TREM2 agonists

Abstract

The application relates to fused pyrimidinone derivatives of the general formula (I) which act as agonists of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) useful for the treatment of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

Description

[0001]F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: P39602 TREM2 AGONISTS Field of the Invention The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Triggering Receptor Expressed on Myeloid cells 2 (TREM2) agonists for the treatment or prevention of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke. Background of the Invention Microglia are immune cells resident in the central nervous system (CNS) which play a crucial role in the CNS development and maintenance of brain homeostasis through synaptic pruning and removal of apoptotic neurons (Paolicelli R.C. et al., Science 2011, 9;333(6048):1456-8 doi: 10.1126 / science.1202529). Microglia are also key players in response to neurodegenerative conditions and neuropathological lesions, whereby they shift into an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to the lesion sites and phagocytosis of dead cells and debris. (Lue L.F. et al., Mol. Neurobiol.2010, 41(2-3):115-28, doi: 10.1007 / s12035-010-8106-8). Microglia express a multitude of receptors on their surface, which play a key role in sensing the environmental changes and enabling the complex crosstalk regulating their physiological functions. TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is one of these cell surface receptors, which in brain is selectively expressed on microglia and plays a key role in their survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445–453 (2003). https: / / doi.org / 10.1038 / nri1106). TREM2 is a single-pass transmembrane receptor that belongs to the Immunoglobulin superfamily (Ig-SF). It is composed of a ligand binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs. CNE / 19.09.2025 Downstream signal transduction is mediated through its interaction with the effector protein DAP12, a transmembrane disulphide-linked adapter dimer which expression and cellular localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem.2015;290(25):15866–77). Given its short extracellular domain, DAP12 lacks ligand-binding capabilities. Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and Aβ oligomers. Stimulation of the TREM2 / DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of DAP12, which results in recruitment of Syk kinase to activate downstream signaling molecules. Activation of TREM2 plays a key role in microglia signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris clearance and the transition from the homeostatic to the disease-associated microglia (DAM) state in the context of a neurodegenerative environment (Condello, C. et al., Nat Commun 6, 6176, 2015, doi: org / 10.1038 / ncomms7176; Poliani et al., J Clin Invest, 2015 May;125(5):2161-70, doi: 10.1172 / JCI77983; Zhao et al., Neuron, 2018 Mar 7;97(5):1023-1031.e7, doi: 10.1016 / j.neuron.2018.01.031; Keren-Shaul H. et al., Cell, 2017 Jun 15;169(7):1276-1290.e17. doi: 10.1016 / j.cell.2017.05.018). Genetic variants of TREM2 have been implicated in a multitude of neurodegenerative diseases (Hou J. et al. Molecular Neurodegeneration (2022) 17:84; doi: org / 10.1186 / s13024-022-00588- y). TREM2 variants resulting in lack of TREM2 expression were identified as the cause of the Nasu-Hakola Disease (NHD), or Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy (PLOSL), a fatal condition manifesting with progressive pre-senile dementia and characterized by loss of myelin and bone abnormalities, consistent with TREM2 expression in myeloid cells microglia and osteoclasts (Paloneva, J. et al., Am J Hum Genet. 2002,71(3):656-62, doi: 10.1086 / 342259). Similarly, missense mutations of TREM2 have been associated with increased risk of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several of these TREM2 variants have been implicated with impaired microglia function and their reduced response to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med.2014, 6, 243ra86). Moreover, genomic-wide association studies (GWAS) showed a strong link between a number of rare loss of function (LoF) variants of TREM2 and an increased risk of late onset Alzheimer’s disease (LOAD) (Guerreiro R. et al., N Engl J Med.2013, 368(2):117–27; Jonsson T. et al., N Engl J Med.2013, 368(2):107–16). Amongst those, the R47H variant, a LoF mutation associated with structural alterations within the extracellular domain of TREM2 resulting in impaired ability to bind endogenous ligands, was linked to a ca.3 fold increased risk of LOAD (Sudom, A. et al., J Biol Chem.201810;293(32):12634-12646; doi: 10.1074 / jbc.RA118.002352). Studies are ongoing to elucidate the mechanism by which TREM2 LoF mutations contribute to AD. It is likely that patients carrying these mutations have impaired microglia function including reduced clearance of extracellular aggregates (e.g. amyloid and myelin debris) and apoptotic neurons, ultimately reducing their capacity to fight the disease and increasing their susceptibility to neurodegeneration. Indeed decreased microglia activation and failure to cluster around the amyloid plaque were observed in mouse models deficient for TREM2 or DAP12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks. In light of all this evidence, pharmacological activation of TREM2 appears to be a viable therapeutic intervention. The small molecules disclosed herein are potent and selective agonists of TREM2. of the Invention In a first aspect, the present invention provides compounds of formula (I) wherein A1, A2, X1, X2, R1, R2, R3, R3’, R4, R4’, and R7are as defined herein. In further aspects, the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I). Detailed 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 6 carbon atoms (“C1-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non- limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, yet non-limiting example of 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 6 carbon atoms (“C1-6-alkoxy”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In 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 tert-butoxy. A particularly preferred, yet non- limiting example of alkoxy is methoxy. The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl). The term “cycloalkyl” as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C3-10-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a 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. Preferably, the cycloalkyl group is a 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, cyclohexyl, cycloheptyl, 1- bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl and cyclohexyl. The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C6-C10-aryl”), wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g.9H-fluoren-9-yl). A particularly preferred, yet non-limiting example of aryl is phenyl. The term "heteroaryl" refers to a mono- or multivalent, monocyclic ring system having a total of 5 to 6 ring members, wherein the ring system is aromatic and contains one or more heteroatoms. Preferably, the heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, the heteroaryl comprises 1 to 2 heteroatoms independently selected from O, S and N. Some preferred, yet non-limiting examples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g.2- pyridyl); pyrazolyl (e.g. pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; and imidazolyl (e.g. imidazole-1-yl). Some preferred, yet non-limiting examples of heteroaryl include pyridyl and pyrazolyl. The term “heterocyclyl” refers to a saturated or partly unsaturated monocyclic ring system of 3 to 6 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. Some non-limiting examples of heterocyclyl groups include azetidinyl, piperidyl, pyrrolidinyl, oxetanyl, piperidyl, 1,2-dihydropyridiynl, piperidyl, pyrrolidinyl, tetrahydrothiophenyl, and thietanyl. Preferred, yet non-limiting examples of heterocyclyl groups include 1,2-dihydropyridiynl and oxetanyl. The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, and 2,2,2-trifluoroethyl. The term “halocycloalkyl” refers to a cycloalkyl group as defined herein, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “halocycloalkyl” refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of halocycloalkyl include 2,2- difluorocyclopropyl and 4,4-difluorocyclohexyl. The term “alkoxyalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, preferably methoxy. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, most preferably methoxy. A particularly preferred, yet non-limiting example of alkoxyalkyl is 2-methoxyethyl. The term “cycloalkylalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group, preferably cyclopropyl. Preferably, “cycloalkylalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred, yet non-limiting example of cycloalkylalkyl is cyclopropylmethyl. The term “cycloalkylalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, preferably cyclopropyl. Preferably, “cycloalkylalkoxy” refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred, yet non-limiting example of cycloalkylalkoxy is cyclopropylmethoxy. The term “cycloalkyoxy” refers to a cycloalkyl group as defined herein, wherein the cycloalkyl group is bound to the parent molecule trough an oxygen atom. A particularly preferred, yet non- limiting example of cycloalkyoxy is cyclobutyloxy. The term “heterocyclylalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a heterocyclyl group, preferably oxetanyl. Preferably, “heterocyclylalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a heterocyclyl group, most preferably oxetanyl. A particularly preferred, yet non-limiting example of heterocyclylalkyl is oxetanylmethyl. The term “heterocyclylalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, preferably oxetanyl. Preferably, “heterocyclylalkoxy” refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, most preferably oxetanyl. A particularly preferred, yet non-limiting example of heterocyclylalkoxy is oxetanylmethoxy. The term “heterocyclyloxy” refers to a heterocyclyl group as defined herein, wherein the heterocyclyl group is bound to the parent molecule trough an oxygen atom. A particularly preferred, yet non-limiting example of heterocyclyloxy is oxetanyloxy. 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. 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. The abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2. 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. Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1and X2are each independently selected from the group consisting of N and CH; A1is selected from the group consisting of N and CR8; A2is selected from the group consisting of O and CR5R6; R1is selected from the group consisting of C1-C6-alkyl and halo-C1-C6-alkyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo- C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6- alkyl, C3-C10-cycloalkyl-C1-C6-alkoxy, C3-C10-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl- C1-C6-alkyl, 3- to 6-membered heterocyclyl-C1-C6-alkoxy and 3- to 6-membered heterocyclyloxy; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl; R4is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl; R4’is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl; R5and R6are each independently selected from the group consisting of hydrogen and halogen; R7is selected from the group consisting of hydrogen and C1-C6-alkyl; and R8is selected from the group consisting of hydrogen, halogen, hydroxy, and C1-C6- alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is selected from the group consisting of O and CR5R6; R1is selected from the group consisting of C1-C6-alkyl and halo-C1-C6-alkyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2- one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin- 2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6- one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy- C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10- cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C3-C10-cycloalkyl-C1-C6-alkoxy, C3-C10- cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-C1-C6-alkyl, 3- to 6-membered heterocyclyl-C1-C6- alkoxy and 3- to 6-membered heterocyclyloxy; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl; R4is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl; R4’is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl; R5and R6are each independently selected from the group consisting of hydrogen and halogen; R7is C1-C6-alkyl; and R8is selected from the group consisting of hydrogen, halogen, hydroxy, and C1-C6- alkyl; provided that said compound of formula (I) is not 7-[2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-9-(2, 4-difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4- one (II) In one embodiment, said compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1and X2are each independently selected from the group consisting of N and CH; A1is selected from the group consisting of N and CR8; A2is selected from the group consisting of O and CR5R6; R1is selected from the group consisting of C1-C6-alkyl and halo-C1-C6-alkyl; R3is selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein said 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo- C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6- alkyl, C3-C10-cycloalkyl-C1-C6-alkoxy, C3-C10-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl- C1-C6-alkyl, 3- to 6-membered heterocyclyl-C1-C6-alkoxy and 3- to 6-membered heterocyclyloxy; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl; R4is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl; R4’is selected from the group consisting of hydrogen and halogen; R5and R6are each independently selected from the group consisting of hydrogen and halogen; R7is selected from the group consisting of hydrogen and C1-C6-alkyl; and R8is selected from the group consisting of hydrogen, halogen, hydroxy, and C1-C6- alkyl. In one embodiment, said compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein A2, X1, X2, R1, R2, R3, R3’, R4, R4’, R7, and R8are as described herein. In one embodiment, said compound of formula (I) is a compound of formula (Ic) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein A2, X1, X2, R1, R2, R3, R3’, R4, R4’, R7, and R8are as described herein. In one embodiment, said compound of formula (I) is a compound of formula (Id) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein A2, X1, X2, R1, R2, R3, R3’, R4, R4’, R7, and R8are as described herein. In one embodiment, said compound of formula (I) is a compound of formula (Ie) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein A2, X1, X2, R1, R2, R3, R3’, R4, R4’, R7, and R8are as described herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1is N and X2is CH. In another preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1is CH and X2is N. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: A1is CR8; and R8is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein A2is O. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is C1-C6-alkyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 5- to 6-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo, C1- C6-alkyl, and C3-C10-cycloalkyl; and R3’is selected from the group consisting of hydrogen and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2- one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin- 2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6- one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of C1-C6- alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; and R3’is selected from the group consisting of hydrogen and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2- one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin- 2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6- one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, 1H-pyridin-2-one, 1H- pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6-one, 5- oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl, C1- C6-alkoxy, and C3-C10-cycloalkyl; and R3’is selected from the group consisting of hydrogen and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, 1H-pyridin-2-one, 1H- pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6-one, 5- oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of pyrazolyl, 1,2,4-oxadiazolyl, 1H-pyridin-2- one, and 1H-pyridazin-6-one, wherein said pyrazolyl, 1,2,4-oxadiazolyl, 1H-pyridin- 2-one, and 1H-pyridazin-6-one are optionally substituted with 1-2 substituents independently selected from the group consisting of methyl and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of pyrazolyl, 1,2,4-oxadiazolyl, 1,2- dihydropyridyl, and 1,6-dihydropyridazine, wherein said pyrazolyl and 1,2,4- oxadiazolyl are optionally substituted with 1-2 substituents independently selected from the group consisting of methyl and cyclopropyl; and wherein said 1,2- dihydropyridyl and 1,6-dihydropyridazine are substituted with oxo and optionally with 1-2 further substituents independently selected from the group consisting of methyl and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of pyrazolyl, 1,2,4-oxadiazolyl, and 1,2- dihydropyridyl, wherein said pyrazolyl and 1,2,4-oxadiazolyl are optionally substituted with 1-2 substituents independently selected from the group consisting of methyl and cyclopropyl; and wherein said 1,2-dihydropyridyl is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo, methyl and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of O O N N N O N N N NN; and R3’is selected from the group consisting of hydrogen and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of O O N N In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3 N O N N N ; and R3’is selected from the group consisting of hydrogen and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3 R3’is selected from the group consisting of hydrogen and methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 5- to 6-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 5- to 6-membered heteroaryl is substituted with a C3-C10-cycloalkyl substituent; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl, and C3-C10-cycloalkyl; and R3’is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is a 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 3- to 6- membered heterocyclyl is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo, C1-C6-alkyl, and C3-C10-cycloalkyl; and R3’is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of pyrazolyl and 1H-pyridin-2-one, wherein said pyrazolyl is substituted with a C3-C10-cycloalkyl substituent; and wherein said 1H-pyridin-2-one is substituted with a substituent selected from the group consisting of C1-C6-alkyl, and C3-C10-cycloalkyl; and R3’is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of pyrazolyl and 1H-pyridin-2-one, wherein said pyrazolyl is substituted with a cyclopropyl substituent; and wherein said 1H- pyridin-2-one is substituted with a substituent selected from the group consisting of methyl, and cyclopropyl; and R3’is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3’is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of hydrogen, fluoro, and methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of hydrogen and C1-C6-alkyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of hydrogen and methyl. In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4’is selected from the group consisting of hydrogen, methyl and fluoro. