3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel

Article abstract of DOI:10.1016/j.bmc.2019.02.026

Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.

Full text of DOI:10.1016/j.bmc.2019.02.026

Accepted Manuscript
3
,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis
agents with minimal inhibition of the hERG channel
Hamish S. Sutherland, Amy S.T. Tong, Peter J. Choi, Adrian Blaser, Daniel
Conole, Scott G. Franzblau, Manisha U. Lotlikar, Christopher B. Cooper, Anna
M. Upton, William A. Denny, Brian D. Palmer
PII:
S0968-0896(18)31745-0
https://doi.org/10.1016/j.bmc.2019.02.026
BMC 14762
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
11 October 2018
6 February 2019
14 February 2019
Please cite this article as: Sutherland, H.S., Tong, A.S.T., Choi, P.J., Blaser, A., Conole, D., Franzblau, S.G., Lotlikar,
M.U., Cooper, C.B., Upton, A.M., Denny, W.A., Palmer, B.D., 3,5-Dialkoxypyridine analogues of bedaquiline are
potent antituberculosis agents with minimal inhibition of the hERG channel, Bioorganic & Medicinal Chemistry
(
2019), doi: https://doi.org/10.1016/j.bmc.2019.02.026
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3
,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with
minimal inhibition of the hERG channel
a
a
a
a
Hamish S. Sutherland , Amy S.T. Tong , Peter J. Choi , Adrian Blaser , Daniel Conole,
c
d
d
d
Scott G. Franzblau , Manisha U. Lotlikar , Christopher B. Cooper , Anna M. Upton ,
William A. Denny , Brian D. Palmer
a,b,*
a,b,
a
Affiliations Auckland Cancer Society Research Centre, School of Medical Sciences, and
b
Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New
c
Zealand; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at
Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA; Global Alliance for TB
d
Drug Development, 40 Wall St, New York 10005, USA
Keywords
CFU; colony-forming units; hERG (human Ether-a-go-go Related Gene), HPLC, high-
performance liquid chromatography; LDA, lithium diisopropylamide; LiTMP, lithium
tetramethylpiperidide; LORA, low oxygen recovery assay; MABA, microplate alamar blue
assay; MDR, multidrug-resistant; MIC90, minimum concentration for 90% inhibition of
growth; M. tb, Mycobacterium tuberculosis; TB, tuberculosis
Abstract
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically
effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the
QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG.
Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the
potential for more-than-desired accumulation in tissues during the relatively long treatment
durations required to cure TB. The present work is part of a program that seeks to identify a
diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with
lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led
to the identification of compounds with greatly-reduced lipophilicity compounds that retain
good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the
hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a
3
,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity,
with greatly attenuated hERG blockade. Two examples of this series are in preclinical
development.
1
. Introduction
Bedaquiline (TMC207, Sirturo, Janssen Pharmaceuticals; 1; Table 2), a diarylquinoline, is the
first example of a new class of drug that has proven clinically effective against drug-resistant
1
tuberculosis (TB). It has a novel mechanism of action, selectively inhibiting the
2
mycobacterial ATP synthase enzyme. In attempts to develop improved second-generation
analogues of 1, we have focused on two areas. One is to lower its very high lipophilicity
(clogP 7.25), which may contribute to its long terminal elimination half-life and tissue

3
accumulation at high doses. The other aim is to attenuate its inhibition (IC 1.6 µM) of the
5
0
4
cardiac potassium channel protein coded by the human ether-a-go-go-related gene (hERG).
This forms the pore-forming subunit of the rapidly activating delayed rectifier potassium
channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes
long QT syndrome and can increase the risk of sudden death in patients with cardiac ischemia
a potential safety issue that all drug candidates seeking regulatory approval must currently
-
address. In our attempts to develop analogues of lower lipophilicity, we have reported on the
utility of replacing the 6-Br substituent on the A-unit quinoline with a more polar cyano
5
6
group, replacing the B-unit phenyl with heterocycles, and replacing the C-unit naphthalene
7
8
with either bicyclic heterocycles or substituted pyridines. These studies provided a diverse
range of potent diarylquinolines with much lower lipophilicity, and defined structure-activity
relationships between antitubercular activity and lipophilicity. While they were, in the main,
less successful in identifying active compounds with significantly attenuated potency against
8
the hERG channel, we recently reported encouraging results (hERG IC values around or
5
0
>10 µM) in a small number of compounds containing a 4-pyridyl-3,5-dialkoxy C-unit,
suggesting this substitution is a promising one for mitigation of hERG potency. In the
present paper, we follow up on that observation with a more extensive structure-activity study
of this motif, which has allowed selection of two candidate compounds for preclinical
development.
2
. Results and Discussion
2
.1. Chemistry
5
-9
The bedaquiline analogues of Table 2 were prepared as previously described, by LDA-
mediated coupling of the appropriate benzylquinoline A/B-units and 1-(2,6-dialkoxypyridin-
4
-yl)-3-(dimethylamino)propan-1-one (Mannich base) C/D-units (Scheme 1). The 6-cyano
derivatives were prepared by palladium-catalyzed cyanation of the corresponding bromo
analogues. The resulting diarylquinolines were formed as a racemic mixture of four
diastereomers, and the desired 1R,2S diastereomer (depicted) was isolated by super-critical
fluid HPLC at BioDuro LLC (Beijing).
Scheme 1: Synthesis of substituted analogues of 1

o
o
Reagents and conditions: (i) LiTMP, THF, -75 C, 1.5 h then the appropriate aldehyde B, -75 C, 4 h;
(
1
(
ii) Et SiH, TFA, DCM; (iii) MsCl, Et N, DMF, then NaBH ; (iv) Cs CO , Pd(PPh ) , PhMe/DMF,
3 3 4 2 3 3 4
o
o
10 C (sealed tube), 5 h; (v) LDA, THF, -75 C, 1.5 h then the appropriate ketone C/D, then HOAc;
o
vi) Zn/Zn(CN) , Pd (dba) /P(o-tol) , DMF, 50 C, then separation of the diastereomers by SFC
2 2 3 3
HPLC.
6
,8
Having previously established the utility of a range of substituted pyridyl B- and/or C-units
in lowering overall clogP values, in the present SAR study we report 3,5-dialkoxy-4-pyridyl
C-unit analogues bearing a wide range of different B-unit substitutions, with the focus on
mitigation of hERG potency. Thirty-four different A/B-units were used, apart from the
unsubstituted parent; syntheses of many of these (for compounds 7, 9, 10, 13, 14, 16, 17, 23-
5
-8
2
6, 34, 40-42, 48, 50 of Table 2) have already been reported. The remainder were prepared
as outlined in Scheme 1 and Table 1.
Table 1: Synthesis of new A/B units
Y
Name
Steps Overall
yield (%)
For Table 3
compounds
a
2
2
2
3
2
2
3
3
3
4
4
4
,3-(CH2)3
,3-(CH ) -
-F, 3-Me
AB-1
AB-2
AB-3
AB-4
AB-5
AB-6
AB-7
AB-8
AB-9
AB-10
AB-11
AB-12
3
3
1
3
1
3
2
4
5
5
3
4
84
41
76
37
76
52
43
20
40
16
21
37
2,3
4
5-7
11
15, 16
21
24-26
29, 30
31, 32
34
2
4
-F, 4-OMe
,3-OCH O-
2
,3-OCH=CH-
-aza, 4-NEt2
i
-aza, 2-OMe, 5-O Pr
-aza, 2,4,5-triOMe
-aza, 2,5-diOMe
-aza, 3,5-diSMe
-aza, 3,5-diSEt
36
37

i
4
4
4
4
4
4
4
4
-aza, 2-OMe, 5-O Pr
AB-13
9
5
5
8
2
3
4
5
11
55
58
13
51
42
37
12
38, 39
43
44, 45
46
47, 48
49, 50
51
cy
-aza, 3-OMe, 5-O Bu AB-14
i
-aza, 3-OEt, 5-O Pr
-aza, 2,3,5-triOMe
-aza, 3-OMe, 5-NMe2
-aza, 3-OEt, 5-NMe2
-aza, 3-SEt, 5-NMe2
AB-15
AB-16
AB-17
AB-18
AB-19
AB-20
-aza, 2-F, 3-OMe
52
a
Footnote for Table 1. The yield quoted is for the mixture of four stereoisomers formed in the condensation
reaction
The acid chlorides derived from I were reacted with N,O-dimethylhydroxylamine to give the
N-methoxyacetamides (Weinreb amides) (II), which were converted to the required Mannich
bases (III) in high yields by reaction with vinyl magnesium bromide to generate an
intermediate (IIa), followed by reaction with dimethylamine. Mannich bases IV to VII were
prepared to evaluate the role of varying D unit pKa on hERG inhibition (see Table 4). In the
absence of an additional dialkylamine source, the N,O-dimethylhydroxylamide liberated in
the formation of IIa itself reacts with IIa to give IV. The imidazole (VI) and triazole (VII)
derivatives required the isolation of crude IIa before subsequent reaction with imidazole or
triazole, this avoided the competitive reaction between IIa and the more nucleophilic N,O-
dimethylhydroxylamine.
Scheme 2: Synthesis of dialkoxypyridyl Mannich bases (III-VII)
Reagents and conditions: (i) COCl , DMF, DCM, then MeNH(OMe).HCl, pyridine; (ii)
2
vinylmagnesium bromide, THF; (iii) dimethylamine, water; (iv) for IV, water; V,
morpholine, water; VI and VII, isolation of crude IIa then imidazole or triazole.
2
.2. Structure-activity relationships
8
In previous work, we demonstrated the ability of a range of analogues with substituted
pyridyl C-units to significantly lower lipophilicity (clogP values between about 5.5-4.0)

while producing compounds only slightly less effective than 1 against both replicating and
non-replicating cultures of M.tb in vitro, and in a mouse TB infection model. While these
compounds, as a class, did not show useful reductions in potency in hERG channel blockade,
the 3,5-dimethoxy-4-pyridyl unit did appear to have some utility, prompting the present study
of 3,5-dimethoxy-4-pyridyl and 3,5-diethoxy-4-pyridyl analogues with a wide range of B-
units.
Table 2 provides data on analogues of 1 (2 - 52), where the naphthalene C-unit has been
replaced by either a 3,5-dimethoxy-4-pyridyl or a 3,5-diethoxy-4-pyridyl unit. The
compounds were evaluated for bacterial growth inhibition (MIC values) in cultures of M.tb
9
0
1
0
11
(
strain H37Rv) under both replicating (MABA assay ) and non-replicating (LORA assay )
conditions.
Table 2. Inhibitory properties of 3,5-dialkoxy-4-pyridyl analogues of bedaquiline
b
c
No
X
Y
Z
Yld
MIC (µg/mL)
MABA
0.04
clogP
9
0
a
(%)
LORA
0.08
1
2
3
4
5
6
7
8
9
7.25
6.81
5.45
7.38
6.44
7.50
6.14
5.80
4.44
6.86
5.80
5.06
3.70
6.11
5.76
4.41
5.72
4.90
6.78
5.42
6.36
Br 2,3-(CH
CN 2,3-(CH
Br 2,3-(CH
Br 2-F, 3-Me
Br 2-F, 3-Me
CN 2-F, 3-Me
Br 2-F, 3-OMe
CN 2-F, 3-OMe
Br 2-F, 3-OMe
Br 3-F, 4-OMe
Br 2, 3-diOMe
CN 2, 3-diOMe
Br 2,3-diOMe
Br 2,3-OCH
CN 2,3-OCH
Br 2,3-O(CH
CN 2,3-O(CH
Br 2,3-O(CH
CN 2,3-O(CH
)
)
)
Me 24d
Me 71
Me 13
Me 61
Et 67d
Et 74
Me 52d
Me 80
Et 70
Me 38
Me 63d
Me 80
Et 64
Me 66d
Me 85
Me 72d
Me 76
Et 52d
Et 62
Me 16
0.01
0.02
2
2
2
3
3
4
-
-
0.02
0.02
<0.004
<0.01
<0.02
<0.02
0.006
0.09
0.01
<0.01
<0.02
<0.02
<0.02
0.09
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
0.02
0.08
0.01
0.01
<0.01
0.12
<0.01
0.14
<0.02
0.06
<0.02
<0.02
0.06
O-
O-
2
0.07
2
)
2
)
2
)
2
)
2
O-
O-
O-
O-
0.02
0.02
2
2
2
2
0.02
0.02
0.07
0.13
0.03
0.03
Br 2,3-OCH=CH-
<0.004
0.01
2
2
2
3
Br 3-aza, 2-OMe
CN 3-aza, 2-OMe
Me 65d
Me 68
<0.02
0.04
<0.02
0.25
4.72
3.36

