Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline

Article abstract of DOI:10.1016/j.bmc.2019.02.025

The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC₉₀) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC₅₀ values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.

Full text of DOI:10.1016/j.bmc.2019.02.025

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Structure-activity relationships for unit C pyridyl analogues of the
tuberculosis drug bedaquiline
Adrian Blasera, Hamish S. Sutherlanda, Amy S.T. Tonga, Peter J. Choia, Daniel Conolea,
Scott G. Franzblauc, Christopher B. Cooperd, Anna M. Uptond, Manisha Lotlikard,
⁎
William A. Dennya,b, , Brian D. Palmera,b
a Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
b Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
c Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA
d Global Alliance for TB Drug Development, 40 Wall Street, NY 10005, USA
A R T I C L E I N F O
A B S T R A C T
InChIKeys:
The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic
(clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac
hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular
monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to
produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct
correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, po-
tency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The
bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions
where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably
higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and
similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two
compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in
vivo, suggesting further exploration of C-ring pyridyls is worthwhile.
PASFCMLJOBVMGB-UHFFFAOYSA-N
LMUZDMHAKVEGQS-UHFFFAOYSA-N
ZTFCPPTXTSXGHL-UHFFFAOYSA-N
HNLXEIWQRWVUSU-UHFFFAOYSA-N
KFLWHJBGGARORU-UHFFFAOYSA-N
JVCNZHZTRWJWNW-UHFFFAOYSA-N
IAKNWKILKBWHHJ-UHFFFAOYSA-N
DVOLLEJITIXUFG-UHFFFAOYSA-N
LARJMJRNXJABKH-UHFFFAOYSA-N
YKGQSYUYXSJGSV-UHFFFAOYSA-N
BSRVKFLFLKCSCR-UHFFFAOYSA-N
SXCCYDONNDYDMT-UHFFFAOYSA-N
ZCVOKXSJKIJDQO-UHFFFAOYSA-N
VPFXWXMRHHCWLE-UHFFFAOYSA-N
ZCRAGXDCNCYQPH-UHFFFAOYSA-N
XGCMXAGODXCXKN-UHFFFAOYSA-N
GDQXVRZSDDBPMP-UHFFFAOYSA-N
HEJXQMJYSQFQOX-UHFFFAOYSA-N
XYHYFQQKCCCZDE-UHFFFAOYSA-N
CMBKOLOWRXXJAQ-UHFFFAOYSA-N
GOBWKUISNQAVSD-UHFFFAOYSA-N
AHYCPVQTWZSXTI-UHFFFAOYSA-NKeywords:
Bedaquiline
Bedaquiline analogues
Lipophilicity
Tuberculosis
Drug development
1. Introduction
has demonstrated clinical efficacy against multidrug-resistant TB,
where treatment options are limited.2 Potential limitations of 1 include
Bedaquiline (TMC207, Sirturo, Janssen Pharmaceuticals; Fig. 1; 1)
is an exciting new drug for tuberculosis, with a novel mechanism of
inhibition of the mycobacterial ATP synthase.1 Of particular interest, it
very high lipophilicity (a calculated clogP of 7.25),3 with the attendant
risks of ultra-long half-life,4 phospholipidosis,5 and drug insolubility. In
attempts to develop analogues with similar or improved potency
⁎ Corresponding author at: Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New
Zealand.
E-mail address: b.denny@auckland.ac.nz (W.A. Denny).
https://doi.org/10.1016/j.bmc.2019.02.025
Received 10 October 2018; Received in revised form 30 January 2019; Accepted 14 February 2019
0968-0896/©2019PublishedbyElsevierLtd.
Pleasecitethisarticleas:AdrianBlaser,etal.,Bioorganic&MedicinalChemistry,https://doi.org/10.1016/j.bmc.2019.02.025

A. Blaser, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
Scheme 2. Synthesis of new pyridyl 3-(dimethylamino)propan-1-one C/D
units. Reagents and conditions: (i) COCl2, cat. DMF, DCM, then MeNH(OMe).
HCl, pyridine; (ii) vinylMgBr, then Me2NH, THF.
Fig. 1. Bedaquiline and C-unit pyridyl analogues.
against Mycobacterium tuberculosis, but with lower lipophilicity than
bedaquiline, anticipating a desirably shorter half-life, we have recently
reported on the beneficial effects of replacing the lipophilic 6-Br group
on the A-unit quinoline ring with a more hydrophilic cyano group,6
replacing the B-unit phenyl group with monoheterocycles,7 and repla-
cing the very lipophilic C-unit naphthalene with a series of less lipo-
philic bicyclic heterocycles.8 In the present work we take the latter
theme further by looking at a range of even less lipophilic pyridine C-
units, with a further comparison of paired Br/CN derivatives. A recent
paper9 on the 1.7 Å resolution crystal structure of 1 bound to the c
subunit of the ATP synthase Fo of the genetically-similar myco-
bacterium M. phlei (83.7%), found that the quinoline and naphthalene
units appear to play a role in positioning the dimethylaminoethyl side
chain in the ion-binding site of the enzyme. Following on from this, it
was of interest to see whether analogues with smaller, more hydro-
philic, monocyclic pyridyl C-units would be as effective at binding. The
only other study1 on non-naphthalene analogues of 1 showed that 2-
fluoro- and 2,5-difluorophenyl compounds had MIC90 values (in My-
cobacterium smegmatis) comparable to that of 1, but pyridyl analogues
were not examined.
Table 1
New Mannich base C/D units prepared via Scheme 2.
Class
N
Xa
% yields I/II/III
A
B
C
D
E
2-
2-
2-
2-
2-
2-
2-
3-
3-
3-
3-
3-
3-
3-
3-
3-
3-
3-
4-
4-
4-
4-
4-
4-
4-
3-Me
95/97
31/99
46/99
88/98
23/99
92/95
72/99
83/75
95/97
87/93
66/99
92/98
93/99
78/99
83/99
61/90
85/83
94/92
90/31
79/99
62/99
82/99
41/67
97/99
91//99
5-Me
6-Me
3,5-diMe
4,6-diMe
3-OMe
F
G
H
I
5-OMe
2-Me
4-Me
J
5-Me
K
L
2,4-diMe
4,5-diMe
4,6-diMe
2-OMe
M
N
O
P
4-OMe
2,5-diOMe
4,5-diOMe
2,4,5-triOMe
2-Me
Q
R
S
2. Results and discussion
T
U
V
W
X
X
3-Me
3,5-diMe
3,5-diEt
2,5-diOMe
3-OMe, 5-nPr
3-OMe, 5-iPr
2.1. Chemistry
The bedaquiline analogues 2–62 were synthesized from appropriate
benzylquinoline A/B-units and 3-(dimethylamino)-1-arylpropan-1-one
a
3,6
For clarity, substituent numbering is consistent with that in Table 2, and is
not necessarily IUPAC.
C/DL-uitnhiitus,masteptrreavmioeuthslyylprieppeorridteidd,e (LiTMP) mediated condensation of
and as shown in Scheme 1.
quinoline A and substituted benzaldehydes B gave the intermediate
alcohols, which were deoxygenated by triethylsilane under acid con-
ditions to give the corresponding A/B units. Alternatively, palladium
mediated coupling of the boronic acid A1 with an appropriately sub-
stituted benzyl halide or (halomethyl)pyridine B1 gave the A/B units,
all of which have been reported previously.3,6,7 The Mannich bases
required for the C/D units of the final compounds were prepared from
the appropriate commercial carboxypyridines as shown in Scheme 2
and Table 1. Lithiation of the A/B subunit with lithium diisopropyla-
mide (LDA) and subsequent reaction with the C/D subunit gave the
bromo bedaquiline analogues. The cyano derivatives were synthesised
from their corresponding bromo derivatives by palladium-catalysed
cyanation.
