Imidazopyridazines as Akt kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9604989-B2
Application number	US-201514792205-A
Country	US
Kind code	B2
Filing date	Jul 6, 2015
Priority date	Apr 7, 2011
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

The present invention relates to a method for the treatment of a cancer that is sensitive to Pi3K/Akt pathway inhibition by administering a therapeutically effective amount of a compound of formula (I)

First claim

The invention claimed is:

1. A method for the treatment of a cancer that is responsive to inhibition of an AKT kinase in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)

in which
R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-6C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,
wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O) 2 R11, 3-7-cycloalkyl, 3-7C-heterocyclyl, aryl,

R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-6C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,
wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O) 2 R11, 3-7C-heterocyclyl, aryl,

R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-6C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, NHC(O)(1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl,
wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O) 2 R11, 3-7C-heterocyclyl, aryl,

R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom;
R5 is hydrogen, 1-6C-alkyl,
R6 is hydrogen, 1-6C-alkyl,
R8 is hydrogen, 1-6C-alkyl which optionally is substituted with hydroxy,
R9 is hydrogen, 1-6C-alkyl,
R10 is hydrogen, 1-6C-alkyl,
R11 is hydrogen, 1-6C-alkyl,
X, Y is CH 2 ;
n is 0, 1, 2;
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

2. A method for inhibiting AKT kinase activity in cells in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)

in which
R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-6C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,
wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O) 2 R11, 3-7-cycloalkyl, 3-7C-heterocyclyl, aryl,

R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHC(O)(1-6C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-6C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy, 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, 2-6C-alkenyl, 2-6C-alkynyl,
wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O) 2 R11, 3-7C-heterocyclyl, aryl,

R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-6C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-6C-alkyl, 1-6C-alkoxy 3-7C-cycloalkyl, aryl, heteroaryl, -(1-6C-alkyl)-aryl, -(1-6C-alkyl)-heteroaryl, —O-(3-7C-cycloalkyl), —O-aryl, —O-(3-7C-heterocyclyl), —O-heteroaryl, —O-(1-6C-alkyl)-heteroaryl, —O-(1-6C-alkyl)-(3-7C-heterocyclyl), —O-(1-6C-alkyl)-aryl, NHC(O)(1-6C-alkyl), 2-6C-alkenyl, 2-6C-alkynyl,
wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
hydroxy, halogen, 1-6C-alkyl, 1-4C-haloalkyl, 1-6C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O) 2 R11, 3-7C-heterocyclyl, aryl,

R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom;
R5 is hydrogen, 1-6C-alkyl,
R6 is hydrogen, 1-6C-alkyl,
R8 is hydrogen, 1-6C-alkyl which optionally is substituted with hydroxy,
R9 is hydrogen, 1-6C-alkyl,
R10 is hydrogen, 1-6C-alkyl,
R11 is hydrogen, 1-6C-alkyl,
X, Y is CH 2 ;
n is 0, 1, 2;
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

3. The method as in claim 1 or 2 ,
wherein
R1 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHC(O)(1-6C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-3C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl, —O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl, —O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl, 2-3C-alkenyl, 2-3C-alkynyl,
wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from:
hydroxy, halogen, 1-3C-alkyl, 1-3C-haloalkyl, 1-3C-alkoxy, —NR8R9, cyano, —C(O)NR8R9, —C(O)OR10, —NHC(O)R11, —NHC(O)NHR11, —NHS(O) 2 R11, 3-6-cycloalkyl, 3-6C-heterocyclyl, aryl,

R2 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHC(O)(1-3C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-3C-alkyl, —S(O) 2 NR5R6 or a group selected from 1-3C-alkyl, 1-3C-alkoxy, 3-6C-cycloalkyl, aryl, heteroaryl, -(1-3C-alkyl)-aryl, -(1-3C-alkyl)-heteroaryl, —O-(3-6C-cycloalkyl), —O-aryl, —O-(3-6C-heterocyclyl), —O-heteroaryl, —O-(1-3C-alkyl)-heteroaryl, —O-(1-3C-alkyl)-(3-6C-heterocyclyl), —O-(1-3C-alkyl)-aryl, 2-3C-

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

• Bärfacker Lars
• Scott William
• Hägebarth Andrea
• Ince Stuart
• Rehwinkel Hartmut
• Politz Oliver
• Neuhaus Roland
• Briem Hans
• Bömer Ulf

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P15/14

  for lactation disorders, e.g. galactorrhoea · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title