3-(3-aryl-4-thiazolinone)-N-arylbenzamide compounds and their preparation and application

Abstract

The present invention discloses a 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof and a preparation method thereof. The present invention also discloses the use of the compound or a pharmaceutical composition thereof in treating osteosarcoma, colorectal cancer, pancreatic cancer, leukemia and other related diseases, which is of great significance in the study of tumor diseases.

Description

Technical Field

[0001] The present invention relates to the field of synthetic pharmaceutical chemicals, and mainly relates to a 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound and a preparation method and application thereof. Background Art

[0002] Osteosarcoma, also known as osteosarcoma, is a common malignant bone tumor that occurs in adolescents or children under the age of 20 (Link MP: Osteosarcoma in adolescents and young adults: new developments and controversies. Commentary on the use of presurgical chemotherapy. Cancer Treat Res 62: 383-385, 1993.). According to epidemiological studies of osteosarcoma, it is the most common bone malignancy in children, accounting for about 5% of pediatric tumors. Osteosarcoma is still a disease with a high mortality rate among malignant tumors in children and adolescents, second only to lymphoma and brain cancer, but early detection and timely treatment have greatly improved the survival rate of the disease.

[0003] Treatment methods for different types of osteosarcoma usually use combined medication after surgery. It is worth noting that the cancer metastasis rate of osteosarcoma patients is as high as 80%. Among patients with metastasis, 90% are lung metastases. The recurrence rate is 20-30%, and recurrence is possible in both in situ and in situ tissues. In addition, the survival rate after recurrence has not improved in the past few decades, despite adjustments such as increasing the dose, changing the number of times, and combining multiple chemotherapy drugs.

[0004] At present, the research on therapeutic targets for osteosarcoma mainly focuses on the cell surface receptor tyrosine kinase family (PTKs) and intracellular signaling targets. For these targets, the main therapeutic drugs are divided into three categories: 1) immunomodulators; 2) receptor tyrosine kinase inhibitors; 3) intracellular signaling pathway inhibitors. In addition, new targets and treatment options for osteosarcoma include NK-kB ligands, folic acid inhibitors, etc., but they are all in the experimental research stage. Summary of the invention

[0005] The inventors have noticed that in previous literature reports, compounds with a thiazolinone skeleton structure have various pharmacological activities, such as the compound represented by formula (V) having anti-inflammatory activity and the compound represented by formula (VI) having anti-AIDS activity:

[0006]

[0007] Prior to the present invention, there were no reports on the evaluation of osteosarcoma cell activity test for this type of framework. The inventors have discovered and proposed that this framework compound may produce a series of new compound molecules with significant structure and activity, which may provide a new source of compounds for biological activity screening.

[0008] The present invention provides a 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof as shown in formula (I), (II), (III) and (IV). The compound is a new compound and there is no related report:

[0009]

[0010] in,

[0011] V is N or CH;

[0012] W is O, NR 3 , S or CH2; among which, R 3 is alkyl, aryl, alkoxy, phenyl;

[0013] X is O, NR 4 , S or CH2; among which, R 4 is alkyl, aryl, alkoxy, phenyl;

[0014] Z is O, NR 5 , S or CH2; among which, R 5 is alkyl, aryl, alkoxy, phenyl;

[0015] In the present invention, the aromatic group includes a benzene ring, a nitrogen-containing, an oxygen-containing, or a sulfur-containing heteroaromatic ring;

[0016] Y is O, NR 6 , S or CH2; among which, R 6 is alkyl, aryl, alkoxy, phenyl;

[0017] R 1 is halogen, alkoxy, alkyl, nitro, cyano, trifluoromethyl, hydrogen, etc.;

[0018] R 2 is alkyl, aryl, alkoxy, phenyl;

[0019] n = 1, 2;

[0020] is an alkyl heterocycle, a phenyl heterocycle or an aryl heterocycle;

[0021] Preferably,

[0022] V is N or CH;

[0023] W is O, NR3 or CH2; where R 3 is C1-C10 alkyl, naphthyl, C1-C10 alkoxy, phenyl;

[0024] X is O, NR 4 or CH2; where R 4 is C1-C10 alkyl, naphthyl, C1-C10 alkoxy, phenyl;

[0025] Z is O, NR 5 or CH2; where R 5 is C1-C10 alkyl, naphthyl, C1-C10 alkoxy, phenyl;

[0026] Y is O, NR 6 or CH2; where R 6 is C1-C10 alkyl, naphthyl, C1-C10 alkoxy, phenyl;

[0027] R 1 is halogen, C1-C10 alkoxy, C1-C10 alkyl, nitro, cyano, trifluoromethyl, hydrogen, etc.;

[0028] R 2 is C1-C10 alkyl, naphthyl, C1-C10 alkoxy, phenyl;

[0029] n = 1, 2;

[0030] is an alkyl heterocycle, a phenyl heterocycle or a naphthyl heterocycle;

[0031] More preferably,

[0032] V is N or CH;

[0033] W is O, NR 3 Or CH2, where R 3 is C1-C5 alkyl, C1-C5 alkoxy;

[0034] X is O, NR 4 Or CH2, where R 4 is C1-C5 alkyl, C1-C5 alkoxy;

[0035] Z is O, NR 5 Or CH2, where R 5 is C1-C5 alkyl, C1-C5 alkoxy;

[0036] Y is O, NR 6 or CH2; where R 6 is C1-C5 alkyl, C1-C5 alkoxy;

[0037] R 1 is halogen, C1-C5 alkoxy, methyl, ethyl, isopropyl, nitro, cyano, trifluoromethyl, hydrogen, etc.;

[0038] R 2 is C1-C5 alkyl, naphthyl, C1-C5 alkoxy, phenyl;

[0039] n = 1, 2;

[0040] It is an alkyl heterocycle, a phenyl heterocycle or an aryl heterocycle.

