Journal of Medicinal Chemistry
ARTICLE
purified by reverse phase HPLC (yields ranged from 21 to 52%).
Analytical data for 42-47 are provided in the Supporting Information.
3-Amino-N-phenylpyrazine-2-carboxamide (7). To a solu-
tion of 3-aminopyrazine-2-carboxylic acid 55 (100 mg, 0.72 mmol) in
DME (2 mL) were added aniline (67 mg, 66 μL, 0.72 mmol), diethoxy-
phosphorylformonitrile (130 mg, 119 μL, 0.72 mmol), and triethyla-
mine (132 mg, 182 μL, 1.3 mmol). The reaction mixture was stirred at
room temperature for 2 h and then partitioned between water and
CH2Cl2 (3 ꢀ 50 mL). The combined organic layers were dried over
MgSO4 and concentrated to give an oil, which solidified upon standing.
The solid was redissolved in MeCN and then purified by reverse phase
HPLC to give 3-amino-N-phenylpyrazine-2-carboxamide 7 (66 mg,
m/z 440 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H),
9.08 (d, 1H), 8.60 (d, 2H), 8.00 (d, 2H), 7.94 (s, 2H), 7.82 (d, 2H), 7.42
(t, 2H), 7.18 (t, 1H), 4.09 (s, 1H), 3.34 (d, 1H), 2.83 (s, 3H), 2.80 (s, 3H),
2.55 (t, 1H), and 1.29 (d, 3H) ppm. 13C NMR (101.0 MHz, DMSO-d6):
δ 164.73, 155.14, 145.79, 141.06, 138.20, 137.06, 136.69, 129.21, 128.99,
126.41, 124.87, 124.68, 121.64, 58.77, 57.26, 45.59, and 12.40 ppm.
HRMS (ESþ) calcd for C22H26N5O3S (M þ H)þ, 440.1756; found,
440.1741.
3-Amino-N-cyclohexyl-6-(4-(methylsulfonyl)phenyl)pyrazine-
2-carboxamide (48). To a suspension of methyl 3-amino-6-bromo-
pyrazine-2-carboxylate 54 (10 g, 43.1 mmol) in DME (125 mL) at room
temperature were added (4-methylsulfonylphenyl)boronic acid (10.35 g, 51.7
mmol) followed by PdCl2(PPh3)2 (1.51 g, 2.15 mmol) and Na2CO3 (64.6
mLof2 M, 129.3 mmol). The reaction mixture washeated at 90°C for 9 h.
After it was cooled to room temperature, the solid was collected by
filtration, washed with DME, and dissolved into water. The aqueous
solution was acidified to pH 1 with 1 M HCl. The precipitate was collected
by filtration and dried under vacuum to give 3-amino-6-(4-methylsulfo-
nylphenyl)pyrazine-2-carboxylic acid 57 asa yellow solid (11.5 g, 91%). 1H
NMR (400 MHz, DMSO-d6): δ 13.20 (br s, 1H), 9.03 (s, 1H), 8.35 (d,
2H), 8.00 (d, 2H), 7.70 (br s, 2H), and 3.25 (s, 3H) ppm. 13CNMR(101.0
MHz, DMSO-d6): δ 167.95, 155.70, 146.08, 141.08, 140.19, 137.52,
127.82, 126.21, 123.15, 43.95 ppm. MS (ESþ) m/z 294 (M þ H)þ.
To a solution of 3-amino-6-(4-methylsulfonylphenyl)pyrazine-2-car-
boxylic acid 57 (100 mg, 0.34 mmol) in DME (1 mL) were added
cyclohexylamine (51 mg, 59 μL, 0.51 mmol), diethoxy-phosphorylfor-
monitrile (111 mg, 0.68 mmol), and DIPEA (132 mg, 178 μL, 1.02
mmol). The reaction mixture was heated at 100 °C for 10 min under
microwave conditions. The reaction mixture was then filtered and
purified by reverse phase HPLC to give the title product as a yellow
1
44%) as a brown solid. MS (ESþ) m/z 215 (M þ H)þ. H NMR
(400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.29 (d, 1H), 7.93 (d, 1H),
7.85-7.82 (m, 2H), 7.62 (s, 2H), 7.36 (dd, 2H) and 7.12 (dd, 1H) ppm.
