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2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors

A technology of derivatives and amino groups, applied in the field of compounds of Wee-1 kinase activity inhibitors

Active Publication Date: 2015-12-30
ALMAC DISCOVERY LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Irradiation is known to increase phosphorylation of the Tyr15 and Thr14 residues of cdc2, resulting in a radioresistant phenotype

Method used

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  • 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors
  • 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors
  • 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0250] Example 1: 6-(2,6-dichlorophenyl)-2-((4-(piperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidine -5(6H)-one

[0251]

[0252] Step 1: N-(2,6-dichlorophenyl)-4-methyl-2-(methylthio)pyrimidine-5-carboxamide: Phosphorus trichloride (2.37 mL , 27.1 mmol) was added to 4-methyl-2-(methylthio)pyrimidine-5-carboxylic acid (5.00 g, 27.1 mmol) [commercially available] and 2,6-dichloroaniline (4.40 g, 27.1 mmol) In a stirred solution in chlorobenzene (100 mL). After 3 h, the solvent was removed under vacuum and the remaining residue was partitioned between DCM and 2M sodium carbonate (aq) solution, separated, extracted (DCM x 2) and dried (phase separator) and removed under vacuum solvent to give the title compound (6.86 g, 77%) as a light yellow solid. LCMS (Method A): R T = 1.14 minutes, m / z = 328, 330 [M+H] + .

[0253] Step 2: 6-(2,6-Dichlorophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one: at room temperature under nitrogen, DMF -DMA (2.49mL, 18.6mmol) was adde...

Embodiment 2

[0257] Example 2: 6-(2,6-dichlorophenyl)-8-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrido[4,3-d] pyrimidine pyridin-5(6H)-one

[0258]

[0259] Step 1: 8-bromo-6-(2,6-dichlorophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one: at 80°C under nitrogen 6-(2,6-Dichlorophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidine-5 In a stirred solution of (6H)-ketone (10.0 mg, 0.030 mmol) in acetonitrile (1.0 mL). After 16 hours, LCMS analysis showed a 2:1 product / SM mixture. Additional NBS (2.6 mg, 0.5 equiv) was added. After another 1 h, the reaction mixture was quenched with 10% sodium bisulfite and partitioned with DCM, separated, extracted (DCM x 2), dried (phase separator), solvent removed in vacuo and flash chromatography (in ring Purification of the remaining residue (EtOAc in hexanes 0% to 100%) gave the title compound (9.5 mg, 77%) as a pale yellow solid. LCMS (Method A): R T = 1.47 minutes, m / z = 418 [M+H] + .

[0260] 1 HNMR (500MHz, CDCl 3 ): δ9.36(s, 1H), 7.56(s...

Embodiment 3

[0265] Example 3: 6-(2-chloropyridin-3-yl)-2-((4-(piperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidine -5(6H)-one

[0266]

[0267] Step 1: N-(2-Chloropyridin-3-yl)-4-methyl-2-(methylthio)pyrimidine-5-carboxamide: Phosphorus trichloride (0.047 mL , 0.543mmol) was added to 4-methyl-2-(methylthio)pyrimidine-5-carboxylic acid (100mg, 0.543mmol) and 2-chloropyridin-3-amine (69.8mg, 0.543mmol) in chlorobenzene ( 2.0 mL) in a stirred solution. After 16 hours, the solvent was removed in vacuo and the remaining residue was purified by flash chromatography (0% to 100% EtOAc in cyclohexane) to give the title compound (53.3 mg, 33%) as a pale yellow solid. LCMS (Method A): R T = 0.98 minutes, m / z = 295 [M+H] + .

[0268] Step 2: 6-(2-Chloropyridin-3-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one: DMF at room temperature under nitrogen -DMA (0.048mL, 0.362mmol) was added to N-(2-chloropyridin-3-yl)-4-methyl-2-(methylthio)pyrimidine-5-carboxamide (53.3mg, 0.181mmol) in A st...

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Abstract

The present invention relates to compounds of formula (I) that are useful as inhibitors of the activity of Wee-1 kinase. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.

Description

[0001] The present invention relates to compounds useful as inhibitors of Wee-1 kinase activity. The invention also relates to compositions comprising these compounds, and to methods of using these compounds in the treatment of cancer and methods of treating cancer. Background technique [0002] Cells are constantly under attack on a daily basis, resulting in the formation of multiple lesions in the DNA. Because the damage, if not repaired, can lead to mutation or cell death, complex signaling networks exist to ensure that damage is detected and repaired to maintain DNA integrity. [0003] Detection of DNA damage initiates a cascade of events critical in maintaining the genome. Cell cycle checkpoints are engineered to terminate the cell cycle and allow damage to be repaired before allowing cells to proceed with mitosis. [0004] Two critical checkpoints were identified, one at the end of G1 and the second at G2, which work in tandem to ensure that all damage is identified an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61P35/00
CPCC07D471/04A61K31/519A61K31/5377A61K31/541A61P35/00A61P43/00
Inventor 科林·罗德里克·奥多德詹姆士·塞缪尔·沙恩·朗特里弗兰克·布尔坎普安德鲁·约翰·威尔金森
Owner ALMAC DISCOVERY LIMITED
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