[0041] Furthermore, the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compounds or pharmaceutically acceptable salts of the present invention include the structures shown in formula (VII) and formula (VIII):

[0042]

[0043] Among them, R in formula (VII) and formula (VIII) 2 , W, Z, X, V, and n are defined the same as those in formula (I), formula (II), formula (III), and formula (IV).

[0044] The 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compounds or pharmaceutically acceptable salts of the present invention include but are not limited to the following:

[0045] 3-(3-(2-methoxyphenyl)-4-thiazolinone)-5-methyl-N-(4-phenylbutyl)benzamide;

[0046] 3-(3-(2-methoxyphenyl)-4-thiazolinone)-5-fluoro-N-(4-phenylbutyl)benzamide;

[0047] 3-(3-(2-fluorophenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0048] 4-(3-(2-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0049] 3-(3-(3-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0050] 3-(3-(4-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0051] 3-(3-(2,5-dimethoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0052] 3-(3-(2,3-dimethoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0053] 3-(3-(2,4-dimethoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0054] 3-(3-(5-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0055] 3-(3-(4-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0056] 3-(3-(3-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0057] 3-(3-(5-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0058] 3-(3-(4-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0059] 3-(3-(3-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0060] 3-(3-(2-fluorophenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0061] 3-(3-(3-fluorophenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0062] 3-(3-(4-Fluorophenyl)-4-thiazolinone-yl)-N-(4-1N-pyrazolbutyl)benzamide;

[0063] 3-(3-(2-chlorophenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0064] 3-(3-(3-chlorophenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0065] 3-(3-(4-chlorophenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0066] 3-(3-(2-methylphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0067] 3-(3-(3-methylphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0068] 3-(3-(4-methylphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0069] 3-(3-(2-trifluoromethylphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0070] 3-(3-(3-trifluoromethylphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0071] 3-(3-(4-trifluoromethylphenyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0072] 3-(3-(3-methoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0073] 3-(3-(4-methoxyphenyl)-4-thiazolinone)-N-(4-phenyl(4-fluoro)butyl)benzamide;

[0074] 3-(3-(2,5-dimethoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0075] 3-(3-(2,3-dimethoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0076] 3-(3-(2,4-dimethoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0077] 3-(3-(5-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0078] 3-(3-(4-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0079] 3-(3-(3-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0080] 3-(3-(5-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0081] 3-(3-(4-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0082] 3-(3-(3-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-fluoro)phenylbutyl)benzamide;

[0083] 3-(3-(2-fluorophenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0084] 3-(3-(3-fluorophenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0085] 3-(3-(4-fluorophenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0086] 3-(3-(2-chlorophenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0087] 3-(3-(3-chlorophenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0088] 3-(3-(4-chlorophenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0089] 3-(3-(2-methylphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0090] 3-(3-(3-methylphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0091] 3-(3-(4-methoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0092] 3-(3-(2,5-dimethoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0093] 3-(3-(2,3-dimethoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0094] 3-(3-(2,4-dimethoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0095] 3-(3-(5-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0096] 3-(3-(4-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0097] 3-(3-(3-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0098] 3-(3-(5-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0099] 3-(3-(4-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0100] 3-(3-(3-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(4-chloro)phenylbutyl)benzamide;

[0101] 3-(3-(2-fluorophenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0102] 3-(3-(3-fluorophenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0103] 3-(3-(4-Fluorophenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0104] 3-(3-(2-chlorophenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0105] 3-(3-(3-chlorophenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0106] 3-(3-(4-chlorophenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0107] 3-(3-(2-methylphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0108] 3-(3-(3-methylphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0109] 3-(3-(4-methylphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0110] 3-(3-(2-trifluoromethylphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0111] 3-(3-(3-trifluoromethylphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0112] 3-(3-(4-trifluoromethylphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0113] 3-(3-(3-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0114] 3-(3-(4-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0115] 3-(3-(2,5-dimethoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0116] 3-(3-(2,3-dimethoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0117] 3-(3-(2,4-dimethoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0118] 3-(3-(5-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0119] 3-(3-(4-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0120] 3-(3-(3-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0121] 3-(3-(5-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0122] 3-(3-(4-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0123] 3-(3-(3-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0124] 3-(3-(2-methoxyphenyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0125] 3-(3-(3-methoxyphenyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0126] 3-(3-(4-methoxyphenyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0127] 3-(3-(2,5-dimethoxyphenyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0128] 3-(3-(2,3-dimethoxyphenyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0129] 3-(3-(2,4-dimethoxyphenyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0130] 3-(3-(5-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0131] 3-(3-(2-methoxyphenyl)-4-thiazolinone)-N-(4-N-benzotriazolylbutyl)benzamide;

[0132] 3-(3-(2-methoxyphenyl)-4-thiazolinone)-N-(4-Boc-piperazinebutyl)benzamide;

[0133] 3-(3-(3-methoxyphenyl)-4-thiazolinone)-N-(4-Boc-piperazinebutyl)benzamide;

[0134] 3-(3-(4-methoxyphenyl)-4-thiazolinone)-N-(4-Boc-piperazinebutyl)benzamide;

[0135] 3-(3-(2,5-dimethoxyphenyl)-4-thiazolinone)-N-(4-Boc-piperazinebutyl)benzamide;

[0136] 3-(3-(2,3-dimethoxyphenyl)-4-thiazolinone)-N-(4-Boc-piperazinebutyl)benzamide;

[0137] 3-(3-(2,4-dimethoxyphenyl)-4-thiazolinone)-N-(4-Boc-piperazinebutyl)benzamide;

[0138] (E)-3-(3-(2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)but-3-en-1-yl)benzoyl;

[0139] (E)-3-(3-(2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(phenyl)but-3-en-1-yl)benzoyl;

[0140] (E)-3-(3-(5-fluoro-2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)but-3-en-1-yl)benzamide;

[0141] (Z)-3-(3-(2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)but-3-en-1-yl)benzoyl;

[0142] (Z)-3-(3-(2-methoxyphenyl)-4-thiazolinone)-N-(4-(phenyl)but-3-en-1-yl)benzoyl;

[0143] (Z)-3-(3-(5-fluoro-2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)but-3-en-1-yl)benzamide;

[0144] 3-(3-(2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0145] 3-(3-(2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)benzamide;

[0146] 3-(3-(5-Fluoro-2-methoxyphenyl)-4-thiazolinonyl)-N-(4-(thiophen-2-yl)butyl)benzamide.