Bedaquiline (1) and C-unit pyridyl analogues 2–62 were evaluated
for their ability to inhibit bacterial growth (measured as MIC90 values in
Scheme 1. General synthesis of bedaquiline analo-
gues. Reagents and conditions: (i) LiTMP, THF,
−75 °C, 1.5 h then the appropriate aldehyde B,
−75 °C, 4 h; (ii) Et3SiH, TFA, DCM; (iii) Cs2CO3, Pd
(PPh3)4, PhMe/DMF, 110 °C (sealed tube), 5 h; (iv)
LDA, THF, −75 °C, 1.5 h then the appropriate ke-
tone C/D, then HOAc; (v) Zn/Zn(CN)2, Pd2(dba)3/P
(o-tol)3, DMF, 50 °C, then separation of the diaster-
eomers by SFC HPLC.
2

A. Blaser, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
Table 2
Table 2 (continued)
Structures and biological activity of bedaquiline C-unit pyridyl analogues.
b
No
X
Y
Z
Yielda
MIC90
clogPc
LORA
0.29
3.3
AB/CD MABA
35 Br
36 CN
37 Br
38 Br
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
2,3-diOMe
L: 3-aza, 4,5-
diMe
52
70d
14
32
0.31
2.4
5.53
4.17
5.53
4.79
L: 3-aza, 4,5-
diMe
M: 3-aza, 4,6-
diMe
0.53
0.02
0.29
0.24
M: 3-aza, 4,6-
diMe
39 Br
40 CN
41 Br
42 CN
43 Br
44 CN
45 Br
46 Br
3-Me
N: 3-aza, 2-OMe
N: 3-aza, 2-OMe
N: 3-aza, 2-OMe
N: 3-aza, 2-OMe
O: 3-aza, 4-OMe
O: 3-aza, 4-OMe
O: 3-aza, 4-OMe
P: 3-aza, 2,5-
diOMe
50
82
53
78d
57
90d
33
29
0.13
0.52
0.66
2.1
0.14
0.76
1.1
5.90
4.04
5.36
4.01
4.66
3.30
5.40
5.80
3-Me
2,3-OCH2O-
2,3-OCH2O-
2,3-diOMe
2,3-diOMe
2-F, 3-OMe
2-F, 3-OMe
ND
0.28
2.1
0.54
2.1
0.12
0.09
0.08
0.04
47 Br
48 Br
49 Br
2-F, 3-OMe
Q: 3-aza, 4,5-
diOMe
30
83
42
0.07
0.06
0.57
0.11
0.45
1.4
5.45
4.42
4.80
4-aza, 2,3-
diOMe
Q: 3-aza, 4,5-
diOMe
4-aza, 2,3-
diOMe
R: 3-aza, 2,4,5-
triOMe
50 Br
51 Br
52 CN
53 Br
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
3-Me
S: 4-aza, 2-Me
T: 4-aza, 3-Me
T: 4-aza, 3-Me
U: 4-aza, 3,5-
diMe
54
47
82d
20
1.0
1.1
5.03
5.08
3.72
6.08
0.47
> 5
0.11
0.58
3.8
b
No
X
Y
Z
Yielda
MIC90
clogPc
LORA
0.49
AB/CD MABA
0.08
54 Br
55 CN
56 Br
57 CN
2-F, 3-OMe
2-F, 3-OMe
2,3-diOMe
2,3-diOMe
U: 4-aza, 3,5-
diMe
46
0.11
0.60
0.04
0.24
0.30
0.91
0.07
0.61
5.58
4.22
4.79
4.01
1
2
3
4
5
6
7
8
9
0.12
0.13
1.9
7.25
4.34
2.98
5.55
4.26
5.08
5.03
3.67
4.84
U: 4-aza, 3,5-
diMe
59d
Br
2,3-diOMe
2,3-diOMe
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
2,3-diOMe
A: 2-aza, 3-Me
A: 2-aza, 3-Me
A; 2-aza, 3-Me
A: 2-aza, 3-Me
B: 2-aza, 5-Me
C: 2-aza, 6-Me
C: 2-aza, 6-Me
D: 2-aza, 3,5-
diMe
69
0.40
4.1
CN
Br
45d
79
U: 4-aza, 3,5-
diMe
63
0.29
1.1
2.0
CN
Br
93d
56
1.8
U: 4-aza, 3,5-
diMe
75d
0.6
2.1
Br
77
0.19
3.0
0.40
3.5
58 Br
59 CN
60 Br
2-F, 3-OMe
2-F 3-OMe
2-F, 3-OMe
V: 4-aza, 3,5-diEt 45
V: 4-aza, 3,5-diEt 67
0.03
0.19
0.11
0.21
0.28
0.12
7.10
5.81
5.80
CN
Br
83d
56
0.28
0.30
W: 4-aza, 2,5-
diOMe
55
10 CN
11 Br
12 CN
13 Br
2,3-diOMe
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
D: 2-aza, 3,5-
diMe
66d
0.54
0.14
2.3
0.62
0.11
2.8
3.48
5.58
4.22
5.53
61 Br
4-aza, 2,3-
diOMe
X: 4-aza, 3-OMe, 45
5-OnPr
0.01
D: 2-aza, 3,5-
diMe
65
0.06 5.83
62 Br
4-aza, 3,5-
diOMe
X: 4-aza, 3-OEt,
5-OiPr
59
< 0.02 < 0.02 6.89
D: 2-aza, 3,5-
diMe
50d
43
E: 2-aza, 4,6-
diMe
0.30
0.46
a
Yields in the AB/CB coupling step to give bedaquiline analogues (as ra-
cemic mixtures; these were then separated by super-critical fluid HPLC at
BioDuro LLC (Beijing) and the desired RS,SR diastereomers (depicted) were
evaluated).
14 CN
15 Br
16 CN
17 Br
18 CN
19 Br
20 Br
21 Br
22 Br
23 CN
24 Br
25 CN
26 Br
27 CN
28 Br
29 CN
30 Br
31 CN
32 Br
3-Me
F: 2-aza, 3-OMe
F: 2-aza, 3-OMe
F: 2-aza, 3-OMe
G: 2-aza, 5-OMe
G: 2-aza, 5-OMe
H: 3-aza, 2-Me
H: 3-aza, 2-Me
H: 3-aza, 2-Me
I: 3-aza, 4-Me
I: 3-aza, 4-Me
I: 3-aza, 4-Me
I: 3-aza, 4-Me
J: 3-aza, 5-Me
J: 3-aza, 5-Me
J: 3-aza, 5-Me
J: 3-aza, 5-Me
J: 3-aza, 5-Me
J: 3-aza, 5-Me
K: 3-aza, 2,4-
diMe
36d
46
0.60
0.54
1.2
0.29
0.58
ND
4.54
5.36
4.01
5.00
3.65
5.54
4.29
4.99
5.55
3.72
4.34
2.98
5.22
3.87
4.34
2.98
5.08
3.72
5.53
2,3-OCH2O-
2,3-OCH2O-
2-F, 3-OMe
2-F, 3-OMe
3-Me
85
b
MIC90 (µg/mL); minimum inhibitory concentration for 90% inhibition of
56
1.2
0.61
2.2
78d
26
2.3
growth of M.tb strain H37Rv, determined under aerobic (replicating; MABA)
(ref. 10) or non-replicating (LORA) (Ref. 11) conditions, determined at the
Institute for Tuberculosis Research, University of Illinois at Chicago.
0.15
0.30
0.45
0.30
4.7
0.25
0.59
0.56
0.28
> 5
0.51
> 5
0.08
0.98
0.57
3.8
2,3-diOMe
2,3-OCH2O-
2-F, 3-OMe
2-F, 3-OMe
2,3-diOMe
2,3-diOMe
3-F
46
c
d
23
clogP calculated by ChemDraw Ultra v12.0.2. (CambridgeSoft).
59
Yields for the Br/CN conversion.
93d
59
0.60
> 5
0.28
1.2
µg/mL against M. tb (strain H37Rv)) under both replicating (MABA)10
or non-replicating (LORA)11 conditions. In these assays, 1 is a potent
inhibitor, with MICs of 0.08 and 0.12 µg/mL, respectively. Replacement
of the naphthalene C-unit of 1 with various pyridyls produced analo-
gues of considerably lower lipophilicity, with clogP values ranging from
6.89 down to 2.98.
