Journal of Medicinal Chemistry
Article
Preparation of 47−48 and 50−59. General Procedure C. To a
solution of 46 (100 mg, 0.219 mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (0.063 g, 0.329 mmol), N-hydrox-
ybenzotriazole (0.034 g, 0.219 mmol), and N,N-diisopropylethylamine
(0.153 mL, 0.878 mmol) in DMF (0.439 mL) was added a benzoic
acid (0.219 mmol). The reaction was stirred at 50 °C for 2 h and then
stirred at ambient temperature overnight. The reaction mixture was
diluted with ethyl acetate and washed with water and brine; the
organic layer was dried over sodium sulfate, filtered, and concentrated.
The crude product was purified via reverse-phase preparative HPLC to
provide the desired product.
(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-
((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]-
imidazol-2(3H)-ylidene)benzamide (47). The title compound was
prepared by general procedure C using benzoic acid. The crude
product was purified using a gradient of 20−80% [0.1% TFA in
acetonitrile] in [0.1% TFA in water] to produce 47 (27 mg, 22.3%
yield). 1H NMR (400 MHz, DMSO-d6) δ 12.75 (br s, 1 H), 8.26 (d, J
= 7.2 Hz, 2 H), 7.63 (d, J = 7.6 Hz, 1 H), 7.56 (s, 1 H), 7.43−7.53 (m,
4 H), 7.15 (d, J = 8.1 Hz, 1 H), 4.79−4.93 (m, 1 H), 4.03−4.12 (m, 1
H), 4.01 (s, 1 H), 3.51 (s, 2 H), 2.82−2.96 (m, 2 H), 2.65−2.78 (m, 2
H), 2.51−2.56 (m, 1 H), 2.11−2.21 (m, 2 H), 1.78−1.93 (m, 2 H),
1.55−1.78 (m, 6 H), 1.20−1.32 (m, 2 H), 1.13−1.18 (m, 1 H), 1.11
(d, J = 6.6 Hz, 6 H), 1.02 (s, 6 H). HRMS (m/z): [MH+] calcd for
C33H46N5O3, 560.3595; found, 560.3598.
TFA in acetonitrile] in [0.1% TFA in water] to produce 50 (27 mg,
21.3% yield). H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1 H), 8.70
1
(dd, J = 1.5 Hz, 4.5 Hz, 2H), 8.11 (dd, J = 1.5 Hz, 4.5 Hz, 2 H), 7.63
(d, J = 7.6 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.18 (d, J
= 8.1 Hz, 1 H), 4.80−4.91 (m, 1 H), 4.02−4.11 (m, 1 H), 4.00 (s, 1
H), 3.50 (s, 2 H), 2.85−2.93 (m, 2 H), 2.69−2.81 (m, 2 H), 2.52−2.56
(m, 1 H), 2.12−2.20 (m, 2 H), 1.79−1.88 (m, 2 H), 1.68−1.79 (m, 2
H), 1.58−1.68 (m, 4 H), 1.20−1.31 (m, 2 H), 1.12−1.18 (m, 1 H),
1.10 (d, J = 6.5 Hz, 6 H), 1.02 (s, 6 H). HRMS (m/z): [MH+] calcd
for C32H45N6O3, 561.3548; found, 561.3548.
(E)-4-Cyano-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)-
methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-
benzo[d]imidazol-2(3H)-ylidene)benzamide (51). The title com-
pound was prepared by general procedure C using 4-cyanobenzoic
acid. The crude product was purified using a gradient of 20−80%
[0.1% TFA in acetonitrile] in [0.1% TFA in water] to produce 51 (32
mg, 20.5% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.83 (br s, 1 H),
8.41 (d, J = 8.4 Hz, 2 H), 7.91 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 7.6 Hz,
1 H), 7.58 (s, 1 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.18 (d, J = 8.2 Hz, 1 H),
4.81−4.92 (m, 1 H), 4.01−4.09 (m, 1 H), 4.00 (s, 1 H), 3.50 (s, 2 H),
2.83−2.93 (m, 2 H), 2.66−2.80 (m, 2 H), 2.52−2.56 (m, 1 H), 2.10−
2.19 (m, 2 H), 1.79−1.89 (m, 2 H), 1.68−1.79 (m, 2 H), 1.58−1.67
(m, 4 H), 1.18−1.31 (m, 2 H), 1.13−1.17 (m, 1 H), 1.11 (d, J = 6.5
Hz, 6 H), 1.02 (s, 6 H). HRMS (m/z): [MH+] calcd for C34H45N6O3,
585.3548; found, 585.3549.
