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Aryl-bipyridine amine derivatives as phosphatidylinositol phosphate kinase inhibitors

An aryl and heteroaryl technology, applied to compounds containing elements of group 3/13 of the periodic table, drug combinations, medical preparations containing active ingredients, etc.

Active Publication Date: 2020-12-15
拉文纳制药公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Currently, no known therapeutic agent effectively inhibits PIP5KII-β synthesis

Method used

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  • Aryl-bipyridine amine derivatives as phosphatidylinositol phosphate kinase inhibitors
  • Aryl-bipyridine amine derivatives as phosphatidylinositol phosphate kinase inhibitors
  • Aryl-bipyridine amine derivatives as phosphatidylinositol phosphate kinase inhibitors

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0715] Compound preparation

[0716] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below. Compounds of the present invention can be synthesized by following the steps outlined in general scheme 1, which include the assembly of intermediates or different sequences of compound (II). Starting materials are commercially available or prepared by methods known in the reported literature or as shown below.

[0717] Compounds of formula (I) can be obtained (Scheme 1) by starting from, for example, compounds of formula (II), where T represents a coupling metal, including but not limited to b...

Embodiment 1

[0777] Example 1: 4-([3,4'-bipyridyl]-5-yl)-N,N-dimethylbenzamide

[0778]

[0779] in N 2 Down to 3,5-dibromopyridine (200mg, 0.84mmol), 4-pyridylboronic acid (52mg, 0.42mmol) and K 2 CO 3 (0.47g, 3.38mmol) in 1,4-dioxane (3ml) and water (0.75ml) was added Pd(PPh 3 ) 4 (49 mg, 0.04 mmol). The resulting mixture was stirred at 70 for 3 hours, then [4-(dimethylcarbamoyl)phenyl]boronic acid (81 mg, 0.42 mmol) was added, and the mixture was stirred at 90 for 2 hours. More [4-(dimethylcarbamoyl)phenyl]boronic acid (81 mg, 0.42 mmol) and PdCl2 (Amphos) (15 mg, 0.02 mmol) were added and stirring was continued at 90 overnight. When cooled to room temperature, water and EtOAc were added, the organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, washed with Na 2 SO 4 Drying, filtration, concentration, and purification by preparative HPLC afforded the product as a solid (18 mg, 7%). 1 H NMR (500MHz, chlorofo...

Embodiment 2

[0780] Example 2: 4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)-N,N-dimethylbenzamide

[0781]

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Abstract

The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula (I): whereinA, X, Y, Z, Q, R1, R2, R3, R4, R5, and n are described herein.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to US Provisional Application No. 62 / 609,604, filed December 22, 2017, the entire disclosure of which is incorporated herein by reference in its entirety. [0003] field of invention [0004] The present invention relates to inhibitors of phosphatidylinositol-5-phosphate-4-kinase (PI5P4K), which are useful in the treatment of diseases or conditions associated with the PI5P4K enzyme. In particular, the invention relates to compounds and compositions that inhibit PI5P4K, methods of treating diseases or conditions associated with PI5P4K, and methods of synthesizing these compounds. [0005] Background of the invention [0006] Phosphoinositide lipids, a minor but ubiquitous component of cells, are key players in many intracellular signal transduction pathways. Phosphoinositide lipids are formed when phosphatidylinositols (PtdIns) are converted to polyphosphoinositides by the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D213/56A61P35/00A61P37/00A61K31/435C07D401/04C07D405/04C07D471/04C07D471/10C07D471/14C07D487/04C07D491/048C07D495/04C07D519/00
CPCC07D401/14C07D401/04C07D405/04C07D471/04C07D471/10C07D471/14C07D487/04C07D491/048C07D495/04C07D519/00C07D213/56A61P35/00A61P37/00C07D491/056C07D513/04C07F5/025
Inventor E·A·科斯克基K·K·拉维J·林德斯特罗姆L·B·佩尔森M·里温达尔J·维克伦德T·吉恩曼R·弗斯布罗姆F·拉姆E·R·海基M·K·达尔戈林A·I·格拉斯尤托
Owner 拉文纳制药公司
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