Journal of Medicinal Chemistry
Article
120.0, 119.7, 115.0, 41.7, 41.3, 25.1, 22.9, 21.3, 14.0, 13.1; HRMS (pos.
ESI): calcd for C12H17O2N2 [M + H]+, 456.15636; found, 456.15636.
4.31. N-(5-(N,N-Diethylsulfamoyl)-2-methoxyphenyl)-3-
methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-
carboxamide (8). To a solution of 3-methyl-4-oxo-2,4,5,6,7,8-
hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (100 mg, 0.48
mmol, 1.00 equiv, 31) and 3-amino-N,N-diethyl-4-methoxybenzene-
sulfonamide (156 mg, 0.60 mmol, 1.25 equiv, 39) in dry DMF (1.9 mL)
at 0 °C were added DIEA (0.42 mL, 2.41 mmol, 5.00 equiv) and HCTU
(250 mg, 0.60 mmol, 1.25 equiv). The reaction was allowed to warm at
rt. After 4 h, the mixture was heated at 100 °C for 16 h. Then, DMF was
evaporated. Water was added, and the aqueous phase was extracted
three times with EtOAc. The combined organics were washed with 1 M
HCl, saturated Na2CO3, brine, and dried over Na2SO4. Purification on a
silica gel column eluting with 20−100% EtOAc in CyH to afford the
desired product (139 mg, 0.31 mmol, 64%) as a light yellow solid. 1H
NMR (400 MHz, CDCl3): δ 10.13 (br s, 1H), 8.84 (d, J = 2.3 Hz, 1H),
8.22 (s, 1H), 7.52 (dd, J = 8.5, 2.3 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H),
3.98 (s, 3H), 3.22 (q, J = 7.1 Hz, 4H), 3.15−3.06 (m, 2H), 2.72−2.62
(m, 2H), 2.49 (d, J = 0.5 Hz, 3H), 2.00−1.80 (m, 4H), 1.11 (t, J = 7.2
Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 199.5, 159.8, 150.6, 138.6,
132.8, 128.1, 127.9, 123.5, 123.2, 120.7, 118.1, 109.6, 56.5, 42.2, 41.9,
25.8, 24.5, 21.8, 14.3, 13.7; HRMS (pos. ESI): calcd for
C22H29N3O5SNa M + Na+, 470.1720; found, 470.1720; Rf: 0.57
(66% AcOEt in CyH).
4.32. N-(5-(Azepan-1-ylsulfonyl)-2-methoxyphenyl)-3-
methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-
carboxamide (9). The compound was synthesized as reported for N-
(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-methyl-4-oxo-
2,4,5,6,7,8-hexahydrocyclohepta[c]-pyrrole-1-carboxamide (8) to af-
ford the desired compound (167 mg, 0.35 mmol, 73%) as a light yellow
solid. 1H NMR (400 MHz, CDCl3): δ 10.07 (br s, 1H), 8.83 (d, J = 2.3
Hz, 1H), 8.23 (s, 1H), 7.51 (dd, J = 8.6, 2.3 Hz, 1H), 6.94 (d, J = 8.6 Hz,
1H), 3.99 (s, 3H), 3.31−3.23 (m, 4H), 3.12−3.07 (m, 2H), 2.72−2.63
(m, 2H), 2.49 (d, J = 0.5 Hz, 3H), 1.99−1.82 (m, 4H), 1.68 (dtt, J =
10.9, 4.7, 2.4 Hz, 4H), 1.61−1.52 (m, 4H); 13C NMR (101 MHz,
CDCl3): δ 199.5, 159.8, 150.6, 138.6, 132.1, 128.1, 127.9, 123.5, 123.1,
120.8, 117.9, 109.6, 56.5, 48.4, 41.9, 29.2, 27.0, 25.8, 24.5, 21.8, 13.7;
HRMS (pos. ESI): calcd for C24H31N3O5SNa M + Na+, 496.1877;
found, 496.1877; Rf: 0.40 (66% AcOEt in CyH).
