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

[0002] Case: P39641

[0003] TREM2 AGONISTS

[0004] Field of the Invention

[0005] 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.

[0006] Background of the Invention

[0007] 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.

[0008] Neurobiol. 2010, 41(2-3): 115-28, doi: 10.1007 / sl2035-010-8106-8).

[0009] 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.

[0010] 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 / nril 106). 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.

[0011] CNE / 29.08.2025 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 Ap 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 DAP 12, which results in recruitment of Syk kinase to activate downstream signaling molecules.

[0012] 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): 1023-103 l.e7, doi:

[0013] 10.1016 / j .neuron.2018.01.031; Keren-Shaul H. et al., Cell, 2017 Jun 15;169(7):1276-1290.el7. doi: 10.1016 / j. cell.2017.05.018).

[0014] 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 / sl3024-022-00588- 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. 2018 10;293(32): 12634-12646; doi: 10.1074 / jbc.RAl 18.002352). 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.

[0015] 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

[0016] 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.

[0017] 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

[0018] Definitions

[0019] 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.

[0020] The term “substituted” refers to the condition where one or more hydrogen atoms on a designated atom, moiety, or functional group are replaced with a non-hydrogen substituent. A group that is described as "optionally substituted" is understood to include both the unsubstituted form, i.e., where all available valencies are filled by hydrogen atoms, and any substituted form(s).

[0021] 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 (“Ci-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 nonlimiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl.

[0022] 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 (“Ci-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 nonlimiting example of alkoxy is methoxy.

[0023] 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).

[0024] The term “cycloalkyl” as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-io-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[l. l.l]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl. Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl, bicyclo[l. l.l]pentanyl, bicyclo[3.1.0]hexanyl and cyclohexyl.

[0025] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“Ce-Cio-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.

[0026] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 10 ring members, preferably 5 to 9 ring members, more preferably 5 to 6 ring members, wherein at least one ring in 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; l,2,4-oxadiazol-5-yl; pyridyl (e.g. 2- pyridyl); pyrazolyl (e.g. pyrazol-l-yl); triazolyl; tetrazolyl; pyrazinyl; and imidazolyl (e.g. imidazole-l-yl). Some preferred, yet non-limiting examples of heteroaryl include pyridyl and pyrazolyl.

[0027] 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.

[0028] 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.

[0029] The term “haloalkoxy” 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 halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 1,1- difluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0030] 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.

[0031] 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 “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.

[0032] 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.

[0033] 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 term "stereoisomer" refers to any compound that has the same molecular formula and sequence of bonded atoms as a compound of formula (I) but differs in the three-dimensional orientation of its atoms in space.

[0034] The abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2.

[0035] 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.

[0036] 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.

[0037] Compounds of the Invention

[0038] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0039] X1and X2are each independently selected from the group consisting of N and CH;

[0040] A1is selected from the group consisting of N and CR8;

[0041] A2is selected from the group consisting of O and CR5R6;

[0042] R1is selected from the group consisting of Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0043] R2is selected from Ce-Cio-aryl, 5- to 6-membered heteroaryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl, 5- to 6-membered heteroaryl and Cs-Cio-cycloalkyl are optionally substituted with 1-3 substituents independently selected from halogen, Ci- Ce-alkyl and halo-Ci-Ce-alkyl;

[0044] R3is selected from:

[0045] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0046] and

[0047] (ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, C3- Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6-membered heterocyclyl comprising 1-3 heteroatoms independently selected from

[0048] N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N,

[0049] O, and S, the remaining ring atoms being carbon;

[0050] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0051] R4is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl;

[0052] R4is selected from the group consisting of hydrogen, halogen, and Ci -Ce-alkyl; R5and R6are each independently selected from the group consisting of hydrogen and halogen; R7is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0053] R8is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce- alkyl; provided that when at least one of

[0054] R3and R8is not hydrogen.

[0055] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0056] X1and X2are each independently selected from the group consisting of N and CH;

[0057] A1is selected from the group consisting of N and CR8; A2is selected from the group consisting of O and CR5R6;

[0058] R1is selected from the group consisting of Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0059] R2is selected from:

[0060] R3is selected from:

[0061] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of and

[0062] (ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, C3- Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6-membered heterocyclyl comprising 1-3 heteroatoms independently selected from

[0063] N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N,

[0064] O, and S, the remaining ring atoms being carbon;

[0065] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0066] R4is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl;

[0067] R4is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl;

[0068] R5and R6are each independently selected from the group consisting of hydrogen and halogen;

[0069] R7is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0070] R8is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce- alkyl; provided that: (i) when and A1is CR8, at least one of R3and R8is not hydrogen; and hydrogen. In one embodiment, said compound of formula (I) is a compound of formula (la) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0071] X1and X2are each independently selected from the group consisting of N and CH;

[0072] A1is selected from the group consisting of N and CR8;

[0073] A2is selected from the group consisting of O and CR5R6;

[0074] R1is selected from the group consisting of Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0075] R2is selected from Ce-Cio-aryl, 5- to 6-membered heteroaryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl, 5- to 6-membered heteroaryl and Cs-Cio-cycloalkyl are optionally substituted with 1-3 substituents independently selected from halogen, Ci- Ce-alkyl and halo-Ci-Ce-alkyl;

[0076] R3is selected from:

[0077] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0078]

[0079] (ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, C3- Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6-membered heterocyclyl comprising 1-3 heteroatoms independently selected from

[0080] N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N,

[0081] O, and S, the remaining ring atoms being carbon;

[0082] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0083] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0084] R5and R6are each independently selected from the group consisting of hydrogen and halogen;

[0085] R7is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0086] R8is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce- alkyl; provided that when at least one of R3and

[0087] R8is not hydrogen.

[0088] In one embodiment, said compound of formula (I) is a compound of formula (lb) or (Ic) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A2, X1, X2, R1, R2,

[0089] R3, R3, R4, R4, R7, and R8are as defined herein.

[0090] In one embodiment, said compound of formula (I) is a compound of formula (Id) or (le) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A2, X1, X2, R1, R2, R3, R3, R4, R4, R7, and R8are as defined herein.

[0091] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0092] (i) X1is CH and X2is N; or

[0093] (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 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 stereoisomer thereof, wherein X1is N and X2is CH.

[0094] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0095] A1is selected from the group consisting of N and CR8;

[0096] A2is selected from the group consisting of O and CR5R6;

[0097] R5is halogen;

[0098] R6is halogen; and

[0099] R8is selected from the group consisting of hydrogen, halogen, and hydroxyl.

[0100] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0101] A1is selected from the group consisting of N and CR8;

[0102] A2is selected from the group consisting of O and CR5R6;

[0103] R5is fluoro;

[0104] R6is fluoro; and

[0105] R8is selected from the group consisting of hydrogen, fluoro, and hydroxyl.

[0106] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0107] A1is selected from the group consisting of N and CR8;

[0108] A2is O; and

[0109] R8is selected from the group consisting of hydrogen, halogen, and hydroxyl.

[0110] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0111] A1is selected from the group consisting of N and CR8;

[0112] A2is O; and

[0113] R8is selected from the group consisting of hydrogen, fluoro, and hydroxyl.

[0114] In a particularly preferred embodiment, the present invention provides a compound of formula

[0115] (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0116] A1is CR8;

[0117] A2is O; and R8is hydrogen.

[0118] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is Ci- Ce-alkyl.

[0119] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is methyl.

[0120] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and Cs-Cio-cycloalkyl are substituted with 1-3 substituents independently selected from halogen and halo-Ci-Ce-alkyl.

[0121] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected from phenyl, cyclohexyl and bicyclo[l. l.l]pentane, wherein said phenyl, cyclohexyl and bicyclo[l. l.l]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro and CHF2.

[0122] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is C3-C10- cycloalkyl substituted with 1-3 substituents independently selected from halogen and halo-Ci- Ce-alkyl.

[0123] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected from cyclohexyl and bicyclo[l .l. l]pentane, wherein said cyclohexyl and bicyclo[l. l.l]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro and CHF2.

[0124] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected from:

[0125]

[0126] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and Cs-Ce-cycloalkyl are substituted with 1-3 halogen substituents.

[0127] In a particularly preferred embodiment, the present invention provides a compound of formula

[0128] (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected from phenyl and cyclohexyl, wherein said phenyl and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro and chloro. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is C3- Ce-cycloalkyl substituted with 1-3 halogen substituents.

[0129] In a particularly preferred embodiment, the present invention provides a compound of formula

[0130] (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is cyclohexyl substituted with 1-3 fluoro substituents.

[0131] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected from: In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0132] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0133] (ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, C3-C10- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6- membered heterocyclyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon.

[0134] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0135] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0136]

[0137] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-2 substituents independently selected from Ci-

[0138] Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce- alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon.

[0139] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0140] wherein R3is optionally substituted with 1-2 substituents independently selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl.

[0141] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0142] wherein:

[0143] R3ais selected from hydrogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, C3-C10- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon; and

[0144] R3bis selected from hydrogen, Ci-Ce-alkyl, and Cs-Cio-cycloalkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0145]

[0146] R3ais selected from hydrogen, methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl; and

[0147] R3bis selected from hydrogen, methyl, and cyclopropyl.

[0148] In a preferred embodiment, the present invention provides a compound of formula (I) as cribbedbed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl.

[0149] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0150] wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl.

[0151] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3ais selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl.

[0152] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3ais selected from methyl and cyclopropyl.

[0153] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0154]

[0155] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0156]

[0157] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0158] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, provided that when R3is selected from:

[0159] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0160] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0161] (ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, C3-C10- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6- membered heterocyclyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is a 9- to 10- membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein said fused bicyclic heteroaryl is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce- alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6-membered heterocyclyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon.

[0162] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is a 9- membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon, wherein said fused bicyclic heteroaryl is optionally substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, C3-C10- cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci- Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon.

[0163] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is an unsubstituted 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon.

[0164] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is an unsubstituted 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon.

[0165] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0166] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0167] and

[0168] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce- alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3-C10- cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon.

[0169] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0170] wherein R3is optionally substituted with 1 substituent selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl.

[0171] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0172] wherein R3ais selected from hydrogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, C3- Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0173] wherein R3ais selected from hydrogen, methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-m ethyl.

[0174] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3ais selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl.

[0175] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3ais selected from methyl and cyclopropyl.

[0176] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: In a particularly preferred embodiment, the present invention provides a compound of formula

[0177] (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0178] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0179] (ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, C3-C10- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6- membered heterocyclyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0180] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0181] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-2 substituents independently selected from Ci- Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce- alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon.

[0182] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0183] wherein R3is optionally substituted with 1-2 substituents independently selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl.

[0184] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0185] wherein:

[0186] R3ais selected from hydrogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, C3-C10- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon; and

[0187] R3bis selected from hydrogen, Ci-Ce-alkyl, and Cs-Cio-cycloalkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0188]

[0189] R3ais selected from hydrogen, methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl; and

[0190] R3bis selected from hydrogen, methyl, and cyclopropyl.

[0191] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl.

[0192] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3ais selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: wherein R3ais selected from methyl and cyclopropyl.

[0193] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected

[0194]

[0195] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

[0196] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from the group consisting of hydrogen and methyl.

[0197] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is hydrogen.

[0198] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0199] R4is selected from the group consisting of hydrogen and halogen; and

[0200] R4is selected from the group consisting of hydrogen and halogen.

[0201] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0202] R4is selected from the group consisting of hydrogen, fluoro, and methyl; and

[0203] R4is selected from the group consisting of hydrogen, fluoro, and methyl.

[0204] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0205] R4is selected from the group consisting of hydrogen and fluoro; and

[0206] R4is selected from the group consisting of hydrogen and fluoro.

[0207] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0208] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and

[0209] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl.

[0210] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R4is selected from the group consisting of hydrogen and methyl; and

[0211] R4is selected from the group consisting of hydrogen and methyl.

[0212] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is halogen.

[0213] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is halogen.

[0214] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is fluoro.

[0215] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is fluoro.

[0216] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4and R4are both halogen.

[0217] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4and R4are both fluoro.

[0218] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is Ci-Ce-alkyl.

[0219] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is Ci-Ce-alkyl.

[0220] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is methyl.

[0221] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is methyl.

[0222] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4and R4are both Ci-Ce-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4and R4are both methyl.

[0223] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is hydrogen.

[0224] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4is hydrogen.

[0225] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4and R4are both hydrogen.

[0226] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7is Ci- Ce-alkyl.

[0227] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7is methyl.

[0228] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1and R7are both Ci-Ce-alkyl.

[0229] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1and R7are both methyl.

[0230] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0231] R3is selected from:

[0232] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0233] and

[0234] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-2 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, C3-C10- cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon;

[0235] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0236] R4is selected from the group consisting of hydrog and halogen; and

[0237] R4is selected from the group consisting of hydrog and halogen.

[0238] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0239] R3is selected from: wherein R3is optionally substituted with 1-2 substituents independently selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl- methyl;

[0240] R3is selected from the group consisting of hydrogen and methyl;

[0241] R4is selected from the group consisting of hydrogen and fluoro; and

[0242] R4is selected from the group consisting of hydrogen and fluoro. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0243] R3is selected from: wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl; and

[0244] R3, R4, and R4are all hydrogen.

[0245] In a particularly preferred embodiment, the present invention provides a compound of formula

[0246] (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0247] R3is selected from: wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl; and

[0248] R3, R4, and R4are all hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0249] R3is selected from:

[0250] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of and

[0251] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1 substituent selected from Ci-Ce-alkyl, Ci- Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3-

[0252] Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon;

[0253] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl; and R4is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0254] R3is selected from: wherein R3is optionally substituted with 1 substituent selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl;

[0255] R3is selected from the group consisting of hydrogen and methyl; and R4is hydrogen.

[0256] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl; and

[0257] R3and R4are both hydrogen.

[0258] In a particularly preferred embodiment, the present invention provides a compound of formula

[0259] (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0260] R3is selected from: wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl;

[0261] R3and R4are both hydrogen.

[0262] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0263] (i) X1is CH and X2is N; or

[0264] (ii) X1is N and X2is CH;

[0265] A1is selected from the group consisting of N and CR8;

[0266] A2is selected from the group consisting of O and CR5R6;

[0267] R1is Ci-Ce-alkyl;

[0268] R2is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and C3- Cio-cycloalkyl are substituted with 1-3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;

[0269] R3is selected from:

[0270] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group

[0271] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-2 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, C3-C10- cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon;

[0272] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0273] R4is selected from the group consisting of hydrogen and halogen;

[0274] R4is selected from the group consisting of hydrogen and halogen;

[0275] R5is halogen;

[0276] R6is halogen;

[0277] R7is Ci-Ce-alkyl; and

[0278] R8is selected from the group consisting of hydrogen, halogen, and hydroxyl.

[0279] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0280] (i) X1is CH and X2is N; or

[0281] (ii) X1is N and X2is CH;

[0282] A1is selected from the group consisting of N and CR8;

[0283] A2is selected from the group consisting of O and CR5R6; R1is methyl;

[0284] R2is selected from phenyl, cyclohexyl and bicyclofl .1. l]pentane, wherein said phenyl, cyclohexyl and bicyclofl .1.1 ]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro and CHF2;

[0285] R3is selected from: wherein R3is optionally substituted with 1-2 substituents independently selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl- methyl;

[0286] R3is selected from the group consisting of hydrogen and methyl;

[0287] R4is selected from the group consisting of hydrogen and fluoro; R4is selected from the group consisting of hydrogen and fluoro;

[0288] R5is fluoro;

[0289] R6is fluoro;

[0290] R7is methyl; and R8is selected from the group consisting of hydrogen, fluoro, and hydroxyl.

[0291] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0292] (i) X1is CH and X2is N; or

[0293] (ii) X1is N and X2is CH; A1is CR8; A2is O; R1is Ci-Ce-alkyl;

[0294] R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and C3-C6- cycloalkyl are substituted with 1-3 halogen substituents;

[0295] R3 wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl;

[0296] R3is hydrogen;

[0297] R4is hydrogen;

[0298] R4is hydrogen;

[0299] R7is Ci-Ce-alkyl; and

[0300] 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 stereoisomer thereof, wherein:

[0301] (i) X1is CH and X2is N; or

[0302] (ii) X1is N and X2is CH;

[0303] A1is CR8;

[0304] A2is O;

[0305] R1is methyl;

[0306] R2is selected from phenyl and cyclohexyl, wherein said phenyl and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro and chloro;

[0307] R3is selected from: wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl;

[0308] R3is hydrogen;

[0309] R4is hydrogen;

[0310] R4is hydrogen;

[0311] R7is methyl; and

[0312] R8is hydrogen.

[0313] In one embodiment, the present invention provides a compound of formula (la) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0314] (i) X1is CH and X2is N; or

[0315] (ii) X1is N and X2is CH;

[0316] A1is selected from the group consisting of N and CR8;

[0317] A2is O;

[0318] R1is Ci-Ce-alkyl; R2is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and C3- Cio-cycloalkyl are substituted with 1-3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;

[0319] R3is selected from:

[0320] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of and

[0321] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-

[0322] Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3- Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon;

[0323] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl; R4is hydrogen;

[0324] R7is Ci-Ce-alkyl; and

[0325] R8is selected from the group consisting of hydrogen, halogen, and hydroxyl.

[0326] In one embodiment, the present invention provides a compound of formula (la) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) X1is CH and X2is N; or

[0327] (ii) X1is N and X2is CH;

[0328] A1is selected from the group consisting of N and CR8;

[0329] A2is O;

[0330] R1is methyl;

[0331] R2is selected from phenyl, cyclohexyl and bicyclofl .1. l]pentane, wherein said phenyl, cyclohexyl and bicyclofl .1.1 ]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro and CHF2;

[0332] R3is selected from: wherein R3is optionally substituted with 1 substituent selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl;

[0333] R3is selected from the group consisting of hydrogen and methyl;

[0334] R4is hydrogen; R7is methyl; and

[0335] R8is selected from the group consisting of hydrogen, fluoro, and hydroxyl.

[0336] In a preferred embodiment, the present invention provides a compound of formula (la) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0337] (i) X1is CH and X2is N; or

[0338] (ii) X1is N and X2is CH;

[0339] A1is CR8;

[0340] A2is O;

[0341] R1is Ci-Ce-alkyl;

[0342] R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and C3-C6- cycloalkyl are substituted with 1-3 halogen substituents; wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl;

[0343] R3is hydrogen;

[0344] R4is hydrogen;

[0345] R7is Ci-Ce-alkyl; and

[0346] R8is hydrogen.

[0347] In a particularly preferred embodiment, the present invention provides a compound of formula (la) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0348] (i) X1is CH and X2is N; or

[0349] (ii) X1is N and X2is CH;

[0350] A1is CR8;

[0351] A2is O;

[0352] R1is methyl;

[0353] R2is selected from phenyl and cyclohexyl, wherein said phenyl and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro and chloro; R3is selected from: wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl;

[0354] R3is hydrogen;

[0355] R4is hydrogen;

[0356] R7is methyl; and

[0357] R8is hydrogen.

[0358] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0359] (i) X1is CH and X2is N; or (ii) X1is N and X2is CH;

[0360] A1is selected from the group consisting of N and CR8;

[0361] A2is selected from the group consisting of O and CR5R6;

[0362] R1is Ci-Ce-alkyl;

[0363] (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of

[0364]

[0365] (ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-2 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, C3-C10- cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon;

[0366] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0367] R4is selected from the group consisting of hydrogen and halogen;

[0368] R4is selected from the group consisting of hydrogen and halogen;

[0369] R5is halogen;

[0370] R6is halogen;

[0371] R7is Ci-Ce-alkyl; and

[0372] R8is selected from the group consisting of hydrogen, halogen, and hydroxyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0373] (i) X1is CH and X2is N; or

[0374] (ii) X1is N and X2is CH;

[0375] A1is selected from the group consisting of N and CR8;

[0376] A2is selected from the group consisting of O and CR5R6;

[0377] R1is methyl;

[0378] R2is selected from:

[0379] R3is selected from: wherein R3is optionally substituted with 1-2 substituents independently selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl- methyl;

[0380] R3is selected from the group consisting of hydrogen and methyl;

[0381] R4is selected from the group consisting of hydrogen and fluoro;

[0382] R4is selected from the group consisting of hydrogen and fluoro;

[0383] R5is fluoro;

[0384] R6is fluoro;

[0385] R7is methyl; and

[0386] R8is selected from the group consisting of hydrogen, fluoro, and hydroxyl.

[0387] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0388] (i) X1is CH and X2is N; or

[0389] (ii) X1is N and X2is CH;

[0390] A1is CR8;

[0391] A2is O;

[0392] R1is Ci-Ce-alkyl; wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl; R3is hydrogen;

[0393] R4is hydrogen;

[0394] R4is hydrogen;

[0395] R7is Ci-Ce-alkyl; and

[0396] R8is hydrogen.

