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2,4-disubstituted-cycloalkyl[d]pyrimidine compound and its use

A kind of cycloalkyl and pyrimidine technology, which is applied in the field of 2,4-disubstituted-cycloalkyl[d]pyrimidine compounds and their preparation

Inactive Publication Date: 2014-07-09
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Research on activators based on FGFR-1, the site of action is limited to the extracellular ligand-binding domain. These activators are generally protein macromolecular compounds, and research on small molecule activators targeting its intracellular region has not been reported in the literature.

Method used

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  • 2,4-disubstituted-cycloalkyl[d]pyrimidine compound and its use
  • 2,4-disubstituted-cycloalkyl[d]pyrimidine compound and its use
  • 2,4-disubstituted-cycloalkyl[d]pyrimidine compound and its use

Examples

Experimental program
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Effect test

preparation example Construction

[0043] Preparation of the target object:

[0044] 1) Put intermediate XI or XII in an eggplant-shaped flask, add anhydrous N,N-dimethylformamide, stir at 0°C, add NaH, continue stirring for 1 hour, add alkylating reagent R 2 -X (X is an easy-leaving group, which can be halogen, carbonate or sulfate, etc.), reflux for 8-12 hours. Cool down to room temperature, pour into ice-water mixture, stir for half an hour, adjust pH≈8, extract with ethyl acetate, wash organic layer with saturated brine, MgSO 4 Drying, suction filtration, evaporation of the solvent under reduced pressure, the residue was separated by silica gel column chromatography to obtain 2-chloro-5,6,7,8-tetrahydro-[N-R 2 -N-(2-methyl-3-R 1 -2H-indazol-6-yl)]quinazolin-4-amine (intermediate XIII, n=2) or N-R 2 -N-(2-Chloro-6,7-dihydro-5H-cyclopentane[d]pyrimidin-4-yl)-2-methyl-3-R 1 -2H-Indazol-6-amine (Intermediate XIII, n=1).

[0045] 2) Combine intermediate XIII (n=1 or 2) and R 3 NH 2 Place in an eggplant-sh...

Embodiment 1

[0053] Preparation of 2-ethyl-5-nitroaniline (intermediate II-1)

[0054]

[0055] Pour 30 ml of concentrated sulfuric acid into a 100 ml three-necked round-bottomed flask, cool and stir in an ice bath, slowly add 8 ml of 2-ethylaniline dropwise, continue stirring until the reaction solution becomes transparent brown, slowly add to the reaction solution in batches 6.56 g KNO 3 After the addition was complete, the stirring reaction was continued for 1.5 hours. Pour the reaction solution into the ice-water mixture, stir for half an hour, neutralize it with saturated NaOH aqueous solution to pH ≈ 7, a large amount of solid precipitates, filter it with suction, and use a mixed solution of ethyl acetate and petroleum ether (V / V=1:25) After washing and drying, 7.3 g of a yellow solid (Intermediate II-1) was obtained, with a yield of 68%.

[0056] 1 H-NMR (400MHz, CDCl 3 )δ7.60(dd,J 1 =8.3Hz and J 2 =2.3Hz,1H),7.53(d,J=2.3Hz,1H),7.19(d,J=8.3Hz,1H),2.58(q,J=7.5Hz,2H),1.30(d,J...

Embodiment 2

[0058] Preparation of 2-methyl-5-nitroaniline (intermediate II-2)

[0059]

[0060] 2-Ethylaniline was replaced by 2-methylaniline, and the remaining raw materials, reagents and preparation methods were the same as in Example 1 to obtain 8.2 g of the title compound as a yellow solid (Intermediate II-2), with a yield of 72%.

[0061] 1 H-NMR (400MHz, CDCl3 )δ7.55(d,J=8.2Hz,1H),7.51(s,1H),7.16(d,J=8.2Hz,1H),2.24(s,3H).

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Abstract

The invention relates to a 2,4-disubstituted-cycloalkyl[d]pyrimidine compound and its use. The 2,4-disubstituted-cycloalkyl[d]pyrimidine compound is a compound represented by formula I shown in the specification, or its pharmaceutically acceptable salt. Results of the test of activation activity of the 2,4-disubstituted-cycloalkyl[d]pyrimidine compound to the fibroblast growth factor receptor 1 (FGFR-1) show that the 2,4-disubstituted-cycloalkyl[d]pyrimidine compound has an activation effect on the FGFR-1 (parts of the compound has a strong activation effect on the FGFR), and lays a structural foundation for the future designing and development of novel FGFR-1 activator probe molecules or tool molecules.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and chemical biology, and more specifically relates to 2,4-disubstituted-cycloalkyl[d]pyrimidine compounds and their preparation methods and uses. Background technique [0002] Fibroblast growth factor receptor 1 (FGFR-1) is a transmembrane protein composed of extracellular segment, transmembrane region and intracellular segment. significantly expressed in cells. The extracellular part of it as the ligand binding region binds to the ligand bFGF (basic fibroblast growth factor, basic fibroblast growth factor) and undergoes self-dimerization, while the intracellular part tyrosine autophosphorylation. The latter may generate a second messenger by activating adenylate cyclase, guanylate cyclase or phospholipase C, which transmits the signal to the nucleus for cell division by G 1 phase into S phase, or from G 0 The S phase directly enters the S phase, which causes cell proliferation and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/517A61P35/00
CPCC07D403/12
Inventor 李剑许叶春孙玉云刘秋枫
Owner EAST CHINA UNIV OF SCI & TECH
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