Aminopyrimidine derivatives as phosphatidylinositol phosphate kinase inhibitors

a technology of phosphatidylinositol and derivatives, which is applied in the direction of antineoplastic agents, organic chemistry, drug compositions, etc., can solve the problems of no known therapeutic agents which effectively inhibit the synthesis of pip5kii-beta, and achieve the effect of improving the efficacy and safety profil

Inactive Publication Date: 2020-12-17
HIBERCELL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0049]The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known PI5P4K inhibitors. The present disclosure also provides agents with novel mechanisms of action toward PI5P4K enzymes in the treatment of various types of diseases including cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and / or latency, and bacterial infections and diseases. Ultimately the present invention provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with PI5P4K enzymes.

Problems solved by technology

Currently, there are no known therapeutic agents which effectively inhibit the synthesis of PIP5KII-beta.

Method used

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  • Aminopyrimidine derivatives as phosphatidylinositol phosphate kinase inhibitors
  • Aminopyrimidine derivatives as phosphatidylinositol phosphate kinase inhibitors
  • Aminopyrimidine derivatives as phosphatidylinositol phosphate kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

14: N-{5-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]pyridin-3-yl}-4-methoxy-5-[4-(4-methylpyridazin-3-yl)phenyl]pyrimidin-2-amine

[0434]

Example 2: Compound 8: (6S)-12-({5-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-4-(prop-1-en-2-yl)pyridin-2-yl}amino)-8-oxa-2,10-diazatricyclo[7.4.0.02,6]trideca-1(13),9,11-trien-3-one

[0435]

Example 3: Compound 14: (6S)-12-({5-[4-(2-oxopyrrolidin-1-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)8-oxa-2,10-diazatricycloylo[7.4.0.02,6]trideca-1(9),19,12-trien-3-one

[0436]

CompoundNo.StructureCompound Name 12-[(2-{[(6S)-3-oxo-8-oxa-2,10- diazatricyclo[7.4.0.02,6]trideca- 1(9),10,12-trien-12-yl]amino}-5-[4- (2-oxopyrrolidin-1- yl)phenyl]pyrimidin-4- yl)amino]acetic acid 2(6S)-12-[(4-{methyl[(3S)-oxolan-3- yl]amino}-5-[4-(2-oxopyrrolidin-1- yl)phenyl]pyrimidin-2-yl)amino]-8- oxa-2,10- diazatricyclo[7.4.0.02,6]trideca- 1(13),9,11-trien-3-one 3(6S)-12-({4-[methyl(oxolan-3- yl)amino]-5-[4-(2-oxopyrrolidin-1- yl)phenyl]pyrimidin-2-yl}amino)-8- oxa-2,10- diazatricy...

example 4

iochemical Assay

[0437]Dilution series of the compounds were prepared in DMSO at 100 times the final assay concentration (n1=n0 / 3 in 10 points). The compounds were further diluted to three times the assay concentration in assay buffer (20 mM MOPS pH 7.2, 25 mM magnesium chloride, 0.005% Tween 20). 6 μL of the diluted compounds were added to a 384 well assay plate followed by 9 μL of a mix consisting of 4 nM PIP4K2A (full length protein, SignalChem) and 100 M P(5)P diC8 (Tebu-Bio). Enzyme and compounds were pre-incubated at room temperature for 15 minutes.

[0438]Then 3 μL of a solution containing 60 M ATP (Promega) in assay buffer was added to the wells containing compound and enzyme and mixing was performed by pipetting several times. The reaction was incubated at room temperature for 1h. Then 18 μL of ADP-Glo™ Reagent (Promega) was added to stop the kinase reaction and deplete the unconsumed ATP, mixing was performed by pipetting several times. The plate was incubated at room tempera...

example 5

tocol—PIP4KtypeIIA

[0440]GST tagged PIP4KtypeIIA and B enzymes were overexpressed in E. Coli and purified to >80% homogeneity. Phosphatidyl inositol-5-phosphate (PI5P, Cat. #850152, Avanti Polar Lipids Inc.) was used as the lipid substrate and phosphatidyl ethanolamine (DOPE 18:1, Cat. #850725, Avanti Polar Lipids Inc.) was used as the carrier lipid for assays. Ultrapure ATP and GTP was purchased from Bellbrooke Labs. ADP Glo reagents were obtained from Promega. Transcreener FI reagent was obtained from Bellbrooke labs.

Buffers:

[0441]1. HEPES buffer mix: 200 mM HEPES pH 7.4, 50 mM MgCl2, 0.05% v / v triton X 100

2. HNE buffer: 20 mM HEPES, pH 7.4, 100 mM NaCl, 0.5 mM EGTA

3. H:E buffer: 30 mM HEPES, pH 7.4, 1 mM EGTA

[0442]Enzyme preparation: GST-tagged PIP4KtypeIIA (5 μL, 1.43 mg / mL) was diluted (1:10) to 50 μL using HNE buffer. From the 1:10 diluted stock, a 6.4 μL aliquot was diluted further to 5 mL using HNE buffer to yield 5× enzyme stock (2.5 nM).

GST-tagged PIP4KtypeIIB (3.4 μL, 2.77...

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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:
where A, B, R1, X1, X2, and W are described herein.

Description

RELATED APPLICATIONS[0001]This application claims priority to, and the benefit of, U.S. Provisional Application No. 62 / 862,371, filed Jun. 17, 2019, which is incorporated by reference herein in its entirety for all purposes.FIELD OF INVENTION[0002]The present invention is directed to inhibitors of phosphatidylinositol-5-phosphate-4-kinase (PI5P4K) useful in the treatment of diseases or disorders associated with PI5P4K enzymes. In particular, the invention is concerned with compounds and compositions inhibiting PI5P4K, methods of treating diseases or disorders associated with PI5P4K, and methods of synthesis of these compounds.BACKGROUND OF THE INVENTION[0003]A minor but ubiquitous component of cells, phosphoinositol lipids are pivotal players in many intracellular signal transduction pathways. Phosphoinositol lipids are formed when phosphatidylinositol (PtdIns) is converted, by the catalytic action of lipid kinases, to polyphosphoinositides. As a prototypic example, the membrane ass...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D498/14C07D498/04C07D491/056C07D401/14
CPCC07D498/04C07D401/14C07D498/14C07D491/056C07D491/06C07D471/12C07D471/14A61P35/00
Inventor KESICKI, EDWARD A.
Owner HIBERCELL INC
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