Journal of Medicinal Chemistry
Article
(7 mg, 0.03 mmol) were added, and the mixture was stirred at rt
overnight. The crude was directly purified via MDAP (XBridge C18
19 × 150, 30−60% acetonitrile water with 0.1% ammonium
(m, 7H), 7.53 (s, br, 1H), 8.03 (dd, J = 5.3, 1.5 Hz, 1H). UPLC-MS
(long basic) tR 1.79 (512 [M + H]+), 84% purecontains 6% mono-
N-methyl and 3% di-N-methylamine byproducts.
1
hydroxide) to provide 20 (8 mg, 38%) as a pale yellow solid. H
2-((N-(2-Oxo-2-((2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-
pyrrolo[2,3-b]pyridin]-5-yl)amino)ethyl)pivalamido)methyl)-
benzamide (15). 21 (17 mg, 0.033 mmol) was dissolved in DMSO (1
mL). Water (0.17 mL) was added, followed by hydrogen peroxide
solution (3 drops) and NaOH (2.8 mg, 0.07 mmol), and the mixture
was stirred at rt for 2 h. The reaction mixture was quenched with ethyl
acetate and water. The aqueous layer was extracted with ethyl acetate
(repeated twice). The organics were washed with brine, dried over
magnesium sulfate, filtered, and the filtrate was evaporated. The
residue was purified twice via column chromatography (1:0 ethyl
acetate/methanol to 15:1 ethyl acetate/methanol) to provide 15
(10.6 mg, 60%) as a pale yellow solid. 1H NMR (CD3OD, 300 MHz)
δ 1.31 (s, 9H), 3.04 (dd, J = 15.8, 5.2 Hz, 2H), 3.48 (dd, J = 15.9, 7.5
Hz, 2H), 4.11 (s, 2H), 5.06 (s, 2H), 6.86 (dd, J = 7.3, 5.3 Hz, 1H),
7.11 (dd, J = 7.3, 1.6 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.30−7.39
(m, 3H), 7.44−7.55 (m, 3H), 8.03 (dd, J = 5.4, 1.6 Hz, 1H). UPLC-
NMR (CDCl3, 300 MHz) δ 1.30 (s, 9H), 3.01 (dd, J = 15.8, 2.0 Hz,
2H), 3.59 (dd, J = 15.8, 2.8 Hz, 2H), 4.00 (s, 2H), 4.78 (s, 2H), 6.80
(dd, J = 7.3, 5.3 Hz, 1H), 7.05 (dd, J = 7.4, 1.5 Hz, 1H), 7.14−7.17
(m, 2H), 7.24−7.31 (m, 2H), 7.36−7.47 (m, 4H), 7.68 (dt, J = 7.9,
1.9 Hz, 1H), 8.11 (dd, J = 5.3, 1.5 Hz, 1H), 8.42 (br, 1H), 8.57 (d, J =
1.6 Hz, 1H), 8.63 (dd, J = 4.9, 1.6 Hz, 1H), 8.84 (br, 1H). UPLC-MS
t
(short basic) R 2.04 (560 [M + H]+).
N-(2-Bromobenzyl)-N-(2-oxo-2-((2′-oxo-1,1′,2′,3-
tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)amino)-
ethyl)pivalamide (21E). 21C (3.11 g, 9.48 mmol), EDCI.HCl (2.5 g,
13.27 mmol), and HOAt (1.8 g, 13.27 mmol) were dissolved in dry
DMF (60 mL). N,N-Diisopropylethylamine (5.0 mL, 28.44 mmol)
and 21D (2.38 g, 9.48 mmol) were added, and the mixture was stirred
at rt for 18 h. The mixture was diluted with ethyl acetate (250 mL)
and washed with saturated sodium bicarbonate and three times with
brine. The organic layer was dried over magnesium sulfate, filtered,
and the filtrate was evaporated. The residue was purified via flash
silica chromatography (0−100% EtOAc in DCM) to provide 21E
t
MS (short basic) R 1.65 (526 [M + H]+).
Methyl 2-((2-(2-(Diallylamino)ethyl)benzyl)amino)acetate (16B).
