HK1246790B - Ethynyl derivatives - Google Patents

Description

Ethylene derivatives

The present invention relates to compounds of formula I

in

^R1 is hydrogen, F or Cl;

L is a bond or lower alkylene;

^R2 is -( _CH2 ) _nO -lower alkyl, lower alkyl substituted by halogen, -( _CH2 ) _nC (O)O-lower alkyl, phenyl substituted by lower alkyl or halogen, or a 5- or 6-membered heteroaryl selected from pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, said heteroaryl being optionally substituted by lower alkyl, halogen, lower alkoxy, =O, benzyloxy, cycloalkyloxy, hydroxy, cyano, lower alkyl substituted by halogen, or substituted by -( _CH2 ) _nO -lower alkyl;

n is 1, 2, or 3;

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

^R4 is phenyl, pyridinyl or pyrimidinyl, which is optionally substituted with F;

Y is CF or CCl;

Or it relates to its pharmaceutically acceptable salt or acid addition salt, racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer.

It has surprisingly been found that compounds of general formula I are positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGluR4).

Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.

Along with GRM6, GRM7, and GRM8, it belongs to Group III of the metabotropic glutamate receptor family and is negatively coupled to adenylate cyclase via activation of Gαi/o proteins. It is primarily expressed at presynaptic sites, acting as either an autoreceptor or heteroreceptor, and its activation leads to a decrease in transmitter release from presynaptic sites. Currently, mGluR4 has received considerable attention, primarily due to its unique distribution and recent evidence that activation of this receptor plays a key regulatory role in numerous CNS and non-CNS pathways (Celanire S, Campo B, Expert Opinion in Drug Discovery, 2012).

Pop/02.05.2016

The similarity in the ligand-binding domains of Group III mGluRs makes the identification of selective orthosteric agonists for this receptor challenging, although some progress has been made in this area. However, targeting positive allosteric modulators (PAMs) rather than orthosteric agonists offers greater opportunities for identifying molecules with exclusive selectivity among mGluRs.

mGluR4 PAMs emerge as promising targets for the treatment of motor (and non-motor) symptoms via non-dopaminergic means and as disease modifiers in Parkinson's disease.

Parkinson's disease is a progressive neurodegenerative disease that causes the loss of dopaminergic neurons in the substantia nigra (SN). One result of the loss of dopamine in the disease is a series of movement disorders, including bradykinesia, akinesia, tremor, gait disorders, and balance problems. These movement disorders have become the hallmarks of PD, although there are many other non-motor symptoms associated with the disease. In the early stages of the disease, PD symptoms are effectively treated by supplementing or increasing dopamine with dopamine D2 receptor agonists, levodopa, or monoamine oxidase B inhibitors. However, as the disease progresses, these agents become less effective in controlling motor symptoms. In addition, their use is limited to the occurrence of adverse effects, including dyskinesias caused by dopamine agonists. Therefore, there is still a need for new PD treatment methods that improve the effectiveness of motor symptom control.

Activation of metabotropic glutamate receptor 4 (mGluR4) has been proposed as a potential treatment for Parkinson's disease. As a member of the group III mGluR, mGluR4 is a presynaptic glutamate receptor expressed primarily in several key locations in the basal ganglia circuits that control movement. Activation of mGluR4 with group III-preferring agonists reduces inhibitory and excitatory postsynaptic potentials, likely by reducing the release of GABA and glutamate, respectively.

The search for novel drugs that alleviate the motor symptoms of Parkinson's disease while attenuating the ongoing degeneration of nigrostriatal neurons is particularly interesting. The orthosteric mGluR4 agonist L-AP4 has shown neuroprotective effects in the 6-OHDA rodent model of PD, and the first positive allosteric modulator (-)-PHCCC reduced nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These studies provide preclinical evidence that mGluR4 activators constitute a powerful approach not only for the symptomatic treatment of PD but also as potential disease modifiers.

The neuroprotective effects of selective mGluR4 agonists are also described in Neuroreport, 19(4), 475-8, 2008, Proc. Natl. Acad. Sci, USA, 100(23), 13668-73, 2003 and J. Neurosci. 26(27), 7222-9, 2006 and Mol. Pharmacol. 74(5), 1345-58, 2008.

Anxiety disorders are one of the most prevalent psychiatric disorders in the world and occur together with Parkinson's disease (Prediger R et al. Neuropharmacology 2012; 62: 115-24). Excessive glutamatergic neurotransmission is an important feature of the pathophysiology of anxiety. Based on the presynaptic localization of mGluR4 in brain areas involved in anxiety and mood disorders and attenuation of excessive brain excitability, mGluR4 activators may represent a new generation of antianxiety therapeutics (Eur. J. Pharmacol., 498 (1-3), 153-6, 2004).

In 2010, Addex reported that ADX88178 was active in two preclinical rodent models of anxiety: the marble burying test in mice and the EPM in mice and rats. ADX88178 also exhibited anxiolytic-like properties in the rat EPM test after oral administration.

mGluR4 modulators have also been shown to have antidepressant effects (Neuropharmacology, 46(2), 151-9, 2004).

Furthermore, mGluR4 has been shown to be involved in the inhibition of glucagon secretion (Diabetes, 53(4), 998-1006, 2004). Therefore, orthosteric or allosteric modulators of mGluR4 have the potential to treat type 2 diabetes through their blood glucose-lowering effects.

Furthermore, mGluR4 has been shown to be expressed in prostate cancer cell lines (Anticancer Res. 29(1), 371-7, 2009) and colorectal cancer (Cli. Cancer Research, 11(9), 3288-95, 2005). Therefore, mGluR4 modulators may also have potential therapeutic effects on cancer.

Other proposed roles for mGluR4 PAMs could be expected in the treatment of emesis, obsessive-compulsive disorder, and autism.

The compounds of formula I are distinguished by having valuable therapeutic properties. They can be used to treat or prevent disorders associated with allosteric modulation of the mGluR4 receptor.

The most preferred indications for compounds that are allosteric modulators of the mGluR4 receptor are Parkinson's disease, anxiety, emesis, obsessive-compulsive disorder, autism, neuroprotection, cancer, depression and type 2 diabetes.

The present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof, these compounds as pharmaceutically active substances, processes for their preparation and their use in the treatment or prevention of disorders associated with allosteric modulators of mGluR4 receptors, such as Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, anorexia, autism, neuroprotection, cancer, depression and type 2 diabetes, and to pharmaceutical compositions comprising compounds of formula I.

Another object of the present invention is a method for treating or preventing Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, autism, neuroprotection, cancer, depression and type 2 diabetes, which comprises administering an effective amount of a compound of formula I to a mammal in need thereof.

Furthermore, the present invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.

The following definitions of general terms used in this specification apply regardless of whether the terms in question appear alone or in combination.

The following definitions of general terms used in this specification apply regardless of whether the terms in question appear alone or in combination.

As used herein, the term "lower alkyl" refers to a saturated straight or branched chain group containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, etc. Preferred alkyl groups are groups having 1 to 4 carbon atoms.

The term "lower alkyl substituted by halogen" denotes a lower alkyl group as defined above wherein at least one hydrogen atom is replaced by a halogen atom.

The term "lower alkoxy" denotes a lower alkyl group as defined above wherein the group is attached to an oxygen atom.

The term "lower alkylene" refers to a linking group such _{as -CH2-} or _-CH2CH2- .

The term "cycloalkyl" denotes a saturated ring containing from 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "cycloalkoxy" refers to a cycloalkyl group wherein the group is attached to an oxygen atom.

The term "halogen" refers to chlorine, iodine, fluorine and bromine.

The term "5- or 6-membered heteroaryl selected from pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl" refers to the following groups:

The term "pharmaceutically acceptable acid addition salts" includes salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

One embodiment of the invention is a compound of formula Ia,

^R1 is F or Cl;

^R2 is -( _CH2 ) _nO -lower alkyl, lower alkyl substituted by halogen or -( _CH2 ) _nC (O)O-lower alkyl,

n is 1, 2, or 3;

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

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

For example, the following compounds:

(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.

Another object of the present invention is the compound of formula Ib

in

^R1 is F or Cl;

L is a lower alkylene group;

^R2 is phenyl substituted by lower alkyl or halogen;

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

n is 1, 2, or 3;

or its pharmaceutically acceptable salts or acid addition salts, racemic mixtures, or its corresponding enantiomers and/or optical isomers and/or stereoisomers, such as the following compounds

(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.

Another embodiment of the present invention is a compound of formula Ic

in

^R1 is hydrogen, F or Cl;

L is a bond or lower alkylene;

R ² is a 5- or 6-membered heteroaryl selected from pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, said heteroaryl being optionally substituted with lower alkyl, halogen, lower alkoxy, =0, benzyloxy, cycloalkyloxy, hydroxy, cyano, lower alkyl substituted with halogen or with -(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;

^R4 is phenyl, which is optionally substituted with F;

Y is CF or CCl;

or its pharmaceutically acceptable salts or acid addition salts, racemic mixtures, or its corresponding enantiomers and/or optical isomers and/or stereoisomers, such as the following compounds

(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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-9a-methyl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione

(9aRS)-2-(2-chloro-4-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-(cyclopropyloxy)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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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-pyridinyl)-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.

