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high vacuum. The title compound (28 mg, 60%) was then obtained
as an off-white solid. HPLC: tR =5.84 min; 1H NMR (600 MHz): d=
10.63 (s, 1H), 10.54 (s, 1H), 8.12 (d, J=5.3 Hz, 1H), 8.04 (s, 1H),
7.55 (m, 1H), 7.45 (dt, J=9.3, 3.9 Hz, 1H), 7.41 (ddd, J=7.8, 4.9,
3.4 Hz, 1H), 7.28–7.37 (m, 2H), 7.22 (m, 1H), 6.62 (dd, J=5.1,
1.6 Hz, 1H), 3.93 (td, J=9.4, 2.2 Hz, 2H), 3.47 (dt, J=11.6, 1.9 Hz,
2H), 3,38 (m, 1H) 2.07 (s, 3H), 2.01 (m, 2H), 1.76 ppm (m, 2H); LC–
MS-ESI m/z (%): 589 (100) [M+H]+; HRMS-ESI m/z [M+H]+ calcd
for C27H24F3N4O4S2 589.1186, found 589.1187.
1H NMR (600 MHz): d=7.85 (d, J=5.3 Hz, 1H), 7.42 (ddd, J=8.2,
5.3, 3.3 Hz, 1H), 7.36 (m, 1H), 7.31 (dt, J=8.9, 4.2 Hz, 1H), 7.23 (dt,
J=7.9, 1.4 Hz, 1H), 6.96 (t, J=7.9 Hz, 1H), 6.86 (brs, 1H), 6.66 (t,
J=5.2 Hz, 1H), 6.40 (s, 1H), 6.22 (dd, J=5.3, 1.2 Hz, 1H), 3.93 (m,
2H), 3.47 (dt, J=11.6, 1.8 Hz, 2H), 3.29 (m, 1H) 2.86 (m, 2H), 2.56
(s, 6H), 2.0 (m, 2H), 1.74 ppm (m, 2H); LC–MS-ESI m/z (%): 618
(100) [M+H]+; HRMS-ESI m/z [M+H]+ calcd for C29H31F3N5O3S2
618.1815, found 618.1822.
Compounds 12 and 13 were prepared by using the procedure
mentioned above, starting from 38 and the appropriate amino de-
rivatives.
N-{4-[2-(1-Cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)-
sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}ace-
tamide (20): Prepared by using the procedure mentioned above,
starting from 27e (856 mg, 76%). HPLC: tR =5.57 min; 1H NMR
(400 MHz): d=10.54 (s, 1H), 8.12 (d, J=5.2 Hz, 1H), 8.04 (s, 1H),
7.52 (m, 1H), 7.40 (m, 2H), 7.31 (m, 1H), 7.27 (m, 1H), 7.17 (m, 1H),
6.62 (dd, J=5.2, 1.6 Hz, 1H), 3.04 (m, 2H), 2.36 (t, J=11.3 Hz, 2H),
2.07 (m, 5H), 1.68 (m, 3H), 0.43 (m, 2H), 0.34 ppm (m, 2H); LC–MS-
ESI m/z (%): 628 (100) [M+H]+; HRMS-ESI m/z [M+H]+ calcd for
C30H29F3N5O3S2 628.1659, found 628.1659.
N-[2-({4-[4-(3-{[(2,5-Difluorophenyl)sulfonyl]amino}-2-fluorophen-
yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]pyridin-2-yl}ami-
no)ethyl]acetamide (12): (55 mg, 78%). HPLC: tR =5.47 min;
1H NMR (600 MHz): d=10.68 (brs, 1H), 7.91 (t, J=5.4 Hz, 1H), 7.78
(d, J=5.5 Hz, 1H), 7.57 (m, 1H), 7.45 (m, 2H), 7.33 (m, 1H), 7.30 (m,
1H), 7.21 (m, 1H), 6.73 (brs, 1H), 6.38 (brs, 1H), 6.02 (brs, 1H), 3.93
(m, 2H), 3.46 (dt, J=11.6, 1.8 Hz, 2H), 3.30 (m, 1H), 3.24 (m, 2H),
3.16 (m, 2H), 1.99 (m, 2H), 1.80 (s, 3H), 1.74 ppm (m, 2H); LC–MS-
ESI m/z (%): 632 (100) [M+H]+; HRMS-ESI m/z [M+H]+ calcd for
C29H29F3N5O4S2 632.1608, found 632.1625.
2,5-Difluoro-N-{2-fluoro-3-[5-(1-oxidopyridin-4-yl)-2-(tetrahydro-
2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benze-
nesulfonamide (38): 2,5-Difluoro-N-{2-fluoro-3-[5-(pyridin-4-yl)-2-
(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxyme-
thyl)benzenesulfonamide 27a (500 mg, 0.869 mmol) was dissolved
in CH2Cl2 (9 mL) and 70% m-chloroperbenzoic acid was added
(215 mg, 0.869 mmol). After stirring for 1 h an addition of m-chlor-
operbenzoic acid (215 mg, 0.869 mmol) was made, followed by
a second addition of 190 mg after one more hour. After 5 h total,
the mixture was diluted with CH2Cl2 and washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to
dryness. The crude product was purified by flash chromatography
on silica gel (CH2Cl2/MeOH 95:5) to give the title compound
Methyl [(2S)-1-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-
fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]pyri-
din-2-yl}amino)propan-2-yl]carbamate (13): (20 mg, 20%).
