Journal of Medicinal Chemistry
Article
25
1
HRMS, calcd for C H N O [M], 223.0957; found, 223.0957. [α]
mg, 65% yield) as a pale-yellow solid. H NMR (400 MHz, DMSO-d )
10
13
3
3
D
6
=
−29.9° (c 0.500, CHCl ).
δ 8.26 (d, J = 2.7 Hz, 1H), 8.21 (s, 1H), 7.83 (dd, J = 8.8, 2.7 Hz, 1H),
6.92 (dd, J = 8.8, 0.5 Hz, 1H), 6.77 (s, 1H), 5.29 (s, 2H), 4.51−4.46
(m, 1H), 3.66 (ddd, J = 13.0, 8.7, 8.7 Hz, 1H), 3.34 (ddd, J = 13.1, 7.9,
2.2 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, DMSO-
d6) δ 161.9, 158.7, 147.7, 145.3, 139.7, 135.1, 124.1, 112.9, 107.4, 61.7,
3
Ethyl (R)-5-(4-Methoxybenzyl)-7-methyl-4-oxo-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (76). Com-
pound 75 (2.23 g, 10 mmol, 1.0 equiv) was dissolved in DMF (50
mL, 0.2 M), cooled to 0 °C, and treated with 60% sodium hydride in
mineral oil (480 mg, 12 mmol, 1.2 equiv) in five portions. The
reaction mixture was stirred for 15 min, and 4-methoxybenzyl chloride
52.3, 45.6, 17.0. LCMS (method A): R = 0.804 min, m/z = 293.2 [M
T
+
+ H] . HRMS, calcd for C H ClN O [M], 292.0727; found,
13
13
4
2
292.0727. [α]25 = −38.3° (c 0.442, CHCl ).
(
1.63 mL, 12 mmol, 1.2 equiv) was added. After 16 h, the reaction
D
3
mixture was diluted with water and extracted with EtOAc (3×). The
combined extracts were washed with water and brine, dried over
Na SO , filtered, and concentrated in vacuo. The crude material was
(R)-2-(((5-Chloropyridin-2-yl)oxy)methyl)-5-(2-fluoropyridin-
3-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
(
106). Copper(I) iodide (13.7 mg, 0.072 mmol, 2.1 equiv) was added
2
4
to a suspension of compound 79 (10 mg, 0.035 mmol, 1.0 equiv), 3-
bromo-2-fluoropyridine (7.40 μL, 0.072 mmol, 2.1 equiv), potassium
carbonate (10 mg, 0.072 mmol, 2.1 equiv), and N,N′-dimethylethy-
lenediamine (20.7 μL, 0.19 mmol, 5.5 equiv) in toluene (0.44 mL) in a
sealed reaction vial. The reaction mixture was stirred at 120 °C. After
purified by flash chromatography on silica gel to provide the title
compound (2.51 g, 73% yield) as a pale-yellow solid. H NMR (400
1
MHz, CDCl ) δ 7.37 (s, 1H), 7.23 (d, J = 14.1, 2H), 6.87 (d, J = 14.1,
3
2
H), 4.76 (d, J = 14.5, 1H), 4.59−4.50 (m, 2H), 4.44−4.36 (m, 2H),
3
.79 (s, 3H), 3.69 (dd, J = 13.1, 4.6 Hz, 1H), 3.35 (dd, J = 13.1, 6.3
13
1
6 h, the mixture was diluted with EtOAc, filtered through a Celite pad
Hz, 1H), 1.47 (d, J = 6.6 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H). C NMR
100 MHz, CDCl ) δ 161.7, 159.5, 137.1, 143.9, 134.8, 129.9 (2C),
which was rinsed with EtOAc (2×), and concentrated in vacuo.
Purification using reserve phase HPLC method 1 with 39−71%
CH CN in H O (0.1% TFA) over 4 min provided the title compound
(
3
1
27.9, 114.3, 110.9 (2C), 61.2, 55.3, 52.9, 50.4, 48.8, 17.5, 14.3. LCMS
+
(
method A): R = 0.955 min, m/z = 344.2 [M + H] . HRMS, calcd for
3
2
T
1
25
(7.2 mg, 53% yield) as a white powder. H NMR (400 MHz, DMSO-
C H N O [M], 343.1532; found, 343.1533. [α] = −8.1° (c 0.157,
CHCl3).
R)-2-(Hydroxymethyl)-5-(4-methoxybenzyl)-7-methyl-6,7-
1
8
21
3
4
D
d6) δ 8.27 (dd, J = 2.7, 0.5 Hz, 1H), 8.23 (ddd, J = 4.8, 2.7, 2.7 Hz,
1
H), 8.09 (ddd, J = 9.6, 7.7, 1.8 Hz, 1H), 7.84 (dd, J = 8.8, 2.7 Hz,
(
dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (77). Sodium borohy-
dride (1.16 g, 30.6 mmol, 5.0 equiv) was added slowly to a solution of
compound 76 (2.1 g, 6.11 mmol, 1.0 equiv) in THF (20 mL) and
MeOH (5.0 mL) at 0 °C. The reaction was heated to 60 °C, and after
1H), 7.50 (ddd, J = 9.0, 4.9, 1.3 Hz, 1H) 6.95 (s, 1H), 6.92 (d, J = 0.5
Hz, 1H), 5.35 (s, 2H), 4.82−4.75 (m, 1H), 4.27 (dd, J = 12.8, 4.3 Hz,
1
3
1H), 3.98 (dd, J = 12.8, 7.2 Hz, 1H) 1.55 (d, J = 6.5 Hz, 3H).
