Journal of Medicinal Chemistry
ARTICLE
purified by preparative HPLC (C18 XBridge 30 mm ꢁ 100 mm; aq
NH4HCO3 pH 9/MeCN gradient from 80/20 to 0/100), affording
compound 13 as a colorless oil. The compound was made solid after
triturating with Et2O/heptane, yielding final product 13 as a white foam
(0.023 g, 7.2%). 1H NMR (400 MHz, DMSO-d6) δ 4.50 (dt, J = 27.8,
4.7 Hz, 2 H), 4.85 (dt, J = 47.2, 4.6 Hz, 2 H), 5.31 (s, 2 H), 7.09 (d, J =
8.8 Hz, 2 H), 7.22 (d, J = 6.0 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2 H), 7.89 (d,
J = 7.9 Hz, 1 H), 7.89 (d, J = 7.6 Hz, 1 H), 8.18 (t, J = 7.9 Hz, 1 H), 8.24
(s, 1 H), 8.46 (d, J = 6.0 Hz, 2 H). C23H18F4N4O. LCMS (ESI): Rt 3.73,
m/z 443 [M + H]+, purity 91%.
from 100/0 to 95/5) to give compound 17 as a colorless oil that was
converted into the corresponding succinic acid salt in a similar way as
describedabove for final compound 3, yielding the succinic acid salt of final
compound 17 as a white solid (0.09 g, 25.6%); mp 126.6 °C (DSC). 1H
NMR (400 MHz, DMSO-d6) δ 2.24 (dquin, J = 26.4, 6.2 Hz, 2 H), 2.41 (s,
2 H), 3.84 (s, 3 H), 4.27 (t, J = 6.9 Hz, 2 H), 4.52 (dt, J = 47.2, 5.7 Hz, 2 H),
5.11 (s, 2 H), 7.03 (br d, J = 8.8 Hz, 2 H), 7.17ꢀ7.25 (m, 2 H), 7.31 (br d,
J = 8.8 Hz, 2 H), 7.43 (dd, J = 8.3, 3.0 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 1 H),
8.23 (s, 1 H), 8.29 (d, J = 2.8 Hz, 1 H), 8.40ꢀ8.48 (m, 2 H), 12.18 (br s,
1 H). C24H23FN4O2 0.5C4H6O4. LCMS (ESI): Rt 3.97, m/z 419
3
[M + H]+.
2-Cyclopropyl-6-[[4-[1-(2-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-
3-yl]phenoxy]methyl]-pyridine succinate (14). A mixture of com-
2-[[4-[1-(2-Fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]-
methyl]-3-methoxy-pyridine succinate (18). Compound 18 was syn-
3
pound 12 (0.14 g, 0.263 mmol), cyclopropyl-boronic acid (0.029 g,
0.341 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol) in a mixture of aq
Na2CO3/dioxane 1:1 (5 mL) was heated in a microwave oven at 130 °C
for 15 min. After cooling to rt, the crude mixture was diluted with water
and extracted with DCM. The organic solvent was dried over Na2SO4
and evaporated to dryness. The residue was purified by column chro-
matography (silicagel; EtOAc), the desired fractions were collected, and
the solvent was evaporated to give the desired compound as an oil, which
contained PPh3O as a main impurity. This oil was further purified by
preparative HPLC (C18 XBridge 19 mm ꢁ 100 mm; aq NH4HCO3 pH
9/MeCN gradient from 80/20 to 0/100), affording 14 as a colorless oil.
