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Compound containing pyrimidine heterocyclic structure as well as preparation method and application of compound

A compound and heterocyclic technology, applied in the field of medicine, can solve the problems of drug resistance and achieve high inhibitory activity and selectivity

Active Publication Date: 2021-12-31
WEIFANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, AZD9291 has been successfully marketed, but the trend of drug resistance is gradually emerging

Method used

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  • Compound containing pyrimidine heterocyclic structure as well as preparation method and application of compound
  • Compound containing pyrimidine heterocyclic structure as well as preparation method and application of compound
  • Compound containing pyrimidine heterocyclic structure as well as preparation method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: N-(3-((4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)pyrimidin-2-yl)amino)-4-methyl Oxyphenyl) propanamide (I-1), prepared by the method of synthetic route 1

[0079] Step 1: 5-(2-Chloropyrimidin-4-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Intermediate B1)

[0080] Under ice bath conditions, 2,4-dichloropyrimidine (10.0g, 67.5mmol) was added into 1:1 dichloromethane and methanol (100mL), then potassium carbonate (23.3g, 169mmol) and 4,5 , 6,7-Tetrahydrothiopheno[3,2,c]pyridine hydrochloride (11.3 g, 81.0 mmol). React at 0°C for 4 hours. After the reaction was completed, the solvent was evaporated, the residue was added with water, and a solid was precipitated, which was filtered with suction. The crude product was washed with ether, filtered with suction, and the filter cake was dried to obtain 16.7 g of a yellow solid, with a yield of 82.1%.

[0081] Step 2: 4-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidine-2 Amine (Inte...

Embodiment 2

[0088] Example 2: N-(3-((4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)pyrimidin-2-yl)amino)4-methoxy phenyl)acrylamide (I-2)

[0089] According to the synthetic method of embodiment 1, intermediate E 1 Compound I-2 of Example 2 was obtained by reacting with acryloyl chloride.

[0090] ESI-MS m / z:408.1[M+H] + .

Embodiment 3

[0091] Example 3: N-(3-((5-chloro-4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)pyrimidin-2-yl)amino) -4-methoxyphenyl) propionamide (I-3)

[0092]According to the synthesis method of Example 1, 2,4,5-trichloropyrimidine is used as a raw material, and after reacting with 4,5,6,7-tetrahydrothiophene[3,2,c]pyridine hydrochloride, through substitution, Reduction, Intermediate E 1 Compound I-3 of Example 3 was obtained by reacting with propionyl chloride.

[0093] MS(ESI)m / z(%):466.1[M+Na] + ; 1 H NMR (400MHz, DMSO-d 6 )δ9.73(s,1H),8.49(s,1H),8.11(s,1H),7.85(s,1H),7.35(d,J=5.1Hz,1H),7.10(d,J=8.8 Hz,1H),6.96(t,J=6.5Hz,2H),4.70(s,2H),3.91(t,J=5.3Hz,2H),3.82(s,3H),2.98(s,2H), 2.32(q,J=7.5Hz,2H),1.10(t,J=7.5Hz,3H).

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Abstract

The invention discloses a compound containing a pyrimidine heterocyclic structure as well as a preparation method and application thereof, belongs to the technical field of medicines, and relates to a compound containing a pyrimidine heterocyclic structure represented by a general formula I and pharmaceutically acceptable salts, hydrates or prodrugs thereof, wherein substituent groups X, Z, R1, R2, R3, A and B have meanings given in the specification. The invention also relates to an effect of inhibiting EGFR kinase and mutants of the compound represented by the general formula I, and also relates to an application of the compound and the pharmaceutically acceptable salts, hydrates or prodrugs thereof in preparation of medicines for treating diseases related to EGFR kinase activity, and in particular, relates to an application in preparation of medicines for treating and / or preventing cancers.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a new compound containing a pyrimidine heterocyclic structure and a preparation method thereof, the compound and its pharmaceutically acceptable salt, hydrate, prodrug thereof, or a pharmaceutical composition containing the compound Use in the preparation of medicines for treating diseases related to epidermal growth factor receptor kinase mutations. Background technique [0002] Epidermal growth factor receptor (EGFR) regulates the cell cycle and is closely related to cell growth, proliferation and migration. Its coding gene is a proto-oncogene, which is inactive under physiological conditions and has no carcinogenicity. If the gene encoding this receptor is mutated, too much EGFR will be produced, leading to enhanced cell signaling, which can easily induce tumors. Studies have shown that EGFR is highly expressed or abnormally expressed in many solid tumor cells, s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D471/04C07D519/00A61K31/506A61K31/519A61P35/00
CPCC07D495/04C07D471/04C07D519/00A61P35/00
Inventor 胡金星刘悦
Owner WEIFANG MEDICAL UNIV
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