Field of the Invention

The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to monoacylglycerol lipase (MAGL) inhibitors for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine and/or depression in a mammal.

Background of the Invention Endocannabinoids (ECs) are signaling lipids that exert their biological actions by interacting with cannabinoid receptors (CBRs), CB1 and CB2. They modulate multiple physiological processes including neuroinflammation, neurodegeneration and tissue regeneration (Iannotti, F.A., et al, Progress in lipid research 2016, 62, 107-28.). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacyglycerol lipases (DAGL) and hydrolyzed by the monoacylglycerol lipase, MAGL. MAGL hydrolyses 85% of 2-AG; the remaining 15% being hydrolysed by ABHD6 and ABDH12 (Nomura, D.K., et al , Science 2011, 334, 809.). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes and microglia cells (Chanda, P.K., et al. , Molecular pharmacology 2010, 78, 996; Viader, A., et al, Cell reports 2015, 12, 798.). 2-AG hydrolysis results in the formation of arachidonic acid (AA), the precursor of prostaglandins (PGs) and leukotrienes (LTs). Oxidative metabolism of AA is increased in inflamed tissues. There are two principal enzyme pathways of arachidonic acid oxygenation involved in inflammatory processes, the cyclo oxygenase which produces PGs and the 5-lipoxygenase which produces LTs. Of the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at sites of inflammation, e.g. in the

CNE/07.12.2018 cerebrospinal fluid of patients suffering from neurodegenerative disorders and are believed to contribute to inflammatory response and disease progression. Mice lacking MAGL (Mgll-/-) exhibit dramatically reduced 2- AG hydrolase activity and elevated 2- AG levels in the nervous system while other arachidonoyl-containing phospho- and neutral lipid species including anandamide (AEA), as well as other free fatty acids, are unaltered.

Conversely, levels of AA and AA-derived prostaglandins and other eicosanoids, including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2), are strongly decreased. Phospholipase A ₂ (PLA ₂ ) enzymes have been viewed as the principal source of AA, but cPLA2-deficient mice have unaltered AA levels in their brain, reinforcing the key role of MAGL in the brain for A A production and regulation of the brain inflammatory process.

Neuroinflammation is a common pathological change characteristic of diseases of the brain including, but not restricted to, neurodegenerative diseases (e.g. multiple sclerosis, Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy and mental disorders such as anxiety and migraine). In the brain, production of eicosanoids and prostaglandins controls the neuroinflammation process. The pro-inflammatory agent lipopoly saccharide (LPS) produces a robust, time-dependent increase in brain eicosanoids that is markedly blunted in Mgll-/- mice. LPS treatment also induces a widespread elevation in pro-inflammatory cytokines including interleukin-1 -a (IL-l-a), IL-lb, IL-6, and tumor necrosis factor-a (TNF-a) that is prevented in Mgll-/- mice.

Neuroinflammation is characterized by the activation of the innate immune cells of the central nervous system, the microglia and the astrocytes. It has been reported that anti inflammatory drugs can suppress in preclinical models the activation of glia cells and the progression of disease including Alzheimer’s disease and mutiple sclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403.). Importantly, genetic and/or pharmacological disruption of MAGL activity also blocks LPS -induced activation of microglial cells in the brain

(Nomura, D.K., et al , Science 2011, 334, 809.).

In addition, genetic and/or pharmacological disruption of MAGL activity was shown to be protective in several animal models of neurodegeneration including, but not restricted to, Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. For example, an irreversible MAGL inhibitor has been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, J.Z., el al, Nature chemical biology 2009, 5, 37.). Systemic injection of such inhibitor recapitulates the Mgll-/- mice phenotype in the brain, including an increase in 2-AG levels, a reduction in AA levels and related eicosanoids production, as well as the prevention of cytokines production and microglia activation following LPS-induced neuroinflammation (Nomura, D.K., et al, Science 2011, 334, 809.), altogether confirming that MAGL is a dmggable target.

Consecutive to the genetic and/or pharmacological disruption of MAGL activity, the endogenous levels of the MAGL natural substrate in the brain, 2-AG, are increased. 2-AG has been reported to show beneficial effects on pain with, for example, anti-nociceptive effects in mice (Ignatowska-Jankowska B. et al, J. Pharmacol. Exp. Ther. 2015, 353,

424.) and on mental disorders, such as depression in chronic stress models (Zhong P. et al, Neuropsychopharmacology 2014, 39, 1763.).

Furthermore, oligodendrocytes (OLs), the myelinating cells of the central nervous system, and their precursors (OPCs) express the cannabinoid receptor 2 (CB2) on their membrane. 2-AG is the endogenous ligand of CB1 and CB2 receptors. It has been reported that both cannabinoids and pharmacological inhibition of MAGL attenuate OLs’s and OPCs’s vulnerability to excitotoxic insults and therefore may be neuroprotective (Bernal- Chico, A., et al, Glia 2015, 63, 163.). Additionally, pharmacological inhibition of MAGL increases the number of myelinating OLs in the brain of mice, suggesting that MAGL inhibition may promote differentiation of OPCs in myelinating OLs in vivo (Alpar, A., et al , Nature communications 2014, 5, 4421.). Inhibition of MAGL was also shown to promote remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A. et al, Journal of Neuroscience 2017, 37 (35), 8385.).

Finally, in recent years, metabolism is talked highly important in cancer research, especially the lipid metabolism. Researchers believe that the de novo fatty acid synthesis plays an important role in tumor development. Many studies illustrated that

endocannabinoids have anti-tumorigenic actions, including anti-proliferation, apoptosis induction and anti-metastatic effects. MAGL as an important decomposing enzyme for both lipid metabolism and the endocannabinoids system, additionally as a part of a gene expression signature, contributes to different aspects of tumourigenesis (Qin, FL, et al. ,

Cell Biochem. Biophys. 2014, 70, 33; Nomura DK et al, Cell 2009, 140(1), 49-61;

Nomura DK et al, Chem. Biol. 2011, 18(7), 846-856). Suppressing the action and/or the activation of MAGL is a promising new therapeutic strategy for the treatment or prevention of neuroinflammation,

neurodegenerative diseases, pain, cancer and mental disorders. Furthermore, suppressing the action and/or the activation of MAGL is a promising new therapeutic strategy for providing neuroprotection and myelin regeneration. Accordingly, there is a high unmet medical need for new MAGL inhibitors.

Summary of the Invention

In a first aspect, the present invention provides a compound of formula (Ie)

or a pharmaceutically acceptable salt thereof, wherein:

R ^la is selected from the group consisting of

(i) C _j. e-alkyl;

(ii) Ci- ₆ -alkoxy; and

(iii) aryl substituted with R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , or a possible combination thereof; R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

each of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkoxy, hydroxy, amino, -NFLalkyl, -N(alkyl) ₂ and cyano;

R ⁷ is selected from the group consisting of hydrogen, halogen, alkoxy, cycloalkyloxy and hydroxy;

each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is independently selected from the group consisting of hydrogen, hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl, haloalkyl, alkylsulfanyl, amino, -NFLalkyl, -N(alkyl) ₂ , -NFLaryl, -NFLheteroaryl

and a group R ¹³ is selected from the group consisting of hydrogen, oxo, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of a covalent bond, -CH=CH-, -0-, -CH ₂ 0-, -OCH2-, -CH _2- and -CH ₂ CH _2- ; and

A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl; with the proviso that the compound of formula (Ie) is not (4-fluorophenyl)-[7-(4- fluorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin -2-yl]methanone. In a further aspect, the present invention provides a process of manufacturing the compounds of formula (Ie) described herein, comprising the steps of: a) reacting an amine 13, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described herein,

acid 14, wherein R ¹ is as described herein

b) reacting an amine 13, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described herein,

acid chloride 15, wherein R ¹ is as described herein

to form said compound of formula (Ie).

In a further aspect, the present invention provides a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the processes described herein. In a further aspect, the present invention provides a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (Ie), preferably a compound of formula (I), described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

In a further aspect, the present invention provides the use of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for inhibiting monoacylglycerol lipase (MAGL) in a mammal.

In a further aspect, the present invention provides the use of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.

In a further aspect, the present invention provides the use of a compound of formula (Ie), preferably a compound of formula (I), as described herein for the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal.

In a further aspect, the present invention provides a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting monoacylglycerol lipase in a mammal.

In a further aspect, the present invention provides a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.

In a further aspect, the present invention provides a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal.

In a further aspect, the present invention provides the use of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting

monoacylglycerol lipase in a mammal.

In a further aspect, the present invention provides the use of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.

In a further aspect, the present invention provides the use of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal.

In a further aspect, the present invention provides a method for inhibiting monoacylglycerol lipase in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described herein, or of a pharmaceutically acceptable salt thereof, to the mammal.

In a further aspect, the present invention provides a method for the treatment of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described herein, or of a pharmaceutically acceptable salt thereof, to the mammal.

In a further aspect, the present invention provides a method for the prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described herein, or of a pharmaceutically acceptable salt thereof, to the mammal. In a further aspect, the present invention provides a method for the treatment of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

In a further aspect, the present invention provides a method for the prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

Detailed Description of the Invention

Definitions

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The term“alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In some preferred embodiments, the alkyl group contains 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec -butyl, ZerZ-butyl, and 2,2- dimethylpropyl. In a particularly preferred embodiment, alkyl is methyl.

The term“alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms. In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and ZerZ-butoxy. In a preferred embodiment, alkoxy is methoxy, ethoxy or isopropoxy. In a particularly preferred embodiment, alkoxy is methoxy.

The term“alkylsulfanyl” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via a sulfur atom. Unless otherwise specified, the

alkylsulfanyl group contains 1 to 12 carbon atoms. In some embodiments, the

alkylsulfanyl group contains 1 to 6 carbon atoms. In other embodiments, the alkylsulfanyl group contains 1 to 4 carbon atoms. In still other embodiments, the alkylsulfanyl group contains 1 to 3 carbon atoms. A preferred, yet non-limiting example of an alkylsulfanyl group is methylsulfanyl.

The term“halogen” or“halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). In a preferred embodiment, the term“halogen” or“halo” refers to fluoro (F), chloro (Cl) or bromo (Br).

The term“haloalkyl” or“haloalkoxy”, respectively, refers to an alkyl or alkoxy group, as the case may be, substituted with one or more halogen atoms, wherein each of the alkyl or alkoxy is defined as described herein. In a preferred embodiment, the haloalkyl or haloalkoxy group, respectively, contains 1, 2 or 3 halogen atoms, most preferably 1, 2 or 3 F atoms. Examples of such groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl (CF ₃ ), 2,2,2-trifluoroethyl, trifluoromethoxy, 2,2,2- trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, and the like. A particularly preferred haloalkyl group is trifluoromethyl (CF ₃ ).

The term“alkoxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. In a preferred

embodiment,“alkoxyalkyl” refers to an alkyl group wherein 1 hydrogen atom of the alkyl group has been replaced by an alkoxy group. In a particularly preferred embodiment, alkoxy alkyl is methoxymethyl.

The terms“cycloalkyl” and“carbocycle” are used herein synonymously and refer to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In some embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.“Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. In a preferred embodiment, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term“heterocyclyl” refers to a saturated or partly unsaturated mono- or bicyclic ring system of 3 to 10 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from the group consisting of N, O and S, the remaining ring atoms being carbon. Preferably, 1, 2, or 3 of said ring atoms are N, the remaining ring atoms being carbon “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl include piperidyl, morpholinyl, oxetanyl and azetidinyl.

The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, preferably, 6 to 12 ring members, and more preferably 6 to 10 ring members, and wherein at least one ring in the system is aromatic. A particular, yet non-limiting example of aryl is phenyl.

The term "heteroaryl" refers to a mono- or multivalent, monocyclic or bicyclic ring system having a total of 5 to 12 ring members, preferably, 5 to 10 ring members, and more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. In one embodiment, a 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of O, S and N. Some non-limiting examples of heteroaryl rings include pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), 2,3-dihydrobenzofuranyl (e.g. 2,3- dihydrobenzofuran-7-yl), indolyl (e.g. lH-indol-4-yl), pyrrolo[2,3-b]pyridyl (e.g. 1H- pyrrolo[2,3-b]pyridin-5-yl and lH-pyrrolo[2,3-b]pyridin-4-yl), benzothiazolyl (e.g. 1,3- benzothiazol-5-yl), thiazolopyridyl (e.g. [l,3]thiazolo[5,4-b]pyridin-6-yl), benzothiophenyl (e.g. l-benzothiophen-4-yl), thieno[3,2-c]pyridyl (e.g. thieno[3,2-c]pyridin-7-yl), 2,3- dihydroindolyl (e.g. 2,3-dihydroindol-4-yl), pyrazolo[3,4-b]pyridyl (e.g. pyrazolo[3,4- b]pyridin-5-yl), benzofuranyl (e.g. l-benzofuran-4-yl), imidazo[l,2-a]pyridyl (e.g.

imidazo[l,2-a]pyridin-5-yl), pyrazolyl (e.g. lH-pyrazol-4-yl), pyridazinyl (e.g. pyridazin- 3-yl) and thiazolyl (e.g. l,3-thiazol-4-yl). The term“amino” refers to an N 11 ₂ group.

The term“hydroxy” refers to an -OH group.

The term“cyano” refers to a -CN group.

The term“carbamoyl” refers to a group -C(0)-NH ₂ .

The term“alkoxycarbonyl” refers to a group -C(0)-0-alkyl. The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride salts. The term“protecting group” (PG) denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy- protecting groups or hydroxy-protecting groups. Particular protecting groups are the tert- butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protecting groups are the tert- butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protecting group is the tert- butoxycarbonyl (Boc). Exemplary protecting groups and their application in organic synthesis are described, for example, in“Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the "R" or "S" configuration.

The abbreviation“MAGE” refers to the enzyme monoacylglycerol lipase. The terms “MAGL” and“monoacylglycerol lipase” are used herein interchangeably.

The term“treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

The term“prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

The term“neuroinflammation” as used herein relates to acute and chronic inflammation of the nervous tissue, which is the main tissue component of the two parts of the nervous system; the brain and spinal cord of the central nervous system (CNS), and the branching peripheral nerves of the peripheral nervous system (PNS). Chronic

neuroinflammation is associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Acute neuroinflammation usually follows injury to the central nervous system immediately, e.g., as a result of traumatic brain injury (TBI).

The term“traumatic brain injury” (“TBI”, also known as“intracranial injury”), relates to damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile.

The term“neurodegenerative diseases” relates to diseases that are related to the progressive loss of stmcture or function of neurons, including death of neurons. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis,

Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.

The term“mental disorders” (also called mental illnesses or psychiatric disorders) relates to behavioral or mental patterns that may cause suffering or a poor ability to function in life. Such features may be persistent, relapsing and remitting, or occur as a single episode. Examples of mental disorders include, but are not limited to, anxiety and depression.

The term“pain” relates to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain, phantom pain and phsychogenic pain. A particular example of pain is neuropathic pain, which is caused by damage or disease affecting any part of the nervous system involved in bodily feelings (i.e., the somatosensory system). In one embodiment,“pain” is neuropathic pain resulting from amputation or thoracotomy. The term“neurotoxicity” relates to toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances (neurotoxins) alter the normal activity of the nervous system in such a way as to cause damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, neurotoxicity resulting from exposure to substances used in chemotherapy, radiation treatment, dmg therapies, drug abuse, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances.

The term“mammal” as used herein includes both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term “mammal” refers to humans.

Compounds of the Invention

In a first aspect, the present invention provides a compound of formula (Ie)

or a pharmaceutically acceptable salt thereof, wherein:

R ^la is selected from the group consisting of

(i) C _j. e-alkyl;

(ii) Ci- ₆ -alkoxy; and

(iii) aryl substituted with R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , or a possible combination thereof; R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

each of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkoxy, hydroxy, amino, -NH-alkyl, -N(alkyl) ₂ and cyano;

R ⁷ is selected from the group consisting of hydrogen, halogen, alkoxy, cycloalkyloxy and hydroxy;

each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is independently selected from the group consisting of hydrogen, hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl, haloalkyl, alkylsulfanyl, amino, -NH-alkyl, -N(alkyl) ₂ , -NH-aryl, -NH-heteroaryl

and a group

R 13 is selected from the group consisting of hydrogen, oxo, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of a covalent bond, -CH=CH-, -0-, -CH ₂ 0-, -OCH2-, -CH ₂ - and -CH ₂ CH ₂ -; and

A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl.

In one embodiment, the present invention provides a compound of formula (Ie) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (Ie) is not (4-fluorophenyl)-[7-(4-fluorophenyl)-l,3,4,6,7,8,9,9a- octahydropyrido[ 1 ,2-a]pyrazin-2-yl]methanone.

