Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22 7025
HRMS (ESþ) expected for C37H47N6O6S2 (M þ Hþ) 735.2993;
found 735.3029.
off-white solid (19 mg, 24% yield from thiazole 34a). 1H NMR
(300 MHz, CDCl3) δ 11.55 (bs, 1H), 9.95 (bs, 1H), 7.30-7.20 (m,
2H), 7.15 (s, 1H), 6.00-5.88 (m, 3H), 5.72 (m, 1H), 5.52 (m, 1H),
5.29 (d, J = 12.0 Hz, 1H), 5.16 (d, J = 6.5 Hz, 1H), 4.76-4.69 (m,
2H), 4.48-4.40 (m, 2H), 4.24 (m, 1H), 4.08 (m, 1H), 3.94 (m, 1H),
3.64 (m, 1H), 3.05 (m, 1H), 2.95 (m, 1H), 2.59 (m, 2H), 2.68-2.49
(m, 7H), 2.14 (m, 1H), 2.03 (m, 1H), 1.48-1.33 (m, 3H), 1.15 (d,
J = 6.0 Hz, 3H), 1.05 (d, J = 6.0 Hz, 3H). HRMS (ESþ) expected
for C35H43N6O6S2 (M þ Hþ) 723.2629; found 723.2639.
(3R,5S,8S)-8-Cyclohexyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)-
amino] carbonyl}-2-ethenylcyclopropyl)-7-oxo-2-oxa-11-thia-6,9,24,
27-tetraazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24),10-
(27),12,18,20,22,25-heptaene-5-carboxamide (50). The title com-
pound was prepared using ester 40a(sat) and 13A; off-white solid
(33 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s,
1H), 8.81 (s, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.91 (s, 1H), 7.83 (d,
J = 8.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 5.8 Hz,
1H) 6.47 (bs, 1H), 5.98 (m, 1H), 5.56 (m, 1H), 5.22 (d, J = 17.2
Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.79 (m, 1H), 4.41 (t, J = 8.3
Hz, 1H), 4.28 (m, 1H), 3.98 (bd, J = 12.1 Hz, 1H), 2.98-1.85 (m,
9H), 1.83-1.46 (m, 9H), 1.45-0.84 (m, 11H). HRMS (ESþ)
expected for C38H47N6O6S2 (M þ Hþ) 746.2993; found
747.2947.
(1R,12E,22S,25S)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]-
carbonyl}-2-ethenylcyclopropyl)-22-(1,1-dimethylethyl)-3,23-dioxo-
2-oxa-19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.14,7.117,20.06,11]-
nonaacosa-6,8,10,12,17,20(28)-hexaene-25-carboxamide (55). The
title compound was prepared using ester 43b(E-db) and 13A; off-
white solid (50 mg, 45% yield from thiazole 35b). 1H NMR (600
MHz, DMSO-d6) δ10.48 (s, 1H), 9.73 (s, 1H), 8.72 (bs, 1H), 7.28 (t,
J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H),
6.39 (d, J = 16.1 Hz, 1H), 6.29 (s, 1H), 6.00 (dt, J1 = 16.1 Hz, J2 =
J3 = 6.9 Hz, 1H), 5.62 (dt, J1 = 17.2, J2 = J3 = 10.0 Hz, 1H), 5.25
(bs, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.09 (d, J = 10.0 Hz, 1H), 4.77
(d, J = 14.8 Hz, 1H), 4.72-4.64 (m, 3H), 4.61-4.52 (m, 2H), 4.34
(t, J = 8.2 Hz, 1H), 4.24 (d, J = 11.9 Hz, 1H), 4.07 (dd, J = 11.9,
5.2 Hz, 1H), 2.93 (m, 1H), 2.67 (m, 1H), 2.54 (m, 1H), 2.42(dd, J =
13.4, 7.2 Hz, 1H), 2.34-2.28 (m, 2H), 2.24-2.14 (m, 2H),
1.88-1.76 (m, 2H), 1.69 (dd, J = 7.9, 5.5 Hz, 1H), 1.35 (dd, J =
9.4, 5.5 Hz, 1H), 1.11-1.02 (m, 4H), 1.06 (s, 9H). HRMS (ESþ)
expected for C37H47N6O7S2 (M þ Hþ) 751.2942; found 751.2956.
