Journal of Medicinal Chemistry
Article
General Procedure (Suzuki Reaction) for 80−102. Method A.
A mixture of compound 42 (1 equiv), aryl bromide (1.2 equiv), and
PdCl2(dppf) (0.1 equiv) in dimethoxyethane/2 M Na2CO3 aqueous
solution (10:1) was stirred at 50 °C. After cooling at room
temperature, this mixture was partitioned with ethyl acetate and
water. The aqueous layer was extracted with ethyl acetate twice, and
then the combined organic layer was washed with brine, dried
(MgSO4), filtered, and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane/
ethyl acetate) to afford the condensed compounds as white solids.
Method B. A mixture of compound 42 (1 equiv) and aryl bromide
(1.2 equiv) in DMF/H2O (20:1; 20 mM) was purged with nitrogen
gas for 30 min, and then Pd(PPh3)4 (0.05 equiv) and Na2CO3 (3
equiv) were added to the mixture, which was stirred for 1 h at 40−120
°C. The aqueous layer was extracted with ethyl acetate twice, and then
the combined organic layer was washed with brine, dried (MgSO4),
filtered, and evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate)
to afford the condensed compounds as white solids.
Methyl 3-(5-(N-(2-((tert-Butoxycarbonyl)amino)ethyl)sulfamoyl)-
thiophen-2-yl)-5-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-
yl)benzoate (80). Method A; Yield 44%; 1H NMR (400 MHz,
CDCl3) δ 8.46 (s, 1H), 8.37 (t, J = 1.2 Hz, 1H), 8.35 (t, J = 2.0 Hz,
1H), 8.34 (t, J = 1.4 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.4
Hz, 2H), 7.64 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 3.6 Hz, 1H), 5.64
(broad s, 1H), 4.93 (broad s, 1H), 4.05 (s, 3H), 3.33 (t, J = 5.8 Hz,
2H), 3.27 (t, J = 5.6 Hz, 2H), 1.45 (s, 9H).
Methyl 3-(5-(N-(3-((tert-Butoxycarbonyl)amino)propyl)-
sulfamoyl)thiophen-2-yl)-5-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-
triazol-1-yl)benzoate (81). Method A; Yield 44%; 1H NMR (400
MHz, CDCl3) δ 8.45 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.34 (s, 1H),
8.08 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 3.6 Hz,
1H), 7.46 (d, J = 4.0 Hz, 1H), 6.03 (broad s, 1H), 4.71 (broad s, 1H),
4.05 (s, 3H), 3.26 (q, J = 6.2 Hz, 2H), 3.16 (q, J = 6.2 Hz, 2H), 1.73−
1.70 (m, 2H), 1.41 (s, 9H); MS (ESI, m/z) 566.1 [M + 1-Boc]+, 666.2
[M + 1]+; ESI-HRMS calcd. m/z for C29H31N5O6F3S 666.1668, found
666.1676 [M + 1]+.
Methyl 3-(5-(N-(4-((tert-butoxycarbonyl)amino)butyl)sulfamoyl)-
thiophen-2-yl)-5-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-
yl)benzoate (82). Method A; Yield 62%; 1H NMR (400 MHz,
CDCl3) δ 8.45 (s, 1H), 8.38 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.08
(d, J = 8.0 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 3.2 Hz, 1H),
7.47 (d, J = 3.2 Hz, 1H), 5.01 (broad s, 1H), 4.58 (broad s, 1H), 4.09
(s, 3H), 3.16−3.14 (m, 4H), 1.63 (m, merged with water peak), 1.45
(s, 9H); MS (ESI, m/z) 792.0 [M-1+TFA]−, 678.2 [M − 1]−; ESI-
HRMS calcd. m/z for C30H31N5O6F3S2 678.1668, found 678.1666 [M
− H]−.
m/z) 509.0 [M + 1]+; ESI-HRMS calcd. m/z for C21H16N4O4F3S2
509.0565, found 509.0565 [M + 1]+.
tert-Butyl 4-((3′-(Methoxycarbonyl)-5′-(4-(4-(trifluoromethyl)-
phenyl)-1H-1,2,3-triazol-1-yl)-[1,1′-biphenyl]-4-yl)sulfonyl)-
piperazine-1-carboxylate (86). Method A; Yield 40%; 1H NMR (400
MHz, CDCl3) δ 8.45 (s, 1H), 8.45−8.44 (m, 1H), 8.42−8.40 (m, 2H),
8.09 (d, J = 8.04 Hz, 2H), 7.92 (d, J = 8.60 Hz, 2H), 7.88 (d, J = 8.60
Hz, 2H), 7.77 (d, J = 8.16 Hz, 2H), 4.06 (s, 3H), 3.56 (t, J = 4.90 Hz,
4H), 3.07 (t, J = 4.70 Hz, 4H), 1.43 (s, 9H); MS (ESI, m/z) 616.1 [M
+ 1-isobutyl]+, 672.2 [M + 1]+; ESI-HRMS calcd. m/z for
C32H33N5O6F3S 672.2104, found 672.2098 [M + 1]+.
