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Quinazoline compound, and preparation method and applications thereof

A kind of technology of compound and medicinal salt, applied in the field of quinazoline compounds and preparation thereof

Active Publication Date: 2017-03-22
CHINESE NAT HUMAN GENOME CENT AT SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, FAK inhibitors that have entered clinical research mainly include PF-562271 from Pfizer, PND-1186 from Poniad Pharmaceuticals, and Defactinib from Verastem (structural formula is as follows), but no drug has been approved for clinical cancer treatment

Method used

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  • Quinazoline compound, and preparation method and applications thereof
  • Quinazoline compound, and preparation method and applications thereof
  • Quinazoline compound, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The synthesis of embodiment 1 compound 1

[0055]

[0056] 297mg (1.28mmol) compound A-1, 275mg (1.28mmol) compound N-(3-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide and 0.356mL (2.56mmol) triethylamine Dissolve in 15mL of dichloromethane and stir at room temperature. After 4 hours, the reaction was stopped, and the solvent was evaporated under reduced pressure. The obtained crude product was washed with diethyl ether to obtain white solid B-1 with a yield of 43.0%.

[0057] 100mg (0.24mmol) of compound B-1 and 36mg (0.24mmol) of 5-aminoindolin-2-one were dissolved in 3mL of isopropanol, and microwaved at 100°C for 1h. The reaction liquid was filtered, and the filter cake was washed with a small amount of isopropanol and ether, and dried to obtain a pale yellow solid, namely compound 1, with a yield of 61.9%. m.p.183-190℃. 1 H NMR (DMSO-d 6 ,400MHz)δ=3.03(s,3H),3.10(s,3H),3.27(s,2H),4.89(s,2H),6.66(brs,1H),7.05(brs,1H),7.16(s ,1H),7.39(dd,J=7.52Hz,J=4.7...

Embodiment 2

[0058] The synthesis of embodiment 2 compound 1b

[0059]

[0060] 297mg (1.28mmol) compound A-2, 275mg (1.28mmol) compound N-(3-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide and 0.356mL (2.56mmol) triethylamine Dissolve in 15mL of dichloromethane and stir at room temperature. The reaction was stopped after 4 hours, and the solvent was evaporated under reduced pressure. The obtained crude product was washed with diethyl ether to obtain off-white solid B-2 (540 mg), with a yield of 99.0%.

[0061] 100mg (0.24mmol) of compound B-2 and 36mg (0.24mmol) of 5-aminoindolin-2-one were dissolved in 3mL of isopropanol, and microwaved at 100°C for 1h. The reaction solution was filtered, and the filter cake was washed with a small amount of isopropanol and ether, and dried to obtain 62 mg of a light green solid, namely compound 1b, with a yield of 48.8%. m.p.209-213℃. 1 H NMR (DMSO-d 6 ,400MHz)δ=3.06(s,3H),3.11(s,3H),3.35(s,2H),4.84(brs,2H),6.70(brs,1H),7.11(d,J=5.44Hz,1H ...

Embodiment 3

[0062] The synthesis of embodiment 3 compound 1c

[0063]

[0064] 297mg (1.28mmol) compound A-3, 275mg (1.28mmol) compound N-(3-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide and 0.356mL (2.56mmol) triethylamine Dissolve in 15mL of dichloromethane and stir at room temperature. The reaction was stopped after 4 hours, and the solvent was evaporated under reduced pressure. The obtained crude product was washed with ether to obtain white solid B-3 with a yield of 70.3%.

[0065] 100mg (0.24mmol) of compound B-3 and 36mg (0.24mmol) of 5-aminoindolin-2-one were dissolved in 3mL of isopropanol, and microwaved at 100°C for 1h. The reaction liquid was filtered, and the filter cake was washed with a small amount of isopropanol and ether, and dried to obtain a pale yellow solid, namely compound 1c, with a yield of 50.5%. m.p.>250℃. 1 H NMR (DMSO-d 6,400MHz)δ=3.05(s,3H),3.11(s,3H),4.84(s,2H),6.70(s,1H),7.10(s,1H),7.21(s,1H),7.41(t ,J=5.16Hz,1H),7.53(d,J=8.76Hz,1H),7.67(s,1...

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Abstract

The invention discloses a quinazoline compound represented by formula I, or a pharmaceutical salt thereof, and also discloses a preparation method of the quinazoline compound, and applications of the quinazoline compound in preparing drugs used for treating cancer. The quinazoline compound is capable of inhibiting the activity of FAK (focal adhesion kinase), and inhibiting cancer cell proliferation effectively, possesses excellent treatment effect on a plurality of cancers, especially possesses obvious treatment effect on liver cancer, and is promising in application prospect.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a quinazoline compound and a preparation method and application thereof. Background technique [0002] Focal adhesion kinase (FAK) is a 120KDa non-receptor tyrosine kinase, named after it was first discovered in cell adhesion, and plays a central role in the integrin-mediated cell signaling pathway character of. FAK has two conformations: active and inactive. Under the action of integrin, the conformation of FAK in the inactive state changes, which makes the tyrosine residue Y397 phosphorylated, and FAK turns into an active state. The activated FAK and Src The family proteins combine to form complexes, jointly activate downstream complex signaling pathways, and regulate cell adhesion, migration, proliferation, differentiation and angiogenesis in organisms. Studies have shown that FAK is significantly highly expressed in a variety of tumor cells. At the same time, the increase ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D487/04C07D239/95C07D401/12A61K31/519A61K31/517A61P35/00
CPCC07D239/95C07D401/12C07D401/14C07D487/04
Inventor 黄健张倩刘星谈寒一
Owner CHINESE NAT HUMAN GENOME CENT AT SHANGHAI
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