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

A phosphoryl quinazoline and derivative technology, applied in chemical instruments and methods, active ingredients of phosphorus compounds, drug combinations, etc., can solve problems such as differences in biological functions, and achieve low toxicity, high safety, and druggability. Effects with low risk of drug-drug interactions

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0343] Example 1: Preparation of Compound I-1

[0344] The synthetic route is as follows:

[0345]

[0346] The first step: the synthesis of methyl 2-amino-4-methoxybenzoate (B1-2)

[0347]

[0348] To a solution of compound B1-1 (5 g, 29.91 mmol) in methanol (60 mL) was added dropwise thionyl chloride (299 mmol, 21.7 mL) at 5°C, and the reaction solution was reacted at 70°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by beating with ethyl acetate, and filtered to obtain compound B1-2 (4.34 g, yield 80%).

[0349] The second step: the synthesis of methyl 2-amino-5-iodo-4-methoxybenzoate (B1-3)

[0350]

[0351] To a solution of Compound B1-2 (4 g, 22.1 mmol) in DMF (60 mL) was added N-iodosuccinimide (5.22 g, 23.2 mmol) at room temperature, followed by reaction at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which wa...

Embodiment 2

[0363] Example 2: Preparation of Compound 1-2

[0364] (R)-Diethyl(7-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline Synthesis of -6-yl)phosphine oxide (I-2)

[0365]

[0366] Compound B1-5 (100 mg, 0.2 mmol) was dissolved in DMF (3 mL), and diethylphosphine oxide (31 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (0.016 mmol, 14.7 mmol) were added under nitrogen protection mg), 4,5-bis(diphenylphosphonium)-9,9-dimethylxanthene (0.032 mmol, 18.5 mg) and triethylamine (0.08 mL, 0.6 mmol). The reaction solution was reacted at 90°C. After the reaction was completed, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by column chromatography to obtain the target compound I-2 (75 mg, yield 78%).

[0367] 1 H NMR (400MHz, CDCl 3 ):δ8.38(d,1H),7.62-7.52(m,1H),7.28-7.24(m,1H),7.10(d,1H),6.34(d,1H),5.87-5.80(m,1H) ),3.92(s,3H),2.63(d,3H),2.52(s,3H),2.14-1.96(m,4H),...

Embodiment 3

[0369] Example 3: Preparation of Compound 1-3

[0370] The synthetic route is as follows:

[0371]

[0372] The first step: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-iodo-7-methoxy-2-methylquinazoline Synthesis of -4-amine (B3-1)

[0373]

[0374] To a solution of compound B1-4 (350 mg, 1.11 mmol) in dichloromethane (9 mL) was added 2,4,6-triisopropylbenzenesulfonyl chloride (368 mg, 1.22 mmol), 4-dimethylaminopyridine (13.4 mg) , 0.11 mmol), triethylamine (0.46 mL, 3.33 mmol). The reaction solution was then reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the crude product, and triethylamine (0.46 mL, 3.33 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane were added to the DMSO solution of the crude product -1-amine hydrochloride (250 mg, 1.11 mmol), then reacted at 80°C overnight. The reaction solution was cooled to room temperature. Water was added to the reaction solution, extracte...

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Abstract

The invention provides a 6-substituted phosphoryl quinazoline derivative as well as a preparation method and application thereof. The invention provides a 6-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 6-substituted phosphoryl quinazoline derivative. The 6-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 6-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): C07F9/6512C07F9/6561C07F9/6584C07F9/6558C07F9/6568A61P35/00A61K31/675
CPCC07F9/65128C07F9/65616C07F9/6584C07F9/65586C07F9/65583C07F9/65685A61P35/00A61K31/675C07F9/6512C07F9/6558C07F9/6561C07F9/6568C07D487/04A61K31/517A61K31/66
Inventor 张学军常少华李学强叶大炳刘礼飞杨俊李莉娥
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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