Journal of Medicinal Chemistry
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NMR (500 MHz, DMSO-d6): δ (ppm) 2.38 (s, 3 H), 3.75 (dd, J = 4.9,
4.3 Hz, 4 H), 4.15 (t, J = 4.6 Hz, 4 H), 5.25 (q, J = 9.2 Hz, 2 H), 7.39
(d, J = 4.6 Hz, 1 H), 7.64 (d, J = 4.6 Hz, 1 H), 7.98 (s, 1 H), 8.33 (s, 1
H). Mp: 137.9−138.9 °C.
water and DCM. The organic layer was separated, dried (Na2SO4),
and filtered, and the solvents were evaporated in vacuo. The crude
product was purified by flash column chromatography (silica; 7 M
solution of ammonia in MeOH in DCM, 1/99). The desired fractions
were collected, and the solvent was evaporated in vacuo to yield 103
mg (82%) of 2-methyl-1-[4-(2-methyl-8-morpholin-4-ylimidazo[1,2-
a]pyrazin-3-yl)pyrazol-1-yl]propan-2-ol as a colorless oil.
2-Methyl-8-morpholin-4-yl-3-[1-(2-fluoroethyl)-1H-pyrazol-
4-yl]imidazo[1,2-a]pyrazine (22). 22 was prepared according to a
protocol analogous to that of compound 2 from 7b and 12f. Flash
column chromatography (silica; AcOEt in heptane, 30/70 to 0/100)
yielded compound 22 as a pale yellow solid (49%). UPLC/ESI-
HRMS: m/z for C16H20FN6O (M + H)+ calcd 331.1682, found
Step 2. Synthesis of 29. A 60% suspension of sodium hydride in
mineral oils (163 mg, 4.09 mmol) was added to a stirred solution of 2-
methyl-1-[4-(2-methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazin-3-yl)-
pyrazol-1-yl]propan-2-ol (486 mg, 1.36 mmol) in THF (15 mL). The
mixture was stirred at 0 °C for 5 min, and then dimethyl sulfate (0.324
mL, 4.86 mmol) was added. The mixture was stirred at 70 °C for 18 h.
Then a saturated solution of NaHCO3 was added. The organic layer
was separated, dried (Na2SO4), and filtered, and the solvents were
evaporated in vacuo. The crude product was purified twice by flash
column chromatography (silica; 7 M solution of ammonia in MeOH in
DCM, 1/99) and by reversed-phase HPLC. The desired fractions were
collected, and the solvent was evaporated in vacuo to yield 29 (197
mg, 39%). UPLC/ESI-HRMS: m/z for C19H27N6O2 (M + H)+ calcd
1
331.1685 (0.9 ppm). tR = 1.31 min. H NMR (400 MHz, CDCl3): δ
(ppm) 2.43 (s, 3 H), 3.95−3.83 (m, 4 H), 4.29−4.19 (m, 4 H), 4.60−
4.43 (m, 2 H), 4.79 (t, J = 4.6 Hz, 1 H), 4.91 (t, J = 4.6 Hz, 1 H), 7.35
(d, J = 4.4 Hz, 1 H),), 7.43 (d, J = 4.6 Hz, 1 H), 7.68 (s, 1 H), 7.72 (s,
1 H). Mp: 151.5 °C.
3-[1-(2-Chlorobenzyl)-1H-pyrazol-4-yl]-2-methyl-8-morpho-
lin-4-ylimidazo[1,2-a]pyrazine (23). 23 was prepared according to
a protocol analogous to that for compound 2 from 7b and 12g.
Reversed-phase HPLC yielded compound 23 as a gray solid (34%).