16A (116 mg, 0.516 mmol) was dissolved in methanol (2 mL), and
then methyl glycinate hydrochloride (191 mg, 1.52 mmol) and
sodium cyanoborohydride (55 mg, 0.88 mmol) were added and the
mixture was stirred at rt for 18 h. The reaction mixture was poured
into water, and the pH was adjusted to 4 with 2 M HCl before the
mixture was washed twice with dichloromethane. The aqueous layer
was basified with sodium carbonate and extracted twice with
dichloromethane. This organic extract was dried over magnesium
sulfate, filtered, and evaporated to provide 16B (53 mg, 35%) as a
colorless oil. 1H NMR (CDCl3, 300 MHz) δ 2.63−2.88 (m, 4H), 3.19
(d, J = 6.5 Hz, 4H), 3.44 (s, 2H), 3.73 (s, 3H), 3.79 (s, 2H), 5.11−
5.24 (m, 4H), 5.80−5.95 (m, 2H), 7.12−7.32 (m, 4H). UPLC-MS
1
(4.38 g, 83%) as a pale yellow solid. H NMR (CDCl3, 300 MHz) δ
1.31 (s, 9H), 3.04 (dd, J = 15.7, 6.4 Hz, 2H), 3.61 (dd, J = 15.8, 6.0
Hz, 2H), 4.07 (s, 2H), 4.91 (s, 2H), 6.81 (dd, J = 7.2, 5.4 Hz, 1H),
7.07 (d, J = 7.1 Hz, 1H), 7.12−7.24 (m, 3H), 7.34 (t, J = 7.5 Hz, 1H),
7.55−7.62 (m, 2H), 8.12 (dd, J = 5.2 Hz, 1H), 8.49 (s, 1H), 9.29 (s,
t
1H). UPLC-MS (short basic) R 0.84 (561, 563 [M + H]+).
N-(2-Cyanobenzyl)-N-(2-oxo-2-((2′-oxo-1,1′,2′,3-
tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)amino)-
ethyl)pivalamide (21). 21E (4.40 g, 7.84 mmol) was dissolved in dry
DMF (88 mL) and was degassed by bubbling argon through the
solution. Zinc(II) cyanide (1.66 g, 14.12 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (1.8 g, 1.57 mmol) were added,
and the mixture was stirred at 130 °C for 2 h. UPLC-MS indicated
complete conversion. The heat was removed, and the mixture was
stirred at rt for 18 h. The mixture was then diluted with ethyl acetate
(400 mL) and washed twice with saturated sodium bicarbonate and
three times with brine. The organic layer was dried over magnesium
sulfate, filtered, and the filtrate was evaporated. The residue was
triturated with diethyl ether to provide 21 (3.85 g, 96%) as an off-
white solid. 1H NMR (CD3OD, 300 MHz) δ 1.24 (s, 9H), 3.03 (dd, J
= 16.0, 10.7 Hz, 2H), 3.30 (dd, J = 16.0, 9.2 Hz, 2H), 4.04 (s, 2H),
5.02 (s, 2H), 6.82 (dd, J = 7.3, 5.3 Hz, 1H), 6.90 (d, J = 6.9 Hz, 1H),
7.10−7.55 (m, 7H), 8.00−8.05 (m, 2H), 9.75 (s, 1H), 10.94 (s, 1H).
N-(2-(Aminomethyl)benzyl)-N-(2-oxo-2-((2′-oxo-1,1′,2′,3-
tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)amino)-
ethyl)pivalamide (12). 21 (2.3 g, 4.53 mmol) was dissolved in 15%
ammonia in methanol (180 mL) under an argon atmosphere in an
autoclave. Raney nickel (250 mg, 0.45 mmol) was added, and
hydrogen was introduced to 500 psi. The vessel was stirred at 60 °C
for 6 h and then at rt for 18 h. UPLC-MS showed 20% conversion, so
extra Raney nickel (400 mg, 0.72 mmol) was added and hydrogen was
reintroduced to 500 psi. The vessel was stirred at 60 °C for 6.5 h.
