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Heterocyclic compounds as BCL-2 inhibitors

A technology of compounds and solvates, applied in the preparation of said compounds, for the treatment or prevention of related diseases and dysfunctions mediated by BCL-2, in the field of B-cell lymphoma-2 (BCL-2) inhibitors, capable of Solve problems such as susceptibility to infection

Pending Publication Date: 2022-02-18
BEIJING INNOCARE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Venetoclax (ABT-199), jointly developed by AbbVie and Roche, is a highly selective BCL-2 inhibitor (Andrew, J.; Joel, D. et al. Nature Medicine, 2013, 19(2), 202), in the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), multiple myeloma (MM), etc. Both the objective response rate (ORR) and complete response rate (CR) have been greatly improved (Valentin, R.; Grablow, S. et al. Blood, 2018, 132(12), 1248), but there are still side effects such as leukopenia and thrombocytopenia, anemia, diarrhea, dizziness, fatigue, and susceptibility to infection. Serious side effects include pneumonia, anemia, high fever, etc.

Method used

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  • Heterocyclic compounds as BCL-2 inhibitors
  • Heterocyclic compounds as BCL-2 inhibitors
  • Heterocyclic compounds as BCL-2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0224] ( R )-2-((1 H -pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro -[1,1'-biphenyl]-2-yl)methyl)-3-methylpiperazin-1-yl)- N -((3-fluoro-5-nitro-4-(((tetrahydro-2 H -pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

[0225]

[0226] first step

[0227] ( R )-2-((1 H -pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(3-methylpiperazin-1-yl)methyl benzoate

[0228] Compound 2-((1 H-Methyl pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-fluorobenzoate (synthetic reference: Journal of Organic Chemistry, 84(8), 4814-4829; 2019) (2.86 g , 10.00 mmol), ( R )-2-methylpiperazine (3.00 g, 30.00 mmol), N , N - Diisopropylethylamine (3.12 g, 24.18 mmol) and dimethyl sulfoxide (20 mL) were mixed. Stir at 60°C for 16 hours. The mixture was diluted with 50 mL of water and extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 3). Dry the organic phase with anhydrous sodium sulfate, filter to remove the desiccan...

Embodiment 8

[0246] ( R )-2-((1 H -pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro -[1,1'-biphenyl]-2-yl)methyl)-2-methylpiperazin-1-yl)- N -((3-nitro-4-(((tetrahydro-2 H -pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

[0247]

[0248] first step

[0249] ( R )-4-(3-((1 H -Pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-cyanophenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0250]Compound 2-((1 H -pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-fluorobenzonitrile (synthesis reference: WO2017212431) (0.51 g, 2.00 mmol) and ( R )-3-Methylpiperazine-1-carboxylic acid tert-butyl ester (1.20 g, 6.00 mmol) was dissolved in dimethyl sulfoxide (15 mL), dipotassium hydrogen phosphate (1.05 g, 6.00 mmol) was added at room temperature, 110 o C was stirred for 36 hours. Cool to room temperature, dilute the reaction solution with water, extract with ethyl acetate (30 mL × 2), combine the organic phases and wash with saturated brine (30 mL × 2), dry and concentrate t...

Embodiment 31

[0283] ( R )-2-((1 H -pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(4-((6-(4-chlorophenyl)-8,8-dimethylspiro[2.5]octyl- 5-en-5-yl)methyl)-3-methylpiperazin-1-yl)- N -((3-nitro-4-(((tetrahydro-2 H -pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

[0284]

[0285] first step

[0286] ( R )-2-((1 H -pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(4-((6-(4-chlorophenyl)-8,8-dimethylspiro[2.5]octyl- 5-en-5-yl)methyl)-3-methylpiperazin-1-yl)methyl benzoate

[0287] 5-(Chloromethyl)-6-(4-chlorophenyl)-8,8-dimethylspiro[2.5]oct-5-ene (Intermediate 8) (0.17 g, 0.58 mmol), ( R )-2-((1 H -pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(3-methylpiperazin-1-yl)methyl benzoate and N , N - Diisopropylethylamine (0.37 g, 2.90 mmol) was dissolved in acetonitrile (15 mL) and heated to reflux for 3 hours. After cooling, concentrate under reduced pressure, dissolve the residue in ethyl acetate (30 mL), wash with water (30 mL × 3) and saturated brine (30 mL), respectively, dry the organic phase over anhydrous sodium ...

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Abstract

The present invention relates to compounds, pharmaceutical compositions containing the same, processes for their preparation, and their use as BCL-2 inhibitors. The compound is a compound as shown in formula (I), or an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof. The invention also relates to application of the compound in treating or preventing related diseases mediated by BCL-2, such as tumors, and a method for treating the diseases by using the compound.

Description

technical field [0001] The present invention relates to compounds, pharmaceutical compositions containing them and their use as B-cell lymphoma-2 (BCL-2) inhibitors. More specifically, the present invention provides novel compounds as BCL-2 inhibitors, pharmaceutical compositions containing such compounds and the use of said compounds for treating or preventing related diseases and dysfunctions mediated by BCL-2, The relevant diseases are, for example, tumors. The invention also relates to processes for the preparation of said compounds. Background technique [0002] The BCL-2 protein family is one of the core regulatory mechanisms of apoptosis (also called programmed cell death), which can receive and transmit internal intracellular signals or external environmental stress signals, such as nutritional or hypoxic stress, DNA damage, carcinogenesis Gene overactivation, endoplasmic reticulum stress, etc., mainly play a leading role in the intrinsic apoptotic pathway (Intrins...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00A61P35/02A61K31/635
CPCC07D471/04A61P35/00A61P35/02A61K31/496A61K31/437
Inventor 孔祥龙周超郑之祥
Owner BEIJING INNOCARE PHARMA TECH CO LTD
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