2
2
2
2
2
2
3
3
3
4
5
6
7
8
9
0
1
2
Br 3-aza, 4-NEt
Br 3-aza, 4-NEt
CN 3-aza, 4-NEt
Br 3-aza, 2,5-diOMe
CN 3-aza, 2,5-diOMe i
Br 3-aza, 2-OMe, 5-O Pr
CN 3-aza, 2-OMe, 5-O Pr
Br 3-aza, 2,4,5-triOMe
CN 3-aza, 2,4,5-triOMe
2
2
2
Et 26
Me 46d
Me 68
Me 38d
Me 44
Me 38
Me 56
Me 38d
Me 39
<0.02
0.003
<0.01
<0.02
0.02
<0.004
<0.004
<0.01
<0.01
<0.02
0.008
<0.02
<0.02
0.04
0.016
<0.004 4.60
<0.01
<0.01
7.13
6.07
4.71
5.12
3.76
5.96
i
5.15
3.79
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
Br 4-aza, 2,3-diOMe
Br 4-aza, 2,5-diOMe
Br 4-aza, 2,3-diOMe
Br 4-aza, 3,5-diSMe
Br 4-aza, 3,5-diSEt
Br 4-aza, 2-OMe, 5-O Pr
CN 4-aza, 2-OMe, 5-O Pr
Br 4-aza, 3-OMe, 5-O Pr
CN 4-aza, 3-OMe, 5-O Pr
Br 4-aza, 3-OMe, 5-O Pr
Br 4-aza, 3-OMe, 5-O Bu Me 16
Br 4-aza, 3-OEt, 5-O Pr
CN 4-aza, 3-OEt, 5-O Pr
Br 4-aza, 2,3,5-triOMe
Br 4-aza, 3-OMe, 5-NMe
CN 4-aza, 3-OMe, 5-NMe
Br 4-aza, 3-OEt, 5-NMe
CN 4-aza, 3-OEt, 5-NMe
Me 62
Me 77
Et 32
Me 26
Me 28
Me 54d
Me 39
<0.02
<0.01
<0.02
<0.01
<0.02
<0.004
0.05
0.07
0.04
<0.02
<0.01
<0.02
0.008
0.09
0.06
0.01
0.01
0.12
0.10
0.01
0.01
0.03
0.09
0.03
0.05
0.01
<0.05
4.77
5.12
5.83
6.18
7.24
5.96
4.60
6.36
5.00
6.58
6.43
6.88
5.53
5.15
5.83
4.48
6.36
5.01
6.68
5.10
i
i
i
Me 57 d 0.04
i
Me 57
Me 52
0.01
0.01
0.01
0.05
0.01
0.01
n
cy
i
Me 61d
Me 80
Me 47
Me 21 d 0.01
i
2
2
Me 71
Me 58d
Me 90
Me 52
Me 54
0.03
>0.004
0.03
0.01
<0.01
2
2
Br 4-aza, 3-SEt, 5-NMe
Br 4-aza, 2-F, 3-OMe
2
Footnotes for Table 2
a
Yields (Yld) in the AB/CD coupling step to give bedaquiline analogues (as racemic mixtures). The
b
desired 1R, 2S diastereomer was then isolated by SFC HPLC at BioDuro LLC, Beijing. MIC
9
0
(
µg/mL); minimum inhibitory concentration for 90% inhibition of 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.
c
d
clogP calculated by ChemDraw Ultra v12.0.2. (CambridgeSoft). Yields for the Br/CN conversion.
The new bedaquiline analogues characterized in the present work have calculated clogP
values between 7.50 and 3.36, with the majority between 6.25 and 4.25 (Table 2). Nearly all
have MIC values significantly superior (many by more than 10-fold) to 1 against both
9
0
7
,8
replicating and non-replicating cultures of M.tb. As shown previously, the more lipophilic
compounds appear more potent, but as so many had indeterminate endpoint values (below the
8
testing range of the assay), this could not be quantified. We have previously shown that
different B-units have little specific effect on inhibitory activity (MIC s) apart from their
9
0
contribution to overall lipophilicity. This appears to also be the case for the analogues tested
here.
Representative compounds in the series were evaluated in vitro for a range of ADME and
toxicological properties (Table 3). Compounds were tested for cytotoxicity in Vero green

1
2
monkey-derived epithelial kidney cells, and for inhibition of CYP 3A4, the major
1
2
metabolising enzyme for 1. All tested compounds had IC s >10 µg/mL in the Vero assay,
5
0
except for compound 9, which had a value of 7.3, and compounds 28 and 34, where this was
not measured. In comparison, the value for 1 in repeat assays was between 4-16 µg/mL.
Where tested, compounds had IC s >10 µM for CYP3A4 inhibition (bedaquiline IC > 40
5
0
50
µM), however, compounds 3-7, 11, 19-21, 24, 27-28, 30-31, 33, 36, 41-42, 45-49, 51-52
were not tested in this assay.

Table 3. Additional biological data on selected compounds of Table 2
a
i
No hERG
Aq. Sol
Microsomal
stbability
IV Cl Vz
AUCinf
F
Log redn. in
mouse lung CFU
clogP
b
e
IC50
pH 7.4 HClint MClint
µM
Aq. Sol. HClint MClint
mL/min L/kg
/kg
µg*hr/
%
Test
Beda- h
d
g
(
µM) a
mL
compd quiline
b
b
c
d
e
f
No hERG
IV Cl
Vz
22
51
29
34
22
15
95
53
32
30
29
27
22
16
18
24
37
67
26
94
47
69
42
27
73
12
38
31
49
38
54
30
20
AUCinf
20.9
5.54
7.06
12.8
9.11
28.8
1.72
4.95
21.7
2.39
7.74
1.18
1.08
20.0
6.11
14.2
1.58
4.74
3.12
0.96
1.39
2.69
5.33
10.9
2.44
20.6
4.21
5.61
12.3
3.31
1.70
5.33
22.7
F
1
3
4
5
6
7
8
1.6
4.5
< 0.06
0.05
< 0.06
< 0.04
< 0.02
3
4
6
4
3
7
8
8
6
6
1
18
10
7
15
7
36
27
2
7
56
75
39
69
39
54
48
53
94
26
45
29
28
56
47
66
26
39
46
23
43
53
79
57
22
46
32
44
41
45
20
28
84
4.5-6.2 7.25
23
9.3
10
8.2
3.2
48
19
7.0
23
10
41
44
5.2
13
8.8
28
14
25
41
52
25
25
6.2
21
4.1
13
13
3.6
24
20
7.0
6.8
>5.0
>5.0
>5.0
4.0
>5.0
5.2
4.4
5.5
1.2
4.0
2.6
4.8
4.4
>5.0
>5.0
4.0
4.6
>5.0
4.2
5.0
5.0
4.6
4.6
4.5
6.1
4.9
>5
5.45
7.38
6.44
7.50
6.14
5.80
6.86
5.80
5.06
6.11
4.41
4.90
6.78
5.42
6.36
4.72
7.13
5.12
3.76
4.60
5.15
4.77
6.18
5.00
6.58
5.53
5.15
5.83
4.48
5.01
6.68
5.10
>10
>10
>10
>10
13
10
>10
2.2
5.5
1.6
4.4
13.3
4.5
>10
1.7
9.9
2.2
3.1
2.4
5.9
2.6
>10
10.6
>30
>30
>30
>10
9.4
>10
>10
>10
< 0.06 0.7
< 0.06
< 0.06
< 0.02
0.42
< 0.02
0.70
2.2
< 0.06
0.96
< 0.06
0.38
< 0.02 65
0.38
12.5
0.28
0.03
0.40
< 0.04 stable 6
< 0.02 29
< 0.02 stable 4
< 0.02
< 0.02
< 0.02
0.59
0.57
< 0.02
< 0.2
2
3
6
14
1
6
7
4
1
3
6
1
0
1
2
4
6
8
9
0
1
2
4
7
8
0
1
3
6
1
2
5
6
7
8
0
1
2
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
3
4
4
4
4
4
4
5
5
5
5.7
5.6
5.3
5.6
4.6
5.0
5.0
5.3
5.6
5.0
6.1
4.9
5.0
5.3
5.5
5.6
5.5
4.6
>5.5
5.0
5.0
4.9
5.5
>5
2
10
33
15
20
51
16
57
24
6
6
2
9
8
4.8
>5.0
4.8
5.0
4.9
2
5.5
2
2
9
13
4
21
22
9
25
58
11
6
>5.0
>5.5
4.8
2.5
3.8
4
4
4.7
>5.5
Footnotes for Table 3
a
b
Inhibition of hERG (IC in µM); Clearance of compound by human or mouse liver microsomes
50
c
d
(
μL/min/mg protein); IV clearance, mouse (mL/min/kg); IV apparent volume of distribution during
e
terminal phase, mouse (L/kg); Oral exposure, area under the curve 0 to infinity, in mice (µg*h/mL);
f
g
Oral bioavailability in mice; Log reduction in lung colony-forming units (CFU) compared to vehicle
h
of analogues or 1 when dosed in the same assay at 20 mg/kg daily in mice for 12 days, beginning 10
i
days after M.tb inoculation via the aerosol route; clogP calculated by ChemDraw Ultra v12.0.2.
(
CambridgeSoft).

The most interesting result of this study was the very positive effect of the 3,5-dialkoxy-4-
pyridyl C-unit substitution on hERG potassium channel inhibition. Of the 33 compounds
evaluated, 19 had IC values of >10 µM, in strong contrast with previous studies of different
5
0
6
-8
sets of analogues, where no compound had IC values even approaching 10 µM. The data
5
0
suggest that, for this series, potent hERG inhibition is broadly related to higher compound
lipophilicity; the 14 analogues with hERG values less than 10 µM had an average clogP of
4
.57, whereas the 19 analogues with hERG values >10 µM had an average clogP of 6.17
(
Table 2). Put another way, 15/17 compounds with clogP >5.5 had hERG IC s >10 µM,
50
compared to only 4/16 with clogP <5.5.
Table 3 also provides data on the in vitro clearance of the analogues from human and mouse
liver microsomes. The very slow clearance (CL 3 μL/min/mg) and concomitantly long half-
int
life (231 min) of 1 in human liver microsomes is improved upon 2-fold by many of the
analogues but a 3-fold or more increase in human microsomal clearance was seen for a
handful of analogues only. The mouse liver microsome data did not always reflect the
corresponding human data. For example, for several compounds (16, 18, 22, 28, 41, 45, 46
and 50), the Cl in human microsomes is similar to, or 2-fold higher than, that of 1, but in
int
mouse microsomes, they show at least 3-fold higher clearance than 1. This may be due to
differing relative contributions to metabolism of these compounds versus 1 for CYP isoforms
in human versus mouse microsomes. The human microsome data may better predict the
human clearance for these compounds, if microsomal metabolism is representative of
metabolism overall, for these compounds. Studies of pharmacokinetics in several species,
followed by modelling work, will be needed to provide a better prediction of human PK.
The pharmacokinetics in mice were evaluated after administration of a single oral dose and a
single intravenous administration. Clearance in vivo ranged from low (similar to that of 1) to
moderate, around 50ml/min/kg, and did not always reflect the in vitro Clint values. In
particular, a significantly higher in vitro Cl than 1 did not always lead to much higher in
int
vivo clearance (eg compounds 31 and 41). Although all compounds shown demonstrated high
volumes of distribution (12 L/kg and higher), compounds such as 31 and 41 showed
particularly high volume of distribution values, and higher tissue levels in these cases may
have contributed to lower in vivo clearance than predicted by in vitro Clint.
Bioavailability (F) ranged from moderate (20% for compound 50) to very high (94% for
compound 11) and, after oral administration, a range of AUC values was seen. The AUC
values correlated broadly with clearance values, suggesting that for the large part, plasma
exposures varied depending on relative clearance. Regarding bioavailability, for the
compounds with F of 30% or lower, while they showed clearance in mice of 20ml/min/kg
and higher (except compound 51, which showed lower clearance), they did not necessarily
show the highest in vivo clearance values overall. Of note, compounds with F of 30% and
below had clogP values of 5.53 and below, except for compound 51, suggesting perhaps
lower clogP was one factor associated with lower %F for this series. All compounds tested
demonstrated human plasma protein binding of greater than 99.9%, with the exceptions of
compounds 18, 28, and 30, which were 99.85%, 99.78%, and 99.86% bound, respectively
(data not shown). Assuming mouse plasma protein binding is similar, relative PPB
presumably does not play a role in relative PK for these compounds.
Evaluation of the compounds for in vivo efficacy used a mouse model of TB. Female
BALB/c mice (n = 7 per group) were dosed at 20 mg/kg daily, by oral gavage, for 12 days,

beginning 10 days after M.tb H37Rv inoculation by the aerosol route. Compounds were
formulated in hydroxy-beta-cyclodextrin 20%. The relative in vivo activity was assessed by
the log reduction in colony-forming units (CFU) from lung homogenates, an indicator of
bacterial burden in the lungs, following treatment with a test compound compared to that
effected by vehicle administration only, and to that demonstrated by bedaquiline, dosed at 20
mg/kg in the same assay run. In this mouse model of TB, the CFU reach approximately 5-6
log in the lungs in the vehicle-treated control group. Hence a reduction in lung CFU of 5 of
more log units implies complete clearance of the recoverable lung CFU following 12 days of
treatment. Therefore, for compounds in Table 3 where a reduction of approximately 5 log
CFU is shown, complete clearance was achieved, and it is not possible to further distinguish
the relative efficacy between these compounds. Reductions of 4 log CFU and higher mean
only very few bacteria were remaining in the lungs of mice and these compounds can
therefore be considered to show similar efficacy to bedaquiline within the range of these
experiments.
Gratifyingly, and in contrast to a previous study of bedaquiline analogues with differently-
8
configured substituted C-unit pyridyl substituents, most of the compounds showed in vivo
activities similar to that of 1, at the same dose, with only compounds 12, 14 and 48 being less
active, showing CFU reductions of less than 4 log units (Table 3). It was interesting to note
that the compounds demonstrating smaller CFU reductions in vivo were not the compounds
with the lowest AUC values and, indeed, several compounds demonstrated CFU reductions
that were at least similar to that effected by bedaquiline (within the limits of the assay), with
substantially lower AUC values. For example, compounds 8, 30 , 31, and 41 demonstrated
CFU reductions within one log unit of the CFU reduction effected by bedaquiline, with AUC
values of 2.69 µg*hr/mL or below, compared to 20.9 µg*hr/ml for 1. In general, for the
tested compounds, where similar efficacy was achieved with lower AUCs, this is likely due
to the lower MICs for these compounds than for bedaquiline, and consistent with previous
work that has demonstrated AUC/MIC as the driver of efficacy against murine TB for
bedaquiline. It may also be due to formation of metabolites that are active against M.tb, as is
1
3
seen for bedaquiline. One exception was compound 10, where efficacy in the range of that
of bedaquiline was seen, with a 4-fold lower AUC, and a similar MIC. In this case, it is
possible that some other factor such as tissue distribution, contributed to the CFU reduction
seen at the lower AUC.
Several compounds presented here, namely 3, 8, 10, 18, 22, 24, 27, 28, 30, 31, 33, 41 45, 46,
5
0 and 51 demonstrated 4 log unit CFU reductions in mice, at an AUC at least approximately
4
-fold lower than that of bedaquiline. This suggests these analogues may have potential to
demonstrate efficacy against TB in patients at lower plasma levels than bedaquiline. Of these,
compounds 8, 10, 24, 41, 45, 46, 50 and 51 exhibited hERG IC s of 9.9 µM or higher,
5
0
compared to 1.6 µM for bedaquiline. Taken together, a higher IC against hERG along with
5
0
a lower efficacious exposure may predict a lower risk of QTc prolongation in patients for
these analogues compared to bedaquiline. Although not all of these compounds showed
higher human microsome Cl than bedaquiline, the possible lower risk of QTc prolongation
int
along with potential for lower overall adverse effects based on a lower efficacious exposure,
resulted in selection of these compounds, as well as others in Table 3 that demonstrated
similar efficacy to bedaquiline with lower potency against hERG, for further evaluation.
Electrocardiography studies in animals and ultimately in human subjects will be needed to
determine whether the decreases in potency against hERG seen here, along with the
decreased plasma levels needed for efficacy for some of these compounds, translates into an
absence of QTc prolongation at a therapeutic dose and exposure.

