Pyrazolopyrazines acting on cancers via inhibition of cdk12

Patent metadata

Field	Value
Publication number	US-2023192700-A1
Application number	US-202117909636-A
Country	US
Kind code	A1
Filing date	Mar 5, 2021
Priority date	Mar 6, 2020
Publication date	Jun 22, 2023
Grant date	—

Abstract

The present invention provides compounds of general formula (I) in which X, R1, R2 and R3 are as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative disorders such as cancer disorders, as a sole agent or in combination with other active ingredients.

First claim

1 . A compound of formula (I):

wherein
R 1 is selected from a halogen atom, a C 1 -C 6 -alkyl group, a C 1 -C 6 -haloalkyl group, a C 3 -C 8 -cycloalkyl group, a (C 3 -C 8 -cycloalkyl)-(C 1 -C 6 -alkyl)- group, a cyano group, a phenyl group, a heterocycloalkyl group and a heteroaryl group,
wherein said C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, heterocycloalkyl or heteroaryl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -haloalkoxy group, a C 3 -C 8 -cycloalkyl group, a C 3 -C 8 -cycloalkoxy group and a R 5 R 6 N— group;

R 2 is selected from a C 1 -C 6 -alkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -hydroxyalkyl group, a (C 1 -C 3 -alkoxy)-(C 1 -C 5 -alkyl)- group, a C 3 -C 8 -cycloalkyl group, a (C 3 -C 8 -cycloalkyl)-(C 1 -C 2 -alkyl)- group, a (R 5 R 6 N—)—(C 1 -C 5 -alkyl)- group, a phenyl group, a heteroaryl group,a heterocycloalkyl group, a 7- to 9-membered bridged compound and a 7- to 11-membered spiro compound,
wherein said heterocycloalkyl group, 7- to 9-membered bridged compound or 7- to 11-membered spiro compound is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said 7- to 9-membered bridged compound or 7- to 11-membered spiro compound each optionally contains one heteroatom independently selected from nitrogen and oxygen,
wherein said C 3 -C 8 -cycloalkyl group, phenyl group, heteroaryl group or heterocycloalkyl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a hydroxy group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -hydroxyalkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkoxy group, a R 7 OOC— group and a R 5 R 6 N— group;

X is selected from a nitrogen atom and a CR 4 group;
R 3 is selected from a C 3 -C 8 -cycloalkyl group, a heterocycloalkyl group, a phenyl group and a heteroaryl group,
wherein said heterocycloalkyl, phenyl or heteroaryl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a hydroxy group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -hydroxyalkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkoxy group, a C 3 -C 8 -cycloalkyl group, a R 5 R 6 N— group, and a R 7 OOC— group;

R 4 is selected from a hydrogen atom, a C 1 -C 3 -alkyl group and a C 1 -C 3 -haloalkyl group;
or, where X is a CR 4 group, R 3 and R 4 , together with the carbon atoms to which they are attached form a 5- to 7-membered cycloalkenyl, heterocycloalkenyl, phenyl or heteroaryl group,
wherein said heterocycloalkenyl or heteroaryl group contains one or two heteroatoms independently selected from nitrogen, oxygen and sulfur,
and wherein said cycloalkenyl, heterocycloalkenyl, phenyl or heteroaryl group is each optionally substituted one, two or three times, each substituent independently selected from a halogen atom, a cyano group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -hydroxyalkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkoxy group, a C 3 -C 5 -cycloalkyl group, a C 3 -C 5 -cycloalkoxy group, a R 5 R 6 N— group, a (R 5 R 6 N)—(C 1 -C 6 -alkyl)- group, and a R 7 OOC— group;

R 5 and R 6 are each independently selected from a hydrogen atom, a C 1 -C 6 -alkyl group, a C 3 -C 8 -cycloalkyl group, a C 1 -C 6 -haloalkyl group, a (C 3 -C 8 -cycloalkyl)-(C 1 -C 6 -alkyl)- group, a C 1 -C 6 -hydroxyalkyl group, a (C 1 -C 6 -alkoxy)-(C 1 -C 6 -alkyl)- group, a formyl (HCO—) group, an acetyl (H 3 CCO—) group, a heterocycloalkyl group, a heteroaryl group and a phenyl group;
R 7 is selected from a hydrogen atom and a C 1 -C 4 -alkyl group;
or a tautomer, or an N-oxide, or a salt thereof, or a salt of a tautomer, or a salt of an N-oxide, or a mixture of same.

