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Biphenyl compound as well as preparation method and medical application thereof

A compound and biphenyl technology, applied in the field of biomedicine, can solve problems such as poor chemical stability and affecting drugability

Active Publication Date: 2020-11-10
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent application 2019102477713 discloses a benzoxadiazole PD-L1 inhibitor, however, the chemical stability of this type of compound is very poor, which seriously affects its druggability

Method used

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  • Biphenyl compound as well as preparation method and medical application thereof
  • Biphenyl compound as well as preparation method and medical application thereof
  • Biphenyl compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0193] (2-(Benzo[c][1,2,5]oxadiazol-5-ylmethoxy)-4-((2-fluoro-[1,1'-biphenyl]-3-yl) Methoxy)benzyl)-D-serine (compound 1)

[0194]

[0195] synthetic route:

[0196]

[0197] Synthesis of Compound XA-2

[0198]Compound XA-1 (3.71 g) was dissolved in concentrated sulfuric acid (30 mL), and fuming nitric acid (1.4 mL) was added dropwise in an ice bath. The reaction stopped after about 3 hours. The reaction solution was poured into 100 mL of ice water, and a light yellow solid was precipitated, which was filtered by suction to obtain compound XA-2 (3.0 g) as a light yellow solid.

[0199] Synthesis of Compound XA-3

[0200] Get compound XA-2 (3.0g) and dissolve in DMSO (50mL), slowly add NaN 3 (1.5g). The reaction stopped after about 1 hour. The reaction solution was poured into 50 mL of water, solids were precipitated, and filtered by suction to obtain light yellow-green solid compound XA-3 (3.1 g).

[0201] Synthesis of compound XA-4

[0202] Compound XA-3 (1.5 g...

Embodiment 2

[0226] 2-((2-(Benzo[c][1,2,5]oxadiazol-5-ylmethoxy)-4-((2-fluoro-[1,1'-biphenyl]-3 -yl)methoxy)benzyl)amino)ethan-1-ol (compound 2)

[0227]

[0228] Referring to the method of Example 1, the D-serine ethyl ester hydrochloride in Example 1 was replaced by ethanolamine to obtain compound 2: 1 H NMR (300MHz, DMSO-d 6 )δ8.16(s,1H),8.10(d,J=9.3Hz,1H),7.72(d,J=9.4Hz,1H),7.65–7.39(m,8H),7.30(t,J=7.6 Hz,1H),6.91(d,J=2.3Hz,1H),6.79(d,J=8.3Hz,1H),5.35(s,2H),5.25(s,3H),4.18(s,2H), 3.70(d,J=5.3Hz,1H),3.66(d,J=5.3Hz,1H),2.97(t,J=5.3Hz,2H).HRMS(ESI):m / z 500.1982[M+H] + .

Embodiment 3

[0230] (2-((2-(Benzo[c][1,2,5]oxadiazol-5-ylmethoxy)-4-((2-fluoro-[1,1'-biphenyl]- 3-yl)methoxy)benzyl)amino)ethyl)acetamide (Compound 3)

[0231]

[0232] Referring to the method of Example 1, the D-serine ethyl ester hydrochloride in Example 1 was replaced by N-acetylethylenediamine to obtain compound 3: 1 H NMR (300MHz, DMSO-d 6 )δ8.08(d,J=8.8Hz,2H),7.96(s,1H),7.67(d,J=9.5Hz,1H),7.60–7.39(m,6H),7.38–7.22(m,2H ),6.85(d,J=2.4Hz,1H),6.72(dd,J=8.4,2.3Hz,1H),5.32(s,2H),5.21(s,2H),3.96(s,2H),3.24 (d,J=6.0Hz,2H),2.77(t,J=6.5Hz,2H),1.77(s,3H).HRMS(ESI):m / z 541.2245[M+H] + .

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Abstract

The invention discloses a biphenyl compound as well as a preparation method and medical application thereof, the structure of the biphenyl compound is shown as a formula (I) or a formula (II), and thebiphenyl compound or pharmaceutically acceptable salt, tautomer, meso-isomer, raceme, stereoisomer, metabolite, metabolite precursor, prodrug or solvate thereof is a PD-L1 inhibitor. The compound hasa remarkable inhibiting effect on the interaction of PD-1 and PD-L1 protein, so that the compound can be applied to the preparation of PD-L1 inhibitors and immunomodulator drugs for preventing or treating tumors, autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a biphenyl compound with PD-L1 inhibitory activity. The invention also relates to a preparation method of the compound and its medical use as a PD-L1 inhibitor and immunomodulatory treatment pharmaceutical composition. Background technique [0002] Programmed death receptor 1 (PD-1) is mainly expressed on the surface of T cells and is an important factor in the immune checkpoint pathway of the body. The PD-1 ligand highly expressed on the surface of tumor cells, that is, programmed death ligand 1 (PD-L1), when it binds to PD-1 on the surface of T cells, ITIM (Tyr223) and ITSM ( Tyr248) tyrosine motifs were phosphorylated, respectively, and subsequently recruited protein tyrosine phosphatases SHP-2 and SHP-1, which dephosphorylated signaling intermediates (such as CD3ζ and PLCγ1, etc.), resulting in T cell receptor ( The downregulation of TCR) signal enables tumor cells to...

Claims

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Application Information

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IPC IPC(8): C07D271/12C07D413/12C07D417/12C07D417/14C07D285/14A61P35/00A61P35/02A61K31/454A61K31/4245A61K31/433A61K31/541
CPCC07D271/12C07D413/12C07D417/12C07D417/14C07D285/14A61P35/00A61P35/02
Inventor 孙宏斌刘鎏王仕军姚智颖解涛邬国庆李幸柳军袁浩亮温小安许庆龙陈彩萍潘燕红张璞吴耀军
Owner CHINA PHARM UNIV
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