The preparation of the compound of formula I of the present invention can be carried out in a sequential or convergent synthetic route. The synthesis of the compound of the present invention is shown in the following scheme 1. The skills required for carrying out the reaction and purifying the resulting product are known to those skilled in the art. The substituents and symbols used in the following method descriptions have the meanings given above.

The compound of formula I can be prepared by the method given below, by the method given in the examples or by similar methods. The appropriate reaction conditions for the individual reaction steps are well known to those skilled in the art. The reaction sequence is not limited to the sequence shown in the scheme, however, depending on the starting material and its respective reactivity, the order of the reaction steps can be freely changed. The starting material is commercially available or can be prepared by a method similar to the method given below, by the method described in the references cited in the specification or in the examples, or by methods known in the art.

The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the process variations described below, which include

a) making a compound of formula IV

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

Obtaining a compound of formula I

And, if necessary, the obtained compound is converted into a pharmaceutically acceptable acid addition salt.

The preparation of compounds of formula I is also described in more detail in Schemes 1 and 2 and Examples 1-112.

Solution 1

Substituted pyrimidine-2,6-diones of general formula I can be obtained, for example, by Sonogashira coupling of an appropriately substituted aniline or aminopyridine 1 with a phenyl-acetylene 2 to produce the desired ethynyl compound of formula II. The ethynyl compound of formula II is reacted with an appropriately substituted aminoester or amino acid of formula III and phosgene or a phosgene equivalent such as triphosgene or carbonyldiimidazole (CDI) in the presence or absence of a base such as triethylamine in a solvent such as toluene or dioxane to form the desired ethynyl-phenyl, ethynyl-pyridyl or ethynyl-pyrimidyl substituted imidazolidine-2,4-diones of general formula IV (Scheme 1). The two steps involving the reaction of intermediates II and III to form a urea derivative, which is then reacted with an ester group to form the pyrimidinedione of formula IV, can be carried out as a one-pot two-step reaction, or, depending on the available starting materials, the two steps can be carried out sequentially in normal or reverse order (amide formation followed by urea formation). Introduction of the LR ² substituent can also be achieved at various points in the synthetic sequence by functionalization of the corresponding intermediates III or IV.

The R ⁴ substituent can also be introduced by reacting a compound of formula I with trimethylsilyl acetylene followed by another Sonogashira reaction with an aryl iodide or bromide R ⁴ —X in the presence of fluorine to give the corresponding R ⁴ substituted acetylene derivative II.

In general, the order of the steps for synthesizing compounds of formula I may also be further varied in certain circumstances. Racemic mixtures of compounds of formula I, III or IV may also be separated on a chiral stationary phase to yield the corresponding optically pure enantiomers. Intermediates of formula IV may also be synthesized, for example, using the following method (Scheme 2):

Option 2

The appropriately substituted epoxide (1) is ring-opened under basic or acidic conditions using an alcohol (2) with an attached protecting group moiety, such as allyl alcohol or myristyl alcohol. The resulting secondary alcohol (3) is oxidized to the corresponding ketone 4, which is then converted to the corresponding α,β-unsaturated ester 5 using Wittig or Wittig-Horner conditions. The ester is then treated with ammonia to produce the Michael-addition product 6, which is cyclized using the same conditions as described above to produce compound 8. The urea nitrogen is then alkylated using an appropriately protected bromoethylamino-derivative to produce the alkylated compound 9. Deprotection of the alcohol followed by oxidation to the carboxylic acid gives the cyclized product (10), which is deprotected to produce intermediate V, which can then be further transformed to form the compound of formula I.

Biological Assays and Data:

_EC50 values were determined using an in vitro Ca2+ mobilization assay against recombinant human mGlu4 expressed in HEK293 cells:

Generate a monoclonal HEK-293 cell line stably transfected with a cDNA encoding the human mGlu4 receptor; for work with mGlu4 positive allosteric modulators (PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was selected to allow differentiation of agonist activity from PAM activity. Cells were cultured in high glucose Dulbecco's Modified Eagle Medium (Dulbecco's Modified Eagle Medium) supplemented with 1 mM glutamine, 10% (vol/vol) heat-inactivated calf serum, penicillin/streptomycin, 50 μg/ml hygromycin, and 15 μg/ml blasticidin according to standard protocols (Freshney, 2000).

About 24 hours before the experiment, ^5x104 cells/well were seeded in a 96-well plate with a black/clear bottom coated with poly-D-lysine. The cells were loaded with 2.5 μM Fluo-4 AM in a loading buffer (1xHBSS, 20 mM HEPES) at 37°C for 1 hour and washed five times with loading buffer. The cells were transferred to a Functional Drug Screening System 7000 (Hamamatsu, Paris, France) and 11 half-log serial dilutions of the test compound were added at 37°C, and the cells were incubated for 10-30 minutes and fluorescence was recorded online. After this preincubation step, the agonist (2S)-2-amino-4-phosphonobutyric acid (L-AP4) was added to the cells at a concentration corresponding to the _EC20 , and fluorescence was recorded online; to account for day-to-day changes in the responsiveness of the cells, the _EC20 of L-AP4 was determined by recording a full dose-response curve of L-AP4 immediately before each experiment.

The response was measured as the peak increase in fluorescence minus the baseline (i.e., fluorescence without added L-AP4), normalized to the maximum stimulatory effect obtained with a saturating concentration of L-AP4. The % maximal stimulation was plotted using XLfit, a curve fitting program that iteratively plots the data using the Levenburg Marquardt algorithm. The equation used for the single-site competition assay was y = A + ((B-A)/(1+((x/C)D))), where y is the % maximal stimulatory effect, A is the minimum y, B is the maximum y, C is the _EC50 , x is the log10 of the concentration of the competing compound, and D is the slope of the curve (Hill Coefficient). From these curves, the _EC50 (drug concentration that achieves 50% maximal receptor activation), the Hill coefficient, and the maximum response expressed as a percentage of the maximal stimulatory effect obtained with a saturating concentration of L-AP4 were calculated (see Figure 1).

A positive signal obtained during pre-incubation with a PAM test compound (i.e., before applying an EC ₂₀ concentration of L-AP4) indicates agonist activity, while the absence of such a signal demonstrates the absence of agonist activity. A decrease in the signal observed after addition of an EC ₂₀ concentration of L-AP4 indicates inhibitory activity of the test compound.

Figure 1: Graphical representation of the experimental outline of the mGlu4 PAM Ca2 ⁺ mobilization screening assay and determination of _EC50 and %Emax values.

Examples and data lists:

The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicines, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, they can also be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of injections.

The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as carriers for tablets, coated tablets, lozenges and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, depending on the properties of the active substance, a carrier is generally not required in the case of soft gelatin capsules. Suitable carriers for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Excipients, such as alcohols, polyols, glycerol, vegetable oils, etc., can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but generally speaking this is not essential. Carriers suitable for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned previously, medicaments containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as are processes for the preparation of such medicaments, which comprise bringing one or more compounds of formula I or a pharmaceutically acceptable salt thereof and, if desired, one or more other therapeutically valuable substances into galenic form together with one or more therapeutically inert carriers.

As also mentioned previously, the use of the compounds of formula (I) for the preparation of medicaments useful for the prevention and/or treatment of the above-mentioned diseases is also an object of the present invention.

Dosage can vary within a wide range and will, of course, be adapted to individual needs in each specific case. Typically, the effective dose for oral or parenteral administration is between 0.01 and 20 mg/kg/day, with 0.1 to 10 mg/kg/day being preferred for all described indications. The daily dose for an adult weighing 70 kg is correspondingly between 0.7 and 1400 mg/day, preferably between 7 and 700 mg/day.

Preparation of pharmaceutical compositions containing the compounds of the present invention:

Tablets having the following composition are prepared in a conventional manner:

mg/tablet

Experimental part:

Example 1

(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

Step 1: 2,6-Difluoro-4-phenylethynyl-phenylamine

Bis-(triphenylphosphine)-palladium(II) dichloride (826 mg, 1.18 mmol, 0.02 eq) was dissolved in 100 ml of THF. 2,6-difluoro-4-iodoaniline (15 g, 58.8 mmol) and phenylacetylene (7.2 g, 7.8 ml, 70.6 mmol, 1.2 eq) were added at room temperature. Triethylamine (29.8 g, 41 ml, 0.29 mol, 5 eq), triphenylphosphine (617 mg, 2.35 mmol, 0.04 eq) and copper(I) iodide (112 mg, 0.58 mmol, 0.01 eq) were added and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled and extracted with saturated NaHCO ₃ solution and twice with ethyl acetate. The organic layer was washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient of 0:100 to 40:60. The desired 2,6-difluoro-4-phenylethynyl-phenylamine (12.6 g, 93% yield) was obtained as a yellow solid, MS: m/e = 230.1 (M+H ⁺ ).

Step 2: (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3,4,9,9a-tetrahydro-2H-pyrazine 1,6,8-trione

2,6-Difluoro-4-phenylethynyl-phenylamine (Example 1, Step 1) (100 mg, 0.44 mmol) and toluene (2.5 ml) were introduced into a 6 ml sealed container. Carbonyldiimidazole (149 mg, 0.92 mmol, 2.1 equivalents) was added at room temperature. The mixture was stirred at 115° C. for 40 min. Ethyl 2-(3-oxopiperazin-2-yl)acetate [Abelman & al., Tetrahedron Lett. 44, 1823 (2003)] (81 mg, 0.44 mmol, 1.0 equivalents) was added to the mixture and stirred at 115° C. for 16 hours. The reaction mixture was cooled, concentrated in vacuo and directly loaded onto a silica gel column. The crude product was purified by flash chromatography eluting with a 10:90 to 100:0 ethyl acetate:heptane gradient. The title compound (50 mg, 29% yield) was obtained as a light yellow solid, MS: m/e = 396.1 (M+H ⁺ ).

