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Substituted benzo or pyridopyrimidine amine inhibitor as well as preparation method and application thereof

A pyrimidine amine and benzo-based technology is applied in the field of substituted benzo- or pyrido-pyrimidine amine inhibitors and their preparation, and can solve the problems of lowering and lowering of tumor cell proliferation rate and survival rate.

Pending Publication Date: 2022-04-22
SUZHOU ZELGEN BIOPHARML +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reduction of SOS1 levels resulted in decreased proliferation and survival of tumor cells harboring KRAS mutations but not in KRAS wild-type cell lines

Method used

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  • Substituted benzo or pyridopyrimidine amine inhibitor as well as preparation method and application thereof
  • Substituted benzo or pyridopyrimidine amine inhibitor as well as preparation method and application thereof
  • Substituted benzo or pyridopyrimidine amine inhibitor as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0205] The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.

[0206] The present invention also provides a treatment method, which includes the steps of: administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to the subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting SOS1.

[0207] Compared with the prior art, the present invention has the following main advantages:

[0208] (1) The compound has a good selective inhibitory effect on SOS1;

[0209] (2) The compound has better in vivo and in vitro pharmacodynamics, pharmacokineti...

Embodiment 1

[0219] Example 1 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((S)-1-methyl Preparation of ylpyrrolin-2-yl)methoxy)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-alcohol

[0220]

[0221] The first step: the preparation of (S)-2-(chloromethyl)-1-methylpyrroline

[0222] N-methyl-L-prolinol (500.0 mg, 4.34 mmol) was dissolved in toluene (5 mL), and thionyl chloride (2.0 mL) was added. The resulting reaction solution was stirred at 100° C. for 2.0 h, and then concentrated under reduced pressure. The obtained crude product was directly submitted to the next step without further purification.

[0223] The second step: the preparation of (S)-7-methoxy-2-methyl-6-((1-methylpyrrolin-2-yl)methoxy)quinazolin-4(3H)-one

[0224] 6-Hydroxy-7-methoxy-2-methylquinazolin-4(3H)-one (120 mg, 0.58 mmol) was added to N,N-dimethylformamide (10 mL), followed by the previous step (S)-2-(Chloromethyl)-1-methylpyrroline (77.8 mg, 0.58 mmol) and potassium carbonate (402.2 mg,...

Embodiment 2

[0233] Example 2N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)- Preparation of 1-methylpyrrolin-2-yl)methoxy)quinazolin-4-amine

[0234]

[0235] LC-MS: m / z 490 (M+H) + .

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Abstract

The invention relates to a substituted benzo or pyridopyrimidine amine inhibitor as well as a preparation method and application thereof. Specifically, the compound has a structure as shown in a formula (I), the invention further discloses a preparation method of the compound and application of the compound as an SOS1 inhibitor, and the compound has a very good selective inhibition effect on SOS1 and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a substituted benzo or pyridopyrimidine amine inhibitor and a preparation method and application thereof. Background technique [0002] Lung cancer is one of the important causes of human cancer death. According to cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which NSCLC accounts for 85% of all lung cancer patients. According to statistics, the global NSCLC market in 2016 was about 20.9 billion US dollars, of which the US market accounted for half, followed by Japan, Germany and China. Judging from the existing trends, the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018; 553(7689):446-454). [0003] At present, the main treatment drugs for NSCLC are divided into chemotherapy drugs, molecular targeted dru...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D405/14C07D401/14C07D239/94A61P35/00A61P35/02A61P29/00A61P9/00A61P31/00A61P37/02A61P3/00A61K31/517
CPCC07D403/12C07D405/14C07D401/14C07D239/94A61P35/00A61P35/02A61P29/00A61P9/00A61P31/00A61P37/02A61P3/00
Inventor 吕彬华崔大为张青柴传柯梁辉
Owner SUZHOU ZELGEN BIOPHARML
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