Substituted imidazopyridazines

Patent metadata

Field	Value
Publication number	US-9512126-B2
Application number	US-201314384828-A
Country	US
Kind code	B2
Filing date	Mar 11, 2013
Priority date	Mar 14, 2012
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The present invention relates to substituted imidazopyridazine compounds of general formula I in which R 3 , R 5 and A are as defined in the claims, to methods of 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 a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of general formula I:

in which:
A represents

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

R 2 represents a cyclopropyl- group;
R 3 represents
—C(R 3a )(R 3b )(R 3c );

R 3a , R 3b
represent, independently from each other, a hydrogen atom or a fluorine atom or a hydroxy-, or a methyl- group, with the proviso that not both of R 3a and R 3b represent a hydrogen atom and not both of R 3a and R 3b represent a hydroxy group;

or
R 3a , R 3b
together represent ═O or ═C(R 3d )(R 3e );

or
R 3a , R 3b
together with the carbon atom they are attached to, form a cyclopropyl- ring;

R 3c represents a phenyl group;
wherein said phenyl group is substituted, identically or differently, with 1, 2, or 3 R 7 groups;

R 3d , R 3e
represent a hydrogen atom;

R 4 represents a methyl group;
R 5 represents —CH 2 —CF 3 ;

R 7 represents a fluorine atom, or a hydroxy-, or a methoxy group;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. A compound according to claim 1 , wherein
R 3a , R 3b
together with the carbon atom they are attached to, form a cyclopropyl-ring; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. A compound according to claim 1 , which is selected from the group consisting of:
N-cyclopropyl-4-{6-[1-(3-fluoro-4-methoxyphenyl)ethenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[difluoro(3-fluoro-4-methoxyphenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(RS)—N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(R)—N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(S)—N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(RS)—N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-[(3,3, 3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(R)—N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(S)—N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(RS)—N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(R)—N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
(S)—N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[difluoro(3-fluorophenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-(3-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[1-(3-methoxyphenyl)vinyl]-8-[(3,3, 3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-(4-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[1-(4-methoxyphenyl)vinyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1, 2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[(2,5-difluorophenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-(2,5-difluorobenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-(3-fluoro-4-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-(2,3-difluorobenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[1-(2,3-difluorophenyl)vinyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[difluoro(4-methoxyphenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[1-(2,3-difluorophenyl)cyclopropyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[(2,3-difluorophenyl)(difluoro)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[1-(2,5-difluorophenyl)vinyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[1-(2,5-difluorophenyl)cyclopropyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[(2,5-difluorophenyl)(difluoro)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
N-cyclopropyl-4-{6-[1-(5-fluoro-2-hydroxyphenyl)ethenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, and
N-cyclopropyl-4-{6-[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. A method of preparing a compound according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula Ia:

in which R 3 and R 5 are as defined in claim 1 ;
and A′ is

wherein * indicates the point of attachment of said group with the rest of the molecule; R 4 is as defined in claim 1 , and Z′ represents a group selected from: —C(═O)OH and —C(═O)O—(C 1 -C 6 -alkyl);

to react with a compound of general formula Ib:
H 2 NR 2    Ib

in which R 2 is as defined in claim 1 , thereby giving, upon optional deprotection, a compound of general formula I:

in which R 3 , R 5 and A are as defined claim 1 .

5. A method of preparing a compound according to claim 1 , said method comprising the step of allowing an intermediate compound of general formula VII:

in which R 3 and A are as defined in claim 1 , and Q 1 is a leaving group,
to react with a compound of general formula VIIa:

in which R 5 is as defined in claim 1 ,
thereby giving, upon optional deprotection, a compound of general formula I:

in which R 3 , R 5 and A are as defined in claim 1 .

6. A method of preparing a compound according to claim 1 , said method comprising t

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

• Koppitz Marcus
• Klar Ulrich
• Wengner Antje Margret
• Neuhaus Roland
• Siemeister Gerhard

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title