Step 3: (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(3-pyridinyl)-3,4,9,9a- Tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3,4,9,9a-tetrahydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8-trione (70 mg, 0.177 mmol) was dissolved in dioxane (2.0 ml).

_Cs2CO3 (115 _mg , 0.354 mmol, 2.0 equiv), 3-bromopyridine (31 mg, 0.195 mmol, 1.1 equiv), palladium(II) acetate (8.0 mg, 0.035 mmol, 0.2 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30.7 mg, 0.053 mmol, 0.3 equiv) were added at room temperature. The mixture was stirred at 110°C for 4 hours. The reaction mixture was evaporated and directly loaded onto a silica gel column. The crude product was purified by flash chromatography eluting with a gradient of ethyl acetate:heptane 0:100 to 100:0. The title compound (47 mg, 56% yield) was obtained as a white solid, MS: m/e = 473.2 (M+H+).

Example 2

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3,4,9,9a-tetrahydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 1, Step 2) and 4-bromopyrimidine hydrochloride, the title compound was obtained as a white solid, MS: m/e = 474.2 (M+H ⁺ ).

Example 3

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3,4,9,9a-tetrahydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 1, Step 2) and 2-bromopyrimidine, the title compound was obtained as a light yellow solid, MS: m/e = 473.2 (M+H ⁺ ).

Example 4

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

Step 1: (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyridine Azino[1,2-c]pyrimidine-1,6,8-trione (4.1):

Using similar chemistry to that described in Example 1, Step 2, starting from 2,6-difluoro-4-phenylethynyl-phenylamine (Example 1, Step 1) and methyl 2-[(2RS)-2-methyl-3-oxo-piperazin-2-yl]acetate [Abelman & al., Tetrahedron Lett. 44, 1823 (2003)], the title compound was obtained as a white solid, MS: m/e = 410.2 (M+H ⁺ ).

Step 2: (9aS)- and (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4- 9-Tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (4.2a and 4.2b):

Chiral separation of the enantiomers was achieved by chiral HPLC using a Chiralpak IE column with (hexanes/EtOH/DCM/ _Et2N -70/20/10/0.1%) to afford (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (4.2a) as an off-white solid (MS: 410.1 (M+H ⁺ )); and (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (4.2b) as an off-white solid (MS: 410.1 (M+H ⁺ )).

Step 2: (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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (4.1) (Example 4, Step 1) and 2-bromopyridine, the title compound was obtained as a light yellow solid, MS: m/e = 487.2 (M+H ⁺ ).

Example 5

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

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (4.2a) (Example 4, Step 2) (60 mg, 0.15 mmol), 2-iodopyridine (60.1 mg, 0.29 mmol, 2.0 equiv) and _K2CO3 (40.5 mg, 0.29 mmol, 2.0 equiv) were combined in _dioxane (1.8 ml) to give a brown suspension. After sonication under argon for 3 minutes, copper(I) iodide (5.58 mg, 0.29 mmol, 0.2 equiv) and trans-N,N'-dimethylcyclohexane-1,2-diamine (8.34 mg, 9.27 μl, 0.59 mmol, 0.4 equiv) were added. The reaction mixture was stirred at 140 °C under argon for 2 h.

The reaction mixture was concentrated in vacuo and absorbed onto aminophase silica gel. The crude material was purified by flash chromatography on 20 g of silica gel eluting with a 20% to 100% EtOAc/heptane gradient. The title compound (46 mg, 65% yield) was obtained as a white solid, MS: m/e=487.3 (M+H ⁺ ).

Example 6

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

Using similar chemistry as described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-bromopyridine, the title compound was obtained as an off-white solid, MS: m/e = 487.2 (M+H ⁺ ).

Example 7

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 3-iodopyridine, the title compound was obtained as an off-white solid, MS: m/e = 487.3 (M+H ⁺ ).

Example 8

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-bromopyridine, the title compound was obtained as an off-white solid, MS: m/e = 487.2 (M+H ⁺ ).

Example 9

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 487.3 (M+H ⁺ ).

Example 10

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromo-6-methylpyridine, the title compound was obtained as a white solid, MS: m/e = 501.2 (M+H ⁺ ).

Example 11

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-bromo-2-methylpyridine, the title compound was obtained as a light yellow solid, MS: m/e = 501.3 (M+H ⁺ ).

Example 12

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromo-4-methylpyridine, the title compound was obtained as a white solid, MS: m/e = 501.2 (M+H ⁺ ).

Example 13

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 2-bromo-4-methylpyridine, the title compound was obtained as a white solid, MS: m/e = 501.3 (M+H ⁺ ).

Example 14

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-bromo-5-methylpyridine, the title compound was obtained as a white solid, MS: m/e = 501.2 (M+H ⁺ ).

Example 15

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-bromo-5-methylpyridine, the title compound was obtained as an off-white solid, MS: m/e = 501.2 (M+H ⁺ ).

Example 16

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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 5-bromo-2-methylpyridine, the title compound was obtained as a white crystalline solid, MS: m/e = 501.3 (M+H ⁺ ).

Example 17

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-bromo-3,5-dimethylpyridine hydrochloride, the title compound was obtained as a light yellow solid, MS: m/e = 515.2 (M+H ⁺ ).

Example 18

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-chloro-4-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 521.2, 523.2 (M+H ⁺ ).

Example 19

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

Using similar chemistry as described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 2-chloro-4-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 521.2, 523.2 (M+H ⁺ ).

Example 20

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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-chloro-5-iodopyridine, the title compound was obtained as a crystalline light yellow crystalline solid, MS: m/e = 521.2, 523.2 (M+H ⁺ ).

Example 21

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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 2-chloro-5-iodopyridine, the title compound was obtained as a crystalline light yellow crystalline solid, MS: m/e = 521.2, 523.2 (M+H ⁺ ).

Example 22

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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 5-iodo-2-methoxypyridine, the title compound was obtained as a white crystalline solid, MS: m/e = 517.4 (M+H ⁺ ).

Example 23

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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-iodo-2-methoxypyridine, the title compound was obtained as a white crystalline solid, MS: m/e = 517.3 (M+H ⁺ ).

Example 24

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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-bromo-1-methylpyridin-2(1H)-one, the title compound was obtained as a white crystalline solid, MS: m/e = 517.3 (M+H ⁺ ).

Example 25

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromopyrimidine, the title compound was obtained as a light yellow solid, MS: m/e = 488.1 (M+H ⁺ ).

Example 26

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-bromopyrimidine hydrochloride, the title compound was obtained as a white solid, MS: m/e = 488.2 (M+H ⁺ ).

Example 27

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-bromopyrimidine hydrochloride, the title compound was obtained as a white crystalline solid, MS: m/e = 488.3 (M+H ⁺ ).

Example 28

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 5-bromopyrimidine, the title compound was obtained as a white solid, MS: m/e = 488.2 (M+H ⁺ ).

Example 29

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-bromo-2,6-dimethylpyrimidine, the title compound was obtained as a light yellow solid, MS: m/e = 516.2 (M+H+).

Example 30

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-bromo-2-methylpyrimidine, the title compound was obtained as a white solid, MS: m/e = 502.4 (M+H+).

Example 31

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-bromo-2-methylpyrimidine, the title compound was obtained as a white solid, MS: m/e = 502.3 (M+H+).

Example 32

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromopyrazine, the title compound was obtained as a white crystalline solid, MS: m/e = 488.2 (M+H ⁺ ).

Example 33

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 2-bromopyrazine, the title compound was obtained as a white solid, MS: m/e = 488.4 (M+H+).

Example 34

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromopyrazine, the title compound was obtained as a white crystalline solid, MS: m/e = 502.2 (M+H ⁺ ).

Example 35

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-bromo-6-methylpyrimidine, the title compound was obtained as a white solid, MS: m/e = 502.2 (M+H+).

Example 36

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-bromo-6-methylpyrimidine, the title compound was obtained as a white solid, MS: m/e = 502.3 (M+H+).

Example 37

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-bromo-2-methoxypyrimidine, the title compound was obtained as a light yellow solid, MS: m/e = 518.3 (M+H+).

Example 38

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-bromo-2-(tert-butoxy)pyrimidine, the title compound was obtained as a white solid, MS: m/e = 504.3 ([M-tBu]+).

Example 39

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-bromo-2-ethoxypyrimidine, the title compound was obtained as a white solid, MS: m/e = 532.3 (M+H+).

Example 40

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-bromo-2-isopropoxypyrimidine, the title compound was obtained as a light yellow solid, MS: m/e = 546.3 (M+H+).

Example 41

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 2-(benzyloxy)-5-bromopyrimidine, the title compound was obtained as a light yellow solid, MS: m/e = 594.3 (M+H+).

