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2-amino-4-(isoindoline-2-yl) pyrimidine-5-formamide derivative, preparation method and application thereof

A substance, phenyl technology, applied in the field of preparation of 2-amino-4-pyrimidine-5-carboxamide derivatives, can solve problems such as no effective method, and achieve the effect of good anti-tumor or immune disease pharmacological activity

Active Publication Date: 2020-11-06
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no effective method for RA, and the main treatment is based on inflammation and sequelae, such as drugs, physical therapy and surgery, among which drug therapy is the basis, and drug therapy usually includes non-steroidal and steroidal anti-inflammatory drugs, immune regulation Drugs, etc., these drugs can only relieve pain, reduce or delay the development of inflammation

Method used

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  • 2-amino-4-(isoindoline-2-yl) pyrimidine-5-formamide derivative, preparation method and application thereof
  • 2-amino-4-(isoindoline-2-yl) pyrimidine-5-formamide derivative, preparation method and application thereof
  • 2-amino-4-(isoindoline-2-yl) pyrimidine-5-formamide derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] 4-(isoindoline 2-yl)-2-((6-methoxypyridin-3-yl)amino)pyrimidine-5-carboxamide

[0049]

[0050] Synthesis of Intermediate 1c:

[0051] Dissolve compound 1a (19.1g, 100.0mmol), compound 1b (11.9g, 100.0mmol), cesium carbonate (39.0g, 120.0mmol) in DMF (500ml), raise the temperature to 80°C and stir for 8 hours, then detect the reaction by TLC After the reaction was completed, the reaction was quenched with water (300ml), then extracted twice with ethyl acetate (500ml), the organic layer was concentrated, and separated by column chromatography to obtain 20.4g of a light yellow solid (compound 1c), with a yield of 74.5%.

[0052] Synthesis of compound 1:

[0053] Compound 1c (2.7g, 10.0mmol), compound 1d (1.2g, 10.0mmol), Pd(dppf) 2 Cl 2 (732 mg, 1.0 mmol), K 2 CO 3 (1.7g, 12.0mmol) was dissolved in DMF (50ml), heated to 90°C and reacted for 8 hours, after the reaction was completed, water (50ml) was added to quench the reaction, ethyl acetate (100ml) was extracted...

Embodiment 2

[0055] 2-((3,4-Dimethoxyphenyl)amino)-4-(isoindoline-2-yl)pyrimidine-5-carboxamide

[0056]

[0057] The synthesis of intermediate 1c was carried out as in Example 1.

[0058] Synthesis of compound 2:

[0059] Compound 1c (2.7g, 10.0mmol), compound 2a (1.5g, 10.0mmol), Pd(dppf) 2 Cl 2 (732 mg, 1.0 mmol), K 2 CO 3 (1.7g, 12.0mmol) was dissolved in DMF (50ml), heated to 90°C and reacted for 8 hours, after the reaction was completed, water (50ml) was added to quench the reaction, ethyl acetate (100ml) was extracted twice, the organic layer was dried, filtered, Column chromatography separated to obtain 2.1 g of an off-white solid (compound 2), with a yield of 53.7%, ESI(+) m / z=392.2.

Embodiment 3

[0061] 2-((3-fluoro-4-methoxyphenyl)amino)-4-(isoindoline-2-yl)pyrimidine-5-carboxamide

[0062]

[0063] The synthesis of intermediate 1c was carried out as in Example 1.

[0064] Synthesis of compound 3:

[0065] Compound 1c (2.7g, 10.0mmol), compound 3a (1.4g, 10.0mmol), Pd(dppf) 2 Cl 2 (732 mg, 1.0 mmol), K 2 CO 3 (1.7g, 12.0mmol) was dissolved in DMF (50ml), heated to 90°C and reacted for 8 hours, after the reaction was completed, water (50ml) was added to quench the reaction, ethyl acetate (100ml) was extracted twice, the organic layer was dried, filtered, Column chromatography separated to obtain 2.5 g of off-white solid (Compound 3), with a yield of 66.0%, ESI(+) m / z=380.1.

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Abstract

The invention belongs to the technical field of biological medicines, and provides a 2-amino-4-(isoindoline-2-yl)pyrimidine-5-formamide derivative, a preparation method and application thereof, wherein the 2-amino-4-(isoindoline-2-yl)pyrimidine-5-formamide derivative is a compound with a structure represented by a formula I or a pharmaceutically acceptable salt, a hydrate, a solvate and an isotopecompound thereof, the structure represented by the formula I is defined in the specification, R1 represents a mono-substituted, di-substituted or non-substituted phenyl group or an aromatic heterocyclic group, and R2 represents H, a methoxy group, a cyano group, halogen, an aminocarbonyl group, an acetylamino group or an aminosulfonyl group. The 2-amino-4-(isoindoline-2-yl) pyrimidine-5-formamidederivative can be used as an effective SYK inhibitor, and the pharmaceutical composition of the 2-amino-4-(isoindoline-2-yl) pyrimidine-5-formamide derivative has good pharmacological activities forresisting various tumors or immune diseases.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a 2-amino-4-(isoindoline-2-yl)pyrimidine-5-carboxamide derivative, a preparation method and an application. Background technique [0002] Cancer is one of the major diseases that threaten human health. At present, the main treatment methods for cancer include drug therapy, surgical treatment, radiotherapy, etc., among which drug therapy is one of the most commonly used treatment methods. Traditional cytotoxic drugs cannot distinguish between tumor cells and normal cells, often causing serious side effects, while targeted drugs use tumor cells as specific targets, can accurately act on tumors, and can effectively improve the treatment level of cancer. Reduce the rate of adverse reactions. [0003] SYK (Spleen tyrosine kinase, spleen tyrosine kinase), is a non-receptor protein tyrosine kinase, which is generally expressed in hematopoietic cells, high-level expressio...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/04C07D403/14A61K31/506A61P35/00A61P37/00A61P29/00A61P19/02A61P17/00A61P25/00
CPCA61P17/00A61P19/02A61P25/00A61P29/00A61P35/00A61P37/00C07D401/14C07D403/04C07D403/14
Inventor 王永广常俊美万晓梦苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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