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7-substituted phosphoryl quinazoline derivative as well as preparation method and application thereof

A technology for phosphoryl quinazolines and derivatives, which is applied in the field of 7-substituted phosphoryl quinazoline derivatives and their preparation, can solve problems such as differences in biological functions, and achieves low toxicity, high purity and high yield Effect

Pending Publication Date: 2022-07-08
WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Humans have two SOS homologues—SOS1 and SOS2, which are highly similar in structure and sequence, with 70% homology, but there are certain differences in biological functions

Method used

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  • 7-substituted phosphoryl quinazoline derivative as well as preparation method and application thereof
  • 7-substituted phosphoryl quinazoline derivative as well as preparation method and application thereof
  • 7-substituted phosphoryl quinazoline derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] Example 1: Synthesis of Compound I-1

[0204] The synthetic route is as follows:

[0205]

[0206] The first step: Synthesis of (S)-4-bromo-2-nitro-5-((tetrahydrofuran-3-yl)oxy)benzoic acid methyl ester (B1-2)

[0207]

[0208] Compound B1-1 (5.0 g, 18 mmol) was dissolved in DMF (50 mL), potassium carbonate (3.7 g, 27 mmol) and (S)-3-hydroxytetrahydrofuran (1.74 g, 19.8 mmol) were added, and the reaction was carried out at 80°C. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. Water was added to the crude product, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain compound B1-2 (3.73 g, yield 60%).

[0209] The second step: Synthesis of (S)-2-amino-4-bromo-5-((tetrahydrofuran-3-yl)...

Embodiment 2

[0223] Example 2: Synthesis of Compound 1-2

[0224] The synthetic route is as follows:

[0225]

[0226] The first step: the synthesis of (S)-5-(3-acetamidopyrrolidin-1-yl)-4-bromo-2-nitrobenzoic acid methyl ester (B2-2)

[0227]

[0228] Compound B1-1 (2.0 g, 7.22 mmol) was dissolved in DMF (20 mL), potassium carbonate (1.49 g, 10.8 mmol) and (3S)-(-)-3-acetamidotetrahydropyrrole (compound B2-1) were added. ) (1.02g, 7.94mmol), reacted at 80°C for 5h. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. Water was added to the crude product, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain compound B2-2 (2.36 g, yield 85%).

[0229] The second step: the synthesis of (S)-5-(3-acetamidopyrrol...

Embodiment 3

[0243] Example 3: Synthesis of Compound 1-3

[0244] The synthetic route is as follows:

[0245]

[0246] The first step: the synthesis of (S)-5-((1-acetylpyrrolidin-3-yl)oxy)-4-bromo-2-nitrobenzoic acid methyl ester (B3-1)

[0247]

[0248] Compound B1-1 (1.6 g, 5.76 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.20 g, 8.64 mmol) and 1-[(3S)-3-hydroxypyrrolidine were added -1-yl]Ethan-1-one (0.82 g, 6.34 mmol), reacted at 80°C overnight. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. Water was added to the crude product, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product B3-1 (1.8 g, yield 81%).

[0249] The second step: the synthesis of (S)-5-((1-acetylpyrrolidin-3-yl)oxy)-2-amino-4-bromobenzoic acid methyl ester (B3-2)

[0250]

[02...

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PUM

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Abstract

The invention provides a 7-substituted phosphoryl quinazoline derivative as well as a preparation method and application thereof. The invention provides a 7-substituted phosphoryl quinazoline derivative as shown in a formula I, and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the 7-substituted phosphoryl quinazoline derivative. The 7-substituted phosphoryl quinazoline derivative disclosed by the invention has a relatively good SOS1 inhibition effect.

Description

technical field [0001] The present invention relates to a 7-substituted phosphoryl quinazoline derivative and its preparation method and application. Background technique [0002] The RAS protein is a membrane-bound protein with intrinsic GTPase activity that is activated by many extracellular stimuli, cycling between a GDP-bound (off) state and a GTP-bound (on) state. When it is in the GTP-bound (on) state, it can activate downstream pathways and promote a series of processes such as cell proliferation, differentiation, migration, and immunity. [0003] The RAS protein family includes three highly homologous isoforms: KRAS (Kirsten rat sarcoma virus oncogene), HRAS (Harvey rat sarcoma virus oncogene) and NRAS (Neuroblastoma rasoncogene). KRAS contains two alternative splicing variants: KRAS4A and KRAS4B . RAS family proteins have weak endogenous GTPase activity and slow nucleotide exchange rates (Hunter et al. Mol. Cancer Res. 2015, 13(9): 1325-1335). [0004] Activation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6512C07F9/6558C07F9/6561A61P35/00A61K31/675
CPCC07F9/65586C07F9/65583C07F9/65128C07F9/6561A61P35/00Y02P20/55
Inventor 张学军常少华王洪强李群丁肖华雷四军张辛杨俊李莉娥
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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