphenyl type I series in an initial screen, no more
compounds with the meta-biphenyl moiety were prepared for this
study.
A small library of 1,2- 1,3- and 1,4-biphenyl inhibitors of type II
was produced from the three tetrahydro-b-carboline derivatives
10a–c (Scheme 3). The ortho-biphenyls 11a–d (in 56–82% yields),
meta-biphenyls 12a–h (in 61–88% yields) and the para-biphenyl
derivatives 13a–h (in 66–91% yields).
p
interaction between the terminal phenyl ring of compound 2 and
two phenylalanine residues (Phe 93 and Phe 159) within the active
site of CDK4 (Fig. 2),9b possibly analogous to the ‘Phe 80 pocket’ of
CDK2,11 where the amino acid residue Phe 93 of CDK4 would be
equivalent to Phe 80 in CDK2.
In this paper, taking compound 2 as a lead, a series of bi- and
tri-phenyl derivatives of type I and II (Fig. 1) were synthesised
using the Suzuki–Miyaura reaction in an effort to investigate the
nature and scope of the
p-stacking interaction in the proposed
‘Phe 93 pocket’ of CDK4 as a possible target for the development
of future inhibitors of this enzyme.
2. Results and discussion
2.1. Synthesis
In some cases, the terminal phenyl ring of the biphenyl unit in
type I and II compounds was replaced by a pyridine ring. Pyridine
boronic acids have been used extensively in the Suzuki–Miyaura
reaction; however, only very few examples involving indole and
tryptamine substrates17,16 have been reported. The compounds
shown in Figure 3 further illustrate the range of structures that
can be prepared using the highly versatile Suzuki–Miyaura reac-
tion. For this purpose, key intermediates 5b, 5d and 10c were
Compound 2 was originally synthesised from N-x-methyl
tryptamine and biphenyl carbonyl chloride;9a,9b however, this syn-
thetic route does not lend itself to the synthesis of the target com-
pounds of type I/II, so a new strategy was designed using the
Br
N
NH
Br
Ph
O
N
N
H
H
N
NH2
+
+
OH
B
O
N
H
N
H
Cl
OH
Lead compound 2
O
Scheme 1. Retrosynthetic analysis for lead compound 2.

7730
P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
NH
b)
N
Br
R
a)
N
H
N
H
N
H
N
H
R
5c
O
3
4
: R = H
O
'
8a
: R = p-F
R'
: R = Me
8b: R' = p-tBu
5a: R = H, p-Br
5b
: R = H, m-Br
8c: R' = p-OMe
+
5c: R = H, o-Br
8d: R' = m-OMe
5d: R = Me, p-Br
'
5e
: R = Me, m-Br
8e
8f
: R = o-OMe
Br
Cl
5f: R = Me, o-Br
b) 5a/d
'
: R = m-F
8g: R' = m-Me
b) 5b
O
R'
N
R
N
HN
N
H
H
O
O
7
6a
2
: R = Me, R' = H 6g: R = H, R' = H
=
6b: R = Me, R' = F
6h: R = H, R' = F
6c: R = Me, R' = Me
6i
: R = H, R' = Me
t
t
6d
6e
: R = Me, R' = Bu
6j: R = H, R' = Bu
: R = Me, R' = OMe 6k: R = H, R' = OMe
6f: R = Me, R' = Ph
Scheme 2. Synthetic route to type I target compounds. Reagents and conditions: (a) CH2Cl2, NaOH (4 M, aq, 1 equiv), 0 °C 15 min then rt. 3 h; (b) Pd(PPh3)4, toluene, EtOH,
(HO)2BC6H4R0, K2CO3 (2 M, aq), 90 C, 24 h.
Br
NH
R'
b)
N
N
N
H
+
N
H
N
H
a)
9
10c
O
O
'
11a
: R = p-F
R'
10a: R = p-Br
11b: R' = m-F
10b
: R = m-Br
10c: R = o-Br
Cl
11c: R' = o-F
'
11d
: R = m-Me
O
b)
b)
10a
10b
R'
N
N
N
HN
H
R'
O
O
13e
12a
12b
13a: R' = p-F
13b
: R' = m-Me
: R' = p-F 12e: R' = m-Me
13f
: R' = m-F
: R' = m-F
: R' = o-Me
12f: R' = o-Me
12c: R' = o-F
13c: R' = o-F 13g
: R' = m-OMe
12g: R' = m-OMe
: R' = p-Me
12h: R' = o-OMe
12d
13d
: R' = p-Me 13h: R' = o-OMe
Scheme 3. Synthetic route to type II target compounds (for reagents and conditions see Scheme 2).
reacted with 3- and 4-pyridineboronic acids to produce com-
2.2. Biological evaluation
pounds 14, 15 and 16a–b (54–80% yields).
The para-biphenyl compound 6g, Table 1 has an IC50 for CDK4
inhibition of 16 M. The addition of a para-methyl group in 6i leads
to a small increase in the IC50 to 18 M. However, with a tert-butyl
group in 6j the IC50 falls to 9.2 M. One possible explanation for
this is the existence of a synergy between the proposed -stacking
interaction and a strong lipophilic component in the binding mode
of the inhibitors in the proposed ‘Phe 93 pocket’ of CDK4. A para-
fluoro substituent in 6h gives an IC50 of 15 lM, which is the same
as the parent compound 6g, within experimental error. A para-
l
l
R3
l
p
N
R2
N
R1
N
H
N
H
O
O
R
1
2
3
14
15
: R = Me, R = H, R = 4-pyridyl
16a
: R = 4-pyridyl
: R = 3-pyridyl
1
2
3
16b
: R = H, R = 3-pyridyl, R = H
electron donating group such as OMe in 6k leads to a substantially
higher IC50 of 48 lM.
Figure. 3. Type I/II pyridinyl substituted inhibitors.

P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
7731
Table 1
Type II tetrahydro-b-carboline inhibitors 11a–d, 12a–h and
13a–h show a range of IC50 values from 70 to 9 M. In the para-
biphenyl series, 13a–h, three have IC50 less than 20 M, the best
compound 13d, with a para-Me group, has an IC50 of 9 M, ortho-
and para-fluoro derivatives 13c and 13a show IC50 of 17 and
12 M, respectively. The best meta-biphenyl substituent is the
meta-methyl compound 12e (IC50 11 M) and the best ortho-
biphenyl compound is the ortho-fluoro compound 11c (IC50
19 M). Following the trend of the type I compounds, the para-
biphenyl molecules showed, in general, higher IC50 values than
the ortho/meta-biphenyl series.
Inclusion of a pyridine moiety in the outer phenyl ring of type I
and II target compounds (Fig. 3) leads to decreased CDK4 inhibition
activities with respect to the lead compound 2.
CDK4 activity versus CDK2 activity
l
CDK4 inhibitiona IC50
/
l
M
CDK2 inhibitionb (IC50
/lM)
l
Compound
1 Fascaplysin
2 (6a)
l
0.55
6
500
1
3
521 12
l
6b
6c
6d
6e
6f
6g
6h
6i
21
875
70
9
4
l
24 1.5
11.2 1.3
745 20
289 10
l
49
2
35 2.5
16 2.1
15 1.5
18 1.9
9.2 0.8
48 3.1
91
6
855 7.5
764 14
816 12
790 18
1085 17
6j
6k
7
86
4
1002 13
1216 19
8a
8b
8c
8d
8e
8f
38 2.6
38 2.5
3. Conclusions
262
9
79
53 1.8
26
20 1.5
15
4
921 12
926 17
375 10
We have synthesised a library of biphenyl derivatives of trypt-
amine and tetra-hydro-b-carboline of type I/II using the Suzuki–
Miyaura reaction, clearly showing the versatility of this important
process.
2
417
9
8g
2
406 12
Most of the compounds exhibit a clear CDK4/cyclin D1 selectiv-
ity (compared with CDK2/cyclin A). Additionally, para-biphenyl
tryptamine and tetrahydro-b-carboline based compounds showed,
in general, better biological results than the ortho- and meta-biphe-
nyl analogues, pointing out the preferred orientation of the biphe-
nyl moiety of the inhibitor within the proposed ‘Phe 93 pocket’ of
the enzyme.
Three of the most active compounds 6d, 6j and 13d (IC50 = 9.2,
11.2 and 9 lM, respectively) are para-substituted biphenyls with
tert-butyl or Me in the para-position. This suggests that a strong
lipophylic component in the binding mode of these compounds,
11a
11b
11c
11e
23 1.5
357 10
480 10
434 13
386 11
35
19
26
3
2
2
12a
12b
12c
12d
12e
12f
25
27
1
1
318 11
611 12
335 12
466 10
465 16
665 13
18 2.5
24
11
75
33
2
1
3
3
12g
12h
362
1109
9
9
79 2.4
13a
13b
13c
13d
13e
13f
12 1.2
21 1.5
438 12
296
as well as the proposed
p-stacking interaction of the inhibitors
9
within the ‘Phe 93 pocket’, could be responsible for the observed
CDK4/cyclin D1 inhibition results.
17
9
25
32
28
22
2
0.8
3
2
2
310 15
736 14
405 12
340 18
424 12
321 13
4. Experimental
4.1. Bio assays
13g
13h
1
14
15
26 2.5
30 2.5
92
3
150 3.5
Expression and purification of CDK4/GST-cyclinD1, CDK2/GST-
cyclinA and GST-RB152. Fusion proteins of human cyclins A and
D1, covalently linked to glutathione S-transferase (GST), were co-
expressed with the catalytic subunits CDK2 and CDK4 in Sf-9 insect
cells as described previously.18–21
16a
16b
39
36
3
4
354
312
5
7
a
CDK4-cyclin D1 assay, using GST-RB152 fusion protein as the substrate.
CDK2-cyclin A assay using histone H1 as the substrate.
b
Active enzyme complexes, containing a catalytic subunit bound
to GST-Cyclin, were bound to glutathione–agarose columns (Sig-
ma, Catalogue No. G3907) and were eluted from the columns with
reduced glutathione. The reduced glutathione was removed by dia-
lysing the enzymes in 10,000 MCO dialysis cassettes (Pierce, Cata-
logue No. 66830) with two buffer changes.
The GST-RB152 fusion construct was transformed into the Esch-
erichia coli strain BL21(DE3)pLysS (Novagen Catalogue No. 69451-
4). For expression of GST-RB152, the cells were induced in the
presence of a final concentration of 4 mM isopropyl-b-thiogalacto-
pyranoside (IPTG, Invitrogen Catalogue No. 15529-091) and were
allowed to grow for 4 h in a shaking incubator at 37 °C and
220 rpm. Purification of the GST-RB152 protein was carried out
as described previously.21 Protein estimation was performed using
the Bradford protein assay (Bio-Rad Laboratories) with bovine ser-
um albumin (BSA) as the standard and the purity of the fusion pro-
tein was assessed by SDS–PAGE analysis. Proteins were stained
with Coomassie blue for visualisation.
The trend described above for structures 6g–k is also exhibited
by derivatives of 2 (6a), 6b–f. Compound 2 (6a) shows an IC50 for
inhibition of CDK4 of 6 M. The para-methyl group in compound
6c leads to a higher IC50 of 24 M, the figure then falls in the case
of the para(tert-butyl) group in 6d IC50 11.2 M and the para-phe-
nyl of 6f leads to an IC50 of 35 M. In this series, the para-fluoro
compound 6b has a higher IC50 of 21 M compared to the parent
compound 2 (6a). Compound 6e with a para-OMe group is a weak-
er inhibitor, IC50 49 M, a similar figure to 6k.
l
l
l
l
l
l
Conversion to an ortho-biphenyl structure leads to compounds
8a–g, where the IC50 values are in general higher than parent com-
pounds 6g–k. The most active compounds in the ortho-biphenyl
series are 8e ortho-OMe IC50 26
lM, meta-fluoro 8f 20
lM and fi-
nally the best compound is 8g meta-Me IC50 15
lM.
The overall conclusion of the results of type I compounds is that
the best IC50 is obtained for the para-biphenyl compounds 6d and
6j (both with a tert-butyl group in the para-position of the outer
phenyl ring) with IC50 values in the same range as for the lead com-
pound 2 (6a).
