Click-based synthesis of triazolobithiazole Δf508-CFTR correctors for cystic fibrosis

Article abstract of DOI:10.1016/j.bmc.2012.06.046

Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of previously unknown 5-(1H-1,2,3-triazol-1-yl)-4,5′- bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones. These novel triazolobithiazoles are shown to have cyst

Full text of DOI:10.1016/j.bmc.2012.06.046

Bioorganic & Medicinal Chemistry 20 (2012) 5247–5253
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Click-based synthesis of triazolobithiazole
for cystic fibrosis
DF508-CFTR correctors
Michael B. Donald a, Kevin X. Rodriguez a, Hannah Shay a, Puay-Wah Phuan b, A. S. Verkman b,
Mark J. Kurth b,
⇑
a Department of Chemistry, University of California, Davis, CA 95616, USA
b Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of pre-
viously unknown 5-(1H-1,2,3-triazol-1-yl)-4,50-bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones.
These novel triazolobithiazoles are shown to have cystic fibrosis (CF) corrector activity and, compared
to the benchmark bithiazole CF corrector corr-4a, improved logP values (4.5 vs 5.96).
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 May 2012
Revised 21 June 2012
Accepted 27 June 2012
Available online 6 July 2012
Keywords:
CuAAC
Triazolobithiazole
Cystic fibrosis
CF corrector
1. Introduction
mediate (Fig. 1) and that a second bromination, now alpha to
both the carbonyl and triazole moieties, might allow for a-bromo-
Cystic fibrosis (CF) is a genetic disease affecting ꢀ1 in 2500 Cau-
casians1 which, in its most common form, is caused by the deletion
of phenylalanine at position 508 in the CF transmembrane conduc-
ketone?thiazole formation.
2. Results and discussion
2.1. Chemistry
tance regulator protein (
discovery program identified bithiazoles that partially rescue
F508-CFTR cellular misprocessing (CF ‘correctors’; Fig. 1). In
D
F508-CFTR).2,3 Our CF small molecule
D
The requisite starting thiazoles (1a,b: R1 = t-Bu and Ph, respec-
tively) were prepared as detailed in Scheme 1. Thiourea was
condensed with 3-chloro-2,4-pentadione to afford 1-(2-amino-4-
methylthiazol-5-yl)ethanone in nearly quantitative yield.6 The
amino group in this 2-aminothiazole was then coupled with either
pivalic (?1a; 85%) or benzoic (?1b; 79%) acid in CDI-mediated
reactions to give the targeted amidothiazoles. After some experi-
mentation, bromination alpha to the ketone carbonyl in 1 was
effectively accomplished with pyridinium tribromide and 33 wt.%
hydrobromic acid in acetic acid. Bromides 2a and 2b were thus ob-
tained on ꢀ1 g scale in 75% and 63% overall yield, respectively,
from 3-chloro-2,4-pentadione.
exploring this structural class, positions ‘a’, ‘b’, and ‘c’ on the
bithiazole scaffold were extensively modified.4 The work reported
here follows from earlier studies targeting pyrazolothiazoles where
we had shown that this compound class, which uniquely allows ac-
cess to analogs exploring position ‘d’ (not addressable with bithiaz-
oles), was found to afford improved water solubility vis-à-vis
bithazoles–albeit with lower CF corrector activity.5
This reduction in CF corrector activity in going from bithiazoles
to pyrazolothiazoles caused us to consider exploring position ‘e’ on
the bithiazole scaffold, hypothesizing that placing a triazole moiety
at C5 might give improved aqueous solubility while maintaining or
perhaps improving corrector activity. Herein, we report the devel-
opment of chemistry for the construction of novel 5-(1H-1,2,3-tria-
zol-1-yl)-4,50-bithiazoles, along with CF corrector activity and logP
data. Retrosynthetic analysis suggested that triazole formation
might be accomplished by copper catalyzed azide-alkyne cycload-
diton (CuAAC) through a 2-bromo-1-(thiazol-5-yl)ethanone inter-
a-Bromoketone 2 was next stirred in DMF with sodium azide at
room temperature to obtain, in situ, the corresponding azido com-
pound. On completion of the displacement, as monitored by TLC
(1:1 EtOAc:hexanes), the appropriate alkyne, copper catalyst, so-
dium ascorbate, and water (250 lL per mL of DMF) were added
to the reaction flask and the contents were stirred for an additional
6 h. Workup, consisting of dilution with water and extraction with
EtOAc, followed by flash column chromatographic purification,
⇑
Corresponding author. Tel.: +1 530 554 2145; fax: +1 530 752 8995.
E-mail address: mjkurth@ucdavis.edu (M.J. Kurth).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.06.046

5248
M. B. Donald et al. / Bioorg. Med. Chem. 20 (2012) 5247–5253
copper(I) iodide as catalyst (see Table 2)—which allowed for short-
er reaction times; with these modifications, three of the alkynes
delineated in Table 1 led to product (see Table 2).
bithiazoles
pyrazolothiazoles
H
N
c
H
H
N
N
N
a
N
N
S
S
S
This unexpected click reaction problem with 2-bromo-1-(thiaz-
olo-5-yl)ethanone 2b led us to investigate the cause of these poor
yielding cycloadditions. Thinking the amide proton may be the
problem (either its increased acidity or the fact that it is less
sterically encumbered than in 2a), we decided to synthesize the
N-methylated version of 2b (e.g., 6; Scheme 2). Heating a DMF
O
N
O
N
d
b
e
this work
H
N
R2
solution of 1-(4-methyl-2-(methylamino)thiazol-5-yl)ethanone5
4
H
N
H
N
O
N
S
R1
R1
S
with benzoyl chloride delivered the acylated product 5, which
was subsequently brominated in an analogous procedure to that
used to prepare 2b. Bromide 6 was then subjected to a CuSO4/so-
dium ascorbate click reaction with propargyl alcohol and provided
the targeted cycloadduct 7 in fair yield [45%; in contrast, the non-
methyl analog of 6 (e.g., 2b) gave no cycloadduct with propargyl
alcohol (result not shown)]. While other modifications such as
the use of a Cu(I) ligand to stabilize the copper(I)-oxidation state
might benefit these reactions,7 the results with close analogs 2a
and 6 suggest that the benzamide moiety is the root cause of the
failed cycloadditions with 2b.
