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

A method of preparing a compound of general formula (I)

• wherein
• R1 is a hydrogen atom, a halogen atom, a C1-C3-alkyl group, or a C1-C3-haloalkyl group;
• R2 is a hydrogen atom, or a halogen atom;
• with the proviso that both, R1 and R2, may not be a hydrogen atom at the same time with the exception if R3 is an ortho substituted phenyl group, both, R1 and R2, may also be a hydrogen atom;
• R3 is
• a C1-C3-alkyl group which is substituted one or more times with a group independently selected from a C1-C3-alkyl group, a C1-C3-alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a C1-C3-alkyl group,
• a C2-C6-alkenyl group, which is optionally substituted with a C1-C3-alkoxy group,
• a C5-C6-cycloalkenyl group,
• a phenyl group which is substituted one or more times with a group independently selected from halogen atom, C1-C3-alkyl group, and a C1-C3-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 C1-C3-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 C1-C3-haloalkyl group,
• a C1-C6-alkoxy group which is optionally substituted with a group independently selected from C1-C3-haloalkyl group, a hydroxy group, a C1-C3-alkyoxy group, a C4-C6-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 NR5R6 group, and
• a
• group,
• R4 is a hydrogen atom or a C1-C3-alkyl group;
• R5 is a hydrogen atom
• R6 is selected from
• a C1-C3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a C1-C3-alkoxy group, a hydroxy group, a C1-C3-haloalkyl group, and a C4-C6-cycloalkyl group which itself is optionally substituted with a C1-C3-hydroxyalkyl group,
• and
• a C5-C6-cycloalkyl group;
• or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, 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,
• said method comprising the step of allowing an intermediate compound of general formula (IV):
• in which R1, R2 and R3 are as defined for the compound of general formula (I) where functional groups contained in R3 optionally are suitably protected, and Pg means a protecting group for an amine group,
• to react in
• step 1):
• with H2NNHCOOCH3, under acidic conditions in an alcoholic solution, and in
• step 2):
• with trifluoroacetic acid (TFA) in dichloromethane (DCM), at 0° C.-20° C.;
• and in
• step 3):
• under basic conditions at room temperature, particularly with NaOEt/EtOH or NaOMe/MeOH, at 20° C.;
• optionally deprotecting any still protected functional groups,
• thereby giving a compound of general formula (I).

A method for the treatment or prophylaxis of a disease in a subject in need thereof, comprising administering the compound according to general formula (I) to the subject:

• wherein
• R1 is a hydrogen atom, a halogen atom, a C1-C3-alkyl group, or a C1-C3-haloalkyl group;
• R2 is a hydrogen atom, or a halogen atom;
• with the proviso that both, R1 and R2, may not be a hydrogen atom at the same time with the exception if R3 is an ortho substituted phenyl group, both, R1 and R2, may also be a hydrogen atom;
• R3 is
• a C1-C3-alkyl group which is substituted one or more times with a group independently selected from a C1-C3-alkyl group, a C1-C3-alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a C1-C3-alkyl group,
• a C2-C6-alkenyl group, which is optionally substituted with a C1-C3-alkoxy group,
• a C5-C6-cycloalkenyl group,
• a phenyl group which is substituted one or more times with a group independently selected from halogen atom, C1-C3-alkyl group, and a C1-C3-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 C1-C3-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 C1-C3-haloalkyl group,
• a C1-C6-alkoxy group which is optionally substituted with a group independently selected from C1-C3-haloalkyl group, a hydroxy group, a C1-C3-alkyoxy group, a C4-C6-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 NR5R6 group, and
• a
• group,
• R4 is a hydrogen atom or a C1-C3-alkyl group;
• R5 is a hydrogen atom
• R6 is selected from
• a C1-C3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a C1-C3-alkoxy group, a hydroxy group, a C1-C3-haloalkyl group, and a C4-C6-cycloalkyl group which itself is optionally substituted with a C1-C3-hydroxyalkyl group,
• and
• a C5-C6-cycloalkyl group;
• or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, 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.

A method of treating a hyperproliferative disease comprising administering an effective amount of at least one compound of general formula (I)

• wherein
• R1 is a hydrogen atom, a halogen atom, a C1-C3-alkyl group, or a C1-C3-haloalkyl group;
• R2 is a hydrogen atom, or a halogen atom;
• with the proviso that both, R1 and R2, may not be a hydrogen atom at the same time with the exception if R3 is an ortho substituted phenyl group, both, R1 and R2, may also be a hydrogen atom;
• R3 is
• a C1-C3-alkyl group which is substituted one or more times with a group independently selected from a C1-C3-alkyl group, a C1-C3-alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a C1-C3-alkyl group,
• a C2-C6-alkenyl group, which is optionally substituted with a C1-C3-alkoxy group,
• a C5-C6-cycloalkenyl group,
• a phenyl group which is substituted one or more times with a group independently selected from halogen atom, C1-C3-alkyl group, and a C1-C3-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 C1-C3-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 C1-C3-haloalkyl group,
• a C1-C6-alkoxy group which is optionally substituted with a group independently selected from C1-C3-haloalkyl group, a hydroxy group, a C1-C3-alkyoxy group, a C4-C6-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 NR5R6 group, and
• a
• group,
• R4 is a hydrogen atom or a C1-C3-alkyl group;
• R5 is a hydrogen atom
• R6 is selected from
• a C1-C3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a C1-C3-alkoxy group, a hydroxy group, a C1-C3-haloalkyl group, and a C4-C6-cycloalkyl group which itself is optionally substituted with a C1-C3-hydroxyalkyl group,
• and
• a C5-C6-cycloalkyl group:
• or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, 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.

A compound of general formula (IV):

• R1 is a hydrogen atom, a halogen atom, a C1-C3-alkyl group, or a C1-C3-haloalkyl group;
• R2 is a hydrogen atom, or a halogen atom;
• with the proviso that both, R1 and R2, may not be a hydrogen atom at the same time with the exception if R3 is an ortho substituted phenyl group, both, R1 and R2, may also be a hydrogen atom;
• R3 is
• a C1-C3-alkyl group which is substituted one or more times with a group independently selected from a C1-C3-alkyl group, a C1-C3-alkoxy group, a heterocycloalkyl group, and an amino group which is substituted once or twice with a C1-C3-alkyl group,
• a C2-C6-alkenyl group, which is optionally substituted with a C1-C3-alkoxy group,
• a C5-C6-cycloalkenyl group,
• a phenyl group which is substituted one or more times with a group independently selected from halogen atom, C1-C3-alkyl group, and a C1-C3-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 C1-C3-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 C1-C3-haloalkyl group,
• a C1-C6-alkoxy group which is optionally substituted with a group independently selected from C1-C3-haloalkyl group, a hydroxy group, a C1-C3-alkyoxy group, a C4-C6-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 NR5R6 group, and
• a
• group,
• R5 is a hydrogen atom
• R6 is selected from
• a C1-C3-alkyl group which is substituted one or more times with a group selected from a 5- to 6-membered heteroaryl group, a C1-C3-alkoxy group, a hydroxy group, a C1-C3-haloalkyl group, and a C4-C6-cycloalkyl group which itself is optionally substituted with a C1-C3-hydroxyalkyl group,
• and
• a C5-C6-cycloalkyl group;
• and
• Pg means a protecting group for an amine group.