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Triazolopyridine compounds as PIM kinase inhibitors

A technology of compound and solvate, applied in the field of manufacturing said compound

Inactive Publication Date: 2014-01-01
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 current therapies are only moderately 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

[0399] The following examples illustrate the invention. In the examples described below, all temperatures are expressed in degrees Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Acros, Lancaster, TCI or Maybridge unless otherwise stated and were used without further purification unless otherwise stated. Unless otherwise stated, tetrahydrofuran (THF), dichloromethane (DCM), toluene and dioxane were purchased from Aldrich in Sure sealed vials and used as received.

[0400] The reactions described below are typically carried out in anhydrous solvents under positive pressure of nitrogen or argon or with drying tubes (unless otherwise stated), and the reaction flasks are usually fitted with rubber septa for introduction of substrates and reagents via syringes . Glassware is oven-dried and / or heat-dried. Column chromatography was performed on a Biotage system (Manufacturer: Dyax Corporation) with a silica gel c...

Embodiment A

[0402] Enzyme PIM-1 assay

[0403] The assay used to measure PIM-1 activity is based on the 33 P]ATP[ 33 P]PO 4 PIM2tide substrate was incorporated and radiolabeled peptides were captured on Whatman P81 (phosphocellulose) filter plates. Subsequently, the amount of radiolabeled product was determined by liquid scintillation counting. Final buffer conditions were as follows: 20 mM K + MOPS (pH 7.4), 10 mM MgCl 2 , 0.005% Tween-20, 1 mM DTT. The assay mixture contains 35 μM [γ- 33 P]ATP (20 μCi / mL), 7.5 μM PIM2tide and 0.25 nM PIM-1. Incubate for 60 min at 22°C with 75 μL of 200 mM H 3 PO 4 Quenched, filtered through Whatman P81 plates, and washed with 200 mM H 3 PO 4 Wash (1 x 200 [mu]L and 5 x 100 [mu]L). Subsequently, 50 μL of liquid scintillation mix was added to each well, and the plate was counted for 30 sec / well using TopCount NXT.

[0404] IC 50 Assay:

[0405] Compounds were prepared by 3-fold serial dilutions from 500-μM intermediate dilutions at ...

Embodiment B

[0407] PIM-2 determination

[0408] As described in Example A, 4 μM [γ- 33 P]ATP (20 μCi / mL), 1.0 μM PIM2tide and 1.5 nM GST-labeled recombinant full-length human Pim-2 were assayed in place of PIM-1. Average IC of compounds tested in this assay 50 Values ​​are provided in Table 1.

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PUM

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Abstract

Compounds of Formula I: in which R1, R2, R3, R4 and R10 have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of diseases mediated by PIM-1 and / or PIM-2 and / or PIM-3 kinases.

Description

technical field [0001] The present invention relates to novel compounds, pharmaceutical compositions comprising the compounds, methods for making the compounds, and use of the compounds in therapy. More specifically, the present invention relates to certain triazolopyridine compounds useful in the treatment and prevention of diseases treatable with PIM kinase inhibitors, including diseases mediated by PIM kinase. Certain compounds of the present invention have been found to act as inhibitors of PIM-1 and / or PIM-2 and / or PIM-3. Background technique [0002] Protein kinases constitute a family of structurally related enzymes responsible for the control of a wide range of cellular processes. [0003] The PIM kinase subfamily consists of three distinct serine / threonine protein kinase isoforms (PIM-1, PIM-2, and PIM-3) that belong to the calmodulin-dependent protein kinase-related protein kinase-related; CAMK) group. PIM-2 and PIM-3 are 58% and 69% identical to PIM-1 at the am...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D471/04C07D519/00A61K31/4709A61P29/00
CPCC07D519/00C07D401/06C07D491/048C07D471/04C07D487/04C07D487/10A61P1/00A61P1/04A61P11/00A61P17/00A61P17/02A61P19/02A61P25/00A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00A61K31/437
Inventor J.F.布莱克R.K.德莱尔L.A.德米斯J.M.格雷厄姆Y.莱修罗M.莱昂J.E.罗宾逊E.M.华莱士王斌徐睿
Owner ARRAY BIOPHARMA
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