Oxadiazole-containing heterocyclic compounds, and preparation method and application thereof

Abstract

The invention provides oxadiazole-containing heterocyclic compounds, and a preparation method and an application thereof. The oxadiazole-containing heterocyclic compounds have a structural general formula shown in the description. Cell level experiments find that the oxadiazole-containing heterocyclic compounds can inhibit proliferation of K562-3d, HL60 and KG1a cells, and especially the compound (compound 10c) in the embodiment 11 also realize K562-3d, HL60 and KG1a cell proliferation inhibition effects when the concentration of the compound 10c is lower than a that of a positive control medicine imatinib, so the oxadiazole-containing heterocyclic compounds can be used for treating leukemia.

Description

Technical field

[0001] The invention relates to an oxadiazole-containing heterocyclic compound and a preparation method and application thereof. Background technique

[0002] Leukemia, also known as blood cancer, is a type of clonal malignant disease with abnormal hematopoietic stem cells. The leukemia cells in the clone lose the ability to further differentiate and mature and are stagnated at different stages of cell development. In the bone marrow and other hematopoietic tissues, leukemia cells proliferate and accumulate in large numbers and infiltrate other organs and tissues, while suppressing normal hematopoiesis. The clinical manifestations are symptoms of anemia, bleeding, infection and infiltration of various organs.

[0003] Leukemia is usually divided into: 1) acute leukemia; 2) chronic leukemia; 3) special types of leukemia.

[0004] Acute leukemia is a clonal malignant disease with abnormal hematopoietic stem cells. The leukemia cells in the clone lose the ability to f...

Examples

Embodiment 1

[0088] Example 1 Chemical synthesis and structural identification of oxadiazole-containing heterocyclic compounds provided by the present invention

[0089] 1. The oxadiazole-containing heterocyclic compound provided by the present invention has the following general structural formula:

[0090]

[0091] In the above general structural formula, the substituent -R includes the following groups:

[0092]

[0093] 2. The experimental procedures of chemical synthesis of heterocyclic compounds containing oxadiazole provided by the present invention:

[0094] 2.1 The general synthetic route is:

[0095]

[0096] 2.2.1 Synthesis of compound 5a-5h

[0097] 2.2.1.1 Compound 2: Synthesis of 4-methyl-3-[4-(pyridin-3-yl)pyrimidinyl-2-yl]aminobenzoic acid methyl ester

[0098]

[0099] Add 30mL of anhydrous methanol, compound 1 (1g, 3.26mmol) into a three-necked flask, slowly drop 2mL of concentrated sulfuric acid into it, after the addition is complete, the reaction solution is heated to reflux at 65...

example 1-8

[0142] Example 1-8 Synthesis of Compound 6a-6h

[0143]

example 1

[0144] Example 1 Compound 6a: N-(2-methyl-5-{5-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-1, Synthesis and structure identification of 3,4-oxadiazol-2-yl)phenyl)-4-(3-pyridyl)-pyrimidin-2-amine

[0145]

[0146] Add 167 mg of triphenoxy phosphine and 2 mL of dry dichloromethane to a three-necked flask, slowly add 50 μL of trifluoromethanesulfonic anhydride at 0°C, stir at 0°C for 5 min, and slowly rise to room temperature, a white solid is formed , Add compound 5a (114.5mg, 0.2mmol), the solution turns into bright yellow, stir the reaction at room temperature for 3h, then use 10% NaHCO 3 The aqueous solution was quenched, the aqueous layer was extracted with dichloromethane, and the dichloromethane layer with anhydrous Na 2 SO 4 Dry, filter, spin off the solvent from the filtrate, and purify the residue by column chromatography with CH 2 Cl 2 :MeOH=50:1,CH 2 Cl 2 : MeOH=30:1 gradient elution to obtain 65 mg of white solid, yield: 58.61%.

[0147] MS(ESI + ): 554.98; ...

Technical field

[0001] The invention relates to an oxadiazole-containing heterocyclic compound and a preparation method and application thereof. Background technique

[0002] Leukemia, also known as blood cancer, is a type of clonal malignant disease with abnormal hematopoietic stem cells. The leukemia cells in the clone lose the ability to further differentiate and mature and are stagnated at different stages of cell development. In the bone marrow and other hematopoietic tissues, leukemia cells proliferate and accumulate in large numbers and infiltrate other organs and tissues, while suppressing normal hematopoiesis. The clinical manifestations are symptoms of anemia, bleeding, infection and infiltration of various organs.

[0003] Leukemia is usually divided into: 1) acute leukemia; 2) chronic leukemia; 3) special types of leukemia.

[0004] Acute leukemia is a clonal malignant disease with abnormal hematopoietic stem cells. The leukemia cells in the clone lose the ability to f...

Examples

Embodiment 1

[0088] Example 1 Chemical synthesis and structural identification of oxadiazole-containing heterocyclic compounds provided by the present invention

[0089] 1. The oxadiazole-containing heterocyclic compound provided by the present invention has the following general structural formula:

[0090]

[0091] In the above general structural formula, the substituent -R includes the following groups:

[0092]

[0093] 2. The experimental procedures of chemical synthesis of heterocyclic compounds containing oxadiazole provided by the present invention:

[0094] 2.1 The general synthetic route is:

[0095]

[0096] 2.2.1 Synthesis of compound 5a-5h

[0097] 2.2.1.1 Compound 2: Synthesis of 4-methyl-3-[4-(pyridin-3-yl)pyrimidinyl-2-yl]aminobenzoic acid methyl ester

[0098]

[0099] Add 30mL of anhydrous methanol, compound 1 (1g, 3.26mmol) into a three-necked flask, slowly drop 2mL of concentrated sulfuric acid into it, after the addition is complete, the reaction solution is heated to reflux at 65...

example 1-8

[0142] Example 1-8 Synthesis of Compound 6a-6h

[0143]

example 1

[0144] Example 1 Compound 6a: N-(2-methyl-5-{5-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-1, Synthesis and structure identification of 3,4-oxadiazol-2-yl)phenyl)-4-(3-pyridyl)-pyrimidin-2-amine

[0145]

[0146] Add 167 mg of triphenoxy phosphine and 2 mL of dry dichloromethane to a three-necked flask, slowly add 50 μL of trifluoromethanesulfonic anhydride at 0°C, stir at 0°C for 5 min, and slowly rise to room temperature, a white solid is formed , Add compound 5a (114.5mg, 0.2mmol), the solution turns into bright yellow, stir the reaction at room temperature for 3h, then use 10% NaHCO 3 The aqueous solution was quenched, the aqueous layer was extracted with dichloromethane, and the dichloromethane layer with anhydrous Na 2 SO 4 Dry, filter, spin off the solvent from the filtrate, and purify the residue by column chromatography with CH 2 Cl 2 :MeOH=50:1,CH 2 Cl 2 : MeOH=30:1 gradient elution to obtain 65 mg of white solid, yield: 58.61%.

[0147] MS(ESI + ): 554.98; ...

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