54d
61
3-F
62d
67
2,3-diOMe
2,3-diOMe
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
0.30
4.2
68d
22
0.16
3.3
0.20
2.5
74d
22
0.07
0.23
2.2. Structure-activity relationships
33 Br
34 Br
2–3-diOMe
2–3-diOMe
K: 3-aza, 2,4-
diMe
29
70
0.07
0.07
0.11
0.14
4.84
4.80
L: 3-aza, 4,5-
diMe
This work explored SAR for much less lipophilic analogues of be-
daquiline, with clogP values between 6.89 and 2.98 (0.36 to 4.27 log
3

A. Blaser, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
units less lipophilic than bedaquiline). Overall, that resulted in com-
pounds that are slightly less potent than bedaquiline (1) against both
replicating (MABA) and non-replicating (LORA) M.tb in culture
(Table 2). As expected from earlier SAR work on this series,6–8 there
was a good overall correlation between the MABA and LORA MIC90
values for the compounds:
value for 1 in repeat assays was between 4 and 16 µg/mL). All com-
pounds also had IC50s > 10 µM for CYP3A4 inhibition (bedaquiline
IC50 > 40 µM), except for compound 15, which had an IC50 of 7.6 µM,
and compounds 4, 27, 33, 38, 46, 48, 49, 57–59, 60–62, which were
not tested in this assay.
Since bedaquiline’s relatively potent inhibition of the hERG po-
tassium channel (IC50 1.6 µM14 (see Table 3) has been associated with
QTc prolongation observed in the clinic (cardiovascular toxicity), the
analogue compounds were also evaluated for inhibition of hERG po-
tassium current in vitro. This was determined either by a full (5-con-
centration) dose–response study resulting in an IC50, or by determining
% inhibition of channel current at 0.3 and 1 µM, using the same manual
patch clamp electrophysiology assay setup. While several of the com-
pounds (38, 46, 48, 49, 57, 61, 62) were less potent inhibitors of this
channel than 1, several others (e.g., 15, 33, 39, 40, 59, 60) were similar
or considerably more potent. Lipophilicity did not seem to be a factor,
with both 1 (clogP 7.25) and compound 27 (clogP 3.87) being similarly
potent against the hERG channel. Compounds 61 and 62, bearing 4-aza,
3,5-dialkoxy C-units, were notable for their much lower hERG potencies
(IC50 values around or > 10 µM), suggesting this motif as a promising
one for mitigation of hERG risk.
log (MABA) = 0.98 log (LORA) 0.08
Also, as expected, there was a reasonable correlation between in-
hibitory activity (illustrated here for MABA data) and compound lipo-
philicity, with the more lipophilic compounds being more potent; an
overall trend repeatedly seen in other classes of TB drugs.12,13
(1)
n = 58, R = 0.85, p < 0.001, F2,56 = 144
logMABA = 0.50 clogP + 1.97
(2)
n = 58, R = 0.71, P < 0.001, F2,56 = 55
However, this overall correlation masks a trend seen to some extent
previously,8 that for this general class of compound, MIC90 potency falls
off quite sharply for compounds (e.g., 3, 8, 16, 18, 23, 25, 27, 29, 31,
42, 44, 52) of lower lipophilicity (clogP values around 4 or below).
Of the many different C-units employed in this study, there were
nine (A, D, I, J, K, L, M, O, and U) that had identical A-units (6-Br) and
examples of both 2-F, 3-OMe, and 2,3-diOMe B-units, allowing an
analysis of any effects of these B-unit changes on activity. However, the
averaged MIC90 values for each series was identical (0.23 µg/mL),
suggesting these B-unit changes have minimal effects on activity.
Representative compounds in the series were evaluated for a range
of ADME and toxicological properties in vitro (Table 3). Compounds
were tested for cytotoxicity in Vero green monkey-derived epithelial
kidney cells,14 and for inhibition of CYP 3A4, the major metabolising
enzyme for 1.15 All tested compounds had IC50s > 10 µg/mL in the
Vero assay, except for compound 38, where this was not measured (the
One of the cited issues with 1 is its very long terminal half-life in
humans.16 This can result in undesirable levels of accumulation of drug
in tissues. Table 3 also shows in vitro clearance rates of the analogues in
human and mouse microsomes as well as the in vivo clearance observed
in mice. All of the pyridyl compounds had (desirably) higher rates of
clearance in vitro than 1, with several (4, 19, 21, 22, 27) possibly being
cleared too rapidly. This was also true for those pyridyl compounds
evaluated in vivo, with several demonstrating clearance > 50 mL/min/
kg (19, 22, 33, 55, 57) compared to 7 mL/min/kg for bedaquiline.
Several analogues were also evaluated for oral bioavailability in
mice, and while being less bioavailable than the very lipophilic 1, still
had acceptable values. As seen in Table 3, in general, higher in vivo
Table 3
Additional biological data for selected representative compounds of Table 2.
No.
in vitro parameters
in vivo parameters
hERGa
HClint
MClint
IV Cld
7
Vz
22
AUCf
20.9
Fg
CFUh
0.3
CFUi
4.9
AUC/MIC90 MABA
b
c
e
1
1.6
3
7.3
39
25
71
51
99
249
17
46
20
53
19
53
59
7
56
ND
45
10
19
8
261
4
34%/3
0.24
10
8
15
19
21
22
27
33
38
39
40
41
46
48
49
55
57
58
59
60
61
62
13
59
44
67
ND
79
28
ND
48
27
ND
19
10
130
71
ND
ND
ND
7
10
5.60
0.40
0.82
0.25
ND
10.4
26%/3
13%/3
17%/3
42%/1
1.1
35
71
24
122
7
33
21
10
ND
77
ND
72
34
ND
33
46
ND
48
52
25
54
ND
ND
ND
50
58
1.39
2.08
2.51
1.17
3.78
ND
3.5
0.7
0.6
0.5
0.3
5.0
19.9
104
3.9
13
10
11
36
7
23
> 4.5
4.9
0.45
ND
6.6
20
19.3
2.25
5.73
0.30
6.2
26%/3
2.9
5.5
ND
6.0
12
3.6
5
4.28
9.13
0.35
1.48
ND
0.9
> 5
5.8
71.3
2.7
5
37%/3
5.2
12
7
51
7
53
82
1.9
6.17
63%/3
48%/1
1.7
8
20
27
25
7
ND
ND
ND
44
10
7
ND
ND
7.8
8
10.9
33.0
5
5.5
1090
1650
> 10
1
2.3
3
20
4.5
> 5
a
Inhibition of hERG (IC50 in µM or % inhibition at 1 or 3 µM in the manual assay or 3 µM in the (less accurate) QPatch assay.
Clearance of compound by human liver microsomes (μL/min/mg protein).
Clearance of compound by mouse liver microsomes (µL/min/mg protein).
IV clearance, mouse (mL/min/kg).
b
c
d
e
f
IV apparent volume of distribution during terminal phase, mouse (L/kg).
Exposure; mouse AUCinf (µg*h/mL); gOral bioavailability in mice (%).
h,i
Log reduction in colony-forming units (CFU) of new compoundsh compared to 1i run in the same assay, when dosed at 20 mg/kg daily in mice for 12 days,
beginning 10 days after M.tb inoculation via the aerosol route.
4

A. Blaser, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
clearance values predicted lower in vivo AUC and lower %F, suggesting
oral bioavailability for these compounds is primarily driven by clear-
ance as opposed to absorption. The volume of distribution for these
compounds was at least 6 L/kg in all cases (22 L/kg for bedaquiline)
and varied among the compounds (see Table 3), but did not appear to
relate to clogP. All compounds tested demonstrated human plasma
protein binding of > 99.9% (data not shown).
demonstrated similar efficacy to bedaquiline with similar clearance
values, also showed considerably less potent hERG inhibition, sug-
gesting that further exploration of pyridyl-based C units might be
fruitful.
4. Experimental
Ten representative compounds with a range of MABA MICs, volume
of distribution and AUC values were evaluated for efficacy in a mouse
model of TB. In this model, the infected mice are dosed daily with
20 mg/kg of the test compound for 12 days, beginning 10 days after
M.tb infection. Efficacy is measured by the log reduction in colony-
forming units (CFU) recovered from the lungs, compared to 1 as a
positive control in the same assay. The studies sought to identify
compounds that demonstrated similar efficacy to 1 at the same dose (a
lung CFU reduction of similar magnitude).
