IP Library › Granted Patent US 10,011,607
Granted Patent B2
US 10,011,607 · App. 15/867,097 · Granted Jul 3, 2018

Ethynyl derivatives

Inventors: Georg Jaeschke (Basel, CH); Fionn O'Hara (Basel, CH); Jean-Marc Plancher (Hagenthal-le-Bas, FR); Antonio Ricci (Birsfelden, CH); Daniel Rueher (Raedersdorf, FR); Eric Vieira (Frenkendorf, CH)
Assignee: Hoffman-La Roche Inc.
C07D487/04A61P3/08A61P25/00A61P25/16A61P25/22A61P25/24A61P35/00C07B2200/07C07B2200/09
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Quick Facts
Patent No.
US 10,011,607
App. No.
15/867,097
Granted
Jul 3, 2018
Kind
B2
Abstract

The present invention relates to compounds of formula I wherein R 1 is hydrogen, F or Cl; L is a bond or lower alkylene; R 2 is —(CH 2 ) n O-lower alkyl, lower alkyl substituted by halogen, —(CH 2 ) n C(O)O-lower alkyl, phenyl substituted by lower alkyl or halogen, or is a 5 or 6-membered heteroaryl group, selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, which are optionally substituted by lower alkyl, halogen, lower alkoxy, ═O, benzyloxy, cycloalkyloxy, hydroxy, cyano, lower alkyl substituted by halogen, or by —(CH 2 ) n O-lower alkyl; n is 1, 2 or 3; R 3 is hydrogen, lower alkyl or —(CH 2 ) n O-lower alkyl; R 4 is phenyl, pyridinyl or pyrimidinyl, optionally substituted by F; Y is CF or CCl; or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomers thereof. The compounds may be used for the treatment of Parkinson's disease, anxiety, emesis, obsessive compulsive disorder, autism, neuroprotection, cancer, depression and diabetes type 2.

Claims (156)

1. A compound of formula I

wherein

R 1 is hydrogen, F or Cl;

L is a bond or lower alkylene;

R 2 is —(CH 2 ) n O-lower alkyl, lower alkyl substituted by halogen, —(CH 2 ) n C(O)O-lower alkyl, phenyl substituted by lower alkyl or halogen, or is a 5 or 6-membered heteroaryl group, selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, which are optionally substituted by lower alkyl, halogen, lower alkoxy, ═O, benzyloxy, cycloalkyloxy, hydroxy, cyano, lower alkyl substituted by halogen, or by —(CH 2 ) n O-lower alkyl;

n is 1, 2 or 3;

R 3 is hydrogen, lower alkyl or —(CH 2 ) n O-lower alkyl;

R 4 is phenyl, pyridinyl or pyrimidinyl, each optionally substituted by F;

Y is CF or CCl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomers thereof.

2. The compound of formula Ia according to claim 1 ,

wherein

R 1 is F or Cl;

R 2 is —(CH 2 ) n O-lower alkyl, lower alkyl substituted by halogen or —(CH 2 ) n C(O)O-lower alkyl,

n is 1, 2 or 3;

R 3 hydrogen, lower alkyl or —(CH 2 ) n O-lower alkyl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomers thereof.

3. The compound of formula Ia according to claim 1 , wherein said compound is:

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-methoxyethyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(3-methoxypropyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2,2,2-trifluoroethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione; or,

Ethyl 4-[(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-1,6,8-trioxo-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidin-2-yl]butanoate.

4. The compound of formula Ib according to claim 1

wherein

R 1 is F or Cl;

L is lower alkylene;

R 2 is phenyl substituted by lower alkyl or by halogen;

R 3 hydrogen, lower alkyl or —(CH 2 ) n O-lower alkyl;

n is 1, 2 or 3;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomers thereof.

5. The compound of formula Ib according to claim 4 , wherein said compound is:

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(m-tolylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(p-tolylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(o-tolylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(2,6-dimethylphenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-2-[(2-chlorophenyl)methyl]-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-2-[(3-chlorophenyl)methyl]-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(2-fluorophenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(3-fluorophenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione; or,

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(4-fluorophenyl)methyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione.

6. The compound of formula I according to claim 1

wherein

R 1 is hydrogen, F or Cl;

L is a bond or lower alkylene;

R 2 is a 5 or 6-membered heteroaryl group, selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, which are optionally substituted by lower alkyl, halogen, lower alkoxy, ═O, benzyloxy, cycloalkyloxy, hydroxy, cyano, lower alkyl substituted by halogen, or by —(CH 2 ) n O-lower alkyl;

n is 1, 2 or 3;

R 3 is hydrogen, lower alkyl or —(CH 2 ) n O-lower alkyl;

R 4 is phenyl, pyridinyl or pyrimidinyl, each optionally substituted by F;

Y is CF or CCl;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomers thereof.

7. The compound of formula I according to claim 1 , wherein said compound is:

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(3-pyridyl)-3,4,9,9a-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-pyrimidin-4-yl-3,4,9,9a-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-pyridyl)-3,4,9,9a-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methyl-2-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methyl-4-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-(2,6-difluoro-4-(phenylethynyl)phenyl)-9a-methyl-2-(4-methylpyridin-2-yl)tetrahydro-1H-pyrazino[1,2-c]pyrimidine-1,6,8(2H,7H)-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methyl-3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methyl-3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methyl-3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(3,5-dimethyl-4-pyridyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-2-(2-chloro-4-pyridyl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-2-(2-chloro-4-pyridyl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-2-(6-chloro-3-pyridyl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-2-(6-chloro-3-pyridyl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(6-methoxy-3-pyridyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(6-methoxy-3-pyridyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methyl-6-oxo-3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrimidin-5-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2,6-dimethylpyrimidin-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methylpyrazin-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methylpyrimidin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-methoxypyrimidin-5-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione

(9aS)-2-(2-tert-butoxypyrimidin-5-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione

(9aS or 9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-ethoxypyrimidin-5-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-isopropoxypyrimidin-5-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-2-(2-benzyloxypyrimidin-5-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-hydroxypyrimidin-5-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-2-[2-(cyclopropoxy)pyrimidin-5-yl]-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(5-methoxypyrazin-2-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-2-(5-benzyloxypyrazin-2-yl)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridazin-3-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyrazin-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(6-methylpyridazin-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methyl-6-oxo-pyridazin-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-pyridazin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methyl-6-oxo-pyridazin-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-thiazol-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methylthiazol-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(4-methylthiazol-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

2-[(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-1,6,8-trioxo-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidin-2-yl]thiazole-4-carbonitrile;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[4-(trifluoromethyl)thiazol-2-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[5-(trifluoromethyl)thiazol-2-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylimidazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(1,4-dimethylimidazol-2-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(1,2-dimethylimidazol-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-methyl-1-(2,2,2-trifluoroethyl)imidazol-4-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-methylpyrazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2,5-dimethylpyrazol-3-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(1-ethylpyrazol-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(1-isopropylpyrazol-4-yl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1H-pyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[1-(3-methoxypropyl)pyrazol-4-yl]-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methyl-1,2,4-triazol-3-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(4-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(4-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(4-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(2-pyridylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(4-pyridylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(pyrimidin-4-ylmethyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[(1-methylpyrazol-4-yl)methyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[(2-methylpyrazol-3-yl)methyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-imidazol-1-ylethyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-(2-methylimidazol-1-yl)ethyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-(2-methylpyrazol-3-yl)ethyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[2-(1-methylpyrazol-4-yl)ethyl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aRS)-7-[2-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2-(3-pyridyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2-pyrimidin-4-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione;

(9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione; or,

(9aS)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(1-methylpyrazol-4-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione.

8. A process for the preparation of a compound of formula I according to claim 1 which process comprises:

(a) the step of reacting a compound of formula IV

with a compound of formula XLR 2 , wherein X is halogen, to afford a compound of formula I

and, (b) if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

9. A pharmaceutical composition comprising a compound of formula I according to claim 1 and at least one pharmaceutically acceptable excipients.

10. A method for the treatment of Parkinson's disease, anxiety, emesis, obsessive compulsive disorder, autism, neuroprotection, depression and diabetes type 2, which method comprises administering a therapeutically effective amount of a compound of formula I according to claim 1 to a patient in need thereof.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 25, 2018
From: JAESCHKE, GEORG; PLANCHER, JEAN-MARC; RICCI, ANTONIO; RUEHER, DANIEL; VIEIRA, ERIC; O'HARA, FIONN
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 045907/0348 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 25, 2018
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 045907/0626 →
Priority Claims (1)
EP 15179550 · Aug 3, 2015 · regional
Continuity (2)
Continuation PCTEP2016068359 · Feb 8, 2016
Related Publication 20180127429A1 · May 10, 2018