Journal of Medicinal Chemistry
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were added to a solution of 24a (1 g, 1.2 mmol) in 1,4-dioxane (8 mL).
The resulting mixture was degassed, and then PdCl2(dppf) (0.044 g,
0.06 mmol) was added. The reaction mixture was heated at 110 °C for
16 h in a sealed tube. After cooling to room temperature, the mixture
was filtered through a Celite pad. The filtrate was diluted with water
(25 mL) and extracted with EtOAc (3 × 25 mL). The organic layer was
separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo.
The crude product was purified by flash column chromatography (silica
gel, MeOH in CH2Cl2, 0/100 to 10/90) to yield 13g as an oil (0.21 g,
4.44−4.54 (m, 1H), 6.55 (dd, J = 3.2, 0.5 Hz, 1H), 7.21 (d, J = 3.2 Hz,
1H), 7.38 (d, J = 8.6 Hz, 1H), 7.65 (dd, J = 8.3, 1.2 Hz, 1H), 8.17 (s,
1H). LC−MS: m/z 328 [M + H]+.
7-Chloro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-
1H-indole (13k). Starting from 23b (1.5 g, 4.55 mmol) and following
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general procedure B, compound 13k was obtained (0.95 g, 75%). H
NMR (400 MHz, CDCl3) δ 1.36 (s, 12H), 6.61 (dd, J = 3.1, 2.2 Hz,
1H), 7.23−7.27 (m, 1H), 7.63 (s, 1H), 8.05 (s, 1H), 8.42 (broad s,
1H). LC−MS: m/z 277 [M]−.
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58%). H NMR (500 MHz, CDCl3) δ 0.33−0.38 (m, 2H), 0.58−0.63
4-[5-(4,4,5,5-Tetramethyl[1,2,3]dioxaborolan-2-yl)indol-1-
yl]cyclohexanol (13l). Starting from 26 (1.80 g, 6.11 mmol) and
following general procedure A, compound 13l was obtained as a
(m, 2H), 1.22−1.30 (m, 1H), 1.36 (s, 12H), 3.99 (d, J = 6.6 Hz, 2H),
6.51 (d, J = 3 0.2 Hz, 1H), 7.20 (d, J = 3.2 Hz, 1H), 7.36 (d, J = 8.4 Hz,
1H), 7.65 (dd, J = 8.2, 0.7 Hz, 1H), 8.16 (broad s, 1H). LC−MS: m/z
298 [M + H]+.
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yellow foam (1.35 g, 65%). H NMR (400 MHz, CDCl3) δ 1.36 (s,
12H), 1.48−1.69 (m, 3H), 1.74−1.90 (m, 2H), 2.11−2.21 (m, 4H),
3.78 (tt, J = 10.95, 3.96 Hz, 1H), 4.22−4.31 (m, 1H), 6.52 (d, J =
3.24 Hz, 1H), 7.16 (d, J = 3.24 Hz, 1H), 7.35 (d, J = 8.55 Hz, 1H),
7.64 (dd, J = 8.32, 0.92 Hz, 1H), 8.15 (s, 1H). LC−MS: m/z 341.21
[M + H]+.
[2-Chloro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-
phenyl](tetrahydropyran-4-yl)amine (13b). Starting from com-
pound 17 (3.66 g, 12.6 mmol) and following general procedure B,
compound 13b was obtained as a colorless oil (2.87 g, 67%). 1H NMR
(400 MHz, CDCl3) δ 1.32 (s, 12H), 1.49−1.62 (m, 2H), 1.99−2.09
(m, 2H), 3.49−3.65 (m, 3H), 4.01 (dt, J = 11.8, 3.7 Hz, 2H), 4.48
(broad d, J = 7.9 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 7.55 (dd, J = 8.2,
