Journal of Medicinal Chemistry
Article
solid. LC/MS (high-pH method): retention time 0.79 min, [M + H]+ =
479.26. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 11.39−11.64 (br s,
1H), 9.05 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.21 (t, J = 2.1 Hz,
2H), 7.78 (s, 1H) 7.65 (s, 1H), 7.53 (s, 1H), 6.89−6.96 (m, 1H), 4.15−
4.29 (m, 1H), 3.88−3.98 (m, 2H), 2.91−3.08 (m, 2H), 2.09 (s, 3H),
1.97−2.05 (m, 2H), 1.43 (br s, 11H). Step 2: A solution of tert-butyl 4-
((5-(5-carbamoylpyridin-3-yl)-3-methyl-2-oxo-1,2-dihydro-1,7-naph-
thyridin-8-yl)amino)piperidine-1-carboxylate (61.2 mg, 0.128 mmol) in
1,4-dioxane (2 mL) at room temperature was treated with a 4 N HCl
solution in 1,4-dioxane (1 mL, 4 mmol), and the resulting mixture was
stirred at this temperature for 3 h and then concentrated in vacuo.
Purification of the residue by MDAP (high-pH method) gave 62 (23
mg, 47%). LC/MS (high-pH method): retention time 0.45 min, [M +
H]+ = 379. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.05 (d, J = 2.0
Hz, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.21 (t, J = 2.0 Hz, 2H), 7.76 (s, 1H),
7.64 (br s, 1H), 7.52 (d, J = 1.3 Hz, 1H), 6.92 (d, J = 7.1 Hz, 1H), 4.09
(dd, J = 10.5, 3.9 Hz, 1H), 3.01 (d, J = 12.1 Hz, 2H), 2.53−2.65 (m, 2H),
2.09 (d, J = 1.0 Hz, 3H), 1.97 (d, J = 11.1 Hz, 2H), 1.31−1.46 (m, 2H).
Two NH groups were not seen.
piperidine-1-carboxylate (114 mg, 0.197 mmol) in 1,4-dioxane (4 mL)
at room temperature was treated with K2CO3 (40.8 mg, 0.295 mmol),
cataCXium A (7.06 mg, 0.020 mmol), Pd(OAc)2 (4.42 mg, 0.020
mmol), and 3-bromo-4,5-dimethylpyridine (73.3 mg, 0.394 mmol), and
the resulting mixture was stirred at 100 °C under microwave irradiation
for 40 min, then cooled to room temperature, and concentrated in
vacuo. Purification of the residue by flash chromatography on silica gel
(25 g column, gradient 0−4% (2 N NH3 in MeOH) in CH2Cl2 (20
CVs)) followed by purification by MDAP (high-pH method) gave tert-
butyl- 4-((2(benzyloxy)-5-(4,5-dimethylpyridin-3-yl)-3-methyl-1,7-
naphthyridin-8-yl)amino)piperidine-1-carboxylate as a pale yellow
solid (16 mg, 14%). LC/MS (high-pH method): retention time 1.53
min, [M + H]+ = 554. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.43 (s,
1H), 8.29 (s, 1H), 7.74 (s, 1H), 7.51 (d, J = 7.3 Hz, 2H), 7.39−7.45 (m,
2H), 7.36 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 1.0 Hz, 1H), 6.29−6.38 (m,
1H), 5.53 (s, 2H), 4.25−4.38 (m, 1H), 4.03−4.19 (m, 2H), 3.09 (br s,
2H), 2.38 (s, 3H), 2.32 (d, J = 0.7 Hz, 3H), 2.17 (br s, 2H), 2.05 (s, 3H),
1.45−1.57 (m, 11H). Step 5: tert-Butyl 4-((2-(benzyloxy)-5-(4,5-
dimethylpyridin-3-yl)-3-methyl-1,7-naphthyridin-8-yl)amino)-
piperidine-1-carboxylate (16 mg, 0.029 mmol) was dissolved in
CF3CO2H (5 mL, 64.9 mmol), and the solution was refluxed for 2 h,
then cooled to room temperature, and concentrated in vacuo. The
residue was dissolved in MeOH (5 mL) and loaded onto a 2 g SCX
cartridge. This was washed with MeOH (10 mL) and then eluted with a
2 N NH3 solution in MeOH (10 mL). The ammoniac fractions were
concentrated in vacuo to give 63 (12 mg, 85%) as a pale yellow solid.
LC/MS (high-pH method): retention time 0.66 min, [M + H]+ = 364.
