Journal of Medicinal Chemistry
ARTICLE
(m, 2H), 3.81 (m, 2H), 3.90 (m, 2H), 4.80 (s, 2H), 5.79 (s, 2H), 7.21
(m, 2H), 7.43 (m, 2H), 7.60 (m, 1H), 7.65ꢀ7.75 (2H), 8.13 (m, 1H),
8.43 (brs, 1H), 8.61 (m, 1H). LC/MS (APCI) m/z 447.2 (M þ H)þ.
mmol) was treated with HCl in dioxane to give the HCl salt of 40d (0.135 g,
50%) as an ivory solid. 1H NMR (300 MHz, DMSO-d6) δ 1.02 (d, J =
7.0 Hz, 6H), 3.40ꢀ3.55 (7H), 3.75 (m, 2H), 4.62 (s, 2H), 5.52 (s, 2H),
7.16 (m, 2H), 7.81 (s, 1H), 8.85 (s, 1H), 9.74 (s, 1H). LC/MS (APCI)
Anal. Calcd for: C25H23FN4O3 2HCl: C, 57.81; H, 4.85; N, 10.79.
3
m/z 428.2 (M þ H)þ. Anal. Calcd for C23H26FN3O4 HCl: C, 59.54; H,
Found: C, 57.81; H, 4.91; N, 10.86.
3
5.87; N, 9.06. Found: C, 59.38; H, 5.59; N, 8.93.
1-[(2-Pyridinylmethoxy)methyl]-3-(4-fluorobenzyl)-7-{[2-(trimethyl-
silyl)ethoxy]methoxy}-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c][1,7]naphthy-
ridin-6-one (39b). As described for the preparation of 39a, dimethyla-
minomethyl compound 34 (0.90 g, 1.80 mmol) was converted to
chloromethyl compound 36, which was reacted with 2-pyridyl-methanol
(0.49 g, 4.50 mmol) to provide SEMꢀether 39b (0.82 g, 81%). 1H NMR
(300 MHz, CDCl3) δ 0.06 (s, 9H), 0.96 (m, 2H), 3.55 (m, 2H),
3.80ꢀ4.00 (4H), 4.68 (s, 2H), 4.80 (s, 2H), 5.15 (s, 2H), 5.30 (s, 2H),
7.00 (m, 2H), 7.04ꢀ7.22 (5H), 7.58 (m, 1H), 8.60 (brs, 1H), 8.80
(s, 1H). LC/MS (APCI) m/z 563.2 (M þ H)þ. Anal. Calcd for
C30H35FN4O4Si: C, 64.03; H, 6.27; N, 9.96. Found: C, 64.14; H,
6.39; N, 9.78.
1-[[3-(2-Pyridinyl)propoxy]methyl]-3-(4-fluorobenzyl)-7-{[2-(trimethyl-
silyl)ethoxy]methoxy}-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c][1,7]
naphthyridin-6-one (39e). As described for the preparation of 39a,
dimethylaminomethyl compound 34 (0.80 g, 1.58 mmol) was converted
to chloromethyl compound 36, which was reacted with 3-(2-pyridyl)-
propan-1-ol (0.54 g, 3.95 mmol) to provide SEMꢀether 39e (0.72 g,
77%). 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 0.97 (m, 2H), 1.85
(m, 2H), 2.87 (m, 2H), 3.50ꢀ3.75 (6H), 3.90 (m, 2H), 4.71 (s, 2H),
5.10 (s, 2H), 5.36 (s, 2H), 7.00 (m, 2H), 7.10ꢀ7.20 (3H), 7.24ꢀ7.32
(2H), 7.60 (m, 1H), 8.39 (m, 1H), 8.79 (s, 1H). LC/MS (APCI) m/z
591.2 (M þ H)þ. Anal. Calcd for C32H39FN3O4Si: C, 65.06; H, 6.65; N,
9.48. Found: C, 65.04; H, 6.72; N, 9.36.
1-[(2-Pyridinylmethoxy)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7,8,
9-tetrahydro-6H-pyrrolo[2,3-c][1,7]naphthyridin-6-one (40b). As de-
scribed for the preparation of 40a, SEMꢀether 39b (0.70 g, 1.24 mmol)
was treated with HCl in dioxane to give the bis-HCl salt of 40b (0.48 g,
76%) as a pale-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 3.67 (m,
2H), 3.95 (m, 2H), 4.76 (s, 2H), 4.95 (s, 2H), 5.77 (s, 2H), 7.20 (m,
2H), 7.40 (m, 2H), 7.53 (m, 1H), 7.65 (m, 1H), 8.06 (m, 1H), 8.54 (brs,
1H), 8.65 (m, 1H), 9.36 (s, 1H). LC/MS (APCI) m/z 433.2 (M þ H)þ.
