Journal of Medicinal Chemistry
Article
5.8 Hz, 2H), 4.17 (m, 2H). 13C NMR (CDCl3): δ 170.7, 151.5, 148.9,
147.6, 142.6, 138.5, 137.2, 134.3, 133.3, 129.2, 128.6, 128.1, 127.5,
124.2, 123.0, 45.8.68 HRMS: calcd 416.1278, found 416.1292,
C23H19N5OCl.
(CDCl3): δ 170.1, 165.7, 162.4, 153.3, 151.1, 149.0, 147.4, 137.4,
130.9, 129.4 (d), 124.5, 123.3, 116.3 (d), 48.1, 46.1, 38.3, 20.0. 19F
NMR (CDCl3): δ −98.1. HRMS: calcd 338.1417, found 338.1433,
C18H17N5OF.
(4′-Methoxy-[1,1′-biphenyl]-4-yl)(3-(pyridin-2-yl)-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (14). Starting from
99 and 4′-methoxy-[1,1′-biphenyl]-4-carbonyl chloride as per general
procedure E to obtain 70 mg (68%). LCMS (method A) m/z 412 (M
+ 1). HPLC purity >98% (254 nm). 1H NMR (CDCl3): δ 8.66 (d, J =
4.4 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.86 (dt, J = 1.8, 7.8 Hz, 1H),
7.65 (d, J = 8.4 Hz, 2H), 7.57 (m, 4H), 7.38 (ddd, J = 1.0, 4.9, 7.5 Hz,
1H), 7.02 (d, J = 8.8 Hz, 2H), 5.17 (bs, 2H), 4.78 (t, J = 5.5 Hz, 2H),
4.14 (m, 2H), 3.88 (s, 3H). 13C NMR (CDCl3): δ 170.9, 159.8, 151.4,
149.0, 148.9, 147.6, 143.4, 137.1, 132.4, 132.2, 128.3, 128.0, 127.0,
124.1, 122.9, 114.4, 55.4, 45.8.68 HRMS: calcd 412.1774, found
412.1760, C24H22N5O2.
(R)-(4-Fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (20). Starting from
101 and 4-fluorobenzoyl chloride as per general procedure E to obtain
74 mg (99%). LCMS (method A) m/z 338 (M + 1). HPLC purity
99% (254 nm). Chiral LC (method H) 95.4% ee (tR(S) = 6.0 min, tR(R)
= 8.0 min). 1H NMR (DMSO-d6): δ 8.68 (d, J = 4.3 Hz, 1H), 8.17 (d,
J = 7.9 Hz, 1H), 8.00 (dt, J = 1.5, 7.7 Hz, 1H), 7.60 (m, 2H), 7.51 (m,
1H), 7.33 (t, J = 8.8 Hz, 2H), 5.67 (m, 1H), 4.74 (m, 1H), 4.32 (m,
1H), 4.01 (bm, 1H), 3.62 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H). 13C NMR
(CDCl3): δ 170.0, 165.6, 162.3, 153.3, 151.2, 148.9, 147.7, 137.2,
131.0, 129.4 (d), 124.2, 123.2, 116.2 (d), 48.1, 46.1, 38.3, 20.0. 19F
NMR (CDCl3): δ −98.1. HRMS: calcd 338.1417, found 338.1429,
C18H17N5OF.
(R)-(4-Fluorophenyl)(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihy-
dro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (21). Starting
from 102 and 4-fluorobenzoyl chloride as per general procedure E to
obtain 90 mg (53%). LCMS (method A) m/z 352 (M + 1). HPLC
purity 97% (254 nm). Chiral LC (method I) 98.4% ee (tR(S) = 13.7
min, tR(R) = 16.6 min). 1H NMR (CDCl3): δ 8.10 (d, J = 7.8 Hz, 1H),
7.71 (t, J = 7.8 Hz, 1H), 7.48 (m, 2H), 7.17 (m, 3H), 5.64 (m, 1H),
5.03 (dd, J = 3.8, 13.8 Hz, 1H), 4.61 (m, 1H), 4.34 (m, 1H), 3.49 (m,
1H), 2.57 (s, 3H), 1.74 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3): δ
170.1, 165.6, 162.3, 157.9, 153.1, 151.3, 147.0, 137.5, 131.0, 129.4 (d),
123.7, 120.2, 116.2 (d), 47.6, 45.9, 37.3, 24.5, 20.0. 19F NMR
(CDCl3): δ −105.9. HRMS: calcd 352.1574, found 352.1588,
C19H19N5OF.
