Substituted imidazopyrazines as Akt kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9260435-B2
Application number	US-201314370831-A
Country	US
Kind code	B2
Filing date	Jan 8, 2013
Priority date	Jan 10, 2012
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

Compounds of formula (I)

which are effective inhibitors of the Pi3K/Akt pathway, processes for their production and their use as pharmaceuticals.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
R 1 is hydrogen, hydroxy, or
a group selected from 1-6C-alkyl, 1-6C-alkoxy,
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, —NR 7 R 8 , cyano, (═O), —C(O)NR 7 R 8 , —C(O)OR 9 , —NHC(O)R 10 , —NHS(O) 2 R 10 , heteroaryl,
wherein said substituent can be optionally substituted with 1-6C-alkoxy,

R 2 is hydrogen, halogen, C(O)OR 9 , CO(NR 7 R 8 ), or
a 1-6C-alkyl group
wherein said group is 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, —NR 7 R 8 , cyano, —C(O)NR 7 R 8 , —C(O)OR 9 , —NHC(O)R 10 , —NHS(O) 2 R 10 , —NH-(1-6C-alkylen)-O-(1-6C-alkyl),

R 3 is hydrogen, 1-6C-alkyl,
R 4 is phenyl optionally substituted by 1-6C-alkyl, halogen, cyano,
R 5 is hydrogen, halogen,
R 6 is hydrogen, 1-6C-alkyl,
X is —CH 2 —,
Y is —CH 2 —, —CH(OH)—,
R 7 , R 8 which can be the same or different, is hydrogen, hydroxy, 3-7C-cycloalkyl or a group selected from 1-4C-alkyl, 1-6C-alkoxy, wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from:
halogen, hydroxy, mono- or di-(1-4C-alkylamino), 1-4C-alkoxy, or 3-7C-cycloalkyl or,

R 7 and R 8 together with the nitrogen to which they are attached may also form a saturated or unsaturated 3-6C-heterocyclic ring,
which is optionally substituted by (═O)

R 9 is hydrogen, 1-6C-alkyl,
R 10 is 1-4C-alkyl (optionally substituted in the same way of differently one or more times with halogen, hydroxy) or 3-7C-cycloalkyl,
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 of formula (I) according to claim 1 ,
wherein
R 1 is hydrogen, hydroxy, 1.-6C-alkyl, 1-6C-alkoxy,
R 2 is hydrogen, halogen, 1-6C-alkyl, (CO)OR 9 , (CO)NR 7 R 8 ,
R 3 is hydrogen,
R 4 is phenyl optionally substituted by 1-6C-alkyl, halogen, cyano,
R 5 is hydrogen,
R 6 is hydrogen,
X is —CH 2 —,
Y is —CH 2 —, —CH(OH)—,
R 7 , R 8 which can be the same or different, is hydrogen, hydroxy, or
a group selected from 1-4C-alkyl, 1-6C-alkoxy, wherein said group is optionally substituted, one or more times, identically or differently, with a substituent selected from:
halogen, hydroxy, mono- or di-(1-4C-alkylamino), 1-4C-alkoxy, or 3-7C-cycloalkyl, or,
R 7 and R 8 together with the nitrogen to which they are attached may also form a saturated or unsaturated 3-6C-heterocyclic ring,
which is optionally substituted by (═O)

R 9 is hydrogen, 1-6C-alkyl,
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 of formula (I) according to claim 1 ,
wherein
R 1 is hydrogen, hydroxy, 1.-6C-alkyl, 1-6C-alkoxy,
R 2 is hydrogen, halogen, 1-6C-alkyl, (CO)OR 9 , (CO)NR 7 R 8 ,
R 3 is hydrogen,
R 4 is phenyl
R 5 is hydrogen,
R 6 is hydrogen,
X is —CH 2 —,
Y is —CH 2 —,
R 7 , R 8 which can be the same or different, is hydrogen, 1-4C-alkyl,)
R 9 is hydrogen, 1-6C-alkyl,
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. The compound of formula (I) according to claim 1 ,
wherein,
R 1 is hydrogen, hydroxy, 1.-3C-alkyl, 1-3C-alkoxy,
R 2 is hydrogen, halogen, 1-3C-alkyl, (CO)O(1-3C-alkyl), (CO)NH 2 ,
R 3 is hydrogen,
R 4 is phenyl,
R 5 is hydrogen,
R 6 is hydrogen,
X is —CH 2 —,
Y is —CH 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.

5. Compounds of formula (I) according to claim 1 , which is selected from the group consisting of:
2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-a]pyrazin-8-ol,
1-[4-(6,8-Dimethyl-3-phenylimidazo[1,2-a]pyrazin-2-yl)phenyl]-cyclobutanamine,
1-[4-(6-Bromo-8-methoxy-3-phenylimidazo[1,2-a]pyrazin-2-yl)phenyl]cyclobutanamine,
1-[4-(6-Ethyl-8-methoxy-3-phenylimidazo[1,2-a]pyrazin-2-yl)phenyl]-cyclobutanamine,
Ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-a]pyrazine-6-carboxylate,
2-[4-(1-Aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-a]pyrazine-6-carboxamide,
Methyl 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-a]-pyrazine-6-carboxylate, and
2-[4-(1-Aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo[1,2-a]pyrazine-6-carboxamide,
or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

6. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 , together with at least one pharmaceutically acceptable auxiliary.

7. A combination comprising one or more first active ingredients selected from a compound of formula (I) according to claim 1 , and one or more second active ingredients selected from chemotherapeutic anti-cancer agents.

8. A method for the treatment of breast cancer or benign or malignant neoplasia comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1 .

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

• Bärfacker Lars
• Scott William
• Hägebarth Andrea
• Ince Stuart
• Rehwinkel Hartmut
• Politz Oliver
• Neuhaus Roland
• 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

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

• A61K31/4985

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