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Naphthyridines as inhibitors of hpk1

A heteroaryl and heterocyclyl technology, applied in the field of compounds that regulate the function of HPK1, can solve the problems that surgical resection is not feasible and damages cells

Active Publication Date: 2020-01-10
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 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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  • Naphthyridines as inhibitors of hpk1
  • Naphthyridines as inhibitors of hpk1
  • Naphthyridines as inhibitors of hpk1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0792] Embodiment 1: synthetic intermediate

Embodiment I1

[0794] Intermediate 1: tert-butyl N-(6,8-dichloro-2,7-naphthyridine-3-yl)carbamate

[0795]

[0796] Step 1: 2,6-Dichloro-4-iodopyridine-3-carboxylic acid

[0797]

[0798] At -78°C, N 2 , to a solution of 2,6-dichloro-3-iodo-pyridine (13.69 g, 50 mmol) in anhydrous THF (150 mL) was added LDA (2.0 M in THF, 27.5 mL, 55 mmol) dropwise. After the addition was complete, the reaction solution was stirred at -78°C for 2 hours. in CO 2 After bubbling for 5 minutes, the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with concentrated HCl, and extracted with dichloromethane. The combined organic layers were in Na 2 SO 4 Drying on , filtered and concentrated gave 2,6-dichloro-4-iodo-pyridine-3-carboxylic acid (8.1 g, 51% yield) as a light yellow solid. LCMS(ESI)[M+H] + = 317.8.

[0799] Step 2: (2,6-Dichloro-4-iodopyridin-3-yl)methanol

[0800]

[0801] A mixture of 2,6-dichloro-4-iodo-pyridine-3-carboxylic acid (6 ...

Embodiment I2

[0824] Intermediate 2: 6,8-dichloro-2,7-naphthyridine-3-amine

[0825]

[0826] To the vial add tert-butyl N-(6,8-dichloro-2,7-naphthyridine-3-yl)carbamate (1.05 g, 3.34 mmol), HCl / 1,4-dioxane (10 mL, 4N, 40 mmol) and dichloromethane (5 mL). The mixture was stirred at 40°C for 4 hours. The mixture was concentrated and dried in vacuo to give 6,8-dichloro-2,7-naphthyridine hydrochloride (823 mg, 96% yield) as a yellow solid. LCMS(ESI)[M+H] + = 214.1.

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Abstract

Naphthyridine compounds and their use as inhibitors of HPK1 are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods ofinhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the naphthyridine compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to International Patent Application No. PCT / CN2017 / 078792, filed March 30, 2017, and International Patent Application No. PCT / CN2018 / 076909, filed February 15, 2018, the contents of which are incorporated by reference in their entirety Incorporated into this article. [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 26, 2018, is named P34139_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 classic che...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61K31/4375A61P35/00
CPCC07D471/04A61K31/55A61P35/00A61K31/444A61K31/4375A61K31/506C07D519/00A61K31/4545A61K31/4725A61K31/5383A61K31/496A61K31/5377A61K31/5025A61K31/551A61K31/5517C07D487/04C07D487/14C07D497/04C07D491/052A61K45/06
Inventor B·陈B·丹尼尔斯J·德罗布尼克L·加扎德T·赫夫伦M·赫斯特斯梁军S·马尔霍特拉R·门登卡N·拉贾帕克萨M·肖C·斯蒂瓦拉J·泰利斯王炜如魏斌清周爱和M·W·卡特赖特E·甘西亚G·琼斯M·兰奇伯里A·马丁E·西沃德D·法沃K·C·方胡永韩A·古德胡百华陆爱军
Owner F HOFFMANN LA ROCHE & CO AG
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