(1R,22S,25S)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]-
carbonyl}-2-ethenylcyclopropyl)-22-(1,1-dimethylethyl)-3,23-dioxo-
2-oxa-19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.14,7.117,20.06,11]-
nonaacosa-6,8,10,17,20(28)-pentaene-25-carboxamide (56). The ti-
tle compound was prepared using ester 43b(sat) and 13A; off-white
solid (50 mg, 33% yield from thiazole 35b). 1H NMR (400 MHz,
DMSO-d6) δ 10.54 (s, 1H), 8.78 (s, 1H), 7.23 (t, J = 7.4 Hz, 1H),
7.15 (d, J = 7.4 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.27 (bs, 1H),
5.64 (m, 1H), 5.26 (m, 1H), 5.22 (d, J = 17.2 Hz, 1H), 5.09 (d, J =
11.1 Hz, 1H), 4.77-4.46 (m, 5H), 4.28 (t, J = 8.1 Hz, 1H), 4.22 (d,
J = 11.4 Hz, 1H), 4.04 (m, 1H), 2.93 (m, 1H), 2.68-2.29 (m, 6H),
2.24 (app q, J = 8.6 Hz, 1H), 2.13 (m, 1H), 1.78-1.62 (m, 3H),
1.58-1.41 (m, 3H), 1.37 (dd, J = 9.6, 5.5 Hz, 1H), 1.15-0.93 (m,
13H). HRMS (ESþ) expected for C37H49N6O7S2 (M þ Hþ)
753.3099; found 753.3110.
(3R,5S,8S)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]car-
bonyl}-2-ethenylcyclopropyl)-8-(1,1-dimethylethyl)-7-oxo-2-oxa-
11-thia-6,9,24,27-tetraazapentacyclo[16.6.2.13,6.110,13.021,25]oct-
acosa-1(24),10(27),12,16,18,20,22,25-octaene-5-carboxamide (51).
The title compound was prepared using ester 39a(sat) and 13A;
off-white solid (30 mg, 22% yield). 1H NMR (600 MHz, DMSO-
d6 þ TFA) δ 10.74 (s, 1H), 10.08 (bs, 1H), 8.61 (s, 1H), 7.96 (d,
J = 5.7 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.78 (bs, 1H), 7.58 (d,
J = 7.8 Hz, 1H), 7.38 (d, J = 5.7 Hz, 1H), 6.70 (s, 1H), 5.64 (bt,
J = 3.6 Hz, 1H), 5.57 (ddd, J = 17.2, 10.1, 9.0 Hz, 1H), 5.22 (d,
J = 17.2 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 4.98 (d, J = 9.1 Hz,
1H), 4.77 (d, J = 12.3 Hz, 1H), 4.51 (t, J = 8.4 Hz, 1H), 3.86 (dd,
J = 12.3 Hz, 3.8 Hz, 1H), 2.93 (m, 1H), 2.87-2.79 (m, 2H),
2.80-2.63 (m, 3H), 2.30 (m, 1H), 2.19 (app q, J = 9.0 Hz, 1H),
1.84 (m, 1H), 1.73 (dd, J = 7.8, 5.6 Hz, 1H), 1.72-1.61 (m, 2H),
1.52 (m, 1H), 1.32 (dd, J = 9.4, 5.6 Hz, 1H), 1.08 (s, 9H),
1.10-1.02 (m, 4H). HRMS (ESþ) expected for C36H45N6O6S2
(M þ Hþ) 721.2837; found 721.2799.
(3R,5S,8S)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]car-
bonyl}-2-ethenylcyclopropyl)-8-(1-methylethyl)-7-oxo-23-phen-
yl-2-oxa-11-thia-6,9,22,27-tetraazapentacyclo[16.6.2.13,6.110,13.021,25]-
octacosa-1(24),10(27),12,18,20,22,25-heptaene-5-carboxamide (52).
The title compound was prepared using ester 41a (sat) and13A; off-
1
white solid (30 mg, 26% yield). H NMR (600 MHz, C5D5N) δ
10.58 (s, 1H), 8.46 (d, J=7.3Hz,2H),8.29(d,J= 8.5 Hz, 1H), 8.11
(s, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.55-7.49 (m, 4H), 7.30 (s, 1H),
6.33 (s, 1H), 6.10 (dt, J1 = 16.9, J2 = J3 = 10.0 Hz, 1H), 5.27-5.18
(m, 2H), 5.07 (d, J = 10.0 Hz, 1H), 4.89 (t, J = 8.1 Hz, 1H), 4.59 (d,
J = 12.1 Hz, 1H), 4.35 (bd, J = 12.1 Hz, 1H), 3.30 (m, 1H),
2.80-2.47 (m, 11H), 2.24 (t, J = 6.9 Hz, 1H), 1.87-1.79 (m, 2H),
1.77-1.70 (m, 3H), 1.44 (m, 1H), 1.35 (m, 1H), 1.25 (d, J = 6.7 Hz,
3H), 1.21 (d, J = 6.7 Hz, 3H), 0.97-0.84 (m, 2H). MS (ESþ)
C41H46N6O6S2 requires 782; found 783 (M þ Hþ).
(1R,12E,22S,25S)-22-Cyclohexyl-N-((1R,2S)-1-{[(cyclopropyl-
sulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3,23-dioxo-2-oxa-
19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.14,7.117,20.06,11]-
nonacosa-6,8,10,12,17,20(28)-hexaene-25-carboxamide (57).
