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Heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof

A technology of compounds and hydrates, applied in the fields of drug combination, organic chemistry, antitumor drugs, etc., to achieve the effects of excellent biological activity and druggability, superior pharmacological activity and pharmacokinetic properties

Pending Publication Date: 2022-05-06
GANJIANG NEW DISTRICT BRIGHTGENE INNOVATIVE MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, several SHP2 allosteric inhibitors have entered the clinical research stage, such as TNO-155 developed by Novartis, RMC-4630 developed by Revolution Medicine, and JAB-3068 of Beijing Jiakesi and other compounds have entered the clinical research stage , but there is no SHP2 inhibitor developed and marketed for the preparation of Noonan syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer

Method used

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  • Heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
  • Heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof
  • Heterocyclic compound as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0201] Embodiment 1: the preparation of compound 1

[0202]

[0203] Concrete synthetic route is as follows:

[0204]

[0205] Step 1: Synthesis of Compound 1B

[0206] Compound 1A (104mg, 0.5mmol) was dissolved in dioxane (5ml), and intermediate Q2 (182mg, 1mmol), Pd 2 (dba) 3 (22.73mg, 0.025mmol), Xantphos (14.36mg, 0.025mmol) and DIEA (190mg, 1.5mmol). After heating up to 90°C and stirring for 1 h under nitrogen protection, the reaction mixture was spin-dried and concentrated, and the residue was subjected to silica gel chromatography (eluent: V 二氯甲烷 :V 甲醇 =50:1~10:1) to obtain compound 1B (107 mg, light yellow solid), 75% yield.

[0207] MS(ESI):m / z 287[M+H] + .

[0208] Step 2: Synthesis of Compound 1C

[0209] Compound 1B (100mg, 0.35mmol), DIEA (154mg, 1.2mmol), intermediate Q3 (147mg, 0.7mmol) and HATU (456mg, 1.2mmol) were added to DMF, stirred at room temperature for 12h, TLC showed that after the reaction , the reaction solution was diluted with dichl...

Embodiment 2

[0215] Embodiment 2: the preparation of compound 2

[0216]

[0217] Concrete synthetic route is as follows:

[0218]

[0219] Step 1: Synthesis of Compound 2B

[0220] Compound 2A (1.0 g, 3.6 mmol), Compound Q1 (808 mg, 4.0 mmol) and DIEA (4.6 g, 36 mmol) were added to MeCN (2240 ​​mL), and the resulting solution was stirred at 80° C. for 2 hours. TLC showed the reaction was complete. The mixture was cooled to 25°C, and the Boc 2 O (1.6 g, 7.2 mmol) was added to the solution. The reaction was stirred at 50 °C for 2 hours. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=1 / 2, V / V) to obtain compound 2B (953 mg, pale yellow solid), with a yield of 48.4%.

[0221] MS(ESI):m / z 547.1[M+H] + .

[0222] Step 2: Synthesis of Compound 2C

[0223] Compound 2C (900mg, 1.6mmol) was dissolved in NMP (10ml), and intermediate Q4 (895mg...

Embodiment 3

[0229] Embodiment 3: the preparation of compound 3

[0230]

[0231] Concrete synthetic route is as follows:

[0232]

[0233] Step 1: Synthesis of Compound 3B

[0234] Compound 3A (6g, 24.80mmol) was dissolved in DMF (50mL), and a DMF solution of DIEA (8.66mL, 49.61mmol) and aminoacetaldehyde dimethyl acetal (2.90g, 27.28mmol) was added dropwise at 0°C. Reaction at room temperature for 2h. After TLC showed that the reaction was finished, water was added and extracted with ethyl acetate, the organic phase was washed with brine, and the organic phase was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: PE:EA=5:1( Volume ratio)) to obtain compound 3B (7.4 g, light yellow solid), yield 91%.

[0235] MS(ESI):m / z310[M+H] + .

[0236] Step 2: Synthesis of Compound 3C

[0237] Compound 3B (5 g, 16.10 mmol) was slowly added to concentrated sulfuric acid (15 mL) in batches under an ice bath, and the temperature w...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a heterocyclic compound and a preparation method, a pharmaceutical composition and application thereof. Particularly, the invention relates to a heterocyclic compound as shown in a formula I, a pharmaceutical composition containing the heterocyclic compound and application of the heterocyclic compound as an SHP2 inhibitor in the field of medicine. The heterocyclic compound provided by the invention shows excellent biological activity and druggability, and has great drug development prospects.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of heterocyclic compounds, a preparation method of the compound and its intermediate, a pharmaceutical composition containing the compound and its application in the field of medicine. Background technique [0002] The tyrosine phosphatase SHP2 consists of two N-terminal Src homology 2 domains (N-SH 2 and C-SH 2 ) and a protein tyrosine phosphatase catalytic domain (PTP). In base state, N-SH 2 It can combine with PTP to form a ring structure, thereby hindering the combination of PTP and the substrate, so that the catalytic activity of the enzyme is inhibited; when the tyrosine of the upstream receptor protein is phosphorylated, N-SH 2 In conjunction with this, the PTP catalytic domain is released to exert phosphatase activity. [0003] At the cellular level, SHP2 participates in multiple tumor cell signaling pathways, such as RTK / Ras / MAPK, JAK / STAT, and P...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/519A61P35/00A61P35/02A61P43/00
CPCC07D519/00A61P35/00A61P35/02A61P43/00A61K31/519C07D487/10A61K31/438A61K31/495
Inventor 袁建栋方华祥黄仰青顾家宁王晨英李宸杰吴敬浩
Owner GANJIANG NEW DISTRICT BRIGHTGENE INNOVATIVE MEDICINE CO LTD
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