US-12617788-B2 - Bridged bicyclic compounds as BTK inhibitors

Abstract

The present invention relates to bridged bicyclic Compounds A and B or their pharmaceutically acceptable salts thereof as inhibitors of Bruton's tyrosine kinase (BTK) and its C481 mutant. The present invention also relates to methods for preparing Compounds A and B or their pharmaceutically acceptable salts thereof. Compounds of the present invention can be used to treat and/or prevent related diseases mediated by BTK or its C481 mutant, especially cancer and autoimmune diseases.

Inventors

• Xiangyang Chen
• Yucheng Pang

Assignees

• BEIJING INNOCARE PHARMA TECH CO., LTD.

Dates

Publication Date

20260505

Application Date

20230215

Priority Date

20200820

Claims (5)

1. 1 . Compound A, or B, or a pharmaceutically acceptable salt, stable isotope derivative, or stereoisomer thereof:
2. 2 . The compound of claim 1 , which is Compound A.
3. 3 . A pharmaceutical composition comprising the compound of claim 2 , or a pharmaceutically acceptable salt, stable isotope derivative, or stereoisomer thereof, and a pharmaceutically acceptable carrier thereof.
4. 4 . The compound of claim 1 , which is Compound B.
5. 5 . A pharmaceutical composition comprising the compound of claim 4 , or a pharmaceutically acceptable salt, stable isotope derivative, or stereoisomer thereof, and a pharmaceutically acceptable carrier thereof.

Description

This application is a continuation of PCT/CN2021/113538, filed Aug. 19, 2021, which claims the priority of Chinese Application No. 202010836243.4, filed Aug. 20, 2020. The contents of the above-identified applications are incorporated herein by reference in their entireties. TECHNICAL FIELD The invention relates to bridged bicyclic compounds or their pharmaceutically acceptable salts thereof, suitable for regulating or inhibiting activities of Bruton tyrosine kinase (BTK) and its C481 mutant. The present invention also relates to methods for preparing the compounds or their pharmaceutically acceptable salts thereof. The present invention further relates to the uses and methods of use of the compounds or their pharmaceutically acceptable salts thereof in the treatment and/or prevention of cancer and autoimmune diseases. BACKGROUND ART BTK is an important non-receptor tyrosine kinase that mediates cell signal transduction, which exists in plasma cells including B-cells. B-cells are activated through B-cell receptor (BCR) and BTK plays an important role in the BCR-mediated signaling pathway. After BCR on B-cells is activated, it causes the activation of BTK which leads to an increase in the concentration of downstream phospholipase C (PLC) and activates the IP3 and DAG signaling pathways. This signaling pathway can promote cell proliferation, adhesion and survival, and plays an important role in the development of B-cell lymphoma. BTK inhibitors inhibit the proliferation of B lymphoma cells by inhibiting the activity of BTK, destroy adhesion of tumor cells, and promote tumor cell apoptosis, making BTK a compelling drug target for B-cell related cancers, such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), marginal zone Lymphoma (MZL), central nervous system leukemia (CNSL), etc. Several BTK inhibitors are currently on the market, including Abbvie/JNJ's ibrutinib, AZ's acalabrutinib, Beigene's zanubrutinib and Gilead/Ono's tirabrutinib, and more BTK inhibitors are in clinical research. In addition to treating B-cell associated lymphomas, BTK inhibitors can also inhibit the production of B-cell autoantibodies and cytokines. In autoimmune diseases, B-cells present their own antigens, promote T-cell activation, secrete inflammatory factors that cause tissue damage, and at the same time activate B-cells to produce a large number of antibodies to trigger an autoimmune response. T- and B-cells interact to each other to form a positive feedback regulatory chain which leads to uncontrolled autoimmune responses and aggravates tissue pathological damage. Studies have shown that there are regulatory B-cells in the body which can negatively regulate the immune response and inhibit immune-mediated inflammation through the secretion of interleukin 10 (IL-10) or transforming growth factor β1 (TGF-β1) and other mechanisms. Therefore, BTK can be a drug target for autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), pemphigus, etc. For autoimmune indications, BTK inhibitors are still in clinical research. Among them, Sanofi's rilzabrutinib and Merck Serono's evobrutinib have achieved effective results in the treatment of pemphigus and multiple sclerosis, respectively. Most of BTK inhibitors on the market and under research are irreversible inhibitors which inhibit the activity of BTK by covalently binding to the cysteine residue located at 481 of the BTK protein. After some B-cell lymphoma patients received ibrutinib treatment for a period of time, BTK's C481 mutation, such as C481S, made ibrutinib lose its covalent binding point with the protein, resulting in a decrease in the activity of ibrutinib, thereby making patients resistant to the ibrutinib treatment (Quinquenel, et. al Blood 2019, 134, 641-644). There exists a need for BTK inhibitors which effectively inhibit the activities of BTK and its C481 mutant, thereby overcoming the drug resistance caused by the C481 mutation associated with irreversible BTK inhibitors. DETAILED DESCRIPTION OF THE INVENTION Definitions Unless otherwise stated, the following terms used in this application have the following meanings. “CSF/plasma ratio (Kp, CSF)” refers to the ratio of a compound concentration in cerebrospinal fluid (CSF) vs. in plasma. The ability of a compound to cross blood-brain barrier (BBB) is assessed by measuring its concentrations in CSF and plasma in rodents, and determining the ratio (Kp, CSF). “Isomers” refer to compounds that have the same molecular formula, but their atomic binding position or spatial arrangement is different. Isomers with different arrangement of their atoms in space are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers, and conformational isomers. Compounds of the present invention can exist as optical isomers. Optical isomers include