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4’is selected from the group consisting of hydrogen and methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4’is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4and R4’are both halogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4and R4’are both fluoro. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4and R4’are both C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4and R4’are both methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R7is C1-C6-alkyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R7is methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1and R7are both C1-C6-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1and R7are both methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is C1-C6-alkyl; R3is selected from the group consisting of 5- to 6-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo, C1- C6-alkyl, and C3-C10-cycloalkyl; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl; R4is selected from the group consisting of hydrogen and C1-C6-alkyl; R4’is selected from the group consisting of hydrogen and C1-C6-alkyl; R7is C1-C6-alkyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is methyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of pyrazolyl, 1,2,4-oxadiazolyl, 1,2- dihydropyridyl, and and 1,6-dihydropyridazine, wherein said pyrazolyl and 1,2,4- oxadiazolyl are optionally substituted with 1-2 substituents independently selected from the group consisting of methyl and cyclopropyl; and wherein said 1,2- dihydropyridyl and and 1,6-dihydropyridazine are substituted with oxo and optionally with 1-2 further substituents independently selected from the group consisting of methyl and cyclopropyl; R3’is selected from the group consisting of hydrogen and methyl; R4is selected from the group consisting of hydrogen and methyl; R4’is selected from the group consisting of hydrogen and methyl; R7is methyl; and R8is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: is N; is CH; A1is CR8; A2is O; R1is C1-C6-alkyl; R2 ; R3is selected from the group consisting of 5- to 6-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 5- to 6-membered heteroaryl is substituted with a C3-C10-cycloalkyl substituent; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and a further substituent selected from the group consisting of C1-C6-alkyl, and C3-C10-cycloalkyl; R3’is hydrogen; R4is selected from the group consisting of hydrogen and C1-C6-alkyl; R4’is hydrogen; R7is C1-C6-alkyl; and R8is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1is N; X2is CH; A1is CR8; A2is O; R1is methyl; R3’is hydrogen; R4is selected from the group consisting of hydrogen and methyl; R4’is hydrogen; R7is methyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is C1-C6-alkyl; R3is selected from the group consisting of 5- to 6-membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, and 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl and C3-C10- cycloalkyl; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo, C1- C6-alkyl, and C3-C10-cycloalkyl; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl; R4is hydrogen; R7is C1-C6-alkyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is methyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of pyrazolyl, 1,2,4-oxadiazolyl, and 1,2- dihydropyridyl, wherein said pyrazolyl and 1,2,4-oxadiazolyl are optionally substituted with 1-2 substituents independently selected from the group consisting of methyl and cyclopropyl; and wherein said 1,2-dihydropyridyl is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo, methyl and cyclopropyl; R3’is selected from the group consisting of hydrogen and methyl; R4is hydrogen; R7is methyl; and R8is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1is N; X2is CH; A1is CR8; A2is O; R1is C1-C6-alkyl; R3is a 3- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon, wherein said 3- to 6- membered heterocyclyl is optionally substituted with 1-2 substituents independently selected from the group consisting of oxo, C1-C6-alkyl, and C3-C10-cycloalkyl; R3’is hydrogen; R4is hydrogen; R7is C1-C6-alkyl; and R8is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1is N; X2is CH; A1is CR8; A2is O; R1is methyl; 2 R is ; R3’is hydrogen; R4is hydrogen; R7is methyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is C1-C6-alkyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2- one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin- 2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6- one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-oneare substituted with 1-2 substituents independently selected from the group consisting of C1-C6- alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl; R4is selected from the group consisting of hydrogen and C1-C6-alkyl; R4’is selected from the group consisting of hydrogen and C1-C6-alkyl; R7is C1-C6-alkyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is methyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2- one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin- 2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6- one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl;; R3’is selected from the group consisting of hydrogen and methyl; R4is selected from the group consisting of hydrogen and methyl; R4’is selected from the group consisting of hydrogen and methyl; R7is methyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1is N; X2is CH; A1is CR8; A2is O; R1is C1-C6-alkyl; R2is ; R3is selected from the group consisting of pyrazolyl and 1H-pyridin-2-one, wherein said pyrazolyl issubstituted with a C3-C10-cycloalkyl substituent; and wherein said 1H-pyridin-2-one is substituted with a substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl; R3’is hydrogen; R4is selected from the group consisting of hydrogen and C1-C6-alkyl; R4’is hydrogen; R7is C1-C6-alkyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: X1is N; X2is CH; A1is CR8; A2is O; R1is methyl; N N R3’is hydrogen; R4is selected from the group consisting of hydrogen and methyl; R4’is hydrogen; R7is methyl; and R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from the group consisting of: 4-[7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 4-[2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4-oxopyrazino[1,2- a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4-oxopyrazino[1,2- a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[7-[(2S,4R)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3-dimethyl-4-oxopyrazino[1,2- a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[7-[(2R,4S)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3-dimethyl-4-oxopyrazino[1,2- a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2R,4S)-2-(1-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2S,4R)-2-(1-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2S,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo- pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2R,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo- pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro-benzonitrile; 7-[(2R,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)- 2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)- 2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(2-keto-1-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(2-keto-1-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[rac-(2S,4S)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(5,5-difluorotetrahydropyran-2-yl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)-2-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S,6R)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4S,6R)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4R,6S)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R,6S)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S,6R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6- methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4S,6R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6-methyl- tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4R,6S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6- methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R,6S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6-methyl- tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 7-[(4R,6R)-6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(4S,6S)-6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(4R,6R)-2,2-difluoro-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(4R,6R)-6-(1-cyclopropyl-6-oxo-3-pyridyl)-2,2-difluoro- tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluoropiperidino)-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)-2-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-7-[(4S,6S)-2,2-dimethyl-6-(1-methyl-6-oxo-3-pyridinyl)oxan-4-yl]-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(4R,6R)-2,2-dimethyl-6-(1-methyl-6-oxo-3-pyridinyl)oxan-4-yl]-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(4,6-dimethyl-5-oxo-pyrazin-2-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(4,6-dimethyl-5-oxo-pyrazin-2-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(1,5-dimethyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(1,5-dimethyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[(1S,6R)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[(1S,6R)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[(1R,6S)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; and 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[(1R,6S)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from the group consisting of: 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(2-keto-1-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one; and 7-[(2R,4S)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(2-keto-1-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9- (2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9- (2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 7-[(2R,4S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S,6R)-2-methyl-6- (1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4S,6R)-2-methyl-6- (1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S,6R)-2-(1- cyclopropyl-6-oxo-3-pyridyl)-6-methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4S,6R)-2-(1- cyclopropyl-6-oxo-3-pyridyl)-6-methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one. In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free bases or acids. In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur,fluorine, chlorine, and iodine, such as, but not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O,18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Certain isotopically-labeled compounds offormula (I), for example, those incorporating a radioactive isotope, are useful in drug and / orsubstrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.Substitution with heavier isotopes, such as deuterium, i.e. 2H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention. In one embodiment, 1 to 6, e.g.1, 2, 3, 4, 5, or 6 of the hydrogen atoms of the compounds of formula (I) according to the invention are substituted with deuterium. In a preferred embodiment, 1 to 3, e.g.1, 2, or 3 of the hydrogen atoms of the compounds of formula (I) according to the invention are substituted with deuterium.Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful inPositron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed. Processes of Manufacturing The preparation of compounds of formula (I) 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 (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective 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 protective 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 (I) 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. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I). A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) - 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 protective groups in the molecule. The principle of orthogonal protection is well known in the artand 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 (I) 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. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section. The following abbreviations are used in the present text:°C degrees celsius1H protonÅ ångströmAlk alkylc concentrationCAS Chemical Abstracts Service registry numberCH3CN acetonitrileCO2carbon dioxideDIPEA N,N-DiisopropylethylamineDMEM Dulbecco's modified eagle mediumDMF N,N-DimethylformamideDMSO dimethylsulfoxideDMSO-d6 hexadeuterodimethylsulfoxide EC50 half maximal effective concentrationeq equivalentESI electron spray ionizationEx. exampleFBS fetal bovine serumg gramg / L gram per literh hourHATU hexafluorophosphate azabenzotriazole tetramethyl uroniumHBTU hexafluorophosphate benzotriazole tetramethyl uroniumHCOOH formic acidHEK human embryonic kidneyHPLC high performance liquid chromatographyJ coupling constantkg kilogramM molarm / z mass-to-charge ratioMeOH methanolmg milligramMgSO4 magnesium sulfateMHz megahertzmin minuteml millilitermm millimetermmol millimoleMPLC medium pressure liquid chromatographyMS mass spectrometryNa2SO3 sodium sulfite Na2SO4sodium sulfate NaHCO3sodium bicarbonateneg. negativeNH4Cl ammonium chloridenm nanometerNMR nuclear magnetic resonance spectroscopykPa kilopascalpH potential of hydrogenpos. positivepsi pounds per square inchR Rectus according to the Cahn–Ingold–Prelog priority rulesRP reverse phaseRPM revolutions per minutes secondS Sinister according to the Cahn–Ingold–Prelog priority rulesSFC supercritical fluid chromatographyTLC thin layer chromatographyµl microliterµm micrometerµmol micromolesXantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)αD specific rotation at 589 nmδ chemical shift in parts per millionScheme 1 Compounds of general formula Ia can be prepared as described in Scheme 1 by reacting intermediate II first with a boronic acid (or a boronic acid derivative) III under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)- ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound IV. This intermediate can be reacted with amine Va in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N- methylpyrrolidone to form Ia (nucleophilic substitution). In addition, compound IV can be reacted with amine Va using palladium-catalysed coupling conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(0), a suitable ligand such as Xantphos and a base such as cesium carbonate or sodium tert.