0.8 Hz, 1H), 7.70 (d, J = 0.7 Hz, 1H). LC−MS: m/z 338 [M + H]+.
4-[2-Chloro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-
phenylamino]cyclohexanol (13c). Starting from 19 (1.66 g, 5.45
mmol) and following general procedure B, compound 13c was
Synthesis of Final Compounds 27a−p. 7-[3-Chloro-4-
(tetrahydropyran-4-yloxy)phenyl]-3-(2,2,2-trifluoroethyl)-
imidazo[1,2-a]pyridine-8-carbonitrile (27a). To a mixture of 6a
(0.20 g, 0.50 mmol) and 13a (0.27 g, 0.81 mmol) in a saturated
aqueous solution of NaHCO3 (2 mL) and 1,4-dioxane (2 mL) was
added Pd(PPh3)4 (0.057 g, 0.051 mmol). The mixture was heated at
150 °C for 10 min under microwave irradiation. The mixture was
cooled to room temperature and filtered through a Celite pad. The
filtrate was diluted with water (10 mL) and extracted with EtOAc (2 ×
10 mL). The organic layer was washed with brine (10 mL), dried over
anhydrous Na2SO4, and the volatiles were evaporated in vacuo. The
residue thus obtained was purified by flash column chromatography
(silica gel, EtOAc in CH2Cl2, 0/100 to 20/80) to give 27a as a white
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obtained as a white solid (1 g, 52%). H NMR (400 MHz, CDCl3) δ
1.23−1.38 (m, 14H), 1.39−1.52 (m, 3H), 1.96−2.20 (m, 4H), 3.29−
3.41 (m, 1H), 3.66−3.76 (m, 1H), 4.36−4.43 (m, 1H), 6.62 (d, J = 8.1
Hz, 1H), 7.55 (dd, J = 8.1, 1.4 Hz, 1H), 7.68 (d, J = 1.4 Hz, 1H). LC−
MS: m/z 352 [M + H]+.
4-[2-Chloro-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-
phenyl]morpholine (13d). Starting from commercially available 20
(1.99 g, 7.196 mmol) and following general procedure A, compound
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solid (0.080 g, 38%). Mp 232.9 °C. H NMR (500 MHz, CDCl3) δ
1.87−1.95 (m, 2H), 2.04−2.12 (m, 2H), 3.65 (ddd, J = 11.4, 7.4, 3.8
Hz, 2H), 3.80 (q, J = 10.0 Hz, 2H), 4.04 (ddd, J = 11.5, 7.4, 3.6 Hz,
2H), 4.68 (tt, J = 7.1, 3.5 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 7.10 (d,
J = 8.7 Hz, 1H), 7.64 (dd, J = 8.4, 2.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H),
7.80 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H). LC−MS: m/z 425 [M + H]+.
7-[3-Chloro-4-(tetrahydropyran-4-ylamino)phenyl]-3-(2,2,2-
trifluoroethyl)-8-cyanoimidazo[1,2-a]pyridine (27b). To a mix-
ture of 6a (0.25 g, 0.67 mmol) and 13b (0.273 g, 0.81 mmol) in a
saturated aqueous solution of NaHCO3 (2 mL) and 1,4-dioxane
(2 mL) was added Pd(PPh3)4 (0.078 g, 0.067 mmol). The mixture was
heated at 150 °C for 10 min under microwave irradiation. The mixture
was cooled to room temperature and filtered through a Celite pad.
The filtrate was diluted with water (10 mL) and extracted with EtOAc
(2 × 10 mL). The organic layer was washed with brine (10 mL), dried
over anhydrous Na2SO4, and the volatiles were evaporated in vacuo.
The residue thus obtained was purified by flash column chromatog-
raphy (silica gel, MeOH−NH3 in CH2Cl2, 0/100 to 10/90) to give
1
13d was obtained as a white solid (1.34 g, 58%). Mp 130.4 °C. H
NMR (400 MHz, CDCl3) δ 1.33 (s, 12 H), 3.07−3.13 (m, 4 H),
3.85−3.91 (m, 4 H), 7.01 (d, J = 7.9 Hz, 1 H), 7.65 (dd, J = 8.0, 1.5
Hz, 1 H), 7.80 (d, J = 1.4 Hz, 1 H). LC−MS: m/z 324 [M + H]+
7-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-3,4-dihy-
dro-2H-benzo[1,4]oxazine (13e). Starting from commercially
available 21 (0.6 g, 2.8 mmol) and following general procedure B,
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compound 13e was obtain as a solid (0.55 g, 75%). H NMR (500
MHz, CDCl3) δ 1.31 (s, 12 H), 3.41−3.47 (m, 2 H), 3.95 (broad s,
1 H), 4.17−4.26 (m, 2 H), 6.56 (d, J = 8.1 Hz, 1 H), 7.19−7.25 (m,
2 H). LC−MS: m/z 262 [M + H]+.
8-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-2,3-dihy-
dro-5H-benzo[f ][1,4]oxazepine-4-carboxylic Acid tert-Butyl
Ester (13f). Starting from commercially available 22 (0.492 g, 1.5
mmol) and following general procedure A, compound 13e was
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obtained (0.396 g, 70%). H NMR (500 MHz, CDCl3) δ ppm 1.34
(broad s, 12H), 1.40 (s, 9H), 3.79 (broad s, 2H), 3.97−4.07 (m, 2H),
4.42 (broad s, 1.4H), 4.49 (br s, 0.6H), 7.19 (d, J = 6.9 Hz, 0.7H), 7.32
(d, J = 6.6 Hz, 0.3H), 7.43−7.50 (m, 2H).
