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Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer

A technology of compounds and medicinal salts, applied in the field of cinnoline compounds and HPK1-dependent diseases such as cancer, which can solve problems such as damage to healthy cells, drug resistance, and easy mutation of tumor cells

Pending Publication Date: 2021-09-28
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, for many tumors or many types of cancer, surgical removal is not a viable option
Also, radiation and chemotherapy drugs don't just target diseased cells, so they end up damaging healthy cells
Tumor-specific expression of antigens or inappropriate overexpression or activation of specific proteins within tumor cells are being exploited to develop more specific tumor cell-targeting therapies, but tumor cells are prone to mutations and may be critical for specifically targeting tumor cells. Drug resistance in cells

Method used

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  • Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer
  • Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer
  • Cinnoline compounds and for the treatment of hpk1-dependent disorders such as cancer

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Experimental program
Comparison scheme
Effect test

example

[0385] abbreviation

[0386]

[0387]

[0388] All samples were pre-purified by an achiral system and checked for purity prior to chiral purification by SFC.

[0389] General analysis method

[0390] LCMS method

[0391] Method A: Agilent 1100HPLC coupled with Agilent MSD mass spectrometer was used in the experiment. The system used ESI as the ion source, Agilent SunFire-C18 chromatographic column (3.5μm, 4.6×50mm), and the flow rate was 2.0mL / min. The solvent system was a gradient starting with 95% of 0.05% TFA in water (solvent A) and 5% of 0.05% TFA in acetonitrile (solvent B) to 100% solvent B in 1.3 minutes. The final solvent system was held constant for 1.2 minutes.

[0392] Method B: Agilent 1200HPLC coupled with Agilent MSD mass spectrometer was used in the experiment. The system used ESI as the ion source, Agilent SunFire-C18 chromatographic column (3.5μm, 4.6×50mm), and the flow rate was 2.0mL / min. The solvent system was a gradient starting with 95% 0.01% T...

example I-1

[0403] Intermediate 1: 6-Bromo-8-chlorocinnolin-3-amine

[0404]

[0405] Step 1: (4-Bromo-2-chlorophenyl)hydrazine

[0406]

[0407] To a mixture of 4-bromo-2-chloroaniline (5 g, 24 mmol) in concentrated hydrochloric acid (9 mL) was added NaNO dropwise at 0 °C 2 (1.8g, 26mmol) in water (8mL). The mixture was stirred at 0 °C for 1 h. Add SnCl to the reaction mixture 2 (9g, 48mmol) in concentrated hydrochloric acid (16mL). The mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0 °C and 40% NaOH solution was added to adjust the mixture to pH=8. The mixture was extracted with EtOAc (500 mL x 2). The organic layer was washed with brine (200 mL), washed with Na 2 SO 4 Dry, filter and concentrate. Diethyl ether (100 mL) and 5 drops of methanol were added. The resulting slurry was filtered to give the desired (4-bromo-2-chloro-phenyl)hydrazine (4.8 g, 49% yield) as a yellow solid. LCMS(ESI)[M+H] + = 221.1.

[0408] Step 2: N'...

example 1

[0415] (1S,2S)-N-(8-amino-6-(1-ethyl-1H-pyrazol-4-yl)cinnolin-3-yl)-2-fluorocyclopropanecarboxamide (compound 1a)

[0416]

[0417] Step 1: 8-Chloro-6-(1-ethyl-1H-pyrazol-4-yl)cinnolin-3-amine

[0418]

[0419] 1-Ethyl-1H-pyrazole-4-boronic acid (86mg, 0.39mmol), Pd(dppf)Cl 2 (28mg, 0.04mmol) and K 2 CO 3 (160 mg, 1.2 mmol) was added successively to a solution of 6-bromo-8-chloro-cinnolin-3-amine (200 mg, 0.39 mmol) in 1,4-dioxane (15 mL) and water (2 mL). The reaction mixture was stirred overnight at 100°C, then filtered. Partition the filtrate in H 2 O (10mL) and CH 2 Cl 2 (2×10mL). The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate. The residue was purified by reverse phase (C-18) column chromatography (A: containing 10 mM NH 4 HCO 3 , B: ACN) to give 8-chloro-6-(1-ethylpyrazol-4-yl)cinnolin-3-amine (50 mg, 47% yield) as a yellow solid. LCMS(ESI)[M+H] + = 365.1.

[0420] Step 2: (1S,2S)-N-(8-Chloro-6-(1-ethyl-1H-pyrazol-4...

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Abstract

Cinnoline compounds of formula (I), variations thereof, and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the cinnoline compounds.

Description

[0001] Cross references to related patent applications [0002] This application claims priority to International Patent Application No. PCT / CN2018 / 109003 filed on September 30, 2018, the disclosure of which is incorporated herein by reference in its entirety. Background technique [0003] The main modalities that oncologists treat cancer are surgical resection, radiation therapy and classical chemotherapy drugs. Unfortunately, for many tumors or many types of cancer, surgical removal is not a viable option. In addition, radiation and chemotherapy drugs do not only target diseased cells, thus ultimately damaging healthy cells. Tumor-specific expression of antigens or inappropriate overexpression or activation of specific proteins within tumor cells are being exploited to develop more specific tumor cell-targeting therapies, but tumor cells are prone to mutations and may be critical for specifically targeting tumor cells. Cells develop drug resistance. [0004] A new cancer ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/28C07D403/04C07D405/14C07D417/04C07D487/04A61K31/502A61P35/00
CPCC07D403/04C07D405/14C07D237/28C07D417/04C07D487/04A61P35/00C07D401/04C07D401/14
Inventor S·马尔霍特拉M·肖王炜如B·魏A·周B·K·陈L·J·加扎德T·赫夫隆M·莱恩斯伯里A·马登E·M·西沃德M·W·卡特莱特E·甘恰D·法沃K·C·方A·古德胡永韩
Owner F HOFFMANN LA ROCHE & CO AG
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