阅读说明：本技术 3-[5-(1-萘基氨基)-1,3,4-噻二唑-2-基]-2h-1-苯并吡喃-2-酮的衍生物的用途 (Use of derivatives of 3- [5- (1-naphthylamino) -1,3, 4-thiadiazol-2-yl ] -2H-1-benzopyran-2-one ) 是由 李书艳 张鹏翼 于 2019-07-21 设计创作，主要内容包括：本发明公开一类已知化合物3-[5-(1-萘基氨基)-1,3,4-噻二唑-2-基]-2H-1-苯并吡喃-2-酮的衍生物在制备ALK抑制剂中的用途。本发明的化合物与目前已被发现的ALK抑制剂具有完全不同的骨架结构,可作为潜在的非小细胞肺癌药物先导化合物在治疗ALK融合阳性非小细胞肺癌以及对抗其耐药性方面具有很高的社会价值和临床意义,并具有广阔的应用前景。(The invention discloses application of derivatives of a known compound 3- [5- (1-naphthylamino) -1,3, 4-thiadiazole-2-yl ] -2H-1-benzopyran-2-one in preparation of an ALK inhibitor. The compound has completely different skeleton structures with the ALK inhibitor discovered at present, can be used as a potential lead compound of the non-small cell lung cancer medicament, has high social value and clinical significance in the aspects of treating ALK fusion positive non-small cell lung cancer and resisting the drug resistance of the ALK fusion positive non-small cell lung cancer, and has wide application prospect.)

1. Formula 1 shows the application of a 3- [5- (1-naphthylamino) -1,3, 4-thiadiazole-2-yl ] -2H-1-benzopyran-2-one derivative or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof in the preparation of an ALK inhibitor,

wherein: r₁、R₂、R₃、R₄And R₅Each independently selected from hydrogen atom, halogen atom, hydroxyl, amino, nitrile group, carboxyl, nitro, sulfonic group, aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, sulfonyl C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-6Alkylamino or (C)_1-6)₂Amino group, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonyloxy, C_1-6Alkylsulfonylamino group, C_1-6Alkylaminosulfonyl radical, C_1-6An alkylsulfonyl group;

or R₁And R₂Unsubstituted or substituted 3-to 8-membered cycloalkyl, unsubstituted or substituted 3-to 8-membered heterocyclyl, unsubstituted or substituted 6-to 8-membered aryl, unsubstituted or substituted 5-to 8-membered heteroaryl, formed together with the carbon adjacent thereto;

or R₂And R₃Unsubstituted or substituted 3-to 8-membered cycloalkyl, unsubstituted or substituted 3-to 8-membered heterocyclyl, unsubstituted or substituted 6-to 8-membered aryl, unsubstituted or substituted 5-to 8-membered heteroaryl, formed together with the carbon adjacent thereto;

or R₃And R₄Unsubstituted or substituted 3-to 8-membered cycloalkyl group, unsubstituted or substituted 3-to 8-membered heterocyclyl group, unsubstituted or substituted 6-to 8-membered aryl group, unsubstituted or substituted5-8 membered heteroaryl.

2. Use of a compound according to claim 1, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the preparation of an ALK inhibitor, wherein:

R₁、R₂、R₃、R₄and R₅Are respectively and independently selected from hydrogen atom, halogen atom, hydroxyl, amino and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy radical, C_1-6Alkylamino or (C)_1-6)₂An amino group;

or R₁And R₂Unsubstituted or substituted 3-to 8-membered cycloalkyl, unsubstituted or substituted 3-to 8-membered heterocyclyl formed together with the carbon adjacent thereto;

or R₂And R₃Unsubstituted or substituted 3-to 8-membered cycloalkyl, unsubstituted or substituted 3-to 8-membered heterocyclyl formed together with the carbon adjacent thereto;

or R₃And R₄Together with the carbon adjacent thereto, an unsubstituted or substituted 3-to 8-membered cycloalkyl group, an unsubstituted or substituted 3-to 8-membered heterocyclyl group.

3. Use of a compound according to claim 2, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the preparation of an ALK inhibitor, wherein:

R₁、R₂、R₃、R₄and R₅Each independently selected from hydrogen atom, halogen atom, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino or (C)_1-4)₂An amino group.