Methyl 4′-Sulfamoyl-5-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-
triazol-1-yl)-[1,1′-biphenyl]-3-carboxylate (87). Method A; Yield
1
44%; H NMR (400 MHz, CD3OD) δ 9.31 (s, 1H), 8.63 (s, 1H),
8.52 (s, 1H), 8.45 (s, 1H), 8.17 (d, J = 7.92 Hz, 2H), 8.08 (d, J = 8.32
Hz, 2H), 8.00 (d, J = 8.36 Hz, 2H), 7.80 (d, J = 8.08 Hz, 2H), 4.04 (s,
3H); MS (ESI, m/z) 503.1 [M + 1]+; ESI-HRMS calcd. m/z for
C23H18N4O4F3S 503.1001, found 503.0998 [M + 1]+.
tert-Butyl 4-((5-(3-(Methoxycarbonyl)-5-(4-(4-(trifluoromethyl)-
phenyl)-1H-1,2,3-triazol-1-yl)phenyl)thiophen-2-yl)methyl)-
piperazine-1-carboxylate (88). Method A; Yield 61%; 1H NMR (400
MHz, CDCl3) δ 8.41 (s, 1H), 8.35 (t, J = 1.46 Hz, 1H), 8.31 (t, J =
1.86 Hz, 1H), 8.26 (m, 1H), 8.08 (d, J = 8.08 Hz, 2H), 7.76 (d, J =
8.24 Hz, 2H), 7.38 (d, J = 3.60 Hz, 1H), 6.98 (s, 1H), 4.03 (s, 3H),
3.79−3.63 (m, 2H), 3.51 (s, 4H), 2.53 (s, 4H), 1.48 (s, 9H); MS (ESI,
m/z) 572.2 [M + 1-isobutyl]+, 628.2 [M + 1]+; ESI-HRMS calcd. m/z
for C31H33N5O4F3S 628.2205, found 628.2200 [M + 1]+.
Methyl 3-(5-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)-
thiophen-2-yl)-5-(4-(4-(trifluoromethyl) phenyl)-1H-1,2,3-triazol-1-
yl)benzoate (89). Method A; Yield 48%; 1H NMR (400 MHz,
CDCl3) δ 8.42 (s, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.09
(d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.54 (s,
1H), 4.87 (s, 0.5H; NH), 4.04 (s, 3H), 3.54 (s, 2H), 3.32 (s, 2H), 1.76
(s, 2H), 1.50 (s, 9H); MS (ESI, m/z) 530.1 [M + 1-Boc]+, 574.1 [M +
1-isobutyl]+, 652.2 [M + Na]+; ESI-HRMS calcd. m/z for
C30H30N5O5F3SNa 652.1817, found 652.1818 [M + Na]+.
tert-Butyl 4-(5-(3-(Methoxycarbonyl)-5-(4-(4-(trifluoromethyl)-
phenyl)-1H-1,2,3-triazol-1-yl)phenyl)thiophene-2-carbonyl)-
piperazine-1-carboxylate (90). Method A; Yield 67%; 1H NMR (400
MHz, CDCl3) δ 8.43 (s, 1H), 8.37 (s, 2H), 8.34 (s, 1H), 8.08 (d, J =
8.04 Hz, 2H), 7.76 (d, J = 8.00 Hz, 2H), 7.46 (d, J = 3.56 Hz, 1H),
7.36 (d, J = 3.56 Hz, 1H), 4.05 (s, 3H), 3.79 (t, J = 4.84 Hz, 4H), 3.56
(t, J = 5.00 Hz, 4H), 1.51 (s, 9H); MS (ESI, m/z) 586.1 [M + 1-
isobutyl]+, 642.2 [M + 1]+; ESI-HRMS calcd. m/z for C31H31N5O5F3S
642.1998, found 642.2000 [M + 1]+.
Methyl 3-(5-((3-((tert-Butoxycarbonyl)amino)propyl)carbamoyl)-
furan-2-yl)-5-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)-
benzoate (91). Method A; Yield 25%; 1H NMR (400 MHz, CDCl3) δ
8.53 (s, 2H), 8.44 (s, 1H), 8.42 (s, 1H), 8.06 (d, J = 8.08 Hz, 2H), 7.75
(d, J = 8.16 Hz, 2H), 7.48 (broad s, 1H), 7.25 (d, J = 3.48 Hz, 1H),
7.00 (d, J = 3.48 Hz, 1H), 4.04 (s, 3H), 3.59−3.56 (m, 2H), 3.36−3.33
(m, 2H), 1.82−1.76 (m, 2H), 1.40 (s, 9H); MS (ESI, m/z) 514.1 [M
+ 1-Boc]+; ESI-HRMS calcd. m/z for C25H23N5O4F3 514.1702 found
514.1703 [M + 1-Boc]+.