1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.38 (s, 1H), 8.16 (s, 1H),
5-(4,5-Dimethylpyridin-3-yl)-3-methyl-8-(piperidin-4-ylami-
no)-1,7-naphthyridin-2(1H)-one (63). Step 1: To make tert-butyl 4-
((2-(benzyloxy)-3-methyl-1,7-naphthyridin-8-yl)amino)piperidine-1-
carboxylate, tert-butyl 4-aminopiperidine-1-carboxylate (3.35 g, 16.7
mmol) was added to a mixture of 20 (3.17 g, 11.1 mmol), Pd2(dba)3
(0.816 g, 0.891 mmol), BrettPhos (0.598 g, 1.11 mmol), and sodium
tert-butoxide (4.28 g, 44.6 mmol) in THF (50 mL) at room temperature,
and the resulting mixture was stirred at 60 °C for 4 h, then cooled to
room temperature, and concentrated in vacuo. The residue was
dissolved in CH2Cl2 (100 mL), and the organic phase was washed
with water (100 mL), dried using a hydrophobic frit, and concentrated
in vacuo. Purification of the residue by flash chromatography on silica gel
(2 × 100 g columns, gradient 0−60% EtOAc in cyclohexane) gave tert-
butyl 4-((2-(benzyloxy)-3-methyl-1,7-naphthyridin-8-yl)amino)-
piperidine-1-carboxylate (7.99 g, 96%) as an orange solid. LC/MS
7.59 (s, 1H), 7.06 (d, J = 1.2 Hz, 1H), 6.85 (d, J = 6.8 Hz, 1H), 4.02−4.14
(m, 1H), 3.03 (m, 2H), 2.57−2.66 (m, 2H), 2.31 (s, 3H), 2.04 (d, J = 1.0
Hz, 3H), 1.95−2.01 (m, 5H), 1.36−1.45 (m, 2H). Two NH groups were
not seen.
5-(5-Aminopyridin-3-yl)-3-methyl-8-(piperidin-4-ylamino)-
1,7-naphthyridin-2(1H)-one (64). Compound 64 was prepared from
(5-aminopyridin-3-yl)boronic acid (63.1 mg, 0.457 mmol) and 44 (100
mg, 0.229 mmol) analogously to compound 55 (pale yellow solid, 39
mg, 49% over two steps). LC/MS (formate method): retention time
0.48 min, [M + H]+ = 351. 1H NMR (400 MHz, DMSO-d6): δ (ppm)
7.96 (d, J = 2.7 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.66 (s, 1H), 7.54 (d, J
= 1.2 Hz, 1H), 6.89 (t, J = 2.2 Hz, 1H), 6.81 (d, J = 6.8 Hz, 1H), 5.42 (s,
2H), 3.98−4.15 (m, 1H), 3.17 (s, 1H), 2.98 (d, J = 12.2 Hz, 2H), 2.54−
2.61 (m, 2H), 2.08 (d, J = 1.2 Hz, 3H), 1.91−1.97 (m, 2H), 1.29−1.43
(m, 2H). One NH was not seen.
1
(high-pH method): retention time 0.99 min, [M + H]+ = 449.17. H
NMR (400 MHz, DMSO-d6): δ (ppm) 7.89 (d, J = 0.98 Hz, 1H), 7.79
(d, J = 5.6 Hz, 1H), 7.54 (d, J = 7.3 Hz, 2H), 7.36−7.42 (m, 2H), 7.32
(m, 1H), 6.78 (d, J = 5.6 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 5.59 (s, 2H),
4.15−4.27 (m, 1H), 4.00 (m, 2H), 2.81−3.03 (m, 2H), 2.32 (d, J = 0.7
Hz, 3H), 1.94 (dd, J = 12.6, 2.8 Hz, 2H), 1.52 (m, 2H), 1.43 (s, 9H). Step
2: To make tert-butyl 4-((2-(benzyloxy)-5-bromo-3-methyl-1,7-naph-
thyridin-8-yl)amino)piperidine-1-carboxylate, a solution of tert-butyl 4-
((2-(benzyloxy)-3-methyl-1,7-naphthyridin-8-yl)amino)piperidine-1-
carboxylate (7.99 g, 17.81 mmol) in CHCl3 (200 mL) at room
temperature was treated with NBS (3.49 g, 19.59 mmol), and the
resulting mixture was stirred for 18 h at this temperature. The mixture
was then diluted with water (100 mL), and the layers were separated.