In one embodiment, the present invention provides a compound of formula (Ie) wherein said compound of formula (Ie) is of formula (I)

wherein:

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ,

each of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkoxy, hydroxy, amino, -NH-alkyl, -N(alkyl) ₂ and cyano;

R ⁷ is selected from the group consisting of hydrogen, halogen, alkoxy,

cycloalky loxy and hydroxy;

each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is independently selected from the group consisting of hydrogen, hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl, haloalkyl, alkylsulfanyl, amino, -NH-alkyl, -N(alkyl) ₂ , -NH-aryl, -NH-heteroaryl

and a group

R ¹³ is selected from the group consisting of hydrogen, oxo, halogen, alkyl,

carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of a covalent bond, -CH=CH-, -0-, - CH ₂ 0-, -OCH _2- , -CH _2- and -CH ₂ CH _2- ; and

A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and

heterocyclyl.

In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

each of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkoxy, hydroxy, amino, -NH-alkyl, - N(alkyl) ₂ and cyano;

R ⁷ is selected from the group consisting of hydrogen, halogen and hydroxy; each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is independently selected from the group consisting of hydrogen, hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl,

haloalkyl, alkylsulfanyl and a group

R ¹³ is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of a covalent bond, -CH=CH-, -0-, - CH ₂ 0-, -OCH _2- , -CH _2- and -CH ₂ CH _2- ; and A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl.

In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

each of R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkoxy, hydroxy, amino, -NH-alkyl, -N(alkyl) ₂ and cyano;

R ⁷ is selected from the group consisting of hydrogen, halogen and hydroxy; each of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² is independently selected from the group consisting of hydrogen, hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl,

haloalkyl, alkylsulfanyl and a group ;

R ¹³ is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of a covalent bond, -CH=CH-, -0-, - CH ₂ 0- -OCH _2- , -CH _2- and -CH ₂ CH _2- ; and

A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and

heterocyclyl;

with the proviso that the compound of formula (I) is not (4-fluorophenyl)-[7-(4- fluorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin -2-yl]methanone. In one embodiment, the compound of formula (Ie) according to the invention is a compound of formula (la)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein.

In one embodiment, the compound of formula (Ie) according to the invention is a compound of formula (lb)

wherein R , R , R , R , R , R and R are as defined herein.

In one embodiment, the compound of formula (Ie) according to the invention is a compound of formula (Ic)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein. In one embodiment, the compound of formula (Ie) according to the invention is a compound of formula (Id)

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ; R is selected from the group consisting of hydroxy, alkoxy, cyano, alkoxyalkyl,

haloalkoxy, halogen, alkyl, haloalkyl and a group ;

R ⁹ is hydrogen or halogen;

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylsulfanyl;

R ¹² is selected from the group consisting of hydrogen, halogen and alkyl;

is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of -CH=CH-, -O- and -CH ₂ 0-; and

A is aryl or heteroaryl.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of:

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

R ⁸ is selected from the group consisting of hydroxy, alkoxy, cyano, alkoxyalkyl,

haloalkoxy, halogen, alkyl, haloalkyl and a group ;

R ⁹ is hydrogen or halogen;

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylsulfanyl;

R ¹² is selected from the group consisting of hydrogen, halogen and alkyl;

R ¹³ is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen; L is selected from the group consisting of a covalent bond, -CH=CH-, -O- and -CH2O-; and

A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and

heterocyclyl. In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

R ⁸ is selected from the group consisting of alkoxy, haloalkoxy, alkyl and a group

R ⁹ is halogen;

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, alkyl and alkylsulfanyl; R ¹² is selected from the group consisting of hydrogen, halogen and alkyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is -CH2O-; and

A is heteroaryl. In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

R ⁸ is selected from the group consisting of alkoxy, haloalkoxy, alkyl and a group

R ⁹ is halogen;

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, alkyl and alkylsulfanyl; R ¹² is selected from the group consisting of hydrogen, halogen and alkyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is a covalent bond or -CH ₂ 0-; and

A is heteroaryl or heterocyclyl.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of

(i) phenyl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² , wherein said heteroaryl is selected from the group consisting of indolyl, pyrrolo[2,3-b]pyridyl, 1,3- benzothiazolyl, thiazolo[5,4-b]pyridyl and pyrazolo[3,4-b]pyridyl;

R ⁸ is selected from the group consisting of methoxy, 2,2,2-trifluoroethoxy, methyl and a group

R ⁹ is Cl or Br;

R ¹⁰ is hydrogen or F;

R ¹¹ is selected from the group consisting of hydrogen, methyl and methylsulfanyl; R ¹² is selected from the group consisting of hydrogen, Cl and methyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is -CH ₂ 0-; and

A is thiazolyl or pyrazolyl.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of

(i) phenyl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² , wherein said heteroaryl is selected from the group consisting of indolyl, pyrrolo[2,3-b]pyridyl, 1,3- benzothiazolyl, thiazolo[5,4-b]pyridyl, lH-indazol-5-yl, thieno[2,3- b]pyridin-5-yl, and pyrazolo[3,4-b]pyridyl;

R ⁸ is selected from the group consisting of methoxy, 2,2,2-trifluoroethoxy, methyl and a group

R ⁹ is Cl or Br;

R ¹⁰ is hydrogen or F;

R ¹¹ is selected from the group consisting of hydrogen, methyl and methylsulfanyl; R ¹² is selected from the group consisting of hydrogen, Cl and methyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is a covalent bond or -CH ₂ 0-; and

A is thiazolyl, pyrazolyl or 2-oxa-6-azaspiro[3.3]heptan-6-yl.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein

R 1 is phenyl substituted with R 8 , R9 and R 10 , wherein R 8 is a group

wherein the group is selected from the group consisting of (1- methylpyrazol-4-yl)methoxy; thiazol-4-ylmethoxy; [4-(methylcarbamoyl)phenyl]methoxy; (l-tert-butoxycarbonylpyrazol-4-yl)methoxy; lFl-pyrazol-4-ylmethoxy; pyridazin-3- ylmethoxy; 4-pyridylmethoxy; 3-pyridylmethoxy; (Z)-2-cyclopropylvinyl; (Z)-2-[2- bromo-3-(methylcarbamoyl)phenyl]vinyl; 2-oxa-6-azaspiro[3.3]heptan-6-yl.

In a preferred embodiment, there is provided a compound of formula (Ie), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ^la is aryl

2 3 4 5 6 2 3 substituted with R , R , R , R and R , or a possible combination thereof, wherein R , R , R ⁴ , R ⁵ and R ⁶ are as defined herein.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ^la is phenyl substituted with R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , or a possible combination thereof, wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of:

(i) phenyl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² , wherein said heteroaryl is

selected from the group consisting of indolyl, pyrrolo[2,3-b]pyridyl, 1,3- benzothiazolyl, thiazolo[5,4-b]pyridyl, lH-indazol-5-yl, thieno[2,3- b]pyridin-5-yl, and pyrazolo[3,4-b]pyridyl;

wherein R ⁸ , R ⁹ R ¹⁰ , R ¹¹ and R ¹² are as defined herein.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from the group consisting of hydrogen and halogen.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from the group consisting of hydrogen and Cl.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from the group consisting of hydrogen and halogen.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from the group consisting of hydrogen, F and Cl.

In a further particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from the group consisting of hydrogen and

Cl. In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is hydrogen.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from the group consisting of hydrogen, F, methoxy and hydroxy.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from the group consisting of hydrogen, F and hydroxy.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydroxy.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is F.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is hydrogen.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² , R ⁵ , R ⁶ and R ⁷ are hydrogen and R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen.

In another preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² , R ⁵ and R ⁶ are hydrogen; R ⁷ is selected from the group consisting of hydrogen, halogen, alkoxy and hydroxy and R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen. In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² , R ⁵ , R ⁶ and R ⁷ are hydrogen and R ³ and R ⁴ are independently selected from the group consisting of hydrogen and Cl. In another particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² , R ⁵ and R ⁶ are hydrogen; R ⁷ is selected from the group consisting of hydrogen, F, methoxy and hydroxy; R ³ is selected from the group consisting of hydrogen and Cl; and R ⁴ is selected from the group consisting of hydrogen, F and Cl.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from the group consisting of hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy,

halogen, alkyl, haloalkyl and a group ; wherein A, L, R ¹³ and R ¹⁴ are as defined herein. In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from the group consisting of alkoxy, haloalkoxy, alkyl and a group ; wherein A, L, R ¹³ and R ¹⁴ are as defined herein.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from the group consisting of methoxy, 2,2,2- trifluoroethoxy, methyl and a group ; wherein A, L, R ¹³ and R ¹⁴ are as defined herein.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is hydrogen or halogen. In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is Cl or Br.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is hydrogen or halogen. In a particularly preferred embodiment, there is provided a compound of formula

(Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is hydrogen or F.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and

alkylsulfanyl.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is selected from the group consisting of hydrogen, alkyl and alkylsulfanyl. In a particularly preferred embodiment, there is provided a compound of formula

(Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is selected from the group consisting of hydrogen, methyl and methylsulfanyl.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹² is selected from the group consisting of hydrogen, halogen and alkyl.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹² is selected from the group consisting of hydrogen, Cl and methyl. In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is hydrogen.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is hydrogen or halogen.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is hydrogen.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl.

In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein A is heteroaryl or heterocyclyl.

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of thiazolyl, pyrazolyl and 2-oxa- 6-azaspiro[3.3]heptan-6-yl.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a covalent bond, -CH=CH-, -O- and -CH ₂ 0-

In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein L is a covalent bond or -CH ₂ 0-. In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

R ² , R ⁵ , R ⁶ and R ⁷ are hydrogen;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen;

R ⁸ is selected from the group consisting of hydroxy, alkoxy, cyano, alkoxyalkyl,

haloalkoxy, halogen, alkyl, haloalkyl and a group ;

R ⁹ is hydrogen or halogen;

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylsulfanyl;

R ¹² is selected from the group consisting of hydrogen, halogen and alkyl;

R ¹³ is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of -CH=CH-, -O- and -CI I ₂ 0-; and

A is aryl or heteroaryl.

In one embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ^la is selected from the group consisting of

(i) Ci-e-alkyl;

(ii) Ci _ ₆ - alkoxy; and

(iii) aryl substituted with R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , or a possible combination thereof;

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

R ² , R ⁵ and R ⁶ are hydrogen; R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen;

R ⁷ is selected from the group consisting of hydrogen, halogen, alkoxy and

hydroxy;

R ⁸ is selected from the group consisting of hydroxy, alkoxy, cyano, alkoxyalkyl,

haloalkoxy, halogen, alkyl, haloalkyl and a group ;

R ⁹ is hydrogen or halogen;

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and alkylsulfanyl;

is selected from the group consisting of hydrogen, halogen and alkyl; is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;

R ¹⁴ is hydrogen or halogen;

L is selected from the group consisting of a covalent bond, -CH=CH-, -O- and -CH ₂ 0-; and

A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and

heterocyclyl. In a preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

R ² , R ⁵ , R ⁶ and R ⁷ are hydrogen;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen;

R ⁸ is selected from the group consisting of alkoxy, haloalkoxy, alkyl and a group

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, alkyl and alkylsulfanyl; R ¹² is selected from the group consisting of hydrogen, halogen and alkyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is -CH2O-; and

A is heteroaryl.

In another preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein

R ^la is aryl substituted with R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , or a possible combination thereof;

R ¹ is selected from the group consisting of

(i) aryl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² ;

R ² , R ⁵ and R ⁶ are hydrogen;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and halogen;

R ⁷ is selected from the group consisting of hydrogen, halogen, alkoxy and

hydroxy;

R ⁸ is selected from the group consisting of alkoxy, haloalkoxy, alkyl and a group

R ⁹ is halogen;

R ¹⁰ is hydrogen or halogen;

R ¹¹ is selected from the group consisting of hydrogen, alkyl and alkylsulfanyl; R ¹² is selected from the group consisting of hydrogen, halogen and alkyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is a covalent bond or -CH2O-; and

A is heteroaryl or heterocyclyl. In a particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of

(i) phenyl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² , wherein said heteroaryl is selected from the group consisting of indolyl, pyrrolo[2,3-b]pyridyl, 1,3- benzothiazolyl, thiazolo[5,4-b]pyridyl and pyrazolo[3,4-b]pyridyl;

R ² , R ⁵ , R ⁶ and R ⁷ are hydrogen;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen and Cl;

R ⁸ is selected from the group consisting of methoxy, 2,2,2-trifluoroethoxy, methyl and a group

R ⁹ is Cl or Br;

R ¹⁰ is hydrogen or F;

R ¹¹ is selected from the group consisting of hydrogen, methyl and methylsulfanyl; R ¹² is selected from the group consisting of hydrogen, Cl and methyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is -CH ₂ 0-; and

A is thiazolyl or pyrazolyl.

In another particularly preferred embodiment, there is provided a compound of formula (Ie), preferably of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein

R ^la is phenyl substituted with R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , or a possible combination thereof;

R ¹ is selected from the group consisting of

(i) phenyl substituted with R ⁸ , R ⁹ and R ¹⁰ ; and

(ii) heteroaryl substituted with R ¹¹ and R ¹² , wherein said heteroaryl is

selected from the group consisting of indolyl, pyrrolo[2,3-b]pyridyl, 1,3- benzothiazolyl, thiazolo[5,4-b]pyridyl, lH-indazol-5-yl, thieno[2,3- b]pyridin-5-yl, and pyrazolo[3,4-b]pyridyl; R ² , R ⁵ and R ⁶ are hydrogen;

R ³ is selected from the group consisting of hydrogen and Cl;

R ⁴ is selected from the group consisting of hydrogen, F and Cl;

R ⁷ is selected from the group consisting of hydrogen, F, methoxy and hydroxy;

R ⁸ is selected from the group consisting of methoxy, 2,2,2-trifluoroethoxy, methyl and a group

R ⁹ is Cl or Br;

R ¹⁰ is hydrogen or F;

R ¹¹ is selected from the group consisting of hydrogen, methyl and methylsulfanyl; R ¹² is selected from the group consisting of hydrogen, Cl and methyl;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

L is a covalent bond or -CH ₂ 0-; and

A is thiazolyl, pyrazolyl or 2-oxa-6-azaspiro[3.3]heptan-6-yl.

In one embodiment, there is provided a compound of formula (Ie) as described herein, selected from the group consisting of:

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (3 -phenoxyphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-3 -methylphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-bromo- 3 -methoxyphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-bromo-3-methoxyphenyl)methanone;hydrochloride;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [3 - (3 , 5 -difluorophenoxy)phenyl] methanone ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-bromo- 3 -methoxypheny l)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-3 -methoxypheny l)methanone; [(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-methoxyphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [2- (trifluoromethoxy)phenyl] methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(2, 3-dihydro- l-benzofuran-7-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(lH-indol-4-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-chloro-6-fluorophenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chlorophenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-fluoro-3 -methylphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(4-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(lH-pyrrolo[2,3-b]pyridin-4-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [2-chloro- 3 - (trifluoromethyl)phenyl] methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-4-fluoro-3-methylphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (3 -chloro-2-methylphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(4-chloro-6-methylpyridin-3-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2, 4-dimethyl- l,3-benzothiazol-5-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (7-chloro-2-methylsulfanyl-[l,3]thiazolo[5,4-b]pyridin-6-yl) methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- ( 1 -benzothiophen-4-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-bromo-3-methylphenyl)methanone; [(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [2- (trifluoromethyl)pheny 1] methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-3-phenoxyphenyl)methanone;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-chloro-

3 -methy lphenyl)methanone ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-chloro- 3 -methy lphenyl)methanone ;hydrochloride ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-chloro- 5-fluoro-3-methylphenyl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-bromo- 3 -(methoxymethyl)pheny 1] methanone ;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(lH-indol-

4-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-(l- methylindol-4-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(4-chloro- 1 H-pyrrolo [2,3 -b]pyridin- 5 -yl)methanone ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-chloro- 3-hydroxyphenyl)methanone;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(3- methylthieno[3,2-c]pyridin-7-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-(l-methyl- 2,3-dihydroindol-4-yl)methanone;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(l-propan-

2-ylindol-4-yl)methanone;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-chloro-

3-propan-2-yloxyphenyl)methanone;hydrochloride;

3-[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2 -a]pyrazine-2-carbonyl]- 2-chlorobenzonitrile;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(4-chloro- 1 -methy lpyrrolo [2 ,3 -b]pyridin- 5 -yl)methanone ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-[2-chloro- 3-[(l-methylpyrazol-4-yl)methoxy]phenyl]methanone; [(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(4-chloro- l-propan-2-ylpyrrolo[2,3-b]pyridin-5-yl)methanone;

[(7S,9aS)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-bromo- 3 -methoxyphenyl)methanone ;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-(4-chloro- lH-pyrazolo[3,4-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(l- benzofuran-4-yl)methanone;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(3-chloro- 2-methoxypyridin-4-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(4-chloro-l-methylpyrrolo[2,3-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro- 3 - ( 1 , 3 - thiazol-4-ylmethoxy)phenyl] methanone ;

