Journal of Medicinal Chemistry
Article
m/z calcd for C16H15N4O [M + H]+ = 279.1240, found 279.1238;
white solid; purity = 99%, tR = 0.59 min, method B.
133.17, 132.33, 130.73, 123.51, 119.73, 113.54, 104.03, 71.87, 22.26;
LCMS (ESI) m/z calcd for C16H15N6O2 [M-H]− = 323.3, found
323.1; beige solid; purity > 99%, tR = 0.70 min, method B.
4-[5-(1-Methyl-1H-pyrazol-4-yl)pyridin-3-yl]benzamide (36). 1H
NMR (400 MHz, DMSO-d6) δ (ppm) 8.86 (S, 1H), 8.77 (s, 1H),
8.38 (s, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 8.02 (d, 2H, J =
8.3 Hz), 7.90 (d, 2H, J = 8.3 Hz), 7.43 (s, 1H), 3.90 (s, 3H); 13C
NMR (101 MHz, DMSO) δ 167.85, 145.98, 145.55, 140.09, 137.08,
136.36, 135.21, 134.22, 130.49, 129.17, 129.12, 128.67, 127.25,
4-[5-(1-Methyl-1H-pyrazol-4-yl)pyridin-3-yl]-2-(propan-2-yloxy)-
benzamide (37). 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.1
Hz, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.36 (s, 1H), 8.26 (t, J = 2.1 Hz,
1H), 8.09 (d, J = 0.9 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.62 (d, J =
9.2 Hz, 2H), 5.05 (p, J = 6.1 Hz, 1H), 3.90 (s, 3H), 1.38 (d, J = 6.0
Hz, 6H); HRMS (ESI) m/z calcd for C19H21N4O2 [M + H]+
=
118.81; HRMS (ESI) m/z calcd for C16H15N4O [M + H]+
=
337.1659, found 337.1656; off-white solid; purity > 99%, tR = 0.72
min, method B.
279.1249, found 279.1238; white solid; purity = 99%, tR = 0.54 min,
method B.
2-(Propan-2-yloxy)-4-[5-(pyrrolidin-1-yl)pyridin-3-yl]benzamide
2-(Cyclohexylmethoxy)-4-[5-(1-methyl-1H-pyrazol-4-yl)pyridin-
3-yl]benzamide (49). 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =
2.1 Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.36 (s, 1H), 8.27 (d, J = 2.2
Hz, 1H), 8.09 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 26.5 Hz,
2H), 7.49−7.41 (m, 2H), 3.90 (s, 3H), 1.93−1.61 (m, 7H), 1.18
(ddd, J = 50.4, 25.4, 12.3 Hz, 6H); LCMS (ESI) m/z calcd for
C23H27N4O2 [M + H]+ = 390.5, found 390.3; pale-yellow oil; purity >
99%, tR = 0.95 min, method B.
7-[5-(1-Methyl-1H-pyrazol-4-yl)pyridin-3-yl]-1,2,3,4-tetrahydroi-
soquinolin-1-one (50, SI Table 1). 1H NMR (400 MHz, DMSO-d6) δ
8.85 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.29
(t, J = 2.1 Hz, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.95 (d, J = 8.7 Hz,
1H), 7.79 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H),
3.43 (td, J = 6.2, 2.5 Hz, 2H), 3.00 (t, J = 6.5 Hz, 2H); LCMS (ESI)
m/z calcd for C18H17N4O [M + H]+ = 305.13, found 305.2; off-white
solid; purity > 99%, tR = 0.59 min, method B.
Alkylation of Aniline: Preparation of Compound 20. To the
solution of intermediate IIIb (0.2 mmol, 42 mg) in dry DMF (3 mL)
was added sodium hydride (57% suspension in mineral oil, 0.4 mmol,
17 mg) at 0 °C, followed by ethyl bromide (0.4 mmol, 44 mg), and
the reaction mixture was brought to 90 °C and stirred for 1 h. After
this time, the heating bath was removed and additional sodium
hydride (0.4 mmol, 17 mg) and ethyl bromide were added (0.4 mmol,
44 mg). The reaction was then continued at 90 °C for an additional 1
h. On completion (LC-mass monitoring), the reaction mixture was
cooled to room temperature, diluted with ethyl acetate (20 mL), and
washed with water (1×) and brine (2×). The organic layer was then
dried over sodium sulfate and evaporated. The crude product was
purified by flash silica gel chromatography eluting with a gradient of
ethyl acetate/hexane to afford 2-(ethylamino)-4-(pyridin-3-yl)-
benzamide (20, 19 mg) as an off-white solid.
