Substituted imidazopyrazines as Akt kinase inhibitors
Compounds of formula (I) which are effective inhibitors of the Pi3K/Akt pathway, processes for their production and their use as pharmaceuticals.
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 .