13C NMR (100 MHz, DMSO-d6): δ 164.91, 155.82, 147.71, 138.51,
131.31, 128.99, 125.73, 124.26, 120.79 ppm. HRMS (ESþ) calcd for
C11H11N4O (M þ H)þ, 215.0933; found, 215.0943.
3-Amino-6-bromo-N-phenylpyrazine-2-carboxamide (8). To
a solution of 3-amino-6-bromo-pyrazine-2-carboxylic acid 56 (10 g, 46
mmol) in DMSO (100 mL) were added CDI (15 g, 92 mmol), DIPEA
(6.5 g, 8.8 mL, 50 mmol), and DMAP (280 mg, 2.3 mmol). The reaction
mixture was stirred for 30 min, and then, aniline (4.3 g, 4.2 mL, 46 mmol)
was added, and the resulting solution was stirred at room temperature for
18 h. Water was then added, and the product was collected by filtration to
give 3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide 8 (13 g, 92%)
as a brown powder. MS (ESþ) m/z 294 (M þ H)þ. 1H NMR (400 MHz,
DMSO-d6): δ 10.22 (s, 1H), 8.36 (d, 1H), 7.73-7.71 (m, 2H), 7.68 (s,
2H), 7.29 (dd, 2H), and 7.06 (t, 1H) ppm. HRMS (ESþ) calcd for
C11H10BrN4O, 293.0038; found, 293.0049.
1
solid (88 mg, 69%). MS (ESþ) m/z 375 (M þ H)þ. H NMR (400
3-Amino-6-cyclohexyl-N-phenylpyrazine-2-carboxamide
(9). A solution of 3-amino-6-(cyclohex-1-en-1-yl)-N-phenylpyrazine-2-
carboxamide 10 (30 mg) in EtOH (5 mL) was passed though an H-cube
fitted with a Pd/C catalyst cartridge with a flow rate of 0.5 mL/min at
35 °C. The solvent was removed in vacuo, and the resulting pale yellow
solid was purified by reverse phase HPLC to yield 3-amino-6-cyclohexyl-
N-phenylpyrazine-2-carboxamide 9 (11 mg, 36%) as a yellow solid. MS
(ESþ) m/z 297 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6): δ 10.19
(s, 1H), 8.24 (s, 1H), 7.78 (d, 2H), 7.41 (br s, 2H), 7.40-7.36 (m, 2H),
7.14(t, 1H), 2.73-2.65 (m, 1H), 1.88 (d, 2H), 1.82 (d, 2H), 1.72 (d, 1H),
1.59 (td, 2H) and 1.43-1.24 (m, 3H) ppm. HRMS (ESþ) calcd for
C17H21N4O, 297.1715; found, 297.1723.
3-Amino-6-(cyclohex-1-en-1-yl)-N-phenylpyrazine-2-car-
boxamide (10). To a solution of 3-amino-6-bromo-N-phenyl-
pyrazine-2-carboxamide 8 (300 mg, 1 mmol) and 2-(1-cyclohexenyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (330 μL, 1.5 mmol) in DMF
(3 mL) were added Pd(PPh3)4 (118 mg, 0.1 mmol) and a 2 M aqueous
solution of Na2CO3 (1.5 mL, 3 mmol). The resulting solution was stirred
at 90 °C for 3 h. The solution was then allowed to cool, water was added,
and the mixture was extracted with CH2Cl2 (3 ꢀ 10 mL). The combined
organic layers were concentrated, and the residue was purified by reverse
phase HPLC to give 3-amino-6-(1-cyclohexenyl)-N-phenyl-pyrazine-2-
carboxamide 10 (134 mg, 40%) as an orange solid. MS (ESþ) m/z 295
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.50 (d,
1H), 7.78 (d, 2H), 7.50 (s, 2H), 7.41-7.36 (m, 2H), 7.14 (t, 1H), 6.71 (t,
1H), 2.23 (d, 2H), and 1.78-1.62 (m, 6H) ppm. 13C NMR (101.0 MHz,
DMSO): δ 164.95, 154.08, 143.93, 141.08, 138.22, 133.49, 129.04,
126.04, 124.41, 123.06, 120.97, 25.61, 25.06, 22.68, and 22.11 ppm.
