Journal of Medicinal Chemistry
Article
(s, 1H), 6.69 (s, 1H), 4.28−4.15 (m, 6H), 3.23 (d, J = 12.5 Hz, 2H),
2.82−2.70 (m, 2H), 1.85 (d, J = 12.5 Hz, 2H), 1.62 (q, J = 6.6 Hz,
2H), 1.48−1.36 (m, 1H), 1.33−1.20 (m, 2H); LC−MS [M + H+]
491.2.
calcd for C21H21BrN6O2S [M + H+] 501.0728, found 501.0705; HPLC
purity, 99.9% (tR = 7.45 min).
4-[2-[6-Amino-8-(6-bromoindan-5-yl)sulfanylpurin-9-yl]-
ethyl]piperidine-1-carbaldehyde (34f). The title compound was
prepared from 26d and 25b in a manner similar to that described for
4-[2-[6-Amino-8-[(5-bromo-2,3-dihydrobenzofuran-6-yl)-
sulfanyl]purin-9-yl]ethyl]piperidine-1-carbaldehyde (34a). To
solution of aryl sulfide 45 (235 mg, 0.566 mmol) in THF (2.8 mL)
and EtOH (0.28 mL) was added NaOEt (41 mg, 0.57 mmol). The
mixture was stirred for ∼2 h at room temperature and concentrated in
vacuo. The crude sodium thiolate was dissolved in THF (2.8 mL)−
EtOH (0.28 mL), and 8-bromopurine 33b (100 mg, 0.283 mmol) was
added. After being stirred for 10 h at 70 °C, the mixtue was quenched
with water and the product portion was extracted with EtOAc. The
combined organic layers were washed with water, brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was
1
28a. H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.92 (s, 1H),
7.59 (s, 1H), 7.56−7.45 (brs, 2H), 6.91 (s, 1H), 4.16 (t, J = 6.8 Hz,
2H), 4.05 (m, 1H), 3.60 (m, 1H), 2.88−2.81 (m, 3H), 2.69 (t, J = 7.2
Hz, 2H), 2.44 (m, 1H), 1.96 (qn, J = 7.2 Hz, 2H), 1.72−1.61 (m, 2H),
1.61−1.55 (m, 2H), 0.98 (m, 1H), 0.96 (qd, J = 12.4, 4.4 Hz, 1H),
0.85 (qd, J = 11.6, 2.8 Hz, 1H); HRMS (ESI-TOF) calcd for
C22H25BrN6OS [M + H+] 501.10667, found 501.1067; HPLC purity,
99.0% (tR = 7.7 min).
4-[2-[6-Amino-8-[(6-bromo-2,3-dihydro-1,4-benzodioxin-7-
yl)sulfanyl]purin-9-yl]ethyl]piperidine-1-carbaldehyde (34g).
The title compound was prepared in 75% yield from 26b and 25b
1
triturated with EtOAc to provide 34a (87 mg, 61%). H NMR (400
1
in a manner similar to that described for 28a. H NMR (400 MHz,
MHz, DMSO-d6) δ 8.19 (s, 1H), 7.93 (s, 1H), 7.57 (s, 1H), 7.56−7.46
(brs, 2H), 6.33 (s, 1H), 4.52 (t, J = 8.0 Hz, 2H), 4.17 (t, J = 7.2 Hz,
2H), 4.07 (brd, J = 13.2 Hz, 1H), 3.60 (brd, J = 12.8 Hz, 1H), 3.17 (t,
J = 8.0 Hz, 2H), 2.86 (td, J = 12.8, 2.8 Hz, 1H), 2.44 (td, J = 12.4, 3.2
Hz, 1H), 1.76−1.64 (m, 2H), 1.59 (q, J = 6.8 Hz, 2H), 1.39 (m, 1H),
0.97 (qd, J = 12.8, 4.4 Hz, 1H), 0.87 (qd, J = 12.4, 4.4 Hz, 1H); HRMS
(ESI-TOF) calcd for C21H23BrN6O2S [M + H+] 503.0859, found
503.0857; HPLC purity, 95.4% (tR = 7.28 min).
DMSO-d6) δ 8.17 (s, 1H), 7.93 (s, 1H), 7.62−7.44 (brs, 2H), 7.28 (s,
1H), 6.68 (s, 1H), 4.25−4.15 (m, 6H), 4.09 (d, J = 13.6 Hz, 1H), 3.62
(d, J = 13.2 Hz, 1H), 2.88 (td, J = 12.4, 2.4 Hz, 1H), 2.47 (td, J = 12.4,
2.8 Hz, 1H), 1.76−1.65 (m, 2H), 1.58 (q, J = 7.2 Hz, 2H), 1.39 (m,
1H), 0.99 (qd, J = 12.0, 4.4 Hz, 1H), 0.89 (qd, J = 11.2, 4.0 Hz, 1H);
HRMS (ESI-TOF) calcd for C21H23BrN6O3S [M + H+] 519.0809,
found 519.0797, HPLC purity, 99.9% (tR = 7.19 min).