Finally, the overall good activity profile of this series of 3,5-dialkoxy-4-pyridyl analogues
was utilized to explore the results of changes in the pKa values of the D-unit side chain. This
9
was explored previously by Guillemont et al. in their original paper, where they concluded
that a sidechain with a pKa of >8 was needed to retain activity against the related
mycobacterium, M. smegmatis. We were thus motivated by the idea that utilising a much
weaker base in the side chain in analogue series with intrinsically higher potency might
further attenuate hERG blockade while retaining good M.tb potency. The results in Table 4
suggest that a weaker base did lead to reduced hERG inhibition (compare hERG data for 4
and 54, 13 and 57, 46 and 61), but there was also a large increase in the MICs for inhibition
of M.tb.
Table 4. Exploration of alternative C/D-units
a
b
c
d
No
Y
Z
I
Yld
13
MIC (mg/mL)
hERG clogP
pKa
9
0
MABA LORA
1
5
5
5
2
3
4
5
2,3-diOMe
2,3-diOMe
2,3-diOMe
2,3-diOMe
<0.01
>5
<0.01
>5
2.2
11
5.06
4.99
4.65
5.04
9.05
6.84
6.85
2.85
II 53
III 20
IV 71
0.39
>5
2.37
2.47
8
5
5
5
5
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
2-F, 3-OMe
I
80
0.003
>5
2.42
2.54
0.79
<0.02
>5
2.2
>5
2.4
13
5.80
5.74
5.39
5.78
4.32
9.04
6.83
6.85
2.84
2.80
6
7
8
9
II 92
III 51
IV 51
>30
V
65
3
6
6
6
3
0
1
2
4-aza, 2,3-diOMe
4-aza, 2,3-diOMe II 70
4-aza, 2,3-diOMe III 32
I
47
<0.02
4.2
0.07
2.02
0.07
5.0
0.46
2.37
2.6
5.8
4.77
4.71
4.36
3.29
8.98
6.76
6.83
2.77
4-aza, 2,3-diOMe
V
45
a-c
d
Footnotes for Table 4: As for Table 1. pKa values for the D-unit side chain calculated
using ACD/PhysChem Suite v12: ACD Labs, Toronto, Canada.
3
. Conclusions

In previous publications in this series, we have shown that less lipophilic analogues of 1
clogP 7.25) retain substantial in vitro and in vivo activity against M.tb, down to compounds
(
with a clogP of about 4; this shows that one of the potential drawbacks of 1 can be
ameliorated. In the present paper, we show that substitution of the C-unit naphthalene of 1
with a 3,5-dialkoxy-4-pyridyl group provide analogues with not only higher potency and
substantially lower clogP than 1, but also with a greatly reduced potential cardiotoxicity risk
profile, due to significantly reduced blockade of the hERG potassium channel. This work has
14,15
16
recently allowed the selection of analogues 8 (TBAJ-587)
and 46 (TBAJ-876) as
compounds for pre-clinical development. Based on the preliminary data presented in this
paper, several compounds (including 8 and 46), with activity against murine TB similar to
bedaquiline at the same dose, with lower clogP, higher IC against hERG, and, in most
5
0
cases, higher Cl values in human microsomes, were selected to progress to further studies.
Those advanced studies evaluated the PK in rodents and non-rodents, MICs against clinical
isolates of M. tb, efficacy against a model of chronic murine TB, and toxicity in a preliminary
rat toxicity and toxicokinetics study. Based on that data, compounds 8 and 46 were selected
due to their lower MICs than bedaquiline against clinical isolates of M.tb, efficacy
demonstrated against murine TB at lower exposures than bedaquiline, lower potency against
hERG, predicted higher human clearance, and an acceptable safety margin, based on the safe
exposure in rats compared to the efficacious exposure in mice. Further reports on the
development of these two compounds will be published in due course.
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 CN/20% H O (v/v) in 45 mM
3
2
NH HCO at pH 3.5 and 0.5 mL/min. Purity was determined by monitoring at 330 ± 50 nm
4
2
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
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
4
.1.1. Scheme 1. New A/B units
.1.1.1. 6-Bromo-3-((2,3-dihydro-1H-inden-4-yl)methyl)-2-methoxyquinoline (AB-1)
To a solution of 2,3-dihydro-1H-indene-4-carboxylic acid (6.12 g, 28.4 mmol) in THF (100
mL, dist. Na) at 0 °C was added lithium aluminium hydride (8.09 mL, 85.3 mmol) in small
o
portions. The reaction mixture was stirred at 0 °C for 30 min and then at 20 C for a further
2
5
4 h. The reaction mixture was washed with water (100 mL) and extracted with EtOAc (3 x
0 mL). The organic phase was dried with Na SO and concentrated under reduced pressure
2
4
1
to obtain 2,3-dihydro-1H-inden-4-yl)methanol (2.45 g, 99%) as a yellow oil. H NMR
CDCl ) δ 7.22-7.12 (m, 3H), 4.67 (s, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H),
(
3
2
.09 (p, J = 7.6 Hz, 2H). Found: [M+H-18]=131.5.
To a solution of 2,3-dihydro-1H-inden-4-yl)methanol (4.33 g, 36.4 mmol) in DCM (50 mL)
at 0 °C was added thionyl chloride (2.45 g, 16.5 mmol). The reaction mixture was stirred at

o
2
0 C for 24 h and solvent was removed under reduced pressure. The residue was diluted
with DCM (100 mL) and quenched with ice-water (100 mL). The organic phase was washed
with sat. aq. NaHCO , dried with Na SO and concentrated to give a yellow residue.
3
2
4
Purification by flash column chromatography using hexanes:EtOAc (1:1) gave 4-
1
(
chloromethyl)-2,3-dihydro-1H-indene (2.36 g, 86%) as a colourless oil. H NMR (CDCl ) δ
3
7
7
.22-7.13 (m, 3H), 4.59 (s, 2H), 2.99 (t, J = 7.5 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.11 (p, J =
.6 Hz, 2H). Found: [M+H]=167.5.
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (3.69 g, 12.9 mmol), 4-
chloromethyl)-2,3-dihydro-1H-indene (2.36 g, 14.2 mmol) and Cs CO (9.67 g, 29.7 mmol)
(
2
3
in toluene:DMF (60 mL, 2:1) was degassed under N , then Pd(PPh ) (0.745 g, 0.645 mmol),
2
3 4
was added and the mixture was heated at 90 °C for 3 h. The reaction mixture was cooled to
o
2
0 C, filtered through a plug of Celite, water (150 mL) was added the mixture was extracted
with EtOAc (3 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 a yellow
2
4
residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave 6-
bromo-3-((2,3-dihydro-1H-inden-4-yl)methyl)-2-methoxyquinoline (AB-1) (4.70 g, 99%) as
1
a yellow oil. H NMR (CDCl ) δ 7.71 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.60 (dd,
3
J = 8.9, 2.2 Hz, 1H), 7.33 (s, 1H), 7.18-7.11 (m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 4.11 (s, 3H),
3
.98 (s, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H).
Found: [M+H]=368.5.
4
.1.1.2. 6-Bromo-2-methoxy-3-((5,6,7,8-tetrahydronaphthalen-1-yl)methyl)quinolone (AB-2)
To a solution of 1-tetrahydronaphthoic acid (5.70 g, 32.3 mmol) in THF (100 mL, dist. Na) at
°C was added lithium aluminium hydride (2.46 g, 64.7 mmol) in small portions. The
0
o
reaction mixture was stirred at 0 °C for 30 min and then stirred for further 24 h at 20 C. The
reaction mixture was washed with water (100 mL) and extracted with EtOAc (3 x 50 mL).
The organic phase was dried with Na SO and concentrated under reduced pressure to obtain
2
4
1
(5,6,7,8-tetrahydronaphthalen-1-yl)methanol (5.23 g, 99%) as colourless oil. H NMR
(
CDCl ) δ 7.18 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.67 (s,
3
2
1
H), 2.80 (t, J = 6.2 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 1.88-1.77 (m, 4H). Found: [M+H-
8]=145.5.
To a solution of (5,6,7,8-tetrahydronaphthalen-1-yl)methanol (5.24 g, 32.3 mmol) in DCM
200 mL) at 0 °C was added thionyl chloride (8.45 g, 71.1 mmol). The reaction mixture was
(
o
stirred at 20 C for 24 h, then solvent was removed under reduced pressure. The residue was
diluted with DCM (100 mL) and quenched with ice-water (100 mL). The organic phase was
washed with sat. aq. NaHCO , dried with Na SO and concentrated to give 5-(chloromethyl)-
3
2
4
1
1
,2,3,4-tetrahydronaphthalene (3.25 g, 56%) as a brown oil. H NMR (CDCl ) δ 7.16-7.05
3
(m, 3H), 4.59 (s, 2H), 2.86 (t, J = 6.3 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 1.88-1.77 (m, 4H).
Found: [M+H]=181.6.
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (4.69 g, 16.4 mmol), 5-
(
chloromethyl)-1,2,3,4-tetrahydronaphthalene (3.25 g, 18.0 mmol) and Cs CO (12.29 g, 37.7
2 3
mmol) in toluene:DMF (60 mL, 2:1) was degassed under N , then Pd(PPh ) (0.948 g, 0.82
2
3 4
mmol) was added and the mixture was heated at 90 °C for 3 h. The reaction mixture was
o
cooled to 20 C, filtered through a plug of Celite, water (150 mL) was added and the mixture
was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with
brine (100 mL), dried over Na SO , filtered and concentrated under reduced pressure to
2
4
obtain a yellow residue. Purification by flash column chromatography using hexanes:EtOAc

(
9:1) gave 6-bromo-2-methoxy-3-((5,6,7,8-tetrahydronaphthalen-1-yl)methyl)quinolone (AB-
1
2
2
2
) (4.64 g, 74%) as a white solid. H NMR (CDCl ) δ 7.71-7.69 (m, 2H), 7.60 (dd, J = 8.9,
3
.2 Hz, 1H), 7.23 (s, 1H), 7.12-7.04 (m, 2H), 6.92 (d, J = 6.9 Hz, 1H), 4.11 (s, 3H), 3.96 (s,
H), 2.83 (bs, 2H), 2.57 (bs, 2H), 1.76 (p, J = 3.5 Hz, 4H). Found: [M+H]=382.1.
4
.1.1.3. 6-Bromo-3-(2-fluoro-3-methylbenzyl)-2-methoxyquinoline (AB-3)
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (3.00 g, 10.5 mmol), 1-
bromomethyl)-2-fluoro-3-methylbenzene (S7) (4.24 g, 20.9 mmol) and Cs CO (7.87 g, 24.2
(
2
3
mmol) in toluene:DMF (60 mL, 2:1) was degassed under N , then Pd(PPh ) (0.607 g, 0.525
2
3 4
mmol) was added, and the mixture was heated at 90 °C for 2 h. The reaction mixture was
o
cooled to 20 C, filtered through a plug of Celite, water (150 mL) was added and the mixture
was extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine (100 mL),
dried over Na SO , filtered and concentrated under reduced pressure to obtain a yellow
2
4
residue. Purification by flash column chromatography using hexanes:EtOAc (9:1) gave 6-
bromo-3-(2-fluoro-3-methylbenzyl)-2-methoxyquinoline (AB-3) (2.87 g, 76%) as a white
1
solid. H NMR (CDCl ) δ 7.75 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.9,
3
2
3
.2 Hz, 1H), 7.50 (s, 1H), 7.11-6.96 (m, 3H), 4.09 (s, 3H), 4.03 (s, 2H), 2.28 (d, J = 2.1 Hz,
H). Found: [M+H]=360.6.
4
.1.1.4. 6-Bromo-3-(3-fluoro-4-methoxybenzyl)-2-methoxyquinoline (AB-4)
Borane−dimethylsulfide complex (2.79 mL, 29.40 mmol) and trimethyl borate (3.34 mL,
9.40 mmol) were added to a solution of 3-fluoro-4-methoxybenzoic acid (2.50 g, 14.69
2
o
mmol) in THF (80 mL, dist. Na) at 0 °C, and the solution warmed to 20 C and stirred
overnight. The mixture was then cooled to 0 °C, and quenched with MeOH (10 mL). The
solvent was then evaporated and the residue was partitioned between EtOAc and water. The
organic layer was then dried and evaporated to afford (3-fluoro-4-methoxyphenyl)methanol,
1
(
2
2.35 g, 100%). H NMR (CDCl )  7.11 (1H, dd, J = 2.0, 11.9 Hz), 7.06 (1H, ddd, J = 0.9,
3
.0, 9.1 Hz), 6.94 (1H, dd, J = 8.4, 8.4 Hz), 4.61 (2H, s), 3.89 (3H, s), 1.73 (1H, s). Found:
[
M-OH] =139.7.
To a solution of (3-fluoro-4-methoxyphenyl)methanol (2.35 g, 15.05 mmol) and
o
triethylamine (3.15 mL, 22.58 mmol) in DCM (50 mL, anhydrous) at 20 C was added mesyl
chloride (1.414 mL, 18.06 mmol) dropwise. After 15 min, the reaction was diluted with DCM
(
50 mL) and the organic layer washed with sat. aq. NaHCO , dried and evaporated. The
3
residue was dissolved in acetone (100 mL, anhydrous), lithium bromide (excess) added, and
the mixture heated at reflux for 30 min. The solution was then cooled and the solvent
evaporated, and the residue partitioned between EtOAc and water. The aqueous layer was
extracted twice with EtOAc and the organic layer was dried and evaporated to afford 4-
1
(
(
bromomethyl)-2-fluoro-1-methoxybenzene (3.00 g, 91%). H NMR (CDCl )  7.16-7.07
3
2H, m), 6.90 (1H, dd, J = 8.3, 8.4 Hz), 4.45 (2H, s), 3.89 (3H, s).
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (3.51 g, 12.45 mmol), 4-
bromomethyl)-2-fluoro-1-methoxybenzene (3.00 g, 13.69 mmol) and cesium carbonate (8.93
(
g, 27.40 mmol) in toluene (60 mL, anhydrous) and DMF (30 mL, anhydrous) was purged
with nitrogen. Pd(PPh ) (0.58 g, 0.50 mmol) was then added, the mixture purged with
3
4
nitrogen then heated to 80 °C under nitrogen for 5 hours. The reaction was partitioned
between EtOAc and water and the organic fraction was dried and evaporated. Column
chromatography (19:1 hexanes/EtOAc) gave 6-bromo-3-(3-fluoro-4-methoxybenzyl)-2-
1
methoxyquinoline (AB-4) (2.10 g, 41%). H NMR (CDCl )  7.76 (1H, d, J = 2.2 Hz), 7.69
3

