Phenylquinazoline PI3Kdelta inhibitors

A technology of alkyl and amino groups, applied in anti-inflammatory agents, non-central analgesics, active ingredients of heterocyclic compounds, etc.

Inactive Publication Date: 2012-12-26
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there are no PI3Kδ inhibitor drugs on the market. Therefore, it is necessary to develop more structural types of PI3Kδ inhibitors and select compounds with better efficacy and safety for the treatment of cancer and inflammation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] Example 1 Preparation of 2-(1-(9H-purin-6-yl)azetidinyl-3-ylamino)-5-fluoro-3-phenylquinazolin-4(3H)-one (compound 1)

[0141]

[0142] (1) Preparation of 2-fluoro-6-nitro-N-phenylbenzamide

[0143]

[0144] Add 2-fluoro-6-nitrobenzoic acid (5.5g, 30mmol) into 40mL of dichloromethane, add DMF 1mL dropwise, add oxalyl chloride (6.7g, 50mmol) dropwise within 30min under ice-cooling, and stir at room temperature for 2h , the reaction solution was spin-dried, dissolved in dichloromethane, slowly added dropwise to the dichloromethane solution of aniline (3.1g, 30mmol) and triethylamine (5.05g, 50mmol) under ice bath, controlled temperature at 10°C, stirred for 2h , add water 300mL, precipitate out, filter and dry to obtain product 7.02g, yield: 90%.

[0145] (2) Preparation of 2-amino-6-fluoro-N-phenylbenzamide

[0146]

[0147] Add 2-fluoro-6-nitro-N-phenylbenzamide (26g, 1000mmol), zinc powder (195g, 300mmol), ammonium chloride (160g, 300mmol) into 100mL tetr...

Embodiment 2

[0165] Example 2 Preparation of 2-(3-(9H-purin-6-ylamino)azetidin-1-yl)-5-fluoro-3-phenylquinazolin-4(3H)-one (compound 2)

[0166] Steps 1-4 are the same as in Example 1.

[0167] (5) Preparation of 1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazolin-2-yl)azetidin-3-yl tert-butyl carboxylate

[0168]

[0169] In 50 mL of dichloromethane was added 2-chloro 5-fluoro-3-phenylquinazolin-4(3H)-one (1.4 g, 5.1 mmol), 3-aminoazetidine-1-tert-butyl Carboxylate (0.86g, 5mmol), triethylamine (1.0g, 10mmol), refluxed for 15h, the reaction solution was washed with saturated brine, dried and spin-dried to obtain 0.90g of product, yield: 45%.

[0170] (6) Preparation of 2-(3-aminoazetidin-1-yl)-5-fluoro-3-phenylquinazolin-4(3H)-one

[0171]

[0172] In 50 mL of dichloromethane was added 1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazolin-2-yl)azetidin-3-yl tert-butylcarboxylate Acid ester (0.9g, 2.2mmol), 3mL of trifluoroacetic acid was added under ice-cooling, stirred for...

Embodiment 3

[0178] Example 3 Preparation of 2-(3-(9H-purin-6-ylamino)cyclobutyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (compound 3)

[0179]

[0180] Step 1 is the same as Step 1 in Example 1.

[0181] Step 2 Preparation of 3-((2-fluoro-6-nitrobenzoyl(phenyl)formyl)cyclobutyl tert-butoxycarboxylate

[0182]

[0183] 2-Fluoro-6-nitro-N-phenylbenzamide (13g, 50mmol), DMF (1mL) and thionyl chloride (29.8g, 250mmol) were mixed, stirred at 85°C for 5h, the mixture was spin-dried, and washed with Dichloromethane was dissolved in 100mL, and 3-(tert-butoxycarbonylamino)cyclobutylcarboxylic acid (11.8g, 55mmol) and triethylamine (7.7mL, 55mmol) were added, and the temperature was controlled not to exceed 10°C. Stir at room temperature for 3h, respectively. Wash with water, saturated saline, and protected sodium bicarbonate, dry the organic layer with anhydrous sodium sulfate, and purify by column to obtain 10.5 g of the product, yield: 46%.

[0184] Step 3 Preparation of 3-(5-fluoro-4-c...

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Abstract

The present invention belongs to the technical field of medicine, and particularly relates to phenylquinazoline PI3Kdelta inhibitors represented by a general formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof, wherein X1, X2, X3, X4, Y, Z, B, W, R1 and R2 are defined in an instruction. The present invention further relates to preparation methods for the compounds, pharmaceutical preparations containing the compounds, and uses of the compounds in preparations of drugs for treatments and / or preventions of inflammatory diseases or cancers.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to phenylquinazoline PI3Kδ inhibitors, pharmaceutically acceptable salts thereof, stereoisomers or deuterated products thereof, preparation methods of these compounds, and pharmaceutical preparations containing these compounds , and the use of these compounds in the preparation of medicines for treating inflammatory diseases or tumors. 2. Background technology [0002] Tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in the genetic material of cells, resulting in abnormal gene expression and abnormal proliferation of cells. Tumor cells lose their normal growth regulation function and have the ability to grow independently or relatively independently. When the tumorigenic factors are stopped, they can continue to grow and consume a large amount of nutrients in the human body. If not found and treated in time, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34C07D473/00C07D473/30A61K31/52A61P29/00A61P35/00
Inventor 吴永谦松山皓治
Owner KBP BIOSCIENCES CO LTD
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