The residue was dissolved in MeOH (2 mL), and a solution of succinic
acid (0.017 g, 0.144 mmol) in MeOH (1 mL) was slowly added. The
solvent was evaporated to dryness, and the residue was treated with
DCM/DIPE, yielding the succinic acid salt of final compound 14 as a
white solid (0.076 g, 54.4%); mp 91.3 °C (DSC). 1H NMR (400 MHz,
DMSO-d6) δ 0.87ꢀ0.99 (m, 4 H), 2.05ꢀ2.16 (m, 1 H), 2.42 (s, 4 H),
4.49 (dt, J = 27.7, 4.6 Hz, 2 H), 4.85 (dt, J = 47.2, 4.7 Hz, 2 H), 5.10 (s,
2 H), 7.04 (d, J = 9.0 Hz, 2 H), 7.20ꢀ7.24 (m, 3 H), 7.26 (d, J = 7.4 Hz,
1 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.68 (t, J = 7.7 Hz, 1 H), 8.24 (s, 1 H), 8.45
3
thesized according to the general procedure starting from compound 8b
(0.15 g, 0.52 mmol) and (3-methoxypyridin-2-yl)methanol.26 The crude
mixture was purified by chromatography (silicagel; EtOAc/MeOH from
100/0 to 95/5) to give compound 18 as a colorless oil, which was con-
verted into the corresponding succinic acid salt in a similar way as des-
cribed above for compound 3, yielding the succinic acid salt of final com-
1
pound 18 as a white solid (0.09 g, 32.5%); mp 178.9 °C (DSC). H
NMR (400 MHz, DMSO-d6) δ 2.41 (s, 4 H), 3.86 (s, 3 H), 4.49 (dt, J =
27.7, 4.8 Hz, 2 H), 4.85 (dt, J = 47.2, 4.8 Hz, 2 H), 5.13 (s, 2 H),
7.03 (br d, J = 8.8 Hz, 2 H), 7.18ꢀ7.26 (m, 2 H), 7.31 (br d, J = 8.8 Hz, 2
H), 7.41 (dd, J = 8.3, 4.6 Hz, 1 H), 7.52 (dd, J = 8.4, 1.0 Hz, 1 H), 8.16
(dd, J = 4.6, 1.4 Hz, 1 H), 8.23 (s, 1 H), 8.43ꢀ8.48 (m, 2 H), 12.16
(br s, 2 H). C23H21FN4O2 C4H6O4. LCMS (ESI): Rt 3.52, m/z 405
3
[M + H]+.
3-Fluoro-2-[[4-[1-(2-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-
phenoxy]methyl]-pyridine 1.2succinate (19). Compound 19 was
3
synthesized according to the general procedure starting from compound
8b (0.10 g, 0.35 mmol) and (3-fluoropyridin-2-yl)methanol. The crude
mixture was purified by chromatography (silicagel; EtOAc) to give
compound 19 as a colorless oil that was converted into the correspond-
ing succinic acid salt, in a similar way as described above for final com-
pound 3, yielding the succinic acid salt of final compound 19 as an
(d, J = 6.2 Hz, 2 H), 12.17 (br s, 1 H). C25H23FN4O C4H6O4. LCMS
3
(ESI): Rt 4.19, m/z 415 [M + H]+.
3-Methoxy-2-[[4-[4-(4-pyridinyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-
3-yl]phenoxy]methyl]-pyridine (15). Compound 15 was synthesized
according to the general procedure starting from compound 8a (0.15 g,
0.47 mmol) and (3-methoxypyridin-2-yl)methanol.26 The crude mix-
ture was purified by chromatography (silicagel; EtOAc/MeOH from
100/0 to 95/5) to give compound 15 as a white solid that was further
crystallized from DIPE (0.12 g, 58%); mp 147 °C. 1H NMR (400 MHz,
CDCl3) δ 3.89 (s, 3 H), 4.77 (q, J = 8.3 Hz, 2 H), 5.26 (s, 2 H),
7.02ꢀ7.07 (m, 2 H), 7.17ꢀ7.21 (m, 2 H), 7.23 (dd, J = 8.3, 1.6 Hz, 1 H),
7.27 (dd, J = 8.3, 4.6 Hz, 1 H), 7.34ꢀ7.41 (m, 2 H), 7.70 (s, 1 H), 8.25
(dd, J = 4.4, 1.6 Hz, 1 H), 8.49ꢀ8.53 (m, 2 H). C23H19F3N4O2. LCMS
(ESI): Rt 3.01, m/z 441 [M + H]+.
2-[[4-[1-(3-Fluoropropyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]-
methyl]-3-methoxy-pyridine (16). Compound 16 was synthesized ac-
cording to the general procedure starting from compound 8c (0.16 g,
0.54 mmol) and (3-methoxypyridin-2-yl)methanol.26 The crude mix-
ture was purified by chromatography (silicagel; EtOAc/MeOH from
100/0 to 95/5) to give compound 16 as a white solid (0.09 g, 40%); mp
165.9 °C. 1H NMR (500 MHz, CDCl3) δ 2.34 (dquin, J = 26.9, 6.0, 6.0,
6.0, 6.0 Hz, 2 H), 3.89 (s, 3 H), 4.33 (t, J = 6.8 Hz, 2 H), 4.51 (dt, J =
47.1, 5.5 Hz, 2 H), 5.25 (s, 2 H), 7.01ꢀ7.06 (m, 2 H), 7.16ꢀ7.20 (m,
2 H), 7.23 (dd, J = 8.4, 1.2 Hz, 1 H), 7.27 (dd, J = 8.4, 4.7 Hz, 1 H),
7.34ꢀ7.41 (m, 2 H), 7.63 (s, 1 H), 8.25 (dd, J = 4.5, 1.6 Hz, 1 H),
8.45ꢀ8.50 (m, 2 H). C24H23FN4O2. LCMS (ESI): Rt 3.78, m/z 419
[M + H]+.
