Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles

Article abstract of DOI:10.1016/j.bmc.2018.02.026

Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC₉₀s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.

Full text of DOI:10.1016/j.bmc.2018.02.026

Accepted Manuscript
Structure-activity relationships for analogs of the tuberculosis drug bedaquiline
with the naphthalene unit replaced by bicyclic heterocycles
Hamish S. Sutherland, Amy S.T. Tong, Peter J. Choi, Daniel Conole, Adrian
Blaser, Scott G. Franzblau, Christopher B. Cooper, Anna M. Upton, Manisha
U. Lotlikar, William A. Denny, Brian D. Palmer
PII:
S0968-0896(17)32339-8
https://doi.org/10.1016/j.bmc.2018.02.026
BMC 14212
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
30 November 2017
13 February 2018
16 February 2018
Please cite this article as: Sutherland, H.S., Tong, A.S.T., Choi, P.J., Conole, D., Blaser, A., Franzblau, S.G., Cooper,
C.B., Upton, A.M., Lotlikar, M.U., Denny, W.A., Palmer, B.D., Structure-activity relationships for analogs of the
tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles, Bioorganic & Medicinal
Chemistry (2018), doi: https://doi.org/10.1016/j.bmc.2018.02.026
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Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with
the naphthalene unit replaced by bicyclic heterocycles
a
a
a
a
a
Hamish S. Sutherland , Amy S.T. Tong , Peter J. Choi , Daniel Conole , Adrian Blaser , Scott
c
d
d
d
G. Franzblau , Christopher B. Cooper , Anna M. Upton , Manisha U. Lotlikar , William A.
Denny , Brian D. Palmer
a,b,*
a,b
a
b
Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins
c
Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Institute for
Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood
d
Street, Chicago, Illinois 60612, USA; Global Alliance for TB Drug Development, 40 Wall St, New
York, New York 10005, USA.
*
Corresponding author. Dr William A. Denny, Auckland Cancer Society Research Centre,
School of Medical Sciences, The University of Auckland. Tel: +64 9 923 6156, Fax: (+649)
73 7502, Email: b.denny@auckland.ac.nz
3
Keywords
Bedaquiline, bedaquiline analogs, tuberculosis, drug development

Abstract
Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of
bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in
clogP values. The biological results for these compounds indicate on average a lower clogP
limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against
M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of
hERG channel potassium current compared with bedaquiline, but there was no common
structural feature that distinguished these.

1
. Introduction.
Bedaquiline (TMC207, Sirturo®, Janssen Pharmaceuticals; Figure 1; 1) is an exciting new
drug for the treatment of tuberculosis (TB). It exhibits a novel mechanism of action compared
1
to other TB drugs namely inhibition of the ATP synthase of Mycobacterium tuberculosis
(
M.tb), the etiological agent of TB. Resistance to other TB drugs occurs primarily due to
mutations in genes encoding their respective bacterial drug targets. Due to its novel drug
target, bedaquiline is active against M.tb strains resistant to other drugs, and demonstrates
2
efficacy against multi-drug-resistant (MDR) TB. Bedaquiline was approved by the US FDA
in 2012 for specific use in pulmonary MDR-TB, and does show improved outcomes when it
3
is used in combination with standard MDR-TB drugs. A recent study adding bedaquiline to a
standard regimen for the treatment of MDR-TB showed a positive cost-benefit analysis by
4
shortening hospital stays. Potential drawbacks of bedaquiline include inhibition of the hERG
5
(
human Ether-à-go-go-Related Gene; KCNH2) potassium channel (with the concomitant
6
7
risk of cardiac toxicity), hepatic toxicity, and possibly a risk of phospholipidosis (related to
its high lipophilicity [calculated clogP of 7.25]). There are also potential pharmacokinetic
8
(
PK)-based drug-drug interactions with the common TB drugs rifampicin and rifapentine,
9
which are potent inducers of CYP3A4, the major metabolising enzyme for bedaquiline.
Figure 1. Bedaquiline (1)
The development of analogs of bedaquiline designed to improve on some of these properties
is thus of high interest. We have previously explored the effects of more polar 6-substituents
1
0
on the quinoline ring and replacement of the unsubstituted phenyl ring with various
1
1
heterocycles. In this paper, we explore the effects of a variety of (mostly) more hydrophilic
bicyclic C units (Fig. 1) in place of the naphthalene unit of bedaquiline. In addition to being
another way to lower the overall lipophilicity of analogs, a particular interest in exploring
1
2
unit C structure is highlighted by a recent paper on the 1.7 Å resolution crystal structure of
bedaquiline bound to the c subunit of the ATP synthase F of the mycobacterium M. phlei
84% sequence identity with M.tb). This shows the dimethylaminoethyl unit D making an H-
o
(
bond to Glu65 in the ion-binding site of the enzyme, with the rest of the molecule
demonstrating multiple hydrophobic contacts with the enzyme, including the naphthalene
unit C with Tyr68 and Leu72, but clashing with Tyr70. Bicyclic alternatives to the
naphthalene are thus of interest from a structural point of view, and in this paper, we prepare
and evaluate a series of these, with the major focus on less lipophilic examples than
naphthalene.

2
2
. Results and discussion
.1. Chemistry
8,10
The 6-bromo compounds of Table 1 were prepared as previously described, by
LiTMP/LDA-mediated coupling of appropriate benzylquinoline A/B-units and 3-
(
dimethylamino)-1-phenylpropan-1-one (Mannich base) C/D-units. The cyano derivatives
were prepared by Pd-mediated cyanation of the corresponding bromo analogs (Scheme 1).
The resulting diarylquinolines were formed as a racemic mixture of four diastereomers, and
the desired RS,SR diastereomer (depicted) was isolated by super-critical fluid HPLC at
BioDuro LLC (Beijing). Twelve different A/B units were used, apart from the unsubstituted
1
0,11
parent; syntheses of many of these been reported previously.
The remainder were
1
0
prepared as outlined in Scheme 2. In previous work, we noted that the yields in the final
condensation reaction (Scheme 1) seemed to correlate positively with the expected degree of
electron density at the benzylic position of the AB-subunit, but this was not obvious in the
present study.
Scheme 1. Synthesis of the compounds of Table 1
B
Y
D NMe
Y
Y
O
2
OH
OH
Br
Br
NMe2 NC
ii
NMe2
+
Z
i
Z
N
OMe
O
Z
O
A
C
bromo compounds of Table 1
cyano compounds of Table 1
o
Footnote for Scheme 1. (i) (a) HN(iPr)
h; (c) Mannich base, THF, -78°C, 4 h; (ii) Zn, Zn(CN)
2
, n-BuLi, THF, -40 C, 0.25 h; (b) A/B-unit, THF, -78°C, 1.5
o
2
, Pd
2
(dba) , P(o-tol)3, DMF, 50 C.
3
The A/B subunits were synthesised by directed ortho lithiation of the methoxyquinoline (I),
followed by quenching with a suitably functionalised aldehyde (II) to give the benzylic
alcohols (III); subsequent reduction to the corresponding dihydro adducts (IV) was
performed using Et SiH/TFA (Scheme 1). Alternatively, the A/B subunits were synthesised
3
by a Suzuki reaction between the boronic acid (V) and suitably functionalised benzyl
bromides (VI).
Scheme 2. Synthesis of the required A/B units

Footnote for Scheme 2. Y = Me (ref 8): Y = H; 3-F; 2-F, 3-OMe; 2,3-diOMe (ref 10): 3-aza, 2-OMe;
-aza, 4,5-diOMe; 4-aza, 2,3-diOMe (ref 11); Y = 2,3-O(CH O- (route 2, yield 52%); 4-aza, 3,5-
3
)
2 2
diOEt (route 2, yield 56%); 4-aza, 3-OMe, 5-OEt (route 2, yield 68%); 4-aza, 3-OMe, 5-OiPr (route 2,
yield 78%) 4-aza, 3-OMe, 5-OnPr (route 2, yield 75%), 4-aza, 3-OEt, 5-OnPr (route 2, yield 78%)
o
(
this paper). (i) LiTMP, then AcOH; (ii) Et
3
SiH, TFA, DCM, 20 C; (iii) Cs
2
CO
3
, Pd(PPh
3
)
4
,
o
PhMe/DMF, 110 C (sealed tube), 5h.
The Mannich bases (III) for Table I compounds 2-4 (class A), 5-6 (class B), 41-43 (class D-
), and class G (51-54) were in the literature or commercially available. The remainder were
2
prepared from the requisite bicyclic acids (I) via the corresponding Weinreb amides (II).
Scheme 3: Synthesis of Mannich base C/D units
A: Via Weinreb amides
B: Via methyl ketones
Table 1 reports data on 63 analogs of 1 (Fig. 1) where the naphthalene C-unit has been
replaced by a variety of bicyclic moieties, grouped in decreasing order of lipophilicity of the
C-unit bicycle. The concentrations of these compounds needed for growth inhibition of
cultures of M.tb (strain H37Rv) were determined as MIC90 values under both replicating
1
3
14
(
MABA assay ) and non-replicating (LORA assay ) conditions. Selected representative
compounds (7, 9, 14, 16-18, 22, 23, 30, 31, 37-43, 52-57, 62) were evaluated for mammalian
1
5
cell toxicity in Vero (African green monkey kidney) cells ; all had IC50s >10 µg/mL except

for 39 (4 µg/mL), 40 (8 µg/mL), and 41 (8.6 µg/mL). All measured analogs, including
bedaquiline, showed very high binding to human plasma protein (>99.9%) with the exception
of one compound, 50, which showed 98.6% binding (Table S1)
Table 1. Bicyclic “C-unit” (Z) analogs of bedaquiline
a
b
MIC90 (µg/mL) clogP
c
No
X
Y
Z
yld
MABA LORA
1
0.07
0.04
52# 0.09
0.11
0.03
0.06
0.05
0.04
0.12
0.08
0.09
0.07
0.07
0.08
0.008
<0.02
0.07
0.08
0.08
0.13
0.55
0.54
0.06
1.1
7.25
8.15
6.79
7.79
7.11
5.75
7.09
5.73
6.35
4.99
7.09
7.01
6.06
6.64
5.28
5.42
5.78
5.56
4.20
6.43
6.48
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
Br 3-Me
CN 3-Me
Br 3-F
A
A
A
B
B
C
C
C
C
C
C
C
32
8
38
0.04
0.02
Br
CN H
Br
H
84# 0.07
65 0.07
83# 0.15
49 0.05
54# 0.07
H
CN H
Br 2,3-diOMe
CN 2,3-diOMe
Br 2-F, 3-OMe
0
1
2
3
4
5
6
7
8
9
0
1
46
42
77
<0.02
0.015
<0.02
0.06
Br 2,3-O(CH
Br 4-aza, 2,3-diOMe
Br
2 2
) O-
H
D-7 33
CN H
CN 3-F
CN 3-Me
Br 3-aza, 2-OMe
CN 3-aza, 2-OMe
Br 3-aza, 2,5-diOMe
Br 3-aza, 4,5-diOMe
D-7 72# 0.12
D-7 73# 0.04
D-7 76# 0.08
D-7 38
0.49
D-7 48# 0.60
D-7 68
D-7 27
0.02
0.93

