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Substituted bicyclic aromatic heterocyclic amine inhibitor as well as preparation method and application thereof

An unsubstituted, heterocyclic-based technology, applied in the field of substituted bicyclic and aromatic heterocyclic amine inhibitors and its preparation, can solve the problems of reducing tumor cell proliferation rate and survival rate

Pending Publication Date: 2022-08-02
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 bicyclic aromatic heterocyclic amine inhibitor as well as preparation method and application thereof
  • Substituted bicyclic aromatic heterocyclic amine inhibitor as well as preparation method and application thereof
  • Substituted bicyclic aromatic heterocyclic amine inhibitor as well as preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0223] 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 the pharmaceutical composition.

[0224] The present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting SOS1.

[0225] Compared with the prior art, the present invention has the following main advantages:

[0226] (1) The compound has a good selective inhibitory effect on SOS1;

[0227] (2) The compound has better in vitro and in vivo pharmacodynami...

Embodiment 1

[0237] Example 1(R)-N-(1-(3-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8-dihydro-[1, 4] Preparation of dioxin[2,3-g]quinazolin-4-amine

[0238]

[0239] The first step: preparation of 2,3-dihydrobenzo[b][1,4]dioxin-6-carbonitrile

[0240] 3,4-Dihydroxybenzonitrile (5g, 37mmol) was added to N,N-dimethylformamide (50mL), followed by 1,2-dibromoethane (28g, 148mmol) and potassium carbonate (26g, 185 mmol). The obtained reaction solution was stirred at 80 degrees overnight, then cooled down, poured into 500 mL of water, and extracted three times with 100 mL of ethyl acetate. The combined organic phases were dried and filtered, the filtrate was concentrated, and the obtained residue was separated by silica gel column chromatography (PE:EA=5:1) to obtain the target product (3.5 g, yield: 58%).

[0241] LC-MS: m / z 162 (M+H) + . 1 H NMR (400MHz, CDCl 3 )δ7.15-7.13(m,2H),6.92-6.90(m,1H),4.33-4.31(m,2H),4.29-4.27(m,2H).

[0242] Step 2: Preparation of 7-nitro-2,3-dih...

Embodiment 2

[0258] Example 2 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(methoxymethyl)-2-methyl-7,8 -Dihydro-[1,4]dioxo[2,3-g]quinazolin-4-amine and N-((R)-1-(3-amino-5-(trifluoromethyl) Phenyl)ethyl)-8-(methoxymethyl)-2-methyl-7,8-dihydro-[1,4]dioxo[2,3-g]quinazoline-4 - Preparation of amine mixtures

[0259]

[0260] LC-MS: m / z 449 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.98-7.91(m,2H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.52-5.47(m,3H),4.49 -4.40(m, 2H), 4.15-4.09(m, 1H), 3.64-3.62(m, 2H), 3.34-3.33(m, 3H), 2.33(s, 3H), 1.52-1.50(m, 3H) .

[0261] Example 2 Four isomers were obtained by chiral separation

[0262]

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Abstract

The invention relates to a substituted bicyclic aromatic heterocyclic 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 medicine, in particular to a substituted bicyclic aromatic heterocyclic amine inhibitor and a preparation method and application thereof. Background technique [0002] Lung cancer is one of the important causes of human cancer death. Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, and NSCLC accounts for 85% of all lung cancer patients. According to statistics, the global NSCLC market in 2016 was about US$20.9 billion, 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 drugs and tumor immunotherapy...

Claims

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Application Information

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IPC IPC(8): C07D491/056C07D491/147C07D498/04C07D487/04C07D491/20C07D239/70C07D491/22C07D471/14C07D491/048C07D491/153A61K31/519A61K31/527A61K31/5383A61P35/00
CPCC07D491/056C07D491/147C07D498/04C07D487/04C07D491/20C07D239/70C07D491/22C07D471/14C07D491/048C07D491/153A61P35/00A61K31/519A61K31/527A61K31/5383A61K31/517
Inventor 吕彬华崔大为
Owner SUZHOU ZELGEN BIOPHARML
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