Example 42

(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)-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 (Example 36) (60 mg, 0.116 mmol) was dissolved in chloroform (3.0 ml). 0.139 ml (0.139 mmol, 1.2 eq) of a 1 M solution of boron tribromide in dichloromethane in 0.5 ml of chloroform was added over a period of 5 min. The mixture was stirred at room temperature for 3.5 h and then quenched by the addition of _a 5% NaHCO solution (0.6 ml). The reaction mixture was diluted with 30 ml of ethyl acetate and evaporated. This operation was repeated twice. The crude product was purified by flash chromatography using a gradient of ethyl acetate: heptane 50: 50 to 100: 0, then MeOH: ethyl acetate 6: 94, then MeOH: dichloromethane 15: 85. The title compound (19 mg, 33% yield) was obtained as a light yellow solid, MS: m / e = 504.2 (M + H +).

Example 43

(9aS)-2-[2-(cyclopropyloxy)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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-bromo-2-cyclopropyloxypyrimidine, the title compound was obtained as a white solid, MS: m/e = 544.2 (M+H+).

Example 44

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 2-bromo-5-methoxypyrazine, the title compound was obtained as a light yellow crystalline solid, MS: m/e = 518.3 (M+H+).

Example 45

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 2-(benzyloxy)-5-bromopyrazine, the title compound was obtained as a light yellow solid, MS: m/e = 594.3 (M+H+).

Example 46

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-iodopyridazine, the title compound was obtained as a light yellow crystalline solid, MS: m/e = 488.3 (M+H+).

Example 47

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 3-iodopyridazine, the title compound was obtained as an off-white solid, MS: m/e = 488.3 (M+H+).

Example 48

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-iodo-6-methylpyridazine, the title compound was obtained as a white solid, MS: m/e = 502.2 (M+H+).

Example 49

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 6-bromo-3-methylpyridazin-3(2H)-one (CAS: 1123169-25-4), the title compound was obtained as a light yellow crystalline solid, MS: m/e = 518.3 (M+H+).

Example 50

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-bromopyridazine hydrobromide, the title compound was obtained as a yellow solid, MS: m/e = 488.2 (M+H+).

Example 51

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 5-iodo-3-methylpyridazin-3(2H)-one (CAS: 153239-91-9), the title compound was obtained as a light red solid, MS: m/e = 518.2 (M+H+).

Example 52

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromothiazole, the title compound was obtained as a light yellow crystalline solid, MS: m/e = 493.1 (M+H+).

Example 53

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromo-5-methylthiazole, the title compound was obtained as a white solid, MS: m/e = 507.1 (M+H+).

Example 54

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromo-4-methylthiazole, the title compound was obtained as a yellow solid, MS: m/e = 507.1 (M+H+).

Example 55

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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromothiazole-4-carbonitrile, the title compound was obtained as a light yellow solid, MS: m/e = 518.1 (M+H+).

Example 56

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[4-(trifluoromethyl)thiazole

-2-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromo-4-(trifluoromethyl)thiazole, the title compound was obtained as a yellow solid, MS: m/e = 561.1 (M+H+).

Example 57

(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

Using similar chemistry to that described in Example 1, Step 3, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromo-5-(trifluoromethyl)thiazole, the title compound was obtained as a light yellow solid, MS: m/e = 561.1 (M+H+).

Example 58

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-bromo-1-methyl-1H-imidazole, the title compound was obtained as a light yellow solid, MS: m/e = 490.2 (M+H+).

Example 59

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-bromo-1,4-dimethyl-1H-imidazole, the title compound was obtained as a light yellow solid, MS: m/e = 504.2 (M+H+).

Example 60

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-bromo-1,2-dimethyl-1H-imidazole, the title compound was obtained as a light yellow solid, MS: m/e = 504.2 (M+H+).

Example 61

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-iodo-2-methyl-1-(2,2,2-trifluoroethyl)-1H-imidazole, the title compound was obtained as a white solid, MS: m/e = 572.2 (M+H+).

Example 62

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-bromo-1-methyl-1H-pyrazole, the title compound was obtained as a white solid, MS: m/e = 490.2 (M+H+).

Example 63

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 3-bromo-1-methyl-1H-pyrazole, the title compound was obtained as a white solid, MS: m/e = 490.2 (M+H+).

Example 64

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 5-iodo-1-methyl-1H-pyrazole, the title compound was obtained as a white crystalline solid, MS: m/e = 490.2 (M+H+).

Example 65

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-iodo-1-methyl-1H-pyrazole, the title compound was obtained as a white crystalline solid, MS: m/e = 490.2 (M+H+).

Example 66

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 5-bromo-1,3-dimethyl-1H-pyrazole, the title compound was obtained as a white solid, MS: m/e = 504.2 (M+H+).

Example 67

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-bromo-1-methyl-1H-pyrazole, the title compound was obtained as a light yellow solid, MS: m/e = 490.2 (M+H+).

Example 68

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 3-bromo-1-methyl-1H-pyrazole, the title compound was obtained as a white crystalline solid, MS: m/e = 490.3 (M+H+).

Example 69

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 1-ethyl-4-iodo-1H-pyrazole, the title compound was obtained as a white crystalline solid, MS: m/e = 504.3 (M+H+).

Example 70

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 1-isopropyl-4-iodo-1H-pyrazole, the title compound was obtained as a white crystalline solid, MS: m/e = 518.3 (M+H+).

Example 71

(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

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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (CAS: [220299-49-0]), the title compound was obtained as a white solid.

Step 2: (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 :

To a well-stirred solution of (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione (85 mg, 0.140 mmol) in 2 ml of dioxane was added 0.35 ml (1.4 mmol, 10 equiv) of a 4 M solution of HCl in dioxane. The reaction was stirred at 55° C. for 4 h and at room temperature for 16 h. The solution was adjusted to >8 by the addition of 25% ammonium hydroxide solution (0.48 ml, 3.08 mmol, 22 equiv) and concentrated in vacuo. The residue was dissolved in ethyl acetate. The organic phase was washed with water and concentrated in vacuo. The crude material was purified by flash chromatography on _SiO2 (20 g) using a 50:50 to 0:100 heptane-ethyl acetate gradient followed by 4% MeOH in ethyl acetate as eluent. The title compound (43 mg, 64% yield) was obtained as a white solid, MS: m/e = 476.2 (M+H ⁺ ).

Example 72

(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

To a solution of (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 (36 mg, 0.076 mmol) in DMF (2 ml) at 0°C was added a 60% suspension of sodium hydride in mineral oil (3.9 mg, 0.1 mmol, 1.3 eq). The reaction was stirred for 5 min and 1-bromo-3-methoxypropane (12.7 mg, 9.3 μl, 0.083 mmol, 1.1 eq) was added. The yellow solution was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with water. After standard workup with ethyl acetate/water, the organic layer was dried over _MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography ( _SiO2 (20 g)) using a gradient of 50% to 100% ethyl acetate in heptane. The title compound (16 mg, 39% yield) was obtained as an off-white solid, MS: m/e = 548.2 (M+H ⁺ ).

Example 73

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 3-iodo-1-methyl-1,2,4-triazole, the title compound was obtained as a white crystalline solid, MS: m/e = 491.2 (M+H+).

Example 74

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

Step 1: 2-Chloro-6-fluoro-4-phenylethynyl-phenylamine

Using similar chemistry as described in Example 1, Step 1, starting from 2-chloro-6-fluoro-4-iodoaniline and phenylacetylene, the title compound was obtained as an orange solid, MS: m/e = 246.1, 248.1 (M+H ⁺ ).

Step 2: (9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydro Pyrazino[1,2-c]pyrimidine-1,6,8-trione:

Using similar chemistry as described in Example 1, Step 2, starting from 2-chloro-6-fluoro-4-phenylethynyl-phenylamine (Example 73, Step 1) and methyl 2-[(2RS)-2-methyl-3-oxo-piperazin-2-yl]acetate, the title compound was obtained as a white solid, MS: m/e = 424.3, 426.2 (M+H ⁺ ).

Step 3: (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 :

Using similar chemistry as described in Example 5, starting from (9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 73, Step 2) and 3-iodopyridine, the title compound was obtained as a light yellow solid, MS: m/e = 503.2, 505.2 (M+H ⁺ ).

Example 75

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

Using similar chemistry as described in Example 5, starting from (9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 73, Step 2) and 4-iodopyridine, the title compound was obtained as a light brown solid, MS: m/e = 503.2, 505.2 (M+H ⁺ ).

Example 76

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

Using similar chemistry as described in Example 5, starting from (9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 73, Step 2) and 2-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 503.2, 505.1 (M+H ⁺ ).

Example 77

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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2-chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 73, Step 2) and 4-iodo-1-methyl-1H-pyrazole, the title compound was obtained as an off-white solid, MS: m/e = 506.2, 508.2 (M+H ⁺ ).

Example 78

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

Using a similar separation technique as described in Example 4, Step 2; chiral separation of the enantiomers was achieved by chiral HPLC using a Chiralpak AD column with (heptane/EtOH/ _NH4OAc -60/39.9/0.1%) as eluent to afford (9aS)-7-[2-chloro-6-fluoro-4-(2-ethynylphenyl)phenyl]-9a-methyl-2-(4-pyridinyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione (1:1 mixture of stable atropisomers) as a light brown solid, MS: m/e = 506.3, 508.2 (M+H ⁺ ); and (9aR)-7-[2-chloro-6-fluoro-4-(2-ethynylphenyl)phenyl]-9a-methyl-2-(4-pyridinyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione (1 stable atropisomer = Entity A) as a light brown solid, (MS: 506.2, 508.2 (M+H ⁺ )); and (9aR)-7-[2-chloro-6-fluoro-4-(2-ethynylphenyl)phenyl]-9a-methyl-2-(4-pyridinyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione (1 stable atropisomer = Entity B) as a light brown solid (MS: 506.2, 508.1 (M+H ⁺ )).

