3-amino-1,5,6,7-tetrahydro-4H-indol-4-ones

Patent metadata

Field	Value
Publication number	US-10428044-B2
Application number	US-201515317924-A
Country	US
Kind code	B2
Filing date	Jun 17, 2015
Priority date	Jun 17, 2014
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

Compounds of formula (I) which are inhibitors of Bub1 kinase, processes for their production and their use as pharmaceuticals.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R 1 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, or phenyl,
wherein said phenyl is optionally independently substituted, one or more times, with R 3 , and
wherein said C 3 -C 6 -cycloalkyl is optionally independently substituted, one or more times, with halogen;

R 2 is hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl;
or
R 1 and R 2 are taken together with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl ring;
ring A is a group selected from the group consisting of:

wherein * indicates the point of attachment of said group with the rest of the molecule and said group is optionally independently substituted, one or more times, with R 3 ;

G 1 is O, S, or NR 21 ;
G 2 and G 3 are independently CR 21 or N;
R 3 is hydrogen, halogen, hydroxy, amino, nitro, cyano, C 3 -C 6 -cycloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkyl-C(O)—, R 18 —O—C(O)—, R 7 R 8 N—C(O)—, C 1 -C 4 -alkyl-C(O)—NH—, R 7 R 8 N—, R 7 R 8 N—SO 2 —,
or a group selected from the group consisting of

wherein * indicates the point of attachment of said group with the rest of the molecule, and
wherein said C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl or C 1 -C 4 -haloalkoxy groups are optionally substituted with one or two hydroxy groups;

G 4 is O, S, or NR 21 ;
G 5 and G 6 are independently CR 21 or N;
each R 6 is independently halogen, hydroxy, amino, nitro, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl or C 1 -C 4 -haloalkoxy;
ring B is a group selected from the group consisting of:

wherein * indicates the point of attachment of said group with the rest of the molecule;

X is CR 4 or N;
Y is CR 4 or N,
wherein when one of X and Y is N, the other is CR 4 ;

each R 4 is independently hydrogen, halogen, hydroxy, cyano, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-S—, C 1 -C 4 -alkyl-SO—, C 1 -C 4 -alkyl-SO 2 —, R 9 R 10 N—, R 11 —C(O)—(NR 7 )—, (R 11 —C(O)—)(R 12 —C(O)—)N—, R 9 R 10 N—C(O)—(NR 7 )—, R 9 R 10 N—C(S)-(NR 7 )—, R 18 —O—C(O)—(NR 7 )—, R 9 R 10 N—SO 2 — or C 1 -C 4 -alkyl-SO 2 —NH—,
wherein said C 1 -C 4 -alkyl is optionally independently substituted, one or more times, with a substituent selected from hydroxy and halogen,
wherein said C 1 -C 4 -alkoxy is optionally independently substituted, one or more times, with a substituent selected from hydroxy, halogen, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl and phenyl,
wherein said phenyl is optionally independently substituted, one or more times, with R 3 , and

wherein said C 3 -C 4 -cycloalkyl is optionally independently substituted, one or more times, with halogen;
each R 5 is independently halogen, hydroxy, amino, nitro, cyano, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy or phenyl-C 1 -C 4 -alkyl,
wherein said phenyl group is optionally independently substituted, one or more times, with a substituent selected from halogen, hydroxy, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl and C 1 -C 3 -alkoxy, and
wherein said C 3 -C 6 -cycloalkyl group is optionally independently substituted, one or more times, with halogen;

J is hydrogen or hydroxy;
E is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 2 -C 4 -alkyl, R 17a R 17b R 17c Si—O—C 2 -C 4 -alkyl, C 1 -C 4 -alkyl-SO 2 —C 1 -C 4 -alkyl, R 18 —O—C(O)—C 1 -C 4 -alkyl, R 7 R 8 N—C 2 -C 4 -alkyl, R 7 R 8 N—C(O)—C 1 -C 4 -alkyl or phenyl-C 1 -C 4 -alkyl,
wherein said C 1 -C 4 -alkyl is optionally independently substituted, one or more times, with a substituent selected from hydroxy and halogen, and
wherein said phenyl group is optionally independently substituted, one or more times, with R 5 ;

Q is O or N—OR 16 ;
R 7 and R 8 are independently hydrogen, C 1 -C 1 -alkyl or tert-butyl-O—C(O)—;
R 9 and R 10 are independently hydrogen, C 1 -C 1 -alkyl, C 3 -C 6 -cyclo-alkyl-, C 1 -C 4 -haloalkyl-, phenyl or heteroaryl,
wherein said phenyl or heteroaryl group is optionally independently substituted, one or more times, with R 5 , and
wherein said C 1 -C 4 -alkyl is optionally independently substituted, one or more times, with a substituent selected from the group consisting of hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-S—, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, heteroaryl and R 18 —O—C(O)—,
wherein said C 3 -C 6 -cycloalkyl or 4- to 6-membered heterocycloalkyl is optionally independently substituted, one or more times, with a substituent selected from the group consisting of halogen, C 1 -C 4 -alkyl and tert-butyl-O—C(O)—, and
wherein said phenyl or heteroaryl group is optionally independently substituted, one or more times, with R 5 ;

or
R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from the group consisting of O, NH and S, and which is optionally independently substituted, one or more times, with R 5 ;
R 11 and R 12 are independently C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, heteroaryl, or R 13 —(C 1 -C 4 -alkyl)-O—CH 2 —,
wherein said C 1 -C 4 -alkyl is optionally independently substituted, one or more times, with a substituent selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 4 -alkoxy, R 7 R 8 N—, R 14 , R 15 , —O—, and phenyl optionally independently substituted, one or more times, with R 5 ,
wherein said C 3 -C 6 -cycloalkyl is optionally independently substituted, one or more times, with a substituent selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and phenyl optionally independently substituted, one or more times, with R 5 ,
wherein said 4- to 6-membered heterocycloalkyl is optionally independently substituted, one or more times, with a substituent selected from the group consisting of hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, R 7 R 8 N— and R 18 —O—C(O)—, and
wherein said phenyl or heteroaryl is optionally independently substituted, one or more times, with R 5 ;

R 13 is branched C 3 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl,
wherein said phenyl or heteroaryl is optionally independently substituted, one or more times, with R 5 ;

R 14 is C 1 -C 4 -alkyl-S—, C 1 -C 4 -alkyl-SO 2 —, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl,
wherein said phenyl or heteroaryl is optionally independently substituted, one or more times, with R 5 ;

R 15 is phenyl or heteroaryl,
wherein said phenyl or heteroaryl is optionally independently substituted, one or more times, with R 5 ;

R 16 is hydrogen, C 1 -C 6 -alkyl, phenyl or C 1 -C 4 -alkyl-C(O)—,
wherein said phenyl group is optionally independently substituted, one or more times, with R 5 ;

Assignees

• Bayer Pharma AG

Inventors

• Graham Keith
• Klar Ulrich
• Briem Hans
• Hitchcock Marion
• Bärfacker Lars
• Eis Knut
• Schulze Volker
• Siemeister Gerhard
• Bone Wilhelm
• SCHRÖDER Jens
• Holton Simon
• Lienau Philip
• Tempel René
• Sonnenschein Helmut
• Bálint Jozsef
• Graubaum Heinz

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title