Kinase assays and IC50 determination. The assay measures the
depletion in ATP concentration as a result of phosphorylation of

7732
P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
retinoblastoma (GST-RB152) and Histone H1 (Upstate Biotech Cat-
alogue No. 14-155) by CDK4 and CDK2, respectively. The assay was
run in a 96-well format and all steps in one assay were carried out
in a single white polystyrene plate (Sarstedt, Catalogue No. DPS-
134-050A). The compounds were dissolved in DMSO as 10 mM
stock solutions. Compounds were further serially diluted in kinase
buffer (40 mM Tris (pH 7.5), 20 mM MgCl2 and 0.1 mg/mL BSA) in
order to obtain the desired concentrations. The kinase assay was
4.2.2. [2-(1H-Indol-3-yl)-ethyl]-methyl-amine 49b,22
To a solution of [2-(1H-indol-3-yl)-ethyl]-carbamic acid ethyl
ester (13.78 g, 59.4 mmol) in dry THF (110 mL) under N2 at 0 °C
was added portionwise LiAlH (6.76 g, 178 mmol). After the addi-
tion was complete, the mixture was heated under reflux for 1 h.
The reaction was then cooled to 0 °C and the excess of LiAlH4
was hydrolysed by adding successively and very carefully; water
(13.25 mL), 15% aqueous solution of NaOH (13.25 mL) and water
(3ꢀ 13.25 mL). During these steps, it was necessary to add THF
(100 mL) to avoid the mixture becoming very thick. The suspen-
sion was filtered and the white solid, made up of LiOH and Al(OH)3,
was washed with THF (30 mL). The organic layer was dried
(MgSO4) and evaporated under reduced pressure to give the title
performed in 50
GST-RB152 (in case of Cdk4/GST-cyclin D1) or 3
(in case of Cdk2/GST-cyclin A) and 6 M ATP. The phosphatase
l
l of kinase buffer containing 2
lg of purified
lg of Histone H1
l
and protease inhibitor cocktail containing b-glycerophosphate, so-
dium fluoride and sodium orthovanadate in the presence of reduc-
ing agent dithiothreitol was added at the final concentrations of 10,
0.1, 0.1 and 1, respectively. The assay was initiated by adding
200 ng of active enzyme complexes, and the plate was incubated
for 30 min at 30 °C in a humidified incubator. The reaction was
stopped by addition of equal volume of the Kinase Glow ReagentTM
(Promega Catalogue No. V6711). The luminescence was measured
using the Packard Luminometer (Fusion 3.50) and the rate of ATP
depletion (rate of reaction) in the control blank reactions (i.e.,
without substrate or enzyme) was calculated and used to deter-
mine the IC50 concentrations of compounds. In case of CDK4/cyclin
D1 assay, the two compounds fascaplysin and flavopiridol with
known IC50 values were used to validate the assay. For the CDK2/
cyclin A assay, roscovitine and flavopiridol were used as standards
for the assay.
compound
4 (9.24 g, 89%) as a beige solid; mp 82 °C; dH
(300 MHz, CDCl3) 1.47 (1H, s), 2.35 (3H, s), 2.81–2.86 (2H, m),
2.89–2.94 (2H, m), 6.80 (1H, s), 7.03 (1H, td, J 7.4 and 1.2), 7.10
(1H, td, J 7.4 and 1.2), 7.19 (1H, d, J 7.6), 7.54 (1H, d, J 7.6), 9.52
(1H, s); dC (75 MHz, CDCl3) 25.4 (CH2), 36.0 (CH3), 51.8 (CH2),
111.3 (CH), 112.9, 118.7 (CH), 118.9 (CH), 121.6 (CH), 122.5 (CH),
127.3, 136.5; m/z (FAB) 175.12354 (M+H+ C11H15N2 requires
175.12352). Found: C, 75.74; H, 8.04; N, 16.00. C11H15N2 requires
C, 75.82; H, 8.10; N, 16.08.
4.3. General procedure for the synthesis of 5a–c
To a stirred solution of tryptamine 3 (1.2 mmol) in dichloro-
methane (3 mL) at 0 °C was added slowly an aqueous solution of
sodium hydroxide 4 M (1.2 mmol). After 5 min stirring at 0 °C
was added dropwise the benzoyl chloride derivative (1.2 mmol).
The mixture was stirred for 5 min at 0 °C and then for 3 h at room
temperature. H2O (20 mL) was added. The two layers were sepa-
rated and the aqueous phase was extracted with dichloromethane
(3ꢀ 20 mL). The organic layers were dried (MgSO4) and evaporated
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel. Elution was made succes-
sively with; ethyl acetate/petroleum ether 50:50 and ethyl acetate,
to give the title compound.
4.2. Chemistry
NMR spectra were recorded on Bruker DPX 300 (1H,
300.13 MHz ; 13C, 75.47 MHz; 19F 282.39 MHz) or DPX 400 (1H,
400.13 MHz; 13C, 100.61 MHz) spectrometers as indicated. Chem-
ical shifts were measured relative to chloroform (1H d 7.26, 13C d
77.0) or dimethylsulfoxide (1H d 2.50, 13C d 39.43) and are
expressed in ppm. Coupling constants J are expressed in Hertz
and the measured values are corrected to one decimal place. Fast
atom bombardment (FAB) mass spectra were recorded on a
Kratos Concept 1H using xenon and m-nitrobenzyl alcohol as
the matrix. Electrospray (ES) mass spectra were recorded on a
Micromass Quattro LC spectrometer. Accurate mass was mea-
sured on a Kratos Concept 1H spectrometer using peak matching
to stable reference peak. Flash column chromatography was car-
ried out using Merck Kiesegel 60 (230–400 mesh). Dry solvents
4.3.1. 4-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-benzamide (5a)
Pale yellow solid; yield 67%; mp 148–149 °C; dH (300 MHz,
(CD3)2SO) 3.0 (2H, t, 7.4) 3.6 (2H, q, 6.9), 7.0 (1H, t, 7.4), 7.1 (1H,
t, 7.4), 7.2 (1H, d, 1.5), 7.4 (1H, d, 8.1), 7.6 (1H, d, 7.8), 7.7 (2H, d,
8.7), 7.8 (2H, d, 8.4), 8.7 (1H, t, 5.4), 10.8 (1H, s); dC (75 MHz;
(CD3)2SO) 25.1 (CH2), 40.3 (under solvent peak, CH2), 111.4 (CH),
111.8, 118.2 (CH, d), 120.9 (CH), 122.7 (CH), 126.2, 127.2, 128.1
(CH, 2C), 129.0 (CH, 2C), 136.2, 136.5, 167.0; m/z (FAB)
343.04453 (M+H+ C17H16N2OBr requires 343.04467). Found:
C,59.38; N, 8.16; H,4.35. C17H15N2OBr requires C, 59.49; N, 8.16;
H, 4.40.
TM
were provided by a PURE SOLV system from Innovative Technol-
ogy Inc.
4.2.1. [2-(1H-Indol-3-yl)-ethyl]-carbamic acid ethyl ester9b,22
To a solution of tryptamine 5 (10.00 g, 62.4 mmol) in CHCl3
(156 mL) at 0 °C was added ethylchloroformate (5.97 mL,
62.4 mmol) and an aqueous solution of NaOH (15.60 mL, 4 M,
62.4 mmol). After addition, the mixture was stirred for 3 h at
room temperature and then washed with water (150 mL), the
aqueous phase was extracted with dichloromethane (2ꢀ
150 mL), and the combined organic layers were dried (MgSO4)
and evaporated under reduced pressure to give an orange oil,
no purification was necessary. The oil was dried in vacuo to give
the title compound 3 (13.78 g, 95%); dH (300 MHz, CDCl3) 1.33
(3H, t, J 7.0), 3.05 (2H, t, J 6.5), 3.60 (2H, q, J 6.5), 4.24 (2H, q, J
7.0), 5.12 (1H, br s), 6.99 (1H, s), 7.23 (1H, t, J 6), 7.30 (1H, td, J
6 and 1.2), 7.42 (1H, d, J 7.7), 7.71 (1H, d, J 7.7), 8.75 (1H, s); dC
(75 MHz, CDCl3) 14.57 (CH3), 25.64 (CH2), 41.21 (CH2), 60.72
(CH2), 111.33 (CH), 112.33, 118.54 (CH), 119.11 (CH), 121.83
(CH), 122.26 (CH), 127.18, 136.39, 156.93; m/z (FAB+) 232 M+,
233 (M+H)+, 465 (2M+H)+. Found: M+, 232.12126. C13H16N2O2 re-
quires M, 232.12118.
4.3.2. 3-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-benzamide (5b)
Off white solid; yield 79%; mp 132–135 °C, dH (300 MHz;
(CD3)2SO) 3.0 (2H, t, 7.6,), 3.6 (1H, aq, 7.0), 7.0 (1H, t, 7.0), 7.1
(1H, t, 7.0), 7.2 (1H, d, 2.1), 7.4 (1H, t, 7.9), 7.6 (1H, d, 8.9), 7.7
(1H, d, 8.9), 7.9 (1H, d, 7.9), 8.1 (1H, s), 10.8 (1H, s), dC (75 MHz;
(CD3)2SO) 25.0 (CH2), 40.3 (CH2), 111.4, 111.8, 118.2, 120.9,
121.6, 122.6, 126.3, 127.3, 129.9, 130.5, 133.8, 136.2, 136.9,
164.6. m/z (FAB) 343.04427 (M+H+ C17H16BrN2O requires
343.04460).
4.3.3. 2-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-benzamide (5c)
Off white solid; yield 86%; mp 144–145 °C; dH (300 MHz;
(CD3)2SO) 3.0 (2H, t, 7.7), 3.5 (2H, aq, 6.9), 7.0 (1H, dt, 1.2, 7.9),
7.1 (1H, dt, 1.2, 6.9), 7.2 (1H, d, 2.2), 7.3–7.5 (4H, br m), 7.6 (1H,
d, 7.7), 8.6 (1H, t, 5.7), 10.9 (1H, s); dC (75 MHz; (CD3)2SO) 25.5
(CH2), 40.4 (CH2), 111.9 (CH), 112.1, 118.7 (CH) (2C), 119.5, 121.4

P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
7733
(CH), 123.3 (CH), 127.7, 128.0 (CH), 129.2 (CH), 131.2 (CH), 133.1
(CH), 136.7, 139.8, 167.7. m/z (FAB) 343.04417 (M+H+ C17H16BrN2O
requires 343.04460).
22.9 (CH2), 36.5 (CH3), 47.7 (CH2), 111.6, 118.7 (CH), 118.9, 121.4
(CH), 123.4 (CH), 127.3, 130.9 (CH), 132.9 (CH), 136.8, 139.2,
168.2; m/z (ES+) 358; (ESꢁ) 356 (MꢁH)ꢁ; m/z (FAB+) 357.06015
(M+ C18H17BrN2O requires 357.06025). Found: C, 60.38; H, 4.81;
N, 7.81. C18H17BrN2O requires C, 60.52; H, 4.80; N, 7.84.
4.4. General procedure for the synthesis of 5d/e
To a stirred solution of 2-(1H-indol-3-yl)-ethyl]-methyl-amine
4 (1.2 mmol) in dichloromethane (3 mL) at 0 °C was added slowly
an aqueous solution of sodium hydroxide 4 M (1.2 mmol). After
5 min stirring at 0 °C was added dropwise the appropriate benzoyl
chloride derivative (1.2 mmol). The mixture was stirred for 5 min
at 0 °C and for 3 h at room temperature. Water (20 mL) was added
and the two layers were separated, the aqueous phase was ex-
tracted with dichloromethane (3ꢀ 20 mL). The organic layers were
then dried (MgSO4) and evaporated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel. Elution was made successively with; ethyl acetate/petro-
leum ether 50:50 and ethyl acetate, to give the expected
compound.
4.5. General procedure for the preparation of compounds 2
(6a), 6b–k, 7, 8a–g, 11a–d, 12a–h, 13a–h, 14, 15 and 16a–b: The
Suzuki coupling reaction
To a stirred solution of the corresponding brominated interme-
diate (5a–f, 10a–c, 1 mmol) in toluene (10 mL), under nitrogen,
were added K2CO3 (1 mmol, 2 M aqueous) and Pd(PPh3)4 (5 mol%,
0.05 mmol). The solution was stirred for 20 min at room tempera-
ture before the addition of a solution of the appropriately substi-
tuted boronic acid, (1.2 mmol) in EtOH (10 mL). The reaction
mixture was heated to 90 °C for 24 h, then allowed to cool to room
temperature before the addition of H2O2 (30%, 1 mL), the reaction
mixture was then stirred for a further 1 h. The desired product
was extracted into CHCl3, washed with saturated brine solution
(2ꢀ 25 mL) and H2O (2ꢀ 25 mL), aqueous washings being re-ex-
tracted with CH2Cl2 (3ꢀ 50 mL), the combined organic phases were
then dried over anhydrous sodium or magnesium sulfate, filtered
and isolated under reduced pressure. The crude product was then
purified by flash column chromatography on silica from ethyl ace-
tate–petroleum ether (40–60 °C).