-butoxide to form compound Ia (metal-catalysed coupling). Furthermore, this intermediate can be reacted with boronic acid derivative Vb using a palladium catalyst and a base to form intermediate VI, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound Ib. Preferred catalysts are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or triethylamine. Scheme 2 Y1, Y2R1, R7, X1= C, X2l, Br, Iaccordingto claim definition Alk = alkyl chain like Me, Et Compounds of general formula II can be prepared as described in Scheme 2 by reacting heterocyclic compound VII with ketoester VIII in presence of an acid like polyphosphoric acid or a Lewis acid such as bismuth trichloride at elevated temperatures. Scheme 3 12 71 2R, R, R and Y, Y = Cl, Br, I 12X , X according to claim definition Alk = alkyl chain like Me, Et Furthermore compounds of general formula IV can be prepared as described in Scheme 3 by first 2 reacting heterocyclic compound VII with a boronic acid (or a boronic acid derivative, R is preferably aromatic or heteroaromatic) III under palladium catalysed coupling conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound IX. This intermediate can then react with ketoester VIII in presence of an acid like polyphosphoric acid or a Lewis acid such as bismuth trichloride at elevated temperatures to form compound IV. Scheme 4 Y1= Cl, Br, I R1, R2, R7and X1, X2according to claim definition Alk = alkyl chain like Me, Et Furthermore compounds of general formula IVa (R2ist preferably non-aromatic) can be prepared as described in Scheme 4 by first reacting heterocyclic compound X with a carboxylic acid XI under oxydative coupling conditions (using for example ammonium persulfate in dimethylsulfoxide and / or water at temperatures of 0 °C to 50 °C with or without addition of silver nitrate, Minisci reaction) to form compound IXa. This intermediate can then react with ketoester VIII in presence of an acid like polyphosphoric acid or a Lewis acid such as bismuth trichloride at elevated temperatures to form compound IVa. Scheme 5 Furthermore, compounds of general formula Ib can be prepared as described in Scheme 5. Intermediate IV can be reacted with bororic ester derivative XII under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form as well compound XIII. In the next step this intermediate is reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound XIV. The ester functionality can then be transformed into various heterocyclic residues R3by multi-step reactions known to people skilled in the art and published in various literature reviews such as J. Chem. Rev., 2022, 4(3), 255-271. Scheme 6 A2, X1, X2according to claim definition Furthermore, compounds of general formula Ic can be prepared as described in Scheme 6 by late stage modification of compound XV. Such transformations of residue R3a to residue R3 include removal of a protecting group, halogen-carbon-exchange reactions (such as bromine to methyl) or alkylation reactions (for instance on NH-pyridones) and can be performed according to known conditions for related compounds published in the literature. In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the process is as described in any one of schemes 1 to 6. In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, when manufactured according to any one of the processes described herein. TREM2 Agonistic Activity Compounds of the present invention are TREM2 agonists. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for restoring the function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of restoring the function of human TREM2 in a subject in need thereof. 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 restoring the function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject. TREM2 agonist potency of the compounds of formula (I) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit. To perform the assay, frozen HEK293-TREM2 / DAP12 cells were thawed, adjusted and plated by using Certus at 20,000 cells per well in a 384 well plate, in 10 μL of DMEM media without Phenolred and supplemented with 5% FBS. Compounds in dose response (1:3) were diluted in DMSO (highest concentration 10mM) and added to the cells from a Low Dead Volume plate using the ECHO (0-20 uM), diluting 500x (20 nL in 10 µl cell suspension; highest concentration 20uM, DMSO concentration 0.2% in all wells). Neutral (DMSO) and stimulator (1µM tool compound) controls were also added. Cells were incubated for 30 minutes at 37°C, 5% CO2 and 95% humidity. After compound addition and incubation, 2.5μL of lysis buffer was added by using the Certus. After a quick spin, plates were shaken for 30 minutes at 450 RPM, at room temperature and in the dark. After complete lysis, AlphaLisa reagents were added by Certus to the lysate, and fluorescence intensity was measured using a Pherastar plate reader (Excitation: 680nm / Emission: 615nm). EC50 values were calculated by using Genedata Screener, normalized to DMSO and 100% activity to the tool compound. TREM2 agonistic potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in table 1. TREM2 agonistic potencies of reference compounds as measured in the assay described above are presented in table 2. Table 1 hTREM2 hTREM2 Ex. Ex. EC50 (µM) EC50 (µM) 10.009 23 0.0282 0.034 24 0.0033 0.022 25 6.04 0.09926 0.0075 0.00427 0.0886 0.1147 0.432 28 0.0388 0.051 29 0.0029 0.075 30 0.06010 0.034 31 0.25711 0.028 32 0.14212 2.87 33 0.15613 0.01534 0.04414 3.6835 0.26915 2.6316 0.494 36 0.00817 0.292 37 0.10618 1.82 38 0.01619 0.111 39 0.04420 0.006 40 0.00521 0.006 41 0.02222 0.154 42 0.006 hTREM2 hTREM2 Ex. Ex. EC50 (µM) EC50 (µM) 43 0.012 58 0.07944 0.016 59 0.05645 0.104 60 2.72446 0.070 61 0.28749 0.047 62 0.03350 0.040 63 0.08751 0.034 64 0.04452 0.009 65 0.03053 0.009 66 0.02454 0.010 67 0.00755 0.022 68 0.00656 0.004 69 0.01057 0.088Table 2 Reference hTREM2 Example EC50 (µM) 10.332 1.353 0.284 0.0655 0.88Using the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as described herein for use as a therapeutically active substance. In a further aspect, the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition described herein. In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In one embodiment, said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is rheumatoid arthritis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Alzheimer’s disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke. Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier. In one embodiment, there is provided a pharmaceutical composition according to Example 70 or 71. The compounds of formula (I) 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, dragées, 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 (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées 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, dragées 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 syrups 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. 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. 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 diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold- Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration. For the compounds described in the patent the absolute stereochemistry was arbitrarily assigned. All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise. The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. The following intermediates were prepared according to the procedures provided herein, are commercially available or can be prepared according to literature procedures. Intermediate A1: 4-(7-chloro-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluoro- benzonitrile Step 1: 9-bromo-7-chloro-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one To a solution of 3-bromo-5-chloro-pyrazin-2-amine (CAS 76537-18-3, 5.0 g, 24 mmol) in toluene (50 ml) were added ethyl 2-methylacetoacetate (17.3 g, 120 mmol) and p-toluenesulfonic acid (0.83 g, 4.8 mmol, 0.2 eq). The mixture was degassed with nitrogen three times, stirred at 120 °C for 16 h using a Dean-Stark apparatus, then poured into water (200 ml). A large amount of yellow solid precipitated. The solid was filtered, washed with ethyl acetate (30 ml) and dried in vacuo to afford 9-bromo-7-chloro-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (1.0 g, 9% yield) as yellow solid. MS m / z: 290.0 [M+H]+, ESI pos. Step 2: 4-(7-chloro-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluoro-benzonitrile To a solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (900 mg, 3.12 mmol) and 4-cyano-2-fluorophenylboronic acid pinacol ester (CAS 1035235-29-0, 771 mg, 3.12 mmol) in 1,4-dioxane (30 ml) and water (3 ml) was added cesium carbonate (3.05 g, 9.36 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (127 mg, 0.16 mmol, 0.05 eq). Then the reaction mixture stirred at 20 °C for 1 h under nitrogen. The reaction mixture was poured into water (30 ml), a large amount of solid precipitated out. The solid was collected by filtration and triturated with ethyl acetate (20 ml) to afford the title compound (1.0 g, 97% yield) as light green solid, MS m / z: 329.0 [M+H]+, ESI pos. Intermediate A2: 7-chloro-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one Step 1: 5-chloro-3-(2,4-difluorophenyl)pyrazin-2-amine To a solution of (3-bromo-5-chloro-pyrazin-2-yl)amine (1 g, 4.8 mmol) in 1,4-dioxane (20 ml) was added (2,4-difluorophenyl)boronic acid (909 mg, 5.76 mmol) and 3 M aqueous cesium carbonate solution (4.8 ml, 14.39 mmol) at room temperature. The mixture was degassed with argon. Then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (392 mg, 0.480 mmol, 0.10 eq) was added and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to yield 5-chloro-3-(2,4-difluorophenyl)pyrazin-2-amine as light red solid (1.19 g, 94% yield), MS m / z: 242.2 [M+H]+, ESI pos. Step 2: 7-chloro-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one 5-Chloro-3-(2,4-difluorophenyl)pyrazin-2-amine (1.13 g, 4.68 mmol), ethyl 2- methylacetoacetate (6.74 g, 6.81 ml, 46.8 mmol) and polyphosphoric acid (565 mg) were mixed at room temperature. The mixture was stirred for 6 h at 120 °C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4and concentrated to dryness. The crude material was suspended with heptane and stirred for 5 min before it was filtered off. The solids were washed once with heptane and twice with methyl tert-butyl ether to obtain the title compound (656 mg, 35%) as light yellow solid, MS m / z: 322.0 [M+H]+, ESI pos. Intermediate A3: 7-chloro-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one Step 1: 6-chloro-4-(2,4-difluorophenyl)pyridazin-3-amine The title compound was prepared in analogy to 5-chloro-3-(2,4-difluorophenyl)pyrazin-2-amine using 4-bromo-6-chloro-pyridazin-3-amine instead of (3-bromo-5-chloro-pyrazin-2-yl)amine (see Intermediate A2), yellow solid, MS m / z: 242.0 [M+H]+, ESI pos. Step 2: 7-chloro-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one To a solution of 6-chloro-4-(2,4-difluorophenyl)pyridazin-3-amine (2.8 g, 11.6 mmol) in toluene (50 ml) was added ethyl 2-methylacetoacetate (8.35 g, 57.9 mmol) and p-toluenesulfonic acid (0.2 g, 1.16 mmol, 0.1 eq). The mixture was degassed with nitrogen three times, stirred at 130 °C for 16 h using a Dean-Stark apparatus. The mixture was concentrated in vacuo and purified by column chromatography (silica gel, 60% ethyl acetate in petroleum ether) to afford the title compound (3.57 g, 96% yield) as yellow solid, MS m / z: 322.0 [M+H]+, ESI pos. Intermediate A4: 4-(7-chloro-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-9-yl)-3-fluoro- benzonitrile The title compound was prepared in analogy to Intermediate A3 using 4-cyano-2- fluorophenylboronic acid pinacol ester instead of (2,4-difluorophenyl)boronic acid in step 1. Brown solid, MS m / z: 329.0 [M+H]+, ESI pos. Intermediate A5: 7-chloro-9-(5,5-difluorotetrahydropyran-2-yl)-2,3-dimethyl-pyrimido[1,2- b]pyridazin-4-one Step 1: 6-chloro-4-(5,5-difluorotetrahydropyran-2-yl)pyridazin-3-amine To a solution of 3-amino-6-chloropyridazine (0.6 g, 4.63 mmol) and 5,5-difluorotetrahydro- pyran-2-carboxylic acid (1.54 g, 9.26 mmol) in water (10 ml) were added trifluoroacetic acid (0.36 ml, 4.63 mmol) and silver nitrate (0.39 g, 2.32 mmol). The reaction mixture was wrapped in aluminum foil, warmed to 70 °C and ammonium persulfate (5.28 g, 23.16 mmol) was slowly added to the mixture in small portions. After heating the mixture to 70 °C for another hour it was cooled to room temperature and diluted with ethyl acetate (50 ml). To bring the pH to 8, ammonium hydroxide was added and after 20 min, the organic layer was separated and evaporated to dryness. The residue was purified by chromatography (silica gel, chloroform / acetonitrile 0 - 100%) to afford 6-chloro-4-(5,5-difluorotetrahydropyran-2-yl)pyridazin-3-amine (0.45 g, 37% yield) as a white solid, MS m / z: 250.0 [M+H]+, ESI pos. Step 2: 7-chloro-9-(5,5-difluorotetrahydropyran-2-yl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4- one Bismuth chloride (26.5 mg, 0.08 mmol) was added to a mixture 6-chloro-4-(5,5- difluorotetrahydropyran-2-yl)pyridazin-3-amine (140 mg, 0.56 mmol) in ethyl 2- methylacetoacetate (1.21 g, 8.41 mmol). The mixture was heated at 110 °C for 18 h, then it was poured into ethyl acetate (10 ml), washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by chromatography (silica gel, hexane / ethyl acetate = 1:1) to afford the title compound (130 mg, 67% yield) as a yellow solid, MS m / z: 330.0 [M+H]+, ESI pos. Intermediate A6: 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin- 4-one Step 1: 7-bromo-9-iodo-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one A mixture of 5-bromo-3-iodo-pyridin-2-amine (CAS 381233-96-1, 2.0 g, 6.69 mmol), ethyl 2- methylacetoacetate (CAS 609-14-3, 965 mg, 0.97 ml, 6.69 mmol) and polyphosphoric acid (1.0 g, 6.69 mmol) was stirred for 90 min at 120°C. The reaction mixture was taken up with water, basified with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to give the title compound (1.07 g, 40% yield) as off-white solid, MS m / z: 378.8 [M+H]+, ESI pos. Step 2: 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one To a solution of 7-bromo-9-iodo-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one (260 mg, 0.68 mmol) in dioxane (7 ml) were added (4-chloro-2-fluoro-phenyl)boronic acid (179 mg, 1.03 mmol) and 2 M aqueous cesium carbonate solution (1.03 ml, 2.06 mmol) at room temperature. The mixture was degased with argon before 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (56 mg, 0.069 mmol, 0.100 eq) was added. The mixture was stirred over night at 60°C, then diluted with water and extracted two times with ethyl acetate. The organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (on silica, ethyl acetate in heptane 0-50%) to obtain the title compound (221 mg, 81% yield) as white solid, MS m / z: 383.0 [M+H]+, ESI pos. Intermediate A7: 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2-methyl-pyrido[1,2-a]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A6 using 3-bromo-5-chloro- pyridin-2-amine instead of 5-bromo-3-iodo-pyridin-2-amine and 3-ketobutyric acid ethyl ester (CAS 141-97-9) instead of ethyl 2-methylacetoacetate in step 1. White solid, MS m / z: 323.1 [M+H]+, ESI pos. Intermediate A8: 7-chloro-9-(4,4-difluoro-1-piperidyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin- 4-one Step 1: 5-bromo-3-(4,4-difluoro-1-piperidyl)pyrazin-2-amine A mixture of (3,5-dibromopyrazin-2-yl)amine (1 g, 3.95 mmol), triethylamine (2.0 g, 2.76 ml, 19.8 mmol) and 4,4-difluoropiperidine (479 mg, 0.443 ml, 3.95 mmol) in dimethyl sulfoxide (5 ml) was stirred at 120°C overnight. After cooling to room temperature, the reaction mixture was poured into cold water (30 ml) and the solid was filtered, washed with water and dried to afford 5-bromo-3-(4,4-difluoro-1-piperidyl)pyrazin-2-amine (1.04 g, 85%) as light brown solid, MS m / z: 293.3 [M+H]+, ESI pos. Step 2: 7-chloro-9-(4,4-difluoro-1-piperidyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one To a suspension of 5-bromo-3-(4,4-difluoro-1-piperidyl)pyrazin-2-amine (948 mg, 3.23 mmol) in ethyl 2-methylacetoacetate (4.66 g, 4.71 ml, 32.3 mmol) was added bismuth(III) chloride (102 mg, 0.323 mmol) and the mixture was stirred at 100°C for 3 days. The reaction mixture was poured into NaHCO3solution and extracted with dichloromethane twice. The combined organic layers were dried with Na2SO4and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to afford the title compound (448 mg, 42%) as brown solid, MS m / z: 329.4 [M+H]+, ESI pos. Intermediate B1: 1-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyrazole Intermediate B1 is known, CAS 2738495-81-1. Intermediate B2: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridine To a solution of 2-methoxyisonicotinaldehyde (1.0 g, 7.29 mmol) in dichloromethane (10 ml) was added at 3-butyn-1-ol (767 mg, 0.833 ml, 10.94 mmol) under argon. Then the mixture was cooled to -10 ℃ and trifluoromethanesulfonic acid (3.28 g, 1.92 ml, 21.9 mmol) was added. After stirring for 30 min at -10 °C the mixture was warmed to room temperature and stirring was continued overnight. The reaction mixture was diluted with saturated NaHCO3-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl] trifluoromethanesulfonate (870 mg, 32% yield) as colorless oil, MS m / z: 340.1 [M+H]+, ESI pos. tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- To a solution of [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (870 mg, 2.31 mmol) in 1,4-dioxane (15 ml) were added bis(pinacolato)diboron (1.17 g, 4.62 mmol), potassium acetate (906 mg, 9.23 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (189 mg, 0.231 mmol, 0.10 eq). The mixture was purged and backfilled with argon three times, then stirred at 90 °C for 2 h. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-80%) to afford 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridine (656 mg, 81% yield) as colorless oil, MS m / z: 318.3 [M+H]+, ESI pos. Intermediate B3: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridine The title compound was prepared in analogy to Intermediate B2 from 6-methoxynicotinaldehyde instead of 2-methoxyisonicotinaldehyde. Yellow oil, MS m / z: 318.3 [M+H]+, ESI pos. Intermediate B4: 1-cyclopropyl-4-[6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,3-dihydropyran-6-yl]pyrazole Step 1: [6-(1-cyclopropylpyrazol-4-yl)-6-methyl-2,3-dihydropyran-4-yl] trifluoromethanesulfonate To a solution of 1-(1-cyclopropylpyrazol-4-yl)ethanone (CAS 1784673-98-8, 5.35 g, 35.6 mmol) and 3-butyn-1-ol (3.0 g, 42.8 mmol) in dichloromethane (50 ml) was added dropwise at -30 °C trifluoromethane sulfonic acid (9.46 ml, 107 mmol), then the mixture was stirred at -30 °C to 20 °C for 16 h under nitrogen. The reaction mixture was diluted with saturated NaHCO3-solution (200 ml) and extracted two times with dichloromethane (100 ml x 3). The combined organic layers were washed with brine (300 ml), dried over MgSO4and concentrated to dryness. The crude material was purified by preparative HPLC (column: Phenomenex Luna C18250 x 100 mm x 10 µm, mobile phase: water / 0.25% formic acid - acetonitrile, 0-100%, flow rate 260 ml / min) to give [6-(1-cyclopropylpyrazol-4-yl)-6-methyl-2,3-dihydropyran-4-yl] trifluoromethanesulfonate (2.9 g, 23% yield) as colorless oil, MS m / z: 353.1 [M+H]+, ESI pos. Step 2: 1-cyclopropyl-4-[6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3- dihydropyran-6-yl]pyrazole To a solution of [6-(1-cyclopropylpyrazol-4-yl)-6-methyl-2,3-dihydropyran-4-yl] trifluoromethanesulfonate (2.9 g, 8.23 mmol) in 1,4-dioxane (30 ml) was added bis(pinacolato)diboron (2.51 g, 9.88 mmol), potassium acetate (2.42 g, 24.7 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.67 g, 0.82 mmol, 0.1 eq). Then the reaction was degassed with nitrogen three times and the reaction mixture was stirred at 90 °C for 1 h under nitrogen atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4and evaporated. The residue was purified by preparative MPLC (column: Welch Ultimate XB-CN, 250 x 70 mm x 10 µm, mobile phase: hexane / ethanol, 0-100%, flow rate 140 ml / min) to give the title compound (1.9 g, 70% yield) as light yellow solid, MS m / z: 331.1 [M+H]+, ESI pos. Intermediate B5: (+)- 2-(1-methylpyrazol-4-yl)morpholine 2-(1-Methylpyrazol-4-yl)morpholine (CAS 1375963-52-2) was separated by chiral SFC (column AD-H, 5 um, 100 x 4.6 mm, 20-40% MeOH + 0,2% diethylamine) to yield (+)- 2-(1- methylpyrazol-4-yl)morpholine (+)-C1 as the first eluting enantiomer and (-)- 2-(1- methylpyrazol-4-yl)morpholine (-)-C1 as the second eluting enantiomer. (+)- 2-(1- methylpyrazol-4-yl)morpholine: yellow oil, αD(589nm) 20 °C = +13.36° (c = 0.1 g / l, MeOH). Intermediate Name Structure SourceB6 3-(1-methylpyrazol-4-commercial, yl)piperidine CAS 1340528- 88-2 B7 4,4-difluoro-3-(1-known, methylpyrazol-4- CAS yl)piperidine 2738350- 76-8B8 2-(1-cyclopropylpyrazol-4-N known, yl)-6-methyl-morpholine NNH CAS O 2738496- 25-6 Intermediate B9: 1-cyclopropyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyran-6-yl]pyrazole The title compound was prepared in analogy to Intermediate B2 from 1-cyclopropylpyrazole-4- carbaldehyde (CAS 1082066-00-9) instead of 2-methoxyisonicotinaldehyde and 4-pentyn-2-ol instead of 3-butyn-1-ol. Brown oil MS m / z: 331.2 [M+H]+, ESI pos. Intermediate B10: 2-methoxy-5-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyridine In a three-necked flask, to 6-methoxy-3-pyridinecarboxaldehyde (12.0 g, 87.5 mmol) was added under nitrogen a solution of 4-penten-2-ol (11.3 g, 131 mmol) in dichloromethane (120 ml) at 25 ℃. While still being stirred, trifluoroacetic acid (117 ml, 1.57 mol) was added dropwise at -10 °C, then the reaction mixture was stirred at 0 °C for 1 h and at 20 °C for 16 h under nitrogen. The reaction mixture was concentrated under vacuum and the residue was dissolved in methanol (60 ml). Lithium hydroxide monohydrate (1.50 g, 37.6 mmol) was added and the mixture was stirred at 20 °C for 2 h. The reaction mixture was added into water (50 ml), the pH was adjusted to 6 with 1 M hydrochloric acid, and then extracted with ethyl acetate (100 ml x 5). The combined organic layers were washed with brine (50 ml) and dried over Na2SO4, then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate 0-100%) to give 2-(6-methoxy-3-pyridyl)-6-methyl-tetrahydropyran-4-ol (3.0 g, 72% yield) as yellow oil, MS m / z: 224.1 [M+H]+, ESI pos. 4-one To a solution of 2-(6-methoxy-3-pyridyl)-6-methyl-tetrahydropyran-4-ol (3.0 g, 13.44 mmol) in dichloromethane (30 ml) was added Dess-Martin periodinane (8.55 g, 20.15 mmol) at 0 °C and the mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (200 ml) and extracted with dichloromethane (100 ml x 3). The combined organic layers were washed with brine (100 ml) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate 0-100%) to give 2- (6-methoxy-3-pyridyl)-6-methyl-tetrahydropyran-4-one (2.5 g, 84% yield) as yellow oil, MS m / z: 222.1 [M+H]+, ESI pos. Step 3: [6-(6-methoxy-3-pyridyl)-2-methyl-3,6-dihydro-2H-pyran-4-yl] 1,1,2,2,3,3,4,4,4- nonafluorobutane-1-sulfonate To a solution of 2-(6-methoxy-3-pyridyl)-6-methyl-tetrahydropyran-4-one (100 mg, 0.45 mmol) in tetrahydrofuran (2 ml) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (138 mg, 0.9 mmol) and nonafluorobutanesulfonyl fluoride (205 mg, 0.68 mmol) at 0 ℃, then mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The reaction mixture was diluted with saturated NaHCO3-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to give [6-(6-methoxy-3- pyridyl)-2-methyl-3,6-dihydro-2H-pyran-4-yl] 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (100 mg, 44% yield), yellow oil, MS m / z: 504.1 [M+H]+, ESI pos. Step 4: 2-methoxy-5-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyridine To a solution of [6-(6-methoxy-3-pyridyl)-2-methyl-3,6-dihydro-2H-pyran-4-yl] 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (100 mg, 0.2 mmol) in 1,4-dioxane (2 ml) were added bis(pinacolato)diboron (60 mg, 0.2 mmol), potassium acetate (58.5 mg, 0.6 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16 mg, 0.02 mmol, 0.1 eq). The mixture was purged and backfilled with argon three times, then stirred at 90 °C for 1 h. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under vacuum to give 2-methoxy-5-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (65 mg, 98% yield) as brown oil, MS m / z: 332.1 [M+H]+, ESI pos. Intermediate B11: 2-methyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridazin-3-one Intermediate B11 was prepared in analogy to Intermediate B2 using 1-methyl-6-oxo-pyridazine- 4-carbaldehyde (CAS 1001620-75-2) instead of 2-methoxyisonicotinaldehyde, white solid, MS m / z: 319.1 [M+H]+, ESI pos. Intermediate B12: 3-methoxy-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridazine Intermediate B12 was prepared in analogy to Intermediate B2 using 6-methoxypyridazine-3- carbaldehyde (CAS 90237-25-5) instead of 2-methoxyisonicotinaldehyde, brown oil, MS m / z: 319.1 [M+H]+, ESI pos. Intermediate B13: 1-cyclopropyl-4-[6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2,5-dihydropyran-2-yl]pyrazole Step 1: 1-(1-cyclopropylpyrazol-4-yl)-1-hydroxy-5-methyl-hex-4-en-3-one To a solution of mesityl oxide (10.8 g, 110.2 mmol) in tetrahydrofuran (200 ml), degassed with nitrogen three times, was added slowly at -70 °C lithium diisopropylamide solution (2 M in THF, 73.5 ml, 147 mmol) over 30 min, and the mixture was stirred for 0.5 h under nitrogen. Then 1- cyclopropylpyrazole-4-carbaldehyde (10.0 g, 73.5 mmol) was slowly added and the mixture was stirred at -70 °C for 1 h under nitrogen. The mixture was slowly poured into ammonium chloride solution (100 ml) at 10 °C and stirred for 10 min, then it was extracted with ethyl acetate (30 ml x 3). The combined organic layers was washed with brine (30 ml) and dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; petroleum ether / ethyl acetate 0 - 30%) to give 1-(1-cyclopropylpyrazol-4-yl)-1-hydroxy-5- methyl-hex-4-en-3-one (9.8 g, 57% yield) as light yellow oil, MS m / z: 235.1 [M+H]+, ESI pos. Step 2: 6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-one To a solution of 1-(1-cyclopropylpyrazol-4-yl)-1-hydroxy-5-methyl-hex-4-en-3-one (9.0 g, 38.4 mmol) in dichloromethane (200 ml) was added Amberlyst 15 (36.0 g), then the mixture was stirred at 25 °C for 8 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate 0-60%) to give 6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-one (1.1 g, 4.69 mmol, 12% yield) as light yellow oil. MS m / z: 235.2 [M+H]+, ESI pos. Step 3: 1-cyclopropyl-4-[6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydropyran-2-yl]pyrazole The title compound was prepared in analogy to Intermediate B10 using 6-(1-cyclopropylpyrazol- 4-yl)-2,2-dimethyl-tetrahydropyran-4-one instead of 2-(6-methoxy-3-pyridyl)-6-methyl- tetrahydropyran-4-one in step 3, light yellow oil, MS m / z: 345.2 [M+H]+, ESI pos. Intermediate B14: 5-[6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydropyran-2-yl]-2-methoxy-pyridine Intermediate B14 was prepared in analogy to Intermediate B13 using 6-methoxy-3- pyridinecarboxaldehyde instead of 1-cyclopropylpyrazole-4-carbaldehyde, brown oil, MS m / z: 346.3 [M+H]+, ESI pos. Intermediate B15: 2-methoxy-3-methyl-5-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyrazine To a solution of 5-bromo-2-methoxy-3-methyl-pyrazine (CAS 1393541-34-8, 1.8 g, 8.87 mmol) in 1,4-dioxane (30 ml) and water (3 ml) were added potassium vinyltrifluoroborate (1.78 g, 13.3 mmol), cesium carbonate (5.78 g, 17.7 mmol) and [1,1'‑bis(diphenylphosphino)- ferrocene]palladium(II)dichloride (724 mg, 0.89 mmol). Then the air in the mixture was replaced three times by nitrogen and the mixture was stirred at 90 °C for 4 h. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with saturated brine (20 ml), dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to give 2-methoxy-3-methyl-5-vinyl-pyrazine (1.16 g, 87% yield) as colorless oil, MS m / z: 151.1 [M+H]+, ESI pos. 2: 5-methoxy-6-methyl-pyrazine-2-carbaldehyde In a continuous flow reactor (Chip reactor, 1 / 8", 20 ml) a solution of 2-methoxy-3-methyl-5- vinyl-pyrazine (100 mg, 0.67 mmol) in dichloromethane (10 ml) was treated with ozone at a flow rate of 500 ml / min and a pressure of 103 kPa (15 Psi) at 0°C. The reaction mixture was collected after 30 s and the solution was quenched with triphenylphosphine immobilized on a polymeric support. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate 1:0 to 5:1) to give 5-methoxy-6-methyl-pyrazine-2-carbaldehyde (580 mg, 49% yield) as white solid, MS m / z: 153.1 [M+H]+, ESI pos. (4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- In the following two steps Intermediate B15 was prepared in analogy to Intermediate B2 using 5- methoxy-6-methyl-pyrazine-2-carbaldehyde instead of 2-methoxyisonicotinaldehyde and 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bi(1,3,2-dioxaborolane) (CAS 2247367-07-1) instead of bis(pinacolato)diboron, yellow oil, MS m / z: 389.3 [M+H]+, ESI pos. Intermediate B16: 4-methoxy-2-methyl-6-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyridazin-3-one To a solution of 4-bromo-6-chloro-2-methyl-pyridazin-3-one (CAS 1178884-53-1 , 9.0 g, 40.3 mmol) in methanol (90 ml) was added sodium methoxide (10.9 g, 201 mmol) and the reaction was stirred at 30 °C for 2 h. The reaction was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate, 1:1) to give a 6-chloro-4-methoxy-2-methyl-pyridazin-3-one (5.0 g, 71% yield) as white solid, MS m / z: 175.1 [M+H]+, ESI pos. 2: 4-methoxy-2-methyl-6-vinyl-pyridazin-3-one To a solution of 6-chloro-4-methoxy-2-methyl-pyridazin-3-one (5.0 g, 28.6 mmol) in 1,4- dioxane (80 ml) and water (8 ml) were added 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.7 g, 0.86 mmol, 0.03 eq), cesium carbonate (18.7 g, 57.3 mmol) and potassium vinyltrifluoroborate (5.75 g, 43 mmol) and the reaction was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Ethyl acetate (100 ml) and water (100 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 ml x 2) and the combined extracts were washed with brine (60 ml), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate, 1:1) to give 4-methoxy-2-methyl-6-vinyl-pyridazin-3-one (3.1 g, 65% yield) as yellow solid, MS m / z: 167.1 [M+H]+, ESI pos. 3-carbaldehyde Ozone was bubbled through a solution of 4-methoxy-2-methyl-6-vinyl-pyridazin-3-one (3.1 g, 18.6 mmol) in dichloromethane (20 ml) and methanol (20 ml) at -70 °C for 30 min. Then nitrogen was bubbled into the mixture at -70°C to remove ozone. It was warmed to 0 ℃ and a solution of triphenylphosphine (7.33 g, 28 mmol) in dichloromethane (20 ml) was added to this solution dropwise. The mixture was stirred at 25 ℃ for 1 h under nitrogen, then it was concentrated. The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate, 1:1) to give 5-methoxy-1-methyl-6-oxo-pyridazine-3-carbaldehyde (1.9 g, 61% yield) as yellow solid, MS m / z: 169.1 [M+H]+, ESI pos. (4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- In the following two steps Intermediate B16 was prepared in analogy to Intermediate B2 using 5- methoxy-1-methyl-6-oxo-pyridazine-3-carbaldehyde instead of 2-methoxyisonicotinaldehyde and 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bi(1,3,2-dioxaborolane) (CAS 2247367-07-1) instead of bis(pinacolato)diboron, yellow oil, MS m / z: 405.3 [M+H]+, ESI pos. Intermediate B17: 2,4-dimethyl-6-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridazin-3-one Intermediate B17 was prepared in analogy to Intermediate B15 using 6-chloro-2,4-dimethyl- pyridazin-3-one (CAS 1114563-58-4) instead of 5-bromo-2-methoxy-3-methyl-pyrazine, yellow oil, MS m / z: 389.3 [M+H]+, ESI pos. Intermediate B18: 3-methyl-5-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]-3,4-diazabicyclo[4.1.0]hept-4-en-2-one To a solution of methylhydrazine (17.6 ml, 134 mmol) in acetonitrile (75 ml) was added dropwise at 0 °C a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (CAS 5617-74-3, 15.0 g, 134 mmol) in acetonitrile (60 ml). The mixture was warmed to room temperature and heated to 85 °C for 16 h. The reaction mixture was purified by column chromatography (silica gel, ethyl acetate / methanol 1:0 to 10:1) to give 3-methyl-3,4-diazabicyclo[4.1.0]heptane-2,5-dione (8.75 g, 47% yield) as white solid. MS m / z: 141.1 [M+H]+, ESI pos. Step 2: (4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2-yl) trifluoromethanesulfonate To a solution of 3-methyl-3,4-diazabicyclo[4.1.0]heptane-2,5-dione (9.0 g, 64.2 mmol) in dichloromethane (90 ml) was added triethylamine (14.3 ml, 102.7 mmol). Under nitrogen the reaction mixture was cooled to -30 °C, then trifluoromethanesulfonic anhydride (16.0 ml, 77.07 mmol) was added dropwise and the mixture was stirred at -30 °C for 0.5 h. The reaction mixture was poured into saturated NaHCO3 solution (500 ml) and extracted with dichloromethane (200 ml x 3). The combined organic layers were washed with brine (200 ml), dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate 1:0 to 1:1) to give (4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl) trifluoromethanesulfonate (16.7 g, 95% yield) as colorless oil. MS m / z: 273.1 [M+H]+, ESI pos. Step 3: 3-methyl-5-vinyl-3,4-diazabicyclo[4.1.0]hept-4-en-2-one To a solution of (4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2-yl) trifluoromethanesulfonate (16.8 g, 61.72 mmol) in 1,4-dioxane (300 ml) were added potassium vinyltrifluoroborate (12.4 g, 92.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (2.52 g, 3.09 mmol), cesium carbonate (40.2 g, 123.4 mmol, 2.0 eq) and water (30 ml). The air of the flask was exchanged by nitrogen three times then the mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was poured into water (500 ml), then extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (200 ml), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate 1:0 to 1:1) to give 3-methyl-5-vinyl-3,4-diazabicyclo[4.1.0]hept-4-en-2-one (7.85 g, 85% yield) as yellow oil. MS m / z: 151.1 [M+H]+, ESI pos. Step 4: 4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-ene-2-carbaldehyde A solution of 3-methyl-5-vinyl-3,4-diazabicyclo[4.1.0]hept-4-en-2-one (7.85 g, 52.3 mmol) in dichloromethane (80 ml) was cooled to -70 °C and ozone was bubbled through the reaction mixture until the color turned brown. Remaining ozone was removed by bubbling nitrogen through the mixture, then a solution of triphenylphosphine (27.4 g, 104.5 mmol) in dichloromethane (30 mL) was added at 0°C. The reaction was stirred at 20 °C for 0.5 h under nitrogen, then concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate 1:0 to 1:1) to give 4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-ene-2-carbaldehyde (3.7 g, 47% yield) as yellow oil. MS m / z: 153.1 [M+H]+, ESI pos. Step 5: [6-(4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate To a solution of 4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-ene-2-carbaldehyde (3.7 g, 24.3 mmol) in dichloromethane (50 ml) was added 3-butyn-1-ol (2.05 g, 29.2 mmol) and the air of the flask was exchanged by nitrogen three times. The reaction mixture was cooled down to -10 °C, then trifluoromethanesulfonic acid (6.45 ml, 72.9 mmol) was added dropwise and the mixture was stirred at -10 °C for 2 h. The reaction mixture was quenched by adding saturated NaHCO3 solution (20 ml), then extracted with dichloromethane (3 x 10 ml). The combined organic layers were washed with saturated brine (100 ml), dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by HPLC (column: spherical C1820-45 mm 100 Å; mobile phase water / acetonitrile 0-100%). The eluent was extracted with dichloromethane (200 ml x 3), the organic phase was washed with brine (100 ml), dried over anhydrous Na2SO4and concentrated under vacuum to give [6-(4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2-yl)- 3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (3.4 g, 39% yield) as yellow oil. MS m / z: 355.1 [M+H]+, ESI pos. Step 6: 3-methyl-5-[4- tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]- 3,4-diazabicyclo en-2-one To a solution of [6-(4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2-yl)-3,6-dihydro-2H- pyran-4-yl] trifluoromethanesulfonate (3.4 g, 9.6 mmol) in 1,4-dioxane (70 ml) were added 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.22 g, 11.52 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (392 mg, 0.48 mmol) and potassium acetate (2.83 g, 28.79 mmol). The air of the flask was exchanged by nitrogen three times. Then the reaction mixture was heated to 90 °C and stirred for 1 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (30 ml), and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate 1:0 to 1:1) to give 3-methyl-5-[4- (4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]-3,4- diazabicyclo[4.1.0]hept-4-en-2-one (3.0 g, 81% yield) as yellow oil, MS m / z: 389.2 [M+H]+, ESI pos. Example 1 and Example 2: 4-[7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile and 4-[7-[(2S,4R)-2- (1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin- 9-yl]-3-fluoro-benzonitrile Step 1: 4-[7-[6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile To a solution of 4-(7-chloro-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluoro- benzonitrile (Intermediate A1, 250 mg, 0.76 mmol) in 1,4-dioxane (12 ml) and water (2.4 ml) were added 1-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyrazole (Intermediate B1, 321 mg, 0.91 mmol), sodium carbonate (242 mg, 2.28 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (62 mg, 0.08 mmol, 0.1 eq) at room temperature. Then the reaction was degassed with nitrogen three times and the reaction mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (25ml x 3). The combined extracts were washed with brine, dried over Na2SO4and evaporated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 0 - 100%) to give 4-[7-[6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl- 4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile (260 mg, 71% yield) as light yellow solid, MS m / z: 483.3 [M+H]+, ESI pos. 4-yl]-2,3-dimethyl-4-oxo- benzonitrile and 4-[7-[(2S,4R)-2-(1- 4-yl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9- To a solution of 4-[7-[6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl- 4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile (260 mg, 0.54 mmol) in ethyl acetate (5 ml) was added palladium on charcoal (10%, 115 mg) under nitrogen atmosphere. The reaction mixture was degassed in vacuo and hydrogen was added three times, then stirred at 30 °C for 3 h under hydrogen atmosphere (103 kPa, 15 Psi). The crude mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, mobile phase: water / 0.25% formic acid - acetonitrile, 0-100%, flow rate 25 ml / min) to give racemic 4-[7-[2-(1- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9- yl]-3-fluoro-benzonitrile. This material was separated into enantiomers by chiral SFC (Daicel Chiralpak AD, 250 mm x 30 mm, 10 µm, CO2 / isopropanol with 0.1% ammonium hydroxide) to obtain 4-[7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile (16 mg, 26% yield) as first eluting enantiomer and 4-[7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl- 4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile (17 mg, 29% yield) as second eluting enantiomer, light yellow solids, MS m / z: 485.