[0397] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0398] (i) X1is CH and X2is N; or

[0399] (ii) X1is N and X2is CH;

[0400] A1is CR8;

[0401] A2is O;

[0402] R1is methyl; wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl;

[0403] R3is hydrogen;

[0404] R4is hydrogen;

[0405] R4is hydrogen;

[0406] R7is methyl; and

[0407] R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is selected from:

[0408] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(3-methyl-l,2,4-oxadiazol-5-yl)morpholin-

[0409] 4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0410] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(3-methyl-l,2,4-oxadiazol-5-yl)morpholin- 4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0411] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(3-methyl-l,2,4-oxadiazol-5-yl)morpholin- 4-yl]pyrazino[l,2-a]pyrimidin-4-one;

[0412] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0413] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0414] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0415] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(3-methyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0416] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(3-methyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0417] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(3-methyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0418] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0419] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0420] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0421] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0422] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0423] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one; 7-[(2S,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0424] 7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)oxan-4-yl]-9-[3-(difluoromethyl)-l- bicyclof 1.1.1 ]pentanyl]-2,3 -dimethylpyrimidof 1 ,2-b]pyridazin-4-one;

[0425] 7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)oxan-4-yl]-9-[3-(difluoromethyl)-l- bicyclof 1.1.1 ]pentanyl]-2, 3 -dimethylpyrimidof 1 ,2-b]pyridazin-4-one;

[0426] 9-(4-chloro-2,6-difluoro-phenyl)-7-[rac-(2R,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0427] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0428] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0429] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-hydroxy-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0430] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-hydroxy-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0431] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-fluoro-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0432] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-fluoro-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0433] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-fluoro-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0434] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-methyl-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0435] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2S,4S)-2-methyl-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0436] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0437] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0438] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-l,2,4-triazol-3-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0439] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-l,2,4-triazol-3-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclopropyl-l,2,4-triazol-3-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0440] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropyl-l,2,4-triazol-3-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0441] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0442] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0443] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-

[0444] 2.3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0445] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(2-methylpyrimidin-5-yl)tetrahydropyran-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0446] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0447] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methylpyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0448] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-methyl-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0449] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0450] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0451] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-

[0452] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0453] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one;

[0454] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one;

[0455] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0456] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0457] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0458] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0459] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-

[0460] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0461] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-

[0462] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0463] 9-(4,4-difluorocyclohexyl)-7-[rac-(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-

[0464] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0465] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0466] 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0467] 9-(4-chl oro-2, 6-difluoro-phenyl)-2, 3 -dimethyl-7- [(2R,4 S)-2-( 1 -methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0468] 9-(4-chl oro-2, 6-difluoro-phenyl)-2, 3 -dimethyl-7- [(2 S,4R)-2-( 1 -methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0469] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-3-yl)tetrahydropyran-4-yl]-

[0470] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0471] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-3-yl)tetrahydropyran-4-yl]-

[0472] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0473] 7-[(2R,4S)-2-(2-cyclopropylpyrimidin-5-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-

[0474] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0475] 7-[(2S,4R)-2-(2-cyclopropylpyrimidin-5-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-

[0476] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0477] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-cyclopropylpyrimidin-5-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0478] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-cyclopropylpyrimidin-5-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0479] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxopyridazin-3-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0480] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxopyridazin-3-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0481] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0482] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0483] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-methoxypyrazin-2-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0484] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-methoxypyrazin-2-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0485] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0486] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0487] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazinof 1 ,2-a]pyrimidin-4-one;

[0488] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0489] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0490] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0491] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one;

[0492] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one;

[0493] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0494] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0495] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0496] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrimido[l,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0497] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-lH-pyridin-4-yl)tetrahydropyran-4-yl]-

[0498] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0499] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-oxo-lH-pyridin-4-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0500] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-keto-lH-pyridin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0501] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0502] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0503] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0504] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2S,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0505] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0506] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0507] 2.3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0508] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0509] 2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0510] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0511] 2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0512] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0513] 2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0514] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(2-methylpyrimidin-4-yl)tetrahydropyran-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0515] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0516] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0517] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0518] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0519] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0520] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0521] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-methylpyrimidin-4-yl)tetrahydropyran-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0522] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0523] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0524] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0525] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0526] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-methylpyrimidin-4-yl)tetrahydropyran-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0527] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0528] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0529] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0530] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0531] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0532] 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0533] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0534] 2.3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0535] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0536] 2.3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0537] 7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-

[0538] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one; -n -

[0539] 7-[(2R,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-

[0540] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0541] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0542] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0543] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-

[0544] 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0545] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(4-pyrimidyl)tetrahydropyran-4-yl]pyrazino[l,2- a]pyrimidin-4-one;

[0546] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(4-pyrimidyl)tetrahydropyran-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0547] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-pyrimidyl)tetrahydropyran-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0548] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-(2,2-difluoroethoxy)-3-pyridyl]tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0549] 7-[(2R,4S)-2-[6-(cyclopropylmethoxy)-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0550] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[6-(2,2,2-trifluoroethoxy)-3- pyridyl]tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0551] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-isopropoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0552] 9-(4-chloro-2-fluoro-phenyl)-7-[2-[6-(2,2-difluoroethoxy)-3-pyridyl]tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0553] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[6-(2,2,2-trifluoroethoxy)-3- pyridyl]tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0554] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-isopropoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrimidof 1 ,2-b]pyridazin-4-one;

[0555] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-(2,2-difluoroethoxy)pyridin-3-yl]oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0556] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-(2,2-difluoroethoxy)pyridin-3-yl]oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0557] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[6-(2,2,2-trifluoroethoxy)pyridin-3- yl]oxan-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0558] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[6-(2,2,2-trifluoroethoxy)pyridin-3- yl]oxan-4-yl]pyrimido[l,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6-propan-2-yloxypyridin-3-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0559] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-propan-2-yloxypyridin-3-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0560] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclobutyl-2-oxopyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0561] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclobutyl-2-oxopyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0562] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[l-(cyclopropylmethyl)-2-oxopyridin-4-yl]oxan-4-yl]-

[0563] 2.3-dimethylpyrimido[l,2-b]pyridazin-4-one;

[0564] 7-[(2R,4S)-2-[l-(cyclopropylmethyl)-2-keto-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0565] 7-[(2S,4R)-2-[l-(cyclopropylmethyl)-2-keto-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0566] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[2-keto-l-(oxetan-3-ylmethyl)-4- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0567] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0568] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0569] 7-[(2S,4R)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4-difluorocyclohexyl)-2,3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one;

[0570] 7-[(2R,4S)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4-difluorocyclohexyl)-2,3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one;

[0571] 7-[(2R,4S)-2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-

[0572] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0573] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0574] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0575] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0576] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one; 9-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0577] 9-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0578] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(4-methyl-5-oxopyrazin-2-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0579] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-methyl-5-oxopyrazin-2-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0580] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-methyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0581] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(4-methyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0582] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxo-pyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0583] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-2-oxo-pyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0584] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(3-cyclopropyl-lH-l,2,4-triazol-5-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0585] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyridazin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0586] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0587] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-pyrazolo[l,5-a]pyrimidin-6- yltetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one; and

[0588] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-([l,2,4]triazolo[l,5-a]pyridin-6-yl)oxan- 4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one.

[0589] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is selected from: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0590] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0591] 9-(4-chl oro-2, 6-difluoro-phenyl)-2, 3 -dimethyl-7- [(2R,4 S)-2-( 1 -methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0592] 7-[(2R,4S)-2-(2-cyclopropylpyrimidin-5-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-

[0593] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0594] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxopyridazin-3-yl)oxan-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0595] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0596] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0597] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-

[0598] 2.3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0599] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0600] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0601] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0602] 7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-

[0603] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0604] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0605] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0606] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-methyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0607] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyridazin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0608] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-([l,2,4]triazolo[l,5-a]pyridin-6-yl)oxan- 4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0609] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0610] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0611] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0612] 9-[3 -(difluoromethyl)- 1 -bicyclof 1.1. l]pentanyl]-7-[(2S,4R)-2-(6-methoxypyridin-3-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;

[0613] 9-[3 -(difluoromethyl)- 1 -bicyclof 1.1. l]pentanyl]-7-[(2R,4S)-2-(6-methoxypyridin-3-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;

[0614] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(6-methoxy-3-pyridyl)-2-methyl-tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0615] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)-2-methyl-tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0616] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)-2-methyl-tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0617] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(2-methoxy-4-pyridyl)-2-methyl-tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0618] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)-2-methyl-tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0619] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)-2-methyl-tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0620] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0621] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-methyl-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0622] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0623] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-methyl-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0624] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;

[0625] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxypyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxypyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0626] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0627] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0628] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0629] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-2-methyl-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0630] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-2-methyl-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0631] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-5-methyl-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0632] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-5-methyl-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0633] 9-(4-chloro-2-fluoro-phenyl)-7-[(lR,3S)-4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexyl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0634] 9-(4-chloro-2-fluoro-phenyl)-7-[(lS,3R)-4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexyl]-2,3- dimethyl-pyrimidof 1 ,2-b]pyridazin-4-one;

[0635] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxypyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0636] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxypyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0637] 7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-l- bicyclof 1.1.1 ]pentanyl]-2, 3 -dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0638] 7-[(2S,4R)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-l- bicyclof 1.1.1 ]pentanyl]-2, 3 -dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;

[0639] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0640] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclopropyl-2-oxopyrimidin-5-yl)oxan-4-yl]-2,3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one;

[0641] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxopyrimidin-5-yl)oxan-4-yl]-2,3- dimethylpyrazinof 1 ,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-2-oxo-pyrimidin-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0642] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0643] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0644] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0645] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(4-methyl-5-oxopyrazin-2-yl)oxan-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0646] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-methyl-5-oxopyrazin-2-yl)oxan-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0647] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(4-cyclopropyl-5-oxopyrazin-2-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0648] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(4-cyclopropyl-5-oxopyrazin-2-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one;

[0649] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(4-cyclopropyl-5-oxo-pyrazin-2-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0650] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(4-cyclopropyl-5-oxo-pyrazin-2-yl)tetrahydropyran-

[0651] 4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0652] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0653] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0654] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0655] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;

[0656] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0657] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0658] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-l-methyl-pyridazin-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-l-methyl-pyridazin-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;

[0659] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-2-methyl-l,2,4-triazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0660] 9-(4,4-difhrorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-([l, 2, 4]tri azolof l,5-a]pyridin-7- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0661] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-([l, 2, 4]tri azolof l,5-a]pyridin-7- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0662] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(4R,6R)-2,2-difluoro-6-(l-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;

[0663] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyl-3-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0664] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyl-3-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0665] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0666] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;

[0667] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;

[0668] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(4-cyclopropylpyrimidin-2-yl)tetrahydropyran-4-yl]-

[0669] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one; and

[0670] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(4-cyclopropylpyrimidin-2-yl)tetrahydropyran-4-yl]-

[0671] 2.3-dimethyl-pyrimido[l,2-b]pyridazin-4-one.

[0672] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2- methylpyrimidin-5-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one.

[0673] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,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 stereoisomer thereof, wherein said compound of formula (I) is 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one.

[0674] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l- methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one.

[0675] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(2-cyclopropylpyrimidin-5-yl)tetrahydropyran-4- yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one.

[0676] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(l- methyl-6-oxopyridazin-3-yl)oxan-4-yl]pyrimido[l,2-b]pyridazin-4-one.

[0677] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l- methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one.

[0678] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l- methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one.

[0679] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one.

[0680] In a particularly preferred embodiment, the present invention provides a compound of formula

[0681] (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one.

[0682] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one.

[0683] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one.

[0684] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one.

[0685] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l- methyl-2-oxopyridin-4-yl)oxan-4-yl]pyrazino[l,2-a]pyrimidin-4-one;

[0686] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one.

[0687] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4- methyl-5-oxo-pyrazin-2-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one.

[0688] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6- methylpyridazin-4-yl)tetrahydropyran-4-yl]pyrazino[l,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 stereoisomer thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran- 4-yl]-9-[3-(difhioromethyl)-l-bicyclo[l. l.l]pentanyl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4- one.

[0689] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl- 2-oxo-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one.

[0690] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l- methyl-6-oxo-pyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one.

[0691] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6- oxo-pyridazin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one.

[0692] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-l-methyl- pyridazin-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one.

[0693] 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.

[0694] 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,nC,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate 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.

[0695] Substitution with heavier isotopes, such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention.

[0696] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron 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 nonlabeled reagent previously employed.

[0697] Processes of Manufacturing

[0698] 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.

[0699] 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).

[0700] 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 art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0701] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0702] 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.

[0703] 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.

[0704] The following abbreviations are used in the present text:

[0705] °C degrees Celsius

[0706] 'H proton

[0707] A angstrom

[0708] Aik alkyl c concentration

[0709] CAS Chemical Abstracts Service registry number

[0710] CH3CN acetonitrile

[0711] CO2 carbon dioxide

[0712] DIPEA N,N-Diisopropylethylamine

[0713] DMEM Dulbecco's modified eagle medium

[0714] DMF N,N-Dimethylformamide

[0715] DMSO dimethylsulfoxide

[0716] DMSO-d6 hexadeuterodimethyl sulfoxide

[0717] EC50 half maximal effective concentration eq equivalent

[0718] ESI electron spray ionization

[0719] Ex. example

[0720] FBS fetal bovine serum g gram g / L gram per liter h hour

[0721] HATU hexafluorophosphate azabenzotri azole tetramethyl uronium

[0722] HBTU hexafluorophosphate benzotriazole tetramethyl uronium

[0723] HCOOH formic acid

[0724] HEK human embryonic kidney HPLC high performance liquid chromatography

[0725] J coupling constant kg kilogram

[0726] M molar m / z mass-to-charge ratio

[0727] MeOH methanol mg milligram

[0728] MgSO4 magnesium sulfate

[0729] MHz megahertz min minute ml milliliter mm millimeter mmol millimole

[0730] MPLC medium pressure liquid chromatography

[0731] MS mass spectrometry

[0732] Na2SOs sodium sulfite

[0733] Na2SO4 sodium sulfate

[0734] NaHCCh sodium bicarbonate neg. negative

[0735] NH4CI ammonium chloride nm nanometer

[0736] NMR nuclear magnetic resonance spectroscopy pH potential of hydrogen pos. positive psi pounds per square inch

[0737] R Rectus according to the Cahn-Ingold-Prelog priority rules

[0738] RP reverse phase

[0739] RPM revolutions per minute s second

[0740] S Sinister according to the Cahn-Ingold-Prelog priority rules

[0741] SFC supercritical fluid chromatography

[0742] TLC thin layer chromatography pl microliter pm micrometer pmol micromoles

[0743] Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) aD specific rotation at 589 nm

[0744] 5 chemical shift in parts per million

[0745] Scheme 1

[0746] Compounds of general formula la and lb 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 (l,l'-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 V 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 la (nucleophilic substitution). In addition, compound IV can be reacted with amine V using palladium-catalysed coupling conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(O), a suitable ligand such as Xantphos and a base such as cesium carbonate or sodium tert.-butoxide to form compound la (metal-catalysed coupling). For the synthesis of C-linked derivatives lb, intermediate IV can either be directly reacted with an organozinc reagent VI using palladium-catalysed conditions, or first with boronic acid derivative VII using a palladium catalyst and a base to form intermediate VIII, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound lb. 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.

[0747] Scheme 2

[0748] IX

[0749] Y1, Y2= CI, Br, I R1, R7, X1, X2according to claim definition

[0750] Aik = alkyl chain like Me, Et Compounds of general formula II can be prepared as described in Scheme 2 by reacting heterocyclic compound IX with ketoester X in presence of an acid like polyphosphoric acid or a Lewis acid such as bismuth trichloride at elevated temperatures.

[0751] Scheme 3

[0752] YI, Y2= CI, Br, I R1, R2, R7and X1, X2according to claim definition

[0753] Aik = alkyl chain like Me, Et Furthermore compounds of general formula IV can be prepared as described in Scheme 3 by first reacting heterocyclic compound IX with a boronic acid (or a boronic acid derivative, R2is preferably aromatic or heteroaromatic) III under palladium catalysed coupling conditions (a palladium source such as (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound XI. This intermediate can then react with ketoester X 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

[0754] Furthermore, compounds of general formula lb can be prepared as described in Scheme 4 by reacting intermediate IV first with bis(pinacolato)diboron under palladium catalysed conditions (a palladium source such as (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound XII. This intermediate can be reacted with triflate XIII using a palladium catalyst and a base to form intermediate VIII, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound lb. Scheme 5

[0755] YI= CI, Br, I R1, R2, R7and

[0756] X1, X2according to claim definition

[0757] Aik = alkyl chain like Me, Et

[0758] Furthermore compounds of general formula IVa (R2is preferably cycloaliphatic) can be prepared as described in Scheme 5 by first reacting heterocyclic compound XIV with a carboxylic acid XV under oxidative coupling conditions (using for example ammonium persulfate in dimethylsulfoxide at temperatures of 0 °C to 50 °C, Minisci reaction) to form compound Xia. This intermediate can then react with ketoester X in presence of an acid like polyphosphoric acid or a Lewis acid such as bismuth trichloride at elevated temperatures to form compound IVa.

[0759] Scheme 6

[0760] Furthermore, compounds of general formula lb can be prepared as described in Scheme 6. Intermediate XII is first reacted with triflate XVI under palladium catalysed conditions (a palladium source such as (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound XVII. Likewise, intermediate IV can be reacted with bororic ester derivative XVIII under palladium catalysed conditions (a palladium source such as (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)- palladium(O) and a base such as cesium carbonate or sodium carbonate) to form as well compound XVII. In the next step this intermediate is reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound XIX. 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.

[0761] Scheme 7 , , , , , , an

[0762] A2, X1, X2according to claim definition Furthermore, compounds of general formula lb can be prepared as described in Scheme 7 by late stage modification of compound XX. Such transformations of residue R3’ 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, NH-pyrimidones and the like) and can be performed according to known conditions for related compounds published in the literature. Scheme 8

[0763] Furthermore, compounds of general formula Ic can be prepared as described in Scheme 8. Intermediate XII is first reacted with unsaturated lactone XXI under rhodium-catalysed conditions (for instance chloro(l,5-cyclooctadiene)rhodium(I) dimer and a base such as potassium phosphate) to form compound XXII which is further reacted with bistriflimide or 2- [N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine and a base to form vinyl triflate XXIII. Palladium catalysed coupling (using a palladium source such as bis(triphenyl- .phosphine)palladium(II) chloride and a base like cesium carbonate) of this intermediate with the corresponding boronic acid (or boronic acid derivative) XXIV leads to compound XXV which upon hydrogenation gives rise to compound Ic. Preferred hydrogenation 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.

[0764] Scheme 9

[0765] R1, R2, R3, R3', R4, R4', R7and

[0766] A2, X1, X2according to claim definition

[0767] Furthermore, compounds of general formula Id can be prepared by selerctive oxydation of Intermediate VIII using conditions like oxygen in presence of triethylsilane and a catalyst like cobalt(II) tetraphenylporphyrin. In addition, compounds of general formula le can be prepared by reaction of compound Id with a fluorination reagent like diethylaminosulfur trifluoride or morpholinosulfur trifluoride in a suitable solvent like dichloromethane.

[0768] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the process is as described in any one of schemes 1 to 9.

[0769] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, when manufactured according to any one of the processes described herein. TREM2 Agonistic Activity

[0770] 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.

[0771] 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.

[0772] 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.

[0773] 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.

[0774] 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.

[0775] 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 pL of DMEM media without Phenolred and supplemented with 5% FBS.

[0776] Compounds in dose response (1 :3) were diluted in DMSO (highest concentration lOmM) and added to the cells from a Low Dead Volume plate using the ECHO (0-20 uM), diluting 500x (20 nL in 10 pl cell suspension; highest concentration 20uM, DMSO concentration 0.2% in all wells). Neutral (DMSO) and stimulator (IpM tool compound) controls were also added.

[0777] Cells were incubated for 30 minutes at 37°C, 5% CO2 and 95% humidity. After compound addition and incubation, 2.5pL 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). ECso values were calculated by using Genedata Screener, normalized to DMSO and 100% activity to the tool compound.

[0778] 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.

[0779] Table 1

[0780] Table 2 the Compounds of the Invention

[0781] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, as described herein for use as a therapeutically active substance.

[0782] 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 stereoisomer thereof, or a pharmaceutical composition described herein.

[0783] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt or 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.

[0784] 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.

[0785] 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.

[0786] 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.

[0787] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease.

[0788] 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.

[0789] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis.

[0790] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease.

[0791] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia.

[0792] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis.

[0793] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease.

[0794] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke.

[0795] Pharmaceutical Compositions and Administration

[0796] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0797] In one embodiment, there is provided a pharmaceutical composition according to Example 230 or 231.

[0798] 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, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

[0799] 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, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0800] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0801] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0802] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0803] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0804] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosityincreasing 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.

[0805] 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.

[0806] 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.

[0807] 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.

[0808] 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.

[0809] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0810] 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.

[0811] The following intermediates were prepared according to the procedures provided herein, are commercially available or can be prepared according to literature procedures.

[0812] Intermediate Al 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[l,2- a]pyrimidin-4-one

[0813] 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[l,2-a]pyrimidin-4-one (1.0 g, 9% yield) as yellow solid. MS m / z: 290.0 [M+H]+, ESI pos.