With triazolothiazole 3 in hand, we addressed the two key
questions central of the strategy alluded to in Figure 1: (i) would
bromination of 3 result in the formation of a stable and useable
2-bromo-1-(thiazol-5-yl)-2-(1H-1,2,3-triazol-1-yl)ethanone and
(ii)wouldthe2-bromo-2-(1H-1,2,3-triazol-1-yl)ethanonesubstruc-
ture in this bis-heterocycle react with N-substituted thioureas to
give 5-(1H-1,2,3-triazol-1-yl)-4,50-bithiazoles? Given that a pivala-
mide moiety at C20 proved to be slightlymore efficacious in corrector
activity than the corresponding benzamide analog,4,5 we addressed
both questions using 1-(thiazol-5-yl)-2-(1H-1,2,3-triazol-1-yl)eth-
anone 3a. After some experimentation, we found that bromination
of 3a proceeded most effectively by treatment with elemental bro-
mine in dioxane at 60 °C.8 Workup, consisting of quenching with
10% NaHSO3 and EtOAc extraction, delivered 2-bromo-1-(thiazol-
5-yl)-2-(1H-1,2,3-triazol-1-yl)ethanone 8a in 45% yield (Scheme
3). While the yield for 3a?8a was modest, product isolation was
straightforward and 8a was stable to manipulation. The Knorr con-
densation9 of 8a with various thioureas was also straight- forward,
yielding 5-(1H-1,2,3-triazol-1-yl)-4,50-bithiazoles 9–14 obtained in
56–92% yield. Saponification of the ester moiety in 14 (aq. KOH,
THF) delivered acid analog 15.
S
Br
O
N
O
N
N
N
N
2-bromo-1-(thiazol-
5-yl)ethanone
R3
5-(1
H
-1,2,3-triazol-1-yl)
-4,5'-bithiazole
Figure 1. Bithiazole, pyrazolothiazole, and triazolobithiazole CF correctors.
O
H2N
O
S
S
EtOH, 60 °C
>95 %
Cl
H2N
+
N
NH3
RCO2H
CDI, DMF
100 °C
O
H
N
H
R1
R1
O
Pyr Br3
S
N
O
S
HBr/AcOH
O
N
O
N
Br
2a; R1 = t-Bu (87%)
1a; R1 = t-Bu (85%)
1b; R1 = Ph (79%)
2b; R1 = Ph (85%)
Scheme 1. Synthesis of 2-bromo-1-(thiazol-5-yl)ethanones 2a,b.
Table 1
One-pot synthesis of 1-(thiazol-5-yl)-2-(1H-1,2,3-triazol-1-yl)ethanones 3a–i
H
N
H
N
O
O
S
S
a) NaN3, DMF
O
N
O
N
R
b)
Br
N
CuSO4 5 H2O
Sodium Ascorbate
4:1 DMF:H2O
N
N
2a
3a-i
R
2.2.
DF508-CFTR corrector activity
Entry
Compound
R
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
–Ph
–CH2OH
–CH2OCH3
85
76
73
56
68
74
52
95
70
The
DF508-CFTR corrector activities of triazolobithiazoles
9–1510 were evaluated by measurement of Iꢁ influx in epithelial
–CH2N(CH3)2
–(CH2)3CN
cells expressing
DF508-CFTR and a fluorescent halide sensor as
previously described.11 The resulting vmax and EC50 data are
–CH2N(CH2CH2)Oa
–COOCH3
tabulated in Scheme 3. While none of the triazolobithiazoles had
–4-Cl-Ph
–CH2CH2OH
Table 2
Two-pot synthesis of 1-(thiazol-5-yl)-2-(1H-1,2,3-triazol-1-yl)ethanones 3j–l
a
Morpholine.
H
N
H
N
O
O
S
S
1) NaN3, THF
O
N
O
N
delivered the targeted 1-(thiazol-5-yl)-2-(1H-1,2,3-triazol-1-
yl)ethanone (3). Using this methodology, a small collection of
R
2)
Br
N
N
N
CuI, Et3N, THF
2b
3j-l
analogs was synthesized in moderate to good yield from a-bromo-
ketone 2a (Table 1).
R
Surprisingly, it was discovered that employing a-bromoketone
Entry
Compound
R
Yield (%)
2b as the starting material generally failed to give triazolo-thiazole
products under the one-pot conditions outlined in Table 1; there
was extensive product decomposition under the required
prolonged reaction times. As a result, reactions employing 2b were
modified—two-pot reaction with isolated azide and the use of
1
2
3
3j
3k
3l
–Ph
69
75
55
–CH2OCH3
–CH2N(CH2CH2)Oa
a
Morpholine.

M. B. Donald et al. / Bioorg. Med. Chem. 20 (2012) 5247–5253
5249
O
CH3
HN
CH3
N
Cl
O
O
S
S
O
N
N
DIPEA, DMF
100 °C
89 %
4
5
Pyr•Br3
33% HBr / AcOH
CH3
N
85 %
O
N
S
CH3
N
O
N
a) NaN3, DMF
O
S
b)
HC CH2OH
O
N
N
N
CuSO4 5 H2O
Sodium Ascorbate
4:1 DMF:H2O
Br
7
6
HO
45 %
Figure 2. Dose-response showing Iꢁ influx in
with triazolobithiazoles 13–15 or corr-4a and stimulated by
(forskolin) and potentiator (genistein) (S.E., n = 4).
D
F508-CFTR cells treated for 24 h
Scheme 2. Synthesis of N-methyl 1-(thiazol-5-yl)-2-(1H-1,2,3-triazol-1-yl)etha-
none 7.
a cAMP agonist
3. Conclusions
H
N
H
N
O
O
S
S
In summary, we have developed a practical synthesis of triazol-
obithiazoles, a previously unknown heterocyclic system. Several of
Br
R1
Br2
O
N
O
N
N
N
N
the novel compounds reported here had
DF508-CFTR corrector
dioxane, 60 o
C
N
N
N
N
activity and improved logP compared to benchmark corrector
corr-4a. These results will allow more extensive examination of
triazolobithiazoles as potential development candidates for CF
therapy.