1H NMR (600 MHz): d=10.66 (brs, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.57
(brs, 1H), 7.46 (m, 2H), 7.33 (t, J=6.8 Hz, 1H), 7.27 (brs, 1H), 7.19
(m, 1H), 7.01 (d, J=7.3 Hz, 1H), 6.63 (brs, 1H), 6.40 (s, 1H), 5.96 (d,
J=4.9 Hz, 1H), 3.93 (td, J=9.5, 2.0 Hz, 2H), 3.64 (dq, J=13.9,
6.8 Hz, 1H), 3.50 (s, 3H), 3.47 (dt, J=11.6, 1.9 Hz, 3H), 3.19 (brs,
2H), 2.00 (m, 2H), 1.74 (m, 2H), 1.03 ppm (d, J=6.6 Hz, 3H); LC–
MS-ESI m/z (%): 662 (100) [M+H]+; HRMS-ESI m/z [M+H]+ calcd
for C30H31F3N5O5S2 662.1713, found 662.1714.
1
(420 mg, 82%) as an amorphous solid. HPLC: tR =5.40 min; H NMR
(600 MHz): d=8.11 (m, 2H), 7.63 (m, 2H), 7.55 (m, 1H), 7.51 (m,
1H), 7.32 (m, 2H), 7.15 (m, 2H), 4.99 (s, 2H), 3.95 (m, 2H), 3.48 (dt,
J=11.6, 2.0 Hz, 2H), 3.26 (s, 3H), 2.02 (m, 2H), 1.76 ppm (m, 2H);
LC–MS-ESI m/z (%): 592 (100) [M+H]+; HRMS-ESI m/z [M+H]+
calcd for C27H25F3N3O5S2 592.1182, found 592.1188.
Tetrahydro-2H-pyran-4-carbothioamide (26a):
A
mixture of
methyl tetrahydro-2H-pyran-4-carboxylate (7 g, 48.6 mmol) and
30% aqueous ammonia (20 mL) was stirred in a closed bottle at
room temperature for 18 h. Excess ammonia was removed under
reduced pressure, and the residue was crystallized from EtOH af-
fording tetrahydro-2H-pyran-4-carboxamide (5.6 g, 89%). 1H NMR
(400 MHz): d=7.21 (brs, 1H) 6.73 (brs, 1H) 3.80–3.90 (m, 2H) 3.27
(m, 2H) 2.30 (m, 1H) 1.47–1.66 ppm (m, 4H); LC–MS-ESI m/z (%):
130 [M+H]+. Tetrahydro-2H-pyran-4-carboxamide (2 g, 15.5 mmol)
was suspended in dry THF (20 mL) and Lawesson’s reagent (3.13 g,
7.75 mmol) was added. After holding at reflux for 4 h, the mixture
was poured into a saturated NaHCO3 aqueous solution (200 mL)
and then extracted with Et2O (4ꢁ100 mL). The organic layer was
dried over Na2SO4 and evaporated to dryness, to afford the title
compound (1.2 g, 54%). HPLC: tR =min 2.79; 1H NMR (600 MHz):
d=9.38 (brs, 1H) 9.08 (brs, 1H) 3.87 (dd, J=11.3, 4.4 Hz, 2H) 3.31
(m, 2H) 2.71 (tt, J=11.7, 3.7 Hz, 1H) 1.75 (qd, J=12.5, 4.5 Hz, 2H)
1.56 ppm (m, 2H); LC–MS-ESI m/z (%): 146 (100) [M+H]+; HRMS-
ESI m/z [M+H]+ calcd for C6H12NOS 146.0634, found 146.0634.
N-{3-[5-(2-{[2-(Dimethylamino)ethyl]amino}pyridin-4-yl)-2-(tetra-
hydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-di-
fluorobenzenesulfonamide (11): To a solution of 2,5-Difluoro-N-{2-
fluoro-3-[5-(1-oxidopyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-
thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide
38
(104 mg, 0.175 mmol) in CH2Cl2 (1.5 mL), DIPEA (0.112 mL,
0.656 mmol) was added, followed by PyBroP (106 mg, 0.228 mmol)
and N,N-dimethylaminoethylamine (0.024 mL, 0.219 mmol) and the
mixture was stirred at room temperature overnight. Further addi-
tions of both N,N-dimethylaminoethylamine (0.01 mL) and PyBroP
(20 mg) were made and, after an addition 2 h stirring, the mixture
was diluted with CH2Cl2 and washed with H2O and brine, dried
over Na2SO4 and evaporated to dryness. The crude product was
purified by flash chromatography on silica gel (CH2Cl2/MeOH 96:4)
to give N-{3-[5-(2-{[2-(dimethylamino)ethyl]amino}pyridin-4-yl)-2-
(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-di-
fluoro-N-(methoxymethyl)benzenesulfonamide (118 mg, 85%). This
intermediate (100 mg, 0.15 mmol) was treated with a 9:1 TFA/H2O
mixture (2 mL) and stirred at 608C for 5 h. The mixture was evapo-
rated to dryness, taken up with CH2Cl2 and washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel (CH2Cl2/MeOH 95:5) to give the title
compound (71 mg, 66%) as an off-white solid. HPLC: tR =5.33 min;
1-Cyclopropylpiperidine-4-carbothioamide (26b): To a solution of
piperidine-4-carboxamide (1 g, 7.8 mmol) in MeOH (80 mL) 1-
ethoxy-1-trimethylsilyloxycyclopropane (2.35 mL, 11.7 mmol) was
added, followed by AcOH (1.34 mL, 23.4 mmol) and NaBH3CN
(923 mg, 12.48 mmol) and the mixture was stirred at 608C over-
night. The solvent was then concentrated under reduced pressure,
and the residue was purified by flash chromatography on silica gel
(CH2Cl2/MeOH/NH4OH 7n in MeOH 90:9:1) affording 1-cyclopropyl-
piperidine-4-carboxamide. This intermediate was suspended in dry
THF (20 mL) and Lawesson’s reagent (2.7 g, 6.67 mmol) was added.
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