[0814] Step 2: 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazinorE2-a]pyrimidin-4-one To a solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (290 mg, 1.01 mmol) in 1,4-di oxane (6 ml) was added (4-chloro-2-fluoro-phenyl)boronic acid (263 mg, 1.51 mmol) and aqueous cesium carbonate solution (1.51 ml, 3.02 mmol) at room temperature. The mixture was degassed with argon before l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (82 mg, 0.10 mmol, 0.10 eq) was added. The mixture was stirred for 3 h at 60 °C, then diluted with water and extracted two times with ethyl acetate. The combined organic layers were dried over MgSC and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) and the obtained material was triturated with methyl tert-butyl ether to obtain the title compound (177 mg, 49% yield) as yellow solid, MS m / z: 338.0 [M+H]+, ESI pos. Intermediate A2: 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[l,2- b]pyridazin-4-one

[0815] Step 1 : 6-chloro-4-(4-chloro-2-fluoro-phenyl)pyridazin-3 -amine

[0816] To a solution of 4-bromo-6-chloro-pyridazin-3-amine (CAS 446273-59-2, 1.00 g, 4.8 mmol) in 1,4-dioxane (20 ml) were added (4-chloro-2-fluoro-phenyl)boronic acid (836 mg, 4.8 mmol) and cesium carbonate (4.69 g, 14.4 mmol). The mixture was degased with argon, 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride di chloromethane (392 mg, 0.48 mmol, 0.10 eq) was added and the reaction mixture was stirred for 2 h at room temperature. The 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 to dryness. The residue was purified by flash chromatography (silica gel, dichloromethane / methanol 0-10%) to yield 6-chloro-4-(4-chloro-2-fluoro-phenyl)pyridazin-3 -amine as dark brown solid (852 mg, 69% yield), MS m / z: 258.0 [M+H]+, ESI pos.

[0817] Step 2: 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimidorE2-b]pyridazin-4-one

[0818] To a suspension of 6-chloro-4-(4-chloro-2-fluoro-phenyl)pyridazin-3-amine (100 mg, 0.388 mmol) in ethyl 2-methylacetoacetate (559 mg, 564 pl, 3.87 mmol) was added bismuth trichloride (12 mg, 0.038 mmol, 0.10 eq) at room temperature and the mixture was stirred for 16 h at 120 °C. The reaction mixture was diluted with saturated NaHCCh-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-50%) to yield the title compound as light yellow solid (62 mg, 43% yield), MS m / z: 338.1 [M+H]+, ESI pos. - I l l -

[0819] Intermediate A3: 7-chloro-9-(4-chl oro-2, 6-difluoro-phenyl)-2,3-dimethyl-pyrazino[ 1,2- a]pyrimidin-4-one

[0820] Step 1 : 5-chloro-3-(4-chloro-2,6-difluoro-phenyl)pyrazin-2-amine

[0821] In a glove box, to a solution of (3-bromo-5-chloro-pyrazin-2-yl)amine (500 mg, 2.4 mmol) in toluene (7.5 ml) was added (4-chloro-2,6-difluoro-phenyl)boronic acid (600 mg, 3.12 mmol) and diisopropyl ethylamine (930 mg, 7.2 mmol). The mixture was degassed with argon before chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (CAS 1334497-00-5, 48 mg, 0.12 mmol) was added and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate followed by five times with dichloromethane. The combined organic layers were dried over MgSC and concentrated to dryness. The crude material was purified by flash chromatography (C18, acetonitrile in water 10-100%) to yield 5- chloro-3-(4-chloro-2,6-difluoro-phenyl)pyrazin-2-amine as yellow solid (193 mg, 29% yield). MS m / z: 276.0 [M+H]+, ESI pos.

[0822] Step 2: 7-chloro-9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrazinolE2-a1pyrimidin-4-one

[0823] 5-Chloro-3-(4-chloro-2,6-difluoro-phenyl)pyrazin-2-amine (170 mg, 0.616 mmol), ethyl 2- methyl acetoacetate (888 mg, 897 pl, 6.16 mmol) and polyphosphoric acids (85 mg) were mixed at room temperature and 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 MgSC and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-50%). The obtained material was suspended with tert-butyl methyl ether and stirred for 5 min before filtering it off. The solids were washed with tert-butyl methyl ether, then dried in vacuum to obtain the title compound (156 mg, 71% yield) as yellow solid. MS m / z: 356.1 [M+H]+, ESI pos.

[0824] Intermediate A4: 7-chloro-9-(4-chl oro-2, 6-difluoro-phenyl)-2,3-dimethyl-pyrimido[ 1,2- b]pyridazin-4-one

[0825] Step 1 : 6-chloro-4-(4-chloro-2,6-difluoro-phenyl)pyridazin-3 -amine

[0826] To a solution of (4-bromo-6-chloro-pyridazin-3-yl)amine (491 mg, 2.36 mmol) in t-amyl alcohol (7.5 ml) was added (4-chloro-2,6-difluoro-phenyl)boronic acid (680 mg, 3.53 mmol) and diisopropyl ethylamine (913 mg, 7.07 mmol). The mixture was degassed with argon before PdC12(amphos) (CAS 887919-35-9, 250 mg, 0.15 mmol) was added and the mixture was stirred at 50 °C for 2.5 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate followed by five times with dichloromethane. The combined organic layers were dried over MgSC and concentrated to dryness. The crude material was purified by flash chromatography (Cl 8, acetonitrile in water 10-70%) to yield 6-chl oro-4-(4-chl oro-2, 6-difluoro- phenyl)pyridazin-3 -amine as light brown solid (214 mg, 33% yield). MS m / z: 276.1 [M+H]+, ESI pos.

[0827] Step 2: 7-chloro-9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrimidorE2-b]pyridazin-4-one

[0828] To a mixture of 6-chloro-4-(4-chloro-2,6-difluoro-phenyl)pyridazin-3-amine (210 mg, 0.76 mmol) and ethyl 2-methylacetoacetate (1.1 g, 1.11 ml, 7.61 mmol) was added bismuth trichloride (24 mg, 0.076 mmol, 0.10 eq) at room temperature and the mixture was stirred over night at 120 °C. The reaction mixture was diluted with saturated NaHCCh solution and extracted two times with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-40%) to obtain the title compound (152 mg, 55% yield) as brown solid, MS m / z: 356.1 [M+H]+, ESI pos. Intermediate A5: 7-chloro-9-[3-(difluoromethyl)-l-bicyclo[l .1. l]pentanyl]-2,3-dimethyl- pyrimidof 1 ,2-b]pyridazin-4-one

[0829] Step 1 : 6-chloro-4-r3-(difluoromethyl)-l-bicyclol 1.1. Hpentanyllpyridazin-3 -amine

[0830] To a solution of 3-amino-6-chloropyridazine (600 mg, 4.63 mmol) in 9 dimethylsulfoxide / water (600 / 1; 9 ml) was added 3 -(difluoromethyl)bicyclo[l.l. l]pentane-l -carboxylic acid (7.5 g, 46.3 mmol). The reaction mixture was degassed while bubbling nitrogen through it. A freshly prepared solution of ammonium persulfate (6.34 g, 27.79 mmol) in purged dimethylsulfoxide / water (600 / 1) was added under nitrogen and the mixture was stirred at 40 °C for 20 h. The reaction mixture was quenched with a saturated solution of NaHCCh , the pH was adjusted to 8-9 and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated to dryness. The residue was first purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 pm, mobile phase: water + 0.25% formic acid / acetonitrile 10-15%, flow rate 25 ml / min) to give a crude product which was purified further by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 : 1 to 1 : 1) to afford 6-chloro-4-[3-(difhioromethyl)-l-bicyclo[l.l. l]pentanyl]pyridazin-3-amine (190 mg, 17% yield) as light yellow solid, MS m / z: 246.1 [M+H]+, ESI pos.

[0831] 2 : 7-chl oro-9- 13 -(difluorom ethyl)- 1 -bi .1. |-2,3-dimethyl-pyrimido|T,2- in-4-one

[0832] To a solution of 6-chloro-4-[3-(difluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyridazin-3-amine (190 mg, 0.77 mmol) in toluene (5 ml) was added ethyl 2-methylacetoacetate (556 mg, 3.87 mmol) and p-toluene sulfonic acid (27 mg, 0.15 mmol) and the mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. The reaction mixture was poured into water (150 ml), neutralized with saturated sodium bicarbonate aqueous solution to pH=8, then extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to give the title compound (200 mg, 79% yield) as light yellow solid, MS m / z: 326.1 [M+H]+, ESI pos.

[0833] Intermediate A6: 7-chloro-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-

[0834] 4-one

[0835] The title compound was prepared in analogy to Intermediate A5 using 4,4-difluorocyclohexane carboxylic acid instead of 3-(trifluoromethyl)bicyclo[l .1. l]pentane-l -carboxylic acid in step 1).

[0836] Yellow solid, MS m / z: 328.1 [M+H]+, ESI pos.

[0837] Intermediate A7 : 7-bromo-9-(4,4-difluorocyclohexen- 1 -yl)-2,3-dimethyl-pyrazino[ 1 ,2- a]pyrimidin-4-one

[0838] Step 1 : 5-bromo-3-(4,4-difluorocyclohexen-l-yl)pyrazin-2-amine

[0839] To a suspension of 2-amino-3, 5 -dibromopyrazine (5.0 g, 19.77 mmol) and 2-(4,4- difluorocyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.83 g, 19.77 mmol) in 1,4-dioxane (50 ml) and water (5 ml) was added cesium carbonate (19.33 g, 59.31 mmol) and l,T-bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (0.81 g, 0.99 mmol, 0.05 eq). After degassing with nitrogen three times, the resulting mixture was stirred at 20 °C for 16 h under nitrogen atmosphere. Then the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3:1 to 1 : 1) to give 5-bromo-3-(4,4-difluorocyclohexen-l- yl)pyrazin-2-amine (3.8 g, 66% yield) as yellow solid, MS m / z: 289.9 / 291.9 [M+H]+, ESI pos.

[0840] Step 2: 7-bromo-9-(4,4-difluorocyclohexen-l-yl)-2,3-dimethyl-pyrazinorE2-a]pyrimidin-4-one

[0841] To a solution of 5-bromo-3-(4,4-difluorocyclohexen-l-yl)pyrazin-2-amine (3.8 g, 13.1 mmol) in toluene (40 mL) were added ethyl 2-methylacetoacetate (9.44 g, 65.49 mmol) and p- toluenesulfonic acid (451 mg, 2.62 mmol). The reaction mixture was stirred at 110 °C for 16 h with water separator under nitrogen. Then the reaction mixture was quenched with saturated sodium bicarbonate solution (40 ml) at room temperature and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (40 ml x 3), dried over Na2SO4 and concentrated in vacuum. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate = 1 :0 to 3 : 1) and the solid product was triturated with petroleum ether / ethyl acetate = 5: 1 (10 ml) for 10 min to give the title compound (2.5 g, 52% yield) as yellow solid, MS m / z: 370.0 / 372.0 [M+H]+, ESI pos.

[0842] Intermediate A8: 9-(4-chloro-2-fluoro-phenyl)-2, 3-dimethyl-7-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyrazino[ 1 ,2-a]pyrimidin-4-one To a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 4-one (Intermediate Al, 1.5 g, 4.44 mmol) in 1,4-dioxane (27 ml) were added under argon bis(pinacolato)diboron (1.35 g, 5.32 mmol), potassium acetate (1.31 g, 13.3 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (367 mg, 0.445 mmol, 0.10 eq). The reaction mixture was heated to 80 °C and stirred for 20 h. After cooling to room temperature the reaction mixture was filtered over Celite and washed with ethyl acetate. The filtrate was concentrated and purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to afford 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazino[l,2-a]pyrimidin-4-one (1.8 g, 85% yield) as orange oil.

[0843] Intermediate A9: 9-(4-chloro-2-fluoro-phenyl)-2, 3-dimethyl-7-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyrimido[l,2-b]pyridazin-4-one

[0844] To a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin- 4-one (Intermediate A2, 650 mg, 1.92 mmol) in 1,4-dioxane (10 ml) were added potassium acetate (755 mg, 7.69 mmol), bis(pinacolato)diboron (537 mg, 2.11 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride di chloromethane complex (157 mg, 0.19 mmol, 0.1 eq) at 20°C. Then the mixture was degassed by nitrogen three times, heated to 90 °C and stirred for 2 h. Due to an observed instability during purification attempts the reaction mixture was used directly in the next step.

[0845] Intermediate A10: 7-bromo-9-[3-(difluoromethyl)-l-bicyclo[l .1. l]pentanyl]-2,3-dimethyl- pyrazinof 1 ,2-a]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A5 using (5-bromopyrazin-2- yl)amine instead of 3-amino-6-chloropyridazine in step 1). Light yellow solid, MS m / z: 370.1 [M+H]+, ESI pos.

[0846] Intermediate All: 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[l,2-a]pyrimidin- 4-one

[0847] Step 1 : 7-bromo-9-iodo-2,3-dimethyl-pyridolL2-a1pyrimidin-4-one

[0848] A mixture of 5-bromo-3-iodo-pyridin-2-amine (CAS 381233-96-1, 2.0 g, 6.69 mmol), ethyl 2- methyl acetoacetate (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.

[0849] Step 2: 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyridolL2-a]pyrimidin-4-one

[0850] To a solution of 7-bromo-9-iodo-2,3-dimethyl-pyrido[l,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, l'-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.

[0851] Intermediate A12: 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2-methyl-pyrido[l,2-a]pyrimidin-4- one

[0852] The title compound was prepared in analogy to Intermediate Al 1 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.

[0853] Intermediate Bl: l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyrazole

[0854] Intermediate Bl is known, CAS 2738495-81-1.

[0855] Intermediate B2: [6-methyl-6-(l-methylpyrazol-4-yl)-2,3-dihydropyran-4-yl] trifluoromethanesulfonate

[0856] To a solution of l-(l-methylpyrazol-4-yl)ethanone (500 mg, 4.03 mmol) and 3-butyn-l-ol (436 mg, 0.475 pl, 6.04 mmol) in dichloromethane (10 ml) was added trifluoromethane sulfonic acid (1.81 g, 1.07 ml, 12.08 mmol) dropwise at -10 °C. After addition, the mixture was stirred for 30 min at -10 °C, then overnight at room temperature. The reaction mixture was diluted with saturated NaHCCh-solution and extracted two times with dichloromethane. The combined organic layers were dried over MgSCU and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, methanol in dichloromethane, 0-4%) to obtain [6- methyl-6-(l-methylpyrazol-4-yl)-2,3-dihydropyran-4-yl] trifluoromethanesulfonate (549 mg, 40% yield) as light yellow oil, MS m / z: 327.0 [M+H]+, ESI pos. Intermediate B3: l-methyl-4-[6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydropyran-6-yl]pyrazole

[0857] To a solution of [6-methyl-6-(l-methylpyrazol-4-yl)-2,3-dihydropyran-4-yl] trifluoromethanesulfonate (Intermediate B2, 620 mg, 1.9 mmol) in 1,4-dioxane (9 ml) was added bis(pinacolato)diboron (724 mg, 2.85 mmol) and potassium acetate (746 mg, 7.6 mmol) at room temperature. The mixture was degassed with argon before l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (155 mg, 0.190 mmol, 0.10 eq) was added and the mixture was stirred for 3 h at 90 °C. 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 MgSCU and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate, in heptane 0-80%) to obtain the title compound (587 mg, 90% yield) as light yellow oil, MS m / z: 305.2 [M+H]+, ESI pos.

[0858] Intermediate B4: 2-methyl-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyrimidine

[0859] Intermediate B4 is known, CAS 2738495-83-3, see WO2022236272,

[0860] Intermediate B5: 2-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]tri azole

[0861] Intermediate B5 is known, CAS 2864339-52-4, see WO2022236272.

[0862] Intermediate B6: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-

[0863] 2H-pyran-6-yl]pyridine Intermediate B6 is known, CAS 2864339-47-7, see WO2022236272.

[0864] Intermediate B7: [6-(l cyclopropyltri azol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[0865] To a suspension of l-cyclopropyl-lH-l,2,3-triazole-4-carboxylic acid (CAS 1188375-37-2, 4.0 g, 20.9 mmol) in dimethylformamide (40 ml) was added N,N-diisopropyl ethylamine (8.1 g, 62.7 mmol). After stirring under nitrogen at room temperature for 30 min, HATU (10.33 g, 27.16 mmol) was added and stirring was continued at room temperature for 1 h. The reaction was diluted with water (300 ml) and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex Luna, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.1% formic acid - acetonitrile, 0-35%, flow rate 60 ml / min) to give l-cyclopropyl-N-methoxy-N-methyl-triazole-4-carboxamide (3.7 g, 83% yield) as colorless oil. MS m / z: 197.0 [M+H]+, ESI pos.

[0866] :-4-carbaldehyde

[0867] To a solution of l-cyclopropyl-N-methoxy-N-methyl-triazole-4-carboxamide (3.3 g, 16.82 mmol) in dichloromethane (35 ml) was added diisobutylaluminium hydride (1 M in hexanes, 42.0 ml, 42.0 mmol) dropwise slowly at -70 °C under nitrogen atmosphere. After stirring the reaction mixture at -70 °C for 2 h, hydrochloric acid (1 M in water, 126 ml, 126 mmol) was added at -70 °C and the mixture was stirred for at 20 °C for 20 min, then diluted with water (20 ml) and extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with saturated sodium bicarbonate aqueous solution (30 ml), dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil that was used without further purification for the next step.

[0868] Step 3: r6-(l-cyclopropyltriazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[0869] To a solution of l-cyclopropyltriazole-4-carbaldehyde (1.32 g, 9.63 mmol) and 3-butyn-l-ol (1.01 g, 14.44 mmol) in dichloromethane (15 ml) was added dropwise trifluoromethane sulfonic acid (2.31 ml, 28.9 mmol) at -10 °C under nitrogen atmosphere and the mixture was stirred at - 10 °C for 2 h. Then the reaction mixture was poured into aqueous sodium hydrogencarbonate solution (50 ml) and extracted with dichloromethane (50 ml x 3). The combined organic layers were washed with brine (20 ml) and dried over ISfeSCU, then concentrated in vacuum. The residue was purified by preparative HPLC (column Phenomenex Luna, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%, flow rate 80 ml / min) to give [6-(l-cyclopropyltriazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (280 mg, 9% yield) as brown oil, MS m / z: 340.0 [M+H]+, ESI pos.

[0870] Intermediate B8: l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]tri azole

[0871] To a solution of [6-(l-cyclopropyltriazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (Intermediate B7, 150 mg, 0.442 mmol) in 1,4-di oxane (3 ml) was added bis(pinacolato)diboron (118 mg, 0.465 mmol), potassium acetate (130 mg, 1.33 mmol) and l,T-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (18 mg, 0.02 mmol, 0.05 eq). Then the mixture was degassed with nitrogen and stirred at 90 °C for 2 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 brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound (140 mg, 99% yield) as a brown oil, MS m / z: 318.2 [M+H]+, ESI pos.

[0872] Intermediate B9: [6-(l-cyclopropylpyrazol-3-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[0873] To a solution of l-cyclopropylpyrazole-3-carbaldehyde (CAS 1823349-88-7, 500 mg, 3.67 mmol) in dichloromethane (11.5 ml) was added 3-butyn-l-ol (398 mg, 0.433 ml, 5.51 mmol) at room temperature. After cooling the mixture to -10 °C, trifluoromethane sulfonic acid (1.65 g, 0.978 ml, 11.0 mmol) was added dropwise and the mixture was stirred for 30 min at -10°C, then overnight at room temperature. The reaction mixture was diluted with saturated NaHCCh solution and extracted two times with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 to 5% methanol in di chloromethane) to obtain the title compound (720 mg, 55% yield) as yellow oil. MS m / z: 339.1 [M+H]+, ESI pos.

[0874] Intermediate B10: l-cyclopropyl-3 [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyrazole Intermediate BIO was prepared in analogy to Intermediate B8 using Intermediate B9 instead of Intermediate B7, dark red oil, MS m / z: 317.2 [M+H]+, ESI pos.

[0875] Intermediate Bll: [6-(l-methyl-2-oxo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[0876] To a solution of 2-keto-l-methyl-isonicotinaldehyde (2.01 g, 14.65 mmol) in dichloromethane (75 ml) was added 3-butyn-l-ol (1.54 g, 1.67 ml, 22.0 mmol) at room temperature. The mixture was cooled to -10 °C and trifluoromethane sulfonic acid (6.6 g, 3.9 ml, 44.0 mmol) was added dropwise. The mixture was stirred at -10 °C for 30 min then for 4 h at room temperature. The reaction mixture was diluted with aqueous NaHCCh solution and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over ISfeSCU and concentrated to dryness to give the title compound (4.94 g, 70% purity, 70% yield) as a dark brown liquid. The crude material was used for the next step without additional purification. MS m / z: 340.2 [M+H]+, ESI pos.

[0877] Intermediate B12: l-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridin-2-one

[0878] To a solution of [6-(l-methyl-2-oxo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (Intermediate Bl 1, 4.94 g, 70% purity, 7.29 mmol) in 1,4-dioxane (54 ml) were added under argon bis(pinacolato)diboron (2.76 g, 10.85 mmol) and potassium acetate (2.21 g, 22.5 mmol) at room temperature. Then l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (603 mg, 0.729 mmol) was added and the mixture was stirred at 90°C for 6 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 0 to 10% methanol in dichloromethane) to give the title compound (1.5 g, 65% yield) as a light yellow solid, MS m / z: 318.2 [M+H]+, ESI pos.

[0879] Intermediate B13: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridine

[0880] To a solution of 2-methoxyisonicotinaldehyde (1.0 g, 7.29 mmol) in dichloromethane (10 ml) was added at 3-butyn-l-ol (767 mg, 0.833 ml, 10.94 mmol) under argon. Then the mixture was cooled to -10 °C 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 NaHCCh-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over ISfeSCU 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.

[0881] Step 2: 2-methoxy-4-14-(4,4,5,5-tetramethyl-E3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yllpyridine

[0882] 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 l,l'-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 Na2SO4 and 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-l,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.