Example 79

(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

To a solution of (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 (60 mg, 0.147 mmol) in DMF (2 ml) at 0°C was added a 60% suspension of sodium hydride in mineral oil (12 mg, 0.3 mmol, 2 eq). The reaction was stirred for 10 min and 2-bromo-2-methoxyethane (61 mg, 42 μl, 0.44 mmol, 3 eq) was added. The solution was stirred at 0°C for 2 h then warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water. After standard workup with ethyl acetate/water, the organic layer was dried over _MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography ( _SiO2 (20 g)) using a gradient of 20% to 100% ethyl acetate in heptane. The title compound (18 mg, 26% yield) was obtained as a white solid, MS: m/e = 468.2 (M+H ⁺ ).

Example 80

(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

Using similar chemistry to that described in Example 79, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 1-bromo-3-methoxypropane, the title compound was obtained as a white crystalline solid, MS: m/e = 482.2 (M+H+).

Example 81

(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

To a solution of (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 (60 mg, 0.147 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (61 mg, 38 μl, 0.26 mmol, 1.8 eq) in DMF (2 ml) was added K ₂ CO ₃ (61 mg, 0.44 mmol, 3 eq) at room temperature. The reaction was stirred for 10 min and 2-bromo-2-methoxyethane (61 mg, 42 μl, 0.44 mmol, 3 eq) was added. The solution was stirred at room temperature for 1 h and then warmed to 65° C. and stirred for 6 h. Then add trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (20 μ l) and the reaction is stirred at 65 ℃ for 16 h. Add another 20 μ l of trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester and the mixture is stirred at 65 ℃ for 1 h. The reaction mixture is quenched with water. After standard workup with ethyl acetate/water, the organic layer is dried over MgSO ₄ and concentrated in vacuo. The crude material is purified by flash chromatography (SiO ₂ (20 g)) using a gradient of 10% to 100% ethyl acetate in heptane and separated from the unreacted starting material. The title compound is obtained as a white crystalline solid, MS: m/e=492.2 (M+H ).

Example 82

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

To a solution of (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 (Example 4, Step 2) (55 mg, 0.134 mmol) and ethyl 4-bromobutyrate (52 mg, 39 μl, 0.27 mmol, 2.0 equiv) in DMF (1.5 ml) was added Cs ₂ CO ₃ (88 mg, 0.27 mmol, 2.0 equiv) at room temperature. The reaction was stirred at 70° C. for 16 h. The reaction mixture was quenched with water. After standard workup with ethyl acetate/water, the organic layer was dried over MgSO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography ( _SiO2 (20 g)) using a gradient of 10% to 100% ethyl acetate in heptane and separated from unreacted starting material. The title compound was obtained as a pale yellow waxy solid, MS: m/e = 524.3 (M+H+).

Example 83

(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

To a solution of (9aRS)-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 (Example 4, Step 1) (50 mg, 0.122 mmol) and 1-(bromomethyl)-3-methylbenzene (27 mg, 20 μl, 0.147 mmol, 1.2 equiv) in DMF (1.8 ml) was added _CsCO (80 mg, 0.24 _mmol , 2.0 equiv) at room temperature. The reaction was stirred at room temperature for 24 h. The reaction mixture was quenched with water. After standard workup with ethyl acetate/water, the organic layer was dried over _MgSO and concentrated in vacuo. The crude material was purified by flash chromatography ( _SiO2 (20 g)) using a gradient of 10% to 80% ethyl acetate in heptane and separated from unreacted starting material. The title compound (59 mg, 94%) was obtained as a white solid, MS: m/e = 514.3 (M+H+).

Example 84

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 1-(bromomethyl)-4-methylbenzene, the title compound was obtained as a white crystalline solid, MS: m/e = 514.3 (M+H+).

Example 85

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 1-(bromomethyl)-2-methylbenzene, the title compound was obtained as a white crystalline solid, MS: m/e = 514.3 (M+H+).

Example 86

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-(bromomethyl)-1,3-dimethylbenzene, the title compound was obtained as a white solid, MS: m/e = 528.4 (M+H+).

Example 87

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 1-(bromomethyl)-2-chlorobenzene, the title compound was obtained as a white solid, MS: m/e = 534.3, 536.3 (M+H+).

Example 88

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 1-(bromomethyl)-3-chlorobenzene, the title compound was obtained as a white solid, MS: m/e = 534.3, 536.3 (M+H+).

Example 89

(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

Using similar chemistry to that described in Example 83, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 1-(bromomethyl)-2-fluorobenzene, the title compound was obtained as a white crystalline solid, MS: m/e = 518.3 (M+H+).

Example 90

(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

Using similar chemistry to that described in Example 83, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 1-(bromomethyl)-3-fluorobenzene, the title compound was obtained as a white solid, MS: m/e = 518.3 (M+H+).

Example 91

(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

Using similar chemistry to that described in Example 83, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 1-(bromomethyl)-3-fluorobenzene, the title compound was obtained as a white solid, MS: m/e = 518.3 (M+H+).

Example 92

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 2-(bromomethyl)pyridine hydrobromide, the title compound was obtained as a light yellow crystalline solid, MS: m/e = 501.3 (M+H+).

Example 93

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 3-(bromomethyl)pyridine hydrobromide, the title compound was obtained as a white solid, MS: m/e = 501.3 (M+H+).

Example 94

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-(bromomethyl)pyridine hydrobromide, the title compound was obtained as a light yellow solid, MS: m/e = 501.3 (M+H+).

Example 95

(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

Using similar chemistry to that described in Example 83, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-(bromomethyl)pyrimidine hydrobromide, the title compound was obtained as a light yellow solid, MS: m/e = 502.3 (M+H+).

Example 96

(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

Using similar chemistry to that described in Example 79, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 1) and 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide, the title compound was obtained as a light brown solid, MS: m/e = 504.3 (M+H+).

Example 97

(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

Using similar chemistry to that described in Example 79, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-(bromomethyl)-1-methyl-1H-pyrazole, the title compound was obtained as a light yellow solid, MS: m/e = 504.3 (M+H+).

Example 98

(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

Using similar chemistry to that described in Example 79, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-(bromomethyl)-1-methyl-1H-pyrazole, the title compound was obtained as a white solid, MS: m/e = 504.2 (M+H+).

Example 99

(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

Using similar chemistry to that described in Example 79, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 1-(2-bromoethyl)-2-methyl-1H-imidazole hydrobromide, the title compound was obtained as a white solid, MS: m/e = 518.2 (M+H+).

Example 100

(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

Using similar chemistry to that described in Example 79, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 5-(2-bromoethyl)-1-methyl-1H-pyrazole, the title compound was obtained as a light yellow solid, MS: m/e = 518.3 (M+H+).

Example 101

(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

Using similar chemistry to that described in Example 79, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 4, Step 2) and 4-(2-bromoethyl)-1-methyl-1H-pyrazole, the title compound was obtained as a white solid, MS: m/e = 518.2 (M+H+).

Example 102

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

Step 1: 1-[(E)-cinnamyl]oxy-3-methoxy-propan-2-ol:

NaH (60% in oil) (5.44g, 136.2mmol) is added to a stirred solution of trans-myristanol (18.27g, 136.2mmol) in THF (150ml) at 0°C and the reaction mixture is stirred at 25°C for 30min. Then glycidyl methyl ether (10g, 113.5mmol) is added to the reaction mixture and the reaction mixture is stirred at 70°C for 16h. The reaction mixture is quenched with water and extracted with ethyl acetate (2x250ml). The combined organic layers are washed with brine, dried over Na ₂ SO ₄ , and concentrated. The crude material obtained is purified by column chromatography on silica gel (10-12% EtOAc/ hexane). The title compound (8.4g, 25%) is obtained as a yellow liquid.

Step 2: 1-[(E)-cinnamyl]oxy-3-methoxy-propan-2-one:

Dess-Martin periodinane (6.93g, 16.4mmol) is added to a stirred solution of 1-[(E)-cinnamyl] oxy-3-methoxy-propane-2-ol (Example 102, Step 1) (2.42g, 10.9mmol) in dichloromethane (60ml) at 25°C, and the reaction mixture is stirred at 25°C for 3h, quenched with water and extracted with dichloromethane (2x60ml). The combined organic layers are washed with saturated _NaHCO3 aqueous solution and brine, dried _{over Na2SO4} , and concentrated. The crude material obtained is purified by column chromatography on silica gel (15% EtOAc/hexane). The title compound (2.00g, 83%) is obtained as a yellow oil.

Step 3: (Z)-3-[[(E)-cinnamyl]oxymethyl]-4-methoxy-but-2-enoic acid ethyl ester:

To a solution of 1-[(E)-cinnamyl]oxy-3-methoxy-propan-2-one (Example 102, Step 2) (3.00 g, 13.6 mmol) in dichloromethane (150 ml) was added (ethoxycarbonylmethylene)triphenyl-phosphane (9.50 g, 27.3 mmol) and the reaction mixture was stirred at 25° C. for 24 h. The solvent was evaporated and the resulting crude material was purified by column chromatography (10-15% EtOAc/hexanes). The title compound (3.26 g, 82%) was obtained as a light yellow oil, MS: m/e=291.3 (M+H+).

