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Isoquinolines as inhibitors of HPK1

An alkyl and compound technology, applied in the field of compounds that modulate HPK1 function, can solve problems such as damage to cells and surgical resection is not feasible

Pending Publication Date: 2020-01-17
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 forms of cancer, surgical removal is not a viable option
In addition, radiation therapy and chemotherapy drugs do not target only diseased cells, thus ultimately damaging healthy cells

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0572] Materials and methods

[0573] Method A: Experiments were performed on an Agilent 1100HPLC (equipped with an Agilent MSD mass spectrometer), using ESI as the ionization source, using an Agilent SunFire-C18 3.5 μm, 4.6x50 column and a flow rate of 2.0 ml / min. The solvent system was a gradient starting with 95% water and 0.05% TFA (solvent A) and 5% acetonitrile and 0.05% TFA (solvent B) to 100% solvent B in 1.3 minutes. The final solvent system was held constant for a further 1.2 minutes.

[0574] Method B: Experiments were performed on an Agilent 1200HPLC (equipped with an Agilent MSD mass spectrometer), using ESI as an ionization source, using an Agilent SunFire-C18 3.5 μm, 4.6x50 column and a flow rate of 2.0 ml / min. The solvent system was a gradient starting from 95% water and 0.01% TFA (solvent A) and 5% acetonitrile and 0.01% TFA (solvent B) to 5% solvent A and 95% solvent B in 1.4 minutes. The final solvent system was held constant for a further 1.0 minutes.

...

Embodiment I1

[0598] Intermediate 1: 6-Bromo-8-chloro-isoquinolin-3-amine

[0599]

[0600] Step 1: Methyl 2,2-diethoxyacetimidate

[0601]

[0602] To a stirred solution of diethoxyacetonitrile (7.0 g, 54.2 mmol) in dry methanol (50 mL) was added sodium methoxide in methanol (4.2 mL, 20%, 8.4 mmol). After the addition, the reaction mixture was stirred at room temperature for 48 hours. The reaction was concentrated to dryness and the residue was dissolved in chloroform, and the organic layer was washed with water, dried and concentrated to give methyl 2,2-diethoxyacetimidate (8.37 g, 95% yield), which As a colorless oil, it was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.95 (s, 1H), 4.82 (s, 1H), 3.65 (s, 3H), 3.51 (q, J = 7.2Hz, 4H), 1.14 (t, J = 7.2Hz, 6H).

[0603] Step 2: 4-Bromo-2-chloro-phenyl)methanamine

[0604]

[0605] Add BH to a 50 mL round bottom flask 3 -THF (1.0M in THF, 32.5 mL, 32.5 mmol) and 4-bromo-2-chlorobenzonitril...

Embodiment I2

[0613] Intermediate 2: N-(6-bromo-8-chloro-3-isoquinolyl)cyclopropanecarboxamide

[0614]

[0615] To a cooled (0° C.) mixture of 6-bromo-8-chloro-isoquinolin-3-amine (900 mg, 2.1 mmol) and pyridine (166 mg, 2.1 mmol) in dichloromethane (10 mL) was added cyclopropane Carbonyl chloride (263 mg, 2.52 mmol). The reaction was stirred at 0 °C for 1 hour. The reaction mixture was added NH 4 Quenched with saturated aqueous Cl and extracted with dichloromethane. The organics were dried, filtered and concentrated. The crude product was purified by flash column chromatography (40% dichloromethane in petroleum ether) to give (N-(6-bromo-8-chloro-3-isoquinolinyl)cyclopropanecarboxamide (550 mg, 74% yield ) as a yellow solid. LCMS (ESI) [M+H] + = 324.9.

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Abstract

Isoquinoline compounds 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. Alsodescribed are methods of inhibiting HPK1, methods of treating HPK1 -dependent disorders, methods for enhancing an immune response, and methods for preparing the isoquinoline compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority of International Patent Application No. PCT / CN2017 / 078790 filed on March 30, 2017 and International Patent Application No. PCT / CN2018 / 076908 filed on February 15, 2018, the contents of which are incorporated by reference It is incorporated herein in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been filed electronically in ASCII format, and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 13, 2018, is named P34138_WO-2_SL.TXT and is 21KB in size. technical field [0005] The present invention relates to compounds that modulate the function of HPK1, which are useful in the treatment of diseases and conditions mediated by HPK1, such as cancer. Background technique [0006] The main treatments that oncologists use to treat cancer are surgical resection, radiation therapy, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D405/14C07D413/14C07D487/14C07D217/22C07D401/04C07D409/14C07D413/04C07D417/04C07D471/04C07D487/04C07D491/04C07D498/04C07D513/04C07D519/00
CPCC07D401/14C07D405/14C07D413/14C07D487/14C07D217/22C07D401/04C07D409/14C07D413/04C07D417/04C07D471/04C07D487/04C07D491/04C07D498/04C07D513/04C07D519/00A61K31/549A61P35/00A61K31/4725A61K31/506A61K31/501A61K31/5377A61K31/4985A61K31/551A61K31/5383C07D498/14A61K31/554A61K31/55A61K31/472A61K45/06
Inventor B·陈J·德罗布尼克L·加扎德T·赫夫伦J·梁S·马尔霍特拉R·门登卡N·拉贾帕克萨C·斯蒂瓦拉J·泰利斯W·王B·魏A·周M·W·卡特赖特M·兰奇伯里E·甘西亚E·西沃德A·马丁D·法沃K·C·方Y·胡A·古德
Owner F HOFFMANN LA ROCHE & CO AG
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