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.The following Examples 3 to 6 were prepared according to Example 1 and 2 by starting from theindicated intermediates. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MSEx. Structure Name Intermediates(ESI): m / z 7-[(2R,4S)-2-(1- cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]- 478.2 3 9-(2,4-difluorophenyl)- A3 and B1 [M+H]+2,3-dimethyl- pyrimido[1,2-b]pyridazin- 4-one 7-[(2S,4R)-2-(1- cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]- 478.2 4 9-(2,4-difluorophenyl)- A3 and B1 [M+H]+2,3-dimethyl- pyrimido[1,2-b]pyridazin- 4-one 7-[(2R,4S)-2-(1- cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]- 478.2 5 9-(2,4-difluorophenyl)- A2 and B1 [M+H]+2,3-dimethyl- pyrazino[1,2-a]pyrimidin- 4-one 7-[(2S,4R)-2-(1- cyclopropylpyrazol-4- 478.2 6 yl)tetrahydropyran-4-yl]- A2 and B1 [M+H]+9-(2,4-difluorophenyl)- 2,3-dimethyl- pyrazino[1,2-a]pyrimidin- 4-one Example 7 and Example 8: 4-[2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4- yl]-4-oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile and 4-[2,3-dimethyl-7-[(2R,4S)-2- (1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4-oxopyrazino[1,2-a]pyrimidin-9-yl]-3- fluorobenzonitrile Step 1: 3-fluoro-4-[7-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]benzonitrile To a solution of 2-methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyridine (Intermediate B3, 1.63 g, 5.14 mmol) in 1,4-dioxane (30 ml) and water (3 ml) were added 4-(7-chloro-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluoro- benzonitrile (Intermediate A1, 1.30 g, 3.95 mmol), sodium carbonate (1.26 g, 11.85 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (161 mg, 0.2 mmol, 0.05 eq). Then the reaction was degassed with nitrogen three times and resulting mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The mixture was poured into water (150 ml), the aqueous layer was separated and extracted with dichloromethane (100 ml x 3). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 : 1 to 1 : 1, then dichloromethane / ethyl acetate = 1:1) to afford 3-fluoro-4-[7-[6- (6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-4-oxo-pyrazino[1,2- a]pyrimidin-9-yl]benzonitrile (1.7 g, 89% yield) as yellow solid, MS m / z: 484.2 [M+H]+, ESI pos. 4-yl]-2,3-dimethyl-4-oxo- To a suspension of palladium on charcoal (10%, 616 mg) in ethyl acetate (10 ml) was added under argon a solution of 3-fluoro-4-[7-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]- 2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]benzonitrile (1.40 g, 2.9 mmol) in ethyl acetate (30 ml) and dimethylformamide (8 ml), magnesium oxide (1.17 g, 29 mmol) and triethylamine (352 mg, 3.47 mmol). The reaction was degassed in vacuo and hydrogen was added three times, then stirred at 25 °C for 3 h under hydrogen atmosphere (103 kPa, 15 Psi). The reaction was filtered through a pad of diatomaceous earth, then poured into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 40 mm x 15 µm, mobile phase: water / 0.1% HCl - acetonitrile, 0-100%, flow rate 25 ml / min) to give 3-fluoro-4-[7-[2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]benzonitrile (550 mg, 39% yield) as yellow solid, MS m / z: 486.2 [M+H]+, ESI pos. Step 3: 4-[2,3-dimethyl-4-oxo-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrazino[1,2- a]pyrimidin-9-yl]-3-fluoro-benzonitrile To a solution of 3-fluoro-4-[7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-4- oxo-pyrazino[1,2-a]pyrimidin-9-yl]benzonitrile (550 mg, 1.13 mmol) in acetonitrile (10 ml) was added trimethylsilyl iodide (453 mg, 0.32 ml, 2.27 mmol) at 0 ℃, then the resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (50 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with brine (50 ml) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative MPLC (column: Spherical C18, 20 - 45 µm, mobile phase: water / 0.1% formic acid - acetonitrile, 0-60%, flow rate 60 ml / min) to give 4-[2,3-dimethyl-4- oxo-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro- benzonitrile (260 mg, 49% yield) as brown solid, MS m / z: 472.1 [M+H]+, ESI pos. Step 4: 4-[2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4- oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile and 4-[2,3-dimethyl-7-[(2R,4S)-2-(1- methyl-6-oxopyridin-3-yl)oxan-4-yl]-4-oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile To a solution of 4-[2,3-dimethyl-4-oxo-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4- yl]pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile (100 mg, 0.21 mmol) in dimethylformamide (4 ml) was added cesium carbonate (207 mg, 0.64 mmol) and iodomethane (90 mg, 0.04 ml, 0.64 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, mobile phase: water / 0.1% trifluoroacetic acid - acetonitrile, 35-65%, flow rate 25 ml / min) to give racemic 4-[2,3-dimethyl-7-[2-(1-methyl-6- oxo-3-pyridyl)tetrahydropyran-4-yl]-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile. This material was separated into enantiomers by chiral SFC (Daicel Chiralpak AD, 250 mm x 30 mm, 10 µm, CO2 / acetonitrile / isopropanol with 0.1% ammonium hydroxide) to obtain 4-[2,3- dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4-oxopyrazino[1,2-a]pyrimidin- 9-yl]-3-fluorobenzonitrile (25 mg, 24% yield) as first eluting enantiomer and 4-[2,3-dimethyl-7- [(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4-oxopyrazino[1,2-a]pyrimidin-9-yl]-3- fluorobenzonitrile (22 mg, 21% yield) as second eluting enantiomer. Yellow solids, MS m / z: 486.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 9 and Example 10: 4-[7-[(2S,4R)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3- dimethyl-4-oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile and 4-[7-[(2R,4S)-2-(1- cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3-dimethyl-4-oxopyrazino[1,2-a]pyrimidin-9-yl]-3- fluorobenzonitrile A mixture of 4-[2,3-dimethyl-4-oxo-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4- yl]pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile (160 mg, 0.34 mmol), copper diacetate (68 mg, 0.37 mmol), cyclopropylboronic acid (58 mg, 0.68 mmol), sodium carbonate (72 mg, 0.68 mmol) and 2,2’-bipyridine (58 mg, 0.37 mmol) in 1,2-dichloroethane (5 ml) was stirred at 70 °C for 2 h under oxygen atmosphere (103 kPa, 15 Psi). The reaction mixture was poured into water (50 ml, contained 5% ammonium hydroxide) and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, mobile phase: water / 0.1% trifluoroacetic acid - acetonitrile, 0 - 100%, flow rate 25 ml / min) to give racemic 4-[7-[2-(1-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro- benzonitrile. This material was separated into enantiomers by chiral SFC (Daicel Chiralpak AD, 250 mm x 30 mm, 10 µm, CO2 / acetonitrile / isopropanol with 0.1% ammonium hydroxide) to obtain 4-[7-[(2S,4R)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3-dimethyl-4- oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile (47 mg, 27% yield) as first eluting enantiomer and 4-[7-[(2R,4S)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3-dimethyl-4- oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile (44 mg, 25% yield) as second eluting enantiomer. Yellow solids, MS m / z: 512.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 11 and Example 12: 4-[2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile and 4- [2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-4-oxo- pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile The title compounds were prepared in analogy to Example 7 and 8 from Intermediate B2 instead of Intermediate B3 in step 1. Yellow solids, MS m / z: 486.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 13 and Example 14: 4-[7-[(2R,4S)-2-(1-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro- benzonitrile and 4-[7-[(2S,4R)-2-(1-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile The title compounds were prepared in analogy to Example 9 and 10 from 4-[2,3-dimethyl-4-oxo- 7-[2-(2-oxo-1H-pyridin-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro- benzonitrile (intermediate for Examples 11 and 12) instead of 4-[2,3-dimethyl-4-oxo-7-[2-(6- oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile. Yellow solids, MS m / z: 512.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 15 and Example 16: 4-[7-[(2S,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro- benzonitrile and 4-[7-[(2R,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3- dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro-benzonitrile Step 1: ethyl 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7- yl]-3,6-dihydro-2H-pyran-2-carboxylate To a solution of 4-(7-chloro-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-9-yl)-3-fluoro- benzonitrile (Intermediate A4, 450 mg, 1.37 mmol) in 1,4-dioxane (6 ml) and water (0.6 ml) was added ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate (502 mg, 1.78 mmol), cesium carbonate (1.34 g, 4.11 mmol) and 1,1'-bis(diphenylphosphino)- ferrocene-palladium(II)dichloride dichloromethane complex (112 mg, 0.14 mmol, 0.1 eq) at room temperature. Then the reaction was degassed with nitrogen three times and stirred at 25 °C for 2 h under nitrogen atmosphere. The mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried over Na2SO4, then concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 : 1 to 0 : 1) to afford ethyl 4-[9-(4-cyano-2-fluoro-phenyl)- 2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (400 mg, 65% yield) as brown solid, MS m / z: 449.1 [M+H]+, ESI pos. Step 2: ethyl 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7- yl]tetrahydropyran-2-carboxylate To a suspension palladium of charcoal (10%, 119 mg) in ethyl acetate (2 ml) was added under argon a solution of ethyl 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2- b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (250 mg, 0.56 mmol) in ethyl acetate (20 ml) and dimethylformamide (5 ml) at room temperature. The reaction mixture was degassed in vacuo and hydrogen was added three times, then stirred at 30 °C for 8 h under hydrogen atmosphere (103 kPa, 15 Psi). The crude mixture was filtered through a pad of diatomaceous earth and evaporated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, mobile phase: water / 0.25% formic acid - acetonitrile, 0- 100%, flow rate 25 ml / min) to give ethyl 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo- pyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (150 mg, 60% yield) as yellow solid, MS m / z: 451.3 [M+H]+, ESI pos. Step 3: 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7- yl]tetrahydropyran-2-carboxylic acid To a solution of ethyl 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2- b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (130 mg, 0.29 mmol) in tetrahydrofuran (3 ml) and water (1 ml) was added lithium hydroxide hydrate (24 mg, 0.58 mmol) at room temperature and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (30 ml) and the pH was adjusted to 3 with 1M hydrochloric acid, then extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with brine (80 ml) and dried over Na2SO4, then concentrated in vacuum to give 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo- pyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid (110 mg, 90% yield) as yellow solid, MS m / z: 423.1 [M+H]+, ESI pos. 4-yl]-2,3-dimethyl- 4-oxo-pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro-benzonitrile and 4-[7-[ 1,2,4-oxadiazol-5-yl)oxan-4-yl]-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-9-yl]-3- fluorobenzonitrile To a solution of 4-[9-(4-cyano-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin- 7-yl]tetrahydropyran-2-carboxylic acid (110 mg, 0.26 mmol) in dimethylformamide (3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.52 mmol), N,N-diisopropyl ethylamine (135 mg, 1.04 mmol), 1-hydroxybenzotriazole (35 mg, 0.26 mmol) and N-hydroxycyclopropanecarboximidamide (52 mg, 0.52 mmol) at room temperature. The mixture was stirred at 20 °C for 16 h, then heated to 80 °C and stirred at 80 °C for 2 h . After cooling to room temperature, the mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150 x 25 mm x 10 µm, mobile phase: water / 0.25% formic acid - acetonitrile, 0-100%, flow rate 25 ml / min) to afford racemic 4-[7-[2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro-benzonitrile. This material was separated into enantiomers by chiral SFC (column Regis S,S-WHELK-O1, 250 mm x 25 mm, 10 µm, CO2 / acetonitrile / isopropanol with 0.1% ammonium hydroxide) to obtain 4-[7-[(2S,4S)-2- (3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrimido[1,2- b]pyridazin-9-yl]-3-fluoro-benzonitrile (6 mg, 5% yield) and 4-[7-[(2R,4S)-2-(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)oxan-4-yl]-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-9-yl]-3- fluorobenzonitrile (21 mg, 16% yield). Yellow solids. MS m / z: 487.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 17 and Example 18: 7-[(2R,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 7-[(2S,4R)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one The title compounds were prepared in analogy to Example 15 and 16 from Intermediate A3 instead of Intermediate A4 in step 1. White solids, MS m / z: 480.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 19 and Example 20: 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(2,4- difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one The title compounds were prepared in analogy to Example 7 and 8 from Intermediate A2 instead of Intermediate A1 in step 1. Yellow solids, MS m / z: 479.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 21 and Example 22: 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(2-keto-1-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(2,4- difluorophenyl)-7-[(2S,4R)-2-(2-keto-1-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one The title compounds were prepared in analogy to Example 7 and 8 from Intermediate A2 instead of Intermediate A1 and Intermediate B2 instead of Intermediate B3 in step 1. Yellow solids, MS m / z: 479.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 23 and Example 24: 7-[(2S,4R)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9- (2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one and 7-[(2R,4S)-2-(1- cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2- a]pyrimidin-4-one The title compounds were prepared in analogy to Example 9 and 10 from 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (intermediate for Examples 19 and 20) instead of 4-[2,3-dimethyl-4-oxo-7-[2-(6-oxo-1H-pyridin- 3-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile. Yellow solids, MS m / z: 505.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 25 and Example 26 and Example 27: 7-[(2S,4R)-2-(1-cyclopropyl-2-oxopyridin-4- yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one and 7- [(2R,4S)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethylpyrazino[1,2-a]pyrimidin-4-one and 7-[rac-(2S,4S)-2-(1-cyclopropyl-2-oxopyridin-4- yl)oxan-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one The title compounds were prepared in analogy to Example 9 and 10 from 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[2-(2-oxo-1H-pyridin-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (intermediate for Examples 21 and 22) instead of 4-[2,3-dimethyl-4-oxo-7-[2-(6-oxo-1H-pyridin- 3-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile. Yellow solids, MS m / z: 505.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.The following Examples 28 to 29 were prepared according to Example 1 and 2 by starting fromthe indicated intermediates. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex. Structure Name Intermediates(ESI): m / z 9-(5,5- difluorotetrahydropyran- 2-yl)-2,3-dimethyl-7-[rac- (2R,4S)-2-(1- 486.2 28 A5 and B1 cyclopropylpyrazol-4-[M+H]+yl)tetrahydropyran-4- yl]pyrimido[1,2- b]pyridazin-4-one 7-[(2S,4R)-2-(1- cyclopropylpyrazol-4-yl)- 492.2 29 2-methyl-tetrahydropyran- A2 and B4 [M+H]+4-yl]-9-(2,4- difluorophenyl)-2,3- dimethyl-pyrazino[1,2- a]pyrimidin-4-oneThe following Examples 30 to 34 were prepared according to Example 1 and 2 by starting fromthe indicated intermediates. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex. Structure Name Intermediates(ESI): m / z 7-[(2R,4S,6R)-2-(1- cyclopropylpyrazol-4-yl)- 6-methyl-tetrahydropyran- 492.2 30 4-yl]-9-(2,4- A3 and B9 [M+H]+difluorophenyl)-2,3- dimethyl-pyrimido[1,2- b]pyridazin-4-one 7-[(2R,4S,6S)-2-(1- cyclopropylpyrazol-4-yl)- 6-methyl-tetrahydropyran- 492.2 31 4-yl]-9-(2,4- A3 and B9 [M+H]+difluorophenyl)-2,3- dimethyl-pyrimido[1,2- b]pyridazin-4-one 7-[(2S,4R,6R)-2-(1- cyclopropylpyrazol-4-yl)- 492.2 32 6-methyl-tetrahydropyran- A3 and B9 [M+H]+4-yl]-9-(2,4- difluorophenyl)-2,3- dimethyl-pyrimido[1,2- b]pyridazin-4-one 7-[(2S,4R,6S)-2-(1- cyclopropylpyrazol-4-yl)- 6-methyl-tetrahydropyran- 492.2 33 4-yl]-9-(2,4- A3 and B9 [M+H]+difluorophenyl)-2,3- dimethyl-pyrimido[1,2- b]pyridazin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2R,4S)- 2-(1-methyl-6-oxo- 34 pyridazin-4- A2 and B11 yl)tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-oneThe following Examples 35 to 44 were prepared according to Examples 7 to 10 by starting fromthe indicated intermediates. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex. Structure Name Intermediates(ESI): m / z 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2R,4S,6R)-2-methyl-6- 493.3 (1-methyl-6-oxo-3- A2 and B10 [M+H]+pyridyl)tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2S,4S,6R)-2-methyl-6- (1-methyl-6-oxo-3- A2 and B10 pyridyl)tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2R,4R,6S)-2-methyl-6- (1-methyl-6-oxo-3- A2 and B10 pyridyl)tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2S,4R,6S)-2-methyl-6- 493.3 (1-methyl-6-oxo-3- A2 and B10 [M+H]+pyridyl)tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2R,4S,6R)-2-(1- cyclopropyl-6-oxo-3- A2 and B10 pyridyl)-6-methyl- tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2S,4S,6R)-2-(1- cyclopropyl-6-oxo-3- A2 and B10 pyridyl)-6-methyl- tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2R,4R,6S)-2-(1- cyclopropyl-6-oxo-3- A2 and B10 pyridyl)-6-methyl- tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7- [(2S,4R,6S)-2-(1- A2 and B10 cyclopropyl-6-oxo-3- pyridyl)-6-methyl- tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2R,4S)- 2-(1-methyl-6-oxo- 43 pyridazin-3- A2 and B12 yl)tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2R,4S)- 2-(1-cyclopropyl-6-oxo- 44 pyridazin-3- A2 and B12 yl)tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-one Example 45 and Example 46: 7-[(4R,6R)-6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl- tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 7-[(4S,6S)-6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one The title compounds were prepared in analogy to Examples 1 and 2 using Intermediate A3 instead of A1 and Intermediate B13 instead of B1, light yellow solids, MS m / z: 506.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 47: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(4R,6R)-2,2-difluoro-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one The title compound can be prepared in analogy to Examples 7 to 10. Example 48: 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(4R,6R)-6-(1-cyclopropyl-6-oxo-3- pyridyl)-2,2-difluoro-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one The title compound can be prepared in analogy to Examples 7 to 10. Example 49: 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4- difluoropiperidino)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one The title compounds were prepared in analogy to Examples 1 and 2 using Intermediate A8 instead of A1, off-white solid, MS m / z: 485.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.Example 507-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)-2-methyl-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one Step 1: 7-[6-(1-cyclopropylpyrazol-4-yl)-6-methyl-2,3-dihydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one To a solution of 7-chloro-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (Intermediate A3, 200 mg, 0.62 mmol) in 1,4-dioxane (5 ml) was added 1-cyclopropyl-4-[6- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyran-6-yl]pyrazole (Intermediate B4, 308 mg, 0.93 mmol), cesium carbonate (608 mg, 1.87 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (51 mg, 0.06 mmol, 0.1 eq) and water (0.5 ml). The air in the flask was replaced by nitrogen three times and the mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml x 3). The combined organoic layers were washed by brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 0:1) to give 7-[6-(1-cyclopropylpyrazol-4-yl)-6-methyl-2,3-dihydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (146 mg, 48% yield) as dark green solid, MS m / z: 490.3 [M+H]+, ESI pos. 4-yl]-9-(2,4- [1,2-b]pyridazin-4-one Palladium on charcoal (10%, 63 mg) was added to ethyl acetate (5 ml) and the air in the flask was changed with nitrogen three times. Then 7-[6-(1-cyclopropylpyrazol-4-yl)-6-methyl-2,3- dihydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (146 mg, 0.3 mmol) in ethyl acetate (10 ml) was added to this suspension under nitrogen. The nitrogen was now replaced by hydrogen three times and the mixture was stirred at 20 °C for 12 h under hydrogen atmosphere (345 kPa, 50 Psi). The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18150 x 25 mm x 10 µm, water with 0.225% formic acid / acetonitrile, flow rate 25ml / min) to give a diastereomeric mixture of the product 7-[2-(1-cyclopropylpyrazol-4-yl)-2-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one. The isomers were separated by chiral SFC (WHELK-O1250 mm × 30 mm, 10 µm, CO2, ethanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to give 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (7 mg, 7% yield) as the first eluting enantiomer, white solid, MS m / z: 492.1 [M+H]+, ESI pos. The following Examples 51 to 56 were prepared according to Examples 7 to 10 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily, the relative stereochemistry was determined by NMR. MS Ex. Structure Name Intermediates(ESI): m / z 9-(2,4-difluorophenyl)-7- [(4S,6S)-2,2-dimethyl-6- (1-methyl-6-oxo-3- 507.1 51 A2 and B14 pyridinyl)oxan-4-yl]-2,3- [M+H]+dimethylpyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)-7- [(4R,6R)-2,2-dimethyl-6- (1-methyl-6-oxo-3- 507.1 52 A2 and B14 pyridinyl)oxan-4-yl]-2,3- [M+H]+dimethylpyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2S,4R)- 2-(1-methyl-6-oxo- 480.2 53 pyridazin-3- A2 and B12 [M+H]+yl)tetrahydropyran-4- yl]pyrazino[1,2- a]pyrimidin-4-one 7-[(2S,4R)-2-(1- cyclopropyl-6-oxo- pyridazin-3- yl)tetrahydropyran-4-yl]- 506.3 54 A2 and B12 9-(2,4-difluorophenyl)- [M+H]+2,3-dimethyl- pyrazino[1,2-a]pyrimidin- 4-one 9-(2,4-difluorophenyl)-7- [(2S,4R)-2-(4,6-dimethyl- 5-oxo-pyrazin-2- 494.2 55 yl)tetrahydropyran-4-yl]- A2 and B15 [M+H]+2,3-dimethyl- pyrazino[1,2-a]pyrimidin- 4-one 9-(2,4-difluorophenyl)-7- [(2R,4S)-2-(4,6-dimethyl- 5-oxo-pyrazin-2- 494.2 56 yl)tetrahydropyran-4-yl]- A2 and B15 [M+H]+2,3-dimethyl- pyrazino[1,2-a]pyrimidin- 4-oneExample 57 and Example 587-[(2R,4S)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 7-[(2S,4R)-2-(2- cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl- pyrimido[1,2-b]pyridazin-4-one Step 1: 4-[9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7- yl]tetrahydropyran-2-carboxylic acid The title compound was prepared in analogy to Example 15 steps 1-3 from Intermediate A3 instead of Intermediate A4 in step 1, yellow solid, MS m / z: 416.1 [M+H]+, ESI pos. Step 2: 4-[9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7-yl]-N- methoxy-N-methyl-tetrahydropyran-2-carboxamide To a solution of 4-[9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7- yl]tetrahydropyran-2-carboxylic acid (460 mg, 1.11 mmol) in dimethylformamide (8 ml) was added N,N-diisopropylethylamine (572 mg, 4.43 mmol) and HATU (547 mg, 1.44 mmol), and the mixture was stirred for 30 min. To this solution N,O-dimethylhydroxylamine hydrochloride (162 mg, 1.66 mmol) was added and the reaction mixture was stirred at 20 °C for 2 h. The mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 µm, 100Å; mobile phase: water with 0.1% formic acid / acetonitrile, flow rate: 80 ml / min) to give 4-[9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin- 7-yl]-N-methoxy-N-methyl-tetrahydropyran-2-carboxamide (420 mg, 83% yield) as yellow solid, MS m / z: 459.2 [M+H]+, ESI pos. 4- A solution of ethynylmagnesium bromide (0.5 M in THF, 10 ml, 5.0 mmol) was purged with nitrogen three times and cooled to -70 °C. Then a solution of 4-[9-(2,4-difluorophenyl)-2,3- dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7-yl]-N-methoxy-N-methyl-tetrahydropyran-2- carboxamide (270 mg, 0.59 mmol) in tetrahydrofuran (0.5 ml) was added dropwise at -70 °C under nitrogen atmosphere. The mixture was warmed to 0 °C over 15 min, then stirred at 0 °C for 2 h. The reaction mixture was added dropwise to an aqueous ammonium chloride solution (30 ml), then it was extracted three times with ethyl acetate (20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 : 1 to 1 : 4) to afford 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-prop-2-ynoyltetrahydropyran-4- yl)pyrimido[1,2-b]pyridazin-4-one (200 mg, 80% yield) as yellow solid, MS m / z: 424.2 [M+H]+, ESI pos. Step 4: 7-[(2R,4S)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 7-[(2S,4R)-2-(2- cyclopropylpyrimidin-4-yl) pyrimido[1,2-b]pyridazin-4-one To a solution of 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-prop-2-ynoyltetrahydropyran-4- yl)pyrimido[1,2-b]pyridazin-4-one (180 mg, 0.43 mmol) in acetonitrile (5 ml) was added cyclopropanecarboximidamide hydrochloride (256 mg, 2.13 mmol) and sodium carbonate (450 mg, 4.25 mmol), and the mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (50 ml) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 µm; mobile phase water with 0.225% formic acid / acetonitrile, flow rate: 25 ml / min) to give racemic 7-[2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrimido[1,2-b]pyridazin-4-one. The enantiomers were separated by chiral SFC (column: Daicel CHIRALPAK IK, 250 mm x 25 mm, 10 µm; mobile phase CO2 and isopropanol / acetonitrile = 4:1 with 0.1% ammonium hydroxide) to give 7-[(2R,4S)-2-(2- cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl- pyrimido[1,2-b]pyridazin-4-one as the first eluting compound, yellow solid, MS m / z: 490.2 [M+H]+, ESI pos. and 7-[(2S,4R)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one as the second eluting compound, yellow solid, MS m / z: 490.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.Example 59 and Example 609-(2,4-difluorophenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(2,4- difluorophenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one The title compounds were prepared in analogy to Example 50 from Intermediate A2 instead of Intermediate A3 and Intermediate B3 instead of Intermediate B4 and a reaction temperature of 60 °C in step 1, light yellow solids, MS m / z: 479.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.Example 61 and Example 62 and Example 639-(2,4-difluorophenyl)-7-[(2R,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2- a]pyrimidin-4-one and 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(5-methoxy-1-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(2,4- difluorophenyl)-7-[(2S,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one Step 1: 9-(2,4-difluorophenyl)-7-[6-(5-methoxy-1-methyl-6-oxo-pyridazin-3-yl)-3,6-dihydro- 2H-pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one To a solution of 7-chloro-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (Intermediate A2, 400 mg, 1.24 mmol) in 1,4-dioxane (10 ml) and water (1 ml) were added 4- methoxy-2-methyl-6-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridazin-3-one (Intermediate B16, 603 mg, 1.49 mmol), sodium carbonate (395 mg, 3.73 mmol) and Xphos Pd G2 (98 mg, 0.12 mmol, 0.1 eq). The reaction mixture was stirred at 90°C for 2 h under nitrogen atmosphere, then it was cooled to room temperature. Ethyl acetate (40 ml) and water (40 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (60 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, ethyl acetate and 10% methanol) to give 9-(2,4- difluorophenyl)-7-[6-(5-methoxy-1-methyl-6-oxo-pyridazin-3-yl)-3,6-dihydro-2H-pyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (500 mg, 79% yield) as yellow solid, MS m / z: 508.2 [M+H]+, ESI pos. methoxy-1-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2- a]pyrimidin-4-one Palladium on charcoal (10%, 210 mg) was suspended in ethyl acetate (5 ml) at room temperature, then the air of the flask was exchanged with nitrogen three times. To this mixture were added 9-(2,4-difluorophenyl)-7-[6-(5-methoxy-1-methyl-6-oxo-pyridazin-3-yl)-3,6- dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (500 mg, 1.0 mmol), magnesium oxide (397 mg, 9.85 mmol) and triethylamine (0.16 ml, 1.18 mmol) in ethyl acetate (5 ml) and dimethylformamide (12 ml) at room temperature. The nitrogen in the flask was exchanged with hydrogen three times, then the mixture was stirred at 20 °C for 3 h at 103 kPa (15 Psi) of hydrogen. The reaction mixture was filtered under nitrogen and the filter cake was washed and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18150 x 25 mm 10 µm; mobile phase: water with 0.1% trifluoroacetic acid / acetonitrile, flow rate 60.00 ml / min) to give 9-(2,4-difluorophenyl)-7-[2-(5- methoxy-1-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2- a]pyrimidin-4-one (200 mg) as a mixture of diastereomers. The enantiomers were separated by chiral SFC (column: REGIS WHELK-O1250 mm x 30 mm, 10 µm; mobile phase CO2and isopropanol / acetonitrile = 4:1 with 0.1% ammonium hydroxide) to give 9-(2,4-difluorophenyl)- 7-[(2R,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one (3 mg, 1.5% yield) as first eluting compound, yellow solid, MS m / z: 510.2 [M+H]+, ESI pos., 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(5-methoxy-1-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (72 mg, 36% yield) as the second eluting compound, yellow solid, MS m / z: 510.2 [M+H]+, ESI pos. and 9- (2,4-difluorophenyl)-7-[(2S,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (73 mg, 35% yield) as third eluting compound, yellow solid, MS m / z: 510.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.The following Examples 64 to 69 were prepared according to Example 61 to 63 by starting fromthe indicated intermediates. The absolute stereochemistry was assigned arbitrarily; the relative stereochemistry was determined by NMR. MS Ex. Structure Name Intermediates(ESI): m / z 9-(2,4-difluorophenyl)-7- [(2R,4S)-2-(1,5-dimethyl- 6-oxo-pyridazin-3- 494.2 64 yl)tetrahydropyran-4-yl]- A2 and B17 [M+H]+2,3-dimethyl- pyrazino[1,2-a]pyrimidin- 4-one 9-(2,4-difluorophenyl)-7- [(2S,4R)-2-(1,5-dimethyl- 6-oxo-pyridazin-3- 494.2 yl)tetrahydropyran-4-yl]- A2 and B17 [M+H]+2,3-dimethyl- pyrazino[1,2-a]pyrimidin- 4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2R,4S)- 2-[(1S,6R)-4-methyl-5- oxo-3,4- 494.1 A2 and B18 diazabicyclo[4.1.0]hept-2- [M+H]+en-2-yl]tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2S,4R)- 2-[(1S,6R)-4-methyl-5- oxo-3,4- 494.1 A2 and B18 diazabicyclo[4.1.0]hept-2- [M+H]+en-2-yl]tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2R,4S)- 2-[(1R,6S)-4-methyl-5- oxo-3,4- 494.2 A2 and B18 diazabicyclo[4.1.0]hept-2- [M+H]+en-2-yl]tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one 9-(2,4-difluorophenyl)- 2,3-dimethyl-7-[(2S,4R)- 2-[(1R,6S)-4-methyl-5- oxo-3,4- 494.2 69 A2 and B18 diazabicyclo[4.1.0]hept-2- [M+H]+en-2-yl]tetrahydropyran- 4-yl]pyrazino[1,2- a]pyrimidin-4-one Reference Example 1: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one To a suspension of 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin- 4-one (Intermediate A6, 75 mg, 0.196 mmol) in 1,4-dioxane (2 ml) was added (2S)-2-(1- methylpyrazol-4-yl)morpholine (Intermediate B5, 39 mg, 0.235 mmol), cesium carbonate (192 mg, 0.589 mmol) at room temperature. The mixture was degassed with argon before tris(dibenzylideneacetone)dipalladium (9 mg, 0.0098 mmol, 0.05 eq) and Xantphos (11 mg, 0.0196 mmol, 0.10 eq) was added. The reaction mixture was stirred overnight at 100 °C, then it was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0-5%) to obtain the title compound (38 mg, 41% yield) as light yellow solid, MS m / z: 468.1 [M+H]+, ESI pos., absolute stereochemistry arbitrarily assigned.The following Reference Examples 2 to 5 were prepared in analogy to Reference Example 1 bystarting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily. MS Ref. Structure Name Intermediate(ESI): Ex. m / z 9-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-7- 466.2 2 [(3S)-3-(1-methylpyrazol-4- A6 and B6 [M+H]+yl)-1-piperidyl]pyrido[1,2- a]pyrimidin-4-one 9-(4-chloro-2-fluoro- phenyl)-7-[(3S)-4,4- difluoro-3-(1- 502.1 3 methylpyrazol-4-yl)-1- A6 and B7 [M+H]+piperidyl]-2,3-dimethyl- pyrido[1,2-a]pyrimidin-4- one 9-(4-chloro-2-fluoro- phenyl)-7-[(2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6- 508.2 4 A6 and B8 methyl-morpholin-4-yl]-2,3- [M+H]+dimethyl-pyrido[1,2- a]pyrimidin-4-one 9-(4-chloro-2-fluoro- phenyl)-2-methyl-7-[(2S)-2- 454.4 5 (1-methylpyrazol-4- A7 and B5 [M+H]+yl)morpholino]pyrido[1,2- a]pyrimidin-4-one Example 70 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 tabletActive ingredient 200 mgMicrocrystalline cellulose 155 mgCorn starch 25 mgTalc 25 mgHydroxypropylmethylcellulose 20 mg425 mg Example 71 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 capsuleActive ingredient 100.0 mgCorn starch 20.0 mgLactose 95.0 mgTalc 4.5 mgMagnesium stearate 0.5 mg220.0 mg