4-[[3-[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido [l,2-a]pyrazine-2- carbonyl]-2-chlorophenoxy]methyl]-N-methylbenzamide;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(4-chloro-l-methylpyrazolo[3,4-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahydrop yrido[l,2-a]pyrazin-2- yl] - (2-bromo- 3 -methoxyphenyl)methanone ;

[(7S,9aS)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahydrop yrido[l,2-a]pyrazin-2- yl] - (2-bromo- 3 -methoxyphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

[2-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(6-methoxypyridin-2-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- imidazo [ 1 , 2- a] pyridin- 5 - y lmethanone ;

/e/ - butyl 4-[[3-[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l, 2- a]pyrazine-2-carbonyl]-2-chlorophenoxy]methyl]pyrazole-l-car boxylate;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro-

3-(lH-pyrazol-4-ylmethoxy)phenyl]methanone;hydrochloride;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro-

3-(pyridazin-3-ylmethoxy)phenyl]methanone; [(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro-

3-(pyridin-4-ylmethoxy)phenyl]methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro- 3 -(pyridin- 3 -ylmethoxy)pheny 1] methanone ;

3-[(E)-2-[4-[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a -octahydropyrido[l,2- a]pyrazine-2-carbonyl]phenyl]vinyl]-2-bromo-N-methyl-benzami de;

3-[(E)-2-[4-[(7S,9aS)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazine-2-carbonyl]phenyl]vinyl]-2-bromo-N-methyl-benzami de;

3-[(E)-2-[4-[(7S,9aS)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazine-2-carbonyl]-3-bromo-phenyl]vinyl]-N-methyl-benzam ide;

3-[(E)-2-[4-[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazine-2-carbonyl]-3-bromo-phenyl]vinyl]-N-methyl-benzam ide;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

[2-chloro-3-[(E)-2-cyclopropylethenyl]phenyl]methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (4-chloro-5-methoxypyridin-3-yl)methanone;

(4-chloro-lH-pyrazolo[3,4-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3 -chloro-4- fluorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin -2-yl]methanone;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazin-2-yl]-(4-chloro-lH-pyrazolo[3,4-b]pyridin-5-yl)met hanone;

[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazin-2-yl]-(4-chloro-lH-pyrazolo[3,4-b]pyridin-5-yl)met hanone;

(3-methyl-lH-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluor ophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-(3-methyl-lH-indazol-5-yl)methanone;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-(3-methyl-lH-indazol-5-yl)methanone;

(3-methyl-[l,2,4]triazolo[4,3-a]pyridin-6-yl)-[rac-(7R,9aR)- 7-(3-chloro-4- fluorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin -2-yl]methanone; (3-chloroimidazo[l,2-a]pyridin-6-yl)-[rac-(7R,9aR)-7-(3-chlo ro-4-fluorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

(4-chlorothieno[2,3-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3-chlor o-4-fluorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazin-2-yl]-(4-chlorothieno[2,3-b]pyridin-5-yl)methanone ;

[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-(4-chlorothieno[2,3-b]pyridin-5-yl)methanone ;

(4-chloro-3-methyl-[l,2]oxazolo[5,4-b]pyridin-5-yl)-[rac-(7R ,9aR)-7-(3-chloro-4- fluorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin -2-yl]methanone;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazin-2-yl]-(4-chloro-3-methyl-[l,2]oxazolo[5,4-b]pyridi n-5-yl)methanone;

[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazin-2-yl]-(4-chloro-3-methyl-[l,2]oxazolo[5,4-b]pyridi n-5-yl)methanone; (4-chloro-lH-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluor ophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aR)-7-(3-chlo ro-4-fluorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-[2-chloro-3-(difluoromethoxy)phenyl]methanon e;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl] - [2-chloro-3 -(difluoromethoxy)phenyl]methanone ;

(4-chloro-3-methyl-lH-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chlor o-4-fluorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

(4-chloro-[l,2]thiazolo[5,4-b]pyridin-5-yl)-[rac-(7R,9aR) -7-(3-chloro-4- fluorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin -2-yl]methanone;

(6-amino-4-chloropyridin-3-yl)-[rac-(7R,9aR)-7-(3-chloro- 4-fluorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

(4-chloro-3-methyl-lH-indazol-5-yl)-[rac-(7R,9aR)-7-(4-chlor ophenyl)-7-hydroxy- 3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanon e;

(4-chloro-3-methyl-lH-indazol-5-yl)-[rac-(7R,9aS)-7-(4-chlor ophenyl)-7-hydroxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydr o-lH-pyrido[l,2- a]pyrazin-2-yl]-(4-chloro-3-methyl-lH-indazol-5-yl)methanone ; [(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydr o-lH-pyrido[l,2- a]pyrazin-2-yl]-(4-chloro-3-methyl-lH-indazol-5-yl)methanone ;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chlorophenyl)- 7-hydroxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

[(7S,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexah ydro-lH-pyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydr o-lH-pyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)- 7-hydroxy- 3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanon e;

[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydr o-lH-pyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

[(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydr o-lH-pyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aR)-7-(4-c hlorophenyl)-7-hydroxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aS)-7-(4-chlo rophenyl)-7-hydroxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-[rac-( 7R,9aR)-7-(4- chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2 -a]pyrazin-2- yl]methanone;

[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-[rac-( 7R,9aS)-7-(4- chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2 -a]pyrazin-2- yl]methanone;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chloropheny l)-7-fluoro-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)- 7-fluoro-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chlorophenyl)- 7-methoxy- 3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanon e;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)- 7-methoxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-methyl-l,3,4,6,7, 8,9,9a- octahydropyrido[l,2-a]pyrazin-2-yl]methanone; (2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-methyl-l,3,4,6,7, 8,9,9a- octahydropyrido[l,2-a]pyrazin-2-yl]methanone;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(2-methylpropoxy) -l,3,4,6,7,8,9,9a- octahydropyrido[l,2-a]pyrazin-2-yl]methanone; and

(l,3-dimethylthieno[2,3-c]pyrazol-5-yl)-[rac-(7R,9aR)-7-(3-c hloro-4-fluorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, selected from the group consisting of:

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(3 -phenoxyphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-chloro-3 -methylphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-bromo-3 - methoxypheny 1) methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-bromo- 3 -methoxypheny 1) methanone ;hydrochloride ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [3 - (3 , 5 -difluorophenoxy)phenyl] methanone ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-bromo-

3 -methoxypheny l)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-chloro-3 -methoxypheny l)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-methoxyphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [2- (trifluoromethoxy)phenyl] methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2, 3-dihydro- l-benzofuran-7-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(lH-indol-4-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-6-fluorophenyl)methanone; [(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chlorophenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-fluoro-3 -methylphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(4-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(lH-pyrrolo[2,3-b]pyridin-4-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [2-chloro- 3 - (trifluoromethyl)phenyl] methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-4-fluoro-3-methylphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (3 -chloro-2-methylphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(4-chloro-6-methylpyridin-3-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2, 4-dimethyl- l,3-benzothiazol-5-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (7-chloro-2-methylsulfanyl-[l,3]thiazolo[5,4-b]pyridin-6-yl) methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- ( 1 -benzothiophen-4-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-bromo-3-methylphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

[2-(trifluoromethyl)phenyl]methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-3-phenoxyphenyl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(2-chloro- 3-methylphenyl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(2-chloro- 3 -methy lphenyl)methanone ;hydrochloride ;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(2-chloro-

5-fluoro-3-methylphenyl)methanone; [(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-bromo- 3 -(methoxymethyl)pheny 1] methanone ;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(lH-indol-

4-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-(l- methylindol-4-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(4-chloro- 1 H-pyrrolo [2,3 -bjpyridin- 5 -yl)methanone ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-chloro- 3-hydroxyphenyl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(3- methylthieno[3,2-c]pyridin-7-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(l-methyl-

2,3-dihydroindol-4-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-(l-propan-

2-ylindol-4-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(2-chloro-

3-propan-2-yloxyphenyl)methanone;hydrochloride;

3-[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2 -a]pyrazine-2-carbonyl]- 2-chlorobenzonitrile;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(4-chloro- 1 -methy lpyrrolo [2 ,3 -b]pyridin- 5 -yl)methanone ;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-[2-chloro- 3-[(l-methylpyrazol-4-yl)methoxy]phenyl]methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-(4-chloro-

1-propan-2-ylpyrrolo[2,3-b]pyridin-5-yl)methanone;

[(7S,9aS)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(2-bromo- 3 -methoxyphenyl) methanone ;

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(4-chloro- lH-pyrazolo[3,4-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(l- benzofuran-4-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-(3-chloro-

2-methoxypyridin-4-yl)methanone; [(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(4-chloro-l-methylpyrrolo[2,3-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro-

3-(l,3-thiazol-4-ylmethoxy)phenyl]methanone;

4-[[3-[(7R, 9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazine-2- carbonyl]-2-chlorophenoxy]methyl]-N-methylbenzamide;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(4-chloro-l-methylpyrazolo[3,4-b]pyridin-5-yl)methanone;

[(7R,9aR)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahydrop yrido[l,2-a]pyrazin-2- yl] - (2-bromo- 3 -methoxyphenyl)methanone ;

[(7S,9aS)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahydrop yrido[l,2-a]pyrazin-2- yl] - (2-bromo- 3 -methoxyphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

[2-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(6-methoxypyridin-2-yl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- imidazo [ 1 , 2- a] pyridin- 5 - y lmethanone ;

/e/ - butyl 4-[[3-[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l, 2- a]pyrazine-2-carbonyl]-2-chlorophenoxy]methyl]pyrazole-l-car boxylate;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro-

3-(lH-pyrazol-4-ylmethoxy)phenyl]methanone;hydrochloride;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro-

3-(pyridazin-3-ylmethoxy)phenyl]methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-[2-chloro-

3-(pyridin-4-ylmethoxy)phenyl]methanone;

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]py razin-2-yl]-[2-chloro- 3 -(pyridin- 3 -ylmethoxy)pheny 1] methanone ;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

(4-chloro-lH-pyrazolo[3,4-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3 -chloro-4- fluorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin -2-yl]methanone;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-oc tahydropyrido[l,2- a]pyrazin-2-yl]-(4-chloro-lH-pyrazolo[3,4-b]pyridin-5-yl)met hanone; (3-methyl-lH-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluor ophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-(3-methyl-lH-indazol-5-yl)methanone;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl]-(4-chlorothieno[2,3-b]pyridin-5-yl)methanone ;

[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2- a]pyrazin-2-yl] - [2-chloro-3 -(difluoromethoxy)phenyl]methanone ;

(4-chloro-3-methyl-lH-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chlor o-4-fluorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]methanon e;

(4-chloro-3-methyl-lH-indazol-5-yl)-[rac-(7R,9aS)-7-(4-chlor ophenyl)-7-hydroxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydr o-lH-pyrido[l,2- a]pyrazin-2-yl]-(4-chloro-3-methyl-lH-indazol-5-yl)methanone ;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chlorophenyl)- 7-hydroxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydr o-lH-pyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;

[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aS)-7-(4-chlo rophenyl)-7-hydroxy- 3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanon e;

[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-[rac-( 7R,9aS)-7-(4- chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2 -a]pyrazin-2- yl]methanone;

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)- 7-fluoro- 3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanon e; and

(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)- 7-methoxy-

3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]metha none;

or a pharmaceutically acceptable salt thereof.

In a particularly preferred embodiment, there is provided a compound of formula (I) as described herein, selected from the group consisting of:

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-chloro-3 -methylphenyl)methanone ; [(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-bromo- 3 -methoxyphenyl)methanone ;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]-

(2-chloro-3-methoxyphenyl)methanone;

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(lH-indol-4-yl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (4-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]- (1 H-pyrrolo [2,3 -b]pyridin-4-yl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (2-chloro-4-fluoro-3-methylphenyl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]- (2, 4-dimethyl- l,3-benzothiazol-5-yl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(7-chloro-2-methylsulfanyl-[l,3]thiazolo[5,4-b]pyridin-6- yl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]- (2-bromo-3-methylphenyl)methanone

[(7R,9aR)-7 -phenyl- 1,3, 4, 6, 7,8,9, 9a-octahydropyrido[l, 2-a]pyrazin-2-yl]-(2-chloro- 3-methylphenyl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- (4-chloro-l-methylpyrrolo[2,3-b]pyridin-5-yl)methanone

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-[2-chloro- 3 - ( 1 , 3 - thiazol-4-ylmethoxy)phenyl] methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-

(4-chloro-l-methylpyrazolo[3,4-b]pyridin-5-yl)methanone

[(7R,9aR)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahyd ropyrido[l,2-a]pyrazin-2- yl] - (2-bromo- 3 -methoxyphenyl)methanone

[(7S,9aS)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahyd ropyrido[l,2-a]pyrazin-2- yl] - (2-bromo- 3 -methoxyphenyl)methanone

[(7R,9aR)-7-(4-chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropyrid o[l,2-a]pyrazin-2-yl]- [2-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanone; and

[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-[2-chloro- 3-(lH-pyrazol-4-ylmethoxy)phenyl]methanone;hydrochloride; or a pharmaceutically acceptable salt thereof.

In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (Ie) as described herein, especially hydrochloride salts. In a further particular embodiment, the present invention provides compounds according to formula (Ie) as described herein.

Processes of Manufacturing

The preparation of compounds of formula (Ie) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.

If one of the starting materials, intermediates or compounds of formula (Ie) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g., in“Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. If starting materials or intermediates contain stereogenic centers, compounds of formula (Ie) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent.

A person skilled in the art will acknowledge that in the synthesis of compounds of formula (Ie) - insofar not desired otherwise - an“orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew.

Chem. Int. Ed. Engl. 1996, 35, 2056).

A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates. In more detail, the compounds of formula (Ie) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999).

It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

The following abbreviations are used in the present text:

AcOH = acetic acid, aq. = aqueous, Boc = / e rt -butyl o x y c arbo n y 1 , BnBr =

Benzylbromide, n-BuLi = n-butyllithium, n-BuOH = Butanol, CAS RN = chemical abstracts registration number, CHCI ₃ = Chloroform, CyPrI = Cyclopropyl iodide, DAST = diethylaminosulfur trifluoride, DCM = dichloromethane, DCE = 1 ,2-dichloroethane, DCC = N, iV’-dicyclohexylcarbodiimide, DIC = N,N'-diisopropylcarbodiimide, DMA = N,N- dimethylacetamide, DMAP = 4-dimethylaminopyridine, DME = dimethoxyethane, DMF = A A-di methyl lormamidc, EDCI = /V-(3-di methylami nopropyl )-N’-ethylcarbodiimide hydrochloride, EtOAc = ethylacetate, EtOH = ethanol, Etl = Ethyl iodide, HATU = 0-(7- azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate, HC1 = hydrogen chloride, HPLC = high performance liquid chromatography, HOBt = l-hydroxybenzo- triazole, Huenig’s base = iPr ₂ NEt = /V-cthy 1 diisopropylamine, iPrl = isopropyl iodide, K2CO3 = potassium carbonate, KH = potassium hydride, LDA = lithium diisopropylamide, LiHMDS = lithium bis(trimethylsilyl)amide, L-selectride = lithium tri-sec- butyl(hydrido)borate, MeOH = methanol, RT = room temperature, Mel = methyl iodide, MS = mass spectmm, MsOH = methyl sulfonic acid, NaH = sodium hydride, NaHC03 = sodium hydrogen carbonate, Na ₂ C03 = sodium carbonate, NaHMDS = sodium

bis(trimethylsilyl)amide, NaOH = sodium hydroxide, Na ₂ S0 ₄ = sodium sulfate, NH4CI = ammonium chloride, sat. = saturated, Pd/C = palladium on activated carbon, Pd(OH) ₂ = palladium hydroxyde = Pearlman’s catalyst, Pt0 ₂ = platinum dioxide, PE = petroleum ether, PMB = 4-methoxy benzyl ether, SFC = Supercritical Fluid Chromatography, TBTU = 0-benzotriazol-l-yl-iV,iV, V’, V’-tetramethyl-uronium tetrafluoroborate, TEA = triethylamine, TFA = trifluoroacetic acid, Tf ₂ NPh = A-phenyltrifluoromethanesulfonimide, Tf ₂ 0 = trifluoromethanesulfonic anhydride, TfOH = triflic acid, THF = tetrahydrofuran, TsOH = paratoluene sulfonic acid, T3P = propylphosphonic anhydride.

Compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is hydrogen may be synthesized according to the general procedure outlined in Scheme 1.

