Journal of Medicinal Chemistry Compound 28 was prepared from compound 8 (R1 = R2 = Me) in the following fashion using a slightly modiﬁed route to the one described in Scheme 2. To a stirred solution of compound 8 (1.48 g, 6.04 mmol) and NEt3 (6.0 g, 59.4 mmol) in dichloromethane (20 mL) was added 2-bromo- 2-methylpropanoyl bromide (14 g, 60.9 mmol) dropwise at rt. After being stirred for 3 h at rt, the reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with 3 × 30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in crude product as a dark solid, which was washed with EtOAc:petroleum ether (1:10) to remove the impurities to produce compound 8-1 as a gray solid. m/z 396 (M + H). To a solution of compound 8-1 (2.0 g, 5.08 mmol, 1.00 equiv) in DMF (10 mL) was NaN3 (1.0 g, 15.38 mmol, 3.00 equiv) at rt. The reaction mixture was stirred overnight at rt. The resulting solution was diluted with 300 mL of ethyl acetate. The resulting mixture was washed with 3 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/EtOAc (5:1) to give compound 8-2 as a white solid. m/z 357 (M + H). To a stirred solution of compound 8-2 (1.2 g, 3.37 mmol, 1.00 equiv) in methanol (20 mL) was added Pd/C (80 mg, 0.75 mmol, 0.20 equiv) at rt. The reaction mixture was evacuated and backﬁlled with H2. The reaction mixture was stirred overnight at rt. The solids were ﬁltered out. The resulting mixture was concentrated under vacuum. The solid was washed with petroleum ether. This resulted in compound 8-3 as a white solid. m/z 331 (M + H). To a stirred solution of compound 8-3 (910 mg, 2.76 mmol, 1.00 equiv) in THF (50 mL) was added BOC anhydride (3.2 g, 14.68 mmol, 5.00 equiv), followed by aqueous NaOH (1N, 6 mL, 2.0 equiv) at rt. The resulting solution was stirred for 24 h at 40 °C. The resulting solution was concentrated under vacuum. The mixture was diluted with EtOAc (60 mL). The organic layer was washed with 3 × 10 mL of brine, dried over Na2SO4, and concentrated under vacuum. The solid was collected by ﬁltration and washed with n-hexane (5 mL) to give compound 8-4 as a white solid. 1H NMR (300 MHz, CDCl3) δ Article 7.75−7.71 (m, 2H), 7.09−7.02 (m, 3H), 4.84(s, NH), 4.09−4.0 (m, 4H), 1.98 (s, 6H), 1.55 (s, 6H), 1.45 (s, 9H). To a stirred solution of compound 8-4 (32 mg, 0.074 mmol) in dichloromethane (3 mL) was added Br2 (4.2 μL, 0.082 mmol) in acetic acid (1 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 chro- matography (4 g, 0−60% ethyl acetate in hexane, 16 min) puriﬁcation to give the compound 8-5 as colorless oil, was collected by ﬁltration, and washed with n-hexane (5 mL) to give compound 8-4 as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.91−7.88 (m, 2H), 7.10−7.04 (m, 2H), 5.11(s, NH), 4.01 (m, 2H), 3.96 (s, 2H), 1.94 (s, 6H), 1.51 (s, 6H), 1.41 (s, 9H). Compound 28 was prepared from compound 8-5 by a Pd2(dba)3 mediated amination reaction with 4-ﬂuoroaniline followed by a TFA mediated deprotection. 1H NMR (400 MHz, MeOH-d4) δ 7.66 (dd, J = 9.2, 5.2 Hz, 2H), 7.11 (t, J = 8.8 Hz, 2H), 6.81 (t, J = 8.8 Hz, 2H), 6.72−6.68 (m, 2H), 4.04−3.99 (m, 4H), 2.01 (s, 6H), 1.66 (s, 6H). m/z = 440.1 (M + 1). Synthesis of 29. 