(E)-3-Fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)-
methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-
benzo[d]imidazol-2(3H)-ylidene)benzamide (48). The title com-
pound was prepared by general procedure C using 3-fluorobenzoic
acid. The crude product was purified using a gradient of 20−80%
[0.1% TFA in acetonitrile] in [0.1% TFA in water] to produce 48 (33
mg, 39.5% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.80 (br s, 1 H),
8.11 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 9.9 Hz, 1 H), 7.43−7.69 (m, 4
H), 7.29−7.39 (m, 1 H), 7.11−7.23 (m, 1 H), 4.80−4.92 (m, 1 H),
3.94−4.13 (m, 2 H), 3.44−3.58 (m, 2 H), 2.81−2.96 (m, 2 H), 2.64−
2.80 (m, 2 H), 2.51−2.56 (m, 1 H), 2.09−2.21 (m, 2 H), 1.54−1.92
(m, 8 H), 1.20−1.37 (m, 2 H), 1.13−1.19 (m, 1 H), 1.10 (d, J = 6.6
Hz, 6 H), 1.02 (s, 6 H). HRMS (m/z): [MH+] calcd for
C33H45FN5O3, 578.3501; found, 578.3500.
(E)-3,5-Difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-
yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-
benzo[d]imidazol-2(3H)-ylidene)benzamide (49). To a solution
of 44 (8.98 g, 20.9 mmol) in THF (80 mL) at 0 °C was added a
solution of 45 (4.57 g, 22.9 mmol) in THF. The reaction was stirred at
0 °C for 30 min and then warmed to 20 °C and stirred for 1.5 h to
form the thiourea intermediate.
(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-
((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]-
imidazol-2(3H)-ylidene)nicotinamide (52). The title compound
was prepared by general procedure C using nicotinic acid. The crude
product was purified using a gradient of 15−75% [0.1% TFA in
acetonitrile] in [0.1% TFA in water] to produce 52 (27 mg, 23.2%
yield). 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1 H), 9.36 (d, J =
1.4 Hz, 1 H), 8.69 (dd, J = 1.7 Hz, 4.7 Hz, 1 H), 8.56 (d, J = 7.8 Hz, 1
H), 7.63 (d, J = 7.6 Hz, 1 H), 7.58 (s, 1 H), 7.46−7.53 (m, 2 H), 7.18
(d, J = 8.2 Hz, 1 H), 4.85−4.94 (m, 1 H), 4.02−4.11 (m, 1 H), 4.01 (s,
1 H), 3.50 (s, 2 H), 2.83−2.93 (m, 2 H), 2.66−2.77 (m, 2 H), 2.51−
2.56 (m, 1 H), 2.12−2.19 (m, 2 H), 1.80−1.88 (m, 2 H), 1.69−1.80
(m, 2 H), 1.58−1.69 (m, 4 H), 1.20−1.32 (m, 2 H), 1.13−1.17 (m, 1
H), 1.11 (d, J = 6.5 Hz, 6 H), 1.02 (s, 6 H). HRMS (m/z): [MH+]
calcd for C32H45N6O3, 561.3548; found, 561.3552.