3a/b/g
8a/b/g
H
R1
N
R2
EtOH
H
a : R1 = Ph
60 o
C
N
S
S
b : R1 = CH2OH
g : R1 = COOMe
H
R2
O
N
N
H2N
4. Experimental section
4.1. Chemistry
N
N
9-15
S
N
yield EC50
(%) (µM)
R1
vmax
// R1
// Ph
// R2
//
cmpd
(µmol)
H
4.1.1. General experimental procedures
77
92
56
1.5
4.9
n/a
152
9
All solvents and reagents were purchased from commercial
suppliers and used without further purification. For reactions run
in sealed microwave vials, oven-dried 5–10 mL or 10–20 mL vials
containing a Teflon-coated stirrer bar and sealed with a Teflon-
lined septum were used. Analytical thin layer chromatography
// CH3
//
// Ph
// Ph
183
n/a
10
11
Cl
Cl
Cl
Cl
67
64
80
0.14
1.6
146
// Ph
//
12
13
14
was carried out on pre-coated plates (Silica gel 60 F254, 250
lm
MeO
//
thickness) and visualized with UV light. Flash chromatography
287 // CH2OH
260 // COOMe
was performed with 60 Å, 35–70 lm silica gel. Concentration re-
fers to rotary evaporation under reduced pressure. 1H NMR spectra
were recorded on spectrometers operating at 300, 400 or 600 MHz
at ambient temperature with DMSO-d6, MeOH-d4, CD3CN, acetone-
d6 or CDCl3 as solvents. 13C NMR spectra were recorded on
spectrometers operating at 75, 100 or 150 MHz at ambient temper-
MeO
//
4.6
KOH (aq),
THF
MeO
//
62
n/a
n/a // COOH
15
MeO
Scheme 3. Synthesis and corrector data for 5-(1H-1,2,3-triazol-1-yl)-4,50-bithiaz-
oles 9–15.
D
F508-CFTR corrector activity as good as benchmark bithiazole
corr-4a, the results with analogs 13 and 14 are encouraging (Fig. 2).
2.3. Measured logP values
Encouraged by these results, we measured logP values
(a measure of a compound’s hydrophilicity/hydrophobicity)12 of
triazolobithiazoles 13–15. The reference for this study is the 5.96
logP of corr-4a, which Lipinski’s rules flag as a limitation.13 We
determined the capacity factor from HPLC retention times to give
correlated logP values. As shown in Fig. 3, the logP values for com-
pounds 13–15 were in the range 4.8–5.5.
Figure 3. LogP measurement of triazolobithiazoles 13–15.

5250
M. B. Donald et al. / Bioorg. Med. Chem. 20 (2012) 5247–5253
ature. Data for 1H NMR are recorded as follows: chemical shift (d,
ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet; br, broad), integration, coupling constant
(Hz). Chemical shifts are reported in parts per million relative to
DMSO-d6 (1H, d 2.50; 13C, d 39.52), CDCl3 (1H, d 7.26; 13C, d
77.16), or TMS (1H, d 0.00; 13C, d 0.00). Infrared spectra were re-
corded on an ATI-FTIR spectrometer. The specifications of the
LC/MS are as follows: electrospray (+) ionization, mass range
150–1500 Da, 20 V cone voltage, and C18 column (2.1 ꢂ 50 ꢂ
1H NMR (600 MHz, CD3CN) d 8.06 (s, 1H), 5.76 (s, 2H), 5.09 (s,
1H), 4.02 (s, 2H), 2.62 (s, 3H), 2.51 (s, 6H), 1.32 (s, 9H); 13C NMR
(150 MHz, CD3CN) d 185.0, 177.9, 161.3, 157.6, 140.4, 127.3,
122.2, 57.7, 52.8, 52.3, 42.7, 39.4, 26.3, 18.2; HRMS (ESI): Calcd
for [C16H24N6O2S+H]+365.1759. Found 365.1753.
4.1.8. N-(5-(2-(4-(3-Cyanopropyl)-1H-1,2,3-triazol-1-yl)acetyl)-
4-methylthiazol-2-yl)pivalamide (3e)
White solid (76 mg, 68%); mp 72–73 °C (decomp); IR (neat) vmax
2969, 2853, 1679, 1537, 1493, 1368, 1315, 1226, 1137, 1039,
3.5 l
m). LogP measurements were made as previously described.5
977 cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.51 (s, 1H), 5.55 (s, 2H),
;
4.1.2. N-(5-Acetyl-4-methylthiazol-2-yl)pivalamide (1a), N-(5-acetyl-
4-methylthiazol-2-yl)benzamide (1b), N-(5-(2-bromoacetyl)-4-meth-
ylthiazol-2-yl)pivalamide (2a), and N-(5-(2-bromoacetyl)-4-
methyl thiazol-2-yl)benzamide (2b)
2.89 (t, J = 7, 2H), 2.60 (s, 3H), 2.42 (t, J = 7, 2H), 2.07 (p, J = 7,
2H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) d 183.7, 177.3, 160.5,
158.9, 146.0, 123.6, 121.1, 119.7, 57.3, 39.6, 27.2, 25.1, 24.4, 18.8,
16.7; HRMS (ESI): Calcd for [C17H22N6O2S+H]+ 375.1603. Found
375.1596.
These compounds were prepared according to published
methods and spectral data are in accord with established values.3
4.1.9. N-(4-Methyl-5-(2-(4-(morpholinomethyl)-1H-1,2,3-triazol-
1-yl)acetyl)thiazol-2-yl)pivalamide (3f)
4.1.3. General procedure for copper catalyzed azide alkyne
cycloaddition
White solid (91 mg, 75%); mp 183–184 °C; IR (neat) vmax 2964,
A mixture of
a-bromoketone (0.30 mmol) and sodium azide
2929, 1675, 1533, 1497, 1426, 1372, 1319, 1146, 1110 cmꢁ‘1 1H
;
(22 mg, 0.34 mmol) were stirred in DMF (2 mL) at room tempera-
ture for 1 h. Alkyne (0.36 mmol) was added to the reaction
followed by water (1 mL), CuSO4 (4 mg, 0.016 mmol), and sodium
NMR (600 MHz, CDCl3) d 9.51 (s, 1H), 7.62 (s, 1H), 5.56 (s, 2H),
3.67 (s, 6H), 2.59 (s, 3H), 2.49 (s, 4H), 1.31 (s, 9H); 13C NMR
(150 MHz, CDCl3) d 183.5, 177.2, 160.3, 158.9, 144.6, 124.9,
121.2, 67.1, 57.3, 53.8, 53.5, 39.6, 27.2, 18.8; HRMS (ESI): Calcd
for [C18H26N6O3S+H]+ 407.1865. Found 407.1861.
