DiscoVery of SCH446211
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2755
mg, 0.118 mmol, 86% yield) as a mixture of two diastereomers.
1H NMR (DMSO-d6, 500 MHz, mixture of two diastereomers) δ
8.77-8.73 (m, 1H), 8.56 (t, J ) 7.8 Hz, 1H), 8.46 and 8.39 (d, J
) 7.0 and 7.6 Hz, 1H), 7.39-7.30 (m, 5H), 6.63-6.59 (m, 1H),
5.82 (d, J ) 7.8 Hz, 1H), 5.15-5.11 and 5.07-5.03 (m, 1H), 4.36
and 4.35 (bs, 1H), 4.05-4.01 (m, 1H), 3.90-3.74 (m, 4H), 2.92
(s, 3H), 2.85 (s, 3H), 1.72-1.64 and 1.61-1.58 (m, 2H), 1.47-
1.39 (m, 2H), 1.36 (s, 9H), 0.98 and 0.95 (s, 3H), 0.91 (s, 9H),
0.88 and 085 (s, 3H), 0.80-0.74 (m, 1H), 0.43-0.34 (m, 2H),
0.16-0.09 (m, 1H), 0.08-0.01 (m, 1H). 13C NMR (DMSO-d6, 125
MHz, mixture of two diastereomers) δ 197.6, 196.9, 171.9, 171.6,
170.8, 170.6, 170.1, 167.8, 161.7, 161.3, 156.8, 138.4, 129.5, 128.7,
79.0, 60.3, 60.1, 59.6, 55.3, 55.1, 53.9, 53.8, 48.4, 46.5, 42.4, 37.5,
36.2, 35.8, 34.9, 31.6, 29.0, 28.9, 27.8, 27.2, 27.1, 27.0, 19.5, 13.4,
13.3, 12.4, 12.2, 8.8, 8.6, 5.9, 5.2, 4.9. HRMS Calcd for
C38H57N6O8: 725.4238 (M + H)+. Found: 725.4231.
N-[(2-Methylpropoxy)carbonyl]cyclohexylglucyl-N-[1-[2-[[2-
[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-
amino]-1,2-dioxoethyl]butyl]prolinamide (9). Coupling and oxi-
dation procedures for the preparation of 9 were carried out in a
manner similar to that described above for the preparation of 24.
1H NMR (DMSO-d6, 500 MHz, mixture of two diastereomers) δ
8.77-8.52 and 8.04-8.01 (m, 3H), 7.50-7.24 (m, 6H), 5.82 (d, J
) 7.6 Hz, 1H), 5.09-4.88 (m, 1H), 4.38-4.29 (m, 1H), 4.06 and
4.00 (t, J ) 7.3 Hz and J ) 8.8 Hz, 1H), 3.88-3.69 (m, 4H), 3.67-
3.59 (m, 1H), 3.56-3.48 (m, 1H), 2.93 (s, 3H), 2.85 (s, 3H), 2.05-
1.08 (m, 20H), 0.98-0.80 (m, 9H). 13C NMR (DMSO-d6, 125 MHz,
mixture of two diastereomers) δ 197.5, 197.4, 172.4, 172.1, 171.4,
171.0, 170.1, 167.8, 161.6, 157.7, 157.5, 138.4, 129.5, 128.7, 70.9,
70.8, 68.2, 60.4, 59.7, 58.2, 54.3, 53.9, 53.8, 47.8, 42.5, 40.9, 39.9,
39.8, 37.5, 36.2, 32.4, 30.4, 29.8, 29.5, 29.3, 28.5, 26.7, 26.5, 26.3,
24.8, 24.6, 23.7, 19.7, 19.4, 14.4, 14.2. HRMS Calcd for
C36H55N6O8: 753.4163 (M + H)+. Found: 753.4133.
166.81, 160.66, 160.55, 156.39, 156.32, 137.42, 128.49, 127.75,
127.70, 127.69, 69.82, 69.77, 68.40, 66.90, 66.87, 61.24, 59.95,
59.10, 56.89, 55.73, 53.39, 52.93, 52.91, 44.09, 41.51, 41.44, 38.47,
38.44, 36.49, 35.26, 35.25, 32.00, 31.69, 31.48, 29.50, 28.48, 28.46,
27.89, 27.56, 25.75, 25.43, 25.41, 25.33, 18.79, 18.61, 18.54, 13.38.
HRMS Calcd for C38H57N6O8S2: 789.3679 (M + H)+. Found:
789.3678.
