Phenyl-substituted five-membered heterocyclic compounds as well as preparation method, application and pharmaceutical composition thereof

A five-membered heterocyclic, phenyl-substituted technology, applied in the fields of compounds and their preparation methods, uses and pharmaceutical compositions, can solve problems such as adverse reactions, expensive and difficult production, and difficult to control immune responses

Active Publication Date: 2020-09-29
YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The PD-1 / PD-L1 signaling pathway inhibitors currently on the market are all monoclonal antibody drugs, but the oral bioavailability of monoclonal antibody drugs is poor, and the production is relatively expensive and difficult
Clinical studies have also shown that monoclonal antibody drugs have caused a variety of immune-related adverse reactions due to their long half-life and difficult to control immune response
So far, there are still no non-antibody small molecule inhibitors of PD-1 / PD-L1 signaling pathway on the market

Method used

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  • Phenyl-substituted five-membered heterocyclic compounds as well as preparation method, application and pharmaceutical composition thereof
  • Phenyl-substituted five-membered heterocyclic compounds as well as preparation method, application and pharmaceutical composition thereof
  • Phenyl-substituted five-membered heterocyclic compounds as well as preparation method, application and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052]

[0053] synthetic route:

[0054]

[0055] Synthesis of compound 1-A

[0056] Dissolve 2.58g of the compound 2-methyl-3-bromobenzoic acid in 20mL of 1:1 toluene / ethanol, then add 417mg of tetrakistriphenylphosphine palladium and 5mL of 2mol / L sodium carbonate aqueous solution, under nitrogen protection, stir at room temperature for 10min Then, 1.79 g of phenylboronic acid was added, and the mixture was moved to 80° C. and stirred overnight. TLC monitoring showed that the reaction of the raw materials was complete, and the reaction was stopped, the solvent was spin-dried, and 120 mL of ethyl acetate was added, washed once with water and once with saturated brine, 20 mL each time. The organic phase was concentrated and purified by column chromatography (the volume ratio of petroleum ether: ethyl acetate was 10:1) to obtain 2.2 g of compound 1-A.

[0057] Synthesis of compound 1-B

[0058] Dissolve 2 g of aminobenzyl alcohol and 5.38 g of triethylenediamine in 50...

Embodiment 2

[0068]

[0069] Referring to the synthesis method of Example 1, replacing p-aminobenzyl alcohol with p-methoxyaniline, Compound 2 can be prepared. 1 HNMR (300MHz, DMSO-d6) δ8.18(t, J=5.4Hz, 1H), 7.87(m, 2H), 7.65(d, J=7.6Hz, 2H), 7.59–7.35(m, 7H), 4.02(s,3H).

Embodiment 3

[0071]

[0072] Referring to the synthesis method of Example 1, replacing N-acetylethylenediamine with ethanolamine, Compound 3 can be prepared. 1 H NMR (300MHz, Methanol-d 4 )δ7.89–7.77(m,2H),7.59(dd,J=8.6,2.5Hz,3H),7.50–7.38(m,5H),7.37–7.26(m,2H),3.85(s,2H) ,3.72(t,J=5.6Hz,2H),2.80(t,J=5.2Hz,2H),2.51(s,3H).

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PUM

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Abstract

The invention discloses immune checkpoint inhibitor phenyl-substituted five-membered heterocyclic compounds capable of blocking a PD-1/PD-L1 signal path as well as a preparation method, application and a pharmaceutical composition thereof. The phenyl-substituted five-membered heterocycle compounds are shown as a formula I. The phenyl-substituted five-membered heterocycle compounds or pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof are disclosed.

Description

technical field [0001] The present invention relates to compounds and their preparation methods, uses and pharmaceutical compositions, in particular to phenyl-substituted five-membered heterocyclic compounds and their preparation methods, uses and pharmaceutical compositions. Background technique [0002] Malignant tumors are a class of diseases that seriously threaten human health and life. Currently, tumor treatments include surgery, radiotherapy, chemotherapy, and targeted therapy. Tumor immunotherapy refers to a treatment method that stimulates the body's immune system to improve the anti-tumor immune effect, thereby inhibiting and killing tumor cells. The research on immunotherapy has a history of nearly a hundred years. With the comprehensive development and cross-infiltration of oncology, immunology and molecular biology, immunotherapy has achieved various results and brought new hope for tumor treatment. [0003] Immune checkpoint inhibitors are currently the hotte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/113C07D413/12C07D413/10C07D285/135C07D271/07C07D249/14C07D417/12C07D413/14A61K31/4245A61K31/454A61K31/4439A61K31/433A61K31/4196A61K31/444A61P35/00
CPCA61P35/00C07D249/14C07D271/07C07D271/113C07D285/135C07D413/10C07D413/12C07D413/14C07D417/12
Inventor 蒋晟郝海平王天雨王敏敏张婉衡倪勇邱亚涛吴筱星
Owner YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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