UPLC/ESI-HRMS: m/z for C21H22ClN6O (M + H)+ calcd 409.1543,
found 409.1546 (0.7 ppm). tR = 2.27 min. 1H NMR (300 MHz,
CDCl3): δ (ppm) 2.35 (s, 3 H), 3.81 (t, J = 4.5 Hz, 4 H), 4.17 (t, J =
4.7 Hz, 4 H), 5.46 (s, 2 H), 7.09−7.16 (m, 1 H), 7.21−7.26 (m, 2 H),
7.27 (d, J = 4.7 Hz, 1 H), 7.35 (d, J = 4.5 Hz, 1 H), 7.38 (dd, J = 4.3,
2.8 Hz, 1 H), 7.59 (s, 1 H), 7.66 (s, 1 H). Mp: 122.30−128.33 °C.
2-Methyl-8-morpholin-4-yl-3-(1-pyridin-4-ylmethyl-1H-pyr-
azol-4-yl)imidazo[1,2-a]pyrazine (24). 24 was prepared according
to a protocol analogous to that for 2 from 7b and 12h. Flash column
chromatography (silica; AcOEt in heptane, 30/70 to 100/0) yielded
compound 24 as a beige solid (54%). UPLC/ESI-HRMS: m/z for
C20H22N7O (M + H)+ calcd 376.1886, found 376.1886 (0.0 ppm). tR =
1
371.2195, found 371.2208 (3.5 ppm). tR = 1.67 min. H NMR (500
MHz, DMSO-d6): δ (ppm) 1.13 (s, 6 H), 2.38 (s, 3 H), 3.21 (s, 3 H),
3.75 (t, J = 4.9 Hz, 4 H), 4.16 (t, J = 4.6 Hz, 4 H), 4.23 (s, 2 H), 7.38
(d, J = 4.6 Hz, 1 H), 7.64 (d, J = 4.3 Hz, 1 H), 7.80 (s, 1 H), 8.05 (s, 1
H).
3-(1-Ethyl-1H-pyrazol-4-yl)-2-methyl-8-morpholin-4-
ylimidazo[1,2-a]pyrazine (30). 30 was prepared according to a
protocol analogous to that for 29 (step 1) from 28 and iodoethane.
Flash column chromatography (silica; AcOEt in heptane, 50/50 to
100/0) yielded compound 30 (0.103 g, 62%) as a white solid. UPLC/
ESI-HRMS: m/z for C16H21N6O (M + H)+ calcd 313.1777, found
313.1793 (5.1 ppm). tR = 1.42 min. 1H NMR (500 MHz, DMSO-d6):
δ (ppm) 1.45 (t, J = 7.2 Hz, 3 H), 2.38 (s, 3 H), 3.74 (t, J = 4.6 Hz, 4
H), 4.15 (t, J = 4.6 Hz, 4 H), 4.24 (q, J = 7.2 Hz, 2 H), 7.36 (d, J = 4.6
Hz, 1 H), 7.69 (d, J = 4.3 Hz, 1 H), 7.79 (s, 1 H), 8.19 (s, 1 H).
3-Bromo-2-methyl-8-pyrrolidin-1-ylimidazo[1,2-a]pyrazine
(31). 31 was prepared according to a protocol analogous to that for 7a
from 6b and pyrrolidine. Flash column chromatography (silica; AcOEt
in DCM) yielded 31 as a white solid (85%).
1
1.33 min. H NMR (500 MHz, DMSO-d6): δ (ppm) 2.39 (s, 3 H),
3.65−3.78 (m, 4 H), 4.15 (d, J = 4.9 Hz, 4 H), 5.51 (s, 2 H), 7.22 (d, J
= 5.8 Hz, 2 H), 7.33−7.42 (m, 1 H), 7.68−7.73 (m, 1 H), 7.90 (s, 1
H), 8.39 (s, 1 H), 8.56 (d, J = 5.8 Hz, 2 H).
3-[[4-(2-Methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazin-3-
yl)pyrazol-1-yl]methyl]isoquinoline (25). 25 was prepared accord-
ing to a protocol analogous to that for 2 from 7b and 12i. Flash
column chromatography (silica; AcOEt in heptane, 60/40 to 100/0)
yielded compound 25 as a solid (98%). UPLC/ESI-HRMS: m/z for
C24H24N7O (M + H)+ calcd 426.2042, found 426.2047 (1.2 ppm). tR =
3-[1-(2-Methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-pyrroli-
din-1-ylimidazo[1,2-a]pyrazine (32). 32 was prepared according to
a protocol analogous to that for compound 2 from 31 and 12a. Flash
column chromatography (silica; 7 M solution of ammonia in MeOH in
DCM, 10/90) yielded compound 32 as a white solid (23%). UPLC/
ESI-HRMS: m/z for C17H23N6O (M + H)+ calcd 327.1933, found
1
1.98 min. H NMR (500 MHz, CDCl3): δ (ppm) 2.43 (s, 3 H), 3.88
(t, J = 4.9 Hz, 4 H), 4.24 (t, J = 4.6 Hz, 4 H), 5.73 (s, 2 H), 7.30−7.36
(m, 2 H), 7.44 (d, J = 4.3 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.70−
7.78 (m, 2 H), 7.80 (s, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 8.09 (d, J = 8.4
Hz, 1 H), 8.19 (d, J = 8.7 Hz, 1 H).
1
327.1938 (1.5 ppm). tR = 1.57 min. H NMR (400 MHz, CDCl3): δ
3-[1-(2-Methoxypropyl)-1H-pyrazol-4-yl]-2(S)-methyl-8-mor-
pholin-4-ylimidazo[1,2-a]pyrazine (26). 26 was prepared accord-
ing to a protocol analogous to that for compound 2 from 7b and 12j.