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% CH3CN/20% H2O (v/v) in 45 mM
NH4HCO2 at pH 3.5 and 0.5 mL/min. Purity was determined by mon-
itoring at 330
50 nm and was ≥95% for all final products. Melting
points were determined on an Electrothermal 9100 melting point ap-
paratus. NMR spectra were obtained on a Bruker Avance 400 spectro-
meter at 400 MHz for 1H. Low-resolution atmospheric pressure che-
mical ionization (APCI) mass spectra were measured for organic
solutions on a ThermoFinnigan Surveyor MSQ mass spectrometer,
connected to a Gilson autosampler.
Of the compounds evaluated in vivo, only compounds 61 and 62
effected a lung CFU reduction similar to that of 1, at the same dose.
These compounds were also the only analogues with both AUCs and
MABA MICs comparable to that of 1. These two compounds had the
highest AUC/MIC ratios of the novel analogues tested, and were the
only compounds evaluated for efficacy with AUC/MIC similar or higher
than AUC/MIC of 1. The resultant efficacy is consistent with the results
of a detailed previous study that identified plasma AUC/MIC as the
driver of the in vivo efficacy of 1 in a similar mouse model of TB.16 Of
interest, compounds 33 and 57 demonstrated efficacy superior to that
of the other analogues (except for 61 and 62), despite low AUC/MIC
ratios. It is notable that these compounds demonstrated extremely high
volumes of distribution, suggesting especially high tissue levels. It is
also possible that these two compounds generate active metabolites in
vivo that contribute to efficacy; bedaquiline is known to generate an
active metabolite that contributes to efficacy in mice.17 Further studies
will be needed to determine whether active metabolites are also present
in mice, following oral dosing of the analogues described here.
4.1.1. New C/D units (Table 1)
4.1.1.1. 3-(Dimethylamino)-1-(6-methylpyridin-2-yl)propan-1-one (class
A). Oxalyl chloride (1.85 mL, 21.88 mmol) was added to a suspension
of 6-methylpicolinic acid (2.50 g, 18.23 mmol) in DCM (75 mL,
anhydrous) and DMF (1.3 mmol) at 20 °C. The mixture was stirred at
20 °C for 1 h to give a colorless solution which was cooled to 0 °C. N,O-
Dimethylhydroxylamine hydrochloride (1.95 g, 20.1 mmol) and
pyridine (3.25 mL, 40.11 mmol) were added sequentially and the
mixture was stirred at 20 °C for 18 h, then partitioned between EtOAc
and sat. aq. NaHCO3. Column chromatography with hexanes:EtOAc 1:1
gave N-methoxy-N,6-dimethylpicolinamide as an oil (2.68 g, 82%). 1H
NMR (CDCl3) δ 7.66 (t, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.21 (dd, J = 7.6,
0.4 Hz), 3.76 (s, 3H), 3.39 (s, 3H), 2.59 (s, 3H). Found: [M
+H] = 181.1.
3. Conclusions
Vinylmagnesium bromide solution in THF (1 M, 45 mL, 44.6 mmol)
In this study we prepared and evaluated a set of much more polar
analogues of bedaquiline (1), by replacing the naphthalene C-unit with
a series of substituted pyridyls. As shown previously, the potency
(MIC90 values) of these compounds against M.tb in culture correlated
positively with high lipophilicity, but this study was able to set a lower
bound to lipophilicity (clogP about 4), below which in vitro potency
decreased sharply. Encouragingly, many of the C-pyridyl analogues
proved to be slightly less potent inhibitors of the hERG potassium
channel than bedaquiline itself, and two examples (61 and 62) de-
monstrated IC50 values of 7.8 and > 10 µM.
was added to a solution of N-methoxy-N,6-dimethylpicolinamide
(2.68 g, 14.87 mmol) in THF (130 mL, dist. Na) at 0 °C, the brown so-
lution was warmed to 20 °C for 1 h then dimethylamine in THF (2 N,
45 mL, 89.2 mmol) and water (23 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 3-(dimethylamino)-1-(6-
methylpyridin-2-yl)propan-1-one as a yellow oil (2.78 g, 97%). 1H NMR
(CDCl3) δ 7.83 (dd, J = 7.7, 0.4 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.31
(dd, J = 7.7, 0.4 Hz, 1H), 3.40 (t, J = 7.2 Hz, 2H), 2.77 (t, J = 7.2 Hz,
2H), 2.61 (s, 3H), 2.29 (s, 6H). Found: [M+H] = 192.8.
This set demonstrated varying in vitro and in vivo clearance values,
with some compounds demonstrating clearance values desirably higher
than those of bedaquiline. However, in part due to higher clearance
values and resultant lower AUCs, this set of compounds, in general, had
poor in vivo activity against murine TB compared to bedaquiline given
at the same dose. The exceptions were compounds 61 and 62, which
had comparable in vivo activity to 1 and were the only tested com-
pounds with AUC/MIC ratios at least as high as that of 1. Other tested
compounds had lower AUCs or higher MICs or both, compared to be-
daquiline, with lower AUC/MIC ratios as a result. The observation that
higher AUC/MIC results in superior efficacy for this class is consistent
with previous studies of bedaquiline that indicated AUC/MIC as the
driver of efficacy for that compound against murine TB.
4.1.1.2. 3-(Dimethylamino)-1-(4-methylpyridin-2-yl)propan-1-one (Class
B). This was prepared similarly from 4-methylpicolinic acid to give
N-methoxy-N,4-dimethylpicolinamide in 31% yield. 1H NMR (CDCl3) δ
8.46 (d, J = 5.0 Hz, 1H), 7.49 (br, 1H), 7.17 (dd, J = 5.0, 0.8 Hz, 1H),
3.77 (br s, 3H), 3.40 (br s, 3H), 2.40 (s, 3H). Found: [M+H] = 181.1.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(4-methylpyridin-2-yl)propan-1-one in 99% yield. 1H NMR
(CDCl3) δ 8.53 (d, J = 4.9 Hz, 1H), 7.86 (m, 1H), 7.28 (m, 1H), 3.39 (t,
J = 7.2 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.84 (s, 6H).
Found: [M+H] = 193.0.
4.1.1.3. 3-(Dimethylamino)-1-(3-methylpyridin-2-yl)propan-1-one class
C). This was prepared similarly from 3-methylpicolinic acid to give
N-methoxy-N,3-dimethylpicolinamide in 46% yield. 1H NMR (CDCl3) δ
8.44 (dd, J = 4.7, 0.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.25 (dd,
J = 7.7, 4.8 Hz, 1H), 3.56 (s, 3H), 3.40 (s, 3H), 2.35 (s, 3H). Found: [M
+H] = 181.0.
Thus, while higher clearance than bedaquiline is a goal for this
program of work, it appears that this must be accompanied by lower
MICs than 1 in order to maintain the AUC/MIC ratio required to pro-
duce similar efficacy to bedaquiline, at the same dose. Although the
present work did not identify a compound with lower MIC and higher
clearance than bedaquiline, compounds 61 and 62, which
This Weinreb amide was similarly converted into 3-
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A. Blaser, et al.
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(dimethylamino)-1-(3-methylpyridin-2-yl)propan-1-one in 99% yield.
1H NMR (CDCl3) δ 8.50 (dd, J = 4.6, 1.1 Hz, 1H), 7.57 (dq, J = 7.8,
0.7 Hz, 1H), 7.31 (dd, J = 7.7, 4.6 Hz, 1H), 3.36 (t, J = 7.2 Hz, 2H),
2.73 (t, J = 7.2 Hz, 2H), 2.56 (s, 3H), 2.27 (s, 6H). Found: [M
+H] = 192.8.
methoxy-N,5-dimethylnicotinamide in 95% yield. 1H NMR (CDCl3) δ
8.87 (d, J = 1.8 Hz, 1H), 7.95 (dd, J = 8.0, 2.2 Hz, 1H), 7.21 (d,
J = 8.0 Hz, 1H), 3.56 (s, 3H), 3.38 (s, 3H), 2.61 (s, 3H). Found: [M
+H] = 181.1
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(4-methylpyridin-3-yl)propan-1-one in 97% yield. 1H NMR
(CDCl3) δ 9.06 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 8.1, 2.3 Hz, 1H), 7.27
(d, J = 8.1 Hz, 1H), 3.14 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 7.2 Hz, 2H),
2.63 (s, 3H), 2.29 (s, 6H). Found: [M+H] = 193.0
4.1.1.4. 3-(Dimethylamino)-1-(4,6-dimethylpyridin-2-yl)propan-1-one
(Class D). This was prepared similarly from 4,6-dimethylpicolinic acid
to give N-methoxy-N,4,6-trimethylpicolinamide in 88% yield. 1H NMR
(CDCl3) δ 7.26 (s, 1H), 7.04 (s, 1H), 3.77 (br s, 1H), 3.38 (br s, 3H), 2.54
(s, 3H), 2.34 (s, 3H). Found [M+H] = 195.0.
