Piperidinothieno small-molecular organic compounds and applications thereof

Abstract

The invention discloses piperidinothieno small-molecular organic compounds, related analogues thereof or pharmaceutically acceptable salts as well as related compounds. The invention also discloses applications of the piperidinothieno small-molecular organic compounds or pharmaceutical composition thereof in preparation of drugs for preventing and / or treating growth, transfer and relapse of malignant tumor and other diseases as well as applications in prevention and / or treatment of STAT3 medicated diseases as an STAT3 inhibitor. The invention also provides a preparation method of the piperidinothieno small-molecular organic compounds and derivatives thereof.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a piperidothiophene small-molecule organic compound and its application. technical background [0002] Cancer is a kind of malignant disease that seriously threatens human health. According to statistics, the total mortality rate is about 23% and has remained high for more than half a century. With the impact of multiple factors such as environmental pollution, aging population and lifestyle changes, China has become the country with the largest number of new cancer cases in the world. According to the statistics of "Cancer Statistics in China, 2015", the incidence of cancer in China is severe, and the incidence and mortality rates are on the rise. There are about 4.292 million new cancer cases and about 2.814 million cancer deaths every year. In the next few decades, the number of cancer patients in China will continue to increase. At the same time, the therapeutic effect of chemot...

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Problems solved by technology

[0004] STAT3 has received more and more attention as a new target for tumor therapy. There have been a large number of research reports on STAT3 inhibitors and their anti-tumor activities, including nucleic acid inhibitors such as siRNA, antisense oligonucleotides, G - Quadruplet oligodeoxynucleotides, decoy oligonucleotides and dominant negative plasmids, etc., block cell surface receptors upstream of STAT3 or tyrosine kinase inhibitors such as IL-6 neutralizing antibody, gp130 neutralization Antibodies, JAK kinase inhibitors TG-101348, WP1066, INCB018424, S-Ruxolitinib and EGFR kinase inhibitors gefitinib, erlotinib, afatinib, etc., regulate SOCS, PIAS, SHP and other STAT3 endogenous regulation protein, as well as some STAT3-specific inhibitors such as Stattic and S3I-201 that inhibit STAT3 dimerization, but most of the current research on the anti-tumor effect of STAT3 inhibitors is still at the level of preliminary screening of in vitro activity. Pharmacological and toxicological studies are less. As of the end of 2017, only 4 candidate compounds have entered the clinical research stage. Therefore, finding new small-molecule STAT3 inhibitors with novel structures, high efficiency and low toxicity, and good physical and chemical properties has become the current research and development of anti-tumor drugs. One of the hot spots in the field

[0005] At present, the research on STAT3 inhibitors is mainly focused on the inhibition of tumor cell proliferation, and there are few studies on tumor drug resistance. One of the main reasons for the failure of tumor treatment is the diverse drug resistance of tumors. Therefore, it is hoped to develop a class that has both Small molecule STA3 inhibitors against tumor growth and reversal of drug resistance

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