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

Patent metadata

Field	Value
Publication number	US-10227299-B2
Application number	US-201615737182-A
Country	US
Kind code	B2
Filing date	Jun 14, 2016
Priority date	Jun 17, 2015
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

Compounds of formula (I) as described herein processes for their production and their use as anti-cancer agents.

First claim

The invention claimed is:

1. A compound of formula (I),

wherein:
R 1 is hydrogen or C 1 -C 6 -alkyl;
R 2 is hydroxy, C 2 -C 4 -alkenyl, R 7 R 8 N—, R 10 —O—C(O)—, R 7 R 8 N—C(O)—, R 6 —C(O)—NR 9 —, or R 11 —(C 1 -C 4 -alkyl)-,
wherein said C 2 -C 4 -alkenyl is optionally substituted with halogen, R 10 —O—C(O)—, R 7 R 8 N- or phenyl, wherein said phenyl group is optionally substituted, one or more times with R 4 ;

R 3 is hydrogen or C 1 -C 6 -alkyl;
A is a group selected from:

wherein * indicates the point of attachment of said group with the rest of the molecule and said group is optionally substituted, one or more times with R 4 ;

each R 4 is independently halogen, hydroxy, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -alkyl-C(O)—, R 10 —O—C(O)—, R 7 R 8 N—C(O)—, C 1 -C 4 -alkyl-C(O)—NH—, R 7 R 8 N—, or R 7 R 8 N—SO 2 —;
E is a group

wherein * indicates the point of attachment of said group with the rest of the molecule;
each R 5 is independently halogen, hydroxy, nitro, cyano, R 9 R 10 N—, (R 13 —C(O)—)(R 14 —C(O)—)N—, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 6 -haloalkoxy, R 6 —C(O)—NR 9 — or R 7 R 8 N—C(O)—NR 9 —,
wherein said C 1 -C 4 -alkoxy is optionally substituted, one or more times, independently from each other, with a substituent selected from hydroxy, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, and 4- to 6-membered heterocycloalkyl;

Q is O or N—OH;
each R 6 is independently C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl,
wherein said C 1 -C 6 -alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, nitro, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -cycloalkyl, R 7 R 8 N- or phenyl optionally substituted, one or more times with R 4 ,
wherein said C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, nitro, cyano, C 1 -C 6 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, R 10 —O—C(O)— or C 1 -C 4 -haloalkoxy;

R 7 and R 8 are independently hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, R 10 —O—C(O)— or phenyl,
wherein said C 1 -C 6 -alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -cycloalkyl optionally substituted one time with hydroxy, 4- to 6-membered heterocycloalkyl, heteroaryl, or R 9 R 10 N—,
wherein said phenyl group is optionally substituted, one or more times with R 4 ;
or,

R 7 and R 8 together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom selected from O, NR 9 and S, and which may be optionally substituted, one or more times with R 12 ;
wherein two R 12 substituents attached to the same ring carbon atom are optionally taken together with the carbon atom to which they are attached to form a cyclobutane, azetidine, or oxetane group;
said azetidine being optionally substituted one time with C 1 -C 3 -alkyl;

or,
R 7 and R 8 together with the nitrogen atom to which they are attached form a group selected from:

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

R 9 is hydrogen or C 1 -C 6 -alkyl;
R 10 is hydrogen, C 1 -C 6 -alkyl or C 3 -C 6 -cycloalkyl;
R 11 is hydroxy, nitro, cyano, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, C 1 -C 4 -alkyl-C(O)—, R 10 —O—C(O)—, R 7 R 8 N—C(O)—, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, R 7 R 8 N—, N 3 —, R 6 —C(O)—NR 9 —, R 6 —O—C(O)—NR 9 —, R 7 R 8 N—C(O)—NR 9 —, R 6 —SO 2 —NR 9 —, R 6 —S—, R 6 —SO—, R 6 —SO 2 —, or R 7 R 8 N—SO 2 —,
wherein said C 3 -C 6 -cycloalkyl or 4- to 6-membered heterocycloalkyl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl or C 1 -C 4 -haloalkoxy,
wherein said C 1 -C 4 -alkoxy is optionally substituted with phenyl,
wherein said phenyl group is optionally substituted, one or more times with R 4 ;

each R 12 is independently halogen, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, or R 9 R 10 N—;
R 13 and R 14 are independently C 1 -C 4 -alkyl, or C 3 -C 6 -cycloalkyl,
wherein said C 3 -C 6 -cycloalkyl is optionally substituted, one or more times, independently from each other, with halogen; and

m is 0, 1 or 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 is hydrogen or C 1 -C 4 -alkyl;
R 2 is hydroxy, C 2 -C 4 -alkenyl, R 7 R 8 N—, R 7 R 8 N—C(O)—, R 6 —C(O)—NR 9 —, or R 11 —(C 1 -C 4 -alkyl)-;
wherein said C 2 -C 4 -alkenyl is optionally substituted with halogen, R 10 —O—C(O)—, R 7 R 8 N— or phenyl, wherein said phenyl group is optionally substituted, one or more times with R 4 ;

R 3 is hydrogen or C 1 -C 4 -alkyl;
A is a group selected from:

wherein * indicates the point of attachment of said group with the rest of the molecule and said group is optionally substituted, one or more times with R 4 ;

each R 4 is independently halogen, hydroxy, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, or C 1 -C 4 -haloalkoxy;
E is a group

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

each R 5 is independently halogen, hydroxy, cyano, R 9 R 10 N—, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, R 6 —C(O)—NR 9 — or R 7 R 8 N—C(O)—NR 9 —,
wherein said C 1 -C 4 -alkoxy is optionally substituted, one or more times, independently from each other, with a substituent selected from hydroxy, C 1 -C 4 -alkoxy, and C 3 -C 6 -cycloalkyl;

Q is O or N—OH;
each R 6 is independently C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl,
wherein said C 1 -C 6 -alkyl is optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -cycloalkyl, R 7 R 8 N- or phenyl optionally substituted, one or more times with R 4 ,
wherein said C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently from each other, with halogen, hydroxy, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, R 10 —O—C(O)— or C 1 -C 4 -haloalkoxy;

R 7 and R 8 are independently hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, R 10 —O—C(O)— or phenyl,
wherein said C 1 -C 6 -alkyl is optionally substituted, one

Assignees

• Bayer Pharma AG

Inventors

• Graham Keith
• Klar Ulrich
• Briem Hans
• Siemeister Gerhard
• Mönning Ursula
• Balint Jozsef

Classifications

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• A61K31/403

  condensed with carbocyclic rings, e.g. carbazole · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07C327/46

  having carbon atoms of thiocarboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title