LY3039478

Uses

LY 3039478 is used in the preparation of medicaments for combination antitumor therapy with Notch and PD-1 or PD-Li inhibitors.

Biological Activity

ly3039478 is a novel and potent notch inhibitor with ic50 of 0.41 nm.the novel and unique notch inhibitor, ly3039478, has progressed into clinical development by lilly co. ltd. ly3039478 displays the best overall profile and is unique within the sar investigated. ly3039478 displays interesting atropisomer phenomena. the average ly3039478 major/minor rotational isomer ratio ranged between 14 and 28 in plasma. the crystalline monohydrate form of ly3039478 consists of a single rotational isomer and is chemically and physically stable for at least 14 days under accelerated stability test conditions.

Synthesis

1421438-84-7

1421438-88-1

1421438-81-4

At 0 °C, (2S)-2-(4,4,4-trifluorobutanoylamino)propanoic acid (28.9 g, 135.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.7 g, 155.1 mmol) were sequentially added to (7S)-7-amino-5-(2-hydroxyethyl)-7H-pyrido[2,3-d][3] A suspension of benzo-acridoheptan-6-one (34.8 g, 129.2 mmol) in dichloromethane (696 mL) was stirred for 5 minutes. Subsequently, 1-hydroxybenzotriazole monohydrate (24.7 g, 155.1 mmol) was added and after continued stirring for 1 h, the reaction mixture was warmed to room temperature. Then (2S)-2-(4,4,4-trifluorobutanoylamino)propanoic acid (0.6 g, 2.6 mmol) was added and stirred at room temperature for 15 minutes. After completion of the reaction, water (600 mL) was added and the white solid was collected by filtration and the filtrate layer was separated. The organic layer was washed with water (3 x 200 mL), dried over sodium sulfate and concentrated to give a light brown foam. The foam was made into a slurry in 50% methyl tert-butyl ether/hexane (500 mL), filtered to collect the solid, and dried under high vacuum to give 65 g of solid. The resulting solid (65.0 g, 140.0 mmol) was dissolved in methanol (195 mL), water (195 mL) and potassium bicarbonate (14.0 g, 140.0 mmol) were added, and stirred at 10 °C for 29 hours. The reaction mixture was concentrated and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water (3 x 20 mL), dried over sodium sulfate and concentrated. The residue was purified by fast chromatography using methanol:dichloromethane (98:2,7N aqueous ammonia solution) as eluent. The purified product was ground successively with 50% methyl tert-butyl ether/hexane and methyl tert-butyl ether (500 mL). Finally, the solid was washed with methyl tert-butyl ether (200 mL) and hexane (200 mL) and dried under high vacuum to afford 4,4,4-trifluoro-N-((S)-1-(((S)-5-(2-hydroxyethyl)-6-oxo-6,7-dihydro-5H-benzo[d]pyrido[2,3-b]azepin-7-yl)amino)-1-oxopropan-2-yl)butyramide , as an off-white solid (42.0 g, 90.4 mmol, 65% yield). Mass spectrum (m/z): 270 (M+1); [α]Na25 = -153.40° (c = 5.0, methanol).

in vivo

References

warren j. porter. discovery of a novel notch inhibitor. the 8th sci-rsc symposium on proteinase inhibitor design april 15-16, 2013, basel, switzerland.