Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 10 4163
1.95 (m, 1H), 1.80-1.30 (m, 10H). MS m/z calcd for C37H45-
N5O2S: 623.8. Found 624.3 [M þ 1]þ. HPLC purity: system A,
tR=8.406 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-bBen-
zyl-4-[4-(1-methyl-1H-pyrrole-2-carbonyl)piperazin-1-yl]butyl-
carbamoyl}cyclopentyl)amide Trifluoroacetate Salt (67o). 1H NMR
(δ, DMSO-d6, 400 MHz): 9.60 (brs, 1H), 8.55 (s, 1H), 8.20 (s, 1H),
8.50 (m, 2H), 8.72 (s, 1H), 7.45 (d, 1H), 7.20 (m, 6H), 7.00 (s, 1H),
6. 45 (s, 1H), 6.10 (s, 1H), 4.40 (m, 1H), 4.00 (m, 1H), 3.70 (s,
3H), 3.10 (m, 6H), 2.75 (m, 2H), 2.45 (s, 3H), 2.15 (m, 1H), 1.95
(m, 1H), 1.90-1.30 (m, 11H). MS m/z calcd for C37H45N5-
O3S: 639.8. Found 640.3 [M þ 1]þ. HPLC purity: system A,
tR=9.056 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid {1-[(S)-1-Ben-
zyl-4-(4-formylpiperazin-1-yl)butylcarbamoyl]cyclopentyl}amide
(67p). 1H NMR (δ, DMSO-d6, 400 MHz): 8.40 (s, 1H), 8.15 (s,
1H), 7.90 (s, 1H), 7.80 (m, 2H), 7.30 (m, 2H), 7.15 (m, 5H), 4.00
(m, 1H), 3.25 (m, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 2.42 (s, 3H),
2.20 (m, 6H), 1.90 (m, 3H), 1.75-1.30 (m, 9H). MS m/z calcd for
C32H40N4O3S: 560.75. Found 561.5 [M þ 1]þ. HPLC purity:
system B, tR=9.62 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Ben-
zyl-4-[4-(morpholine-4-carbonyl)piperazin-1-yl]butylcarbamoyl}-
cyclopentyl)amide Trifluoroacetate Salt (67q). 1H NMR (δ,
DMSO-d6, 400 MHz): 9.40 (brs, 1H), 8.58 (brs, 1H), 8.25 (s,
1H), 7.88 (d, 1H), 7.80 (s, 1H), 7.45 (d, 1H), 7.20 (m, 6H), 4.25
(m, 1H), 3.50 (m, 12H), 3.10 (m, 6H), 2.75 (m, 2H), 2.45 (s, 3H),
2.15 (m, 1H), 2.00-1.30 (m, 11H). MS m/z calcd for
C36H47N5O4S: 645.85. Found 646.3 [M þ 1]þ. HPLC purity:
system A, tR=8.37 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Ben-
zyl-4-[4-(morpholine-4-sulfonyl)piperazin-1-yl]butylcarbamoyl}-
cyclopentyl)amide Trifluoroacetate Salt (67r). 1H NMR (δ, DMSO-
d6, 400 MHz): 9.50 (brs, 1H), 8.55 (s, 1H), 8.25 (s, 1H), 7.85 (m,
1H), 7.80(s, 1H), 7.45 (m, 1H), 7.20(m, 6H), 4.05(m, 1H), 3.60(M,
8H), 3.15 (m, 10H), 2.75 (m, 2H), 2.45 (s, 3H), 2.20 (m, 1H),
1.90-1.30 (m, 11H). MS m/z calcd for C35H47N5O4S2: 681.9.