Scheme 1

Treatment of protected ketone intermediates 10 (obtainable e.g. by the general procedure outlined in Scheme 3), wherein PG is a protective group, such as Boc (see e.g. intermediate 1-1) with an aryl Grignard reagent in a solvent like diethylether or THF, preferably THF and in a temperature range between -78 °C and 25 °C, preferably at 0°C affords the corresponding tertiary alcohol intermediate 11 ( Scheme 1, step a). Following dehydration reaction of the hydroxy intermediate with concomitant cleavage of the protective group PG, in presence of an acid such as HC1, TsOH or MsOH, preferably MsOH in a solvent like DCM, MeOH, EtOH, toluene or a mixture thereof, preferably in DCM and in a temperature range between 0°C and the boiling point of the solvent, preferably at room temperature, gives the enamine intermediates 12 ( Scheme 1, step b). Subsequent heterogeneous catalytic hydrogenation of the alkene using a transition metal catalyst such as Pt0 ₂ or Pd/C, preferably Pd/C in presence of MgO in a solvent like MeOH, EtOH, THF or EtOAc, preferably EtOAc at around room temperature and under atmospheric pressure of hydrogen, gives the amine intermediates 13 ( Scheme 1, step c, see e.g. intermediate A-l). Finally, amide coupling reaction with carboxylic acid compounds 14 (X = OH, either commercially available, or prepared by the methods described in Schemes 4, 5, 6 and 7 or in literature), wherein R ¹ is as defined herein in connection with compounds of formula (I), can be accomplished by using coupling reagents such as, DCC, HATU, EDCI, HOBt, TBTU, T4\ etc. and a base like Huenig’s base, triethyl amine or DMAP in a suitable solvent solvent like /V,/V-di methyl formamide, DMA, DCM or dioxane, preferably between 0°C and room temperature to give the compounds of formula (I)

(Scheme i, step d).

Alternatively, reaction of amine intermediates 13 with acid chloride compounds 15 (X = Cl, either commercially available, or prepared by treatment of the corresponding carboxylic acid compounds 14 with e.g., thionyl chloride or oxalyl chloride, neat or optionally in a solvent such as DCM, Scheme 1 , step e) in an appropriate solvent such as DCM or DMF and a base, e.g. NEt ₃ , Huenig’s base, pyridine or DMAP at temperatures ranging from 0°C to the reflux temperature of the solvent also yields compounds of formula (I) (Scheme 1, step d). Compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is hydroxy, alkoxy or halogen, in particular hydroxy, methoxy or F, may be synthesized according to the general procedure outlined in Scheme la.

Scheme la

Accordingly, the PMB protected secondary amine 6 (obtainable e.g. by the general procedure outlined in Scheme 3), can be acylated with a suitable carboxylic acid 14 using coupling reagents such as, DCC, HATU, EDCI, HOBt or TBTU, preferably T ₃ P and a base like Huenig’s base, triethyl amine or DMAP in a suitable solvent solvent like N,N- dimethylformamide, DMA, DCM or dioxane, preferably between 0°C and 50°C to afford the corresponding intermediate 8. Alternatively, reaction of amine intermediates 6 with acid chloride compounds 15 (X = Cl, either commercially available, or prepared by treatment of the corresponding carboxylic acid compounds 14 also yields the

corresponding intermediate 8, wherein R ¹ is as defined herein ( Scheme la, step a).

Removal of the PMB protective group using acidic conditions, such as treatment with neat AcOH, TfOH, MsOH, TsOH, or preferably TFA in a solvent like toluene or DCM, optionally in the presence of anisole or 1 ,3 dimethoxybenzene, preferably in DCM and in a temperature range between room temperature and the boiling point of the reaction mixture, preferably at room temperature gives the ketone compound 9 (see e.g. intermediate 1-2, step b). Treatment of ketone intermediates 9 with a phenyl Grignard reagent in a solvent like diethylether or THF, preferably THF and in a temperature range between -78°C and 25°C, preferably at 0°C affords the corresponding compound of formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is hydroxy (step c). The tertiary alcohol moiety of (I) may be further transformed to a halogen, preferably to F, using conditions known in the art (e.g. by reacting (I) with F1C1, FlBr, HI, POCI3, SOCl ₂ or PBr ₃ or with a suitable amino sulfurane reagent such as DAST or by first converting the alcohol of (I) to a sulfonate ester, such as mesylate, in the first stage, followed by reacting said sulfonate ester with e.g. NaF), to yield compound of formula (I), wherein R ¹ , R ² , R ³ , R ⁴ ,

R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is halogen ( Scheme la, step d). In addition, compounds of formula (I) wherein R ⁷ is one halogen may be transformed to compounds of formula (I) wherein R ⁷ is another halogen by methods known in the art. The tertiary alcohol moiety of (I) may be further transformed to an alkoxy, preferably to methoxy, by treatment with an appropriate base, such as NaH, KH, NaHMDS, LiHMDS or LDA, preferably with NaH in a solvent like DMF, THF, dioxane, or a mixture thereof, preferably DMF and in a temperature range between -78°C and room temperature, preferably at 0°C, followed by addition of an electrophile, e.g. an alkyl or cycloalkyl halide, such as Mel, Etl, ¾ ^' PrI or CyPrI to give the corresponding compound of formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is methoxy ( Scheme la, step e).

Alternatively, compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is hydroxy, halogen or alkoxy, in particular hydroxy, F or methoxy, may be synthesized according to the general procedure outlined in Scheme lb.

Scheme lb Accordingly, treatement of protected ketone intermediate 10 (obtainable e.g. by the general procedure outlined in Scheme 3), wherein PG is a protective group, such as Boc (see e.g. intermediate 1-1) with a phenyl Grignard reagent in a solvent like diethylether or THF, preferably THF and in a temperature range between -78°C and 25°C, preferably at 0°C affords the corresponding interemdiate 11, wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is hydroxy ( Scheme lb, step a). Removal of the BOC protective group under suitable conditions, e.g. using acidic conditions, such as treatment with HC1 in a solvent like EtOAc or MeOH or treatment with TFA in DCM, preferably at around room temperature affords the amine intermediates 16 (step b, see e.g. intermediate A-6). Subsequent, amide coupling reaction with carboxylic acid compounds 14, wherein R ¹ is as defined herein, can be accomplished by using coupling reagents such as DCC, HATU, EDCI, HOBt, TBTU, TT\ etc. and a base like Huenig’s base, triethyl amine or DMAP in a suitable solvent solvent like N, A-dimethylformamide, DMA, DCM or dioxane, preferably between 0°C and room temperature gives compounds of formula (I) (step c).

The tertiary alcohol moiety of (I) may be further transformed to a halogen, preferably to F, using conditions known in the art (e.g. by reacting (I) with HC1, HBr, HI, POCI3, SOCl ₂ or PBr ₃ or with a suitable amino sulfurane reagent such as DAST or by first converting the alcohol of (I) to a sulfonate ester, such as mesylate, in the first stage, followed by reacting said sulfonate ester with e.g. NaF), to yield compound of formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is halogen ( Scheme lb, step d). In addition, compounds of formula (I) wherein R ⁷ is one halogen may be transformed to compounds of formula (I) wherein R ⁷ is another halogen by methods known in the art. The tertiary alcohol moiety of (I) may be further transformed to an alkoxy, preferably to methoxy, by treatment with an appropriate base, such as NaH, KH, NaHMDS, LiHMDS or LDA, preferably with NaH in a solvent like DMF, THF, dioxane, or a mixture thereof, preferably DMF and in a temperature range between -78°C and room temperature, preferably at 0°C, followed by addition of an electrophile, e.g. an alkyl or cycloalkyl halide, such as Mel to give the corresponding compound of formula (I), wherein R ¹ , R ² ,

R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is methoxy ( Scheme lb, step e).

Alternatively, compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined herein and wherein R ⁷ is hydrogen may be synthesized according to the general procedure outlined in Scheme 2.

Scheme 2

Treatment of protected ketone intermediate 10, wherein PG is a protective group, such as Boc (see e.g. intermediate 1-1) with a suitable base such as NaHMDS, L-selectride, LDA or LiHMDS, preferably with LiHMDS in a solvent like dioxane, DME, THF or a mixture thereof, preferably THF and in a temperature range between -78 °C and room temperature, preferably at around -70°C, followed by addition of Tf ₂ 0 or Tf ₂ NPh, preferably TFNPh in THF gives the corresponding vinyl triflate compounds 21 ( Scheme 1, step a). Then, Suzuki cross-coupling reaction with aryl boronic acids or aryl boronic esters (e.g. pinacol or trimethylene glycol ester, either commercially available or prepared using literature procedures as described for example in“Boronic Acids - Preparation and Applications in Organic Synthesis and Medicine” by Dennis G. Hall (ed.) lst Ed., 2005, John Wiley & Sons, New York), using a suitable catalyst (e.g.,

bis(triphenylphosphine)palladium (II) chloride, dichloro[l,l'-bis(diphenylphosphino)- ferrocene]palladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) or palladium(II)acetate with triphenylphosphine) in an appropriate solvent (e.g. dioxane, DME, water, toluene, DMF or mixtures thereof) and a suitable base (e.g. Na ₂ C0 ₃ ,

Nal IC0 ₃ , KF, K ₂ C0 ₃ or NEt ₃ ) at temperatures between room temperature and the boiling point of the reaction mixture, yields compounds 22 ( Scheme 2, step b). Subsequent heterogeneous catalytic hydrogenation of the olefin moiety using a transition metal catalyst such as Pt0 ₂ or Pd/C, preferably Pd/C in presence of MgO in a solvent like MeOH, EtOH, THF or EtOAc, preferably EtOAc at around room temperature and under atmospheric pressure of hydrogen, gives intermediates 23 ( Scheme 2, step c). Removal of the protective group under suitable conditions, e.g. using acidic conditions, such as treatment with HC1 in a solvent like EtOAc or MeOH or treatment with TFA in DCM, preferably at around room temperature affords the amine intermediates 13 ( Scheme 2, step d). Finally, amide coupling reaction with carboxylic acid compounds 14 (X = OH, either commercially available, or prepared by the methods described in Schemes 4, 5, 6 and 7 or in literature) or the respective acid chlorides 15, wherein R ¹ is as defined herein, can be accomplished by using coupling reagents such as DCC, HATU, EDCI, HOBt, TBTU, TT\ etc. and a base like Huenig’s base, triethyl amine or DMAP in a suitable solvent solvent like /V,/V-di methyl formamide, DMA, DCM or dioxane, preferably between 0°C and room temperature gives compounds of formula (I) ( Scheme 2, step e).

Intermediates 10 may be synthesized by a variety of conditions, which may be exemplified by the general procedure outlined in Scheme 3.

Scheme 3

Starting from commercially available 3-bromo-6-pyridinecarbonitrile (1), a nucleophilic aromatic substitution reaction can be performed using 4-methoxybenzyl alcohol in presence of a suitable base, such as NaOH, KOH, KH, preferably with NaH in a solvent like DMF, THF, dioxane, or a mixture thereof, preferably in a mixture of DMF and THF and in a temperature range preferably between 0°C and room temperature, to give the corresponding PMB protected compound 2 ( Scheme 3, step a). Reduction of the nitrile group can be achieved using a suitable reducing agent such as borane, lithium borohydride or lithium aluminium hydride in a solvent like ether, DME, THF or a mixture thereof and in a temperature range between 0°C and the boiling point of the solvent, or preferably using catalytic hydrogenation conditions such as Raney Nickel in a solvent like MeOH in presence of ammonium hydroxide around 50°C and under 3.5 bar of hydrogen atmosphere, to give the corresponding amine 3 ( Scheme 3, step b). Following, amide coupling reaction with bromoacetic acid using a suitable coupling agent such as DCC, DCI or preferably EDCI in a solvent like DCM, THF, DMF, DCE or CH ₃ CN, preferably DCM and in a temperature range between 0°C and the boiling point of the solvent, preferably at room temperature gives the amide compound 4a ( Scheme 3, step c). Subsequent heating of intermediate 4a in a solvent like EtOH, MeOH, preferably CH3CN and preferably around 50°C gives the pyridinium intermediate 4b ( Scheme 3, step d). Following treatment with a suitable reducing agent, such as sodium borohydride in a solvent like MeOH, preferably at around round temperature gives the lactam compound 5 ( Scheme 3, step d’). Reduction of the amide using a suitable reducing agent such as borane, lithium borohydride or preferably lithium aluminium hydride in a solvent like ether, DME or a mixture thereof, preferably THF and in a temperature range between 0°C and the boiling point of the reaction mixure, preferably at reflux, gives the corresponding amine compound 6 ( Scheme 3, step e). Following removal of the PMB protective group using acidic conditions, such as treatment with neat AcOH, TfOH, MsOH, TsOH, or preferably TFA in a solvent like toluene or DCM, optionally in the presence of anisole or 1,3 dimethoxybenzene, preferably in DCM and in a temperature range between room temperature and the boiling point of the reaction mixture, preferably at room temperature gives the ketone compound 7 ( Scheme 3, step f). Finally, the secondary amine in 7 is protected with a suitable protective group ( Scheme 3, step g) to afford intermediate 10. Thus, for example, treatment with di- tert- butyldicarbonate optionally in presence of a base such as DMAP, TEA, Nal ICO3 or preferably Na^ CT in a suitable solvent like CH3CN, DCM, dioxane or THF, preferably in CH3CN and in a temperature range between 0°C and room temperature, preferably at room temperature yields the Boc protected ketone intermediate 1-1.

In one embodiment, carboxylic acid compound 14 is an intermediate of type B, C,

D, E or F. Intermediates of type B, C, D, E and F can be prepared e.g., as exemplified by the synthetic procedures outlined in Schemes 4, 5, 6, 7 and 8.

Intermediates of type B, wherein R ⁹ , R ¹⁰ , R ¹³ , R ¹⁴ and A are as defined herein and wherein B is aryl, in particular phenyl can be prepared by a variety of conditions, which may be exemplified by the general synthetic procedure outlined in Scheme 4.

Scheme 4 Chan-Lam coupling reaction between hydroxy aryl compounds 40, wherein B is aryl, in particular phenyl, and R ⁹ and R ¹⁰ are as defined herein, and a boronic acid 41 (R=H) or a boronic acid ester 41 (R¹H, e.g. pinacol or trimethylene glycol ester), which are either commercially available or may be prepared by methods known to the man skilled in the art, wherein A, R ¹³ and R ¹⁴ are as defined herein, can be performed by using a suitable catalyst, such as copper(II) acetate or copper(II) acetate monohydrate in a solvent like DCM, THF, dioxane, DME, or a mixture thereof, preferably in DCM and preferably at room temperature to give the corresponding ether intermediates 42 ( Scheme 4, step a). Subsequent alkaline hydrolysis of the ester moiety with a suitable base, such as aqueous lithium, sodium or potassium hydroxide, preferably lithium hydroxide, in a solvent like MeOH, EtOH, THF or a mixture thereof and in a temperature range between 0°C and the boiling point of the reaction mixture, preferably at around room temperature gives intermediates of type B (step b, Scheme 4).

Intermediates of type C, wherein R ⁹ and R ¹⁰ are as defined herein, R ⁸ is alkoxy and B is aryl, in particular phenyl, can be prepared by a variety of conditions, which may be exemplified by the general synthetic procedure outlined in Scheme 5.

Scheme 5

Starting from halo methyl aryl compounds 50, wherein B is aryl, in particular phenyl, and R ⁹ and R ¹⁰ are as defined herein and Y is a suitable leaving group such as Cl, Br, I or OTf, an alcoholysis can be performed in the presence of a suitable base, such as Na ₂ C0 ₃ , K ₂ C0 _3, Na0H, KOH in solvent such as MeOH, EtOH, iPrOH, nBuOH, tBuOH and in a temperature range between room temperature and reflux, preferably at reflux to give the corresponding ether intermediates 51, wherein R ⁸ is alkoxy and R ⁹ and R ¹⁰ are as defined herein ( Scheme 5, step a). Subsequent alkaline hydrolysis with a suitable base, such as aqueous sodium or potassium hydroxide, preferably lithium hydroxide in a solvent like MeOH, EtOH, THF or a mixture thereof and in a temperature range between 0°C and the boiling point of the solvent, preferably around room temperature gives intermediates of type C ( Scheme 5, step b). Intermediates of type D, wherein R ¹¹ is as defined herein, R ¹² is alkyl, cycloalkyl or heterocyclyl and B is heteroaryl comprising a secondary amino group, can be prepared by a variety of conditions, which may be exemplified by the general synthetic procedure outlined in Scheme 6.

