S. Ayesa et al. / Bioorg. Med. Chem. 17 (2009) 1307–1324
1319
to Method A using P3 acid 6g. Subsequent treatment of 10 as above.
Yield: 49%. 1H NMR (500 MHz, CDCl3) d 0.97 (t, 3H), 1.01 (s, 3H),
1.36–1.48 (m, 8H), 1.58–1.68 (m, 2H), 1.74–1.80 (m, 1H), 1.88–
1.99 (m, 1H), 3.07 (s, 3H), 3.79–3.83 (m, 1H), 4.04–4.07 (m, 1H),
4.07–4.18 (dd, J = 2H), 4.79–4.84 (m, 1H), 7.16–7.18 (m, 2H), 7.52
(br s, NH, 1H), 7.65–7.68 (m, 2H), 7.84 (br s, NH, 1H), 8.55 (br s,
NH, 1H). 13C NMR (125.68 MHz, CDCl3) d 9.2, 23.51, 24.1, 25.2,
26.8, 39.7, 40.0, 40.0, 41.9, 43.5, 51.9, 59.9, 71.0, 80.3, 118.6, 128.3,
128.8, 140.9, 166.6, 173.9, 211.9. HRMS (ES+): m/z calcd for
C23H33N3O6S: 480.2095; found: 480.2173 [H+M]+. LC–MS System
A: tR = 3.45 min, System B: tR = 3.70 min.
Compound 12: N-[1-(2S-Ethyl-4-oxo-tetrahydro-furan-3S-ylcarba-
moyl)-2S-(1-methyl-cyclopentyl)-ethyl]-3-methanesulfonylamino-benz-
amide: The corresponding resin 10 was synthesized according to
Method A using P3 acid 6f. Subsequent treatment of 10 as above. Yield:
69%. 1H NMR (500 MHz, CDCl3) d 1.02 (t, J = 7.4 Hz, 3H), 1.05 (s, 3H),
1.40–1.48 (m, 4H), 1.63–1.65 (m, 4H), 1.73–2.00 (m, 4H), 3.02 (s, 3H),
3.92–3.96 (m, 1H), 4.06–4.11 (m, 1H), 4.10–4.22 (dd, overlapped, 2H,
J = 17.3 Hz), 5.02–5.05 (m, 1H), 7.37–7.48 (m, NH, 2H), 7.56 (d,
J = 8.2 Hz, NH), 7.68 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H). 13C NMR
(125.68 MHz, CDCl3) d 9.5, 23.7, 24.4, 25.4, 27.0, 39.4, 40.0, 40.2, 42.1,
44.9, 51.6, 59.9, 71.2, 80.8, 121.0, 122.1, 123.2, 130.1, 134.0, 138.9,
166.3, 173.6, 211.6. HRMS (ES+): m/z calcd for C23H33N3O6S:
480.2095; found: 480.2178 [H+M]+. LC–MS System A: tR = 3.48 min,
System B: tR = 3.74 min.
Compound13: N-[1-(2S-Ethyl-4-oxo-tetrahydro-furan-3S-ylcarba-
moyl)-2S-(1-methyl-cyclopentyl)-ethyl]-4-(methanesulfonyl-methyl-
amino)-benzamide: The corresponding resin 10 was synthesized
according to Method A using P3 acid 6j. Subsequent treatment of
10 as above. Yield: 49%. 1H NMR (500 MHz, CDCl3) d 1.02 (s, 3H),
1.03 (t, 7.3 Hz, 3H), 1.44 (m, 4H), 1.62–1.84 (m, 7H), 2.12–2.16 (dd,
J = 4.6 Hz, 14.3 Hz, 1H), 2.88 (s, 3H), 3.37 (s, 3H), 3.84–3.88 (m,
1H), 3.97–4.01 (m, 1H), 4.06–4.22 (dd, J = 17.1 Hz, 2H), 4.73–4.77
(m, J = 4.6 Hz, 8.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, NH), 7.05 (s, J = 7.6 Hz
NH), 7.46 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H). 13C NMR
(125.68 MHz, CDCl3) d 9.4, 23.7, 24.4, 25.4, 26.9, 36.0, 37.9, 40.1,
40.3, 41.9, 43.3, 51.8, 60.1, 71.2, 81.1, 125.5, 128.4, 131.9, 144.9,
166.8, 172.8, 211.7. HRMS (ES+): m/z calcd for C24H35N3O6S:
494.2247; found: 494.2325 [H+M]+. LC–MS System A: tR = 3.70
min, System B: tR = 3.97 min.
Compound 14: N-[1-(2S-Ethyl-4-oxo-tetrahydro-furan-3S-ylcar-
bamoyl)-2S-(1-methyl-cyclopentyl)-ethyl]-4-methylsulfamoyl-benz-
amide: The corresponding resin 10 was synthesized according to
Method A using P3 acid 6e. Subsequent treatment of 10 as above.
