Imidazopyridazines as Akt kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9206185-B2
Application number	US-201214007427-A
Country	US
Kind code	B2
Filing date	Apr 5, 2012
Priority date	Apr 7, 2011
Publication date	Dec 8, 2015
Grant date	Dec 8, 2015

Abstract

The application relates to imidazopyridazines of formula (I)

which are useful as Akt inhibitors suitable for the treatment of cancer, and processes for their production and the use thereof.

First claim

The invention claimed is:

1. 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, 3-7C-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 CH2;
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. The compound according to claim 1
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)2NR5R6 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, 3-6C-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-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, 3-6C-heterocyclyl, aryl,

R3 is hydrogen, hydroxy, NR5R6, halogen, cyano, CO(NR8R9), C(O)OR8, C(O)(1-3C-alkyl), NHS(O) 2 R11, NHC(O)NHR11, —S(O) n -1-3C-alkyl, —S(O)2NR5R6 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, NHC(O)(1-3C-alkyl), 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, 3-6C-heterocyclyl, aryl,

R4 is phenyl which is optionally substituted one, two or three times, identically or differently, with a halogen atom;
R5 is hydrogen, 1-3C-alkyl,
R6 is hydrogen, 1-3C-alkyl,
R8 is hydrogen, 1-3C-alkyl which optionally is substituted with hydroxy,
R9 is hydrogen, 1-3C-alkyl,
R10 is hydrogen, 1-3C-alkyl,
R11 is hydrogen, 1-3C-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 compound according to claim 1
wherein
R1 is hydrogen, hydroxy, NR5R6, CO(NR8R9), C(O)OR8, NHC(O)(1-6C-alkyl), or a group selected from 1-6C-alkyl, 3-7C-cycloalkyl, aryl, heteroaryl, 1-4C-alkoxy, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, 1-6C-alkyl, 1-6C-alkoxy, —C(O)OR10, 3-7-cycloalkyl, aryl,
R2 is hydrogen, 1-6C-alkyl,
R3 is hydrogen, hydroxy, NR5R6, halogen, CO(NR8R9), C(O)OR8, C(O)(1-6C-alkyl), NHS(O) 2 R11, S(O)n-1-6C-alkyl, or a group selected from 1-6C-alkyl, 1-6C-alkoxy aryl, NHC(O)(1-6C-alkyl), 2-6C-alkenyl, wherein said group being optionally substituted, one or more times, identically or differently, with a substituent selected from: halogen, —C(O)OR10,
R4 is phenyl,
R5 is hydrogen,
R6 is hydrogen,
R8 is hydrogen, 1-4C-alkyl, which optionally is substituted with hydroxy,
R9 is hydrogen, 1-4C-alkyl,
R10 is, 1-4C-alkyl,
R11 is 1-4C-alkyl,
X, Y is CH2
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.

4. A compound according to claim 1
wherein
R1 is hydrogen, hydroxyl, amino, methoxy, ethoxy, butoxy, pyridine-3-yl, pyridine-4-yl, pyrazol-3-yl, 1-methyl-pyrazol-3-yl, imidazole-2-yl, methyl, propyl, —O—(CH 2 )—O—CH 3 , —O—CH 2 -phenyl, —O—CH 2 -cyclopropyl, —O(O)OCH 3 , —C(O)—NHCH 3 , —C(O)—NH 2 , 4-fluoro-phenyl, —(CH 2 ) 2 —C(O)OCH 3 , cyclopropyl, —NH—C(O)CH 3 ,
R2 is hydrogen, methyl,
R3 is hydrogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, —O—CH 2 —C(O)OCH 3 , —S—CH 3 , —SO 2 —CH 3 , bromine, chlorine, trifluoromethyl, C(O)NH 2 , COOH, C(O)OCH 3 , C(O)OCH 2 CH 3 , C(O)NH 2 , C(O)NHCH 3 , C(O)N(CH 3 ) 2 , C(O)NH(CH 2 ) 2 —OH, —CH═CH 2 , 4-fluoro-phenyl, NHC(O)CH 3 , NHC(O)CF 3 , NH—SO 2

Assignees

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

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

• A61K31/5025

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