1-[4-[2-[6-Amino-8-[(6-bromo-2,3-dihydro-1,4-benzodioxin-
7-yl)sulfanyl]purin-9-yl]ethyl]-1-piperidyl]-2-hydroxyethanone
(34h). The title compound was prepared in 64% yield by the EDCI
coupling method described for the preparation of 34j using 40b with
2-hydroxyacetic acid. 1H NMR (400 MHz, DMOS-d6) δ 8.16 (s, 1H),
7.52−7.42 (brs, 2H), 7.29 (s, 1H), 6.68 (s, 1H), 4.44 (brs, 1H), 4.29
(m, 1H), 4.27−4.15 (m, 6H), 4.07 (d, J = 14.4 Hz, 1H), 4.02 (d, J =
14.4 Hz, 1H), 3.59 (brd, J = 13.2 Hz, 1H), 2.80 (brt, J = 12.0, 1H),
2.50 (m, 1H), 1.72−1.65 (m, 2H), 1.58 (q, J = 6.8 Hz, 2H), 1.38 (m,
1H), 1.04 (m, 1H), 0.94 (m, 1H); HRMS (ESI-TOF) calcd for
C22H25BrN6O4S [M + H+] 549.0914, found 549.0913; HPLC purity,
95.0% (tR = 7.03 min).
(2S)-1-[4-[2-[6-Amino-8-[(5-bromo-2,3-dihydrobenzofuran-
6-yl)sulfanyl]purin-9-yl]ethyl]-1-piperidyl]-2-hydroxypropan-
1-one (34b). The title compound was prepared in 55% yield by the
EDCI coupling method described for the preparation of 34j using 40a
1
and L-lactic acid. H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.54
(s, 1H), 6.68 (s, 1H), 4.57 (t, J = 8.0 Hz, 2H), 4.53 (m, 1H), 4.44 (br
d, J = 11.6 Hz, 1H), 4.29 (t, J = 7.6 Hz, 2H), 3.97 (br t, J = 14.0 Hz,
1H), 3.23 (t, J = 8.0 Hz, 2H), 2.97 (m, 1H), 2.58 (m, 1H), 1.88−1.76
(m, 2H), 1.75−1.67 (m, 2H), 1.55 (m, 1H), 1.31−1.25 (m, 3H),
1.24−1.04 (m, 2H); HRMS (ESI-TOF) calcd for C23H27BrN6O3S [M
+ H+] 547.1122, found 547.1126; HPLC purity, 93.3% (tR = 7.25
min).
(2S)-1-[4-[2-[6-Amino-8-[(6-bromo-2,3-dihydro-1,4-benzo-
dioxin-7-yl)sulfanyl]purin-9-yl]ethyl]-1-piperidyl]-2-hydroxy-
propan-1-one (34i). The title compound was prepared in 77% yield
by the EDCI coupling method described for the preparation of 34j
using 40b and L-lactic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s,
1H), 8.14−7.90 (brs, 2H), 7.30 (s, 1H), 6.79 (s, 1H), 4.39 (m, 1H),
4.30 (m, 1H), 4.26−4.17 (m, 6H), 3.91 (m, 1H), 2.85 (m, 1H), 2.45
(m, 1H), 1.77−1.65 (m, 2H), 1.63−1.56 (m, 2H), 1.41 (m, 1H),
1.17−1.15 (m, 3H), 1.09−0.88 (m, 2H); HRMS (ESI-TOF) calcd for
C23H27BrN6O4S [M + H+] 563.1071, found 563.1071; HPLC purity,
98.3% (tR = 8.21 min).
(2R)-1-[4-[2-[6-Amino-8-[(6-bromo-2,3-dihydro-1,4-benzo-
dioxin-7-yl)sulfanyl]purin-9-yl]ethyl]-1-piperidyl]-2-hydroxy-
propan-1-one (34j). To a mixture of 40b (5.0 g, 10.18 mmol) in a
1:1 (v/v) mixture of DMF/THF (45 mL) were added (R)-sodium
lactate (1.36 g, 12.21 mmol), HOBt (1.60 g, 12.2 mmol), and EDCI
(2.90 g, 15.3 mmol) at room temperature, and the mixture was stirred
overnight. Upon completion, the mixture was diluted with water (200
mL) and stirred for 15 min at room temperature. The solid was
collected by filtration, washed with water, and air-dried to give the
crude product that was purified by trituration with MeOH to provide
34j (89%, 5.15 g). 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.27
(s, 1H), 7.23 (s, 1H), 4.55 (m, 1H), 4.48 (m, 1H), 4.36 (t, J = 7.4 Hz,
2H), 4.32−4.26 (m, 4H), 4.00 (brd, J = 14.4 Hz, 1H), 3.03 (m, 1H),
2.63 (m, 1H), 1.94−1.85 (m, 2H), 1.85−1.78 (m, 2H), 1.67−1.54 (m,
1H), 1.32 (m, 3H), 1.28−1.1 (m, 2H); HRMS (ESI-TOF) calcd for
C23H27BrN6O4S [M + H+] 563.1071, found 563.1055; HPLC purity,
99.9% (tR = 7.21 min).