4.1.1.10. 3-(Dimethylamino)-1-(5-methylpyridin-3-yl)propan-1-one (Class
J). This was prepared similarly from 5-methylnicotinic acid to give N-
methoxy-N,5-dimethylnicotinamide in 87% yield. 1H NMR (CDCl3) δ
8.75 (d, J = 1.7 Hz, 1H), 8.52 (d, J = 1.7 Hz, 1H), 8.03 (m, 1H), 3.57 (s,
3H), 2.85 (s, 3H), 3.17 (s, 3H). Found: [M+H] = 181.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(4,6-dimethylpyridin-2-yl)propan-1-one in 98% yield. 1H NMR
(CDCl3) δ 7.64 (s, 1H), 7.11 (s, 1H), 3.36 (t, J = 7.1 Hz, 2H), 2.74 (t,
J = 7.1 Hz, 2H), 2.54 (s, 3H), 2.34 (s, 3H), 2.27 (s, 6H). Found: [M
+H] = 207.2.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(5-methylpyridin-3-yl)propan-1-one in 93% yield. 1H NMR
(CDCl3) δ 8.98 (d, J = 1.9 Hz, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.03 (m,
1H), 3.15 (t, J = 7.0 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.29 (s, 6H).
Found: [M+H] = 193.0.
4.1.1.5. 3-(Dimethylamino)-1-(3,5-dimethylpyridin-2-yl)propan-1-one
(Class E). This was prepared similarly from 3,5-dimethylpicolinic acid
to give N-methoxy-N,3,5-trimethylpicolinamide in 23% yield. 1H NMR
(CDCl3) δ 8.25 (d, J = 0.6 Hz, 1H), 7.36 (s, 1H), 3.56 (s, 3H), 3.37 (s,
3H), 2.33 (s, 3H), 2.31 (s, 3H). Found: [M+H] = 195.1.
4.1.1.11. 3-(Dimethylamino)-1-(2,6-dimethylpyridin-3-yl)propan-1-one
(Class K). This was prepared similarly from 2,6-dimethylnicotinic acid
to give N-methoxy-N,2,6-trimethylnicotinamide in 66% yield. 1H NMR
(CDCl3) δ 7.50 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 3.48 (s,
3H), 3.34 (s, 3H), 2.55 (s, 3H), 2.54 (s, 3H). Found: [M+H] = 195.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(2,6-dimethylpyridin-3-yl)propan-1-one in 99% yield. 1H NMR
(CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.04 (t,
J = 7.2 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.69 (s, 3H), 2.57 (s, 3H),
2.26 (s, 6H). Found: [M+H] = 207.0.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(3,5-dimethylpyridin-2-yl)propan-1-one in 99% yield. 1H NMR
(CDCl3) δ 8.32 (dd, J = 1.3, 0.5 Hz, 1H), 7.37 (dd, J = 1.3, 0.7 Hz, 1H),
3.35 (t, J = 7.2 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.36 (s,
3H), 2.27 (s, 6H). Found: [M+H] = 207.2.
4.1.1.6. 3-(Dimethylamino)-1-(6-methoxypyridin-2-yl)propan-1-one
(Class F). This was prepared similarly from 6-methoxypicolinic acid to
give N,6-dimethoxy-N-methylpicolinamide in 92% yield. 1H NMR
(CD3SOCD3) δ 7.86 (dd, J = 8.3, 7.3 Hz, 1H), 7.66 (dd, J = 7.3,
0.7 Hz, 1H), 7.05 (dd, J = 8.3, 0.7 Hz, 1H), 3.90 (s, 3H), 3.28 (bs,
3H). Found: [M+H] = 197.0.
4.1.1.12. 4,1.1.12.
3-(Dimethylamino)-1-(5,6-dimethylpyridin-3-yl)
propan-1-one (Class L). This was prepared similarly from 5,6-
The Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(6-methoxypyridin-2-yl)propan-1-one in 69% yield. 1H NMR
(CDCl3) δ 7.69 (t, J = 7.3 Hz, 1H), 7.64 (dd, J = 7.3, 1.0 Hz, 1H), 6.93
(dd, J = 8.0, 1.0 Hz, 1H), 3.99 (s, 3H), 3.36 (t, J = 7.2 Hz, 2H), 2.77 (t,
J = 7.2 Hz, 2H), 2.29 (s, 3H). Found: [M+H] = 209.1.
dimethylnicotinic
acid
to
give
N-methoxy-N,5,6-
trimethylnicotinamide in 92% yield. 1H NMR (CDCl3) δ 8.69 (d,
J = 1.8 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 3.57 (s, 3H), 3.37 (s, 3H),
2.55 (s, 3H), 2.32 (s, 3H). Found: [M+H] = 195.1.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(5,6-dimethylpyridin-3-yl)propan-1-one in 98% yield. 1H NMR
(CDCl3) δ 8.89 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 3.13 (t,
J = 7.3 Hz, 2H), 2.76 (t, J = 7.3 Hz, 2H), 2.57 (s, 3H), 2.35 (s, 3H),
2.29 (s, 6H). Found: [M+H] = 207.0.
4.1.1.7. 3-(Dimethylamino)-1-(4-methoxypyridin-2-yl)propan-1-one
(Class G). This was prepared similarly from 4-methoxypicolinic acid to
give N,4-dimethoxy-N-methylpicolinamide in 72% yield. 1H NMR
(CDCl3) δ 8.42 (d, J = 5.7 Hz, 1H), 7.19 (s, 1H), 6.87 (dd, J = 5.7,
2.6 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.41 (s, 3H). Found: [M
+H] = 197.1.
4.1.1.13. 3-(Dimethylamino)-1-(4,6-dimethylpyridin-3-yl)propan-1-one
(Class M). This was prepared similarly from 4,6-dimethylnicotinic acid
to give N-methoxy-N,4,6-trimethylnicotinamide in 93% yield. 1H NMR
(CDCl3) δ 8.40 (s, 1H), 7.03 (s, 1H), 3.50 (s, 3H), 3.48 (s, 3H), 2.54 (s,
3H), 2.32 (s, 3H). Found: [M+H] = 195.1.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(4-methoxypyridin-2-yl)propan-1-one in 99% yield. 1H NMR
(CDCl3) δ 8.48 (d, J = 5.6 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 6.97 (dd,
J = 5.6, 2.6 Hz, 1H), 3.90 (s, 3H), 3.38 (t, J = 7.2 Hz, 2H), 2.77 (t,
J = 7.2 Hz, 2H), 2.28 (s, 6H). Found: [M+H] = 209.0.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(4,6-dimethylpyridin-3-yl)propan-1-one in 99% yield. 1H NMR
(CDCl3) δ 8.82 (s, 1H), 7.05 (s, 1H), 3.09 (t, J = 7.2 Hz, 2H), 2.72 (t,
J = 7.2 Hz, 2H), 2.55 (s, 3H), 2.50 (s, 3H), 2.26 (s, 6H). Found: [M
+H] = 207.1.
4.1.1.8. 3-(Dimethylamino)-1-(2-methylpyridin-3-yl)propan-1-one (Class
H). This was prepared similarly from 2-methylnicotinic acid to give
N-methoxy-N,2-dimethylnicotinamide in 83% yield. 1H NMR (CDCl3) δ
8.55 (dd, J = 4.9, 1.8 Hz, 1H), 7.60 (dd, J = 7.7, 1.8 Hz, 1H), 7.16 (dd,
J = 7.7, 4.9 Hz, 1H), 3.46 (br s, 3H), 3.36 (br s, 3H), 2.57 (s, 3H).
