302 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 2
Menichincheri et al.
(bs, 1 H) 8.21 (d, J ) 6.71 Hz, 1 H) 12.32 (bs, 1 H). HRMS (M
+ H)+ calcd 272.1506, found 272.1501. Anal. (C14H15N3O): C, H,
N.
Hz, 2 H) 8.72 (d, J ) 6.95 Hz, 2 H) 12.59 (bs, 1 H). HRMS (M +
H)+ calcd 290.1288, found 290.1291. Anal. (C18H15N3O) H; C:
calcd 74.72, found, 75.79; N: calcd 14.52, found 13.98.
2-(2-Aminopyrimidin-4-yl)-6-cyclopropyl-1,5,6,7-tetrahydropy-
rrolo[3,2-c]pyridin-4-one (73). H (400 MHz, DMSO-d6) δ ppm
2-(2-Aminopyrimidin-4-yl)-7-methyl-1,5,6,7-tetrahydropyrrolo[3,2-
c]pyridin-4-one (85). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29
(d, J ) 6.58 Hz, 3 H) 3.06-3.24 (m, 2 H) 3.41-3.56 (m, 1 H)
7.30 (s, 1 H) 7.35 (d, J ) 6.83 Hz, 1 H) 7.51 (s, 1 H) 8.03 (s, 2 H)
8.23 (d, J ) 6.71 Hz, 1 H) 12.24 (s, 1 H). HRMS (M + H)+ calcd
244.1193, found 244.1189. Anal. (C12H13N5O): C, H, N.
1
0.21-0.28 (m, 1 H) 0.30-0.36 (m, 1 H) 0.39-0.51 (m, 2 H)
0.95-1.04 (m, 1 H) 2.78-2.91 (m, 2 H) 2.97-3.05 (m, 1 H) 6.38
(bs, 2 H) 6.93 (d, J ) 5.37 Hz, 1 H) 7.05 (d, J ) 2.07 Hz, 1 H)
7.07 (bs, 1 H) 8.16 (d, J ) 5.24 Hz, 1 H) 11.78 (bs, 1 H). HRMS
(M + H)+ calcd 270.1349, found 270.1351. Anal. (C14H15N5O):
C, H, N.
2-(2-Aminopyrimidin-4-yl)-6-isobutyl-1,5,6,7-tetrahydropyrro-
lo[3,2-c]pyridin-4-one (74). 1H NMR (400 MHz, DMSO-d6) δ ppm
0.81-0.97 (m, 6 H) 1.27-1.42 (m, 1 H) 1.42-1.58 (m, 1 H)
1.64-1.81 (m, 1 H) 2.70 (dd, J ) 16.58, 8.41 Hz, 1 H) 3.04 (dd,
J ) 16.58, 5.24 Hz, 1 H) 3.63-3.80 (m, 1 H) 7.29 (s, 1H) 7.31 (d,
J ) 6.71 Hz, 1 H) 7.51 (s, 1 H) 8.08 (s, 2 H) 8.21 (d, J ) 6.71 Hz,
1 H) 12.35 (s, 1 H). HRMS (M + H)+ calcd 286.1662, found
286.1665. Anal. (C15H19N5O): C, H, N.
2-(2-Aminopyrimidin-4-yl)-7-ethyl-1,5,6,7-tetrahydropyrrolo[3,2-
c]pyridin-4-one (86). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94
(t, J ) 6.95 Hz, 3 H) 1.7 (m, 2 H) 2.9 (m, 1 H) 3.3 (m, 2 H) 7.25
(bs, 1 H) 7.35 (d, J ) 6.83 Hz, 1 H) 7.5 (s, 1 H) 8.04 (bs, 2 H)
8.22 (d, J ) 6.83 Hz, 1 H) 12.25 (bs, 1 H). HRMS (M + H)+
calcd 258.1349, found 258.1350. Anal. (C13H15N5O): C, H, N.
