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Pyrazolo[1,5-a]pyridine compound as well as preparation method and application thereof

A compound and alkyl technology, applied in the field of medicine, can solve problems such as drug resistance mutations

Pending Publication Date: 2022-01-04
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

LOXO-292 is disclosed in WO2018071447A1 and developed by LoxoOncology. Its structure is as follows, and it has been approved for marketing by FDA in May 2020; but it is reported in the literature (Journal of Thoracic Oncology, Volume 15, Issue 4, April 2020, Pages 541-549) Patients with RET fusion NSCLC developed a RET G810R resistance mutation leading to LOXO-292 resistance

Method used

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  • Pyrazolo[1,5-a]pyridine compound as well as preparation method and application thereof
  • Pyrazolo[1,5-a]pyridine compound as well as preparation method and application thereof
  • Pyrazolo[1,5-a]pyridine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161]Example 1: 6-(2,2-difluoroethylamine)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo [3.1.1] Heptane-3-yl)pyridin-3-yl)pyrazol[1,5-a]pyridine-3-carbonitrile

[0162]

[0163] Step 1: 6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0164]

[0165] Add 4,6-dibromopyrazol[1,5-a]pyridine-3-carbonitrile (33.0g, 0.11mol), 2-fluoro-5-pyridineboronic acid (14.1g, 0.10mmol) into a 500ml three-necked flask , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.7g, 3.70mmol), potassium fluoride dihydrate (31.0g, 0.33mmol) and 150ml N,N-dichloride Methylformamide was reacted overnight at 60°C under the protection of argon. Cool to room temperature after the reaction, and add 500ml of water. The reaction solution was filtered, and the filter cake was rinsed with acetonitrile and ethyl acetate. Drying under reduced pressure gave 30 g of 6-bromo-4-(6-fluoropyridin-3-yl)pyrazol[1,5-a]pyridine-3-carbonitrile. The yield was 86%.

[0...

Embodiment 2

[0186] Example 2: 6-(ethylamine)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane Alkyl-3-yl)pyridin-3-yl)pyrazol[1,5-a]pyridine-3-carbonitrile

[0187]

[0188] The synthesis of this compound is the same as in Example 1. Using intermediate 2A and ethylamine as raw materials, the target compound 6-(ethylamine)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-di Azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazol[1,5-a]pyridine-3-carbonitrile. The yield is 30%.

[0189] MS m / z: 481.5[M+1] + .

[0190] 1 H NMR (400MHz, DMSO-d 6 )δ8.39(s, 1H), 8.34(s, 1H), 8.09(s, 1H), 7.93(s, 1H), 7.78(d, J=8.7Hz, 1H), 7.71(s, 1H), 7.07(s, 1H), 6.90-6.67 (m, 2H), 6.01(s, 1H), 3.82(s, 3H), 3.72(s, 4H), 3.53(s, 4H), 3.14-2.98(m, 2H), 2.07(s, 1H), 1.59(s, 1H), 1.22(t, J=6.9Hz, 3H).

Embodiment 3

[0191] Example 3: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine -3-yl)-6-(n-propylamine)pyrazol[1,5-a]pyridine-3-carbonitrile

[0192]

[0193] The synthesis of this compound is the same as in Example 1. Using intermediate 2A and n-propylamine as raw materials, the target compound 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1] was obtained heptan-3-yl)pyridin-3-yl)-6-(n-propylamine)pyrazol[1,5-a]pyridine-3-carbonitrile. The yield was 13%.

[0194] MS m / z: 495.3[M+1] + .

[0195] 1 H NMR (400MHz, DMSO-d 6 )δ8.40(s, 1H), 8.35(d, J=2.0Hz, 1H), 8.09(s, 1H), 7.95(d, J=2.0Hz, 1H), 7.80(d, J=8.0Hz, 1H), 7.70(d, J=8.0Hz, 1H), 7.07(d, J=2.0Hz, 1H), 6.85-6.74(m, 2H), 5.98(t, J=8.0Hz, 1H), 3.83( s, 3H), 3.80-3.63 (m, 4H), 3.62-3.45 (m, 4H), 3.10-2.98 (m, 2H), 2.50 (s, 1H), 1.68-1.54 (m, 3H), 0.99 ( t, J = 6.0 Hz, 3H).

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Abstract

The invention relates to pyrazolo[1,5-a]pyridine compounds as shown in a general formula (I) which is described in the specification, and a preparation method, a pharmaceutical composition and application thereof. In the formula, R1, R2, R3, R4, R5, X, Y and Z are as defined in the specification. The pyrazol[1,5-a]pyridine compound provided by the invention can effectively inhibit fusion of a wild type RET, a mutant type RET, especially a G810R mutant type RET, and RET fusion of KIF5B-RET, CCDC6-RET and the like, is good in safety, and can be used for treating RET-mediated diseases, such as cancers and irritable bowel syndromes.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to pyrazol[1,5-a]pyridine compounds which can be used as RET inhibitors, a preparation method of such compounds, a pharmaceutical composition containing such compounds, such compounds and their drugs Use of the composition in the treatment of diseases mediated by RET. Background technique [0002] Transfection rearrangement gene RET (rearranged during transfection) gene is a proto-oncogene, located on chromosome 10. The RET protein encoded by the RET gene is a receptor tyrosine kinase (RTK) present on the cell membrane and belongs to the cadherin superfamily. The ligands of RET are the glial-derived neurotrophic factor family, including glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN). When the ligand binds to the extracellular region of RET, it will lead to RET dimerization and intracellular kinase domain autophosphoryla...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61P35/00A61P1/00A61K31/4995
CPCC07D519/00A61P35/00A61P1/00A61K31/4995A61K31/437C07D471/04Y02P20/55
Inventor 罗会兵周华勇李庆
Owner SHANGHAI ALLIST PHARM CO LTD