(4-Fluorophenyl)(3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl) methanone (22). Starting from 103
and 4-fluorobenzoyl chloride as per general procedure E to obtain 32
mg. LCMS (method A) m/z 338 (M + 1). HPLC purity 96% (254
nm). 1H NMR (DMSO-d6): δ 7.97 (d, J = 7.8 Hz, 1H), 7.88 (t, J = 7.8
Hz, 1H), 7.64 (dd, J = 5.7, 8.0 Hz, 2H), 7.35 (m, 3H), 4.97 (bs, 2H),
4.60 (t, J = 5.3 Hz, 2H), 3.90 (m, 2H), 2.56 (s, 3H). 13C NMR
(CDCl3): δ 170.2, 165.9, 162.5, 158.0, 151.6, 148.8, 146.7, 137.5,
130.0 (d), 123.9, 120.2, 116.2 (d), 45.7,68 24.5. 19F NMR (DMSO-d6):
δ −107.5. HRMS: calcd 338.1417, found 338.1433, C18H17N5OF.
(4-Fluorophenyl)(3-(5-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (23). Starting from 104
and 4-fluorobenzoyl chloride as per general procedure E to obtain 15
mg (22%). LCMS (method A) m/z 338 (M + 1). HPLC purity 98%
(254 nm). 1H NMR (CDCl3): δ 8.44 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H),
7.64 (d, J = 8.1 Hz, 1H), 7.51 (m, 2H), 7.15 (t, J = 7.5 Hz, 2H), 5.06
(bs, 2H), 4.70 (t, J = 5.0 Hz, 2H), 4.06 (m, 2H), 2.40 (s, 3H). 13C
NMR (CDCl3): δ 170.1, 165.9, 162.5, 151.6, 149.4, 148.7, 144.8,
137.8, 134.4, 129.9 (d), 122.7, 116.2 (d), 45.7,68 18.6. 19F NMR
(CDCl3): δ −105.3. HRMS: calcd 338.1417, found 338.1422,
C18H17N5OF.
(4-Fluorophenyl)(3-(4-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl) methanone (24). Starting from 105
and 4-fluorobenzoyl chloride as per general procedure E to obtain 82
mg (50%). LCMS (method A) m/z 338 (M + 1). HPLC purity 98%
(254 nm). 1H NMR (CDCl3): δ 8.48 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H),
7.53 (m, 2H), 7.16 (m, 3H), 5.10 (bs, 2H), 4.74 (t, J = 5.4 Hz, 2H),
4.07 (m, 2H), 2.44 (s, 3H).13C NMR (CDCl3): δ 170.1, 165.9, 162.4,
151.7, 148.7, 147.2, 131.7 (d), 129.9 (d), 125.4, 123.8, 116.2 (d),
44.8,68 21.2. 19F NMR (CDCl3): δ −105.1. HRMS: calcd 338.1417,
found 338.1428, C18H17N5OF.
(4-Benzylphenyl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl)methanone (15). Starting from 99 and 4-
benzylbenzoyl chloride as per general procedure E to obtain 57 mg
(58%). LCMS (method A) m/z 396 (M + 1). HPLC purity 97% (254
1
nm). H NMR (CDCl3): δ 8.63 (d, J = 4.6 Hz, 1H), 8.36 (d, J = 8.0
Hz, 1H), 7.85 (dt, J = 1.7, 7.7 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.37−
7.18 (m, 8H), 5.11 (bs, 2H), 4.74 (t, J = 5.5 Hz, 2H), 4.10 (m, 2H),
4.03 (s, 2H). 13C NMR (CDCl3): δ 170.9, 168.7, 151.3, 148.9, 148.8,
147.5, 144.3, 140.1, 137.1, 131.9, 130.2, 129.3, 129.0, 128.8, 128.6,
127.6, 126.4, 124.1, 122.9, 45.8,68 41.7. HRMS: calcd 396.1824, found
396.1833, C24H22N5O.
(3-(Pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-
yl)(4-(thiophen-2-yl)phenyl) methanone (16). Starting from 99 and
4-(thiophen-2-yl)benzoyl chloride as per general procedure E to
obtain 42 mg. LCMS (method A) m/z 388 (M + 1). HPLC purity
>98% (254 nm). 1H NMR (CDCl3): δ 8.61 (d, J = 3.4 Hz, 1H), 8.31
(d, J = 7.9 Hz, 1H), 7.81 (dt, J = 1.5, 7.9 Hz, 1H), 7.68 (d, J = 8.2 Hz,
2H), 7.51 (d, J = 8.2 Hz, 2H), 7.39 (dd, J = 1.1, 3.6 Hz, 1H), 7.36 (dd,
J = 1.1, 5.1 Hz, 1H), 7.32 (m, 1H), 7.11 (dd, J = 3.7, 5.1 Hz, 1H), 5.10
(bs, 2H), 4.73 (t, J = 5.3 Hz, 2H), 4.08 (m, 2H). 13C NMR (DMSO-
d6): δ 169.5, 150.8, 149.2, 147.4, 142.3, 137.7, 135.5, 133.7, 128.8,
128.3, 126.7, 125.5, 124.8, 124.4, 122.4, 45.4.68 HRMS: calcd
388.1232, found 388.1242, C21H18N5OS.
