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2,4-disubstituted pyrimidine derivative as well as preparation method and application thereof

A pyrimidine derivative and di-substitution technology, applied in the field of chemical medicine, can solve the problems of poor enzyme activity and low oral bioavailability

Active Publication Date: 2020-12-29
CHENGDU ZENITAR BIOMEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing JAK2 / FLT3 dual-target inhibitors have poor enzymatic activity and low oral bioavailability, which still cannot meet medical needs. Attribute inhibitors are currently a hot topic in research and development

Method used

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  • 2,4-disubstituted pyrimidine derivative as well as preparation method and application thereof
  • 2,4-disubstituted pyrimidine derivative as well as preparation method and application thereof
  • 2,4-disubstituted pyrimidine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1 6-hydroxypropyl-N-(4-(1-isopropyl-1H-pyrazol-4-yl)5-methylpyrimidin-2-yl)-5,6,7,8-tetra Preparation of hydronaphthyridine-2-amine (CLJ-100)

[0160]

[0161] Step 1: Synthesis of 1-propylpyrazole-4-boronic acid pinacol ester (compound of formula 2)

[0162] Add 4-boronic acid pinacol ester (1.9g, 10mmol), 2-iodopropane (3.4g, 20mmol), cesium carbonate (6.5g, 20mmol) into acetonitrile (50ml), and react in an oil bath at 80°C 2 hours. After the reaction is completed, filter while hot and concentrate the filtrate to obtain the compound of formula 2.

[0163] Step 2: Synthesis of 2-chloro-5-methyl-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidine (compound of formula 3) Formula 2 compound (1.9g, 10mmol), 2 , 4-dichloro-5-fluoropyrimidine (1.7g, 10mmol), potassium carbonate (3.4g, 25mmol) and dppf (Pd2Cl2) (0.75g, 1mmol) join in the 250mL three-necked flask, add dioxane / Ethanol / water=7:3:4 (total 70mL) was used as solvent, nitrogen was replaced three times, and the...

Embodiment 2

[0170] Example 2 2-Hydroxyethyl-N-(4-(1-isopropyl-1H-pyrazol-4-yl)5-methylpyrimidin-2-yl)-1,2,3,4-tetra Preparation of Hydroisoquinoline-6-Aminol (CLJ-101)

[0171]

[0172] The synthesis of CLJ-101 is the same as in Example 1, with 6-amino-N-Boc-1,2,3,4-tetrahydroisoquinoline replacing 2-amino-N-Boc-5,6,7,8-tetrahydro Hydronaphthyridine, 2-iodoethanol can replace 3-bromo-1-propanol to obtain the final product CLJ-101. 1 H NMR (400MHz, DMSO-d 6 )δ:9.20(s,1H),8.29(d,J=22.7Hz,2H),8.08(s,1H),7.65(d,J=2.3Hz,1H),7.46(dd,J=8.3,2.3 Hz,1H),6.94(d,J=8.4Hz,1H),4.62(h,J=6.6Hz,1H),4.46(s,1H),3.67–3.46(m,4H),2.80(d,J =5.8Hz, 2H), 2.71(t, J=5.8Hz, 2H), 2.57(t, J=6.2Hz, 2H), 2.31(s, 3H), 1.48(d, J=6.7Hz, 6H). 13 C NMR(101MHz,DMSO)δ:159.88,159.00,157.63,139.42,139.31,134.44,129.38,127.92,126.71,120.74,118.31,116.72,116.35,60.74,59.30,56.07,53.83,51.64,29.63,23.03,17.15 .m / z:393.5070[M+H] + .

Embodiment 3

[0173] Example 3 2-Hydroxyethyl-N-(4-(1-isopropyl-1H-pyrazol-4-yl)5-methylpyrimidin-2-yl)-1,2,3,4-tetra Preparation of Hydroisoquinolin-7-fluoro-6-amine (CLJ-102)

[0174]

[0175] The pyrimidine part of CLJ-102 was synthesized as in Example 2;

[0176] Aromatic amines are partially synthesized as follows:

[0177] Step 1: Synthesis of 4-fluorophenethylamine trifluoroacetamide (compound of formula 2)

[0178] Dissolve 4-fluorophenethylamine (7g, 50mmol) and triethylamine (13g, 125mmol) in dichloromethane (100mL), add trifluoroacetic anhydride (12.6g, 60mmol) dropwise, react at room temperature for 30min, add a large amount of Water (about 200 mL) was stirred vigorously, separated, the organic phase was concentrated by distillation under reduced pressure, and slurried with ether to obtain the compound of formula 2.

[0179] Step 2: Synthesis of 7-fluoro-1,2,3,4-tetrahydroisoquinoline trifluoroacetamide (compound of formula 3)

[0180] Dissolve 4-fluorophenethylamine trif...

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Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a 2,4-disubstituted pyrimidine derivative as well as a preparation method and application thereof. The invention provides the 2,4-disubstituted pyrimidine derivative, which has a structure as shown in a formula IV. The invention also provides a preparation method and application of the 2,4-disubstituted pyrimidine derivative. The 2,4-disubstituted pyrimidine derivative provided by the invention not only can be used as a kinase inhibitor with JAK2 and FLT3 bifunctional targets, but also can be used as a kinaseinhibitor with an independent JAK2 or FLT3 functional target, so that a new choice is provided for preparing a multi-target inhibitor.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and specifically relates to 2,4-disubstituted pyrimidine derivatives and their preparation methods and uses. In particular, it relates to the use of a 2,4-disubstituted pyrimidine derivative as an inhibitor of Janus tyrosine kinase 2 and FMS-like tyrosine kinase 3 (JAK2-FLT3). Background technique [0002] Myeloproliferative neoplasms (MPNs) are a group of malignant myeloproliferative diseases originating from pluripotent hematopoietic stem cells, characterized by the excessive proliferation of one or more lines of myeloid cells, and the increase of one or more lines of peripheral blood There is a tendency to form thrombus, extramedullary hematopoiesis, myelofibrosis and transform into acute leukemia. Such diseases include polycythaemia vera (PV), primary thrombocytosis (PT) and primary myelofibrosis (PMF). [0003] Current clinical treatment methods still cannot cure MPNs diseases. Recen...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D401/14C07D403/14A61K31/506A61K31/5377A61P35/00A61P35/02A61P29/00A61P37/02
CPCC07D471/04C07D401/14C07D403/14A61P35/00A61P35/02A61P29/00A61P37/02
Inventor 陈俐娟
Owner CHENGDU ZENITAR BIOMEDICAL TECH CO LTD
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