Yield: 64%. 1H NMR (500 MHz, CDCl3) d 0.40–0.42 (m, 3H), 0.9 (s,
3H), 1.32–1.49 (m, 4H), 1.50–1.71 (m, 4H), 1.72–1.81 (m, 1H),
1.83–1.90 (m, 1H), 2.04–2.13 (m, 1H), 2.54 (s, 3H), 3.88–3.93 (m,
1H), 3.99–4.05 (m, 1H), 4.07–4.15 (m, 2H), 4.98–5.02 (m, 1H),
7.44 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 8.12 (br d, NH),
9.96 (br s, NH). 13C NMR (125.68 MHz, CDCl3) d 11.9, 24.2, 26.3,
27.9, 29.3, 40.3, 43.0, 43.6, 51.4, 60.1, 71.2, 80.7, 126.2, 129.5,
138.8, 141.1, 167.1, 173.1, 221.7. HRMS (ES+): m/z calcd for
C23H33N3O6S: 480.2076; found: 480.2155 [H+M]+. LC–MS System
A: tR = 3.56 min, System B: tR = 3.82 min.
134.7, 139.8, 166.2, 172.9, 212.8. HRMS (ES+): m/z calcd for
23H33N3O6S: 480.2092; found: 480.2170 [H+M]+. LC–MS System
A: tR = 3.59 min, System B: tR = 3.86 min.
C
Compound 16: 4-Ethanesulfonylamino-N-[1-(2S-ethyl-4-oxo-tetrahy-
dro-furan-3S-ylcarbamoyl)-2S-(1-methyl-cyclopentyl)-ethyl]-benzamide:
The corresponding resin 10 was synthesized according to Method A
using P3 acid 7v. Subsequent treatment of 10 as above. Yield: 96%. 1H
NMR (500 MHz, CDCl3) d 0.98–1.03 (m, 6H), 1.25–1.87 (m, 12H),
1.99–2.06 (m, 1H), 2.17–2.24 (m, 2H), 3.17–3.21 (m, 2H), 3.86 (m,
1H), 3.96 (m, 1H), 4.05–4.22 (q, J = 17.1 Hz, 2H), 4.70 (m, 1H), 6.37 (d,
J = 8.3 Hz, NH), 6.62 (br s, NH), 6.44 (d, J = 7.3 Hz, NH), 7.26 (d, 2H),
7.75 (d, J = 8.8 Hz, 2H). 13C NMR (125.68 MHz, CDCl3) d 8.7, 9.3, 25.2,
29.5, 40.3, 40.4, 43.7, 47.0, 51.6, 60.2, 70.2, 81.4, 119.4, 128.6, 129.3,
141.1, 166.7, 175.5, 211.5. HRMS (ES+): m/z calcd for C24H36N3O6S:
494.2325; found: 494.2336 [H+M]+. LC–MS System A: tR = 3.61 min,
System B: tR = 3.87 min.
Compound 17: 4-(Butane-1-sulfonylamino)-N-[1-(2S-ethyl-4-oxo-tetrahy-
dro-furan-3S-ylcarbamoyl)-2S-(1-methyl-cyclopentyl)-ethyl]-benzamide: The
corresponding resin 10 was synthesized according to Method A using P3 acid
7w. Subsequent treatment of 10 as above. Yield: 34%. 1H NMR (500 MHz,
CDCl3) d 0.89–0.93 (m, 3H), 0.94–1.03 (m, 6H), 1.40–1.47 (m, 4H), 1.59–
1.69 (m, 8H), 1.70–1.85 (m, 4H), 2.08–2.12 (m, 1H), 3.15–3.18 (m, 2H),
3.84–3.87 (m, 1H), 4.00–4.03 (m, 1H), 4.08–4.21 (dd, 2H), 6.81 (br s, 1H)
7.19–7.21 (d, 2H), 7.27 (s, 1H), 7.69–7.71 (d, 2H). 13C NMR (125.68 MHz,
CDCl3) d 9.2, 13.5, 21.4, 23.5, 24.2, 25.2, 25.4, 26.7, 39.9, 40.0, 41.0, 41.7,
51.6, 52.2, 59.9, 71.0, 80.7, 118.4, 128.8, 140.9, 166.6, 173.0. HRMS (ES+):
m/z calcd for C26H39N3O6S: 522.2558; found: 522.2637 [H+M]+. LC–MS Sys-
tem A: tR = 4.09 min, System B: tR = 4.38 min.