L-ascorbate pentahydrate (6 mg, 0.032 mmol). The solution was
stirred for 6 h then diluted with water (10 mL) and extracted with
EtOAc (3 ꢂ 15 mL). The combined organics were washed with
water (45 mL) and brine (45 mL), dried over sodium sulfate, fil-
tered, and concentrated. The resulting crude material was purified
by flash chromatography.
4.1.10. Methyl 1-(2-(4-methyl-2-pivalamidothiazol-5-yl)-2-oxoethyl)-
1H-1,2,3-triazole-4-carboxylate (3g)
White solid (57 mg, 52%); mp 211–213 °C; IR (neat) vmax 3278,
3130, 2981, 1726, 1646, 1544, 1373, 1316, 1224, 1156, 996; 1H
NMR (600 MHz, CDCl3) d 9.40 (s, 1H), 8.27 (s, 1H), 5.64 (s, 2H),
3.96 (s, 3H), 2.66 (s, 3H), 1.36 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 182.12, 176.86, 160.99, 160.25, 159.01, 140.20, 129.55, 120.73,
57.05, 52.24, 39.39, 27.01, 18.54; HRMS (ESI) Calcd for
[C15H19N5O4S+H]+ 366.1236. Found 366.1233.
4.1.4. N-(4-Methyl-5-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetyl)
thiaz-ol-2-yl)pivalamide (3a)
White solid (102 mg, 90%); mp 208–210 °C; IR (neat) vmax 3151,
3115, 2964, 2875, 1666, 1524, 1372, 1319, 1284, 1150, 1115,
968 cmꢁ1 1H NMR (600 MHz, CDCl3) d 9.13 (s, 1H), 7.94 (s, 1H),
;
7.86 (d, J = 7, 1H), 7.43 (t, J = 7, 2H), 7.34 (t, J = 7, 2H), 5.63 (s,
2H), 2.68 (s, 3H), 1.36 (s, 9H); 13C NMR (150 MHz, CDCl3) d 183.5,
177.0, 160.2, 159.0, 148.4, 130.8, 129.1, 128.5, 126.2, 121.8,
121.5, 57.4, 39.7, 27.4, 18.9; HRMS (ESI): Calcd for
[C19H21N5O2S+H]+ 384.1494. Found 384.1486.
4.1.11. N-(5-(2-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)-
4-methylthiazol-2-yl)pivalamide (3h)
White solid (124 mg, 95%); mp 255–256 °C; IR (neat) vmax 3120,
2969, 2933, 1679, 1661, 1528, 1457, 1368, 1315, 1235, 1137, 968;
1H NMR (400 MHz, DMSO-d6) d 12.39 (s, 1H), 8.55 (s, 1H), 7.90 (d,
J = 8.5, 2H), 7.51 (d, J = 8.5, 2H), 6.01 (s, 2H), 2.67 (s, 3H), 1.25 (s,
9H); 13C NMR (100 MHz, DMSO-d6) d 185.74, 178.31, 162.24,
157.19, 145.79, 132.95, 130.28, 129.65, 127.51, 124.06, 122.68,
57.98, 39.71, 27.02, 19.12; HRMS (ESI): Calcd for
[C19H20ClN5O2S+H]+ 418.1104. Found 418.1096.
4.1.5. N-(5-(2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)acetyl)-
4-methylthiazol-2-yl)pivalamide (3b)
White solid (77 mg, 76%); mp 185–186 °C; IR (neat) vmax 3324,
3235, 3138, 2977, 2933, 1688, 1670, 1493, 1324, 1137, 1039,
968 cmꢁ1 1H NMR (600 MHz, CDCl3) d 7.68 (s, 1H), 5.57 (s, 2H),
;
4.76 (s, 1H), 2.57 (s, 2H), 2.07 (s, 3H), 1.31 (s, 9H); 13C NMR
(150 MHz, CDCl3) d 183.6, 178.2, 162.1, 157.6, 148.3, 124.2,
120.8, 57.4, 56.4, 39.8, 27.0, 18.1; HRMS (ESI): Calcd for
[C14H19N5O3S+H]+ 338.1287. Found 338.1286.
4.1.12. N-(5-(2-(4-(3-Hydroxypropyl)-1H-1,2,3-triazol-1-yl)acetyl)-
4-methylthiazol-2-yl)pivalamide (3i)
White solid (76 mg, 70%); mp 193–196 °C; IR (neat) vmax 3144,
2930, 2872, 1685, 1529, 1489, 1374, 1315, 1140, 1043, 975 cmꢁ1
;
4.1.6. N-(5-(2-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)acetyl)-
4-methylthiazol-2-yl)pivalamide (3c)
1H NMR (600 MHz, DMSO-d6) d 12.34 (s, 1H), 7.76 (s, 1H), 5.83
(s, 2H), 3.44 (t, J = 6.4, 2H), 2.66 (t, J = 7.6, 2H), 2.63 (s, 2H), 1.78–
1.70 (m, 2H), 1.24 (s, 9H); 13C NMR (150 MHz, DMSO-d6) d 185.8,
178.0, 161.8, 156.6, 147.0, 123.9, 122.5, 60.5, 57.4, 39.5, 32.8,
26.8, 22.1, 18.8; HRMS (ESI): Calcd for [C16H23N5O3S+H]+
366.1592. Found 366.1603.
White solid (76 mg, 73%); mp 154–156 °C; IR (neat) vmax 22977,
2933, 1679, 1537, 1493, 1368, 1315, 1226, 1146, 977 cmꢁ1 1H
;
NMR (400 MHz, CDCl3) d 7.69 (s, 1H), 5.57 (s, 2H), 4.61 (s, 2H),
3.40 (s, 3H), 2.62 (s, 3H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 183.42, 177.20, 160.37, 158.84, 145.50, 124.65, 121.17, 66.08,
58.46, 57.27, 39.60, 27.21, 18.76; HRMS (ESI): Calcd for
[C15H21N5O3S+H]+ 352.1443. Found 352.1437.