Found 682.1 [M þ 1]þ. HPLC purity: >98%, system B, tR =
11.14 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid {1-[(S)-1-Ben-
zyl-4-(4-dimethylsulfamoylpiperazin-1-yl)butylcarbamoyl]cyclo-
pentyl}amide Trifluoroacetate Salt (35s). 1H NMR (δ, DMSO-
d6, 400 MHz): 9.50 (brs, 1H), 8.55 (s, 1H), 8.25 (s, 1H), 7.90 (m,
1H), 7.80 (s, 1H), 7.45 (m, 1H), 7.25 (m, 6H), 4.05 (m, 1H), 3.60
(m, 4H), 3.15 (m, 6H), 2.80 (s, 6H), 2.75 (m, 2H), 2.45 (s, 3H),
2.20 (m, 1H), 1.95 (m, 1H), 1.90-1.30 (m, 10H). MS m/z calcd
for C33H45N5O4S2: 639.9. Found 641.0 [M þ 1]þ. HPLC purity:
system B, tR=9.046 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid {1-[(S)-1-Ben-
zyl-4-(4-methylsulfamoylpiperazin-1-yl)butylcarbamoyl]cyclo-
pentyl}amide Trifluoroacetate Salt (67t). 1H NMR (δ, DMSO-d6,
400 MHz): 9.40 (brs, 1H), 8.50 (s, 1H), 8.20 (s, 1H), 7.85 (d, 1H),
7.75 (s, 1H), 7.45 (d, 2H), 7.20 (m, 5H), 4.00 (m, 1H), 3.70 (m, 4H),
3.10 (m, 6H), 2.75 (m, 2H), 2.60 (s, 3H), 2.45 (s, 3H), 2.15 (m, 1H),
1.95 (m, 1H), 1.90-1.30 (m, 11H). MS m/z calcd for
C32H43N5O4S2: 625.8. Found 626.4 [M þ 1]þ. HPLC purity:
system B, tR=10.63 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Ben-
zyl-4-[4-(propane-2-sulfonyl)piperazin-1-yl]butylcarbamoyl}cyclo-
pentyl)amide Trifluoroacetate Salt (67u). A solution of 66 (100 mg,
0.188 mmol) in dry DCM (5 mL) was stirred at room temperature.
i-PrSO2Cl (32.1 mg, 0.22 mmol) and DIPEA (33 μL, 0.188 mmol)
were added. At the end of the reaction (HPLC control) the mixture
was diluted with DMC and washed with 0.1 N NaOH and brine.
The resulting organic phase was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by preparative HPLC to obtain pure 35u (22 mg, 18%).
1H NMR (δ, DMSO-d6, 400 MHz): 9.45 (brs, 1H), 8.55 (brs, 1H),
8.20 (s, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.45 (m, 1H), 7.20 (m, 6H),
4.00 (m, 1H), 3.70 (m, 1H), 3.60-3.00 (m, 10H), 2.70 (m, 2H), 2.45
(s, 3H), 2.20 (m, 1H), 2.00-1.30 (m, 11H), 1.20 (d, 6H). MS m/z
calcd for C34H46N4O4S2: 638.9. Found 639.4 [M þ 1]þ. HPLC
purity: system B, tR=11.44 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid {1-[(S)-1-Ben-
zyl-4-(4-thiophen-2-ylmethylpiperazin-1-yl)butylcarbamoyl]cyclo-
pentyl}amide Trifluoroacetate Salt (67h). 1H NMR (δ, DMSO-d6,
400 MHz): 9.20 (brs, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 7.85 (d, 1H),
7.75 (s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 7.30 (d, 1H), 7.20 (m, 5H),
7.10 (m, 2H), 4.10 (m, 1H), 3.95 (m, 2H), 3.45 (m, 2H), 3.00
(m, 6H), 2.75 (m, 2H), 2.45 (s, 3H), 2.40 (m, 2H), 2.20 (m, 1H), 1.95
(m, 1H), 1.90-1.30 (m, 10H). MS m/z calcd for C36H44N4-
O2S2: 628.9. Found 629.3 [M þ 1]þ. HPLC purity: system A,
tR=8.455 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid {1-[(S)-1-Ben-
zyl-4-(4-thiophen-3-ylmethylpiperazin-1-yl)butylcarbamoyl]cyclo-
pentyl}amide Trifluoroacetate Salt (67i). 1H NMR (δ, DMSO-
d6, 400 MHz): 9.45 (brs, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.80 (d,
1H), 7.75 (s, 1H), 7.60 (d, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.30 (d,
1H), 7.20 (m, 6H), 4.00 (m, 1H), 3.90 (m, 2H), 3.50 (m, 2H), 3.00
(m, 6H), 2.70 (m, 2H), 2.65 (m, 2H), 2.45 (s, 3H), 0.20 (m, 1H),
1.95 (m, 1H), 1.85-1.30 (m, 10H). MS m/z calcd for
C36H44N4O2S2: 628.9. Found 629.3 [M þ 1]þ. HPLC purity:
system A, tR=8.119 min.