(1H, d, J = 12.3 Hz), 7.62 (1H, dd, J = 2.2, 8.9 Hz), 7.49 (1H, s), 7.00-6.86 (3H, m), 4.07
(3H, s), 3.95 (2H, s), 3.88 (3H, s). Found: [M+H]=376.0
4
.1.1.5. 3-(Benzo[d][1,3]dioxol-4-ylmethyl)-6-bromo-2-methoxyquinoline (AB-5)
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (1.5 g, 5.32 mmol), 4-
bromomethyl)benzo[d][1,3]dioxole (1.2 g, 5.59 mmol) and 2M Na CO (5 mL) in DME (25
(
2
3
mL) was purged with nitrogen. Pd(PPh ) (0.31 g, 0.27 mmol) was added, the mixture was
3
4
purged with nitrogen then heated to 95 °C under nitrogen for 4 h. The reaction was
partitioned between EtOAc and water and the organic fraction was dried and evaporated.
Column chromatography with hexanes:EtOAc (100:0 to 95:5) gave 3-(benzo[d][1,3]dioxol-4-
1
ylmethyl)-6-bromo-2-methoxyquinoline (AB-5) (1.52 g, 76%). H NMR (CDCl ) δ 7.77 (d, J
3
=
6
[
2.2 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.53 (s, 1H) , 6.82-
.73 (m, 2H), 6.70 (dd, J = 7.4, 1.7 Hz, 1H), 5.94 (s, 2H), 4.09 (s, 3H), 3.98 (s, 2H). Found:
M+H]=373.1
4
.1.1.6. 3-(Benzofuran-7-ylmethyl)-6-bromo-2-methoxyquinoline (AB-6)
A solution of methyl benzofuran-7-carboxylate(3.59 g, 20.4 mmol) in Et O (100 mL, dist.
2
o
Na) at 0 °C was treated with LiAlH (1.54 g, 40.6 mmol) then stirred at 20 C for 3 h and
4
quenched with ice. The mixture was partitioned between Et O and sat. aq. sodium potassium
2
tartrate and then filtered through Celite. The aqueous layer was extracted with Et O and the
2
organic phases were combined and dried. Column chromatography (0-5% EtOAc:DCM)
1
gave benzofuran-7-ylmethanol (2.60 g, 86%). H NMR (CDCl ) δ 7.65 (d, J = 2.2 Hz, 1H),
3
7
.56 (dd, J = 7.7, 1.2 Hz, 1H), 7.31 (dd, J = 7.3, 0.6 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.80 (d,
J = 2.2 Hz, 1H), 5.02 (d, J = 6.2 Hz, 2H), 1.93 (t, J = 6.2 Hz, 1H).
A solution of benzofuran-7-ylmethanol (4.72 g, 31.8 mmol) in DCM (100 mL, anhydrous) at
0
°C was treated sequentially with triethylamine (8.9 mL, 63.9 mmol) then mesyl chloride
(3.70 mL, 47.8 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 (27.6 g, 318 mmol) was added and the mixture was refluxed for 0.5 h
and then evaporated. The residue was partitioned between DCM and water; the organic
fraction was dried and evaporated. Column chromatography (DCM) gave 7-
1
(
bromomethyl)benzofuran (6.08 g, 90%). H NMR (CDCl ) δ 7.69 (d, J = 2.2 Hz, 1H), 7.57
3
(dd, J = 7.7, 1.2 Hz, 1H), 7.32 (dd, J = 7.4, 0.7 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.80 (d, J =
2
.2 Hz, 1H), 4.81 (s, 2H).
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (8.00 g, 28.4 mmol), 7-
(bromomethyl)benzofuran (5.99 g, 28.4 mmol) and Cs CO (18.5 g, 56.7 mmol) in toluene
2 3
(
100 mL) and DMF (50 mL) was purged with nitrogen. Pd(PPh ) (0.66 g, 0.57 mmol) was
3
4
added, the 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 3:1 hexanes:DCM eluted impurities, then elution
with 1:1 hexanes:DCM then DCM gave 3-(benzofuran-7-ylmethyl)-6-bromo-2-
1
methoxyquinoline (AB-6) (6.95 g, 67%). H NMR (CDCl ) δ 7.71 (d, J = 2.2 Hz, 1H), 7.68
3
(
d, J = 8.8 Hz, 1H), 7.58 -7.62 (m, 2H), 7.50-7.54 (m, 2H) , 7.20 (t, J = 7.4 Hz, 1H), 7.13 (dd,
J = 7.4, 0.6 Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 4.32 (s, 2H), 4.10 (s, 3H). Found:
M+H]=368.8
[
4
.1.1.7. 5-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-N,N-diethylpyridin-2-amine (AB-7)

To a solution of freshly distilled N,N,N,N,-tetramethylpiperidine (1.60 mL, 9.56 mmol) in
freshly distilled THF (13 mL) was added at -30 C under nitrogen , n-BuLi (4.40 mL, 8.76
o
mmol) dropwise. The mixture was maintained at about -30 C for 15 minutes, then cooled to -
7
8 C. A solution of 6-bromo-2-methoxyquinoline (1.90 g, 7.96 mmol) in dry THF (15 mL)
was added dropwise at -78 C. The resultant organic mixture was stirred at the same
temperature for 75 minutes. A solution of 6-(diethylamino)nicotinaldehyde (1.42 g, 7.96
mmol) in dry THF (6 mL) was added dropwise at -78 C, the reaction mixture remained
orange brown, stirred at -78 C for 2.5 hours. The mixture was quenched with acetic acid
(
0.68 mL) at -65 C. Water was added, the aqueous mixture was extracted with ethyl acetate
(2x), and the combined extract was washed with brine, dried (MgSO ) and concentrated in
4
vacuo to give the crude product as a yellow solid. Flash chromatography of the crude product
using 10-100% ethyl acetate in hexane as eluent afforded product (6-bromo-2-
methoxyquinolin-3-yl)(6-(diethylamino)pyridin-3-yl)methanol (1.90 g, 57%) as an off-white
1
solid. H NMR (CDCl )  8.15 (d, J = 2.4 Hz, 1H), 8.01 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H),
3
7
.70-7.64 (m, 2H), 7.39 (dd, J = 8.9, 2.5 Hz, 1H), 6.43 (d, J = 8.9 Hz, 1H), 5.94 (d, J = 3.7
Hz, 1H), 4.04 (s, 3H), 3.53-3.47 (m, 4H), 2.65 (d, J = 3.9 Hz, 1H), 1.17 (t, J = 7.0 Hz, 6H).
To a sparingly soluble solution of 2-methoxyquinolin-3-yl)(6-(diethylamino)pyridin-3-
yl)methanol (1.90 g, 4.57 mmol) in freshly distilled THF (19 mL) was added at 2 C under
nitrogen sodium borohydride (0.86 g, 23.0 mmol) in 3 portions over 10 minutes. The mixture
was stirred at 2-4 C for 1 hour. The mixture was cooled to 2 C again, aluminium chloride
(1.83 g, 13.7 mmol) was added in 4 batches over 15 minutes. The mixture was stirred at 2 C
for 10 minutes, then refluxed for 2 hours. The mixture was then quenched with water
cautiously at 2 C, until gas evolution ceased. The white slurry was filtered through celite.
The milky white filtrate was diluted in water, and the organic phase was collected. The
aqueous phase was extracted with ethyl acetate (3x). The organic extract was washed with
brine, dried (MgSO ) and concentrated in vacuo to furnish the crude product as a brownish
4
residue. Flash chromatography of the crude product using 10% ethyl acetate in hexane as
eluent afforded product 5-((6-bromo-2-methoxyquinolin-3-yl)methyl)-N,N-diethylpyridin-2-
1
amine (AB-7) (1.39 g, 76%) as a white solid. H NMR (CDCl )  8.06 (d, J = 2.1 Hz, 1H),
3
7
7
.76 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.52 (s, 1H),
.28 (dd, J = 8.7, 2.4 Hz, 1H), 6.42 (dd, J = 8.7, 0.3 Hz, 1H), 4.09 (s, 3H), 3.85 (s, 2H), 3.50
(q, J = 7.0 Hz, 4H), 1.18 (t, J = 7.0 Hz, 6H).
4
.1.1.8. 6-Bromo-3-((5-isopropoxy-2-methoxypyridin-3-yl)methyl)-2-methoxyquinoline (AB-
8
)
A mixture of 5-hydroxy-2-methoxynicotinaldehyde (1.00 g, 6.53 mmol) and potassium
carbonate (1.35 g, 9.80 mmol) in DMF (30 mL, anhydrous) was heated at 50 °C for 10 min.
Isopropyl iodide (0.78 mL, 7.84 mmol) was then added and the mixture stirred at this
temperature for 2 hours. The resultant solution was diluted with EtOAc and washed with
brine three times. The organic layer was dried and evaporated to afford 5-isopropoxy-2-
1
methoxynicotinaldehyde (0.90 g, 71%). H NMR (CDCl )  10.34 (1H, s), 8.07 (1H, d, J =
3
3
.2 Hz), 7.66 (1H, d, J = 3.2 Hz), 4.48 (1H, sp, J = 6.1 Hz), 4.03 (3H, s), 1.33 (6H, d, J = 4.8
Hz).
A mixture of isopropoxy-2-methoxynicotinaldehyde (0.90 g, 4.61 mmol) and sodium
o
borohydride (0.35 g, 9.22 mmol) in MeOH (15 mL, anhydrous) was stirred at 20 C for 1
hour. The solvent was then removed and the residue partitioned between EtOAc and water.
The organic layer was dried and evaporated. Column chromatography with 9:1

1
hexanes/EtOAc afforded (5-isopropoxy-2-methoxypyridin-3-yl)methanol (0.68 g, 75%). H
NMR (CDCl )  7.72 (1H, s), 7.25 (1H, d, J = 3 Hz), 4.61 (2H, s), 4.42 (1H, sp), 3.93 (3H, s),
3
2
.92-2.19 (1H, br s), 1.32 (6H, d, J = 6.1 Hz).
To a solution of (5-isopropoxy-2-methoxypyridin-3-yl)methanol (0.68 g, 3.45 mmol) and
o
triethylamine (0.72 mL, 5.18 mmol) in DCM (10 mL, anhydrous) at 20 C was added mesyl
chloride (0.32 mL, 4.14 mmol) dropwise. After 15 min, the reaction was diluted with DCM
(
10 mL) and the organic layer washed with sat. NaHCO , dried and evaporated. The residue
3
was redissolved in acetone (20 mL, anhydrous), lithium bromide (excess) added, and the
mixture heated at reflux for 30 min. The solution was then cooled and the solvent evaporated,
and the residue partitioned between EtOAc and water. The aqueous layer was extracted twice
with EtOAc and the organic layer was dried and evaporated to afford 3-(bromomethyl)-5-
1
isopropoxy-2-methoxypyridine (0.70 g, 78%). H NMR (CDCl )  7.76 (1H, dd, J = 2.6, 3.4
3
Hz), 7.25 (1H, dd, J = 2.4, 2.4 Hz), 4.5 (2H, d, J = 2.2 Hz), 4.42 (1H, sp, J = 2.6, 6.0 Hz),
3
.96 (3H, d, J = 2.9 Hz), 1.32 (6H, dd, J = 3.0, 6.1 Hz).
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (0.80 g, 2.82 mmol), 3-
(
(
bromomethyl)-5-isopropoxy-2-methoxypyridine (0.70 g, 2.69 mmol) and cesium carbonate
1.75 g, 5.38 mmol) in toluene (10 mL, anhydrous) and DMF (5 mL, anhydrous) was purged
with nitrogen. Pd(PPh ) (0.12 g, 0.11 mmol) was then added, and the mixture then heated to
3
4
8
0 °C under nitrogen for 4 hours. The reaction was partitioned between EtOAc and water
and the organic fraction was dried and evaporated. Column chromatography (19:1
hexanes/EtOAc) gave 6-bromo-3-((5-isopropoxy-2-methoxypyridin-3-yl)methyl)-2-
1
methoxyquinoline (AB-8) (0.57 g, 48%). H NMR (CDCl )  7.77 (1H, d, J = 2.2 Hz), 7.71
3
(1H, d, J = 2.9 Hz), 7.69 (1H, d, J = 8.9 Hz), 7.62 (1H, dd, J = 2.2, 8.9 Hz), 7.56 (1H, s), 7.02
(1H, d, J = 2.9 Hz), 4.38 (1H, sp, J = 6.0 Hz), 4.08 (3H, s), 3.92 (2H, s), 3.90 (3H, s), 1.29
(6H, d, J = 6.1 Hz).
4
.1.1.9. 6-Bromo-2-methoxy-3-((2,4,5-trimethoxypyridin-3-yl)methyl)quinolone (AB-9)
To a mixture of 2,6-dimethoxypyridin-3-ol (8.05 g, 51.9 mmol) and imidazole (7.42 g,
o
1
6
08.99 mmol) in DMF (130 mL) at 20 C was added triisopropylsilyl chloride (13.33 mL,
o
2.23 mmol), and the resultant mixture stirred at 20 C for 2 hours. The solution was then
partitioned between EtOAc and water, and the aqueous layer extracted three times. The
combined organic layers were washed with brine three times, dried and evaporated. Column
chromatography with 19:1 hexanes/EtOAc afforded the product 2,6-dimethoxy-3-
1
(
6
(triisopropylsilyl)oxy)pyridine (15.59 g, 96%). H NMR (CDCl )  7.07 (1H, d, J = 8.2 Hz),
3
.13 (1H, d, J = 8.2 Hz), 3.92 (3H, s), 3.86 (3H, s), 1.27-1.18 (3H, m), 1.08 (18H, d, J = 7.1
Hz). Found: [M+H]=312.8.
To a solution of 2,6-dimethoxy-3-((triisopropylsilyl)oxy)pyridine (8.00 g, 25.69 mmol) and
N,N-diisopropylamine (0.18 mL, 1.28 mmol) in THF (100 mL, dist. Na) at -40 °C under
nitrogen was added n-BuLi (15.41 mL, 30.83 mmol) dropwise. The resultant solution was
stirred at -40 °C for 5 min, and then warmed to 0 °C and stirred at this temperature for a
further 3 hours. The solution was then again cooled to -40 °C, and formylpiperidine (4.28
o
mL, 38.54 mmol) was added dropwise, and the mixture stirred at 20 C for another 1 hour.
Acetic acid (8 mL) was added and the solvent was removed in vacuo. The resultant mixture
was partitioned between EtOAc and water, and the organic fraction dried and evaporated.
Column chromatography with 49:1 hexanes/EtOAc afforded the product 2,6-dimethoxy-5-
1
(
(triisopropylsilyl)oxy)nicotinaldehyde (7.55 g, 87%). H NMR (CDCl )  10.17 (1H, s), 7.51
3