4.1.13. N-(4-Methyl-5-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetyl)thiaz-ol-
2-yl)benzamide (3j)
a-Bromoketone 2b (50 mg, 0.147 mmol) was stirred at room
4.1.7. N-(5-(2-(4-((Dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)-
acetyl)-4-methylthiazol-2-yl)pivalamide (3d)
temperature in DMF (4 mL) with sodium azide (10 mg,
0.161 mmol) for 2 h. The reaction was then diluted with water
(10 mL) and extracted with EtOAc (3 ꢂ 15 mL). The combined
organics were washed with brine (30 mL), dried over sodium
Beige solid(61 mg,56%); mp 70–71 °C (decomp); IR (neat) vmax
3138, 2960, 1679, 1528, 1368, 1310, 1230, 1141, 1035, 972 cmꢁ1
;

M. B. Donald et al. / Bioorg. Med. Chem. 20 (2012) 5247–5253
5251
sulfate, and filtered. The reaction was concentrated, dissolved in
dry THF (2 mL) in a flask covered with tin foil, and triethylamine
(77 lL, 0.558 mmol), copper(I) iodide (70 mg, 0.372 mmol), and
0.400 mmol) were added to a round bottom flask under a nitrogen
atmosphere. The flask was charged with 1.5 mL of 33% HBr in ace-
tic acid, then stirred at room temperature overnight. The reaction
was quenched by the addition of water (2 mL) and a precipitate
formed, which was collected by filtration. The filtrate was ex-
tracted with ethyl acetate (3 ꢂ 10 mL) and the precipitate was
added to the combined organic extracts. These combined extracts
were washed with brine, dried over sodium sulfate, filtered, and
concentrated. The crude material was purified by flash chromatog-
raphy (2:1 EtOAc:hexanes) to afford 6 as an amorphous beige solid
(108 mg, 85%); IR (neat) 2927, 1656, 1477, 1446, 1415, 1368, 1306,
1189, 1096, 1018 cmꢁ1; 1H NMR (600 MHz, CDCl3) d 7.58–7.43 (m,
5H), 4.25 (s, 2H), 3.65 (s, 3H), 2.69 (s, 3H); 13C NMR (150 MHz,
CDCl3) d 184.6, 170.8, 161.1, 157.8, 133.5, 131.4, 128.7, 127.6,
122.4, 38.4, 34.1, 18.6; HRMS Calcd for [C14H13BrN2O2S+H]+
352.9951 found 352.9927.
phenylacetylene (16 mg, 0.161 mmol) were added. The reaction
was stirred 12 h at room temperature and quenched by the addi-
tion of aq. NH4OH. The mixture was extracted with EtOAc
(3 ꢂ 10 mL) and the combined organics were washed with brine,
dried over sodium sulfate, filtered and concentrated. The crude
material was purified by recrystallization in EtOAc/hexanes to
yield 3j as a white solid (38 mg, 69%); mp 222–224 °C; IR (neat)
vmax 2910, 1682, 1533, 1481, 1192, 1030, 965 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6) d 8.53 (s, 1H), 8.14 (d, J = 7.3, 2H), 7.89 (d,
J = 7.2, 2H), 7.69 (t, J = 7.4, 1H), 7.58 (t, J = 7.6, 2H), 7.48 (t, J = 7.7,
2H), 7.36 (t, J = 7.4, 1H), 6.06 (s, 2H), 2.73 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) d 185.1, 184.9, 161.4, 146.0, 133.0, 131.2,
130.5, 128.7, 128.5, 128.2, 127.7, 125.0, 122.8, 122.1, 57.1, 26.1.;
HRMS Calcd for [C21H17N5O2S+H]+ 404.1181. Found 404.1171.
4.1.19. N-(5-(2-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)acetyl)-
4-methylthiazol-2-yl)-N-methylbenzamide (7)
4.1.14. N-(5-(2-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)acetyl)-
4-methylthiazol-2-yl)benzamide (3k)
N-(5-(2-Bromo-acetyl)-4-methylthiazol-2-yl)-N-methylbenza-
mide (6; 93.5 mg, 0.260 mmol) was dissolved in DMF (1.4 mL) and
sodium azide (21.0 mg, 0.316 mmol) was added and stirred at room
temperature for 30 min. The reaction was diluted with water
(10 mL) and extracted with EtOAc (3 ꢂ 15 mL). The combined
organics were washed with brine (30 mL), dried over sodium sul-
fate, filtered, and concentrated. This crude azide was reconstituted
in a 4:1 DMF:H2O solution (1.5 mL) and copper(II) sulfate, sodium
ascorbate, and propargyl alcohol were added. The reaction was stir-
red at room temperature for 2 h and monitored by thin layer chro-
matography. When complete, the reaction mixture was diluted
with water (10 mL) and extracted with EtOAc (3 ꢂ 15 mL); the com-
bined organics were washed with brine, dried over sodium sulfate,
filtered, and concentrated. The resulting crude material was purified
by flash chromatography (EtOAc) to yield 7 as a beige solid (44 mg,
45%); mp 161–163 °C; IR (neat) vmax 3321, 1684, 1655, 1475, 1410,
1299, 1016, 3064 cmꢁ1; 1H NMR (600 MHz, DMSO-d6) d 7.92 (s, 1H),
7.68 (d, J= 6, 2H), 7.59 (t, J = 7.5, 1H), 7.54 (t, J = 7.5, 2H), 5.94 (s, 2H),
White solid (42 mg, 75%); mp 225–226 °C; IR (neat) vmax 3158,
2924, 1670, 1536, 1488, 1322, 1283, 1098, 965 cmꢁ1 1H NMR
;
(600 MHz, CDCl3) d 9.91 (s, 1H), 7.97–7.95 (m, 2H), 7.72 (s, 1H),
7.70–7.68 (m, 1H), 7.59–7.55(m, 2H), 5.63 (s, 2H), 4.65 (s, 2H),
3.44 (s, 3H), 2.66 (s, 3H); 13C NMR (150 MHz, CDCl3) d 183.1,
164.9, 160.4, 133.7, 130.9, 129.2, 127.6, 124.4, 121.1, 65.9, 58.3,
57.1, 50.9, 30.4, 18.5; HRMS (ESI): Calcd for [C17H17N5O3S+H]
+372.1130. Found 372.1131.
4.1.15. N-(4-Methyl-5-(2-(4-(morpholinomethyl)-1H-1,2,3-triazol-
1-yl)acetyl)thiazol-2-yl)benzamide (3l)
White solid (690 mg, 55%); mp 232–233 °C; IR (neat) vmax 2943,
2355, 2140, 2049, 1908, 1671, 1488, 1219, 1057, 965 cmꢁ1 1H
;
NMR (600 MHz, DMSO-d6) d 8.18 (s, 1H), 8.00 (s, 1H), 7.72 (s,
1H), 7.62 (s, 1H), 5.95 (s, 1H), 3.66 (d, J = 28.1, 3H), 3.25 (s, 2H),
2.75 (s, 1H), 2.55 (s, 2H); 13C NMR (150 MHz, DMSO-d6) d 185.2,
166.0, 161.4, 156.2, 142.7, 132.9, 131.5, 128.6, 128.3, 125.4,
122.1, 66.0, 57.0, 52.7, 18.2; HRMS (ESI): Calcd for
[C20H22N6O3S+H]+ 427.1552. Found 427.1543.
