Quinazoline derivatives as antitumor agents

A compound and pharmaceutical technology, applied in the field of novel quinazoline compounds

Pending Publication Date: 2021-04-13
SUZHOU ZANRONG PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Limited clinical efficacy was observed when treating BCBM patients with the aforementioned non-brain penetrating antibodies, ADCs and TKIs

Method used

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  • Quinazoline derivatives as antitumor agents
  • Quinazoline derivatives as antitumor agents
  • Quinazoline derivatives as antitumor agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0463] N-(4-([1,2,4]triazol[4,3-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-(3-(dimethylamino) Azetidin-1-yl)-6-methoxyquinazolin-4-amine

[0464]

[0465] Step 1: 4-Chloro-6-hydrazinopyrimidine

[0466]

[0467] To a solution of 4,6-dichloropyrimidine (100 g, 675.7 mmol) in EtOH (900 mL) was added 50 wt% aqueous hydrazine (130 mL) dropwise at 45°C over 2 hours. The reaction was then stirred at 45-50°C for 2 hours. The crude mixture was filtered and the solid was washed with water to give the desired product (91 g, 94%) as a yellow solid. MS(ESI)m / z:145.1(M+H) + .

[0468] Step 2: 7-Chloro-[1,2,4]triazolo[1,5-c]pyrimidine

[0469]

[0470] 4-Chloro-6-hydrazinopyrimidine (91 g, 632 mmol) was dissolved in HC (OMe) 3 The solution in was stirred overnight at 90 °C. The crude mixture was concentrated and washed with NaHCO 3 Dilute with aqueous solution (500 mL). The resulting mixture was extracted with EtOAc (500 mL×2). The organic phase was washed with water and brin...

Embodiment 2

[0513] (R)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-(3-(di Methylamino)pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine

[0514]

[0515] The title compound was prepared using a method similar to Example 1 to afford the desired product as a white solid. MS:m / z512(M+H) + . 1 H NMR (400MHz, CDCl 3 )δ13.66(d, J=24.1Hz, 1H), 9.20(dd, J=3.6, 1.2Hz, 1H), 8.57(s, 1H), 8.32(d, J=4.1Hz, 1H), 8.06- 7.63(m,4H),7.49(dd,J=9.2,4.3Hz,1H),7.12(dd,J=13.5,8.7Hz,1H),6.88(dd,J=16.3,1.3Hz,1H),4.01 (d, J=3.7Hz, 3H), 3.69-3.24(m, 4H), 3.02(d, J=33.0Hz, 1H), 2.44-2.20(m, 11H).

Embodiment 3

[0517] (S)-N-(4-([1,2,4]triazol[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-(3-(two Methylamino)pyrrolidin-1-yl)-6-methoxyquinazolin-4-amine

[0518]

[0519] The title compound was prepared using a method similar to Example 1 to give the desired product as a yellow solid. MS:512(M+H) + . 1 H NMR (400MHz, CDCl 3 )δ13.68(d, J=23.0Hz, 1H), 9.20(d, J=3.6Hz, 1H), 8.57(s, 1H), 8.32(d, J=4.0Hz, 1H), 8.07-7.63( m,4H),7.48(dd,J=9.2,4.0Hz,1H),7.11(dd,J=13.9,8.7Hz,1H),6.88(d,J=16.3Hz,1H),4.01(d,J =2.7Hz, 3H), 3.70-3.22(m, 4H), 3.12-2.89(m, 1H), 2.59-2.03(m, 11H).

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PUM

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Abstract

The present application relates to novel quinazoline compounds as inhibitors of type I receptor tyrosine kinases, the pharmaceutical compositions comprising one or more of the compounds and salts thereof as an active ingredient, and the use of the compounds and salts thereof in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals and especially in humans.

Description

technical field [0001] The application relates to novel quinazoline compounds as type I receptor tyrosine kinase inhibitors, pharmaceutical compositions comprising one or more of the compounds and their salts as active ingredients, and the compounds and their salts in mammals, especially are uses in the treatment of hyperproliferative diseases such as cancer and inflammation in humans. Background technique [0002] The type I tyrosine kinase receptor family consists of four structurally related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4) (Riese and Stern, Bioessays (1998) 20 :41-48; reviewed in Olayioye et al., EMBO Journal (2000) 19:3159-3167; and Schlessinger, Cell (2002) 110:669-672). All four family members have a nearly identical structure consisting of an extracellular region or extracellular domain or ligand-binding domain, a single transmembrane domain, and an intracellular cytoplasmic tyrosine kinase domain. [0003] HER2 has been ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/517A61P35/00
CPCA61P35/00A61K31/517A61K31/7068A61K31/5025C07D487/04A61K2300/00A61K31/519A61K45/06A61P29/00A61K31/5377A61K39/3955C07D519/00
Inventor 周鼎程子强
Owner SUZHOU ZANRONG PHARMA LTD
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