Journal of Medicinal Chemistry
ARTICLE
N-(6-(2-(4-Methoxybenzyloxy)pyrimidin-4-yl)benzo[d]
thiazol-2-yl)acetamide (28). Using (4-methoxyphenyl)methanol
and following the procedure used to prepare 6 gave 28 in 31% yield. This
compound was purified by washing with Et2O, MeOH, and Et2O instead
of by HPLC. MS (ESI pos ion) m/z: 407 (M þ Hþ). 1H NMR
(400 MHz, DMSO-d6, δ): 12.50 (br s, 1H), 8.77 (br s, 1H), 8.63 (d, J =
5.02 Hz, 1H), 8.22 (d, J = 8.53 Hz, 1H), 7.73 (d, J = 5.02 Hz, 2H), 7.46
(d, J = 8.03 Hz, 2H), 6.96 (d, J = 8.53 Hz, 2H), 5.43 (s, 2H), 3.76 (s, 3H),
2.16 (s, 3H).
N-(6-(2-(Pyridin-4-ylmethoxy)pyrimidin-4-yl)benzo[d]
thiazol-2-yl)acetamide (29). Using 4-(hydroxymethyl)pyridine
and following the procedure used to prepare 6 gave 29 in 51% yield. This
compound was purified by washing with Et2O instead of by HPLC. MS
(ESI pos ion) m/z: 378 (M þ Hþ). 1H NMR (400 MHz, DMSO-d6, δ):
8.81 (s, 1H) 8.67 (d, J = 5.02 Hz, 1H), 8.59 (d, J = 5.52 Hz, 2H), 8.23 (d,
J = 8.53 Hz, 1H), 7.81-7.76 (m, 2H), 7.49 (d, J = 5.52 Hz, 2H), 5.57 (s,
2H), 2.20 (s, 3H).
8.67 (s, 1H), 8.27 (d, J = 6.53 Hz, 1H), 7.84 (d, J = 7.03 Hz, 1H), 7.77 (s,
1H), 7.60-7.29 (m, 5H), 5.51 (s, 2H), 2.23 (s, 3H).
N-(6-(2-(Benzylamino)pyrimidin-4-yl)benzo[d]thiazol-2-
yl)acetamide (11). Using benzylamine and following the proce-
dure used to prepare 9 gave 11 in 22% yield. MS (ESI pos ion) m/z:
1
376 (M þ Hþ). H NMR (400 MHz, DMSO-d6, δ): 12.48 (s, 1H),
8.73 (s, 1H), 8.36 (d, J = 5.52 Hz, 1H), 8.19 (d, J = 8.53 Hz, 1H), 7.93
(br s, 1H), 7.81 (d, J = 9.03 Hz, 1H), 7.44-7.36 (m, 2H), 7.32 (d, J =
14.56 Hz, 2H), 7.29-7.18 (m, 2H), 4.63 (br s, 2H), 2.23 (s, 3H).
N-(6-(2-(3-Fluorobenzyloxy)pyrimidin-4-yl)benzo[d]thiazol-
2-yl)acetamide (23). Using (3-fluorophenyl)methanol and follow-
ing the procedure used to prepare 9 gave 23 in 22% yield. The mixture
was reheated a second time in the microwave at 120 ꢀC and 300 W with a
5 min ramp time and 10 min run time. MS (ESI pos ion) m/z: 395 (M þ
Hþ). 1H NMR (400 MHz, DMSO-d6, δ): 12.51 (br s, 1H), 8.87 (s, 1H),
8.68 (d, J = 3.51 Hz, 1H), 8.27 (d, J = 8.03 Hz, 1H), 7.84 (d, J = 8.03 Hz,
1H), 7.78 (d, J = 3.51 Hz, 1H), 7.52-7.29 (m, 3H), 7.22-7.11 (m, 1H),
5.53 (s, 2H), 2.23 (s, 3H).
N-(6-(2-(3-(Pyridin-4-yl)propoxy)pyrimidin-4-yl)benzo[d]
thiazol-2-yl)acetamide (30). Using 3-(pyridin-4-yl)propan-1-ol
and following the procedure used to prepare 6 gave 30 in 18% yield.
This compound was purified by washing with Et2O instead of by HPLC.
MS (ESI pos ion) m/z: 406 (M þ Hþ). 1H NMR (400 MHz, DMSO-
d6, δ): 12.48 (br s, 1H), 8.83 (s, 1H), 8.64 (d, J = 5.52 Hz, 1H), 8.47 (d,
J = 5.52 Hz, 2H), 8.24 (d, J = 8.53 Hz, 1H), 7.84 (d, J = 8.53 Hz, 1H),
7.74 (d, J = 5.02 Hz, 1H), 7.30 (d, J = 5.52 Hz, 2H), 4.43 (t, J = 6.53 Hz,
2H), 2.80 (t, J = 7.78 Hz, 2H), 2.23 (s, 3H), 2.16-2.08 (m, 2H).