[0883] Intermediate B14: 2-cyclopropyl-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyrimidine Intermediate B14 was prepared in analogy to Intermediate B13 using 2-cyclopropylpyrimidine-

[0884] 5-carbaldehyde instead of 2-methoxyisonicotinaldehyde, yellow oil, MS m / z: 329.2 [M+H]+, ESI pos.

[0885] Intermediate B15: 2-methyl-6-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridazin-3-one

[0886] Intermediate B15 was prepared in analogy to Intermediate B13 using l-methyl-6-oxo- pyridazine-3-carbaldehyde instead of 2-methoxyisonicotinaldehyde, off-white solid, MS m / z: 319.2 [M+H]+, ESI pos. Intermediate B16: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyrazine

[0887] Intermediate B16 was prepared in analogy to Intermediate B13 using 5-methoxypyrazine-2- carbaldehyde instead of 2-methoxyisonicotinaldehyde, light yellow solid, MS m / z: 319.2 [M+H]+, ESI pos.

[0888] Intermediate B17: l-methyl-5-[6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydropyran-6-yl]pyridin-2-one

[0889] Intermediate B17 was prepared in analogy to Intermediate B13 using 5-acetyl-l-methyl-pyridin- 2-one instead of 2-methoxyisonicotinaldehyde, yellow oil, MS m / z: 332.2 [M+H]+, ESI pos.

[0890] Intermediate B18: l-methyl-4-[6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydropyran-6-yl]pyridin-2-one

[0891] Intermediate B18 was prepared in analogy to Intermediate B13 using 4-acetyl-l-methyl-pyridin- 2-one instead of 2-methoxyisonicotinaldehyde, yellow oil, MS m / z: 332.2 [M+H]+, ESI pos.

[0892] Intermediate B19: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyrimidine

[0893] Intermediate B16 was prepared in analogy to Intermediate B13 using 2-methoxypyrimidine-5- carbaldehyde instead of 2-methoxyisonicotinaldehyde, brown oil, MS m / z: 319.2 [M+H]+, ESI pos. Intermediate B20: [6-(l-cyclopropylpyrazol-4-yl)-6-methyl-2,3-dihydropyran-4-yl] trifluoromethanesulfonate

[0894] To a solution of l-(l-cyclopropylpyrazol-4-yl)ethanone (CAS 1784673-98-8, 5.35 g, 35.6 mmol) and 3-butyn-l-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 NaHCCh-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 MgSCU and concentrated to dryness. The crude material was purified by preparative HPLC (column: Phenomenex Luna Cl 8 250 x 100 mm x 10 pm, mobile phase: water / 0.25% formic acid - acetonitrile, 0-100%, flow rate 260 ml / min) to give [6-(l-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.

[0895] Intermediate B21: (+)- 2-(l-methylpyrazol-4-yl)morpholine

[0896] 2-(l-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-(l- methylpyrazol-4-yl)morpholine (+)-Cl as the first eluting enantiomer and (-)- 2-(l- methylpyrazol-4-yl)morpholine (-)-Cl as the second eluting enantiomer. (+)- 2-(l- methylpyrazol-4-yl)morpholine: yellow oil, aD(589nm) 20 °C = +13.36° (c = 0.1 g / 1, MeOH). Intermediate B25: 6-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyrazolo[l,5-a]pyrimidine

[0897] Intermediate B25 was prepared in analogy to Intermediate B13 using pyrazolo[l,5-a]pyrimidine- 6-carbaldehyde instead of 2-methoxyisonicotinaldehyde, light yellow liquid, MS m / z: 328.0 [M+H]+, ESI pos.

[0898] Intermediate B26: 6-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]-[l,2,4]triazolo[l,5-a]pyridine Intermediate B26 was prepared in analogy to Intermediate B13 using [l,2,4]triazolo[l,5- a]pyridine-6-carbaldehyde instead of 2-methoxyisonicotinaldehyde, light yellow liquid, MS m / z: 328.3 [M+H]+, ESI pos.

[0899] Intermediate B27: 2-methoxy-5-[6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydropyran-6-yl]pyridine

[0900] Intermediate B27 was prepared in analogy to Intermediate B13 using l-(6-methoxy-3- pyridyl)ethanone (CAS 213193-32-9) instead of 2-methoxyisonicotinaldehyde in step 1, yellow solid, MS m / z: 332.1 [M+H]+, ESI pos. Intermediate B28: 2-methoxy-4-[6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydropyran-6-yl]pyridine

[0901] Intermediate B28 was prepared in analogy to Intermediate B13 using l-(2-methoxy-4- pyridyl)ethenone (CAS 764708-20-5) instead of 2-methoxyisonicotinaldehyde in step 1, yellow solid, MS m / z: 332.1 [M+H]+, ESI pos.

[0902] Intermediate B29: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyrimidine Intermediate B29 was prepared in analogy to Intermediate B13 using 2-methoxypyrimidine-4- carbaldehyde (CAS 164738-44-7) instead of 2-methoxyisonicotinaldehyde in step 1, brown oil, MS m / z: 319.1 [M+H]+, ESI pos.

[0903] Intermediate B30: 6-methoxy-2-methyl-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyridine

[0904] Intermediate B30 was prepared in analogy to Intermediate B13 using 6-methoxy-2-methyl- nicotinaldehyde (CAS 156094-77-8) instead of 2-methoxyisonicotinaldehyde, brown oil, MS m / z: 332.2 [M+H]+, ESI pos. Intermediate B31: 2-methoxy-3-methyl-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyridine

[0905] Intermediate B31 was prepared in analogy to Intermediate B13 using 6-methoxy-5-methyl- nicotinaldehyde (CAS 123506-67-2) instead of 2-methoxyisonicotinaldehyde, brown oil, MS m / z: 332.2 [M+H]+, ESI pos.

[0906] Intermediate B32: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyrimidine Intermediate B32 was prepared in analogy to Intermediate B13 using 2-methoxypyrimidine-5- carbaldehyde (CAS 90905-32-1) instead of 2-methoxyisonicotinaldehyde, brown oil, MS m / z: 319.2 [M+H]+, ESI pos.

[0907] Intermediate B33: 4-methoxy-6-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyrimidine

[0908] Intermediate B33 was prepared in analogy to Intermediate B13 using 6-methoxypyrimidine-4- carbaldehyde (CAS 1780366-57-5) instead of 2-methoxyisonicotinaldehyde in step 1, brown oil, MS m / z: 319.2 [M+H]+, ESI pos. Intermediate B34: 2-methoxy-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-

[0909] 2H-pyran-6-yl]pyridine

[0910] Intermediate B34 was prepared in analogy to Intermediate B13 using 2-methoxy-3- pyridinecarboxaldehyde (CAS 71255-09-9) instead of 2-methoxyisonicotinaldehyde in step 1, white solid, MS m / z: 318.1 [M+H]+, ESI pos.

[0911] Intermediate B35: 2-methoxy-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyrazine Intermediate B35 was prepared in analogy to Intermediate B13 using 5-methoxypyrazine-2- carbaldehyde (CAS 32205-72-4) instead of 2-methoxyisonicotinaldehyde, yellow solid, MS m / z: 319.2 [M+H]+, ESI pos.

[0912] Intermediate B36: 5-[6,6-difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-2- en-l-yl]-2-methoxy-pyridine

[0913] Step 1: 7-(6-methoxy-3-pyridyl)-E4-dioxaspirol4.51decan-8-one

[0914] To a solution of sodium tert-butoxide (38.5 g, 400 mmol) in tetrahydrofuran (380 ml) were added l,4-dioxaspiro[4.5]decan-8-one (25.0 g, 160 mmol) and 5-bromo-2-methoxypyridine (30.1 g, 160 mmol). After 5 min, tri-tert-butylphosphine (37.6 ml, 16.0 mmol) and palladium(II)- acetate (3.59 g, 16.0 mmol) were added to the reaction mixture. The air of the flask was changed to nitrogen and the mixture was stitrred for 16 h at 42°C. The reaction mixture was poured into water (2 1), then extracted with ethyl acetate (1 1 x 3), the organic phase was washed with saturated brine (100 ml x 3) and the combined organic phases were dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 1 :0 to 0: 1) to give 7-(6-methoxy-3-pyridyl)-l,4- dioxaspiro[4.5]decan-8-one (15.0 g, 36% yield) as yellow solid, MS m / z: 264.0 [M+H]+, ESI pos.

[0915] Step 2: 5-(8,8-difluoro-E4-dioxaspirol4.51decan-7-yl)-2-methoxy-pyridine

[0916] To a solution of 7-(6-methoxy-3-pyridyl)-l,4-dioxaspiro[4.5]decan-8-one (14.0 g, 53.2 mmol) in dichloromethane (140 ml) was added dropwise diethylaminosulfur trifluoride (13.2 ml, 106 mmol) at 0 °C and the mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated NaHCCh solution (500 ml) at 0 °C, then extracted with ethyl acetate (100 ml x 3), and the combined organic layers were washed with saturated brine (100 ml x 3), dried over Na2SO4, then concentrated under vacuum. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate = 1 :0 to 3: 1) to give 5-(8,8-difluoro-l,4-dioxaspiro[4.5]decan-7- yl)-2-methoxy-pyridine (12.0 g, 79% yield) as yellow solid, MS m / z: 286.1 [M+H]+, ESI pos.

[0917] Step 3: 4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexanone

[0918] To a solution of 5-(8,8-difluoro-l,4-dioxaspiro[4.5]decan-7-yl)-2-methoxy-pyridine (12.0 g, 42.0 mmol) in tetrahydrofiiran (88 ml) was added hydrochloric acid (1 M, 87.8 ml, 87.8 mmol) and the reaction mixture was stirred at 50 °C for 16 h. Water (500 ml) was added dropwise at room temperature to the mixture, then the pH was changed to 6~7 by careful addition of saturated NaHCCh solution. The mixture was extracted with ethyl acetate (500 ml x 3), and the combined organic layers were washed with brine (300 ml x 3), dried over ISfeSCU and concentrated in vacuum. The residue was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 1 :0 to 3: 1) to give 4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexanone (1.1 g, 10% yield) as yellow oil, MS m / z: 242.2 [M+H]+, ESI pos. y-3-pyridyl)cyclohexen-l-yl] trifluoromethanesulfonate

[0919] To a solution of 4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexanone (3.0 g, 12.4 mmol) in tetrahydrofuran (30 ml) was added lithium hexamethyldisilazide solution (1 M in THF, 16.2 ml, 16.2 mmol) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 0.5 h, then a solution of N,N-bis(trifluoromethylsulfonyl)aniline (4.89 g, 13.7 mmol) in tetrahydrofuran (10 ml) was added dropwise and the mixture was stirred at -78°C for 0.5 h, then at 25°C for 16 h. The reaction mixture was quenched with water (200 ml), the aqueous layer was separated and extracted with dichloromethane (100 ml x 3). The combined organic layers were washed with brine (100 ml x 2), dried over ISfeSCU and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 1 :0 to 5: 1) to give [4,4- difluoro-3-(6-methoxy-3-pyridyl)cyclohexen-l-yl] trifluoromethanesulfonate (2.6 g, 56% yield) as yellow oil, MS m / z: 374.0 [M+H]+, ESI pos. Step 5: 5-r6,6-difluoro-3-(4A5,5-tetramethyl-l J,2-dioxaborolan-2-yl)cyclohex-2-en-l-yl1-2- methoxy -pyridine

[0920] To a solution of [4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexen-l-yl] trifluoromethane- sulfonate (2.6 g, 7.0 mmol) in 1,4-dioxane (40 ml) were added bis(pinacolato)diboron (2.12 g, 8.4 mmol), potassium acetate (2.05 g, 20.9 mmol) and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (568 mg, 0.7 mmol, 0.1 eq) and the mixture was stirred at 90 °C for 1 h. The reaction mixture was poured into water (20 ml), and then extracted with ethyl acetate (20 ml x 3), the combined organic layers were washed with saturated brine (20 ml x 3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 1 :0 to 5: 1) to give the title compound (2.1 g, 77% yield) as colorless gum, MS m / z: 352.1 [M+H]+, ESI pos.

[0921] Intermediate B37: l-cyclopropyl-4-[6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 2,3-dihydropyran-6-yl]pyrazole

[0922] Intermediate B37 was prepared in analogy to Intermediate B12 using Intermediate B20 instead of Intermediate Bl 1, light yellow solid, MS m / z: 331.1 [M+H]+, ESI pos.

[0923] Intermediate B38: 3-methoxy-6-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-

[0924] 2H-pyran-6-yl]pyridazine

[0925] Intermediate B38 was prepared in analogy to Intermediate B13 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 B39: 7-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]-[l,2,4]triazolo[l,5-a]pyridine

[0926] Intermediate B39 was prepared in analogy to Intermediate B13 using [l,2,4]triazolo[l,5- a]pyridine-7-carbaldehyde instead of 2-methoxyisonicotinaldehyde, light yellow liquid, MS m / z: 328.3 [M+H]+, ESI pos.

[0927] Intermediate B40: 2-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyridazin-3-one A mixture of 5-methyl-lH-pyridazin-6-one (5.0 g, 45.4 mmol), copper diacetate (9.07 g, 50 mmol), cyclopropylboronic acid (7.8 g, 90.8 mmol), sodium carbonate (9.62 g, 90.8 mmol) and [2,2]bipyridinyl (7.8 g, 50 mmol) in 1,2-dichloroethane (130 ml) was stirred at 70 °C for 2 h under oxygen atmosphere (15 Psi). The reaction mixture was poured into water (200 ml), extracted with dichloromethane (80 ml x 3). The combined organic layers were washed with brine (20 ml) and dried over ISfeSCU, then concentrated in vacuum. The residue was purified by preparative HPLC (column: YMC-Gel SiL-HG 250 x 70mm x 10 pm, ethanol in hexane 0-20%) to give 2-cyclopropyl-4-methyl-pyridazin-3-one (5.8 g, 85% yield) as yellow solid, MS m / z: 151.1 [M+H]+, ESI pos.

[0928] Step 2: 4-(bromomethyl)-2-cyclopropyl-pyridazin-3-one

[0929] To a solution of 2-cyclopropyl-4-methyl-pyridazin-3-one (5.8 g, 38.62 mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide (20.62 g, 115.8 mmol) and dibenzoylperoxide (936 mg, 3.86 mmol). The reaction mixture was stirred at 80 °C for 16 h, then it was poured into water (200 ml), and then extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 3), dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether : ethyl acetate = 1 :0 to 3: 1) to give 2-cyclopropyl-4- (dibromomethyl)pyridazin-3-one (2.5 g, 12% yield) as green solid and 4-(bromomethyl)-2- cyclopropyl-pyridazin-3-one (1.2 g, 13.5% yield) as green solid, MS m / z: 229.0; 231.0 [M+H]+, ESI pos.

[0930] Step 3: 2-cyclopropyl-3-oxo-pyridazine-4-carbaldehyde

[0931] 4-(Bromomethyl)-2-cyclopropyl-pyridazin-3-one (560 mg, 2.44 mmol) and N-methylmorpholine

[0932] N-oxide (1.15 g, 9.78 mmol) were placed in a flask. The air of the flask was replaced with nitrogen, and acetonitrile (10 ml) was added to the flask at 0 °C. The reaction mixture was stirred for 5 min at 0 °C, then warmed to 20 °C and stirred for 16 h. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 3), 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 2-cyclopropyl-3-oxo-pyridazine-4-carbaldehyde (290 mg, 73% yield) as a yellow solid, MS m / z: 165.1 [M+H]+, ESI pos.

[0933] Step 4: r6-(2-cyclopropyl-3-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[0934] To a solution of 2-cyclopropyl-3-oxo-pyridazine-4-carbaldehyde (290 mg, 1.77 mmol) in dichloromethane (5 ml) was added 3-butyn-l-ol (149 mg, 2.12 mmol), then the mixture was degassed with nitrogen three times and cooled to -10 °C. Trifluoromethanesulfonic acid (0.47 ml, 5.3 mmol) was added dropwise under nitrogen and the mixture was stirred at -10 °C for 2 h. The reaction mixture was poured into saturated NaHCCh solution (20 ml) and then extracted with di chloromethane (20 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 3) and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by preparative HPLC (column: spherical Cl 8 20-45 mm 100A 80g, mobile phase: water / acetonitrile 0-100%). The solution was concentrated to remove acetonitrile and extracted with dichloromethane (100 ml x 3). The combined organic layers were washed with brine (50 ml x 3), dried over Na2SO4 and concentrated in vacuum at 10 °C to give [6-(2- cyclopropyl-3-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (328 mg, 43% yield) as yellow oil, MS m / z: 367.2 [M+H]+, ESI pos.

[0935] Step 5: 2-cyclopropyl-4-r4-(4A5,5-tetramethyl-E3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran- 6-yl]pyridazin-3-one

[0936] To a solution of [6-(2-cyclopropyl-3-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (328 mg, 0.895 mmol) in 1,4-dioxane (2 mL) were added bis(pinacolato)diboron (232 mg, 0.917), potassium acetate (224 mg, 2.28 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride di chloromethane complex (62 mg, 0.076 mmol, 0.1 eq). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was poured into water (20 ml), then extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with saturated brine (20 mL x 3), 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 the title compound (199 mg, 61% yield) as colorless oil, MS m / z: 345.1 [M+H]+, ESI pos.

[0937] Intermediate B41: 2-methyl-5-[4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyridazin-3-one Step 1 : r6-(l-methyl-6-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] tri fluoromethanesulfonate

[0938] To a solution of l-methyl-6-oxo-pyridazine-4-carbaldehyde (6.0 g, 43.4 mmol) in dichloromethane (80 ml) was added 3-butyn-l-ol (3.65 g, 52.1 mmol), then the mixture was degassed with nitrogen three times and cooled to 0 °C. Trifluoromethanesulfonic acid (11.5 ml, 130 mmol) was added dropwise under nitrogen and the mixture was stirred at -10 °C for 1 h. The reaction mixture was poured into saturated NaHCCh solution (50 ml), then extracted with dichloromethane (30 ml x 3), and the combined organic layers were washed with saturated brine (20 ml x 3), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative MPLC (column: spherical Cl 8 20-45 mm 100 A; mobile phase water / acetonitrile 0-100%). The eluent was partly concentrated to remove acetonitrile, then extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuum to give to [6-(l-methyl-6-oxo-pyridazin-4-yl)- 3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (3.5 g, 24% yield) as light-yellow oil. MS m / z: 341.1 [M+H]+, ESI pos.

[0939] Step 2: 2-methyl-5-r4-(4,4,5,5-tetraethyl-E3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridazin-3-one

[0940] To a solution of [6-(l-methyl-6-oxo-pyridazin-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (2.0 g, 5.88 mmol) in 1,4-dioxane (50 ml) were added 4, 4, 5, 5- tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.58 g, 7.05 mmol), potassium acetate (1.73 g, 17.63 mmol) and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (240 mg, 0.29 mmol, 0.05 eq). Then the mixture was degassed with nitrogen three times, and the reaction was stirred at 90 °C for 1 h under nitrogen. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate 0-30%) and concentrated in vacuo to afford 2-methyl-5-[4-(4,4,5,5-tetraethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridazin-3-one (1.2 g, 55% yield) as yellow solid, MS m / z: 375.3 [M+H]+, ESI pos.

[0941] Intermediate B42: 2 cyclopropyl 5 [4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-

[0942] 2H-pyran-6-yl]pyridazin-3-one

[0943] Step 1 : 2-cyclopropyl-5-vinyl-pyridazin-3-one

[0944] To a solution of 5-chloro-2-cyclopropyl-pyridazin-3-one (CAS 825633-94-1, 16.0 g, 46.89 mmol) in 1,4-di oxane (200 ml) and water (20 ml) were added potassium vinyltrifluoroborate (9.42 g, 70.3 mmol) and cesium carbonate (30.6 g, 93.8 mmol). The air of the flask was replaced with nitrogen three times, then l,T-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.91 g, 2.34 mmol, 0.05 eq) was added to the reaction mixture under nitrogen and the mixture was stirred at 90 °C for 2 h. Water (200 ml) was added and the mixture was extracted with ethyl acetate (200 ml x 2). The combined organic layers were washed with brine (300 ml), dried over lSfeSCU, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 3 : 1) to give 2- cyclopropyl-5-vinyl-pyridazin-3-one (6.8 g, 89% yield) as yellow solid, MS m / z: 163.2 [M+H]+, ESI pos.

[0945] -6-oxo-pvridazine-4-carbaldehyde

[0946] Through a solution of 2-cyclopropyl-5-vinyl-pyridazin-3-one (9.0 g, 55.5 mmol) in a mixture of dichloromethane (40 ml) and methanol (40 ml) at -70°C was bubbled ozone for 30 min. Then, nitrogen was bubbled into the mixture at -70°C to remove excess ozone, and it was warmed to 0 °C. A solution of triphenylphosphine (29.1 g, 111 mmol) in di chloromethane (40 ml) was added dropwise to this solution and the mixture was stirred at 25 °C for 1 h under nitrogen. Most of the solvent was evaporated and methanol (30 ml) was added. A large quantity of white precipitate was formed which was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna Cl 8 150 x 25 mm x 10 pm, water / acetonitrile) to give l-cyclopropyl-6-oxo-pyridazine-4-carbaldehyde (7.2 g, 79% yield) as pink solid, MS m / z: 183.2 [M+H]+, ESI pos.