2-Methylpropyl [1-Cyclohexyl-2-[3(S)-[[[1-[2-[[2-[[2-(Dime-
thylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-
dioxoethyl]butyl]amino]carbonyl]-6,10-dithia-2-azaspiro[4.5]-
decan-2-yl]-2-oxoethyl]carbamate (14). Coupling procedures for
the preparation of 14 were carried out in a manner similar to that
described for the preparation of 24. For the oxidation of the
intermediate hydroxyl amide to the corresponding ketoamide, the
Moffat procedure was used. 1H NMR (DMSO-d6, 500 MHz,
mixture of two diastereomers) δ 8.75 (q, J ) 5.9 Hz, 1H), 8.56
and 8.55 (d, J ) 7.7 and 7.5 Hz, 1H), 8.46 and 8.31 (d, J ) 7.9
and 6.9 Hz, 1H), 7.39-7.26 (m, 6 H), 5.83 and 5.82 (d, J ) 7.6
and 7.7 Hz, 1H), 5.02-4.95 (m, 1H), 4.71 and 4.63 (d, J ) 11.0
and 11.3 Hz, 1H), 4.52-4.46 (m, 1H), 4.07 (t, J ) 8.9 Hz, 1H),
3.86-3.57 (m, 5H), 3.08-2.97 (m, 2H), 2.92 (s, 3H), 2.89-2.82
(m, 1H), 2.84 (s, 3H), 2.63-2.54 (m, 1H), 2.02-1.90 (m, 2 H),
1.84-1.58 (m, 10 H), 1.47-1.23 (m, 3 H), 1.11-1.06 (m, 3 H),
0.89-0.76 (m, 11 H). 13C NMR (DMSO-d6, 125 MHz) δ 196.5,
196.4, 170.4, 170.31, 170.27, 170.2, 170.1, 169.2, 166.8, 160.7,
160.6, 156.45, 156.35, 137.4, 128.5, 128.3, 127.8, 127.71, 127.68,
127.65, 127.6, 69.9, 69.8, 69.7, 59.8, 59.7, 59.6, 58.8, 58.0, 56.9,
55.7, 53.4, 53.1, 53.0, 52.95, 52.94, 52.86, 52.1, 42.59, 42.58, 42.55,
41.55, 41.47, 38.7, 36.5, 35.27, 35.26, 31.7, 31.5, 29.5, 28.6, 28.33,
28.29, 28.2, 27.6, 26.6, 25.84, 25.80, 25.5, 25.4, 24.8, 20.7, 18.8,
18.64, 18.58, 14.0, 13.42, 13.40. HRMS Calcd for C39H59N6O8S2:
803.3836 (M + H)+. Found: 803.3835.
2-Methylpropyl [1-Cyclohexyl-2-[2-[[[1-[2-[[2-[[2-(dimethyl-
amino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-di-
oxoethyl]butyl]amino]carbonyl]-4(S)-[(1,1-dimethylethyl)thio]-
1-pyrrolidinyl]-2-oxoethyl]carbamate (15). Coupling procedures
for the preparation of 15 were carried out in a manner similar to
that described for the preparation of 24. For the oxidation of the
intermediate hydroxyl amide to the corresponding ketoamide, the
Moffat procedure was used. 1H NMR (DMSO-d6, 500 MHz,
mixture of two diastereomers) δ 8.76-8.72 (m, 1H), 8.57 (d, J )
7.5 Hz, 1H), 8.25 and 8.01 (d, J ) 7.0 and 7.9 Hz, 1H), 7.38-7.29
(m, 6H), 5.83 (d, J ) 7.5 Hz, 1H), 5.06-5.01 and 4.97-4.93 (m,
1H), 4.51-4.48 and 4.45-4.43 (m, 1H), 4.08-3.96 (m, 2H), 3.87-
3.68 (m, 4H), 3.49-3.37 (m, 4H), 2.93 (s, 3H), 2.85 (s, 3H), 2.27-
2.22 and 2.19-2.14 (m, 1H), 1.96-1.90 (m, 1H), 1.85-1.57 (m,
9H), 1.32 and 1.31 (s, 9H), 1.30-1.28 (m, 1H), 1.12-1.10 (m,
2H), 0.89-0.86 (m, 11H). 13C NMR (DMSO-d6, 125 MHz, mixture
of diastereomers) δ 196.47, 196.30, 171.14, 171.00, 169.98, 169.15,
166.83, 160.64, 156.42, 156.35, 137.42, 137.41, 128.50, 127.76,
127.70, 127.69, 69.80, 69.77, 68.40, 59.15, 58.42, 56.82, 56.71,
55.73, 54.07, 53.53, 53.31, 52.93, 52.91, 42.92, 42.89, 41.50, 41.47,
38.06, 37.88, 37.67, 36.50, 35.26, 32.01, 31.53, 31.30, 31.15, 31.14,
31.08, 29.50, 28.92, 28.52, 28.22, 28.09, 27.56, 25.80, 25.60, 25.57,
25.44, 18.80, 18.67, 18.60, 13.39, 13.35. HRMS Calcd for
C40H63N6O8S: 787.4428 (M + H)+. Found: 787.4437.
