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Novel HPK1 inhibitor as well as preparation method and application thereof

A C1-C6, selected technology, applied in the field of small molecule drugs

Pending Publication Date: 2021-09-07
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.

Method used

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  • Novel HPK1 inhibitor as well as preparation method and application thereof
  • Novel HPK1 inhibitor as well as preparation method and application thereof
  • Novel HPK1 inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0088] The preparation of formula I compound

[0089] Compounds of formula I of the present invention can be prepared by the following exemplary methods:

[0090] method 1:

[0091]

[0092] Substitution and coupling reactions are carried out with five- and six-membered compounds, and the compound of formula I is obtained after modification by substituents.

[0093] Among them, a class of compounds where A is an unsaturated ring can be prepared by method 2:

[0094]

[0095] A cyclization reaction with a compound of Ia affords a compound of formula I'.

[0096] Pharmaceutical compositions and methods of administration

[0097] 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 pharmaceuti...

Embodiment 1

[0148] Example 1: (2-((3,5-difluoro-4-((5-(2-fluoro-4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Base) oxo) phenyl) amino) -5-methyl-5,6-dihydro-4H-1,3-oxazin-5-yl)methanol

[0149] 3,5-Difluoro-4-((5-(2-fluoro-4-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo [2,3-d]pyrimidin-4-yl)oxo)aniline

[0150]

[0151] Under argon protection, 3,5-difluoro-4-((5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)oxo)aniline (A1, 400 mg, 0.945 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (178 mg, 1.04 mmol), potassium phosphate (401 mg, 1.89 mmol) and a mixture of 1,4-dioxane (6.0 mL) / water (2.0 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium chloride dichloromethane complex (76 mg, 0.094 mmol). The reaction solution was heated to 100° C. and stirred for 2 hours. The reaction was checked by LCMS. After the reaction solution was cooled to room temperature, ethyl acetate (10 mL×2) was added for extraction...

Embodiment 2

[0159] Example 2: 2-((3,5-difluoro-4-((5-(2-fluoro-4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Base) oxo) phenyl) amino) -5-fluoro-5,6-dihydro-4H-1,3-oxazin-5-yl)methanol

[0160]

[0161] 1-(3,5-difluoro-4-((5-(2-fluoro-4-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl Base)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxo)phenyl)-3-((3-fluorooxetan-3-yl)methyl)urea

[0162]

[0163] To a 50 mL round bottom flask equipped with a magnetic stirrer was added 3,5-difluoro-4-((5-(2-fluoro-4-methoxyphenyl)-7-((2-(trimethyl Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxo)aniline (100 mg, 0.193 mmol) and triethylamine (79 mg, 0.77 mmol) in anhydrous dichloromethane (3.0 mL), replaced with argon three times, and then cooled the reaction solution in an ice bath. Then triphosgene (40 mg, 0.135 mmol) was added to the reaction solution, and the reaction solution was stirred at 0°C for 20 minutes. Then (3-fluorooxetan-3-yl)methanamine (102 mg, 0.969 mmol) was added to th...

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Abstract

The invention provides an HPK1 kinase inhibitor as well as preparation and application thereof. Specifically, the invention provides a compound as shown in a formula I. The definition of each group is 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 application. 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 tu...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00C07D471/04A61K31/5355A61K31/537A61K31/5383A61K31/5377A61K31/541A61K31/547A61K31/519A61K31/496A61K31/5025A61K31/53A61P35/00A61P35/02A61P35/04
CPCC07D487/04C07D519/00C07D471/00A61P35/00A61P35/02A61P35/04A61K31/5025A61K31/519A61K31/496A61K31/5355A61K31/537A61K31/5377A61K31/5383A61K31/541A61K31/547A61K31/53C07D471/04A61K31/437
Inventor 江磊冯志勇金贤石倩寿建勇徐圆张建华赵海霞
Owner ENNOVABIO ZHEJIANG PHARM CO LTD
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