Substituted5-(3,5-dimethylisoxazol-4-yl)indoline-2-ones

A C2-C8, C6-C14 technology, applied in the field of substituted 5-(3,5-dimethylisoxazol-4-yl)indoline-2-one derivatives

Active Publication Date: 2015-11-25
BEIGENE BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The persistence of HIV-1 viral latency is a great challenge to eradicate its infection

Method used

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  • Substituted5-(3,5-dimethylisoxazol-4-yl)indoline-2-ones
  • Substituted5-(3,5-dimethylisoxazol-4-yl)indoline-2-ones
  • Substituted5-(3,5-dimethylisoxazol-4-yl)indoline-2-ones

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Embodiment 1: synthetic compound 1.1 to 1.34

[0186] Compound 1.1

[0187]

[0188] Step 1: 5'-Bromospiro[[1,3]dioxolane-2,3'-indoline]-2'-one

[0189]

[0190] Using a Dean-Stark apparatus, 5-bromoindoline-2,3-dione (226g, 1.0mol, 1eq.), ethylene glycol (186g, 3.0mol, 3eq.), p-toluenesulfonic acid (30g , 0.16mol, 16mol%) and toluene (1500mL) magnetic stirring solution was refluxed overnight. After complete consumption of 5-bromoindoline-2,3-dione, EtOAc (1500 mL) and water (1000 mL) were added to remove excess diol. The aqueous layer was extracted twice with EtOAc (500 mL). The organic layer was collected and washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting pale yellow solid was washed with diethyl ether to obtain the desired compound as a pale yellow solid (236 g, 87%). 1 HNMR (400MHz, DMSO-d 6 ):δ H 10.56(s,1H),7.31-7.33(m,2H),6.93(d,J=8.0Hz,1H),4.27-4.35(m,4H),2.35(s,3H),2.18(s,3H) .MS(ESI)m / e[M+1]+ 270,272. ...

Embodiment 2

[0229] Embodiment 2: synthetic compound 2.1-2.58

[0230] Compound 2.1

[0231]

[0232] 5-(3,5-Dimethylisoxazol-4-yl)-3-(2-hydroxyethylamino)-3-phenylindolin-2-one

[0233] 34 mg (0.1 mmol) of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one and 86 mg (10 mmol) of 2-aminoethanol Dissolved in THF (5 mL), the reaction solution was stirred at room temperature for 16 h. Next, dilute the solution with water. CH for aqueous phase 2 Cl 2 (2 x 10 mL) extraction. Combined organic phases with NaHCO 3 Washed with aqueous solution and water, dried and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (elution system: EtOAc / MeOH=50 / 1) to give the product (20 mg, 55%) as a white solid. 1 HNMR (400MHz, DMSO-d 6 ):δ10.67(s,1H),7.44(d,J=8.0Hz,1H),7.18-7.34(m,5H),7.18(s,1H),6.99(d,J=8.0Hz,1H) ,4.51(t,J=5.6Hz,1H),3.40-3.42(m,2H),2.96-2.99(m,1H),2.40-2.42(m,1H),2.35(s,3H),2.27-2.29 (m,1H),2.17(s,3H).MS(ESI)m / e[M+1] + 364.

[0234...

Embodiment 3

[0321] Embodiment 3: synthetic compound 3.1 to 3.10

[0322] Compound 3.1

[0323]

[0324] 5-(3,5-Dimethylisoxazol-4-yl)-3-phenylindolin-2-one

[0325] To 5-(3,5-dimethylisoxazol-4-yl)-3-(2-hydroxyethylamino)-3-phenylindolin-2-one (32g, 0.1mmol) in di To a solution in methyl chloride (500 mL), trifluoroacetic acid (20 g) and triethylsilane (20 g) were added. The brown solution was stirred at ambient temperature for 3 hours, and concentrated to dryness in vacuo. The residue was diluted with dichloromethane (500 mL), washed with saturated ammonium chloride solution (200 mL) and brine (3 x 400 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried in vacuo. The residue was recrystallized from ether to give the title compound. 1 HNMR (400MHz, DMSO-d 6 ):δ H 10.63(s,1H),7.18-7.36(m,6H),6.99-7.04(m,2H),4.82(s,1H),2.32(s,3H),2.15(s,3H).MS(ESI) m / e[M+1] + 305.

[0326] Compound 3.2

[0327]

[0328] 5-(3,5-Dimethylisoxaz...

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Abstract

Disclosed are substituted5-(3,5-dimethylisoxazol-4-yl)indoline-2-one compounds, pharmaceutical compositions comprising at least one such4substituted5-(3,5-dimethylisoxazol- 4-yl)indoline-2-one compound processes for the preparation thereof,and the use thereof for inhibiting BET family of bromodomains and for treating disorders mediated thereby,such as certain cancers.

Description

technical field [0001] The present application relates to methods and compounds for inhibiting BRD4 and treating diseases associated with undesired BRD4 activity. Background technique [0002] The ε-N-acetylation of lysine residues is one of the most frequently occurring protein post-translational modifications (Choudhary et al., 2009) and is widely related to cell signaling and disease biology. Lysine acetylation of histones widely exists in macromolecular complexes involved in chromatin remodeling, DNA damage repair and cell cycle regulation (Choudhary et al., 2009). Targeting chromatin-modifying enzymes [also known as "writing" proteins (histone acetyltransferases, HATs) and "wiping" proteins (histone deacetylases, HDACs)] that control cellular acetylation levels The field has been well-studied, whereas regulation of "reader" proteins (bromodomains) that recognize acetylation sites has not been reported until recently (Nicodeme et al 2010, Filippakopoulose et al 2010). ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D209/04A61K31/41A61P35/00
CPCC07D413/04C07D413/14
Inventor 任博周昌友王鹤翔
Owner BEIGENE BEIJING CO LTD
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