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Bicyclic heteroaryl substituted compounds

A compound and heteroaryl technology, applied in the direction of drug combination, organic chemistry, medical preparations containing active ingredients, etc., can solve the problems of increasing the risk of massive bleeding

Active Publication Date: 2019-04-26
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, in the TRACER phase III clinical trial in patients with ACS, vorapasar did not significantly reduce cardiovascular events, but significantly increased the risk of major bleeding (Tricoci, P. et al., N.Eng.J.Med., 366 (1): 20-33 (2012)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0222] 4) Preparation of washed platelets (WP)

[0223] Human blood was collected in ACD (85 mM trisodium citrate, 78 mM citric acid, 110 mM D-glucose, pH 4.4) at a rate of 1.4 ml per 10 ml of blood. PRP was isolated by centrifugation at 170g for 14 minutes and platelets were further pelleted by centrifugation at 1300g for 6 minutes. Platelets were washed once with 10 ml ACD containing 1 mg / ml bovine serum albumin. In Tyrode buffer (137mM NaCl, 2mM KCl, 1.0mM MgCl 2 , 1mM CaCl 2 , 5mM glucose, 20mM HEPES pH 7.4) at about 2.5X10 8 / ml resuspended platelets.

[0224] FLIPR assay in HEK293 cells expressing PAR4

[0225] PAR4 antagonism, agonism and selectivity for PAR1 were measured using a FLIPR-based calcium mobilization assay in HEK293 cells. By monitoring H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH 2 Induced Intracellular Calcium Mobilization, PAR4 antagonists of the invention were tested for activity in cells expressing PAR4. A counter screen for agonist activi...

Embodiment 1

[1609] 5-(benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

[1610]

[1611] Intermediate I-1G (40 mg, 0.138 mmol), benzofuran-2-ylboronic acid (28.0 mg, 0.173 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloride A mixture of palladium(II) complex with dichloromethane (1:1) (6.78 mg, 8.30 μmol) in toluene (1.8 mL) and EtOH (0.600 mL) was degassed with argon for 2.0 min. To this solution was added sodium carbonate (2M, 0.121 mL, 0.242 mmol). The mixture was heated at 100 °C for 30 minutes in a microwave reactor. The reaction mixture was diluted with EtOAc / water. The organic layer was collected and dried over sodium sulfate. The crude residue was redissolved in DMSO / acetonitrile (6 mL / 6 mL) and purified using preparative HPLC (Method A, 70-100% B, 10 min, flow rate 40 mL / min). The desired fraction was placed in a SpeedVac overnight to remove the solvent, then lyophilized to afford Example 1 (28 mg, 0.085 mmol, 61.4% yield) as a yellow lyophilizate. 1 H NMR...

Embodiment 2

[1613] 2-(Difluoromethoxy)-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline

[1614]

[1615] Intermediate 2A: (5-methoxybenzofuran-2-yl)boronic acid

[1616]

[1617] To a solution of 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL) was added 1.6 N n-BuLi / hexane (1.190 mL, 1.903 mmol) dropwise at -78 °C. The solution turned slightly yellow. The reaction mixture was stirred at -78 °C for 20 minutes, then triisopropyl borate (0.737 mL, 3.17 mmol) was added. After stirring at -78°C for 30 minutes, the cooling bath was removed and stirring was continued at room temperature for 1.5 hours. The reaction mixture was diluted with EtOAc and quenched with 3.0 mL of 1.0N HCl. After stirring at room temperature for 25 minutes, the organic layer was collected, washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was dissolved in a small amount of chloroform / one drop of MeOH and loaded onto a 4 g silica gel column, which was ...

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PUM

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Abstract

Disclosed are compounds of Formula (I) to (VIII); or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to three R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using the compounds as PAR4 inhibitors, and pharmaceutical compositions comprising the compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of thromboembolic disorders or the primary prophylaxis of thromboembolic disorders.

Description

[0001] Cross References to Related Applications [0002] This application is entitled to claim priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application 62 / 362,113, filed July 14, 2016, which is hereby incorporated in its entirety. technical field [0003] The present invention generally relates to bicyclic heteroaryl substituted compounds useful as inhibitors of platelet aggregation. Provided herein are bicyclic heteroaryl-substituted compounds, compositions comprising the compounds, and methods of using them. The present invention further relates to pharmaceutical compositions containing at least one compound according to the invention, which are useful for the prophylaxis or treatment of thromboembolic disorders. Background technique [0004] Although anticoagulants such as warfarin are available Heparin, low molecular weight heparin (LMWH) and synthetic pentasaccharides) and antiplatelet agents (such as aspirin and clopidogrel ), but thromboembolic dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D403/04C07D405/04C07D417/04C07D417/14C07D471/04C07D513/04C07D519/00A61K31/498A61P7/04
CPCC07D405/14C07D403/04C07D405/04C07D417/04C07D417/14C07D471/04C07D513/04C07D519/00A61P11/00A61P13/12A61P43/00A61P7/02A61P7/04A61P9/10A61K31/498C07D487/04
Inventor 张晓军E·S·普里斯特利J·A·贝茨O·S·哈尔彭S·K·列兹尼克J·M·里希特
Owner BRISTOL MYERS SQUIBB CO
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