N-(substituted-phenyl)-sulfonamide derivatives as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10918642-B2
Application number	US-201916721267-A
Country	US
Kind code	B2
Filing date	Dec 19, 2019
Priority date	Jun 21, 2016
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

The invention relates to N-(substituted-phenyl)-sulfonamide compounds, which are extremely useful as inhibitors of protein kinases (e.g. PERK kinase) and accordingly can be used for the treatment of cell proliferative disorders, such as cancer, or diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (I)

wherein
n is 0, 1 or 2;
R1 is an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl;
R2 and R3 are independently halogen, cyano, OR4 or an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl, wherein
R4 is an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl;
E1 and E2 are independently CH or N;
A is O, S or NR5, wherein
R5 is hydrogen or an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl;
or a pharmaceutically acceptable salt thereof, which comprises the step of cross-coupling of an intermediate of formula (II)

wherein E1 and E2 are independently CH or N;
A is O, S or NR5, wherein
R5 is hydrogen or an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl and heteroaryl; and
X is halogen or a leaving group, alternatively with the following compounds:
Step a) a derivative of formula (IV)

wherein R2 and R3 are independently halogen, cyano, OR4 or an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl, wherein
R4 is an optionally substituted group selected from straight or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl and (C3-C8) cycloalkyl;
n is 0, 1 or 2;
M is an organometal group and Pg is a nitrogen protecting group; followed by
Step e) selective removing of the Pg group from the resultant intermediate of formula (V)

wherein E1, E2, A, R2, R3, n and Pg are as defined above; and
Step f) reacting the resultant intermediate of formula (VII)

wherein E1, E2, A, R2, R3 and n are as defined above, with a derivative of formula (XI)

wherein R1 is as defined above, to obtain a compound of formula (I)

as defined above;
OR:
Step b) a derivative of formula (VI)

wherein R2, R3, n and M are as defined above; followed by
Step f) reacting the resultant intermediate of formula (VII), as defined above, with a derivative of formula (XI), as defined above, to obtain a compound of formula (I)

as defined above;
OR:
Step c) a derivative of formula (VIII)

wherein R1, R2, R3, n and M are as defined above;
OR:
Step d) a derivative of formula (IX)

wherein R1, R2, R3, n, Pg and M are as defined above; followed by:
Step g) selective removing of the Pg group from the resultant intermediate of formula (X)

wherein E1, E2, A, R1, R2, R3, n and Pg are as defined above, to obtain a compound of formula (I)

as defined in claim above;
optionally converting said compound of formula (I) into another compound of formula (I), converting said compound of formula (I) into a pharmaceutically acceptable salt thereof, or converting said salt into a free compound (I).

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Bindi Simona
• Carenzi Davide
• Motto Ilaria
• Pulici Maurizio

Classifications

• A61K31/4355 Primary

  the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title