Step 4: (3RS)-3-amino-3-[[(E)-cinnamyl]oxymethyl]-4-methoxy-butyric acid ethyl ester:

(Z)-3-[[(E)-cinnamyl]oxymethyl]-4-methoxy-but-2-enoic acid ethyl ester (Example 102, Step 3) (3.62 g, 12.5 mmol) was dissolved in a saturated solution of NH ₃ in ethanol (4 ml) in a sealed tube and heated at 90° C. for 24 h. The solvent was evaporated and the resulting crude material was purified by column chromatography (EtOAc). The title compound (1.9 g, 85% based on recovered starting material) was obtained as a yellow oil, MS: m/e=307.9 (M+H+).

Step 5: (3RS)-3-[[(E)-cinnamyl]oxymethyl]-3-[[2,6-difluoro-4-(2-phenylethynyl)benzene [4-Methoxy-2-amino-4-amino ...

Triphosgene (1.29 g, 4.37 mmol) was added to a stirred solution of 2,6-difluoro-4-phenylethynyl-phenylamine (Example 1, Step 1) (1.00 g, 4.37 mmol) in toluene (100 ml) at 25°C and the reaction mixture was stirred at 90°C for 4 h. The solvent was evaporated and the resulting isocyanate was diluted with dichloromethane (50 ml) and added to a stirred solution of (3RS)-3-amino-3-[[(E)-cinnamyl]oxymethyl]-4-methoxy-butyric acid ethyl ester (Example 102, Step 4) (1.34 g, 4.37 mmol) and _Et3N (1.82 ml, 13.1 mmol) in dichloromethane (30 ml) at ₀ °C. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over _Na2SO4 and concentrated. The resulting crude material was purified by column chromatography on silica gel (30-40% EtOAc/hexanes) to give the title compound (1.38 g, 56%) as an off-white solid, MS: m/e = 563.2 (M+H+).

Step 6: (6RS)-6-[[(E)-cinnamyl]oxymethyl]-3-[2,6-difluoro-4-(2-phenylethynyl)benzene methyl]-6-(methoxymethyl)hexahydropyrimidine-2,4-dione:

A solution of (3RS)-3-[[(E)-cinnamyl]oxymethyl]-3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]-carbamoylamino]-4-methoxy-butyric acid ethyl ester (Example 102, Step 5) (3.00 g, 5.34 mmol) in THF (30 ml) was added at 0° C. to a well-stirred solution of NaH (60% in oil) (320 mg, 8.01 mmol) in THF (40 ml) and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×120 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated. The resulting crude material was purified by column chromatography on silica gel (20-30% EA/hexanes) to afford the title compound (2.50 g, 91%) as an off-white solid, MS: m/e=517.0 (M+H+).

Step 7: N-[2-[(6RS)-6-[[(E)-cinnamyl]oxymethyl]-3-[2,6-difluoro-4-(2-phenylethynyl)] [methyl)phenyl]-6-(methoxymethyl)-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamic acid tert-butyl ester:

To a solution of (6RS)-6-[[(E)-cinnamyl]oxymethyl]-3-[2,6-difluoro-4-(2-phenylethynyl)-phenyl]-6-(methoxymethyl)hexahydropyrimidine-2,4-dione (Example 102, Step 6) (1.00 g, 1.94 mmol) in DMF (6.7 ml) was added tert-butyl (2-bromoethyl)carbamate (0.868 g, 3.87 mmol) and cesium carbonate (1.39 g, 4.26 mmol). The reaction mixture was stirred at 55° C. for 16 h. The solvent was evaporated in vacuo, and the residue was dissolved in 60 ml of EtOAc/heptane 3:1. The insoluble material was filtered off, and the filtrate was washed with water, brine, dried over Na ₂ SO ₄ , and concentrated. The resulting crude material was purified by flash chromatography on silica gel using a gradient of 0-40% EtOAc in hexanes to afford the title compound (1.18 g, 92%) as a white foam, MS: m/e = 560.2 ((M-Boc)+H+).

Step 8: N-[2-[(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-(hydroxymethyl)-6-(methyl [oxymethyl]-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamic acid tert-butyl ester:

To a solution of tert-butyl N-[2-[(6RS)-6-[[(E)-cinnamyl]oxymethyl]-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-(methoxymethyl)-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamate (Example 102, Step 7) (1.150 g, 1.74 mmol) in nitromethane (30 ml) was added cerium (III) chloride heptahydrate (0.714 g, 1.92 mmol), sodium iodide (0.287 g, 1.92 mmol) and 1,3-propylene glycol (0.208 g, 194 μl, 1.92 mmol). The mixture was stirred at 100° C. for 32 h. The reaction mixture was concentrated in vacuo and dissolved in 60 ml of dichloromethane/MeOH 93:7. The solid was filtered off and the filtrate was washed with water. The organic phase was concentrated and the residue was purified by flash chromatography on a Silica-Aminophase column using 1:1 EtOAc/heptane, then EtOAc and finally EtOAc/MeOH 95:5 as eluent to yield 490 mg of a pale yellow solid containing debocified material and difficult-to-isolate impurities. This material was dissolved in THF (22 ml), triethylamine (0.168 g, 231 μl, 1.66 mmol) and di-tert-butyl dicarbonate (0.289 g, 1.33 mmol) were added, and the mixture was stirred at 25° C. for 2 h. The mixture was concentrated and the residue was purified by flash chromatography on silica gel using a 0-100% EtOAc gradient in heptane to yield the title compound (0.362 g, 38%) as a white solid, MS: m/e=444.2 ((M-Boc)+H+).

Step 9: (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-1,6,8- Trioxo-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-2-carboxylic acid tert-butyl ester:

To a solution of tert-butyl N-[2-[(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-(hydroxymethyl)-6-(methoxymethyl)-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamate (Example 102, Step 8) (0.260 g, 0.478 mmol) in dichloromethane (11 ml) and DMF (1.6 ml) was added 0.900 g of powdered activated 4A molecular sieves, pyridinium dichromate (0.675 g, 1.79 mmol, 3.75 equivalents) and acetic acid (0.124 g, 118 μl, 2.06 mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with 50 ml of EtOAc, then Speedex (approximately 5 g) was added and the suspension was stirred for 5 min. The solid was filtered and washed with 50 ml of EtOAc. The filtrate was dried _{over Na2SO4} and evaporated. The crude material obtained was purified by column chromatography on silica gel using a gradient of 0-80% EtOAc in heptane to afford the title compound (0.114 g, 54%) as a white solid, MS: m/e = 440.2 ((M-Boc)+H+).

Step 10: (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2,3- 4,9-Tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione:

A solution of (9aRS)-tert-butyl 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-1,6,8-trioxo-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-2-carboxylate (Example 102, Step 9) (0.140 g, 0.259 mmol) in 7 ml of dichloromethane was cooled to 0-2°C. A 4N solution of HCl/dioxane (0.519 ml, 2.08 mmol, 8 equiv) was then added. After stirring at room temperature for 2 h, the solution was diluted with 20 ml of dichloromethane, quenched by the addition of 5 ml of ₅ % NaHCO₃ solution, and then extracted with dichloromethane. The organic layer was washed with brine, dried _{over Na₂SO₄} , and concentrated to yield the title compound (0.109 g, 96%) as a crystalline white solid, MS: m/e = 440.2 (M+H⁺).

Step 11: (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:

Using similar chemistry as described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 102, Step 10) and 3-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 517.2 (M+H ⁺ ).

Example 103

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

Chiral separation of the racemate of Example 102 was achieved by chiral HPLC on a Reprosil Chiral-NR column using (hexane/EtOH/ _NH4OAc -70/30/0.1%) as eluent to yield (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(3-pyridinyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione as a white solid (MS: 517.3 (M+H ⁾ )); and (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2-(3-pyridinyl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-1,6,8-trione as a white solid (MS: 517.3 (M+H ⁺ )).

Example 104

(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

Using similar chemistry to that described in Example 5, starting from (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-(methoxymethyl)-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 102, Step 10) and 4-iodo-1-methyl-1H-pyrazole, the title compound was obtained as a white solid, MS: m/e = 520.2 (M+H ⁺ ).

Example 105

(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

The title compound was obtained by chiral HPLC separation of racemic (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 (Example 104) on a Chiralpak AD column using (heptane/EtOH/ _NH4OAc -60/40/0.1%) as eluent, as an off-white solid, MS: m/e = 520.2 (M+H ⁺ ).

Example 106

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

Step 1: 1-allyloxybutan-2-ol:

By 1,2-butylene oxide (19.33g, 332.82mmol) solution in THF (100ml) joins in the suspension of NaH (13.31g, 332.82mmol) in THF (130ml) at 0 ℃ and reaction mixture is stirred 30min at 25 ℃.Then add the solution of allyl alcohol (20.0g, 277.35mmol) in THF (70ml) at 25 ℃ and reaction mixture is refluxed 16h.After quenching with water and extracting with EtOAc (2x500ml), by the organic layer Na ₂ SO ₄ that merges and concentrate.The crude material obtained is passed through the column chromatography (15-20%EtOAc/ hexane) purification on silica gel.Obtain title compound (13g, 36%), be yellow liquid.