N-[(2-Methylpropoxy)carbonyl]-(S)-tert-leucyl-n-[1-[2-[[2-[[2-
(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]ami-
no]-1,2-dioxoethyl]butyl]-4(R)-(1,1-dimethylethoxy)-(S)-proli-
namide (16). Coupling and oxidation procedures for the preparation
of 16 were carried out in a manner similar to that described for the
preparation of 24. 1H NMR (DMSO-d6, 500 MHz, mixture of two
diastereomers) δ 8.73 (t, J ) 6.0 Hz, 1H), 8.57 (t, J ) 7.9 Hz,
1H), 8.26 and 8.15 (d, J ) 7.9 and 6.9 Hz, 1H), 7.38-7.29 (m,
5H), 7.11 and 7.04 (d, J ) 9.1 and 9.5 Hz, 1H), 5.82 (d, J ) 7.6
Hz, 1H), 5.03-4.95 (m, 1H), 4.49-4.41 (m, 1H), 4.35-4.30 (m,
1H), 4.18-4.14 (m, 1H), 3.83-3.79 (m, 2H), 3.77-3.70 (m, 4H),
2.93 (s, 3H), 2.85 (s, 3H), 1.97-1.91 (m, 2H), 1.86-1.79 (m, 1H),
1.72-1.66 (m, 1H), 1.46-1.23 (m, 3H), 1.15-1.13 (m, 9H), 0.92-
0.95 (m, 9H), 0.90-0.82 (m, 9H). 13C NMR (DMSO-d6, 125 MHz,
mixture of two diastereomers) δ 197.6, 172.4, 172.2, 170.1, 167.8,
N-[(2-Methylpropoxy)carbonyl]-(S)-tert-leucyl-N-[1(S)-[2-[[2-
[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]-
amino]-1,2-dioxoethyl]butyl]-4(R)-methyl-(S)-prolinamide (10).
Coupling and oxidation procedures for the preparation of 10 were
carried out in a manner similar to that described for the preparation
1
of 24. H NMR (DMSO-d6, 500 MHz, mixture of two diastereo-
mers) δ 8.75-8.69 (m, 1H), 8.57 (t, J ) 7.9 Hz, 1H), 8.21 and
8.20 (d, J ) 6.9 and 7.0 Hz, 1H), 7.41-7.28 (m, 5H), 6.95 (d, J )
8.8 Hz, 1H), 5.83 (d, J ) 7.6 Hz, 1H), 5.08-4.96 (m, 1H), 4.37-
4.30 (m, 1H), 4.19-4.11 (m, 2H), 4.03-3.95 (m, 1H), 3.87 3.66
(m, 4H), 2.93 (s, 3H), 2.85 (s, 3H), 2.33-2.22 (m, 1H), 2.20-
2.09 (m, 1H), 1.83 (sept, J ) 6.6 Hz, 1H), 1.73-1.66 (m, 1H),
1.54-1.19 (m, 4H), 1.01 (d, J ) 6.6 Hz, 3H), 0.94-0.86 (m, 18H).
13C NMR (DMSO-d6, 125 MHz, mixture of two diastereomers) δ
197.4, 174.1, 172.5, 172.4, 170.3, 170.1, 167.9, 167.8, 161.9, 161.5,
157.5, 138.4, 135.3, 133.3, 132.6, 132.5, 132.0, 130.9, 129.5, 129.4,
128.7, 70.8, 68.3, 60.9, 60.5, 60.1, 60.0, 56.0, 54.0, 53.9, 42.5, 42.4,
40.9, 39.9, 38.9, 38.1, 37.5, 36.2, 35.6, 34.1, 32.8, 32.6, 30.7, 29.2,
28.5, 27.3, 27.2, 24.1, 23.3, 19.8, 19.5, 19.4, 17.4, 14.8, 14.4, 14.3,
11.7. HRMS Calcd for C35H55N6O8: 687.4081 (M + H)+. Found:
687.4061.
2-Methylpropyl [1-Cyclohexyl-2-[2-[8(S)-[[[1-[2-[[2-[[2-(di-
methylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-
1,2-dioxoethyl]butyl]amino]carbonyl]-1,4-dithia-7-azaspiro[4.4]-
nonan-7-yl]-2-oxoethyl]carbamate (13). Coupling procedures for
the preparation of 13 were carried out in a manner similar to that
described for the preparation of 24. For the oxidation of the
intermediate hydroxyl amide to the corresponding ketoamide, the
Moffat procedure was used (ref 14). 1H NMR (DMSO-d6, 500 MHz,
mixture of two diastereomers) δ 8.77-8.72 (m, 1H), 8.57 (d, J )
7.5 Hz, 1H), 8.32 and 8.13 (d, J ) 6.7 and 7.9 Hz, 1H), 7.38-7.23
(m, 6H), 5.83 (d, J ) 7.8 Hz, 1H), 5.04-4.96 (m, 1H), 4.45 and
4.38 (t, 1H), 4.31-4.26 (m, 1H), 4.03-3.99 (m, 1H), 3.88-3.71
(m, 4H), 3.43-3.32 (m, 5H), 2.93 (s, 3H), 2.85 (s, 3H), 2.60-
2.55 (m, 1H), 2.35-2.25 (m, 1H), 1.87-1.79 (m, 1H), 1.75-1.54
(m, 7H), 1.46-1.34 (m, 3H), 1.13-1.07 (m, 3H), 0.96-0.84 (m,
11H). 13C NMR (DMSO-d6, 125 MHz, mixture of two diastereo-
mers) δ 196.50, 196.38, 170.14, 170.08, 169.99, 169.80, 169.15,