SGI-1027

SGI-1027 is a DNMT inhibitor with IC50 of 6, 8, 7.5 μM for DNMT1, DNMT3A, and DNMT3B in cell-free assays, respectively.

To a solution of 4-(quinolin-4’-ylamino)benzoic acid 17 (45 mg, 0.17 mmol) and NA sealed tube was charged with Pd(OAc)To a solution of 4-(quinolin-4?-ylamino)benzoic acid 17 (45 mg, 0.17 mmol) and N4-(4?-aminophenyl)-2, 4-diamino-6-methylpyrimidine 9 (37 mg, 0.17 mmol) in DMF (1.7 mL) was added N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (0.06 g, 0.34 mmol) and 1-hydroxybenzotriazole hydrate (0.03 g, 0.17 mmol) and the reaction was stirred for 24 h at 65 ºC. When the reaction was complete the solvent was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 85:13:2 CH2Cl2/MeOH/Et3N) to afford 0.05 g (59%) of the titled compound as an amorphous yellow solid.A sealed tube was charged with Pd(OAc)2 (1 mg, 1.32 mmol) and XPhos (2 mg, 3.97 mmol) and degassed t-BuOH/water (1 mL, 2:1 v/v) was added. The resulting solution was heated for 1 min at 80 ºC and then cannulated into another sealed tube charged with 4-amino-N-[4-(2-amino-6-methylpyrimidine-4-ylamino)phenyl]benzamide 12 (0.07g, 0.20 mmol), 4-chloroquinoline 13 (22.0 mg, 0.13 mmol) and potassium carbonate (0.03 g, 0.18 mmol) in DMF (1 mL). The resulting mixture was stirred for 24 h at 110 ºC. When the reaction was complete the solvent was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 85:13:2 CH2Cl2/MeOH/Et3N) to afford 0.045 g (73% by 1H-NMR) of the titled compound as an amorphous yellow solid. 1H-NMR (400.13 MHz, DMSO-d6): d 10.22 (s, 1H, CONH), 9.98 (s, 1H, NH), 8.59 (d, J = 5.6 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 8.00-7.94 (m, 2H), 7.86 - 7.75 (m, 3H), 7.74 - 7.61 (m, 4H), 7.57 - 7.50 (m, 3H), 7.44 - 7.37 (m, 1H), 7.15 (d, J = 5.6 Hz, 1H), 6.04 (s, 1H, H5??), 2.22 (s, 3H, CH3) ppm. 13C-NMR (100.62 MHz, DMSO-d6): d 164.7 (s, CONH), 161.4 (s), 157.1 (s), 154.9 (s), 149.5 (s), 147.8 (d), 145.0 (s), 142.9 (s), 135.4 (s), 134.2 (s), 131.3 (d), 130.2 (s), 129.3 (d, 2x), 125.9 (d, 2x), 123.0 (d, 2x), 121.7 (d), 121.6 (d, 2x), 120.8 (d, 2x), 119.4 (s), 102.5 (d), 96.4 (d), 19.4 (q, CH3) ppm. HRMS (ESI+): Calcd for C27H24N7O ([M + H]+), 462.20368; found, 462.20330. IR (neat): n 3400-3000 (br, N-H), 2976 (w, C-H), 2891 (w, C-H), 1584 (m), 1510 (m), 1444 (m), 1380 (m), 1318 (m), 1228 (w), 1180 (w), 1095 (w) cm-1. UV (DMSO): lmax 258, 355 nm.

Molecular Weight:461.5
XLogP3:4.8
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:6
Exact Mass:461.19640838
Monoisotopic Mass:461.19640838
Topological Polar Surface Area:118
Heavy Atom Count:35
Complexity:676
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes