US-12624042-B2 - Compound for targeted degradation of BTK and anti-tumour use thereof

US12624042B2US 12624042 B2US12624042 B2US 12624042B2US-12624042-B2

Abstract

Provided in the present invention are a compound for the targeted degradation of BTK and the anti-tumor use thereof. In particular, in the present invention, a series of compounds are prepared and screened, the inhibitory and degradation activities of said compounds against Bruton's tyrosine kinase (BTK) are verified, and finally a compound with good druggability is found. The compound can be used for treating diseases associated with the activity or the expression quantity of Bruton's tyrosine kinase (BTK).

Inventors

Yongzhi SHU
Fengjun LUO

Assignees

SHANGHAI MEIZER PHARMACEUTICALS CO., LTD.

Dates

Publication Date: 20260512
Application Date: 20211026
Priority Date: 20201026

Claims (7)

1 . A compound, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein the compound is selected from the group consisting of: No. Structure 1 2 and 3
2 . The compound of claim 1 , or the pharmaceutically acceptable salt thereof, or the deuterated compound thereof, wherein the compound is:
3 . A pharmaceutical composition, wherein the composition comprises the compound according to claim 1 , or the pharmaceutically acceptable salt thereof, or the deuterated compound thereof, and a pharmaceutically acceptable carrier.
4 . The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition further comprises one or more antineoplastic agents.
5 . A method for treating a lymphoma, comprising: administering to a subject in need thereof a therapeutically effective amount of the compound according to claim 1 , or the pharmaceutically acceptable salt thereof, or the deuterated compound thereof; or administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition wherein the pharmaceutical composition comprises the compound according to claim 1 , or the pharmaceutically acceptable salt thereof, or the deuterated compound thereof, and a pharmaceutically acceptable carrier.
6 . The method of claim 5 , wherein the lymphoma is non-Hodgkin's lymphoma (NHL) or B cell lymphoma.
7 . A method for inhibiting or degrading Bruton's tyrosine protein kinase (Btk) activity, comprising administering to a subject in need thereof an inhibitory effective amount of the compound according to claim 1 , or the pharmaceutically acceptable salt thereof, or the deuterated compound thereof, or administering to a subject in need thereof an inhibitory effective amount of a pharmaceutical composition wherein the pharmaceutical composition comprises the compound according to claim 1 , or the pharmaceutically acceptable salt thereof, or the deuterated compound thereof, and a pharmaceutically acceptable carrier.

Description

TECHNICAL FIELD The present invention belongs to the field of medicine, and in particular relates to a compound for targeted degradation of Btk and anti-tumour use thereof. BACKGROUND Btk, i.e. Bruton's tyrosine kinase, is a member of the Tec family of non-receptor tyrosine kinases. It is an essential gene for cell differentiation and proliferation, and is expressed in B-cell lymphoma, acute lymphoblastic leukemia (ALL) and plasmacytoma. Btk is a key component of the B cell receptor (BCR) signaling pathway and is a good site for targeted treatment of diseases such as B-cell lymphoma. Btk is a key regulator of B cell development, activation, signal transduction and survival, and is involved in the regulation of angiogenesis, cell proliferation and apoptosis, and cell motility. In addition, Btk is also involved in many other hematopoietic cell signaling pathways, for example, in the signaling pathway mediated by Toll-like receptors and cytokine receptors in macrophages, and in the signal transduction of IgE receptors in mast cells, etc. Recent studies have shown that Btk signaling pathway is a new hotspot currently in clinical treatment research for non-Hodgkin's lymphoma (NHL), especially chronic lymphocytic leukemia (CLL), B-cell lymphoma and autoimmune diseases (rheumatoid arthritis, psoriasis, etc.) Therefore, those skilled in the art are committed to developing compounds that can effectively inhibit and degrade Btk. SUMMARY OF THE INVENTION The object of the present invention is to provide a compound with good permeability for inhibiting and degrading Btk, and its application. In the first aspect of the present invention, there is provided a compound as follows, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a deuterated compound thereof: NO.Structure1 2 3 In the second aspect of the present invention, there is provided a pharmaceutical composition, which comprises the compound according to the first aspect or an isomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another preferred example, the pharmaceutical composition further comprises one or more antitumor agents. In another preferred example, the pharmaceutical composition is used for inhibiting the activity of Bruton's tyrosine protein kinase (Btk) or reducing the level of Bruton's tyrosine protein kinase (Btk). In another preferred example, the pharmaceutical composition is used for treating diseases related to the activity or expression level of Bruton's tyrosine kinase (Btk). In the third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention for: (a) preparation of drugs for the treatment of diseases related to the activity or expression level of Bruton's tyrosine kinase (Btk);(b) preparation of Bruton's tyrosine kinase (Btk) targeting inhibitors or degradation agents;(c) non-therapeutic inhibition or degradation of the activity of Bruton's tyrosine kinase (Btk) in vitro;(d) non-therapeutic inhibition of tumor cell proliferation in vitro; and/or(e) treatment of diseases related to the activity or expression level of Bruton's tyrosine kinase (Btk). In another preferred example, the diseases include tumors and autoimmune diseases; preferably, the tumors include non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), B-cell lymphoma, etc.; the autoimmune diseases include rheumatoid arthritis, psoriasis, etc. DETAILED DESCRIPTION OF THE INVENTION After extensive and intensive research, the present inventors have prepared and screened a series of compounds, and verified the inhibitory and degradation activities of these compounds on Bruton's tyrosine protein kinase (Btk). Although these compounds all showed Btk inhibitory and degradation activities, the research found that the activities of different compounds were quite different, and the membrane permeability test of each compound unexpectedly found a compound with excellent permeability. Compared with other similar compounds, it has achieved unexpected excellent technical effects, and thus has good druggability. So it can be used to treat diseases related to the activity or expression of Bruton's tyrosine protein kinase (Btk), such as tumors. The present invention has been completed on this basis. Term In the present invention, the term “containing”, “comprising” or “including” means that various ingredients can be used together in the mixture or composition of the present invention. Thus, the terms “consisting essentially of” and “consisting of” are included in the term “containing”. In the present invention, the term “pharmaceutically acceptable” ingredient refers to a substance suitable for human and/or animals without excessive adverse side effects (such as toxicity, irritation and allergy), that is, with a reasonable benefit/risk ratio. In the present invention, the term “effective amount” refers to an amount of a