Novel heterocyclic compound and preparation method therefor and use thereof as kinase inhibitor

A compound and inert solvent technology, which is applied in the field of new heterocyclic compounds and its preparation, can solve the problems that patients cannot take medicine on time, affect the effect of drug treatment, and the patient's drug concentration fluctuates too much.

Inactive Publication Date: 2016-01-06
SHANGHAI HAIHE PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in actual operation, patients often fail to take medicine on time, which causes excessive fluctuations in drug concentration in the patient's body and affects the therapeutic effect of the drug.

Method used

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  • Novel heterocyclic compound and preparation method therefor and use thereof as kinase inhibitor
  • Novel heterocyclic compound and preparation method therefor and use thereof as kinase inhibitor
  • Novel heterocyclic compound and preparation method therefor and use thereof as kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0049] A particularly preferred preparation process is as follows:

[0050]

[0051](1) At a certain temperature (such as 70-100°C), in an inert solvent (such as acetonitrile, DMF, DMSO, THF, etc.), in a base (such as DBU, triethylamine, diisopropylethylamine, pyridine, K 2 CO 3 、Na 2 CO 3 , NaOH, KOH, etc.), compound 2 and compound 3 were subjected to Michael addition reaction for a period of time (such as 4-20 hours) to obtain compound 4;

[0052] (2) At a certain temperature (such as 70-100 ° C), in an inert solvent (such as dioxane and water, toluene and water, DMSO, THF, DMF, etc.), in a catalyst (such as tetrakis (triphenylphosphine) ) palladium, three (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), bis(dibenzylideneacetone)palladium, dichlorobis(triphenylphosphine)palladium, triphenylphosphinepalladium acetate, bis(tri-orthophenylmethylphosphine)palladium dichloride, 1,2-bis( Diphenylphosphino) ethane dichloride palladium, etc.) and bases (such as potassiu...

Embodiment 1

[0075]

[0076] Compound 2 (250mg, 2.1mmol) and compound 10 (400mg, 2.1mmol) were placed in a 50mL single-necked bottle, under nitrogen protection, DBU (1g, 4.2mmol) was added dropwise at room temperature, and stirred evenly. Then heated to 80 ° C, the reaction 8h. After the reaction was completed, the solvent was spin-dried, and column chromatography (ethyl acetate:petroleum ether=5:1) gave 250 mg of a white solid with a yield of 36%.

[0077] 1 HNMR (CDCl 3 , 400MHz) δppm7.67 (s, 1H), 4.04 (td, 1H, J = 10.2Hz, 4.0Hz), 3.03 (dd, 1H, J = 8.4Hz, 17.2Hz), 2.84 (dd, J = 4Hz, 17.2Hz),2.49(m,1H),2.38(s,3H),1.89(m,1H),1.45-1.70(m,4H),1.20-1.32(m,15H).

[0078]

[0079] Compound 11 (160mg, 0.5mmol), compound 12 (153mg, 0.5mmol), tetrakistriphenylphosphine palladium (29mg, 0.025mmol) and potassium carbonate (207mg, 1.5mmol) were placed in a 50mL single-port reaction flask, nitrogen Under protection, 1,4-dioxane (4 mL) and H 2 O (1 mL), stirred until uniformly dispersed in t...

Embodiment 2

[0087]

[0088] Compound 17 (190 mg, 0.7 mmol) and compound 2 (169 mg, 1.4 mmol) were placed in a 50 mL single-necked bottle, and DBU (425 mg, 2.8 mmol) was added dropwise at room temperature under nitrogen protection, and stirred evenly. Then heated to 80 ° C, the reaction 8h. After the reaction was completed, the solvent was spin-dried, and column chromatography (ethyl acetate:petroleum ether=5:1) gave 60 mg of a colorless oil with a yield of 17%.

[0089] 1 HNMR (CDCl 3 , 400MHz) δppm7.56(s, 1H), 4.21(td, 1H, J=10.2Hz, 4.0Hz), 3.05(m, 1H), 2.85(m, 1H), 2.53(m, 1H), 1.93( m,1H),1.45-1.80(m,4H),1.20-1.32(m,15H).

[0090]

[0091] Compound 18 (60mg, 0.16mmol), compound 12 (48mg, 0.16mmol), tetrakistriphenylphosphine palladium (9mg, 0.008mmol) and potassium carbonate (207mg, 1.5mmol) were placed in a 50mL single-port reaction flask, nitrogen Under protection, 1,4-dioxane (4 mL) and H 2 O (1 mL), stirred until uniformly dispersed in the system, then heated to 80°C, an...

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Abstract

The invention relates to a novel heterocyclic compound and a preparation method therefor and use thereof as a kinase inhibitor. Specifically, the invention discloses a compound with a structure represented by a formula 1 shown in the description and a preparation method therefor. The compound is an effective kinase inhibitor and has very high bioavailability.

Description

technical field [0001] The invention belongs to the field of biomedicine. Specifically, the present invention relates to a novel heterocyclic compound, its preparation method and its use as a kinase inhibitor. Background technique [0002] Tyrosine kinases play a very important role in the occurrence and development of tumors, one of which is the non-receptor tyrosine kinase JAK. The JAK family has four members: JAK1, JAK2, JAK3, and TYK2. Currently, JAK2 is the most detailed and clear study on the correlation between JAK family members and tumors. Abnormal activation of the JAK2 signaling pathway is most closely related to the occurrence and development of tumors. Early studies focused on the role of various abnormal activation forms of JAK2 gene fusion, amplification, and mutation in blood-type tumors. At present, more studies are focused on the role of JAK2V617F (the 617th valine on the pseudokinase domain JH2 is mutated to phenylalanine) in myeloproliferative neoplasm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02
CPCA61K31/519C07D487/04
Inventor 江磊耿美玉丁健刘磊黄敏查传涛艾菁
Owner SHANGHAI HAIHE PHARMACEUTICAL CO LTD
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