12
M. Getlik et al. / European Journal of Medicinal Chemistry 48 (2012) 1e15
(400 MHz, DMSO-d6)
d
10.84 (s, 1H), 8.98 (s, 1H), 7.38 (d, J ¼ 8.4 Hz,
J ¼ 6.6 Hz, 2H), 1.28 (s, 9H); 13C NMR (101 MHz, DMSO-d6)
d 173.29,
2H), 7.31 (m, 4H), 7.13 (t, J ¼ 8.9 Hz, 2H), 6.74 (s,1H), 6.41 (s,1H), 4.43
161.69, 159.72, 151.51, 148.70, 139.30, 137.60, 137.12, 135.25, 131.17,
129.04, 128.30, 128.20, 125.05, 108.24, 96.01, 72.55, 69.20, 32.91,
32.20, 31.02, 30.44. HRMS (ESI-MS) Calc.: 534.21695 for
C28H32O4N5S [M þ Hþ], Found: 534.21614.
(s, 2H), 3.59 (t, J ¼ 6.4 Hz, 2H), 2.76 (t, J ¼ 6.6 Hz, 2H), 2.36 (s, 3H),1.27
(s, 9H); 13C NMR (101 MHz, DMSO-d6)
d 162.68, 160.66, 160.26,
150.36, 148.12, 137.04, 136.25, 135.70, 134.67, 129.76, 129.52
(3JCeF ¼ 8.2 Hz, 2C),124.47,114.95 (2JCeF ¼ 21.2 Hz, 2C),107.40, 94.79,
70.90, 68.29, 32.05, 31.37, 30.20, 20.62; HRMS (ESI-MS) Calc.:
508.21770 for C27H31O2N5F1S1 [M þ Hþ], Found: 508.21688.
7.1.14.3. [3-(5-{[({4-[2-(Benzyloxy)ethyl]-1,3-thiazol-2-yl}amino)
carbonyl]amino}-3-cyclopentyl-1H-pyrazol-1-yl)phenyl]acetic acid
(16g). Prepared as described above in the general procedure
using 8a (22 mg, 0.09 mmol), 15e (60 mg, 0.13 mmol), DIPEA
(83 mL, 0.49 mmol), DMSO (2 mL), LiOH (8 mg, 0.28 mmol) and
MeOH/H2O (2 mL). The crude product was purified using
7.1.13.3. N-[3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N0-{4-
[2-(4-pyridinylmethoxy)ethyl]-1,3-thiazol-2-yl}urea (16c). Prepared
as described above in the general procedure using 8c (40 mg,
0.15 mmol), 15a (60 mg, 0.15 mmol), DIPEA (101
DMSO (2 mL). The product was obtained as 12 mg (16%) of an off-
white solid: 1H NMR (400 MHz, DMSO-d6)
10.90 (bs, 1H), 9.01
m
L, 0.59 mmol) and
preparative HPLC (MeCN/H2O with 0.1% TFA) to furnish 11 mg
(22%) of 16g: 1H NMR (400 MHz, DMSO-d6)
d 10.90 (bs, 1H), 9.01
d
(bs, 1H), 8.50 (d, J ¼ 5.8 Hz, 2H), 7.38 (d, J ¼ 8.4 Hz, 2H), 7.32 (d,
J ¼ 8.3 Hz, 2H), 7.26 (d, J ¼ 5.6 Hz, 2H), 6.76 (s, 1H), 6.40 (s, 1H),
4.51 (s, 2H), 3.65 (t, J ¼ 6.5 Hz, 2H), 2.80 (d, J ¼ 6.5 Hz, 2H), 2.36 (s,
(bs, 1H), 8.50 (d, J ¼ 5.8 Hz, 2H), 7.38 (d, J ¼ 8.4 Hz, 2H), 7.32 (d,
J ¼ 8.3 Hz, 2H), 7.26 (d, J ¼ 5.6 Hz, 2H), 6.76 (s, 1H), 6.40 (s, 1H), 4.51
(s, 2H), 3.65 (t, J ¼ 6.5 Hz, 2H), 2.80 (d, J ¼ 6.5 Hz, 2H), 2.36 (s, 3H),
3H), 1.27 (s, 9H); 13C NMR (101 MHz, DMSO-d6)
d 160.66, 157.98,
1.27 (s, 9H); 13C NMR (101 MHz, DMSO-d6)
d
160.66, 157.98, 157.68,
157.68, 150.55, 149.43, 147.74, 137.03, 136.24, 135.74, 129.76,
124.43, 121.74, 107.51, 95.01, 70.00, 68.87, 32.06, 31.32, 30.21,
20.63; HRMS (ESI-MS) Calc.: 491.22237 for C26H31O2N6S1
[M þ Hþ], Found: 491.22154.