4.4.1. 4-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-N-methyl-
benzamide (5d)9b
White solid; yield 73%; mp 160 °C; rotamers 1/1.5 (from the
duplicated triplet signal (1H) at 3.45 and 3.77 ppm); dH
(300 MHz, CDCl3) d (major rotamer) 2.83 (2H, t, J 6.3), 3.07 (3H,
s), 3.45 (2H, t, J 6.3), 6.71–7.62 (9H, m), 8.41 (1H, br s); d (distinct
peaks for minor rotamer) 2.76 (3H, s), 3.77 (2H, distorted t, J 7.1); dC
(75 MHz, CDCl3) d ( major rotamer) 24.2 (CH2), 33.0 (CH3), 51.7
(CH2), 111.4 (CH), 112.7, 118.0 (CH), 119.4 (CH), 122.1 (CH),
122.4 (CH), 123.3, 127.0, 128.1 (2CH), 131.3 (2ꢀ CH), 135.0,
136.3, 171.4; d (distinct peaks for minor rotamer) 22.9 (CH2), 38.2
(CH3), 48.6 (CH2), 118.7 (CH), 123.7, 127.5, 128.7 (CH), 131.6
(CH), 135.5, 170.4; m/z (ES+) 358 MH+; (ESꢁ) 356 (MꢁH)ꢁ; m/z
(FAB) M+, 357.06027 (M+ C18H17BrN2O requires 357.06025).
Found: C, 60.58; H, 4.96; N, 7.76. C18H17BrN2O requires C, 60.52;
H, 4.80; N, 7.84.
4.5.1. N-(2-(1H-Indol-3-yl)ethyl)-40-fluoro-N-methylbiphenyl-
4-carboxamide (6b)
Pale yellow solid; yield 65%; mp 181–183 °C; dH (300 MHz;
(CD3)2SO) rotamers 1/1.25 (from the duplicated triplet signal (1H)
at 3.47 and 3.74 ppm); 2.91 (3H, br), 3.08 (2H, br), 3.47 (2H, br),
6.72 (distorted t), 6.93–7.06 (4H, m), 7.19–7.34 (7H, m), 7.45 (1H,
br d, 7.2), 7.54 (2H, br d, 7.6), 7.70 (5H, m), 10.83 (1H, br s); d (dis-
tinct peaks for minor rotamer) 3.74 (2H, br), 2.91 (3H, br), 3.08 (2H,
br), 10.87 (1H, br s); dC (75 MHz; (CD3)2SO) 24.4 (CH2), 32.8 (CH3),
2
51.9 (CH2) 110.9, 111.9 (CH), 116.3 (d, JCF, 21, CH), 118.3 (CH),
4.4.2. 3-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-N-methyl-benza-
mide (5e)9b
118.7 (CH), 121.4 (CH), 123.7 (CH), 126.8 (CH), 127.4 (CH), 128.0,
3
1
129.2 (d, JCF 8, CH), 136.2, 136.4, 136.7, 140.0, 162.5 (d, JCF
,
White solid; yield 76%; mp 166 °C; rotamers 1/1.4 (from the
duplicated triplet signal (1H) at 3.46 and 3.78 ppm); dH
(300 MHz, CDCl3) d (major rotamer) 2.87 (2H, t, J 6.9), 3.09 (3H,
s), 3.46 (2H, t, J 6.9), 6.76–7.61 (9H, m), 8.25 (1H, br s); d (distinct
peaks for minor rotamer) 2.76 (3H, s), 3.78 (2H, t, J 6.9); dC (75 MHz,
CDCl3) d (major rotamer) 24.2 (CH2), 33.1 (CH3), 51.9 (CH2), 111.4
(CH), 112.7, 118.0 (CH), 119.4 (CH), 122.1 (CH), 122.3 (CH), 125.0
(CH), 127.0, 129.8 (CH), 129.9 (CH), 132.1 (CH), 133.0, 136.2,
138.2, 170.7; d (distinct peaks for minor rotamer) 22.9 (CH2), 38.2
(CH3), 48.6 (CH2), 118.7 (CH), 125.5 (CH), 127.5, 129.5 (CH),
130.1 (CH), 132.5 (CH), 136.0, 138.6, 169.7; m/z (ES+) 357 M+,
358 MH+; (ESꢁ) 356 (MꢁH)ꢁ; m/z (FAB) 357.06030 (M+
C18H17BrN2O requires 357.06025). Found: C, 60.38; H, 4.80; N,
7.73. C18H17BrN2O requires C, 60.52; H, 4.80; N, 7.84.
245), 171.0; ( distinct peaks for minor rotamer) 23.1 (CH2), 37.9
(CH3), 48.4 (CH2), 123.3 (CH), 128.0, 170.0. Found: C, 77.32; N,
7.42; H, 5.60. C24H21N2OF requires C, 77.40; N, 7.52; H, 5.68.
4.5.2. N-(2-(1H-Indol-3-yl)ethyl)-N,40-dimethylbiphenyl-4-car-
boxamide (6c)
Off white solid; yield 44%; mp 215–217 °C; dH (300 MHz;
(CD3)2SO) Rotomers 1/2.1 (from the duplicated triplet signal (1H)
at 3.46 and 3.73 ppm), 2.91 (3H, br), 3.07 (2H, br), 3.46 (2H, br),
6.70 (1H, br), 6.91–7.05 (3H, m), 7.19–7.30 (4H, m), 7.42–7.44
(1H, m), 7.56–7.67 (4H, m), 10.8 (1H, br s); d (distinct peaks for min-
or rotamer) 3.73 (2H, br), 10.83 (1H, br s); dH (400 MHz; (CD3)2SO;
353 K) 2.38 (3H, s), 2.99 (5H, m), 3.64 (2H, br s), 6.89 (1H, br s), 7.05
(1H, t, 7.5), 7.10 (1H, br s), 7.23–7.36 (3H, m), 7.56–7.58 (2H, m),
7.61 (5H, d, 8.0), 10.60 (1H, s); dC (75 MHz; (CD3)2SO) 20.6 (CH3),
23.9 (CH2), 32.3 (CH3), 51.4 (CH2), 110.3, 111.3 (CH), 117.8 (CH),
118.2 (CH), 120.8 (CH), 123.0 (CH), 126.1 (CH, 2C), 126.5 (CH,
2C), 129.5 (CH, 4C), 135.4, 136.1, 136.5, 137.1, 140.4, 140.7,
170.5; d (distinct peaks for minor rotamer) 22.5 (CH2), 37.3 (CH3),
47.8 (CH2), 126.9 (CH), 127.4 (CH).
4.4.3. 2-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-N-methyl-benza-
mide (5f)9b
Tan solid; yield 48%; mp 205 °C; rotamers 1/1.2 (from the dupli-
cated triplet signal (1 H) at 3.34 and 3.79 ppm); dH (400 MHz,
363 K, (CD3)2SO) d (major rotamer) 2.92 (2H, t, J 7.3), 3.10 (3H, s),
3.34 (2H, t, J 7.3), 6.90–7.10 (3H, m), 7.19–7.44 (5H, m), 7.63 (1H,
br t, estimated J 9.4), 10.61 (1H, br s); d (distinct peaks for minor
rotamer) 2.77 (3H, s), 3.79 (2H, t, J 7.6), 6.84 (1H, t, J 7.4); dC
(75 MHz, (CD3)2SO) d (major rotamer) 24.3 (CH2), 32.4 (CH3), 51.3
(CH2), 110.7, 111.9 (CH), 118.1 (CH), 118.7 (CH), 118.8, 121.4
(CH), 123.5 (CH), 127.7, 128.2 (CH), 128.5 (CH), 130.7 (CH), 132.7
(CH), 136.6, 138.8, 168.3; d (distinct peaks for minor rotamer)
4.5.3. N-(2-(1H-Indol-3-yl)ethyl)-40-tert-butyl-N-methyl
biphenyl-4-carboxamide (6d)
Off white solid; yield 51%; mp 178–180 °C, overlaping rotom-
ers; dH (300 MHz; (CD3)2SO) 1.36 (9H, s, C(CH3)3), 2.86 (3H, br s),
3.04–3.14 (2H, br), 3.60–3.82 (2H, br), 7.08–7.62 (13H, br), 10.05
(1H, br s); dC (75 MHz; (CD3)2SO) 22.6 (CH2), 23.9 (CH2), 31.0

7734
P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
(CH3), 32.3 (CH3), 34.2 (C), 37.4 (CH3), 47.9 (CH2), 51.4 (CH2), 110.4
(C), 111.4 (CH), 117.9 (CH), 120.9 (CH), 123.0 (CH), 125.7 (CH),
126.2 (CH), 126.4 (CH), 126.9 (CH), 127.5 (CH), 135.5 (C), 136.2
(C), 140.5 (C), 140.8 (C), 150.2 (C), 169.6 (C), 170.6 (C). Found: C,
81.81; N, 6.72; H, 7.27. C28H30N2O requires C, 81.91; N, 6.82; H,
7.36; m/z (ES+) 411 [M+H+], 433 [M+Na+], (ESꢁ) 409 [MꢁHꢁ]; m/z
(FAB) 411.24347 (M+H+ C28H31N2O requires 411.24364).
359.15593 (M+H+ C23H20N2OF requires 359.15597). Found: C,
76.97; N, 7.75; H, 5.51. C23H19N2OF requires C, 77.08; N, 7.82; H,
5.34.
4.5.8. N-(2-(1H-Indol-3-yl)ethyl)-40-methylbiphenyl-4-carbo-
xamide (6i)
Off white solid; yield 42%; mp 204–206 °C; dH (300 MHz;
(CD3)2SO) 2.39 (3H, s), 3.02 (2H, t, 7.5), 3.62 (2H, dt, 7.5, 5.6),
7.03 (1H, ddd, 7.4, 7.4, 1.1), 7.12 (1H, ddd, 7.4, 7.4, 1.1), 7.24 (1H,
d, 2.2), 7.33 (2H, d, 8.1), 7.39 (1H, d, 8.1), 7.35 (1H, d, 8.1), 7.66
(2H, d, 8.1), 7.78 (2H, d, 8.4), 7.98 (2H, d, 8.4), 8.69 (1H, t, 5.6),
10.86 (1H, br); dC (75 MHz; (CD3)2SO) 21.2 (CH2), 25.7 (CH3), 40.7
(CH2), 111.9 (CH), 112.4, 118.7 (CH), 118.8 (CH), 121.4 (CH),
123.1 (CH), 126.6 (CH, 2C), 127.1 (CH, 2C), 127.8, 128.3 (CH, 2C),
130.1 (CH, 2C), 133.7, 136.8 (2C), 137.9, 143.0, 166.3; m/z (FAB)
355.18110 (M+H+ C24H23N2O requires 355.18104). Found: C,
79.20; N, 7.40; H, 5.84. C24H22N2O requires C, 81.33; N, 7.90; H,
6.26.
4.5.4. N-(2-(1H-Indol-3-yl)ethyl)-40-methoxy-N-methylbiphe-
nyl-4-carboxamide (6e)
Off white solid; yield 46%; mp 201–202 °C; dH (300 MHz;
(CD3)2SO) Rotomers 1/1.8 (from the duplicated triplet signal (1H)
at 3.47 and 3.73 ppm), 2.91 (3H, br), 3.07 (2H, br), 3.46 (2H, br),
3.80 (3H, s), 6.71 (1H, m), 6.92–7.05 (4H, m), 7.18–7.20 (2H, m),
7.29–7.31 (1H, m), 7.41–7.53 (2H, m), 7.62 (3H, br m), 10.81 (1H,
br s); d (distinct peaks for minor rotamer) 3.07 (3H, br), 2.91 (2H,
br), 3.73 (2H, br), dC (75 MHz; (CD3)2SO) 23.9 (CH2), 32.3 (CH3),
51.4 (CH2), 55.1 (CH3), 110.3, 111.3 (CH), 114.3 (CH, 4C), 117.8
(CH), 118.0 (CH) 120.8 (CH), 123.0 (CH), 125.8 (CH, 2C), 127.7
(CH, 2C), 131.7, 134.9, 136.1, 140.2, 140.5, 159.1, 170.5; d (distinct
peaks for minor rotamer) 22.5 (CH2), 37.4 (CH3), 47.8 (CH2), 122.7
(CH), 126.8 (CH), 127.4 (CH); dC (100 MHz; (CD3)2SO, 353 K) 22.9
(CH2), 54.8 (CH3), 110.7, 110.8 (CH), 114.1 (CH), 117.5 (CH),
117.7 (CH), 120.4 (CH), 122.3 (CH), 125.3 (CH), 126.6 (CH), 126.8,
127.3 (CH), 131.5, 134.8, 135.9, 140.0, 158.9, 169.8.