4. Use of a compound according to claim 3, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the preparation of an ALK inhibitor, wherein:

R₁、R₂、R₄and R₅Are each a hydrogen atom, R₃Is a chlorine atom or a bromine atom or a methoxy group.

5. Use of a compound according to claim 3, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the preparation of an ALK inhibitor, wherein:

R₁、R₃、R₄and R₅Are each a hydrogen atom, R₂Is diethylamino.

6. Use of a compound of claims 1-5, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of an ALK-mediated associated disease.

7. Use of a compound of claims 1-5, or a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of non-small cell lung cancer.

Technical Field

The invention relates to application of a known compound, in particular to application of a 3- [5- (1-naphthylamino) -1,3, 4-thiadiazole-2-yl ] -2H-1-benzopyran-2-one derivative in preparation of an ALK inhibitor.

Background

Lung cancer is one of the most serious malignant tumors in the world, has become the most common cancer in China, and is also the leading cause of cancer death. Among lung cancer patients in China, non-small cell lung cancer (NSCLC) patients account for about 85 percent. Anaplastic Lymphoma Kinase (ALK) gene fusion mutation is a common driver gene of non-small cell lung cancer, accounts for about 5.1% of non-small cell lung cancer, and has a high incidence rate in non-smoking people and young patients. The ALK inhibitor is a commonly used targeted drug for treating non-small cell lung cancer caused by ALK gene fusion mutation, according to NCCN non-small cell lung cancer guide-2019. V3 published by the United states National Comprehensive Cancer Network (NCCN), the crizotinib, the ceritinib, the anitinib and the brigatinib are recommended to be first-line treatment drugs of ALK fusion positive patients, and in CSCO primary lung cancer diagnosis guide 2019 published by the Chinese clinical oncology institute (CSCO), the anitinib and the crizotinib are also recommended to be first-line treatment for ALK fusion positive NSCLC, wherein the anitinib is preferentially recommended. However, after the targeted drug is used for a period of time, the patient is easy to generate drug resistance, and the targeted drug must be replaced by a new targeted drug. Therefore, the development of the ALK inhibitor with a brand-new skeleton as a potential lead compound of the non-small cell lung cancer medicament has high social value and clinical significance.

Disclosure of Invention

The invention provides an application of a known compound or a pharmaceutically acceptable salt of the compound in preparing an ALK inhibitor.

The compound is 3- [5- (1-naphthylamino) -1,3, 4-thiadiazole-2-yl shown as a formula 1]Use of a derivative of-2H-1-benzopyran-2-one, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the preparation of an ALK inhibitor, wherein: r₁、R₂、R₃、R₄And R₅Are respectively provided with

Independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitrile group, a carboxyl group, a nitro group, a sulfonic group, an aryl group, a substituted aryl group, a heterocyclic aryl group, a substituted heterocyclic aryl group, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, sulfonyl C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_1-6Alkylamino or (C)_1-6)₂Amino group, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonyloxy, C_1-6Alkylsulfonylamino group, C_1-6Alkylaminosulfonyl radical, C_1-6An alkylsulfonyl group;

or R₁And R₂Together with its neighboursAn unsubstituted or substituted 3-to 8-membered cycloalkyl group, an unsubstituted or substituted 3-to 8-membered heterocyclyl group, an unsubstituted or substituted 6-to 8-membered aryl group, an unsubstituted or substituted 5-to 8-membered heteroaryl group;

or R₂And R₃Unsubstituted or substituted 3-to 8-membered cycloalkyl, unsubstituted or substituted 3-to 8-membered heterocyclyl, unsubstituted or substituted 6-to 8-membered aryl, unsubstituted or substituted 5-to 8-membered heteroaryl, formed together with the carbon adjacent thereto;

or R₃And R₄And an unsubstituted or substituted 3-to 8-membered cycloalkyl group, an unsubstituted or substituted 3-to 8-membered heterocyclyl group, an unsubstituted or substituted 6-to 8-membered aryl group, and an unsubstituted or substituted 5-to 8-membered heteroaryl group, which are formed together with the carbon adjacent thereto.