late (12). To a solution of 3-methyl-4-oxo-2,4,5,6,7,8-
hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (50 mg, 0.24 mmol,
1.0 equiv, 31) in dry CH2Cl2 (2.4 mL) was added dropwise 1-chloro-
N,N,2-trimethyl-1-propenylamine (36 μL, 0.27 mmol, 1.1 equiv). The
reaction was stirred for 30 min at rt. Subsequently, 1-((4-methoxy-3-
nitrophenyl)sulfonyl)piperidine (98 mg, 0.36 mmol, 1.5 equiv, 44) and
DIEA (47 μL, 0.48 mmol, 2.0 equiv) were added to the reaction
mixture. After stirring overnight at rt, the solvent was evaporated. The
residue was purified by reversed phase chromatography eluting with 5−
95% MeCN in H2O to afford the desired compound as a colorless solid
(75 mg, 0.16 mmol, 6 8%). 1H NMR (400 MHz, CDCl3): δ 9.66 (br s,
1H), 8.81 (d, J = 2.3 Hz, 1H), 8.22 (s, 1H), 7.50 (dd, J = 8.6, 2.3 Hz,
1H), 6.99 (d, J = 8.6 Hz, 1H), 4.01 (s, 3H), 3.15−3.08 (m, 2H), 3.06−
3.01 (m, 4H), 2.73−2.67 (m, 2H), 2.51 (s, 3H), 2.01−1.86 (m, 4H),
1.66−1.62 (m, 4H), 1.47−1.35 (m, 2H); 13C NMR (101 MHz,
CDCl3): δ 199.5, 159.7, 150.8, 138.4, 129.1, 128.1, 127.6, 123.9, 123.7,
120.7, 118.9, 109.6, 56.6, 47.1, 42.0, 25.9, 25.3, 24.7, 23.7, 21.9, 13.8;
HRMS (pos. ESI): calcd for C23H29O5N3NaS [M + Na]+, 482.1720;
found, 482.1723; Rf: 0.21 (50% AcOEt in CyH).
4.36. N-(2-Methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)-
phenyl)-3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]-
pyrrole-1-carboxamide (13). The compound was synthesized as
reported for N-(5-(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-meth-
yl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carboxamide
(8) to afford the desired compound (94 mg, 0.20 mmol, 41%) as a light
yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.98 (br s, 1H), 8.83 (d, J
= 2.3 Hz, 1H), 8.23 (s, 1H), 7.47 (dd, J = 8.6, 2.3 Hz, 1H), 6.98 (d, J =
8.7 Hz, 1H), 4.00 (s, 3H), 3.14−2.99 (m, 6H), 2.73−2.62 (m, 2H), 2.49
(d, J = 0.4 Hz, 3H), 2.45 (t, J = 5.0 Hz, 4H), 2.24 (s, 3H), 2.00−1.81 (m,
4H); 13C NMR (101 MHz, CDCl3): δ 199.5, 159.7, 151.0, 138.6, 128.3,
127.9, 127.7, 123.9, 123.6, 120.8, 118.8, 109.7, 56.6, 54.2, 46.1, 45.8,
41.9, 25.9, 24.6, 21.8, 13.8; HRMS (pos. ESI): calcd for C23H31N4O5S
M + H+, 475.2010; found, 475.2010; Rf: 0.36 (12% MeOH in CH2Cl2 +
0.1% NEt3) (Scheme 3).
a
Scheme 3. Synthesis of Final Compounds 6−13 .
4.33. N-(2-Methoxy-5-(morpholinosulfonyl)phenyl)-3-meth-
yl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrrole-1-carbox-
amide (10). The compound was synthesized as reported for N-(5-
(N,N-diethylsulfamoyl)-2-methoxyphenyl)-3-methyl-4-oxo-
2,4,5,6,7,8-hexahydrocyclohepta[c]-pyrrole-1-carboxamide (8) to af-
ford the desired compound (84 mg, 0.18 mmol, 3 8%) as a light yellow
solid. 1H NMR (400 MHz, CDCl3): δ 9.90 (br s, 1H), 8.83 (d, J = 2.3
Hz, 1H), 8.25 (s, 1H), 7.48 (dd, J = 8.6, 2.3 Hz, 1H), 7.01 (d, J = 8.7 Hz,
1H), 4.02 (s, 3H), 3.77−3.65 (m, 4H), 3.13−3.07 (m, 2H), 3.05−2.98
(m, 4H), 2.71−2.66 (m, 2H), 2.50 (s, 3H), 2.01−1.85 (m, 4H); 13C
NMR (101 MHz, CDCl3): δ 199.5, 159.8, 151.1, 138.7, 128.3, 127.8,
127.7, 124.0, 123.6, 120.7, 118.9, 109.8, 66.2, 56.6, 46.2, 41.9, 25.9,
24.7, 21.8, 13.8; HRMS (pos. ESI): calcd for C22H27N3O6SNa M + Na+,
484.1513; found, 484.1513; Rf: 0.19 (66% AcOEt in CyH).