[0947] Step 3: 2-cyclopropyl-5-14-(4,4,5,5-tetraethyl-L3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yllpyridazin-3-one

[0948] The title compounds were prepared in analogy to Intermediate B41 1 from l-cyclopropyl-6-oxo- pyridazine-4-carbaldehyde instead of l-methyl-6-oxo-pyridazine-4-carbaldehyde in step 1, yellow gum, MS m / z: 401.1 [M+H]+, ESI pos.

[0949] Intermediate Cl: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2- a]pyrimidin-7-yl]tetrahydropyran-2-carboxylic acid

[0950] Step 1: ethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate

[0951] To a mixture of 4-ketotetrahydropyran-2-carboxylic acid ethyl ester (CAS 287193-07-1, 2.32 g, 2 ml, 13.5 mmol) and 2,6-di-tert-butyl-4-methylpyridine (3.33 g, 16.2 mmol) in dichloromethane (46 ml) was added trifluoromethanesulfonic anhydride (7.62 g, 4.56 ml, 27.0 mmol) at 0°C. The ice bath was removed after the addition and the mixture was stirred at 35 °C overnight. The reaction mixture was poured into ice cold sodium hydrogencarbonate solution (60 ml) under stirring, then diluted with water. The aqueous layer was separated and back extracted with dichloromethane. The combined organic layers were washed with brine, dried over ISfeSCU and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to afford ethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H- pyran-2-carboxylate (1.67 g, 41% yield) as colorless liquid.

[0952] Step 2: ethyl 4-19-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazinorE2-a]pyrimidin-7- yl1-3,6-dihydro-2H-pyran-2-carboxylate

[0953] To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazino[l,2-a]pyrimidin-4-one (Intermediate A8, 2.33 g, 5.42 mmol) in 1,4- dioxane (108 ml) and water (18 ml) were added under argon stream ethyl 4- (trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate (1.65 g, 5.42 mmol), potassium carbonate (2.25 g, 16.3 mmol) and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride (402 mg, 0.542 mmol, 0.10 eq) and the reaction mixture was stirred at 60 °C for 2.5 h. The reaction mixture was filtered over dicalite. The filtrate was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 10% methanol in di chloromethane). The product was suspended in ethyl acetate then filtered to afford ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.07 g, 79% yield) as yellow solid. MS m / z: 458.2 [M+H]+, ESI pos. i-2,3 -dimethyl-4-oxo-i ,2-a]pyrimidin-7- -2-carboxylate

[0954] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-4-keto-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 7-yl]-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (400 mg, 0.874 mmol) in ethyl acetate (60 ml) were added under argon triethylamine (106 mg, 146 pl, 1.05 mmol), magnesium oxide (352 mg, 8.74 mmol) and palladium on charcoal (10%, 186 mg). The mixture was degassed with argon several times then stirred under hydrogen gas atmosphere (balloon pressure) at room temperature for 40 min. The reaction mixture was filtered over dicalite and washed with ethyl acetate. The filtrate was concentrated and the crude material was purified by flash chromatography (HP C18 RediSep Gold, 0% to 70% acetonitrile in water) to afford ethyl 4-[9- (4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]tetrahydropyran- 2-carboxylate (230 mg, 52% yield) as yellow foam. MS m / z: 460.2 [M+H]+, ESI pos.

[0955] Step 4: 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazinori,2-a1pyrimidin-7- ylltetrahydropyran-2-carboxylic acid To a solution of ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2- a]pyrimidin-7-yl]tetrahydropyran-2-carboxylate (246 mg, 0.535 mmol) in tetrahydrofuran (2 ml) and ethanol (1 ml) was added aqueous lithium hydroxide solution (1 M, 1.6 ml, 1.6 mmol) and the reaction mixture was stirred at room temperature. Then aqueous hydrochloric acid (IM, 1.6 ml, 1.6 mmol) was added and the mixture was poured into water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (248 mg, 97% yield) as yellow foam. MS m / z: 432.2 [M+H]+, ESI pos.

[0956] Intermediate C2 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2- b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid , , , hyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2- carboxylate

[0957] To a solution of ethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate (see Intermediate Cl step 1, 24.3 g, 79.87 mmol) in 1,4-dioxane (240 ml) was added bis(pinacolato)diboron (21.3 g, 83.9 mmol), potassium acetate (23.52 g, 240 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.96 g, 2.4 mmol, 0.03 eq). Then the mixture was degressed with nitrogen three times and the reaction was stirred at 90 °C for 2 h under nitrogen atmosphere. The mixture was poured into water (500 ml) and extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine (300 ml) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 : 1 to 3: 1) to afford ethyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate (14.0 g, 62% yield) as light yellow oil. MS m / z: 283.2 [M+H]+, ESI pos. Step 2: ethyl 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidorE2-b]pyridazin-7- yl1-3,6-dihydro-2H-pyran-2-carboxylate

[0958] To a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin- 4-one (Intermediate A2, 2.1 g, 6.21 mmol) in 1,4-dioxane (50 ml) and water (5 ml) was added ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate (2.45 g, 8.69 mmol), cesium carbonate (6.07 g, 18.63 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (254 mg, 0.31 mmol, 0.05 eq). 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 (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 : 1 to 1 : 3) to afford ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2- b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.6 g, 91% yield) as light yellow solid. MS m / z: 458.1 [M+H]+, ESI pos.

[0959] Step 3: ethyl 4-r9-(4-chloro-2-fluoro-phenyl)-2 -dimethyl-4-oxo-pyrimidc>ri,2-b1pyridazin-7- ylltetrahydropyran-2-carboxylate To a suspension of platinum oxide (198 mg, 0.87 mmol, 0.2 eq) in ethyl acetate (25 ml) under nitrogen was added a solution of ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo- pyrimido[l,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.0 g, 4.37 mmol) in ethyl acetate (25 ml) and dimethylformamide (10 mL), magnesium oxide (1.76 g, 43.7 mmol) and triethylamine (530 mg, 5.24 mmol). The reaction was degassed with hydrogen three times, then stirred at 25 °C for 4 h under hydrogen (15 Psi). The reaction mixture was filtered through a pad of diatomaceous earth, then poured into water (150 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (50 ml x 3) and dried over ISfeSCU, then concentrated in vacuum. The residue was purified by preparative HPLC (Phenomenex Luna C18, 250 x 70 mm x 10 pm, water + 0.225% formic acid / acetonitrile, flow rate 140 ml / min) to give ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin-7- yl]tetrahydropyran-2-carboxylate (1.3 g, 65% yield) as light yellow solid. MS m / z: 460.2 [M+H]+, ESI pos.

[0960] Step 4: 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidolL2-b1pyridazin-7- ylltetrahydropyran-2-carboxylic acid

[0961] To a solution of ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2- b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (1.3 g, 2.83 mmol) in tetrahydrofuran (12 ml) and water (4 ml) was added lithium hydroxide monohydrate (178 mg, 4.24 mmol) and the reaction was stirred at 20 °C for 1 h. The mixture was poured into water (100 ml), the pH was adjusted to 6 with IM hydrochloric acid, then extracted with ethyl acetate (80 ml x 3). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, then concentrated in vacuum to give the title compound (1.2 g, 98% yield) as yellow solid. MS m / z: 432.1 [M+H]+, ESI pos. Intermediate C3: 4-[9-(4,4-difluorocyclohexyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin- 7-yl]tetrahydropyran-2-carboxylic acid

[0962] The title compound was prepared in analogy to Intermediate C2 using Intermediate A6 instead of Intermediate A2 in step 2. White solid, MS m / z: 422.1 [M+H]+, ESI pos.

[0963] Intermediate C4: 4-[9-[3-(difluoromethyl)-l-bicyclo[l .1. l]pentanyl]-2,3-dimethyl-4-oxo- pyrimido[l,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid

[0964] The title compound was prepared in analogy to Intermediate C2 using Intermediate A5 instead of Intermediate A2 in step 2. Yellow solid, MS m / z: 420.1 [M+H]+, ESI pos.

[0965] Intermediate C5: 4-[9-(4-chl oro-2, 6-difluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[ 1,2- b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid

[0966] The title compound was prepared in analogy to Intermediate C2 using Intermediate A4 instead of Intermediate A2 in step 2. Yellow solid, MS m / z: 450.0 [M+H]+, ESI pos.

[0967] Intermediate DI: N' -hydroxyacetamidine

[0968] Intermediate DI is commercial, CAS 22059-22-9.

[0969] Intermediate D2: N' -hy droxy cy cl opropanecarb oxi mi dami de

[0970] Intermediate D2 is commercial, CAS 51285-13-3. Intermediate D3: acetamidine hydrochloride

[0971] Intermediate D3 is commercial, CAS 124-42-5.

[0972] Intermediate D4: cyclopropanecarboxamidine hydrochloride CI H

[0973] Intermediate D4 is commercial, CAS 57297-29-7.

[0974] Intermediate D5: propyne

[0975] Intermediate D5 is commercial and was purchased as a 1 M solution in tetrahydrofuran, CAS 74- 99-7.

[0976] Intermediate D6: ethynylcyclopropane

[0977] Intermediate D6 is commercial, CAS 6746-94-7.

[0978] Intermediate D7: trimethylsilylacetylene

[0979] Intermediate D7 is commercial, CAS 1066-54-2.

[0980] Example 1 and Example 2 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(3-methyl- 1 ,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one and 9-(4-chloro-2- fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(3-methyl-l,2,4-oxadiazol-5-yl)morpholin-4- yl]pyrimido[ 1 ,2-b]pyridazin-4-one

[0981] Step 1: methyl 4-19-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidorL2-b]pyridazin-7- yllmorpholine-2-carboxylate To a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin- 4-one (Intermediate A2, 180 mg, 0.53 mmol) in dimethylsulfoxide (5 ml) was added N,N- diisopropyl ethylamine (0.37 mL, 2.13 mmol) and methyl morpholine-2-carboxylate hydrochloride (116 mg, 0.64 mmol) and the mixture was stirred at 120 °C for 2 h. The reaction mixture was extracted with ethyl acetate (10 ml x 2). The combined organic layers were washed with brine (10 ml x 2) and dried over ISfeSCU, then concentrated in vacuum. The residue was purified preparative HPLC (Phenomenex Luna, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.25% formic acid - acetonitrile, 0-100%, flow rate 25 ml / min) to give methyl 4-[9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin-7-yl]morpholine-2-carboxylate (140 mg, 59 yield) as yellow solid. MS m / z: 447.1 [M+H]+, ESI pos. Step 2: 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidolL2-b1pyridazin-7- yllmorpholine-2-carboxylic acid

[0982] To a solution of methyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2- b]pyridazin-7-yl]morpholine-2-carboxylate (100 mg, 0.22 mmol) in tetrahydrofuran (3 ml) / water (1 ml) was added lithium hydroxide monohydrate (28.2 mg, 0.67 mmol) and the mixture was stirred at 20 °C for 1 h. The pH of reaction mixture was changed to 6 with IM hydrochloric acid, then extracted with ethyl acetate (10 ml x 3. The combined organic layers were washed with brine (10 ml), dried over Na2SO4 and concentrated under reduced pressure to give 4-[9-(4- chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin-7-yl]morpholine-2- carboxylic acid (96 mg, 99% yield) as yellow solid and used directly. MS m / z: 433.1 [M+H]+, ESI pos.

[0983] Step 3: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-r(2S)-2-(3-methyl- oxadiazol-5- yl)morpholin-4-yl]pyrimidorE2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-2,3- dimethyl-7-r(2R)-2-(3-methyl- oxadiazol-5-yl)morpholin-4-yl]pyrimidorE2-b]pyridazin-4- one

[0984] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin- 7-yl]morpholine-2-carboxylic acid (96 mg, 0.22 mmol) in dimethylformamide (5 ml) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimid (64 mg, 0.33 mmol), 1 -hydroxybenzotriazole (30 mg, 0.22 mmol) and N'-hydroxyacetamidine (CAS 22059-22-9, 24.5 mg, 0.33 mmol). The mixture was stirred at 80 °C for 4 h, then added into water (10 ml) and extracted with ethyl acetate (10 ml x 3). The combined organic layers were washed with brine (10 ml x 3), dried over Na2SO4 and concentrated in vacuum. The residue was purified by preparative HPLC (Phenomenex Luna, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.25% formic acid - acetonitrile, 0-100%, flow rate 25 ml / min) to give 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7- [2-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one. The enantiomers were separated by chiral SFC (Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, ethanol / 0.1% ammonium hydroxide, flow rate 80 ml / min) to give 9-(4-chloro-2-fluorophenyl)- 2,3-dimethyl-7-[(2S)-2-(3-methyl-l,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimido[l,2- b]pyridazin-4-one (17 mg, 16% yield) as white solid, MS m / z: 471.2 [M+H]+, ESI pos. and 9-(4- chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(3-methyl-l,2,4-oxadiazol-5-yl)morpholin-4- yl]pyrimido[l,2-b]pyridazin-4-one 20 mg, 19% yield) as white solid. MS m / z: 471.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0985] Example 3 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(3-methyl-l,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrazino[l,2-a]pyrimidin-4-one

[0986] The title compound was prepared in analogy to Example 2 using Intermediate Al instead of Intermediate A2 in step 1, yellow solid, MS m / z: 471.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0987] Example 4 and Example 5 and Example 6 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(3- cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro- phenyl)-7-[rac-(2R,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one

[0988] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin- 7-yl]tetrahydropyran-2-carboxylic acid (Intermediate Cl, 130 mg, 0.3 mmol) in dimethylformamide (3 ml) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimid (115 mg, 0.6 mmol), N,N-diisopropylethylamine (156 mg, 1.2 mmol), 1 -hydroxybenzotriazole (41 mg, 0.3 mmol) and N'-hydroxycyclopropanecarboximidamide (CAS 51285-13-3, 60 mg, 0.6 mmol). The mixture was stirred at 25 °C for 12 h, then heated to 80 °C and stirred for 4 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 (40 ml x 2) and dried over ISfeSCU, then concentrated in vacuum. The residue was purified by preparative HPLC (column Phenomenex Luna Cl 8, 250 x 70 mm x 10 pm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min) to give a product 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4- oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one. This product was separated by chiral SFC (column Daicel OD 250 mm x 30 mm, 10 pm, ethanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2- (3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2- a]pyrimidin-4-one (23 mg, 29% yield), and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(3- cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 4-one (24 mg, 30% yield) and 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(3-cyclopropyl- l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one, (14 mg, 17% yield), light yellow solids with MS m / z: 496.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0989] The following Examples 7 to 21 were prepared in analogy to Examples 4 to 6 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[0990]

[0991] Example 22 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-hydroxy-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one Step 1 : 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-r6-(l-methylpyrazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]pyrazinc>ri,2-a]pyrimidin-4-one

[0992] To a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 4-one (Intermediate Al, 1.5 g, 4.44 mmol) in 1,4-dioxane (30 ml) and water (3 ml) was added 1- methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]-4H- pyrazole (Intermediate Bl, 1.54 g, 5.32 mmol), sodium carbonate (1.41 g, 13.31 mmol) and l,T-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (181 mg, 0.22 mmol, 0.05 eq). The mixture was degassed with nitrogen three times and stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (80 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate 0-100%) and concentrated to give 9-(4-chloro-2-fluoro-phenyl)- 2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]pyrazino[l,2-a]pyrimidin- 4-one (1.0 g, 48% yield) as orange soild, MS m / z: 466.1 [M+H]+, ESI pos.

[0993] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-r4-hydroxy-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2 -dimethyl-pyrazinc>ri,2-a]pyrimidin-4-one

[0994] To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(l-methylpyrazol-4-yl)-3,6- dihydro-2H-pyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (820 mg, 1.76 mmol) in dichloromethane (6 ml) and isopropanol (6 ml) was added cobalt(II) tetraphenylporphyrin (CAS 14172-90-8, 118 mg, 0.18 mmol, 0.1 eq) and triethylsilane (409 mg, 3.52 mmol) at 0 °C and the mixture was stirred at 0 °C for 2 h under oxygen atmosphere. The reaction mixture was poured into water (200 ml) and extracted with dichloromethane (200 ml x 3). The combined organic extracts were washed with brine (200 ml), dried over Na2SO4 and concentrated in vacuum. The residue was purified by preparative HPLC (column Phenomenex Luna, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%, flow rate 60 ml / min) to give 9-(4-chloro-2-fluoro-phenyl)-7-[4-hydroxy-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[l,2-a]pyrimidin-4-one (570 mg, 48% yield) as yellow solid, MS m / z: 484.2 [M+H]+, ESI pos. Step 3 : 9-(4-chloro-2-fluoro-phenyl)-7-l(2R,4R)-4-hydroxy-2-(T-methylpyrazol-4- yl)tetrahydropyran-4-yl1-2,3-dimethyl-pyrazinolE2-a1pyrimidin-4-one

[0995] 9-(4-Chloro-2-fluoro-phenyl)-7-[4-hydroxy-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[l,2-a]pyrimidin-4-one was separated by chiral SFC (Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-hydroxy-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (5 mg, 8% yield), first eluting enantiomer as yellow solid and 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-hydroxy-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (5 mg, 8% yield) second eluting enantiomer as yellow solid, MS m / z: 484.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0996] Example 23 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-hydroxy-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one The title compound was prepared in analogy to Example 22 using Intermediate A2 instead of Intermediate Al in step 1, white solid, MS m / z: 484.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0997] Example 24 and Example 25 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-fluoro-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one and 9- (4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-fluoro-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one

[0998] Step 1 : 9-(4-chloro-2-fluoro-phenyl)-7-14-fluoro-2-(T-methylpyrazol-4-yl)tetrahydropyran-4-yl1- 2,3-dimethyl-pyrazinolE2-a1pyrimidin-4-one

[0999] To a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[4-hydroxy-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (see Example 22, 160 mg, 0.33 mmol) in dichloromethane (3 ml) was added morpholinosulfur trifluoride (CAS 51010- 74-3, 0.12 ml, 0.99 mmol) at 0 °C under nitrogen and the mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. The reaction mixture was quenched by adding NaHCCE solution (20 ml) and extracted with dichloromethane (30 ml x 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous ISfeSCU and concentrated in vacuum. The residue was purified by preparative HPLC (column Phenomenex Luna, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%, flow rate 60 ml / min) to give 9-(4-chloro- 2-fluoro-phenyl)-7-[4-fluoro-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[l,2-a]pyrimidin-4-one (100 mg, 62% yield) as yellow solid. MS m / z: 486.2 [M+H]+, ESI pos.

[1000] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-r(2S,4S)-4-fluoro-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl1-2,3-dimethyl-pyrazinolL2-a1pyrimidin-4-one and 9-(4-chloro-2-fluoro- phenyl)-7-l(2R,4R)-4-fluoro-2-(l -methylpyrazol -4-yl )tetrahydropyran-4-yl 1-2.3-dimethyl- pyrazinolL2-a1pyrimidin-4-one

[1001] The compounds have been obtained by two consecutive SFC separations of 9-(4-chloro-2- fluoro-phenyl)-7-[4-fluoro-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[l,2-a]pyrimidin-4-one (100 mg). The first separation was aiming at the separation of cis- and trans-isomers (Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to give 30 mg of 9-(4-chloro-2-fluoro- phenyl)-7-[rac-(2R,4S)-4-fluoro-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[l,2-a]pyrimidin-4-one which was further separated by chiral SFC (Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to obtain 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-fluoro-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (14 mg, 47% yield), first eluting enantiomer as yellow solid, MS m / z: 486.1 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro- phenyl)-7-[(2R,4R)-4-fluoro-2-(l -methylpyrazol -4-yl)tetrahydropyran-4-yl]-2, 3-dimethyl- pyrazino[l,2-a]pyrimidin-4-one (10 mg, 31% yield), second eluting enantiomer as yellow solid, MS m / z: 486.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 26 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-fluoro-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one

[1002] The title compound was prepared in analogy to Example 24 using 9-(4-chloro-2-fluoro-phenyl)- 7-[(2R,4R)-4-hydroxy-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrimido[l,2-b]pyridazin-4-one (see Example 23) instead of 9-(4-chloro-2-fluoro-phenyl)-7-[4- hydroxy-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 4-one in step 1, yellow solid, MS m / z: 486.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 27 and Example 28 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2- methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one and 9-(4- chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2S,4S)-2-methyl-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one Step 1 : 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-16-methyl-6-(l-methylpyrazol-4-yl)-2,3- dihydropyran-4-yllpyrazinor 1 ,2-a1pyrimidin-4-one

[1003] To a suspension of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazino[l,2-a]pyrimidin-4-one (Intermediate A8, 200 mg, 0.465 mmol) in 1,4-di oxane (3 ml) was added [6-methyl-6-(l-methylpyrazol-4-yl)-2,3-dihydropyran-4-yl] trifluoromethanesulfonate (Intermediate B2, 228 mg, 0.70 mmol) and an aqueous potassium carbonate solution (3 M, 465 pl, 1.4 mmol) at room temperature. The mixture was degassed with argon before [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg, 46.5 pmol, 0.10 eq) was added. The reaction mixture was stirred for 2 h at 60°C, then it was diluted with water and extracted two times with ethyl acetate. The organic layers were dried over MgSCU and concentrated to dryness. The crude material was purified by flash chromatography (silica gel C18, acetonitrile in water 10-100%) to obtain 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6- methyl-6-(l-methylpyrazol-4-yl)-2,3-dihydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (186 mg, 83% yield) as light brown solid, MS m / z: 480.1 [M+H]+, ESI pos.

