Series of Protein Kinase B/Akt Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13 2999
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synthesized as 3× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.36 (s, 3H), 2.62 (s, 3H), 3.16 (dd, J ) 14.19, 6.71
Hz, 1H), 3.23 (m, 1H), 3.97 (m, 1H), 4.29 (dd, J ) 10.45, 4.84
Hz, 1H), 4.42 (dd, J ) 10.61, 3.12 Hz, 1H), 6.95 (td, J ) 8.42,
2.81 Hz, 1H), 7.04 (dd, J ) 9.67, 2.81 Hz, 1H), 7.25 (dd, J )
8.42, 5.93 Hz, 1H), 7.63 (d, J ) 8.74 Hz, 1H), 7.73 (dd, J ) 8.73,
1.56 Hz, 1H), 8.05 (s, 1H), 8.09 (s, 1H), 8.42 (s, 1H), 8.71 (s, 1H).
MS (APCI): m/z 391 (M + 1)+. Anal. (C23H23FN4O‚2.6TFA) C,
H, N.
3.28 Hz, 1H), 7.58 (d, J ) 8.42 Hz, 1H), 7.61 (d, J ) 7.49 Hz,
1H), 7.65 (s, 1H), 7.66 (s, 1H), 7.69 (dd, J ) 8.74, 1.56 Hz, 1H),
7.73 (s, 1H), 7.75 (m, 1H), 8.07 (s, 1H), 8.22 (s, 3H), 8.33 (d, J )
2.50 Hz, 1H), 8.64 (d, J ) 1.56 Hz, 1H). MS (ESI): m/z 427 (M
+ H)+.
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(4-tri-
fluoromethyl-benzyl)-ethylamine (13ad). The title compound was
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synthesized as 3× TFA salt by method B. H NMR (500 MHz,
CD3OD): δ 2.63 (s, 3H), 3.28 (m, 2H), 4.05 (m, 1H), 4.32 (dd, J
) 10.61, 5.30 Hz, 1H), 4.47 (dd, J ) 10.61, 2.81 Hz, 1H), 7.56 (d,
J ) 7.80 Hz, 2H), 7.63 (d, J ) 8.74 Hz, 1H), 7.69 (d, J ) 8.11
Hz, 2H), 7.74 (dd, J ) 8.74, 1.56 Hz, 1H), 8.12 (d, J ) 6.55 Hz,
2H), 8.45 (br s, 1H), 8.74 (br s, 1H). MS (APCI): m/z 428 (M +
1)+. Anal. (C23H21F3N4O‚2.7TFA) C, H, N.
(1S)-1-(4-Bromo-3-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13w). The title compound was
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synthesized as 3× TFA salt by method B. H NMR (500 MHz,
CD3OD): δ 2.37 (s, 3H), 2.63 (s, 3H), 3.11 (m, 2H), 3.97 (m, 1H),
4.29 (dd, J ) 10.61, 5.62 Hz, 1H), 4.44 (dd, J ) 10.61, 3.12 Hz,
1H), 7.07 (dd, J ) 8.11, 1.87 Hz, 1H), 7.27 (s, 1H), 7.54 (d, J )
8.11 Hz, 1H), 7.63 (d, J ) 8.73 Hz, 1H), 7.73 (d, J ) 8.73 Hz,
1H), 8.06 (s, 1H), 8.10 (s, 1H), 8.41 (s, 1H), 8.71 (s, 1H). MS
(ESI): m/z 452 (M + 1)+. Anal. (C23H23BrN4O‚2.7TFA) C, H, N.
(1S)-1-(4-Fluoro-3-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13x). The title compound was
(1S)-1-(3,5-Bis-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-in-
dazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ae). The title com-
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pound was synthesized as 3× TFA salt by method C. H NMR
(500 MHz, CD3OD): δ 2.62 (s, 3H), 3.35 (m, 1H), 3.42 (m, 1H),
4.12 (m, 1H), 4.31 (dd, J ) 10.61, 5.30 Hz, 1H), 4.49 (dd, J )
10.61, 3.12 Hz, 1H), 7.63 (d, J ) 8.73 Hz, 1H), 7.73 (dd, J )
8.74, 1.87 Hz, 1H), 7.94 (s, 1H), 8.01 (s, 2H), 8.05 (s, 1H), 8.08
(s, 1H), 8.43 (s, 1H), 8.72 (s, 1H). MS (APCI): m/z 495 (M +
1)+. Anal. (C24H20F6N4O‚2.8TFA) C, H, N.
