Journal of Medicinal Chemistry
Article
(m, 4H), 8.04 (dd,
J
=
8.59, 5.31 Hz, 2H). Anal.
(s, 6H), 2.55 (dd, J = 13.64, 3.03 Hz, 1H), 2.95 (dd, J = 13.52, 9.73
Hz, 1H), 3.53−3.65 (m, 1H), 3.90−4.01 (m, 1H), 4.07−4.17 (m, 1H),
4.50 (br s, 1H), 4.66−4.82 (m, 2H), 5.89 (dd, J = 9.35, 1.52 Hz, 1H),
7.26−7.45 (m, 5H). Anal. (C24H33N5O4·0.1cyclohexane·0.5H2O) C,
H, N. HRMS: [M + H]+ calcd 456.2606; found 456.2597, error −1.92
ppm.
(C25H28FN5O3·0.35H2O) C, H, N, F. HRMS: [M + H]+ calcd
466.22489; found 466.22468; error −0.46 ppm.
(S)-N-(2-(Dimethylamino)-1-phenylethyl)-3-(2-fluorobenza-
mido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-
carboxamide (20). By the method used to make compound 4,
compound 32 (120 mg, 0.29 mmol) and (S)-N1,N1-dimethyl-2-
phenylethane-1,2-diamine (15a) (71 mg, 0.43 mmol) yielded, after
reverse-phase prep HPLC and lyophilization, 20 (50 mg, 36%) as a
5-tert-Butyl 1-Ethyl 6,6-Dimethyl-3-(3,3,3-trifluoro-2,2-
dimethylpropanamido)pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-di-
carboxylate (38). DMF (0.8 mL) was added to a cooled (0 °C)
solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (3.0 g, 20
mmol) in dichloromethane (60 mL), and then a solution of freshly
distilled oxalyl chloride (2.8 g, 22 mmol) in dichloromethane (15 mL)
was added dropwise, causing slight gas evolution. The mixture was
stirred for 6 h, allowing it to gradually warm to room temperature and
then recooled to 0 °C. 5-tert-Butyl 1-ethyl 3-amino-6,6-
dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate (11−2)
(2.7 g, 8.3 mmol) was added, followed by diisopropylethylamine
(11.4 mL). The mixture was stirred for 15 h, allowing it to gradually
warm to room temperature. The solution was cooled again to 0 °C and
treated with 5% aqueous HCl (25 mL). The layers were separated, and
the aqueous layer extracted with dichloromethane (25 mL). The
combined organic layers were dried over sodium sulfate, filtered, and
concentrated. The crude product was purified on a silica plug, eluting
with 30% ethyl acetate in heptane, affording 38 (2.48 g, 64%) as a
1
white solid. H NMR (400 MHz, methanol-d4) δ ppm 1.68 (s, 3H),
1.75 (s, 3H), 2.45 (s, 6H), 2.62 (dd, J = 12.72, 4.41 Hz, 1H), 2.91−
3.03 (m, 1H), 4.67−4.82 (m, 2H), 5.07 (dd, J = 10.70, 4.41 Hz, 1H),
7.21−7.43 (m, 7H), 7.52−7.66 (m, 1H), 7.78−7.89 (m, 1H). Anal.
(C25H29N6O2F·0.2HOAc·0.4H2O) C, H, N. HRMS: [M + H]+ calcd
465.240879, found 465.241357, error 1.03 ppm.
(S)-2-(Dimethylamino)-1-phenylethyl 3-(2,4-Difluorobenza-
mido)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-
carboxylate (21). By the method used to make compound 18,
compound 33 (240 mg, 0.56 mmol) and alcohol 15b (139 mg, 0.84
mmol) yielded, after reverse-phase prep HPLC and lyophilization, 21
as a white solid (54.9 mg, 19%). 1H NMR (400 MHz, methanol-d4) δ
ppm 1.63 (s, 3H), 1.74 (s, 3H), 2.57 (s, 6H), 2.81 (dd, J = 13.39, 3.03
Hz, 1H), 3.15−3.26 (m, 1H), 4.75−4.85 (m, 2H), 5.99 (dd, J = 9.85,
3.03 Hz, 1H), 7.11−7.21 (m, 2H), 7.33−7.45 (m, 5H), 7.84−7.96 (m,
1H). Anal. (C25H27N5O3F2·0.4HOAc) C, H, N. HRMS: [M + H]+
calcd 484.215473, found 484.214847, error −1.29 ppm.