(E)-3,4-Difluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-
yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-
benzo[d]imidazol-2(3H)-ylidene)benzamide (53). The title com-
pound was prepared by general procedure C using 3,4-difluorobenzoic
acid. The crude product was purified using a gradient of 30−90%
[0.1% TFA in acetonitrile] in [0.1% TFA in water] to produce 53 (35
To the reaction mixture were added N,N-diisopropylethylamine
(4.37 mL, 25.02 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide hydrochloride (4.80 g, 25.02 mmol), and the reaction
was stirred at 60 °C for 1 h. The reaction mixture was diluted with
ethyl acetate, washed with water and brine, and concentrated. The
crude product was adsorbed onto a silica gel loading column and
purified by column chromatography, eluting with 1:1 ethyl acetate/
hexanes, followed by 5−10% [9:1 DCM/methanol with 1%
ammonium hydroxide] in DCM. The product fractions were
combined and concentrated; the residue was recrystallized from
acetonitrile to produce 49 (8.95 g, 72% yield) as an off-white
1
mg, 16.4% yield). H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1 H),
8.15−8.22 (m, 1 H), 8.09−8.15 (m, 1 H), 7.63 (d, J = 7.7 Hz, 1 H),
7.56 (s, 1 H), 7.44−7.52 (m, 2 H), 7.16 (d, J = 8.3 Hz, 1 H), 4.77−
4.88 (m, 1 H), 4.01−4.10 (m, 1 H), 4.00 (s, 1 H), 3.49 (s, 2 H), 2.84−
2.93 (m, 2 H), 2.68−2.80 (m, 2 H), 2.51−2.56 (m, 1 H), 2.07−2.18
(m, 2 H), 1.79−1.88 (m, 2 H), 1.68−1.79 (m, 2 H), 1.55−1.68 (m, 4
H), 1.20−1.32 (m, 2 H), 1.12−1.17 (m, 1 H), 1.10 (d, J = 6.6 Hz, 6
H), 1.02 (s, 6 H). HRMS (m/z): [MH+] calcd for C33H44F2N5O3,
596.3407; found, 596.3406.
(E)-3-Cyano-5-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)-
piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)-
cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide
(54). The title compound was prepared by general procedure C using
3-cyano-5-fluorobenzoic acid. The crude product was purified using a
gradient of 30−90% [0.1% TFA in acetonitrile] in [0.1% TFA in
1
crystalline solid. H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1 H),
7.85 (dd, J = 2.3 Hz, 8.4 Hz, 2 H), 7.56−7.64 (m, 2 H), 7.50 (d, J = 8.2
Hz, 1 H), 7.38 (tt, J = 9.0 Hz, 2.4 Hz, 1 H), 7.18 (dd, J = 8.2 Hz, 8.2
Hz, 1 H), 4.78−4.90 (m, 1 H), 4.00−4.11 (m, 1 H), 3.99 (s, 1 H), 3.50
(s, 2 H), 2.85−2.92 (m, 2 H), 2.63−2.82 (m, 2 H), 2.51−2.56 (m, 1
H), 2.06−2.19 (m, 2 H), 1.69−1.91 (m, 4 H), 1.56−1.69 (m, 4 H),
1.18−1.35 (m, 2 H), 1.12−1.18 (m, 1 H), 1.09 (d, J = 3.6 Hz, 6 H),
1.02 (s, 6 H). HRMS (m/z): [MH+] calcd for C33H43F2N5O3,
596.3407; found, 596.3409.
(E)-N-(6-((4-(2-Hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-
((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]-
imidazol-2(3H)-ylidene)isonicotinamide (50). The title com-
pound was prepared by general procedure C using isonicotinic acid.
The crude product was purified using a gradient of 15−75% [0.1%
1
water] to produce 54 (36 mg, 17.6% yield). H NMR (400 MHz,
DMSO-d6) δ 12.87 (br s, 1 H), 8.43 (s, 1 H), 8.32 (d, J = 1.0 Hz, 1 H),
7.96−8.03 (m, 1 H), 7.58−7.65 (m, 2 H), 7.52 (d, J = 8.1 Hz, 1 H),
7.19 (d, J = 8.2 Hz, 1 H), 4.78−4.90 (m, 1 H), 4.02−4.13 (m, 1 H),
4.00 (s, 1 H), 3.50 (s, 2 H), 2.85−2.92 (m, 2 H), 2.72−2.84 (m, 2 H),
2.52−2.57 (m, 1 H), 2.06−2.15 (m, 2 H), 1.68−1.90 (m, 4 H), 1.58−
1.67 (m, 4 H), 1.19−1.31 (m, 2 H), 1.11−1.18 (m, 1 H), 1.08 (d, J =
6.5 Hz, 6 H), 1.02 (s, 6 H). HRMS (m/z): [MH+] calcd for
C34H44FN6O3, 603.3453; found, 603.3452.
O
dx.doi.org/10.1021/jm3005866 | J. Med. Chem. XXXX, XXX, XXX−XXX