N-(6-(2-(4-Methoxyphenylsulfonamido)pyrimidin-4-yl)
benzo[d]thiazol-2-yl)acetamide (37). Using 4-methoxyben-
zenesulfonamide and DMSO and following the procedure used to
prepare 6 gave 37 in 29% yield. The reaction was run at 125 ꢀC
overnight, and following HPLC purification, the material was washed
with Et2O, MeOH, and Et2O to afford the product. MS (ESI pos ion)
m/z: 456 (M þ Hþ). 1H NMR (400 MHz, DMSO-d6, δ): 12.53 (s,
1H), 11.66 (br s, 1H), 8.59-8.52 (m, 2H), 8.15 (d, J = 8.53 Hz, 1H),
7.98 (d, J = 8.53 Hz, 2H), 7.85 (d, J = 8.53 Hz, 1H), 7.65 (d, J =
4.52 Hz, 1H), 7.10 (d, J = 9.03 Hz, 2H), 3.81 (s, 3H), 2.24 (s, 3H).
N-(6-(2-(4-Methoxy-N-methylphenylsulfonamido)pyrimidin-
4-yl)benzo[d]thiazol-2-yl)acetamide (38). Using 4-methoxy-N-
methylbenzenesulfonamide and DMSO and following the procedure
used to prepare 6 gave 38 in 25% yield. The reaction was run at 125 ꢀC
overnight. MS (ESI pos ion) m/z: 470 (M þ Hþ). 1H NMR (400 MHz,
DMSO-d6, δ): 12.52 (br s, 1H), 8.64 (d, J = 5.02 Hz, 1H), 8.56 (s, 1H),
8.14 (d, J = 8.53 Hz, 1H), 7.99 (d, J = 8.53 Hz, 2H), 7.84 (d, J = 8.53 Hz,
1H), 7.71 (d, J = 5.02 Hz, 1H), 7.10 (d, J = 9.03 Hz, 2H), 3.82 (s, 3H),
3.69 (s, 3H), 2.23 (s, 3H).
N-(6-(2-(3-(Pyridin-3-yl)propoxy)pyrimidin-4-yl)benzo[d]
thiazol-2-yl)acetamide (31). Using 3-pyridinepropanol and fol-
lowing the procedure used to prepare 9 gave 31 in 18% yield. MS
(ESI pos ion) m/z: 406 (M þ Hþ). 1H NMR (400 MHz, DMSO-d6, δ):
12.51 (s, 1H), 8.86-8.80 (m, 2H), 8.72 (d, J = 5.02 Hz, 1H), 8.64 (d, J =
5.52 Hz, 1H), 8.39 (d, J = 8.03 Hz, 1H), 8.25 (dd, J = 8.53, 1.51 Hz, 1H),
7.91-7.82 (m, 2H), 7.75 (d, J = 5.02 Hz, 1H), 4.47 (t, J = 6.27 Hz, 2H),
2.98 (t, J = 7.53 Hz, 2H), 2.23 (s, 3H), 2.22-2.14 (m, 2H).
N-(6-(2-(3-Phenylpropoxy)pyrimidin-4-yl)benzo[d]thiazol-
2-yl)acetamide (32). Using 3-phenylpropan-1-ol and following the
procedure used to prepare 9 gave 32 in 6% yield. MS (ESI pos ion) m/z:
405 (M þ Hþ). 1H NMR (400 MHz, DMSO-d6, δ): 12.50 (s, 1H), 8.83
(s, 1H), 8.64 (d, J = 5.02 Hz, 1H), 8.25 (d, J = 8.53 Hz, 1H), 7.84 (d, J =
8.53 Hz, 1H), 7.74 (d, J = 5.52 Hz, 1H), 7.34-7.24 (m, 4H), 7.23-7.16
(m, 1H), 4.42 (t, J = 6.53 Hz, 2H), 2.78 (t, J = 7.53 Hz, 2H), 2.23 (s, 3H),
2.14-2.04 (m, 2H).
N-(6-(2-(3-Morpholinopropoxy)pyrimidin-4-yl)benzo[d]
thiazol-2-yl)acetamide (33). Using 4-(3-hydroxypropyl)morpho-
line and following the procedure used to prepare 9 gave 33 in 5% yield as
a TFA salt. Before HPLC purification, the crude material was filtered
through silica gel (15:1 DCM/MeOH f 5:1 DCM/2 N ammonia in
MeOH). MS (ESI pos ion) m/z: 414 (M þ Hþ). 1H NMR (400 MHz,
DMSO-d6, δ): 12.52 (br s, 1H), 9.83 (br s, 1H), 8.85 (s, 1H), 8.67 (d, J =
5.52 Hz, 1H), 8.27 (d, J = 8.03 Hz, 1H), 7.86 (d, J = 8.53 Hz, 1H), 7.78
(d, J = 5.02 Hz, 1H), 4.51 (t, J = 5.77 Hz, 2H), 4.05-3.95 (m, 2H),
3.71-3.61 (m, 2H), 3.51 (d, J = 11.04 Hz, 2H), 3.40-3.29 (m, 2H),
3.16-3.05 (m, 2H), 2.30-2.16 (m, 5H).
