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A class of saturated six-membered ring heterocyclic compounds, preparation method and use

A compound and six-membered ring technology, which is applied in the field of preparation, compounds that inhibit the activity of Ras mutant proteins, saturated six-membered rings and heterocyclic compounds, can solve the problems of unsuccessful development of targeted drugs and little effect

Active Publication Date: 2021-12-07
RUDONG RINGENE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, more than 30 years have passed since the Kras oncogene was first discovered, and several generations of targeted drugs for common proto-oncogenes such as EGFR and BCL have gone through, but the targeted drug for Kras has never been successfully developed
For a long time, targeted drugs against KRas pathway mutant tumors have mainly focused on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but with little success

Method used

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  • A class of saturated six-membered ring heterocyclic compounds, preparation method and use
  • A class of saturated six-membered ring heterocyclic compounds, preparation method and use
  • A class of saturated six-membered ring heterocyclic compounds, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Example 1: (S) -1- (4- (8- (5- methyl -1H- indazol-4-yl) -1- (1-methyl-pyrrolidin-2-yl) - 6,7 , 8,9-tetrahydro-pyrido [4,3-e] [1,2,4] triazolo [4,3-a] pyrimidin-5-yl) piperazin-1-yl) propan-2- - en-1-one

[0203]

[0204] Step: 2,4-dichloro-5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate (10.4g, 34.3 mmol) and piperazine - 1- carboxylic acid benzyl ester (7.5g, 34.1mmol) was dissolved in 1,4-dioxane (200mL) was added DIPEA (13.2g, 102mmol). At room temperature for 2 days, concentrated under reduced pressure, the residue was purified by column chromatography to give 4- (4 - ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - carboxylate (11g, white solid). LC-MS: ESI [M + H] + = 488.5; 1 HNMR (400MHz, DMSO-D 6 ): Δ7.33-7.39 (m, 5H), 5.11 (s, 2H), 4.37 (brs, 2H), 3.50 (brs, 10H), 2.63-2.65 (m, 2H), 1.44 (s, 9H).

[0205] Step: 4- (4 - ((benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-5,8-dihydro-pyrido [3,4-d] pyrimidin...

Embodiment 2

[0214] Example 2: Preparation of 1- (4- (8- (5-methyl -1H- indazol-4-yl) -6,7,8,9-tetrahydro-pyrido [4,3-e] [1, 2,4] triazolo [4,3-a] pyrimidin-5-yl) piperazin-1-yl) prop-2-en-1-one

[0215]

[0216] Step: 4- (2-hydrazino-7- (5-methyl-1 - ((2- (trimethylsilyl) ethoxy) methyl) lH-indazol-4-yl ) - 5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (0.5g, 0.79mmol) was dissolved in dichloromethane (15mL ) was added trimethyl orthoformate (340mg, 3.2mmol), stirred ten minutes, then trifluoroacetic acid (95mg, 0.83mmol). After continued stirring at room temperature for 1 hour and concentrated under reduced pressure, and the residue to give 4- (8- (5-methyl-1 isolated and purified by silica gel column chromatography - ((2- (trimethylsilyl) ethoxy) methyl yl) lH-indazol-4-yl) - 6,7,8,9-tetrahydro-pyrido [4,3-e] [1,2,4] triazole [4,3-a] pyrimidine 5-yl) piperazine-1-carboxylic acid benzyl ester (320mg, yellow solid). LC-MS: ESI [M + H] + = 654.7;...

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Abstract

The invention discloses a class of saturated six-membered ring and heterocyclic compounds, a preparation method and application. A saturated six-membered ring heterocyclic compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, twist Isomers, solvates, polymorphs or prodrugs, their preparation methods and pharmaceutical applications, wherein the definition of each group is as described in the description.

Description

Technical field [0001] The invention belongs to the field of pharmaceutical chemistry, and in particular, to a compound of saturated six-membered ring and a heterocyclic compound having a compound, preparation method, and use of RAS mutant protein activity. Background technique [0002] Ras is the first carcinogen generated in human tumors, which was first sent in two mice viruses. The Ras gene family has three members, namely HRAS, KRAS, NRAS, respectively. In human tumors, KRAS mutation is most common, accounting for 85%. Previous studies have shown that KRAS mutations can cause cancer, because the codon, which has caused the miscibility mutation, and changes the structure of the Kras protein and keeps it in an active state. Ras in signal passage is mainly activated to activate kinases of gene transcription, thereby regulating cell differentiation and proliferation, closely related to the survival, proliferation, migration, metastasis and angiogenesis of tumor cells. According ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14C07D498/22A61P35/00A61P35/02A61K31/519A61K31/5383A61K31/496
CPCA61P35/00A61P35/02C07D471/14C07D498/22
Inventor 万惠新查传涛马金贵潘建峰
Owner RUDONG RINGENE PHARMA CO LTD
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