Step 2: 1-allyloxybutan-2-one:

To a solution of 1-allyloxy-butane-2-ol (Example 106, Step 1) (5.0 g, 38.5 mmol) in dichloromethane (100 ml) was added pyridinium dichromate (20.72 g, 96.15 mmol) at 25° C. and the reaction mixture was stirred at 25° C. for 5 h, filtered through celite, and the filtrate was concentrated. The title compound (4.3 g, 87%) was obtained as a brown oil that was pure enough to be used directly in the next step.

Step 3: Ethyl (EZ)-3-(allyloxymethyl)pent-2-enoate:

To a suspension of NaH (405 mg, 10.1 mmol) in THF (20 ml) was added triethyl phosphinoacetate (2.62 g, 11.7 mmol) at 0° C. and the reaction mixture was stirred at 25° C. for 30 min. A solution of 1-allyloxy-butane-2-one (Example 106, Step 2) (1 g, 7.80 mmol) in THF (5 ml) was then added and the reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was quenched with saturated NH ₄ Cl aqueous solution and extracted with EtOAc (2x40 mL). The combined organic layers were dried over Na ₂ SO ₄ , concentrated, and the resulting crude material was purified by column chromatography on silica gel (10-15% EtOAc/hexane). The title compound (1.0 g, 65%) was obtained as a yellow liquid.

Step 4: (3RS)-3-(allyloxymethyl)-3-amino-pentanoic acid ethyl ester:

Ethyl (EZ)-3-(allyloxymethyl)pent-2-enoate (Example 102, Step 3) (2.8 g, 14.12 mmol) was dissolved in a saturated solution of _NH in ethanol (5 ml) in a sealed tube and heated at 90° C. for 16 h. The solvent was evaporated and the resulting crude material was purified by column chromatography on silica gel (80-100% EtOAc/hexanes). The title compound (1.5 g, 49% based on recovered starting material (1.0 g)) was obtained as a light yellow liquid.

Step 5: (3RS)-3-(allyloxymethyl)-3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]-amino [Formylamino] ethyl valerate:

Triphosgene (2.76 g, 9.3 mmol) was added to a stirred solution of 2,6-difluoro-4-phenylethynyl-phenylamine (Example 1, Step 1) (2.13 g, 9.3 mmol) in toluene (100 ml) at 25°C and the reaction mixture was stirred at 90°C for 4 h. The solvent was evaporated and the resulting isocyanate was diluted with dichloromethane (50 ml) and added to a stirred solution of (3RS)-3-(allyloxymethyl)-3-amino-pentanoic acid ethyl ester (Example 106, Step 4) (2.0 g, 9.3 mmol) and _Et3N (3.91 ml, 27.9 mmol) in dichloromethane (50 ml) at 0°C. The reaction mixture was then stirred at 25°C for 16 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried _{over Na2SO4} and concentrated. The resulting crude material was purified by column chromatography on silica gel (15% EtOAc/hexanes) to give the title compound (2.0 g, 46%) as an off-white solid, MS: m/e = 471.1 (M+H+).

Step 6: (6RS)-6-(allyloxymethyl)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-ethyl Hexahydropyrimidine-2,4-dione:

A solution of (3RS)-3-(allyloxymethyl)-3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]-carbamoylamino]pentanoic acid ethyl ester (Example 106, Step 5) (3.1 g, 5.51 mmol) in THF (20 ml) was added at 0° C. to a well-stirred suspension of NaH (60% in oil) (0.220 g, 5.51 mmol) in THF (20 ml) and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×200 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated. The resulting crude material was purified by column chromatography on silica gel (20% EtOAc/hexanes) to afford the title compound (2.0 g, 85%) as an off-white solid, MS: m/e=425.4 (M+H ).

Step 7: N-[2-[(6RS)-6-(allyloxymethyl)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]- 6-ethyl-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamic acid tert-butyl ester:

To a solution of (3RS)-3-(allyloxymethyl)-3-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]-carbamoylamino]pentanoic acid ethyl ester (Example 106, Step 6) (1.00 g, 2.36 mmol) in DMF (8.0 ml) was added tert-butyl (2-bromoethyl)carbamate (1.06 g, 4.71 mmol) and cesium carbonate (1.69 g, 5.18 mmol). The reaction mixture was stirred at 55° C. for 16 h and at 70° C. for 6 h. The solvent was evaporated in vacuo, and the residue was dissolved in 60 ml of EtOAc/heptane 3:1. The insoluble material was filtered off, and the filtrate was washed with water, brine, dried over Na ₂ SO ₄ , and concentrated. The resulting crude material was purified by flash chromatography on silica gel using a gradient of 0-40% EtOAc in hexanes to afford the title compound (1.34 g, 92%) as a light yellow foam, MS: m/e = 468.3 ((M-Boc)+H+).

Step 8: N-[2-[(6RS)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-ethyl-6-(hydroxymethyl)- [1-yl]-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamic acid tert-butyl ester:

In a 25 ml glass pressure vessel, a solution of tert-butyl N-[2-[(6RS)-6-(allyloxymethyl)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-6-ethyl-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamate (Example 106, Step 7) (0.525 g, 0.925 mmol) and 1,3-dimethylbarbituric acid (0.289 g, 1.85 mmol) in methanol (10 ml) was degassed using an argon stream and Pd(TPP) ₄ catalyst (53.4 mg, 46.2 μmol, 5 mol%) was added. The vessel was sealed and the mixture was stirred at 80° C. for 3 h and then at room temperature for an additional 16 h. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel using a 0-100% EtOAc in heptane gradient to give the title compound (0.34 g, 70%) as a non-crystalline colorless resin, MS: m/e = 428.3 ((M-Boc) + H+).

Step 9: (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-1,6,8-trioxo- tert-Butyl 4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-2-carboxylate:

To a solution of tert-butyl N-[2-[(6RS)-6-(allyloxymethyl)-3-[2,6-difluoro-4-(2-phenylethynyl)ethynyl]-6-ethyl-2,4-dioxo-hexahydropyrimidin-1-yl]ethyl]carbamate (Example 106, Step 8) (0.620 g, 1.18 mmol) in dichloromethane (33 ml) and DMF (3.5 ml) was added 1.5 g of powdered activated 4A molecular sieves, pyridinium dichromate (1.55 g, 4.11 mmol), and acetic acid (0.282 g, 269 μl, 4.7 mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with 60 ml of EtOAc, then Speedex (approximately 5 g) was added and the suspension was stirred for 5 min. The solid was filtered and washed with 60 ml _of EtOAc. The filtrate was dried over _Na₂SO₄ and evaporated. The resulting crude material was purified by column chromatography on silica gel using a gradient of 0-80% EtOAc in heptane to afford the title compound (0.274 g, 45%) as a white solid, MS: m/e = 424.2 ((M-Boc)+H+).

Step 10: (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4,9-tetrahydro Pyrazino[1,2-c]pyrimidine-1,6,8-trione:

A solution of (9aRS)-tert-butyl 7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-1,6,8-trioxo-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidine-2-carboxylate (Example 106, Step 9) (0.280 g, 0.535 mmol) in 12 ml of dichloromethane was cooled to 0-2°C. A 4N solution of HCl in dioxane (1.07 ml, 4.28 mmol, 8 equiv) was then added. After stirring at room temperature for 2 h, the solution was diluted with 20 ml of dichloromethane, quenched by the addition of 5 ml of ₅ % NaHCO₃ solution, and then extracted with dichloromethane. The organic layer was washed with brine, dried over _Na₂SO₄ , and concentrated to yield the title compound (0.221 _g , 98%) as a crystalline white solid, MS: m/e = 424.2 (M+H⁺).

Step 11: (9aS)- and (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4- 9-Tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione:

Chiral separation of the enantiomers was achieved by chiral HPLC using a Chiralpak IE column with (hexane/EtOH/DCM/ _Et2N -70/20/10/0.1%) as eluent to afford (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione as a light yellow solid (MS: 424.2 (M+H ⁺ )); and (9aR)-7-[2,6-difluoro-4-(2-phenylethynyl)-phenyl]-9a-ethyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione as a light yellow solid (MS: 424.2 (M+H ⁺ )).

Step 12: (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:

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 106, Step 11) and 3-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 501.3 (M+H+).

Example 107

(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

Using similar chemistry as described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-ethyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 106, Step 11) and 4-iodo-1-methyl-1H-pyrazole, the title compound was obtained as a white solid, MS: m/e = 504.3 (M+H ⁺ ).

Example 108

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

Step 1: 2-Fluoro-4-phenylethynyl-phenylamine

Using similar chemistry as described in Example 1, Step 1, starting from 2-fluoro-4-iodoaniline and phenylacetylene, the title compound was obtained as a tan solid, MS: m/e = 212.2 (M+H ⁺ ).

Step 2: (9aRS)-7-[2-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c]pyrimidine-1,6,8-trione:

Using similar chemistry as described in Example 1, Step 2, starting from 2-fluoro-4-phenylethynyl-phenylamine (Example 107, Step 1) and methyl 2-[(2RS)-2-methyl-3-oxo-piperazin-2-yl]acetate, the title compound was obtained as a white solid, MS: m/e = 392.2 (M+H ⁺ ).