Found: [M = H] = 181.1
4.1.1.14. 3-(Dimethylamino)-1-(2-methoxypyridin-3-yl)propan-1-one
(Class N). This was prepared similarly from 2-methoxynicotinic acid to
give N,2-dimethoxy-N-methylnicotinamide in 78% yield. 1H NMR
(CDCl3) δ 8.22 (dd, J = 5.0, 1.8 Hz, 1H), 7.60 (bd, J = 6.3 Hz, 1H),
6.93 (dd, J = 7.2, 5.0 Hz, 1H), 3.99 (s, 3H), 3.54 (bs, 3H), 3.33 (bs, 3H).
Found: [M+H] = 197.0.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(2-methylpyridin-3-yl)propan-1-one in 75% yield. 1H NMR
(CDCl3) δ 8.58 (dd, J = 4.9, 1.7 Hz, 1H), 7.90 (dd, J = 7.8, 1.7 Hz, 1H),
7.22 (dd, J = 7.8, 4.9 Hz, 1H), 3.05 (t, J = 7.0 Hz, 2H), 2.71 (t,
J = 7.0 Hz, 2H), 2.71 (s, 3H), 2.25 (s, 6H). Found: [M+H] = 193.0
The Weinreb amide was similarly converted to 3-(dimethylamino)-
1-(2-methoxypyridin-3-yl)propan-1-one in 95% yield. 1H NMR (CDCl3)
δ 8.30 (dd, J = 4.8, 2.0 Hz, 1H), 8.08 (dd, J = 7.6, 2.0 Hz, 1H), 6.98
(dd, J = 7.5, 4.8 Hz, 1H), 4.05 (s, 3H), 3.21 (t, J = 7.1 Hz, 2H), 2.71 (t,
J = 7.1 Hz, 2H), 2.27 (s, 6H). Found: [M+H] = 209.1.
4.1.1.9. 3-(Dimethylamino)-1-(4-methylpyridin-3-yl)propan-1-one (Class
I). This was prepared similarly from 4-methylnicotinic acid to give N-
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4.1.1.15. 3-(Dimethylamino)-1-(6-methoxypyridin-3-yl)propan-1-one
(Class O). This was prepared similarly from 6-methoxynicotinic acid to
give N,6-dimethoxy-N-methylnicotinamide in 83% yield. 1H NMR
(CDCl3) δ 8.65 (dd, J = 2.4, 0.5 Hz, 1H), 8.00 (dd, J = 8.7, 2.4 Hz,
1H), 6.76 (dd, J = 8.7, 0.7 Hz, 1H), 3.99 (s, 3H), 3.58 (s, 3H), 3.38 (s,
3H). Found: [M+H] = 197.0.
(CDCl3) δ 8.68 (dd, J = 5.1, 0.4 Hz, 1H), 7.59 (s, 1H), 7.52 (dd, J = 5.1,
1.0 Hz, 1H), 3.12 (t, J = 7.2 Hz, 2H), 2.75 (t, J = 7.2 Hz, 2H), 2.64 (s,
3H), 2.28 (s, 6H). Found: [M+H] = 193.1.
4.1.1.21. 3-(Dimethylamino)-1-(2,6-dimethylpyridin-4-yl)propan-1-one
(Class U). This was prepared similarly from 2,6-dimethylisonicotinic
acid to give N-methoxy-N,2,6-trimethylisonicotinamide in 49% yield.
1H NMR (CDCl3) δ 7.15 (s, 2H), 3.56 (s, 3H), 3.35 (s, 3H), 2.57 (s, 6H).
Found: [M+H] = 195.0.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(6-methoxypyridin-3-yl)propan-1-one in 99% yield. 1H NMR
(CDCl3) δ 8.81 (dd, J = 2.3, 0.4 Hz, 1H), 8.15 (dd, J = 8.7, 2.4 Hz, 1H),
6.79 (dd, J = 8.7, 0.6 Hz, 1H), 4.00 (s, 3H), 3.09 (t, J = 7.3 Hz, 2H),
2.75 (t, J = 7.3 Hz, 2H), 2.29 (s, 6H). Found: [M+H] = 209.0.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(2,6-dimethylpyridin-4-yl)propan-1-one in 99% yield. 1H NMR
(CDCl3) δ 7.38 (s, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H),
2.61 (s, 6H), 2.28 (s, 6H). Found: [M+H] = 207.1.
4.1.1.16. 1-(2,5-Dimethoxypyridin-3-yl)-3-(dimethylamino)propan-1-one
(Class P). This was prepared similarly from 2,5-dimethoxynicotinic
acid to give N,2,5-trimethoxy-N-methylnicotinamide in 61% yield. 1H
NMR (CDCl3) δ 7.87 (br s, 1H), 7.24 (br s, 1H), 3.94 (s, 3H), 8.82 (s,
3H), 3.56 (br s, 3H), 3.32 (br s, 3H). Found: [M+H] = 227.0.
This Weinreb amide was similarly converted into 1-(2,5-dimethox-
ypyridin-3-yl)-3-(dimethylamino)propan-1-one in 90% yield. 1H NMR
(CDCl3) δ 8.00 (d, J = 3.2 Hz, 1H), 7.69 (d, J = 3.2 Hz, 1H), 4.01 (s,
3H), 3.83 (s, 3H), 3.22 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.27
(s, 6H). Found: [M+H] = 239.2.
4.1.1.22. 1-(2,6-Diethoxypyridin-4-yl)-3-(dimethylamino)propan-1-one
(Class V). This was prepared similarly from 2,6-diethoxyisonicotinic
acid to give 2,6-diethoxy-N-methoxy-N-methylisonicotinamide in 69%
yield. 1H NMR (CDCl3) δ 6.43 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.59 (br
s, 3H), 3.32 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). Found: [M+H] = 255.1.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(2,6-dimethylpyridin-4-yl)propan-1-one in 96% yield. 1H NMR
(CDCl3) δ 6.71 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.05 (t, J = 7.0 Hz,
2H), 2.72 (t, J = 7.0 Hz, 2H), 2.26 (s, 6H), 1.40 (t, J = 7.0 Hz, 3H).
Found: [M+H] = 267.0.
4.1.1.17. 1-(5,6-Dimethoxypyridin-3-yl)-3-(dimethylamino)propan-1-one
(Class Q). This was prepared similarly from 5,6-dimethoxynicotinic
acid to give N,5,6-trimethoxy-N-methylnicotinamide in 85% yield. 1H
NMR (CDCl3) δ 8.26 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 4.11
(s, 3H), 3.91 (s, 3H), 3.61 (s, 3H), 3.39 (s, 3H). Found: [M
+H] = 227.1.
4.1.1.23. 1-(2,5-Dimethoxypyridin-4-yl)-3-(dimethylamino)propan-1-one
(Class W). This was prepared similarly from 2,5-dimethoxyisonicotinic
acid to give N,2,5-trimethoxy-N-methylisonicotinamide in 41% yield.
1H NMR (CDCl3) δ 7.82 (s, 1H), 6.60 (br s, 1H), 3.90 (s, 3H), 3.89 (s,
3H), 3.51 (br s, 1H), 3.35 (br s, 3H). Found: [M+H] = 227.1.
This Weinreb amide was similarly converted into 1-(2,5-dimethox-
ypyridin-4-yl)-3-(dimethylamino)propan-1-one in 67% yield. 1H NMR
(CDCl3) δ 7.89 (s, 1H), 6.86 (d, J = 0.4 Hz, 1H), 3.91 (s, 3H), 3.90 (s,
3H), 3.10 (t, J = 7.1 Hz, 2H), 2.67 (t, J = 7.1 Hz, 2H), 2.24 (s, 6H).
Found: [M+H] = 239.2.
The Weinreb amide was similarly converted to 1-(5,6-dimethox-
ypyridin-3-yl)-3-(dimethylamino)prpoan-1-one in 32% yield. 1H NMR
(CDCl3) δ 8.40 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 4.09 (s,
3H), 3.92 (s, 3H), 3.11 (t, J = 7.1 Hz, 2H), 2.77 (t, J = 7.1 Hz, 2H), 2.30
(s, 6H). Found: [M+H] = 239.1.