2 . The compound of formula (I) according to claim 1 , wherein
R 1 is selected from a halogen atom, a C 1 -C 6 -alkyl group, a C 1 -C 6 -haloalkyl group, a C 3 -C 8 -cycloalkyl group, a (C 3 -C 8 -cycloalkyl)-(C 1 -C 6 -alkyl)- group, a cyano group, a phenyl group, a heterocycloalkyl group and a heteroaryl group,
wherein said C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, heterocycloalkyl or heteroaryl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -haloalkoxy group, a C 3 -C 8 -cycloalkyl group, a C 3 -C 8 -cycloalkoxy group and a R 5 R 6 N— group;
R 2 is selected from a C 1 -C 6 -alkyl group, a C 1 -C 6 -haloalkyl group, a C 3 -C 8 -cycloalkyl group, a phenyl group, a heteroaryl group and a heterocycloalkyl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said C 3 -C 8 -cycloalkyl group, phenyl group, heteroaryl group or heterocycloalkyl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a hydroxy group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -hydroxyalkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkoxy group, a R 7 OOC— group and a R 5 R 6 N— group;
X is selected from a nitrogen atom and a CR 4 group; R 3 is selected from a C 3 -C 8 -cycloalkyl group, a heterocycloalkyl group, a phenyl group and a heteroaryl group,
wherein said heterocycloalkyl, phenyl or heteroaryl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a hydroxy group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -hydroxyalkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkoxy group, a C 3 -C 8 -cycloalkyl group, a R 5 R 6 N— group, and a R 7 OOC— group;
R 4 is selected from a hydrogen atom, a C 1 -C 3 -alkyl group and a C 1 -C 3 -haloalkyl group; or, where X is a CR 4 group, R 3 and R 4 , together with the carbon atoms to which they are attached form a 5- to 7-membered cycloalkenyl, heterocycloalkenyl, phenyl or heteroaryl group,
wherein said heterocycloalkenyl or heteroaryl group contains one or two heteroatoms independently selected from nitrogen, oxygen and sulfur,
and wherein said cycloalkenyl, heterocycloalkenyl, phenyl or heteroaryl group is each optionally substituted one, two or three times, each substituent independently selected from a halogen atom, a cyano group, a C 1 -C 6 -alkyl group, a C 1 -C 6 -hydroxyalkyl group, a C 1 -C 6 -haloalkyl group, a C 1 -C 6 -alkoxy group, a C 1 -C 6 -haloalkoxy group, a C 3 -C 5 -cycloalkyl group, a C 3 -C 5 -cycloalkoxy group, a R 5 R 6 N— group, a (R 5 R 6 N)—(C 1 -C 6 -alkyl)- group, and a R 7 OOC— group;
R 5 and R 6 are each independently selected from a hydrogen atom, a C 1 -C 6 -alkyl group, a C 3 -C 8 -cycloalkyl group, a C 1 -C 6 -haloalkyl group, a (C 3 -C 8 -cycloalkyl)-(C 1 -C 6 -alkyl)- group, a C 1 -C 6 -hydroxyalkyl group, a (C 1 -C 6 -alkoxy)-(C 1 -C 6 -alkyl)- group, a formyl (HCO—) group, an acetyl (H 3 CCO—) group, a heterocycloalkyl group, a heteroaryl group and a phenyl group; R 7 is selected from a hydrogen atom and a C 1 -C 3 -alkyl group; or a tautomer, or an N-oxide, or a salt thereof, or a salt of a tautomer, or a salt of an N-oxide, or a mixture of same.

3 . The compound of formula (I) according to claim 1 , wherein
R 1 is selected from a halogen atom, a C 1 -C 3 -alkyl group, a C 1 -C 3 -haloalkyl group, a C 3 -C 6 -cycloal

Assignees

• Bayer Ag
• Deutsches Krebsforsch

Inventors

• Berger Markus
• Buchmann Bernd
• Thede Kai
• Buchgraber Philipp
• Siemeister Gerhard
• Steigemann Patrick
• Wengner Antje Margret
• Bömer Ulf
• Barak Naomi
• Lienau Philip

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D493/10

  Spiro-condensed systems · CPC title