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is selected from the group consisting of O and CR5R6; R1is selected from the group consisting of C1-C6-alkyl and halo-C1-C6-alkyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H- pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin- 2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo- C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl- C1-C6-alkyl, C3-C10-cycloalkyl-C1-C6-alkoxy, C3-C10-cycloalkyloxy, 3- to 6- membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6- membered heterocyclyl-C1-C6-alkyl, 3- to 6-membered heterocyclyl-C1-C6- alkoxy and 3- to 6-membered heterocyclyloxy; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl;R4is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl; R4’is selected from the group consisting of hydrogen, halogen, and C1-C6-alkyl; R5and R6are each independently selected from the group consisting of hydrogen and halogen; R7is C1-C6-alkyl; and R8is selected from the group consisting of hydrogen, halogen, hydroxy, and C1- C6-alkyl; provided that said compound of formula (I) is not 7-[2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-9-(2, 4-difluorophenyl)-2,3-dimethyl-pyrazino[1,2- a]pyrimidin-4-one (II)2. or a pharmaceutically acceptable salt or a stereoisomer thereofThe compound offormula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1is N and X2is CH.

3. or a pharmaceutically acceptable salt or a stereoisomer thereofThe compound offormula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein A2is O.

4. The compound of formula (I) according to any one of claims 1 to 3, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is C1-C6- alkyl.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein R1is methyl.