4-[2-[6-Amino-8-[(6-bromo-2,3-dihydrobenzofuran-5-yl)-
sulfanyl]purin-9-yl]ethyl]piperidine-1-carbaldehyde (34c). The
title compound was prepared from 33b and 48 in a manner similar to
that described for 34a except that the purification was performed by
preperative RP-HPLC. 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H),
7.99 (s, 1H), 7.60 (s, 1H), 7.19 (s, 1H), 4.67 (t, J = 9.7 Hz, 2H), 4.37
(t, J = 7.2 Hz, 2H), 4.31 (brd, J = 13.2 Hz, 1H), 3.72 (brd, J = 13.6 Hz,
1H), 3.22 (t, J = 9.7 Hz, 2H), 3.10 (td, J = 12.8, 2.8 Hz, 1H), 2.66 (td,
J = 12.8, 3.2 Hz, 1H), 1.98−1.85 (m, 2H), 1.79 (q, J = 7.2, Hz, 2H),
1.64 (m, 1H), 1.22 (qd, J = 11.6, 4.8 Hz, 1H), 1.13 (qd, J = 12.0, 4.4
Hz, 1H); HRMS (ESI-TOF) calcd for C21H23BrN6O2S [M + H+]
503.0859, found 503.0860; HPLC purity, 99.9% (tR = 7.29 min).
4-[2-[6-Amino-8-(5-bromobenzofuran-6-yl)sulfanyl-purin-9-
yl]ethyl]piperidine-1-carbaldehyde (34d). The title compound
was prepared in 65% yield from 33b and 46 in a manner similar to that
1
described for 34a. H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H),
8.07 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.89 (s, 1H), 7.48−7.43 (brs,
2H), 7.42 (d, J = 0.8 Hz, 1H), 6.95 (dd, J = 2.0, 0.8 Hz, 1H), 4.19 (t, J
= 6.8 Hz, 2H), 4.03 (brd, J = 12.4, 1H), 3.55 (br d, J = 13.5 1H), 2.81
(td, J = 12.4, 2.8 Hz, 1H), 2.39 (td, J = 12.4, 2.8 Hz, 1H), 1.67−1.55
(m, 4H), 1.37 (m, 1H), 0.92 (qd, J = 12.4, 4.0 Hz, 1H), 0.83 (qd, J =
12.4, 3.6 Hz, 1H); HRMS (ESI-TOF) calcd for C21H21BrN6O2S [M +
H+] 501.0728, found 501.0698; HPLC purity, 99.9% (tR = 7.42 min).
4-[2-[6-Amino-8-(6-bromobenzofuran-5-yl)sulfanyl-purin-9-
yl]ethyl]piperidine-1-carbaldehyde (34e). The title compound
was prepared from 33b and 49 in a manner similar to that described
for 34a except that the purification was performed by preperative RP-
1
HPLC. H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 8.09 (s, 1H),
4-[2-[6-Amino-8-[(6-bromo-4-methyl-2,3-dihydro-1,4-ben-
zoxazin-7-yl)sulfanyl]purin-9-yl]ethyl]piperidine-1-carbalde-
hyde (34k). The title compound was prepared from 33b and 51 in a
manner similar to that described for 34a. 1H NMR (DMSO-d6) δ 8.24
(s, 1H), 7.94 (s, 1H), 6.95 (s, 1H), 6.68 (s, 1H), 4.22−4.15 (m, 4H),
4.12−4.08 (m, 2H), 3.64−3.57 (m, 1H), 3.29−3.26 (m, 2H), 2.95−
8.05 (d, J = 1.2 Hz, 1H), 7.98 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 6.94
(dd, J = 2.4, 1.2 Hz, 1H), 4.41 (t, J = 7.6 Hz, 2H), 4.30 (brd, J = 13.6,
1H), 3.71 (brd, J = 13.6 1H), 3.09 (td, J = 12.8, 2.8 Hz, 1H), 2.64 (td,
J = 12.4, 2.8 Hz, 1H), 1.95−1.84 (m, 4H), 1.63 (m, 1H), 1.21 (qd, J =
12.0, 4.0 Hz, 1H), 1.13 (qd, J = 12.4, 4.4 Hz, 1H); HRMS (ESI-TOF)
R
dx.doi.org/10.1021/jm3004619 | J. Med. Chem. XXXX, XXX, XXX−XXX