Hz, 1H) 3

Hz, 1H) 3.78 (s, 3H), 2.89 (m, 2H), 2.70 (s, 3H), 2.51 (d, = 1.48 Hz, 6H), 2.35 (m, 2H), 2.24 (s, 6H); LC/MS (ESI) 587.20 RU.521 (RU320521) [M+H]+; HRMS (ESI) calcd for C27H36FN8O4S [M+H]+ 587.2559; found 587.2551. 4.1.1.7 N-(5-((5-Chloro-4-((2-(N,N-dimethylsulfamoyl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (7k) The procedure that used to synthesize 7c was applied to prepare 7k from compounds 1-3 and 2-3. the dimethylphosphine oxide analogs showed superior microsomal stability and lower CYP enzyme inhibition than the corresponding isopropylsulfone analogs and the dimethylsulfonamide analogs which displayed 30 C 60 %60 % inhibition of CYP 3A4 and approximately 20 % inhibition of other CYP enzymes. Our lead compound 7c was not stable in liver microsomes of all species whereas corresponding dimethylphosphine oxide analog 7g displayed good microsomal stability. This result was not surprising because the dimethylphosphine oxide analogs showed lower clog values than the isopropylsulfone analogs and dimethylsulfonamide analogs. Table 3 Metabolic Stability in Liver Microsome and Cytochrome P450 Enzyme Inhibition of Compound 7a-l. using ChemDraw Professional version 16.0.0.82. 7c displayed affordable mouse pharmacokinetic properties with a moderate Lung Tissue Availability of Compound 7c. (%)= 3.30), chloroform (= 7.24) or dimethyl sulfoxide (= 2.50) for 1H NMR and 13C NMR. Data are reported as (= broad, = singlet, = doublet, = triplet, = quartet, = multiplet). 4.1.1 Representative procedure for the synthesis of compounds 7a C 7d and 7i RU.521 (RU320521) C 7l 2,5-Dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (3c) To a solution of 2-(isopropylsulfonyl)aniline (3.0 g, 15.1 mmol) in DMF (80 mL) was added sodium hydride (1.2 g, 30.1 mmol, 60 %60 % in mineral oil) at 0 C. After stirring for 30 min, 2,4,5-trichloropyrimidine was added to the reaction mixture followed by warming the mixture to room temperature. After stirring for 2 h, the reaction mixture was quenched with ice and diluted with excess water. The precipitate was filtered and the solid was dried by blowing nitrogen gas to obtain 3c as an off-white solid (3.75 g, 72 %). 1H NMR (500 MHz, DMSO-= 7.9, 1.5 Hz, 1H), 7.88 C 7.84 (m, 1H), 7.48 (td, = 7.6, 1.2 Hz, 1H), 3.58 C 3.48 (m, 1H), 1.16 (d, = 6.7, 6H); LC/MS (ESI) 346.18 [M+H]+. 5-Chloro-N2-(4-fluoro-2-methoxy-5-nitrophenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (4c) To a suspension of 2,5-dichloro-= 8.2 Hz, 1H), 8.44 (d, = 7.3 Hz, 1H), 8.33 (s, 1H), 7.82 (dd, = 7.9, 1.5 Hz, 1H), 7.62 C 7.55 (m, 1H), 7.37 C 7.31 (m, 2H), 3.95 (s, 3H), 3.50 C 3.40 (m, 1H), 1.16 (d, Pfdn1 = 6.7, 6H); LC/MS (ESI) 496.36 [M+H]+. 5-Chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (5c) To a solution of 5-chloro-= 7.9, 1.5 Hz, 1H), 7.60 C 7.51 (m, 1H), 7.34 C 7.29 (m, 1H), 6.84 (s, 1H), 3.90 (s, 3H), 3.49 C 3.40 (m, 1H), 3.40 C 3.24 (m, 2H), 2.88 (br, 2H), 2.83 (s, 1H), 2.47 (br, 6H), 1.16 (d, = 6.7, 6H); LC/MS (ESI) 578.59 [M+H]+. N4-(5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine (6c) To a suspension of RU.521 (RU320521) 5-chloro-= 8.6 Hz, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 7.80 (dd, = 7.9, 1.5 Hz, 1H), 7.69 C 7.63 (m, 1H), 7.33 C 7.27 (m, 1H), 7.08 (bs, 1H), 6.81 (s, 1H), 3.70 (s, 3H), 3.49 C 3.39 (m, 1H), 3.27 (br t, = 6.0 Hz, 2H), 3.19 (br t, = 5.8 Hz, 2H), RU.521 (RU320521) 2.80 (s, 6H), 2.55 (s, 3H), 1.17 (d, = 6.7 Hz, 6H); LC/MS (ESI) 548.58 [M+H]+. N-(5-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (7c) To a solution of = 7.9, 1.5 Hz, 1H), 7.47 (t, = 7.0 Hz, 1H), 7.23 (t, = 7.5 Hz, 1H), 7.00 (s, 1H), 6.48 C 6.30 (m, 1H), 6.15 (dd, = 16.8, 1.8 Hz, 1H), 5.72 (dd, = 10.2, 1.8 Hz, 1H), 3.76 (s, 3H), 3.47 C 3.38 (m, 1H), 2.90 (br s, 2H), 2.71 (s, 3H), 2.36 (br s, 2H), 2.24 (br s, 6H), 1.16 (d, = 6.7 Hz, 6H); 13C NMR (125 MHz, DMSO-602.69 [M+H]+; HRMS (ESI) calcd for C28H37ClN7O4S [M+H]+ 602.2311; found 602.2304. 4.1.1.1 N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propionamide (7c-R) 7c-R was synthesized using the analog method that used to synthesize 7c. To a solution of = 7.9 Hz, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.78 (d, = 7.9 Hz, 1H), 7.52 (br s, 1H), 7.26 (t, = 7.5 Hz, 1H), 6.96 (s, 1H), 3.76 (s, 3H), 3.47.