[0147] 3-(3-(3-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0148] 3-(3-(4-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0149] 3-(3-(2,5-dimethoxyphenyl)-4-thiazolinone)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0150] 3-(3-(2,3-dimethoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0151] 3-(3-(2,4-dimethoxyphenyl)-4-thiazolinone)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0152] 3-(3-(4-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0153] 3-(3-(3-fluoro-2-methoxyphenyl)-4-thiazolinone)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0154] 3-(3-(5-methyl-2-methoxyphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0155] 3-(3-(4-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0156] 3-(3-(3-methyl-2-methoxyphenyl)-4-thiazolinone)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0157] 3-(3-(2-fluorophenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0158] 3-(3-(3-fluorophenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0159] 3-(3-(4-fluorophenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0160] 3-(3-(2-chlorophenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0161] 3-(3-(3-chlorophenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0162] 3-(3-(4-chlorophenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0163] 3-(3-(2-methylphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0164] 3-(3-(3-methylphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0165] 3-(3-(4-methylphenyl)-4-thiazolinone-yl)-N-(4-(thiophen-2-yl)butyl)benzamide;

[0166] 3-(3-(2-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide

[0167] 3-(3-(3-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0168] 3-(3-(4-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0169] 3-(3-(2-ethoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0170] 3-(3-(3-ethoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0171] 3-(3-(4-ethoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0172] 3-(3-(2,5-dimethoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0173] 3-(3-(2,3-dimethoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0174] 3-(3-(2,4-dimethoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0175] 3-(3-(5-fluoro-2-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0176] 3-(3-(4-fluoro-2-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0177] 3-(3-(3-fluoro-2-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0178] 3-(3-(5-methyl-2-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0179] 3-(3-(4-methyl-2-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0180] 3-(3-(3-methyl-2-methoxyphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0181] 3-(3-(2-fluorophenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0182] 3-(3-(3-fluorophenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0183] 3-(3-(4-Fluorophenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0184] 3-(3-(2-chlorophenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0185] 3-(3-(3-chlorophenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0186] 3-(3-(4-chlorophenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0187] 3-(3-(2-methylphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0188] 3-(3-(3-methylphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0189] 3-(3-(4-methylphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0190] 3-(3-(2-trifluoromethylphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0191] 3-(3-(3-trifluoromethylphenyl)-5-methyl-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0192] 3-(3-(4-Trifluoromethylphenyl)-5-methyl-4-thiazolinone-yl)-N-(4-phenylbutyl)benzamide.

[0193] The present invention also provides the raw materials used in the compounds represented by formula (I), (II) and (III) The synthesis method.

[0194] In a specific embodiment, the synthesis method of the raw materials used in the compounds represented by formula (I), (II) and (III) specifically includes the following four methods:

[0195] Method 1:

[0196]

[0197] Add S1 and sodium hydride to a dry three-necked flask, protect with nitrogen, then add dry DMSO or DMF, stir at 110°C for 10 min, then dissolve N-(6-bromohexyl)phthalimide and a catalytic amount of KI in dry DMSO or DMF solution and add to the reaction solution, continue stirring at 110°C, and monitor the reaction by thin layer chromatography. After the reaction is complete, add saturated sodium chloride, extract three times with dichloromethane, collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and separate and purify by column chromatography (petroleum ether / ethyl acetate = 9:1).

[0198] Methanol and hydrazine were added to the product obtained by separation and purification above, and the mixture was reacted at 65° C. for 15 h. The reaction was monitored by thin layer chromatography. After the reaction was complete, 1 M sodium hydroxide solution was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and used directly in the reaction without purification.

[0199] Method 2:

[0200]

[0201] S1, potassium carbonate, N-(6-bromohexyl)phthalimide and a catalytic amount of KI were added to a dry three-necked flask, followed by dry acetonitrile, and the reaction was refluxed and monitored by thin layer chromatography. After the reaction was complete, saturated sodium chloride was added, and the mixture was extracted three times with dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1).

[0202] Methanol and hydrazine were added to the product obtained by separation and purification above, and the mixture was reacted at 65° C. for 15 h. The reaction was monitored by thin layer chromatography. After the reaction was complete, 1 M sodium hydroxide solution was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and used directly in the reaction without purification.

[0203] Method 3:

[0204]

[0205] Add N-(3-bromopropyl)phenylenediamine, S1 and THF to a dry three-necked flask. Cool to -55°C under nitrogen protection and add potassium tert-butoxide. After the addition, raise the reaction mixture to 10°C, react for 4 hours, and pour into water. Extract with ethyl acetate, combine the organic phases, wash with water, and dry with magnesium sulfate. Concentrate under reduced pressure to obtain an oily crude product, purify by column chromatography, and use in the next step;

[0206] The above product was dissolved in ethanol, hydrazine hydrate was added, refluxed overnight, the white insoluble matter was filtered out, and the solvent was removed under reduced pressure. The obtained oil was dissolved in ethyl acetate and washed with 2M NaOH; the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and dried with magnesium sulfate. The solvent was removed under reduced pressure and used directly in the reaction without purification.

[0207] Method 4:

[0208]

[0209] Add N-(3-bromopropyl)phenylenediamine, S1 and THF to a dry three-necked flask. Cool to -55°C under nitrogen protection and add potassium tert-butoxide. After the addition, raise the reaction mixture to 10°C, react for 4 hours, and pour into water. Extract with ethyl acetate, combine the organic phases, wash with water, and dry with magnesium sulfate. Concentrate under reduced pressure to obtain an oily crude product, purify by column chromatography, and use in the next step;

[0210] The above product was dissolved in ethanol, hydrazine hydrate was added, refluxed overnight, the white insoluble matter was filtered out, and the solvent was removed under reduced pressure. The obtained oil was dissolved in ethyl acetate and washed with 2M NaOH; the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and dried with magnesium sulfate. The solvent was removed under reduced pressure and used directly in the reaction without purification.

