Journal of Medicinal Chemistry 5.79 (calculated). C = 62.54/62.44; N = 16.35/16.29; H = 5.52/5.61 (experimental). The regiochemistry of the diMe groups was unambiguously assigned using 2-D NMR techniques (Table 8). Article sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/EtOAc Synthesis of 23. 2-Amino-1-(2-(4-ﬂuorophenyl)-8,8-dimethyl-3- (p-tolylamino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)- ethanone: Compound 23 was prepared from compound 10 (R1 = Me, R2 = Me) by a Pd2(dba)3 mediated amination reaction with 4- methylaniline followed by a TFA mediated deprotection in a protocol similar to compound 22. 1H NMR (MeOH-d4, 400 MHz) δ 7.79−7.69 (m, 2H), 7.21 (t, J = 8.4 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.2 Hz, 2H), 4.11 (s, 2H), 3.88 (m, 4H), 2.22 (s, 3H), 2.12 (s, 6H). LC/MS major mass: 408.1 (M + H). Synthesis of 24. 2-Amino-1-(3-((3,4-diﬂuorophenyl)amino)-2-(4- ﬂuorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)- yl)ethanone: Compound 24 was prepared from compound 10 (R1= Me, R2 = Me) by a Pd2(dba)3 mediated amination reaction with 3,4- diﬂuoroaniline followed by a TFA mediated deprotection in a protocol similar to compound 22. 1H NMR (MeOH-d4, 400 MHz) δ 7.73−7.69 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 7.06−7.03 (m, 1H), 6.76−6.65 (m, 1H), 6.53−6.51 (m, 1H), 4.08−4.06 (m, 4H), 3.86−3.83 (m, 2H), 2.07 (s, 6H). Elemental analysis (compound +2.9 HCl): %C, 49.37; %H, 4.69; %N, 13.09; (calc). %C = 49.43/ 49.06; %N = 12.89/12.77; %H = 4.7/4.81 (experimental). m/z = 430.2 (M + 1). Synthesis of 13. tert-Butyl 2-(3-bromo-2-(4-ﬂuorophenyl)-6,6- dimethyl-5,6-dihydroimidazo [1,2-a]pyrazin-7(8H)-yl)-2-oxoethylcar- bamate. 13 was prepared from compound 5a by the following way: To a stirred solution of compound 5a (1.1 g, 3.38 mmol, 1.00 equiv) in DMF (30 mL) was added 3-chloro-2-methylprop-1-ene (500 mg, 5.49 mmol, 1.50 equiv), potassium carbonate (560 mg, 4.06 mmol, 1.10 equiv), and potassium iodide (1.12 g, 6.75 mmol, 2.00 equiv) at rt. The reaction mixture was stirred for 48 h at 40 °C. The reaction mixture was diluted with ethyl acetate (100 mL). The mixture was washed with brine (3 × 10 mL), dried over (5:1) to give 0.7 g (55%) of compound 5a-1 as a light-yellow solid. m/z = 380 (M + 1). Into a 30 mL sealed tube, was placed compound 5a-1 (2.0 g, 5.28 mmol, 1.00 equiv), acetic acid (12 mL), and methanesul- fonic acid (2 mL). The reaction mixture was stirred for 12 h at 260 °C (the temperature of the sand bath). The reaction mixture was cooled to rt. The mixture was poured into 20 mL of water. The aqueous layer was washed with ethyl acetate (3 × 10 mL). Aqueous sodium hydroxide (1N) was added to adjust pH to 8. The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over sodium sulfate, and concentrated under vacuum. The solid was collected by ﬁltration and washed with 5 mL of n-hexane to give 500 mg (39%) of compound 5a-2 as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.70−7.65 (m, 2H), 7.04−6.9 (m, 2H), 6.96 (s, 1H), 4.12 (s, 2H), 3.69 (s, 2H), 1.23 (s, 6H). To a stirred solution of compound 5a-2 (280 mg, 1.14 mmol, 1.0 equiv) in DMF (10 mL) was added 2-(tert-butoxycarbonyl)- acetic acid (600 mg, 3.43 mmol, 3.0 equiv), HATU (1.3 g, 3.42 mmol, 3.0 equiv), and DIEA (880 mg, 6.82 mmol, 6.0 equiv) at rt. The reaction mixture was stirred overnight at rt. The reac- tion mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with brine (3 × 10 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with CH2Cl2/MeOH (10:1) to give 280 mg (57%) of compound 13 as a brown solid. 1H NMR (400 MHz, CDCl3) δ 7.72−7.68 (m, 2H), 7.23 (s, 1H), 7.13−7.07 (m, 2H), 5.46 (s, NH), 4.65 (s, 2H), 4.05−4.04 (m, 2H), 3.97 (s, 2H), 1.55−1.39 (m, 15H). The structure of 13 was veriﬁed by HMQC, COSY, HMBC, and ROESY (Table 9). Synthesis of 25 (Analogue of Compound 14 in Scheme 3). 2-Amino-1-(2-(4-ﬂuorophenyl)-3-(4-ﬂuorophenylamino)-6,6- d i m e t h y l - 5 , 6 - d i h y d r o i m i d a z o [ 1 , 2 - a] p y r a z i n - 7 ( 8 H) - y l ) - ethanone: To a stirred solution of compound 13 (386 g, 0.96 mmol) in 6 mL of dichloromethane was added Br2 (55 μL, 1.06 mmol) in acetic acid (2 mL). The reaction mixture was stirred at rt for 30 min. Solvent was removed via rotavap at a temperature no higher than 20 °C. After neutralization, the residue was subjected to ﬂash chromatography (40 g, 0−100% ethyl acetate in hexane, 50 min, dry loading) puriﬁcation to give 256 mg (55%) of the title compound 13a as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.87−7.83 (m, 2H), 7.03 (t, J = 8.8 Hz, 2H), 5.46 (s, 1H), 4.5 (s, 2H), 3.97 (d, J = 4.2 Hz, 2H), 3.81 (s, 2H), 1.45 (s, 6H), 1.39 (s, 9H). 4259 dx.doi.org/10.1021/jm300041e | J. Med. Chem. 2012, 55, 4244−4273