(
1H, s), 4.02 (3H, s), 4.01 (3H, s), 1.30-1.19 (3H, m), 1.08 (18H, d, J = 7.3 Hz). Found: [M-
+
CHO] = 312.8.
Tetrabutylammonium fluoride in THF (1N, 33.36 mL, 33.36 mmol) was added to a solution
of 2,6-dimethoxy-5-((triisopropylsilyl)oxy)nicotinaldehyde (7.55 g, 22.24 mmol) in THF (35
o
mL, dist. Na) at 0°C. The reaction was then warmed to 20 C and stirred for 4 hours. The
solvent was removed and the residue partitioned between EtOAc and water. The aqueous
layer was extracted with EtOAc three times, and the organic layer dried and evaporated.
Column chromatography with DCM followed by 3:1 DCM/EtOAc afforded the product 5-
1
hydroxy-2,6-dimethoxynicotinaldehyde (3.15 g, 77%). H NMR (CDCl )  10.20 (1H, s),
3
7
.59 (1H, s), 5.15-4.80 (1H, br s), 4.10 (3H, s), 4.01 (3H, s).
A mixture of 5-hydroxy-2,6-dimethoxynicotinaldehyde (3.15 g, 17.20 mmol) and potassium
carbonate (3.57 g, 25.80 mmol) in DMF (80 mL, anhydrous) was heated at 50 °C for 10 min.
Methyl iodide (1.29 mL, 20.64 mmol) was then added and the mixture stirred at this
temperature for 2 hours. The resultant solution was diluted with EtOAc and washed with
brine three times. The organic layer was dried and evaporated to afford the product 2,5,6-
1
trimethoxynicotinaldehyde (3.39 g, 100%). H NMR (CDCl )  10.21 (1H, s), 7.53 (1H, s),
3
4
.10 (3H, s), 4.02 (3H, s), 3.87 (3H, s).
A solution of N,N,N,N-tetramethylpiperidine (3.59 mL, 21.03 mmol) in THF (40 mL, dist.
Na) was cooled to -40 °C, n-BuLi (10.52 mL, 21.03 mmol) was added and the solution was
stirred at -40 °C for 15 min, then cooled to -78 °C. A solution of 6-bromo-2-
methoxyquinoline (17.53 mmol) in THF (40 mL, dist. Na) was added dropwise, the orange
solution was stirred at -78 °C for 1.5 hours, then a solution of 2,5,6-
trimethoxynicotinaldehyde (3.42 g, 17.53 mmol) in THF (40 mL, dist. Na) was added. The
mixture was stirred at -78 °C for 2 hours, then acetic acid (2.5 mL) was added and the
o
solution was allowed to warm to 20 C. The solvent was removed and the residue partitioned
between EtOAc and water, and the organic fraction was dried and evaporated. Column
chromatography with 9:1 hexanes/EtOAc followed by 4:1 hexanes/EtOAc gave the product
(
6-bromo-2-methoxyquinolin-3-yl)(2,5,6-trimethoxypyridin-3-yl)methanol (5.50 g, 72%) as a
1
white solid. H NMR (CDCl )  7.85 (1H, d, J = 2.1 Hz), 7.79 (1H, s), 7.70 (1H, d, J = 8.9
Hz), 7.65 (1H, dd, J = 2.1, 8.9 Hz), 7.15 (1H, s), 6.14 (1H, d, J = 5.2 Hz), 4.08 (3H, s), 4.02
3
(3H, s), 3.90 (3H, s), 3.78 (3H, s), 3.48 (1H, d, J = 5.4 Hz). Found: [M+H]=436.1
Trifluoroacetic acid (11.30 mL, 148.2 mmol) and triethylsilane (17.76 mL, 111.2 mmol) were
added sequentially to a solution of (6-bromo-2-methoxyquinolin-3-yl)(2,5,6-
trimethoxypyridin-3-yl)methanol (5.35 g, 12.35 mmol) in DCM (125 mL) and the solution
o
was stirred for 1 hour at 20 C, then ice water was added. The solution was partitioned
between sat. aq. NaHCO and DCM and the aqueous fraction was extracted with DCM. The
3
organic fractions were combined, dried and evaporated. Column chromatography with 9:1
hexanes/EtOAc gave 6-bromo-2-methoxy-3-((2,4,5-trimethoxypyridin-3-yl)methyl)quinolone
1
(
(
AB-9) (4.45 g, 86%) as a white solid. H NMR (CDCl )  7.76 (1H, d, J = 2.2 Hz), 7.68
3
1H, d, J = 8.9 Hz), 7.60 (1H, dd, J = 2.2, 8.4 Hz), 7.49 (1H, s), 7.05 (1H, s), 4.09 (3H, s),
4
.01 (3H, s), 3.89 (5H, s), 3.79 (3H, s). Found: [M+H]=419.0
4
.1.1.10. 6-Bromo-3-((2,5-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline (AB-10)
To a solution of 6-methoxypyridin-3-ol (3.20 g, 25.57 mmol) in E (50 mL, anhydrous) at 0

C was added sodium hydride (60% in mineral dispersion, 1.23 g, 30.69 mmol) in portions.
The mixture was warmed to 20 C and stirred for 1 h. Chloromethyl ethyl ether (2.73 ml,
o

o
2
9.41 mmol) was then added, and the resultant mixture stirred at 20 C for a further 2 h. The
reaction was diluted with water and extracted with EtOAc (x3). The organic layer was
washed with brine (x3), dried and evaporated. Column chromatography with 9:1 X4:EtOAc
1
afforded 5-(ethoxymethoxy)-2-methoxypyridine (4.09 g, 87%). H NMR (CDCl )  7.95 (d, J
3
=
3.0 Hz, 1H), 7.34-7.31 (m, 1H), 6.67 (d, J = 9.0 Hz, 1H), 5.13 (s, 2H), 3.88 (s, 3H), 3.72 (q,
J = 7.1 Hz, 2H), 1.22 (t, J = 7.0 Hz, 3H). Found: [M+H]=184.4.
To a solution of 5-(ethoxymethoxy)-2-methoxypyridine (6.20 g, 33.84 mmol) and
diisopropylamine (0.24 ml, 1.69 mmol) in THF (100 mL, dist. Na) at -40 C under nitrogen
was added n-BuLi (25.4 mL, 50.76 mmol) dropwise. The resultant solution was stirred at -40

C for 5 min, and then warmed to 0 C and stirred at this temperature for a further 3 h. The
solution was then again cooled to -40 C, and n-formylpiperidine (6.76 ml, 60.91 mmol) was
added dropwise, and the mixture stirred at 20 C for another 1 h. Acetic acid (15 mL) was
o
added and the solvent was removed in vacuo. The resultant mixture was partitioned between
EtOAc and water, and the organic fraction dried and evaporated. Column chromatography
with 9:1 X4:EtOAc afforded 5-(ethoxymethoxy)-2-methoxyisonicotinaldehyde (4.00 g,
1
5
3
6%). H NMR (CDCl )  10.43 (s, 1H), 8.27 (s, 1H), 7.07 (d, J = 0.4 Hz, 1H), 5.30 (s, 2H),
3
.92 (s, 3H), 3.78 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).
A solution of 5-(ethoxymethoxy)-2-methoxyisonicotinaldehyde (4.00 g, 18.85 mmol) and 3M
HCl (60 mL) in THF (40 mL, dist. Na) was heated at 40 C for 3 h. The solution was then
cooled, diluted with water, and the pH adjusted to 7 using potassium carbonate. The aqueous
layer was then extracted with EtOAc three times, and the organic layer dried and evaporated.
Column chromatography with 9:1 X4:EtOAc afforded 5-hydroxy-2-
1
methoxyisonicotinaldehyde (2.50 g, 87%). H NMR (CDCl )  9.97 (d, J = 0.7 Hz, 1H), 9.46
3
(
s, 1H), 8.08 (s, 1H), 6.93 (d, J = 0.6 Hz, 1H), 3.94 (s, 3H).
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (2.50 g, 16.33 mmol) and potassium
carbonate (3.39 g, 24.45 mmol) in DMF (80 mL, anhydrous) was heated at 50 C for 10 min.
Methyl iodide (1.22 ml, 19.59 mmol) was then added and the mixture stirred at this
temperature for 2 h. The resultant solution was diluted with EtOAc and washed with brine
three times. The organic layer was dried and evaporated to afford 2,5-
1
dimethoxyisonicotinaldehyde (2.25 g, 82%). H NMR (CDCl )  10.4 (s, 1H), 8.01 (s, 1H),
3
7
.07 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H). Found [M+MeOH]= 200.4
A mixture of 2,5-dimethoxyisonicotinaldehyde (2.25 g, 13.46 mmol) and sodium borohydride
o
(
1.02 g, 26.92 mmol) in MeOH (50mL, anhydrous) was stirred at 20 C for 1 h. The solvent
was then removed and the residue partitioned between EtOAc and water. The organic layer
1
was dried and evaporated to afford (2,5-dimethoxypyridin-4-yl)methanol (2.17 g, 95%). H
NMR (CDCl )  7.70 (s, 1H), 6.77 (s, 1H), 4.66 (d, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.87 (s,
3
3
H), 2.23 (t, J = 6.4 Hz, 1H).
To a solution of (2,5-dimethoxypyridin-4-yl)methanol (2.05 g, 12.12 mmol) and triehylamine
o
(
2.53 ml, 18.18 mmol) in DCM (35 mL, anhydrous) at 20 C was added methanesulfonyl
chloride (1.13 ml, 14.50 mmol) dropwise. After 15 min, the reaction was diluted with DCM
20 mL) and the organic layer washed with sat. sodium hydrogen carbonate, dried and
evaporated. The residue was redissolved in acetone (70 mL, anhydrous), Lithium bromide
10 g, excess) added, and the mixture heated at reflux for 30 min. The solution was then
cooled and the solvent evaporated, and the residue partitioned between EtOAc and water. The
(
(

aqueous layer was extracted twice with EtOAC and the organic layer was dried and
1
evaporated to afford 4-(bromomethyl)-2,5-dimethoxypyridine (2.54 g, 90%). H NMR
(
CDCl )  7.75 (s, 1H), 6.75 (s, 1H), 4.40 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
3
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (2.80 g, 9.95 mmol), 4-
bromomethyl)-2,5-dimethoxypyridine (2.54 g, 10.94 mmol) and cesium carbonate (6.50 g,
9.9 mmol) in toluene (50 mL, anhydrous) and DMF (25 mL, anhydrous) was purged with
nitrogen. Pd(PPh ) (0.046 g, 0.40 mmol) was then added, the mixture purged with nitrogen
(
1
3
4
then heated to 80 C under nitrogen for 4 h. The reaction was partitioned between EtOAc
and water and the organic fraction was dried and evaporated. Column chromatography (19:1
x4:EtOAc) gave 6-bromo-3-((2,5-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline (AB-
1
1
0) (2.20 g, 51%). H NMR (CDCl )  7.77 (d, J = 2.2 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 8.9
3
Hz, 1H), 7.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.53 (s, 1H), 6.48 (s, 1H), 4.07 (s, 3H), 3.97 (s, 2H),
3
.86 (s, 3H), 3.83 (s, 3H). Found: [M+H]=389.7.
4
.1.1.11. 3-((2,6-Bis(methylthio)pyridin-4-yl)methyl)-6-bromo-2-methoxyquinoline (AB-11)
2
,6-Dichloroisonicotinic acid (4.00 g, 20.8 mmol) in DMF (40 ml) was added sodium
thiomethoxide (4.38 g, 65.5 mmol) at 0 C in batches. Mixture was stirred at 150 C for 18 h.
Water (40 ml) was added to the resultant solution and pH was adjusted to 3 using 2M HCl
solution. Extracted with EtOAc (3x), dried with MgSO , filtered and the solvent was
4
evaporated to give 2,6-bis(methylthio)isonicotinic acid (4.01 g, 90%) as an orange solid. The
solid was recrystallized from methanol and was used without further purification for the next
1
step. H NMR (CDCl )  7.44 (s, 2H), 2.61 (s, 6H). Found: [M+H]=216.5.
3
Borane dimethyl sulfide complex (8.09 ml, 85.3 mmol) and trimethyl borate (9.68 ml, 85.3
mmol) were added to a solution of 2,6-bis(methylthio)isonicotinic acid (6.12 g, 28.4 mmol)
in THF (100 mL, dist. Na) at 0 C. The solution was then warmed to room temperature and
o
was stirred for 21 h at 20 C. The reaction mixture was cooled to 0 C, MeOH (20 ml) was
added to quench the reaction and the solvent was evaporated in the fume hood. The residue
was partitioned between EtOAc and water, extracted with EtOAc (3x), dried with MgSO4,
filtered and the solvent was evaporated. Column chromatography (4:1 hexanes:EtOAc) gave
(
2,6-bis(methylthio)pyridin-4-yl)methanol (4.56 g, 80%) as a white solid. M.p. 88 – 90 C.
1
H NMR (CDCl )  6.87 (s, 2H), 4.61 (s, 2H), 2.58 (s, 6H). Found: [M+H]=202.5.
3
Phosphorus tribromide (2.97 ml, 31.4 mmol) was added to a solution of (2,6-
bis(methylthio)pyridin-4-yl)methanol (5.26 g, 26.1 mmol) in DCM (300 mL) at 0 C. The
o
reaction mixture was stirred at 20 C for 18 h then solvent was evaporated. The residue was
diluted with DCM (100 mL) and quenched with ice, the organic layer was washed with sat.
aq. NaHCO , dried with MgSO , filtered and the solvent was evaporated. Column
3
4
chromatography (6:1 hexanes:EtOAc) gave 4-(bromomethyl)-2,6-bis(methylthio)pyridine
1
(
2
3.44 g, 50%) as a white solid. M.p. 100 – 102 C. H NMR (CDCl )  6.86 (s, 2H), 4.23 (s,
3
H), 2.58 (s, 6H). Found: [M+H]=266.4.
A mixture of 4-(bromomethyl)-2,6-bis(methylthio)pyridine (3.44 g, 15.0 mmol), (6-bromo-2-
methoxyquinolin-3-yl)boronic acid (4.31 g, 15.0 mmol), and Cs CO (11.24 g, 34.5 mmol)
2
3
in toluene-DMF (60 ml, 2:1) was degassed under N , then added Pd(PPh ) (0.867 g, 0.750
2
3 4
o
mmol), and heated at 90 C for 2 h. Reaction mixture was cooled to 20 C, filtered through a
plug of celite, added water and extracted with EtOAc (x4). Organic layer washed with brine,
dried with Na SO , filtered and the solvent was evaporated to give a yellow residue.
2
4