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synthesized as 3× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.24 (s, 3H), 2.63 (s, 3H), 3.11 (dd, J ) 7.64, 3.90
Hz, 2H), 3.94 (m, 1H), 4.29 (dd, J ) 10.61, 5.62 Hz, 1H), 4.44
(dd, J ) 10.61, 2.81 Hz, 1H), 7.03 (m, 1H), 7.16 (m, 1H), 7.21 (d,
J ) 7.18 Hz, 1H), 7.63 (d, J ) 8.73 Hz, 1H), 7.74 (d, J ) 1.87
Hz, 1H), 8.06 (s, 1H), 8.10 (s, 1H), 8.42 (s, 1H), 8.71 (s, 1H). MS
(APCI): m/z 392 (M + 1)+. Anal. (C23H23FN4O‚3TFA) C, H, N.
(1S)-1-(4-Fluoro-2-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13y). The title compound was
(1S)-1-(4-Fluoro-3-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13af). The title com-
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pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.23 (m, 2H), 4.02 (m, 1H),
4.28 (dd, J ) 10.8, 4.5 Hz, 1H), 4.44 (dd, J ) 10.8, 3.0 Hz, 1H),
7.36 (t, J ) 9.0 Hz, 1H), 7.62 (d, J ) 8.1 Hz, 1H), 7.68 (m, 1H),
7.74 (d, J ) 8.1 Hz, 1H), 8.04 (s, 1H), 8.09 (s, 1H), 8.41 (s, 1H),
8.70 (s, 1H). MS (DCI/NH3): m/e 445 (M + 1)+.
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synthesized as 3× TFA salt by method C. H NMR (500 MHz,
CD3OD): δ 2.40 (s, 3H), 2.62 (s, 3H), 3.15 (dd, J ) 14.19, 6.40
Hz, 1H), 3.22 (m, 1H), 3.94 (m, 1H), 4.29 (dd, J ) 10.61, 4.99
Hz, 1H), 4.42 (dd, J ) 10.61, 2.81 Hz, 1H), 6.91 (td, J ) 8.42,
2.50 Hz, 1H), 7.00 (dd, J ) 9.83, 2.34 Hz, 1H), 7.26 (dd, J )
8.42, 5.93 Hz, 1H), 7.63 (d, J ) 8.74 Hz, 1H), 7.73 (dd, J ) 8.74,
1.25 Hz, 1H), 8.08 (s, 1H), 8.10 (s, 1H), 8.43 (s, 1H), 8.72 (s, 1H).
MS (APCI): m/z 392 (M + 1)+. Anal. (C23H23FN4O‚2.8TFA) C,
H, N.
(1S)-1-(3-Fluoro-5-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ag). The title com-
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pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.30 (m, 2H), 4.06 (m, 1H),
4.29 (dd, J ) 10.51, 5.09 Hz, 1H), 4.45 (dd, J ) 10.85, 3.05 Hz,
1H), 7.45 (dd, J ) 7.80, 5.76 Hz, 2H), 7.55 (s, 1H), 7.62 (d, J )
8.81 Hz, 1H), 7.73 (d, J ) 8.48 Hz, 1H), 7.98 (s, 1H), 8.07 (s,
1H), 8.42 (br s, 1H), 8.73 (br s, 1H). MS (APCI): m/z 445 (M +
1)+.
(1S)-1-(3-Fluoro-4-methyl-benzyl)-2-[5-(3-methyl-1H-indazol-
5-yl)-pyridin-3-yloxy]-ethylamine (13z). The title compound was
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synthesized as 3× TFA salt by method C. H NMR (300 MHz,
(1S)-1-(2-Fluoro-5-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ah). The title com-
CD3OD): δ 2.24 (d, J ) 1.70 Hz, 3H), 2.63 (s, 3H), 3.11 (d, J )
8.14 Hz, 2H), 3.96 (m, 1H), 4.31 (dd, J ) 10.51, 5.76 Hz, 1H),
4.46 (dd, J ) 10.85, 3.05 Hz, 1H), 7.03 (t, J ) 8.48 Hz, 1H), 7.15
(m, 1H), 7.21 (d, J ) 7.46 Hz, 1H), 7.64 (d, J ) 8.48 Hz, 1H),
7.74 (dd, J ) 8.81, 1.70 Hz, 1H), 8.14 (m, 2H), 8.45 (d, J ) 2.37
Hz, 1H), 8.75 (d, J ) 1.36 Hz, 1H). MS (APCI): m/z 391 (M +
1)+. Anal. (C23H23FN4O‚2.9TFA) C, H, N.
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pound was synthesized as 3× TFA salt by method C. H NMR
(500 MHz, CD3OD): δ 2.63 (s, 3H), 3.26-3.31 (m, 1H), 3.34-
3.39 (m, 1H), 4.03-4.10 (m, 1H), 4.32 (dd, J ) 10.53, 5.03 Hz,
1H), 4.49 (dd, J ) 10.68, 3.05 Hz, 1H), 7.38 (t, J ) 9.15 Hz, 1H),
7.63 (d, J ) 8.85 Hz, 1H), 7.70-7.72 (m, 1H), 7.72-7.76 (m,
1H), 7.78 (d, J ) 6.71 Hz, 1H), 8.10 (d, J ) 1.83 Hz, 1H), 8.11 (s,
1H), 8.43 (s, 1H), 8.73 (s, 1H). MS (ESI): m/z 445 (M + H)+.