[0211] The crude product obtained in the previous step was placed in a three-necked flask, and 10% palladium carbon was added. Methanol was added under nitrogen protection, and then the nitrogen was replaced by hydrogen. After the entire reaction system was reacted under a hydrogen atmosphere and room temperature for 16 hours, the reaction solution was filtered through diatomaceous earth, the filtrate was collected, the solvent was spin-dried, and it was directly used in the next reaction.

[0212] The present invention also proposes a method for synthesizing a 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof as shown in formula (I) or formula (II) or formula (III) or formula (IV), which specifically comprises the following steps, including (A), (B) and (C): (the synthetic routes of the compounds designed in the present invention are consistent with the following method, the following method only describes the synthetic method of formula (I), and the synthetic methods of formula (II), formula (III) and formula (IV) all refer to formula (I))

[0213]

[0214] In the first step, o-anisidine (10 mmol, 1.0 eq) and methyl 3-formaldehyde benzoate (10 mmol, 1.0 eq) were reacted under toluene reflux conditions for 30 minutes to generate the corresponding imine compound. The reaction system was then cooled to room temperature, and thioglycolic acid (10 mmol, 1.0 eq) was added to continue refluxing. After reacting for 5 hours, the reaction system was cooled to room temperature, and the reaction was monitored by spot plate to complete. The ester compound was then separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1).

[0215]

[0216] In the second step, the ester compound (5 mmol, 1.0 eq) obtained in the first step and LiOH (5.25 mmol, 1.05 eq) were reacted in a methanol: water (4:1) solvent at room temperature for 20 hours. The substrate was completely consumed by spot plate monitoring. After the reaction, the methanol in the solvent was removed by rotary evaporation, and the remaining reaction solution was poured into 50 mL of water. 3N HCl was added dropwise for acidification. A large amount of white solid precipitated. The pH was monitored with pH paper until pH = 1. The white solid was filtered out with a Buchner funnel, dissolved with ethyl acetate, dried over anhydrous sodium sulfate, and then rotary evaporated to obtain the carboxylic acid product.

[0217]

[0218]

[0219] In the third step, the carboxylic acid product (1.5mmol, 1.0eq) obtained in the second step and 1-hydroxybenzotriazole (i.e., HOBt, 3.0mmol, 2.0eq) were dissolved in 20mL tetrahydrofuran, and N,N-diisopropylethylamine (DIPEA, 4.5mmol, 3.0eq) was added under ice bath conditions. After stirring for 20 minutes, the compound phenylbutylamine was added and continued to stir for 10 minutes. Subsequently, the condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 3mmol, 2.0eq) was added in batches. After two hours of reaction, the plate was monitored and the raw materials were completely consumed. An appropriate amount of saturated sodium bicarbonate was added to the reaction solution in sequence, washed with saturated brine, and extracted with ethyl acetate three times. The crude product obtained by rotary evaporation was finally obtained by column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain the target product.

[0220] Among them, in reaction formula (A), (B) and reaction formula (C), R 1 , R 2 , V, X, Z, and W are defined the same as in formula (I).

[0221] The present invention also provides an acid addition salt formed by the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound and an acid; wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, salicylic acid, tartaric acid, lactic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, pyruvic acid or succinic acid, etc.

[0222] The present invention also provides a pharmaceutical composition, which comprises the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0223] Wherein, the pharmaceutical composition is formulated into pills, capsules, creams, gels, excipients, injectable fluids, aerosols, syrups or transdermal patches, etc.

[0224] The present invention also proposes the use of the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or pharmaceutically acceptable salt, or pharmaceutical composition in the preparation of drugs for preventing and / or treating tumors.

[0225] The 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compounds are used to inhibit the proliferation, growth, migration, infiltration, metastasis and recurrence of tumor cells, or promote the apoptosis of tumor cells.

[0226] Wherein, the tumor cells are osteosarcoma cells, colorectal cancer cells, leukemia cells, lung cancer cells, pancreatic cancer cells and the like.

[0227] The osteosarcoma cells include SJSA-1, U2OS, HOS, MNNG / HOS, MG63, and 143b;

[0228] The pancreatic cancer cells include PANC-1;

[0229] The lung cancer cells include A549;

[0230] The colorectal cancer cells include HCT116;

[0231] The leukemia cells include Jurkat.

[0232] The beneficial effects of the present invention are as follows: the present invention discloses a 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof and a preparation method thereof; the compound or composition has an inhibitory activity on tumor cells and can be used to treat osteosarcoma, colorectal cancer, pancreatic cancer, leukemia and other related diseases, and is of great significance in the study of tumor diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0233] Figure 1 The product 1 obtained in Example 1 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0234] Figure 2 The product 2 obtained in Example 2 of the present invention 1 HNMR, 13 CNMR and 19 Schematic diagram of FNMR.

[0235] Figure 3 The product 3 obtained in Example 3 of the present invention 1 HNMR, 13 CNMR and 19 Schematic diagram of FNMR.

[0236] Figure 4 The product 4 obtained in Example 4 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0237] Figure 5 The product 5 obtained in Example 5 of the present invention 1 HNMR, 13 CNMR and 19 Schematic diagram of FNMR.

[0238] Figure 6 The product 6 obtained in Example 6 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0239] Figure 7 The product 7 obtained in Example 7 of the present invention 1 HNMR, 13 CNMR and 19 Schematic diagram of FNMR.

[0240] Figure 8 The product 8 obtained in Example 8 of the present invention 1 HNMR, 13 CNMR and 19 Schematic diagram of FNMR.