C
NMR (100 MHz, DMSO-d
) δ 161.9, 158.2 (d, JC,F = 239 Hz), 156.6,
48.4, 146.4 (d, JC,F = 14 Hz), 145.3, 133.9 (d, JC,F = 13 Hz), 139.8,
34.0, 124.4 (d, JC,F = 28 Hz), 124.2, 123.2 (d, JC,F = 4 Hz), 112.9,
08.7, 61.6, 54.0, 52.7, 17.1. LCMS (method A): R = 0.944 min, m/z
6
1
1
1
3
0 min at that temperature, the reaction mixture was diluted with
water and extracted with dichloromethane. The aqueous layer was
acidified with a 1 M aqueous HCl solution and extracted with
dichloromethane (2×). The combined extracts were dried over
Na SO and concentrated in vacuo. Purification by flash chromatog-
T
+
=
388.2 [M + H] . HRMS, calcd for C H ClFN O [M], 387.0898;
18 15 5 2
25
found, 387.0899. [α] = −23.6° (c 0.100, DMSO).
D
2
4
raphy on silica gel provided the title compound as a viscous oil (1.55 g,
1
8
6
4% yield). H NMR (400 MHz, CDCl ) δ 7.23−7.21 (m, 2H), 6.87−
3
ASSOCIATED CONTENT
■
.84 (m, 3H), 4.72 (d, J = 14.5 Hz, 1H), 4.68 (s, 2H), 4.59 (d, J = 14.4
Hz, 1H), 4.43−4.35 (m, 1H), 3.78 (s, 3H), 3.60 (dd, J = 13.0, 4.6 Hz,
H), 3.31 (dd, J = 13.0, 7.4 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H). 13
NMR (100 MHz, CDCl ) δ 159.4, 157.8, 152.6, 134.5, 129.8 (2C),
*
S
Supporting Information
1
C
3
1
28.2, 114.3 (2C), 106.5, 58.7, 55.3, 52.0, 50.8, 48.7, 17.2. LCMS
+
(
method A): R = 0.680 min, m/z = 302.2 [M + H] . HRMS, calcd for
T
25
C H N O [M], 301.1426; found, 301.1428. [α] = −5.3° (c 0.98,
Experimental procedures and spectroscopic data for
additional compounds, molecular pharmacology meth-
ods, DMPK methods, behavioral pharmacology methods,
and the ancillary pharmacology profile details of 106
1
6
19
3
3
D
CHCl3).
R)-2-(((5-Chloropyridin-2-yl)oxy)methyl)-5-(4-methoxyben-
zyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
78). To a solution of compound 77 (1.5 g, 4.98 mmol, 1.0 equiv) in
DMF (25 mL, 0.2 M) at 0 °C was added NaH (300 mg, 12.44 mmol,
(
(
2
2
.5 equiv). The resulting mixture was stirred for 15 min, and 5-chloro-
-fluoropyridine (1.25 mL, 12.44 mmol, 2.5 equiv) was added. The
Molecular formula strings (CSV)
mixture was stirred overnight and extracted with EtOAc (3×). The
combined extracts were concentrated in vacuo. Purification by flash
AUTHOR INFORMATION
■
chromatography on silica gel afforded the title compound (1.72 g, 84%
1
Corresponding Author
yield) as a viscous oil. H NMR (400 MHz, CDCl ) δ 8.13 (d, J = 2.6
3
Hz, 1H), 7.54 (dd, J = 8.8, 2.6 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.98
(
2
(
1
s, 1H), 6.88 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.8 Hz, 1H), 5.39 (s,
H), 4.75 (d, J = 14.5 Hz, 1H), 4.63 (d, J = 14.5 Hz, 1H), 4.50−4.42
m, 1H), 3.81 (s, 3H), 3.64 (dd, J = 13.0, 4.6 Hz, 1H), 3.35 (dd, J =
Present Addresses
§
3.0, 7.4 Hz, 1H), 1.48 (d, J = 6.5 Hz, 3H). 1 C NMR (100 MHz,
3
Incyte Corporation, Experimental Station, E336/131A, Route
CDCl ) δ 161.6, 159.4, 157.7, 148.9, 145.1, 138.6, 134.5, 129.8 (2C),
141 and Henry Clay Road, Wilmington, Delaware 19880,
United States.
3
1
28.2, 124.4, 114.2 (2C), 112.3, 108.2, 61.6, 55.3, 52.1, 50.8, 48.8, 17.2.
+
∥
LCMS (method A): R = 1.080 min, m/z = 413.2 [M + H] . HRMS,
calcd for C H ClN O [M], 412.1302; found, 412.1305. [α]
Sano Informed Prescribing, Cool Springs Life Sciences Center,
T
25
=
21
21
4
3
D
393 Nichol Mill Lane, Suite 34, Franklin, Tennessee 37067,
United States.
−
10.3° (c 1.512, CHCl3).
(
R)-2-(((5-Chloropyridin-2-yl)oxy)methyl)-7-methyl-6,7-
dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (79). Compound 78
1.65 mg, 4.0 mmol, 1.0 equiv) was dissolved in MeCN (40 mL, 0.1
⊥
Covance Inc., 671 South Meridian Road, Greenfield, Indiana
4
6140, United States.
(
#
Department of Pharmaceutical Sciences, UNT System College
of Pharmacy, University of North Texas Health Science Center,
3500 Camp Bowie Boulevard, Fort Worth, Texas 76107,
United States.
M). and a solution of ceric ammonium nitrate (6.57 g, 12 mmol, 4.0
equiv) in water (12 mL) was added. After 30 min at room
temperature, solvents were removed in vacuo. Purification using
flash chromatography on silica gel provided the title compound (764
L
J. Med. Chem. XXXX, XXX, XXX−XXX