7-Chloro-1-methyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-
2-yl)-1H-indole (13). Starting from 24b (0.35 g, 1.41 mmol) and
following general procedure B, compound 13h was obtained (0.13 g,
33%) as a white solid. Mp 169.4 °C. GC−MS (EI/CI): m/z 291 [M]+.
1H NMR (500 MHz, CDCl3) δ 1.36 (s, 12 H), 4.14 (s, 3 H), 6.47 (d,
1
27b as a white solid (0.068 g, 23%). Mp 230.7 °C. H NMR (500
MHz, DMSO-d6) δ 1.61 (qd, J = 11.8, 4.3 Hz, 2H), 1.84−1.92 (m,
2H), 3.45 (td, J = 11.6, 1.7 Hz, 2H), 3.65−3.75 (m, 1H), 3.86−3.93
(m, 2H), 4.30 (q, J = 10.9 Hz, 2H), 5.49 (d, J = 8.4 Hz, 1H), 7.04 (d,
J = 9.0 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.60 (dd, J = 8.7, 2.3 Hz,
1H), 7.73 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 7.2 Hz, 1H).
LC−MS: m/z 435 [M + H]+.
7-(3-Chloro-4-morpholin-4-ylphenyl)-3-(2,2,2-trifluoroethyl)-
imidazo[1,2-a]pyridine-8-carbonitrile (27c). To a stirred sus-
pension of 13d (0.15 g, 0.38 mmol) and 6b (0.12 g, 0.39 mmol) in a
saturated aqueous solution of NaHCO3 (0.5 mL) and 1,4-dioxane
(2 mL) was added Pd(PPh3)4 (0.022 g, 0.02 mmol). The mixture was
heated at 150 °C for 10 min under microwave irradiation. The mix-
ture was cooled to room temperature and filtered through a Celite pad.
The filtrate was diluted with water (20 mL) and extracted with EtOAc
(2 × 15 mL). The organic layer was washed with brine (15 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The residue thus ob-
tained was purified by flash column chromatography (silica gel, EtOAc in
CH2Cl2, 0/100 to 30/70) to give 27c as a solid (0.10 g, 60%). 1H NMR
(500 MHz, CDCl3) δ 3.14−3.19 (m, 4H), 3.80 (q, J = 10.0 Hz, 2H),
3.89−3.94 (m, 4H), 7.07 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H),
J = 3.2 Hz, 1 H), 6.97 (d, J = 2.9 Hz, 1 H), 7.56 (s, 1 H), 7.98 (s, 1 H).
LC−MS: m/z 292 [M + H]+.
7-Chloro-1-cyclopropylmethyl-5-(4,4,5,5-tetramethyl[1,3,2]-
dioxaborolan-2-yl)-1H-indole (13i). Starting from 24c (0.71 g, 2.48
mmol) and following general procedure A, compound 13i was
obtained (0.36 g, 44%). 1H NMR (500 MHz, CDCl3) δ 0.29−0.42 (m,
2H), 0.49−0.63 (m, 2H), 1.34−1.38 (m, 1H), 1.36 (s, 12H), 4.41 (d,
J = 6.6 Hz, 2H), 6.52 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H),
7.58 (s, 1H), 8.01 (s, 1H). GC−MS (EI/CI): m/z 331 [M]+.
1-(Tetrahydropyran-4-yl)-5-(4,4,5,5-tetramethyl[1,3,2]-
dioxaborolan-2-yl)-1H-indole (13j). Starting from 24d1 (0.38 g,
1.4 mmol) and following general procedure A, compound 13j was
obtained (0.31 g, 70%). 1H NMR (400 MHz, CDCl3) δ 1.26 (s, 12H),
1.99−2.18 (m, 4H), 3.58−3.67 (m, 2H), 4.12−4.19 (m, 2H),
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dx.doi.org/10.1021/jm201561r | J. Med. Chem. 2012, 55, 2688−2701