Pyrazolopyridine compounds for ire1 inhibition

A compound and solvate technology, applied in the field of pyrazolopyridine compounds for IRE1 inhibition, can solve problems such as instability of ER protein folding mechanism

Pending Publication Date: 2021-12-14
奥普提卡拉公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As mRNA degradation continues, transcripts encoding ER-resident enzymes are also depleted, thereby destabilizing the entire ER protein folding machinery

Method used

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  • Pyrazolopyridine compounds for ire1 inhibition
  • Pyrazolopyridine compounds for ire1 inhibition
  • Pyrazolopyridine compounds for ire1 inhibition

Examples

Experimental program
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Effect test

Embodiment

[0427] The invention will now be described with reference to the following examples. These examples are provided for illustrative purposes only, and the invention is not limited to these examples but encompasses all variations apparent as a result of the teaching provided herein.

[0428] Materials and methods

[0429] General Experimental Details

[0430] Unless otherwise stated, reactions were not performed under an inert atmosphere and all solvents and commercial reagents were used as received.

[0431] Purification by chromatography refers to the use of Companion purification system or Biotage SP1 purification system for purification. In use In the case of SPE Si II cartridges (cartridges) for product purification, 'Isolute SPE Si cartridges' refer to prepacked polypropylene columns containing unbonded reactive silica gel, with irregular particles, with an average particle size of 50 μm, and labeled porosity Fractions containing the desired product (identified by...

Embodiment approach

[0920] The following exemplary embodiments are provided, the numbering of which should not be construed as specifying a level of importance:

[0921] Embodiment 1 provides a compound of formula (Ia), or a salt, solvate, enantiomer, diastereoisomer, isotope or tautomer thereof: in:

[0922] R 1 Yes

[0923] R 2 selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, CF 3 、CHF 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and 1-methylcyclopropyl;

[0924] L is the key;

[0925] R 3 selected from optionally substituted C 3 -C 8 Cycloalkyl, optionally substituted C 3 -C 8 Cycloalkenyl, optionally substituted C 3 -C 8 Heterocycloalkyl and optionally substituted C 2 -C 8 cycloheteroalkenyl;

[0926] R 4 Yes-NH 2 ;

[0927] 0-3 Z's are N and the remaining Z's are independently CR 5 ;

[0928] each R 5 independently selected from halogen, -OH, optionally substituted C 1 -C 6 Alkyl and optiona...

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Abstract

The present invention provides novel pyrazolopyridine compounds compounds, compositions and methods for treating or preventing an IRE1[alpha]-related disease or disorder. In certain embodiments, the disease or disorder is selected from the group consisting of a neurodegenerative disease, a demyelinating disease, cancer, an eye disease, a fibrotic disease, and diabetes.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Application No. 62 / 811,237, filed February 27, 2019, and U.S. Provisional Patent Application No. 62 / 813,975, filed March 5, 2019, all of which Both applications are incorporated herein by reference in their entirety. Background technique [0003] Cells frequently experience situations in which the protein folding machinery of the endoplasmic reticulum ("ER") is overloaded beyond its capacity, resulting in ER stress. ER stress can be caused by secretory workload overload, expression of fold-defectively secreted proteins, nutrient or oxygen deprivation, changes in luminal calcium concentrations, and deviations from the resting redox state. Under ER stress, secreted proteins accumulate in an unfolded form within the organelle to trigger a set of intracellular signaling pathways called the unfolded protein response (UPR). UPR signaling incr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4985C07D487/04A61P25/28
CPCA61P25/28C07D471/04A61K31/437A61P35/00A61P3/10A61P27/02
Inventor R·基南J·萨顿G·亨德
Owner 奥普提卡拉公司
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