4.5.9. N-(2-(1H-Indol-3-yl)ethyl)-40-tert-butylbiphenyl-4-carbo-
xamide (6j)
Off white solid; yield 61%; mp 201–203 °C; dH (300 MHz;
(CD3)2SO) 1.37 (9H, s), 3.03 (2H, t, 7.3), 3.63 (2H, td, 7.3, 5.5),
7.04 (1H, br dd, 7.5, 7.5), 7.13 (1H, br dd, 7.5, 7.5), 7.25 (1H, d,
1.6), 7.40 (1H, d, 7.5), 7.55 (2H, d, 8.4), 7.66 (1H, d, 7.5), 7.71 (2H,
d, 8.4), 7.80 (2H, d, 8.3), 7.99 (2H, d, 8.3), 8.70 (1H, dd, 5.5),
10.87 (1H, br s); dC (75 MHz; (CD3)2SO) 25.7 (CH2), 31.6 (CH3,
3C), 34.8, 40.7 (CH2), 111.9, 112.4 (CH), 118.7 (CH), 118.8 (CH),
121.4 (CH), 123.1 (CH), 126.3 (CH, 2C), 126.7 (CH, 2C), 127.0 (CH,
2C), 127.8, 128.3 (CH, 2C), 133.7, 136.7, 136.8, 142.9, 151.0,
166.3; m/z (FAB) 397.22798 (M+H+ C27H29N2O requires
397.22799). Found: C, 81.76; N, 6.97; H, 7.03. C27H28N2O requires
C, 81.78; N, 7.06; H, 7.12.
4.5.5. N-(2-(1H-Indol-3-yl)ethyl)-40-phenyl-N-methylbiphenyl-
4-carboxamide (6f)
Off white solid; yield 52%; mp 230–234 °C; dH (300 MHz;
(CD3)2SO) rotamers 1/1.58 (from the duplicated triplet signal (1H)
at 3.49 and 3.75 ppm) 2.93 (3H, br), 3.09 (2H, br), 3.49 (2H, br),
6.74 (1H, br t, 7.0), 6.95–7.07 (2H, m), 7.23 (2H, br d, 7.4), 7.32
(1H, br d, 7.9), 7.37–7.42 (2H, m), 7.47–7.52 (3H, m), 7.63 (1H, d,
7.5), 7.74 (2H, br d, 7.4), 7.79 (4H, br s), 10.83 (1H, br s), d (distinct
peaks for minor rotamer) 3.75 (2H, br), 10.86 (1H, br s); dC
(100 MHz; (CD3)2SO, 363 K) (some peaks not observed due relaxation
time) 23.9, 111.9, 118.5, 118.7, 121.4, 123.3, 126.8, 127.0, 127.7,
128.0, 129.4, 136.6, 137.0, 139.0, 140.2, 140.2, 140.8, 170.7; m/z
(FAB) 431.21230 (M+H+ C30H27N2O requires 431.21234). Found:
C, 3.56; N, 6.42; H, 5.94. C30H26N2O requires C, 83.69; N, 6.51; H,
6.09.
4.5.10. N-(2-(1H-Indol-3-yl)ethyl)-40-methoxybiphenyl-4-car-
boxamide (6k)
Off white solid; yield 45%; mp 200–205 °C; dH (300 MHz;
(CD3)2SO) 2.99 (2H, t, 7.4), 3.59 (2H, td, 7.4, 5.6), 3.81 (3H, s),
7.00 (1H, ddd, 7.4, 7.4, 1.1), 7.05 (2H, d, 8.8), 7.09 (1H, ddd, 7.4,
7.4, 1.1), 7.21 (1H, d, 2.2), 7.36 (1H, d, 7.4), 7.62 (2H, d, 7.4), 7.69
(2H, d, 8.8), 7.72 (2H, d, 8.5), 7.94 (2H, d, 8.5), 8.65 (1H, t, 5.6),
10.83 (1H, br s); dC (75 MHz; (CD3)2SO) 25.7 (CH2), 40.7 (CH2),
55.7 (CH3),111.9 (CH), 112.4, 114.9 (CH), 118.7 (CH), 118.8 (CH),
121.4 (CH), 123.1 (CH), 126.3 (CH), 127.8, 128.3 (CH), 128.5 (CH),
129.2 (CH), 129.3 (CH), 131.9 (CH), 132.5 (CH), 133.2, 136.7,
159.8, 166.3. Found: C, 77.92; N, 7.41; H, 5.89. C24H22N2O2 requires
C, 77.81; N, 7.56; H, 5.99.
4.5.6. N-(2-(1H-Indol-3-yl)ethyl)biphenyl-4-carboxamide (6g)
Off white solid; yield 63%; mp 183–185 °C; dH (300 MHz;
(CD3)2SO) 3.02 (2H, t, 7.5), 3.62 (2H, ap-q, 7.5, 5.6), 7.03 (1H, ddd,
7.5, 7.5, 1.1), 7.11 (1H, ddd, 7.5, 7.5, 1.1), 7.23 (1H, d, 2.2), 7.39
(1H, d, 7.5), 7.44 (1H, dd, 7.4, 1.1), 7.51 (2H, dd, 7.4, 7.4), 7.64
(1H, d, 7.4), 7.76 (2H, d, 7.4), 7.80 (2H, d, 8.4), 8.00 (2H, d, 8.4),
8.71 (1H, t, 5.6), 10.86 (1H, br s); d13 (75 MHz; (CD3)2SO) 25.2,
40.3, 111.4, 111.9, 118.2, 118.3, 120.9, 122.6, 126.4, 126.8, 127.3,
127.8, 128.0, 129.0, 133.5, 136.2, 139.2, 142.5, 165.8; m/z (FAB)
341.16532 (M+H+ C23H21N2O requires 341.16546). Found: C,
81.09; N, 8.18; H, 5.95. C23H20N2O requires C, 81.15; N, 8.23; H,
5.92.
4.5.11. N-(2-(1H-Indol-3-yl)ethyl)biphenyl-3-carboxamide (7)
Off white solid; yield 62%; mp 59–69 °C; dH (300 MHz; (CD3)2SO)
2.98(2H, t, 7.5), 3.58 (2H, td, 7.5, 5.5), 6.98(1H, ddd, 7.5, 7.5, 1.1), 7.07
(1H, ddd, 7.5, 7.5, 1.1), 7.20 (1H, d, 2.2), 7.35 (1H, br d, 8.0), 7.42 (1H,
br d, 7.3), 7.50 (2H, dd, 7.9, 7.9), 7.57 (1H, d, 7.9, 7.9), 7.60 (1H, d, 7.9),
7.73 (2H, dd, 7.9, 1.4), 7.80–7.86 (2H, m), 8.12 (1H, dd, 1.5, 1.5), 8.74
(1H, dd, 5.5, 5.5), 10.82 (1H, br s); dC (75 MHz; (CD3)2SO) 25.1 (CH2),
40.3 (CH2), 111.3 (CH), 111.8, 118.2 (CH), 118.2 (CH), 120.8 (CH),
122.6 (CH), 125.2 (CH), 126.3 (CH), 126.8 (CH, 2C), 127.2, 127.7
(CH), 128.9 (CH, 2C), 129.1 (CH), 135.3, 136.2, 139.5, 140.1, 165.9;
m/z (FAB) 341.16544 (M+H+ C23H21N2O requires 341.16539). Found:
C, 77.39; N, 7.89; H, 5.78. C23H20N2O requires C, 81.15; N, 8.23; H,
5.92.
4.5.7. N-(2-(1H-Indol-3-yl)ethyl)-40-fluorobiphenyl-4-carbo-
xamide (6h)
Off white solid; yield 59%; mp 181–183 °C; dH (300 MHz;
(CD3)2SO) 3.03 (2H, dd, 7.4, 7.4), 3.62 (2H, td, 7.4, 5.6), 7.04 (1H,
td, 7.4, 1.1), 7.13 (1H, ddd, 7.4, 7.4, 1.1), 7.25 (1H, d, 2.2), 7.34–
7.41 (3H, m), 7.65 (1H, d, 7.7), 7.79–7.86 (2H, m), 7.81 (2H, d,
8.4), 8.00 (2H, d, 8.4), 8.72 (1H, t, 5.6), 10.87 (1H, br s); dC
(75 MHz; (CD3)2SO) 25.7 (CH2), 40.7 (CH2), 111.9 (CH), 112.4,
4.5.12. N-(2-(1H-Indol-3-yl)ethyl)-40-fluorobiphenyl-2-carbo-
xamide (8a)
White solid; yield 28%; mp 157–159 °C; dH (300 MHz; (CD3)2SO)
2.78(2H, t, 7.3), 7.04(1H, t, 6.9), 7.12(1H, t, 6.9), 7.16(1H, d, 2.3), 7.19
2
116.3 (d, JCF, 21, CH), 118.7 (CH), 121.4 (CH), 123.1 (CH), 126.9
3
(CH, 2C), 127.8, 128.3 (CH, 2C), 129.4 (d, JCF, 8, CH), 136.2 (d,
1
4JCF, 3), 136.7 (CH), 142.0, 162.7 (d, JCF, 245) 166.2; m/z (FAB)

P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
7735
(1H, t, 8.9), 7.43 (2H, d, 5.3), 7.44–7.47 d (6H, m), 7.55 (1H, d, 7.4),
8.34 (1H, t, 5.7), 10.86 (1H, br s); dF (282 MHz, CDCl3) ꢁ114.37 d;
dC (75 MHz; (CD3)2SO) 24.6 (CH2), 39.6 (CH2), 111.3 (CH), 111.6,
(1H, d, 1.7), 7.14–7.24 (2H, m), 7.21 (1H, d, 5.5), 7.33 (1H, d, 7.9),
7.38–7.51 (4H, m), 7.43 (1H, d, 6.4), 7.50 (1H, d, 6.0), 8.36 (1H, t,
5.7), 10.81 (1H, br s); dC (75 MHz; CDCl3) 24.6 (CH2), 39.7 (CH2),
2
2
2
114.8 (d, JCF, 21, CH, 2C), 118.1 (CH, 2C), 120.8 (CH), 122.3, 122.5
111.3 (CH), 111.5, 113.8 (d, JCF, 21, CH), 115.1 (d, JCF, 22, CH),
3
4
(CH), 127.0 (CH), 127.5 (CH), 129.2 (CH), 129.7 (CH), 130.2 (d, JCF
,
118.0 (CH), 118.1 (CH), 120.8 (CH), 122.4 (CH), 124.5 (d, JCF, 2,
8, CH, 2C), 136.1, 136.5 (d, 4JCF, 3), 137.3, 137.9, 161.5 (d, 1JCF, 243),
168.8;); m/z (ESꢁ) 357 (100%, MꢁHꢁ) (ES+) 359 (100% M+H+); m/z
(FAB) 359.1559 (M+H+ C23H19N2OF requires 279.14981). Found: C,
74.99;N, 7.35;H, 4.62. C23H19N2OF requiresC, 77.08;N, 7.82;H, 5.34.
CH), 127.1, 127.5 (CH), 127.5 (CH), 129.3 (CH), 129.6 (CH), 130.0
3
4
3
(d, JCF, 8, CH), 136.1, 137.4, 137.6 (d, JCF, 2), 142.5 (d, JCF, 8),
1
161.8 (d, JCF, 243), 167.8; dF (282 MHz, CDCl3) ꢁ112.66; m/z
(FAB) 359.15607 (M+H+ C23H20FN2O requires 359.15597).
