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Heteroaryl compounds and their use as therapeutic drugs

a technology of heteroaryl compounds and therapeutic drugs, applied in the field of heteroaryl compounds, can solve the problems of limited potency and lack of selectivity of inhibitors, and it is difficult to find inhibitors that are specific for mer,

Active Publication Date: 2017-12-14
DONG A SOCIO HLDG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0106]Novel heterocyclic compounds according to the present invention, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof exhibit the effect of effectively inhibiting Mer kinase.
[0107]Novel heterocyclic compounds according to the present invention, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt can be used for the prevention or treatment of cancer or immune-related disease.MODE FOR INVENTION
[0108]Based on the studies conducted and the results obtained so far, it is believed that the following compounds (numbered 1 to 458), including isomers, mixtures of isomer as well as pharmaceutically acceptable salts and solvates thereof, are particularly interesting.General Synthetic MethodsExamples
[0109]Embodiments of the present invention are described in the following examples, which are meant to illustrate and not limit the scope of this invention. Common abbreviations well known to those with ordinary skills in the synthetic art used throughout.
[0110]All chemical reagents were commercially available. Flash column chromatography means silica gel chromatography unless specified otherwise, which was performed on Teledyne Combiflash-RF200 System. 1H NMR spectra (δ, ppm) are recorded on 400 MHz or 600 MHz instrument. Mass spectroscopy data for a positive ionization method are provided. Preparative HPLC was performed on Agilent technologies G1361A.

Problems solved by technology

For this reason, it is challenging to find an inhibitor that is specific for the Mer.
This inhibitor has, however, limited potency and lack of selectivity.

Method used

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  • Heteroaryl compounds and their use as therapeutic drugs
  • Heteroaryl compounds and their use as therapeutic drugs
  • Heteroaryl compounds and their use as therapeutic drugs

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[0117]To a mixture of intermediate 2 (43 mg, 0.2 mmol) and triethylamine (24 mg, 0.24 mmol) in 2 ml of DMF was added HATU (91 mg, 0.24 mmol) followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine (38 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 46 mg of the title compound.

[0118]1H NMR (600 MHz, CD3OD) δ ppm 1.57-1.69 (m, 1H) 1.72-1.86 (m, 3H) 1.90-2.08 (m, 1H) 2.11-2.21 (m, 1H) 3.93 (s, 3H) 3.96 (dt, J=6.75, 4.26 Hz, 1H) 4.39 (td, J=7.34, 4.11 Hz, 1H) 4.61 (s, 2H) 7.13-7.24 (m, 1H) 7.27 (t, J=7.46 Hz, 2H) 7.32 (d, J=7.04 Hz, 2H) 7.79-7.90 (m, 1H) 8.00 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.46 (d, J=2.35 Hz, 1H);

[0119]MS (ESI, m / z): 392.2 [M+H]+

example 2

2-amino-N-(1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1-pyrazol-4-yl)nicotinamide

[0120]Using (1R,2R)-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.

[0121]MS (ESI, m / z): 392.2 [M+H]+

example 3

2-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[0122]Using trans-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.

[0123]MS (ESI, m / z): 392.2 [M+H]+

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PUM

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Abstract

The present invention provides heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt, which are capable of modulating the activity of Mer receptor tyrosine kinase (MERTK). This invention also provides pharmaceutical compositions thereof, methods to prepare the said compounds, and the use of such compounds as a medicament.The present invention is directed to MERTK inhibitory compounds with marked potency, thereby having an outstanding potential for a pharmaceutical intervention of cancer and any other diseases related to MERTK dysregulation.

Description

RELATED APPLICATION[0001]This application claims the benefit of priority under U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 62 / 212,520 filed Aug. 31, 2015, which is incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates to novel heterocyclic compounds having Mer kinase inhibitory activity, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, the use for preparing pharmaceutical compositions, pharmaceutical compositions comprising the same, methods of treating diseases using these compositions.BACKGROUND ART[0003]Transmembrane receptor tyrosine kinases (RTKs) comprise an evolutionarily conserved family of structurally related proteins. The gene Mer is a member of the Tyro3 / Axl / Mer (TAM) receptor kinase family and a proto-oncogene. Its abnormal expression and activation is found in conjunction with human cancers such as pituitary adenomas, mantle cell lymphomas, and T-cell acute lymphoblastic leuke...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/14C07D405/14C07D417/04C07D213/82C07D403/04C07D401/04C07D417/14C07D409/14C07D401/12
CPCC07D401/14C07D409/14C07D405/14C07D417/04C07D401/12C07D403/04C07D401/04C07D417/14C07D213/82C07D401/10A61P31/04A61P35/00A61P35/02A61P35/04A61P37/02A61P43/00A61K31/4439A61K31/497A61K31/4545A61K31/4709A61K31/496A61K31/5377C07D409/04
Inventor KIM, MYEONG-SEOPKIM, SUMINKIM, JIN KWANKIM, HADONGRYU, KI MOONPARK, SEONG JINPARK, TAESUNSHEEN, JOON-HOYOON, TAEYOUNGJANG, MI YEON
Owner DONG A SOCIO HLDG CO LTD
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