1
amorphous solid (0.045 g, 24%). H NMR (400 MHz, DMSO-d6) δ
2.41 (s, 4.8 H), 4.50 (dt, J = 27.7, 4.6 Hz, 2 H), 4.85 (dt, J = 46.9, 4.9 Hz,
2 H), 5.25 (d, J = 2.1 Hz, 2 H), 7.04ꢀ7.10 (m, 2 H), 7.19ꢀ7.25 (m, 2 H),
7.30ꢀ7.37 (m, 2 H), 7.54 (dt, J = 8.5, 4.4 Hz, 1 H), 7.78ꢀ7.84 (m, 1 H),
8.24 (s, 1 H), 8.42ꢀ8.51 (m, 3 H), 12.26 (br s, 2.4 H). C22H18F2N4O
3
1.2C4H6O4. LCMS (ESI): Rt 2.63, m/z 393 [M + H]+.
5-Bromo-2-[[4-[1-(2-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-
phenoxy]methyl]-pyridine (20). Compound 20 was synthesized ac-
cording to the general procedure starting from compound 8b (0.10 g,
0.35 mmol) and (5-bromopyridin-2-yl)methanol. The crude mixture
was purified by chromatography (silicagel; EtOAc/heptane 90:10) to
give compound 20 that after treatment with Et2O was obtained as a
white solid (0.025 g, 15.6%); mp 125.8 °C. 1H NMR (400 MHz, CDCl3)
δ 4.47 (dt, J = 27.0, 4.6 Hz, 2 H), 4.84 (dt, J = 46.9, 4.9 Hz, 2 H), 5.18 (s,
2 H), 6.93ꢀ6.98 (m, 2 H), 7.17ꢀ7.20 (m, 2 H), 7.38ꢀ7.42 (m, 2 H),
7.45 (dd, J = 8.3, 0.7 Hz, 1 H), 7.70 (d, J = 0.5 Hz, 1 H), 7.85 (dd, J = 8.3,
2.3 Hz, 1 H), 8.47ꢀ8.51 (m, 2 H), 8.66 (dd, J = 2.3, 0.5 Hz, 1 H).
C22H18BrFN4O. LCMS (ESI): Rt 3.29, m/z 453 [M + H]+.
6-[[4-[1-(2-Fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]
methyl]-3-pyridinecarbonitrile (21). Compound 21 was synthesized
according to the general procedure starting from compound 8b (0.18 g,
0.63 mmol) and 6-(hydroxymethyl)nicotinonitrile. The crude mixture
was purified by chromatography (silicagel; EtOAc) to give compound
21 as white solid (0.1 g, 39.4%); mp >300 °C (dec). 1H NMR (500 MHz,
CDCl3) δ 4.48 (dt, J = 27.2, 4.6 Hz, 2 H), 4.85 (dt, J = 46.8, 4.6 Hz, 2 H),
5.28 (s, 2 H), 6.96 (br d, J = 9.0 Hz, 2 H), 7.16ꢀ7.21 (m, 2 H),
7.39ꢀ7.45 (m, 2 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.71 (s, 1 H), 8.00 (dd, J =
8.1, 2.0 Hz, 1 H), 8.49 (br d, J = 6.1 Hz, 2 H), 8.87 (d, J = 1.4 Hz, 1 H).
C23H18FN5O. LCMS (ESI): Rt 3.11, m/z 400 [M + H]+.
2-[[4-[1-(3-Fluoropropyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy-
methyl]-5-methoxy-pyridine 0.5succinate (17). Compound 17 was
3
synthesized according to the general procedure starting from compound
8c (0.25 g, 0.84 mmol) and 5-methoxy-2-hydroxymethylpyridine.25 The
crude mixture was purified by chromatography (silicagel; MeCN/MeOH
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dx.doi.org/10.1021/jm200536d |J. Med. Chem. 2011, 54, 5820–5835