Journal of Medicinal Chemistry Synthesis of (R/S)-2-Methyl-4,6-diphenyl-3-(2-(piperidin-1-yl)ethyl)- 3,4-dihydroquinazoline (16a). Prepared according to method F from 6-bromo-2-methyl-4-phenyl-3-(2-(piperidin-1-yl)ethyl)-3,4-dihydroqui- nazoline (15c) (41 mg, 0.1 mmol) and phenylboronic acid (18 mg, 0.15 mmol). The crude product was purified by flash column chromatography (0.5 M NH3 (MeOH)/CH2Cl2 0:100 f 10:90) to give a brown solid (26 mg, 63%). 1H NMR (500 MHz, CDCl3): δ 7.48 4.46 (m, 2H, 2 ArH), 7.40 7.30 (m, 7H, 7 ArH), 7.28 7.24 (m, 2H, 2 ArH), 7.18 (d, 1H, J = 8.0 Hz, ArH), 7.03 (d, 1H, J = 2.5 Hz, ArH), 5.65 (s, 1H, H-4), 3.51 (ddd, 1H, J = 15.0, 9.0, 6.0 Hz, CHH), 3.23 (ddd, 1H, J = 15.0, 9.0, 6.0 Hz, CHH), 2.57 (ddd, 1H, J = 12.5, 9.0, 5.5 Hz, CHH), 2.44 2.31 (m, 8H, CHH, 2 CH2, CH3), 1.59 1.54 (m, 4H, 2 CH2), 1.46 1.41 (m, 2H, CH2). LRMS (ES+): m/z (%) 410 (100) [M + H]+. HRMS (ES+): calcd for C28H32N3 [M + H]+ 410.2591, found 410.2599 ( 2.08 ppm). (R/S)-3-(6-Chloro-2-methyl-4,8-diphenylquinazolin-3(4H)-yl)-N,N- dimethylpropan-1-amine (19). Prepared according to general method E from 3-(6-bromo-8-chloro-2-methyl-4-phenylquinazolin-3(4H)-yl)- N,N-dimethylpropan-1-amine (18) (42 mg, 0.1 mmol) and phenyl- boronic acid (12 mg, 0.1 mmol). The crude product was purified by preparative HPLC to give a white solid (17 mg, 41%). 1H NMR (500 MHz, CDCl3): δ 7.64 7.62 (m, 2H, 2 ArH), 7.41 7.37 (m, 2H, 2 ArH), 7.32 7.25 (m, 6H, 6 ArH), 7.16 (d, 1H, J = 2.5 Hz, ArH), 6.79 (dd, 1H, J = 2.5, 0.5 Hz, ArH), 5.48 (s, 1H, CH), 3.46 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 3.11 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 2.33 2.22 (m, 5H, CH2 and CH3), 2.20 (s, 6H, 2 NCH3), 1.82 1.65 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 156.0 (C), 143.9 (C), 138.7 (C), 137.4 (C), 136.9 (C), 130.5 (CH), 129.5 (CH), 129.1 (CH), 128.3 (CH), 127.7 (CH), 127.4 (C), 127.0 (CH), 126.6 (CH), 125.1 (CH), 62.6 (CH), 56.3 (CH2), 46.8 (CH2), 45.4 (CH3), 26.3 (CH2), 22.9 (CH3). [Note: one quaternary carbon resonance is absent, possibly due to it having an identical chemical shift to another quaternary carbon resonance]. LRMS (ES+): m/z (%) 209.5 (42) [35Cl M + 2H]2+, 210.5 (13) [37Cl M + 2H]2+, 418 (100) [35Cl M + H]+, 420 (38) [37Cl M + H]+. HRMS (ES+): calcd for C26H29Cl1N3 [M + H]+ 418.2045, found 418.2034 (2.54 ppm). N-(4-Chloro-2-(4-methylbenzoyl)phenyl)acetamide (27a). p-Tolyl- magnesium bromide (1.0 M in THF, 10 mL, 10 mmol) was slowly added to a solution of benzoxazinone (24) (1.96 g, 10 mmol) in anhydrous THF (40 mL) at 0 C. The reaction mixture was allowed to warm to 25 C over 30 min and stirred for an additional 1.5 h before the reaction was quenched by the addition of NaCl solution (satd aq 50 mL). The resultant biphasic mixture was separated and the aqueous layer extracted with EtOAc (3 50 mL). Subsequently, the combined organic layers were dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography over silica (Et2O/hexanes 0:100 f 50:50) to give a white solid (511 mg, 18%). 