N-(6-(2-(2-Morpholinoethoxy)pyrimidin-4-yl)benzo[d]
thiazol-2-yl)acetamide (34). Using 4-(2-hydroxyethyl)morpho-
line and following the procedure used to prepare 9 gave 34 in 5% yield as
a TFA salt. MS (ESI pos ion) m/z: 400 (M þ Hþ). 1H NMR (400 MHz,
DMSO-d6, δ): 12.53 (br s, 1H), 9.74 (br s, 1H), 8.87 (s, 1H), 8.71 (d, J =
5.52 Hz, 1H), 8.29 (d, J = 8.53 Hz, 1H), 7.89-7.82 (m, 2H), 4.80 (br s,
2H), 3.99-3.89 (m, 2H), 3.76-3.71 (m, 2H), 3.69-3.64 (m, 2H),
3.23-3.18 (m, 2H), 2.24 (s, 3H). (The additional two methylene
protons could be buried under the H2O peak, which ranges from
3.64-3.35.)
N-(6-(2-(3-Methoxypropoxy)pyrimidin-4-yl)benzo[d]thiazol-
2-yl)acetamide (35). Using 3-methoxypropan-1-ol and following the
procedure used to prepare 9 gave 35 in 7% yield. MS (ESI pos ion) m/z: 359
(M þ Hþ). 1H NMR (400 MHz, DMSO-d6, δ): 12.50 (s, 1H), 8.85 (s,
1H),8.64(d,J=5.02 Hz, 1H), 8.27 (d, J=9.03 Hz, 1H), 7.85 (d, J=8.53 Hz,
1H), 7.74 (d, J = 5.02 Hz, 1H), 4.46 (t, J = 6.27 Hz, 2H), 3.51 (t, J = 6.27 Hz,
2H), 3.27 (s, 3H), 2.23 (s, 3H), 2.02 (quin, J = 6.40 Hz, 2H).
N-(6-(2-(N-Ethyl-4-methoxyphenylsulfonamido)pyrimidin-
4-yl)benzo[d]thiazol-2-yl)acetamide (39). Using 4-methoxy-N-
ethylbenzenesulfonamide and DMSO and following the procedure used
to prepare 6 gave 39 in 12% yield. The reaction was run at 125 ꢀC
overnight. MS (ESI pos ion) m/z: 484 (M þ Hþ). 1H NMR (400 MHz,
DMSO-d6, δ): 12.51 (br s, 1H), 8.63 (d, J = 5.02 Hz, 1H), 8.48 (s, 1H),
8.08 (d, J = 8.53 Hz, 1H), 7.98 (d, J = 8.53 Hz, 2H), 7.83 (d, J = 8.53 Hz,
1H), 7.68 (d, J = 5.02 Hz, 1H), 7.10 (d, J = 8.53 Hz, 2H), 4.37-4.26 (m,
2H), 3.82 (s, 3H), 2.23 (s, 3H), 1.42 (t, J = 6.53 Hz, 3H).
Procedure for the Synthesis of 9, 11, 23, 31-35, 40, and
42-44. N-(6-(2-(Benzyloxy)pyrimidin-4-yl)benzo[d]thiazol-
2-yl)acetamide (9). Compound 5 (60.8 mg, 0.200 mmol) and
benzyl alcohol (0.20 mL, 1.9 mmol) were suspended in pyridine (0.84
mL) and sealed in a microwave vial. The vial was heated in the CEM
microwave at 120 ꢀC and 300 W with a 5 min ramp time and 20 min run
time. The mixture was cooled to room temperature, concentrated, and
purified on HPLC (10% f 95% MeCN/H2O with 0.1% TFA over 28-
40 min) to afford 9 (4.4 mg, 6% yield). MS (ESI pos ion) m/z: 377 (M þ
Hþ). 1H NMR (400 MHz, DMSO-d6, δ): 12.51 (br s, 1H), 8.87 (s, 1H),
N-(6-(2-(2-Fluorophenylsulfonamido)pyrimidin-4-yl)benzo-
[d]thiazol-2-yl)acetamide (40). Using 2-fluorobenzenesulfonamide
1802
dx.doi.org/10.1021/jm1014605 |J. Med. Chem. 2011, 54, 1789–1811