Anal. (C23H20F4N4O‚2.7TFA) C, H, N.
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2,4,6-
trimethyl-benzyl)-ethylamine (13aa). The title compound was
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synthesized as 2× TFA salt by method C. H NMR (500 MHz,
(1S)-1-(3-Fluoro-4-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13ai). The title com-
CD3OD): δ 2.21 (s, 3H), 2.34 (s, 6H), 2.62 (s, 3H), 3.14 (dd, J )
14.19, 5.46 Hz, 2H), 3.92 (m, J ) 8.73, 4.99 Hz, 1H), 4.26 (dd, J
) 10.45, 4.84 Hz, 1H), 4.36 (m, 1H), 6.89 (s, 2H), 7.63 (d, J )
8.74 Hz, 1H), 7.72 (dd, J ) 8.73, 1.56 Hz, 1H), 8.11 (s, 2H), 8.42
(s, 1H), 8.75 (s, 1H). MS (APCI): m/z 402 (M + 1)+. Anal.
(C25H28N4O‚2.5TFA) C, H, N.
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pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.28 (m, 2H), 4.08 (m, 1H),
4.32 (dd, J ) 10.8, 4.5 Hz, 1H), 4.48 (dd, J ) 10.8, 3.0 Hz, 1H),
7.38 (d, J ) 8.1 Hz, 1H), 7.40 (d, J ) 12.0 Hz, 1H), 7.43 (d, J )
8.4 Hz, 1H), 7.70 (t, J ) 8.4 Hz, 1H), 7.75 (d, J ) 8.1 Hz, 1H),
8.13 (m, 2H), 8.44 (s, 1H), 8.74 (s, 1H). MS (DCI/NH3): m/e 445
(M + 1)+.
(1S)-1-(5-Fluoro-2-methoxy-benzyl)-2-[5-(3-methyl-1H-inda-
zol-5-yl)-pyridin-3-yloxy]-ethylamine (13ab). The title compound
was synthesized as 3× TFA salt by method C. 1H NMR (500 MHz,
CD3OD): δ 2.63 (s, 3H), 3.16 (d, J ) 7.18 Hz, 2H), 3.84 (s, 3H),
4.02 (m, 1H), 4.30 (dd, J ) 10.61, 5.93 Hz, 1H), 4.45 (dd, J )
10.45, 2.96 Hz, 1H), 7.04 (m, 3H), 7.64 (d, J ) 8.73 Hz, 1H), 7.74
(d, J ) 8.74 Hz, 1H), 8.12 (s, 2H), 8.43 (s, 1H), 8.74 (s, 1H). MS
(APCI): m/z 408 (M + 1)+. Anal. (C23H23FN4O2‚3.5TFA) C, H,
N.
(1S)-1-(2-Fluoro-4-trifluoromethyl-benzyl)-2-[5-(3-methyl-1H-
indazol-5-yl)-pyridin-3-yloxy]-ethylamine (13aj). The title com-
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pound was synthesized as 3× TFA salt by method C. H NMR
(300 MHz, CD3OD): δ 2.62 (s, 3H), 3.31 (m, 2H), 4.04 (m, 1H),
4.29 (dd, J ) 10.85, 5.09 Hz, 1H), 4.45 (dd, J ) 10.85, 3.39 Hz,
1H), 7.54 (d, J ) 8.81 Hz, 1H), 7.55 (s, 1H), 7.60 (dd, J ) 4.07,
3.39 Hz, 1H), 7.63 (s, 1H), 7.72 (dd, J ) 8.81, 1.70 Hz, 1H), 7.96
(s, 1H), 8.07 (s, 1H), 8.39 (s, 1H), 8.67 (s, 1H). MS (APCI): m/z
445 (M + 1)+.
(1S)-2-(5-(3-methyl-1H-indazol-5-yl)-pyridin-3-yloxy)-1-(3-tri-
fluoromethyl-benzyl)-ethylamine (13ac). The title compound was
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synthesized as 2× TFA salt by method A. H NMR (500 MHz,
(1S)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-yloxy]-1-(2-tri-
fluoromethoxy-benzyl)-ethylamine (13ak). The title compound
was synthesized as 3× TFA salt by method C. 1H NMR (300 MHz,
DMSO-d6): δ 2.55 (s, 3H), 3.16 (dd, J ) 7.33, 2.34 Hz, 2H), 3.97
(s, 1H), 4.16 (dd, J ) 10.61, 5.62 Hz, 1H), 4.34 (dd, J ) 10.76,