Triazolopyridine compound and preparation method and application thereof

A technology of azolopyridine and compound, applied in the direction of digestive system, organic chemistry, drug combination, etc., can solve the problems of immunogenic side effects, decomposition, and only injection administration

Active Publication Date: 2019-06-18
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although monoclonal antibody drugs have shown advantages in clinical treatment, there are also obvious defects such as difficulty in preparation and purification, high production costs; easy to be decomposed by proteases, and short half-life; they cannot be taken orally and can only be administered by injection; the immunogen of monoclonal antibody Sex causes serious toxic side effects

Method used

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  • Triazolopyridine compound and preparation method and application thereof
  • Triazolopyridine compound and preparation method and application thereof
  • Triazolopyridine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: 6-(((2-hydroxyethyl)amino)methyl)-N-(2-methyl-[1,1'-biphenyl]-3-yl)-[1,2,4 ]Triazolo[4,3-a]pyridine-8-carboxamide (I-1)

[0064]

[0065] Step 1: 2-Methyl-[1,1'-biphenyl]-3-amine

[0066]

[0067] At room temperature, 3-bromo-2-methylaniline (15g, 0.081mol), phenylboronic acid (12.2g, 0.1mol), palladium acetate (1.82g, 8.1mmol), potassium carbonate (24.9g, 0.18mol) were added into a mixed solution of ethanol / water (volume ratio 1:1, 100mL), in N 2 The reaction was stirred for 5 hours under protection. After completion of the reaction, filter with suction, evaporate the filtrate to dryness, and separate by column chromatography to obtain 12.6 g of a light yellow solid with a yield of 85.2%.

[0068] Step 2: Methyl 5-bromo-2-hydrazinonicotinate

[0069]

[0070] At room temperature, dissolve methyl 5-bromo-2-chloronicotinate (13.55g, 0.054mol) in 1,4-dioxane (150mL), add hydrazine hydrate (6g, 0.096mol), at 60°C React for 3 hours. After the react...

Embodiment 2

[0091] Example 2: 6-(((2-hydroxyethyl)(methyl)amino)methyl)-N-(2-methyl-[1,1'-biphenyl]-3-yl)-[1 ,2,4]triazolo[4,3-a]pyridine-8-carboxamide (I-2)

[0092]

[0093] ESI-MS m / z:416.2[M+H] + ; 1 H NMR (600MHz, DMSO-d 6 )δ11.40(s,1H),9.19(s,1H),8.75(s,1H),8.48(d,J=1.3Hz,1H),8.19(d,J=7.9Hz,1H),7.48( t,J=7.5Hz,2H),7.42–7.33(m,4H),7.09(d,J=7.3Hz,1H),4.51(t,J=5.4Hz,1H),3.72(s,2H), 3.56(q, J=6.0Hz, 2H), 2.54(t, J=6.1Hz, 2H), 2.35(s, 3H), 2.24(s, 3H).

Embodiment 3

[0094] Example 3: 6-(((2,3-dihydroxypropyl)(methyl)amino)methyl)-N-(2-methyl-[1,1'-biphenyl]-3-yl) -[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (I-3)

[0095]

[0096] ESI-MS m / z:446.2[M+H] + ; 1 H NMR (600MHz, DMSO-d 6 )δ11.40(s,1H),9.20(s,1H),8.75(s,1H),8.48(s,1H),8.20(d,J=8.0Hz,1H),7.48(t,J=7.5 Hz,2H),7.40(t,J=7.4Hz,1H),7.38–7.36(m,2H),7.34(d,J=7.9Hz,1H),7.09(d,J=7.5Hz,1H), 4.54(br,2H),3.74(s,2H),3.69(dd,J=9.9,5.0Hz,1H),3.38(d,J=5.3Hz,1H),3.32(d,J=5.8Hz,1H ),2.54(dd,J=12.8,4.6Hz,1H),2.40(dd,J=12.7,7.1Hz,1H),2.35(s,3H),2.25(s,3H).

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Abstract

The invention belongs to the technical field of medicine and relates to a triazolopyridine compound and a preparation method and application thereof, in particular to a triazolopyridine compound having the structure of general formula I and its stereoisomers and pharmaceutically acceptable salts, wherein R1, R2, R3 and R4 are described as in the claims and the description. All the triazolopyridinecompound, its stereoisomers and pharmaceutically acceptable salts, and a composition containing the triazolopyridine compound can evidently inhibit interaction of PD-1/PD-L1 protein/protein, are suitable for treating the various diseases, such as cancers and viral infections, and therefore, are applicable to the preparation of drugs to prevent and/or treat diseases associated with PD-1/PD-L1 signal pathway.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to triazolopyridine compounds, their stereoisomers and pharmaceutically acceptable salts, their preparation methods and pharmaceutical compositions containing the compounds. The present invention also relates to such compounds and their stereoisomers and pharmaceutically acceptable salts in the preparation of drugs for treating diseases related to PD-1 / PD-L1 signaling pathways, such as cancer, infectious diseases, and autoimmune diseases the use of. Background technique: [0002] Immunotherapy is a hot field of tumor treatment in recent years, and was rated as the top ten scientific breakthroughs by "Science" in 2013. Programmed death 1 (PD-1) is a T cell surface receptor that produces negative immunoregulatory signals when it binds to programmed death ligand 1 (PD-L1), thereby inhibiting T cell activation , proliferation and the release of cytokines such as interleukin 2 (IL-2), ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00A61P35/02A61P37/02A61P31/04A61P31/12A61P5/14A61P5/16A61P3/10A61P1/04A61P25/00A61P29/00A61P19/02A61P7/06
Inventor 秦铭泽宫平赵燕芳刘亚婧
Owner SHENYANG PHARMA UNIVERSITY
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