1H NMR (500 MHz, CDCl3): δ 10.54 (br s, 1H, NH), 8.57 (d, 1H, J = 9.5 Hz, ArH), 7.63 7.61 (m, 2H, AA0BB0, 2 ArH), 7.51 7.49 (m, 2H, 2 ArH), 7.32 7.30 (m, 2H, AA0BB0, 2 ArH), 2.46 (s, 3H, CH3), 2.21 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ 198.0 (CO), 169.1 (C), 144.1 (C), 138.7 (C), 135.1 (C), 133.6 (CH), 132.4 (CH), 130.2 (CH), 129.3 (CH), 127.2 (C), 125.0 (C), 123.1 (CH), 25.2 (CH3), 21.7 (CH3). LRMS (ES+): m/z (%) 288 (100) [35Cl M + H]+, 290 (31) [37Cl M + H]+. N-(4-Chloro-2-((3-(dimethylamino)propylimino)(p-tolyl)methyl)- phenyl)acetamide (28a). Prepared according to general method B from N-(4-chloro-2-(4-methylbenzoyl)phenyl)acetamide (27a) and 3-(di- methylamino)-1-propylamine. The crude product was purified by flash column chromatography over silica (0.5 M NH3 in MeOH/CHCl3 1:99 f 4:96) to give a white solid (485 mg, 65%). 1H NMR (500 MHz, CDCl3): δ 13.66 (s, 1H, NH), 8.71 (d, 1H, J = 9.0 Hz, H-6), 7.29 7.25 (m, 3H, AA0BB0 and H-5), 6.99 6.97 (m, 2H, AA0BB0), 6.86 (d, 1H, J = 2.5 Hz, H-3), 3.33 (t, 2H, J = 7.0 Hz, CH2), 2.42 (s, 3H, CH3), 2.30 (t, 2H, J = 7.5 Hz, CH2), 2.21 (s, 3H, CH3), 2.19 (s, 6H, 2 CH3), ARTICLE 1.89 1.84 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 171.7 (C), 169.3 (C), 139.1 (C), 138.9 (C), 132.4 (C), 132.2 (CH), 130.6 (CH), 129.6 (CH), 127.1 (CH), 126.6 (C), 124.4 (C), 121.5 (CH), 57.7 (CH2), 51.8 (CH2), 45.6 (CH3), 29.7 (CH2), 25.4 (CH3), 21.4 (CH3). LRMS (ES+): m/z (%) 186.5 (100) [35Cl M + 2H]2+, 187.5 (32) [37Cl M + 2H]2+, 372 (61) [35Cl M + H]+, 374 (18) [37Cl M + H]+. 3-(6-Chloro-2-methyl-4-p-tolylquinazolin-3( 4H)-yl)-N,N-dimethyl- propan-1-amine (29a). Prepared according to general method C2 from N-(4-chloro-2-((3-(dimethylamino)propylimino)(p-tolyl)methyl)phe- nyl)acetamide (28a). The crude product was purified by flash column chromatography over silica (MeOH/CH2Cl2 0:100 f 10:90) to give a clear gum (99 mg, 28%). 1H NMR (500 MHz, CDCl3): δ 7.20 7.17 (m, 2H, AA0BB0,2 ArH), 7.15 7.13 (m, 2H, AA0BB0, 2 ArH), 7.09 (dd, 1H, J = 8.5, 2.5 Hz, H-7), 7.05 (d, 1H, J = 8.5 Hz, H-8), 6.77 (d, 1H. J = 2.5 Hz, H-5), 5.46 (s, 1H, H-4), 3.46 (ddd, 1H, J = 14.5, 8.0, 6.5 Hz, CHH), 3.11 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 2.33 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.29 2.21 (m, 2H, CH2), 2.20 (s, 6H, 2 NCH3), 1.81 1.64 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 156.5 (C), 140.9 (C), 139.8 (C), 138.1 (C), 129.7 (CH), 128.7 (C), 128.2 (CH), 126.6 (CH), 126.5 (C), 126.0 (CH), 125.1 (CH), 62.1 (CH), 56.2 (CH2), 46.8 (CH2), 45.4 (CH3), 26.2 (CH2), 22.4 (CH3), 21.1 (CH3). LRMS (ES+): m/z (%) 178.5 (27) [35Cl