4, 6, 7-trisubstituted 1, 2-dihydropyrrolo [3, 4-c] pyridine/pyrimidine-3-ketone derivative and application thereof

An unsubstituted, compound technology for applications

Active Publication Date: 2022-05-13
SHANGHAI HAIYAN PHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, only ibrutinib, the only BTK inhibitor, has been approved for marketing, so it is necessary to develop more active, safer and more effective BTK inhibitors

Method used

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  • 4, 6, 7-trisubstituted 1, 2-dihydropyrrolo [3, 4-c] pyridine/pyrimidine-3-ketone derivative and application thereof
  • 4, 6, 7-trisubstituted 1, 2-dihydropyrrolo [3, 4-c] pyridine/pyrimidine-3-ketone derivative and application thereof
  • 4, 6, 7-trisubstituted 1, 2-dihydropyrrolo [3, 4-c] pyridine/pyrimidine-3-ketone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0227] Example 2 6-(1-acryloylpiperidin-3-ylamino)-7-fluoro-4-(4-(2-methoxyethoxy)phenylamino)-1H-pyrrolo[3, 4-c] Preparation of pyridin-3(2H)-one (G-2)

[0228]

[0229] Step 1: Add compound 2.1 (600mg, 3mmol) and DIPEA (780mg, 6mmol) to a solution of compound 1a (740mg, 2mmol) in NMP (10mL), and react the mixture with microwave at 180°C for 30min under argon atmosphere. LC-MS tracked until the reaction was complete. The reaction solution was cooled to room temperature, diluted with DCM, washed with water and saturated brine respectively, the organic layer was dried, concentrated and purified by combiflash to obtain 300 mg of compound 2-1. MS m / z(ESI):535[M+H] + .

[0230] Step 2: Compound 2-1 (250mg, 0.5mmol), Compound 2.2 (102mg, 0.6mmol), Pd 2 (dba) 3 (45mg, 0.05mmol), Xantphos (54mg, 0.1mmol), and cesium carbonate (326mg, 1mmol) in 1,4-dioxane (15mL) were microwaved at 160°C for 50min under an argon atmosphere. LC-MS tracked until the reaction was complete. The ...

Embodiment 3

[0233] Example 3 6-(1-acryloylazepan-3-ylamino)-7-fluoro-4-(4-(2-methoxyethoxy)phenylamino)-1H-pyrrolo Preparation of [3,4-c]pyridin-3(2H)-one (G-3)

[0234]

[0235] Step 1: The preparation method is the same as that of compound 2-1, except that compound 2.1 in the preparation method of compound 2-1 is replaced by compound 3.1. MS m / z(ESI):549.3[M+H] + .

[0236] Step 2: The preparation method is the same as that of compound 2-2, except that compound 2-1 in the preparation method of compound 2-2 is replaced by compound 3-1. MS m / z(ESI):680.5[M+H] + .

[0237] Step 3: To a solution of compound 3-2 (83 mg, 0.001 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h. LC-MS tracked until the reaction was complete. Remove most of TFA under reduced pressure, add saturated sodium bicarbonate solution, adjust pH to 7-8, extract with DCM, combine organic layers, dry and concentrate to obtain compound 3-3, which is directly used in the ...

Embodiment 7

[0240] Example 7 6-(1-acryloylpiperidin-3-ylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4- c] Preparation of pyridin-3(2H)-one (G-7)

[0241]

[0242] Step 1: Compound 2-1 (150mg, 0.3mmol), Compound 7.1 (150mg, 0.5mmol), Pd(dppf)Cl 2(25mg, 0.03mmol), a mixture of potassium carbonate (130mg, 0.9mmol) in 1,4-dioxane (10mL) and water (1mL) was microwaved at 130°C for 30min under an argon atmosphere. LC-MS tracked until the reaction was complete. The solvent was evaporated to dryness under reduced pressure, and the residue was purified by combiflash to obtain 140 mg of compound 7-1. MS m / z(ESI):581[M+H] + .

[0243] Step 2: A solution of compound 7-1 (140 mg, 0.2 mmol) in TFA (3 mL) was stirred at 80° C. for 3 h. LC-MS tracked until the reaction was complete. The reaction solution was added with saturated sodium carbonate solution to adjust the pH to 7, extracted with DCM, washed with saturated brine, and the organic layer was dried and concentrated to obtai...

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Abstract

The invention relates to a 4, 6, 7-trisubstituted 1, 2-dihydropyrrolo [3, 4-c] pyridine / pyrimidine-3-ketone derivative, and a preparation method and a medical application thereof. Specifically, the invention discloses a compound shown as a formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, and a preparation method and application thereof, and the definition of each group in the formula is shown in the specification and the claims.

Description

technical field [0001] The invention belongs to the technical field of medicine. Specifically, the present invention particularly relates to a 4,6,7-trisubstituted 1,2-dihydropyrrolo[3,4-c]pyridine / pyrimidin-3-one derivative and its preparation method and as a BTK inhibitor The application of the agent, and the pharmaceutical composition prepared therefrom. Background technique [0002] BTK kinase is a non-receptor tyrosine kinase in the TEC kinase family. It is a key regulator of the BCR signaling pathway and plays an important role in the maturation, proliferation and survival of B cells. BTK is overexpressed in a variety of B-cell lymphomas and is currently the only clinically proven target for effective drug development in the TEC kinase family. Inhibition of BTK inhibits the proliferation of a range of B-cell lymphomas. [0003] The activation of B cell antigen receptor (BCR) signaling pathway plays an important role in the induction and maintenance of B cell maligna...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04C07D519/00A61K31/4545A61K31/55A61K31/519A61P35/00A61P37/08A61P37/06A61P29/00A61P35/02A61P19/02A61P17/00A61P17/06
CPCC07D487/04C07D471/04C07D519/00A61P35/00A61P37/08A61P37/06A61P29/00A61P35/02A61P19/02A61P17/00A61P17/06A61K31/437A61K31/519A61P37/00Y02P20/55A61P35/04
Inventor 郭淑春周福生陈祥赵金柱黄栋谢婧乔长江何宛张凯陈曦兰炯
Owner SHANGHAI HAIYAN PHARMA TECH
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