Preferably, the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, is used for preparing an ALK inhibitor, wherein:

R₁、R₂、R₃、R₄and R₅Are respectively and independently selected from hydrogen atom, halogen atom, hydroxyl, amino and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy radical, C_1-6Alkylamino or (C)_1-6)₂An amino group;

or R₁And R₂Unsubstituted or substituted 3-to 8-membered cycloalkyl, unsubstituted or substituted 3-to 8-membered heterocyclyl formed together with the carbon adjacent thereto;

or R₂And R₃Unsubstituted or substituted 3-to 8-membered cycloalkyl, unsubstituted or substituted 3-to 8-membered heterocyclyl formed together with the carbon adjacent thereto;

or R₃And R₄Together with the carbon adjacent thereto, an unsubstituted or substituted 3-to 8-membered cycloalkyl group, an unsubstituted or substituted 3-to 8-membered heterocyclyl group.

Further, the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof is used for preparing an ALK inhibitor, wherein:

R₁、R₂、R₃、R₄and R₅Each independently selected from hydrogen atom, halogen atom, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino or (C)_1-4)₂An amino group;

further, the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the preparation of an ALK inhibitor, wherein:

R₁、R₂、R₄and R₅Are each a hydrogen atom, R₃Is a chlorine atom or a bromine atom or a methoxy group;

further, the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the preparation of an ALK inhibitor, wherein:

R₁、R₃、R₄and R₅Are each a hydrogen atom, R₂Is diethylamino.

The compound or the pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof can be applied to preparation of medicines for treating and/or preventing ALK-mediated related diseases or medicines for treating and/or preventing non-small cell lung cancer.

The compound related to the invention has a completely different framework structure from the ALK inhibitor discovered at present, and is a brand-new ALK inhibitor. The compound as a potential lead compound of the non-small cell lung cancer medicament has high social value and clinical significance in the aspects of treating ALK fusion positive non-small cell lung cancer and resisting drug resistance of the ALK fusion positive non-small cell lung cancer, and has wide application prospect.

Detailed Description

The invention is illustrated below in connection with the best examples in which the specific compounds involved are as follows:

each of the above compounds was purchased from specs corporation and had a purity of not less than 95%.

ALK used in the experiments of the present invention was purchased from Thermo Fisher (Sammer), and substrate (poly [ Glu, Tyr ]4:1) was purchased from Sigma Aldrich (sigma-aldrich).

The implementation of the invention is to dissolve the compound to be tested in DMSO according to the following steps: 50nM HEPES,10nM MgCl₂ALK kinase buffer was prepared at a ratio of 1mM EGTA, 0.01% Brij-35, pH 7.5. Before the reaction, 2.5 times of ALK solution, 2.5 times of substrate and 2.5 times of ATP mixed solution and 2 times of continuously diluted solution of the compound to be detected are prepared. The specific experiment is that 2 mul of the compound solution to be detected, 4 mul of LALK solution and 4 mul of the mixed solution of substrate and ATP are added in a 384 micro-porous plate in turn. The final reaction solution contained 0.1. mu.g/mL of the test compound, 200. mu.g/mL of the substrate, 10. mu.MATP, and a gradient concentration. After keeping the temperature constant at 30 ℃ for 1 hour, 10 mu LPromega Kinase-The luminescense KinaseAssay Platform kit detects the chemiluminescence intensity of each hole, and the luminescence intensity is in direct proportion to the concentration of the residual ATP in the reaction solution.

The inhibition ratio in the experimental results is (maximum-sample value)/(maximum-minimum) x 100%, where the maximum is the mean chemiluminescence intensity of the positive control group to which the test compound was not added, and the minimum is the mean chemiluminescence intensity of the negative control group to which the enzyme was not added. Curve fitting was performed using GraphPad Prism software to obtain IC₅₀The value is obtained.

The results of the experiments are shown in the following table.

From experimental results, 4 compounds in the invention have inhibitory activity on ALK, have the potential to be lead compounds of ALK fusion-positive non-small cell lung cancer treatment drugs, and the compound 1 has the best effect.