KRAS G12C inhibitor and application thereof

A use and compound technology, applied in the field of KRASG12C inhibitors, can solve the problems of lack of multidrug resistance, reducing the killing effect of anti-tumor drugs on tumors, reducing the sensitivity of tumors to anti-tumor drugs, etc.

Active Publication Date: 2021-01-15
NANJING RUIJIE PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The multidrug resistance of tumors can significantly reduce the sensitivity of tumors to anti-tumor drugs, thereby reducing the killing effect of anti-tumor drugs on tumors. The existing clinical drugs lack effective inhibition or reversal of multi-drug resistance of tumor anti-tumor drugs Drug-resistant drugs, therefore, the development of drugs that inhibit or reverse the multidrug resistance of tumors to anti-tumor drugs has become a hot topic in today's research

Method used

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  • KRAS G12C inhibitor and application thereof
  • KRAS G12C inhibitor and application thereof
  • KRAS G12C inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0121]Compound preparation method

[0122]The compounds disclosed herein can be synthesized by many specific methods. Summarizing examples of specific synthetic routes and the following general schemes are intended to provide guidance for ordinary skilled synthetic chemists. Those skilled in the art will easily understand the solvent, concentration, reagents, protecting groups, sequence of synthetic steps, time, temperature, etc. Make modifications as needed within the scope of the skill and judgment of ordinary technicians.

[0123]The compound of formula (IIa) as disclosed herein can be synthesized as described in Method 1:

[0124]

[0125]The compound of formula (IIb) as disclosed herein can be synthesized as described in Method 2:

[0126]

[0127]The compound of formula (IIc) as disclosed herein can be synthesized as described in Method 3:

[0128]

[0129]use

[0130]The present invention also provides a use of the compound of the present invention to prepare a pharmaceutical composition for: (i) preve...

Embodiment

[0180]The present invention can be better understood according to the following examples. However, for those skilled in the art, it is easy to understand that the contents described in the embodiments are only intended to illustrate the present invention, and not to limit the present invention described in detail in the claims.

[0181]In this example, the compound AMG510 is prepared by referring to the method of WO2018217651A1:

[0182]

[0183]Example 1 Preparation of compound of formula I1

[0184]Compound of formula I1

[0185]4-(4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methyl Pyridin-3-yl)-1,8-naphthyridin-2(1H)-one (I1 compound)

[0186]

[0187]Step 1: Preparation of compound I-03

[0188]

[0189]Under nitrogen, to compound I-01 (10.0g, 52.36mmol) in 1,4-dioxane / H2Compound I-02 (13.3g, 78.53mmol) was added to the solution in O (100 / 10mL), Na2CO3(16.6 g, 157.08 mmol) and Pd(PPh3)4 (6.1 g, 5.24 mmol), the reaction mixture was heated to 110°C and stirred o...

Embodiment 5

[0315]Example 5: Compound of formula I5

[0316]Compound of formula I5

[0317]4-(4-acryloyl-2-methylpiperazin-1-yl)-3,6-difluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl- 4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0318]

[0319]Step 1: Synthesis of I5-03

[0320]

[0321]To the dioxane / H2O (100mL / 10mL) solution of compound I5-01 (10g, 52.36mmol) was added compound I5-02 (10.68g, 62.83mmol), Na2CO3(16.6 g, 157.08 mmol) and Pd(pph3)4 (6.1 g, 5.24 mmol). The resulting mixture was stirred at 110°C overnight.

[0322]Use H2The reaction solution was diluted with O (100 mL), and extracted with EA (200 mL×2). The combined organic layer was washed with brine (100 mL×2), and washed with Na2SO4Dry, filter and concentrate. The residue was purified by silica gel chromatography (PE / EA=10 / 1) to obtain compound I5-03 (4.96 g, 34% yield) as a yellow solid.

[0323]MS Calcd.:280; MS Found:281[M+H]+.

[0324]Step 2: Synthesis of I5-05

[0325]

[0326]To a solution of compound I5-03 (2g, 7.13mmol) in toluene (30mL) was a...

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Abstract

The invention relates to a KRAS G12C inhibitor and application thereof, and particularly provides a compound shown as a formula (I), or a stereoisomer, or a resistance isomer, or a pharmaceutically acceptable salt, or a tautomer, or a prodrug thereof.

Description

Technical field[0001]The present invention relates to the field of medicine, in particular, the present invention relates to KRAS G12C inhibitors.Background technique[0002]RAS represents a group of closely related monomeric globular proteins of 189 amino acids (molecular weight 21kDa), which are associated with the plasma membrane and bind GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a static or closed state, and is in an "inactive state." In response to cell exposure to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. After binding to GTP, RAS is "turned on" and can interact with and activate other proteins (its "downstream targets"). The RAS protein itself has a very low intrinsic capacity and cannot hydrolyze GTP back to GDP, thus making itself in a closed state. Turning off RAS requires extrinsic proteins called GTPase activating proteins (GAPs), which interact with RAS and greatly accelerate the conversion ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61K31/444A61K31/496A61K31/4545A61K45/06A61P35/00
CPCA61P35/00C07D471/04C07D519/00
Inventor 张军波朱曙灏齐晓昕
Owner NANJING RUIJIE PHARMATECH CO LTD
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