[0241] Fig. 9 The product 9 obtained in Example 9 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0242] Fig.10 The product 10 obtained in Example 10 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0243] Fig.11 The product 11 obtained in Example 11 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0244] Fig.12 The product 12 obtained in Example 12 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0245] Fig.13 The product 13 obtained in Example 13 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0246] Fig.14 The product 14 obtained in Example 14 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0247] Fig.15 The product 15 obtained in Example 15 of the present invention 1 HNMR, 13 CNMR and 19 Schematic diagram of FNMR.

[0248] Fig.16 The product 16 obtained in Example 16 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0249] Fig.17 The product 17 obtained in Example 17 of the present invention 1 HNMR and 13 Schematic diagram of CNMR.

[0250] Fig.18 The product 18 obtained in Example 18 of the present invention 1 HNMR, 13 CNMR and 19 Schematic diagram of FNMR. DETAILED DESCRIPTION

[0251] The present invention is further described in detail in conjunction with the following specific embodiments and drawings, and the protection content of the present invention is not limited to the following embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the attached claims.

[0252] The preparation methods of the compounds in the following examples of the present invention refer to the preparation of the compound represented by formula (I) mentioned above. Determination method: low-resolution mass spectrometry (molecular weight) and nuclear magnetic resonance instrument (hydrogen spectrum, carbon spectrum and fluorine spectrum).

[0253] Embodiment 1:

[0254]

[0255] 1 H NMR (400MHz, Chloroform-d) δ7.68(d,J=12.4Hz,1H),7.58(d,J=7.6Hz,1H),7.48(d,J=7.4Hz,1H),7.31(dd,J=16.3Hz,8.2Hz,3H),7.18( q,J=6.2Hz,5.7Hz,3H),3.92(t,J=9.1Hz,2H),3.82(s,2H),3.53(s,0H),3.44(q,J=6.3Hz,2H),2.67(t,J=7.0Hz,2H),1.31–1.22(m,5H).

[0256] 13 C NMR (101MHz, CDCl3) δ171.45,166.80,154.81,142.00,139.78,134.97,129.72,128.76,128.4 1,127.25,126.51,125.88,120.92,112.15,64.35,55.78,39.97,35.47,33.17,29.18,28.70.

[0257] Example 2:

[0258]

[0259] 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.40–7.25 (m, 4H), 7.18 (d, J = 6.9 Hz, 5H), 7.08–6.97 (m, 5H), 6.12 (s, 1H), 4.15–3.76 (m, 2H), 3.40 (d, J = 22.2 Hz, 2H), 2.65 (d, J = 7.1 Hz, 3H), 1.66 (dd, J = 19.2 Hz, 11.2 Hz, 8H).

[0260] 13 C NMR (101 MHz, CDCl3) δ 170.99, 166.62, 142.00, 139.12, 135.25, 130.40, 129.90, 129.42, 128.41, 127.65, 126.13, 125.89, 124.71, 116.82, 116.62, 64.61, 39.99, 35.47, 33.11, 29.14, 28.69.

[0261] 19 F NMR (376 MHz, CDCl3) δ -118.96.

[0262] Example 3:

[0263]

[0264] 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.49 (s, 1H), 7.38 (dd, J = 17.1 Hz, 8.6 Hz, 7H), 7.27 (d, J = 6.8 Hz, 3H), 7.17 (d, J = 6.9 Hz, 4H), 6.17 (s, 1H), 6.12 (s, 1H), 3.99 (d, J = 16.0 Hz, 1H), 3.88 (d, J = 15.9 Hz, 1H), 3.43 (d, J = 5.6 Hz, 2H), 2.64 (d, J = 6.8 Hz, 3H), 1.83–1.52 (m, 8H).

[0265] 13C NMR (101MHz, CDCl3) δ171.04,166.52,141.98,139.60,137.84,135.58,129.79,129.62,129.34,12 8.65,128.37,127.21,126.01,125.88,123.71,122.13,64.86,40.03,35.46,33.37,29.13,28.68.

[0266] 19 F NMR (376MHz,CDCl3)δ-62.73.

[0267] Embodiment 4:

[0268]

[0269] 1 H NMR (400MHz, Chloroform-d) δ7.81 (s, 1H), 7.59 (d, J = 6.7Hz, 1H), 7.47 (d, J = 6. 6Hz,1H),7.25(d,J=6.3Hz,3H),7.16(s,5H),7.05(t,J=8.0Hz,2H),6.52(s,1H ),6.42(d,J=8.0Hz,1H),6.30(d,J=8.0Hz,1H),6.16(s,1H),3.94–3.81(m,2H) ,3.78(s,3H),3.51(s,3H),3.39–3.26(m,4H),2.61(s,3H),1.67–1.48(m,7H).

[0270] 13 C NMR (101MHz, CDCl3) δ170.75,166.98,156.62,156.13,141.99,139.19,134.52,131.09,129.90,128.41,128. 11,127.50,126.50,125.89,113.80,105.14,104.23,63.57,56.08,56.00,39.94,35.48,33.16,29.26,28.72.

[0271] Embodiment 5:

[0272]

[0273] 11H NMR (400 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 20.6 Hz, 7.3 Hz, 3H), 7.31–7.26 (m, 4H), 7.18 (t, J = 8.1 Hz, 7H), 6.98 (dd, J = 23.9 Hz, 9.0 Hz, 3H), 6.85 (t, J = 8.1 Hz, 2H), 6.15 (d, J = 12.9 Hz, 3H), 3.97 (d, J = 16.0 Hz, 1H), 3.85 (d, J = 16.0 Hz, 1H), 3.43 (d, J = 6.0 Hz, 3H), 2.65 (t, J = 6.6 Hz, 4H), 1.78–1.47 (m, 5H).

[0274] 13 13C NMR (101 MHz, CDCl3) δ 170.97, 166.59, 142.66, 139.94, 135.51, 130.24, 129.44, 129.30, 128.41, 127.11, 125.88, 125.84, 120.64, 114.19, 113.98, 112.85, 112.61, 64.87, 40.03, 35.46, 33.40, 29.14, 28.69.