1
(39). H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 1.9 Hz, 1H),
7.97 (d, J = 2.7 Hz, 1H), 7.94 (s, 1H), 7.59 (d, J = 10.9 Hz, 2H), 7.38
(d, J = 1.6 Hz, 1H), 7.33 (dd, J = 8.0, 1.6 Hz, 1H), 7.09 (t, J = 2.3 Hz,
1H), 5.00 (p, J = 6.0 Hz, 1H), 3.39−3.34 (m, 4H), 2.02−1.95 (m,
4H), 1.37 (d, J = 6.0 Hz, 6H); 13C NMR (101 MHz, DMSO) δ
166.48, 156.35, 143.97, 142.85, 135.32, 135.19, 134.15, 132.17,
123.07, 119.67, 116.21, 113.47, 71.77, 47.58, 25.37, 22.23; HRMS
(ESI) m/z calcd for C19H24N3O2 [M + H]+ = 326.1863, found
326.1861; pale-yellow oil; purity > 99%, tR = 0.67 min, method B.
4-[5-(Morpholin-4-yl)pyridin-3-yl]-2-(propan-2-yloxy)benzamide
1
(40). H NMR (400 MHz, DMSO-d6) d (ppm) 8.37 (d, 1H, J = 1.8
Hz), 8.34 (d, 1H J = 2.8 Hz), 7.93 (d, 1H, J = 8.0 Hz), 7.61−7.59 (m,
2H), 7.55 (t, 1H, J = 4.6 Hz), 7.42−7.41 (m, 1H), 7.36 (dd, 1H, J =
1.58, 8.08 Hz), 5.05−4.99 (m, 1H), 3.79−3.77 (m, 4H), 3.29−3.26
(m, 4H), 1.37 (d, 6H, J = 6.0 Hz); LCMS (ESI) m/z calcd for
C19H23N3O3 [M + H]+ = 342.2, found 342.2; light-brown solid;
purity = 99%, tR = 0.65 min, method A.
5-[4-Carbamoyl-3-(propan-2-yloxy)phenyl]-N-methylpyridine-3-
1
carboxamide (41). H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J =
2.3 Hz, 1H), 8.99 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 4.7 Hz, 1H), 8.46
(t, J = 2.2 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.63 (s, 2H), 7.53 (d, J =
1.7 Hz, 1H), 7.43 (dd, J = 8.1, 1.6 Hz, 1H), 5.03 (p, J = 6.0 Hz, 1H),
2.85 (d, J = 4.5 Hz, 3H), 1.38 (d, J = 5.9 Hz, 6H); 13C NMR (101
MHz, DMSO) δ 166.44, 165.53, 156.50, 150.46, 148.29, 140.99,
134.74, 133.34, 132.33, 130.48, 123.77, 119.72, 113.61, 71.93, 26.69,
22.24; HRMS (ESI) m/z calcd for C17H20N3O3 [M + H]+
=
314.1499, found 314.1495; off-white solid; purity = 95%, tR = 0.67
min, method B.
4-{5-[1-(Propan-2-yl)-1H-pyrazol-4-yl]pyridin-3-yl}-2-(propan-2-
yloxy)benzamide (42). 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J
= 2.1 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.46 (d, J = 0.8 Hz, 1H), 8.28
(t, J = 2.2 Hz, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H),
7.62 (d, J = 6.0 Hz, 2H), 7.51 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 8.1,
1.6 Hz, 1H), 5.05 (hept, J = 5.9 Hz, 1H), 4.54 (hept, J = 6.6 Hz, 1H),
1.47 (d, J = 6.7 Hz, 6H), 1.38 (d, J = 6.0 Hz, 6H); 13C NMR (101
MHz, DMSO) δ 166.46, 156.45, 146.12, 145.70, 141.74, 136.61,
135.28, 132.22, 130.66, 129.29, 126.05, 123.43, 119.75, 118.29,
113.56, 71.87, 53.76, 23.16, 22.26; HRMS (ESI) m/z calcd for
C21H25N4O2 [M + H]+ = 365.1972, found 365.1971; off-white solid;
purity 95%, tR = 6.67 min, method A.