The racemate was subjected to separation by chiral chromatog-
raphy on a Chiralpack AS column (5 cm × 50 cm). Mobile phase:
n-hexane/isopropanyl alcohol/ethanol/methanol 3:3:3:1. First eluted
peak (86-1): ee 98.5%, second eluted peak (86-2): ee 97%.
2-(2-Aminopyrimidin-4-yl)-7-isopropyl-1,5,6,7-tetrahydropyr-
6,6-Dimethyl-2-(2-aminopyrimidin-4-yl)-1,5,6,7-tetrahydropyr-
1
1
rolo[3,2-c]pyridin-4-one (75). H NMR (400 MHz, DMSO-d6) δ
rolo[3,2-c]pyridin-4-one (87). H NMR (400 MHz, DMSO-d6) δ
ppm 1.3 (m, J ) 2.7, 0.9, 0.5 Hz, 3 H) 1.5 (m, J ) 2.7, 0.9, 0.5
Hz, 3 H) 2.5 (m, J ) 15.6, 1.5, 0.9, 0.5 Hz, 1 H) 2.6 (m, J ) 15.6,
1.5, 0.9, 0.5 Hz, 1 H) 7.5 (d, J ) 0.9 Hz, 1 H) 7.7 (d, J ) 4.8 Hz,
1 H) 8.2 (d, J ) 4.8 Hz, 1 H) 9.2 (m, 1 H). HRMS (M + H)+
calcd 258.1349, found 258.1356. Anal. (C13H15N5O): C, H, N.
(R)-2-(2-Aminopyrimidin-4-yl)-6-benzyloxymethyl-1,5,6,7-tet-
ppm 0.91 (t, J ) 6.95 Hz, 6 H) 1.07 (t, J ) 6.95 Hz, 1 H) 1.96-2.10
(m, 1 H) 2.66-2.74 (m, 1 H) 3.40-3.54 (m, 1 H) 6.28-6.39 (m,
2 H) 6.95 (d, J ) 5.37 Hz, 1 H) 6.97 (s, 1 H) 7.03 (d, J ) 2.19 Hz,
1 H) 8.16 (d, J ) 5.24 Hz, 1 H) 11.64 (s, 1 H). HRMS (M + H)+
calcd 272.1506, found 272.1512. Anal. (C14H17N5O): C, H, N.
The racemate was subjected to separation by chiral chromatog-
raphy on a Chiralpack AS column (5 cm × 50 cm). Mobile phase:
n-hexane/isopropyl alcohol/ethanol/methanol 3:3:3:1. First eluted
peak (87-1): ee 99%, second eluted peak (87-2): ee 99%.
2-(2-Aminopyrimidin-4-yl)-7-cyclobutyl-1,5,6,7-tetrahydropyr-
1
rahydropyrrolo[3,2-c]pyridin-4-one (76). H (400 MHz, DMSO-
d6) δ ppm 2.88 (dd, J ) 7.32, 16.71 Hz, 1 H), 2.97 (dd, J ) 5.90,
16.71 Hz, 1 H), 3.46 (m, 2 H), 3.82 (m, 1 H), 4.49 (s, 2 H), 6.28
(bs, 2 H), 6.87 (d, J ) 5.24 Hz, 1 H), 6.93 (m, 1 H), 6.99 (s, 1 H),
7.30 (m, 5 H), 8.13 (d, J ) 5.24 Hz, 1 H), 11.74 (bs, 1 H). HRMS
(M + H)+ calcd 350.1611, found 350.1614. Anal. (C19H19N5O2):
C, H, N.