[0275] 19 19F NMR (376 MHz, CDCl3) δ -110.67.

[0276] Example 6:

[0277]

[0278] 1 1H NMR (400 MHz, Chloroform-d) δ 7.74 (s, 1H), 7.59 (d, J = 7.1 Hz, 1H), 7.39 (d, J = 6.9 Hz, 1H), 7.30–7.21 (m, 5H), 7.15 (t, J = 8.9 Hz, 5H), 7.07 (t, J = 7.5 Hz, 2H), 6.97 (s, 1H), 6.89 (dd, J = 17.9 Hz, 7.2 Hz, 3H), 6.56 (s, 1H), 6.07 (s, 1H), 3.92 (d, J = 15.7 Hz, 1H), 3.78 (d, J = 15.7 Hz, 1H), 3.39–3.27 (m, 3H), 2.61 (s, 3H), 2.19 (s, 3H), 1.70–1.49 (m, 7H).

[0279] 13C NMR (101MHz, CDCl3) δ171.14,166.74,142.19,140.08,137.10,135.26,129.70,128.96,1 28.44,128.38,126.45,125.86,122.79,65.34,39.98,35.53,33.50,29.08,28.77,21.35.

[0280] Embodiment 7:

[0281]

[0282] 1 H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.57(d,J=7.8Hz,1H),7.47(d,J=7 .8Hz,1H),7.38–7.27(m,3H),7.22–7.15(m,3H),6.83(t,J=7.4Hz,1H),6.58( d,J=10.3Hz,1H),6.48(t,J=8.6Hz,1H),6.04(d,J=10.6Hz,2H),3.90(dd,2H) ,3.80(s,3H),3.45(q,J=6.7Hz,2H),2.67(t,J=7.4Hz,2H),1.76–1.62(m,4H).

[0283] 13 C NMR (101MHz, CDCl3) δ171.55,166.69,164.28,161.82,141.99,139.64,135.06,131.20,131.10,128.78,128.38,1 27.22,126.78,125.89,121.18,107.56,107.34,100.63,100.36,64.32,56.07,39.99,35.47,33.03,29.17,28.71.

[0284] 19 F NMR (376MHz,CDCl3)δ-109.07.

[0285] Embodiment 8:

[0286]

[0287] 11H NMR (400 MHz, Chloroform-d) δ 7.44 (s, 1H), 7.31–7.25 (m, 4H), 7.23–7.15 (m, 4H), 6.93 (d, J=7.9 Hz, 1H), 6.90–6.78 (m, 2H), 6.11 (s, 1H), 5.96 (s, 1H), 3.92 (d, J=816.0 Hz, 2H), 3.83 (s, 3H), 3.47–3.37 (m, 2H), 2.66 (t, J=7.4 Hz, 2H), 1.74–1.60 (m, 4H).

[0288] 13 13C NMR (101 MHz, CDCl3) δ 165.49, 154.76, 142.47, 141.96, 137.12, 129.87, 128.40, 125.91, 125.00, 121.96, 121.04, 117.56, 117.33, 114.87, 114.64, 112.25, 63.84, 55.78, 40.05, 35.45, 33.02, 29.06, 28.67.

[0289] 19 19F NMR (376 MHz, CDCl3) δ -110.98.

[0290] Example 9:

[0291]

[0292] 1 1H NMR (400 MHz, Chloroform-d) δ 7.45 (s, 1H), 7.40 (s, 1H), 7.29 (d, J=4.7 Hz, 3H), 7.18 (t, J=7.3 Hz, 5H), 6.90 (d, J=7.8 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.79 (t, J=7.8 Hz, 1H), 6.08 (s, 1H), 5.96 (d, J=7.7 Hz, 1H), 3.96 (d, J=15.7 Hz, 1H), 3.89 (d, J=15.6 Hz, 1H), 3.82 (s, 3H), 3.43 (q, J=6.7 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 2.33 (s, 3H), 1.75–1.58 (m, 4H).

[0293] 13C NMR (101MHz, CDCl3) δ171.46,167.00,154.84,142.02,139.78,138.79,131.14,129.99,129.70,128. 41,128.14,125.88,123.44,120.91,112.17,64.36,55.78,39.92,35.48,33.16,29.20,28.69,21.31.

[0294] Embodiment 10:

[0295]

[0296] 1 H NMR (400MHz, CDCl3) δ7.87 (s, 1H), 7.80 (d, J = 7.3Hz, 2H), 7.42 (t, J = 7.4Hz, 2H), 7.34 (t, J = 7.3Hz, 1H), 6.34 (d, J = 5.0Hz, 1H), 4.20 (dd,J=14.2Hz,7.4Hz,1H),4.05(dd,J=14.0Hz,7.3Hz,1H),2.75–2.64(m,1H),2.42(dd,J=23.9Hz,12.0Hz,2H),2.14–2.03(m,1H).

[0297] 13 C NMR(101MHz, CDCl3)δ148.08,131.29,130.20,128.84,128.52,126.05,92.25,69.59,31.37,24.50.HRMS(ESI)C 12 H 13 N3OCalcd.for(M+H) + ,216.1137,Found:216.1124

[0298] Embodiment 11:

[0299]

[0300] 11H NMR (400 MHz, Chloroform-d) δ 7.63 (s, 1H), 7.49 (dd, J = 12.9 Hz, 7.9 Hz, 1H), 7.41 (dd, J = 15.8 Hz, 7.6 Hz, 1H), 7.22–7.17 (m, 5H), 7.09 (q, J = 10.6 Hz, 9.4 Hz, 6H), 6.83–6.60 (m, 4H), 6.17 (s, 0H), 5.99 (d, J = 13.4 Hz, 1H), 4.24–3.91 (m, 1H), 3.71 (s, 3H), 3.31 (s, 2H), 2.56 (d, J = 5.9 Hz, 3H), 1.63 (dt, J = 18.3 Hz, 9.1 Hz, 7H), 1.52 (s, 3H).