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

Using similar chemistry as described in Example 5, starting from (9aRS)-7-[2-fluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 107, Step 2) and 3-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 469.3 (M+H ⁺ ).

Example 109

(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

Step 1: (9aRS)-7-(2,6-difluoro-4-iodo-phenyl)-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c] Pyrimidine-1,6,8-trione:

To a solution of 2,6-difluoro-4-iodo-phenylamine (3.00 g, 11.8 mmol) in toluene (80 ml) was added CDI (5.72 g, 35.3 mmol) and the reaction mixture was stirred at 110° C. for 1 h. (2-Methyl-3-oxo-piperazin-2-yl)-acetic acid methyl ester (2.63 g, 14.1 mmol) was then added and the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated and the resulting crude product was purified by column chromatography on silica gel (70% EA/hexane) to afford the title compound (4.37 g, 85%) as an off-white solid, MS: m/e=436.2 (M+H ⁺ ).

Step 2: (9aRS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9- tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione:

To a solution of (9aRS)-7-(2,6-difluoro-4-iodophenyl)-9a-methyltetrahydro-1H-pyrazino[1,2-c]pyrimidine-1,6,8(2H,7H)-trione (Example 109, Step 1) (2.5 g, 5.74 mmol) in THF (15 ml) under argon was added 1-ethynyl-2-fluorobenzene (1.04 g, 977 μl, 8.62 mmol), _Et3N (2.91 g, 4 ml, 28.7 mmol), bis(triphenylphosphine)palladium(II) chloride (80.6 mg, 115 μmol, 0.02 equiv), triphenylphosphine (15.1 mg, 57.4 μmol, 0.01 equiv) and copper(I) iodide (5.47 mg, 28.7 μmol, 0.005 equiv). The reaction mixture was heated to 50°C and stirred for 2 h. The crude material was purified by flash chromatography (silica gel, 50 g, 50% to 100% EtOAc in heptane). Fractions were concentrated in vacuo to give 2.00 g of the title compound as a white powder, MS: m/e = 428.2 (M+H ⁺ ).

Step 3: (9aS)- and (9aR)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl- 2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione:

Chiral separation of the enantiomers was achieved by chiral HPLC using a Chiral AD column with (heptane/EtOH-60/40) to afford (9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione as a light yellow solid (MS: 428.3 (M+H ⁺ )); and (9aR)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione as a light yellow solid (MS: 428.3 (M+H ⁺ )).

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

Using similar chemistry as described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 109, Step 3) and 3-iodopyridine, the title compound was obtained as a white solid, MS: m/e = 505.3 (M+H ⁺ ).

Example 110

(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

Using similar chemistry as described in Example 1, Step 3, starting from (9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 109, Step 3) and 4-bromopyrimidine hydrochloride, the title compound was obtained as a light yellow solid, MS: m/e = 506.2 (M+H ⁺ ).

Example 111

(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

Using similar chemistry to that described in Example 5, starting from (9aS)-7-[2,6-difluoro-4-[2-(2-fluorophenyl)ethynyl]phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 109, Step 3) and 4-iodo-1-methyl-1H-pyrazole, the title compound was obtained as a light yellow crystalline solid, MS: m/e = 508.3 (M+H ⁺ ).

Example 112

(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

Step 1: 2-Chloro-4-phenylethynyl-phenylamine

Using similar chemistry as described in Example 1, Step 1, starting from 2-chloro-4-iodoaniline and phenylacetylene, the title compound was obtained as a light brown solid, MS: m/e = 228.1, 230.0 (M+H ⁺ ).

Step 2: (9aRS)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino [1,2-c]pyrimidine-1,6,8-trione:

Using similar chemistry as described in Example 1, Step 2, starting from 2-chloro-4-phenylethynyl-phenylamine (Example 112, Step 1) and methyl 2-[(2RS)-2-methyl-3-oxo-piperazin-2-yl]acetate, the title compound was obtained as a white solid, MS: m/e = 406.3, 408.2 (M+H ⁺ ).

Step 3: (9aS)- and (9aR)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrakis Hydropyrazino[1,2-c]pyrimidine-1,6,8-trione:

Chiral separation of the enantiomers was achieved by chiral HPLC using a Reprosil Chiral NR column with (heptane/EtOH - 60/40) to afford (9aS)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione as a white solid (MS: 428.3 (M+H ⁺ )); and (9aR)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione as a white solid (MS: 428.3 (M+H ⁺ )).

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

Using similar chemistry as described in Example 5, starting from (9aS)-7-[2-chloro-4-(2-phenylethynyl)phenyl]-9a-methyl-2,3,4,9-tetrahydropyrazino[1,2-c]pyrimidine-1,6,8-trione (Example 112, Step 3) and 4-iodo-1-methyl-1H-pyrazole, the title compound was obtained as an off-white solid, MS: m/e = 488.2, 490.2 (M+H ⁺ ).

Claims (14)

1. A compound of formula I, in ^R1 is hydrogen, F, or Cl; L is a bond or a _C1-7 alkylene group; ^R2 is –( _CH2 ) _nOC1-7 alkyl, halogen-substituted _C1-7 alkyl, –( _CH2 ) _nC (O) _OC1-7 alkyl, phenyl substituted with _C1-7 alkyl or halogen, or _a 5- or 6-membered heteroaryl group selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, wherein the heteroaryl group is optionally substituted with _C1-7 alkyl, halogen, _C1-7 alkoxy, =O, benzyloxy, _C3-7 cycloalkyloxy, hydroxyl, cyano, halogen-substituted _C1-7 alkyl _or –( _CH2 ) _nOC1-7 alkyl; n is 1, 2, or 3; ^R3 is hydrogen, _C1-7 alkyl _, or -( _CH2 ) _nOC1-7 alkyl; ^R4 is phenyl, pyridinyl, or pyrimidinyl, which may optionally be substituted with F; Y is CF or CCl; Or its medicinal salt, or its stereoisomer. 2. The compound according to claim 1, wherein the compound is as shown in formula Ia: in ^R1 is F or Cl; ^R2 is –( _CH2 ) _nOC1-7 alkyl, halogen-substituted _C1-7 alkyl _, or –( _CH2 ) _nC (O) _OC1-7 alkyl. n is 1, 2, or 3; ^R3 is hydrogen, _C1-7 alkyl _, or -( _CH2 ) _nOC1-7 alkyl; Or its medicinal salt, or its stereoisomer. 3. The compound according to claim 2, wherein the 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]butyrate. 4. The compound according to claim 1, wherein the compound is as shown in formula Ib: in ^R1 is F or Cl; L is a _C1-7 alkylene group; ^R2 is a phenyl group substituted with a _C1-7 alkyl group or a halogen; ^R3 is hydrogen, _C1-7 alkyl _, or -( _CH2 ) _nOC1-7 alkyl; n is 1, 2, or 3; Or its medicinal salt, or its stereoisomer. 5. The compound according to claim 4, wherein the 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 according to claim 1, wherein the compound is as shown in formula Ic: in ^R1 is hydrogen, F, or Cl; L is a bond or a _C1-7 alkylene group; ^R2 is a 5- or 6-membered heteroaryl group selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, wherein the heteroaryl group is optionally substituted with a _C1-7 alkyl, halogen, _C1-7 alkoxy, =O, benzyloxy, _C3-7 cycloalkyloxy, hydroxyl, cyano, a _C1-7 alkyl group substituted with a halogen, or substituted with –( _CH2 ) _{nOC1-7 alkyl} . n is 1, 2, or 3; ^R3 is hydrogen, _C1-7 alkyl _, or -( _CH2 ) _nOC1-7 alkyl; ^R4 is phenyl, pyridinyl, or pyrimidinyl, which may optionally be substituted with F; Y is CF or CCl; Or its medicinal salt, or its stereoisomer. 7. The compound according to claim 6, wherein the 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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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-pyrazin[1,2-c]pyrimidin-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-thiazo-2-yl-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidin-1,6,8-trione (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-(5-methylthiazo-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-methylthiazo-2-yl)-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidin-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]thiazolyl-4-carboxynitrile (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[4-(trifluoromethyl)thiazo-2-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidin-1,6,8-trione (9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methyl-2-[5-(trifluoromethyl)thiazo-2-yl]-4,9-dihydro-3H-pyrazino[1,2-c]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-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. The compound according to any one of claims 1-2, 4 and 6, wherein the pharmaceutical salt is an acid addition salt and the stereoisomer is an optical isomer. 9. The compound according to claim 8, wherein the optical isomer is an enantiomer or a racemic mixture. 10. A method for preparing a compound as defined in any one of claims 1 to 7, the method comprising: a) Compounds of formula IV It reacts with compounds of formula XLR ² , where X is a halogen. Compound of Formula I was obtained Furthermore, if necessary, the obtained compound can be converted into a pharmaceutical acid addition salt. 11. The compound according to any one of claims 1-7, which is used as a therapeutically active substance. 12. The compound according to any one of claims 1-7, for the treatment of Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, autism, neuroprotection, cancer, depression and type 2 diabetes. 13. A pharmaceutical composition comprising a compound as described in any one of claims 1-9 and a pharmaceutical excipient. 14. Use of the compound according to any one of claims 1-9 for the preparation of a medicament for the treatment of Parkinson's disease, anxiety, vomiting, obsessive-compulsive disorder, autism, neuroprotection, cancer, depression, and type 2 diabetes.