Journal of Medicinal Chemistry
ARTICLE
(m, 2H), 3.76ꢀ3.85 (m, 4H), 4.62 (sept, J = 6.1 Hz, 1H), 6.66 (s, 2H),
6.71ꢀ6.75 (m, 1H), 7.19ꢀ7.29 (m, 2H), 7.46 (t, J = 2.2 Hz, 1H), 8.20
(s, 1H), 8.54 (s, 1H) ppm. MS (DCI/NH3) m/z 368 (M + H)+. Anal.
ppm 2.86ꢀ3.02 (m, 2H), 3.19ꢀ3.29 (m, 4H), 3.39ꢀ3.72 (m, 8H),
3.91ꢀ4.05 (m, 1H), 4.61 (br s, 1H), 6.68 (s, 2 H; C4H4O4), 7.04ꢀ7.25
(m, 5H), 8.00 (br s, 1H), 8.12 (d, J = 2.7 Hz, 1H). MS (APCI) m/z 349
(C20H25N5O2 C4H4O4) C, H, N.
(M + H)+. Anal. (C21H24N4O 1.4C4H4O4) C, H, N.
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3
Representative Procedure for Boc-Deprotection, Isolation
of the TFA Salt. (3aR,6aS)-tert-Butyl N-(3,5-Dimethylphenyl)-
6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyra-
zine-2-carboxamide (22). Compound 51 (106.8 mg, 0.24 mmol)
was dissolved in CH2Cl2 (5 mL). TFA (1 mL, 13 mmol) was added to
the reaction mixture. The reaction was stirred at ambient temperature
for 1 h and then concentrated. The residue was dissolved in a minimal
amount of MeOH and then triturated by slow addition of Et2O/MeOH
9:1. The product was isolated by filtration, washed with additional Et2O
(5 ꢁ 1 mL), and dried in the vacuum oven overnight to afford the TFA
N-(2,3-Dihydro-1H-inden-1-yl)-5-((3aR,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrol-2(1H)-yl)nicotinamide (29). Prepared from
1
73 and 1-aminoindane according to the procedures for 51 and 20. H
NMR (300 MHz, MeOH-d4) δ ppm 1.93ꢀ2.12 (m, 1H), 2.52ꢀ2.66 (m,
1H), 2.85ꢀ2.99 (m, 1H), 3.01ꢀ3.13 (m, 1H), 3.20ꢀ3.35 (m, 4H),
3.41ꢀ3.66 (m, 6H), 5.65 (t, J = 7.8 Hz, 1H), 6.67 (s, 2 H; C4H4O4),
7.15ꢀ7.32 (m, 4H), 7.55 (dd, J = 2.9, 1.9 Hz, 1H), 8.13 (d, J = 3.1 Hz,
1H), 8.37 (d, J = 2.0 Hz, 1H). MS (ESI) m/z 349 (M + H)+. Anal.
(C21H24N4O 1.4C4H4O4) C, H, N.
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N-(2-Fluorophenethyl)-5-((3aR,6aS)-hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl)nicotinamide (30). Prepared from 73 and
2-(2-fluorophenyl)ethanamine according to the procedures for 51 and
22. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.89 (t, J = 7.1 Hz, 2H),
3.04ꢀ3.24 (m, 4H), 3.33ꢀ3.48 (m, 9H), 7.08ꢀ7.21 (m, 2H),
7.22ꢀ7.36 (m, 2H), 7.38ꢀ7.45 (m, 1H), 8.14 (d, J = 3.1 Hz, 1H),
8.33 (d, J = 1.7 Hz, 1H), 8.74 (t, J = 5.8 Hz, 1H), 8.82 (br s, 2 H; TFA).
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salt of title compound as a white powder (74.6 mg, 69%). H NMR
(MeOH-d4, 400 MHz) δ 2.32 (s, 6H), 3.29ꢀ3.35 (m, 4H), 3.63ꢀ3.68
(m, 2H), 3.74ꢀ3.84 (m, 4H), 6.83 (s, 1H), 7.34 (s, 2H), 8.17 (s, 1H),
8.53 (s, 1H) ppm. MS (DCI/NH3) m/z 338 (M + H)+. Anal. (C19H23-
N5O TFA) C, H, N, F.
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N-(3,5-Difluorophenyl)-6-((3aR,6aS)-hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide (23). Prepared
MS (ESI) m/z 355 (M + H)+. Anal. (C20H23FN4O 2TFA) C, H, N.