Scheme 6

Intermediates 60, wherein R ¹¹ is as defined herein and ring B is heteroaryl comprising a secondary amino group (i.e., such as in indolyl) can be N- functionalized by treatment with an appropriate base, such as NaH, KH, NaHMDS, LiHMDS or LDA, preferably with NaH in a solvent like DMF, THF, dioxane, or a mixture thereof, preferably DMF and in a temperature range between -78°C and room temperature, preferably at 0°C, followed by addition of an electrophile, e.g. an alkyl or cycloalkyl halide, such as Mel, Etl, iPrl or CyPrI to give the corresponding /V-functionalized compounds 61 ( Scheme 6, step a), wherein R ¹¹ is as defined herein and R ¹² is alkyl, cycloalkyl or heterocyclyl. Intermediate 61 is subsequently hydrolyzed with a suitable base, such as aqueous LiOH, NaOH or KOH, preferably aqueous LiOH in a solvent like MeOH, EtOH, THF or a mixture thereof and in a temperature range between 0°C and the boiling point of the reaction mixture, preferably at around room temperature to give carboxylic acid intermediates of type D (step b, Scheme 6). Intermediates of type E, wherein R ⁸ is alkyl, cycloalkylalkyl, arylalkyl,

heteroarylalkyl or heterocyclylalkyl, R ⁹ and R ¹⁰ are as defined herein, and B is aryl, in particular phenyl, can be prepared by a variety of conditions, which may be exemplified by the general synthetic procedure outlined in Scheme 7.

Scheme 7 Intermediates 40, wherein B is aryl, in particular phenyl, and R ⁹ and R ¹⁰ are as defined herein, can be //-alkylated by treatment with an appropriate base, such as Na ₂ C03, K2CO3 or CS2CO3 in a solvent like DMF, DCM, DCE, or a mixture thereof, preferably DMF and in a temperature range between room temperature and reflux, preferably at around 40°C, followed by addition of an electrophile, e.g. an alkyl-, cycloalkylalkyl-, arylalkyl-, heteroarylalkyl- or heterocyclylalkyl halide, such as Mel, Etl, iPrl,

iodomethylcyclopropane, 4-(chloromethyl)-l-methyl-pyrazole or ferf-butyl 4- (bromomethyl)pyrazole-l-carboxylate, to give the corresponding ether intermediates 62 (Scheme 7, step a), wherein R ⁸ is selected from the group consisting of alkyl,

cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl and R ⁹ and R ¹⁰ are as defined herein. Intermediate 62 is subsequently hydrolyzed with a suitable base, such as aqueous LiOFl, NaOFl or KOF1, preferably aqueous LiOFl in a solvent like MeOFl, EtOFl, TF1F or a mixture thereof and in a temperature range between 0°C and the boiling point of the reaction mixture, preferably at around room temperature to give carboxylic acid intermediates of type E ( Scheme 7, step b).

Intermediates of type F, wherein R ⁹ and R ¹⁰ are as defined herein, B is aryl, in particular phenyl, R 8 is alkyl, aryl, heteroaryl, or a group -N(R 21 R 22 ), wherein R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl or wherein R ²¹ and R ²² , taken together with the N-atom to which they are attached, form a mono- or bicyclic heterocycloalkyl, can be prepared by a variety of conditions, which may be exemplified by the general synthetic procedure outlined in Scheme 8.

Scheme 8 The hydroxy group of intermediates 40, wherein B is aryl, in particular phenyl, and

R ⁹ and R ¹⁰ are as defined herein, can be transformed into a suitable leaving group such as a mesylate, tosylate or preferably triflate (OTf) by treatment with a suitable base such as, Fluenig’s base or TEA in a solvent like DMF or DCM and in a temperature range between 0°C and room temperature, followed by addition of TFO or Tf2NPh, preferably TFNPh gives the corresponding triflate compounds 70 ( Scheme 8, step a). Subsequent, Suzuki cross-coupling reaction with aryl boronic acids or esters, alkyl boronic acids or esters, such as (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxabo rolane, using a suitable catalyst (e.g. bis(triphenylphosphine)palladium (II) chloride, dichloro[l,r- bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct,

tetrakis(triphenylphosphine)palladium(0) or palladium(II)acetate with triphenylphosphine) in an appropriate solvent (e.g. dioxane, DME, water, toluene, DMF or mixtures thereof) and a suitable base (e.g. Na ₂ C03, NaHC03, KF, K ₂ CO ₃ or NEt3) at temperatures between room temperature and the boiling point of the reaction mixture, yields ester compounds 71 (step b), wherein R ⁸ is selected from the group consisting of alkyl, aryl and heteroaryl, and R ⁹ and R ¹⁰ are as defined herein. Finally, alkaline hydrolysis of the ester moiety with a suitable base, such as aqueous lithium, sodium or potassium hydroxide, preferably lithium hydroxide, in a solvent like MeOH, EtOH, THF or a mixture thereof and in a temperature range between 0°C and the boiling point of the reaction mixture, preferably at around room temperature gives intermediates of type F (step c).

Alternatively, intermediates 70, wherein B is aryl, in particular phenyl, X is a suitable leaving group such as Br, I (commercial compounds) or OTf (synthezised according to the step a described above) and R ⁹ and R ¹⁰ are as defined herein, can be transformed to intermediates 71 by applying cross -coupling reactions such as Buchwald- Hartwig. Treatment of intermediates 70 with primary or secondary amines of the type

HN(R R ), such as 2-oxa-6-azaspiro[3.3]heptane, using a suitable catalyst system such as Pd ₂ (dba)3 and Davephos in the presence of a base such as K3PO4 in an appropriate solvent such as dioxane or toluene at temperatures ranging from room temperature up to the boiling point of the solvent, optionally applying microwave heating ( Scheme 8, step b). Finally, alkaline hydrolysis of the ester moiety with a suitable base, such as aqueous lithium, sodium or potassium hydroxide, preferably lithium hydroxide, in a solvent like MeOH, EtOH, THF or a mixture thereof and in a temperature range between 0°C and the boiling point of the reaction mixture, preferably at around room temperature gives intermediates of type F (step c). In one aspect, the present invention provides a process of manufacturing the compounds of formula (I) described herein, comprising the steps of: a) reacting an amine 13, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described herein, acid 14, wherein R ¹ is as described herein

b) reacting an amine 13, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described herein,

acid chloride 15, wherein R ¹ is as described herein

to form said compound of formula (I).

In one embodiment, the present invention provides a process of manufacturing the compounds of formula (I) described herein, comprising reacting an amine 13, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described herein,

with an acid 14, wherein R ¹ is as described herein

to form said compound of formula (I).

In one embodiment, the present invention provides a process of manufacturing the compounds of formula (I) described herein, comprising reacting an amine 13, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described herein, with an acid chloride 15, wherein R ¹ is as described herein

to form said compound of formula (I).

In one aspect, the present invention provides a compound of formula (I) as described herein, when manufactured according to any one of the processes described herein.

MAGT, Inhibitory Activity

Compounds of the present invention are MAGL inhibitors. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for inhibiting MAGL in a mammal. In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

In a further aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal. In a further aspect, the present invention provides a method for inhibiting MAGL in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.

Compounds were profiled for MAGL inhibitory activity by measuring the enzymatic activity of MAGL by following the hydrolysis of 4-nitrophenylacetate resulting in 4- nitrophenol, which absorbs at 405-412 nm (G.G. Muccioli, G. Labar, D.M. Lambert,

Chem. Bio. Chem. 2008, 9, 2704-2710). This assay is hereinafter abbreviated“4-NPA assay”.

The 4-NPA assay was carried out in 384 well assay plates (black with clear bottom, non-binding surface treated, Corning Ref. 3655) in a total volume of 40 pL. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in 3-fold dilution steps to give a final concentration range in the assay from 25 pM to 1.7 nM. 1 pL compound dilutions (100% DMSO) were added to 19 pL MAGL

(recombinant wild-type) in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-l00ml)). The plate was shaked for 1 min at 2000 rpm (Variomag Teleshake) and then incubated for 15 min at RT. To start the reaction, 20 p E 4- Nitrophenlyacetate (Sigma N-8130) in assay buffer with 6% EtOH was added. The final concentrations in the assay were 1 nM MAGL and 300 mM 4-Nitrophenylacetate. After shaking (1 min, 2000 rpm) and 5 min incubation at RT, the absorbance at 405 nm was measured for a fist time (Molecular Devices, SpectraMax Paradigm). A second measurement was then done after incubation for 80 min at RT. From the two

measurements, the slope was calculated by substracting the first from the second measurement.

Alternatively, compounds were profiled for MAGL inhibitory activity by determining the enzymatic activity by following the hydrolysis of the natural substrate, 2- arachidonoylglycerol, resulting in arachidonic acid, which can be followed by mass spectrometry. This assay is hereinafter abbreviated“2-AG assay”.

The 2-AG assay was carried out in 384 well assay plates (PP, Greiner Cat# 784201) in a total volume of 20 pL. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in 3-fold dilution steps to give a final concentration range in the assay from 12.5 mM to 0.8 pM. 0.25pL compound dilutions (100% DMSO) were added to 9 pL MAGL in assay buffer (50 mM TRIS (GIBCO, 15567- 027), 1 mM EDTA (Fluka, 03690-l00ml), 0.01% (v/v) Tween. After shaking, the plate was incubated for 15 min at RT. To start the reaction, 10 pL 2-arachidonoylglycerol in assay buffer was added. The final concentrations in the assay was 50 pM MAGL and 8 mM 2-arachidonoylglyerol. After shaking and 30 min incubation at RT, the reaction was quenched by the addition of 40pL of acetonitrile containing 4pM of d8-arachidonic acid. The amount of arachidonic acid was traced by an online SPE system (Agilent Rapidfire) coupled to a triple quadmpole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used in an acetonitrile/water liquid setup. The mass spectrometer was operated in negative electrospray mode following the mass transitions 303.1 259.1 for arachidonic acid and 311.1 267.0 for d8-arachidonic acid. The activity of the compounds was calculated based on the ratio of intensities [arachidonic acid / d8- arachidonic acid]. Table 1

* measured in 2- AG assay; if nothing else is indicated (i.e. *), the activity was measured in the 4-NPA assay.

In one aspect, the present invention provides compounds of formula (Ie) and their pharmaceutically acceptable salts as described herein, wherein said compounds of formula (Ie) and their pharmaceutically acceptable salts have ICso’s for MAGL inhibition below 25 mM, preferably below 10 pM, more preferably below 5 pM as measured in the MAGL assay described herein.

In one embodiment, compounds of formula (Ie) and their pharmaceutically acceptable salts as described herein have IC50 (MAGL inhibition) values between

0.000001 pM and 25 pM, particular compounds have IC50 values between 0.000005 pM and 10 pM, further particular compounds have IC50 values between 0.00005 pM and 5 pM, as measured in the MAGL assay described herein.

In one embodiment, the present invention provides compounds of formula (Ie) and their pharmaceutically acceptable salts as described herein, wherein said compounds of formula (I) and their pharmaceutically acceptable salts have an IC50 for MAGL below 25 pM, preferably below 10 pM, more preferably below 5 pM.

In one embodiment, the present invention provides compounds of formula (Ie) and their pharmaceutically acceptable salts as described herein, wherein said compounds of formula (Ie) and their pharmaceutically acceptable salts have an IC50 for MAGL below 25 pM, preferably below 10 pM, more preferably below 5 pM as measured in an assay comprising the steps of: a) providing a solution of a compound formula (Ie), or a pharmaceutically

acceptable salt thereof, in DMSO; b) providing a solution of MAGL (recombinant wild-type) in assay buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid); c) adding 1 pL of compound solution from step a) to 19 pL of MAGL solution from step b); d) shaking the mixture for 1 min at 2000 rpm; e) incubating for 15 min at RT; f) adding 20 pL of a solution of 4-nitrophenlyacetate in assay buffer (50 mM

tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid, 6% EtOH); g) shaking the mixture for 1 min at 2000 rpm; h) incubating for 5 min at RT; i) measuring the absorbance of the mixture at 405 nm a fist time; j) incubating a further 80 min at RT; k) measuring the absorbance of the mixture at 405 nm a second time; l) substracting the absorbance measured under i) from the absorbance measured under k) and calculating the slope of absorbance; wherein: i) the concentration of the compound of formula (Ie), or the pharmaceutically acceptable salt thereof in the assay after step f) is in the range of 25 pM to 1.7 nM;

ii) the concentration of MAGL in the assay after step f) is 1 nM;

iii) the concentration of 4-nitrophenylacetate in the assay after step f) is 300 pM; and

iv) steps a) to 1) are repeated for at least 3 times, each time with a different concentration of the compound of formula (Ie), or the pharmaceutically acceptable salt thereof. Using the Compounds of the Invention

In one aspect, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance. In a further aspect, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal. In one embodiment, the present invention provides the use of compounds of formula

(Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of cancer in a mammal.

In one aspect, the present invention provides the use of compounds of formula (Ie), preferably of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal.

In a preferred embodiment, the present invention provides the use of compounds of formula (Ie), preferably of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease and/or Parkinson’s disease in a mammal.

In a particularly preferred embodiment, the present invention provides the use of compounds of formula (Ie), preferably of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of multiple sclerosis in a mammal. In one aspect, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.

In one embodiment, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancer in a mammal.

In one embodiment, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of neurodegenerative diseases in a mammal.

In one aspect, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal.

In a preferred embodiment, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease and/or Parkinson’s disease in a mammal.

In a particularly preferred embodiment, the present invention provides compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a

pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of multiple sclerosis in a mammal.

In one aspect, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of neurodegenerative diseases in a mammal.

In one embodiment, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of cancer in a mammal.

In a further aspect, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, cancer and/or pain in a mammal.

In a preferred embodiment, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a

pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease and/or Parkinson’s disease in a mammal.

In a particularly preferred embodiment, the present invention provides the use of compounds of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis in a mammal. In one aspect, the present invention provides a method for the treatment of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

In one embodiment, the present invention provides a method for the treatment of neuroinflammation and/or neurodegenerative diseases in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described, or a pharmaceutically acceptable salt thereof, herein to the mammal.

In one embodiment, the present invention provides a method for the treatment of neurodegenerative diseases in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described, or a pharmaceutically acceptable salt thereof, herein to the mammal.

In one aspect, the present invention provides a method for the treatment of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression and/or pain in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

In a preferred embodiment, the present invention provides a method for the treatment of multiple sclerosis, Alzheimer’s disease and/or Parkinson’s disease in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

In a particularly preferred embodiment, the present invention provides a method for the treatment of multiple sclerosis in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

In one aspect, the present invention provides a method for the prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

In one embodiment, the present invention provides a method for the prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described, or a pharmaceutically acceptable salt thereof, herein to the mammal.

In one embodiment, the present invention provides a method for the prophylaxis of neurodegenerative diseases in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably of a compound of formula (I), as described, or a pharmaceutically acceptable salt thereof, herein to the mammal.

In one aspect, the present invention provides a method for the prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression and/or pain in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal.

In a preferred embodiment, the present invention provides a method for the prophylaxis of multiple sclerosis, Alzheimer’s disease and/or Parkinson’s disease in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a

pharmaceutically acceptable salt thereof, to the mammal.

In a particularly preferred embodiment, the present invention provides a method for the prophylaxis of multiple sclerosis in a mammal, which method comprises administering an effective amount of a compound of formula (Ie), preferably a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, to the mammal. Pharmaceutical Compositions and Administration

In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (Ie), preferably a compound of formula (I), described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. The compounds of formula (Ie) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The

pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

The compounds of formula (Ie) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

Suitable adjuvants for the production of solutions and symps are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

Examples

The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.

All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise. Intermediate 1-1

/e/ - Butyl 7-oxo-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazine-2-carb oxylate

Step GA1 5-r(4-methoxyphenyl)methoxy1pyridine-2-carbonitrile

To a solution of (4-methoxyphenyl)methanol (75.5 g, 546.4 mmol) in DMF (1000 mL) cooled at 0°C was added 65 % NaH dispersion in mineral oil (32.8 g, 819.6 mmol) portionwise and the mixture was stirred at this temperature for 30 min. Then, 3-bromo-6- pyridinecarbonitrile (CAS RN 97483-77-7, 100.0 g, 546.4 mmol) was added in portions and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into a sat. NH ₄ Cl aq. solution (3000 mL), filtered and washed with EtOAc (3 x 200 mL). The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the cmde title compound (112 g, 85.3%) as a pink solid; MS (ESI): m/z =

241.1 [M+H] ⁺ .

