Substituted phenylimidazopyrazoles and their use

Patent metadata

Field	Value
Publication number	US-9394309-B2
Application number	US-201313748043-A
Country	US
Kind code	B2
Filing date	Jan 23, 2013
Priority date	Jan 25, 2012
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

The present application relates to novel 1-phenyl-1H-imidazo[1,2-b]pyrazole derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular angiogenic disorders and hyperproliferative disorders, where neovascularization plays a role, such as, for example, neoplastic disorders and tumor disorders. Such treatments can be carried out as monotherapy or else in combination with other medicaments or further therapeutic measures.

First claim

The invention claimed is:

1. Compound of the formula (I)

in which
Ar N represents 5- or 6-membered azaheteroaryl selected from the group consisting of

in which * marks the attachment to the imidazopyrazole grouping
and
Y represents O, S or NH,

R 1 represents hydrogen or fluorine,
R 2 represents hydrogen or (C 1 -C 4 )-alkyl,
R 3 represents hydrogen,
R 4A and R 4B independently of one another represent hydrogen, fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethyl, hydroxy, methoxy or trifluoromethoxy,
R 5 represents hydrogen, fluorine, chlorine or methyl,
R 6 represents hydrogen, fluorine, methyl or hydroxy,
Z 1 represents C—R 7A or N,
Z 2 represents C—R 7B or N,
Z 3 represents C—R 8 or N,
Z 4 represents C—R 9 or N
and
Z 5 represents C—R 10 or N,
where in total at most one of the ring members Z 1 , Z 2 , Z 3 , Z 4 and Z 5 represents N
and in which
R 7A and R 7B independently of one another represent hydrogen, fluorine, chlorine, methyl, hydroxy or methoxy,
R 8 represents hydrogen, fluorine, chlorine or methyl,
R 9 represents hydrogen, pentafluorosulphanyl, (trifluoromethyl)sulphanyl, trimethylsilyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 3 -C 6 )-cycloalkyl, oxetanyl or tetrahydropyranyl,
where (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy may be substituted up to six times by fluorine
and
(C 3 -C 6 )-cycloalkyl, oxetanyl and tetrahydropyranyl may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, methyl, trifluoromethyl and hydroxy,

and
R 10 represents hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, hydroxy, (C 1 -C 6 )-alkoxy, (C 1 -C 4 )-alkylsulphonyl, (C 3 -C 6 )-cycloalkyl, phenyl, 5- or 6-membered heteroaryl or a group of the formula -L 1 -C(═O)—OR 11 , -L 1 -NR 12A R 12B , -L 1 -C(═O)—NR 13A R 13B , -L 2 -S(═O) 2 —NR 13A R 13B or -L 3 -R 14 ,
where (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy may be substituted by a radical selected from the group consisting of hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, amino, methylamino and dimethylamino or up to six times by fluorine
and
(C 3 -C 6 )-cycloalkyl may be substituted up to two times by identical or different radicals selected from the group consisting of methyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino
and
phenyl and 5- or 6-membered heteroaryl may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl and trifluoromethyl,
and in which
L 1 represents a bond or —CH 2 —,
L 2 represents a bond or —CH 2 —,
L 3 represents a bond or —O—,
R 11 represents hydrogen or (C 1 -C 4 )-alkyl,
R 12A , R 12B , R 13A and R 13B independently of one another represent hydrogen or (C 1 -C 4 )-alkyl,
where (C 1 -C 4 )-alkyl may in each case be substituted by a radical selected from the group consisting of hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino,

or
R 12A and R 12B and R 13A and R 13B , respectively, are attached to one another and together with the nitrogen atom to which they are respectively attached form a 4- to 6-membered heterocycle which may contain a further ring heteroatom from the group consisting of N, O and S and which may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, cyano, (C 1 -C 4 )-alkyl, hydroxy, (C 1 -C 4 )-alkoxy and oxo,
and
R 14 represents a 4- to 6-membered heterocycle which is attached via a ring carbon atom and contains a ring heteroatom from the group consisting of N, O and S and which may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, cyano, (C 1 -C 4 )-alkyl, hydroxy, (C 1 -C 4 )-alkoxy and oxo,

where R 10 does not represent hydrogen, fluorine, chlorine or bromine if Z 4 represents CH or N, and Z 5 does not represent N if Z 4 represents CH,

and its salts, solvates and solvates of the salts.

2. Compound of the formula (I) according to claim 1 in which
Ar N represents 5- or 6-membered azaheteroaryl selected from the group consisting of

in which * marks the attachment to the imidazopyrazole grouping
and
Y represents S or NH,

R 1 represents hydrogen or fluorine,
R 2 represents hydrogen or (C 1 -C 4 )-alkyl,
R 3 represents hydrogen,
R 4A and R 4B independently of one another represent hydrogen, fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl or methoxy,
R 5 represents hydrogen, fluorine, chlorine or methyl,
R 6 represents hydrogen, fluorine, methyl or hydroxy,
Z 1 represents C—R 7A or N,
Z 2 represents C—R 7B or N,
Z 3 represents C—R 8 or N,
Z 4 represents C—R 9
and
Z 5 represents C—R 10 or N,
where in total at most one of the ring members Z 1 , Z 2 , Z 3 , Z 4 and Z 5 represents N
and in which
R 7A and R 7B independently of one another represent hydrogen or fluorine,
R 8 represents hydrogen or fluorine,
R 9 represents hydrogen, pentafluorosulphanyl, (trifluoromethyl)sulphanyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, cyclopropyl, cyclobutyl or oxetanyl,
where (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy may be substituted up to six times by fluorine
and
cyclopropyl, cyclobutyl and oxetanyl may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, methyl, trifluoromethyl and hydroxy,

and
R 10 represents hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, hydroxy, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylsulphonyl, 5-membered azaheteroaryl or a group of the formula -L 1 -C(═O)—OR 11 , -L 1 -NR 12A R 12B , -L 1 -C(═O)—NR 13A R 13B , -L 2 -S(═O) 2 —NR 13A R 13B or -L 3 -R 14 ,
where (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy may be substituted by a radical selected from the group consisting of hydroxy, methoxy, ethoxy and amino or up to three times by fluorine
and
5-membered azaheteroaryl may be substituted up to two times by methyl,
and in which
L 1 represents a bond or —CH 2 —,
L 2 represents a bond,
L 3 represents a bond or —O—,
R 11 represents hydrogen or (C 1 -C 4 )-alkyl,
R 12A , R 12B , R 13A and R 13B independently of one another represent hydrogen or (C 1 -C 4 )-alkyl
or
R 12A and R 12B and R 13A and R 13B , respectively, are attached to one another and together with the nitrogen atom to which they are respectively attached form a 4- to 6-membered heterocycle which may contain a further ring heteroatom from the group consisting of N and O and which may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, cyano, methyl, ethyl, hydroxy, methoxy and ethoxy,
and
R 14 represents a 4- to 6-membered heterocycle which is attached via a ring carbon atom and contains a ring heteroatom from the group consisting of N and O and which may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, cyano, methyl, ethyl, hydroxy, methoxy and ethoxy,

where R 10 does not represent hydroge

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

• Süβmeier Frank
• Lobell Mario
• Grünewald Sylvia
• Härter Michael
• Buchmann Bernd
• Telser Joachim
• Jöriβen Hannah
• Heroult Melanie
• Kahnert Antje
• Lustig Klemens
• Lindner Niels

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/4188

  condensed with other heterocyclic ring systems, e.g. biotin, sorbinil · CPC title