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N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-amine compound and preparation method thereof

A compound and hydrate technology, applied in organic chemistry, drug combination, pharmaceutical formula, etc., can solve the problems of cancer and other problems, and achieve the effect of low requirements for production equipment, simple operation and easy control

Active Publication Date: 2021-01-29
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

In addition, existing studies have also shown that RET is a poor prognostic factor for cancer, and some reports have pointed out that ectopic RET and its enhanced activation level are also negatively correlated with cancer prognosis

Method used

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  • N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-amine compound and preparation method thereof
  • N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-amine compound and preparation method thereof
  • N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-amine compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] N-(3-fluorophenyl)-4-(6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)piperazine-1-carboxamide

[0092]

[0093] first step:

[0094] Compound 1a (29.4g, 200.0mmol), compound 1b (19.4g, 200.0mmol), cesium carbonate (77.8g, 240.0mmol) were dissolved in N,N-dimethylformamide (DMF) (300mL), and the temperature was raised Stir at 80°C for 12 hours, monitor the reaction with TLC, cool down to room temperature after the reaction, add 300mL of water to quench the reaction, add ethyl acetate (400mLx2) for two extractions, combine the organic layers, dry, concentrate, and separate by column chromatography 28.5 g of compound 1c was obtained with a yield of 68.5%. Compound 1c is an off-white solid.

[0095] Step two:

[0096] Compound 1c (28.0g, 134.6mmol), compound 1d (30.1g, 161.5mmol), Pd(dppf)Cl 2 (5.8g, 8mmol), K 2 CO 3 (27.9g, 201.9mmol) was placed in DMF (200mL), heated to 100°C, stirred for 6 hours, monitored by TLC, cooled to room temperature after the reaction, ...

Embodiment 2

[0102] N-(3-methoxyphenyl)-4-(6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)piperazine-1-carboxamide

[0103]

[0104] Compound 1f was synthesized according to the method of the first step, the second step and the third step in Example 1.

[0105] Dissolve compound 1f (258mg, 1.0mmol), compound 2a (123mg, 1.0mmol), triethylamine (303mg, 3.0mmol), CDI (162mg, 1.0mmol) in dichloromethane (30mL), stir at room temperature overnight , The reaction was monitored by TLC. After the reaction was completed, it was directly concentrated and separated by column chromatography to obtain 298 mg of an off-white solid (compound 2), with a yield of 73.2%, and ESI (+) m / z=408.2.

Embodiment 3

[0107] N-(3-cyanophenyl)-4-(6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)piperazine-1-carboxamide

[0108]

[0109] Compound 1f was synthesized according to the method of the first step, the second step and the third step in Example 1.

[0110] Compound 1f (258mg, 1.0mmol), compound 3a (118mg, 1.0mmol), triethylamine (303mg, 3.0mmol), CDI (162mg, 1.0mmol) were dissolved in dichloromethane (30mL), stirred at room temperature overnight , The reaction was monitored by TLC. After the reaction was completed, it was directly concentrated and separated by column chromatography to obtain 254 mg of an off-white solid (compound 3), with a yield of 63.2% and ESI (+) m / z=403.2.

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Abstract

The invention belongs to the field of medicines, and provides an N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-amine compound and a preparation method thereof. The N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-amine compound is a compound with a structure shown as a formula I, and pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or isotope compound of the compound. The structure of the formulaI is shown in the specification, and in the formula I, R1 is a monosubstituted, polysubstituted or unsubstituted benzene ring or heteroaromatic ring. The N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-aminecompound can be used as an effective RET kinase inhibitor, and is relatively strong in inhibition activity and relatively small in side effect. The pharmaceutical composition containing the N-(5-methyl-1H-pyrazol-3-yl) pyridine-2-amine compound also has good anti-tumor pharmacological activity.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to an N-(5-methyl-1H-pyrazol-3-yl)pyridin-2-amine compound and a preparation method thereof. Background technique [0002] Rearranged transfection (RET) is a nerve growth factor receptor tyrosine kinase. RET is involved in cell proliferation, nerve conduction, cell migration and cell differentiation, and is activated after binding to one of the neurotrophic factor (GDNF) receptors α-1, 2, 3, 4, and its activation is involved in cell proliferation and survival Multiple downstream pathways, induce cell proliferation. Existing studies have shown that RET fusion proteins are associated with some cancers, including non-small cell carcinoma, thyroid cancer, breast cancer, and pancreatic cancer. Misplacement, mutation, or overexpression of the RET gene enhances its activation, thereby contributing to tumor cell growth, formation, or tissue invasion. In addition, existing studies hav...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D405/14C07D413/14C07D401/14C07D409/14A61P35/00A61P35/02A61K31/496A61K31/5377
CPCA61P35/00A61P35/02C07D401/12C07D401/14C07D405/14C07D409/14C07D413/14
Inventor 王永广杨水凤张佳琪苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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