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Pyrimidopyrimidinones useful as Wee-1 kinase inhibitors

A kind of medicinal salt, C1-C6 technology, applied in the compound field of Wee-1 kinase activity inhibitor

Active Publication Date: 2016-08-03
ALMAC DISCOVERY LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Radiation is known to elevate phosphorylation of Tyr15 and Thr14 residues of cdc2, resulting in a radioresistant phenotype

Method used

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  • Pyrimidopyrimidinones useful as Wee-1 kinase inhibitors
  • Pyrimidopyrimidinones useful as Wee-1 kinase inhibitors
  • Pyrimidopyrimidinones useful as Wee-1 kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0303] Example 1: 3-(2,6-dichlorophenyl)-1-methyl-7-((4-(piperazin-1-yl)phenyl)amino)-2,3-dihydro pyrimido[4,5-d]pyrimidin-4(1H)-one

[0304]

[0305] Step 1: N-(2,6-Dichlorophenyl)-4-(methylamino)-2-(methylthio)pyrimidine-5-carboxamide:

[0306]4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylic acid [Bioorg.Med.Chem.2005,13(16),4936](0.5g, 2.51mmol) was suspended in chlorobenzene ( 10 mL) and added 2,6-dichloroaniline (0.407 g, 2.51 mmol). Phosphorus trichloride (0.220 mL, 2.51 mmol) was added and the mixture was stirred at 120°C for 16 hours. React with 2M Na 2 CO 3 The aqueous solution was quenched, then extracted with ethyl acetate (x2). The combined organic extracts were washed with brine and dried (MgSO 4 ), filtered and concentrated (azeotrope with toluene). The residue was triturated with diethyl ether and the title compound was collected by filtration to give the title compound (180 mg, 21%) as a yellowish solid. The mother liquor was concentrated to ...

Embodiment 2

[0317] Example 2: 3-(2,6-dichlorophenyl)-1-methyl-7-((4-(2-(methylamino)ethoxy)phenyl)amino)-2, 3-Dihydropyrimido[4,5-d]pyrimidin-4(1H)-one

[0318]

[0319] According to the method of Example 1, 3-(2,6-dichlorophenyl)-1-methyl-7-(methylthio)-2,3-dihydropyrimido[4,5-d]pyrimidine -4(1H)-Kone (82 mg, 0.231 mmol) was reacted with (2-(4-aminophenoxy)ethyl)(methyl)carbamate tert-butyl ester (61.5 mg, 0.231 mmol) to give The title compound (27mg, 24%).

[0320] 1 HNMR (500MHz, DMSO-d 6 ): δ9.71(s, 1H), 8.45(s, 1H), 7.69(m, 4H), 7.47(m, 1H), 6.89(d, 2H), 4.88(s, 2H), 3.97(m, 2H), 3.10(s, 3H), 2.81(t, 2H), 2.32(s, 3H).

[0321] LCMS (Method A): R T = 0.77 minutes, m / z = 473 [M+H] + .

Embodiment 3

[0322] Example 3: 3-(2,6-dichlorophenyl)-7-((3-methoxy-4-(piperazin-1-yl)phenyl)amino)-1-methyl - 2,3-Dihydropyrimido[4,5-d]pyrimidin-4(1H)-one

[0323]

[0324] According to the method of Example 1, 3-(2,6-dichlorophenyl)-1-methyl-7-(methylthio)-2,3-dihydropyrimido[4,5-d]pyrimidine - 4(1H)-one (50 mg, 0.141 mmol) was reacted with tert-butyl 4-(4-amino-2-methoxyphenyl)piperazine-1-carboxylate (43 mg, 0.14 mmol) to give The title compound as a solid (34 mg, 47%).

[0325] 1 HNMR (500MHz, DMSO-d 6 ): δ9.75(s, 1H), 8.48(s, 1H), 7.65(m, 3H), 7.47(m, 1H), 7.21(d, 1H), 6.85(d, 1H), 4.97(s, 2H), 3.69(s, 3H), 3.13(s, 3H), 2.92(m, 8H).

[0326] LCMS (Method A): R T = 0.75 minutes, m / z = 514 [M+H] + .

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Abstract

The invention discloses pyrimidopyrimidinones useful as Wee-1 kinase inhibitors. The present invention relates to compounds 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 pharmaceutical 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. If the damage is not repaired, it can lead to mutation or cell death, so a complex signaling network exists to ensure that the 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 have been identified, one at the end of G1 and the second at G2, which work in tandem to ensure that a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/519A61P35/00C07D487/14
CPCC07D487/14C07D519/00C07D475/00C07D487/04A61P35/00A61K31/519A61K45/06A61K2300/00
Inventor 蒂莫西·哈里森格雷厄姆·特雷维特彼得·罗宾·休伊特科林·罗德里克·奥多德弗兰克·布尔坎普安德鲁·约翰·威尔金森史蒂文·D·谢泼德休斯·米尔
Owner ALMAC DISCOVERY LIMITED
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