C6-aryl and heteroaryl substituted pyrido[2,3-D] pyrimidin-7-ones

(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-acetic acid

[0309] To LiHMDS (21.03 mL, 126.4 mmol, 1.0 M, in THF) diluted in THF (75 mL) cooled to −78° C. was added diethyl succinate neat, this mixture was stirred for 10 min. To this mixture was added 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10 g, 42.14 mmol) dissolved in THF (50 mL). The reaction was stirred for an additional 30 min., then warmed to room temperature. After 16 hours the reaction mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was washed with ethyl acetate twice. A precipitate formed as the aqueous layer was acidified to pH 2 with conc. HCl. The precipitate was filtered off, then washed with hexanes to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-acetic acid as a white solid (8.48 g, 63%). 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.62 (s,1H), 5.92-6.03 (m, 1H), 4.66 (s, 2H), 2.61

(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-acetic acid N′-acetyl-hydrazide

[0310] To a solution of (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-acetic acid (1.0 g, 3.13 mmol) in THF (15 mL) was added 1,1′-carbonyl diimidazole (609 mg, 3.76 mmol, 1.2 eq) and the solution was stirred at room temperature for 2 h. Acetic hydrazide (283 mg, 3.44 mmol, 1.1 eq) was added and after 1 h a precipitate formed. The mixture was stirred overnight at room temperature. The reaction mixture was filtered and the solid was washed with THF / Et2O and dried in a vacuum oven to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-acetic acid N′-acetyl-hydrazide as a white solid (847 mg, 2.26 mmol, 72%). The structure was confirmed by NMR and mass spectrometry. MS: APCl: M+1: 376.0 (Exact Mass: 375.14). 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.80 (s, 1H), 8.81 (s, 1H), 7.82 (s, 1H), 5.78-5.83 (m, 1H), 3.37

Preparation of 8-Cyclopentyl-6-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0311] A suspension of (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-acetic acid N′-acetyl-hydrazide (300 mg, 0.799 mmol) in POCl3 (8 mL) was heated to 95° C. After 2 h, the reaction became homogeneous. The reaction mixture was heated for one more hour and then concentrated. The residue was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with H2O and brine, dried over Na2SO4 and concentrated to give a yellow oil. Purification by chromatography (2% MeOH / ethyl acetate) gave 8-cyclopentyl-6-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (200 mg, 0.56 mmol, 70%). The structure was confirmed by NMR and mass spectrometry. MS: APCl: M+1: 358.0 (Exact Mass: 357.13).