(4-(5-Methylfuran-2-yl)phenyl)(3-(pyridin-2-yl)-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methanone (17). Starting
from 99 and 4-(5-methylfuran-2-yl)benzoyl chloride as per general
procedure E to obtain 29 mg. LCMS (method A) m/z 386 (M + 1).
1
HPLC purity >98% (254 nm). H NMR (CDCl3): δ 8.61 (d, J = 4.3
Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.81 (dt, J = 1.5, 7.7 Hz, 1H), 7.68
(d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 5.0, 7.3 Hz,
1H), 6.64 (d, J = 2.9 Hz, 1H), 6.09 (d, J = 2.9 Hz, 1H), 5.08 (bs, 2H),
4.70 (t, J = 5.1 Hz, 2H), 4.05 (m, 2H), 2.37 (s, 3H). 13C NMR
(CDCl3): δ 170.9, 153.2, 151.5, 151.1, 149.1, 148.9, 147.7, 137.2,
133.6, 131.8, 128.1, 128.3, 124.2, 123.4, 123.0, 108.2, 107.9, 45.8,
13.9.68 HRMS: calcd 386.1617, found 386.1617, C22H20N5O2.
(3-(4-Chlorophenyl)-1H-pyrazol-5-yl)(3-(pyridin-2-yl)-5,6-dihy-
dro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (18). Starting
from 99 and 3-(4-chlorophenyl)-1H-pyrazole-5-carbonyl chloride as
per general procedure E to obtain 30 mg (30%). LCMS (method A)
1
m/z 406 (M + 1). HPLC purity >98% (254 nm). H NMR (DMSO-
d6) 2 isomers in a 3/2 ratio: δ 13.89 (s, 0.6H), 13.85 (s, 0.4H), 8.71 (d,
J = 4.6 Hz, 1H), 8.18 (d, J = 6.8 Hz, 1H), 8.00 (dt, J = 1.0, 7.5 Hz,
1H), 7.86 (d, J = 7.8 Hz, 2H), 7.57 (m, 3H), 7.19 (s, 1H), 5.61 (bs,
0.8H), 5.06 (bs, 1.2H), 4.64 (m, 2H), 4.45 (m, 0.8H), 4.15 (m, 1.2).
HRMS: calcd 406.1183, found 406.1176, C20H17N7OCl.
(S)-(4-Fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (19). Starting from
100 and 4-fluorobenzoyl chloride as general procedure E to obtain 140
mg (97%). LCMS (method A) m/z 338 (M + 1). HPLC purity 98%
(254 nm). Chiral LC (method H) 89.6% ee (tR(S) = 6.0 min, tR(R) = 8.0
(4-Fluorophenyl)(3-(3-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl) methanone (25). Starting from 106
and 4-fluorobenzoyl chloride as per general procedure E to obtain 35
mg (37%). LCMS (method A) m/z 338 (M + 1). HPLC purity 93%
1
(254 nm). H NMR (CDCl3): δ 8.50 (m, 1H), 7.70 (d, J = 7.8 Hz,
1
min). H NMR (DMSO-d6): δ 8.68 (d, J = 4.3 Hz, 1H), 8.17 (d, J =
1H), 7.53 (m, 2H), 7.28 (m, 1H), 7.16 (t, J = 8.5 Hz, 2H), 5.09 (bs,
2H), 4.50 (t, J = 5.4 Hz, 2H), 4.05 (m, 2H), 2.69 (s, 3H). 13C NMR
(CDCl3): δ 170.1, 165.8, 162.4, 151.6, 147.9, 146.4, 145.4, 137.7,
135.1, 130.3, 130.0 (d), 123.9, 116.1 (d), 45.0,68 20.5. 19F NMR
7.9 Hz, 1H), 7.99 (dt, J = 1.5, 7.7 Hz, 1H), 7.60 (m, 2H), 7.51 (m,
1H), 7.33 (t, J = 8.8 Hz, 2H), 5.67 (m, 1H), 4.74 (m, 1H), 4.31 (m,
1H), 4.01 (bm, 1H), 3.61 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H). 13C NMR
R
J. Med. Chem. XXXX, XXX, XXX−XXX