Substituted benzylindazoles for use as BUB1 kinase inhibitors in the treatment of hyperproliferative diseases

Patent metadata

Field	Value
Publication number	US-10604532-B2
Application number	US-201916360811-A
Country	US
Kind code	B2
Filing date	Mar 21, 2019
Priority date	Oct 6, 2011
Publication date	Mar 31, 2020
Grant date	Mar 31, 2020

Abstract

Compounds of formula (I) which are inhibitors of Bub 1 kinase, processes for their production and their use as pharmaceuticals.

First claim

The invention claimed is:

1. A compound which is selected from the group consisting of:
5-methoxy-2-{1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-1H-indazol-3-yl}-N-(pyridin-4-yl)pyrimidin-4-amine;
5-methoxy-2-{1-[4-(pentafluoro-λ 6 -sulfanyl)benzyl]-1H-indazol-3-yl}-N-(pyridin-4-yl)pyrimidin-4-amine;
2-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzonitrile;
5-methoxy-N-(pyridin-4-yl)-2-(1-{3-[(trifluoromethyl)sulfanyl]benzyl}-1H-indazol-3-yl)pyrimidin-4-amine;
5-methoxy-2-{1-[4-(1H-pyrazol-1-yl)benzyl]-1H-indazol-3-yl}-N-(pyridin-4-yl)pyrimidin-4-amine;
5-methoxy-N-(pyridin-4-yl)-2-(1-{4-[(trifluoromethyl)sulfanyl]benzyl}-1H-indazol-3-yl)pyrimidin-4-amine;
5-methoxy-2-[1-(4-propylbenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)pyrimidin-4-amine;
7-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)-3,4-dihydroquinolin-2(1H)-one;
7-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)-4-methyl-2H-chromen-2-one;
ethyl [3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)phenyl]acetate;
2-[1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine;
N-cyclopropyl-4-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzenesulfonamide;
6-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)-1-benzofuran-2(3H)-one;
ethyl 2-[3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)phenyl]-2-methylpropanoate;
4-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzonitrile;
5-methoxy-2-{1-[4-(morpholin-4-ylsulfonyl)benzyl]-1H-indazol-3-yl}-N-(pyridin-4-yl)pyrimidin-4-amine;
3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzonitrile;
5-methoxy-N-(pyridin-4-yl)-2-{1-[3-(1H-pyrrol-1-yl)benzyl]-1H-indazol-3-yl}pyrimidin-4-amine;
2-[1-(4-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol;
5-[2-(dimethylamino)ethoxy]-2-[1-(4-fluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)pyrimidin-4-amine;
2-[3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)phenyl]ethanol;
2-[3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)phenyl]-2-methylpropan-1-ol;
1-[3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)phenyl]-2-methylpropan-2-ol;
4-({5-methoxy-2-[1-(4-propylbenzyl)-1H-indazol-3-yl]pyrimidin-4-yl}amino)nicotinonitrile; and
4-({5-methoxy-2-[1-(4-propylbenzyl)-1H-indazol-3-yl]pyrimidin-4-yl}amino)pyridine-3-carboxamide,

or an N-oxide, a salt, a tautomer or a stereoisomer thereof, or a salt of said N-oxide, tautomer or stereoisomer.

2. A method for treating a cervical-, breast-, non-small cell lung-, prostate-, colon- or melanoma tumor in a mammal in need thereof, comprising administering a therapeutically effective amount of the compound of claim 1 , or an N-oxide, a pharmaceutically acceptable salt, a tautomer or a stereoisomer thereof, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer, to the mammal.

3. A pharmaceutical composition comprising at least one compound according to claim 1 , or an N-oxide, a pharmaceutically acceptable salt, a tautomer or a stereoisomer thereof, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer, together with at least one pharmaceutically acceptable auxiliary.

4. A method for treating a cervical-, breast-, non-small cell lung-, prostate-, colon- or melanoma tumor in a mammal in need thereof comprising administering the composition according to claim 3 to the mammal.

5. A combination comprising one or more first active ingredients selected from a compound according to claim 1 , or an N-oxide, a pharmaceutically acceptable salt, a tautomer or a stereoisomer thereof, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer, and one or more second active ingredients selected from chemotherapeutic anti-cancer agents and target-specific anti-cancer agents.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

• Hitchcock Marion
• Mengel Anne
• Pütter Vera
• Siemeister Gerhard
• Wengner Antje Margret
• Briem Hans
• Eis Knut
• Schulze Volker
• Fernandez-Montalvan Amaury Ernesto
• Prechtl Stefan
• Holton Simon
• Fanghänel Jörg
• Lienau Philip
• Preusse Cornelia
• Gnoth Mark Jean

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K31/5377

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P43/00

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