Substituted pyrazolopyrimidines as Akt kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9370517-B2
Application number	US-201314371567-A
Country	US
Kind code	B2
Filing date	Jan 8, 2013
Priority date	Jan 10, 2012
Publication date	Jun 21, 2016
Grant date	Jun 21, 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, a 1-6C-alkyl group,
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,

R 2 is hydrogen,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 which is optionally substituted one or more times with halogen,
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, a 1-6C-alkyl group,
wherein said group being optionally substituted, one or more times with halogen,

R 2 is hydrogen,
R 3 is hydrogen, a 1-6C-alkyl group,
wherein said group being optionally substituted, one or more times with halogen,

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)—,
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, a 1-3C-alkyl group,
wherein said group being optionally substituted, one or more times with halogen,

R 2 is hydrogen,
R 3 is hydrogen, a 1-3C-alkyl group,
wherein said group being optionally substituted, one or more times with halogen,

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.

4. The compound of formula (I) according to claim 1 ,
wherein,
R 1 is hydrogen, 1-3C-alkyl optionally substituted with fluorine,
R 2 is hydrogen,
R 3 is hydrogen or 1-3C-alkyl optionally substituted with fluorine,
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. A compound of formula (I) according to claim 1 , which is selected from the group consisting of:
1-[4-(5,7-Dimethyl-3-phenylpyrazolo[1,5-a]pyrimidin-2-yl)phenyl]cyclobutanamine, 1-[4-(5,7-Diethyl-3-phenylpyrazolo[1,5-a]pyrimidin-2-yl)phenyl]cyclobutanamine, and 1-{4-[3-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl]phenyl}cyclo-butanamine.

6. A method for the treatment of breast cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1 or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

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

8. A combination comprising one or more first active ingredients selected from a compound of formula (I) according to claim 1 , or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a 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.

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG
• Bayer Pharma Aktiengesselschaft

Inventors

• Bärfacker Lars
• Scott William
• Hägebarth Andrea
• Rehwinkel Hartmut
• Politz Oliver
• Neuhaus Roland
• Bömer Ulf

Classifications

• 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

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title