1-[[3-(2-Pyridinyl)propoxy]methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,
7,8,9-tetrahydro-6H-pyrrolo[2,3-c][1,7]naphthyridin-6-one (40e). As
described for the preparation of 40a, SEMꢀether 39e (0.60 g, 1.01
mmol) was treated with HCl in dioxane to give the bis-HCl salt of 40e
(0.275 g, 51%) as a pale-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ
1.94 (m, 2H), 2.76 (m, 2H). 3.45ꢀ3.62 (4H), 3.81 (m, 2H), 4.62 (s,
2H), 5.54 (s, 2H), 7.10ꢀ7.22 (4H), 7.32 (m, 2H), 7.60 (m, 1H), 7.83
(s, 1H), 8.44 (m, 1H), 8.88 (s, 1H), 9.77 (brs, 1H). LC/MS (APCI) m/z
Anal. Calcd for C24H21FN4O3 2HCl: C, 57.04; H, 4.59; N, 11.09.
3
461.2 (M þ H)þ. Anal. Calcd for C26H25FN4O3 2HCl: C, 58.54; H,
Found: C, 57.01; H, 4.73; N, 10.72.
3
5.10; N, 10.50. Found: C, 58.15; H, 5.14; N, 10.43.
1-(Tetrahydro-2H-pyran-4-yl)methoxy]methyl]-3-(4-fluorobenzyl)-
7-{[2-(trimethylsilyl)ethoxy]methoxy}-3,7,8,9-tetrahydro-6H-Pyrrolo-
[2,3-c][1,7]naphthyridin-6-one (39c). As described for the preparation
of 39a, dimethylaminomethyl compound 34 (1.00 g, 2.00 mmol) was
converted to chloromethyl compound 36, which was reacted with
(tetrahydro-2H-pyran-4-yl)methanol (0.58 g, 5.00 mmol) to provide
SEMꢀether 39c (0.97 g, 85%). 1H NMR (300 MHz, CDCl3) δ 0.06 (s,
9H), 0.97 (m, 2H), 1.30 (m, 4H), 1.55ꢀ2.00 (6H), 3.20ꢀ3.42 (4H),
3.52 (m, 1H), 3.67 (m, 2H), 4.62 (s, 2H), 5.15 (s, 2H), 5.35 (s, 2H),
6.95ꢀ7.05 (3H), 7.12 (m, 2H), 8.79 (s, 1H). LC/MS (APCI) m/z 570.3
(M þ H)þ. Anal. Calcd for C30H40FN3O5Si: C, 63.24; H, 7.08; N, 7.38.
Found: C, 63.19; H, 7.21; N, 7.29.
1-[[(2-Fluorophenyl)methoxy]methyl]-3-(4-fluorobenzyl)-3,7,8,9-
tetrahydro-7-{[2-(trimethylsilyl)ethoxy]methoxy}-6H-pyrrolo[2,3-c]-
[1,7]naphthyridin-6-one (37f). As described for the preparation of 39a,
dimethylaminomethyl compound 34 (0.45 g, 0.90 mmol) was converted
to chloromethyl compound 36, which was reacted with 2-fluoro-benzyl
alcohol (0.29 g, 2.25 mmol) to provide SEMꢀether 39f (0.41 g, 79%).
1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.01 (m, 2H), 3.61 (m,
2H), 3.80ꢀ3.92 (4H), 4.60 (s, 2H), 4.70 (s, 2H), 5.14 (s, 2H), 5.34
(s, 2H), 6.95ꢀ7.15 (6H), 7.23 (m, 1H), 7.27 (s, 1H), 7.35 (m, 1H), 8.76
(s, 1H). LC/MS (APCI) m/z 580.2 (M þ H)þ. Anal. Calcd for
C31H35F2N3O4Si: C, 64.23; H, 6.09; N, 7.25. Found: C, 64.19; H,
6.18; N, 7.22.