(S)-2-(Dimethylamino)-1-phenylethyl 6,6-Dimethyl-3-(picoli-
namido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
(22). By the method used to make compound 18, compound 34 (120
mg, 0.306 mmol) and alcohol 15b (76 mg, 0.46 mmol) yielded, after
reverse-phase prep HPLC and lyophilization, 22 as a white solid (54
mg, 37%). 1H NMR (400 MHz, MeOD) δ ppm 1.61 (s, 3H), 1.72 (s,
3H), 2.54 (s, 6H), 2.77 (d, J = 13.60 Hz, 1H), 3.08−3.24 (m, 1H),
4.56−4.79 (m, 1H), 4.91−5.03 (m, 1H), 5.90−6.05 (m, 1H), 7.29−
7.36 (m, 1H), 7.36−7.49 (m, 4H), 7.58−7.69 (m, 1H), 7.99−8.09 (m,
1H), 8.21 (d, J = 7.81 Hz, 1H), 8.71 (d, J = 4.78 Hz, 1H). Anal.
(C24H28N6O3·0.4HOAc·0.2H2O) C, H, N. HRMS: [M + H]+ calcd
449.229565, found 449.229005, error −1.25 ppm.
1
white solid. H NMR (400 MHz, chloroform-d) δ ppm 1.46 (d, J =
6.80 Hz, 3H), 1.48−1.60 (m, 15H), 1.78 (d, J = 6.04 Hz, 3H), 1.80 (s,
3H), 4.60 (q, J = 7.22 Hz, 2H), 4.84 (s, 1H), 4.92 (d, J = 53.38 Hz,
1H), 10.83 (br s, 1H).
Ethyl 6,6-Dimethyl-3-(3,3,3-trifluoro-2,2-dimethylpropana-
mido)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate
(39). A solution of 38 (3.2 g, 6.9 mmol) in ethyl acetate (60 mL) was
treated with 4.0 M HCl solution in dioxane (40 mL) for 14 h at room
temperature. The solvents were evaporated, and the residual solid
triturated with ether to give the monohydrochloride salt of 39 (2.2 g,
80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.36 (t, J
= 7.18 Hz, 3H), 1.49 (s, 6H), 1.65 (s, 6H), 4.46 (q, J = 7.13 Hz, 2H),
4.51 (s, 2H), 10.16 (br s, 2H), 10.59 (s, 1H). Anal.
(C15H21F3N4O3·1.0HCl) C, H, N, F, Cl.
(S)-2-(Dimethylamino)-1-phenylethyl 6,6-Dimethyl-3-pivala-
mido-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
(23). By the method used to make compound 18, compound 35
(250.9 mg, 0.677 mmol), and alcohol 15b (237.0 mg, 1.434 mmol)
yielded, after silica gel chromatography and trituration from cyclo-
Ethyl 5-(Chlorocarbonyl)-6,6-dimethyl-3-(3,3,3-trifluoro-2,2-
dimethylpropanamido)-5,6-dihydropyrrolo[3,4-c]pyrazole-
1(4H)-carboxylate (40). A solution of monohydrochloride salt 39
(1.2 g, 3.0 mmol) in dichloromethane (40 mL) was cooled to −78 °C.
Diisopropylethylethylamine (1.9 mL) was added, followed by a
solution of triphosgene (630 mg, 2.1 mmol) in dichloromethane (10
mL). The mixture was stirred for 20 min and then quenched while
cold with saturated aqueous sodium bicarbonate solution (25 mL).
The resulting biphasic mixture was allowed to warm to room
temperature, the layers were separated, and the aqueous layer was
extracted with dichloromethane (25 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated to a
white solid. The crude product was purified by passing through a silica
plug, eluting with 20% ethyl acetate in heptane, to give 40 (1.13 g,
88%) as a white solid. H NMR (400 MHz, chloroform-d) δ ppm
1.45−1.56 (m, 9H), 1.78 (s, 6H), 4.60 (q, J = 7.05 Hz, 2H), 4.98 (s,
2H), 10.83 (br s, 1H).