The organic phase was dried using a hydrophobic frit and concentrated
in vacuo. Purification of the residue by flash chromatography on silica gel
(2 × 100 g columns, gradient 0−50% EtOAc in cyclohexane) gave tert-
butyl 4-((2-(benzyloxy)-5-bromo-3-methyl-1,7-naphthyridin-8-yl)-
amino)piperidine-1-carboxylate (8.17 g, 87%) as an orange solid. LC/
MS (high-pH method): retention time 1.67 min, [M + H]+ = 527.2 (1
Br). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.01 (s, 1H), 7.96 (d, J = 1.0
Hz, 1H), 7.51−7.46 (m, 2H), 7.44−7.31 (m, 3H), 6.19 (d, J = 8.1 Hz,
1H), 5.51 (s, 2H), 4.27−4.14 (m, 1H), 4.14−3.98 (m, 2H), 3.05 (m,
2H), 2.45 (d, J = 1.0 Hz, 3H), 2.18−2.08 (m, 2H), 1.54−1.45 (m, 11H).
Step 3: To make 45, a flask was charged with tert-butyl 4-((2-
(benzyloxy)-5-bromo-3-methyl-1,7-naphthyridin-8-yl)amino)-
piperidine-1-carboxylate (104 mg, 0.197 mmol), K2CO3 (40.8 mg, 0.295
mmol), bis(pinacolato)diboron (150 mg, 0.591 mmol), cataCXium A
(7.1 mg, 0.020 mmol), and Pd(OAc)2 (4.4 mg, 0.020 mmol) and then
filled with 1,4-dioxane (4 mL), the resulting mixture was stirred at 100
°C under microwave irradiation for 40 min and then cooled to room
temperature, and the crude solution was taken on to the next step. LC/
MS (high-pH method): retention time 1.71 min, [M + H]+ = 575. Step
4: To make tert-butyl 4-((2-(benzyloxy)-5-(4,5-dimethylpyridin-3-yl)-
3-methyl-1,7-naphthyridin-8-yl)amino)piperidine-1-carboxylate, a sol-
ution of tert-butyl 4-((2-(benzyloxy)-3-methyl-5-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,7-naphthyridin-8-yl)amino)-
N-(5-(3-Methyl-2-oxo-8-(piperidin-4-ylamino)-1,2-dihydro-
1,7-naphthyridin-5-yl)pyridin-3-yl)methanesulfonamide (65).
Compound 65 was prepared from N-(5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (136 mg, 0.457
mmol) and 44 (100 mg, 0.229 mmol) analogously to compound 55
(pale yellow solid, 8.3 mg, 8% over two steps). LC/MS (formate
1
method): retention time 0.41 min, [M + H]+ = 429. H NMR (400
MHz, DMSO-d6): δ (ppm) 8.28 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 1.5 Hz,
1H), 7.74 (s, 1H), 7.61 (d, J = 1.3 Hz, 1H), 7.43 (s, 1H), 6.88 (d, J = 6.6
Hz, 1H), 4.07−4.21 (m, 1H), 3.11 (d, J = 12.4 Hz, 2H), 2.94 (s, 3H),
2.69−2.80 (m, 2H), 2.08 (s, 3H), 1.95−2.08 (m, 2H), 1.45−1.50 (m,
2H). Three NH groups were not seen.
(5-(3-Methyl-2-oxo-8-(piperidin-4-ylamino)-1,2-dihydro-1,7-
naphthyridin-5-yl)pyridin-3-yl)methyl carbamate (66). Step 1:
To make tert-butyl 4-((5-(5-(hydroxymethyl)pyridin-3-yl)-3-methyl-2-
oxo-1,2-dihydro-1,7-naphthyridin-8-yl)amino)piperidine-1-carboxylate,
six 20 mL microwave vials were charged with K2CO3 (630 mg, 4.57
mmol), diacetoxypalladium (25 mg, 0.114 mmol), (5-(hydroxymethyl)-
pyridin-3-yl)boronic acid (350 mg, 2.287 mmol), 44 (500 mg, 1.143
mmol), and cataCXium A (41.0 mg, 0.114 mmol) and then filled with
1,4-dioxane (12 mL) and water (6 mL). The resulting mixtures were
stirred at 100 °C for 1 h under microwave irradiation and then cooled to
room temperature. The reaction mixtures were combined and
concentrated in vacuo. The residue was partitioned between CH2Cl2
(100 mL) and water (100 mL), and the layers were separated. The
organic layer was dried over MgSO4 and concentrated in vacuo.
Purification of the residue by flash chromatography on silica gel
V
J. Med. Chem. XXXX, XXX, XXX−XXX