US 11,649,218 B2Granted

C-Abl tyrosine kinase inhibitory compound embodiments and methods of making and using the same

AssigneesThe United States of America, as represented by the Secretary, Department of Health and Human Services, Pontificia Universidad Catolica De Chile

InventorsJuan J. Marugan, Marc Ferrer, Noel T. Southall, Andres E. Dulcey, Xin Hu, Christopher R. Dextras, Daniel C. Talley, Alejandra Alvarez, Silvana Zanlungo, Rommy M. Von Bernhardi

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Abstract

Disclosed herein are embodiments of a compound that inhibits c-Abl tyrosine kinase (also referred to herein as “c-Abl”). The compound embodiments described herein are novel c-Abl inhibitors that can bind to c-Abl at an allosteric site and inhibit its activity in various pathways. The compound embodiments also are capable of crossing the blood brain barrier and therefore are useful in inhibiting c-Abl activity as it affects pathways and/or proteins in the brain. The compound embodiments described herein are effective therapeutic agents for treating diseases involving c-Abl, such as cancers, motor neuron diseases, and neurodegenerative diseases. Also disclosed herein are embodiments of methods for making and using the c-Abl inhibitory compound embodiments.

Claims18

Dependent claims

A compound, having a structure satisfying any of Formulas IIA-IIF

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
X is oxygen;
for Formulas IIA and IID, Y is oxygen, NR′, or CR′R″ wherein each R′ and R″ independently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, aliphatic-aromatic, or heteroaliphatic-aromatic;
for Formulas IIB and IIE, Y is hydrogen, or NR′R″ wherein each R′ and R″ independently is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, aliphatic-aromatic, or heteroaliphatic-aromatic;
for Formulas IIC and IIF, Y is hydrogen;
at least one of R1 and R3 is aromatic, haloheteroaliphatic, or boronic acid and the other of R1 and R3 is heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or boronic acid;
R2 and R4, if present, independently are aliphatic, heteroaliphatic, or halogen;
R5 is selected from hydrogen, aliphatic, heteroaliphatic, aromatic, aliphatic-aromatic, or heteroaliphatic-aromatic;
and
each of n and m independently is an integer selected from 0 to 3.

7 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/976,012Filed 8 Mar 2019 · us provisional application
Priority: 9 Mar 2018
Published: US 2021/0101872 A18 Apr 2021
Granted: 16 May 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification34 codes

C07D 243/38
Condensed with carbocyclic rings or ring systems: [b, e]- or [b, f]-condensed with six-membered rings
A61K 31/5513
Having two nitrogen atoms, e.g. dilazep: 1,4-Benzodiazepines, e.g. diazepam or clozapine
A61K 31/553
Having seven-membered rings, e.g. azelastine, pentylenetetrazole: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine,…
A61K 31/554
Having seven-membered rings, e.g. azelastine, pentylenetetrazole: having at least one nitrogen and one sulfur as ring hetero atoms, e.g.…