A similar three-step procedure was used to make the following two
compounds
E t h y l 5 - ( C h l o r o c a r b o n y l ) - 6 , 6 - d i m e t h y l - 3 - ( 1 -
(trifluoromethyl)cyclopropanecarboxamido)-5,6-
dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (41). 1H NMR
(400 MHz, chloroform-d) δ ppm 1.39−1.44 (m, 2H), 1.47−1.54 (m,
3H), 1.56 (br s, 2H), 1.76−1.81 (m, 6H), 4.61 (q, J = 7.13 Hz, 2H),
4.77 (s, 1H), 4.92 (s, 1H), 11.06 (br s, 1H).
E t h y l 5 - ( C h l o r o c a r b o n y l ) - 6 , 6 - d i m e t h y l - 3 - ( 1 -
(trifl uoromethyl)cyclobutanecarboxamido)-5, 6-
dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (42). 1H NMR
(400 MHz, chloroform-d) δ ppm 1.48 (t, J = 7.05 Hz, 3H), 1.78 (s,
6H), 1.97−2.21 (m, 2H), 2.51−2.72 (m, 4H), 4.57 (q, J = 7.22 Hz,
2H), 5.00 (s, 2H), 10.57 (br s, 1H).
1
hexane, 23 (109.3 mg, 35%) as a white powder. H NMR (400 MHz,
methanol-d4) δ ppm 1.30 (s, 9H), 1.58 (s, 3H), 1.69 (s, 3H), 2.38 (s,
6H), 2.55 (dd, J = 13.52, 3.16 Hz, 1H), 2.97 (dd, J = 13.39, 9.60 Hz,
1H), 4.63−4.81 (m, 2H), 5.90 (dd, J = 9.35, 3.03 Hz, 1H), 7.26−7.45
(m, 5H). Anal. (C23H33N5O3·0.7H2O·0.3cyclohexane) C, H, N.
HRMS: [M + H]+ calcd 428.265616, found 428.265349, error
−0.62 ppm.
(S)-2-(Dimethylamino)-1-phenylethyl 6,6-Dimethyl-3-(tetra-
hydrofuran-2-carboxamido)-4,6-dihydropyrrolo[3,4-c]-
pyrazole-5(1H)-carboxylate (24). By the method used to make
compound 18, compound 36 (225.0 mg, 0.585 mmol) and alcohol
15b (145 mg, 0.877 mmol) yielded, after silica gel chromatography
and trituration from cyclohexane, 24 (121.5 mg, 45%, mixture of
diastereomers) as a white powder. 1H NMR (400 MHz, methanol-d4)
δ ppm 1.59 (s, 3H), 1.69 (s, 3H), 1.91−2.15 (m, 3H), 2.38 (s, 6H),
2.56 (dd, J = 13.52, 3.16 Hz, 1H), 2.96 (dd, J = 13.39, 9.60 Hz, 1H),
3.87−3.98 (m, 1H), 4.02−4.12 (m, 1H), 4.46 (dd, J = 8.08, 6.32 Hz,
2H), 4.62−4.80 (m, 2H), 5.89 (dd, J = 9.35, 3.03 Hz, 1H), 7.26−7.46
(m, 5H). Anal. (C23H31N5O4·0.15cyclohexane·0.6H2O) C, H, N.
HRMS: [M + H]+ calcd 442.2449; found 442.2446, error −0.62 ppm.
(S)-2-(Dimethylamino)-1-phenylethyl 6,6-Dimethyl-3-(tetra-
hydro-2H-pyran-2-carboxamido)-4,6-dihydropyrrolo[3,4-c]-
pyrazole-5(1H)-carboxylate (25). By the method used to make
compound 18, compound 37 (229.8 mg, 0.576 mmol) and alcohol
15b (143 mg, 0.864 mmol) yielded, after silica gel chromatography
and trituration from cyclohexane, 25 (162.9 mg, 60%, mixture of
1
1
diastereomers) as an off-white foam. H NMR (400 MHz, methanol-
(S)-2-(Dimethylamino)-1-phenylethyl 6,6-Dimethyl-3-(3,3,3-
trifluoro-2,2-dimethylpropanamido)-4,6-dihydropyrrolo[3,4-
d4) δ ppm 1.48−1.67 (m, 6H), 1.69 (s, 3H), 1.89−2.11 (m, 2H), 2.37
K
dx.doi.org/10.1021/jm300204j | J. Med. Chem. XXXX, XXX, XXX−XXX