Compound 18: N-[1-(2S-Ethyl-4-oxo-tetrahydro-furan-3S-ylcarba-
moyl)-2S-(1-methyl-cyclopentyl)-ethyl]-4-trifluoromethanesulfonylami-
no-benzamide: The corresponding resin 10 was synthesized according
to Method B using 2,2,2-trifluoromethane sulfonyl chloride. Subse-
quent treatment of 10 as above. Yield: 45% (2 steps). 1H NMR
(500 MHz, CDCl3) d 0.89–1.02 (m, 6H), 1.42–1.83 (m, 11H), 2.06–2.08
(m, 1H), 3.78–3.89 (m, 3H), 4.02–4.06 (m, 1H), 4.14 (dd, J = 17.2 Hz,
2H), 4.72–4.76 (m, 1H), 6.88 (br s, NH, 1H), 7.17–7.31 (m, 2H), 7.18
(br s, overlapped, NH, 1H), 7.67–7.70 (m, 2H). 13C NMR (125.68 MHz,
CDCl3) d 9.2, 23.5, 24.1, 25.2, 26.7, 39.8, 40.0, 41.7, 43.3, 51.7, 57.5,
60.0, 70.9, 80.5, 119.6, 119.7, 128.7, 128.8, 130.5, 138.3, 166.5, 190.1,
218.6. HRMS (ES+): m/z calcd for C24H32F3N3O6S: 548.1968; found:
548.2047 [H+M]+. LC–MS Purity System A: tR = 3.83 min, System B:
tR = 4.29 min.
Compound 19: N-[1-(2S-Ethyl-4-oxo-tetrahydro-furan-3S-ylcar-
bamoyl)-2S-(1-methyl-cyclopentyl)-ethyl]-4-(propane-2-sulfonylami-
no)-benzamide: The corresponding resin 10 was synthesized
according to Method A using P3 acid 7b. Subsequent treatment
of 10 as above. Yield: 58%. 1H NMR (500 MHz, CDCl3) d 0.95 (t,
J = 7.3 Hz, 3H), 1.01 (s, 3H), 1.39–1.49 (m, 6H), 1.59–1.65 (m, 4H),
1.67–1.79 (m, 6H), 1.88–1.93 (m, 1H), 2.00–2.02 (m, 1H), 3.34–
3.90 (m, 1H), 3.87–3.90 (m, 1H), 4.00–4.05 (m, 1H), 4.14 (dd,
J = 17.3 Hz, 2H), 4.83–4.87 (m, 1H), 7.17–7.19 (m, 2H), 7.31–7.32
(m, NH, 1H), 7.67–7.69 (m, 2H), 7.77–7.80 (m, NH, 1H), 8.63 (br
s, NH, 1H). 13C NMR (125.68 MHz, CDCl3) d 9.4, 16.6, 16.8, 23.7,
24.3, 25.4, 26.9, 39.9, 40.2, 42.0, 43.7, 52.1, 53.9, 59.9, 71.2, 80.6,
118.3, 118.4, 127.9, 128.8, 128.9, 141.9, 166.8, 174.1, 211.9. HRMS
(ES+): m/z calcd for C25H37N3O6S: 508.2412; found: 508.249
[H+M]+. LC–MS System A: tR = 3.79 min, System B: tR = 4.05
min.
Compound 15: N-[1-(2S-Ethyl-4-oxo-tetrahydro-furan-3S-ylcar-
bamoyl)-2S-(1-methyl-cyclopentyl)-ethyl]-3-methylsulfamoyl-benzam-
ide: The corresponding resin 10 was synthesized according to
Method A using P3 acid 6h. Subsequent treatment of 10 as above.
Yield: 77% 1H NMR (500 MHz, CDCl3) d 1.00 (s, 3H), 1.05 (t, 3H),
1.37–1.45 (m, 4H), 1.60–1.65 (m, 4H), 1.74–1.88 (m, 3H), 2.15
(dd, J = 4.5, 14.7 Hz, 1H), 2.65 (s, 3H), 3.90–3.93 (m, 1H), 4.07–
4.21 (m, 3H), 4.76–4.80 (m, 1H), 5.67 (br d, J = 5.9 Hz, NH, 1H),
7.41 (br d, J = 7.7 Hz, NH, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.58 (br d,
J = 8.7 Hz, NH, 1H), 7.88–7.92 (m, 2H), 8.24 (s, 1H). 13C NMR
(125.68 MHz, CDCl3) d 9.43, 23.7, 24.4, 25.4, 26.9, 29.5, 39.9, 40.2,
41.7, 41.9, 43.3, 52.1, 60.2, 71.2, 80.8, 125.9, 129.6, 130.6, 131.4,
Compound 20: 4-Cyclopropanesulfonylamino-N-[1-(2S-ethyl-4-
oxo-tetrahydro-furan-3S-ylcarbamoyl)-2S-(1-methyl-cyclopentyl)-
ethyl]-benzamide: The corresponding resin 10 was synthesized
according to Method A using P3 acid 7f. Subsequent treatment of
10 as above. Yield: 62%. 1H NMR (500 MHz, CDCl3) d 0.97 (t,
J = 7.3 Hz, 3H), 1.00 (s, 3H), 1.01 (s, 3H), 1.24 (m, 2H), 1.40–1.48
(m, 4H), 1.60–1.66 (m, 4H), 1.69–1.81 (m, 2H), 1.87–1.91 (m, 1H),
2.02–2.04 (m, 1H), 2.59–2.62 (m, 1H), 3.85–3.90 (m, 1H), 4.02–