5.21 (t, J = 5.6, 1H), 4.56 (d, J = 5.6, 2H), 3.57 (s, 3H), 2.69 (s, 3H); 13
C
NMR (150 MHz DMSO-d6) d 186.3, 171.0, 161.8, 155.7, 148.3, 134.1,
131.6, 129.0, 128.1, 124.8, 123.9, 57.6, 55.5, 38.6, 19.1; HRMS (ESI)
Calcd for [C17H17N5O3S+H]+ 372.1122 found 372.1097.
4.1.16. 1-(4-Methyl-2-(methylamino)thiazol-5-yl)ethanone (4)
Prepared following a published method; spectral data in accor-
dance with established values.5
4.1.20. N-(5-(2-Bromo-2-(4-phenyl-1H-1,2,3-triazol-1-yl) acetyl)-
4-methylthiazol-2-yl)pivalamide (8a)
4.1.17. N-(5-Acetyl-4-methylthiazol-2-yl)-N-methylbenzamide
(5)
N-(4-Methyl-5-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetyl)thi-azol-
2-yl)pivalamide (3a; 50 mg, 0.14 mmol) was dissolved in dioxane
(0.65 mL), the reaction flask was wrapped with tin foil, and the solu-
1-(4-Methyl-2-(methylamino)thiazol-5-yl)ethanone
(1.27 g,
7.47 mmol) and N,N-diisopropylethylamine (1.55 mL, 8.96 mmol)
were added to a flask charged with DMF (40 mL). The reaction flask
was then heated to 100 °C and benzoyl chloride (1.29 mL,
11.2 mmol) was added. The reaction was stirred at 100 °C for
12 h and monitored by thin-layer chromatography. Upon comple-
tion, the reaction was poured into ice-cold water and a precipitate
formed. The precipitate was collected by filtration and the beige
solid (5) was used without further purification (1.82 g, 89%); mp
128–130 °C; IR (neat) vmax 2917, 1664, 1516, 1477, 1415, 1360,
tion was heated to 60 °C. Elemental bromine (72 lL, 0.14 mmol) was
added and the reaction was stirred for 5 h. The reaction was
quenched by the addition of NaHSO3 (2 mL) and the resulting mix-
ture was extracted with EtOAc (3 ꢂ 4 mL). The combined organics
were washed with water and brine, dried over sodium sulfate, fil-
tered, and concentrated. The crude material was purified by flash
chromatography (2:1 EtOAc:hexanes) to afford 8a as a yellow amor-
phous solid (27 mg, 45%); IR (neat) vmax 2910, 2850, 1634, 1524,
1369, 1200, 1145, 1039, 970 cmꢁ11H NMR (400 MHz, CDCl3) d 9.19
(s, 1H), 8.49 (s, 1H), 7.91–7.85 (m, 2H), 7.56 (s, 1H), 7.43 (t, J = 7.6,
2H), 7.35 (t, J = 7.3, 1H), 3.69 (s, 2H), 2.70 (s, 3H), 1.35 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 179.6, 176.9, 162.0, 161.0, 149.2, 130.1,
129.1, 128.8, 126.1, 121.5, 119.2, 55.6, 39.6, 27.4, 19.1; HRMS (ESI)
Calcd for [C19H20BrN5O2S+H]+ 462.0591. Found 462.0589.
1306, 1251, 1103, 1010, 946 cmꢁ1 1H NMR (600 MHz, CDCl3) d
;
7.58–7.52 (m, 3H), 7.52–7.47 (m, 2H), 3.66 (s, 3H), 2.69 (s, 3H),
2.53 (s, 3H); 13C NMR (150 MHz, CDCl3) d 191.2, 170.7, 160.3,
154.9, 133.8, 131.2, 128.7, 127.6, 126.0, 38.2, 30.6, 18.4; HRMS
(ESI) Calcd for [C14H14N2O2S+H]+ 275.0840. Found 275.0855.
4.1.18. N-(5-(2-Bromoacetyl)-4-methylthiazol-2-yl)-N-methylbenz-
amide (6)
4.1.21. N-(5-(2-Bromo-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-
yl)-acetyl)-4-methylthiazol-2-yl)pivalamide (8b)
N-(5-Acetyl-4-methylthiazol-2-yl)-N-methyl-benzamide
100 mg, 0.36 mmol) and pyridinium tribromide (127 mg,
(5;
Yellow solid (16 mg, 35%); mp 120–121 °C; IR (neat) vmax 3170,
2964, 2930, 1686, 1527, 1367, 1321, 1139, 1036 cmꢁ1 1H NMR
;

5252
M. B. Donald et al. / Bioorg. Med. Chem. 20 (2012) 5247–5253
(600 MHz, DMSO-d6) d 11.46 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 5.18
(d, J = 5.8, 3H), 3.07 (s, 3H), 1.82 (s, 9H); 13C NMR (150 MHz, DMSO-
d6) d 180.1, 178.0, 162.5, 161.5, 150.4, 124.1, 119.4, 57.9, 56.3, 39.9,
26.8, 18.8; HRMS (ESI) Calcd for [C14H18BrN5O3S+H]+ 416.0392
found 416.0388.
147.2, 146.3, 136.8, 130.0, 129.9, 129.1, 128.8, 126.5, 126.3,
122.6, 121.7, 118.0, 117.5, 117.0, 111.2, 56.3, 39.3, 27.4, 16.2;
HRMS (ESI): Calcd for [C27H26ClN7O2S2+H]+ 580.1356. Found
580.1351.
