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Tetrahydropyrido[3,4-d]pyrimidine-2-(1H)-ketone compound as well as preparation method and medical application thereof

A technology of compounds and solvates, which is applied in the field of medicine and can solve problems such as cancer

Active Publication Date: 2020-12-08
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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  • Tetrahydropyrido[3,4-d]pyrimidine-2-(1H)-ketone compound as well as preparation method and medical application thereof
  • Tetrahydropyrido[3,4-d]pyrimidine-2-(1H)-ketone compound as well as preparation method and medical application thereof
  • Tetrahydropyrido[3,4-d]pyrimidine-2-(1H)-ketone compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1: Preparation of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-1-(2-isopropylphenyl)-7-(5-methyl-1H -Indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2(1H)-one (Z1)

[0184]

[0185] Step 1: Add (S)-7-benzyl-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-1-(2-isopropyl) to a 100 mL round bottom flask phenyl)-2-oxo-1,2-dihydropyrido[3,4-d]pyrimidine-7-bromide (1.3g, 2.05mmol) and 30ml methanol, at 0~5℃, Sodium borohydride (775 mg, 20.5 mmol) was slowly added in portions, and the reaction was stirred at room temperature for 3 hours. Obtaining (S)-4-(7-benzyl-1-(2-isopropylphenyl)-2-oxo-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidine The reaction solution of -4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester was directly used in the next step reaction. ES-API:[M+H] + = 556.7.

[0186] Step 2: Add (S)-4-(7-benzyl-1-(2-isopropylphenyl)-2-oxo-1,2,7,8-tetrahydropyrido[3, 4-d] Pyrimidin-4-yl)-(-)3-methylpiperazine-1-formic acid tert-butyl ester was a...

Embodiment 2

[0190] Example 2: Preparation of 4-(4-acryloyl-piperazin-1-yl)-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2(1H)-one (Z2)

[0191]

[0192] Step 1: Add 7-benzyl-4-(4-(tert-butoxycarbonyl)-piperazin-1-yl)-1-(2-isopropylphenyl)-2-oxo to a 100 mL round bottom flask Substituent-1,2-dihydropyrido[3,4-d]pyrimidine-7-bromide (500mg, 0.807mmol) and 30ml of methanol, slowly add sodium borohydride (307mg , 8.07mmol), stirred at room temperature for 5 hours. 4-(7-Benzyl-1-(2-isopropylphenyl)-2-oxo-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl )-piperazine-1-formic acid tert-butyl ester reaction solution, directly used in the next step reaction. ES-API:[M+H] + = 542.3.

[0193]Step 2: Add 4-(7-benzyl-1-(2-isopropylphenyl)-2-oxo-1,2,7,8-tetrahydropyrido[3,4-d] to the above Add 5% Pd / C (250 mg) to the reaction solution of pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester, replace with hydrogen three times, then stir under...

Embodiment 3

[0197] Example 3: Preparation of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-methyl-1H-indazol-4-yl)-1-benzene Base-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2(1H)-one (Z3)

[0198]

[0199] Step 1: Add (S)-7-benzyl-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-oxo-1- Phenyl-1,2-dihydropyrido[3,4-d]pyrimidine-7-bromide (340mg, 0.574mmol) and 20ml methanol, slowly added sodium borohydride (225mg, 5.95 mmol), stirred at room temperature for 1 hour. 20 mL of water was added to the reaction solution, extracted twice with 20 mL of dichloromethane, the organic phase was dried and concentrated to obtain the crude product (S)-4-(7-benzyl-2-oxo-1-phenyl-1,2, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-carboxylic acid-1-tert-butyl ester was directly used in the next reaction. ES-API:[M+H] + = 514.6.

[0200] Step 2: To the above-mentioned crude product containing (S)-4-(7-benzyl-2-oxo-1-phenyl-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidine- Add 20ml of iso...

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Abstract

The invention discloses a tetrahydropyrido[3,4-d]pyrimidine-2-(1H)-ketone compound with a selective inhibition effect on KRAS gene mutation and pharmaceutically acceptable salt, stereoisomer, solventcompound or prodrug thereof, the compound is shown as a formula I, and the definition of each group in the formula is shown in the specification in detail. In addition, the invention also discloses apharmaceutical composition containing the compound and application of the compound in preparation of cancer drugs.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a tetrahydropyrido[3,4-d]pyrimidin-2(1H)-one compound, its application as a selective inhibitor of KRAS gene mutation, and its Prepared pharmaceutical composition. 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 mo...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61P35/00
CPCC07D471/04A61P35/00
Inventor 周福生蒋涛何宛赵金柱杨华彬彭灵蔡礼健兰炯
Owner GENFLEET THERAPEUTICS SHANGHAI INC
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