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Novel HPK1 inhibitor, and preparation method and application thereof

A selected and unsubstituted technology applied in the field of small molecule drugs

Pending Publication Date: 2021-09-03
ENNOVABIO ZHEJIANG PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, there is no drug on the market for this target. In order to meet the huge clinical needs in the future, we hope to design and develop a selective and highly active small molecule HPK1 inhibitor to provide a new oral drug for the treatment of immune-related diseases, especially tumors. Drugs, alone or in combination with tumor chemotherapy, radiotherapy, tumor-targeted drugs, other tumor immunotherapeutic agents (small molecule compounds and antibodies) and tumor vaccines, etc. to treat tumors and other related diseases

Method used

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  • Novel HPK1 inhibitor, and preparation method and application thereof
  • Novel HPK1 inhibitor, and preparation method and application thereof
  • Novel HPK1 inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0082] The preparation of formula I compound

[0083] Compounds of formula I of the present invention can be prepared by the following methods:

[0084]

[0085] In an inert solvent, react with a brominated reagent and boronic acid to obtain a compound of formula I;

[0086] or

[0087]

[0088] In an inert solvent, a brominated reagent is used to react with a boric acid ester to obtain a compound of formula I.

[0089] Pharmaceutical compositions and methods of administration

[0090] Since the compound of the present invention has excellent HPK1 kinase inhibitory activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the compound of the present invention as the main active ingredient The pharmaceutical composition of can be used to prevent and / or treat diseases related to HPK1 kinase activity or expression level (for example, cancer).

[00...

Embodiment 1

[0109] Example 1: 2-(2-fluoro-6-methylphenyl)-8-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1,6-diazepine Xanaphthyl-5-amine

[0110]

[0111] 5-Chloro-1,6-naphthyridine-1-oxide

[0112]

[0113] 5-Chloro-1,6-naphthyridine (500 mg, 3.04 mmol) and chloroform (10 mL) were added to a 50 mL eggplant-shaped flask equipped with a magnetic stirrer, and the reaction solution was placed in an ice bath Let cool for 20 minutes. To the solution was added m-chloroperoxybenzoic acid (purity: 85%, 926 mg, 4.56 mmol) in portions. The reaction mixture was then stirred overnight at room temperature. The reaction was checked by LCMS. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a solid residue, which was separated through a flash silica gel column (dichloromethane:methanol=100:1) to obtain a yellow solid 5-chloro-1,6-naphthyridine- 1-oxide (597 mg, purity: 90%, yield: 100%). MS(ESI):m / z=181.0,183.0[M+H] + .

[0114] 5-Chloro-1,6-nap...

Embodiment 2

[0135] Example 2: 1-amino-6-(2-fluoro-6-methylphenyl)-4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)iso Quinoline-7-carbonitrile

[0136]

[0137] 6-Chloroisoquinoline-7-carbonitrile

[0138]

[0139] Under the protection of argon, the N,N-dimethylformamide (15 mL) into the mixture, tetrakis-triphenylphosphopalladium (457 mg, 0.39 mmol) was added, and the reaction solution was heated to 100° C. and stirred for 2 hours. The reaction was checked by LCMS. After the reaction was completed, the reaction liquid was cooled to room temperature, the reaction liquid was poured into water (50 ml), and then extracted with ethyl acetate (20 ml × 2), the organic layers were combined, followed by water (20 ml × 2), saturated Wash with brine (20 ml), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by flash silica gel column (petroleum ether:ethyl acetate=5:1) to ob...

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Abstract

The invention provides an HPK1 kinase inhibitor, and a preparation method and application thereof. Specifically, the invention provides a compound as shown in a formula I. All groups in the formula I are as described in the specification. The compound has excellent HPK1 inhibitory activity, so that the compound can be used for preparing pharmaceutical compositions for treating cancers and other diseases related to HPK1 activity.

Description

technical field [0001] The invention relates to the field of small molecule drugs, in particular, the invention relates to a kinase inhibitor and its preparation and use. Background technique [0002] T cells and B cells and dendritic cells (DCs) are powerful weapons that the body's immune system uses to fight against foreign invaders such as viruses and bacteria, as well as self-infected or abnormal cells such as cancerous cells. The human body has a complex and sophisticated regulatory system to ensure the normal operation of the immune system. When cancerous cells appear in the human body, if the immune system cannot completely kill them, these immune-evading cancer cells proliferate abnormally and form tumors. Traditional tumor treatment is mainly through surgery, radiotherapy, chemotherapy and molecular targeted drugs. However, surgical resection is often not a viable option for many forms of tumor or cancer. While radiation therapy and chemotherapy target tumor cell...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D401/04C07D417/14C07D401/14C07D405/14A61P35/00A61P35/02A61P35/04A61P29/00A61K31/496A61K31/4725A61K31/506A61K31/4545
CPCC07D471/04C07D401/04C07D417/14C07D401/14C07D405/14A61P35/00A61P35/02A61P35/04A61P29/00A61K31/4545A61K31/4725A61K31/506A61K31/496C07D217/22A61K31/4375A61K31/47
Inventor 江磊冯志勇金贤刘胜洋石倩寿建勇徐圆张建华赵海霞
Owner ENNOVABIO ZHEJIANG PHARM CO LTD
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