[0301] 13 13C NMR (101 MHz, CDCl3) δ 174.76, 174.35, 166.82, 154.24, 142.04, 140.08, 139.17, 134.99, 134.85, 131.05, 130.57, 130.44, 129.61, 129.43, 128.77, 128.64, 128.41, 127.18, 127.04, 126.51, 126.02, 125.87, 125.72, 120.70, 112.86, 64.12, 62.51, 42.24, 39.94, 35.49, 29.17, 28.72, 20.59, 19.68, 14.96.

[0302] Example 12:

[0303]

[0304] 1 1H NMR (400 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.48–7.35 (m, 2H), 7.32 (s, 1H), 7.29–7.17 (m, 2H), 7.13–7.02 (m, 2H), 6.80 (dd, J = 18.2 Hz, 6.7 Hz, 5H), 6.71 (d, J = 6.7 Hz, 2H), 6.18 (s, 1H), 6.05 (s, 1H), 4.11 (s, 2H), 3.84 (q, J = 15.7 Hz, 3H), 3.73 (s, 3H), 3.32 (s, 2H), 1.86 (s, 2H), 1.50 (s, 2H).

[0305] 13C NMR (101MHz, CDCl3) δ170.49,165.87,153.74,138.71,138.18,133.76,129.66,129.12,128.71,128.29,1 27.68,126.48,125.61,124.17,119.87,111.07,104.52,63.36,54.72,50.24,38.51,32.13,26.96,25.04.

[0306] Embodiment 13:

[0307]

[0308] 1 H NMR (400MHz, Methanol-d4) δ7.79 (s, 1H), 7.60 (d, J = 7.5Hz, 1H), 7.46 (s, 1H) ,7.26(d,J=14.6Hz,1H),7.12(t,J=7.8Hz,1H),6.87(t,J=7.4Hz,2H),6.69(t ,J=7.7Hz,1H),6.15(s,1H),3.93(d,J=15.8Hz,1H),3.83(d,J=15.9Hz,1H),3 .73(s,3H),3.42(s,4H),3.30(s,2H),2.62(s,6H),1.55(s,4H),1.36(s,8H).

[0309] 13 C NMR (101MHz, CDCl3) δ176.34,171.96,159.01,158.54,143.67,138.38,134.95,133.53,132.26,131.27, 130.61,129.00,124.16,115.77,84.24,68.55,61.15,58.77,56.05,42.93,36.33,31.10,30.63,26.50.

[0310] Embodiment 14:

[0311]

[0312] 11H NMR (400 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 11.1 Hz, 3H), 7.18 (t, J = 7.1 Hz, 2H), 7.10 (d, J = 7.3 Hz, 2H), 6.88 (dd, J = 18.3 Hz, 7.8 Hz, 2H), 6.78 (t, J = 7.6 Hz, 1H), 4.00–3.86 (m, 2H), 3.82 (s, 3H), 3.43 (d, J = 5.8 Hz, 2H), 1.66 (d, J = 8.3 Hz, 3H).

[0313] 13 13C NMR (101 MHz, CDCl3) δ 171.45, 166.79, 154.82, 140.41, 139.84, 134.92, 131.57, 130.70, 130.10, 129.75, 128.76, 128.45, 127.23, 126.50, 125.23, 120.91, 112.14, 64.33, 55.77, 39.87, 34.78, 33.16, 29.12, 28.58.

[0314] Example 15:

[0315]

[0316] 1 1H NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.26 (t, J = 7.4 Hz, 4H), 7.16 (t, J = 7.6 Hz, 4H), 6.96–6.86 (m, 1H), 6.79 (q, J = 7.8 Hz, 2H), 6.70 (d, J = 7.7 Hz, 1H), 6.58 (s, 1H), 6.08 (s, 1H), 3.94 (s, 3H), 3.86 (t, J = 14.3 Hz, 2H), 3.40–3.35 (m, 2H), 2.62 (t, J = 6.9 Hz, 3H), 1.72–1.51 (m, 7H).

[0317] 13C NMR (101MHz, CDCl3) δ171.47,166.73,156.92,154.45,144.09,143.98,142.06,139.09,135.23,130.73,130.41,128.82,1 28.36,127.81,126.26,125.85,124.60,123.17,117.35,117.16,64.82,61.48,61.41,39.99,35.49,33.17,29.12,28.72.

[0318] 19 F NMR (376MHz,CDCl3)δ-127.80.

[0319] Embodiment 16:

[0320]

[0321] 1 H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.56(d,J=7.6Hz,1H),7.39(d,J=7.5Hz,1H),7. 23(dd,J=16.6Hz,8.9Hz,1H),7.11(s,1H),6.81(dd,J=16.9Hz,8.0Hz,2H),6.71(t,J=7.6H z,1H),6.63(s,1H),6.34(s,1H),6.06(s,1H),3.86(q,J=15.6Hz,2H),3.75(s,2H),3.49(t ,J=6.8Hz,2H),3.36(q,J=6.4Hz,3H),1.59(q,J=7.2Hz,3H),1.52(q,J=5.7Hz,4.8Hz,2H).

[0322] 13 C NMR (101MHz, CDCl3) δ171.46,170.90,166.82,154.83,139.87,134.81,134.15,130.74,130.13,129.7 3,128.75,127.36,126.51,125.22,120.92,112.13,64.34,55.77,39.49,37.28,33.16,26.55,26.11.

[0323] Embodiment 17:

[0324]

[0325] 1 1H NMR (400 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.37–7.31 (m, 2H), 7.23 (d, J = 7.3 Hz, 3H), 7.21–7.09 (m, 8H), 6.19 (s, 1H), 6.13 (s, 1H), 3.97 (d, J = 15.8 Hz, 1H), 3.86 (d, J = 15.8 Hz, 1H), 3.48–3.30 (m, 4H), 2.64 (d, J = 6.8 Hz, 4H), 1.64 (dd, J = 23.6 Hz, 6.7 Hz, 6H).