1
rolo[3,2-c]pyridin-4-one (88). H (400 MHz, DMSO-d6) δ ppm
1.71-1.85 (m, 4 H) 1.99-2.10 (m, 2 H) 2.50-2.61 (m, 1 H) 2.94
(dd, J ) 9.27, 3.66 Hz, 1 H) 3.14-3.21 (m, 1 H) 3.51 (dd, J )
12.74, 4.82 Hz, 1 H) 7.19 (d, J ) 4.15 Hz, 1 H) 7.34 (d, J ) 6.58
Hz, 1 H) 7.48 (d, J ) 2.07 Hz, 1 H) 7.97 (bs, 3 H) 8.24 (d, J )
6.71 Hz, 1 H) 12.26 (bs, 1 H). HRMS (M + H)+ calcd 284.1506,
found 284.1506. Anal. (C15H17N5O.0.5 H2O): C, H, N.
7-Ethyl-2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-
1
4-one (78). H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (t, J )
7.44 Hz, 3 H) 1.59 (m, 1 H) 1.82 (m, 1 H) 2.86 (m, 1 H) 3.21(m,
1 H) 3.53 (m, 1 H) 7.00 (s, 1 H) 7.01 (s, 1 H) 7.65 (m, 2 H) 8.49
(m, 2 H) 11.75 (s, 1 H). HRMS (M + H)+ calcd 242.1288, found
242.1291. Anal. (C14H15N3O): C, H, N.
The racemate was subjected to separation by chiral chromatog-
raphy on a Chiralpack AS column (5 cm × 50 cm). Mobile phase:
n-hexane/ethanol/methanol 55:30:15. First eluted peak (88-1) ee
99%, second eluted peak (88-2): ee 97%.
2-(2-Aminopyrimidin-4-yl)-7-(2-fluoroethyl)-1,5,6,7-tetrahydro-
pyrrolo[3,2-c]pyridin-4-one (89). 1H (400 MHz, DMSO-d6) δ ppm
1.92 (m, 1 H), 2.15 (m, 1 H), 3.11 (m, 1 H), 3.32 (m, 1 H), 3.52
(dd, J ) 5.12 Hz, J ) 12.33 Hz, 1 H), 4.52 (t, J ) 6.04 Hz, 1 H),
4.64 (t, J ) 6.04 Hz, 1 H), 6.33 (s, 2 H), 6.94 (d, J ) 5.31 Hz, 1
H), 7.04 (s, 1 H), 7.07 (s, 1 H), 8.17 (d, J ) 5.31 Hz, 1 H), 11.68
(s, 1 H). HRMS (M + H)+ calcd 276.1255, found 276.1258. Anal.
(C13H14FN5O): C, H, N.
The racemate was subjected to separation by chiral column
chromatographyc on a Chiralcell OJ column and eluting with
n-hexane/ethanol/methanol 60:35:5. (S)-isomer, first eluted peak:
ee 99%, (R)-isomer: second eluted peak: ee 96%.
2-(2-Aminopyrimidin-4-yl)-7,7-dimethyl-1,5,6,7-tetrahydropyr-
rolo[3,2-c]pyridin-4-one (90). 1H (500 MHz, DMSO-d6) δ ppm 1.37
(s, 6 H) 3.20 (s, 2 H) 7.39-7.43 (m, 1 H) 7.46 (d, J ) 6.70 Hz, 1
H) 7.52 (s, 1 H) 8.16 (s, 2 H) 8.28 (d, J ) 6.70 Hz, 1 H) 12.20 (s,
1 H). HRMS (M + H)+ calcd 258.1349, found 258.1349. Anal.
(C13H15N5O): C, H, N.
7-Cyclobutyl-2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]py-
ridin-4-one (80). 1H (400 MHz, DMSO-d6) δ ppm 1.75-1.87 (m,
4 H) 2.00-2.08 (m, 2 H) 2.55-2.64 (m, 1 H) 2.88-2.94 (m, 1 H)
3.18-3.23 (m, 1 H) 3.54 (dd, J ) 12.62, 4.82 Hz, 1 H) 7.18 (bd,
J ) 4.39 Hz, 1 H) 7.55 (d, J ) 2.19 Hz, 1 H) 8.20 (d, J ) 7.07
Hz, 2 H) 8.70 (d, J ) 6.95 Hz, 2 H) 12.46 (bs, 1 H). HRMS (M +
H)+ calcd 268.1444, found 268.1440. Anal. (C16H17N3O): C, H,
N.
