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Spiro-substituted pyrimido-cyclic compound, and preparation method and medical application thereof

A compound and solvate technology, applied in the field of medicine, can solve problems such as cancer

Active Publication Date: 2020-12-22
GENFLEET THERAPEUTICS (SHANGHAI) INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since this signaling causes cells to grow and divide, overactivated RAS signaling can eventually lead to cancer

Method used

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  • Spiro-substituted pyrimido-cyclic compound, and preparation method and medical application thereof
  • Spiro-substituted pyrimido-cyclic compound, and preparation method and medical application thereof
  • Spiro-substituted pyrimido-cyclic compound, and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Embodiment 1: Preparation Z1

[0193]

[0194] Step 1: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (298mg, 0.9mmol) was dissolved in dichloromethane / acetonitrile (3mL / 3mL) and cooled to 0°C. Triethylamine (136 mg, 1.35 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.94 mmol) were added thereto, and stirred at room temperature for 3 hours. Dichloromethane (30x 2mL) was extracted, the organic phase was washed with water, washed with brine, dried over anhydrous sodium sulfate, and evaporated to obtain 6-(7-bromo-2,6-dichloro-8-fluoroquinazoline-4- yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (yellow solid, 620 mg, Y: crude product). ES-API: [M+H]+=506.

[0195] Step 2: tert-butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (620mg, 1.2mmol) was dissolved in N,N-dimethylformamide (10mL), to which was added cesium carbonate (1.17g, 3.6mmol), triethylenediamine (20mg, 0.18mmol) and 1...

Embodiment 2

[0199] Example 2: Preparation of Z2

[0200]

[0201] Step 1: tert-butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid salt (200mg, 0.395mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (140mg, 1.185mmol), cesium carbonate (687mg, 0.185mmol) and 1,4-diazabicyclo [2.2.2] Octane (10mg, 0.079mmol) was added to dry tetrahydrofuran (5.0mL) and N,N-dimethylformamide (5.0mL), and replaced with argon three to five times. After the reaction solution was stirred at 60°C for 16 hours, it was cooled to room temperature and poured into ice water. Extracted three times with ethyl acetate (10 mL x 3), and combined the organic phases. The organic phase was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. Concentration under vacuum afforded crude product (S)-tert-butyl 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy) as a yellow solid Quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-...

Embodiment 3

[0205] Embodiment 3: Preparation Z3

[0206]

[0207] Step 1: tert-butyl 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid salt (200mg, 0.395mmol), methylpiperazine (119mg, 1.185mmol), cesium carbonate (687mg, 0.185mmol) and 1,4-diazabicyclo[2.2.2]octane (10mg, 0.079mmol) Add dry tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL), and replace with argon three to five times. After the reaction solution was stirred at 60°C for 16 hours, it was cooled to room temperature and poured into ice water, and extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, and dried over anhydrous sodium sulfate. It was then concentrated under vacuum to give the crude product 6-(7-bromo-6-chloro-8-fluoro-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2 as a yellow solid, tert-butyl 6-diazaspiro[3.4]octane-2-carboxylate (225 mg, yield: 100%). ES-API: [M+H]+=586.3....

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Abstract

The invention discloses a spiro-substituted pyrimido-cyclic compound with selective inhibition effect on KRAS gene mutation and a pharmaceutically acceptable salt, a stereoisomer, a solvent compound or a prodrug thereof; the spiro-substituted pyrimido-cyclic compound is represented by a formula (I), and the definition of each group or symbol in the formula is shown in the specification in detail.In addition, the invention also discloses a pharmaceutical composition containing the compound and an application of the compound in preparation of cancer drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a spirocyclic substituted pyrimidocyclic compound, its application as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom. Background technique [0002] Lung cancer is the cancer with the highest incidence rate in the world. In China, the incidence rate of lung cancer ranks first among all cancers. It is also the cancer with the highest incidence and mortality in China. According to the data released by the American Cancer Society in 2016, about 1.8 million people suffer from lung cancer, and nearly 80% of lung cancers are non-small cell lung cancer (NSCLC). [0003] The RAS are a group of closely related monomeric globular proteins (21 kDa molecular weight) of 188-189 amino acids that bind either guanosine diphosphate GDP or guanosine triphosphate GTP. Members of the RAS subfamily include HRAS, KRAS, and NRAS. RAS acts as a molecul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10C07D487/10C07D519/00A61P35/00A61P35/02A61K31/517A61K31/519
CPCC07D471/10C07D487/10C07D519/00A61P35/00A61P35/02
Inventor 周福生蒋涛彭灵赵金柱何宛兰炯
Owner GENFLEET THERAPEUTICS (SHANGHAI) INC
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