Triazolopyridine compounds as pim kinase inhibitors

A kind of compound, technology of alkyl, applied in the field of triazolopyridine compound

Inactive Publication Date: 2011-09-14
ARRAY BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

MS affects more than 2.5 million people worldwide (www.nationalmssociety.org); however, many existing therapies are only modestly effective and have questionable risk factors

Method used

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  • Triazolopyridine compounds as pim kinase inhibitors
  • Triazolopyridine compounds as pim kinase inhibitors
  • Triazolopyridine compounds as pim kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0440] PIM-1 enzyme assay

[0441] Regarding the PIM activity assay experiment, will be obtained from [γ- 33 P]ATP [ 33 P]PO 4 Incorporation into PIM2tide matrix and capture of radiolabeled peptides onto Whatman P81 (phosphoryl cellulose) filter plates was based. The amount of radiolabeled product is then measured by liquid scintillation counter. The final buffer condition is as follows: 20mMK+MOPS, pH7.4, 10mMMgCl 2 , 0.005% Tween-20, 1mMDTT. 35 μM [γ- 33 P]ATP (20 μCi / ml), 7.5 μMPIM2tide and 0.25 nMPIM-1. Incubate at 22 °C for 60 min with 75 µl of 200 mM H 3 PO 4 Quench the reaction, filter through a Whatman P81 plate, and wash with 200mMH 3 PO 4 Washes (1x200 microliters vs. 5x100 microliters). Next, liquid scintillation fluid (50 microliters) was added per well, and the plate was counted for 30 sec / well using a TopCount NXT.

[0442] IC 50 Determination:

[0443] Compounds were prepared by performing 3-fold serial dilutions at 50x final concentration in DMSO ...

example B

[0445] PIM-2 enzyme assay

[0446] Detection was as described in Example A, using 4 μM [γ- 33 P]ATP (20 μCi / ml), 1.0 μM IM2tide and 1.5 nM GST-labeled recombinant full-length human PIM-2 were performed instead of PIM-1. When tested in this assay, compounds of formula I were found to have an average IC 50 below 10μM. Specific IC 50 Values ​​are provided in Table 2.

example C

[0448] PIM-3 enzyme detection

[0449] Detection was performed as described in Example A, using 30 μM [γ- 33 P]ATP (20μCi / ml), 3.75μMPIM2tide and 0.5nM recombinant rat PIM-3 instead of PIM-1. When tested in this assay, compounds of formula I were found to have an average IC 50 below 10μM. Specific IC 50 Values ​​are provided in Table 2.

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PUM

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Abstract

Compounds of Formula (I), in which A, B, R1, R1a, R2, R3, R4, R5, R6, and R7 have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of immune cell-associated diseases and disorders, such as inflammatory and autoimmune diseases.

Description

technical field [0001] The present invention relates to a new compound, a pharmaceutical composition containing the compound, a method for preparing the compound, and the use of the compound in therapy. More specifically, it relates to certain triazolopyridine compounds useful in the treatment and prevention of diseases amenable to PIM kinase inhibitors, including diseases mediated by PIM kinases. Particular compounds of the invention have been found to be inhibitors of PIM-1 and / or PIM-2 and / or PIM-3. Background technique [0002] Protein kinases constitute a family of structurally related enzymes that are responsible for the regulation of a large number of cellular processes. [0003] The PIM kinase subfamily consists of three distinct serine / threonine protein kinase isoforms (PIM-1, -2 and -3) belonging to the calmodulin-dependent protein kinase-related (CAMK) group. PIM-2 and PIM-3 have 58% and 69% identity with PIM-1 at the amino acid level, respectively. [0004] Ov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/47
CPCC07D471/04A61P1/00A61P1/04A61P17/00A61P17/02A61P25/00A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00
Inventor 谢利·艾伦劳拉·L·西莉斯特T·G·戴维斯罗伯特·K·德莱尔朱莉·M·格雷斯查克斯蒂芬·D·格罗斯埃里克·J·希肯利拉·J·杰克逊约瑟夫·P·利西卡托斯尼古拉斯·C·卡兰弗雷德里克·P·马姆萨特马克·C·芒森杰德·费尼格布赖森·拉斯特约翰·E·鲁宾逊斯蒂芬·T·施拉赫特乔治·T·托帕洛夫A·D·赖特赵千
Owner ARRAY BIOPHARMA
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