4.1.27. N-(2-(5-Chloro-2-methoxyphenylamino)-5-(4-(hydroxyl-
methyl)-1H-1,2,3-triazol-1-yl)-40-methyl-4,50-bithiazol-20-yl)piv-
alamide (13)
4.1.22. Methyl 1-(1-bromo-2-(4-methyl-2-pivalamidothiazol-5-
yl)-2-oxoethyl)-1H-1,2,3-triazole-4-carboxylate (8g)
Yellow solid (15 mg, 64%); mp 172–173 °C; IR (neat) vmax 2977,
Yellow solid (71 mg, 60%); mp 52–53 °C (decomp); IR (neat)
vmax 3284, 2964, 1737, 1666, 1524, 1479, 1372, 1212, 1141,
1679, 1599, 1528, 1484, 1412, 1297, 1252, 1172, 1030 cmꢁ1 1H
;
1035, 972 cmꢁ1 1H NMR (600 MHz, CDCl3) d 9.42 (br s, 1H), 8.81
;
NMR (400 MHz, acetone-d6) d 10.37 (s, 1H), 9.44 (s, 1H), 8.69 (d,
J = 2.3, 1H), 7.93 (d, J = 6.2, 1H), 7.02–6.88 (m, 2H), 4.67 (s, 2H),
3.83 (s, 3H), 2.85 (s, 1H), 2.06 (s, 3H), 1.28 (s, 9H); 13C NMR
(100 MHz, acetone-d6) d 176.5, 160.1, 158.1, 149.2, 146.9, 137.4,
131.0, 125.4, 125.1, 121.7, 117.9, 116.6, 111.7, 111.0, 109.0, 78.5,
55.9, 39.1, 26.5, 15.9; HRMS (ESI): Calcd for [C22H24ClN7O3S2+H]+
534.1149. Found 534.1139.
(s, 1H), 7.51 (s, 1H), 3.99 (s, 3H), 2.70 (s, 3H), 1.37 (s, 9H); 13C
NMR (150 MHz, CDCl3) d 178.9, 177.2, 162.4, 161.5, 160.8, 141.0,
130.1, 118.7, 54.5, 52.6, 39.6, 27.2, 19.1; HRMS (ESI) Calcd for
[C15H18BrN5O4S+H]+ 444.0341 found 444.0340.
4.1.23. N-(2-Amino-40-methyl-5-(4-phenyl-1H-1,2,3-triazol-1-
yl)-4,50-bithiazol-20-yl)pivalamide (9)
4.1.28. Methyl 1-(2-(5-chloro-2-methoxyphenylamino)-40-methyl-
20-pivalamido-4,50-bithiazol-5-yl)-1H-1,2,3-triazole-4-carboxyl-
ate (14)
N-(2-Amino-40-methyl-5-(4-phenyl-1H-1,2,3-triazol-1-yl)-4,50-
bithiazol-20-yl)pivalamide (20 mg, 0.043 mmol) and thiourea
(3 mg, 0.047 mmol) were dissolved in ethanol (0.210 mL) and the
mixture was stirred at 60 °C for 3 h. The reaction was then concen-
trated and the crude material dissolved in EtOAc (3 mL). The
organics were washed with water (4 mL) and brine (4 mL), dried
over sodium sulfate, filtered, and concentrated. The crude product
was purified by flash chromatography (3:1 EtOAc:hexanes) to af-
ford 9 (14 mg, 77%); mp 196–200 °C; IR (neat) vmax 2964, 2920,
White solid (19 mg, 80%); mp 198–200 °C; IR (neat) vmax 3169,
2955, 1737, 1693, 1675, 1541, 1497, 1435, 1372, 1292, 1221,
1043 cmꢁ1 1H NMR (600 MHz, acetone-d6) d 10.43 (s, 1H), 9.59
;
(s, 1H), 8.77 (s, 1H), 8.75 (d, J = 2.4, 1H), 7.03 (dt, J = 5.5, 8.7, 2H),
3.91 (s, 3H), 3.87 (s, 3H), 2.90 (s, 3H), 1.33 (s, 9H); 13C NMR
(150 MHz, acetone-d6) d 176.5, 160.8, 160.5, 158.1, 147.4, 147.0,
139.9, 139.2, 131.9, 130.8, 125.4, 122.0, 118.0, 116.0, 115.9,
111.8, 55.9, 51.6, 39.1, 26.5, 16.2. HRMS (ESI): Calcd for
[C23H24ClN7O4S2+H]+ 562.1098. Found 562.1092.
1684, 1630, 1515, 1479, 1372, 1310, 1132, 970 cmꢁ1 1H NMR
;
(600 MHz, CDCl3) d 7.81 (d, J = 8.0, 2H), 7.56 (s, 1H), 7.48 (t,
J = 8.0, 2H), 7.43 (t, J = 8.0, 2H), 2.81 (s, 3H), 1.37 (s, 9H); 13C
NMR (150 MHz, CDCl3) d 176.8, 171.0, 163.6, 157.2, 154.6, 129.1,
128.9, 126.7, 126.4, 125.3, 123.6, 39.4, 29.7, 27.1, 18.9; HRMS
(ESI): Calcd for [C20H21N7OS2+H]+ 440.1327. Found 440.1318.
4.1.29. 1-(2-(5-Chloro-2-methoxyphenylamino)-40-methyl-20-
pival-amido-4,50-bithiazol-5-yl)-1H-1,2,3-triazole-4-carboxylic
acid (15)
4.1.24. N-(40-Methyl-2-(methylamino)-5-(4-phenyl-1H-1,2,3-triazol-
1-yl)-4,50-bithiazol-20-yl)pivalamide (10)
Beige solid (14 mg, 62%); mp 206–208 °C; IR (neat) vmax 3169,
2955, 1737, 1693, 1675, 1541, 1497, 1435, 1372, 1292, 1221,
1043 cmꢁ1 1H NMR (400 MHz, DMSO-d6) d 13.57–13.19 (m, 1H),
;
Brown solid (18 mg, 92%); mp 136–137 °C; IR (neat) vmax 3231,
2964, 2929, 1675, 1533, 1400, 1301, 1221, 1150, 1026 cmꢁ1 1H
;
11.92 (s, 1H), 10.32 (s, 1H), 9.07 (d, J = 0.9, 1H), 8.66 (s, 1H),
7.13–7.02 (m, 2H), 3.90 (s, 3H), 2.29 (s, 3H), 1.20 (s, 9H); 13C
NMR (100 MHz, acetone-d6) d 187.2, 161.4, 161.2, 158.8, 148.1,
140.7, 140.0, 132.6, 131.6, 126.1, 122.7, 118.8, 116.8, 116.4,
112.6, 56.6, 52.4, 39.8, 27.2, 17.0. HRMS (ESI): Calcd for
[C22H22ClN7O4S2+H]+ 548.0941. Found 548.0933.
