Piperazinotriazines as PI3K inhibitors for use in the treatment antiproliferative disorders

A compound, ethyl technology, applied in the field of piperazino triazine compounds used as PI3K inhibitors for the treatment of anti-proliferative disorders, which can solve the problems of control mechanism failure and other problems

Inactive Publication Date: 2013-03-27
UNIVERSITY OF BASEL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This may be caused directly or indirectly by failure of the control mechanism due to mutation, overexpression or inappropriate activation of the enzyme

Method used

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  • Piperazinotriazines as PI3K inhibitors for use in the treatment antiproliferative disorders
  • Piperazinotriazines as PI3K inhibitors for use in the treatment antiproliferative disorders
  • Piperazinotriazines as PI3K inhibitors for use in the treatment antiproliferative disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0100] Compounds were synthesized according to the procedure in Scheme 2 5-7 , 11 and 12 :

[0101] Process 2

[0102]

[0103] Substitute morpholine for Cyanuric chloride in dichloromethane at -50°C 1 After 20 min, an intermediate was generated 2 . K in DMF at -5°C 2 CO 3 In the presence of , the second chloride was replaced by 2-difluoromethyl-1H-benzimidazole for 30 min, and further stirred at room temperature for 4 h to generate the intermediate 3 . at room temperature through the K 2 CO 3 and the presence of DMF to make the intermediate 3 After 45 minutes of amination, the final step yields the product 4-7、11 and 12 . compound 4 is a known compound ZSTK474 prepared for comparison purposes.

[0104] Amination with BOC-protected piperazine, followed by BOC deprotection and reaction with acrylic anhydride, from intermediate 3 get compound 8 . The phthalimide protecting group is cleaved by amination with 2-(2-(piperazin-1-yl)ethyl)isoindoline-1,3-dione...

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Abstract

The invention relates to compounds of formula (I) R<1> is methyl, n-hexyl, aminoethyl, methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, acryloylaminoethyl, methacryloylaminoethyl, methoxyethyl, ethoxyethyl, C1-C4-alkyl- sulfonyl, acryloyl, or methacryloyl; or R<1> is aminoethyl, acryloyl or acryloylaminoethyl carrying a linker and a tag, and R<2> and R<3>, independently of each other, are hydrogen or C1-C4-alkyl, or R<2> and R<3> together form a methylene or an ethylene bridge; and tautomers, solvates and pharmaceutically acceptable salts thereof. These compounds are effective in preventing or treating a disease or disorder modulated by PI3 kinases and / or mTOR, in particular treating a hyperproliferative disorder.

Description

field of invention [0001] The present invention relates to novel triazines bearing benzimidazolyl (benzimidazo), morpholino and 4-substituted piperazino (piperazino) substituents, which inhibit phosphoinositide 3-kinase (PI3K), mammalian Pamycin target protein (mTOR), DNA-PK and ATM kinase, and pharmaceutically acceptable salts thereof. The invention also relates to methods of using said compounds for the treatment of related pathological conditions. Background of the invention [0002] Protein kinases are involved in signaling events that control the activation, growth, differentiation, survival and migration of cells in response to extracellular mediators or stimuli, including growth factors, cytokines or chemokines. Generally, these kinases fall into two groups, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and / or threonine residues. Tyrosine kinases include transmembrane growth factor receptors, such as epi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/53A61P35/00C07D403/04
CPCC07D413/14C07D403/04A61K31/53C07D409/14A61P1/16A61P17/00A61P17/06A61P19/02A61P21/02A61P25/00A61P25/14A61P25/16A61P25/24A61P25/28A61P29/00A61P35/00A61P35/02A61P37/08A61P43/00A61P9/00A61P9/04A61P9/10A61P3/10
Inventor V.克米尔贾诺维奇N.克米尔加诺维奇B.吉泽M.维曼
Owner UNIVERSITY OF BASEL
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