150.55, 149.43, 147.74, 137.03, 136.24, 135.74, 129.76, 124.43, 121.74,
107.51, 95.01, 70.00, 68.87, 32.06, 31.32, 30.21, 20.63; HRMS (ESI-MS)
Calc.: 491.22237 for C26H31O2N6S1 [M þ Hþ], Found: 491.22154.
7.1.14. General procedure for the preparation of thiazolo-pyrazole-
urea-acids (16deh)
7.1.14.4. [3-(5-{[({4-[2-(Benzyloxy)ethyl]-1,3-thiazol-2-yl}amino)
carbonyl]amino}-3-tert-butyl-1H-pyrazol-1-yl)phenyl]acetic acid
(16f). Prepared as described above in the general procedure
using 8a (32 mg, 0.12 mmol), 15d (70 mg, 0.15 mmol), DIPEA
(33 mL, 0.18 mmol), DMSO (2 mL), LiOH (6 mg, 0.24 mmol) and
MeOH/H2O (2 mL). The crude product was purified using
A Schlenk tube was flushed with argon and charged with 8a,
anhydrous DMSO and DIPEA. The reaction mixture was stirred at rt
for 10 min before carbamate (15bef) was added in one portion. The
reaction mixture was heated to 60 ꢁC for overnight. After cooling to
rt the mixture was portioned between EtOAc and H2O. The aqueous
layer was extracted with EtOAc (3 ꢂ 10 mL). The combined organic
layer was washed with brine and H2O, dried over Na2SO4 and
evaporated in vacuo. The residue was redissolved in MeOH/H2O
(1:1) and an aqueous solution of LiOH (2 eq.) was added. The
reaction mixture was stirred for 1e2 h and then diluted with EtOAc
and diluted formic acid. The organic layer was dried over Na2SO4,
before the volatiles were removed in vacuo. The crude product was
then purified using preparative HPLC (MeCN/H2O with 0.1% TFA).
preparative HPLC (MeCN/H2O with 0.1% TFA) to furnish 23 mg
(35%) of 16f: 1H NMR (400 MHz, DMSO-d6)
d 9.02 (s, 1H),
7.49e7.23 (m, 9H), 6.75 (s, 1H), 6.43 (s, 1H), 4.46 (s, 2H), 3.68 (s,
2H), 3.62 (t, J ¼ 6.7 Hz, 2H), 2.79 (t, J ¼ 6.7 Hz, 2H), 1.29 (s, 9H); 13C
NMR (101 MHz, DMSO-d6)
d 172.43, 160.94, 158.80, 158.45,
158.10, 138.48, 138.06, 136.49, 136.35, 129.12, 128.64, 128.21,
127.48, 127.37, 125.63, 122.46, 107.41, 95.29, 71.72, 68.39, 40.30,
32.10, 31.40, 30.21; HRMS (ESI-MS) Calc.: 534.21695 for
C28H32O4N5S1 [M þ Hþ], Found: 534.21622.