HRMS (ESþ) calcd for C17H19N4O (M þ H)þ, 295.1559; found,
295.1558. Purity, 89% (method 2).
MHz, DMSO-d6): δ 8.95 (s, 1H), 8.47 (d, 1H), 8.40 (d, 2H), 7.99 (d,
2H), 3.82 (d, 1H), 3.26 (s, 3H), 1.84-1.74 (m, 4H), 1.64 (d, 1H), 1.50
(dd, 2H), 1.34 (d, 2H), and 1.19 (s, 1H) ppm. 13C NMR (101.0 MHz,
DMSO): δ 165.06, 159.94, 145.06, 141.15, 140.11, 136.59, 127.72,
126.40, 125.25, 48.30, 43.96, 32.44, 25.55, and 25.28 ppm. HRMS (ESþ)
calcd for C18H23N4O3S (M þ H)þ, 375.1491; found, 375.1491.
3-(1H-Benzo[d]imidazol-2-yl)-5-(4-(methylsulfonyl)phenyl)-
pyrazin-2-amine (49). To a solution of 3-amino-6-bromo-pyrazine-2-
carboxylic acid 56 (900 mg, 4.1 mmol) in DME (27 mL) were added
phenylenediamine (491 mg, 4.5 mmol), diethoxyphosphorylformonitrile
(741 mg, 673 μL, 4.5 mmol), and triethylamine (835 mg, 1.2 mL, 8.3
mmol). The reaction mixture was heated in the microwave at 170 °C for
20 min and cooled to room temperature before water was added. The
formed precipitate was collected and washed with a small amount of
ether to give 3-(1H-benzo[d]imidazol-2-yl)-5-bromopyrazin-2-amine 58
(553 mg, 43%) as a yellow solid. MS (ESþ) m/z 291 (M þ H)þ. 1H NMR
(400 MHz, DMSO-d6): δ 13.09 (s, 1H), 8.29 (s, 1H), 7.76 (d, 1H), 7.58
(d, 1H), and 7.33-7.24 (m, 2H) ppm.
To a solution of 3-(1H-benzimidazol-2-yl)-5-bromo-pyrazin-2-amine
58 (100 mg, 0.3 mmol) in DME (1.25 mL) were added (4-methylsulfo-
nylphenyl)boronic acid (69 mg, 0.3 mmol) followed by Pd(PPh3)2Cl2
(12 mg, 0.02 mmol) and a 2 M aqueous solution of sodium carbonate
(517 μL, 1 mmol). The reaction mixture was heated in microwave for 3 h
at 150 °C, cooled to room temperature, diluted with EtOAc (50 mL),
washed with water (50 mL), and extracted with EtOAc (3 ꢀ 50 mL).
The combined organic layers were dried (MgSO4) and concentrated.
The residue was purified by reverse phase HPLC to give 3-(1H-benzo-
[d]imidazol-2-yl)-5-(4-(methylsulfonyl)-phenyl)pyrazin-2-amine 49 as
a yellow solid (53 mg, 48%). MS (ESþ) m/z 366 (M þ H)þ. 1H NMR
(400 MHz, DMSO-d6): δ 13.2 (s, 1H), 8.95 (s, 2H), 8.58 (d, 2H), 8.05
(d, 2H), 7.8 (d, 1H), 7.67 (d, 1H), 7.2-7.38 (m, 2H), 3.4 (s, 3H) ppm.
13C NMR (101.0 MHz, DMSO): δ 153.44, 150.50, 143.31, 142.30,
141.56, 140.03, 137.12, 134.41, 127.71, 126.11, 125.41, 124.21, 122.54,
3-Amino-6-(4-((1-(dimethylamino)propan-2-yl)sulfonyl)-
phenyl)-N-phenylpyrazine-2-carboxamide (45). Prepared from
2-(4-bromophenyl)sulfonyl-N,N-dimethyl-propan-1-amine (see the Sup-
porting Information) according to method C; yellow solid. MS (ESþ)
2327
dx.doi.org/10.1021/jm101488z |J. Med. Chem. 2011, 54, 2320–2330