Purification by flash column chromatography with silica using hexane:EtOAc (9:1) to gave 3-
(2,6-bis(methylthio)pyridin-4-yl)methyl)-6-bromo-2-methoxyquinoline (AB-11) (2.90 g,
(
4
1
6%) as a white solid. M.p. 129 – 131 C. H NMR (CDCl )  7.80 (d, J = 2.1 Hz, 1H), 7.70
3
(d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.9, 2.2 Hz), 7.57 (s, 1H), 6.72 (s, 2H), 4.05 (s, 3H), 3.87 (s,
2
H), 2.57 (s, 6H). Found: [M+H]=421.8.
4
.1.1.12. 3-((2,6-Bis(ethylthio)pyridin-4-yl)methyl)-6-bromo-2-methoxyquinoline (AB-12)
Sodium hydride (60% w/w, 1.44 g, 36.1 mmol) in DMF (25 ml) at 0 C was added
ethanethiol (2.70 ml, 36.1 mmol) dropwise. The mixture foamed up as hydrogen gas was
released. The mixture was stirred at 0 C for 15 minutes, then a solution of 2,6-
dichloroisonicotinic acid (2.05 g, 11.6 mmol) in anhydrous DMF (9 mL) was added dropwise
at 0 C. The mixture was then stirred at 150 C for 17 hours. The mixture was diluted in
water, dissolving the white salts. The aqueous mixture was purged with air to remove most of
the stench. 2M hydrochloric acid was added until pH reached ~3, when white solids crashed
out. The solids were collected by filtration, washed with ice-cold water, dried to yield 2,6-
bis(ethylthio)isonicotinic acid (2.82 g, 100%) as light yellow solid which was used directly in
1
the next step. H NMR (CDCl ) δ 7.40 (s, 2H), 3.19 (q, J = 7.3 Hz, 4H), 1.39 (t, J = 7.3 Hz,
3
6
H). Found: [M+H]=244.5.
Borane dimethyl sulfide complex (3.30 ml, 34.8 mmol) and trimethyl borate (3.90 ml, 34.8
mmol) were added to a solution of 2,6-bis(ethylthio)isonicotinic acid (2.82 g, 11.6 mmol) in
o
THF (100 mL, dist. Na) at 0 C. The solution was then warmed to 20 C and was stirred for
o
1
8 h at 20 C. The reaction mixture was cooled to 0 C, MeOH (20 ml) was added to quench
the reaction and the solvent was evaporated in the fume hood. The residue was partitioned
between EtOAc and water, extracted with EtOAc (3x), dried with MgSO , filtered and the
4
solvent was evaporated. Column chromatography (4:1 hexanes:EtOAc) gave (2,6-
1
bis(ethylthio)pyridin-4-yl)methanol (2.50 g, 94%) as a white solid. H NMR (CDCl )  6.87
3
(s, 2H), 4.61 (s, 2H), 2.58 (s, 6H). Found: [M+H]=202.5.
To a solution of (2,6-bis(ethylthio)pyridin-4-yl)methanol (2.48 g, 10.8 mmol) in anhydrous
DCM (42 mL) was added triethylamine (2.20 mL, 16.2 mmol) dropwise, followed by
methanesulfonyl chloride (1.10 mL, 14.2 mmol). The mixture was stirred at 0 C for 10
o
minutes, then allowed to stir at 20 C for 1 hour. The mixture was quenched with saturated
sodium bicarbonate solution. The aqueous mixture was extracted with dichloromethane (2x).
The combined extract was washed with brine, dried with MgSO and concentrated to afford
4
the crude product as a yellow oil. The crude intermediate was diluted in acetone (84 mL).
Lithium chloride (1.85 g, 43.64 mmol) was added. The suspension was stirred at room
temperature overnight. The mixture was concentrated in vacuo and adsorbed onto silica.
Flash chromatography using a mixture of 98:2 hexane/ethyl acetate gave 4-(chloromethyl)-
1
2
2
,6-bis(ethylthio)pyridine (2.26 g, 84%) as a light yellow oil. H NMR (CDCl )  6.87 (s,
3
H), 4.61 (s, 2H), 2.58 (s, 6H). Found: [M+H]=202.5.
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (2.56 g, 9.10 mmol), 4-
chloromethyl)-2,6-bis(ethylthio)pyridine (2.25 g, 9.10 mmol) and Cs CO (5.93 g, 18.19
(
2
3
mmol) in toluene-DMF (60 ml, 2:1) was degassed under N , then added Pd(PPh ) (0.52 g,
2
3 4
o
0
.45 mmol), and heated at 90 C for 1.5 h. Reaction mixture was cooled to 20 C, filtered
through a plug of celite, added water and extracted with EtOAc (x4). Organic layer washed
with brine, dried with Na SO , filtered and the solvent was evaporated to give a yellow
2
4
residue. Purification by flash column chromatography with silica using hexane:EtOAc (9:1)

gave 3-((2,6-bis(ethylthio)pyridin-4-yl)methyl)-6-bromo-2-methoxyquinoline (AB-12) (1.80
1
g, 47%) as a white solid. H NMR (CDCl )  7.80 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.9 Hz,
3
1
6
H), 7.65 (dd, J = 8.9, 2.2 Hz), 7.57 (s, 1H), 6.72 (s, 2H), 4.05 (s, 3H), 3.87 (s, 2H), 2.57 (s,
H). Found: [M+H]=421.8.
4
1
.1.1.13. 6-Bromo-3-((2-isopropoxy-5-methoxypyridin-4-yl)methyl)-2-methoxyquinoline (AB-
3)
Sodium metal (2.04 g, 85.0 mmol) was added to a solution of isopropanol (150 mL) and the
mixture stirred at reflux for 3 h. The solution was then cooled to room temperature and 5-
bromo-2-fluoropyridine (10.0 g, 56.67 mmol) was added, and the reaction heated at 80 °C for
0
.5 h. The solvent was then removed and the residue partitioned between EtOAc and water,
and the organic extract was dried and evaporated to afford 5-bromo-2-isopropoxypyridine
1
(
6
10.9 g, 89%). H NMR (CDCl )  8.16 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 8.8, 2.6 Hz, 1H),
3
.58 (d, J = 8.8 Hz, 1H), 5.23 (sep, J = 6.2 Hz, 1H), 1.34 (s, 3H), 1.32 (s, 3H). Found:
[
M+H]=215.5.
To a solution of 5-bromo-2-isopropoxypyridine (9.85 g, 45.6 mmol) in THF (200 mL, dist.
Na) at -78 °C was added n-BuLi (2.0 M in cyclohexane, 36.48 ml, 72.96 mmol) dropwise
over 10 min. The reaction was stirred for 20 min and then trimethyl borate (13.24 ml, 72.96
mmol) was added dropwise over 5 min. The resulting mixture was stirred for 2 h at -78 °C,
then peracetic acid solution (32 wt. % in dilute acetic acid, 25.69 ml, 72.96 mmol) was added.
After 10 min at -78 °C, the reaction was warmed to 0 °C and stirred for 1 h. The reaction was
then quenched with aqueous sodium bisulfite and stirred for 15 min at 0 °C. The solvent was
then concentrated, sodium bicarbonate added and the aqueous layer extracted with EtOAc.
The combined organic extracts were dried and evaporated. Column chromatography with 4:1
1
x4:EtOAc afforded 6-isopropoxypyridin-3-ol (5.40 g, 65%). H NMR (CDCl )  7.76 (dd, J =
3
3
.1, 0.4 Hz, 1H), 7.17 (dd, J = 8.9, 3.1 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 6.16 (br s, 1H), 5.09
(sep, J = 6.1 Hz, 1H), 1.34 (s, 3H), 1.32 (s, 3H).
To a solution of 6-isopropoxypyridin-3-ol (6.00 g, 32.97 mmol) in DMF (80 mL, anhydrous)
at 0 °C was added sodium hydride (60% in mineral dispersion, 1.57 g, 39.54 mmol) in
o
portions. The mixture was warmed to 20 C and stirred for 1 h. Chloromethyl ethyl ether
o
(
3.50 ml, 37.71 mmol) was then added, and the resultant mixture stirred at 20 C for a further
2
h. The reaction was diluted with brine (100 mL) and extracted with EtOAc (x3) times. The
organic layer was washed with brine (x3), dried and evaporated. Column chromatography
1
with 19:1 x4:EtOAc afforded 5-(ethoxymethoxy)-2-isopropoxypyridine (6.50 g, 82%). H
NMR (CDCl )  7.94 (d, J = 3.0 Hz, 1H), 7.33-7.30 (m, 1H), 6.61 (d, J = 8.9 Hz, 1H), 5.20
3
(
(
sep, J = 6.2 Hz, 1H), 5.14 (s, 2H), 3.73 (q, J = 7.0 Hz, 2H), 1.33 (s, 3H), 1.32 (s, 3H), 1.23
t, J = 7.1 Hz, 3H). Found: [M+H]=211.5.
To a solution of 5-(ethoxymethoxy)-2-isopropoxypyridine (6.50 g, 26.97 mmol) and
diisopropylamine (0.19 ml, 1.35 mmol) in THF (80 mL, dist. Na) at -40 °C under nitrogen
was added n-BuLi (2.0 M in cyclohexane, 16.18 ml, 32.36 mmol) dropwise. The resultant
solution was stirred at -40 °C for 5 min, and then warmed to 0 °C and stirred at this
temperature for a further 3 h. The solution was then again cooled to -40 °C, and n-
formylpiperidine (4.49 ml, 40.46 mmol) was added dropwise, and the mixture stirred at 20 C
for another 1 h. Acetic acid (12 mL) was added and the solvent was removed in vacuo. The
resultant mixture was partitioned between EtOAc and water, and the organic fraction dried
o
and evaporated. Column chromatography with 19:1 x4:EtOAc afforded 5-(ethoxymethoxy)-
1
2
-isopropoxyisonicotinaldehyde (5.51 g, 76%). H NMR (CDCl )  10.41 (s, 1H), 8.25 (s,
3

1
H), 7.01 (d, J = 0.5 Hz, 1H), 5.29 (s, 2H), 5.23-5.16 (m, 1H), 3.79 (q, J = 7.1 Hz, 2H), 1.34
(s, 3H), 1.32 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
A solution of 5-(ethoxymethoxy)-2-isopropoxyisonicotinaldehyde (5.51 g, 20.48 mmol) and
M HCl (65 mL) in THF (45 mL, dist. Na) was heated at 40 °C for 1.5 h. The solution was
3
then cooled, diluted with water, and the pH adjusted to 7 using sodium hydrogen carbonate.
The aqueous layer was then extracted with EtOAc (x3), and the organic layer dried and
1
evaporated to afford 5-hydroxy-2-isopropoxyisonicotinaldehyde (3.71 g, 100%). H NMR
(
1
CDCl )  9.96 (s, 1H), 8.06 (s, 1H), 6.87 (s, 1H), 5.21 (sep, J = 6.2 Hz, 1H), 1.34 (s, 3H),
3
.32 (s, 3H).
A mixture of 5-hydroxy-2-isopropoxyisonicotinaldehyde (3.80 g, 20.99 mmol) and potassium
carbonate (4.35 g, 31.49 mmol) in DMF (100 mL, anhydrous) was heated at 50 °C for 10
min. Methyl iodide (1.57 ml, 25.19 mmol) was then added and the mixture stirred at this
temperature for 2 h. The resultant solution was diluted with EtOAc and washed with brine
(
x3). The organic layer was dried and evaporated. Column chromatography with 19:1
1
x4:EtOAc afforded 2-isopropoxy-5-methoxyisonicotinaldehyde (2.60 g, 63%). H NMR
(
1
CDCl )  10.42 (s, 1H), 7.99 (s, 1H), 7.02 (d, J = 0.5 Hz, 1H), 5.17 (sep, J = 6.2 Hz, 1H),
3
.34 (s, 3H), 1.32 (s, 3H).
A mixture of 2-isopropoxy-5-methoxyisonicotinaldehyde (2.60 g, 13.32 mmol) and sodium
o
borohydride (1.01 g, 26.65 mmol) in methanol (50 mL, anhydrous) was stirred at 20 C for 1
h. The solvent was then removed and the residue partitioned between EtOAc and water. The
organic layer was dried and evaporated to afford (2-isopropoxy-5-methoxypyridin-4-
1
yl)methanol (2.59 g, 99%). H NMR (CDCl )  7.68 (s, 1H), 6.71 (s, 1H), 5.17 (sep, J = 6.2
3
Hz, 1H), 4.64 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 2.40 (t, J = 6.1 Hz, 1H), 1.33 (s, 3H), 1.31 (s,
3
H).
To a solution of (2-isopropoxy-5-methoxypyridin-4-yl)methanol (2.59g, 13.14 mmol) and
o
triethylamine (2.74 ml, 19.71 mmol) in DCM (40 mL, anhydrous) at 20 C was added
methanesulfonyl chloride (1.23 ml, 15.77 mmol) dropwise. After 15 min, the reaction was
diluted with DCM (40 mL) and the organic layer washed with sat. sodium hydrogen
carbonate, dried and evaporated. The residue was redissolved in acetone (80 mL, anhydrous),
Lithium bromide (10 g, excess) added, and the mixture heated at reflux for 30 min. The
solution was then cooled and the solvent evaporated, and the residue partitioned between
EtOAc and water. The aqueous layer was extracted with EtOAC (x2) and the organic layer
was dried and evaporated to afford 4-(bromomethyl)-2-isopropoxy-5-methoxypyridine (3.42
1
g, 100%). H NMR (CDCl )  7.73 (s, 1H), 6.69 (s, 1H), 5.17 (sep, J = 6.2 Hz, 1H), 4.38 (s,
3
2
H), 3.90 (s, 3H),1.33 (s, 3H), 1.31 (s, 3H).
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (3.92 g, 13.92 mmmol), 4-
(
(
bromomethyl)-2-isopropoxy-5-methoxypyridine (3.45 g, 13.26 mmol) and cesium carbonate
8.64 g, 26.52 mmol) in toluene (50 mL, anhydrous) and DMF (25 mL, anhydrous) was
purged with nitrogen. Pd(PPh ) (0.61 g, 0.53 mmol) was then added, the mixture purged
3
4
with nitrogen then heated to 80 °C under nitrogen for 4 h. The reaction was partitioned
between EtOAc and water and the organic fraction was dried and evaporated. Column
chromatography (19:1 x4:EtOAc) gave 6-bromo-3-((2-isopropoxy-5-methoxypyridin-4-
1
yl)methyl)-2-methoxyquinoline (AB-13) (2.85 g, 49%). H NMR (CDCl )  7.77 (d, J = 2.2
3
Hz, 1H), 7.72 (s, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.54 (s, 1H),