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1
from 52 according to the procedures for 22. H NMR (MeOH-d4,
5-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-
N-(3-iodophenyl)nicotinamide (31). Prepared from 73 and 3-io-
300 MHz) δ 3.26ꢀ3.36 (m, 4H), 3.63ꢀ3.69 (m, 2H), 3.77ꢀ3.84 (m,
4H), 6.75 (tt, J = 9.11, 2.25 Hz, 1H) 7.47ꢀ7.54 (m, 2H), 8.22 (s, 1H),
8.55 (s, 1H) ppm. MS (DCI/NH3) m/z 346 (M + H)+. Anal.
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doaniline according to the procedures for 51 and 20. H NMR (300
MHz, MeOH-d4) δ ppm 3.23ꢀ3.35 (m, 4H), 3.42ꢀ3.68 (m, 6H), 6.69
(s, 2H; C4H4O4), 7.13 (t, J = 8.1 Hz, 1H), 7.52 (ddd, J = 7.9, 1.6, 1.0 Hz,
1H), 7.59 (dd, J = 2.7, 2.0 Hz, 1H), 7.69 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H),
8.15ꢀ8.25 (m, 2H), 8.44 (d, J = 2.0 Hz, 1H). MS (ESI) m/z 435 (M +
H)+. Anal. (C18H19IN4O 1.7C4H4O4 0.1 H2O) C, H, N.
(C17H17F2N5O TFA) C, H, N, F.
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5-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-
N-((S)-1-phenylethyl)nicotinamide (24). Prepared from 73 and
(S)-1-phenylethanamine according to the procedures for 51 and 20. 1H
NMR (300 MHz, MeOH-d4) δ ppm 1.57 (d, J = 6.8 Hz, 3H), 3.16ꢀ3.28
(m, 4H), 3.39ꢀ3.65 (m, 6H), 5.24 (q, J = 7.0 Hz, 1H), 6.66 (s, 2 H;
C4H4O4), 7.20ꢀ7.27 (m, 1H), 7.29ꢀ7.42 (m, 4H), 7.48 (dd, J = 2.9,
1.9 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 8.36 (d, J = 1.7 Hz, 1H). MS (ESI)
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3
5-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-
(3-isopropoxyphenyl)nicotinamide (32). Prepared from 73 and
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3-isopropoxyaniline according to the procedures for 51 and 20. H
NMR (300 MHz, MeOH-d4) δ ppm 1.33 (d, J = 6.1 Hz, 6H), 3.19ꢀ3.37
(m, 4H), 3.42ꢀ3.69 (m, 6H), 4.60 (hept, J = 6.1 Hz, 1H), 6.66 (s, 2 H;
C4H4O4), 6.72 (td, J = 4.6, 2.4 Hz, 1H), 7.16ꢀ7.29 (m, 2H), 7.38 (t,
J = 1.9 Hz, 1H), 7.58 (dd, J = 2.7, 2.0 Hz, 1H), 8.17 (d, J = 2.7 Hz, 1H),
8.44 (d, J = 1.7 Hz, 1H). MS (ESI) m/z 367 (M + H)+. Anal.
(C21H26N4O2 1.1C4H4O4 0.1H2O) C, H, N.
m/z 337 (M + H)+; [α]20 = ꢀ11.2° (c = 0.10, MeOH). Anal.
D
(C20H24N4O 1.5C4H4O4 0.1H2O) C, H, N.
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5-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-
N-((R)-1-phenylethyl)nicotinamide (25). Prepared from 73 and
(R)-1-phenylethanamine according to the procedures for 51 and 20. 1H
NMR (300 MHz, MeOH-d4) δ ppm 1.57 (d, J = 6.8 Hz, 3H), 3.17ꢀ3.28
(m, 4H), 3.39ꢀ3.66 (m, 6H), 5.24 (q, J = 7.0 Hz, 1H), 6.66 (s, 2 H;
C4H4O4), 7.20ꢀ7.27 (m, 1H), 7.29ꢀ7.42 (m, 4H), 7.48 (dd, J = 2.9,
1.9 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 8.36 (d, J = 1.7 Hz, 1H). MS (ESI)
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N-(4-Chlorophenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]-
pyrrol-2(1H)-yl)nicotinamide (33). Prepared from 73 and 4-chlor-
oaniline according to the procedures for 51 and 20. 1H NMR (300 MHz,
MeOH-d4) δ ppm 3.22ꢀ3.35 (m, 4H), 3.43ꢀ3.68 (m, 6H), 6.70 (s, 3
H; C4H4O4), 7.33ꢀ7.41 (m, 2H), 7.59 (dd, J = 2.7, 2.0 Hz, 1H),
7.67ꢀ7.80 (m, 2H), 8.18 (d, J = 2.7 Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H).
m/z 337 (M + H)+; [α]20 = +11.7° (c = 0.11, MeOH). Anal.
