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Spirocyclic compounds and their use as therapeutic agents and diagnostic probes

A compound, solvate technology, applied in the field of treatment of related pathological conditions

Inactive Publication Date: 2013-02-20
UNIVERSITY OF BASEL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This can be caused directly or indirectly by mutation, overexpression or inappropriate activation of the enzyme leading to ineffective control mechanisms

Method used

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  • Spirocyclic compounds and their use as therapeutic agents and diagnostic probes
  • Spirocyclic compounds and their use as therapeutic agents and diagnostic probes
  • Spirocyclic compounds and their use as therapeutic agents and diagnostic probes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0288] The chemical reactions described in the examples can be readily adapted to prepare a variety of other lipid kinase inhibitors of the invention, and alternative methods of preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplary compounds of the invention can be successfully performed with modifications apparent to those skilled in the art, such as by appropriate protection of interfering groups, by the use of other suitable reagents known in the art than those described herein, And / or by routinely modifying the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be deemed to have applicability for preparing other compounds of the invention.

[0289] Abbreviations: hours (h), minutes (min), room temperature (RT), dichloromethane (DCM), dimethylformamide (DMF), ethyl acetate (EtOAc), methanol (MeOH), tetrahydrofuran (THF). Reagents were purchased ...

Embodiment P1

[0299] Example P1: 6-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-methylpiperazin-1-yl)-1, 3,5-Triazin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (306)

[0300]

[0301] Steps a) and b) are completed according to the procedure of Georg, W. et al., Angew. Chem. Int. Ed. 47:4512-4515 (2008).

[0302] Step c): 6-(4,6-dichloro-1,3,5-triazin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (21).

[0303]Following general procedure A-2, 2-oxa-azaspiro[3.3.]heptane (50.0 mg, 173 μmol, 1.0 eq.) was deprotonated with sodium hydride, and cyanuric chloride (32.0 mg, 173 μmol , 1.0 eq.) to give the title compound (37.0 mg, 86%) as a white solid. R F : 0.85 (DCM / MeOH, 9:1 v / v); 1 H NMR (CDCl 3 , 400 MHz): δ 4.83 (s, 4H), 4.39 (s, 4H). 13 C NMR (100 MHz, CDCl 3 ): δ 170.4, 163.9, 80.5, 59.6, 39.0; EI-MS (70 eV, C 8 h 8 Cl 2 N 4 O): calculated value 247.02 (M + ), the measured value is 248.00.

[0304] Step d): 6-(4-Chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl...

Embodiment P2

[0308] Example P2: 6-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazine-2- Base) -2-oxa-6-azaspiro[3.3]heptane (299)

[0309]

[0310] Step a): 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (24).

[0311] Cyanuric chloride (10.0 g, 54.2 mmol, 1.0 eq.) was reacted with morpholine (4.70 ml, 54.2 mmol, 1.0 eq.) following general procedure A-1. The reaction mixture was purified by flash column chromatography on silica gel (70% hexane / ethyl acetate) to afford the title compound (3.60 g, 28%) as a colorless solid. R F : 0.72 (Hexane / EtOAc 1:1 v / v); 1 H NMR (CDCl 3 , 400 MHz) δ 3.88 (t, J = 4.9 Hz, 4H), 3.75 (t, J = 4.8 Hz, 4H); 13 C NMR (CDCl 3 , 100 MHz) δ 170.85, 164.50, 66.79, 44.87; ESI-MS (C 7 h 8 Cl 2 N 4 O): Calculated 258.0 (M+Na) + , the measured value is 258.6.

[0312] Step b): 4-(4-Chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl ) Morpholine (25).

[0313] Compound 24 (425 μmol, 1.0 eq.) was dissolved i...

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Abstract

The invention relates to new triazines (G = Q = U are N), pyrimidines (two out of G, Q and U are N), and pyridopyrimidines (one of G and U together with R2 forms an anullated pyridine ring) of formula (I) carrying a spirocyclic substituent, wherein E1 is CR4 or N; X1 is CHR4, CH2CH2, NR4, NR4?0, or O; and the other substituents are as defined in the specification. The compounds inhibit phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), DNA-PK and ATM kinase, and may be used as therapeutic agents or diagnostic probes. The invention also relates to methods of using the compounds for treatment of associated pathological conditions.

Description

field of invention [0001] The present invention relates to novel triazines and pyrimidines bearing spirocyclic substituents and pharmaceutically acceptable salts thereof, which inhibit phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), DNA- PK and ATM kinases. The invention also relates to methods of using these compounds for the treatment of related pathological conditions. Background of the invention [0002] Protein kinases are involved in the 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. In general, these kinases fall into two groups, a group that preferentially phosphorylates tyrosine residues and a group that preferentially phosphorylates serine and / or threonine residues. Tyrosine kinases include transmembrane growth factor receptors such as epidermal growth factor receptor (EGFR) and cytopl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/10C07D491/10C07D519/00A61K31/5386A61P35/00
CPCC07D519/00C07D491/10C07D487/10A61P1/16A61P17/06A61P19/08A61P25/00A61P25/04A61P25/06A61P25/28A61P29/00A61P31/00A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08A61P43/00A61P5/00A61P7/02A61P9/00A61P9/10A61P3/10A61K31/53A61K31/5386
Inventor V.克米尔贾诺维奇N.克米尔贾诺维奇B.吉泽M.维曼
Owner UNIVERSITY OF BASEL
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