The title compound was prepared using ester 44b(E-db) and
13A; off-white solid (58 mg, 24% yield). 1H NMR (400 MHz,
DMSO-d6) δ 10.64 (s, 1H), 8.80 (s, 1H), 7.32-7.20 (m, 3H),
6.40 (bs, 1H), 6.36 (d, J = 16.2 Hz, 1H), 6.05 (dt, J1 = 16.2 Hz,
J2 = J3 = 6.7 Hz, 1H), 5.58 (m, 1H), 5.27 (m, 1H), 5.23 (d, J =
17.1 Hz, 1H), 5.11 (d, J = 11.1 Hz, 1H), 4.79 (d, J = 14.6 Hz,
1H), 4.72-4.56 (m, 4H), 4.29 (t, J = 8.3 Hz, 1H), 4.15 (d, J =
11.9 Hz, 1H), 3.97 (m, 1H), 2.93 (m, 1H), 2.66-2.36 (m, 4H),
2.35-2.09 (m, 9H), 1.90-1.59 (m, 7H) 1.34-0.99 (m, 7H).
HRMS (ESþ) expected for C39H49N6O7S2 (M þ Hþ)
777.3099; found 777.3068.
(1R,12E,22S,25S)-22-Cyclohexyl-N-((1R,2S)-1-{[(cyclopropyl-
sulfonyl) Amino]carbonyl}-2-ethylcyclopropyl)-3,23-dioxo-2-oxa-
19-thia-4,21,24,28-tetraazapentacyclo[22.2.1.14,7.117,20.06,11] nona-
cosa-6,8,10,12,17,20(28)-hexaene-25-carboxamide (58). The title
compound was prepared using ester 44b(E-db) and 13B; off-white
solid (58 mg, 29% yield). 1H NMR (600 MHz, DMSO-d6 þ TFA)
δ 10.62 (s, 1H), 8.59 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.27 (t, J =
7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.63 (s, 1H), 6.28 (d, J =
16.2 Hz, 1H), 6.09 (dt, J1 = 16.2 Hz, J2 = J3 = 7.0 Hz, 1H), 5.32
(bt, J = 3.8 Hz, 1H), 4.87 (bs, 1H), 4.77 (d, J = 14.8 Hz, 1H), 4.70
(d, J = 14.8 Hz, 1H), 4.64-4.57 (m, 2H), 4.33 (t, J = 8.8 Hz,
1H). 4.22 (d, J = 11.9 Hz, 1H), 3.87 (dd, J = 11.9, 3.8 Hz, 1H),
2.94 (m, 1H), 2.63-2.57 (m, 2H), 2.40 (dd, J = 14.0, 7.6 Hz, 1H),
(1R,12E,22S,25S)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]-
carbonyl}-2-ethenylcyclopropyl)-22-(1-methylethyl)-3,23-dioxo-2-
oxa-19-thia-4,21,24,28-tetraazapentacyclo [22.2.1.14,7.117,20.06,11
]
octacosa-6,8,10,12,17,20(28)-hexaene-25-carboxamide (53). The
title compound was prepared using ester 42b(E-db) and 13A;
off-white solid (36 mg, 24% yield from thiazole 34b). 1H NMR
(600 MHz, DMSO-d6) δ 10.62(s, 1H), 8.84 (s, 1H), 7.31-7.21 (m,
3H), 6.38 (d, J = 16.2 Hz, 1H), 6.36 (bs, 1H), 6.05 (dt, J1 = 16.2
Hz, J2 = J3 = 6.9 Hz, 1H), 5.60 (ddd, J = 17.2, 10.3, 9.8 Hz, 1H),
5.29 (bt, 1H), 5.23(d, J = 17.2Hz, 1H), 5.10 (d, J = 10.3Hz, 1H),
4.71-4.59 (m, 6H), 4.30 (bt, J = 8.4 Hz, 1H), 4.16 (d, J = 11.8
Hz, 1H), 3.97 (m, 1H), 2.93 (m, 1H), 2.59 (m, 2H), 2.34-2.13 (m,
6H), 1.89-1.76 (m, 2H), 1.71 (dd, J = 7.7, 5.2 Hz, 1H), 1.32 (dd,
J = 9.2, 5.2 Hz, 1H), 1.10-1.03 (m, 6H), 0.93 (d, J = 6.7Hz, 3H).
HRMS (ESþ) expected for C36H45N6O6S2 (M þ Hþ) 737.2786;
found 737.2788.
(1R,12E,21S,24S)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]-
carbonyl}-2-ethenylcyclopropyl)-21-(1-methylethyl)-3,22-dioxo-2-
oxa-18-thia-4,20,23,27-tetraazapentacyclo[21.2.1.14,7.116,19.06,11]-
octacosa-6,8,10,12,16,19(27)-hexaene-24-carboxamide (54). The
title compound was prepared using ester 42a(E-db) and 13A;