[1004] Step 2: 9-(4-chloro-2-fluoro-phenyl)-2 -dimethyl-7-rrac-(2R,4S)-2-methyl-2-(l-methylpyrazol- 4-yl )tetrahydropyran-4-yl1pyrazinori,2-a1pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-7-rrac-(2S,4S)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazinc>ri,2- a]pyrimidin-4-one

[1005] To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-methyl-6-(l-methylpyrazol-4- yl)-2,3-dihydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (180 mg, 0.375 mmol) in ethyl acetate (4 ml) and triethylamine (45 mg, 63 pl, 0.45 mmol) at room temperature was added magnesium oxide (151 mg, 3.75 mmol) followed by palladium on carbon (10%, 80 mg) and the mixture was stirred under hydrogen atmosphere for 4 h. The reaction mixture was filtered through a syringe filter and washed with di chloromethane / methanol = 9:1 and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel Cl 8, acetonitrile in water 10-100%) to obtain 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac- (2R,4S)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (5 mg, 3% yield) as light yellow solid, MS m / z: 482.2 [M+H]+, ESI pos. and 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[rac-(2S,4S)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran- 4-yl]pyrazino[l,2-a]pyrimidin-4-one (8 mg, 4% yield) as light yellow solid, MS m / z: 482.2 [M+H]+, ESI pos.

[1006] Example 29 and Example 30 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl- 2-( 1 -methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one and 9-(4-chloro- 2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one

[1007] Racemic 9-(4-chloro-2-fluoro-phenyl)-2, 3 -dimethyl-7- [rac-(2R,4 S)-2-m ethyl -2-( 1 - methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one was separated by chiral SFC (column Chiral NR, 250 mm x 20 mm, 5 pm, 45% methanol) to give 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[l,2-a]pyrimidin-4-one as first eluting enantiomer with retention time 3.887 min, light yellow solid, MS m / z: 482.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-7-[(2S,4R)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[l,2- a]pyrimidin-4-one as second eluting enantiomer with retention time 4.449 min, light yellow solid, MS m / z: 482.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1008] Example 31 and Example 32 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-l,2,4- triazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro- 2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-l,2,4-triazol-3-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one

[1009] Step 1 : 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazinorE2-a]pyrimidin-7-yl]-N'- cyclopropyl-tetrahydropyran-2-carbohydrazide

[1010] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin- 7-yl]tetrahydropyran-2-carboxylic acid (Intermediate Cl, 300 mg, 0.69 mmol) in dimethylformamide (6 ml) was added N,N-diisopropylethylamine (359 mg, 2.78 mmol) and HATU (396 mg, 1.04 mmol) and the mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with brine (30 ml x 2) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative MPLC (column: Spherical Cl 8, 20 - 45 pm, 100 A, water with 0.1% formic acid / acetonitrile, flow rate 50 ml / min) to give 4-[9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]-N'-cyclopropyl- tetrahydropyran-2-carbohydrazide (250 mg, 74% yield) as light yellow solid. MS m / z: 486.1 [M+H]+, ESI pos.

[1011] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-r(2R,4S)-2-(l-cyclopropyl- triazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazinorE2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro- pyrazinori,2-a]pyrimidin-4-one

[1012] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin- 7-yl]-N'-cyclopropyl-tetrahydropyran-2-carbohydrazide (250 mg, 0.51 mmol) in trimethyl orthoformate (8.0 ml, 73.1 mmol) was added ammonium formate (649 mg, 10.29 mmol) and the mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column Waters Xbridge Cl 8, 150 x 25 mm x 10 pm, eluent: 10 mM ammonium hydrogen carbonate / acetonitrile, flow rate 25 ml / min) and the eluent was lyophilized to give racemic 9-(4-chloro-2-fluoro-phenyl)-7-[2-(l-cyclopropyl-l,2,4-triazol- 3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one. This compound was separated by chiral SFC (column Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, acetonitrile / ethanol + 0.1% ammonium hydroxide, flow rate 25 ml / min) to obtain 9-(4-chloro-2-fluoro- phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-l,2,4-triazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrazino[l,2-a]pyrimidin-4-one (10 mg, 22% yield), first eluting enantiomer as light yellow solid, 495.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl- l,2,4-triazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (9.5 mg, 21% yield), second eluting enantiomer as light yellow solid, 495.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1013] Example 33 and Example 34 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclopropyl-l,2,4- triazol-3-yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one and 9-(4-chloro-2- fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropyl-l,2,4-triazol-3-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one

[1014] The title compounds were prepared in analogy to Example 31 and Example 32 using Intermediate C2 instead of Intermediate Cl in step 1, light brown solids, MS m / z: 495.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 35 and Example 36 and Example 37 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2- cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(2- cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one

[1015] Step 1 : 9-(4-chloro-2-fluoro-phenyl)-7-r6-(2-cyclopropyltriazol-4-yl)-3,6-dihydro-2H-pyran-4- yl1-2,3-dimethyl-pyrazinolE2-a1pyrimidin-4-one To a solution of 2-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]triazole (Intermediate B 5, 94 mg, 0.3 mmol) in 1,4-dioxane (1 ml) and water (0.2 ml) was added 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4- one (Intermediate Al, 50 mg, 0.15 mmol), sodium carbonate (47 mg, 0.44 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (12 mg, 0.01 mmol, 0.1 eq) at room temperature. Then the mixture was degassed with nitrogen three times and stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into water (20 ml) and the aqueous layer was extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 to 40% ethyl acetate in petroleum ether) to give 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-cyclopropyltriazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (70 mg, 96% yield) as yellow oil. MS m / z: 493.1 [M+H]+, ESI pos.

[1016] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-r(2R,4S)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4- yl1-2,3-dimethyl-pyrazinori,2-a1pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl )-7-l(2S,4R)-2- (2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2 -dimethyl-pyrazinc>ri,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-rrac-(2R,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran- 4-yl]-2 -dimethyl-pyrazinc>ri,2-a]pyrimidin-4-one

[1017] To a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-cyclopropyltriazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (50 mg, 0.1 mmol) in ethyl acetate (5 ml) was added magnesium oxide (41 mg, 1.01 mmol) and palladium on charcoal (10%, 22 mg) under nitrogen. The reaction mixture was degassed with hydrogen three times, then stirred at 30 °C for 50 min under hydrogen atmosphere (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, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%, flow rate 60 ml / min) to give 9-(4-chloro-2-fluoro- phenyl)-7-[2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2- a]pyrimidin-4-one (30 mg) as yellow solid. This diastereomeric racemate was separated by chiral SFC (column Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, isopropanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2- cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (10 mg, 32% yield), first eluting enantiomer as yellow solid, MS m / z: 495.3 [M+H]+, ESI pos. and 9- (4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[l,2-a]pyrimidin-4-one (10 mg, 32% yield), second eluting enantiomer as yellow solid, MS m / z: 495.3 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)- 2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (5 mg, 16% yield) as yellow solid, MS m / z: 495.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1018] The following Examples 38 to 71 were prepared in analogy to Examples 35 to 37 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[1019]

[1020] Example 78 and Example 79 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol- 3-yl)oxan-4-yl]-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluorophenyl)-7- [(2S,4R)-2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one

[1021] Step 1 : 9-(4-chloro-2-fluoro-phenyl)-7-r6-(l-cyclopropylpyrazol-3-yl)-3,6-dihydro-2H-pyran-4- yl1-2J-dimethyl-pyrazinc>ri,2-a1pyrimidin-4-one

[1022] To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimido[l,2-b]pyridazin-4-one (Intermediate A8, 263 mg, 0.61 mmol) in 1,4-di oxane (4 ml) was added at room temperature [6-(l-cyclopropylpyrazol-3-yl)-3,6-dihydro- 2H-pyran-4-yl] trifluoromethanesulfonate (Intermediate B9, 311 mg, 0.92 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (51 mg, 0.061 mmol, 0.1 eq) and a solution of potassium carbonate (254 mg, 1.84 mmol) in water (0.65 ml). The mixture was stirred for 1 h at 60 °C, then it was diluted with saturated NaHCCh solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by reversed phase chromatography (column: spherical C18, 20-45 mm, 100 A, mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%) to yield 9-(4-chloro-2-fluoro-phenyl)-7-[6-(l- cyclopropylpyrazol-3-yl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4- one (170 mg, 54% yield), yellow solid, MS m / z: 492.2 [M+H]+, ESI pos.

[1023] Step 2: 9-(4-chloro-2-fluorophenyl)-7-r(2R,4S)-2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3- dimethylpyrazinori,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluorophenyl)-7-r(2S,4R)-2-(l- cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3-dimethylpyrazinc>ri,2-a]pyrimidin-4-one

[1024] To a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(l-cyclopropylpyrazol-3-yl)-3,6-dihydro-2H- pyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (160 mg, 0.325 mmol) in ethyl acetate (13 ml) was added at room temperature triethylamine (39.5 mg, 0.39 mmol), magnesium oxide (131 mg, 3.25 mmol) and palladium on charcoal (10%, 69 mg) and the mixture was stirred under hydrogen atmosphere at room temperature for 1.5 h. The reaction mixture was filtered through a syringe filter and washed with dichloromethane / methanol = 9: 1. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, dichloromethane in methanol 0 - 5%) to yield racemic 9-(4-chloro-2-fluorophenyl)-7-[2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3- dimethylpyrazino[l,2-a]pyrimidin-4-one. The enantiomers were separated by chiral SFC (column Waters IA, 250 mm x 20 mm, 5 pm, CO2 / methanol + 0.2% diethylamine) to give 9-(4- chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3- dimethylpyrazino[l,2-a]pyrimidin-4-one as first eluting enantiomer (15 mg, 9% yield), light yellow solid, MS m / z: 494.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l- cyclopropylpyrazol-3-yl)oxan-4-yl]-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one as second eluting enantiomer (17 mg, 11% yield), light yellow solid. MS m / z: 494.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1025] The following Examples 80 to 84 were prepared in analogy to Examples 78 and 79 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[1026] Example 85 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-lH-pyridin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one i-3,6-dihydro-2H-pyran-4-yl]-

[1027] 2,3-dimethyl-pyrimidori,2-b]pyridazin-4-one

[1028] To a suspension of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[l,2- b]pyridazin-4-one (Intermediate A2, 1.77 g, 5.23 mmol) and 2-methoxy-4-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (Intermediate B13, 2.49 g, 7.85 mmol) in 1,4-dioxane (26 ml) under nitrogen at room temperature, was added aqueous cesium carbonate solution (3 M, 5.2 ml, 15.7 mmol). The mixture was degassed with argon 3 times, then l,T-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (433 mg, 0.52 mmol, 0.10 eq) was added and the mixture was stirred at 65 °C for 2 h. The reaction mixture was cooled to room temperature. Ethyl acetate and water were added and both layers were separated. The aqueous one was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in heptane and acetate 0 to 30%) to obtain 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (2.03 g, 74% yield) as yellow foam, MS m / z: 491.2 [M-H]’, ESI neg. -4-yl]-2,3- dimethyl-pyrimidor 1 ,2-b]pyridazin-4-one

[1029] To a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (1.53 g, 3.1 mmol) in ethyl acetate (29 ml) under nitrogen at room temperature, was added palladium on charcoal (10%, 991 mg) and the mixture was stirred under a hydrogen atmosphere at room temperature for 26 h. The reaction mixture was flushed with argon, then filtered over a Sartorius filter and well rinsed with ethyl acetate and methanol. The mother liquor was evaporated. The residue was purified with flash column chromatography (silica, ethyl acetate in heptane 0% to 80%) to get a yellow oil, which was precipitated with ethyl acetate and washed with diethyl ether. The resulting solid was dried to provide 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (400 mg, 22% yield) as light yellow solid, MS m / z: 539.2 [M+HCOO]’, ESI neg.

[1030] To a suspension of 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (400 mg, 0.81 mmol) in acetonitrile (16 ml) under nitrogen at room temperature, were added sodium iodide (182 mg, 1.21 mmol) and trimethyl silyl chloride (132 mg, 0.15 ml, 1.21 mmol) and the resulting orange suspension was stirred at 65 °C for 5 h. The mixture was cooled to room temperature and quenched with water. Ethyl acetate was added. Both layers were separated. The aqueous one was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified with reversed phase chromatography (column: spherical Cl 8 20-45 mm, 100 A, mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%) to provide 9-(4- chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-lH-pyridin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimido[l,2-b]pyridazin-4-one (339 mg, 76% yield) as yellow solid, MS m / z: 481.2 [M+H]+, ESI pos.

[1031] Example 86 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-oxo-lH-pyri din-4- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one The enantiomers of 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-lH-pyridin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (Example 85, 35 mg) were separated by chiral SFC (Chiral IH 250 mm x 20 mm, 5 pm, CO2 with 65% methanol / 0.2% diethylamine) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-keto-lH-pyridin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (11 mg, 31% yield) as yellow foam, MS m / z: 481.1 [M+H]+, ESI pos.

[1032] Example 87 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-keto-lH-pyridin-4-yl)tetrahydropyran-

[1033] 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one The title compounds were prepared in analogy to Example 85 and 86 using Intermediate A6 instead of Intermediate A2 in step 1, light yellow solid, MS m / z: 471.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1034] Example 88 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one

[1035] Step 1 : rac-(2R,4S)-4-19-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazinorE2- a1pyrimidin-7-yl1-N-methoxy-N-methyl-tetrahydropyran-2-carboxamide and rac-(2S,4S)-4-19-

[1036] (4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazinorE2-a1pyrimidin-7-yl1-N-methoxy-N- methyl-tetrahydropyran-2-carboxamide

[1037] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-4-keto-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 7-yl]tetrahydropyran-2-carboxylic acid (Intermediate Cl, 225 mg, 0.521 mmol) in N,N- dimethylformamide (4 ml) were added HATU (238 mg, 0.625 mmol), N,O- dimethylhydroxylamine hydrochloride (56 mg, 0.573 mmol) and diisopropyl ethylamine (269 mg, 364 pl, 2.08 mmol) and the solution was stirred at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (2 x). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give rac-(2R,4S)-4-[9- (4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]-N-methoxy-N- methyl-tetrahydropyran-2-carboxamide (165 mg, 66% yield) as yellow foam, MS m / z: 475.1 [M+H]+, ESI pos and rac-(2S,4S)-4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo- pyrazino[l,2-a]pyrimidin-7-yl]-N-methoxy-N-methyl-tetrahydropyran-2-carboxamide (66 mg, 26% yield) as yellow foam, MS m / z: 475.1 [M+H]+, ESI pos.

[1038] Step 2: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-rrac-(2R,4S)-2-prop-2- ynoyltetrahydropyran-4-yllpyrazinor 1.2-alpyri mi di n-4-one

[1039] To a solution of rac-(2R,4S)-4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2- a]pyrimidin-7-yl]-N-methoxy-N-methyl-tetrahydropyran-2-carboxamide (161 mg, 0.34 mmol) in tetrahydrofuran (2.5 ml) was added at 0°C ethynylmagnesium bromide (0.5 M in THF, 1.36 ml, 0.678 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0 °C, then quenched with 1 N aqueous KHSO4 solution, poured into water and extracted with ethyl acetate twice. The , combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 80% ethyl acetate in heptane) to afford 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-prop-2- ynoyltetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (119 mg, 76% yield) as light yellow foam, MS m / z: 440.2 [M+H]+, ESI pos.

[1040] Step 3 : 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-rrac-(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl1pyrazinol 1.2-alpyri mi di n-4-one

[1041] A mixture of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-prop-2- ynoyltetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (119 mg, 0.27 mmol), acetamidine hydrochloride (Intermediate D3, 48 mg, 0.514 mmol), sodium carbonate (113 mg, 1.07 mmol) in ethyl acetate (3 ml) and water (20 pl) was stirred for 2 h at 80 °C. After cooling to room temperature the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (Si-Amine, 0% to 80% ethyl acetate in heptane) to afford 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (92 mg, 66% yield) as light yellow foam, MS m / z: 480.1 [M+H]+, ESI pos.

[1042] Example 89 and Example 90 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-4-yl)tetrahydropyran-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one

[1043] The enantiomers of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (Example 88, 92 mg) were separated by chiral SFC (Chiral AD 250 mm x 20 mm, 5 pm, CO2 with 28% methanol / 0.2% diethylamine) to give 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (27 mg, 32% yield) as light yellow solid, MS m / z: 480.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin- 4-one (26 mg, 30% yield) as light yellow solid, MS m / z: 480.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1044] Example 91 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2S,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one

[1045] The title compounds were prepared in analogy to Example 88 using rac-(2S,4S)-4-[9-(4-chloro- 2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]-N-methoxy-N-methyl- tetrahydropyran-2-carboxamide (minor diastereomer in step 1) instead of rac-(2R,4S)-4-[9-(4- chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]-N-methoxy-N- methyl-tetrahydropyran-2-carboxamide in step 2, light yellow foam, MS m / z: 480.2 [M+H]+, ESI pos. The following Examples 92 to 102 were prepared in analogy to Examples 88 to 91 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[1046] Example 103 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one

[1047]

[1048] Step 1 : 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazinolE2-a1pyrimidin-7-yl1-N- methoxy-N-methyl-tetrahydropyran-2-carboxamide To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-4-keto-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 7-yl]tetrahydropyran-2-carboxylic acid (Intermediate Cl, 443 mg, 1.03 mmol) in N,N- dimethylformamide (8 ml) were added HATU (468 mg, 1.23 mmol), N,O- dimethylhydroxylamine hydrochloride (110 mg, 1.13 mmol) and diisopropyl ethylamine (530 mg, 0.717 ml, 4.1 mmol) and the solution was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate (2 x). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate + ethanol 3 / 1 in heptane 0% to 80%) to afford 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7- yl]-N-methoxy-N-methyl-tetrahydropyran-2-carboxamide (400 mg, 74% yield) as yellow foam, MS m / z: 475.2 [M+H]+, ESI pos.

[1049] Step 2: 7-(2-but-2-ynoyltetrahydropyran-4-yl)-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- pyrazinolE2-a1pyrimidin-4-one

[1050] To a cooled (-78°C) solution of propyne (Intermediate D5, ca. 5% in tetrahydrofuran, ca. 1 M, 3.47 ml, 3.47 mmol) in tetrahydrofuran (15 ml) was added dropwise n-butyl lithium (1.6 M in BuLi in hexanes, 2.0 ml, 3.16 mmol) and the mixture was stirred for 30 min at this temperature. This solution was then added to a cooled (-78°C), stirred solution of 4-[9-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]-N-methoxy-N-methyl- tetrahydropyran-2-carboxamide (300 mg, 0.632 mmol) in tetrahydrofuran (15 ml) and the reaction mixture was stirred for 30 min at -78°C. The reaction mixture was quenched with 1 M aqueous KHSO4 solution at -78°C, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to afford 7-(2-but-2-ynoyltetrahydropyran-4-yl)-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- pyrazino[l,2-a]pyrimidin-4-one (270 mg, 90% yield) as yellow foam, MS m / z: 454.2 [M+H]+, ESI pos.

[1051] Step 3 : 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-r2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl1pyrazinol 1.2-alpyri mi di n-4-one

[1052] To a solution of 7-(2-but-2-ynoyltetrahydropyran-4-yl)-9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-pyrazino[l,2-a]pyrimidin-4-one (236 mg, 0.52 mmol) in acetonitrile (16 ml) were added sodium carbonate (661 mg, 6.24 mmol) and formamidine acetate (325 mg, 3.12 mmol) and the mixture was stirred at 80°C overnight. After cooling to room temperature, the reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (Si-Amine, 0% to 80% ethyl acetate in heptane) to afford 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (90 mg, 35% yield) as yellow foam, MS m / z: 480.2 [M+H]+, ESI pos.

[1053] Example 104 and Example 105 and Example 106 and Example 107 9-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6-methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2- a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-(6-methylpyrimidin-4-yl)tetrahydropyran-4- yl]pyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2- (6-methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one The diastereomers and enantiomers of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (Example 103, 90 mg) were separated by chiral SFC (Chiral OJ 250 mm x 20 mm, 5 pm, CO2 with 20% methanol / 0.2% diethylamine) to give 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (29 mg, 32% yield) as light yellow solid, MS m / z: 480.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-7-[(2R,4S)-2-(6-methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin- 4-one (28 mg, 31% yield) as light yellow solid, MS m / z: 480.2 [M+H]+, ESI pos. and 9-(4- chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-(6-methylpyrimidin-4-yl)tetrahydropyran-4- yl]pyrazino[l,2-a]pyrimidin-4-one (5 mg, 5% yield) as light yellow solid, MS m / z: 480.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2-(6- methylpyrimidin-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (5 mg, 5% yield) as light yellow solid, MS m / z: 480.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. The following Examples 108 to 122 were prepared in analogy to Examples 103 to 107 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[1054] Example 124 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-(2,2-difluoroethoxy)-3- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one Step 1 : 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-F(2R,4S)-2-(6-oxo-lH-pyridin-3- yl )tetrahvdropyran-4-yl Ipyri mi dof 1.2-blpyri dazi n-4-one

[1055]

[1056] To a solution of 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (Example 49, 29 mg, 0.06 mmol) in acetonitrile (1.2 ml) were added sodium iodide (18 mg, 0.12 mmol) and trimethyl silyl chloride (13 mg, 15 pl, 0.12 mmol) and the mixture was left stirring at 65 °C for 3 h. The solvent was removed under reduced pressure, the crude was diluted with dimethylsulfoxide and purified by reversed phase chromatography (column: spherical C18 20-45 mm, 100 A, mobile phase: water - acetonitrile, 10-100%) to 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-oxo-lH- pyri din-3 -yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one (18 mg, 64% yield) as off- white solid, MS m / z: 471.3 [M+H]+, ESI pos.

