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CN-116685585-B - High-activity HPK1 kinase inhibitor

CN116685585BCN 116685585 BCN116685585 BCN 116685585BCN-116685585-B

Abstract

A compound having a structure of formula (I) that inhibits HPK1 kinase activity and pharmaceutical compositions comprising the same. Also provided is the use of the compounds in the prevention and/or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Inventors

  • CHEN YUFENG
  • WANG YOUPING
  • LU PINGPING
  • HE NANHAI
  • LIU CANFENG
  • LV MENG
  • WEN QIAODONG
  • SHI YONGQIANG
  • WU PENG
  • CHEN KAIXUAN
  • YANG HAN
  • CHENG WANLI

Assignees

  • 杭州阿诺生物医药科技有限公司

Dates

Publication Date
20260505
Application Date
20211026
Priority Date
20201028

Claims (4)

  1. 1. A compound or pharmaceutically acceptable salt, stereoisomer having the structure:
  2. 2. a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
  3. 3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention and/or treatment of a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease.
  4. 4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention and/or treatment of cancer.

Description

High-activity HPK1 kinase inhibitor The present application claims priority from chinese patent application 202011168944.1 entitled "a highly active HPK1 kinase inhibitor" filed on 28 th month 10 2020 to the chinese patent office, the contents of which are incorporated herein by reference in their entirety. Technical Field The invention relates to a heterocyclic compound, in particular to a high-activity HPK1 kinase inhibitor and application thereof. Background HPK1 is one of the members of the MAP4K family, is mainly expressed in hematopoietic cells, and acts as an intracellular negative regulator of T cell proliferation and signaling. Antigen stimulation of T cells causes recruitment of cytoplasmic linker protein SLP-76 to the lipid membrane TCR complex, providing binding sites for signal transduction-related kinases to effect TCR-mediated signaling to induce T cell activation. During this process HPK1 is activated by phosphorylation of tyrosine kinases Lck and Zap70, involved in regulating T cell receptor protein interactions. HPK1 blocks TCR signaling by phosphorylating the Ser376 site of the linker protein SLP-76, allowing SLP-76 to bind to the scaffold protein 14-3-3 epsilon and be degraded by the proteasome, and this effect allows SLP-76 to bind less to signal transduction-related kinases, blocking T cell activation and proliferation. On the other hand, HPK1 is also involved in regulating maturation and activation of Dendritic Cells (DCs), and in particular, inhibits the expression of proteins involved in the activation of T cells, such as CD80, CD86 and MHC complexes, in DCs, thereby affecting the effect of DCs in regulating T cell activation, and presentation of tumor antigens by activated DCs and the interaction of DCs and T cells are one of the most important links in the anti-tumor immune system. Furthermore, there are a large number of immunosuppressive molecules such as PGE2 and TGF- β in the tumor microenvironment, and these factor-mediated immunosuppression effects are also important in connection with HPK 1. In general, small molecule compounds that specifically target and inhibit HPK1 can exert the effect of inhibiting tumor growth by taking improvement of T cell function as a main, enhancing DCs cell function and simultaneously reversing tumor immunosuppressive microenvironment and the like to exert the effect of enhancing anti-tumor immunity. Disclosure of Invention The invention provides a compound capable of inhibiting HPK1 kinase activity and pharmaceutically acceptable salts, isotopic derivatives and stereoisomers thereof. Wherein R 1 represents hydrogen, halogen, (C 1-C6) alkyl, (C 2-C6) alkenyl, (C 1-C6) alkoxy; Wherein R 2 represents hydrogen, halogen, hydroxy, (C 1-C6) alkyl, (C 2-C6) alkenyl, - (C 0-C6 alkylene) (C 1-C6) alkoxy, - (C 0-C6 alkylene) (C 6-C10) aryl, - (C 0-C6 alkylene) (5-10) membered heteroaryl, - (C 0-C6 alkylene) (4-10) membered heterocycloalkyl, - (C 0-C6 alkylene) (C 3-C8) cycloalkyl, -NR LRL'、-ORL'、-SRL,, wherein R 3 represents hydrogen, Halogen, hydroxy, (C 1-C6) alkyl, (C 2-C6) alkenyl, - (C 0-C6 alkylene) (C 3-C8) cycloalkyl, - (C 0-C6 alkylene) (4-8 membered) heterocycloalkyl, (C 1-C6) alkoxy, - (C 0-C6 alkylene) (C 3-C8) cycloalkyloxy, - (C 0-C6 alkylene) (4-8 membered) heterocycloalkyloxy; Wherein R 4 and R 4' each independently represent hydrogen, C 1-C6 alkyl, (C 2-C6) alkenyl, halogen; Or R 4 together with R 4' form a 3-6 membered ring with the carbon atom to which it is attached, which ring may optionally contain 0, 1,2 heteroatoms selected from N, O, S; Wherein R 5 represents hydrogen, C 1-C6 alkyl, (C 3-C6) alkenyl, (C 3-C8) cycloalkyl, (4-8 membered) heterocycloalkyl; Wherein R 6 and R 6' each independently represent hydrogen, C 1-C6 alkyl, (C 2-C6) alkenyl, halogen; or R 6 together with R 6' form a 3-6 membered ring with the carbon atom to which it is attached, which ring may optionally contain 0, 1,2 heteroatoms selected from N, O, S; wherein X 1 represents N or CH; Wherein X 2 represents N or CR 7; Wherein X 3 represents N or CR 8; Wherein R 7 represents hydrogen, halogen, (C 1-C6) alkyl, (C 2-C6) alkenyl, (C 3-C8) cycloalkyl, (C 1-C6) alkoxy; Wherein R 8 represents hydrogen, halogen, (C 1-C6) alkyl, (C 2-C6) alkenyl, - (C 0-C6 alkylene) (C 3-C8) cycloalkyl, - (C 0-C6 alkylene) (4-10 membered) heterocycloalkyl, - (C 0-C6 alkylene) (C 6-C10) aryl, - (C 0-C6 alkylene) (5-10) membered heteroaryl, Or R 8 may form together with the adjacent R 3 a (5-10 membered) cycloalkyl or a (5-10 membered) heterocycloalkyl; Wherein R L and R L' each independently represent hydrogen, (C 1-C6) alkyl, (C 3-C6) alkenyl, (C 3-C6) cycloalkyl, (C0-C6 alkylene) (C 6-C10) aryl, - (C 0-C6 alkylene) (5-10) membered heteroaryl, - (C 0-C6) alkylene- (CR MRM')-(C0-C6) alkyl, - (C 0-C6) alkylene- (CR MRM') -halogen; Or R L and R L' together with the nitrogen atom to which they are attached form a 4-8 membered ring which may additionally contain 0,1, 2 heteroatoms s