4.5.13. N-(2-(1H-Indol-3-yl)ethyl)-40-tert-butylbiphenyl-2-
carboxamide (8b)
4.5.18. N-(2-(1H-Indol-3-yl)ethyl)-30-methylbiphenyl-2-
carboxamide (8g)
White solid; yield 16%; mp 149–151 °C; dH (300 MHz; CDCl3)
1.35 (9H, s) 2.62 (2H, t, 6.8) 3.50 (2H, td, 6.8, 5.4) 5.30 (1H, t,
5.4), 6.55 (1H, d, 2.0), 7.05 (1H, dd, 6.9, 6.9), 7.15 (1H, dd, 6.9,
6.9), 7.31 (1H, d, 8.1), 7.31–7.41 (4H, m), 7.37 (2H, d, 8.5), 7.45
(2H, d, 8.5), 7.64 (1H, d, 7.5), 7.87 (1H, br s); dC (75 MHz; CDCl3)
24.5 (CH2), 31.0 (CH3, 3C), 34.1, 36.9 (CH2), 111.3 (CH), 111.6,
118.0 (CH, 2C), 120.8 (CH), 122.4 (CH), 124.8 (CH, 2C), 126.7
(CH), 127.0, 127.5 (CH), 127.9 (CH, 2C), 129.1 (CH), 129.6 (CH),
136.1, 137.1, 137.3, 138.7, 149.4, 169.0; m/z (FAB) 397.2280
(M+H+ C27N2OH29 requires 397.22799).
Pale yellow solid; yield 52%; mp 121–122 °C; dH NMR
(300 MHz, (CD3)2SO) 2.62 (2H, t, 7.2), 2.37 (3H, s), 6.96 (1H, t,
7.8), 7.03 (1H, t, 7.8), 7.07 (1H, d, 2.3), 7.13 (1H, d, 7.0), 7.18–
7.25 (3H, m), 7.24 (1H, s), 7.34 (1H, d, 8.0), 7.37–7.42 (2H, m),
7.46 (1H, d, 7.3), 7.48 (1H, d, 7.3), 8.21 (1H, t, 5.7), 10.78 (1H, br
s); dC (75 MHz; (CD3)2SO) 21.0 (CH3), 24.7 (CH2), 39.7 (CH2),
111.3 (CH), 111.6, 118.0 (CH), 118.1 (CH), 120.8 (CH), 122.4 (CH),
125.4 (CH), 126.8 (CH), 127.1, 127.5 (CH), 127.7 (CH), 128.0 (CH),
128.9 (CH), 129.1 (CH), 129.6 (CH), 136.1, 137.0, 137.4, 139.0,
140.1, 169.0; m/z (FAB) 355.18098 (M+H+ C24H23N2O requires
355.18103).
4.5.14. N-(2-(1H-Indol-3-yl)ethyl)-40-methoxybiphenyl-2-
carboxamide (8c)
4.6. General procedure for the synthesis of phenyl-(1,3,4,9-
White solid; yield 34%; mp 155–157 °C; dH (300 MHz; CDCl3)
2.72 (2H, t, 6.8), 3.55 (2H, dt, 6.8), 3.80 (3H, s), 5.34 (1H, t, 4.8),
6.66 (1H, d, 2.3), 6.89 (2H, d, 8.8), 7.07 (1H, t, 6.9), 7.16 (1H, t,
6.9), 7.28–7.32 (2H, m), 7.30 (2H, d, 8.7), 7.36 (1H, d, 7.4), 7.41
(1H, d, 7.4), 7.48 (1H, d, 7.8), 7.64 (1H, d, 7.6), 7.99 (1H, br s); dC
(75 MHz; CDCl3) 24.6 (CH2), 39.6 (CH2), 55.0 (CH3), 111.2 (CH),
111.6, 113.5 (CH, 2C), 118.1 (CH, 2C), 120.8 (CH), 122.5 (CH),
126.4 (CH), 127.1, 127.5 (CH), 129.1 (CH), 129.4 (CH, 2C), 129.5
(CH), 132.4, 136.1, 137.2, 138.5, 158.5, 169.1; m/z (FAB) 371.1759
(M+H+ C24N2O2H23 requires 371.17595).
tetrahydro-b-carbolin-2-yl)-methanone derivatives 10a–c
To a suspension of carboline 9 (1.2 mmol) in CH2Cl2 (3 mL) at
0 °C was added slowly an aqueous solution of sodium hydroxide
4 M (1.2 mmol). After 5 min stirring at 0 °C the appropriate benzoyl
chloride derivative (1.2 mmol) was added dropwise. The mixture
was stirred for 5 min at 0 °C and for a further 3 h at room temper-
ature. H2O (20 mL) was added. The two layers were separated and
the aqueous phase was extracted with dichloromethane (3ꢀ
20 mL). The organic layer was dried (MgSO4) and evaporated under
reduced pressure. The crude product was purified by flash column
chromatography on silica. Elution was made successively with;
ethyl acetate/petroleum ether (40–60 °C) 50:50 and ethyl acetate,
to give the expected compound.
4.5.15. N-(2-(1H-Indol-3-yl)ethyl)-30-methoxybiphenyl-2-
carboxamide (8d)
Pale orange solid; yield 38%; mp 156–158 °C; dH NMR (300 MHz,
(CD3)2SO) 2.76 (2H, t, 7.3), 3.84 (3H, s), 6.99 (1H, d, 7.7), 7.04 (1H, t,
7.1), 7.07 (1H, s), 7.14 (1H, t, 7.1), 7.18 (1H, d, 1.6), 7.35 (1H, d, 7.9),
7.40–7.45 (2H, m), 7.42 (1H, d, 7.9), 7.50–7.55 (2H, m), 7.50 (1H, d,
6.9), 7.57 (2H, d, 7.2), 8.34 (1H, t, 5.7), 10.89 (1H, br s); dC (75 MHz;
CDCl3) 24.6 (CH2), 39.7 (CH2), 54.9 (CH3), 111.3 (CH), 111.6, 112.6
(CH), 114.0 (CH), 118.1 (CH), 118.1 (CH), 120.7 (CH), 120.8 (CH),
122.4 (CH), 127.0 (CH), 127.1, 127.5 (CH), 129.1(CH, 2C), 129.6
(CH), 136.1, 137.4, 138.8, 141.5, 158.9, 169.0; m/z (FAB) 371.17598
(M+H+ C24H23N2O2 requires 371.17595).
4.6.1. (4-Bromo-phenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-
methanone (10a)
White solid; yield 62%; mp 217 °C; rotamers 1/1.7 (from the
duplicated singlet signal (1H) at room temperature at 4.59 and
4.83 ppm); dH (400 MHz, (CD3)2SO, 363 K) 2.79 (2H, t, J 5.8), 3.79
(2H, br s), 4.75 (2H, s), 6.99 (1H, td, J 7.4 and 0.8), 7.07 (1H, td, J
7.6 and 1.2), 7.32 (1H, d, J 8.0), 7.40–7.44 (4H, m), 7.67 (1H, dt, J
8.8 and 2.4), 10.55 (1H, br s); dC (75 MHz, CDCl3) d 22.0 (CH2),
40.9 (CH2), 45.9 (CH2), 107.1, 111.6 (CH), 118.0 (CH), 119.1 (CH),
121.4 (CH), 123.5, 127.0, 129.5 (2CH), 131.0, 132.0 (2CH), 135.8,
136.5, 169.6; m/z (ES+) 356 (M+2H)+; (ESꢁ) 353 (MꢁH)ꢁ. m/z
(FAB) 354.03677 (M+H+ C18H15BrN2O requires 354.03677). Found:
C, 60.87; H, 4.20; N, 7.70. C18H15BrN2O requires C, 60.86; H, 4.26;
N, 7.89.
4.5.16. N-(2-(1H-Indol-3-yl)ethyl)-20-methoxybiphenyl-2-
carboxamide (8e)
Off white solid; yield 72%; mp 137–139 °C; dH NMR (300 MHz,
CDCl3) 2.57 (2H, t, 7.0), 3.42 (2H, q, 6.9), 3.51 (3H, s), 5.58 (1H, t,
4.2), 6.64 (1H, d, 2.0), 6.71 (1H, d, 8.1), 6.88 (1H, t, 7.4), 6.99 (1H, t,
7.0), 7.06–7.11 (m, 2H), 7.15–7.20 (m, 2H), 7.24 (1H, d, 8.2), 7.32
(1H, d, 7.5), 7.36 (1H, d, 7.3), 7.40 (1H, d, 7.4), 7.68 (1H, d, 7.4), 8.10
(br s); dC (75 MHz; (CD3)2SO) 24.8 (CH2), 39.6 (CH2), 54.9 (CH3),
110.7 (CH), 111.3 (CH), 111.6, 118.1 (CH, 2C), 120.1 (CH), 120.8
(CH), 122.4 (CH), 126.7 (CH), 127.1, 127.1 (CH), 128.6 (CH), 129.0
(CH), 129.3, 130.2 (CH), 130.8 (CH), 136.1, 136.3, 137.7, 155.9,
168.5; m/z (FAB)371.17602(M+H+ C24H23N2O2 requires 371.17595).
4.6.2. (3-Bromo-phenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-
methanone (10b)
White solid; yield 91%; mp 207 °C; rotamers 1/1.6 (from the
duplicated broad singlet signal (1H) at room temperature at 4.60
and 4.84 ppm); dH (400 MHz, (CD3)2SO), 373 K) 2.80 (2H, t, 5.8),
3.81 (2H, br s), 4.77 (2H, s), 7.00 (1H, td, 7.5, 1.2), 7.08 (1H, td,
7.5, 1.2), 7.34 (1H, d, 7.6), 7.41–7.48 (3H, m), 7.64–7.69 (2H, m),
10.52 (1H, br s); dC (100 MHz; (CD3)2SO); 373 K) 21.7 (CH2), 43.1
(CH2), 44.1 (CH2), 107.5, 111.5 (CH), 118.0 (CH), 119.1 (CH),
121.4 (CH), 122.2, 126.1 (CH), 127.3, 129.9 (CH), 131.1 (CH),
131.1, 132.8 (CH), 136.9, 139.3, 168.8; m/z (ES+) 355 MH+; (ESꢁ)
4.5.17. N-(2-(1H-Indol-3-yl)ethyl)-30-fluorobiphenyl-2-carbo-
xamide (8f)
Pale beige solid; yield 33%; mp 96–99 °C; dH NMR (300 MHz,
(CD3)2SO) 2.67 (2H, t, 7.4), 6.96 (1H, t, 7.0), 7.05 (1H, t, 7.0), 7.10

7736
P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
4.6.6. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(20-fluoro-
biphenyl-2-yl)methanone (11c)
353 (MꢁH)ꢁ;. m/z (FAB) 355.04478 (M+H+ C18H15BrN2O requires
355.04460). Found: C, 60.94; H, 4.17; N, 7.93. C18H15BrN2O re-
quires C, 60.86; H, 4.26; N, 7.87.
Off white amorphous solid; 82% yield; mp 188–190 °C; 3:2 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.36 (1H, br s), 2.56 (1H, br
s), 3.13 (1H, br s), 3.57 (1H, br s), 4.21 (1H, dAB, J 16.7), 4.99 (1H, dAB
J 16.4), 6.40–7.40 (12H, m, ArH), 8.62 (1H, br s); (distinct signals for
minor rotamer) 2.32 (1H, br s), 2.52 (1H, br s), 3.44 (1H, br s), 4.00–
4.09 (3H, m), 7.82 (1H, br s, NH); dC(75.5 MHz, CDCl3) 21.5 (CH2),
4.6.3. (2-Bromo-phenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-
methanone (10c)
White solid; yield 64%; mp 190 °C; rotamers 1/3.3 (from the
duplicated broad singlet signal (1H) at 8.03 and 8.59 ppm); dH
(300 MHz, CDCl3) ( major rotamer) 2.66 (1H, t, 6.5), 2.73 (1H, t,
5.0), 3.49 (2H, t, 5.7), 4.77 (1H, d, 16.8), 5.06 (1H, d, 16.8), 6.93–
7.56 (8H, m), 8.59 (1H, br s); d (distinct peaks for minor rotamer)
2.61 (1H, apparent t, J 6.3), 2.79 (1H, t, 5.0), 2.85 (2H, t, 5.7), 4.24
(1H, d, 16.1), 4.38 (1H, d, 16.1), 8.03 (1H, br s); dC (75 MHz, CDCl3)
d (major rotamer) 21.9 (CH2), 40.5 (CH2), 45.2 (CH2), 107.6, 111.3
(CH), 117.8 (CH), 119.3, 119.5 (CH), 121.8 (CH), 126.7, 127.6
(CH), 127.9 (CH), 129.7, 130.5 (CH), 133.0 (CH), 136.4, 138.2,
168.9; d (distinct peaks for minor rotamer) 21.0 (CH2), 44.9 (CH2),
109.2, 111.0 (CH), 118.2 (CH), 119.1, 119.7 (CH), 121.9 (CH),
126.8, 129.2, 132.9, 136.3, 138.3, 168.4; m/z (ES+) 355 MH+; (ESꢁ)
354 (M)ꢁ; m/z (FAB) 354.03678 (M+ C18H15BrN2O requires
354.03677). Found: C, 60.75; H, 4.17; N, 7.92. C18H15BrN2O re-
quires C, 60.86; H, 4.26; N, 7.89.