Step GB1 r5-r(4-methoxyphenyl)methoxy1-2-pyridyl1methanamine

To a solution of 5-[(4-methoxyphenyl)methoxy]pyridine-2-carbonitrile (50.0 g,

208.1 mmol) in methanol (2000 mL) was added Raney Nickel (10.0 g, 170.4 mmol) followed by ammonium hydroxide (20.0 mL, 266.7 mmol). The reaction mixture was then heated to 50 °C under 3.5 bar of 11 ₂ atmosphere for 12 hours. The mixture was filtered and the resulting filtrate was concentrated in vacuo to give the cmde title compound (50 g, 98.3% yield) as a dark red solid; MS (ESI): m/z = 245.3 [M+H] ⁺ . Step TCI 2-bromo-/V-l 15-1 (4-mcthoxynhcnyl)mcthoxyl-2-nyridyl I methyl I acetamide

To a solution of [5-[(4-methoxyphenyl)methoxy]-2-pyridyl]methanamine (43.6 g, 178.5 mmol) in DCM (200 mL) cooled at 0°C was added EDCI (34.1 g, 178.5

mmol) followed by bromoacetic acid (24.8 g, 178.5 mmol) in portions and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into a sat. NaHC0 ₃ aq. solution (200 mL). The organic layer was separated, washed with more sat. NaHC0 ₃ aq. solution (3 x 50 mL), brine (50 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo to give the cmde title compound (60.6 g, 93% yield) as a dark red oil; MS (ESI): m/z = 367.2 [M+2] ⁺

Step GR1 7-r(4-methoxyphenyl)methoxy1-l.2.4.6.9.9a-hexahvdropyridorl. 2-a1pyrazin-3- one

2-bromo-/V-| 1-5-1 (4-methoxyphenyl )methoxy|-2-py ridyl | methyl ] acetamide (11.60 g, 31.76 mmol, 1 eq) was dissolved in CH ₃ CN (150 mL) and stirred at 50 °C for 12 hours.

The reaction mixture was concentrated in vacuo to remove the solvent, the residue was re dissolved in MeOH (150 mL) and cooled to 0°C. Then, sodium borohydride (12.01 g, 317.5 mmol) was carefully added to the reaction mixture which was stirred at room temperature for 12 hours. The mixture was evaporated to dryness and the residue was purified by silica gel flash chromatography eluting with a 1 to 10% MeOH in DCM gradient to give the cmde product. This material was then triturated with EtOAc (50 mL), filtered and further dried under high vacuum to give the title compound (3.1 g, 33.9%) as a yellow solid; MS (ESI): m/z = 289.1 [M+H] ⁺ .

Step GE1 7-r(4-methoxyphenyl)methoxy1-2,3,4,6,9,9a-hexahvdro-lH-pyrid orl,2-a1pyrazine

To a solution of 7-[(4-methoxyphenyl)methoxy]-l,2,4,8,9,9a-hexahydropyrido [1,2- a] pyrazin-3-one (3.10 g, 10.7 mmol) in THE (100 mL) cooled at 0°C, was carefully added L1AIH ₄ (1.02 g, 26.9 mmol) and the reaction mixture was heated to 80 °C for 2 hours. The mixture was cooled to 0°C, quenched with water (4 mL) and a 20% aq.

NaHC0 ₃ solution (4 mL). The mixture was filtered, washed with THE (3 x 20 mL) and the resulting filtrate was concentrated in vacuo to give the crude title compound (2.9 g,

98%) as a yellow solid; MS (ESI): m/z = 275.3 [M+H] ⁺ .

Step TF1 /er/-butyl 7-oxo-3.4.6.8.9.9a-hexahvdro-lH-pyridorl.2-a1pyrazine-2-carb oxylate

To a solution of 7-[(4-methoxyphenyl)methoxy]-2,3,4,8,9,9a-hexahydro-lH-pyrid o [l,2-a]pyrazine (2.9 g, 10.6 mmol) in DCM (50 mL) was added TFA (10.0 mL, 10.57 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to remove the solvent, the residue was re-dissolved in CPpCN (50 mL) and cooled to 0°C. Then, Na ₂ C0 ₃ (3.3 g, 31.13 mmol) followed by di -tert- butyldicarbonate (6.8 g, 31.1 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (100 mF) and extracted with EtOAc (3 x 100 mF). The combined organic layers were washed with water (3 x 30 mF), brine (50 mF), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 10 to 30% of EtOAc in PE to give the title compound (2.62 g, 99.3%) as a light yellow solid. Intermediate 1-2

2-(2-Chloro-3-methoxybenzoyl)-3,4,6,8,9,9fl-hexahydro-l/7 -pyrido[l,2-a]pyrazin-7-one

Step GA1 (2-Chloro-3-methoxyphenyl)-r7-r(4-methoxyphenyl)methoxy1-l.3 ,4,6, 9,9a- hexahvdropyridorl.2-a1pyrazin-2-yl1methanone

To a solution of 2-chloro-3-methoxybenzoic acid (2.94 g, 15.75 mmol) and 7-[(4- methoxyphenyl)methoxy]-2,3,4,6,9,9a-hexahydro-lH-pyrido[l,2- a]pyrazine (Intermediate 1-1 [E], 3.6 g, 13.12 mmol) in DMF (50 mF) cooled at 0°C was added TEA (5.6 mF, 39.36 mmol) followed by T ₃ P (9.06 g, 19.68 mmol), then the reaction mixture was heated to 50 °C for 12 hours. The reaction was diluted with water (100 mF) and extracted with EtOAc (2 x 80 mF). The combined organic layer was washed with water (2 x 50 mF) and brine (50 mF), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by silica flash chromatography, eluting with a 50 to 100% EtOAc-heptane gradient to give the title compound (3.9 g, 67.1%) as a yellow solid; MS (ESI): m/z = 443.2 [M+H] ⁺ .

Step GB1 2-(2-(Tiloro-3-incthoxyhcn/oyl)-3,4,6,8,9,9n-hcxahvdro- 1 //-pyridol 1 ,2- alpyrazin-7-one To a solution of (2-chloro-3-methoxy-phenyl)-[7-[(4-methoxyphenyl)methoxy]- l,3,4,6,9,9a-hexahydropyrido[l,2-a]pyrazin-2-yl]methanone (3.9 g, 8.8 mmol) in DCM (50 mL) cooled to 0°C was added TFA (3.39 mL, 44 mmol), then the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, the residue taken up in EtOAc, poured into a saturated aq. NaHCCF solution (100 mL) and the aqueous layer was extracted with EtOAc (2 x 50 mL). Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 50 to 100% EtOAc -heptane gradient to give the title compound (2.1 g, 73.9%) as a light yellow foam. MS (ESI): m/z = 341.2

[M+H ₂ 0+H] ⁺ .

Intermediate 1-3

2-[2-chloro-3-(difluoromethoxy)benzoyl]-3,4,6,8,9,9a-hexa hydro-lH-pyrido[l,2- a]pyrazin-7-one

Intermediate 1-3 was prepared in analogy to intermediate 1-2, but using in step [A] 2-chloro-3-(difluoromethoxy)benzoic acid (CAS RN 1427432-41-4) to give the title compound as an off-white foam. MS (ESI): m/z = 377.2 [M+H ₂ 0+H] ⁺ .

Intermediate 1-4

2-[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoyl]- 3,4,6,8,9,9a-hexahydro-lH- pyrido[ 1 ,2-a]pyrazin-7 -one Intermediate 1-4 was prepared in analogy to intermediate 1-2, but using in step [A] 2- chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoic acid (Intermediate E-l) to give the title compound as a colorless foam. MS (ESI): m/z = 408.3 [M+ELO+E1] ¹ .

Intermediate A-l

(7R,9aR)-7 -(4-Chlorophenyl)octahydro- 1 El-pyrido [ 1 ,2-a]pyrazine Step GA1 tert- butyl 7-(4-chlorophenyl)-7-hvdroxy-3.4.6.8.9.9a-hexahvdro-lEl-pyri dorL2- al pyrazine-2-carboxylate

To a solution of ferf-butyl 7-oxo-3,4,6,8,9,9a-hexahydro-lELpyrido[l,2-a] pyrazine- 2-carboxylate (Intermediate 1-1, 1.0 g, 3.93 mmol) in TE1F (30 mL) cooled at 0 °C was added 4-chlorophenylmagnesium bromide (1M solution in TE1F, 7.08 mL, 7.08 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into a saturated NH ₄ Cl aq. solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by silica flash chromatography, eluting with a 5% to 25% EtOAc-PE gradient to give the title compound (0.820 g, 56.8%) as a light yellow oil; MS (ESI): m/z = 367.1 [M+H] ⁺ .

Step GB1 7-(4-chlorophenyl)-2.3.4.8.9.9a-hexahvdro-lH-pyridorl.2-a1py razine

To a solution of / _< 3 /7-butyl 7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro- lH-pyrido [l,2-a]pyrazine-2-carboxylate (0.820 g, 2.24 mmol) in DCM (25 mL) was added methane sulfonic acid (5.0 mL, 164 mmol) and the reaction mixture was stirred at 20 °C for 48 hours. The mixture was poured into a sat. NaHC0 ₃ aq. solution (100 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the crude title compound (0.560 g,) as a light yellow oil; MS (ESI): m/z = 249.1 [M+H] ⁺ . Step TCI rac-(7R,9aR)-7-(4-chlorophenyl)-2,3,4,6,7,8,9,9a-octahvdro-l H-pyridorl,2- alpyrazine

To a solution of 7-(4-chlorophenyl)-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2- ajpyrazine (0.560 g, -2.24 mmol) and magnesium oxide (0.272 g, 6.75 mmol) in EtOAc (60 mL) was added Pd/C (0.250 g, 2.25 mmol) and the mixture was stirred at room temperature under H ₂ atmosphere for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (MeCN and 0.1% of TFA in water, 0-30%) and the solution containing product was basified with a sat.

NaHC0 ₃ aq. solution to pH~8, followed by extraction with EtOAc. The organic phase dried over Na ₂ S0 ₄ filtered and concentrated in vacuo to give the title compound (0.180 g, 31.8%) as an off-white foam; MS (ESI): m/z = 251.1 [M +H] ⁺ .

Step GR1 (7R,9aR)-7-(4-chlorophenyl)-2,3,4,6,7,8,9,9a-octahydro-lH-py ridorl,2- alpyrazine

7-(4-Chlorophenyl)-2,3,4,6,7,8,9,9a-octahydro-lH-pyrido[l ,2-a]pyrazine (0.16 g, 0.640 mmol) was separated by preparative chiral HPLC (Daicel Chiralpak) to give (7R,9aR)-7-(4-chlorophenyl)-2,3,4,6,7,8,9,9a-octahydro-lH-py rido[l,2-a]pyrazine (0.064 g, 36.3%) as light yellow solid; MS (ESI): m/z = 251.0 [M+H] ⁺ . Intermediate A-2

(7S,9aS)-7-(4-Chlorophenyl)octahydro-lH-pyrido[l,2-a]pyra zine

7-(4-Chlorophenyl)-2,3,4,6,7,8,9,9a-octahydro-lH-pyrido[l ,2-a]pyrazine

(Intermediate A-l[C], 0.16 g, 0.64 mmol) was separated by preparative chiral HPLC (Daicel Chiralpack AY) to give the title compound (0.061 g, 33%) as a light yellow solid; MS (ESI): m/z = 251.0 [M+H] ⁺ .

Intermediate A-3

(7R,9aR)-7-Phenyloctahydro-lH-pyrido[l,2-a]pyrazine

Intermediate A-3 was prepared in analogy to intermediate A-l, but using in step [A] phenylmagnesium bromide (1M solution in THF) to give the title compound as a white solid. MS (ESI): m/z = 217.2 [M+H] ⁺ .

Intermediate A-4 rac-(7R,9aR)-7-(3,4-Dichlorophenyl)-2,3,4,6,7,8,9,9a-octahyd ro-lH-pyrido[l,2-a]pyrazine

Step GA1 tert- butyl 7-(trifluoromethylsulfonyloxy)-l,3,4,8,9,9a-hexahydropyridor l,2-a1 pyrazine-2-carboxylate

To a solution of ferf-butyl 7-oxo-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazine- 2-carboxylate (Intermediate 1-1, 0.5 g, 1.97 mmol) in THF (10 mL) cooled at -78 °C was added a 1M solution of lithium bis(trimethylsilyl)amide in THF (2.36 mL, 2.36 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 hour. A solution of /V-phenyl trifluoromethanesulfonimide (0.77 g, 2.16 mmol) in THF (5 mL) was then added dropwise to the mixture which was warmed up to room temperature and stirred for another 3 hours. The mixture was poured into a sat. Na ₂ C0 ₃ aq. solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with a 10 to 35% EtOAc in PE gradient to give the title compound (0.62 g, 81.6%) as a yellow oil; MS (ESI): m/z = 331.5 [M+H] ⁺ .

Step GB1 tert- butyl 7-(3,4-dichlorophenyl)-l, 3,4,8, 9,9a-hexahydropyridorl,2-a1pyrazine-2- carboxylate In a sealed tube, 3,4-dichlorophenylboronic acid (0.296 g, 1.55 mmol), tert- butyl 7- (trifluoromethylsulfonyloxy)- 1 ,3 ,4,8,9,9a-hexahydropyrido[ 1 ,2-a]pyrazine-2-carboxylate (0.6 g, 1.55 mmol), sodium carbonate (0.658 g, 6.21 mmol) were mixed in dioxane (16 mL) and water (4 mL). Then, tetrakis(triphenylphosphine)palladium (0.179 g, 0.160 mmol) was added and the reaction mixture was heated to 110 °C for 12 hours. The mixture was filtered and the resulting filtrate concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with a 10 to 25% EtOAc in PE gradient to give the title compound (0.27 g, 45.4%) as a light yellow oil; MS (ESI): m/z = 383.1 [M+H] ⁺ .

Step TCI fert-butyl 7-(3,4-dichlorophenyl)-l, 3,4, 6,7,8, 9,9a-octahvdropyridorl,2- alpyrazine-2-carboxylate

To a solution of ½ /7-butyl 7-(3,4-dichlorophenyl)-l,3,4,8,9,9a-hexahydropyrido[l,2- a] pyrazine-2-carboxylate (0.24 g, 0.630 mmol) and magnesium oxide (0.32 g, 7.94 mmol) in EtOAc (50 mL) was added Pd/C (0.16 g, 1.76 mmol) and the mixture was stirred at room temperature under 11 ₂ atmosphere for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the cmde title compound (0.25 g) as a light yellow oil; MS (ESI): m/z = 385.1 [M+H] ⁺ .

Step GR1 rac-(7R,9aR)-7-(3,4-dichlorophenyl)-2,3,4,6,7,8,9,9a-octahvd ro-lH-pyridorl,2- alpyrazine

To a solution of ½ /7-butyl 7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a- octahydropyrido[l,2-a] pyrazine-2-carboxylate (0.25 g, -0.630 mmol) was added 4M HC1 in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated in vacuo and the residue was purified by prep-HPLC (MeCN and 0.1% of TFA in water, 0-30%) to give the title compound (0.093 g, 35.9%) as an off-white solid as TFA salt; MS (ESI): m/z = 285.0 [M+H] ⁺ . Intermediate A-5 rac-(7R,9aR)-7-(3-Chloro-4-fluoro-phenyl)-2,3,4,6,7,8,9,9a-o ctahydro-lH-pyrido[l,2- ajpyrazine

Intermediate A-5 was prepared in analogy to intermediate A-4, but using in step [B] 3-chloro-4-fluorophenylboronic acid to give the title compound as an off-white solid as TFA salt; MS (ESI): m/z = 269.3 [M+H] ⁺ . Intermediate A-6 rac-(7R,9aR)-7-(4-chlorophenyl)-l,2,3,4,6,8,9,9a-octahydropy rido[l,2-a]pyrazin-7-ol

Step GA1 tert- Butyl 7-(4-chlorophcnyl)-7-hvdroxy-3,4,6,8,9,9u-hcxahydro- 1 /7-pyridol 1 ,2- alpyrazine-2-carboxylate To a solution of ½ /7-butyl 7-oxo-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a] pyrazine-2- carboxylate (Intermediate A-l, 0.5 g, 1.97 mmol) in THF (15 mL) cooled at 0°C was added a 1M solution of 4-chlorophenylmagnesium bromide in THF (3.54 mL, 3.54 mmol) dropwise while keeping the temperature below 5°C, then the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, poured into a sat. NH ₄ CI aq. solution (10 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (10 mL), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with a 0 to 50% EtOAc- heptane gradient to give the title compound (0.164 g, 22.7%) as a pink solid; MS (ESI): m/z = 367.4 [M+H] ⁺ . Step GB1 7-(4-chlorophenyl)-l,2,3,4,6,8,9,9a-octahvdropyridorl,2-a1py razin-7-ol

To a solution of ferf-butyl 7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9rt-hexahydro- 1 H- pyrido[l,2-a]pyrazine-2-carboxylate (0.164 g, 0.447mmol) in dioxane (1.2 mL) was added 4M HC1 in dioxane (1.12 mL, 4.47 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated to dryness and further dried on the high vacuum to give the cmde title compound (0.160 g) as a yellow oil as the

hydrochloride salt. MS: 267.2 (M+H ⁺ ).

Step TCI rac-(7R,9aR)-7-(4-chlorophenyl)-l,2,3,4,6,8,9,9a-octahvdropy ridorl,2-a1pyrazin- 7-ol

7-(4-chlorophenyl)-l,2,3,4,6,8,9,9a-octahydropyrido[l,2-a ]pyrazin-7-ol (0.160 g) was separated by preparative preparative HPLC to give the title compound (0.030 g, 25.2%) as a yellow foam; MS (ESI): m/z = 267.2 [M+H] ⁺ .