6
1
.38 (s, 1H), 5.17 (sep, J = 6.2 Hz, 1H), 4.07 (s, 3H), 3.96 (s, 2H), 3.83 (s, 3H), 1.31 (s, 3H),
.29 (s, 3H).
4
.1.1.14. 6-Bromo-3-((2-cyclobutoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline
(AB-14)
A solution of methyl 2-hydroxy-6-methoxyisonicotinate (3.00 g, 16.4 mmol) in DMF (50
mL, anhydrous) was treated with K CO (4.52 g, 32.7 mmol) and bromocyclobutane (2.00
2
3
o
mL, 25.0 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 combined organic fractions were
washed with water, dried and evaporated. Column chromatography (DCM) gave methyl 2-
1
cyclobutoxy-6-methoxyisonicotinate (2.215 g, 57%) as a colourless oil. H NMR (CDCl ) δ
3
6
3
.84 (d, J = 1.0 Hz, 1H), 6.79 (d, J = 1.0 Hz, 1H), 5.08 (pd, J = 7.4, 0.8 Hz, 1H), 3.91 (s, 3H),
.90 (s, 3H), 2.42-2.52 (m, 2H), 2.12-2.24 (m, 2H), 1.80-1.90 (m, 1H), 1.62-1.75 (m, 1H).
Found: [M + H] = 238.2.
A solution of LiOH (0.71 g, 29.6 mmol) in water (20 mL) was added to a solution of methyl
2
-cyclobutoxy-6-methoxyisonicotinate (2.205 g, 9.29 mmol) in MeOH (20mL) and THF (20
o
mL); the solution was stirred at 20 C for 18 h and then evaporated. The residue was
dissolved in water (80 mL) and acidified to pH 3 with 2 M HCl. The resulting precipitate was
filtered and dried to give 2-cyclobutoxy-6-methoxyisonicotinic acid (2.02 g, 97%) as a white
1
6
solid. M.p. 170-171 °C. H NMR (DMSO-d ) δ 13.56 (bs, 1H), 6.74 (d, J = 1.0 Hz, 1H), 6.67
(d, J = 1.0 Hz, 1H), 5.07 (pd, J = 7.1, 0.7 Hz, 1H), 3.85 (s, 3H), 2.37-2.46 (m, 2H), 2.14-2.22
(m, 2H), 1.74-1.83 (m, 1H), 1.59-1.72 (m, 1H). Found: [M + H] = 224.2.
Trimethyl borate (1.03 mL, 9.0 mmol) and borane dimethyl sulphide complex were added
sequentially to a solution of 2-cyclobutoxy-6-methoxyisonicotinic acid (1.01 g, 4.52 mmol)
o
in anhydrous THF (20 mL) at 0 °C. The solution was stirred at 20 C for 18 h and then
quenched with MeOH. Removal of the solvent gave an oil, chromatography (3:1
hexanes:EtOAc) of the crude product gave (2-cyclobutoxy-6-methoxypyridin-4-yl)methanol
1
(
0.91 g, 96%) as a colourless oil. H NMR (CDCl ) δ 6.29 (d, J = 0.9 Hz, 1H), 6.23 (d, J =
3
0
.9 Hz, 1H), 5.06 (pd, J = 7.2, 0.9 Hz, 1H), 4.62 (d, J = 6.2 Hz, 2H), 3.88 (s, 3H), 2.41-2.49
(m, 2H), 2.11-2.22 (m, 2H), 1.79-1.89 (m, 1H), 1.63-1.75 (m, 2H). Found: [M + H] = 210.2
A solution of (2-cyclobutoxy-6-methoxypyridin-4-yl)methanol 0.842 g, 4.04 mmol) in DCM
(
25 mL) at 0 °C was treated sequentially with Et N (2.25 mL, 16.1 mmol) and mesyl chloride
3
(0.47 mL, 6.1 mmol), the solution was stirred for 1 h at 0 °C and then partitioned with water,
the organic fraction was dried and evaporated. The residue was dissolved in acetone (50 mL),
LiBr (3.50 g, 40.3 mmol) was added and the mixture was refluxed for 0.5 h and 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-
1
cyclobutoxy-6-methoxypyridine (0.994 g, 90%) as a colourless oil. H NMR (CDCl ) δ 6.30
3
(d, J = 1.0 Hz, 1H), 6.25 (d, J = 1.0 Hz, 1H), 5.07 (pd, J = 7.1, 0.9 Hz, 1H), 4.27 (s, 2H), 3.88
(s, 3H), 2.41-2.49 (m, 2H), 2.11-2.22 (m, 2H), 1.79-1.89 (m, 1H), 1.61-1.75 (m, 1H). Found:
[M + H] = 272, 274.
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (1.010 g, 3.58 mmol), 4-
(
bromomethyl)-2-cyclobutoxy-6-methoxypyridine (0.975 g, 3.58 mmol) and Cs CO (2.33 g,
2 3
7
.2 mmol) in toluene/DMF (2:1, 50 mL) was purged with nitrogen. Pd(PPh ) (0.083 g, 0.072
3 4
mmol) was added and the mixture was heated to 80 °C for 3h under an atmosphere of
nitrogen. The mixture was partitioned between EtOAc and water, the organic fraction was

dried and evaporated. Column chromatography using a gradient of 3:1 hexanes:DCM to
DCM gave 6-bromo-3-((2-cyclobutoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline
o
1
(
AB-14) (1.195 g, 78%) as a white solid. M.p. 101-102 C. H NMR (CDCl ) δ 7.77 (d, J =
3
2
0
2
1
.2 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.9, 2.2 Hz, 1H), 7.52 (s, 1H), 6.16 (d, J =
.3 Hz, 1H), 6.10 (d, J = 0.3 Hz, 1H), 5.06 (pd, J = 7.9, 0.9 Hz, 1H), 4.06 (s, 3H), 3.90 (s,
H), 3.87 (s, 3H), 2.38-2.48 (m, 2H), 2.09-2.21 (m, 2H), 1.77-1.87 (m, 1H), 1.62-1.72 (m,
H). Found: [M + H] = 429.1, 431.1.
4
1
.1.1.15. 6-Bromo-3-((2-ethoxy-6-isopropoxypyridin-4-yl)methyl)-2-methoxyquinoline (AB-
5)
Potassium carbonate (8.65 g, 125 mmol) and 2-iodopropane (12.8 mL, 128 mmol) were
added to a solution of ethyl 2-ethoxy-6-hydroxyisonicotinate (10.82 g, 51.2 mmol) in
o
anhydrous DMF (125 mL) and the mixture was stirred at 20 C for 48 h. 2-Iodopropane (12.8
mL, 128 mmol) and potassium carbonate (8.65 g, 125 mmol) were added and the mixture was
stirred for a further 24 h and then partitioned between DCM and water. The organic fraction
was dried and evaporated, chromatography using DCM as an eluent gave ethyl 2-ethoxy-6-
1
isopropoxyisonicotinate (11.557 g, 89%) as a colourless oil. H NMR (CDCl ) δ 6.81 (s, 2H),
3
5
1
.23 (sp, J = 6.2 Hz, 1H), 4.36 (t, J = 7.2 Hz, 2H), 4.32 (t, J = 7.1 Hz, 2H), 1.33-1.42 (m,
2H). Found: [M+H]=254.2.
A solution of LiOH (3.25 g, 136 mmol) in water (60 mL) was added to a solution of ethyl 2-
ethoxy-6-isopropoxyisonicotinate (11.424 g, 45.1 mmol) in THF (60 mL) and MeOH (60
o
mL), the solution was stirred at 20 C for 60 h then evaporated. The residue was dissolved in
water (200 mL) and the solution was adjusted to pH 6 with 2 M HCl. The oily solid was
extracted with EtOAc, the organic fractions were washed with water, dried and evaporated to
give 2-ethoxy-6-isopropoxyisonicotinic acid (10.034 g, 99%) as a white solid. M.p. >300 °C.
1
6
H NMR (DMSO-d ) δ 13.48 (bs, 1H), 6.66 (d, J = 1.0 Hz, 1H), 6.64 (d, J = 1.0 Hz, 1H),
.17 (sp, J = 6.2 Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 1.28-1.34 (m, 9H). No diagnostic peak in
5
the mass spectrum.
Trimethylborate (3.03 mL, 26.7 mmol) and then borane-dimethylsulfide (2.53 mL, 26.7
mmol) were added to a solution of 2-ethoxy-6-isopropoxyisonicotinic acid (3.00 g, 13.3
o
mmol) in THF (50 mL, dist. Na) at 0 °C and the mixture was stirred at 20 C for 18 hr. The
solution was cooled to 0 °C and methanol was cautiously added to quench the reaction.
Removal of the solvent gave a solid, this was partitioned between EtOAc and water, and the
organic fraction was dried and evaporated. Column chromatography (3:1 hexanes:EtOAc)
1
gave (2-ethoxy-6-isopropoxypyridin-4-yl)methanol (2.72 g, 97%) as a colourless oil. H
NMR (CDCl ) δ 6.24 (s, 1H), 6.23 (s, 1H), 5.21 (sp, J = 6.2 Hz, 1H), 4.60 (d, J = 6.2 Hz,
3
2
6
H), 4.30 (q, J = 7.0 Hz, 2H), 1.70 (t, J = 6.2 Hz, 1H), 1.38 (t, J =7.0 Hz, 3H), 1.34 (d, J =
.2 Hz, 6H). Found: [M+H]=212.2.
A solution of (2-ethoxy-6-isopropoxypyridin-4-yl)methanol (2.60 g, 12.3 mmol) in DCM (50
mL, anhydrous) at 0 °C was treated sequentially with triethylamine (3.43 mL, 24.6 mmol)
then mesyl chloride (1.43 mL, 18.5 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 (10.7 g, 123 mmol) was added and the
mixture was refluxed for 1 h and then evaporated. The residue was partitioned between DCM
and water; the organic fraction was dried and evaporated. Column chromatography (DCM)
1
gave 4-(bromomethyl)-2-ethoxy-6-isopropoxypyridine (3.04 g, 100%) as a colourless oil. H

NMR (CDCl ) δ 6.26 (s, 1H), 6.25 (s, 1H), 5.20 (sp, J = 6.2 Hz, 1H), 4.26-4.33 (m, 4H), 1.38
3
(t, J = 7.0 Hz, 3H), 1.34 (d, J = 6.2 Hz, 6H). Found: [M+H]=274.1.
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (3.27 g, 11.6 mmol), (4-
bromomethyl)-2-ethoxy-6-isopropoxypyridine (3.18 g, 11.6 mmol) and Cs CO (7.56 g, 23.2
(
2
3
mmol) in toluene (66 mL) and DMF (33 mL) was purged with nitrogen. Pd(PPh ) (0.27 g,
3
4
0
.23 mmol) was added, the 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 3:1 hexanes:DCM eluted
impurities, then elution with DCM gave 6-bromo-3-((2-ethoxy-6-isopropoxypyridin-4-1
yl)methyl)-2-methoxyquinoline (AB-15) (3.42 g, 68%) as white solid. M.p. 78-80 °C. H
NMR (CDCl ) δ 7.77 (d, J = 2.1 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz,
3
1
2
H), 7.58 (s, 1H), 6.11 (s, 1H), 6.10 (s, 1H), 5.20 (sp, J = 6.2 Hz, 1H), 4.28 (q, J = 7.1 Hz,
H), 4.06 (s, 3H), 3.89 (s, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.32 (d, J = 6.2 Hz, 6H). Found:
[
M+H]=431.1.
4
.1.1.16. 6-Bromo-2-methoxy-3-((2,3,5-trimethoxypyridin-4-yl)methyl)quinolone (AB-16)
To a solution of 2,6-dimethoxypyridine (10 g, 71.84 mmol) and N,N-diisopropylamine (0.50
mL, 3.59 mmol) in THF (200 mL, dist. Na) at -40°C under nitrogen was added n-BuLi (43.10
mL, 86.21 mmol) dropwise. The resultant solution was stirred at -40°C for 5 min, and then
warmed to 0 °C and stirred at this temperature for a further 3 hours. The solution was then
again cooled to -40 °C, and triisopropylborate (24.87 mL, 107.76 mmol) was added
o
dropwise, and the mixture stirred at 20 C for another 1 hour. Water (50 mL) was added and
the solvent was removed in vacuo. To the residue was added 1M NaOH (100 mL) and the
aqueous layer washed with EtOAc (2 x 100 mL). The aqueous layer was then acidified to pH
3
and a solid precipitated. This solid was filtered and dried to afford 2,6-dimethoxypyridin-3-
1
yl)boronic acid (8.10 g, 61%). H NMR (DMSO-d )  7.87 (1H, d, J = 7.9 Hz), 6.36 (1H, d, J
=
6
7.9 Hz), 3.90 (3H, s), 3.87 (3H, s).
To a solution of 2,6-dimethoxypyridin-3-yl)boronic acid (8.00 g, 43.49 mmol) in THF (150
mL, dist. Na) at 0 °C was added dropwise 32% peracetic acid in acetic acid (21.53 mL, 86.98
o
mmol) over 10 min. The resultant solution was stirred at 20 C. for 2 h. A 10% solution of
o
sodium sulfite (75 mL) was then added and the mixture stirred at 20 C for 0.5 hour. The
solvent was evaporated and the residue partitioned between EtOAc and water. The aqueous
layer was extracted twice and the organic layer dried and evaporated. Column
chromatography with 9:1 hexanes/EtOAc afforded 2,6-dimethoxypyridin-3-ol (6.05 g, 90%).
1
H NMR (CDCl )  7.12 (1H, d, J = 8.3 Hz), 6.21 (1H, d, J = 8.2 Hz), 4.90 (1H, s), 7.00 (3H,
3
s), 3.86 (3H, s). Found: [M+H]=156.7.
To a solution of 2,6-dimethoxypyridin-3-ol (6.45 g, 40.97 mmol) in DMF (70 mL,
anhydrous) at 0 °C was added 60% sodium hydride in mineral oil (41.97 g, 9.16 mmol) in
o
portions. The mixture was warmed to 20 C and stirred for 1 hour. 1-Chloro-2-
methoxyethane (4.37 mL, 47.11 mmol) was then added, and the resultant mixture stirred at
o
2
0 C for a further 2 hours. The reaction was diluted with brine (100 mL) and extracted with
EtOAc three times. The organic layer was washed with brine three times, dried and
evaporated. Column chromatography with 19:1 hexanes/EtOAc afforded 3-(ethoxymethoxy)-
1
2
,6-dimethoxypyridine (8.14 g, 93%). H NMR (CDCl )  7.41-7.33 (1H, m), 6.26-6.17 (1H,
3
m), 5.15 (2H, d, J = 1.9 Hz), 3.98 (3H, d, J = 1.8 Hz), 3.87 (3H, d, J = 2.0 Hz), 3.77 (2H, dq,
J = 1.8, 7.1 Hz), 1.22 (3H, dt, J = 2.9, 7.0 Hz).