22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
Br 4-aza, 2,3-diOMe
CN 4-aza, 2,3-diOMe
Br 4-aza, 3,5-diOEt
CN 4-aza, 3,5-diOEt
Br 4-aza, 3-OMe, 5-OEt
D-7 45
D-7 75# 0.27
D-7 83 0.02
D-7 36# <0.02
D-7 65 <0.02
D-7 48# <0.02
<0.02
0.06
0.13
0.30
0.03
0.03
<0.02
0.07
<0.02
0.08
0.01
0.05
0.13
2.2
5.61
4.25
7.41
6.06
6.87
5.53
7.19
5.84
7.42
6.06
6.64
5.28
6.64
5.28
5.61
5.61
6.89
7.20
5.84
5.28
5.42
5.61
6.53
6.53
5.18
6.53
6.50
5.18
6.50
6.13
4.77
5.10
3.75
6.54
5.18
6.71
4.33
4.32
4.97
3.61
5.14
4.11
4.55
CN 4-aza, 3-OMe, 5-OEt
i
Br 4-aza, 3-OMe, 5-O Pr D-7 65
i
CN 4-aza, 3-OMe, 5-O Pr D-7 50# <0.02
n
Br 4-aza, 3-OMe, 5-O Pr D-7 37
0.01
D-7 49# 0.02
D-6 50 0.04
D-6 78# 2.3
n
CN 4-aza, 3-OEt, 5-O Pr
Br
CN H
Br
H
H
D-5 53
0.11
0.16
0.18
0.02
CN H
D-5 76# 0.19
Br 4-aza, 2,3-diOMe
Br 4-aza, 2,3-diOMe
Br 4-aza, 3-OMe,5-OEt
D-5 63
D-4 48
D-4 52
D-4 40
0.03
<0.004 0.007
0.01
0.01
0.01
0.01
0.16
0.22
0.11
0.06
0.14
0.25
0.2
0.15
0.11
0.36
0.06
0.07
0.77
0.08
0.58
0.08
0.16
0.15
1.8
i
Br 4-aza, 3-OMe,5-O Pr
i
CN 4-aza, 3-OMe, 5-O Pr D-4 39# 0.05
CN H
CN 3-F
Br 4-aza, 2,3-diOMe
D-2 73# 0.21
D-2 62# 0.08
D-2 27
0.03
0.47
0.53
Br
Br
H
H
E-6
E-4
E-4
E-2
F-6
F-6
F-4
G
26
44
CN H
38# 0.08
47
39
56# 0.37
19
54
Br
H
0.27
0.11
Br
H
CN H
Br
Br
H
H
<0.02
0.15
CN H
G
G
G
H
83# 0.72
79 0.14
68# 0.58
42 0.04
70# 0.23
Br 4-aza, 2,3-diOMe
CN 4-aza, 2,3-diOMe
Br 3-Me
CN 3-Me
Br 3-Me
Br 4-aza, 2,3-diOMe
Br 4-aza, 2,3-diOMe
Br 4-aza, 2,3-diOMe
CN 4-aza, 2,3-diOMe
H
I
J
K
L
50
28
29
86
0.13
1.3
1.0
1.9
>2.5
4.5
0.23
0.12
3.3
>2.5
L
65# 4.6
Br
H
M
M
N
59
75
57
0.12
0.07
2.3
Br 4-aza, 2,3-diOMe
Br 4-aza, 2,3-diOMe
a
Footnotes for Table 1: Yield in the final AB/CD coupling step for the 6-Br compounds, or (#) for the
b
cyanation step for the 6-CN compounds; MIC90 (µg/mL); minimum inhibitory concentration for 90%
inhibition of growth of M.tb strain H37Rv, determined under aerobic (replicating; MABA) (ref. 13) or
non-replicating (LORA) (ref. 14) conditions, determined at the Institute for Tuberculosis Research,
c
University of Illinois at Chicago; clogP calculated by ChemDraw Ultra v12.0.2. (CambridgeSoft).

The compounds in Table 1 cover a range of 4.4 clogP units; compare, for example,
compounds 5 and 63. Within each C unit subset there was also limited variation of
substituents in the B subunit, and only Br and CN substituents on the A subunit.
Compounds 2-6 contain either a 5-linked tetrahydronaphthalene unit or a 7-linked
benzo[b]thiophenes, and are the most lipophilic compounds; all showed in vitro activity
against M. tb comparable to bedaquiline. Compounds 7-13 explore the 4-linked 2,3-dihydro-
1
H-indene unit, which still provides quite potent yet lipophilic compounds. The 7-linked 2,3-
dihydrobenzofuran unit was explored with a larger number of compounds (14-31), including
more polar unit B substituents and a number of Br/CN pairs. These covered a wide range of
overall lipophilicity (from clogP 7.4 to 4.2). Compounds 32-43 have the 2,3-
dihydrobenzofuran unit linked through other available positions (2-, 4-, 5- and 6-). There is
less variation in lipophilicity within this set, which makes it easier to compare the effect of
positioning to activity against M.tb. Overall, this effect does not seem large, although 33 and
3
7 are exceptions. Compounds 44-50 contain relatively lipophilic N-methylindoles and N-
methylindolines, and show somewhat reduced potency than the comparable
dihydrobenzofurans. Two 6-linked N-methylindolines (48, 49) had similar activity to the
other methylindolines but the 4-linked analog 50 was much more potent (cf with 37). The 7-
linked 2,3-dihydrobenzofurans (51-54) included the very polar compound 54 (clogP 3.75)
which was less effective. The two 4-linked benzo[d][1,3]dioxoles (55, 56) and the 5-linked
2
,3-dihydrobenzo[b][1,4]dioxin (57) had relatively lipophilic substituents in the B-subunit
and retained reasonable potency. However, the 7-linked [1,3]dioxolo[4,5-b]pyridine (58),
furo[3,2-b]pyridine K (59) and 8-linked 2,3-dihydro-[1,4]dioxino[2,3-b]pyridines (60, 61),
with a polar unit B, were among the most polar compounds in the set, with clogP values
between 3.6-5.0, and overall showed more modest anti-TB activity in vitro. Finally, of the 4-
linked furo[3,2-c]pyridines (62, 63) and the 7-linked furo[2,3-c]pyridine (64), the latter was
very polar and had attenuated activity.
2
.2. Structure-activity relationships
Across all of the compounds, which encompass a 4.4-fold range in clogP value, high potency
low MIC90) correlates positively with overall lipophilicity (equation 1); a trend noted
(
1
0
15
16
previously for this and other classes of M.tb inhibitors). This has been suggested to be
due to the very lipophilic cell wall of Mycobacteria.
logMIC90(MABA) = –0.40(±0.06)(clogP) + 1.39(±0.38)
n = 64, r = 0.63, P = <0.001, F2,61 = 41
(1)
However, inspection of individual compounds shows MIC90 potency dropping off by more
than predicted by equation 1 for compounds with clogP values below about 5 (e.g.,
compounds 23, 52, 58-61). It is not clear if this is a result of less target engagement or less
penetration into, and/or more efflux out of, the bacterium. Nevertheless, many compounds
(
e.g., 13, 25, 27, 29, 37, 63) were similarly potent and more hydrophilic than bedaquiline.

1
0
We have previously discussed the use of 6-substituents other than Br on the quinoline ring
of bedaquiline, and showed that the polar but electron-withdrawing CN substituent provided
a substantial decrease in drug lipophilicity (about 1.4 clogP units), at the expense of only a 2-
3
fold increase in MIC values against M.tb. The inclusion of 19 pairs of compounds where
the 6-Br group of 1 was exchanged for a 6-CN group allowed a further evaluation of this
trend. For the 15 pairs where we had definitive MIC90 data for both members (Table 1), the
average increase in MABA and LORA MIC90s were similar, being 2.76- and 2.81-fold
respectively.
Using a dummy variable for the presence of the CN substituent shows that the CN group
provides, on average, a further small (0.18 log) reduction in MIC90, after the effect of its
lower lipophilicity is allowed for.
logMIC90(MABA) = – 0.45(±0.08)(clogP) – 0.18(±0.16)X + 1.66(±0.50)
n = 64, r = 0.61, F3,62 = 18, where X = 1.0 for CN, 0.0 for Br
(2)
Note that in equations 1 and 2 the absolute values for the logMIC(MABA) data in Table 1 were used;
removal of the < and > qualified data points from the calculation did not change the nature of the
result.
A representative subset of the compounds of Table 1 were also evaluated for a number of
pharmacological properties, and compared against bedaquiline (1) (Table 2). For the
compounds with measured values, all except for 18, 34, and 36 had IC50’s >10 µM for
inhibition of the common CYP 3A4 oxidative metabolizing enzyme, and all showed no
1
5
toxicity toward Vero green monkey kidney cells at a concentration of 10 µg/mL (data not
shown). Bedaquiline itself (1) is a potent inhibitor of the hERG potassium channel (IC50 1.6
1
6
µM in our assay, but also reported as 0.37 µM), which is seen as a potential cardiovascular
liability, and has prompted comments that its use should be confined to settings where
carefully selected patients can be closely monitored, and that combination with other QTc-
1
7
prolonging drugs should be avoided. The IC50 for inhibition of hERG current for
bedaquiline, measured in the patch clamp assay we utilized for this study, was 1.6 µM, which
is in the same range as the published value. Compared to this, a few of the analogs (5, 24, 28,
3
0) showed a significant (5-8 fold) improvement in this parameter, but there was no common
feature to distinguish them from others which were much more potent hERG inhibitors (e.g.,
4, 16, 34, 36, 55, 56). All of the compounds except 24, 26-28 (which were four of the most
lipophilic compounds) had significantly faster clearance rates in human liver microsomes
HClint) and concomitantly shorter half-lives (Ht½) than did 1 (Table 2), which is in line with
1
(
1
1
previous SAR observations. The same trend was observed across the whole set of
compounds for which defined human liver microsome clearance data was obtained, with a
modest correlation seen between lower lipophilicity and faster clearance.
log(HClint) = -0.26 (clogP) + 2.60
(3)
n = 28, r = 0.52, P = <0.0001, F = 9.54

For the compounds profiled in Table 2, half-lives on incubation with human liver microsomes
were extended by nearly 5-fold on average in the presence of the microsome inhibitor
ketoconazole (Supplementary Data; Table S1), suggesting that the majority of the
metabolism comes from CYP3A4, as for bedaquiline.
While these compounds were also similar to bedaquiline in their low aqueous solubility and
high plasma protein binding (Supplementary Data; Table S1), most had acceptable
1
0,11
bioavailability (F > 25% in mice). Finally, as shown previously,
the oral bioavailability of
the compounds in mice was broadly inversely correlated with compound lipophilicity.
Several of the compounds were further evaluated for efficacy in vivo against acute murine
TB. For these assessments, female BALB/c mice, infected via aerosol with M. tuberculosis
1
8
Erdman, were treated by oral gavage with a dose of 20 mg/kg once daily for 12 continuous
days, beginning on day 11 post-infection. Compounds were administered as a solution in
2
0% hydroxypropyl-beta-cyclodextrin, in water, adjusted to pH 3. Bedaquiline, dosed orally
once daily at either 10 mg/kg or at 20 mg/kg, was administered as a comparator, and vehicle-
treated mice were evaluated as a negative control. Mice were sacrificed on day 25, and the
numbers of colony forming units (CFU) in the lungs were determined by plating on agar
containing charcoal (to absorb compound and prevent drug carryover effects) and compared
with the CFUs for bedaquiline and vehicle alone-treated mice. Of the compounds evaluated,
the most effective analogs, where 20 mg/kg/day effected a reduction in lung CFU at least as
great as that demonstrated by 10 mg/kg/day bedaquiline, tested alongside, (i.e., 5, 7, 16, 24,
2
6, 28, 29, 36) had lipophilicities (clogPs) ranging from 7.41 to 5.61, including two with CN-
substituted A units, again suggesting the viability of a CN substituent to lower overall drug
lipophilicity without compromising in vivo efficacy.
Table 2. Biochemical profiling of selected representative compounds of Table 1
IC50 (µM)
No CYPa
A4
>50
Log CFU redn
b
c
d
e
f
BDQ
10mpk
BDQ
20mpk
i
hERG HClint
Ht½ F (%) 20mpk
g
h
clogP
3
1
5
7
1
1.6
12
3
231
33
52
56
33
34
25
3.3-5.5 4.5-6.2
7.25
7.11
7.09
4.99
j
ND
>10
ND
ND
>10
>10
7.8
ND
>10
>10
ND
ND
ND
ND
21
13
31
4.6
5.7
ND
4.6
4.5
ND
4.6
5.6
ND
ND
4
5.7
ND
ND
5.7
5.3
ND
4.5
ND
4.5
3.8
1-3
~3
0.8
0.6
ND
j
0
1
23
1
9
14
11
20
16
18
3
75
50
64
35
42
51
52
42
13
ND
ND
ND
4.3
4.1
ND
ND
4.1
4.3
ND
3.3
ND
3.3
7.09
1
1
1
2
2
2
2
4
6
8
1
2
4
5
3.3
>5.7
ND
ND
0.9
5.28
6.64
5.56
6.48
5.61
7.41
6.06
6.87
5.53
7.19
j
1-3
0.9
>10
3.3
7.5
<1
39
37
248
49
4.2
65
<2.3
3
11
21
ND
2
2
2
6
7
8
>300
277
>300
73
ND
41
5.6
ND
5.4
>10
<2.3

