1,2,4-triazin-3(2H)-one compounds for the treatment of hyperproliferative diseases

Patent metadata

Field	Value
Publication number	US-12427153-B2
Application number	US-202117389940-A
Country	US
Kind code	B2
Filing date	Jul 30, 2021
Priority date	Feb 1, 2019
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

The present invention includes name compounds of general formula (I): (I) in which R1, R2, R3 and R4 are as defined herein, methods for their preparation, pharmaceutical compositions and combinations comprising said compounds, and their use for the treatment of hyperproliferative diseases.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is a hydrogen atom, a halogen atom, a C 1 -C 3 -alkyl group, or a C 1 -C 3 -haloalkyl group;
R 2 is a hydrogen atom, or a halogen atom;
with the proviso that both, R 1 and R 2 , may not be a hydrogen atom at the same time with the exception if R 3 is an ortho substituted phenyl group, both, R 1 and R 2 , may also be a hydrogen atom;
R 3 is
a C 1 -C 3 -alkyl group which is substituted one or more times with a group independently selected from a C 1 -C 3 -alkyl group, a C 1 -C 3 -alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a C 1 -C 3 -alkyl group,
a C 2 -C 6 -alkenyl group, which is optionally substituted with a C 1 -C 3 -alkoxy group,
a C 5 -C 6 -cycloalkenyl group,
a phenyl group which is substituted one or more times with a group independently selected from halogen atom, C 1 -C 3 -alkyl group, and a C 1 -C 3 -haloalkyl group,
a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a C 1 -C 3 -alkyl group,
a

 group, a

 group, a

 group,
a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a halogen atom, and a C 1 -C 3 -haloalkyl group,
a C 1 -C 6 -alkoxy group which is optionally substituted with a group independently selected from C 1 -C 3 -haloalkyl group, a hydroxy group, a C 1 -C 3 -alkyoxy group, a C 4 -C 6 -cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 5- to 6-membered heteroaryl group, with the proviso that an unsubstituted methoxy group is excluded;
a NR 5 R 6 group, and
a

 group,

R 4 is a hydrogen atom or a C 1 -C 3 -alkyl group;
R 5 is a hydrogen atom
R 6 is selected from
a C 1 -C 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a C 1 -C 3 -alkoxy group, a hydroxy group, a C 1 -C 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a C 1 -C 3 -hydroxyalkyl group,
and
a C 5 -C 6 -cycloalkyl group;

or a stereoisomer, a tautomer, an N-oxide, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.

2. The compound according to claim 1 , wherein:
R 1 is a hydrogen atom, a halogen atom, a C 1 -C 3 -alkyl group, or a C 1 -C 3 -haloalkyl group;
R 2 is a hydrogen atom, or a halogen atom;
with the proviso that both, R 1 and R 2 , may not be a hydrogen atom at the same time
R 3 is
a phenyl group which is substituted one or more times with a group independently selected from halogen atom, C 1 -C 3 -alkyl group, and a C 1 -C 3 -haloalkyl group,
a 4- to 6-membered heterocycloalkyl group which is substituted one or more times with a group independently selected from a fluorine atom, a hydroxy group, and a C 1 -C 3 -alkyl group,
a

 group, a

 group, a

 group,
a 5- to 10-membered heteroaryl group which is substituted one or more times with a group independently selected from an amino group, a chlorine atom, a fluorine atom, a trifluormethyl group, and a difluoromethyl group,
a NR 5 R 6 group, and
a

 group,

R 4 is a hydrogen atom or a C 1 -C 3 -alkyl group;
R 5 is a hydrogen atom
R 6 is selected from
a C 1 -C 3 -alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a C 1 -C 3 -alkoxy group, a hydroxy group, a C 1 -C 3 -haloalkyl group, and a C 4 -C 6 -cycloalkyl group which itself is optionally substituted with a C 1 -C 3 -hydroxyalkyl group,
and
a C 5 -C 6 -cycloalkyl group;

or a stereoisomer, a tautomer, an N-oxide, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.

3. The compound according to claim 1 , wherein:
R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group;
R 2 is a hydrogen atom, a fluorine atom, or a chlorine atom;
with the proviso that both, R 1 and R 2 , may not be a hydrogen atom at the same time;

R 3 is selected from a —(CH 2 )—CH(CH 3 ) 2 group, a —(CH 2 ) 3 —O—CH 3 group, a —CH 2 -(morpholin-4-yl) group, a —CH 2 —N(CH 3 ) 2 group,
a —CH═C(CH 3 ) 2 group, a —CH═CH—CH 2 —O—CH 3 group, a —CH═CH—CH 2 —O—CH 2 —CH 3 group,
a cyclopent-1-en-1-yl group,
a 4-chlorophenyl group, a 4-fluoro-phenyl group, a 4-fluoro-2-methyl-phenyl group, a 3-fluoro-4-methyl-phenyl group, a 4-fluoro-2-trifluoromethyl-phenyl group,
a piperidin1-yl group, a 3-hydroxy-piperidin-1-yl group, a 4,4-difluoro-piperidin-1-yl group,
a 4-ethyl-4-hydroxy-piperidin-1-yl group, a

 group, a

 group, a

 group, a 3-hydroxy-3-methyl-pyrrolidin-1-yl group, a 4-methyl-piperazin-1-yl group, a morpholin-4-yl group,
a pyridin-4-yl group, a 2-amino-pyridin-4-yl group, a 3-chloro-pyridin-6-yl group, a 3-fluoro-pyrazol-1-yl group, a 3-trifluoromethyl-pyrazol-1-yl group, a 1-difluoromethylpyrazol-4-yl group, a 4-trifluoromethyl-1,2,3-triazol-2-yl group,

a —NH—CH 2 -(pyrazol-3-yl) group, a —NH—CH 2 -(pyrazol-5-yl) group, a —NH—CH 2 -pyrazin-2-yl group, a —NH—(CH 2 ) 2 —O—CH 3 group, a —NH—CH 2 —CH(OH)CF 3 group, a

 group, a NH-cyclopentyl group,
a —O—(CH 2 ) 2 —CH 3 group, a —O—(CH 2 ) 2 —C(CH 3 ) 3 group, a —O—(CH 2 )—CH(CH 3 )—OH group, a —O—(CH 2 )—C(CH 3 ) 2 —OH group, a —O—CH 2 -(pyrazol-3-yl) group, a —O—(CH 2 ) 2 —O—CH 3 group, a —O—CH 2 -cyclobutyl group, a —O—CH 2 -tetrahydofuran-2-yl group, a —O—(CH 2 ) 2 —CF 3 group, and a —O—(CH 2 ) 3 CH 3 group,

R 4 is a hydrogen atom or a methyl group;
or a stereoisomer, a tautomer, an N-oxide, or a salt thereof, or a salt of a stereoisomer, a salt of a tautomer, a salt of an N-oxide or a mixture of same.

Assignees

• Bayer Ag
• Broad Inst Inc

Inventors

• Gradl Stefan Nikolaus
• Ellermann Manuel
• Lienau Philip
• Kopitz Charlotte Christine
• Lange Martin
• Tersteegen Adrian
• Sülzle Detlev
• Lewis Timothy A
• Greulich Heidi
• Wu Xiaoyun

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D253/06

  1,2,4-Triazines · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C271/18

  to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms · CPC title