NMR (400 MHz, CDCl3) d 7.74–7.66 (m, 3H), 7.35 (t, J = 7.5, 2H),
7.28 (d, J = 7.4, 1H), 6.68 (s, 1H), 2.91 (d, J = 4.7, 3H), 1.88 (s, 3H),
1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) d 167.8, 158.4, 148.0,
146.2, 137.0, 129.8, 129.3, 129.1, 128.8, 126.1, 125.5, 121.9,
117.2, 39.4, 32.0, 27.4, 15.8; HRMS (ESI): Calcd for
[C21H23N7OS2+H]+ 454.1483. Found 454.1473.
Acknowledgments
4.1.25. N-(2-(Allylamino)-40-methyl-5-(4-phenyl-1H-1,2,3-triazol-
1-yl)-4,50-bithiazol-20-yl)pivalamide (11)
The authors thank the Tara K. Telford Fund for Cystic fibrosis
Research at the University of California, Davis, the National Insti-
tutes of Health (Grants DK072517, GM089153 and HL073856),
and the National Science Foundation [CHE-0910870; grants CHE-
0910870, CHE-0443516, CHE-0449845, and CHE-9808183 sup-
porting NMR spectrometers].
White solid (11 mg, 56%); mp 204–206 °C; IR (neat) vmax 2969,
2924, 2720, 1679, 1617, 1519, 1484, 1368, 1324, 1146, 977 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 8.82 (s, 1H), 7.78 (d, J = 7.4, 2H), 7.73
(s, 1H), 7.41 (t, J = 7.4 3H), 7.33 (t, J = 7.4, 1H), 6.20 (s, 1H), 5.88
(ddd, J = 5.5, 10.2, 17.1, 1H), 5.32 (d, J = 17.1, 1H), 5.22 (d, J = 10.2,
1H), 3.92 (t, J = 5.5, 3H), 1.96 (s, 3H), 1.29 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 176.1, 166.2, 157.9, 148.0, 146.5, 136.6,
132.9, 130.0, 129.1, 128.7, 126.2, 121.7, 118.1, 117.5, 116.7, 48.0,
39.3, 27.4, 15.9; HRMS (ESI) Calcd for [C23H25N7OS2+H]+
480.1632. Found 480.1630.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2012.06.046.
4.1.26. N-(2-(5-Chloro-2-methoxyphenylamino)-40-methyl-5-(4-
phenyl-1H-1,2,3-triazol-1-yl)-4,50-bithiazol-20-yl)pivalamide (12)
White solid (16 mg, 67%); mp 150–154 °C; IR (neat) vmax 2964,
References and notes
1. Bobadilla, J. L.; Macek, M.; Fine, J. P.; Farrell, P. M. Hum. Mutat. 2002, 19, 575.
2. Sharma, M.; Benharouga, M.; Hu, W.; Lukacs, G. L. J. Biol. Chem. 2001, 276, 8942.
3. As reported by the cystic fibrosis foundation (http://www.cff.org/treatments/
Therapies/Kalydeco/), ‘Kalydeco™ (generic name, ivacaftor; previously known
as VX-770) is a new oral medication for the treatment of cystic fibrosis,
approved by the US. Food and drug administration (FDA) in January 2012. The
FDA approved Kalydeco for people ages 6 and older with the G551D mutation
of CF’.
1675, 1604, 1533, 1479, 1284, 1257, 1035 cmꢁ1
;
1H NMR
(600 MHz, CDCl3) d 8.89 (s, 1H), 8.17 (d, J = 2.5, 1H), 7.82–7.77
(m, 3H), 7.41 (t, J = 7.6, 2H), 7.34 (t, J = 7.6, 1H), 6.98 (dd, J = 2.5,
8.6, 1H), 6.81 (d, J = 8.6, 1H), 3.90 (s, 3H), 2.11 (s, 3H), 1.29 (s,
9H); 13C NMR (150 MHz, CDCl3) d 176.1, 159.9, 158.1, 148.3,

M. B. Donald et al. / Bioorg. Med. Chem. 20 (2012) 5247–5253
5253
4. Yu, G.; Yoo, C. L.; Yang, B.; Lodewyk, M. W.; Meng, L.; El-Idreesy, T. T.; Fettinger,
J. C.; Tantillo, D. J.; Verkman, A. S.; Kurth, M. J. J. Med. Chem. 2008, 51, 6044.
5. Ye, L.; Knapp, J. M.; Sangwung, P.; Fettinger, J. C.; Verkman, A. S.; Kurth, M. J. J.
Med. Chem. 2010, 53, 3772.
6. Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill, R.; Thomas,
M.; Mezna, M.; Jackson, W.; Midgley, C.; Griffiths, G.; Fleming, I.; Green, S.;
McNae, I.; Wu, S.; McInnes, C.; Zheleva, D.; Walkinshaw, M. D.; Fischer, P. M. J.
Med. Chem. 2004, 47, 1662.
7. Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.; Williams, S. J. Chem.
Commun. 2008, 2459.
8. Katritzky, A. R.; Wu, J.; Wrobel, L.; Rachwal, S.; Steel, P. J. Acta Chem. Scand.
1993, 167.
(a) In our previously reported SAR study of 148 methylbithiazole analogues
focused on the peripheral amide and aniline substructures (e.g., circled regions
‘a’ and ‘c’, respectively, of the bithiazole depicted in Fig. 1, we established that
piv-4a (see right) is a more effective corrector than corr-4a.10b This, coupled
with the click chemistry problems associated with the benzamide series,
suggested to us that proceeding with only the pivalamide series (e.g.,
triazolobithiazoles 9–15) was appropriate; (b) Yoo, C. L.; Yu, G. J.; Yang, B.;
Robins, L. I.; Verkman, A. S.; Kurth, M. J. Bioorg. Med. Chem. Lett. 2008, 18, 2610.
11. Yang, H.; Shelat, A. A.; Guy, R. K.; Gopinath, V. S.; Ma, T.; Du, K.; Lukacs, G. L.;
Taddei, A.; Folli, C.; Pedemonte, N.; Galietta, L. J. V.; Verkman, A. S. J. Biol. Chem.
2003, 278, 35079.
12. Malik, I.; Sedlarova, M. A.; Csollei, C. S.; Andrianainty, P.; Kurfurst, P.; Vanco, J.
Chem. Pap. 2006, 60, 42.
9. Hantzsch, A. Justus Liebigs Ann. Chem. 1889, 250, 257.
10.
13. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55.
Cl
HN
S
N
O
N
S
O
NH
corr-4a: R = -C6H5
R
piv-4a: R = -C(CH3)3