29
30
34
36
37
42
43
48
50
54
55
56
57
60
ND
ND
9.7
>2
>10
0.4
0.6
4.9
5
141
133
20
38
59
16
23
151
56
31
99
47
182
91
25
46
42
52
ND
33
50
ND
35
21
5.3
ND
3.4
5.2
ND
3.7
3.8
ND
ND
ND
0.8
0.2
ND
ND
5
6.1
ND
5.3
5.3
ND
5.7
5.7
ND
ND
ND
4.9
6.2
ND
ND
5.84
7.42
6.64
5.61
5.61
5.42
5.61
6.50
6.50
3.75
6.54
5.18
6.71
4.97
ND
4.3
4.3
ND
4.1
4.1
ND
ND
ND
3.9
5.5
ND
ND
34
18
12
43
30
4.6
12
23
7
6.9
j
ND
>10
>10
ND
ND
>10
>10
>10
>10
ND
1-3
0.9
0.8
<1
1.3
>1
0.5
0.3
ND
>3
28
38
ND
61
15
4
8
a
Footnotes for Table 2: Inhibition of CYP3A4 (human liver microsomes, 20 min exposure);
b
c
Inhibition of the hERG channel (5-point manual patch-clamp assay, conducted at WuXi); Clearance
d
(
µL/min/mg) in human liver microsomes at 60 min (1 µM concentration); half-life (min) in human
e
liver microsomes (1 µM concentration); Oral bioavailability (in male CD-1 mice, when given at 10
mg/kg); Log reduction of colony-forming units from the lungs of BALB/c mice compared to the
untreated (vehicle only) control after daily oral dosing at 20 mg/kg/day for each test compound,
compared to 10 and 20 mg/kg/day bedaquiline tested in the same assay, with 12 continuous days of
f,g,h
f
g
h
i
j
once per day dosing. clogP calculated by ChemDraw Ultra v12.0.2. (CambridgeSoft); ND: not done.
3
. Conclusions
This work, part of a programme seeking improved analogs of bedaquiline (1), sought to
evaluate the effects of replacing the naphthalene C-unit with a variety of bicyclic moieties of
widely differing structures and lipophilicities. The results, which show an MIC90/lipophilicity
relationship (equation 1) broadly similar to that seen for other series of TB drugs, suggest that
changes in the C-subunit are well-tolerated for this series. Encouragingly, many analogs with
lower clogP values than bedaquiline were at least as potent against M.tb. Further, where
tested, most analogs with at least similar potency to bedaquiline against M.tb had higher
clearance in human liver microsomes, suggesting they may show shorter terminal half-lives
than bedaquiline in vivo, with less risk of tissue over-accumulation. Among the analogs,
there was a significant range in potency for hERG channel block (IC50’s from 0.4 to >10
µM). While there was no discernible SAR pattern to this, it is encouraging that such
improvements in hERG liability can be seen for what is still a lipophilic aromatic strong base,
and that anti-mycobacterial potency is still maintained when hERG inhibition is reduced. The
four best compounds in his regard (24, 26, 28, 30) were all of one class (D-7; 7-benzofuran),
suggest that exploration of further C-unit variations might be of interest in this regard. The
value of the A-unit CN substituent is also confirmed for its ability to lower overall drug
lipophilicity (thus contributing to desirable physiochemical properties) without compromising
in vivo efficacy.
4
. Experimental

4
.1. Chemistry
Final products were analysed by reverse-phase HPLC (Alltima C18 5 µm column, 150 × 3.2
mm; Alltech Associated, Inc., Deerfield, IL) using an Agilent HP1100 equipped with a diode-
array detector. Mobile phases were gradients of 80% CH
NH HCO at pH 3.5 and 0.5 mL/min. Purity was determined by monitoring at 330 ± 50 nm
and was ≥95% for all final products. Melting points were determined on an Electrothermal
100 melting point apparatus. NMR spectra were obtained on a Bruker Avance 400
3
CN/20% H
2
O (v/v) in 45 mM
4
2
9
1
spectrometer at 400 MHz for H. Low-resolution atmospheric pressure chemical ionization
APCI) mass spectra were measured for organic solutions on a ThermoFinnigan Surveyor
MSQ mass spectrometer, connected to a Gilson autosampler.
(
4
6
.1.1. Scheme 2. Synthesis of A/B units
-Bromo-3-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-methoxyquinoline (VI: Y=2,3-
2 2
O(CH ) O-).
To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (5.00 g, 28.0 mmol) in
THF (150 mL) at 0 °C was added lithium aluminium hydride (2.13 g, 56.0 mmol) in small
portions. The reaction mixture was stirred at 0 °C for 10 min and stirred for a further 18 h at
o
2
0 C. Water (150 mL) was added to the reaction mixture which was extracted with EtOAc (2
x 100 mL). The combined organic layers were washed with brine (100 mL), dried over
Na SO , filtered and concentrated under reduced pressure to obtain (2,3-
dihydrobenzo[b][1,4]dioxin-5-yl)methanol as a yellow oil (3.22 g, 99%). H NMR (CDCl
2
4
1
3
,
4
1
00 MHz) δ 6.87-6.79 (m, 3H), 4.66 (s, 2H), 4.32-4.30 (m, 2H), 4.28-4.25 (m, 2H), 2.19 (bs,
H). Found: [M+H-18]=149.5.
2
A solution of the above alcohol (3.75 g, 32.3 mmol) in Et O (80 mL) was cooled to 0 °C and
phosphorous tribromide (3.67 mL, 38.8 mmol) was added dropwise. The solution was stirred
o
at 0 °C for 10 min, then at 20 C for 1 h. Water (10 mL) was added cautiously to quench the
excess of reagent and the mixture was diluted with diethyl ether and washed with water (3 x
5
0 mL). The combined organic layers were washed with brine (100 mL), dried over Na
2
SO ,
4
filtered and concentrated under reduced pressure to obtain 5-(bromomethyl)-2,3-
1
dihydrobenzo[b][1,4]dioxine as a brown solid (4.61 g, 62%). H NMR (CDCl
.91-6.77 (m, 3H), 4.52 (s, 2H), 4.35-4.33 (m, 2H), 4.29-4.27 (m, 2H). Found: [M+H-
Br]=149.5.
3
, 400 MHz) δ
6
A mixture of the above bromide (4.6 g, 20.0 mmol), (6-bromo-2-methoxyquinolin-3-
yl)boronic acid (V) (4.42 g, 15.4 mmol) and Cs
2
CO
3
(11.54 g, 0.77 mmol) in toluene:DMF
(
60 mL, 2:1) was degassed under N , then Pd(PPh
2
3
)
4
(0.890 g, 0.77 mmol) was added, and
o
the mixture heated at 110 °C for 4 h. The mixture was cooled to 20 C, filtered through a plug
of Celite, water (150 mL) was added and extracted with EtOAc (3 x 100 mL). The combined
organic layers were washed with brine (100 mL), dried over Na
2
SO , filtered and
4
concentrated under reduced pressure to obtain a yellow residue. Purification by flash column
chromatography using hexanes:EtOAc (9:1) gave 6-bromo-3-((2,3-
dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-methoxyquinoline (VI: Y=2,3-O(CH
2
)
2
O-) as
) δ 7.75 (d, J = 2.2 Hz, 1H), 7.73-7.70 (m, 1H),
.61-7.59 (m, 1H), 7.43 (s, 1H), 6.84-6.78 (m, 2H), 6.72-6.70 (m, 1H), 4.27-4.22 (m, 4H),
.10 (s, 3H), 3.98 (s, 2H). Found: [M+H]=386.6.
1
white solid (3.1 g, 52%). H NMR (CDCl
3
7
4

6
-Bromo-3-((2,6-diethoxypyridin-4-yl)methyl)-2-methoxyquinoline (VI: Y = 4-aza, 3,5
diOEt)
Trimethylborate (3.88 mL, 34.2 mmol) and borane-dimethylsulfide (3.25 mL, 34.3 mmol)
were added sequentially to a solution of 2,6-diethoxyisonicotinic acid (2.41 g, 11.4 mmol) in
o
THF (100 mL, dist. Na) at 0 °C and the mixture was stirred at 20 C for 18 h. The solution
was cooled to 0 °C and methanol was cautiously added to quench excess borane. Removal of
the solvent gave a solid which was partitioned between EtOAc and water, the organic fraction
was dried and evaporated. Column chromatography (3:1 hexanes:EtOAc) gave 2,6-
1
diethoxypyridin-4-yl)methanol (2.13 g, 95%). M.p. 54-56 °C. H NMR (DMSO-d
6
) δ 6.27 (d,
J = 0.6 Hz, 2H), 4.62 (d, J = 6.2 Hz, 2H), 4.31 (q, J = 7.1 Hz, 4H), 1.72 (t, J = 6.2 Hz, 1H),
.38 (t, J = 7.1 Hz, 6H). Found: [M+H]=198.1.
1
A solution of the above alcohol (2.07 g, 10.5 mmol) in DCM (100 mL, anhydrous) at 0 °C
was treated sequentially with Et N (2.93 mL, 21.0 mmol) and mesyl chloride (1.22 mL, 15.8
3
mmol), the mixture was stirred at 0 °C for 1 h then partitioned between DCM and water. The
organic fraction was dried and evaporated and the residue was dissolved in acetone (100 mL),
LiBr (9.15 g, 105 mmol) was added and the mixture was refluxed for 1 h then evaporated.
The residue was partitioned between DCM and water and the organic fraction was dried and
evaporated. Column chromatography (DCM) gave 4-(bromomethyl)-2,6-diethoxypyridine
o
1
(
(
2.63 g, 92%), mp 37-39 C. H NMR (CDCl
3
) δ 6.28 (s, 2H), 4.31 (q, J = 7.1 Hz, 4H), 4.28
s, 2H), 1.38 (t, J = 7.1 Hz, 6H). Found: [M+H]=260.5
A mixture of the above bromide (2.20 g, 7.80 mmol), 4-(bromomethyl)-2,6-diethoxypyridine
2.13 g, 8.20 mmol) and Cs CO (5.13 g, 15.6 mmol) in toluene (40 mL) and DMF (20 mL)
was purged with nitrogen. Pd(PPh (0.18 g, 0.156 mmol) was added, the mixture was
(
2
3
3 4
)
purged with nitrogen, then heated to 80 °C under nitrogen for 3 h. The reaction was
partitioned between EtOAc and water and the organic fraction was dried and evaporated.
Column chromatography with 3:1 hexanes:DCM eluted non polar impurities, elution with 1:1
hexanes:DCM gave 6-bromo-3-((2,6-diethoxypyridin-4-yl)methyl)-2-methoxyquinoline (VI:
1
Y = 4-aza, 3.5 diOEt) (2.35 g, 72%), mp 91-92°C. H NMR (CDCl
3
) δ 7.77 (d, J = 2.2 Hz,
1
H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.58 (s, 1H), 6.13 (s, 2H), 4.29
(
q, J = 7.1 Hz, 4H), 4.06 (s, 3H), 3.90 (s, 2H), 1.36 (t, J = 7.1 Hz, 6H). Found: [M+H]=417.1
6
-Bromo-3-((2-isopropoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline (VI: Y = 4-
i
aza, 3-OMe, 5-O Pr)
A suspension of 2,6-dihydroxyisonicotinic acid (10.00 g, 64.5 mmol) in MeOH (60 mL) was
treated dropwise with H
and then evaporated. The residue was treated with sat. aq. NaHCO
with EtOAc (3 x 200 mL). The organic extracts were washed with sat. aq. NaHCO
brine, then dried and evaporated to give methyl 2-hydroxy-6-methoxyisonicotinate (3.55 g,
2
SO
4
(10 mL, 18.4 M, 184 mmol). The solution was refluxed for 72 h
to pH 8 and extracted
and
3
3
1
3
0%) as a tan solid, mp 183-185°C. H NMR (DMSO-d
6
) δ 11.2 (bs, 1H), 6.61 (bs, 2H), 3.84
(
s, 3H), 3.83 (s, 3H). Found: [M+H]=184.2.
A solution of the above alcohol (5.04 g, 27.5 mmol) in DMF (100 mL, anhydrous) was
treated with K CO (4.75 g, 34.4 mmol) and then 2-iodopropane (3.43 mL, 34.4 mmol). The
2
3