7.1.14.1. [3-(5-{[({4-[2-(Benzyloxy)ethyl]-1,3-thiazol-2-yl}amino)
carbonyl]amino}-3-cyclopropyl-1H-pyrazol-1-yl)phenyl]acetic acid
(16d). Prepared as described above in the general procedure using
7.1.14.5. [4-(5-{[({4-[2-(Benzyloxy)ethyl]-1,3-thiazol-2-yl}amino)
carbonyl]amino}-3-cyclopentyl-1H-pyrazol-1-yl)phenyl]acetic acid
(16h). Prepared as described above in the general procedure
using 8a (22 mg, 0.08 mmol), 15f (60 mg, 0.13 mmol), DIPEA
8a (88 mg, 0.33 mmol), 15b (150 mg, 0.33 mmol), DIPEA (168 mL,
0.98 mmol), DMSO (2 mL), LiOH (17 mg, 0.66 mmol) and MeOH/
H2O (2 mL). The crude product was purified twice using prepara-
tive HPLC (MeCN/H2O with 0.1% TFA) to furnish 16 mg (9%) of 16d:
(63 mL, 0.37 mmol), DMSO (2 mL), LiOH (11 mg, 0.5 mmol) and
MeOH/H2O (2 mL). The crude product was purified using
preparative HPLC (MeCN/H2O with 0.1% TFA) to furnish 28 mg
1H NMR (400 MHz, DMSO-d6)
d
12.31 (bs, 1H), 10.87 (bs, 1H), 8.93
(64%) of 16h: 1H NMR (400 MHz, DMSO-d6)
d 8.97 (s, 1H),
(s, 1H), 7.48e7.23 (m, 9H), 6.74 (s, 1H), 6.19 (s, 1H), 4.45 (s, 2H), 3.67
(s, 2H), 3.62 (t, J ¼ 6.7 Hz, 2H), 2.78 (t, J ¼ 6.6 Hz, 2H), 1.94e1.84 (m,
1H), 0.92e0.85 (m, 2H), 0.73e0.66 (m, 2H); 13C NMR (101 MHz,
7.49e7.37 (m, 3H), 7.35e7.23 (m, 6H), 6.74 (s, 1H), 6.37 (s, 1H),
4.45 (s, 2H), 3.67 (s, 2H), 3.61 (t, J ¼ 6.6 Hz, 2H), 3.07e2.98 (t,
J ¼ 6.7 Hz, 2H), 2.03e1.93 (m, 2H), 1.76e1.58 (m, 6H); 13C NMR
DMSO-d6)
d
173.23, 163.75, 159.55, 155.35, 139.31, 138.75, 137.39,
(101 MHz, DMSO-d6) d 172.46, 158.60, 156.65, 138.51, 137.99,
137.34, 129.95, 129.46, 129.05, 128.31, 128.21, 126.40, 123.11, 108.26,
95.80, 72.54, 69.21, 41.09, 32.21, 10.25, 8.61. HRMS (ESI-MS) Calc.:
518.18565 for C27H28O4N5S [M þ Hþ], Found: 518.18488.
136.55, 129.18, 128.68, 128.25, 127.52, 127.42, 125.64, 125.49,
122.38, 107.48, 96.12, 71.76, 68.40, 40.32, 32.73, 31.40, 25.04;
HRMS (ESI-MS) Calc.: 546.21695 for C29H32O4N5S1 [M þ Hþ],
Found: 546.21675.
7.1.14.2. [4-(5-{[({4-[2-(Benzyloxy)ethyl]-1,3-thiazol-2-yl}amino)car-
bonyl]amino}-3-tert-butyl-1H-pyrazol-1-yl)phenyl]acetic acid (16e).
Prepared as described above in the general procedure using 8a
7.1.15. 2-{2-[(tert-Butoxycarbonyl)amino]-1,3-thiazol-4-yl}ethyl 4-
methylbenzenesulfonate (9)
(44 mg, 0.15 mmol), 15c (70 mg, 0.15 mmol), DIPEA (75
m
L,
7 (350 mg, 0.41 mmol) was dissolved in ice-cold anhydrous
pyridine (5 mL) and a solution of tosylchloride (78 mg, 0.41 mmol)
in anhydrous pyridine (3 mL) was added dropwise. The reaction
mixture was stirred at rt for 3h. The mixture was diluted with EtOAc
(5 mL) and water (5 mL) and the organic layer was extracted with
EtOAc (3 ꢂ 5 mL). The organic layer was then dried over Na2SO4 and
evaporated in vacuo. The crude product was purified using column
0.44 mmol), DMSO (2 mL), LiOH (17 mg, 0.66 mmol) and MeOH/H2O
(2 mL). The crude product was purified using preparative HPLC
(MeCN/H2O with 0.1% TFA) to furnish 23 mg (29%) of the white solid
16e: 1H NMR (400 MHz, DMSO-d6)
d
9.01 (s, 1H), 7.45 (d, J ¼ 8.5 Hz,
2H), 7.40 (d, J ¼ 8.6 Hz, 2H), 7.34e7.18 (m, 5H), 6.74 (s, 1H), 6.42 (s,
1H), 4.45 (s, 2H), 3.65 (s, 2H), 3.61 (t, J ¼ 6.7 Hz, 2H), 2.77 (t,