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Pyridopyrimidine KRAS G12C mutant protein inhibitor

A technology of selecting and compounding compounds, applied in the field of medicine, can solve the problem of insufficient high-efficiency and high-safety K-RASG12C inhibitors, etc.

Active Publication Date: 2021-06-01
GUANGZHOU BIOTING PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The K-RAS G12C covalent inhibitor is a small molecular compound designed by utilizing the nucleophilic reactivity of the mutated 12th cysteine, which is modified with a disulfide bond to enter the K-RAS G12C allosteric pocket and block K The activation of -RAS G12C mutant protein inhibits tumor growth, but so far there are still no new K-RAS G12C inhibitors with sufficient efficacy and safety to obtain regulatory approval for marketing

Method used

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  • Pyridopyrimidine KRAS G12C mutant protein inhibitor
  • Pyridopyrimidine KRAS G12C mutant protein inhibitor
  • Pyridopyrimidine KRAS G12C mutant protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082]

[0083] Compound (S)-1-(4-(7-(naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[2,3-d]pyrimidine The synthesis of -4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction scheme (A) and (B); MS (ESI) m / z509.26[M+H] + .

[0084] The synthetic route and specific method are as follows:

[0085]

[0086] first step

[0087]Compound A (500.0 mg, 2.9 mmol, 1.00 eq) was dissolved in 5 mL of toluene, and oxalyl chloride (443.8 mg, 3.5 mmol, 1.20 eq) was added under nitrogen protection. The mixture was stirred at 110°C for 15 hours. Cool to room temperature, filter, wash the filter residue with toluene (5 mL×2), and dry. The crude compound B (528 mg, light yellow solid) was obtained, and the product was directly carried out to the next reaction without purification.

[0088] second step

[0089] Crude compound B (100.0mg, 0.5mmol, 1.00eq) was dissolved in 0.6mL of toluene, and N,N-diisopropylethylamine (196.3mg, 1.5mmol, 3.00eq) was added under ...

Embodiment 2

[0101]

[0102] Compound 1-((S)-3-methyl-4-(7-(naphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridine [2,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one is synthesized according to the general reaction scheme (A) and (B); MS (ESI)m / z 523.28[M+H] + .

[0103] The synthetic route and specific method are as follows:

[0104]

[0105] first step

[0106] Compound A (100.0mg, 0.5mmol, 1.00eq) was dissolved in 0.6mL of toluene, and N,N-diisopropylethylamine (196.3mg, 1.5mmol, 3.00eq) was added under nitrogen protection. The mixture was stirred at 70°C for 30 minutes, phosphorus oxychloride (232.8mg, 1.5mmol, 3.00eq) was added, and stirred under reflux at 100°C for 2.5 hours. After the reaction was complete, the solvent was spin-dried under reduced pressure, added water (1 mL), extracted with ethyl acetate (1 mL×3), the combined organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and ...

Embodiment 3

[0116]

[0117] Compound 1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[2,3-d]pyrimidin-4-yl) The synthesis of piperazin-1-yl)prop-2-en-1-one refers to the general reaction scheme (A) and (B); MS (ESI) m / z 499.24 [M+H] + .

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pyridopyrimidine KRAS G12C mutant protein inhibitor shown in a general formula (I), pharmaceutically acceptable salts, stereoisomers and deuterated substances thereof. The invention also relates to a preparation method of the compounds, and a preparation method of the pharmaceutically acceptable salts, pharmaceutical preparations and pharmaceutical compositions containing the compounds. The invention also relates to the application of the compounds, pharmaceutically acceptable salts containing the compounds, pharmaceutical preparations and pharmaceutical compositions of the compounds in treatment of cancer proliferative diseases caused by KRAS G12C mutant protein.

Description

technical field [0001] The present invention belongs to the technical field of medicine; the present invention relates to new substituted pyridopyrimidine derivatives, in particular to compounds represented by general formula (I), its isomers or their deuterated products, their pharmaceutically acceptable salts, The application of its pharmaceutical preparation and pharmaceutical composition in the preparation and treatment of cancer proliferative diseases. Background technique [0002] RAS proteins play an important role in regulating normal cell growth and proliferation. According to the conservation degree of RAS amino acid sequence, it can be divided into three types: KRAS, HRAS, and NRAS. RAS is in different "activated" or "inactivated" states by binding to low molecular weight guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP). Under normal circumstances, RAS protein binds to GDP on the plasma membrane of quiescent cells to form GDP-RAS, wh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00A61P35/02A61K31/519
CPCC07D471/04A61P35/00A61P35/02A61K31/519A61K31/525
Inventor 徐伟吴曙光
Owner GUANGZHOU BIOTING PHARM TECH CO LTD
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