4.1.1.18. 3-(Dimethylamino)-1-(2,4,5-trimethoxypyridin-3-yl)propan-1-
one (Class R). This was prepared similarly from 2,4,5-
4.1.1.24. 3-(Dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)
propan-1-one (Class X).. A solution of methyl 2-hydroxy-6-
methoxyisonicotinate (6.00 g, 32.8 mmol) in DMF (100 mL,
anhydrous) was treated with K2CO3 (6.80 g, 49.2 mmol) and then 1-
iodopropane (4.8 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-6-propoxyisonicotinate (6.59 g, 89%). 1H NMR (CDCl3) 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.
trimethoxynicotinic
acid
to
give
N,2,4,5-tetramethoxy-N-
methylnicotinamide in 94% yield. 1H NMR (CDCl3) δ 7.20 (s, 1H),
4.03 (s, 3H), 3.94 (s, 3H), 3.83 (s, 3H), 3.64 (br s, 3H), 3.30 (s, 3H).
Found [M+H] = 257.1.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(2,4,5-trimethoxypyridin-3-yl)propan-1-one in 92% yield. . 1H
NMR (CDCl3) δ 7.71 (s, 1H), 4.07 (s, 3H), 4.02 (s, 3H), 3.86 (s, 3H),
3.19 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.29 (s, 6H). Found:
[M+H] = 269.2.
4.1.1.19. 3-(Dimethylamino)-1-(3-methylpyridin-4-yl)propan-1-one (Class
S). This was prepared similarly from 3-methylisonicotinic acid to give
N-methoxy-N,3-dimethylisonicotinamide in 90% yield. 1H NMR
(CDCl3) δ 8.51 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 7.18 (d, J = 4.9 Hz,
1H)), 3.38 (s, 3H), 3.37 (s, 3H), 2.32 (s, 3H). Found: [M+H] = 181.1.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(3-methylpyridin-4-yl)propan-1-one in 31% yield. 1H NMR
(CDCl3) δ 8.57 (dd, J = 5.0, 0.4 Hz, 1H), 8.55 (s, 1H), 7.37 (d,
J = 5.0 Hz, 1H), 3.03 (t, J = 7.1 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 2.43
(s, 3H), 2.24 (s, 6H). Found: [M+H] = 193.0.
A solution of LiOH (2.04 g, 85.2 mmol) in water (60 mL) was added
to a solution of methyl 2-methoxy-6-propoxyisonicotinate (6.40 g,
28.4 mmol) in THF (60 mL) and MeOH (60 mL), the solution was stirred
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-propoxyisonicotinic acid (5.39 g,
90%). 1H NMR (DMSO‑d6) 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, 2H), 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.
Oxalyl chloride (2.76 mL, 32.6 mmol) was added to 2-methoxy-6-
propoxyisonicotinic acid (5.74 g, 27.2 mmol) in DCM (100 mL, anhy-
drous) and DMF (0.4 mL, 5.2 mmol) at 20 °C. The mixture was stirred at
20 °C for 1 h to give a colourless solution which was cooled to 0 °C. N,O-
Dimethylhydroxylamine hydrochloride (3.18 g, 32.6 mmol) and pyr-
idine (6.6 mL, 81.6 mmol) were added sequentially and the mixture was
stirred at 20 °C for 18 h, then partitioned between DCM and water.
Column chromatography on alumina with DCM gave N,2-dimethoxy-N-
methyl-6-propoxyisonicotinamide (6.29 g, 91%). 1H NMR (CDCl3) δ
4.1.1.20. 3-(Dimethylamino)-1-(2-methylpyridin-4-yl)propan-1-one (Class
T). This was prepared similarly from 2-methylisonicotinic acid to give
N-methoxy-N,2-dimethylisonicotinamide in 79% yield. 1H NMR
(CDCl3) δ 8.58 (dd, J = 5.0, 0.5 Hz, 1H), 7.37 (s, 1H), 7.30 (d,
J = 5.0 Hz, 1H), 3.55 (s, 3H), 3.36 (s, 3H), 2.61 (s, 3H). Found: [M
+H] = 181.1.
This Weinreb amide was similarly converted into 3-(dimethyla-
mino)-1-(2-methylpyridin-4-yl)propan-1-one in 99% yield. 1H NMR
7

A. Blaser, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
6.42 (s, 1H), 6.41 (s, 1H), 5.24 (sp, J = 6.2 Hz, 1H), 3.90 (s, 3H), 3.59
(bs, 3H), 3.32 (s, 3H), 1.35 (d, J = 6.2 Hz, 6H). Found: [M
+H] = 255.1.
solution was stirred at 20 °C. for 1 h then partitioned between EtOAc
and water. The solution was dried and evaporated, to give 3-(di-
methylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)propan-1-one
(5.57 g, 100%) as a brown oil. 1H NMR (CDCl3) δ 6.68 (d, J = 1.0 Hz,
1H), 6.67 (d, J = 1.0 Hz, 1H), 5.22 (sp, J = 6.2 Hz, 1H), 4.33 (q,
J = 7.0 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.26
(s, 6H), 1.40 (t, J = 6.2 Hz, 3H), 1.36 (d, J = 7.0 Hz, 6H). Found: [M
+H] = 281.7.
Vinylmagnesium bromide (43 mL, 1 M in THF, 43 mmol) was added
to a solution of N,2-dimethoxy-N-methyl-6-propoxyisonicotinamide
(5.78 g, 21.7 mmol) in THF (100 mL, dist. Na) at 0 °C, the brown solu-
tion was stirred at 0 °C for 1 h and then dimethylamine (43 mL, 2 M in
THF, 86 mmol) and water (40 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 3-(dimethylamino)-1-(2-methoxy-6-
propoxypyridin-4-yl)propan-1-one (5.75 g, 100%). 1H NMR (CDCl3) δ
6.73 (d, J = 1.1 Hz, 1H), 6.72 (d, J = 1.1 Hz, 1H), 4.26 (t, J = 6.7 Hz,
2H), 3.93 (s, 3H), 3.06 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.27
(s, 6H), 1.80 (qt, J = 7.4, 6.7 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). Found:
[M+H] = 267.2.
4.1.2. Scheme 1: Preparation of the 6-bromo compounds of Table 1 example
of
1-(7-bromo-3-methoxynaphthalen-2-yl)-1-(2,3-dimethoxyphenyl)-4-
(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)butan-2-ol (56)
A solution of dry diisopropylamine (1.30 mL, 9.28 mmol) in dry THF
(10 mL) was cooled to −40 °C under an atmosphere of dry nitrogen. N-
Butyllithium (4.65 mL of a 2.0 N solution in cyclohexane, 9.28 mmol)
was added dropwise, then stirring was continued for a further 15 min.
The solution was cooled to −70 to −78 °C and a solution of 6-bromo-3-
(2,3-dimethoxybenzyl)-2-methoxyquinoline6 (3.00 g, 7.73 mmol) in dry
THF (6 mL) was added dropwise. The resulting purple solution was
stirred at this temperature for 90 min. A solution of 3-(dimethylamino)-
4.1.1.25. 3-(Dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)
propan-1-one (Class X). A suspension of 2,6-dihydroxyisonicotinic acid
(40.00 g, 258 mmol) in EtOH (300 mL) was treated dropwise with
H2SO4 (40 mL, 18.4 M, 752 mmol). The solution was refluxed for 72 h
then evaporated; the residue was treated with sat. aq. NaHCO3 to pH 8
and then extracted with EtOAc (3 × 500 mL). The organic extracts were
washed with sat. aq. NaHCO3, brine, then dried and evaporated to give
ethyl 2-ethoxy-6-hydroxyisonicotinate (10.86 g, 20%). 1H NMR
(DMSO‑d6) δ 11.15 (bs, 1H), 6.59 (d, J = 1.0 Hz, 1H), 6.57 (bs, 1H),
4.29 (q, J = 7.1 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.298 (t, J = 7.1 Hz,
3H), 1.296 (t, J = 7.1 Hz, 3H). Found: [M+H] = 212.2.
