Fluoro-substituted 3,5-dicyano-4-(1H-indazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine derivatives and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9422263-B2
Application number	US-201013496722-A
Country	US
Kind code	B2
Filing date	Oct 1, 2010
Priority date	Oct 6, 2009
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The present invention relates to novel fluoro-substituted 3,5-dicyano-4-(1H-indazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine derivatives having protein tyrosine kinase inhibitory activity, to a process for the manufacture thereof and to the use thereof for the treatment of c-Met-mediated diseases or c-Met-mediated conditions, particularly cancer and other proliferative disorders.

First claim

We claim:

1. A compound of formula (I)

wherein
R 1 is hydrogen, fluoro, methyl or ethyl,
R 2 is methyl, difluoromethyl or trifluoromethyl,
R 3 is hydrogen or fluoro,
R 4 is hydrogen, methyl or ethyl,
and
R 5 is hydrogen or methyl,
or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1 , wherein
R 5 is hydrogen,
or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) according to claim 1 , wherein
R 1 is hydrogen or fluoro,
or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) according to claim 1 , wherein
R 1 is hydrogen or fluoro,
R 2 is methyl or difluoromethyl,
R 3 is hydrogen or fluoro,
R 4 is hydrogen or methyl,
and
R 5 is hydrogen,
or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) according to claim 1 , wherein the compound is selected from the group consisting of
rac-2-Methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
(4R)-2-Methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
(4S)-2-Methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
rac-2-(Difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile;
(4R)-2-(Difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile;
(4S)-2-(Difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarbonitrile;
2,6-Bis(difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile;
2,6-Bis(difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile;
and
rac-4-(6-Fluoro-1H-indazol-5-yl)-2-methyl-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile;
or a pharmaceutically acceptable salt thereof.

6. A salt of a compound of formula (I) according to claim 1 , having a formula (I-A)

wherein
R 1 , R 2 , R 3 and R 4 have the meanings defined in claim 1 ,
and
Q + is an alkali metal cation or a quaternary ammonium cation.

7. The salt of formula (I-A) according to claim 6 , wherein
Q + is a sodium or potassium cation or a 2-hydroxyethyltrimethyl ammonium (choline) cation.

8. The salt of formula (I-A) according to claim 6 , wherein
Q + is a 2-hydroxyethyltrimethyl ammonium (choline) cation.

9. A pharmaceutical composition comprising a compound as defined in claim 1 , and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising a salt as defined in claim 6 , and a pharmaceutically acceptable excipient.

Assignees

• Michels Martin
• Follmann Markus
• Vakalopoulos Alexandros
• Zimmermann Katja
• Teusch Nicole
• Lobell Mario
• Bierer Donald
• Engel Karen
• Kissel Maria
• Bayer Pharma AG

Inventors

• Michels Martin
• Follmann Markus
• Vakalopoulos Alexandros
• Zimmermann Katja
• Teusch Nicole
• Lobell Mario
• Bierer Donald
• Engel Karen
• Kissel Maria

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/04 Primary

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

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title