6. The compound of formula (I) according to any one of claims 1 to 5, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is7. The compound of formula (I) according to any one of claims 1 to 6, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H- pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin- 2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, and C3-C10- cycloalkyl; and R3’is selected from the group consisting of hydrogen and C1-C6-alkyl.

8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H- pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin- 2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl.

9. The compound of formula (I) according to any one of claims 1 to 6, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, 1H-pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one are substituted with 1-2 substituents independently selectedfrom the group consisting of C1-C6-alkyl, C1-C6-alkoxy, and C3-C10- cycloalkyl; and R3’is selected from the group consisting of hydrogen and C1-C6-alkyl.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein: R3is selected from the group consisting of 1,2,4-oxadiazolyl, 1H-pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl.

11. The compound of formula (I) according to any one of claims 1 to 6, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of pyrazolyl, 1,2,4-oxadiazolyl, 1H- pyridin-2-one, and 1H-pyridazin-6-one, wherein said pyrazolyl, 1,2,4- oxadiazolyl, 1H-pyridin-2-one, and 1H-pyridazin-6-one are optionally substituted with 1-2 substituents independently selected from the group consisting of methyl and cyclopropyl; and R3’is selected from the group consisting of hydrogen and methyl.

12. The compound of formula (I) according to any one of claims 1 to 6, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

13. or a pharmaceutically acceptable salt or a stereoisomer thereofThe compound offormula (I) according to claim 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R3is selected from the group consisting of O O N NN N ; and14. The compound of formula (I) according to any one of claims 1 to 13, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of hydrogen, fluoro, and methyl.

15. The compound of formula (I) according to any one of claims 1 to 13, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of hydrogen and C1-C6-alkyl.

16. The compound of formula (I) according to any one of claims 1 to 13, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is selected from the group consisting of hydrogen and methyl.

17. The compound of formula (I) according to any one of claims 1 to 16, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R4’is selected from the group consisting of hydrogen and methyl.

18. The compound of formula (I) according to any one of claims 1 to 16, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R4’is hydrogen.

19. or a pharmaceutically acceptable salt or a stereoisomer thereofThe compound offormula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R7is methyl.

20. The compound of formula (I) according to claim 1, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8;A2is O; R1is C1-C6-alkyl; R2is selected from the group consisting of F N F F R3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H- pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin- 2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-oneare substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; R3’is selected from the group consisting of hydrogen and C1-C6-alkyl; R4is selected from the group consisting of hydrogen and C1-C6-alkyl; R4’is selected from the group consisting of hydrogen and C1-C6-alkyl; R7is C1-C6-alkyl; and R8is hydrogen.

21. The compound of formula (I) according to claim 1, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein: (i) X1is CH and X2is N; or (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is methyl; R2is selected from the group consisting of F N F FR3is selected from the group consisting of 1,2,4-oxadiazolyl, pyrazolyl, 1H- pyridin-2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H-pyrazin-2-one, wherein said 1,2,4-oxadiazolyl, pyrazolyl, 1H-pyridin- 2-one, 1H-pyridazin-6-one, 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-enyl, and 1H- pyrazin-2-one are substituted with 1-2 substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl;; R3’is selected from the group consisting of hydrogen and methyl; R4is selected from the group consisting of hydrogen and methyl; R4’is selected from the group consisting of hydrogen and methyl; R7is methyl; and R8is hydrogen.

22. The compound of formula (I) according to claim 1, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein: X1is N; X2is CH; A1is CR8; A2is O; R1is C1-C6-alkyl;; R3is selected from the group consisting of pyrazolyl and 1H-pyridin-2-one, wherein said pyrazolyl issubstituted with a C3-C10-cycloalkyl substituent; and wherein said 1H-pyridin-2-one is substituted with a substituent selected from the group consisting of C1-C6-alkyl and C3-C10-cycloalkyl; R3’is hydrogen; R4is selected from the group consisting of hydrogen and C1-C6-alkyl; R4’is hydrogen; R7is C1-C6-alkyl; and R8is hydrogen.

23. The compound of formula (I) according to claim 1, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein: X1is N; X2is CH; A1is CR8; A2is O; R1is methyl;R3’is hydrogen; R4is selected from the group consisting of hydrogen and methyl; R4’is hydrogen; R7is methyl; and R8is hydrogen.

24. The compound of formula (I) according to claim 1, or a pharmaceutically acceptablesalt or a stereoisomer thereof, wherein said compound of formula (I) is selected from the group consisting of: 4-[7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4- oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile;4-[7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4- oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 4-[2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4- oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxan-4-yl]-4- oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[7-[(2S,4R)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3-dimethyl-4- oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[7-[(2R,4S)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3-dimethyl-4- oxopyrazino[1,2-a]pyrimidin-9-yl]-3-fluorobenzonitrile; 4-[2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-4- oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-4- oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2R,4S)-2-(1-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- 4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2S,4R)-2-(1-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- 4-oxo-pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2S,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3- dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro-benzonitrile; 4-[7-[(2R,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3- dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-9-yl]-3-fluoro-benzonitrile; 7-[(2R,4S)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(2-keto-1-methyl-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(2-keto-1-methyl-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9-(2,4-difluorophenyl)- 2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-9-(2,4-difluorophenyl)- 2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4-difluorophenyl)- 2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4-difluorophenyl)- 2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 7-[rac-(2S,4S)-2-(1-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(5,5-difluorotetrahydropyran-2-yl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)-2-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S,6R)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4S,6R)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4R,6S)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R,6S)-2-methyl-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S,6R)-2-(1-cyclopropyl-6-oxo-3- pyridyl)-6-methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4S,6R)-2-(1-cyclopropyl-6-oxo-3- pyridyl)-6-methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4R,6S)-2-(1-cyclopropyl-6-oxo-3- pyridyl)-6-methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R,6S)-2-(1-cyclopropyl-6-oxo-3- pyridyl)-6-methyl-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-pyridazin- 3-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 7-[(4R,6R)-6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-9- (2,4-difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(4S,6S)-6-(1-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(4R,6R)-2,2-difluoro-6-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(4R,6R)-6-(1-cyclopropyl-6-oxo-3-pyridyl)- 2,2-difluoro-tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4- difluoropiperidino)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)-2-methyl-tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-7-[(4S,6S)-2,2-dimethyl-6-(1-methyl-6-oxo-3- pyridinyl)oxan-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(4R,6R)-2,2-dimethyl-6-(1-methyl-6-oxo-3- pyridinyl)oxan-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(4,6-dimethyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(4,6-dimethyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(5-methoxy-1-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2R,4S)-2-(1,5-dimethyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-7-[(2S,4R)-2-(1,5-dimethyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[(1S,6R)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2- a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[(1S,6R)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2- a]pyrimidin-4-one; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[(1R,6S)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2- a]pyrimidin-4-one; and9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[(1R,6S)-4-methyl-5-oxo-3,4- diazabicyclo[4.1.0]hept-2-en-2-yl]tetrahydropyran-4-yl]pyrazino[1,2- a]pyrimidin-4-one.

25. The compound of formula (I) according to any one of claims 1 to 24, or apharmaceutically acceptable salt or a stereoisomer thereof, for use as a therapeutically active substance.

26. A pharmaceutical composition comprising a compound of formula (I) according toany one of claims 1 to 24, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a therapeutically inert carrier.

27. A method of treating or preventing a condition associated with a loss of function ofhuman TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or a stereoisomer thereof, or the pharmaceutical composition according to claim 26.

28. The method according to claim 27, wherein said condition associated with a loss offunction of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

29. A compound according to any one of claims 1 to 24, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, or a pharmaceutical composition according to claim 26, for use in a method according to claim 27 or 28.

30. Use of a compound according to any one of claims 1 to 24, or of a pharmaceuticallyacceptable salt thereof, or of a pharmaceutical composition according to claim 26, in a method according to claim 27 or 28.

31. Use of a compound according to any one of claims 1 to 24, or of a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for use in a method according to claim 27 or 28.

32. The invention as described hereinbefore.

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