6-Methyl-benzo[b]thiophene-2-carboxylic Acid {1-[(S)-1-Ben-
zyl-4-(4-furan-3-ylmethylpiperazin-1-yl)butylcarbamoyl]cyclo-
pentyl}amide Trifluoroacetate Salt (67j). 1H NMR (δ, DMSO-d6,
400 MHz): 9.15 (brs, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 8.03 (d, 1H),
7.88 (s, 1H), 7.70-7.40 (m, 3H), 7.30-7.05 (m, 6H), 6.10 (d, 1H),
4.00-3.95 (m, 1H), 3.60 (s, 2H), 2.80-2.65 (m, 2H), 2.43 (s, 3H),
2.50-2.35 (m, 10H), 2.09-1.85 (m, 4H), 1.56-1.51 (m, 4H),
1.46-1.30 (m, 4H). MS m/z calcd for C36H44N4O3S: 612.8. Found
613.3 [M þ 1]þ. HPLC purity: system A, tR=7.922 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Ben-
zyl-4-[4-(3H-imidazol-4-ylmethyl)piperazin-1-yl]butylcarbamoyl}-
cyclopentyl)amide Trifluoroacetate Salt (67k). 1H NMR (δ,
DMSO-d6, 400 MHz): 9.20 (brs, 1H), 9.10 (s, 1H), 8.55 (s, 1H),
8.25 (s, 1H), 7.85 (dd, 1H), 7.75 (s, 1H), 7.60 (s, 1H), 7.45 (m, 1H),
7.30 (m, 1H), 7.20 (m, 5H), 4.05 (m, 1H), 3.70 (brs, 2H), 3.48 (m,
2H), 3.10 (m, 1H), 2.95 (m, 5H), 2.70 (m, 2H), 2.45 (s, 3H), 2.45 (m,
2H), 2.25 (m, 1H), 1.95 (m, 1H), 2.85-1.30 (m, 10H). MS m/z
calcd for C35H44N6O2S: 612.8. Found 613.3 [M þ 1]þ. HPLC
purity: system A, tR=7.922 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Ben-
zyl-4-[4-(2-methyl-2H-tetrazol-5-ylmethyl)piperazin-1-yl]butyl-
carbamoyl}cyclopentyl)amide Trifluoroacetate Salt (67l). 1H NMR
(δ, DMSO-d6, 400 MHz): 9.10 (brs, 1H), 8.55 (s, 1H), 8.20 (s, 1H),
7.85 (m, 2H), 7.45 (d, 1H), 7.30 (d, 1H), 7.20 (m, 5H), 7.35 (s, 3H),
4.00 (m, 1H), 3.85 (s, 2H), 3.70 (m, 2H), 3.45 (m, 2H), 3.00 (m, 6H),
2.70 (m, 2H), 2.45 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.85-1.30
(m, 10H). MS m/z calcd for C34H44N8O2S: 628.8. Found 629.4 [M
þ 1]þ. HPLC purity: system A, tR=8.329 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Ben-
zyl-4-[4-(3-ethoxypropyl)piperazin-1-yl]butylcarbamoyl}cyclo-
pentyl)amide Trifluoroacetate Salt (67m). 1H NMR (δ, DMSO-d6,
400 MHz): 8.50 (brs, 1H), 8.20 (s, 1H), 7.85 (d, 1H), 7.80 (s, 1H),
7.40 (brs, 1H), 7.30 (d, 1H), 7.20 (M, 5H), 4.05 (m, 1H), 3.40 (m,
6H), 3,00 (m, 10H), 2.75 (m, 2H), 2.50 (s, 3H), 2.20 (m, 1H),
2.00-1.30 (m, 13H), 1.10 (t, 3H). MS m/z calcd for C36H50N4-
O3S: 618.9. Found 619.3 [M þ 1]þ. HPLC purity: system A,
tR=7.844 min.
6-Methylbenzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Ben-
zyl-4-[4-(tetrahydropyran-4-carbonyl)piperazin-1-yl]butylcarba-
moyl}cyclopentyl)amide Trifluoroacetate Salt (67n). 1H NMR (δ,
DMSO-d6, 400 MHz): 9.55 (brs, 1H), 8.55 (s, 1H), 8.25 (s, 1H),
7.85 (d, 1H), 7.80 (s, 1H), 7.45 (d, 1H), 7.30 (d, 1H), 7.20 (m, 5H),
4.40-4.00 (m, 3H), 2.85 (m, 2H), 3.45 (m, 5H), 3.00 (m, 6H), 2.75
(m, 2H), 2.45 (s, 3H), 2.15 (m, 1H), 2.00-1.30 (m, 15H). MS m/z
calcd for C37H48N4O4S: 644.8. Found 645.2 [M þ 1]þ. HPLC
purity: system A, tR=8.302 min.