2
40.4 (CH2), 45.1 (CH2), 107.5, 111.1 (CH), 115.6 (CH, d, JCF 22.3),
3
117.6 (CH), 119.2 (CH), 121.4 (CH), 124.1 (CH, d, JCF 3.7), 126.5,
2
126.9 (Cq, d, JCF 16.8) 127.0 (CH), 128.2 (CH), 129.2 (CH), 129.6,
3
4
4
129.7 (CH, d, JCF 8.2), 131.0 (CH, d, JCF 1.9), 131.4 (CH, d, JCF
1
3.0), 133.2, 136.2, 136.2, 159.4 (d, JCF 246), 170.6; (distinct signals
for minor rotamer) 20.6 (CH2), 40.3 (CH2), 44.8 (CH2), 108.7, 110.7
2
(CH), 115.0 (CH, d, JCF 22.3), 117.8 (CH), 119.3 (CH), 121.5 (CH),
3
2
123.7 (CH, d, JCF 3.6), 126.3 (Cq, d, JCF 14.8), 127.1 (CH), 127.3,
3
128.3 (CH), 128.9 (CH), 129.0, 129.5 (CH, d, JCF 8.2), 130.7 (CH, d,
4JCF 2.1), 131.2 (CH, d, JCF 2.8), 132.6 (136.1, 136.4, 159.0 (d, JCF
245), 169.6; m/z (ES+) 371 ([M+H]+, 100%); m/z (FAB) 370.14821
(M+ C24H19FN2O requires 370.14814).
4
1
4.6.7. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-methy-
lbiphenyl-2-yl)methanone (11d)
Off white amorphous solid; yield 97%; mp 187–191 °C; 1.7:1
mixture of rotamers; dH (300 MHz, CDCl3) 2.04–2.19 (1H, m,
CH2), 2.14 (3H, s, CH3), 2.38–2.50 (1H, m, CH2), 2.91 (1H, ddd, J
4.6.4. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(40-
fluorobiphenyl-2-yl)methanone (11a)
Off White amorphous solid; 63% yield; mp 136–139 °C; 2.2:1
mixture of rotamers; dH (300 MHz, CDCl3) 2.14–2.21 (1H, m),
2.42–2.52 (1H, m), 2.89–2.96 (1H, m), 3.35–3.42 (1H, m), 4.23
(1H, dAB, J 17.0), 5.03 (1H, dAB, J 17.0), 6.62 (1H, at, J 8.7), 6.87–
7.13 (5H, m), 7.20–7.43 (6H, m), 8.70 (1H, s), distinct signals for min-
or rotamer: 2.58–2.65 (1H, m), 3.64–3.73 (1H, m), 3.82 (1H, dAB, J
16.0), 3.82–3.90 (1H, m), 4.03 (1H, dAB, J 16.1), 7.94 (1H, s); dC
(75.5 MHz, CDCl3) 21.4 (CH2), 40.2 (CH2), 44.8 (CH2), 107.4, 111.0
13.0, 8.5, 4.7, CH2), 3.39 (1H, dat, J 13.3, 5.0, CH2), 4.27 (1H, dAB
,
pseudo J 17.0, CH2), 5.01 (1H, dAB, pseudo J 17.0, CH2), 6.84–7.40
(12H, m), 8.84 (1H, m, CH2); (distinct signals for minor rotamer)
1.89 (3H, s, CH3), 2.38–2.50 (1H, m, CH2), 2.54–2.62 (1H, m, CH2),
3.56 (1H, ddd, J 12.6, 7.8, 4.8, CH2), 3.03 (1H, dAB, pseudo J 16.4,
CH2), 3.97 (1H, dAB, J 16.4, CH2), 3.94–4.01 (1H, m, CH2), 8.00
(1H, s, NH); dC(75.5 MHz, CDCl3), 21.1 (CH2), 21.3 (CH3), 40.2
(CH2), 44.7 (CH2), 107.2, 111.0 (CH), 117.5 (CH), 119.0 (CH),
121.3 (CH), 125.4 (CH), 126.4, 127.2 (CH), 127.6 (CH), 128.3 (CH),
128.4 (CH), 129.0 (CH), 129.4, 129.5 (CH), 129.5 (CH), 135.2,
136.2, 138.0, 138.9, 139.5, 171.1; ( distinct signals for minor rot-
amer) 20.5 (CH2), 21.0 (CH3), 40.2 (CH2), 44.7 (CH2), 108.5, 110.7
(CH), 117.7 (CH), 119.1 (CH), 121.3 (CH), 125.3 (CH), 126.7, 127.0
(CH), 127.5 (CH), 127.9 (CH), 128.2 (CH), 128.5 (CH), 129.0, 129.4
(CH), 129.4 (CH), 135.3, 136.0, 137.7, 138.9, 139.1, 170.3; m/z
(ES+) 367 ([M+H]+ 100%); m/z (FAB) 366.17324 (M+ C25H22N2O re-
quires 366.17321).
2
(CH), 115.4 (CH, d, JCF 21.5), 117.6 (CH), 119.2 (CH), 121.5 (CH),
126.4, 127.1 (CH), 127.8 (CH), 129.4, 129.6 (CH), 129.6 (CH),
3
4
130.1 (CH, d, JCF 8.4), 135.4, 135.7 (d, JCF, 3.6), 136.2, 137.7,
2
162.4 (d, JCF 247), 170.1; (distinct signals for minor rotamer) 20.6
(CH2), 40.2 (CH2), 44.7 (CH2), 108.7, 110.6 (CH), 115.0 (CH, d, JCF
2
21.5), 117.9 (CH), 119.4 (CH), 121.7 (CH), 126.7, 127.1 (CH),
3
127.7 (CH), 128.8, 129.4 (CH), 129.5 (CH), 129.8 (CH, d, JCF 8.4),
4
2
135.1 (d, JCF, 3.6), 135.5, 136.0, 137.8, 162.2 (d, JCF 248), 170.9;
m/z (ES+) 371 ([M+H]+, 100%); m/z (FAB) 370.14821 (M+
C24H19N2OF requires 370.14814).
4.6.5. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-
fluorobiphenyl-2-yl)methanone (11b)
4.6.8. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(40-fluoro-
biphenyl-3-yl)methanone (12a)
Off white amorphous solid; 56% yield; mp 203–207 °C; 2:1
mixture of rotamers; dH (300 MHz, CDCl3) 2.55–2.76 (2H, m,
CH2), 3.09 (1H, ddd, J 13.2, 8.5, 4.7), 3.52 (1H, dat, 13.2, 4.8),
4.41 (1H, dAB, J 17.0), 5.14 (1H, dAB, J 17.0), 6.95–7.17 (12H, m,
ArH), 8.59 (1H, s, ArH), (distinct signals for minor rotamer) 2.25–
2.30 (2H, m, CH2), 3.80 (1H, ddd, J 12.6, 7.4, 5.2, CH2), 3.99 (1H,
Off white amorphous solid; 83% yield; mp 132–135 °C; 5:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.81 (2H, br s), 2.72 (2H, br
s), 4.93 (2H, br s), 7.05–7.64 (12H, m, Ar), 8.75 (1H, br s); (distinct
signals for minor rotamer) 2.90 (2H, br s), 4.10 (2H, br s), 4.58 (2H,
br s), 8.10 (1H, br s); dC (75.5 MHz, CDCl3) 22.1 (CH2), 44.1 (CH2),
2
46.0 (CH2), 107.6, 111.1 (CH), 115.8 (CH, d, JCF 21.4), 117.7 (CH),
dAB, J 16.3, CH2), 4.07 (1H, m, CH2), 4.19 (1H, dAB, J 16.3, CH2),
119.4 (CH), 121.7 (CH), 125.4 (CH), 125.5 (CH), 126.7, 128.4 (CH),
3
5
7.88 (1H, s, NH); dC (75.5 MHz, CDCl3) 21.4 (CH2), 40.2 (CH2),
128.7 (CH, d, JCF 8.1), 129.1 (CH), 129.9, 136.2 (d, JCF 1.3), 136.2
2
4
1
44.8 (CH2), 107.5, 111.0 (CH), 114.6 (CH, d, JCF 21.0), 115.4 (CH,
(d, JCF 4.8), 136.6, 140.7, 162.1 (Cq, d, JCF, 247), 171.3; m/z (ES+)
371 ([M+H]+, 100%); m/z (FAB) 370.14822 (M+ C24H19FN2O requires
370.14814).
2
d, JCF 22.0), 117.7 (CH), 119.3 (CH), 121.6 (CH), 124.3 (CH, d,
4JCF 2.7), 126.5, 127.3 (CH), 128.2 (CH), 129.3 (CH), 129.4, 129.6
3
3
(CH, d, JCF 6.6), 129.6 (CH), 135.5, 136.2, 137.5, 141.8 (d, JCF
1
7.8), 162.9 (Cq, d, JCF 247), 170.7; (distinct signals for minor rot-
4.6.9. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-fluoro-
biphenyl-3-yl)methanone (12b)
Off white amorphous solid; 72% yield; mp 134–138 °C; 5:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.85 (2H, br s, CH2), 3.76
(2H, br s, CH2), 4.97 (2H, br s, CH2), 7.07–7.72 (12H, m, ArH),
8.90 (1H, br s); (distinct signals for minor rotamer) 2.95 (2H, br s,
CH2), 4.14 (2H, br s, CH2), 4.62 (2H, br s, CH2), 8.28 (1H, br s); dC
amer) 20.5 (CH2), 40.3 (CH2), 44.8 (CH2), 108.9, 110.7 (CH),
2
2
114.4 (CH, d, JCF 20.9), 115.1 (CH, d, JCF 22.0), 117.9 (CH),
4
119.4 (CH), 121.7 (CH), 124.0 (CH, d, JCF 2.7), 126.8, 127.4 (CH),
128.2 (CH), 128.8, 129.7 (CH), 130.0 (CH, d, JCF 8.4), 135.5,
136.0, 137.5, 141.2 (Cq, d, JCF 7.8), 162.4 (Cq, d, JCF 247),
169.9; m/z (ES+) 371 ([M+H]+, 100%); m/z (FAB) 370.14815 (M+
C24H19FN2O requires 370.14814).
3
3
1

P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
7737
(75.5 MHz, CDCl3), 22.0 (CH2), 41.2 (CH2), 4.60 (CH2), 107.4, 111.1
s), 8.30 (1H, br s); dH (75.5 MHz, CDCl3) 22.0 (CH2), 41.0 (CH2), 46.0
(CH2), 55.2 (CH3), 107.5, 111.1 (CH), 112.7 (CH), 113.2 (CH), 117.7
(CH), 119.3 (CH), 119.5 (CH), 121.6 (CH), 125.5 (CH), 125.7 (CH),
126.6, 128.6 (CH), 129.0 (CH), 129.9 (CH), 136.2, 135.5, 141.5,
141.5, 159.9, 171.4 (C@O); m/z (ES+) 383 ([M+H]+ 100%); m/z
(FAB) 382.16820 (M+ C25H22N2O2 requires 382.16813).
2
2
(CH), 113.9 (CH, d, JCF 22.1), 114.5 (CH, d, JCF 20.9), 117.7 (CH),
4
119.4 (CH), 121.6 (CH), 122.7 (CH, d, JCF 2.7), 125.4 (CH), 126.1
3
(CH), 126.6, 128.5 (CH), 129.2 (CH), 129.9, 130.3 (CH, d, JCF, 8.4),
4
3
1
136.2, 136.6, 140.3 (d, JCF 1.2), 142.2 (d, JCF 7.8), 163.1 (d, JCF
246), 171.2; m/z (ES+) 371 ([M+H]+, 100%); m/z (FAB) 370.14806
(M+ C24H19FN2O requires 370.14814).
