Tricyclic heteroaryl-substituted quinoline and azaquinoline compounds as par4 inhibitors

A compound, cycloalkyl technology, used in the field of prevention or treatment of thromboembolic disorders, can solve problems such as increased risk of major bleeding

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

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Problems solved by technology

Recently, in the TRACER phase III clinical trial of ACS patients, 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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  • 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

preparation example Construction

[0476] 4) Preparation of washed platelets (WP)

[0477] 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.

[0478] FLIPR assay in HEK293 cells expressing PAR4

[0479] 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

[1206] (6-Methoxypyridin-3-yl)carbamic acid (R)-(4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-di Hydrogen-[1,4]dioxino[2',3':3,4]benzo[1,2-d]thiazol-7-yl)methyl ester

[1207]

[1208]Intermediate 1A: Chloroformic acid [7-chloro-4-(2-methoxy-7-methylquinoxalin-5-yl)-10,13-dioxa-3-thia-5-aza Tricyclo[7.4.0.0^{2,6}]trideca-1(9),2(6),4,7-tetraen-11-yl]methyl ester

[1209]

[1210] To a solution of Intermediate I-6 (77 mg, 0.179 mmol) in THF (2.0 mL) was added 15% phosgene / toluene (0.632 mL, 0.896 mmol) at room temperature and the mixture was stirred at room temperature overnight. HPLC indicated the reaction was complete. The solvent was removed in vacuo to afford Intermediate 1A (87 mg). It was used in the next step without any purification.

[1211] Intermediate 1B: (6-methoxypyridin-3-yl)carbamic acid (4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-di Hydrogen-[1,4]dioxino[2',3':3,4]benzo[1,2-d]thiazol-7-yl)methyl ester

[1212]

[1213] To a solution ...

Embodiment 2

[1217] (6-Methoxypyridin-3-yl)carbamic acid (S)-(4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-di Hydrogen-[1,4]dioxino[2',3':3,4]benzo[1,2-d]thiazol-7-yl)methyl ester

[1218]

[1219] Example 2 (27.6 mg, 0.045 mmol, 37.5% yield) was obtained from the second peak (slow eluting fraction, RT=22.7 min) in the isolation of intermediate 1B: 1 H NMR (400MHz, THF) δ8.91(br.s., 1H), 8.78(d, J=2.0Hz, 1H), 8.58(s, 1H), 8.16(br.s., 1H), 7.84( d,J=8.4Hz,1H),7.80-7.76(m,1H),7.15(s,1H),6.66(d,J=8.8Hz,1H),4.62-4.54(m,2H),4.45(d , J=4.8Hz, 2H), 4.29(dd, J=11.8, 7.8Hz, 1H), 4.11(s, 3H), 3.83(s, 3H), 2.66(s, 3H); LC-MS: BEH C18 2.1x50mm; A: water +0.05%

[1220] TFA; B: acetonitrile+0.05%TFA; wavelength 220nm; flow rate 0.8mL / min; gradient time 1.5min; 2 to 98%B. RT=1.27min, MS(ESI)m / z:580.1(M+H) + . Analytical HPLC (Method A): RT = 12.36 min, 95% purity.

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Abstract

Disclosed are compounds of Formula (I) to (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a tricyclic heteroaryl group substituted withR3a and zero to two R3b; and R1, R2, R3a, R3b, 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 a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.

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 / 362,121, filed July 14, 2016, which is hereby incorporated in its entirety. technical field [0003] The present invention generally relates to tricyclic heteroaryl substituted compounds useful as inhibitors of platelet aggregation. The application provides tricyclic heteroaryl-substituted compounds, compositions comprising the compounds, and methods of use thereof. The 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 di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00
CPCC07D519/00C07D493/04C07D513/04A61P7/02A61K31/497A61K31/506C07D515/14
Inventor 张晓军E·S·普里斯特利O·S·哈尔彭蒋文S·K·列兹尼克J·M·里希特
Owner BRISTOL MYERS SQUIBB CO
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