Intermediate A-7 rac-(7R,9aS)-7-(4-chlorophenyl)-l,2,3,4,6,8,9,9a-octahydropy rido[l,2-a]pyrazin-7-ol 7-(4-chlorophenyl)-l,2,3,4,6,8,9,9a-octahydropyrido[l,2-a]py razin-7-ol

(Intermediate A-6[B], 0.160 g) was separated by preparative HPLC to give the title compound (0.020 g, 15.9%) as a yellow oil; MS (ESI): m/z = 267.2 [M+H] ⁺ .

Intermediate B-l 2-Chloro-3-(3,5-difluorophenoxy)benzoic acid

Step GA1 methyl 2-chloro-3-(3.5-difluorophenoxy)benzoate

In a flask, methyl 2-chloro-3 -hydroxy-benzoate (0.1 g, 0.53 mmol), 3,5- difluorophenylboronic acid (0.083 g, 0.53 mmol), copper(II) acetate (0.095 g, 0.53 mmol), triethylamine (0.07 mL, 0.53 mmol) and molecular sieves were mixed in DCM (10 mL) and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with a 0 to 10% EtOAc- heptane gradient to give the title compound (0.035 g, 21%) as a colorless liquid.

GB1 2-chloro-3-(3,5-difluorophenoxy)benzoic acid To a stirred solution of methyl 2-chloro-3-(3,5-difluorophenoxy)benzoate (0.03 g,

0.1 mmol) in a mixture of THF (2 mL), water (2 mL) and methanol (2 mL) was added LiOH (0.021 g, 0.5 mmol) and the reaction mixture was stirred at room

temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified to pH 3 with 2N aqueous HC1 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the crude title compound (0.02 g, 69%) as off white solid.

Intermediate B-2

2-Chloro-3-phenoxy-benzoic acid Intermediate B-2 was prepared in analogy to intermediate B-l, but using in step [A] phenylboronic acid to give the title compound as a light yellow solid.

Intermediate C-l

2-Bromo-3-(methoxymethyl)benzoic acid Step GAΊ methyl 2-bromo-3-(methoxymethyl)benzoate

A mixture of methyl 2-bromo-3-(bromomethyl)benzoate (CAS RN 750585-90-1,

0.05 g, 0.162 mmol) and K ₂ C0 ₃ (0.22 g, 0.162 mmol) in MeOH (2 mL) was heated to 80°C for 2 hours. The solvent was removed under vacuum, the residue taken up in EtOAc and washed with water. The organic phase was washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash

chromatography, eluting with a 0 to 40% EtOAc-heptane gradient to give the title compound (0.035 g, 83%) as a colorless oil.

Step GB1 2-bromo-3-(methoxymethyl)benzoic acid To a solution of methyl 2-bromo-3-(methoxymethyl)benzoate (0.032 g, 0.124 mmol) in THF (0.5 mL) was added a 1M LiOH aqueous solution (0.247 mL, 0.247 mmol) and the reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with EtOAc, poured into 1M HC1 and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the crude title compound (0.023 g, 76%) as colorless solid. MS (ESI): m/z = 243.2 [M-H] .

Intermediate D-l

4-Chloro-l-methylpyrrolo[2,3-b]pyridine-5-carboxylic acid

Step GA1 ethyl 4-chloro-l-methylpyrrolor2,3-b1pyridine-5-carboxylate To a solution of ethyl 4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (0.050 g,

0.223 mmol) in DMF (0.5 mL) cooled to 0°C with an ice bath was added 65% NaH dispersion in mineral oil (0.011 g, 0.289 mmol) and the reaction was stirred at this temperature for 10 minutes. Then, methyl iodide (0.018 mL, 0.289 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, poured into a sat. NH ₄ Cl aq. solution and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0- 30% EtOAc-heptane gradient to give the title compound (0.042 g, 79%) as a colorless oil. MS (ESI): m/z = 239.2 [M+H] ⁺ .

Step GB1 4-chloro-l-methylpyrrolor2,3-b1pyridine-5-carboxylic acid To a solution of ethyl 4-chloro-l-methyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (0.04 g, 0.168 mmol) in THF (1 mL) was added a 1M aqueous solution of LiOH (0.335 mL, 0.335 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, poured into a 1M HC1 aq. solution and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated to dryness to afford the crude title compound (0.028 g, 79%) as a white solid. MS (ESI): m/z = 211.1 [M+El] ⁺ .

Intermediate D-2

4-Chloro-l-propan-2-ylpyrrolo[2,3-b]pyridine-5-carboxylic acid Step GA1 ethyl 4-chloro-l-propan-2-ylpyrrolor2.3-b1pyridine-5-carboxylate

To a solution of ethyl 4-chloro-lEl-pyrrolo[2,3-b]pyridine-5-carboxylate (0.050 g, 0.223 mmol) in DMF (0.5 mL) cooled to 0°C with an ice bath was added 65% NaEl dispersion in mineral oil (0.010 g, 0.267 mmol) and the reaction was stirred at this temperature for 10 minutes. Then, 2-iodopropane (0.027 mL, 0.267 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, poured into water and the aqueous layer was extracted with EtOAc.

Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0-30% EtOAc- heptane gradient to give the title compound (0.034g, 57%) as a colorless oil. MS (ESI): m/z = 267.3 [M+H] ⁺ .

Step GB1 4-chloro-l-propan-2-ylpyrrolor2.3-b1pyridine-5-carboxylic acid

To a solution of ethyl 4-chloro-l-propan-2-ylpyrrolo[2,3-b]pyridine-5-carboxylate (0.032 g, 0.120 mmol) in TE1F (1 mL) was added a 1M aqueous solution of LiOEl (0.240 mL, 0.240 mmol) and the reaction mixture was heated to 40 °C for 6 hours. The mixture was diluted with EtOAc, poured into a 1M E1C1 aq. solution and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to afford the crude title compound (0.028 g, 97%) as a white solid. MS (ESI): m/z = 239.2 [M+H] ⁺ .

Intermediate D-3

1 -Isopropylindole-4-carboxylic acid Intermediate D-3 was prepared in analogy to intermediate D-2, but using in step [A] methyl lH-indole-4-carboxylate to give the title compound as a white solid.

Intermediate E-l

2-Chloro-3-propan-2-yloxybenzoic acid Step GA1 methyl 2-chloro-3-propan-2-yloxybenzoate

To a solution of methyl 2-chloro-3-hydroxybenzoate (0.1 g, 0.536 mmol) in DMF (1 mL) was added CS2CO3 (0.210 g, 0.643 mmol) followed by 2-iodopropane (0.080 mL, 0.804 mmol) drop wise and the reaction mixture was heated to 40°C for 2 hours. The mixture was diluted with EtOAc, poured into water and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 20% EtOAc-heptane gradient to give the title compound (0.111 g, 91%) as a colorless liquid. MS (ESI): m/z = 229.1 [M+H] ⁺ .

Step GB1 2-Chloro-3-propan-2-yloxybenzoic acid was prepared in analogy to intermediate D-2[B] to give the title compound as a white solid. MS (ESI): m/z = 215.1 [M+H] ⁺ .

Intermediate E-2

2-Chloro-3-[(l-methylpyrazol-4-yl)methoxy]benzoic acid

Intermediate E-2 was prepared in analogy to intermediate E-l, but using in step [A] 4-(chloromethyl)-l -methyl- lH-pyrazole hydrochloride (CAS RN 735241-98-2) to give the title compound as a white solid. MS (ESI): m/z = 267.3 [M+H] ⁺ .

Intermediate E-3

2-Chloro-3 -( 1 ,3 -thiazol-4-ylmethoxy)benzoic acid

Intermediate E-3 was prepared in analogy to intermediate E-l, but using in step [A] 4-(chloromethyl)thiazole hydrochloride (CAS RN 7709-58-2) to give the title compound as a white solid. MS (ESI): m/z = 270.1 [M+H] ⁺ . Intermediate E-4

2-Chloro-3-[[4-(methylcarbamoyl)phenyl]methoxy]benzoic acid

Intermediate E-4 was prepared in analogy to intermediate E-l, but using in step [A] 4-(chloromcthyl)-A ^/ -mcthylbcnzamide (CAS RN 220875-88-7) to give the title compound as a white solid; MS (ESI): m/z = 320.1 [M+H] ⁺ .

Intermediate E-5

2-Chloro-3-(2,2,2-trifluoroethoxy)benzoic acid

Intermediate E-5 was prepared in analogy to intermediate E-l, but using in step [A] l,l,l-trifluoro-2-iodoethane to give the title compound as a white solid; MS (ESI): m/z = 253.2 [M-H] ^· .

Intermediate F-l

2-Chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoic acid

Step GA1 Methyl 2-chloro-3-(2-oxa-6-azaspiror3.31heptan-6-yl)benzoate

In a sealed tube, methyl 3-bromo-2-chlorobenzoate (CAS RN 871224-19-0, 0.250 g, 1 mmol), 2-oxa-6-azaspiro[3.3]heptane (CAS RN 174-78-7, 0.199 g, 2 mmol), K3PO4 (0.425 g, 2 mmol), Pd ₂ (dba) ₃ (0.092 g, 0.1 mmol) and DavePhos (0.059 g, 0.150 mmol) were combined in Toluene (4 mL). The reaction mixture was degassed with Argon and then heated to l00°C overnight. The mixture was evaporated to dryness and the residue purified by silica gel flash chromatography, eluting with a 0 to 50% EtOAc-heptane gradient to give the title compound (0.21 g, 78.3%) as a dark red oil. MS (ESI): m/z = 268.3 [M+H] ⁺ .

Step GB1 2-Chloro-3-(2-oxa-6-azaspiror3.31heptan-6-yl)benzoic acid

To a solution of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate (0.21 g, 0.784 mmol) in THF (5 mL) was added a 1M LiOH aq. solution (1.57 mL, 1.57 mmol) and the reaction mixture was heated to 50°C for 4 hours. The mixture was acidified to pH 4 with a 1M HC1 aq. solution, poured into 2-methyltetrahydrofuran (50 mL) and then Na ₂ S0 ₄ was added in excess. The mixture was stirred vigorously for 1 hour, filtered and concentrated in vacuo to give the crude title compound (0.233 g, 93.7%) as a light yellow solid. MS (ESI): m/z = 254.2 [M+H] ⁺ .

Intermediate F-2

(E)-2-chloro-3-(2-cyclopropylvinyl)benzoic acid Step GA1 methyl 2-chloro-3-(trifluoromethylsulfonyloxy)benzoate

To a solution of methyl 2-chloro-3-hydroxybenzoate (CAS RN 1125632-11-2, 0.1 g, 0.536 mmol) in DCM (1 mL) was added TEA (0.090 mL, 0.643 mmol) followed by l,l,l-trifluoro-A-phenyl-/V-((trifluoromethyl)sulfonyl)metha nesulfonamide (0.307 g, 0.858 mmol) and the reaction mixture was stirred at room temperature for 6 hours. The reaction was diluted with DCM, poured into water and the aqueous layer was extracted with DCM. Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 100% EtOAc -heptane gradient to give the title compound (0.15 g, 87.8%) as a colorless oil. MS (ESI): m/z = 319.0 [M+H] ⁺ . Step GB1 methyl (E)-2-chloro-3-(2-cvclopropylvinyl)benzoate

In a sealed tube, methyl 2-chloro-3-(trifluoromethylsulfonyloxy)benzoate (0.1 g, 0.314 mmol) and (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxabo rolane (CAS RN 849061-99-0, 0.067 g, 0.345 mmol) were mixed in DMF (1 mL). Then, bis(triphenylphosphine)palladium (II) chloride (0.022 g, 0.031 mmol), followed by a 1M Na ₂ C0 ₃ aq. solution (0.941 mL, 0.941 mmol) were added and the reaction mixture was heated to 80°C overnight. The mixture was diluted with EtOAc, filtered through a plug of Dicalite and washed with EtOAc. The filtrate was washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. The residue was purified by silica gel flash

chromatography, eluting with a 0 to 20% EtOAc-heptane gradient to give the title compound (0.022, 29%) as an off-white solid; MS (ESI): m/z = 237.1 [M+H] ⁺ .

Step 1C1 (E)-2-chloro-3-(2-cvclopropylvinyl)benzoic acid

To a solution of methyl (E)-2-chloro-3-(2-cyclopropylvinyl)benzoate (0.022 g, 0.093 mmol) in THF (0.75 mL) was added a 1M LiOH aq. solution (0.279 mL, 0.279 mmol) and the reaction mixture was stirred at 50°C overnight. The mixture was acidified with 2M HC1 aq. solution and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give the crude title compound (0.018, 87%) as a light yellow solid; MS (ESI): m/z = 233.1 [M+H] ⁺ .

Example 1

[(7R,9aR)-7-(4-Chlorophenyl)-l,3,4,6,7,8,9,9a-octahydropy rido[l,2-a]pyrazin-2-yl]-(3- phenoxyphenyl)methanone

In a flask, (7R,9aR)-7-(4-chlorophenyl)octahydro-lH-pyrido[l,2-a]pyrazin e

(Intermediate A-l, 0.04 g, 0.160 mmol), 3 -phenoxy benzoic acid (0.034 g, 0.160 mmol) and HATU (0.073 g, 0.191 mmol) were mixed in DMF (0.5 mL). Then, Hiinig's base (0.084 mL, 0.479 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with EtOAc, poured into water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ S0 _4. filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.05 g, 70%) as a colorless amorphous solid; MS (ESI): m/z = 447.2 [M+H] ⁺ .

The following examples listed in Table 2 were prepared in analogy to the procedures described for the preparation of example 1 by using the indicated intermediates and/or commercial compounds and using the mentioned purification method such as preparative HPLC (Gemini NX column), silica gel flash chromatography or preparative chiral HPLC (Daicel Chiralpack column).

Table 2

Examples 46 and 47

[(7R,9aR)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahyd ropyrido[l,2-a]pyrazin-2- yl]-(2-bromo-3-methoxyphenyl)methanone and [(7S,9aS)-7-(3,4-dichlorophenyl)- l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyrazin-2-yl]-(2-brom o-3- methoxyphenyl)methanone

In a flask, rac-(7R,9aR)-7-(3,4-dichlorophenyl)-2,3,4,6,7,8,9,9a-octahyd ro-lH- pyrido[l,2-a]pyrazine (Intermediate A-4, 0.085 g, 0.210 mmol), propylphosphonic anhydride 50% solution in DMF (0.108 g, 0.230 mmol) and 2-bromo-3-methoxy-benzoic acid (0.052 g, 0.220 mmol) were mixed in DMF (2 mL) and cooled to 0 °C with an ice bath. Then, Huenig’s base (0.09 mL, 0.530 mmol) was added and the reaction mixture stirred at room temperature for 12 hours. The mixture was diluted with a sat. Na ₂ C(L aq. solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with a 50 to 100% EtOAc- heptane gradient to give rac-(7R,9aR)-[7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a- octahydropyrido[l,2-a]pyrazin-2-yl]-(2-bromo-3-methoxy-pheny l)methanone (0.042 g, 39.6%) as an off-white solid-This material was separated by preparative chiral HPLC (DAICEL CHIRALCEL OD(250mm*50mm,l0um), eluent: 0.1%NH ₃ .H ₂ O IPA, 60%) to give respectively [(7S,9aS)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahydrop yrido[l,2- a]pyrazin-2-yl]-(2-bromo-3-methoxy-phenyl)methanone (Example 47, 0.014 g, 33.7%) and [(7R,9aR)-7-(3,4-dichlorophenyl)-l,3,4,6,7,8,9,9a-octahydrop yrido[l,2-a]pyrazin-2- yl]-(2-bromo-3-methoxy-phenyl)methanone (Example 46, 0.015 g, 34.8%) as white solids; MS (ESI): m/z = 499.2 [M+3H] ⁺ .

The following examples listed in Table 3 were prepared in analogy to the procedure described for the preparation of examples 46 and 47 by reacting the indicated

intermediates and commercial compounds and using the mentioned purification method such as preparative HPLC (Gemini NX column), silica gel flash chromatography or chiral separation method such as preparative chiral HPLC or SFC.

