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Substituted pyrazole fused ring derivative as well as preparation method and application thereof

A compound and heterocyclic group technology, applied in the field of substituted pyrazole fused ring derivatives and its preparation, can solve problems such as off-target toxicity, poor ORR, and limited treatment options for patients

Active Publication Date: 2020-04-07
APPLIED PHARMA SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no approved drug that can be used to specifically target this unanimous oncogene. The current treatment methods for RET-specific cancers are limited to multikinase inhibitors and chemotherapy, but these non-specific treatments have clinically manifested ORR (objective sustained release rate) is not high. Good with significant off-target toxicity
Furthermore, one of the biggest challenges in cancer treatment is that tumor cells develop drug resistance after a certain period of treatment. Once drug resistance occurs, the patient's treatment options are usually very limited, and in most cases, the cancer continues to progress and is not suppressed

Method used

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  • Substituted pyrazole fused ring derivative as well as preparation method and application thereof
  • Substituted pyrazole fused ring derivative as well as preparation method and application thereof
  • Substituted pyrazole fused ring derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0186] 2-amino-4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (APS069)

[0187]

[0188] Step A: tert-Butyl((methylsulfonyl)oxy)carbamate

[0189]

[0190] Under stirring in an ice bath, add 2,4,6-trimethylbenzenesulfonyl chloride (20.0g, 91.5mmol) and tert-butyl N-hydroxycarbamate (12.2g, 91.5mmol) to methyl tert-butyl ether (500mL) solution, triethylamine (13.0mL, 93.3mmol) was slowly added dropwise through a constant pressure dropping funnel, and the temperature of the reaction system was kept below 5°C during the dropwise addition. Under ice bath, the reaction system was stirred for 4.0 hours, filtered under reduced pressure to remove triethylamine hydrochloride, and rinsed with methyl tert-butyl ether three times, all the filtrate was concentrated under reduced pressure at a water bath temperature of less than 15°C to remove most of the methyl Tert-butyl ether; under ice bath...

Embodiment 2

[0237] 2-amino-6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridine-3- base) pyrazolo[1,5-a]pyridine-3-carbonitrile (APS070)

[0238]

[0239] Step A: 1-tert-butoxycarbonyl-4-(pyridin-2-ylmethyl)piperidine

[0240]

[0241] 1-tert-butoxycarbonyl-4-methylenepiperidine (6.0g, 30.4mmol) and 9-borabicyclo[3,3,2]nonane (60.8mL, 30.4mmol, the concentration of the THF solution formed was 2M) mixture was heated to reflux under nitrogen protection for 3 hours, cooled to room temperature, 2-bromopyridine (5.28g, 33.44mmol), 1,1'-bis(diphenylphosphino)ferrocene di Palladium(II) chloride (666mg, 0.91mmol), potassium carbonate (5.04g, 36.48mmol), DMF (80mL), H 2 O (12mL); the reaction mixture was stirred overnight at 60°C, after the TLC spot plate reaction was completed, water was added, and the pH value of the reaction mixture was adjusted to 11 with 10% aqueous sodium hydroxide solution, extracted with ethyl acetate, the combined organic phases, and wa...

Embodiment 3

[0256] 2-Methyl-4-(6-(4-(2-(5-fluoropyridin-2-yl)acetyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl -1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (APS071)

[0257]

[0258] Step A: Ethyl 2-methyl-6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate

[0259]

[0260] At room temperature, add 2,4,6-trimethylbenzenesulfonic acid 1-amino-3-bromo-5-methoxypyridin-1-ium (2.79g, 6.91mmol) in DMF (25mL) solution Triethylamine (1.93mL, 13.82mmol) was added; the reaction system was cooled to 0°C, ethyl butynoate (1.62mL, 13.82mmol) was added in batches, raised to room temperature and stirred overnight; the reaction was completed, quenched with water, Extract with ethyl acetate, combine the organic phases, wash with water, concentrate under reduced pressure, and separate by column chromatography to obtain the product 2-methyl-6-bromo-4-methoxypyrazolo[1,5-a]pyridine- Ethyl 3-carboxylate (510 mg, 24% yield).

[0261] 1 HNMR (400MHz, CDCl 3 )δ8.13(d, J=1.2Hz, 1H), 6.58(...

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Abstract

The invention relates to the field of medicinal chemistry, and mainly relates to a compound represented by a formula I, a stereoisomer, a despinner, a tautomer, an isotope marker, NOx or a pharmaceutically acceptable salt thereof, a preparation method of the compound, and an application of the compound in preparation of a medicine for treating RET kinase mediated diseases.

Description

[0001] This application claims the priority rights of the prior patent application with the application number 201811162497.1 and the title of the invention "Substituted pyrazole fused ring derivatives and their preparation method and application" submitted to the State Intellectual Property Office of China on September 30, 2018 . The entirety of this prior patent application is incorporated herein by reference. technical field [0002] The invention relates to the field of medicinal chemistry, in particular to substituted pyrazole condensed ring derivatives and their preparation methods and applications. Background technique [0003] RET (Rearranged During Transfection) proto-oncogene was first confirmed in 1985 by transfecting NIH3T3 (mouse embryonic fibroblast cell line) cells with human lymphoma DNA (Cell, 1985, 42(2): 581-588 ). The RET proto-oncogene is located on chromosome 10q11.2, its DNA is 60kb in full length, contains 21 exons, and encodes a RET protein consist...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61K31/496A61K31/4427A61K31/444A61K31/4545A61P35/00A61P1/00A61P29/00A61P1/12
CPCC07D471/04C07D519/00A61P35/00A61P1/00A61P29/00A61P1/12A61K45/06A61K31/496A61K31/4545A61K31/4162A61K31/4427A61K31/444C07D487/04A61K31/4995
Inventor 王志健钟俊王雪冰
Owner APPLIED PHARMA SCI
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