To a solution of 3-(ethoxymethoxy)-2,6-dimethoxypyridine (4.00 g, 18.78 mmol) and N,N-
diisopropylamine (0.13 mL, 0.94 mmol) in THF (60 mL, dist. Na) at -40 °C under nitrogen
was added n-BuLi (2.0 M in cyclohexane, 14.09 mL, 28.17 mmol) dropwise. The resultant
solution was stirred at -40 °C for 5 min, and then warmed to 0 °C and stirred at this
temperature for a further 3 hours. The solution was then again cooled to -40 °C, and 1-
formylpiperidine (3.75 mL, 33.80 mmol) was added dropwise, and the mixture stirred at 20
o
C for another 1 hour. Acetic acid (7.5 mL) was added and the solvent was removed in vacuo.
The resultant mixture was partitioned between EtOAc and water, and the organic fraction
dried and evaporated. Column chromatography with 19:1 hexanes/EtOAc afforded 3-
1
(
(
(
ethoxymethoxy)-2,6-dimethoxyisonicotinaldehyde (2.30 g, 51%). H NMR (CDCl )  10.39
3
1H, s), 6.61 (1H, s), 6.19 (2H, s), 4.02 (3H, s), 3.88 (3H, s), 3.78 (2H, q, J = 10.1 Hz), 1.21
3H, t, J = 7.1 Hz).
A solution of 3-(ethoxymethoxy)-2,6-dimethoxyisonicotinaldehyde (2.30 g, 9.54 mmol) and
M hydrochloric acid (60 mL) in THF (30 mL, dist. Na) was heated at 40 °C for 1.5 hours.
3
The solution was then cooled, diluted with water, and the pH adjusted to 7 using NaHCO3.
The aqueous layer was then extracted with EtOAc three times, and the organic layer dried
and evaporated. Column chromatography with 19:1 hexanes/EtOAc afforded 3-hydroxy-2,6-
1
dimethoxyisonicotinaldehyde (1.36 g, 78%). H NMR (CDCl )  9.96 (1H, s), 9.61 (1H, s),
3
6
.46 (1H, s), 4.06 (3H, s), 3.91 (3H, s).
A mixture of 3-hydroxy-2,6-dimethoxyisonicotinaldehyde (1.35 g, 7.38 mmol) and potassium
carbonate (1.53 g, 11.07 mmol) in DMF (40 mL, anhydrous) was heated at 50 °C for 10 min.
Methyl iodide (0.56 mL, 8.86 mmol) was then added and the mixture stirred at this
temperature for 2 hours. The resultant solution was diluted with EtOAc and washed with
brine three times. The organic layer was dried and evaporated to afford the product 2,3,6-
1
trimethoxyisonicotinaldehyde (1.40 g, 96%). H NMR (CDCl )  10.40 (1H, s), 6.58 (1H, s),
3
4
.04 (3H, s), 3.93 (3H, s), 3.91 (3H, s).
A mixture of 2,3,6-trimethoxyisonicotinaldehyde (1.40 g, 7.11 mmol) and sodium
borohydride (0.54 g, 14.21 mmol) in MeOH (30 mL, anhydrous) was stirred at 20 C for 1
hour. The solvent was then removed and the residue partitioned between EtOAc and water.
o
The organic layer was dried and evaporated to afford the product (2,3,6-trimethoxypyridin-4-
1
yl)methanol (1.35 g, 95%). H NMR (CDCl )  6.30 (1H, s), 4.68 (2H, d, J = 5.6 Hz), 3.99
3
(
3H, s), 3.88 (3H, s), 3.79 (3H, s), 2.21 (1H, t, J = 5.9 Hz).
To a solution of (2,3,6-trimethoxypyridin-4-yl)methanol (1.35 g, 6.78 mmol) and
o
triethylamine (1.42 mL, 10.78 mmol) in DCM (20 mL, anhydrous) at 20 C was added mesyl
chloride (0.63 mL, 8.14 mmol) dropwise. After 15 min, the reaction was diluted with DCM
(
20 mL) and the organic layer washed with sat. aq. NaHCO , dried and evaporated. The
3
residue was dissolved in acetone (40 mL, anhydrous), lithium bromide (excess) added, and
the mixture heated at reflux for 30 min. The solution was then cooled and the solvent
evaporated, and the residue partitioned between EtOAc and water. The aqueous layer was
extracted twice with EtOAc and the organic layer was dried and evaporated to give the
1
product 4-(bromomethyl)-2,3,6-trimethoxypyridine (1.69 g, 95%). H NMR (CDCl )  6.27
3
(
1H, s), 4.40 (2H, s), 3.98 (3H, s), 3.87 (3H, s), 3.87 (3H, s). Found: [M+H]=262.5
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (1.89 g, 6.69 mmol), 4-
bromomethyl)-2,3,6-trimethoxypyridine (1.67 g, 6.37 mmol) and cesium carbonate (4.15 g,
2.74 mmol) in toluene (40 mL, anhydrous) and DMF (20 mL, anhydrous) was purged with
(
1

nitrogen. Pd(PPh ) (0.29 g, 0.26 mmol) was then added, the mixture purged with nitrogen
3
4
then heated to 80 °C under nitrogen for 4 hours. The reaction was partitioned between
EtOAc and water and the organic fraction was dried and evaporated. Column
chromatography (19:1 hexanes/EtOAc) gave the product 6-bromo-2-methoxy-3-((2,3,5-
1
trimethoxypyridin-4-yl)methyl)quinoline (AB-16) (1.44 g, 54%). H NMR (CDCl ) δ 7.76
3
(1H, d, J = 2.2 Hz), 7.68 (1H, d, J = 8.9 Hz), 7.61 (1H, dd, J = 2.2, 8.8 Hz), 7.54 (1H, s), 6.04
(1H, s), 4.07 (3H, s), 4.00 (3H, s), 4.39 (2H, s), 3.85 (3H, s), 3.72 (3H, s). Found:
[M+H]=420.0
4
.1.1.17. 4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-methoxy-N,N-dimethylpyridin-2-
amine (AB-17)
To a solution of (2-(dimethylamino)-6-methoxypyridin-4-yl)methanol (3.30 g, 18.1 mmol) in
anhydrous DCM (54 mL) was added at 2 °C under nitrogen triethylamine (3.8 mL, 27.2
mmol) dropwise, followed by mesyl chloride (1.7 mL, 21.7 mmol). The mixture was stirred
o
from 2 °C for 10 min, then at 20 C. for 2 hours. The mixture was quenched with sat. aq.
NaHCO solution. The aqueous mixture was extracted with DCM (2x) and the combined
3
extract was washed with brine, dried (MgSO ) and concentrated to afford the crude product
4
as a beige solid. The crude intermediate was dissolved in acetone (60 mL). Lithium bromide
(1.53 g, 36.2 mmol) was added and the suspension was refluxed for 2 hours. Flash
chromatography using a mixture of 3-5% Et O in hexanes as eluent gave 4-(bromomethyl)-6-
2
1
methoxy-N,N-dimethylpyridin-2-amine (3.78 g, 85%) as a mobile yellow oil. H NMR
(
CDCl )  6.02 (1H, d, J = 0.8 Hz), 6.00 (1H, d, J = 0.4 Hz), 4.27 (2H, s), 3.88 (3H, s), 3.06
3
(6H, s).
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (4.34 g, 15.4 mmol), 4-
bromomethyl)-6-methoxy-N,N-dimethylpyridin-2-amine (3.77 g, 115.4 mmol) and cesium
(
carbonate (10.03 g, 30.8 mmol) in a mixture of toluene (40 mL) and DMF (20 mL) was
purged with nitrogen. Pd(PPh ) (0.890 g, 0.774 mmol) was added and the mixture was
3
4
purged again with nitrogen and heated at 85 °C under nitrogen for 3.5 hours. The mixture
was partitioned between water and EtOAc and the mixture was extracted with EtOAc (2x).
The extract was washed with water (2x), brine, dried (MgSO ) and concentrated to afford the
4
crude product as a brown solid which was chromatographed using 3-10% Et O in hexanes as
2
eluent to yield the product 4-((6-bromo-2-methoxyquinolin-3-yl)methyl)-6-methoxy-N,N-
1
dimethylpyridin-2-amine (AB-17) (3.69 g, 60%) as a light yellow solid. H NMR (CDCl ) 
7
5
3
.76 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 8.8 Hz), 7.61 (1H, dd, J = 2, 8.8 Hz), 7.55 (1H, s),
.92 (1H, s), 5.86 (1H, s), 4.07 (3H, s), 3.87 (5H, s), 3.04 (6H, s). Found: [M+H]=402.0
4
.1.1.18. 4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-ethoxy-N,N-dimethylpyridin-2-
amine (AB-18)
To a glass tube was charged ethyl 2-chloro-6-ethoxyisonicotinate (WO 2010/080864) (1.00 g,
4
.37 mmol), diphenylphosphino-1,1'-binaphthol (0.44 g, 0.70 mmol) and cesium carbonate
(1.99 g, 6.12 mmol) under continuous nitrogen flow. Anhydrous toluene (24 mL) was added.
The mixture was purged with nitrogen 5 min. Palladium acetate (0.079 g, 0.35 mmol) was
added, the mixture was purged again with nitrogen. Dimethylamine in THF (2N, 2.6 mL,
5
.246 mmol) was added and the mixture was sealed in the tube and heated at 80 °C overnight.
The mixture was filtered through Celite, washing with EtOAc and the filtrate was
concentrated in vacuo to yield the crude product as a dark red liquid. Flash chromatography
using 2-4% Et O in hexanes gave ethyl 2-(dimethylamino)-6-ethoxyisonicotinate (0.85 g,
2
1
8
2%) as a light yellow oil. H NMR (CDCl )  6.60 (1H, d, J = 0.8 Hz), 6.51 (1H, d, J = 0.8
3

Hz), 4.35 (2H, q, J = 7.0 Hz), 4.33 (2H, q, J = 7.1 Hz), 3.09 (6H, s), 1.38 (3H, t, J = 7.2 Hz),
.37 (3H, t, J = 7.2 Hz).
1
To a solution of ethyl 2-(dimethylamino)-6-ethoxyisonicotinate (4.40 g, 18.50 mmol) in
freshly distilled THF (90 mL) was added at -78 °C under nitrogen lithium aluminium hydride
o
(
0.91 g, 24.0 mmol) in 3 batches. The mixture was stirred at -78 °C for 15 min then at 20 C
for 1 hour. The mixture was quenched cautiously with water at 2 °C until gas evolution
ceased. 1M NaOH (32 mL) was added and the mixture was stirred for 1 hour, then the
aqueous mixture was diluted with water and extracted with EtOAc (3x). The combined
organic extract was washed with brine, dried (Na SO ) and concentrated to give the product,
2
4
which was purified via flash chromatography eluting with mixtures of 6:1 then 4:1
hexanes/EtOAc to give the alcohol intermediate (3.27 g, 90%) as a light yellow oil. The
material was used directly in the next step without further characterisation.
To a solution of the alcohol intermediate (3.27 g, 16.7 mmol) in anhydrous DCM (50 mL)
was added at 2 °C under nitrogen triethylamine (3.5 mL, 25.0 mmol) dropwise, followed by
mesyl chloride (1.6 mL, 20.0 mmol). The mixture was stirred from 2 °C for 10 min, then at
o
2
0 C for 0.5 hour. The mixture was quenched with sat. aq. NaHCO solution. The aqueous
3
mixture was extracted with DCM (3x) and the combined extract was washed with brine, dried
and concentrated to afford the crude product as a brown oil. This was diluted in acetone (60
mL), lithium bromide (1.42 g) was added. And the suspension was refluxed for 2 hours. Flash
chromatography using a mixture of 2-3% Et O in hexanes as eluent gave 4-(bromomethyl)-6-
2
1
ethoxy-N,N-dimethylpyridin-2-amine (3.84 g, 89%) as a mobile yellow oil. H NMR (CDCl )
3

6.011 (1H, s), 5.99 (1H, s), 4.30 (2H, q, J = 6.8 Hz), 4.27 (2H, s), 3.05 (6H, s), 1.37 (3H, t,
J = 7.2 Hz).
A mixture of (6-bromo-2-methoxyquinolin-3-yl)boronic acid (4.13 g, 14.7 mmol), 4-
(bromomethyl)-6-ethoxy-N,N-dimethylpyridin-2-amine (3.80 g, 14.7 mmol) and cesium
carbonate (9.58 g, 29.4 mmol) in a mixture of toluene (40 mL) and DMF (20 mL) was purged
with nitrogen. Pd(PPh ) (0.68 g) was added. The mixture was purged again with nitrogen
3
4
and heated at 85 °C under nitrogen for 3 hours. The mixture was partitioned between water
and EtOAc and the aqueous mixture was extracted with EtOAc (2x).The extract was washed
with water (2x), brine, dried and concentrated to afford the crude product as a brown oil. This
was chromatographed using 3-10% Et O in hexanes as eluent to give the product as a yellow
2
solid (3.83 g), which was triturated in diethyl ether to afford yield 4-((6-bromo-2-
methoxyquinolin-3-yl)methyl)-6-ethoxy-N,N-dimethylpyridin-2-amine (AB-18) (3.51 g,
1
5
7%) as a pale yellow solid. H NMR (CDCl )  7.76 (1H, d, J = 2.2 Hz), 7.68 (1H, d, J = 8.8
3
Hz), 7.61 (1H, dd, J = 2.2, 8.8 Hz), 7.55 (1H, s), 5.91 (1H, s), 5.84 (1H, s), 4.30 (2H, q, J =
7
.1 Hz), 4.07 (3H, s), 3.87 (2H, s), 3.03 (6H, s), 1.36 (3H, t, J = 7.1 Hz).
4
.1.1.19. 4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-(ethylthio)-N,N-dimethylpyridin-2-
amine (AB-19)
To a glass tube was charged methyl 2-chloro-6-(dimethylamino)isonicotinate (WO
2
1
010/100475) (2.44 g, 11.40 mmol), rac-bis(diphenylphosphino)-1,1'-binaphthol (0.71 g,
.140 mmol) and cesium carbonate (4.43 g, 13.60 mmol) under continuous nitrogen flow.
Anhydrous toluene (30 mL) was added. The mixture was purged with nitrogen for 5 min
Palladium acetate (0.26 g, 1.158 mmol) was added and the mixture was purged again with
nitrogen. Ethanethiol (1.0 mL, 13.60 mmol) was added and the mixture was sealed in the tube
and heated at 150 °C for 22 hours. The mixture was filtered through Celite, washing with
EtOAc. The filtrate was concentrated in the fume hood by heating the solution while purging