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CN-115433212-B - Biphenyl compound as immunomodulator as well as preparation method and application thereof

CN115433212BCN 115433212 BCN115433212 BCN 115433212BCN-115433212-B

Abstract

A biphenyl compound shown in formula (I), a preparation method and application thereof. Also relates to a pharmaceutical composition comprising said compound as an active ingredient. The compounds are novel small molecule immunomodulators with excellent orally absorbable characteristics useful for the treatment and/or prevention of a variety of immune related diseases.

Inventors

  • YANG QIANJIAO
  • LI ZHIBIN
  • LU XIANPING
  • SHAN SONG
  • XIN LIJUN
  • PAN DESI
  • WANG XIAOLIANG
  • SONG YONGLIAN
  • ZHANG YU
  • HUANG HUIYUN
  • WEI QI

Assignees

  • 深圳微芯生物科技股份有限公司

Dates

Publication Date
20260508
Application Date
20211028
Priority Date
20201029

Claims (8)

  1. 1. A compound of formula (I), Or a pharmaceutically acceptable salt thereof, Wherein, the R 1 and R 2 may be the same or different and are selected from C 1 -C 6 alkyl, cyano, halogen; R 3 is selected from C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl; R 4 is hydrogen; X is-O-; m is selected from 1,2 and 3; n is selected from 1,2 and 3.
  2. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, Wherein, the R 1 and R 2 may be the same or different and are selected from methyl, cyano, fluoro, chloro, bromo; R 3 is selected from C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl; R 4 is hydrogen; X is-O-; m is selected from 1,2 and 3; n is selected from 1,2 and 3.
  3. 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, Wherein, the R 1 and R 2 may be the same or different and are selected from methyl, cyano, fluoro, chloro; R 3 is selected from C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl; R 4 is hydrogen; X is-O-; m is selected from 1 and 2; n is selected from 1,2 and 3.
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl, cyano, fluoro, chloro, and R 2 is selected from methyl, chloro.
  5. 5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
  6. 6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with a target PD-L1, or Use in the manufacture of a medicament for inhibiting PD-L1 activity, or Use in the preparation of a medicament as a PD-L1 inhibitor, or Use in the manufacture of a medicament as an immunomodulator targeting a PD-L1 signalling pathway.
  7. 7. The use of claim 6, wherein the disease associated with targeting PD-L1 comprises a tumor or other immune-related disease.
  8. 8. The use of claim 6, wherein the disease associated with targeting PD-L1 is cancer.

Description

Biphenyl compound as immunomodulator as well as preparation method and application thereof Technical Field The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a biphenyl compound serving as an immunomodulator, and a preparation method and application thereof. Description of the background Tumor immunotherapy is a new therapeutic approach to suppress or kill tumor cells by stimulating the immune system of the human body and enhancing the anti-tumor immunity itself. The method has made breakthrough progress through more than hundred years of efforts. In 2013, journal of Science has listed tumor immunotherapy as the first of ten major scientific breakthroughs in the year (Couzin-Frankel J.,2013, science, 342:1432-1433) and has become one of the most promising areas of anti-tumor therapy. Compared with normal cells, tumor cells have various genetic and epigenetic changes, and the immune system can distinguish the tumor cells by utilizing surface antigens generated by the tumor cells so as to trigger anti-tumor immune response. In the course of T cell anti-tumor immunity, after it is activated by antigen recognition signals mediated by T Cell Receptors (TCR), T cell effects are regulated by co-stimulation and co-suppression signals, including Cytotoxic T lymphocyte-associated antigen 4 (cytotoxin T-lymphocyte associated antigen, ctla 4), programmed death receptor 1 (Programmed death protein 1, pd-1), T cell activated immunoglobulin inhibitory V-domain (VISTA), inhibitory receptors for inhibitory signals such as molecule 3 (T cell immunoglobulin and mucin domain-condensing-3, tim 3) of T cell immunoglobulin and mucin domain, lymphocyte activating gene 3 (Lymphocyte activation gene 3, lag 3), and activating receptors for stimulating signals such as CD28, CD134 (OX 40), glucocorticoid-induced TNFR-related protein (Glucocorticoid-induced TNFR-reduced protein, tr), CD137, CD27, HVEM (melli, coukos g, 2011-480. Under normal physiological conditions, immune checkpoints are involved in maintaining the immune tolerance of autoantigens on the one hand, avoiding autoimmune diseases, and avoiding tissue damage caused by overactivation of immune responses on the other hand. However, in tumor cells, it can evade immune killing by suppressing T cell activation through immune checkpoints. Thus, it is desirable to reactivate T cells to attack tumor cells by activating the co-stimulatory signal (stepping on the "accelerator") and inhibiting the co-inhibitory signal (releasing the "brake") to achieve tumor immunotherapy. PD-1 is expressed in activated T cells, B cells and bone marrow cells, belongs to the CD28 family, is a type1 transmembrane glycoprotein on T cells, and consists of 288 amino acids. The molecular structure of PD-1 consists of an extracellular region with immunoglobulin IgV-like (amino acids 35-145), a transmembrane region, a cytoplasmic tail with a signal peptide-binding function, on which the extracellular region plays an important role in ligand binding (Cheng X.. Veverka V.. RADHAKRISHNAN A., et al.2013, J.biol. Chem., 288:11771-11785). Programmed death ligand 1 (Programmed death protein ligand 1, PD-L1) is one of the ligands of PD-1, belonging to the B7 family, and is sustainably expressed in a variety of tumor cells, T cells, antigen Presenting Cells (APC) and a variety of non-hematopoietic cells, also type1 transmembrane glycoprotein, consisting of 290 amino acids. The interaction of PD-1 and PD-L1 can inhibit T cell activation, which is important for maintaining immune tolerance of normal organisms, while in tumor cells and virus infection, PD-1 on the T cells is induced to be expressed highly, the expression of PD-L1 is up-regulated, the PD-1 signal channel is continuously activated to inhibit T cell proliferation, and the immune escape (Fuller M.J.,Callendret B.,Zhu B.,et al.2013,Proc.Natl.Acad.Sci.USA.,110:15001-15006;Dolan D.E.,Gupta S.,2014,Cancer Control,21:231-237;Chen L.,Han X.,2015,J.Clin.Invest.,125:3384-3391;Postow M.A.,Callahan M.K.,Wolchok J.D.,2015,J.Clin.Oncol.,33:1974-1982). of tumor cells and pathogens in recent years is caused by a plurality of antibody drugs of PD-1 and PD-L1, which fully prove that blocking the interaction of PD-1/PD-L1 is a very effective treatment means in the immunotherapy of tumors and other various diseases related to the immunity. It was found that PD-L1 is capable of interacting with CD80 and inhibiting the binding of PD-L1 to PD-1, as well as the ability to inhibit T cell activation. Thus, blocking immune activation caused by CD80/PD-L1 interactions may also promote enhanced T cell activity, thereby providing new therapeutic opportunities for immune-related diseases (Sugiura D., maruhashi T., okazaki ll-mi, et al 2019, science, 364:558-566). To date, significant progress has been made in targeting PD-1/PD-L1 antibody drugs. However, all antibody drugs have to be administered by injection, have various ADMET problems, seriou