Amino-substituted isothiazoles

Patent metadata

Field	Value
Publication number	US-9682995-B2
Application number	US-201414764853-A
Country	US
Kind code	B2
Filing date	Jan 28, 2014
Priority date	Jan 30, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present invention relates to isothiazoles of general formula (I) which inhibit the mitotic checkpoint: in which A, R1 and R2 are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of formula (I)

in which:
A represents a heteroaryl group selected from:

wherein one of X 1 , X 2 and X 3 represents an N, O or S as ring atom and the others of X 1 , X 2 and X 3 represent carbon as ring atoms, and
wherein X 4 , X 5 , X 6 and X 7 represent carbon as ring atoms or one of X 4 , X 5 , X 6 and X 7 represent an N atom, and the others of X 4 , X 5 , X 6 and X 7 represent carbon as ring atoms, and
wherein X 1 and X 2 or X 2 and X 3 or X 4 and X 5 or X 5 and X 6 or X 6 and X 7 optionally form part of an additional 5-membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of O, N and S, and which ring is unsaturated or partially saturated, and
wherein * indicates the point of attachment of said groups with the rest of the molecule,
said heteroaryl group, which is monocyclic or bicyclic, being optionally substituted, one or two times, identically or differently, with a substituent selected from:
C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, hydroxy, a halogen atom, cyano, phenyl, 5-membered heteroaryl, COORS, CONR 4 R 5 , NR 4 R 5 ,
said phenyl and 5-membered heteroaryl being optionally substituted, one or two times, identically or differently, with a substituent selected from:
a halogen atom, or a C 1 -C 3 -alkyl-, or a C 1 -C 3 -alkoxy-group,

R 1 represents a C 1 -C 3 -alkyl-group,
R 2 represents a group selected from:
phenyl or pyridinyl,
said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from:
C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, hydroxy, a halogen atom, phenyl, phenyloxy,
said phenyl and phenyloxy group being optionally substituted, one or two times, identically or differently, with a substituent selected from:
a halogen atom, or a C 1 -C 3 -alkyl-, or a C 1 -C 3 -alkoxy-group,

R 3 represents:
a hydrogen atom, or a group selected from C 1 -C 6 -alkyl,

R 4 represents:
a hydrogen atom, or a group selected from C 1 -C 6 -alkyl,

R 5 represents:
a hydrogen atom, or a group selected from C 1 -C 6 -alkyl, or,

R 4 and R 5 together with the nitrogen to which they are attached represent:
a 5- to 6-membered heterocycloalkyl which optionally contains one further heteroatom selected from the group consisting of O, N and S,

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound according to claim 1 , wherein:
A represents a heteroaryl group selected from:

wherein one of X 1 , X 2 and X 3 represents an N, O or S as ring atom and the others of X 1 , X 2 and X 3 represent carbon as ring atoms, and
wherein X 4 , X 5 , X 6 and X 7 represent carbon as ring atoms or one of X 4 , X 5 , X 6 and X 7 represent an N atom, and the others of X 4 , X 5 , X 6 and X 7 represent carbon as ring atoms, and
wherein X 1 and X 2 or X 2 and X 3 or X 4 and X 5 or X 5 and X 6 or X 6 and X 7 optionally form part of an additional 5-membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of O, N and S, and which ring is unsaturated or partially saturated, and
wherein * indicates the point of attachment of said groups with the rest of the molecule,
said heteroaryl group, which is monocyclic or bicyclic, being optionally substituted, one or two times, identically or differently, with a substituent selected from:
C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, hydroxy, a halogen atom, cyano, phenyl, 5-membered heteroaryl, COORS, CONR 4 R 5 , NR 4 R 5 ,
said phenyl and 5-membered heteroaryl being optionally substituted, one or two times, identically or differently, with a substituent selected from:
a halogen atom, or a C 1 -C 3 -alkyl-, or a C 1 -C 3 -alkoxy-group,

R 1 represents a methyl group,
R 2 represents a group selected from:
phenyl or pyridinyl,
said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from:
C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, hydroxy, a halogen atom, phenyl, phenyloxy,
said phenyl and phenyloxy group being optionally substituted, one or two times, identically or differently, with a substituent selected from:
a halogen atom, or a C 1 -C 3 -alkyl-, or a C 1 -C 3 -alkoxy-group,

R 3 represents:
a hydrogen atom, or a group selected from C 1 -C 6 -alkyl,

R 4 represents:
a hydrogen atom, or a group selected from C 1 -C 6 -alkyl,

R 5 represents:
a hydrogen atom, or a group selected from C 1 -C 6 -alkyl, or,

R 4 and R 5 together with the nitrogen to which they are attached represent:
a 5- to 6-membered heterocycloalkyl which optionally contains one further heteroatom selected from the group consisting of O, N and S,

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. The compound according to claim 1 , wherein:
A represents a heteroaryl group selected from:

wherein one of X 1 , X 2 and X 3 represents an N, O or S as ring atom and the others of X 1 , X 2 and X 3 represent carbon as ring atoms, and
wherein X 4 , X 5 , X 6 and X 7 represent carbon as ring atoms or one of X 4 , X 5 , X 6 and X 7 represent an N atom, and the others of X 4 , X 5 , X 6 and X 7 represent carbon as ring atoms, and
wherein X 1 and X 2 or X 2 and X 3 or X 4 and X 5 or X 5 and X 6 or X 6 and X 7 optionally form part of an additional 5-membered or 6-membered ring, which optionally contains one further heteroatom selected from the group consisting of O, N and S, and which ring is unsaturated or partially saturated, and
wherein * indicates the point of attachment of said groups with the rest of the molecule,
said heteroaryl group, which is monocyclic or bicyclic, being optionally substituted, one or two times, identically or differently, with a substituent selected from:
C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, hydroxy, a halogen atom, cyano, phenyl, 5-membered heteroaryl, COORS, CONR 4 R 5 , NR 4 R 5 ,
said phenyl and 5-membered heteroaryl being optionally substituted, one or two times, identically or differently, with a substituent selected from:
a halogen atom, or a C 1 -C 3 -alkyl-, or a C 1 -C 3 -alkoxy-group,

R 1 represents a methyl group,
R 2 represents a group selected from:
phenyl or pyridinyl,
said phenyl and pyridinyl being optionally substituted, one or two times, identically or differently, with a substituent selected from:

C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyloxy, a halogen atom, phenyloxy,
said phenyloxy group being optionally substituted, one or two times, identically or differently, with a substituent selected from:
a halogen atom, o

Assignees

• Bayer Pharma AG

Inventors

• Bärfacker Lars
• Prechtl Stefan
• Siemeister Gerhard
• Wengner Antje Margret
• Ackerstaff Jens
• Nowak-Reppel Katrin
• Bader Benjamin
• Lienau Philip
• Stöckigt Detlef
• Heinrich Tobias

Classifications

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title