4.6.15. Biphenyl-3-yl(3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-
yl)methanone (12h)
4.6.10. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(20-fluoro-
biphenyl-3-yl)methanone (12c)
Beige solid; 92% yield; mp 104–106 °C; 3.6:1 mixture of rota-
mers; dH (300 MHz, CDCl3) 2.71 (2H, br s), 3.63 (2H, br s), 4.84
(2H, br s), 6.95–7.60 (13H, m, Ar), 8.67 (1H, br s); d (distinct signals
for minor rotamer) 2.80 (2H, br s), 3.99 (2H, br s), 4.47 (2H, br s),
8.04 (1H, br s); dC (75.5 MHz, CDCl3) 22.1 (CH2), 41.1 (CH2), 46.1
(CH2), 107.6, 111.1 (CH), 117.7 (CH), 119.4 (CH), 121.7 (CH),
125.5 (CH), 125.6 (CH), 126.7, 127.1 (CH), 127.7 (CH), 128.6 (CH),
128.9 (CH), 129.1 (CH), 129.9, 136.3, 136.5, 140.0, 143.6, 171.5;
m/z (ES+) 353 ([M+H]+, 100%).
Off white amorphous solid; 83% yield; mp 125–127 °C; 5:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.71 (2H, br s), 3.52–3.63
(2H, m), 4.76-4.81 (2H, m), 6.96–7.56 (12H, m), 8.80 (1H, br s); (dis-
tinct signals for minor rotame): 2.76 (2H, br s), 3.96 (2H, br s), 4.36–
4.47 (2H, m), 8.13 (1H, br s); dC (100 MHz, CDCl3) 22.0 (CH2), 41.1
2
(CH2), 46.1 (CH2), 107.5, 111.1 (CH), 116.1 (CH, d, JCF 22.7), 117.7
3
(CH), 119.3 (CH), 121.5 (CH), 124.5 (CH, d, JCF 3.6), 126.1 (CH),
3
126.6, 127.4 (CH), 127.8, 128.8 (CH), 129.4 (CH, d, JCF 8.4), 129.9,
4
4
2
130.4 (CH, d, JCF 3.0), 130.6 (CH, d, JCF 3.3), 136.1, 136.1 (d, JCF
1
13.5), 137.8, 159.6 (d, JCF 248), 171.2.
4.6.16. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(40-
fluorobiphenyl-4-yl)methanone (13a)
4.6.11. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(40-
methylbiphenyl-3-yl)methanone (12d)
Off white amorphous solid; 80% yield; mp 227ꢁ229 °C; 5:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.88 (2H, br s), 3.79 (2H, br s),
4.97 (2H, br s), 7.09 (12H, m, ArH), 8.34 (1H, br s, NH); d (distinct sig-
nals for minor rotamer) 2.95 (2H, br s), 4.13 (2H, br s), 4.69 (2H, br s),
7.83 (1H br s); dC (100 MHz, (CD3)2SO) 21.5 (CH2), 45.4 (CH2), 54.8
Off white amorphous solid; yield 61%; mp 166–168 °C; 5:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.27 (3H, br s), 2.67 (2H, br
s), 3.58 (2H, br s), 4.80 (2H, br s), 6.93–7.57 (12H, m), 8.80 (1H, br
s); (distinct signals for the minor rotamer) 2.78 (2H, br s), 3.96 (2H,
br s), 4.43 (2H, br s), 8.20 (1H, br s); dC (75.5 MHz, CDCl3) 21.0
(CH3), 22.0 (CH2), 41.0 (CH2), 46.0 (CH2), 107.4, 111.1 (CH), 117.6
(CH), 119.2 (CH), 121.5 (CH), 125.1 (CH), 125.2 (CH), 126.5, 126.8
(CH), 128.3 (CH), 129.0 (CH), 129.5 (CH), 129.9, 136.1, 136.3,
137.1, 137.5, 141.4, 171.5; m/z (ES+) 367 ([M+H]+ 100%); m/z
(FAB) 366.17309 (M+ C25H22N2O requires 366.17321).
2
(CH2), 106.5, 111.0 (CH), 115.7 (CH, d, JCF 21.6), 117.4 (CH), 118.5
3
(CH), 120.8 (CH), 126.4, 126.6 (CH), 127.4 (CH), 128.7 (CH, d, JCF
5
4
8.4), 130.6, 135.0, 135.7 (d, JCF 2.4), 135.9 (Cq, d, JCF 2.8), 140.2,
162.0 (d, 1JCF 245), 169.7; m/z (ES+) 371 ([M+H]+, 100%); m/z (FAB)
370.14821 (M+ C24H19FN2O requires 370.14814).
4.6.17. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-
fluorobiphenyl-4-yl)methanone (13b)
4.6.12. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-
methylbiphenyl-3-yl)methanone (12e)
Pale yellow amorphous solid; 84% yield; mp 212–216 °C; 5:1
mixture of rotamers; dH (300 MHz, CDCl3) 2.77 (2H, br s, CH2),
3.67 (2H, br s, CH2), 4.86 (2H, br s, CH2), 6.97–7.56 (12H, m, Ar),
8.57 (1H, br s); d (distinct signals for minor rotamer) 4.02 (2H, br
s, CH2), 4.56 (2H, br s, CH2), 7.97 (1H, br s); dC (75.5 MHz, CDCl3),
22.1 (CH2), 41.2 (CH2), 46.1 (CH2), 107.7, 111.1 (CH), 114.0 (CH,
Off white amorphous solid; yie;d 88%; 5:1 mixture of rotamers;
dH (300 MHz, CDCl3) 2.29 (3H, br s), 2.69 (2H, br s), 3.60 (2H, br s),
4.38 (2H, br s), 6.94–7.59 (12H, m), 8.79 (1H, br s); (distinct signals
for the minor rotamer) 2.79, (2H, br s), 3.98 (2H, br s), 4.45 (2H, br
s), 8.17 (1H, br s); dC (75.5 MHz, CDCl3) 21.4 (CH3), 22.0 (CH2), 41.1
(CH2), 46.0 (CH2), 107.4, 111.1 (CH), 117.6 (CH), 119.3 (CH), 121.5
(CH), 124.1 (CH), 125.4 (CH), 126.6, 127.8 (CH), 128.4 (CH), 128.6
(CH), 128.7 (CH), 128.7 (CH), 129.0 (CH), 129.9, 136.2, 136.3,
138.5, 140.0, 141.7, 171.5.
2
2
d, JCF 22.1), 114.6 (CH, d, JCF 20.9), 117.8 (CH), 119.5 (CH), 121.8
4
(CH), 122.8 (CH, d, JCF 2.7), 126.7, 127.3 (CH), 127.6 (CH), 129.9,
3
4
130.4 (CH, d, JCF 8.4), 135.3, 136.3, 141.5 (d, JCF 1.5), 142.4 (d,
3JCF 7.5), 163.2 (d, JCF 246), 171.2; m/z (ES+) 371 ([M+H]+, 100%);
1
m/z (FAB) 370.14819 (M+ C24H19FN2O requires 370.14814).
4.6.13. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(20-
methylbiphenyl-3-yl)methanone (12f)
4.6.18. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(20-
fluorobiphenyl-4-yl)methanone (13c)
Off white amorphous solid; yield 80%; mp 139–141 °C; 3:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.15 (3H, br s), 2.67 (2H, br
s), 3.60 (2H, br s), 4.79 (2H, br s), 6.60–6.65 (1H, m), 6.80–7.58
(11H, m), 8.74 (1H, br s); d (distinct signals for minor rotamer)
2.75 (2H, br s), 3.94 (2H, br s), 4.40 (2H, br s), 8.24 (1H, br s); dC
(75.5 MHz, CDCl3) 20.5 (CH3), 22.1 (CH2), 41.1 (CH2), 46.1 (CH2),
107.4, 111.0 (CH), 117.8 (CH), 119.6 (CH), 121.8 (CH), 125.4 (CH),
125.9 (CH), 126.8, 127.5 (CH), 127.6 (CH), 128.5 (CH), 129.8 (CH),
130.4 (CH), 130.4, 130.7 (CH), 135.2, 135.9, 136.2, 140.8, 142.2,
171.5; m/z (ES+) 367 ([M+H]+ 100%); m/z (FAB) 366.17322 (M+
C25H22N2O requires 366.17321).
Pale yellow amorphous solid; 79% yield; mp 197–200 °C; 5:1
mixture of rotamers; dH (300 MHz, CDCl3) 2.89 (2H, br s, CH2),
3.81 (2H, m, CH2), 4.96 (2H, br s, CH2), 7.01–7.80 (12H, m, ArH),
8.36 (1H, br s, NH); d (distinct signal for minor rotamer) 4.10 (2H,
m, CH2), 4.69 (2H, m, CH2), 9.08 (1H, br s); dC (100 MHz, CDCl3)
21.5 (CH2), 40.3 (CH2), 45.5 (CH2), 106.5, 111.0 (CH), 116.1 (CH,
2
3
d, JCF 22.5), 117.4 (CH), 118.5 (CH), 120.8 (CH), 125.0 (CH, d, JCF
2
4
3.5), 126.4, 127.0 (CH), 127.4 (d, JCF 13.1), 128.8 (CH, d, JCF 3.0),
3
4
129.9 (CH, d, JCF 8.3), 130.6, 130.7 (CH, d, JCF 3.2), 135.5, 135.9,
136.2, 159.0 (d, JCF 246), 169.5; m/z (ES+) 371 ([M+H]+, 100%);
1
m/z (FAB) 370.14821 (M+ C24H19FN2O requires 370.14814).
4.6.14. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-
methoxybiphenyl-3-yl)methanone (12g)
4.6.19. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(40-
methylbiphenyl-4-yl)methanone (13d)
Off white amorphous solid; yield 74%; 4:1 mixture of rotamers;
dH (300 MHz, CDCl3) 2.85 (2H, br s), 3.77 (2H, br s), 3.87 (3H, br s)
4.97 (2H, br s), 6.95–7.75 (12H, m), 8.88 (1H, br s); d (distinct sig-
nals for minor rotamer) 2.95 (2H, br s), 4.13 (2H, br s), 4.61 (2H, br
Off white amorphous solid; yield 66%; mp 223–226 °C; 4:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.32 (3H, br s), 2.78 (2H, br
s), 3.68 (2H, br s), 4.84 (2H, br s), 6.99–7.61 (12H, m), 8.53 (1H, br
s); d (distinct signals for minor rotamer) 1.81 (3H, br s), 3.99 (2H, br

7738
P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
s), 4.57 (2H, br s), 8.11 (1H, br s); dC (75.5 MHz, CDCl3) 21.1 (CH3),
22.1 (CH2), 41.1 (CH2), 46.1 (CH2), 107.8, 111.1 (CH), 117.8 (CH),
119.5 (CH), 121.7 (CH), 126.8, 126.9 (CH), 127.0 (CH), 127.5 (CH),
129.6 (CH), 134.4, 136.3, 137.2, 137.7, 142.7, 171.4 (C@O), d (dis-
tinct signals for minor rotamer) 128.4 (CH), 128.6 (CH), 132.0 (CH),
132.0 (CH), 132.1 (CH); m/z (ES+) 367 ([M+H]+ 100%); m/z (FAB)
366.17324 (M+ C25H22N2O requires 366.17321).
363 K, (CD3)2SO) 2.97 (3H, s), 3.00 (2H, t, 6.7), 3.64 (2H, dd, 6.7,
6.7), 6.88 (1H, t, 7.4), 7.05 (1H, t, 7.4), 7.09 (1H, s), 7.35 (2H, d,
8.0), 7.37 (2H, d, 6.0), 7.67 (2H, d, 6.0), 7.73 (2H, d, 8.0), 8.66 (2H,
d, 6.0), 10.55 (1H, br s); dC (75 MHz, CD2Cl2) d (major rotamer)
24.5 (CH2), 33.0 (CH3), 52.1 (CH2), 111.7 (CH), 111.9, 113.2, 118.4
(CH), 119.4 (CH), 122.2 (CH, 2C), 122.9 (CH), 127.1 (CH, 2C),
127.5 (CH, 2C), 128.1 (CH), 136.8, 137.7, 138.7, 147.9, 150.4 (CH,
2C), 171.8; d (distinct peaks for minor rotamer) 23.3 (CH2), 38.2
(CH3), 48.8 (CH2), 119.0 (CH), 122.8 (CH, 2C), 127.4 (CH, 2C); m/z
(ES+) 356 (M+H+), (ESꢁ) 354 (MꢁHꢁ); m/z (FAB) 356.17627
(M+H+ C23H22N3O requires 356.17629). Found: C, 77.80; H, 5.86;
N, 11.90. C23H21N3O requires C, 77.72; H, 5.96; N, 11.82%.