Table 3

Example 50

/e/ - Butyl 4-[[3-[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l, 2-a]pyrazine-2- carbonyl]-2-chlorophenoxy]methyl]pyrazole-l-carboxylate To a solution of [(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2- a]pyrazin-2-yl]-(2-chloro-3-hydroxyphenyl)methanone (example 32, 0.04 g, 0.108 mmol) and K2CO ₃ (0.045 g, 0.324 mmol) in DMF (1 mL) was added tert- butyl 4-(bromomethyl)- lH-pyrazole-l-carboxylate (42.2 mg, 162 pmol, Eq: 1.5) followed by KI (0.002 g, 0.011 mmol) and the reaction mixture was stirred to 60°C overnight. The mixture was diluted with EtOAc, poured into a saturated aq. NaHC0 ₃ solution and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 100% EtOAc -heptane gradient to give the title compound (0.035 g, 59%) as a white foam. MS (ESI): m/z = 551.5 [M+H] ⁺ . Example 51

[(7R,9aR)-7-Phenyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a ]pyrazin-2-yl]-[2-chloro-3-

(lH-pyrazol-4-ylmethoxy)phenyl]methanone To a solution of ferf-butyl 4-[[3-[(7R,9aR)-7-phenyl-l,3,4,6,7,8,9,9a- octahydropyrido[l,2-a]pyrazine-2-carbonyl]-2-chlorophenoxy]m ethyl]pyrazole-l- carboxylate (Example 50, 0.032 g, 0.058 mmol) in MeOH (1 mL) was added 4M HC1 in dioxane (0.073 mL, 0.290 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness and the residue triturated in diisopropylether, filtered off and further dried on the high vacuum to give the title compound (0.02 g, 66%) as a white solid as the hydrochloride salt. MS: 451.4 (M+H ⁺ ).

The following examples listed in Table 4 were prepared in analogy to the procedures described for the preparation of example 50 by reacting example 32 and the indicated commercial compounds and using the mentioned purification method such as preparative HPLC (Gemini NX column) or silica gel flash chromatography.

Table 4

Examples 72 and 73

(2-Chloro-3-methoxyphenyl)-[rao(7R,9aR)-7-(4-chlorophenyl )-7-hydroxy-3,4,6,8,9,9a- hcxahydro- 17/-pyrido[ 1 ,2-a]pyrazin-2-yl ]nicthanonc and (2-chloro-3-methoxyphenyl)- [rac-(7/?,9fl5)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9fl-h exahydro-l 7-pyrido[l,2- a]pyrazin-2-yl]methanone.

To a solution of 2-(2-chloro-3-methoxy-benzoyl)-3,4,6,8,9,9a-hexahydro-lH- pyrido[l,2-a]pyrazin-7-one (Intermediate 1-2, 0.2 g, 0.620 mmol) in THF (10 mL) cooled at 0°C was added a 1M solution of 4-chlorophenylmagnesium bromide in THF (1.86 mL, 1.86 mmol) dropwise while keeping the temperature below 5°C, then the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc, poured into a sat. NH ₄ Cl aq. solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with water (2 x 30 mL), brine (10 mL), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give respectively (2-chloro-3-methoxyphenyl)-[rao(7R,9aR)-7-(4-chlorophenyl)-7 - hydroxy-3,4,6,8,9,9 _<7 -hexahydro- 17/-pyrido[ 1 ,2-a]pyrazin-2-yl ]mcthanonc (Example 72) and (2-chloro-3-methoxyphenyl)-[rac-(7/?,9fl5')-7-(4-chloropheny l)-7-hydroxy- 3,4,6,8,9,9 _<7 -hexahydro- 17/-pyrido[ 1 ,2-a]pyrazin-2-yl ]mcthanonc (Example 73) as light yellow solids; MS (ESI): m/z = 435.3 [M+H] ⁺ . Examples 72-A and 72-B

[(7S,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexah ydro-lH-pyrido[l,2-a]pyrazin- 2-yl]-(2-chloro-3-hydroxy-phenyl)methanone and [(7R,9aR)-7-(4-chlorophenyl)-7- hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl] -(2-chloro-3-hydroxy- phenyl)methanone (2-Chloro-3-methoxyphenyl)-[rac-(7R,9flR)-7-(4-chlorophenyl) -7-hydroxy-

3,4,6,8,9,9 _<7 -hexahydro- 17/-pyrido[ 1 ,2-a]pyrazin-2-yl ]mcthanonc (Example 72) was separated by preparative chiral HPLC (DAICEL CHIRALCEL AY-3 (50x4.6mm, 3um), eluent: 0.05%DEA in MeOH, 40%) to give respectively [(7S,9aS)-7-(4-chlorophenyl)-7- hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl] -(2-chloro-3-hydroxy- phenyl)methanone (Example 72-A, 0.009 g, 4.2%) and [(7R,9aR)-7-(4-chlorophenyl)-7- hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl] -(2-chloro-3-hydroxy- phenyl)methanone (Example 72-B, 0.012 g, 3.2%) as light yellow solids; MS (ESI): m/z = 435.1 [M+H] ⁺ .

Examples 73-A and 73-B

[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexah ydro-lH-pyrido[l,2-a]pyrazin- 2-yl]-(2-chloro-3-hydroxy-phenyl)methanone and [(7R,9aS)-7-(4-chlorophenyl)-7- hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl] -(2-chloro-3-hydroxy- phenyl)methanone

(2-Chloro-3-methoxyphenyl)-[rac-(7R,9fl5')-7-(4-chlorophe nyl)-7-hydroxy- 3,4,6,8,9,9u-hexahydro- 17/-pyrido[ 1 ,2-a]pyrazin-2-yl ]nicthanonc (Example 73) was separated by preparative chiral HPLC (DAICEL CHIRALCEL AD-3(50x4.6mm, 3um), eluent: 0.05%DEA in MeOH, 40%) to give respectively [(7S,9aR)-7-(4-chlorophenyl)-7- hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl] -(2-chloro-3-methoxy- phenyl)methanone (Example 73-A, 0.004 g, 1.4%) and [(7R,9aS)-7-(4-chlorophenyl)-7- hydroxy-3,4,6,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl] -(2-chloro-3-methoxy- phenyl)methanone (Example 73-B, 0.002 g, 0.7%) as light yellow solids; MS (ESI): m/z = 435.3 [M+H] ⁺ .

The following examples listed in Table 5 were prepared in analogy to the procedure described for the preparation of examples 72 and 73 by reacting the indicated

intermediates and commercial compounds and using the mentioned purification method such as preparative HPLC (Gemini NX column), silica gel flash chromatography or chiral separation method such as preparative chiral HPLC or SFC.

Table 5

Example 78

(2-Chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chloropheny l)-7-fluoro-3,4,6,8,9,9a- hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanone

To a solution of (2-chloro-3-methoxyphenyl)-[rao(7R,9aS)-7-(4-chlorophenyl)-7 - hydroxy-3,4,6,8,9,9u-hexahydro- 17/-pyrido[ 1 ,2-a]pyrazin-2-yl ]nicthanonc (Example 73, 0.2 g, 0.460 mmol) in DCM (1 mL) cooled at -78 °C, was carefully added DAST (1.11 g, 6.89 mmol) dropwise and the reaction mixture was stirred at this temperature for 3 hours. The mixture was diluted with DCM, poured into a sat. Na ₂ C0 ₃ aq. solution (30 mL) and the aqueous layer was extracted with DCM (3 x 30 mL). Combined organics were washed with water (2 x 20 mL), brine (20 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (0.023 g, 10.8%) as a pink solid; MS (ESI): m/z = 437.2 [M+H] ⁺ .

Example 79

(2-Chloro-3-methoxyphenyl)-[rao(7R,9aS)-7-(4-chlorophenyl )-7-fluoro-3,4,6,8,9,9a- hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanone

Example 79 was prepared in analogy to example 78, but using (2-chloro-3- methoxyphenyl)-[rac-(7R,9flR)-7-(4-chlorophenyl)-7-hydroxy-3 ,4,6,8,9,9fl-hexahydro-l/7- pyrido[l,2-a]pyrazin-2-yl]methanone (Example 72) to give the title compound (0.010 g, 4.8%) as a light yellow solid; MS (ESI): m/z = 437.2 [M+H] ⁺ . Example 80

(2-Chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chloropheny l)-7-methoxy-3,4,6,8,9,9a- hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanone

To a solution of (2-chloro-3-methoxyphenyl)-[rao(7R,9aR)-7-(4-chlorophenyl)-7 - hydroxy-3,4,6,8,9,9u-hexahydro- 17/-pyrido[ 1 ,2-a]pyrazin-2-yl ]mcthanonc (Example 72, 0.190 g, 0.440 mmol) in THF (1 mL) cooled at 0°C, was added 65% NaH dispersion in mineral oil (0.035 g, 0.870 mmol) and the reaction mixture was stirred for 30 minutes. Then, Mel (0.186 g, 1.31 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc, poured into a sat. NH ₄ Cl aq. solution (20 mL) and the aqueous layer was extracetd with EtOAc (3 x 20 mL). The combined organic layer was washed with water (2 x 10 mL), brine (10 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (0.037 g, 18.6%) as a white solid; MS (ESI): m/z = 449.3 [M+H] ⁺ .

Example 81 (2-Chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)- 7-methoxy-3,4,6,8,9,9a- hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methanone

Example 81 was prepared in analogy to example 80, but using (2-chloro-3- methoxyphenyl)-[rao(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4 ,6,8,9,9a-hexahydro-l/7- pyrido[l,2-a]pyrazin-2-yl]methanone (Example 73) to give the title compound (0.015 g, 7.1%) as a white solid; MS (ESI): m/z = 449.2 [M+H] ⁺ .

Example 82 and 83

(2-Chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-methyl-l,3,4,6 ,7,8,9,9a- octahydropyrido[l,2-a]pyrazin-2-yl]methanone and (2-Chloro-3-methoxyphenyl)-[rac- (7R,9aR)-7-methyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyr azin-2-yl]methanone Step GA1 (2-Chloro-3-methoxyphenyl)(7-methylenehexahvdro-lH-pyridori, 2-a1pyrazin- 2(6H)-yl)methanone

To a solution of methyltriphenylphosphonium bromide (0.283 g, 1.02 mmol) in THF (10 mL) cooled at 0°C, was added a 1M solution of lithium bis(trimethylsilyl)amide (1.39 mL, 1.39 mmol) in THF dropwise and the reaction mixture was stirred for 1 hour. Then, a solution of 2-(2-chloro-3-methoxy-benzoyl)-3,4,6,8,9,9a-hexahydro-lH-pyr ido[l,2- a]pyrazin-7-one (Intermediate 1-2, 0.3 g, 0.930 mmol) in THF (5 mL) was added dropwise then the mixture was allowed to warm up to room temperature and stirred for 2 hours. The mixture was diluted with EtOAC, poured into a sat. NH ₄ Cl aq. solution (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phase was washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (0.080 g, 26.8%) as a light yellow oil. MS (ESI): m/z = 321.0 [M+H] ⁺ .

Step GB1 (2-Chloro-3-methoxyphenyl)-rrac-(7R.9aS)-7 -methyl-1, 3,4.6.7.8,9.9a- octahvdropyridori.2-a1pyrazin-2-yl1methanone and (2-Chloro-3-methoxyphenyl)-rrac- (7R,9aR)-7-methyl-l,3,4,6,7,8,9,9a-octahvdropyridori,2-a1pyr azin-2-yl1methanone To a solution of (2-Chloro-3-methoxy-phenyl)-(7-methylene-3,4,6,8,9,9a- hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl)methanone (0.6 g, 0.190 mmol) and magnesium oxide (0.038 g, 0.940 mmol) in EtOAc (5 mL) was added wet Pd/C (CAS RN 7440-05-3, 0.030 g) and the reaction mixture was stirred at room temperature under 11 ₂ atmosphere for 4 hours. The mixture was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give respectively (2-chloro-3- methoxyphenyl)-[rac-(7R,9aS)-7-methyl-l,3,4,6,7,8,9,9a-octah ydropyrido[l,2-a]pyrazin- 2-yl]methanone (Example 82, 0.019 g, 31.4%) and (2-Chloro-3-methoxyphenyl)-[rac- (7R,9aR)-7-methyl-l,3,4,6,7,8,9,9a-octahydropyrido[l,2-a]pyr azin-2-yl]methanone (Example 83, 0.008 g, 12.4%) as white solids; MS (ESI): m/z = 323.1 [M+H] ⁺ .

Example 84

(2-Chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(2-methylpropo xy)-l,3,4,6,7,8,9,9a- octahydropyrido[ 1 ,2-a]pyrazin-2-yl]methanone

Step GA1 (2-Chloro-3-methoxy-phenyl)-rrac-(7R.9aS)-7-r(4-methoxypheny l)methoxy1-9a- methyl-3, 4, 6,7,8, 9-hexahvdro-lH-pyridorl,2-a1pyrazin-2-yl1methanone

To a solution of (2-chloro-3-methoxy-phenyl)-[7-[(4-methoxyphenyl)methoxy]- l,3,4,6,9,9a-hexahydropyrido[l,2-a]pyrazin-2-yl]methanone (Intermediate 1-2 [A], 0.6 g, 1.35 mmol) and magnesium oxide (0.120 g, 1.35 mmol) in methanol (10 mL) was added wet Pd/C (CAS RN 7440-05-3, 0.06 g) and the reaction mixture was stirred under H ₂ atmosphere at room temperature for 12 hours. The mixture was filtered off and the filtrate was concentrated in vacuo to get the crude title compound (0.6 g, 99.5%) as a yellow oil; MS (ESI): m/z = 445.3 [M+H] ⁺ .

Step GB1 (2-Chloro-3-methoxy-phenyl)-rrac-(7R,9aS)-7-hvdroxy-9a-methy l-3,4,6,7,8,9- hexahvdro-lH-pyridorl,2-a1pyrazin-2-yl1methanone To a solution of 2-chloro-3-methoxy-phenyl)-[rac-(7R,9aS)-7-[(4- methoxyphenyl)methoxy]-9a-methyl-3,4,6,7,8,9-hexahydro-lH-py rido[l,2-a]pyrazin-2- yl ]mcthanonc (0.5 g, 1.12 mmol) and para-toluene sulfonamide (0.104 g, 0.560 mmol) in l,4-dioxane (10 mL) was added triflic acid (0.084. g, 0.560 mmol) dropwise and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography to give the cmde title compound (0.45 g) as a colorless solid; MS (ESI): m/z = 325.1 [M+H] ⁺ . Step TCI (2-Chloro-3-methoxy-phenyl)-rrac-(7R,9aS)-9a-methyl-7-(2-met hylallyloxy)-

3.4.6.7.8.9-hexahYdro-lH-PYridorl,2-a1pyrazin-2-Yl1methan one

To a solution of (2-chloro-3-methoxy -phenyl)- [rac-(7R,9aS)-7-hydroxy-9a-methyl-

3.4.6.7.8.9-hexahydro-lH-pyrido[l,2-a]pyrazin-2-yl]methan one (0.1 g, crude) in DMF (1 mL) cooled at 0°C, was added 65% NaH dispersion in mineral oil (0.015 g, 0.370 mmol) portionwise and the reaction mixture was stirred for 30 minutes. Then, 3-bromo-2- methylpropene (0.125 g, 0.920 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc, poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with water (2 x 10 mL), brine (10 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude title compound (0.1 g, 85.7%) as a colorless solid; MS (ESI): m/z = 379.3 [M+H] ⁺ .

Step GR1 (2-Chloro-3-methoxyphenyl)-rrac-(7R,9aS)-7-(2-methylpropoxy) - L3.4.6.7.8.9.9a-octahvdropyridorl.2-a1pyrazin-2-yl1methanone To a solution of (2-chloro-3-methoxy-phenyl)-[rac-(7R,9aS)-9a-methyl-7-(2- methylallyloxy)-3,4,6,7,8,9-hexahydro-lEl-pyrido[l,2-a]pyraz in-2-yl]methanone (0.1 g, 0.260 mmol) and magnesium oxide (0.03 g, 0.750 mmol) in methanol (10 mL) was added wet Pd/C (CAS RN 7440-05-3, O.Olg) and the reaction mixture was stirred under H ₂ atmosphere at room temperature for 12 hours. The mixture was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (0.033 g, 31.9%) as a colorless solid; MS (ESI): m/z = 381.1 [M+H] ⁺ .

Example 85

(l,3-Dimethylthieno[2,3-c]pyrazol-5-yl)-[rac-(7R,9flR)-7- (3-chloro-4-fluorophenyl)- 1 ,3,4,6,7,8,9,9c/-octahydropyrido[ 1 ,2-a]pyrazin-2-yl ]mcthanonc Example 85 is prepared in analogy to e.g. Example 60, starting from Intermediate A- 5 and 1 ,3-dimethylthieno[2,3-c]pyrazole-5-carboxylic acid.

Example 86

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

Per tablet Active ingredient 200 mg

Microcrystalline cellulose 155 mg

Corn starch 25 mg

Talc 25 mg

Hydroxypropylmethylcellulose 20 mg

425 mg

Example 87

A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule

Active ingredient 100.0 mg

Com starch 20.0 mg

Lactose 95.0 mg

Talc 4.5 mg

Magnesium stearate 0 5 mg

220.0 mg