o
mixture was stirred at 20 C for 24 h, more 2-iodopropane (3.43 mL, 34.3 mmol) was added
and the mixture was stirred for a further 72 h then partitioned between EtOAc and water and
the aqueous layer was extracted further with EtOAc. The organic fractions were washed with
water, dried and evaporated. Chromatography (DCM) gave methyl 2-isopropoxy-6-
1
methoxyisonicotinate (6.21 g, 100%) as a colourless oil. H NMR (CDCl
3
) δ 6.81 (s, 2H),
5
.24 (sp, J = 6.2 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 1.36 (d, J = 6.2 Hz, 6H). Found:
[
M+H]=226.2.
A solution of LiOH (1.98 g, 82.7 mmol) in water (60 mL) was added to a solution of the
above ester (6.20 g, 27.5 mmol) in MeOH (60mL) and THF (60 mL) and the solution was
o
stirred at 20 C for 18 h and then evaporated. The residue was dissolved in water (150 mL)
and acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 2-
1
isopropoxy-6-methoxyisonicotinic acid (5.33 g, 92%) as a white solid, mp 120-121°C.
NMR (DMSO-d
sp, J = 6.2 Hz, 1H), 3.86 (s, 3H), 1.31 (d, J = 6.2 Hz, 6H). Found: [M+H]=212.1.
H
6
) δ 13.50 (bs, 1H), 6.70 (d, J = 1.0 Hz, 1H), 6.66 (d, J = 1.0 Hz, 1H), 5.20
(
Trimethylborate (6.81 mL, 59.6 mmol) and borane dimethylsulfide complex (5.66 mL, 59.7
mmol) were added sequentially to a solution of the above acid (6.30 g, 29.8 mmol) in THF
o
(
100 mL, dist. Na) at 0 °C, the mixture was stirred at 20 C for 18 h. The solution was cooled
to 0 °C and quenched with methanol. Removal of the solvent gave a white solid, which was
partitioned between EtOAc and water, the organic fraction was dried and evaporated to give
2
-isopropoxy-6-methoxypyridin-4-yl)methanol (5.86 g, 99%) as white solid, mp 121-122 °C.
1
H NMR (CDCl
3
) δ 6.26 (t, J = 0.8 Hz, 1H), 6.25 (t, J = 0.8 Hz, 1H), 5.23 (sp, J = 6.2 Hz,
1
H), 4.61 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 1.73 (t, J = 6.2 Hz, 1H), 1.34 (d, J = 6.2 Hz, 6H).
Found: [M+H]=212.2 (M – OH + MeO).
A solution of the above alcohol (5.86 g, 29.9 mmol) in DCM (100 mL, anhydrous) at 0 °C
was treated with Et N (8.3 mL, 59.5 mmol) and then MsCl (3.47 mL, 44.8 mmol), the
3
mixture was stirred at 0 °C for 1 h then partitioned between DCM and water. The organic
fraction was dried and evaporated and the residue was dissolved in acetone (200 mL), LiBr
(
25.9 g, 299 mmol) was added and the mixture was refluxed for 1 h then evaporated. The
residue was partitioned between DCM and water; the organic fraction was dried and
evaporated. Column chromatography (DCM) gave 4-(bromomethyl)-2-isopropoxy-6-
1
methoxypyridine (6.98 g, 90%) as a colourless oil. H NMR (CDCl
3
) δ 6.28 (s, 1H), 6.27 (s,
1
H), 5.23 (sp, J = 6.2 Hz, 1H), 4.27 (s, 2H), 3.88 (s, 3H), 1.35 (d, J = 6.3 Hz, 6H). Found:
[
M+H]=260.1
A mixture of the above bromide (7.45 g, 26.4 mmol), 4-(bromomethyl)-2-isopropoxy-6-
methoxypyridine (6.84 g, 26.4 mmol) and Cs CO (17.3 g, 52.7 mmol) in toluene (100 mL)
and DMF (50 mL) was purged with nitrogen. Pd(PPh (0.61 g, 0.528 mmol) was added, the
2
3
3 4
)
mixture was purged with nitrogen and then heated to 80 °C under nitrogen for 3 h. The
reaction mixture was partitioned between EtOAc and water and the organic fraction was
dried and evaporated. Column chromatography with 3:1 hexanes:DCM eluted impurities,
then elution with 1:1 hexanes:DCM gave 6-bromo-3-((2-isopropoxy-6-methoxypyridin-4-
i
yl)methyl)-2-methoxyquinoline (VI: Y = 4-aza, 3-OMe, 5-O Pr) (8.59 g, 78%) as a white
1
solid, mp 90-91 °C. H NMR (CDCl
3
) δ 7.78 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H),

7
5
.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.58 (s, 1H), 6.14 (d, J = 0.9 Hz, 1H), 6.10 (d, J = 0.9 Hz, 1H),
.22 (sp, J = 6.2 Hz, 1H), 4.06 (s, 3H), 3.90 (s, 2H), 3.87 (s, 3H), 1.33 (d, J = 6.2 Hz, 6H).
Found: [M+H]=417.1
6
-Bromo-3-((2-ethoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline (VI: Y = 4-aza, 3-
OMe, 5-OEt)
A solution of methyl 2-hydroxy-6-methoxyisonicotinate (6.96 g, 38.0 mmol) in DMF (100
mL, anhydrous) was treated with K
2 3
CO (6.57 g, 47.6 mmol) and then iodoethane (3.85 mL,
o
4
7.6 mmol). The mixture was stirred at 20 C for 24 h, partitioned between EtOAc and water
and the aqueous layer was extracted with EtOAc. The organic fractions were washed with
water, dried and evaporated, chromatography (DCM) gave methyl 2-ethoxy-6-
o
1
methoxyisonicotinate (6.20 g, 77%) as a white solid, mp 38-431 C. H NMR (CDCl
(
[
3
) δ 6.84
s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). Found:
M+H]=212.1.
A solution of LiOH (2.10 g, 87.7 mmol) in water (60 mL) was added to a solution of the
above ester (6.20 g, 29.4 mmol) in MeOH (60 mL) and THF (60 mL), the solution was stirred
o
at 20 C for 18 h and then evaporated. The residue was dissolved in water (150 mL) and
acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 2-ethoxy-6-
1
methoxyisonicotinic acid (5.61 g, 97%) as a white solid, mp 137-139 °C. H NMR (DMSO-
d
2
6
) δ 13.54 (bs, 1H), 6.73 (d, J = 1.0 Hz, 1H), 6.71 (d, J = 1.0 Hz, 1H), 4.32 (q, J = 7.0 Hz,
H), 3.87 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). Found: [M+H]=198.2.
Trimethylborate (6.06 mL, 53.1 mmol) and then borane-dimethylsulfide (5.04 mL, 53.1
mmol) were added to a solution of the above acid (5.24 g, 26.6 mmol) in THF (100 mL, dist.
o
Na) at 0 °C and the mixture was stirred at 20 C for 18 h. The solution was cooled to 0 °C and
quenched with methanol. Removal of the solvent gave a solid which was partitioned between
EtOAc and water, the organic fraction was dried and evaporated to give (2-ethoxy-6-
1
methoxypyridin-4-yl)methanol (4.79 g, 98%), mp 68-71 °C. H NMR (CDCl
3
) δ 6.29 (bd, J =
0
.7 Hz, 1H), 6.28 (bd, J = 0.7 Hz, 1H), 4.63 (d, J = 6.2 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.90
(
s, 3H), 1.76 (t, J = 6.2 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H). Found: [M + H]= 184.2.
A solution of the above alcohol (4.72 g, 25.9 mmol) in DCM (100 mL, anhydrous) at 0 °C
was treated sequentially with Et N (7.22 mL, 51.8 mmol) and mesyl chloride (3.00 mL, 38.8
3
mmol), the mixture was stirred at 0 °C for 1 h then partitioned between DCM and water. The
organic fraction was dried and evaporated and the residue was dissolved in acetone (200 mL),
LiBr (22.5 g, 259 mmol) was added and the mixture was refluxed for 1 h then evaporated.
The residue was partitioned between DCM and water; the organic fraction was dried and
evaporated. Column chromatography (DCM) gave 4-(bromomethyl)-2-ethoxy-6-
o
1
methoxypyridine (5.78 g, 91%) as a white solid, mp 41-42 C. H NMR (CDCl
H), 4.33 (q, J = 7.1 Hz, 2H), 4.28 (s, 2H), 3.90 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). Found:
M+H]=246.0
3
) δ 6.30 (s,
2
[
A mixture of the above acid (5.77 g, 23.4 mmol), (6-bromo-2-methoxyquinolin-3-yl)boronic
acid (V; 6.61 g, 23.4 mmol) and Cs CO (15.25 g, 46.5 mmol) in toluene (100 mL) and DMF
50 mL) was purged with nitrogen. Pd(PPh (0.54 g, 0.465 mmol) was added, the mixture
was purged with nitrogen then heated to 80 °C under nitrogen for 3 h. The reaction mixture
2
3
(
3 4
)

was partitioned between EtOAc and water and the organic fraction was dried and evaporated.
Column chromatography with 3:1 hexanes:DCM eluted impurities, then elution with 1:1
hexanes:DCM gave 6-bromo-3-((2-ethoxy-6-methoxypyridin-4-yl)methyl)-2-
methoxyquinoline (VI: Y = 4-aza, 3-OMe, 5-OEt) (6.69 g, 71%) as a white solid, mp 104-
1
1
8
3
06 °C. H NMR (CDCl
3
) δ 7.78 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.63 (dd, J =
.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.15 (d, J = 8.0 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H),
.91 (s, 2H), 3.88 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). Found: [M+H]=403.1
6
3
-Bromo-2-methoxy-3-((2-methoxy-6-propoxypyridin-4-yl)methyl)quinoline (VI: Y = 4-aza,
n
-OMe, 5-O Pr)
A solution of methyl 2-hydroxy-6-methoxyisonicotinate (6.00 g, 32.8 mmol) in DMF (100
mL, anhydrous) was treated with K CO (6.80 g, 49.2 mmol) and then 1-iodopropane (4.8
2
3
o
mL, 49.2 mmol). The mixture was stirred at 20 C for 48 h, partitioned between EtOAc and
water and the aqueous layer was extracted with EtOAc. The organic fractions were washed
with water, dried and evaporated. Column chromatography (DCM) gave methyl 2-methoxy-
1
6
-propoxyisonicotinate (6.59 g, 89%) as a colourless oil. H NMR (CDCl
3
) δ 6.85 (d, J = 1.0
Hz, 1H), 6.83 (d, J = 1.0 Hz, 1H), 4.24 (t, J = 6.7 Hz, 2H), 3.93 (s, 3H) , 3.91 (s, 3H), 1.80
qt, J = 7.4, 6.7 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). Found: [M+H]=226.1.
(
A solution of LiOH (2.04 g, 85.2 mmol) in water (60 mL) was added to a solution of the
above ester (6.40 g, 28.4 mmol) in THF (60 mL) and MeOH (60 mL), the solution was stirred
o
at 20 C for 18 h and then evaporated. The residue was dissolved in water (200 mL) and
acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 2-methoxy-6-
1
propoxyisonicotinic acid (5.39 g, 90%) as a white solid, mp 141-143 °C. H NMR (DMSO-
d
2
6
) δ 13.53 (bs, 1H), 6.73 (d, J = 1.0 Hz, 1H), 6.72 (d, J = 1.0 Hz, 1H), 4.23 (t, J = 6.6 Hz,
H), 3.87 (s, 3H), 1.73 (qt, J = 7.4, 6.6 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). Found:
[
M+H]=212.1.
Trimethylborate (5.8 mL, 50.8 mmol) and borane dimethylsulfide complex (4.8 mL, 50.6
mmol) were added sequentially to a solution of the above acid (5.39 g, 25.5 mmol) in THF
(
100 mL, dist. Na) at 0 °C, and the mixture was stirred at 20 oC for 16 hr. The solution was
cooled to 0 °C and methanol was cautiously added to quench the reaction. Removal of the
solvent gave a solid which was partitioned between EtOAc and water, the organic fraction
was dried and evaporated. Column chromatography (3:1 hexanes:EtOAc) gave (2-methoxy-
1
6
-propoxypyridin-4-yl)methanol (5.04 g, 100%) as a colourless oil. H NMR (CDCl
3
) δ 6.28
(
d, J = 0.8 Hz, 1H), 6.26 (d, J = 0.8 Hz, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.31 (q, J = 7.1 Hz,
2
3
H), 4.20 (t, J = 6.8 Hz, 2H), 1.72-1.83 (m, 3H), 1.38 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.4 Hz,
H). Found: [M+H]=198.2.
A solution of the above alcohol (5.00 g, 25.4 mmol) in DCM (100 mL, anhydrous) at 0 °C
was treated with Et N (7.07 mL, 50.7 mmol) and then mesyl chloride (2.94 mL, 38.0 mmol),
3
the mixture was stirred at 0 °C for 1 h then partitioned between DCM and water. The organic
fraction was dried and evaporated and the residue was dissolved in acetone (150 mL), LiBr
(
22.0 g, 253 mmol) was added and the mixture was refluxed for 1 h then evaporated. The
residue was partitioned between DCM and water; the organic fraction was dried and
evaporated. Column chromatography (DCM) gave 4-(bromomethyl)-2-methoxy-6-

