Tricyclic heteroaryl-substituted quinoline and azaquinoline compounds as par4 inhibitors

a technology of azaquinoline and quinoline, which is applied in the field of tricyclic heteroaryl substituted compounds, can solve the problems of limited efficacy, increased risk of bleeding, and limited current anti-platelet therapy

Inactive Publication Date: 2019-10-17
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]Other features and advantages of the invention will be apparent from the following detailed description and claims.

Problems solved by technology

Current anti-platelet therapies have limitations including increased risk of bleeding as well as partial efficacy (relative cardiovascular risk reduction in the 20 to 30% range).

Method used

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  • Tricyclic heteroaryl-substituted quinoline and azaquinoline compounds as par4 inhibitors
  • Tricyclic heteroaryl-substituted quinoline and azaquinoline compounds as par4 inhibitors
  • Tricyclic heteroaryl-substituted quinoline and azaquinoline compounds as par4 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0830]Intermediate 1B (70 mg, 0.121 mmol) was subject to a chiral SFC separation using the following condition: Instrument: Berger Multigram II Prep SFC Column: Chiralpak AS-H, 30×250 mm, 5 micron; Mobile Phase: 30% MeOH / 70% CO2; Flow Conditions: 85 mL / min, 150 Bar, 40° C.; Detector Wavelength: 234 nm. Two peaks were obtained corresponding to the two enantiomers. The fast eluting fraction (RT=18.5 min) was combined, concentrated, lyophilized to give Example 1 (26 mg, 0.043 mmol, 35.3% yield) as a slightly yellow solid. 1H NMR (400 MHz, THF) δ 8.80 (br. s., 1H), 8.67 (d, J=1.5 Hz, 1H), 8.47 (s, 1H), 8.06 (br. s., 1H), 7.73 (d, J=7.3 Hz, 1H), 7.68 (d, J=0.9 Hz, 1H), 7.05 (s, 1H), 6.55 (d, J=8.8 Hz, 1H), 4.51-4.44 (m, 2H), 4.35 (d, J=4.6 Hz, 2H), 4.18 (dd, J=11.9, 7.7 Hz, 1H), 4.00 (s, 3H), 3.72 (s, 3H), 2.55 (s, 3H); LC-MS: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL / min; gradient time 1.5 min; 2 to 98% B. RT=1.27 min, MS (ESI)...

example 2

(S)-(4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl (6-methoxypyridin-3-yl)carbamate

[0831]

[0832]Example 2 was obtained from the second (slow eluting fraction, RT=22.7 min) peak in the separation of Intermediate 1B (27.6 mg, 0.045 mmol, 37.5% yield): 1H NMR (400 MHz, THF) δ 8.91 (br. s., 1H), 8.78 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.16 (br. s., 1H), 7.84 (d, J=8.4 Hz, 1H), 7.80-7.76 (m, 1H), 7.15 (s, 1H), 6.66 (d, J=8.8 Hz, 1H), 4.62-4.54 (m, 2H), 4.45 (d, J=4.8 Hz, 2H), 4.29 (dd, J=11.8, 7.8 Hz, 1H), 4.11 (s, 3H), 3.83 (s, 3H), 2.66 (s, 3H); LC-MS: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL / min; gradient time 1.5 min; 2 to 98% B. RT=1.27 min, MS (ESI) m / z: 580.1 (M+H)+. Analytical HPLC (method A): RT=12.36 min, 95% purity.

Example 3

(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-7,8-dihydro-[1,4] dioxino [2′,3′: 3,4]benzo [1,2-d]thiazol-7-yl)methyl (2-hydroxypy...

example 3

[0836]To a solution of 4-aminopyridin-2-ol (18.67 mg, 0.170 mmol) in DCM (0.8 mL) was added DIEA (0.074 mL, 0.424 mmol), followed by addition of Intermediate 3A (20 mg, 0.042 mmol) in THF (0.8 mL). The reaction mixture was stirred at room temperature for 1.0 h. HPLC and LCMS indicated a completion of reaction. The reaction was quenched by addition of a small amount of MeOH / water / 0.1% TFA. Solvent was removed under vacuum. The crude was dissolved in DMSO and purified via preparative LC / MS (method D, 70-100% B over 10 minutes, then a 5-minute hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 3 (12.0 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.63 (br. s., 1H), 8.75 (s, 1H), 8.59 (s, 1H), 8.24 (d, J=5.5 Hz, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.43 (d, J=5.8 Hz, 1H), 6.99 (s, 1H), 4.67 (br. s., 1H), 4.61 (d, J=11.6 Hz, 1H), 4.56-4.43 (m, 2H), 4.33-4.26 (m, 1H), 4.09 (s, 3H), 2.69 (s, 3H), 2.65 (s, 3H); LC-MS: method H, RT=...

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Abstract

Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a tricyclic heteroaryl group substituted with R3a and zero to 2 R3b; and R1, R2, R3a, R3b, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is entitled to priority pursuant to 35 U.S.C. § 119(e) to U.S. provisional patent application No. 62 / 362,121, filed Jul. 14, 2016, which is incorporated herein in its entirety.FIELD OF THE INVENTION[0002]The present invention generally relates to tricyclic heteroaryl substituted compounds useful as inhibitors of platelet aggregation. Provided herein are tricyclic heteroaryl substituted compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful in preventing or treating thromboembolic disorders.BACKGROUND OF THE INVENTION[0003]Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), synthetic pentasaccharides, and antiplatelet a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D519/00A61P7/02C07D515/14
CPCC07D519/00C07D515/14A61P7/02C07D493/04C07D513/04A61K31/497A61K31/506
Inventor ZHANG, XIAOJUNPRIESTLEY, ELDON SCOTTHALPERN, OZ SCOTTJIANG, WENREZNIK, SAMUEL KAYERICHTER, JEREMY M.
Owner BRISTOL MYERS SQUIBB CO
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