[0326] 13 13C NMR (101 MHz, CDCl3) δ 171.01, 166.68, 142.01, 140.22, 137.22, 135.36, 129.73, 129.23, 129.14, 128.38, 127.28, 127.12, 125.93, 125.88, 125.64, 65.21, 40.00, 35.47, 33.48, 29.15, 28.70.

[0327] Example 18:

[0328]

[0329] 1 1H NMR (400 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.58 (d, J = 6.6 Hz, 1H), 7.45 (d, J = 6.6 Hz, 1H), 7.29–7.23 (m, 6H), 7.16 (s, 4H), 6.84 (s, 1H), 6.78–6.62 (m, 3H), 6.49 (s, 1H), 6.12 (s, 1H), 3.94–3.80 (m, 3H), 3.75 (s, 3H), 3.44–3.27 (m, 4H), 2.62 (s, 3H), 1.69–1.50 (m, 8H).

[0330] 13C NMR (101MHz, CDCl3) δ171.41,166.64,157.32,154.93,151.30,142.09,139.24,135.05,130.49,128.78,128.42,128.3 6,127.48,126.78,125.85,117.36,117.12,116.03,115.80,112.68,64.19,56.23,39.96,35.48,33.10,29.12,28.72.

[0331] 19 F NMR (376MHz,CDCl3)δ-121.95.

[0332] Embodiment 19:

[0333] Antitumor activity test

[0334] The present invention adopts the CCK-8 method to determine the proliferation inhibitory effects of 30 compounds NL-1 to NL-30 prepared by the present invention on 6 osteosarcoma cells (SJSA-1, U2OS, HOS, MNNG / HOS, MG63, 143b), 1 pancreatic cancer cell (PANC-1), 1 lung cancer cell (A549), 1 colorectal cancer cell (HCT116) and 1 leukemia cell (Jurkat).

[0335] 1. Inoculation of cells:

[0336] 1) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 SJSA-1 osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0337] 2) A single cell suspension was prepared using DMEM culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 MNNG / HOS osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0338] 3) A single cell suspension was prepared using McCoy'5A culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 U-2-OS osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0339] 4) A single cell suspension was prepared using DMEM culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 MG63 osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0340] 5) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 HOS osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0341] 6) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 143B osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0342] 7) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 A549 lung cancer cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0343] 8) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 Jurkat leukemia cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0344] 9) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 HCT116 colorectal cancer cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0345] 10) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 PANC-1 pancreatic cancer cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0346] 2. Then, 30 compounds (NL-1 to NL-30) prepared in the present invention were dissolved in DMSO, and the corresponding cell culture medium was used to prepare a drug solution with a final concentration of 1 μM, and added to ten different cells (100 μL / well), respectively. 1‰ DMSO was added to the control group, and cultured in a CO2 incubator for 72 hours;

[0347] 3. After 72 hours of culture, the culture medium was removed and 100 μL of 1:10 diluted CCK-8 solution was added. After incubation at 37°C for 2 hours, the absorbance A at 450 nm was measured using a LabServK3 microplate reader with a reference wavelength of 620 nm to calculate the survival rate of tumor cells and leukemia cells (see Table 1).

[0348] 4. Cell proliferation activity (%) = [A(drug added) - A(blank)] / [A(0 drug added) - A(blank)]×100.

[0349] Table 1

[0350]

[0351] From the data in Table 1, it can be seen that under the action of 14 compounds including compounds 1, 3, 4, and 5, the survival rate of osteosarcoma cells SJSA-1 was less than 30%, indicating that these 14 compounds had a very good inhibitory effect on osteosarcoma cells SJSA-1; compound 17 had a certain inhibitory effect on osteosarcoma cells U2OS; under the action of 12 compounds including compound 1, the survival rate of osteosarcoma cells HOS was less than 50%, indicating that these 12 compounds had a good inhibitory effect on HOS cells; compound 1 and 15 compounds had a very good inhibitory effect on MNNG / HOS cells. Compound 3 and other 14 compounds have a good inhibitory effect on MG63 cells; Compound 1 and other 10 compounds have a good inhibitory effect on 143b cells; Compound 1 and other 14 compounds have a good inhibitory effect on leukemia cells Jurkat; Compound 4 and other 9 compounds have a good inhibitory effect on colorectal cancer cells HCT116; Compound 1 and other 12 compounds have a good inhibitory effect on lung cancer cells A549; Compound 1 and other 12 compounds have a certain inhibitory effect on pancreatic cancer cells PANC-1. (The bold part is the data with inhibitory activity)

[0352] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the essence of the content of the present invention are covered within the protection scope of the present invention.

Claims

1. A 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof, characterized in that: Its structure is as follows:

2. The 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or pharmaceutically acceptable salt according to claim 1, characterized in that: The compound forms an acid addition salt with an acid; wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, salicylic acid, tartaric acid, lactic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, pyruvic acid, or succinic acid.

3. A pharmaceutical composition, characterized in that It comprises the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition is formulated into pills, capsules, creams, gels, excipients, injectable fluids, aerosols, syrups or transdermal patches.

5. Use of the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for preventing and / or treating a tumor, wherein the tumor is osteosarcoma, leukemia, pancreatic cancer, lung cancer, or colorectal cancer.

6. The use according to claim 5, characterized in that: The 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or pharmaceutically acceptable salt or pharmaceutical composition is used to inhibit the proliferation, growth, migration, infiltration, metastasis and recurrence of tumor cells, or promote tumor cell apoptosis.

7. The use according to claim 5, characterized in that: The osteosarcoma cells are SJSA-1, U2OS, HOS, MNNG / HOS, MG63, and 143b; the pancreatic cancer cells are PANC-1; the lung cancer cells are A549; the colorectal cancer cells are HCT116; and the leukemia cells are Jurkat.

Images