1
propoxypyridine (6.15 g, 93%) as a colourless oil. H NMR (CDCl
1
7
3
) δ 6.31 (d, J = 1.0 Hz,
H), 6.30 (d, J = 1.0 Hz, 1H), 4.28 (s, 2H), 4.22 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 1.79 (qt, J =
.4, 6.7 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). Found: [M+H]=260.5
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (V; 6.62 g, 23.5 mmol) and the
above bromide (6.11 g, 23.5 mmol) and Cs CO (15.3 g, 47.0 mmol) in toluene (66 mL) and
DMF (33 mL) was purged with nitrogen. Pd(PPh (0.54 g, 0.47 mmol) was added, the
2
3
3 4
)
mixture was purged with nitrogen then heated to 80 °C under nitrogen for 3 h. The reaction
was partitioned between EtOAc and water and the organic fraction was dried and evaporated.
Column chromatography with 1:1 DCM:hexanes gave an impure product which was
rechromatographed using a gradient of 2:1 hexanes:DCM to1:1 hexanes:DCM to give 6-
bromo-2-methoxy-3-((2-methoxy-6-propoxypyridin-4-yl)methyl)quinoline (VI: Y = 4-aza, 3-
n
1
OMe, 5-O Pr) (6.63 g, 68%) as a white solid, mp 68-71 °C. H NMR (CDCl
3
) δ 7.78 (d, J =
2
6
6
.2 Hz, 1H), 7.69 (d, J =8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 7.58 (s, 1H), 6.15 (s, 1H),
.14 (s, 1H), 4.21 (t, J = 6.8 Hz, 2H), 4.06 (s, 3H), 3.91 (s, 2H), 3.88 (s, 3H), 1.79 (qt, J = 7.4,
.8 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). Found: [M+H]=417.1
6
-Bromo-3-((2-ethoxy-6-propoxypyridin-4-yl)methyl)-2-methoxyquinoline(VI: Y = 4-aza, 3-
OEt, 5-OPr)
A suspension of 2,6-dihydroxyisonicotinic acid (40.00 g, 258 mmol) in EtOH (300 mL) was
treated dropwise with H
and then evaporated. The residue was treated with sat. aq. NaHCO
with EtOAc (3 x 200 mL). The organic extracts were washed with sat. aq. NaHCO
brine, then dried and evaporated to give ethyl 2-ethoxy-6-hydroxyisonicotinate (10.86 g,
2
SO
4
(40 mL, 18.4 M, 752 mmol). The solution was refluxed for 72 h
to pH 8 and extracted
and
3
3
1
2
0%) as a tan solid, mp 102-104 °C. H NMR (DMSO-d
Hz, 1H), 6.57 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.298 (t, J = 7.1 Hz,
H), 1,296 (t, J = 7.0 Hz, 3H).
6
) δ 11.45 (bs, 1H), 6.59 (d, J = 1.0
3
A solution of the above hydroxyester (10.0 g, 47.3 mmol) in DMF (100 mL, anhydrous) was
treated with K CO (5.8 g, 59.2 mmol) and then 2-iodopropane (8.17 mL, 59.4 mmol). The
2
3
o
mixture was stirred at 20 C for 72 h. The mixture was partitioned between EtOAc and water
and the aqueous layer was extracted further with EtOAc. The organic fractions were washed
with water, dried and evaporated. Chromatography (DCM) gave ethyl 2-ethoxy-6-
1
propoxyisonicotinate (8.98 g, 75%) as a colourless oil. H NMR (CDCl
3
) δ 6.84 (d, J = 1.1
Hz, 1H), 6.83 (d, J = 1.1 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.23 (t, J
6.7 Hz, 2H), 1.80 (qt, J = 7.4, 6.8 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H),
.02 (t, J = 7.4 Hz, 3H).
=
1
A solution of LiOH (2.53 g, 106 mmol) in water (60 mL) was added to a solution of the
above ester (8.96 g, 35.4 mmol) in MeOH (60mL) and THF (60 mL), the solution was stirred
o
at 20 C for 18 h and then evaporated. The residue was dissolved in water (150 mL) and
acidified to pH 3 with 2 M HCl. The precipitate was filtered and dried to give 2-ethoxy-6-
1
propoxyisonicotinic acid (S20) (7.96 g, quant.) as a white solid. H NMR (DMSO-d
6
) δ 13.52
(
bs, 1H), 6.80 (d, J = 1.0 Hz, 1H), 6.70 (d, J = 1.0 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H), 4.20 (t, J
=
6.6 Hz, 2H), 1.73 (qt, J = 7.4, 6.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H).

Trimethylborate (5.3 mL, 46 mmol) and borane dimethylsulfide complex (4.4 mL, 46 mmol)
were added sequentially to a solution of the above acid (5.23 g, 23.2 mmol) in THF (100 mL,
o
dist. Na) at 0 °C, the mixture was stirred at 20 C for 18 hr. The solution was cooled to 0 °C
and quenched with methanol. Removal of the solvent gave a white solid, which was
partitioned between EtOAc and water, the organic fraction was dried and evaporated. Column
chromatography (3:1 hexanes:EtOAc) gave (2-ethoxy-6-propoxypyridin-4-yl)methanol
1
(
4.764 g, 97%) as a white solid, mp 36-39 °C. H NMR (CDCl
3
) δ 6.28 (d, J = 0.8 Hz, 1H),
6
2
=
.26 (d, J = 0.8 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.20 (t, J = 6.8 Hz,
H), 1.78 (qt, J = 7.4, 6.8 Hz, 2H), 1.74 (t, J = 6.2 Hz, 1H), 1.38 (t, J = 7.0 Hz, 3H), 1.00 (t, J
7.4 Hz, 3H).
A solution of the above alcohol (4.73 g, 22.4 mmol) in DCM (100 mL, anhydrous) at 0 °C
was treated with Et N (6.24 mL, 44.8 mmol) and then MsCl (2.6 mL, 33.6 mmol), the
3
mixture was stirred at 0 °C for 1 h then partitioned between DCM and water. The organic
fraction was dried and evaporated and the residue was dissolved in acetone (200 mL), LiBr
(
19.5 g, 225 mmol) was added and the mixture was refluxed for 1 h then evaporated. The
residue was partitioned between DCM and water; the organic fraction was dried and
evaporated. Column chromatography (DCM) gave 4-(bromomethyl)-2-ethoxy-6-
1
propoxypyridine (5.817 g, 95%) as a colourless oil. H NMR (CDCl
3
) δ 6.29 (d, J = 1.0 Hz,
1
1
H), 6.27 (d, J = 1.0 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.28 (s, 2H), 4.20 (t, J = 6.7 Hz, 2H),
.78 (qt, J = 7.4, 6.8 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H).
A mixture of the above bromide (5.81 g, 21.2 mmol), (6-bromo-2-methoxyquinolin-3-
yl)boronic acid (V, 5.98 g, 21.2 mmol), and Cs CO (13.8 g, 42.4 mmol) in toluene (133 mL)
and DMF (66 mL) was purged with nitrogen. Pd(PPh (0.49 g, 0.42 mmol) was added, the
2
3
3 4
)
mixture was purged with nitrogen and then heated to 80 °C under nitrogen for 3 h. The
reaction mixture was partitioned between EtOAc and water and the organic fraction was
dried and evaporated. Column chromatography with 3:1 hexanes:DCM eluted impurities,
then elution with 1:1 hexanes:DCM gave 6-bromo-3-((2-ethoxy-6-propoxypyridin-4-
yl)methyl)-2-methoxyquinoline (VI: Y = 4-aza, 3-OEt, 5-OPr) (6.644 g, 73%) as a white
1
solid, mp 69-71 °C. H NMR (CDCl
3
) δ 7.77 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H),
7
2
.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.14 (s, 1H), 6.12 (s, 1H), 4.29 (q, J = 7.1 Hz,
H), 4.19 (t, J = 6.7 Hz, 2H), 4.06 (s, 3H), 3.90 (s, 2H), 1.77 (qt, J = 7.4, 6.7 Hz, 2H), 1.36 (t,
J = 7.1 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). Found: [M+H]=433.21, 431.1.
4
1
.1.2. Scheme 3A: synthesis of Mannich base C/D units via Weinreb amides
-(2,3-Dihydro-1H-inden-4-yl)-3-(dimethylamino)propan-1-one (class C)
To a solution of 2,3-dihydro-1H-indene-4-carboxylic acid (4.40 g, 27.5 mmol) in DCM (250
mL) was added DMF (0.426 mL) followed by dropwise addition of oxalyl chloride (4.19 g,
3
3.0 mmol). The reaction mixture was stirred for 1 h, cooled to 0 °C, then N,O-
dimethylhydroxylamine hydrochloride (2.95 g, 30.3 mmol) and pyridine (7.32 mL, 90.7
o
mmol) were added and the reaction was stirred at 20 C for 18 h. The mixture was poured
onto sat. aqueous NaHCO
organic layers were dried over Na
obtain crude N-methoxy-N-methyl-2,3-dihydro-1H-indene-4-carboxamide, which was used
3
(150 mL) and extracted with DCM (3 x 100 mL). The combined
2
SO , filtered and concentrated under reduced pressure to
4
1
directly (5.64 g, 100%). H NMR (CDCl
3
) δ 7.21-7.13 (m, 3H), 3.56 (s, 3H), 3.31 (s, 3H),
2
.98-2.91 (m, 4H), 2.11-2.04 (m, 2H). Found: [M+H]=206.5.

A solution of the above crude amide (5.64 g, 27.5 mmol) in THF (150 mL) at 0 °C was
treated with vinylmagnesium bromide (1M solution in THF, 57.7 mL, 57.7 mmol) and the
solution was stirred for 3.5 h at 0 °C. Dimethylamine (2M solution in THF, 57.7 mL, 115.5
mmol) was added to the reaction mixture followed by water (60 mL). After 30 minutes
o
stirring at 20 C, the reaction mixture was concentrated under reduced pressure to obtain a
brownish residue. This was extracted with EtOAc (3 x 200 mL). The combined organic layers
2 4
were washed with brine (100 mL), dried over Na SO , filtered and concentrated under
reduced pressure to obtain 1-(2,3-dihydro-1H-inden-4-yl)-3-(dimethylamino)propan-1-one as
1
a brown oil (5.66 g, 95%). H NMR (CDCl
H), 7.20 (t, J = 7.6 Hz, 1H), 3.24 (t, J = 7.5 Hz, 2H), 3.11 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.5
Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.27 (s, 6H), 2.04 (t, J = 7.5 Hz, 2H). Found: [M+H]=218.6.
3
) δ 7.66 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.4 Hz,
1
1
-(Benzofuran-2-yl)-3-(dimethylamino)propan-1-one (class D-2)
Oxalyl chloride (3.13 mL, 3.70 mmol) was added to a suspension of benzofuran-2-carboxylic
acid (5.00 g, 3.08 mmol) in DCM (100 mL, anhydrous) and DMF (0.1 mL, 1.3 mmol) at 20
o
o
C. The mixture was stirred at 20 C for 1 h to give a colourless solution which was cooled to
0
9
°C. N,O-Dimethylhydroxylamine hydrochloride (3.31 g, 3.39 mmol) and pyridine (7.5 mL,
.27 mmol) were added sequentially and the mixture was stirred at 20 C for 18 h, then
o
partitioned between EtOAc and sat. aq. NaHCO
hexanes:EtOAc) gave N-methoxy-N-methylbenzofuran-2-carboxamide (6.32 g, 100%). H
NMR (CDCl ) δ 7.69 (ddd, 7.9, 1.2, 0.7 Hz, 1H), 7.61 (ddd, J = 8.4, 1.7, 0.9 Hz, 1H), 7.51 (d,
J = 1.0 Hz, 1H), 7.48 (ddd, J = 7.9, 7.2, 1.3 Hz, 1H), 7.30 (ddd, J = 7.5, 7.3, 0.9 Hz, 1H), 3.84
s, 3H), 3.43 (s, 3H). Found: [M+H]=206.2.
3
. Column chromatography (3:1
1
3
(
Vinylmagnesium bromide (58 mL, 58 mmol, 1 M in THF) was added to a solution of the
above amide (3.95 g, 19.2 mmol) in THF (200 mL, anhydrous) at 0 °C, the brown solution
o
was warmed to 20 C for 1 h then dimethylamine (58 mL, 116 mmol, 2 M in THF) and water
o
(
40 mL) were added. The solution was stirred at 20 C for 1 h, and then partitioned between
EtOAc and water. The solution was dried and evaporated to give 1-(benzofuran-2-yl)-3-
1
(
dimethylamino)propan-1-one (4.17 g, 100%). H NMR (CDCl ) δ 7.72 (ddd, J = 7.9, 1.0, 0.8
3
Hz, 1H), 7.59 (dd, J = 8.4, 0.8 Hz, 1H), 7.53 (d, J =0.9 Hz, 1H), 7.48 (ddd, J = 7.8, 7.2, 1.2
Hz, 1H), 7.32 (ddd, J = 7.5, 7.2, 1.0 Hz, 1H), 3.14 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H),
2
.31 (s, 6H). Found: [M+H]=218.2.
1
-(Benzo[b]thiophen-7-yl)-3-(dimethylamino)propan-1-one (class B)
A suspension of 2-mercaptobenzoic acid (10.00 g, 6.49 mmol) in EtOH (50 mL) was treated
with 2-bromo-1,1,-dimethoxyethane (10 mL, 8.5 mmol) and NaOH (5.70 g, 14.3 mmol) and
the mixture was refluxed for 3 h. The solvent was evaporated and the residue was dissolved
in DMF (100 mL), MeI (6.0 mL, 9.6 mmol) and K
2
CO (27.0 g, 19.5 mmol) were added and
3
o
the mixture was stirred at 20 C for 1 h, then partitioned between EtOAc and water, the
organic layer was washed with water and brine, dried and evaporated. The residue was
dissolved in chlorobenzene (50 mL), polyphosphoric acid (33 g) was added and the mixture
was heated to 130°C for 2 h. The gummy residue was poured onto ice and extracted with
EtOAc, the organic fractions were washed with water, brine, dried and evaporated. Column
chromatography with 10:1 hexanes:EtOAc gave methyl benzo[b]thiophene-7-carboxylate
1
(
6.46 g, 52%). H NMR (CDCl
3
) δ 8.12 (ddd, J = 6.9, 1.0, 0.4 Hz, 1H), 8.03 (dd, J = 7.9, 1.2
Hz, 1H), 7.58 (dd, J = 5.6, 0.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 5.6 Hz, 1H), 4.03
s, 3H).
(