D
(C20H24N4O 1.1C4H4O4 0.2H2O) C, H, N.
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MS (ESI) m/z 343 (M + H)+. Anal. (C18H19ClN4O 1.65C4H4O4)
N-Benzyl-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-
2(1H)-yl)-N-methylnicotinamide (26). Prepared from 73 and N-
methylbenzylamine according to the procedures for 51 and 20. 1H NMR
(300 MHz, MeOH-d4) δ ppm 2.92, 3.07 (s, s, 3H; rotamers), 3.20ꢀ3.33
(m, 4H), 3.36ꢀ3.67 (m, 6H), 4.55, 4.76 (s, s, 2H; rotamers), 6.70 (s, 3H;
C4H4O4), 7.07ꢀ7.24 (m, 2H), 7.27ꢀ7.42 (m, 4H), 7.99 (s, 1H), 8.04ꢀ
8.14 (m, J = 10.9, 1.7 Hz, 1H). MS (ESI) m/z 337 (M + H)+. Anal.
(C20H24N4O 1.6C4H4O4 0.45H2O) C, H, N.
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C, H, N.
5-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-
m-tolylnicotinamide (34). Prepared from 73 and m-toluidine
according to the procedures for 51 and 20. 1H NMR (300 MHz,
MeOH-d4) δ ppm 2.36 (s, 3H), 3.21ꢀ3.35 (m, 4H), 3.43ꢀ3.53 (m,
2H), 3.54ꢀ3.68 (m, 4H), 6.69 (s, 2 H; C4H4O4), 6.95ꢀ7.03 (m, 1H),
7.25 (t, J = 7.8 Hz, 1H), 7.45ꢀ7.53 (m, 2H), 7.59 (dd, J = 2.9, 1.9 Hz,
1H), 8.18 (d, J = 2.7 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H). MS (DCI/NH3)
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3
5-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-
N-(2-(trifluoromethyl)benzyl)nicotinamide (27). Prepared from
73 and 2-trifluoromethylbenzylamine according to the procedures for 51
and 20. 1H NMR (300 MHz, MeOH-d4) δ ppm 2.37 (s, 3H), 3.20ꢀ3.28
(m, 3H), 3.38ꢀ3.73 (m, 7H), 4.59 (s, 2), 6.70 (s, 2H; C4H4O4),
7.11ꢀ7.21 (m, 3H), 7.24ꢀ7.32 (m, 1H), 7.50ꢀ7.57 (m, 1H), 8.14 (d,
J = 2.7 Hz, 1H), 8.37 (d, J = 1.7 Hz, 1H). MS (ESI) m/z 337 (M + H)+.
Anal. (C20H24N4O 1.3C4H4O4 0.5H2O) C, H, N.
m/z 323 (M + H)+. Anal. (C20H24N4O 0.95C4H4O4) C, H, N.
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N-(3,5-Dimethylphenyl)-5-((3aR,6aS)-hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl)nicotinamide(35). Prepared from 73 and
3,5-dimethylaniline according to the procedures for 51 and 20. 1H
NMR (300 MHz, MeOH-d4) δ ppm 2.31 (s, 6H), 3.22ꢀ3.36 (m, 4H),
3.44ꢀ3.69 (m, 6H), 6.69 (s, 2 H; C4H4O4), 6.83 (s, 1H), 7.31
(s, 2H), 7.58 (dd, J = 2.7, 2.0 Hz, 1H), 8.17 (d, J = 3.1 Hz, 1H), 8.44
(d, J = 1.7 Hz, 1H). MS (DCI/NH3) m/z 337 (M + H)+. Anal.
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(3,4-Dihydroisoquinolin-2(1H)-yl)(5-((3aR,6aS)-hexahydro-
pyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)methanone (28).
Prepared from 73 and 1,2,3,4-tetrahydroisoquinoline according to
(C20H24N4O 1.5C4H4O4) C, H, N.
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N-(3,5-Dimethoxyphenyl)-5-((3aR,6aS)-hexahydropyrrolo
[3,4-c]pyrrol-2(1H)-yl)nicotinamide (36). Prepared from 73 and
1
the procedures for 51 and 20. H NMR (300 MHz, MeOH-d4) δ
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dx.doi.org/10.1021/jm201045m |J. Med. Chem. 2011, 54, 7678–7692