Flash column chromatography (silica; AcOEt in heptane, 70/30 to
100/0) and reversed-phase HPLC yielded compound 26 as a beige
solid (56%). UPLC/ESI-HRMS: m/z for C18H25N6O2 (M + H)+ calcd
(ppm) 1.97−2.05 (m, 4 H), 2.43 (s, 3 H), 3.38 (s, 3 H), 3.81 (t, J =
5.2 Hz, 2 H), 4.05 (br s, 4 H), 4.39 (t, J = 5.2 Hz, 2 H), 7.29 (s, 2 H),
7.68 (d, J = 5.3 Hz, 2 H).
2-Methyl-8-pyridin-4-ylimidazo[1,2-a]pyrazine (33a). 33a
was prepared according to a protocol analogous to that for compound
2 from 5b and 4-pyridylboronic acid. Flash column chromatography
(silica; MeOH in DCM, 5/95) yielded 33a (53%) as a pale brown
1
357.2039, found 357.2063 (6.7 ppm). tR = 1.48 min. H NMR (500
MHz, DMSO-d6): δ (ppm) 1.10 (d, J = 6.4 Hz, 3 H), 2.38 (s, 3 H),
3.21 (s, 3 H), 3.74 (br t, J = 4.6 Hz, 4 H), 3.75−3.81 (m, 1 H), 4.15
(br t, J = 4.3 Hz, 4 H), 4.22 (dd, J = 5.6, 2.5 Hz, 2 H), 7.38 (d, J = 4.6
Hz, 1 H), 7.65 (d, J = 4.6 Hz, 1 H), 7.81 (s, 1 H), 8.14 (s, 1 H).
2-Methyl-8-morpholin-4-yl-3-(1H-pyrazol-4-yl)imidazo[1,2-
a]pyrazine (28). 28 was prepared according to a protocol analogous
to that for compound 2 from 7b and commercially available 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylic acid tert-
butyl ester (27). Flash column chromatography (silica; AcOEt)
yielded 28 as a solid (81%).
3-[1-(2-Methoxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-meth-
yl-8-morpholin-4-ylimidazo[1,2-a]pyrazine (29). Step 1: Syn-
thesis of 2-Methyl-1-[4-(2-methyl-8-morpholin-4-ylimidazo[1,2-a]-
pyrazin-3-yl)pyrazol-1-yl]propan-2-ol. A mixture of 28 (0.10 g, 0.35
mmol), 1-chloro-2-methyl-2-propanol (0.05 g, 0.46 mmol), and
cesium carbonate (0.17 g, 0.53 mmol) in DMF (3 mL) was stirred
at 160 °C for 40 min under microwave irradiation. Then the mixture
was concentrated in vacuo, and the residue was partitioned between
1
solid. MS: m/z 211 [M + H]+. tR = 0.62 min. H NMR (400 MHz,
CDCl3): δ (ppm) 2.58 (d, J = 0.7 Hz, 3 H), 7.55 (d, J = 0.7 Hz, 1 H),
7.98 (d, J = 4.4 Hz, 1 H), 8.05 (d, J = 4.4 Hz, 1 H), 8.61 (dd, J = 4.4,
1.6 Hz, 2 H), 8.81 (dd, J = 4.4, 1.6 Hz, 2 H).
2-Methyl-8-pyridin-3-ylimidazo[1,2-a]pyrazine (33b). 33b
was prepared according to a protocol analogous to that for compound
2 from 5b and 3-pyridylboronic acid. Flash column chromatography
(silica; MeOH in DCM, 1/99) yielded 33b as a pale brown solid
1
(63%). MS: m/z 211 [M + H]+. tR = 0.75 min. H NMR (400 MHz,
CDCl3): δ (ppm) 2.57 (d, J = 0.5 Hz, 3 H), 7.47 (ddd, J = 8.0, 4.8, 0.8
Hz, 1 H), 7.53 (s, 1 H), 7.96 (d, J = 4.4 Hz, 1 H), 8.01 (d, J = 4.4 Hz, 1
H), 8.72 (dd, J = 4.9, 1.6 Hz, 1 H), 9.04 (dt, J = 8.1, 2.0 Hz, 1 H), 9.84
(dd, J = 2.1, 0.7 Hz, 1 H).
3-Bromo-2-methyl-8-pyridin-4-ylimidazo[1,2-a]pyrazine
(34a). 34a was prepared according to a protocol analogous to that for
6a from 33a. Precipitation from diethyl ether yielded 34a as a pale
brown solid (86%). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 2.48 (s,
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dx.doi.org/10.1021/jm500073h | J. Med. Chem. 2014, 57, 4196−4212