7-(2-Fluoroethyl)-2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-
c]pyridin-4-one (81). 1H (400 MHz, DMSO-d6) δ ppm 1.92 (m, 1
H) 2.19 (m, 1 H) 3.10 (m, 1 H) 3.26 (m, 1 H) 3.53 (m, 1 H) 4.54
(m, 1 H) 4.63 (m, 1 H) 7.01 (d, J ) 2.29 Hz, 1 H) 7.07 (s, 1 H)
7.65 (d, J ) 6.12 Hz, 2 H) 8.49 (d, J ) 6.12 Hz, 2 H) 11.80 (s, 1
H). HRMS (M + H)+ calcd 260.1194, found 260.1199. Anal.
(C14H14FN3O): C, H, N.
7,7-Dimethyl-2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]py-
1
ridin-4-one (82). H (400 MHz, DMSO-d6) δ ppm 1.38 (s, 6 H)
3.20 (s, 2 H) 7.37 (s, 1 H) 7.56 (d, J ) 2.32 Hz, 1 H) 8.36 (d, J )
6.95 Hz, 2 H) 8.72 (d, J ) 6.95 Hz, 2 H) 12.34 (s, 1 H). HRMS
(M + H)+ calcd 242.1288, found 242.1287. Anal. (C14H15N3O):
C, H, N.
2-(2-Aminopyrimidin-4-yl)-7,7-diethyl-1,5,6,7-tetrahydropyrro-
lo[3,2-c]pyridin-4-one (91). 1H NMR (400 MHz, DMSO-d6) δ ppm
0.80 (t, J ) 7.44 Hz, 6 H) 1.73-1.85 (m, 4 H) 3.27 (d, J ) 2.56
Hz, 2 H) 7.31 (s, 1 H) 7.37-7.43 (m, 1 H) 7.46 (s, 1 H) 7.91 (s,
2 H) 8.24 (d, J ) 6.58 Hz, 1 H) 11.98 (s, 1 H). HRMS (M + H)+
calcd 286.1662, found 286.1658. Anal. (C15H19N5O) C: calcd 55.99,
found 50.51; H: calcd 6.26, found 6.21; N: calcd 21.76, found 19.65.
2-(2-Aminopyrimidin-4-yl)-7-phenyl-1,5,6,7-tetrahydropyrrolo[3,2-
7,7-Diethyl-2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyri-
din-4-one (83). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 (t, J )
7.50 Hz, 6 H) 1.70-1.88 (m, 4 H) 3.28 (d, J ) 2.44 Hz, 2 H) 7.31
(bs, 1 H) 7.59 (d, J ) 2.32 Hz, 1 H) 8.32 (d, J ) 6.71 Hz, 2 H)
8.72 (d, J ) 7.07 Hz, 2 H) 11.99 (bs, 1 H). HRMS (M + H)+
calcd 270.1601, found 270.1602. Anal. (C16H19N3O): C, H, N.
7-Phenyl-2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-
4-one (84). 1H (400 MHz, DMSO-d6) δ 3.87 (ddd, J ) 12.71, 5.46,
0.98 Hz, 1 H) 4.42 (t, J ) 4.51 Hz, 1 H) 7.17-7.22 (m, 2 H)
7.26-7.40 (m, 4 H) 7.69 (d, J ) 2.44 Hz, 1 H) 8.22 (d, J ) 7.07
1
c]pyridin-4-one (92). H NMR (400 MHz, DMSO-d6) δ ppm 3.7
(m, J ) 13.0, 8.0, 4.0 Hz, 1 H) 3.8 (m, J ) 8.0, 6.0, 1.5, 0.9, 0.6
Hz, 1 H) 3.9 (m, J ) 13.0, 6.0, 3.0 Hz, 1 H) 7.0 (m, J ) 7.3, 7.1,