[1057] Step 2: 9-(4,4-difluorocyclohexyl)-7-r(2R,4S)-2-16-(2,2-difluoroethoxy)-3- pyridyl1tetrahydropyran-4-yl1-2,3-dimethyl-pyrimidolE2-b1pyridazin-4-one

[1058] To a solution of 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-oxo-lH-pyridin-3- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one (25 mg, 0.053 mmol) in acetonitrile (1.4 ml) were added cesium carbonate (52 mg, 0.16 mmol) and a solution of 2,2- difluoroethyltrifluoromethanesulfonate (24 mg, 15 uL, 0.106 mmol) in acetonitrile (1.4 ml) and the mixture was stirred at 60°C for 1 h. The reaction mixture was concentrated and purified on reverse phase chromatography (column: spherical C18 20-45 mm, 100 A, mobile phase: water - acetonitrile, 10-100%) to afford 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[l-(2,2-difluoroethyl)- 6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (8 mg, N- alkylated product) and 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-(2,2-difluoroethoxy)-3- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (6 mg, 22% yield) as white solid, MS m / z: 535.3 [M+H]+, ESI pos.

[1059] The following Examples 125 to 127 were prepared in analogy to Examples 123 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[1060] The following Examples 128 to 136 were prepared in analogy to Examples 124 by starting from 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimido[l,2-b]pyridazin-4-one (racemic version of Example 47) instead of Example 49 in step 1 and the indicated alkylating agent in step 2. Enantiomers were separated by chiral SFC (column Waters Chiral SZ 250 mm x 20 mm, 5 pm, CO2 / methanol). The absolute stereochemistry was assigned arbitrarily.

[1061] Example 137 and Example 138 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclobutyl-2- oxopyridin-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one and 9-(4-chloro-2- fluorophenyl)-7-[(2R,4S)-2-(l-cyclobutyl-2-oxopyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one

[1062] To a suspension of 9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-lH-pyridin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (Example 85, 50 mg, 0.091 mmol) in acetonitrile (2.4 ml) under nitrogen at room temperature, were added cesium carbonate (88 mg, 0.271 mmol) and iodocyclobutane (33 mg, 17 pl, 0.181 mmol) and the reaction mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and quenched with water. Ethyl acetate was added and both layers were separated. The aqueous one was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in heptane 0% to 100%, then methanol in ethyl acetate 0% to 20%) to provide 9-(4- chloro-2-fluorophenyl)-7-[rac-(2S,4R)-2-(l-cyclobutyl-2-oxopyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one. The enantiomers were separated by chiral SFC (Chiral H4250 mm x 20 mm, 5 pm, CO2 + methanol / 0.1% diethylamine) to give 9-(4-chloro-2- fluorophenyl)-7-[(2S,4R)-2-(l-cyclobutyl-2-oxopyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one (4 mg, 8% yield) as yellow solid, MS m / z: 535.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l -cyclobutyl -2-oxopyridin-4- yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one (4 mg, 8% yield) as yellow solid, MS m / z: 535.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1063] The following Examples 139 to 142 were prepared in analogy to Examples 137 and 138 by starting from the indicated starting materials. The absolute stereochemistry was assigned arbitrarily.

[1064] Example 143 and Example 144 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(l- methyl-2-oxopyridin-4-yl)oxan-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one and 9-(4,4- difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one

[1065] Step 1 : 9- difluorocyclohexen-l-yl)-7-r6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4- yl]-2 -dimethyl-pyrazinc>ri,2-a]pyrimidin-4-one To a solution of 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyridine (Intermediate Bl 3, 411 mg, 1.3 mmol) in 1,4-dioxane (8 ml) and water (0.8 ml) was added 7-bromo-9-(4,4-difluorocyclohexen-l-yl)-2,3-dimethyl-pyrazino[l,2-a]pyrimidin- 4-one (Intermediate A7, 400 mg, 1.08 mmol), cesium carbonate (1.06 g, 3.24 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride di chloromethane complex (88 mg, 0.11 mmol, 0.1 eq). Then the mixture was degassed with nitrogen three times and stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to the room temperature, poured into water (50 ml) and the aqueous layer was separated and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried over ISfeSCU and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 0 : 1 to 1 : 1) to afford 9-(4,4-difluorocyclohexen-l-yl)-7-[6-(2-methoxy-4- pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (420 mg, 81% yield) as yellow oil, MS m / z: 481.2 [M+H]+, ESI pos.

[1066] Step 2: 9-(4,4-difluorocyclohexyl)-7-r2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl1-2,3- dimethyl-pyrazinol 1.2-alpyri mi di n-4-one

[1067] Palladium on charcoal (10%, 186 mg) was suspended in methanol (4 ml), then the air in the flask was changed for argon three times. To the suspension was added a solution of 9-(4,4- difluorocyclohexen-l-yl)-7-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl- pyrazino[l,2-a]pyrimidin-4-one (420 mg, 0.87 mmol) in ethyl acetate (1 ml). The air of reaction mixture was changed to hydrogen three times, then the mixture was stirred at 20 °C for 2 h under hydrogen atmosphere (15 Psi). The reaction 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, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.02% formic acid - acetonitrile, 0-100%, flow rate 25 ml / min) to give 9-(4,4-difluorocyclohexyl)-7-[2-(2- methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (110 mg, 26% yield) as yellow solid, MS m / z: 485.2 [M+H]+, ESI pos. clohexvl)-2,3-dimethvl-7-r2-(2-oxo-lH-pvridin-4-vl)tetrahvdropvran-4- in-4-one

[1068] To a solution of 9-(4,4-difluorocyclohexyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (110 mg, 0.23 mmol) in acetonitrile (5 ml) was added trimethyl silyl iodide (91 mg, 0.45 mmol) at 0 °C under nitrogen and the mixture was heated to 70 °C and stirred for 2 h .The reaction mixture was quenched with saturated NaHCCh solution (20 ml) at room temperature, and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml x 3) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative TLC (silica gel, dichloromethane / methanol = 10 / 1) to give 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (100 mg, 94% yield) as yellow oil, MS m / z: 471.3 [M+H]+, ESI pos.

[1069] Step 4: 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-r(2S,4R)-2-(l-methyl-2-oxopyri din-4- yl)oxan-4-yl1pyrazinori,2-a1pyrimidin-4-one and 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7- r(2R,4S)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4-yl]pyrazinc>ri,2-a]pyrimidin-4-one

[1070] To a suspension of 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (60 mg, 0.13 mmol) and cesium carbonate (125 mg, 0.38 mmol) in dimethylformamide (2 ml) was added iodomethane (0.02 ml, 0.38 mmol) at 0 °C and the mixture was stirred at 25 °C for 2 h under nitrogen. The reaction mixture was poured into water (20 ml), then extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 3), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC (column Waters Xbridge 150 x 25 mm x 10 pm, mobile phase: water / 10 mM NH4HCO3 - acetonitrile, 0- 100%, flow rate 25 ml / min) to give racemic 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[rac- (2S,4R)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4-yl]pyrazino[l,2-a]pyrimidin-4-one. The enantiomers were separated by chiral SFC (Daicel Chiralpak AS 250 mm x 30 mm, 5 pm, CO2 + acetonitrile + isopropanol / 0.1% ammonium hydroxide) to give 9-(4,4-difluorocyclohexyl)-2,3- dimethyl-7-[(2S,4R)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4-yl]pyrazino[l,2-a]pyrimidin-4-one (17 mg, 27% yield) as white solid, MS m / z: 485.2 [M+H]+, ESI pos. and 9-(4,4- difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxopyridin-4-yl)oxan-4- yl]pyrazino[l,2-a]pyrimidin-4-one_(13 mg, 20% yield) as white solid, MS m / z: 485.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1071] Example 145 and Example 146 7-[(2S,4R)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9- (4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one and 7-[(2R,4S)-2-(l- cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[l,2- a]pyrimidin-4-one

[1072] To a solution of 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one (see Example 144, 60 mg, 0.13 mmol) in 1,2-di chloroethane (2 ml) was added cyclopropylboronic acid (22 mg, 0.26 mmol), copper(II) acetate (25.5 mg, 0.14 mmol), 2,2’-bipyridine (22 mg, 0.14 mmol) and sodium carbonate (27 mg, 0.26 mmol) and the mixture was stirred at 70 °C for 2 h under oxygen atmosphere (15 Psi). The reaction mixture was poured into water (20 ml) then extracted with ethyl acetate (20 ml x 3). The organic phase was washed with saturated brine (20 ml x 3), and the combined organic layers were dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was purified by preparative HPLC (column Waters Xbridge 150 x 25 mm x 10 pm, mobile phase: water / 10 mM NH4HCO3 - acetonitrile, 0-100%, flow rate 25 ml / min) to give racemic 7-[rac-(2S,4R)-2-(l- cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[l,2- a]pyrimidin-4-one. The enantiomers were separated by chiral SFC (Daicel Chiralpak AS 250 mm x 30 mm, 10 pm, CO2 + acetonitrile + isopropanol / 0.1% ammonium hydroxide) to give 7- f(2S,4R)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4-difluorocyclohexyl)-2,3- dimethylpyrazino[l,2-a]pyrimidin-4-one (19 mg, 30% yield) as white solid, MS m / z: 511.2 [M+H]+, ESI pos. and 7-[(2R,4S)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one (17 mg, 26% yield) as white solid, MS m / z: 511.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. The following Examples 147 to 149 were prepared in analogy to Examples 145 and 146 by starting from the indicated starting material instead of 9-(4,4-difluorocyclohexyl)-2,3-dimethyl- 7-[2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one. The absolute stereochemistry was assigned arbitrarily.

[1073] Example 150 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one Step 1 : 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-rrac-(2R,4S)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrimidor 1 ,2-b]pyridazin-4-one

[1074] The compound was prepared in analogy to Example 85 using Intermediate A4 instead of Intermediate A2 in step 1, light yellow solid, MS m / z: 499.2 [M+H]+, ESI pos. Step 2: 9-(4-chloro-2,6-difluoro-phenyl)-7-r(2R,4S)-2-(T-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl1-2,3-dimethyl-pyrimidori,2-b1pyridazin-4-one

[1075] The compound was prepared in analogy to Examples 145 by starting from 9-(4-chloro-2,6- difluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4- yl]pyrimido[l,2-b]pyridazin-4-one instead of 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(2- oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one, light yellow solid, MS m / z: 539.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1076] Example 151 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one

[1077] Step 1 : 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-rrac-(2R,4S)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazinor 1.2-alpyri mi di n-4-one

[1078] The compound was prepared in analogy to Example 85 using Intermediate Al instead of Intermediate A2 in step 1, yellow solid, MS m / z: 481.2 [M+H]+, ESI pos.

[1079] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-r(2R,4S)-2-(T-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl1-2,3-dimethyl-pyrazinolE2-a1pyrimidin-4-one

[1080] The compound was prepared in analogy to Examples 145 by starting from 9-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4- yl]pyrazino[l,2-a]pyrimidin-4-one instead of 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(2- oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one, yellow solid, MS m / z: 521.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1081] Example 152 and Example 153 9-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dimethyl- 7-[(2R,4S)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one and 9-[3-(difhroromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-2- oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one

[1082] The compounds were prepared in analogy to Example 143 and 144 using Intermediate A10 instead of Intermediate A7 in step 1, yellow solids, MS m / z: 483.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. The following Examples 154 to 159 were prepared in analogy to Examples 143 and 144 by starting from the indicated intermediates instead of A7 and B13 in step 1. The absolute stereochemistry was assigned arbitrarily. Example 160 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(3-cyclopropyl-lH-l,2,4-triazol-5- yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one

[1083] Step 1 : 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidolE2-b1pyridazin-7- ylltetrahydropyran-2-carbohydrazide

[1084] To a solution of ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2- b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (300 mg, 0.65 mmol) in ethanol (5.5 ml) under nitrogen at room temperature, was added hydrazine monohydrate (145 mg, 141 pl, 2.89 mmol) and the reaction mixture was stirred at 80 °C for 15 h. The mixture was cooled to room temperature, evaporated and the residue was purified with flash column chromatography (silica, ethyl acetate in heptane 0% to 100%, then methanol in ethyl acetate 0% to 20%) to provide 4-[9- (4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin-7-yl]tetrahydropyran- 2-carbohydrazide (252 mg, 87% yield) as yellow foam, MS m / z: 446.2 [M+H]+, ESI pos. Step 2: 9-(4-chloro-2-fluorophenyl)-7-r(2R,4R)-2-(3-cyclopropyl-lH-E2,4-triazol-5-yl)oxan-4- yl1-2,3-dimethylpyrimidolE2-b1pyridazin-4-one

[1085] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin- 7-yl]tetrahydropyran-2-carbohydrazide (251 mg, 0.562 mmol) in methanol (1 ml) under nitrogen at room temperature were added cyclopropanecarboximidic acid methyl ester hydrochloride (74 mg, 0.546 mmol) and sodium hydroxide (22 mg, 0.557 mmol) and the reaction mixture was stirred at 70 °C for 24 h. After that time, the mixture was cooled to room temperature and more cyclopropanecarboximidic acid methyl ester hydrochloride (74 mg, 0.546 umol) was added again. The mixture was stirred at 70 °C for 17 h, then it was cooled to room temperature and the solvent was evaporated. The residue was purified by flash column chromatography (silica, ethyl acetate in heptane 0% to 100%, then methanol in ethyl acetate 0% to 20) to give 9-(4-chloro-2- fluorophenyl)-7-[rac-(2R,4R)-2-(3-cyclopropyl-lH-l,2,4-triazol-5-yl)oxan-4-yl]-2,3- dimethylpyrimido[l,2-b]pyridazin-4-one (34 mg, 13% yield) and 9-(4-chloro-2-fluorophenyl)-7- [rac-(2R,4S)-2-(3-cyclopropyl-lH-l,2,4-triazol-5-yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2- b]pyridazin-4-one (60 mg, 20% yield). The enantiomers of 9-(4-chloro-2-fluorophenyl)-7-[rac- (2R,4R)-2-(3 -cyclopropyl- 1H- 1 ,2,4-triazol-5-yl)oxan-4-yl]-2,3 -dimethylpyrimidof 1 ,2- b]pyridazin-4-one were separated by chiral SFC (column Chiral SZ 250 mm x 20 mm, 5 pm, CO2 + methanol / 0.2% diethylamine) to give 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(3- cyclopropyl-lH-l,2,4-triazol-5-yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one as first eluting enantiomer, yellow foam, MS m / z: 495.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1086] Example 161 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyridazin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one

[1087] Step 1 : 9-(4-chloro-2-fluoro-phenyl )-2 ,3-dimethyl-7-(2-oxotetrahydropyran-4-yl )pyrazinolE2- alpyrimidin-4-one To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazino[l,2-a]pyrimidin-4-one (Intermediate A8, 1 g, 2.33 mmol) in 1,4- dioxane (12 ml) was added at 22 °C under inert atmosphere 5,6-dihydro-2H-pyran-2-one (685 mg, 0.61 ml, 6.98 mmol) followed by potassium phosphate tribasic (445 mg, 2.09 mmol). The mixture was degassed by bubbling nitrogen through the mixture for 10 min, then chloro(l,5- cyclooctadiene)rhodium(I) dimer (115 mg, 0.233 mmol, 0.1 eq) was added and degassing was repeated ad described. The reaction mixture was heated to 90 °C for 4 h, then it was poured into an aqueous saturated NaHCCh solution (30 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with aqueous saturated NaHCCh solution (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate + ethanol 3 / 1 in heptane 0% to 50%) to give 9-(4- chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(2-oxotetrahydropyran-4-yl)pyrazino[l,2-a]pyrimidin-4- one (592 mg, 63% yield) as brown foam, MS m / z: 402. [M+H]+, ESI pos.

[1088] Step 2: r4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazinolE2-a1pyrimidin-7-yl1-3,4- dihydro-2H-pyran-6-yl1 trifluoromethanesulfonate

[1089] To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(2-oxotetrahydropyran-4- yl)pyrazino[l,2-a]pyrimidin-4-one (460 mg, 1.14 mmol) and 2-[N,N- bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (1.35 g, 3.43 mmol) in tetrahydrofuran (16 ml) was added dropwise at -78 °C a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 2.29 ml, 2.29 mmol) and the mixture was stirred at -78 °C for 30 min. The reaction mixture was poured into an aqueous saturated NaHCCh solution (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-50% ethyl acetate in heptane) to give the [4-[9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin-7-yl]-3,4-dihydro-2H-pyran-6-yl] trifluoromethanesulfonate (347 mg, 57% yield) as light brown foam, MS m / z: 534.5 [M+H]+, ESI pos.

[1090] Step 3 : 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-16-(6-methylpyridazin-4-yl)-3,4-dihydro- 2H-pyran-4-yl1pyrazinol 1 ,2-a]pyrimidin-4-one

[1091] To a solution of [4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin- 7-yl]-3,4-dihydro-2H-pyran-6-yl] trifluoromethanesulfonate (73 mg, 0.137 mmol) and 3-methyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (CAS 1350543-95-1, 60 mg, 0.273 - il - mmol) in tetrahydrofuran (7.2 ml) was added a solution of cesium carbonate (223 mg, 0.684 mmol) in water (1.8 ml) and nitrogen was bubbled through for 10 min. Then bis(triphenylphosphine)palladium(II) chloride (5 mg, 6.8 pmol, 0.05 eq) was added and degassing was continued for 5 min. The tube was sealed and heated to 65 °C while vigorous stirring for 2 h. The reaction mixture was poured into an aqueous saturated NaHCCh solution (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, ethyl acetate + ethanol 3 / 1 in heptane 0% to 100%) to give 9-(4- chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(6-methylpyridazin-4-yl)-3,4-dihydro-2H-pyran-4- yl]pyrazino[l,2-a]pyrimidin-4-one (55 mg, 84% yield) as yellow solid, MS m / z: 478.5 [M+H]+, ESI pos.

[1092] Step 4: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-r(2R,4S)-2-(6-methylpyridazin-4- yl)tetrahydropyran-4-yl1pyrazinol 1.2-alpyri mi di n-4-one

[1093] To a suspension of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(6-methylpyridazin-4-yl)- 3,4-dihydro-2H-pyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (45 mg, 0.094 mmol) in ethyl acetate (4 ml) was added methanol (2 ml), triethylamine (11.5 mg, 16 pl, 0.113 mmol) and magnesium oxide (38 mg, 0.942 mmol) and the flask was evacuated and filled with nitrogen 3 times. Then palladium on carbon (10%, 20 mg) was added, the flask was filled with nitrogen again and afterwards with hydrogen (evacuation and back-filling for 5 times). The mixture was vigorously stirred at 22 °C for 1.5 h, then the catalyst was filtered off, washed with ethyl acetate (2 x 2 ml) and the solution was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, ethyl acetate + ethanol 3 / 1 in heptane 0% to 100%), followed by another chromatography (RP18, 10-100% acetonitrile in water) to give racemic 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyridazin-4-yl)tetrahydropyran-4- yl]pyrazino[l,2-a]pyrimidin-4-one (16 mg, 35% yield). The enantiomers were separated by chiral SFC (column Chiral OJ 250 mm x 20 mm, 5 pm, CO2 + methanol) to give 9-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyridazin-4-yl)tetrahydropyran-4- yl]pyrazino[l,2-a]pyrimidin-4-one (7 mg, 15% yield) as first eluting enantiomer, light yellow oil, MS m / z: 480.5 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 162 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one

[1094] The title compounds were prepared in analogy to Examples 27 to 30 using Intermediate B20 instead of Intermediate B2 in step 1, light yellow solid, MS m / z: 508.4 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1095] Example 163 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-pyrazolo[l,5- a]pyrimidin-6-yltetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one

[1096] The title compounds were prepared in analogy to Example 35 using Intermediate A6 instead of Intermediate Al and Intermediate B25 instead of Intermediate B5 in step 1, light yellow solid,

[1097] MS m / z: 495.2 [M+H]+, ESI pos.

[1098] Example 164 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-([l,2,4]triazolo[l,5- a]pyridin-6-yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one

[1099] The title compounds were prepared in analogy to Example 35 using Intermediate A6 instead of Intermediate Al and Intermediate B26 instead of Intermediate B5 in step 1, light brown solid, MS m / z: 495.3 [M+H]+, ESI pos. The following Examples 164 to 195 were prepared in analogy to Examples 35 to 37 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[1100] The following Examples 196 to 216 were prepared in analogy to Examples 143 to 146 by starting from the indicated starting materials. The absolute stereochemistry was assigned arbitrarily.