1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 2.4 Hz, 1H), 8.59
(dd, J = 4.8, 1.6 Hz, 1H), 8.18 (t, J = 5.1 Hz, 1H), 8.09 (dt, J = 7.9,
2.0 Hz, 1H), 7.88 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.48 (dd, J = 7.9,
4.8 Hz, 1H), 7.17 (s, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 8.1,
1.8 Hz, 1H), 3.24 (qd, J = 7.1, 5.0 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H);
LCMS (ESI) m/z calcd for C14H16N3O [M + H]+ = 242.12, found =
242.1; purity %, tR = 0.56 min, method B.
Generation of Tetrazole. To the solution of 3-bromo-5-
cyanopyridine (183 mg, 1 mmol) in DMF (10 mL) were added
ammonium chloride (105 mg, 2 mmol) and sodium azide (130 mg, 2
mmol). The reaction mixture was then stirred at 100 °C for 4 h and
monitored by LC mass. Upon completion, the reaction mixture was
cooled to room temperature and 10 mL of 1M aqueous hydrochloric
acid was added, resulting in precipitation of the desired product. After
stirring of the mixture for an additional 10 min, the precipitate was
collected, washed with water, dried in vacuo, and identified via LC
mass (purity = 92%, tR = 0.36 min, method B) as the desired
intermediate VIII (quantitative yield). No further characterization
was undertaken, and the intermediate was used for the next step
(Suzuki coupling according to the general procedure described
above), leading to the final compound 38.
4-{5-[1-(Oxetan-3-yl)-1H-pyrazol-4-yl]pyridin-3-yl}-2-(propan-2-
1
yloxy)benzamide (43). H NMR (400 MHz, DMSO-d6) δ (ppm)
8.89 (d, 1H, J = 2.1 Hz), 8.78 (d, 1H, J = 2.2 Hz), 8.63 (s, 1H), 8.32
(t, 1H, J = 2.1 Hz), 8.26 (s, 1H), 7.97 (d, 1H, J = 8.1 Hz), 7.62−7.61
(m, 2H), 7.51−7.50 (m, 1H), 7.45 (dd, 1H, J = 1.6, 8.1 Hz), 5.66−
5.59 (m, 1H), 5.08−5.02 (m, 1H), 4.99−4.92 (m, 1H), 1.38 (d, 6H, J
= 6.0 Hz); 13C NMR (400 MHz, DMSO-d6) δ (ppm) 165.4, 155.4,
145.2, 144.9, 140.6, 136.9, 134.2, 131.2, 129.8, 127.8, 126.9, 122.4,
118.7, 118.1, 112.5, 75.9, 70.8, 54.2, 21.2; LCMS (ESI) m/z calcd for
C21H23N4O3 [M + H]+ = 379.4, found 379.2; brown solid; purity
95%, tR = 6.67 min, method A.
4-{5-[1-(Oxolan-3-yl)-1H-pyrazol-4-yl]pyridin-3-yl}-2-(propan-2-
yloxy)benzamide (44). 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J
= 2.1 Hz, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 0.9 Hz, 1H), 8.30
(t, J = 2.2 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H),
7.62 (s, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.1, 1.6 Hz, 1H),
5.13−4.99 (m, 2H), 4.09−4.00 (m, 2H), 4.00−3.93 (m, 1H), 3.85
(td, J = 8.3, 5.4 Hz, 1H), 2.47−2.40 (m, 1H), 2.35 (ddd, J = 8.0, 5.6,
2-(Propan-2-yloxy)-4-[5-(5H-1,2,3,4-tetrazol-5-yl)pyridin-3-yl]-
1
benzamide (38). H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H),
8.86 (s, 1H), 8.38 (t, J = 2.1 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.82
(d, J = 2.3 Hz, 1H), 7.62 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 1.6 Hz, 1H),
7.42 (dd, J = 8.1, 1.6 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 5.05 (hept, J
= 6.0 Hz, 1H), 3.93 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H); 13C NMR (101
MHz, DMSO) δ 166.46, 156.48, 147.49, 147.18, 146.18, 141.61,
O
J. Med. Chem. XXXX, XXX, XXX−XXX