4.6.20. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-
methylbiphenyl-4-yl)methanone (13e)
Pale beige amorphous solid; yield 91%; mp 158–161 °C; 5:1
mixture of rotamers; dH (300 MHz, CDCl3) 2.31 (2H, br s, CH3),
2.72 (2H, br s, CH2), 3.62 (2H, br s, CH2), 4.81 (2H, br s, CH2),
6.96–7.54 (12H, m, Ar), 8.77 (1H, br s); d (distinct signals for minor
rotamer) 2.75 (2H, br s, CH2), 3.96 (2H, br s, CH2), 4.51 (2H, br s,
CH2), 8.24 (1H, br s); dC (300 MHz, CDCl3) 21.5 (CH3), 22.0 (CH2),
41.1 (CH2), 46.1 (CH2), 107.4, 111.1 (CH), 117.7 (CH), 119.3 (CH),
121.5 (CH), 124.2 (CH), 126.6, 127.2 (CH), 127.4 (CH), 127.8 (CH),
128.5 (CH), 128.7 (CH), 130.0, 134.4, 136.2, 138.5, 140.0, 142.9,
171.5; m/z (ES+) 367 ([M+H]+ 100%); m/z (FAB) 366.17320 (M+
C25H22N2O requires 366.17321).
4.6.25. N-(2-(1H-Indol-3-yl)ethyl)-3-(pyridin-3-yl)benzamide
(15)
White solid; yield 80%; mp 59 °C; dH (300 MHz, (CD3)2SO) 3.04
(2H, t, 7.2), 3.64 (2H, t, 7.2), 7.04 (1H, td, 7.9, 1.2), 7.13 (1H, td, 7.0,
1.2), 7.25 (1H, s), 7.41 (1H, d, 7.9), 7.57–7.72 (3H, m), 7.94 (2H, dd,
7.9, 2.0), 8.17 (2H, dd, 7.9, 2.0), 8.66 (1H, s), 8.87 (1H, t, 6.0), 8.99
(1H, br s), 10.87 (1H, br s); dC (75 MHz, 363K, CDCl3) 25.2 (CH2),
40.7 (CH2), 111.5 (CH), 112.7, 118.7, 119.4 (CH), 122.1 (CH), 125.9
(CH), 126.5 (CH), 127.4, 128.5 (CH), 129.3 (CH), 129.8 (CH), 132.0
(CH), 134.5 (CH), 135.7, 136.6, 138.0, 148.0 (CH), 148.6 (CH), 167.3;
m/z (ES+) 342 (M+H+), (ESꢁ) 340 (MꢁHꢁ); m/z (FAB) 342.16061
(M+H+ C22H20N3O requires 342.16064). Found: C, 74.33; H, 5.28; N,
11.70. C22H19N3O requires C, 77.40; H, 5.61; N, 12.31%.
4.6.21. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(20-
methylbiphenyl-4-yl)methanone (13f)
Off white amorphous solid; yield 69%; mp 185–188 °C; 6:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.19 (3H, br s), 2.77 (2H, br
s), 4.85 (2H, br s), 6.96–7.54 (12H, m), 8.74 (1H, br s); d (distinct sig-
nals for minor rotamer) 2.70 (2H, br s), 3.55 (2H, br s), 4.80 (2H, br
s), 8.07 (1H, br s); dC (75.5 MHz, CDCl3) 20.4 (CH3), 22.1 (CH2), 41.2
(CH2), 46.1 (CH2), 107.6, 111.1 (CH), 117.7 (CH), 119.4 (CH), 121.6
(CH), 125.8 (CH), 126.7, 126.8 (CH), 127.6 (CH), 129.4 (CH), 129.6
(CH), 130.0, 130.4 (CH), 134.3, 135.2, 136.3, 140.8, 143.7, 171.5;
m/z (ES+) 367 ([M+H]+ 100%); m/z (FAB) 366.17316 (M+
C25H22N2O requires 366.17321).
4.6.26. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(2-
(pyridin-4-yl)phenyl)methanone (16a)
Off white amorphous solid; 73% yield; mp 135–138 °C; 2.0:1.0
mixture of rotamers; dH (300 MHz, CDCl3) 2.14–2.21 (1H, m),
2.61–2.64 (1H, m) 3.11 (1H, br s), 3.51 (1H, br s), 4.35 (1H, dAB, J
15.8), 5.12 (1H, dAB, J 16.2), 7.02–7.70 (10 H, m), 8.59 (2H, br s), d
(distinct signals for minor rotamer) 2.68 (1H, br s), 2.76 (1H, br s),
3.90–3.93 (2H, m), 3.98–4.04 (1H, m), 4.20–4.25 (1H, m), 8.33
(2H, br s); dC (75.5 MHz, CDCl3) 21.5 (CH2), 40.2 (CH2), 44.9
(CH2), 107.1, 111.0 (CH), 117.6 (CH), 119.2 (CH), 121.5 (CH),
123.3 (CH), 126.4, 127.2 (CH), 128.4 (CH), 129.1 (CH), 129.3,
129.4 (CH), 129.7 (CH), 132.0 (CH), 135.5, 135.9, 136.3, 147.6,
149.6 (CH), 170.0; d (distinct signals for minor rotamer) 20.5 (CH),
40.4 (CH), 45.0 (CH), 108.8, 110.7 (CH), 118.0 (CH), 119.5 (CH),
121.8 (CH), 123.0 (CH), 126.6, 127.2 (CH), 128.6 (CH), 128.6,
129.0 (CH), 129.2 (CH), 129.7 (CH), 131.9 (CH), 135.5, 136.0,
136.1, 147.2, 149.1 (CH), 169.4; m/z (ES+) 354 ([M+H]+, 100%); m/
z (FAB) 354.16054 (M+H+ C23H20N3O requires 354.16064).
4.6.22. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(30-
methoxybiphenyl-4-yl)methanone (13g)
Pale yellow amorphous solid; yield 68%; mp 182–185 °C; 4:1
mixture of rotamers; dH (300 MHz, CDCl3) 2.71 (2H, br s), 3.62
(2H, br s), 3.74 (3H, br s), 4.80 (2H, br s), 6.83–7.53 (12H, m),
8.78 (1H, br s); d (distinct signals for minor rotamer) 3.97 (2H, br
s), 4.49 (2H, br s), 8.25 (1H, br s); dC (75.5 MHz, CDCl3) 22.0
(CH2), 41.1 (CH2), 46.0 (CH2), 55.2 (CH3), 107.8, 111.1 (CH), 112.8
(CH), 113.1 (CH), 117.7 (CH), 119.3 (CH), 119.5 (CH), 121.6 (CH),
126.7, 127.3 (CH), 127.4 (CH), 129.9 (CH), 130.0, 134.8, 136.2,
141.5, 142.6, 159.9, 171.3 (C@O); m/z (ES+) 383 ([M+H]+ 100%);
m/z (FAB) 382.16821 (M+ C25H22N2O2 requires 382.16813).
4.6.27. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(2-
(pyridin-3-yl)phenyl)methanone (16b)
Off white amorphous solid; 54% yield; 2:1 mixture of rotamers;
dH (300 MHz, CDCl3) 2.15–2.20 (1H, m), 2.50–2.55 (1H, m), 3.04–
3.10 (1H, m), 3.40–3.45 (1H, m), 4.36 (1H, dAB, J 16.8), 5.02 (1H,
4.6.23. (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(20-
methoxybiphenyl-4-yl)methanone (13h)
Off white amorphous solid; yield 96%; mp 167–171 °C; 3:1 mix-
ture of rotamers; dH (300 MHz, CDCl3) 2.89 (2H, br s, CH2), 3.81–
3.85 (2H, m, CH2), 5.01 (2H, br s, CH2), 7.05–7.71 (12H, m, ArH),
9.14 (1H, br s); d (distinct signals for minor rotamer) 2.96 (2H, br
s, CH2), 4.15 (2H, br s, CH2), 4.60 (2H, br s CH2), 8.42 (1H, br s);
dC (75.5 MHz, CDCl3), 22.0 (CH2), 41.1 (CH2), 46.0 (CH2), 55.3
(OCH3), 107.3, 111.1 (CH), 117.6 (CH), 119.1 (CH), 120.8 (CH),
121.4 (CH), 126.5 (CH), 126.6, 126.7 (CH), 129.1 (CH), 129.3,
129.6 (CH), 130.0, 130.7 (CH), 134.1, 136.2, 140.2, 156.2, 171.5;
m/z (ES+) 383 ([M+H]+ 100%); m/z (FAB) 382.16814 (M+
C25H22N2O2 requires 382.16813).
dAB, J 16.8), 6.88–7.61 (10 H, m), 8.42–8.44 (2H, m), 8.66–8,67
(1H, m), 9.08 (1H, br s), d ( distinct signals for minor rotamer)
2.62–2.66 (1H, m), 2.53–2.54 (1H, m), 3.69–3.76 (1H, m), 3.86–
3.97 (2H, m), 4.09–4.14 (1H, m), 8.07–8.08 (1H, m, Ar), 8.46 (1H,
br s), 8.53 (1H, br s); dC (75.5 MHz, CDCl3) 21.4 (CH2), 40.3 (CH2),
44.9 (CH2), 107.3, 108.6, 111.0 (CH), 117.7 (CH), 119.2 (CH),
121.5 (CH), 123.3 (CH), 126.5, 127.3 (CH), 128.6 (CH), 129.4,
129.7 (CH), 131.9 (CH), 135.1, 135.5, 135.7, 136.0 (CH), 148.7
(CH), 148.9 (CH), 170.2; d (distinct signals for minor rotamer) 20.6
(CH2), 40.4 (CH2), 44.8 (CH2), 107.3, 108.6, 110.9 (CH), 117.8
(CH), 119.3 (CH), 121.7 (CH), 122.9 (CH), 126.7, 127.5 (CH), 128.4
(CH), 129.4 (CH), 129.7 (CH), 129.4, 132.0 (CH), 134.8, 136.1,
136.3, 148.0 (CH), 148.9 (CH), 169.5; m/z (ES+) 354 ([M+H]+,
100%); m/z (FAB) 354.16066 (M+H+ C23H20N3O requires
354.16064).
4.6.24. N-(2-(1H-Indol-3-yl)ethyl)-N-methyl-4-(pyridin-4-
yl)benzamide (14)
White solid; yield 68%; mp 195 °C; rotomers 1.6/1 (from the
duplicated triplet signal at 3.47 and 3.75 ppm); dH (400 MHz,

P. R. Jenkins et al. / Bioorg. Med. Chem. 16 (2008) 7728–7739
8. Hormann, A.; Chaudhuri, B.; Fretz, H. Bioorg. Med. Chem. 2001, 9, 917.
7739
Acknowledgments
9. (a) Aubry, C. A.; Jenkins, P. R.; Mahale, S.; Chaudhuri, B.; Marechal, J.-D. ;
Sutcliffe, M. J. Chem. Commun. 2004, 15, 1696; (b) Aubry, C. A.; Wilson, A. J.;
Jenkins, P. R.; Mahale, S.; Chaudhuri, B.; Maréchal, J.-D.; Sutcliffe, M. J. Org.
Biomol. Chem. 2006, 4, 787; (c) Garcia, M. D.; Wilson, A. J.; Emmerson, D. P. G.;
Jenkins, P. R. Chem. Commun. 2006, 24, 2586; (d) Garcia, M. D.; Wilson, A. J.;
Emmerson, D. P. G.; Jenkins, P. R.; Mahale, S.; Chaudhuri, B. Org. Biomol. Chem.
2006, 424, 4478.
This work was made possible by financial support from Cancer
Research UK. We are also grateful to Johnson Matthey PLC (‘‘JM”)
for the kind loan of palladium chloride; M.D.G. thanks the Xunta
de Galicia (Programa Isidro Parga Pondal) for financial support.
10. Mahale, S.; Wilson, A. J.; Aubry, C.; Maréchal, J.-D.; Sutcliffe, M. J.; Chaudhuri,
B.; Jenkins, P. R. Bioorg. Med. Chem. Lett. 2006, 16, 4272.
11. Davies, T. G.; Pratt, D. J.; Endicott, J. A.; Johnson, L. N.; Noble, M. E. M.
Pharmacol. Ther. 2002, 93, 125.
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