A solution of LiOH (2.10 g, 87.7 mmol) in water (25 mL) was added to a solution of the
above ester (5.61 g, 29.2 mmol) in THF (50 mL) and MeOH (50 mL) and the solution was
o
stirred at 20 C for 18 h then evaporated. The residue was dissolved in water (150 mL) and
acidified to pH 2 with conc. HCl. The precipitate was extracted into EtOAc, the organic
fractions were dried and evaporated to give benzo[b]thiophene-7-carboxylic acid (4.69 g,
1
9
0%). H NMR (DMSO-d
6
) δ 13.42 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.4 Hz,
1
H), 7.86 (d, J = 5.6 Hz, 1H), 7.50-7.56 (m, 2H). Found: [M-H] = 177.1.
Oxalyl chloride (2.67 mL, 31.6 mmol) was added to a suspension of the above acid (4.69 g,
o
2
1
6.3 mmol) in DCM (200 mL, anhydrous) and DMF (0.5 mL, 6.5 mmol) at 20 C, stirred for
h then cooled to 0 °C. N,O-Dimethylhydroxylamine hydrochloride (3.08 g, 31.6 mmol) and
pyridine (6.38 mL, 78.9 mmol) were added sequentially and the mixture was stirred at 20 C
o
for 18 h, then partitioned between EtOAc and sat. aq. NaHCO
with DCM gave N-methoxy-N-methylbenzo[b]thiophene-7-carboxamide (5.48 g, 94%). H
NMR (CDCl ) δ 7.92 (dd, J = 7.9, 1.0 Hz, 1H), 7.81 (dd, J = 7.5, 0.5 Hz, 1H), 7.53 (dd, J =
.5, 0.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 5.5 Hz, 1H), 3.61 (s, 3H), 3.43 (s, 3H).
3
. Column chromatography
1
3
5
Found: [M+H]=222.1.
Vinylmagnesium bromide (49 mL, 1 M, 49 mmol) was added to a solution of the above
amide (5.38 g, 24.3 mmol) in THF (250 mL, dist. Na) at 0 °C, the brown solution was
o
warmed to 20 C for 1 h and then dimethylamine in THF (49 mL, 2 M, 98 mmol) and water
o
(
25 mL) were added. The solution was stirred at 20 C for 1 h, then partitioned between
EtOAc and water. The solution was dried and evaporated to give 1-(benzo[b]thiophen-7-yl)-
1
3
7
2
3
-(dimethylamino)propan-1-one (5.45 g, 96%). H NMR (CDCl ) δ 8.07 (d, J = 7.8 Hz, 2H),
.64 (d, J = 5.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 3.34 (t, J = 7.7 Hz,
H), 2.87 (t, J = 7.7 Hz, 2H), 2.33 (s, 6H). Found: [M+H]=234.1.
1
-(Benzofuran-5-yl)-3-(dimethylamino)propan-1-one (class D-5)
A mixture of 5-bromobenzofuran (4.00 g, 20.3 mmol), DPPP (0.42 g, 1 mmol), triethylamine
6.3 mL, 45 mmol) and Pd(OAc) (0.23 g, 1 mmol) in DMSO (30 mL) and MeOH (30 mL) in
(
2
a Berghof pressure reactor was evacuated then purged three times with carbon monoxide. The
mixture was heated to 80 °C for 18 h under 60 psi of carbon monoxide pressure, cooled and
partitioned between EtOAc and water. Column chromatography with 3:1 hexanes:DCM
eluted traces of impurities while elution with DCM gave methyl benzofuran-5-carboxylate
1
(
2.77 g, 78%). H NMR (CDCl
3
) δ 8.35 (d, J = 1.4 Hz, 1H), 8.03 (dd, J = 8.7, 1.7 Hz, 1H),
7
3
.69 (d, J =2.2 Hz, 1H), 7.53 (dt, J = 8.7, 0.8 Hz, 1H), 6.84 (dd, J = 2.2, 1.0 Hz, 1H), 3.94 (s,
H).
A solution of LiOH (1.13 g, 47.2 mmol) in water (20 mL) was added to a solution of the
above ester (2.77 g, 15.7 mmol) in THF (40 mL) and MeOH (40 mL) and the solution was
o
stirred at 20 C for 18 h and then evaporated. The residue was dissolved in water (50 mL) and
acidified with conc. HCl to pH 2. The precipitate was dissolved in EtOAc, the organic
fraction was dried and evaporated to give benzofuran-5-carboxylic acid (2.49 g, 98%). H
1
6
NMR (DMSO-d ) δ 12.86 (s, 1H), 8.30 (d, J = 1.4 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.92 (dd,
J = 8.6, 1.8 Hz, 1H), 7.68 (dt, J = 8.6, 0.7 Hz, 1H), 7.08 (dd, J = 2.2, 0.9 Hz, 1H).
Oxalyl chloride (1.55 mL, 18.3 mmol) was added to a suspension of trhe above acid (2.48 g,
o
1
5.3 mmol) in DCM (100 mL, anhydrous) and DMF (0.05 mL, 0.64 mmol) at 20 C. The
o
mixture was stirred at 20 C for 1 h to give a colourless solution which was cooled to 0 °C.
N,O-Dimethylhydroxylamine hydrochloride (1.64 g, 16.8 mmol) and pyridine (3.71 mL, 45.9

o
mmol) were added sequentially and the mixture was stirred at 20 C for 18 h, then partitioned
between EtOAc and sat. aq. NaHCO . Column chromatography with 95:5 DCM:EtOAc gave
N-methoxy-N-methylbenzofuran-5-carboxamide (2.28 g, 73%) as a pale brown oil. H NMR
3
1
(
(
CDCl
3
) δ 7.99 (d, J = 1.4 Hz, 1H), 7.65-7.69 (m, 2H), 7.52 (dt, J = 8.6, 0.6 Hz, 1H), 6.82
dd, J = 2.2, 0.9 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H). Found: [M+H]=206.2.
Vinylmagnesium bromide (33.2 mL, 1 M in THF, 33.2 mmol) was added to a solution of the
above anide (2.27 g, 11.1 mmol) in THF (100 mL, dist. Na) at 0 °C, the brown solution was
stirred at 0 °C for 1 h then dimethylamine (33.2 mL, 2 M in THF, 66.4 mmol) and water (20
o
mL) were added. The solution was stirred at 20 C for 1 h, and then partitioned between
EtOAc and water. The solution was dried and evaporated to give 1-(benzofuran-5-yl)-3-
1
(
dimethylamino)propan-1-one (2.33 g, 97%). H NMR (CDCl
3
) δ 8.27 (d, J = 1.8 Hz, 1H),
7
2
.98 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.84 (dd, J =
.2, 0.8 Hz, 1H), 3.22 (t, J = 7.1 Hz, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.31 (s, 6H). Found:
[
M+H]=218.2.
1
-(Benzofuran-4-yl)-3-(dimethylamino)propan-1-one (class D-4)
A solution of benzofuran-4-ol (2.61 g, 19.5 mmol), DMAP (0.060 g, 0.49 mmol) and
pyridine (2.37 mL, 29.3 mmol) in DCM (60 mL, anhydrous) at 0 °C was treated with TFAA
(
4.92 mL, 29.2 mmol) and then stirred at 0 °C for 2 h. The mixture was partitioned between
DCM and water; the organic fractions were dried and evaporated. Column chromatography
1
(
7
1
hexanes) gave benzofuran-4-yl trifluoromethanesulfonate (3.93 g, 76%). H NMR (CDCl
3
) δ
.70 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.20 (d, J =8.1 Hz,
H), 6.90 (dd, J = 1.9, 1.0 Hz, 1H). Found: [M+H]=267.0.
A mixture of the above sulfonate (3.88 g, 14.6 mmol), DPPP (0.180 g, 0.44 mmol),
triethylamine (4.07 mL, 29.2 mmol) and Pd(OAc) (0.098 g, 0.44 mmol) in DMSO (50 mL)
2
and MeOH (50 mL) in a Berghof pressure reactor was evacuated then purged three times
with carbon monoxide. The mixture was heated to 80 °C for 18 h under 60 psi of carbon
monoxide pressure, cooled and partitioned between EtOAc and water. Column
chromatography with 3:1 hexanes:DCM eluted traces of impurities while elution with DCM
1
gave methyl benzofuran-4-carboxylate (2.08 g, 81%). H NMR (CDCl
3
) δ 7.99 (dd, J = 7.7,
0
.9 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.70 (dt, J = 8.2, 0.9 Hz, 1H), 7.33-7.39 (m, 2H), 3.99
(
s, 3H).
A solution of LiOH (1.44 g, 34.3 mmol) in water (20 mL) was added to a solution of the
above ester (2.02 g, 11.4 mmol) in THF (20mL) and MeOH (20 mL) and the solution was
o
stirred at 20 C for 16 h and then evaporated. The residue was dissolved in water (50 mL) and
acidified with conc. HCl and the precipitate was filtered and dried to give benzofuran-4-
1
carboxylic acid (1.83 g, 99%). H NMR (DMSO-d
6
) δ 13.10 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H),
7
1
.85-7.91 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.33 (dd, J = 2.1, 1.0 Hz, 1H). Found: [M-H] =
61.1.
Oxalyl chloride (1.14 mL, 13.5 mmol) was added to a suspension of thew above acid (1.82 g,
o
1
1.2 mmol) in DCM (100 mL, anhydrous) and DMF (0.2 mL, 2.5 mmol) at 20 C. The
o
mixture was stirred at 20 C for 1 h to give a colourless solution which was cooled to 0 °C.
N,O-Dimethylhydroxylamine hydrochloride (1.31 g, 13.5 mmol) and pyridine (2.72 mL, 33.6
o
mmol) were added sequentially and the mixture was stirred at 20 C for 18 h, then partitioned
between DCM and water. Column chromatography with 95:5 DCM:EtOAc gave N-methoxy-
1
N-methylbenzofuran-4-carboxamide (2.13 g, 93%). H NMR (CDCl
3
) δ 7.68 (d, J = 2.2 Hz,