UPLC-MS analysis showed 58% conversion. The mixture was
decanted (from the nickel solids) and filtered through celite, washing
with 15% ammonia in methanol, and the filtrate was evaporated. The
residue was dissolved in 15% ammonia in methanol (180 mL) under
an argon atmosphere in an autoclave. Raney nickel (400 mg, 0.72
mmol) was added, and hydrogen was reintroduced to 500 psi. The
vessel was stirred at 50 °C for 6 h, then rt for 18 h, 55 °C for 6 h, rt
for 42 h, and 55 °C for 8 h. The mixture was decanted (from the
nickel solids) and filtered through celite, washing with 15% ammonia
in methanol, and the filtrate was evaporated. The residue was purified
via flash silica chromatography (EtOAc and then 5% MeOH in DCM,
then 10−15% MeOH with ammonia in DCM) to provide 12 (240
mg, 10%) as a white powder after freeze-drying from an aqueous
solution. 1H NMR (CD3OD, 300 MHz) δ 1.32 (s, 9H), 3.04 (dd, J =
15.9, 5.4 Hz, 2H), 3.49 (dd, J = 15.8, 9.8 Hz, 2H), 3.81 (s, 2H), 4.06
(br s, 2H), 4.93 (br s, 2H), 6.86 (dd, J = 7.3, 5.4 Hz, 1H), 7.09−7.41
t
(short basic) R 0.84 (303 [M + H]+), 80% pure.
Methyl 2-(N-(2-(2-(Diallylamino)ethyl)benzyl)pivalamido)-
acetate. 16B (54 mg, 0.18 mmol) was dissolved in dichloromethane
(1 mL) under an argon atmosphere, and N,N-diisopropylethylamine
(93 μL, 0.53 mmol) was added. Trimethylacetyl chloride (26 μL, 0.21
mmol) was added dropwise, and the mixture was stirred at rt for 4
days. The mixture was poured into saturated sodium bicarbonate and
extracted three times with dichloromethane. The organic extracts
were evaporated to provide methyl 2-(N-(2-(2-(diallylamino)ethyl)-
benzyl)pivalamido)acetate (68 mg, 99%) as a colorless oil. UPLC-MS
t
(short basic) R 0.96 (387 [M + H]+), 89% pure.
2-(N-(2-(2-(Diallylamino)ethyl)benzyl)pivalamido)acetic Acid
(16C). Methyl 2-(N-(2-(2-(diallylamino)ethyl)benzyl)pivalamido)-
acetate (68 mg, 0.176 mmol) was dissolved in methanol (1 mL),
and then 2.5 M sodium hydroxide (0.22 mL, 0.55 mmol) was added
and the mixture was stirred at rt for 18 h. The volatiles were removed,
the material was diluted with water, and the pH was adjusted to 5
with 2 M HCl. This was then concentrated to dryness to provide 16C
(assume 0.176 mmol) as a glass that was used directly in the next step.
N-(2-(2-(Diallylamino)ethyl)benzyl)-N-(2-oxo-2-((2′-oxo-
1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)-
amino)ethyl)pivalamide (16E). 16C (∼0.176 mmol), EDCI.HCl (53
mg, 0.28 mmol), and HOAt (38 mg, 0.28 mmol) were dissolved in
dry DMF (1 mL). N,N-Diisopropylethylamine (0.11 mL, 0.64 mmol)
and 16D (44.5 mg, 0.177 mmol) were added, and the mixture was
stirred at rt for 18 h. The mixture was poured into saturated sodium
bicarbonate and extracted three times with ethyl acetate. The
combined organic layers were washed with brine, dried over
magnesium sulfate, filtered, and the filtrate was evaporated. The
residue was purified via flash silica chromatography (EtOAc) to
1
provide 16E (77 mg, 72%) as a pale yellow glass. H NMR (CDCl3,
400 MHz) δ 1.32 (s, 9H), 2.61−2.79 (m, 4H), 3.03 (dd, J = 15.8, 8.8
Hz, 2H), 3.17 (d, J = 6.1 Hz, 4H), 3.61 (dd, J = 15.5, 8.3 Hz, 2H),
4.02 (br s, 2H), 4.90 (s, 2H), 5.07−5.23 (m, 4H), 5.78−5.90 (m,
2H), 6.80 (dd, J = 7.3, 5.4 Hz, 1H), 7.03−7.27 (m, 7H), 7.56 (s, 1H),
t
8.15 (br s, 1H), 8.45 (s, 1H). UPLC-MS (long basic) R 2.65 (606
[M + H]+), 98% pure.
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J. Med. Chem. 2021, 64, 3299−3319