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Substituted pyrimidine compound, and preparation method, intermediate and application thereof

A technology of pyrimidines and compounds, applied in the field of substituted pyrimidines

Active Publication Date: 2021-09-14
SHANGHAI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is to provide a kind of substituted pyrimidine compound, its preparation method, intermediate and application

Method used

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  • Substituted pyrimidine compound, and preparation method, intermediate and application thereof
  • Substituted pyrimidine compound, and preparation method, intermediate and application thereof
  • Substituted pyrimidine compound, and preparation method, intermediate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0245] Example 1: N 1 -(6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(5-methylfuran-2-yl)pyrimidin-4-yl)-N 6 -Hydroxyadipamide (Compound I-1)

[0246]

[0247] Step 1: Refer to literature (Slee et al., J Med Chem 2008, 51, 1719-1729) to prepare intermediate INT-1: 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2 -(5-Methylfuran-2-yl)-4-aminopyrimidine. After dissolving monomethyl adipate (432 mg, 2.70 mmol) in dichloromethane (10 mL), benzotriazole (650 mg, 5.40 mmol) and thionyl chloride (0.40 mL, 5.40 mmol) were added successively, and the reaction was carried out at room temperature. 1 hour. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to obtain an orange-yellow oily liquid. After dissolving INT-1 (122 mg, 0.45 mmol) in dichloromethane (5 mL), pyridine (0.5 mL) was added successively, and the above obtained orange-yellow oily liquid was stirred at room temperature for 12 hours. After the reaction was completed, water (5 mL) was added to dilute,...

Embodiment 2

[0251] Example 2: N 1 -(6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(5-methylfuran-2-yl)pyrimidin-4-yl)-N 7 -Hydroxypimelamide (Compound I-2)

[0252]

[0253] Using the same method as in Example 1, replacing "monoethyl adipate" with "monomethyl pimelic acid", compound I-2 can be prepared as a white solid. HRMS(ESI)C 21 H 27 N 6 O 4 + [M+H] + Calculated value: 427.2088, measured value: 427.2091; 1 H NMR (600MHz, DMSO-d 6 )δ11.05(s,1H),10.34(s,1H),8.35(s,1H),7.19(d,J=3.3Hz,1H),6.35(dd,J=3.3,1.2Hz,1H), 6.21(s, 1H), 2.72(s, 3H), 2.45(t, J=7.3Hz, 2H), 2.38(s, 3H), 2.22(s, 3H), 1.94(t, J=7.4Hz, 2H) ), 1.60-1.54 (m, 2H), 1.53-1.48 (m, 2H), 1.29-1.25 (m, 2H); HPLC: 96.9%.

Embodiment 3

[0254] Example 3: N 1 -(6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(5-methylfuran-2-yl)pyrimidin-4-yl)-N 8 -Hydroxysuberamide (Compound I-3)

[0255]

[0256]Using the same method as in Example 1, replacing "monoethyl adipate" with "monomethyl suberate", compound I-3 can be prepared as a white solid. HRMS(ESI)C 22 H 29 N 6 O 4 + [M+H] + Calculated value: 441.2245, measured value: 441.2250; 1 H NMR (800MHz, DMSO-d 6 )δ11.02(s,1H),10.32(s,1H),8.35(s,1H),7.20–7.14(m,1H),6.35(dd,J=3.2,1.0Hz,1H),6.20(s ,1H),2.72(s,3H),2.45(t,J=7.4Hz,2H),2.38(s,3H),2.22(s,3H),1.94(t,J=7.4Hz,2H),1.60 - 1.54 (m, 2H), 1.52 - 1.45 (m, 2H), 1.31 - 1.24 (m, 4H); HPLC: 96.9%.

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Abstract

The invention discloses a substituted pyrimidine compound, and a preparation method, an intermediate and application thereof. The invention provides a substituted pyrimidine compound as shown in a formula I or pharmaceutically acceptable salt thereof. The substituted pyrimidine compound disclosed by the invention can be used as an adenosine A2A receptor antagonist or a histone deacetylase HDAC inhibitor. Furthermore, the substituted pyrimidine compound provided by the invention can simultaneously have adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity. The substituted pyrimidine compound provided by the invention can be used for treating and / or preventing diseases related to adenosine A2A receptor and / or histone deacetylase HDAC, such as tumors and central nervous system diseases.

Description

technical field [0001] The present invention relates to a substituted pyrimidine compound, its preparation method, intermediate and application. Background technique [0002] Adenosine is an endogenous purine nucleoside, which mainly exerts its physiological function by binding to adenosine receptors on the cell membrane. The "adenosine-adenosine receptor" signaling pathway plays an important regulatory role in cardiovascular function, central nervous system function, and tumor microenvironment. Adenosine receptors belong to G protein-coupled receptors (GPCRs, or 7-transmembrane receptors, 7TMRs) and are divided into 4 subtypes, A1, A2A, A2B, and A3. Among them, A2A receptors are distributed at higher levels in the central nervous system (such as striatum) and peripheral (heart, liver, lung, kidney, etc.). In the central nervous system, A2A has a high density distribution and is closely related to the pathogenesis of various degenerative central nervous system diseases suc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D401/14C07D403/04A61K31/506A61P35/00A61P25/00A61P25/16A61P25/28A61P25/14
CPCC07D405/14C07D401/14C07D403/04A61P35/00A61P25/00A61P25/16A61P25/28A61P25/14
Inventor 程建军刘瑞全徐越溟
Owner SHANGHAI TECH UNIV
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