1-(Tetrahydro-2H-pyran-4-yl)methoxy]methyl]-3-(4-fluorobenzyl)-
7-hydroxy3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c][1,7]naphthyridin-6-one
(40c). As described for the preparation of 40a, SEMꢀether 39c (0.75 g,
1.31 mmol) was treated with HCl in dioxane to give the HCl salt of 40c
(0.42 g, 61%) as an ivory solid. 1H NMR (300 MHz, DMSO-d6) δ 1.16
(m, 2H), 1.55 (m, 2H), 1.78 (m, 1H), 3.15ꢀ3.32 (4H), 3.64 (m, 2H),
3.77 (m, 2H), 3.96 (m, 2H), 4.69 (s, 2H), 5.75 (s, 2H), 7.20 (m, 2H),
7.40 (m, 2H), 8.44 (s, 1H), 9.35 (s, 1H), 10.35 (brs, 1H)). LC/MS
1-[[(2-Fluorophenyl)methoxy]methyl]-3-(4-fluorobenzyl)-3,7,8,9-
tetrahydro-7-hydroxy-6H-pyrrolo[2,3-c][1,7]naphthyridin-6-one (40f).
As described for the preparation of 40a, SEMꢀether 39f (0.340 g,
0.58 mmol) was treated with HCl in dioxane to give the HCl salt of 40f
(0.141 g, 50%) as an ivory solid. 1H NMR (300 MHz, DMSO-d6) δ 3.62
(m, 2H), 3.92 (m, 2H), 4.61 (s, 2H), 4.80 (s, 2H), 5.76 (s, 2H),
7.10ꢀ7.22 (4H), 7.30ꢀ7.46 (4H), 8.49 (s, 1H), 9.35 (s, 1H), 10.56 (brs,
1H). LC/MS (APCI) m/z 450.2 (M þ H)þ. Anal. Calcd for
(APCI) m/z 440.2 (M þ H)þ. Anal. Calcd for C24H26FN3O4 HCl: C,
3
C25H21F2N3O3 HCl: C, 61.79; H, 4.56; N, 8.65. Found: C, 61.84; H,
60.57; H, 5.72; N, 8.83. Found: C, 60.62; H, 5.69; N, 8.91.
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4.49; N, 8.63.
1-[[2-(1-Methylethoxy)ethoxy]methyl]-3-(4-fluorobenzyl)-)-7-{[2-(tri-
methylsilyl)ethoxy]methoxy}-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c][1,7]
naphthyridin-6-one (39d). As described for the preparation of 39a,
dimethylaminomethyl compound 34 (0.40 g, 0.79 mmol) was converted
to chloromethyl compound 36, which was reacted with 2-isopropox-
yethanol (0.21 g, 1.98 mmol) to provide SEMꢀether 39d (0.35 g, 79%).
1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 0.97 (m, 2H), 1.15 (d, J =
7.0 Hz, 6H), 1.30 (m, 4H), 3.50ꢀ3.75 (7H), 3.85 (m, 2H), 3.97 (m,
2H), 4.69 (s, 2H), 5.13 (s, 2H), 5.34 (s, 2H), 6.98 (m, 2H), 7.18 (m,
2H), 7.27 (s, 1H), 8.82 (s, 1H). LC/MS (APCI) m/z 558.2 (M þ H)þ.
Anal. Calcd for C29H40FN3O5Si: C, 62.45; H, 7.23; N, 7.53. Found: C,
62.47; H, 7.29; N, 7.36.
3-(4-Fluorobenzyl)-1-(3-(4-morpholinyl)-prop-1-yn-1-yl)-7-{[2-(tri-
methylsilyl)ethoxy]methoxy}-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c]-1,
7-naphthyridin-6-one (41b). To a stirring solution of iodide 35a (9.97 g,
17.6 mmol), 4-prop-2-yn-1-ylmorpholine (2.20 g, 17.6 mmol), and
TEA (3.56 g, 4.90 mL, 35.2 mmol) in DMF (100 mL) was added
Pd(PPh3)2Cl2 (0.625 g, 0.88 mmol) and CuI (0.334 g, 1.76 mmol). After
the addition was complete, the color of the solution went from pale-yellow,
to orange, to black, and after 20 min, the reaction was judged to be
complete by HPLC-MS analysis. The reaction was diluted with dichlor-
omethane (1.0 L), washed with a satd aq ammonium chloride
(2 ꢁ 1.0 L), water (1.0 L), and brine (0.75 L), dried over sodium sulfate,
and concentrated in vacuo, yielding a brown residue. The crude 41b was
purified on silica gel using a Biotage SP4 chromatography system (eluent:
0ꢀ6% EtOH in DCM over 16CV). The purified fractions were combined
1-[[2-(1-Methylethoxy)ethoxy]methyl]-3-(4-fluorobenzyl)-7-hydro-
xy-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c][1,7]naphthyridin-6-one (40d).
As described for the preparation of 40a, SEMꢀether 39d (0.324 g, 0.58
3411
dx.doi.org/10.1021/jm200208d |J. Med. Chem. 2011, 54, 3393–3417