1-(2,6-dimethylpyridin-4-yl)propan-1-one (class
U Mannich base)
(1.75 g, 8.50 mmol) in THF (6 mL) was then 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 EtOAc. 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 DCM gave fore fractions, followed by isomer A of 56 (1.90 g,
41%).
A
solution of ethyl 2-ethoxy-6-hydroxyisonicotinate (10.82 g,
51.2 mmol) in DMF (125 mL, anhydrous) was treated with K2CO3
(8.65 g, 62.5 mmol) and then 2-iodopropane (6.4 mL, 64 mmol). The
mixture was stirred at 20 °C. for 48 h, K2CO3 (8.65 g, 62.5 mmol) and 2-
iodopropane (6.4 mL, 64 mmol) were added and the mixture was stirred
for a further 24 h, partitioned between EtOAc and water and the aqu-
eous layer was extracted with EtOAc. The organic fractions were wa-
shed with water, dried and evaporated. Chromatography (DCM) gave
ethyl 2-ethoxy-6-isopropoxyisonicotinate (11.56 g, 89%). 1H NMR
(DMSO‑d6) δ 6.81 (s, 2H), 5.23 (sp, J = 6.2 Hz, 1H), 4.20–4.38 (m, 4H),
1.35–1.42 (m, 12H). Found: [M+H] = 254.1.
Isomer A, white solid. 1H NMR (CDCl3, 400 MHz) δ 8.21 (s, 1H),
7.83 (d, J = 2.2 Hz, 1H), 7.71–7.66 (m, 2H), 7.60 (dd, J = 8.9, 2.2 Hz,
1H), 7.20–7.13 (m, 3H), 6.83 (t, J = 8.1 Hz, 1H), 6.59 (dd, J = 8.2,
1.4 Hz, 1H), 5.60 (s, 1H), 4.23 (s, 3H), 3.68 (s, 3H), 3.47 (s, 3H), 2.47
(s, 6H), 2.28–2.20 (m, 1H), 2.00–1.96 (m, 1H), 1.99 (s, 6H), 1.85–1.80
(m, 2H). Found: [M+H] = 594.6.
Elution with DCM:MeOH (92:8) gave isomer B (1.01 g, 22%).
Isomer B, white solid. 1H NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H),
7.81 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 8.9, 2.0 Hz, 1H), 7.62 (d,
J = 8.9 Hz, 1H), 7.28–7.21 (m, 4H), 7.05 (t, J = 8.0 Hz, 1H), 6.87 (d,
J = 8.6 Hz, 1H), 4.95 (s, 1H), 3.99 (s, 3H), 3.90 (s, 3H), 3.90 (s, 3H),
2.23–2.18 (m, 2H), 2.43 (s, 6H), 2.03 (s, 6H), 1.95–1.80 (m, 2H).
Found: [M+H] = 594.6.
A solution of LiOH (3.25 g, 136 mmol) in water (60 mL) was added
to a solution of ethyl 2-ethoxy-6-isopropoxyisonicotinate (11.42 g,
45.1 mmol) in THF (60 mL) and MeOH (60 mL), the solution was 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-ethoxy-6-isopropoxyisonicotinic acid
(10.03 g, 99%). 1H NMR (DMSO‑d6) δ 13.48 (bs, 1H), 6.66 (d,
J = 0.9 Hz, 1H), 6.64 (d, J = 0.9 Hz, 1H), 5.17 (sp, J = 6.2 Hz, 1H),
4.29 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.30 (d, J = 6.2 Hz,
6H). Found: [M+H] = 226.1.
Each coupled product was resolved into its four optical isomers
using preparative chiral HPLC at BioDuro LLC (Beijing).
The other 6-bromo analogues of Table 1 were prepared similarly:
4.1.3. Scheme 1: Preparation of the 6-cyano compounds of Table 1 7-(1-
(2,3-Dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)-2-
hydroxybutyl)-6-methoxy-2-naphthonitrile (57)
Oxalyl chloride (3.13 mL, 37 mmol) was added to 2-ethoxy-6-iso-
propoxyisonicotinic acid (6.95 g, 30.8 mmol) in DCM (100 mL, anhy-
drous) and DMF (5.2 mmol) at 20 °C. The mixture was stirred at 20 °C
for 1 h to give a colourless solution which was cooled to 0 °C. N,O-
Dimethylhydroxylamine hydrochloride (3.61 g, 37.0 mmol) and pyr-
idine (7.5 mL, 92.7 mmol) were added sequentially and the mixture was
stirred at 20 °C for 18 h, then partitioned between EtOAc and water. The
organic fractions were washed with water, dried and evaporated.
Column chromatography with 95:5 DCM:EtOAc gave 2-ethoxy-6-iso-
propoxy-N-methoxy-N-methylisonicotinamide (7.98 g, 97%). 1H NMR
(CDCl3) δ 6.40 (s, 1H), 6.39 (s, 1H), 5.22 (sp, J = 6.2 Hz, 1H), 4.33 (q,
J = 7.1 Hz, 2H), 3.60 (bs, 3H), 3.31 (s, 3H), 1.39 (t, J = 6.2 Hz, 3H),
1.34 (d, J = 7.1 Hz, 6H). Found: [M+H] = 269.2.
A solution of 56 (1.62 g, 2.73 mmol) in DMF (10 mL, anhydrous)
was purged with nitrogen and heated to 55 °C for 10 min. Tri(o-tolyl)
phosphine (0.125 g, 0.41 mmol), zinc dust (0.018 g, 0.273 mmol) and
tris(dibenzylideneacetone)dipalladium(0) (0.188 g, 0.205 mmol) were
then added, and the reaction was again purged with nitrogen and he-
ated for another 10 min at 55 °C. Zinc cyanide (0.177 g, 1.50 mmol) was
then added and the reaction mixture was heated to 65 °C for 4 h. The
reaction was diluted with water and extracted with EtOAc three times.
The organic layer was washed with brine three times, dried and eva-
porated. Column chromatography with DCM followed afforded isomer
A of 57 (0.65 g, 44%) followed by isomer B of 57 (0.46 g, 31%) as white
solids.
Vinylmagnesium bromide (40 mL, 1 M in THF, 40 mmol) was added
to a solution of 2-ethoxy-6-isopropoxy-N-methoxy-N-methylisonicoti-
namide (5.33 g, 19.9 mmol) in THF (100 mL, dist. Na) at 0 °C, the
brown solution was stirred at 0 °C for 1 h and then dimethylamine
(40 mL, 2 M in THF, 80 mmol) and water (40 mL) were added. The
Isomer A, white solid. 1H NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H),
8.16 (s, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H),
7.73–6.98 (m, 2H), 7.21–7.11 (m, 2H), 6.84 (t, J = 8.1 Hz, 1H), 6.60
(dd, J = 8.2, 1.4 Hz, 1H), 5.60 (s, 1H), 4.28 (s, 3H), 3.68 (s, 3H), 3.49
8

A. Blaser, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
(s, 3H), 2.47 (s, 6H), 2.21–2.13 (m, 1H), 2.02–1.96 (m, 1H), 1.95 (s,
6H), 1.85–1.72 (m, 2H). Found: [M+H] = 542.4.
this article can be found online at https://doi.org/10.1016/j.bmc.2019.
02.025. These data include MOL files and InChiKeys of the most im-
portant compounds described in this article.
Isomer B, white solid. 1H NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H),
8.21 (s, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.62
(dd, J = 8.6, 1.8 Hz, 1H), 7.37 (dd, J = 8.0, 1.4 Hz, 1H), 7.13–7.06 (m,
2H), 7.00 (t, J = 8.0 Hz, 1H), 6.82 (dd, J = 8.0, 1.4 Hz, 1H), 5.54 (s,
1H), 4.01 (s, 3H), 3.90 (s, 3H), 3.90 (s, 3H), 2.43 (s, 6H), 2.20–2.12 (m,
1H), 2.02 (s, 6H), 2.01–1.93 (m, 2H), 1.74–1.68 (m, 1H). Found: [M
+H] = 542.4.
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Appendix A. Supplementary data
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Supplementary data (MOL files for the compounds of Table 2) to
9