1
6
H), 7.59 (dt, J = 8.3, 0.8 Hz, 1H), 7.51 (dd, J = 7.5, 0.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H),
.95 (dd, J = 2.2, 0.9 Hz, 1H), 3.56 (s, 3H). 3.40 (s, 3H). Found: [M+H]=206.2.
Vinylmagnesium bromide (20.5 mL, 20.5 mmol) was added to a solution of the above amide
(
2.11 g, 10.3 mmol) in THF (100 mL, dist. Na) at 0 °C, the brown solution was warmed to 20
o
C for 1 h, then dimethylamine in THF (20.5 mL, 2 M, 41 mmol) and water (20 mL) were
added. The solution was stirred at 20 C for 1 h, then partitioned between EtOAc and water.
o
The solution was dried and evaporated to give 1-(benzofuran-4-yl)-3-
1
(
dimethylamino)propan-1-one (1.83 g, 82%). H NMR (CDCl
3
) δ 7.86 (dd, J = 7.6, 0.6 Hz,
1
H), 7.76 (d, J = 2.1 Hz, 1H), 7.71 (dt, J = 8.2, 0.8 Hz, 1H), 7.55 (dd, J = 2.2, 1.0 Hz, 1H),
7
.37 (t, J = 7.9 Hz, 1H), 3.27 (t, J = 7.1 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H), 2.32 (s, 6H). Found:
[
M+H]=218.2.
-(Benzo[b]thiophen-7-yl)-3-(dimethylamino)propan-1-one (class D-7)
1
A suspension of 2-mercaptobenzoic acid (10.00 g, 6.49 mmol) in EtOH (50 mL) was treated
with 2-bromo-1,1,-dimethoxyethane (10 mL, 8.5 mmol) and NaOH (5.70 g, 14.3 mmol) and
the mixture was refluxed for 3 h. The solvent was evaporated and the residue was dissolved
in DMF (100 mL), MeI (6.0 mL, 9.6 mmol) and K
2
CO (27.0 g, 19.5 mmol) were added and
3
o
the mixture was stirred at 20 C for 1 h, then partitioned between EtOAc and water, the
organic layer was washed with water and brine, dried and evaporated. The residue was
dissolved in chlorobenzene (50 mL), polyphosphoric acid (33 g) was added and the mixture
was heated to 130°C for 2 h. The gummy residue was poured onto ice and extracted with
EtOAc, the organic fractions were washed with water, brine, dried and evaporated. Column
chromatography with 10:1 hexanes:EtOAc gave methyl benzo[b]thiophene-7-carboxylate
1
(
6.46 g, 52%). H NMR (CDCl
3
) δ 8.12 (ddd, J = 6.9, 1.0, 0.4 Hz, 1H), 8.03 (dd, J = 7.9, 1.2
Hz, 1H), 7.58 (dd, J = 5.6, 0.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 5.6 Hz, 1H), 4.03
(
s, 3H).
A solution of LiOH (2.10 g, 87.7 mmol) in water (25 mL) was added to a solution of the
above ester (5.61 g, 29.2 mmol) in THF (50 mL) and MeOH (50 mL) and the solution was
o
stirred at 20 C for 18 h then evaporated. The residue was dissolved in water (150 mL) and
acidified to pH 2 with conc. HCl. The precipitate was extracted into EtOAc, the organic
fractions were dried and evaporated to give benzo[b]thiophene-7-carboxylic acid (4.69 g,
1
9
0%). H NMR (DMSO-d
6
) δ 13.42 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.4 Hz,
1
H), 7.86 (d, J = 5.6 Hz, 1H), 7.50-7.56 (m, 2H). Found: [M-H] = 177.1.
Oxalyl chloride (2.67 mL, 31.6 mmol) was added to a suspension of the above acid (4.69 g,
o
2
6.3 mmol) in DCM (200 mL, anhydrous) and DMF (0.5 mL, 6.5 mmol) at 20 C. The
o
mixture was stirred at 20 C for 1 h then cooled to 0 °C. N,O-Dimethylhydroxylamine
hydrochloride (3.08 g, 31.6 mmol) and pyridine (6.38 mL, 78.9 mmol) were added
o
sequentially and the mixture was stirred at 20 C for 18 h, then partitioned between EtOAc
and sat. aq. NaHCO
methylbenzo[b]thiophene-7-carboxamide (5.48 g, 94%). H NMR (CDCl
.9, 1.0 Hz, 1H), 7.81 (dd, J = 7.5, 0.5 Hz, 1H), 7.53 (dd, J = 5.5, 0.3 Hz, 1H), 7.41 (t, J = 7.8
3
. Column chromatography with DCM gave N-methoxy-N-
1
3
) δ 7.92 (dd, J =
7
Hz, 1H), 7.37 (d, J = 5.5 Hz, 1H), 3.61 (s, 3H), 3.43 (s, 3H). Found: [M+H]=222.1.
Vinylmagnesium bromide (49 mL, 1 M, 49 mmol) was added to a solution of the abovew
amide (5.38 g, 24.3 mmol) in THF (250 mL, dist. Na) at 0 °C, the brown solution was
o
warmed to 20 C over 1 h and then dimethylamine in THF (49 mL, 2 M, 98 mmol) and water
o
(
25 mL) were added. The solution was stirred at 20 C for 1 h, then partitioned between

EtOAc and water. The solution was dried and evaporated to give 1-(benzo[b]thiophen-7-yl)-
1
3
7
2
-(dimethylamino)propan-1-one (5.45 g, 96%). H NMR (CDCl ) δ 8.07 (d, J = 7.8 Hz, 2H),
3
.64 (d, J = 5.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 3.34 (t, J = 7.7 Hz,
H), 2.87 (t, J = 7.7 Hz, 2H), 2.33 (s, 6H). Found: [M+H]=234.1.
1
-(Benzofuran-5-yl)-3-(dimethylamino)propan-1-one (class D-5)
A mixture of 5-bromobenzofuran (4.00 g, 20.3 mmol), DPPP (0.42 g, 1 mmol), triethylamine
6.3 mL, 45 mmol) and Pd(OAc) (0.23 g, 1 mmol) in DMSO (30 mL) and MeOH (30 mL) in
(
2
a Berghof pressure reactor was evacuated then purged three times with carbon monoxide. The
mixture was heated to 80 °C for 18 h under 60 psi of carbon monoxide pressure, cooled and
partitioned between EtOAc and water. Column chromatography with 3:1 hexanes:DCM
eluted traces of impurities while elution with DCM gave methyl benzofuran-5-carboxylate
1
(
2.77 g, 78%). H NMR (CDCl
3
) δ 8.35 (d, J = 1.4 Hz, 1H), 8.03 (dd, J = 8.7, 1.7 Hz, 1H),
7
.69 (d, J =2.2 Hz, 1H), 7.53 (dt, J = 8.7, 0.8 Hz, 1H), 6.84 (dd, J = 2.2, 1.0 Hz, 1H), 3.94 (s,
3
H).
A solution of LiOH (1.13 g, 47.2 mmol) in water (20 mL) was added to a solution of the
above ester (2.77 g, 15.7 mmol) in THF (40 mL) and MeOH (40 mL) and the solution was
o
stirred at 20 C for 18 h and then evaporated. The residue was dissolved in water (50 mL) and
acidified with conc. HCl to pH 2. The precipitate was dissolved in EtOAc, the organic
fraction was dried and evaporated to give benzofuran-5-carboxylic acid (2.49 g, 98%). H
1
NMR (DMSO-d ) δ 12.86 (s, 1H), 8.30 (d, J = 1.4 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.92 (dd,
6
J = 8.6, 1.8 Hz, 1H), 7.68 (dt, J = 8.6, 0.7 Hz, 1H), 7.08 (dd, J = 2.2, 0.9 Hz, 1H).
Oxalyl chloride (1.55 mL, 18.3 mmol) was added to a suspension of the above acid (2.48 g,
o
1
5.3 mmol) in DCM (100 mL, anhydrous) and DMF (0.05 mL, 0.64 mmol) at 20 C. The
o
mixture was stirred at 20 C for 1 h to give a colourless solution which was cooled to 0 °C.
N,O-Dimethylhydroxylamine hydrochloride (1.64 g, 16.8 mmol) and pyridine (3.71 mL, 45.9
o
mmol) were added sequentially and the mixture was stirred at 20 C for 18 h, then partitioned
between EtOAc and sat. aq. NaHCO
N-methoxy-N-methylbenzofuran-5-carboxamide (2.28 g, 73%) as a pale brown oil. H NMR
3
. Column chromatography with 95:5 DCM:EtOAc gave
1
(
(
CDCl
3
) δ 7.99 (d, J = 1.4 Hz, 1H), 7.65-7.69 (m, 2H), 7.52 (dt, J = 8.6, 0.6 Hz, 1H), 6.82
dd, J = 2.2, 0.9 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H). Found: [M+H]=206.2.
Vinylmagnesium bromide (33.2 mL, 1 M in THF, 33.2 mmol) was added to a solution of the
above amide (2.27 g, 11.1 mmol) in THF (100 mL, dist. Na) at 0 °C, the brown solution was
stirred at 0 °C for 1 h then dimethylamine (33.2 mL, 2 M in THF, 66.4 mmol) and water (20
o
mL) were added. The solution was stirred at 20 C for 1 h, and then partitioned between
EtOAc and water. The solution was dried and evaporated to give 1-(benzofuran-5-yl)-3-
1
(
dimethylamino)propan-1-one (2.33 g, 97%). H NMR (CDCl
3
) δ 8.27 (d, J = 1.8 Hz, 1H),
7
2
.98 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.84 (dd, J =
.2, 0.8 Hz, 1H), 3.22 (t, J = 7.1 Hz, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.31 (s, 6H). Found:
[
M+H]=218.2.
Similarly were prepared from known acids:
-(Dimethylamino)-1-(1-methyl-1H-indol-6-yl)propan-1-one (class E-6):
3
1
H NMR (CDCl
3
) δ 8.05 (t, J = 0.6 Hz, 1H), 7.74 (dd, J = 8.4, 1.5 Hz, 1H), 7.61 (dd, J = 8.4,
.5 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 6.52 (dd, J = 3.0, 0.8 Hz, 1H), 3.87 (s, 3H), 3.29 (t, J =
.2 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 2.35 (s, 6H).
0
7

3
-(Dimethylamino)-1-(1-methyl-1H-indol-4-yl)propan-1-one (III; class E-4):
) δ 7.78 (dd, J = 7.5, 0.6 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.30-7.25 (m,
1
H NMR (CDCl
3
2
2
H), 7.22 (d, J = 3.1 Hz, 1H), 3.84 (s, 3H), 3.29 (t, J = 7.2 Hz, 2H), 2.85 (t, J = 7.8 Hz, 2H),
.33 (s, 6H).
3
-(Dimethylamino)-1-(1-methyl-1H-indol-2-yl)propan-1-one (III; class E-2):
1
H NMR (CDCl
m, 1H), 4.08 (s, 3H), 3.16 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.31 (s, 6H). Found:
M+H]=231.5.
3
) δ 7.71 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 3.5 Hz, 2H), 7.33 (s, 1H), 7.17-7.14
(
[
3
-(Dimethylamino)-1-(1-methylindolin-6-yl)propan-1-one (III; class F-6):
1
H NMR (CDCl
3
) δ 7.30 (dd, J = 7.5, 1.5 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 1.4
Hz, 1H), 3.36 (t, J = 8.3 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 8.1 Hz, 2H), 2.80 (s,
3
H), 2.74 (t, J = 7.2 Hz, 2H), 2.29 (s, 6H).
1
-([1,3]Dioxolo[4,5-b]pyridin-7-yl)-3-(dimethylamino)propan-1-one (III; class J):
1
H NMR (CDCl
3
) δ 7.72 (d, J = 5.7 Hz, 1H), 7.20 (d, J = 5.7 Hz, 1H), 6.20 (s, 2H), 3.14 (t, J
=
7.0 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H), 2.28 (s, 6H).
1
L):
-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3-(dimethylamino)propan-1-one (III; class
1
H NMR (CDCl
3
) δ 7.86 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 4.51-4.49 (m, 2H),
4
.37-4.35 (m, 2H), 3.15 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.26 (s, 6H).
3
-(Dimethylamino)-1-(furo[3,2-c]pyridin-4-yl)propan-1-one (III; class M):
1
3
H NMR (CDCl ) δ 8.57 (d, J = 5.5 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 5.5, 1.0
Hz, 1H), 7.59 (dd, J = 2.2, 1.0 Hz, 1H), 3.50 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.31
s, 6H). Found [M+H]=219.
(
3
-(Dimethylamino)-1-(furo[2,3-c]pyridin-7-yl)propan-1-one (III; Class N):
1
H NMR (CDCl
H), 6.87 (d, J = 2.2 Hz, 1H), 3.50 (t, J = 7.1 Hz, 2H), 2.85 (t, J = 7.1 Hz, 2H), 2.31 (s, 6H).
Found [M+H]=219.
3
) δ 8.50 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 5.1 Hz,
1
4
1
.1.3. Scheme 3B: synthesis of Mannich base C/D units via methylketones
-(Benzofuran-7-yl)-3-(dimethylamino)propan-1-one (V: class D-7)
A solution of 7-bromobenzofuran (2.05 g, 10.4 mmol) in dry THF (20 mL) was prepared.
Approximately 4 mL of this solution was added to a flask containing magnesium (0.75 g,
3
0.9 mmol) and the mixture was agitated until an exothermic reaction occurred. The
remaining solution was added and the mixture was refluxed for 1 h, cooled and transferred by
cannula to a dry flask. The solution was cooled to 0 °C and acetaldehyde (0.70 mL, 12.3
mmol) was added, the mixture was stirred at 0 °C for 1 h then partitioned between EtOAc
and water, the organic fractions were dried and evaporated. Column chromatography with
hexanes:DCM (1:1) eluted non polar impurities, elution with DCM gave 1-(benzofuran-7-
yl)ethan-1-ol (1.21 g, 72%). 1H NMR (CDCl
.2 Hz, 1H), 7.34 (bd, J = 7.3 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 5.38
td, J = 6.5, 4.8 Hz, 1H), 2.16 (d, J = 4.8 Hz, 1H), 1.67 (d, J = 6.5 Hz, 3H). Found: [M –
H2O] = 145.
3
) δ 7.64 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 7.7,
1
(

