KRAS G12C mutant protein inhibitor, pharmaceutical composition comprising same, preparation method and application

A compound and pharmaceutical technology, applied in the field of preparation of KRASG12C mutant protein inhibitor and its pharmaceutical composition, can solve the problems of prolonging protein activation time and prolonging signal transduction cells

Active Publication Date: 2021-10-22
SUZHOU INTRAGRAND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Any mutation in RAS that affects the ability of RAS to interact with GAP or to convert GTP back to GDP will result in prolonged activation of the protein and thus a prolonged signaling cell, prompting the cell to continue growing and dividing
Because this signaling causes cells to grow and divide, overactive RAS signaling can eventually lead to cancer

Method used

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  • KRAS G12C mutant protein inhibitor, pharmaceutical composition comprising same, preparation method and application
  • KRAS G12C mutant protein inhibitor, pharmaceutical composition comprising same, preparation method and application
  • KRAS G12C mutant protein inhibitor, pharmaceutical composition comprising same, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1： example 1

[0191] Embodiment 1: the synthesis of example 1 compound and its intermediate

[0192] Referring to the synthesis method of WO2019141250A1, the synthetic routes of Intermediate J and Intermediate K are designed as follows:

[0193]

[0194] Synthesis of compound 1-2:

[0195] Compound 1-1 (1 g, 7.09 mmol, 1 eq) and compound 1-1A (1.26 g, 9.21 mmol, 982.46 uL, 1.3 eq) were dissolved in a solution in DCM (20 mL), TEA (1.43 g, 14.17 mmol , 1.97mL, 2eq), the mixture was stirred at 15-20°C for 2 hours. The mixture was diluted with DCM (30 mL), washed with 5% hydrochloric acid (50 mL) and saturated brine (30 mL), the organic phase was separated, washed with Na 2 SO 4 It was dried, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (0-100% gradient elution, petroleum ether / ethyl acetate) to obtain compound 1-2 as a yellow solid (660 mg, yield 38.62%).

[0196] 1 H-NMR (400MHz, CDCl 3 )δ=8.58(s,1H),7.23-7.15...

example 1

[0238] Example 1b (1.5 mg, 13.20% yield, 98.9% purity). 1 H NMR (400MHz, CDCl 3 )δ=7.41-7.31(m,3H),7.24-7.17(m,1H),7.06(d,J=7.6Hz,1H),6.90(s,1H),6.78-6.69(m,2H),6.67 -6.57(m,1H),6.40(dd,J=1.6,16.8Hz,1H),5.85-5.78(m,1H),4.09-3.78(m,8H),3.71(s,3H),2.73-2.63 (m, 1H), 1.22 (d, J=6.8Hz, 3H), 1.11 (d, J=6.8Hz, 3H). MS: (M+H): 612.1.

[0239] The second preparation route of example 1a and example 1b is as follows:

[0240]

[0241] Synthesis of Compound 1-13:

[0242] Intermediate J (2g, 6.11mmol, 1eq), 2-isopropylphenylboronic acid (2g, 12.22mmol, 2eq), Cu 2 O (1.75g, 12.22mmol, 2eq) was dissolved in methanol (40mL), the mixture was stirred at 50°C for 2 hours under an oxygen atmosphere, concentrated under reduced pressure, diluted with water (80mL), extracted with ethyl acetate (80mL*2), and combined The organic phase was washed with saturated brine (50 mL), anhydrous Na 2 SO 4 It was dried, filtered, concentrated under reduced pressure, and purified by prep-TLC (petroleu...

Embodiment 2

[0257] Embodiment 2: the preparation of example 2 compound

[0258] Example 1a is demethylated by boron tribromide to obtain example 2 compound, MS: (M+H): 598.1

[0259]

[0260] Example 1a (120.0 mg, 182.47 μmol, 1 eq) was dissolved in DCM (3 mL), and BBr was added at 0 °C 3 (0.3mL), stirred for 1 hour, and the reaction solution was poured into iced NaHCO 3 (20mL), added water (10mL) and dichloromethane extraction (10mL*2), combined organic layer, dried over anhydrous sodium sulfate, concentrated crude product, preparative HPLC purified to obtain target product Example 2 (6.9mg, yield 6.1%) ).

[0261] 1 H NMR (400MHz, CDCl 3 )=7.39-7.31(m,2H),7.23-7.09(m,2H),7.00(d,J=6.4Hz,1H),6.91(s,1H),6.72-6.52(m,3H),6.45- 6.34(m,1H),5.85-5.78(m,1H),4.01-3.61(m,8H),2.65(q,J=6.7Hz,1H),1.21(d,J=6.8Hz,3H),1.10 (d,J=6.8Hz,3H).LCMS:(M+H) + :598.0

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Abstract

The invention provides a compound with irreversible inhibitor activity of G12C mutant KRAS protein, and a racemate, a stereoisomer, a pharmaceutically acceptable salt, a polymorphic substance or a solvate of the compound. The structure of the compound is shown as a formula (I) in the specification. Also provided are methods related to the preparation and use of the compounds, a pharmaceutical composition comprising the compounds, and a method of modulating G12C mutant KRAS protein activity for the treatment of conditions such as cancer.

Description

[0001] This application claims to have the prior patent application number 202010313445.0 and the invention name is "KRAS G12C mutant protein inhibitor and its pharmaceutical composition, preparation method and use" submitted by the applicant to the State Intellectual Property Office of China on April 20, 2020. Application priority. The entirety of this application is incorporated by reference into this application. technical field [0002] The invention belongs to the field of pharmaceuticals, and in particular relates to a class of KRAS G12C mutant protein inhibitors and pharmaceutical compositions, preparation methods and uses thereof. Background technique [0003] RAS gene mutation is a gene with a high mutation frequency in tumors and other diseases, and targeted intervention for its mutated protein is an important goal for the development of drugs for mutated Ras protein-related diseases. RAS represent a group of closely related monomeric globular proteins (21 kDa mol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61K31/519A61P35/00A61P35/02
CPCC07D471/04C07D519/00A61P35/00A61P35/02Y02P20/55
Inventor 朱加望姚瑶
Owner SUZHOU INTRAGRAND PHARMA CO LTD
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