3-amino-2-[2-(acylamino)pyridin-4-yl]-1,5,6,7-tetrahydro-4h-pyrrolo[3,2-c]pyridin-4-one as CSNK1 inhibitors

Patent metadata

Field	Value
Publication number	US-12227501-B2
Application number	US-202017428730-A
Country	US
Kind code	B2
Filing date	Feb 6, 2020
Priority date	Feb 7, 2019
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

Abstract

The present invention relates to compounds of formula (I)processes for their production and their use as pharmaceuticals. The compounds are inhibitors of Casein kinase 1 alpha and/or delta (CSNK1α and/or β) useful for the treatment of proliferative disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R 1 represents hydrogen or a group selected from C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl-, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, and C 1 -C 5 -hydroxyalkyl, wherein said groups are each independently optionally substituted, one or more times, with halogen;
R 2a represents hydrogen, hydroxy, halogen, cyano, —NH 2 , —NHMe, —NMe 2 , C 1 -C 2 -alkoxy, C 1 -C 2 -haloalkyl, or C 1 -C 2 -haloalkoxy;
R 2b represents hydrogen, hydroxy, halogen, cyano, —NH 2 , —NHR 9 , or —NMe 2 ;
R 2c represents hydrogen, halogen, cyano, —NMe 2 , C 1 -C 2 -alkoxy, or C 1 -C 2 -haloalkoxy;
X represents methylene or ethylene,
wherein said methylene and ethylene groups are each independently optionally substituted, one or more times, with R 3 ;

Y represents phenyl or a heteroaryl group,
wherein said phenyl and heteroaryl groups are each independently optionally substituted, one or more times, with R 4 ;

R 3 represents hydroxy, halogen, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkyl, C 1 -C 2 -haloalkoxy, C 3 -C 4 -cycloalkyl, —NHR 6 , R 5 O—C 1 -C 3 -alkyl, R 6 R 7 N—C 1 -C 5 -alkyl, or R 6 R 7 N—X′—C(R 10 )(R 11 )—C 1 -C 2 -alkyl-;
X′ represents methylene or ethylene;
R 4 represents hydroxy, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, —NMe 2 , —CO 2 R 14 , —CONR 15 R 16 , or —SO 2 Me;
R 5 represents hydrogen, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, or C 3 -C 4 -cycloalkyl;
R 6 represents hydrogen, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, or C 3 -C 4 -cycloalkyl and
R 7 represents hydrogen, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, C 3 -C 4 -cycloalkyl, or —CO 2 -C 1 -C 4 -alkyl, or
R 6 and R 7 , together with the nitrogen atom to which they are attached, represent a 4- to 7-membered heterocyclic ring, wherein said heterocyclic ring optionally contains one or more further heteroatoms selected from N, O, S, C(═O), S(═O), and SO 2 , and is independently optionally substituted, one or more times, with halogen, C 1 -C 3 -alkyl, C 3 -cycloalkyl-C 1 -C 2 -alkyl-, —NH 2 , —NHR 9 , —NR 9 R 9a , or hydroxy;
A represents a group selected from:

wherein * indicates the point of attachment of said group to the —NH— of formula (I);

R 8a represents hydrogen, hydroxy, halogen, cyano, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl;
R 8b represents hydrogen, hydroxy, halogen, cyano, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl;
R 8c represents hydrogen, hydroxy, halogen, cyano, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl;
R 8d represents hydrogen, hydroxy, halogen, cyano, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl;
R 8e represents hydrogen, hydroxy, halogen, cyano, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl;
R 8f represents hydrogen, hydroxy, halogen, cyano, C 1 -C 2 -alkyl, or C 1 -C 2 -haloalkyl;
R 8g represents hydrogen or halogen;
R 9 represents C 1 -C 3 -alkyl or cyclopropyl;
R 9a represents C 1 -C 3 -alkyl or cyclopropyl;
R 10 represents methyl, halogen, or hydroxy;
R 11 represents methyl, halogen, or hydroxy;
R 13a represents hydrogen, or a group selected from C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 4 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl-, and C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, wherein said groups are each independently optionally substituted, one or more times, with halogen and
R 13b represents hydrogen, or a group selected from C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl-, and C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl-, wherein said groups are each independently optionally substituted, one or more times, with halogen, or,
R 13a and R 13b , together with the carbon atom to which they are attached, form a C 3 -C 5 -cycloalkyl ring or a 4- to 5-membered heterocyclic ring;
R 14 represents hydrogen, methyl, or ethyl; and
R 15 represents hydrogen, methyl, or ethyl and
R 16 represents hydrogen, methyl, ethyl, methoxyethyl, or dimethylaminoethyl, or
R 15 and R 16 , together with the nitrogen atom to which they are attached, represent a 5- to 6-membered heterocyclic ring, wherein said heterocyclic ring optionally contains one or two further heteroatoms selected from N, O, S, C(═O), S(═O), and SO 2 ;
or an N-oxide, a salt, a tautomer, or a stereoisomer of said compound, or a salt of said N-oxide, tautomer, or stereoisomer.

