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Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds as notch inhibitors

A technology of benzodiazepines and compounds, applied in the field of pharmaceutical compositions, capable of solving problems such as tumor formation

Inactive Publication Date: 2015-08-05
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Aberrant activation of the Notch pathway leads to tumor formation

Method used

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  • Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds as notch inhibitors
  • Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds as notch inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0499] (2R,3S)-3-((3,3-difluorocyclobutyl)methyl)-N-((3S)-9-methyl-2-oxo-5-phenyl-2,3- Dihydro-1H-1,4-benzodiazepine -3-yl)-2-(3,3,3-trifluoropropyl)succinamide

[0500]

[0501] Example 1A: (2S,3R)-2-((3,3-difluorocyclobutyl)methyl)-6,6,6-trifluoro-3-(((S)-9-methyl- 2-Oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine -3-yl)carbamoyl)hexanoic acid tert-butyl ester

[0502]

[0503] To a solution of Intermediate B-1,2 hydrobromide (308 mg, 0.721 mmol), Intermediate S-1 (225 mg, 0.601 mmol) and TBTU (289 mg, 0.902 mmol) in DMF (4 mL) was added TEA ( 0.335 mL, 2.404 mmol). The mixture was stirred at room temperature for 50 min. Add NaHCO 3 dilution while stirring. The resulting solid was collected by filtration, rinsed with water, dried, and purified by silica gel chromatography (12g column, EtOAc / Hexane = 0-70%) to give Example 1A (327 mg, 99% yield). HPLC: RT=3.400min (H 2 O / MeOH with TFA, SpeedROD, 4.6x50mm, gradient=4min, wavelength=220nm) MS(ES): m / z=622[...

Embodiment 2

[0507] (2R,3S)-3-(4,4-difluorocyclohexyl)-N-((3S)-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H -1,4-Benzodiazepine -3-yl)-2-(3,3,3-trifluoropropyl)succinamide

[0508]

[0509] Example 2 was prepared from Intermediate B-2 and Intermediate S-3 according to the general procedure shown in Example 1. Example 2 was obtained. HPLC: RT=10.27min (H 2 O / CH 3 CN, containing TFA, SunFire C18 3.5μm, 4.6x150mm, gradient=15min, wavelength=220and 254nm); MS(ES):m / z=595[M+H + ]; 1 H NMR (400MHz, methanol-d 4 )δ10.08(s,1H),9.48(d,J=7.5Hz,1H),7.60-7.42(m,5H),7.38-7.19(m,2H),6.96(br.s.,1H), 6.92-6.83(m,1H),5.27(d,J=7.5Hz,1H),3.94(s,2H),3.05-2.89(m,1H),2.57(d,J=5.1Hz,1H),2.31 -2.19 (m, 1H), 2.10-1.90 (m, 3H), 1.87-1.75 (m, 1H), 1.73-1.41 (m, 5H), 1.37-1.22 (m, 1H).

Embodiment 3

[0511] (2R,3S)-N-((3S)-9-(cyclopropyloxy)-5-(3-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4 - Benzodiazepines -3-yl)-3-(4,4-difluorocyclohexyl)-2-(3,3,3-trifluoropropyl)succinamide

[0512]

[0513]Example 3 was prepared according to the general procedure shown in Example 1 from Intermediate B-6 and Intermediate S-3. The solid was chromatographed by preparative SFC (Welk O(RR) 250x 30mm ID, 5 μm, 84 / 16CO 2 / MeOH, 120mL / min) to obtain Example 3. HPLC: RT=10.95min (H 2 O / CH 3 CN with TFA, SunFire C18 3.5μm, 4.6x150mm, gradient = 15min, wavelength = 220 and 254nm); MS (ES): m / z = 639 [M+H + ]; 1 H NMR (400MHz, methanol-d 4 )δ10.05(s,1H),9.47(d,J=7.3Hz,1H),7.60(dd,J=8.3,1.2Hz,1H),7.55-7.45(m,2H),7.44-7.24(m ,4H),6.94(dd,J=7.9,1.1Hz,2H),5.27(d,J=7.3Hz,1H),4.03(tt,J=5.9,2.9Hz,1H),3.05-2.91(m, 1H),2.32-2.17(m,1H),2.00(d,J=12.1Hz,4H),1.77-1.41(m,8H),1.38-1.20(m,2H),0.99-0.92(m,1H) ,0.90-0.81(m,2H),0.80-0.67(m,1H).

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Abstract

Disclosed are compounds of Formula (I): (Formula (I)) wherein: R1 is -CH2CH2CF3; R2 is -CH2CH2CH2F, -CH2CF2CH3, -CH2CH2CF3, -CH2CH(CH3)CF3, -CH2CH2CF2CH3, (Formulae (II), (III), (IV), (V) or (VI): R3 is H or -CH3; Ring A is phenyl or pyridinyl; and Rx, Ry, Ra, Rb, y, and z are defined herein. Also disclosed are methods of using such compounds to inhibit the Notch receptor, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as cancer.

Description

technical field [0001] The present invention generally relates to benzodiazepines useful as Notch inhibitors Ketone compounds. The present invention further relates to pharmaceutical compositions comprising at least one compound of the present invention, suitable for the treatment of disorders associated with the Notch pathway, such as cancer and other proliferative diseases. Background technique [0002] Notch signaling is involved in multiple cellular processes such as cell fate specification, differentiation, proliferation, apoptosis and angiogenesis. (Bray, Nature Reviews Molecular Cell Biology, 7:678-689 (2006); Fortini, Developmental Cell 16:633-647 (2009)). Notch proteins are single heterodimeric transmembrane molecules. The Notch family includes 4 receptors, Notch 1 to 4, which are activated upon binding to ligands of the DSL family (Delta-like 1, 3, 4 and Jagged 1 and 2). [0003] The activation and maturation of Notch requires a series of processing steps, inc...

Claims

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Application Information

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IPC IPC(8): C07D243/18A61K31/55C07D243/26
CPCA61K31/337C07D243/18A61K31/5513A61K31/138A61K31/506A61K31/555C07D243/26A61K2300/00C07D243/24A61P35/00A61K45/06
Inventor 赵玉芬A·V·加瓦伊P·吉尔S-H·金B·E·芬克L·陈M·G·索尔尼尔W-C·韩
Owner BRISTOL MYERS SQUIBB CO