2-Amino-1-(2-(4-ﬂuorophenyl)-8,8-dimethyl-3- (p-tolylamino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methyl- propan-1-one: Compound 29 was prepared from 35 by the following way: To a stirred solution of 35 (21 mg, 0.06 mmol) and Et3N (83 μL, 0.60 mmol) in dry dichloromethane (6 mL) was added 2-bromo-2- methylpropanoyl bromide (71 μL, 0.60 mmol). The reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated and subjected to mass-triggered LC/MS puriﬁcation directly. The obtained solution was concentrated to give 22 mg (73%) of compound 35-1 as yellow oil after neutralization. 1H NMR (400 MHz, MeOH-d4) δ 7.71−7.66 (m, 2H), 7.23−7.19 (m, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.31 (m, 2H), 4.09 (m, 2H), 2.21 (s, 3H), 2.06 (s, 6H), 2.00 (s, 6H). To a solution of compound 35-1 (22 mg, 0.044 mmol) in DMF (3 mL) was added NaN3 (8.6 mg, 0.132 mmol) at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was directly subjected to mass-triggered HPLC puriﬁcation directly. The obtained MeCN/aqueous solution was combined and concentrated to give 15 mg (75%) of compound 35-2 as yellow oil after neutralization. 1H NMR (400 MHz, MeOH-d4) δ 7.70 −7.66 (m, 2H), 7.23−7.19 (m, 2H), 7.04 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.26 (m, 2H), 4.07−4.05 (m, 2H), 2.24 (s, 3H), 2.03 (s, 6H), 1.58 (s, 6H). To a solution of compound 35-2 (15 mg, 0.033 mmol) in MeOH (3 mL) was added 10% Pd/C (4 mg, 0.003 mmol) at rt. Air was removed, and H2 was ﬁlled. The reaction mixture was stirred at rt for 2 h. Solid was ﬁltered oﬀ, and solvent was removed. The reaction mix- ture was directly subjected to mass-triggered HPLC puriﬁcation to give 15 mg (100%) of the title compound yellow oil. 1H NMR (MeOH-d4, 400 Hz) δ 7.78−7.75 (m, 2H), 7.06−6.97 (m, 4H), 6.56 (d, J = 8.4 Hz, 2H), 5.16 (s, NH), 4.33 (t, J = 4.8 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 2.29 (s, 3H), 1.95 (s, 6H), 1.45 (s, 6H). m/z = 436.2 (M + 1). Synthesis of 30. 2-Amino-1-(3-(3,4-diﬂuorophenylamino)-2- (4-ﬂuorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl)-2-methylpropan-1-one: Compound 30 was prepared from compound 8-5 by a Pd2(dba)3 mediated amination reaction with 3,4-diﬂuoroaniline followed by a TFA mediated deprotection.1H NMR (400 MHz, MeOH-d4) δ 7.63− 7.60 (m, 2H), 7.14 (t, J = 8.4 Hz, 2H), 7.01 (dd, J = 18.8, 8.8 Hz, 1H), 6.68−6.63 (m, 1H), 6.5 (m, 1H), 4.03 (m, 2H), 4.01 (m, 2H), 2.01 (s, 6H), 1.66 (s, 6H). m/z = 458.1 (M + 1). Synthesis of 31. 2-(4-Fluorophenyl)-N-(p-tolyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-amine: The details of the synthesis involving an Ugi reaction between 4- ﬂuorobenzaledehyde, 2-aminopyrazine, and 1-isocyano-4-methylben- zene has been reported in the previous communication.5 1H NMR (400 MHz, MeOH-d4) δ 7.73 (d, J = 6.8 Hz, 2H), 7.00−6.99 (m, 4H), 6.49 (d, J = 8.0 Hz, 2H), 4.01 (s, 2H), 3.72 (m, 2H), 3.15 (m, 2H), 2.19 (s, 3H). m/z = 324.2 (M + 1). Synthesis of 32. 2-(4-Fluorophenyl)-3-(p-tolylamino)-7,8- dihydroimidazo[1,2-a]pyrazin-6(5H)-one: 4271 dx.doi.org/10.1021/jm300041e | J. Med. Chem. 2012, 55, 4244−4273