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Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use

A compound, unsubstituted technology, applied in the direction of drug combination, antineoplastic drugs, medical preparations containing active ingredients, etc., can solve the problem of tumor immunotherapy enhancement

Pending Publication Date: 2021-06-22
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As each of these immunosuppressive pathways has been identified as a mechanism by which tumors evade host responses, include A2a and / or A2b receptor antagonism alone or with one or more other therapeutic agents aimed at alleviating immunosuppression Drug-based cancer immunotherapy regimens may lead to enhanced tumor immunotherapy

Method used

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  • Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use
  • Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use
  • Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0462] Example 1.2, 2-((1S,2S and 1R,2R)-2-(8-bromo-6-(3-fluorophenyl)-5-methyl-[1,2,4]triazole And[1,5-a]pyrazin-2-yl)cyclopropyl)propan-2-ol preparation of

[0463] plan 1

[0464]

[0465] Step 1 - Intermediate 1.1, 2-((1 S ,2 S and 1 R ,2 R )-2-(8-bromo-6-(3-fluorophenyl)-5-methyl-[1,2,4]triazolo[1,5 -a Synthesis of ]pyrazin-2-yl)cyclopropyl)propan-2-ol

[0466] Intermediate M.2 (22 mg, 0.052 mmol) and THF (525 µL) were charged in a 20 mL scintillation vial. The resulting mixture was cooled to -30 °C, then methylmagnesium bromide (3 M in Et 2 O, 44 µL, 0.131 mmol). The reaction mixture was warmed to 25 °C over 15 min and stirred for another 30 min. Then with saturated NH 4 Aqueous Cl solution (1 mL) quenched the reaction. DCM (1 mL) was added and the biphasic mixture was stirred for 5 min. The mixture was then diluted with water (2 mL) and extracted with DCM (3 x 4 mL). The combined organic layers were washed with anhydrous NaSO 4 Dried, filtered and co...

Embodiment 21

[0469] Example 2.1, (S)-2-(4,4-Difluoropyrrolidin-2-yl)-7-phenyl-[1,2,4]triazolo[1,5-c]pyrimidine Pyridine-5-amine, TFA salt preparation of

[0470] Scenario 2

[0471]

[0472] Will( S )-2-(5-((2,4-dimethoxybenzyl)amino)-7-phenyl-[1,2,4]triazolo[1,5 -c A mixture of tert-butyl]pyrimidin-2-yl)-4,4-difluoropyrrolidine-1-carboxylate (65 mg, 0.117 mmol) and TFA (1 mL) was heated at 60 °C for 1 h. Upon completion, the reaction was concentrated. The resulting crude residue was dissolved in DMSO (3 mL), filtered, and purified by reverse phase HPLC [Method A] to provide ( S )-2-(4,4-difluoropyrrolidin-2-yl)-7-phenyl-[1,2,4]triazolo[1,5 -c ] Pyrimidin-5-amine, TFA salt (Example 2.1). MS (ESI) m / z C 15 h 15 f 2 N 6 [M+H] + The calculated value is 317,1, and the measured value is 317.0. 1 H NMR (500 MHz, MeOD- d 4 ) δ 8.12-8.13 (m, 2 H), 7.46–7.50 (m, 4 H),5.42 (t, J = 8.5 Hz, 1 H), 3.95-4.91 (m, 2 H), 3.11-3.25 (m, 2 H). A2a IC 50 12.0 nM (A).

[0473] Table ...

Embodiment 2

[0480] Example 2.5-1 / 2.5-2

[0481] 5-methyl-2-(1-(1-methyl-1 H -pyrazol-4-yl)piperidin-3-yl)-6-(oxazol-2-yl)-[1,2,4]triazolo[1,5 -a ]pyrazin-8-amine by CHIRAL-Prep SFC [column: CC4, 21x250mm; 40% (0.1% NH 4 OH in MeOH) / CO 2 ; flow rate: 70 mL / min; 220 nm; the first elution peak (Example 2.5-1); the second elution peak (Example 2.5-2)] purification.

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Abstract

In its many embodiments, the present invention provides certain substituted amino triazolopyrimidine and amino triazolopyrazine compounds of Formula (IA) and Formula (IB): or and pharmaceutically acceptable salts thereof, wherein, R1, R2, and R3 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutically active agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2a and / or A2b receptors, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and / or the adenosine A2b receptor.

Description

[0001] field of invention [0002] The present invention relates to novel compounds that inhibit at least one of A2a and A2b adenosine receptors, and pharmaceutically acceptable salts thereof, compositions comprising such compounds and salts, methods of synthesizing such compounds, and their use in the treatment of Use in various diseases, conditions or disorders mediated at least in part by adenosine A2a receptors and / or adenosine A2b receptors. Such diseases, conditions and disorders include, but are not limited to, cancer and immune-related disorders. The invention further relates to combination therapies, including but not limited to combinations comprising a compound of the invention and a PD-1 antagonist. [0003] Background of the invention [0004] Adenosine is a purine nucleoside compound consisting of adenine and ribofuranose (a ribose sugar molecule). Adenosine occurs naturally in mammals and plays an important role in various biochemical processes, including energ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P35/00C07D487/04
CPCC07D487/04A61P35/00A61K31/519A61K2300/00A61K31/4985A61K45/06A61K2039/505C07K16/2818
Inventor Z·G·布里尔A·阿利J·卡明D·德蒙邓巧临T·H·格雷厄姆邝荣泽林延姬C·W·普卢默J·L·里科杜克H·王张永连赵卡克
Owner MERCK SHARP & DOHME BV
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