2
A mixture of the above alcohol (1.16 g, 7.15 mmol) and MnO (3.10 g, 35.6 mmol) in
benzene (40 mL) was refluxed for 1 h, filtered through Celite and the solvent was evaporated.
Column chromatography with hexanes:DCM (3:1 to 1:1) gave 1-(benzofuran-7-yl)ethan-1-
one (0.98 g, 86%). 1H NMR (CDCl
Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 2.86 (s,
H). Found: [M+H]=161.1.
3
) δ 7.92 (dd, J = 7.6, 1.2 Hz, 1H), 7.81 (dd, J = 7.7, 1.2
3
A mixture of the above methylketone (4.95 g, 30.9 mmol), dimethylamine HCl (3.78 g, 46.4
mmol) and paraformaldehyde (1.39 g, 46.3 mmol) in EtOH (50 mL) and HCl (0.5 mL, 12 M,
6
mmol) was refluxed in a sealed tube for 18 h. The solvent was evaporated and the solid
residue was triturated with Et O and filtered. The solid was washed with Et2O, dissolved in
2
water and basified with 2M NaOH, then extracted with EtOAc (3 x 100 mL). The organic
fractions were dried and evaporated to give 1-(benzofuran-7-yl)-3-(dimethylamino)propan-1-
1
one (4.63 g, 69%). H NMR (CDCl
3
) δ 7.93 (dd, J = 7.6, 1.1 Hz, 1H), 7.81 (dd, J = 7.7, 1.3
Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 3.46 (t, J
7.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.32 (s, 6H). Found: [M+H]=218.2.
=
Similarly were prepared:
3
-(Dimethylamino)-1-(1-methylindolin-4-yl)propan-1-one (V; class E-4):
1
H NMR (CDCl
3
) δ 7.17 (m, 2H), 6.60 (t, J = 3.9 Hz, 1H), 3.38-3.28 (m, 4H), 3.09 (t, J = 7.1
Hz, 2H), 2.78 (s, 3H), 2.73 (t, J = 7.1 Hz, 2H), 2.28 (s, 6H).
1
-(Benzo[d][1,3]dioxol-4-yl)-3-(dimethylamino)propan-1-one (V; class H):
1
H NMR (CDCl
.9 Hz, 1H), 6.08 (s, 2H), 3.15 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.28 (s, 6H).
Found: [M+H]=222.7.
3
) δ 7.39 (dd, J = 8.2, 1.2 Hz, 1H), 6.98 (dd, J = 7.6, 1.2 Hz, 1H), 6.88 (t, J =
7
3
-(Dimethylamino)-1-(furo[3,2-b]pyridin-7-yl)propan-1-one (V; class K):
1
H NMR (CDCl
H), 7.11 (d, J = 2.3 Hz, 1H), 3.46 (t, J = 6.9 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.31 (s, 6H).
Found: [M+H]=219.4.
3
) δ 8.70 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 5.0 Hz,
1
4
.1.4. Scheme 1: Preparation of the 6-bromo compounds of Table 1
Example of 1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-1-(2,3-
dimethoxyphenyl)-4-(dimethylamino)butan-2-ol (9)
A solution of dry diisopropylamine (0.92 ml, 6.49 mmol) in dry THF (10 ml) was cooled to -
o
4
0 C under an atmosphere of dry nitrogen. N-Butyllithium (3.25 ml of a 2.0 N solution in
cyclohexane, 6.49 mmol) was added dropwise, then stirring was continued for a further 15
o
min. The solution was cooled to -70 to -78 C and a solution of 6-bromo-3-(2,3-
1
dimethoxybenzyl)-2-methoxyquinoline (2.10 g, 5.41 mmol) in dry THF (6 ml) was added
dropwise. The resulting purple solution was stirred at this temperature for 60 min. A solution
of 19 (1.07 g, 4.92 mmol) in THF (6 ml) was added dropwise and the mixture was stirred at
this temperature for 5 h. Glacial acetic acid (0.70 ml) was added in one portion and the
mixture was allowed to warm to room temperature. Water was added and the mixture was
extracted with ethyl acetate. The extract was washed with water and dried over sodium
sulfate. Removal of the solvent under reduced pressure left an oil, which was

chromatographed on silica. Column chromatography with hexanes:EtOAc (1:1) gave fore
fractions, followed by isomer A of 9 (0.452 g, 14%). Elution with EtOAc gave isomer B of 9
(
1.15 g, 35%).
1
Isomer A, pale yellow solid. H NMR (CDCl
7
6
3
, 400 MHz) δ 8.19 (s, 1H), 7.86-7.81 (m, 2H),
.72-7.66 (m, 2H), 7.59 (dd, J = 8.8, 2.2 Hz, 1H), 7.08-6.98 (m, 3H), 6.82 (t, J = 8.1 Hz, 1H),
.57 (dd, J = 8.2, 1.3 Hz, 1H), 5.91 (s, 1H), 4.24 (s, 3H), 3.65 (s, 3H), 3.34 (s, 3H), 3.30-3.21
(
1
m, 1H), 3.10-2.98 (m, 1H), 2.77 (t, J = 7.3 Hz, 2H), 2.20-2.05 (m, 2H), 2.03-1.96 (m, 2H),
.93 (s, 6H), 1.75-1.59 (m, 2H). Found: [M+H]= 605.7.
1
Isomer B, white solid. H NMR (CDCl
H), 7.62 (d, J = 7.1 Hz, 1H), 7.52-7.45 (m, 2H), 7.28-7.23 (m, 1H), 6.99-6.92 (m, 3H), 6.79
dd, J = 8.1, 1.4 Hz, 1H), 5.82 (s, 1H), 4.03 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H), 3.32-3.24 (m,
3
, 400 MHz) δ 8.79 (s, 1H), 7.95 (br s, 1H), 7.81 (s,
1
(
1
6
H), 3.08-3.00 (m, 1H), 2.82-2.71 (m, 2H), 2.18-2.07 (m, 2H), 2.05-1.98 (m, 2H), 1.95 (s,
H), 1.93-1.79 (m, 2H). Found: [M+H]= 605.7.
Each coupled product was resolved into its four optical isomers using preparative chiral
HPLC at BioDuro LLC (Beijing).
4
.1.5. Scheme 1: Preparation of the 6-cyano compounds of Table 1
Example of 3-(2-(2,3-dihydro-1H-inden-4-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-
hydroxybutyl)-2-methoxyquinoline-6-carbonitrile (10)
A solution of 9 (2.41 g, 3.98 mmol) in DMF (10 mL, anhydrous) was purged with nitrogen
and heated to 55 °C for 10 min. Tri(o-tolyl)phosphine (0.242 g, 0.796 mmol), zinc dust
(
0.026 g, 0.398 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.364 g, 0.398 mmol)
were then added, and the reaction was again purged with nitrogen and heated for another 10
min at 55 °C. Zinc cyanide (0.327 g, 2.79 mmol) was then added and the reaction mixture
was heated to 65 °C for 4 hours. The reaction was diluted with water and extracted with
EtOAc three times. The organic layer was washed with brine three times, dried and
evaporated. Column chromatography with 1:1 hexane/EtOAc followed by 4:1 hexane/EtOAc
afforded isomer A of 10 (0.26 g, 12%) followed by isomer B of 10 (0.92 g, 42%) as white
solids.
1
Isomer A, pale yellow solid. H NMR (CDCl
3
, 400 MHz) δ 8.30 (s, 1H), 8.05 (d, J = 1.8 Hz,
1
(
1
H), 7.88-7.81 (m, 2H), 7.71-7.66 (m, 2H), 7.08-6.98 (m, 3H), 6.83 (t, J = 8.1 Hz, 1H), 6.58
dd, J = 8.2, 1.3 Hz, 1H), 5.91 (s, 1H), 4.28 (s, 3H), 3.66 (s, 3H), 3.38 (s, 3H), 3.29-3.22 (m,
H), 3.10-2.99 (m, 1H), 2.78 (t, J = 7.1 Hz, 2H), 2.20-2.06 (m, 2H), 2.03-1.96 (m, 2H), 1.92
(
s, 6H), 1.75-1.60 (m, 2H). Found: [M+H]= 552.5.
1
Isomer B, white solid. H NMR (CDCl
3
, 400 MHz) δ 8.92 (s, 1H), 8.03 (d, J = 1.2 Hz, 1H),
7
(
2
[
.66-7.58 (m, 3H), 7.25-7.22 (m, 1H), 7.00-6.93 (m, 4H), 6.81 (dd, J = 8.2, 1.4 Hz, 1H), 5.82
s, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.84 (s, 3H), 3.30-3.21 (m, 1H), 3.09-3.01 (m, 1H), 2.82-
.71 (m, 2H), 2.19-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.96 (s, 6H), 1.89-1.79 (m, 2H). Found:
M+H]=552.5.

In each case, the coupled 6-cyano product was then resolved into its four optical isomers
using preparative chiral HPLC at BioDuro LLC (Beijing).
Acknowledgements
This work was supported by the Bill & Melinda Gates Foundation, Seattle, USA
(
#OPP1017459), the U.S. Agency for International Development (USAID), Ronald Reagan
Building Washington, DC, USA (GHS-A-00-08-00012-00, the U.K. Department for
International Development (DFID), 22 Whitehall, London, England, and Irish Aid, 23-27
Henry Street, Limerick, Eire. We thank Baojie Wan and Yuehong Wang (UIC) for the MIC
and mouse efficacy data.
Supplementary data
Supplementary data (additional biological data on the compounds of Table 2) associated with
this article can be found in the online version, at http://***
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Supplementary Data
for
Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with
the naphthalene unit replaced by bicyclic heterocycles
Hamish S. Sutherland, Amy S.T. Tong, Peter J. Choi, Daniel Conole, Adrian Blaser, Scott G.
Franzblau, Christopher B. Cooper, Anna M. Upton, Manisha U. Lotlikar, William A. Denny,
Brian D. Palmer
Table S1. Additional ADME data for the compounds of Table 2
a
b
c
d
HLM +3A4
inhibitor
f
No
Solubility
PPB
F
HLM
T½
e
clogP
%
T½
(min)
µM
%
(
min)
1
5
7
< 0.06
<0.06
<0.06
ND
<0.06
<0.06
0.3
0.13
ND
0.15
<0.06
<0.06
<0.02
ND
0.016
<0.06
<0.02
<0.06
0.22
100
100
100
ND
100
100
99.997
ND
ND
99.86
99.99
100
100
ND
100
100
100
100
100
ND
56
33
54
25
51
50
42
13
ND
37
49
21
73
ND
41
25
50
42
52
ND
33
50
ND
35
182
36
87
ND
62
46
54
36
ND
53
224
10
161
ND
131
173
204
22
42
ND
33
1733
47
7.25
7.11
7.09
4.99
7.09
5.28
6.64
5.56
6.48
5.61
7.41
6.06
6.87
5.53
7.19
5.84
7.42
6.64
5.61
5.61
5.42
5.61
6.5
990
ND
347
108
630
120
ND
267
315
154
248
ND
267
NA
154
42
10
11
14
16
18
21
22
24
25
26
27
28
29
30
34
36
37
42
43
48
50
96
ND
90
36
ND
347
ND
<0.2
<0.02
ND
100
100
ND
25
ND
51
<0.2
98.6
6.5