2. The compound of formula (I) according to claim 1 , wherein:
R 1 represents hydrogen or a group selected from C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl-, and C 1 -C 5 -hydroxyalkyl, wherein said groups are each independently optionally substituted, one or more times with halogen;
R 2a represents hydrogen or halogen;
R 2b represents hydrogen, halogen, —NH 2 , or —NHR 9 ;
R 2 c represents hydrogen or halogen;
X represents methylene, wherein said methylene group is independently optionally substituted, one or more times, with R 3 ;
Y represents phenyl or a pyridyl group,
wherein said phenyl and pyridyl groups are each independently optionally substituted, one or more times, with R 4 ;

R 3 represents hydroxy, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, —NHR 6 , R 5 O—C 1 -C 3 -alkyl, or R 6 R 7 N—C 1 -C 5 -alkyl;
R 4 represents halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, methoxy, —OCF 3 , —NMe 2 , —CO 2 R 14 , —CONR 15 R 16 , or —SO 2 Me;
R 5 represents hydrogen, methyl, or trifluoromethyl;
R 6 represents hydrogen, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, or C 3 -C 4 -cycloalkyl and
R 7 represents hydrogen, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, C 3 -C 4 -cycloalkyl, or —CO 2 -tert-butyl, or
R 6 and R 7 , together with the nitrogen atom to which they are attached, represent a 4- to 7-membered heterocyclic ring, wherein said heterocyclic ring optionally contains one or more further heteroatoms selected from N, O, and S, or a group C(═O), and is independently optionally substituted, one or more times, with halogen, C 1 -C 3 -alkyl, C 3 -cycloalkyl-C 1 -C 2 -alkyl-, —NH 2 , —NHR 9 , or —NR 9 R 9a ;
A represents a group selected from:

wherein * indicates the point of attachment of said group to the —NH— of formula (I);

R 8a represents hydrogen, hydroxy, halogen, or C 1 -C 2 -alkyl;
R 8b represents hydrogen, hydroxy, halogen, or C 1 -C 2 -alkyl;
R 8c represents hydrogen, hydroxy, halogen, or C 1 -C 2 -alkyl;
R 8d represents hydrogen, hydroxy, halogen, or C 1 -C 2 -alkyl;
R 8e represents hydrogen, hydroxy, halogen, or C 1 -C 2 -alkyl;
R 8f represents hydrogen, hydroxy, halogen, or C 1 -C 2 -alkyl;
R 8g represents hydrogen or halogen;
R 9 represents C 1 -C 3 -alkyl or cyclopropyl;
R 9a represents C 1 -C 3 -alkyl or cyclopropyl;
R 13a represents hydrogen or C 1 -C 2 -alkyl, wherein said C 1 -C 2 -alkyl is independently optionally substituted, one or more times, with halogen and
R 13b represents hydrogen or C 1 -C 2 -alkyl, wherein said C 1 -C 2 -alkyl is independently optionally substituted, one or more times, with halogen, or
R 13a and R 13b , together with the carbon atom to which they are attached, form a C 3 -C 5 -cycloalkyl ring;
R 14 represents hydrogen, methyl or ethyl; and
R 15 represents hydrogen or methyl and
R 16 represents methy

Assignees

• Bayer Ag
• Dana Farber Cancer Inst Inc
• Broad Inst Inc

Inventors

• Schulze Volker
• Mengel Anne
• SCHRÖDER Jens
• Faria Alvares De Lemos Adelaide Clara
• Bone Wilhelm
• Bömer Ulf
• Sülzle Detlev
• Christ Clara
• Hillig Roman
• Lechner Christian
• Corsello Steven
• Handing Katarzyna
• Caliman Alisha
• Rauh Ulrike
• Kaulfuss Stefan
• Mortier Jérémie Xavier G

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title