a
Reagents and conditions: (i) Ghosez’s reagent, CH2Cl2, rt, then
MeNH2 in THF or 43−44, DIEA, rt, 29−68%; (ii) CDI, 40, NEt3, rt
to 65 °C, 9%; (iii) HCTU, 39, 41−42 or 45, DIEA, DMF, 0−100 °C,
38−73%.
4.37. N-(2-Methoxy-5-(piperidin-1-ylsulfonyl)phenyl)-2,3-
dimethyl-4-oxo-2,4,5,6,7,8-hexahydro-cyclohepta[c]pyrrole-
1-carboxamide (14). Ghosez’s reagent (14 μL, 14 mg, 0.11 mmol, 1.2
equiv) was added to a solution of 2,3-dimethyl-4-oxo-2,4,5,6,7,8-
hexahydrocyclohepta[c]pyrrole-1-carboxylic acid (32 mg, 0.14 mmol,
1.0 equiv) in dry CH2Cl2 (0.9 mL). The reaction mixture was stirred for
30 min before 2-methoxy-5-(piperidin-1-ylsulfonyl)aniline (37 mg,
0.14 mmol, 1.5 equiv) and DIEA (46 μL, 35 mg, 0.27 mmol, 2% 1% 3.0
equiv) were added. The reaction was stirred overnight at rt. The
solvents were evaporated, and the residue was purified by reversed
phase column chromatography (MeCN/H2O). The desired compound
was obtained as a colorless oil (25 mg, 53 μmol, 5 9%). 1H NMR (500
MHz, CDCl3): δ 1.44 (td, J = 7.2, 6.2, 4.4 Hz, 2H), 1.66 (p, J = 5.8 Hz,
4H), 1.88 (p, J = 2.9 Hz, 4H), 2.53 (s, 3H), 2.64−2.70 (m, 2H), 2.97−
3.03 (m, 2H), 3.04−3.10 (m, 4H), 3.73 (s, 3H), 3.99 (s, 3H), 7.00 (d, J
= 8.6 Hz, 1H), 7.54 (dd, J = 8.6, 2.3 Hz, 1H), 8.04 (s, 1H), 8.87 (d, J =
2.2 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ 11.5, 19.0, 21.8, 23.7,
4.34. N-(5-((2-Oxa-6-azaspiro[3.3]heptan-6-yl)sulfonyl)-2-
m e t h o x y p h e n y l ) - 3 - m e t h y l - 4 - o x o - 2 , 4 , 5 , 6 , 7 , 8 -
hexahydrocyclohepta[c]pyrrole-1-carboxamide (11). The com-
pound was synthesized as reported for 2-methoxy-5-(piperidin-1-
ylsulfonyl)phenyl 3-methyl-4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]-
pyrrole-1-carboxylate (12) in CH2Cl2 (1.8 mL) to afford the desired
1
compound (25 mg, 0.05 mmol, 2 9%) as a colorless solid. H NMR
(500 MHz, CDCl3): δ 10.00 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.23 (s,
1H), 7.55 (dd, J = 8.6, 2.3 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 4.58 (s,
4H), 4.03 (s, 3H), 3.94 (s, 4H), 3.13−3.08 (m, 2H), 2.72−2.66 (m,
2H), 2.51 (s, 3H), 1.99−1.87 (m, 4H); 13C NMR (126 MHz, CDCl3):
δ 199.6, 159.8, 151.5, 138.8, 128.3, 128.0, 126.7, 124.5, 123.6, 120.6,
119.4, 109.8, 80.4, 59.8, 56.7, 41.9, 37.6, 25.9, 24.6, 21.8, 13.8; HRMS
(pos. ESI): calcd for C23H27O6N3SNa [M + Na]+, 496.1513; found,
496.1511.
4.35. 2-Methoxy-5-(piperidin-1-ylsulfonyl)phenyl 3-methyl-
4-oxo-2,4,5,6,7,8-hexahydrocyclohepta[c]-pyrrole-1-carboxy-
N
J. Med. Chem. XXXX, XXX, XXX−XXX