Methyl 3-(5-(N-(4-Hydroxybutyl)sulfamoyl)thiophen-2-yl)-5-(4-
(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)benzoate (83).
Method A; Yield 65%; 1H NMR (400 MHz, CDCl3) δ 9.30 (s,
1H), 8.57 (s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 8.17 (d, J = 8.08 Hz,
2H), 7.81 (d, J = 8.24 Hz, 2H), 7.70 (d, J = 3.92 Hz, 1H), 7.65 (d, J =
3.96 Hz, 1H), 4.04 (s, 3H), 3.56 (t, J = 7.84 Hz, 2H), 3.06 (t, J = 6.58
Hz, 2H), 1.63−1.57 (m, 4H); MS (ESI, m/z) 581.1 [M + 1]+; ESI-
HRMS calcd. m/z for C25H24N4O5F3S2 581.1140, found 581.1143 [M
+ H]+.
Methyl 3-(5-Carbamoylfuran-2-yl)-5-(4-(4-(trifluoromethyl)-
phenyl)-1H-1,2,3-triazol-1-yl)benzoate (92). Method B; Yield 57%;
1H NMR (400 MHz, CD3OD) δ 9.24 (s, 1H), 8.64 (s, 1H), 8.56 (s,
tert-Butyl 4-((5-(3-(Methoxycarbonyl)-5-(4-(4-(trifluoromethyl)-
phenyl)-1H-1,2,3-triazol-1-yl)phenyl)thiophen-2-yl)sulfonyl)-
piperazine-1-carboxylate (84). Method A; Yield 63%; 1H NMR (400
MHz, CDCl3) δ 8.43 (s, 1H), 8.39−8.38 (m, 2H), 8.37 (s, 1H), 8.09
(d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 3.6 Hz, 1H),
7.54 (d, J = 3.6 Hz, 1H), 4.06 (s, 3H), 3.60 (t, J = 4.8 Hz, 4H), 3.14 (t,
J = 4.8 Hz, 4H), 1.45 (s, 9H); MS (ESI, m/z) 622.1 [M + 1-isobutyl]+,
678.2 [M + 1]+; ESI-HRMS calcd. m/z for C30H31N5O6F3S 678.1668,
found 678.1671 [M + 1]+.
Methyl 3-(5-Sulfamoylthiophen-2-yl)-5-(4-(4-(trifluoromethyl)-
phenyl)-1H-1,2,3-triazol-1-yl)benzoate (85). Method A; Yield 40%;
1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.37 (s, 2H), 8.36 (s,
1H), 8.08 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 4.0
Hz, 1H), 7.47 (d, J = 4.0 Hz, 1H), 5.11 (s, 2H), 4.05 (s, 3H); MS (ESI,
1H), 8.53 (s, 1H), 8.15 (d, J = 8.12 Hz, 2H), 7.80 (d, J = 8.20 Hz, 2H),
7.69−7.54 (m, POPh3), 7.29 (d, J = 3.64 Hz, 1H), 7.23 (d, J = 3.64
Hz, 1H), 4.03 (s, 3H); MS (ESI, m/z) 457.1 [M + 1]+; ESI-HRMS
calcd. m/z for C22H16N4O4F3 457.1124 found 457.1125 [M + 1]+.
Methyl 3-(4-((3-((tert-Butoxycarbonyl)amino)propyl)carbamoyl)-
thiophen-2-yl)-5-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-
yl)benzoate (93). Method A; Yield 73%; 1H NMR (400 MHz,
CDCl3) δ 8.44 (s, 1H), 8.38 (s, 1H), 8.34 (s, 2H), 8.08 (d, J = 7.00 Hz,
2H), 8.00 (s, 1H), 7.95 (s, 1H), 7.76 (d, J = 6.96 Hz, 2H), 4.04 (s,
3H), 3.55 (s, 2H), 3.32 (s, 2H), 1.76 (s, 2H), 1.49 (s, 9H); MS (ESI,
m/z) 530.1 [M + 1-Boc]+; ESI-HRMS calcd. m/z for C25H23N5O3F3S
530.1474, found 530.1476 [M + 1-Boc]+.
Methyl 3-(5-((3-((tert-Butoxycarbonyl)amino)propyl)carbamoyl)-
thiophen-3-yl)-5-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-
R
J. Med. Chem. XXXX, XXX, XXX−XXX