[1101] Examples 217 and 218 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-l-methyl-pyridazin- 4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one and 9-(4-chloro-2- fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-l-methyl-pyridazin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one

[1102] Step 1 : 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-r6-(l-methyl-6-oxo-pyridazin-4-yl)-3,4- dihydro-2H-pyran-4-yl1pyrazinc>r 1.2-alpyrimi di n-4-one

[1103] To a solution of [4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[l,2-a]pyrimidin- 7-yl]-3,4-dihydro-2H-pyran-6-yl] trifluoromethanesulfonate (see Example 161, 260 mg, 0.487 mmol) in 1,4-dioxane (5 ml) was added bis(pinacolato)diboron (186 mg, 0.73 mmol) and potassium acetate (191 mg, 1.95 mmol) at room temperature. The mixture was degassed with argon before l,T-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40 mg, 0.049 mmol, 0.10 eq) was added. The reaction mixture was stirred for 90 min at 90°C, then it was diluted with water and extracted two times with ethyl acetate. The combined organic layers were dried over MgSCU and concentrated to dryness. The crude material was dissolved in 1,4-dioxane (5 ml), then 5-iodo-2-methyl-pyridazin-3-one (138 mg, 0.584 mmol) and cesium carbonate solution (3 M in water, 0.487 ml, 1.46 mmol) were added at room temperature. The mixture was degassed with argon before l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (40 mg, 0.049 umol, 0.10 eq) was added. The reaction mixture was stirred for 45 min at 60°C, then it was diluted with water and extracted two times with ethyl acetate. The combined organic layers were dried over MgSC and concentrated to dryness. The crude material was purified by reversed phase flash chromatography (silica gel C18, acetonitrile in water, 10-100%) to obtain 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6- (l-methyl-6-oxo-pyridazin-4-yl)-3,4-dihydro-2H-pyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (70 mg, 28% yield) as yellow solid, MS m / z: 494.5 [M+H]+, ESI pos.

[1104] To a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(l-methyl-6-oxo-pyridazin-4- yl)-3,4-dihydro-2H-pyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one (70 mg, 0.142 mmol) in ethyl acetate (2.5 ml) was added triethylamine (17 mg, 24 pl, 0.17 mmol) and magnesium oxide (57 mg, 1.42 mmol) followed by palladium on charcoal (30 mg, 0.028 mmol, 0.20 eq). The mixture was stirred under hydrogen atmosphere at room temperature for 9 h, then it was filtered through a syringe filter and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel Cl 8, acetonitrile in water 10-100%) to obtain racemic 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (32 mg, 42% yield). The enantiomers were separated by chiral SFC (column Chiral OJ-H 250 mm x 20 mm, 5 pm, CO2 + 35% methanol) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (10 mg, 14% yield) as first eluting enantiomer, light yellow solid, MS m / z: 496.5 [M+H]+, ESI pos. and 9-(4-chloro-2- fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-l-methyl-pyridazin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazino[l,2-a]pyrimidin-4-one (11 mg, 15% yield) as second eluting enantiomer, light yellow solid, MS m / z: 496.5 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1105] Example 219 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-2-methyl-l,2,4-triazol- 3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one

[1106] The enantiomers of 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(3-cyclopropyl-lH-l,2,4- triazol-5-yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one (see Example 160) were separated by chiral SFC (column Chiral SZ 250 mm x 20 mm, 5 pm, CO2 + methanol / 0.2% diethylamine) to give 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(3-cyclopropyl-lH-l,2,4-triazol- 5-yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one as second eluting enantiomer. This compound (10 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (0.75 ml), then potassium carbonate (4.2 mg, 0.03 mmol) and iodomethane (3.4 mg, 1.5 pl, 0.024 mmol) were added at room temperature. The mixture was stirred for 2 h, then it was purified by reversed phase chromatography (silica gel Cl 8, acetonitrile in water 10-100%) to obtain 9-(4-chloro-2- fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-2-methyl-l,2,4-triazol-3-yl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (4 mg, 27%) as light yellow solid, MS m / z: 509.5 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1107] Example 220 and Example 221 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2- ([l,2,4]triazolo[l,5-a]pyridin-7-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one and 9- (4,4-difhiorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-([l,2,4]triazolo[l,5-a]pyridin-7- yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one

[1108] Examples 220 and 221 were prepared in analogy to Examples 35 to 37 by starting from Intermediate A6 instead of Al and Intermediate B39 instead of B5, light yellow solids, MS m / z:

[1109] 495.6 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily. Example 222 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(4R,6R)-2,2-difluoro-6-(l-methyl-6- oxo-pyridazin-3-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one

[1110] Example 222 can be prepared in analogy to Examples 143 to 146. The absolute stereochemistry was assigned arbitrarily. The following Examples 223 to 227 were prepared in analogy to Examples 35 to 37 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

[1111] Examples 228 and 229 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(4-cyclopropylpyrimidin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro- phenyl)-7-[(2S,4R)-2-(4-cyclopropylpyrimidin-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrimido[l,2-b]pyridazin-4-one

[1112] Step 1 : 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidori,2-b1pyridazin-7- A solution of ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2- b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (Intermediate C2 step3, 1.7 g, 3.7 mmol) in ammonia in methanol (7 M, 16.4 ml, 114.7 mmol) was stirred at 60 °C for 12 h in a sealed tube. The reaction mixture was concentrated in vacuo to give 4-[9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-4-oxo-pyrimido[l,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxamide (1.5 g, 94% yield) as light yellow solid, MS m / z: 431.0 [M+H]+, ESI pos.

[1113] Step 2: 4-r9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidolE2-b1pyridazin-7- ylltetrahydropyran-2-carboxamidine

[1114] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin- 7-yl]tetrahydropyran-2-carboxamide (1.56 g, 3.62 mmol) in dichloromethane (30 ml) was added trimethyloxonium tetrafluoroborate (1.34 g, 9.05 mmol) in portions at 0 °C. The suspension was degassed with nitrogen three times and stirred at 20 °C for 24 h under nitrogen atmosphere. The mixture was concentrated in vacuo, the residue was dissolved in ammonia in methanol (7 M, 30 ml, 210 mmol) and the mixture was stirred at 20 °C for 16 h under nitrogen atmosphere. Then it was concentrated in vacuo to give the crude product 4-[9-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-4-oxo-pyrimido[l,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxamidine (2.1 g, 72% yield) as a light yellow solid, MS m / z: 430.0 [M+H]+, ESI pos.

[1115] Step 3 : 9-(4-chloro-2-fluoro-phenyl)-7-r(2R,4S)-2-(4-cyclopropylpyrimidin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidolE2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro- phenyl)-7-r(2S,4R)-2-(4-cyclopropylpyrimidin-2-yl)tetrahydropyran-4-yl1-2,3-dimethyl- pyrimidolE2-b1pyridazin-4-one

[1116] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimido[l,2-b]pyridazin- 7-yl]tetrahydropyran-2-carboxamidine (500 mg, 0.58 mmol) in acetonitrile (10 ml) were added l-cyclopropylprop-2-yn-l-one (205 mg, 0.87 mmol) and sodium carbonate (185 mg, 1.74 mmol) and the reaction was stirred at 80 °C for 2 h. The mixture was poured into water (40 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (30 ml) and dried over ISfeSCU, then concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 40 mm x 15pm, mobile phase: gradient water with 0.225% formic acid in acetonitrile, flow rate 60 ml / min) to give racemic 9- (4-chloro-2-fluoro-phenyl)-7-[2-(4-cyclopropylpyrimidin-2-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrimido[l,2-b]pyridazin-4-one (150 mg) as yellow solid. Separation on chiral SFC (column Daicel CHIRALCEL OD 250 mm x 30 mm, 10 pm, mobile phase: CO2 in isopropanol / acetonitrile with 0,1% ammonium hydroxide) gave 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2- (4-cyclopropylpyrimi din-2 -yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4- one (30 mg, 20% yield) as first eluting compound, yellow solid, MS m / z: 506.2 [M+H]+, ESI pos. and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(4-cyclopropylpyrimidin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one (25 mg, 17% yield) as second eluting compound, yellow solid. MS m / z: 506.2 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[1117] Example 230

[1118] 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:

[1119] Per tablet

[1120] Active ingredient 200 mg

[1121] Microcrystalline cellulose 155 mg

[1122] Com starch 25 mg

[1123] Talc 25 mg

[1124] Hydroxypropylmethylcellulose 20 mg

[1125] 425 mg

[1126] Example 231

[1127] 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:

[1128] Per capsule

[1129] Active ingredient 100.0 mg

[1130] Com starch 20.0 mg

[1131] Lactose 95.0 mg

[1132] Talc 4.5 mg Magnesium stearate 0.5 mg

[1133] 220.0 mg

[1134] Reference Example 1: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrido[l,2-a]pyrimidin-4-one

[1135] To a suspension of 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[l,2-a]pyrimidin- 4-one (Intermediate Al l, 75 mg, 0.196 mmol) in 1,4-dioxane (2 ml) was added (2S)-2-(l- methylpyrazol-4-yl)morpholine (Intermediate B21, 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.

[1136] The following Reference Examples 2 to 5 were prepared in analogy to Reference Example 1 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily.

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or 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 Ci-Ce-alkyl and halo-Ci-Ce-alkyl;R2is selected from:R3is selected from:(i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the groupand(ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci- Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3-C10- cycloalkyl-Ci-Ce-alkoxy, 3- to 6-membered heterocyclyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon;R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;R4is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl;R4is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl;R5and R6are each independently selected from the group consisting of hydrogen and halogen;R7is selected from the group consisting of hydrogen and Ci-Ce-alkyl; andR8is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce-alkyl; provided that:(i) whenleast one of R3and R8is not hydrogen; and(ii) whenis not hydrogen.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1is N and X2is CH.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:A1is selected from the group consisting of N and CR8;A2is selected from the group consisting of O and CR5R6;R5is halogen;R6is halogen; andR8is selected from the group consisting of hydrogen, halogen, and hydroxyl.

4. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:A1is selected from the group consisting of N and CR8;A2is selected from the group consisting of O and CR5R6;R5is fluoro;R6is fluoro; andR8is selected from the group consisting of hydrogen, fluoro, and hydroxyl.

5. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:A1is CR8;A2is O; andR8is hydrogen.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is Ci-Ce-alkyl.

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is methyl.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2is selected9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from: (i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group consisting of(ii) a 9- to 10-membered fused bicyclic heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkyl, halo-Ci-Ce-aloxy, C3- Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, 3- to 6-membered heterocyclyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1-3 heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon.

10. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:(i) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group(ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-2 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, C3-C10- cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon.

11. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selectedwherein R3is optionally substituted with 1-2 substituents independently selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl- methyl.

12. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:R3ais selected from hydrogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, C3- Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce- alkoxy, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon; andR3bis selected from hydrogen, Ci-Ce-alkyl, and Cs-Cio-cycloalkyl.

13. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:wherein:R3ais selected from hydrogen, methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl; and R3bis selected from hydrogen, methyl, and cyclopropyl.

14. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl.

15. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl.

16. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:wherein R3ais selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl.

17. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:wherein R3ais selected from methyl and cyclopropyl.

18. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

19. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from:

20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is selected from the group consisting of hydrogen and methyl.

21. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is hydrogen.

22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R4is selected from the group consisting of hydrogen and halogen; and R4is selected from the group consisting of hydrogen and halogen.

23. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R4is selected from the group consisting of hydrogen and fluoro; andR4is selected from the group consisting of hydrogen and fluoro.

24. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4and R4are both hydrogen.

25. The compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7is Ci-Ce-alkyl.

26. The compound of formula (I) according to claim 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R7is methyl.

27. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1is N and X2is CH;A1is selected from the group consisting of N and CR8;A2is selected from the group consisting of O and CR5R6;R1is Ci-Ce-alkyl;R2is selected from:R3is selected from:(ii) a 5- to 6-membered heteroaryl or heterocyclyl selected from the group(ii) a 9-membered fused bicyclic heteroaryl comprising 3 nitrogen atoms, the remaining ring atoms being carbon; wherein R3is optionally substituted with 1-2 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-aloxy, Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, and 3- to 6- membered heterocyclyl-Ci-Ce-alkyl comprising 1 oxygen atom, the remaining ring atoms being carbon;R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;R4is selected from the group consisting of hydrogen and halogen;R4is selected from the group consisting of hydrogen and halogen;R5is halogen;R6is halogen;R7is Ci-Ce-alkyl; andR8is selected from the group consisting of hydrogen, halogen, and hydroxyl.

28. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:(i) X1is CH and X2is N; or(ii) X1is N and X2is CH;A1is selected from the group consisting of N and CR8;A2is selected from the group consisting of O and CR5R6;R1is methyl;R2is selected from:R3is selected from:wherein R3is optionally substituted with 1-2 substituents independently selected from methyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, and oxetan-3-yl-methyl;R3is selected from the group consisting of hydrogen and methyl;R4is selected from the group consisting of hydrogen and fluoro;R4is selected from the group consisting of hydrogen and fluoro;R5is fluoro;R6is fluoro;R7is methyl; andR8is selected from the group consisting of hydrogen, fluoro, and hydroxyl.

29. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:(i) X1is CH and X2is N; or (ii) X1is N and X2is CH;A1is CR8;A2is O;R1is Ci-Ce-alkyl;R2is selected from:wherein R3is substituted with 1 substituent selected from Ci-Ce-alkyl and C3- Cio-cycloalkyl;R3is hydrogen;R4is hydrogen;R4is hydrogen;R7is Ci-Ce-alkyl; andR8is hydrogen.

30. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or 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:wherein R3is substituted with 1 substituent selected from methyl and cyclopropyl;R3is hydrogen;R4is hydrogen;R4is hydrogen;R7is methyl; andR8is hydrogen.

31. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound of formula (I) is selected from: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(3-methyl-l,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(3-methyl-l,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(3-methyl-l,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(3-methyl-l,2,4-oxadiazol- 5-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(3-methyl-l,2,4-oxadiazol- 5-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(3-methyl-l,2,4-oxadiazol- 5-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4- oxadiazol-5-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2, 3-dimethyl-7-[(2S, 4R)-2-(3-cy cl opropyl- 1,2,4- oxadiazol-5-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;7-[(2S,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)oxan-4-yl]-9-[3-(difluoromethyl)-1 -bicyclof 1.1.1 ]pentanyl]-2,3 -dimethylpyrimidof 1 ,2-b]pyridazin-4-one;7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)oxan-4-yl]-9-[3-(difluoromethyl)-1 -bicyclof 1.1.1 ]pentanyl]-2, 3 -dimethylpyrimidof 1 ,2-b]pyridazin-4-one;9-(4-chloro-2,6-difluoro-phenyl)-7-[rac-(2R,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol- 5-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-hydroxy-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-hydroxy-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-fluoro-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-4-fluoro-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-4-fluoro-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-methyl-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2S,4S)-2-methyl-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l -cyclopropyl- 1,2, 4-tri azol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l -cyclopropyl- 1,2, 4-tri azol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l -cyclopropyl- 1,2, 4-tri azol-3-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l -cyclopropyl- 1,2, 4-tri azol-3-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyltriazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyltriazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(2-cyclopropyltriazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(2-methylpyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methylpyrimidin-5- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-methyl-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)oxan-4-yl]-2,3- dimethylpyrimidof 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyltriazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(2-cyclopropyltriazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[rac-(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chl oro-2, 6-difluoro-phenyl)-2, 3 -dimethyl-7- [(2R,4 S)-2-( 1 -methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chl oro-2, 6-difluoro-phenyl)-2, 3 -dimethyl-7- [(2 S,4R)-2-( 1 -methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;7-[(2R,4S)-2-(2-cyclopropylpyrimidin-5-yl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;7-[(2S,4R)-2-(2-cyclopropylpyrimidin-5-yl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-cyclopropylpyrimidin-5-yl)oxan-4-yl]- 2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-cyclopropylpyrimidin-5-yl)oxan-4-yl]- 2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxopyridazin-3- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxopyridazin-3- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin- 3-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyridazin- 3-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2-(l-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-methoxypyrazin-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-methoxypyrazin-2-yl)tetrahydropyran- 4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrazinof 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chl oro-2, 6-difluoro-phenyl)-7 - [(2R,4 S)-2-(2-keto- 1 -methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]- 2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-3-yl)oxan-4-yl]- 2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrimidof 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l -cyclopropyltri azol -4-yl)oxan-4-yl]-2, 3- dimethylpyrimidof 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(2-keto-lH-pyridin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-oxo-lH-pyri din-4- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-keto-lH-pyridin-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[rac-(2S,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(2-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(2-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;- Til -9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4R)-2-(6-methylpyrimidin-4- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4S)-2-(6-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[rac-(2R,4R)-2-(6-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;7-[(2R,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-cyclopropylpyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(4-pyrimidyl)tetrahydropyran-4- yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(4- pyrimidyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4- pyrimidyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-(2,2-difluoroethoxy)-3- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;7-[(2R,4S)-2-[6-(cyclopropylmethoxy)-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[6-(2,2,2-trifluoroethoxy)-3- pyridyl]tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-isopropoxy-3-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[2-[6-(2,2-difluoroethoxy)-3- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2, 3 -dimethyl-7 - [2- [6-(2,2,2-trifluoroethoxy)-3 - pyridyl]tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-isopropoxy-3-pyridyl)tetrahydropyran-4-yl]- 2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-(2,2-difluoroethoxy)pyridin-3-yl]oxan- 4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-(2,2-difluoroethoxy)pyridin-3-yl]oxan- 4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[6-(2,2,2- trifluoroethoxy)pyridin-3-yl]oxan-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[6-(2,2,2- trifluoroethoxy)pyridin-3-yl]oxan-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(6-propan-2-yloxypyri din-3- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-propan-2-yloxypyri din-3- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclobutyl-2-oxopyridin-4-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclobutyl-2-oxopyridin-4-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[l -(cy cl opropylmethyl)-2-oxopyri din-4- yl]oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;7-[(2R,4S)-2-[l-(cyclopropylmethyl)-2-keto-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;7-[(2S,4R)-2-[l-(cyclopropylmethyl)-2-keto-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[2-keto-l-(oxetan-3-ylmethyl)-4- pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-2-oxopyri din-4- yl)oxan-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxopyridin-4- yl)oxan-4-yl]pyrazino[l,2-a]pyrimidin-4-one;7-[(2S,4R)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one;7-[(2R,4S)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one;7-[(2R,4S)-2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-keto-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-2-keto-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chl oro-2, 6-difluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dimethyl-7-[(2R,4S)-2-(l- methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dimethyl-7-[(2S,4R)-2-(l- methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(4-methyl-5-oxopyrazin-2- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-methyl-5-oxopyrazin-2- yl)oxan-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-methyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(4-methyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxo-pyrimidin-5-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-2-oxo-pyrimidin-5-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(3-cyclopropyl-lH-l,2,4-triazol-5- yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(6-methylpyridazin-4- yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-pyrazolo[l,5-a]pyrimidin- 6-yltetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-([l,2,4]triazolo[l,5-a]pyridin- 6-yl)oxan-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-([l,2,4]triazolo[l,5-a]pyridin- 6-yl)oxan-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-7-[(2S,4R)-2-(6-methoxypyridin-3- yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-7-[(2R,4S)-2-(6-methoxypyridin-3- yl)oxan-4-yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(6-methoxy-3-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-3-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-3-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(2-methoxy-4-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-methyl-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-methyl-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4S)-2-methyl-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-methyl-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrimido[ 1 ,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxypyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxypyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-2-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-2-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxy-5-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxy-5-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(lR,3S)-4,4-difluoro-3-(6-methoxy-3- pyridyl)cyclohexyl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(lS,3R)-4,4-difluoro-3-(6-methoxy-3- pyridyl)cyclohexyl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-methoxypyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-methoxypyrimidin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-l -bicyclofl .

1. l]pentanyl]-2,3-dimethyl-pyrazino[l,2- a]pyrimidin-4-one;7-[(2S,4R)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-l -bicyclofl .

1. l]pentanyl]-2,3-dimethyl-pyrazino[l,2- a]pyrimidin-4-one;9-(4-chl oro-2, 6-difluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(l-cyclopropyl-2-oxopyrimidin-5-yl)oxan- 4-yl]-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxopyrimidin-5-yl)oxan- 4-yl]-2,3-dimethylpyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-2-oxo-pyrimidin-5- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyrimidin- 4-yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyrimidin- 4-yl)tetrahydropyran-4-yl]pyrazino[ 1 ,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-oxo-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(4-methyl-5-oxopyrazin-2- yl)oxan-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(4-methyl-5-oxopyrazin-2- yl)oxan-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(4-cyclopropyl-5-oxopyrazin-2-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(4-cyclopropyl-5-oxopyrazin-2-yl)oxan-4- yl]-2,3-dimethylpyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(4-cyclopropyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(4-cyclopropyl-5-oxo-pyrazin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyridazin-3-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(l-cyclopropyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-l-methyl-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-2-methyl-l,2,4-triazol-3- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-([l,2,4]triazolo[l,5-a]pyridin-7-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-([l,2,4]triazolo[l,5-a]pyridin-7-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(4R,6R)-2,2-difluoro-6-(l-methyl-6- oxo-pyridazin-3-yl)tetrahydropyran-4-yl]pyrazino[l,2-a]pyrimidin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyl-3-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyl-3-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-methyl-6-oxo-pyridazin- 4-yl)tetrahydropyran-4-yl]pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one;9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(4-cyclopropylpyrimidin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one; and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(4-cyclopropylpyrimidin-2- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[l,2-b]pyridazin-4-one.

32. The compound of formula (I) according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as a therapeutically active substance.

33. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, and a therapeutically inert carrier.

34. 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 the compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 38.

35. The method according to claim 39, wherein 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.

36. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 38, for use in a method according to claim 39 or 40.

37. Use of a compound according to any one of claims 1 to 36, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 38, in a method according to claim 39 or 40.

38. Use of a compound according to any one of claims 1 to 36, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to claim 39 or 40.

39. The invention as described hereinbefore.

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