M + 2H]2+, 356 (100) [35Cl M + H]+, 358 (31) [37Cl M + H]+. HRMS (ES+): calcd for C21H2735Cl1N3 [M + H]+ 356.1888, found 356.1881 (1.84 ppm). (2-Amino-5-chlorophenyl)(4-tert-butylphenyl)methanone (26b). Prepared according to general method G from 1-bromo-4-(tert-bu- tyl)benzene (3.75 g, 17.6 mmol). The final product was purified by flash column chromatography over silica (EtOAc/hexanes 0:100 f 50:50) to give a yellow solid (679 mg, 59%). 1H NMR (500 MHz, CDCl3): δ 7.61 7.58 (m, 2H, AA0BB0, 2 ArH), 7.50 7.48 (m, 2H, AA0BB0, 2 ArH), 7.47 (d, 1H, J = 2.5 Hz, H-6), 7.24 (dd, 1H, J = 9.0, 2.5 Hz, H-4), 6.69 (d, 1H, J = 9.0 Hz, H-3), 1.37 (s, 9H, 3 CH3). 13C NMR (125 MHz, CDCl3): δ 197.8 (CO), 155.3 (C), 149.2 (C), 136.4 (C), 133.9 (CH), 133.2 (CH), 129.3 (CH), 125.3 (CH), 120.0 (C), 119.2 (C), 118.4 (CH), 35.1 (C), 31.2 (CH3). LRMS (ES+): m/z (%) 288 (100) [35Cl M + H]+, 290 (33) [37Cl M + H]+. 4-(4-tert-Butylphenyl)-6-chloro-2-methyl-3-(2-(piperidin-1-yl)ethyl)- 3,4-dihydroquinazoline (29b). Prepared in three steps from 26b, acetyl chloride, and 1-(2-aminoethyl)piperidine following general methods A, B, and C2. The final product was purified by reverse phase preparative HPLC to give a white solid (40 mg, 6% over 3 steps). 1H NMR (500 MHz, CDCl3): δ 7.33 7.31 (m, 2H, AA0BB0), 7.21 7.19 (m, 2H, AA0BB0), 7.07 (dd, 1H, J = 8.5, 2.0 Hz, H-7), 7.01 (d, 1H, J = 8.5 Hz, H-8), 6.77 (d, 1H, J = 2.0 Hz, H-5), 5.51 (s, 1H, H-4), 3.45 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 3.20 (ddd, 1H, J = 14.5, 8.5, 6.0 Hz, CHH), 2.52 (ddd, 1H, J = 13.0, 8.5, 6.0 Hz, CHH), 2.40 2.31 (m, 5H, CHH and 2 CH2), 2.28 (s, 3H, CH3), 1.58 1.53 (m, 4H, 2 CH2), 1.45 1.40 (m, 2H, CH2), 1.29 (s, 9H, 3 CH3). 13C NMR (125 MHz, CDCl3): δ 156.4 (C), 151.2 (C), 140.9 (C), 139.9 (C), 128.6 (C), 128.2 (CH), 126.5 (C), 126.3 (CH), 126.00 (CH), 125.95 (CH), 125.0 (CH), 62.8 (CH), 57.4 (CH2), 55.1 (CH2), 46.9 (CH2), 34.6 (C), 31.3 (CH3), 26.0 (CH2), 24.2 (CH2), 22.5 (CH3). LRMS (ES+): m/z (%) 424 (100) [35Cl M + H]+, 426 (34) [37Cl M + H]+. HRMS (ES+): calcd for C26H3535Cl1N3 [M + H]+ 424.2514, found 424.2520 ( 1.52 ppm). 6-Chloro-4-(4-chlorophenyl)-2-methyl-3-(2-(piperidin-1-yl)ethyl)- 3,4-dihydroquinazolin-4-ol (31a). Prepared according to general meth- od H using 4-chlorophenylmagnesium bromide (1.0 M solution in Et2O, 8 mL, 8 mmol). The final product was purified by recrystallization from MeCN to give a white solid (339 mg, 41%). 1H NMR (500 MHz, CDCl3): δ 9.48 (br s, 1H, OH), 7.49 7.46 (m, 2H, AA0BB0, 2 ArH), 7.35 7.32 (m, 2H, AA0BB0, 2 ArH), 7.14 (dd, 1H, J = 8.5, 2.5 Hz, H-7), 7.11 (d, 1H, J = 8.5 Hz, H-8), 6.79 (d, 1H, J = 2.5 Hz, H-5), 3.51 3.47 (m, 1H, CHH), 3.10 3.05 (m, 1H, CHH), 2.60 2.55 (m, 1H, CHH), 2.50 2.45 (m, 2H, 2 CHH), 2.35 2.31 (m, 3 CHH 6527 dx.doi.org/10.1021/jm200312v |J. Med. Chem. 2011, 54, 6514–6530