2-amino-4-indolyl pyrimidine compound as well as preparation method and application thereof

A compound, amino technology, applied in the field of chemical medicine, can solve problems such as drug resistance

Active Publication Date: 2022-04-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Purpose of the invention: In order to solve the drug resistance problem of the EGFR inhibitor osimertinib in the prior art due to target mutatio

Method used

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  • 2-amino-4-indolyl pyrimidine compound as well as preparation method and application thereof
  • 2-amino-4-indolyl pyrimidine compound as well as preparation method and application thereof
  • 2-amino-4-indolyl pyrimidine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1: N-(1-(2-(dimethylamino)ethyl)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino) -1H-indazol-7-yl)acrylamide (I-1)

[0076]

[0077] The synthetic route is as follows:

[0078]

[0079] Step 1. Preparation of 5,7-dinitro-1H-indazole (2):

[0080] Under ice bath, 5-nitro-1H-indazole (1) (16.32g, 100mmol) was dissolved in sulfuric acid solution, and concentrated nitric acid (40ml, 400mmol) was added dropwise under ice bath. After the reaction was completed, the reaction solution was Slowly pour into ice water, stir well, and filter with suction to obtain 20.61 g of white filter cake of 5,7-dinitro-1H-indazole (2), with a yield of 99%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 14.57(s, 1H), 9.30 (d, J = 2.0 Hz, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H).

[0081] Step 2. Preparation of 2-(5,7-dinitro-1H-indazol-1-yl)-N,N-dimethyl-1-ethylamine (3):

[0082]Dissolve 5,7-dinitro-1H-indazole (2) (10.41g, 50mmol) in THF, add sodium hydrogen (1.44g, 60mmol) un...

Embodiment 2

[0095] Example 2: (E)-N-(1-(2-(Dimethylamino)ethyl)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2- Base)amino)-1H-indazol-7-yl)-2-butenamide (I-2)

[0096]

[0097] Referring to the synthetic method of (I-1), the yield was 66%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.26 (s, 1H),8.38 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.19 – 7.99 (m, 3H), 7.93(s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.33 – 7.27 (m, 1H), 7.24 – 7.21 (m, 1H),7.13 – 7.07 (m, 1H), 7.05 (s, 1H), 6.06 (d, J = 15.2 Hz, 1H), 4.69 (dd, J =5.9, 3.6 Hz, 2H), 3.89 (s, 3H), 2.92 (s, 2H), 2.24 (s, 6H), 1.95 (d, J = 6.9Hz, 3H).

Embodiment 3

[0098] Example 3: N-(1-(2-(dimethylamino)ethyl)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino) -1H-indazol-7-yl)-3-methyl-2-butenamide (I-3)

[0099]

[0100] Referring to the synthetic method of (I-1), the yield is 57%. 1 H NMR (400 MHz, Chloroform- d ) δ 11.18(s, 1H), 8.41 (dt, J = 7.8, 1.0 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.12 –7.91 (m, 4H), 7.39 – 7.28 (m, 2H), 7.25 – 7.18 (m, 2H), 7.05 (d, J = 5.4 Hz,1H), 5.86 – 5.80 (m, 1H), 4.71 – 4.66 (m, 2H), 3.88 (s, 3H), 2.90 (s, 2H),2.29 (d, J = 1.3 Hz, 3H), 2.24 (s, 6H), 1.94 (s, 3H).

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Abstract

The invention discloses a 2-amino-4-indolyl pyrimidine compound as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. In particular to pyrimidine compounds, stereoisomers or pharmaceutically acceptable salts thereof, preparation methods of the pyrimidine compounds and the stereoisomers or the pharmaceutically acceptable salts thereof, and application of the pyrimidine compounds and the stereoisomers or the pharmaceutically acceptable salts in antitumor drugs. Pharmacological experiment results show that the compound can inhibit proliferation of various tumor cells, and the cancer or tumor related diseases comprise various solid tumors and hematoma such as brain glioma, pituitary tumor, glioma, melanoma, breast cancer, lung cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, prostate cancer, testicular cancer, multiple myeloma, leukemia and the like. The compound provided by the invention is expected to be developed into a new generation of anticancer drugs.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and specifically relates to 2-aminomeridine compounds and their preparation methods and applications. Background technique [0002] EGFR (epidermal growth factor receptor, referred to as EGFR, ErbB-1 or HER1) is a member of the epidermal growth factor receptor (HER) family, a transmembrane receptor located on the surface of the cell membrane, with a molecular weight of 170KDa, activated by binding to ligands , including EGF and TGFα (transforming growth factor α); further, activate intracellular kinase pathways, including Y992, Y1045, Y1068, Y1148 and Y1173 alleles, guide the phosphorylation of downstream MAPK, Akt and JNK pathways, and induce cell proliferation . The activation of EGFR can be divided into three steps: (1) EGFR can lead to the formation of homodimers after binding with ligands, and can also form heterodimers with other EGFR families; (2) dimerization Phosphorylation of 6 s...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D413/14C07D417/14A61P35/00A61P35/02A61K31/506A61K31/5377
CPCC07D403/14C07D413/14C07D417/14A61P35/00A61P35/02
Inventor 杨鹏肖易倍董豪杰叶秀全朱亚胜袁凯陈伟娇姬明慧王晓王丽萍
Owner CHINA PHARM UNIV
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